MXPA96005192A - Sulfonamides substituted as agonistasó3selectivas for the treatment of diabetes yobesi - Google Patents

Abstract

The present invention relates to a compound having the formula I: wherein 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 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen, (2) a benzene ring fused to a 5- or 6-membered heterocyclic ring with 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen, (3) a 5 or 6 heterocyclic ring members with 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen fused to a 5- or 6-membered heterocyclic ring with 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen, (4) phenyl, or (5) a fused benzene ring to a C3-C8 cycloalkyl ring: R1 is (1) hydroxyl, (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 with hydroxyl, 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, (3) C1-C10 alkyl with 1 to 4 substituents selected from hydroxyl, C1-C10 alkoxy, and halogen; X is (1) -CH2-, (2) -CH2-CH2 -; (3) -CH = CH-, (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

Description

ULFONAMIDES SUBSTITUTED AS SELECTIVE ß3 AGONISTS FOR THE TREATMENT OF DIABETES AND OBESITY CROSS REFERENCE This is a continuation in part of the co-pending North American application S.N. 08 / 233,166, filed on April 26, 1994, which is incorporated in the present report in its entirety.

BACKGROUND OF THE INVENTION The 3-adrenoceptors have been classified as Pi and β2 since 1967. The increased heart rate is the primary consequence of receptor stimulation (3%), whereas typically bronchodilation and relaxation of the smooth stimulation n / O (32. Initially it was thought that adipocyte lipolysis was only a process mediated by Pl - However, recent results indicate that receptor-mediated lipolysis is atypical in nature.These atypical receptors, called after β3 - < - * drenoreceptors, are located On the surface of the cell both white and brown adipocytes in «Jonde» or stimulation promotes both lipolysis (fat breakage) and energy expenditure.Early developments in this area produced compounds with higher agonist activity for the stimulation of ipolysis (ß3 activity) that for stimulation of arterial frequency (ßi) and tracheal relaxation (2) - These early developments US, which are described in Flinsworth et al., US Pat. Nos. 4,478,849 and 4,396,627, were derivatives of phenylethanolamines. Such selectivity for β3 -adrenoreceptors could make compounds of this type potentially useful as anti-obesity agents. In addition, it has been reported that these -Compounds show antihyperglycemic effects in animal models of diabetes mellitus not dependent on insulin. A major disadvantage in the treatment of chronic diseases with β3 agonists is the potential for stimulation of other β-receptors and the subsequent side effects. The most likely of these include muscle tremor (ß2) and increased heart rate (ßi). Although these phenylethanolarnine derivatives possess some selectivity, • side effects of this type have been observed in human volunteers. It is reasonable to expect that these side effects result from partial ßi and / or ß2 agonism - more recent developments in this area are described in Rinsworth et al., US Patent 5,153,210, Caulkett et al., US Patent 4,999,377, Alig et al., US Patent 5,017,619, Lecount and others; European Patent 427480, and Bloorn et al., European Patent 455006. flun when these more recent developments are opposed to describe compounds with higher ß3 selectivity on the ßi and ß2 activities this selectivity was determined using rodents, rats in particular, co or the animal of proof. Because even the highly selective compounds, determined with these assays, still show signs of side effects due to residual β1 and β2 agonist activity, when the compounds are tested in humans, it becomes clear that the rodent is not a good model for predict ß3 selectivity Recently, tests have been developed that more accurately predict the effects that can be expected in humans. These tests use cloned human ß3 receptors which have been expressed in Chinese hamster ovary cells. See Emopne et al., Science, 1989, 245: 1118-1121; and Liggett, Mol. Pharmacol. , 1992, 42: 634-637. The agonist and antagonist effects of the different compounds on the < r. the cultivated ones provide an indication of the antiobesity and anti-diabetes effects of the compounds in humans.

BRIEF DESCRIPTION OF THE INVENTION The present invention relates to substituted sulfonarnides which are useful as anti-obesity and anti-diabetes 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 sulfones idas. A further object is to describe procedures for the preparation of such patches. Another object is to describe methods and compositions using the co compounds or the active ingredient thereof. Additional objects will become apparent from reading the following description.

DESCRIPTION OF THE INVENTION The present invention provides compounds having the formula I: where ^ g fi0 a 5 ní is 0 O 1 r is 0 to 3 A is (1) a 5- or 6-membered heterocyclic ring with 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen, (2) a benzene ring fused to a 5- or 6-membered heterocyclic ring with 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen, (3) a 5- or 6-membered heterocyclic ring with 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen attached to a ring 5 or 6 membered heterocyclic with 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen, (4) phenyl, or (5)? n benzene ring fused to C3-C8 cycloalkyl ring Rl is (1) hydroxyl (2) oxo, (3) halogen, (4) cyano, (5) NR8R8, (6) SR8, (7) trifluoromethyl, (8) C1-C10 alkyl, (9) 0R8, (10) SO2R9, ( 11) 0C0R9, (12) NRß COR9, (13) COR9, (14) R8S02 9, (15) NR8CO2R8,? (16) C 1 -C 10 alkyl, substituted with hydroxyl, halogen, cyano, NRβR8, SR8, trifluoromethyl, 0R8, C3-C8 cycloalkyl, phenyl, NR8COR9, COR9, SO2 R9, 0C0R9, NRβ S02 R9 or NRβ C02 R8; R2 and R3 are independently (1) hydrogen, (2) C1-C10 alkyl, (3) Ci-Clio alkyl with 1 to 4 substituents selected from hydroxyl, Ci-Cio alkoxy, and halogen; X is (1) -CH2-, (2) -CH2-CH2-, (3) -CH = CH- or (4) -CH2O-; R * and R5 are independently "• - (1) hydrogen, (2) C1-C10 alkyl (3) halogen, () NHR8, (5) 0R8 (6) SO2R9 or (7) NHSO2R9; RS is (1) hydrogen or (2) C 1 -C 10 alkyl, R 7 is Z- (R 1")"; R 1"is (1) R 1, with the proviso that when ñ is phenyl, R 1" is not C 1 -C 10 alkyl. (2) C3 -Ce cycloalkyl, (3) optionally substituted phenyl with up to 4 groups independently selected from R8, NR8R8, 0R8, SR8 and halogen, or (4) 5- or 6-membered heterocycle with 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen, optionally substituted with up to four groups independently selected from oxo, Rβ, NRßRβ, ORβ and SRβ halogen; Z is (1) phenyl, (2) naphthyl (3)? N 5- or 6-membered heterocyclic ring with 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen, (4) a benzene ring fused to a chloroalkyl ring of C3 -Ce, (5) a benzene ring fused to a 5- or 6-membered heterocyclic ring with 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen, (6) a 5- or 6-membered heterocyclic ring with 1 to 4 selected heterogeneous oxygen, sulfur, and nitrogen alloys fused to a 5- or 6-membered heterocyclic ring with 1 to 4 heteroatoms selected from oxygen, azide, and nitrogen, or (7) a 5- or 6-membered heterocyclic ring with 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen fused to a cycloalkyl ring of C 3 -Ce; R8 is (1) hydrogen, (2) C1-C10 alkyl, (3) C3-C3 cycloalkyl, (4) Z having optionally the 4 substituents selected from halogen, nitro, oxo, NR10R10, Ci-Clio alkyl , C 1 -C 10 alkoxy, C 1 -C 10 -thioxium, and Ci-Cι alkyl with 1 to 4 substituents selected from h roxyl, allogen, CO 2 H, CO 2 -C 1 -C 10 alkyl, SO 2 -C 1 -C 10 alkyl, cycloalkyl of C3 -Ca, C1-C10alkoxy, and Z optionally substituted with 1 to 3 of halogen, C1-C10alkyl or Ci-Cioalkoxy, or (5) C1-C10alkyl which has 1 to 4 s-selected hydroxyl, halogen, CO-2H, alkyl of CO2H, C 1 -C 10 alkyl, SO 2 - C 1 -C 10 alkyl, C 3 -C 8 cycloalkyl, C 1 -C 10 alkoxy, C1-C10alkyl, and Z optionally substituted with the 4-halogen, C1-C10alkyl or C?-C alcoalkoxy; R9 is (1) Rβ or (2) NRβR8; Rio is (1) C1-C10 alkyl, or (2) two Rio groups together with the N to which they are attached form a ring of 5 or 6 members s optionally substituted with C1-C10 alkyl; or a maceutically acceptable salt thereof. In one embodiment of the present invention, fi is a 5- or 6-membered heterocyclic ring with 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen.; a benzene ring fused to a 5- or 6-membered heterocyclic ring with 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen; or a 5 or 6 membered heterocyclic ring with 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen fused to a 5 or 6 membered heterocyclic ring with 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen.

In another embodiment of the present invention, phenyl or benzene are fused to a C3-C8 cycloalkyl ring. Preferred compounds of the present invention are made when in structural formula I above: R2 and R3 are hydrogen or methyl; X is -CH2-; is 0 to 3; "" S S 1; r ee 0 to 2; and R *, RS and Rβ are hydrogen.Other preferred compounds of the present invention are made when in structural formula I above: fl is phenyl or a 6-membered heterocyclic ring with 1 or 2 heteroatoms selected from nitrogen and sulfur, R is hydroxyl, halogen, cyano, trifluoromethyl, NRßRβ N ^ SC ^ R9, NR8COR9, NR8CO2R8, Ci-Ce alkyl optionally substituted by hydroxyl; and r is 0 or 2. Preferred compounds are represented by the formula: the e > i where n ee 0 to 3; ee 1 R1 is (1) halogen or (2) NRβ R8; R2, R3 is independently hydrogen or methyl; Rl »ee (1) halogen, (2) Ci-Cio alkyl, (3) NRß Rß, (4) NRß COR9, (5) NRß CO2 Rß, (6) COR9, (7) 0C0R9, or (8) a 5 or 6-membered heterocycle with 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen, optionally substituted with up to 4 groups "Selectively selected from oxo, halogen, Rß, NR8R8 0R8, and SR8; Z is (1) phenyl, (2) naphthyl, (3) a 5- or 6-membered heterocyclic ring with 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen, (4) benzene ring fused to a 5- or 6-membered heterocyclic ring with 1 to 3 heteroatoms selected from oxygen, sulfur and nitrogen, or (5) a 5- or 6-membered heterocyclic ring with 1 vi heteroatoms selected from oxygen, sulfur and nitrogen, fused to a cycloalkyl ring of C3-Ce; X is -CH2-; and Rβ and R9 are co or defined under formula I. Very preferred compounds are those represented by the formula Id: Go where n ee 0 to 1; Rl is NRß ß; 2 and R3 are independently (1) hydrogen, or (2) methyl; B is (1) hydrogen, (2) benzene fused to the benzene ring to form naph1o, or (3) a 5-6 membered heterocycle with 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen fused to the benzene ring; R1 'is (1) halogen, (2) C1-C10 alkyl, (3) NRβR8, (4) NR8C0R9, (5) NR8 C02 R8, (6) COR9, or (7) a heterocycle of 5 or 6 members with 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen, optionally substituted with up to four independently selected groups of oxo, Rβ, SRβ, ORβ and NRβRβ; when B and the benzene ring form an i-4-ring system, Rl * is attached to any ring; Rβ is (1) hydrogen, (2) Ci-Cio (3) Z alkyl optionally having the 4 substituents selected from nitro, oxo and NRi ° Ri °, or (5) Ci-Cio alkyl having 1 to 4 substituents selected from hydroxyl, halogen, Ci-Cio alkyl C3-C8 cycloalkyl, and Z optionally substituted with from 1 to; x ^ H e halogen, C1-C10 alkyl or C1-C10 alkoxy; R9 is (1) Rß or (2) NRßRβ; Rio is (1) C 1 -C 10 alkyl, or (2) two R groups or together with the N to which they are attached form a 5 or 6 membered ring optionally substituted with C 1 -C 10 alkyl; VZ is (1) phenyl (2) a 5- or 6-membered heterocyclic ring with 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen, (3)? N benzene ring f? Eted to? 5 or 6 heterocyclic ring members with 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen, or (4) a 5- or 6-membered heterocyclic ring with 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen fused to a cycloalkyl ring of C3 -Ce . Other preferred rnuy compounds are represented by the formula Ib: Ib where n is 0 to 3; m is 1 R- ^ s (1) hydroxyl (2) cyano (3) NR8R8 or (4) halogen R "is (1) halogen (2) NR8R8 (3) NR8COR9, (4) NR8C02RT, (5) 0C0R9, or (6) a 5 or 6 membered heterocycle with 1 to 4 h pteroatornoe selected from oxygen, sulfur and nitrogen, optionally substituted with up to 3 independently selected groups of oxo, halogen, Rβ, NRβRβ or Rβ and SRβ; Z is (1) phenyl, (2) naphthyl or (3) benzene ring fused to a 5- or 6-membered heterocyclic ring with 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen; x is -CH2-; and R2 and R3 are independently hydrogen or methyl. Representative anti-obesity and anti-diabetes compounds of the present invention include the following: N-C4-C2-CU2-hydroxy-2- (6-aminopyridin-3-yl) ethyl-3-amino-3-ethyl-3-phenyl-4- (-alkylaminocarbonyl) -benzensulfonamide. 4-C 2- [C 2 -hydroxyl-2- (6-amino-di-din-3-yl) -ethyl] -amino] -ethyl] -phenyl] -4-iodobenzens [alpha] -phenonide. N- [4-C2-CC2-hydroxy-2- (6-arninopyridin-3-i1) et i 1] arni no] et i 1] pheni 1] -benzeneul f onarn i da. N-C4-C2- CC2-hydroxy-2- (6-aminopyridin-3-yl) ethyl 3-arnino-3-thi-13-phenyl-13-2-nalenesulfonamide. N-C4-C2-CC2-hydroxy-2- (6-ami.nopyr.idin-3-yl) ethyl 3 arni no 3 eti 1 pheni 1-3- qui noli nsul fonarni da. N- C - [2-C C 2 - i d rox i-2 - (6-aminopyridinyl) -yl-3-amino-3-phenyl-3-benzisoxazole sulfonamide.

N- "4- [2-C- [2-hydroxy-2- (5-aminopyridin-3-yl) ethyl ami-3-ethyl-3-phenyl-13-4- (hexylmethylaminocarbonyl) amino-3-benzensulfonarnide. N-C4-C2-C C2-hydroxy-2- (6-aminopyridin-3-yl) ethyl-3-amino-3-ethyl-3-phenyl-3-4-C (dimethylaminocarbonyl) amino-3-benzens? Lponarnide. NC-C2-C [2-hydroxy-2- (6-aminopyridin-3-yl) ethyl-3-amino-3-ethyl-3-phenyl-3-4- (3-hexy-1-2-imidazolidon-1-i / * "" benzensul fonarnide, N-C4 -C3-CC2-hydroxy-2- (6-aminopyridin-3-yl) eti13amino-3-propyl-3-pheny13-4- (he-lamino-r -bonylamino) -benzene-1-phononamide NC 4-C3- [C2-hydroxy-2- (6- aminopyridin-3-yl) et.yl 3-amino-3-propyl-3-phenyl-3-iodobenzene-1-pfonnide N- [4-C3-CC2-hydroxy-2- (6-arninopyridin-3-yl) ethyl-3-amino-3-propyl-phenyl-benzens? ^ - [3- CC 2 -hy drox i-2 - (6-arni nopi ri din -3 • - • il) ethyl 3amino3pro? Il3 phenyl3-2-naphthalenesulfonarni.da. N-C4-C3-CC2-hydroxy-2 - (6-amino? Iridin-3-yl) ethyl-3-amino-3-propyl-enyl 3 -3-q? Inolins? -fonphonamide N-C4-C2-CC2-hydroxy-2- (3-pyridinyl) ethyl-3-amino-3-phenyl-3-4- (hexylaminocarbonylamino ) benzene? lfonanide N_ [_ [- CC2-hydroxy-2- (3-pi Ridinetyl 3-amino-3-ethyl-3-phenyl-3-4-isopropyl-1-onamide-N-C4-2-CC2-hydroxy) 2- (3-pyridinyl) ethyl-arnino-3-ethyl-3-phenyl-3-2-naphthalenes-lfonamide. -4-C2-C 2-hydroxy-2- (3-pyridinyl) ethyl 3-amino-3-methylphenyl? 3 -3-q? I nol i ne? Onamide. N- C 4- [2-C C 2 -hydroxy-2- (3-? Iridi nyl) ethyl 3-arnino-3-phenyl-13-4- [(hexylmethylaminocarbonyl) amino-3-benzensulfonamide. N-C4-C2- CC2-hydroxy-2- (3-pyridinyl) ethyl3amino3ethyl3phenyl3-4- (3-hexyl-2-imidazolium inon-l-yl) benzene-lfonamide. N-C4-C2-CC2-hydroxy-2- (3-pyridinyl) ethyl arnino3ethyl3-phenyl3-4-iodobenzens? ^ -C2- C2-hydroxy-2- (3-? Irid? Nyl) et? 13arn? No3ethyl3phen? 3-4-C5- (3-c? Clopentylpropyl) -Cl, 2,43-oxadiazole-3 il benzensulfonarnida.

N-C4-C2-CC2-hydroxy-2- (3-? Ipdinyl) et? 33 aminoquinethyl) phen? 3-4C- (1 -oxoheptyl) am? No3benzens? Lfonamide. N-C4-C2 - [[2-hydrox? -2- (3-pyridinyl) ethyl3am? No3et? L3phenyl3-4C (l-oxo-4-phenylbutyl) arnino3benzensul fonarnide. N-C4-C2-2-hydroxy? -2- (3-pyridinyl) et? 3-arnino-3-ethyl-3-phenyl? -34-C (propoxycarbonyl) a? No3 benzensul fonamide. W- '4-C2- [C2-H? Droxi-2- (3-??? d? Dinil) ethyl3arn? No3et? L3fen? L "4 ~ C C (f? R2-ilrnet il) mmo3carboni l3am? No3benzens? Fonamide. N-C -C2- 2-hydroxy-2- (3-? Iridinyl) ethyl3 arni no 3 et? L3femll -4-CCC (2-phenylethyl) arn? o3carbonil3am? no3benzen ul fonarni n. N-C4-C2 ~ CC2-hydroxy-2- (3-p? Ri < in? L) ethyl3amino3ethyl phenyl? -CC (2-indol-3-ylethyl) amino3carbonyl3-amino-3-benzens? Onam? gives.

N-C -C2- C2-hydrox? -2- (3-p? Ri inyl) et? A? O 3 et? L3fen? 13-4- C C (octi larni no) carbom 13 am? No benzens? L fonami da. N-C4-C2-CC2-h? Drox? -2- (3-pyridine?) Ethyl3arn? No3et? L3ferull-l-i (hex i lamino) carbon i 13 -5-? dol i sul fonamida. l \ £ 4- 2-C 2-hydroxy-2- (3-pyridinyl) ethyl] arne-3-ethyl phenyl3- (octylamino) carbonyl3-5-indolins? -phonamide. N-C4-C2-CC2-hydroxy-2- (3-pd? Nyl) ethyl3am? No3ethyl3phenyl3l-C (Nrnethyl-N-octylamino) carbonyl3-5-indolinsulfonamide. N-C4-C2-CC2-hydroxy-2- (3-? Iridinyl) ethyl amino3ethyl3phen? 3-l- (l-oxononyl) -5-indolinsul fonamide. N-4-C2-CC2-hydroxy-2- (3-? Iridinyl) ethyl3amino3ethyl3phenyl3-l- (4-methylthiazol-2-yl) -5-i ndol i ns? L fonamide. "-C2-C2-hydroxy-2- (3-? Iridinyl) ethyl3arn? No3et? L3 phenyl 3-1- (4-octyl? Azol-2-yl) -5-indolins? Lponarn? Da. C4-C2-CC2-hydroxy-2- (3-pi-ridinyl) ethyl-3-amino3-ethyl-3-phenol3-l- (4- et? L-5-methyl-t-azol-2-yl) -5-indole? Ns? N-C4-C2-CC2-hydroxy-2- (3-pyridinyl) et? I3amino3ethyl3phen? 3-4- (3-octyl-2-im? dazolidinon-1-yl) benzens? lfonam? da. _ NC-C2- 2-hydroxy-2- (3-p? r? dinyl) ethyl-3-ane-3-ene-3-phenyl? 3-4-C3- (4, 4, 4-tr? Fl? Orob? T? L) -2-? M? Dazol? D? Non-l-il3benzensul fonamide. fv '- "* 4- [2-CC2-h? drox? -2- (3 -? r? d? nl) et? 3am? no3et? l3 in? l3 - C3- (3-phen? l? ropil) -2-? midazolidinon-l-il3benzens? lfonam? da N-C4-C2-2-h? dro i-2- (3-p? ridin? l) ethyl3arn? no3ethyl3phen? 3-4-3 (4,4,5,5,5-penta f 1 uo rope n 111) - 2 - irni dazol i di non - 1 - i 13 benzensul fonamide N - C4 - 2- C2 - hydrox? -2- (3 -pyridinyl) ethyl 3-arn-3-ene-3-phenyl-4-C3- (2-c-cloheyl-ethyl) -2-? rnidazolidinon-1-yl-3-benzensulfonamide.

N- 4-C2-C 2 -hydroxy-2- (3-γ-ridinyl) and il-3-n-n-3-ethyl en.l34- 3- C 3- (4-chlorophenyl) propyl-3-7-imi azol i di non-1- l benzensul fonamide.

N -4-C2- 2-hydroxy-2- (3-pyridinyl) ethyl-3-aminoethyl-3-phenyl3-4- (3-penti-1-2-imidazole idinone-1-i Dbenzens? -phonamide. N-C4-C2-C2-hydroxy- 2- (3-pyridinyl) ethyl 3-amino3-ethyl-phenyl-3-4-C3- (3-cyclopentyl-ro-pyl) -2-irnidazolidin-1-yl-3-benzene-1-fonamide N-C4-C2-CC2-hydroxy-2- (3-pyridinyl) ethyl arnino3ethyl3phenyl3-4-C3- (2-cyclopentylethyl) -2-imidazolidinon-l-yl 3 enzeneul fonamide.

N- C 4- C 2-C [2-hydroxy-2- (3-pyridinyl) etyl 1,3-amino-3-ethyl-3-phenyl-3-6- (3-cyclohexylpropyl) -2-imidazolidinon-1-benzensul fonamida. hf 4-C 2 -C 2 -hydroxy-2- (3-pyridinyl-ethyl-3-aminophenyl) -phenyl-3- (2, 2-dimethylhexyl) -2-imidazole idinon-1-yl-3 benzensul-fonamide .

N-C4-C2- C2-hydroxy-2- (3-pyridinyl) ethyl3amino3ethyl3phenyl3-4- (3-hexyl-2-irnidazolon-1-yl) benzensul fonarnide. N-C4-C2-C 2-hydroxy-2- (3-pyridinyl) ethyl amino-3-ethyl-3-phenyl-3-4-C3- (4, 4, 4-t rifl? Orobicyl) -2-irnidazolon-1-i 13 benzensul fonarnide . N-C 4- C-C C 2 -hydroxy-2- (3-pyridinyl) ethyl 3-arnino-3-ethylphenyl-3-octy 1 -2-. Imidazo Ion -l -i 1) enzensul fonamide. N, '-C2-CC2-hydroxy-2 ~ (3-? Iridinyl) ethyl 3-arnino-3-ethyl-3-phenyl-3- (3-cyclopentyl-propyl) -2-irnidazolon-1-yl-3-enenesulfonam.i.da. NC 4- C2-CC2-hydro i-2- (3-? Iridinyl) ethyl 3-arnino-3-ethyl-3-phenyl-3-4- (2-octi-1-3-oxo-C 1,2,43-triazole-4-yl) -enzyme fonamida. N-C4-C2-CC2-hydroxy-2- (3-? Iridinyl) ethyl3amino3ethyl3phenyl3-4- (4-hexy-5-tetrazolon-1-yl) benzeneulonamide. N-C4-C2- 2-hydroxy-2- (3-pyridinyl) ethyl-3-aminoethyl-3-phenyl-3-4- (4-octyl-5-tetrazolon-1-yl) benzensul-fonamide. N- 4-C2-CC2-hydroxy-2- (3-pyridinyl) ethyl-3-amino-3-ethyl-3-phenyl-3-4-C (3-cyclopentyl-propyl) -5-tetrazolon-1-yl-3-benzene-fonnamide.

N-, -C2- C2-h? Drox? -2- (3-p? R? D? N? L) et? 3am? No3et? L3phen? 3-4- (2-pentyloxazole -5-? 1) benzensul fona i da. N-C4-C2-CC2-h? Drox? -2- (3-p? Pd? M Detyl3am? Nolet? L3phen? -4- (2-oct? Loxazole-5?) Benzensul fonarnide. 4-C2-CC2-h? Drox? -2- (3-p? R? D? Nil) et? Ln? No3et? L3fen? 3-4-C2- (2-c? Clopent? Le? I) oxazole-5-l3-benzensulfonamide, N-C4-C2-C 2 -h? drox? -2- (3-?? r? d? n? l) et? 3am? no3et? l3fen? -4- C (4-et? L-5-rnet? Lt? Azole-2? 1) am? No3 benzensul ona N '* -C2-CC2-h? Drox? -2- (3-?? r? D (n) l) e? l am? no3et? l3 eml] -4- (4,5,6, 7-tetrah? drobenzot? azol -2-? l) am? no3 benzensul fonamide.

N-C4-C2- C2-hydrox? -2- (3-p? Pd? N? L) et? 3am? No3et? L phen? 3-4- (2-hex 11? I dazol - 4 - 11) benzens? 1 f onarní da. N-C4-C2-CC2-h? Drox? -2- (3-p? R? D? N? L) et? 3am? No3et? L3fen? 3-4- (l-rnet? L-2-oct ? l? rn? dazol-5-? l) benzensul fonarida. N-C4- -CC2-h? Drox? -2- (3-p? R? D? Ml) et? 3am? o3et? l3 phen3-3-Cl-rnet? i-2- (2-c? cl? ent? iiet?)) m? dazol ~ 5-? 3benzensul phona ida.

N- "" r-C2-CC2-h? Drox? -2- (3 -? R? D? N? L) et? Ln? No3e? I in? L3 ~ 4- l-? Net? L -2-C2- (4-fluorophen? L) et? L3? M? Dazol-5-? 3-benzens? Fonamide.

N-C4-C2-CC2-h? Drox? -2- (3-p? Pd? N? L) et? L3arn? No3et? L3phen? -4 ~ (5-pentyl-C 1,2,43 ~ oxad? azol-3-? l) benzensul fonani a. N- 4-C2-C2-hydrox? -2- (3-p? R? D? Ml) et? 3am? No3et? L3phen? 3-4-C5- (2-c? Clopent? Let? L ) - 1, 2, 43 -oxad? azole-3? 3-benzensulfonamide.

N-4- 2- 2-hydroxy? -2-f 3-?? r? D? N? L) e? 3am? Nole? 3 pheny 13-4- (5 heptyl-C 1,2,4 -oxad? azol-3-? l) benzensul fonarní da. N-C4-C2-CC2-h? Drox? -2- (3-p? Pd? N? L) et? L3arn? No3et? L3fen? 3-4- (5-oct? L-l, 2, 43 -oxad? azol-3-1) benzensul fonarní da. N-C4-C2-rC2-h? Drox? -2- (3-?? r? D? N? L) et? L3arn? No3et ?? faith? 3-4- (5- • Ithio-C1,2,3-triazol-3-yl) benzensulfonamide. N-C4-C2-CC2-hydroxy-2- (3-? Iridinyl) ethyl amino3etii fenii3-4-CC4- (4-propylpi? Eridin-1-yl) -l / l-dioxo- l, 2.53- thiadiazol-3-yl amino3 enzensul fonamide. N-C4-C2- 2-hydroxy-2- (3-pyridinyl) ethyl3amino3etii fenii -4- CC4- (hexylmethylamino) -l, l-dioxo-Cl, 2,53-thiadiazol-3-yl3amino3 benzeneul fonami a. NC-C2-CC2-hydroxy-2- (3-pyridinyl) ethyl-3-aminoethyl-3-phenyl-4-CC4- (N-heyltyl, N-ritylamino) -l, l-dioxo-Cl, 2,53-thiadiazol-3-yl ) amino3benzensul fonamide. N- C 4- C 2 -C 2 C 2 -hydroxy-2- (3-pyridinyl) ethyl 3-arnino-3-ethyl-3-phenyl-3-ethyl-2, 4-imidazole and dinedion-3-yl) -benzeneul-fonamide. N- 4-C2-C2-hydroxy-2- (3-pyridinyl) ethyl arnino3ethyl phenyl3-4- (3-n-t-phenyl-1) -5-pyrazolon-1- i.1) benzensul fonarnide. N- 4- C 2- CC 2 -hydroxy-2- (3-pyridinyl) ethyl 3-arnino-3-ethyl-phenyl-3-4- [4- (1-hydroxy-1-hexylhexyl) -5-rnethyl-2, 33-triazol-2-yl3-benzeneul fonarnide. N-C4-C2- C2-hydroxy-2- (3-pyridinyl) ethyl-3-aminoethyl-ethyl-3-phenyl) -4- 4- (1-hydroxyhepty) -5-? Nitrile-Cl, 2,33-triazol-2-yl-3-benzene? fonamida. N-C4-C2- C2-hydroxy -2- (3-p >; ri di ni 1) eti 1) ami no 3-2 -met. i 1 p ropi 13-phenyi-4 - (3-hex i l-2-j. * i dazol i di non-1 -yl) benzens? l fonamide. N-C4-C2-C 2-hydroxy-2- (3-pyridinyl) ethyl-3-amino-3-rnethyl-ro-p-phenyl-3-iodobenzene-sulfonadnide. N-C4-C2-CC2-Hydryloxy-2 ~ (3-pyridinyl) ethyl-3-arnino-3-rnethyl-yl-phenyl-3,4-C (hexyllamino) carbonyl) ami no 3 benzensul fonamide. N-C4-C2-C (2-hydroxy-2-phenylethyl) amino3ethyl3-phenyl3-4-iodobenzen-eul-fonamide. N-C4-C2-C (2-hydroxy-2-phenylethyl) amino3ethyl3-enyl3-2-naphthalene-sulphonamide. N- 4-C2-C (2-hydroxy-2-phenylethyl) arnino3ethyl3 enyl3-3-q? I noli sulphonamide. N- C2-C (2-hydroxy-2- (3-chlorophenyl) ethyl-3-amino-3-ethyl-3-phenyl-3-isopropyl-benzene-fonarnide N-C4-C2-C (2-hydroxy-2- (3-chloro-phenyl) -ethyl-3-arnino-3-yl-3-phenyl} -2- phthalene-sulfone-ida N-C2-C2-hydroxy 2- (3-chloro-phenyl) -ethyl-amino-3-ethyl-phenyl-3-3-q-inol and N-C4-C2-C2-hydroxy-2- (4-amino-3,5-dichlorophenyl) ethyl 3-amino-3-ethyl-phenyl-3-4- (indocarboni lamino) benzensul fonamide N-4-C2-CC2-hydro i-2- (4-amino-3,5-dichloro phenyl) ethyl 3-amino-3-ethyl-3-phenyl-3-1-C (octylamino) carbonyl 3 -5-indolyl nsul fonarnide N-4-C2-C 2 -hydroxy-2- (4-am.in-3,5-dichlorophenyl) ) ethyl 3amino3 eti 13 phenyl-4- (3-hexyl-2-irnidazolidinon-l-yl) benzensul fonamide., -C4-C2-CC2-hydroxy-2- (4-arnino-3,5-dichloro phenyl) ethyl 3-aminoquinethyl 3-phenyl3-4- (3-octyl-2-imidazolidinon-1-yl) benzensul fonamide, N-C4-C2-C2-hydroxy-2- (4-hydroxyphenyl) ethyl arnino-3-ethylphenyl3-benzene-1-fonamide. - 2-C C2-hydroxy-2- (4-hydroxy-phenyl) -ethyl-3-amino-3-3-phenyl-3-4-iodobenzensul-fonarnide N-C4-C2- 2-h.idrox i-2- (3-cyano-phenyl) -ethyl-3-aminoethyl-phenyl-3-4- (hex and laminocarbonyl) benzeneul-fonamide. N7r4-C2-CC2-hydroxy-2- (3-cyanophenyl) ethyl3-arnino-3-ethylphenyl3 -3- < -I noli nsul fonstrni da. N-C4- 2-CC2-hydroxy-2- (3-? Iridinyl) ethyl3amino3ethyl3phenyl3-4- (5-hexyl-C-1,2, -3-oxadiazole-3-yl) benzensul fonarn. Going. N-C 4- 2-C C 2 -hydroxy -2- (3-pyridinyl) ethyl 3-arnino-3-ethyl-3-phenyl-3-4- (4-heptyl-5-methyl-1,2,3-triazol-2-yl) -benzensul-fonamide. N- 4-C-C 2 -hydroxy-2- (3-iridinyl) ethyl 3-amino-3-ethyl-3-phenyl-3-4- (3-hex., L-2, -nic-azole and di-n-1-yl) benzens? Lf ona . N- 4- C 2- C'C2-hydroxy-2- (3-pyridinyl) eti.l3arnino3et.il 3 phenyl 3-4- (3-octyl-2,4-irnidazolidinadion-l-yl) benzens? fonanid. N-C4-C2-CC2-hydroxy-2- (3-? Iridinyl) et.yl3-amino3-ethylphenyl3-4-C3- (3-cyclopentyl-ro-pyl) -2,4-irnidazolidinedione-yl-3-benzensul-fonamide. NC 4- C 2- CC 2 -hy drox i -2- (3-pyridinyl) ethyl 3-amino-3-ethyl-3-phenyl 3-4- (3-pentyl-C 1,2,43-oxadiazol-5-yl) -benzens? fonarnida.

N "4-C2-C [2-Hydroxy-2- (3-pyridinyl) ethyl arnino-3-phenyl-3-4- (3-hexyl-C 1, 2, 3-oxadiazol-5-yl) benzens? L fonamid. -C4-C2-CC2-hydroxy-2- (3-pyridinyl) ethyl arnino3eti 13 phenyl-13-4- (3-hexyethyl-C 1, 2, 3-oxadiazol-5-yl) enzeneul fonamide NC -C2 -C [2-hydroxy-2- (3-pyridinyl) ethyl-3-aminoethyl-3-phenyl-4- (3-octy-1,2, 3-oxadiazol-5-yl) -benzens? -phonamide, N- 4- 2- C2-hydroxy -2- (3-pyridinyl) ethyl 3-amino-3-ethyl-3-phenyl-3- (2-cyclopentylethyl) -Cl, 2,3,4-oxadiazol-5-yl benzensul fonnamide, N-C4-C2-2-hydroxy-2- (3-pyridinyl) ) ethyl 3-amino3-ethyl-3-enyl3-4-C3- (3-cyclopentyl-propyl) -Cl, 2,43-oxadiazol-5-yl-3-benzensulfonarnide, ri-C4-C2-2-hydroxy-2- (3-pyridinyl) ethyl-3-amino-3-phenyl-3-4- ( 3-ethyl-Cl, 2,43-thiadiazol-5-yl) benzens? L phonamide, N- 4- 2-C 2 -hydroxy-2- (3-pyridinyl) ethyl-3-amino) ethyl-3-phenyl-3- (3-hexyl) -Cl, 2,43-thiadiazol-5-di-benzene-1-fonamide, N-4-C2-CC2-hydroxy-2- (3-pyridinyl) ethyl-3-aminoethyl-3-phenyl-3-34- (3-heptyl-Cl,, 43 -thiadiazole -5-yl) benzensul fonami da N-C4-C2-C 2-hydroxy-2- (3 -pyridinyl) ethyl 3 ami no) ethyl 3 phenyl -4- (3-octyl-Cl, 2,3,4-thiadiazol-5-yl) benzene-α-fonami at N-C4-2-CC2-hydroxy-2- (3 -pyridinyl) ethyl) amino) ethyl 3-phenyl-34-C3- (2-cyclopentyl-lethyl) -Cl, 2, 43-thiadiazol-5-yl-3-benzene-1-fonarnide.

N r4-C2-CC2-hydroxy-2- (3-pyridinyl) ethyl-3-amino) ethyl-3-phenyl-3-4-C3- (^ -cyclopentyl-propyl) -Cl, 2,43-thiadiazol-5-yl-3-benzeneul-phonamide. N-C4-C2-CC2-hydroxy-2 - (3-pyridinyl) ethyl-3-aminophenyl-3-phenyl-3-4- (5-pentyl-Cl, 2,43-thiadiazol-3-yl) enzeneul-fonamide. N- 4- 2-CC2-hydroxy-2- (3-pyridinyl) ethyl-3-aminoethyl-3-phenyl-4- (5-hexyl-Cl, 2,43-thiadiazol-3-yl) -benzens-l-fonarnide. N-C4-C2-CC2-hydroxy-2- (3-pyridinyl) ethyl-3-aminoethyl-3-phenyl-3-4- (5-heptyl-Cl, 2,4-thiadiazol-3-yl) benzensulonamide. N-C4-C2-C2-hydroxy-2- (3-pyridinyl) ethyl-3-amino-3-phenyl-13-4- (5-octyl-Cl, 2,4-thiadiazol-3-yl) benzensul fonarnide N-4-C2- C 2 -hydroxy-2- (3-pi-idinyl) -ethyl-3-aminoethyl-3-phenyl-3-4-C5 - (2-cyclopentylethyl-D, 2,4-thiadiazol-3-yl) enzeneul-fonarnide. N-C4-C2- [C2-hydroxy-2- (3-pyridinyl) ethyl-3a-nino-3-ethyl-3-phenyl-3-4-C5- (3-cyclopentyl-propyl) -Cl, 2, 43-thiadiazol-3-yl-3-benzensul-fonamide.

N 1-C2-2-hydroxy-2- (3-pyridinyl) ethyl-3-aminoethyl-3-phenyl-3-4-penti-3-oxo-C 1,2,43-triazol-2-yl) -benzensul-fonamide. N-C4-C2-C2-hydroxy-2- (3-? Iridinyl) ethyl 3-amino-3-phenyl-3-phenyl-4-hexyl-3-oxo-Cl, 2-triazol-2-yl) benzens? Onamide. N-C -C2- C2-hydroxy-2- (3-? Iridinyl) ethyl arnino3ethyl phenyl3-C4- (4-heptyl-3-oxo-C 1,2,43-triazol-2-yl) benzens? Fonamide. N-C4- 2- C2-hydroxy-2- (3-pyridinyl) ethyl-3-aminoethyl-3-phenyl-4- (4-octyl-3-oxo-Cl, 2,3,4-triazole-2-yl) -benzens? -family N-C4- C2-CC2-hydroxy-2- (3-pyridinyl) ethyl-3a-ino3ethyl-phenyl-3-4-C4- (2-cyclopentylethyl) -3-oxo-Cl, 2,4-triazol-2-yl-benzens-1-onamide. N-C4- 2-CC2-hydroxy-2- (3-p ..ridiniDethyl 3-arnino-3-ethyl-3-phenyl-4-C 4- (3-cyclopentyl-1-propyl) -3-oxo-C 1,2,43-triazole- 2-yl 3 -amino acid-N-C4-C2-CC2-hydroxy-2- (3-iridinyl) ethyl-3-aminoethyl-3-phenyl-4- (5 -pentyloxazol-2-yl) -enzymesulfonamide N-C4-C2-CC2 -hydroxy-2- (3-pyridinyl) ethyl3amino3ethyl3phenyl3-4- ( -hexyloxazol-2-yl) benzens? L fonarnide. N-C4-C2- C2-hydroxy-2- (3-pyridinyl) ethyl-amino-3-phenyl-3-4- (5 -hexyloxazol-2-yl) benzensul-phona ida. N-C4-C2-C2-hydrO i-2- (3 -? Iridyl) ethyl 3-arnino-3-ethylphenyl3-4- (5-o? T.iloxazol-2-yl) benzens? L fonarni. gives. N-. -C2-CC2-hydro i-2- (3-pyridini1) ethyl lamino le i 1] phenyl] -4-C5- (2-cyclopentylethyl) oxazole-2-i 13 benzens? Onami da. N-C4- 2- C2-hydroxy-2- (3-pyridinyl) ethyl-3-indoxyethyl-phenyl-3-4- [5- (3-cyclopentyl-propyl) -oxazol-2-yl-3-benzens? -phononide. N-C4-C2-C2-hydroxy-2- (3-pyridinyl) ethylyl-amino3-ethyl-3-phenyl-4- (4-pentyloxazol-2-yl) -benzensul-fonamide. N-C4- 2- C2-hydroxy-2- (3-pyridinyl) ethyl-3-aminoethyl-3-phenyl-3-4- (4-hexyloxazol-2-yl) benzensulonamide. N-C4-C2- CC2-hydroxy-2- (3-? Iridinyl) ethyl arnino3ethyl-3-phenyl-3-4- (4-heptyl-loxazol-2-yl) -benzeneul-fonarni da. N-C 4 -C 2 -C 2 -hydroxy-2- (3-? I ridiniDet.il 3-amino3-ethyl-3-phenyl-3-4- (4-octyloxazol-2-yl) -benzensul-fonarnide N-C4- 2-C 2-hydroxy-2- (3-pyridinyl) ethyl amino-3-ethyl-3-phenyl-3-4-C4- (2-cyclopentyl-let; Doxazol-2-yl-3-benzeneul-fonarni da h 4-C2-C2-hydroxy-2- ( 3-? Iridinyl) ethylamino3ethyl phenyl3-4-C4- (3-cyclopentylpropyl) oxazol-2-yl-3-enanthenes? Fonamide NC-C2-C2-hydroxy-2- (3-pi ridinylDethyl-3-amino3-ethyl-3-phenyl-3-4 - 2-hexioxazol-5-yl) benzensul fonami da N-4-C 2-C C3-hydroxy-2- (3-pi ridinyl-ethyl-3-aminophenyl-3-phenyl-134- (2-heptyloxazol-5-yl) -amine-N-fonamide -C4- 2-C-2-hydroxy-2- (3-pyridinyl) ethyl-3-aminoethyl-phenyl-3-4-C2- (3-cyclopentyl-propyl) -oxazol-5-yl-3-enzens l f f f f f f N N-C4-C2- 2-hydroxy- 2- (3-pyridinyl) ethyl 3-amino-3-ethyl-3-phenyl-3-4- 2- (4-cyclohexyl-butyl) -oxazol-5-yl-3-benzens-1-fonarnide - C 4 -C 2 -CC 2 -hydroxy-2- (3-yl-di-ethyl-3-amino-3-yl) 3-phenyl-3 -4-C 2- ^ .β- (4-fluoro-phenyl) -ethyl-oxazol-5-yl) -benzensul-fonarnide N-C4-2-CC2-hydroxy-2- (3'-iridinyl) ethyl-3-aminoethyl-3-phenyl3 -4- (2-pentyloxazol-4-yl) benzensul fonami da. NC 4- C 2-C C2-hydroxy-2- (3-? I ridiniDethyl 3-arnino-3-ethyl-3-phenyl) l 3-4- (2-Hexyloxazol-4-yl) benzeneul fonamide. N-C4-12- 2-hydroxy-2- (3-pyridinyl) ethyl-3-aminoethyl-3-phenyl-3-4- (2-heptyloxazol-4-yl) benzensul fonarni da. N-C4-C2-CC2-hydroxy-2- (3-pyridinyl) ethyl3amino3ethyl phenyl3-4- (2-octyloxazol-4-yl) benzensul fonarnide. N-, C 4-C 2-C C 2 -hydroxy-2- (3-pi ri iniDetyl 3 ami no 3 eti 13 phenyl 3 -4-C 2 - and t. "Cyclopentylethyl) oxazol-4-yl3benzensul fonamide. C -C 2-C 2-hydroxy-2- (3-pi-Ridinyl-Dethyl-lamino-ethyl-phenyl-1-4-2- (3-cyclopentyl-propyl) -oxazole-4-illbenzensul-fonarnide.) N-C4- C 2- CC2-hydrox i- 2- (3-pi ridiniDetil 3arnino3etil fen.il -4- (5 -pent iltiazol-2- i 1) benzeneul fonarnide. N- C4-C 2-C 2-hydroxy-2- (3-pi-Ridinyl-Dethyl-amino-3-ethyl-3-phenyl-3-4- (5-hexylthiazol-2-yl) -benzeneul-fonamide-N-C4-C2-CC2-hydroxy-2- (3-pyridinyl) ethyl 3-amino-3-ethyl-3-phenyl-3-4- (5-heptylthiazol-2-yl) -enosyl-onamide NC 4-C 2-C C 2 -hydroxy-2- (3-pi-ridinyl-ethyl-3-amino-3-yl-3-phenyl-3 -4- ( -octylthiazol-2-yl) benzens? Loneone. N- C 4-C 2-C 2 -hydroxy -2- (3-pi rid.in.il) ethyl 3arnino3eti 13 phenyl 3 -4-C 5- (2-cyclopentylethyl) thiazol-2-yl 3benzens? Fonamide NC 4-C 2- C 2 -hydroxy-2- (3-pyridinyl) ethyl-3-aminoethyl-3-phenyl-3-C-5-cyclopentyl-p-di-thiazol-2-yl-3-benzens? -phonamide. N-C4-C2-C [2-hydroxy-2- (3-pyridinium-Dethyl-3-amino-3-ethyl-phenyl-3-4- (4-pentyl-thiazol-2-yl) -benzeneul-fonamide-NC 4-C2-C-C2-hydroxy-2- (3- pyridiniumethyl3-amino3ethyl-3-phenyl-3-4- (4-hexylthiazol-2-yl) -benzensulfonamide N-C4-C2-C2-hydroxy-2- (3-pyridinyl) ethyl-3-aminoethyl-3-phenyl-3-4- (4-heptylthiazol-2-yl) -benzeneul-fonmnamide. N- C 4- 2-C C 2 -hydroxy-2- (3-pyridine-Dethyl-3-amino-3-yl-1-phenyl-3-4- (4-octyl-thiazol-2-yl) -benzeneul-fonarnide N-C4-C2-CC2-hydroxy- 2- (3-pi Ridini-Dethyl-3-arnino-3-ethyl-3-phenyl-3-4-C4-2-cyclopentylethyl) thiazole-2-yl-3-benzensul-fonamide • C4-C2-C2-hydroxy-2- (3-pyridinyl) ethyl-3-aminoethyl-3-phenyl3-4- C4- (3-cyclopentylpropyl) thiazol-2-yl) -benzeneul-fonarni da N-4-C2-CC2-hydroxy-2- (3-pyridinyl) ethyl-3-aminophenyl-3-enyl-3- (2-pentylthiazol-4-yl) benzensul-fonamide NC 4-C2- C2-hydroxy-2- (3-pi ridini.Det.il 3 ami no 3 ethyl 3-phenyl-13-4- (2-hexylthiazol-4-yl) benzens? Onami a. -C 2- C2-hydroxy -2- (3-pyridinyl) ethyl 3arn.ino3etillfen.il] -4 - (2-he? Tiltiazol-4-yl) benzens? lfonanide. NC 4-C 2-C C 2 -hydroxy-2- (3-pyridine-Dethyl-3-arnino-3-ethyl-3-phenyl) 3-4- (2-qjpti-11-azole-4-yl) -benzensul-fonami da. 4-C 2 -CC 2 - hi drox i - 2 - (3-pi ri di ni 1) et i 1 a? ni no 3 et i 1 f eni 13-4-C2- (2-cyclopentiietil) thiazol-4-yl 3 benzensul fonami da. 4- C2-CC 2-hydroxy-2- (3-pi) di-ethyl-3-amino-3-yl-3-phenyl-3-4- 2- (3-cyclopentyl-propyl) -thiazol-4-yl-benzensul-onaride, NC 4- 2- C 2 -hydroxy- 2- (3-pi RidinylDethyl-3-amino-3-ethyl-3-phenyl-3-4- (2-pentylthiazol-5-yl) benzensul fonnarnide.) N-C 4-C 2-C C 2 -hydroxy-2- (3-? I-ridine-Dethyl-3-ane-3-eeti-13) phenyl 3-4- (2-hexylthiazol-5-yl) enzensul fonami a.N-C4-C2-CC2-hydroxy-2- (3-? iridini.l) ethyl arnino3ethyl3fen.ill-4- (2-hepty) Itazole -5-. 1) benzensul fonnarnide, N-C4-C2-C2-hydroxy-2- (3-pyridinium-3-methyl-3-phenyl-phenyl-2- (2-octyl-thiazol-5-yl) -benzens-phonamide. N-C4-C2-C C2-hydroxy-2- (3-? I-di-methyl-3-methyl3-ethyl-phenyl-4-C2- (2-cyclopentylethyl) thiazol-5-yl-3-benzens? -phonamide. ^ '14- C2-CC2-hydroxy-2- (3-? I ridiniDetyl-arnino-3-ethyl-phenyl-3-4- 2- (3-cyclopentyl-propyl) -thiazol-5-yl-3-benzene-1-phonamide N- C 4-C 2- CC 2 -hydroxy-2- (3-pi-Ridinyl-Dethyl-3-amino-3-ethyl-3-phenyl-3-1- (5-methylthiazol-2-yl) -5-indoline-sulfonamide) N-C-C2-CC2-hydroxy-2- (3-pi RidiniDethyl] amino3ethyl-3-phenyl-3-1- (5-? - entylthiazol-2-yl) -5-indoline-sulfonamide N- C4-C2- 2 -hydroxy-2- (3-pi-di-phenyl-3-amino-3-ethyl-3-phenyl) 3-1- (5-hexylthiazol-2-yl) -5-i ndol ineulphanumide N-C4-C2- 2-hydroxy-2- (3-pi ridi il) eti3amino3eti 13 phenyl 3-1- (5-Heptylthiazol-2-yl) -5-indolinesulfonamide.-y- C4-C2-C 2 -hydroxy-2- (3-pyridine-Dethyl-3-amino-3-ethyl-3-phenyl-1- (5-c, cytothiazol-2-yl) ) ~ 5-indolinsulfonarnide N-4-C2-C 2 -hydroxy-2- (3-pi-ridinyl) ethyl-3-aminoethyl-3-phenyl-1-C5- (2-cyclopentylethyl) thiazol-2-yl-5-indolinesulfonarnide N-C4 -C2-C 2-hydroxy-2- (3-? Iñdinyl) ethyl) amino3ethyl phenyl3-l-C5- (3-cyclopentylpropyl) thiazol-2-yl 3 -5-indolins? L fonarnide N-C4-C 2 - C2-hydroxy-2- (3-pi idinyl) ethyl lamino leti11 fenill-l- (4-penti11iazol-2-iD-5-indolineul fonamide. N-C4-C2- 2-hydroxy-2- (3-pyridinium-1) -ethylamino] -ethyl] -phenyl] -l- (4-hexylthiazol-2-yl) -5-indolinsul-fonarnide. N ^ - * 4-C2-CC2-hydroxy-2- (3-pyridinyl) ethyl laminoletyl phenyl 1-1- (4-methyl-thiazol-2-yl) -5-indolineul fonarnide. N- C 4-C 2-C C 2 -hydroxy-2- (3-pi) ridinyl-ethyl-lamino let i 11-phenyl-11-1- C 4- (2-cyclopentylethyl) thiazol-2-yl-5-indoline-sulfonamide. N-C4-C2-CC2-hydroxy-2- (3-? Iridinyl) ethyl] amino3ethyl3-phenyl3-l-C4- (3-cyclopentylpropyl) thiazol-2-yl3-5-indolinsulfonarnide. NC 4 -C 2 -C 2 -hydroxy-2- (3-pi) di-ethyl-3-amino-3-yl-3-phenyl-3-1- (5-rityloxazol-2-yl) -5-indolineul-fonarnide N- C 4- 2- C 2 -hydroxy -2 - (-pi ridinyl) ethyl laminoletill feni 11-1- (5-pentyloxazol-2-yl) -5-indolineulfonarnide N- C -C 2- C2-hydroxy-2- (3-pyridine.iDet pillaminolet.il] fen.il 1-1- (5-hexyloxazol-2-yl) -5-indolineul fonamide N- 4-C2-CC2-hydroxy-2- (3-? i ridiniDethyl 3amino3ethyl3phen.il 31- (5-heptyloxazol-2-yl) -5- i ndol i nsul fonarnide N - [* - [2- C2-hydroxy-2- (3-pyridinyl) ethyl-3-aminoethyl-3-phenyl-3- (5- t-oxazol-2-yl ) -5-indolins? L phonamide N-C 4-C 2-CC 2 -hydroxy-2- (3-pi-ridinyl-ethyl-3-amino-3-ethyl-3-phenyl-3-1-C-5- (2-cyclopentyl) -oxazol-2-yl -5-indolins? L Fonamide N- 4-C2-C 2-hydroxy-2- (3-pyridinyl) ethyl-3-aminoethyl-3-phenyl-1-C5- (3-cyclopentylpropyl) -oxazol-2-yl3-5-indolinsulfonatenide N-C4 -C2-CC2-hydroxy-2- (3-iridinyl) ethyl amino-3-ethyl-3-phenyl-1- (4-rityloxazol-2-yl) -5-indolineulphonamide, N- C 4- C2-CC2-hydroxy-2- (3 -? i ridiniDetil 3amino3ethyl 3 phenyl 3-1- (4-pentyloxazol-2-yl) -5-indolins? L fonarnide N-4-C2-C [2-hydroxy-2- (3-pyridinyl) ethyl arnino-3-ethyl-3-phenyl-3- (4-exoxi- 2-yl) 5-indol i nsul fonarnide u- C4-C 2-CC 2 -hydroxy-2 - (-pi idinyl) ethyl 3-amino-3-ethyl-3-phenyl-3- (4-heptyl-loxazole-2-i.1) - 5 - i ndol i nsul fonarni da. N-C4-C2-CC2-hydroxy-2- (3-pyridine-D-methyl-amino] -ethyl] -phenyl] - l- (4-octyloxazol-2-yl) -5-indolinsul-fonnamide. N- 4-C2-C-C2-hydroxy -2- (3 ~ pi ridinyl) ethyl larninolethyl lphenyl 1-1- C 4- (2-cyclopentylethyl-oxazol-2-ill-5-indolins? L onamide N- 4-C 2-C C2-hydroxyl) i -2- (3-? iridinyl) ethyl larninolethyl] pheni 11-1- 4- (3-cyclopentylpropyl) oxazole -2-. 3 -5- i ndol i nsul fonarni da. NC 4-C 2- CC2 -hydrox i -2- (3-? i rid.iniDet.il 3arnino3etil 3 phenyl 3 -l- (3-reptil- l, 2, 43-oxadiazol-5-yl) -5-indolinsulfonarnide. N-C4-C 2- C2-hydroxy-2- (3-pi-ridinyl) ethyl-lamino-3-ethyl-3-phenyl-3-1- (3-pentyl-Cl, 2,3,4-oxadiazol-5-yl) -5-indolyl-sulphonamide . N- C 4 -C 2 -CC 2-hydroxy-2- (3-pi ridinyl) ethyl lamino ethyl 3-phenyl 3-1- (3-hexyl-C 1,2,4-oxadiazol-5-yl) -5- indolinsul fonarnida. N-C4-C 2-C 2-hydroxy-2- (3-pi-ridinyl-ethyl-amino-3-ethyl-1-phenyl-3-1- (3-heptyl-Cl, 2,43-ocadiazol-5-yl) -5-indolins? N-C4-C2-CC2-hydroxy-2- (3-iridinyl) ethyl-3-aminoethyl-3-phenyl-3-l- (3-octyl-Cl, 2,3,4-okadiazol-5-yl) -5-indolineul-fonarnide NC 4 C 2- C 2 -hydroxy-2- (3-pi ridinyl) ethyl 3-arnino-3-ethyl-3-phenyl-3-C 3- (2-cyclopentylethyl) -Cl, 2,43-oxadiazol-5-iD-5-indolinsul-fonamide NC 4 -C 2-CC 2 -hydroxy -2- (3-pi ridinyl) ethyl larninolet.il 1 phenyl 3-1- C 3- (3-cyclopentylpropyl) -Cl, 2,43 -oxadiazole-5-yl 1-5 -i ndol i nsul fonarni da.

L4-C2- x2-hydroxy-2- (3-pyridinyl) ethyl amino3ethyl3 phenyl3-1- (5-ethyl-Cl, 2,43-oxadiazol-3-yl) -5-indoline-sulfonamide N-C4- 2- 2 -hydroxy-2- (3-pyridinyl) ethyl 3-amino-3-phenyl-3-l- (5-pentyl-1,2,2,4-oxadiazol-3-yl) -5-indolins-lfonamide NC 4-C2-C 2 -hydroxy-2 - (3-pyridinium-Dethyl-3-phenyl-3- (5-hexyl-1,2,4-oxadiazol-3-yl) -5-indolinsul-fonamide, N-C4-C2-C-C2-hydroxy-2- (3-pyridinyl) ethyl amino3eti13 phenyl13-1- (5-heptyl-Cl, 2,43-oxadiazol-3-yl) -5-indolinsul fonamide. -L4-C2-C C2-hydroxy-2- (3-pyridiniumDethyl3amino3ethyl3 phenyl3-1- ( 5-octyl-C1,2, 43-oxadiazol-5-yl) -3-indolins? Lponarnide N-C4- 2-C C-2-hydroxy-2- (3-pi idiniDetil amino3ethyl3 phenyl3-1- C5- (2-cyclopentylethyl) -Cl, 2,43-oxadiazol-3-yl) -5-indolineulfonamide, N-C4-C2-CC2-hydroxy-2- (3-pi ridinyl) ethyl larnin leti13 phenyl3-l-C5- (3-cyclopentylpro-yl) -Cl, 2,43-oxadiazol-3-yl-5-i < v1olinsul fonamide All the co-factors of the present invention have at least one asymmetric center, denoted by the asterisk in the fó Structural formula I. Additional asymmetric centers may be present on the molecule, depending on the nature of the different substituents on the molecule, in particular R2 and R3. Each of these asymmetric centers produces two optical isomers and it is intended that all of these optical isomers, such as separate, pure or partially purified optical isomers or racemic mixtures thereof, be included within the scope of this invention. In the case, Jel asymmetric center represented by the asterisk in formula I, it has been found that the compound in which the hydroxyl substituent is above the plane of the structure, as observed in the formula le, is more active and therefore highly preferred over the compound in which the hydroxyl substitution is below the plane of the structure. The following stereospecific structure represents the stereoisomers of the present invention: Where n, rn, r, fl, Rl, R2, R3, R «, RS, R6 R? and X, SOGI as defined under formula I above. Throughout the present application, the following terms have the indicated meanings: It is intended that the alkyl groups specified above include those alkyl groups of designated length in either straight or branched configuration. Exemplary of such alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tertiary butyl, pentyl, isopentyl, hexyl, and the like. It is intended that the alkoxy groups specified above include those alkoxy groups of the indicated length either in straight or branched configuration.

Exemplary of such alkoxy groups are ethoxy, ethoxy, propoxy, isopropoxy, b? Toxyl, isobutoxy, tertiary butoxy, pentoxy, isopentoxy, hexoxy, isohexoxy, and the like. The term "halogen" is intended to include the halogen atoms fluorine, chlorine, bromine and iodine. Examples of 5- and 6-membered heterocycles and • * fused cycloalkyl of fl, Z and Ri "include pyridyl, quinolinyl, pyrirnidinyl, pyrrolyl, thienyl, imidazolyl, beninidazolyl, thiadiazolyl, benzodiodiazolyl, indolyl, benzodioxolyl, benzodioxanil, benzothiophenyl, benzofuranyl, benzoxazinyl, benzisoxazolyl, benzothiazolyl, te rahidronaftilo, di idrobenzofuranyl, tetrahydroqinolinyl, furopyridine and thienopyridine. Preferred values of fl and Z are phenyl, naphthyl, benzene-idylide fused to a heterocyclic ring of 5 or 6 members with 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen, with heterocycloe with 1 to 4 heteroatoms independently selected from oxygen or sulfur, and / or 1 to 4 nitrogen atoms. The highly preferred values of fl are phenyl, pyridyl, quinolinyl, pyrinidinyl, pyrrolyl, thienyl, imidazolyl, and thiazolyl. The most preferred values of Z are phenyl, naphthyl, quinolinyl, thienyl, benzimidazolyl, thiadiazolyl, enezythiadiazolyl, indolyl, indolinyl, benzodioxolyl, benzodioxanyl, benzothiophenyl, benzofuranyl., benzoxazinyl, benzisoxazolyl, benzothiazolyl, tetrahydronaphthyl, dihydrobenzofuranyl, triazolyl, tetrazolyl, oxadiazolyl, imidazolyl, oxazolyl, thiazolyl, imidazolidinyl, pyrazolyl, isoxazolyl, pyridyl, pyrirnidyl, pyrazolyl, tetrahydrobenzothiazolyl and tetrahydroquinolinyl. When Z is attached to -NSO2 (CH2) r-, it is preferably phenyl, naphthyl or benzene n * * ring fused to a 5- or 6-membered heterocyclic ring with 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen. When Z is part of the definition of Rβ, it is preferably phenyl, a 5-6 membered heterocyclic ring with 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen, a benzene ring fused to a 5- or 6-membered heterocyclic ring with 1 to 4 selected heteroatoms of oxygen, sulfur and nitrogen or a ring- '5 or 6 membered hercyclic with 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen fused to a cycloalkyl ring of C3-Ce. Preferred R1-heterocycles are thienyl, thiadiazolyl, triazolyl, tetrazolyl, oxadiazolyl, irnidazolyl, oxazolyl, thiazolyl, inidazolidinolyl, pyrazolyl, isoxazolyl, pyridyl, pyrimidyl, and pyrazolyl. Certain of the previously defined terms may occur more than once in the previous formula and in such an occurrence each term shall be defined independently. The other; thus for example, NRßRβ can represent NH2, NHCH3, N (CH3) CH2CH3, and the like. The following abbreviations are used throughout the entire specification: Boc: tert-butyloxycarbonyl Cbz: carbobenzyloxy DIP-C1: diiso? Inocanfeylchloroborane DMF: dimethyl formamide DMSO: dirnetylsulfoxide HPLC: high pressure chromatography Me: methyl MPLC: liquid pressure chromatography mean Ms: methanes? lfonil (nesynes) NBS: N-bromosuccinimide NC? : N-chloros? Ccinimide nHex: n-hexyl TBflF: tetrabutyl onion flower TBS (TBDMS): t-b? Tildimetilsiiiio TFA: tri f luoroacetic acid THF: tet rahi d ro fu rano The compounds (I) of the present invention can be prepared from epoxide intermediates such as formula II and amine intermediates such as those of formula III. The preparation of estoe inter ediarioe is described in the following schemes, where n, m, r, fl, Rl, R2, R3, R4, RS, R6 t R7 and X are as defined above. Compounds II are known in the literature or can conveniently be prepared with a variety of methods familiar to those skilled in the art. A common route is illustrated in scheme l. Acid chloride, which may be commercially available or easily prepared from the corresponding acid by treatment with, for example, thiomyl chloride or oxalyl chloride, is treated with diazo ethane in a solvent + diethyl ether The resulting diazoketone • then binds with hydrogen chloride to give chloroketone 2 (X = Cl). Haloketone 2 is then reduced with a reducing agent such as sodium borohydride. The resulting alcohol 3 is treated with a base such as potassium carbonate in refluxing acetone to provide the desired epoxide II. The enantiomerically enriched (R) and () epoxides are readily available by asymmetric reduction of 2-haloketones using such reducing agents as (-) or (+) - ÜIP-C1, (R) or (S) -fllpm- borane or (R) or (S) -tetrah? dro-l-rnetil-3, 3-d? phenyl-1H, 3H-pyrrolid, 2-c3Cl, 3,23-oxazaborol-borane ((R) or (S) -, AB • BH3).

SCHEME 1 An alternate route for the desired haloketones 2 is illustrated in scheme 2. Netyl ketone can be converted to the corresponding haloketone using a variety of reagents known to those skilled in the art and summarized in Laroc Comprehensive Organic Trials for Ations; VC: New York, 1989, 369-372. Suitably, the methyl ketone. 4 is treated with chlorine or N-chlorosuccinimide in acetic acid with an additional acid source such as hydrogen chloride or aluminum chloride. For the synthesis of 2 (X = Br), you can use bromine, dibrornobarbitic acid or NBS with hydrogen bromide or aluminum bromide. In some cases, the chloro- or t-ornoketones 2 may be commercially available.

SCHEME 2 Many of the 4-ethylketones are commercially available or are readily prepared by methods described in the literature and known to those skilled in the art. Substituents R on the acid chlorides 1 or methyl ketones 4 may need to be protected during subsequent processes. A description of such protection groups can be found in: Protective Groups i.n Organic Synthesis; 2nd Ed., T.U. Greene and P. G. M. Uuts, John Uiley and Sons, New York, 1991. Comets III can conveniently be prepared with a variety of methods familiar to those skilled in the art. A convenient route for its preparation when R6 is hydrogen, is illustrated in Scheme 3. Compound 5 is selectively protected as a suitable carbamate derivative 6, with for example, di-tert-b-tyl di carbonate or carbobenzyloxy chloride. This compound is then treated with a sulfonyl ester, preferably sulfonyl chloride 7., and a bath such as pyridine in an anhydrous solvent such as dichloromethane or chloroform for 0.5 to 24 hours at temperatures of -20 to 50 ° C. , preferably 0 ° C, to provide the sulfonamide 8_. The protecting group is then removed with, for example, trifluoroacetic acid in the case of Boc or catalytic hydrogenation in the case of Cbz, to give the desired amine 9.

SCHEME 3 Compounds III wherein R6 is not hydrogen can conveniently be prepared as illustrated in scheme 4. The phonamide 8, prepared as described above, is alkylated with an appropriate alkylating agent 10. in the presence of base to provide ? lfonarnida 1_1. Removal of the protecting group as before gives the desired compound 9a.

SCHEME 4 2 ^ R3 5 A1K k = C6 alkyl aa Sulfonyl chlorides, many of which are commercially available, can also be easily prepared by a number of family methods for those skilled in the art. A suitable method includes the addition of an organolithium reagent or a Grignard reagent to sulfuryl chloride following the procedure of S.N. Bhattacharya, et al., 3. Chem. Soc. (C), 1265-1267 (1969). Another convenient method includes 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). The phonic acids are also conveniently converted to the corresponding sulfonyl chloride by treatment with PClg_, PCI3, or SOCI2 O-March, Advanced Organic Chemistry, 4th Ed., John Uiley and Sons, New York: 1992, pl297 and references. cited there). The aromatic and heteroaromatic compounds can be chlorosulfonilated directly by treatment with Vilsmeier's reagent or chloroeulonic acid (Organic Synthesis, I, 8). The diamines 5eethan are commercially available or easily prepared by methods described in the literature or known to those skilled in the art. Compound 5 wherein R 2 or R 3 is methyl can be prepared from the corresponding amino acid following the method of J. D. Bloorn et al., J. Med. Chern., 35, 3081-3084 (1992). As illustrated in scheme 5 for R3 = methyl, the appropriate (R) amino acid 12 is esterified, conveniently by acid treatment The hydrocarbon is then treated with di-tert-butyl dicarbonate to give compound 13. The ether group is reduced with a hydride source such as lithium borohydride and the resulting alcohol is converted to a leaving group as a mesylate. The elimination of the Boc protection groups gives the diamma J_4. This compound is subjected to catalytic hydrogenation in the presence of base such as sodium acetate to give the desired a-methyl amine 15. The other enantiomer is available through an analogous sequence by starting with the corresponding (S) amino acid.

SCHEME 5 The diamine 5 or the sulphonated amines 9 wherein X is -CH2.0- and rn is one are also easily prepared by methods < experts in the literature or for those experts in the field. For example, as shown in scheme 6, the sodium salt of 4-nitrophenol 16 is alkylated with 1-brorno-2-chloroethane, conveniently refluxing 2-butanone with base such as potassium carbonate to give the Chlorine derivative 17. The chloride is converted to the corresponding amine by treatment with lithium acid followed by reduction with, for example, triphenyl phosphine in aqueous tetrahydrofuran. The protection of the resulting amine, suitably co or its t-butyl carbonate, by treatment with di-tert-butyldicarbonate gives the derivative 18.

The nitro group is then reduced, for example by catalytic hydrogenation, to provide the amine 19. Acylation of intermediate 19 with sulfonyl chloride 7, followed by acid deprotection such as tri luoroacetic acid gives the desired intermediate 20.

SCHEME 6 1 £ 2O Alternatively, diamine 5 wherein X ee -CH2O- and m is 1 is available from intermediate 19 by treatment with trifluoroacetic acid. This diamine can then be modified as illustrated in Scheme 3. Diarnines 5 and sulfonamide amines 9 where X is -CH2CH2- and m is 1 are also easily prepared by methods described in the literature or known to those skilled in.-J » matter. For example, as ee mueetra in scheme 7, the bromo derivative 21 is treated with eodium cyanide to provide the nitrile 22. The nitro group is selectively reduced by treatment with hydrogen and catalytic palladium to provide amine 23. The amine 23 is acylate with sulfonyl chloride 7 to give the corresponding sulfonamide 24. Reduction of compound 24 with cobalt chloride and eodium borohydride provides the amine 25.

H2, Pd / C R7 (CH2) rSO, Cl (7) MeOH NH2 pyridine. CH2Cl2 21? L T < Alternatively, diamine 5 wherein X is -CH2CH2- and m ee 1eta available from intermediate 23 by reduction of the nitrile group with, for example, cobalt chloride and boron sodium hydride. This diarrine can be modified in the same way as illustrated in scheme 3.

Intermediates II and III are coupled by heating them pure or as a solution in polar solvent such as methanol, acetonitrile, tetrahydrofuran, dimethylsulfoxide or N-rnethyl pyrrolidone for 1 to 24 hours at temperatures of 30 to 150 ° C to provide the compound I as shown in scheme 8. The reaction is conveniently carried out in refluxing methanol. Alternatively, an amine III salt, such as the trifluoroacetate salt or hydrochloride, may be used. In cases where a base such as sodium bicarbonate or diethylisopropylamine is added to the reaction mixture. The product is purified from unwanted byproducts by recrietalization, trituration, cap chromatography. a preparative thin, cro atrography of inert vaporization on silica gel as described in U. C. Still, and other 3. Org. Chem. 43, 2923 (1978), medium pressure liquid chromatography, or HPLC. Compounds that are purified by HPLC can 4, be alarmed as the corresponding salt. The purification of intermediaries is achieved in the same way.

SCHEME 8 In some cases, the coupling product I from the reaction described in scheme 8 can be further modified, for example, by the elimination of protecting groups or the manipulation of substituents on, in particular, R1 and R7. These manipulations may include, but are not limited to, reduction, oxidation, fillation, 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 the coupling of intermediates II and III (scheme 8) to give the aniline derivative. The secondary amine is selectively protected, for example, as a carbamate by treatment with d-er-butyl dicarbonate to provide carbamate 29. Ally, nitro amine is used in the coupling reaction for ctoveer 28. After protection as described above, the nitro group is reduced for example, by catalytic hydrogenation with palladium catalyst or Raney nickel to provide intermediate 29. In some cases, another group can be reduced concomitantly. For example, if R1 is halogen in the intermediate 28, it can be converted to hydrogen in the intermediate 29. Treatment with a sulfonyl chloride in the presence of a base such as pyridine followed by removal of the protection group with, in the case of a tertiary butylcarbonate, acid such as trifluoroacetic acid or methanolic hydrogen chloride, provides sulfonamide I.

SCHEME 9 1) R7 (CH2) r-S02CI, base 2) TFA HCI / eOH In some cases, the composition I from the reaction sequence illustrated in scheme 9 can be further modified, for example, by the removal of the protection groups or the manipulation of substituents on, in particular, R and R7, as described above. In addition, there may be manipulation of substituents on any of the intermediates in the reaction sequence illustrated in Scheme 9. One such example is illustrated in Scheme 10. Compound 30, which is prepared as described in Scheme 9 from the corresponding epoxide, it is subjected to reduction using tin (II) chloride to provide compound 31. Other examples of substituent on compound I that can be reduced to the corresponding amine by methods commonly known to those skilled in the art include nitro groups, nitriles and azides.

SCHEME 10 The compounds (I) of the present invention can also be prepared from amine intermediates such as those of formula III and haloketone intermediates such as those of formula 2, as shin scheme 11. Amine III is alkylated with haloketone derivative 2, conveniently by treatment of a mixture of III and 2 with base such as potassium carbonate or triethylamine in a polar solvent such as acetonitrile, acetone or irnetylforrnarnide. . The resulting arninoketone 32 is reduced with, for example, sodium borohydride in methanol to give the desired aminoalcohol I.

SCHEME 11 [H] In some cases, the product I of the reaction described in scheme 11 can be further modified, for example, by removal of the protecting groups or the manipulation of substituents, in particular ßobre l and 7. , 3rd manipulations may include, but not be limited to, reduction, oxidation, alkylation, acylation, and hydrolysis reactions, which are commonly known to those skilled in the art. An alternate synthesis of the key intermediate 29 is shown in scheme 12. The alcohol of the intermediate 3 is protected, for example, as s? t-butyldimethylsilyl ether to give the derivative TBS 33. This compound is then treated with imine 5 and a base such as diisopropylethylamine in a solvent, typically aprotic polar such as acetonitrile, at temperatures of 25 to 150 ° C for 1 to 72 hours . Typically, a source of iodine such as sodium iodide is added to facilitate the reaction. The protecting group is then removed, in the case of eilyl ether, by treatment of the resulting amine with a fluoride source such as tetrab-tilammonium fluoride. The protection of the secondary amine as before, gives the key intermediary 29.

SCHEME 12 In some cases, the composition I can be synthesized straight from the intermediate 27 without protection of the secondary amine. For example, when R2 and R3 are both methyl, the aniline derivative 27 is treated with sulfonyl chloride 7 and a base such as pyridine in a solvent such as dichloromethane at a temperature of -30 to 50 ° C, typically 0 ° C. , to provide the compound I. In some cases, the product I of the reaction described in scheme 13 can be further modified, for example, with the removal of protecting groups or the manipulation of substituents on, in particular, R1 and R7, , as described above.

SCHEME 13 R7 (CHs) r-S02CI (Z) The compounds (I) of the present invention wherein R2 and R3 are hydrogen can also be prepared from the acid intermediates of formula 36 and aminoalcohols of formula 37, as shown in scheme 14. Acid 36 is available through of the corresponding ester 35, typically a methyl or ethyl ester, by treatment with Ifonyl 7 and a base such as pyridine, followed by ester hyrolysis with aqueous acid or base. The acid 36 is coupled to the amine 37, which is known in the literature or is readily prepared by methods known to those skilled in the art, using a coupling agent such as benzotriazolyl-N-oxy-trisyl hexa fluoro-phosphate. dimethylamino) phosphonium or l- (3-dirnethylaminopropyl) -3-ethylcarbodiirnidenetnetylidene, to provide the amide 88. This is treated with a reducing agent, typically boron, to provide the desired compound I.

SCHEME 14 R4 .. «, v, jf ^ H 1) CIS02 (CH2), - R7 (Z) .basß p ° -cpí | - \ R | l5 E 2) aqueous de-base acid ÜR = Meo Et.etc.

A? HCH2"N-9C (X) m- A. - S02 (CH2) r-R7 a [H] The compounds of general formula I can be separated into diastereoisomer pairs of enantiomers by, for example, fractional crystallization from a suitable solvent, for example methanol or ethyl acetate or a mixture thereof. The pair of enantiomers thus obtained can be separated into individual steroisomers by conventional methods, for example with the use of an optically active acid as a resolving agent. Alternatively, any enantiomer of a compound of the general formula I can be obtained by stereospecific synthesis using optically pure starting materials of known configuration. The present compounds can be isolated in the form of their pharmaceutically acceptable acid addition salts.

Examples of such salts are derived from the use of inorganic and organic acids Examples of such acids are hydrochloric, nitric, sulfuric, phosphonic, formic, acetic, trifluoroacetic, propionic, rnalene, succinic, malonic and sirnilaree. They contain an acid function such a carboxyl or tetrazole can be isolated in the form of their inorganic salt in which the counter ion can be selected from sodium, potassium, lithium, calcium, magnesium, and the like, as well as 1, organic ses. As previously indicated, the compounds of the present invention have valuable pharmacological properties. The present invention also provides a compound of the general formula I or a pharmaceutically acceptable salt thereof for use as a therapeutically active substance. In one aspect, the present invention provides a compound of the general formula I or a pharmaceutically acceptable ester thereof; or a pharmaceutically acceptable salt of the same for use in the treatment of obesity in humans or non-human subjects. The present invention further provides a compound of the general formula I, or a pharmaceutically acceptable ester thereof; or a pharmaceutically acceptable salt thereof for use in the treatment of hyperglycemia (diabetes) in humans or non-human animals. The diabetes mellitus disease is characterized by rnetabolic defects in the production and utilization of glucose "" > which results in failure to maintain the proper levels of blood sugar. The result of these defects is elevated blood glucose or hyperglycemia. Research on the treatment of diabetes has focused on fasting and postprandial blood glucose levels. Treatments have included parenteral administration of exogenous insulin, oral drug adninistration, and dietary therapies. Two main forms of diabetes mellitus < íe currently recognize. Type I diabetes, or insulin-dependent diabetes, is the result of an aberrant deficiency of ineulin, the hormone that regulates glucose utilization. Type II diabetes or diabetes independent of ineulin, often occurs despite normal or even high levels of insulin and appears to be the result of the inability of the tissues to respond appropriately to insulin. The majority of type II diabetics are also obese.

In addition, the compounds of the present invention decrease the levels of triglycerides and cholesterol levels and increase the levels of high density lipoprotein and p > therefore they are of use in the combat of medical conditions where it is thought that such decrease (and increase) is beneficial. Thus, they can be used in the treatment of hypertriglyceridemia, hypercholesterolemia and conditions of low HDL (high density lipoprotein) levels, in addition to the treatment of atherosclerotic disease such as coronary, cerebrovascular and peripheral arteries, disease cardiovascular and related conditions Therefore, in another aspect of the present invention, a method of lowering triglyceride and / or cholesterol levels and / or increasing the levels of high density lipoprotein, which comprises administration to a animal in need of it, a • Therapeutically effective entity of a compound of formula I or a pharmaceutically acceptable salt thereof. The ingredients are formulated and administered in the same general manner as detailed below for the treatment of diabetes and obesity. They may also contain other known active ingredients for use in the treatment of atherosclerosis and related conditions, for example fibrates such as clofibrate, bezafibrate and gemfibrozil; inhibitors of cholesterol biosynthesis such as inhibitors of the? ctase HMG-CoA network, for example lovastatin, sinvastitin and i'avastitin; inhibition of cholesterol absorption, for example, beta-sitosterol and inhibitors of acyl-CoA: cholesterol acyltransferase, for example elinamide; anion exchange resins for example cholestyranine, colestipol or a dialkyl-aminoalkyl derivative of an entangled dextran; nicotinyl alcohol, nicotinic acid or urea thereof; Vitamin E; and thyrornirnetics. The compounds of the present invention also have the effect of reducing intestinal motility and thus find utility as adjuvants in the treatment of different gaetrointestinal disorders such as irritable bowel syndrome. It has been proposed that the non-sphincter smooth muscle contraction is mediated by activity in the adrenoreceptors 33. The availability of a specific β3 agonist with little activity in the ßl and ß2 receptors will help in the pharmacological control and intestinal motility, without concurrent cardiovascular effects. The present compounds are generally administered as described below, with dosages similar to those used for the treatment of diabetes and obesity. It has also unexpectedly been found that compounds that act as agomstae in adrenoreceptors (33 may be useful in the treatment of gastrometypenelee disorders, especially peptic ulcers, esophagitis, gastritis and duodemitis, (including H. pylori-induced), intestinal ulcerations (including inflammatory bowel disease, ulcerative colitis, Crohn's disease, and proctitis) and gastrointestinal ulcerations, In addition, it has been indicated that receptors (33 have an effect on inhibiting the release of neuropeptides in certain sensory fibers in the lung. How sensitive nerves can play an important role in neurogenic inflammation of the airways including ) S, the preeentee agonistae (33 specific may be useful in treatment of neurogenetic inflammation, such as asthma, with minimal effects on cardiopul system onar. The adrenoreceptors ß3 may also be able to produce antidepressant effects selective stimulating ß3 receptors in the brain and thus an additional contemplated utility of compuestoe of EETA ee invention horn agents antidrepresi os. the active compueetos of the present invention may be administered orally as a pharmaceutical composition, for example, with an inert diluent or with an assimilable edible carrier, or they may be enclosed in capsules of hard or soft gelatin or they may be compressed into tablets, or may be incorporated directly with the food of the diet. for oral therapeutic administration includes sublingual administration, these active compounds may be incorporated with excipients and uearse in forrna tablets, pill, capsules, ampule the sachets, elixirs, suspensions, syrups and the like. Such compositions and preparations should contain at least 0.1% of the active compound. The percentage of the active compound in these compositions can of course be varied and is conveniently between 2 to 60% by weight approximately of the unit. The amount of active compound in such therapeutically useful compositions is such that an effective dose can be obtained. The active compounds can also be administered intranasally as for example in liquid or spray drops. The effective doefication of an active ingredient employed may vary depending on the particular compound employed, the mode of administration, the condition to be treated and the severity of the condition to be treated. When diabetes mellitus and / or hyperglycemia is generally satisfactory results are obtained when the compounds of the present invention n are administered a daily ossification of 0.1 milligrams to 100 milligrams per kilogram of animal body approximately, preferably given in divided doses of 2 to 6 times a day, or in a sustained release form. For the vast majority of mammals, the total daily dosage is 1.0 milligrams to 1000 milligrams, preferably 1 milligram to 50 milligrams. In the case of a 70 kg adult human, the total daily dosage is usually between 7 milligrams to 350 milligrams approximately. This doeification regimen can be adjusted to provide the optimal therapeutic response.

When treating obesity, in conjunction with diabetes and / or hyperglycemia, or alone, generally satisfactory results are obtained when the compounds of the present invention are administered at a daily dosage of 1 milligram to 1000 milligrams per kilogram of body weight. of the animal approximately, given preferably in divided doses of 2 to 6 vecee a day, or in the form of eostenida release. For the vast majority of mammals, the total daily dosage is * e 10 milligrams to 10,000 milligrams approximately, preferably from 10 milligrams to approximately 500 milligrams. In the case of an adult human 70 kilograms, the total daily dose will generally be between 70 milligrams to 3500 milligrams approximately. This dosage regimen can be adjusted to provide the optimal therapeutic response. Tablets, pills, capsules and the like can * also have a binder such as gum tragacanth, acacia, corn starch or gelatin. Excipients such as diclatous phosphate, a disintegrating agent such as corn starch, potato starch, alginic acid; A lubricant such as magnesium stearate; a sweetening agent such as sucrose, lactose or saccharin. When a unit dose form is a capsule, it may contain, in addition to the materials of the above type, a liquid carrier such as a graea oil. Various other materials may be present as coatings or to modify the physical form of the dosed unit. For example, the tablets can be coated with shellac, sugar or both. A syrup or elixir may contain, in addition to the active ingredient, sucrose as a sweetening agent, methyl and propylparabens as preservatives, a dye and a flavoring such as cherry or orange flavor. These active compounds can also be administered parenterally. Solutions or suspensions of these active taxes can be prepared in water suitably mixed with a surfactant such as hydroxypropyl cellulose. Disperesions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms. The pharmaceutical forms suitable for injectable use include sterile aqueous solutions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispereionee. In all cases the form must be sterile and must be fluid to the degree that they are easily injectable. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or a dispersion medium containing for example water, ethanol, polyol (for example, glycerol, propylene glycol and liquid polyethylene glycol), suitable mixtures thereof and vegetable oils. The following examples are provided so that the invention is more fully understood. They are not designed to limit the invention in any way.

EXAMPLE 1 (R) -N-C2-C4- (ammoniophenyl) 3-ethyl-3-2-hydroxy-2- (tetrazoloCl / 5-a] pyrid-6-yl) ethylamine. A solution of 1.62 g (10 rnmolee) of (R) -2- (tetrazoloCl, 5-a3pyrid-6-yl) oxirane is heated at reflux for 5 hours.

(See Fisher and Uyvratt, European Patent Application No. 0318 2 A2, for the synthesis of this compound), and 4.1 g (30 mmol.) Of 2- (4-aminophenyl) ethylamine in 30 ml of methanol. The reaction mixture is concentrated and the residue is chromatographed on silica gel (2% rnetanol / 98% rnetylene chloride to give 1.69 g (56%) of the title compound: H NMR (400 MHZ, CD3OD) S 9.01 (d, 1H, 3 = 1.3 Hz), 8.02 (d, l H, 3 = 9.2 Hz), 7.82 (dd, 1H, 3 = 1.3, 9.2 Hz), 6.94 (d, 2H, 3 = 6.3 Hz), 6. 63 (d, 2H, 3 = 6.3 Hz), 4.91 (m, 4H), 2.67 (T, 2 H, 3 = 7.1Hz).

EXAMPLE 2 1,1, Dimethyl ester of (R) -M-C2-C4- (aminophenyl) 3-ethyl] -2-hydroxy-2- (tet razoloCl, 5-a] pyrid-6-yl) ethylcarbamate was stirred for 2 hours a solution of 1.69 g (56.7 mmoles) of the amine of Example 1 and 1.23 g (56.7 min) of di-tert-bicycladicarbonate in 10 nr of tetrahydrofuran (THF) at ° C. The reaction mixture was concentrated and the residue was chromatographed on ethyl acetate (4% rnetanol / 96% rnetylene chloride) to give 2.2 g (97%) of the title compound: H NMR (400 MHZ, CD30D) d8 .96 (s, 1H), 8.05 (rn, 2H), 7.85 (rn, 2H), b. »J3 (dd, 2H, D = 7.7 8.3 Hz), 6.66 (d, 2H, J = 8.3 Hz), 4.99 (rn, 1H), 3.49 (rn 4H), 2.70 (t, 2H, 3 = 6.5 Hz), .1.26 (s, 9H).

EXAMPLE 3 4- (Hexylaminocarbonylamino) benzenesulfonyl chloride. Hexylamine 12.15 ml (9.2 mmol), in the form of drops, was added to a solution of (9.2 mmol) of phenyl isocyanate in THF (150 ml) at 0 ° C, and stirring was continued for 1 hour. The solvent was removed in vacuo and the resulting ilphenylurea was used without further purification. A 6 g portion (2.7 mmoles) was added for 20 minutes to chlorosulfonic acid at 0 ° C, followed by heating at 60 ° C for 2 hours. After cooling, the mixture was added to ice / water (100 nmol) and the aqueous phase was extracted with EtOAc. (3x100 rnl). The organic phase was washed with brine (50 ml), dried with MgSO *, concentrated and purified by flash chromatography (silica gel, 75% hexane / 25% ethyl acetate) to give 6 g (70%). ) of the title compound: 1 H NMR (CDC13) 67.85 (d, 2 H, 3 = 9.6 Hz), 7.54 (d, 2H, D = 9.6 Hz), 5.79 (br.s. 1H), 4.71 (br, s, 1.H), 3.23 (t, 2H, ^ = 8 Hz), 1.54-1.44 (m, 2H), 1.33-120 (rn, 6H), 0.91-0.79 (rn, 3H) "EXAMPLE 4 ^ RH- [4-C2- [H-l, l-dimethylethoxycarbonyl] -H-C2-hydroxy-2- (tetrazoloCl, 5-a] pyrid-6-yl] ethyl3amino] ethyl3phenyl] -4- (hexylaminocarbonylamino) benzenesulfonam To a stirred solution of 0.200 g (0.502 mmol) of the Boc compound of Example 2 in 3 mL of methylene chloride, 80 mg (1.00 mmol) of pridine is added followed by 0.16 g (0.75 mmol) of the sulfonyl chloride. from Example 3. After stirring for 5 hours, the reaction mixture is concentrated / the residue is subjected to chromatography on silica gel (10% methanol / 90% methylene chloride) to give 0.303 g (88%) of the title: * H NMR (400 Hz, CD3OD) or 8.95 (s, 1H), 8.0-8.08 (m, 1H), 7.75-7.87 (m, 1H), 7.40-7.62 (m, 4H), 7.00 (, 4H) ), 4.95 (, 2H), 3.47 (, 2H), 3.15 (rn, 2H), 2.75 (rn, 2H), 1.52 (t, 2H, 3 = 6.0 Hz), 1.33 (m, 8H), 1.21 (s, 9H), 0.90 (t, 3H, 3 = 6.0 Hz).

EXAMPLE 5 (R) -N-C4-C2-CC2-hydroxy-2- (6-aminopyridin-3-yl) ethyl] aminoDethyl] phenyl3-4- (hexylaminocarbonylamino) benzenesulfonamide. A mixture of 0.302 g (0.44 rnoles) of the tetrazine of Example 4, 0.20 g, is refluxed for 5 hours. (0.88 mol) of tin (II) chloride dihydrate and 0.3 ml of concentrated aqueous hydrochloric acid in 2 ml of rnetanol. The reaction mixture is concentrated and the residue is purified by reverse faeff MPLC (C8, 47% rnetanol / 53 trifluoroacetic acid regulator 0.1%) to give 0.32 g (78%) of the title compound as its bistrifluoroacetate salt: * H NMR (400 MHz, CD3 OD) or 7.96 (dd, 1H, 3 = 2.0, 9.2 Hz), 7.86 (d, 1H, 3 = 2.0 Hz); 7.59 (d, 2H, 3 = 8.8 Hz), 7.43 (d, 2H, 3 = 8.8 Hz), 7.14 (d, 2H, 3 = 8.4 Hz), 7.07 (d, 2H, 3 = 8.4 Hz), 7.03 ( d, 1H, 3 = 9.2 Hz), 4.92 (rn, 1H), 3.23 (rn, 2H), 3.15 (m, 2H), 2.93 (rn, 2H, 4.0 Hz), 1.49 (t, 2H, 3 = 6.0 Hz), 1.32 (, 8H), 0.91 (t, 3H, 3 = 6.0 Hz), Cl MS rn / z 555 (m + l). Following the procedures delineated for examples 1-5, the compounds listed in Table 1 were prepared.

TABLE 1 Example R Selected data of 1 H NMR (CD3OD) 6 Salt of trifluoroacetate 7.74 (m, 2H), 7.53 Ph (rn, 1H), 7.45 (in, 2H) 7-trifluoroacetate salt 7.93 (rn, 4H), 7.75 (d, 2-naphthyl 1H, 3 = 1.7 Hz), 7.61 (rn, 2H) 8 trifl-oroacetate salt 9.00 (d, 1H, 3 = 2.3 Hz), of 3-quinolinyl 8.06 (m, 2H), 7.94 (, 2H, 7.72 (t, 1H, 3 = 7.2 Hz). 9 trifl? Oroacetate salt 9.02 (s, 1H), 8.30 (d, of 1 , 2-benzisoxazole-5- 1H, 3 = 1.3 Hz), 7.90 (rn, ilo 1H), 7.77 (rn, 1H) 10 trifluoroacetate salt 7.83 (d, 2H, 3 = 8.6 Hz), 4-iodine feni lo 7.46 (d, 2H, 3 = 8.6 Hz) 11 salt of tri l-oroacetate 7.62 (d, 2H = 4.6 Hz), of 4-C (N-hexyl, N-rnet il- 7.48 (d, 2H, 3 = 4.6 Hz) ami noca rboni 1) ami no 3 - 2.99 (s, 3H)., Femlo 12 trifl? Oroacetate salt 3.0 (s, 6H). of 4-C (N, N-dirneti lamino ca bonyl) amino] -fen the 13 trifl? oroacetate salt 3.88-3.83 (? n, 2H), of 4- (3-hexyl-2-irnida- 3.57-3.50 (in, 2H), zolidinon ~ l-? l) enyl 2.89-2.95 (in, 2H), 1.61-1.52 (? n, 2H), 1.37-1.30 (n, 6H), and 0.93-0.88 (rn, 3H) EXAMPLE 14 3- (2-Chloroacetyl) pyridine hydrochloride To a solution of 12 g (11 rnl, 100 mol) of 3-acetylpipdine in 100 rnl of ethyl ether is added 100 rn1 of 1 M ethereal hydrogen chloride. The resulting precipitate is filter and collect 15.0 g (95.2 rnmoles) and place in a 500 ml round bottom flask equipped with a magnetic stir bar, add 95 ml of 1 M hydrogen chloride in acetic acid. After the mixture is stirred and the solid dissolved, is added 12.7 g (95.2 mmolee) of N-chloroeuccimide? (NCS) in a portion. The solution turns yellow and the NCS gradually dissolves. After 4 hours, a white precipitate forms. The mixture is left stirring for 2.5 days. Then it is filtered. The collected solid was washed with 10 nl of acetic acid and 200 rnl of ethyl ether to give 15.2 g (83% of the title compound or a white solid: 1 H NMR (200 MHz, dg-DMSO) 69.22 (t, 1 H , 3 = 1 Hz), 8.29 (dd, 1H, 3 = 1.6, 5.1 Hz), 8.55 (td, 1H, 3 = 2, 8.1 Hz), 7.82 (ddd, IH, 3 = 0.8, 5.1, 8.1 Hz) , 5.27 (s, 2H).

EXAMPLE 15 (Ra-chloromethyl-3-pyridinemethanol) a stirred solution of 3.67 g (11.5 mmol) of (-) - B-chlorodiisopmocanfeylborane C (-) - DIP-Cl] in 11 nm of THF at -25 ° C, is added a suspension of 1.00 g (5.21 mmol) of the product of example 14 in 5 ml of THF through a cannula After the addition of 0.80 ml (5.79 mmolee) of triethylanine, the reaction mixture is stirred at -25 ° C. for 4 days, 10 ml of water are added to the mixture and then it is allowed to warm to room temperature, 20 ml of ethyl acetate are added to the mixture and the organic phase is separated. with saturated NaHCO 3 solution, then extracted six times with ethyl acetate, The combined organic phase is concentrated in vacuo to give a yellow oil, Instantaneous evaporation chromatography (silica gel, 75-100% ethyl acetate). hexane) gives 561 g (68%) of the title compound as? n light yellow oil: H NMR (400 MHz, CD30D) 68.58 (d, 1H, 3 = 1.8 Hz), 8.46 (dd, IH, 3 = 4.9, 1.5 H), 7.90 (d, IH, 3 = 7.9 Hz), 7.44 (dd, IH, 3 = 7.9, 4.9 Hz), 4.93 (rn, 1H) , 3.75 (rn, 2H).

EXAMPLE 16 (R) - (Pyrid-3-yl) oxy anus. To a solution of 557 mg (3.55 mmol) of the product of Example 15 in 16 ml of acetone is added 1.80 g of potassium carbonate. The mixture is refluxed for 20 hours after cooling to room temperature. The mixture is filtered and the filtrate is evaporated in vacuo. Flash chromatography (silica gel, 2%, rnetanol-methylene chloride) gives 262 mg (61%) of the title compound as light yellow oil: 1 H NMR (200 MHz, CDC13) 68.54 (, 2H ), 7.52 (rn, 1H), 7.24 (rn, 1H), 3.86 (dd, 1H, 3 = 4.0, 2.5 Hz), 3.17 (dd, 1H, 3 = 5.4, 4.0 Hz), 2.80 (dd, 1H, 305.4, 2.5 Hz).EXAMPLE 17 () ~ N-C2-C4- (Aro-phenyl-ethyl-ethyl) -2-hydroxy-2- (pyrid-3-yl) ethylamide a. Stirred solution of 377 mg (2.44 mmol) of 4-aminophenethylamine in 10 ml of methanol add a 300-g (2.48 mmol) solution of the product of Example 16 in 15 mL of methanol.The mixture is heated at reflux for 16 hours then cooled to room temperature.The methanol is removed under vacuum and the residue chromatograph (silica gel, 6-8% methanol, 1% ammonia-methylene chloride) to give 101 mg (16%) of the title compound together with 279 mg of a mixture which is again subjected to chromatography (5%). % methanol, 1% ammonia-rnetylene chloride) to give an additional 54 rng (9%) of the title compound as a white solid: * H NMR (500 MHz, CD30D) 68.52 (m, 1H), 6.95 (d, 2H, 3 = 8.3 Hz), 6.67 (d, 2H, 3 = 8.3 HZ), 4.81 (, 1H), 2.90-2.65 (m, 5H).

EXAMPLE 18 (1-) -N-C2-C4-aminophenyl) 3-ethyl-2-hydroxy-2- (pyrid-3-yl) ethylcarbamic acid 1,1-dimethyl ester A 386-in (1.77 mmol) solution is added of di-t-butylcarbonate in 3.5 nl of THF through a cannula, to a stirred suspension of 456 mg (1.77 mmol) of the product of the Example 17 in 3"6rnl of THF cooled to 0 ° C. The yellow solution is stirred at 0 ° C for 3 hours, then the THF is removed in vacuo. Flash chromatography (silica gel, 10% methanol, 1% ammonia-netylene chloride) gives 549 mg (87%) of the title compound as a white solid: * H NMR (500 MHz, CD30D 68.45 (m, 2H), 7.83 (d, 0.6H, 3 = 7.4 Hz), 7.78 (d, 0.4H, 306.9 Hz), 7.41 (m, 1H), 6.94 (d, 0.8H, 3 = 8.0 Hz), 6.89 (d , 1.2H, 3 = 7.8 Hz), 6.66 (d, 2H, 3 = 7.3 Hz), 4.89 (rn, 1H), 3.42-3.21 (rn, 4H), 2.67 (m, 2H), 1.39 (s, 5.4 H), 1.36 (s, 3.6H) As an alternative eynthesis of the aniline derivative in Example 18, examples 19-23 are illustrated: EXAMPLE 19 2-Chloro-5- (2-broraoacetyl) pyridine hydrochloride. A solution of 784 mg of 2-chloro-5-acetylpyridine in 10 ml of THF is added via cannula to a solution of 1.44 g of dibro-obarbituric acid (DBBfl) in 10 ml of THF. The resulting solution is heated at 50- ^ 5 ° C for 12 hours, and then an additional 0.72 g DBBfl is added. After stirring at 50-55 ° C for 2.5 hours, 0.36 g of DBBfl is added. The mixture is allowed to stir for 2 hours at which point the aliquot NMR analysis indicates 37% conversion. The reaction mixture is cooled, diluted with ethyl acetate, washed with two portions of saturated aqueous sodium bicarbonate, water and brine, dried over magnesium sulfate and concentrated. Purification by flash chromatography (silica gel, 15% ethyl acetate / hexane) gives 0.86 g (73%) of the title compound as a white solid: iH NMR (400 MHz, CDC13) 6 8.96 (d, 1H, 3 = 2.6 Hz), 8.21 (dd, 1H, 3 = 2.5, 8.3 Hz), 7.46 (d, 1H, 3 = 8.4 Hz), 4.37 (e, 2H) .E1 NMR also indicates the presence of the corresponding 2-bromine derivative . The mixture ~ 4: 1 was carried out through the synthesie.

EXAMPLE 2Q (R) -a-Bromomethyl-3- (6-chloropyridine) methanol. To a solution of 602 rng (1.88 nm) of (-) - DIP-Cl in 0.5 ml of THF at -25 ° C, 200 rng of the ketone of example 19 is added via canula in 1.5 ml of THF to -25. ° C. The reaction mixture is allowed to stir at -25 ° C for 17 hours. Then it is quenched with the addition of water and extracted with ether. The etheric phase is diluted with ethyl acetate, washed with doe portions of saturated aqueous sodium bicarbonate, water and brine, dried over magnesium sulfate and concentrated. Chromatography purification (silica gel, 15 and 25% ethyl acetate / hexane) by flash evaporation gives 170 mg (84%) of the title compound: H NMR (400 MHz, CDCl 3) 6 8.38 (d, 1H) , 7.70 (dd, 1H), 7.32 (d, 1H), 4.97 (, 1H), 3.61 (dd, 1H), 3.50 (dd, 1H), 2.85 (d, 1H).

EXAMPLE 21 (R) - (2-Chloropyrid-45-yl) oxirane. To a solution of 100 rng briolalcohol of Example 20 in 2 ml of THF: water 1: 1 is added 1 ml of 5 N aqueous sodium hydroxide solution. The mixture is allowed to stir for .1.0 minutes. It is then extracted with 3 portions of dichloromethane. The combined organic phases are washed with two portions of water and brine, dried over magnesium sulfate, and concentrated to give 98 mg (93%) of the title compound which was used without further purification: H NMR (400 MHz, CDCl 3) 6 8.34 (d, 1H), 7.48 (dd, 1H); 7.29 (d, 1H), 3.86 (dd, 1H), 3.18) dd, 1H), 2.78 (dd, 1H).

EXAMPLE 22 1,1-dimethylethyl ester of (R) -N-C2-C4- (nitrophenyl) 3-ethyl-3-2-hydroxy-2- (2-chloropyrid-5-yl) ethylcarbamic acid. After the procedure outlined in examples 17 and 18, the title compound is prepared from the epoxide of example 21 and 4-nitrophenylethylaniline: * H NMR (400 MHZ, CDC13) 6 8.32 (d, 1 H, 3 = 1.3 Hz) , 8.13 (d, 2H, 3 = 8.6 Hz), 7.66 (br, 1H), 7.30 (d, 2H, 3 = 8.1 Hz), 7.27 (br, m, 1H), 4.94 (br rn), 3.38 (br m, 4H), 2.84 (br rn, 2H), 1.40 (s, 9H).

EXAMPLE 23 1,1-Dimethylethyl ester of (R) -N-C2-C4- (aminophenyl) 1-ethyl-3-2-hydroxy-2- (pyrid-3-yl) ethylcarbamic acid. A solution of 80 mg (0.19 mol) of the nitro compound of Example 22 in 2 ml of ethanol was added with 0.11.4 ml (0.57 mol) of 5 N sodium hydroxide solution and 20 rn of Raney nickel. The reaction mixture is stirred at room temperature under 3.3 kg / cm * of hydrogen for 16 hours. The mixture is neutralized with saturated aqueous sodium monobasic phosphate and extracted with 3 portions of ethyl acetate. The organic phases are washed with water and dryness, dried (magnesium sulfate), and concentrated to give 40 mg (59%) of the title compound which is identical to the sample prepared in example 18.

EXAMPLE 24 Chloro of 4-3-hexyl-2-imidazolon-1-yl) phenylsulfonyl. Hexyl iodide (50 mole, 7.38 ml) is added to a mixture of dimethylacetal 2-a-ino-acetaldehyde (100 mole, 11 ml) and potassium carbonate (50 rnmole, 5.9 g) in DMF (10 ml) at 0 °. C. Stirring is continued for 16 hours before diluting with ethyl acetate (200 ml), and the solution is filtered through a plug of celite. Concentration in vacuo is followed by column chromatography (eluent ethyl acetate) to give dimethylacetal N-hexyl-2-arnino-acetaldehyde (7.39 g, 78%) as a colorless oil. The amine (38.6 mmol, 7.3 g) in methylene chloride (100 mmol) was added at 0 ° C 4- (chloro-sulfonyl) phenyl-isocyanate (38.6 mmol, 8.4 g). The reaction mixture is stirred for 20 minutes until a clear solution has formed, and water: trifluoroacetic acid 1: 1 (100 ml total) is added. The vigorous stirring is continued for 16 hours, the layers are separated, the organic layer is diluted with ethyl acetate (500 ml) and washed with saturated sodium bicarbonate solution (4x50 ml), brine (50 ml), dried with anhydrous magnesium sulfate and concentrated in vacuo. Column chromatography (eluent 3 hexane / 1 ethyl acetate) gives the title compound as light yellow crystals (8.8 g, 67%).

(R) -N-C4-C2-Ct2-Hydroxy-2- (pyridin-3-yl-amino) ethyl-3-enyl] -4- (exino -carbonyloxy) -benzenesulfonamide, a solution of 302 mg (0.845 mmol) of the product of the example 18 and 137 rnl (1.69 rnmoles) of pyridine in 10 ml of methylene chloride are added to 296 g (0.928 mol) of 4- (hexylaminocarbonylamino) benzene chloride of Example 3. The reaction is stirred for 12 hours after the solvent is removed in vacuo Inentaneous evaporation chromatography (eilice gel, 6% methanol, 0.5% ammonia-methylene chloride) gives 468 mg (87%) of the BOC-protected title compound.A solution of 468 mg is stirred (0.731 mmoles) of the BOC-protected title compound in 5 ml of methylene chloride and 5 rnl of trifluoroacetic acid for 30 minutes, then the volatile components are removed in vacuo.The residue is azeotropically distilled twice with rnetanol // toluene 10%, twice with methanol, then dried under vacuum to give 521 mg (93%) of The title compound as its trifluoroacetate salt: H NMR (400 MHz, CD3O.D) 6 8.88 (s, 1H), 8.79 (d, 1H, 3 = 5.5 Hz), 8.53 (d, 1H, 3 = 8.2 Hz), 7.99 (rn, 1H), 7.59 (dd, 2H, 3 = 6.9, 1.9 Hz), 7.43 (dd, 2H, 3 = 6.9, 1.9 Hz), 7.15 (dd, 2H, 3 = 8.6, 2.1 Hz), 7.08 (dd, 2H, 3 = 8.6 2.1 Hz), 5.23 (m, 1H), 3.40-3.10 (m, 6H), 2.94 (, 2H), 1.49 (rn, 2H), 1.32 (rn, 5H), 0.90 (n, 2H).

EXAMPLE 26 (N) -C4-C2- (Phenylmethoxycarbonyl) amino3ethyl3-phenyl] -4-cyanobenzenesulfonamide. Deepuée the procedure outlined in example 4, the title compound is prepared from 2- (4-aminophenyl) ethylcarbamate phenylmethyl ester (see Fisher, et al., Eur.Pat.Appl. 0 611 003 Al, 1994) and sodium chloride. -cyanobenzene sulfonyl: * H NMR (400 MHz, CD3OD) 6 iH NMR (400 MHz, CDCl 3) 6 7.81 (d, 2 H, 3 = 8.7 Hz), 7.69 (d, 2 H, 3 = 8.7 Hz), 7.32 (rn, 5H), 7.05 (d, 2H, 3 = 8.7 Hz), 7.69 (d, 2H, 3 = 8.7 Hz), 7.32 (m, 5H), 7.06 (d, 2H, 3 = 8.4 Hz), 6.96 (d, 2H, 3 = 8.4 Hz), 6.75 (s, 1H), 5.06 (s, 2H), 4.71 (t, br, 1H), 3.38 (q, 2H, 3 = 6.9 H), 2.74 (t, 2H, 3 = 7.0 H).

EXAMPLE 27 (N) -C4-C2-C (enylmethoxycarbonyl) amino] ethyl_ffenyl3-4-aminooximidomethyl) encensulfonamide. A mixture of the nitro of example 26 (2.71 g, 6.23 mol) absolute ethanol (65 ml), K2CO3 (5.17 g 37.4 mol) finely divided, and hydroxylanine hydrochloride (2.17 g, 31.2 mol), are refluxed for 6 hours . The ethanol is removed under reduced pressure. The resulting solid is dissolved in ethyl acetate and washed with water three times. The organic phase is concentrated in vacuo to give 2.87 g (98%) of the title compound as a white powder which is of sufficient purity to be used in subsequent steps: i H NMR (400 MHz, CD30D) 6 7.71 (s, 4H ), 7.31 (m, 5H), 7.04 (d, 2H, 3 = 8.4 Hz), 6.99 (d, 2H, 3 = 8.4 Hz), 5.02 (s, 2H), 3.25 (t, 2H, 3 = 6.8 Hz) ), 2.67 (t, 2H, 3 = 6.7 Hz).

EXAMPLE 28 (N) -C4-C2-C (Phenylmethoxycarbonyl) amino] ethyl enyl3-4- [5- (3-cyclopentylpropyl) -Cl, 2,4] -oxadiazol-3-yl-3-benzenesulfonamide. To a solution of the compound of example 27 (0.468 g, 1.00 rnmoles) in dry pyridine (5.0 ml) is added 4-cyclo-entlybutyryl chloride (0.175 g, 1.00 mol). The mixture is refluxed for 3.5 hours. The pyridine is removed under reduced pressure. The resulting residue is purified by silica gel chromatography (35% ethyl acetate in hexanes) to give 0-152 g (25%) of the title compound: H NMR (400 MHz, CDCl 3) 6 8.12 (d, 2H, 3 = 8.7 Hz), 7.81 (d, 2H, 3 = 8.7 Hz), 7.31 (rn, 5H), 7.03 (d, 2H, 3 = 8.1 Hz), 6.97 (d, 2H, 3 = 8.4 Hz), 5.67 (s, 1H), 5.05 (s, 2H), 4.70 (t, br, 1H), 3.37 (q, H, 3 = 6.5 Hz), 2.91 (t, 2H, 3 = 7.6 Hz), 2.72 (t, 2H, 3 = 7.0), 1.90-1.70 (m, 5H), 1.65-1.30 (m, 6H), 1.06 (m, 2H).

N-C4- (2-Aminoethyl) phenyl3-4-C5- (3-cyclopentylpropyl) -Cl, 2,43-oxadiazol-3-yl-3-benzensulfonamide. A mixture of Cbz amine of example 28 (0.145 g, 0. 246 rnmoles), palladium hydroxide on carbon (0.02 g), and glacial acetic acid (5.0 rnl) is hydrogenated for 7 hours. The acetic acid is removed under reduced pressure. The residue is purified by silica gel chromatography (1: 9 of 10% ammonium hydroxide in methanol: methylene chloride) to give 0.058 g (52%) of the title compound: H NMR (400 MHz, CD3OD) 6 8.11 (d, 2H), 3 = 8.6 Hz), 7.87 (d, 2H, 3 = 8.5 Hz), 7.06 (d, 2H, 3 = 8.6 Hz), 7.02 (d, 2H, 3 = 8.7 Hz), 2.97 ( t, 2H, 3 = 7.5 Hz), 2.84 (t, 2H, 3 = 6.9 Hz), 2.67 (t, 2H, 3 = 7.5 Hz), 1.90-1.75 (rn, 5H), 1.70-1.40 (rn, 6H ), 1.12 (n, 2H).

EXAMPLE 30 (R) -N-C -C2-CC2-Hydroxy-2- (pyridin-3-yl) ethyl-3-amino-3-ethyl-3-phenyl-3-4-C5-y3-cyclopentyl-propyl) -Cl, 2,3-oxadiazol-3-yl-enzensul-fonami da. To an amine solution of Example 29 (0.053 g, 0.117 mmol) is added 3- ir iridine epoxide of Example 1.6 (30.0 rnl). The resulting solution is refluxed overnight. After concentration, the residue is purified by chromatography on silica gel (.13% rnetanol in methylene chloride) to give 0.01 g (15%) of the title compound: 1 H NMR (400 MHz, CD3OD) 6 8.52 (d, 1H, 3 = 1.9 Hz), 8.42 (dd, 1H, 3 = 1.5, 4.8 Hz), 8.13 (d, 2H, 3 = 8.6 Hz), 7.85 (rn, 3H), 7.40 (dd, 1H, 3 = 4.8 , 7.8 Hz), 7.10 (d, 1H, 3 = 8.6 Hz), 7.03 (d, 2H, 3 = 8.6 Hz), 4. 81 (dd, 1H, 3 = 4.9, 8.1 Hz), 2.96 (t, 2H, 3 = 7.5 Hz), 2.93-2.70 (rn, 6H), 1.90-1.72 (rn, 5H), 1.68-2.48 (rn, 4H), 1.42 (m, 2H), 1.11 (rn, 2H).

EXAMPLE 31 (R) -N-C4-C2-CC2-Hydroxy-2- (pyridin-3-yl) ethyl-3-amino-3-3-phenyl-3-4-C4- (l-hydroxy-l-hexylheptyl) -5-methyl-Cl, 2.33 -triazol-2-yl3 benzenesul fonamide and (R) -N-C4-C2-CC2-H? droxi-2- (pyridin-3-yl) ethyl3am? no3ethyl in? 3-4-C4- (l- (R , S) -hydroxyheptyl) -5-methyl-Cl, 2,33-triazol-2-yl-3-benzensulonamide To a solution of 180 rng of (R) -N-C4-C2-C2-C? -H? Drox? - 2- (p? Pd? N -3? L) et? 3am? No] et? L] phen? L] -4-C4-? Nexac? Carbon? L-5-inethyl-C 1,2,33 -ti azol-2-? l) benzens? l fonarní da (prepared according to the procedures delineated in examples 14-19), in 2 i of THF distilled under argon at 0 ° C, they are added in the form of drops 2 ml of a 2.0M solution of n-hexylrnagnesium bromide in ether. After 5 minutes, the reaction is quenched with the careful addition of 5 ml of aqueous ammonium chloride followed by extraction with ethyl acetate from the aqueous layer. The combined organic extracts are dried over sodium sulfate, filtered and concentrated in vacuo to give the crude products. Preparative layer chromatography (PLC) on silica gel plates of 2X0.5 mm thick with 9: 1 (v / v) dichloromethane: methanol gives two bands A (20 mg) and B (60 mg). 1H NMR (500 MHz, CD30D) at A: 6 8.51 (d, 1H, 3 = 2 Hz), 8.41 (dd, 1H, 3 = 1.5, 5 Hz), 8.01 (dd, 2H, 3 = 2.5, 6.5 Hz ), 7.81 (m, 1H), 7.78 (dd, 2H, 3 = 2.0, 9.0 Hz), 7.37 (m, 1H), 7.78 (dd, 2H, 3 = 2.0, 9.0 Hz), 7.37 (m, lH) 7.07; 7.02 (ABq, 4H, 3ab = 8.5 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, 3 = 7 Hz) indicating the adduct of diethyl tertiary alcohol, spec. expected loop 677 found 677. 1H NMR (500 MHz, CD3OD) to B: 8.51 (d, 1H, 3 = 2 Hz), 8.41 (dd, lH, 3 = 1.5 Hz), 8.03 (d, 2H, 3 = 9 Hz), 7.78 (d, 2H, 3 = 9 Hz), 7.37 (dd, 1H, 3 = 4.8, 7.7 Hz), 7.07; 7.02 (ABq, 4H, 3ab = 8 Hz), 4. 86 (s, CD3OH), 4.80 (n, 2H), 2.9-2.7 (, 6H), 2.38 (s, 3H), 1. 87 (m, 2H), 1.44 (m, 1H), 1.4-1.2 (m, 7H), 0.87 (t, 3H, 3 = 7 Hz), which indicates the rnonohexyl adduct. spec. expected 519 (for hexyl ketone) found 593 (hexyl alcohol, intermediate ketone reduced by Grignard reagent in situ). Following the procedures delineated for examples 14-31, the compounds listed in quad-2 were prepared.

TABLE 2 Example R I Selected data of RHN H (CD3OD) 32 4-isopropylphenyl 7.64 (d, 2H, J = 8.0 Hz), 7.33 (d, 2H, J = 8.0 Hz), 4.80 (m, 1H), 2.95- 2.70 (m, 7H), 1.22 (d, 6H, J = 6.7 Hz) 33 bistrifluoroacetate salt 7.84 (d, 2H, J = 8.6 Hz), 7.47 (d, of 4-iodophenyl 2H, J = 8.6 Hz), 5.19 (dd, 1H, J = 10.1, 3.0 Hz), 3.40-3.20 (m, 4H), 2.96 m.2H 34 2-naphthyl 8.28 (s, 1H), 7.94 (m, 3H), 7.72 (dd, 1H, J = 8.7, 1.9 Hz), 7.60 (m, TH ) '' 5 salt of bistrifluoraceta 9.01 (d, 1H, J = 2.3 Hz), 8.76 (d, to 3-quinolimile 1H, 1.8 Hz), 8.08 (d, 1H, J = 8.7 Hz), 8.04 id, 1H, J = 8.0 Hz), 7.93 μm. lH.7.73 (m.1H) 36 salt of bistrifluora- 5.12 id.1H. J = 8.7 Hz;, 3.40-3.10 cetato of 4- (* M? Exil, (m.6H), 2.99 (s, 3H), 2.95 (m.2H), N, petil-arainocarbonyl) - aminolyphenyl 1.56 (m , 2H), 1.31 (m.6H), 0.88 (m, 3H) 37 bistrifluoride salt- 5.15 (m, 1H), 3.85 (m, 2H), 3.53 4- (hexyl-2-imidazolidinon-1-yl) cetate (m, 2H), 3.40-3.15 (m, 6H), 2.94 phenyl (m, 2H), 1.55 (m, 2H), 1.32 (m, 6H), 0.89 (m.3H). 10 38 bistrifluoride salt- 2.35 (tr, 2H, J = 7.5 Hz), 1.65 4 - [(1-oxo-hexyl) -aminogenyl acetate (quint., 2H, J = 7.1 Hz), 1.32 (m, 6H ), 0.892 ítr.3H. J = 6.8Hz). 39 bistrifluoride salt- 7.34-7.25 (m, 4H), 7.15-7.05 (m, 4 - [(1-OXD-4-phenyl-butylJaminoj '5H) cetate, 2.71 (tr, 2H, J = 7.7Hz) , 2.36 phenyl 15 (tr, 2H.J-7.4 Hz), 1.96 (m.2H). 40 bistrifluora salt-4.07 (tr, 2H, J = 6.6 Hz), 1.67 4 - [(propoxy-carboni1) -aminoglyne cetate (sextet, 2H, J = 7.0 Hz) .0.968 (tr, 3H, J = 7.4 Hz). 41 bistrifluoride salt- 7.40 (d, 1H, J = 0.9 Hz), 6.32 (dd, 4- l-l-acetate (fur-2-ylmethyl-J-aminolcar-1H, J = 2.9, 1.8 Hz), 6.23 (d, 1H , J bonillaminolfenilo = 2.9 Hz), 4.34 (s, 2H) 42 bistrifluoride salt- 7.38-7.02 (m, 9H), 3.50-3.15 (m, 4 £ tC cetate (2-phenylethyl-aminolcar-6H), 2.80 (m, 2H) 25 bonyl3 amino-phenyl 43 bistrifluoride salt- 7.58-7.53 (m, 3 H), 7.42-7.30 (m, 4 4-UKoctyl-amino] carboni 1 lamino! H), 7.08-6.94 (m, 7H), 3.48 (tr , 2 phenyl H, J = 6.9 Hz) 2.94 (tr, 2H, J = 6.8 Hz). 44 bistrifluoride salt- 2.94 (m, 2H), 1.51 (tr, 2H, J = 6.8 4- [t (octyl-amino) carbonyl-amino). Hz), 1.30 (m, 10H), 0.884 (tr, 3H, phenyl J = 6.9 Hz). 84 4-í5-hexythio, - [1,2,4] - 3.11ít.2H = 7.3Hz. 2.98-2.84 triazoI-3-yl) phenyl (m, 4H), 2.76 (t, 2H.J = 7.3Hz), 1.65 (q, 2HJ = 7.3Hz), 1.37 (q, 2H, J = 7.1Hz), 1.28-1.23 ím, 4H), 0.84 ít.3H.J = 6.9Hz) 85 4 - [[4- (4- 8.84 (s, 1H), 8.75 (d, 1H, J = 5.07 prop i lpiperidin- 1 - J 1) - Hz), 8.46 (d, 1H, J = 8Hz), 7.15 & l, l-dioxo- [l, 2.5J- 7.08 each (d, 2H, J = 8Hz), 0.92 (t, thiadiazol-3- 3H, J = 7Hz) illaminol phenyl 86 4 - [[4- 7.15 ( d, 2H, J = 8.5Hz), 7.12 (d, 2H, (hexylmethylamino) - J = 8.5Hz), 5.19 (dd, 1H, 3.1Hz, 9Hz), 1, l-dioxo- [1,2,5] -2.93 (m, 2H), 0.90 (t, 3H, 6.8Hz) thiadiazol-3-ii] amino] phenyl 87 4 - [[4- 7.16 (d, 2H, J = 8.8Hz), 7.11 (d, 2H, (hepti let i lamino 0- J = 8.8 Hz), 5.01 (dd, J = 3.2Hz, 1, l-dioxo- [1,2,5] - 9.9Hz), 2.92 (m, 2H), 1.68 (m, 2H) thiadiazol-3i] amino] phenyl 88 4- (1 -octi 1-2.4- 4.09 (s, 2H), 3.41 (t , 2H, 7hz), imidazolidinedion-3 - 1.65-1.56 (m, 2H), 1.30-1.25 (m, ii) phenyl 10H), 0.91-0.86 m3H.89 4- [3- (3-nitrophenyl) - 5-8.55 (t, lH, J = 1.9Hz), 8.47 (d, pyrazolon-1-ü] 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, 3HJ = 8.9Hz), 7.56 (t, lH, J = 8.0 Hz), 7.33 (dd, lH, J = 4.8 Hz), 7.04 (dd.4H, J = 6.6Hz), 4.75 (t, lHJ = 2.1Hz), 2.83-2.69 (m.6H) Starting with (R) -styrene epoxide and following the procedures outlined for the examples 17, 18 and 25, the compounds listed in Table 3 were prepared.

TABLE 3 Selected NMR data Example? Ü (CD3OD) 90 Salt of trifluoroace7.84 (d, 2H, J = 8.6 Hz), 7.45 (d, 4-iodophenyl, 2H, J = 8.5 Hz) 91 Exit of trifluoroace8.31 ( s, 1H), 7.96 ^ 7.90 (m, 3H), 2-naphthyl acetate 7.74 (dd, 1H, J = 1.8, 8.7 Hz), 7.63 (t, 1H) .7.58 ít.1H) 92 Trifluoroacetate salt 9.01 (d, 1H, J = 2.2 Hz), 8.75 (d, 3-quinolinyl-1H, J = 2.1 Hz), 8.07 (d, 1H, J = 8.4 Hz), 8.03 (d, 1H, J = 8.3 Hz), 7.92 (t, 1H, J = 7.0 Hz), 7.72 (t, 1H, J = 7.1 Hz) EXAMPLE 93 (R) -N-C4-C2-CC2-Hydroxy-2- (pyridin-3-yl) ethyl] amino3-2-methylpropyl] enyl 3-4- (3-hexyl-2-2-imidazolidinon-1-yl) benzensul onami gives. A solution of pyridine epoxide (160 mg, 1.32 min.) Of Example 16 is heated at reflux for 16 hours. 4-arnino-a, a-dimethylphenylalanine (1.2 g, 7.3 rnnols), prepared according to 3. Biol. Chem. 1981, 256, 11944-50, in methanol (8 ml). After cooling, the reaction mixture is concentrated and purified by flash chromatography (silica gel, 95: 5 CH 2 Cl 2: 102 NH 4 OH / CH-3OH) of the product 23 g (0.080 mmol) as an oil. The previous product (18 rnG, 0.063 mmol) is dissolved in CH2Cl2 (1 rnl) and pyridine (0.05 rnl). The resulting solution is cooled to 0 ° C and treated with 4- (3-hexyl-2-imidazolidin-1-yl) benzensul fonyl chloride (22 rnG, 0.063 mrnol). The mixture was allowed to stir at 0 ° C for 20 hours and then purified by flash chromatography fgel silica 95: 5 CH2d2: 10% NH4OH / CH3OH) to give the desired product (21 rng, 0.035 mmol) as an oil : 1HNMR (CD30D) d 8.53 (s, 1H), 8.44 (d, lH, 3 = 5.0), 7.83 (d, 1H, 3 = 7.9), 7.63 (m, 4H), 7.40 (dd, 1H, 3 = 5.0, 7.9), 6.98 (m, 4H), 4.72 (dd, 1H, 3 = 4.0, 8.4), 3.80 (, 2H), 3.49 (rn, 2H), 3.22 (t, 2H, 3 = 7.2), 2.78 (rn, 2H), 2.62 (n, 2H), 1.55 (m, 2H), 1.31 (n, 6H), 1.01 (s, 3H), 0.99 (s, 3H), 0.89 (m, 3H). Following the procedure outlined above, the compounds were prepared in Table 4.

CURDRO 4 Example R Selected data from MNiH (CD3OD) 94 4-iodophenyl 7.82 (d, 2H, 3 = 8.6), 7.42 (d, 2H, 3 = 8.6) 95 4-CC (hexylamino) car- 7.55 (d, 2H, 3 = 8.8), 7.42 bonylHamino] phenyl (d, 2H, 3 = 8.8), 3.11 (t, 2H, 3 = 7.0), 1.49 (in, 2H), 1.30 (m, 6H), .089 (rn, 3H) E3EMPL0 96 Dimethyl-1, 1-dimethylethylsilyl ether, (R) -4-amino-a- (broomethyl) -3,5-dichlorobenzenemethanol. A solution of t-butyldimethylsilyl chloride (1.67 g, 11.1 rnmoles) in DMF (15 nl) to a stirred solution of (R) -4-amino-a- (bromomethyl) -3,5-diclorobenzenornetanoi slowly added (2.1 g, 7.4 mmoles, see 3udkins, and others, European patent application 0 460 924) and imidazole (0.75 g, 11. 1 rnmoles) in DUS (6 rnl), with cooling in an ice-water bath. After being stirred at RT for 3 hours, the reaction mixture was poured into water (300 ml) and the product was extracted with ether. The organic phase is washed with saturated aqueous sodium bicarbonate solution, brine, dried (MgSOA) and evaporated to dryness. The crude product is purified on silica (95/5 hexane / ethylacetate) to give the title compound (2.73 g, 93%): H NMR (400 MHz, CDC.I.3) d 7.14 (s, 2H), 4. 67 (dd, 1H, 3 = 2.1, 5.4 Hz), 3.33 (rn, 2H), 0.87 (s, 9H), 0.89 (s, 6H).

EXAMPLE 97 (R) -N-C2-C4-amino enyl) ethyl] -2- (dimethyl-1,1-di ethylethylsilyl) oxy 1 -2- (4-amino-3,5-dichlorophenyl) ethylamine. The compound bromo- 0-TBDMS Example 96 (2.73 g, 6.86 rnmoles) is dissolved in CH3CN (50 ml) and add 4-arnino-phenethylamine (1.86 g, 13.72 rnmoles), followed by addition of N, N '-diisopropylethylamine (3.58 mmol, 20.6 mmol) and sodium iodide (1.03 g, 6.86 mmol). After being heated to reflux for 48 hours, the reaction mixture is concentrated and the residue is chromatographed on silica (50/50 ethyl acetate / hexane) to provide the title compound (2.3 g, 75%): H NMR (400 MHz, CDC.I3) d 7.08 (s, 2H), 6.94 (fifi ', 2H, 3 = 8.4 Hz), 6.60 (BB', 2H, 3 = 8.4 Hz), 4.63 (rn, 1H), 4.37 (s, 2H), 3.53 (br s, 2H), 2.87-2.60 (rn, 6H), 0.80 (s, 9H), -0.03 (s, 6H).

EXAMPLE 98 (R) -N-C2-C4-Imino-enyl)] ethyl] -2-hydroxy-2- (4-amino, 3,5-dichloropheniDethylamphylate) a stirred solution of the silyl compound of example 97 (2.2 g , 5.8 mmoles) in THF (20 ml) at Tfi is added abutilarnonio tet fluoride (10 rnl of 1.0 M solution in THF) in one portion After having been stirred at Tfi for 2 hours, the reaction mixture is concentrated and chromatograph on silica (10/90 CH3OH / CH2Cl2) to give the title compound (1.59 g, 97%): H RNN (400 11Hz, CD3OD) d 7.15 (s, 2H), 6.92 (fifi ', 2H = 38.3 Hz), 6.60 (BB ', 2H, 8.3 Hz), 4.58 (m, 1H), 2.83-265 (m, 5H).

EXAMPLE 99 (R) -N-C4-C2-CC2-idroxy-2- (4-amino-3,5-dichlorophenyl) ethyl3amino3ethyl] -phenyl3-4- (exylaminocarbonylamino) benzenesulfonamide. Following the procedure outlined in Example 18 and 25, the title compound is prepared from the aniline derivative of Example 98: NMR (400 MHz, CD3OD) 7.57 (fifi ', 2H, 3 = 2.7 Hz), 7.42 (BB ', 2H, 3 = 2.7 Hz), 7.16 (s, 2H), 7.04 (fifi', 2H, 3 = 2.0 Hz), 7.00 (BB ', 2H, 3 = 2.0 Hz), 4.58) t, 1H, j = 7.1 Hz), 3.14 (t, 1H, 3 = 7.0 Hz), 2.80 (m, 2H), 2.73 (rn, 4H), 1.49 (rn, 2H), 1.32 (rn, 6H), 0.90 (t, 3H , 3 = 6.7 Hz). ESI MS M / z 622 (M). Following the procedure outlined in Examples 96-99, the compounds were prepared in Table 5.

TABLE 5 EXAMPLE 103 (R) -N-r; 4-C2-CC2-hydroxy-2- (4-hydroxyphenyl) ethyl araino3ethyl phenyl3-benzensulfonaraide. Silylation is carried out with a solution of 5 g of 4-aminophenethyl alcohol in 50 nl of DMF with 5.5 g of t-bldildimethyleryl chloride (TBDMS-C1) and 2.5 g of imidazole overnight at room temperature. Extraction of the product after a treatment with aqueous ammonium chloride gives 6.6 g of the ether 0-TBDMS. This aniline derivative is then coupled to benzenesul fonyl chloride in pyridine-dichloromethane to give the sulfonarnide in a yield greater than 80% after chromatographic purification. The TBDM group of the eulphonainide was removed with rnetanol HCl at room temperature for 30 minutes. The crude alcohol is oxidized to the corresponding carboxylic acid with 3-fold reagent in acetone (RT, 30 minutes, extraction with e + ethyl acetate). A solution of 180 rng of (R) -octoparin and 300 rng of the resulting 4-N-benzenesulfonam-dofemlaceate in 7 ml of DMF was added 0.5 ml of triethylamine and 490 rng of benzotriazolyl-N hexafluorophosphate. -oxi-tris (dimethylamino) phosphonium. The reaction mixture is stirred at RT for 3 hours, flash chromatography on silica gel is applied with 95: 5 chloroform-methanol to give 322 mg of purified amide. After a solution of 220 mg of this amide in 13 ml borane-THF 1.0 M, reflux under argon for 2 hours followed by the addition of 3 rnl of N, N-dimethylaminoethanol and subsequent reflux for another hour. The solvent and excess volatiles are removed in vacuo and the residual solid is added in acetone and purified by PLC on silica gel ((9: 1 ethyl acetate: methanol) to give 61 mg of the title compound: NMR (500 MHz, CD3OD), d 7.73 (dt, 2H, 3 = 2.1, 8.2 Hz), 7.53 (tt, 1H, 3 = 1.4, 7.6 Hz), 7.44 (t, 2H, 3 = 8 Hz), 7.18 (d, 2H, 3 = 8.4 Hz), 7.05 (RBq, 4H, 3ab = 8.5 Hz), 7.76 (d, 2H, 3 = 8.4 Hz), 4.75 (dd, 1H, 3 = 7.5, 7.6 Hz), 3.05-2.90 (rn, 4H), 2.81 (t, 2H, ^ -7.5 Hz), Spec. of calculated mass 412.5 found 413.2.

EXAMPLE 104 (R) -N-C4-C2-CC2-Hydroxy-2- (4-hydroxy-enyl) -ethyl-3-amino-3-ethyl-3-enyl-3-4-iodo-bensensulfonamide. The title compound is prepared following the procedure outlined in Example 103: * H NMR (500 MHz, CD3 OD) d 7.7 (d, 2H, 3 = 8.5 Hz), 7.43 (d, 2H, 3 = 8.5 Hz), 7.15 (d, 2H, 3 = 8.5 Hz), 7.02 (flBq, 4H, 3at > = 8.7 Hz), 6.75 (d, 2H, 3 = 8.5 Hz), 4.67 (dd, 1H, 3 = 4.4, 6.6 Hz), 2.90-266 (rn, 6H), Spec. of calculated mass. 538.4 Found 538.9.

EXAMPLE 105 3- (2-Bromoacetyl) benzonitrile. a solution of 1.02 g (7.04 mol) of 3-acetylbenzonitrile in 70 nl of ethyl ether and add 1.02 g (3.52 rnmoles), 0.5 equiv) of dibromobarbituric acid. The mixture is allowed to stir at room temperature overnight. The resulting white suspension is filtered and the filtrate is concentrated. Purification by flash evaporation chromatography (silica gel, 20% ethyl acetate / hexane) gives 1.28 g (81%) of the title compound as a white solid: * H NMR (400 MHz, CDCl 3) d 8.26 (+, 1H, 3 = 1.4 Hz), 8.20) td, 1H, J-1.5, 8.0 Hz), 7.87 (dd, 1H, 3 = 1.3, 7.3 Hz), 7.64 (t, 1H, 3 = 7.9 Hz), 4.40 ( s, 2H).

EXAMPLE 106 (R) -a-bromomethyl-3-cyanophenylmethanol. A suspension of 181 mg (0.623 nmrnols) of (R) -tetrahydro-1-methyl-3,3-diphenii-1H, 3H-pyrroloCl, 2c, 3,2] oxazaborol-borane (R-OfiB catalyst) in 6 ml of THF at 0 ° C is added in the form of drops 6.24 ml (6.24 mmol) of a 1 M solution of borane in THF. The resulting clear solution is allowed to stir for 5 minutes and then a solution of 1.27 g (5.67 rnmoles) of bromoketone is added to the example 105 in 6 i of THF slowly for 1 hour. After the reaction has been allowed to stir for an additional 30 minutes, it is quenched with the dropwise addition of 6 ml of rnetanol and concentrated. Puncturing by flash chromatography (silica gel 20-25% ethyl acetate / hexane) gives 944 rng (74%) of the title compound as a clear oil which is crystallized: * H NMR (400 MHz, CDCl 3) μ 7.70 (d, 1H, 3 = 1.5 Hz), 7.63-7.60 (, 2H), 7.48) t, 1H, 3 = 7.7 Hz), 4.95 (dd, 1H, 3 = 3.4, 8.4 HZ), 3.63 (dd, 1H, 3 = 3.4 Hz), 3.49 (dd, 1H, 3 = 8.4 Hz),.

EXAMPLE 107 (R) - (3-Cyanophenyl) oxirane. a solution of 937 mg (4.14 mmol) of bromohydrin from Example 106 in 8 mL of methanol are added 601 rng (4.35 inmol, 1.05 equiv) of potassium carbonate. The reaction mixture is allowed to stir at room temperature for 7 hours. It is then diluted with ethyl acetate, washed with water, dried over magnesium sulfate and concentrated. Purification by flash evaporation chromatography (silica gel, 20% aceta + or e + i lo / hexane) provides ^ 7 g (95%) of the title compound: 1 H NMR (400 MHz, CDCI 3) d 7.S9-7 .. 55 (rn, 2H), 7.49 (dd, 1H, 3 = 1.6, 7.9 Hz), 7.44 (t, 1H, J-7.7 Hz), 3. 87 (dd, 1H, 3 = 2.5, 4.0 Hz), 3.17 (dd, 1H, 3 = 4.1, 5.5 Hz), 2.74 (dd, 1H, 3 = 2.5, 5.4 Hz).

EXAMPLE 108 1,1-Dimethylethyl ester of (R) -N-C2-C4- (aminophenyl) 3-ethyl-3-2-hydroxy-2- (3-cyanophenyl) ethylcarbamic acid. Following the procedures delineated in Examples 1.7 and 18, the title compound was prepared from the epoxide of Example 1.07: i H NMR (400 MHz, CDCl 3) d 7.58-7.52 (br m, 3H), 7.41 (t, 1H , 3 = 7.5 Hz), 5.89 (br d, 2H, 3 = 7.6 Hz), 5.65 (br d, 2H, 3 = 7.8 Hz), 4.82 (br dd, 1H, 3 = 2.7, 7.9 Hz), 3.42- 3.05 (br rn, 4 H), 2.75-2.55 (br rn, 2 H).

EXAMPLE 109 (R) -N-C4- 2-C 2-Hydroxy-2- (3-cyanophenyl) ethyl-3-aminoethyl-3-phenyl-3-4- (hexylaminocarbonylamino) benzensulfonamide. Following the procedure outlined in -? 1 example 25, the title compound is prepared from the Boc aniline derivative of example 108: H NMR (400 MHz, CD3 OD) d 7.70 (s, 1H), 7.63-7.57 (rn , 4H), 7.48 (t, 1H, 3 = 7.7 Hz), 7.43 (d, 2H, 3 = 8.9 Hz), 7.06 (d, 2H, 3 = 8.5 Hz), 6.99 (d, 2H, H = 8.5 Hz ), 4.77 (dd, 1H, 3 = 3.9, 8.5 Hz), 3.15 (t, 2H, 3 = 7.0 Hz), 2.86-2.69 (m, 6H), 1.49 (br m, 2H), 1.31 (br rn, F > H), 0.90 (br t, 3H).

EXAMPLE 110 R) -N-C -C2-CC2-Hydroxy-2- (3-cyano-phenyl) -ethyl-3-amino-3-ethyl-3-phenyl3-3-quinolinesulfonamide. Following the procedure outlined in Example 25, the title compound is prepared from the aniline derivative Boc of Example 108 and 3-qu? Nol? Ns? Lfon? L chloride: 1 H NMR (400 MHz, CD3OD) 6 9.02 (d, IH, 3 = 2.3 Hz), 8.68) d, 1H, 3 = 1.9 Hz), 8.06 (d, 1H, 3 = 8.3 Hz), 8.02 (d, 1H, 3 = 7.9 Hz), 7. 90 (ddd, 1H, 3 = 1.4, 7.0, 8.4 Hz), 7.72-7.69 (rn, 2H), 7.62-7.58 (rn, 2H), 7.47 (t, 1H, 3 = 7.7 Hz), 7.07 (d, 2H, 3 = 8.7 Hz), 7.03 (d, 2H, 3 = 8.7 Hz), 4.76 (dd, 1H, 3 = 4.0, 8.5 Hz), 2.85-2.68 (rn, 5H). Following the procedures outlined for Examples 14-31, the compounds listed in Table 6 were prepared.

TABLE 6

Claims (16)

NOVELTY OF THE INVENTION CLAIMS

1. - A compound that has the formula I: 02 (CH2) r- • R7 where n is 0 to 5; rn is 0 or 1; r is 0 to 3; fl is (1) a 5- or 6-membered heterocyclic ring with 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen, (2) a benzene ring fused to a 5- or 6-membered heterocyclic ring with 1 to 4 selected heteroatoms of oxygen, sulfur and nitrogen, (3) a het rocicl ring of 5 or 5 members with 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen fused to a 5- or 6-membered heterocyclic ring with 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen, (4) femlo, or (5) a benzene ring fused to a cycloalk ring? C3-C8; R1 is (1) hydroxyl, (2) oxo, (3) halogen, (4) cyano, (5) NR8R8 / (5) R8, (7) tnfluromethyl, (8) Ci-Clio alkyl, (9) 0R8 , (10) O2R9, (11) 0C0R9, (12) NR800R9, (13) COR9, (14) NRβ S02 R9, (15) NR8CO2R8, or (16) C1-C10 alkyl, substituted with hydroxyl, halogen, iano, NRßRß, < 5R8 trifluoro and ilo, 0R8, C3-C8 cycloalkyl, phenyl, NR8COR9, COR9, SO2R9, 0C0R9, NR8SO2R9 or NR8CO2R8 R2 and R3 are independently (1) hydrogen, (2) CiCio alkyl, (3) C1-C10 alkyl with 1 to 4 selected substituents of hydroxyl, C1-C10 alkoxy, and halogen; X is (l) -CH2-, (2) -CH2-OH2-; (3) -CH = CH-, (4) -CH2O-; R * and RS -on independently (1) hydrogen, (2) C1-C10 alkyl, (3) halogen, (4) NHRβ t (5) ORß, (6) SO2 R9 or (7) NHS02 R97 R * is (1) hydrogen or (2) C 1 -C 10 alkyl; R7 is Z- (Ri »)"; R1"is (1) R1, with the proviso that when p is phenyl, R *" is not C? -C? Alkyl, or (2) C3-C8 cycloalkyl, (3) femlo optionally substituted with up to 4 groups independently selected from Rβ, NRβRβ t OR8, Rβ and halogen, or (4) 5 or 5-member heteroexy with 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen, optionally substituted with up to four groups independently selected from oxo, R8, RßRβ, QR8, 8 and halogen; Z is (l) phenyl, (2) naf-t or (3) a hetoi ocicl co ring of members with 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen, (4) a benzene ring fused to? N C3-C8 pcloalkyl ring, (5)? n benzene ring fused to a 5- or 6-membered heterocyclic ring with 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen, (6) a heterocyclic ring of 5 or 6 members were 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen fused to a 5- or 6-membered heterocyclic ring with 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen, or (7) a 5- or 6-membered heterocyclic ring with 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen fused to a cycloalkyl ring of C3-Ce; R8 is (1) hydrogen, (2) C1-C10 alkyl, (3) C3-C3 cycloalkyl, (4) Z having optionally 1 to 4 substituents selected from halogen, nitro, oxo, NRi ° R * °, alkyl of C1-C10, C1-C10 alkoxy, C1-O10 alkylthio, and C1-C10 alkyl with 1 to 4 substit and selected from hydroxyl, halogen, CO2H, OO2-C1-C10 alkyl, -2.0 -alkyl of C 1 -C 10, C 3 -Ce cycloalkyl / C 1 -C 10 alkoxy, and Z optionally substituted with 1 to 3 of halogen, C 1 -C 10 alkyl or C 1 -C 10 alkoxy, or (5) C 1 -C 10 alkyl which has 1 to 4 selected substituents of hydroxyl, halogen, CO-2H, alkyl of CO2H, alkyl of C02 ~ C1-C10, O2 -alkyl of C1-C10, cycloalkyl of C3-Ce, 'Ucoxyl of C1-C10, C 1 -C 0 alkyl, and Z optionally substituted with 4 halogen, C 1 -C 10 alkyl or C 1 -C 10 alkoxy; R9 is (l) Rß or (2) NRßRβ; RIO GS (L) C 1 -C 10 alkyl, or (2) two R 10 groups together with the N to which they are attached form a 5- or 6-membered ring, optionally substituted with Ci-Cι alkyl; Or a pharmaceutically acceptable salt thereof.

2. A compound, according to claim 1, wherein n is 0 to 3; rn is 1; r is H to 2; is phenyl or a 5 to 6 membered hetero ring with 1 to 4 nitrogen atoms; X is - OH - 7 R1 is (1) hydroxyl, (2) halogen, (1) cyano, (4) tpfluoro etiio, (5) NRßR8, (6) NR8SO2R9, (7) NRßCOR9, (8) R8C02R8, or C 1 -C 4 alkyl, (9) Ci-Cι alkyl, optionally substituted by hydroxyl; R2 and R3 are independently, (1) hydrogen, or (2) methyl; R *, R5, and Rβ are each hydrogen; R? is Z- (R *) n; and R8, R9, Z and R1"are as defined in claim 1, and when R1 is part of the definition of R1", it has the meaning defined in claim 1.

3. A compound according to claim 1. which has the formula: where n is 0 to 3; rn e 1; R1 is (l) hal geno or (?) NRßRβ; p2 / p? 3 n independently hydrogen or methyl; Ría p? (1) halogen, (?) C? -C? Alkyl, (3) NR? R?, (4) NR? COR9, (5) NR8 02R8, (6) COR9, (7) 0C0R9, or (8)? N heterocycle of 5 or 6 members with 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen, optionally substituted with up to 4 independently selected groups of oxo, halogen, Rβ, RSRS, ORβ, and Rβ; z is (l) phenyl, (2) naphthyl, (3) a 6-membered heterocyclic ring with 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen, (4) benzene ring fused to a 5 or 5-membered heterocyclic ring. 6 members with 1 to 3 heteroatoms selected from oxygen, sulfur and nitrogen, or (5) a 5- or 6-membered heterocyclic ring with 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, according to claim 3, further characterized in that R2 and R3 are each hydrogen.

5. A compound in accordance with the claim 1 that has the formula Ib: Ib where n is 0 to 3; in is 1; Ri is (1) hydroxyl, (2) cyano, (3) NRßRβ or (4) halogen; Rl "is (1) hal (2) NRßRß (-j) NRßCOR9, (4) NR8C02R8, (5) OCOR9, or (6)? N 5- or 6-membered heterocycle with 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen, optionally substituted with up to 3 independently selected groups of oxo, halogen, Rβ, Rβ, ORβ and cjRβ; -is (1) phenyl, (2) naphthyl or (3) benzene ring fused to a hetero ring; the ion with 5 6 members with the 4 heteroathoins selected from oxygen, sulfur and nitrogen; X c-.s CH2-; and R2 and R3 j0n independently, hydrogen or methyl 6. - A compound according to claim 1 Which has the formula Id: Go where n is 0 to 1; R1 is NRβ R8; 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 fused to the benzene ring; R1 * is (1) halogen, (2) Ci-Cio alkyl, (3) NRβ R8, (4) NRßCOR9, (5) NR8C02R8, (

6) COR9, or (7) a 5- or 6-membered heterocycle with 1 to 4 selected heteroatoms of oxygen, sulfur and nitrogen, optionally substituted with up to four independently selected groups of oxo, Rβ, < Rβ t OR8 and NRßRβ; when B and the benzene ring form a fused ring system, R1 is attached to any ring; R8 is (1) hydrogen, (2) Ci-Cio alkyl, (3) Z having optionally 1 to 4 substituents selected from nitro, oxo and NRi? Rioy or (5) Ci-Cio alkyl having 1 to 4 selected substituents of hydroxyl, halogen, Ci-Cio alkyl, C3-C8 cycloalkyl, and optionally Z-substituted Z with 1 to 4 halogen, C1-C10 alkyl or C1-C10 alkoxy; R9 is (1) R8 or (2) NRßRβ; Rio eß (1) Ci-Cio alkyl, or (2) two Rio groups together with the N to which they are attached form a 5 or 6 membered ring optionally substituted with Ci-C alkyl or; and Z is (1) phenyl, (2) a 5- or 6-membered heterocyclic ring with 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen, (3) a benzene ring fused to a 5- or 6-membered heterocyclic ring with 1 to 4 selected heteroatoms of oxygen, sulfur and nitrogen, or (4) a 5- or 6-membered heterocyclic ring with 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen fused to a cycloalkyl ring of C 3 -Ce.

7. A compound according to claim 1, selected from the group consisting of, N-C4-C2-C (2-hydroxy-2-phen? Let? L) arnmo3et? I3fen? 3-4-iodobenzen-sulfonamide; N-T4-r2-f (2-h? Drox? -2- phenylethyl) a? mo et? i fenill - -nafta len-ulfonarnida; and N-C4 -T2 -C (2-hydroxy-2-phenylethyl) ammo3et? i3 phenyl 3-3 -qui or 11 nsul phonation; N-C4-T2-CC2-hydro-2- (4-arn? No-3,5-d? Chloroten? L) et? L nn3et? I - phen? Ll-4- (hex? Larn? Nocarbon? larn? no) benzens? lfona? ?gives; N-Tí -G? ~ GG2-h? rox? -? - (4-am? no-3,5 -di cío r-o fem 1) et? l3a? nmo3et? 13-f-in 13-1-C (oct? Iarn? No) carhon? L3-5-? Ndol ns? L fonai i a; NC? -r2-r [2-h? Drox? -2- (4-am? N-3,5-dichlorophenyl) et? 3am? No3 ethyl 3 fem-4- (3-hex? L-2? m? dazol? d? non-1 -ll) benzensulfonamide; N-C4-r? -rC2-hydroxy -2- (4-arn? No-3,5-d? Chlorofeml) et? L3arn? No3et? I - phen? 3 - - (3-oct? L-2- ? pudazol? d? non-l-? 1) benzensul fonar ida; N-T4-U2-CC2- h? Drox? -2- (4-h? Drox? Phen? L) et? L3arn? No3et 113 feml3-benzens? L fonarní da; N-C4-C2- 2 -h? Drox? -2- (4-h? Drox? Phen? L) et? I3am? No3et? I eml3-4-iodobenzensul onam; N-C4-C2-CC2-h? Drox? -2- (3-c? Anophen?) Et? Ia? No3et? L fen? L3-4- (hex? Lam? Nocarbon? Lam?) Benzens? lfona? da, and N-C4-C2-CC2-h? drox? -2- (3-c? anophen? l) e? l3am? no3et? feml -3-qumolins? l fonaini a.

8. A compound according to claim 1 selected from the group consisting of: N-C4-C2-rC2-h? Drox? -2- (6-arn? Nop? P dm-3-? L) et? l arnmo3et? l Ifeni 1 -4 - (I have 11 ai oca rbon i lamino) benzonsul fonam id; N- 4-C2-CC2-h? Dro? -2- (6 ~ am? Nop? Pd? N -3? L) et? L arn? no 3 e ti 1 eni 13-4-iodine benzensul fonarní da; N-C4-C2-CC2 ~ h? Drox? -2 - (6-arn? Nop? R? D? N ~ 3-benzensulfone ida; NC 4-C 2- 2 -h? Drox? -2 ~ (6 -arn? nop? pd? n-3-? l) et? la? no3et? l in? l3 -2-naphthalenes? l fonarní da; N-C4-C2-CC2-hydr-oxy- 2- (6- a? n? nop? pd? n-3-? 1) et? l3arn? no3et? l 3 fen? l-3-t? jinol i nsul fonarní da; N-C4-C2-CC2-h? drox? -2- (6 -ami nop? Pd? N-3 ~? L) et? L3arn? No3et? L3fen? L3-5-benz soxazols? L fonarní da; N-C4-C2-C C2-h? Drox? -2- (6 -a? N? Nop? R? D? N-3- il) et? L 3a? N? No3et? L3 feml 3 - 4-C (hexellinilarní noca rbom l) arn? No 3 benzens? L fonarní N-C4-C2-fT2-hydroxy-2- (6-arn? nop? pd? n -3? l) e? l3arn? no3et? l3 phen? -4-C (dirnet iarní noca rbonil) a ino 3 benzensul fonarní da; N-C4-T2-CC2-hydroxy -2- (6-am? nop? pd? n -3? 1 let? l arn? no et? 13 fen? l3-4- ( 3-hexyl -2-? Rn? Dazol? Don-l -ll) benzensul fonarní da; N-C4-T2-r 2-hydroxy -2- (3 -? Pd? N? L) et-? L3l- trn? no3et? l 3fen? 13 4 - (hexaryl noca r boni lamino) benzensul fonam ida; N-T4-C2-CC2-h? drox? -2- (3-p? pd? nil) et? i3am? no3et? i] fen? l3 -4-isopropyl benzensul fon arní da; N-C4-C2-CC2-h? drox? -2- (3-p? r? d? n? l) et? l am? no3et? l feml -2-na talens? lfonam? da; N-C 4-C 2-C 2 -h? Drox? -2- (3-p.? Ridinyl) ethyl 3-ane-3-yet? Llfen? 3-3-qumolinsulfonarnide; N-C4-C2-CC2-h? Drox? -2- (3-p? R? D? N? L) et? L am? No3et? Llfeml3-4- [(hex ílrneti lamí noca rbonil) arm no 3 benzens? l fonarní da; N-C4-C2- [C2-h? Drox? -2- (3-p? Pd? N? L) et? 3am? No3et? L3 feml -4- (3-hex? L-2-? Rn? dazol? d? non-1-? l) benzens? l fonami da; N-C2-C2-h? Drox? ~ 2- (3-p? R? D? N? L) et? Ln? No3et? I eml3-i-iodobenzens? Fonarní da; N- [4-C2- C2-h? Drox? -2- (3-p? Rid? N? L) et? L am? No3et? L3phen? 3 -4-C 3- (3-c? Clopent ? l? rop? l? -2?? rn? dazol? d? non-l-l3benzensulfonarn? da; N-C4- 2-C 2 -h? Drox? -2- (3-p? R? D? Ni Detyl 3 ammo3et? L3 phen? 3-4- (3-oct? L-2-? Rn? Dazol? d? non-1-? l) benzensul fonarní da; N-C4-C2-CC2-h? drox? -2- (3-p? r? < l? n? l) et? i3arn? no3et? l3fen l3-4- (3-hex? l-2-- rn? dazolon-1-? l) t> gn; enzensulon? n? da; N-C4-C-CC2-h? drox -2- (3 -pi ri di n 11) Pt 113 arní no 3 et 113 f eni 134 - (3-oc 111 - 2 - irní dazo 1 on - 1 --il) benzens? fonm ida; N-C4-C2-rr2- H? drox? -? - (3- iri ini l) et? 3ammo3et? l in? l í - - (3-cyclopentylpropyl) 2 -? rn? dazolon-l-? l3benzensulfonam? da; N- 4-C2- CC2-h? Drox? -2- (3-p? R? D? N? L) et? L ammo3et? L3fen? L -l- (4-oct? Lt? Azol-2-? 1) -5- í ndol i nsul fonami a; N- 4-C2-CC2 - h? drox? -2- (3-p? r? d? n) l? et? 3am? no3et? l3fen? 3-4- (5- pent? i-Cl, 2, 43-oxad? azole-3-? l) benzensulfonate, N-C4-C2-CC2-hydrox? -2- (3-pyridinyl) et? i3a? n? no3et L3fen? -4 ~ (5-hex? l, l, 2,43-oxad? azol ~ 3- il) benzens? L fonarní da; N-C4- 2- 2-h? Drox? -2- (3- p? R? D? N? L) et? 3am? No e? Pfen? l] -4- (5-heptyl, 2,43-oxad? azole-3?) benzensulfonate; N-C4-C2-CC2-h? Drox? -2- (3-p? Nd? N? L) et? L am? No3et? Lpfen? -4- (5-oct? L-Cl, 2,43-oxad? Azol-3-? L) benzensul fonarní da; N-C4-C2- 2-h? Drox? -2- (3-p? R? D? N? L) et? 3am? No3et? L fen? -4-C5- (2-c? Clopent? Iet? L) - T 1,2, 43 - oxadiazol -3-yl) benzensul fonarní da; N-C4-C2-CC2-h? Drox? -? - (3 - ?? p di ni 1) et 113arn? no 3et 113 f eni 1 - 4 - C 5 - (3-cyclopentiipropyl) -Cl, 2, 43 -oxad? azole ~ 3-? 1) benzens? L fonarní da; N- [4 - C 2 - CC 2 - hid rox i - 2 - (3 - pi ri di ni l) et 113 aini no 3 et 113 f in 13 - 4 - (2 -pent? Loxazol-5? ) benzensul fonarní da; N- -C2-C2-hydrox? -2- (3-p? R? D? Ml) et? I3am? No3et? L] phenol4- (2-hex? Loxazol-5-yl) ) benzensul fonarní da; N-C4-C2-CC2-h? D ox? -2 ~ (3-p? R? D? N? L) et? I am? No3et? Lpfen? -4- (2-he? T? Loxazole -5-Dbenzeneulfonarni; NT-C2-C2-hydrox? -2- (1 -p? R? D? N? L) et l arn? No3et? I en? I -4- (2-oct? loxazol-5-yl) benzens? l fonarní da; N-C4-C2-CC2-h? drox? -2- (3 -? r? d? n? l) et? i arn? no3Gt? l3 en? L 1 -4-T2 (2-cyclopentylethi) oxazole-5? 3 -someone-N-C4-C2-CC2 h? DrOx? -? - (3-p? R? D? N? L) et ? 3arn? no3et-? l feml -4-C2 - (3-cyclopentiipropyl) oxazole-5-? 3-benzensulphonic acid; N-r4-T2-CC2-hydrox? -2- (3-?? r? d? n? l) et? 3a? n? no3et? l] feml3-4- (4-hex? -5-tetrazolon-1-yl) benzensul fonami a; N-C4-C2-C2-h? drox -2- (3-p ipdinil) et? 3am? No3et? L3 phenyl 3-4- (4-octyl-5-tetrazolon-1-l) benzenesulfon? N? N-C4- 2-2 -h? drox? -2- (3-pyridi il) et? l 3ammo3et? i in 13 -? - (3-c? clo? ent 11 pro? pf ~, -t-et razolon-ii l! > enzens? l fonain da.

9. - A compound according to claim 1, with the structural formula Te: Where n, rn, r, Rl, R2, R3, A J RS I ß t 7 t x sor? as defined in claim 1.

10. A method for the treatment of diabetes, which comprises administering an effective amount of a compound of claim 1 to a diabetic patient.

11. A method for the treatment of obesity, which comprises the administration of an effective amount of a compound of claim 1 to an obese patient.

12.- An e-todo for the decrease of levels of t glyglect and cholesterol levels or increase "Lipoprotein levels of < This density comprises the administration of an effective amount of compound of claim 1 to a patient in need of lower levels of triglyceride and cholesterol or higher levels of high density lipoprotein.

13. A method for decreasing intestinal motility which comprises administering an effective amount of a compound of claim 1 to a patient in need of decreased intestinal motility.

14. - A method for reducing neogrogenic airway inflammation which comprises administering an effective amount of a compound of claim 1 to a patient in need of decreased neurogenic inflammation.

15. A method for the reduction of depression which comprises the adiection of an effective amount of a compound of claim 1 to a depressed patient.

16. A method for the treatment of gastrointestinal disorders which comprises administering an effective amount of a compound of claim 1 to a patient with gastrointestinal disorders. 17.- A composition for the. diabetes treatment? obesity or for the reduction of triglyceride or cholesterol levels or increase of high density lipoprotein levels, or for the decrease of intestinal motility or for the reduction of neogynous inflammation, or for the treatment of depression, or for the treatment of gastrointestinal disorders, which comprises an inert carrier and an effective amount of a compound of claim 1.