CA2288439C - Biphenylsulfonamides and derivatives thereof that modulate the activity of endothelin - Google Patents

Abstract

Biphenylsulfonamides and methods for modulating or altering the activity of the endothelin family of peptides are provided. In particular, N-(isoxazolyl)biphenylsulfonamides and methods using these sulfonamides for inhibiting the binding of an endothelin peptide to an endothelin receptor by contacting the receptor with the sulfonamide are provided.
Methods for treating endothelia-mediated disorders by administering effective amounts of one or more of these sulfonamides or prodrugs thereof that inhibit or increase the activity of endothelia are also provided. The biphenylsulfonamides have formula I:

where Ar2 is:

Description

BIPHENYL;SULFONAMIDES AND DERIVATIVES THEREOF
THAT MODULATE THE ACTIVITY OF ENDOTHELIN
This is a divisional application of Canadian Patent Application Serial No. 2,,217,169 filed on April 4, 1996.

FIELD OF THE INVEZJTION
The present invention relates to the compounds that modulate the acti~rity of the endothelin family of peptides. In particular, the invention relates to the use of sulfonamides and sulfonamide pro-drugs a;s endothelin agonists and antagonists.
The subject-matter of this divisional application is directed to biphenylsul:fonamides described more in detail hereinunder. The subject matter of the parent application was restricted to other compounds disclosed herein. However, it should be understood that the expression "the invention" and the like encompasses t:he subject-matter of both the parent and the divisional application.

BACKGROUND OF THE INVENTION
The vascular endothelium releases a variety of vasoactive substances, including the endothelium-derived vasoconstrictor peptide, endothel~Ln (ET) (see, e.g., Vanhoutte et al. (1986) Annual Rev. Physiol. 48: 307-320; Furchgott and Zawadski (1980) Nature 288: 373-3',i6). Endothelin, which was originally identified in the culture supernatant of porcine aortic endothelial cells (see, Yanagisawa et al. (1988) Nature 332:
411-415), is a potent twenty-one amino acid peptide vasoconstrictor. It is the most potent vasopressor known and is produced by numerous ce:l1 types, including the cells of the endothelium, trachea, kidney and brain.

Endothelin is syntlhesized as a two hundred and three amino acid precursor pre:proendothelin that contains a signal sequence which is cleaved by an endogenous protease to produce a thirty-eight (human) or tshirty-nine (porcine) amino acid peptide. This intermediate, referred 1:,o as big endothelin, is processed in vivo to the mature: biologically active form by a putative endothelin-converging enzyme (ECE) that appears to be a metal-dependent neutral prote;~se (see, eg., Kashiwabara et al. (1989) FEBS Lttrs. 247: a37-340). Cleavage is required for induction of physiological respon:aes (see, eg., von Geldern et al. (1991) Peptide Res. 4: 3~!-35). In porcine acrtic endothelial cells, the thirty-nine amino acid intermediate, big endothelin, is hydrolyzed at the Trp21-Valz2 bond to generate endothelin-1 and a C-terminal fragment. A similar cleavage occurs in human cells from a thirty-eigYit amino acid intermediate. Three distinct endothelin isopept:ides, endothelin-1, endothelia-2 and endothelia-3, that exhibit potent vasoconstrictor activity have been identified.
The family of three isopeptides endothelia-1, endothelia-2 and endothelin-3 are encoded by a family of three genes (see, Inoue et al. (1989) Proc. Natl.
Acad. Sci. USA 86: 2863-2867; see, also Saida et al. (1989)J. Biol. Chem.
264: 14613-146161. The nucleotide sequences of the three human genes are highly conserved within the region encoding the mature 21 amino acid peptides and the C-terminal portions of the peptides are identical. Endothelia-2 is (Trp6,Leu') endothelia-1 and endothelia-3 is (Thrz,Phe',ThrS,Tyr6,Lys',Tyr") endothelia-1. These peptides are, thus, highly conserved at the C-terminal ends.
Release of endothelins from cultured endothelial cells is modulated by a variety of chemical and physic<31 stimuli and appears to be regulated at the level of transcription and/or translation. Expression of the gene encoding endothelia-1 is increased by chemical stimuli, including adrenaline, thrombin and Caz' ionophore. The producaion and release of endothelia from the endothelium is stimulated by angiotensin II, vasopressin, endotoxin, cyclosporine and other factors (see, Brooks et al. (1 991 ) Eur. J. Pharm. 1 94:1 1 5-1 17), and is inhibited by nitric oxide. Endothelial cells appear to secrete short-lived endothelium-derived relaxing factora (EDRF), including nitric oxide or a related substance (Palmer et al. (1987) Mature 327: 524-5261, when stimulated by vasoactive agents, such as acetylcholine and bradykinin. Endothelia-induced vasoconstriction is also attenuated by atrial natriuretic peptide (ANP).
The endothelia ,peptides exhibit numerous biological activities in vitro and in vivo. Endothelia provokes a strong and sustained vasoconstriction in vivo in rats and in isolated va~~cular smooth muscle preparations; it also provokes the release of eicosanoids and endothelium-derived relaxing factor (EDRF) from perfused vascular beds. Intravenous administration of endothelia-1 and in vitro addition to vascular and other smooth muscle tissues produce long-lasting pressor effects and contraction, respectively (see, e-a., Bolger et al. (1991 ) Can.
J. Phvsiol. Pharmacol. 69: 40Ei-4131. In isolated vascular strips, for example, endothelia-1 is a potent (ECS° _= 4 x 10''° M1, slow acting, but persistent, contractile agent. In v_ivo, a single dose elevates blood pressure in about twenty to thirty minutes. Endothelia-induced vasoconstriction is not affected by antagonists to known neurotransmitters or hormonal factors, but is abolished by calcium channel antagonists. The effect of calcium channel antagonists, however, is most likely the result of inhibition of calcium influx, since calcium influx appears to be required for the long-lasting contractile response to endothelia.
Endothelia also mediates renin release, stimulates ANP release and induces a positive inotropic acaion in guinea pig atria. In the lung, endothelia-1 acts as a potent bronchoconstrictor (Maggi et al. (1989) Eur. J. Pharmacol.
160:
179-1821. Endothelia increases renal vascular resistance, decreases renal blood flow, and decreases glomerular filtrate rate. It is a potent mitogen for glomerular mesangial cells and invokes the phosphoinoside cascade in such cells (Simonson et al. (1990) J. Clin. Invest. 85: 790-797).
There are specific high affinity binding sites (dissociation constants in the range of 2-6 x 10-'° fVl) for the endothelins in the vascular system and in other tissues, including the intestine, heart, lungs, kidneys, spleen, adrenal glands and brain. Binding is not inhibited by catecholamines, vasoactive peptides, neurotoxins or calcium channel antagonists. Endothelia binds and interacts with receptor sites that are distinct from other autonomic receptors and voltage dependent calcium ch~3nnels. . Competitive binding studies indicate that there are multiple classes of receptors v~rith different affinities for the endothelia isopeptides. The saravfotoxins, a group of peptide toxins from the venom of the snake Atractaspis einqadensis that cause severe coronary vasospasm in snake bite victims, have structural and functional homology to endothelia-1 and bind competitively to the same cardiac membrane receptors (Kloog et al. (1989) Trends Pharmacol. Sci, 10: 21.2-214).
Two distinct endothelia receptors, designated ETA and ETe, have been identified and DNA clones encoding each receptor have been isolated (Arai _et _a1.
(1990) Nature 348: 7:I0-732; ;5akurai et al. (1990) Nature 348: 732-7351.
Based on the amino acid sequences of the proteins encoded by the cloned DNA, it appears that each receptor contains seven membrane spanning domains and exhibits structural similarity to 'G-protein-coupled membrane proteins.

_7_ Messenger RNA encoding both receptors has been detected in a variety of tissues, including heart, lung, kidney and brain. The distribution of receptor subtypes is tissue :specific 1'Martin et al. ( 19891 8iochem. Bioohvs Res Commun. 162: 13e7-137). ET" receptors appear to be selective for endothelia-1 and are predominant in cardiovascular tissues. ET9 receptors are predominant in noncardiovascular tissues, including. the central nervous system and kidney, and interact with the three endcthelin isopeptides (Sakurai et al. (1990) Nature 348:
732-734). In additcon, ET,, receptors occur on vascular smooth muscle, are linked to vasoconstriction and have been associated with cardiovascular, renal and central nervous system diseases; whereas E T 9 receptors are located on the vascular endothelium, linkecl to vasodilation (Takayanagi et al. (1991 ) FE3S
Lttrs. 282: 103-lOEi) and have been associated with bronchoconstrictive disorders.
By virtue of t:he distribution of receptor types and the differential affinity of each isopeptide for each receptor type, the activity of the endothelia isopeptides varies in different tissues. For example, endothelia-1 inhibits 'isl-labelled endothelia-1 binding in cardiovascular tissues forty to seven hundred times more potently than endothelia-3. 'Z51-labelled endothelia-1 binding in non-cardiovascular tissue's, such as kidney, adrenal gland, and cerebellum, is inhibited to the samE: extent by endothelia-1 and endothelia-3, which indicates that ET" receptors predominate in cardiovascular tissues and ETB receptors predominate in non-c;ardiova~~cular tissues.
Endothelia plasma levels are elevated in certain disease states (see, e.g , International PCT Application WO 94!27979, and U.S. Patent No. 5,382,569) .
Endo thelin-1 plasma level:; in heah:hy individuals, as measured by radioimmunoassay (RIA), are about 0.2Ei-5 pg/ml. Blood levels of endothelia-1 and its precursor, big endothelia, are elevated in shock, myocardial infarction, vasospastic angina, kidney failure and a variety of connective tissue disorders. In patients undergoing hemodial~,rsis or kidney transplantation or suffering from cardiogenic shock, myocardial infarction or pulmonary hypertension levels as high as 35 pglml have been obsE~rved (see, Stewart et al. (1991) Annals Internal Med.
114:

_g_ 464-469). Because endothelia is likely to be a local, rather than a systemic, regulating factor, it is probable that the levels of endothelia at the endo-thelium/smooth muscle interface are much higher than circulating levels.
Elevated levels of endothelia have also been measured in patients suffering from ischemic heart disease (Yasuda et al. (19901 Amer. Heart J.
1 19:801-806, Ray e~_ al. (1992) Br. Heart J. 67:383-386). Circulating and tissue endothelia immunoreactivity is increased more than twofold in patients with advanced atherosclerosis (Lerman et al. (1991 ) New Engl. J. Med.
325:997-1001 ). Increased endothelia immunoreactivity has also been asscciated with Buerger's disease (Kanno et al. (1990) J. Amer. Med. Assoc. 264:2868) and Raynaud's phenomenon (Zamora et al. ( 1 990) Lancet 336 1 144-1 147).
Increased circulating endothelia levels were observed in patients who underwent percutaneous translurninal coronary angioplasty (PTCA) (Tahara et al. (1991 ) Metab. Clin. Ex~. 40:1235-12'37; Sanjay et al. (1991 ) Circulation 84(Suppl.
4:726), and in individuals (Miyauchi et al. (1992) Jpn. J. Pharmaco1.58:279P;
Stewart et al. (1 991 ) Ann.lnternal Medicine 1 14:464-4691 with pulmonary hypertension. Thus, there is clinical human data supporting the correlation between increased endothelia levels and numerous disease states.
Endothelia agonists and antagonists Because endothelia is associated with certain disease states and is implicated in numerous physiological effects, compounds that can interfere with or potentiate endothelia-associated activities, such as endothelia-receptor interaction and vasoconstrictor activity, are of interest. Compounds that exhibit endothelia antagonistic activity have been identified. For example, a fermentation product of Streptomvces misakiensis, designated BE-182578, has been identified as an f=T,, receptor antagonist. BE-182578 is a cyclic pentapeptide, cyclo(D-Glu-L-Ala-alto-D-Ile-L-Leu-D-Trp), which inhibits '251-labelled endothelia-1 binding in cardiovascular tissues in a concentration-dependent manner (ICSa 1.4 NP/1 in aortic smooth muscle, 0.8 NM in ventricle membranes and 0.5 NM in cultured aortic smooth muscle cells), but fails to inhibit binding to receptors in tissues in which ETB receptors predominate at concentrations up to 100 NM. Cyclic pentapeptides related to BE-182578, such _g_ as cyclofD-Asp-Pro-D-Vaf-Leu-D-Trp/ (BQ-1231, have been synthesized and shown to exhibit activity as ETA receptor antagonists fsee, U.S. Patent No.
5,1 14,918 to Ishikawa et al.,; see, also, EP A1 0 436 189 to BANYU
PHARMACEUTICAL CO., LTD (October 7, 1991 )/. Studies that measure the inhibition by these cyclic peptides of endothelia-1 binding to endothelia-specific receptors indicate that these cyclic peptides bind preferentially to ETA
receptors.
Other peptide and non-pepticlic ETA antagonists have been identified (see, e.4., 5,352,800, 5,334,598, 5,3Ei2,659, 5,248,807, 5,240,910, 5,198,548, 5,187,195, 5,082,838). These include other cyclic pentapeptides, acyltripeptides, hexapeptide ;analogs, certain antraquinone derivatives, indanecarboxylic acid's, certain N-pyriminylbenzenesulfonamides, certain benzenesulfonamides, and certain naphthalenesulfonamides (Nakajima et al.
(1991 ) J. Antibiot. 44:1348-1356; Miyata et al. (1992) J. Antibiot. 45:74-8;
Ishikawa et al. (199:'.) J.Med. Chem. 35:2139-2142; U.S. Patent No.
5,114,918 to Ishikawa et al.;; EP A1 0 569 193; EP A1 0 558 258; EP A1 0 436 189 to BANYU PHARMACEUTICAL CO., LTD (October 7, 1991 ); Canadian Patent Application 2,067,288; Canadian Patent Application 2,071,193; U.S.
Patent No. 5,208,213; U.S. Patent No. 5,270,313; U.S. Patent No. 5,464,853 to Chan et al.; Cody et al. (1993) Med. Chem. Res. 3:154-162; Miyata et al.
(1992) J. Antibiot 4~i:1041-1046; Miyata et al. (1992) J. Antibiot _45:1029-1040, Fujimoto et al. (1992) FEBS Lett. 305:41-44; Oshashi et al. (1002) J.
Antibiot 45:1684-1685; EP A,1 0 496 452; Clozel et al. (1993) Nature 365:759-761; International Patent Application W093/08799; Nishikibe et al. (1993) Life Sci. 52:717-724; and Benigni et al. (1993) Kidnev Int. 44:440-444). In general, the identified compounds have activities in in vitro assays as ETA antagonists at concentrations on the: order of about 50-100 NM or less. A number of such compounds have also been shown to possess activity in in vivo animal models.
Very few selective El-a antagonists have been identified.
Endothelia antagonists and agonists as therapeutic agents It has been recognized that compounds that exhibit activity at ICso or ECso concentrations on the order of 10-' or lower in standard in vitro assays that assess endothelia antagonist or agonist activity have pharmacological utility (see, e-a., U.S. Patent Nos. 6,352,800, 5,334,598, 5,352,659, 5,248,807, 5,240,910, 5,198,548, 5,187,195, 5,082,8381. By virtue of this activity, such compounds are considered to be useful for the treatment of hypertension such as peripheral circulatory failure, heart disease such as angina pectoris, cardio-myopathy, arteriosclerosis, myocardial infarction, pulmonary hypertension, vasospasm, vascular restenoais, Raynaud's disease, cerebral stroke such as cerebral arterial spasm, cerebral ischemia, late phase cerebral spasm after subarachnoid hemorrhage, asthma, bronchoconstriction, renal failure, particularly post-ischemic renal failure, cyclosporine nephrotoxicity such as acute renal failure, colitis, as well as other inflammatory diseases, endotoxic shock caused by or associated with endoth~elin, and other diseases in which endothelia has been implicated.
In view of the numerous physiological effects of endothelia and its asso-ciation with certain diseases, endothelia is believed to play a critical role in these pathophysiological conditions Isee, e-g., Saito et al. (19901 Hypertension _15:
734-738; Tomita et y1. (1989) N. Engl. J. Med. 321: 1 127; Kurihara et al (1989) J. Cardiovasc. Pharmacol. 131Suool. 51: S13-S17; Doherty (1992) J.
Med. Chem. 35: 1493-1508; Morel et al. (1989) Eur. J. Pharmacol. 167: 427-428). More detailed knowledge of the function and structure of the endothelia peptide family should provide insight in the progression and treatment of such conditions.
To aid in gaining further understanding of and to develop treatments for endothelia-mediated or related disorders, there is a need to identify compounds that modulate or alter endothc;lin activity. Identification of compounds that modulate endothelia activity, such as those that act as specific antagonists or agonists, may not only aid in .elucidating the function of endothelia, but may yield in therapeutically useful compounds. In particular, compounds that specifically interfere with the interaction of endothelia peptides with the ET,, or ETB receptors should be useful in identifying essential characteristics of endothelia peptides, should aid in the design of therapeutic agents, and may be useful as disease specific therapeutic agents.

_11_ Therefore, it is an object herein to provide compounds that have the ability to modulate the biological activity of one or more of the endothelia isopeptides. It is another object to provide compounds that have use as specific endothelia antagonists. It is also an object to use compounds that specifically interact with or inhibit the interaction of endothelia peptides with ETA or ETB
receptors. Such compounds should be useful as therapeutic agents for the treatment of endothelia-mediated diseases and disorders and also for the identification of endovthelin receptor subtypes.

Sulfonamides ~3nd methods for modulating the interaction of an endothelia peptide v~ith ETA and/or ET8 receptors are provided. In particular, sul-fonamides and methods for inhibiting the binding of an endothelia peptide to ETA
or ET8 receptors are provided. The methods are effected by contacting the receptors with one or more sulfonamides prior to, simultaneously with, or subsequent to contacting the receptors with an endothelia peptide. The sulfona-mides are substituted or unsubstituted monocyclic or polycyclic aromatic or heteroaromatic sulfonamides, such as benzene sulfonamides, naphthalene sul-fonamides and thiophene sulfonamides. Particularly preferred sulfonamides are N-isoxazolyl sulfonamides. More particularly preferred among such sulfonamides are those in which Arr~ is a heterocycle that contains one ring, multiple rings or fused rings, typically two or three rings and one or two heteroatoms in the ring or nags.
The sulfonamides have formula I:
Ar2 S02 I~- Ar' t fl) in which Ar' is a substituted or unsubstituted aryl group with one or more substituents, including an alkyl group, an aryl group, a substituted aryl group. a vitro group, an amino group or a halide or is an alkyl group. In particular, Ar' is alkyl or is a five or six membered substituted or unsubstituted aromatic or heteroaromatic ring, particularly 3- or 5- isoxazolyl and pyridazinyl, and also including thiazolyl, including 2-thiazolyl, pyrimidinyl, including 2-pyrimidinyl, or WO 96131492 PCTlUS96/04759 substituted benzene groups, including aryloxy substituted benzene groups or is a bicyclic or tricyclic carbon or heterocyclic ring.
Ar' is, in certain embodiments, selected from groups such as:
R R R
N
° .
R H R N_N . /
R
50~ NN ~ S
R \ I I
o R ~ . N ~R
.
R
R R
/ /
and " T
~o N r and R is selected from H, NHz,, halide, pseudohalide, alkyl, alkylcarbonyl, formyl, an aromatic or hetero;sromatic group, alkoxyalkyl, alkylamino, alkylthio, arylcarbonyl, aryloxy, arylamino, arylthio, haloalkyl, haloaryl, carbonyl, in which the aryl and alkyl portions, are unsubstituted or substituted with any of the preceeding groups, and straight or branched chains of from about 1 up to about 10-12 carbons, preferably, 1 to about 5 or 6 carbons. R is preferably H, NH2, halide, CH3, CH30 or another aromatic group. Arz is any group such that the resulting sulfonamide inhibits binding by 50%, compared to binding in the absence of the sulfonamide, o1' an endothelin peptide to an endothelin receptor at a concentration of less than about 100 NM, except that Are is not phenyl or naphthyl when Ar' is IV-(5-isoxazolyl) or N-(3-isoxazolyl) unless the isoxazole is a 4-halo-isoxazole, a 4-higher alW;yl (CB to C,5)-isoxazole, or the compound is a 4-biphenyl that is unsubstituted .at the 2 or 6 position on the sulfonamide-linked phenyl group.
In the embodiments described in detail herein, Ar' is an isoxazole and compounds are represented by the formulae II:

R' R' R' R
Af? SO~ N ~ ~ N or. Af? SO~ N ~ ~ O
I O I N (1l) H H
in which R' and R~ are either (i), (ii) or (iii) as follows:
(i) R' and R2 are: each independently selected from H, NHz, NOz, halide, pseudohalide, alkyl, alkenyl, alkynyl, aryl, arylalkyl, heteroaryl, alkoxy, alkylamino, alkylthio, alkyloxy, haloalkyl, alkylsufinyl, alkylsulfonyl, aryloxy, arylamino, arylthio, arylsufinyl, arylsulfonyl, haloalkyl, haloaryl, alkoxycarbonyl, alkylcarbonyl, aminoc:arbonyl, arylcarbonyl, formyl, substituted or unsubstituted amido, substituted or unsubstituted ureido, in which the alkyl, alkenyl and alkynyl portions contain from 1 up to about 14 carbon atoms and are either straight or branched chains or cyclic, and the aryl portions contain from about 4 to about 16 carbons, except that Rz is not halide or pseudohalide; or, (ii1 R' and RZ together form -fCH2)", where n is 3 to 6; or, (iii) R' and Rz together form 1 ,3-butadienyl, and with the above proviso that Ar2 is not phenyl or naphthyl when Ar' is N-(5-isoxazolyl) or N-(3-isoxazolyl) unless the isoxazole is a 4-halo-isoxazole, a higher alkyl (C8 to C,.;)-isoxazole, or the compound is a 4-biphenylsulfonamide that is unsubstituted at the 2 or 6 position on the sulfonamide-linked phenyl group.
In preferred embodiments herein, R' and R2 are each selected independently from a~~nong alkyl, lower alkenyl, lower alkynyl, lower haloalkyl, halide, pseudohalide or H, except that RZ is not halide;
Arz is any group such that the resulting sulfonamide inhibits binding by 50%, compared to binding in the absence of the sulfonamide, of an endothelia peptide to an endothe;lin receptor at a concentration of less than about 100 NM, with the above proviso. In particular, Are is a substituted or unsubstituted group selected from among groups including, but not limited to, the following:

WO 96!31492 PCTlLTS96/04759 naphthyl, phenyl, biphenyl, quinolyl, styryl, thienyl, fury!, isoquinolyl, pyrrolyl, benzofuranyl, pyridinyl, thionaphthalyl, indolyl, alkyl, and alkenyl. It is understood that the positions indicated for substituents, including the sulfona-mide groups, may be varied. Thus, for example, compounds herein encompass groups that include thiophene-3-sulfonamides and thiophene-2-sulfonamides.
In certain embodiments described in detail herein, Are is a 4-biphenyl or is a single ring heterocycle, particularly a 5-membered ring, or is a fused bicyclic or tricyclic heterocycle that contains one or or more, particularly one, heteroatom selected from S, O and NR°~,, in the ring, where R°Z contains up to about 30 carbon atoms, preferably 1 to 10, more preferably 1 to 6 and is selected from hydrogen, alkyl, alke~nyl, alkynyl, aryl, alkylaryl, heterocycle, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl, C(0)R'S and S10)"R'S in which n is 0-2;
R'S is hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, heterocycle, aralkyl, aralkoxy, cycloalkyl, cycloalk.enyl, cycloalkynyl; R°Z and R'S are unsubstituted or are substituted with one or more substituents each selected independently from Z, which is hydrogen, halide, pseudoahlide, alkyl, alkoxy, alkenyl, a(kynyl, aryl, heterocycle, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl, OH, CN, C(0)R'6, COzR'6, SH, S(O)"R'6 in which n is 0-2, NHOH, NR'~R'6, NOz, N~, OR'6, R'~NCOR'6 and CONR'~R'6; R'6 is hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, heterocycle, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl or cycloalkynyl;
R'~, which is selected independently from R°Z and Z, is selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, heterocycle, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl, C(O)R" and S(O)"R" in which n is 0-2; and R" is hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, heterocycle, aralkyl, aralkoxy, cycloalkyl, cycloalkeinyl or cycloalkynyl; each of R°2, R'2, R'S and R'6 may be fur-ther substituted with the any of the groups set forth for Z.
In preferred embodiments herein, R'z is aryl, such as phenyl or alkyl phenyl, hydrogen or loweralkyl.
Thus, in the compounds provided herein ArZ includes thienyl, fury! and pyrrolyl, benzofuryl, benzopyrolyl, benzothienyl, benzo(b]fury!, benzo[b]thienyl, and indolyl (benzo(b],pyrrolyl) and 4-biphenyl, and Ar' is preferably N-(5 isoxazolyl) or N-(3-isoxazolyl). The sulfonamides are N-isoxazolyl sulfonamides and the compounds have either have formula III:
R~ R' ,o R R~
R~o R
R. -i~
I ~~~ so= N ~ , o R~~SO= N ~O~N R ~ I N
H x H
in which X is S, O or NR" in which R" contains up to about 30 carbon atoms, preferably 1 to 10, more preferably 1 to 6 and is selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, heterocycle, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl, C(O)R'S and S(O)"R'S in which n is 0-2; R'S is hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, heterocycle, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl; R" and R'S are unsubstituted or are substituted with one or more substituents each selected independently from Z, which is hydrogen, halide, pseudoahlide, alkyl, alkoxy, alkenyl, alkynyl, aryl, heterocycle, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl, OH, CN, C(O)R'6, COZR'6, SH, S(O)"R'6 in which n is 0-2, NHOH, NR'~R'6, NO2, N,, OR's, R'ZNCOR'6 and CONFI'~R'6; R'6 is hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, heterocycle,. aralkyl, aralkoxy, cycloalkyl, cycloalkenyl or cycloalkynyl;
R'Z, which is selectea' independently from R" and Z, is selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, heterocycle, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl, C(0)R" and S(O)"R" in which n is 0-2; and R" is hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, heterocycle, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl or cycloalkynyl; each of R", R'~, R'S and R'6 may be fur-ther substituted with the any of the groups set forth for Z, and R" is preferably hydrogen, aryl, such as phenyl or alkyl phenyl, loweralkyl;
or the compounds are are 4-biphenylsulfonides in which Ar' is preferably N-(5-isoxazolyl) or N-(3-isoxazolyl.
Among the embodiments described in detail herein, Are is thienyl, furyl, pyrrolyl or a group that is a derivative or analog, as described below, of a thienyl, furyl or pyrrolyl group, including benzo(b] derivatives such as a benzo[b]-thienyl, Ar' is N-(5-isoxazolyl) or N-(3-isoxazolyl). Are has the formula IV:

R~o R,o R.
~a 3 or ~.~ 3T
R 5 t ~ R. R 5 t X X
A g in which X is O, S or NR", where R" is as defined above;
that can be substituted at any or all positions or is an analog or derivative ef the groups of formula (IV) in which the substituents form fused aromatic, aliphatic or heterocyclic rings; and Re, R9 and R'° are each independently selected as follows from (i1 or (ii):
(i) R8, 1~9 and R'°, which each contain hydrogen or up to about 50 carbon atoms, generally up to about 30, more generally 20 or fewer, are each independently selected from hydrogen, halide, pseudohalide, alkyl, alkoxy, alkenyl, alkynyl, aryl, aryloxy, heterocycle, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl, 0~1, CN, C(O)R'8, (OAC)CH=CHR'e-, COzR'e, SH, (CH2),C(O)(CHz)"R'e, (CHz),(CHI=CH),(CHZ)"R'8, (CH~),C(O)(CH=CH),(CHz)"R'8, (CHz),(CH=CH),C(O)(I~Hz)"R'8, (CH2),NH(CH=CH),(CHz)"R'8, C=N(OHI(CHz),R'a (CHz),(CH=CH)~NH(CI-Iz)"R'e, I'CHz),C(O)NH(CHz)"R'e, C(OI(CHz),NH(CHz)"R'e, (CHz),NH[CHz)"R'e, (CHz),R'8, :i(OImR'8 in which m is 0-2, s, n and r are each independently 0 to 6, preferably 0-3, HNOH, NR'8R'9, N02, N~, OR'e, R'9NCOR'e and CONR'9R'°, in which R'9 is selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, alkoxy, aryloxy, heterocycle, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl, C(t))RZ°, S(O)~R~° in which n is 0-2; and R'e and R2°
are independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, alkylaryl, h~eterocyc;le, alkoxy, aryloxy, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl or cycloalkynyl; and any of the groups set forth for R8, R9 and R'°
are unsubstituted or substituted with any substituents set forth for Z, which is hydrogen, halide, pseudoahlide, alkyl, alkoxy, alkenyl, alkynyl, aryl, aryloxy, heterocycle, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl, OH, CN, C(O)RD', COiR2', SH, 'S(0)~R2' in which n is 0-2, NHOH, NRZZRZ', NOz, N3, ORZ', RZZNCORZ' and CONR~ZRz'; RZ' is selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, heteroc:ycle, aralkyl, alkoxy, aralkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl,~ C(O)RZ' and S(O)"Rz' in which n is 0-2; and Rz' and RZ' are independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, heterocycle, aralkyl, ~~ralkoxy, cycloalkyl, cycloalkenyl or cycloalkynyl, with the proviso that if R8 is NR'8R'9, OR'8, R'9NCOR'8 and CONR'9R'e COzR'8, (CHZ),NH(CH=CH),(CI-I21"R'8, I'CHZ),(CH=CH),NH(CH~)"R'e, (CHz),C(OINH(CH2)"R"3, C(O)(C:Hz),NH(CH~)"R'e, (CH~),NH(CH~)"R'8 or (CH2),R'8 and R'e is an aryl group containing 5 or 6 members, then the aryl group has at least two substituent;~, and preferably one substituent at the 2-position relative to the linkage to the thienyl, furyl or pyrrolyl;
(ii) any 'two of R8, R9 and R'° with the carbon to which each is attached form an aryl, aromatic ring, heteroaromatic ring, carbocyclic or heterocyclic ring, which is saturated or unsaturated, containing from about 3 to about 16 members, preferably 3 to about 10 members, more preferably 5 to 7 members that is substituted with one or more substituents, each substituent is independently selected from Z; the other of R°, R9 and R'° is selected as in (i);
and the heteroatoms are NR", O, or S, with the proviso that Ar2 is not 5-halo-loweralkylbenzo[b]thienyl, 5-halo-3-loweralkylbenzo(b]furyl, 5-halo-3-loweralkylbenzo[b]pyrrolyl.
In the embodiments provided herein, the alkyl, alkynyl and alkenyl portions of each listed substitupnt are straight or branched chains, acyclic or cyclic, and preferably have fronn about 1 up to about 10 carbons; in more preferred embodiments they have from 1-6 carbons. The aryl, alicyclic, aromatic rings and het:erocyclic; groups can have from 3 to 16, generally, 3-7, more often 5-7 members in thc: rings, and may be single or fused rings. The ring size and carbon chain length are selected up to an amount that the resulting molecule binds and retains actiivity as an endothelia antagonist or agonist, such that the resulting compound inhibits binding by 50%, compared to binding in the absence of the sulfonamide, of an endothelia peptide to an endothelia receptor at a concentration of less than about 100 NM.
In preferred embodiments of interest herein, R9 and R'° are hydrogen, halide or methyl, more preferably hydrogen or halide, and RB is selected from 77718-14D(S) C02R18 , ( CH2 ) rC ( O ) ( CH2 ) nRls ~ ( CH2 ) r ( CH=CH ) s ( CH2 ) nRla C=N (OH) (CH2) rRlB, (CH2) rC (O) (CH=CH) g (CH2) nRle, ( CH2 ) r ( CH=CH ) gC ( O ) ( CHZ ) nRla , ( CH2 ) rNH ( CH=CH ) S ( CH2 ) nRls , ( CH2 ) r ( CH=CH ) sNH ( CH2 ) nRla , ( CH2 ) rC ( O ) NH ( CH2 ) nRl a , C (O) (CH2) rNH (CH2) nRle, (CH2) rNH (CH2) nRls, (CH2) rRle, With the proviso that if Re is CO2R18, (CH2) rC (O) NH (CH2) nRle, C ( O ) ( CH2 ) rNH ( CH2 ) nRle , ( CH2 ) rC ( O ) NH ( CH2 ) nRls or ( CH2 ) rRlB and Rls is phenyl, the phenyl group is substituted at at least two positions, and preferably, at least one of those positions is ortho.
In the preferred compounds, R18 is aryl or heteroaryl, preferably having 5 or 6 members in the ring, more preferably phenyl or pyrimidinyl, most preferably phenyl.
In the most preferred compounds herein, R1$ is phenyl, which is substituted at more than one position, and most preferably at least one substituent is at the ortho position, R9 and R1° are each hydrogen, halide or lower alkyl, preferably hydrogen, and R8 is C (O) NHR18, C (O) CH2R18, (CH2) Rle, with the proviso that if R8 is C (O) NHRlB, then the phenyl group must have at least two substituents, preferably one of the substituents is in the ortho position.
In other preferred embodiments, Ar2 is a benzo [b] thienyl, benzo [b] furyl, or indolyl (benzo[b]pyrrolyl), with the proviso that the benzene ring is substituted and the substituents are other than 5 halo, 3-loweralkyl. Preferred substituents on the benzene ring, include, but are not limited to, one or more selected from alkylenedioxy, particularly methylenedioxy, preferably 3,4-methylenedioxy, ethylenedioxy, aryl, particularly phenyl, dimethylamino, diethylamino, benzyl, alkoxy, particularly 77718-14D(S) 18a lower alkoxy, such as methoxy and ethoxy, halide, and alkyl, preferably lower alkyl.
In the preferred compounds herein, R2 is preferably, selected from among alkyl, lower alkenyl, lower alkynyl, lower haloalkyl or H; and R1 is halide or lower alkyl, and more preferably, R1 is bromide or chloride, methyl or ethyl. In the most active compounds provided herein, as evidenced by in vitro binding assays, R1 is bromide or chloride. For use in vivo R1 is preferably chloride.
In a particularly preferred embodiment, the invention provides a compound or a pharmaceutically acceptable salt, acid or ester thereof, that has formula VII:
,a Ru \ R' Rz I \ R' R' /
\ SO-N ~ N ~~ SO; N ~ ~O
I s R I N
/ I O / H
H
R (VII) wherein the biphenyl group is substituted with one or more than one R13 substituent, each independently selected from Cl_salkyl and haloalkyl; R26 is hydrogen; and R1 and RZ are each independently selected from halide and alkyl, in which the alkyl portion contains from 1 to 14 carbon atoms and is either straight or branched chain or is cyclic, except that R2 is not halide; and with the proviso that the compound of formula VII is a 4-biphenyl-sulfonamide that is substituted with hydrogen at the 2 and 6 positions of the sulfonamide-linked phenyl group.
The invention further provides a pharmaceutical composition, comprising a compound as described above, or a 77718-14D(S) 18b pharmaceutically acceptable salt, acid or ester thereof, in a pharmaceutically acceptable carrier.
The invention further contemplates use of one or more compounds as described above, or pharmaceutically acceptable salts, acids or esters thereof, for inhibiting the binding of an endothelin peptide to endothelinA (ETA) or endothelinB (ETB) receptors, or for altering endothelin receptor-mediated activity.
The invention also provides a pharmaceutical composition formulated for single dosage administration, comprising an effective amount of one or more compounds as described above, or pharmaceutically acceptable salts, acids or esters thereof, wherein the amount is effective for ameliorating the symptoms of an endothelin-mediated disease.
The invention also provides an article of manufacture comprising packaging material and an effective amount of one or more compounds as described above, or pharmaceutically acceptable salts, acids or esters thereof, contained within the packaging material, wherein the compound is effective for antagonizing the effects of endo-thelin, ameliorating the symptoms of an endothelin-mediated disorder, or inhibiting the binding of an endothelin peptide to an ET receptor with an ICso of less than about 10 ~M, and the packaging material includes a label that indicates that the sulfonamide or salt thereof is used for antagonizing the effects of endothelin, inhibiting the binding of endothelin to an endothelin receptor or treating an endothelin-mediated disorder.
The invention also extends to use of a compound as described above, or a pharmaceutically acceptable salt, acid or ester thereof, for formulation of a medicament for treatment of an endothelin-mediated disorder.

77718-14D(S) 18c The invention further extends to use of a compound as described above, or a pharmaceutically acceptable salt, acid or ester thereof, for treatment of an endothelin-mediated disorder.
Of the compounds described herein, those that inhibit or increase an endothelin-mediated activity by about 50% at concentrations of less than about WO 9G/31492 PCTlLJS96/04759 NM are preferred. More preferred are those that inhibit or increase an endothelin-mediated activity by about 50% at concentrations of less than about 1 NM, more preferably less than about 0.1 NM, even more preferably less than about 0.01 NM, and most preferably less than about 0.001 NM. It is noted 5 that, as described below, the ICS° concentration determined in the in vitro assays is a non-linear function of incubation temperature. The preferred values recited herein refer to the assays that are performed at 4° C. When the assays are performed at 24° C, somewhat higher (see, Table 1 ) ICS°
concentrations are observed. Accordingly, the preferred ICS° concentrations are about 10-fold 10 higher.
Also among the most preferred compounds for use in methods provided herein, are those that are ET" selective, i.e., they interact with ET"
receptors at substantially lower concentrations (at an ICS° at least about 10-fold lower, preferably 100-fold lower) than they interact with ET8 receptors. In particular, compounds that interact with ET" with an ICS° of less than about 10 NM, preferably less than 1 NM, more preferably less than 0.1 NM, but with ETB with an ICS° of greater than about about 10 NM or compounds that interact with ETB
with an ICS° of less than about 10 NM, preferably less than 1 NM, more preferably less than 0.1 NM, but with ET" with an ICS° of greater than about 10 NM are preferred.
Preferred compounds also include compounds that are ETe receptor selective or that bind to ETB receptors with an ICS° of less than about 1 NM. ETe selective compounds interact with ETB receptors at ICS° concentrations that are at least about 10-fold lower than the concentrations at which they interact with ET,, receptors. In theae compounds, R~ is selected from among alkyl, lower alkenyl, lower alkynyl, lower haloalkyl, halide or H; and R' is halide or loweralkyl, and in preferred embodiments,, R' is bromide or chloride, preferabaly chloride; R9 and R'° are selected independently from hydrogen, loweralkyl, preferably methyl or ethyl, or halide, and Re, which is the substituent at the 5-position (see, e_g., formulae III and IV1, is aryl or a heterocycle, particularly phenyl and isoxazolyl, which are unsubstituted or substituted with Z, which is preferably loweralkyl or halide.

Pharmaceutical compositions formulated for administration by an appropriate route and means containing effective concentrations of one or more of the compounds provided h~srein or pharmaceutically acceptable salts or acids thereof that deliver amounts Effective for the treatment of hypertension, stroke, asthma, shock, ocular hypertension, glaucoma, renal failure, inadequate retinal perfusion and other conditions that are in some manner mediated by an endothelia peptide or that involve vasoconstriction or whose symptoms can be ameliorated by administration of an endothelia antagonist or agonist, are also provided. Particularl~~ preferred compositions are those that deliver amounts effective for the treatment of hypertension or renal failure. The effective amounts and concentrations are effective for ameliorating any of the symptoms of any of the disorders.
Methods for inhibiting binding of an endothelia peptide to an endothelia receptor are provided. These methods are practiced by contacting the receptor with one or more of the compounds provided herein simultaneously, prior to, or subsequent to contacting the receptor with an endothelia peptide.
Methods for trE:atment of endothelia-mediated disorders, including but not limited to, hypertension, aathma, shock, ocular hypertension, glaucoma, inadequate retinal perfusion and other conditions that are in some manner mediated by an endothelia peptide, or for treatment of disorder that involve vasoconstriction or th~3t are ameliorated by administration of an endothelia antagonist or agonist ~jre provided.
In particular, methods of treating endothelia-mediated disorders by administering effective: amounta of the sulfonamides, prodrugs or other suitable derivatives of the sulfnnamide~; are provided. (n particular, methods for treating endothelia-mediated disorders, including hypertension, cardiovascular diseases, cardiac diseases including myocardial infarction, pulmonary hypertension, erythropoietin-mediated hypertension, respiratory diseases and inflammatory diseases, including asthma, bronchoconstriction, ophthalmologic diseases, gastroenteric diseases, renal failure, endotoxin shock, menstrual disorders, obstetric conditions, wounds, anaphylactic shock, hemorrhagic shock, and other diseases in which endothelia mediated physiological responses are implicated, by administering effective amounts of one or more of the compounds provided herein in pharmaceutically acceptable carriers are provided. Preferred methods of treatment are methods for treatment of hypertension and renal failure.
More preferred methods of treatment are those in which the compositions contain at least one compound that inhibits the interaction of endothelia-1 with ETA receptors at an ICso of less than about 10 NM, and preferably less than about 5 NNt, more preferably less than about 1 NM, even more preferably less than 0.1 NM, and most preferably less than 0.05 NM
Other preferred methods are those in which the compositions contain one or more compounds that is (are) ETA selective or one or more compounds that is (are) ETB selective. Methods in which the compounds are ETA selective are for treatment of disorders, such as hypertension; and methods in which the compounds are ET8 selective are for treatment of disorders, such as asthma, that require bronchodilation.
In practicing the methods, effective amounts of compositions containing therapeutically effective concentrations of the compounds formulated for oral, intravenous, local and topical application for the treatment of hypertension, cardiovascular diseases, cardiac. diseases, including myocardial infarction, respiratory diseases, including asthma, inflammatory diseases, ophthalmologic diseases, gastroenteric diseases, renal failure, immunosuppressant-mediated renal vasoconstriction, erythropoietin-mediated vasoconstriction, endotoxin shock, anaphylactic shock, hemorrhagic shock, pulmonary hypertension, and other diseases in which endothe~lin mediated physiological responses are implicated are administered to an individual exhibiting the symptoms of one or more of these disorders. The amounts are effective to ameliorate or eliminate one or more symptoms of the disorders.
Methods for the identification and isolation of endothelia receptor subtypes are also provided. In particular, methods for detecting, distinguishing and isolating endothelia receptors using the disclosed compounds are provided.
In particular, methods are provicled for detecting, distinguishing and isolating endothelia receptors using the compounds provided herein.

In addition, methods for identifying compounds that are suitable for use in treating particular diseases. based on their preferential affinity for a particular endothelia receptor :subtype are also provided.
Articles of manufacture containing packagir~, material, a compound provided herein, which is effective for ameliorating the symptoms of an endothelia-mediated disorder, antagonizing the effects of endothelia or inhibiting binding of an endothelia peptide to an cT receptor with an ICso of less than about 10 NM, within the pac~;aging material, and a label that indicates that the compound or salt thereof is used for antagonizing the effects of endothelia, treating an endothelia-mediated disorder, or inhibiting the binding of an endothelia peptide to an ET rs:ceptor are provided.
Also provided herein are substituted biphenyl sulfonamides that have ET9 activity.

Definitions Unless defined otherwise, all technical and scientific terms used herein have the same meani~~g as is commonly understood by one of skill in the art to which this invention belongs.
As used herein., endothelia /ET) peptides include peptides that have substantially the amino acid sequence of endothelia-1, endothelia-2 or endothelia-3 and that act as potent endogenous vasoconstrictor peptides.
As used herein, an endothelia-mediated condition is a condition that is caused by abnormal endothelia activity or one in which compounds that inhibit endothelia activity ha~~e therapeutic use. Such diseases include, but are not limited to hypertension, cardiovascular disease, asthma, inflammatory diseases, ophthalmologic disease, menstrual disorders, obstetric conditions, gastroenteric disease, renal failure, pulmonary hypertension, endotoxin shock, anaphylactic shock, or hemorrhagic shock. Endothelia-mediated conditions also include conditions that result from therapy with agents, such as erythropoietin and immunosuppressants, that elevate endothelia levels.

WO 96131492 PCTlUS96/04759 As used herein an effective amount of a compound for treating a particular disease is an amount: that is sufficient to ameliorate, or in some manner reduce the syrnptoms associated with the disease. Such amount may be administered as a single dosage or may be administered according to a regimen, whereby it is effective. The amount may cure the disease but, typically, is administered in ordler to ameliorate the symptoms of the disease.
Typically, repeated administration is required to achieve the desired amelioration of symptoms.
As used herein, an endothelia agonist is a compound that potentiates or exhibits a biological activity as:>ociated with or possessed by an endothelia peptide.
As used herein, an endothelia antagonist is a compound, such as a drug or an antibody, that inhibits endothelia-stimulated vasoconstriction and contraction and other e;ndothelin-mediated physiological responses. The antagonist may act by interfering with the interaction of the endothelia with an endothelia-specific receptor or by interfering with the physiological response to or bioactivity of an endothelia iaopeptide, such as vasoconstriction. Thus, as used herein, an endothelia antagonist interferes with endothelia-stimulated vasoconstriction or other response or interferes with the interaction of an endothelia with an end~~thelin-specific receptor, such as ET" receptors, as assessed by assays known to those of skill in the art.
The effectiveness of potentieil agonists and antagonists can be assessed using methods known 1:o those of skill in the art. For example, endothelia agonist activity can be identified by its ability to stimulate vasoconstriction of isolated rat thoracic aorta or portal vein ring segments (Gorges et al. 11989) "Tissue selectivity of endothelia" Eur. J. Pharmacol. 165: 223-230).
Endothelia antagonist activity can be assessed by the ability to interfere with endothelin-induced vasoconstriction. Exemplary assays are set forth in the EXAMPLES. As noted above, the preferred ICSO concentration ranges are set forth with reference to assays in which the test compound is incubated with the ET receptor-bearing cells at 4° C. Data presented fcr assays in which the incubation step is performed at the less pi~eferred 24° C are identified. It is understood that for purposes of comparison, these concentrations are somewhat higher than the concentrations determined at 4° C.
As used herein, the biological activity or bioactivity of endothelia includes any activity induced, potentia~ted or influenced by endothelia in vivo. It also includes the ability to bind to particular receptors and to induce a functional response, such as vasoconstriction. It may be assessed by in vivo assays or by in vitro assays, such as those exemplified herein. The relevant activities include, but are not limited to, vasoconstriction, vasorelaxation and bronchodilation. For example, ETB receptors appear to be expressed in vascular endothelial cells and irnay mediate vasodilation and other such responses;
whereas ETA receptors, which are endothelia-1-specific, occur on smooth muscle and are linked to vasoconstriction Any assay known to those of skill in the art to measure or detect such activity may be used to assess such activity (see, e-a., Spokes et al. (198f3) J. Cardiovasc. Pharmacol. 13(Suppl. 5):S191-S192; Spinella et al. 1;1991) Proc. Natl. Acad. Sci. USA 88: 7443-7446;
Cardell et al. (1991) Neurochem. lat. 18:571-574); and the Examples herein).
As used herein, the ICS° refers to an amount, concentration or dosage of a particular test comF~ound that achieves a 50% inhibition of a maximal response, such as binding of e;ndothelin to tissue receptors, in an assay that measures such response.
As used herein, ECso refers to a dosage, concentration or amount of a particular test compound that elicits a dose-dependent response at 50% of maximal expression of a particular response that is induced, provoked or potentiated by the particular test compound.
As used herein a sulfonamide that is ETA selective refers to sulfonamides that exhibit an ICSO that is at least about 10-fold lower with respect to ETA
receptors than ETB receptors.
As used herein, a sulfonamide that is ETB selective refers to sulfonamides that exhibit an ICSO th~3t is at least about 10-fold lower with respect to ETB
receptors than ETA receptors.
As used herein, pharmaceutically acceptable salts, esters or other derivatives of the corc~pounds include any salts, esters or derivatives that may WO 96!31492 PCTIUS96/04759 be readily prepared b~,r those of skill in this art using known methods for such derivatization and that produce compounds that may be administered to animals or humans without substantial toxic effects and that either are pharmaceutically active or are prodrugs;. For e~;ample, hydroxy groups can be esterified or etherified.
As used herein., treatment means any manner in which the symptoms of a conditions, disorder or disease are ameliorated or otherwise beneficially altered. Treatment also encornpasses any pharmaceutical use of the compositions herein, ouch as use as contraceptive agents.
As used herein, amelioration of the symptoms of a particular disorder by administration of a particular pharmaceutical composition refers to any lessening, whether permanent or temporary, lasting or transient that can be attributed to or associated with administration of the composition.
As used herein, substantially pure means sufficiently homogeneous to appear free of readily detectable impurities as determined by standard methods of analysis, such as thin layer chromatography (TLC1, gel electrophoresis and high performance liquid chromatography (HPLC), used by those of skill in the art to assess such purity, or sufficiently pure such that further purification would not delectably alter the physical and chemical properties, such as enzymatic and biological activities, of the substance. Methods for purification of the compounds to producE: substantially chemically pure compounds are known to those of skill in the art.. A substantially chemically pure compound may, However, be a mixture of stereoisomers. In such instances, further purification might increase the specific activity of the compound.
As used herein, biological activity refers to the in vivo activities of a compound or physiolol~ical responses that result upon in vivo administration of a compound, composition or other mixture. Biological activity, thus, encompasses therapeutic effects anti pharmaceutical activity of such compounds, compositions and mixtures.
As used herein, a prodrug is a compound that, upon in vivo administration, is metabolized or otherwise converted to the biologically, pharmaceutically or th~erapeutic;ally active form of the compound. To produce a WO 96!31492 PCT/US96/04759 -2s-prodrug, the pharmaceutically active compound is modified such that the active compound will be regenerated by metabolic processes. The prodrug may be designed to alter the metabolic stability or the transport characteristics of a drug, to mask side effects or toxicity, to improve the flavor of a drug or to alter other characteristics or properties of a drug. By virtue of knowledge of pharmacodynamic processes .and drug metabolism in vivo, those of skill in this art, once a pharmace~~tically active compound is known, can design prodrugs of the compound (see, e~, Nogrady (1985) Medicinal Chemistry A Biochemical Approach, Oxford University E'ress, New York, pages 388-392). For example, succinyl-sulfathiazole is a prodrug of 4-amino-N-(2-thiazoyl)benzenesulfonamide (sulfathiazole) that exhibits altered transport characteristics.
As used herein, acid isostere means a group that is significantly ionized at physiological pH. Examples of suitable acid isosteres include sulfo, phosphono, alkylsulfonylcarbamoyl, tetrazolyl, arylsulfonylcarbamoyl or heteroarylsulfonylcarbamoyl.
As used herein, halo or halide refers to the halogen atoms; F, CI, Sr and I.
As used herein, pseudohalides are compounds that behave substantially similar to halides. Such compounds can be used in the same manner and treated in the same manner as halides (X', in which X is a halogen, such as CI
or Br). Pseudohalides in~:lude, but are not limited to cyanide, cyanate, thiocyanate, selenocyanate and azide.
As used herein, haloalkyl refers to a loweralkyl radical in which one or more of the hydrogen atoms are replaced by halogen including, but not limited to, chloromethyl, trifluoromethyl, 1-chloro-2-fluoroethyl and the like.
As used herein, alkyl means an aliphatic hydrocarbon group that is a straight or branched chain preferably having about 1 to 12 carbon atoms in the chain. Preferred alkyl groups are loweralkyl groups which are alkyls containing 1 to about 6 carbon atoms in thc: chain. Branched means that one or more loweralkyl groups such as methyl, ethyl or propyl are attached to a linear alkyl chain. The alkyl group may beg unsubstituted or independently substituted by one or more groups, such as, but not limited to: halo, carboxy, formyl, sulfo, sulfino, carbamoyl, amino and imino. Exemplary alkyl groups include methyl, WO 96131492 PCTlL1S96104759 ethyl, propyl, methanoic acid, ethanoic acid, propanoic acid, ethanesulfinic acid and ethane sulfonic ac:id.
As used herein the term lower describes alkyl, alkenyl and alkynyl groups containing about 6 carbon atoms or fewer. It is also used to describe aryl groups or heteroaryl groups that contain 6 or fewer atoms in the ring.
Loweralkyl, lower alkenyl, and lower alkynyl refer to carbon chains having less than about 6 carbons. In preferred embodiments of the compounds provided herein that include alkyl, alkenyl, or alkynyl portions include loweralkyl, lower alkenyl, and lower alkynyl portions.
As used herein, alkenyl means an aliphatic hydrocarbon group containing a carbon-carbon double bond and which may be straight or branched chained having from about 2 to about '10 carbon atoms in the chain. Preferred alkenyl groups have 2 to about 4 carbon atoms in the chain. Branched means that one or more loweralkyl or lower alkenyl groups are attached to a linear alkenyl chain.
The alkenyl group may be unsubstituted or independently substituted by one or more groups, such as halo, carboxy, formyl, sulfo. sulfino, carbamoyl, amino and imino. Exemplary alkenyl groups include ethenyl, propenyl, carboxyethenyl, carboxypropenyl, sulfinoethenyl and sulfonoethenyl.
As used herein, alkynyl means an aliphatic hydrocarbon group containing a carbon-carbon triple bond and which may be straight or branched having about 2 to 10 carbon atoms in the chain. Branched means that one or more loweralkyl, alkenyl or alkynyl groups are attached to a linear alkynyl chain.
An exemplary alkynyl group is ethynyl.
As used herein, aryl me-ans an aromatic monocyclic or multicyclic hydrocarbon ring system containing from 3 to 15 or 16 carbon atoms, preferably from 5 to 10. Aryl groups include, but are not limited to groups, such as phenyl, substituted phenyl, napthyl, substituted naphthyl, in which the substitunent is loweralkyl, halogen, or lower alkoxy. Preferred aryl groups are lower aryl groups that contain less than 7 carbons in the ring structure.
As used herein, the nomenclature alkyl, alkoxy, carbonyl, etc. are used as is generally understood by those of skill in this art. For example. as used herein alkyl refers to saturated carbon chains that contain one or more carbons; the chains may be straigf~it or branched or include cyclic portions or be cyclic.
As used herein, alicyclic refers to aryl groups that are cyclic.
As used herein, cycloailkyl refers to saturated cyclic carbon chains;
cycloalkyenyl and cycloalkynyl refer to cyclic carbon chains that include at least one unsaturated double or triple bond, respectively. The cyclic portions of the carbon chains may include one ring or two or more fused rings.
As used herein, cycloalkenyl means a non-aromatic monocyclic or multicyclic ring systern containing a carbon-carbon double bond and having about 3 to about 10 carbon atoms. Exemplary monocyclic cycloalkenyl rings include cyclopentenyl or cyclohexenyl; preferred is cyclohexenyl. An exemplary multicyclic cycloalkenyl ring is norbornylenyl. The cycloalkenyl group may be independently substituted by one or more halo or alkyl.
As used herein, "haloalkyl" refers to a loweralkyl radical in which one or more of the hydrogen atoms are replaced by halogen including, but not limited to, chloromethyl, trifluoromethyl, 1-chloro-2-fluoroethyl and the like.
As used herein, "haloallcoxy" refers to RO- in which R is a haloalkyl group.
As used herein" "carboxamide" refers to groups of formula RpCONH~ in which R is selected from alkyl or aryl, preferably loweralkyl or lower aryl and p is 0 or 1 .
As used herein, "alkylarninocarbonyl" refers to -C(O)NHR in which R is hydrogen, alkyl, preferably loweralkyl or aryl, preferably lower aryl.
As used herein "dialkylaminocarbonyl" as used herein refers to -C(01NR'R
in which R' and R are independently selected from alkyl or aryl, preferably loweralkyl or loweraryl; "carboxamide" refers to groups of formula NR'COR.
As used herein, "alkoxycarbonyl" as used herein refers to -C(O)OR in which R is alkyl, preferably loweralkyl or aryl, preferably lower aryl.
As used herein, "alkoxy" and "thioalkoxy" refer to RO- and RS-, in which R is alkyl, preferably loweralkyl or aryl, preferably lower aryl.
As used herein, "haloalwcoxy" refers to RO- in which R is a haloalkyl group.
As used herein, "aminoc:arbonyl" refers to -C(O1NH1.

WO 96!31492 PCT/US96/04759 As used herein, "alkylaminocarbonyl" refers to -C(O)NHR in which R is alkyl, preferably loweralkyl or aryl, preferably lower aryl.
As used herein, "alkoxycarbonyl" refers to -C(O)OR in which R is alkyl, preferably loweralkyl.
As used herein, cycloalkyl refers to satured cyclic carbon chains;
cycloalkyenyl and cyc:loalkynyi refer to cyclic carbon chains that include at least one unsaturated triple bond. 'the cyclic portions of the carbon chains may include one ring or two or more fused rings.
As used herein, alkylenedioxy means an -O-alkyl-O- group in which the alkyl group is as previously described. A replacement analog of alkylenedioxy means an alkylenedioxy in which one or both of the oxygen atoms is replaced by a similar behaving atom or group of atoms such as, S, N, NH, Se. An exemplary replacement alkylenedioxy group is ethylenebis(sulfandiyl). Alkylenethioxyoxy is -S-alkyl-O- , -O-alftyl-S- and alkylenedithioxy is -S-alkyl-S-.
As used herein, heteroaryl means an aromatic monocyclic or fused ring system in which one or more of the carbon atoms in the ring system is(are) replaced by an elements) other than carbon, for example nitrogen, oxygen or sulfur. Preferred cyclic groups contain one or two fused rings and include from about 3 to about 7 members in each ring. Similar to "aryl groups", the heteroaryl groups may be unsubstituted or substituted by one or more substituents. Exemplary heteroaryl groups include pyrazinyl, pyrazolyl, tetrazolyl, furanyl, (2- or 3-)thi~enyl, (2-,3- or 4-)pyridyl, imidazoyl, pyrimidinyl, isoxazolyl, thiazolyl, isothiazolyl, quinolinyl, indolyl, isoquinolinyl, oxazolyl and 1,2,4-oxadiazolyl. Preferred heteroaryl groups include 5 to 6-membered nitrogen-containing rings, such as pyrmidinyl.
As used herein, alkoxycarbonyl means an alkyl-O-CO- group. Exemplary alkoxycarbonyl groups include methoxy- and ethoxycarbonyl.
As used herein, carbamoyl means -CONH2. As with all groups described herein, these groups may be unsubstituted or substituted. Substituted carbamoyl includes groups such as -CONYzY' in which YZ and Y' are independently hydrogen, alkyl, cyano(loweralkyl), aryalkyl, heteroaralkyl, carboxy(loweralkyll, c<jrboxy(aryl substituted loweralkyl), carboxylcarboxy substituted loweralk~~l), carboxy(hydroxy substituted loweralkyl), carboxy(heteroaryl substituted loweralkyl), carbamoyl(loweralkyl), ' alkoxycarbonyl(loweralkyl) or alkoxycarbonyl(aryl substituted loweralkyl), provided that only one of YZ and Y' may be hydrogen and when one of YI and Y' is carboxy(loweralkyl), carboxy(aryl substituted loweralkyl), carbamoyl(loweralkyl), alkoxycarbonyl(loweralkyl) or alkoxycarbonylfaryl substituted loweralkyl) then the other of YZ and Y' is hydrogen or alkyl.
Preferred for Ya and 'f' are independently hydrogen, alkyl, cyano(loweralkyl), aryalkyl, heteroaralkyi, carbo~;y(loweralkyl), carboxy(aryl substituted loweralkyl) and carbamoyl(lower~3lkyl).
As used herein, any corresponding N-(4-halo-3-methyl-5-isoxazolyl), N-(4-halo-5-methyl-3-isoxazolyl), N-(3,4-dimethyl-5-isoxazolyl), N-(4-halo-5-methyl-isoxazolyl), N-(4-halo-3-methyl-5-isoxazolyl), N-(4,5-dimethyl-3-isoxazolyl) derivative thereof ref<:rs to compounds in which Are is the same as the compound specifcally set forth, but Ar' is N-(4-halo-3-methyl-5-isoxazolyl), N-(4-halo-5-methyl-3-isoxazolyl), N-(3,4-dimethyl-5-isoxazolyll, N-(4-halo-5-methyl-isoxazolyl), N-(4-halo-3-methyl-5-isoxazolyll, or N-(4,5-dimethyl-3-isoxazolyl) in which halo is any halide, peferably CI or Br.
As used herein, the abbreviations for any protective groups, amino acids and other compounds, are, unless indicated otherwise, in accord with their common usage, recognized abbreviations, or the IUPAC-IUB Commission on Biochemical Nomenclature (see, (1972) Biochem. 11:942-944).
A. Compounds for use in treating endothelin-mediated diseases Compounds and methods for treating endothelin-mediated diseases using the compounds of formulae I and II are provided. In particular, in the compounds provided herein, ArZ is thienyl, furyl, pyrrolyl or a group, such as benzofuryl, thionaphthyl or indolyl, that is a derivative or analog, as described below, of a thienyl, furyl or pyrrolyl group or a 4-biphenyl group, Ar' is preferably N-(5-isoxaz~~lyl) or N-(3-isoxazolyl).

WO 96f31492 PCTIUS96/04759 1. Ar2 is a thiophene, pyrrole, furan, benzo[b)thiophene, indolyl (benzo[hjpyrrole), or benzo[b)furan Among the compounds provided herein are those represented by the formula V:
R, R~
R~ R= R,o R,o I ~ ~ SOi N ~ , O
SO~ IN ~ N I5 ZI I N
' I5 X ZI , I'i O R~ X Re H
R R
R,o R,o R, R~
Re ~R~ R' R, (S 7I IS 2II _ R, X~SO~ N- O~N R X/-S01 N- ~N~O
H H
in which R' and Rz are either (i;l, (ii) or (iii) as follows:
(i) R' and R~ are each independently selected from H, NHz, NOz, halide, pseudohalide, alkyl, alke:nyl, alkynyl, aryl, arylalkyl, heterolaryl, alkoxy, alkylamino, alkylthio, haloalkoxy, haloalkyl, alkylsufinyl, alkylsulfonyl, aryloxy, arylamino, arylthio, arylsufinyl, arylsulfonyl, aminocarbonyl, aryfaminocarbonyl, haloalkyl, haloaryl, alkoxycarbonyl, alkylcarbonyl, arylcarbonyl, formyl, substituted or unsubstituted amido, substituted or unsubstituted ureido, in v~rhich the alkyl, alkenyl and alkynyl portions are either straight or branched chains that contain from 1 up to about 10 carbon atoms, and the aryl portions contain from about 4 to about '14 carbons, except the RZ is not halide, pseudohalide or higher alkyl; or,.
(ii) R' and RZ together form -/CHI)", where n is 3 to 6; or, /iii) R' and RZ togE~ther form 1,3-butadienyl; and X is S, 0 or NR" in which R" contains up to about 30 carbon atoms, preferably 1 to 10, more preferably 1 to 6 and is selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, heterocycle, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl, C(O)R'S and S(O)"R'S in which n is 0-2; R'S is hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, heterocycle, aralkyl, aralkoxy, cycloalkyl, cycloalke~nyl, cycloalkynyl; R" and R'S are unsubstituted or are substituted with one or more substituents each selected independently from Z, which is hydrogen, halide, pseudoahlide, alkyl, alkoxy, alkenyl, alkynyl, aryl, heterocycle, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl, OH, CN, C(O)R'6, COZR'6, SH, S(OI"R''S in which n is 0-2, NHOH, NR'~R'6, NOZ, N3, OR'6, R'zNCOR'6 and CON13'zR'6; R'6 is hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, heterocycle, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl or cycloalk~;~nyl;
R'Z, which is selected independently from R" and Z, is selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, heterocycle, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl, cycloalE;ynyl, C(0)R" and S(O)"R" in which n is 0-2; and R" is hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, heterocycle, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl or cyc:loalkynyl; each of R", R'Z, R'S and R'6 may be fur-ther substituted with the any of the groups set forth for Z, and R" is preferably hydrogen, aryl, such as phenyl or alkyl phenyl, loweralkyl; and Re, R9 and R'°, which each contain hydrogen or up to about 50 carbon atoms, generally up to about 30, more generally 20 or fewer, are each independently selected as described above, and more preferably from (i) or (ii) as follows:
(i) R' and R'° sire selected from hydrogen, halide, pseudohalide, alkyl, alkoxy, alkenyl, alkynyl, aryl, ;aryloxy, heterocycle, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl, Of-I, CN, C(O)R'8, (OAC)CH=CHR'e, COZR'8, SH, (CH2),C(O)(CHz)"R'e, (CH~),(Ct~l=CH),(CHz)"R'8, (CHZ),C(O)(CH=CH),(CHz)"R'8, (CH2),(CH=CH),C(O)(CH~)"R'e, (CHz),NH(CH=CH),(CH~)"R'e, C=N(OH)(CH~),R'°, (CHZ),(CH=CH),NH(CI-i2)"R'8, ~ICH~),C(O)NH(CHZ)"R'8, C(O)ICHz),NH(CHZ)"R'8, (CH2),NH(CHz)"R'e, (CHZ),R'8, S(O)mR'e in which m is 0-2, s, n and r are each independently 0 to 6, prefera~~ly 0-3, HNOH, NR'BR'9, NO2, N3, OR'8, R'9NCOR'e and CONR'9R'e, in which R'9 i.s selected from hydrogen. alkyl, alkenyl, alkynyl, aryl, alkylaryl, alkoxy, aryloxy, heterocycle, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl, C(O)RZ°, S(O)"RZ° in which n is 0-2;
and R'e and R2°
are independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, alkylaryl, hreterocyc:le, alkoxy, aryloxy, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl or cycloz~lkynyl;

i Re is selected from C;(OIR'8, (OAC)CH=CHR'8, COzR'°, (CHZ),C(O)fCHz)"R'e, (CHZ),(CH=CH),(CHZ)"R'e, (CHz),C(OIICH=CH),(CH~)"R'8, (CH~),(CH=CH),C(0)(CH~)"R','e, (CHZ),NH(CH=CH),(CHz)~R'8, C=N(OH)(CHZ),R'8, (CHz),(CH=CH),NH(CHz)"R'E', (CH~),C(O)NH(CHz)"R'e, C(0)(CHz),NH(CH~)"R'°, (CHz),NH(CHz)"R'e, (CHz),R"', in which m is 0-2, s, n and r are each independently 0 to 6, preferably 0-3, in which R'8 is aryl, preferably phenyl, with the proviso that, if RB is (CI-I~),C(0)NH(CHz)"R'e, C(O)(CH~),NH(CHz)"R'8, (CHz),NH(CHz)"R'e, (CHz),R'8, particularly if r is 0 and/or n is 0, and R'e is aryl, particularly phenyl, then R'8 must have two or more substituents, with preferably at least one ortho substituent;
where any ovf the groups set forth for Re, R9 and R'° are unsubstituted or substituted with arn,l substituents set forth for Z, which is hydrogen, halide, pseudoahlide, alkyl, alkoxy, alkenyl, alkynyl, aryl, aryloxy, heterocycle, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl, OH, CN, C(O)RZ', COzRZ', SH, S(O)"R~' in which n is 0-2, NHOH, NRZ~R~', NOZ, N3, OR2', R~~NCORZ' and CONRZ~R~'; R~~ is selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, heterocycle, aralkyl, alkoxy, aralkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl, C(O)RD' and S(O1"Rz' in which n is 0-2; and RZ' and RZ' are independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, heterocycle, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl or cycloalkynyl; or (ii) any two of R°, R9 and R'° form an aryl, aromatic ring, heteroaromatic ring, carbocyclic or heterocyclic ring, which is saturated or unsaturated, containing from about 3 to about 16 members, preferably 3 to about 10 members, more preferably 5 to 7 members that is substituted with one or more substituents, each substituent being independently selected from Z;
the other of Re, R9 and R'° is selected as from the groups set forth for R9 and R'° in (i); and the heteroatoms are NR", O, or S, with the proviso that ArZ is not 5-halo-3-loweralkylben:zo(b]thienyl, 5-halo-3-loweralkylbenzo(b]furyl, 5-halo-3-loweralkylbenzo(b]pyrrolyl.
In these embodiments,. Ar2 is, thus, represented by the formulae (/VA
and IVB):

Rye y /a 3~ or /a R 5 t R~ R 5 t X ~X
A g that can be substituted at any or all positions or is an analog of compounds of formula (IV) in which the substituents form fused aromatic, aliphatic or heterocyclic rings; and in whiich X is NR", 0, or S, and R", which is hydrogen or contains up to about 30 carbon atoms, preferably 1 to 10, more preferably 1 to 6. and is selected as defirned above. Re, R9, R'° are selected as described above.
In the embodiments provided herein, when R8, R9 and R'° are selected as in (i), above, Re is preferably selected from among (CHz),C(O)(CHz)"R'8, (CHi),NH(CHz)"R'e, ((:Hz),NH(CHz)"R'e, (CHi),(CH=CH1,(CHZ)"R'8, (CH~),C(O)(CH=CH),~~CH2)"R'8, (CHz),(CH=CH),C(O)(CHZ)"R'8, (CHz),(CH=CH),NHIC:H2)"R'8, C=N(OH)(CHZ),R'e, (CHZI,C(O)NH(CH~)"R'8, C(O)(CHZ),NH(CHi)"R'8, (CHi),NH(CH=CH),ICH21"R'8, (CH~),C(01NH(CHz)"R'8, (CHZ),NH(CHz)"R'8, ((:Hz),R'°, with the proviso that if Re is (CH~),C(O)NH(CHiI"R'°, (CH~),C(O)NH(CHz1"R'e, or (CHz),R'8, and R'e is phenyl, the phenyl group is substituted at least two positions, and preferably, at least one of those positions is ortho.
In preferred ov' these compounds, R'° is aryl or heteroaryl, preferably having 5 or 6 members in the: ring, more preferably phenyl or pyrimidinyl, most preferably phenyl. R9 and R"' are preferably hydrogen, halide, loweralkyl, or halo loweralkyl The more preferred compounds provided herein are compounds in which the alkyl, alkynyl and. alkenyl portions are straight or branched chains, acyclic or cyclic, and have from about 'I up to about 10 carbons; in certain of the more preferred embodiments they have from 1-6 carbons, and they can have fewer than 6 carbons. The aryl, homocyclic and heterocyclic groups can have from 3 to 16, generally, 3-7, more o~hen 5-7 members in the rings, and may be single or WO 96/31492 ~ PGTIUS96/04759 fused rings. The rin~~ size and carbon chain length are selected such that the resulting molecule exhibits activity as an endothelin antagonist or agonist as evidenced by in vitro or in vivo tests, particularly the tests exemplified herein.
In any of the above preferred embodiments: R' and Ri are preferably selected independently from alkyl, lower alkenyl, lower alkynyl, lower haloalkyl, halide, pseudohalide and H, except that R~ is not halide or pseudohalide, and in preferred embodiments is also not higher alkyl.
In preferred ernbodiments: X is S, 0, NR" in which R" is aryl, hydrogen, or loweralkyl, preferably, a substituted or unsubstituted aryl, particularly phenyl, preferably unsubstituted or substituted with loweralkyl or halogen hydrogen or loweralkyl; R' is hydrogen, halide, pseudohalide, loweralkyl or lower haloalkyl, most preferably halides; R~ is hydrogen, loweralkyl or lower haloalkyl.
The aryl groups are unsubstituted or is substituted with groups such as alkyl, alkoxy, alkoxyalkyl, halogen, alkylenedioxy, particularly methylene dioxy, amino, vitro and other such groups. The alkyl substituents are preferably loweralkyl, more pref~srably containing 1-3 carbons.
In more preferred embodiments, two of R' and R'° are hydrogen, halide or loweralkyl and RB is C~(O)NHR"8 or C(OICHiR'e in which R'° is a phenyl group that is substituted at least two positions, most preferably at least one substitutent at the ort:ho position and also 3,4 or 4,5 alkylenedioxy substituents. In more preferred of these embodiments X is S.
In all embodiments, R' is preferably halide, H, CH, or CzHS, and R2 is H, CH,, C~HS, CzFs or CF',. In yet more preferred embodiments, R' preferably Br, CI
or CH,; RZ is H, CH,, CZHS, or CF3.
In other embodiments t:wo of Re, R' and R'° form a ring so that Art is benzo[b)thienyl, benzo[b)furyl, or indolyl, with the proviso that there is one or more substituents anti they are other than 5-halo and 3-loweralkyl, and the other of R8, R9 and R'° is selected from aryl, (CHz),R'e, C(O)R'e, COZR'e, NR'°R'9, SH, S(O)"R'8 in which n is 0-2, HNIOH, NOZ, N3, OR'e, R"NCOR'8 and CONR'9R'°.
Arz may be further substituted with any of the groups set forth for R8, R9 and R'°, and are preferabl~,r selected from among alkyl, alkoxy, alkoxyalkyl, aryl, alkylaryl, aminoalkyl, arylamino, aryl-substituted amino, and NR".

In embodiments in which ET8 antagonists are desired, it is preferred that R8 and R'° are H or loweralkyl and R' includes heterocyclic or aromatic ring of preferably from 3 to 14, more preferably, 5 to 7, members in the ring. In particular, if X is S, IR8 and R'° are H or loweralkyl; and R9, includes an aryl group, particularly a substituted phenyl, such as a 2-loweralkyl substituent.
The aryl portion is substituted with groups such as alkyl, alkoxy, alkoxyalkyl, halogen, alkylenedio:xy, particularly methylenedioxy, amino, vitro and other such groups. The alkyl substituents are preferably loweralkyl, more preferably containing 1-3 carbons.
If X is NR", then R" is aryl, particularly unsubstituted phenyl or substituted phenyl, such as iaopropylphenyl.
Other preferred compounds, which are ETB active, are those in which Ar=
has formula IVB in v~~hich R9 is aryl or Z-substituted aryl, particularly phenyl, and Z is loweralkyl or lov~eralkoxy.
In all embodiments of all of the compounds herein R' is preferably halide or loweralkyl, most preferabh~ Br, and the compounds are, with reference to formulae IV, 2- or 3-sulfonamides, particularly thiophene sulfonamides. In certain embodiments provided herein, Are is a benzo(b]thienyl, benzo(b]furyl or indolyl (benzo[b]pyrrolyl) group and the compounds provided herein are prefera-bly benzo(b]thienyl-, benzo[b]furyl- or indolylsuifonamides.
Benzo[b]thiophene, benzo[b]furyl and indolyl 2- or 3-sulfonamides are among the compounds preferred herein. TH~e benzo[b]thiophene, benzo[b]furyl and indolyl 2- or 3-sul-fonamides provided herein are selected with the proviso that the benzene group has at least one substituent and that substituent is other than 5-halo and 3-loweralkyl.
Compounds of particular interest include those of formula III in which Ar2 is a phenyl-, benzothienyl, benzofuryl or indolyl [benzopyrrolyl] group or in which Ari is a substituted phenylaminocarbonylthienyl, substituted phenylaminocar-bonylfuryl, substituted aminocarbonyipyrrolyl group in which there are at least two substitutents or Are is phenylacetylthiophene, phenylacetylfuran, or phenyl-acetylpyrrole, is an acetoxystyrylthiophene, acetoxystyrylfuran or acetoxystyrylpyrrole.

The most preferred compounds provided herein have an ICsa for ET"
receptors in the assays exemplified herein less khan 0.1 NM, more prefereably less than 0.01 NM, and more preferably less than 0.001 (see, e-g., Table 1 for representative experimental results), when measured at 4° C, as described in the Examples. When measured at 24° C, the ICso concentrations are somewhat higher (2- to 10-fold; see, Table 1 for some comparative values).
Among the preferred compounds of interest herein are those in which Are has formula VI:
~ ~ R»
\ I~m I
i I~a~
R~ I~
R
in which M is (CHzlm(~(O)(CHi)" (CHz)mC(OINH(CHz)" (CHz)m(CH=CH)ICHz),, (CHZ)mC(O)(CHz),NH((:HZ)" (CHZ)m(CH=CH)(CH~)" C=N(OH)(CHZ)"
(CHz)mC(OI(CH=CH),NH(CHz)", CH(OH)(CH~)" CH(CH,)C(O)(CH2)"
CH(CH3)C(O)(CHZ)m(CH=CH)(CH~)" (CHI)" ICH~),0, C(O)O, in which m.s and r are each independently 0 to E~, preferably 0 to 3, more preferably M is fCHz)mC(O)(CHZ),, (CFiZ)mC(O)NH(CHz)" (CHi)m(CH=CH)(CHz),, (CH~)mC(O)(CHZ),NH((:H~)" (CHz)m(CH=CH)(CH~)" C=N(OH)(CHZ)"
CH(OH)(CHZ)" (CH?)" (CHz),O, C(O)O;
R", R'~, R", R" and R'S are each independently selected from (i) or (ii) as follows:
(i) R", R'~, R",, R" and R'S are each independently selected from among H, OH, NHR'e, CONR'BR'9 , NOi, cyano, halide, pseudohalide, alkyl, alkenyl, alkynyl, aryl, ary)alkyl, heteroaryl, alkoxy, alkylamino, alkylthio, haloalkyl, alkylsulfinyl, alkylsulfonyl, alkoxycarbonyl, alkylcarbonyl, alkenyithio, alkenylamino, alkenyloxy, alk~:nyl sulfinyl, alkenylsulfonyl, alkoxycarbonyl, arylaminocarbonyl, alkylaminocarbonyl, aminocarbonyl, (alkyl-aminocarbonyl)alkyl, carboxyl, carboxyalkyl, carboxyalkenyl, alkylsulfonylamino-alkyl, cyanoalkyl, acetyl, acetoxyalkyl, hydroxyalkyl, alkyoxyalkoxy, hydroxyalkyl, (aceto~:y)alkoxy, (hydroxy)alkoxy and formyl; or (ii) at least two of R", R'~, R", R" and R'°, which substitute adjacent carbons on the ring,. together form alkylenedioxy, alkylenethioxyoxy or alkylenedithioxy (i.e. -O-(CHz)" O-, -S-(CH~)"O-, -S-(CHi)"S-, where n is 1 to 4, preferably 1 or 2,;1 which is unsubstituted or substituted by replacing one or more hydrogens with halide, loweralkyl, loweralkoxy or halo loweralkyl, and the others of R", R'~, R", R" and R'S are selected as in (t); and R'$ and R'9 are each independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, haloalkyl alkylaryl, heterocycle, arylalkyl, arylalkoxy, alkoxy, aryloxy, cycloalkyl, cycloalkenyl and cycloalkynyl, and is preferably hydrogen, loweralkyl, loweralkoxy and lowerhaloalkyl, with the proviso that when M is (CHi)mC(OINH(CHz)" then at least two of R", R'Z, R", R" and R'S are not hydrogen.
M is most preferably H
I
\ \~ ~ \
O , IOI and , O
In general, ho~rvever, in all of these compounds in which Ar= has formula V or VI or in which R8 includes an aryl group, regardless of the selection of M,it is preferred that the aryl substituent have more than one substituent or at least one substituent in th~~ ortho position. Aryl is preferably phenyl that is preferably substituted at the ortho position and, more preferably at at least one additional position, particularly 4 and 6, or adjacent positions, such as 3,4 or 4,5 when the subsitutents are linked to forrn an alkylenedioxy (or analog thereof in which one or both oxygens is(are) replaced with S.
In all compounds, at least one of R" and R'S is other than hydrogen.
In more preferred compounds, M is C(O)CH2, C(OINH, -CH=CH-, CHZCHZC(01(CH)z, CF~iCHC(0)CHz, and most preferably has formula VII:

t ' WO 96/31492 ~ PCTILTS96104759 R"
in which W is CHZ or NH.
'10 M is even more preferably selected from among:
H
I
N~ O~
O O o . H ' O Ry anC R
OR~°
O
in which R'° is prefer~3bly hydrogen, alkyl, alkoxy, alkoxyalkyl, haloalkyl, and more preferably loweralkyl, Io~Neralkoxy, or halo loweralkyl, and is more preferably hydrogen or loweralkyl, particularly methyl or ethyl, and is most preferably hydrogen.
M is most preferably:
H
I
N. p and 0 0 « . .
R"
~W Rai X
i ~R~a R
In preferred compounds R", R'2, R", R" and R'S are selected from (i1 or (i) R", R'~, R", R" and R'° are each independently selected from loweralkyl, haloloweralkyl, phenyl, alkoxy, loweralkylsulfonylaminoloweralkyl, cyanoloweralkyl, acetyl, lower,slkoxycarbonyl, cyano, OH, acetoxyloweralkyl, hydroxy lowerallkyl, acetoxy loweralkoxy or loweralkoxycarbonyl; or (ii) R'Z and R" or R" and R" form alkylene dioxy, preferably methylenedioxy, and the other:; of R", R'~, R", R" and R'S are selected as in (i).

In preferred a;mbodiments, R", R", R's are other then hydrogen and are preferably loweralkyl or lower alkoxy, or R" or R's is other than hydrogen, preferably loweralkyl or lower alkoxy, and R'= and R" or R" and R" form methylenedioxy.
In all embodiments, preferred substituents also can be determined by reference to Table 1, which sets forth exemplary compounds.
Preferred compounds are those of Table 1 that have the highest activities, and preferred substituents are those on the compounds with the highest activit.es.

t;OMPOUND ET" (ErMI~ ETs (~rM]-N-(3.4-dimethyl-5-isoxazolyl)-2- 0.167 16.6 methyfbenzo[b)thiophene-3-sulfonamide N-(4-bromo-3-methyl-5-isoxazolyl)-2-0.0486 3.5 methylbenzo(b]thiophene-3-sulfonamide N-(4-bromo-3-methyl-5-isoxazolyl)-2-0.0067 5.13 ethylbenzo[b]thiophe;ne-3-sulfonamide N-(4-bromo-3-methyl-5-isoxazolyl)-2-n-0.0182 -1 benzylbenzo[b]thiophene-3-sulfonamide N-(4-bromo-3-methyl-5-isoxazolyll-2-0.0226 -3 butylbenzo(b]thiophe~ne-3-sulfonamide N-(4-bromo-3-methyli-5-isoxazolyl)-2-i-0.005 5.7 propylbenzo(b]thiophene-3-sulfonamide0.031 10.7' N-(4-bromo-3-methyl-5-isoxazolyl)-2-n-0.024 7.95 propylbenzo(b]thiophene-3-sulfonamide0.074' 16.6' N-(4-bromo-3-methyl-5-isoxazolyl)-2-(4-0.048' 1.1' ethylbenzyl)benzo(b]thiophene-3-sulfonamide N-14-bromo-3-methyl-5-isoxarolyl)-2-(3,4-o.oo~s=o.ooi<0.32410.78 fmethylenedioxy)benzyl]benzo(b]thiophene-3-sulfon-0.004=0.00~~'o.939zo.262' amide N-(4-bromo-3-methyl-5-isoxaz~olyl)-2-(3,4,5-0.013' 1.2' trimethoxybenzyl)-benzo(b]-thiophene-3-sulfonamide N-(4-bromo-3-methyl-5-isaxazolyl)-2-ethyl-5-t.89zo.43t'Sa.3x2.6' methylbenzo(b]thiophene-3-sulfonamide N-(4-chloro-3-methyl-5-isoxazolyl)-2-((3,4-methy-O.Ot t =0.005'0.936 =0.095' lenedioxy)benzyl]benzo(b]thiophene-3-sulfonamide COMPOUMD ~A (f,M)' a WM) N-(4-bromo-3-methyl-!5-isoxazolyl)-2-(3,4-O.o2t~o.ot7'2.941.32' ' dimethoxybenzyllbenzo(bjthiophene-3-sulfonamide N-(4-bromo-3-methyl-!5-isoxazolyl)-5-(benzo[b)thien-16' O,gpT

2-yl)thiophene-2- sulfonamide N-(4-bromo-3-methyl-!i-isoxazo~lyl)-2-(4-0.051' 1.51 methoxybenzyllbenzo(b)thiophe~ne-3-sulfonamide .

N-(4-bromo-3-methyl-!i-isoxozolyl)-2-(2-0.19' 2.2' methoxybenzyl)-benzo(bjthioph~ene-3-sulfonamide N-(3,4-dimethyl-5-isoxazolyl)-2-(4-0.21' 4 7' chlorobenzyl)benzo(b)thiophene-3-sulfonamide .

N-(4-chloro-3-methyl-5.-isoxazolyl)-2-(4-0.041' 1,31 dimethylaminobenzyl)benzo[blthiophene-3-sulfona-0.014 0.477 mide N-(4-chloro-3-methyl-5-isoxazolyl)-2-0.15' 221 ethylbenzo(bjfuran-3-sulfonamide N-(4-chloro-3-methyl-5-isoxazolyl)-2-phenylben-0.932' 46.8' zo[bjthiophene sulfonamide N-(4-chloro-3-methyl-5-isoxazolyl)-6-methoxy-2--2 "'1 2.39' (3,4-(methylenedioxy)t~enzyl)benzo(bjthiophene-3-sulfonamide N-(4-chloro-5-methyl-3-isoxazolyl)-2-[3,4-(methyl-0.00551 0.364' enedioxylbenzyljbenzol;b)thioph<~ne-3-sulfonamide N-(4-chloro-3-methyl-5-isoxazolyl)-2-0.631 53.2 methoxycarbonylthiophene-3-sulfonamide N-(4-bromo-3-methyl-5-isoxazolyl)-4-(4-0.9621 0.4351 propylphenyl)thiophene~-2-sulfonamide N-(4-bromo-3-methyl-5-isoxazolyl)-3-0.08011 3.68 (phenylthio)thiophene-:'.-sulfonarnide N-(3,4-dimethyl-5-isoxazolyl))-3- 0.163 > 100 (phenylaminocarbonyllthiophene-2-sulfonamide N-(4-chloro-3-methyl-5-~isoxazolyl)-2-((4-tolyl)amino-0.00116 2.93 carbonyljthiophene-3-sulfonamide 0.0105' 14' N-(4-bromo-3-methyl-5-isoxazolyl)-5-(4-8.69 0.363 methoxyphenyl)thiophene-2-sulfonamide26.3' 2,41 N-(4-bromo-3-methyl-5-isoxazolyl)-5-(3-3.26 0.776 methoxyphenyl)thiophene-2-sulfonamide23.4' 4,71 WO 96!31492 PCTIUS96104759 CDMPOUfIID )?~ (E,MJ~ETs (NM1' N-(4-bromo-3-methyl-5-isoxazolyl)-5-I3-4.49 0.380 thienyl)thiophene-2-sulfonamide N-(4-bromo-3-methyl-5-isoxazolyl)-3-0.651 7,15 methylthiophene-2-sulfonamide:

N-(4-bromo-3-methyl-5-isoxazodyl)-3-0.16 10.77 (phenethyl)thiophene-2-sulfonamide 0.676' 37.2' N-(4-bromo-3-methyl-5-isoxazolyl)-4-6.64 3.97 (phenethyllthiophene-2-sulfonamide N-(3,4-dimethyl-5-isoxazolyt)-2-[14-methylphenyl)-0.00336 11.3 aminocarbonyl]thiophene-3-sulfonamide N-(4-bromo-3-methyl-5-isoxazolyl)-2,5-dimethyl-4-1.40 -100 phenylthiophene-3-sulfonamide N-(4-bromo-3-methyl-!5-isoxazoilyl]-2-0.188 16.0 ((methyl)phenylaminoc;arbonyl]thiophene-3-sulfona-5 mide N-(4-bromo-3-methyl-!i-isaxazolyl)-2-(a-0.337 9.37 hydroxybenzyllthiophe~ne-3-sulfonamide N-(4-bromo-5-methyl-;3-isoxazolyl)-5-(4-7.10 0.3593 methylphenyl)thiophene-2-sulfonamide15.8' 0.251 N-(4-bromo-3-methyl-fi-isoxazolyl)-5-3.53 0.417 phenylthiophene-2-sulfonamide 36.6' 2.4' N-(4-bromo-3-methyl-Ei-isoxazolyl)-5-(4-6.39 0.0835 (trifluoromethyl)phenyl]thiophene-2-sulfonamide6.31 ' .282' N,N'-bis{3-[(4-bromo-a-methyl-ti- 0.0692 0.290 isoxazolyl)aminosulfonyl)thien-2-yl}0.295' 1.19' urea N-(4-bromo-3-methyl-5-isoxazolyrl)-2-0.160 44.1 (hydroxymethyl)thioph~ene-3- sulfonamide1.55' N-(4-bromo-3-methyl-5-isoxazolyl)-5-(2-3.46 0.529 formylphenyl)thiophene-3-sulfonamide12.31' 1.28Ø71' N,N'-bis{3-(3,4-dimethyl-5- 1.01 1.033.7 t 2.7 isoxazolyl)aminosulfon~~l]thien-2-yl}urea2.7' S.9' N-(3,4-dimethyl-5-isoxazolyl))-2-[(3-0.214 5.34 methoxyanilino)methyl]thiophene-3- 0.933' 7,7' sulfonamide N-(4-bromo-3-methyl-5-isoxazolyl)-5-(3-0.537 1,07 aminophenyl)thiophene-2-sulfonamide1.44' 2.63' N-(4-bromo-3-methyl-5-isoxazolyl)-5-(3,5-0.784 12.0 bis(triflouromethyl)phenyl)thiophene-2-sulfonamide5.9' 15.5' WO 96!31492 PCT/US96/04759 COMPOUWD ETA (pMl' ET, (pM)' N-(4-bromo-3-methyl-~5-isoxazolyl)-5-(3,3-1.12 24.0 dimethylbutyn-1-yl)thiophene-~!-sulfonamide7.24' 35.5' N-(4-bromo-3-methyl- 5-isoxazolyll-5-(2-0.381 1.097 methoxyphenyllthiophene-2- sulfonamide N-(4-bromo-3-methyl-5-isoxazolyl)-5-(2-0.432 0.313 tolyllthioptiene-2-sulf~~namide N-(4-bromo-3-methyl-5-isoxazolyl)-2-((3-0.062' > 100' carboxyphenyl)amino~~arbonyl]t:hiophene-3-sulfona-mide N-(4-bromo-3-methyl-5-isoxazodyl)-2-(Z-0.21' 20' carboyxylphenyl)aminocarbonyl)-thiophene-3-sulfon-amide N-(4-bromo-3-methyl-5-isoxazolyll-2-0.84' > 100' (aminocarbonyllthiophene-3-sulfonamide N-(4-bromo-3-methyl-5-isoxazolyll-2-((5-dimethy!amino-1-naphthypsulfonyl- O.g7' 3.9' aminocarbonyl]thiophene-3-suli'onamide N-(4-bromo-3-methyl-5-isoxazolyll-5-(5-methyl-2-17' 0.21 thienyl)thiophene-2-sulfonamide N-(4-bromo-3-methyl-5-isoxazolyl)-2-((3,4-0.0171 9.8' methylenedioxyphenyl)aminocarbonyl]thiophene-3-sulfonamide N-(4-bromo-3-methyl-5-isoxazolyl)-2-((3,4-0.0073' 6.0' methylenedioxylphenoxycarbonyl]thiophene-3-sul-fonamide N-(4-bromo-3-methyl-5-isoxazolyl)-3-((3,4-0.50' 79' methylenedioxylphern/I]thiophene-2-sulfonamide N-(4-bromo-3-methyl-5-isoxazolyl)-3-((3,4-8.1' 3.2' methylenedioxy)benzyl]thiophe~ne-2-sulfonamide N-(4-bromo-3-methyl-5-isoxazolyl)-3-1.6' 39' benzytthiophene-2-sulfonamide N-(4-bromo-3-methyl-5-isoxazolyl)-5-(3-15' 4.2' tolyl)thiophene-2-sulfonamide N-(4-bromo-3-methyl-5-isoxazolyll-2-((3,4-0.27' 7.7' methylenedioxy)benzyl]thiophe~ne-3-sulfonamide N-(4-bromo-3-methyl-5-isoxazolyl)-2-((3,4-2.0' 15t methylenedioxylbenzoyl]thiophene-3-sulfonamide C~OMPOUPJD ET" (~rM)'ETs (~rM)' N-(4-bromo-3-methyl-5-isoxazolyl)-2-((2-0.013' 3g' hydroxyphenyl)aminocarbonyl)thiophene-3-sulfona-mide N-(3,4-dirnenthyl-5-isoxazolyll-2-[3,4-6,1 t > _ 50r (methylenedioxy)phenoxycarbonyl]thiophene-3-sul-fonamide N-(4-bromo-3-methyl-5-isoxazolyl)-5-(5-ethylthien-2-24' 7,7r yl)thiophene-2- sulfonamide N-(4-bromo-3-methyl-5-isoxazolyl)-2-((3,4-p,Og methylenedioxylbenzoyl]aminoc:arbonyl]thiophene-3-sulfonamide N-(4-chloro-3-methyl-5-isoxazolyl)-2-(3,4-0.0065' 7.4' (methylenedioxy)phenoxycarbonyl]thiophene-3-sul-fonamide N-(4-bromo-3-methyl-5-isoxazolyl)-5-(1-29' S.6' pentynyl)thiophene-2-sulfonamide N-(4-chloro-3-methyl-!i-isoxazolyl)-5-(5-ethylthien-2-12' 0.71' yl)thiophene-2- sulfonamide N-(4-bromo-3-methyl-5-isoxazolyl)-2-((3,4-0.0091' 5.5' methylenedioxy)phenylacetyl]thiophene-3-sulfona-mide N-(4-bromo-3-methyl-!5-isoxazollyl)-2-(3,4-O,pg7t 5-gt (methylenedioxy)phenoxycarbonyfamino]thiophene-3-sulfonamide N-(4-bromo-3-methyl-'.~-isoxazolyl)-2-((2-chloro-3,4-13' 0.7fit methylenedioxy)phenoxymethyl]thiophene-3-sulfon-amide N-(4-bromo-3-methyl-!i-isoxazolyl)-2-(traps-(3,4-0,14' 1.4' methylenedioxy)cinnarnyl]thiophene-3-sulfonamide N-(4-bromo-3-methyl-!i-isoxazolyl)-5-(1-naphthyl)-14' 1.4, thiophene-2-sulfonamide N-(4-bromo-3-methyl-!i-isoxazolyll-5-(3-2g' 4,5T

nitrophenyllthiophene-2-sulfonamide N-(4-bromo-3-methyl-!i-isoxazolyl)-2-((3,4-0,57' 1.3' methylenedioxylphenylureido]thiophene-3-sulfona-mide N-(4-chloro-3-methyl-fi-isoxazolyl)-2-((3,4-0.021' 6.5' (methylenedioxy)phen~ylacetyt]thiophene-3-sulfona-mide COMPOUND ET" (~rM)'ET, (NM)' N-(4-bromo-3-methyl-5-isoxazolyll-5-(4-> 100' 17' methyoxycarbonylphenyl)thiophene-2-sulfonamide N-(4-bromo-3-methyl-5-isoxazolyl)-5-(4-> 100' 31' carboxyphenyl)thiophene-2-sulfonamide N-(4-bromo-3-methyl-5-isoxazolyl)-5-(4-2gt g.6' tolyllaminocarbonyl)thiophene-2-sulfonamide N-(4-bromo-3-methyl-5-isoxazolyl)-5-(2-32 ' 7.5' methyfuranyl)thiophene-2-sulfonamide N-(4-chloro-3-methyl~~5-isoxazolyl)-2-(3,4-.42 ' 12 ' (methylenedioxy)ben;lyloxycarbonyl)thiophene-3-sul-.

fonamide N-(4-chloro-3-methyl-~5-isoxazolyl)-2-(2-(3,4-.23' 6.2 methylenedioxyphenyi)]ethoxycarbonyl-3-sulfona-mide N-(4-chloro-3-methyl-5-isoxazolyl)-2-{(4-(3,4-20' > -100' methylenedioxybenzyl)piperazin-1-yljcarbonyl}thiophene~-3-sulfonamide N-(4-chloro-3-methyl-5-isoxazolyl)-2-14' 6.2 ' aminothiophene-3-sulfonamide N-(4-bromo-3-methyl-5-isoxazolyl)-5-12' ~ 9.0' (benzyloxymethyl)thiophene-2-sulfonamide N-(4-chloro-3-methyl-5-isoxazolyll-2-{1-cyano-1-2.11 27' ((3,4-methylenedioxy;iphenyljac:etyl}thiophene-3-sul-fonamide N-(4-bromo-3-methyl-5-isoxazo~lyl)-2-((3,4-0.21 ' 9.2' methylenedioxy)phenethyljthiophene-3-sulfonamide N-(4-chloro-3-methyl-5-isoxazolyl)-2-[(3-1.4' 60' dimethylamino)pheno:Kycarbonyljthiophene-3-sulfon-amide N-(4-bromo-3-methyl-5-isoxazolyl)-1-methylindole-2-77' -1001 sulfonamide N-(4-chloro-3-methyl-5-isoxozolyl-2-0.44' 341 (cyclohexyloxycarbonyl)thiophe;ne-3-sulfonamide N-(4-chloro-3-methyl-!5-isoxazolyl)-2-(~-hydroxy(3,4-0.053' 16' methylenedioxy)phenylethyl)thiophene-3-sulfona-mide N-(4-bromo-3-methyl-5-isoxazolyll-2-carboxyl-1-0.59' 104' methylidole-3-sulfonamide 1.

(:OMPOIIND ET" (pM]~ ET, (pMl~

N-(4-chloro-3-methyl-5-isoxazolyl)-2-((4-1.37' _ oxacyclohexylloxycarbonyl]thiophene-3-sulfonamide N-2-(3,4-(methylene~dioxy)phe;nylacetyl]thiophene-3-1.8' 32.5' sulfonamide N-(4-chloro-3-methyl'-5-isoxazolyl)-{2-(3,4-(methyl-_ enedioxy)phenyl]acetyl}thiophene-3-sulfonamide oxime N-(4-chloro-3-methyl-5-isoxazolyl]-2-((4-31.3' 14.7' tolyl)aminocarbonyl]-1-methyllindole-3-sulfonamide N-(4-chloro-3-methyl-5-isoxaz~olyl)-2-((4Ø023' 15' methoxyphenoxy)carbonyl]thiophene-3-sulfonamide N-(4-bromo-3-methyl-5-isoxazolyl)-1-(3,4-(methyl-5.29' 18.6' enedioxy)benzyl]indole-Z-sulfonamide N-(4-bromo-3-methyl-5-isoxazolyl)-2-((4-122' 9 7' methylphenoxy)carbonyl]thiophene-3-sulfonamide , N-(4-chloro-3-methyl-5-isoxazolyl)-2-((4-methoxy-0.043' 10.1' phenyl)acetyl]thiophe~ne-3-sulfonamide N-(4-bromo-3-methyl-5-isoxazolyl)-3-[(4.1.64' 22.8' methylphenoxy)methyl]thiopheene-2-sulfonamide N-(4-bromo-3-methyl-5-isoxazolyl)-2-((4-1.2' 15' methylphenoxy)methyl]thiophe~ne-3-sulfonamide N-(4-bromo-3-methyl-5-isoxazolyll-3-(4-methyl-0.94' 0.66' irans-styryl)thiophene-2-sulfonamide .

N-(4-bromo-3-methyl-5-isoxazolyl)-3-(4-methyl-0.347' 4' phenethyl)thiophene-:2-sulfonamide .

N-(4-bromo-3-methyl-5-isoxazolyl)-2-((4-methyl-0.198' 9.13' phenyl)acetyl]thiophene-3-sulfonamide N-(4-bromo-3-methyl-5-isoxazolyl)-2-[(3-0.030' 19.1' methoxyphenylacetyl]thiophene-3-sulfonamide N-(4-bromo-3-methyl-5-isoxazolyl)-3-(4-methyl-6.1 ' 2.09' phenethyl)-5-(4-tolyl)t:hiophene-2-sulfonamide N-(4-bromo-3-methyl-5-isoxazolyl)-3-(4-4.69' 1.56' methylbenzyl)-5-(4-tolyl)thioph~ene-2-sulfonamide N-(4-bromo-3-methyl-5-isoxazolyll-3-(4-methyl-6.9' 1 58' traps-styryl)-5-(4-tolyl)thiophene-2-sulfonamide .

r, i COMP17UND ET" (ErM)'ETs (frM]' N-(4-chloro-3-methyl-5-isoa:azolyl)-2-(~,~-(ethylene-0.128' 2.09' dioxy)-3,4-(methylenedioxy)phenethyl]thiophene-3-sulfonamide N-(4-chloro-3-methyl-5-iso~;azolyl)-2-(~-(dimethyl-20.9' -100' amino)-3,4-(methylenedioxy)phenethy)thiophene-3-sulfonamide N-(4-chloro-3-methyl-5-isox,azolyl)-2-{o-hydroxy-2.5' 30' (3,4-(methylenedioxy)phenyl)acetyl}thiophene-3-sul-fonamide N-(4-chloro-3-methyl-5-isoxazolyll-2-(15-methyl-3-0.056' 92' isoxazolyllaminoc.~rbonyl]thiophene-3-sulfonamide N-(4-bromo-3-methyl-5-isox;azolyl)-2-[(3-hydroxyl-6-0.066' 81.3' pyridazinyllaminocarbonyl]thiophene-3-sulfonamide N-(4-chloro-3-methyl-5-isoxazolyi)2-{(2-acetyl-4,5-0.010' 31.6' (methylenedioxy)phenyl)amiinocarbonyl}thiophene-3-sulfonamide N-(4-bromo-3-methyl-5-isoxazolyll-3-{(3,4-0.513' 9.6' (methylenedioxy)phenoxy)methyl}thiophene-2-sul-fonamide N-(4-bromo-3-methyl-5-isoxazolyl)-2-((4-0.26' 0.413?

methyll(cinnamyl)] thiophene-3-sulfonamide N-(4-chloro-3-methyl-5-isox,azolyl)-2-((4,5-0.55' --dimethoxy-2-methoxycarbonylphenyllaminocar-bonyl]thiophene-3-sulfonamide N-(4-chloro-3-methyl-5-isox;azolyl)-2-((2-methyl-0,131 _-1,3,4-thiadiazol-5-yl)aminocarbonyl]thiophene-3-sul-fonamide N-(4-chloro-3-methyl-5-isox~azolyl)3.80 ' --2-{[4,5-dimethoxy-2,4,5-dimethoxy~2-methoxycar-bonyl)phenyl]phenylaminocarbonyl}thiophene-3-sul-fonamide N-(4-chloro-3-methyl-5-isoxazolyll2-{[2-carboxyl-1.43' _ 4,5-(methylenedioxy)phenyl]aminocarbonyl}thio-phene-3-sulfonamide N-14-bromo-3-methyl-5-isox:azolyl)-3-(3,4-0.236' 18' (methylenedioxy)phenethyl]thiophene-2-sulfonamide N-(4-bromo-3-methyl-5-isox;azolyl)-3-(3,4-0.218' 10' (methylenedioxy)-tpans-styryl]thiophene-2-sulfona-mide WO 96131492 PCTlUS96104759 COMPO~JND ET" (ErM)'ETs (pM)' N-(4-bromo-3-methyl-5-isoxazolyl)-2-((4-methyl)-0.106' 40.1' phenethyl]thiophen~~-3-sulfonamide N-(3,4-dimethyl-5-isoxazolyl)-2-{(2-acetyl-4,5-0.0321 (methylenedioxy)phenyl]aminocarbonyl}thiophene-3-sulfonamide N-(4-chloro-3-methyl-5-isaxazolyl)-2-(4-methoxy-2-0.027' 0.141 methylphenyl)aminocarbonyljthiophene-3-sulfona-mide N-(4-chloro-3-methyl-5-isoxa zolyl)-2-({2-cyano-4,5-0.0039' 12 2' dimethoxyphenyl)arninocarbonyljthiophene-3-sulfon- .

amide N-(3,4-dimethyl-5-isoxazolyl)-2-(4-tolylacetylphenyl)-.0027' 29.2' thiophene-3-sulfonamide N-(3,4-dimethyl-5-isoxazolyl)-2-(3,4-(methylene-0.0273' 12 dioxylphenylacetyl]thiophene-3-sulfonamide .

N-(4-chloro-3-methyl-5-isoxaz:olyl)-2-((2,4-0.158' 63.1' dimethoxyphenyl)aminocarbo;nyl]thiophene-3-sulfon-amide N-(4-chloro-3-methyl-5-isoxazolyl)-2-((3-methyl-6-0.023' 43 7' pyridyt)aminocarbonyl]thiophe:ne-3-sulfonamide .

N-(4-chloro-3-methyl-5-isoxazolyl)-2-(2-hydroxy-4-.006' _ methylphenyllaminocarbonyl]t:hiophene-3-sulfona-mide N-(4-chloro-3-methyl-5-isoxazolyl)-2-{(2-cyano-4,5-0.0034' 40 4' (methylenedioxy)phE:nyl]aminocarbonyl}thiophene-3- .

sulfonamide N-(4-chloro-3-methyl-5-isoxazolyll-2-(2-methyl-4,5-0.0030' 3551 (methylenedioxy)phe:nylaminocarbonyl]thiophene-3-sulfonamide N-(4-chloro-3-methyl-5-isoxarolyl)-2-(2-0.011' 61' carboxamido-4,5-dimethoxyphenylamino-carbonyl)thiophene-3-sulfonannide N-(3,4-dimethyl-5-isoxazolyl)-2-(2,4-0.0027' 17.4' dimethylphenylacetyl)thiophene-3-sulfonamide N-(4-chloro-3-methyl-5-isoxazolyll-2-(2,4-dimethyl-0.0004' 4.gT

phenylacetyl)thiophene-3-sulfonamide N-(4-bromo-3-methyl-5-isoxazolyl)-2-(2,4-0.0008'" 3.6' dimethylphenylacetyll)thiophene-3-sulfonamide WO 96!31492 PCZYUS96/04759 I~OMPOIINO ET" (NM]~ ETs (pM]~

N-(4-chloro-3-methyl-5-isoxa~:olyl]-2-(3,4-0.0073' 9.2' (methylenedioxy)]phenylamirnocarbonyl-3-thiophenesuifonamide N-(4-chloro-3-methyl-5-isoxaz:olyll-2-[2-methyl-4,5-0.0032' 9' (methylenedioxy)phe;nylacetyl]thiophene-3-sulfonamide N-(4-chloro-3-methyl-5-isoxaz.olyl)-2-[3,4-0.0045' 25.7' (methylenedioxyl-6-1;2-acetoxyethyl)phenylamino-carbonyl]thiophene-3-sulfonamide N-(4-chloro-3-methyl-5-isoxazolyll-2-(3,4-0.0056' 16.8' (methylenedioxy)-6-(2-hydroxyethyl)phenyl-aminocarbonyl]thiophene-3-sulfonamide N-(4-chloro-3-methyl-5-isoxazolyl)-2-(3,5-dimethyl-0.045' 17.7' phenylacetyllthiophene-3-sulfonamide N-(4-chloro-3-methyl!-5-isoxazolyl-2-(2,5-0.007' 18' dimethylphenylacetylthiophene-3-sulfonamide N-(4-chloro-3-methyl-5-isoxazolyl)-2-(2-0.0068' 19.8' methanesulfonylaminomethyl)-4,5-(methylenedioxy)phenyiaminocarbonyl]thiophene-3-sulfonamide N-(4-chloro-3-methyl-5-isoxazolyl)-2-(2-0.0038' 25' cyanomethyl-4,5-Imethylenedioxy)-6-cyanomethyl]- -phenylaminocarbonyl-3-thiophenesulfonamide N-(4-chloro-3-methyl-5-isoxaz~olyll-2-(2-hyroxyproyl-0.0073' 8.3' 4,5-(methylenedioxyiphenylaminocarbonyl]-thiophene-3-sulfonarnide N-(4-bromo-3-methyl-5-isoxazolyl)-3-[2-methyl-4,5--0,1' -6 (methylenedioxy)cinnamyl]thiophene-2-sulfonamide N-(4-bromo-3-methyl-5-isoxazolyl)-3-(2-methyl-4,5--0.1' -5' (methylenedioxy)phenethyl]thiophene-2-sulfonamide N-(4-bromo-3-methyl-5-isoxazolyl)-3-{(2-propyl-4,5--0.2' -1.5' (methylenedioxy)phenoxy]methyl}thiophene-2-sulfonamide N-(4-chloro-3-methyl-5-isoxazolyll-2-(3,4--0.02' -18' (methylenedioxy)-6-(2-acetoxyethoxy)]phenylamino-carbonyl]thiophene-3-sulfonamide N-(4-chloro-3-methyl-5-isoxazolyl)-2-(3,4-_0.01' -18' (methylenedioxy)-6-(.2-hydroxyethoxy)phenyl-aminocarbonyl]thiophene-3-sulfonamide WO 96f31492 PCT/US96/04759 COMPOUND ET" (~rM)'ET, (NM)' N-(4-chloro-3-methyl-5-isoxanolyl)-2-(2-cyano-4,5--0.3'" -p,7 fmethylenedioxy)phenylacetyl)thiophene-3-sulfonamide N-(4-chloro-3-meth~~l-5-isoxazolyp-2-{2-0.009r 13.8' ((dimethylamino)carbonylmet:hyl)-4,5-(methylene-dioxy)phenylaminoc:arbonyl}t:hiophene-3-sulfonamide N-(4-chloro-3-methyl-5-isoxazolyl)-2-(2-methyl-4,5-0.794' 6.49' (methylenedioxy)phenylhydroxyimino)thiophene-3-sulfonamide N-(4-bromo-3-meth~~l-5-isoxazolyll-2-(2-methyl-4,5-0.0619' 8.90' (methylenedioxy)phenethyl)thiophene-3-sulfonamide N-(4-bromo-3-methyl-5-isoxazolyl)-3-(2-0.0795' 3.24' (hydroxymethyl)-4,..i-(methylenedioxy)cinnamyl)thiiophene-2-sulfonamide N-(4-bromo-3-methyl-5-isoxazolyl)-3-{2-((tetrahydro-0.0967' 4.14 4H-pyran-2-ylxoy)methyl)-4, fi-(methylenedioxy)cinnamyl}thiophene-2-sulfonamide N-(4-bromo-3-methyl-5-isoxazolyl)-3-(2,4-0.1006' 4.30' dimethylphenethyl)thiophene-2-sulfonamide N-(4-bromo-3-methyl-5-isoxa:zolyl)-3-(2,4-0.180' 2.97' dimethylcinnamyl)thiophene-:2-sulfonamide N-(4-bromo-3-methyl-5-isoxa:zolyl)-2-(2,4-0.166' 2.97' dimethylcinnamyl)thiophene-;3-sulfonamide~

N-(4-bromo-3-methyl-5-isoxazolyl)-3-((2,4-0.346' 7.45 dimethylphenoxy)meahyl]thiophene-2-sulfonamide N-(4-bromo-3-methyl-5-isoxazolyl)-2-((2,4-0.308' 4.48' dimethylphenoxy)meahyl)thiophene-3-sulfonamide N-(4-chloro-3-methyl-5-isoxa~:olyl)-5-28.1 t 60.6' (phenylaminocarbonyl)thioph<~ne-2-sulfonamide N-(4-chloro-3-methyl-5-isoxa~:olyl)-2-(~-acetoxy-2-0.00544 3.74' methyl-4, 5-Imethylenedioxy).~tyryl )thiophene-3-sulfonamide N-(4-chloro-3-methyl-5-isoxaa:olyl)-2-((2,3,4-0.000169' 12.5' trimethoxy-6-cyano)phenylaminocarbonyl)thiophene-3-sulfonamide N-(4-chloro-3-methyl-5-isoxa~:olyl)-2-(2-6.33' 8.82' (cyano)phenylJbenzc[b)thiophene-3-sulfonamide WO 96!31492 PCTIUS9GI04759 (:OMPOU~ND ET" (~rM)~ ETs (pM)~

N-(4-chloro-3-methyl-5-isoxazolyll-2-(3,4-(methyl-0.550' 52.61 enedioxy)phenyl]benzo[b)thiophene-3-sulfonamide N-(4-bromo-3-methyl-5-isoxazolyl)-3-(2-0.324' 55.1' tolyllthiophene-2-sulfonamide N-(4-bromo-3-methyl-5-isoxazolyl)-3-(3-0.832' 21.2' tolyllthiophene-2-sulfonamide N-(4-bromo-3-methyl-5-isoxazolyl)-3-(2-0.302' 3191;@100' tolylthiophene-2-sulfonamide N-(4-bromo-3-methyl-5-isoxazolyl)-3-(3-0.334' methoxyphenyllthiophene-2-sulfonamide N-(4-bromo-3-methyl-5-isoxazolyl)-3-!3-1.32' 56.3' methoxyphenyl)thiophene-2-sulfonamide N-!4-bromo3-methyl-5-isoxazolyl)-3-!2-1.71' 59.1' methoxyphenyl)thiophene-2-sulfonamide N-(4-bromo-3-methyl-5-isoxazolyl)-3-(4-0.184 43.9' ethylphenyllthiophene-2-sulfonamide N-(4-bromo-3-methyl'-5-isoxarolyl)-3-!4-0.0873 8.48' propylphenyllthiophene-2-sulfonamide N-(4-bromo-3-methyl-5-isoxazolyl)-3-(4-iso-0.218 28.3' propylphenyllthiophene-2-sulfonamide N-(4-bromo-3-methyl-5-isoxazolyll-3-(4-0.160 6.11' butt'lphenyl)thiophene-2-sulfonamide N-(3,4-dimethyl-5-isoxazolyll-:?-(2-methyl-4,5-0.00328' 34.3' (methylenedioxy)phenylacetylJthiophene-3-sulfonamide N-(4-chloro-3-methyl-5-isoxazolyl)-2-(2,4,6-0.000626' 8.27' trimethylphenylaminocarbonyl)thiophene-3-sulfonamide N-(4-chloro-3-methyl-5-isoxazolyll-2-(2,4,6-tri-0.000238' 3.82' methylphenylacetyl)thiophene-3-sulfonamide N-(4-chloro-5-methyl-3-isoxazolyl)-2-(2-methyl-4,5-0.000625' 3.69' (methylenedioxy)phenylacetyl)thiophene-3-sulfonamide N-(4-bromo-3-methyl-5-isaxazolyl)-2-(2-methyl-4,5-0.0804' 3.28' (methylenedioxylcinr~amyl)thiophene-3-sulfonamide N-(4-bromo-3-methyl-5-isoxazolyll-2-(2,4-0.0555' 3.48' dimethylphenethyl)thiophene-I-sulfonamide WO 96!31492 PCT/US96/04759 COMPOUIND ET" (pM]' ETs (pM]' N-(4-chloro-3-methyl-5-isoxazolyp-2-[(4-0.000266' 9.78' methoxycarbonyl-2,6.-dimethyl)-phenylaminocarbonyl]thiophene-3-sulfonamide N-(4-chloro-3-methyl-5-isoxazolyl)-2-4.41 ' 3196@100' (phenoxycarbonyl)thiophene-3-sulfonamide N-(4-bromo-3-methyl-5-isoxazolyll-2-2.71' 20i6@100' Iphenoxycarbonyl)thiophene-3-sulfonamide N-(3,4-dimethyl-5-isoxazolyl)-2-{(3,4-3.61' 30%@1 JO' Imethylenedioxy)phenoxy)carbonyl}thiophene-3-sulfonamide N-(4-bromo-3-methyl-5-isoxazolyll-2-((2-0.684' 105' methylphenoxy)carbonyl]thiophene-3-sulfonamide N-(4-bromo-3-methyl-5-isoxazolyl)-2-(13-1.20' 111' methylphenoxy)carbonyl]thiophene-3-sulfonamide N-(4-bromo-3-methyl..5-isoxazolyl)-2-((2,4-0.291' 43.2' dimethylphenoxylcarbonyl]thiophene-3-sulfonamide ' N-(4-bromo-3-methyl-5-isoxazolyl)-2-((2-0.761' 29~@100' methoxylphenoxy)carbonyl]thiophene-3-sulfonamide N-(4-bromo-3-methyl-5-isoxazolyl)-2-((3-0.78' 90' methoxylphenoxylcarbonyl]thiophene-3-sulfonamide N-(4-bromo-3-methyl-5-isoxazolyll-2-[(4-1.73' 111' .

methoxylphenoxy)carbonyl]thiophene-3-sulfonamide N-(3,4-dimethyl-5-isoxazolyl)-2-[(4-'0.324 68.5' methoxylphenoxy)carbonyl]thiophene-3-sulfonamide N-(3,4-dimethyl-5-isoxazolyll-2-((4-0.324' 68.5' ~

methylphenoxy)carbonyl]thiophene-3-sulfonamide N-(4-chloro-3-methyl-5-isoxazolyl)-2-((4-2.52' 19%@100' methylphenoxy)carbonyl]thiophene-3-sulfonamide N-(4-chloro-3-methyl-5-isoxazolyl)-2-((2,4-3.22' 43~@100' dimethylphenoxy)carbonyl]thiophene-3-sulfonamide N-(3,4-dimethyl-5-iso;Kazolyl)-2-((2,4-0.648' 68.5' dimethylphenoxy)carbonyl]thiophene-3-sulfonamide N-(4-bromo-3-methyl-5-isoxazolyl)-2-{(2-propyl-4,5-0.274' 21 ~@100' (methylenedioxy)phenoxy]carbonyl}thiophene-3-sulfonamide N-14-chloro-3-methyl-5-isoxazolyll-2-(3-0.138' 11.9' methoxycarbonyl-2,4"6-trimethylphenylamino-carbonyf)thiophene-3-sulfonamide WO 96!31492 P~.'TIUS96/04759 COMPOUND ET" (pM)' ETs (pM)' N-(4-bromo-3-methyl-5-isoxazolyll-3-(2,4-0.1002' 60.3' dimethylphenyl)thiophene-2-sulfonamide N-(3,4-dimethyl-5-is,oxazolyl)~2- 2.85' 31 %' (phenoxycarbonyl)thiophene-3-sulfonamide N-(4-bromo-3-methyl-5-isoxazolyll-3-(4-iso-0.0823' 2.76' butt'lphenyl)thiophene-2-sulfonamide N-(4-bromo-3-methyl-5-isoxazolyl)-3-(4-iso-0.1551 3.31' pentylphenyl)thiophene-2-sulfonamide N-(4-bromo-3-methyl-5-isoxazolyl)-3-[(2,4,6-0.0457' 4.68' trimethylphenoxy)methyl]thiophene-2-sulfonamide~

N-(4-bromo-3-meth~rl-5-isoxa:zolyl)-2-((2,4,6-0.0562' 3.39' trimethylphenoxy)methyl]thiophene-3-sulfonamide N-(4-bromo-3-methyl-5-isoxazolyl)-3-(2,4,6-0.04901 1.86' trimethylcinnamyllthiophene-2-sulfonamide N-(4-bromo-3-methyl-5-isoxazolyl)-3-(2-methyl-4-0.0468' 3.63' propylphenyl)thiophene-2-sulvfonamide N-(4-bromo-3-methyl-5-isoxazolyl)-3-(4-iso-butyl-2-0.0468' 1.66' methylphenyl)thioph~ene-2-sulfonamide N-(4-bromo-3-methyl-5-isoxa zolyl)-3-(4-iso-pentyl-2-0.107' 2.40' methylphenyllthioph~ene-2-sulfonamide N-(4-bromo-3-methyl-5-isoxaz olyl)-2-{[3,4-0.302' 6.611 (methylenedioxy)phenoxy]methyl}thiophene-3-sulfonamide N-(4-bromo-3-methyl-5-isoxaolyl)-2-{[4,5-0.107' 0.407' (methylenedioxy)-2-propylphe:noxy]methyl}thio-phene-3-sulfonamide N-(4-bromo-3-methyl-5-isoxaz olyl)-2-(2,4,6-0.0417' 1.23' trimethylphenethyl)thiophene-3-sulfonamide N-(4-bromo-3-methyl-5-isoxaz olyl)-3-(2,4,6-0.055' 1.62' trimethylphenethyl)thiophene-2-sulfonamide N-(3,4-dimethyl-5-isoxazolyl)-2-((2,4,6-0.537' 8~@100' trimethylphenoxy)carbonyl]thiophene-3-sulfonamide N-(4-chloro-3-methyl-5-isoxaa:olyl)-2-((2,4,6-0.0776' 30.2' trimethylphenoxy)ca.rbonyl]thiophene-3-sulfonamide N-(4-bromo-3-methyl-5-isoxaz olyl)-2-[(2,4,6-0.479' 24.5' trimethylphenoxylcarbonyl]thiophene-3-sulfonamide R'O 96!31a92 PCTIUS96/04759 ' results are generally the: average of 2 to 5 experiments " preliminary re::ults or results in which one or more data points were only determined approximately ' assay performed with incubation at 24° C. As described in the Examples, incubation at the higher temperature reduces the activity by a factor of 2- to about 10-compared to the activity at 4° C
- data not available o~~ measure:d as 96 inhibition @ 100 pM
= 96 inhibition @ 100 pM
It is understood that ~4-bromo or 4-chloro groups can be replaced by other 4-halo substituents or other suitable substituents for R', such as alkyl.
2. ArZ is a substituted 4-biphenyl group Compounds of formulae I in which Ar' is N-(5-isoxazolyl) or N-(3-isoxazolyl) in which Are is selected from biphenyl derivatives. These compounds can be represented by the following formulae (VII):
Ru Ra \ R. R~ I \ R. R~
/ /
\ I \~
2O ~ so= N ~ ~ N or Ri~ soz N ~ N ~ o / I O // H
H
Rn in which Rzfi and R" are each independently selected from H, OH, OHNH, NHz, NO~, halide, pseudohalide, alkyl, alkenyl, alkynyl, aryl, arylalkyl, heterolaryl, alkoxy, alkylamino, dialkylamino, alkylthio, haloalkoxy, haloalkyl, alkylsufinyl, alkylsulfonyl, aryloxy, arylamino, arylthio, arylsufinyl, arylsulfonyl, haloalkyl, haloaryl, alkoxycarbonyl, carbonyl, alkylcarbonyl, aminocarbonyl, arylcarbonyl, formyl, substituted cr unsub=,tituted amido, substituted or unsubstituted ureido, in which the alkyl, alkenyl and alkynyl portions contain from 1 up to about 14 carbon atoms, preferably from 1 to 6 atoms, and are either straight or branched chains or cyclic, and the aryl portions contain from about 4 to about 16 carbons, preferably 4 to 10 carbons. Ft" and R~6 are preferably each selected from from H, loweralkyl, haloalkyl and halide. Again, it is understood that Arz may be substituted with more than one substituent, each of which is selected independently from the selections set forth for R~6 and R", and R2 and R' are as defined above.

WO 96!31492 PCTIUS96/04759 _r~5_ In the embodiments herein, the biphenylsulfonamides are substituted 4-biphenylsulfonamidEa, R" is preferably at the para position and Rzs, if it is not hydrogen, is at any position except the 2-position.
In more preferred embodiments, R' is halide or methyl or higher (C9-C,3) alkyl. R' is selected from halide, CH,, CzHs, CF,, CzFS, n-C3H, and cyclo-C,H,, preferably halide or CH3, anti R~ is selected from H, CH3, CZHS, CF3, C~Fs, n-C~H, and cyclo-C3H ~, more preferably R' is halide or CH3, and RZ are selected from H, CH3, CzHs, or CF3.
In more preferred embodiments, R' is CI or Br, or if greater ETB activity is preferred a higher alkyl (C9H,9 to C"H2,; RZ is selected from H, CH,, CzHs, CF3, CZFS, n-C~H" cyclo-C3H,, nC,~Hi, and nC9H,9 In yet more preferred embodiments, R' is Br, CI or C9H,9 to C,~Hz,; Ri is H, CHI, CZHS, or CFA .
The biphenyl compounds provided herein are generally ETB active or ETB
selective (see, e-a., Table 2); i.e. the compounds provided herein inhibit binding of endothelin to ETa receptors at concentrations about 10- to about 30-fold less than they inhibit binding of e~ndothelin to ET" receptors. In particular the 4-biphenylsulfonamides are ETB selective.
In general in all embodiments herein, 4-haloisoxazolyl sulfonamides exhibit substantially enhanced activity with respect to at least one of the ET
receptors (about two-fold to twenty-fold greater activity), as assessed by assays, such as those provided herein, that measure binding to ET,, and/or ETB
receptors. compared to corresponding sulfonamides in which the substituent at the 4 position in the isoxazolyl is other than halo, such as alkyl. For example:
the ICSa of N-(3,4-dimethyl-5-isoxazolyl)-2-biphenylsulfonamide for ET,, receptors is about 0.008 NM, whereas, the ICso of N-(4-bromo-3-methyl-5-isoxazolyl)-2-biphenylsulfonamide is about. 0.0016 NM (see, Table below); and (3) the ICso of N-(3,4-dimethyl-5-isoxazolyl)-3-biphenylsulfonamide for ETB receptors is about 3.48 ~M; whereas, ~:he ICSO of N-(4-bromo-3-methyl-5-isoxazolyl)-3-biphenylsul-fonamide for ETe receptors i:~ about 0.76 NM and the ICso of N-f4-chloro-3-methyl-5-isoxazolyl)-3-biphenylsulfonamide for ET8 receptors is about 0.793 NM
(see, Table below).

WO 96!31492 PCT/US96I04759 Exemplary biphenyl sulfonamides are the following and those set forth in Table 2, and include, but are not limited to:
N-(3-methyl-5-isoxaz ofyll-4'-methy!phenyl-4-biphenylsulfonamide, N-(4-bromo-3-methyl-5-isoxazolyl)-4'-methy!phenyl-4-biphenylsulfonamide, N-(4-chloro-3-methyl-5-isoxazolyll-4'-meth,rlphenyl-4-biphenylsulfonamide, (3-methyl-5-isoxazolyl)-4'-trifluorophenyl-4-biphenylsulfonamide, (4-bromo-3-methyl-5-isoxazolyl)-4'-trifluorophenyl-4-biphenylsulfonamide, (3-methyl-5-isoxazolyl)-4'-methyoxyphenyl-4-biphenylsulfonamide, (4-bromo-3-methyl-5-isoxazolyl)-4'-methoxyphenyl-4-biphenylsulfonamide, (4-bromo-3-methyl-5-isoxazolyl)-3'-methoxyphenyl-4-biF~henylsulfonamide, (4-bromo-3-methyl-5-isoxazolyll-2'-methoxyphenyl-4-biphenylsulfonamide, N-(4-bromo-3-methyl-5-isoxazolyl)-3',4'-methylenedioxyphenyl-4-biphenylsulfonamide and (4-bromo-3-methyl-5-isoxazolyl)-3'-methyl phenyl-4-biphenylsulfonamide. Corresponding 4-chloro and 4-fluoro isoxazolyl compounds are also encompassed herein.
Exemplary biphenyl compounds were tested using the exemplified assays (see, EXAMPLES) and the results, which are intended to be exemplary or provided for comparison with compounds provided herein, and are not limiting, are as set forth in the following table (Table 21:

COMPOUAID ET" (pM)' ETs (NM)~

N-(4-bromo-3-methyl-5-isoxazolyl)-4-biphenylsul-3,3 _0_17 I

I
fonamide 49r 1.23' I

N-(4-bromo-5-methyl-3-isoxazolyl)-4-biphenylsul-6.4 t 2 0.29 t 0.02 fonamide 49r 1.78, N-(4-chloro-3-methyl-5-isoxazolyll-4-biphenylsul-4.93 t 0.29 t 0.1 fonamide N-(3,4-dimethyl-5-isoxazolyl)-4- 9.9 t 1.4 0.770.32 biphenylsufonamide 6.3r 0.15' N-(4-ohloro-5-methyl-3-isoxazolyl)-4-biphenylsul-3.7 0.2310 fonamide 18.6' .
1.29' N-(4-Methyl-3-trifluoromethyl-5-isoxazolyl)-4-19.0 1.7 biphenylsulfonamide _ 5.62r N-(4-Tridecyl-3-trifluoromethyl-5-isoxazolyl)-4-34.0 t 0.99 t 0.2 biphenylsulfonamide 33.0' 0.95' WO 96r31492 PCT/US96/04759 COMPOUND ET" (NM)' ETs (pM)' N-(3,4-dimethyl-5-isoxazolyl)-2-biphenylsulfon-o.ooe3~o.oot412.8 amide N-(4-bromo-3-methyl-5-isoxa~:olyl)-2-biphenylsul-0.00127" 8.54"

fonamide N-(4-chloro-3-methyl-5-isoxazolyl)-2-biphenlsulfon-0.00123" _ 14"

amide N-(3,4-dimethyl-5-isoxazolyl)-3-biphenylsulfon->0.03" 3.48"

amide N-(4-bromo-3-methyl-5-isoxazolyl)-3-biphenylsul--0.03" 0 76"

fonamide .

N-(4-chloro-3-methyl-5-isoxaz~olyl)-3-biphenylsul->0.03" 0.793"

fonamide N-(4-bromo-3-methyl-5-isoxazolyl)-4'-14.53 O.Oa6 x 0.044 9.6 methylphenyl-4-biphenylsulfonamide22.17 =3.77'0.168 _-0.0032' N-(4-bromo-3-methyl-5-isoxazolyll-4'-5.40.3 0.083Ø02 trifluorophenyl-4-biphenylsulfonamide25.9113.7'0.71 10.43' N-(4-bromo-3-methyl-5-isoxazolyl)-4'-14.7 t 1.1 5 y 0.44 5.6 methoxyphenyl-4-biphenylsulfonamide121.5=2.12'3.94=0.89' N-(4-bromo-3-methyl-5-isoxazolyp-3'-4.97 3.4 0.66 t 0 methoxyphenyl-4-biphenylsulfonamide162.6=7.t4~.
2.0810.23' N-(4-bromo-3-methyl-5-isoxazolyl)-2'-3.3 t 3.5 0.41 Ø14 methoxyphenyl-4-biphenylsulfonamide N-(4-bromo-3-methyl-5-isoxazolyl)-3',4'-38.214.95'3.00.78' methylenedioxyphen~~l-4-biphenylsulfonamide N-(4-bromo-3-methyl-5-isoxazolyl)-3'-_ . --methylphenyl-4-biphe~nylsulfonamide ' results generally from 1, 2 or 3 experiments with the same preparation ""' preliminary results Preferred cornpounds are those in which Arz is a 4-biphenyl in which, referring to formula VII and at least one substitutent R'3 is at the para position. Preferred substitutents are loweralkyl, halo loweralkyl and lower alkoxy. Such compounds are ETB active.
The preparatlion of tine above and other compounds that possess the requisite acitivities are aet forth in the Examples.

B. Preparation of the compounds The preparation of some of the above and other compounds that possess the requisite acitivities are set forth in the Examples. Com-pounds whose syinthesis is not explicitly exemplified can be synthesized by routine modification of one or more methods described in detail in the Examples by substituting appropriate readily available reagents.
The preparation of the above compounds are described in detail in the examples. Any such compound or similar compound may be synthesized according to a method discussed in general below and set forth in the Examples by selecting appropriate starting materials as exemplified.
In general, most of the syntheses involve the condensation of a sulfonyl chloride with an aminoisoxazole in dry pryidine or in tetrahydrofuran (THF) and sodium hydride. The sulfonyl chorides and 75 aminoisoxazoles either can be obtained commercially or synthesized according to methods described in the Examples or using other methods available to those of skill iln this art (see, ela., U.S. Patent Nos.
4,659,369, 4,861,366 and 4,753,672).
The N-(alkylisoxazolyl)sulfonamides can be prepared by condensing an aminoisoxazole with a sulfonyl chloride in dry pyridine with or without the catalyst 4-(dirt~ethylamino)pyridine. The N-(3,4-dimethyl-5-isoxazolyl)sulfonarnides and N-(4,5-dimethyl-5-isoxazolyl)sulfonamides can be prepared from the corresponding aminodimethyiisoxazole, such as 5-amino-3,4-dimethylisoxazole. For example, N-(3,4-dimethyl-5-isoxa-zolyl)-2-(carbomethoxy)thiophene-3-sulfonamide was prepared from 2-methoxycarbonylthiophene-3-sulfonyl chloride and 5-amino-3,4-dimethyl-isoxazole in dry pyridine.
The N-(4-haloisoxaz:olyl)sulfonamides can be prepared by condensa-tion of amino-4-haloisoxazole with a sulfonyl chloride in THF with sodium WO 96!31492 PCT/US96/04759 hydride as a base. For example, N-(4-bromo-3-methyl-5-isoxazolyl)thio-phene-2-sulfonamide was. prepared from 5-amino-4-bromo-3-methylisoxa-zole and thiophene-2-sulfonyl chloride in THF and sodium hydride. N-(4-bromo-3-methyl-~i-isoxazolyl)-5-(3-isoxazolyl)thiophene-2-sulfonamide was prepared from 5-amino-4-bromo-3-methylisoxazole and 5-(3-isoxa-zolyl)thiophene-2-sulphor~yl chloride.
Alternatively, compounds, such as those in which Arz is thienyl, fury! and pyrrolyl herein, may be prepared by reacting an appropriate sulfonyl chloride with a 5-aminoisoxazole substituted at the 3 and 4 positions, such as. 5-amino-4-bromo-3-methylisoxazole, in tetrahydrofuran (THF) solution containing a base, such as sodium hydride. Following the reaction, the THF is removed under reduced pressure, the residue dissolved in water, acidified and extracted with methylene chloride. The organic layer is washed and then dried over anhydrous magnesium 'i 5 sulfate, the solvents are evaporated and the residue is purified by recrystallization uaing hex;anes/ethylacetate to yield pure product.
These sulfonamides also can be prepared from the corresponding sulfonyl chloride and the ;aminoisoxazole in pyridine with or without a catalytic amount of 4-dimethylaminopyridine (OMAP). In some cases, the bis-sulfonyl compound is obtained as the major or exclusive product. The bis-sulfonated products c;an be readily hydrolyzed to the sulfonamide using aqueous socjium hydroxide and a suitable co-solvent, such as methanol or tetrahydrofuran, generally at room temperature. For example:
(a) N-(4-bromo-3-methyl-5-isoxazolyll-2-(N-phenyl-aminocarbonyl)thiophene-3-sulfonamide was prepared from N-(4-bromo-3-methyl-5-isoxazolyl)-2-carboxylthiophene-3-sulfonamide and aniline and 1-ethyl-3'-[3-dimethylaminopropyl]carbodiimide (EDCI). N-(4-bromo-3-methyl-5-isoxazol~yl)-2-((4-methoxyphenyl)aminocarbonyl]thiophene-3-sul-fonamide was prepared from 4-methoxyaniline, N,N'-diisopropylethyl-amine and N-(4-bromo-3-rnethyl-5-isoxazolyl)-2-carboxyithiophene-3-sul-fonamide. N-(4-bromo-3-methyl-5-isoxazolyl)-2-(benzylaminocarbonyl)-thiophene-3-sulfonamide was prepared from N-(4-bromo-3-methyl-5-isoxazolyl)-2-carboxylthiophene-3-sulfonamide and benzylamine as described above.
N-(4-bromo-3-methyl-5-isoxazolyl)-2-carboxylthiophene-3-sulfona-mide was prepared from N-(4-bromo-3-methyl-5-isoxazolyl)-2-(carbo-methoxy)thiophene-3-sulfonamide, which was prepared from the conden-sation of 5-amino-4-bromo-3-methylisoxazole and 2-(carbomethoxy)thio-phene-3-sulfonyl chloride.
(b) N-(4-bromo-3-methyl-5-isoxazolyl)-1-(4'-isopropyl-phenyl)pyrrole-2-sulfonamiide and N-(4-bromo-3-methyl-5-isoxazolyl)-1-(4'-isopropylphenyl)pyrrole~-3-sulfonamide were prepared from 5-amino-4-bromo-3-methylisoxazole and a mixture of 1-(4'-isopropylphenyl)pyrrole-2-sulfonyl chloride and 1-(~4'-isopropylphenyl)pyrrole-3-sulfonyl chloride.
These sulfonyl chlorides were prepared from 1-(4'-isopropylphenyl)pyr-role-2-sulfonic acid in phosphorus oxychloride and phosphorus penta-chloride. 1-(4'-isopropylphenyl)pyrrole-2-sulfonic acid was prepared from 1-(4'-isopropylphenyl)pyrrole and chlorosulfonic acid. 1-(4'-isopropyl-phenyl)pyrrole was prepared from 4-isopropylaniline and 2,5-dimethoxy-tetrahydrofuran.
Prodrugs and other derivatives of the compounds suitable for administration to humans may also be designed and prepared by methods known to those of skill in t:he art (see, e-4., Nogrady (1985) Medicinal Chemistry A Biochemical ~~pproach, Oxford University Press, New York, pages 388-392).
Compounds described herein have been synthesized and tested for activity in in vitro assays and, in some cases, in in vivo animal models.

Nuclear magnetic resonance spectroscopic (NMR), mass spectrometric, infrared spectroscopic and high performance liquid chromatographic analyses indicated) that the synthesized compounds have structures consistent with those expected for such compounds and are generally at least about 98% pure. All) of the compounds exemplified or described herein exhibited activity as endothelia antagonists.
C. Evaluation of t:he bioactivity of the compounds Standard physiological, pharmacological and biochemical proce-dures are available: for testing the compounds to identify those that possess any biological activities of an endothelia peptide or the ability to interfere with or inhibit endothelia peptides. Compounds that exhibit in vitro activities, su~:h as the ability to bind to endothelia receptors or to compete with one or more: of the endothelia peptides for binding to endo-thelia receptors can be used in the methods for isolation of endothelia receptors and the method for distinguishing the specificities of endo-thelia receptors, and are candidates for use in the methods of treating endothelia-mediated disorders.
Thus, other preferred compounds of formulas I and II, in addition to those specifically identified herein, that are endothelia antagonists or agonists may be identified using such screening assays.
1. Identifying compounds that modulate the activity of an endothelia peptide The compounds are tested for the ability to modulate the activity of endothelia-1 . ~lumerous assays are known to those of skill in the art for evaluating the ability of compounds to modulate the activity of endothelia (see, e.g:, U.S. Patent No. 5,114,918 to Ishikawa et al.; EP
A1 0 436 189 to 13ANYU PHARMACEUTICAL CO., LTD. (October 7, 1991 ); Borges et al. ( 1989) Eur. J. Pharm. 165: 223-230; Filep et al.
( 1991 ) Biochem. E~io~hys. Res. Commun. 177: 171-176). In vitro studies may be corroborated with in vivo studies (see, e~4., U.S. Patent No.

5,114,918 to Ishikawa et; al.; EP A1 0 436 189 to BANYU PHARMACEU-TICAL CO., LTD. (October 7, 1991 )) and pharmaceutical activity thereby evaluated. Such ;assays are described in the Examples herein and include the ability to comlcete for binding to ETA and ETB receptors present on membranes isolat~:d from cell lines that have been genetically engineered to express either I=TA or ETB receptors on their cell surfaces.
The properties of a potential antagonist may be assessed as a func-tion of its ability t~~ inhibit an endothelia induced activity in vitro using a particular tissue, such as rat portal vein and aorta as well as rat uterus, trachea and vas d~eferens (see e-4., Gorges, R., Von Grafenstein, H. and Knight, D.E., "Tis:>ue selectivity of endothelia," Eur. J. Pharmacol 165:223-230, (1989)). T'he ability to act as an endothelia antagonist in vivo can be tested in hype~rtensive rats, ddy mice or other recognized animal models (see, Kaltenbronn et al. (19901 J. Med. Chem. 33:838-845, see, also, U.S. Patent No. 5,114,918 to Ishikawa et al.; and EP A1 0 436 189 to BA~JYU PH~4RMACEUT1CAL CO., LTD (October 7, 1991 );
see, also Bolger et al. (1983) J. Pharmacol. Exp. Ther 225291-309).
Using the results of such animal studies, pharmaceutical effectiveness may be evaluated and pharmaceutically effective dosages determined. A
potential agonist may also be evaluated using in vitro and in vivo assays known to those of skill in the art.
Endothelia activity c:an be identified by the ability of a test compound to stimulate constriction of isolated rat thoracic aorta (Gorges et al. ( 1989) "Tissue selecaivity of endothelia" Eur. J. Pharmacol. 165:
223-230). To perform the: assay, the endothelium is abraded and ring segments mounted under 'tension in a tissue bath and treated with endothelia in the presence of the test compound. Changes in endothelia induced tension are recorded. Dose response curves may be generated and used to provide information regarding the relative inhibitory potency WO 96!31492 PCTIUS96/04759 of the test compound. Other tissues, including heart, skeletal muscle, kidney, uterus, trachea and vas deferens, may be used for evaluating the effects of a particular test: compound on tissue contraction.
Endothelia isotype specific antagonists may be identified by the ability of a test compound to interfere with endothelia binding to different tissues or cells expressingi different endothelia-receptor subtypes, or to interfere with the biological effects of endothelia or an endothelia isotype (Takayanagi et al. (1991) ReQ. Pea. 32: 23-37, Panek et al. (1992) Biochem. Bioahys, Res. C~ommun. 183: 566-571 ). For example, ET8 re-ceptors are expressed in vascular endothelial cells, possibly mediating the release of prostac~yclin and endothelium-derived relaxing factor (De Nucci et al. (1988) Proc. Nat!. Acad. Sci. USA 85:9797). ETA receptors are not detected in cultured endothelial cells, which express ETB receptors.
The binding of compounds or inhibition of binding of endothelia to ETB receptors can be assessed by measuring the inhibition of endothelin-1-mediated releases of pros;tacyclin, as measured by its major stable metabolite, 6-keto PGF,o, 'from cultured bovine aortic endothelial cells (see, e-4., Filep et al. (1991) 8iochem. and Bioohys Res Commun 177:
171-1761. Thus, ,the relative affinity of the compounds for different endothelia receptors may be evaluated by determining the inhibitory dose response curves u:;ing tissues that differ in receptor subtype.
Using such ;essays, the relative affinities of the compounds for ETA receptors and ETB receptors have been and can be assessed.
Those that possess the desired properties, such as specific inhibition of binding of endothelia-1, are selected. The selected compounds that exhibit.desirable acaivities may be therapeutically useful and are tested for such uses using the above-described assays from which in vivo effective-ness may be evaluated (see, ela., U.S. Patent No. 5,248,807; U.S.
Patent No. 5,240,910; U.!~. Patent No. 5,198,548; U.S. Patent No.

5,187,195; U.S. Patent No. 5,082,838; U.S. Patent No. 5,230,999;
published Canadian Application Nos. 2,067,288 and 2071193; published Great Britain Application No. 2,259,450; Published International PCT
Application No. WO 93/08799; Benigi et al. ( 1993) Kidnev International 44:440-444; and Nirei et al. (1993) Life Sciences 52:1869-1874). Com-pounds that exhibit in vitro activities that correlate with in vivo effectiveness will then be formulated in suitable pharmaceutical compositions and used as therapeutics.
The compounds also may be used in methods for identifying and isolating endotheiin-specific receptors and aiding in the design of compounds that are more potent endothelin antagonists or agonists or that are more specific for a particular endothelin receptor.
2. Isolation of endothelia receptors A method for identifying endothelia receptors is provided. In practicing this method, one or more of the compounds is linked to a support and used in methods of affinity purification of receptors. By selecting compounds with particular specificities, distinct subclasses of ET receptors may be identified.
One or more of the compounds may be (inked to an appropriate resin, such as Affi-gel, covaiently or by other linkage, by methods known to those of skill in the art for linking endothelia to such resins (see, Schvartz et al. ( 1990) Endocrinoloav 126: 3218-3222). The linked compounds can be those that are specific for ETA or ETB receptors or other subclass of receptors.
The resin is pre-equilibrated with a suitable buffer generally at a physiological pH (7 to 8). A composition containing solubilized receptors from a selected tissue are mixed with the resin to which the compound is linked and the receptors are selectively eluted. The receptors can be identified by testing them for binding to an endothelia isopeptide or *Trade-mark analog or by other methods by which proteins are identified and characterized. Preparation of the receptors, the resin and the elution method may be performed by modification of standard protocols known to those of skill in the art .(see, e_o., Schvartz et al. (1990) EndocrinoloQy 126: 327 8-3222).
Other methods for distinguishing receptor type based on differential affinity to any of the compounds herein are provided. Any of the assays described herein for measuring the affinity of selected compounds for endothelia receptors may also be used to distinguish receptor subtypes based on affinity for particular compounds provided herein. In particular, an unknown recep~:or may be identified as an ETA or ETB receptor by measuring the binding affinity of the unknown receptor for a compound provided herein that has a known affinity for one receptor over the other.
Such preferential interaction is useful for determining the particular disease that may be treated with a compound prepared as described herein. For example, compounds with high affinity for ETA receptors and little or no affinity for ETB receptors are candidates for use as hypertensive agent:;; whereas, compounds that preferentially interact with ETB receptors are candidates for use as anti-asthma agents.
D. Formulation and administration of the compositions Effective concentrations of one or more of the sulfonamide compounds of formula I or II or pharmaceutically acceptable salts, esters or other derivatives thereof are mixed with a suitable pharmaceutical carrier or vehicle. In instances in which the compounds exhibit insufficient solubility, methods for solubilizing compounds may be used.
Such methods are W:nown to those of skill in this art, and include, but are not limited to, using cosolvents, such as dimethylsulfoxide (DMSO), using surfactants, such a:, tween, or dissolution in aqueous sodium bicarbonate. Derivatives of the compounds, such as salts of the WO 96/31492 PC?lLTS96/04759 compounds or prodrugs of the compounds may also be used in formulating effective pharmaceutical compositions.
The concentrations or the compounds are effective for delivery of an amount, upon administration, that ameliorates the symptoms of the endothelin-mediated diseaae. Typically, the compositions are formulated for single dosage administration.
Upon mixing or addiltion of the sulfonamide compound(s), the resulting mixture may be a solution, suspension, emulsion or the like.
The form of the re:5ulting rnixture depends upon a number of factors, including the intended mode of administration and the solubility of the compound in the selected carrier or vehicle. The effective concentration is sufficient for ameliorating the symptoms of the disease, disorder or condition treated and may be empirically determined.
Pharmaceutical carriers or vehicles suitable for administration of the compounds provided herein include any such carriers known to those skilled in the art to be suitable for the particular mode of administration.
In addition, the cornpounds may be formulated as the sole pharmaceutically acaive ingredient in the composition or may be combined with other active ingredients.
The active compounds can be administered by any appropriate route, for example, orally, parenterally, intravenously, intradermally, subcutaneously, or topically, in liquid, semi-liquid or solid form and are formulated in a manner suitable for each route of administration.
Preferred modes of administration include oral and parenteral modes of administration.
The active compound is included in the pharmaceutically acceptable carrier in an amount sufficient to exert a therapeutically useful effect in the absence of undesirable side effects on the patient treated.
The therapeutically effective concentration may be determined -s~-empirically by testing the compounds in known in vitro and in vivo systems (see, e.~C.,, U.S. Patent No. 5,114,918 to Ishikawa et al.; EP A1 0 436 189 to BANYU PHARMACEUTICAL CO., LTD (October 7, 1991 );
Borges et al. (198~t) Eur. J. Pharm. 165: 223-230; : Filep et al. (1991) Biochem. Biophys. Res. Commun. 177: 171-176) and then extrapolated therefrom for dosages for humans.
The concentration of active compound in the drug composition will depend on absorption, inacaivation and excretion rates of the active compound, the do:;age schedule, and amount administered as well as other factors known to those of skill in the art. For example, the amount that is delivered is sufficient to treat the symptoms of hypertension. The effective amounts 'for treating endothelin-mediated disorders are expected to be higher than tile amount of the sulfonamide compound that would be administered for' treating bacterial infections.
Typically a therapeutically effective dosage should produce a serum concentration of active ingredient of from about 0.1 ng/ml to about 50-100 Ng/ml. The pharmacen~tical compositions typically should provide a dosage of from about 0.01 mg to about 2000 mg of compound per kilo-gram of body weight per dray. The active ingredient may be administered at once, or may be divided into a number of smaller doses to be adminis-feted at intervals of time. It is understood that the precise dosage and duration of treatment is a function of the disease being treated and may be determined empirically using known testing protocols or by extrapola-tion from in vivo or in vitro test data. It is to be noted that concentra-lions and dosage v~jlues may also vary with the severity of the condition to be alleviated. It is to be further understood that for any particular subject, specific dosage regimens should be adjusted over time according to the individual need and the professional judgment of the person ad-ministering or supervising the administration of the compositions, and ~68-that the concentration ranges set forth herein are exemplary only and are not intended to limit the scope or practice of the claimed compositions.
If oral administration is desired, the compound should be provided in a composition that protects it from the acidic environment of the stomach. For example, they composition can be formulated in an enteric coating that maintains its integrity in the stomach and releases the active compound in the intestine. The composition may also be formulated in combination with an antacid or other such ingredient.
Oral compositions will generally include an inert diluent or an edible carrier and may be ~~ompressed into tablets or enclosed in gelatin capsules. For the purpose of oral therapeutic administration, the active compound or compounds can be incorporated with excipients and used in the form of tablets, capsules or troches. Pharmaceutically compatible binding agents and adjuvant materials can be included as part of the composition.
The tablets, pills, capsules, troches and the like can contain any of the following ingredients, or compounds of a similar nature: a binder, such as microcrystalline cellulose, gum tragacanth and gelatin; an excipient such as starch and lactose, a disintegrating agent such as, but not limited to, alginic acid and corn starch; a lubricant such as, but not limited to, magnesium stearate; a glidant, such as, but not limited to, colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin;
and a flavoring agent such as peppermint, methyl salicylate, and fruit flavoring.
When the do:aage unit form is a capsule, it can contain, in addition to material of the above type, a liquid carrier such as a fatty oil. In addition, dosage unit forms can contain various other materials which modify the physical form of the dosage unit, for example, coatings of sugar and other ent~sric agents. The compounds can also be administered as a component of an elixir, suspension, syrup, wafer, chewing gum or the like. A~syrup rnay contain, in addition to the active compounds, sucrose as a sweetening agent and certain preservatives, dyes and colorings and flavors.
The active materials can also be mixed with other active materials which do not impair the deaired action, or with materials that supplement the desired action, such a.. antacids, H2 blockers, and diuretics. For example, if the cornpound is used for treating asthma or hypertension, it may be used with ether bronchodilators and antihypertensive agents, respectively.
Solutions or suspensions used for parenteral, intradermal, subcutaneous, or topical application can include any of the following components: a sterile diluent, such as water for injection, saline solution, fixed oil, polyethylene glycol, glycerine, propylene glycol or other synthetic solvent; antimicrobial agents, such as benzyl alcohol and methyl parabens; antioxidants, such as ascorbic acid and sodium bisulfite;
chelating agents, such as eahylenediaminetetraacetic acid (EDTA);
buffers, such as acetates, citrates and phosphates; and agents for the adjustment of tonicity such as sodium chloride or dextrose. Parenteral preparations can be' enclosed in ampules, disposable syringes or multiple dose vials made of glass, plastic or other suitable material.
If administered intravenously, suitable carriers include physiological saline or phosphate. buffered saline (PBS), and solutions containing thickening and solubilizing agents, such as glucose, polyethylene glycol, and polypropylene ~~lycol and mixtures thereof. Liposomal suspensions, including tissue-tan~eted liposomes, may also be suitable as pharmaceutically acceptable carriers. These may be prepared according to methods known to those skilled in the art. For example, liposome formulations may be prepared as described in U.S. Patent No. 4,522,811.

WO 96!31492 PCTILIS96I04759 The active compounds may be prepared with carriers that protect the compound againat rapid elimination from the body, such as time release formulations or coatings. Such carriers include controlled release formulations, such a;~, but not limited to, implants and microencapsulated delivery systems, and biodegradable, biocompatible polymers, such as collagen, ethylene vinyl acetate, polyanhydrides, polyglycolic acid, polyorthoesters, polylactic acid and others. Methods for preparation of such formulations are: known to those skilled in the art.
The compounds may be formulated for local or topical application, such as for topical application to the skin and mucous membranes, such as in the eye, in the form of gels, creams, and lotions and for application to the eye or for intr<~cisternal or intraspinal application. Such solutions, particularly those intf:nded for ophthalmic use, may be formulated as 0.01 % - 10% isotoniic solutions, pH about 5-7, with appropriate salts.
The compounds may be formulated as aeorsols for topical application, such as by inhalation (see, e.g,, U.S. Patent Nos. 4,044,126, 4,414,209, and 4,364,923, which describe aerosols for delivery of a steroid useful for treatment inflammatory diseases, particularly asthma).
Finally, the compound:~ may be packaged as articles of manufacture containing packaging material, a compound provided herein, which is effective for antagonizing the effects of endothelin, ameliorating the symptoms of an ~~ndothelin-mediated disorder, or inhibiting binding of an endothelin peptide. to an ET receptor with an ICSo of less than about 10 NM, within the packaging material, and a label that indicates that the compound or salt thereof is used for antagonizing the effects of endothelin, treating endothelin-mediated disorders or inhibiting the binding of an endothelin peptide to an ET receptor.
The following examples are included for illustrative purposes only and are not intended to limit the scope of the invention.

N-(4-Bromo-3-methyl-5-isoxazolyl)thiophene-2-sulfonamide A solution of 5-amino-4-bromo-3-methylisoxazole (177 mg, 1.0 mmol) in dry tetrahydrofuran (THF, 2 ml) was added to a suspension of sodium hydride (60°ro disperaion in mineral oil, 90 mg, 2.2 mmol) in dry THF ( 1 ml) at 0 - 5 ° C. After stirring at 0 - 5 ° C for 5 min., the reaction was stirred at room Temperature for 10 min to complete the reaction.
The reaction mixture was re-cooled to 0° C and thiophene-2-sulfonyl chloride (200 mg, 1.1 mmol) dissolved in dry THF (2 ml) was added dropwise. Stirring was contiinued for 1 h; during this period the reaction mixture slowly attained ambiient temperature. THF was removed under reduced pressure. The residue was dissolved in water (10 ml), the pH
was adjusted to 10 - 1 1 by adding 5 N sodium hydroxide solution, and was extracted with eahyl acEaate (3 X 10 ml) to remove the neutral impurities. The aqueous layer was acidified with concentrated HCI
(pH 2 - 3) and extrar.ted with methylene chloride (3 X 10 ml). The combined organic layers was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give N-(4-bromo-3-methyl-5-isoxazolyl)thiophene-2-sulfonamide. The pure material was obtained by recrystallization using hexanea/ethyl acetate (110 mg, 34 % yield), m.p.
125 - 127 ° C.

N-(4-8romo-3-methyl-5-isoxazolyl)-5-(3-isoxazolyl)thiophene-2-sulfona-mide A solution of ~i-amino-4-bromo-3-methylisoxazole (177 mg, 1.0 mmol) in dry THF (2 ml) was added to a suspension of sodium hydride (60% dispersion in mineral oiil, 90 mg, 2.2 mmol) in dry THF ( 1 ml) at 0 - 5 ° C. After sti«ing at 0 - 5 ° C for 5 min, the reaction was warmed to room temperature for 10 ruin to complete the reaction. The reaction mixture was re-cooled to 0° C, and 5-(3-isoxazolyl)thiophene-2-sulphonyl chloride (273 mg, 1 .1 mmoll), which had been dissolved in dry THF (2 ml), was added slomly. Stirring was continued for 1 h; during this period the reaction mixture slowly attained ambient temperature. THF was removed under reduced pre:>sure. The residue was dissolved in water (10 ml), the pH was adjusted to 2 - 3 by adding concentrated HCI, and was extracted with methylene chloride (3 X 10 ml). The combined organic layers was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give N-(4-bromo-3-methyl-5-isoxazolyl)-5-(-isoxazolyl)thiophene-2-sulfonamide. The pure material was obtained by recrystallization using hexanes/ethyl acetate ( 160 mg, 41 % yield), m.p.
120 - 123 ° C.

N-(4-Bromo-3-methyl-5-isox;~zolyl)-5-(2-pyridyl)thiophene-2-sulfonamide N-(4-bromo-3-methyl-5-isoxazolyl)-5-(2-pyridyl)thiophene-2-sulfona-mide was prepared in the same manner as described in Example 2 from 5-amino-4-bromo-3-me,thylisox;azole and 5-(2-pyridyl)thiophene-2-sulphonyl chloride in 40% yield. Purification was achieved by recrystallization from ethyl acetate to give a crystalline solid, m.p. 186 - 188° C.

N-(4-Bromo-3-methy'I-5-isoxazolyl)-4,5-dibromothiophene-2-sulfonamide N-(4-bromo-3-methyl-!~-isoxazolyl)-4, 5-dibromothiophene-2-sulfona-mide was prepared in the same manner as described in Example 2 from 5-amino-4-bromo-3-methylisoxazole and 4,5-dibromothiophene-2-sulphonyl chloride in 45% yielcl. Purification was achieved by recrystallization from ethyl acetate/hexanes to give a crystalline solid, m.p. 153 - 155° C.

N-(4-8romo-3-methyl-5-isoxazolyl)-5-chloro-3-methylbenzo(b)thiophene-2-suifonamide N-(4-bromo-~I-methyl-5-isoxazolyl)-5-chloro-3-methylbenzo(bJthio-phene-2-sulfonamide was prepared in the same manner as described in Example 2 from 5-amino-4-bromo-3-methylisoxazole and 5-chloro-3-methylbenzo(bjthiophene-2-sulphonyl chloride in 18% yield. Purification was achieved by recrystallization from ethyl acetate/hexanes to give a crystalline solid, m.p. 153 - 155° C.

N-(4-Bromo-3-methyl-5-isoxazolyl)-5-(4-chlorobenzamidomethyl)thio-phene-2-sulfonamide N-(4-Bromo-3-methyl-5-isoxazolyl)-5-(4-chlorobenzamidomethyl)-thiophene-2-sulfonamide wets prepared in the same manner as described 7 5 in Example 2 from 5-amino-4-bromo-3-methylisoxazole and 5-(4-chloro-benzamidomethyl)thiophene-2-sulphonyl chloride in 27% yield. The crude product was passed through a silica gel column using hexanes/ethyl acetate as eluent. Purification was effected by recrystallization from ethyl acetate/hexanea to give a crystalline solid, m.p. 210° C (dec).

N-(4-Bromo-3-methyl-5-isox;jzolyl)-4-(benzenesulfonyl)thiophene-2-sutfon-amide N-(4-Bromo-3-methyl-5-isoxazolyl)-4-(benzenesulfonyl)thiophene-2 sulfonamide was prepared in the same manner as described in Example 2 25 from 5-amino-4-bromo-3-methylisoxazole and 4-benzenesulfonylthio phene-2-sulphonyl chloride in 26% yield. Purification was achieved by recrystallization from ethyl acetate/hexanes to give a crystalline solid, m.p. 181 - 184° C.

N-(4-Bromo-3-methyl-5-iso~xazolyl)-4.-bromo-5-chloro-thiophene-2-sulfona-mide N-(4-Bromo-3-methyl-5-isoxazolyl)-4-bromo-5-chloro-thiophene-2-sulfonamide was prepared in the same manner as described in Example 2 from 5-amino-4-bromo-3-methylisoxazole and 4-bromo-5-chlorothiophene-2-sulphonyl chloride in 25°,~o yield. Purification was achieved by recrystallization from ethyl acetate/hexanes to give a crystalline solid, m.p. 143 - 145 ° (:.

N-(4-Bromo-3-methyl-5-iso:Kazolyl)-2,5-dichlorothiophene-3-sulfonamide N-(4-Bromo-3-methyl-5-isoxazolyl)-2, 5-dichlorothiophene-3-sulfona-mide was prepared in the same manner as described in Example 2 from 5-amino-4-bromo-3-methylisoxazole and 2,5-dichlorolthiophene-3-sulphonyl 1b chloride in 47% yield. Purification was achieved by recrystallization from ethyl acetate/hexanes to give a crystalline solid, m.p. 135 - 138° C.

N-(4-Bromo-3-methyl-5-isox:azolyl)-2,5-dimethylthiophene-3-sulfonamide N-(4-Bromo-3-methyl-5-isoxazolyl)-2, 5-dimethylthiophene-3-sulfon-20 amide was preparedl in the same manner as described in Example 1 from 5-amino-4-bromo-3-methylisoxazole and 2,5-dimethylthiophene-3-sulphonyl chloride in 55% yield. Purification was achieved by ' recrystallization from ethyl acetate/hexanes to give a crystalline solid, m.p. 77 - 80° C.

N-(4-Bromo-3-methyl-5-isox.azolyl)-4, 5-dichlorothiophene-2-sulfonamide N-(4-Bromo-3-methyl-5-isoxazolyl)-4, 5-dichlorothiophene-2-sulfona-mide was prepared in the same manner as described in Example 1 from 5-amino-4-bromo-3-me;thyliso>;azole and 4,5-dichlorothiophene-2-sulphonyl WO 96!31492 PCTIUS96104759 chloride in 42% yielcj. Purification was achieved by recrystallization from ethyl acetate/hexanea to give a crystalline solid, m.p. 135 - 138° C.

N-(4-8romo-3-methyl-5-isoxazolyl)-2,5-dichToro-4-bromothiophene-3-sul-fonamide N-(4-8romo-3-methyl-5-isoxazolyl)-2,5-dichloro-4-bromothiophene-3-sulfonamide was F~repared in the same manner as described in Example 1 from 5-amino-4-bn~mo-3-methylisoxazole and 4-bromo-2,5-dichlorothio-phene-3-sulfonyl chloride in 'S8% yield. Purification was achieved by recrystallization from ethyl acetate/hexanes to give a crystalline solid, m.p. 146 - 149° C.

N-(4-Bromo-3-methy'~I-5-isoxazolyl)-2-{3-[ 1-methyl-5-(trifluoro-methyl)pyrazolyl]}thiophene-5-sulfonamide N-(4-Bromo-3-methyl-ti-isoxazolyl)-2-{3-(1-methyl-5-(trifluoro-methyl)pyrazolyl]}thiophene-5-sulfonamide was prepared in the same manner as described in Example 1 from 5-amino-4-bromo-3-methylisoxa-zole and 2-{3-[1-methyl-5-(trifluoromethyl)pyrazolyl]}thiophene-5-sulphony! chloride in 30% yield. Purification was achieved by recrystallization from ethyl ac:etate/hexanes to give a crystalline solid, m.p. 121 - 123° C.

N-(4-8romo-5-methyl-3-isoxazolyl)thiophene-2-sulfonamide Thiophene-2-s~uffonyl chloride (183 mg, 1 mmol) was added to a solution of 3-amino-~~-bromo-~5-methylisoxazole ( 177 mg,1 mmol) in dry pyridine (0.5 ml). The reaction mixture was stirred at room temperature for 3 h. Pyridine wa:~ removed under reduced pressure and the residue was partitioned between wager and ethyl acetate. The organic layer was washed with 1 N HCI (3 X 10 ml), brine ( 10 ml) and dried over anhydrous magnesium sulfate. Evaporation of the solvents left an oily residue which -~s-was solidified at -20° C and then purified by recrystallization from ethyl acetate/hexanes, to give the pure product (51 % yield) as a tan solid, m.p. 156 - 158° C.

N-(4-Bromo-3-methyl-5-isoxa::olyl)-5-(benzenesulfonyl)thiophene-2-sulfon-amide N-(4-Bromo-3-methyl-5-isoxazolyl)-5-(benzenesulfonyl)thiophene-2-sulfonamide was prepared in 'the same manner as described in Example 2 from 5-amino-4-brorrno-3-mel:hylisoxazole and 5-benzenesulfonylthio-phene-2-sulfonyl chloride in 59% yield. Purification was achieved by recrystallization from ethyl acetate/hexanes to give a crystalline solid, m.p. 139 - 142° C.

N-(4-Bromo-3-methyl-5-isoxazolyl)-2-(carbomethoxy)thiophene-3-sulfona-mide N-(4-Bromo-3-methyl-5-isoxazolyl)-2-(carbomethoxy)thiophene-3-sulfonamide was prepared in the same manner as described in Example 2 from 5-amino-4-bromo-3-methylisoxazole and 2-(carbomethoxy)thio-phene-3-sulfonyl chloride in 73% yield. Purification was achieved by recrystallization from ethyl acetate/hexanes to give a crystalline solid, m.p. 198 - 200° C.

N-(4-Bromo-3-methyl-5-isoxazolyl)-2-(carboxyl)thiophene-3-sulfonamide N-(4-Bromo-3-rnethyl-5-isoxazolyl)-2-(carbomethoxy)thiophene-3-sulfonamide (Example 16) ( 1.5 g, 3.95 mmol) was dissolved in methanol (10 ml). Sodium hydroxide pellets (1 g, 25 mmol) and a few drops of water were then added. The resultant solution was stirred for 16 h at ambient temperature. Methanol was removed under reduced pressure.
The residue was diluted withi water and was extracted with ethyl acetate (2 X 10 ml). The aqueous layer was acidified (pH = 2) with WO 96!31492 PCT/US96/04759 concentrated hydrochloric acid and was extracted with ethyl acetate (2 X
60 ml). The combined organic layers was dried over anhydrous magnesium sulfate and filtered. Removal of the solvent gave N-(4-bromo-3-methyl-5-isoxazolyl)-2-(carbomethoxy)thiophene-3-sulfonamide (1.2 g, 82% yield), which was puriified by silica gel column chromatography using ethyl acetate as eluent, m.p. 188 - 194° C.

N-(4-Bromo-3-meth~~l-5-isox;azolyl)-2-(N-phenylaminocarbonyl)thiophene-3-sulfonamide Aniline (0.093 g, 1 mmol) and 1-ethyl-3'[3-dimethylaminopropyl)-carbodiimide (EDCI) (0.191 g, 1 mmol) were added to N-(4-bromo-3-methyl-5-isoxazolyl)-2-(carboxyl)thiophene-3-sulfonamide (0.368 g, 1 mmol) that had been suspended in methylene chloride (5 ml) to produce a clear solution. Stirring was continued for 1 h at ambient temperature.
The reaction mixturE: was diluted with methylene chloride (50 ml) and washed with 3 N hydrochloric acid solution (3 X 50 ml). The combined organic layers was dried over anhydrous magnesium sulfate and filtered.
Removal of the solvent under reduced pressure gave N-(4-bromo-3-methyl-5-isoxazolyl)-2-(N-phenylaminocarbonyl)thiophene-3-sulfonamide.
The crude product thus obtained was purified by column chromatography using ethyl acetate <js eluent to yield the product f0.32 g, 72% yield, m.p. 168 - 170° C.

N-(4-Bromo-3-methyl-5-isoxazolyl) 1-(4'-isopropylphenyl)pyrrole-2-suifon-amide and N-(øbronno-3-methyl-5-isoxazolyl) 1-(4'-isopropylphenyl)pyrrole-3-sulfonamide A. 1-(4'-isopropylphenyl)pyrrole Glacial acetic acid ( 100 ml) was added to a mixture of 4-isopropylaniline (10 ml, 72.4 mmol) and 2,5-dimethoxytetrahydrofuran (9.6 ml, 72.4 mmol) and the: resulting mixture was refluxed for 1.5 h.

Wu 96131492 PC'TIUS96/04759 The reaction mixture was allowed to cool and acetic acid was removed under reduced pressure. The resulting brown syrup was dissolved in ethyl acetate (200 ml) and washed with water (2 X 200 ml). The organic layer was dried over magnesium sulfate and filtered. Removal of the solvent gave 1-(4'-isopropylphenyl)pyrrole (13.28 g, 99% yield) as a brown syrup.
B. 1-(4'-isopropylphenyl)pyrrole-2-sulfonic acid Chlorosulfonic acid ( 1.82 ml, 27.08 mmol) was slowly added to a solution of 1-(4'-is;opropyl'phenyl)pyrrole (5.01 g, 27.08 mmol) in chloroform (100 ml) at 0" C. The resulting solution was stirred at 0° C
for 1 h and for an additional 1 h at room temperature. Chloroform was removed under reduced pressure. The resultant brown liquid was diluted with ethyl acetate (200 ml) and washed with 1 N sodium hydroxide. The aqueous layer wa;~ then acidified with concentrated hydrochloric acid (pH < 1 ) and then extracted with chloroform (2 X 150 ml). The combined organic layers vvas dried over magnesium sulfate and was filtered. Removal of the solvent gave 1-(4'-isopropylphenyl)pyrrole-2-sulfonic acid as a brown syrup (3 g, 42 % yield).
C. 1-(4'-isopropylphenyl)pyrrole-2-sulfonyl chloride and 1-(4'-iso-propylphenyl)pyrrole-3-sulfonyl chloride Phosphorus pentachloride (4.7 g, 22.64 mmol) was slowly added to a solution of 1-~(4'-isopropylphenyl)pyrrole-2-sulfonic acid (3 g, 1 1.32 mmol)in phosphorus oxychloride (8.4 ml, 90.57 mmol). The resulting mixture was heated at 70° C for 10 h. The reaction mixture was allowed to cool to room temperature, then carefully poured on to crushed ice (500 g) and extracted with chloroform (200 ml). The combined organic layers was dried over anhydrous magnesium sulfate. This was filtered and re-moval of the solvent yielded a 4:1 mixture of 1-(4'-isopropylphenyl)-pyrrole-2-sulfonyl chloride and 1-[4'-isopropylphenyl)pyrrole-3-sulfonyl chloride (2.5 g, 7E1%) as a brown oil.

Wv 96131492 PCT/US96104759 D. N-(4-bromo-3-methyl-5-isoxazoiyl) 1-(4'-isopropylphenyl)pyrrole-2-sulfonamide and N-(4-bromo-3-methyl-5-isoxazolyl) 1-(4'-isopropylphenyl)pyrrole-3-sulfonamide N-(4-bromc~-3-methyl-5-isoxazolyl) 1-(4'-isopropylphenyl)pyrrole-2-sulfonamide and IV-(4-bromo-3-methyl-5-isoxazolyl) 1-(4'-isopropylphenyl)p~yrrole-:l-sulfonamide were prepared in the same manner as described in E;cample 2 from 5-amino-4-bromo-3-methylisoxazole and a mixture of 1-(4'-i:~opropylphenyl)pyrrole-2-sulfonyl chloride and 1-(4'-isopropylphenyl)pyrrole-3-sulfonyl chloride in 65% combined yield. The mixture was subjected to preparative HPLC to give N-(4-bromo-3-methyl-5-isoxazolyl) 1-(4'-isopropylphenyl)pyrrole-2-sulfonamide (retention time 22.85 min, 5% to 95% acetonitrile in water with 0.1 % TFA over 30 min period, C,e analytical column) and N-(4-bromo-3-methyl-5-isoxazolyl) 1-(4'-isopropylphenyl)pyrrole-3-sulfonamide (retention time 24.56 min, 5%
to 95% acetonitrile in water with 0.1 % TFA over 30 min period, C,e analytical column;) as oils.

N-(4-Bromo-3-meithyl-5-is oxazolyl)-5-bromothiophene-2-sulfonamide N-(4-Bromo-3-methyl-5-isoxazolyl)-5-bromothiophene-2-sulfona-mide was prepared in the same manner as described in Example 2 from 5-amino-4-bromo-3-methylisoxazole and 5-bromothiophene-2-sulfonyl chloride in 30% yield. Purification was achieved by recrystallization from ethyl acetate/hex~3nes to give a crystalline solid, m.p. 240° C (dec).

N-(4-Bromo-3-met:hyl-5-isoxazolyl)-2-(N-(4-methoxyphenyl)aminocarbonyl]-thiophene-3-sulfonamide 4-Methoxyaniline (0.246 g, 2 mmol), bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (Py8rop) (0.466 g, 1 mmol) and N,N'-diisopropylethylarnine (0.15 ml) were added to N-(4-bromo-3-methyl-5-isoxazolyl)-2-(carboxyl)thiophene-3-sulfonamide (0.368 g, 1 mmol), which A v 96131492 PCT/DS96/04759 had been suspended in methylene chloride (3 ml), resulting in a clear solution. Stirring was continued for 24 h at ambient temperature. The reaction mixture vvas diluted with methylene chloride (50 ml) and washed with 3 N hydrochloric acid solution (3 X 50 ml) followed by 5% sodium carbonate solution (2 X 50 ml). The combined organic layers was dried over anhydrous magnesium sulfate and filtered. Removal of the solvent under reduced pressure gave N-(4-bromo-3-methyl-5-isoxazolyl)-2-[N-l4-methoxyphenyl)arninocarbonyl]thiophene-3-sulfonamide. The crude product thus obtained was purified by column chromatography using ethyl acetate as elluent. This was recrystallized from ethyl acetate/hexanes to give a crystalline solid, m.p. 202 - 205 ° C
(0.08 g, 17% yield).

N-(4-Bromo-3-methyl-5-is~oxazolyl)-2-(N-(3-methoxyphenyl)amino-carbonyl]thiophen~e-3-sulfonamide N-(4-Bromo~-3-methyl-5-isoxazolyl)-2-[N-(3-methoxyphenyl)ami-nocarbonyl]thioph~ene-3-sulfonamide was prepared in the same manner as described in Example 21 from N-(4-bromo-3-methyl-5-isoxazolyl)-2-(carboxyl)thiopher~e-3-suli~onamide and 3-methoxyaniline in 23% yield.
The crude product was purified by column chromatography using ethyl acetate as eluent. This was recrystallized from ethyl acetate/hexanes to give a crystalline solid, m.p. 200 - 202° C.

N-(4-Bromo-3-methyl-5-isoxazolyl)-2-[N-(2-methoxyphenyl)aminocar-bonyl]thiophene-3-sulfonamide -N-(4-bromo-3-methyl-5-isoxazolyl)-2-(N-(2-methoxyphenyl)ami-nocarbonyl]thioph~:ne-3-sulfonamide was prepared in the same manner as described in Example 21 from N-(4-bromo-3-methyl-5-isoxazolyl)-2-(carboxyl)thiophene-3-sulfonamide and 2-methoxyaniline in 26% yield.
The crude product was purified by column chromatography using ethyl WO 96f31d92 PGTIUS95I04759 ' acetate as eluent. This was recrystaltized from ethyl acetate/hexanes to give a crystalline solid, m.p. 74 - 80° C.

N-(4-Bromo-3-methyl-5-isoxazolyl)-2-(N-benzylaminocarbonyl)thiophene-3-sulfonamide Benzylamine (0.214 g, 2 mmol), benzotriazole-1-yl-oxy-tris(di-methylamino)pho;~phonium hexafluorophosphate (Bop) (0.442 g, 1 mmol) and N,N'-diisopropylethylamine (0.15 ml) were added to N-(4-bromo-3-methyl-5-isoxazolyl)-2-(carboxyl)thiophene-3-sulfonamide (0.368 g, 1 mmol), which hacl been suspended in methylene chloride (3 ml). The resultant solution was stirred for 14 h at ambient temperature. This was diluted with methylene chloride (50 ml) and washed with 3 N
hydrochloric acid (3 X 50 ml) followed by 5% sodium carbonate solution (2 X 50 ml). The combined organic layers was dried over anhydrous magnesium sulfates and filtered. Removal of the solvent under reduced pressure gave N-(~4-bromo-3-methyl-5-isoxazolyl)-2-(N-benzylami-nocarbonyl)thiophene-3-sulfonamide. The crude product was purified by column chromatography using ethyl acetate as eluent. Recrystallization from ethyl acetateJhexanea gave a crystalline solid, m.p. 186 - 190° C
(0.14 g, 30% yield).

N-(4-Bromo-3-methyl-5-isoxazolyl)-2-[N-(4-ethylphenyl )aminocarbonyl]-thiophene-3-sulfonamide N-(4-bromo-~3-methyl-5-isoxazolyl)-2-(N-(4-ethylphenyl)aminoca-rbonyl]thiophene-3-sulfonamide was prepared in the same manner as described in Example 24 from N-(4-bromo-3-methyl-5-isoxazolyl)-2-(carboxyl)thiophen~e-3-sulfonamide and 4-ethylaniline in 31 % yield. The crude product way; purified by column chromatography using ethyl acetate as eluent. This was recrystallized from ethyl acetate/hexanes to give a crystalline solid, m.p. 187 - 190° C.

N-(4-Bromo-3-methyl-5-i:~oxazolyl)-2-[N-(4-biphenyl)aminocarbonyi]-thiophene-3-sulfonamide N-(4-bromo-3-methyl-5-isoxazolyl)-2-[N-(4-biphenyl)aminocarbonyl]
thiophene-3-sulfonamide compound was prepared in the same manner as described in Example 24 from N-(4-bromo-3-methyl-5-isoxazolyl)-2-(carboxyl)thiophe~ne-3-sulfonamide and 4-phenylaniline in 26% yield. The crude product was purified by column chromatography using ethyl acetate as eluent. This vvas recrystallized from ethyl acetate/hexanes to give a crystalline solid, m.p. 205 - 212° C (dec).

N-(3,4-dimethyl-5-isoxazolyl)-2-(carbomethoxy)thiophene-3-sulfonamide 2-Methoxyc:arbonylthophene-3-sulfonyl chloride (2.50 g, 10.05 mmol) was added to a solution of 5-amino-3,4-dimethylisoxazole(0.98 g, 8.75 mmol) in dry pyridine (5.0 ml). The reaction mixture was stirred at room temperature for 16 h. Pyridine was removed under reduced pressure and the residue ~rvas partitioned between water and dichloromethane. The organic layer was washed with 1 N HCI (2 X 50 ml) and dried over anhydrous magnesium sulfate. Evaporation of the solvents left an oily residue, which, after purification by column chromatography over silica gel ( 1:1 hexanes/ethyl acetate as eluent), yielded 2.20 mg (fi5%) of a brown solid. Further purification was achieved by recrys;tallizati~on from ethyl acetate/hexanes, giving the pure product as a white solid, m.p. 113-116° C.

N-(3,4-dimethyl-5-isoxazo lyl)-2-(carboxyl)thiophene-3-sulfonamide N-(3,4-dimethyl-5-is;oxazolyl)-2-(carboxyl)thiophene-3-sulfonamide was prepared in the same manner as described in Example 17 from N-(3,4-dimethyl-5-isoxazolyl;l-2-(carbomethoxy)thiophene-3-sulfonamide by basic hydrolysis in 94% yield. Purification was achieved by t A _ X6/31492 PCT/US96/04759 recrystallization from ethyl acetate/hexanes to give a crystalline solid, m.p. 202 - 203° C.

N-(3,4-dimethyl-5-isoxazoUyl)-2-(N-phenylaminocarbonyl)thiophene-3-sul-fonamide N-(3,4-dimethyl-5-is;oxazolyl)-2-(N-phenylaminocarbonyl)thiophene-3-sulfonamide was. prepared in the same manner as described in Example 18 from ~J-(3,4-dimethyl-5-isoxazolyl)-2-(carboxyl)thiophene-3 sulfonamide in 40~% yield. Purification was achieved by recrystallization from ethyl methan~~l/water to give a crystalline solid, m.p. 176 - 178 C.

N-(4-Bromo-3-methyl-5-isoxazolyl)-5-(2-thienyl)thiophene-2-sulfonamide A. 5-bromo-2,2'-bithiophe:ne N-Bromosuccinimide; (NBS, 1.12 g, 6.3 mmol) was added in small portions to a stirs ed solution of 1.0 g (6.01 mmol) of 2,2'-bithiophene in 10 ml of glacial acetic acid and 10 ml of chloroform. After stirring for 1 h at room temperature, thcs mixture was poured into ice-water and extracted into chloroform (75 ml). The organic layer was washed with aqueous sodium bicarbonate solution, water, and then dried over magnesium sulfate and evaporated. The residue was subjected to flash chromatography on silica del using hexane to give 1.3 g (88%) of a light green solid, m.p. 55 - 56° C.
B. 5-Chlorosulfonyl-2,2'-bithiophene A stirred solution of 5-bromo-2,2'-bithiophene (1.5 g, 6.1 mmol) in 10 ml of dry ether was placed under an argon atmosphere, cooled to -78 ° C and 4.3 ml of a 1.'7 M solution of t-butyllithium was added over 20 min. Stirring was continued at this temperature for an additional 20 min. Sulfur dioxide gas was then bubbled in at -78 ° C until a yellow precipitate formed. Bubbling of the sulfur dioxide gas was continued for an additional 3 min and w~ss immediately followed by a dropwise addition W V 96!31492 PCT1US96/04759 1 of N-chlorosuccinimide (NCS, 902 mg, 6.76 mmol) that had been dissolved in THF. The mi;Kture was warmed to room temperature and stirring was continued for an additional 1.5 h. The mixture was then concentrated and 'the residue dissolved in ether. The organic layer was washed with water, brine solution and dried over magnesium sulfate.
Evaporation of solvent left a pale yellow solid, which was recrystallized from hexane to give 700 mg (44%) of a yellow solid, m.p. 63-64° C.
C. N-(4-Bromo-3-methyl-5-isoxazolyl)-5-(2-thienyl)thiophene-2-suifona-mide N-(4-bromo-3-methyl-5-isoxazolyl)-5-(2-thienyl)thiophene-2-sulfcna-mide was prepared in the same manner as described in Example 2.
Reaction of 2-chlorosulfonyl-5,2'-bithiophene (300 mg, 1.14 mmol) with 5-amino-4-bromo-:3-methylisoxazole (183 mg, 1.03 mmol) yielded, after flash chromatography using 10% MeOH/CHC13, 430 mg (94%) of a pale brown solid, m.p. 210° C.

N-(4-Bromo-3-metlhyl-5-isoxazolyl)thiophene-3-sulfonamide A. Thiophene-3-sulfonyl chloride A stirred soliution of 3-bromothiophene ( 1.5 g, 9.2 mmol) in 10 ml of dry ether was placed under an argon atmosphere and cooled to -78° C. Over the course of 20 min, a solution of t-butyllithium (5.6 ml of a 1 .7 M) was added and stirring was continued at this temperature for an additional 20 min. Sulfur dioxide gas was then bubbled in at -78 ° C
and the solution was vvarmed to 0° C, whereupon NCS (1.47 g, 12 mmol) in 8 ml of THF, was added dropwise. After warming to room temperature, stirring was confirmed for an additional 1 hour, after which, evaporation of solvents left 1.!i5 g of a brown oil. Flash chromatography over silica gel using hexanes yielded 1.24 g (74%) of a yellow oil which solidified on standing to give a yellow crystalline solid, m.p. 38-39° C.

r Wa 96/31492 PCTlUS96104759 1 B. N-(4-Bromo-3-methyl-5~-isoxazolyl)thiophene-3-sulfonamide N-I4-bromo-3-methyl-5-isoxazolyl)thiophene-3-sulfonamide was prepared in the sanne manner as described in Example 2 from thiophene-3-sulfonyl chloride with 5-amino-4-bromo-3-methylisoxazole in 22% yield.
Purification by column chromatography using 10% MeOH/CHC13 as eluent gave a pale brown oil.

N-(3,4-dimethyl-5-i.soxazolyl)-5-phenyfthiophene-2-sulfonamide A. N-(3,4-dimethyll-5-isoxazolyll-5-bromothiophene-2-sulfonamide A solution of 5-bromothiophene-2-sulfonyl chloride (2.75 g, 10 mmol) and 5-amino-3,4.-dimethylisoxazole ( 1.07 g, 9.57 mmol) in pyri-dine containing a catalytic amount of 4-dimethylaminopyridine (DMAP, 10 mg) was stirred at room temperature for a period of 3 h. The solution was heated at 50° C for an additional 1.5 h to drive the reaction to com-pletion as judged b~y TLC. The pyridine was removed under reduced pres-sure and the residue, after extraction into ethyl acetate, was washed with 1 N HCI (2 x 25 ml), water' ( 1 x 25), brine solution, ( 1 x 25 ml) and dried over magnesium sulfate. Evaporation of solvent left a viscous brown gum, which was subjected to flash chromatography. Elution with 3%
methanol hexanes c3ave 246 mg ( 10%) of pure sulfonamide.
B. N-(methoxyethoxymethyl)-N-(3,4-dimethyl-5-isoxazolyl)-5-bromothioph~ene-2-scrlfonamide N-(3,4-dimet;hyl-5-isoxazolyl)-5-bromothiophene-2-sulfonamide (680 mg, 2 mmol) iin dry THF (2 ml) was added to sodium hydride (121 mg of a 60% oil dispersion, 3 mmol) in dry THF (1 ml). The resulting suspension was conled to 0° C and methoxyethoxymethyl chloride (334 mg, 2.68 mmol) was added dropwise via syringe. The solution was warmed to room temperature, and stirring continued overnight.
Evaporation of solvent left an oil that was extracted into ethyl acetate, washed with brine, dried over magnesium sulfate and evaporated. Flash ', _.96!31492 PCT/US96/04759 chromatography ~of the residue on silica gel using 10-15% ethylace-tate/hexanes yiel~~ed 480 mg (56%) of a colorless oil.
C. N-(methoxyethoxymethyl)-N-(3,4-dimethyl-5-isoxazolyl)-5-phenyithiophene-2. sulfonamide Sodium carbonate (2 ml of a 2 M aqueous solution) followed by phenyl boronic acrid (86 rng, 0.71 mmol) in 2 ml of 95% ethanol were added to a solution of N-(methoxyethoxymeihyl)-N-(3,4-dimethyl-5-isoxazolyl)-5-brornothioplhene-2-sulfonamide (200 mg, 0.47 mmol) and tetrakis (triphenylphosphine) palladium (0) (23 mg, 0.02 mmol) in dry benzene (4 ml) under argon. The mixture was refluxed for 12 h, diluted with 5 ml of water and extracted into ethyl acetate (3 X 25 ml). The combined organic. extracts was washed with brine (1 x 25 ml), dried and evaporated. The residue was flash chromatographed on silica gel using 25% ethylacetate~/hexanes to afford 123 mg (62%) of the sulfonamide as a colorless gum.
D. N-(3,4-dimethyl-5-isoxazolyl)-5-phenylthiophene-2-sulfonamide HCI (3 ml of a 3 N aqueous solution) was added to a solution of N-(methoxyethoxymethyl)-N-(3,4-dimethyl-5-isoxazolyl)-5-phenylthiophene-2-sulfonamide (100 mg, 0.24 mmol) in 3 ml of 95% ethanol and the resulting mixture was refluxed for 6 h. The mixture was then concentrated, diluted with 5 ml of water, neutralized with saturated aqueous sodium bicarbonate solution and acidified to pH 4 using glacial acetic acid. The mixture was extracted with ethyl acetate (2 x 25 ml) and the combined organic extract was washed with brine (1 x 5 ml), dried and evaporated. Flash chromatography of the residue on silica gel using 2% MeOH/~CHC13 and further purification by reverse phase HPLC
yielded 33.4 mg (42%) of the pure sulfonamide as a white powder, m.p. 176-178° C.

N-(4.-8romo-3-met:hyl-5-isoxazolyi)-5-(4-ethylphenyl)thiophene-2-sulfona-mide A. N-(5-bromothiophene-2-sulfonyl)-pyrroie Sodium hyclride (fi0% oil dispersion, 191 m.g., 4.78 mmol) was suspended in dry tetrahydrofuran (2 ml) and the resulting cloudy suspension was cooled to 0° C. in an ice bath. Pyrrole (385 mg, 5.75 mmol) in dry tetrahydrofuran (2 ml) was added dropwise over a period of min. The ice Math waa removed and the solution was stirred at room 10 temperature until gas evolution ceased (15 minutes), whereupon 5-bromothiophene-2-sulfonyl chloride (1.0 g, 3.82 mmol) previously dissolved in tetrahydrofuran (4.0 ml) was added dropwise through a steel . cannula. After stirring for 1 h at room temperature, the mixture was filtered through Ce~lite. The filter pad was rinsed with tetrahydrofuran, and the filtrate wars evaporated, which left a light brown solid that was recrystailized from methanol to produce the sulfonamide (821 mg, 74%
yield) as a white powder.
B. 4-Ethylphenylboronic acid A solution cf 1-bromo-4-ethyl benzene (2.0 g, 1 1 mmol) in dry ether (5 ml) was added to magnesium turnings (31 1 mg, 13 mmol), which had been suspended in dry ether, by dropwise addition. After addition was complete, the suspension was refluxed for a period of 15 min, by which time nearly all ~of the magnesium had reacted. The solution was then added to trimethy borate ( 1.12 g, 1 1 mmol), previously dissolved in ether (5 ml) at -78° C, warmed to room temperature and stirred for 90 min. The reaction was quenched by the addition of 10°'0 aqueous HCI (2 ml) and the solution was extracted with ether. The combined ether extract w,as extracted with 1 M NaOH (2 X 20 ml), the aqueous extracts were acidified with dilute HC1 to pH 2 and extracted with ether (2 X 2~~ ml). The resulting combined ether extract was * Trade-mar'.<

~'.. J 96131492 PCT/US96/04759 -88_ washed once with water (10 ml), dried and evaporated to produce a white solid (676 mg, 38'% yield), m.p. 138-140° C.
C. N-[5-(4-ethylphenyl)thiophene-2-sulfonyl]pyrrole N-[5-(4-ethylphenyl)thiophene-2-sulfonyl]pyrrole was prepared, in the same manner as described in Example 32C, from 4-ethylphenyl-boronic acid and N-(5-bromothiophenesulfonyl)pyrrole. Purification by column chromatography using 10% ethyl acetate/hexanes gave the pure sulfonamide as a tan solid in 81 % yield.
D. 5-Chlorosulfonyl-~?-(4-ethylphenyl)thiophene A solution of N-[5-(4-ethylphenyl)thiophene-2-sulfonyljpyrrole (100 mg, 0.32 mmol) and 6 N sodium hydroxide (1 ml) in methanol (1.5 ml) was refluxed for approximately 6 h. Evaporation of solvents and drying in vacuo resulted in an oil. Phosphorus oxychloride (258 ml, 2.52 mmol) and phosphorus pentachloride (131 mg, 0.63 mmol) were added to the oil and the resulting brovvn suspension was heated at 50° C for 3 h.
The resulting clear brown solution was carefully added to about 20 ml of crushed ice and then extracted with ethyl acetate (3x25 ml). The combined organic; layers was washed with brine (2x5 ml), dried (MgS04) and evaporated t~~ leave an oily residue. Flash chromatography over silica gel using 2% ethyl acetate/hexanes yielded (53 mg, 59%) of the pure sulfonyl chloride .as a pale yellow oil.
E. N-(4-bromo-3-metlnyl-5-isoxazolyl)-5-(4-ethylphenyl)thiophene-2-sulfonamide . N-(4-bromc>-3-methyl-5-isoxazolyl)-5-(4-ethylphenyl) thiophene-2-sulfonamide was prepared in the same manner as described in Example 2.
Reaction of 5-chlorosulfonyl-2-(4-ethylphenyl) thiophene (47.1 mg, 1 1.16 mmol) with 5-amino-4-bromo-3-methyl isoxazole (29 mg, 0.16 mmol) yielded, after flash chromatography using 10°~o MeOH/CHC13, a pale brown solid (46 rng, 66°io yield), m.p. 172-175° C.

i N-(3,4-dimethyl-5~-isoxaz~olyl)benzo[b]thiophene-2-sulfonamide A. Benzo[b)thiiophene-2-sulfonyl chloride Benzo[b)thiophene (1.50 g, 11.2 mmol) was stirred at 0° C in 20 ml of THF. t-l3utyllithium ( 1.7 M, 16.8 mmol, 9.9 ml) was slowly added over a 5 minute period. Fifteen minutes later, S02 was flushed into the reaction iflask and a thick white precepitate formed. The reaction mixture was stirred for 15 minutes at 0° C and then NCS (1.64 g, 12.3 mmol) was added. The reaction was warmed to 25° C and stirred for 30 min. It was then poured into ethyl acetate ( 150 ml) and washed with brine (3x100 ml). The organic phase was dried with MgSOd, filtered and concentrated to collect 2.29 g of a brown oil. The brown oil was subjected to flash chromatography (5% ethyl acetate/hexanes), which provided a yellow tan solid (1.39 g, 53% yield).
B. N-(3,4-Dimethyl-5-isoxazolyl)benzo[b)thiophene-2-sulfonamide 3,4-Dimethyl-5-amino-isoxazole (0.224 g, 2.0 mmol) and 50 mg of DMAP were stirred in 5 rnl of pyridine at 25° C. The benzo[b)thiophene-2-sulfonyl chloride (0.16 g, 2.6 mmol) was added and the dark brown-yellow reaction mixture vvas stirred for 18 h at ambient temperature, poured into 100 rnl of ethyl acetate and washed with 2% HCI (3x50 ml).
The organic phasE: was dried with MgS04, filtered and concentrated to collect 0.61 g of .a brown oil/solid. The brown oil/solid was subjected to flash chromatography (30% ethyl acetate/hexanes) to provide 0.37 g of a light brown solid. This was stirred in 10 ml of methanol and 0.5 g of NaOH. The methanolic solution was heated for reflux for 1 h, then cooled to 25 ° C and the methanol was removed in vacuo. The resulting residue was acidified to pH 1 with 2% HCI (100 ml) and extracted with ethyl acetate (2x~i0 ml) 'The organic phase was dried with MgS04, filtered and concentrated to collect 0.225 g of a yellow-orange solid.

i r WU 96/31492 PCTlUS96/04759 This was recrystallized from CHCI3/hexanes to produce a light tan-yellow solid (0.194 g, 31 ~% yield), m.p. 157-160° C.

N-(3,4-Dimethyl-5-iisoxazollyl)benzo[b]furan-2-sulfonamide A. Benzo[b]furan-2-sulifonyl chloride Benzo(b]furan-2-sulfonyl chloride was prepared as in Example 34A
from benzo[b]furan ( 1.61 c3, 13.6 mmol), t-BuLi ( 1.7 M, 17.7 mmol, 10.4 ml) and NCS (2.0 d, 15.0 mmol). Flash chromatography (5% ethyl ace-tate/hexanes) yielded a brown solid (1.84 g, 62% yield).
B. N-(3,4-Dimerhyl-5-isoxazolyllbenzo[b]furan-2-sulfonamide N-(3,4-Dime:hyl-5-isoxazolyl)benzo(b]furan-2-sulfonamide was pre-pared, in the same manner as described in Example 34B, from 3,4-di-methyl-5-amino isoxazole (78 mg, 0.70 mmol) and benzo(b]furan-2-sul-fonyl chloride (0.4fi g, 2.1 mmol) Flash chromatography (30% ethyl ace-tate/hexanes) provided 0.186 g of a light yellow solid, which was treated with 31 mg of NaC~H in 10 ml of methanol at 25 ° C for 30 minutes. Re-crystallization from CHC13/hexanes yielded a light tan solid (90 mg, 44%
yield), m.p. 160.5-163 ° C.

N-(3,4-dimethyl-5-isoxazolyl)furan-2-sulfonamide A. I=uran-2-suifonyl chloride Furan-2-sulfonyl chloride was prepared as in Example 34A from furan (0.96 g, 14.2 mmol), t-BuLi (1.7 M, 17 mmol, 10 ml) and NCS
(2.27 g, 17 mmol) using et:her (30 ml) as the solvent. Flash chromatography (5'% ethyl acetate/hexanes) produced a yellow liquid ( 1.22 g, 52% yield 1.
B. N-(3,4-dimet!hyl-5-isoxazolyl)furan-2-sulfonamide N-(3,4-dimetihyl-5-isoxazolyl)furan-2-sulfonamide was prepared as described in Example 34B 'from 3,4-dimethyl-5-amino isoxazole (0.122 g, h.! 96/31492 PCTIUS96/04759 1.0 mmol), furan-2-sulfonyl chloride (0.50 g, 3.0 mmol) and NaOH (64 mg). Flash chrom,atograp~hy (50% ethyl acetate/hexanes) yielded 70 mg of a yellow solid. Recrystallization from CHC13/hexanes produced an off-white solid (46 mg, 29% yield), m.p 107 - 110° C.

N-(3,4-Dimethyl-5-isoxazolyl)-3-methoxy-2-thiophene sulfonamide A. 3-methoxy-2-thiophenesulfonyl chloride Chlorosulfonic acid (CIS03H, 2.31 g, 19.62 mmol) was slowly added to a solution of 3-methoxythiophene (2.29 g, 19.62 mmol) in CHC13 (80 ml) at 0° C. The resulting mixture was stirred at 0° C for 30 min. The solvent was evaporated under reduced pressure at room temperature, the residue was suspended in POC13 (15 ml, 156.96 mmol), and PCIS (8.2 g, 3'.9.24 mrnol) was added slowly. The reaction was stirred at 60° C for 18 h, then cooled to room temperature and poured onto crushed ice (.200 g). The aqueous mixture was extracted with CHC13 (2x150 ml) and the combined organic layers was dried (MgS04).
The solid was removed by filtration and the filtrate was concentrated to give 3-methoxy-2-thiophenesulfonyl chloride as a brown oil ( 1.81 g, 43% yield).
B. N-(3,4-dimethyl-5-i:~oxazolyl)-3-methoxy-2-thiophene sulfonamide Sodium hydride (1.t)2 g, 25.56 mmol, 60% dispersion in mineral oil) was slowly adcjed to a solution of 3-methoxy-2-thiophenesulfonyl chloride ( 1.18 g, 8.52 mmol) and 3,4-dimethyl-5-aminoisoxazole ( 1.05 g, 9.37 mmol) in THF (20 ml) at room temperature. The resulting mixture was refluxed for 4 h. THF was removed under reduced pressure. The residue was dissol~~ed in water ( 10 ml), the pH was adjusted to 10 - 1 1 by adding 5 N sodiium hydroxide solution, and was extracted with ethyl acetate (3 X 10 ml!) to remove the neutral impurities. The aqueous layer was acidified with concentrated HCI (pH 2 - 3) and extracted with ~. , 96!31492 PCTIUS96/04759 methylene chloridle (3 X 10 ml). The combined organic layers was dried over anhydrous magnesium sulfate to produce a crude oil. Further purification by reverse phase HPLC yielded a yellow oil (retention time 14.94 min, 5% to 95% acetonitrile in H20 with 0.1 % TFA over 30 min period, C,8 analytical column).

N-(4-Bromo-3-mel:hyl-5-isoxazolyl)-3-phenyl-2-thiophene sulfonamide and N-(4-bromo-3-methyl-5-isoxazolyl)-4-phenyl-2-thiophene sulfonamide A. 3-phenyl-2-thiophenesulfonyl chloride and 4-phenyl-2-0 thiophenesulfonyl chloride n-Butyllithium (2.38 M, 17.2 ml, 41.03 mmol) was slowly added to a solution of 3-phenylthiophene (5.47 g, 34.2 mmol) in Et=O (25 ml) at 0° C. The ice bath was removed, the mixture was stirred at roam temperature for 2 h, coolf:d to -30° C (COZ/acetone) and SOz gas was bubbled through the reaction mixture for 20 min. A solution of NCS
(6.06 g, 44.5 mmol) in THF (20 ml) was then added. The reaction was allowed to warm to room temperature and stirred for 16 h. The crude mixture was filtered, and the solid was washed with Et20. The combined organic layers was concentrated and the residue was chromatographed (hexanes/CHC13) to give 3~-phenyl-2-thiophenesulfonyl chloride and 4-phenyl-2-thiophen~aulfonyl chloride as a 1:1 mixture ( 1.46 g, 16.5 %, while solid).
B. N-(4-Bromo-3-methyl-5-isoxazolyl)-3-phenyl-2-thiophene sulfona-mide and N-{4-bromo-3-methyl-5-isoxazolyl)-4-phenyl-2-thiophene sulfonamide N-(4-bromo-3-methyrl-5-isoxazolyl)-3-phenyl-2-thiophene sulfona-mide and N-(4-brorno-3-mcahyl-5-isoxazolyl)-4-phenyl-2-thiophene sulfon-amide were prepared as dcacribed in Example 1. A fraction of the crude mixture of products was purified by HPLC to give N-(4-bromo-3-methyl-5-isoxazolyl)-3-phenyl-2-thiophene sulfonamide (light brown solid, retention time 20.48 min, 5~% to 95% acetonitrile in water with 0.1 % TFA over 30 WO 96!31492 PCTIUS96/04759 min C,e analytical column, m.p. 105-107° C) and N-(4-bromo-3-methyl-5-isoxazolyl)-4-phenyl-2-thiophene sulfonamide (dull yellow solid, m.p. 108-1 10°C, retention 'time 21.35 min, same conditions).

4-tent-Butyl-N-(4-bromo-3-methyl-5-isoxazolyl)benzenesulfonamide A solution of 5-amino-4-bromo-3-methylisoxazole (354 mg, 2.0 mmol) in dry THF ( 1 ml) was added to a suspension of sodium hydride (60% dispersion in mineral oil, 188 mg, 4.4 mmol) in dry THF (1 ml) at 0-5° C. After stirring at 0-5° C for 10 min., the reaction was warmed to room temperature for 10 rein. to complete the reaction. The reaction mixture was re-cooled to O° C and 4-tent-butylbenzenesulfonyl chloride (512 mg, 2.2 mmol) was .added slowly. Stirring was continued for 20 min. at 0-5° C. Excess sodium hydride was decomposed by addition of methanol (0.4 ml) followed by water (0.5 ml). The mixture was acidified ';I5 with hydrochloric acid and extracted with dichloromethane. The extract was dried over anhydrous magnesium sulfate and the solvent was re-moved under reduced pressure to give a crude product, which was puri-fied by recrystallization from ethyl acetate/hexanes to give a white solid in 21 % yield, m.p. 170° C (dec.!.

N-(3,4-Dimethyl-5-isoxazollyl)-2-methylbenzo(b)thiophene-3-sulfonamide A. 2-Methylbenzo[b]thiophene t-BuLi (1.7 M, 26 mmoles, 15 ml) was added to a stirred solution of benzo(b)thiophene (17 rnmoles, 2.3 g) and THF (30 mf) at -50°C. The resulting bright yellow reacaion mixture was warmed to -30°C, and iodomethane (26 mmoles, 1.6 ml) was added. After 10 min. at -30°C, the solution was warmed t:o ambient temperature and stirred an additional min., then diluted with ether (100 ml) and washed with brine (2 x 100 ml). The organic phase was dried (MgS04), filtered and 1. I
' WO 96!31492 PCTIUS96104759 concentrated to collect 2.48 g (98%) of 2-methylbenzo(b]thiophene as a tight yellow solid.
B. 2-Methylbenzo[b]thiophene-3-sulfonyl chloride Sulfuryl chloride (9.5 mmoles, 0.76 ml) was added to a stirred solution of dimetf,~~y)formamide (DMF; 11.2 mmoles, 0.87 ml) at 0°C, and the resulting faint yellow solution was stirred for 20 min at 0°C. 2-Methylbenzo[b]thiophene (5.6 mmoles, 0.83 g) was then added, the reac-tion mixture was cjiluted with 2 ml of DMF, and then heated to 85°C.
After 2.5 hrs at 8!5°C, the brown reaction mixture was cooled to ambient temperature and added to ice ( =100 ml). The aqueous phase was extracted with ethyl acetate (100 ml), and the organic phase was dried (MgS04), filtered and concentrated to collect an orange-brown solid.
Flash chromatography (4°.o ethyl acetate/hexanes) provided 0.89 g (64%) of 2-methylbenzo[ib]thiophene-3-sulfonyl chloride as a yellow solid.
75 C. N-(3,4-Dimethyl-5-isoxazolyl)-2-methylbenzo(b]thiophene-3-sulfona-mide 2-Methylbenzo(b]thiophene-3-sulfonyl chloride (1.7 mmoles, 0.41 g) was added to a solution of 3,4-dimethyl-5-aminoisoxazole (0.75 mmoles, 84 mg), 4l-dimethylaminopyridine (DMAP; 50 mg) and pyridine (5 ml) at ambient temperature. After 24 h, the reaction mixture was diluted with ethyl acetate (50 ml) and washed with 2% HCI (3 x 50 ml).
The organic phase was dried (MgS04), filtered and concentrated to collect a brown-orange solid, which was dissolved in a solution of methanol (10 ml) and NaOH (60 mg!. The solution was stirred 1 h at ambient temperature, then t:he methanol was evaporated and the resulting residue was diluted with 2'% HCI (50 ml), and extracted with ethyl acetate (75 ml). The organic phase was dried (MgS04), filtered and concentrated to collect a tan solid. Recrystallization from chloroform and hexanes resulted in 93 mg (38%) of N-(3,4-dimethyl-5-isoxazolyl)-2-' ' WO 96/31492 PGT/US96/04759 methylbenzo[b]thiophene-3-sulfonamide as light yellow crystals, m.p. 174-176 ° C.

N-(4-Bromo-3-methyl-5-isoxazolyl)-2-methylbenzo[b]thiophene-3-sulfona-mide NaH (60% oil disp<:rsion, 2.5 mmoles, 100 mg) was added to a solution of 4-bromo-3-methyl-5-aminoisoxazole (1.0 mmoles, 0.177 g).
THF (5 ml) at 0°C; was added, and the resulting reaction mixture was stirred 10 min at 0°C. 2-Methylbenzo[b]thiophene-3-sulfonyl chloride (1.2 mmoles, 0.28 g) ~Nas adcled, and the reaction mixture was stirred for 20 min at 0°C, then warmed to ambient temperature for 1 hr followed by addition of 2 ml of water,. The mixture was diluted with ethyl acetate (100 ml) and washed with 2% HCI (2 x 50 ml), then brine (50 ml). The organic phase waa dried I'MgS04), filtered and concentrated. Recrystalli-zation of the crude reaction mixture resulted in 0.24 g (63%) of N-(4-bromo-3-methyl-5-isoxazolyl)-2-methylbenzo(bJthiophene-3-sulfonamide as an off-white solid, m.p. 131-133°C.

N-(4-Bromo-3-met:hyl-5-isoxazolyll-2-ethylbenzo[b]thiophene-3-sulfona-mide A. 2-Ethylbenz:o [b]thiophene 2-Ethylbenz:o[b]thiophene was prepared by the method 'of Example 40A with benzo[b]thiophene (7.5 mmoles, 1.0 g), t-BuLi (1.7 M, 8.9 mmoles, 5.3 ml), iodoeth;ane (8.9 mmoles, 0.72 ml) and THF (20 ml).
1.2 g (99%) of a yellow liquid was isolated.
B. 2-Ethylbenz:o(b]thiophene-3-sulfonyl chloride 2-Ethylbenz:o(b)thiophene-3-sulfonyl chloride compound was prepared by the method of Example 40B with dimethylformamide (DMF;
13.6 mmoles, 1.1 ml), sulfonyl chloride (11.5 mmoles, 0.93 ml). Flash '.. J 96131492 PCTIUS96/04759 chromatography (2% ethyl acetate/hexanes) provided 1.34 g (76%) of a light yellow solid.
C. N-(4-bromo-3-methyl-5-isoxazolyl)-2-ethylbenzo[b]thiophene-3-sul-fonamide N-(4-bromo-3-mett-~yl-5-isoxazolyl)-2-ethylbenzo[b]thiophene-3-sul-fonamide was prepared by the method of Example 41 with 4-bromo-3-methyl-5-aminoisoxazole (1.0 mmoles, 0.177 g), NaH (2.5 mmoles, 100 mg), 2-ethylbenzo(b]thiophene-3-sulfonyl chloride (1.2 mmoles, 0.31 g) and THF (7 ml). Recrystallization from chloroform and hexanes provided 0.24 g (60%) of a tan crystalline solid, m.p. 118.5-120°C.

N-(4-Bromo-3-methyl-5-is~oxazolyl)-2-benzylbenzo[b]thiophene-3-sulfona-mide A. 2-Benzylbenzo[b]thiophene '15 2-8enzylbenzo[b]thiophene was prepared by the method of Example 40A with benzo(b]thiophene (7.5 mmoles, 1.0 g), t-BuLi (1.7 M, 11.2 mmoles, 6.6 ml), benzyi bromide (10.2 mmoles, 1.3 ml) and THF
(20 ml). Flash chromatography (hexanes) provided 0.66 g (39%) of a yellow solid.
B. 2-Benzylbenzo[b]thiophene-3-sulfonyl chloride 2-Benzylbenzo(b]thiophene-3-sulfonyl chloride was prepared by the method of Example 40B with DMF (5.4 mmoles, 0.41 ml), sulfuryl chloride (4.6 mmolles, 0.37 ml) and 2-benzylbenzo[b]thiophene. Flash chromatography (~i% ethyl acetate/hexanes) provided 0.55 g (64%) of a yellow solid.
C. N-(4-bromo-3-methyl-5-isoxazolyl)-2-benzylbenzo[b]thiophene-3-sulfonamide N-(4-bromo-3-methyl-5-isoxazolyl)-2-benzylbenzo[b]thiophene-3-sulfonamide was prepared by the method of Example 41 with 4-bromo-3-methyl-5-aminoiso:Kazole (1.0 mmoles, 0.177 g), NaH (2.5 mmoles, t 96131492 PCTlUS96/04759 _97-100 mg), 2-benzylbenzo(b]thiophene-3-sulfonyl chloride ( 1.2 mmoles, 0.39 g) and THF ('7 ml). f=lash chromatography (5%
methanol/chloroform) followed by recrystallization from chloroform and hexanes provided 0.1 1 g (24%) of a tan crystalline solid, m.p. 120-123°C.

N-(4-Bromo-3-methyl-5-isoxazolyl)-2-butylbenzo (b]thiophene-3-sulfona-mide A. 2-Butylbenzo[b]thiophene 2-n-Butylbenzo[b]thiophene was prepared by the method of Example 40A with benzo(b]thiophene (7.5 mmoles, 1.0 g), t-BuLi ( 1.7 M, 9.7 mmoles, 5.7 ml), 1-bromobutane (9.7 mmoles, 1.0 ml) and THF
(20 ml). 0.65 g (4.6%) of a yellow liquid was isolated.
B. 2-n-Butylbenzo[b]thiophene-3-sulfonyl chloride 2-n-Butylbenzo(b]thiophene-3-sulfonyl chloride was prepared by the method of Exampl<: 40B with DMF (6.6 mmoles, 0.51 ml), sulfuryl chloride (5.6 mmoles, 0.45 ml) and 2-n-butylbenzo[b]thiophene (3.3 mmoles, 0.63 g). Flash chromatography (2% ethyl acetate/hexanes) provided 0.68 g (71 %) of an orange solid.
C. N-(4-bromo-3-methyl-5-isoxazolyl)-2-n-butylbenzo(b]thiophene-3-sulfonamide N-(4-bromo-3-methyl-5-isoxazolyl)-2-n-butylbenzo [b)thiophene-3-sulfonamide was prepared by the method of Example 41 with 4-bromo-3-methyl-5-aminoiso;tazole ( 1.0 mmoles, 0.177 g), NaH (2.5 mmoles, 100 mg), 2-n-butyllbenzo[b]thiophene-3-sulfonyl chloride (1 .2 mmoles, 0.35 g) and THF (Ei ml). Flecrystallization from ethyl acetate and hexanes provided 0.24 g (56%) of a yellow solid, m.p. 124.5-126°C.

WO 96!31492 PCTIUS96104759 N-(4-Bromo-3-methyl-5-isoxazolyl]-2-n-propylbenzo[b]thiophene-3-sulfona-mide A. 2-n-propylbe nzo [b]tlhiophene 2-n-Propylbenzo[b]tlniophene was prepared by the method of Example 40A with benzo[b]thiophene (7.5 mmoles, 1.0 g), t-BuLi (1.7 M, 9.7 mmoles, 5.7 ml), n-bromopropane (9.7 mmoles, 0.88 ml) and THF
(20 ml). 1.1 1 g (85%) of a light yellow liquid was isolated.
B. 2-propyibem:o(b]thiophene-3-sulfonyl chloride 2-Propylben~:o[b]thiophene-3-sulfonyl chloride was prepared by the method of Example 40B with DMF (3.6 mmoles, 0.28 ml), sulfuryl chloride (3.1 mmoles, 0.2ri ml) and 2-propylbenzo(b]thiophene (1.8 mmoles, 0.32 g). I=lash chromatography (3% ethyl acetate/hexanes) provided 0.28 g (5~5%) of a yellow solid.
C. N-(4-bromo-:3-methyl-5-isoxazolyl)-2-n-propylbenzo[b]thiophene-3-sulfonamide N-(4-bromo-3-methyl-5-isoxazolyl)-2-n-propylbenzo[b]thiophene-3-sulfonamide was prepared by the method of Example 41 with 4-bromo-3-methyl-5-aminoisox:azole (0.68 mmoles, 0.12 g) NaH ( 1.7 mmoles, 6.8 mg), 2-n-propylbenzo(b]thiophene-3-sulfonyl chloride (0.82 mmoles, 0.23 g) and THF (3 ml). Recrystallization from chloroform and hexanes provided 0.19 g (67%) of a yellow crystalline solid, m.p. 136-138°C.

N-(4-Bromo-3-methyl-5-isoxazolyl)-2-i-propylbenzo[b]thiophene-3-sulfona-mide A. 2-i-propylbenzo[b]thiophene 2-i-Propylbenzo[b]thiophene was prepared by the method of Example 40A with Ibenzo[b)thiophene (7.5 mmoles, 1.0 g), t-BuLi ( 1 .7 M, 11.2 mmoles, 6.6 m11, 2-iodopropane (11.2 mmoles, 1.12 ml) and THF

i . - Wa.96131492 PCTILTS96I04759 (20 ml) with stirrincf at ambient temperature for 24 hrs. It was isolated as a yellow oil (1.1 1 g; 85'% yield).
B. 2-i-propylbenzo[b]thiophene-3-suffonyl chloride 2-i-propylbenzo[b]thiophene-3-sulfonyl chloride compound was prepared by the method of Example 40B with DMF (5.2 mmoles, 0.40 ml), using sulfuryl chloride (4.2 mmoles, 0.34 ml) and 2-i-propyl-benzo(b]thiophene (2.1 mmoles, 0.37 g). Flash chromatography (1 ethyl acetate/hexanes) provided 0.17 g (29%) of a yellow solid.
C. N-(4-bromo-3.-methyl-5-isoxazolyl)-2-i-propylbenzo[b]thiophene-3-sulfonamide N-(4-bromo-3-methyl-5-isoxazolyl)-2-i-propylbenzo[b]thiophene-3-sulfonamide was prepared by the method of Example 41 using 4-bromo-3-methyl-5-aminoisoxazole (0.55 mmoles, 9.7 mg), NaH (1.4 mmoles, 5.5 mg), 2-i-propylbenzo[b]thiophene-3-sulfonyl chloride (0.60 mmoles, 0.17 g) and THF (2 ml). Re:crystallization from chloroform and hexanes provided 89 mg (39%) of a tan crystalline solid, m.p. 157.5-159°C.

N-(4-8romo-3-methyl-5-isox:azolyl)-2-(4-ethylbenzyl)benzo [b]-thiophene-3-sulfonamide A. a-(2-benzo[b]thiophen~e)-4-ethylbenzyl alcohol a-(2-Benzo[b]thiophene)-4-ethylbenzyl alcohol was prepared by the method of Example 40A with benzo[b]thiophene (7.5 mmoles, 1.0 g), t-BuLi (9.7 mmoles, 1.7 M, 5.7 ml), 4-ethylbenzaldehyde (8.9 mmoles, 1.22 ml) and THF (~'.0 ml). Flash chromatography (10% ethyl acetate/hexanes) provided '1.79 g (89%) of a yellow solid.
B. 2-(4-ethylben,zyl)benz:o[b]thiophene To a solution of a-(2-benzo[b]thiophene)-4-ethylbenzyl alcohol (4.0 mmoles, 1.1 g), triethylsilane (4.4 mmoles, 0.1 1 ml) and CHZCIz (20 ml) at 0°C was added ~'FA (8.1 mmoles, 0.62 ml). The solution was stirred 30 min at 0 ° C, then diluted with ether ( 100 ml) and washed with sat.

~ ~ 96/31492 PCTIUS96/04759 --NaHC03 (100 ml). The organic phase was dried (MgS04), filtered and concentrated. Flash chromatography (2% ethyl acetate/hexanes) provided 0.69 g (fib%) of a white solid.
C. 2-(4-Ethylbe:nzyl)benzo[b]thiophene-3-sulfonyl chloride 2-(4-Ethylbenzyl)benzo[b]thiophene-3-sulfonyl chloride was prepared by the method of Example 40B with DMF (5.4 mmoles, 0.42 ml), sulfuryl chloride (4.6 mmoles, 0.37 ml) and 2-(4-ethylbenzyl)benzo(b]thiophene (2.7 mmoles, 0.69 g). Flash chromatography (~~% ethyl acetate/hexanes) provided 0.43 g (45%) of an orange solid.
D. N-(4-bromo-3-methyl-5-isoxazolyl)-2-(4-ethylbenzyl)benzo[b]-thiophene-3~-sulfonaimide N-(4-bromo-3-methyl-5-isoxazolyl)-2-(4-ethylbenzyl)benzo(b]-thiophene-3-sulfonamide was prepared by the method of Example 41 using 4-bromo-3-methyl-5-aminoisoxazole ( 1.0 mmoles, 0.177 g), NaH
(2.5 mmoles, 100 mg), 2-(4-ethylbenzyl)benzo(b]thiophene-3-sulfonyl chloride (1.2 mmoles, 0.42 g) and THF (6 ml). Flash chromatography (50% ethyl acetate:/hexan~es) followed by recrystallization from chloroform and hexanes provided 0.21 g (43%) of a tan solid, m.p. 128-130°C.

N-(4-Bromo-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)benzyl]-benzo[b]thiophene-3-sulfonamide A. o-(2-benzo[b]thienyl)-3,4-(methylenedioxy)benzyl alcohol a-(2-Benzo[b]thienyl)-3,4-(methylenedioxy)benzyl alcohol was prepared by the method of Example 40A using benzo(b]thiophene (7.5 mmoles, 1.0 g), t-E3uLi (1.'7 M, 9.7 mmoles, 5.7 ml), piperonal (8.9 mmoles, 1.0 g) and THF ( 20 ml). Flash chromatography (20% ethyl acetate/hexanes) provided 1.6 g (74%) of a yellow solid.

W U 96/31492 ~ PCT/LJS96I04759 _ -101-B. 2-[3,4-(methylenedioxy)benzyl]benzo[b]thiophe~e 2-[3,4-(methylenedioxy)benzyl]benzo[b]thiophene was prepared by the method of Example 4~7B using a-(2-benzo[b]thienyl)-3,4-(methylene-dioxy)benzyl alcohol (6.2 mmoles, 1.8 g), triethylsilane (6.8 mmoles, 1.1 ml) CHZCIZ (50 ml) and TFA (12.4 mmoles, 0.95 ml). Recrystalli zation from hexanes provided 1.2 g (73%) of a light orange solid.
C. 2-[3,4-(met:hylenedioxy)benzyl]benzo[b]thiophene-3-su)fonyl chloride 2-[3,4-(methylenedioxy)benzyl]benzo(b]thiophene-3-sulfonyl chloride was prepared by the method of Example 40B using DMF (9.1 mmoles, 0.70 ml), sulfur~~l chloride (7.7 mmoles, 0.62 ml) and 2-[3,4-(methylenedioxy)benzyl]benzo(b]thiophene (4.6 mmoles, 1.2 g). Flash chromatography (5% ethyrl acetate/hexanes) provided 0.71 g (42%) of a light yellow solid.
D. N-(4-bromo-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)benzyl]-benzo(b]thiophene-3-sulfonamide N-(4-bromo-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)benzyl)-benzo[b)thiophene-3-sulfonamide was prepared by the method of Exam-ple 41 using 4-bromo-3-methyl-5-aminoisoxazole (1.0 mmoles, 0.177 g), NaH (2.5 mmoles, 100 mg), 2-(3,4-(methylenedioxy)benzyl]benzo(b]thio-phene-3-sulfonyl chloride (1.1 mmoles, 0.40 g) and THF (7 ml). Flash chromatography (=i0% ethyl acetate/hexanes) followed by recrystalliza-tion from chloroform and hexanes provided 0.23 g (45%) of a tan crystalline solid, m.p. 164.-165°C.

N-(4-l3romo-3-methyl-5-isoxazolyl)benzo-2,1,3-thiadiazole-4-sulfonamide N-(4-bromo-3-methyl-5-isoxazolyl)benzo-2,1,3-thiadiazole-4-sulfon-amide was prepared from 5-amino-4-bromo-3-methylisoxazole and 2,1,3-thiadiazole-4-sulfonyl chloride according to the procedures described in Example 39. The crude product was purified by recrystallization from VhaJ 96I3I492 PCT/US96/04759 1~' ethyl acetate/hexanes to give a crystalline solid, m.p. 177-179° C, yield 34%.

N-(4-Bromo-3-methyl-5-is;oxazolyl)-1-methylindole-2-sulfonamide A. 2-Methyiindole-2-sulfonyl chloride 2-Methylindole-2-sulfonyl chloride was prepared by the method of Example 34 with 1-methylindole (7.8 mmols, 1.0 ml), t-BuLi (1.7 m, 9.4 mmols, 5.5 ml), sulfur dioxide, NCS (8.6 mmols, 1.2 g) and THF (15 ml).
Flash chromatography (2~% ethyl acetate/hexanes) provided 0.66 g (36%) of a yellow solid.
B. N-(4-bromo~-3-methyl-5-isoxazolyl)-1-methyiindole-2-sulfonamide N-(4-bromo-3-methyl-5-isoxazolyl)-1-methylindole-2-sulfonamide was prepared by the methiod of Example 41 with 4-bromo-3-methyl-5 aminoisoxazole (1.0 mmolls, 0.18 g), NaH (2.5 mmols, 60 mg), 1 methylindole-2-sulfonyl chloride (1.2 mmols, 0.26 g) and THF (7 ml).
Recrystallization from chloroform and hexane provided 0.28 g (77%) of a brown solid, m.p. 132-13.4° C.

N-(3,4-Dimethyl-5-isoxazolyl)-2-dibenzofuransulfonamide A. 2-Dibenzofmransulfo~nyl chloride 2-Dibenzofuransulfonic acid (12.8 mmol) was heated at 70° C with phosphorus oxychloride (1.30 ml, 14.0 mol) for 2 h. Excess phosphorus oxychloride was removed under reduced pressure. The residue was decomposed with ice water and extracted with ethyl acetate. The extract was washed with '.~% sodium bicarbonate solution, dried over anhydrous magnesium sulfate and concentrated to yield 2.9 g crude 2-di-benzofuransulfonyl chloride.

WV 96!31492 PCT/US96/04759 B. N-(3,4-Dimet:hyl-5-isoxazolyl)-2-dibenzofmansulfonamide The 2-benzofuransulfonyl chloride from step (a) was added to a solution of 5-amino-3,4-diimethylisoxazole (250 mg, 2.2 mmol) and 4-(dimethyl)aminopyridine (5 mg) in dry pyridine (2.0 ml). The reaction mixture was stirred at roam temperature for 4 h. Pyridine was removed under reduced preasure and the residue was partitioned between water and ethyl acetate. The organic layer was washed with 1 N HCI (2 X 25 ml), brine (25 ml) and dried over anhydrous magnesium sulfate.
Evaporation of the solventa left an oily residue that, after purification by column chromatography over silica gel (1 % methanol in chloroform as eluent), yielded white solid (32% yield). Purification was achieved by recrystallization from chloroform/hexanes to give a white "cotton-like"
solid, m.p. 173-175° C (dec.).

N-(4-chloro-3-methyl-5-isoxazolyl)-2-[2-(3,4-methylenedioxy)phenylJ-ethoxycarbonyl-3-suifonarnide N-(4-chloro-:3-methyl-5-isoxazolyl)-2-(2-(3,4-methylenedioxy)-phenyl)ethoxycarbonyl-3-sulfonamide was prepared by the same method as described in Example 9'7 with the exception that 2-(3,4-methylene-dioxy)phenylethanol was used instead of sesamol. The final product was obtained by HPLC purification as a yellowish oil, (500mg, 25% yield).

N-(4-Bromo-3-methyl-5-isoxazolyl)-2-phenylthiophene-3-sulfonamide A. 3-bromo-2-phenyl-thiophene Tetrakis (triphenylphosphine) palladium (400 mg), NaZC03 (4 M, 80 ml, 320 mmol) and phenylboric acid (3.81 g, 30.3 mmol) as a solution in ethanol (80 ml) were seqmentially added to a solution of 2,3-dibromothiophene f7.33 g, 30.3 mmol) in benzene (100 ml). The mixture was heated at reflux for 1:? hours. The aqueous layer of the crude mixture was removed and the organic layer was diluted with Et20 (200 '. .r 96131492 ml), washed with 1 N NaOH (2 x 150 ml) and was dried (MgS02), filtered and the solvent was evaporated. The residue was chromatographed using hexane as the eluent to give 3-bromo-2-phenylthiophene as a clear oil (3.31 g, 47% yield).
B. 2-Phenylthiophene-~3-suifonylchloride n-BuLi (2.38 M, 1 1.5 ml, 27.28 mmol) was slowly added to a solution of 3-bromo-2-phE:nyl-thiophene (22.73 mmol) in ether (50 ml) at 0° C. The reaction was ;stirred at 0° C for 1 h. S02 was bubbled through the mixture for 15 minutes at 0 °C followed by the addition of NCS (3.95 g, 29.ti5 mmol) as a suspension in THF (20 ml). The crude products were purified by column chromatography (hexanes) to give 2-phenylthiophene-3~-sulfonylchioride as a white solid (1.23 g, 34% yield).
C. N-(4-bromo-3-methyl-5-isoxazolyl)-2-phenylthiophene-3-suffona-mide N-(4-bromo-3-methyl-5-isoxazolyl)-2-phenyl-thiophene-3-sulfona-mide was prepared from ~!-phenyl-3-thiophene sulfonylchloride using the method described in Example 1. The product was purified by HPLC, 77%
yield, reddish solid, mp 8E.-89 ° C.

3-Phenoxy-N-(4-bromo-3-methyl-5-isoxazolyl)thiophene-2-sulfonamide A. 3-Phenoxythiophene.
Cuprous chloride (3.08 g, 31.1 mmol) and phenol (8.78 g, 93.3 mmol) were sequentially added to a solution of 3-bromothiophene (5.06 g, 31.1 mmol) in pyridine (150 ml). Sodium hydride (3.73 g, 93.3 mmol, 60% dispersion in mineral oil) was then slowly added. The reaction was heated at refiux for 20 hours under Argon. The pyridine was removed under reduced pressure. The residue was diluted with Et20 (200 ml) and washed with 1 N ~daOH (3 x 100 ml), 1 N HCI (2 x 150 ml) and 1 N
NaOH (150 ml). The organic layer was dried (MgS04), filtered, and the W v 96131492 PGTIUS96/04759 solvent was evaporated. The residue was chromatographed using hex-anes to give 3-phe;noxy-thiophene as a clear oil (4.0 g, 74% yield).
B. 3-Phenoxytlhiophene-2-sulfonyl chloride BuLi (2.38 ~V1, 11.5 ml, 27.28 mmol) was slowly added to a solution of 3-phenoxythiophene (4.0 g, 22.73 mmol) in ether (50 ml) at 0° C. The reaction was stirred at 0° C for 1 h. SOI was bubbled through the mixture for 15 minutes at 0 °C followed by the addition of NCS (3.95 g, 29.~i5 mmol) as a suspension in THF (20 ml). The mixture was allowed to warm up 1:0 25° C and stirred for 2 more h. The precipitate was filtered, and the filtrate was concentrated and chromatographed l;hexanes) to give 3-phenoxythiophene-2- sulfonyl chloride as a yellowish solid (1.03 g, 17% yield).
C. N-(4-bromo-3-methyl-5-isoxazolyl)-3-phenoxythiophene-2-sulfona-mide 75 N-(4-bromo-3-methyl-5-isoxazolyl)-3-phenoxythiophene-2-sulfona-mide was prepared from 3-phenoxythiophene-2-sulfonyl chloride and 5-amino-4-bromo-3-rnethylisoxazole using the method described in Example 1 . The product was recrystallized from acetonitrile/HZO to give a solid m.p. 121-1:23°C, Ei1 % yield.

N-(4-Bromo-3-methyl-5-isoxazolyl)-2-(N-(4-isopropyiphenyl)aminocarbonyl)-thiophene-3-sulfonamide N-(4-bromo-:3-methyl-5-isoxazolyl)-2-[N-(4-isopropylphenyl)-aminocarbonyl)thiophene-3-sulfonamide was prepared in the same manner as described in Example 24 from N-(4-bromo-3-methyl-5-isoxazolyl)-2-(carboxyl)thiophene-3-sulfonamide and 4-isopropylaniline in 19% yield. The crude product was passed through silica gel column using ethyl acetate as eluent. This was further purified by HPLC (5%
CH3CN to 100% CH3CN over 30 min.) to give a solid.

WO 96r31492 PCT/US96/04759 N-(4-Bromo-3-methyl-5-isoxazoly!)-2-[N-(4-sec-butylphenyl)amino-carbonyl]thiophenie-3-sulfonamide N-(4-bromo-3-methyl-5-isoxazolyl)-2-[N-(4-sec-butylphenyl)amino-carbonyl]thiophene-3-sulfonamide was prepared in the same manner as described in Example 24 from N-(4-bromo-3-methyl-5-isoxazolyl)-2-(carboxyl)thiophene-3-sulfonamide and 4-sec-butylaniline in 25% yield.
The crude product was passed through silica gel column using ethyl acetate as eluent. This was further purified by HPLC (5% CH3CN to 100% CH3CN over 30 min.) give a solid, m.p. 205 - 208°C.

N-(4-Bromo-3-methyl-5-isoxazolyl)-2-[N-(4-teri-butylphenyl)amino-carbonyl]thiophene-3-sulfonamide N-(4-bromo~-3-methyl-5-isoxazolyl)-2-[N-(4-tent-butylphenyl)-aminocarbonyl]thiophene-3-sulfonamide was prepared in the same manner as described in Example 24 from N-(4-bromo-3-methyl-5-isoxazolyl)-2-(carboxyl)thiophene-3-sulfonamide and 4-tent-butylaniline in 28% yield. The crude product was passed through silica gel column using ethyl acetate: as elu~ent. This was further purified by HPLC f5%
CH3CN to 100% C;H3CN over 30 min.) give a solid, m.p. 76 - 86°C.

N-(4-Bromo-3-methyl-5-isoxazolyl)-2-[N-(4-butylphenyl)aminocarbonyl]-thiophene-3-sulfonamide N-(4-bromo-3-methyl-5-isoxazolyl)-2-[N-(4-butylphenyl)aminocar-bony)]thiophene-3-sulfonamide was prepared in the same manner as described in Example 24 from N-(4-bromo-3-methyl-5-isoxazolyl)-2-(carboxyl)thiophene-3-sulfonamide and 4-butylaniline in 18% yield. The crude product was passedl through silica gel column using ethyl acetate as eluent. This was further Purified by HPLC (5% CH3CN to 100%
CH3CN over 30 min.) give a solid.

96!31492 PCTlUS96/04759 N-(4-bromo-3-methyl-5-isoxazolyt)thiazole-2-sulfonamide A. Thiazole-2-sulfonyl chloride Thiazole (0.51 g, E~ mmol) was dissolved in THF (5 ml) and cooled to -78°C under argon atmosphere. n-Butyllithium (2.5 M solution in hexane, 2.4 ml, 6 mmol) was added dropwise under constant stirring.
The resultant reaction mixture was stirred at -78°C for 40 min.
Sulfur dioxide was bubbled through the reaction mixture for 15 min at -78°C.
The reaction mixture was allowed to attain ambient temperature slowly and stirred for 30 min. NCS was added and stirring was continued for 30 min. The reaction mixture was diluted with water (50 ml), extracted with ethyl acetate (2 X 50 ml) and the combined organic layers was dried over anhydrous MgSO,. Removal of the solvent under reduced pressure gave crude product which was purified by column chromatography, using hexane as eluent, to give thiazole-2-sulfonyl chloride as a liquid(0.6 g, 54% yield).
B. N-(4-bromo-3-methyl-5-isoxazolyl)thiazole-2-sulfonamide N-(4-bromo-3-methyl-5-isoxazolyl)thiazole-2-sulfonamide was prepared in the same manner as described in Example 2 from 5-amino-4-bromo-3-methylisoxazole .and thiazole-2-sulfonyl chloride in 57% yield.
This was purified by HPLC: (5% CH3CN to 100% CH3CN over 30 min.) to give a solid., m.p. 175 - 177°C.

N-(4-chloro-3-methyl-5-isc~xazolyl)thiazole-2-sulfonamide N-(4-chloro-3-methyl-5-isoxazolyl)thiazole-2-sulfonamide was prepared in the same manner as described in Example 2 from 5-amino-4-chloro-3-methylisoxazole and thiazole-2-sulfonyl chloride in 33% yield.
This was purified by HPLC: (5% CH3CN to 100% CH3CN over 30 min.) to give a solid, m.p. '171-17:1°C.

A .. 96131492 PCT/US96J04759 N-(3,4-dimethyl-5-isoxazolyi)thiazole-2-sulfonamide N-(3,4-methyl-5-isoxazolyl)thioazole-2-sulfonamide was prepared in the same manner as described in Example 14 from 5-amino-3,4-dimethylisoxazole and thiazole-2-sulfonyl chloride in 37% yield. This was - purified by HPLC (5% CHI3CN to 100% CH3CN over 30 min.) give a solid, m.p. 118 - 120°C.

5-benzyl-N-(4-Bromo-3-methyl-5-isoxazolyl)thiophene-2-sulfonamide A. 1-(2-Thienyl)benzyl' alcohol Sodium borohydride (0.37 g, 10 mmol) was added to 2-benzoylthiophene ( 1.88 g, 10 mmol) dissolved in methanol/THF mixture (1:10 ratio, 11 ml). This was stirred at room temperature for 10 h. The reaction mixture vas decomposed by addition of saturated ammonium chloride solution (50 ml) and was extracted with ethyl acetate (2 X 50 ml). The combined organic layers was dried over anhydrous MgS04.
Removal of the solvent gave 1-(2-thienyl)benzyl alcohol as a solid ( 1.75 g, 92% yield).
B. 2-Benzylthiophene Acetic anhydride (5 ml) was added to a solution of 1-(2-thienyl)benzyl alcohol in pyridine. The resultant solution was stirred at 70°C for 3h. Wal:er (50 ml) was added and the reaction mixture was stirred at room tennperature for 2h. This was extracted with ethyl acetate (2 X 50 ml) and tine combined organic layers dried over anhydrous MgS04. Removal of the solvent gave crude product, which was purified by passing through silica c3el using 3:1 hexane/ethyl acetate mixture to give 1-(2-thienyl)benzyl acetate.
A solution of 1-(2-tlhienyl)benzyl acetate in THF (5 ml) was added carefully to dry liquid ammonia (100 ml). Lithium metal was added in W v 96131491 PCT/US9G/04759 small portions untiil the blue color persisted. The resulting reaction mixture was stirred for 30 min, and the reaction was quenched by addition of solid ammonium chloride. The residue, after complete evaporation of liquid ammonia, was dissolved in water (50 ml) and was extracted with methylene chloride (2 X 50 ml). The combined organic layers was dried over MgS04 and filtered. Removal of the solvent gave crude product, which was. purified by column chromatography using hexane as eluent to give :?-benzylthiophene (1.2 g, 68 % yield).
C. 5-Benzylthiophene-:2-sulfonyl chloride To a solution of 2-benzylthiophene (0.875 g, 5 mmol) in chloro-form (2 ml) at 0°C; was added chlorosulfonic acid dropwise and the reac-tion was stirred at 0°C for 30 min. The reaction mixture was decom-posed by pouring onto crushed ice (20 g). The mixture was extracted with ethyl acetate, dried over MgS04 and filtered. The solvent was re-moved under reduced pressure to give 5-benzylthiophene-2-sulfonic acid.
Phosphorous pentac;hloride (2.08 g, 40 mmol) was added to a solu-tion of 5-benzylthiophene-2-sulfonic acid in phosphorous oxychloride (6.0 g, 40 mmol) at 0°~~. The reaction mixture was kept at 50°C for 1 h, cooled to room temperature, then poured onto crushed ice f50 g) and extracted with eth~,rl acetate (2 X 30 ml). Removal of the solvent under reduced pressure gave a crude product, which was purified by column chromatography using 3% ethyl acetate in hexane to give 2-benzylthio-phene-5-sulfonyl chloride (0.6 g, 39 % yield).
D. N-(4-bromo-3-methyl-5-isoxazolyl)-5-benzyithiophene-2-sulfonamide N-(4-Bromo-.3-methyl-5-isoxazolyl)-5-benzylthiophene-2-sulfona-mide was prepared in the Name manner as described in Example 2 from 5-amino-4-bromo-3-methylisoxazole and 5-benzyl-2-thiophenesulfonyl chloride in 22% yield. ThE; product was purified by HPLC (5% CH3CN to 100% CH3CN over 30 min.) to give a solid, m.p. 49 - 50°C.

a ~ 46131492 PCTIUS9G/04759 N-(4-Bromo-3-methyl-5-isoxazolyl)-3-phenethyithiophene-2-sulfonamide A. 1-(3-Thienyl)phenethyl alcohol Benzyl bromide (25.65 g, 150 mmol) was added drvpwise over 8 h to a suspension of magnesium (3.6 g, 150 mmol) in ether (75 ml) dissolved in ether (30 ml). The resulting mixture was cooled to -10°C.
3-thiophenecarboxaldehyde in ether (45 ml) over 30 min was then added and the resultant reaction mixture was stirred at room temperature for 6 h. This was cooled to 0°C; and the reaction mixture was decomposed by addition of 0.1 N HCI. ThE: ether layer was separated and the aqueous phase was extracted with ethyl acetate (2 X 50 ml). The combined organic layers was dried over MgS04 and filtered. Removal of the solvent gave 1-(3-thienyl)phenethyl alcohol (16 g, 78% yield).
B. 1-(3-Thienyl)phenethyl acetate 1-(3-Thienyl)phenethyl alcohol (10 g, 49 mmol) was dissolved in a 2:1 pyridine and acetic anhydride mixture (50 ml). This was stirred at 80°C for 4 h. ExcEas of pyridine and acetic anhydride mixture was removed under reduced pressure and the residue was dissolved in water ( 100 ml). This was extracted with methylene chloride (3 X 75 ml) and the combined organic layers was dried over MgS04 and filtered. Removal of the solvent gave 1-(3-thienyl)phenethyl acetate (10.2 g, 84% yield).
C. 3-Phenethylthiophene 1-(3-thienyl)F~henylethyl acetate dissolved in THF (20 ml) was added carefully to dry liquid ammonia (300 ml). Lithium metal was added in small portions until the blue color persisted. The resulting reaction mixture was stirred for 30 min and the reaction was quenched by addition of solid ammonium chloride. The residue, after the complete evaporation of liquid ammonia, was dissolved in water (100 ml) and was extracted with methylene chloride (4 X 50 ml). The combined organic A .. 96!31492 PCT/LJS96/04759 layers was dried over MgSO, and filtered. Removal of the solvent gave a crude product, wihich was purified by column chromatography using hexane followed by mixture of ethyl acetate in hexane as eluent to give 3-phenethylthiophene (3..2 g, 34 % yield) and 1-(3-thienyl)phenethyl acetate (starting material, 7g).
D. 3-Phenethylthiophe~ne-2-sulfonyl chloride and 4-phenethylthiophene-2-sulfonyl chloride 3-Phenethylthiophene (0.94 g, 5 mmol) was dissolved in THF (12 ml) and cooled to -78°C under argon atmosphere. n-Butyllithium (2.5 M
solution in hexane, 4.4 mil, 5.5 mmol) was added dropwise with constant stirring under an argon atmosphere. The resultant reaction mixture was stirred at -10°C to 0°C for 3 h, cooled to -78°C and sulfur dioxide was bubbled through the reaction mixture for 15 min. The reaction mixture was allowed to attain amtrient temperature slowly and stirring continued for 30 min. NCS ( 1 g) was added and stirring was continued for 1 h. The reaction mixture was diluted with water (50 ml), extracted with methylene chloride (2 X 5!J ml) and the combined organic layers was dried over anhydrous MgS04. Removal of the solvent under reduced pressure gave a crude product which was purified by column chromatography, using 0.2% ethyl acetate in hexane as eluent, to give 3-phenethyl-2-thiophenesulfonyl chloride (0.06 g, 4% yield) and 4-phenethyl-2-thiophenesulfonyl chloride (0.72 g, 45% yield).
E. N-(4-bromo-:3-methyl-5-isoxazolyl) -3-phenethylthiophene-2-sulfona-mide N-(4-bromo-;3-methyl-5-isoxazolyl)-3-phenethylthiophene-2-sulfona-mide was prepared in the same manner as described in Example 2 from 5-amino-4-bromo-3-methylisoxazole and 3-phenethyl-2-thiophenesulfonyl chloride in 48% yield. This was purified by HPLC (5% CH3CN to 100%
CH3CN over 30 min.) to give a solid.

Wv 96131492 PCT/US96104759 EXAMPLE fi4 N-(4-Bromo-3-methyl-5-isoxazoiyl)-4-phenethyithiophene-2-sulfonamide N-(4-bromo-3-methyl-5-isoxazolyl)-4-phenethylthiophene-2-sulfona-mide was prepared in the Name manner as described in Example 2 from 5-amino-4-bromo-3-methylisoxazole and 4-phenethyl-2-thiophenesulfonyl chloride in 32% yield. This was purified by HPLC (5% CH3CN to 100%
CH3CN over 30 min.) to give a gum.

N-(4-Bromo-3-methyl-5-isoxazolyl)-5-(3-methoxyphenyl)thiophene-2-sul-fonamide A. 5-bromothiophene-2-sulfonyl chloride Chlorosulfonic acid vvas added dropwise over 20 min. to a cold solution (-78 °C) of 2-bromothiophene ( 16.3 g, 100 mmol) in methylene chloride (50 ml) was added After addition of chlorosulfonic acid was complete, the cold bath wars removed. The reaction mixture was allowed to attain room temperature slowly (2 h), was added dropwise onto the crushed ice ( 1000 d) and was extracted with methylene chloride (4 X
100 ml). The combined orc3anic layers was dried over MgS04, filtered and the solvent was. removed under reduced pressure to give a crude product. This was purified by column chromatography using hexane as eluent to give 5-bromothiophene-2-sulfonyl chloride (22 g, 75% yield).
B. N-(5-bromothiophene-2-sulfonyl)pyrrole N-(5-bromothiiophene-2-sulfonyl)pyrrole was prepared in the same manner as described in Example 33A from 5-bromothiophene-2-sulfonyl chloride and pyrrole in 88% yield. This was purified by recrystallization using hexane/ethyf acetate as a solvent.
C. 3-MethoxyphE:nylboronic acid 3-Methoxyphf:nylboronic acid was prepared in the same manner as described in Example: 33B from 3-bromoanisole and triisopropyl borate in R~,~ 96131492 PGTIUS96/04759 82% yield. This was used in the next step without any further purification.
D. N-[5-(3-met:hoxyphenyl)thiophene-2-sulfonyl]pyrrole N-[5-(3-met:hoxyphenyl)thiophene-2-sulfonyl]pyrrole was prepared in the same manner as de;scribed in Example 32C from 3-methoxyphenylboronic acid and N-(5-bromothiophene-2-sulfonyl)pyrrole in 93% yield. This was purified by recrystallization using hexane/ethyl acetate as solvent.
E. 5-(3-Metho;Kyphenyl)thiophene-2-sulfonyl chloride To a suspension of N-[5-(3-methoxyphenyl)thiophene-2-sul-fonyl)pyrrole (1.4 g, 4.5 rnmol) in ethanol (15 ml) was added 6 N sodium hydroxide solution, ( 15 ml) and the resultant reaction mixture refluxed for 14 h. The reaction mixture was cooled to room temperature. Ethanol was removed under reduced pressure and the resultant precipitate was filtered and dried under vacuum (1.1 g, 91 % yield).
Phosphorous pentachloride (2.08 g, 10 mmol) was added to the suspension of sodium slat: of sulfonic acid (0.62 g, 2.5 mmol) (obtained from above step) in phosphorousoxy chloride (0.93 ml, 10 mmol) and the resultant reaction mixture stirred at room temperature for 3 h. This was decomposed by adding on to crushed ice and the product was extracted with methylene cf,~loride (:2 X 50 ml). The combined organic layers dried over MgS04 and filtered. Removal of the solvent gave the crude product which was purified by column chromatography using 2% ethyl acetate in hexane to give 5-(3-methoxyphenyl)thiophene-2-sulfonyl chloride (0.51 g, 75%).

a F. N-(4-bromo-3-methyl-5-isoxazolyl)-5-(3-methoxyphenyl)thiophene-2-sulfonamide N-(4-bromo-3-methyl-5-isoxazolyl)-5-(3-methoxyphenyl)thiophene-2-sulfonamide ways prepared in the same manner as described in Example 2 from 5-amino-4-bromo-~3-methylisoxazole and 5-(3-methoxyphenyl)thio-phene-2-sulfonyl chloride in 48% yield. This was purified by HPLC (5%
CH3CN to 100% ~~H3CN .over 30 min.) give a solid.

N-(4-Bromo-3-met:hyl-5-isoxazolyl)-5-(2-methylfuranyl)thiophene-2-sulfon-amide A. N-(pyrrole)-5-(2-methylfuranyl)thiophene-2-sulfonamide t-BuLi (1.7 m solution in hexane, 7.9 ml, 14.6 mmol) was added dropwise under constant stirring under a nitrogen atmosphere to a solution of 2-methnyl furan (1.0 g, 12 mmol) in THF (20 ml) at -78° C.
The solution was then warmed to -10° C and stirring was continued for 45 min. The solution was then added to a solution of zinc chloride (27 ml of a 0.5 M solution in THF) at -30° C and then warmed to room temperature wherE: stirring continued for 1 hr. resulting in a pale yellow clear solution. Th~~ solution was then transferred via a steel canula under nitrogen to a solution of N-(pyrrole)-5-bromothiophene-2-sulfonamide (Example 33A, 3.5 g, 12 mmol) and tetrakis(triphenylphosphine)-palladium (0) (693 mg, 0. 6 mmol) in THF ( 15 ml) at -78 ° C. The solution was then warmed to room temperature and stirred for a period of 2 hours. Purification by column chromatography using 2% ethyl acetate gave 680 mg of N~-(pyrrole:)-5-(2-methylfuranyl)thiophene-2-sulfonamide as a pale yellow powder ('t 9% yield).
B. 2-(2-methylfuranyl)t:hiophene-5-sulfonyl chloride 2-(2-methylfuranyl)thiophene-5-sulfonyl chloride was prepared in the same manner as described in Example 33D from N-(pyrrole)-5-(2-methylfuranyl)thiophene-2-sulfonamide (300 mg, 1.02 mmol).

A _ X6131492 PCT/US96/04759 Purification by column chromatography using 2% ethyl acetate/hexanes gave 145 mg (53%) of the sulfonyl chloride as a pale yellow solid.
C. N-(4-bromo-a-methyll-5-isoxazolyl)-5-(2-methyl-furanyl)thiophene-2-suifonamide N-(4-bromo-~~-methyl-5-isoxazolyl)-5-(2-methyl-furanyl)thiophene-2-sulfonamide was prepared in the same manner as described in Example 2.
Reaction of 2-(2-methylfuranyl)thiophene-5-sulfonyl chloride (55 mg, 0.21 mmol) with 5-amino-4.-bromo-3-methyl isoxazole (41 mg, 0.21 mmol), after purification by column chromatography using 10%
MeOH/CHC13, gave 45 mg of the pure sulfonamide as a brown semisolid, 54% yield, m.p. 12:3-124° C.

N-(4-8romo-3-methyl-5-isoxazolyl)-5-(4-methoxyphenyl)thiophene-2-sul-fonamide A. N-(5-(4-methoxyphenyl)thiophene-2-suifonylJpyrrole N-(5-(4-methoxyphenyl)thiophene-2-sulfonylJpyrrole was prepared, in the same manner as described in Example 32C, from 4-methoxyphenyl-boronic acid and N-(5-bromothiophene-2-sulfonyl)pyrrole.
Recrystallization using hexane/ethyl acetate gave a solid in quantative yield.
B. 5-chlorosuffon~yl-2-(4-methoxyphenyl)thiophene A solution of 1V-(5-(4-methoxyphenyl)thiophene-2-sulfonylJpyrrole (1.4 g, 4.5 mmol) was suspended in ethanol (15 ml). A 6N sodium hydroxide solution was added, and the resulting suspension was refluxed for 14 hr. to give a clear solution. This was cooled to room temperature.
Ethanol was removecj under reduced pressure. A precipitate was formed on standing at room temperature which was filtered and washed with methylene chloride and dried under vacuum giving a solid (1.2 g, 91 %).
The solid (0.6'7 g, 2.5 mmol) was suspended in phosphorous oxychloride (0.92 ml, 10 mmole) and phosphorous pentachloride (2.08 g, ~6I31492 PCT/US96/04759 mmole) was added. The resulting mixture was stirred at room temperature for 3 hr. The reaction mixture was decomposed by pouring onto crushed ice (~~0 g). l-he mixture was extracted with methylene chloride (2 x 50 ml) and the combined organic layers was dried over 5 MgS04. Removal of solvent under reduced pressure gave a crude product which was purified by column chromatography using 2% EtOAc in hexane as solvent to give 5-chlorosulfonyl-2-(4-methoxyphenyl)-thiophene (530 mg, 86%).
C. N-(4-bromo-:I-methyl-5-isoxazolyl)-5-(4-methoxyphenyl)thiophene-'10 2-sulfonamide N-(4-bromo-~~-methyl-5-isoxazolyl)-5-(4-methoxyphenyl)thiophene-2-sulfonamide was prepared in the same manner as described in Example 1. Reaction of 5-cf~ilorosulfonyl-2-(4-methoxyphenyl)thiophene with 5-amino-4-bromo-3-methylisoxazole gave N-(4-bromo-3-methyl-5-isoxazolyl)-5-(4-methoxyphenyl)thiophene-2-sulfonamide in 50% yield, m.p. 128-130° C.

N-(4-8romo-3-methyl-5-iso~;azolyl)-5-(3-thienyl)thiophene-2-sulfonamide A. 3-Thiopheneboric acid n-Butyllithium (2.5 M solution in hexane, 20 ml, 50 mmol) was added dropwise to a solution of 3-bromothiophene (8.15 g, 50 mmol) in THF (20 ml) at -78°C under an argon atmosphere. The resulting solution was stirred at -78°C; for 45 min, and then added to a solution of triisopropyl borate (~a.4 g, 50 mmol) in THF at -78°C over 30 min through a steel cannula. The: resulting reaction mixture was stirred at room temperature for 12 h and was decomposed by the addition of 100 ml 1 N
HCI. The aqueous layer was extracted with ether (2 X 100 ml) and the combined organic la~,rers was extracted with 1 M NaOH (3 X 30 ml), the aqueous extract wa:~ acidifif:d with concentrated HCI to pH 2 and ~. . 96!31492 PCTlUS96/04759 extracted with ether (3 ~: 50 ml). The combined ether extract was washed once witlh water, dried over MgS04 and filtered. Removal of the solvent gave 3-thenylboronic acid as a solid (5.2 g, 80% yield).
B. N-[5-(3-thiE;nyl)thiophene-2-sulfonyl]pyrrole N-[5-(3-thie;nyl)thiophene-2-sulfonyl]pyrrole was prepared in the same manner as described in Example 32C from 3-thienylboronic acid and N-(5-bromothiophene-2-sulfonyl)pyrrole in quantative yield. This was purified by recrystallization using hexane/ethyl acetate as solvent.
C. 5-(3-Thienyl)thiophene-2-sulfonyl chloride 5-(3-thienyl')thioph~ene-2-sulfonyl chloride was prepared in the same manner as descrit>ed in Example 64E from N-[5-(4-methoxyphenyl)thio-phene-2-sulfonyl]pyrrole in 74% yield.
D. N-(4-bromo-3-methyl-5-isoxazolyl)-5-(3-thienyl)thiophene-2-sulfona-mide N-(4-bromo-3-methyl-5-isoxazolyl)-5-(3-thienyl)thiophene-2-sulfona-mide was prepared in the same manner as described in Example 2 from 5-amino-4-bromo-3-methyliaoxazole and 5-(3-thienyl)thiophene-2-sulfonyl chloride in 40% yield. This was purified by HPLC (5% CH3CN to 100%
CH3CN over 30 min.) give: a solid.

N-(4-Bromo-3-methyl-5-isoxazolyl)furan-2-sulfonamide N-(4-bromo-3-methyl-5-isoxazolyl)furan-2-sulfonamide was prepared by the method of Example 1 with 5-amino-4-bromo-3-methyl-isoxazole (0.266 d, 1.5 mmol), NaH (60% oil dispersion) (0.15. g, 3.8 mmol) and furan-~:-sulfonyl chloride (Example 36A) (0.30 mg, 1.8 mmol).
Flash chromatography (50% EtOAc/hexane) and recrystallization from CHC13 and hexane provided 90 mg (20% yield) of light yellow crystals (m.p. 117-119°C).

R e6/31492 PCTJUS96/04759 N-(4-bromo-3-methyl-5-isoxazolyl)-5-(phenylthio)furan-2-sulfonamide A. 2-(phenylthio )furan t-BuLi (1.7 m, 10 ml, 1.7 mmol) was added to a solution of furan (1.24 ml, 17 mmol) in 20 m! of THF at -60°C. Thirty minutes later diphenyldisulfide (3.7 g, 17 mmol) was added via cannula in 8 ml of THF.
The reaction was warmed to ambient temperature for 30 minutes, then diluted with 150 ~ml of ether and washed with 3% NaOH (3 x 100 ml).
The organic was dried (IVIgS04), filtered and concentrated to collect 2.92 g (97% yield) of a light yellow liquid.
B. 5-phenytthiofuran-:2-sutfonyl chloride 5-phenylthiofuran-:2-sulfonyl chloride was prepared by the method of Example 34A vvith 5-phenylthiofuran (1.5 g, 8.5 mmol), t-BuLi (1.2 m, 8.9 mmol, 5.3 ml) and NCS (1.14 g, 8.5 mmol). Flash chromatography (5% EtOAc/hexar~e) provided 1.61 g (69% yield) of a yellow-orange liquid.
C. N-(4-bromo-3-methyl-5-isoxazolyl)-5-(phenylthio)furan-2-sulfona-mide N-(4-bromo-3-methyl-5-isoxazolyl)-5-(phenylthio)furan-2-sulfona-mide was prepared by the: method of Example 1 with 4-bromo-3-methyl-2-aminoisoxazole (0.354 g, 2.0 mmol), NaH (60% oil dispersion) (0.20 g, 5.0 mmol) and 5-phenylthiofuran-2-sulfonyl chloride (0.66 g, 2.4 mmol).
Flash chromatography (50% EtOAc/hexane) and recrystallization from CHC13/hexane provided 8:2 mg (10% yield) of a tan solid (m.p. 90-91.5°C).

W.. ~6f31492 PCT/US96/04759 N-(4-Bromo-3-methyl-5-iso:Kazolyl)-5-phenylfuran-2-sulfonamide A. 2-Phenylfuran 2-phenylfuran was prepared by the method of Example 32C from 2-bromofuran (0.93 g, 6.3 mmol), sodium carbonate ( 18 ml of 2 M
aqueous solution), phenyl boric acid f0.93 g, 7.6 mmol) and tetrakis (triphenylphosphine) palladium (0) (0.36 g, 0.32 mmol). Flash chroma-tography with hexane provided 0.79 g (87% yield) of a colorless liquid.
B. 5-phenylfuran-2-sulfonyl chloride 5-phenylfuran-2-sulfonyl chloride was prepared by the method of Example 34A with :?-phenylfuran (0.79 g, 5.5 mmol), t-BuLi (1.7 m, 6.0 mmol, 3.6 ml) and PJCS (0.73 g, 5.5 mmol). Flash chromatography (5%
EtOAc/hexane) provided 0.84 g (63% yield) of a light red solid.
C. N-(4-bromo-3-methyl-5-isoxazolyl)-5-phenylfuran-2-sulfonamide N-(4-bromo-3-methyl-5-isoxazolyl)-5-phenylfuran-2-sulfonamide was prepared by they method of Example 1 with 4-bromo-3-methyl-2-amino isoxazole (0.354 g, 2.0 mmol), NaH (60% oil dispersion) (0.20 g, 5.0 mmol) and 5-ph~enylfur~~n-2-sulfonyl chloride (0.58 g, 2.4 mmol).
Flash chromatography (50°/« EtOAc/hexane) and recrystallization from CHC13/hexane provided 0.23 g (29% yield) of light yellow crystals (m.p.
124-126°C).

N-(4-Bromo-3-methyl-5-isoxazolyl)-5-(4-isopropylphenyl)thiophene-2-sul-fonamide A. 4-Isopropylph~enyl boronic acid 4-Isopropylphenyl boronic acid was prepared in the same manner as described in Example 33E3 from 1-bromo-4-ethyl benzene. The boronic acid was isolated as a white. powder in 63% yield, m.p. 133-135°C.
B. N-[5-(4-isopropylphenyl)thiophene-2-sulfonyl]pyrrole Wv 96r31492 PCT/US96/04759 N-[5-(4-isopropylphE:nyl)thiophene-2-sulfonyl)pyrrole was prepared in the same manner as de~~cribed in Example 33C, from 4-isopropylphenyl boronic acid and N-~(5-bromothiophene sulfonyl)-pyrrole. Purification by column chromatography u:>ing 10% ethyl acetate/hexanes gave the pure sulfonamide as an off white colored solid in 84% yield, m.p. 1 12-114°C.
C. 5-chlorosulfont'l-2-(4-ethylphenyl)thiophene 5-chlorosulfont'l-2-(4-ethylphenyl)thiophene was prepared in the same manner as described in Example 33D. Hydrolysis of 526 mg ( 1.59 mmol) of N-(5-(4-isopropyl):hiophene)-2-sulfonyl)pyrrole with 6N sodium hydroxide followed by chlorination using phosphorous oxychloride and phosphorous pentac;hloride gave the crude sulfonyl chloride as dark oil.
Flash column chromatography over silica gel using 2% ethyl acetate/hexanes yielded 262 mg (55%) of the pure sulfonyl chloride as a light brown oil.
D. N-(4-bromo-3-methyl-5-isoxazolyl)-5-(4-isopropylphenyl)thiophene-2-sulfonamide N-(4-bromo-3-methyl-5-isoxazolyl)-5-(4-isopropylphenyl)thiophene-2-sulfonamide was prepared in the same manner as described in Example 2. Reaction of 5-chlorosu)font')-2-(4-isopropyl)thiophene (260 mg, 0.87 mmol) with 5-amino-4-bromo-3-methylisoxazole ( 161 mg, 0.91 mmol) yielded after flash chromatography using 10% MeOH/CHC13 a pale brown solid (265 mg) which was further purified using preparative HPLC to give the pure sulfonamidc: as a light tan colored solid, m.p. 114-1 16°C.

N-(4-Bromo-3-methyl-5-isoxazolyl)-5-(4-propylphenyl)thiophene-2-sulfona-mide A. 1-bromo-4-propylbenzene A solution of 1-bromopropane (1.32 g, 0.6 mmol) was added dropwise at room temperature at a rate such that a gentle reflux was maintained to a su~spensio~n of magnesium (258 mg, 12 mmol) in dry tetrahydrofuran. l-he cloudy suspension was stored at room temperature for an additional 30 minutes to produce a gray solution that was then added dropwise over 15 minutes to a mixture of 1-iodo-4-bromobenzene (3.0 g, 10.6 mmol) and tetrakis (triphenylphosphine) palladium (0) in 50 mL of dry benzene at roonn temperature. The mixture was stirred for 2 hours, diluted with 50 mL of water, the organic layer was separated and the aqueous layer 'was extracted with ether (2 x 50 mL). The combined organic extracts was dried and evaporated to yield 1.69 g (80%) of a light brown oil, which was used in the next step without further purification.
B. 4-propylphenyl boronic acid To a suspen:;ion of magnesium shavings (217 mg, 8.9 mmol) in 3 mL of dry tetrahydrofuran under argon, a crystal of iodine along with a solution of 4-bromopropylt>enzene (1.69 g, 8.5 mmol) dissolved in 6 mL
of tetrahydrofuran was added at such a rate that a gentle reflux was maintained. The solution was refluxed for an additional 0.5 h, cooled to room temperature and added in portions over 10 min to a solution of trimethyiborate (924 mg, 8.9 mmol) previously dissolved in 4 mL of dry ether at -78°C. After 30 rninutes, the solution was warmed to room temperature; and starring was continued for 90 min. The reaction was then quenched by the addition of 2 mL of a 10% hydrochloric acid solution. The tetrahydrofu~ran was removed under reduced pressure and the remaining residue was extracted into diethyl ether (3 x 25 mL). The combined ether extracts was extracted with 1 M NaOH (3 x 25 mL) and the resulting aqueous layer was acidified to pH 2.0 using 6N HCI, then reextracted back into diethyl ether (3 x 25 mL). The combined organic layers was washed with water ( 1 x 25 mL), brine ( 1 x 25 mL) and dried over magnesium sullfate. Evaporation of solvent left a brown solid which Vr.. 96131492 PCTIUS96/04759 was filtered through a small plug of silica gel using 10% MeOH/CHC13.
Evaporation left 448 mg (32%) of a brown solid, m.p. 90-93°C.
C. N-[5-(4-propy iphenyl)thiophene-2-sulfonyl]pyrrole N-[5-(4-propylphenyl)thiophene-2-sulfonyl]pyrrole was prepared in the same manner as described in Example 33C, from 4-propylphenyl boronic acid and N-(5-bromothiophenesulfonyl)pyrrole. Purification by column chromatography using 10% ethyl acetate/hexanes gave the pure sulfonamide as~ a white solid in 55% yield, m.p. 106-108°C.
D. 5-chlorosulfonyl-2-(4'.-propylphenyl)thiophene '10 5-chlorosulfonyl-2-(4.-propylphenyl)thiophene was prepared in the same manner as described in Example 33D. Hydrolysis of 240 mg (0.73 mmol) of N-[5-(4-propylphe~nylthiophene)-2-sulfonyl]pyrrole with 6N NaOH
followed by chlorination using phosphorous oxychloride and phosphorous pentachloride gave the crude sulfonyl chloride as a greenish-brown oil.
Flash chromatography over silica gel using 2% ethyl acetate/hexanes yielded 83 mg (81 °/;) of the' pure sulfonyl chloride as a pale yellow oil.
E. N-(4-bromo-3-methyl-5-isoxazolyl)-5-(4-propylphenyl)thiophene-2-sulfonamide N-(4-bromo-3-methyl-5-isoxazolyl)-5-(4-propylphenyl)thiophene-2-sulfonamide was prepared in the same manner as described in Example 2.
Reaction of 5-chlorosulfonyl-2-(4-isopropyl)thiophene (260 mg, 0.87 mmol) with 5-amino-4-bromo-3-methylisoxazole ( 161 mg, 0.91 mmol) yielded after flash chromatography using 10% MeOH/CHC13 a brown solid (76.1 mg) which was further purified using preparative HPLC to give the pure sulfonamide as a tan colored oil.

Wt, ~6I31492 PCT/US96/04759 N-(4-Bromo-3-meth»I-5-isoa;azolyl)-2-(3,4,5-trimethoxybenzyl)-benzo[b]-thiophene-3-sulfonamide A. a-(2-benzo[b]thienyl)~-3,4,5-trimethoxybenzyl alcohol a-(2-benzo[b]ihienyl)-3,4,5-trimethoxybenzyl alcohol was prepared in the same manner as described in Example 40A. Reaction of benzo(b]thiophene ('7.5 mmoles, t .0 g), t-BuLi (1.7m, 9.7 mmoles, 5.7 mls) and 3,4,5-trime~thoxybenzaldehyde (8.9 mmoles, 1.8 g) in THF (20 ml) yielded, after flash chromatography using 50% ethyl acetate/hexanes, 2.4 g (97%) of a yellow-white solid.
B. 2-(3,4,5-trimethoxybE:nzly)-benzo[b]thiophene 2-(3,4,5-trimethoxybe:nzly)-benzo[b]thiophene was prepared in the same manner as described in Example 47B. Reaction of a-(2-benzo[b]-thienyl)-3,4,5-trimethoxybenzyl alcohol (4.5 mmoles, 1.5 g), triethylsilane (5.0 mmoles, 0.80 mls), CHZCIZ (50 ml) and TFA (9.1 mmoles, 0.70 mls) yielded, after flash chromatography using 20% ethyl acetate/hexanes, 0.77 g (54%) of a white solid.
C. 2-(3,4,5-trimethoxybe~nzyl)-benzo[b)thiophene-3-sulfonylchloride 2-(3,4,5-trime2hoxybenzyl)-benzo(b]thiophene-3-sulfonylchloride was prepared in the came manner as described in Example 40B. Reaction of dimethylformamide (DMF; 4.8 mmoles, 0.40 mls), sulfuryl chloride (4.1 mmoles, 0.33 mls) and 2-(3,4,5-trimethoxybenzyl)-benzo[b]
thiophene (2.4 mmoles, 0.75 g) yielded, after flash chromatography using 20% ethyl acetate/h~:xanes, 0.29 g (30%) of a yellow-orange oil.
D. N-(4-bromo-3-methyl-5-isoxazolyl)-2-(3,4,5-trimethoxybenzyl)-benzo[b]thiophene-3-sulfonamide N-(4-bromo-3-methyl-5-isoxazolyl)-2-(3,4, 5-trimethoxybenzyl)-benzo[b]thiophene-3-sulfonamide was prepared in the same manner as described in Example 41. Reaction of 4-bromo-3-methyl-5-amino-isoxazole (0.55 mmoles, 97 mg), NaH (1.4 mmoles, 55 mg), and 2-A _ X6131492 PCT/US96/04759 (3,4,5-trimethoxylbenzyl)-ibenzo[b)thiophene-3-sulfonyl chloride (0.66 mmoles, 0.27 g) in THF (2'. ml) yielded, after flash chromatography using 50% ethyl acetate/haxanes and recrystallization from chloroform and hexanes, 94 mg of a tan solid, m.p. 154-156°C.

N-(4-bromo-3-methyl-5-isoxazolyl) 2-ethyl-5-methylbenzo[b)thiophene-3-sulfonamide A. 2-ethyl-5-methylbenzo [b]thiophene 2-ethyl-5-methylbenzo[b)thiophene was prepared in the same manner as described in Example 40A. Reaction of 5-methylbenzo[b)thiophene (.3.4 mmoles, 0.50 g), t-BuLi (1.7 m, 5.1 mmoles, 3.0 ml) and ethyl iodide (6.8 mmoles, 0.54 ml) in THF (10 ml) yielded 0.58g (97%~) of a light yellow liquid.
15 B. 2-ethyl-5-mevthylben:~-o[bJthiophene-3-sulfonylchloride 2-ethyl-5-methylbenzo(b)thiophene-3-sulfonylchloride was prepared in the same manner as described in Example 40B. Reaction of DMF (6.5 mmoles, 0.50 ml), sulfurylc;hloride (5.5 mmoles, 0.44 ml) and 2-ethyl-5-methylbenzo[b]thiophene (3.2 mmoles, 0.57 g) yielded, after flash 20 chromatography, using 2% ethyl acetate/hexanes, 0.58 g (66%) of an orange solid.
C. N-(4-bromo-3-methyl-5-isoxazolyl)-2-ethyl-5-methylbenzo[b]thio-phene-3-sulfonamide N-(4-bromo-3-methyl-5-isoxazolyl)-2-ethyl-5-25 methylbenzo[b]thiophene-3-sulfonamide was prepared in the same manner as described in Example 41. Reaction of 4-bromo-3-methyl-5-aminoisoxazole (1.0 mmole,, 0.18 g), NaH (2.5 mmoles, 0.10g), and 2-ethyl-5-methylbenzo[b)thiophene-3-sulfonylchloride (1.3 mmoles, 0.36 g) in THF (6 ml) yieldecj, after recrystallization from chloroform and hexanes, 30 0.258 (60%) of a light brown crystalline solid, m.p. 176-178° C.

A .. 96/31492 PCT/US96/04759 N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)benzyl]-benzo(b]thiophene-:3-sulfonamide N-(4-chloro-3~-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)benzyl]-benzo(b]thiophene-3-sulfonamide was prepared in the same manner as described in Example 41. Reaction of 4-chloro-3-methyl-5-aminoisoxazole (0.61 mmoles, 81 rng), Nal-i (1.5 mmoles), 61 mg), and 2-[3,4-(methylenedioxy)benzyl]benzo(b]thiophene-3-sulfonyl chloride (0.74 mmoles, 0.27 g) in THF (4rnl) yielded, after flash chromatography using 50% ethyl acetate/hexanes followed by recrystallization from ethyl acetate and hexanea, 0.23 g (81 %) of a light brown solid, m.p. 178-181 ° C.

N-(4-i3romo-3-methyl-5-isor;azolyl)-2-(3,4-dimethoxybenzyl)-benzo(b]thiophene-:3-sulfonamide A. a-(2-benzo[b]thienyl)-3,4-dimethylbenzyl alcohol a-(2-benzo(b)thienyl)-3,4-dimethylbenzyl alcohol was prepared in the same manner as described in Example 40A. Reaction of benzo[b]-thiophene (7.5 mmoles, 1.0 g), t-BuLi (1.7 m, 97 mmoles, 5.7 ml) and 3,4-dimethoxybenza~ldehyde: (8.9 mmoles, 1.5 g) in THF (20 ml) yielded, after flash chromatography using 30% ethyl aceteate/hexanes, 2.25 g ( =
100%) of a white gummy solid.
B. 2-(3,4-dimethoxybenzyl)benzo(b]thiophene 2-(3,4-dimethoxybenzyl)benzo[b)thiophene was prepared in the same manner as described in Example 47B. Reaction of a-(2-benzo[b]thienyl)-3-4-dimethoxybenzyl alcohol (7.5 mmoles, 2.25 g), triethylsilane (8.2 mmoles, 'I .3 ml) and CHz CIZ (20 ml) in TFA ( 15 mmoles, 1 .2 mls) yielded, after flash chromatography using 10% ethyl acetate/hexanes, 1.'~7g (84%) of a colorless oil.

,_ 96131492 PCTIUS96/04759 , -~ 2s-C. 2-(3,4-dimethoxybenzyll-benzo[b]thiophene-3-sulfonylchloride 2-(3,4-dime~thoxybe~nzyl)-benzo(b)thiophene-3-sulfonylchloride was prepared in the same manner as described in Example 40B. Reaction of DMF (90 mmoles, 7 ml) and 2-(3,4-dimethoxybenzyl)-benzo[b)thiophene (6.0 mmoles, 1.7 d) yielded, after flash chromatography using 15% ethyl acetate/hexanes, 1.24g (5~4%) of a green oil.
D. N-(4-bromo-3-methyl-5-isoxazolyl)-2-(3,4-dimethoxybenzyl)-benzo[b]thiophene-3-sulfonamide N-(4-bromo-.3-methyl-5-isoxazolyl)-2-(3,4-dimethoxy-benzyl)-benzo[b]thiophene-3-sulfonamide was prepared in the same manner as described in Example 41. Reaction of 4-bromo-3-methyl-5-aminoisoxazole (1.17 mmolca, 0.18 g), NaH (2.5 mmoles, 60 mg), and 2-(3,4-dimethoxyben:zyl)benzo(b]thiophene-3-sulfonylchloride (1.2 mmoles, 0.44g) in THF (6m1), after recrystallization from chloroform and hexanes, yielded 0.42 g (80~%) of a brown solid, m.p. 151-153° C.

N-(3,4-dimethyl-5-i:~oxazolyl)-2-(3,4-methylenedioxy)benzo(b]thiophene-3-suifonamide N-(3,4-dimetlnyl-5-isoxazolyl)-2-(3,4-methylenedioxy)benzo[b)thio-phene-3-sulfonamide was prepared in the same manner as described in Example 41. Reaction of 3'.,4-dimethyl-5-aminoisoxazole ( 1.0 mmoles, 0.11 g), NaH (2.5 rnmoles, 60 mg) and 2-[3,4-(methylenedioxy)benzyl]-benzo[b)thiophene-:3-sulfonylchloride (1.1 mmoles, 0.40 g) in THF (6 ml) yielded, after flash c:hromat:ography using 50% ethyl acetate/hexanes followed by recryst~~llization from chloroform and hexanes, 0.35 g (79%) of a tan solid, m.p. 135-137° C.

~, ,~ 96/31492 PCTIUS96/04759 N-(4-Bromo-3-met:hyl-5-isoxazolyl)-2-(4-methoxybenzyl)benzo[b]-thiophene-3-sulfonamide A. a-(2-benzo[b)thienyl)-4-methyoxybenzol alcohol a-(2-benzo['b]thienyl)-4-methyoxybenzol alcohol was prepared by the method of Example 40A with benzo[b]thiophene (7.5 mmoles. 1.0 g), t-BuLi ( 1.7 m, 10.4 mmoles, 6.1 ml), 4-methoxy-benzaldehyde (8.9 mmoles, 1.1 ml) and THF f20 ml). Flash chromatography (20% ethyl acetate/hexanes) provided 1.75 g (87%) of a yellow solid.
B. 2-(4-methyoxybenzyl)-benzo[b)thiophene 2-(4-methyaxybenzyl)-benzo[b)thiophene was prepared by the method of Example 47B with a-(2-benzo[b]thienyl)-4-methoxybenzyl alcohol ( 1.9 mmoles) 0.50 g), triethysilane (2.0 mmoles, 0.32 mls), CHZCIz (20 ml) and TFA (3.7 mmoles, 0.30 ml). Recrystallization with hexanes and chloroform provided 0.40 (85%) of a pink solid.
C. 2-(4-methoxybenzyl')-benzo[b]thiophene-3-sulfonylchloride 2-(4-methoxybenzyl)-benzo[b]thiophene-3-sulfonylchloride was prepared by the method of Example 40B with DMF (3.2 mmoles, 0.24 ml), sulfurylchloride (2.7 mmoles, 0.22 ml) and 2-(4-methoyxybenzyl)-benzo[b]thiophene (1.6 mmoles. 0.4 g). Flash chromatography using 2%
ethyl acetate/hexanes provided 0.19 g (33%) of a light yellow solid.
D. N-(4-bromo-3-methyl-5-isoxazolyl)-2-(4-methoxybenzyl)-benzo[b]thiophene-3-sulfonamide N-(4-bromo-.3-methyl-5-isoxazolyl)-2-(4-methoxybenzyl)-benzo[b]thiophene-3-sulfonamide was prepared by the method of Example 41 with 4-bromo-3-methyl-5-aminoisoxazole (0. 48 mmoles, 85 mg), NaH (1.2 mmoles, 4~~ mg), 2-(4-methoxybenzyl)-benzo[b]thiophene-3-sulfonyichloride (0.53 mmoles, 0.19 g) and THF (3 ml). Flash chromatography (50% ethyl acetate/hexanes) followed by i w v 96131492 PCTltJS96/04759 recrystallization from methanol and water provided 46mg (20%) of a white crystalline solid, m.F~. 120-122° C.
EXAMPL~ 80 N-(4-Bromo-3-methyl-5-isoxozolyl)-2-(2-methoxybenzyl)-benzo[b]thiophene-3-sulfonamide A. a-(2-benzo[b;~thiophe;ne)-2-methoxybenzyl alcohol a-(2-Benzo[b:lthiophe:ne)-2-methoxybenzyl alcohol was prepared by the method of Example 47,4 with benzo[b]thiophene (7.5 mmoles, 1.C g) t-BuLi (1.7 m, 9.7 rnmoles, 5.7 ml), 2-methoxybenzaldehyde (8.9 mmoles, 1.1 ml) and THF (20 m11. Flash chromatography (20% ethyl acetate/hexanes) provided 1.9 g (96%) of a yellow oil.
B. 2-(2-Methoxybenzyl)-benzo[b]thiophene 2-(2-Methoxybenzyl)-benzo[b]thiophene was prepared by the method of Example 47B a-(2-benzo[b]thiophene)-2-methoxybenzyl alcohol (7.1 mmoles, 1.9 g/, triethylsilane (7.9 mmoles, 1.3 ml) and CH2CIZ
(30 ml) at 0°C was added 'TFA (14.3 mmoles, 1.1 ml). Flash chroma-tography (2% ethyl acetate/hexanes) provided 1.31 g (72%) of a yellow solid.
C. 2-(2-methoxybenzyl)-~benzo[b]thiophene-3-sulfonyl chloride 2-(2-methoxybenzyl)-benzo(b]thiophene-3-sulfonyl chloride was prepared by the method of Example 40B with suifuryl chloride ~(8.4 mmoles, 0.7 ml), DMF (9.8 mmoles, 0.8 ml) and 2-(2-methoxybenzyl)-benzo(b)thiophene (~1..9 mmoles, 1.25 g). Flash chromatography (2%
ethyl acetate/hexanea) provided 0.94 g (54%) of a yellow solid.
D. N-(4-bromo-3-methyl-~5-isoxozolyl)-2-(2-methoxybenzyl)-benzo[b]thioplhene-3-sulfonamide N-(4-bromo-3-methyl-5-isoxozolyl)-2-(2-methoxybenzyl)-benzo[b]-thiophene-3-sulfonamide was prepared by the method of Example 41 with 5-amino-4-bromo-3-methylisoxazole (1.0 mmoles, 0.18 g), NaH (2.5 mmoles, 100 mg), 2-(2-methoxybenzyl)-benzo[b]thiophene-3-sulfonyl WU 96!31492 PCT/US96/04759 chloride (1.4 mmol~es, 0.49 g) and THF (7m!). Flash chromatography (50% ethyl acetate/hexanEa) followed by recrystallization from chloroform and hex;anes provided 0.30 g (61 %) of a brown solid, m.p.
80-84 ° C.

N-(3,4-dimethyl-5-isoxazolyl)-2-(4-chlorobenzyl)-benzo(b)thiophene-3-sul-fonamide A. a-(2-benzo[b;~thienyll~-4-chlorobenzyl alcohol a-(2-benzo[bjlthienyl)-4-chlorobenzyl alcohol was prepared by the method of Example 40A with benzo[b)thiophene (7.5 mmoles, 1.0 g), t-BuLi (1.7 m, 9.7 mmoles, fi.7 ml), 4-chlorobenzaldehyde (9.7 mmoles, 1.4 g) and THF (20 ml). The crude material (2.45 g) was taken forward without further purification.
B. 2-(4-chlorobenzyl)be:nzo[b]thiophene 2-(4-chlorobenzyl)benzo[b]thiophene was prepared by the method of Example 47B with a-(2-benzo[b]thiophene)-4-chlorobenzyl alcohol (8.9 mmoles, 2.45 g), triethylsil;ane (9.8 mmoles, 1.6 ml), CH2CIZ (40 ml) and TFA ( 13.4 mmoles, 1.0 ml). Flash chromatography ( 1 % ethyl ace-tate/hexanes) provided 1.3 g (67% - 2 steps) of an off-white solid.
C. 2-(4-chlorobenzyl)benzo[b]thiophene-3-sulfonylchloride 2-(4-chlorobenzyl)benzo[b]thiophene-3-sulfonylchloride was prepared by the method of Example 40B with DMF (70 mmoles, 5.4 ml), sulfurylchloride (2.3 mmoles, 1.9 ml) and 2-(4-chlorobenzyl)-benzo[b]thio-phene (4.6 mmoles, 1.2 g). Flash chromatography (2% ethyl ace-tate/hexanes) provided 0.51 g (31 %) of an orange-yellow oil.
D. N-(3,4-dimethyl-5-isoxazolyll-2-(4-chlorobenzyl)-benzo[b]thiophene-3-sulfonamide N-(3,4-dimethyl-5; isoxazolyl)-2-(4-chlorobenzyl)-benzo[b]thiophene-3-sulfonamide was prepared by the method of Example 41 with 3,4-dimethyl-5-aminoisoxazole (1.2 mmoles, 1.4 g), NaH (3.0 mmoles, 73 ' - WO 96131492 PCTlL1S96/04759 mg), 2-(4-chlorobenzyl)-be:nzo[b)thiophene-3-sulfonylchloride ( 1.4 mmoles, 0.50 g) and THF (8 ml). Flash chromatography (50% ethyl acetate/hexanes) followed by recrystallization from methanol and water provided 1.04 g (27%) of a yellow solid, m.p. 100-102° C.

N-(4-chloro-3-methyl-5-isoxazolyl)-2-(4-dimethylaminobenzyl)benzo[b]thio-phene-3-sulfonamide A. a-(2-benzo[b]thienyl)-4-dimethylaminobenzyl alcohol '10 a-(2-benzo[b]thienyl~-4-dimethylaminobenzyl alcohol was prepared by the method of Example 40A with benzo(b]thiophene (7.5 mmoles, 1.0 g), t-BuLi (1.7 M, 8..9 mmoles, 5.3 ml), 4-dimethylaminobenzaldehyde (8.9 mmoles, 1.3 g) and TIHF (20 ml). The crude product (2.4 g) was carried forward witlhout further purification.
B. 2-(4-dimethyaminobenzy!)benzo[b]thiophene 2-(4-dimethyaminobenzyl)benzo(b]thiophene was prepared by the method of Example 47B with a-(2-benzo[b]thienyl)-4-dimethylaminobenzl alcohol (7.5 mmole:;, 2.1 g), triethylsilane (2.8 mmoles, 1.3 m11, CHzCI~
(50 ml) and TFA (1 1.2 mmoles, 0.9 ml). Flash chromatography (10%
ethyl acetate/hexanes) provided 1.5 g (73% - for two steps) of a white solid.
C. 2-(4-dimethylaminob~enzyl)-benzo[b)thiophene-3-sulfonylchloride Chlorosulfonic acid (l3.4 mmoles, 0.6rn1) was added to 2-(4-dimethylaminobenzyl)-benzo[b]thiophene (3.7 mmoles, 1.0 g) in CH2CIZ
( 100 ml) at -78 ° C. The solution was stirred 20 min. at -78 °
C.
Phosphorous oxychloride ( 1 1.2 mmoles, 1.0 ml) and phosphorous pentachloride ( 1 1.2 mmole:>, 2.3 g) were added to the reaction mixture.
The reaction mixture: was warmed to ambient temperature and stirring was continued an additional 1.5 hr. followed by dilution with ice ( = 200 ml) and extraction with ethyl acetate (200 ml). The organic layer was ~ v 96131492 PCT/US96104759 washed carefully with sat. NaHC03 (3 x 100 ml), then dried (MgS04), filtered and concentrated. Flash chromatography (5% ethyl acetate/hexanes) provided 0.61 g (45%) of a yellow solid.
D. N-(4-chloro-3.-methyl-5-isoxazolyl)-2-(4-dimethylaminobenzyl)-benzo(b]thiophene-3-sulfonamide N-(4-chloro-3-methyl-5-isoxazolyl)-2-(4-dimethylaminobenzyl)-benzo(b]thiophene-3-sulfonamide was prepared by the method of Exam-ple 41 with 4-chloro-3-methyl-5-aminoisoxazole (0.52 mmoles, 69 mg), NaH (1.3 mmoles, '.31 mg), 2-(4-dimethylaminobenzyl)-benzo(b]thiophene-3-sulfonylchloride (0.58 mrnoles, 0.21 g) and THF (4 ml). Flash chromatography (5~% meth<3nol/chloroform) provided 0.16 g (66%) of a yellow gummy solid, m.p. 1105-110° C.

N-(4-bromo-3-methyl-5-isor:azolyl)-2,5-dimethylfuran-3-sulfonamide A. 2,5-dimethyl-furan-3-~sulfonylchloride 2,5-dimethyl-furan-3-~sulfonylchloride was prepared by the method of Example 40B with DMF (28 mmoles, 2.2 ml), sulfurylchloride (24 mmoles, 1.9 ml) an~j 2,5-dimethyl-furan (14 mmoles, 1.5 ml). Flash chromatography (5°,~o ethyl acetate/hexanes) provided 0.61 g (22%) of a yellow liquid.
B. N-(4-bromo-3-methyl-5-isoxazolyl)-2,5-dimethyl-furan-3-sulfona-mide N-(4-bromo-3-methyl-5-isoxazolyl)-2, 5-dimethyl-furan-3-sulfona-mide was prepared by the method of Example 41 with 4-bromo-3-methyl-5-amino-isoxazole (:?.0 mmoles, 0.35 g), NaH (5.0 mmoles, 200 mg), 2,5-dimethyl-furan-3-sulfonylchloride (2.4 mmoles, 0.47 g) and THF (9 ml). Flash chromatography (5% methanol/chloroform) followed by recrystallization from chloroform and hexanes provided 0.21 g (31 %) of a light brown solid, m.p. 85.~i-87° C.

v. ,I 96!31492 PCT/US96104759/~

N-(4-Bromo-3-methyl-5-isoxazolyl)-2,5-dimethyl-4-phenyls:hiophene-3-sul-fonamide A. 2,5-dimethyl-3,4-dibromothiophene NBS (13.2 mmoles" 2.4 g) was added to 2,5-dimethylthiopene (5.3 mmoles, 0.5~! g) in C:HC13 (30 ml). The reaction mixture was stirred at ambient temperature fc~r 1.5 hr., then diluted with ether (50 ml) and washed with water (3 x 50 ml). The organic was dried (MgS04), filtered and concentrated. Flash chromatography (hexanes) provided 1.2 g (84%) of a white solid.
B. 2, 5-dimethyl-3-bronno-4-phenylthiophene Phenyl boronic acid (5.0 mmoles, 0.61 g) was added to 2,5-dimethyl-3,4-bromothiophene (4.5 mmoles, 1.2 g), tetrakis (triphenyl-phosphine) palladium(0) (C).23 mmoles, 0.26 g) and NaZC03 (2 M, 26 mmoles, 13 ml) in benzene (20 ml). The biphasic reaction mixture was heated to reflux for 24 hr. then cooled to ambient temperature and diluted with ether 1;100 ml) and washed with water (100 ml). The organic later was dried (MgSOa), filtered and concentreated. Flash chromatography (hexanes) provided 0.60 g (49%) of a yellow solid.
C. 2, 5-dimethyl'-4-phenyl-3-sulfonylchloridethiophene t-BuLi ( 1.7 h~l, 2.7 mmoles, 1.6 ml) was added to 2, 5-dimethyl-3-bromo-4-phenyl thiophene (2.2 mmoles, 0.59 g) in THF (8 mls.) at -30° C. The solution was stirred 20 min. at -30°C, then the flask was evacuated with sulfur dioxide, and warmed to -20° C upon which NCS
(2.2 mmoles, 0.30 g) was added. The reaction mixture was warmed to ambient temperature for 30 min., then diluted with ethyl acetae (50 ml) and washed with water (2 x 50 ml). The organic layer was dried (MgS04), filtered and concentrated. Flash chromatography (2% ethyl acetate/hexanes) provided 0.26 g (41 %) of a light yellow solid.

D. N-(4-bromo-~3-methyl-5-isoxazole)-2,5-dimethyl-4-phenyithiophene-3-sulfonamide N-(4-bromo-3-methyl-5-isoxazole)-2, 5-dimethyl-4-phenylthiophene-3-sulfonamide wa:; prepared by the method of Example 41 with 4-bromo-3-methyl-5-amino isoxazolle (0.79 mmoles, 0.14 g), NaH (2.0 mmoles, 80 mg), 2.5-dimethyl-4-phenylthiophene-3-sulfonylchloride (0.91 mmoles, 0.26 g) and THF (;3 m11. F~ecrystallization twice from chloroform and hexanes provided 0.15g (45%) of a white crystalline solid, m.p.
166 - 168 ° C.

N-(4-Bromo-3-methyl-5-isoxazolyl)-2-(hydroxymethyl)thiophene-3-sulfona-mide 8H3~THF (3.62 ml, 1 M in THF) was added to a solution of N-(4-bromo-3-methyl-5-isoxazolyl)-2-carboxyfthiophene-3-sulfonamide (1.0g, 2.72 mmol) in dry THF (1 Ei ml) at room temperature. After stirring at room temperature 'for 10 nninutes, the mixture was refluxed for 1 hour.
The reaction was cooled with an ice-bath and 1 N HCI (10 ml) was added.
The resulting mixture was concentrated. The aqueous residue was then partitioned betweein 1 N H(:I and EtOAc. The organic layer was dried (MgS04). The solid was filtered and the filtrate concentrated. The resi-due was treated with MeO~H and concentrated again. This process was repeated 3 more times to c3ive N-(4-bromo-3-methyl-5-isoxazolyl)-2-(hy-droxymethyl)thiophene-3-sulfonamide (680 mg, 71 % yield) as a yellow oil.

N-(4-Bromo-3-methyl-5-isoxazolyl)-2-[(3-methoxyphenyl)aminomethyl]-thiophene-3-sulfon,3mide BH3~THF (15 ml, 1 M in THF) was added to a solution of N-(4-bromo-3-methyl-5-isoxazolyl)-2-[N-(3-methoxyphenyl)aminocarbonyl]thio-phene-3-sulfonamide (Exarnple 22) ( 1.0 g, 2.12 mmol) in dry THF

s WO 96!31492 PCTIUS96/04759 (15 ml). The mixture was refluxed for 8 hours and cooled. THF was evaporated on a rotavap and MeOH was added to the residue. The resulting solution was concentrated. The final residue was purified by HPLC to give N-(4-bromo-;3-methyl-5-isoxazolyl)-2-[(3-methoxyphenyl)-aminomethyl]thiophene-3-;>ulfonamide (113 mg., 12% yield) as a grey powder, m.p. 70-73°C.

N-(4-bromo-3-methyl-5-iso xazolyl)-2-[N-(3-carboxyphenylarninocarbonyl]-thiophene-3-sulfonamide Et3N (2.27 ml. 16. mmol), ethyl 3-aminobenzoate (836 ml, 5.44 mmol) and phosphc~nitrilic chloride trimer (1.89 g, 5.44 mmol) were sequentially added 'to a solution of N-(4-bromo-3-methyl-5-isoxazolyl)-2-(carbonyl)thiophene-3-sulfonamide (Example 17) ( 1 g, 2.27 mmol) in dry THF (20 ml). The reaction was stirred at room temperature for 1 hour and cooled. Water (5 ml) was added to quench the reaction. The resulting solution was concentrated on a rotavap. The residue was diluted with EtOAc and waahed with 2N HCI (2 x 150 ml). The organic layer was dried (MgS04). The solid was filtered off and the filtrate was concentrated. The residue was treated with 1 N NaOH (200 ml) and stirred at 0° C for 15 minutes. The mixture was then acidified with conc. HCI to pH -1. The resulting yellow precipitate was filtered off and recrystalized from C:H3CN/HI20 to give N-(4-bromo-3-methyl-5-isoxazolyl)-2-[N-(3-carboxyphenyl)aminocarbonyl]thiophene-3-sulfonamide (153 mg., 11.6%) as a yellowiish powder, m.p. 183-185° C.

N-(4-Bromo-3-methyl-5-isox.azolyl)-2-[N-(2-carboxylphenyl)aminocarbo~nyl]thiophene-3-sulfonamide N-(4-bromo-3-methyl-5-isoxazolyl)-2-[N-(2-carboxylphenyl)amino-carbonyl]thiophene-3-sulfonamide was prepared by the same method as ~..96J31492 PCTIUS96/04759 described in Example 87, with the exception of using ethyl-2-aminobenzoate instead of ethyl-3-aminobenzoate.

N-(4-bromo-3-methyl-5-isoxazolyl)-2-(aminocarbonyl)thiophene-3-sulfona-mide Carbonydiimidazole (485 mg, 2.99 mmol) was added to a solution of N-(4-bromo-3-methyl-5-isoxazolyl)-2-carboxylthiophene-3-sulfonamide ( 1 g, 2.72 mmol) in THF ( 110 ml) at room temperature. The mixture was 1o stirred for 15 minutes. Aqueous NH3 (5 ml) was then added, and the mixture was stirred at roorn temperature for 30 minutes. The solvent was evaporated and the residue was partitioned between EtOAc and 1 N
HCI. The organic layer was dried (MgS04). The solid was filtered and the filtrate concentrated. The oily residue was recrystalized from EtOAc to give N-(4-bromo-3-methyl-5-isoxazolyl)-2-(aminocarbonyl)thiophene-3 sulfonamide (946 mg, 95%~ yield) as a white solid, m.p. 168-170° C.

N-(4-Bromo-3-methyl-5-iso:Kazolyl)-2-((5-dimethylamino-1-naphthyl)-sulfonylaminocarbonyl]thio~phene-3-sulfonamide Dansylchloricle (90.2 mg, 0.328 mmol) was added to a solution of N-(4-bromo-3-methyl-5-isoxazolyl)-2-(aminocarbonyl)thiophene-3-sulfona-mide (Example 89) (100 mc3, 0.273 mmol) and NaH (43.7 mg, 60%
dispersion in mineral oil, 1.10 mmol). The reaction was stirred at room temperature for 1 hour. Water was added to quench the reaction and THF was stripped off on a rotavap. The aqueous residue was partitioned between 1 N HCI and EtOAc:. The organic layer was dried (MgS04). The solid was filtered and the filtrate concentrated. The residue was recrystalized from EtOAc to give N-(4-bromo-3-methyl-5-isoxazolyl)-2-[(5-dimethylamino-1-naphthyl)s~ulfonylaminocarbonyl]thiophene-3-sulfonamide (55 mg., 34% yield) as a white powder (m.p. 184-186° C).

i 96131492 PCT/US96/04759 N-(4-Bromo-3-methyl-5-iso~xazolyl)-2-[(3,4-methylenedioxyphenyllamino-carbonyl]thiophene-3-sulfonamide N-(4-bromo-;3-methyl-5-isoxazolyl)-2-[(3,4-methylenedioxyphenyl)-aminocarbonyl]thiophene-3-sulfonamide was prepared by the same method as described in Example 89 with the exception that 3,4-methylenedioxyaniline was used in place of ammonium hydroxide. N-(4-bromo-3-methyl-5-isoxazolyl)-2-[(3,4-methylenedioxyphenyl)aminocar-bonyl]thiophene-3-sulfonarnide was purified by HPLC to give 15% yield of the desired product as a dark grey powder, m.p. 138-140° C.

N-(4-Bromo-3-methyl-5-iso;Kazolyl)-2-[(3,4-methylenedioxy)phenoxy-carbonyl]thiophene-3-sutfomamide Carbonyldiimidazole [530 mg., 3.26 mmol.) was added to a solution of N-(4-bromo-3-methyl-5-isoxazolyl)-2-carboxylthiophene-3-sul-fonamide (Example 17) (1.0g, 2.72 mmol) in dry THF (10 m11. The mixture was stirred at room temperature for 15 minutes. Sesamol (767 mg., 5.44 mmol) and imidazole (185 mg, 2.72 mmol) were added simultaneously. The resulting mixture was refluxed for 1 hour and allowed to cool to room temperature. The solvent was evaporated. The residue was partitioned betwveen 1 N HCI and EtOAc. The organic layer was dried (MgS04). The solid was filtered and the filtrate concentrated to give a yellow oil which was recrystalized from EtOAc/Et20/Hexane. N-(4-bromo-3-methyl-Ei-isoxazolyl)-2-[(3,4-methylenedioxy)phenoxycar-bonyl]thiophene-3-sulfonamide was obtained as a white powder (494 mg, 37% yield), m.p. 174-176° C.

. X6131492 PCTJLTS96/04759 N-(4-Bromo-3-meth!~I-5-isoxazolyl)-2-((3,4-methylenedioxy)benzoyl]-thiophene-3-sulfonamide A. N-(4-bromo-3-methyl-5-isoxazolyl)-2-((N-methoxy-N-methyl)aminocarbonyl]thiophene-3-sulfonamide N-(4-bromo-3-methyl-5-isoxazolyl)-2-((N-methoxy-N-methyl)carboxamide]thioph~ene-3-sulfonamide was prepared by the same method as described in Example 89 with the exception that N,0-dimethylhydroxylamine was used in place of ammonium hydroxide. The yield was 90%.
B. N-(4-Bromo-3-methyl-5-isoxazolyl)-2-[(3,4-methylenedioxy)-benzoyl]thiophene-3-sulfonamide Freshly prepared (3,4-methylenedioxy)phenyl magnesium bromide (1.28 g of (3,4-methylenedioxy)bromobenzene and 172 mg Mg turnings) was added to a solution of IV-(4-bromo-3-methyl-5-isoxazolyl)-2-[(N-methoxy-N-methyl)aminocarbonyl)thiophene-3-sulfonamide (A) (652 mg, 1.59 mmol) in THF (10 ml) at room temperature. The resulting mixture was refluxed for 30 minute:.. To workup, the mixture was allowed to cool to room temperature and was quenced with 1N HCI (10 ml). THF
was then evaporated. The aqueous residue was partitioned between 1 N
HCI and ~tOAc. The: organic layer was concentrated and the residue was purified by HPLC to give N-(4-bromo-3-methyl-5-isoxazolyl)-2-((3,4-methylenedioxy)benzoyl]thiophene-3-sulfonamide (90 mg, 12% yield) as a dark yellow powder, m.p. 47-49° C.

N-(4-Bromo-3-methyl-5-isoxazolyl)-2-[(2-hydroxyphenyl)aminocarbonyl]-thiophene-3-sulfonarnide N-(4-bromo-3-methyl-5-isoxazolyl)-2-[(2-hydroxyphenyl)amino-carbonyl]thiophene-a-sulfonamide was prepared by the same method as described in Example: 89 with the exception that 3-aminophenol was used l R~ . 6/31492 PCT/US96/04759 in place of ammonium hydroxide. The product was purified by HPLC to give N-(4-bromo-3-methyl-5-isoxazolyl)-2-((2-hydroxyphenyl)amino-carbonyl]thiophene-3-sulfonamide (50 mg, 18% yield) as a dull yellow solid, m.p. 42-44° C.

N-(3,4-dimethyl-5-i:~oxazolyl)-2[(3,4-methylenedioxy)phenoxy-carbonyl]thiophene-3-sulfonamide N-(3,4-dimethyl-5-isoxazolyl)-2(3,4-(methylenedioxy)phenoxy-carbonyl]thiophene-3-sulfonamide was prepared by the same method as described in Examplle 92 with the exception that N-(3,4-dimethyl-5-isoxazolyl)-2-carbox:ylthiophene-3-sulfonamide was used instead of N-(3-bromo-4-methyl-5-isoxazolyl)-2-carboxylthiophene-3-sulfonamide. N-(3,4-dimethyl-5-isoxazolyl)-2[(3,4-methylenedioxy)phenoxycarbonyl]thiophene-3-sulfonamide was ;purified by HPLC and was obtained as an orange oil (200 mg., 15% yield).

N-(4-Bromo-3-methyl-5-isor;azolyl)-2-{[(3,4-methylenedioxy)benzoyl]-aminocarbonyl}thiophene-3-sulfonamide Carbonyldiimidazole (213 mg. 1.31 mmol) was added to a solution of piperonylic acid ( 181.5 mg., 1.09 mmol) in dry THF ( 10 ml). The resulting mixture w~~s stirred for 15 minutes. N-(4-bromo-3-methyl-5-isoxazolyl)-2-aminocarbonylthiophene-3-sulfonamide (Example 89) (400 mg, 1.09 mmol) and NaH (1175 mg, fi0% in mineral oil, 4.37 mmol) were added sequentially. The mi:Kture was stirred at room temperature for 8 hours. Water was added to destroy the excess NaH. The solvent was then evaporated and' the residue was partitioned between 1 N HCI and EtOAc. The organic layer was dried (MgS04), the solid filtered and the filtrate concentrated. The residue was recrystalized from EtOAc to give N-(4-bromo-3-methyl-5-isoxazolyl)-2-{((3,4-methylenedioxy)benzoyl]-aminocarbonyl}thiophene-;3-sulfonamide (20 mg, 3.6% yield) as a yellowish powder (m.p. 9O-93° C1.

N-(4-chloro-3-methyl-5-isoxazolyl)-2-[(3,4-methylenedioxy)phenoxy-carbonyl]thiophene-3-sulfonamide N-(4-chloro-;3-methyl-5-isoxazolyl)-2-[(3,4-methylenedioxy)phenoxy-carbonyl]thiophene-3-sulfonamide was prepared by the same method as described in Example 93 with the exception that N-(4-chloro-3-methyl-5-isoxazolyl)-2-carbo;Kylthiophene-3-sulfonamide was used instead of N-(4-bromo-3-methyl-5-isoxazolyl)-2-carboxylthiophene-3-sulfonamide. N-(4-chloro-3-methyl-5-i;soxazolyl)-2-[(3,4-methylenedioxy)phenoxycarbonyl]-thiophene-3-sulfonamide was recrystalized from EtOAc (49% mg, 20%
yield) as a white solid, m.p. 189-191 ° C.
~ 5 EXAMPLE 98 N-(4-Bromo-3-methyl-5-iso;cazolyl)-2-[(3,4-methylenedioxy)phenyl-acetyl]thiophene-3-sulfonamide N-(4-bromo-~~-methyl-5-isoxazolyl)-2-((3,4-rnethylene dioxy)phenylacetyl]thiophene-3-sulfonamide was prepared by the same method as described in Example 93 with the exception that piperonylmagnesium chloride was used instead of (3,4-methylenedioxy)-phenylmagnesium bromide and the reaction mixture was stirred overnight at room temperature instead of refluxing for 30 minutes. The crude mixture was purifiecj by HPLC to give N-(4-bromo-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)phenylacetyl]thiophene-3-sulfonamide (20 mg, 40% yield) as a yellow oil.

- '' I96l31492 PCT/US96/04759 N-(4-Bromo-3-methyl-5-isoxazolyl)-2-[(3,4-methylenedioxy)phenoxy-carbonylamino]thia~phene-:3-sulfonamide Triethylamine (2.28 ml, 16.35 mmol) and diphenylphosphorylazide (773 mg., 2.72 mrnol) were sequentially added to a solution of N-(4-bromo-3-methyl-5-iisoxazollyl)-2-carboxylthiophene-3-sulfonamide (Example 17) (1.0 g, 2.72 mmol) in dry THF (40 ml). The mixture way stirred for 8 hours. Sesamol (1.54 g, 10.9 mmol) was added and the mixture was refluxed for 2 hr. The mixture was allowed to cool to room temperature. The solvent was stripped off on a rotavap and the residue was partitioned between EtOAc and 1 N HCI. The organic layer was dried (MgSOd). The solid was filltered and the filtrate concentrated. The residue was purified by HPLC to afford N-(4-bromo-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)phenoxycarbonylamino]thiophene-3-sulfonamide (400 mg, 29°°°°/; yield) as a beige powder, m.p. 39-43° C.

N-(4-Bromo-3-methyl-5-iso:xazolyl)-2-[(3,4-methylenedioxy)phenylureido)-thiophene-3-sulfonamide N-(4-bromo-~t-methyl-5-isoxazolyl)-2-[(3,4-methylenedioxy)phenyl-ureido]thiophene-3-sulfonamide was prepared by the same method as described in Example 99 with the exception that 3,4-methylenedioxy-aniline was used instead of sesamol. N-(4-bromo-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)phe;nylureido]thiophene-3-sulfonamide (157 mg, 12% yield) was obtained viia HPLC purification as a brownish-greyish powder, m.p. 62-65° C.

N-(4-chloro-3-methyl-5-isoxazolyl)-2-[(3,4-methylenedioxy)benzyloxy-carbonyl]thiophene-3-sulfonamide N-(4-chloro-3-methyl-5-isoxazolyl)-2-[(3,4-methylenedioxy)benzyloxy-carbonyl]thiophene-3-sulfonamide was prepared by the same method as described in Example 97 vvith the exception that piperonyl alcohol was used instead of se:~amol. N-(4-chloro-3-methyl-5-isoxazolyl)-2-[(3,4-(methylenedioxy)b~snzyloxycarbonyl]thiophene-3-sulfonamide (210 mg, 15% yield) was obtained via HPLC purification as a yellowish powder, m.p. 35-38° C.

N-(4-chloro-3-methyl-5-isoxazolyl)-2-[(3,4-methylenedioxy)phenylacetyl]-thiophene-3-sulfonamide N-(4-chloro-;3-methyl-5-isoxazolyl)-2-[(3,4-methylenedioxy)phenyl-acetyl]thiophene-3-sulfonamide was prepared by the same method as described in ExamF~le 98 with the exception that N-(4-chloro-3-methyl-5-isoxazolyl)-2-carbo;Kylthiophene-3-sulfonamide was used instead of N-(4-bromo-3-methyl-5-isoxazolyll-2-carboxylthiophene-3-sulfonamide. N-(4-chloro-3-methyl-5-i;5oxazol~yl)-2-[(3,4-methylenedioxy)phenylacetyl]thio-phene-3-sulfonamicle (3g, 50% yield) was obtained via HPLC purification as a yellow solid, m.p. 35-38° C.

N-(4-chloro-3-methyl-5-isoxazolyl)-2-[(3,4-methylenedioxy)phenethyloxy-carbonyl]thiophene-3-sulfonamide N-(4-chloro-3-methyl-5-isoxazolyl)-2-[(3,4-methylenedioxy)-phenethyloxycarbonyl]thiophene-3-sulfonamide was prepared by the same method as described in Example 97 with the exception that (3,4-methylenedioxy)phe:nethyl alcohol was used instead of sesamol. N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)phenethyloxy-' ~ ~~.. ~ 96131492 PCT/US96104759 carbonyl]thiophene-3-sulfonamide (500 mg, 34% yield) was obtained via HPLC purification as a yellowish oil.

N-(4-chloro-3-methiyl-5-isoxazolyl)-2-{[4-(3,4-methylenedioxybenzyl)-piperazin-1-yl]carbonyl}thiophene-3-sulfonamide N-(4-chloro-:3-methyl-5-isoxazolyl)-2-{[4-(3,4-methylenedioxyben-zyl)piperazin-1-yl]carbonyl}thiophene-3-sulfonamide was prepared by the same method as dEacribed in Example 89 with the exception that N-(4-chloro-3-methyl-5-isoxazolyl)-2-carboxylthiophene-3-sulfonamide was used instead of N-(4-bromo-3-methyl-5-isoxazolyl)-2-carboxylthiophene-3-sulfonamide, and 1-piperonylpiperazine was used instead of ammonium hydroxide. N-(4-chloro-3-rnethyl-5-isoxazolyl)-2-{[4-(3,4-methylenedioxy-benzyl)piperazin-1-~yl]carbonyl}thiophene-3-sulfonamide (872 mg, 54% yield) was obtained via HPLC purification as a white powder, m.p.
221-223 ° C.

N-(4-chloro-3-methyl-5-isoxazolyl)-2-aminothiophene-3-sulfonamide N-(4-chloro-a-methyll-5-isoxazolyl)-2-aminothiophene-3-sulfonamide was prepared by the same method as described in Example 99 except that the mixture was reflux;ed without the addition of sesamol. N-(4-chloro-3-methyl-5-isoxazolyl)-2-aminothiophene-3-sulfonamide (298 mg, 31 % yield) was obtained via HPLC as a yellow solid, m.p. 39-42° C.

N-(4-chloro-3-methyl-5-isoxazolyl)-2-{ 1-cyano-1-[(3,4-methylenedioxy)-phenyl]acetyl}thiophene-3-sulfonamide Carbonyldiimidazole (603 mg, 3.72 mmol) was added to a solution of N-(4-chloro-3-methyl-5-isoxazolyl)-2-carboxylthiophene-3-sulfonamide (Example 17) (1.0g, 3.1 mmol) in dry THF (40 ml). The mixture (I) was stirred at room temperature; for 15 minutes.

.-' ~ W..96I31492 PCTlUS96/04759 ' NaH (868 mg, 60% in mineral oil, 21.7 mmol) was added to a solution of (3,4-met:hylenedioxy)phenylacetonitrile in THF (100 ml). The mixture (II) was refluxed for 30 minutes and then allowed to warm to room temperature.
The mixture (I) was then cannulated into mixture (II) while cooled by ice-bath and the resulting mixture was allowed to warm to room temperature. Water was added to quench excess NaH. THF was then stripped off on a ro~:avap. 'The residue was partitioned between 1 N NaOH
and Et20. The aqueous layer was acidified with concentrated HCI with cooling to pH - 1 and extracted with EtOAc. The organic layer was dried (MgS04), the :>olid filtered and the filtrate concentrated. The residue was purified- by HPl_C to give N-(4-chloro-3-methyl-5-isoxazolyl)-2-{ 1-cyano-1-[3,4-(rnethylenedioxy)phenyl]acetyl}thiophene-3-sulfona-mide (277 mg, 19%. yield) ;as a yellowish powder, m.p. 142-142°C.

N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3-(dimethylamino)phenoxy-carbonyl]thiophene-3-sulfonamide N-(4-chloro-3-methyl-~5-isoxazolyl)-2-[3-(dimethylamino)phenoxy-carbonyl]thiophene-3-sulfonamide was prepared by the same method as described in Example 97 with the exception that 3-dimethylaminophenol was used instead of sesamol. N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3-(dimethylamino)phenoxycarbonyl]thiophene-3-sulfonamide (50 mg, 7.3%
yield) was obtained via HPLC purification as a dark brown oil.

N-(4-chloro-3-methyl-5-isoxazolyl)-2-(cyclohexyloxycarbonyl)thiophene-3-sulfonamide N-(4-chloro-3-methyl-5-isoxazolyl)-2-(cyclohexyloxycarbonyl)-thiophene-3-sulfonamide was prepared by the same method as described in Example 97 with the exception that cyclohexanol was used instead of i ~. .96131492 PCT/US96/04759 _1e~_ sesamol. N-(4-chloro-3-methyl-5-isoxazolyl)-2-(cyclohexyloxycarbonyl)-thiophene-3-sulfonamide (:Z9 mg, 5% yield) was obtained via HPLC
purification as an off-whitE: solid, m.p. 134-137° C.

N-(4-chloro-3-methyl-5-iso:xazolyl)-2-[~3-hydroxy(3,4-methylene-dioxy)phenylethyl]thiophene-3-sulfonamide LiBH4 (36.6 mg, 1.68 mmol) was added slowly to a solution of f~l-(4-chloro-3-methyl-5-isoxa:zolyl}-2-[3,4-methylenedioxy)phi:nylacetyl]thiophene-3-sulfonamide (Example 102) i74 mg, 0.168 mmol) in the THF (10 ml). The resulting mixture was stirred for 8 hours. Saturated NH,CI (aq) was added to quench the excess LiBHa. The resulting mixture was concentrated on a rotavap. The residue was partitioned between EtOAc and 1 N HCI. The organic layer was dried (MgS04), and the solid was filtered.

N,N'-bis{3-[(3,4-din~ethyl-5-isoxazolyl)aminosulfonyl]thien-2-yl}urea Triethylamine (1.4 ml, 9.93 mmol) and diphenylphosphorylazide (9.39 mg., 3.31 mrnol) were sequentially added to a solution of N-(3,4-dimethyl-5-isoxazol~,rl)-2-(carboxyl)thiophene-3-sulfonamide (Example 17) (1.0 g, 3.31 mmol) in THF (50 ml). The resulting mixture was stirred for minutes at room temperature and then refluxed for 1 hour. The mixture was allowen to cool to room temperature. THF was stripped off by use of a rotavap. The residue was partitioned between EtOAc and 1 N
25 HCI. The organic layer was dried (MgS04), the solid filtered, and the filtrate concentrated. N,N'-bis{3-[(3,4-dimethyl-5-isoxazolyl)amino-sulfonyl]thien-2-yl}urea (140 mg, 14% yield) was obtained via HPLC
purification as a pale powder, m.p. 112-114°C.

a Wv 96131492 PCTIUS96104759 N,N'-bis{3-[(4-bromo-3-mEahyl-5-isoxazolyl)aminosulfonyl]thien-2-yl}urea N,N'-bis{3-[(4-bromo-3-methyl-5-isoxazolyl)aminosulfonyl]thien-2-yl}urea was prepared by the same method as described in Example 1 10 with the exception that N-(4-bromo-3-methyl-5-isoxazolyl)-2-carboxythio-phene-3-sulfonamide was used instead of N-(3,4-dimethyl-5-isoxazolyll-2-carboxylthiopehene~-3-sulfonamide. N,N'-bis{3-[(4-bromo-3-methyl-5-isoxazolyl)aminosulfonyl]thien-2-yl}urea (80 mg, 15.5% yield) was obtained via HPLC purification as an off-white solid, m.p. 127-129° C.

N-(4-Bromo-3-methyl-5-isoxazolyl)-5-(benzyloxymethy!)thiophene-2-sul-fonamide A. 2-(benzyloxymethyl)thiophene Sodium hydride (0.41 mg, 20 mmol) was added to a solution of 2-thiophene methanol (2.0g, 0.18mmol) in THF (20 ml) at -40°C. The reaction was stirred at -40° C for 25 min., then neat benzylbromide (3.6 g, 20 mmol) was added by syringe. The solution was stirred at -40 ° C
for 0.5 hr, then at room temperature for 1 hr. The THF was evaporated off and the remaining residue was taken up in ether ( - 50 ml). The organic solution was washed with water (1 x 10 ml), brine (1 x 10 ml) and dried over MgS04. Evaporation of solvents left an oil which was purified by column chromatography using 1 % ether-hexanes to give 2.fi g of the thiophene as a pale yellow oil (78% yield).
B. 2-chlorosulfonyl-5-(benzyloxymethyl)thiophene 2-chlorosulfonyl-5-(benzyloxymethyl)thiophene was prepared in the same manner as described in Example 132A from 2-(benzyloxymethyl)-thiophene (1.0 g, 5.25 mmol). Purification by column chromatography using 2.5% ethyl acetate/hexanes gave 520 mg of the pure thiophene as a brown oil (32% yield).

r '. ,~ 96/31492 PCTIUS96/04759 -14s-C. N-(4-bromo-3-methyl-5-isoxazolyl)-5-(benzyloxymethyl)thiophene-2-sulfonamide N-(4-bromo-3-methyl-5-isoxazolyl)-5-(benzyloxymethyl)thiophene-2-sulfonamide was prepared as described in Example 2 from 2-chlorosulfonyl-5-(benzylox;ymethyl)thiophene (520 mg, 1.72 mmol) and 5-amino-4-bromo-3-methyl iaoxazole (319 mg, 1.8 mmol). Purification by column chromatography using 10% MeOH/CHC13) gave 238 mg of pure N-(4-bromo-3-methyl-5-isc~xazolyl)-5-(benzyloxymethyl)thiophene-2-sul-fonamide as brown semisolid (31 % yield, m.p. 92° C).

N-(4-Chloro-3-methyl-5-isoxazolyl)-2-ethylbenzo(b]furan-3-sulfonamide A. 2-Ethylbenzo[b]furan 2-Ethylbenzo[b]furan was prepared by the method of example 40A
with benzo(b]furan (7.3 mmols), 0.86 g) t-BuLi ( 1.7 m, 9.4 mmols) iodoethane (4 mmc~ls, 0.9 mls) and THF (15 ml). 1.0 g (95%) of a yellow liquid was isolated.
B. 2-Ethylbenzo(b]furan-3-sulfonyl chloride 2-Ethylbenzo(b]furan-3-sulfonyl chloride was prepared by the method of Example 82C with 2-ethylbenzo(b]furan (6.9 mmols, 1.0 g), chlorosulfonic acid (8.9 mmols, 0.6 ml) phosphorous oxychloride (21 mmols, 1.9 ml), phosphorous pentachloride (6.9 mmols, 1.4 g) and CH2C12 (10 ml). Flash chromatography (2% ethyl acetate/hexanes) provided 0.71 g (42%) of .an orange solid.
C. N-(4-chloro-:3-methyl-5-isoxazolyl)-2-ethylbenzo[b]furan-3-sulfona-mide N-(4-chloro-3-methyl-5-isoxazolyll-2-ethylbenzo(b]furan-3-sulfona- -mide compound was prepared by the method of Example 41 with 4-chloro-3-methyl-5-amino-isoxazole (1.0 mmols, 0.13 g), NaH (2.5 mmols, 60 mg), 2-ethylbenzo[b]furan-3-sulfonyl chloride (1.2 mmols, 0.28 g) and THF (7 ml). Flash chromatography (20% ethyl acetate/hexanes) followed ~ .~ 96131492 PCTIUS96/04759 by recrystallization from chloroform and hexane provided 97 mg (28%) of a white solid, m.p. 132-1;:13.5 ° C.

N-(4-Bromo-3-methyl-5-isoxazolyl)-2-[(3,4-methylenedioxy)benzyl] )thio-phene-3-sulfonamide A. N-(2-carbomethoxythiophene-3-sulfonyl)pyrrole N-(2-carbom~ethoxythiophene-3-sulfonyl)pyrrole was prepared in the same manner as described in Example 33A by reacting 2-carbomethoxy-thiophene-3-sulfon~il chloride with pyrrole, 50% yield.
B. N-[(2-hydroxymethyl!)thiophene-3-sulfonyl]pyrrole To a stirred :solution of N-(2-carbomethoxythiophene-3-sulfonyl)pyrrole (3.0 g, 1 1.02 mmole) in a mixture of THF and methanol (3:1 mixture, 40 ml) was added sodium borohydride (1.2 g) in six lots over a 30 min. period (exothermic reaction) with constant stirring. The solvent was removf:d under reduced pressure and the residue was dissolved in saturated ammonium chloride solution (50 ml). The crude product was extracted with ethyl acetate, and the combined organic layers was dried over MgS04, and evaporated to give a crude product (2.4 g, 90%1, which was used directly in the next step. , C. N-[2-(bromomethyl)thiophene-3-sulfonyl]pyrrole Bromine was added t:o a stirred mixture of triphenylphosphine (3.1 g, 12 mmole) in methylene chloride (50 ml) at 0° C under nitrogen atmosphere with stirring until the yellow color persisted. A few crystals of triphenylphosphine were added to consume excess bromine followed by pyridine (1.21 ml), and N-((2-hydroxymethyl)-3-sulfonyl]pyrrole dissolved in methyle:ne chloride ( 10 ml) was added. The reaction was stirred at 0° C for 1 hr and concentrated to give a crude product. The crude product was purified by flash chromatography on silica gel using - t W V 96!31492 PCTIUS96/04759 10:1 hexane in ethyl acetate to give N-[2-(bromomethyl)thiophene-3-sulfonyl]pyrrole (2.7 g, 80% yield).
D. N-{2-[(3,4-nnethylenedioxy)benzyl]thiophene-3-sutfonyl]}pyrrole N-{2-((3,4-methylenedioxy)benzyl]thiophene-3-sulfonyl]}pyrrole was prepared in the same manner as described in Example 32C using N
(2-(bromomethyl)thiophene-3-sulfonyl]pyrrole and 3,4-methylenedioxy-phenylboronic acid, 53% yield.
E. 3-chlorosulfonyl-2-[(3,4-methylenedioxy)benzyl]thiophene 3-chlorosulfonyl-2-(3,4-methylenedioxybenzyl)thiophene was prepared in the sarne manner as described in Example 65E from N-{2-[(3,4-methylenedioxy)benzyl]-3-sulfonyl}pyrrole by basic hydrolysis of the sulfonamide to the sodium salt of sulfonic acid and by conversion of this salt to the corresponding :;ulfonyl chloride, 54% yield.
F. N-(4-bromo-3-methyl-5-isoxazolyl)-2-((3,4-methylenedioxybenzyl]-thiophene-3-sulfonamide N-(4-bromo-3-methyl-5-isoxazolyl)-2-((3,4-methylenedioxy)benzyl]-thiophene-3-sulfonamide was prepared in the same manner as described in Example 2 by reacting 5~-amino-4-bromo-3-methylisoxazole and 3-chlorosulfonyl-2-[(:3,4-methylenedioxy)benzyl]thiophene. The crude product was purified by Hf'LC, 37% yield.

N-(4-Bromo-3-methyl-5-isoxazolyl)-5-(2-methoxyphenyl)thiophene-2-sul-fonamide A. N-[5-(2-methoxyphenyl)thiophene-2-sulfonyl]pyrrole N-[5-(2-methoxyphenyl)thiophene-2-sulfonyl]pyrrole was prepared in the same manner as described in Example 32C using 2-methoxyphenyl-boronic acid and N-(5-b~orr~othiophenesulfonyl)pyrrole, 74% yield.
B. 5-chlorosulfont'l-2-(2-methoxyphenyl)thiophene 5-chlorosulfont'l-2-(~!-methoxyphenyl)thiophene was prepared in the same manner as described in Example 65E from N-[5-(2-methoxyphenyl)-PCTIUS96/04759 '!

thiophene-2-sulfonyl]pyrrolle by hydrolysis of the sulfonamide to the sodium salt of suifonic acid (83%) followed by conversion of the salt to the corresponding sulfonyl chloride, resulting in a 24% yield.
C. N-(4-bromo-;3-methyl-5-isoxazolyl)-5-(2-methoxyphenyl)thiophene-2-sulfonamide N-(4-bromo-;3-methyl-5-isoxazolyl)-5-(2-methoxyphenyl)thiophene-2-sulfonamide was prepared in the same manner as described in Example 1. Reaction of 2-chlorosulfonyl-5-(2-methoxyphenyl)thiophene with 5-amino-4-bromo-3-methylisoxazole gave N-(4-bromo-3-methyl-5-isoxazolyl)-5-(2-methyoxyphenyl)thiophene-2-sulfonamide in 32% yield, m.p. 114-117° C.
EXAMPLE 11 fi N-(4-Bromo-3-methyl-5-isoxazolyl)-5-(2-tolyl)thiophene-2-sulfonamide A. 2-(2-tolyl)thinphene Sodium carbonate (5 ml., 2M aqueous solution) followed by 2-methylphenylboronic acid (0.294 g, 2.4 mmol) were added to a solution of 2-bromothiophene (0.54.2 g, 2 mmol) and tetrakis(triphenylphosphine)-palladium(0) (100 rug) in toluene (5 ml) and ethanol (5 ml) under nitrogen.
The mixture was re:fluxed for 2 hours, cooled to room temperature and extracted with ethyl acetat:e (2 x 50 ml). The combined organic layers was dried over Mg:~04 and evaporated. The residue was flash chromatographed on silica gel using hexane as eluent to afford 1.2 g of 2-(2-tolyl)thiophene: as a colorless gum.
B. 2-chlorosulfonyl-5-(:?-tolyllthiophene To the cold (-5 to 0" C) solution of 2-(2-tolyl)thiophene (0.87 g, 5 mmole) was added chloros;ulfonic acid (0.33 ml, 5 mmole) over a 15 min.
period with constant stirring. After 10 min., phosphorous oxychloride (2 ml) and phosphorous pentachloride were added. The reaction mixture was slowly allowed to attain ambient temperature and stirred for 3 hours.
The mixture was then poured onto crushed ice (50 g) and was extracted 1~. .r 96!31492 PCT/US96I04759 with ethyl acetate (2 x 5t1 ml). The combined organic layers was dried over MgS04 and evaporated. The residue was purified by flash column chromatography one silica gel using 2% ethyl acetate in hexane to give 2-chlorosulfonyl-5-(2-tolyl)thiophene, (1.1 g, 72% yield).
C. N-(4-bromo-3-methyrl-5-isoxazolyl)-5-(2-tolyl)thiophene-2-sulfona-mide N-(4-bromo-3-methyl-5-isoxazolyl)-5-(2-tolyl)thiophene-2-sulfona-mide was prepared in the same manner as described in Example 2.
Reaction of 5-chlorosulfonyl-2-(2-tolyl)thiophene with 5-amino-4-bromo-3-methylisoxazole gave the crude product which was purified by column chromatography giving the pure product (gum). This gum was dissolved in 5 ml of NH40H, concentrated and dried under high vacuum to get the ammonium salt of IV-(4-bromo-3-methyl-5-isoxazolyl)-5-(2-tolyl)thiophene-2-sulfonamide in 6'7% yield, m.p. 180-184° C (NH3+ salt).
~ 5 EXAMPLE 117 N-(4-Bromo-3-methyl-5-isoxazolyl)-5-(3-tolyl)thiophene-2-sulfonamide A. 2-(3-tolyl)thiophene 2-(3-tolyl)thiophene was prepared in the same manner as described in Example 1 17A using 2-bromothiophene and 3-methylphenylboronic acid. The crude product was purified by flash chromatography on silica gel using hexane as. the eluent (86% yield).
B. 2-chlorosulfonyl-5-(3'.-tolyl)thiophene 2-chlorosulfonyl-5-(3-tolyl)thiophene was prepared in the same manner as described in Example 1178 from 2-(3-tolyl)thiophene, 22%
yield.
C. N-(4-bromo-3.-methyl-5-isoxazolyl)-5-(3-tolyl)thiophene-2-sutfona-mide N-(4-bromo-3-methyl-5-isoxazolyl)-5-(3-tolyllthiophene-2-sulfona-mide was prepared in the same manner as described in the Example 1 17C
using 2-chlorosulfonyl-5-(3-tolyl)thiophene and 5-amino-4-bromo-3-~ .i 96/31492 PGT/US96/04759 methylisoxazole. 'fo obtain the ammonium salt of the final product, aqueous NH40H was used (31 % yield; hygroscopic).

N-(4-Bromo-3-methyl-5-isoxazolyl)-3-benzylthiophene-2-sulfonamide A. 3-benzylthio;phene 3-benzylthiophene was prepared in the same manner as described in Example 32C using 3-thienylboronic acid and benzyl bromide, 74%
yield.
8. 2-chlorosulfo~nyl-3-b~enzylthiophene 2-chlorosulfonyl-3-benzylthiophene was prepared in the same manner as described in Example 1178 using 3-benzylthiophene, 78%
yield.
C. N-(4-bromo-3;-methyll-5-isoxazolyll-3-benzylthiophene-2-sulfonamide N-(4-bromo-3-methyl-5-isoxazolyl)-3-benzylthiophene-2-sulfonamide was prepared in the same rnanner as described in Example 2 by reacting 2-chlorosulfonyl-3-benzyithiophene with 5-amino-4-bromo-3-methylisoxazole resulting in a 24% yield, m.p. 180-183° C.

N-(4-Bromo-3-methyl-5-isox.azolyl)-5-(2-methylfuranyl)thiophene-2-sulfon-amide A. N-[5-(2-methyl-5-fury))thiophene-2-sulfonyl)pyrrole t-BuLi ( 1.7 m solution in hexane, 7.9 ml, 14.6 mmol) was added dropwise under con:ctant stirring under a nitrogen atmosphere to a solution of 2-methyl~furan (1.0 g, 12 mmol) in THF (20 ml) at -78° C.
The solution was them warmed to -10° C and stirring continued for min. The solution was then added to a solution of zinc chloride (27 ml of a 0.5 M solution in ~'HF) at -30° C and then warmed to room temperature where stirring continued for 1 hr. resulting in a pale yellow clear solution. The solution was then transferred via a steel canula under nitrogen to a solution of N-(5-bromothiophene-2-sulfonyl)pyrrole (Example i ~, _ 96r31492 PGT/US96/04759 33A, 3.5 g, 12 mrnol) andl tetrakis(triphenylphosphine)-palladium (0) (693 mg, 0.6 mmol) in if HF ( 15 ml) at -78 ° C. The solution was then warmed to room temperature and stirred for a period of 2 hours. Purification by column chromatography using 2% ethyl acetate gave 680 mg of N-[5-(2-methyl-5-furyl)thiophene-2-sulfonyl]pyrrole as a pale yellow powder (19%
yield).
B. 2-(2-methyl-Ei-furyl)thiophene-5-sulfonyl chloride 2-(2-methyl-5-furyllthiophene-5-sulfonyl chloride was prepared in the same manner as descril'~ed in Example 33D from N-[5-(2-methyl-5-furyl)thiophene-2-sulfonyl)pyrrole (300 mg, 1.02 mmol). Purification by column chromatogr~3phy using 2% ethyl acetate/hexanes gave 145 mg (53%) of the sulfonyl chloride as a pale yellow solid.
C. N-(4-bromo-3-methyl-5-isoxazolyl)-5-(2-methyl-5-furyl)thiophene-2-sulfonamide ~ 5 N-(4-bromo-3-methyl-5-isoxazolyl)-5-(2-methyl-5-furyl)thiophene-2-sulfonamide was prepared in the same manner as described in Example 2.
Reaction of 2-(2-methyl-5-furyl)thiophene-5-sulfonyl chloride (55 mg, 0.21 mmol) with 5-amino-4-bromo-3-methylisoxazole (41 mg, 0.21 mmol), after purification by column chromatography using 10% MeOH/CHC13, dove 45 mg of the pure sulfonamide as a brown semisolid ( 54% yield, m.p. 123-124° C).

N-(4-Bromo-3-methyl-5-isoxazolyll-4-(phenethyl)thiophene-2-sulfonamide N-(4-bromo-3-methyl-5-isoxazolyl)-4-(phenethyl)thiophene-2-sulfon-amide was prepared in the s;sme manner as described in Example 2 using 5-amino-4-bromo-3-methyl-i;;oxazole ( 132.75 mg, 0.75 mmole) and 4-(phenethyl)thiophene-2-sulfonyl chloride (Example 1 19D; 225.62 mg, 0.75 mmol). The product w;as purified by HPLC (5-95% acetonitrile with 0.1 % TFA over 30 min.) to dive N-(4-bromo-3-methyl-5-isoxazolyl)-4-(phenethyl)thiophene-2-sulfonamide as a brownish oil 72.3mg, 32% yield.

A~.~ 96131492 PCT/US96104759 N-(3,4-dimethyl-5-isoxazolyl)-2-((4-methylphenyi)aminocarbonyl]-thiophene-3-sulfonamide Phosphonitrilic chloride trimer dissolved in THF (5 ml) was added to a suspension of N-(3,4-dimethyl-5-isoxazolyl)-2-(carboxyl)thiophene-3-sul fonamide (2.0 g, 6.6 mmol) (Example 28) in THF (5 ml) and Et3N at 0° C.
The cold bath was iremoved and the reaction mixture stirred at room temperature for 2 hours. The mixture was diluted with water ( 150 ml) and acidified to pH 2 using concentrated hydrochloric acid. The reaction mixture was then extracted with methylene chloride (2 x 100 ml), and the combined organic layer:; was washed with 2N hydrochloric acid (3 x 100 ml), dried over MgSO" and concentrated be get crude product. The crude product was dissolved in ether and allowed to stand at room temperature to give a precipitate which was filtered and washed with cold ether giving N-(3,4-dimethyl-5-isoxazolyl)-2-((4-methylphenyl)amino-carbonyl]thiophene-;3-sulfonamide (1.6 g, 61 % yield).

N-(4-Bromo-3-methyl-5-isox~azolyl)-5-[(4-tolyl)aminocarbonyl]thiophene-2-sulfonamide N-(4-bromo-3-methyl-5-isoxazolyl)-5-[(4-tolyl)aminocarbonyl]-thiophene-2-sulfonarnide was prepared in the same manner as described in Example 24 from IV-(4-bromo-3-methyl-5-isoxazolyl)-5-(4-carboxyben-zene)thiophene-2-sulfonamide (Example 148), 1 10 mg, 0.25 mmol) and 4-methylanifine (53 mg, 0.49 mmol). Purification by recrystallization from methanol/water gave 91 mg of the pure sulfonamide as a light tan powder (61 % yield, rn.p. 18.8° C).

/ ., R., 96131492 ~ PCTIUS96/04759 N-(4-chloro-3-methyl-5-iso xazolyl)-2-[(4-tolyl)aminocarbonyl]thiophene-3-sulfonamide A. N-(4-chloro-3-methyl-5-isoxazolyl)-2-(carboxyl)thiophene-3-sulfona-mide N-(4-chloro-:.-methyil-5-isoxazolyl)-2-(carboxyl)thiophene-3-sulfona-mide was prepared in the same manner as described in Example 17 using N-(4-chloro-3-methyl-5-isoa;azolyl)-2-(carbomethoxy)thiophene-3-sulfomanide (ExamF>le 123), 78% yield.
B. N-(4-chloro-3-methyl-5-isoxazofyl)-2-[(4-tolyl)aminocarbonyl]-thiophene-3-sulfonamide N-(4-chloro-3-methyl-5-isoxazolyl)-2-[(4-tolyl)aminocarbonyl]-thiophene-3-sulfonamide was prepared in the same manner as described in Example 122 using N-(4-~chloro-3-methyl-5-isoxazolyl)-2-(carboxyl)thiophene-3-sulfonamide. The crude product was dissolved in a small quantity of EtOAc (2 ml) and ether ( 15 ml) was added. The resulting precipitate was filtered and washed with cold ether (50 ml) giving N-(4-chloro-3-methyl-5-isoxazolyl)-2-[(4-tolyl)aminocarbonyl]-thiophene-3-sulfonamide in .53% yield (m.p. 177-179°).

N-(4-Bromo-3-methyl-5-isoxazolyl)-2-[(N-methyl)-N-phenylaminocarbonyl]-thiophene-3-sulfonamide A solution of PJ-(4-bromo-3-methyl-5-isoxazolyl)-2-(carboxyl)-thiophene-3-sulfonannide ( 18'3.6 mg, 0.5 mmol) in dry THF (I ml) was added to a solution o~f N-methyl-4-methylaniline (0.066 ml, 0.6 mmol) in THF (0.5 ml). Trieth~ylamine (0.63 ml, 4.2 mmol) was added to the mixture and, after 10 min., a solution of phosphonitriiic chloride trimer (210.7 mg, 0.6 mmol) was added. The mixture was stirred for 1 hr. at 50°C, cooled, neutralized with 10 ml 1 N HCI (pH 3) and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and the solvent was removed under reduced pressure to give a crude a,. 96/31492 PCT/US96/04759 I

product which was purified by HPLC (5-95% acetonitrile with 0.1 % TFA
over 30 min.) resulting in N-(4-bromo-3-methyl-5-isoxazolyl)-2-j(N-methyl)-N-phenylaminocarbonyl)thiophene-3-sulfonamide as a white solid (92.1 mg, 39.4% yield, m.p. 51-55°C).

N-(4-Bromo-3-methyl-5-isoxazolyl)-3-[3,4-(methylenedioxy)phenyl]-thiophene-2-sulfonamide A. 3-bromothiophene-2-sulfonyl chloride Chlorosulfonic: acid (:>_0 ml, 300 mmol) was added to a solution of 3-bromothiophene f:3.15 g, 50 mmol) in methylene chloride (50 ml) at -78° C over a 20 min. period. After the completion of addition, the cold bath was removed and stirriing continued at ambient temperature for 1 hr.
The reaction mixture: was c<3refully added, dropwise, to crushed ice (100 g). The mixture was extracted with methylene chloride (2 x 100 ml). The combined organic layers was dried over MgS04 and evaporated.
The crude product v~~as purii~ied by flash chromatography on silica gel using hexane as the eluent resulting in 3-bromothiophene-2-sulfonyl chloride (4 g, 30% yield) and 4-bromothiophene-2-sulfonyl chloride (200 mg, S 1 %).
B. N-(3-bromothiophene-2-sulfonyl)pyrrole N-(3-bromothiophene-2-sulfonyl)pyrrole was prepared in the same manner as described in Example 33A by reacting 3-bromothiophene-2-sulfonylchloride with pyrrole (for 16 hr.). N-(3-bromothiophene-2-sulfonyl)pyrrole was obtained in 54% yield.
C. N-{(3-(3,4-methylenediioxy)phenyl)thiophene-2-sulfonyl}pyrrole N-{[3-(3,4-methylenedioxy)phenyl)thiophene-2-suffonyl)pyrrole was prepared in the same manner as described in Example 32C using 3,4-methylenedioxyphenylboroni~~ acid and N-(3-bromothiophene-2-sulfonyl)pyrrole. The crude product was purified by flash column l a _ X6/31492 PCTIUS96104759 chromatography on silica gel using 2% EtOAc in hexane as the eluent resulting in N-{[3-(3,4-methylenedioxy)phenyl]thiophene-2-sulfonyl}-pyrrole in a 90% yi~:ld.
D. 2-chlorosulfonyl-3-[3,4-(methylenedioxy)phenyl]thiophene 2-chlorosulfonyl-3-[3,,4-(methylenedioxy)phenyl)hiophene was prepared in the same manner as described in Example 1 12B using N-{[3-(3,4-methylenedioxy)phenyl]thiophene-2-sulfonyl}pyrrole by basic hydrolysis of the sulfonamicle to the sodium sulfonate (100% yield) followed by conversion of the salt to the corresponding sulfonyl chloride resulting in a 34% yield of the final product.
E. N-(4-bromo-3-methyl-5-isoxazolyl)-3-[3,4-(methylenedioxy)phenyl]-thiophene-2-sulfonamide N-(4-bromo-3-methyl-5-isoxazolyl)-3-(3,4-(methylenedioxy)phenyl]-thiophene-2-sulfonamide was prepared in the same manner as described in Example 1 by reaction of :2-chlorosulfonyl-3-[3,4-(methylenedioxy)-phenyl]thiophene with 5-ami.no-4-bromo-3-methylisoxazole resulting in a 60% yield, m.p. 183-186° C.

N-(4-Bromo-3-methyl-5-isoxazolyl)-2-[(2-chloro-3,4-methylenedioxy)-phenoxymethyl]thiophene-3-sulfonamide A. N-{2-[(3,4-metlhylenedioxy)phenoxymethyl)thiophene-3-sulfonyl}-pyrrole Sodium hydride (100 mg, 5 mmole) was added to a stirred solution of 3,4-methylenediox~yphenol (0.607 g, 4.5 mmol) in DMF (dry, 5 ml) at 0° C under a nitrogen. atmosphere with stirring. The reaction mixture was permitted to attaiin room temp and stirring continued for 1 hr. The reaction mixture was cooled to 0° C and N-[(2-bromomethyl)thiophene-3-sulfonyl]pyrrole was added. Stirring was continued at ambient temperature for 16 hr, The reaction mixture was diluted with water (100 ml), extracted with ethyl acetate (2 x 50 ml) and washed with 1 N NaOH

i~
.

_ -157-(2 x 25 ml) to rem~we phenol derivative. The mixture was dried over MgS04 and concentrated resulting in N-{2-[(3,4-methylenedioxy)phenoxy-methyl]thiophene-3-sulfonyl}pyrrole, which was recrystallized using hexane/EtOAc (1.0~ g, 92°/~ yield).
B. 3-chlorosulfonyl-2-[(2-chloro-3,4-methylenedioxy)phenoxymethyl]-thiophene 3-chlorosulfonyl-2-[(2-chloro-3,4-methylenedioxy)phenoxymethyl]-thiophene was prepared in the same manner as described in Example 64E
using N-{2-[(3,4-methylene:dioxy)phenoxyrnethyl)thiophene-3-sulfonyl}-pyrrole by conducting a basic hydrolysis (using potassium hydroxide in iso-propanol) to the potassium sulfonate followed by conversion of the salt to the corresponding sulfonyl chloride in an overall yield of 50%.
C. N-(4-bromo-3-methyl-5-isoxazolyll-2-[(2-chloro-3,4-methylene-dioxy)phenoxymethyl]thiophene-3-sulfonamide N-(4-bromo-:I-methyll-5-isoxazolyl)-2-((2-chloro-3,4-methylenedioxy-phenoxy)methyl)thiophene-3-sulfonamide was prepared in the same manner as described in Example 1 by reaction of 3-chlorosulfonyl-2-[(2-chloro-3,4-methylenedioxyphenoxy)methyl]thiophene with 5-amino-4-bromo-3-methylisoxazole, 4.7% yield, m.p. 152-154°C:

N-(4-Bromo-3-methyl-5-iso~;azolyl)-2-[traps-3,4-(methylenedioxy)cinnamyl]-thiophene-3-sulfonamide A. Diethyl2-{3-((N-pyrrolyl)sulfonyl)thienylmethyl}phosphonate N-[2-bromom~ethyl)thiiophene-3-sulfonyl]pyrrole (0.915 g, 3 mmol) was suspended in triethylphosphite (5 ml) and was heated to 140° C for 1 hr. with stirring under nitrogen atmosphere. Excess triethylphosphate was removed under reduced pressure and the residue was dried under vacuum resulting in 0.9g, 83% yield of diethyl 2-{3-[(N-pyrrolyl)sulfonyl]-thienylmethyl}phosF~honate.

R _ ~6f31492 PCTIUS96/04759 B. N-{2-[traps-3,4-(methylenedioxy)cinnamyl]thiophene-3-sulfonyl}-pyrrole Sodium hydride (200 mg, 60% dispersion) was added in two lots to the stirred solution of dicahyl 2-{3-[(N-pyrrolyl)sulfonyl]thienylmethyl}-phosphonate (900 rng, 2.48 mmol) in dry THF (10 ml) at 0° C. The mixture was stirred at room temperature for 1 hr. then piperonal (600 mg) was added. Stirring was continued for 12 hours. The mixture was diluted with water (100 ml) and extracted with methylene chloride (2 'c 50 ml). The combined organic layers was dried over MgSOa, evaporated, and the residue was. flash chromatographed on silica gel using 0.5% ethyl acetate in hexane to give N-{2-(mans-(3,4-methylenedioxy)cinnamyl]
thiophene-3-sulfonyl}pyrrole (750 mg, 84% yield).
C. 3-chlorosulfonyl-2-[tans-3,4-(methylenedioxy)cinnamyl)thiophene 3-chlorosulfonyl-2-[traps-3,4-(methylenedioxy)cinnamyl]thiophene was prepared in the same manner as described in Example 64E from N-{2-(traps-3,4-(methylenedioxy)cinnamyllthiophene-3-sulfonyl}pyrrole by basic hydrolysis (using isopropanol and potassium hydroxide) to the corresponding potassium sulfonate ( 100%) followed by conversion of the salt to the corresponding sulfonyl chloride in a 31 % overall yield.
D. N-(4-bromo-3-methyl-5-isoxazolyl)-2-(traps-3,4-(methylene-dioxy)cinnamyl]thiophene-3-sulfonamide N-(4-bromo-3-methyl-5-isoxazolyl)-2-[traps-3,4-(methylenedioxy)-cinnamyl]thiophene-3-sulfonamide was prepared in the same manner as described in Example 1 by reaction of 3-chlorosulfonyl-2-[traps-3,4-(methylenedioxy)cinnamyl]thiophene with 5-amino-4-bromo-3-methyl-isoxazole. The crude product was purified by HPLC resulting in a 33%
yield, m.p. 147-149°C.

a .. 96!31492 PCTIUS96I04759 N-(4-Bromo-3-methyl-5-iso~xazo~yl)-2-[3,4-(methylenedioxy)phenethyl]-thiophene-3-sulfornamide A. N- f 2-[3,4-(methylenedioxy)phenethyl]thiophene-3-sulfonyl~pyrrole An ethyl acetate (1 Ei ml) solution of N-{2-[traps-3,4-(methylene-dioxy)cinnamyl)thic~phene-3-sulfonyl}pyrrole (Example 1278, 0.6 g, 1.67 mmol) was subjected to catalytic hydrogenation using 10% Pd-C (100 mg) at 55 psi for 1.4 hr. The catalyst was filtered:a~d the filtrate concentrated to resulting in N-{2-(3,4-(methylenediox.y)phenethyl)thio-phene-3-sulfonyl}p~~rrole (0.55 g, 91 % yield).
S. 3-chlorosulfonyl-2-[3.,4-(methylenedioxy)phenethyl)thiophene 3-chlorosulfonyl-2-[3,4-(methylenedioxy)phenethyl)thiophene was prepared in the same manner as described in the Example 64E using N-{2-[3,4-(methylenedioxy)phenethyl)thiophene-3-sulfonyl}pyrrole by conducting basic hydrolysis; (iso-propanol and potassium hydroxide) of the sulfonamide to the potassium salt of sulfonic acid (93%) followed by conversion of the salt to the corresponding sulfonyl chloride in a 42%
yield.
C. N-(4-bromo-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)-phenethyl]thiophene-3-sulfonamide N-(4-bromo-3-methyl-5-isoxazolyl) -2-(3,4-(methylenedioxy) phenethyl)thiophene-3-sulfonamide was prepared in the same manner as described in Example 2. By reacting 3-chlorosulfonyl-2-[3,4-(methylenedioxy)phc:nethyl)thiophene with 5-amino-4-bromo-3-methylisoxazole and purifying the crude product by HPLC, N-(4-bromo-3-methyl-5-isoxazolyl)-2-(3,4-(methylenedioxy)phenethyl)thiophene-3-sul-fonamide was obtained in a 30% yield, m.p. 180° (dec.).

'. _ 96131492 PCT/US96/04759 N-(4-Bromo-3-methyl-5-isoxazolyl)-3-(phenylthio)thiophene-2-sulfonamide A. 3-phenylthiol:hiophene-2-sulfonyl chloride A stirred solution of 3-(phenylthio)thiophene ( 1.0 g, 5.2 mmol) in 5 ml of dry THF was placed under an argon atmosphere and cooled to -78 °
C. n-butyl lithium (2.78 ml of 2.3M solution) was added over 20 min.
and stirring was continued at this temperature for an additional 20 min.
Sulfur dioxide gas vas then bubbled in at -78 ° C for a period of 30 min., resulting in the formation of a yellow percipitate. This was immediately followed by dropwi:,e addition of N-chlorosuccinimide (764 mg, 5.72 mmol) dissolved in -UHF. The mixture was warmed to room temperature and stirring continued for an additional 1.5 hr. The mixture was then concentrated and the residue dissolved in ether. The organic layer was washed with water, brine solution and dried over magnesium sulfate.
Evaporation of solvents left a light brown oil which was subjected to flash chromatography. Elution with 2% ethylacetate-hexanes gave 840 mg (56%) of a pale yellow solid.
B. N-(4-bromo-3-methyl-6-isoxazolyl)-3-(phenylthio)thiophene-2-sul-fonamide N-(4-bromo-3-methyl-6-isoxazolyl)-3-(phenylthio)thiophene-2-sul-fonamide was prepared in the same manner as described in Example 2 using 5-amino-4-bromo-3-methylisoxazole ( 192 mg, 1.1 mmol) and 3-phenylthiothiophene-2-sulfonyl chloride (300 mg, 1.0 mmol). Purification by column chromatography using 10% MeOH/CHC13 yielded 358 mg (83%) of the pure sulfonamide as a brown oil.

r Wv 96131492 PCT/US96/04759 ~XAMPL~ 130 N-(3,4 dimethyl-5-isoxazolyl)-3-(phenylaminocarbonyl)thiophene-2-sulfon-amide A. N-(3,4-dimethyl-5-isoxazolyl)thiophene-2-sulfonamide N-(3,4-dimethyl-5-isoxazolyl)thiophene-2-sulfonamide was prepared in the same manner as described in Example 14 using thiophene-2-sulfonyl chloride and 3,4-dimethylaminoisoxazole. Purification by column chromatography using 3% MeOH/CHC13 yielded 48% N-(3,4-dimethyl-5-isoxazolyl)thiophene-2-sulfonamide.
B. N-(methyoxye~thoxymethyl)-N-(3,4-dimethyl-5-isoxazolyl)thiophene-2-sulfonamide N-(methyoxye~thoxymethyl)-N-(3,4-dimethyl-5-isoxazolyl)thiophene-2-sulfonamide was prepared in the same manner as described in Example 32B using N-(3,4-dirnethyl-5-isoxazolyl)thiophene-2-sulfonamide and methoxyethoxymethyl chloride resulting in 34% yield. HPLC analysis of the crude oil obtained after workup showed that the oil was approximately 96% pure and so was used in the next step without further purification.
C. N-(methyoxyethoxymethyl)-N-(3,4-dimethyl-5-isoxazolyl)-5-trimethylsilyl)thiophene-2-sulfonamide A stirred solution of N-(methyoxyethoxymethyl)-N-(3,4-dimethyl-5 isoxazolyl)thiophene-2-sulfonamide (300 mg, 0.87 mmol) in 5.0 ml of dry THF was placed under an argon atmosphere and cooled to -78° C.
Over the course of 20 min, a solution of t-BuLi in hexanes (461 ml of a 2.25 M
solution) was added dropwise and stirring was continued at this temperature for about 25 min. Then neat trimethylsilychloride (135 ml, 1 mmol) was added dropwise and the solution was stirred at -78 ° C for 15 min. then at room temp. for 1.5 hr. TLC (1 % CHC13 in MeOH) showed complete reaction of starting material at this time thus, the reaction was quenched by addition of 2.0 ml of water. After evaporation of solvents 96131492 PC'TIUS96I04759 the remaining residue was extracted into ethyl acetate, washed with brine solution and dried over magnesium sulfate. Purification by column chromatography using 20% ethyl acetate/hexanes gave the pure sulfona-mide as a clear oil I',52% yield).
D. N-(methyoxyethoxymethyl)-N-(3,4-dimethyliisoxazolyl)-3-(phenyl-aminocarbonyl)-5-(trimethylsilyl)thiophene-2-sulfonamide A stirred solution of N-(methyoxyethoxymethyl)-N-(3,4-dimethyl-5-isoxazolyl)-5-trimethylsilyl)thiophene-2-sulfonamide ( 180 mg, 0.43 mmol) in 4 ml of dry THF eras placed under an argon atmosphere and cooled to -78° C. At this temperature a solution of t-BuLi in hexanes (215 NI at a 2.55 M solution) was added dropwise and stirring was continued at -78°
C for 0.5 hr. resulting in a clear yellow solution. Phenylisocyanate (77 NI, 0.65 mmol) was added dropwise at -78 ° C and the solution allowed to reach room temperature. The solution was then worked up as above in part C. Purification of the final product was achieved by column chromatography using 30% ethyl acetate/hexanes to give 108 mg of the sulfonamide a 54% yield.
E. N-(3,4 dimethyl-5-isoxazolyl)-3-(phenylaminocarbonyl)thiophene-2-sulfonamide N-(3,4 dimethyl-5-isoxazolyl)-3-(phenylaminocarbonyl)thiophene-2-sulfonamide was prepared in the same manner as described in Example 32D using N-(methyoxyethoxymethyl)-N-(3,4-dimethyliisoxazolyl)-3-(N-phenylcarboxamide-5-trimethylsilyl)thiophene-2-sulfonamide (108 mg, 0.23 mmol). Purification was achieved by recrystallization from acetonitrile/water to give 62 mg (71 % yield) N-(3,4 dimethyl-5-isoxazolyl)-3-(phenyl~aminocarbonyl)thiophene-2-sulfonamide as a brown powder, m.p. 152°C.

W ~ ~6I31492 PCT/US96104759 I

N-(3,4-dimethyl-5-iaoxazoly!)-2-f a-hydroxybenzyl)thiophene-3-sulfonamide A. Thiophene-3-~sulfonyl chloride n-BuLi (2.38P~1, 17m1) was slowly added to a solution of 3-bromo-thiophene (6.5 g, 40 mmol) in ether (30 ml) at -78 ° C. The reaction was stirred at -78° C for 45 min. SOZ was bubbled through the mixture for minutes at -78 ° C followed by the addition of NCS (6.4 g, 48 mmol) as a suspension in ~f HF (40 ml). The crude product was purified by column chromatogr~3phy using 5% ethyl acetate/hexanes to give 3.92 g 10 thiophene-3-sulfonyl chloride as a pale yellow solid (54% yield).
B. N-(3,4-dimethyl-5-isoxazolyi)thiophene-3-sulfonamide N-(3,4-dimethyl-5-isoxazolyl)thiophene-3-sulfonamide was prepared in the same manner as described in Example 14 using thiophene-3-sulfonyl chloride and 3,4-dimethylaminoisoxazole resulting in 66% yield 15 as a pale brown solid.
C. 2-[2-(trimethylsilyl)ethoxymethyl]-N-(3,4-dimethyl-5-isoxazolyl)thio~phene-3-sulfonamide N,N-diisoproplyethylamine (222 NI, 128 mmol) was added to a solution of N-(3,4-dimethyl-5-isoxazolyl)thiophene-3-sulfonamide (300 mg, 1.16 mmol) in methylene chloride (5 ml), and the mixture was stirred at room temperature for 15 min. The mixture was then cooled to 0° C
and 2-(trimethysilyl)eahoxy methyl chloride (SEM chloride) (226 N1, 1.28 mmol) was added dropwise via syringe, and the resultant yellow solution was stirred at room temperature for 5 hours. Evaporation of solvents left an oil which was extracted into ethyl acetate, washed with water and brine solution and dried over magnesium sulfate. Flash chromatography of the residue using '10% ethyl acetate/hexanes yielded 321 mg 2-(2-(trimethylsilyl)ethoxymethyl]-N-(3,4-dimethyl-5-isoxazolyl)thiophene-3-sul-fonamide as a clear colorless oil which solidified into a white solid upon standing (71 % yield)., ~. , 96/31492 PCT/US96/04759 D. 2-(2-(trimethylsilyl)ethoxymethyl]-N-(3,4-dimethyl-5-isoxazolyl)-2-(n-hydroxybenzyl)thiophene-3-sulfonamide n-BuLi (2.39 M, 177 NI) was slowly added to a solution of (2-trimethylsilylethoxymethyl)-N-(3,4-dimethyl-5-isoxazolyl)thiophene-3-sul-fonamide (156 mg, 0.38 mmol) in THF at -78° C under nitrogen. The reaction was stirred at -78° C for 45 min., then benzaldehyde (45 NI, 0.42 mmol) was added in one lot at -78 ° C and the solution was allowed to come to room temperature. Stirring was continued for 1 hr.
Purification was achieved by column chromatography using 10% ethyl acetate/hexanes to give 179 mg 2-(2-(trimethylsilyl)ethoxymethyl)-N-(3,4-dimethyl-5-isoxazolyl)-2-(o-hydroxybenzyl)thiophene-3-sulfonamide as a yellow viscous oil (90% yield).
E. N-(3,4-dimethyl-5-isoxazolyl)-2-(a-hydroxybenzyllthiophene-3-sul-fonamide To a solution of 2-(2-(trimethy(silyl)ethoxymethyl)-N-(3,4-dimethyl-5-isoxazolyl)-2-(o-hydroxybenzyl)thiophene-3-sulfonamide (70 mg, 0-14 mmol) in DMF (2 ml') was added cesium fluoride (26 mg, 0.17 mmole) in one portion. The resulting mixture was heated to 100° C for 10 hours.
The solvents were removed by evaporation under vacuum and the remaining residue was extracted into ethyl acetate, washed with water, brine, and dried over MgS04. The product was then purified by chromatography using 50-70% ethyl acetate/hexanes to give 26.2 mg N-(3,4-dimethyl-5-isoxazolyl)-2-(a-hydroxybenzyl)thiophene-3-sulfonamide as a pale white semisolid (51 % yield).

N-(4-l3romo-5-methyl-3-isoxazolyl)-5-(4-methylphenyl)thiophene-2-sulfon-amide A. N-(5-(4-methylphenyl)thiophene-2-sulfonyljpyrrole N-(5-(4-methylphenyl)thiophene-2-sulfonyl]pyrrole was prepared in the same manner as described in Example 32C using 4-methyl-phenyl-~. .~ 96131492 PGTIUS96I04759 boronic acid and N-(5-bromothiophenesulfonyl)pyrrole. Purification by column chromatography using 2% ethyl acetate/hexanes gave N-[5-(4-methylphenyl)thio~phene-2-sulfonyl]pyrrole as a pale yellow solid in 77 % yield.
B. 2-chlorosulfonyl-5-(4-methylphenyl)thiophene 2-chlorosulfonyl-5-(4-methylphenyl)thiophene was prepared in the same manner as described in Example 33D using N-[5-(4-methylphenyl)-thiophene-2-sulfonyljpyrrole. Purification by column chromatography using 2% ethyl acetate/hexanes gave 2-chlorosulfonyl-5-(4-methylphenyl)thiophene as a pale yellow powder (61 % yield).
C. N-(4-bromo-3-methyl-5-isoxazolyl)-5-(4-methylphenyl)thiophene-2-sulfonamide N-(4-bromo-3-methyl-5-isoxazolyl)-5-(4-methylphenyl)thiophene-2-sulfonamide was prepared in the same manner as described in Example 2.
Reaction of 2-chlorosulfonyl-5-(4-methylphenyl)thiophene ( 100 mg, 0.37 mmol) with 5-amino-4-bromo-3-methylisoxazole (65 mg, 0.37 mmol) yielded, after column chromatography using 10% MeOH/CHC13, 96 mg final product as a pale yellow solid, (63% yield, m.p. 175° C).

N-(4-Bromo-3-methyl-5-isoxazolyl)-5-(4-phenyl)thiophene-2-sulfonamide A. N-(pyrrole)-5-(4-phenyl)thiophene-2-sulfonamide N-(pyrrole)-5-(4-phenyl)thiophene-2-sulfonamide was prepared in the same manner as described in Example 32C using phenyl boronic acid and N-(5-bromothiophenesulfonyl)pyrrole. Purification by column chromatography usiing 2% ethyl acetate/hexanes gave the pure sulfona-mide as a yellow powder in 67% yield.
B. 2-chiorosulfonyl-5-(4-phenyl)thiophene 2-chlorosulfonyl-5-(4-phenyl)thiophene was prepared in the same manner as in Example 33D from N-(pyrrole)-5-(4-phenyl)thiophene-2-sui-fonamide. Purification by column chromatography using 2% ethyl t 96/31492 PCTIUS96/04759 -1 fi6-acetate/hexanes gave the pure thiophene in 77% yield as a yellow powder.
C. N-(4-bromo-3-methyl-5-isoxazolyl)-5-(4-phenyl)thiophene-2-sulfona-mide N-(4-bromo-3-methyl-5-isoxazolyl)-5-(4-phenyl)thiophene-2-sulfona-mide was prepared in the same manner as described in Example 2.
Reaction of 2-chlorosulfonyl-5-(4-phenyl)thiophene (94 mg, 0.36 mmol) with 5-amino-4-bromo-3-methyl isoxazole (64 mg, 0.36 mmol) yielded.
after column chromatography using 10% MeOH/CHC13, 85 mg of N-(4-bromo-3-methyl-5-isoxazolyl)-5-(4-phenyl)thiophene-2-sulfonamide as a fight brown solid, (59% yield, m.p. 132 ° C1.

N-(4-bromo-3-methyl-5-isoxazolyl)-5-[4-(trifluoromethyl)phenyl)thiophene-2-sulfonamide A. N-{5-[4-(trifluoromethyl)phenyl]thiophene-2-sulfonyl}pyrrole N-{5-[4-(trifluoromethyl)phenyl)thiophene-2-sulfonyl}pyrrole was prepared in the same manner as described in Example 32C using 4-trifluoromethylbenz~sne boronic acid and N-(5-bromothiophene sulfonyl)-pyrrole. Purification by column chromatography using 2% ethyl ace-tate/hexanes gave the pure sulfonamide as a white powder in 75% yield.
B. 2-chlorosulfonyl-5-[4-(trifluoromethyl)phenyl]thiophene 2-chlorosulfonyl-5-(4-(trifluoromethyl)phenyl)thiophene was prepared in the same manner as Example 33D from N-{5-[4-(trifluoro-methyl)phenyl)thiophene-2-sulfonyl}pyrrole. Purification by column chromatography using 2% ethyl acetate/hexanes gave the pure thiophene as a white powder in 41 % yield.
C. N-(4-bromo-3-methyl-5-isoxazolyl)-5-(4-(trifluoromethyl)phenyl)-thiophene-2-sulfonamide N-(4-bromo-3-methyl-5-isoxazolyl)-5-[4-(trifluoromethyl)phenyl]-thiophene-2-sulfonamide was prepared in the same manner as described in Example 2. Reaction of 2-chlorosulfonyl-5-(4-(trifluoromethyl)-phenyl)thiophene ( 100 mg, 0.31 mmol) with 5-amino-4-bromo-3-methyl isoxazole (54 mg, '0.31 mmol) yielded, after column chromatography, 39 mg of N-(4-bromo-3-methyl-5-isoxazolyl)-5-[4-(trifluoromethyl)phenyl)-thiophene-2-sulfonamide as a pale yellow powder, (27% yield, m.p.
132° C).

N-(4-Bromo-3-methyl-5-isoxazolyl)-5-(2-formylphenyl)thiophene-2-sulfona-mide A. N-(3-methyl-!5-isoxazolyl)-5-bromothiophene-2-sulfonamide N-(3-methyl-5-isoxazolyl)-5-bromothiophene-2-sulfonamide was prepared in the same manner as described in Example 14 from 5-bromothiophene-2-sulfonyl chloride and 5-amino-3-methyl isoxazole.
Purification was achieved by extraction of the crude sulfonamide into aqueous 2N NaOH, washing of the aqueous layer with ethyl acetate and acidification, using concentrated HCI, to pH - 2. Re-extraction into ethyl acetate was followed by washing of the organic material with water, brine and drying over magnesium sulfate. After evaporation of solvents, a brownish solid remained which was sufficiently pure to use in the next step.
B. N-(3-methyl-5-isoxazolyl)-5-(2-formylphenyl)thiophene-2-sulfona-mide N-(3-methyl-5-isoxazolyl)-5-(2-formylphenyl)thiophene-2-sulfona-mide was prepared in the same manner as described in Example 32C
from 2-formylbenzeneboronic acid (281 mg, 1.87 mmol) and N-(3-methyl-5-isoxazolyl)-5-bromothiophene-2-sulfonamide (550 mg, 1.7 mmol).
Purification by column chromatography using 1 5% MeOH/CHC13 gave 163 mg (28%) of this pure sulfonamide as a brown oil.
C. N-(4-brorno-3-methyl-5-isoxazolyl)-5-(2-formylphenyl)thiophene-2-sulfonamide ~16I31492 PCTIUS96/04759 -~ ss-N-bromosuccinamide (81 mg, 0.45 mmol) was added to a solution of N-(3-methyl-5-isoxazolyl)-5-(2-formylphenyl)thiophene-2-sulfonamide (155 mg, 0.45 mmol) in CHC13 (5 ml). The resulting brownish solution was stirred at room temperature for 3 hours. The solvent was stripped off and the material extracted into ethyl acetate and washed with brine solution. Evaporation of solvents gave 85 mg of the product (45% yield).
A portion of this w;ss further purified by preparative HPLC. N-(4-bromo-3-methyl-5-isoxazolyl~-5-(2-formylphenyl)thiophene-2-sulfonamide was isolated as a pale b~~own oil.

N-(4-Bromo-3-methyl-5-isoxazolyl)-5-(3-aminophenyl)thiophene-2-sulfona-mide A. N-(3-methyl-fi-isoxazolyl)-5-(3-aminophenyl)thiophene-2-sulfona-mide N-(3-methyl-E~-isoxazolyl)-5-(3-aminophenyl)thiophene-2-sulfona-mide was prepared in the same manner as described in Example 32C
from 3-amino benzene boronic acid (256 mg, 1.87 mmol) and N-(3-methyl-5-isoxazolyl)-5-bromothiophene-2-sulfonamide (55 mg, 1.7 mmol).
Purification by column chromatography using 1 5% MeOH/CHC13 gave 20 318 mg (56%) of the product.
B. N-(4-bromo-3-methyl-5-isoxazolyl)-5-(3-aminophenyl)thiophene-2-sulfonamide N-(4-bromo-3-methyl-5-isoxazolyl)-5-(3-aminophenyl)thiophene-2 sulfonamide was prepared in the same manner as described in Example 25 30A (without acetic acid) using N-(3-methyl-5-isoxazolyll-5-(3 aminophenyl)thiophene-2-sulfonamide resulting in a 33% yield. Further purification was achieved using preparative HPLC giving pure N-(4-bromo-3-methyl-5-isoxazolyl)-5-(3-aminophenyl)thiophene-2-sulfonamide as a clear colorless oil.

N-(4-Bromo-3-methyl-5-isoxazolyl)-5-(3,3-dimethylbutyn-1-yl)thiophene-2-sulfonamide A. N-(5-(3,3-dimethylbutyn-1-yl)thiophene-2-sulfonyl]pyrrole A mixture of N-(5-bromothiophene-2-sulfonyl)pyrrole (600 mg, 2.05 mmol), 3,3-dirnethyl-1-butyne (338 mg, 4.1 mmol), copper iodide (39 mg, 0.21 mmol;l, tetrakistriphenylphosphine palladium [Pd(PPh3)4]
(118 mg, 0.1 mmol) and piperidine (5 ml) was stirred at room temperature for a pesriod of 24 hours under a nitrogen, atmosphere. The mixture was then dilluted with water (10 ml) and extracted with 3 x 25 ml portions of ether. The combined ether extracts are washed with brine and dried over MgS04. The solvent was removed under reduced pressure and crude product purified by column chromatography using 2% ethyl acetate/hexanes to dive 423 mg N-[5-(3,3-dimethylbutyn-1-yl)thiophene-2-sulfonyl]pyrrole as a yellow powder (70% yield).
B. 2-chlorosulfonyl-5-(3,3-dimethylbutyn-1-yl)thiophene 2-chlorosulfonyl-5-(t-butylethynyl)thiophene was prepared in the same manner as described in Example 33D from N[5-(3,3-dimethylbutyn-1-yl)thiophene-2-sulfonamide. Purification by column chromatography using 2% ethyl acetate/hexanes gave the pure sulfonamide in 33% yield.
C. N-(4-bromo-3-methyl-5-isoxazolyl)-5-(3,3-dimethylbutyn-1-yl)thiophene-2-sulfonamide N-(4-bromo-3-methyl-5-isoxazolyl)-5-(3,3-dimethylbutyn-1-yl)thiophene-2-sulfonamide was prepared in the same manner as described in Example 2. Reaction of 2-chlorosulfonyl-5-(3,3-dimethylbutyn-1-yl)thiophene (120 mg. 0.46 mmol) with 5-amino-4-bromo-3-methylisoxa;zole (85 mg, 0.48 mmol) yielded, after column chromatography usin~3 10% MeOH/CHC13, 1 16 mg N-(4-bromo-3-methyl-5-isoxazolyl)-5-(3,3-dimethylbutyn-1-yl)thiophene-2-sulfonamide as a viscous clear oil (63°/~).

~ 96131492 PGTIUS96/04759 N-(4-Bromo-3-methyl-5-isoxazolyl)-5-[3, 5-bis(trifluoromethyl)phenyl]-thiophene-2-sulfonamide A. N-{5-[3,5-bia(trifluoromethyl)phenyl]thiophene-2-sulfonyl}pyrrole N-{5-[3,5-bis(trifluoromethyl)phenyl)thiophene-2-sulfonyl}pyrrole was prepared in the same manner as described in Example 32C from 3,5-bis(trifluoromethyl)benzeneboronic acid (619 mg, 2.26 mmol) and N-[5-bromothiophene-2-sulfonyl)pyrrole (60 mg, 2.05 mmol). Purification by column chromatography using 2% ethyl acetate/hexanes gave the pure sulfonamide as a white solid in 93% yield.
B. 2-chlorosulfonyl-5-(3,5-bis(trifluoromethyl)phenyl]thiophene 2-chlorosulfonyl-5-[3,5-bis(trifluoromethyl)phenyl]thiophene was prepared in the same manner as described in Example 33D from N-{5-[3,5-bis(trifluoromethyl)phenyl]thiophene-2-sulfonyl}pyrrole. Purification by column chromatography using 2% ethyl acetate/hexanes gave the pure thiophene in 73% yield as a brownish clear oil.
C. N-(4-bromo-3-methyl-5-isoxazolyl)-5-[3,5 bis(trifluoromethyl)-phenyl]thioph~ene-2-sulfonamide N-(4-bromo-3-methyl-5-isoxazolyl)-5-(3,5 bis(trifluoromethyl)-phenyl]thiophene-2-sulfonamide was prepared in the same manner as in Example 2. Reaction of 2-chlorosulfonyl-5-(3,5-bis(trifluoromethyl)-phenyl]thiophene (250 mg, 0.63 mmol) with 5-amino-4-bromo-3-methyl-isoxazole (118 mg, 0.67 mmol) yielded, after column chromatography using 5% MeOH/CHC13, 115.2 mg N-(4-bromo-3-methyl-5-isoxazolyl)-5-[3,5 bis(trifluoromethyl)phenyl]thiophene-2-sulfonamide as a white powder (34% yield). A portion of this sample was further purified by preparative HPLC, m.p. 140° C.

R~..96I31492 PCTIUS96104759 , N-(4-Bromo-3-methyl-5-isoxazolyl)-5-(5-methyl-2-thienyl)thiophene-2-sul-fonamide A. 2-methylthiophene-5-boronic acid n-BuLi (2.38 M, 16 ml) was slowly added to a solution of 2-methyl thiophene (3.0 g, 31 mmol) in THF (20 ml) at -78 ° C. The solution was kept at -78° C for 7 0 min. then warmed to 0° C for an additional 0.5 hr.
The solution was then transferred by steel canula under nitrogen into a vessel containing triisopropylborate (6.3 g, 33 mmol) in ether (15 ml) at -78 ° C. The resulting milky white solution was stirred at -78 °
C for 20 min. then at room temperature for 2 hours. The reaction was quenched by the addition of 1 O% aqueous HCI (5.0 ml) and the solution was extracted into ether. The combined ether extracts were extracted with 10 M NaOH (2 x 30 ml), the aqueous extracts were acidified with dilute HCI to pH 2 and exmacted into ether (3 x 25 ml). The combined ether extracts were washed once with water (10 ml), once with brine (10 ml) and dried and evaporated to give 3.91 g 2-methylthiophene-5-boronic acid as a light brown solid. This was used in the next step with no further purification.
B. N-[5-(5-methyll-2-thienyl)thiophene-2-sulfonyl]pyrrole N-(5-(5-methyl-2-thienyl)thiophene-2-sulfonyl]pyrrole was .prepared in the same manner as described in Example 32C from 2-methyl-thiophene-5-boronic acid and N-(5-bromothiophene-2-sulfonyl)pyrrole.
Purification by column chromatography using 2% ether/hexanes gave the pure sulfonamide in ~~2% yield as a white solid.
C. 2-chlorosulfonyl-5-(5-methyl-2-thienyl)thiophene 2-chlorosulfon~,rl-5-(5-methyl-2-thienyl)thiophene was prepared in the same manner as described in Example 33D from N-(5-(5-methyl-2-thienyl)thiophene-2-sulfonyl]pyrrole (570 mg, 1.84 mmol). Purification by R !6/31492 PCTIL1S96/04759 column chromatography using 2% ethyl acetate/hexanes gave 258 mg (50%) of the sulfonyl chloride as a light green solid.
D. N-(4-bromo-3-methyl-5-isoxazolyl)-5-(5-methyl-2-thienyl)thiophene-2-sulfonamide N-(4-bromo-3-methyl-5-isoxazolyl)-5-(5-methyl-2-thienyl)thiophene-2-sulfonamide was prepared in the same manner as described in Example 2. Reaction of 2-chlorosulfonyl-5-(5-methyl-2-thienyl)thiophene (200 mg, 0.72 mmol) with 5-amino-4-bromo-3-methylisoxazole ( 127 mg, 0.72 mmol) yielded 273 mg (90%) of the crude sulfonamide. After passing through a small plug of silica gel, a portion of the product was further purified by preparative HPLC to give the pure sulfonamide as a white powder, m.p. 161-'162° C.

N-(4-8romo-3-methyl-5-isoxazolyl)-5-(5-ethyl-2-thienyl)thiophene-2-sulfon-amide A. 2-ethyfthiophene-5-boronic acid 2-ethylthiophene-5-boronic acid was prepared in the same manner as described in Example 140A from 2-ethylthiophene (2.0 g, 18 mmol).
Evaporation of solvents after workup gave 2.168 (78%) of 2-ethylthiophene-5-boronic acid as a white sold which was used on the next step with no further purification.
8. N-[5-(5-ethyl-2-thienyl)thiophene-2-sulfonyl]pyrrole N-[5-(5-ethyl-2-thienyl)thiophene-2-sulfonyl]pyrrole was prepared in the same manner as. described in Example 32C from 2-ethylthiophene-5-boronic acid (411 mg, 2.64 mmol) and N-(5-bromothiophene-2-sulfonyl)-pyrrole (700 mg, 2.39 mmol). Purification by column chromatography using 2% ethyl acetate/hexanes gave 6.30 mg of the pure product as a dark brown solid (90% yield).
C. 2-chlorosulfonyl-5-(5-ethyl-2-thienyl)thiophene 11, 0 96131492 PCT/US96/04759 2-chlorosulfonyl-5-(5-ethyl-2-thienyl)thiophene was prepared in the same manner as described in Example 33D from N-(pyrrole)-5-(5-ethyl-2-thienyl)thiophene-:?-sulfonamide (630mg, 2.16 mmol). Purification by column chromatography using 1 % ethyl acetate/hexanes gave 400.3 mg of the pure sulfonyl chloride as a bright yellow solid (57% yield).
D. N-(4-bromo-3-methyl-5-isoxazolyl)-5-(5-ethyl-2-thienyl)thiophene-2-sulfonamide N-(4-bromo-3-methyl-5-isoxazolyl)-5-(5-ethyl-2-thienyl)thiophene-2-sulfonamide was prepared in the same manner as described in Example 2.
Reaction of 2-chlorosulfonyl-5-(5-ethyl-2-thienyl)thiophene (200 mg, 0.68 mmol) with 5-amino-4-bromo-3-methyl isoxazole ( 121 mg, 0.68 mmol) yielded 174 mg N-~;4-bromo-3-methyl-5-isoxazolyl)-5-(5-ethyl-2-thienyl)-thiophene-2-sulfonamide (59% yield). After passing through a small plug of silica gel with elution using 10% MeOH/CHC13, a small fraction of the product was further purified using preparative HPLC to give the sulfona-mide as a light tan colored powder, m.p. 126°C.

N-(4-chloro-3-methyl-5-isoxazolyl)-5-(5-ethyl-2-thienyl)thiophene-2-sulfon-amide N-(4-chloro-a-methyl-5-isoxazolyl)-5-(5-ethyl-2-thienyl)thiophene-2-sulfonamide was prepared in the same manner as in Example 2. Reaction of 2-chlorosulfonyl- 5-(5-ethyl-2-thienyl)thiophene (Example 141 C, 200 mg, 0.68 mmol) with 5-amino-4-chloro-3-methylisoxazole (91 mg, 0.68 mmol) yielded 188 mg of the final product (71 % yield). A small portion of the product was further purified by preparative HPLC to give the pure sulfonamide as a tan colored solid.

R'v 96/31492 PCT/US96/04759 N-(4-Bromo-3-methyl-5-isoxazolyl)-5-(benzo[b]thien-2-yl)thiophene-2-sul-fonamide A. Benzo[b]thiophene-2-boronic acid Benzo[b]thioE>hene-2-boronic acid was prepared in the same manner as described in Example 140A from benzo(b]thiophene except that t-BuLi was used as the base in place of n-BuLi resulting in a tan solid in 78% yield.
B. N-(5-(benzojb~]thien-2-yl)thiophene-2-sulfonyl]pyrrole N-[5-fbenzo(b]thien-2-yl)thiophene-2-sulfonyl]pyrrole was prepared in the same manner as described in Example 32C from benzo[b]-thiophene-2-boronic acid (426 mg, 2.39 mmol) and N-(5-bromothiophene-2-sulfonyl)pyrrole (700 mg, 2.39 mmol). Purification by column chromatography using 2% ethyl acetate/hexanes gave the pure sulfona-mide in 68% yield as a brownish-red solid.
C. 2-chlorosulfonyl-5-(benzo[b]thien-2-yl)thiophene 2-chlorosulfonyl-5-(benzo[b)thien-2-yl)thiophene was prepared in the same manner as in Example 33D from N-(5-(benzo[b]thien-2-yl)thio-phene-2-sulfonyl]pyrrole (520 mg, 1.5 mmol). Purification by column chromatography using 2% ethyl acetate/hexanes gave 153 mg (32%
yield) of the pure sulfonyl chloride as a white solid.
D. N-(4-bromo-3~-methyl-5-isoxazolyl)-5-(benzo[b]thien-2-yl)thiophene-2-sulfonamide N-(4-bromo-3-methyl-5-isoxazolyl)-5-(benzo[b]thien-2-yl)thiophene-2-sulfonamide was prepared in the same manner as in Example 2.
Reaction of 2-chlorosulfonyl-5-(benzo[b]thien-2-yl)thiophene (150 mg, 0.48 mmol) with 5-amino-4-bromo-3-methyl isoxazole (84 mg, 0.48 mmol) resulted in 9T mg of pure N-(4-bromo-3-methyl-5-isoxazolyl)-5-(benzo[b]thien-2-yl)thiophene-2-sulfonamide as a light tan powder, (45%
yield, m.p. 164° C).

W O 96!31492 PCT/US96I04759 N-(Bromo-3-methyl-5-isoxazolyl)-5-(1-pentynyl)thiophene-2-sulfonamide A. N-[5-(1-pentynyl)thiophene-2-sulfonyl)pyrrole N-[5-(1-pentynyl)thiophene-2-sulfonyl)pyrrole was prepared as in Example 138A from N-(5-bromothiophene-2-sulfonyllpyrrole (600 mg, 2.05 mmol) and 1-pentynel (280 mg, 4.1 mmoll. Purification by column chromatography using 2% ethyl acetate/hexanes gave 424 mg of the pure sulfonamide as a brown oil (74% yield).
B. 2-chlorosulfonyl-5-(1-pentynyl)thiophene 7 0 2-chlorosulfonyl-5-( 1-pentynyl)thiophene was prepared in the same manner as described in Example 33D from N-[5-(1-pentynyl)thiophene-2-sulfonyl]pyrrole (4~!0 mg, 1.5 mmol). Purification by column chromatography using 1 % ethyl acetate/hexanes gave 55 mg of the pure thiophene as a bro~rvn oil (15% yield).
75 C. N-(bromo-3-methyl-5-isoxazolyl)-5-(1-pentynyl)thiophene-2-sulfona-mide N-(bromo-3-methyl-5-isoxazolyl)-5-( 1-pentynyl)thiophene-2-sulfona-mide was prepared in the same manner as described in Example 2.
Reaction of 2-chlorosulfon,yl-5-(1-pentynyl)thiophene (55 mg. 0.22 mmol) 20 with 5-amino-4-bromo-3-methylisoxazole (43 mg, 0.22 mmol) yielded 75 mg of N-(bromo-3-methyl-5-isoxazolyl)-5-(1-pentynyl)thiophene-2-sul-fonamide (87% yield). A portion of the product was further purified by preparative HPLC t« give the pure sulfonamide as a light brown oil.

25 N-(4-Bromo-3-methyl-5-isoxazolyll-5-(1-napthyl)thiophene-2-sulfonamide A. N-[5-(1-napthyl)thiophene-2-sulfony(]pyrrole N-[5-(1-napthyl)thiophene-2-sulfonyl]pyrrole was prepared in the same manner as described in Example 32C from 1-napthaleneboronic acid (353 mg, 2.05 mmol) and N-(5-bromothiophene-2-sulfonyl)pyrrole (600 30 mg, 2.05 mmol). Purification by column chromatography using 2% ethyl a _ 96131492 PCTIUS96/04759 acetate/hexanes gave the pure sulfonamide in 87% yield as a pale yellow clear oil.
B. 2-chlorosulfonyl-5-( 1-napthyl)thiophene 2-chlorosulfonyl-5-( 1-napthyl)thiophene was prepared as described in Example 330 from N-(5-(1-napthyl)thiophene-2-sulfonyl]pyrrole (604 mg, 1.28 mmol). Purification by column chromatography using 2% ethyl acetate/hexanes gave 376 mg of the pure thiophene in 68% yield.
C. N-(4-bromo-:3-methyl-5-isoxazolyl)-5-(1-napthyl)thiophene-sulfona-mide ' N-(4-bromo-a-methyl-5-isoxazolyl)-5-( 1-napthyl)thiophene-sulfona-mide was prepared in the same manner as described in Example 2.
Reaction of 2-chlorosulfonyl-5-(1-napthyl)thiophene (200 mg, 0.65 mmol) with 5-amino-4-broimo-3-methylisoxazole (0.65 mmol), after purification by column chromatography using 1 % MeOH/CHC13, gave 65.3 mg of pure N-(4-bromo-3-methyl-5-isoxazolyl)-5-( 1-napthyl)thiophene-sulfona-mide as a brown solid, (22% yield, m.p. 118° C).

N-(4-Bromo-3-methyl-5-isoxazolyl)-5-(3-nitrophenyl)thiophene-2-sulfona-mide A. N-(3-methyl-5-isoxazolyl)-5-(3-nitrophenyl)thiophene-2-sulfonamide N-(3-methyl-5-isoxazolyl)-5-(3-nitrophenyl)thiophene-2-sulfonamide was prepared in the same manner as described in Example 32C from 3-nitrobenzene boronic acid (362 mg, 2.17 mmol) and N-(3-methyl-5-isoxazolyl)-5-bromo~thiophene-2-sulfonamide (700 mg, 2.17 mmol).
Purification by column chromatography using 10% MeOH/CHC13 gave 166 mg of the pure sulfonamide (21 % yield).
B. N-(4-bromo-3-methyl-5-isoxazolyl)-5-(3-nitrophenyl)thiophene-2-sul-fonamide N-(4-bromo-3-methyl-5-isoxazolyl)-5-(3-nitrophenyl)thiophene-2-su1-fonamide was prepared in the same manner as described in Example r W v 96/31492 PCTIUS96/04759 136C. Reaction of N-(3-methyl-5-isoxazolyl)-5-(3-nitrophenyl)thiophene-2-sulfonamide (328 g, 0.90 mmol) with N-bromosuccinamide ( 160 mg, 0.90 mmol) gave the final product. A fraction of this material was further purified by preparative HPLC to give the pure sulfonamide as a brown solid, m.p. 132°C.

N-(4-Bromo-3-methyl-5-isoxazolyl)-5-(4-methyoxycarbonylphenyl)-thiophene-2-sulfonamide A. 2-(4-methoxycarbonylphenyl)thiophene 2-(4-methoxycarbonylphenyllthiophene was prepared in the same manner as described in Example 32C from thiophene-2-boronic acid (1.0 g, 7.81 mmol) and methyl-4-bromobenzoate (1.68 g, 7.81 mmol).
Purification by column chromatography using 2% ethyl acetate/hexanes gave 1.1 g of 2-(4-methoxycarbonylphenyl)thiophene as a white solid (65% yield).
8. 2-chlorosulfonyl-5-(4-methoxycarbonylphenyl)thiophene Chlorosulfoni~ acid (1.06 g, 9.16 mmol) was slowly added to a solution of 2-(4-methoxycarbonylphenyl)thiophene (500 mg, 2.29 mmol) in CH2Clz ( 10 ml) at -78 ° C. The resulting solution was stirred at -78 ° C
for 1 hr. by which time the sulfonic acid had completely formed as judged by TLC using 10% ~ahyl acetate/hexanes. Phosphorous oxychloride (2 ml) was then added at -78° C followed immediately by addition of phosphorous pentac:hloride (954 mg, 4.58 mmol). The resulting solution was stirred at -78° C for 0.5 hr. and then at room temperature for 25 min. The solution was then carefully poured onto crushed ice (100 g) and extracted into diethyl ether (100 ml). The combined organic layers was washed with brine ( 1 x 25 ml) and dried over MgSO,. After filtration, removal of solvents left a light.greenish solid which was further purified by column chromatography using 2% ethyl acetate/hexanes to t 96131492 PCT/US96/04759 give 620 mg of pure 2-chlorosulfonyl-5-(4-methoxycarbonylphenyl)-thiophene as a pale yellow solid (85% yield).
C. N-(4-bromo-~3-methyl-5-isoxazolyl)-5-(4-methoxycarbonylphenyl)-thiophene-2-sulfonamide N-(4-bromo-3-methyl-5-isoxazolyl)-5-(4-methoxycarbonylphenyl)-thiophene-2-sulfonamide was prepared in the same manner as described in Example 2 from 2-chlorosulfonyl-5-(4-methoxycarbonylphenyl)thio-phene (646 mg, 2.04 mmol) and 5-amino-4-bromo-3-methylisoxazole (361 mg, 2.04 mmol). Purification by column chromatography using 10% MeOH/CHC13 gave 384 mg of N-(4-bromo-3-methyl-5-isoxazolyl)-5 (4-methoxycarbonylphenyl)thiophene-2-sulfonamide as a brown oil (41 % yield).

N-(4-Bromo-3-methyl-5-isoxazolyl)-5-(4-carboxyphenyl)thiophene-2-sul-fonamide Lithium hydroxide ( 13.3 mg, 0.32 mmol) in methanol (2 ml) was added to a solution of N-(4-bromo-3-methyl-5-isoxazolyl)-5-(4-methoxycarbonylphenyl)thiophene-2-sulfonamide (Example 147C, 121 mg, 0.27 mmol) previously dissolved in methanol (5 ml). The solution was stirred at room temperature for a period of 18 hours. The methanol was removed in vacuo and the remaining residue dissolved in water. 4N
HCI was added until pH 2.0 was reached, and then the aqueous solution was extracted with ethyl acetate (3 x 25m1). The combined organic layers was washed with water ( 1 x 10 ml), brine ( 1 x 1 Oml) and dried over MgS04. Evaporation left 50 mg (43% yield) of a pale yellow residue which was further purified by preparative HPLC to give N-(4-bromo-3-methyl-5-isoxazolyl)-5-(4-carboxyphenyl)thiophene-2-sulfonamide as a white solid, m.p. 2'19-228° C.

'. ~ 96131492 PCT/US96/04759 N-(4-chloro-3-metlhyl-5-isoxazolyl)2-{[2-acetyl-4,5-(methylenedioxy)-phenyl]aminocarbonyl}thiophene-3-sulfonamide Carbonyldiirnidazole (553 mg, 3.41 mmol) was added to a solution of N-(4-chloro-3-methyl-5-isoxazolyl)-2-carboxylthiophene-3-sulfonamide (1.0 g, 3.1 mmol) in dry DMF (10 ml). The mixture was stirred at room temperature for 15 minutes to give mixture (I).
NaH (60% dispersion in mineral oil, 521 mg, 13.02 mmol) was added to a solution of 2'-amino-4',5'-(methylenedioxy)acetophenone (1.13 g, 6.2 mmoll in dry DMF (10 ml) at 0°C. The mixture was stirred at 0°C for 15 minutes to give mixture (II). Mixture (I) was slowly cannulated into mi;Kture (II) at 0°C. The resulting mixture was stirred at 0°C for 4 hours. The reaction mixture was poured into 2 N HCI (aq., 200 ml) and the resulting precipitate was filtered. The solid was washed with water (2x10 rnl) and ethyl ether (2x10 ml) to give N-(4-chloro-3-methyl-5-isoxazolyl)2-{[2-acetyl-4,5-(methylenedioxy)phenyl)aminocar-bonyl}thiophene-3-sulfonamide (730 mg, 49% yield) as a dull yellow powder, m.p. 191-193° C.

N-(4-chloro-3-methyl-5-isoxazolyl)-2-[(4,5-dimethoxy-2-methoxycarbonyl-phenyl)aminocarbonyl]thiophene-3-sulfonamide and N-(4-chloro-3-methyl-5-isoxazolyl)2-{[4,5-dimethoxy-2]4,5-dimethoxy-2-methoxycar-bonyl)phenyl]phenylaminocarbonyl}thiophene-3-sulfonamide The title compounds were prepared by the method set forth for N-(4-chloro-3-methyl-5-isoxazolyl)2-{[2-acetyl-4,5-(methy(enedioxy)phenyl]-aminocarbonyl}thiophene-3-sulfonamide (EXAMPLE 148) except that methyl-2-amino-4,5-dimethoxybenzoate was used instead of 2'-amino-4',5'-(methylenedioxy)acetophenone. The crude product was purified via HPLC to give N-(4-c:hloro-3-methyl-5-isoxazolyl)-2-[(4,5-dimethoxy-2-methoxycarbonylphenyl)aminocarbonyl]thiophene-3-sulfonamide as a yellow powder (13°,~o yield, m.p. 167-168° C) and N-(4-chloro-3-methyl-5-° ~ a 46131492 PCTIITS96/04759 isoxazolyl)2-{(4, 5-dimethoxy-2,4, 5-dimethoxy-2-methoxycarbonyl)-phenyl]phenylaminocarbonyl}thiophene-3-sulfonamide as a dull yellow solid (1 % yield, m.p. 228-230° C).

N-(4-chloro-3-methyl-5-isoxazolyl)-2-[(2-methyl-1,3,4-thiadiazol-5-yl)aminocarbonyl]thuophene-3-sulfonamide Carbonyldiimidazole (553 mg, 3.41mmol) was added to a solution of N-(4-chloro-3-methyl-5-isoxazolyl)-2-carboxyl-thiophene-3-sulfonamide (10 g, 3.1 mmol) in dry DMF (10 ml). The mixture was stirred at room temperature for 15 minutes before the sequential addition of 2-amino-5-methyl-1,3,4-thiadiazole (736 mg, 6.2 mmol) and pyridine (10 ml). The resulting mixture was stirred at room temperature overnight. To work up, the reaction mixture was poured into 1 N HCI ( 1 50 ml) and extracted with EtOAc. The organic layer was dried (MgS04), the solid was filtered and the filtrate was concentrated. The residue was purified via HPLC to give N-(4-chloro-3-methyl-5-isoxazolyl)-2-[(2-methyl-1,3,4-thiadiazol-5-yl)aminocarbonyl]thiophene-3-sulfonamide as a white powder (15% yield, m.p. 192-194° C).

N-(4-chloro-3-methyl-5-isoxazolyl)2-{[2-carboxyl-4,5-fmethylenedioxy)phenyl]aminocarbonyl}thiophene-3-sulfonamide NaOH (1.5 N, 250 ml) was added to N-(4-chloro-3-methyl-5-isoxazolyl)-2-[(4,5-dimethoxy-2-methoxycarbonylphenyl)aminocar-bonyl]thiophene-3-sulfonamide (EXAMPLE 149); 410 mg). The resulting suspension was stirred at room temperature overnight to give a clear solution. The mixture was acidified using concentrated HCI with cooling.
The resulting precipi~:ate was filtered, washed with water (3x50 ml) and dried on a lyophilyze~ to give N-(4-chloro-3-methyl-5-isoxazolyl)2-{(2-carboxyl-4, 5-(methylenedioxy)phenyl]aminocarbonyl}thiophene-3-sulfona-mide as a yellow povvder (87% yield, m.p. 192-195° C).

N-(3,4-dimethyl-5-isoxazolyl)-2-{(2-acetyl-4,5-(methylene-dioxy)phenyl]amin ocarbonyl}thiophene-3-sulfonamide N-(3,4-dimethyl-5-isoxazolyl)-2-{[2-acetyl-4, 5-(methylene-dioxy)phenyl)aminocarbonyl}thiophene-3-sulfonamide was prepared by the method set forth for N-(4-chloro-3-methyl-5-isoxazolyl)2-{(2-acetyl-4, 5-(methylenedioxy)phenyl]aminocarbonyl}thiophene-3-sulfonamide (EXAMPLE 148) e~:cept that N-(3,4-dimethyl-5-isoxazolyl)-2-carboxylthiophene-3-sulfonamide was used instead of N-(4-chloro-3-methyl-5-isoxazolyl)-2-carboxylthiophene-3-sulfonamide. N-(3,4-dimethyl-5-isoxazolyl)-2-{(2-acetyl-4, 5-(methylenedioxy)phenyl]aminocarbonyl}thio-phene-3-sulfonamide was obtained as a yellow powder (8% yield, m.p. 228-231 ° C).

N-(4-chloro-3-methyl-5-isoxazolyl)-2-[(4-methoxy-2-methylphenyl)amino-carbonyl]thiophene-3-sulfonamide N-(4-chloro-3-methyl-5-isoxazolyl)-2-((4-methoxy-2-methylphenyl)-aminoarbonyl]thiophene-3-sulfonamide was prepared by the method set forth for N-(4-chlorc>-3-methyl-5-isoxazolyl)-2-((2-methyl-1,3,4-thiadiazol-5-yl)aminocarbonyl]thiophene-3-sulfonamide (EXAMPLE 150), except that 4-methoxy-2-methylaniline was used instead of 2-amino-5-methyl-1,3,4-thiadiazole and that pyridine was not used. The title compound was obtained via HPLC purification as a dull yellow powder (66% yield, m.p.
58-62° C).

N-(4-chloro-3-methyl-5-isoxazolyl)-2-[(2-cyano-4,5-dimethoxyphenyl)aminocarbonyl]thiophene-3-sulfonamide N-(4-chloro-3-methyl-5-isoxazolyl)-2-[(2-cyano-4,5-dimethoxy-phenyl)aminocarbon~,rl]thiophene-3-sulfonamide was prepared by the method set forth for N-(4-chloro-3-methyl-5-isoxazolyl)2-{[2-acetyl-4,5-R'v .if31492 PCT/US96/04759 (methylenedioxy)phenyl]aminocarbonyl}thiophene-3-sulfonamide (EXAMPLE 148) e~:cept that 2-amino-4,5-dimethoxybenzonitrile was used in stead of 2'-amino-4',5'-(methylenedioxy)acetophenone. N-(4-chloro-3-methyl-5-isoxazolyl)-2-[{2-cyano-4,5-dimethoxyphenyl)aminocarbonyl]-thiophene-3-sulfon~smide was obtained via HPLC purification as a light brown powder (36'% yield, m.p. 53-56° C).

N-(4-chloro-3-methyl-5-isoxazolyl)-2-[(2,4-dimethoxyphenyl)aminocar-bonyl]thiophene-3-:sulfonamide N-(4-chloro-3-methyl-5-isoxazolyl)-2-((2,4-dimethoxyphenyl)amino-carbonyl]thiophene-3-sulfonamide was prepared by the method set forth for N-(4-chloro-3-m~athyl-5-isoxazolyl)-2-(4-methoxy-2-methylphenyl)-aminocarbonyl]thiophene-3-sulfonamide (EXAMPLE 153), except that 2,4-dimethoxyaniline was used in stead of 4-methoxy-2-methylaniline. N-(4-chloro-3-methyl-5-isoxazolyl)-2-[(2,4-dimethoxyphenyl)aminocarbonyl]-thiophene-3-sulfonamide was obtained via recrystalization (CH3CN/H20) as yellow crystals ('16% yield, m.p. 162-164° C).

N-(4-chloro-3-methyl-5-isoxazolyl)-2-[(3-methyl-6-pyridyl)aminocar-bony)]thiophene-3-sulfonamide N-(4-chloro-3-methyl-5-isoxazolyl)-2-((3-methyl-6-pyridyl)aminocar-bonyl]thiophene-3-sulfonamide was prepared by the method set forth for N-(4-chloro-3-methyl-5-isoxazolyl)2-{[2-acetyl-4,5-(methylenedioxy)-phenyl]aminocarbonyl}thiophene-3-sulfonamide (EXAMPLE 148), except that 2-amino-5-picoline was used in stead of 2'-amino-4',5'-(methylene-dioxy)acetophenone, N-(4-chloro-3-methyl-5-isoxazolyl)-2-[(3-methyl-6-pyridyl)aminocarbonyl]thiophene-3-sulfonamide was obtained, via HPLC
purification of the crude reaction mixture, as a bright yellow powder (17% yield, m.p. 1513-160° C).

V~ _ !6!31492 PC'TNS96104759 N-(4-bromo-3-methyl-5-isoxazolyl)-2-[(4-methylphenyl)acetyl]thiophene-3-sulfonamide N-(4-bromo-3-methyl-5-isoxazolyl)-2-[(4-methylphenyl)-acetyl]thiophene-3-sulfonamide was prepared in the same manner as described in Example 938 by reacting 4-methylbenzylmagnesium chloride with N-(4-bromo-3-methyl-5-isoxazolyl)-2-[N-methoxy(methylamino-carbonyl)]thiophene-3-sulfonamide in THF (see Example 93A) at -78° C to room temperature, resulting in 78% yield., m.p. 146-150° C.8 N-(4-bromo-3-methyl-5-isoxazolyl)-2-[(4-methyl)(cinnamyl)] thiophene-3-sulfonamide A. N-[2-(4-methyl-traps-styryl)-3-sulfonyl}pyrrole N-[2-(4-methyl-traps-styryl)-3-sulfonyl}pyrrole was prepared in the same manner as described in example 1278 using diethyl{3-[(N-pyrrolylsulfonyl)thien-2-[yl]methyphosphonate and 4-methylbenzaldehyde in 30% yield.
B. 2-(4-methyl-traps-styryl)thiophene-3-sulfonyl chloride 2-(4-methyl-traps-styryl)thiophene-3-sulfonyl chloride was prepared in the same manner as described in Example 64E from N-[2-(4-methyl-trans-styryl)-3-sulfonyl}pyrrole by basic hydrolysis (using ethanol and sodium hydroxide) t:o the corresponding sodium sulfonate followed by conversion to the corresponding sulfonyl chloride in 13% yield.
C. N-(4-bromo-3.-methyl-5-isoxazolyl)-2-(4-methyl-trans-styryl)thiophene-3-sulfonamide N-(4-bromo-3-methyl-5-isoxazolyl)-2-(4-methyl-traps-styryl)thio-phene-3-sulfonamide was prepared in the same manner as described in Example 2 by reaction of 2-(4-methyl-traps-styryl)thiophene-3-sulfonyl chloride with 5-amino-4-bromo-3-methylisoxazole. The crude product R . X6/31492 PCTlUS96/04759 was purified by HPLC followed by crystallization resulting in a 34% yield, m.p. 101-105 °C.

N-(4-bromo-3-methyl-5-isoxazolyl)-2-[(4-methyl)phenethyl)thiophene-3-sulfonamide A. N-{2-[(4-metlhyl)phenethyl)thiophene-3-sulfonyl}pyrrole N-{2-[(4-methyl)phenethyl]thiophene-3-sulfonyl}pyrrole was prepared as described in Example 128A by the catalytic hydrogenation of N-[2-(4-methyl-tran;~-styryl)-3-sulfonyl}pyrrole in 80% yield.
'10 B. 2-[(4-methyl)~phenethyl]thiophene- 3-sulfonylchloride 2-[(4-methyl)lohenethyl)thiophene- 3-sulfonylchloride was prepared, as described in Example 64E, using N-{2-((4-methyl)phenethyl)thiophene-3-sulfonyl}pyrrole b~y basic hydrolysis (KOH/ethanol) of the sulfonamide to this potassium salt followed by conversion of salt to the corresponding sulfonyl chloride in 51 % yield.
C. N-(4-bromo-3-methyl-5-isoxazolyl)-2-[(4-methyl)phenethyl)thio-phene-3-sulfonamide N-(4-bromo-3-methyl-5-isoxazolyl)-2-[(4-methyl)phenethyl]thio-phene-3-sulfonamides was prepared, as described in Example 2, using 2-[(4-methyl)phenethyl)thiophene-3-sulfonylchloride and 5-amino-4-bromo-3-methylisoxazole in 52% yield.

N-(4-bromo-3-methyl-5-isoxazolyl)-2-[(4-methylphenoxy)methyl)thiophene-3-sulfonamide A. N-{2-[(4-meth~ylphenoxy)methyl)thiophene-3-sulfonyl}pyrrole N-{2-[(4-methylphenoxy)methyl]thiophene-3-sulfonyl}pyrrole was prepared, as describE:d in Example 126A, by reacting N-[2-bromo-methyl)thiophene-3-s:ulfonyl]pyrrole with 4-methylphenol, in 81 % yield.

~. ~ 96/31492 PGT/US96/04759 B. 2-[(4-methylphenoxy)methyl]thiophene-3-sulfonyl chloride 2-[(4-methylphenoxy)methyl]thiophene-3-sulfonyl chloride was prepared, as described in Example 64E, using N-{2-[(4-methylphenoxy-methyl]thiophene-3-sulfonyl}pyrrole by basic hydrolysis (NaOH/EtOH) followed by conversion to the corresponding sulfonyl chloride, in 46%
yield.
C. N-(4-bromo-3-methyl-5-isoxazolyl)-2-[(4-methylphenoxy)methyl]-thiophene-3-sulfonamide N-(4-bromo-3-methyl-5-isoxazolyl)-2-[(4-methylphenoxy)methyl]-thiophene-3-sulfonamide was prepared, as described in Example 2, by reacting 3-chlorosulfonyl-2-[(4-methylphenoxy)methyl)thiophene with 5-amino-4-bromo-3-rnethyfisoxazole,resulting in a 64% yield, m.p. 128-130° C.

N-(3,4-dimethyl-5-isoxazoly!)-2-(4-tolylacetylphenyl)thiophene-3-sulfonamide A. N-(3,4-dimethyl-5-isoxazolyl)-2-[N-methoxy(methylaminocarbonyl)-thiophene-3-sulfonamide N-(3,4-dimethyl-5-isoxazolyl)-2-[N-methoxy(methylaminocarbonyl) thiophene-3-sulfon~3mide was prepared, as described in Example 93A, by reacting N-(3,4-dimethyl-5-isoxazolyl)-2-(carboxyl)thiophene-3 sulfonamide with N-0-dimethylhydroxylamine hydrochloride using triethylamine as baae and carbonyldiimidazole,resulting in a 23% yield.
Crude product purified by column chromatography using 1:1 hex-anes/EtOAc as the eluent.
B. N-(3,4-dimetihyl-5-isoxazolyl)-2-(4-tolylacetyl)thiophene-3-sulfonamide N-(3,4-dimethyl-5-isoxazolyl)-2-(4-tolylacetyl)thiophene-3-sulfonamide was prepared, as described ~n Example 93B, by reacting N-(3,4-dimethyl-5-iso;<azolyl)-2-(N-methoxy(methylaminocarbonyl)]thio-', ~ 96!31492 PCTJUS96/04759 phene-3-sulfonamide with 4-tolylmagnesium chloride,resulting in a 65%
yield, m.p. 95-100° C.

N-(3,4-dimethyl-5-isoxazolyl)-2-(3,4-(methylenedioxy)phenylacetyl]-thiophene-3-sulfonamide N-(3,4-dimethyl-5-isoxazolyl)-2-(3,4-(methylenedioxy)phenylacetyl)-thiophene-3-sulfonamide was prepared, as described in Example 93B, by reacting N-(3,4-dirnethyl-5-isoxazolyl)-2-(N-methoxy(methyl-aminocarbonyl))thiophene-3-sulfonamide with 3,4-methylenedioxy)phenyl-magnesium chloride, resulting in a 65% yield, m.p. 95-100° C.

N-(4-chloro-3-methyl-5-isoxazoly()-2-{(2-cyano-4,5-(methylenedioxy)-phenyl)aminocarbonyl}thiophene-3-sulfonamide N-(4-chloro-3-methyl-5-isoxazolyll-2-{(2-cyano-4, 5-(methylene-dioxy)phenyl]aminocarbonyl}thiophene-3-sulfonamide was prepared as described in EXAN1PLE 148, except that 2'-amino-4',5'-(methylene-dioxy)benzonitrile was used instead of 2'-amino-4',5'-(methylenedioxy)-acetophenone. It 'was obtained via HPLC purification as a yellowish solid in -40% yield, m.,p. 167-168° C.

N-(4-chloro-3-methyl-5-isoxazolyl)-2-(3-rnethoxycarbonyl-2,4,6-trimethyl)phenylaminocarbonyl-3-thiophenesulfonamide A. Meth,rl3-amino-2,4,6-trimethylbenzoate Methyl 3-amino-2,4,6-trimethylbenzoate was synthesized in the same manner as (:3,4-methylenedioxy)-6-methylaniline (see Example 177, below).
B. N-(4-chloro-3-methyl-5-isoxazolyl)-2-(3-methoxycarbonyl-2,4,6-trimethyl)phenylaminocarbonyl-3-thiophenesulfonamide N-(4-chloro-3-methyl-5-isoxazolyl)-2-(3-methoxycarbonyl-2,4,6-trimethyl)phenylaminocarbonyl-3-thiophenesulfonamide was synthesized in the same manner as for Example 94 except that DMF was used instead Ww , 6!31492 PCT/US96/04759 of THF and the reaction was heated at 80°C for 5 hours. The crude product was purified via preparative HPLC to give N-(4-chloro-3-methyl-5-isoxazolyl)-2-(3-methoxycarbonyl-2,4,6-trimethyllphenylaminocarbonyl-3-thiophenesulfonamide as an off-white powder (48 mg, 1 % yield, m.p. 66-70°C).

N-(4-chloro-3-methyl-5-isoxazolyl)-2-(2,4,6-trimethyl)phenylacetyl-3-thiophenesulfonamide N-(4-chloro-3-methyl-5-isoxazolyl)-2-(2,4,6-trimethyl)phenylacety!-3-thiophenesulfonamide was synthesized in the same manner as for Example 102 using 2,4,6-trimethylbenzyl chloride and N-(4-chloro-3-methyl-5-isoxazolyl)-2-(N-methyl-N'-methoxy)aminocarbonyl-3-thiophenesulfonamide. The crude product was purified by flash column chromatography (eluent 1 % methanol in CHZCIZ) to give N-(4-chloro-3-methyl-5-isoxazolyl)-2-(2,4,6-trimethyl)phenylacetyl-3-thiophenesulfonamide as a solid (31 % yield, m.p. 42-46°C).

N-(4-chloro-3-methyl-5-isoxazolyl)-2-(2,4,6-trimethyl)phenylamino-carbonyl-3-thiophenesulfonamide N-(4-chloro-a-methyl-5-isoxazolyl)-2-(2,4,6-trimethyl)phenylamino-carbonyl-3-thiophenesulfonamide was synthesized in the same manner as Example 94. The crude product was purified via preparative HPLC to give N-(4-chloro-3-methyl-5-isoxazolyl)-2-(2,4,6-trimethyl)phenylaminocarb~nyl-3-thiophenesulfonamide as a yellowish-brownish powder (~~10 mg, 30% yield, m.p. 45-48°C).

N-(3,4-dimethyl-5-isoxazolyl)-2-(2,4-dimethyl)phenylacetyl-3-thiophene-sulfonamide N-(3,4-dim~ethyl-5-isoxazolyl)-2-(2,4-dimethyl)phenylacetyl-3-thiophenesulfonamide was synthesized by the same method as described for Example 102 using 2,4-dimethylbenzyl chloride and N-(3,4-dimethyl-5-isoxazolyl)-2-(N-methyl-N'-methoxy)aminocarbonyl-3-thio-phenesuifonamid~:. The crude product was purified by flash column chromatography (eluent 1 % methanol in CHZC11) and further by prepara-tive HPLC to give N-(3,4-dimethyl-5-isoxazolyll-2-(2,4-di-methyl)phenylacetyl-3-thiophenesulfonamide as a semi-solid (34% yield).

N-(4-chloro-3-methyl-5-isoxazolyl)-2-(2,4-dimethyl)phenylacetyl-3-thiophenesulfonamide N-(4-chloro-3-methyl-5-isoxazolyl)-2-(2,4-dimethyl)phenylacetyl-3-thiophenesulfonamide was synthesized in the same manner as for Example 102 using 2,4-dimethylbenzyl chloride and N-(4-chloro-3-methyl-5-isoxazolyl)-2-(N-methyl-N'-methoxy)aminocarbonyl-3-thiophene-sulfonamide. The crude product was purified by flash column chromatography (eluent 1 % methanol in CH2C1~) to give N-(4-chloro-3-methyl-5-isoxazolyl)-2-(2,4-dimethyl)phenylacetyl-3-thiophenesulfonamide as a solid (52% yield, m.p. 48-54°C).

N-(4-bromo-3-methyl-5-isoxazolyl)-2-(2,4-dimethyl)phenylacetyl-3-thiophenesulfonamide N-(4-bromo-3-methyl-5-isoxazolyl)-2-(2,4-dimethyl)phenylacetyl-3-thiophenesulfonamide was synthesized in the same manner as for Example 102 using 2,4-dimethylbenzyl chloride and N-(4-bromo-3-methyl-5-isoxazolyl)-2-(N-methyl-N'-methoxy)aminocarbonyl-3-thiophenesulfonamide. The crude product was purified by flash column W.. ~6I31492 PCT/US96/04759 chromatography (eluent 1 % methanol in CHZCIz) and further by preparative HPLC to give N-(4-bromo-3-methyl-5-isoxazolyl)-2-(2,4-dimethyl)phenylac:etyl-3-thiophenesulfonamide as a solid (28% yield, m.p.
58-63°C1.

N-(4-chloro-3-methyl-5-isoxazolyl)-2-(3,5-dimethyl)phenylacetyl-3-thiophenesulfonarnide N-(4-chloro-3-methyl-5-isoxazolyl)-2-(3, 5-dimethyl)phenylacetyl-3-thiophenesulfonarnide was synthesized in the same manner as for Example 102 using 3,5-dimethylbenzyl bromide and N-(4-chloro-3-methyl-5-isoxazolyl)-2-(N-methyl-N'-methoxy) aminocarbonyl-3-thiophenesulfonarnide. The crude product was purified by flash column chromatography (eluent 2% methanol in CHZCIZ) to give N-(4-chloro-3-methyl-5-isoxazol~yl)-2-(3, 5-dimethyl)phenylacetyl-3-thiophenesulfonamide as a solid (57% yield, m.p. 45-50°C).

N-(4-chloro-3-methyl-5-isoxazolyl)-2-(2,5-dimethyl)phenylacetyl-3-thiophenesulfonarnide N-(4-chloro-3-methyl-5-isoxazolyl)-2-(2, 5-dimethyl)phenylacetyl-3-thiophenesulfonarnide was synthesized in the same manner as for Example 102 using 2,5-dimethylbenzyl chloride and N-(4-chloro-3-methyl-5-isoxazolyl)-2-(N-methyl-N'-methoxy)aminocarbonyl-3-thiophenesulfonarnide. The crude product was purified by flash column chromatography (eluent 2% methanol in CHZCIZ) to give N-(4-chloro-3-methyl-5-isoxazolyl)-2-(2,5-dimethyl)phenylacetyl-3-thiophenesulfonamide as a solid (33°,% yield, m.p. 72-76°C).

~, 96!31492 PCT/US96/04759 ', N-(4-chloro-3-me;thyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)-6-(2-acetoxyethyl)]phenylaminocarbonyl-3-thiophenesulfonamide A. 2-(3.,4-methylenedioxy)phenyl-1-ethanol To a solution of 2-(3,4-methylenedioxy)phenylacetic acid (5 g, 25.75 mmol) in anhydrous THF (20 ml) at 0°C was added BH3~THF (40 ml, 1.0 M in THF). The mixture was stirred at room temperature for 1 h.
To work up, THF was evaporated on a rotavap. The residue was treated with water (100 ml) Acidified and extracted with ether (2 x 100m1).
Removal of the solvent under reduced pressure gave 2-(3,4 methylenedioxy)phenyl-1-ethanol as an oil (4.7g, 98% yield).
B. 1-acetoxy-2-((3,4-methylenedioxy)phenyl]ethane To a stirred solution of 2-(3,4-methylenedioxy)phenyl-1-ethanol (1.68 g, 10 mmol) in dry pyridine was added acetic anhydride and the resultant reaction mixture was stirred at 80°C for 1 h. The reaction mixture was poured into ice-water and was extracted with ether (2 x 75 ml). The combined ether extract was washed with water (2 x 50 ml), 5% Hcl (2 x 50 rnl) and then with 5% NaHC03 (2 x 50 ml). The organic layer was dried over magnesium sulfate and the solvent was removed under reduced pressure to give 1-acetoxy-2-[(3,4-methylenedioxy)phenyl]ethane as a solid (1.7 g, 81 % yield).
C. 1-acetoxy-2-[(3,4-methylenedioxy)-6-nitrophenyl]ethane To a stirred solution of 1-acetoxy-2-[(3,4-methylenedioxy)-phenyl]ethane ( 1..7 g, 8.09 mmol) in acetic acid ( 10 ml) was added, dropwise, concentrated HNO~ (4.5 ml). This was stirred at room temperature for ~~0 min. The reaction mixture was poured into water (100 ml). The precipeated solid was filtered, washed with water and dried under high ~~acuum to get 1-acetoxy-2-[(3,4-methylenedioxy)-6-nitrophenyl]ethane (1.8 g, 88% yield).

R ~ X6131492 PCTIUS96/04759 D. 1-acetoxy-2-[(3,4-methylenedioxy)-6-aminophenyl]ethane The solution of 1-acetoxy-2-[(3,4-methylenedioxy)-6-nitrophenyl]ethane (0.8 g, 3.13 mmol) in ethyl acetate (25 ml) was subjected to catalytic hydrogenation using 10% palladium on carbon (100 mg) at 50 psi for 30 min. The catalyst was filtered and the solvent was removed under reduced pressure to give 1-acetoxy-2-[(3,4-methylenedioxy)-6 aminophenyl]ethane as a solid (0.69 g, 98% yield).
E. N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)-6-(2-ac:etoxyethyl)]phenylaminocarbonyl-3-thiophenesulfonamide N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methyfenedioxy)-6-(2-acetoxyethyl)]phenylaminocarbonyl-3-thiophenesulfonamide was synthesized in the same manner as Example 87. The crude product was purified by preparative HPLC to give N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4.-(methylenedioxy)-6-(2-acetoxyethyl)]phenylamino-carbonyl-3-thioph~~nesulfonamide as a dull yellow powder ( 12% yield, m.p. 78-82°C).

N-(4-chloro-3-metlhyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)-6-(2-hydroxyethyl)]phenylaminocarbonyl-3-thiophenesulfonamide To a stirred solution of N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)-~6-(2-acetoxyethyl)]phenylaminocarbonyl-3-thio-phenesulfonamide (35 mg, 0.066 mmol) in methanol was added NaOH
powder (40 mg) and stirred at room temperature for 30 min. HPLC
analysis showed complete consumption of starting material. The reaction mixture was diluted with water and acidified to pH 2 -3. This was extracted with ethyl acetate (2 x 25 ml). The combined organic layer was dried over magnesium sulfate and the solvent removed under reduced pressure to give N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-R ~ ~6131Q92 PCTJUS96I04759 (methylenedioxy)-6-(2-hydroxyethyl)]phenylaminocarbonyl-3-thiophene-sulfonamide as a solid (84% yield, m.p. 47-52°C).

N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)-fi-(2-acetoxyethoxy)]phenylaminocarbonyl-3-thiophenesulfonamide A. Methyl 2-[3,4-(methylenedioxy)phenoxy]acetate and 2-[3,4-(methylenedioxy)phenoxy]acetic acid The mixture of sesamol (13.8 g, 100 mmol, methyl bromoacetate (15.3 g, 100 mmol) and potassium carbonate in acetone (200 ml) was refluxed for 24h with stirring. Acetone was removed under reduced pressure. The re;;idue was dissolved in water (200m1) and was extracted with ether (2 x 100 ml). the combined organic layer was dried over magnesium sulfate and the solvent removed under reduced pressure to give methyl 2-[3,4-(methylenedioxy)phenoxy]acetate as an oil (12 g, 57%
yield). The aqueous phase was neutralized to pH 2 - 3 with concentrated HCI and the precipitated solid was filtered to get 2-[3,4-(methylenedioxy)phenoxy]acetic acid as a solid (6 g, 31 % yield).
B. 2-3,4-(methylenedioxy)phenoxy-1-ethanol 2-(3,4-methylenedioxy)phenoxy-1-ethanol was synthesized in the same manner as for Example 172(A) using 2-(3,4-(methylenedioxy)-phenoxy]acetic acid and BH3~THF complex. The reaction was carried out for 12 hours at room temperature (98% yield).
C. 1-acetoxy-2-[3,4-(methyienedioxy)phenoxy]ethane 1-Acetoxy-2-[3,4-(methylenedioxy)phenoxy]ethane was synthesized in the same manner as for Example 172(8) by acetylation of 2-(3,4-methylenedioxy)phenoxy-1-ethanol using acetic anhydride and pyridine (92% yield).
D. 1-aces:oxy-2-[3,4-(methylenedioxy)-6-nitrophenoxy]ethane 1-acetoxy-2-[3,4-(methylenedioxy)-6-nitrophenoxy]ethane was synthesized in the came manner as for Example 172(C) by nitration of 1-acetoxy-2-[3,4-(methylendioxy)phenoxy]ethane. The reaction was carried out between 0°C and 5°C for 30 min (78 % yield).
E. 1-acetoxy-2-[3,4-(methylenedioxy)-6-aminophenoxy]ethane 1-acetoxy-2-[3,4-(methylenedioxy)-6-aminophenoxy]ethane was synthesized in the same manner as for Example 172(D) by reduction of 1 acetoxy-2-[3,4-(methylenedioxy)-6-nitrophenoxy)ethane ( 100% yield).
F. N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)-6-(2-acetoxyethoxy)]phenylaminocarbonyl-3-thio;phenesuffonamide N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)-6-(2-acetoxyethoxy)]phenylaminocarbonyl-3-thiophenesulfonamide was synthesized in the same manner as Example 87 using 1-acetoxy-2-[3,4-(methylenedioxy)-6-aminophenoxy]ethane and N-(4-chloro-3-methyl-5-isoxazolyl)-2-carb~oxylthiophene-3-sulfonamide. The crude product was ~ 5 purified by preparative HPLC to give N-(4-chloro-3-methyl-5-isoxazolyl)-2-(3,4-(methylenedioxy)-6-(2-acetoxyethoxy)]phenylaminocarbonyl-3-thiophenesulfonarnide as a dull yellow powder (21 % yield, m.p. 1 17-119°C).

20 N-(4-chloro-3-methyl-5-isoxazolyl)-2-(3,4-(methylenedioxy)-6-(2-hydroxyethoxy)]plhenylaminocarbonyl-3-thiophenesulfonamide N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)-6-(2-hydroxyethoxy)]phenylaminocarbonyl-3-thiophenesulfonamide was synthesized in the same manner as Example 173 by basic hydrolysis of 25 N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)-6-(2-acetoxy-ethoxy)]phenylaminocarbonyl-3-thiophenesulfonamide (86% yield, m.p.
158-161 °C).

. 96131492 PCT/US96/04759 N-(4-chloro-3-methyl-5-isoxazolyl)-2-(4-methoxycarbonyl-2,6-dimethyl)phenylaminocarbonyl-3-thiophenesulfonamide A. N-(4.-chloro-3-methyl-5-isoxazolyl)-N-(methoxyethoxymethyl)-2-ca~rboxylthiophene-3-sulfonamide To a mixture of N-(4-chloro-3-methyl-5-isoxazolyl)-2-carboxyl-thiophene-3-sulfonamide (3.23 g, 100 mmol) and diisopropylethyl amine (3 ml) in ethyl acetate (20 ml) was added methoxyethoxymethyl chloride and the resultant reaction mixture was stirred at room temperature '.-'or 12 hours. This was diluted with ethyl acetate ( 100 ml) and washed with 1 N HCI (2 x 50 rnl). The organic layer was dried over magnesium sulfate and the solvent removed under reduced pressure to give N-(4-chloro-3-methyl-5-isoxazol~yl)-N-(methoxyethoxymethyl)-2-(carbomethoxy)-thiophene-3-sulfonamide as light brown oil.
~ 5 The crude N-(4-chloro-3-methyl-5-isoxazolyl)-N-(methoxyethoxy-methyl)-2-(carbomethoxy)thiophene-3-sulfonamide was dissolved in methanol (50 ml) and potassium hydroxide (5 g) and water (5 ml) were added. The reaction mixture was stirred at room temperature for 12 hours and extracted with ethyl acetate (2 x 50 ml). The aqueous phase was neutralized to pH 2 - 3 and was extracted with ethyl acetate (2 x 50 ml). The combined organic layer was dried over magnesim sulfate and solvent removed to give N-(4-chloro-3-methyl-5-isoxazolyl)-N-(methoxyethoxymcahyl)-2-carboxyithiophene-3-sulfonamide as light brown solid (3.5 g, 85% yield).
B. 4-Carlbomethoxy-2,6-dimethylaniline To a warm solution of 3,5-dimethyl benzoic acid (5 g, 33.33 mmol) in acetic acid (30 rnl) was added fuming nitric acid (30 ml), dropwise.
After completion of the addition the reaction mixture was warmed with a heat gun. This was stirred for an additional 2 hours during which period W~. ~6I31492 PCT/US96/04759 a solid was precipitated. The reaction mixture was diluted with water (200 ml) and filtered. The solid was dried under reduced pressure.
To the above solid was added 20 ml of oxalyl chloride and a catalytic amount of DMF (2 drops). This was stirred at room temperature for 3 hours during which period a clear solution was formed. Excess oxalyl chloride was. removed under reduced pressure to give yellow solid.
To the yellow solid was added dry methanol (100 ml) and the mixture stirred at room temperature for 1 hour. Excess methanol was removed under reduced pressure and the residue dissolved in ether (200 ml). This was washed with water (100 ml) followed by saturated NaHC03 solution (100 ml). The oganic layer was dried over magnesium sulfate and the solvent removed giving 4-carbomethoxy-2,6-dimethyl-nitrobenzene as a yellow solid (5.8 g, 83% yield).
4-Carbomethoxy-2,6-dimethylnitrobenzene (2 g, 9.5 mmol) was dissolved in in ethyl acetate (20 ml) and subjected catalytic fiydrogenation usin~~ 10% palladium on carbon (300 mg) at 55 psi for 30 min. The catalyst was filtered and solvent removed to give 4-carbo-methoxy-2,6-dimethylaniline as a solid (1.7 g, 100% yield).
C. N-(4-clhloro-3-methyl-5-isoxazolyl)-2-(4-methoxycarbonyl-2,6-dirnethyl)phenylaminocarbonyl-3-thiophenesulfonamide N-(4-chloro-?.-methyl-5-isoxazolyl)-N-(methoxyethoxymethyl)-2-carboxylthiophene-:3-sulfonamide (3.5 g, 8.5 mmol) (from step A) was dissolved in oxalyl chloride (5 ml) and a drop of DMF was added. This was stirred at room temperature for 6 hours. Excess oxalyl chloride was removed under reduced pressure and the mixture dried under high vacuum.
To a solution of 4-Carbomethoxy-2,6-dimethylaniline (0.9 g) (from step B) and triethyl amine (2 ml) in methylene chloride (20 ml) at 0°C
was added the acid chloride in 10 ml of methylene chloride (2.4 g, 4.98 mmol) prepared in the above step. The reaction mixture was permitted to w 96!31492 PCT/US96/04759 warm to room te:mperture, was diluted with methylene chloride (50 ml) and was washed with 1 N HCI followed by saturated NaHCO~ solution.
The organic layer was dried over magnesium sulfate and the solvent removed giving the crude product. This was purified by column chromatography using 4:6 ethyl acetate and hexane as a eluent to give N-(4-chloro-3-methyl-5-isoxazolyl)-N-(methoxyethoxymethyl)2-(4-methoxycarbonyl!-2,6-dimethyl)phenylaminocarbonyl-3-thiophenesulfonamide an oil (0.6 g, 20% yield).
N-(4-chloro-3-methyl-5-isoxazolyl)-N-(methoxyethoxymethyl) 2-(4-methoxycarbonyl-2,6-dimethyl)phenylaminocarbonyl-3-thiophene-sulfonamide (0.6g) was dissolved in a mixture of methanol (8 ml) and concentrated HCI ( 1.5 ml) and the reultant reaction mixture was refluxed under stirring for 8 hours. Excess methanol was removed under reduced pressure and the residue dissolved in ethyl acetate (50 ml). This was washed with saturated sodium chloride solution. The organic layer was dried over magnesium sulfate and the solvent removed giving N-(4-chloro-3-methyl-5-isoxazolyl)-2-(4-methoxycarbonyl-2, 6-dimethyl)phenylamino-carbonyl-3-thiophenesulfonamide which was crystallized using methylene chloride and hexane 10.23 g, 47% yield, m.p' 152-154°C).

N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)-6-methyl)phenylaminocarbonyl-3-thiophenesulfonamide A. (3,4-rnethylenedioxy)-6-methyianiline To a solution of (3,4-methylenedioxy)toluene (5 ml) in acetic acid (20 ml) cooled with a cold water bath was added, dropwise, nitric acid (70%, 5 ml). The mixture was stirred for 45 min. To work up, water (100 ml) was added and the resulting yellow precipitate was filtered and washed with water until the aqueous filtrate was colorless. The yellow solid was dissolved in EtOAc (250 ml) and dried (MgS04), and the solid was filtered off. The filtrate was subjected to catalytic hydrogenation W. X6131492 ~ PCTIUS96/04759 (10% Pd/C, 1 atm) for 12 hours. The reaction mixture was then filtered off the catalyst and the filtrate was concentrated on a rotavap to give (3,4-methylenedioxy)-6-methylaniline as a brownish grey solid (5.49g, 87% yield).
B. N-(4~chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)-6-methyl]phenylaminocarbonyl-3-thiophenesulfonamide N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)-6-methyl]phenylaminocarbonyl-3-thiophenesulfonamide was synthesized in the same manner as Example 94 using (3,4-methylenedioxy)-6-methylaniline. The crude product was purified by preparative HPLC to give N-(4-chloro-~~-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)-6-methyl]phenylaminocarbonyl-3-thiophenesulfonamide as a yellow solid (45% yield, m.p. 60-62°C).

N-(4-chloro-3-methyl-5-isoxazolyl)-2-(3,4-dimethoxy-6-amino carbonyl)phenylarninocarbonyl-3-thiophenesulfonamide N-(4-chioro-3-methyl-5-isoxazolyl)-2-(3,4-dimethoxy-6-amino-carbonyl)phenylarninocarbonyl-3-thiophenesulfonamide was synthesized in the same manner as for Example 94 using N-(4-chloro-3-methyl-5-isoxazolyl)2-{[2-c<3rboxyl-4,5-(methylenedioxy)phenyl]aminocar-bonyl}thiophene-3-sulfonamide (Example 151 ) and ammonium hydroxide.
The crude product was purified by preparative HPLC to give N-(4-chloro-3-methyl-5-isoxazolyl)-2-(3,4-dimethoxy-6-aminocarbonyf)phenyl-aminocarbonyl-3-t:hiophenesulfonamide as yellow powder (66% yield, m.p. 189-192°C)..

t 96131492 ~ PCTIiJS96/04759 N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)-6-methyl]-pheny!acetyl-3-thiophenesulfonamide A. (3,4-methylenedioxyl-6-methylbenzyl chloride To a 1:1 mixture of ethyl ether (100 ml) and conc. HCI (100 ml) at 0°C was added (3,4-methylenedioxy)toluene (10 ml). Formaldehyde (20 ml, 37% in water) was then added dropwise. The reaction was stirred at 0°C for 2 hours and at room temperature for an additional 10 hours. The reaction mixture v~ras then diluted with ethyl ether (100 ml) and the two layers were separated. The organic layer was dried (MgS04), the solid was filtered and the filtrate was concentrated. The residue was then heated with hexane (200 ml) and the insolubles were filtered off the hot solution. The filtrate was concentrated to give a mixture of (3,4-methylenedioxy)-E~-methylbenzyl chloride (9.4 g, 63% yield) and bis[(3,4-methylenedioxy)-6.-methyl]phenylmethane (3.6 g) as a white solid. This mixture was carried on to the next step without further purification.
B. N-(4-~.hlorv-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)-6-meth~~i]pheny!acetyl-3-thiophenesulfonamide N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)-6-methyl]pheny!acetyl-3-thiophenesulfonamide was synthesized in the same manner as for Example 102 using (3,4-methylenedioxy)-6-methylbenzyl chloride instead of (3,4-methylenedioxy)benzyl chloride. The crude product was purified by preparative HPLC to give N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-l;methylenedioxy)-6-methyl]phenylacetyl-3-thiophenesulfonamide as a yellow powder (71 % yield, m.p. 42-45 °C) ' \ 96!31492 PCT/US96/04759 '~

EXAMPL>= 180 N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)-6-methanesuifonylaminomethyl]phenylaminocarbonyl-3-thiophene-sulfonamide A. N-(3,4-methylenedioxy)benzyl-methanesuifonamide To a solution of piperonylamine (6.07 g, 38.95 mmol) and triethylamine (5.37 g, 53.12 mmol) in dichloromethane (100 ml) at 0°C -was added methanesulfonyl chloride (4.14 g, 35.41 mmol). The reaction was stirred at 0°C for 7 hour. The mixture was then diluted with dichloromethane (100 ml) and washed with 1 N HCI (2 x 100 ml). The organic layer was dried (MgS04), the solid was filtered and the filtrate was concentrated to give N-(3,4-methylenedioxy)benzyl-methane-sulfonamide as a grey solid (8.4 g, 92% yield).
N-[:;~,4-(methylenedioxy)-6-amino]benzyl-methanesulfonamide N-[3,4-(methylenedioxy)-6-amino)benzyl-methanesulfonamide was synthesized in the same manner as for (3,4-methylenedioxy)-6-methyl-aniline (Example 177).
C. N-(4-chloro-3-methyl-5-isoxazolyl)-2-(3,4-(methylenedioxy)-6-methanesulfonylaminomethyl]phenylaminocarbonyl-3-thioF~henesulfonamide N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)-6-methanesulfonylanninomethyl]phenylaminocarbonyl-3-thiophene-sulfonamide was synthesized in the same manner as Example 94. The crude product was recrystalized from acetonitriie and water to give N-(4-chloro-3-methyl-5-~isoxazolyl)-2-[3,4-(methylenedioxy)-6-methanesulfonyl-aminomethyl]phenylaminocarbonyl-3-thiophenesulfonamide as an off-white solid (13% yield, m.p. 147-150°C).

/' _ _ 96131492 PCT/US96/04759 ~, N-(4-chloro-3-methyl-5-isoxazolyl)-2-(3,4-(methylenedioxy)-6-cyano-methyl]phenylamiinocarbonyl-3-thiophenesulfonamide A. [3,4-(methylenedioxy)-fi-amino]phenylacetonitrile (3,4-(methylenedioxy)-6-amino]phenylacetonitrile was synthesized in the same manner as for (3,4-methylenedioxy)-6-methylaniline (Example 177).
B. N-(4-chloro-3-methyl-5-isoxazolyl)-2-(3,4-(methylenedioxy)-6-cyanomethyl]phenylaminocarbonyl-3-thiophenesulfonamide N-(4-chloro-3-methyl-5-isoxazolyl)-2-(3,4-(methylenedioxy)-6-cyanomethyl]phenylaminocarbonyl-3-thiophenesulfonamide was synthesized in they same manner as in Example 94. The crude product was recrystalized from acetonitrile/water to give N-(4-chloro-3-methyl-5-isoxazolyl)-2-(3,4-(methylenedioxy)-fi-cyanomethyl]phenylaminocarbonyl-3-thiophenesulfonamide as a red-brownish powder (15% yield, m.p. 190-193°C).

N-(4-chloro-3-methyl-5-isoxazolyl)-Z-[3,4-(methylenedioxy)-S-(3-hydroxypropyl)]phienylaminocarbonyl-3-thiophenesulfonamide A. 3-(3,~4-methylenedioxy)phenyl-1-propanol To a solution of 3-(3,4-methylenedioxy)phenylpropanoic acid (5 g, 25.75 mmol) in anhydrous THF (20 ml) at 0°C was added BH3~THF (51.5 ml, 1.0 M in THF, 51.5 mmol). The mixture was refluxed.for.1 hour.
Then the THF was evaporated on a rotavap. The residue was treated with methanol (20 ml) and the solution was concentrated. This process was repeated 6 times t;o give 3-(3,4-methylenedioxy)phenyl-1-propanol as an oil (4.7g, -100 yield).

WO 96131492 PCTIUS9G/04759 ' ' B. 3-(3,4-(methylenedioxy)-6-amino)phenyl-1-propanol 3-[3,4-(metlnylenedioxy)-6-amino]phenyl-1-propanol was synthesized in the same manner as for (3,4-methyfenedioxy)-6-methylaniline (Example 177).
C. N-(4-~.hloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)-~6-(3-hy~droxypropyl)]phenylaminocarbonyl-3-thiophene-sulfonamide N-(4-chloro-3-methyl-5-isoxazolyl)-2-(3,4-(methylenedioxy)-6-(3-hydroxypropyl)]ph~enylaminocarbonyl-3-thiophenesulfonamide was synthesized in the same manner as Example 94. The crude product was purified by preparative HPLC to give N-(4-chloro-3-methyl-5-isoxazolyl)-2-(3,4-(methylenedioxy)-6-(3-hydroxypropyl)]phenylaminocarbonyl-3-thiophenesulfonamide as a dull yellow powder (18% yield, m.p. 66-69°C).

N-(4-chloro-3-methyl-5-isoxazolyl)-2-(3,4-(methylenedioxy)-6-cyano)phenylacetyl-3-thiophenesulfonamide A. Methyl (3,4-methylenedioxy)phenylacetate Methyl (3,4-methylenedioxy)phenylacetate was prepared as described by known methods (see, Rachele (1963) Journal of Organic Chemistry 28:2898).
B. Methyl B-~bromo-(3,4-methylenedioxy)phenylacetate To a solution of methyl (3,4-methylenedioxy)phenylacetate (5 g, 25.8 mmol) in acetic acid (15 ml) was added, dropwise, bromine until a red-brown color persisted. After stirring at RT for 30 minutes, the reaction mixture was partitioned between water (200 ml) and ether (200 ml). The organic layer was washed with water (3 x 200 ml), dried (MgSO,), the solid 'was filtered off and the filtrate was concentrated to give methyl 6-bromo-(3,4-methylenedioxy)phenylacetate as an oil (5.9 g, 84% yield). .

~. ~ 96/31492 PCT/US96I04759 ~~-C. Methyl (3,4-methyienedioxy)-6-cyanophenylacetate Methyl (3,4-methylenedioxy)-6-cyanophenylacetate was prepared as described by L. Friedman and H. Shechter in the Journal of Organic Chemistry 26:2522 (1961).
D. t-Butyl (3,4-methylenedioxy)-fi-cyanophenylacetate To a solution of methyl (3,4-methylenedioxy)-6-cyanophenylacetate (5 g, 18.32 mmol) in methanol (100 ml) was added 1 N NaOH (50 ml).
The reaction was stirred at room temperature for 1.5 hours. Methanol was then stripped off on a rotavap. The aqueous residue was acidified with conc. HCI to pH - 1 and extracted with ethyl acetate. The organic layer was dried (NlgSO'), the solid was filtered and the filtrate was concentrated to give a solid. The solid was treated with thionyl chloride (50 ml) and the mixture was refluxed for 10 min before the volatiles were stripped off on a rotavap. The residue was dissolved in dichloromethane (15 ml) and the solution was added dropwise to a solution of 2-methyl-2-propanol (6.8 g, 91.6 mmol) and triethylamine (9.3 g, 91.6 mmol) in dichloromethane ('100 ml) at 0°C. The mixture was stirred at 0°C
for 1 hour and at room temperature for 2 hours. The mixture was then washed with water (3x150 ml). The organic layer was dried (MgS04), the solid was filtered and the filtrate was concentrated to give t-butyl (3,4-methylenedioxy)-6-cyanophenylacetate as a solid (335 mg, 7% yield).
E. N-(4-c:hloro-3-methyl-5-isoxazolyl)-2-(3,4-(methylenedioxy)-6-cyanc~]pheny!acetyl-3-thiophenesulfonamide To a solution of N-(4-chloro-3-methyl-5-isoxazolyl)-2-carboxyl-3-thiophenesulfonamide (2.78 g, 8.63 mmol) in anhydrous DMF (30 ml) was added carbon~~ldiimidazole (1.40 g, 8.63 mmol). The mixture was stirred at room temperature for 20 min to give mixture I.
To a solution of t-butyl (3,4-methylenedioxy)-6-cyanophenylacetate (1.5 g, 5.75 mmol) in anhydrous DMF (15 m!) was added NaH (1.2 g, 60% dispersion in mineral oil, 29.9 mmol) at 0°C. The mixture was ~, ~ 96!31492 ~ PCT/US96/04759 stirred at room temperature for 30 min to give mixture II. Mixture I
was syringed to mixture II at 0°C and the resulting mixture was stirred at 0°C for 1 hour and at RT for 10 hours. The crude mixture was poured to a 2:2:1 mixture of acetonitrile/water/conc. NCI and the resulting mixture was heated at 40°C for 12 hours. Acetonitrile was then removed on a rotavap and the ~3queous residue was partitioned between ethyl acetate (200 ml) and 1 N HCI (150 ml). The organic layer was washed with 1 N
HCI (3 x 150 ml) and dried (MgS04), the solid was filtered off and the filtrate was concentrated. The residue was purified by preparative HPLC
to give N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)-6-cyano]pheny!acetyl-3-thiophenesulfonamide as a light dull yellow powder (450 mg, 17% yield, m.p. 105-108°C).

N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)-6-dimethylaminocarbonyimethyl]phenylaminocarbonyl-3-thiophene-sulfonamide A. N,N-~dimethyl (3,4-methylenedioxy)phenylacetamide N,N-dimethyl (3,4-methylenedioxy)phenylacetamide was synthesized in the same manner as described in Example 94.
B. N,N-dimethyl (3,4-methylenedioxy)-6-aminophenylacetamide N,N-dimethyl (3,4-methylenedioxy)-6-aminophenylacetamide was synthesized in the same manner as (3,4-methylenedioxy)-6-methylaniline (see Example 177).
C. N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)-6-dime:hylaminocarbony!methyl]phenylaminocarbonyl-3-thiopihenesulfonamide N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)-6-dimethylaminocarbonylmethyl]phenylaminocarbonyl-3-thiophene-sulfonamide was synthesized in the same manner as Example 94. The crude product wa:; recrystalized from acetonitrile/water to give N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)-6-dimethylamino-t 96r31492 ~ PCT/US96104759 carbonylmethyl]phenylaminocarbonyl-3-thiophenesulfonamide as a greyish powder ( 400 m~g, 19% yield, m.p. 190-193°C).

N-(4-chloro-3-methyl-5-isoxazolyl)-2-(3,4-(methylenedioxy)-6-methyl]phenylhydroxyimino-3-thiophenesulfonamide To N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)-6-methyl]phenylacetyl-3-thiophenesulfonamide f100 mg) was added NHZOH~HCI (30O mg) and water (15 ml). After stirring for 5 min, NaOH
pellet (300 mg) and methanol (2 ml) were added. The warm mixture was heated at 80°C for 20 min and was cooled to 0°C. It was then poured into a dilute HCI solution ( - 30 ml). The resulting white precipitate was filtered to give N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)-6-methyl]phenylhydroxyimino-3-thiophenesulfonamide as a white solid ( 72 mg, 70% yield, m.p. 154-156°C).
~ 5 EXAMPLE 186 N-(4-chloro-3-methyl-5-isoxazolyl)-2-{1-acetoxy-2- cis-[3,4-(methylenedioxy)-6-methyl]phenyl}vinyl-3-thiophenesulfonamide To a solution of N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)~-6-methyl]phenylacetyl-3-thiophenesulfonamide (50 mg, 0.11 mmol) in anhydrous DMF (1 ml) was added NaH (11 mg, 60%
dispersion in mineral oil, 0.275 mmol). After stirring at room temperature for 5 min, acetic anhydride ( 16.8 mg, 0.165 mmol) was added. After stirring at room temperature for an additional 10 min., the mixture was poured into dilute HCI solution and the resulting precipitate was filtered to give N-(4-chloro-a-methyl-5-isoxazolyl)-2-{1-acetoxy-2- cis-[3,4-(methylenedioxy)-6-methyl]phenyl}vinyl-3-thiophenesulfonamide as a yellowish powder (40 mg, 73%, m.p. 55-58°C).

A .r 96/31492 PC'T/US96/04759 ' N-(4-chloro-3-methyl-5-isoxazolyl)-2-( 1,2.3-trimethoxy-6-cyano)phenylaminocarbonyl-3-thiophenesulfonamide A. 2-amino-3,4,5-trimethoxybenzonitrile 2-amino-3,~4, 5-trimethoxybenzonitrile was synthesized in the same manner as (3,4-methylenedioxy)-6-methylaniline (see Example 177), and the crude product was recrystalized from methanol/water to give a yellow powder (13% yield).
B. N-(4-chloro-3-methyl-5-isoxazolyl)-2-(1,2,3-trimethoxy-fi-cyan~o)phenylaminocarbonyl-3-thiophenesulfonamide N-(4-chloro-3-methyl-5-isoxazolyl)-2-( 1,2,3-trimethoxy-6-cyano)phenyfaminocarbonyl-3-thiophenesulfonamide was synthesized in the same manner as Example 148. The crude product was purified via preparative HPLC to give N-(4-chloro-3-methyl-5-isoxazolyl)-2-(1,2,3-tri-methoxy-6-cyano)phenylaminocarbonyl-3-thiophenesulfonamide as a yellow powder (180 mg, 10% yield, m.p. 88-90°C).

N-(3,4-dimethyl-5-isoxazolyl)-2-(3,4-(methylenedioxy)-6-methyl]-phenylacetyl-3-thiophenesulfonamide N-(3,4-dimethyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)-6-methyl)phenylacetyl-3-thiophenesulfonamide was synthesized in the same manner as Example 179. The crude product was purified via preparative HPLC to give N-(3,4-dimethyl-5-isoxazolyl)-2-(3,4-(methylenedioxy)-6-methyl]phenylacetyl-3-thiophenesulfonamide as a yellow powder (417 mg, 14% yield, m"p. 45-50°C).

A !6I31492 PCTlUS96104759 N-(4-chlo~o-5-methyl-3-isoxazolyl)-2-[3,4-(methylenedioxy)-6-methyl]-phenylacetyl-3-thiophenesulfonamide N-(4-chloro-5-methyl-3-isoxazolyl)-2-(3,4-(methylenedioxy)-6-methyl]phenylacEayl-3-thiophenesulfonamide was synthesized in the same manner as Example 179.. The crude product was purified via preparative HPLC to give N-(4-chlora-5-methyl-3-isoxazolyl)-2-[3,4-(methylened;oxy)-6-methyl]phenylacetyl-3-thiophenesulfonamide as a yellowish powaer (330 mg, 16% yield, m.;p. 46-50°C).

Other compounds that have been prepared by the above methods or routine modifications 'thereof, include, but are not limited to:
N-(4-chloro-3-methyl-5-isoxazolyl)-2-[(4-methoxyphenoxy)carbonyl]thio-phene-3-sulfonannide, N-(4-bromo-3-methyl-5-isoxazolyl)-2-((4-methylphenoxy)carbonyl]thiophene-3-sulfonamide, N-(4-bromo-3-methyl-5-isoxazofyl)-3-[(.4-methylphenoxy)methyl]thiophene-2-sulfonamide, N-(4-bromo-3-methyl-!~-isoxazolyl)-2-[(4-methylphenoxy)methyl]thiophene-3-sulfonamide, N-(~~-bromo-3-methyl-5-isoxazolyl)-3-(4-methyl-tans-styryl)-thiophene-2-sulfonamide, N-(4-bromo-3-methyl-5-isoxazolyl)-3-(4-methyl-phenethyl)thiophene-2-sulfonamide, N-(4-bromo-3-methyl-5-isoxazolyl)-2-[(4-methylphenyl'lacetyl]thiophene-3-sulfonamide, N-(4-bromo-3-methyl-5-isoxazolyl)-2-[(3-i~nethox~,rphenyl)acetyl]thiophene-3-sulfonamide, N-(4-bromo-3-methyl-!5-isoxazolyl)-3-(4-methylphenethyl)-5-(4-tolyl)thiophene-2-sulfonamide, N-(4-bromo-3-methyl-5-isoxazolyl)-3-(4-methylbenzyl)-5-(4-tolyl)thiophene-2-sulfonamide, N-(4-bromo-3-methyl-5-isoxazolyl)-3-(4-methyl-traps-styryl)-5-(4-~tolyl)thiophene-2-sulfonamide, N-(4-chloro-3-methyl-5-isoxazolyl)-2-(3,4-(methyienedioxy)benzyl]thiophene-3-sulfona-mide, N-(4-chlora-3-methyl-5-isoxazolyl)-2-((5-methyl-3-isoxazolyl)amino-carbonyl)thiophene-3-sulfonamide, N-(4-bromo-3-methyl-5-isoxazolyl)-2-((3-hydroxyl-6-pyridazinyl)aminocarbonyl)thiophene-3-sulfonamide, N-(4-r' A .. 96131492 PCT/US96/04759 bromo-3-methyl-5-isoxazolyl)-3-{(3,4-(methylenedioxy)phenoxy]methyl}-thiophene-2-sulfonamide, N-(4-bromo-3-methyl-5-isoxazolyl)-2-[(4-methyl)(cinnamyl)] thiophene-3-sulfonamide, N-(4-bromo-3-methyl-5-isoxazolyl)-3-[3,~4-(methylenedioxy)phenethyl]thiophene-2-sulfonamide, N-(4-bromo-3-methyl-5-isoxazolyl)-3-(3,4-(methylenedioxy)-trans-styryl]thiophene-~2-sulfonamide, N-(4-bromo-3-methyl-5-isoxazolyl)-2-((4-methyl)phenethyl]thiophene-3-sulfonamide, N-(3,4-dimethyl-5-isoxazolyl)-2-(4-tolylacetylplnenyl)thiophene-3-sulfonamide, N-(3,4-dimethyl-5-isoxazolyl)-2-[3,~~-(methylenedioxy)phenylacetyl]thiophene-3-sulfonamide, N-(4-chloro-3-methyl-5-isoxazolyl)-2-[2-hydroxy-4-methylphenyl)aminocar bonyl]thiophene-3-sulfonamide and others, including those set forth in TABLE 1 that are: not specifically exemplified herein.
For example, N-(4-bromo-3-methyl-5-isoxazolyl)-3-(2-methyl-4, 5-(methylenedioxy)cinnamyl]thiophene-2-sulfonamide, N-(4-bromo-3-methyl-5-isoxazolyl)-3-[2;-(hydroxymethyl)-4,5-(methyleriedioxy)-cinnamyl]thiophene-2-sulfonamide, N-(4-bromo-3-methyl-5-isoxazolyl)-3-{2-((tetrahydro-4~H-pyran-2-ylxoy)methyl]-4,5-(methylenedioxy)cinnamyl}-thiophene-2-sulfonamide and N-(4-bromo-3-methyl-5-isoxazolyl)-3-(2,4-dimethylcinnamyl)thioph~ane-2-sulfonamide have been prepared in the same manner as '~N-(4-bromo-3-methyl-5-isoxazolyl)-3-[3,4-(methylenedioxy)-traps-styryl]thiophene-2-sulfonamide. N-(4-bromo-3-methyl-5-isoxazolyl)-3-[2-methyl-4,5-(methylenedioxy)phenethyl]thio-phene-2-sulfonamide and N-(4-bromo-3-methyl-5-isoxazolyl)-2-(2,4,6-trimethylphenethyl)thiophene-3-sulfonamide have been prepared in the same manner as IV-(4-bromo-3-methyl-5-isoxazolyl)-2-[(4-methyl)-phenethyl)thiophene-3-sulfonamide (see, Example 159). N-(4-bromo-3-methyl-5-isoxazolyl)-3-{(:?-propyl-4, 5-(methylenedioxy)-phenoxy]methyl}thiophene-2-sulfonamide has been prepared in the same manner as N-(4-bromo-3-methyl-5-isoxazolyl)-3-[(4-methylphenoxy)-'. J 96/31492 PCT/US96104759 I

methyl]thiophene-2-sulfonamide and N-(4-bromo-3-methyl-5-isoxazolyl)-3-{[3,4-(methylen~edioxy)phenoxy]methyl}thiophene-2-sulfonamide. N-(4-bromo-3-methyl-5-isoxazolyl)-2-[2-methyl-4, 5-(methylenedioxy)F~heneth~yl]thiophene-3-sulfonamide has been prepared in the same manner as N-(4-bromo-3-methyl-5-isoxazolyl)-2-[(3,4-methylenedioxy)phenethyl]thiophene-3-sulfonamide. Compounds, such as N-(4-bromo-3-rnethyl-Fi-isoxazolyl)-3-(2-tolyl)thiophene-2-sulfonamide, N-(4-bromo-3-methyl-5-isoxazolyl)-3-(3-tolyl)thiophene-2-sulfonamide, N-(4-bromo-3-methyl-5-isoxazolyl)-3-(2-tolyl)thiophene-2-sulfonamide, N-(4-bromo-3-methyl-5-isoxazolyl)-3-(3-methoxyphenyl)thiophene-2-sulfonamide, N-(4-bromo-3-methyl-5-isoxazolyl)-3-(3-methoxyphenyl)thiophene-2-sulfonamide, N-(4-bromo-3-methyl-5-isoxazolyl)-3-(2-methoxyphenyl)thiophene-2-sulfonamide, N-(4-bromo-3-methyl-5-isoxazolyl)-3-(4-ethylphenyl)thiophene-2-sulfonamide, N-(4-bromo-3-methyl-5-isoxazolyl)-3-(4-propylphenyl)thiophene-2-sulfonamide, N-(4-bromo-3-methyl-5-isoxazolyl)-3-(4-iso-propylphenyl)thiophene-2-sulfonamide, N-(4-bromo-:3-methyl-5-isoxazolyll-3-(4-butylphenyl)-thiophene-2-sulfonamide, N-(4-bromo-3-methyl-5-isoxazolyl)-3-(2,4-dimethylphenyl)thiophene-2-sulfonamide, N-(4-bromo-3-methyl-5-isoxa-zolyl)-3-(4-iso-but,rlphenyl)thiophene-2-sulfonamide, N-(4-bromo-3-methyl-5-isoxazolyl)-3-(4-iso-pentylphenyl)thiophene-2-sulfonamide, N-(4-bromo-3-methyl-5-isoxazolyl)-3-(2-methyl-4-propylphenyl)thiophene-2-sulfon-amide, N-(4-bromo-3-methyl-5-isoxazolyl)-3-(4-iso-butyl-2-methylphenyl)-thiophene-2-sulfonamide .and N-(4-bromo-3-methyl-5-isoxazolyl)-3-(4-iso-pentyl-2-methylphenyl)thiophene-2-sulfonamide have been prepared in the same manner as ~J-(4-bromo-3-methyl-5-isoxazolyl)-3-[(3,4-methylene-dioxy)phenyl]thioE~hene-2~-sulfonamide (see, Example 125).
N-(4-bromo-3-methyl-5-isoxazolyl)-2-(2-methyl-4,5-(methylene-dioxy)phenethyl]thiophene-3-sulfonamide has been prepared in the same ~.r 96131492 PCTlUS96104759 manner as N-(4-Bromo-3-methyl-5-isoxazolyl)-2-(3,4-(methylene-dioxy)phenethyl]thiophene-3-sulfonamide (Example 128). N-(4-bromo-3-methyl-5-isoxazolyl)-2-(2-methyl-4, 5-(methylenedioxy)cinnamyl]thiophene-3-sulfonamide has been prepared in the same manner as N-(4-bromo-3-methyl-5-isoxazolyl)-2-((4-methyl)(cinnamyl)] thiophene-3-sulfonamide (Example 158).
N-(4-bromo-3-methyl-5-isoxazolyl)-2-{[3,4-(methylenedioxy)-phenoxy]methyl}thioph~ene-3-sulfonamide, N-(4-bromo-3-methyl-5-isoxazolyl)-2-[(2,4, frtrirnethylphenoxy)methyl]thiophene-3-sulfonamide, N-(4-bromo-3-methyl-5-isoxazolyl)-2-{[4,5-(methylenedioxy)-2-propyl-phenoxy]methyl}thiophene-3-sulfonamide have been prepared in the same manner as N-(4-bromo-:3-methyl-5-isoxazolyl)-2-((4-methylphenoxy)-methyl]thiophene-3-sulfonamide (Example 160).
Any corresponding N-(4-halo-3-methyl-5-isoxazolyl), N-(4-halo-5-methyl-3-isoxazolyl), N-(3,4-dimethyl-5-isoxazolyl), N-(4-halo-5-methyl-3-isoxazolyl), N-(4-halo-3-methyl-5-isoxazolyl), N-(4,5-dimethyl-3-isoxazolyl) derivative of any of there compounds or any compound dislosed herein may also be prepared and used as described herein.

Other compounds that can be prepared by the above methods or routine modifications thereof, include, but are not limited to: .
N-(4-chloro-3-mEahyl-5-isoxazolyl)-2-(2,3,4-trimethoxy-6-methylphenyl-aminocarbonyl)thiophene-3-sulfonamide, N-(4-chloro-3-meahyl-5-isoxazolyl)-2-(2, 3,4-trimethoxy-6-acetylphenylaminocarbonyl)thiophene-3-sulfonamide, N-(4-chloro-3-mEahyl-5-isoxazolyl)-2-(2, 3,4-trimethoxy-6-methoxy-carbonylphenylaminocarbonyl)thiophene-3-sulfonamide, N-(4-chloro-3-methyl-5-isoxazolyl)-2-(2,3,4-trimethoxy-6-carboxylphenylaminocarbonyl)thiophene-3-sulfonamide, N-(4-chloro-3-methyl-5-isoxazolyl)-2-(2, 3,4-trimethoxy-6-methanesulfonylphenylaminocarbonyl)thiophene-3-sulfonamide, N-(4-chloro-3-methyl-5-isoxazolyl)-2-(2,3,4-trimethoxy-6-(cyanomethyl)phenylaminocarbonyl]thiophene-3-sulfonamide, N-(4-chloro-3-methyl-5-isoxazolyl)-2-(2,3,4-trimethoxy-6-(2-hydroxyethyl)phenylaminocarbonyl]thiophene-3-sulfonamide, N-(4-chloro-3-methyl-5-isoxazolyl)-2-(3,4-(methylenedioxy)-2-methoxy-6-methylphenylaminocarbonyl]thiophene-3-sulfonamide, N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)-2-metho;cy-6-acetylphenylaminocarbonyl]thiophene-3-sulfonamide, N-(4-chloro-3-methyl-5-isoxazolyl)-2-(3,4-(methylenedioxy)-2-methoxy-6-methoxycarbonylphenylaminocarbonyl]thiophene-3-sulfonamide, N-(4-chloro-3-methyl-5-isoxazolyl)-2-(3,4-(methylenedioxy)-2-methoxy-6-carboxylphenylaminocarb~onyl]thiophene-3-sulfonamide, N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxyl-2-methoxy-6-methanesulfonylphenylaminocarbonyl]thiophene-3-sulfonamide, N-(4-chloro-3-methyl-5-isoxazolyl)-2-(3,4-(methylenedioxy)-2-methoxy-6-cyanophenylamin~~carbonyl]thiophene-3-sulfonamide, N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)-2-methoxy-6-cyanomethylphenylaminocarbonyl]thiophene-3-sulfonamide, N-(4-chloro-3-met:hyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)-2-methoxy-6-(2-hydroxyethyl)phenylarninocarbonyl]thiophene-3-sulfonamide, N-(4-chloro-3-met:hyl-5-isoxazolyl)-2-(3,4-(methylenedioxy)-2, 6-dimethylphenylaminocarbonyl]thiophene-3-sulfonamide, N-(4-chloro-3-met:hyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)-6-acetyl-2-methylphenylaminocarbonyl)thiophene-3-sulfonamide, N-l4-chloro-3-met:hyl-5-isoxazolyl)-2-(3,4-(methylenedioxy)-6-methoxycarbonyl~-2-methylphenylaminocarbonyl]thiophene-3-sulfonamide, N-(4-chloro-3-methyl-5-isoxazolyl)-2-(3,4-(methylenedioxy)-6-carboxyl-2-methylphenylaminocarbonylJthiophene-3-sulfonamide, N-(4-chloro-3-methyl-5-isoxazolyl)-2-(3,4-(methylenedioxy)-6-methoxy-2-methylphenylaminocarbonyl]thiophene-3-sulfonamide, N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)-6-methanesulfonyl-2-methylphenylaminocarbonyl]thiophene-3-sulfonamide, N-(4-chloro-3-methyl-5-isoxazolyl)-2-(3,4-(methylenedioxy)-6-cyano-2-methylphenylaminocarbonyl]thiophene-3-sulfonamide, N-(4-chloro-3-methyl-5-isoxazolyl)-2-(3,4-(methylenedioxy)-6-(cyanomethyl)-2-methylphenylaminocarbonyl)thiophene-3-sulfonamide, N-(4-chloro-3-methyl-5-isoxazolyl)-2-(3,4-(methylenedioxy)-6-(2-hydroxyethyl)-2-methylphenylaminocarbonyl)thiophene-3-sulfonamide, N-(4-chloro-3-methyl-5-iscrxazolyl)-2-(3,4-(methylenedioxy)-2-cyano-6-methylphenylamin~~carbonyl]thiophene-3-sulfonamide, N-(4-chloro-3-methyl-5-isoxazolyl)-2-(3,4-(methylenedioxy)-6-methoxy-2-cyanophenylaminc~carbonyl]thiophene-3-sulfonamide, N-(4-chloro-3-methyl-5-isoxazolyl)-2-(3,4-(methylenedioxy)-2-acetyl-6-methylphenyfamin~~carbon~yl]thiophene-3-sulfonamide, N-(4-chloro-3-methyl-5-isoxazolyl)-2-(3,4-(methylenedioxy)-6-methoxy-2-acetylphenylaminc~carbonyl]thiophene-3-sulfonamide, N-(4-chloro-3-methyl-5-isoxazolyl)-2-(3-cyano-2,4, 6-trimethyl-phenylaminocarbonyl]thiophene-3-sulfonamide, N-(4-chloro-3-methyl-5-isoxazolyl)-2-(3-carboxyl-2,4, 6-trimethylphenylaminocarbonyl]thiophene-3-sulfonamide, N-(4-chloro-3-methyl-5-isoxazolyl)-2-(3-hydroxymethyl-2,4,6-trimethylphenylaminocarbonyl]thiophene-3-sulfonamide, N-(4-chloro-3-methyl-5-isoxazolyl)-2-(3-methanesulfonyl-2,4,6-trimethylphenylam~inocarbonyl]thiophene-3-sulfonamide, . 96131492 PCTl1JS96I04759 N-(4-chloro-3-methyl-5-isoxazolyl)-2-(3-cyanomethyl-2,4, 6-trimethylphenylarninocarbonyl]thiophene-3-sulfonamide, N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3-(2-hydroxyethyl)-2,4, 6-trimethylphenylaminocarbonyl]thiophene-3-sulfonamide, N-(4-chloro-3-methyl-5-isoxazolyl)-2-(3-(carboxylmethyl)-2,4,6-trimethylphenylaminocarbonyl]thiophene-3-sulfonamide, N-(4-chloro-3-methyl-5-isoxazolyl)-2-(4-cyano-2, 6-dimethylphenylanninocarbonyl)thiophene-3-sulfonamide, N-(4-chloro-3-methyl-5-is;oxazolyl)-2-(4-carboxyl-2, 6-dimethylphenylanninocarbonyl)thiophene-3-sulfonamide, N-(4-chloro-3-methyl-5-is~oxazolyl)-2-[4-(hydroxymethyl)-2, 6-dimethylphenylanninocarbonyllthiophene-3-sulfonamide, N-(4-chloro-3-methyl-5-is~oxazolyl)-2-(4-(2-hydroxyethyl)-2, 6-dimethylphenylanninocarbonyl]thiophene-3-sulfonamide, N-(4-chloro-3-methyl-5-is~oxazolyl)-2-(4-(cyanomethyl)-2,6-dimethylphenylanninocarbonyl]thiophene-3-sulfonamide, N-(4-chloro-3-methyl-5-isoxazolyl)-2-[4-(carboxylmethyl)-2, 6-dimethylphenylanninocarbonyl]thiophene-3-sulfonamide, N-(4-chloro-3-methyl-5-isoxazolyl)-2-(4-methanesulfonyl-2, 6-dimethylphenylanninocart>onyl)thiophene-3-sulfonamide, N-(4-chloro-3-methyl-5-is~oxazolyl)-2-(2, 3,4-trimethoxy-6-methylphenylacei:yl)thiophene-3-sulfonamide, N-(4-chloro-3-methyl-5-is~oxazolyl)-2-(2,3,4-trimethoxy-6-acetylphenylacet~,rl)thiophene-3-sulfonamide, N-(4-chloro-3-methyl-5-is;oxazolyl)-2-(2,3,4-trimethoxy-6-methoxycarbonylphenylacetyl)thiophene-3-sulfonamide, N-(4-chloro-3-methyl-5-isoxazolyl)-2-(2, 3,4-trimethoxy-6-carboxylphenylacetyl)thiophene-3-sulfonamide, Wv 96131492 PCT/US96104759 N-(4-chloro-3-methyl-5-isoxazolyl)-2-(2, 3,4-trimethoxy-6-methanesulfonylp~henylacetyl)thiophene-3-sulfonamide, N-(4-chloro-3-methyl-5-isoxazolyl)-2-[2, 3, 4-trimethoxy-6-(cyanomethyl)phenylacetyl)thiophene-3-sulfonamide, N-(4-chloro-3-methyl-5-isoxazolyl)-2-(2, 3,4-trimethoxy-fi-(2-hydroxyethyl)phenylacetyljthiophene-3-sulfonamide, N-(4-chloro-3-methyl-5-isoxazolyl)-2-(3,4-(methylenedioxy)-2-methoxy-6-methylphenylacetyljthiaphene-3-sulfonamide, N-(4-chloro-3-methyl-5-isoxazolyl)-2-(3,4-(methylenedioxy)-2-methoxy-6-acetylphenylacetyiljthiophene-3-sulfonamide, N-(4-chloro-3-methyl-5-isoxazolyl)-2-(3,4-(methylenedioxy)-2-methoxy-6-methoxycarbonylphenylacetyljthiophene-3-sulfonamide, N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)-2-methoxy-6-carboxylphenylacetyljthiophene-3-sulfonamide, N-(4-chloro-3-methyl-5-isaxazolyl)-2-[3,4-(methylenedioxy-2-methoxy-6-methanesulfonyl)phenylacetyljthiophene-3-sulfonamide, N-(4-chloro-3-methyl-5-isoxazolyl)-2-(3,4-(methylenedioxy)-2-methoxy-6-(cyano)phenylacetyljthiophene-3-sulfonamide, N-(4-chloro-3-methyl-5-isaxazolyl)-2-(3,4-(methylenedioxy)-2-methoxy-6-(cyanomethylphenylacetyljthiophene-3-sulfonamide, N-(4-chloro-3-metfnyl-5-isoxazolyl)-2-(3,4-(methylenedioxy)-2-methoxy-6-(2-hydroxyethyl)phenylacetyl)thiophene-3-sulfonamide, N-(4-chloro-3-methyl-5-isoxazolyl)-2-(3,4-(methylenedioxy)-2, 6-dimethylphenylacetyl]thiophene-3-sulfonamide, N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)-6-acetyl-2-methylphenylacetyljthiophene-3-sulfonamide, N-(4-chloro-3-methyl-5-isoxazolyl)-2-(3,4-(methylenedioxy)-6-methoxycarbonyl-2'.-methyiphenylacetyljthiophene-3-sulfonamide, 96!31492 N-(4-chloro-3-methyl-5-isoxazolyl)-2-(3,4-(methylenedioxy)-6-carboxyl-2-methylphenylac:etyl]thiophene-3-sulfonamide, N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)-6-methoxy-2-methylphenylacetyl]thiophene-3-sulfonamide, N-(4-chloro-3-methyl-5~-isoxazolyl)-2-(3,4-(methylenedioxy)-6-methanesulfonyl-2-methylphenylacetyl]thiophene-3-sulfonamide, N-(4-chloro-3-methyl-5~-isoxazolyl)-2-(3,4-(methylenedioxyl-6-cyano- 2-methylphenylacetyl]thiophene-3-sulfonamide, N-(4-chloro-3-methyl-5-isoxazolyl)-2-(3,4-(methylenedioxy)-6-(cyanomethyl)-:?-methylphenylacetyl]thiophene-3-sulfonamide, N-(4-chloro-3-methyl-5-~isoxazolyl)-2-(3,4-(methylenedioxy)-6-(2-hydroxyethyl)-2-methylphenylacetyl]thiophene-3-sulfonamide, N-(4-chloro-3-methyl-5-~isoxazolyl)-2-[3,4-(methylenedioxy)-2-cyano-6-methylphenylacetyl]thiophene-3-sulfonamide, N-(4-chloro-3-methyl-5-~isoxazolyl)-2-(3,4-(methylenedioxy)-6-methoxy-2-cyanophenylaceayl]thiophene-3-sulfonamide, N-(4-chloro-3-methyl-5-~isoxazolyl)-2-[3,4-(methylenedioxy)-2-acetyl-6-methylphenylacetyl]thiophene-3-sulfonamide, N-(4-chloro-3-methyl-5-~isoxazolyl)-2-[3,4-(methylenedioxy)-6-methoxy-2-acetylphenylacetyl]thiophene-3-sulfonamide, N-(4-chloro-3-methyl-5-isoxazolyl)-2-(3-cyano-2,4,6-trimethylphenyl;acetyi)thiophene-3-sulfonamide, N-(4-chloro-3-methyl-5-isoxazolyl)-2-(3-carboxyl-2,4,6-trimethylphenyl~3cetyl)thiophene-3-sulfonamide, N-(4-chloro-3-methyl-5-isoxazolyl)-2-(3-hydroxymethyl-2,4,6-trimethylphenyl;~cetyl)thiophene-3-sulfonamide, N-(4-chloro-3-methyl-5-isoxazolyl)-2-(3-methanesulfonyl-2,4,6-trimethylphenyl~3cetyl)thiophene-3-sulfonamide, ;' PGTIUS96104759 ~.~ 96!31492 N-(4-chloro-3-rnethyl-5-isoxazolyl)-2-(3-(cyanomethyl)-2,4, 6-trimethyiphenylacetyl]thiophene-3-sulfonamide, N-(4-chloro-3-rnethyl-5-isoxazolyl)-2-(3-(2-hydroxyethyl)-2,4, 6-trimethylphenylacetyl)thiophene-3-sulfonamide, N-(4-chloro-3-rnethyl-5-isoxazolyl)-2-(3-(carboxylmethyl)-2,4,6-trimethylphenylacetyl]thiophene-3-sulfonamide, N-(4-chloro-3-rnethyl-5-isoxazolyl)-2-(4-cyano-2, 6-dimethylphenylacetyl)t:hiophene-3-sulfonamide, N-(4-chloro-3-rnethyl-5-isoxazolyl)-2-(4-carboxyl-2; 6-dimethylphenylacetyl)t:hiophene-3-sulfonamide, N-(4-chloro-3-nnethyl-~i-isoxazolyl)-2-(4-hydroxymethyl-2, 6-dimethylphenylacetyl)thiophene-3-sulfonamide, N-(4-chloro-3-methyl-5-isoxazolyl)-2-[4-(2-hydroxyethyl)-2, 6-(dimethyl)phenylacetyl]thiophene-3-sulfonamide, N-(4-chloro-3-methyl-5-isoxazolyl)-2-[4-cyanomethyl-2,6-(dimethyl)phenylacetyl]thiophene-3-sulfonamide, N-(4-chloro-3-methyl-5.-isoxazolyl)-2-[4-(carboxylmethyl)-2, 6-dimethylphenylacetyl]thiophene-3-sulfonamide, and N-(4-chloro-3-methyl-5~-isoxazolyl)-2-(4-methanesulfonyl-2,6-dimethylphenylacetyl)thiophene-3-sulfonamide.

Other compounds, having activity generally at ICso concentrations of 10 NM or substantially less for ETA or ET8 receptors, in which Arz contains a heterocyclic: ring, such as thienyl-, fury!- and pyrrole-sulfona-mides of interest herein, can be or have been prepared (see, e-4., TABLE
1 ) by methods analogous to those set forth in the above Examples. Such compounds include, but are not limited to the following compounds: N-(4-bromo-3-methyl-5-isoxazolyl)-2-carboxyl-1-methylindole-3-sulfonamide, N-(4-chloro-3-methyl-5-isoxazolyl)-2-((4-oxacyclohexyl)oxycarbonyl]thio-.. J 96131492 PGTIUS96/04759 phene-3-sulfonamide, 2-[3,4-(methylenedioxy)phenylacetyl]thiophene-3-sulfonamide, N-(4-chloro-3-methyl-5-isoxazolyl)-{2-[3,4-(methylenedioxy)-phenyl]acetyl}thiophene-3-sulfonamide oxime, N-(4-chloro-3-methyl-5-isoxazolyl)-2-phe~nylben-r_o[b]thiophene sulfonamide, N-(4-chloro-3-methyl-5-isoxazolyl)-2-[I'4-tolyl)aminocarbonyl]-1-methylindole-3-sulfonamide, N-(4-chloro-3-methyl-5-isoxazolyl)-2-((4-methoxyphenoxy)carbonyl]thio-phene-3-sulfonamide, N-(4-bromo-3-methyl-5-isoxazolyl)-1-[3,4-(methyl-enedioxy)benzyl~indole-:?-sulfonamide, N-(4-bromo-3-methyl-5-isoxazolyl)-2-[(4-methylphenoxy)carbonyl]thiophene-3-sulfonamide, N-(4-chloro-3-methyl-5-isoxazolyl)-2-((4-methoxyphenyl)acetyl)thiophene-3-sulfonamide, N-(4-chloro-3-me;thyl-5-isoxazolyl)-6-methoxy-2-(3,4-(methyienedioxy)-benzyl]benzo[b]thiophene-3-sulfonamide, N-(4-bromo-3-methyl-5-isoxa-zolyl)-3-[(4-methylphenoxy)methyl]thiophene-2-sulfonamide, N-(4-bromo-3-methyl-5-isoxazolyl)-2-[(4-methylphenoxy)methyl]thiophene-3-sulfona-mide, N-(4-brom~~-3-methyl-5-isoxazolyl)-3-(4-methyl-traps-styryl)thio-phene-2-sulfonamide, N-(4-bromo-3-methyl-5-isoxazolyl)-3-(4-methylphenethyl'Ithiophene-2-sulfonamide, N-(4-bromo-3-methyl-5-isoxa-zolyl)-2-[(4-methylphenyl)acetyl]thiophene-3-sulfonamide, N-(4-chloro-3-methyl-5-isoxazolyl)-2-((3-methoxyphenyl)acetyl]thiophene-3-sulfonamide, N-(4-chloro-3-methyl-5-isoxazolyl)-2-{1-hydroxy-1-[3,4-(methylenedioxy)-benzyl]ethyl}thiophene-~!-sulfonamide, N-4-(bromo-3-methyl-5-isoxazolyl)-3-(4-methylpheni~thyl)(4-tolyl)thiophene-2-sulfonamide, N-(4-bromo-3-methyl-5-isoxazolyl)-3-(4-methylbenzyl)-5-(4-tolyl)thiophene-2-sulfona-mide, N-(4-brorno-3-methyl-5-isoxazolyl)-3-(4-methyl-traps-styryl)-5-(4-tolyl)thiophene-2-sulfonamide, N-(4-chloro-3-methyl-5-isoxazolyl)-2-[~,Q-(ethylenedioxy)3,4-(methylenedioxy)phenethyl]thiophene-3-sulfonamide, N-(4-chloro-3-methyl-5-isoxazolyl)-2-[~-(dimethylamino)-3,4-(methylene-dioxy)phenethy]thiophene-3-sulfonamide, N-(4-chloro-3-methyl-5-isoxa-zolyl)-2-{a-hydro:Ky-(3,4-(methylenedioxy)phenyl]acetyl}thiophene-3-sul-WO 96/31492 PCTlLTS96l04759 fonamide; N-(4-chloro-5-methyl-3-isoxazolyl)-2-[3,4-(methylenedioxy)-benzyl]benzo[b]tihiophene-3-sulfonamide; N-(4-bromo-3-methyl-5-isoxazolyl)-3-styrylthiophene-2-sulfonamide; N-(4-bromo-3-methyl-5-isoxazolyl)-2-styrylthiophene-3-sulfonamide; N-(4-bromo-3-methyl-5-isoxazolyl)-2-(benzoylamino)thiophene-3-sulfonamide; N-(4-bromo-3-methyl-5-isoxaze~lyl)-2-[(phenyl)methylaminocarbonyl)thiophene-3-sulfona-mide; N-(4-bromo-3-methyl-5-isoxazolyl)-5-(phenylthio)furan-2-sulfona-mide; N-(4-bromo-3-methyl-5-isoxazolyl)-5-(hydroxymethyl)furan-2-sulfon-amide; N-(4-bromo-3-me;thyl-5-isoxazolyl)-5-(carbomethoxy)furan-2-sul-fonamide; N-(4-bromo-3-methyl-5-isoxazolyl)-2,5-dimethylfuran-3-sulfona-mide; N-(4-brom~~-3-methyl-5-isoxazolyl)-2-(diisopropylaminocarbonyl)-thiophene-3-sulfonamide; N-(4-bromo-3-methyl-5-isoxazolyl)-2-(diethyl-aminocarbonyl)thiophene-3-sulfonamide; N-(4-bromo-3-methyl-5-isoxazol-yl)-5-styrylfuran-2-sulfonamide; N-(4-bromo-3-methyl-5-isoxazolyl)-5-styrylthiophene-?-sulfonamide; N-(4-chloro-3-methyl-5-isoxazolyl)-2-(3,4-(methylenedioxy)benzyl]-5-(dimethylamino)benzo(b]thiophene-3-sulfona-mide; N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)benzyl]-7-methoxybenzo(b]thiophene-3-sulfonamide; N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,~~-(meth~ylenedioxy)benzyl]-7-phenoxybenzo[b]thiophene-3-sulfonamide; ~I-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylene-dioxy)benzyl)-5-rnethoxybenzo(b]thiophene-3-sulfonamide; N-(4-chloro-3-methyl-5-isoxazolyl)-2-[:3,4-(methylenedioxy)benzyl]-5-isobutyl-aminobenzo[b]thiophene;-3-sulfonamide; N-(4-chloro-3-methyl-5-isoxa-zolyl)-2-(3,4-(methylenedioxy)benzyl]-5-benzylaminobenzo(b]thiophene-3-sulfonamide; N-(4-chloro-3-methyl-5-isoxazolyl)-2-(3,4-(methylenedioxy)-phenoxy]benzo[b]thiophene-3-sulfonamide; N-(4-chloro-3-methyl-5-isoxa-zolyl)-2-(3,4-(methylenedioxy)phenoxy]-5-dimethylaminobenzo[b]thio-phene-3-sulfonamide; N~-(4-chloro-3-methyl-5-isoxazolyl)-2-[(3,4-methylenedioxy)phenyl]acetyl-5-dimethylaminobenzo[blthiophene-3-sulfon-W O 96131492 PCTlUS96I04759 amide; N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)-benzylcarbonyl]-N-methylindole-3-sulfonamide; N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,~~-(methylenedioxy)phenoxycarbonyl]indole-3-sulfonamide;
N-(4-chloro-3-me;thyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)phenoxycar-bonyl]-N-methylindole-3-sulfonamide; N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)phenoxycarbonyl]indole-3-sulfonamide; N-(4-chloro-3-methyl-.5-isoxazolyl)-2-[3,4-(methylenedioxy)benzyl]-N-methyl-indole-3-sulfonarnide; N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)benzyl]indole-3-sulfonamide; N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4~-(methylenedioxy)benzyloxycarbonyl)-7-(N,N-dimethyl-amino)benzo(b]th~iophene-3-sulfonamide; N-(4-chloro-3-methyl-5-isoxa-zolyl)-2-(3,4-(met:hylenedioxy)benzyl]-7-(N,N-dimethylamino)benzo[blthio-phene-3-sulfonamide; N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)benzoyl]-7-(N,N-dimethyl)amino)benzo[b]thiophene-3-sul-fonamide; N-(4-chloro-3-methyl-5-isoxazolyl)-7-(N,N-dimethyl-amino)benzo[b]thiophene~-3-sulfonamide; N-{4-chloro-3-methyl-5-isoxa-zolyl)-7-(methoxycarbonyl)benzo(b]thiophene-3-sulfonamide; N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)benzyl]-7-(methoxy)-benzo[b]thiophenn-3-sulfonamide; N-(4-chloro-3-methyl-5-isoxazolyl)-7-(methoxy)benzo[E~]thiophene-3-sulfonamide; N-(4-bromo-3-methyl-5-isoxa-zolyl)-2-{4-methyl~ohenett-iyl)thiophene-3-sulfonamide; N-(4-bromo-3-methyl-5-isoxazol~,rl)-2-(t~~~ns-4-methylcinnamyl)thiophene-3-sulfonamide;
N-{4-bromo-3-methyl-5-isoxazolyl)-3-(4-methylphenethyl)thiophene-2-sul-fonamide; N-{4-bromo-3-methyl-5-isoxazolyl)-3-(3-methylphenethyl)thio-phene-2-sulfonamide; N-(.4-bromo-3-methyl-5-isoxazolyl)-3-(2-methyl-phenethyl)thiophene-2-sulfonamide; N-(4-bromo-3-methyl-5-isoxazolyl)-3-(traps-4-methylcinnamyl)thiophene-2-sulfonamide; N-(4-bromo-3-methyl-5-isoxazolyl)-3-(tr~ns-3-methylcinnamyl)thiophene-2-sulfonamide; N-{4-bromo-3-methyl-5-~isoxazolyl)-3-(tans-2-methylcinnamyl)thiophene-2-sul-Wv. X6/31492 PCT/US96/04759 fonamide; N-(4-bromo-3~-methyl-5-isoxazolyl)-3-[(4-methylphenoxy)-methyl]thiophene-2-sulfonamide; N-(4-bromo-3-methyl-5-isoxazolyl)-3-[3,4-(methylened'foxy)phenethyl]thiophene-2-sulfonamide; N-(4-chloro-3-methyl-5-isoxazolyl)-2-{(3,4-(dimethoxy)phenyl]acetyl)}thiophene-3-sulfo-namide; N-(4-chloro-3-methyl-5-isoxazolyl)-2-((3,5-dimethoxyphenyl)-acetyl]thiophene-3-sulfonamide; N-(4-chloro-3-methyl-5-isoxazolyl)-2-((3,4,5-trimethoxyphenyl)acetyl]thiophene-3-sulfonamide; N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)benzylsulfonyl)thiophene-3-sulfonamide; N-(4.-chloro-~3-methyl-5-isoxazolyl)-2-(3,4-(methylenedioxy)-benzylsulfinyl)thiophene-:3-sulfonamide; N-(4-chloro-3-methyl-5-isoxa-zolyl)-2-(3,4-(methylenedioxy)benzylsulfenyl)thiophene-3-sulfonamide; N-(4-chloro-3-methyl-5-isoxazolyl)-2-{ 7 -(dimethylamino)-2-[3,4-(methylene-dioxy)phenyl}ethylthiophe:ne-3-sulfonamide; N-(4-chloro-3-methyl-5-isoxa-zolyl)-2-{ 1-methylamino)-.2-[3,4-(methylenedioxy)phenyl)ethyl}thiophene-3-sulfonamide; N-(4-chloro-3-methyl-5-isoxazolyl)-2-{1-(methoxyliminol-2-[3,4-(methylenedioxy)phenyl)ethyl}thiophene-3-sulfonamide; N-(4-chloro-3-methyl-5-isoxazolyl)-2-{ 1-(carboxyl)-2-(3,4-(methylenedioxy)phenyl]-ethyl}thiophene-3-sulfonamide; N-(4-chloro-3-methyl-5-isoxazolyl)-2-{2-(carboxyl)-1-[3,4-(methyle~nedioxy)benzyl]vinyl}thiophene-3-sulfonamide;
N-(4-chloro-3-methyl-5-isoxazolyl)-2-{3-[3,4-(methylenedioxy)phenyl]-1,2,4-oxadiazol-5-lyl}thiophene-3-sulfonamide; and N-(4-chloro-3-methyl-5-isoxazolyl-2-{3-[,3,4-(methylenedioxy)benzyl]-1,2,4-oxadiazol-5-lyl}thio-phene-3-sulfonamide.
Additional compounds include, but are not limited to: N-(4-chloro-3-methyl-5-isoxazolyl)-2-{[2-(methanesulfonyl)-4,5-(methylenedioxy)-phenyl)aminocarbonyl}thiophene-3-sulfonamide; N-(4-chloro-3-methyl-5-isoxazolyl)-2-{[3,4-(methylenedioxy)-6-carboxylphenyl]aminocar-bonyl}thiophene-3-sulfonamide; N-(4-chloro-3-methyl-5-isoxazolyl)-2-{[4,5-(methyle~edioxy)-2-(~methoxycarbonyl)phenyl}aminocar-R I6l31492 PCTIUS96104759 bonyl}thiophene~-3-sulfonamide; N-(4-chloro-3-methyl-5-isoxazolyl)-2-{[2-cyano-4,5-(methylenedioxy)phenyl]aminocarbonyl}thiophene-3-sulfonamide; N-~'4-chloro-3-methyl-5-isoxazolyl)-2-{(4, 5-(methylenedioxy)-2-hydroxymethyi)phenyl]aminocarbonylthiophene-3-sulfonamide; N-(4-chloro-3-methyl-5-isoxa:zolyl)-2-[(2-acetyl-4-methylphenyl]aminocar-bonyl]thiophene-3-sulfonamide; N-(4-chloro-3-methyl-5-isoxazolyl)-2-{[2-(methanesulfonyl)-4-methylphenyl]aminocarbonyl}thiophene-3--sulfonamide; N-(4-chloro-3-methyl-5-isoxazolyl)-.2-[(2-carboxyl-4-methyl-phenyl)aminocarhonyl]thiophene-3-sulfonamide; N-(4-chloro-3-methyl-5-1o isoxazolyll-2-((2-methoxycarbonyl-4-meihylphenyl)aminocarbonyl]thio-phene-3-sulfonarnide; N-(4-chloro-3-methyl-5-isoxazolyl)-2-[(2-cyano-4-methylphenyl)aminocarbonyl]thiophene-3-sulfonamide; N-(4-chloro-3-methyl-5-isoxazolyl)-2-{[2-(hydroxymethyl)-4-methylphenyl]aminocar-bonyl}thiophene-3-sulfonamide; N-(4-chloro-3-methyl-5-isoxazolyl)-2-[(3,4-dimethoxy-(3-acetylphenyl)aminocarbonyl]thiophene-3-sulfonamide;
N-(4-chloro-3-methyl-5-is;oxazolyl)-2-{[2-(methanesulfonyl)-4, 5-dimethoxy-phenyl]aminocarb~onyl}thiophene-3-sulfonamide; N-(4-chloro-3-methyl-5-isoxazolyl)-2-[(4, 5-dimethoxy-2-carboxylphenyl) aminocarbonyljthiophene-3-sulfonamide; N-(4-chloro-3-methyl-5-isoxazolyl)-2-((4,5-dimethoxy-2-methoxycarboxyl)phenyl)aminocarbonyl]thiophene-3-sulfonamide; N-(4-chloro-3-methyl-5-isoxazolyl)-2-[2-cyano(4, 5-dimethoxyphenyl)aminocar-bonyl]thiophene-3-sulfonamide; N-(4-chloro-3-methyl-5-isoxazolyl)-2-(4,5-dimethoxy-2-hydroxymethyl)phenylaminocarbonylthiophene-3-sulfonamide; N-(4-chloro-3-methyl-5-isoxazolyl)-2-{[2-acetyl-4, 5-(methylenedioxy)phenyl]acetyl}thiophene-3-sulfonamide; N-(4-chloro-3-methyl-5-isoxazolyl)-2-{[2-(methanesulfonyl)-4, 5-(methylenedioxy)phenyl]-acetyl}thiophene-:3-sulfonamide; N-(4-chloro-3-methyl-5-isoxazolyl)-2-{[carboxyl 4, 5-(meahylenedioxy)-2-phenylacetyfthiophene-3-sulfonamide;
N-(4-chloro-3-methyl-5-isoxazolyl)-2-{(4, 5-(methylenedioxy)-2-methoxy-V~ _ 96/31492 PCTJUS96/04759 carbonylphenyl)acetylthiophene-3-sulfonamide; N-(4-chloro-3-methyl-5-isoxazolyl)-2-{2-cyano[4,.5-(methylenedioxy)-phenyl]acetyl}thiophene-3--sulfonamide; N-(~~-chloro-3-methyl-5-isoxazolyl)-2-{2-hydroxymethyl[4,5-(methylenedioxy)-phenylacetyl}thiophene-3-sulfonamide; N-(4-chloro-3-methyl-5-isoxazolyl)-2-[(~?,4-dimethoxy)phenyl)aminocarbonyl]thiophene-3sulfonamide; N-~'4-chloro-3-methyl-5-isoxazolyl)-2-[(4-methoxy-2-methyl-phenyl)aminocarbonyl]thiophene-3-sulfonamide; N-(4-chloro-3-methyl-5-isoxazolyl)-2-((2,~~-dimeth~ylphenyl)aminocarbonyl]thiophene-3-sulfona-mide; N-(4-chloro-3-methyl-5-isoxazolyl)-2-[(2,4-dimethylphenyl)aminocar-bonyl]thiophene-3-sulfonamide; N-(4-chloro-3-methyl-5-isoxazolyl)-2-((2,5-dimethylphe~~yl)aminocarbonyl]thiophene-3-sulfonamide; N-(4-chloro-3-methyl-5-isoxazolyl)-2-((2,6-dimethylphenyl)aminocar-bonyl]thiophene-3-sulfonamide; N-(4-chloro-3-methyl-5-isoxazolyl)-2-[(3,4-dimethylphenyl)aminocarbonyl]thiophene-3-sulfonamide; N-(4-chloro-3-methyl-5-isoxazolyl)-2-[(2,5-dimethylphenyl)aminocar-bonyl]thiophene-3-sulfonamide; N-(4-chloro-3-methyl-5-isoxazolyl)-2-(3,5-dimethyl)phenylaminocarbonylthiophene-3-sulfonamide; N-(4-chloro-3-methyl-5-isoxazolyl)-2-((2-methoxy-6-methylphenyl)aminocar-bonyl]thiophene-3-sulfonamide; N-(4-chloro-3-methyl-5-isoxazolyl)-2-[(2,4,6-trimethylphenyl)aminocarbonyl]-thiophene-3-sulfonamide; N-(4-chloro-3-methyl-5-isoxazolyl)-2-((4-methoxy-2-methylphenyl)aminocar-bonyl]-thiophene-3-sulfonamide; N-(4-chloro-3-methyl-5-isoxazolyl)-2-(2-ethyl(4-methoxy-)phenyl)aminocarbonyt)thiophene-3-sulfonamide; N-(4-chloro-3-methyl-5-isoxazolyl)-2-[(2-isopropyl-4-methoxy-phenyl)aminocar-bonyl]thiophene-3-sulfonamide; N-(4-chloro-3-methyl-5-isoxazolyl)-2-[(2-propyl-4-methoxy-phenyl)aminocarbonyl]-thiophene-3-sulfonamide; N-(4-chloro-3-methyl-5-i:;oxazol~,rl)-2-((4-methoxy-2-biphenylaminocarbonylJ-thiophene-3-sulfonamide; >\1-(4-chloro-3-methyl-5-isoxazolyl)-2-{[3,4-(methylenedioxy)-6-methylphenyl)acetyl]-thiophene-3-sulfonamide; N-(4-V ~ )6131492 PCTIUS96104759 chloro-3-methyl-5-isoxazolyl)-2-{(3,4-(methylenedioxy)-6-ethylphenyl)-acetyl}thiophene-3-sulfon<jmide; N-(4-chloro-3-methyl-5-isoxazolyl)-2-{(3,4-(methylenedioxy)-6-methoxyphenyl)acetyl}thiophene-3-sulfonamide.
EXAMPLE i 93 N-(3,4-Dimethyl-5-isoxazolyl)-4-biphenylsulfonamide (a) 4-Biphenyisulfonyl chloride 4-Biphenylsulfonic acid (3.0 g, 12.8 mmol) was heated at 70° C
with phosphorus oxychloride (1.30 ml, 14.0 mol) for 2 h. Excess phosphorus oxychloride was removed under reduced pressure. The residue was decomposed with ice water and extracted with ethyl acetate.
The extract was washed with 5% sodium bicarbinate solution, dried over anhydrous magnesium sulfate and concentrated to yield 2.9 g of crude 4-biphenylsulfonyl chloride.
(b) N-(3,~L-Dimethyl-5-isoxazolyl)-4-biphenylsulfonamide The 4-biphenylsulfonyl chloride from step (a) was added to a solution of 5-amino-3,4-din~nethylisoxazole (250 mg, 2.2 mmol) and 4-(dimethyl)aminopyridine (5 mg) in dry pyridine (2.0 ml). The reaction mixture was stirred at room temperature for 4 h. Pyridine was removed under reduced pre:~sure and the residue was partitioned between water and ethyl acetate. The organic layer was washed with 1 N HCI (2 X 25 ml), brine (25 ml) and dried over anhydrous magnesium sulfate.
Evaporation of the solvents left an oily residue that, after purification by column chromatography over silica gel ( 1 % methanol in chloroform as eluent), yielded 337 mg (4''.5%) of a white solid. Recrystallization from ethyl acetate/hexanes gave white crystals, m.p. 154-155° C.

~ ~ 96131492 PCTIUS96I04759 ~ /

N-(4-Bromo-3-methyl-5-isoxazolyl)-4-biphenylsulfonamide (a) 5-Amino-4-bromo-3-methylisoxazole 5-Amino-a-methylisoxazole (0.98 g, 10 mmol) was dissolved in chloroform ( 15 ml) and cooled to 0° C. N-Bromosuccinimide ( 1.78 g, 10 mmoles) was adcjed in small portions over a period of 10 min. The stir-ring was continued for another 10 minutes at 0° C. The reaction mixture was diluted with chloroform (50 ml), washed with water (2 X 50 ml) and the organic layer was dried over magnesium sulfate. Removal of the sol-vent under reduced pressure gave the crude product, which was purified by column chromatography using 9:1, hexanes/ethyl acetate as the eluent, to give 5-amino-4-bromo-3-methylisoxazole (1.55 g, 87% yield).
(b) N-(4-Biphenylsulfonyl)-N-(4-bromo-3-methyl-5-isoxazolyl)-4-biph~enylsulfonamide .
5-Amino-4-bromo-3-methyiisoxazole (0.179 g, 1.0 mmol) was dissolved in dry pyridine (2 ml). 4-Biphenylsulfonyl chloride (0.509 g, 2.2 mmol) was added with stirring at ambient temperature. N,N-dimethyl-aminopyridine (5 mg) waa added, and stirring was continued at 50° C for 16 h. The reaction mixture was diluted with dichloromethane (75 ml), washed with 1 N t~Cl (2 ~; 50 ml) and the organic phase was dried over magnesium sulfate. The solvent was removed under reduced pressure to yield a crude product, which was purified by column chromatography us-ing 8:2, hexanes/Eahyl acetate, to give 0.390 g (60% yield) of N-(4-biphenylsulfonyl)-IV-(4-bromo-3-methyl-5-isoxazolyl)-4-biphenylsulfona-mide.
(c) N-(4-':Bromo-3-methyl-5-isoxazolyl)-4-biphenylsulfonamide N-(4-biphenylsulfonyl)-N-(4-bromo-3-methyl-5-isoxazolyl)-4.-bi-phenylsulfonamide~ (0.150 g, 0.233 mmol) was dissolved in tetrahydro-furan (THF). Sodium hydroxide (0.120 g, 3.0 mmol) was added and the .96131492 PCT/US96/04759 solution was warmed to 45° C to dissolve the sodium hydroxide. Stirring was continued for 20 min. Tetrahydrofuran was removed under reduced pressure. The residue was dissolved in water, cooled to 0° C and acidified to pH 3-4. with concentrated HCI. The solid precipitate was filtered off and dried in vacuo to give N-(4-bromo-3-methyl-5-isoxazolyl)-4-biphenylsulfonarnide (94% yield), which was further purified by recrystallization from chloroform/hexanes, m.p. 133-135° C.

N-(3,4-Dimethyl-5-isoxazolyl)-2-dibenzofuransulfonamide N-(3,4-Dimethyl-5-isoxazolyll-2-dibenzofuransulfonamide was prepared, using the: method described in Example 193b, from 5-amino-3,4-dimethylisoxaz;ole and 2-benzofuransulfonyl chloride in 32% yield.
Purification was achieved by recrystallization from chloroform/hexanes to give a white "cotton-like" solid, m.p. 173-175° C (dec.).

fV-(4-Methyl-3-trifluoromethyl-5-isoxazolyl)-4-biphenylsulfonamide N-(4-Methy'I-3-trifluoromethyl-5-isoxazolyl)-4-biphenylsulfonamide was prepared in the same manner as described in Example 194b from 5-amino-4-methyl-3-t:rifluoromethyl-isoxazole and 4-biphenylsulfonyl chloride in 78% yiE:ld. Purification was achieved by recrystallization from methanol/water to give a white solid, m.p. 139-140° C.

N-(4-Tridecyl-3-trifluoromethyl-5-isoxazolyl)-4-biphenylsulfonamide N-(4-Tridecyl-3-trifluoromethyl-5-isoxazolyl)-4-biphenylsulfonamide was prepared, in t1 ie same manner as described in Example 194b, from 5-amino-4-tridecyl-3-trifluoromethyl-isoxazole and 4-biphenylsulfonyl chloride in 81 % yield. Purification was achieved by recrystallization from methanol/water to give an off white solid, m.p. 1 15-1 16° C.

j W V 96131492 . PCT/US96104759 N-(4-Methyl-3-triflluoromethyl-5-isoxazolyl)-4-biphenylsuifonamide N-(4-Methyl-3-trifluoromethyl-5-isoxazolyl)-4-biphenylsulfonamide was prepared, as described in Example 194, from 5-amino-4-methyl-3-trifluoromethyliso;tazole and 4-biphenylsulfonyl chloride in 78% yield.
Purification was achieved by recrystallization from ethyl acetate/hexanes to give a white solid, m.p. 139-140° C.

N-(4-Bromo-5-methyl-3-isoxazolyl)-4-biphenylsulfonamide (a) 3-Amino-4-bromo-5-methylisoxazole 3-Amino-5-methylisoxazole ( 1.96 g, 20 mmol) was dissolved in chloroform ( 10 ml) and cooled to 0° C. N-Bromosuccinimide (3.56 g, 20 mmol) was added in small portions over a period of 10 min. The stirring was continued for another 15 minutes at 0° C. The reaction mixture was diluted with chloroform ( 100 ml), washed with water (2 X 50 ml) and the 75 organic layer was dried over magnesium sulfate. Removal of the solvent under reduced pressure gave the crude product, which was purified by column chromatography, using 9:1 hexanes/ethyl acetate as the eluent, to give 3-amino-4-bromo-5-methylisoxazole (1.40 g, 40 % yield).
(b) N-(4-bromo-fi-methyl-3-isoxazolyl)-4-biphenylsulfonamide N-(4-bromo-5-methyl-3-isoxazolyl)-4-biphenylsulfonamide was prepared, using th~~ method in Example 193b, from 3-amino-4-bromo-5-methylisoxazole and 4-biphenylsulfonyl chloride in 5% yield. The crude product was purified by column chromatography. After recrystallization from ethyl acetate/hexanes, N-(4-bromo-5-methyl-3-isoxazolyl)-4-biphenylsulfonamide (m.p" 154-156° C) was obtained in 51 % yield.

~6131~i92 PCTlUS96I04759 -22s-N-(4-Chloro-3-methyl-5-isoxazolyll-4-biphenylsulfonamide (a) 5-Amino-4-chloro-3-methylisoxazole Using the method ins Example 194a, 5-amino-4-chloro-3-methyli-soxazole was prepared from 5-amino-3-methylisoxazole and N-chloro-succinimide in 90~% yield.
(b) N-(4-~Ohloro-3-methyl-5-isoxazolyl)-4-biphenylsuifonamide Sodium hydride (188 mg, 4.4 mmol) was suspended in dry THF
( 1 ml) and cooled 'to 0° C. A solution of 5-amino-4-chloro-3-methylisoxa-zole (mg, mmol) in dry THF (1 ml) was added with stirring. Once the addition was comF~lete, the reaction mixture was warmed to room temperature for 1 C) min. -fhe solution was recooled to 0° C, and 4-biphenylsulfonyl chloride (0.283 ml, 2.2 mmol) was added. Stirring was continued at 25° C. for 2 h. Excess sodium hydride was decomposed by the addition of methanol (~D.4 ml) followed by water (0.5 ml). The THF
was removed under reduced pressure and the residue was dissolved in water (20 ml) and basified by addition of sodium hydroxide (pH 9 - 10).
Neutral impurities ~Nere removed by extraction with ethyl acetate (2 X 10 ml). The aqueous layer w;as acidified to pH 2-3 using concentrated HCI
and extracted with ethyl acetate (3 X 10 ml). The combined organic layer was dried over magnesium sulfate. Removal of the solvent gave N-(4-chloro-3-methyl-5-isoxazolyl)-4-biphenylsulfonamide in 83% yield.
This product was purified by recrystallization from ethyl acetate/hexanes as a white solid, m.p. 129-132° C.

2,5-Dimethoxy-N-(~4-bromo-3-methyl-5-isoxazolyl)benzenesulfonamide 2, 5-Dimethoxy-N-(4-bromo-3-methyl-5-isoxazolyl)benzenesulfon-amide was prepared from !5-amino-4-brvmo-3-methylisoxazole and 2,5-di methoxybenzenesulfonyl chloride according to the procedures described . 96!31492 PCTIUS96/04759 in Example 200. The crude product was purified by recrystallization from ethyl acetate/hexanes to give a crystalline solid, m.p. 118-120° , yield 58%.

N-(4-bromo-3-methyl-5-isoxazolyl)-2-biphenylsulfonamide A. 2-Biphenylsulfonyl chloride 2-BromobiE~henyl (2.33 g, 10 mmol) was dissolved in ether (10 ml) and cooled to -78 °C. n-iButyllithium (2.5 M solution in hexane, 4.8 ml, 12 mmol) was added dropwise under constant stirring and an argon atmosphere. The resultant reaction mixture was stirred at -70°C to -60°C for 1h. ThE: reaction mixture was cooled to -78°C and sulfuryl chloride (0.88 ml, 1 1 mmol) was added dropwise. After addition, the reaction mixture was allowed to attain ambient temperature slowly and stirred for 1 h. The reaction mixture was diluted with ethyl acetate (50 ml), washed with water and the organic layer dried over anhydrous MgS04. Removal of the solvent under reduced pressure gave a crude product, which was purified by column chromatography, using hexane followed by 5% ethyl aceaate in hexane as eluent, to give 2-bi-phenylsulfonyl chloride as. a solid (1.3 g, 51 % yield).
B. N-(4-bromo-3-methyl-5-isoxazolyl)-2-biphenylsulfonamide N-(4-bromo-3-methyl-5-isoxazolyl)-2-biphenylsulfonamide was prepared in the same manner as described in Example 200b from 5-amino-4-bromo-3-methylisoxazole and 2-biphenylsulfonyl chloride in 71 yield. Purification was achieved by recrystallization from ethyl acetate/hexanes to give a crystalline solid, m.p. 145 - 147°C.

96131492 PCTlUS96/04759 '.

N-(4-Chloro-3-methyl-5-isoxazolyl)-2-biphenyisulfonamide N-(4-Chloro-3-methyl-5-isoxazolyl)-2-biphenylsulfonamide was prepared in the same manner as described in Example 202 from 5-amino 4-chloro-3-methylisoxazole and 2-biphenylsulfonyl chloride in 74% yield.
Purification was achieved by recrystallization from ethyl acetate/hexanes to give a crystalline solid, m.p. 132 - 134°C.

N-(4-Bromo-3-methyl-5-isoxazolyl)-3-biphenylsulfonamide A. 3-Biphenylsulfonyl chloride 3-Bromobiphenyl ( 1.5 g, 6.4 mmol) was dissolved in ether ( 15 ml) and cooled to -78 ° C. t-Butyllithium ( 1.7 M solution in hexane, 3.8 ml, 6.4 mmol) was added dropwise under constant stirring and an argon atmosphere. The resultant reaction mixture was stirred at -10°C to -5°C
for 6h. The reaction mixture was cooled to -78°C and sulfuryl chloride (0.64 ml, 6.4 mmol) was added dropwise. After completion of the addition, the reaction mixture was allowed to attain ambient temperature slowly and stirred for 1 h.. The reaction mixture was diluted with ethyl acetate (50 ml), washed with water and the organic layer dried over anhydrous MgS04. Removal of the solvent under reduced pressure gave crude product, which wa:~ purified by column chromatography, using hexane followed by 5% ethyl acetate in hexane as eluent, to give 3-biphenylsulfonyl chloride as an oil (0.8 g, 49% yield).
B. N-(4-bromo~-3-methyl-5-isoxazolyl)-3-biphenylsulfonamide N-(4-bromo-3-methyl-5-isoxazolyl)-3-biphenylsulfonamide was prepared in the same manner as described in Example 200b from 5-amino-4-bromo-3-methylisoxazole and 3-biphenylsulfonyl chloride in 22%
yield. This was purified by HPLC (5% CH3CN to 100% CH3CN over 30 min.) to give a solid., m.p. 78 - 82° C.

I
W v. 96f31492 PCTlUS96104759 N-(4-chloro-3-metihyl-5-isoxazolyl)-3-biphenylsuifonamide N-(4-chloro-~3-methyl-5-isoxazolyl)-3-biphenylsulfonamide was prepared in the same manner as described in Example 204 from 5-amino-4-chloro-3-methylisoxazole and 3-biphenylsulfonyl chloride in 63% yield.
This was purified by HPL(: (5% CH3CN to 100% CH3CN over 30 min.) to give a solid, m.p. B4 - 86°C.

N-(3-methyl-5-iso~:azolyl)-4-(4-methylphenyl)benzenesulfonamide (a) N-(3-methyl-'~-isoxazolyl)-4-bromobenzenesulfonamide 4-brombenzenesulfonyl chloride (solid) was added, in five portions, to a solution of 3-methyl-'.~-aminoisoxazole (3.82 g, 40 mmol) in dry pyridine (30 ml). This was stirred at room temperature for 3 h and the pyridine was removed under reduced pressure. The residue was dissolved in THF (300 ml) and a 5°/r. NaOH solution (100 ml) was added. Stirring continued for 1 h .at room temperature. The THF was removed under reduced pressure and the resultant residue was neutralized to pH 2 using concentrated hydn~chloric acid. This was extracted with ethyl acetate (3 x 200 ml) and the combined organic layer was dried over MgS04 and ZO concentrated. The crude product was recrystallized using hexane/ethyl acetate giving N-(:3-methyl-5-isoxazolyl)-4-bromobenzenesulfonamide (9.2 g, 72% yield).
(b) N-(3-methyl-5-isoxazolyl)-4-(4-methylphenyl)benzenesulfon-amide Nitrogen was bubbled through a biphasic mixture of ethanol (15 ml), toluene (15 ml) and 2M sodium carbonate solution (15 ml). N-(3-methyl-5-isoxazolyl)-4-bromobenzene sulfonamide (0.951 g, 3 mmol), 4-methylbenzenebor~~nic acid (0.56 g, 4 mmol) and tetrakistriphenyl-phosphine palladium (0) (300 mg) were added. The reaction mixture was kept at 80° C, under a N2 atmosphere for 24 h, with stirring, and was ' ~. i 96!31492 PGTIUS95104759 then diluted with water ('50 ml) and extracted with ether (50 ml) to remove neutral impurities and excess 4-methylbenzeneboronic acid. The aqueous phase was neutralized to pH 2 using concentrated hydrochloric acid and the resultant solid was filtered. This was dried under vacuum and recrystallized using hexane/ethyl acetate giving N-(3-methyl-5-isoxazolyl)-4-(4-methylphenyl)benzenesulfonamide (1.0 g, 100% yield, m.p. 194-198° C).

N-{4-brorno-3-methyl-5-isoxazolyl)-4-(4-methylphenyllbenzenesulfonamide N-bromosuccinimide (NBS) (0.178 g, 1 mmol), in one lot, was added to a stirred suspension of N-(3-methyl-5-isoxazolyl)-4-(4-methyl-phenyl)benzenesulfonamide (0.3278, 1 mmol, Example 206b) in chloro-form (12 ml). The; reaction mixture was stirred for 10 min then diluted with dichloromethane (50 ml). This was washed with water (2 x 50 ml).
The organic layer was dried over MgSOa and concentrated. The crude product was recr~ystallized using hexane/ethyl acetate giving N-(4-bromo-3-methyl-5-isoxa~~olyl)-4-(4-methylphenyl)benzenesulfonamide {350 mg, 86% yield, m.p. 153-156° C).

N-(4-chloro-3-methyl-5-isoxazolyl)-4-(4-methylphenyl)benzenesulfonamide N-chlorosuccinimide (0.266 g, 2 mmol) was added, in one lot, to a stirred suspension of N-(3-methyl-5-isoxazolyi)-4-(4-methylphenyl)ben-zenesulfonamide (0.3278, 1 mmol, Example 206b) in chloroform (10 ml) and stirred at room temperature for 2 h The reaction mixture was diluted with dichloromethane (50 ml) and washed with water (2 x 50m1). The organic layer was. dried aver MgS04 and concentrated. The crude product was purified by column chromatography using ethyl acetate as eluent to give N-(4-chloro-3-methyl-5-isoxazolyl)-4-(4-methylphenyl)ben-zenesulfonamide [210 mg, 58% yield, m.p. 260° C (de coup)].

A ~6I31492 PCT/US96/04759 N-(3-methyl-5-isoxazolyl)-~4-((4.-trifluoromethyl)phenyl]benzenesulfonamide N-(3-methyl-5-isoxazolyl)-4-(4-trifluoromethylphenyl)benzenesulfon-amide was prepare;d in thE; same manner as described in Example 206b, using N-(3-methyl-5-isoxazolyl)-4-bromobenzenesulfonamide and 4-tri-fluoromethylbenze~neboronic acid resulting in the final product in a 78%
yield, m.p. 150-153° C. The product was recrystallized using an acetonirile and water mixture.

N-(4-bromo-3-methyl-5-isoxazolyl)-4-[(4-trifluoromethyl)phenyl]benzene-sulfonamide N-(4-bromo-3-methyl-5-isoxazolyll-4-[(4-trifluoromethyl)phenyl]ben-zenesulfonamide was prepared in the same manner as described in Example 207, usin~~ N-(3-rnethyl-5-isoxazolyl)-4-(4-trifluoromethylphenyl)-benzenesulfonamide (Example 209) and NBS (reaction time 30 min at room temperature).. The crude product was purified by column chromatography on silica gel using ethyl acetate as eluent resulting in the final product in 56'% yield, m.p. 113-117° C.

N-(3-methyl-5-isox~~zolyl)-4-(4-methoxyphenyl)benzenesuifonamide N-(3-methyl-5-isoxazolyl)-4-(4-methoxyphenyl)benzenesulfonamide was prepared in the same manner as described in Example 206b, using N-(3-methyl-5-isoxazolyl)-4-bromobenzenesulfonamide (Example 206a) and 4-methoxybenzeneboronic acid resulting in an 82% yield of the final product, m.p. 194-196° C. The product was recrystallized using hexane/ethyl acetav~te.

f~
~w 0 96/31492 PCTJUS96I04759 N-(4-bromo-3-methyl-5-isoxazolyl)-4-(4-methoxyphenyl)benzenesuifon-amide N-(4-bromo-3-methyl-5-isoxazolyl)-4-(4-methoxyphenyl)benzenesul-fonamide was prepared in the same manner as described in Example 207 using N-(3-methyl-5-isoxazolyl)-4-(4-methoxyphenyl)benzenesulfonamide (Example 21 1 ) and NBS (reaction time 30 min at room temperature). The crude product w;as purified by column chromatography on silica gel using ethyl acetate as ~eluent giving the final product in 78% yield, m.p.
208° C
(dec). The product was recrystallized using hexane/ethyl acetate.

N-(4-bromo-3-methyl-5-isoxazolyi)-4-(3-methoxyphenyl)benzenesulfon-amide '15 (a) N-(3-methyl-5-isoxazolyl)-4-(3-methoxyphenyl)benzenesul-fonamide N-(3-methyl-5-isox:azolyl)-4-(3-methoxyphenyl)benzenesulfonamide was prepared in the same manner as described in Example 206b, using N-(3-methyl-5-isoxazolyl)-4-bromobenzenesulfonamide (Example 206a) and 3-methoxybenzer~eboronic acid resulting in a 77% yield.
(b) N-(4-bromo-3-methyl-5-isoxazolyl)-4-(3-methoxyphenyl)ben-zenesulfonamide N-(4-bromo-3-methyl-5-isoxazolyl)-4-(3-methoxyphenyl)benzenesul-fonamide was prepared in the same manner as described in Example 207 using N-(3-methyl-5-isoxazolyl)-4-(3-methoxyphenyl)benzenesulfonamide and NBS (reactions time 30 min at room temperature). The crude product was purified by column chromatography on silica gel using ethyl acetate as eluent giving the final product, after recrystallization using hexane/ethyl acetate, in 75% yield, m.p. 140-144° C.

WO 96!31492 . PCTIUS9GI04759 N-(4-bromo-3-methyl-5-i:roxazolyl)-4-(2-methoxyphenyl)benzenesulfon-amide (a) N-(3-methyl~-5-isoxazolyl)-4-(2-methoxyphenyl)benzenesul-fonamide N-(3-methyl-5-isoxazolyl)-4-(2-methoxyphenyl)benzenesulfonamide was prepared in the same manner as described in Example 206 using N
(3-methyl-5-isoxazolyl)-4-bromobenzenesulfonamide and 2-methoxyben zeneboronic acid resulting in an 81 % yield of the final product.
(b) N-(4~bromo-3-methyl-5-isoxozolyl)-4-(2-methoxyphenyl)ben-zeneaulfonarnide N-(4-bromo-3-methyl-5-isoxozolyl)-4-{2-methoxyphenyl)benzenesul-fonamide was prepared in the same manner as described in Example 207, using N-(3-methyl-5-isoxazolyl)-4-(2-methoxyphenyl)benzenesulfonamide and NBS (reaction time 30 min at room temp.) The crude product was purified by column chromatography on silica gel using ethyl acetate as eluent to give the final product in 68% yield, m.p. 205-209° C.

N-{4-bromo-3-methyl-5-isoxazolyl)-4-(3,4-methylenedioxyphenyl)benzene-sulfonamide (a) N-(3-methyl-5-isoxazolyl)-4-{3,4-methylenedioxyphenyl)ben-zenes~ulfonamide N-(3-methyl-5-isoxazolyl)-4-(3,4-methylenedioxyphenyl)benzenesul-fonamide was prepared in the same manner as described in Example 206b, using N-{3-methyl-5-isoxazolyl)-4-bromobenzenesulfonamide and 3,4-methylenediox;yphenylboronic acid resulting in a 67% yield of final product.
(b) N-{4-bromo-3-methyl-5-isoxazolyl)-4-(3,4-methylenedioxy-phenyl)benzenesulfonamide N-(4-bromo-3-methyl-5-isoxazolyl)-4-(3,4-methylenedioxyphenyl)-benzenesulfonamide was prepared in the same manner as described in 96!31492 PCTlUS96104759 ~

Example 207, using N-(3-methyl-5-isoxazolyl)-4-(3,4-methylenedioxy-phenyl)benzenesulfonamide and NBS in THF as solvent resulting in a 35%
yield. The crude product was purified by HPLC, m.p. 172-174° C.

N-(4-bromo-3-methyl-5-isoxazolyl)-4-(3-methylphenyl)benzenesulfonamide (a) N-(3-methyl-5-isoxazolyl)-4-(3-methylphenyl)benzenesulfon-amid.
N-(3-methyl-5-isoxazolyl)-4-(3-methylphenyl)benzenesulfonamide was prepared in the same manner as described in Example 206b, using N-(3-methyl-5-isoxa~:olyl)-4-bromobenzenesulfonamide (Example 206a) and 3-methylbenzeneboronic acid resulting in an 82% yield.
(b) N-(4-promo-3-methyl-5-isoxazolyl)-4-(3-methylphenyl)ben-zenesulfonamide N-(4-bromo-3-methyl-5-isoxazolyl)-4-(3-methylphenyl) benzenesul-fonamide was prepared in the same manner as described in Example 207, using N-(3-methyl-5-isoxazolyl)-4-(3-methylphenyl)benzenesulfonamide and NBS in THF as. solvent (reaction time 30 min at room temperature).
The crude product was purified by HPLC resulting in a 31 % yield of the final product, m.p. 186-189° C.

Assays for identifying compounds that exhibit endothelia antagonistic and/or agonist activity Compounds that are potential endothelia antagonists are identified by testing their ability to compete with '251-labeled ET-1 for binding to human ETA receptors or El-8 receptors present on isolated cell membranes. The effectiveness of the test compound as an antagonist or agonist of the biological tissue response of endothelia can also be assessed by measuring the effect on endothelia induced contraction of isolated rat thoracic aortic rings. The ability of the compounds to act as antagonists or agonists for ET8 receptors can be assess by testing the h 96131492 pGT/LTS96/04759 r ability of the compounds are to inhibit endothelin-1 induced prostacyclin release from cultured bovine aortic endothelial cells.
A. Endothellin binding inhibition - Binding Test X11: Inhibition of binding to E:TA receptors TE 671 cells (ATC(: Accession No. HTB 139) express ETA
receptors. These cells were grown to confluence in T-175 flasks. Cells from multiple flasks were collected by scraping, pooled and centrifuged for 10 min at 190 X g. The cells were resuspended in phosphate buffered saline (PBS) containing 10 mM EDTA using a Tenbroeck homogenizer.
The suspension was centrifuged at 4° C at 57,800 X g for 15 min, the pellet was resuspe:nded in 5 ml of buffer A (5mM HEPES buffer, pH 7.4 containing aprotinin (100 KIU/ml)) and then frozen and thawed once. 5 ml of Buffer B (5 mM HEPES Buffer, pH 7.4 containing 10 mM MnCl2 and 0.001 % deoxyribonuclea se Type 11 was added, the suspension mixed by inversion and then incubated at 37° C for 30 minutes. The mixture was centrifuged at 57,800 X c) as described above, the pellet washed twice with buffer A and then resuspended in buffer C (30 mM HEPES buffer, pH 7.4 containing aprotinin (100 KIU/ml) to give a final protein concentration of ~'. mg/ml and stored at -70° C until use.
The membrane suspension was diluted with binding buffer (30 mM
HEPES buffer, pH 7.4 containing 150 mM NaCI, 5mM MgCl2, 0.5%
Bacitracin) to a concentration of 8 Ng/50 NI. '251-endothelin-1 (3,000 cpm, 50 mL) was added 1:0 50 NL of either: (A) endothelin-1 (for non specific binding) to give a final concentration 80 nM); (B) binding buffer (for total binding); or (C) a test compound (final concentration 1 nM to 100 NM). The membrane suspension (50 NL), containing up to 8 Ng of membrane protein, was added to each of (A), (E3), or (C). Mixtures were shaken, and incubated at 4° C for 16-18 hours, and then centrifuged at 4° C for 25 min a~: 2, 500 X g. Alternatively, the incubation was conducted at 24° C. When incubated at 24° C, the ICSO
concentrations ' ' a'' ,6r31492 PCT/US96/U4759 ~/

are 2- to 10-fold higher than when the incubation is conducted at 4° C.
This, must be kept in mind. when comparing IC5° concentrations among compounds provided herein.
The supernatant, containing unbound radioactivity, was decanted and the pellet counted on a Genesys multiwell gamma counter. The degree of inhibition of binding (D) was calculated according to the following equation:
(C1 - (A) D == 100 - X 100 (8) - (A) Each test was generally performed in triplicate.
B. Endothelin binding inhibition - Binding Test #2: Inhibition of binding to El'B receptors COS7 cells were transfected with DNA encoding the ETB receptor, The resulting cells, which express the human ETe receptor, were grown to confluence in T-'150 flasks. Membrane was prepared as described above. The binding assay was performed as described above using the membrane preparation diluted with binding buffer to a concentration of 1 Ng/50 ~l.
Briefly, the COS7 cells, described above, that had been transfected with DNA encoding the ET,a receptor and express the human ETB receptor on their surfaces were grown to confluence in T-175 flasks. Cells from multiple flasks were; collected by scraping, pooled and centrifuged for 10 min at 190 X g. The cells were resuspended in phosphate buffered saline (PBS) containing 10 mM EDTA using a Tenbroeck homogenizer. The suspension was centrifuged at 4° C 57,800 X g for 15 min, the pellet was resuspended in 5 ml of buffer A (5mM HEPES buffer, pH 7.4 containing aprotinin (100 K;IU/ml)) and then frozen and thawed once.
Five ml of Buffer B (5 mM HEPES Buffer, pH 7.4 containing 10 mM
MnCl2 and 0.001 % deoxyribonuclease Type 1 ) was added, the ~~,' 96/31492 - PCT/US96/04759 '.

suspension mixed by inversion and then incubated at 37° C for 30 minutes. The mixture was centrifuged at 57, 800 X g as described above, the pellet washed twice with buffer A and then resuspended in buffer C (30 mM fIEPES buffer, pH 7.4 containing aprotinin ( 100 KIU/ml) to give a final protein concentration of 2 mg/ml.
The binding assay was performed as described above using the membrane preparation diluted to give 1 Ng/50 Ni of binding buffer.
C. Test for activity against endothelin-induced contraction of isolated rjt thoracic aortic rings The effectiv~:ness of the test compound as an antagonist or agonist of the biological tissue response of endothelin also is assessed by measuring the effect on endothelin induced contraction of isolated rat thoracic aortic rings (see, ~,_g_, Borges et al. (1989) Eur. J. Pharmacol.
165:223-230) or by measuring the ability to contract the tissue when added alone.
Compounds to be tested are prepared as 100 NM stocks. If necessary to effect: dissolution, the compounds are first dissolved in a minimum amount c~f DMSO and diluted with 150 mM NaCI. Because DMSO can cause relaxation of the aortic ring, control solutions containing varying concentrations of DMSO were tested.
The thoracic portion of the adult rat aorta is excised, the endothelium abraded by gentle rubbing and then cut into 3 mm ring segments. Segments are suspended under a 2 g preload in a 10 ml organ bath filled with Krebs'- Henseleit solution saturated with a gas mixture of 95% 02 and 5% COZ (118 mM NaCI, 4.7 mM KCI, 1.2 mM MgS04, 1.2 mM KH2P04, 25 mlVl NaHC;03, 2.5 mM CaCIZ, 10 mM D-glucose).
There is a correlation between activity as an antagonist of endothelin-induced thoracic aortic ring contraction and activity as an inhibitor of binding of endathelin to endothelin receptors. The pA2 is a linear function of the log of the ICS°.

- ~. ~ 96/31492 PCTlUS96/04759 D. Assay for identifying compounds that have agonist andlor antagonistic activity against ETB receptors 1. :>timulation of prostacyclin release Since endc~thelin-1 stimulates the release of prostacyclin from cultured bovine aortic endothelial cells, the compounds that have agonist or antagnoist activity are identified by their ability to inhibit endothelia-1 induced prostacyclin release from such endothelial cells by measuring 6-keto PGF,a substantially as described by fFilep et al. (i 991 ) Biochem.
Bioohys. Res. Coy-nmun. 177 171-176. Bovine aortic cells are obtained from collagenase-treated bovine aorta, seeded into culture plates, grown in Medium 199 supplemented with heat inactivated 15% fetal calf serum, and L-glutamine (2 mM), penicillin, streptomycin and fungizone, and subcultured at least four times. The cells are then seeded in six-well plates in the same medium. Eight hours before the assay, after the cells reach confluence, the medium is replaced. The cells are then incubated with a) medium alone, b) medium containing endothelia-1 ( 10 nM), c) test compound alone, and d) test compound + endothelia-1 (10 nM).
After a 15 min incubation, the medium is removed from each well and the concentrations of 6-keto PGF~Q are measured by a direct immunoassay. Prostacyclin production is calculated as the difference between the amount of 5-keto PGF~o released by the cells challenged with the endothelia-1 minus the amount released by identically treated unchallenged cells. Compounds that stimulate 6-keto PGF,o release possess agonist activity and those which inhibit endothelia-1 6-keto PGF,Q release possess antagonist activity.
2. Inhibition of sarafotoxin 6c induced contraction Sarafotoxin 6c is a specific ET8 antagonist that contracts rat fundal stomach strips. l'he effectiveness of tests compounds to inhibit this sarafotoxin 6c-incluced contraction of rat fundal stomach strips is used as a measure ETB antagonist: activity. Two isolated rat fundal stomach strips __ X1..96131492 PCTIUS96104759 are suspended under a 1 g load in a 10 ml organ bath filled with Krebs'-Henseleit solution containing 10 NM cyclo(D-Asp-Pro-D-Val-Leu-D-Trp) (B0.-123; see, U.S. Patent No. 5,114,918 to Ishikawa et al.), 5 NM
indomethacin,'and saturated with a gas mixture of 95% OZ/5% CO2.
Changes in tension are measured isometrically and recorded using a Grass Polygraph coupled to a force transducer. Sarafotoxin 6c is added cumulatively to one strip while the second strip is preincubated for 15 min with a test compound prior to addition of cumulative doses of sarafotoxin 6c. The effects of the test compounds on the concentration-response curve for sarafot:oxin 6c are examined.
E. Deox~rcorticosterone acetate (DOCA)-salt hypertensive rat model for assessing in vivo activity of selected compounds Selected compounds disclosed herein have been tested for activity in the deoxycorticosterone acetate (DOCA)-salt hypertensive rat model.
To perform these tests, silastic MDX4-4210 elastomer implants containing 47 mg (DOCA) were prepared according to the method of Ornmsbee et al. ((1973) the J. Pharm. Sci. 62:255-257). Briefly, DOCA
is incorporated into silicon rubber implants for sustained release. To prepare the implants the DOCA is incorporated into unpolymerized silicone rubber, catalyst is added and the mixture is cast in a hemicylindrical shape.
Sprague Davvley rats (7-8 weeks old) were unilaterally nephrectomized under ketamine anesthesia and a DOCA-implant was placed on the left I;ateral dorsal abdomen of the animal. The rats were allowed to recover for three weeks. During recovery they were permitted free access to normal rat chow and 0.9% NaCI drinking solution in place of drinking water. The rats develop hypertension within 3 weeks.

q ~6r31492 PCTlUS96/04759 All animals ~~nrere used in the tests between 21 and 30 days post surgery. The mean arterial blood presure in these animals ranged from 165-200 mm Hg.
On the day .of experimentation, catheters were inserted under brevital anesthesia into the right femoral artery for measurement of blood pressure, and into the right femoral vein for administration of a selected compound. The animals were placed in a restrainer and allowed to recover for a minimum of 60 min or until a steady mean arterial blood pressure was recorded. At that time, the selected compound or control vehicle was adminiistered either intravenously, as a 60 minute infusion, or orally by oral gava~3e. Blood pressure was recorded continuously for a fruther 10 hrs.
F. Effect of Intravenous administration on ET-1-induced pressor responses in conscious, autonomically blocked rats; a model for assessing in vivo activity of selected compounds Male Sprague Dawley rats (250-450 g) were anesthetized (Brevital 50 mg/kg, IP) and cannulae were placed in the femoral artery to measure mean arterial pressure (MAP) and in the femoral vein for intravenous drug administration. Animals were placed in a restrainer and allowed to regain consciousness. Thirty minutes later autonomic blockade was administered (atro~~ine methyl nitrate, 3 mg/kg, IV, followed tjy propranalol, 2 mg/~;g, IV). An hour later animals received a bolus injection of vehicle (0.5 ml) followed thirty minutes later by intravenous bolus administration of ET-1 (Control, 1 Ng/kg). Following recovery from this challenge, test -compounds were administered by intravenous bolus administration (0.5 ml) and then re-challenged with ET-1 thirty minutes later. Results are expressed as the percent inhibition of the ET-1-induced pressor response ai~ter administration of the test compound compared to the pressor response induced by the control ET-1 challenge. In some PGTlUS96104759 ~; _ 96r31492 ' cases a third ET-1 challenge was administered ninety minutes after administration of the test compound.
G. Results 1. In vitro The ICso for each off the compounds of the preceding Examples for ETA and ETB receptors has. been measured. Almost all of the compounds have an ICsa of less than '10 NM for either or both of the ETA and ETB
receptors. Many of the compounds have an ICSO less than about 10 NM, others have an ICSO less than about 1 NM and some of the compounds have an ICSO less t~~han about 0.1 NM. A number of the compounds have an ICSa for ETA receptors that is substantially less (10 to 100-fold or more) than for ETB receptors, and, thus are selective for ETA receptors.
Others of the compounds are ETB selective.
2. In vivo t5 a. Selected compounds, such as N-(4-chloro-3-methyl-5-isoxazolyl)-2-(N-(4-methyl-phenyl)aminocarbonyl)thiophene-3-sulfonamide, N-(4-promo-:I-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)-benzyl]benzo[b]thiophene-3-sulfonamide, N-(4-chloro-3-methyl-5-isoxa-zolyl)-2-(3,4,-meth~ylenedioxy)benzyl)benzo[b]thiophene-3-sulfonamide, N-(4-chloro-3-methyl-5-isoxazolyl)-2-[~-hydroxy(3,4-methylenedioxy)phenyl-ethyl]thiophene-3-sulfonamide, N-(4-chloro-3-methyl-5-isoxazolyl)-2-(3,4-methylenedioxyben~zylcarbanyl)thiophene-3-sulfonamide, have been tested in the hypertensive rat model, and were effective in decreasing blood pressure.
b. Selected compounds, such as N-(4-chloro-3-methyl-5-isoxazolyl)-2-{[3,4-(methylenedioxy)phenyl]acetyl}thiophene-3-sulfonamide, N-(4-c;hloro-3-methyl-5-isoxazolyl)2-{[2-acetyl-4,5-(methyienedioxy)pf~ienyl]aminocarbonyl}thiophene-3-sulfonamide, N-(4-chloro-3-methyl-5-i;soxazolyl)-2-[(4-methoxy-2-methylphenyl)aminocar-r __ ~I31492 PCTIUS96I04759 bonyl]thiophene-3-sulfonamide and N-(4-chloro-3-methyl-5-isoxazolyl)-2-[2-cyano-4, 5-dimethoxyphenyl)aminocarbonyl]thiophene-3-sulfonamide, and -(4-chloro-3-methyl-5-isoxazolyl)-2-(2-methyl-4,5-(methylenedioxy)-phenylacetyl]thiophene-3-sulfonamide have been tested in the autonomically blocl'Ked, normotensive rat model and shown to have substantial activity, reducing pressure about 30% in 30 min at dosages as low as 30 mg/kg, and more than 50% at dosages of 60 mg/kg. On the average dosagfa of 30-60 mg/kg of the test compound resulted in a 40-f:0% inhibition of pressor response.
Since modifications will be apparent to those of skill in this art, it is intended that this invention be limited only by the scope of the appended claims.

Claims (20)

CLAIMS:

1. A compound or a pharmaceutically acceptable salt, acid or ester thereof, that has formula VII:

wherein R13 is C1-6 alkyl or halo C1-6 alkyl;
R1 is halide; and R2 is C1-6 alkyl.

2. The compound, salt, acid or ester of claim 1, wherein R2 is selected from CH3, C2H5, n-C3H7 and cyclo-C3H5.

3. The compound, salt, acid or ester of claim 1 or 2, wherein R2 is CH3 or C2H5.

4. The compound, N-(4-bromo-3-methyl-5-isoxazolyl)-4'-methylphenyl-4-biphenylsulfonamide, or a pharmaceutically acceptable salt, acid or ester thereof.

5. The compound N-(4-bromo-3-methyl-5-isoxazolyl)-4'-trifluorophenyl-4-biphenylsulfonamide, or a pharmaceutically acceptable salt, acid or ester thereof.

6. A pharmaceutical composition, comprising the compound, salt, acid or ester of any one of claim 1 to 5, and a pharmaceutically acceptable carrier or diluent.

7. Use of one or more compounds, salts, acids or esters of any one of claims 1 to 5, for inhibiting the binding of an endothelin peptide to endothelin A (ET A) or endothelin B (ET B) receptors.

8. Use of one or more compounds, salts, acids or esters of any one of claims 1 to 5, for altering endothelin receptor-mediated activity.

9. A pharmaceutical composition formulated for single dosage administration, comprising an effective amount of one or more compounds, salts, acids or esters of any one of claims 1 to 5 and a pharmaceutically acceptable carrier or diluent, wherein the amount is effective for ameliorating the symptoms of an endothelin-mediated disease.

10. An article of manufacture, comprising packaging material and an effective amount of one or more compounds, salts, acids or esters of any one of claims 1 to 5, contained within the packaging material, wherein the compound, salt, acid or ester is effective for antagonizing the effects of endothelin, ameliorating the symptoms of an endothelin-mediated disorder, or inhibiting the binding of an endothelin peptide to an ET receptor with an IC50 of less than about 10µM, and the packaging material includes a label that provides directions for the use of the contents of the package for antagonizing the effects of endothelin, treating an endothelin-mediated disorder, or inhibiting the binding of endothelin to a endothelin receptor.

11. Use of a compound, salt, acid or ester of any one of claims 1 to 5, for formulation of a medicament for treatment of an endothelin-mediated disorder.

12. Use of a compound, salt, acid or ester of any one of claims 1 to 5, for treatment of an endothelin-mediated disorder.

13. The use of claim 11, wherein the disorder is glaucoma.

14. The use of claim 12, wherein the disorder is glaucoma.

15. The use of claim 11, wherein the disorder is selected from the group consisting of hypertension, cardiovascular disease, asthma, pulmonary hypertension, inflammatory diseases, ophthalmologic disease, menstrual disorders, obstetric conditions, wounds, gastroenteric disease, renal failure, immunosuppressant-mediated renal vasoconstriction, erythropoietin-mediated vasoconstriction, endotoxin shock, anaphylactic shock and hemorrhagic shock.

16. The use of claim 11, wherein the disorder is selected from the group consisting of hypertension, cardiovascular disease, pulmonary hypertension, erythropoietin-mediated vasoconstriction, endotoxin shock, pulmonary hypertension, anaphylactic shock and hemorrhagic shock.

17. The use of claim 11, wherein the disorder is selected from the group consisting of asthma and inflammatory diseases.

18. The use of claim 12, wherein the disorder is selected from the group consisting of hypertension, cardiovascular disease, asthma, pulmonary hypertension, inflammatory diseases, ophthalmologic disease, menstrual disorders, obstetric conditions, wounds, gastroenteric disease, renal failure, immunosuppressant-mediated renal vasoconstriction, erythropoietin-mediated vasoconstriction, endotoxin shock, anaphylactic shock and hemorrhagic shock.

19. The use of claim 12, wherein the disorder is selected from the group consisting of hypertension, cardiovascular disease, pulmonary hypertension, erythropoietin-mediated vasoconstriction, endotoxin shock, pulmonary hypertension, anaphylactic shock and hemorrhagic shock.

20. The use of claim 12, wherein the disorder is selected from the group consisting of asthma and inflammatory diseases.