WO2009155448A1

WO2009155448A1 - Biphenyl sulfonamides as dual angiotensin endothelin receptor antagonists

Info

Publication number: WO2009155448A1
Application number: PCT/US2009/047842
Authority: WO
Inventors: Andrew Cole; Patrick A. Jokiel; Marc-Raleigh Brescia; Lanying Qin; Ian Henderson
Original assignee: Ligand Pharmaceuticals Inc.
Priority date: 2008-06-20
Filing date: 2009-06-18
Publication date: 2009-12-23

Abstract

Biphenyl sulfonamide compounds are disclosed that are combined- angiotensin and endothelin receptor antagonists useful in the treatment of conditions such as hypertension and other diseases. Compounds of the general formula I as disclosed herein and pharmaceutically acceptable salts thereof are disclosed, as are uses thereof and pharmaceutical compositions comprising such compounds.

Description

LIGAND.053VPC PATENT

BIPHENYL SULFONAMIDES AS DUAL ANGIOTENSIN ENDOTHELIN

RECEPTOR ANTAGONISTS Field of the Invention

[0001] The present invention relates to biphenyl sulfonamide compounds which are combined angiotensin and endothelin receptor antagonists, to methods of using such compounds in the treatment of conditions such as hypertension and other diseases, and to pharmaceutical compositions containing such compounds.

BACKGROUND OF THE INVENTION

[0002] Angiotensin II (Angll) and endothelin- 1 (ET-I) are two of the most potent endogenous vasoactive peptides currently known and are believed to play a role in controlling both vascular tone and pathological tissue remodeling associated with a variety of diseases including hypertension, diabetic nephropathy and heart failure. Currently, angiotensin receptor blockers (ARBs), which block the activity of Angll, are widely used as a treatment for hypertension, diabetic nephropathy and heart failure. In addition, there is a growing body of data that demonstrates the potential therapeutic benefits of ET receptor antagonists (ERAs) in blocking ET-I activity.

[0003] It is also known that Angll and ET-I work together in blood pressure control and pathological tissue remodeling. For example, ARBs not only block the action of Angll at its receptor, but also limit the production of ET-I . Similarly, ERAs block ET-I activity and inhibit the production of Angll. Consequently, simultaneously blocking Angll and ET-I activities may offer better efficacy than blocking either substance alone.

[0004] In well-validated rat models of human hypertension, the combination of an ARB and an ERA results in a synergistic effect. Furthermore, although ARBs are the standard of care for patients with diabetic nephropathy, improved efficacy with the coadministration of an ERA has been reported in Phase 2 clinical development.

[0005] There are preclinical and initial clinical data suggesting that compared to either mechanism alone, simultaneously blocking angiotensin II and endothelin 1 at their respective receptors, ATI and ETA, may provide an improved treatment option for several cardiovascular diseases. SUMMARY OF THE INVENTION

[0006] Compounds of general formula I, including the pharmaceutically acceptable salts of compounds of general formula I, are antagonists of both angiotensin and endothelin receptors:

wherein:

X is O or NR⁴;

R¹ is an optionally substituted unsaturated nitrogenous heterocycle, with the provisos that when X is NR⁴, R¹ is not pyridine and when X is oxygen, R¹ is not pyridine or a fused pyridine;

R² is selected from the group consisting of hydrogen, (Ci-C₆)alkyl and alkoxyalkyl;

R³ is a heterocycle; and

R⁴ is selected from the group consisting of hydrogen, (Q-C^alkyl and (d-C₆)acyl.

[0007] The compounds of general formula I are useful as antagonists of angiotensin and endothelin receptors. Furthermore, the compounds of general formula I are useful in indications where angiotensin or endothelin mediation is desired for the treatment of various conditions. [0008] In another aspect, the invention relates to pharmaceutical compositions comprising a therapeutically effective amount of at least one compound of general formula I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0009] Yet another aspect, of the present invention relates to a method of treating an endothelin-dependent or angiotensin II-dependent disorder in a subject in need thereof comprising administering to the subject a therapeutically effective amount of at least one compound of general formula I.

[0010] Still another aspect of the invention relates to a method of treating a disease or disorder selected from hypertension; pulmonary hypertension; primary pulmonary hypertension; low renin hypertension; male erectile dysfunction; male or female sexual dysfunction; heart failure; atherosclerosis; restenosis; endotoxemia; cancer; migraine; asthma; ischemia; subarachnoid hemorrhage; benign prostatic hypertrophy; diabetic nephropathy; renal, glomerular or mesangial cell disorders; or acute or chronic renal failure in a subject in need thereof comprising administering to the subject a therapeutically effective amount of at least one compound of general formula I.

[0011] Yet another aspect of the invention relates to a method of inhibiting cell growth in a subject in need thereof comprising administering to the subject a therapeutically effective amount of at least one compound of general formula I.

DETAILED DESCRIPTION OF THE INVENTION

[0012] Throughout this specification the substituents are defined when introduced and retain their definitions.

[0013] In a first aspect the invention relates to biphenyl sulfonamides, and pharmaceutically acceptable salts thereof, having general formula I:

I

[0014] For the compounds of general formula I, X may be oxygen or NR⁴, wherein R⁴ is hydrogen, alkyl or acyl.

[0015] In certain embodiments, R¹ is an optionally substituted unsaturated nitrogenous heterocycle, particularly a heteroaryl. For instance, R¹ may be pyrazolopyrimidine, thiadiazole, pyrimidine or quinoline, each optionally substituted with one or more of (C]-C₈) hydrocarbon, oxaalkyl, heterocyclylalkyl, halogen, hydroxyalkoxy, hydroxyalkyl, haloalkyl, carboxyl, cyano, aminoalkyl, alkylamino, carboxamido,

heterocyclyl or (Cj-C₆) acyl. An example of such an R¹ may be

, with one of R , R⁷, R or R⁹ as the point of attachment to X and wherein the other three substituents are independently selected from the group consisting of hydrogen, (Ci- C₈)hydrocarbon, (Ci-C₆)acyl, oxaalkyl, heterocyclylalkyl, halogen, hydroxyalkoxy, hydroxyalkyl, haloalkyl, carboxyl, cyano, aminoalkyl, alkylamino, carboxamido and heterocyclyl, specifically hydrogen, methyl, ethyl, propyl, acetyl, 1-hydroxyethyl, iodo, ethenyl, imidazolyl ethyl, chloro, methoxy, cyano, hydroxymethyl, aminomethyl, trifluoromethyl, carboxyl, 1-methoxyethyl, carboxamido, ethoxy, isopropoxy, butoxy, pyrrolidin-1-yl, 2 -methoxy ethoxy, methylamino, propylamino, dimethylamino, ethylamino and hydroxy ethoxy. Further examples of R¹ include, but are not limited to:

[0016] In certain embodiments, X is oxygen and R¹ is pyrimidine or pyrazolopyrimidine, each optionally substituted with one or more of (Ci-C₆) alkoxyl, halogen or (Ci-C₆) alkyl. In other embodiments, X is NR⁴, R⁴ is hydrogen, alkyl or acyl, and in particular hydrogen, methyl or acetyl.

[0017] In yet other embodiments, R³ is heteroaryl. In particular, R³ can be chosen from isoxazolyl, pyridizinyl, pyrazinyl or pyrimidinyl, each optionally substituted with one or more of (Cj-C₆)alkyl, (Cj-C₆)alkoxyl, cyano, nitro, trifluoromethyl, hydrogen or halogen. In preferred embodiments, R³ is isoxazole, optionally substituted with one or more of methyl or fluorine.

[0018] In still other embodiments, R² is chosen from hydrogen, (Ci-C₆) alkyl and alkoxyalkyl. In particular, R² can be hydrogen, propyl or ethoxymethyl.

[0019] Compounds of general formula I are useful as endothelin or angiotensin inhibitors. It may be found upon examination that species and genera not presently excluded are not patentable to the inventors in this application. In this case, the exclusion of species and genera in applicants' claims are to be considered artifacts of patent prosecution and not reflective of the inventors' concept or description of their invention. The invention, in a composition aspect, is all compounds of formula I except those that are in the public's possession. Definitions

[0020] For convenience and clarity certain terms employed in the specification, examples and claims are described herein.

[0021] Alkyl is intended to include linear, branched, or cyclic hydrocarbon structures and combinations thereof. A combination would be, for example, cyclopropylmethyl. Lower alkyl refers to alkyl groups of from 1 to- 6 carbon atoms. Examples of lower alkyl groups include methyl, ethyl, propyl (both n-propyl and isopropyl), butyl (including s-and t-butyl) and the like. Preferred alkyl groups are those of C₂₀ or below; more preferred are Ci-C₈ alkyl. Cycloalkyl is a subset of alkyl and includes cyclic hydrocarbon groups of from 3 to 8 carbon atoms. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbornyl and the like.

[0022] C₁ to C₂₀ hydrocarbon includes alkyl, cycloalkyl, polycycloalkyl, alkenyl, alkynyl, aryl and combinations thereof. Examples include benzyl, phenethyl, cyclohexylmethyl, camphoryl and naphthylethyl. Hydrocarbon refers to any substituent comprised of hydrogen and carbon as the only elemental constituents. The term "carbocycle" is intended to include ring systems in which the ring atoms are all carbon but of any oxidation state. Thus (C₃-C io) carbocycle refers to such systems as cyclopropane, benzene and cyclohexene; (C₈-Ci₂) carbopolycycle refers to such systems as norbornane, decalin, indane and naphthalene. Carbocycle, not otherwise limited, refers to monocycles, bicycles and polycycles.

[0023] Alkoxy or alkoxyl refers to groups of from 1 to 8 carbon atoms of a straight, branched, cyclic configuration and combinations thereof attached to the parent structure through an oxygen. Examples include methoxy, ethoxy, propoxy, isopropoxy, cyclopropyloxy, cyclohexyloxy and the like. Lower-alkoxy refers to groups containing one to four carbons.

[0024] Heteroalkyl refers to alkyl residues in which one or more carbons (and their associated hydrogens) have been replaced by a heteroatom. For example, oxaalkyl refers to alkyl residues in which one or more carbons (and their associated hydrogens) have been replaced by oxygen. Examples include methoxypropoxy, 3,6,9-trioxadecyl and the like. The term oxaalkyl is intended as it is understood in the art [see Naming and Indexing of Chemical Substances for Chemical Abstracts, published by the American Chemical Society, 1J196, but without the restriction of f 127(a)], i.e. it refers to compounds in which the oxygen is bonded via a single bond to its adjacent atoms (forming ether bonds); it does not refer to doubly bonded oxygen, as would be found in carbonyl groups. Similarly, thiaalkyl and azaalkyl refer to alkyl residues in which one or more carbons have been replaced by sulfur or nitrogen, respectively. Examples include ethylaminoethyl and methylthiopropyl.

[0025] Acyl refers to formyl and to groups of 1, 2, 3, 4, 5, -6, 7 and 8 carbon atoms of a straight, branched, cyclic configuration, saturated, unsaturated and aromatic and combinations thereof, attached to the parent structure through a carbonyl functionality. One or more carbons in the acyl residue may be replaced by nitrogen, oxygen or sulfur as long as the point of attachment to the parent remains at the carbonyl. Examples include acetyl, benzoyl, propionyl, isobutyryl, t-butoxycarbonyl, benzyloxycarbonyl and the like. Lower- acyl refers to groups containing one to four carbons.

[0026] Aryl and heteroaryl mean a 5- or 6-membered aromatic or heteroaromatic ring containing 0-3 heteroatoms selected from O, N, or S; a bicyclic 9- or 10-membered aromatic or heteroaromatic ring system containing 0-3 heteroatoms selected from O, N, or S; or a tricyclic 13- or 14-membered aromatic or heteroaromatic ring system containing 0-3 heteroatoms selected from O, N, or S. The aromatic 6- to 14-membered carbocyclic rings include, e.g., benzene and naphthalene. The 5- to 10-membered aromatic heterocyclic rings include, e.g., imidazole, pyridine, indole, indoline, thiophene, benzopyranone, thiazole, furan, benzimidazole, benzodioxole, quinoline, isoquinoline, quinoxaline, pyrimidine, pyrazine, tetrazole and pyrazole.

[0027] Arylalkyl refers to a substituent in which an aryl residue is attached to the parent structure through alkyl. Examples are benzyl, phenethyl and the like. Heteroarylalkyl refers to a substituent in which a heteroaryl residue is attached to the parent structure through alkyl. Examples include, e.g., pyridinylmethyl, pyrimidinylethyl and the like.

[0028] Heterocycle means a cycloalkyl or aryl residue in which from one to three carbons is replaced by a heteroatom selected from the group consisting of N, O and S. The nitrogen and sulfur heteroatoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quaternized. Examples of heterocycles include pyrrolidine, pyrazole, pyrrole, indole, quinoline, isoquinoline, tetrahydroisoquinoline, benzofuran, benzodioxan, benzodioxole (commonly referred to as methylenedioxyphenyl, when occurring as a substituent), tetrazole, morpholine, thiazole, pyridine, pyridazine, pyrimidine, thiophene, furan, oxazole, oxazoline, isoxazole, dioxane, tetrahydrofiiran and the like. It is to be noted that heteroaryl is a subset of heterocycle in which the heterocycle is aromatic. Examples of heterocyclyl residues additionally include piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2- oxo-pyrrolidinyl, 2-oxoazepinyl, azepinyl, 4-piperidinyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyrazinyl, oxazolidinyl, isoxazolidin-yl, thiazolidinyl, isothiazolyl, quinuclidinyl, isothiazolidinyl, benzimidazolyl, thiadiazolyl, benzopyranyl, benzothiazolyl, tetrahydrofuryl, tetrahydropyranyl, thienyl, benzothienyl, thiamorpholinyl, thiamoφholinylsulfoxide, thiamorpholinylsulfone, oxadiazolyl, triazolyl and tetrahydroquinolinyl. A nitrogenous heterocycle is a heterocycle containing at least one nitrogen in the ring; it may contain additional nitrogens, as well as other heteroatoms.

[0029] The term "carbocycle" is intended to include ring systems, including polycyclic structures, consisting entirely of carbon but of any oxidation state. Thus (C₃-Cio) carbocycle refers to such systems as cyclopropane, benzene and cyclohexene; (C₈-Ci₂) carbopolycycle refers to such systems as norbornane, decalin, indane and naphthalene.

[0030] The terms "monocycle" and "bicycle" or "monocyclic" and "bicyclic" refer to carbocycles and heterocycles having one or two rings respectively. Preferred monocycles are 3, 4, 5, 6 or 7-membered rings, which may be aromatic, saturated or partially unsaturated. Non-limiting examples include cyclopropane, cyclopentane, cyclohexane, pyran, furan, tetrahydrofuran, tetrahydropyran, oxepane and phenyl. Preferred bicycles are those having from 8 to 12 ring atoms in total. Non-limiting examples include chroman, tetralin, naphthalene, benzofuran, indole, octahydropentalene and tetrahydrobenzo[b]oxepine. A particular embodiment comprises fused 5:6 and 6:6 systems.

[0031] Substituted alkyl, aryl, cycloalkyl, heterocyclyl etc. refer to alkyl, aryl, cycloalkyl, or heterocyclyl wherein up to three H atoms in each residue are replaced with halogen, haloalkyl, alkyl, aryl, acyl, alkoxyalkyl, alkyloxy, cycloalkyl, heterocyclyl, hydroxy, loweralkoxy, hydroxyloweralkyl, carboxy, carboalkoxy (also referred to as alkoxycarbonyl), carboxamido (also referred to as alkylaminocarbonyl), cyano, carbonyl, nitro, amino, alkylamino, dialkylamino, mercapto, alkylthio, sulfoxide, sulfone, acylamino, amidino, acetoxy, phenyl, benzyl, heteroaryl, phenoxy, benzenesulfonyl, benzyloxy, haloalkyoxy or heteroaryloxy. When the parent is a heterocycle that allows such substitution, the term also includes oxides, for example pyridine-N-oxide, thiopyran sulfoxide and thiopyran-S,S-dioxide. As mentioned above, two hydrogens on a single carbon may be replaced by a carbonyl to form an oxo derivative. Noteworthy oxo-substituted aryl residues include tetralone (3,4-dihydronaphthalen-l(2H)-one) and indanone (2,3- dihydroinden- 1 -one).

[0032] The terms "halogen" and "halo" refer to fluorine, chlorine, bromine or iodine.

[0033] Some of the compounds described herein may contain one or more asymmetric centers and may thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that may be defined, in terms of absolute stereochemistry, as (R)- or (S)-. The present invention is meant to include all such possible isomers, as well as mixtures thereof, including racemic and optically pure forms. Optically active (R)- and (S)- isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, and unless specified otherwise, it is intended that the compounds include both E and Z geometric isomers. Likewise, all tautomeric forms are also intended to be included. The configuration of any carbon-carbon double bond appearing herein is selected for convenience only and is not intended to designate a particular configuration; thus a carbon-carbon double bond depicted arbitrarily herein as trans may be Z, E or a mixture of the two in any proportion.

[0034] The graphic representations of racemic, ambiscalemic and scalemic or enantiomerically pure compounds used herein are taken from Maehr J Chem. Ed. 62, 114- 120 (1985): solid and broken wedges are used to denote the absolute configuration of a chiral element; wavy lines indicate disavowal of any stereochemical implication which the bond it represents could generate; solid and broken bold lines are geometric descriptors indicating the relative configuration shown but denoting racemic character; and wedge outlines and dotted or broken lines denote enantiomerically pure compounds of indeterminate absolute configuration. For example, the graphic representation of the two trans enantiomers

[0035] It will be recognized that the compounds of this invention can exist in radiolabeled form, i.e., the compounds may contain an unnatural ratio of one or more atoms containing an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Radioisotopes of hydrogen, carbon, phosphorous, fluorine, chlorine and iodine include ³H, ¹⁴C, ³⁵S, ¹⁸F, ³⁶Cl and ¹²⁵I, respectively. Compounds that contain those radioisotopes and/or other radioisotopes of other atoms are within the scope of this invention. Tritiated, i.e. ³H, and carbon-14, i.e., ¹⁴C, radioisotopes are particularly preferred for their ease in preparation and detectability. Radiolabeled compounds of this invention can generally be prepared by methods well known to those skilled in the art. Conveniently, such radiolabeled compounds can be prepared by carrying out the procedures disclosed in the Examples by substituting a readily available radiolabeled reagent for a non-radiolabeled reagent. Because of the high affinity for the ET-I and AngII active site, radiolabeled compounds of the invention are useful for these assays. Chemical Synthesis

[0036] Terminology related to "protecting", "deprotecting" and "protected" functionalities occurs throughout this application. Such terminology is well understood by persons of skill in the art and is used in the context of processes that involve sequential treatment with a series of reagents. In that context, a protecting group refers to a group which is used to mask a functionality during a process step in which it would otherwise react, but in which reaction is undesirable. The protecting group prevents reaction at that step, but may be subsequently removed to expose the original functionality. The removal or "deprotection" occurs after the completion of the reaction or reactions in which the functionality would interfere. Thus, when a sequence of reagents is specified, as it is in the processes of the invention, the person of ordinary skill can readily envision those groups that would be suitable as "protecting groups". Suitable groups for that purpose are discussed in standard textbooks in the field of chemistry, such as Protective Groups in Organic Synthesis by T. W. Greene [John Wiley & Sons, New York, 1991], which is incorporated herein by reference.

[0037] A comprehensive list of abbreviations utilized by organic chemists appears in the first issue of each volume of the Journal of Organic Chemistry. The list, which is typically presented in a table entitled "Standard List of Abbreviations", is incorporated herein by reference.

[0038] In general, the compounds of the present invention may be prepared by the methods illustrated in the general reaction schemes as, for example, described below, or by modifications thereof, using readily available starting materials, reagents and conventional synthesis procedures. In these reactions, it is also possible to make use of variants that are in themselves known, but are not mentioned here. The starting materials, for example in the case of suitably substituted benzimidazole ring compounds, are either commercially available, synthesized as described in the examples or may be obtained by the methods well known to persons of skill in the art.

[0039] The present invention further provides pharmaceutical compositions comprising as active agents, the compounds described herein.

[0040] As used herein a "pharmaceutical composition" refers to a preparation of one or more of the compounds described herein, or physiologically acceptable salts or solvates thereof, with other chemical components such as physiologically suitable carriers and excipients.

[0041] Pharmaceutical compositions for use in accordance with the present invention thus may be formulated in conventional manner using one or more physiologically acceptable carriers comprising excipients and auxiliaries, which facilitate processing of the active compounds into preparations which, can be used pharmaceutically. Proper formulation is dependent upon the route of administration chosen.

[0042] Compounds that inhibit angiotensin or endothelin can be formulated as pharmaceutical compositions and administered to a mammalian subject, such as a human patient in a variety of forms adapted to the chosen route of administration, i.e., orally or parenterally, by intravenous, intramuscular, topical, transdermal or subcutaneous routes.

[0043] For oral administration, the compounds can be formulated readily by combining the active compounds with pharmaceutically acceptable carriers well known in the art. Such carriers enable the compounds of the invention to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions, and the like, for oral ingestion by a patient. Pharmacological preparations for oral use can be made using a solid excipient, optionally grinding the resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries if desired, to obtain tablets or dragee cores. Suitable excipients are, in particular, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethyl-cellulose, sodium carbomethylcellulose; and/or physiologically acceptable polymers such as polyvinylpyrrolidone (PVP). If desired, disintegrating agents may be added, such as cross- linked polyvinyl pyrrolidone, agar or alginic acid or a salt thereof such as sodium alginate.

[0044] In addition, enteric coating may be useful as it is may be desirable to prevent exposure of the compounds of the invention to the gastric environment.

[0045] Pharmaceutical compositions, which can be used orally, include push-fit capsules made of gelatin as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. The push- fit capsules may contain the active ingredients in admixture with filler such as lactose, binders such as starches, lubricants such as talc or magnesium stearate and, optionally, stabilizers.

[0046] In soft capsules, the active compounds may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols. In addition, stabilizers may be added. All formulations for oral administration should be in dosages suitable for the chosen route of administration. [0047] For injection, the compounds of the invention may be formulated in aqueous solutions, preferably in physiologically compatible buffers such as Hank's or Ringer's solution or physiological saline buffer. For transmucosal and transdermal administration, penetrants appropriate to the barrier to be permeated may be used in the composition. Such penetrants, including for example DMSO or polyethylene glycol, are known in the art.

[0048] For administration by inhalation, the compounds for use according to the present invention are conveniently delivered in the form of an aerosol spray presentation from a pressurized pack or a nebulizer with the use of a suitable propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichloro-tetrafluoroethane or carbon dioxide. In the case of a pressurized aerosol, the dosage unit may be determined by providing a valve to deliver a metered amount. Capsules and cartridges of, e.g., gelatin for use in an inhaler or insufflator may be formulated containing a powder mix of the compound and a suitable powder base such as lactose or starch.

[0049] Pharmaceutical compositions for parenteral administration include aqueous solutions of the active ingredients in water-soluble form. Additionally, suspensions of the active compounds may be prepared as appropriate oily injection suspensions. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acids esters such as ethyl oleate, triglycerides or liposomes. Aqueous injection suspensions may contain substances, which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol or dextran. Optionally, the suspension may also contain suitable stabilizers or agents, which increase the solubility of the compounds, to allow for the preparation of highly concentrated solutions.

[0050] The compounds of the present invention may also be formulated in rectal compositions such as suppositories or retention enemas, using, e.g., conventional suppository bases such as cocoa butter or other glycerides.

[0051] Depending on the severity and responsiveness of the condition to be treated, dosing can also be a single administration of a slow release composition, with course of treatment lasting from several days to several weeks or until cure is effected or diminution of the disease state is achieved. The amount of a composition to be administered will, of course, be dependent on many factors including the subject being treated, the severity of the affliction, the manner of administration, the judgment of the prescribing physician. The compounds of the invention may be administered orally or via injection at a dose from 0.001 to 2500 mg/kg per day. The dose range for adult humans is generally from 0.005 mg to 10 g/day. Tablets or other forms of presentation provided in discrete units may conveniently contain an amount of compound of the invention which is effective at such dosage or as a multiple of the same, for instance, units containing 5 mg to 500 mg, usually around 10 mg to 200 mg. The precise amount of compound administered to a patient will be the responsibility of the attendant physician. However, the dose employed will depend on a number of factors, including the age and sex of the patient, the precise disorder being treated, and its severity. Also, the route of administration may vary depending on the condition and its severity.

[0052] As used herein, and as would be understood by the person of skill in the art, the recitation of "a compound" is intended to include salts, solvates and inclusion complexes of that compound. The term "solvate" refers to a compound of Formula I or II in the solid state, wherein molecules of a suitable solvent are incorporated in the crystal lattice. A suitable solvent for therapeutic administration is physiologically tolerable at the dosage administered. Examples of suitable solvents for therapeutic administration are ethanol and water. When water is the solvent, the solvate is referred to as a hydrate. In general, solvates are formed by dissolving the compound in the appropriate solvent and isolating the solvate by cooling or using an antisolvent. The solvate is typically dried or azeotroped under ambient conditions. Inclusion complexes are described in Remington: The Science and Practice of Pharmacy 19th Ed. (1995) volume 1, page 176-177, which is incorporated herein by reference. The most commonly employed inclusion complexes are those with cyclodextrins, and all cyclodextrin complexes, natural and synthetic, are specifically encompassed within the claims.

[0053] The term "pharmaceutically acceptable salt" refers to salts prepared from pharmaceutically acceptable non-toxic acids or bases including inorganic acids and bases and organic acids and bases. When the compounds of the present invention are basic, salts may be prepared from pharmaceutically acceptable non-toxic acids including inorganic and organic acids. Suitable pharmaceutically acceptable acid addition salts for the compounds of the present invention include acetic, benzenesulfonic (besylate), benzoic, camphorsulfonic, citric, ethenesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric acid, p-toluenesulfonic, and the like. When the compounds contain an acidic side chain, suitable pharmaceutically acceptable base addition salts for the compounds of the present invention include metallic salts made from aluminum, calcium, lithium, magnesium, potassium, sodium and zinc or organic salts made from lysine, NjN'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine_τ ethylenediamine, meglumine (iV-methylglucamine) and procaine.

[0054] The term "preventing" as used herein refers to administering a medicament beforehand to forestall or obtund an attack. The person of ordinary skill in the medical art (to which the present method claims are directed) recognizes that the term "prevent" is not an absolute term. In the medical art it is understood to refer to the prophylactic administration of a drug to substantially diminish the likelihood or seriousness of a condition, and this is the sense intended herein.

[0055] It should be understood that in addition to the ingredients particularly mentioned above, the formulations of this invention may include other agents conventional in the art having regard to the type of formulation in question, for example those suitable for oral administration may include flavoring agents.

[0056] The compositions may be presented in a packaging device or dispenser, which may contain one or more unit dosage forms containing the active ingredient. Examples of a packaging device include metal or plastic foil, such as a blister pack and a nebulizer for inhalation. The packaging device or dispenser may be accompanied by instructions for administration. Compositions comprising a compound of the present invention formulated in a compatible pharmaceutical carrier may also be placed in an appropriate container and labeled for treatment of an indicated condition. Indications

[0057] The compounds of the present invention are antagonists of both endothelin (especially, ET-I) and angiotensin II (especially, subtype AT₁) receptors ("dual angiotensin endothelin receptor antagonists") and are useful in treatment of conditions associated with increased ET levels and/or increased angiotensin II levels and of all endothelin-dependent or angiotensin II-dependent disorders. They are thus useful as antihypertensive agents. By the administration of a composition having one (or a combination) of the compounds of this invention, the blood pressure of a hypertensive mammalian (e.g., human) host is reduced. They are also useful in portal hypertension, hypertension secondary to treatment with erythropoietin and low renin hypertension.

[0058] The compounds of the present invention are also useful in the treatment of disorders related to renal, glomerular and mesangial cell function, including acute (such as ischemic, nephrotoxic, or glomerulonephritis) and chronic (such as diabetic, hypertensive or immune-mediated) renal failure, glomerular injury, renal damage secondary to old age or related to dialysis, nephrosclerosis (especially hypertensive nephrosclerosis), nephrotoxicity (including nephrotoxicity related to imaging and contrast agents and to cyclosporine), renal ischemia, primary vesicoureteral reflux, glomerulosclerosis and the like. The compounds of this invention are also useful in the treatment of disorders related to paracrine and endocrine function.

[0059] The compounds of the present invention are also useful in the treatment of endotoxemia or endotoxin shock as well as hemorrhagic shock.

[0060] The compounds of the present invention are also useful in hypoxic and ischemic disease and as anti-ischemic agents for the treatment of, for example, cardiac, renal and cerebral ischemia and reperfusion (such as that occurring following cardiopulmonary bypass surgery), coronary and cerebral vasospasm, and the like.

[0061] In addition, the compounds of this invention are also useful as antiarrhythmic agents; anti-anginal agents; anti-fibrillatory agents; anti-asthmatic agents; anti- atherosclerotic and anti-arteriosclerotic agents; additives to cardioplegic solutions for cardiopulmonary bypasses; adjuncts to thrombolytic therapy; and anti-diarrheal agents. The compounds of this invention may be useful in therapy for myocardial infarction; therapy for peripheral vascular disease (e.g., Raynaud's disease and Takayashu's disease); treatment of cardiac hypertrophy (e.g., hypertrophic cardiomyopathy); treatment of primary pulmonary hypertension (e.g., plexogenic, embolic) in adults and in the newborn and pulmonary hypertension secondary to heart failure, radiation and chemotherapeutic injury, or other trauma; treatment of central nervous system vascular disorders, such as stroke, migraine and subarachnoid hemorrhage; treatment of central nervous system behavioral disorders; treatment of gastrointestinal diseases such as ulcerative colitis, Crohn's disease, gastric mucosal damage, ulcer and ischemic bowel disease; treatment of gall bladder or bile duct- based diseases such as cholangitis; treatment of pancreatitis; regulation of cell growth; treatment of benign prostatic hypertrophy; restenosis following angioplasty or following any procedures including transplantation; therapy for congestive heart failure including inhibition of fibrosis; inhibition of left ventricular dilatation, remodeling and dysfunction; and treatment of hepatotoxicity and sudden death.

[0062] The compounds of this invention are useful in the treatment of sickle cell disease including the initiation and/or evolution of the pain crises of this disease; treatment of the deleterious consequences of ET-producing tumors such as hypertension resulting from hemangiopericytoma; treatment of early and advanced liver disease and injury including attendant complications (e.g., hepatotoxicity, fibrosis and cirrhosis); treatment of spastic diseases of the urinary tract and/or bladder; treatment of hepatorenal syndrome; treatment of immunological diseases involving vasculitis such as lupus, systemic sclerosis, mixed cryoglobulinemia; and treatment of fibrosis associated with renal dysfunction and hepatotoxicity. The compounds of this invention are useful in therapy for metabolic and neurological disorders; cancer; insulin-dependent and non insulin-dependent diabetes mellitus; neuropathy; retinopathy; maternal respiratory distress syndrome; dysmenorrhea; epilepsy; hemorrhagic and ischemic stroke; bone remodeling; psoriasis; and chronic inflammatory diseases such as rheumatoid arthritis, osteoarthritis, sarcoidosis and eczematous dermatitis (all types of dermatitis).

[0063] The compounds of this invention are also useful in the treatment of sexual dysfunction in both men (erectile dysfunction, for example, due to diabetes mellitus, spinal cord injury, radical prostatectomy, psychogenic etiology or any other cause) and women by improving blood flow to the genitalia, especially, the corpus cavernosum.

[0064] The present invention thus provides methods for the treatment of all endothelin-dependent or angiotensin II-dependent disorders, comprising the step of administering to a subject in need thereof at least one compound of the formula I in an amount effective therefor. Other therapeutic agents such as those described below may be employed with the inventive compounds in the present methods. In the methods of the present invention, such other therapeutic agent(s) may be administered prior to, simultaneously with or following the administration of the compound(s) of the present invention. [0065] The following examples will further describe the invention, and are used for the purposes of illustration only, and should not be considered as limiting the invention being disclosed.

EXAMPLES

[0066] The following abbreviations and terms have the indicated meaning throughout:

Ac acetyl ACN acetonitrile Boc tørt-butoxycarbonyl BSA bovine serum albumin Bu butyl

BuOH butanol CDCl ₃ Deuterated chloroform CD₃OD Deuterated methanol δ NMR chemical shift referenced to tetramethylsilane

DCM dichloromethane = methylene chloride = CH₂Cl₂ DCE 1 ,2-dichloroethane DEAD diethyl azodicarboxylate DIC diisopropylcarbodiimide DIEA N,N-diisopropylethyl amine DMAP 4-Dimethylaminopyridine DMF N,N-dimethylformamide DMSO dimethyl sulfoxide EtOAc Ethyl Acetate EtOH Ethanol EDC N-(3-Dimethylaminopropyl)-N')ethylcarbodiimide EDTA ethylene diamine tetraacetic acid EtOH ethanol GC gas chromatography h hours

HEPES 4-(2-hydroxyethyl)- 1 -piperazineethanesulfonic acid HMG CoA 3 -hydroxy-3-methyl-glutary 1-CoA reductase HOAc acetic acid HOBt hydroxybenzotriazole

KD dissociation constant m- meta

Me methyl

MeOH methanol = CH₃OH

MS mass spectrometry min minutes

MOM methoxymethyl

N normal NMR = Nuclear Magnetic Resonance

Na(OAc)₃BH = sodium triacetoxy borohydride

0- = ortho

P- = para

Pd(dppf)₂Cl₂ = dichloro [1,1 ' -bis(diphenylphosphinoferrocene]palladium

PDE = phosphodiesterase

PDGF = Platelet-derived growth factor

PG = protecting group

PVT = polyvinyltoluene

Ph = phenyl

PhOH = phenol

Pr = propyl

PrOH = propanol

PS = polystyrene

PS-BEMP = 2-tert-buty limino-2-diethylamino- 1 ,3 -dimethyl -perhydro-

1,3,2-diazo phosphorine on polystyrene

RT = room temperature (rt) sat. = saturated

S- = secondary

SEM = trimethylsilyl ethoxymethyl

SPA = scintillation proximity assay t- = tert- = tertiary

TBAF = tetrabutyl ammonium fluoride

TBDMS = t-butyldimethylsilyl

Tf triflate

TFA = trifluoroacetic acid

THF = tetrahydrofuran

TLC = thin layer chromatography

TMS = trimethylsilyl

[0067] Examples below describe syntheses of certain precursors and intermediates of the invention. Compounds of formula I can be synthesized from key synthetic intermediates of formula II (Scheme 1). By way of illustration, but not limitation, the syntheses of representative compounds of formula I are detailed below.

[0068] Synthetic intermediates of formula II, incorporating a functionalized biaryl framework, can be synthesized according to the synthetic procedures outlined in WO2000/01389, WO2001 //044239, US2002/0143024, J Med. Chem. 2002, 45, 3829, and J. Med. Chem. 2005, 48, 171. PG is a suitable Nitrogen protecting group (typically MOM or SEM) and Y is selected from the group consisting of -OH, -NH₂, Hal (Cl₅^r or I). X, R¹, R² and R³ are as defined within the detailed description of the invention. Conversion of compounds of formula II (Y=Br) to compounds of formula II (Y=NH₂) can be achieved by displacement of the bromide with phthalimide and deprotection to the primary amine with hydrazine under standard conditions.

[0069] General Procedure A: MOM protecting group removal (Scheme 2). To a solution of HIa in absolute ethanol was added an equal volume of 6 M HCl and the mixture heated at 80°C for 3 h. The solvent was evaporated to provide compounds of formula I.

HIa I

Scheme 2.

[0070] General Procedure B: SEM protecting group removal (Scheme 3). To a solution of IHb in DMF was added 2 eq. of a 1.0 M solution of TBAF in THF and the mixture heated at 80°C for 2 h. The solvent was evaporated and the residue purified to provide compounds of formula I.

HIb

Scheme 3. [0071] Compounds of formula I (examples 1 to 7) were synthesized according to the general synthetic route outlined in scheme 4.

Scheme 4.

[0072] The synthetic route outlined in Scheme 4 is exemplified by the synthesis of the following examples:

Λ^r-(4,5-dimethyl-3-isoxazolyl)-iV-(methoxymethyl)-4'-[[(6-chloro-2-methyl- 4-pyrimidinyl)amino]methyl]-2'-(ethoxymethyl)[l,l'-biphenyl]-2-sulfonamide (3)

[0073] To a solution of 41 mg (0.29 mmol, 1.5 eq.) of 6-chloro-2- methylpyrimidin-4-amine (2) in 1.5 mL of anhydrous DMF was added 6.9 mg (0.29 mmol, 1.5 eq.) of sodium hydride and the mixture stirred at room temperature for 30 min. A solution of 100 mg (0.19 mmol) of 7V-(4,5-dimethyl-3-isoxazolyl)-N-(methoxymethyl)-4'- bromomethyl-2'-(ethoxymethyl)[l,l'-biphenyl]-2-sulfonamide (1) was added and the mixture stirred at room temperature for a further 2 h. The mixture was diluted with 3 mL of water and the mixture extracted with 3 x 3 mL of EtOAc. The combined organic extracts were dried (Na₂SO₄) and the solvent removed in vacuo. The residue was purified by flash chromatography (0-70% EtOAc/CH₂Cl₂) to provide 108 mg of N-(4,5-dimethyl-3- isoxazolyl)-N-(methoxymethyl)-4'-[[(6-chloro-2-methyl- 4-pyrimidinyl)amino]methyl]-2'-(ethoxymethyl)[l , 1 '-biphenyl]-2-sulfonamide (3).

7V-(4,5-dimethyI-3-isoxazolyl)-4'-[[(6-chloro-2-methyl-4-pyrimidinyl)amino]methyl]-2'- (ethoxymethyl)[l,l'-biphenyl]-2-sulfonamide (Example 1)

3 Example 1

[0074] N-(4,5-dimethyl-3-isoxazolyl)-iV-(methoxymethyl)-4'-[[(6-chloro-2- methyl-4-pyrimidinyl)amino]methyl]-2'-(ethoxymethyl)[l,r-biphenyl]-2-sulfonamide (3) was deprotected using General Procedure A to provide Λ^r-(4,5-dimethyl-3-isoxazolyl)-4'-[[(6- chloro-2-methyl-4-pyrimidinyl)amino]methyl]-2'-(ethoxymethyl)[l,r-biphenyl]-2- sulfonamide (Example 1) (Example numbers also refer to the compounds identified by number in Tabe 1, below***). δ_H (CD₃OD, 300 MHz) 1.08 (t, 3H), 1.72 (s, 3H), 2.26 (s, 3H), 2.52 (s, 3H), 3.3 (m, obscured by solvent), 4.12 (ABq, 2H), 4.76 (b, 2H), 6.60 (s, IH), 7.07 (d, IH), 7.27 (m, 2H), 7.50 (s, IH), 7.62 (m, 2H), 8.17 (m, IH); m/z found 542.1 [M+H]⁺.

[0075] Reaction of 3 with a primary amine followed by deprotection provides examples 2-7, as exemplified below.

iV-(4,5-dimethyl-3-isoxazolyl)-4'-[[(6-methylamino-2-methyl- 4-pyrimidinyl)amino]methyl]-2'-(ethoxymethyl)[l,l'-biphenyl]-2-sulfonamide (Example

2).

K₂CO₃ 0C 80 ⁰C

[0076] A mixture of 130 mg (0.22 mmol, 1.0 eq.) of N-(4,5-dimethyl-3- isoxazolyl)-Λ'^'-(methoxymethyl)-4'-[[(6-chloro-2-methyl-4-pyrimidinyl)amino]methyl]-2^l- (ethoxymethyl)[l,r-biphenyl]-2-sulfonamide (3), 61 mg (0.44 mmol 2.0 eq.) of potassium carbonate and 3 mL of methylamine (2 M solution in THF) was heated at 130 ⁰C for 24 h in a sealed tube. The mixture was allowed to cool to room temperature and the solvent removed in vacuo. The residue was diluted in 5 mL of CH₂Cl₂, filtered, and the sβlid washed with 3 mL of CH₂Cl₂. The filtrate was concentrated and the residue purified by prep. HPLC. The purified product was deprotected according to General Procedure A to provide JV-(4,5- dimethyl-3 -isoxazoly l)-4'- [ [(6-methy lamino-2-methy 1-

4-pyrimidinyl)amino]methyl]-2'-(ethoxymethyl)[l,r-biphenyl]-2-sulfonamide (Example 2). δ_H (CD₃OD, 300 MHz) 1.07 (t, 3H), 1.73 (s, 3H), 2.25 (s, 3H), 2.46 (s, 3H), 2.90 (s, 3H), 3.3 (m, obscured by solvent), 4.13 (ABq, 2H), 4.64 (b, 2H)₅ 5.48 (s, IH), 7.08 (d, IH), 7.27 (m, 2H), 7.50 (s, IH), 7.62 (m, 2H), 8.14 (d, IH); m/z found 537.1 [M+H]⁺.

[0077] Example 8 was synthesized using a similar procedure from 1 and 5- chloro-2,6-dimethylpyrimidin-4-arnine followed by protecting group removal.

[0078] Example 9 was synthesized using a similar procedure from 1 and 2- methylquinolin-4-amine followed by protecting group removal.

[0079] Compounds of formula I (Examples 10 to 16) were synthesized according to the general synthetic route outlined in scheme 5.

[0080] The synthetic route outlined in Scheme 5 is exemplified by the synthesis of the following examples:

A^r-(4,5-dimethyl-3-isoxazolyI)-4'-[[(6-propyloxy-2-methyl-

4-pyrimidinyl)amino]methyl]-2'-(ethoxymethyl)[l,l'-biphenyl]-2-sulfonamide (Example 10).

°C 80 ⁰C

[0081J To 3 mL of freshly distilled «-PrOH was added 12 mg (0.52 mmol, 2.0 eq.) of sodium metal with stirring in a microwave tube. A solution of 150 mg (0.26 mmol, 1.0 eq.) of N-(4,5-dimethyl-3-isoxazolyl)-iV-(methoxymethyl)-4'-[[(6-chloro-2-methyl-4- pyrimidinyl)amino]methyl]-2'-(ethoxymethyl)[l,r-biphenyl]-2-sulfonamide (3) in 1 mL of DMF was added, followed by 12.7 mg (0.13 mmol, 0.5 eq.) of CuI. The solution was degassed with argon and sealed. The reaction mixture was subjected to microwave irradiation, maintaining an internal reaction temperature of 135 ⁰C for 30 min. The reaction mixture was allowed to cool to room temperature and filtered. The filtrate was concentrated, and the crude product was purified by prep. HPLC. The purified product was deprotected according to General Procedure A to provide iV-(4,5-dimethyl-3-isoxazolyl)-4'-[[(6-propyloxy-2-methyl- 4-pyrimidinyl)amino]methyl]-2'-(ethoxymethyl)[l , 1 '-biphenyl]-2-sulfonamide (Example 10). δ_H (CD₃OD, 400 MHz) 0.95 (m, 6H), 1.60 (s, 3H), 1.76 (m, 2H), 2.14 (s, 3H), 2.41 (s, 3H), 3.3 (m, obscured by solvent), 4.00 (ABq, 2H), 4.16 (m, 2H), 4.70 (m, 2H), 5.93 (bs, IH), 6.98 (d, IH), 7.18 (m, 2H), 7.40 (s, IH), 7.52 (m, 2H), 8.03 (d, IH); m/z found 566.1 [M+H]⁺.

[0082] Substituted pyrimidine intermediates of formula IX can be synthesized as detailed in scheme 6 and outlined in Chem. Pharm. Bull. 1983, 31, 4533. ^RN N '^*S

Cl

VIII IX

Scheme 6.

[0083] Intermediates of formula IX can be used to generate compounds of formula I as outlined in Scheme 7. Compounds of formula I (examples 17 to 25) were synthesized from intermediates of formula IX or their commercially available equivalents according to the general synthetic route outlined in Scheme 7.

H,

X = NH₂, OH

Scheme 7.

[0084] The synthetic route outlined in Scheme 7 is exemplified by the synthesis of the following examples:

iy-(4,5-dimethyl-3-isoxazolyl)-4'-[[(6-ethyl-2-methyl- 4-pyrimidinyl)amino]methyl]-2'-(ethoxymethyl)[l,l'-biphenyl]-2-sulfonamide (Example

17).

[0085] To a solution of 50 mg of N-(4,5-dimethyl-3-isoxazolyl)-iV- (methoxymethyl)-4'-aminomethyl-2'-(ethoxymethyl)[ 1 , 1 '-biphenyl]-2-sulfonamide and 16.8 mg (1 eq.) of 4-chloro-6-ethyl-2-methylpyrimidine in 2 mL of 1-butanol was added 10 mg of sodium carbonate and the mixture heated at 115 °C for 18 h. The solvent was removed in vacuo and the residue purified by flash chromatography (0 - 70% EtOAc/CH₂Cl₂) to provide 26 mg of N-(4,5-dimethyl-3-isoxazolyl) iV-(methoxymethyl)-4'-[[(6-ethyl-2-methyl- 4-pyrimidinyl)amino]methyl]-2'-(ethoxymethyl)[l , 1 '-biphenyl]-2-sulfonamide which was deprotected according to General Procedure A to provide N-(4,5-dimethyl-3-isoxazolyl)-4'- [[(6-ethyl-2-methyl-4-pyrimidinyl)amino]methyl]-2'-(ethoxymethyl)[l,l'-biphenyl]-2- sulfonamide (Example 17). δ_H (CD₃OD, 400 MHz) 1.10 (t, 3H), 1.30 (t, 3H), 1.75 (s, 3H), 2.26 (s, 3H), 2.61 (s, 3H), 2.72 (q, 2H), 3.3 (m, obscured by solvent), 4.15 (ABq, 2H), 4.84 (s, 2H), 6.52 (s, IH), 7.10 (d, IH), 7.27 (m, 2H), 7.51 (s, IH), 7.63 (m, 2H), 8.15 (m, IH); m/z found 536.1, [M+H]⁺.

Λ'-(4,5-dimethyl-3-isoxazolyI)-4'-[[(6-methyl-2-ethyl-4-pyrimidinyl)oxy]methyl]-2'- (ethoxymethyl)[l,l'-biphenyl]-2-sulfonamide (Example 23).

[0086] Following deprotection of 120 mg (0.25 mmol, 1.0 eq.) of N-(4,5- dimethyl-3-isoxazolyl)-N-(methoxymethyl)-4'-bromomethyl-2'-(ethoxymethyl)[l,r- biphenyl]-2-sulfonamide (1) according to General procedure A, 41 mg (0.3 mmol, 1.2 eq.) of 2-ethyl-6-methylpyrimidin-4-ol (6) and 163 mg (0.5 mmol, 2.0 eq.) Of Cs₂CO₃ were added to a solution of the deprotected product in 5 mL of DMF and the mixture stirred at room temperature for 12 h. The resulting mixture was concentrated and the residue was diluted with 10 mL EtOAc. The mixture was filtered and concentrated. The crude product was purified by prep. HPLC to provide iV-(4,5-dimethyl-3-isoxazolyl)-4'-[[(6-methyl-2-ethyl-4- pyrimidinyl)oxy]methyl]-2'-(ethoxymethyl)[l,r-biphenyl]-2-sulfonamide (Example 23). δπ (CD₃OD, 400 MHz) 1.09 (t, 3H), 1.43 (t, 3H), 1.73 (s, 3H), 2.26 (s, 3H), 2.55 (s, 3H), 2.99 (q, 2H), 3.3 (m, obscured by solvent), 4.14 (ABq, 2H), 5.67 (s, 2H), 6.92 (s, IH), 7.13 (d, IH), 7.25 (d, IH), 7.41 (d, IH), 7.64 (m, 3H), 8.18 (m, IH); m/z found 537.1, [M+H]⁺.

[0087] Compounds of formula I (examples 26 to 30) were synthesized according to the general synthetic route outlined in scheme 8 (See also: Chem. Pharm. Bull. 1999, 47, 928, J. Org. Chem. 1959, 24, 787).

Scheme 8.

[0088] The synthetic route outlined in Scheme 8 is exemplified by the synthesis of the following examples:

7V-(4,5-dimethyl-3-isoxazolyl)-4'-[5-methyIpyrazolo[l,5-a]pyrimidin-7-aininomethyI]-2^l- (ethoxymethyl)[l,r-biphenyl]-2-sulfonamide (Example 26).

[0089] To a solution of 100 mg (0.19 mmol, 1.0 eq.) of N-(4,5-dimethyl-3- isoxazolyl)-Λ'^r-(methoxymethyl)-4^I-bromomethyl-2'-(ethoxymethyl)[ 1 , 1 '-biphenyl]-2- sulfonamide (1) in DMF was added 33 mg (0.23 mmol, 1.2 eq.) of 5-methylpyrazolo[l,5- a]pyrimidin-7-amine (7) and 32 mg (0.23 mmol, 1.2 eq.) of potassium carbonate, and the mixture was stirred at room temperature for 18 h. The mixture was diluted with 2 mL of H₂O and extracted with 3 x 4 niL of EtOAc. The combined organic extracts were dried (Na₂SO₄) and the solvent removed in vacuo. The residue was purified by flash chromatography (1-10% MeOH/CH₂Cl₂) to provide 96 mg of N-(4,5-dimethyl-3-isoxazolyl)-N-(methoxymethyl)-4'- [5-methylpyrazolo[l,5-a]pyrimidin-7-aminomethyl]-2'-(ethoxymethyl)[l,r-biphenyl]-2- sulfonamide which was deprotected according to General Procedure A to provide N-(4,5- dimethyl-3-isoxazolyl)-4'-[5-methylpyrazolo[l,5-a]pyrimidin-7-aminomethyl]-2'- (ethoxymethyl)[l,l'-biphenyl]-2-sulfonamide (Example 26). δ_H (CD₃OD, 300 MHz) 1.06 (t, 3H), 1.71 (s, 3H), 2.23 (s, 3H), 2.63 (s, 3H), 3.3 (m, obscured by solvent), 4.15 (ABq, 2H), 5.93 (s, 2H), 6.53 (m, 2H), 7.11 (d, IH), 7.26 (dd, IH), 7.33 (dd, IH), 7.56-7.64 (m, 3H), 8.14 (dd, IH), 8.24 (d, IH); m/z found 547.1 [M+H]⁺.

[0090] Example 50 can be synthesized using a similar procedure from 1 and 5- ethyl-l,3,4-thiadiazol-2-amine followed by deprotection. Example 31 can be synthesized using a similar procedure involving deprotection of 1 followed by bromide displacement with 5-methylpyrazolo[l,5-a]pyrimidin-7-ol.

[0091] Substituted pyrimidine intermediates of formulae XII, XIII and XIV can be synthesized as detailed in Scheme 9 from 5-iodo-2,6-dimethylpyrimidin-4-ol (8). Compound 8 was synthesized according to the procedure detailed by Lin et al, Tetrahedron, 2007, 63, 1931.

Scheme 9.

[0092] 5-Alkoxy-2,6-dimethylpyrimidin-4-ol (XII)

[0093] To a solution of 3 mL of absolute ethanol was added 55 mg (2.4 mmol, 2 eq.) of sodium metal with stirring in a microwave tube. A solution of 300 mg (1.2 mmol, 1 eq.) of 5-iodo-2,6-dimethylpyrimidin-4-ol (8) in 1 mL of DMF was added, followed by 117 mg (1.2 mmol, 0.5 eq.) of CuI. The mixture was de-gassed by argon and sealed. The reaction mixture was subjected to microwave irradiation, maintaining an internal reaction temperature of 140 ⁰C for 1 h. The reaction mixture was filtered and the filtrate was concentrated. The crude product was purified by prep. HPLC to provide 5-ethoxy-2,6-dimethylpyrimidin-4-ol (XII, R = Et). δ_H (CD₃OD, 300 MHz) 1.33 (t, 3H), 2.26 (s, 3H), 2.34 (s, 3H), 4.06 (2H, q).

4-Chloro-5-alkoxy-2,6-dimethylpyrimidine (XIII)

XII XIII

[0094] To a solution of 0.6 g (3.57 mmol, 1 eq.) of 5-ethoxy-2,6- dimethylpyrimidin-4-ol (XII, R = Et) in 20 mL of acetonitrile was added 1.08 g (7.14 mmol, 2 eq.) Of POCl₃ and 0.87 g (7.14 mmol, 2 eq.) of DMAP. The reaction mixture was stirred at reflux for 4 h. The reaction mixture was concentrated, poured into ice, and the resulting mixture was extracted twice with ether. The combined organic extracts were washed with water, dried (MgSO₄) and the solvent removed in vacuo. The residue was purified by prep. TLC to provide 4-chloro-5-ethoxy-2,6-dimethylpyrimidine (XIII, R = Et).

[0095] A mixture of 100 mg XIII and NH₃ in THF (~6 M, 5 mL) was heated at 120 ⁰C for 24 h in a sealed tube. The mixture was allowed to cool to room temperature and the solvent removed in vacuo to provide XIV.

4-Chloro-5-iodo-2,6-dimethylpyrimidine (9)

[0096] To a solution of 1 g (4 mmol, leq.) of 5-iodo-2,6-dimethylpyrimidin-4-ol (8) in 10 mL of toluene was added 1.21 g (8 mmol, 2 eq.) of POCl₃ and the mixture was heated at reflux for 1 h. The mixture was concentrated and ice water was added. The pH was adjusted to 5 with 2.5 N NaOH and extracted with CH₂Cl₂. The combined extracts were washed with brine, dried (Na₂SO₄) and the solvent removed in vacuo. Then the crude product was purified by flash chromatography to provide 4-chloro-5-iodo-2,6-dimethylpyrimidine (9).

[0097] Intermediates 8, 9, XII, XIII and XIV were used to synthesize examples 32-40 as exemplified below.

N-(4,5-dimethyl-3-isoxazolyl)-4'-[[(2,6-dimethyl-5-iodo-4-pyrimidinyl)oxy]methyl]-2^f- (ethoxymethyl)[l,l'-biphenyl]-2-sulfonamide (Example 32).

[0098] 7V-(4,5-dimethyl-3-isoxazolyl)-N-(methoxymethyl)-4'-hydroxymethyl-2'- (ethoxymethyl)[l,l'-biphenyl]-2-sulfonamide (10) was deprotected according to General Procedure A to provide N-(4,5-dimethyl-3-isoxazolyl)-4'-hydroxyrnethyl-2'- (ethoxymethyl)[l,l'-biphenyl]-2-sulfonamide. To a solution of 46 mg (0.11 mmol, 1.0 eq.) of N-(4,5-dimethyl-3-isoxazolyl)-4'-hydroxymethyl-2'-(ethoxymethyl)[l , 1 '-biphenyl]-2- sulfonamide in 1 mL of DMF was added 13 mg (0.33 mmol, 3.0 eq. 60% dispersion in mineral oil) of sodium hydride and the mixture stirred at room temperature for 30 min. A solution of 31 mg (0.16 mmol, 1.05 eq.) of 4-chloro-5-iodo-2,6-dimethylpyrimidine (9) in 0.5 mL of DMF was added and the reaction mixture was stirred at room temperature for 16 h. A portion of 0.5 mL of MeOH was added and the solvent removed in vacuo. The residue was purified by flash chromatography (0-20% MeOH/CH₂Cl₂) to provide 14 mg of iV-(4,5- dimethyl-3-isoxazolyl)-4'-[[(2,6-dimethyl-5-iodo-4-pyrimidinyl)oxy]methyl]-2'- (ethoxymethyl)[l,l'-biphenyl]-2-sulfonamide (Example 32).

7V-(4,5-dimethyl-3-isoxazolyl)-4'-[[(2,6-dimethyl-5-methoxy-4-pyrimidinyl)oxy]methyl]- 2'-(ethoxymethyl)[l,l'-biphenyI]-2-suIfonamide (Example 33).

I) HCl EtOHZH₂O i^li^l)⁾ C^Cs^s ₂2Cp,O°₃3,. D ^C MF

OH 11 Example 33

[0099] N-(4,5-dimethyl-3-isoxazolyl)-N-(methoxymethyl)-4'-bromomethyl-2'- (ethoxymethyl)[l,l'-biphenyl]-2-sulfonamide (1) was deprotected according to General Procedure A to provide N-(4,5-dimethyl-3-isoxazolyl)-4'-bromomethyl-2'- (ethoxymethyl)[l,r-biphenyl]-2-sulfonamide. To a solution of 120 mg (0.25mmol, 1.0 eq.) of N-(4,5-dimethyl-3-isoxazolyl)-4'-bromomethyl-2'-(ethoxymethyl)[l,r-biphenyl]-2- sulfonamide in 5 mL of DMF was added 163 mg (0.5 mmol, 2.0 eq.) of cesium carbonate and 77 mg (0.5 mmol, 2.0 eq.) of 5-methoxy-2,6-dimethylpyrimidin-4-ol (11) and the mixture stirred at room temperature for 12 h. The solvent was removed in vacuo, and the residue resuspended in 10 mL of EtOAc. The mixture was filtered and the solvent removed in vacuo. The product was purified by prep. HPLC to provide N-(4,5-dimethyl-3-isoxazolyl)- 4'-[[(2,6-dimethyl-5-methoxy-4-pyrimidinyl)oxy]methyl]-2'-(ethoxymethyl)[l , 1 '-biphenyl]- 2-sulfonamide (Example 33). δ_H (CD₃OD, 400 MHz) 1.08 (t, 3H), 1.69 (s, 3H), 2.24 (s, 3H), 2.39 (s, 3H), 2.52 (s, 3H), 3.3 (m, obscured by solvent), 3.84 (s, 3H), 4.12 (ABq, 2H), 5.57 (s, 2H), 7.09 (d, IH), 7.27 (dd, IH), 7.39 (dd, IH), 7.63 (m, 3H), 8.19 (dd, IH); m/z found 553.0, [M+H]⁺

Λ^r-(4,5-dimethyl-3-isoxazolyl)-4'-[[(2,6-dimethyI-5-ethoxy-4-pyrimidinyl)amino]methyl]- 2'-(ethoxymethyl)[l,r-biphenyl]-2-sulfonamide (Example 37).

4 Example 37 _

(0100] To a solution of 100 mg (0.22 mmol, 1.0 eq.) of N-(4,5-dimethyl-3- isoxazolyl)-N-(methoxymethyl)-4'-aminomethyl-2'-(ethoxymethyl)[l,r-biphenyl]-2- sulfonamide in 4 mL of THF was added 41 mg (0.22 mmol, 1.0 eq.) of 4-chloro-5-ethoxy- 2,6-dimethylpyrimidine (12) and 61 mg (0.44 mmol, 2.0 eq.) of potassium carbonate and the mixture heated in a sealed tube at 120 ⁰C for 24 h. The mixture was allowed to cool to room temperature and the solvent removed in vacuo. The residue was resuspended in 5 mL of CH₂Cl₂ and filtered. The solid was washed with 3 mL of CH₂Cl₂ and the solvent removed in vacuo. The crude product was deprotected according to general procedure A and the residue purified by prep. HPLC to provide N-(4,5-dimethyl-3-isoxazolyl)-4'-[[(2,6-dimethyl-5- ethoxy-4-pyrimidinyl)amino]methyl]-2'-(ethoxymethyl)[l,r-biphenyl]-2-sulfonamide (Example 37). δ_H (CD₃OD, 400 MHz) 1.08 (t, 3H), 1.46 (t, 3H), 1.74 (s, 3H), 2.26 (s, 3H), 2.44 (s, 3H), 2.57 (s, 3H), 3.3 (m, obscured by solvent), 4.05 (q, 2H), 4.1 1 (ABq, 2H), 4.90 (obscured by solvent), 7.04 (d, IH), 7.26 (m, 2H), 7.47 (m, IH), 7.60 (m, 2H), 8.16 (m, IH); m/z found 566.1 [M+H]⁺

[0101] Compounds of formula I (Type XVII) were synthesized according to the general synthetic route outlined in Scheme 10. Aminopyrimidine intermediates of type XV were synthesized according to J. Med. Chem. 1981, 24, 382.

XVI I, XVH Scheme 10.

[0102] This is exemplified by the synthesis of example 41 :

N-(4,5-dimethyl-3-isoxazolyl)-iV-(methoxymethyl)-4'-[[(6-chloro-2-methyl- 4-pyrimidinyl)amino]methyl]-2'-(ethoxymethyl)[l,l'-biphenyl]-2-sulfonamide (Example

41)

Deprotection

Example 41

[0103] To a solution of 85 mg (0.57 mmol, 2 eq.) of 4-amino-2,6- dimethylpyrimidine-5-carbonitrile (13) in 3 mL of anhydrous DMF was added 14 mg of sodium hydride and the mixture stirred at room temperature for 30 min. A solution of 150 mg (0.29 mmol) of N-(4,5-dimethyl-3-isoxazolyl)-N-(methoxymethyl)-4'-bromomethyl-2'- (ethoxymethyl)[l,l'-biphenyl]-2-sulfonamide (1) in 1 mL of DMF was added and the mixture stirred at room temperature for a further 1 h. The mixture was diluted with 3 mL of water and the mixture extracted with 3 x 5 mL of EtOAc. The combined organic extracts were dried (Na₂SO₄) and the solvent removed in vacuo. The residue was purified by flash chromatography (50% EtOAc/hexanes) to provide 166 mg of N-(4,5-dimethyl-3-isoxazolyl)- N-(methoxymethyl)-4'-[[(2,6-dimethyl-5-cyano-4-pyrimidinyl)amino]methyl]-2'- (ethoxymethyl)[l,r-biphenyl]-2-sulfonamide (14). A portion of N-(4,5-dimethyl-3- isoxazolyl)-N-(methoxymethyl)-4'-[[(2,6-dimethyl-5-cyano-4-pyrimidinyl)amino]methyl]-2'- (ethoxymethyl)[l,l'-biphenyl]-2-sulfonamide (14) was deprotected according to General Procedure A to provide N-(4,5-dimethyl-3-isoxazolyl)- 4'-[[(2,6-dimethyl-5-cyano-4- pyrimidinyl)amino]methyl]-2'-(ethoxymethyl)[l ,1 '-biphenyl]-2-sulfonamide (Example 41). δ_H (CD₃OD, 400 MHz) 1.21 (t, 3H), 1.87 (s, 3H), 2.40 (s, 3H), 2.77 (s, 3H), 2.78 (s, 3H), 3.3 (m, obscured by solvent), 4.27 (ABq, 2H), 5.03 (s, 2H), 7.21 (d, IH), 7.37 (dd, IH), 7.44 (dd, IH), 7.67 (m, IH), 7.76 (m, 3H), 8.27 (dd, IH); m/z found 547.0, [M+H]⁺ Λ^L(4,5-dimethyl-3-isoxazolyl)-4'-[[(2,6-dimethyl-5-aminomethyl-4-pyrimidinyl)amino] methyl)-2'-(ethoxymethyl)[l,l'-biphenyl]-2-sulfonamide (Example 42) and _V-(4,5- dimethyl-3-isoxazoIyl)-4'-[[(2,6-dimethyl-5-hydroxymethyl-4-pyrimidinyI)amino] methyl]-2'-(ethoxymethyl)[l,l'-biphenyl]-2-sulfonamide (Example 43)

H₂O Ni Q

Example 42

[0104] To a solution of 150 mg of iV-(4,5-dimethyl-3-isoxazolyl)-iV- (methoxymethyl)-4'-[[(2,6-dimethyl-5-cyano-4-pyrimidinyl)amino]methyl]-2'- (ethoxymethyl)[l,l'-biphenyl]-2-sulfonamide (14) in 15 niL of 60% aqueous formic acid was added approximately 200 mg of Raney Ni in water and the mixture hydrogenated at 50 psi for 3 h. The mixture was filtered and the solvent evaporated. The components of the reaction mixture were isolated by semi-prep hplc and individually deprotected according to General Procedure A to provide N-(4,5-dimethyl-3-isoxazolyl)-4'-[[(2,6-dimethyl-5-aminomethyl-4- pyrimidinyl)amino] methyl]-2'-(ethoxymethyl)[l,r-biphenyl]-2-sulfonamide (Example 42) δ_H (CD₃OD, 400 MHz) 1.09 (t, 3H), 1.75 (s, 3H), 2.26 (s, 3H), 2.64 (s, 3H), 2.65 (s, 3H), 3.3 (m, obscured by solvent), 4.12 (ABq, 2H), 4.31 (s, 2H), 4.93 (s, 2H), 7.09 (d, IH), 7.23 (dd, IH), 7.39 (dd, IH), 7.63 (m, 4H), 8.14 (dd, IH); m/z found 551.1, [M+H]⁺ and N-(4,5-dimethyl-3-isoxazolyl)-4'-[[(2,6-dimethyl-5-hydroxymethyl-4- pyrimidinyl)amino] methyl]-2'-(ethoxymethyl)[l,r-biphenyl]-2-sulfonamide (Example 43) δ_H (CD₃OD, 400 MHz) 1.07 (t, 3H), 1.73 (s, 3H), 2.25 (s, 3H), 2.50 (s, 3H), 2.59 (s, 3H), 3.3 (m, obscured by solvent), 4.13 (ABq, 2H), 4.69 (s, 2H), 4.92 (s, 2H), 7.07 (d, IH), 7.27 (m, 2H), 7.62 (m, 3H), 8.15 (dd, IH); m/z found 552.1, [M+H]⁺ iV-(4,5-dimethyl-3-isoxazolyl)-4'-[[(2,6-dimethyl-5-carboxy-4-pyrimidinyl)amino] methyl]-2'-(ethoxymethyl)[l,l'-biphenyl]-2-sulfonamide (Example 44) and iV-(4,5- dimethyl-3-isoxazolyl)-4'-[[(2,6-dimethyl-5-carbamoyl-4-pyrimidinyl)amino] methyl]-2'- (ethoxymethyl)[l,r-biphenyI]-2-sulfonamide (Example 45)

Exi imple 44 Example 45

[0105] To a solution of 40 mg of N-(4,5-dimethyl-3-isoxazolyl)-jV- (methoxymethyl)-4'-[[(2,6-dimethyl-5-cyano-4-pyrimidinyl)amino]methyl]-2'- (ethoxymethyl)[l,l'-biphenyl]-2-sulfonamide (14) in 2 mL of MeOH was added 2 mL of 6 M NaOH solution and the mixture heated at 80 °C for 24 h. The mixture was adjusted to pH ~6.5 with sat. ammonium chloride solution and the solvent removed in vacuo. The mixture was deprotected according to General Procedure A and the components separated by semi- prep, hplc to provide N-(4,5-dimethyl-3-isoxazolyl)-4'-[[(2,6-dimethyl-5-carboxy-4- pyrimidinyl)amino] methyl]-2'-(ethoxymethyl)[l,l'-biphenyl]-2-sulfonamide (Example 44) δ_H (CD₃OD, 400 MHz) 1.07 (t, 3H), 1.74 (s, 3H), 2.27 (s, 3H), 2.63 (s, 3H), 2.80 (s, 3H), 3.3 (m, obscured by solvent), 4.14 (ABq, 2H), 4.95 (s, 2H), 7.08 (d, IH), 7.27 (m, 2H), 7.53 (m, IH), 7.63 (m, 2H), 8.16 (dd, IH); m/z found 566.1, [M+H]⁺ and N-(4,5-dimethyl-3-isoxazolyl)-4'-[[(2,6-dimethyl-5-carbamoyl-4-pyrimidinyl)amino] methyl]-2'-(ethoxymethyl)[l,l'-biphenyl]-2-sulfonamide (Example 45) δ_H (CD₃OD, 400 MHz) 1.09 (t, 3H), 1.73 (s, 3H), 2.26 (s, 3H), 2.52 (s, 3H), 2.60 (s, 3H), 3.3 (m, obscured by solvent), 4.15 (ABq, 2H), 4.95 (s, 2H), 7.05 (d, IH), 7.25 (m, 2H), 7.50 (m, IH), 7.61 (m, 2H), 8.17 (dd, IH); m/z found 565.1, [M+H]⁺

Λ^r-(4,5-dimethyI-3-isoxazolyI)-4'-[[(2,6-dimethyl-5-acetyl-4-pyrimidinyl)amino] methyl]- 2'-(ethoxymethyl)[l,l'-biphenyl]-2-sulfonamide (Example 46)

[0106] Compounds 15 and 16 were synthesized using similar procedures to those outlined in J Med. Chem. 1998, 41, 4251. Deprotection of compound 16 according to General Procedure A provided N-(4,5-dimethyl-3-isoxazolyl)-4'-[[(2,6-dimethyl-5-acetyl-4- pyrimidinyl)amino] methyl]-2'-(ethoxymethyl)[l,r-biphenyl]-2-sulfonamide (Example 46). δ_H (CDCl₃, 300 MHz) 1.06 (t, 3H), 1.82 (s, 3H), 2.24 (s, 3H), 2.64 (s, 3H), 2.67 (s, 3H), 2.81 (s, 3H), 3.38 (m, 2H), 4.18 (ABq, 2H), 4.87 (d, 2H), 6.67 (bs, IH), 7.25 (m, 3H), 7.50 (m, 2H), 7.58 (m, IH), 8.02 (d, IH), 9.67 (bs, IH); m/z found 564.1 , [M+H]⁺

(±)-N-(4,5-dimethyl-3-isoxazolyl)-4'-[[(2,6-dimethyl-5-(l-hydroxyethyl)-4- pyrimidinyl)amino] methyl]-2'-(ethoxymethyl)[l,l'-biphenyl)-2-sulfonamide (Example

47)

[0107] Deprotection of enol ether 16 to generate the methyl ketone (17) was achieved using 1 :1 v/v 1 M HCl/acetone for 12 h. To a solution of 60 mg (0.1 mmol, 1.0 eq.) of the resulting methyl ketone in 4 mL of methanol was added 38 mg (1 mmol) of sodium borohydride and the mixture stirred at room temperature for 16 h. The solvent was removed in vacuo and 3 mL of water added. The mixture was extracted with 3 x 3 ml of EtOAc and the combined organic extracted dried (Na₂SO₄). The resulting product was deprotected according to general procedure A to provide (+)-iV-(4,5-dimethyl-3-isoxazolyl)-4'-[[(2,6- dimethyl-5-(l-hydroxyethyl)-4-pyrimidinyl)amino] methyl]-2'-(ethoxymethyl)[l,l'- biphenyl]-2-sulfonamide (Example 47) δ_H (CD₃OD, 400 MHz) 1.08 (t, 3H), 1.52 (d, 2H), 1.75 (s, 3H), 2.26 (s, 3H), 2.45 (s, 3H), 2.57 (s, 3H), 3.3 (m, obscured by solvent), 4.13 (ABq, 2H), 4.94 (m, 2H), 5.28 (q, IH), 7.07 (d, IH), 7.27 (m, 2H), 7.52 (m, IH), 7.63 (m, 2H), 8.16 (dd, IH); m/z found 566.1, [M+H]⁺

7V-(4,5-dimethyl-3-isoxazolyl)-4'-[[(2,6-dimethyl-5-vinyl-4-pyrimidiny^amino] methyl]- 2'-(ethoxymethyl)[l,r-biphenyl]-2-sulfonamide (Example 48) and (+)-iV-(4,5-dimethyl- 3-isoxazolyl)-4'-[[(2,6-dimethyl-5-(l-(lH-imidazol-l-yl)ethyl)-4-pyrimidinyl)amino] methyl]-2'-(ethoxymethyl)[l,r-biphenyl]-2-sulfonamide (Example 49).

Example 49

[0108] To a solution of 20 mg (33 μmol. 1.0 eq) of (±)-N-(4,5-dimethyl-3- isoxazolyl)-Λ^f-(methoxymethyl)4'-[[(2,6-dimethyl-5-(l-hydroxyethyl)-4-pyrimidinyl)amino] methyl]-2'-(ethoxymethyl)[l,r-biphenyl]-2-sulfonamide (17) in 2 mL Of CH₂Cl₂ in a sealed tube was added 5 mg of carbonyl diimidazole. The tube was sealed and the mixture was heated at 60 °C for 18 h. The solvent was removed in vacuo and the residue partitioned between 2 mL of water and 3 mL of EtOAc. The layers were separated and the aqueous phase was extracted with 2 x 3 mL of EtOAc. The combined organic extracts were dried (Na₂SO₄) and the solvent removed in vacuo. The residue was deprotected according to General Procedure A and the components isolated by prep. HPLC to provide N-(4,5- dimethyl-3-isoxazolyl)-4'-[[(2,6-dimethyl-5-vinyl-4-pyrimidinyl)amino] methyl]-2'-

(ethoxymethyl)[l,r-biphenyl]-2-sulfonamide (Example 48), δ_H (CD₃OD, 400 MHz) 1.09 (t, 3H), 1.73 (s, 3H), 2.26 (s, 3H), 2.47 (s, 3H), 2.60 (s, 3H), 3.3 (m, obscured by solvent), 4.13 (ABq, 2H), 4.94 (m, 2H), 5.71 (dd, IH), 5.94 (dd, IH), 6.51 (m, IH), 7.07 (d, IH), 7.25 (m, 2H), 7.51 (m, IH), 7.63 (m, 2H), 8.14 (dd, IH); m/z found 548.1, [M+H]⁺, and (±)-N-(4,5- dimethyl-3-isoxazolyl)-4'-[[(2,6-dimethyl-5-(l-(lH-imidazol-l-yl)ethyl)-4- pyrimidinyl)amino] methyl]-2'-(ethoxymethyl)[l,r-biphenyl]-2-sulfonamide (Example 49), δ_H (CD₃OD, 400 MHz) 1.09 (t, 3H), 1.79 (s, 3H), 2.10 (d, 2H), 2.28 (s, 3H), 2.45 (s, 3H), 2.67 (s, 3H), 3.3 (m, obscured by solvent), 4.15 (2H, ABq), 4.87 (m, 2H), 6.00 (q, IH), 7.07 (m, IH), 7.17 (m, IH), 7.24 (d, 2H), 7.25 (m, IH), 7.42 (m, IH), 7.65 (m, 5H), 8.11 (dd, IH), 9.13 (s, IH); m/z found 616.0, [M+H]⁺.

[0109] Protected intermediates of formula III whereby X = NH can be further functionalized via alkylation and sulfonamide deprotection to generate compounds of formula I (Type XVIII) or acylation and sulfonamide deprotection to generate compounds of formula I (Type XIX) as detailed in Scheme 11 (Examples 51 to 61).

I, XIX HI (X = NH) , XVIII

Scheme 11.

[0110] Alkylation is achieved with an alkyl halide, for example methyl iodide, in DMF using sodium hydride as a base under standard conditions. Acylation is achieved with an anhydride, for example acetic anhydride, in CH₂Cl₂ with DMAP under standard acylating conditions.

[0111] The compounds of the present invention may be employed alone or in combination with each other and/or other suitable therapeutic agents useful in the treatment of endothelin-dependent or angiotensin II-dependent disorders. For example, the compounds of this invention can be formulated in combination with endothelin converting enzyme (ECE) inhibitors, such as phosphoramidon; thromboxane receptor antagonists; potassium channel openers; thrombin inhibitors (e.g., hirudin and the like); growth factor inhibitors such as modulators of PDGF activity; platelet activating factor (PAF) antagonists; renin inhibitors; angiotensin converting enzyme (ACE) inhibitors such as captopril, zofenopril, fosinopril, ceranapril, alacepril, enalapril, delapril, pentopril, quinapril, ramipril, lisinopril and salts of such compounds; neutral endopeptidase (NEP) inhibitors; dual NEP-ACE inhibitors; HMG CoA reductase inhibitors such as pravastatin and mevacor; squalene synthetase inhibitors; bile acid sequestrants such as questran; calcium channel blockers; potassium channel activators; alpha-adrenergic agents, beta-adrenergic agents; antiarrhythmic agents; diuretics, such as chlorothiazide, hydrochlorothiazide, flumethiazide, hydroflumethiazide, bendroflumethiazide, methylchlorothiazide, trichloromethiazide, -polythiazide or benzothiazide as well as ethacrynic acid, tricrynafen, chlorthalidone, furosemide, musolimine, bumetanide, triamterene, amiloride and spironolactone and salts of such compounds; thrombolytic agents such as tissue plasminogen activator (tPA), recombinant tPA, streptokinase, urokinase, prourokinase and anisoylated plasminogen streptokinase activator complex (APSAC); and PDE V inhibitors such as sildenafil. If formulated as a fixed dose, such combination products employ the compounds of this invention within the dosage range described below and the other pharmaceutically active agent within its approved dosage range. The compounds of this invention may also be formulated with, or useful in conjunction with, antifungal and immunosuppressive agents such as amphotericin B, cyclosporins and the like to counteract the glomerular contraction and nephrotoxicity secondary to such compounds. The compounds of this invention may also be used in conjunction with hemodialysis.

[0112] The above other therapeutic agents, when employed in combination with the compounds of the present invention, may be used, for example, in those amounts indicated in the Physicians' Desk Reference (PDR) or as otherwise determined by one of ordinary skill in the art.

[0113] The following assays may be employed in ascertaining the degree of activity of a compound ("drug") as an endothelin and angiotensin II receptor antagonist. Compounds described in the following Examples have been tested in these assays, and have shown activity.

ATI receptor binding assay [0114] Commercially-available membranes (Euroscreen) from CHO-Kl cells expressing the human angiotensin II receptor type 1 (ATI), corresponding to Genbank accession number M91464, were used to establish receptor binding assays. The K_D (180 pM) for [¹²⁵I] [Sar¹ He⁸] angiotensin II binding to ATj was determined as follows: [¹²⁵I] [Sari Ile8] Angiotensin II (PerkinElmer) was allowed to bind for one hour at 25 ⁰C, with agitation, to membrane preparations (0.125 μg/well) in a 96-well polypropylene microtiter plate, in 50 mM Tris-HCl, pH 7.5, 5mM MgCl₂, ImM EDTA, 0.1% bovine serum albumin (BSA). 1 μM unlabeled [Sar¹ VaI⁵ Ala⁸] angiotensin II (Bachem) was used to define nonspecific binding. To terminate the reaction, reaction mixtures (100 μL) were filtered through 0.3% polyethyleneimine-blocked MAFCNOB filter plates (Millipore) and washed three times with ice-cold 50 mM Tris-HCl, pH 7.5, 5 mM MgCl₂. Detection in the TriLux (PerkinElmer) was carried out in the presence of 40 μL/ well scintillation fluid.

[0115] Scintillation proximity format competition binding assays were performed in a reaction volume of 40 μL in white clear-bottom 384-well plates, in 50 mM Tris-HCl, pH 7.5, 5mM MgCl₂, 0.1% BSA, 0.5% dimethylsulfoxide (DMSO) containing 0.125 μg/well ATi membrane preparation, 30 pM [¹²⁵I] [Sar¹ He⁸] angiotensin II, 50 μg/well wheat germ agglutinin (WGA)-PVT scintillation proximity beads (Amersham/ GE Healthcare), and test compound. After five minutes of agitation, reactions were allowed to stand for 16-20 hours before detection in the TriLux (PerkinElmer). Ki values were calculated using the Cheng- Prusoff equation and the predetermined K_D value.

ET_A receptor binding assay

[0116] The K_D value (76 pM) for [¹²⁵I] endothelin-1 at ET_A was measured as follows: a 50 μL reaction containing radioligand (PerkinElmer), 0.25 μg/well membranes from mammalian cells expressing recombinant ET_A (commercially available from Chemicon, accession number S63938), 50 mM HEPES, pH 7.5, 5 mM MgCl₂, 1 mM CaCl₂, 0.2% BSA, 2 mM phosphoramidon, 0.5% DMSO, was carried out for one hour at 25 °C, with agitation. Reaction mixtures were then filtered through 0.3% polyethyleneimine-blocked MAFCNOB filter plates (Millipore) and washed four times with ice-cold 50 mM HEPES, pH 7.5, 0.5 M NaCl, 0.1% BSA. Detection in the TriLux (PerkinElmer) was carried out in the presence of 40 μL/ well scintillation fluid.

[0117] Scintillation proximity format competition binding assays were performed in a reaction volume of 40 μL in white clear-bottom 384-well plates, in 50 mM Tris-HCl, pH 7.5, 5mM MgCl₂, 0.5 mM CaCl₂, 0.1% BSA, 2 mM phosphoramidon, 0.5% DMSO containing 0.25 μg/well ET_A membrane preparation, 35 pM [¹²⁵I] endothelin-1, 50 μg/well wheat germ agglutinin (WGA)-PVT scintillation proximity beads (Amersham/ GE Healthcare), and test compound. After five minutes of agitation, reactions were allowed to stand for 16-20 hours before detection in the TriLux (PerkinElmer). Ki values were calculated using the Cheng-Prusoff equation and the predetermined K_D value.

Analytical hplc data was acquired using a Millenium 2690/996PDA separations system employing a Phenomenex Columbus 5u cl8 colunm 50 x 4.60 mm analytical column. The aqueous acetonitrile based solvent gradient involves;

0 - 0.5 min - Isocratic 10% of (0.05% TFA/ acetonitrile); 0.5 min - 5.5 min - Linear gradient of 10 - 90% of (0.05% TFA/acetonitrile): 5.5 min - 7.5 min - Isocratic 90% of (0.05% TFA/acetonitrile); 7.5 min - 8 min - Linear gradient of 90 - 10% of (0.05% TFA/acetonitrile); 8 min - 10 min - Isocratic 10% of (0.05% TFA/acetonitrile). Flow rate = 0.4 mL/min. Mass Spectroscopy was conducted using Thermo-electron LCQ classic.

Liquid Chromatography Mass Spectroscopy was conducted using a Waters Millenium 2690/996PDA linked Thermo-electron LCQ classic.

¹H NMR spectroscopy was conducted using a Varian 300 MHz Gemini 2000 NMR or a Bruker 400 MHz Ultrashield Avance II NMR.

[0118] Some comparative examples are shown in Table 1, with Ki values for ATI and ETA below 2μM. Table 1.

Claims

WHAT IS CLAIMED IS:

1. A compound of formula I, and pharmacueticaly acceptable salts thereof,

I wherein

X is O or NR⁴;

R³ is heteroaryl; and

^■ R⁴ is selected from the group consisting of hydrogen, (Ci-C₆)alkyl and (Ci- C₆)acyl.

2. A compound according to claim 1 wherein R³ is isoxazolyl, pyridizinyl, pyrazinyl or pyrimidinyl, each optionally substituted with one or more of (Ci-C₆)alkyl, (C₁- C₆)alkoxyl, cyano, nitro, trifluoromethyl, hydrogen or halogen.

3. A compound according to claim 2 wherein R³ is isoxazolyl, optionally substituted with one or two of the following substituents: (Ci-C₆)alkyl, (Ci-C₆)alkoxyl, cyano, nitro, trifluoromethyl, hydrogen or halogen.

4. A compound according to claim 3 wherein R³ is isoxazol-5-yl or isoxazol-3- yl, optionally substituted with one or

or halogen.

5. A compound according to claim 4 wherein R³ is isoxazol-5-yl or isoxazol-3- yl, optionally substituted with one or two of methyl or fluorine.

6. A compound according to claim 1 wherein R² is chosen from hydrogen, propyl and ethoxymethyl.

7. A compound according to claim 1 wherein R¹ is an optionally substituted heteroaryl.

8. A compound according to claim 7 wherein R¹ is selected from the group consisting of pyrazolopyrimidine, thiadiazole, pyrimidine and quinoline, each optionally substituted with one or more substituents selected from the group consisting of (Cr Cg)hydrocarbon, (Ci-C₆)acyl, oxaalkyl, heterocyclylalkyl, halogen, hydroxyalkoxy, hydroxyalkyl, haloalkyl, carboxy, cyano, aminoalkyl, alkylamino, carboxamido and heterocyclyl.

9. A compound according to claim 8 wherein R¹ is

wherein one of R⁶, R⁷, R or R⁹ is the point of attachment to X and wherein the other three substituents are independently selected from the group consisting of hydrogen, (Ci-Cg)hydrocarbon, (Ci-C₆)acyl, oxaalkyl, heterocyclylalkyl, halogen, hydroxyalkoxy, hydroxyalkyl, haloalkyl, carboxyl, cyano, aminoalkyl, alkylamino, carboxamido and heterocyclyl.

10. A compound according to claim 9 wherein one of R⁶, R⁷, R⁸ or R⁹ is the point of attachment to X and wherein the other three substituents are independently selected from the group consisting of hydrogen, methyl, ethyl, propyl, acetyl, 1-hydroxyethyl, iodo, ethenyl, imidazolyl ethyl, chloro, methoxy, cyano, hydroxy methyl, aminomethyl, trifluoromethyl, carboxyl, 1 -methoxyethyl, carboxamido, ethoxy, isopropoxy, butoxy, pyrrolidin-1-yl, 2-methoxy ethoxy, methylamino, propylamino, dimethylamino, ethylamino and hydroxyethoxy.

11. A compound according to claim 8 wherein R¹ is

12. A compound according to claim 8 wherein R¹ is

13. A compound according to claim 8 wherein R is

14. A compound according to claim 1 wherein X is O and R¹ is an optionally substituted pyrimidine or pyrazolopyrimidine.

15. A compound according to claim 14 wherein R¹ is optionally substituted with one or more substituents selected from the group consisting of (Ci-C₆)alkyl, halogen and alkoxy.

16. A compound according to claim 1 wherein X is NR⁴.

17. A compound according to claim 16 wherein R⁴ is selected from the group consisting of hydrogen, methyl and acetyl.

18. A compound according to claim 1 chosen from the group consisting of N-(4,5-dimethyl-3-isoxazolyl)-4'-[[(6-chloro-2-methyl-4-pyrimidinyl)amino]methyl]-

2'-(ethoxymethyl)[l , 1 '-biphenyl]-2-sulfonamide,

7V-(4,5-dimethyl-3-isoxazolyl)-4'-[[(6-methylamino-2-methyl-4- pyrimidinyl)amino]methyl]-2'-(ethoxymethyl)[l , 1 '-biphenyl]-2-sulfonamide,

N-(4,5-dimethyl-3-isoxazolyl)-4'-[[(6-pyrrolidinyl-2-methyl-4- pyrimidinyl)amino]methyl]-2'-(ethoxymethyl)[l,r-biphenyl]-2-sulfonamide,

JV-(4,5-dimethyl-3-isoxazolyl)-4'-[[(6-dimethylamino-2-methyl-4- pyrimidinyl)amino]methyl]-2'-(ethoxymethyl)[l,r-biphenyl]-2-sulfonamide,

N-(4,5-dimethyl-3-isoxazolyl)-4'-[[(6-methyl-2-[l-propylamino]-4- pyrimidinyl)amino]methyl]-2'-(ethoxymethyl) [1,1 '-bipheny 1] -2-sulfonamide,

N-(4,5-dimethyl-3-isoxazolyl)-4'-[[(6-[2-propylamino]-2-methyl-4- pyrimidinyl)amino]methyl]-2'-(ethoxymethyl)[l,r-biphenyl]-2-sulfonamide,

N-(4,5-dimethyl-3-isoxazolyl)-4'-[[(2-methyl-6-ethylamino-4- pyrimidinyl)amino]methyl]-2'-(ethoxymethyl)[l,r-biphenyl]-2-sulfonamide,

N-(4,5-dimethyl-3-isoxazolyl)-4'-[[(2,6-dimethyl-5-chloro-4- pyrimidinyl)amino]methyl] -2'-(ethoxymethyl) [1,1 '-bipheny l]-2-sulfonamide,

N-(4,5-dimethyl-3-isoxazolyl)-4'-[[4-(2-methylquinolin)amino]methyl]-2'-

(ethoxymethyl)[l , 1 '-biphenyl]-2-sulfonamide,

N-(4,5-dimethyl-3-isoxazolyl)-4'-[[(6-propyloxy-2-methyl-

4-pyrimidinyl)amino]methyl]-2'-(ethoxymethyl)[l,r-biphenyl]-2-sulfonamide,

N-(4,5-dimethyl-3-isoxazolyl)-4'-[[(6-ethoxy-2-methyl-

4-pyrimidinyl)amino]methyl]-2'-(ethoxymethyl)[l,r-biphenyl]-2-sulfonamide,

N-(4,5-dimethyl-3-isoxazolyl)-4'-[[(6-methoxy-2-methyl-

4-pyrimidinyl)amino]methyl]-2'-(ethoxymethyl)[l , 1 '-biphenyl]-2-sulfonamide,

N-(4,5-dimethyl-3-isoxazolyl)-4'-[[(6-(2-methoxyethoxy)-2-methyl-

4-pyrimidinyl)amino]methyl]-2'-(ethoxymethyl)[l , 1 '-biphenyl]-2-sulfonamide,

N-(4,5-dimethyl-3-isoxazolyl)-4'-[[(6-(2-propoxy)-2-methyl-

4-pyrimidinyl)amino]methyl] -2'-(ethoxymethyl) [ 1 , 1 '-bipheny l]-2-sulfonamide, iV-(4,5-dimethyl-3-isoxazolyl)-4'-[[(6-(2-hydroxyethoxy)-2-methyl-

4-pyrimidinyl)amino]methyl]-2'-(ethoxymethyl)[l , 1 '-biphenyl]-2-sulfonamide,

N-(4,5-dimethyl-3-isoxazolyl)-4'-[[(6-(l-butoxy)-2-methyl- 4-pyrimidinyl)amino]methyl]-2'-(ethoxymethyl)[l,r-biphenyl]-2-sulfonamide,

N-(4,5-dimethyl-3-isoxazolyl)-4'-[[(6-ethyl-2-methyl-

4-pyrimidinyl)amino]methyl]-2'-(ethoxymethyl)[l , 1 '-biphenyl]-2-sulfonamide,

N-(4,5-dimethyl-3-isoxazolyl)-4'-[[(6-propyl-2-methyl-

4-pyrimidinyl)amino]methyl]-2'-(ethoxymethyl)[l , 1 '-biphenyl]-2-sulfonamide,

N-(4,5-dimethyl-3-isoxazolyl)-4'-[[(6-methyl-2-ethyl-

4-pyrimidinyl)amino]methyl]-2'-(ethoxymethyl)[l , 1 '-biphenyl]-2-sulfonamide,

N-(4,5-dimethyl-3-isoxazolyl)-4'-[[(6-trifluoromethyl-2-methyl-

4-pyrimidinyl)amino]methyl]-2'-(ethoxymethyl)[l , 1 '-biphenyl]-2-sulfonamide,

N-(4,5-dimethyl-3-isoxazolyl)-4'-[[(2₅6-dimethyl-

4-pyrimidinyl)amino]methyl]-2'-(ethoxymethyl)[l , 1 '-biphenyl]-2-sulfonamide,

N-(4,5-dimethyl-3-isoxazolyl)-4'-[[(2,6-dimethyl-

4-pyrimidinyl)oxy]methyl]-[l,r-biphenyl]-2-sulfonamide,

N-(4,5-dimethyl-3-isoxazolyl)-4'-[[(2-ethyl-6-methyl

4-pyrimidinyl)oxy]methyl]-2'-(ethoxymethyl)[ 1 , 1 '-biphenyl]-2-sulfonamide,

N-(4,5-dimethyl-3-isoxazolyl)-4'-[[(2,6-dimethyl-5-fluoro-

4-pyrimidinyl)oxy]methyl] -2'-(ethoxymethyl) [1,1 '-biphenyl] -2-sulfonamide,

N-(4,5-dimethyl-3-isoxazolyl)-4'-[[(2,5,6-trimethyl-

4-pyrimidinyl)oxy]methyl]-2'-(ethoxymethyl)[l,r-biphenyl]-2-sulfonamide,

N-(4,5-dimethyl-3-isoxazolyl)-4'-[5-methylpyrazolo[l,5-a]pyrimidin-7- aminomethyl] -2'-(ethoxymethyl) [1,1 '-biphenyl]-2-sulfonamide,

N-(4-fluoro-5-methyl-3-isoxazolyl)-4'-[5-methylpyrazolo[l,5-a]pyrimidin-7- aminomethyl]-2'-(ethoxymethyl)[l,r-biphenyl]-2-sulfonamide,

N-(4,5-dimethyl-3-isoxazolyl)-4'-[5-methylpyrazolo[l,5-a]pyrimidin-7- aminomethyl] -[1,1 '-biphenyl] -2-sulfonamide,

N-(4-fluoro-5 -methy l-3-isoxazolyl)-4'- [5-methylpyrazolo [ 1 ,5 -a]pyrimidin-7- aminomethyl]-[l , 1 '-biphenyl]-2-sulfonamide, iV-(4-fluoro-5-methyl-3-isoxazolyl)-4'-[5-methylpyrazolo[l,5-a]pyrimidin-7- aminomethyl]-2'-propyl-[l,r-biphenyl]-2-sulfonamide,

N-(4,5-dimethyl-3-isoxazolyl)-4'-[5-methylpyrazolo[l,5-a]pyrimidin-7-oxymethyl]-

[1,1 '-biphenyl]-2-sulfonamide, N-(4,5-dimethyl-3-isoxazolyl)-4'-[[(2, 6-dimethyl-5-iodo- 4-pyrimidinyl)oxy ]methy 1] -2'-(ethoxymethyl) [ 1 , 1 '-biphenyl] -2-sulfonamide, iV-(4,5-dimethyl-3-isoxazolyl)-4'-[[(2, 6-dimethyl-5~methoxy- 4-pyrimidinyl)oxy]methyl]-2'-(ethoxymethyl)[ 1 , l'-biphenyl] -2-sulfonamide, N-(4,5-dimethyl-3-isoxazolyl)-4'-[[(2, 6-dimethyl-5-ethoxy- 4-pyrimidinyl)oxy]methy 1] -2'-(ethoxymethyl) [1,1 '-biphenyl] -2-sulfonamide, N-(4,5-dimethyl-3-isoxazolyl)-4'-[[(2, 6-dimethyl-5-iodo- 4-pyrimidinyl)amino]methyl]-2'-(ethoxymethyl)[l , 1 '-biphenyl]-2-sulfonamide, N-(4,5-dimethyl-3-isoxazolyl)-4'-[[(2, 6-dimethyl-5-methoxy- 4-pyrimidinyl)amino] methyl] -2 '-(ethoxymethy I)[1 , 1 '-biphenyl]-2-sulfonamide, jV-(4,5-dimethyl-3-isoxazolyl)-4'-[[(2, 6-dimethyl-5-ethoxy- 4-pyrimidinyl)amino]methyl]-2'-(ethoxymethyl)[l , 1 '-biphenyl]-2-sulfonamide, N-(4,5-dimethyl-3-isoxazolyl)-4'-[[(2, 6-dimethyl-5-(l -butoxy)- 4-pyrimidinyl)amino]methyl]-2'-(ethoxymethyl)[l , 1 '-biphenyl]-2-sulfonamide, N-(4,5-dimethyl-3-isoxazolyl)-4'-[[(2, 6-dimethyl-5-(l-propoxy)- 4-pyrimidinyl)methylamino]methyl]-2'-(ethoxymethyl)[l,r-biphenyl]-2-sulfonamide, N-(4,5-dimethyl-3-isoxazolyl)-4'-[[(2, 6-dimethyl-5-(l-butoxy)- 4-pyrimidinyl)methylamino]methyl]-2'-(ethoxymethyl)[l,r-biphenyl]-2-sulfonamide, N-(4,5-dimethyl-3-isoxazolyl)-iV-(methoxymethyl)-4^l-[[(6-chloro-2-methyl- 4-pyrimidinyl)amino]methyl]-2'-(ethoxymethyl)[l , 1 '-biphenyl]-2-sulfonamide, N-(4,5-dimethyl-3-isoxazolyl)-4'-[[(2,6-dimethyl-5-aminomethyl-4- pyrimidinyl)amino] methyl]-2'-(ethoxymethyl)[ 1 , 1 '-biphenyl]-2-sulfonamide, jV-(4,5-dimethyl-3-isoxazolyl)-4'-[[(2,6-dimethyl-5-hydroxymethyl-4- pyrimidinyl)amino] methyl]-2'-(ethoxymethyl)[l ,r-biphenyl]-2-sulfonamide, N-(4,5-dimethyl-3-isoxazolyl)-4'-[[(2,6-dimethyl-5-carboxy-4-pyrimidinyl)amino] methyl]-2'-(ethoxymethyl)[l , 1 '-biphenyl]-2-sulfonamide,

N-(4,5-dimethyl-3-isoxazolyl)-4'-[[(2,6-dimethyl-5-carbamoyl-4-pyrimidinyl)amino] methyl]-2'-(ethoxymethyl)[l , 1 '-biphenyl]-2-sulfonamide, N-(4,5-dimethyl-3-isoxazolyl)-4'-[[(2,6-dimethyl-5-acetyl-4-pyrimidinyl)amino] methyl]-2'-(ethoxymethyl)[l , 1 '-biphenyl]-2-sulfonamide, (+)-N-(4,5-dimethyl-3-isoxazolyl)-4'-[[(2,6-dimethyl-5-(l-hydroxyethyl)-4- pyrimidinyl)amino] methyl] -2 '-(ethoxymethy I)[1 ,1 '-biphenyl]-2-sulfonamide, iV-(4,5-dimethyl-3-isoxazolyl)-4'-[[(2,6-dimethyl-5-vinyl-4-pyrimidinyl)amino] methyl]-2'-(ethoxymethyl)[l,r-biphenyl]-2-sulfonamide,

(+)-N-(4,5-dimethyl-3-isoxazolyl)-4'-[[(2,6-dimethyl-5-(l-(lH-imidazol-l-yl)ethyl)-

4-pyrimidinyl)amino] methyl]-2'-(ethoxymethyl)[l,r-biphenyl]-2-sulfonamide,

N-(4,5-dimethyl-3-isoxazolyl)-4'-[5-ethyl-l,3,4-thiadiazol-2-aminomethyl]-2'-

(ethoxymethyl)[l , 1 '-biphenyl]-2-sulfonamide,

N-(4,5-dimethyl-3-isoxazolyl)-4'-[[(2,6-dimethyl-5-acetyl-4- pyrimidinyl)methylamino] methyl]-2'-(ethoxymethyl)[ 1 , 1 '-biphenyl]-2-sulfonamide,

N-(4,5-dimethyl-3-isoxazolyl)-4'-[[(2,6-dimethyl-4-pyrimidinyl)methylamino] methyl]-2'-(ethoxymethyl)[l,r-biphenyl]-2-sulfonamide,

N-(4,5-dimethyl-3-isoxazolyl)-4'-[[(2-methyl-6-ethoxy-4-pyrimidinyl)methylamino] methyl]-2'-(ethoxymethyl)[l,l'-biphenyl]-2-sulfonamide,

N-(4,5-dimethyl-3-isoxazolyl)-4^l-[[(2-methyl-6-ethyl-4-pyrimidinyl)methylamino] methyl]-2'-(ethoxymethyl)[l,r-biphenyl]-2-sulfonamide,

N-(4,5-dimethyl-3-isoxazolyl)-4'-[[(2-methyl-6-(l-propyl)-4- pyrimidinyl)methylamino] methyl]-2'-(ethoxymethyl)[l,r-biphenyl]-2-sulfonamide,

N-(4,5-dimethyl-3-isoxazolyl)-4'-[[(2-ethyl-6-methyl-4-pyrimidinyl)methylamino] methyl]-2'-(ethoxymethyl)[l ,l'-biphenyl]-2-sulfonamide,

N-(4,5-dimethyl-3-isoxazolyl)-4'-[[(2,6-dimethyl-5-vinyl-4- pyrimidinyl)methylamino] methyl]-2'-(ethoxymethyl)[l , 1 '-biphenyl]-2-sulfonamide,

(+)-N-(4,5-dimethyl-3-isoxazolyl)-4'-[[(2,6-dimethyl-5-(l-hydroxyethyl)-4- pyrimidinyl)methylamino] methyl]-2'-(ethoxymethyl) [1,1 '-biphenyl] -2-sulfonamide,

N-(4,5-dimethyl-3-isoxazolyl)-4'-[5-methylpyrazolo[l,5-a]pyrimidin-7- methylaminomethyl]-2'-(ethoxymethyl)[l,r-biphenyl]-2-sulfonamide,

N-(4,5-dimethyl-3-isoxazolyl)-4'-[5-ethyl-l,3,4-thiadiazol-2-acetylaminomethyl]-2'-

(ethoxymethyl)[ 1 , 1 '-biphenyl]-2-sulfonamide,

N-(4,5-dimethyl-3-isoxazolyl)-4'-[5-methylpyrazolo[l,5-a]pyrimidin-7- acetylaminomethyl]-2'-(ethoxymethyl)[ 1 , 1 '-biphenyl]-2-sulfonamide, and pharmaceutically acceptable salts thereof.

19. Use of at least one compound or pharmaceutically acceptable salt thereof according to any of claims 1 to 18 for the treatment of an endothelin-dependent or angiotensin II-dependent disorder.

20. Use of at least one compound or pharmaceutically acceptable salt thereof according to any of claims 1 to 18 for the treatment of hypertension.

21. Use of at least one compound or pharmaceutically acceptable salt thereof according to any of claims 1 to 18 for the treatment of pulmonary hypertension.

22. Use of at least one compound or pharmaceutically acceptable salt thereof according to any of claims 1 to 18 for the treatment of primary pulmonary hypertension.

23. Use of at least one compound or pharmaceutically acceptable salt thereof according to any of claims 1 to 18 for the treatment of low renin hypertension.

24. Use of at least one compound or pharmaceutically acceptable salt thereof according to any of claims 1 to 18 for the treatment of male erectile dysfunction.

25. Use of at least one compound or pharmaceutically acceptable salt thereof according to any of claims 1 to 18 for the treatment of male or female sexual dysfunction.

26. Use of at least one compound or pharmaceutically acceptable salt thereof according to any of claims 1 to 18 for the treatment of heart failure.

27. Use of at least one compound or pharmaceutically acceptable salt thereof according to any of claims 1 to 18 for the treatment of atherosclerosis.

28. Use of at least one compound or pharmaceutically acceptable salt thereof according to any of claims 1 to 18 for the treatment of restenosis.

29. Use of at least one compound or pharmaceutically acceptable salt thereof according to any of claims 1 to 18 for the treatment of endotoxemia.

30. Use of at least one compound or pharmaceutically acceptable salt thereof according to any of claims 1 to 18 for the inhibition of cell growth.

31. Use of at least one compound or pharmaceutically acceptable salt thereof according to any of claims 1 to 18 for the treatment of cancer.

32. Use of at least one compound or pharmaceutically acceptable salt thereof according to any of claims 1 to 18 for the treatment of migraine.

33. Use of at least one compound or pharmaceutically acceptable salt thereof according to any of claims 1 to 18 for the treatment of asthma.

34. Use of at least one compound or pharmaceutically acceptable salt thereof according to any of claims 1 to 18 for the treatment of ischemia.

35. Use of at least one compound or pharmaceutically acceptable salt thereof according to any of claims 1 to 18 for the treatment of subarachnoid hemorrhage.

36. Use of at least one compound or pharmaceutically acceptable salt thereof according to any of claims 1 to 18 for the treatment of benign prostatic hypertrophy, comprising the step of administering to a subject in need thereof an amount effective therefor of at least one compound of claim 1.

37. Use of at least one compound or pharmaceutically acceptable salt thereof according to any of claims 1 to 18 for the treatment of a disorder selected from the group consisting of renal, glomerular and mesangial cell disorders.

38. Use of at least one compound or pharmaceutically acceptable salt thereof according to any of claims 1 to 18 for the treatment of acute or chronic renal failure.

39. Use of at least one compound or pharmaceutically acceptable salt thereof according to any of claims 1 to 18 for the treatment of diabetic nephropathy.

40. A pharmaceutical composition for the treatment of an endothelin-dependent or angiotensin II-dependent disorder, comprising a pharmaceutically acceptable vehicle or diluent and a pharmaceutically effective amount of at least one compound according to claims 1 to 18.