MXPA01000208A - Novel benzothiepines having activity as inhibitors of ileal bile acid transport and taurocholate uptake - Google Patents

Abstract

Novel benzothiepines, derivatives, and analogs thereof;methods of preparing such compounds;pharmaceutical compositions containing such compounds;and methods of using these compounds and compositions in the preparation of a medicament, particularly medicaments for use in the prophylaxis and treatment of hyperlipidemic conditions such as those associated with atherosclerosis or hypercholesterolemia, in mammals.

Description

BENZOTIEPINAS THAT HAVE AN ACTIVITY AS INHIBITORS OF THE TRANSPORT OF THE ILEAL BILIS ACID AND THE ABSORPTION OF TAUROCOLATE BACKGROUND OF THE INVENTION FIELD OF THE INVENTION The present invention describes novel benzothiepins, derivatives and analogs thereof, pharmaceutical compositions containing them, and their use in medicine, particularly in the prophylaxis and treatment of hyperlipidemic conditions such as those associated with atherosclerosis or hypercholesterolemia, in mammals. Description of the Related Art It is well established that hyperlipidemic conditions associated with high concentrations of total cholesterol and low density lipoprotein cholesterol are the main risk factors for coronary heart disease and particularly atherosclerosis. Interfering with the circulation of bile acids within the lumen of the intestinal tract is found to reduce serum cholesterol levels in a casual relationship. Accumulated epidemiological data indicate that such a reduction leads to an improvement in the state of the disease of atherosclerosis. Stedronsky, in "Interaction of bile acids and cholesterol with nonsystemic agents having hypocholesterolemic properties", Biochimica et Biophysica Acta, 1210 (1994) 255-287 discusses the biochemistry, physiology and known active agents surrounding the acids of bile and cholesterol . It is known that pathophysiological alterations by being consistent with the interruption of enterohepatic circulation of bile acids in humans by Heubi, J.E., et al. See "Primary Bile Acid Malabsorption: Detective in vitro Ileal Active Bile Acid Transport", Gastroenterology, 1982: 83: 804-11. In fact, cholestyramine binds bile acids in the intestinal tract, interfering with their normal enterohepatic circulation (Reihnér, et al, in "Regulation of hepatic metabolism in humans: stimulatory effects of cholestyramine on HMG- CoA reductase activity and low density lipoprotein receptor expression in gallstone patients ", Journal of lipid research, volume 31, 1990, 2219-2226 and Suckling et al," lowering cholesterol and bile acid excretion in the hamster with cholestyramine treatment ", Atheroschlerosis, 89 (1991 ) (183-190) This results in an increase in synthesis of "liver bile acid by the liver that uses cholesterol as well as a better regulation of the LDL receptors of the liver which increase the evacuation of cholesterol and decreases serum LDL cholesterol levels." In another approach to reducing cholesterol recirculation of bile acids, the transport system of the ileal bile acid is a putative pharmaceutical target for the treatment of hypercholesterolemia based on the interruption of an enterohepatic circulation with specific transport inhibitors (Kramer, et al, "Intestinal Bile Acid Absorption "The Journal of Biological Chemistry, Vol. 268, No. 24, Issue August 25, pp. 18035-18046, 1993) In a series of patent applications, for example, Patent Application Nos. 2,025,294; 2,078,588; 2,085,782; and 2,085,830; and EP Application No. 0 379 161; 0 549 967; 0 559 064; and 0 563 731, Hoechst Aktiengesellschaft describes polymers of various constituents natural origin of the enterohepatic circulation system and its derivatives, which include the acid of bile, which inhibits the transport of acid from physiological bile in order to reduce the level of LDL cholesterol sufficiently to be effective as a pharmacist and, in particular, for its use as a hypocholesterolemic agent. In vitro inhibition of bile acid transport is disclosed to show hypolipidemic activity in the description of the Wellcome Foundation Limited of the World Patent Application number WO 93/16055 for "Hipolipidemic Benzothiepine Compounds". The selected benzothiepines are described in the World Patent Application number W093 / 321146 for numerous uses including fatty acid metabolism and coronary vascular diseases. Other selected benzothiepins are known for their use as hypolipidemic and hypocholesterolemic agents, especially for the treatment or prevention of atherosclerosis as described by the application Nos. EP 508425, FR 2661676, and WO 92/18462, each of which is limited by an amide attached to the carbon atom adjacent to the phenyl ring of the ring of benzotiepina bicyclo fused. The above references show continuing efforts to find safe effective agents for the prophylaxis and treatment of hyperlipidemic diseases and their usefulness as hypocholesterolemic agents.

The further sectioned benzothiepins are described for use in various disease states not within the utility of the present invention. These are EP 568 898A summarized by Derwent Abstract No. 93-351589; WO 89/1477 / A as summarized in Derwent Abstract No. 89-370688; U.S. 3,520,891 summarized in Derwent 50701R-B; US 3,287,370, US 3,287,370, US 3,389,144; US 3,694,446 summarized in Derwent Abstr. No. 65860T and WO 92/18462. The present invention promotes such efforts by providing novel benzothiepins, pharmaceutical compositions, and methods of use for this.

BRIEF DESCRIPTION OF THE INVENTION According to this, among its various aspects, the present invention provides the compounds of the formula (I): where: q is an integer from 1 to 4; n is an integer from 0 to 2; R and R2 are independently selected from A group consisting of H, alkyl, alkenyl, alkynyl, haloalkyl, alkylaryl, arylalkyl, alkoxy, alkoxyalkyl, dialkylamino, alkylthio, (polyalkyl) aryl, and cycloalkyl, wherein the alkyl, alkenyl, alkynyl, haloalkyl, alkylaryl, arylalkyl, alkoxy, alkoxyalkyl, dialkylamino, alkylthio, (polyalkyl) aryl, and cycloalkyl, are optionally substituted with one or more substituents selected from the group consisting of OR9, NR9R10, N + R9R10RWA ", SR9, S + R9R10A". P + R9R10RUA ", S (0) R9, S02R9, S03R9, C02R9, CN, halogen, oxo, and CONR9R10, wherein the alkyl, alkenyl, alkynyl, alkylaryl, alkoxy, alkoxyalkyl, dialkylamino, alkylthio, (polyalkyl) aryl, and cycloalkyl optionally have one or more carbons replaced by O, NR9, N + R9R10A ", S, SO, S02, S + R9A", P + R9R10A ", or phenylene, wherein R9, R10, and Rw are independently selected from a group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, acyl, heterocycle, ammonioalkyl, arylalkyl, carboxyalkyl, carboxyheteroaryl, carboxyheterocycle, carboalkoxyalkyl, carboxyalkylamino, carboxyalkylaminoalkyl, heteroarylalkyl, heterocyclylalkyl, and alkylammonioalkyl; or R1 and R2 taken together with the carbon to which the They are joined together form C3-C10 cycloalkyl, "R3 and R4 are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, acyloxy, aryl, heterocycle, OR9, NR9R10, SR9, S (0) R9, S02R9, and S03R9, wherein R9 and R10 were defined as above, or R3 and R4 together form = 0, = N0Rn, = S, = NNRnR12, = NR9, or = CRUR12, wherein R11 and R12 are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, aryl, arylalkyl, alkenylalkyl, alkynylalkyl, heterocycle, carboxyalkyl, carboalkoxyalkyl, cycloalkyl, cyanoalkyl, OR9, NR9R10, SR9, S (0) R9, S02R9, S03R9, C02R9, CN, halogen, oxo, and CONR9R10, wherein R9 and R10 are as defined above, with the proviso that both R3 and R4 can not be OH, NH2, and SH, or R11 and R12 together with the nitrogen or carbon atom to which they are join to form a cyclic ring, R5 and R6 are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, quaternary heterocycle, OR9, SR9, S (0) R9, S02R9, and S03R9, wherein alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, quaternary heterocycle, and quaternary heteroaryl can be substituted with one or more substituent groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocycle, arylalkyl, quaternary heterocycle, quaternary heteroaryl, halogen, oxo, OR13, NR13R14, SR13, S (0) R13, S02R13, SOLSRS. NR13OR14, NR13NR14R15, N02, C02R13, CN, OM, S02OM, S02NR13R14, C (0) NR13R14, C (0) OM, COR13, NR13C (0) R14, NR13C (0) NR14R15, NR13C02R14, 0C (0) R13, OC (0) NR13R14, NR13SOR14, NR13S02R14, NR13SONR14R15, NR13S02NR14R15, P (0) R13R14, P + R13R14R15A ~, P (OR13) OR14, S + R13R14A ", and N + R9RnR12A ~, where: A" is an anion pharmaceutically acceptable and M is a pharmaceutically acceptable cation, said alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, and heterocycle can be further substituted with one or more substituent groups selected from the group consisting of OR7, NR7R8, SR7, S (0) R7, S02R7, S03R7, C02R7, CN, oxo, CONR7R8, N + R7R8R9A ", alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, arylalkyl, quaternary heterocycle, quaternary heteroaryl, P (0) R7R8, P + R7R8R9A", and P (O ) (0R7) 0R8, and wherein said alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, and heterocycle optionally may have one or more carbons replaced by 0, NR7, N + R7R8A-, S, SO, S02, S + R7A-, PR7, P (0) R7, P + R7R8A-, or phenylene, and R13, R14, and R15 are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, arylalkyl, alkylarylalkyl, alkylheteroarylalkyl, alkylheterocyclylalkyl, cycloalkyl, heterocycle, heteroaryl, quaternary heterocycle, quaternary heteroaryl, heterocyclylalkyl, heteroarylalkyl, heterocyclylalkyl quaternary, heteroarylalkyl quaternary, alkoxyalkyl, alkylammonioalkyl, and carboxyalkylaminocarbonylalkyl, wherein alkyl, alkenyl, alkynyl, arylalkyl, heterocycle, and polyalkyl optionally may have one or more carbons replaced with O, N + R9R10A-, S, SO, S02, S + R9A ", PR9, P + R9R10A-, P (0) R9, phenylene, carbohydrate, amino acid, peptide, or polypeptide, and R13, R14, and R15 are optionally substituted with one or more groups selected from the group consisting of hydroxy, amino, sulfo, carboxy, alkyl, carboxyalkyl, heterocycle, heteroaryl, sulfoalkyl, quaternary heterocycle, quaternary heteroaryl, quaternary heterocyclylalkyl, quaternary heteroarylalkyl, guanidinyl, A ... _JÍ. * _ ¿Ha ». carboxyalkylethercylcylthio, OR9, NR9R10, N + R9RUR12A ", SR9, S (0) R9, S02R9, SO3R9, oxo, C02R9, CN, halogen, CONR9R10, S02OM, S02NR9R10, P0 (0R16) 0R17, P + R9R10RnA-, S + R9R10A-, and C (0) OM, wherein R16 and R17 are independently selected from the substituents constituting R9 and M; or R13 and R14, together with the nitrogen atom to which they bind to form a mono heterocycle - or polycyclic which is optionally substituted with one or more radicals selected from the group consisting of oxo, carboxy and quaternary salts, or R14 and R15, together with the nitrogen atom to which they are attached, to form a cyclic ring; R7 and R8 are independently selected from the group consisting of hydrogen and alkyl, and one or more of Rx are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, polyalkyl, acyloxy, aryl, arylalkyl, halogen, haloalkyl, cycloalkyl , heterocycle, heteroaryl, polyether, quaternary heterocycle , quaternary heteroaryl, OR13, NR13R14, SR13, S (0) R13, S (0) 2R13, SO3R13, S + R13R14A-, NR130R14, NR13R14R15, N02, C02R13, CN, OM, S02OM, S02NR13R14, NR14c (0) R13 , C (0) NR13R14, NR14C (0) R13, C (0) OM, COR13, OR18, S (0) nNR18, NR13R18, NR18OR14, N + R9RnR12A ", P '*' R9R11R12A", amino acid, peptide, polypeptide, and carbohydrate, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, polyalkyl, heterocycle, acyloxy, arylalkyl, haloalkyl, polyether, quaternary heterocycle, and quaternary heteroaryl can be further substituted with OR9, NR9R10, N + R9RUR12A ~, SR9, S (0) R9, S02R9, S03R9, oxo, C02R9, CN, halogen, CONR9R10, S02OM, S02NR9R10, PO (OR16) OR17, P + R9RUR12A ", S + R9R10A", or C (0) OM, and wherein R18 is selected from the group consisting of acyl, arylalkoxycarbonyl, arylalkyl, heterocycle, heteroaryl, alkyl, wherein the acyl, arylalkoxycarbonyl, arylalkyl, heterocycle, heteroaryl , alkyl, quaternary heterocycle, and quaternary heteroaryl are optionally substituted with one or more substituents selected from the group consisting of OR9, NR9R10, N + R9RnR12A ", SR9, S (0) R9, S02R9, S03R9, OXO, C02R9, CN, halogen, CONR9R10, S03R9, S02OM, S02NR9R10, PO (OR16) OR17, and C (0) OM, where in Rx, one or more carbons are optionally replaced by O, NR13, N + R13R14A-, S, SO, S02, S + R13A ", PR13, P (0) R13, P + R13R14A-, phenylene, amino acid, peptide, polypeptide, carbohydrate, polyether, or polyalkyl, wherein in said polyalkyl, phenylene, amino acid, peptide, polypeptide, carbohydrate, one or more carbons are optionally replaced by 0, NR9, N + R9R10A ", S, SO, S02, S + R9A-, PR9, P + R9R10A- , or P (0) R9, wherein the quaternary heterocycle and the quaternary heteroaryl are optionally substituted with one or more groups selected from the group consisting of alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocycle, arylalkyl, halogen, oxo, OR13, NR13R14, SR13, S (0) R13, S02R13, S03R13, NR130R14, NR13NR14R15, N02, C02R13, CN, OM , S020M, S02NR13R14, C (0) NR13R14, C (0) 0M, COR13, P (0) R13R14, P + R13R14R15A ", P (0R13) 0R14, S + R13R14A", and N + R9RnR12A ", with the proviso that both R5 and R6 can not be hydrogen, OH, or SH and when R5 is OH, R1, R2, R3, R4, R7 and R8 can not all be hydrogen; with the proviso that when R5 or R6 is phenyl, only one of R1 or R2 is H; with the proviso that when q = 1 and Rx is styryl, anuido, or anilmocarbonyl, only one of R5 or R6 is alkyl; with the proviso that when n is 1, R1, R3, R7, and R8 are hydrogen, R2 is hydrogen, alkyl or aryl, R4 is an unsubstituted amino or an amino substituted with one or more alkyl or aryl radicals, and R5 is hydrogen, alkyl or aryl, then R6 is different from hydroxy; or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

Preferably, R5 and R6 are independently selected from the group consisting of H, aryl, heterocycle, quaternary heterocycle, and quaternary heteroaryl, wherein said aryl, heteroaryl, quaternary heterocycle, and quaternary heteroaryl can be substituted with one or more selected substituent groups independently of the group consisting of alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocycle, arylalkyl, halogen, oxo, OR13, NR13R14, SR13, S (0) R13, S02R13, S03R13, NR130R14, NR13NR14R15, N02, C02R13, CN, OM, S02OM, S02NR13R14, C (0) NR13R14, C (0) OM, COR13, NR13C (0) R14, NR13C (0) NR14R15, NR13C02R14, OC (0) R13, OC (0- ) NR13R14, NR13SOR14, NR13S02R14, NR13SONR14R13, NR13S02NR14R15, P (0) R13R14, P + R13R14R15A-, P (OR13) OR14, S + R13R1A-, and N + R9RnR12A ", wherein said alkyl, alkenyl, alkynyl, polyalkyl , polyether, aryl, haloalkyl, cycloalkyl, and heterocycle may optionally have one or more carbon atoms. plated by O, NR7, N + R7R8A-, S, SO, S02, S + R7A-, PR7, P (0) R7, P + R7R8A-, or phenylene, wherein said alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, and heterocycle can be further substituted with one or more substituent groups selected from the group consisting of OR7, NR7R8, SR7, S (0) R7, S02R7 , S03R7, C02R7, CN, oxo, C0NR7R8, N + R7R8R9A ", alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, arylalkyl, quaternary heterocycle, quaternary heteroaryl, P (0) R7R8, P + R7R8A", and P ( O) (0R7) 0R8.

More preferably, R5 or R6 have the formula: -Ar- (Ry) t where: t is an integer from 0 to 5; Ar is selected from the group consisting of phenyl, thiophenyl, pyridyl, piperazinyl, piperonyl, pyrrolyl, naphthyl, furanyl, anthracenyl, quinolinyl, isoquinolinyl, quinoxalinyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, pyrimidinyl, thiazolyl, triazolyl, isothiazolyl, indolyl, benzoimidazolyl, benzoxazolyl, benzothiazolyl, and benzisothiazolyl; and one or more of Ry are independently selected from the group consisting of alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocycle, arylalkyl, halogen, oxo, OR13, NR13R14, SR13, S (0) R13", S02R13, S03R13, NR130R14, NR13NR14R15, N02, C02R13, CN, OM, S02OM, S02NR13R14, C (0) NR13R14, C (0) OM, COR13, NR13C (0) R14, NR13C (0) NR14R15, NR13C02R14, OC (0) R13, 0C (0) NR13R14, NR13SOR14, NR13S02R14, NR13S0NR1 R15, NR13S02NR14R15, P (0) R13R14, P + R13R14R15A ", P (OR13) OR14, S + R13R14A", and N + R9RnR12A ", wherein said alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, and heterocycle can be further substituted with one or more substituent groups selected from the group consisting of OR7, NR7R8, SR7, S (0) R7, S02R7, SO3R7, C02R7, CN, oxo, CONR7R8, N + R7R8R9A ", alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, arylalkyl, quaternary heterocycle, quaternary heteroaryl, P (0) R7R8, P + R7R8A", and P (O) (OR7) OR8, and wherein said alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, and heterocycle may optionally have one or more carbons replaced by O, NR7, N + R7R8A-, S, SO, S02, S + R7A- , PR7, P (0) R7, P + R7R8A-, or phenylene Even more preferably, R5 or R6 has the formula (II): A first class of compounds of particular interest consists of those compounds of formula I wherein q is 1 or 2; n is 2; R1 and R2 are each alkyl; R3 is hydroxy; R4 and R6 are hydrogen; R5 has the formula (II) where t is an integer from 0 to 5; one or more of Ry are OR13; R13 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, polyalkyl, aryl, arylalkyl, alkylarylalkyl, cycloalkyl, heterocycle, heteroaryl, quaternary heterocycle, quaternary heteroaryl, and quaternary heteroarylalkyl; said R13 is alkyl, alkenyl, alkynyl, arylalkyl, heterocycle, and polyalkyl groups optionally have one or more carbons replaced by 0, NR9, N + R9R10A ", S, SO, S02, S + R9A ~, PR9, P + R9R10A ", P (0) R9, phenylene, carbohydrate, amino acid, peptide, or polypeptide; R13 is optionally substituted with one or more groups selected from the group consisting of sulfoalkyl, quaternary heterocycle, quaternary heteroaryl, OR9, NR9R10, N + R9RnR12A ", SR9, S (0) R9, S02R9, SO3R9, oxo, C02R9, CN, halogen , CONR9R10, S020M, S02NR9R10, PO (OR16) OR17, P + R9R10RnA ", S + R9R10A", and C (0) 0M, wherein A "is a pharmaceutically acceptable anion and M is a pharmaceutically acceptable cation, R and R10 is independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, acyl, heterocycle, ammonioalkyl, arylalkyl, and alkylammonioalkyl; R11 and R12 are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, aryl, arylalkyl, alkenylalkyl, alkynylalkyl, heterocycle, carboxyalkyl, carboalkoxyalkyl, cycloalkyl, cyanoalkyl, OR9, NR9R10, SR9, S (0) R9, S02R9 , SO3R9, C02R9, "CN, halogen, oxo, and CONR9R10, wherein R9 and R10 are as defined above, with the proviso that both R3 and R4 can not be OH, NH2, and SH; or R11 and R12 together with the nitrogen or carbon atom to which they are attached form a cyclic ring, and R16 and R17 are independently selected from the substituent constituting R9 and M, R7 and R8 are hydrogen, and one or more of Rx are independently selected from the group consists of alkoxy, alkylamino and dialkylamino, or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

A second class of compounds of particular interest consists of those compounds of formula I wherein q is an integer from 1 to 2; n is an integer from 0 to 2; R1 and R2 are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, haloalkyl, alkylaryl, arylalkyl, alkoxy, alkoxyalkyl, dialkylamino, alkylthio, (polyalkyl) aryl, and cycloalkyl, wherein "alkyl, alkenyl, alkynyl, haloalkyl, alkylaryl, arylalkyl, alkoxy, alkoxyalkyl, dialkylamino, alkylthio, (polyalkyl) aryl, and cycloalkyl are optionally substituted with one or more substituents selected from the group consisting of OR9, NR9R10, N + R9R10RWA-, SR9, S + R9R10A-. P + R9R10RUA-, S (0) R9, S02R9, S03R9, C02R9, CN, halogen, oxo, and CONR9R10, wherein alkyl, alkenyl, alkynyl, alkylaryl, alkoxy, alkoxyalkyl, (polyalkyl) aryl, and cycloalkyl optionally have one or more carbons replaced by O, NR9, N + R9R10A-, S, SO, S02, S + R9A ", P + R9R10A", or phenylene, wherein R9, R10, and Rw are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, acyl, heterocycle, ammonioalkyl, arylalkyl, carboxyalkyl, carboxyheteroaryl, carboxyheterocycle, carboalkoxyalkyl, carboxyalkylamino, heteroarylalkyl, heterocyclylalkyl, and alkylammonioalkyl; or R1 and R2 taken together with the carbon at which are bound together form the cycloalkyl C3-C? 0; R3 and R4 are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, acyloxy, aryl, heterocycle, OR9, NR9R10, SR9, S (0) R9, S02R9, and S03R9, wherein R9 and R10 are as defined above "; or R3 and R4 together form = 0, = N0Rn, = S, = NNRnR12, = NR9, or = CRnR12, wherein R11 and R12 are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, aryl , arylalkyl, alkenylalkyl, alkynylalkyl, heterocycle, carboxyalkyl, carboalkoxyalkyl, cycloalkyl, cyanoalkyl, OR9, NR9R10, SR9, S (0) R9, S02R9, S03R9, C02R9, CM, halogen, oxo, and CONR9R10, wherein R9 and R10 are as defined above, with the proviso that R3 and R4 can not be OH, NH2, and SH, or R11 and R12 together with the nitrogen or carbon atom to which they are attached form a cyclic ring; R5 is substituted aryl with one or more of 0R13a, wherein R13a is selected from the group consisting of alkylarylalkyl, alkylheteroarylalkyl, alkylheterocyclylalkyl, heterocyclylalkyl, heteroarylalkyl, heterocyclylalkyl quaternary, alkylammonioalkyl, and carboxyalkylaminocarbonylalkyl, " R13a is optionally substituted with one or more groups selected from the group consisting of hydroxy, amino, sulfo, carboxy, alkyl, carboxyalkyl, heterocycle, heteroaryl, sulfoalkyl, heterocycle quaternary, "quaternary heteroaryl, quaternary heterocyclylalkyl, quaternary heteroarylalkyl, guanidinyl, OR9, NR9R10, N + R9RnR12A", SR9, S (0) R9, S02R9, SO3R9, oxo, C02R9, CM, halogen, CONR9R10, S02OM, S02NR9R10, PO (OR16) OR17, P + R9R10RnA ", S + R9R10A-, and C (0) OM, wherein A" is a pharmaceutically acceptable anion and M is a pharmaceutically acceptable cation, wherein R16 and R17 are independently selected from the substituents which constitute R9 and M; and R6 is selected from the group consisting of H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, quaternary heterocycle, OR30, SR9, S (0) R9, S02R9, and SO3R9, wherein alkyl, alkenyl, alkynyl, aryl , cycloalkyl, heterocycle, quaternary heterocycle, and quaternary heteroaryl can be substituted with one or more substituent groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocycle, arylalkyl, quaternary heterocycle, heteroaryl quaternary, halogen, oxo, OR13, NR13R14R13, SR13, S (0) R13, S02R13, SO3R13, NR13OR14, NR13NR14R15, N02, C02R13, CM, OM, S02OM, S02NR13R14, C (0) NR13R14, C (0) OM , COR13, NR13CfO) R14, NR13C (0) NR14R15, NR13C02R14, OC (0) R13, 0C (0) NR13R14, NR13S0R14, NR13S02R14, NR13S0NR14R15, NR13S02NR14R15, P (0) R13R14, P + R13R1R15A ", P (0R13) 0R14 , S + R13R1A_, and N + R9RnR12A ", wherein: A" is a pharmaceutically acceptable anion and M is a pharmaceutically acceptable cation, said alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, and heterocycle can be further substituted with one or more substituent groups selected from the group consisting of OR7, NR7R8, SR7, S (0) R7, S02R7, S03R7, C02R7, CN, oxo, C0NR7R8, N + R7R8R9A ", alkyl, alkenyl, alkynyl, aryl , cycloalkyl, heterocycle, arylalkyl, quaternary heterocycle, quaternary heteroaryl, P (0) R7R8, P + R7R8R9A ", P (O) (0R7) 0R8, and wherein said alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl , cycloalkyl, and heterocycle can optionally one or more carbons replaced by O, NR7, N + R7R8A-, S, SO, S02, S + R7A ", PR7, P (0) R7, P + R7R8A- , or phenylene, and R13, R14, and R15 are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, arylalkyl, alkylarylalkyl, cycloalkyl, heterocycle, heteroaryl, heterocycle quaternary, "quaternary heteroaryl, heterocyclylalkyl, heteroarylalkyl, quaternary heterocyclylalkyl, quaternary heteroarylalkyl, alkylammonioalkyl, and carboxyalkylaminocarbonylalkyl, wherein alkyl, alkenyl, alkynyl, arylalkyl, heterocycle, and polyalkyl optionally have one or more carbons replaced by 0, NR9, N + R9R10A-, S, SO, S02, S + R9A ", PR9, P + R9R10A", P (0) R9, phenylene, carbohydrate, amino acid, peptide, or polypeptide, and R13, R14, and R15 are optionally substituted with one or more groups selected from the group consisting of hydroxy, amino, sulfo, carboxy, alkyl, carboxyalkyl, heterocycle, heteroaryl, sulfoalkyl, quaternary heterocycle, quaternary heteroaryl, quaternary heterocyclylalkyl, quaternary heteroarylalkyl, guanidinyl, OR9, NR9R10, N + R9RnR12A ", sR9, S (0) R9, S02R9, S03R9, oxo, C02R9, CN, halogen, C0NR9R10, S020M, S02NR9R10, P0 (0R16) 0R17, P + R9R10RnA ", S + R9R10A-, and C (0) 0M, in where R16 and R17 are selected indepe of the substituents constituting R9 and M; or R13 and R14, together with the nitrogen atom to which they are attached form a mono- or polycyclic heterocycle which is optionally substituted with one or more radicals selected from the group consisting of oxo, carboxy and quaternary salts; or R14 and R15, together with the nitrogen atom to which they are attached, form a cyclic ring; and R30 is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, aryl, acyl, heterocycle, ammonioalkyl, alkylammonioalkyl, arylalkyl, carboxyalkyl, carboxyheteroaryl, carboxyheterocycle, carboalkoxyalkyl, carboxyalkylamino, heteroarylalkyl, heterocyclylalkyl, and alkylammonioalkyl; and R7 and R8 are independently selected from the group consisting of hydrogen and alkyl; and one or more Rx are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, polyalkyl, acyloxy, aryl, arylalkyl, halogen, haloalkyl, cycloalkyl, heterocycle, heteroaryl, polyether, quaternary heterocycle, quaternary heteroaryl, OR13, NR13R14 , SR13, S (0) R13, S (?) 2R13, S03R13, S + R13R1 A-, NR13OR14, NR13NR14R15, N02, C02R13, CN, OM, S020M, S02NR13R14, NR14C (0) R13, C (0) NR13R14, NR14C (0) R13, C ( 0) OM, COR13, OR18, S (0) nNR18, NR13R18, NR180R14, N + R9RUR12A "P + R9RnR12A", amino acid, peptide, polypeptide, and carbohydrate, wherein alkyl, alkenyl, alkynyl, cycloalkyl, aryl, polyalkyl, heterocycle, acyloxy, Arylalkyl, "haloalkyl, polyether, quaternary heterocycle, and quaternary heteroaryl can be further substituted with OR9, NR9R10, N + R9RnR12A", SR9, S (0) R9, S02R9, S03R9, oxo, C02R9, CN, halogen, C0NR9R10, S020M , S02NR9R10, PO (OR16) oR 17, P + R9RnR: A ", or S + R9R10A", or C (0) OM, and wherein R18 is selected from the group consisting of acyl, arylalkoxycarbonyl, arylalkyl, heterocycle, heteroaryl , alkyl, wherein acyl, arylalkoxycarbonyl, arylalkyl, heterocycle, heteroaryl, alkyl, quaternary heterocycle, and quaternary heteroaryl are optionally substituted with one or more substituents selected from the group consisting of OR9, NR9R10, N + R9RnR12A ", SR9, S (0) R9, S02R9, S03R9, oxo, C02R9, CM, halogen, CONR9R10, S03R9, S020M, S02NRR10, PO (OR16) OR17, and C (0) OM, wherein in Rx, one or more carbons are optionally replaced by O, NR13, N + R13R14A ", S, SO, S02, S + R13A", PR13, P (0) R13, P + R13R14A ", femlene, amino acid, peptide, polypeptide, carboh idrato, polyether, or polyalkyl, wherein in said polyalkyl, phenylene, amino acid, peptide, polypeptide, carbohydrate, one or more carbons are optionally replaced by O, NR9, N + R9R10A ", S, SO, S02, S + R9A- , PR9, P + R9R10A-, or P (0) R9; wherein the quaternary heterocycle and the quaternary heteroaryl are optionally substituted with one or more groups selected from the group consisting of alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocycle, arylalkyl, halogen, oxo, OR13, NR13R14 , SR13, s (0) R13, S02R13, S03R13, NR13OR14, NR13NR14R15, N02, C02R13, CN, OM, S020M, S02NR13R14, C (0) NR13R14, C (0) 0M, COR13, P (0) R13R14, P + R13R14R15A ", P (OR13) OR14, S + R13R14A", and N + R9RnR12A ", or an acceptable salt, solvate or prodrug ^ pharmaceutically thereof.

Preferred compounds in this class are compounds wherein: R5 is phenyl substituted with OR13a; R13a is independently selected from the group consisting of alkylarylalkyl, alkylheteroarylalkyl, alkylheterocyclylalkyl, and carboxyalkylaminocarbonylalkyl; and R13a is optionally substituted with one or more groups selected from the group consisting of carboxy, quaternary heterocycle, quaternary heteroaryl and NR9R10.

The most preferred compounds in this class are the compounds wherein: R5 is phenyl substituted with OR13a; R13a is alkylarylalkyl; and R13a is optionally substituted with one or more groups selected from the group consisting of quaternary heterocycle and quaternary heteroaryl.

Even more preferred in this class are the compounds wherein: R5 is phenyl substituted with 0R13a; R13a is alkylphenylalkyl; and R13a is optionally substituted with one or more groups selected from the group consisting of quaternary heterocycle and quaternary heteroaryl.

A third class of compounds of particular interest consists of those compounds of formula I wherein q is an integer from 1 to 4; n is an integer from 0 to 2; R1 and R2 are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, haloalkyl, aryl alkylaryl, alkoxy, alkoxyalkyl, dialkylamino, alkylthio, (polyalkyl) aryl, and cycloalkyl, wherein alkyl, alkenyl, alkynyl, haloalkyl, alkylaryl Arylalkyl, alkoxy, alkoxyalkyl, dialkylamino ", alkylthio, (polyalkyl) aryl, and cycloalkyl optionally substituted with one or more substituents selected from the group consisting of OR9, NR9R10, N + R9R10RWA", SR9, S + R9R10A ", P + R9R10R A-, S (0 ) R9, S02R9, S03R9, C02R9, CN, halogen, oxo, and CONR9R10, wherein alkyl, alkenyl, alkynyl, alkylaryl, alkoxy, alkoxyalkyl, (polyalkyl) aryl and cycloalkyl optionally have one or more carbons replaced by 0, NR9, N + R9R10A-, S, SO, S02, S + R9A ", P + R9R10A", or phenylene, wherein R9, R10 , and Rw are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, acyl, heterocycle, ammonioalkyl, arylalkyl, carboxyalkyl, carboxyheteroaryl, carboxyheterocycle, carboalkoxyalkyl, carboxyalkyl amino, heteroarylalkyl, heterocyclylalkyl, and alkylammonioalkyl; or R 1 and R 2 taken together with the carbon to which they are attached form a C 3 -C 0 cycloalkyl; R3 and R4 are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, acyloxy, aryl heterocycle, OR9, NR9R10, SR9, S (0) R9, S02R9, and S03R9, wherein R9 and R10 are as defined earlier; or R3 and R4 together form = 0, -ÑOR11, = S, = NNRnR12, = NR9, or = CRnR "12, wherein R11 and R12 are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, aryl arylalkyl, alkenylalkyl, alkynylalkyl, heterocycle, carboxyalkyl, carboalkoxyalkyl, cycloalkyl, cyanoalkyl, OR9, NR9R10 , SR9, S (0) R9, S02R9, S03R9, C02R9, CN, halogen, oxo, and CONR9R10, wherein R9 and R10 are as defined above, with the proviso that R3 and R4 can not be OH, NH2, and SH, or R11 and R12 together with the nitrogen or carbon atom to which they are attached form a cyclic ring: R5 is aryl substituted with one or more of OR13b, wherein R13b is selected from the group consisting of alkyl, alkenyl alkynyl, polyalkyl, polyether, arylarylalkyl, alkylarylalkyl, alkylheteroarylalkyl, alkylheterocyclylalkyl, cycloalkyl, heterocycle, heteroaryl quaternary heterocycle, quaternary heteroaryl heterocyclylalkyl, heteroarylalkyl, quaternary heterocyclylalkyl, quaternary heteroarylalkyl, alkylammonioalkyl, and carboxyalkylaminocarbonylalkyl, R 13b is substituted with one or more groups selected from the group consisting of carboxyalkyl, heterocycle, heteroaryl, quaternary heterocyclylalkyl, quaternary heteroarylalkyl, or guanidinyl, and R6 is "selected from the group consisting of H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, quaternary heterocycle, OR30, SR9, S (0) R9, S02R9, and S03R9, wherein alkyl, alkenyl, alkynyl, aryl cycloalkyl, heterocycle, quaternary heterocycle, and quaternary heteroaryl can be substituted with one or more substituent groups are independently selected from the group consisting of alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl haloalkyl, cycloalkyl, heterocycle, arylalkyl, quaternary heterocycle, heteroaryl quaternary, halogen, oxo, OR13, NR13R14, SR13, S (0) R13, S02R13, SO3R13, NR13OR14, NR13NR14R15, N02, C02R13, CN, OM, S02OM, S02NR13R14, C (0) NR13R14, C (0) OM, COR13, NR13C (0) R14, NR13C (0) NR1 R15, NR23C02R14, OC (0) R13, 0C (0) NR13R14, NR13SOR14, NR13S02R14, NR13SONR14R15, NR13S02NR14R15, P (0) R13R14, P + R13R14R15A ", P (OR13) OR14, S + R13R14A", and N + R9RnR12A ", wherein: A" is a pharmaceutically acceptable anion and M is a pharmaceutically acceptable cation, said alkyl , alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, and heterocycle can be further substituted with one or more substituent groups selected from the group consisting of ..a ^^ in OR7, NR7R8, SR7, S (0) R7, S02R7, S03R7, C02R7, CN, oxo, C0NR7R8, N + R7R8R9A ~, alkyl, alkenyl, alkynyl, aryl cycloalkyl, heterocycle, arylalkyl, quaternary heterocycle, quaternary heteroaryl, P ( 0) R7R8, P + R7R8R9A ", and P (0) (0R7) 0R8, and wherein said alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl haloalkyl, cycloalkyl, and heterocycle optionally have one or more carbons replaced by 0 , NR7, N + R7R8A ", S, SO, S02, S + R7A", PR7, P (0) R7, P + R7R8A ", or phenylene, and R13, R14, and R15 are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, polyalkyl, polyether, arylarylalkyl, alkylarylalkyl, alkylheteroarylalkyl, alkylheterocyclylalkyl, cycloalkyl, heterocycle, heteroaryl quaternary heterocycle, quaternary heteroaryl heterocyclylalkyl, heteroarylalkyl, heterocyclylalkyl quaternary, heteroarylalkyl quaternary, alkylammonioalkyl, and carboxyalkylaminocarbonylalkyl, wherein alkyl, alkenyl, alkynyl, arylalkyl, heterocycle, and polyalkyl optionally have one or more carbons replaced by 0, NR9, N + R9R10A ", S, SO, S02, S + R9A", PR9, P + R9R10A-, P (0) R9 , phenylene, carbohydrate, amino acid, peptide, or polypeptide, and R13, R14 and R15, are bptionally substituted with one or more groups selected from the group consisting of hydroxy, amino, sulfo, carboxy, alkyl, carboxyalkyl, heterocycle, heteroaryl sulfoalkyl, quaternary heterocycle, quaternary heteroaryl, quaternary heterocyclylalkyl, heteroarylalkyl quaternary, guanidinyl , OR9, NR9R10, N + R9RnR12A ", SR9, S (0) R9, S02R9, S03R9, oxo, C02R9, CN, halogen, CONR9R10, S020M, S02NR9R10, P0 (0R16) 0R17, P + R9R10RnA", S + R9R10A ", and C (0) 0M, wherein R16 and R17 are independently selected from the substituents that constitute R9 and M; or R13 and R14, together with the nitrogen atom to which they are attached form a mono- or polycyclic heterocycle which is optionally substituted with one or more radicals selected from the group consisting of oxo, carboxy and quaternary salts; or R14 and R15, together with the nitrogen atom to which they are attached, form a cyclic ring; and R30 is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, aryl acyl, heterocycle, ammonioalkyl, alkylammonioalkyl, arylalkyl, carboxyalkyl, carboxyheteroaryl carboxyheterocycle, carboalkoxyalkyl, carboxyalkylamino, heteroarylalkyl, heterocyclylalkyl, and alkylammonioalkyl; and R7 and R8 are independently selected from the group consisting of hydrogen and alkyl; and one or more of Rx are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, polyalkyl, acyloxy, aryl arylalkyl, halogen, haloalkyl, cycloalkyl, heterocycle, heteroaryl polyether, quaternary heterocycle, quaternary heteroaryl, OR13, NR13R14, SR13, S (0) R13, S (0) 2R13, S03R13, S + R13R14A ", NR130R14, NR13NR14R15, N02, C02R13, CN, OM, S020M, S02NR13R14, NR14C (0) R13, C (0) NR13R14, NR14C (0) R13, C (0) 0M, COR13, OR18, S (0) nNR18, NR13R18, NR18OR14, N + R9RnR12A ", P + R9RnR12A ~, amino acid, peptide, polypeptide, and carbohydrate, wherein alkyl, alkenyl, alkynyl, cycloalkyl, aryl, polyalkyl, heterocycle, acyloxy, arylalkyl, haloalkyl, polyether, quaternary heterocycle, and quaternary heteroaryl can be further substituted with OR9, NR9R10, N + R9RnR12A ", SR9, S (0) R9, S02R9, SO3R9, oxo, C02R9, CN, halogen, C0NR9R10, S02OM, S02NR9R10, P0 (0R16) 0R17, P + R9RUR12A ", S + R9R10A", or C (0) 0M, and wherein R is selected from the group consisting of acyl, arylalkoxycarbonyl, arylalkyl, heterocycle, heteroaryl, alkyl, wherein "the acyl, arylalkoxycarbonyl, arylalkyl, heterocycle, heteroaryl alkyl, quaternary heterocycle and quaternary heteroaryl are optionally substituted with one or more substituents selected from the group consisting of OR9, NR9R10, N + R9RnR12A", SR9, S (0) R9 , S02R9, SO3R9, oxo, C02R9, CN, halogen, CONR9R10, S03R9, S020M, S02NR9R10, PO (OR16) OR17, and C (0) OM, wherein in Rx, one or more carbons are optionally replaced by O, NR13 , N + R13R14A ", S, SO, S02, S + R13A", PR13, P (0) R13, P + R13R14A-, phenylene, amino acid, peptide, polypeptide, carbohydrate, polyether, or polyalkyl, wherein said polyalkyl phenylene, amino acid, peptide, polypeptide, carbohydrate, one or more carbons are optionally replaced by O, NR9, N + R9R10A ", S, SO, S02, S + R9A", PR9, P + R9R10A ", or P (0) R9, wherein the quaternary heterocycle and the quaternary heteroaryl are optionally substituted with one or more groups selected from the group consisting of alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl haloalkyl, cycloalkyl, heterocycle, arylalkyl, halogen, oxo, OR13, NR13R14, SR13, S (0) R13, S02R13, SO3R13, NR13OR14, NR13R14R15, N02, C02R13, CN, OM, S02OM, S02NR13R14, C (0) NR13R14, C (0) OM, COR13, P (0) R13R14, P + R13R14R15A ", P (OR13) OR14, S + R13R14A", and N + R9RnR12A ', or A pharmaceutically acceptable salt, solvate or prodrug thereof The preferred compounds in this class are compounds wherein: R5 is phenyl substituted with 0R13b, R13b is independently selected from the group consisting of alkyl, quaternary heteroarylalkyl, and quaternary heterocyclylalkyl; R13b is substituted with one or more groups selected from the group consisting of heterocycle, heteroaryl and guanidinyl.

A fourth class of compounds of particular interest consists of those compounds of formula I wherein q is an integer from 1 to 4; n is an integer from 0 to 2; R1 and R2 are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, haloalkyl, alkylaryl, arylalkyl, alkoxy, alkoxyalkyl, dialkylamino, alkylthio, (polyalkyl) aryl and cycloalkyl, wherein alkyl, alkenyl, alkynyl, haloalkyl, alkylaryl arylalkyl, alkoxy, alkoxyalkyl, dialkylamino, alkylthio, (polyalkyl) aryl and cycloalkyl are optionally substituted with one or more substituents selected from the group consisting of OR9, NR9R10, N + R9R10RA ", SR9, S + R9R10A", P + R9R10RnA ", S (0) R9, S02R9, S03R9 , C02R9, CN, halogen, oxo, and CONR9R10, wherein alkyl, alkenyl, alkynyl, alkylaryl, alkoxy, alkoxyalkyl, (polyalkyl) aryl and cycloalkyl optionally have one or more carbons replaced by 0, NR9, N + R9R10A ", S, SO, S02, S + R9A ", P + R9R10A", or phenylene, wherein R9, R10, and R are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl acyl, heterocycle, ammonioalkyl , arylalkyl, carboxyalkyl, carboxyheteroaryl, carboxyheterocycle, carboalkoxyalkyl, carboxyalkyl amino, heteroarylalkyl, heterocyclylalkyl, and alkylammonioalkyl; or R1 and R2 taken together with the carbon to which they are attached form a C3-C10 cycloalkyl; R3 and R4 are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, acyloxy, aryl heterocycle, OR9, NR9R10, SR9, S (0) R9, S02R9, and SO3R9, wherein R9 and R10 are as defined previously; or R3 and R4 together form = 0, OR11, = S, = NRnR12, = NR9, = CRnR12, wherein R11 and R12 are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, aryl arylalkyl, alkenylalkyl, alkynylalkyl, heterocycle, carboxyalkyl, carboalkoxyalkyl, cycloalkyl, cyanoalkyl, OR9, NR9R10, SR9, S ( ) R9, S02R9, SO3R9, C02R9, CN, halogen, oxo, and CONR9R10, wherein R9 and R10 are as defined above, with the proviso that R3 and R4 can not be OH, NH2, and SH, or R11 and R12 together with the nitrogen or carbon atom to which they are attached form a cyclic ring; R5 is aryl substituted with one or more of OR13b, wherein R13b is selected from the group consisting of alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl arylalkyl, alkylarylalkyl, alkylheteroarylalkyl, alkylheterocyclylalkyl, cycloalkyl, heterocycle, heteroaryl, quaternary heterocycle, heteroaryl quaternary, heterocyclylalkyl, heteroarylalkyl, quaternary heterocyclylalkyl, quaternary heteroarylalkyl, alkoxyalkyl, alkylammonioalkyl, and carboxyalkylaminocarbonylalkyl, R13b is substituted with one or more groups selected from the group consisting of OR9a, NR9aR10, N + R9aRuR12A ", SR9a, S (0) R9a , S02R9a, S03R9a, C02R9a, CONR9aR10, S02NR9aR10, P + R aR10RnA-, and S + R9aR10A ', wherein A "is a pharmaceutically acceptable anion and M is a pharmaceutically acceptable cation, and wherein R9a is selected from the group consisting of carboxyalkyl, carboxyheteroaryl carboxyheterocycle, carboalkoxyalkyl, carboxyalkyl amino and carboxyalkylaminoalkyl; R6 is selected from the group consisting of H, alkyl, alkenyl, alkynyl, aryl cycloalkyl, heterocycle, quaternary heterocycle, OR30, SR9, S (0) R9, S02R9, and S03R9, wherein alkyl, alkenyl, alkynyl , aryl cycloalkyl, heterocycle, quaternary heterocycle, and quaternary heteroaryl can be substituted with one or more substituent groups are independently selected from the group consisting of alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl haloalkyl, cycloalkyl, heterocycle, arylalkyl, quaternary heterocycle , quaternary heteroaryl, halogen, oxo, OR13, NR13R14, SR13, S (0) R13, S02R13, S03R13, NR13OR14, NR13NR1R15, N02, C02R13 , CN, OM, S02OM, S02NR13R14, C (0) NR13R14, C (0) OM, COR13, NR13C (0) R14, NR13C (O) NR14R15, NR13C02R14, OC (0) R13, OC (0) NR13R14, NR13SOR14 , NR13S02R14, NR13SONR14R15, NR13S02NR14R15, P (0) R13R14, P + R13R14R15A ", P (OR13) OR14, S + R13R14A ", and N + R9RnR12A", wherein: A "is a pharmaceutically acceptable anion and M is a pharmaceutically acceptable cation, said alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl haloalkyl, cycloalkyl , and heterocycle can be further substituted with one or more substituent groups selected from the group consisting of OR7, NR7R8, SR7, S (0) R7, S02R7, SO3R7, C02R7, CN, oxo, C0NR7R8, N + R7R8R9A ", alkyl, alkenyl, alkynyl, aryl cycloalkyl, heterocycle, arylalkyl, quaternary heterocycle, quaternary heteroaryl P (0) R7R8, P + R7R8R9A ", and P (O) (07) 08, and wherein said alkyl, alkenyl, alkynyl, polyalkyl, polyether , aryl haloalkyl, cycloalkyl, and heterocycle may optionally have one or more carbons replaced by O, NR7, N + R7R8A ", S, SO, S02, S + R7A", PR7, P (0) R7, P + R7R8A " , or phenylene, and R13, R14, and R15 are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, polyalkyl, pol ether, aryl, arylalkyl, alkylarylalkyl, alkylheteroarylalkyl, alkylheterocyclylalkyl, cycloalkyl, heterocycle, heteroaryl, quaternary heterocycle, quaternary heteroaryl, heterocyclylalkyl, heteroarylalkyl, heterocyclylalkyl quaternary, heteroarylalkyl quaternary, alkoxyalkyl, alkylammonioalkyl, and carboxyalkylaminocarbonylalkyl, wherein alkyl, alkenyl, alkynyl, arylalkyl, heterocycle, and polyalkyl optionally have one or more carbons replaced by O, NR9, N + R9R10A ", S, SO, S02, S + R9A ", PR9, P + R9R10A", P (0) R9, phenylene, carbohydrate, amino acid, peptide, or polypeptide, and R13, R14, and R15 are optionally substituted with one or more groups selected from the group consisting of hydroxy, amino, sulfo, carboxy, alkyl, carboxyalkyl, heterocycle, heteroaryl, sulfoalkyl , quaternary heterocycle, quaternary heteroaryl, quaternary heterocyclylalkyl, quaternary heteroarylalkyl, guanidinyl, OR9, NR9R10, N + R9RnR12A ", SR9, S (0) R9, S02R9, S03R9, oxo, C02R9, CN, halogen, CONR9R10, S02OM, S02NR9R10, PO (OR16) OR17, P + R9R10RnA ", S + R9R10A", and C (0) OM, wherein R16 and R17 are independently selected from the substituents constituting R9 and M; or R13 and R14, together with the nitrogen atom to which they are attached form a mono- or polycyclic heterocycle which is optionally substituted with one or more radicals selected from the group consisting of oxo, carboxy and quaternary salts; or R14 and R1S 'together with the nitrogen atom to which they are attached, form a cyclic ring; and R30 is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, aryl, acyl, heterocycle, ammonioalkyl, alkylammonioalkyl, arylalkyl, carboxyalkyl, carboxyheteroaryl, carboxyheterocycle, carboalkoxyalkyl, carboxyalkylamino, heteroarylalkyl, heterocyclylalkyl, and alkylammonioalkyl; and R7 and R8 are independently selected from the group consisting of hydrogen and alkyl; and one or more of Rx are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, polyalkyl, acyloxy, aryl, arylalkyl, halogen, haloalkyl, cycloalkyl, heterocycle, heteroaryl, polyether, quaternary heterocycle, quaternary heteroaryl, OR13, NR13R14, SR13, S (0) R13, S (0) 2R13, S03R13, S + R13R14A ", NR130R14, NR13R14R15 'N02, C02R13, CN, OM, S020M, S02NR13R14, NR1C (0) R13, C (0) NR13R14 , NR14C (0) R13, C (0) OM, COR13, OR18, S (0) nR18, NR13R18, NR18OR14, N + R9RnR12A ", P + R9RnR12A", amino acid, peptide, polypeptide, and carbohydrate, wherein the alkyl , alkenyl, alkynyl, cycloalkyl, aryl, polyalkyl, heterocycle, acyloxy, arylalkyl, haloalkyl, polyether, heterocycle quaternary, "and quaternary heteroaryl can be further substituted with OR9, NR9R10, N + R9RnR12A", SR9, S (0) R9, S02R9, SO3R9, oxo, C02R9, CN, halogen, CONR9R10, S02OM, S02NR9R10, PO (OR16) OR17, P + R9RnR12A ", S + R9R10A", or C (0) OM, and wherein R18 is selected from the group consisting of acyl, arylalkoxycarbonyl, arylalkyl, heterocycle, heteroaryl, alkyl, wherein the acyl, arylalkoxycarbonyl, arylalkyl , heterocycle, heteroaryl, alkyl, quaternary heterocycle, and quaternary heteroaryl are optionally substituted with one or more substituents selected from the group consisting of OR9, NR9R10, N + R9RUR12A ", SR9, S (0) R9, S02R9, SO3R9, oxo, C02R9, CN, halogen, CONR9R10, SO3R9, S020M, S02NR9R10, PO (OR16) OR17, and C (0) OM, where in Rx, one or more carbons are optionally replaced by O, NR13, N + R13R14A ", S , SO, S02, S + R13A ", PR13, P (0) R13, P + R13R14A", phenylene, amino acid, peptide, polypeptide, carbohydrate, polyether, or polyalkyl, wherein in said polyalk uilo, phenylene, amino acid, peptide, polypeptide, and carbohydrate, one or more carbons are optionally replaced by O, NR9, N + R9R10A ", S, SO, S02, S + R9A", PR9, P + R9R10A ", or P (0) R9; where the quaternary heterocycle and the quaternary heteroaryl are optionally substituted with one or more groups selected from the group consisting of alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocycle, arylalkyl, halogen, oxo, OR13, NR13R14, SR13, S (0) R13, S02R13, S03R13, NR13OR14, NR13NR14R15 'N02, C02R13, CN, OM, S020M, S02NR13R14, C (0) NR13R14, C (0) 0M, COR13, P (0) R13R14, P + R13R14R15A_, P (0R13) 0R14, S + R13R14A ", and N + R9RUR12A", or a pharmaceutically acceptable salt, solvate or prodrug thereof. Preferred compounds in this class are compounds wherein: R5 is phenyl substituted with 0R13b; R13b is selected from the group consisting of alkyl and alkoxyalkyl; and R13b is substituted with one or more groups consisting of OR9a, and NR9aR10; R9a is selected from the group consisting of carboxyalkyl, carboxyheteroaryl, and carboxyheterocycle; and R10 is carboxyalkyl.

A fifth class of compounds of particular interest consists of those compounds of formula I wherein q is a whole number from 1 to 4; n is an integer from 0 to 2; R1 and R2 are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, haloalkyl, alkylaryl, arylalkyl, alkoxy, alkoxyalkyl, dialkylamino, alkylthio, (polyalkyl) aryl, and cycloalkyl, wherein alkyl, alkenyl, alkynyl, haloalkyl, alkylaryl, arylalkyl, alkoxy, alkoxyalkyl, dialkylamino, alkylthio, (polyalkyl) aryl, and cycloalkyl are substituted with one or more substituents selected from the group consisting of OR 9, NR9R10, N + R9R10RWA ", SR9, S + R9R10A ', P + R9R10RUA-, S (0) R9, S02R9, S03R9, C02R9, CN, halogen, oxo, and CONR9R10, wherein alkyl, alkenyl, alkynyl, alkylaryl , alkoxy, alkoxyalkyl, (polyalkyl) aryl, and cycloalkyl optionally have one or more carbons replaced by 0, NR9, N + R9R10A ", S, SO, S02, S + R9A", P + R9R10A ", or phenylene, wherein R9, R10, and R are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, acyl, heterocycle, ammonioalkyl, arylalkyl, carboxyalkyl, carboxyheteroaryl, carboxyheterocycle, carboalkoxyalkyl, carboxyalkylamino, heteroarylalkyl, heterocyclylalkyl, and alkylammonioalkyl; or R1 and R2 taken together with the carbon to which they are attached form C3-C10 cycloalkyl; R3 and R4 are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, acyloxy, aryl, heterocycle, OR9, NR9R10, SR9, S (0) R9, S02R9, and SO3R9, wherein R9 and R10 are as defined earlier; or R3 and R4 together form = 0, = N0Rn, = S, = NNRnR12, = NR9, or = CRUR12, wherein R11 and R12 are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, aryl, arylalkyl, alkenylalkyl, alkynylalkyl, heterocycle, carboxyalkyl, carboalkoxyalkyl, cycloalkyl, cyanoalkyl, OR9 , NR9R10, SR9, S (0) R9, S02R9, SO3R9, S02R9, CN, halogen, oxo, and CONR9R10, wherein R9 and R10 are as defined above, with the proviso that both R3 and R4 can not be OH , NH2, and SH, or R11 and R12 taken together with the nitrogen or carbon atom to which they are attached form a cyclic ring; R5 is aryl substituted with one or more of OR13b, wherein R13b is selected from the group consisting of of alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, arylalkyl, alkylarylalkyl, alkylheteroarylalkyl, alkylheterocyclylalkyl, cycloalkyl, heterocycle, heteroaryl, quaternary heterocycle, quaternary heteroaryl, heterocyclylalkyl, heteroarylalkyl quaternary, heterocyclylalkyl quaternary, heteroarylalkyl quaternary, alkylammonioalkyl, and carboxyalkylaminocarbonylalkyl , R13b is substituted with one or more groups selected from the group consisting of carboxyalkylheterocyclyl, NR9R10a, CONR9R10a, SO2NR9R10a, P + R9R_0aR__A-, and s R10aA-, wherein A "is a pharmaceutically acceptable anion and M is a pharmaceutically acceptable cation, wherein R10a is selected from the group consisting of carboxyalkyl, carboalkoxyalkyl, carboxyalkylamino, heteroarylalkyl, and heterocyclylalkyl; or R6 is selected from the group consisting of H, alkyl , alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, quaternary heterocycle, OR30, SR9, S (0) R9, S02R9, and S03R9, wherein alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, quaternary heterocycle, and quaternary heteroaryl can be substituted with one or more substituent groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocycle, arylalkyl, quaternary heterocycle, quaternary heteroaryl, halogen, oxo, OR13, NR13R14, SR13, S (0) R13, S02R13, S03R13, NR13OR14, NR13NR14R15, N02, C02R13, CN, OM, S02OM, S02NR13R14, C (0) NR13R14, C (0) OM, COR13, NR13C (0) R14, NR13C (0) NR14R15 'NR13C02R14, 0C (0) R13, OC (0) NR13R14, NR13SOR14, NR13S02R14, NR13S0NR14R15, NR13S02NR14R15, P (0) R13R14, P + R13R1R15A ", P (0R13) 0R14, S + R13R14A", and N + R9RnR12A ", wherein: A" is a pharmaceutically acceptable anion and M is a pharmaceutically acceptable cation, said alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, and heterocycle can be substituted with one or more substituent groups selected from the group consisting of OR7, NR7R8, SR7, S (0) R7, S02R7, S03R7 , C02R7, CN, oxo, CONR7R8, N + R7R8R9A ", alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, arylalkyl, quaternary heterocycle, quaternary heteroaryl, P (0) R7R8, P + R7R8R9A", and P (O) (R7) OR8, and wherein said alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloaikyl, and heterocycle may optionally have one or more carbons replaced by 0, NR7, N + R'RSA ", S, SO, S02, S + R7A-, PR7, P (0) R7 , P + R7R8A ", or phenylene, and R13 R14 and R15 are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, arylalkyl, alkylarylalkyl, alkylheteroarylalkyl, alkylheterocyclylalkyl, cycloalkyl, heterocycle, heteroaryl, quaternary heterocycle, quaternary heteroaryl, heterocyclylalkyl, heteroarylalkyl, quaternary heterocyclylalkyl, heteroarylalkyl quaternary, alkylammonioalkyl, - and carboxyalkylaminocarbonylalkyl, wherein alkyl, alkenyl, alkynyl, arylalkyl, heterocycle, and polyalkyl optionally have one or more carbons replaced by 0, NR9, N + R9R10A " , S, SO, S02, S + R9A ", PR9, P + R9R10A", P (0) R9, phenylene, carbohydrate, amino acid, peptide, or polypeptide, and R13, R14, and R15 are optionally substituted with one or more groups selected from the group consisting of hydroxy, amino, sulfo, carboxy, alkyl, carboxyalkyl, heterocycle, heteroaryl, sulfoalkyl, quaternary heterocycle, quaternary heteroaryl, heterocyclylalkyl quaternary, "quaternary heteroarylalkyl, guanidinyl, OR9, NR9R10, N + R9RnR12A ', SR9, S (0) R9, S02R9, S03R9, oxo, C02R9, CN, halogen, C0NR9R10, S020M, S02NR9R10, P0 (0R16) 0R17, P ° RUA ", S + R9R10A", and C (0) 0M, wherein R16 and R17 are independently selected from the substituents constituting R9 and M, or R13 and R14, together with the nitrogen atom to which they are attached form a mono- or polycyclic heterocycle which is optionally substituted with one or more radicals selected from the group consisting of oxo, carboxy and quaternary salts; or R14 and R15, together with the nitrogen atom to which they are attached, form a cyclic ring; and R30 is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, aryl, acyl, heterocycle, ammoniumalkyl, alkylammoniumalkyl, arylalkyl, carboxyalkyl, carboxyheteroaryl, carboxyheterocycle, carboalkoxyalkyl, carboxyalkylamino, heteroarylalkyl, heterocyclylalkyl, and alquilamonioa alkyl, and R and R8 are independently selected from the group consisting of hydrogen and alkyl; and one or more Rx are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, p'olialquilo, acyloxy, aryl, arylalkyl, halogen, haloalkyl, cycloalkyl, heterocycle, heteroaryl, polyether, quaternary heterocycle, quaternary heteroaryl, OR13, NR13R14, SR13, S (0) R13, S (0) 2R13, S03R13, S + R13R14A ", NR13OR14, NR13NR14R15 'N02, C0: R13, CN, OM, S02OM, S02NR13R14, NR 14 (0) R13, C (0) NR13R14, NR 14 (0) R13, C (0) 0M, COR13, OR 18 , S (0) nNR18, NR13R18, NR180R14, N + R9RnR12A "P + R9RnR12A", amino acid, peptide, polypeptide, and carbohydrate, wherein alkyl, alkenyl, alkynyl, cycloalkyl, aryl, polyalkyl, heterocycle, acyloxy, arylalkyl, haloalkyl, polyether, quaternary heterocycle, and quaternary heteroaryl can be further substituted with OR9, NR9R10, N + R9RnR12A ", S02R9, S (0) R9, S02R9, S03R9, oxo, C02R9, CN, halogen, CONR9R10, S02OM, S02NR9R10, PO (OR16) OR17, P + R9RUR12A ", S + R9R10A", or C (0) OM, and wherein R18 is selected from the group consisting of acyl, arylalkoxycarbonyl, arylalkyl, heterocycle, heteroaryl, alkyl, wherein acyl, arylalkoxycarbonyl, arylalkyl, heterocycle, heteroaryl, alkyl, quaternary heterocycle, and quaternary heteroaryl is optionally substituted with one or more substituents selected from the group consisting of OR9, NR9R10, N + R9RnR12A ", SR9, S (0) R9, S02R9, S03R9, oxo, C02R9, CN, halogen, CONR9R10, SO3R9, S02OM, S02NR9R10, PO (OR16) OR 17, and C (0) OM, wherein in Rx , one or more carbons are optionally replaced by or, NR13, N + R13R14A ", S, SO, S02, S + R13A", PR13, P (0) R13, P + R13R1A ", phenylene, amino acid, peptide, polypeptide, carbohydrate, polyether, or polyalkyl, wherein in said polyalkyl, phenylene, amino acid, peptide, polypeptide, and carbohydrate, one or more carbons are optionally replaced by O, NR9, N + R9R10A ", S, SO, S02, S + R9A ", PR9, P + R9R10A-, or P (0) R9; wherein the quaternary heterocycle and quaternary heteroaryl are optionally substituted with one or more groups selected from the group consisting of alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocycle, arylalkyl, halogen, oxo, OR13, NR13R14, SR13, S (0) R13, S02R13, SO3R13, NR13OR14, NR13NR14R1S 'N02, C02R13, CN, OM, S02OM, S02NR13R14, C (0) NR13R14, C (0) OM, COR13, P (0) R13R14, P + R13R14R15A ", P (OR13) OR14, S + R13R1A", and N + R9RnR12A ", or pharmaceutically acceptable salt, solvate or prodrug thereof. Preferred compounds in this class are compounds wherein: R5 is phenyl substituted with OR13b; R 13b is alkyl; and R13b is substituted with NR9R10a; and R9 is hydrogen; and R is heteroarylalkyl.

A sixth class of compounds of particular interest consists of those compounds of formula I wherein q is an integer from 1 to 4; n is an integer from 0 to 2; R1 and R2 are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, haloalkyl, alkylaryl, arylalkyl, alkoxy, alkoxyalkyl, dialkylamino, alkylthio, (polyalkyl) aryl, and cycloalkyl, wherein alkyl, alkenyl, alkynyl, haloalkyl , alkylaryl, arylalkyl, alkoxy, alkoxyalkyl, dialkylamino, alkylthio, (polyalkyl) aryl, and cycloalkyl are optionally substituted with one or more substituents selected from the group consisting of OR9, NR9R10, N + R9R10RA ", SR9, S + R9R10A". P + R9R10RnA ", S (0) R9, S02R9, S03R9, C02R9, CN, halogen, oxo, and CONR9R10, wherein alkyl, alkenyl, alkynyl, alkylaryl, alkoxy, alkoxyalkyl, (polyalkyl) aryl, and cycloalkyl "optionally have one or more carbons replaced by 0, NR9, N + R9R10A", S, SO, S02, S + R9A ", P + R9R10A", or phenylene, wherein R9, R10, and RW are independently selected from the a group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, acyl, heterocycle, ammonioalkyl, arylalkyl, carboxyalkyl, carboxyheteroaryl, carboxyheterocycle, carboalkoxyalkyl, carboxyalkyl amino, heteroarylalkyl, heterocyclylalkyl, and alkylammonioalkyl; or R1 and R2 taken together with the carbon to which they are attached form C3-C10 cycloalkyl; R3 and R4 are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, acyloxy, aryl, heterocycle, OR9, NR9R10, SR9, S (0) R9, S02R9, and S03R9, wherein R9 and R10 as defined previously; or R3 and R4 together form = 0, = NOR11, = S, = NNRnR12, = NR9, or = CRR12, wherein R11 and R12 are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, aryl, arylalkyl , alkenylalkyl, alkynylalkyl, heterocycle, carboxyalkyl, carboalkoxyalkyl, cycloalkyl, J ^ Pf%. "N cyanoalkyl, "OR9, NR9R10, SR9, S (0) R9, S02R9, S03R9, C02R9, CN, halogen, oxo, and CONR9R10, wherein R9 and R10 are as defined above, with the proviso that both R3 and R4 they can not be OH, NH2, and SH, or R11 and R12 together with the nitrogen or carbon atom to which they are attached form a cyclic ring: R5 is aryl substituted with one or more substituent groups independently selected from the group consists of NR13C (0) R14, NR13C (O) NR1 R15, NR13C02R14, OC (0) R13, OC (0) NR13R14, NR13SOR14, NR13S02R14, NR13SONR14R15, and NR13S02NR14R15, wherein: R13, R14, and R15 are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, arylalkyl, alkylarylalkyl, alkylheteroarylalkyl, alkylheterocyclylalkyl, cycloalkyl, heterocycle, heteroaryl, quaternary heterocycle, quaternary heteroaryl, heterocyclylalkyl, heteroarylalkyl, quaternary heterocyclylalkyl, quaternary heteroarylalkyl, alkylammonioalkyl, and carboxyalkylaminocarbonylalkyl, R13, R14, and R15 are optionally substituted with one or more groups selected from the group consisting of hydroxy, aminb, sulfo, carboxy, alkyl, carboxyalkyl, heterocycle, heteroaryl, sulfoalkyl, quaternary heterocycle, quaternary heteroaryl, quaternary heterocyclylalkyl, quaternary heteroarylalkyl, guanidinyl, OR9, NR9R10, N + R9RUR12A ", SR9, S (0) R9, S02R9 , S03R9, oxo, C02R9, CN, halogen, CONR9R10, S02OM, S02NR9R10, PO (OR16) OR17, P + R9R10RUA-, S + R9R10A ", and C (0) OM, wherein A" is a pharmaceutically acceptable anion and M is a pharmaceutically acceptable cation, wherein R16 and R17 are independently selected from the substituents constituting R9 and M, or R13 and R14, together with the nitrogen atom to which they are attached form a mono- or polycyclic heterocycle which is optionally substituted with one or more radicals selected from the group consisting of oxo, carboxy and quaternary salts, or R14 and R15, together with the nitrogen atom to which they are attached, form a cyclic ring, and R6 is selected from the group that consists of H, a alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, quaternary heterocycle, OR30, SR9, S (0) R9, S02R9, and S03R9, wherein alkyl, alkenyl, alkynyl, aryl, cycloalkyl, "heterocycle, heterocycle quaternary, and quaternary heteroaryl can be substituted with one or more substituent groups independently selected from the group consisting of alkylalke alky polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocycle, arylalkyl, quaternary heterocycle, quaternary heteroaryl, halogen, oxo, OR13, NR13R14, SR13, S (0) R13, S02R13, S03R13, NR130R14, NR13NR14R15, N02 , C02R13, CM, CN, S020M, S02NR13R14, C (0) NR13R14, C (0) 0M, COR13, NR13C (0) R14, NR13C (O) NR14R15, NR13C02R14, 0C (0) R13, 0C (0) NR13R14 , NR13SOR14, NR13S02R14, NR13SONR14R15, NR13S02NR14R15, P (0) R13R14, P + R13R14R15A ", P (OR13) OR14, S + R13R1A", and N + R9RnR12A ", wherein: A" is a pharmaceutically acceptable anion and M is a pharmaceutically acceptable cation, said alkyl, alke alky polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, and heterocycle can be further substituted with one or more substituent groups selected from the group consisting of OR7, NR7R8, SR7, S (0) R7, S02R7, S03R7, C02R7, CN, oxo, C0NR7R8, N + R7R8R9A ", alkyl, alke alky aryl, cycloalkyl, heterocycle, arylalkyl, quaternary heterocycle river, quaternary heteroaryl, P (0) R7R8, P + R7R8R9A ", and P (O) (OR7) OR8, and wherein said alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, and heterocycle may optionally have one or more carbons replaced by 0, NR7, N + R7R8A ", S, SO, S02, S + R7A", PR7, P (0) R7, P + R7R8A ", or phenylene, and R13 R14 and R15 are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, arylalkyl, alkylarylalkyl, alkylheteroarylalkyl, alkylheterocyclylalkyl , cycloalkyl, heterocycle, heteroaryl, quaternary heterocycle, quaternary heteroaryl, heterocyclylalkyl, heteroarylalkyl, quaternary heterocyclylalkyl, quaternary heteroarylalkyl, alkylammonioalkyl, and carboxyalkylaminocarbonylalkyl, wherein alkyl, alkenyl, alkynyl, arylalkyl, heterocycle, and polyalkyl optionally have one or more carbons replaced by 0, NR9, N + R9R10A ~, S, SO, S02, S + R9A ", PR9, P + R9R10A", P (0) R ', phenylene, carbohydrate, amino acid, peptide, or polypeptide and R13, R14, and R15 are optionally substituted with one or more groups selected from the group consisting of hydroxy, amino, sulfo, carboxy, alkyl, carboxyalkyl, heterocycle, heteroaryl, sulfoalkyl, quaternary heterocycle, quaternary heteroaryl, heterocyclylalkyl quaternary, "quaternary heteroarylalkyl, guanidinyl, OR9, N + R9R10, N + R9RnR12A_, SR9, S (0) R9, S02R9, S03R9, oxo, C02R9, CN, halogen, CONR9R10, S02OM, S02NR9R10, PO (OR16) OR17, P + R9R10RUA "S + R9R10A-, and C (0) OM, wherein R16 and R17 are independently selected from the substituents constituting R9 and M; or R13 and R14, together with the nitrogen atom to which they are attached form a mono- or polycyclic heterocycle which is optionally substituted with one or more radicals selected from the group consisting of oxo, carboxy and quaternary salts; or R14 and R15, together with the nitrogen atom to which they are attached, form a cyclic ring; and R30 is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, aryl, acyl, heterocycle, ammonioalkyl, alkylammonioalkyl, arylalkyl, carboxyalkyl, carboxyheteroaryl, carboxyheterocycle, carboalkoxyalkyl, carboxyalkylamino, heteroarylalkyl, heterocyclylalkyl, and alkylammonioalkyl; and R7 and R8 are independently selected from the group consisting of hydrogen and alkyl; and one or more of Rx are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, p-bialkyl, acyloxy, aryl, arylalkyl, halogen, haloalkyl, cycloalkyl, heterocycle, heteroaryl, polyether, quaternary heterocycle, quaternary heteroaryl, OR13, NR13R14, SR13, S (0) R13, S (0) 2R13, S03R13, S + R13R14A ", NR13OR14, NR13NR14R15, N02, C02R13, CN, OM, S02OM, S02NR13R14, NR14C (0) R13, C (0) NR13R14, NR14C (0) R13, C (0) 0M, COR13, OR18, S (0 ) nNR18, NR13R18, NR180R14, N + R9RnR12A ", P + R9RnR12A", amino acid, peptide, polypeptide, and carbohydrate, wherein alkyl, alkenyl, alkynyl, cycloalkyl, aryl, polyalkyl, heterocycle, acyloxy, arylalkyl, haloalkyl, polyether, quaternary heterocycle, and quaternary heteroaryl can be further substituted with OR9, NR9R10, N + R9RUR12A ", SR9, S (0) R9, S02R9, S03R oxo, C02R9, CM, halogen, CONR9R10, S020M, S02NR9R10, P0 (0R16) 0R17 , P + R9RnR12A ", S + R9R10A", or C (0) OM, and wherein R18 is selected from the group consisting of acyl, arylalkoxycarbonyl, arylalkyl, heterocycle, heteroaryl, alkyl, wherein acyl, ary ilalcoxycarbonyl, arylalkyl, heterocycle, heteroaryl, alkyl heterocycle, quaternary, and quaternary heteroaryl are optionally substituted with one or more substituents selected from the group consisting of OR9, NR9R10, N + R9R11R12A SR9, S (0) R9, S02R9, "SO3R9, oxo, C02R9, CN, halogen, CONR9R10, SO3R9, S02OM, S02NR9R10, PO (OR16) OR17, and C (0) OM, wherein in Rx, one or more carbons is optionally substituted by O, NR13, N + R13R1 A ", S, SO, S02, S + R13A ~, PR13, P (0) R13, P + R13R14A", phenylene, amino acid, peptide, polypeptide, carbohydrate, polyether, or polyalkyl, wherein in said polyalkyl, phenylene, amino acid, peptide, polypeptide, carbohydrate, one or more carbons are optionally replaced by 0, NR9, N + R9R10A ", S, SO, S02, S + R9A", PR9, P + R9R10A ", or P (0) R9; wherein quaternary heterocycle and quaternary heteroaryl are optionally substituted with one or more groups selected from the group consisting of alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocycle, arylalkyl, halogen, oxo, OR13, NR13R14, SR13 , S (0) R13, S02R13, SO3R13, NR13OR14, NR13NR1 R15, N02, C02R13, CN, OM, S020M, S02NR13R14, C (0) NR13R14, C (0) 0M, COR13, P (0) R13R14, P + R13R1 R15A ", P (0R13) 0R14, S + R13R1 A ", and N + R9RnR12A-, or a pharmaceutically acceptable salt, solvate or prodrug thereof The preferred compounds in this class are compounds wherein: R5 is aryl substituted with a selected radical of the group consisting of NR13C (O) NR14R15 and ¿^^^ asa 1 ^^. V NR13C02R14, The most preferred compounds in this class are compounds wherein: R5 is phenyl substituted with a radical selected from the group consisting of NR13C (0) NR14R15 and NR13C02R14.

Other embodiments of the invention are further directed to the compounds of Formula I, which includes each of the above embodiments, wherein there is at least one or more of the following conditions: (1) R1 and R2 are independently selected from the group It consists of hydrogen and alkyl. Preferably, R1 and R2 are independently selected from the group consisting of C? _6 alkyl. More preferably, R1 and R2 are the same as alkyl C6-6- Even more preferably, R1 and R2 are n-butyl; and / or (2) R3 and R4 are independently selected from the group consisting of hydrogen and OR9 wherein R9 is defined as above. Preferably, R3 is hydrogen and R4 is OR9. Even more preferably, R3 is hydrogen and R4 is hydroxy; and / or (3) R5 is substituted aryl. Preferably, R5 is substituted phenyl. More preferably, R5 is phenyl substituted with a radical selected from the group consisting of OR13, NR13C (0) R14, NR13C (0) NR14R15, NR13C02R14, 0C (0) R13, OC (0) NR13R14, NR13SOR14, NR13S02R14, NR13SONR1R15, and NR13S02NR14R15 wherein R13, R14 and R15 are as described previously. Even more preferably, R5 is phenyl substituted with OR13. Even more preferably, R5 is phenyl substituted in the para or meta position with OR13 wherein R13 comprises a quaternary heterocycle, quaternary heteroaryl or substituted amino; and / or (4) R6 is hydrogen; and / or (5) R7 and R8 are independently selected from the group consisting of hydrogen and alkyl. Preferably, R7 and R8 are independently selected from the group consisting of hydrogen and C? -6 alkyl. Even more preferably, R7 and R8 are hydrogen; and / or (6) Rx is selected from the group consisting of OR13 and NR13R14. Preferably, R x is selected from the group consisting of alkoxy, amino, alkylamino and dialkylamino. Still more preferably, Rx is selected from the group consisting of methoxy and dimethylamino.

The invention is further directed to a compound selected from: »20 R1 * R * 1 (Formula DI) .22 .20, 18. , 21 (Formu the DI I) R22 R20 Rtβ R21 (Formula DI I I) i » wherein R19 is selected from the group consisting of alkandiyl, alkeniyl, alkyndiiyl, polyalkandiyl, alkoxydiyl, polyetherdiyl, polyalkoxydiyl, carbohydrate, amino acid, peptide, and polypeptide, wherein alkandiyl, alkeniyl, alkyndiiyl, polyalkandiyl, alkoxydiyl, polyetherdii, polyalkoxydiyl, carbohydrate , amino acid, peptide, and polypeptide may optionally have one or more carbon atoms replaced by O, NR7, N + R7R8, S, SO, S02, S + R7R8, PR7, P + R7R8, phenylene, heterocycle, quaternary heterocycle, heteroaryl quaternary, or aryl, wherein alkanediyl, alkeniyl, alkyndiiyl, polyalkandiyl, alkoxydiyl, polyetherdiyl, polyalkoxydiyl, carbohydrate, amino acid, peptide, and polypeptide can be substituted with one or more substituent groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocycle, arylalkyl, halogen, oxo, OR13, NR13R14 SR13, S (0) R13, S02R13, S03R13, NR13OR14, NR13NR14R15, N02, C02R13, CN, OM, S02OM, S02NR13R14, C (0) NR13R14, C (0) OM, COR13, P (0) R13R14 , P + R13R14R15A ", P (OR13) 014, S + R13R14A", and N + R9RnR12A-; wherein R19 further comprises functional linkages by which R19 binds R20, R21, or R22 on the compounds of Formulas DII and DIII, and R23 on compounds of Formula DIII. Each of R20, R21, or R22 and R23 comprises a portion of benzothiepine as described above that is therapeutically effective in the transport of acids that inhibit ileal bile. The invention is also directed to a compound selected from Formula DI, Formula DII and Formula DIII in which each of R20, R21, or R22 and R23 comprises a portion of benzothiepin corresponding to the Formula: - - (Formula DIV) or: (Formula DIVA) wherein R1, R2, R3, R4, R5, R6, R7, R8, Rx, q and n are as defined in Formula I as described above, and R55 is either a covalent bond or aplene. In the compounds of Formula DIV, it is particularly preferred that each of R, R, and R in Formulas DII and DIII, and R23 in Formula DIII, are linked in their 7-position or 8-position to the R19 In the compounds of the Formula DIVA, it is particularly preferred that R 55 comprises a portion of phenylene linked in a m-op carbon thereof to R19 The examples of the Formula DI include: In any of the dimeric structures or multimeric "described immediately above, the benzothiepine compounds of the present invention can be used alone or in various combinations In any of the compounds of the present invention, R1 and R2 can be ethyl / butyl or butyl / butyl. of interest includes the following compounds: Me2N H H In another aspect, the present invention provides a pharmaceutical composition for the prophylaxis or treatment of a condition or condition for which the acid transport inhibitor is indicated, such as a condition for example, atherosclerosis. Such compositions may comprise any of the compounds described above, either alone or in combination, in an amount effective to reduce the acid levels of bile in the blood, to reduce the transport thereof through the membranes of the digestive system. , and a pharmaceutically acceptable carrier, excipient, or diluent.

In a further aspect, the present invention also provides a method for the treatment of a disease or condition in mammals, including humans, for which a bile acid transport inhibitor is indicated, comprising administration to a patient in need of any of the compounds described above, either alone or in combination, in an effective amount in the form of unit doses or in divided doses.

In a further aspect, the present invention provides the use of any of the compounds described above, either alone or in combination, in the preparation of a medicament for use in the treatment of a disease or condition in mammals, including human beings, for whom a transport inhibitor of bile acid is indicated.

In another aspect, the present invention also provides a process for the preparation of the compounds of the present invention as will be discussed in great detail below.

An additional field of the applicability of the present invention will be apparent from the detailed description provided below. However, it will be understood that the following detailed description and examples, while indicating preferred aspects of the present invention, are provided only by way of illustration since various changes and modifications within the essence of the present invention become apparent. by those with experience in the scope of this detailed description.

DETAILED DESCRIPTION OF THE INVENTION The following detailed description is provided to assist those persons with skill in the art which will practice the present invention. However, this detailed description will not be constructed to unduly limit the present invention as modifications and variations in the aspects discussed by those of ordinary skill in the art can be made herein without departing from the essence or scope of the present invention. The contents of each of the references cited herein, which include the contents of the reference cited within those main references, are incorporated herein by reference in their entirety.

DEFINITIONS In order to aid reading in the understanding of the following detailed description, the following definitions are provided: "Alkyl", "alkenyl" and "alkynyl" unless otherwise indicated are each chain hydrocarbons straight or branched from one to twenty carbon atoms for the alkyl, or from twenty carbon atoms for the alkyl or from two to twenty carbon atoms for the alkenyl alkynyl of the present invention and therefore mean, for example, methyl ethyl, propyl, butyl, pentyl or hexyl and ethenyl, propenyl, butenyl, pentenyl, or hexenyl and ethynyl, propynyl, butynyl, pentynyl, or hexynyl respectively and isomers thereof. "Aryl" means a fully unsaturated mono or multi-ring carbocycle, including, but not limited to, an unsubstituted phenyl, naphthyl, or anthracenyl. "Heterocycle" means a mono or multi-ring carbocycle, saturated or unsaturated wherein one or more carbon atoms can be replaced by N, S, P, or O. This includes, for example, the following structures: where Z, Z ', Z "° Z"' is C, S, P, 0 or N, with the proviso that one of z, z ', z "or Z'" is other than carbon, but not is the O or S when they are linked to another atom of O or S. In addition, optional substituents are understood to be attached to Z, Z ', Z' 'or Z' '' only when each is C. The term "heteroaryl" means a completely unsaturated heterocycle. In either the "heterocycle" or "heteroaryl", the point of attachment for the molecule of interest may be in the hetero atom or elsewhere within the ring. The term "quaternary heterocycle" means a heterocycle wherein one or more of the heteroatoms, for example, O, N, S, or P, have a number of bonds that are positively charged. The point of attachment of the quaternary heterocycle to the molecule of interest may be in a heteroatom or elsewhere. The term "quaternary heteroaryl" means a heteroaryl wherein one or more of the heteroatoms, for example, O, N, S, or P, have a number of bonds that are positively charged. The point of attachment of the quaternary heteroaryl to the molecule of interest may be in a heteroatom or elsewhere.

The term "halogen" means an iodine, fluorine, chlorine or bromine group. The term "haloalkyl" means an alkyl substituted with one or more halogens. The term "cycloalkyl" means a mono or multi-ring carbocycle wherein each ring contains from three to ten carbon atoms and wherein any ring may contain one or more in double or triple bonds. Examples include radicals such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloalkenyl, and cycloheptyl. The term "cycloalkyl" further encompasses spiro systems wherein the cycloalkyl ring has a carbon atom in common with the heterocyclic ring provided with seven members of the benzothiopine. The term "diyl" means a diradical radical wherein said radical has two binding sites for the molecules of interest. The term "oxo" means a double bonded oxygen. The term "polyalkyl" means an open or branched chain hydrocarbon chain having a molecular weight of up to about 20,000, more preferably up to about 10,000, more preferably up to about 5,000. The term "polyalkoxy" means a polymer of alkylene oxides, wherein the polyalkoxy has a molecular weight of up to about 20,000, more preferably up to about 10,000, more preferably up to about 5,000. The term "cycloalkylidene" means a mono or multi-ring carbocycle wherein a carbon atom within the ring structure is doubly bonded to an atom which is not within the ring structures. The term "carbohydrate" means a mono, di, tri or polysaccharide wherein the polysaccharide can have a molecular weight of up to about 20,000, for example, hydroxypropyl methylcellulose or chitosan. The term "peptide" means a polyamino acid containing up to about 100 amino acid units.

The term "polypeptide" means a polyamino acid containing about 100 amino acid units to about: 1000 amino acid units, more preferably from about 100 amino acid units to about 750 amino acid units, more preferably about 100 amino acid units. amino acid units to about 500 amino acid units.

The term "alkylammonioalkyl" means an NH2 group or a mono, di, or tri substituted amino group, any of which are attached to an alkyl or alkyl wherein said alkyl is attached to the molecule of interest. The term "triazolyl" includes all positional isomers. In all other heterocycles c heteroaryls which contain more than one heteroatom ring and for which isomers are possible, such as isomers are included in the definition of said heterocycles and heteroaryls. The term "sulfo" means a sulfo group, -S03H or its salts. The term "sulfoalkyl" means a cycloalkyl group to which a sulfonate group is attached, wherein said alkyl is attached to the molecule of interest. The term "arylalkyl" means a substituted aryl alkyl radical such as benzyl. The term "Alkylarylalkyl" means an arylalkyl radical that is substituted in the aryl group with one or more alkyl groups. The term "heterocyclylalkyl" means an alkyl radical that is substituted with one or more heterocycle groups. Preferably the radicals heterocyclylalkyl are "heterocyclylalkyl" radicals having one or more heterocycle groups attached to an alkyl radical having from one to ten carbon atoms. The term "heteroarylalkyl" means an alkyl radical that is substituted with one or more heteroaryl groups. Preferably the heteroarylalkyl radicals are the "low heteroarylalkyl" radicals having one or more heteroaryl groups attached to an alkyl radical having from one to ten carbon atoms. The term "quaternary heterocyclylalkyl" means an alkyl radical that is substituted with one or more quaternary heterocycle groups. Preferably the quaternary heterocyclylalkyl radicals are "low quaternary heterocyclylalkyl" radicals having one or more quaternary heterocycle groups attached to an alkyl radical having from one to ten carbon atoms. The term "heteroarylalkyl quaternary" means an alkyl radical that is substituted with one or more quaternary heteroaryl groups. Preferably the quaternary heteroarylalkyl radicals are "low quaternary heteroarylalkyl" radicals having one or more quaternary heteroaryl groups attached to an alkyl radical having from one to ten carbon atoms.

The term "alkylheteroarylalkyl" means a heteroarylalkyl radical which is substituted with one or more alkyl groups. Preferably the alkylheteroarylalkyl radicals are "low alkylheteroarylalkyl" radicals with alkyl portions having from one to ten carbon atoms. The term "alkoxy" is an alkyl radical which is attached to the remainder of the molecule by means of oxygen, such as the methoxy radical. More preferably the radicals are "lower alkoxy" radicals having from one to six carbon atoms. Examples of such radicals include methoxy, ethoxy, propoxy, isopropoxy, butoxy and terbutoxy. The term "carboxy" means a carboxy group, C02H, or its salts. The term "carboxyalkyl" means an alkyl radical that is substituted with one or more carboxy groups. Preferred carboxyalkyl radicals are "low carboxyalkyl" radicals having one or more carboxy groups attached to an alkyl radical having from one to six carbon atoms. The term "carboxyheterocycle" means a heterocycle radical that is substituted with one or more carboxy groups.

The term "carboxy heteroaryl" means a heteroaryl radical that is substituted with one or more carboxy groups. The term "carboalkoxyalkyl" means an alkyl radical that is substituted with one or more alkoxycarbonyl groups. Preferred carboalkoxyalkyl radicals are "low carboalkoxyalkyl" having one or more alkoxycarbonyl groups attached to an alkyl radical having from one to six carbon atoms. The term "carboxyalkylamino" means an amino radical that is mono or disubstituted with the carboxyalkyl. Preferably the carboxyalkyl substituent is a "carboxyalkyl low" radical wherein the carboxy group is attached to an alkyl radical having from one to six carbon atoms. When used in combination, for example "alkylaryl" or "arylalkyl", the individual terms listed above have the meaning indicated above. The term "inhibitor of bile acid transport" means a compound capable of inhibiting the absorption of bile acids from the intestine in the circulatory system of a mammal, such as a human. This £ * _: __ _e ~? ^ includes increased fecal excretion of acids; of bile, as well as reducing blood plasma or serum concentrations of cholesterol and cholesterol ester, and more specifically, reducing LDL and VLDL cholesterol. Conditions or diseases which benefit from prophylaxis or treatment by inhibiting the transport of acid from bile include, for example, a hyperlipidemic condition such as atherosclerosis.

Compounds The compounds of the present invention may have at least two asymmetric carbon atoms, and therefore include racemates and stereoisomers, such as diastereomers and enantiomers, in both cases in pure form or in mixture. Such stereoisomers can be prepared using conventional techniques, either by reacting the enantiomeric starting materials, or by salt separating the isomers of the compounds of the present invention. The isomers may include geometric isomers, for example, cis isomers or trans isomers through a double link. All isomers are contemplated among the compounds of the present invention. The compounds of the present invention also include tautomers. The compounds of the present invention as will be discussed below include their salts, solvates and prodrugs.

Synthesis of the compound The starting materials for use in the preparation of the compounds of the present invention are known or can be prepared by conventional methods known to those skilled in the art or in analogous ways to the processes described in the art. . Generally, the compounds of the present invention can be prepared by the methods described below. For example, as shown in Scheme I, the reaction of aldehyde II with formaldehyde and sodium hydroxide yields hydroxyaldehyde III which is converted to IV mesylate with methanesulfonyl chloride and triethylamine similar to the procedure described in Chem. Ber. 98, 728-734 (1965). The Reaction of IV mesylate with thiophenol V, prepared by the process described in WO 93/16055, in the presence of triethylamine produces ketoaldehyde VI which can be cyclized with the reagent, zinc and titanium trichloride prepared in ethylene dimethyl ether glyco] (DME) refluxes to provide a mixture of 2,3-dihydrobenzothiophene VII and two racemic steroisomerios e 'benzothiopin- (5H) -4-one VIII when R1 and R2 are non-equivalent.The oxidation of VII with three equivalents. of m-chloroperbenzoic acid (MCPBA) provides the isomeric sulfone-epoxide IX wherein in the hydrogenation with palladium on carbon as the catalyst provides a mixture of four racemic steroisomers of 4-hydroxy-2, 3,, 5-terahydrobenzothiopine- 1, X-dioxides and 2 racemic steroisomers of 2,3,4,5-tetrahydrobenzothiopine-1,1-dioxides XI when R 1 and R 2 are not equivalent The optically active compounds of the present invention can be prepared using a i optically active nucleus III or by resolution of the X compounds with optical resolution agents very well known in the art as described in J. Chem. , 39, 3904 (1974), ibid. , 42, 2781 (1977), and ibid. , 44, (1979).

Scheme 1 2Q E¿ (Ms = methanesulfonyl group) XL Alternatively, the keto-aldehyde VI where R ~ is H can be prepared by reacting the thiophenol with a 2-substituted acrolein.

Benzothiepin- (5H) -4-one VIII can be oxidized with MCPBA to produce benzothiepin- (5H) -4-one-l, 1-dioxide XII which can be reduced with sodium borohydride to produce four racemic stereoisomers of X The two stereoisomers of X, Xa and Xb, which have the OH group and R5 on opposite sides of the benzothiepine ring can be converted to the other two isomers of X, Xc and Xd, which have the OH group and R5 in the same sides of the benzothiepine ring by the reaction in methylene chloride with 40-50% sodium hydroxide in the presence of a phase transfer catalyst (PCT). The transformation can also be carried out with potassium t-butoxide in THF. x_ 2__ MLÍ * BA = m-cioroperbenzoic acid PTC s phase transfer catalyst hen R = butyium, R = etiio, R »phenyl, X» H, q ß 4 6a «Xa ób = Xb 6c = Xc 6d = X? The compounds of the present invention wherein R5 is OR, NRR 'and S (0) nR and R4 is hydroxy can be prepared by the reaction of epoxide IX wherein R5 is H with thiol, alcohol, and amine in the presence of a base.

IX, where R- = H R5 - OR. NRR '. Yes} 0R Another route for Xc and Xd of the present invention is shown in scheme 2. Compound VI is oxidized to compound XIII with two equivalents of m-chloroperbenzoic acid. Hydrogenolysis of compound XIII with palladium on carbon produces compound XIV which can be cyclized with each of potassium t-butoxide or sodium hydroxide under phase transfer conditions to a mixture of Xc and Xd. The separation of Xc and Xd can be accompanied by either HPLC or fractional crystallization. The thiophenols XVIII and V used in the present invention can also be prepared according to scheme 3. The alkylation of the phenol XV with an arylmethyl chloride in a non-polar solvent according to the procedure in j.

Chem. Soc., 2431-2432 (1958) provides the phenol L substituted in ortho XVI. Phenol XVI can be converted to thiophenol XVIII via thiocarbateto XVII by e_. procedure described in J. Org. Chem., 31, 3980 (1966). The phenol XVI is reacted with dimethyl thiocarbamoyl chloride and triethylamine to produce the thiocarbamate XVII which is thermally repaired at 200-300 ° C, and the reconditioned product is hydrolyzed with sodium hydroxide to produce thiophenol XVIII. Similarly, Thiophenol V can also be prepared from 2-acylphenol XIX via an intermediate thiocarbamate XX.

Scheme 2 i £ __ Scheme 4 is another route for benzothiepine-1, 1-dioxides Xc and Xd which initiates thiophenol XVIII. Compound XVIII can be reacted with IV mesylate to produce the sulfide-aldehyde XXI. Oxidation of XXI with two equivalents of MCPBA produces the sulfone-aldehyde XIV which can be cyclized with potassium t-butoxide to the mixture of Xc and Xd. Cyclization of sulfur-aldehyde with potassium t-butoxide also provides a mixture of benzothiepin XXII. a,: i i'4 Scheme 4 ? vm v Examples of the amine- and hydroxylamine-containing compounds of the present invention can be prepared as shown in Scheme 5 and Scheme 6. The 2-chloro-4-nitrobenzophenone is reduced with triethylsilane and trifluoromethane sulfonic acid to 2-chloro -4-nitrodiphenylmethane 32. The reaction of 32 with lithium sulfide followed by the reaction of the resulting sulfide with mesylate IV produces sulfur-aldehyde XXIII. Oxidation of XXIII with 2 equivalents of MCPBA produces sulfone-aldehyde XXIV which can be produced by hydrogenation to hydroxylamine XXV. Protecting the hydroxylamine XXV with di-butyldicarbonate yields the N, 0-di- (t-butoxycarbonyl) hydroxylamino derivative. Cyclization of XXVI with potassium t-butoxide and removal of the t-butoxycarbonyl protecting group produces a mixture of hydroxylamino derivatives XXVIIc and XXVIId. The primary amine derivatives XXXIIIc and XXXIIId can also be prepared by the further hydrogenation of XXIV or XXVIIc and XXVIId.

Scheme 5 In Scheme 6, the reduction of the sulfone-aldehyde XXV with hydrogen followed by the reductive alkylation of the resulting amino derivative with hydrogen and an aldehyde catalysed with palladium on carbon in the same reaction vessel produces the derivative of the substituted amine XXVIII. Cyclization of XXVIII with potassium t-butoxide produces a mixture of the substituted amino derivatives of this invention XXIXc and XXIXd. fifteen twenty ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ ^^^^^^^^^^^^^ - ^^^^^^ tó ^^^^^ Scheme 6 twenty Scheme 7 describes one of the methods of introducing a substituent to the aryl ring to the 5-position of the benzothiepine. Iodination of the 5-phenyl derivative XXX with iodine catalyzed by the mercury triflate produces the iodine derivative XXXI which, under a carbonylation with a palladium catalyst in an alcohol, produces the carboxylate XXXII. Hydrolysis of the carboxylate and derivatization of the resulting acid to the acid derivatives are well known in the art.

Scheme 7 The abbreviations used in the above description have the following meanings: THF tetrahydrofuran PCT phase transfer catalyst Aliquot 336 methyltraprylammonium chloride MCPBA m-chloroperbenzoic acid Celite a class of diatomaceous earth filtration aids DMF dimethylformamide DME ethylene glycol dimethyl ether BOC group t-butoxycarbonyl Me methyl Ethyl Bu butyl EtOAc ethyl acetate Et20 dimethyl ether CH2C12 methylene chloride MgSO4 magnesium sulfate NaOH sodium hydroxide CH3OH methanol HCl hydrochloric acid NaCl sodium chloride NaH sodium hydride _ á £ - *. £ & & amp; s < w_. " LaH lithium aluminum hydride LiOH lithium hydroxide Na2S03 sodium sulfite NaHC03 sodium bicarbonate DMSO dimethylsulfoxide KOSiMe3 potassium trimethylsilanolate PEG polyethylene glycol MS mass spectrometry HRMS high resolution mass spectrometry ES electrorrociado NMR nuclear magnetic resonance spectroscopy GC gas chromatography MPLC medium pressure liquid chromatography HPLC high pressure liquid chromatography RPHPLC reverse phase high pressure liquid chromatography RT - room temperature H or hr hour (s) Min minute (s) "enantiomerically enriched" (ee) means that an enantiomer or the indication of pre-weighted diastereomers on the complementary enantiomer or the indication of the diastereomers. The enrichment The enantiomer of a mixture of enantiomers is calculated by dividing the concentration of the enantiomer preponderated by the concentration of another enantiomer, by multiplying the dividend by 100, and by expressing the result as a percentage. The enantiomeric enrichment can be from about 1% to about 100%, preferably from about 10% to about 100%, and more preferably from about 20s = 100%. R1 and R2 can be selected from a substituted and unsubstituted Ci to Cio alkyl wherein the substituent (s) can be selected from alkylcarbonyl, alkoxy, hydroxy, and nitrogen containing heterocycles attached to the Ci to C? 0 alkyl through of an ether bond The substituents on the 3-carbon may include ethyl, n-propyl, n-butyl, n-pentyl, isobutyl, isopropyl, CH2C (= 0) C2H5, -CH2OC2H5, and -CH20- (4 picoline). Ethyl, n-propyl, n-butyl, and isobutyl are preferred. Preferred compounds in a certain particularity of the present invention are the substituents R.sub.1 and R.sub.2, for example n-butyl / n-butyl, so that the compound is non-chiral at carbon 3. Optical isomerism which eliminates carbon. 3 simplifies the selection, the synthesis, the separation, and quality control of the compound used as a transport inhibitor of ileal bile acid. In both compounds having a chiral carbon 3 and those having a non-chiral carbon 3, the substituents (R *) in the benzo ring may include hydrogen, aryl, alkyl, hydroxy, halo, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, haloalkyl, haloalkoxy, (N) -carbonylalkylamine, haloalkylthio, haloalkylsulfinyl, haloalkylsulfonyl, amino, N-alkylamino, N, N-dialkylamino, (N) -alkoxycarbamoyl, (N) -aryloxycarbamoyl, (N) -aralkyloxycarbamoyl, trialkylammonium (especially with an opposite ion of halide), (N) -amindo, (N) -alkylamido, -N-alkylamido, -N, N-dialkylamido, (N) -haloalkylamido, (N) -sulfonamido, (N) -alkylsulfonamido, ( N) -haloalkylsulfonamido, carboxyalkyl amino, trialkylammonium salt, (N) -carbamic acid, alkyl or benzyl ester, N-acylamide, hydroxylamine, haloacylamine, carbohydrate, thiophene a trialkyl ammonium salt having a carboxylic acid or a substituent hydroxy in one or more of the alkyl substituents, a p Alkylene having a substituted ammonium salt on top of this, - [O (CH2)] x-X where x is from 2 to 12, w is 2 or 3 and X is a halo or an ammonium salt quaternary, and (N) -nitrogen containing a heterocycle wherein the nitrogen of said heterocycle is optionally quaternized. Among the preferred species which may constitute R * are methylethyl, isopropyl9, t-butyl, hydroxy, methoxy, ethoxy, isopropoxy, methylthio, iodo, bromo, fluoro, methylsulfinyl, methylsulfonyl, ethylthio, amino, hydroxylamine, N-methylamino, N, N-dimethylamino, N, N-diethylamino , (N) -benzyloxycarbamoyl, trimethylammonium, A ", NHC (= 0) CH3, -NHC (= 0) C5Hn, -NHC (= 0) C6H? 3, carboxyethylamino, (N) -pyrrolidinyl, pyrrolyl (N) - N-methylpyridinium A ", (N) -N-methylmorpholinium A" and NN '-methylpiperazinyl, (N) -bromomethylamido, (N) -N-hexylamino, thiophene, -N "(CH3) 2C02H I", -NCH2CH2C02H, - (N) -N'-dimethylpiperazinium I ", (N) -t-butyloxycarbamoyl, (N) -methylsulfonamido, (N) N'-methylpyrrolidinium, and - (OCH2CH2) 3I, where A" is a pharmaceutically acceptable anion The benzo ring can also be mono-substituted at position 6, 7 or 8, or disubstituted at positions 7- and 8. Compounds 6, 7, 8-trialkoxy, for example compounds 6, 7, are also included. , 8-trimethoxy A variety of other substituents may be present advantageously in the positions s 6,7,8 and / or 9- of the benzo ring, which include, for example, guanidinyl, cycloalguyl, carbohydrate (eg example, a monosaccharide of 5 or 6 carbons), peptide, and salts of cautionary ammonium bonded to the ring via poly (oxyalkylene) linkages, for example, - (OCH2CH2)? - N + R13R1R15A ", where x is from 2 to 10 In the additional compounds of the present invention, R5 and R6 are independently selected from hydrogen and an aryl substituted or unsubstituted with a carbon ring, thiophene, pyridine, pyrrolo, thiazole, imidazole, pyrazolo, pyrimidine, morpholine, N- alkylpyridino, N-alkylpiperazinium, N-alkylmorpholino, or furan in which the substituent (s) is selected from halo, hydroxyl, trihaloalkyl, alkoxy, amino, N-alkylamino, N, N-dialkylamino, quaternary ammonium salts, a Ci to C4 alkylene bridge having a substituted quaternary ammonium salt on it, alkoxycarbonyl, aryloxycarbonyl, alkylcarbonyloxy and arylcarbonyloxy, (O, O) -dioxyalkylene, - [0 (CH2)] xX where x is from 2 to 12, w is 2 or 3 and X comprises halo or a quaternary ammonium salt, ti ofeno, pyridine, pyrrolo, thiazolo, imidazole, pyrazolo, or furan. The aryl group of R5 or R6 is preferably phenyl, phenylene, or triyl benzene, that is, it may be unsubstituted, monosubstituted, or disubstituted. Among the species which can constituting the substituents on the aryl ring of R5 or R6 are fluorine, chlorine, bromine, methoxy, ethoxy, isopropoxy, trimethylammonium (preferably with an iodide or an opposite ion), methoxycarbonyl, ethoxycarbonyl, formyl, acetyl, propanoyl, (N) - hexyl dimethyl ammonium, hexylenetrimethylammonium, tri (oxyethylene) iodide, and tetra (oxyethylene) trimethyl-ammonium iodide each substituted in the p position, the m position, or both in the aryl ring. Other substituents which may be present in a phenylene, triyl benzene or other aromatic ring include 3,4-dioxymethylene (5 membered ring) and 3,4-dioxyethylene (6 membered ring). Among the compounds which have been or can be demonstrated to have inhibitory properties of ileal bile acid transport are those wherein R5 or R6 is selected from phenyl, p-fluorophenyl, m-fluorophenyl, p-hydroxyphenyl, m-hydroxyphenyl, p -methoxyphenyl, m-methoxyphenyl, pN, N-dimethylaminophenyl, mN, N-dimethylaminophenyl, I "p- (CH3) 3-N + -phenyl, I" m- (CH3) 3-N + -phenyl, I "m- ( CH3) 3-N + -CH2CH2- (OCH2CH2) 2-0-phenyl, I "p- (CH3) 3 ~ N + -CH2CH2- (OCH2CH2) 2-0-phenyl, I" m- (N, N-dimethylpiperazinium) -N + -CH2- (OCH2CH2) 2-0-phenyl, 3-methoxy-4-fluorophenyl, thienyl-2-yl, 5-chlorothienyl-2-yl, 3,4-difluorophenyl, I "p- (N, N - "- • -» v "^ - - • * • tisc ~ _. J S »a» a ^ dimethylpiperazinium) - (N ') -CH2- (0CH2CH2) -0-phenyl, 3-fluoro-4-methoxyphenyl, -4-pyridinyl, 2-pyridinyl, 3-pyridinyl, N-methyl-4-pyridinyl, I "N -methyl-3-pyridinium, 3,4-dioxymethylene-phenyl, 3,4-dioxyethylene phenyl, and p-methoxycarbonylphenyl The preferred compounds include the 3-ethyl-3-butyl and 3-butyl-3-butyl compounds each having the above preferred R5 substituents in combination with the Rx substituents shown in Table 1. It is particularly preferred that one but not both of R5 and R6 is hydrogen It is especially preferred that R4 and R6 are hydrogen, that R3 and R5 are not hydrogen and that R3 and R5 are oriented in the same direction relative to the plane of the molecule, that is, both in the a- configuration and in the β configuration, it is further preferred that, where R2 is butyl and R1 is ethyl, then R1 has the same orientation relative to the plane of the molecule as R3 and R5, as shown in Table A are lists of the species illustrated RVR2, R5 / R6 and Rx.

Table ÍA: Altenative R groups Continue on the next page.. ß-η ilo B-ethyl 8-ßo-propyl s-rert-butyl 8 -OH ß-OCH, 8-0 (ß-prspil o) 8-SOCH] T-SO? -HJ 8- H2 5 8 -HH0H 8 --inCTlj 8-MMeCH2C02H 8-? T * tMß) 2CKjCOjK. r 8- (N) -morpholine 8- (N > -azetidine g. (N) -H- m-tilazetldlnio, I * 8- (N) -pyrrolldine β- (H) -N-methyl-10 pyrrolidinium-8- (l) -N- 8thyl-morpholinium, I "8- (N) -Ñ'-methylpxperazine-β-N-N'-rii m-piperazinium, I" 8-RH-CBZ 8-NHC (0) CsHu 8-NRC (0) CB7Br ß-NH-C (NH) NH2 8- (2) - thiof «no Continue on the sisuiente path 20 9. me or 9. ethyl ro ilo 9-eßrt-but i nio, I "9- (N) -pyrrolidine 9- (N) -N- methyl- * pyrroli dinium, I * 9- (N) -N- netll-morpholinium, j> 9 ^ (N) -N ' -methylpiperazine 10 9-CN> -N'-dimethylpiper-azinium, S * 9-NH-CBZ 9-NH (0) C5Hli 9-NHC (0) O-2Br 9-NH-C.NH.NH2 9- ( 2) -thiophene -OCH ,, ß-OCHj 7-SCH ,, ß-OCH, 7-SCH ,, 8 -SCHj 6-OCHJ, 7-OCH ,, ß-OCHj fifteen twenty ~, ¿^^^ _ a ^^ aáaag * «? ^« - Additional preferred compounds of the present invention comprise a core structure having two or more pharmaceutically active benzothiepine structures as described above, covalently linked to the core radical via functional linkages. Such active benzothiepine structures preferably comprise: (Formula DIV) . { Formula DIVA] wherein R1, R2, R3, R4, R5, R6, R7, R8, X, q and n are as defined above, and R55 is each a covalent or arylene bond. The radical of the nucleus may comprise alkane diyl, alkenyl diyl, alkynyl diyl, polyalkane diyl, alkoxy diyl, polyether diyl, polyalkoxy diyl, carbohydrate, amino acid, and peptide, polypeptide, wherein the alkane diyl, alkene diyl, alkynyl diyl, polyalkane diyl, alkoxy diyl, polyether diyl, polyalkoxy diyl, carbohydrate, amino acid, and peptide polypeptide, optionally may have one or more carbons substituted by O, NR7, N + RR8, S, SO, S02, S + R7R8, PR7, P + R7R8, phenylene, heterocycle, quaternary heterocycle, quaternary heteroaryl, or aryl, wherein the alkane diyl, alkene diyl, alkynyl diyl, polyalkanediyl, alkoxy diyl, polyether diyl, polyalkoxy diyl, carbohydrate, amino acid, peptide, and polypeptides can be substituted with one or more substituent groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocycle, arylalkyl, halogen, oxo, OR13 , NR13R14, SR13, S (0) R13, S02R13, S03R13, NR130R14, NR13NR14R15, N02, C02R13, CN, OM, S02OM, S02NR13R14, C (0) NR13R14, C (0) OM, COR13, P (0) R13R14, P + R13R14R15A ", P (OR13) OR14, S + R13R14A ", and N + R9R R12A"; Wherein said alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, and heterocycle may further be substituted with one or more substituent groups selected from the group consisting of OR7, NR7R8, SR7, S (0) R7, S02R7, S03R7, C02R7, CN, oxo, CONR7R8, N + R7R8R9A-, alkyl, alkenyl, alkyl, aryl, cocloalkyl, heterocycle, arylalkyl, quaternary heterocycle, quaternary heteroaryl, P (0) R7R8, P + RR8A ", P ( O) (0R7) 0R8, and wherein said alkyl, alkenyl, alkynyl, polyalkyl, polyether, aplo, haloalkyl, cycloalkyl, and the heterocycle may optionally have one or more carbons replaced by O, N + RR8A ~, S, SO, S02, S + R7A ", PR7, P (0) R7, P + R7R8A ", or phenylene Examples of core radicals include: fe_a @ fo & fcg »- *, s £ A *? * í & . twenty wherein: R25 is selected from the group consisting of C and N, and R24 and R27 are independently selected from the group consisting of:, 30 (O), -N-. = S-. -S • CH. eleven »Í '-C-. -C-, -C-O -.- C-. -N + - .30 -S. -NH-NH-, -NHS02-. and -N = NH 3r NH, 13 wherein R, R, R and R are independently selected from alkyl, alkenyl, alkylaryl, aryl, arylalkyl, cycloalkyl, heterocycle, and heterocycloalkyl, A- is a pharmaceutically acceptable anion, and k = 1 a . In the compounds of Formula DIV, R20, R21, R22 in Formulas DII and DIII, and R23 in Formula DIII can be linked in any of their positions 6-, 7-, 8-, or 9- a R19. In the compounds of the Formula DIVA, it is preferred that R55 comprises a phenylene radical linked to a m- or p- position thereof to R19. In another embodiment, a major chain of the radical of the nucleus, R19, as discussed herein in Formulas DII and DIII can be substituted multiplely with more than four units of active benzothiepin., ie, R20, R21, R22, and R23 as discussed above, through the multiple functional groups within the main chain of the core radical. The unit of the main chain of the radical of the core, R19, can comprise a unit of the radical of the single nucleus, multimers thereof, and multimeric mixtures of the different units of the radical of the nucleus discussed here, that is, alone or in combination. The number of units of the main chain of the single core radical may be in the range of about 1 to about 100, preferably from about 1 to about 80, more preferably from about 1 to about 50, and still more preferably from about 1 to about 25. The number of binding sites of active benzothiepin units of similar or different slope without a single-stranded radical backbone unit may be in the range of about 1 to about 100, preferably from about 1 to about 80, more preferably from about 1 to about 1 to about 25. Said binding points may include links to C, S, 0, N, or P without any of the groups contained by the definition of R19. Most preferred benzothiepine radicals comprise R20, R21, R22 and / or R23 according to the preferred structures as summarized above by the formula I. The carbon 3 in each benzothiepine radical can be achiral, and the substituents R1, R2, R3, R4, R5 and Rx can be selected from the preferred groups and combinations of the substituents are discussed above. The core structures may comprise, for example, poly (ex-alkylene) or oligo (oxalkylene), especially poly-oligo (exethylene) or poly-oligo (oxypropylene).

Doses, formulations, and routes of administration The inhibitory transport compounds of ileal bile acid of the present invention can be administered for the prophylaxis and treatment of hyperlipidemic diseases or conditions by any means, preferably oral, which produces the contact of these compounds with their place of action in the body, for example in the ilium of a mammal, for example a human. For the prophylaxis or treatment of the conditions referred to the compound to the foregoing, the compounds of the present invention can be used as compounds per se. The pharmaceutically acceptable salts are particularly suitable for medical applications due to their high solubilities relative to the main compound. Such salts more clearly have a pharmaceutically acceptable anion or cation. Acceptable pharmaceutically acceptable acid addition salts of the compounds of the present invention when possibly including those derived from organic acids, such as hydrochloric, hydrobromic, phosphoric, metaphoric, nitric, sulfonic, and sulfuric acids, and organic acids such as acetic, benzenesulfonic, benzoic, citric, ethanesulfonic, fumaric, gluconic, glycolic, isothionic, lactic, lactobionic, maieic, malic, methanesulfonic, succinic, toluenesulfonic, tartaric, and trtrifluoroacetic acids. The chloride salt is particularly preferred for medical purposes. The acceptable pharmaceutically acceptable basic salts -,. «_ T» aaESWMU * • > > - » - »- - - ^ -; _ n_a. £ 3 * they include ammonium salts, alkali metal salts such as sodium and potassium salts, and alkaline earth salts such as magnesium and calcium salts. The anions of the definition of A "in the present invention are, of course, also required to be pharmaceutically acceptable and are also selected from the foregoing list The compounds of the present invention may be presented with an acceptable carrier in the form of a composition. The carrier should, therefore, be acceptable in the sense of being compatible with the other ingredients of the composition and should not be harmful to the container.The carrier can be a solid or a liquid, or both, and is preferably formulated with the compound as a unit dose composition, for example, a tablet, which may contain from 0.05% to 95% by weight of the active compound Other pharmacologically active substances may also be present, which include other compounds of the present invention. The pharmaceutical compositions of the invention can be prepared by any of the well-known methods in far macia, which consist essentially of a mixture of components.

These compounds can be administered by any of the conventional means available for use in conjunction with pharmaceuticals, both as individual therapeutic compounds or as a combination of therapeutic compounds. The amount of compound which is required to carry out the desired biological effect will, of course, depend on a number of factors such as choosing the specific compound, the use for which it is proposed., the mode of administration, the clinical condition of the recipient. In general, a daily dose may be in the range of about 0.3 to about 100 mg / Kg of body weight / day, preferably from about 1 mg to about 50 mg / Kg of body weight / day, more preferably from about 3 to about 10 mg / Kg of body weight / day. This total daily dose can be administered to the patient in a single dose, or in multiple proportional sub-doses. Sub-doses can be administered 2 to 6 times per day. The doses may be in the form of effective sustained release to obtain the desired results. Orally administrable unit dose formulations, such as tablets or capsules, may contain, ? - ^ j .. ¿, _art_a? faith «? A i« .- - y. . ) «¿&&*; for example, from about 0.1 to about 100 mg of the benzothiepine compound, preferably from about 1 to about 100 mg of the benzothiepine compound preferably from about 1 to about 75 mg of the compound, more preferably from about 10 to about of 50 mg of the compound. In the case of pharmaceutically acceptable salts, the weights indicated above refer to the weight of the benzothiepine ion derived from the salt. The oral delivery or delivery of an ileal bile acid transport inhibitor of the present invention may include formulations, as are well known in the art, to provide a sustained and sustained release of the drug to the gastrointestinal tract by any number of mechanisms. These include, but are not limited to, a pH-sensitive release of the dosage form based on the change in pH of the small intestine, the slow erosion of a tablet or capsule, retention in the stomach based on the physical properties of the formulation , the bioadhesion of the dosage form for the mucosal lining of the intestinal tract, or the enzymatic release of the active drug from the dosage form. The effect obtained is the extension of the period of time over which the drug molecule Active is released at the site of action (the ileum) by manipulation of the dosage form. Thus, the controlled release formulations of the enteric coating and the enteric coating are outside the scope of the present invention. Suitable enteric coatings include cellulose acetate phthalate, polyvinylacetate phthalate, hydroxypropylmethylcellulose phthalate, and anionic polymers of methacrylic acid and methacrylic acid methyl ester. When administered intravenously, the dose may, for example, be in the range of about 0.1 mg / Kg body weight about 1.0 mg / Kg of body weight, preferably about 0.25 mg / Kg of body weight. body to about 0.75 mg / Kg of body weight, more preferably from about 0.4 mg / Kg of body weight to about 0.6 mg / Kg of body weight. This dose can be conveniently administered as an infusion of about 10 ng / Kg of body weight to about 100 ng / Kg of body weight per minute. Infusion fluids suitable for this purpose may contain, for example, from about 0.1 ng to about 10 ng, preferably from about 1 ng to about 10 mg per milliliter. Unit doses may contain, for example, about 1 mg a about 10 g of the compound of the present invention. In this way, the ampoules for injection may contain, for example, from about 1 mg to about 100 mg. Pharmaceutical compositions according to the present invention include those suitable for oral, rectal, topical, buccal (e.g., sub-tongue), and parenteral (e.g., subcutaneous, intramuscular, intradermal or intravenous) administration, through The most appropriate route in any given case will depend on the nature and severity of the condition to be treated and on the nature of the particular compound which is being used. In many cases, the preferred route of administration is oral. Pharmaceutical compositions suitable for oral administration may be presented in discrete units, such as capsules, lozenges, or tablets, each containing a predetermined amount of at least one compound of the present invention; as a powder or granules; as a solution or suspension in an aqueous or non-aqueous liquid; or as an oil in water or water in oil emulsion. As indicated, said compositions can be prepared by any suitable pharmacy method which includes the production step in association with the > SS_A-sJS. «_-JÉ-i active compound (s) and the carrier (which may constitute one or more additional ingredients). In general, the compositions are prepared by uniformly and intimately mixing the active compound with a liquid or a finely divided solid carrier., or both, and therefore, without the formation of the product is necessary. For example, a tablet may be prepared by compressing or molding a powder or granules of the compound, optionally with one or more additional ingredients. Compressed tablets can be prepared by compression, in a suitable machine the compound in the form of free flow, such as the powder or granules optionally mixed with binding substances, lubricants, inert diluent (s) and / or active / dispersing surface. . The molded tablets can be made by molding, in a suitable machine the powder compound is moistened with an inert liquid diluent. Pharmaceutical compositions suitable for buccal (sub-lingual) administration include pellets comprising a compound of the present invention in a flavoring base, usually sucrose, and acacia tragacanth, and the pellets comprise the compound in an inert base such as gelatin and Glycerin or sucrose and acacia.

Pharmaceutical compositions suitable for parenteral administration conveniently comprise sterile aqueous preparations of a compound of the present invention. These preparations are preferably administered intravenously, although administration can also be effected by means of subcutaneous, intramuscular, or intradermal injection. Such preparations can conveniently be prepared by mixing the compound with water and providing a resulting sterile and isotonic solution with the blood. Injectable compositions according to the invention will generally contain from 0.1 to 5% w / w of a compound described herein. Pharmaceutical compositions suitable for rectal administration are preferably presented as unit dose suppositories. These can be prepared by mixing a compound of the present invention with one or more conventional solid carriers, for example, cocoa butter, and then forming the resulting mixture. Pharmaceutical compositions suitable for topical application to the skin preferably take the form of an ointment, cream, lotion, paste, gel, spray, spray, or oil. Carriers which may be used include petrolatum, lanolin, polyethylene glycols, alcohols, and combinations of two or more thereof. The active compound is generally present at a concentration of 0.1 to 15% w / w of the composition, for example, from 0.5 to 2%. Transdermal administration is also possible. Pharmaceutical compositions suitable for transdermal administration may be present as discrete patches adapted to remain in intimate contact with the epidermis of the container for a prolonged period of time. Said patches suitably contain a compound of the present invention in a buffer optionally, the aqueous solution, dissolved and / or dispersed in an adhesive, or dispersed in a polymer. A suitable concentration of the active compound is about 1% to 35%, preferably about 3% to 15%. In a particular possibility, the compound can be released from the patch by electrotransport or iontophoresis, for example, as described in Pharmaceutical Research, 3 (6), 318 (1986). In any case, the amount of effective ingredient that can be combined with carrier materials for producing a simple dosage form to be administered will vary depending on the host treated and the particular mode of administration. Solid dosage forms for oral administration include capsules, tablets, pills, powders, granules noted above comprising one or more compounds of the present invention mixed with at least one inert diluent such as sucrose, lactose, or starch. Such dosage forms may also comprise, as in normal practice, other additional substances than inert diluents, for example, lubricating agents such as magnesium stearate. In the case of capsules, tablets, and pills the dosage forms may also comprise buffering agents. The tablets and pills can additionally be prepared with enteric coatings. Liquid dosage forms for oral administration may include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs containing inert diluents commonly used in the art, such as water, such compositions may also comprise adjuvants, such as wet agents, . j & t &iiSÉbSzénipi- emulsifying and suspended agents, and sweeteners, flavoring, and flavoring agents. Injectable preparations, for example, sterile or oily injectable aqueous suspensions may be formulated according to the known art using dispersing or solidifying agents and suspending agents. The sterile injectable preparation can also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that can be used are water, Ringer's solution, and an isotonic sodium chloride solution. In addition, fixed, sterile oils are conventionally employed as a solvent or suspension medium. Any soft fixed oil that includes mono or synthetic diglycerides can be used for this purpose. In addition, fatty acids such as oleic acid provide use in the preparation of injectables. Pharmaceutically acceptable carriers encompass all of the above and the like.

Treatment Regimen The dose regimen for prevention provides assistance with, or amelioration of a disease condition having hyperlipemia as an element of the disease, for example, atherosclerosis, or to protect against or further treat high levels of blood cholesterol or Plasma with the compounds and / or compositions of the present invention is selected according to a variety of factors. These include the type, age, weight, sex, diet, and medical condition of the patient, the severity of the disease, the route of administration, pharmacological considerations such as the activity, efficacy, pharmacokinetics, and toxicology profiles of the particular compound employee, if a medication release system. Therefore, the dose regimen currently employed can vary widely and therefore deviate from the stated preferred dose regimen stated above. Initial treatment of a patient suffering from a hyperlipidemic condition can begin with the dose indicated above. The treatment can usually be continuous as necessary over a period of several weeks to several months or years until the condition of the disease has been controlled or eliminated. Patients who are subjected to treatment with the compounds or compositions described herein can be routinely monitored by, for example, measuring serum cholesterol levels by any of the methods well known in the art, to determine the effectiveness of the therapy. Continuous analysis of such data allows modification of the treatment regimen during therapy so that the amounts of compounds of the present invention are administered at any point in time, and so that the duration of treatment can also be determined. In this way, the treatment regimen / dosage schedule can be rationally modified over the course of therapy so that the lowest amount of the ileal bile acid transport inhibitor of the present invention which exhibits satisfactory effectiveness is administered. , and so that the administration is continued only the time necessary to successfully treat the hyperlipidemic condition. The following non-limiting examples serve to illustrate various aspects of the present invention.

EXAMPLES OF THE SYNTHETIC PROCEDURES Preparation 1 2-ethyl-2- (mesyloxymethyl) hexanal (1) To a cold (10 ° C) solution of 12.6 g (0.11 mol) of methanesulfonyl chloride and 10.3 g (0.13 mol) of triethylamine, 15.8 g of 2-ethyl-2- (hydroxymethyl) hexanal, prepared is added dropwise. according to the procedure described in Chem. Ver. 98, 728-734 (1965), while maintaining the reaction temperature below 30 ° C. The reaction mixture is stirred at room temperature for 18 hours, quenched with dilute HCl and extracted with methylene chloride. The methylene chloride extract is dried with MgSO 3 and concentrated in vacuo to provide 24.4 g of a brown oil.

Preparation 2 2- ((2-Benzoylphenylthio) methyl) -2-ethylhexanal (2) A mixture of 31 g (0.144 mol) of 2-mercaptobenzophenone is prepared, according to the procedure described in WO 93/16055, 24.4 g (0.1 mol) of 2-ethyl-2- (mesyloxymethyl) -hexanal are maintained at reflux ( 1), 1.48 g (0.146 mol) of triethylamine, and 80 ml of 2-methoxyethyl ether for 24 hours. The reaction mixture is poured into 3N HCl and extracted with 300 ml of methylene chloride. The layer is washed with methylene chloride with 300 ml of 10% NaOH, dried with MgSO 4 and concentrated in vacuo to remove the methoxyethyl ether. The residue is purified by HPLC (10% EtOAc-hexane) to yield 20.5 g (58%) of an oil.

..TO" Scheme 6 XXDCd ,. ^ Fr__L. fifteen twenty Generic scheme X RSnR3, heat Pd (Ph3P)., Solvent R «H, or C1-C6 alkyl or, t-butoxide «You. ! _. roof tile_ Generic Scheme X: The nucleophilic substitution of a 2-fluorobenzaldehyde appropriately substituted with lithium sulfur1 or another nucleophilic sulfur anion in a polar solvent (such as DMF), DMA, DMSO, etc.), followed by the addition of the dialkyl mesylate aldehyde (X), provides an aldehyde of the dialkyl benzene Y. The reduction of DIBAL of the aldehyde at a low temperature yields the monoaldehyde of the benzyl alcohol Z. conversion of benzyl alcohol to benzyl bromide, followed by oxidation of sulfur to sulphone produces the key intermediate W.

The compounds of this invention can be synthesized using the cyclic sulfate (XL, below) as the reagent as shown in the following XI schemes and XII. The following examples describe a process for using the cyclic sulfate as the reagent.

SCHEME XI XL 3. H2S04 XLJI1 XL? / A XUVb Scheme XI illustrates another route for benzothiop a-1, 1-dioxides, particularly 3,3-dialkyl analogs, starting with thiophenol XVIII. Thiophenol XVIIIA can react with the cyclic sulfate XL to provide the alcohol XLI which is oxidized to provide the aldehyde XLII. The aldehyde can also be oxidized to provide the sulfone XLIII which can be cyclized to provide a stereoisomeric mixture of benzothiopine XLIVa and XLIVb. The thiophenol XVIIIA can be prepared according to scheme 3 as previously discussed and has the following formula: xvi ??; wherein R5, Rx and q are as defined above for the compounds of formula I. The cyclic sulfate XL can be prepared according to the synthetic procedures known in the art and has the following formula: XL wherein R1 and R2 are as defined above for the compounds of formula I. Preferably R1 and R2 alkyl; more preferably, they can be selected from the group consisting of methyl, ethyl, propyl, isopropyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, and pentyl; and more preferably, R1 and R2 are n-butyl. In the process of Scheme XI, thiophenol XVIIIA initially reacts with the cyclic sulfate XL. This reaction is preferably conducted in an aprotic solvent such as methoxyethyl ether. While the reaction conditions such as temperature and time are not critical, the reaction is preferably allowed to proceed at room temperature for about two hours. The reaction preferably employs an approximate stoichiometric ratio of the starting materials, preferring a slight excess of the cyclic sulfate XL. Reaction time and performance can be improved by using about 1.01 to 1.3 equivalents of the XL cyclic sulfate for each thiophenol equivalent XVIIIA present. More preferably, this ratio is about 1.1 equivalents of cyclic sulfate XL for each thiophenol equivalent XVIIIA present. In the process of the invention, thiophenol XVIIIA is also treated with a separating agent. The separating agent may be added to the solvent containing the thiophenol XVIIIA before, concurrently with, or after the addition of the cyclic sulfate XL. Without maintaining a particular theory, it is believed that the separation agent removes the hydrogen atom from the mercaptamo group attached to the benzene ring of thiophenol XVIIIA. The sulfur anion resulting from thiophenol then reacts with the cyclic sulfate XL to open the sulfate ring. The sulfur anion of thiophenol is then bonded to the terminal carbon atom of the open sulfate ring. The terminal group at the unbound end of the open sulfate ring is the sulfate group. The separation agent is generally a base having a pH greater than about 10. Preferably, the base is an alkali metal hydride, such as lithium hydride or potassium hydride; more preferably, the base is sodium hydride. A slight excess of the agent of and L.-¿__ xJ_ a__fea es 5fr * jfc__¿3 .. separation relative to thiophenol XVIIIA. The reaction time and yield are improved by using about 1.0 to about 1.1 equivalents of the separation agent for each equivalent of the thiophenol XVIIIA present. More preferably, this ratio is about 1.1 equivalents of the separation agent for each equivalent of the thiophenol XVIIIA present. The sulphate group of the reaction product of thiophenol XVIIIA with the cyclic sulfate XL is then removed, preferably by hydrolysis, to produce alcohol XLI. Suitable hydrolyzing agents include mineral acids, particularly hydrochloric acid and sulfuric acid. The various reactions involving the thiophenol XVIIIA, the cyclic sulfate XL, the separating agent and the hydrolyzing agent take place in situ without the need to isolate any of the intermediates produced. The XLI alcohol is then isolated, by means of conventional methods (e.g. extraction with aqueous methyl salicylate) and oxidized using standard oxidation agents to the aldehyde XLII. The oxidizing agent is preferably sulfur trioxide or chlorochromate of pyridinium, and more preferably, is pyridinium chlorochromate. The aldehyde XLII is then isolated then it is isolated by conventional methods and further oxidized using standard oxidation agents for the sulfone-aldehyde XLIII. Preferably, the oxidation agent is metachloroperbenzoic acid. The sulfone-aldehyde XLIII is also isolated by conventional methods and then cyclized to form the steroisomeric benzothiopines XLIVa and XLIVb. The cyclization agent is preferably a base having a pH of about 8 and about 9. More preferably, the base is an alkoxide base, and more preferably, the base is potassium tert-butoxide. The two oxidation steps of scheme XI can be inverted without adversely affecting the total reaction. The XLI alcohol can be oxidized first to produce a sulfone-alcohol which is oxidized to produce a sulfone-aldehyde.

SCHEME XII . aaaafefeWJ -.

Scheme XII illustrates another route for the benzothiopine-1, 1-dioxides, particularly 3, 3-dialkyl analogues, starting with the halobenzene L. The halobenzene L can react with the cyclic sulfate XL described above to provide the alcohol Ll which can it can be oxidized to produce the sulfone-alcohol LII. The sulfone-alcohol LII can further be oxidized to provide the sulfone-aldehyde LIII which is cyclized to provide a stereoisomeric mixture of benzothiopine LIVa and LIVb. Halobenzene L (which is commercially available or can be synthesized from commercially available halobenzenes by those skilled in the art) has the following formula: L wherein R5 and Rx, and q are as defined above for the compounds of formula I; Rh is a halogen such as chlorine, bromine, fluorine or iodine; and Re is an electron spacing group in the ortho or para position of the halobenzene, and is preferably a p-nitro group or o- - # - - nitro. The cyclic sulfate XL can be prepared as stated in Scheme XI and can have the following formula: XL wherein R1 and R2 are as defined above for the compounds of formula I. Preferably R1 and R2 alkyl; more preferably, they can be selected from the group consisting of methyl, ethyl, propyl, isopropyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, and pentyl; and more preferably, R1 and R2 are n-butyl. In the process of scheme XII, halobenzene L initially reacts with the cyclic sulfate XL. This reaction is preferably carried out in an aprotic solvent such as dimethyl formamide or N, N-dimethylacetamide, and more preferably, in dimethyl formamide. Although the reaction conditions such as temperature and time are not critical, preferably the reaction is allowed to proceed at a temperature of about 70 ° C and about 90 ° C for about 8 to 12 hours. More preferably, the Reaction temperature is maintained at about 80 ° C. The reaction preferably employs a stoichiometric ratio of approximately the starting materials, preferring a slight excess of the cyclic sulfate XL. The reaction time and yield is improved by using about 1.1 to 1.3 equivalents of the cyclic sulfate XL for each halobenzene equivalent L present. More preferably, this ratio is about 1.1 equivalents of the cyclic sulfate XL for each equivalent of the halobenzene L present. In the process of the invention, halobenzene L is also treated with a separating agent. The separating agent can be added to the solvent containing the hlobenzene L before, concurrently with, or after the addition of the cyclic sulfate XL. Without maintaining a particular theory, it is believed that the separation agent removes the halogen atom attached to the benzene ring from the halobenzene L and replaces the atom with a divalent sulfur atom. The resulting sulfur anion reacts with the cyclic sulfate XL to open the sulfate ring. The sulfur anion of the halobenzene then bonds to the terminal carbon atom of the open sulfate ring. The terminal group at the unbound end of the open sulfate ring is the sulfate group. The separation agent is generally a dialkyl metal sulfide, and preferably it is dilithium sulfide. A slight excess of the separation agent relative to halobenzene L is preferred. The reaction time and yield are improved by using about 1.01 to about 1.3 equivalents of the separation agent for each equivalent of the halobenzene L present. More preferably, this ratio is about 1.05 equivalents of the separation agent for each equivalent of the halobenzene L present. The sulfate group of the reaction product of thiophenol XVIIIA with the cyclic sulfate XL is then removed, preferably by hydrolysis, to produce the alcohol Ll. Suitable hydrolyzing agents include mineral acids, particularly hydrochloric acid and sulfuric acid. The ester is converted to an alcohol Ll by treatment with alkali metal hydroxide, preferably sodium hydroxide. The various reactions involving the halobenzene L, the cyclic sulfate XL, the separating agent and the hydrolyzing agent take place in situ without the need to isolate any of the intermediates produced.

The XL alcohol is then isolated, by means of conventional methods (e.g. extraction with aqueous methyl salicylate) and oxidized using standard oxidation agents for the sulfone-alcohol LII. The oxidation agent preferably is metachloroperbenzoic acid. The reaction is carried out in a suitable organic solvent such as methylene chloride or chloroform. The sulfone-alcohol LII is isolated by conventional methods and further oxidized using standard oxidation agents for the sulfone-aldehyde Lili. Preferably, the oxidation agent is sulfur trioxide or pyridinium chlorochromate, pyridinium chlorochromate is preferred. The reaction is conducted in a suitable organic solvent such as methylene chloride or chloroform. The sulfone-aldehyde XLIII is then converted to the desired benzothiopine-1,1-dioxide compound according to the procedure previously described in Scheme XI. The two oxidation steps can be reversed without adversely affecting the total reaction. The XLI alcohol is first oxidized to produce an aldehyde which is then oxidized to produce the sulfone-aldehyde. The use of a cyclic sulfate reagent instead of a mesylate reagent in Schemes XI and XII improves the total yield and avoids many difficulties encountered relative to those previous reaction schemes through a mesylate intermediate. All yields are significantly improved when a cyclic sulfate is used in place of a mesylate reagent. In addition, separation by chromatography of the intermediate product from the cyclic sulfate binding step of the reaction is not necessary. For example, in Schemes XI and XII the intermediate is an alkaline metal salt soluble in water and the impurities can be removed by extraction with ether. The intermediate is then hydrolyzed to the desired alcohol. __ - _a_fas_ »s? > 3¿fc, _, «__ ¡t.i __ ^ A» - Example corresponding to Scheme XI Step 1: preparation of 2,2-dibutyl-l, 3-propanediol: It is added dropwise to a stirred solution of dibutyl-diethylmalonate (150 g, 0.55 mol) (Aldrich) in dry THF (700 ml), lithium aluminum hydride (662 ml, 1.2 equivalents, 0.66 mol) in 662 ml of 1M. THF then the temperature of the reaction mixture is maintained between about -20 ° C to about 0 ° C using a dry ice / acetone bath. The reaction mixture is stirred at room temperature overnight. The reaction is cooled to -20 ° C and 40 ml of water, 80 ml of 10% NaOH and 80 ml of water are successively added slowly. The resulting suspension is filtered. The filtrate is dried over sodium sulfate and concentrated under vacuum to yield 98.4 g (95% yield) of the diol as an oil. Proton NMR, carbon NMR and MS confirm the product.

Stage 2: dibutyl cyclic sulfite: A solution of dibutyldiol from Step 1 (103 g, 0.5478 mol) in anhydrous methylene chloride (500 ml) and triethylamine (221 g, 4 equivalents, 2.19 mol) is stirred at 0 ° C under nitrogen. Thionyl chloride (97.78 g, 0.82 mol) is slowly added to the mixture. Within 5 minutes the solution turns yellow and then black when the addition is completed within about half an hour. The reaction is completed within 3 hours (gas chromatography confirms that no starting material is left). The mixture is washed with ice water twice, and brine twice. The organic phase is dried over anhydrous magnesium sulfate and concentrated under vacuum to yield 128 g (100% yield) of the cyclic dibutyl sulfite as a black oil. The NMR and MS are consistent with the product.

Stage 3: dibutylcyclic sulfate: Ruthenium (III) chloride (1 g) and sodium periodate (233 g, 1.08 mol) are added to a solution of dibutyl-cyclic sulfite from Step 2 (127.5 g, 0.54 mol) in 600 ml of acetonitrile and 500 ml of water cooled in an ice bath under nitrogen. The reaction is stirred overnight and the color of the solution turns black. Gas chromatography confirms that there is no starting material left. The mixture is extracted once with 300 ml of ether and three times with brine. The organic phase is dried over magnesium sulfate and passed through Celite. The filtrate is concentrated under vacuum and provides 133 g (97.8% yield) of the dibutylcyclic sulfate as an oil. The NMR of the proton, NMR and MS of the carbon confirms the product.

Step 4: 2- [(2-4'-Fluorobenzyl-4-methylphenylthio) methyl] 2-butylhexanol: A 60% dispersion of sodium hydride oil (0.27 g, 6.68 mmol) is washed with hexane. The hexane is decanted and 20 ml of methoxyethyl ether are added to the washed sodium hydride and cooled in an ice bath. A mixture of thiophenol of diphenylmethane (1.55 g, 6.68 mmol) in 10 ml of methoxyethyl ether is added over a period of 15 minutes. A mixture of dibutyl cyclic sulfate from Step 3 (2.17 g, 8.66 mmol) in 10 ml of methoxyethyl ether is then added. The resulting mixture is stirred for 30 minutes at 0 ° C and 1 hour at room temperature under nitrogen. Gas chromatography confirms that there is no left thiol. The solvent is evaporated and washed with water and ether twice. The water layer is separated and 20 ml of 10% NaOH are added. This aqueous mixture is boiled for 30 minutes, cooled, acidified with 6N HCl, and boiled for 10 minutes. Mix it is cooled and extracted with ether. The organic layer is washed successively with water and brine, dried over magnesium sulfate, and concentrated under vacuum to yield 2.47 g (92.5% yield) of the hexanol as an oil. Proton NMR, C13-NMR and MS confirm the product.

Step 5: 2- [(2-4'-Fluorobenzyl-4-methylphenylthio) methyl] -2-butylhexanal: It is added to a solution of hexanol from Step 4 (2 g, 4.9 mmol) in 40 ml of methylene chloride cooled in an ice bath under nitrogen pyridinium chlorochromate (2.18 g, 9.9 mmol). The reaction mixture is stirred for 3 hours and filtered through silica gel. The filtrate is concentrated under vacuum to yield 1.39 g (70% yield) of the hexanal as an oil. The NMR of the carbon NMR proton and MS confirm the product. rZh ^ í ^ J ^ BS = a &faith. »L * _« - »O- -W» - A¡ £ ¿-iüfc. »_._ * ¡¿^ i3bs¿sJ» ¡s Step 6: 2- [(2-4 '-fluorobenzyl-4-methylphenylsulfonyl) methyl] -2-butihexanal To a solution of the hexanal from step 5 (0.44 g, 1.1 mol) in 20 ml of methylene chloride cooled by means of an ice bath under nitrogen is added 70% metachloroperbenzoic acid (0.54 g, 2.2 mmol). The reaction mixture is stirred for 18 hours and filtered. The filtrate is washed successively with 10% NaOH (3X), water, and brine, dried over magnesium sulfate, and concentrated under vacuum to yield 0.42 g (90% yield) of the hexanal as an oil. Proton NMR, carbon NMR and MS confirm the product.

Step 7: cis-3, 3-dibutyl-7-methyl-5- (4'-fluoro-phenyl) -2,3,4,5-tetrahydrobenzothiepin-1,1-dioxide: < fa¿B £, _- -JH ___ B »-._ -. -.-. ^ -. , .- - .. .-, ^, jüt. 6 A mixture of the hexanal from step 6 (0.37 g, 0.85 mmol) in 30 ml of anhydrous THF is stirred in an ice bath at a temperature of about 0 ° C. Then potassium tert-butoxide (102 mg, 0.85 mmol) is added. After 3 hours thin layer chromatography confirms the presence of the product and a small amount of the starting material. The crude reaction mixture is acidified with 10% HCl, extracted with ether, washed successively with water and with brine, dried with MgSO 4, concentrated in vacuo. This concentrate is purified by HPLC (10% EtOAc-hexane). The first fraction comes as 0.1 g of the starting material in the form of an oil. The second fraction yields 0.27 g (75% yield) of the desired benzothiepin as a white solid. Proton NMR, carbon NMR and MS confirm the product. (M + H = 433).

Example corresponding to Scheme XII Step 1: 2- [(2-4'-methoxybenzyl-4-nitrophenylthio) methyl) -2-butylhexanol: Chlorodiphenylmethane (10 g) is dissolved in 25 ml of DME 'and lithium sulfide [1.75 g, 1.05 equivalents] is added. The solution is cooled to 0 ° C and dibutyl cyclic sulfatc (9.9 g, prepared as shown in step 3 of the examples of scheme XI) is added in 10 ml of DMF and stirred at room temperature overnight. The solvent is evaporated and washed successively with water and ether (three times). The aqueous layer is separated and 40 ml of concentrated sulfuric acid are added and the reaction mixture boils overnight. The mixture is cooled and extracted with ethyl acetate. The organic layer is washed successively with water and brine, dried over magnesium sulfate, and concentrated under vacuum. The product is boiled with 3M NaOH for 1 hour. The mixture is cooled and extracted with ethyl acetate. The organic layer is washed successively with water and brine, dried over _ »A» ^ j ^ gfefasL-T-Fia- ^ ae? magnesium sulfate, and concentrated under vacuum. Dissolve the concentrate in methylene chloride, filter through silica gel elute with 20% ethyl acetate and hexane, and concentrate under vacuum to yield 11.9 g (74% yield) of the hexanol as an oil. . The NMR of the proton, C13-NMR and MS confirm the product.

Step 2: 2- [(2-4'-methoxybenzyl-4-nitrophenylthio) -methyl] -2-butylhexanal: 70% MCPBA (8.261 g, 33 mmol) is added to a solution of the hexanol from Step 1 (6 g, 13 mmol) in 50 mL of methylene chloride cooled in an ice bath under nitrogen. The reaction is stirred for 18 hours at room temperature and filtered. The filtrate is washed successively with 10% NaOH (3X), water and brine, dried over magnesium sulfate, and concentrated in vacuo. The concentrate is dissolved in methylene chloride, filtered through silica gel, elute with 20% ethyl acetate and hexane, and concentrate in vacuo to yield 5 g (77.7% yield) of the hexanal as a white solid, M.p. 58-60 ° C. The NMR of the proton, C13-NMR and MS confirm the product.

Example 1398 Step 1. Preparation of 2 To a solution of 6.0 g of dibutyl 4-fluorobenzenedialdehyde from Example 1395 (14.3 mmol) in 72 ml of toluene and 54 ml of ethanol is added 4.7 g of 3-nitrobenzeneboronic acid (28.6 mmol), 0.8 g of tetrakis (triphenylphosphine palladium) (0) (0.7 mmol) and 45 ml of a 2M solution of potassium carbonate in water, this heterogeneous mixture is refluxed for 3 hours, then cooled to room temperature and partitioned between ethyl acetate and water, the organic layer over MgSO4 and concentrated in vacuo. Purification by gel chromatography. silica (Waters Prep-2000) ethyl acetate / hexanes (25/75) is used providing 4.8 g (73%) of the title compound as a yellow solid. XH NMR (CDC13) d 0.88 (t, J = 7.45 Hz, 6H), 0.99-1.38 (m, 8H), 1.62-1.75 (m, 2H), 1.85-2.00 (m, 2H), 3.20 (s, 2H) ), 4.59 (s, 2H), 6.93 (dd, J = 10.5 and 2.4 Hz, 1H), 7.15 (dt, J = 8.4 and 2.85 Hz, 1H), 7.46-7.59 (m, 2H), 8.05-8.16 ( m, 3H), 9.40 (s, 1H).

Stage 3. Preparation of 3 A solution of 4.8 g (10.4 mmol) of 2 in 500 ml of THF is cooled to 0 ° C in an ice bath. Slowly add 20 ml of a 1M solution of potassium t-butoxide, keeping the temperature at < 5 ° C. Stirring is continued for 30 minutes, then the reaction is quenched with 100 ml of saturated ammonium chloride. The mixture is partitioned between ethyl acetate and water; the organic layer is washed with brine, then dried (MgSO4) and concentrated in vacuo. Purification by chromatography with silica gel a through 100 ml filter al. use CH2C12 as eluent which produces 4.3 g (90%) of 3 as a pale yellow foam. lN NMR (CDC13) d, 0.93 (t, J = 7.25 Hz, 6H), 1.00-1.55 (m, 8H), 1.59-1.74 (m, 3H), 2.15-2.95 (m, 1H), 3.16 (qAB, JAB = 15.0 Hz,? V = 33.2 Hz, 2H), 4.17 (d, J = 6.0 Hz, 1H), 5.67 (s, 1H), 6.34 (dd, J = 9.6 and 3.0 Hz, 1H), 7.08 (dt , J = 8.5 and 2.9 Hz, 1H), 7.64 (t, J = 8.1 Hz, 1H), 7.81 (d, J = 8.7 Hz, 1H), 8.13 (dd, J = 9.9 and 3.6 Hz, 1H), 8.23 -8.30 (m, 1H), 8.44 (s, 1H). MS (FABH +) m / e (relative intensity) 464.5 (100), 446.6 (65). HRMS calculated for M + H 464.1907. found 464.1905.

Stage 4. Preparation of 4 To a cooled (0 ° C) solution of 4.3 g (9.3 mmol) of 3 in 30 ml of THF contained in a stainless steel reaction vessel is added 8.2 g of dimethylamine (182 mmol). The vessel is sealed and heated at 110 ° C for 16 hours, the reaction vessel is cooled to room temperature and the contents are concentrated in vacuo. The purification by silica gel chromatography (Waters Prep-2000) using a gradient of ethyl acetate / hexane (10-40% ethyl acetate) gives 4.0 g (88%) of 4 as a yellow solid. 1H NMR (CDC13) d, 0.80-0.95 (m, 6H), 0.96-1.53 • (m, 8H), 1.60-1.69 (m, 3H), 2.11-2.28 (m, 1H), 2.79 (s, 6H) , 3.09 (qAB, JAB = 15.0 Hz, DV = 45.6 Hz, 2H), 4.90 (d, J = 9.0 Hz, 1H), 5.65 (s, 1H), 5.75 (d, J = 2.1 Hz, 1H), 6.52 (dd, J = 9.6 and 2.7 Hz, 1H), 7.59 (t, J = 8.4 Hz, 1H), 7.85 (d, J = 7.80 Hz, 1H), 7.89 (d, J = 9.0 Hz, 1H), 8.20 (dd, J = 8.4 and 1.2 Hz, 1H), 8.43 (s, 1H). MS (FABH +) m / e (relative intensity) 489.6 (100), 471.5 (25). HRMS calculated for M + H 489.2423. Found 489.2456.

Stage 5. Preparation of 5 A suspension of 1.0 g (2.1 mmol) of 4 in 100 ml of ethanol is added to a Parr reactor in stainless steel 1 g of palladium on 10% carbon. The reaction vessel is --g aa tffc - ^ & *? _ 5 * __ Seal is purged twice with H2, then charged with H2 (100 psi) and heated at 45 ° C for 6 hours, the reaction vessel is cooled to room temperature and the contents are filtered to remove the catalyst. The filtrate is concentrated in vacuo to yield 0.9 g (96%) of 5. XH NMR (CDC13) d, 0.80-0.98 (m, 6H), 1.00-1.52 (m, 10H), 1.52-1.69 (m, 1H) , 2.15-2.29 (m, 1H), 2.83 (s, 6H), 3.07 (qAB, JAB = 15.1 Hz, DV = 44.2 Hz, 2H), 3.70 (s, 2H), 4.14 (s, 1H), 5.43 ( s, 1H), 6.09 (d, J = 2.4 Hz, 1H), 6.52 (dd, J = 12.2 and 2.6 Hz, 1H), 6.65 (dd, J = 7.8 and 1.8 Hz, 1H), 6.83 (s, 1H) ), 6.93 (d, J = 7.50 Hz, 1H), 7.19 (t, J = 7.50 Hz, 1H), 7.19 (t, J = 7.6 Hz, 1H), 7.89 (d, J = 8.9 Hz, 1H). MS (FABH +) m / e (relative intensity) 459.7 (100). HRMS calculated for M + H 459.2681. Found 459.2670.

Step 6. Preparation of 6 To a solution of 914 mg (2.0 mmol) of 5 in 50 ml of THF is added 800 mg (4.0 mmol) of 5-bromovaleroyl chloride. Then 4 g (39.6 mmol) of TEA is added. The reaction is stirred 10 minutes, then divided between ethyl acetate and brine. The organic layer is dried (MgSO4) and concentrated in vacuo. Purification by chromatography with silica gel through a column + «¿Tfa ^ jftfe 70 ml MPLC using a gradient of ethyl acetate (20-50%) in hexane as eluent yields 0.9 g (73%) of 6 as a pale yellow oil. XH NMR (CDC13) d, 0.84-0.95 (m, 6H), 1.02-1.53 (, 10H), 1.53-1.68 (m, 3H), 1.80-2.00 (m, 4H), 2.12-2.26 (m, 4H) , 2.38 (t, J = 6.9 Hz, 2H), 2.80 (s, 6H), 3.07 (qAB, JAB = 15.6 Hz, DV = 40.4 Hz, 2H), 3.43 (t, ¿= 6.9 Hz, 2H), 4.10 (s, 1H), 5.51 (s, 1H), 5.95 (d, J = 2.4 Hz, 1H), 6.51 (dd, J = 9.3 and 2.7 Hz, 1H), 7.28 (s, 1H), 7.32-7.41 ( m, 2H), 7.78 (d, J = 8.1 Hz, 1H), 7.90 (d, J = 9.0 Hz, 1H).

Stage 7. Preparation of 7 It is added to a solution of 0.9 g (1.45 mmol) of 6 in 25 ml of acetonitrile, 18 g (178 mmol) of TEA. It is heated at 55 ° C for 16 hours. The reaction mixture is cooled to room temperature and concentrated in vacuo. Purification by reverse phase silica gel chromatography (Waters Delta Prep 3000) using a gradient Acetonitrile / water containing 0.05% TFA (20-65% acetonitrile) provides 0.8 g (7%) of 7 as a white foam. XH NMR (CDC13) d, 0.80-0.96 (m, 6H), 0.99-1.54 (m, 19H), 1.59-1.84 (m, 3H), 2.09-2.24 (, 1H), 2.45-2.58 (m, 2H) , 2.81 (s, 6H), 3.09 (qAB, JAB = 15.6 Hz, DV = 18.5 Hz, 2H), 3.13-3.31 (m, 8H), 4.16 (s, 1H), 5.44 (s, 1H), 6.05 ( d, J = 1.8 Hz, 1H), 6.57 (dd, J = 9.3 and 2.7 Hz, 1H), 7.24 (t, J = 7.5 Hz, 1H), 7.34 (t, J = 8.4 Hz, 1H), 7.56 ( d, J = 8.4 Hz, 1H), 7.56 (d, J = 8.4 Hz, 1H), 7.74 (s, 1H), 7.88 (d, J = 9.0 Hz, 1H), 9.22 (s, 1H). Calculated HRMS 642.4304; observed 642.4343.

Example 1398a Stage 1 Cj.H.eClNC, fw-291._S In an inert atmosphere, weigh 68.3 g of phosphorus pentachloride (0.328 moles) Aldrich 15,777-5) into a 500 ml 2-necked round bottom flask, a flask is equipped with an N2 inlet adapter and a ..- í; S:? i-. .iZ: -:.-Zs, Z & ^ *, - seal goes up. It is removed from the inert atmosphere and the N2 purged. 50 ml of anhydrous chlorobenzene (Aldrich 28,451-3) is added to PC15 via syringe and stirred with a magnetic stir bar. 60 g of 2-chloro-5-nitrobenzoic acid (0.298 mol Aldrich 12.511-3) are weighed. It is added slowly to the chlorobenzene solution while purging under N2. Stir at room temperature overnight. After stirring at room temperature for ~ 20 hours, place in an oil bath and heat at 50 ° C for 1 hour. Chlorobenzene is removed by high vacuum. The residue is washed with anhydrous hexane. The chloride of the dry acid p = 61.95 g. It is stored in an inert and dry atmosphere. In the inert atmosphere, acid chloride is dissolved with 105 ml anhydrous anhydrous (0.97 moles Aldrich 29.629-5). The solution is placed in a 500 ml 2 neck round bottom flask. Weigh 45.1 g of aluminum chloride (0.34 mole Aldrich 29,471-3) and place it in a solid addition funnel. The reaction flask is equipped with the addition funnel and an N2 inlet adapter. It is removed from the inert atmosphere. The reaction solution is cooled with an ice bath and the N2 is purged. A1C13 is slowly added to the cooled solution. After the addition is complete, let it warm to room temperature. It stirs all night. The warm reaction is poured into a solution of 300 ml of IN HCl and ice. It is stirred for 15 minutes. It is extracted twice with ether. The combined organic layers are extracted twice with 2% NaOH, then again with deionized H20. Dry with MgSO 4, filter and centrifuge to dryness. The anisol is removed by high vacuum. The product crystallizes from 90% ethanol and 10% ethyl acetate. It dries in a vacuum line. P = 35.2 g. 41% yield. NMR and mass spectrum are obtained (m / z = 292).

Stage 2 C?, H "ClN03 fw-277.71 38.10 g (0.131 mol) of benzophenone from Step 1 are dissolved in 250 ml of anhydrous methylene chloride. It is placed in a 3-liter flask and equipped with an N2 inlet, an addition funnel and a plug. It is stirred with a magnetic stirring bar. The solution is cooled with an ice bath. A solution of 39.32 g of trifluoromethane sulfonic acid (0.262 moles Aldrich 15,853-4) and 170 ml of anhydrous methylene chloride is prepared. It is placed in an addition funnel and added dropwise to the solution cooled under N2. Stir 5 minutes after the addition is complete. A solution of 22.85 g of trimethyl silane (0.197 moles Aldrich 23.019-7) and 170 ml of anhydrous methylene chloride is prepared. It is placed in an addition funnel and added dropwise to a solution cooled under N2. It shakes 5 minutes after the addition is complete. A second solution of 39.32 g of trifluoromethane sulfonic acid and 170 ml of anhydrous methylene chloride is prepared. It is placed in an addition funnel and added dropwise to a solution cooled under N2. Stir 5 minutes after the addition is complete. A second solution of 22.85 g of triethyl silane and 170 ml of anhydrous methylene chloride is prepared. It is placed in a funnel and added dropwise to a solution cooled under N2. After all the additions are made Let it cool slowly at room temperature overnight. Stir under N2 overnight. Prepare 1300 ml of saturated NaHCO3, in a 4-liter glass. It cools with an ice bath. While stirring vigorously, it is slowly added to the reaction mixture. It is stirred at a cooling temperature for 30 minutes. It is poured into a separating funnel and separation is allowed. The organic layer is removed and the aqueous layer extracted 2 times with methylene chloride. The dried organic layers are dried with MgSO4. It is crystallized from ethanol. It dries in a vacuum line. The dry weight P = 28.8 g. It is confirmed by NMR and the mass spectrum (m / z = 278).

Stage 3 C25H3JNO «S fw-443. 61 Dissolve in 10.12 g (0.036 mol) of product 2 with 200 ml of anhydrous DMSO. Place it in a 500 ml round bottom flask with a magnetic stir bar. The flask equipped with a water condenser, an inlet of N2, and a shutter. 1.84 g of L? 2S (0.040 moles Aldrich 21.324-1) are added. The flask is placed in an oil bath and heated to 75 ° C under N2 overnight after it is cooled to room temperature. We weigh 10.59 mg of butyl mesylate (0.040 moles). It is dissolved with anhydrous DMSO and added to the reaction solution. It is purged well with N2, it is heated overnight at 80 ° C. It is cooled to room temperature. 500 ml of 5% acetic acid are prepared in a 2 liter glass. While stirring, the reaction mixture is slowly added. Stirs for 30 minutes. Extract with ether 3 times. The organic layers are combined and extracted with saturated NaCl water. The organic layer is dried with MgSO 4, filtered and centrifuged to dryness. The oil dries in a vacuum line. The pure product is obtained by column chromatography using 95% hexane and 5% ethyl acetate as the mobile phase. The dry weight P = 7.8 g. NMR is obtained and the mass spectrum (m / z = 444).

Stage 4 CJSK "NO, S fw-475.61 9.33 g (0.021 mole) of product 3 are dissolved with 120 ml of anhydrous methylene chloride. Place it in a 250 ml round bottom flask with a magnetic stir bar. The flask is equipped with an N2 inlet and a shutter. The solution is cooled with an ice bath under a N2 purge. 11.54 g of 3-chloroperbenzoic acid (0.0435 mol, Fluka 25800, -65%) are added slowly. After the addition is complete, it is warmed to room temperature and the reaction is monitored by TLC. The reaction proceeds rapidly to the sulfoxide intermediate but takes 8 hours to convert to sulfone. The solution is cooled overnight in a freezer. The solid is filtered from the reaction, the filtrate is extracted with 10% K2CO3. The layer i.ss? - »aS aift < at «g aqueous is extracted twice with methylene chloride. The organic layers are combined and dried with MgSO4. It is filtered and concentrated to dryness. The crude product is obtained by crystallization from ethanol or is isolated by column chromatography. The NMR and the mass spectrum are obtained (m / z = 476).

Stage 5 Cí7HittJO.S fw-473. 68 The reaction is carried out in a stainless steel Parr stirred shaker. 9.68 g (0.0204 moles) of product 4 are placed in a base reactor. 160 ml of ethanol are added. For safety reasons, two following compounds are added in a glove bag of atmosphere N2. In the glove bag, 15.3 ml of formaldehyde (0.204 moles, Aldrich 25, 254-9, about 37% by weight in water) and 1.45 g Pd / carbon 10% (Aldrich 20, 569-9) are added. The reactor is sealed before the removal of the glove bag. The reactor is purged 3 times with H2. It is heated to 55 ° C under N2. The reaction is carried out at 200 psig H2, 55 ° C and a stirring ratio of 250 rmp. It advances all night under these conditions. The reactor is cooled and vented H2. It is purged with N2. Check the progress of the reaction progress by TLC. The reaction is a mixture of the desired product and the intermediate. The reaction is filtered and mixed on a bed of Celite washed well with ether. Centrifuge and redissolve with ether. It is extracted with water. The organic layer is dried with MgSO 4 filtered and centrifuged to dryness. It dries in a vacuum line. The reactor is charged again with the same amounts, the reactor is sealed and carried out overnight under the same conditions. After the second run all the material has been converted to the desired product. It is cooled and pressurized with H2. It is purged with N2. It is filtered on a Celita bed, washed well with ether. Centrifuge to dryness. It is dissolved with ether and extracted with water, the organic layer is dried with MgSO 4, filtered and centrifuged to dryness. It dries in a vacuum line. The NMR and the mass spectrum are obtained (m / z = 474). r - .. attiSK-afc.-. __,. _ ^ - __ .. «._» _; * ..... "... ._sfc-.IaaS _-.? _- Stage 6 CH "O, S fw- 73.6B 8.97 g (0.0189 mol) of product 5 is dissolved with 135 ml of anhydrous THF. Place it in a 250 ml round bottom flask with a magnetic stir bar. The flask is equipped with an N2 inlet and a shutter. The solution is cooled with an ice / salt bath under a N2 purge. Slowly add 2.55 g of potassium t-butoxide (0.227 moles Aldrichl5, 667-1). After the addition is complete stirring is continued at -10 ° C and monitored by TLC. Once the reaction is complete, it is quenched by the addition of 135 ml of 10% HCl and stirred for 10 minutes. It is extracted three times with ether. The organic layer is dried with MgSO 4, filtered and centrifuged to dryness. It crystallizes from ether. The NMR and the mass spectrum are obtained (m / z = 474).

Stage 7 C ^ B ^ KO.S fw-459.65 4.67 g (0.01 mole) of product 6 are dissolved with 100 ml of anhydrous chloroform. Place it in a 250 ml round bottom flask with a magnetic stir bar. The flask is equipped with an N2 inlet adapter and an up seal. The solution is cooled with a dry ice / acetone bath under a N2 purge. 2.84 ml boron tribromide is added slowly via a syringe (0.03 moles Aldrich 20, 220-7). It is stirred and cooled to cold temperature for 15 minutes after the addition, then it is allowed to warm to room temperature. The progress of the reaction is monitored by TLC. The reaction is usually completed in 3 hours. The solution is cooled with an ice bath. Quench with 100 ml of 10% K2CO3 while stirring rapidly. HE ^^^^^^^ ^^ Stir 10 minutes then transfer to a separatory funnel and allow separation. The aqueous layer is removed. The organic layer is extracted once with 10% HCl, once with H20, and once with a saturated NaCl solution. The organic layer is dried with MgSO 4, filtered and centrifuged to dryness. The product is crystallized from ether. The NMR and the mass spectrum are obtained (m / z = 460).

Stage 8 C "H ,, NOtSI fw« 701.71 Weigh 0.38 g of NaH (9.57 moles Aldrich 19.923-0 60% dispersion in mineral oil.) In a round bottom flask with a magnetic stir bar. The flask is equipped with an N2 inlet and a shutter. The NaH is cooled with an ice bath and a purge of N2 is made. j. *. JB $ £. 4.0 g (8.7 mmoles) of the product 7 are dissolved with 60 ml of anhydrous DMF. It is added to cold NaH. Stir at a cool temperature for 30 minutes. 1.33 g of K2CO3 (9.57 mmole Fisher P-208) are added. 16.1 g of 1,2-bis- (2-iodoethoxy) ethane (43.5 mmoles Aldrich 33.343-3) are dissolved with 60 ml of anhydrous DMF. It is added to the cold reaction mixture. Warm to room temperature and heat at 40 ° C overnight under N2. It is cleaned by dilution with ether and extracted sequentially with 5% NaOH, H20, and saturated NaCl. The organic layer is dried with MgSO 4, filtered and dried. The pure product is obtained by column chromatography on silica gel using 75% hexane 25% ethyl acetate as the mobile phase. The NMR and the mass spectrum are obtained (m / z = 702).

Stage 9 «Ís. * "-«. - miSS ifc, CJtH «, N} C, SI fw = 8C2.90 Dissolve 1.0 g (1.43 mmol) of product 8 with 10 ml of anhydrous acetonitrile. Place it in a 3 oz. Fischer-porter pressure reaction vessel with a magnetic stir bar. 2.9 triethylamine (28.6 mmoles Aldrich 23.962-3) are added and dissolved in 10 ml of anhydrous acetonitrile. It purges well with N2 after the system is closed. It is heated to 45 ° C. The reaction is monitored by TLC. The reaction is usually completed in 48 hours. To carry out the cleaning, the acetonitrile is removed under vacuum. Redissolve with anhydrous chloroform and precipitate a quaternary ammonium salt with ether. It is repeated several times. It is dried to obtain the crystalline product. The NMR and the mass spectrum are obtained (m / z = 675). _ i -.aa Stage 1. Preparation of 1 To a solution of 144 g of KOH (2560 puuol) in 1.1 L of DMSO, 120 g of the 2-bromobenzyl alcohol (641 m ol) are added slowly via an addition funnel. Then 182 g of ethyl iodide (80 mL, 1282 mmol) are added via an addition funnel. Stir at room temperature for 50 minutes. The contents of the reaction are poured into 1.0 L of water and extracted three times with ethyl acetate. The organic layer is dried over MgSO4 and concentrated in vacuo. Purify by chromatography with silica gel through a filter using hexanes (100%) as the eluent yielding 103.2 g (80%) of 1 as a clear colorless liquid. XH NMR (CDC13) d, 3.39 (s, 3H), 4.42 (s, 2H), 7.18-7.27 (m, 2H), 7.12 (d, J = 7.45 Hz, 1H), 7.50 (s, 1H).

Stage 2. Preparation of 2 l ^ N? K > «! Jfa" ___ "-ii ^? F. ^ .. _,? < ???, J? ..-_. 1 _ To a cooled solution (-78 ° C) of 95 g (472 mmol) of 1 in 1.5 L of THF, 240 mL of 2.5 M lithium n-butyl (576 mmol) are added. The mixture is stirred for 1 hour, and then to this 180 g of zinc iodide (566 mmol) are added and dissolved in 500 ml of THF. The mixture is stirred for 30 minutes, allowed to cool to 5 ° C, cooled to -10 ° C and added with 6 g of Pd (PPh3) 4 (5.2 mmol) and 125 g of 2,5-difluorobenzoyl chloride ( 708 mmol). The mixture is stirred at room temperature for 18 hours and cooled to 10 ° C, quenched with water, partitioned between ethyl acetate and water, and the organic layer is washed with IN HCl and IN NaOH. The organic layer is dried over MgSO4 and concentrated in vacuo. The purification is by chromatography with silica gel (Waters Prep-500) using 5% ethyl acetate / hexanes as eluent to provide 53.6 g (43%) of 2 as an orange oil. XH NMR (CDC13) d, 3.40 (s, 3H), 4.51 (s, 2H), 7.12-7.26 (m, 3H), 7.47 (t, J = 7.50 Hz, 1H), 7.57 (d, J = 7.45 Hz , 1H), 7.73 (d, J = 7.45 Hz, 1H), 7.80 (s, 1H).

Stage 3. Preparation of 3 a solution of 53 g (202.3 mmol) of 2 and 11.2 g of Li2S (242.8 mmol) in 250 ml of DMF is heated at 100 ° C for 18 hours. The cooling reaction (0 ° C) and 60.7 g of X '(the cyclic sulfate compound of example 1397) (242.8 mmol) in 50 ml of DMF are added. It is stirred at room temperature for 18 hours then it is condensed in vacuo. The water is added to the organic residue and extracted twice with diethyl ether. The aqueous layer is acidified (pH 1) and refluxed for 2 days. It is cooled to room temperature and extracted with methylene chloride, the organic layer is dried over MgSO4 and condensed in vacuo. Purification is by silica gel chromatography (Waters Prep-500) using 10% ethyl acetate / hexanes as eluent to provide 42.9 g (48%) of 3 as a yellow oil. 1H NMR (CDC13) d, 0.86 (t, J = 7.25 Hz, 6H), 1.10-1.26 (m, 12H), 2.83 (s, 2H), 3.32 (s, 2H), 3.40 (s, 3H), 4.48 (s, 3H), 7.02 (dd, J = 8.26 Hz, 1H), 7.16 (dt, J = 8.19 Hz and 2.82 Hz, 1H), 7.45 (t, J = 7.65 Hz, 1H), 7.56-7.61 (m , 2H), 7.69 (d, J = 7.85 Hz, 1H), 7.74 (s, 1H).

Stage 4. Preparation of 4 21.6 g of trifluoromethane sulfonic acid (12.8 ml, 144 mmol) is added to a cooled solution (-40 ° C) of 42.9 g (96.2 mmol) of 3 in 200 ml of methyl chloride followed by the addition of 22.4 g. of triethium silane (30.7 ml, 192.4 mmol). Stir at -20 ° C for 2 hours, warm with water and warm to room temperature environment. It divides between chloride and methylene and water, the organic layer is dried over MgSO, and condensed in vacuo. The purification is by chromatography with silica gel (Waters Prep-500) using e-cyano acetate / hexanes ai 10% as a solvent providing 24.2. g (60%) of 4 as a oil. * H NMR (CDC13) d, 0.89 (t, J = 7.05 Hz, 6H), 1.17-1.40 (m, 12H), 1.46 (t, J = 5.84 Hz, 1H), 2.81 (s, 2H), 3.38 ( s, 3H), 3.43 (d, J = 5.23 Hz, 2H), 4.16 (s, 2H), 4.42 (s, 2H), 6.80 (d, J = 9.67 Hz, 1H), 6.90 (t, J = 8.46 Hz, 1H), 7.09 \, J = 7.45 Hz, iH), 7.15-7.21 tm, 2H), 7.25-7.32 (m, __u 2H), 7.42 (m, 1H).

Stage 5. Preparation of 5 31.2 g of complex sulfur trioxide pyridine (195 mmol) are added to a cooled solution (15-18 ° C) of 24.2 g (55.8 mmol) of 4 in 100 ml of DMSO. Stir at room temperature for 30 minutes. It is poured into cold water and extracted three times with ethyl acetate. The organics are washed with 5% HCl (300 ml) and then with brine (300 ml), the organics are dried over MgSO4 and condensed in vacuo to yield 23.1 g (96%) of 5 as a light brown oil. XH NMR (CDC13) d, 0.87 (t, J = 7.05 Hz, 6H), 1.01-1.32 (m, 8H), 1.53-1.65 (, 4H), 2.98 (s, 2H), 3.38 (s, 3H), 4.15 (s, 2H), 4.43 (s, 2H), 6.81 (dd, J = 9.66 Hz and 2.82 Hz, 1H), 6.91 (t, J = 8.62 Hz, 1H), 7 * 07 (d, J = 7.46 Hz, 1H), 7.14 (s, 1H), 7.19 (d, J = 7.65 Hz, 1H), 7.26-7.32 (m, 1H), 7.42 (dd, J = 8.66 Hz and 5.64 Hz, 1H), 9.40 ( s, 1H).

Stage 6. Preparation of 6 28.6 g of the meta-chloroperoxy-benzoic acid (112.6 mmol) are added to a cooled (0 ° C) solution of 23.1 g (53.6 mmol) of 5 in 200 ml of methylene chloride. Stir at room temperature for 24 hours. It is quenched with 100 ml of 10% Na 2 SO 3, divided between water and methylene chloride. Dry the organic layer over MgSO4 and condense in vacuo to yield 24.5 g (98%) of 6 as a light yellow oil. XH NMR (CDC13) d, 0.86-1.29 (m, 14H), 1.58-1.63 (m, 2H), 1.82-1.91 (m, 2H), 3.13 (s, 2H), 3.39 (s, 3H), 4.44 ( s, 2H), 4.50 (s, 2H), 6.93 (dd, J = 9.07 Hz and 2.82 Hz, 1H), 7.10-7.33 (m, 5H), 8.05 (s, 1H), 9.38 (s, 1H).

Stage 7. Preparation of 7 100 ml of a 2.0 M solution of dimethylamine and 20 ml of pure dimethylamine are added to a solution of 24.5 g (52.9 mmol) of 6 in 20 ml of THF contained in a stainless steel reaction vessel. The vessel is sealed and heated at 110 ° C for 16 hours, the reaction vessel is cooled to room temperature and the contents are concentrated in vacuo. The purification is by silica gel chromatography (Waters Prep-500) using 15% ethyl acetate / hexanes providing 21.8 g (84%) of 7 as a clear, colorless oil. XH NMR (CDC13) d, 0.85 (t, J = 7.25 Hz, 6H), 0.93-1.29 (m, 8H), 1.49-1.59 (m, 2H), 1.70-1.80 (m, 2H), 2.98 (s, 8H), 3.37 (s, 3H), 4.41 (s, 2H), 4.44 (s, 2H), 6.42 (s, 1H), 6.58 (dd, J = 9.0 Hz and 2.61 Hz, 1H), 7.13 (d, J = 7.45 Hz, 1H), 7.21 (s, 1H), 7.28 (t, J = 7.85 Hz, 1H), 7.82 (d, J = 9.06 Hz, 1H), 9.36 (s, 1H).

Stage 8. Preparation of 8 A solution of 21.8 g (44.8 mmol) of 7 in 600 ml of THF at 0 ° C. 58.2 ml of a 1M solution of potassium t-butoxide are slowly added, the temperature is maintained at < 5 ° C. It is stirred for 30 minutes, then it is quenched with 50 ml of saturated ammonium chloride. The organic layer is partitioned between ethyl acetate and water, dried over MgSO4 and concentrated in vacuo. Purification is by recrystallization from ethyl acetate / hexanes ~ 10% to give 15.1 g of 8 as a white solid. The mother liquor is purified by chromatography with silica gel (Waters Prep-500) using 30% ethyl acetate / hexanes as an eluent to produce 3.0 g of 8 as a white solid. MS (FABLi +) m / e 494.6. HRMS (EI +) calculated for M + H 487. 2756. Found 487.2746.

Stage 9. Preparation of 9 j A 2.0 g solution (4.1 mmol) of water is cooled to -60 ° C. 8 in 20 ml of methylene chloride. 4.1 ml of a 1M solution of boron tribromide are added. It is stirred at temperature «^ ____ ^ _ ^^^^^^^^^^« ¿j ^^ glfoi? Feg ^^? ^ - ^^? environment for 50 minutes. The reaction is cooled to -10 ° C and quenched with 50 ml of water. The organic layer is partitioned between methylene chloride and water, dried over MgSO4 and concentrated in vacuo. Purification is by recrystallization from ethyl acetate / 50% methylene chloride to yield 1.95 g (89%) of 9 as a white solid. MS (FABH +) m / e 537. HRMS (FAB) calculated for M 536.1834. Found 536.1822.

Stage 10. Preparation of 10 A solution of 1.09 g (2.0 mmol) of 9 and 4.9 g (62 mmol) of pyridine in 30 ml of acetonitrile is stirred at room temperature for 18 hours. The reaction is concentrated in vacuo. Purification is by recrystallization from methanol / diethyl ether yields 1.19 g (96%) of 10 as a white solid. MS (FAB +) m / e 535.5.

Example 1400 Stage 1 S ^^ C1.H13 ° 2F íw "= 232.25 A 12-liter 4-neck round bottom flask is equipped with a reflux condenser, a N2 gas adapter, a mechanical stirrer, and an addition funnel.The system is purged with N2 A slurry of sodium hydride (126.0 g / 4.988 mol) in toluene (2.5 L) is added, and the mixture is cooled to 6 ° C. A solution of 4-fluorophenyl (560.5 g / 5,000 mol) in toluene is added ( 2.5 L) via an addition funnel over a period of 2.5 h The reaction mixture (100 ° C) is heated at reflux for 1 h. A solution of 3-methoxybenzyl chloride (783.0 g / 5,000 mol) is added to the toluene (750 ml) via an addition funnel while maintaining reflux.After 15 hours of reflux, the mixture is cooled to room temperature and poured into H20 (2.5 L) After 20 minutes, the layers are separated from agitation , and the organic layer is extracted with a solution of potassium hydroxide (720 g) in MeOH (2.5 L) .The MeOH layer is added to aqueous potassium hydroxide. to 20%, and the mixture is stirred for 30 minutes. The mixture is then washed 5 times with toluene. The washed toluene is extracted with 20% aqueous KOH. All 20% aqueous KOH solutions are combined and acidified with concentrated HCl. The acidic solution is extracted three times with ethyl ether, dried (MgSO 4) filtered and concentrated in vacuo.The crude product is purified by Kugelrohr distillation to produce a clear colorless oil (449.0 g / 39% yield) .Pf 120-130 C / 50 mtorrHg, XH NMR (CDC13) and MS [(M + H) + = 233] confirm the desired structure.

Stage 2 C17K18N02FS íw-319.39 A 12-liter 3-necked round bottom flask is filtered with mechanical agitation and an N2 gas adapter. The system is purged with N2. 4-Fluoro-2- (3-methoxybenzyl) -phenol (455.5 g / 1961 mol) and dimethylformamide are added. The solution is cooled to 6 ° C and sodium hydride (55.5 g / 2197 mol) is added slowly. After it is warmed to room temperature, chloride of * _ fc_ -.J ^^^ fc ^ dimethylthiocarbamoyl (242.4 g / 1961 mol). After 15 hours, the reaction mixture is poured into H20 (4.0 L), extracted twice with ethyl acetate. The combined organic layers are washed with H20 and saturated with aqueous NaCl, dried (MgSO4), filtered and concentrated in vacuo to yield the product (605.3 g, 97% yield). XH NMR and MS [(M + H) + = 320] confirm the desired structure.

Stage 3 C1.K130FS fw-246.32 A 12-liter round bottom flask is equipped with a N2 gas adapter, a mechanical stirrer, and a reflux condenser. The system is purged with N2. 4-Fluoro-2- (3-methoxybenzyl) -phenyldimethylthiocarbamate (605.3 g / 1895 mol) and phenyl ether (2.0 Kg) are added, and the solution is refluxed for 2 hours. The mixture is stirred for 64 hours at room temperature and heated to reflux for 2 hours. After cooling to room temperature, add MeOH (2.0 L) and THF (2.0 L) and the solution is stirred for 15 hours. Potassium hydroxide (425.9 g / 7.590 mol) is added and the mixture is heated to reflux for 4 hours. After cooling to room temperature, the mixture is concentrated by centrifugation, dissolved in ethyl ether (1.0 L), and extracted with H20. The aqueous extracts are combined, acidified with concentrated HCl, and extracted with ethyl ether. The ether extracts are dried (MgSO4), filtered, and concentrated in vacuo to give an amber oil (463.0 g, 98% yield). 1H NMR confirm the desired structure.

Stage 4 C25H35 ° 2FS fw-41E-6_. A 5-liter, 3-necked round bottom flask is equipped with a N2 gas adapter and a mechanical stirrer. The system is purged with N2. 4-Fluoro-2- (3-methoxybenzyl) -thiophenyl (100.0 g / 403.2 mmol) and ether 2- are added methoxyethyl (1.0 L) and the solution is cooled to 0 ° C. Sodium hydride (9.68 g / 383.2 mmol) is added slowly, and the mixture is allowed to warm to room temperature, 2,2-dibuthylpropylene sulfate (110.89 g / 443.6 mmol) is added, and the mixture is stirred for 64 hours. The reaction mixture is concentrated by centrifugation and dissolved in H20. The aqueous solution is washed with ethyl ether, and concentrated H2SO4 is added. The aqueous solution is heated at reflux for 30 minutes, cooled to room temperature, and extracted with ethyl ether. Dry the ether solution (MgSO4), filter and concentrate in vacuo to yield an amber oil (143.94 g / 85% yield). 1tt NMR and MS [(M + H) + = 419] confirms the desired structure.

Stage 5 C2 £ K33C2FS fw "426.59 A 2-liter, 4-neck, round bottom flask is equipped with a N2 gas adapter and a mechanical stirrer, the system is purged with N2. corresponding alcohol (143.94 g / 343.8 mmol) and CHC12 (l.C L) and cooled to 0 ° C. Pyridinic chlorochromate (140.53 g / 651.6 mmol) is added. After 6 h, CH2C12 is added. After 20 minutes, the mixture is filtered through silica gel, washed with CH2C12. The filtrate is concentrated in vacuo to yield a dark red-yellow oil (110.6 g, 77% yield). XH NMR and MS [(M + H) + = 417] confirms the desired structure.

Stage 6 C25H33 ° 4FS fW! "» 4e.59 A 2-liter, 4-neck, round bottom flask is equipped with a N2 gas adapter and a mechanical stirrer. The system is purged with N2. The corresponding sulfide (110.6 g / 265.5 mmol) and CH2C12 (1.0 L) are added. The solution is cooled to 0 ° C, and 3-chloroperbenzoic acid (158.21 g / 531.7 mmol) is added in portions. After 30 minutes, the reaction mixture is allowed to warm to ^ ¡¡¡¡^ ^ ^ ^ ^ ^^^^ room temperature. After 3.5 h, the reaction mixture is cooled to 0 ° C and filtered through a fine fritted funnel. The filtrate is washed with 10% aqueous K2CO3. An emulsion is formed which is extracted with ethyl ether. The organic layers are combined, dried (MgSO 4), filtered and concentrated in vacuo to yield the product (93.2 g, 78% yield). : H NMR confirms the desired structure.

Stage 7 C25H33C4FS fw = 44B.5S A 2-liter round bottom flask is equipped with a N2 gas adapter, a mechanical stirrer, and a powder addition funnel. The system is purged with N2. The corresponding aldehyde (93.2 g / 208 mmol) and THF (1.0 L) are added, and the mixture is cooled to 0 ° C. Potassium t-butoxide (23.35 g / 208.1 mmol) is added via an addition medium. After 1 hour, 10% aqueous HCl is added (1.0 L). After 1 hour, the mixture is extracted three times with ethyl ether, dried (MgSO 4), filtered and concentrated in vacuo. The crude product is purified by recrystallization from hexane / ethyl acetate 80/20 to yield a white solid (32.18 g). The mother liquor is concentrated in vacuo and recrystallized from toluene / ethyl acetate 95/5 to yield a white solid (33.60 g / combined yield: 71%). XH NMR confirms the desired product.

Stage 8 C27H39 ° 4NS fw- 73.67 A Fisher bottle holder is equipped with a line of N2 and a magnetic stirrer. The system is purged with N2. The corresponding fluorine compound (28.1 g / 62.6 mmol) is added, the vessel is sealed and cooled to -78 ° C. The diethylamine (17.1 g / 379 mmol) is condensed via a C02 / acetone bath and added to the reaction vessel, the heat is allowed to cool. _. The S ^ -Sfeal * » mix at room temperature and heat to 60 ° C. After 20 hours, the reaction mixture is allowed to warm and dissolved in ethyl ether. The ether solution is washed with H20, saturated aqueous HCl, dried (mgS04), filtered and concentrated in vacuo to yield a white solid (28.5 g / 96% yield). 1H NMR confirms the desired structure.

Stage 9 C26K3704NS fw = 4SS.64 A 250 ml 3-necked round bottom flask is equipped with a N2 gas adapter and a mechanical stirrer. The system is purged with N2. The corresponding methoxy compound (6.62 g / 14.0 mmol) and CHC13 (150 ml) are added. The reaction mixture is cooled to -78 ° C, and boron tribromide (10.50 g / 41.9 mmol) is added. The mixture is allowed to warm to room temperature. After 4 hours, the reaction mixture is cooled to 0 ° C and quenched with K2C03 at % (100 ml). After 10 minutes, the layers are separated, and the aqueous layer is extracted twice with ethyl ether. Combine CHC13 and ether extracts, wash with saturated aqueous NaCl, dry (MgSO4), filter, and concentrate in vacuo to yield the product (6.27 g / 98% yield). 1HNMR confirms the desired structure.

Stage 10 2-diethylaminoethyl chloride hydrochloride (fw = 172.10 g / mol) Aldrich D8, 720-1 (2.4 mmol, 4.12 g), 34 ml of a 250 ml round neck flask with a stir bar. dry ether and 34 ml of KOH ÍN (aqueous). It is stirred for 15 minutes and then separated by extraction with ether and dried over anhydrous potassium carbonate. - -.- faith,, ^ & »-» & ' & *%, * * > « Sodium hydride (60% dispersion in mineral oil, 100 mg, 2.6 mmol) and 34 ml of DMF are added to a separate 2-neck round bottom flask, 250 ml with a mechanical stirrer. It is cooled to ice temperature. Then a phenol product (preliminary step) 1.1 g (2.4 mmol in 5 ml of DMF and the ether solution prepared above is added) It is heated at 40 ° C for 3 days The product which does not contain starting material by TLC It is diluted with ether and extracted with 1 portion of NaOH, followed by water and then brine.The ether layer is dried over magnesium sulfate and isolated by the ether removal by rotary evaporation (1.3 g). to be purified by chromatography (Si02 99% ethyl acetate / 1% NH4OH in 5 ml / min.). Isolated yield: 0.78 g (mass spectrum, and HL NMR).

Stage 11 Place the product of step 10 (0.57 g, 1.02 mmol fw 558.83 g / mol) and 1.6 g of iodoethane (10.02 mmol) in 5 ml of acetonitrile in a Fisher bottle holder and heat at 45 ° C for 3 days. The solution is evaporated to dryness and redissolved in 5 ml of chloroform. Then ether is added to the chloroform solution and the resulting mixture is cooled. The desired product is isolated as a 0.7272 g precipitate. (mass spectrum M-I = 587.9, N NMR).

Example 1401 Stage 1 iBa_ & > ._ • $ & C14K1302F fw-232.25 A 12-liter, 4-necked round bottom flask is equipped with a reflux condenser, a N2 gas adapter, a mechanical stirrer and an addition funnel. The system is purged with N2. A slurry of sodium hydride (126.09 g / 4,988 mol) in toluene (2.5 L) is added, and the mixture is cooled to 6 ° C. A solution of 4-fluorophenol (560.5 g / 5.00 mol) in toluene (2.5 L) is added via an addition funnel over a period of 2.5 h. The reaction mixture is heated to reflux (100 ° C) for 1 hour. A solution of 3-methoxybenzyl chloride (783.0 g / 5,000 mol) in toluene (750 ml) is added via an addition funnel while maintaining reflux. After 15 hours of reflux, the mixture is cooled to room temperature and poured into H20 (2.5 L). After 20 minutes of stirring, the layers are separated, and the organic layer is extracted with a solution of potassium hydroxide (720 g) in MeOH (2.5 L). The 20% aqueous potassium hydroxide MeOH layer is added, and the mixture is stirred for 30 minutes. After the mixture is washed times with toluene. The washed toluene is extracted with 20% aqueous KOH. All 20% aqueous KOH solutions are combined and acidified with concentrated HCl. The acidic solution is extracted three times with ethyl ether, dried over MgSO4, filtered and concentrated in vacuo. The crude product is purified by Kugelrohr distillation to produce a clear colorless oil (449.0 g / 39% yield). P.f .: 120-130 ° C / 50 mtorrHg. XH NMR and MS [(M + H) + = 233] confirms the desired structure.

Stage 2 C17K18N02FS fw-319.3 A 12-liter, 3-necked round bottom flask is equipped with a N2 gas adapter and a mechanical agitator. The system is purged with N2. 4-Fluoro-2- (3-methoxybenzyl) -phenol (455.5 g / 1961 mol) and dimethylformamide are added. The solution is cooled to 6 ° C, and added ^ ts _g_-. ~ - »» ^ _---: slowly sodium hydride (55.5 g / 2197 mol). After warming to room temperature, dimethylthiocarbamoyl chloride (242.4 g / 1961 mol) is added. After 15 hours, the reaction mixture is poured into H20 (4.0 L) and extracted twice with ethyl ether. The combined organic layers are washed with H20 and saturated aqueous NaCl, dried over MgSO4, filtered, and concentrated in vacuo to yield the product (605.3 g, 97% yield). XH NMR and MS [(M + H) + = 320] confirms the desired structure.

Stage 3 C14K130FS fw * 248.32 A 12-liter, 3-necked round bottom flask is equipped with a N2 gas adapter, a mechanical stirrer and a reflux condenser. The system is purged with N2. 4-Fluoro-2- (3-methoxybenzyl) -phenyldimethylthiocarbamate (605.3 g / 1895 mol) and phenyl ether (2.0 Kg) are added and the solution is refluxed for 2 hours. The mixture is stirred by 64 hours at room temperature and then heated to reflux for 2 hours. After cooling to room temperature, MeOH (2.0 L) and THF (2.0 L) are added, and the solution is stirred for 15 hours. Potassium hydroxide (425.9 g / 7.590 mol) is added, and the mixture is heated to reflux for 4 hours. After cooling to room temperature, the mixture is concentrated by centrifugation, dissolved in ethyl ether (1.0 L), and extracted with H2O. The aqueous extracts are combined and acidified with concentrated HCl, and extracted with ethyl ether. The ether extracts are dried (MgSO 4), filtered and concentrated in vacuo to yield an amber oil (463.0 g, 98% yield). 1H NMR confirms the desired structure.

Stage 4 C25H35 ° 2FS í - 18.61 A 5-liter, 3-necked round bottom flask is eguipated with a N2 gas adapter and an agitator ^ tst- ^ pi ^^ & k mechanic. The system is purged with N2. 4-Fluoro-2- (3-methoxybenzyl) -thiophenol (100.0 g / 403.2 mmol) and 2-methoxyethyl ether (1.0 L) are added and the solution is cooled to 0 ° C. Sodium hydride (9.69 g / 383.2 mmol) is added slowly, and the mixture is allowed to warm to room temperature and 2,2-dibutylpropylene sulfate (110.89 g / 443.6 mmol) is added, and the mixture is stirred for 64 hours. The reaction mixture is concentrated by centrifugation and dissolved in H20. The aqueous solution is washed, washed with ethyl ether, and concentrated H2SO4 is added. The aqueous solution is refluxed for 30 minutes, cooled to room temperature, and extracted with ethyl ether. The ether solution is dried (MgSO4), filtered, and concentrated in vacuo to yield an amber oil (143.94 g / 85% yield). XH NMR and MS [(M + H) + = 419] confirms the desired structure.

Stage 5 C2 5H5 302FS fw-416. 59 S »« > ítS | J ~ jí-.

A 2-liter, 4-neck, round bottom flask is equipped with a N2 gas adapter and a mechanical stirrer. The system is purged with N2. The corresponding alcohol (143.94 g / 343.8 mmol) and CH2C12 (1.0 L) is added and cooled to 0 ° C. It is added to the pyridinium chlorochromate (140.53 g / 651.6 mmol). After 6 hours, CH2C12 is added. After 20 minutes, the mixture is filtered through silica gel, washed with CH2C12. The filtrate is concentrated in vacuo to yield a dark red yellow oil (110.6 g, 77% yield). ? H NMR and MS [(M + H) + = 417] confirms the desired structure.

Stage 6 C25K33 ° 4FS íw-448.59 A 2-liter, 4-neck, round bottom flask is equipped with a N2 gas adapter and a mechanical stirrer. The system is purged with N2. It adds the • * _ .y ^ a corresponding sulfide (110.6 g / 265.5 mmol) and CH2C12 (1.0 L). The solution is cooled to 0 ° C, and chloroperbenzoic acid (158.21 g / 531.7 mmol) is added as a portion. After 30 minutes, the reaction mixture is allowed to warm to room temperature. After 3.5 hours, the reaction mixture is cooled to 0 ° C and filtered through a fine fritted funnel. The filtrate is washed with 10% aqueous K2CO3. An emulsion is formed which is extracted with ethyl ether. The organic layers are combined, dried (MgSO 4), filtered and concentrated in vacuo to yield the product (93.2 g, 78% yield). XHNMR confirms the desired structure.

Stage 7 C25K33 ° 4? = Fw-44fi-5 A round bottom flask, 4-neck, two-liter, with a N2 gas adapter, with a mechanical stirrer, and a powder addition funnel is equipped. The system is purged with N. S and the corresponding aldehyde is added (93.2 g / 208 mmol) and THF (1.0 L), and the mixture is cooled to 0 ° C. Potassium tert-butoxide (23.35 g / 208.1 mmol) is added via an addition funnel. After one now, 10% aqueous HCL (1.0 L) is added. After one hour, the mixture is extracted three times with ethyl ether, dried with MgSO 4, filtered, and concentrated in vacuo. The crude product is purified by recrystallization of 80/20 hexane / ethyl acetate to give a white solid (32.18 g). The mother liquor is concentrated in vacuo and recrystallized from toluene / ethyl acetate 95/5 to give a solid white (33.60 g, combined yield: 71%). : H NMR confirms the desired product.

Stage 8 C27K3904NS fw-473.67 A Fisher bottle holder is equipped with a line of N2 and a magnetic stirrer. The system is purged with N2. The corresponding fluorine compound (28.1 g / 62.6 mmol) is added, and the vessel is sealed and cooled to -78 ° C. Dimethylamine (17.1 g / 379 mmol) is condensed via a C02 / acetone bath and added to the reaction vessel. The mixture is warmed to room temperature and heated to 60 ° C. After 20 hours, the reaction mixture is allowed to cool and dissolved in ethyl ether. The solution is washed with H20 and a saturated aqueous NaCl solution, dried with MgSO4, filtered, and concentrated in vacuo to provide a white solid (28.5 g / 96% yield). XH NMR confirms the desired structure.

Stage 9 C26H3704KS fw = 59.64 A 250 ml round bottom, three-necked flask is fitted with a N2 gas adapter and a magnetic stirrer. The system is purged with N2. The corresponding methoxy compound (6.62 g / 14.0 mmol) and CHCL3 (150 L) are added. The reaction mixture is cooled to -78 ° C, and boron tribromide (10.50 g / 41.9 mmol) is added, the mixture is allowed to warm to room temperature, the reaction mixture is cooled after 4 hours at 0 ° C and the reaction mixture is cooled to 0 ° C. Quench with 10% K2CO3 (100 mL), separate the layers after 10 minutes, and extract twice with ethyl ether, combine CHCl3 and ether extracts, wash with saturated aqueous NaCl, dry with MgSO4. , filter, and concentrate in eafc-.j.-Mt-yg '. vacuum to provide the product (6.27 g / 98% yield). 1H NMR confirms the desired structure.

Stage 10 A 2-diethylaminoethyl chloride hydrochloride (172.10 g / mol), Aldrich D8, 720-1 (2.4 mmol, 4.12 g), 34 ml of ether are placed in a 250 ml round neck flask with a stirrer. dry and 34 ml of KOH (aqueous) IN. The solution is stirred for 15 minutes and then separated by extraction of the ether and dried with anhydrous potassium carbonate. It is added to a separate 250 ml two-neck round bottom flask with a stirrer (a 60% dispersion in mineral oil), 100 mg, (2.6 mmol) and 34 ml of DMF. It cools to an ice temperature. Then 1.1 g are added (2.4 mmol) of the phenol product (previous step) in 5 ml of DMF and the ether solution prepared above. It is heated for three days at 40 ° C. The product which does not contain the starting material is diluted by means of TLC with ether and extracted with a portion of 5% NaOH, followed by water and then by brine. The ether layer is dried with magnesium sulfate and isolated by removing the ether by rotary evaporation (1.3 gms). In addition, the product can be purified by chromatography (ethyl acetate 99% silica / 1% NH40H at 5 ml / min.). Isolated yield: 0.78 g (mass spectrum, and HL NMR).

Stage 11 Place the product from stage 10 (0.57 gms, 1.02 millimoles fw 558.83 g / mol) and iodoethane (1.6 gms (10.02 g)). millimoles) in 5 ml of acetonitrile in a Fisher bottle holder and heated at 45 ° C for three days. The solution is evaporated to dryness and redissolved in 5 ml of chloroform. The ether is then added to the chloroform solution and the resulting mixture is cooled. The desired product is isolated as a precipitate 0.7272 gms. Mass spectrum M-I = 587.9, H NMR).

Example 1402 ±? Acid (4R-cis) -5- [[5- [4- [3, 3-dibutyl-7- (dimethylamino) -2,3,4,5-tetrahydro-4-hydroxy-l, l-dioxide-l -benzothiepin-5-yl] phenoxy] pentyl] thio] -lH-tetrazol-1-acetic Step 1_. Preparation of 4-fluoro-2- ((4-methoxyphenyl) methyl) -phenol It is added to a solution of 23.66 g of 95% sodium hydride (0.94 mol) to 600 ml of dry toluene, 100.0 g of 4- fluorophenol (0.89 mol) at 0 ° C. The mixture is stirred at 90 ° C for one hour until the evolution of the gas stops. The mixture is cooled to room temperature and a solution of 139.71 g of 3-methoxybenzyl chloride (0.89 mol) in 400 ml of dry toluene is added. After refluxing the mixture for 24 hoursThe mixture is cooled to room temperature and quenched with 500 ml of water. Separate the organic layer, dry with MgSO 4, and concentrate under high vacuum. The remaining starting materials are removed by distillation. The crude dark red oil is filtered through a one liter layer of silica gel with pure hexane to yield 53.00 g (25.6%) of the product as a pink solid: 1H NMR (CDCL3) d 3.79 (s, 3H), 3.90 (s, 2H), 4.58 (s, 1H), 6.70-6.74 (m, 1H) 6.79-6.88 (m, 4H), 7.11-7.16 (m, 2H). Step 2. Preparation of 4-fluoro-2- ((4-methoxyphenyl) methyl) -thiophenol Step 2 a. Preparation of thiocarbamate To a stirred solution of 50.00 g (215.30 mol) of 4-fluoro-2- ((4-methoxyphenyl) methyl) -phenol in 500 ml of dry DMF, 11.20 g of a sodium hydride dispersion were added. 60% in mineral oil (279.90 mol) at 2 ° C. Allow the mixture to warm to room temperature and add 26.61 g of dimethylthiocarbamoyl chloride (215.30 mol). The reaction mixture is stirred at room temperature overnight. The mixture is quenched with 100 ml of water in an ice bath. The solution is extracted with 500 ml of water and 500 ml of brine. The ether solution is dried with MgSO 4 and stripped to dryness. The crude product is filtered through a 500 ml silica gel filter using 5% ethyl acetate / hexane to yield 48.00 g (69.8%) of the product as a pale white solid: XH NMR (CDCL3) d 3.21 (s) , 3H), 3.46 (s, 3H), 3.80 (s, 3H), 3.82 (s, 2H), 6.78-6.86 (m, 3H), 6.90-7.00 (m, 2H), 7.09 (d, J = 8.7 Hz, 2H). Stage 2b. Rearrangement and hydrolysis of the thiocarbamate to 4-fluoro-2- ((4-methoxyphenyl) methyl) -thiophenol A solution of 48.00 g (150.29 mol) of thiocarbamate (obtained from step 2 a) in 200 ml of ether is refluxed. diphenyl at 270 ° C at night. The solution is cooled down to room temperature and filtered through an L of silica gel with 2 L of hexane to remove the diphenyl ether. The rearrangement product is washed with 5% ethyl acetate / hexane to give 46.00 g (95.8%) of the product as a pale yellow solid: 1H NMR (CDCL3) d 3.02 (s, 3H), 3.10 (s, 3H) , 3.80 (s, 3H), 4.07 (s, 2H), 6.82- 6. 86 (, 3H), 6.93 (dt, J = 8.4 Hz, 2.7 Hz, 1H), 7.08 (d, J = 8.7 Hz, 2H), 7.49 (dd, J = 6.0 Hz, 8.7 Hz, 1H). To a solution of 46.00 g (144.02 mol) of the rearrangement product (above) in 200 ml of methanol and 20 C ml of THF are added to 17.28 g of NaOH (432.06 mol). The solvents are evaporated and 200 ml of water is added. The aqueous solution is washed with 200 ml of diethyl ether twice and placed in an ice bath. The aqueous mixture is acidified to a pH of 6 with a concentrated HCl solution. The solution is extracted with 300 ml of diethyl ether twice. The ether layers are combined, dried MgSO4 and stripped to dryness to yield 27.00 g (75.5%) of the product as a brown oil: XH NMR (CDCL3) d 3.24 (s, 1H), 3.80 (s, 3H), 3.99 (s, 2H), 6.81-6.87 (m, 4H), 7.09 (d, J = 8.7 Hz, 2H), 7.27-7.33 (m, 1H). Step 3. Preparation of dibutyl cyclic sulfate Step 3a. Preparation of 2, 2-dibutyl-l, 3-propanediol. Add to a solution of di-butyl diethylmalonate (Aldrich) (150g, 0.55 mol in dry THF (700 ml) in acetone / dry ice bath, LAH (1 M THF) 662 ml (1.2 eq., 0.66 mol) drop drop by keeping the temperature between -20 ° C to 0 ° C. The reaction mixture is stirred at RT overnight, the reaction is cooled to -20 ° C. and 40 ml of water and 80 ml of water are added. já_ «fcg_St?« __ v j¿ »ft¿ SS % NaOH and 80 ml of water dropwise. The resulting suspension is filtered. The filtrate is dried with magnesium sulfate and concentrated in vacuo to give the 98.4 g diol (95% yield) as an oil. The mass spectra and the carbon and proton NMR spectra are consistent with the product. Stage 3b. Preparation of dibutyl cyclic sulfite A solution of 2, -dibutyl-1,3-propanediol (103 g, 0.548 mol, obtained from step 3 a) and triethylamine (221 g, 2.19 mol) in anhydrous methylene chloride is stirred ( 500 ml) at a temperature of 0 ° C under a nitrogen atmosphere. Thionyl chloride (97.8 g, 0.82 mol) is added dropwise to the mixture and after 5 minutes the solution turns yellow and then black when the addition is complete in half an hour. The reaction mixture is stirred for 3 hours at 0 ° C. Chromatography shows no starting material. The mixture is washed with an ice bath twice and then with brine twice. The organic phase is dried with magnesium sulfate and concentrated under vacuum to provide 128 g (100%) of the cyclic dibutyl sulfite as a black oil. The mass spectrum (MS) is consistent with the product.

Stage 3c. Oxidation of dibutyl cyclic sulfite to dibutyl cyclic sulfate It is added to a solution of dibutyl cyclic sulfite (127.5 g, 0.54 mol, obtained from Stage 3b in 600 ml of acetonitrile and 500 ml of water cooled in an ice bath under one atmosphere of nitrogen, ruthenium chloride (III) (1 g) and sodium periodate (233 g, 1.08 mol). The reaction is stirred overnight and the color of the solution turns black. Gas chromatography shows that the starting material does not exist. The mixture is extracted with 300 ml of ether and the ether extract is washed three times with brine. The organic phase is dried with magnesium sulfate and passed through celite. The filtrate is concentrated under vacuum to provide 133 g (97.8%) of the dichloric cyclic sulfate as an oil. The carbon and proton NMR and MS are consistent with the product. Step 4. Preparation of ar-l-3-hydroxyl propyl sulfide To a solution of 27.00 g (108.73 mmol) of 4-fluor-2- ((4-methoxyphenyl) methyl) thiophenol (obtained from Step 2) in 270 ml of diglyme, 4.35 g of a sodium hydride dispersion is added. in mineral oil (108.73mmol) at a temperature of 0 ° C. After the evolution of the gas ceases, they are added 29. 94 g (119.60 mmol) of the dibutyl cyclic sulfate (obtained from Step 3c) at a temperature of 0 ° C and stirred for 10 minutes. The mixture is allowed to warm to room temperature and is stirred overnight. The solvent is evaporated and 200 mL of diethyl ether are added. The solution is washed with 200 ml of diethyl ether and 25 ml of concentrated sulfuric acid are added to obtain a 2.0 M solution which refluxes overnight. The solution is extracted with ethyl acetate and the organic solution is dried with MgSO 4 and concentrated in vacuo. The crude aryl-3-hydroxypropyl sulphide was purified by silica gel chromatography (Waters prep 500) using 8% ethyl acetate / hexane to produce a light brown oil: "H NMR (CDCL3) 6 0.90 (t, J = 7.1 Hz, 6H) 1.14-1.34 (m, 12H), 2.82 (s, 2H), 3.48 (s, 2H), 3.79 (s, 3H), 4.10 (s, 2H), 6.77-6.92 (m, 4H), 7.09 (dt, J = 8.7 Hz, 2H), 7.41 (dd, J = 5.7 Hz, 1H) Step 5. Preparation of the enamerically enriched aryl-3-hydroxypropylsulfoxide They are added to a solution of 20.00 g (47.78 mmol) of aryl 3-hydroxypropyl sulphide (obtained from Step 4) in 1 L of methylene chloride, 31.50 g of (IR) - (-) - (8,8-dichloro-10-camphorsulfonyl) oxaziridine 96% (100.34 mmol, Aldrich) at a temperature of 2 ° C. After all the oxaziridine dissolve the mixture is placed in a cooler at -30 ° C for 72 hours. The solvent is evaporated and the crude solid is washed with 1 L of hexane. The white solid is filtered and the hexane solution is concentrated in vacuo. The crude oil is purified on a silica gel column (Waters prep 500) using 15% ethyl acetate / hexane to yield 19.00 g (95%) of the eneomerically enriched aryl-3-hydroxypropylsulfoxide as a colorless oil:: H NMR (CDCL3) d 0.82-0.98 (m, 6H), 1.16-1.32 (m, 12H), 2.29 (d, J = 13.8 Hz, 1H), 2.77 (d, J = 13.5 Hz, 1H), 3.45 (d, J = 12.3 Hz, 1H), 3.69 (d, J = 12.3 Hz, 1H), 3.79 (s, 3H), 4.02 (q, J = 15.6 Hz, 1H), 6.83-6.93 (m, 3H), 7.00 ( d, J = 8.1 Hz, 2H), 7.18-7.23 (m, 1H, 7.99-8.04 (m, 1H) The enameric excess is determined by chiral HPLC on a column (R, R) -Whelk-0 using ethanol % 7hexane as the eluent It is shown to be 78% ee with the first peak of the eluent as the main product Step 6. Preparation of an enamerically enriched aryl-3-propanalsulfoxide They are added to a solution of 13.27 g of triethylamine (131.16 mmol, Aldrich) in 200 mL of dimethyl sulfoxide, 19. 00 g (43.72 mmol) of the enamerically enriched aryl-3-hydroxypropylsulfoxide (obtained from step 5) and . 96 g of trioxide-pyridine sulfur (131.16 mmol, Aldrich) at room temperature. The mixture is then stirred at room temperature for 48 hours, 500 ml of water are added to the mixture and vigorously stirred. The mixture is then extracted with 500 ml of ethyl acetate twice. Separate the ethyl acetate layer, dry with MgSO 4, and concentrate in vacuo. Filter the crude oil through 500 ml of silica gel using 15% ethyl acetate / hexane to provide 17.30 g (91%) of the enamerically enriched aryl-3-propanalsulfoxide as a light orange oil: 1N NMR (CDCL3) d 0.85-0.95 (m, 6H), 1.11-1.17 (m, 4H), 1.21-1.39 (m, 4H), 1.59-1.76 (m, 4H), 1.89-1.99 (m, 1H), 2.57 (d, J = 14.1 Hz, 1H), 2.91 (d, J = 13.8 Hz, 1H), 3.79 (s, 3H), 3.97 (d, J = 15.9 Hz, 1H), 4.12 (d, J = 15.9 Hz, 1H), 6.84-6.89 (m, 3H), 7.03 (d, J = 8.4 Hz, 2H), 7.19 (dt, J = 8.4 Hz, 2.4 Hz, 1H), 8.02 (dd, = 8.7 Hz, 5.7 Hz, 1H), 9.49 (s, 1H). Step 7. Preparation of the enamerically enriched tetrahydrobenzothiepin-1-oxide (4R, 5R) It is added to a solution of 17.30 g (39.99 mmol) of the enamerically enriched aryl-3-propanalsulfoxide. (obtained from Step 6) in 300 ml of dry THF at a temperature of -15 ° C, 48 ml of 1.0 M potassium tert-butoxide. in THF (1.2 equivalents) under a nitrogen atmosphere. The solution is stirred at -15 ° C for 4 hours. The solution is then quenched with 100 ml of water and neutralized with 4 ml of a concentrated HCL solution at 0 ° C. The THF layer is separated, dried with MgSO 4, and concentrated in vacuo. The enantiomerically enriched tetrahydrobenzothiepin-1-oxide (4R, 5R) is purified by chromatography on silica gel (Waters prep 500) using 15% ethyl acetate / hexane to provide 13.44 g (77.7%) of the product as a white solid: XH NMR (CDCL3) d 0.87-0.97 (m, 6H), 1.16-1.32 (m, 4H), 1.34-1.48 (m, 4H), 1.50-1.69 (m, 4H), 1.86-1.96 (m, 1H) , 2.88 (d, J = 13.0 Hz, 1H), 3.00 (d, J = 13.0 Hz, 1H), 3.85 (s, 3H), 4.00 (s, 1H), 4.48 (s, 1H), 6.52 (dd, J = 9.9 Hz, 2.4 Hz, 1H), 6.94 (d, J = 9 Hz, 2H), 7.13 (dt, J = 8.4 Hz, 2.4 Hz, 1H), 7.38 (d, J = 8.7 Hz, 2H), 7.82 (dd, J = 8.7 Hz, 5.7 Hz, 1H). Step 8. Preparation of the enantiomerically enriched tetrahydrobenzothiepin-1, 1-dioxide (4R, 5R). Add to a stirred solution of 13.44 g (31.07 mmol) of the enantiomerically enriched tetrahydrobenzot? Ep? Na-1-oxide (obtained from Step 7). ) in 150 mL of methylene chloride, 9.46 g of 68% m-chloroperoxybenzoic acid (37.28 mmol, sigma) at 0 ° C. After stirring at 0 ° C for two hours, let the mixture cool to room temperature and stir for 4 hours. 50 mL of Na2SO3 is added to the mixture and stirred for 30 minutes. The solution is then neutralized with 50 mL of a NaHCO 3 solution. The methylene chloride layer is separated, dried with MgSO 4, and concentrated in vacuo to provide 13.00 g (97.5%) of the tetrahydrobenzothiepin-1,1-dioxide ( 4R, 5R) enantiomerically enriched as a light yellow solid: 1H NMR (CDCL3) d 0.89-0.975 (m, 6H), 1.09-1.42 (m, 12H), 2.16-2.26 (m, 1H), 3.14 (q, J = 15.6 Hz, 1H), 3.87 (s, 3H), 4.18 (s, 1H), 5.48 (s, 1H), 6.54 (dd, J = 10.2 Hz, 2.4 Hz, 1H), 6.96-7.07 (m, 3H) ), 7.40 (d, J = 10.2 Hz, 2.4 Hz, 1H), 6.96-7.07 (m, 3H), 7.40 (d, J = 8.1 Hz, 2H), 8.11 (dd, J = 8.6 Hz, 5.9 Hz, 1 HOUR) . Stage 9_. Preparation of enantiomerically enriched enriched (epimethyl) tetrahydrobenzotamido-1, 1-dioxide (4R, 5R) They are added to a solution of 13.00 (28.98 mmol) of the enantiomerically enriched tetrahydrobenzothiepin-1,1-dioxide (obtained from Step 8). ) in 73 mL of dimethylamine (2.0 M in THF, 146 mmol) in a Parr Reactor, about 20 mL of pure dimethylamine. The mixture is sealed and stirred at 110 ° C overnight, and cooled to room temperature ».» AsA-aafeWf-A- > ^ »« A > ^ _, j > . ^ -, - ^ E ^^^^^ B ^^ fe ^ ¿»a» ~ ^ Ai > tefe. »3fea ^. - «asfcsfe, .- sZ z -.; ._ jj_é¿arf. ambient. The crude oil is dissolved in 200 L of ethyl acetate and washed with 100 mL of water, dried with MgSO 4 and concentrated in vacuo. Purify on a column on silica gel (Waters Prep 500) using 20% ethyl acetate / hexane to provide 12.43 g (90.5%) of the enantiomerically enriched 7- (dimethylamino) tetrahydrobenzot-epina-1, 1-ddioxide (4R, 5R ) as a colorless solid: 1H NMR (CDCL3) d 0.87-0.93 (m, 6H), 1.10-1.68 (m, 12H), 2.17-2.25 (m, 1H), 2.81 (s, 6H), 2.99 (d, J = 15.3 Hz, 1H), 3.15 (d, J = 15.3 Hz, 1H), 3.84 (s, 3H), 4.11 (d, J = 7. 5 Hz, 1H), 5.49 (s, 1H), 5.99 (d, J = 2.4 Hz, 1H), 6.51 (dd, J = 8.7 Hz, 2.4 Hz, 1H), 6.94 (d, J = 8.7 Hz, 2H), 7.42 (d, J = 8.4 Hz, 2H), 7.90 (d, J = 8.7 Hz, 1H). The product is determined to have e.e. 78% by chiral HPLC on a AD Quiralpak column using 5% ethanol / hexane as the eluent. Recrystallization of this solid from ethyl acetate / hexane gives 1.70 g of the racemic product. The remaining solution is concentrated and recrystallized to provide 9.8 g of a colorless solid. The enantiomeric excess of this solid is determined by chiral HPLC on an AD Quiralpak column using 5% ethanol / hexane as the eluent. This shows that you have e.e. 96% with the first peak of the eluent as the main product.

Step 10 Demethylation of 5- (4'-methoxyphenyl) -7- (dimethylamino) tetrahydrobenzothiepin-1,1-dioxide (4R, 5R) A solution of boron tribromide (297 mL, in methylene chloride 1M, is added dropwise). 297 mmol) was added to a solution of 47 g (99 mmol) of enantiomerically enriched (dimethylamino) tetrahydrobenzothiepine-1,1-dioxide (obtained from step 9) in 500 L of methylene chloride at -10 ° C, and the Solution resulting in cold (-5 ° C to 0 ° C) for one hour or until the reaction is complete. The reaction is cooled in an acetone bath and dry ice at -10 ° C, and quenched slowly with 300 mL of water. The mixture is warmed to 10 ° C, and further diluted with 300 mL of a saturated sodium bicarbonate solution to neutralize the mixture. The aqueous layer is separated and extracted with 300 mL of methylene chloride, and the combined extracts are washed with 200 mL of water, brine, dried over MgSO4, and concentrated in vacuo. The residue is dissolved in 500 mL of ethyl acetate and stirred with 50 mL of glacial acetic acid for 30 minutes at room temperature. The mixture is washed twice with 200 mL of water, 200 mL of brine, dried with MgSO4 and concentrated in vacuo to provide the crude 4-hydroxyphenyl intermediate. The crude solid is recrystallized from the chloride of methylene to provide 37.5 g (82%) of desired 5- (4'-hydroxyphenyl) -7- (dimethylamino) tetrahydrobenzothiepin-1, 1-dioxide, as a white solid: XH NMR (CDCL3) d 0.84-0.97 (m, 6H), 1.1-1.5 (m, 10H), 1.57-1.72 (m, 1H), 2.14-2.28 (m, 1H), 2.83 (s, 6H), 3.00 (d, J = 15.3 Hz, 1H), 3.16 (d, J = 15.3 Hz, 1H), 4.11 (s, 2H), 5.48 (s, 1H), 6.02 (d, J = 2.4 Hz, 1H), 6.55 (dd, J = 9, 2.4 Hz, 1H) , 6.88 (d, 8.7 Hz, 2H) ,. 7.38 (d, J = 8.7 Hz, 2H), 7.91 (d, J = 9 Hz, 2H). Alternatively, the intermediary described can be prepared 5- (4'-hydroxyphenyl) -7- (dimethylamino) tetrahydrobenzothiepin-1,1-dioxide via the non-enantioselective synthesis followed by separation by chiral chromatography. Oxidation of aryl-3-hydroxypropylsulfide (obtained from Step 4) with m-chloroperbenzoic acid (under the same conditions as in Step 8, but with 2.2 equivalent m-CPBA) provides the racemic sulfone intermediate. The sulfone is produced through the synthetic sequences (under the same conditions as in Step 7 and Step 9) to provide 5- (4'-hydroxyphenyl) -7- (dimethylamino) tetrahydrobenzothiepine-1, 1-racemic dioxide . .- • r- »1 * --'-» * - * '. «- .Afa.; _ ^ & Ai & i_ft _ .. ^ __ táSa-. -., ._.-- ~., "", -. ., "-». . ^ -, * «.._. £.

The two enantiomers are separated in the desired 5- (4'-hydroxyphenyl) -7- (dimethylamino) tetrahydrobenzothiepin-1, 1-enantiomerically enriched dioxide by means of purification by appropriate chiral chromatography.

Step 11: Preparation of the ester intermediate. Add to a solution of 1.Og (2.18 mmol) of 4 '-5- (hydroxyphenyl) -7- (dimethylamino) tetrahydrobenzothiepin-1,1-dioxide (obtained from Step 10) in 10 mL of dimethylformamide, 60 g (2.38 mmol) of 95% sodium hydride and stirred for 15 minutes. 400 μL (2.52 mmol) of benzyl 2-bromoacetate are added to the reaction mixture and stirred for two hours. Water is added to the reaction mixture, extracted with ethyl acetate, washed with brine, dried with MgSO 4, filtered and the solvent evaporated to yield 1.30 g (98%) of the ester intermediate: XH NMR (CDCl 3 ) d 0.88-0.94 (m, 6H), 1.13-1.46 (m, 10H), 1.60-1.64 (m, 1H), 2.20-2.24 (m, 1H), 2.81 (s, 6H), 3.00 (d, J) = 15.1 Hz, 1H), 3.16 (d, J = 15.1 Hz, 1H), 4.11 (s, 1H), 5.26 (s, 2H), 5.49 (s, 1H), 6.04 (d, J = 2.4 Hz, 1H ), 6.63 (dd, J = 8.9, 2.4 Hz, 1H), 6.95 (d, J = 8.7 Hz, 2H), 7. 37 (s, 5H), 7.42 (d, J = 8.5 Hz, 2H), 7.93 (d, J = 8.9 Hz, 1H). Step 12. Preparation of acid A solution of 1.30 g (2.14 mmol) of the ester intermediate (obtained from Step 1) in 40 mL of 10% carbon palladium ethanol is placed under an atmosphere of hydrogen gas (40 psi), for three hours. The reaction mixture is filtered through the celite and the solvent is evaporated to yield the desired title compound as a white solid: mp: 119 ° C-123 ° C; XH NMR (CDCL3) d 0.89- 0.94 (m, 6H), 1.19-1.43 (m, 10H), 1.61-1.65 (m, 1H), 2.14-2.21 (m, 1H), 2.85 (s, 6H), 3.02 (d, J = 15.1 Hz, 1H), 3.17 (t, J = 14.9 Hz, 1H), 4.12 (s, 1H), 4.72 (s, 2H), 5.51 (s, 1H), 6.17 (s, 1H) , 6.74 (d, J = 9.1 Hz, 1H), 6.99 (d, J = 8.3 Hz, 2H), 7.46 (d, J = 8.5 Hz, 2H), 7.97 (d, J = 8.7 Hz, 1H). HRMS. Calculated for C28H4oN06S: 518.2576. It is located: 518.2599.

Example 1403 (4R-cis) -N- [[4- [3, 3-Dibutyl-7- (dimethylamino) -2,3,4,5-tetrahydro--hydroxy-1,1-dioxido-1-benzothiepin-5- ilo] phenoxyacetyl] glycine Step 1: Preparation of the glycine ester intermediate They are added to a solution of 6.4 g (13.9 mmol) of 5- (4'-hydroxyphenyl) -7- (dimethylamino) tetrahydrobenzothiepin-1, 1- dioxide (obtained of Example 1402, Step 10) and 2.9 g (21.0 mmol) of potassium carbonate in 100 mL of acetone, 3.8 g (21.0 mmol) of the ethyl ester N- (chloroacetyl) glycine and 50 mg (0.14 mmol) of tetrabutylammonium iodide. The mixture is heated at reflux for two days, cooled to room temperature and stirred for 20 hours, then divided between ethyl acetate and water. The organic layer is washed with brine, dried with MgSO 4, and concentrated in vacuo. Purification by chromatography on silica gel (Waters Prep 500) using 50% ethyl acetate / hexanes yields 7.5 g (90%) of the glycine ester intermediate as a white foam:? H NMR (CDCL3) d 0.86-0.98 (m, 6H), 1.04-1.56 (, 13H) , 1.58-1.71 (m, 1H), 2.14-2.29 (m, 1H), 2.73 (s, 6H), 3.08 (ABq, JAB = 15.3 Hz, J = 48.9, 2H), 4.06-4.19 (m, 6H ), 4.25 (q, J = 7.0 Hz, 2H), 4.57 (s, 2H), 5.50 (s, 1H), 5.98 (s, 1H), 6.56 (d, J = 8.6 Hz, 1H), 6.98 (d , J = 8.5 Hz, 2H), 7.17 (s, 1H), 7.47 (d, J = 8.3 Hz, 2H), 7.91 (d, J = 8.7 Hz, 1H). Step 2: Preparation of the acid A solution of 7.3 g (12.1 mmol) of the ester glycine intermediate (obtained from Step 1) and 1.5 g of LiOH.H20 (36.3 mmol) in 60 mL of THF and 60 mL of water is heated. at 45 ° C for two hours. This is then cooled to room temperature, acidified with IN HCl and divided between ethyl acetate and water. The organic layer is washed with brine, dried with magnesium sulfate, and concentrated in vacuo. Purification by recrystallization from ethyl acetate provides 5.45 g (78%) of the desired title compound as a white crystalline solid: 149 ° C-150 ° C; XH NMR (CD30D) d 0.88-0.98 (m, 6H), 1.06-1.56 (m, 10H), 1.70-1.84 (m, 1H), 2.06-2.20 (m, 1H), 2.79 (s, 6H), 3. 11 (ABq, JAB = 15.3 Hz, J = 21.6 Hz, 2H), 4.01 (s, 2H), 4.07 (s, 1H), 4.61 (s, 2H), 5.31 (s, 1H), 6.04 (s, 1H) ), 6.57 (d, J = 9.0 Hz, 1H), 7.08 (d, J = 7.8 Hz, 2H), 7.44 (d, J == 8.1 Hz, 2H), 7.76 (d, J = 9.0 Hz, 1H) 8.42 (m, 1H). HRMS (ES +) Calculated for C30H42N2O7S: 575.2712. It is 575.2790. Analysis calculated for: C30H 2N2O7S C, 62.69; H, 7.37; N, 4.87. It is found: C, 62.87; H, 7.56; N, 4.87.

Example 1404 (4R-cis) -5- [4- [3, 3-Dibutyl-7- (dimethylamino) -2,3,4,5-tetrahydro-4-hydroxy-l, l-dioxido-l-benzothiepin-5 acid - ilo] phenoxy] pentanoic Step 1: Preparation of the ester intermediate A solution of 5- (4'-hydroxyphenyl) -7- (dimethylamino) tetrahydrobenzothiepin-1,1-dioxide (1.0 g, 2.2 mmol, obtained from Example 1402, Step 10) is treated. in acetone (10 «._. ^ ___.._ ^ S__ > «Í_ &» *; ___. -i ^^^ á, ^^^ k ^^^^^ - s. \ ¿»_ -, - mL) at 25 ° C under a nitrogen atmosphere, with K2C03 (0.45 g, 3.3 mmol, 1.5 equivalent), benzyl 5-bromovalerate (0.88 g, 3.3 mmol, 1.5 equivalent), and a catalytic amount of tetraiodide iodide. n-butylammonium (2 mg), and the resulting solution is stirred at a temperature of 65 ° C for 24 hours. The pale amber-colored slurry is cooled to 25 ° C and concentrated in vacuo to provide a yellow residue. Purification by flash chromatography (2.4 x 30 cm silica, 20-40% EtOAc / hexane) produces the intermediate of the ester (1.2 g, 86%) as a colorless oil: 1 H NMR (CDCL3) d 0.91 (m , 6H), 1.11-1.47 (br m, 10H), 1.64 (m, 1H), 1.86 (m, 2H), 2.21 (m, 1H), 2.47 (m, 2H), 2.81 (s, 6H), 3.05 (ABq, J = 15.1 Hz, J = 47.7 Hz, 2H), 4.10 (d, J = 7.9 Hz, 1H), 5.13 (s, 2H), 5.47 (s, 1H), 6.00 (d, J = 2.5 Hz , 1H), 6.50 (dd, J = 8.9, 2.5 Hz, 1H), 6.91 (d, J = 8.7 Hz, 2H), 7.36 (m, 5H), 7.40 (d, J = 8.5 Hz, 2H) 7.86 ( d, J = 8.9 Hz, 1H) HRMS Calculated for C38H51N06S: 650.3046 Found: 560.3043.

Step 2: Preparation of the acid A solution of the ester intermediate (0.99 g, 1.5 mmol, obtained from Step 1) in ethanol (7.5 mL) at 25 ° C, with 5% palladium on carbon (0.15 g, 10%) is treated. in weigh), then it is stirred under a hydrogen atmosphere via a hydrogen balloon. Hydrogen gas is bubbled every 10 minutes through the slurry for one minute, for a total reaction time of 4 hours. The slurry is placed under a nitrogen atmosphere and this is bubbled through the reaction mixture for 10 minutes. The mixture is filtered through a Celite filter (10 g) and concentrated in vacuo to provide a white foam. Purification by flash chromatography (2.6 x 25 cm of silica, 5% EtOH / CH2Cl2) to yield the desired title compound (0.54 g, 63%) as a white foam: mp: 76-79 ° C; XH NMR (CDCL3) d 0.90 (m, 6H), 1.10-1.46 (br m, 10H), 1.62 (m, 1H), 1.87 (m, 4H), 2.20 (m, 1H), 2.45 (m, 2H) , 2.81 (s, 6H), 3.05 (ABq, J = 15.1 Hz, J = 49.7 Hz, 2H), 4.00 (s, 2H), 4.09 (s, 1H), 5.45 (s, 1H) 5.99 (d, J = 2.4 Hz, 1H), 6.48 (dd, J = 8.9, 2.4 Hz, 1H), 6.91 (d, J = 8.7 Hz, 2H), 7.39 (m, 5H), 7.39 (d, J = 8.3 Hz, 2H 7.84 (d, J = 8.9 Hz, 1H). HRMS. Calculated for C3? H45N06S: 560.3046. It is located: 560.3043.

Example 1405 (4R-c? S) -4- [4- [3, 3-Dibutyl-7- (dimethylamino) -2,3,4,5-tetrahydro-4-hydroxy-l, l-dioxide-l-benzothiepin- 5-yl] phenoxy-1-butanesulfonamide Step 1: Preparation of the sulfonic acid intermediate. A solution of 7.4 g (16.1 mmol) of 5- (4'-hydroxyphenyl) -7- (dimethylamino) tetrahydrobenzothiepin-1,1-dioxide (obtained from Example 1402, Step 10) is treated. ) in acetone (35 mL) at 25 ° C under nitrogen, with powdered potassium carbonate (3.3 g, 24.1 mmol, 1.5 equiv.) and 1,4-butane sultone (2.5 mL, 24.1 mmol, 1.5 equiv.) and stir and warm at 65 ° C for 64 ° C. The solution is allowed to cool to 25 ° C and is quenched by the addition of water (50 mL), until a homogeneous mixture is obtained. The clear, colorless solution is added dropwise to a cooled solution of 4N HCl at 0 ° C for a period of 30 minutes. The vigorous mix for 4 hours and then allow to warm to room temperature and stir for an additional 16 hours. The resulting white precipitate is filtered and washed with water and dried under vacuum to provide 8.8 g (92%) of the desired sulfonic acid as a white solid. A portion of the white solid is recrystallized from CH3CN / Hexane to provide the desired sulfonic acid as colorless needles: mp: 229-236 ° C (decomposed); XH NMR (CDCL3) d 0.82 (m, 6H), 1.02-1.33 (br m, 10H), 1.59 (m, 1H), 1.73 (m, 4H), 2.00 (s, 1H), 2.48 (m, 2H) , 2.71 (s, 6H), 2.98 (s, 1H), 3. 86 (s, 1H), 3.86 (s, 1H) 3.93 (m, 2H), 5.08 (s, 1H), 5.89 (s, 1H), 6.52 (dd, J = 8.9, 2.4 Hz, 1H), 6.92 (d, J = 8.3 Hz, 2H), 7.29 (d, J = 8.1 Hz, 2H), 7.60 (d, J = 8.9 Hz, 1H), Analysis Calculated for C3.H4_N07S2: C 60.48; H, 7.61; N, 2.35. is found: C, 60.53; H, 7.70; N, 2.42.

Step 2: Preparation of 7- (dimethylamino) -oenzot? Epm-5-yl] phenoxy-1-butanesulfonamide It is added to a solution of 1.12 g (1.88 mmol) of sulfonic acid (obtained from Step 1) in 10 mL of CH2CL2, 785 mg (3.77 mmol) of PCL5 and stirred for one hour. Water is added and the mixture is extracted and washed with brine. It dries with MgSO., Filtered and the solvent evaporated. It is added to L residue of 0.5M NH3 in dioxane and stirred for 16 hours. The precipitate is filtered and the solvent is evaporated. The residue is purified by MPLC (33% EtOAc in hexane) to give the desired title compound as a beige solid (125 mg, 11%): mp: 108-110 ° C; XH NMR (CDCL3) d 0.85-0.93 (m, 6H), 1.13-1.59 (m, 10H), 1.60-1.67 (m, 1H), 1.94-2.20 (, 5H), 2.82 (s, 6H), 2.99 ( d, J = 15.3 Hz, 1H), 3.15 (t, J = 15.3 Hz, 1H), 3.23 (t, J = 7.7 Hz, 2H), 4.03 (t, J = 5.8 Hz, 2H), 4.08-4.10 ( m, 1H), 4.79 (s, 3H), 5.47 (s, 1H), 6.02 (d, J = 2.4 Hz, 1H), 6.52 (dd, J = 8.9, 2.6 Hz, 1H), 6.91 (d, J = 8.9 Hz, 2H), 7.41 (d, J = 8.5 Hz, 2H), 7.89 (d, J = 8.9 Hz, 1H) .HRMS. Calculated for C3oH47N02S6: 595.2876. is found: 595.2874.

Example 1406 (4R-cis) -1- [3- [4- [3, 3-Dibutyl-7- (dimethylamino) -2, 3, 4, 5-tetrahydro-4-hydroxy-1,1-dioxide-l-benzothiepin -5-yl] phenoxy] propyl] -4-aza-l-azoniabicyclo [2.2.2] octane, methanesulfonate (salt) Step 1: Preparation of the dimesylate intermediate To a cooled solution (-20 ° C) of 5.0 g (65.7 mmoles) of 1,3-propanediol in 50 ml of triethylamine and 200 ml of methylene chloride is added 15.8 g (137.9 mmoles) of methanesulfonyl chloride. The mixture is stirred for 30 minutes, then warmed to room temperature and partitioned between ethyl acetate and IN HCl. the organic layer is dried with water, dried over Mg30, and concentrated -? .-1 tt _. I I? Dimesylate as a light yellowish oil: NMR XH (CDCI3) d 2.12 (quintet, J = 4.5 Hz, 4H), 3.58 (s, 6H), 4.38 (t, J = 5.4 Hz).

Step 2: Preparation of the propyl mesylate intermediate To a solution of 2.4 g (5.2 mmol) of 5- (4'-hydroxyphenyl) -7- (dimethylamino) tetrahydrobenzothiepin-1, 1-dioxide (obtained from Example 1402, Step 10) and 6.0 g (26.1 mmol) of the compound dimesylate intermediate (obtained in step 1) in 50 ml of acetone is added 3.6 g (26.1 mmoles) of K2C03. The reaction is heated to reflux all the uc? ucy c cuma a uc c j. a? _ u_ d CUIU ICII L C c? ul? c ?? ? The residue is partitioned between ethyl acetate water. The organic layer is washed with brine, dried over MgSO4, and concentrated in vacuo. Purification by silica gel chromatography (Waters-Prep 500) using 36% ethyl acetate / hexanes afforded 2.8 g (90%) of the intermediate propyium mesylate as a white foam: H-NMR (CDC13) d 0.86- 0. 95 (m, 6H), 1.06-1.52 (m, 10H), 1.57-1.70 (m, 1H), 2.14-2.32 (m, 3H), 2.84 (s, SH), 3.02 (s, 3H), 3.08 ( AB,?, «15.0 Hz, J - 46.9 Hz, 4.09-4.18 (m, 3H), 4.48 (t, J, 6.0 HZ, 2H), 5.49 (s, 1H), 6.11 (s, 1H), 6.65 ( d, J «8.7 Hz, 1H), 6.94 (d, J - 8.6 Hz, 2H), 7.43 (d, J - 8.5 HZ, 2H), 7.94 (d, J« 8.9 Hz, 1H).

Step 3: Preparation of quaternary salt To a solution of 1.2 g (2.0 mmol) of the propyl mesylate intermediate (obtained from Step 2) in 20 ml of acetonitrile is added 0.3 g (2.9 mmol) of 1,4-diazabicyclo [2.2.2] octane (DABCO) ). The reaction mixture is stirred at 60 ° C for three hours, then cooled to room temperature and concentrated in vacuo. __IGL ^ uixii.a? ivu? - uii V _.- L.W_ u o v-l? r rp.etile or ethyl ether gave 1.3 Q '91% ^ of the desired title compound as a white solid: m.p. (dec.) 230-235 ° C; 1 ^ NMR (CDCl,) d 0.86-0.95 (m, 6H), 1.04-1.52 (m, 10H), 1.57-1.70 (m, 1H), 2.12-2.25 (m, 3H), 2.28-2.39 (, 2H) ), 2.83 (s, 6H), 3.04 (s, 3H), 3.09 (AB, M - 15.6 Hz, J - 42.2 Hz, 2H) 3.22-3.32 (m, 6H), 3.56-3.66 (m, 6H) , 3.73-3.83 (m, 2H), 4.06-4.17 9m, 3H), 5.47 (s, 1H), 5.97 (s, 1H), 6.51 (d, J - 8.6 Hz, 1H), 6.90 (d, J - 8.6 Hz, 2H), 7.41 (d, J - 8.7 Hz, 2H), 7.89 (d, J -8.9 Hz, 1H). MS (ES +) m / e 612.4. HRMS (ES +) Cale. For C "H54Nj04S *: 612.3835. Encont .: 612.3840.

Example 1407 (4R-cis) -1- [3- [4- [3, 3-Dibutyl-7- (dimethylamino) -2, 3, 4, 5-tetrahydro-4-hydroxy-l, l-dioxide-l- benzothiepin-5-yl] phenoxy] propyl] -4-aza-i-azoniabicyclo [2.2.2] octane, 4-? neiibencensution (salt) Step 1: Preparation of the propyl tosylate intermediate To a solution of 5- (4'-hydroxyphenyl) -7-20 (dimethylamino) tetrahydrobenzothiepin-1,1-dioxide (5.0 g, 10.9 mmol), obtained from Example 1402, Step 10) in acetone (100 ml) at 25 ° C. ° C under N2 is treated with K2C03 (3.8 g, 27.2 mmol, 2.5 equivalents) and di-p-tosylate of 1,3-propanediol (13.0 g, 32.6 rranoles, 3.0 equivalents), and the * _.D • * ? _- A a _ C _. C ° / "• _ O í i.? L?? A. _ _ I- • T ua _ j. »a» < iwa «a».-._ > - ^ ¡¡ . "To» Sa £ »., Jafafe., J .., ^ J ^» «^ - ^» Jsc ^ JgS ^? S ^^, J --Ja? _. »A'_S .-« J- j »» ^^ fe ... "a b, ^. .--». - < ___.

Cream colored suspension was cooled to 25 ° C and filtered through a sintered glass funnel. The filtrate was concentrated and the residue was dissolved in EtOAc (150 mL). The organic layer is washed with saturated aqueous NaHCO3 (2 x 150 ml) and saturated aqueous NaCl (2 x 150 ml), and dried (MgSO4) and concentrated in vacuo to give a faint orange oil. Purification by chromatography Xu S uií ii - / produced the propyl tosylate intermediate (6.0 g, 80%) as a white foam: NMR XH (CDC1,) d 0.91 (m, 6H), 1.11-1.47 (m a, 10H), 1.63 (m, 1H), 2.14 (m, 2H), 2.21 (m, 1H), 2.41 (s, 3H), 2.81 (s, 6H), 3.06 (ABq, J- 15.1 Hz, J - 49.0 Hz, 2H) , 4.01 (t, J - 5.3 Hz, 2H), 4.10 (m, 1H), 4.26 (t, J - 5.9 Hz, 2H), 5.29 (s, 1H), 5.48 (s, 1H), 5.98 (s, 1H), 6.51 (dd, J - 8.9, 1.8 Hz, 1H), 6.83 (d, J «8.4 Hz, 2H), 7.30 (d, J - 8.1 Hz, 2H), 7.39 (d, J - 8.3 Hz, 2H), 7.78 (d, J - 8.3 Hz, 2H), 7.88 (d, J - 8.9 Hz, 1H).

Step 2: Preparation of quaternary salt A solution of the propyl tosylate intermediate (1.05 g, 1.56 mmol, obtained from Step 1) in acetonitrile (15 ml) at 25 ° C under N2 is treated with diazabicyclo [2.2.2] octane (DABCO, 0.26 g, 2.34 mmoles, 1.5 eq.) and stirred at 50 ° C for 6 hours, then at 25 ° C for 14 hours. The dim amber solution is cooled to 25 ° C and concentrated in vacuo in a minimum amount of CH2C12 (5 ml) and diluted with Et20 (100 ml) while stirring vigorously for 4 hours, during which time a solid white. The white solid was collected (washed with Et20) to give the desired title compound (1.11 g, 90%) as a white amorphous solid: m.p. 136. 5-142 ßC (decomposing); RM! .1 !! (CDClj) d 0.89 (m, 6H), 1.12-1.43 (m, 9H), 1.61 (m, 1H), 1.65 (m, 1H), 2.18 (m, 1H), 2.22 (m, 2H), 2.27 ( s, 3H), 2.78 (s, 6H), 3.07 (ABq, J «15.1 Hz, J - 39.5 Hz, 2H), 3.49 (sa, 6H), 3.68 (m, 1H), 3.74 (sa, 6H), 3.96 (sa, 2H), 4.09 (d, J »7.3 Hz, 1H), 5.46 (s, 1H), 5.96 (d, J« 2.4 Hz, 1H), 6.49 (dd, J - 8.9, 2.4 Hz, 1H ), 6.83 (d, J «8.5 Hz, 2H), 7.11 (d, J - 8.1 Hz, 2H), 7.40 (d, J -8.3 Hz, 2H), 7.74 (d, J« 8.1 Hz, 2H), 7.87 (d, J - 8.9 Hz, 1H); HRMS. Cale, for CJJH ^ NJO ^ S: 612.3835. Encont .: 612.3832.

Example 1408 (4R-cis) -1- [4- [4- [3, 3-Dibutyl-7- (dimethylamino) -2,4,5,5-tetrahydro-4-hydroxy-1,1-dioxide-1-benzothiepin -5-yl] phenoxy] but? L] -4-aza-l-azoniabicicio [2.2.2] octanmetansuifonato (sai) Step 1: Preparation of the butyl mesylate intermediate A mixture of 1.00 g (2.18 mmoles) of 5- (4'-hydroxyphenyl) -7- (dimethylamino) tetrahydrobenzothiepin-1,1-dioxide (obtained from Example 1402, Step 10), 2.68 g (10.88 mmoles) of busulfan, and 1.50 g (10.88 mmol) of potassium carbonate in 20 ml of acetone is stirred at reflux overnight. The mixture is concentrated i vacuo and the crude product or -i * i Q 1 TG? C1 * 3? tp-1 I? _ ^ O ^ "? +" ^ ^ __ or í 1 ft Insoluble is removed by filtration and concentrated in vacuo. The resulting white foam is chromatographed through a column of silica gel, and eluted with 30% ethyl acetate / hexane to give 1.02 g (77%) of the butyl mesylate intermediate as a white solid: rur (J _ ± 3> u-su? i, on; _- (m, 12H), 1.98 (m, 4H), 2.22 (m, 1H), 2.83 (s, 6H), 3.04 (s, 3H), 3.08 (ABq, 2H), 4.05 (t, J - 5.55 Hz, 2H), 4.11 (d, J - 6.90 Hz, 1H), 4.35 (t, J - 6.0 Hz, 2H), 5.49 (s, 1H), 6.00 (d, J- 2.4 Hz, 1H), 6.52 (dd, J- 9.0 Hz, 2.7 Hz, 1H), 6.93 (d, J- 9.0 Hz, 2H), 7.42 (d, J - 8.4 Hz, 2H), 7.90 (d, J • 9.0 Hz, 1H).

Step 2: Preparation of the ester intermediate To a solution of 520 mg (0.85 mmol) of the butyl mesylate intermediate (obtained from Step i) and 191 mg (1.71 mmol) of DABCO in 10 ml of acetonitrile is stirred at 80 ° C for 4 hours. The reaction mixture is concentrated vacuo to a white foam. The foam is triturated and washed with ether. The solid phase is removed by filtration and dried in vacuo to give 540 mg (88%) of the desired title compound which was recrystallized from methylene chloride and acetone as a white solid: mp 248-251 ßC; "MN XH (CDCl,) d 0.91 (m, 6H), 1.14-1.47 (m, 14H), 1.63 (m, 1H) 1.96 (m, 4H), 2.21 (m, 1H), 2.77 (s, 3H) , 2.82 (s, 3H), * 3.07 (ABq, 2H), 3.26 (t, J - 7.1 Hz, 6H), 3.60 (m, 8H), 4.08 (m, 3H), 5.47 (s, 1H), 5.99 (d, J - 2.4 Hz, 1H), 6.51 (dd, J - 8.9 Hz, 2.6 Hz, 1H), 6.91 (d, J - 8.7 Hz, 2H), 7.41 (d, J - 8.1 Hz, 2H), 7.89 (d, J-9.0 Hz, 1H).

Example 1409 (4R-cis) -1- [4- [4- [3, 3-Dibutyl-7- (dimethylamino) -2,3,4,5-tetrahydro-4-hydroxy-1,1-dioxide-1-benzothiepin -5-yl] phenoxy] butyl] -4-aza-l-azoniabicyclo [2.2.2] octane-4-methylbenzenesulfonate (salt) Step 1: Preparation of the propyl tosylate intermediate To a solution of 5- (4'-hydroxyphenyl) -7- (dimethylamino) tetrahydrobenzothiepin-1,1-dioxide (5.0 g, 10.9 mmol), obtained from Example 1402, Step 10) in acetone (100 ml) at 25 ° C. C under N2 is treated with K2C03 (3.8 g, 27.2 mmol, 2.5 equivalents) and di-p-tosiiate of 1,4-butanediol (13.0 g, 32.6 mmol, 3.0 equivalents), and the slurry mixture was agi O to UU S? L ¿._. noras The cream-colored suspension was cooled to 25 ° C and filtered through a sintered glass funnel. The filtrate was concentrated and the residue was dissolved in EtOAc (150 mL). The organic layer is washed with saturated aqueous NaHCO3 (2 x 150 ml) and saturated aqueous NaCl (2 x 150 ml). The extract is dried (MgSO4) and concentrated in vacuo to give a faint orange oil. The purification by *, _. i a c CJSJ __ a ±. __ a _u d? i Lauca \ _ • _? ^ j ^, iu -L J- L ^ C, _. u .3 or uc rin n. & r, h ... D. .a-n..n l, ol -? - ml.-nt-n% -o_s .. n - i n..t.- orm.oH - i_n.- H-o- propyl tosylate (6.0 g, 80%) as a white foam : XH NMR (CDC13) d 0.89 (m, 6H), 1.10-1.44 (ma, 10H), 1.61 (ra, 1H), 1.84 (m, 4H), 2.19 (m, 1H), 2.43 (s, 3H), 2.80 (s, 6H), 3.03 (ABq, J- 15.1 Hz, J - 46.3 Hz, 2H), 3.93 (m, 2H), 4.06-4.13 (m, 4H), 5.44 (s, 1H), 5.96 (s, 1H). 6.46 (dd, J «8.9, 1.4 Hz, 1H), 6.85 (d, J - 8.1 Hz, 2H), 7.33 (d, J - 8.1 Hz, 2H), 7.38 (d, J -8.1 Hz, 2H), 7.78 (d, J- 8.9 Hz, 2H), 7.83 (m, 1H).

Step 2: Preparation of quaternary salt A solution of the propyl tosylate intermediate (5.8 g, 8.5 mmol, obtained from Step 1) in acetonitrile (100 ml) at 25 ° C under N2 is treated with diazabicyclo [2.2.2] octane (DABCO, 1.1 g, 10.1 mmoles, 1.2 eq.) and stirred at 45 ° C for 6 hours. The faint yellow solution is cooled to 25 ° C and concentrated in vacuo to provide a colorless socle or cobalt. The residue is dissolved in a minimum amount of CH2C12 (5 ml) and diluted with Et20 (100 ml) while stirring vigorously for 3 hours, during which time a white solid precipitated. The white solid was collected and recrystallized from EtOAc / hexane to give the desired title compound (5.7 g, 85%) as colorless needles: m.p. 223-231 ßC (decomp.); XH NMR (CDCl,) d 0.86 (m, 6H), 1.09-1.43 (m, 12H), 1.61-1.90 (m, 5H), 2.13 (m, 1H), 2.25 (s, 3H), 2.75 (s, 6H), 3.03 (ABq, J - 15.1 Hz, J - 30.0 Hz, 2H), 3.05 (sa, 6H), 3.37 (sa, 6H), 3.89 (m, 2H), 4.07 (d, J »7.5 Hz, 1H), 5.39 (s, 2H), 5.97 (d, J «1.6 Hz, 1H), 6.44 (dd, J - 8.9, 2.0 Hz, 1H), 6.87 (d, J - 8.3 HZ, 2H), 7.08 ( d, J "8.1 Hz, 2H), 7.37 (d, J- 8.3 Hz, 2H), 7.71 (d, J-8.1 Hz, 2H), 7.80 (d, J" 8.9 Hz, 1H); HRMS. Cale, for C, .HSéN, 0 «S: 626.3992. Jan: 626.3994. Anal. Cale, for CoH ^ NjCS,: C, 64.71; H, 7.96; N, 5.27. Jan: C, 64.36; H, 8.10; N, 5.32.

Example 1410 (4R-cis) -1- [4- [4- [3, 3-Dibutyl-7- (dimethylamino) -2,3,4,5-tetrahydro-4-hydroxy-1, 1-dioxide-1-benzothiepin -5-yl] phenoxy] -N, N, N-triethyl-l-butanaminium A solution of 1 g (1.64 mmol) of the butyl mesylate intermediate (obtained from Example 1408, Step 1) and 15 ml of triethylamine in 10 ml of acetonitrile is heated at 50 ° C for 2 days. The solvent is evaporated and the residue is triturated with ether and ethyl acetate to give 500 mg (43%) of the product as a QH? M lu / fT * - '-! \ K? O / rr. £ U \ t -I C r ,. fu.- ni \. ^ s-.x3 / O \ j. CJ Vlu. O c i, x • O V "1, -. ' - &3tgr * - j- - -_. > ._a && amp; amp; faith 24 H), 2.1 (m, 1 H), 2. 6 (s, 3 H), 2.7 (s, 6 H), 2.9 (d, J - 15 Hz, 1 H), 3.0 (d, J - 15 Hz, 1 H), 3.3 (m, 8 H), 4.0 (m, 4 H), 5.3 (s, 1 H), 5.9 (s, 1 H), 6.4 (m, 1 H), 6.8 (d, J, 9 Hz, 2 H), 7.4 (d, J) - 9 Hz, 2 H), 7.8 (d, J - 7 Hz, 1 H). MS m / e 615.

Example 1411 (4R-cis) -l- [4- [4- [3,3-Dibutyl-7- (dimethylamino) -2,3,4,5-tetrahydro-4-hydroxy-1,1-dioxide-1-benzothiepin -5-yl] phenoxy] butyl] -3-hydroxypyridinium, methanesulfonate (salt) A solution of I g (1.64 mmol) of the intermediate butyl mesylate intermediate (obtained from Example 1408, Step 1) and 234 g (2.46 m cles) of the 3-hydroxy pyridine in 1 ml of dimethylformamide is heated at 70 ° C for 20 hours. The solvent evaporates and the residue .i ^ A - Z a ^ _. ty ~ z j f - ^ triturate with ether and ethyl acetate to give 990 mg (86% of the product as an isolide: XH NMR (CDC13) d 0. 9 (, 6 H), 1-1.5 (m, 10 H), 1.7 (m, 1 H), 1.9 (m, 2 H), 2-2.4 (m, 3 H), 2.9 (s, 6 H) , 3.1 (d, J - 15 Hz, 1 H), 3.2 (d, J - 15 Hz, 1 H), 4.1 (m, 3 H), 4.7 (m, 2 H), 5.5 (s, 1 H) , 6.1 (s, 1 H), 6.6 (m, 1 H), 6.9 (d, J - 9 Hz, 2 H), 7.4 (d, J - 9 Hz, 2 H), 7.7 (m, 1 H) , 8.0 (m, 2 H), 8.2 (m, l H), 9.1 (s, 1 H). MS m / e 609.

Example 1412 (4R-cis) -l- [5- [4- [3,3-Dibutyl-7- (dimethylamino) -2,3,4,5-tetrahydro-4-hydroxy-l, l-dioxide-l-benzothiepin -5-yl] phenoxy] pentyl] quinolmium, methanesulfonate (salt) Step 1: Preparation of the pentyl mesylate intermediate compound To a stirred solution of 231 mg (5.79 mmol, 60% disp.) Of NaH in 22 ml of DMF is added 2.05 g (4.45 mmol) of 5- (4 '-hydroxyphenyl) -7- (dimethylamino) -tetrahydrobenzothiepin-1. , 1-dioxide (obtained from Example 4H2, Step 10), and the resulting solution is stirred at room temperature for 1 hour. To the mixture is added 18.02 g (55.63 mol) of 1,5-diiodopentane and the solution is stirred overnight at room temperature. The DMF is removed by high vacuum and the residue is extracted with ethyl acetate and washed with brine. The extract is dried over MgSO4, and the concentrated residue is purified by column chromatography to give the compound pterium mesylate mesylate: XH NMR (CDC13) d 0. 90 (c, 6H), 1.05-2.0 (m, 17H), 2.2 (t, 1H), 2.8 (s, 6), 3.0 (c, 2H), 3.22 (t, 2H), 3.95 (t, 2H) , 4.1 (s, 1H), 5.42 (s, 1H), 6.1 (d, 1H), 6. 6 (d, 1H), 6.9 (d, 2H), 7.4 (d, 2H), 7.9 (d, 1H).

Step 2: Preparation of quaternary salt To 1.0 g (1.53 mmoles) of the pentyl mesylate intermediate compound (obtained from Step 1) are added 3.94 g (30.5 mmoies) of quinoxy and 30 ml of acetonitrile. The solution is heated at 45 ° C under N2 for 10 days. He 1. CO XUU id cíl C18 reversed phase column. The material obtained is exchanged with its mesylate anion by ion exchange chromatography to give the desired title compound as a solid m.p. 136 UC; NMR: H (CDC13) d 0-95 (c, 6H), 1.05- 2. 25 (m, 18H), 2.8 (s, 9H), 3.0 (c, 2H), 3.95 (t, 2H). 4.1 (s, 1H), 5.28 (t, 2H), 5.42 (s, 1H), 5.95 (s, 1H), 6.45 (d, 1H), 6.82 (d, 2H), 7.4 (d, 2H), 7.82 (d, 1H), 7.9 (t, 1H), 8.2 (t, 2H), 8.3 (c, 2H), 8.98 (d, 1H), 10.2 (d, 1H). HRMS. Cale, for C4ßH $, N, 0, S: 657.3726. Jan: 657.3736. Anal. Cale, for C "H $ JN20, S. CH, 0, S: C, 65.40; H, 7.50; N, 3.72; S, 8.52. Jan: C, 62.9; H, 7.42; N, 3.56; S, 8.41.

Example 1413 Acid (4R-cis) -1- [5- [4- [3, 3-Dibutyl-7- (dimethylamino) 2,3,4,5-tetrahydro-4-hydroxy-l, l-dioxide-l-benzothiepin -5- il] phenoxy] pentyl] propandiole Step 1: Preparation of the pentyl bromide intermediate To a stirred solution of 0.63 g (15.72 mmol, 5 60% disp.) Of NaH in 85 ml of DMF is added 6.0 g (13.1 mmol) of 5- (4'-hydroxyphenyl) -7- (dimethylamino) -tetrahydrobenzothiepin- 1,1-dioxide (obtained from Example 1402, Step 10), and the resulting solution is stirred at room temperature for 1 hour. To the solution is it lu y j.cya ?? «, • and \ J. O3. i > uuu ^ / uc, ^ "Jx_ * x IU? ^ C: I1 uu, and xd mixture is stirred overnight at room temperature. The DMF is removed in vacuo and the residue is extracted with ethyl acetate and washed with brine. The extract is dried over MgSO4, and the concentrated residue is purified by column chromatography to give the intermediate compound of pentium bromide: XH NMR (CDCl3) d 0.90 (e 6H), 1.05-2.0 (m, 17H), 2.2 (t, 1H), 2.8 (s, 6H), 3.0 (c, 2H), 3.4 (t, 2H), 3.95 (t, 2H), 4.1 (s, 1H), 5.42 (s, 1H), 6.0 (s, 1H), 6.5 (d, 1H), 6.9 (d, 2H), 7.4 (d, 2H), 7.9 (d, 1H). 0 Step 2: Preparation of dibenzyl ester intermediate ." 1 . «A &aa_tt_o. _ ~ t j * x6KÍS¡P.

To the mixture of 59 mg (1476 mmoles, 60% disp.) Of NaH in 27 ml of THF and 9 ml of DMF at 0 ° C are added 0.84 g (2,952 mmoles) of dibenzyl malonate (Aldrich), and the solution The resulting mixture is stirred at room temperature for 15 minutes. To the solution add 0.5987 g (0.984 mmol) of the pentyl bromide intermediate, and the mixture is stirred at 80 ° C overnight. The solvent is removed in vacuo, and the residue is extracted with methylene chloride and washed with brine. The extract is dried over MgSO4, and the concentrated residue is purified by column chromatography to give the dibenzyl ester intermediate: 1NMR (CDCl,) d 0.90 (c, 6H), 1.05-2.0 (m, 19H), 2.2 (t, 1H), 2.8 (S, 6H), 3.0 (c, 2H), 3.4 (t, 1H) , 3.9 (t, 2H), 4.1 (d, 1H), 5.18 (s, 4H), 5.42 (s, 1H), 5.95 (s, 1H), 6.5 (, 1H), 6.9 (d, 2H), 7.2-7.4 (m, 12H), 7.85 (d, 1H).

Step 3: Preparation of the diacid A suspension of 0.539 g (0.664 mmoles) of the dibenzyl ester intermediate compound (obtained from Step 2) and 25 mg of 10% Pd / C in 30 ml of ethanol is stirred at room temperature under 1.40 kg / cm2 (20 psi) of gas muiv ^ cii? filtration, and the filtrate is concentrated to give the desired title compound as a solid: m.p. 118 ° C; XH NMR (CDC13) d 0.9 (d, 6H), 1.05- 2. 2 (m, 20H), 2.8 (s, 6H), 3.0 (c, 2H), 3.4 (s, 1H), 3.95 (S, 2H), 4.1 (s, 1H), 5.42 (s, 1H), 5.95 (s, 1H), 6.5 (d, 1H), 6.9 (d, 2H), 7.4 (d, 2H), 7.85 (d, 1H). HRMS. Cale, for C ^ H ^ O.S: 632.3257. Jan: 632.3264. Anal. Cale, for C, 4H "O, S: C, 64.63; H, 7.82; N, 2.22; S, 5.08. Jan: C, 63.82; H, 7.89; N, 2.14; S, 4.93.

Example 1414 1,1- (4R-cis) -3,3-Dibutyl-5- [4- [[5- (diethylamino) pentyl] oxy] phenyl] -7- (dimethylamino) -2,3,4,5-dioxide -tetrahydro-1-benzotiepm-4-ol jSitjfa _ * & .. » Step 1: Preparation of the pentyl iodide intermediate To a solution of 5- (4 '-hydroxyphenyl) -7- (dimethylamino) tetrahydrobenzothiepin-1,1-dioxide (3 g, 6.53 mmol, obtained from Example 1402, Step 10) in 100 ml of dimethylformamide is added 198 mg ( 7.83 mmoles) of 95% sodium hydride. The mixture is stirred 15 minutes at room temperature and diiodopentane is added. After one hour at room temperature the mixture is diluted in ethyl acetate and water. The aqueous layer is extracted with ethyl acetate and the combined organic layer is washed with brine, dried over magnesium sulfate and concentrated in vacuo. The residue is subjected to chromatography on silica gel, eluting with hexane / ethyl acetate (i / 5) to give 2.92 g (4.46 mmoies) of the penyl iodide intermediate: H-NMR (CDCl 3) d 0.9 (m, 6 H), 1-1.5 (m, 11 H), 1.6 (m, 3 H), 1.8 (m, 4 H), 2.2 (m, 1 H), 2.8 (s, 6 H) , 3.0 (d, J - 15 Hz, 1 H), 3.2 (d, J - 15 Hz, 1 H), 3.3 (m, 2 H), 4.0 (m, 1 H), 4.1 (s, 1 H), 5.5 (s, 1 H), 6.1 (s, 1 H), 6.6 (m, 1 H), 6.9 (d, J - 9 Hz, 2 H), 7.4 ( d, J - 9 Hz, 2 H), 7.9 (d, J, 7 Hz, 1 H).

Step 2: Preparation of the amine A solution of 550 mg (0.76 mmol) of the pentyl iodide intermediate compound (obtained from Step 1) and 279 mg (3.81 mmol) of diethylamine in 3 ml of acetonitrile is stirred at 100 ° C overnight. The mixture is concentrated in vacuo to give a yellowish brown foam. The foam is dissolved in 10 μl of ethyl acetate and washed with 50 ml of a saturated sodium carbonate solution twice. The ethyl acetate layer is dried over magnesium sulfate and concentrated to give 390 mg (85%) of the desired title compound as a yellow foamy solid: XH NMR (CDC13) d 0.89 (m, 6H), 1.20-1.47 (m, 12H), 1.53-1.67 (m, 4H), 1.76-1.90 (m, 8H), 2.21 (m, 1H), 2.74-2.92 (m, 12H), 3.07 (ABq, 2H), 4.00 (t, J = 6.3 Hz, 2H), 4.10 (d, J = 7.8 Hz, 1H), 5.48 (s, 1H), 6.00 (d, J «2.4 Hz, 1H), 6.51 (dd, J = 9.2 Hz, 2. 6 Hz , 1H), 6.92 (d, J - 8.7 Hz, 2H), 7.41 (d, J, 8.4 Hz, 2H), 7.90 (d, J «9.0 Hz, 1H). ^^ a ^^ s «-fe« ^ i & ife? ^^^ ^ Example 1415 (4R-cis) -N- (Carboxymethyl) -N-15- [4- [3, 3-dibutyl-7- (dimethylamino) -2, 3, 4, 5-tetrahydro-4-hydroxy-1, 1- dioxide-l-benzothiepin-5-yl] phenoxy] pentyl] glycine Step: Preparation of the diester intermediate A mixture of 8.6 g (14.1 mmol) of the pentylbromide intermediate compound (obtained from Example 1413, Step 1), 65 g (0.35 mole) of diethylaminodiacetate and 7.5 g (71 min) of anhydrous Na 2 CO 3 is stirred at 160 ° C. during 3 hours. The reaction mixture is diluted with water and extracted with methylene chloride. The volatiles are removed in vacuo to give 9.6 g (95%) of the diester intermediate. The 1 H NMR spectrum was consistent with the structure; MS (M + H) m / e 717.

Step 2: Preparation of the diacid The mixture of the diester intermediate (obtained from Step 1) and 2.7 g (64.3 mmoles) of LiOH in THF (75 ml) and water (50 ml) is stirred at 40 ° C for 18 hours. The reaction mixture is acidified with 1% HCl and extracted with dichloromethane. The residue is triturated with hexane, filtered to give 8.9 g (93%) of the desired title compound as a solid: m.p. 148-162 ° C; 1H NMR (CD, OD) d 0.92 (t, 6H), 1.1-1.9 (m, 31H), 2.15 (t, lH), 2.8 (e, 6H), 3.15 (ABq, 2H), 3.75 (m, 1H ), 4.1 (m, 6H), 5.3 (s, 1H), 6.1 (e, 1H), 6.6 (d, 1H), 7.0 (d, 2H), 7.4 (d, 2H), 7.8 (d, 1H); MS (M + H) m / e 661. Anal. Cale, for [C "HssNaO, S * 1.5H.O]: C, 61.11; H, 8.06; N, 4.07; S, 4.66. Jan: C, 61.00; H, 7.72; N.3.89; S, 4.47.

Example 1416 ^^ & ^ & 1,1-(4R-cis) -5- [4- [[5- [bis [2- (diethylamino) ethyl] amino] pentyl] oxy] phenyl] -3,3-dibutyl-7- (dimethylamino) dioxide ) -2, 3, 4, 5-tetrahydro-l-benzothiepin-4-ol A solution of 1 g of the pentyl iodide intermediate compound (1.53 mmol, obtained from Example 1414, Step 1) in N, N, N ', N' -tetraethyl diethylenetriamine is heated at 80 ° C for 4 hours. The mixture is dissolved in ethyl acetate and saturated NaHCO3. The organic layer is washed with brine, dried over magnesium sulfate, and concentrated i. i.i. r vra-sC / - * U..O? . t_x "l -i n. rís-r s a T a c f ra rf i pnoc rtn > rnnt- i ono? The residue is dried and concentrated in vacuo to give 840 mg (74%) of the compound in vacuo, dissolved in ethyl acetate and washed with saturated NaHC03. desired title as a thick oil lH NMR (CDC13) d 0.8 (m, or H), 1-1.6 (m, 28 H), 1.8 (m, 2 H), 2.1 (m, 1 H), 2.5 (m, 18 H), 2.7 (s, 6 H), 2.9 (d, J »15 Hz, 1 H), 3.1 (d, J - 15 Hz, 1 H), 3.9 (m, 2 H), 4.0 (m, 1 H), 4.1 (s, 1 H), 5.4 (s, 1 H), 6.0 (s, 1 H), 6.4 (m, 1 H), 6.9 ( d, J «9 Hz, 2 H), 7.4 id. J - 9 HZ, 2 H), 7.8 (d, J - 7 Hz, 1 H). MS (M + H) / e 743. ^^ á ^^^^ - ^^^^^^ j ^ j ^^^^^^^^ Example 1417 1,1- (4R-cis) -3,3-dibutyl-7- (dimethylamino) -2,3,4,5-tetrahydro-5- [4- [[5- [[2- (lH- imidazol-4-yl) ethyl] amino] pentyl] oxy] phenyl] -1-benzothiepin-4-ol A solution of 1 g of the pentyl iodide intermediate compound (1.53 mmoles, obtained from Example 1414, Step 1) and 3.4 g (30.6 mmoles) of histamine is heated at 50 ° C for 17 hours. The mixture is dissolved in ethyl acetate and saturated NaHCO 3. The organic layer is washed with brine, dried over magnesium sulfate, and concentrated in vacuo. The solid is dissolved with ether to give JU "g '60% ^ of the desired title compound as a semi-solid: XH NMR (CDC13) d 0.9 (m, 6 H), 1-1.7 (m, 14 H), 1.9 (m, 3 H), 2.0 (m, 2 H), 2.2 (m, 1 H), 2.8 (s, 6 H), 3.0 (m, 3 H), 3.2 (m, 2 H) , 4.0 (m, 2 H), 4.1 (m, 3 H), 5.5 (s, 1 H). 6.0 (s, 1 H), 6.5 (m, 1 H), 6.8 (s, 1 H), 6.9 (d, J-9 Hz, 2 H), 7.4 (m, 3 H), 7.9 (d, J-8 Hz, 1 H). MS (M + H) m / e 639.

Example 1418 (4R-cis) -N- [5- [4- [3, 3-dibutyl-7- (dimethylamino) -2, 3, 4, 5-tetrahydro-4-hydroxy-l, l-dioxide-1-dichloride -benzothiepin-5-yl] phenoxy] pentyl] -N'-ethyl-N, N, N ', N' -tetramethyl-1,2-etanediamine Step 1: Preparation of the pentyl bromide intermediate A mixture of 5- (4'-hydroxyphenyl) -7- (dimethylamino) tetrahydrobenzothiepin-1,1-dioxide (1680 g, 3. 66 moles, obtained from Example 1402, Step 10) and sodium hydride (0.250 g, 6.25 mmol) in 30 ml of DMF is stirred in a dry bottom 100 ml round bottom container under N2. To this solution is added 1,5-dibromopentane (6.0 ml / 44.0 mmol), and the resulting mixture is stirred for 18 hours. The reaction is diluted with brine (100 ml) and H20 (20 ml), and the mixture is extracted with EtOAc (3x50 ml). The organic layers are combined, dried (Mg304), filtered and concentrated i vacuo. Purification by filtration through silica gel eluting with 20% EtOAc / hexane and evaporation in vacuo gave the pentyl bromide intermediate as a white foamy solid (1783 g, 80%): LH NMR (CDC13) d 0. 84-0.95 (m, 6H), 1.02-1.56 (m, 10H), 1.58-1.70 (m, 3H), 1.78-2.03 (m, 4H), 2.15-2.24 (m, 1H), 2.77 (s, 1H) ), 2.80 (S, 6H), 3.05 (ABq, 2H), 3.42 (t, 2H), 3.98 (t, 2H), 4.10 (s, 1H), 5.47 (s, 1H), 5.99 (d, 1H) , 6.50 (dd, 1H), 6.91 (d, 2H), 7.40 (d, 2H), 7.88 (d, 1H).

Step 2: Preparation of mono-quaternary salt The mixture of the pentyl bromide intermediate compound (0.853 g, 1.40 mmol, obtained from Step 1), the N, N, N ', N' -tetramethylethylenediamine (1.0 ml / 6.62 mmol) in 30 ml of acetonitrile is stirred at 40 ° C. C. for 12 hours, and the reaction mixture is concentrated in vacuo to give a white discolored foamy solid (1.052 g). He The crude product was dissolved in acetonitrile (1.5 ml) and triturated with ethyl ether. The solvent is decanted to give a sticky solid. This trituration method was repeated twice, and the resulting sticky solid was concentrated in vacuo to give mono-quaternary sai as a colorless white foamy solid (0.951 g, 94%): XH NMR (CDClj) d 0.81 (t, 6H), 0.96-1.64 (m, 13H), 1.62-1.85 (m, 4H), 2.03-2.18 (m, 1H), 2.20 (s, 6H), 2.67 (t, 2H), 2.74 (s) , 6H), 2.98 (ABq, 2H), 3.30-3.42 (m, 1H), 3.38 (s, 6H), 3.60-3.75 (tn, 4H), 3.90 (t, 2H), 4.01 (s.1H), 5.37 (s, 1H), 5.92 (s, 1H), 6.41 (dd, 1H), 6.81 (d, 2H), 7.32 (d, H), 7.77 (d, 1H).

Step 3: Preparation of di-quaternary salt The mono-quaternary salt (0.933 g, 1.29 mmol, obtained from Step 2), iodoethane (0.300 mL / 3.75 mmol), and acetonitrile (30.0 mL) were combined in a 114.8 g Fischer Porter bottle (4 oz. ). The reaction vessel was purged with N2, sealed, equipped with a mechanical stirrer, and heated to 50 C. After 24 hours, the reaction mixture was cooled to room temperature. mn íOn l-? i n ira rii? na rs a 1"A SOl ^ sparkling yellow (1,166 g) .The solid dissolved in .J__ methylene chloride / acetonitrile and precipitated with ethyl ether. After cooling to 0 ° C overnight, the resulting solid was filtered, washed with ethyl ether and concentrated in vacuo to give the quaternary salt as a white colorless solid (1.046 g, 92%): 1p NMR (CD, OD) d 0.59 (t, 6H), 0.70-1.10 (m, 9H), 1.16 (t, 3H), 1.22-1.80 (m, 9H), 2.42 (s, 6H), 2.78 (d, 2H), 2.98 (s, 6H), 3.02 (s, 6H), 3.22-3.37 (m, 4H) ), 3.63-3.78 (m, 4H), 3.80 (s, 4H), 4.93 (s, 1H), 5.71 (s, 1H), 6.22 (dd, 1H), 6.61 (d, 2H), 7.02 (d, 2H), 7.40 (d, 1H).

Step 4: Preparation of quaternary dichloride salt The iodobromo salt (obtained from Step 3) was converted to its corresponding dichloride salt using a Biorad AG 2X8 resin and eluting with 70% H: 0 / acetonitrile to give the desired title compound as a white foamed solid (0.746 g , 84%): pf 193-197.0 ° C; 1H NMR (CD, OD) d 0.59 (t, J- 6.0 Hz, 6H), 0.70-1.12 (m, 9H), 1.16 (t, J- 6.6 Hz, 3H), 1.24-1.90 (ra, 9H), 2.50 (s, 6H), 2.78 (s, 2H), 3.08 (s, 6H), 3.11 (s, 6H), .24-3.50 (m, 4H), 3.68 (s, 2H), 3.81 (s, 2H) , 4.16 (s, H), 5.02 (s, 1H), 5.72 (s, 1H), 6.19 (d, J- 8.4 Hz, H), 6.61 (d, J - 8.1 Hz, 2H), 7.10 (d, J - 7.8 Hz, ^ '- * s a ^ t. .-. j ^ ^^^^^ ^ s.s ^ ¿! & ^^^ 2H), 7.46 (d, J-8.7 Hz, 1H). HRMS. Cale, for C "Hí, N, 04SCl: 708.4541. Jan: 708.4598.

Example 1419 [4R- [4a, 5a (4R *, 5R *)]] - N, N'-bis [5- [4- [3, 3-dibutyl-7- (dimethylamino) -2, 3, 4 dichloride, 5-tetrahydro-4-hydroxy-l, 1-dioxido-l-benzothiepin-5-yl] phenoxy] pentyl] -N, N, N ', N' -tetramethyl-1,6-hexanediamine The pentyl bromide intermediate compound (1,002 g, 1.64 mmol, obtained from Example 1418, Step 1) and N, N, N'-N '-tetramethyl-1,6-hexandiamine (O.lOOg, 0.580 mmol) in 5 ml of acetonitrile are placed in a 4-oz. (114.8 g) Fischer Porter bottle. The reaction vessel is purged with N2, sealed, equipped with a •? _ / 1; o¿- > u.umbre uc A < _ * ho as * the reaction mixture is cooled to temperature atmosphere and concentrated in vacuo to give a colorless white foamy solid (1141 g). The solid is dissolved in acetonitrile and precipitated with ethyl ether. After cooling to 0 ° C, the solvent is decanted to give a white, discolored, sticky solid. This method of preparation was repeated, and the resulting sticky solid was concentrated in vacuo to give the desired dibromide salt as a colorless white foamy solid (0.843 g, quantitative): XH NMR (CDC13) d 0.85 (m, 12H) , 1. 01-1.70 (m, 30H), 1.76-2.08 (m, 12H), 2.18 (t, J - 12.3 Hz, 2H), 2.79 (s, 12H), 3.03 (ABq, 4H), 3.35 (s, 12H) , 3.52 (sa, 6H), 3.72 (sa, 4H), 3.97 (sa, 4H), 4.08 (sa, 2H), 5.42 (s, 2H), 6.00 (s, 2H), 6.51 (d, J «9.0 Hz, 2H), 6.86 (d, J - 7.8 Hz, 4H), 7.38 (d, J - 7.8 Hz, 4H), 7.83 (d, J - 8.7 Hz, 2H).

The dibromide salt is converted to its corresponding dichloride salt using a Biorad AG 2X8 resin and eluting with 70% H20 / CH3CN to give the desired title compound as a white foamy solid (0.676 g, 86%): m.p. 178.0-182.0 • C; H-NMR (CDCl,) 0.80-0.90 (m, 12H), 1.01-1.70 (m, 30H), 1.75-2.06 (m, 12H), 2.16 (t, J-12.9 Hz, 2H), 2.79 (s, 12H) ), 3.03 (ABq, 4H). 3.33 (s, 12H), 3.49 (sa, 6H), 3.70 (sa, 4H), 3.96 (t, J- 5.4 Hz, 4H), 4.08 (s, 2H), 5.42 (s, 2H), 5.986 (s) , 1H), 5.993 (s, 1H), * 3-5fe ^: £ _ £. * 6. 49 (d, J - 9.0 Hz, 1H 6.50 (d, J - 9.0 Hz, 1H), 6.87 (d, J - 8.4 HZ, 4H). '* .3β (d, J - 8.1 Hz, 4H), 7.84 (d, J «8.7 Hz, 2 H) HRMS, Cale, for CMHMN304S: 614.4118. Jan: 614.4148.

Example 1420 1,1- (4R-cis) -3,3-dibutyl-7- (dimethylamino) -2, 3, 4, 5-tetrahydro-5- [4- [[5- (lH-tetrazole-5- ií) pentyl] oxy] phenyl] -1-benzotiepm-4-oi Step 1: Preparation of the pentyl bromide intermediate To a stirred suspension of 1.01 g (25.4 mmol, 60% oily dispersion) of sodium hydride in 150 ml of DMF are added 9.0 g (19.5 mmol) of 5- (4'- hydroxyphenyl) -7- (dimethylamino) tetrahydrobenzothiepin-1,1-dioxide (obtained from Example 1402, Step 10) in portions. After 30 minutes the reaction is cooled in a water bath (15 ° C) and 4.48 g (195 mmol) of 1,5-dibromopropane are added. The reaction is stirred at room temperature for 1.5 hours and quenched with 50 ml of saturated NH4C1. The reaction is diluted with ethyl acetate, washed with water, brine, dried over MgSO4, filtered and concentrated in vacuo. Purification by silica gel chromatography (Waters-Prep 500) using 25% ethyl acetate / hexanes afforded 10.17 g (85%) of the pentyl bromide intermediate as a colorless foam: m.p. 65-70 ° C; XH NMR (CDC13) d 0.84-0.98 (M, 6H), 1. 04-1.52 (m, 10H), 1.58-1.65 (m, 3H), 1.82 (p, J- 6.8 Hz, 2H), 1.94 (p, J- 7.0 Hz, 2H), 2.12-2.26 (m, 1H) , 2.82 (s, 6H), 3.06 (AB, J "- 15.2, 45.3 Hz, 2H), 3.44 (t, J - 6.7 Hz, 2H), 3.99 (t, J - 6.3 Hz, 2H), 4.10 ( s, 1H), 5.47 (s, 1H), 6.15 (d, J- 2.7 Hz, 1H), 6.68 (dd, J = 2.5, 8.4 Hz, 1H), 6.91 (d, J - 8.4 Hz, 2H), 7.39 (d, J - 8.4 Hz, 2H), 7.93 (d, J * 8.7 Hz, 1H).

Step 2: Preparation of the pentyl nitrile intermediate To a stirred solution of 378 mg (0.621 mmol) of the pentyl ether intermediate compound (obtained from Step 1) in 1 ml of DMSO is added 37 mg (0.745 mmol) of sodium cyanide. The reaction is stirred at room temperature for 16 hours. The reaction is concentrated under a stream of nitrogen and the residue is partitioned between ethyl acetate and water. The organic layer is washed with brine and dried over MgSO4., filtered, and concentrated in vacuo to give 278 mg (93% purity by RPHPLC, ca. 75%) of the pentyl nitrile intermediate as a colorless foam: iH NMR (CDCl 3) d .0.86-0.96 (m, 6H), 1.02-1.21 (tn, 1H), 1.21-1.52 (m, 19H), 1.58-1.92 (m, 7H), 2.16-2.28 (m, 1H), 2.41 (t, J - 6.9 Hz, 2H), 2.83 (s, 6H), 3.08 (AB ", 15.0, 47.5 Hz, 2H), 4.01 (t, J - 6.2 Hz, 2H), 4.1 (s, 1H), 5.49 (s) , 1H), 6.07 (d, J - 2.1 Hz, 1H), 6.59 (dd, J- 2.4, 8.7 Hz, 1H), 6.92 (d, J- 8.1 Hz, 2H), 7.42 (d, J- 8.4 Hz , 2H), 7.92 (d, J - 8.7 Hz, 1H). MS (ES, M + H) m / e 555.

Step 3: Preparation of tetrazol A solution of 275 mg (0.5 mmol) of the nitrile intermediate (obtained from Step 2) and 666 mg (3.23 mmol) of the azidotrimethyltin in 5 ml of toluene is stirred with heating at 80 ° C for 60 hours. The reaction ¿S ^^^ ÍÉ ^! ¡I ^^^ s ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ Concentrate under a stream of nitrogen. Purification by reverse-phase chromatography (Waters-Delta prep) using 60% water / acetonitrile yielded 226 mg of the desired title compound (75%) as a colorless foam: m.p. 80-85 ° C; XH NMR (CDC13) d 0.83-0.95 (m, 6H), 1. 30-1.52 (m, 10H), 1.52-1.73 (m, 3H), 1.79-1.99 (m, 4H), 2.14-2.26 (m, 1H), 2.91 (s, 6H), 3.02-3.22 (m, 4H) ), 3.92-4.06 (m, 2H), 4.16 (S, 1H), 5.47 (s, 1H), 6. 28 (d, J.2.4 Hz, 1H), 6.74 (dd, J «2.7, 8.8 Hz, 1H), 6.89 (d, J« 8.7 Hz, 2H), 7.37 (d, J - 8.1 Hz, 2H), 7.98 (d, J - 8.7 Hz, 1H). HRMS Cale. for C_2H_.N50 «S: 598.3427. Jan: 598.3443.

Example 1421 '- «£ ¡». . C. .A, - «to. ?? J.- Acid (4R-cis) -4- [[5- [4- [3, 3-dibutyl-7- (dimethylamino) -2,3,4,5-tetrahydro-4-hydroxy-l, l-dioxide-l -benzothiepin-5-yl] phenoxy] pentyl] oxy] -2,6-pyridinecarboxylic acid Step 1; Preparation of the pentyl bromide intermediate To a solution of 0.63 g (15.72 mmol, 60% disp.) Of NaH in 85 ml of DMF is added 6.0 g (13.1 mmol) of 5- (4'-hydroxyphenyl) -7- (dimethylamino) -tetrahydrobenzo-tiepin- 1,1-dioxide (obtained from Example 1402, Step 10), and the resulting solution is stirred at room temperature for 1 hour. The solution is' and * _ _t_ a ^ it overnight at room temperature. The DMF is removed in vacuo and the residue is extracted with ethyl acetate and washed with brine. The extract is dried over MgSO, and the concentrated residue is purified by column chromatography to give the intermediate compound of pentyl oromide: NMR: H (cucl3) d 0.90 (c, 6HJ, 1.05-2.0 (m, 17H), 2.2 (t, 1H), 2.8 (s, 6H), 3.0 (c, 2H), 3.4 (t, 2H), 3.95 (t, 2H), 4.1 (s, 1H), 5.42 ( s, 1H), 6.0 (s, 1H), 6.5 (d, 1H), 6.9 (d, 2H), 7.4 (d, 2H), 7.9 (d, H).

Step 2: Esterification of chelidemic acid A solution of 10 g (54.6 mmol) of the chelideic acid, 23.0 g (120.12 mmol) of the 1- (3-dimethyl-amino propyl) -3-ethyl carbodiimide hydrochloride, 1.33 g (10.8 mmol) of 4-dimethyl amino pyridine, and 12.4 ml (120.12 mmol) of the benzyl alcohol in 100 ml of DMF is stirred at room temperature overnight under N2. The DMF is removed in vacuo and the residue is extracted with methylene chloride, washed with 5% NaHCOs, 5% acetic acid, H20, and brine. The extract is dried over MgSO4, and the concentrated residue is purified by column chromatography to give the dibenzyl kelalamic ester: 1H-NMR (CDC13) d 5.4 (s, 4H), 7.4 (m, 12H).

Step 3: Preparation of the ester intermediate A solution of 79 mg (1972 mmoles, 60% disp.) Of NaH and 0.716 g (1972 mmoles) of the dibenzyl kelasemic ester (obtained from Step 2) in 17.5 ml of DMF is stirred at room temperature for 1 hour. To the solution is added 1.0 g (1643 mmoles) of the pentyl bromide intermediate and the mixture is stirred under N2 overnight at 40 ° C. The DMF is removed in vacuo, and the residue is extract with ethyl acetate and wash with brine. The extract is dried over MgSO4, and the concentrated residue is purified by column chromatography to give the pyridinyl dibenzyl ester intermediate: XH NMR (CDC13) or 0.90 (c, 6H), 1.05-2.0 (m, 19H), 2.2 (t, 1H), 2.8 (ß, 6H), 3.0 (c, 2H), 4.0 (t, 2H), 4.1 (s, 1H), 5.4 (s, 4H), 5.42 ( s, 1H), 6.0 (S, 1H), 6.5 (d, 1H), 6.9 (d, 2H), 7.3-7.5 (m, 12H), 7.78 (S, 2H), 7.9 (d, 1H).

Step 4: Preparation of pyridinyl diacid A suspension of 0.8813 g (0.99 mole) of the dibenzyl ester (obtained from Step 3) and 40 mg of 10% Pd / C in 35 ml of ethanol and 5 ml of THF is stirred at room temperature under 1.40 kg / cm2 (20). psi) of hydrogen gas for 2 hours. The catalyst is removed by filtration, and the filtrate is concentrated to give the desired title compound as a solid: m.p. 143 ° C; NMR XH (THF-d8) 0.95 (c, 6H), 1. 05-1.65 (m, 15H), 1.9 (m, 4H), 2.22 (t, 1H), 2.8 (s, 6H), 3.0 (t, 2H), 4.1 (s, 3H), 4.3 (s, 2H) , 5.4 (s, 1H), 6.05 (s, 1H), 6.5 (d, 1H), 6.9 (d, 2H), 7.4 (d, 2H), 7.78 (d, 1H), 7.82 (s, 2H). HRMS. Cale, for C "H5oN20, S: 711.3315. Jan: 711.3322. Anal. Cale.para ____ É ___________________ ^^^^^^^^^ UÉ _____ j ___ l ___ Í C "HS0N, O, S: C, 64.20; H, 7.09; N,? 3.94; S, 4.51. Jan, C, 62.34; H, 6.97; N, 4.01; S, 4.48.

Example 1422 (4R-cis) - [5- [4- [3, 3-dibutyl-7- (dimethylamino) -2,4,5,5-tetrahydro-4-hydroxy-l, l-dioxide-l-benzothiepin-5 -yl] phenoxy] pentyl] guanidine Step 1: Preparation of the pentyl azide intermediate To a stirred solution of 200 mg (0.328 mmol) to the intermediate compound of pentiium bromide (obtained from Example 1420, Faso i) in 0.75 ml of DMSO is added 32 μl and • * -7J itunic ^ z -LO. to,-_. < Ja uc w -J. inci udiiui a . ^ ¿J »- __-__ WW & ^ a__ room temperature for 64 hours. The reaction is concentrated under a stream of nitrogen and the residue is partitioned between ethyl acetate and water. The organic layer is washed with brine, dried over MgSO 4, filtered, and concentrated in vacuo to give 155 mg (92% purity by RFHFLC, about 76% yield) of the pentyl azide intermediate compound or a a colorless. The sample was used without further purification: p.f. 45-50 ° C; NMR XH (CDCl,) d 0.83-0 93 (m, 6H), 1.03-1.48 (m, 10H), 1.54-1.74 (m, 5H), 1.78-1.86 (ra, 1H), 2.14-2.26 (ra, 1H) , 2.81 (s, 6H), 3.06 (AB "J" - 15.0, 48.0 Hz, 2H), 3.31 (t, J - 6.3 Hz, 2H), 3.98 (t, J «6.3 Hz, 2H), 4.09 (s, 1H), 5.47 (s, 1H), 6.10 (d, J- 1.8 Hz, 1H), 6.63 (dd, J - 2.7, 9.0 Hz, 1H), 6.91 (d, J - 9.0 Hz, 2H), 7.39 (d, "- 8.4 Hz, 2H), 7.91 (d, J - 8.7 Hz, 1H). (FAB, M + H) m / e 571.

Step 2: Preparation of the pentyl amine intermediate To a solution of 0.67 g (1.17 mmoles) of the intermediate azide compound (obtained from Step 1) in 75 ml of ethanol is added 0.10 g of 10% palladium on carbon and the mixture is stirred under 3.44 kg / cm 2 (49 psi). ) from hydrogen at room temperature for 3.5 hours. The reaction is filtered through d * celite and concentrated in vacuo to give 0.62 g (86% purity by RPHPLC, ca. 84%) of the pentyl amine intermediate as a faded white colored foam. The sample was used without further purification: p.f. 70-85 ° C, RMN K (CDCl,) d 0.86-0.96 (m, 6H), 1.06-1.75 (m, 15H), 1.79- 1.93 (m, 4H), 2.15-2.28 (m, 1H), 2.82 (s, 6H), 2.96- 3.20 (m, 4H), 3.99 (t, "- 6.0 Hz, 2H), 4.04-4.14 (m, 1H), 5.49 (s, 1H), 6.00 (d, J- 1.5 Hz, 1H), 6.51 (d , J - 9.0 Hz, 1H), 6.91 (d, J - 8.4 Hz, 2H), 7.41 (d, J -8.1 HZ, 2H), 7.90 (d, J - 8.7 Hz, 1H). + H) m / e 545.

Step 3: Preparation of guanidine To a stirred solution of 258 mg (0.474 mmol) of the intermediate pentyl amino compound (obtained from Step 2) and 81 mg (0.551 mmol) of lH-pyrazole-1-carboxamidine hydrochloride in 1.5 ml of DMF is added 71 mg ( 0.551 mmoies) of diisopropiiethiamine. The reaction is stirred at room temperature for 16 hours. Purification by reverse phase chromatography (Waters-Delta prep) using 60% water / acetonitrile yielded 120 mg (43%) ^ ---__ of the desired title compound as a colorless foamy solid: m.p. 67.0-72.5 ° C; XH NMR (CDC13) d 0.89-0.93 (m, 6H), 1.05-1.17 (m, 1H), 1.26-1.90 (m, 16H), 2.07-2.24 (m, 1H), 2.81 (s, 6H), 2.99-3.19 (m, 4H), 3.98 (sa, 2H), 4.12 (s, 1H), 5.46 (s, 1H), 6.01 (d, J "2.1 Hz, 1H), 6.51 (dd," - 2.1, 8.0 Hz, 1H), 6.92 (d, J - 8.1 Hz, 2H), 7.41 (d, J - 7.8 Hz, 2H), 7.89 (d, J -8.7 Hz, 1H) HRMS, Cale, for CJJHJON ^ S: 586.3552. Jan: (M + H) : 587.3620.

Example 1423 (4R-cis) - [5- [4- [3, 3-dibutyl-7- (dimethylamino) -2,4,5,5-tetrahydro-4-hydroxy-l, l-dioxide-l-benzothiepin-5 - il] phenoxy] pentyl] glycine Step 1: Preparation of the pentyl azide intermediate To a solution of the pentyl ether intermediate (400 mg, 0.657 mmol), obtained from Example 1420, Step 1) in dimethyl sulfoxide (20 ml) is added sodium azide (47 mg, 0.723 mmol, 1.1 eq. .), and the resulting solution was stirred at 23 ° C for 16 h. The reaction solution is diluted with 100 ml of ethyl acetate, then washed with water (2x 100 ml) and brine (1 x 100 ml). The organic layer is dried (MgSO4) and concentrated in vacuo to give 390 mg (quantitative) of the pentyl azide intermediate compound as a yellow oil: XH NMR (CDC13) d 0.82- 0. 90 (m, 7H), 1.05-1.56 (m, 12H), 1.59-1.71 (m, 3H), 1.78-2.01 (m, 4H), 2.20 (t, J- 8.3 Hz, 1H), 2.82 (s, 6H), 3.08 (c, 2H), 3.44 (t, J «7.7 Hz, 2H), 3.99 (t, J» 7.7 Hz, 2H), 4.91 (sa, 1H), 5.47 (s, 1H), 6.13 ( d, J "7.58 Hz, 1H), 6.68 (d, J- 7.7 Hz, 1H), 7.14 (ABq, 4H), 7.91 (d, J - 7.8 Hz, 1H).

Step 2: Preparation of the amino ester intermediate A suspension of the pentyl azide intermediate compound (390 mg, 0.684 mmol, obtained from Step 1) and . ** __.__ »» • _-_ 100 mg of palladium on carbon in ethanol (15 ml) is stirred under an atmosphere of hydrogen gas (48 psi) for 4.5 hours. The ethanolic suspension is filtered through celite and concentrated in vacuo to give a yellow oil. The oil is immediately diluted with acetonitrile (15 ml), followed by the addition of triethylamine (0.156 g, 1.54 mmole, 2.25 eq.) And the benzylic ester of bromoacetic acid (0.212 g 0.925 immoles, 1.35 eq.). The reaction is stirred at 23 ° C for 48 hours. The reaction is concentrated in vacuo, and the residue is dissolved in ethyl acetate (20 ml) and washed with water (2 x 20 ml) and brine (1 x 20 ml). The organic layer is dried (MgSO4) and dried in vacuo to give 420 mg (89%) of the amino ester intermediate as a yellow oil: XH NMR (CDCl,) d 0.82-0.90 (m, 6H), 1.05-1.56 (m, 14H), 1.58-1.71 (m, 3H), 1.78-2.01 (m, 4H), 2.20 (t, J- 8.3 Hz, 1H), 2.75 (d, J - 7.83 Hz, 1H), 2795 (s, 6H), 3.08 (c, 2H), 3.68-3.85 (m, 2H), 3.87-4.04 (m, 2H), 4.09 (s) , 1H), 5.147 (s, 1H), 5.46 (S, 1H), 5.98 (d, J- 7.58, 1H), 6.50 (dd, 1H), 6.85-6.87 (m, 2H), 7.28-7.45 (m, SH), 7.89 (d, J «8.0 Hz, 1H). EM (ES) m / e 693.. t __________ Í ____? _______ M____.

Step 3: Preparation of the acid A suspension of the intermediate compound of the benzyl ester (0.420 g, 0.61 mmol, obtained from Step 2) and 5 100 g of palladium on carbon in ethanol (15 ml) is stirred under an atmosphere of hydrogen gas (3.37 kg / cm2 (48 psi). )) for 16 h. The suspension is filtered through ceite, and concentrated in vacuo to give 0.330 g of a yellow semi-solid. The material is triturated with diethyl ether and the remaining semi-solid is dried in vacuo to give 0.19 g (52%) of the desired title compound as a yellow semisolid: XH NMR (CDC13) d (s a., 7H), 1.0- 1.72 (m, 18H), 1.79 (sa, 2H), 1.98 (s, 2H), 2.09-2.24 (m, 2H), 2.78 (s, 6H), 2.99 (c, 2H), 3.96 (sa, 2H), 4.08 15 (s, 1H), 5.46 (s, 1H), 5.97 (s, 1H), 6.40-6.49 (m, 1H), 7.14 (ABq, 4H), 7.85 (t, J - 7.93 Hz, 1H). MS (ES) m / e 603.

Example 1424 20 i? l lál t ^^ 4 Acid (4R-cis) -4- [[4- [3, 3-dibutyl-7- (dimethylamino) -2, 3, 4, 5-tetrahydro-4-hydroxy-l, l-dioxide-l-benzothiepin- 5-yl] phenoxy] methyl] benzoic Step 1: Preparation of the benzoate intermediate To a solution of 0.53 g (1.15 mmol) of 5- (4'-hydroxyphenyl) -7- (dimethylamino) tetrahydrobenzo-tiepin-1, 1-dioxide (obtained from Example 1402, Step 10) in 10 ml of dimethylformamide are added 35 mg (1.39 mmol) of 95% sodium hydride and stirred for 10 minutes. To the reaction mixture 525 mg (2.29 mmol) of methyl 4- (romomethyl) benzoate are added and stirred for 16 hours. Water is added to the reaction mixture, extracted with ethyl acetate, washed with brine, dried over magnesium sulfate, filtered and the solvent evaporated to give 0.51 g (73%) of the intermediate benzoate: XH NMR (CDC13) d 0.86-0.96 (m, 6H), 1.14- 1. 47 (m, 10H), 1.60-1.64 (m, 1H), 2.20-2.23 (m, 1H), 2.80 (s, 6H), 2.99 (d, J - 15.1 Hz, 1H), 3.15 (t, J « 15.1 Hz, 1H), 3.92 (s, 3H), 4.09-4.15 (m, 1H), 5.17 (s, 2H), 5.49 (s, 1H), 5.94 (d, J - 2.2 Hz, 1H), 6.50 (s) dd, J - 8.9, 2.6 Hz, 1H), 7.00 (d, J - 8.7 Hz, 2H), 7.43 (d, J - 8.5 Hz, 2H), 7.53 (d, J - 8.5 Hz, 2H), 7.93 ( d, J - 8.9 Hz, 1H), 8.06 (d, J - 8.5 Hz, 2H).

Step 2. Acid Preparation A solution of 0.51 g (0.84 mmol) of the benzoate intermediate (obtained from Step 1) and 325 mg (2.53 mmol) of K0Si (CH3) 3 (Aldrich) in 16 ml of THF is stirred for 3.5 hours. The THF is evaporated, water is added, extracted with ethyl acetate, dried over magnesium sulfate, filtered and the solvent is evaporated to give 0.30 g (60%) of the desired title compound as a white solid: m.p. 156-159 ° C; NMR lH (CDC13) d 0.89-0.94 (, 6H), 1.24-1.43 (m, 10H), 1.62-1.66 (m, 1H), 2.20-2.24 (m, 1H), 2.84 (s, 6H), 3.02 (d, J- 15.1 Hz, 1H), 3.17 (d, J - 15.1 Hz, 1H), 4.14 (s, 1H), 5.20 (s, 2H), 5.50 (8, 1H), 6.16 (s, 1H), 6.71 (d, J - 9.1 Hz, 2H) , 7.03 (d, J- 8.3 Hz, 2H), 7.44 (d, J - 8.1 Hz, 2H), 7.57 (d, J = 6- 3 Hz, 2H), 7.95 (d, J - 8.9 Hz, 1H), 8.13 (d, J = 8.1 Hz, 2H). HRMS. Cale, for CJ4H44NO, S: 594.2889. Jan: 594.2913 Example 1425 Chloride of (4R-cis) -l- [[4- [[4- [3, 3-dibutyl-7- (dimethylamino) -2, 3, 4, 5-tetrahydro-4-hydroxy-l, 1-dioxide -l-benzothiepin-5-yl] phenoxy] methyl] phenyl] methyl] -pyridinium Step 1: Preparation of the chlorobenzyl intermediate A solution of 5- (4'-hydroxyphenyl) -7- (dimethylamino) tetrahydrobenzo-tiepin-1,1-dioxide (5.0 g, 10.9 mmol, obtained from Example 1402, Step 10) in acetone (100 ml) at 25 ° C C under N2 is treated with powdered K2C03 (2.3 g, 16.3 mmoles, 1.5 eq.) And, a'-dichloro-p-xylene (6.7 g, 38.1 mmoles, 3.5 eq.), And the resulting solution is stirred at 65 ° C. C for 48 hours. The reaction mixture is cooled to 25 ° C and concentrated to 1/5 of the original volume. The residue is dissolved in EtOAc (150 ml) and washed with water (2 x 150 ml). The aqueous layer is extracted with EtOAc (2 x 150 ml) ^^ A ^ .--- - ^ Í ^ _- ^ a_. and the combined organic extracts were washed with saturated aqueous NaCl (2 x 150 ml). The combined extracts were dried (MgSO4) and concentrated in vacuo to give a yellow oil. Purification by flash chromatography (5.4 x 45 cm silica, 25-40% EtOAc / hexane) yielded the intermediate chlorobenzyl compound (4.7 g, 72%) as a white foam: XH NMR (CDCl,) d 0.89-0.94 (m, 6H), 1.12-1.48 (ma, 10H), 1.63 (m, 1H), 2.22 (m, 1H), 2.81 (s, 6H), 3.05 (ABq, J - 15.1 Hz, J «50.0 Hz, 2H), 4.11 (d, J« 8.1 Hz, 1H), 4.60 (s, 2H), 5.11 (s, 2H), 5.48 (s, 1H), 5.96 (d, J - 2.4 Hz, 1H), 6.48 (dd, J - 8.9, 2.6 Hz, 1H), 7.00 (d, J * 8.9 Hz, 2H), 7.36-7.47 (m, 5H), 7.85 (d, J - 8.9 Hz, 1 HOUR) .

Step 2: Preparation of quaternary salt A solution of the chlorobenzyl intermediate (1.0 g, 1.7 mmol, obtained from Step 1) in acetonitrile (5 ml) at 25 ° C under N2 is treated with pyridine. (5 ml) and stirred at 35 ° C for 36 hours. The light amber solution is cooled to 25 ° C and concentrated in vacuo to give the desired title compound (1.08 g, 96%) as a yellow solid: m.p. 154-156 ° C; NMR XH (CDC13) S 0.83 (m, 6H), 1.06-1.44 (ma, 10H), 1.60 (m, 1H), 2.13 (m, 1H), 2.71 (s, 6H), 3.02 (ABq, "- 15.1 Hz, J - 28.4 Hz, 2H), 4.09 (s, 1H), 5.00 (S, 2H), 5.38 (s, 1H), 5.91 (d, J »2.4 Hz, 1H), 6.26 (s, 2H), 6.41 (dd, J - 8.9, 2.4 Hz , 1H), 6.91 (d, J - 8.7 Hz, 2H), 7.26 (m, 1H), 7.40 (d, J - 7.7 Hz, 4H), 7.73 (d, J "- 7.9 Hz, 2H), 7.78 ( d, J - 8.9 Hz, 2H), 7.93 (t, J «6.8 Hz, 1H), 8.34 (t, J - 7.7 HZ, 1H), 8.58 (sa, 1H), 9.69 (d, J - 5.8 Hz, 2H); HRMS. Cale, for C "H« tN, 0 «S: 641.3413. Jan: 641.3425.

Example 1426 Chloride of (4R-cis) -1- [[4- [[4- [3, 3-dibutyl-7- (dimethylamino) -2, 3, 4, 5-tetrahydro-4-hydroxy-l, 1-dioxide -l-benzothiepin-5-yl] phenoxy] methyl] phenyl] methyl] -4-aza-l-azoniabicyclo [2.2.2] octane _______ H ___ £ ______ i__f.-.--- A * ".

Under N2, a solution of 8.7 g (14.5 mmol) of the chlorobenzyl intermediate (obtained from a procedure similar to that described in Example 1425, Step 1) in 60 ml of acetonitrile is added dropwise over a period of 30 minutes to a solution of 2.9 g (26.2 mmol) of diazabicyclo [2.2.2] octane (DABCO) in 40 ml of acetonitrile at 35 ° C; during the addition, a colorless precipitate formed. The suspension was stirred at 35 ° C for an additional 2 h. The product was collected and washed with 1 liter of acetonitrile to give 9.6 g (93%) of the title compound as a colorless crystalline solid; p.f. 223-230ßC (decomp.); NMR * H (CDCl,) d 0.89 (m, 6H), 1.27-1.52 (ma, 10H), 1.63 (m, 1H), 2.20 (m, 1H), 2.81 (s, 6H), 3.06 (ABq, J «15.1 Hz, J - 43.3 Hz, 2H), 3.16 (S, 6H), 3.76 (s, 6H), 4.11 (d, J- 7.7 Hz, 1H), 5.09 (s, 2H), 5.14 (s, 2H) ), 5.48 (s, 1H), 5.96 (s, 1H), 6.49 (d, J - 8.9 Hz, 1H), 6.99 (d, J - 8.0 Hz, 2H), 7.26 (m, 1H), 7.44 (d, J - 8.0 Hz, 2H), 7.52 (d, J - 7.4 Hz, 2H), 7.68 (d, J «7.4 Hz, 2H), 7.87 (d, J - 8.9 Hz, 1H); HRMS. Cale, for C40H "N, 0, S: 674.3992. Jan.: 674.4005. ^ _ .. «_, -. ^ I _-. T _-.... _ _. > ... XAt _ ^ __.._____ l__A. ___-.___ _._- - _____ »! ___-___.

Example 1426a Chloride of (4R-cis) -1- [[4- [[4- [3, 3-dibutyl-7- (dimethylamino) -2,3,4,5-tetrahydro-4-hydroxy-l, 1-dioxide -l-benzothiepin-5-yl] phenoxy] methyl] phenyl] methyl] -4-aza-l-azoniabicyclo [2.2.2] octane A solution of the chlorobenzyl intermediate (4.6 g, 7.7 mmol, obtained from Example 1425, Step 1) in acetonitrile (100 ml) at 25 ° C under N2 is treated with diazabicyclo [2.2.2] -octane (DABCO, 0.95 g , 8.5 mmol, 1.1 eq.) And stirred at 35 ° C for 2 hours, during which time a white solid precipitated. The white solid was collected, washed with CH3CN and recrystallized from CH3OH / Et20 to give the title compound (4.95 g, 91%) as a white solid: m.p. 223-230 ° C (decomp.); NMR LH (CDCl,) d 0.89 (m, 6H), 1.27-1.52 (ma, 10H), 1.63 (m, 1H), 2.20 (m, 1H), 2.81 (s, 6H), 3.06 (ABq, J- 15.1 Hz, J «43.3 Hz, 2H), 3.16 (S, 6H), 3.76 (s, 6H), 4.11 (d, J- 7.7 Hz, 1H), 5.09 (s, 2H), 5.14 (s, 2H), 5.48 (s, 1H), 5.96 (s, 1H), 6.49 (d, "- 8.9 Hz, 1H), 6. 99 (d, J- 8.0 Hz, 2H), 7.26 (m, 1H), 7.44 (d, J - 8.0 Hz, 2H), 7.52 (d, J «7.4 Hz, 2H), 7.68 (d, J« 7.4 Hz, 2H), 7.87 (d, J- 8.9 Hz, 1H); HRMS. Cale, for C40H "N, 0" S: 674.3992. Jan: 674.4005.

Example 1427 (4R-cis) -N- (Carboxymethyl) -N- [[4- [[4- [3, 3-dibutyl-7- (dimethylamino) -2, 3, 4, 5-tetrahydro-4-hydroxy-1 , 1-dioxido-l-oenzotiepin-5-yl] phenoxy] methyl] phenyl] methyl] glycine Step 1: Preparation of the chlorobenzyl intermediate To a stirred solution of 144 mg (3.59 mmol, 60% disp.) Of NaH in 29 ml of DMF is added 1.5 g (3.26 mmol) of 5- (4'-hydroxyphenyl) -7- (dimethylamino) -tetrahydrobenzothiepin-1. , 1-dioxide (obtained from Example 1402, Step 10), and the resulting solution is stirred at room temperature for 45 minutes. 7.13 g (40.75 mmoles) of dichloro p-xylene are added to the solution, and the mixture is stirred overnight. The DMF is removed in vacuo, and the residue is extracted with ethyl acetate and washed with brine. The extract is dried over MgSO4, and the concentrated residue is purified by column chromatography to give the chlorobenzyl intermediate: XH NMR (CDC13) d 0.90 (c, 6H), 1.05-1.65 (m, 11H), 2.2 (t, 1H), 2.8 (s, 6H), 3.0 (c, 2H), 4.1 (d, 1H), 4.6 (s, 2H), 5.1 (s, 2H), 5.5 ( s, 1H), 6.0 (s, 1H), 6.6 (d, lH), 7.0 (d, 2H), 7.4 (m, 6H), 7.8 (d, lH).

Step 2: Preparation of the amino diester A mixture of 1.03 g (1.72 mmol) of the chlorobenzyl intermediate (obtained from Step 1), 1.63 g (8.6 mmol) of diethyl amino diacetate, and 0.72 g (8.6 mmoles) of NaHCO 3 in 30 ml of DMF is stirred at 100 ° C for 6 hours. The DMF is removed in vacuo and the residue is extracted with ether and washed with brine. The extract is dried over MgSO, and the concentrated residue is purified by column chromatography to give the amino diester intermediate: XH NMR (CDC13) d 0.90 (c, 6H), 1.05-1.65 (m, 17H), 2.2 (t, 1H), 2.8 (s, 6H), 3.0 (c, 2H), 3.55 (s, 4H), 3.95 (s, 2H), 4.1-4.2 (m, 5H), 5.05 (s, 2H), .42 (s, 1H), 5.95 (s, 1H), 6.5 (d, 1H), 7.0 (d, 2H), .4 (s, 6H), 7.8 (d, 1H) .

Step 3: Preparation of amino diacid A solution of 0.863 g (1.15 mmol) of the dibenzyl ester (obtained from Step 2) and 0.232 g (5.52 mmol) of LiOH in 30 ml of THF and 30 ml of water is stirred at 40 ° C under N2 for 4 hours. The reaction mixture is diluted with ether and washed with 1% HCl. The aqueous layer is extracted twice with ether, and the combined extracts are washed with brine, dried over MgSO, and concentrated in vacuo to give the desired title compound as a solid: m.p. 175 ° C; NMR XH (THF-d8) 0. 95 (c, 6H), 1.05-1.65 (m, 11H), 2.22 (t, 1H), 2.8 (s, 6H), 3.0 (t, 2H), 3.5 (s, 4H), 3.9 (s, 2H) , 4.1 (d, 1H), 5.1 (s, 2H), 5.4 (s, 1H), 6.05 (s, 1H), 6.5 (d, 1H), 7.0 (d, 2H), 7.4 (m, 6H), 7.78 (d, 1H) ). HRMS. Cale, for C "H5» NJ0, S: 695.3366. Jan: 695.3359. Anal. Cale, for CJ.HSONJO.S: C, 65.68; H, 7.25; N, 4.03; S, 4.61. Jan: C, 64.95; H, 7.32; N, 3.94; S, 4.62.

Example 1428 (4R-cis) -4- [[4- [3, 3-dibutyl-7- (dimethylamino) -2,3,4,5,5-tetrahydro-4-hydroxy-l, 1-dioxide-1, salt -dioxide-l-benzothiepin-5-yl] phenoxymethyl] -1-methylpyridinium with trifluoroacetic acid (1: 1) Step 1: Preparation of the picolyl intermediate To a stirred solution of 12.0 g (26.1 mmol) of 5- (4 '-hydroxyphenyl) -7- (dimethylamino) tetrahydrobenzo- tiepin-1, l-dioxide (obtained from Example 1402, Step 10) in 200 ml of DMF is added 1.4 g (60% of oily dispersion, 35 mmol) of sodium hydride and the reaction is stirred at room temperature for one hour . 5.99 g (36.5 mmol) of the 4-picolyl chloride hydrochloride are treated with a cold saturated NaHCO3 solution and extracted with diethyl ether. The ethereal extracts were washed with brine, dried over MgSO4, and filtered. The reaction was cooled in an ice bath and the solution of 4-picolyl chloride in diethyl ether was added. The reaction is stirred at room temperature for 17 hours. The reaction is quenched with 25 mL of saturated NH4C1, diluted with 600 mL of ethyl acetate, washed with 4X250 mL of water, brine, dried over MgSO4, filtered and concentrated in vacuo. Purification by chromatography on silica gel (Waters-prep 500) using 60% ethyl acetate / hexanes yielded 11.05 g (77%) of the picolinyl intermediate as a colorless solid: m.p. 95-98 ßC; 1H-NMR (CDCl,) d 0.86-0.96 (m, 6H), 1.02-1.52 (m, 10H), 1.58-1.70 (m, 1H), 2.16-2.29 (m, 1H), 2.81 (s, 6H), 3.07 (ABq, J "« 15.3, 49.6 Hz, 2H), 4.10 (d, J «7.5 Hz, 1H), 5.15 (s, 2H), 5.50 (s, 1H), 5.94 (d, J-2.7 Hz, 1H), 6.51 (dd, J- 2.4, 8.7 Hz, 1H), 7.00 (d, - 9.0 Hz, 2H), 7.39 (d, 6.0 Hz, 2H), 7.44 (s, J - 8.7 Hz, 2H), 7.89 (d, J «9.0 Hz, 2H), 8.63 (dd, J- 1.6, 4. 8 HZ, 2H).

Step 2: Preparation of quaternary salt To a stirred solution of 0.41 g (0.74 mmol) of the picolinyl intermediate (obtained from Step 1) in 10 ml of acetonitrile and 3 ml of dichloromethane are added 137 mg (0.97 mmoles) of iodomethane. The reaction is stirred at room temperature for 16 hours, then concentrated under a stream of nitrogen. Purification by reverse phase chromatography (aters-Delta prep) using 60-55% water / acetonitrile yielded 0.304 g (60%) of the desired title compound as a colorless solid: m.p. 96-99 ßC; XH NMR (CDCl,) d 0.85-0.95 (m, 6K., 1.03-1.52 (ra, 10H), 1.57-1.70 (m, 1H), 2.12-2.27 (m, 1H), 2.84 (s, 6H), 3.09 (AB, J ?, «15.0, 27.9 Hz, 2H), 4.11 (s, 1H), 4.46 (s, 3H), 5.37 (s, 2H), 5.50 (s, 1H), 6.07 (d, J -2.4 Hz, 1H), 6.61 (dd, J - 2.5, 8.7 Hz, 1H), 7.02 (d, J - 8.7 Hz, 2H), 7.48 (d, J- 7.2 Hz, 2H), 7.90 (d, J -8.7 Hz, 1H), 8.14 (d, J- 6.3 Hz, 2H), 8.80 (d, J- 6. 6 Hz, 2H) HRMS Cale, for C "H", N, 0, S: 565.3100. Jan: 565.3125.

Example 1429 (4R-cis) -4- [[4- [3, 3-dibutyl-7- (dimethylamino) -2, 3,4,5-tetrahydro-4-hydroxy-l, 1-dioxide-l, 1-dioxide -l-benzothiepin-5-yl] phenoxy] methyl] -1-methylpyridinium, methanesulfonate (salt) To a stirred solution of 6.5 g (11.8 mmol) of the picolyl intermediate (obtained from Example 1428, Step 1) in 140 ml of acetonitrile heated at 70 ° C is added 1.56 g (14.6 mmol) of methanesulfonic acid methyl ester. The heating was continued at 70 ° C for 15 hours. The reaction is cooled and diluted with 50 ml of ethyl acetate. The solid is collected by vacuum filtration to give 6.14 g (79%). The filtrate is concentrated in vacuo and the residue is crystallized from hot acetonitrile to give 1.09 g (14%). A total of 7.23 g (93%) of the desired title compound was obtained as a colorless white solid: m.p. 232-233.5 ° C; XH NMR (CDC13) d 0. 66-0.76 (m, 6H), 0.85-0.95 (m, 1H), 0.95-1.35 (m, 9H), 1.42- 1.54 (m, 1H), 1.95-2.22 (m, 1H), 2.50 (s, 1H) ), 2.56 (s, 3H), 2.63 (s, 6H), 2.91 (AB, J- 16.5, 24.0 Hz, 2H), 3.88 (s, 1H), 4.40 (s, 3H), 5.21 (s, 3H) ), 5.78 (d, J - 2.4 Hz, 1H), 6.31 (d, J - 2.5, 8.7 Hz, 1H), 6.84 (d, J - 8.7 Hz, 2H), 7.31 (d, J - 8.4 Hz, 2H ), 7.64 (d, J - 8.7 HZ, 1H), 8.0 (d, J - 6.6 Hz, 2H), 9.02 (d, J- 6.6 Hz, 2H). HRMS Cale, for C "H" N, 0 «S: 565.3100. Jan: 656.3087. Anal. Cale, for CJ4H4tNjO, S,: C, 61.79; H, 7.32; N, 4.24; S, 9.70. Jan: C, 61.38, H, 7.47; N, 4.22; S, 9.95.

Example 1430 Acid (4R-cis) -6- [[4- [3, 3-dibutyl-7- (dimethylamino) -2, 3, 4, 5-tetrahydro-4-hydroxy-l, l-dioxide-l-benzothiepin- 5-yl] phenoxy] methyl] -2-pyridinepropanoic acid Step 1: Preparation of the picolinyl chloride intermediate • To a solution of 5- (4'-hydroxyphenyl) -7- (dimethylamino) tetrahydrobenzo-tiepin-1, 1-dioxide (1 g, 2.1 mmol, obtained from Example 1402, Step 10) in acetone (50 ml) is added K2C03 (0.45 g, 3.2 mmol), tetrabutylammonium iodide (0.1 g, 0.2 mmol) and 2,6-bischloromethylpyridine (1.2 g, 10.8 mmol). The vessel was equipped with a hydrogen gas adapter and a magnetic stirrer. The reaction is heated to reflux overnight. After 18 hours, the reaction is diluted with ether and washed with water and brine (30 ml). The organic layers are dried over MgSO, filtered and concentrated in vacuo. Chromatographic purification through silica gel, eluting with 25% EtOAc / hexane gave 0.75 g (55%) of the intermediate compound of picolyl chloride as an oil (0.70 g, 55%): XH NMR (CDC13) d 0. 84-0.95 (m, 6H), 1.02-1.5 (m, 10H), 1.56-1.66 (m, 1H), 2.14-2.24 (m, 1H), 2.80 (s, 6H) 3.05 (ABq, 2H), 4.10 (d, 2H), 4.65 (s, 2H), 5.20 (s, 2H), 5.45 (s, 1H), Mg ^ ¡g ^^^^^^^^ ^ ^^^^^^^^ - ^ _ | _ | ^ - | ----------------- | - -------- ^^^^^^^ g ^^^^ ¿^ ^^^^^^ ^^^^^^ . 95 (s, 1H), 6.50 (d, 1H), 7.0 id, 2H), 7.35-7.50 (m, 4H), 7.70-7.85 (m, 2H).

Step 2: Preparation of 5-pyridinyl malonate intermediate Dibenzyl malonate (1.42 g, 5.01 mmol) in DMF (20.0 ml) and sodium hydride (0.13 g, 3.3 mmol) were placed in a dry three-necked container. He The vessel was equipped with a nitrogen gas adapter and a magnetic stirrer. The intermediate compound of picolyl chloride (1 g, 1.67 mmol) is added and heated at 90 ° C overnight. The reaction is cooled and extracted with 5% HCl with methylene chloride and washed with water. (25 ml), and brine (50 ml). The organic layers are dried over MgSO, filtered and concentrated. The residue is purified by a reversed phase column of C-18 eluting with 50% acetonitrile / water and gave the pyridinyl malonate intermediate as a foamy solid. white (1 g, 71%): XH NMR (CDC13) d 0.84-0.95 (m, 6H), 1. 02-1.5 (m, 10H), 1.56-1.66 (m, 1H), 2.14-2.24 (ra, 1H), 2.80 (s, 6H) 3.05 (ABq, 2H), 3.22 (d, 2H), 4.05 (d , 1H), 4.16 (t, 1H), 5.02 (s, 2H), 5.08 (s, 4H), 5.44 (s, 1H), 5.97 (s, 1H), 6.96-7.10 (m, 3H), 7.20- 7.32 (m, 12H), 7.5 (t, 1H), 7.9 (d, 1H). 25, _ ^. ^ ~ _ - A -.--- ... -, - - t-ftr '-' jtt_jS_if____p Step 3: Preparation of pyridinic acid The pyridinyl malonate intermediate compound (0.6 g, 0.7 mmol, obtained from Step 2), THF / water (25.0 ml, 1: 1) and lithium hydroxide monohydrate (0.14 g, 3.4 mmol) were placed in a 100 ml round bottom flask. The reaction is stirred at room temperature overnight. After 18 hours, the reaction is extracted with 1% HCl and ether and then washed with water (20 ml) and brine (30 ml). ml). The organic layers are dried over MgSO4, filtered and concentrated in vacuo to give the desired title compound as a white solid (0.44 g, 90%): m.p. 105- 107"C; 1H NMR (CDCl,) d 0.84-0.95 (m, 6H), 1.02-1.5 (m, 10H), 1.56-1.66 (m, 1H), 2.14-2.24 (m, 1H), 2.80 (s) , 15 6H), 3.05 (m, 2H), 3.10 (ABq, 2H), 3.22 (m, 2H), 4.05 (s, 1H), 5.30 (s, 2H), 5.50 (s, 1H), 5.97 (s) , 1H), 6.50 (d, 1H), 7.02 (d, 2H), 7.3 (d, 1H), 7.42 (d, 2H), 7.58 (d, 1H), 7.8-7.9 (m, 2H), HRMS. Cale, for 623. 3155. Jan: 623.3188.

Example 1431 jgy ^^ (4R-cis) -N- (Carboxymethyl) -N- [[6- [[4- [3, 3-dibutyl-7- (dimethylamino) -2,3,4,5-tetrahydro-4-hydroxy-l) , 1-dioxido-l-benzothiepin-5-yl] phenoxy] methyl] -2-pyridinyl] methyl] glycine Step 1: Preparation of the pyridinyl diester intermediate A mixture of diethyl aminodiacetate (8 g, 68 mmol) and sodium carbonate (0.63 g, 5.9 mmol) is treated with the intermediate compound of picolyl chloride (0.72 g, 1.2 mmol, obtained from Example 1430, Step 1), and stirred at 160 ° C for three hours. The reaction is cooled and diluted with ether and washed with 1% HCl, water (25 ml), and brine (50 ml). The combined extracts are dried over MgSO, filtered and concentrated in vacuo. The residue is purified by distillation in the Kugerlrohr to give the intermediate diester compound pyridinyl as a yellowish foamy solid (0.72 g, 80%): XH NMR (CDC13) d 0.84-0.95 (m, 6H), 1. 02-1.5 (m, 16H), 1.56-1.66 (m, 1H), 2.14-2.24 (m, 1H), 2.80 (s, 6H) 3.05 (ABq, 2H), 3.70 (s, 4H), 4.2-4.4 (, 6H), 5.30 (s, 2H), 5.56 (s, 1H), 6.02 (s, 1H), 6.60 (d, 1H), 7.10 (d, 2H), 7.50 (m, 3H), 7.61 (d, 1H), 7.80 (t, 1H), 7.95 (d, 1H). HRMS. Cale. for C41H5TN, 0, S: 752.3945. Jan: 752.3948.

Step 2: Preparation of pyridinyl diacid A mixture of the pyridine-aminodiacetate intermediate (0.7 g, 0.93 mmol, obtained from Step 1), and the lithium hydroxide monohydrate (0.18 g, 4.5 mmol) in THF / water (25.0 mL, 1: 1) is stirred at 40 ° C all night (18 hours). The reaction mixture is diluted with ether and washed with 1% HCl, water (20 ml), and brine (30 ml). The organic layers are dried over MgSO4, filtered and concentrated in vacuo to give the desired title compound as a white solid (0.44 g, 90%): m.p. 153- 155 ßC; NMR XH (CDCl,) d 0.84-0.95 (m, 6H), 1.02-1.5 (m, 10H), 1.56-1.66 (m, 1H), 2.14-2.24 (m, 1H), 2.80 (s, 6H), 3.10 (sq, 2H), 3.90 (m, 3H), 4.05 (s, 1H), 4.40 (s, 2H), 5.20 (s, 2H), 5.50 (s, 1H), 5.97 (s, 1H), 6.50 (d, 1H), 7.02 (d, 2H), 7.3 (d, 1H), 7.42 (d, 2H), 7.58 (d, 1H), 7.8-7.9 (m, 2H).

HRMS. Cale, for C, AtNjO | S _ 696 .3319. Jan: 696 .3331 Example 1432 Acid (4R-cis) - [2- [2- [4- [3, 3-dibutyl-7- (dimethylamino) -2,3,4,5-tetrahydro-4-hydroxy-l, l-dioxide-l -benzothiepin-5-yl] phenoxy] ethoxy] ethyl] propandioic Step 1: Preparation of the bromoethyl ether intermediate To a stirred solution of 0.192 g (4.785 mmol, 60% disp.) Of NaH in 28 ml of DMF are added 2.0 g (4.35 mmol) of 5- (4'-hydroxyphenyl) -7- (dimethylamino) -tetrahydrobenzo-tiepin-1,1-dioxide (obtained from Example 1402 , Pa'so 10), and the resulting solution is stirred at room temperature for 30 minutes. To the solution add 13.2 g (54.38 mmoles) of the bis (2-bromoethyl) ether, and stirring is continued at room temperature under N2 overnight. The DMF is removed in vacuo and the residue is extracted with ethyl acetate and washed with brine. The extract is dried over MgSO4, and the concentrated residue is purified by column chromatography to give the intermediate compound of the bromoethyl ether: XH NMR (CDC13) d 0.90 (c, 6h), 1.05- 1. 65 (m, 11H), 2.2 (t, 1H), 2.8 (s, 6H), 3.0 (c, 2H), 10 3.5 (t.2H), 3.9 (m, 4H), 4.1 (d, 1H), 4.2 (d, 2H), 5.42 (s, 1H), 5.95 (s, 1H), 6.5 (d, 1H), 6.95 (d, 2H), 7.4 (d, 2H), 7.9 (d, 1H).

Step 2: Preparation of diester intermediate 15 To a mixture of 94 mg (2.34 mmol, 60% disp.) Of NaH in 45 ml of THF and 15 ml of DMF at 0 ° C is added 1.33 g (4.68 mmol) of the dibenzyl malonate (Aldrich), and the resulting solution is stirred at room temperature for minutes, followed by the addition of 0.95 g (1.56 mmoles) of the bromoethyl ether intermediate (obtained from Step 1). The mixture is stirred under N2 at 80 ° C overnight. The solvent is removed in vacuo and the residue is extracted with methylene chloride and washed with brine. He The extract is dried over MgSO, and the residue fc ^^^^^^^^^^^^^^^^^^^^^^^^^ a ^^^^^^^^^ j ^^ »^^^^^^^^^ ^^^^^^^^^^^ _ ^^^ | ^^^ g ^^^^ Concentrate is purified by column chromatography to give the diester intermediate: XH NMR (CDCl,) d 0.90 (c, 6H), 1.05-1.65 (m, 11H), 2.2-2.3 (m, 3H), 2.8 (s, 6H), 3.0 (c, 2H), 3.6 (t, 2H) , 3.7 (m, 3H), 4.1 (m, 3H), 5.1 (s, 4H), 5.42 (s, 1H), 5.9 (s, 1H), 6.5 (d, 1H), 6.9 (d, 2H), 7.3 (m, 10H), 7.4 (d, 2H), 7.9 (d, 1H).

Step 3: Preparation of the diacid 10 A suspension of 0.761 g (0.935 mmol) of the diester intermediate (obtained from Step 2) and 35 mg of 10% Pd / C in 25 ml of ethanol and 5 ml of THF is stirred at room temperature under 1.40 kg / cm2 (20 psi) of 15 hydrogen gas for 2 hours. The catalyst is removed by filtration, and the filtrate is concentrated to give the desired title compound as a solid: m.p. 119.5 ° C; NMR XH (THF-d8) 0.95 (c, 6H), 1.05-1.65 (m, 11H), 2.1 (c, 2H), 20 2.25 (t, 1H), 2.8 (s, 6H), 3.0 (t, 2H), 3.47 (c, 2H), 3.58 (s, 1H), 3.78 (t, 2H), 4.08 (d, 1H), 4.15 (t, 2H), 5.4 (s, 1H), 6.05 (s, 1H), 6.55 (d, 1H), 6.98 (d, 2H), 7.42 (d, 2H), 7.8 (d, 1H). HRMS. Cale, for CH ^ CS: 632.2893. Jan: 632-2882. Anal. Cale, for C "H", NO, S: ___s. _-__ -_ ,. _- .._-_- -______-_-__ - -. . -. , J __ ^ ___ Ma__? __. _ ^. __. "_," __, .- ___ _. __J ____-____ M_ C, 62.54; H, 7.47; N, 2.21; S, 5.06, Jan C, 61.75; H, 7.56; N, 2.13; S, 4 92. Example 1433 (4R-cis) -a- [[4- [3, 3-dibutyl-7- (dimethylamino) -2, 3, 4, 5-tetrahydro-4-hydroxy-l, l-dioxide-l-benzothiepin-5 -yl] phenoxy] methyl] -w-methoxypoly (oxy-1,2-ethanediyl) Step 1: Preparation of the intermediate compound of monomethyl PEG mesylate To a solution of 20 g of the monomethyl PEG ether in 100 ml of methylene chloride is added 2.2 g (22 mmol) of triethyl amine, and to the resulting solution at 0 ° C are added dropwise 2.5 g (22 mmol) of the chloride. methanesulfonyl. The resulting solution is stirred all __ ___________________ __ ^ ___. ______. _-a-.Ji (_, I ____________ ^ J overnight at room temperature, and the triethyl amine hydrochloride is removed by filtration to give the intermediate compound of monomethyl mesylate PEG which was used in the next Step without further purification and characterization.

Step 2: Preparation of benzothiepene bonded to polyethylene A mixture of 38 mg (1.52 mmol to 95%) of NaH and 0. 7 g (1.52 mmoles) of 5- (4'-hydroxyphenyl) -7- (dimethylamino) tetrahydrobenzo-tiepin-1,1-dioxide (obtained from Example 1402, Step 10) in 5.5 ml of DMF, is stirred at room temperature under N2 for 30 minutes. To the solution is added 0.55 g (0.51 mmol) of the intermediate mesylate PEG (obtained from Step 1) in 5.5 ml of DMF, and the resulting solution is stirred overnight under N2 at 50 ° C. The DMF is removed in vacuo and the residue is extracted with methylene chloride and washed with brine. The extract is dried over MgSO, and the concentrated residue is purified by column chromatography to give the desired title compound as an oil. XH NMR (CDC13) d 0.9 (c, 6h), 1.05- 1-65 (m, 11H), 2.2 (t, 1H), 2.8 (s, 6H), 3.0 (c, 2H), 3.4 (s, 4H), 3.5-3.85 (m, 95H), 4.1 (s, 1H), 4.15 (t, 2H), 5.5 (s, 1H), 6.05 (s, 1H) 6.6 (d, 1H), 6.9 (d, 2H), 7.4 (d, 2H), 7.9 (d, 1H).

Example 1434 Preparation of: The 3-aminobenzothiepene prepared in Step 5 of Example 1398 (0.380 g, 0.828 mmol), sodium hydroxide (0.35 mL, 0.875 mmol, 10% in H20) and toluene (0.50 mL) are combined in a round-bottomed flask. 10 ml. The reaction vessel is purged with N2, equipped with a magnetic stirrer, and cooled to 0 ° C. A solution of 3-chloropropyl chloroformate (1440 g, 1.10 mmol, 12% in CH2C12 / THF) was added. After 3.5 hours, toluene (3.0 ml) was added, and the mixture was washed with H20 (2x4 ml), dried (MgSO4), filtered and concentrated in vacuo. The _., __ M = _- ^ - afeag-s .. purification by flash chromatography on silica gel eluting with 20% EtOAc / hexane and concentration in vacuo gave a white solid (0.269 g, 56%). NMR: H (CDC13) d 0. 87-0.93 (m, 6H), 1.05-1.70 (m, 11H), 2.14 (t, J - 6.3 Hz, 2H), 2.15-2.25 (m, 1H), 2.81 (s, 6H), 3.07 (ABq, 2H), 3.64 (C, J - 6.3 Hz, 2H), 4.11 (d, J - 7.5 Hz, 1H), 4.33 (t, J - 6.0 Hz, 2H), 5.50 (S, 1H), 5.99 (d, J - 2.4 Hz, 1H), 6.51 (dd, J - 9.0, 2.7 Hz, 1H), 6.65 (s, 1H), 7.23 (d, J - 7.8 Hz, 1H? 7.34-7.39 (m, 2H), 7.54 (d, J - 7.2 HZ, 1H), 7.89 (d, 8.7 Hz, 1H) HRMS (M + 10 H) Cale, for C30H44N2O5SCI: 579.2659. Jan: 579.2691.

Example 1435 15 Preparation of: The 1,4-diazabicyclo (2.2.2) octane (0.0785 g, 0.700 mmol) and the acetonitrile (1.0 ml) are combined in a 10 ml round bottom vessel. The reaction vessel is purged with N2, equipped with a magnetic stirrer, and heated to 37 ° C. A solution of the product from Example 1434 (0.250 g, 0.432 mmol) in acetonitrile (2.50 ml) is added. After 2.5 hours, 1, 4-diazabicyclo (2.2.2) octane (0.0200 g, 0.178 mmol) is added. After 64 hours, 1,4-diazabicyclo (2.2.2) octane (0.0490 g, 0.437 mmol) is added. After 24 hours, the reaction mixture is cooled to T.A, (Room Temperature) and concentrated in vacuo. The crude product is dissolved in acetonitrile (2.0 ml) and precipitated with ethyl ether (10.0 ml). The precipitate is filtered to give a white solid. This trituration method is repeated, followed by concentration in vacuo to give a white solid (0.185 g, 62%). p.f. 218.0-225.0 ° C, XH NMR (CD3OD) d 0.90 (m, 6H), 1.05-1.55 (m, 10H), 1.16 (t, J - 6.6 Hz, 2H), 1.78 (m, 1H), 2.12 (m, 3H), 2.76 ( s, 6H), 3.10 (m, 2H), 3.17 (t, J - 7.2 Hz, 6H), 3.30-3.50 (m, 8H), 4.10 (s, 1H), 4.21 (t, J - 5.4 Hz, 2H ), 5.31 (s, 1H), 6.10 (s, 1H), 6.55 (d, J - 7.2 Hz, 1H), 7.25 (d, J - 6.9 Hz, 1H), 7.33-7.42 (m, 2H) , 7.56 (s, 1H), 7.76 (d, J = 9.0 Hz, 1H). HRMS. Cale, for C36H55N4O5SCI: 655.3893. Jan: 655.3880. ^^^^^^^^^^ z ^^^^^^^^^^^^^^^^^^^^^^^^^^? ^^^ É ^^^^^^^ Example 1436 Preparation of: Step 1. Preparation of: The 3-cJ oromethylbenzoyl chloride (2.25 ml / 15fl mmole) and the acetone (8.0 ml) are combined in a 25 ml round bottom vessel. The reaction vessel is cooled to 0 ° C, and an aqueous solution of sodium azide (1.56 g in 5.50 ml / 24.0 mmol) was added. After _ ^ »& _ r - ^ S & 1. 5 hours, the reaction mixture is poured into ice water (80.0 ml), extracted with ethyl ether (2x25 ml), dried (MgSO4), and concentrated in vacuo to give a colorless oil (2.66 g, 86%). H NMR (CDCl 3) d 4.62 (s, 2 H), 7.47 (t, J - 7.8 Hz, 1 H), 7.66 (d, J - 7.8 Hz, 1 H), 7.99 (d, J - 7.8 Hz, 1 H), 8.05 (s, 1H).

Step 2.

The 3-chloromethylbenzoyl azide (0.142 g, 0.726 mmol) and toluene (2.0 ml) are combined in a 10 ml round bottom vessel. The reaction vessel is purged with N2, equipped with a magnetic stirrer, and heated to 110 ° C. After 2 hours, the reaction mixture is cooled to T.A. and the 3-aminobenzothiepene prepared in Step 5 of Example 1398 (0.365 g, 0.796 mmole) was added. After 2.25 hours, the mixture is heated to 50 ° C. After 0.75 hours, the 3-chloromethylbenzoyl azide (0.025 g, 0.128 min) is added, and the reaction mixture is heated to reflux. After 0.5 hours, the reaction mixture is cooled to T.A. and concentrates in vacuo. Purification by flash chromatography on silica gel eluting with 20-30% of f * _ ", - s¿ 5_» ltA EtOAc / hexane and concentration in vacuo gave a white foamy solid (0.309 g, 62%). H NMR (CDC13) d 0.71 (t, J «5.4 Hz, 3H), 0.88 (t, J - 6.3 Hz, 3H), 1.03-1.60 (m, 11H), 1.85 (d, 6.3 Hz, 1H), 2.27 (m, 1H), 2.76 (s, 6H), 3.15 (t, 2H), 4.17 (d, J «6.6 Hz, 1H), 4.48 (s, 2H), 5.42 (s, 1H), 6.07 (s, 1H), 6.99 (d, J - 7.5 Hz), 7.18-7.26 (m, 2H), 7.30-7.41 (m, 3H), 7.63 (s, 1H), 7.86 (d, J - 9.0 Hz, 2H), 7.96 (s, 1H), 8.17 (s) , 1 HOUR) . HRMS (M + Li). Calculated for C34H44N3O4SCILÍ: 632.2901. Jan: 632-2889.

Example 1437 Preparation of: ^^^ í ^^^^^^^^^ j ^^^^^^ & J ^^^^^^^^ - j¡ * Hli¡ ^^ _ * - fc__ -a. ~ _- ~ _..__- * «.___ The 1,4-diazabicyclo (2.2.2) octane (0.157 g, 1.40 mmol) and the acetonitrile (1.00 ml) are combined in a 10 ml round bottom vessel. The reaction vessel is purged with N2 and equipped with a stirrer magnetic. A solution of the product of Example 1436 (0.262 g, 0.418 mmol) in acetonitrile (2.70 ml) was added. After 2.5 hours, a white precipitate has formed. Ethyl ether (6.0 ml) is added, and the precipitate is filtered, e.g., washes with ether Ethyl, and dried in vacuo to give a white solid (0.250g, 80%). P.f. 246.0-248.0 ° C; XH NMR (CD3OD) d 0.88 (m, 6H), 1.03-1.55 (ra, 10H), 1.76 (m, 1H), 2.11 (m, 1H), 2.74 (s, 6H), 3.11 (m, 8H), 3.37 (m, 6H) ), 4.12 (s, 1H), 4.39 (s, 2H), 5.31 (s, 1H), 6.11 (s, 1H), 6.52 15 (dd, J «8.7, 1.8 Hz, 1H), 7.09 (d, J «7.2 Hz, 1H), 7.23 (d, J - 6.9 Hz, 1H), 7.32-7.38 (m, 2H), 7.47 (ra, 2H), 7.58 (S, 1H), 7.73 (d, J - 8.7 Hz , 2H). HRMS. Calculated for: C40H56N5O4SCI: 702.4053. Jan: 702.4064. Anal, calculated for C40H56N5O4SCI: C, 65.06; H, 7.64; N, 9.48; S, 4.34; Cl, 4.80. Jan: C, 64.90; H, 7.77; N, 9.42; S, 4.16; Cl, 4.89. twenty Examples 1438 - 1454 The compounds of Examples 1438 to 1454 can be prepared according to one or more of the synthetic schemes previously described in this application or using methods known to those skilled in the art. _M______M__I____ _É ___ l ___________ áHI ___ «_ _______ l __________________ ^ _ _________ i ____ M_l ____ á .5 p H I 15 1441., C? 2H "? , - rjé * Z? & - 0 ^, 0 1452. ^ N ^ N ^ ^ S03H 20 I 1 H H - ^^^^^^ Ég & ^^^^^^^^^^^^^^^^^^^^^^^^^^ * g ^^ f ^^^^^^^^ Example 1455 Preparation of: The 3-aminobenzothiepine from step 5 of Example 1398 (0.0165 g / 0.0360 mmol), M-NCO-5000 (0.150 g / 0.30 mmol) (Methoxy-PEG-NCO, MW 5000, purchased from Shearwater Polymers Inc., 2130 Memorial Parkway , SW, Huntsville, Alabama 35801), and CDCI3 (0.7 ml) are combined in an 8 mm NMR tube. The tube is purged with N2. After 72 hours, the reaction mixture is heated to 50 ° C. After 24 hours, an additional aliquot of the 3-aminobenzothiepine from step 5 of Example 1398 (0.0077 g / 0.017 mmol) is added. After 24 hours, the reaction mixture is transferred to a 2 ml ampule and evaporated to dryness with a N2 purge. The resulting white solid is dissolved in hot ethyl ether (2.0 ml) and ethyl acetate. i? jakik "-g8" ^ LBgg - ^^^^ - "Z ._ ^ - *. £ * _. ethyl acetate (0.057 ml / 4 drops), cooled to precipitation and filtered. This precipitation procedure is repeated until no starting material was detected in the precipitate (CCD: SiO2 / 80% EtOAc / hexanes). Concentrate in vacuo to give a white solid (0.0838 g / 51%). XH NMR (CDC13) d 0.82-0.90 (m, 6H), 1. 05-1.49 (m, 14H), 1.18 (t, J «6.8 Hz, 2H), 1.59 (ta, 1H), 2.18 (ta, 1H), 2.34 (s, 2H), 2.78 (s, 6H), 3.04 (ABq, 2H), 3.35-3.80 (m, 625H), 4.09 (d, J, 7.2 Hz, 2H), 5.42 (S, 1H), 5.78 (S, 1H), 6.04 (d, J - 1.6 Hz, 1H), 6.47 (d, J - 6.4, 3.2 Hz, 1H), 7.07 (d, J «7.6 Hz, 1H), 7.31 (sa, 1H), 7.60 (d, J «7.6 Hz, 1H), 7.66 (S, 1H), 7.85 (d, J - 8.8 Hz, 1H). The mass spectroscopy data also verified the desired product.

Example 1456 Preparation of: H ^ K ^^ gt A mixture of 0.845 g (10.7 mmol) of 5-R- [4- (2-bromoethoxyethoxy) phenyl-3, 3-dibutyl-7-dimethylamino-4-R-hydroxybenzothiepin-1,1-dioxide (Example 32 , Step 1), 11.45 g of diethyl iminodiacetate, and 1.14 g of sodium carbonate are maintained at 160 ° C for 3.5 hours, diluted with brine and extracted with CH2C12. The CH2C12 layer is washed with brine, dried (MgSO4) and concentrated in vacuo. The residue was distilled at 0.5 torr. at 120 ° C to remove excess diethyl iminodiacetate to give 1.0 g of a residue. A mixture of this residue, 0.8 g of lithium hydroxide, 25 ml of tetrahydrofuran, and 25 ml of water is maintained at 45 ° C for 3 days and concentrated in vacuo to remove the tetrahydrofuran. The residual aqueous solution is diluted with 25 ml of water and acidified to pH 2 and extracted with CH2C12 (2 × 50 ml). The CH2C12 layer is dried (MgSO.) and concentrated in vacuo. The residual solid is dissolved in hot CH2C12 and triturated with ether. The precipitate is collected to give 0.86 g of the solid, MS (negative FAB), m / e 685 (M + + Na). 20 Example 1457 Preparation of: _ .. ". - __.» _-_-. " »» __ .. _ _ ____ __ _ _ - __ ..a_-w_-a -_-- h__a = ____ - ___? ^^ ^ J ^ _._ M _ ^ _ «_? A solution of 500 mg of 5- (4'-hydroxyphenyl) -7-? O (dimethylamino) tetrahydrobenzo-tiepin-1,1-dioxide (obtained from Example 1402, Step 10) (1.09 mmol) in 5 ml of dimethylformamide was add by means of a syringe to a stirred solution of 36 mg of 95% NaH (1.41 mmol) in 5 ml of dimethylformamide at -10 ° C in a dry ice-acetone bath. The resulting solution is stirred at -10 ° C for 30 minutes. A solution of 1.25 g of 1,5-dibromopentane (5.45 mmol) in 5 ml of dimethylformamide was then added. The mixture is stirred at -10 ° C for another 30 minutes and allowed to warm to room temperature 20 and stirred for 1 hour. The reaction mixture is quenched with water at 0 ° C and extracted with ethyl acetate. The ethyl acetate layer is dried over MgSO and concentrated in vacuo. The crude product is subjected to chromatography on a column of silica gel with 15% ethyl acetate. «___. __ __ __. _______ z M & J &Z ^ yt ethyl / hexane to give 470 mg of the bromide intermediate (71%) as a white solid: XH NMR (CDC13) 60. 91 (m, 6H), 1.20-1.67 (m, 13H), 1.80 -2.00 (m, 4H), 2.22 (m, 1H), 2.82 (s, 6H), 3.08 (Abq, 2H), 3.46 (t, J '6 .9 Hz, 2H), 4.00 (t, J - 6.3 Hz, 2H), 4.1 (s, 1H), 5.49 (s, 1H), 6.00 (d, J - 2.4 Hz, 1H), 6.52 ( dd, J -9.0 Hz, 2.7 Hz, 1H), 6.92 (d, J - 8.7 Hz, 2H), 7.41 (d, J - 8.7 Hz, 2H), 7.90 (d, J - 8.7 Hz, 1H).

A stirred solution of 400 mg of the intermediate bromide compound (0.66 mmole) in 2 ml of tris (trimethylsilyl) phosphite is refluxed at 100 ° C overnight. The reaction mixture is cooled to room temperature and 30 ml of the 50% methanol / water solution are added. The mixture is stirred at room temperature for 5 hours. The mixture is concentrated in vacuo and the resulting aqueous solution is extracted with CH2C12. The CH2C12 solution is dried over MgSO4 and concentrated in vacuo to give a yellowish oil. The oil is dissolved in CH2C12 and triturated with ethyl acetate to give 202 mg of the desired product (50%) as a white solid. XH NMR (CDC13) d 0.90 (m, 6H), 1.14-2.10 (ra, 21H), 2.81 (s, 6H), 3.07 (ABq, 3.9B (m, 3H), 4.11 (s, 1H), 5.48 (s, 1H), 6.02 (d, J - 2.4 Hz, 1H) , 6.53 (dd, J »8.9 Hz, 2.6 Hz, 1H), 6.91 (d, J - 8.1 Hz, 2H), ^^^^^^^^ ^^^^^ j ^ ^ v¡ ___ J £££ ^ * H s ^ & ^^ 7. 40 (d, J. 8.1 Hz, 2H), 7.89 (d, J "8.4 Hz, 1H) Example 1458 Preparation of: A mixture of 0.325 g (1.78 mmol) of the sodium salt of 5-mercaptotetrazoleacetic acid, 1.0 g of potassium carbonate, and 30 ml of dimethylformamide is stirred for 2 hours then loaded with 1.06 g (1.74 mmoles) of sodium hydroxide. -R- [4- (5-bromopentoxy) phenyl-3, 3-dibutyl-7-dimethylamino-4-R-hydroxybenzothiepin-1,1-dioxide (Example 1413, Step 1). The The reaction mixture is stirred for 20 hours at room temperature and concentrated in vacuo. The residue is stirred in ether and water (100 ml each). A waxy material resulted that was insoluble in the layers of both ether and water. The waxy material was combined with the aqueous layer and acidified with concentrated HCl and extracted with CH2C12. The CH2C12 layer is dried (MgSO4) and concentrated in vacuo to give 1.35 g of a syrup, MS (negative FAB), m / e 686 (M + -1); NMR (CDCl,), 8.0 (d, 1H, 7 Hz), 7.50 (d, 2H, 7 Hz), 7.00 (d, 2H, 7 Hz), 6.7 (d, 1H, 7 Hz), 6.2 (s, 1H ), 5.6 (s, 1H), 5.15 (s, 2H), 4.2 (s, 1H), 4.1 (s, 2H), .7 (s, 2H), 3.1-3.2 (ABq, 2H), 2.9 (s) , 6H), 2.3 (t, H, 8 Hz), 0.9-2.0 (m, 24H).

Example 1459 Preparation of: Chloride of (4R-cis) -1- [N- [3- [3, 3-dibutyl-7- (dimethylamino) -2,3,4,5-tetrahydro-4-hydroxy-l, l-dioxide-l -benzothiepin-5-yl]] phenylacetamido] -4-aza-l-azoniabicyclo [2.2.2] octane A solution of the aniline derivative prepared in Example 1398, Step 5 (1.0 g, 2.2 mmol) in dichloromethane (10 ml) at 0 ° C under N2 is treated with N, N-diisopropyl-ethylamine (0.53 ml, 3.1 mmoles, 1.4 eq.), followed by the dropwise addition of chloroacetyl chloride (0.21 ml, 2.6 mmol, 1.2 eq.) over a period of 10 minutes. The reaction mixture is stirred and allowed to warm to 25 ° C over a period of 2 hours. The mixture is quenched by the addition of IN HCl (25 ml) and the aqueous layer is extracted with ethyl acetate (2 x 25 ml). The combined organic extracts are washed with saturated aqueous sodium bicarbonate (2 x 25 ml) and brine (30 ml), and dried (MgSO 4) and concentrated to give a faint yellow oil which crystallized on standing. The white crystals were collected and washed with hexane (50 ml) to give an intermediate chloroacetyl compound (0.74 g, 63%) as a pale yellow solid: XH NMR (CDC13) d 0.95 (m, 6H), 1.15- 1.71 (ma, 11H), 2.24 (m, 1H), 2.85 (s, 6H), 3.12 (ABq, J- 15.0 Hz, J - 48.8 Hz, 2H), 4.15 (d, J "- 6.2 Hz, 1H), 4.23 (s, 2H), 5.57 (s, 1H), 6.05 (m, 1H), 6.58 (dd, J - 8. 9, 2.4 Hz, 1H), 7.37-7.49 yjm, 2H), 7.79 (d, J - 8.5 Hz, 2H), 7.94 (d, J «8.9 HZ, 1H), 8.30 (s, 1H).

A solution of the intermediate chloroacetyl compound (26 mg, 0.05 mmol) in acetonitrile (1 ml) at 50 ° C under N2 is treated with diazabicyclo [2.2.2] octane (DABCO, 10 mg, 0.09 mmol, 1.8 eq.) And stir at 50 ° C for 2 hours. The reaction mixture is allowed to cool to 25 ° C and concentrate to form a residue. The residue is dissolved in hot acetonitrile and tert-butyl methyl ether is added. The mixture is allowed to stand overnight, during which time crystals were formed. The resulting white solid was collected and washed with tert-butyl methyl ether (25 ml) to give the title compound (17 mg, 55%) as a white crystalline solid: NMR 1H (CDCl,) d 0.88 (m, 6H), 1.08-1.42 (ma, 8H), 1.45-1.80 (ma, 4H), 2.14 (m, 1H), 2.75 (s, 6H), 3.08 (ABq, J - 15.1 Hz, J - 34.3 Hz, 2H), 3.21 (m, 6H), 3.79 (m, 6H), 4.12 (s, 1H), 4.62 (s, 2H), 5.41 (s, 1H), 5.99 (m , 1H), 6.48 (d, - 8.9 HZ, 1H), 7.33 (m, 1H), 7.70 (sa, 1H), 7.87 (d, J = 8.6 Hz, 1H), 7.93 (s, 1H), 11.3 ( S, 1H); HRMS. Cale, for C, 4H51N404S: 611.3631. Jan: 611.3638. *? ___ i__ a -_ & - ._.-_________. _. _. * ^^^ i ^ • ^ & l ^ fea ^ e¡ ^ ^ MJ »_ ^ - f« - ^^^, ^. ^ -. __,.,. t ^. ^^, _ Example 1460 Preparation of: Step 1: Preparation of diethyl iminodiacetatosulfonamoyl chloride .- - _. a__ ..AA_t¿ ___, ... ^. ^ - ^ A ^. ,, ^^^.-xi'- _ Sulfuryl chloride (27.552 g / 204.1 mmol) and chloroform (50.0 ml) are combined in a 250 ml round bottom vessel. The reaction vessel is purged with N2, equipped with a magnetic stirrer, and cooled to 0 ° C. A solution of diethyl iminodiacetate (18,902 g / 99.9 mmol) and triethylamine (10,112 g / 99.9 mmol) is added dropwise while maintaining the temperature of the solution below 20 ° C. After the addition was completed, the reaction mixture is allowed to warm to room temperature. After 2 hours, the reaction mixture is poured into ice-cold water (100 ml) and mixed well. The organic layer is separated, washed with aq. 10% (50 ml) and chilled water (2 x 50 ml), dried (CaCl2), filtered and concentrated in vacuo to give an amber liquid (5.706g / 20%). X H NMR (CDC13) d 1.30 (t, 6H), 4.23 (c, 4H), 4.38 (s, 4H). HRMS (EI / M + H). Cale, for C8H? 5N06SCl: 288.0309. Found: 288.0300 ^^^ J ij i Step 2: Preparation of: The 3-aminobenzothiepine from step 5 of Example 1398 (0.503 g / 1.097 mmol), toluene (5.00 ml), diisopropylethylamine (0.148 g / 1148 mmol), and sulfonamoyl chloride-diethyl iminodiacetate prepared in step 1 of this Example ( 0.650 g / 2260 mmoles) were combined in a 25 ml round bottom vessel. The reaction vessel is purged with N2 and equipped with a magnetic stirrer. After 18 hours, additional diisopropylethylamine (0.074 g / 0.574 mmol) and diethyl sulfamoyl-iminodiacetate chloride (0.181 g / 0.628 moles) are added. After 24 hours, dichloromethane (75.0 ml) is added. The mixture is washed with aqueous NaHC03 (25.0 ml), aqueous NaCl (25.0 ml), dried (MgSO), and concentrated in vacuo. empty. Purification by flash chromatography on silica gel eluting with 30% ethyl acetate / hexane and concentration in vacuo gave a white solid (0.349 g / 45%).

X H NMR (CDCl 3) d 0.91 (m, 6H), 1.10-1.70 (m, 10H), 1.27 (t, J - 7.2 HZ, 6H), 1.90 (m, 1H), 2.21 (m, 1H), 2.81 ( s, 6H), 3.09 (dd, J «36.6, 15.3 Hz, 2H), 4.11-4.24 (m, 9H), 5.50 (s, 1H), 5.99 (d, J - 2.4 Hz, 1H), 6.51 (dd) , J. 8.7, 2.4 Hz, 1H), 7.24-7.38 (m, 5H), 7.44 (sa.lH), 7.90 (d, J - 9.0 Hz, 1H). HRMS (ESI / M + H). Cale, for C34H52N3O9S2: 710.3145. Jan: 710.3158.

Step 3: Preparation of the Title Compound: The benzothiepin prepared in step 2 of this Example (0.224 g / 0.316 mmol) and tetrahydrofuran (1.0 ml) are combined in a 10 ml round bottom vessel. The reaction vessel is purged with N2 and equipped with a magnetic stirrer. A solution of LiOH.H20 (0.030 g / 0.715 mmole) in water (0.50 ml) was added. After 4 hours, additional LiOH.H20 (0.015 g / 0.357 mmol) is added. After 30 minutes, water (6.0 ml) is added.

The aqueous mixture is washed with diethyl ether (4 x 4.0 ml), and acidified with aqueous 3.0 N HCl (0.40 ml). After 18 hours, a white precipitate has formed, which is filtered, washed with water (2.0 ml) and concentrated in vacuo. ^^ gs ^^ j £ ^^ ¡^^^. x? íZ .y Precipitation from acetonitrile / diethyl ether / hexanes and recrystallization from methyl t-butyl ether / diethyl ether gave a white crystalline solid (0.109 g / 53%). NMR H (CD3OD) d 0.89 (m, 6H), 1.05-1.50 (m, 10H), 1.68 (ra, 1H), 2.16 (m, 1H), 2.89 (s, 6H), 3.13 (m, 2H), 4.07 (s, 4H), 4.18 (s, 1H), 5.45 (s, 1H), 6.52 (s, 1H). 6.93 (d, J - 8.7 Hz, 1H), 7.19 (d, J - 6.6 Hz, 1H), 7.35 (m, 3H), 7.70 (sa > 1H), 7.99 (d, J - 8.7 Hz, 1H) HRMS (ESI / M + H). Cale, for C30H44N3O9S2: 654.2519. Jan: 654.2512.

As will be appreciated by one skilled in the art, where a non-enantioselective synthesis is employed in any of the above examples and a final enantiomeric enriched product is desired, the enantiomeric enriched end product can be obtained by the use of chiral chromatographic purification in a appropriate stage of synthesis. For example, wherein the synthesis proceeds through the intermediate compound of 5- (4-methoxyphenyl) -7- (dimethylamino) tetrahydrobenzothiepin-1, 1-dioxide which is then demethylated to form the intermediate compound of 5- (4 ' -hydroxyphenyl) -7- (dimethylamino) -tetrahydrobenzothiepin-1,1-dioxide, 5- (4'-methoxyphenyl) -7- (dimethylamino) tetrahydrobenzothiepin-1, 1- The dioxide is preferably subjected to a chiral chromatographic step prior to demethylation. The separated enantiomer is then demethylated to give the enantiomerically enriched intermediate of 5- (4'-5-hydroxyphenyl) -7- (dimethylamino) tetrahydrobenzothiepin-1, 1-dioxide for use in the next step of the synthesis. By way of further illustration, chiral chromatographic purification could be effected immediately prior to Step 7 of Example 1398a using a column 10 such as a Chiralpak AD column with a mobile phase of ethanol / heptane (5% -10% ethanol v / v ) at a wavelength of 220 nm. The separated enantiomer is then used as an intermediate in step 7 of the synthesis whereby it leads to a final enantiomeric enriched product. In a similar way, wherein the synthesis proceeds through the intermediate compound of 5- (3'-methoxyphenyl) -7-dimethylamino) -tetrahydrobenzothiepin-1,1-dioxide which is then demethylated to form the intermediate compound of 5- (3 ') -hydroxyphenyl) -7-dimethylamino) -tetrahydrobenzothiepin-1,1-dioxide, 5- (3'-methoxyphenyl) -7-dimethylamino) -tetrahydrobenzothiepin-1,1-dioxide is preferably subjected to a previous chiral chromatographic purification step to demethylation. The separated enantiomer is then demethylated to give the intermediate compound ^ _, .____- _____ -__, 4_ * __¿_5j__fc_a _-.._ ..? Fr- - - __.____ _.- ..__ ^ .. ^ & ^ - i _____-_. ^. > .-._..__..- _ ___________ _ ___. TO____.____. enantiomerically enriched in 5- (3'-hydroxyphenyl) -7-dimethylamino) -tetrahydrobenzothiepin-1, l-dioxide for use in the next step of the synthesis. By way of illustration, chiral chromatographic purification could be effected immediately prior to Step 9 of Example 1400 with the separated enantiomer then used as the intermediate in Step 9 of the synthesis whereby it leads to an enantiomerically enriched end product. In addition, the chiral chromatographic purification can be used wherein the synthesis proceeds through the intermediate of 5- (3 'or 4'-aminophenyl) -7-dimethylamino) -tetrahydro-benzothiepin-1,1-dioxide, such as The Example that Corresponds to Scheme XII. For example, the chiral chromatographic purification could be effected immediately following Step 5 of the Example corresponding to Scheme XII to give the enantiomeric enriched intermediate of 5- (3 'or 4'-aminophenyl) -7-dimethylamino) -tetrahydrobenzothiepin-1 , 1-dioxide for use in the next step of the synthesis. Alternatively, an enantioselective synthesis, such as one described in Example 1461 below, could be used to provide 5- (3 'or 4'-aminophenyl) -7-dimethylamino) -tetrahydro-benzothiepin-1, 1-dioxide enantiomeric enriched wanted. --_._-.._ ,, _, ____, .- - .. .. .. .. - -fc ^ A. ^ ^ JM _ .. ^ _ A, ^^^ & .. J _. ^ ^ - .. ___- x_ > ____, - > ^ __ A_a ____ * ________ Example 1461 Preparation of: Step 1: Preparation of the triflic intermediate A solution of 10.17 g (22.13 mmoles) of 5- (4'-hydroxyphenyl) -7-dimethylamino) -tetrahydrobenzothiepin-1,1-dioxide (prepared in Step 7 of Example 1398a) in pyridine (42 ml) at 0 ° C under nitrogen gas is treated with triflic anhydride (4.1 ml, 24.4 mmol, 1.1 equivalents) by drip. During the addition of the addition, the bath was removed and the reaction was stirred at room temperature for 21 hours. The pyridine was removed in vacuo, the resulting oil is taken up in water (100 ml) and extracted three times with ethyl acetate (45 ml each). The combined organic substances are washed with 2N HCl (100 ml), 10% CuSO 4 (100 ml) and brine (100 ml), and then dried over MgSO 4, filtered and the solvent Gü ^ H ^^^ it evaporates. The residue is purified by chromatography on silica gel (25% ethyl acetate in hexane) to give the desired title compound as a faint yellow foam (11.42). g, 87.2%): NMR * H (CD, 0D) d 0.85-1.0 (m, 6H), 1.0-1.15 (m, 10H), 1.76 (t, J - 12.6 Hz, 1 H), 2.12 (t, J - 13 Hz, 1H), 2.79 (s, 6H), 3.1-3.2 (c *, 2H), 4.05 (s, 1H), 5.42 (S, 1H), 5.88 (d, J - 2.1 Hz, 1H ), 6.59 (dd, J - 8.9, 2.1 Hz, 1H), 7.35 (d, J - 7.8 Hz, 1H), 7.49 (d, J "7.8 Hz, 1H), 7.57 (t, J - 7.8 Hz, 1H), 7.66 (s, 1H), 7.77 (d, J, 8.9 Hz, 1H).

Step 2: Preparing the Imine To a solution of 11.41 g (19.28 mmol) of the triflate (prepared in Step 1 above), palladium (II) acetate (433 mg, 1.93 mmol, 10 mol%), 2,2 '-bis- (biphenyl) phenyl) -1, 1'-racemic (1.41 g, 2.26 mmol, 12 mol%) and cesium carbonate (8.86 g, 27.2 mmol, 2.0 equivalents) in 114 ml of tetrahydrofuran are added 6.6 ml (39.4 mmoles, 2.0 equivalents) of benzophenone imine. The mixture is stirred under reflux for four hours, filtered through celite and the solvent is removed in vacuo to give 19.11 g of a deep red foam: XH NMR (CDOD,) d 0.8-1.45 (m, 16H), 1.6-1.75 (m, 1H), 1.9-2.05 (m, 1 H), 2.78 (s, 6H), 2.98-3.15 (c ^, 2H), 3.88 (6, 1H), 5.17 (s, 1H), 5.92 (d, J - 2.2 Hz, 1H), 6.54 (d, J - 9.1, 2.7 Hz, 1H), 6.74 (d, J «8.1 Hz, 1H ), 6.80 (sa, 1H), 7.0-7.12 (m, 2H), 7.15-7.25 (m, 3H), 7.35-7.52 (m, 7H), 7.52-7.68 (m, 2H), 7.71 (d, J) - 7.9 Hz, 1H).

Step 3: Preparation of Aniline To a solution of 19.1 g (theoretically 19.3 mmol) of the crude imine (prepared in Step 2 above) in methanol (200 ml) is added sodium acetate (6.33 g, 77.2 mmol, 4 equivalents) and hydroxylamine hydrochloride (4.02). g, 57.9 mmol, 3 equivalents). After stirring one hour, IN sodium hydroxide (100 ml) is added and the mixture is extracted with methylene chloride (2 X 100 ml, I X 50 ml). The combined organic substances are washed with brine (100 ml), dried over MgSO, filtered and the solvent evaporated. The residue is purified by chromatography on silica gel (50% ethyl acetate in hexane) to give the desired title compound as a yellow foam (8.64 g, 97.9%). 1 H NMR (CD, OD) d 0.86-0.97 (m, 6H), 1.07-1.52 (m, 10H), 1.76 (t, J - 12.6 Hz, 1 H), 2.10 (t, J - 11.5 Hz, 1H), 2.79 (s, 6H), 3.05-3.18 (c ", 2H), 4.10 (s, 1H), 5.22 (s, 1H), 6.19 (s, 1H), 6.54 (dd, J - 8.9, 1.9 Hz, 1H) 6.68 (d.J - 8 Hz, 1H), 6.82 (s, 1H), 6.86 (d, J - 7.2 Hz, 1H), 7.14 (t, J - 7.8 HZ, 1H), 7.73 (d, J - 8.9 Hz, 1H).

BIOLOGICAL TESTING The utility of the compounds of the present invention is shown by the following tests. These assays are performed in vitro and in animal models using essentially a recognized procedure to show the utility of the present invention.

In Vitro assay of compounds that inhibit IBAT-mediated uptake of [14C] -Taurocholate (TC) in H14 cells The baby hamster kidney (BHK) cells transfected with the human IBAT cDNA (H14 cells) are seeded at 60,000 cells / well in 96-well Top-Count tissue culture plates or plates for test runs within the range of 24 hours of planting, 30,000 cells / cavity for the test runs within ^^^^^^ ^ ^ ^ j ^^^^^ g ^^^^^^^^^^^ and ^^^^^^^^^^ j ^^^^ A ^ íg ^ of the 48 hour interval, and 10,000 cells / cavity for the test runs within the 72 hour interval. On the day of the assay, the cell monolayer is gently washed once with 100 μl of Dulbecco's Modified Eagle's medium buffer solution with 4.5 g / 1 glucose + 0.2% (w / v) serum albumin of free fatty acid bovine- (FAF) BSA). To each cavity is added 50 μl of a concentrate twice of the test compound in the assay buffer in the presence of 50 μl of 6 μM [14 C] -taurocholate in the assay buffer (final concentration of 3 μM [14C] -taurocolato). The plates or culture boxes of the cells are incubated 2 hours at 37 ° C prior to gently washing each cavity twice with 100 μl of a saline solution buffered with Dulbecco's phosphate at 4 ° C containing 0.2% (w / v ) of (FAF) BSA. The cavities are then gently washed once with 100 μl of PBS at 4 ° C without (FAF) BSA. To each 200 μl of the liquid is added a fluid for the count of the scintillations, the plates are thermally sealed and agitated for 30 minutes at room temperature prior to the measurement of the radioactivity in each cavity on a Packard Top-Count instrument. _Éß_É_¡_ii ___ i______ .feAUth .. - ^ ¿^^^ J ^^^ In Vitro Test of the compounds that inhibit the absorption of [1C] -Alanine The alanine absorption test is performed in a manner identical to the taurocholate assay, with the exception that the labeled alanine is replaced by the tagged taurocholate.

In Vivo Test of compounds that inhibit absorption by the ileum of the Rat of [1C] -Taurocholate in Bile (See "Metabolism of 3a, 7β-dihydroxy-7a-methyl-5β-cholanic acid and 3a, 7β-dihydroxy-7a-methyl-5β-cholanic acid in hamsters" in Biochimica et Biophysica 15 Acta 833 (1985) 196-202 by Une and colleagues). Male wistar rats (200-300 g) are anesthetized with inactin at 100 mg / kg. The bile ducts are piped with a length of 25.4 cm (10") of PE10 tubing, the small intestine is exposed and placed on a gauze pad, a cannula (with luer fixation of 0.317 cm (1/8 inch), taper female adapter) is inserted 12 cm from the junction of the small intestine and the cecum.A groove is cut 4 cm from this same junction (using a length of 8 cm of ileus) 20 ml of the solution . »_. . «., -_ - -.....« .., ^^ - ^ __ _. . _ j - ^ - > _____s_l_____t_ ^, -.__.- ^ Mi_ ^ .sfi ^ S ^^ ,, ___.-_-_, ..._ .. "». buffered Dulbecco's hot phosphate, pH 6.5 (PBS) is used to flush the intestine segment. The remote opening is provided with a cannula with a length of 20 cm of silicone tubing (0.0507 cm (0.02") of D.I. x 0.093 cm (0.037") of D.E.). The proximal cannulae are hooked to a peristaltic pump and the intestine is washed for 20 minutes with warm PBS at 0.25 ml / minute. The temperature of the intestine segment is checked continuously. At the beginning of the experiment, 2.0 ml of the control sample of [14 C] -taurocholate at 0.05 ml / ml with 5 mM cold taurocholate) are loaded into the intestine segment with a 3 ml syringe and the collection of the biliary sample. The control sample is infused at a rate of 0.25 ml / minute for 21 minutes. The fractions of the biliary samples are collected every 3 minutes during the first 27 minutes of the procedure. After 21 minutes of infusion of the sample, the ileus loop is washed with 20 ml of warm PBS (using a 30 ml syringe), and then the loop is washed for 21 minutes with warm PBS at 0.25 ml / minute. A second perfusion is started as described above but is with the test compound that is also administered (21 minutes of administration followed by 21 minutes of washing) and the bile is sampled every 3 minutes during the first 27 ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ minutes If necessary, a third perfusion is performed as above which typically contains the control sample.

Measurement of Hepatic Cholesterol Concentration (HEPATIC COL.) The liver tissue was weighed and homogenized in chloroform: methanol (2: 1). After the homogenization and After centrifugation, the supernatant was separated and dried under nitrogen. The residue is dissolved in isopropanol and the cholesterol content is measured enzymatically, using a combination of oxidase and cholesterol peroxidase, as described by Allain, C. A., et al. (1974) Clin. Chem. 20, 470.

Measurement of the Activity of Reductase-Coa Hepatic HMG (HMG COA) Liver microsomes were prepared by homogenizing the liver samples in a phosphate / sucrose buffer, followed by centrifugal separation. The material turned into microspheres, final, was resuspended in a buffer solution and a aliquot was evaluated to verify the activity of the HMG CoA reductase by incubation for 60 minutes at 37 ° C in the presence of 14C-HMG-CoA (Dupont-NEN). The reaction is stopped by adding 6N HCl followed by centrifugation. An aliquot of the supernatant was separated, by thin layer chromatography, and the spot or spot corresponding to the product of the enzyme was scraped off the plate or box, extracted and the radioactivity was determined by scintillation counting. (Reference: Akerlund, J. and Bjorkhem, I. (1990) J. Lipid Res. 31, 2159).

Determination of Serum Cholesterol (SER. CHOL., HDL-CHOL, TGI and VLDL + LDL) Total serum cholesterol (SER.CHOL.) Is measured enzymatically using a set or commercial set from Wako Fine Chemicals (Richmond, VA); Cholesterol Cll, Catalog No. 276-64909. HDL cholesterol (HDL-CHOL) was evaluated using this same set or set after the precipitation of VLDL and LDL with the HDL Cholesterol reagent from Sigma Chemical Co., Catalog No. 352-3 (dextran sulfate method) ). Total serum triglycerides (bleached) (TGI) were evaluated enzymatically with Sigma Chemical Co. GPO-Trinder, Catalog No. 337-B. Concentrations of cholesterol VLDL and LDL (VLDL + LDL) were calculated as the difference between total and HDL cholesterol.

Measurement of the Hepatic Cholesterol 5-a-hydroxylase Activity (7a-OHase) Liver microsomes were prepared by homogenizing the liver samples in a phosphate / sucrose buffer solution, followed by centrifugal separation 10. The material converted to final microspheres was resuspended in the buffer solution and an aliquot was evaluated to verify the activity of 7-α-hydroxylase of cholesterol by incubation for 5 minutes at 37 ° C in the presence of NADPH. After extraction in petroleum ether, the organic solvent was evaporated and the residue dissolved in acetonitrile / methanol. The enzymatic product was separated by the injection of an aliquot of the extract onto a C? 8 reverse phase HPLC column and the quantification of the eluted material using UV detection at 240 nm. (Reference: Horton, J. D., et al., (1994) J. Clin. Invest. 93, 2084). --2 _ *. T___. . ^ _____? --..___ ^ A _ ^ -. ^ L -__.- .... ... ". ,,, ... jfei iJ» & amp; feiSfc «_--, __. .. - < • _., _. ",. -.- __, ..._: 1 _ .. ¿_i_; • _., Rat Fattening Test Male Wistar rats (275-300 g) are administered with inhibitors of IBAT using a method of oral fattening. The drug or vehicle (0.2% Tween 80 in water) is administered once a day (9: 00-10: 0 a.m.) for 4 days at variable dosages in a final volume of 2 ml per kilogram of body weight. The total fecal samples are collected during the final 48 hours of the treatment period and analyzed to check the bile acid content using an enzyme assay as described below. The efficacy of the compound is determined by comparing the increase in fecal bile acid (FBA) concentration in the 5 treated rats with respect to the average FBA concentration of the rats in the vehicle group.

Measurement of Fecal Bile Acid Concentration (FBA) The total fecal production of individually housed hamsters was collected for 24 or 48 hours, dried under a stream of nitrogen, pulverized and weighed. Approximately 0.1 grams are removed by weighing and extracted in an organic solvent (butane / water). Following the separation and drying, the residue dissolved in methanol and the amount of bile acid present was measured enzymatically using the steroid 3a-hydroxysteroid dehydrogenase reaction with the bile acids to reduce NAD. (Reference: Mashige, F., and 5 collaborators, (1981) Clin. Chem. 27, 1352).

Absorption of C ^] taurocholate in the Vesicles of the Membrane Limit of the Tail of the Rabbit (BBMV) The limiting membranes of the tail of the ileum of the rabbit were prepared from the mucosa of the frozen ileus by the calcium precipitation method described by Malathi et al. (Reference: 1979) Biochimica Biophysica Acta, 554, 259). The method to measure The taurocholate was essentially as described by Kramer et al. (Reference: (1992) Biochimica Biophysica Acta, 1111, 93) except that the assay volume was 200 μl instead of 100 μl. Briefly, at room temperature, a 190 μg solution containing 2 μM of [3 H] -taurocholate (0.75 μCi), 20 mM tris, 100 mM NaCl, 100 mM mannitol pH 7.4, was incubated for 5 seconds with 10 μl of the vesicles of the boundary membrane of the tail (60-120 μg of protein). The incubation was initiated by the addition of the BBMV while stirring in a swirl and the reaction is stopped by the addition of 5 ml of the ___ &_ _.,, .__ -_ ._ ___ ..-_____. 3 _.__, | f. . RtYii? YM ÉÍfti? __? Ír_ilfií "* - ~ & ~ __.___-.__ _ - ___- * _.

Ice-cooled buffer solution (20 mM Hepes-tris, 150 mM KCl) followed immediately by filtration through a nylon filter (0.2 μm pore size) and an additional 5 ml wash with the buffer buffer.

Acyl-Coa; Acyl Transferase of Cholesterol (ACAT) The intestinal microsomes of the rat and hamster liver were prepared from the tissue as previously described (Reference: (1980) J. Biol. Chem. 255, 9098) and used as a source of the ACAT enzyme. The assay consisted of a 2.0 ml incubation containing 24 μl of Oleoyl-Coa (0.05 μCi) in a buffer solution of 50 mM sodium phosphate, 2 mM DTT of pH 7.4 containing 0.25% BSA and 200 μg of the microsomal protein. The assay was initiated by the addition of oleoyl-Coa. The reaction was followed for 5 minutes at 37 ° C and terminated by the addition of 8.0 ml of chloroform / methanol (2: 1). At extraction, 125 μg of cholesterol oleate in chloroform methanol was added to act as a carrier and the organic and aqueous phases of the extraction were separated by centrifugation after complete swirling. The chloroform phase was brought to dryness and then applied as spots or spots on a plate or box for CCD of silica gel 60 and is revealed in hexane / ethyl ether (9: 1). The amount of the cholesterol ester formed was determined by measuring the amount of the radioactivity incorporated in the spot or cholesterol oleate spot on the CCD plate or box with a Packard snapshot former. iga ___, u8 «it_. - -? ,. < a ha¡B¡? ífefc .., & - &,. • »~ * ~, nj» A_ v - -A- ^ _. < »E < * t- ..3tot ./ _ TABLE 11 Rat Fattening Assessment Data for Some Additional Compounds of the Present Invention gj ^ H_____l_________ É__üt ___ - ^^. aÉl ^ ... ^,, to- - '- * • - ^ "A'-iS' ^ The examples herein can be repeated with similar success by substituting the reagents and / or the operating conditions generally or specifically described in this invention for those used in the preceding examples. Having thus described the invention, it is evident that it can be varied in different ways. Such variations are not to be considered as a departure from the spirit and scope of the present invention, and all such modifications and equivalents as would be obvious to a person skilled in the art are proposed to be included within the scope of the following claims. ^ tfMMHÉÍidittÍÉ &MÍlli ^ Mtfta ^ fe -_ '_ t "-ir - -'- •' - - It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention. Having described the invention as above, property is claimed as contained in the following: ^^^^^ g ^^^^^^^ ^^^^^^^^^^^^^

Claims (25)

1. CLAIMS 1.- A compound of the formula (1) characterized in that: q is an integer from 1 to 4; n is an integer from 1 to 2; R1 and R2 are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, haloalkyl, alkylaryl, arylalkyl, alkoxy, alkoxyalkyl, dialkylamino, alkylthio, (polyalkyl) aryl, and cycloalkyl, wherein alkyl, alkenyl, alkynyl, haloalkyl, alkylaryl, arylalkyl, alkoxy, alkoxyalkyl, dialkylamino, alkylthio, (polyalkyl) aryl, and cycloalkyl are optionally substituted with one or more substituents selected from the group consisting of of OR9, NR9R10, N + R9R10RWA ", SR9, S + R9R10A". P + R9R10R A ", S (0) R9, S02R9, S03R9, C02R9, CN, halogen, oxo, and C0NR9R10, wherein alkyl, alkenyl, alkynyl, alkylaryl, alkoxy, alkoxyalkyl, (polyalkyl) aryl, and cycloalkyl optionally have one or more carbons replaced by 0, NR9, N + R9R10A-, S, SO, S02, S + R9A ~, P + R9R10A ", 0 phenylene, wherein R9 'R10' and Rw are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, acyl, heterocycle, ammonium alkyl, arylalkyl, carboxyalkyl, carboxyheteroaryl, carboxyheterocycle, carboalkoxyalkyl , carboxyalkylamino, heteroarylalkyl, heterocyclylalkyl, and alkylammoniomalkyl; or R1 and R2 are taken together with the carbon to which they are attached to form C3-C10 cycloalkyl; R3 and R4 are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, acyloxy, aryl, heterocycle, OR9'NR9R10, SR9, S (0) R9, S02R9, and SO3R9, wherein R9 and R10 are defined as above, or R3 and R4 together form = 0, = N0Rn, = S, = NNRnR12 , = NR9, or = CRnR12, wherein R11 and R12 are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, aryl, arylalkyl, alkenylalkyl, alkynylalkyl, heterocycle, carboxyalkyl, carboalkoxyalkyl, cycloalkyl, cyanoalkyl, OR9, NR9R10, SR9, S (0) R9, S02R9, S03R9, C02R9, CN, halogen, oxo, and CONR9R10, wherein R9 and R10 are as defined above, with the proviso that both R3 and R4 can not be OH, NH2 and SH, or R11 and R12 together with the nitrogen or carbon atom to which they are attached to form a cyclic ring; R5 is aryl substituted with one or more 0R13a, wherein R13a is selected from the group consisting of alkylarylalkyl, alkylheteroarylalkyl, alkylheterocyclylalkyl, heterocyclylalkyl, heteroarylalkyl, heterocyclylalkyl quaternary, alkylammoniomalkyl, and carboxyalkylaminocarbonylalkyl, R13a is optionally substituted with one or more groups selected from the group which consists of hydroxy, amino, sulfo, carboxy, alkyl, alkyl, carboxyalkyl, heterocycle, heteroaryl, sulfoalkyl, quaternary heterocycle, quaternary heteroaryl, quaternary heterocyclylalkyl, quaternary heteroarylalkyl, guanidinyl, OR9, NR9R10, N + R9RnR12A ", SR9, S ( 0) R9, S02R9, S03R9, oxo, C02R9, CN, halogen, CONR9R10, S02OM, S02NR9R10, PO (OR16) OR17, P + R9R10RnA-, S + R9R10A ", and C (0) OM, where A" is an anion pharmaceutically acceptable and M is a pharmaceutically acceptable cation, wherein R16 and R17 are independently selected from the substituents constituting R9 and M; and R6 is selected from the group consisting of H; alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, quaternary heterocycle, OR30, SR9, S (0) R9, S02R9, and SO3R9, wherein alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, quaternary heterocycle, and quaternary heteroaryl they can be substituted with one or more substituent groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocycle, arylalkyl, quaternary heterocycle, quaternary heteroaryl, halogen, oxo, OR13, NR13 R14 , SR13, S (0) R13, S02R13, SO3R13, NR13OR14, NR13NR14R15, N02, C02R13, CN, OM, S02OM, S02NR13R14, C (0) NR13R14, C (0) OM, COR13, NR13C (0) R14, NR13C (0) NR14R15, NR13C02R14, 0C (0) R13, OC (O) NR13R14, NR13SOR14, NR13S02R14, NR13S02R14R15, NR13S02NR14R15, P (0) R13R14, P + R13R14R15A ', P (OR13) OR14, S + R13R14A', and N + R9R11R12A-, wherein; A "is a pharmaceutically acceptable anion and M is a pharmaceutically acceptable cation, said alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, and heterocycle may also be substituted with one or more substituent groups selected from the group consisting of OR 7, NR7R8, SR7, S (0) R7, S02R7, S03R7, C02R7, CN, oxo, CONR7R8 'N + R7R8R9A ", alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, arylalkyl, quaternary heterocycle, quaternary heteroaryl, P (0) R 7R8, P + R7R8R9A ~, and P (O) (OR7) OR8, and wherein said alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, and heterocycle "may optionally have one or more carbons replaced by O, NR, N + R7R8A ", S, SO, S02, S + R7A", PR7, P (0) R7, P + R7R8A-, or phenylene, and R13, R14, and R15 are independently selected from the group consisting of hydrogen, alkyl , alkenyl, alkynyl, polyalkyl, polyether, aryl, arylalkyl, alkylarylalkyl, alkylheteroarylalkyl, alkylheterocyclyl alkyl, cycloalkyl, heterocycle, heteroaryl, quaternary heterocycle, quaternary heteroaryl, heterocyclylalkyl, heteroarylalkyl, «____________ £ __ __., _ ^ ._____ S_S __» -_ ^ A ^^^^^ - - ** '"- *" » quaternary heterocyclylalkyl, quaternary heteroarylalkyl, alkylammoniomalkyl, and carboxyalkylaminocarbonylalkyl, wherein alkyl, alkenyl, alkynyl, arylalkyl, heterocycle, and polyalkyl optionally have one or more carbons replaced by 0, NR9, N + R9R10A ", S, SO, S02, S + R9A ", PR9, P + R9R10A", P (0) R9, phenylene, carbohydrate, amino acid, peptide, or polypeptide, and R13, R14, and R15 are optionally substituted with R13a are optionally substituted with one or more groups selected from the group which consists of hydroxy, amino, sulfo, carboxy, alkyl, carboxyalkyl, heterocycle, heteroaryl, sulfoalkyl, quaternary heterocycle, quaternary heteroaryl, quaternary heterocyclylalkyl, quaternary heteroarylalkyl, guanidinyl, OR9, NR9R10, N + R9R11R12A ", SR9, S (0) R9, S02R9, S03R9, oxo, C02R9, CN, halogen, CONR9R10, S020M, S02NR9R10, PO (OR16) OR17, P + R9R10R11A ", S + R9R10A", and C (0) 0M, wherein R16 and R17 are selected independently of the substituents which constitute R9 and M; or R13 and R14, together with the nitrogen atom to which they are attached to form a mono or heterocycle ^ tó ^ ^^^^^^^^^^^^^^^^^^^^^^^^ & ^ yÉ ^^^^ g | ^ j ^^^^^^^^^^ ^^^^^^^^^^^^ g ^ ¿^ »» ^^^ polycyclic which is optionally substituted with one or more radicals selected from the group consisting of oxo, carboxy, and quaternary salts; or R14 and R15, together with the nitrogen atom to which they are attached to form a cyclic ring; and R 30 is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, aryl, acyl, heterocycle, ammonium alkyl, alkylaminoalkyl, arylalkyl, carboxyalkyl, carboxyheteroaryl, carboxyheterocycle, carboalkoxyalkyl, carboxyalkyl amino, heteroarylalkyl, heterocyclylalkyl, and alkylammoniomalkyl; and R 7 and R 8 are independently selected from the group consisting of hydrogen and alkyl; and one or more Rx are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, polyalkyl, acyloxy, aryl, arylalkyl, halogen, haloalkyl, cycloalkyl, heterocycle, heteroaryl, polyether, quaternary heterocycle, quaternary heteroaryl, OR13, NR13R14 , SR13, S (0) R13, S (0) 2R13, S + R13R14A ", NR13OR14, NR13NR14R15, N02, C02R13, CN, OM, S02OM, S02NR13R14, NR14C (0) R13, C (0) NR13R14, NR14C ( 0) R13, C (0) OM, COR13, OR18, S (0) nNR18, NRI3R18, NR, 8OR14, N + R9R11R12A ", P + R9RUR12A-, amino acid, peptide, polypeptide, and carbohydrate, wherein alkyl, alkenyl, alkynyl, cycloalkyl, aryl, polyalkyl, heterocycle, acyloxy, arylalkyl, haloalkyl, polyether, quaternary heterocycle, and quaternary heteroaryl can be further substituted with OR9, NR9R10, N + R9R11R12A ", SR9, S (0) R9, S02R9, S03R9, oxo, C02R9, CN, halogen, CONR9R10, S02OM, S02NR9R10, PO (OR16) OR17, P + R9RnR12A", S + R9R10A ", or C (0) OM, and wherein R18 is selected from the group consisting of acyl, arylalkoxycarbonyl, arylalkyl, heterocycle, heteroaryl, alkyl, wherein alkyl, arylalkoxycarbonyl, arylalkyl, heterocycle, heteroaryl, alkyl, quaternary heterocycle, and heteroaryl quaternary optionally substituted with one or more substituents selected from the group consisting of OR9, NR9R10, N + R9R11R12A ", SR9, S (0) R9, S02R9, S03R9, oxo, C02R9, CN, halogen, C0NR9R10, SO3R9, S02OM, S02NR9R10 , PO (OR16) OR17, and C (0) OM, where Rx one or more carbons are optionally replaced by O, NR13, N + R13R14A ", S, SO, S02, S. + TtR_113JAtv- ", PR, 113J, P (0) R13, P + R13R1A", phenylene, amino acid, peptide, polypeptide, carbohydrate, polyether, or ___ polyalkyl, wherein said polyalkyl, phenylene, amino acid, peptide, polypeptide, and carbohydrate, one or more carbons are optionally replaced by 0, NR, N + R9R10A ", S, SO, S02, S + R9A", PR9, P + R9R10A_, or P (0) R9; wherein the quaternary heterocycle and quaternary heteroaryl are optionally substituted with one or more groups selected from the group consisting of alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocycle, arylalkyl, halogen, oxo, OR13, NR13R14, SR13, S (0) R13, S02R13, S03R13, NR130R14, NR13NR14R15, N02, C02R13, CN, OM; S02NR13R14, C (0) NR13R14, C (0) 0M, COR13, P (0) R13R14, P + R13R14R15A ", P (0R13) 0R14, S + R13R14A ', and N + R9R11R12A ", or a pharmaceutically acceptable salt, solvate, or prodrug thereof 2. A compound of claim 1 characterized in that: R5 is phenyl substituted with OR13a; R13a is independently selected from the group consisting of alkylarylalkyl, alkylheteroarylalkyl, and carboxyalkylaminocarbonylalkyl; Y . < * £ ___.__ £ ______ ._.- '_ .., ^ _ ^^^^^^^^^^^^^^^^: ^^^^: ^^^^^^^^^^ ^^^^^^^ - R13a is optionally substituted with one or more groups selected from the group consisting of carboxy, quaternary heterocycle, quaternary heteroaryl, and NR9R10. 3. A compound of claim 1 characterized in that n is 1 or 2. 4. A compound of claim 1 characterized in that R and R are independently selected from the group consisting of Hydrogen and alkyl. 5. A compound of claim 1 characterized in that R7 and R8 are hydrogen. 6. A compound of claim 1 characterized in that R and R are selected 15 independently of the group consisting of hydrogen and OR9. 7. A compound of claim 1 characterized in that R is hydrogen and R4 is hydroxy. 8. A compound of claim 1 characterized in that one or more Rx are independently selected from the group consisting of OR13 and NR13R14. 9. A compound of claim 1 characterized in that one or more Rx are selected ^^ js ^^^^^^^^^ v ^^^. independently of the methoxy and dimethylamino group. 10. A compound of claim 1 characterized in that R1 and R2 are independently selected from the group consisting of hydrogen and alkyl. 11. A compound of claim 1 characterized in that R1 and R2 are independently selected from the group consisting of alkyl. 12. A compound of claim 1 characterized in that R1 and R2 are the same alkyl. 13. A compound of claim 1 characterized in that R1 and R2 are each n-butyl. 14. A compound of claim 1 characterized in that n is 1 or 2; R1 and R2 are n-butyl; R3 and R6 are hydrogen; R4 is hydroxy; R7 and R8 are hydrogen; and one more are independently selected from methoxy and dimethylamino. 15. A compound of claim 1 characterized in that it has the structural formula: 16. A compound of claim 1 characterized in that it has the structural formula: 17. A compound of claim 1 characterized in that it has the structural formula: 18. A compound of claim 1 characterized in that it has the structural formula: 19. A compound of claim 1 characterized in that it has the structural formula: ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ ^^^^^^^^^^^^^^ j ^^^^^^ 20. A compound of claim 1 characterized in that it has the structural formula: 21. A compound selected from the group consisting of: ^^ ¿^^^ ii «¡¡¡¡¡¡¡^ ^ ^ ^^^^^^^^^^^^^^^^^^^^^^ ^^ g ^^^^^^^^ -_. ___. ^ _______ a _. __. »~ _ St- -A __.- - - - - '- -' - ^^ M _... ^.-._. ", ^ _ .. - ^,. ^^^ > MÍJ _-- if ----. ^ JW ^ fc. ^ r .._ «_ *» - .. & amp; amp; & amp; 1? ^^^^^^^^ j ^^^^^^^^^^^^^ ^^^^^ - ^^^^^^^^^^^^^^^^^^^^^ ^ i ^^^^^ u ^^^^^^^^^^^^^^^^^^^^^^^^ H H H H 22. A compound of the formula (I) characterized in that: q is an integer from 1 to 4; n is an integer from 0 to 2; R1 and R2 are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, Haloalkyl, alkylaryl, arylalkyl, alkoxy, alkoxyalkyl, dialkylamino, alkylthio, (polyalkyl) aryl, and cycloalkyl, wherein alkyl, alkenyl, alkynyl, haloalkyl, alkylaryl, arylalkyl, alkoxy, alkoxyalkyl, dialkylamino, alkylthio, (polyalkyl) aryl, and cycloalkyl are optionally substituted with one or more substituents selected from the group consisting of OR9, NR9R10, N + RR10RWA ", SR9, S + R9R10A". P + R9R10RUA ", S (0) R9, S02R9, S03R9, C02R9, CN, halogen, oxo, and CONR9R10, wherein alkyl, alkenyl, alkynyl, alkylaryl, alkoxy, alkoxyalkyl, (polyalkyl) aryl, and cycloalkyl optionally have one or more carbons replaced by O, NR9, N + R9R10A_, S, SO, S02, S + R9A ", P + R9R10A", or phenylene, wherein R9 'R10' and Rw are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, acyl, heterocycle, ammonioalkyl, arylalkyl, carboxyalkyl, carboxyheteroaryl, carboxyheterocycle, carboalkoxyalkyl, carboxyalkylamino, heteroarylalkyl, heterocyclylalkyl, and alkylammonioalkyl; or R1 and R2 are taken together with the carbon to which they are attached to form C3-C? 0 cycloalkyl, R3 and R4 are independently selected from a group consisting of H, alkyl, alkenyl, alkynyl, acyloxy, aryl, heterocycle, OR9, NR9R10, SR9, S (0) R9, S02R9, and SO3R9, wherein R9 and R10 are defined as above; or R3 and R4 together form = 0, = NORu, = S, = NNRUR12, = NR9, or = CRUR12, wherein R11 and R12 are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, aryl, arylalkyl, alkenylalkyl, alkynylalkyl, heterocycle, carboxyalkyl, carboalkoxyalkyl, cycloalkyl, cyanoalkyl, OR9, NR9R10, SR9, S (0) R9,? 02R9, SO3R9, C02R9, CN, halogen, oxo, and CONR9R10, wherein R9 and R10 are as defined above, with the proviso that both R3 and R4 can not be OH, NH2 and SH, or R11 and R12 together with the nitrogen or carbon atom to which they are attached to form a cyclic ring; R5 is aryl substituted with one or more OR13b, wherein R13b is selected from the group consisting of alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, arylalkyl, alkylarylalkyl, alkylheteroarylalkyl, alkylheterocyclylalkyl, cycloalkyl, heterocycle, heteroaryl, quaternary heterocycle, quaternary heteroaryl, heterocyclylalkyl, heteroarylalkyl, quaternary heterocyclylalkyl, heteroarylalkyl quaternary, alkylammoniomalkyl, and carboxyalkylaminocarbonylalkyl, R 13b is substituted with one or more groups selected from the group consisting of 5-carboxyalkyl, heterocycle, heteroaryl, quaternary heterocyclylalkyl, quaternary heteroarylalkyl, or guanidyl, and R 6 is selected from the group consisting of H, alkyl , alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, quaternary heterocycle, OR30, SR9, S (0) R9, S02R9, and S03R9, wherein alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, quaternary heterocycle, and heteroaryl Quaternary can be substituted with one or more substituent groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocycle, arylalkyl, quaternary heterocycle, quaternary heteroaryl, halogen, oxo, OR13, NR13 R14, SR13, S (0) R13, S02R13, S03R13, NR130R14, NR13NR1 R15, N02, C02R13, CN, OM, S02 OM, S02NR13R14, C (0) NR13R14, C (O) 0M, COR13, NR13C (0) R14, NR13C (O) NR14R15, 25 NR13C02R14, OC (0) R13, OC (O) NR13R14, NR13SOR14, _ *. - »..-_ t __ ^ _ JSZaM.?Z-. * c- ÁJ ,. ? ^ = J ^ = ^ _ 1? ^ _ ^: ^ _ ^ _? ^^ NR13SONR14R15, NR13S02R1 R15, P (O) R13R14, P + R13R14R1 5A ", P (OR13) OR14, S + R13R14A", and N + R9R11R12A-, wherein; A "is a pharmaceutically acceptable anion and M is a pharmaceutically acceptable cation, said alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, and heterocycle, may further be substituted with one or more substituent groups selected from the group consisting of of OR 7, NR7R8, SR7, S (0) R7, S02R7, S03R7, C02R7, CN, oxo, CONR7R8 'N + R7R8R9A ", alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, arylalkyl, quaternary heterocycle, quaternary heteroaryl , P (0) R 7R8, P + R7R8R9A ", and P (O) (OR7) OR8, and wherein said alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, and heterocycle may optionally have one or more carbons replaced by O, NR7, N + R7R A ", S, SO, S02, S + R7A", PR7, P (0) R7, P + R7R8A-, or phenylene, and R13, R14, and R15 are selected independently of the group consisting of hydrogen, alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, arylalkyl, alkylarylalkyl, alky ilheteroarylalkyl, ^^^^^ ^ ^ ^ ^ j ^ ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ Z ^^^^^^^ alkylheterocyclylalkyl, cycloalkyl, heterocycle, heteroaryl, quaternary heterocycle, quaternary heteroaryl, heterocyclylalkyl, heteroarylalkyl, quaternary heterocyclylalkyl, heteroarylalkyl quaternary, alkylammonioalkyl, and carboxyalkylaminocarbonylalkyl, wherein alkyl, alkenyl, alkynyl, arylalkyl, heterocycle, and polyalkyl optionally have one or more carbons replaceable by 0, 10 NR9, N + R9R10A ~, S, SO, S02, S + R9A ", PR9, P + R9R10A", P (0) R9, phenylene, carbohydrate, amino acid, peptide, or polypeptide, and R13, R14, and R15 are optionally substituted with one or more groups selected from the group that 15 consists of hydroxy, amino, sulfo, carboxy, alkyl, carboxyalkyl, heterocycle, heteroaryl, sulfoalkyl, quaternary heterocycle, quaternary heteroaryl, quaternary heterocyclylalkyl, quaternary heteroarylalkyl, guanidinyl, OR9, 20 NR9R10, N + R9RnR12A ", SR9, S (0) R9, S02R9, S03R9, oxo, C02R9, CN, halogen, CONR9R10, S02OM, S02NR9R10, PO (OR16) OR17, P + R9R10R11A ~, S + R9R10A", and C (0) OM, wherein R16 and R17 are independently selected from the substituents that 25 constitute R9 and M; or R13 and R14, together with the atom of V ___; ____. «_, ^^^^ áM ^? ^^^. _.__.__-, .. ... r ..- _ _j__ ¡í ^ j j¡g | § ^^ nitrogen to which they are attached to form a mono or polycyclic heterocycle which is optionally substituted with one or more radicals selected from the group consisting of oxo, carboxy, and quaternary salts; or R14 and R15, together with the nitrogen atom to which it joins to form a cyclic ring; and R30 is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, aryl, acyl, Heterocycle, ammonium alkyl, alkylaminoalkyl, arylalkyl, carboxyalkyl, carboxyheteroaryl, carboxyheterocycle, carboalkoxyalkyl, carboxyalkyl amino, heteroarylalkyl, heterocyclylalkyl, and alkylammoniomalkyl; and R7 and R are independently selected from the group consisting of hydrogen and alkyl; and one or more Rx are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, polyalkyl, acyloxy, 20 aryl, arylalkyl, halogen, haloalkyl, cycloalkyl, heterocycle, heteroaryl, polyether, quaternary heterocycle, quaternary heteroaryl, OR13, NR13R14, SR13, S (0) R13, S (0) 2R13, S03R13, S + R13R1A ", NR130R14, NR13NR14R15, N02, C02R13, CN, OM, S02OM, 25 S02NR1l3JRr.J-4 NR14C (O) R13, C (0 NR1 133R_1144 NR14C (0) R, C (O) OM, -___-. ______ __ .__- ^ ________ aat___. "> __. . .-¿K &Vaí Ak ^^^ Skt A? & k ^. COR13, OR18, S (0) nNR18, NR18R18, NR18OR14, N + R9R R12A-, P + R9R11R12A ", amino acid, peptide, polypeptide, and carbohydrate, wherein alkyl, alkenyl, alkynyl, 5-cycloalkyl, aryl, polyalkyl, heterocycle, acyloxy, arylalkyl, haloalkyl, polyether, quaternary heterocycle, and quaternary heteroaryl can be further substituted with OR9, NR9R10, N + R9R11R12A ", SR9, S (0) R9, S02R9, S03R9, oxo, C02R9, CN, halogen, CONR9R10, S02OM, S02NR9R10, P0 (0R16) 0R17, P + R9R11R12A ", S + R9R10A", or C (0) OM, and wherein R18 is selected from the group consisting of acyl, arylalkoxycarbonyl, arylalkyl, heterocycle, heteroaryl, alkyl, wherein acyl, arylalkoxycarbonyl, arylalkyl, heterocycle, heteroaryl, alkyl, quaternary heterocycle, and quaternary heteroaryl optionally substituted with one or more substituents selected from the group consisting of OR9, NR9R10, N + R9R11R1A ", SR9, S (0) R9, S02R9, SO3R9, oxo, C02R9, CN, halogen, CONR9R10, S03R9, S02OM, S02NR9R10, PO (OR16) OR17, and C (0) OM, wherein Rx 'one or more carbons is they are optionally replaced by O, NR13, N + R13R14A ", S, SO, S02, = ^^ __ ^^^^^^^^^^^^^^^^^^^^^^^^^^ ________ ^ _______ ^^^ g ^^^^^^^^^^^^^ ^^^^^^^^^^^^^^^^^^ a ^^^^^^ S + R13A ", PR13, P (0) R13, P + R13R14A ~, phenylene, amino acid, peptide, polypeptide, carbohydrate, polyether, or polyalkyl, wherein said polyalkyl, phenylene, amino acid, peptide, and carbohydrate, one or more carbons are optionally replaced by 0, NR, N + R9R10A ", S, SO, S02, S + R9A", PR9, P + R9R10A-, or P (0) R9; wherein the quaternary heterocycle, and the quaternary heteroaryl are optionally substituted with one or more groups selected from the group consisting of alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocycle, arylalkyl, halogen, oxo, OR13, NR13R14, SR13, S (0) R13, S02R13 , S03R13, NR13OR14, NR13NR1 R15, N02, C02R13, CN, OM, S020M, S02NR13R14, C (0) NR13R14, C (0) 0M, COR13, P (0) R13R14, P + R13R14R15A ", P (OR13) OR14 , S + R13R14A ", and N + R9RUR12A-, or a pharmaceutically acceptable salt, solvate, or prodrug thereof 23. A compound of claim 22 characterized in that: R is phenyl substituted with OR13; R13b is independently selects from the group consisting of alkyl, quaternary heteroarylalkyl, and quaternary heterocyclylalkyl; Y R13b is optionally substituted with one or more groups selected from the group consisting of heterocycle, heteroaryl, and guanidinyl; 24. A compound of claim 22 characterized in that n is 1 or 2. 25. A compound of claim 22 characterized in that R7 and R8 are independently selected from the group consisting of hydrogen and alkyl. 26. A compound of claim 22 characterized in that R7 and R8 are hydrogen. 27. A compound of claim 22 characterized by R3 and R4 are independently selected from the group consisting of 15 hydrogen and OR9. 28. A compound of claim 22 characterized in that R3 is hydrogen and R4 is hydroxy. 29. A compound of claim 22 characterized in that one or more Rx are selected 20 independently of the group consisting of OR13 and NR13R14. 30. A compound of claim 22 characterized in that one or more Rx are independently selected from the methoxy and dimethylamino group. 31. A compound of claim 22 characterized in that R1 and R2 are independently selected from the group consisting of hydrogen and alkyl. 32. A compound of claim 22 characterized in that R1 and R2 are independently selected from the group consisting of alkyl. 33. A compound of claim 22 characterized in that R1 and R2 are the same alkyl. 34. A compound of claim 22 characterized in that R1 and R2 are each n-butyl. 35. A compound of claim 22 characterized in that n is 1 or 2; R1 and R2 are n-butyl; R3 and R6 are hydrogen; R is hydroxy; R7 and R8 are hydrogen; Y one or more Rx are independently selected from methoxy and dimethylamino. £ * gJS¿, ..._, - t ^ .. ^ siS Pi ^ ~ &? _. 36. A compound of claim 22 characterized in that it has the structural formula: 37. A compound of claim 22 characterized in that it has the structural formula: 38. A compound of the formula (I): 0 _ ____..-._-___ ^ ___._________-. i ... | É | characterized in that: q is an integer from 1 to 4; n is an integer from 0 to 2; R1 and R2 are independently selected from A group consisting of H, alkyl, alkenyl, alkynyl, haloalkyl, alkylaryl, arylalkyl, alkoxy, alkoxyalkyl, dialkylamino, alkylthio, (polyalkyl) aryl, and cycloalkyl, wherein alkyl, alkenyl, alkynyl, Haloalkyl, alkylaryl, arylalkyl, alkoxy, alkoxyalkyl, dialkylamino, alkylthio, (polyalkyl) aryl, and cycloalkyl are optionally substituted with one or more substituents selected from the group consisting of OR9, NR9R10, N + R9R10RWA ", SR9, __ -. - - * - * - ___ _, ____ i _____ £ __ -r .. ^ AtfÉ_ÉÍ_Í__lÉtfl_Í ___ i S + R9R10A ". P + R9R10RUA-, S (0) R9, S02R9, S03R9, C02R9, CN, halogen, oxo, and CONR9R10, wherein alkyl, alkenyl, alkynyl, alkylaryl, alkoxy, alkoxyalkyl, (polyalkyl) aryl, and cycloalkyl optionally have one or more carbons replaced by 0, NR9, N + R9R10A-, S, SO, S02, S + R9A ", P + R9R10A", phenylene, wherein R9 'R10' and Rw are independently selected from the group consisting of H, alkyl, alkenyl , alkynyl, cycloalkyl, aryl, acyl, heterocycle, ammonioalkyl, arylalkyl, carboxyalkyl, carboxyheteroaryl, carboxyheterocycle, carboalkoxyalkyl, carboxyalkylamino, heteroarylalkyl, heterocyclylalkyl, and alkylammonioalkyl; or R1 and R2 taken together with the carbon to which they bind to form C3-C10 cycloalkyl; R3 and R4 are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, acyloxy, aryl, heterocycle, OR9, NR9R10, SR9, S (0) R9, S02R9, and S03R9, wherein R9 and R10 are defined as above; or R3 and R4 together form = 0, = N0Ru, = S, = NNR R12, = NR9, or = CRnR12, wherein R11 and R12 # are independently selected from the group consisting of H, alkenyl, alkynyl, aryl, arylalkyl, alkenylalkyl, alkynylalkyl, heterocycle, carboxyalkyl, carboalkoxyalkyl, cycloalkyl, cyanoalkyl, OR9, NR9R10, SR9, S (0) R9, S02R9, S03R9, C02R9, CN, halogen, oxo, and CONR9R10, in wherein R9 and R10 as defined above, with the proviso that both R3 and R4 can not be OH, NH2 and SH, or R11 and R12 together with the nitrogen or carbon atom to which they bind to form a cyclic ring; R5 is aryl substituted with one or more OR13, wherein R13b is selected from the group consisting of alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, arylalkyl, alkylarylalkyl, alkylheteroarylalkyl, alkylheterocyclic alkyl, cycloalkyl, heterocycle, heteroaryl, quaternary heterocycle, heteroaryl quaternary, heterocyclylalkyl, heteroarylalkyl, quaternary heterocyclylalkyl, quaternary heteroarylalkyl, alkoxyalkyl, alkylammoniomalkyl, and carboxyalkylaminocarbonylalkyl, R13b is substituted with one or more groups selected from the group consisting of OR9a, NR9aR10, N + R9RnR12A_, SR9a, S (0) R9a, S02R9a , S03R9a, C02R9a, CONR9aR10, S02NR9aR10, P + R9aR10RnA-, S + R9aR10A ", where A" is an anion pharmaceutically acceptable and M is a pharmaceutically acceptable cation, wherein R9a is selected from the group consisting of carboxyalkyl, carboxyheteroaryl, carboxyheterocycle, carboalkoxyalkyl, carboxyalkylamino, and carboxyalkylaminoalkyl; R6 is selected from the group consisting of H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, quaternary heterocycle, OR30, SR9, S (0) R9, S02R9, and S03R9, wherein alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, quaternary heterocycle, and quaternary heteroaryl can be substituted with one or more substituent groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocycle, arylalkyl, quaternary heterocycle, heteroaryl quaternary, halogen, oxo, OR13, NR13 R14, SR13, S (0) R13, S02R13, S03R13, NR13OR14 NR13 NR14R15, N02, C02R13, CN, OM, S02OM, S02NR13R14, C (0) NR13R14, C (0) OM , COR13, NR13C (0) R14, NR13C (0) NR14R15, NR13C02R14, OC (0) R13, OC (O) NR13R14, NR13SOR14, NR13S02R14, NR13SONR14R15, NR13S02NR14R15, P (0) R13R14, P + R13R14R15A ", P ( OR13) OR14, S + R13R14A ", and N + R9R11R12A-, wherein; ^^^ ¡^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ A "is a pharmaceutically acceptable anion and M is a pharmaceutically acceptable cation, said alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, and heterocycle may also be substituted with one or more substituent groups selected from the group consisting of OR 7, NR7R8, SR7, S (0) R7, S02R7, S03R7, C02R7, CN, oxo, CONR7R8 ' N + R7R8R9A ", alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, arylalkyl, quaternary heterocycle, quaternary heteroaryl, P (0) R 7R8, P + R7R8R9A", and P (O) (0R7) 0R8, and wherein said alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, and the heterocycle optionally? have one or more carbons replaced by O, NR, N + R7R8A ", S, SO, S02, S + R7A", PR7, P (0) R7, P + R7R8A-, or phenylene, and R13, R14, and R15 are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, arylalkyl, alkylarylalkyl, alkylheteroarylalkyl, alkylheterocyclic alkyl, cycloalkyl, heterocycle, heteroaryl, quaternary heterocycle, heteroaryl ^^^^^ j ^^ Hs¿ ^^. £ S &^ J ^^ g ^^ j ^ £ i ^^^^^^^? ^ "U_w" "_- quaternary, heterocyclylalkyl, heteroarylalkyl, quaternary heterocyclylalkyl, quaternary heteroarylalkyl, alkylammoniomethyl, and carboxyalkylaminocarbonylalkyl, wherein alkyl, alkenyl, alkynyl, arylalkyl, heterocycle, and polyalkyl optionally have one or more carbons replaced by 0, NR9, N + R9R10A ", S, SO, S02, S + R9A", PR9, P + R9R10A ", P (0) R9, phenylene, carbohydrate, amino acid, peptide, or polypeptide, and R13, R14, and R15 are optionally substituted with one or more groups selected from the group consisting of hydroxy, amino, sulfo, carboxy, alkyl, carboxyalkyl, heterocycle, heteroaryl, sulfoalkyl, quaternary heterocycle, heteroaryl quaternary, quaternary heterocyclylalkyl, quaternary heteroarylalkyl, guanidinyl, OR9, NR9R10, N + R9RUR12A ", SR9, S (0) R9, S02R9, S03R9, oxo, C02R9, CN, halogen, CONR9R10, S020M, S02NR9R10, 20 PO (OR16) OR17, P + R9R10R11A ", S + R9R10A", and C (0) OM, wherein R16 and R17 are independently selected from the substituents constituting R9 and M; or R13 and R14, together with the nitrogen atom which they join to form a mono or heterocycle polycyclic which is optionally substituted with one or more radicals selected from the group consisting of oxo, carboxy, and cutaneous salts; or R14 and R15, together with the nitrogen atom to which they are attached to form a cyclic ring; and R is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, aryl, acyl, heterocycle, ammonium alkyl, alkylaminomalkyl, arylalkyl, carboxyalkyl, carboxyheteroaryl, carboxyheterocycle, carboalkoxyalkyl, carboxyalkyl amino, heteroarylalkyl, heterocyclylalkyl, and alkylammoniomalkyl; Y R7 and R8 are independently selected from the group consisting of hydrogen and alkyl; and one or more Rx are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, polyalkyl, acyloxy, aryl, arylalkyl, halogen, haloalkyl, cycloalkyl, heterocycle, heteroaryl, polyether, quaternary heterocycle, quaternary heteroaryl, OR13 , NR13R14, SR13, S (0) R13, S (0) 2R13, S03R13, S + R13R14A-, NR13OR14, NR13NR14R15, N02, C02R13, CN, OM, S02OM, S02NR13R14, NR14C (0) R13, C (0) NR13R14, NR14C (0) R13, C (0) OM, COR13, OR18, S (0) nNR18, NR13R18, NR18OR14, - "* - * - • ^ - - - ^ '- •' -_ ^ _ > ^? '^^ aaa ^.-_-_-__ M _- .. ^.. ^^^ ¿^^. . -____.-__.__ j_e ...- M __... i N + R9R11R12A ", P + R9R11R12A", amino acid, peptide, polypeptide, and carbohydrate, wherein alkyl, alkenyl, alkynyl, cycloalkyl, aryl, polyalkyl, heterocycle, acyloxy, arylalkyl, haloalkyl, polyether, quaternary heterocycle, and quaternary heteroaryl can also be substituted with OR9, NR9R10, N + R9R R12A ", SR9, S (0) R9, S02R9, S03R9, oxo, C02R9, CN, halogen, CONR9R10, S02OM, S02NR9R10, PO (OR16) OR17, P + R9R11R12A" , S + R9R10A ", or C (0) OM, and wherein R1 is selected from the group consisting of acyl, arylalkoxycarbonyl, arylalkyl, heterocycle, heteroaryl, alkyl, wherein acyl, arylalkoxycarbonyl, arylalkyl, heterocycle, heteroaryl, alkyl, quaternary heterocycle, and quaternary heteroaryl optionally substituted with one or more substituents selected from the group consisting of OR9, NR9R10, N + R9R11R12A ", SR9, S (0) R9, S02R9, S03R9, oxo, C02R9, CN, halogen, CONR9R10, SO3R9, S02OM, S02NR9R10, PO (OR16) OR17, and C (0) OM, where Rx 'one or more carbon s are optionally replaced by O, NR13, N + R13R14A ", S, SO, S02, S + R13A", PR13, P (0) R13, P + R13R14A-, phenylene, amino acid, ^^^^^^^^^^ g ^ g ^ > ^^^^^ g »^^^^^^^^ * ^^^^^^ - ^^^^^ jgj ^^^^^^ peptide, polypeptide, carbohydrate, polyether, or polyalkyl, wherein said polyalkyl, phenylene, amino acid, peptide, polypeptide, and carbohydrate, one or more carbons are optionally replaced by 0, NR9, N + R9R10A ", S, SO, S02, S + R9A_, PR9, P + R9R10A ", or P (0) R9; wherein the quaternary heterocycle and the quaternary heteroaryl are optionally substituted with one or more groups selected from the group consisting of alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocycle, arylalkyl, halogen, oxo, OR13, NR13R14 , SR13, S (0) R13, S02R13, S03R13, NR13OR14, NR13NR1 R15, N02, C02R13, CN, OM; S020M, S02NR13R14, C (0) NR13R14, C (0) 0M, COR13, P (0) R13R14, P + R13R14R15A ", P (0R13) 0R14, S + R13R14A", and N + R9RUR12A ", or a pharmaceutically salt acceptable, solvate, or prodrug thereof 39. A compound of claim 38 characterized in that: R5 is phenyl substituted with 0R13b, R13b is selected from the group consisting of alkyl and alkoxyalkyl, and R13b is substituted with one or more groups selected from the group consisting of OR and NR9aR10; and R9a is selected from the group consisting of carboxyalkyl, carboxyheteroaryl, and carboxyheterocycle; and R 10 is carboxyalkyl 40. A compound of claim 38 characterized in that n is 1 or 2. 41. A compound of claim 38 characterized in that R 7 and R 8 are independently selected from the group consisting of hydrogen and alkyl. 42. A compound of claim 38 characterized in that R7 and R are hydrogen. 43. A compound of claim 38 characterized in that R and R are independently selected from the group consisting of hydrogen and OR9. 44. A compound of claim 38 characterized in that R is hydrogen and R4 is hydroxy. 45. A compound of claim 38 characterized by one or more Rx are independently selected from the group consisting of OR13 and ^^^^ _ ^ ^ ^ ^ ^ ^ ^ _ ^ ____ ^^^^^^^^^^ gt ^^^ fe ^^^^^ f ^^ __ ^^^^^^^^^^^^ ^^^^^^ fe ^^^ - - NR13R14 46. A compound of claim 38 characterized in that one or more Rx are independently selected from the methoxy and dimethylamino group. 47. A compound of claim 38 characterized in that R1 and R2 are independently selected from the group consisting of hydrogen and alkyl. 48. A compound of claim 38 characterized in that R1 and R2 are independently selected from the group consisting of alkyl. 49. A compound of claim 38 characterized in that R1 and R2 are the same alkyl. 50. A compound of claim 38 characterized in that R1 and R2 are each n-butyl. 51. A compound of claim 38 characterized in that n is 1 or 2; R1 and R2 are n-butyl; R3 and R6 are hydrogen; R4 is hydroxy; R7 and R8 are hydrogen; and one or more Rx are independently selected from methoxy and dimethylamino. ^ _tj_ ^ 8 ^ '^^ _, j * & O_ & w * ^^^ Kfe¿ ^ g ^^ ^ fe_fesafe-1 52. A compound of claim 31 characterized in that it has the structural formula: 53. A compound of claim 38, characterized in that it has the structural formula: 10 54. A compound of claim 38 characterized in that it has the structural formula: _t_. __-_ > _m _____ »-_. aa» M _____ • * ^ J ™ ^^ - ..___ £ _._-.-, ..._____... 55, A compound of the formula (1) characterized in that: q is an integer from 1 to 4; n is an integer from 1 to 2; R1 and R2 are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, haloalkyl, alkylaryl, arylalkyl, alkoxy, alkoxyalkyl, dialkylamino, alkylthio, (polyalkyl) aryl, and cycloalkyl, wherein alkyl, alkenyl, alkynyl, haloalkyl, alkylaryl, arylalkyl, alkoxy, ______ _ __ ».________« _, -., .- A _____- _____ fe- *. ¿¿Te ^. * »- > , a__fa! Í: ..___ ¿-.-___ alkoxyalkyl, dialkylamino, alkylthio, (polyalkyl) aryl, and cycloalkyl are optionally substituted with one or more substituents selected from the group consisting of OR9, NR9R10, N + R9R10RWA ", SR9, S + R9R10A ', P + R9R10RnA-, S (0) R9, S02R9, S03R9, C02R9, CN, halogen, oxo, and CONR9R10, wherein alkyl, alkenyl, alkynyl, alkylaryl, alkoxy, alkoxyalkyl, (polyalkyl) aryl, and cycloalkyl optionally have one or more carbons replaced by O, NR9, N + RR10A- , S, SO, S02, S + R9A ", P + R9R10A", or phenylene, wherein R9 'R10' and Rw are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, acyl, heterocycle, ammonioalkyl, arylalkyl, carboxyalkyl, carboxyheteroaryl, carboxyheterocycle, carboalkoxyalkyl, carboxyalkyl amino, heteroarylalkyl, heterocyclylalkyl, and alkylammonioalkyl; or R1 and R2 are taken together with the carbon to which they are attached to form C3-C10 cycloalkyl; R3 and R4 are independently selected of the group consisting of H, alkyl or, alkenyl, alkynyl, acyloxy, aryl, heterocycle, OR9, NR9R10, SR9, S (0) R9, S02R9, and S03R9, wherein R9 and R10 are defined as above; or R3 and R4 together form = 0, = NORn, = S, = NNR R12, = NR9, or = CRnR12, wherein R11 and R12 are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, aryl, arylalkyl, alkenylalkyl, alkynylalkyl, heterocycle, carboxyalkyl, carboalkoxyalkyl, cycloalkyl, cyanoalkyl, OR9, NR9R10, SR9, S (0) R9, S02R9, S03R9, C02R9, CN, halogen, oxo, and CONR9R10, wherein R9 and R10 are as defined above, with the proviso that both R3 and R4 can not be OH, NH2 and SH, or R11 and R12 together with the nitrogen or carbon atom to which they join to form a cyclic ring; R5 is aryl substituted with one or more OR13b, wherein R13b is selected from the group consisting of alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, arylalkyl, alkylarylalkyl, alkylheteroarylalkyl, alkylheterocyclylalkyl, cycloalkyl, heterocycle, heteroaryl, quaternary heterocycle, heteroaryl quaternary, heterocyclylalkyl, heteroarylalkyl, quaternary heterocyclylalkyl, quaternary heteroarylalkyl, alkylaminiomalkyl, and carboxyalkylaminocarbonylalkyl, R 13b is substituted with one or more groups selected from the group consisting of carboxyalkylheterocyclylthio, NR9R10a, CONR9R10a, .9 r_ 10a D + n 9D IOaD l l + t, 9r? 10a, S02NR9R,? A, P + R9R,? 'R11A-, and StR > R'uaA-, wherein A "is a pharmaceutically acceptable anion and M is a pharmaceutically acceptable cation, wherein R 1 Oa is selected from the group consisting of carboxyalkyl, carboalkoxyalkyl, carboxyalkylamino, heteroarylalkyl, and heterocyclylalkyl; or R 6 is selected from the group consisting of H , alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, quaternary heterocycle, OR30, SR9, S (0) R9, S02R9, and S03R9, wherein alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, quaternary heterocycle, and heteroaryl Quaternary can be substituted with one or more substituent groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocycle, arylalkyl, quaternary heterocycle, quaternary heteroaryl, halogen, oxo, OR13, NR13R14 , SR13, S (0) R13, S02R13, SO3R13, NR13OR14, NR13NR14R15, N02, C02R13, CN, OM, S02OM, S02NR13R14, C (0) NR13R14, C (0) OM, COR13, NR13C (0) R14, NR13C (O) NR14R15, NR13C02R14, OC (0) R13, OC ( 0) NR13R14, NR13SOR14, NR13S02R14, NR13SONR14R15, NR13S02NR1 R15, P (0) R13R14, P + R13R14R15A5P (0R13) 0R14, S + R13R14A ", and N + R9R1XR12A-, where; A" is an anion pharmaceutically acceptable and M is a pharmaceutically acceptable cation, said alkyl, alkenyl, alkynyl, Polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, and heterocycle may also be substituted with one or more substituent groups selected from the group consisting of OR 7, NR 7R 8, SR 7, S (0) R 7, S02 R 7, S 0 3 R 7, C 0 R 2 , CN, oxo, CONR7R8 ' 15 N + RR R9A ", alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, arylalkyl, quaternary heterocycle, quaternary heteroaryl, P (0) R7R, P + R7R8R9A", and P (O) (OR7) OR8, and wherein said alkyl, alkenyl, Alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, and heterocycle may optionally have one or more carbons replaced by O, NR7, N + R7R8A ", S, SO, S02, S + R7A", PR7, P (0) R7, P + R7R8A-, or phenylene, and R13, R14, and R15 are selected independently of the group consisting of hydrogen, alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, arylalkyl, alkylarylalkyl, alkylheteroarylalkyl, alkylheterocyclic alkyl, cycloalkyl, heterocycle, heteroaryl, quaternary heterocycle, quaternary heteroaryl, heterocyclylalkyl, heteroarylalkyl, quaternary heterocyclylalkyl, heteroarylalkyl quaternary, alkylammonioalkyl, and carboxyalkylaminocarbonylalkyl, wherein alkyl, alkenyl, alkynyl, arylalkyl, heterocycle, and polyalkyl optionally have one or more carbons replaceable by O, NR9, N + R9R10A ", S, SO, S02, S + R9A", PR9, P + R9R10A ", P (0) R9, phenylene, carbohydrate, amino acid, peptide, or polypeptide, and R13, R14, and R15 are optionally substituted with one or more groups selected from the group consisting of hydroxy, amino, sulfo, carboxy, alkyl, carboxyalkyl, heterocycle, heteroaryl, sulfoalkyl, quaternary heterocycle, quaternary heteroaryl, heterocyclylalkyl quat ernary, quaternary heteroarylalkyl, guanidinyl, OR9, NR9R10, N + R9R11R12A ", SR9, S (0) R9, S02R9, SO3R9, oxo, C02R9, CN, halogen, CONR9R10, S02OM, S02NR9R10, PO (OR16) OR17, P + R9R10R11A ", S + R9R10A-, and C (O) 0M, wherein R16 and R17 are independently selected from the substituents constituting R9 and M; or R13 and R14, together with the nitrogen to which they join to form a monocyclic or polycyclic heterocycle which is optionally substituted with one or more radicals selected from the group consisting of oxo, carboxy, and quaternary salts; or R14 and R15, together with the nitrogen atom to which they are attached to form a cyclic ring, and R 30 is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, aryl, acyl, heterocycle, ammonium alkyl, alkylaminoalkyl, arylalkyl, carboxyalkyl, carboxyheteroaryl, carboxyethocycle, carboalkoxyalkyl, carboxyalkyl amino, heteroarylalkyl, heterocyclylalkyl, and alkylammonalkyl; and R 7 and R 8 are independently selected from the group consisting of hydrogen and alkyl; and one or more Rx are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, polyalkyl, acyloxy, aryl, arylalkyl, halogen, haloalguyl, cycloalkyl, heterocycle, heteroaryl, polyether, quaternary heterocycle, quaternary heteroaryl, OR13, NR13R14, SR13, S (0) R13, S (0) 2R13, S03R13, S + R13R1 A-, NR130R14, NR13NR14R15, N02, C02R13, CN, OM, S02OM, S02NR13R14, NR14C ( 0) R13, C (0) NR13R14, NR14C (0) R13, C (0) OM, COR13, OR18, S (0) nNR18, NR13R18, NRI8OR14, N + R9R11R12A ", P + R9R11R12A", amino acid, peptide, polypeptide, and carbohydrate, wherein alkyl, alkenyl, alkynyl, cycloalkyl, aryl, polyalkyl, heterocycle, acyloxy, arylalkyl, haloalkyl, polyether, quaternary heterocycle, and quaternary heteroaryl can be further substituted with OR9, NR9R10, N + R9R11R12A ", SR9 , S (0) R9, S02R9, SO3R9, oxo, C02R9, CN, halogen, CONR9R10, S02OM, S02NR9R10, PO (OR16) OR17, P + R9RnR12A ", S + R9R10A", or C (0) OM, and wherein R 18 is selected from the group consisting of acyl, arylalkoxycarbonyl, arylalkyl, heterocycle, heteroaryl, alkyl, wherein acyl, arylalkoxycarbonyl, arylalkyl, heterocycle, heteroaryl, alkyl, quaternary heterocycle, and quaternary heteroaryl or is optionally substituted with one or more substituents selected from the group consisting of OR9, NR9R10, N + R9R11R12A ", SR9, S (0) R9, S02R9, S03R9, oxo, C02R9, CN, halogen, CONR9R10, S03R9, S02OM, S02NR9R10, PO (OR16) OR17, and C (0) OM, wherein Rx 'one or more carbons are optionally replaced by O, NR13, N + R13R14A ", S, SO, S02, S + R13A ", PR13, P (0) R13, P + R13R14A", phenylene, amino acid, peptide, polypeptide, carbohydrate, polyether, or polyalkyl, wherein said polyalkyl, phenylene, amino acid, peptide, polypeptide, and carbohydrate, one or more carbons are optionally replaced by O, NR9, N + R9R10A ", S, SO, S02, S + R9A", PR9, P + R9R10A-, or P (0) R9; wherein the quaternary heterocycle, and quaternary heteroaryl they are optionally substituted with one or more groups selected from the group consisting of alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocycle, arylalkyl, halogen, oxo, OR13, NR13R14, SR13, S (0) R13, S02R13, S03R13, NR13OR14, NR13NR14R15, N02, C02R13, CN, OM, S02OM, S02NR13R14, C (0) NR13R14, C (0) OM, COR13, P (0) R13R14, P + R13R14R15A ", P (OR13) OR14 , S + R13R1 A ~, and N + R9RnR12A-, or a salt pharmaceutically acceptable, solvate, or prodrug thereof. 56. A compound of claim 55 characterized in that: ".- -3. - »_ í-, i s R5 is phenyl substituted with OR13b; R 13b is alkyl; and R13b is substituted with carboxyalkylheterocyclicthio or NR9R10a; and R9 is hydrogen; and R10 is heteroarylalkyl. 57. A compound of claim 55 characterized in that n is 1 or 2. 58. A compound of claim 55 characterized in that R and R are independently selected from the group consisting of hydrogen and alkyl. 59. A compound of claim 55 characterized in that R7 and R8 are hydrogen. 60. A compound of claim 55 characterized in that R3 and R4 are independently selected from the group consisting of hydrogen and OR9. 61. A compound of claim 55 characterized by R3 is hydrogen and R4 is hydroxy. 62. A compound of claim 55 characterized in that one or more Rx are independently selected from the group consisting of OR13 and NR13R14. ^ 63. A compound of claim 55 characterized in that one or more Rx are independently selected from the methoxy and dimethylamino group. 64. A compound of claim 55 characterized in that R1 and R2 are independently selected from the group consisting of hydrogen and alkyl. 65. A compound of claim 55 characterized in that R1 and R2 are independently selected from the group consisting of alkyl. 66. A compound of claim 55 characterized in that R1 and R2 are the same alkyl. 67. A compound of claim 55 characterized in that R1 and R2 are each n-butyl. 68. A compound of claim 55 characterized in that n is 1 or 2; R1 and R2 are n-butyl; R3 and R6 are hydrogen; R4 is hydroxy; R7 and R8 are hydrogen; and one or more Rx are independently selected from methoxy and dimethylamino. ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ g ^^^^^^^^^^^ ^^^^^^ 69. A compound of claim 55 characterized in that it has the structural formula: 70. A compound of claim 55 characterized in that it has the structural formula: 71 A compound of the formula (I) characterized in that: q is an integer from 1 to 4; 5 n is an integer from 1 to 2; R1 and R2 is independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, haloalkyl, alkylaryl, arylalkyl, alkoxy, alkoxyalkyl, dialkylamino, alkylthio, 10 (polyalkyl) aryl, and cycloalkyl, wherein alkyl, alkenyl, alkynyl, haloalkyl, alkylaryl, arylalkyl, alkoxy, alkoxyalkyl, dialkylamino, alkylthio, (polyalkyl) aryl, and cycloalkyl are optionally substituted with one or more substituents selected from the group consisting of OR9, NR9R10, N + R9R10RWA ", SR9, S + R9R10A " P + R9R10RnA ", S (0) R9, S02R9, S03R9, C02R9, CN, halogen, oxo, and C0NR9R10, _ ^ _ J l ± _j ___ Í_ í 1 - ^ - »^ _______- * - •• -. - * -. < - »---« * '~ - • > & --- & * m ^ wherein alkyl, alkenyl, alkynyl, alkylaryl, alkoxy, alkoxyalkyl, (polyalkyl) aryl, and cycloalkyl optionally have one or more carbons replaced by 0, NR9, N + R9R10A-, S, SO, S02, S + R9A ", P + R9R10A ~, 0 phenylene, wherein R9 'R10 and Rw are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, acyl, heterocycle, ammonium alkyl, arylalkyl, carboxyalkyl, carboxyheteroaryl, carboxyheterocycle, carboalkoxyalkyl, carboxyalkylamino, heteroarylalkyl, heterocyclylalkyl, and alkylammonioalkyl; or R1 and R2 are taken together with the carbon to which they are attached to form C3-C10 cycloalkyl; R3 and R4 are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, acyloxy , aryl, heterocycle, OR9, NR9R10, SR9, S (0) R9, S02R9, and S03R9, wherein R9 and R10 are defined as above, or R3 and R4 together form = 0, = N0Rn, = S, = NNRUR12, = NR9, or = CRUR12, wherein R11 and R12 are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, aryl, arylalkyl, alkenylalkyl, alkynylalkyl, heterocycle, carboxyalkyl, carboalkoxyalkyl, cycloalkyl, cyanoalkyl, OR9, NR9R10, SR9, S (0) R9, S02R9, S03R9, C02R9, CN, halogen, oxo, and CONR9R10, wherein R9 and R10 as defined above, provide that both R3 and R4 can not be OH, NH2 and SH, or R11 and R12 together with the nitrogen or carbon atom to which they are attached to form a cyclic ring; R5 is aryl substituted with one or more substituent groups independently selected from the group consisting of NR13C (0) R14, NR13C (O) NR14R15, NR13C02R14, OC (0) R13, OC (0) NR13R14, NR13SOR14NR13S02R14, NR13SONR14R15, and NR13S02NR14R15, wherein: R13, R14, and R15 are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, arylalkyl, alkylarylalkyl, alkylheteroarylalkyl, alkylheterocyclylalkyl, cycloalkyl, heterocycle, heteroaryl, quaternary heterocycle, quaternary heteroaryl , heterocyclylalkyl, heteroarylalkyl, heterocyclylalkyl quaternary, heteroarylalkyl quaternary, alkylammoniomalkyl, and caboxy 1 qui 1 ami noca rbon i la Iqui lo, R13, R14 'and R15 are optionally substituted with one or more groups selected from the group consisting of hydroxy, amino, sulfo, carboxy, alkyl, carboxyalkyl, heterocycle, heteroaryl, sulfoalkyl, quaternary heterocycle, quaternary heteroaryl, quaternary heterocyclylalkyl, quaternary heteroarylalkyl, OR9, NR9R10, N + R9R11R12A ", SR9, S (0) R9, S02R9, SO3R9, oxo, C02R9, CN, halogen, CONR9R10, S02OM, S02NR9R10, PO (OR16) OR17, P + R9R10RUA", S + R9R10A " , and C (0) 0M, wherein A "is a pharmaceutically acceptable anion and M is a pharmaceutically acceptable cation, wherein R16 and R17 are independently selected from the substituents that constitute R9 and M; or R13 and R14, together with the nitrogen atom to which they are attached to form a polycyclic mono or heterocycle which is optionally substituted with one or more radicals selected from the group consisting of oxo, carboxy, and quaternary salts; or R14 and R15, together with the nitrogen atom to which they are attached to form a cyclic ring; and R6 is selected from the group consisting of H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, quaternary heterocycle, OR30, SR9, S (0) R9, S02R9, and SO3R9, wherein alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, quaternary heterocycle, and quaternary heteroaryl can be substituted with one or more groups substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocycle, arylalkyl, quaternary heterocycle, quaternary heteroaryl, halogen, oxo, OR13, NR13R14, SR13, S (0) R13, S02R13, S03R13, NR130R14, NR13NR14R15, N02, C02R13, CN, OM; S020M, S02NR14R14, C (0) NR13R14, C (0) OM, COR13, NR13C (0) R14, NR13C (0) NR14R15, 0C (0) R13, OC (O) NR13R14, NR13S0R14, NR13S02R14, NR13SONR14R15, P ( 0) R13R14, P + R13R14R15A ", P (0R13) 0R14, S + R13R14A", and NR ^ R ^ A ", wherein: A" is a pharmaceutically acceptable anion and M is a pharmaceutically acceptable cation, said alkyl, alkenyl , alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, and heterocycle may be further substituted with one or more substituent groups selected from the group consisting of OR7, NR7R8, R7, S (0) R7, S02R7, S03R7, CN, oxo, CONR7R8, N + R7R8R9A ~, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, arylalkyl, quaternary heterocycle, quaternary heteroaryl, P (0) R7R8, P + R7R8R9A ", and P (0) (0R7) R8, and wherein said alkyl alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, and heterocycle may optionally have one or more carbons replaceable by 0, NR7, N + R7R8A-, S, SO, S02, S + R7A-, PR7, P (0) R7, P + R7R8A-, or phenylene, and R13, R14, and R15 are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, arylalkyl, alkylarylalkyl, alkylheteroarylalkyl, alkylheterocyclylalkyl, cycloalkyl, heterocycle, heteroaryl, quaternary heterocycle, quaternary heteroaryl, heterocyclylalkyl, heteroarylalkyl, heterocyclylalkyl quaternary, heteroarylalkyl alkylammonalkyl, and carboxyalkylaminocarbonylalkyl, wherein alkyl, alkenyl, alkynyl , ar ilalkyl, heterocycle, and polyalkyl optionally have one or more carbons replaced by O, NR9, . _ * _ -____ - ~ .- *. .to**-. -.----- - ~ a¡ ** ^ a__aafc _ ^ __ ______.-._-..__. ____________ _, «_. ^ = - ^ N + R9R10A ", S, SO, S02, S + R9A", PR9, P + R9R10A ', P (0) R9, phenylene, carbohydrate, amino acid, peptide, or polypeptide, and R13, R14, and R15 are optionally substituted with one or more groups selected from the group consisting of hydroxy, amino, sulfo, carboxy, alkyl, carboxyalkyl, heterocycle, heteroaryl, sulfoalkyl, quaternary heterocycle, quaternary heteroaryl, quaternary heterocyclylalkyl, quaternary heteroarylalkyl, guanidinyl, OR9, NR9R10, N + R9R R12A ", SR9, S (0) R9, S02R9, S03R9, oxo, C02R9, CN, halogen, CONR9R10, S02OM, S02NR9R10, PO (OR16) OR17, P + R9R10R11A", S + R9R10A ", and C (0) OM, wherein R16 and R17 are independently selected from the substituents constituting R9 and M; or R13 and R14, together with the nitrogen atom to which they are attached to form a polycyclic mono or heterocycle which is optionally substituted with one or more radicals selected from the group consisting of oxo, carboxy, and quaternary salts; R14 and R15 'together with the atom to which they are attached to form a cyclic ring; and R30 is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, aryl, acyl, heterocycle, ammonium alkyl, alkylammonalkyl, arylalkyl, carboxyalkyl, carboxyheteroaryl, carboxyheterocycle, carboalkoxyalkyl, carboxyalkylamino, heteroarylalkyl, heterocyclylalkyl, and alkylammoniomalkyl; Y R7 and R8 are independently selected from the group consisting of hydrogen and alkyl; and one or more Rx are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, polyalkyl, acyloxy, aryl, arylalkyl, halogen, haloalkyl, cycloalkyl, heterocycle, heteroaryl, polyether, quaternary heterocycle, quaternary heteroaryl, OR13, NR13 R14, SR13, S (0) R13, S (0) 2R13, S03R13, S + R13R14A ", NR13OR14, NR13NR14R15, N02, C02R13, CN , OM, S020M, S02NR13R14, NR14C (0) R13, C (0) NR13R14, NR14C (0) R13, C (0) OM, COR13, OR18, S (0) nNR18, NR13R18, NR, 8OR14, N + R9R11R12A ", P + RR R12A-, amino acid, peptide, polypeptide, and carbohydrate, wherein alkyl, alkenyl, alkynyl, cycloalkyl, aryl, polyalkyl, heterocycle, acyloxy, arylalkyl, haloalkyl, polyether, quaternary heterocycle, and quaternary heteroaryl may additionally be substituted with OR9, NR9R10, N + R9RnR12A ", ^^^ rtfc ^ sa¿fe _? ^ fc __- < > __..__ l ..- * ..... -..., ___ i- ^ ii _? _- j_ ¿¿«. so ?. SR9, S (0) R9, S02R9 'S03R9, oxo, C02R9, CN, halogen, CONR9R10, S02OM, S02NR9R10, PO (OR16) OR17, N + R9RnR12A ", S + R9R10A" or C (0) OM, and wherein R18 is selected from the group consisting of acyl, arylalkoxycarbonyl, arylalkyl, heterocycle, heteroaryl, alkyl, wherein acyl, arylalkoxycarbonyl, arylalkyl, heterocycle, heteroaryl, alkyl, quaternary heterocycle, and quaternary heteroaryl are optionally substituted with one or more selected substituents of the group consisting of OR9, NR9R10, N + R9RnR12A ~, SR9, S (0) R9, S02R9, S03R9, oxo, C02R9, CN, halogen, CONR9R10, S03R9, S02OM, S02NR9R10, PO (OR16) OR17, and C (O) OM, wherein Rx 'one or more carbons are optionally replaced by O, NR13, N + R13R14A ", S, SO, S02, S + R13A", PR13, P (0) R13, P + R13R14A ", phenylene, amino acid, peptide, polypeptide, carbohydrate, polyether, or polyalkyl, wherein said polyalkyl, phenylene, amino acid, peptide, polypeptide, and carbohydrate, one or more carbons are optionally replaced by r O, NR9, N + R9R10A ', S, SO, S02, S + R9A ", PR9, P + R9R10A-, or P (0) R9; where the quaternary heterocycle, and quaternary heteroaryl are optionally substituted with one or more groups selected from the group consisting of alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocycle, arylalkyl, halogen, oxo, OR13, NR13R14, SR13, S (0) R13, S02R13, S03R13, NR13OR14, NR13NR14R15, N02, C02R13, CN, OM, S02OM, S02NR13R14, C (0) NR13R14, C (0) OM, COR13, P (0) R13R14, P + R13R14R15A ", P (OR13) ) OR14, S + R13R14A ", and N + R9RUR12A-, or a pharmaceutically acceptable salt, solvate, or prodrug thereof. 72. A compound of claim 71 characterized in that: R5 is aryl substituted with a radical selected from the group consisting of NR13C (O) NR14R15 and NR13C02R14. 73. A compound of claim 71 characterized in that R5 is phenyl substituted with a radical selected from the group consisting of NR13C (0) NR14R15 and NR13C02R14'74. A compound of claim 71 characterized in that n is 1 or 2. 75. A compound of claim 71 characterized in that R7 and R8 are independently selected from the group consisting of hydrogen and alkyl. 76. A compound of claim 71 characterized in that R7 and R8 are hydrogen. 77. A compound of claim 71 characterized in that R and R are independently selected from the group consisting of hydrogen and OR9. 78. A compound of claim 71 characterized in that R3 is hydrogen and R is hydroxy. 79. A compound of claim 71 characterized in that one or more Rx are independently selected from the group consisting of OR13 and NR13R14. 80. A compound of claim 71 characterized in that one or more Rx are independently selected from the methoxy and dimethylamino group. 81. A compound of claim 71 characterized in that R1 and R2 are independently selected from the group consisting of hydrogen and alkyl. 82. A compound of claim 71 characterized in that R1 and R2 are independently selected from the group consisting of alkyl. 83. A compound of claim 71 characterized in that R1 and R2 are the same alkyl. j¡ ___ t3_i_á¿a_ v * • j__J »i_gfe» < i- __j »_ & * ^ _. _-__ i_ ^ _ __ ^. ^ - ^ - £ * - _ & ~ - - faV & > * * 84. A compound of claim 71 characterized in that R1 and R2 are each n-butyl. 85. A compound of claim 71 characterized in that n is 1 or 2; R1 and R2 are n-butyl; R3 and R6 are hydrogen; R4 is hydroxy; R7 and R8 are hydrogen; and one plus R * are independently selected from methoxy and dimethylamino. 86. A compound of claim 71 characterized in that it has the structural formula: 87. A compound of claim 71 characterized in that it has the structural formula: A compound of the formula (i; characterized in that: q is 1 or 2; n is 2; R1 and R2 are each alkyl; R3 is hydroxy; *? s? '¿^ - ^ f ^^ §to. > . R4 and R6 are hydrogen; R has the formula (II) R3 is hydroxy; R and R are hydrogen R5 has the formula (Ii; where t is an integer from 0 to 5; , 13 are selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, polyalkyl, aryl, arylalkyl, alkylarylalkyl, cycloalkyl, heterocycle, heteroaryl, quaternary heterocycle, quaternary heteroaryl, quaternary heteroarylalkyl, and alkoxyalkyl; said R13 alkyl, alkenyl, alkynyl, arylalkyl, heterocycle, and polyalkyl groups optionally have one or more carbons replaceable by O, NR9, N + R9R10A ", S, SO, S02, S + R9A", PR9, P + R9R10A ", P (0) R9, phenylene, carbohydrate, amino acid, peptide, or polypeptide; R13 is optionally substituted with one or more groups selected from the group consisting of sulfoalkyl, quaternary heterocycle, quaternary heteroaryl, OR9, NR9R10, N + R9R10R12A ", SR9, S (0) R9, S02R9, SO3R9, oxo, C02R9, CN, halogen, CONR9R10, S02OM, S02NR9R10, P0 (0R16) 0R17, P + R9R10RnA ", S + R9R10A", and C (0) OM, wherein A "is a pharmaceutically acceptable anion and M is a pharmaceutically acceptable cation, R9 and R10 are independently selected from the group consisting of of H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, acyl, heterocycle, ammonium alkyl, arylalkyl, and alkylammoniomalkyl; R11 and R12 are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, aryl, arylalkyl, alkenylalkyl, alkynylalkyl, heterocycle, carboxyalkyl, carboalkoxyalkyl, cycloalkyl, cyanoalkyl, OR9, NR9R10, SR9, S (0) R9, S02R9 , S03R9, C02R9, CN, halogen, oxo, and CONR9R10, wherein R9, and R10, are as defined above, with the proviso that R3 and R4 can not be OH, NH2, and SH; or R11 and R12 together with the nitrogen or carbon atom to which they join to form a cyclic ring; and R16 and R17 are independently selected from the substituent constituting R9 and M; R 7 and R 8 are hydrogen; Y one or more Rx are independently selected from the group consisting of alkoxy, alkylamino and dialkylamino; or "%, To a pharmaceutically acceptable salt, solvate, or prodrug thereof., 89. A compound of claim 88 1 characterized in that R and R are each n-butyl 90. A compound of claim 89 characterized in that t is 1, Ry is OR13 and R13 is as defined in claim 88. 91. A compound of claim 90 characterized in that one or more Rx are independently selected from methoxy and dimethylamino, 92. A compound of claim 90 characterized in that Rx is dimethylamino, 93. A compound of claim 90 characterized in that: t is 1, Ry is para-OR13, and 94. A compound of claim 90 characterized in that: t is 1, Ry is meta-OR13, and R13 is as defined in claim 88. 95. A compound of claim 90 characterized in that it has the configuration AR, 5R. 96. A pharmaceutical composition characterized in that it comprises an anti-hyperlipidemic condition in an effective amount of a compound of any of claims 1 to 95, and a pharmaceutically acceptable carrier. 97. A pharmaceutical composition characterized in that it comprises an anti-atherosclerotic condition in an effective amount of a compound of any of claims 1 to 95, and a pharmaceutically acceptable carrier. 98. A pharmaceutical composition characterized in that it comprises an anti-hypercholesterolemia condition in an effective amount of a compound of any of claims 1 to 95, and a pharmaceutically acceptable carrier. 99. A method for the prophylaxis or treatment of a hyperlipidemic condition characterized in that it comprises administering to a patient in need thereof a composition of claim 96 in a unit dose. 100. A method for the prophylaxis or treatment of an atherosclerotic condition . 3 _ £ -.- aa &aSae¿igft¿li »fr, * _.» - * - y. < ^. * "* - * -. ^ * Z ¡M & íi i¡¡ ^^ characterized in that it comprises administering to a patient in need thereof a composition of claim 97 in a unit dose. 101. A method for the prophylaxis or treatment of hypercholesterolemia characterized in that it comprises administering to a patient in need thereof a composition of claim 98 in a unit dosage form. 102. The use of a compound of any of claims 1 to 95 in the preparation of a medicament characterized in that it is used in the prophylaxis or treatment of a hyperlipidemic condition. 103. The use of a compound of any of claims 1 to 95 in the preparation of a medicament characterized in that it is used in the prophylaxis or treatment of an atherosclerotic condition. 104. The use of a compound of any one of claims 1 to 95 in the preparation of a medicament characterized in that it is used in the prophylaxis or treatment of a hypercholesterolemic condition. 105. A process for the preparation of a compound that has the formula: XLI characterized in that it comprises: treating a thiophenol with an abstraction agent ; coupling the thiophenol and a cyclic sulfate to form an intermediate comprising a sulfate group; and removing the sulfate group from the intermediate to form the compound of formula XLI; where q is an integer from 1 to 4; R1 and R2 are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, haloalkyl, alkylaryl, arylalkyl, alkoxy, alkoxyalkyl, dialkylamino, alkylthio, (polyalkyl) aryl, and cycloalkyl, wherein alkyl, alkenyl, alkynyl, haloalkyl, alkylaryl, arylalkyl, alkoxy, alkoxyalkyl, dialkylamino, alkylthio, (polyalkyl) aryl, and cycloalkyl are optionally substituted with one or more substituents selected from the group consisting of OR9, NR9R10, N + R9R10RWA ", SR9, S + R9R10A". P + R9R10RnA ", S (0) R9, S02R9, S03R9, C02R9, CN, halogen, oxo, and CONR9R10, wherein alkyl, alkenyl, alkynyl, alkylaryl, alkoxy, alkoxyalkyl, (polyalkyl) aryl, and cycloalkyl optionally have one or more carbons replaced by O, NR9, N + R9R10A-, S, SO, S02, S + R9A ", P + R9R10A", or Phenylene, wherein R9 'R10' and Rw are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, acyl, heterocycle, ammonioalkyl, arylalkyl, carboxyalkyl, carboxyheteroaryl, carboxyheterocycle, carboalkoxyalkyl, carboxyalkyl amino, carboxyalkylaminoalkyl, heteroarylalkyl, heterocyclylalkyl, and alkylammonioalkyl; or R1 and R2 are taken together with the carbon at which are linked to form C3-C10 cycloalkyl, R3 is hydroxy, R is hydrogen, R5 and R6 are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, quaternary heterocycle, OR30, SR9, S (0) R9, S02R9, and S03R9, wherein alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, quaternary heterocycle, and quaternary heteroaryl can be substituted with one or more substituent groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocycle, arylalkyl, quaternary heterocycle, quaternary heteroaryl, halogen, oxo, OR13, NR13R14, SR13, S (0) R13, S02R13, S03R13, NR130R14, NR13NR14R15, N02, C02R13, CN, OM, S02OM, S02NR13R14, C (0) NR13R14, C (0) OM, COR13, NR13C (0) R14, NR13C (O) NR14R15, NR13C02R14, OC (0) R13, OC (0) NR13R14, NR13SOR14, NR13S02R14, NR13SONR14R15, NR13S02NR14R15, P (0) R13R14, P + R13R14R15A ", P (0R13) 0R14, S + R13R14A", and N + R9RUR12A ", where : A "is a pharmaceutically acceptable anion and M is a pharmaceutically acceptable cation, said alkyl, alkenyl, alkynyl, polyalkyl it, polyether, aryl, haloalkyl, cycloalkyl, and heterocycle can be further substituted with one or more substituent groups selected from the group consisting of OR7, NR7R8, SR7, S (0) R7, S02R7, SO3R7, C02R7, CN, halogen, oxo, CONR7R8, N + R7R8R9A-, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterococlo, arylalkyl, quaternary heterocycle, quaternary heteroaryl, P (0) R7R8, P + R7R8R9A ", and P (0) ( OR7) OR8, and wherein said alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, and heterocycle, may have one or more carbons replaced by 0, NR7, N + R7R8A-, S, SO, S02, S + R7A-, PR7, P (0) R7, P + R7R8A-, or phenylene, and R13, R14, and R15 are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, arylalkyl, alkylarylalkyl, alkylheteroarylalkyl, alkylheterocyclylalkyl, cycloalkyl, heterocycle, heteroaryl, quaternary heterocycle, quaternary heteroaryl, heterocyclylalkyl, heteroarylalkyl, quaternary heterocyclylalkyl, heteroarylalkyl quaternary, alkylammoniomalkyl, and carboxyalkylaminocarbonylalkyl, wherein alkyl, alkenyl, alkynyl, arylalkyl, tercycle, and polyalkyl optionally have one or more carbons replaceable by 0, NR9, N + R9R10A-, S, SO, So2, S + R9A ', PR9, P + R9R10A-, R (0) R9, phenylene, carbohydrate, amino acid , peptide, or polypeptide, and R13, R14, and R15 are optionally substituted with one or more groups selected from the group consisting of hydroxy, amino, sulfo, carboxy, alkyl, carboxyalkyl, heterocycle, heteroaryl, sulfoalkyl, quaternary heterocycle, quaternary heteroaryl, quaternary heterocyclylalkyl, quaternary heteroarylalkyl, guanidinyl, carboxyalkylheterocyclicthio, OR9, NR9R10, N + R9RnR12A ", SR9, S (0) R9, S02R9, S03R9, oxo, C02R9, CN, halogen, CONR9R10, S020M, S02NR9R10, PO (OR16) OR17, P + R9R10RnA", S + R9R10A ", and C (0) OM, wherein R16 and R17 are independently selected from the substituents constituting R9 and M; or R13 and R14, together with the nitrogen atom which is attached to form a mono or heterocycle polycyclic which is optionally substituted with one or more radicals selected from the group consisting of oxo, carboxy, and quaternary salts, or R14 and R15, together with the nitrogen atom to which they are attached to form a cyclic ring, and R30 is selected from group that cons alkyl, alkenyl, alkynyl, cycloalkyl, aryl, acyl, heterocycle, ammonium alkyl, alkylaminoalkyl, arylalkyl, carboxyalkyl, carboxyheteroaryl, carboxylocycle, carboalkoxyalkyl, carboxyalkylamino, heteroarylalkyl, heterocyclylalkyl, and alkyß-lamoniomalkyl; and R 7 and R 8 are hydrogen; and one or more Rx are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, polyalkyl, acyloxy, aryl, arylalkyl, halogen, haloalkyl, cycloalkyl, heterocycle, heteroaryl, polyether, 10 quaternary heterocycle, quaternary heteroaryl, OR13, NR13R14, SR13, S (0) R13, S (0) 2R13, S + R13R14A ", NR13OR14, NR13NR14R15, N02, C02R13, CN, OM, S02OM, S02NR13R14, NR14C (0) R13, C (0) NR13R14, NR14C (0) R13, C (0) OM, COR13, OR, 1.8 °, S (0) nNR, 1.8 °, NR > 1i3JR_1'8 °, M + T NtR.9aRT.1X1iTR-1i2¿A, ", P + R9R R12A", 15 amino acid, peptide, polypeptide, and carbohydrate, wherein alkyl, alkenyl, alkynyl, cycloalkyl, aryl, polyalkyl, heterocycle, acyloxy, arylalkyl, haloalkyl, polyether, quaternary heterocycle, and quaternary heteroaryl 20 can also be substituted with OR9, NR9R10, N + R9RUR12A ", SR9, S (0) R9, S02R9, S03R9, oxo, C02R9, CN, halogen, CONR9R10, S020M, S02NR9R10, PO (OR16) OR17, P + R9R11R12A ", S + R9R10A", or C (0) OM, and wherein R 18 is selected from the group consists of acyl, arylalkoxycarbonyl, arylalkyl, heterocycle, heteroaryl, and alkyl, wherein acyl, arylalkoxycarbonyl, arylalkyl, heterocycle, heteroaryl, alkyl, quaternary heterocycle, and quaternary heteroaryl optionally substituted with one or more substituents selected from the group consisting of OR9, NR9R10, N + R9R R12A ", SR9, S (0) R9, S02R9, S03R9, oxo, C02R9, CN, halogen, CONR9R10, S03R9, S020M, S02NR9R10, P0 (0R16) 0R17, and C (0) 0M, in where Rx 'one or more carbons are optionally replaced by O, NR13, N + R13R14A ", S, SO, S02, S + R13A", PR13, P (0) R13, P + R13R14A ", phenylene, amino acid, peptide, polypeptide, carbohydrate, polyether, or polyalkyl, wherein said polyalkyl, phenylene, amino acid, peptide, polypeptide, and carbohydrate, one or more carbons are optionally replaced by O, NR9, N + R9R10A ", S, SO, S02, S + R9A ", PR9, P + R9R10A ', or P (0) R9; wherein the quaternary heterocycle and the quaternary heteroaryl are optionally substituted with one or more groups selected from the group consisting of alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocycle, arylalkyl, halogen, oxo, OR13, NR13R14, SR13, S (0) R13, S02R13, S03R13, NR130R14, NR13NR14R15, N02, C02R13, CN, OM, S020M, S02NR13R14, C (0) NR13R14, C ( 0) OM, COR13, P (0) R13R14, P + R13R14R15A ", P (0R13) OR14, S + R13R14A", and N + R9RnR12A ", 106. The process of claim 105 characterized in that the cyclic sulfate has the formula: XL and thiophenol have the formula XVIIIA characterized in that R, R, R, Ro * x and q are . -iSgj as defined in claim 105. 107. The process of claim 105 characterized in that the sulfate group is removed by treating the intermediate with a hydrolyzing agent. 108. The process of claim 107 characterized in that the hydrolyzing agent is an acid mineral. 109. The process of claim 107 characterized in that the hydrolyzing agent is selected from the group consisting of hydrochloric acid and sulfuric acid. 110. The process of claim 106 characterized in that the abstracting agent is a base having a pH of at least about 10. 111. The process of claim 106 characterized in that the abstraction agent is an alkali metal hydride. 112. The process of claim 106 characterized in that the abstraction agent is a sodium hydride. 113. The process of claim 106 characterized in that R1 and R2 are independently selected from alkyl. -________ ¿__¿_ ^ 1J faith% _ ^ 3 & 8 114. The process of claim 106 characterized in that R1 and R2 are independently selected from the group consisting of ethyl, n-butyl, iso-butyl and pentib. 115. The process of claim 106 characterized in that R1 and R2 are n-butyl. 116. A process for the preparation of a compound having the formula I: characterized in that it comprises: reacting a cyclic sulfate with a thiophenol to form an alcohol; oxidizing said alcohol to form a sulfone-aldehyde; and cyclizing said sulfone-aldehyde to form the compound of formula I; where : A & * q is an integer from 1 to 4; n is 2; R1 and R2 are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, haloalkyl, alkylaryl, arylalkyl, alkoxy, alkoxyalkyl, dialkylamino, alkylthio, (polyalkyl) aryl, and cycloalkyl, wherein alkyl, alkenyl, alkynyl, haloalkyl, alkylaryl, arylalkyl, alkoxy, alkoxyalkyl, dialkylamino, alkylthio, (polyalkyl) aryl, and cycloalkyl are optionally substituted with one or more substituents selected from the group consisting of OR9, NR9R10, N + R9R10RWA ", SR9, S + R9R10A \ P + R9R10RnA ", S (0) R9, S02R9, S03R9, C02R9, CN, halogen, oxo, and C0NR9R10, wherein alkyl, alkenyl, alkynyl, alkylaryl, alkoxy, alkoxyalkyl, (polyalkyl) aryl, and cycloalkyl optionally has one or more carbons replaced by O, NR9, N + R9R10A-, S, SO, S02, S + R9A ", P + R9R10A", O phenylene, wherein R9 'R10' and Rw are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, acyl, heterocycle, ammonioalkyl, arylalkyl, carboxyalkyl, carboxyheteroaryl, carboxyheterocycle, carboalkoxyalkyl, carboxyalkylamino, carboxyalkylaminoalkyl, heteroarylalkyl, heterocyclylalkyl, and alkylammonioalkyl; or R1 and R2 taken together with the carbon to which they bind to form C3-C10 cycloalkyl; R3 is hydroxy; R4 is hydrogen; R5 and R6 are selected from the group consisting of H; alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, quaternary heterocycle, OR30, SR9, S (0) R9, S02R9, and SO3R9, wherein alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, quaternary heterocycle, and quaternary heteroaryl they can be substituted with one or more substituted groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocycle, arylalkyl, quaternary heterocycle, quaternary heteroaryl, halogen, oxo, OR13, NR13R14, SR13, S (0) R13, S02R13, S03R13, NR13OR14, NR13NR14R15, N02, C02R13, CN, OM, S02OM, S02NR13R14, C (0) NR13R14, C (0) OM, COR13R14, C (0) OM, COR13, NR13C (0) R14, NR13C (O) NR14R15, NR13C02R14, OC (0) R13, OC (0) NR13R14, NR13SOR14, NR13 S02NR14R15, P (0) R13R14, NR13S02R14R15, P (0) R13R14, P + R13R14R15A ", P (OR13) OR14, S + R13R14A ', and N + R9R R12A-, where; A "is a pharmaceutically acceptable anion and M is a pharmaceutically acceptable cation, said alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, and heterocycle, may also be substituted with one or more substituent groups selected from the group consisting of of OR 7, NR7R8, SR7, S (0) R7, S02R7, S03R7, C02R7, CN, oxo, CONR7R8 'N + R7R8R9A ", alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, arylalkyl, quaternary heterocycle, quaternary heteroaryl, P (0) R 7R8, P + R7R8R9A ", and P (O) (OR7) OR8, and wherein said alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, and the heterocycle may optionally have one or more carbons replaced by O, NR7, N + R7R8A ", S, SO, S02, S + R7A", PR7, P (0) R7, P + R7R8A-, or phenylene, and R13, R14, and R15 were independently selected from the group consisting of hydrogen , alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, arylalkyl, alkylarylalkyl, alkylheteroarylalkyl, alkylheterocyclylalkyl, cycloalkyl, heterocycle, heteroaryl, quaternary heterocycle, quaternary heteroaryl, heterocyclylalkyl, heteroarylalkyl, quaternary heterocyclylalkyl, heteroarylalkyl quaternary, alkylammoniomalkyl, and carboxyalkylaminocarbonylalkyl, wherein alkyl, alkenyl, alkynyl, arylalkyl, heterocycle, and polyalkyl optionally have one or more carbons replaced by 0, NR9, N + R9R10A ", S, SO, S02, S + R9A", PR9, P + R9R10A ", P (0) R9, phenylene, carbohydrate, amino acid, peptide, or polypeptide, and R13, R14, and R15 are optionally substituted with one or more groups selected from the group consisting of hydroxy, amino, sulfo, carboxy, alkyl, carboxyalkyl, heterocycle, heteroaryl, sulfoalkyl, quaternary heterocycle, quaternary heteroaryl, quaternary heterocyclylalkyl, quaternary heteroarylalkyl, guanidinyl, carboxyalkylheterocyclicthio, OR9, NR9R10, N + R9RnR12A ", SR9, S (0) R9, S02R9, S03R9, oxo, C02R9, CN, halogen, CONR9R10, S020M, S02NR9R10, PO (OR16) OR17, P + R9R10R11A", S + R9R10A ", and C (0) OM, wherein R 16 and R 17 are independently selected from the substituents that constitute R 9 and M; or .-j_tfJfa__afe, fa__ -fei R13 and R14, together with the nitrogen atom to which they are attached to form a polycyclic mono or heterocycle which is optionally substituted with one or more radicals selected from the group consisting of oxo, carboxy, and quaternary salts; or R14 and R15, together with the nitrogen atom to which they join to form a cyclic ring; and R30 is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, aryl, acyl, heterocycle, ammonium alkyl, alkylaminomalkyl, arylalkyl, carboxyalkyl, carboxyheteroaryl, carboxyethocycle, carboalkoxyalkyl, carboxyalkyl amino, heteroarylalkyl, heterocyclylalkyl, and alkylammoniomalkyl; and R7 and R8 are hydrogen; and one or more Rx are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, polyalkyl, acyloxy, aryl, arylalkyl, halogen, haloalkyl, cycloalkyl, heterocycle, heteroaryl, polyether, quaternary heterocycle, quaternary heteroaryl, OR13, NR13R14 , SR13, S (0) R13, S (0) 2R13, S03R13, S + R13R14A ", NR13OR14, NR13NR1R15, N02, C02R13, CN, OM, S02OM, S02NR13R14, NR14C (0) R13, C (0) NR13R14, NR14C (0) R13, C (0) OM, COR13, OR18, S (0) nNR18, NR13OR18, N + R9R R12A ", P + R9R11R12A", amino acid, peptide, polypeptide, and carbohydrate, wherein alkyl, alkenyl, alkynyl, cycloalkyl, aryl, polyalkyl, heterocycle, acyloxy, arylalkyl, haloalkyl, polyether, quaternary heterocycle, and quaternary heteroaryl can be further substituted with OR9, NRR, N + R9R11R12A ", SR9, S (0) R9, S02R9, S03R9, oxo, C02R9, CN, halogen, CONR9R10, S020M , S02NR9R10, PO (OR16) OR17, P + R9R11R12A ", S + R9R10A", or C (0) OM, and wherein R1 is selected from the group consisting of acyl, arylalkoxycarbonyl, arylalkyl, heterocycle, heteroaryl, and alkyl, wherein acyl, arylalkoxycarbonyl, arylalkyl, heterocycle, heteroaryl, alkyl, quaternary heterocycle, and quaternary heteroaryl optionally substituted with one or more substituents selected from the group consisting of OR9, NR9R10, N + R9RUR12A ", SR9, S (0) R9 , S02R9, S03R9, oxo, C02R9, CN, halogen, CONR9R10, S03R9, S02OM, S02NR9R10, PO (OR16) OR17, and C (0) OM, wherein Rx 'one or more carbons are optionally replaced by O, NR13, N + R13R14A ", S, SO, S02, S + R13A-, PR13, P (0) R13, P + R13R14A", phenylene, ^ ¡^^ _______________ ii___________ » amino acid, peptide, polypeptide, • carbohydrate, polyether, or polyalkyl, wherein said polyalkyl, phenylene, amino acid, peptide, polypeptide, and carbohydrate, one or more carbons are optionally replaced by 0, NR9, N + R9R10A ", S, SO , S02, S + R9A ", PR9, P + R9R10A", OP (0) R9, wherein the quaternary heterocycle and quaternary heteroaryl are optionally substituted with one or more groups selected from the group consisting of alkyl, alkenyl, alkynyl, polyalkyl , polyether, aryl, haloalkyl, cycloalkyl, heterocycle, arylalkyl, halogen, oxo, OR13, NR13R14, SR13, S (0) R13, S02R13, S03R13, NR13OR14, NR13NR14R15, N02, C02R13, CN, OM, S020M, S02NR13R14, C (0) NR13R14, C (0) 0M, COR13, P (0) R13R14, P + R13R14R15A ", P (0R13) 0R14, S + R13R1A", and N + R9RnR12A ". 117. The process of claim 116 characterized in that the cyclic sulfate has the formula: _ * _ & XL and thiophenol has the formula XVIIIA where R, R; R, Rx and q are as defined in claim 116. The process of claim 117 characterized in that R and R are independently selected from alkyl. 119. The process of claim 117 characterized in that R 'are selected independently of the group consisting of ethyl, n-butyl, iso-butyl and pentyl. 120. The process of claim 117 characterized in that R1 and R2 are n-butyl. 121. The process of claim 117 characterized in that the alcohol is oxidized with an oxidizing agent to form an aldehyde. 122. The process of claim 121 characterized in that the aldehyde is oxidized with an oxidizing agent to form a sulfone-aldehyde. 123. The process of claim 117 characterized in that the sulfone-aldehyde is cyclized with a cyclizing agent having a base with a pH between about 8 to about 9. 124. The process of claim 117 characterized in that the sulfone-aldehyde is cyclized with a cyclizing agent which is an alkaline alkoxide base. 125. The process of claim 117 characterized in that the sulfone-aldehyde is cyclized with tert-butoxide potassium. 126. The process of claim 117 characterized in that the alcohol is oxidized with pyridinium chlorocromatro to form an aldehyde; the aldehyde is oxidized with metachloroperbenzoic acid to form a sulfone-aldehyde; and the sulfone-aldehyde is cyclized with potassium tert-butoxide. 127. A process for the preparation of a compound that has the formula Ll: characterized in that it comprises: treating a halobenzene with an abstraction agent; coupling the halobenzene and a cyclic sulfate to form an intermediate comprising a sulfate group; and removing the sulfate group from the intermediate to form the compound of formula Ll; where g is an integer from 1 to 4; R and R2 are independently selected from a group consisting of H, alkyl, alkenyl, alkynyl, haloalkyl, alkylaryl, arylalkyl, alkoxy / alkoxyalkyl, dialkylamino, alkylthio, (polyalkyl) aryl, and cycloalkyl, wherein alkyl, alkenyl, alkynyl, haloalkyl, alkylaryl, arylalkyl, alkoxy, alkoxyalkyl, dialkylamino, alkylthio, (polyalkyl) aryl, and cycloalkyl are optionally substituted with one or more substituents selected from the group consisting of OR9, NR9R10, N + R9R10RWA ", SR9, S + R9R10A". P + R9R10RUA ", S (O) R9, S02R9, S03R9, C02R9, CN, halogen, oxo, and C0NR9R10, wherein alkyl, alkenyl, alkynyl, alkylaryl, alkoxy, alkoxyalkyl, (polyalkyl) aryl, and cycloalkyl optionally have one or more carbons replaced by O, NR9, N + R9R10A-, S, SO, S02, S + R9A ", P + R9R10A", or phenylene, wherein R9 'R10 and R are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, acyl, heterocycle, ammonioalkyl, arylalkyl, carboxyalkyl, carboxyheteroaryl, carboxyheterocycle, carboalkoxyalkyl, carboxyalkylamino, carboxyalkylaminoalkyl, heteroarylalkyl, heterocyclylalkyl, and alkylammonioalkyl; or _ - R and R taken together with the carbon to which they are linked to form C3-C10 cycloalkyl; R3 is hydroxy; R4 is hydrogen; R5 and R6 are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, hetrocycle, quaternary heterocycle, OR30, SR9S (0) R9, S02R9, and S03R9, wherein alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, quaternary heterocycle, and quaternary heteroaryl can be substituted with one or more substituent groups independently selected from the group consisting of alkyl alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocycle, arylalkyl, quaternary heterocycle, quaternary heteroaryl, halogen, oxo, OR13, NR13 R14, SR13, S (O) R13, S02R13, SO3R13, NR13 NR13OR14, NR13NR14R15 'N02, C02R13, CN, OM, S02OM, S02NR13R14, C (0) NR13R14, C (0) OM, COR13, NR13C (0) R14, NR13C (0) NR14R15, NR13C02R14, OC (0) R13, OC (O ) NR13R14, NR13SOR14, NR13S02R14, NR13SONR14R15, NR13S02NR14R15, NR13S02R14R15, P (0) R13R14, P + R13R14R15A ", P (OR13) OR14, S + R13R14A ', and N + R9R R12A-, * __ > fa ^ »afeafc» » where; A "is a pharmaceutically acceptable anion and M is a pharmaceutically acceptable cation, said alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, and heterocycle, may also be substituted with one or more substituent groups selected from the group consisting of of OR, NR7R, SR7, S (0) R7, S02R7, S03R7, C02R7, CN, oxo, CONR7R8 'N + R7R8R9A ", alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, arylalkyl, quaternary heterocycle, quaternary heteroaryl, P (0) R7R, P + R7R8R9A ", and P (O) (OR7) OR8, and wherein said alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, and the heterocycle may optionally have one or more carbons replaced by O, NR7, N + R7R8A ", S, SO, S02, S + R7A ~, PR7, P (0) R7, P + R7R8A-, or phenylene, and R13, R14, and R15 are independently selected from A group consisting of hydrogen, alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, arylalkyl, alkylarylalkyl, alkylheteroarylalkyl, alkylheterocyclylalkyl, cycloalkyl, heterocycle, heteroaryl, quaternary heterocycle, quaternary heteroaryl, heterocyclylalkyl, heteroarylalkyl, quaternary heterocyclylalkyl, heteroarylalkyl quaternary, alkylammoniomalkyl, and 5-carboxyalkylaminocarbonylalkyl, wherein alkyl, alkenyl, alkynyl, arylalkyl, heterocycle, and polyalkyl optionally have one or more carbons replaced by 0, NR9, N + R9R10A ", S, SO, S02, S + R9A", PR9, P + R9R10A ", P (0) R9, phenylene, carbohydrate, amino acid, peptide, or polypeptide, and R13, R14, and R15 are optionally substituted with one or more groups selected from the group consisting of hydroxy, amino, sulfo, carboxy, alkyl , Carboxyalkyl, heterocycle, heteroaryl, sulfoalkyl, quaternary heterocycle, quaternary heteroaryl, quaternary heterocyclylalkyl, quaternary heteroarylalkyl, guanidinyl, carboxyalkylheterocyclicthio, OR9, NR9R10, N + R9RUR12A ", 20 SR9, S (0) R9, S02R9, S03R9, oxo, C02R9, CN, halogen, CONR9R10, S02OM, S02NR9R10, PO (OR16) OR17, P + R9R10R11A ", S + R9R10A", and C (0) 0M, wherein R16 and R17 are independently selected from the substituents they are R and M; or R13 and R14, together with the nitrogen atom to which they are attached to form a monocyclic or polycyclic heterocycle which is optionally substituted with one or more radicals selected from the group consisting of oxo, carboxy, and quaternary salts; or R14 and R15, together with the nitrogen atom to which they join to form a cyclic ring; and R30 is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, aryl, acyl, heterocycle, ammonium alkyl, alkylaminomalkyl, arylalkyl, carboxyalkyl, carboxyheteroaryl, carboxyheterocycle, carboalkoxyalkyl, carboxyalkylamino, heteroarylalkyl, heterocyclylalkyl, and alkylammoniomalkyl; and R7 and R8 are hydrogen; and one or more Rx are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, polyalkyl, acyloxy, aryl, arylalkyl, halogen, haloalkyl, cycloalkyl, heterocycle, heteroaryl, polyether, quaternary heterocycle, quaternary heteroaryl, OR13, NR13R14 , SR13, S (0) R13, S (0) 2R13, S03R13, S + R13R14A ", NR13OR14, NR13NR1 R15, N02, C02R13, CN, OM, S02OM, S = rfwJ fe S02NR13R14, NR14C (0) R13, C (0) NR13R14, NR14C (0) R13, C (0) OM, COR13, OR18, S (0) nNR18, NR13R18, NR18OR14, N + R9RX1R12A ", P + R9R ?: "R12A", amino acid, peptide, polypeptide, and carbohydrate, wherein alkyl, alkenyl, alkynyl, cycloalkyl, aryl, polyalkyl, heterocycle, acyloxy, arylalkyl, haloalkyl, polyether, quaternary heterocycle, and quaternary heteroaryl can be further substituted with OR9, NR9R10, N + R9RnR12A ", SR9, S (0) R9, S02R9, S03R9, oxo, C02R9, CN, halogen, CONR9R10, S02OM, S02NR9R10, PO (OR16) OR17, P + R9RnR12A", S + R9R10A ~, or C (0) OM, and wherein R 1 is selected from the group consisting of acyl, arylalkoxycarbonyl, arylalkyl, heterocycle, heteroaryl, and alkyl, wherein acyl, arylalkoxycarbonyl, arylalkyl, heterocycle, heteroaryl, alkyl, quaternary heterocycle, and quaternary heteroaryl optionally substituted with one or more substituents selected from the group consisting of OR9, NR9R10, N + R9R R12A_, SR9, S (0) R9, S02R9, S03R9, oxo, C02R9, CN, h alkogen, CONR9R10, S03R9, S02OM, S02NR9R10, PO (OR16) OR17, and C (0) OM, where Rx 'one or more carbons are replaced optionally by 0, NR13, N + R13R1A ", S, SO, S02, S + R13A", PR13, P (0) R13, P + P4 * fl4A ~, phenylene, amino acid, peptide, polypeptide, carbohydrate, polyether, or polyalkyl, wherein said polyalkyl, phenylene, amino acid, peptide, polypeptide, and carbohydrate, one or more carbons are optionally replaced by 0, NR9, N + R9R10A ", S, SO, S02, 'S + R9A", PR9, P + R9R10A ", or P (0) R9; wherein the quaternary heterocycle and quaternary heteroaryl are optionally substituted with one or more groups selected from the group consisting of alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocycle, arylalkyl, halogen, oxo, 0R .1i3J, NR, 113JRn1X4% SR > 1i3J, S (0) R1J, S02R .1i3J, S03R .113J, NR, 13JMNRD1i4R_1150, N02, C02R .1i3J, CN, OM, S020M, S02NRiJRx \ CIOJ C (0) 0M, C0R, 1i3J, P (0) RiJRiß, P R1JRI4R15A ", P (0R, r_1 t_14 S c. + TR13JR 4A_, and o Re is an electron donor group located in the position for or ortho. 128. The process of claim 127 characterized in that the cyclic sulfate has the formula: XL and halobenzene has the formula wherein Rh is halogen, and R1, R2, R5, R ?, Re and q are as defined in claim 127. 129. The process of claim 128 characterized in that the sulfate group was removed by the treatment of an intermediate with a hydrolyzing agent. 130. The process of claim 129 characterized by the agent, hydrolyzate is an acid mineral. 131. The process of claim 129 characterized in that the hydrolyzing agent is selected from the group consisting of hydrochloric acid and sulfuric acid. 132. The process of claim 128 characterized in that the abstraction agent is a dialkali metal sulfide. 133. The process of claim 128 characterized in that the abstraction agent is a dilithium metal sulfide. 13 «- The process of claim 128 characterized by R < V R2 and R are independently selected from alkyl. 135 * E1 Pr ° Ceso of claim 128 characterized in that R1; R1 and R2 are independently selected from the group consisting of ethyl, n-butyl, iso-butyl and pentyl. 13 The process d. .a relvind.cac..n i2ß characterized by "" and R > they are n-butn ^ 137. The process according to claim 128 characterized in that Rh is chloro. 138. The process of claim 128 characterized in that ^ fs p-nitro. 139. A process for the preparation of a compound that has the forrr? L. I: characterized in that it comprises: reacting a cyclic sulfate with a halobenzene to form an alcohol; oxidizing said alcohol to form a sulfone-aldehyde; and cyclizing said sulfone-aldehyde to form the compound of formula I; where q is an integer from 1 to 4; n is 2; R1 and R2 are independently selected from the group consisting of H, alkyl, alkenyl, alkyl, - haloalkyl, alkylaryl, arylalkyl, alkoxy, alkoxyalkyl, dialkylamino, alkylthio, (polyalkyl) aryl, and cycloalkyl, wherein alkyl, alkenyl, alkynyl, haloalkyl, alkylaryl, arylalkyl, alkoxy, alkoxyalkyl, dialkylamino, alkylthio, (polyalkyl) aryl, and cycloalkyl are optionally substituted by one or more substituents selected from the group consisting of OR9, NR9R10, N + R9R10A_, SR9, S + R10A ", P + R9R10RUA", S (0) R9, S02R9, S03R9, C02R9, CN, halogen, oxo, and CONR9R10, wherein alkyl, alkenyl, alkynyl, alkylaryl, alkoxy, alkoxyalkyl, (polyalkyl) aryl, and cycloalkyl are optionally substituted with one or more carbons replaced by O, NR9, NR9R10A ", S, SO, S02, S + R9A", P + R9R10A ". Or phenylene, wherein R9, R10, and Rw are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, acyl, heterocycle, ammonioalkyl, arylalkyl, carboxyalkyl, carboxyheteroaryl, carboxyheterocycle, carboalkoxyalkyl, carboxyalkylamino, carboxyalkylaminoalkyl, heteroarylalkyl, heterocyclylalkyl, and alkylammoniomalkyl; or R and R take together with the carbon to which they are joined to form C3-C10 cycloalkyl; R3 is hydroxy; R4 is hydrogen; R5 and R6 are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, quaternary heterocycle, OR30, SR9S (0) R9, S02R9, and SO3R9, wherein alkyl, alkenyl, alkynyl, aryl , cycloalkyl, heterocycle, quaternary heterocycle, and quaternary heteroaryl can be substituted with one or more substituent groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocycle, arylalkyl, quaternary heterocycle, heteroaryl quaternary, halogen, oxo, OR13, NR13 R14, SR13, S (0) R13, S02R13, SO3R13, NR13OR14, NR13NR14R15 'N02, C02R13, CN, OM, S02OM, S02NR13R14, C (0) NR13-R14, C ( 0) OM, COR13, NR13C (0) R14, NR13C (0) NR14R15, NR13C02R14, OC (0) R13, OC (O) NR13R14, NR13SOR14, NR13S02R14, NR13SONR14R15, NR13S02NR14R15, P (0) R13R14, P + R13R14R15A " , P (0R13) 0R14, S + R13R14A ", and N + R9R11R12A-, wherein; A "is a pharmaceutically acceptable anion and .lAC. M is a pharmaceutically acceptable cation, said alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, and heterocycle, may also be substituted with one or more substituent groups selected from the group consisting of OR 7, NR7R8, SR7, S (0) R7, S02R7, S03R7, C02R7, CN, oxo, CONR7R8 'N + R7R8R9A ", alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, arylalkyl, quaternary heterocycle, quaternary heteroaryl, P (0) R7R8, P + R7R8R9A ", and P (O) (OR7) OR8, and wherein said alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, and heterocycle may optionally have one or more carbons replaced by O, NR7, N + R7R8A ", S, SO, S02, S + R7A", PR7, P (0) R7, P + R7R8A-, or phenylene, and R13, R14, and R15 are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, arylalkyl, alkylarylalkyl, alkylheteroarylalkyl, alkylheterocyclyl alkyl, cycloalkyl, heterocycle, heteroaryl, quaternary heterocycle, quaternary heteroaryl, heterocyclylalkyl, heteroarylalkyl, handle. --afeto -., «_ .. TO ~ ¡t - * - *, > * .'- & »*« 9 ««? * ~ - ^ -.? «3fe-j _» _ i_ ._ quaternary heterocyclylalkyl, quaternary heteroarylalkyl, alkylammoniomalkyl, and carboxyalkylaminocarbonylalkyl, wherein alkyl, alkenyl, alkynyl, arylalkyl, heterocycle, and polyalkyl optionally have one or more carbons replaced by 0, NR9, N + R9R10A ", S, SO, S02, S + R9A ", PR9, P + R9R10A", P (0) R9, phenylene, carbohydrate, amino acid, peptide, or polypeptide, and R13, R14, and R15 are optionally substituted with one or more groups selected from the group consisting of hydroxy, Not me, sulfo, carboxy, alkyl, carboxyalkyl, heterocycle, heteroaryl, sulfoalkyl, quaternary heterocycle, quaternary heteroaryl, quaternary heterocyclylalkyl, quaternary heteroarylalkyl, guanidinyl, carboxyalkylheterocyclicthio, OR9, NR9R10, N + R9R11R12A ", SR9, S (0) R9, S02R9, S03R9, oxo, C02R9, CN, halogen, C0NR9R10, S020M, S02NR9R10, PO (OR16) OR17, P + R9R10R11A ", S + R9R10A", and C (0) OM, wherein R16 and R17 are independently selected from the substituents which constitute R9 and M; or R13 and R14, together with the nitrogen atom at ¿^ K ^^^^^ Bj ^ * ***** * **. "____________," * - *: & & > & ££ * .: which join to form a mono or polycyclic heterocycle which is optionally substituted with one or more radicals selected from the group consisting of oxo, carboxy, and quaternary salts; or R14 and R15, together with the nitrogen atom to which they join to form a cyclic ring; and R30 is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, aryl, acyl, heterocycle, ammonium alkyl, alkylaminomalkyl, arylalkyl, carboxyalkyl, carboxyheteroaryl, carboxyheterocycle, carboalkoxyalkyl, carboxyalkylamino, heteroarylalkyl, heterocyclylalkyl, and alkylammoniomalkyl; and R7 and R8 are hydrogen; and one or more Rx are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, polyalkyl, acyloxy, aryl, arylalkyl, halogen, haloalkyl, cycloalkyl, heterocycle, heteroaryl, polyether, quaternary heterocycle, quaternary heteroaryl, OR13, NR13R14 , SR13, S (0) R13, S (0) 2R13, S03R13, S + RI3R14A ", NR13OR14, NR13NR14R15, N02, C02R13, CN, OM, S02OM, S02NR13R14, NR14C (0) R13, C (0) NR13R14, NR1 C (0) R13, C (0) OM, COR13, OR18, S (0) nNR18, NR13R18, NRl8OR14, N + R9R? AR12A-, 'HM ^ - P + R9R11R12A ", amino acid, peptide, polypeptide, and carbohydrate, wherein alkyl, alkenyl, alkynyl, cycloalkyl, aryl, polyalkyl, heterocycle, acyloxy, arylalkyl, haloalkyl, polyether, quaternary heterocycle, and quaternary heteroaryl can be further substituted with OR9 , NR9R10, N + R9RUR12A ", SR9, S (0) R9, S02R9, S03R9, oxo, C02R9, CN, halogen, CONR9R10, S02OM, S02NR R10, PO (OR16) OR17, P + R9RnR12A", S + R9R10A " , or C (0) OM, and wherein R 18 is selected from the group consisting of acyl, arylalkoxycarbonyl, arylalkyl, heterocycle, heteroaryl, and alkyl, wherein acyl, arylalkoxycarbonyl, arylalkyl, heterocycle, heteroaryl, alkyl, quaternary heterocycle, and quaternary heteroaryl optionally substituted with one or more substituents selected from the group consisting of OR9, NR9R10, N + R9R11R12A ", SR9, S (0) R9, S02R9, S03R9, oxo, C02R9, CN, halogen, CONR9R10, S03R9, S02OM , S02NR9R10, PO (OR16) OR17, and C (0) OM, where Rx 'one or more carbons is replaced optionally by O, NR13, N + R13R14A ", S, SO, S02, S + R13A_, PR13, P (0) R13, P + R13R1A", phenylene, amino acid, , -, .. ^ - -_- «_-« ^ .- ^. ___ »*. ? fet, .-, _fc - »* --- wt. - ^ & ..- ¡--i __, a__ > peptide, polypeptide, carbohydrate, polyether, or polyalkyl, wherein said polyalkyl, phenylene, amino acid, peptide, polypeptide, and carbohydrate, one or more carbons are optionally replaced by 0, NR9, N + R9R10A ", S, SO, S02, S + R9A ", PR9, P + R9R10A", or P (0) R9, wherein the quaternary heterocycle and quaternary heteroaryl are optionally substituted with one or more groups selected from the group consisting of alkyl, alkenyl, alkynyl, polyalkyl, polyether , aryl, haloalkyl, cycloalkyl, heterocycle, arylalkyl, halogen, oxo, OR13, NR13R14, SR13, S (0) R13, S02R13, SO3R13, NR13OR14, NR13NR14R15, N02, C02R13, CN, OM, S020M, S02NR13R14, C (0 ) NR13R14, C (0) 0M, COR13, P (0) R13R14, P + R13R14R15A ", P (0R13) 0R14, S + R13R14A ', and N + R9R R12A-, and Re is an electron donor group located in the position for or ortho. 140. The process of claim 139 characterized in that the cyclic sulfate has the formula: XL and halobenzene have the formula: wherein R1, R2, R5, Rx and Re are as defined in claim 139, and Rh is halogen. 141. The process of claim 140 characterized in that the sulfate group was removed by treating the intermediate with a hydrolyzing agent. 142. The process of claim 141 «FisS characterized in that the hydrolyzing agent is an acid mineral. 143. The process of claim 140 characterized in that the hydrolyzing agent is selected from the group consisting of hydrochloric acid and sulfuric acid. 144. The process of claim 140 characterized in that the abstraction agent is a dialkali metal sulfide. 145. The process of claim 140 characterized in that the abstraction agent is a dilithium sulfide. 146. The process of claim 140 characterized in that R1 and R2 are independently selected from alkyl. 147. The process of claim 140 characterized in that R1 and R2 are independently selected from the group consisting of ethyl, n-butyl, iso-butyl and pentyl. 148. The process of claim 140 characterized in that R1 and R2 are n-butyl. 149. The process of claim 140 characterized in that Rh is chloro. 150. The process of claim 140 .__ * ____- h? JBftfc __ characterized in that Re is p-nitro. 151. The process of claim 140 characterized in that the alcohol is oxidized with an oxidizing agent to form a sulfone. 152. The process of claim 140 characterized in that the sulfone is oxidized with an oxidizing agent to form a sulfone-aldehyde. 10 153. The process of claim 140 characterized in that the sulfone-aldehyde is cyclized with a cyclizing agent which is a base having a pH between about 8 to about 9. 15 154. The process of claim 140 characterized in that the sulfone -aldehyde is cyclized with a cyclising agent which is an alkaline alkaline base. 155. The process of claim 140 characterized in that the sulfone-aldehyde is cyclized with potassium tert-butoxide. 25 156. The process of claim 140 ___faith" «._" «^ _ & - ^" * * &? ^ R ^? 3y ¿is ^^^^^ is ^ characterized in that the alcohol is oxidized with metachloroperbenzoic acid to form a sulfone; the aldehyde is oxidized with pyridine chlorochromate to form a sulfone-aldehyde; and the sulfone-aldehyde is cyclized with potassium tert-butoxide.