CA2362147A1 - 1,2-benzothiazepines for the treatment of hyperlipidemic diseases - Google Patents

1,2-benzothiazepines for the treatment of hyperlipidemic diseases Download PDF

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CA2362147A1
CA2362147A1 CA002362147A CA2362147A CA2362147A1 CA 2362147 A1 CA2362147 A1 CA 2362147A1 CA 002362147 A CA002362147 A CA 002362147A CA 2362147 A CA2362147 A CA 2362147A CA 2362147 A1 CA2362147 A1 CA 2362147A1
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heterocyclyl
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Steve A. Kolodziej
David B. Reitz
Michael B. Tollefson
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GD Searle LLC
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    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
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Abstract

Novel 1,1-dioxido-1,2-benzothiazepines, derivatives and analogs thereof, pharmaceutical compositions containing them, and their use in medicine, particularly in the prophylaxis and/or treatment of hyperlipidemic diseases, conditions and/or disorders, such as those associated with atherosclerosis and/or hypercholesterolemia.

Description

NOVEL 1,2-BENZOTHIAZEPINES HAVING ACTIVITY AS
INHIBITORS OF ILEAL BILE ACID TRANSPORT AND
TAUROCHOLATE UPTAKE
Field of the Invention S The present invention relates to novel 1,2-benzothiazepines, derivatives and analogs thereof, pharmaceutical compositions containing them, and their use in medicine, particularly in the prophylaxis and/or treatment of hyperlipidemic diseases, conditions and/or disorders, such as those associated with atherosclerosis and/or hypercholesterolemia, in mammals.
Description of Related Art It is well-settled that hyperlipidemic conditions associated with elevated concentrations of total cholesterol and low-density lipoprotein ("LDL") cholesterol are major 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 the levels of serum cholesterol in a causal relationship. Epidemiological data has accumulated which indicates such reduction leads to an improvement in the disease state of atherosclerosis. Stedronsky, "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 relating to bile acids and cholesterol.
Pathophysiologic alterations are shown to be consistent with interruption of the enterohepatic circulation of bile acids in humans in Heubi, J.E., et al., "Primary Bile Acid Malabsorption: Defective In Vitro heal Active Bile Acid Transport", GastroenteroloQV, 1982:83:804-11.
In fact, cholestyramine binds the bile acids in the intestinal tract, thereby interfering with their normal enterohepatic circulation. Reihner, E.
et al, in "Regulation of Hepatic Cholesterol 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. This results in an increase in liver bile acid synthesis by the liver using cholesterol as well as an upregulation of the liver LDL receptors which enhances clearance of cholesterol and decreases serum LDL cholesterol levels. Suckling el al, "Cholesterol Lowering And Bile Acid Excretion In The Hamster With Cholestyramine Treatment", Atherosclerosis, 89(1991) 183-190), also discloses the results of cholestyramine treatment to lower serum cholesterol levels.
In another approach to the reduction of recirculation of bile acids, the deal bile acid transport system is a putative pharmaceutical target for the treatment of hypercholesterolemia based on an interruption of the enterohepatic circulation with specific transport inhibitors. Kramer, et al, "Intestinal Bile Acid Absorption", The Journal of Biological Chemistry, Vol.
268, No. 24, Issue of August 25, pp. 18035-18046, 1993.
In a series of patent applications, Hoechst Aktiengesellschaft discloses polymers of various naturally occurnng constituents of the enterohepatic circulation system and their derivatives, including bile acid, which inhibit the physiological bile acid transport with the goal of reducing the LDL
cholesterol level sufficiently to be effective as pharmaceuticals and, in particular for use as hypocholesterolemic agents. See, e.g., Canadian Patent Application Nos.
2,025,294; 2,078,588; 2,085,782; and 2,085,830; and EP Application Nos. 0 379 161; 0 549 967; 0 559 064; and 0 563 731.
In vitro bile acid transport inhibition is disclosed to show hypolipidemic activity in The Wellcome Foundation Limited disclosure of the CA 02362147 2001-08-03 ~ ~. .-world patent application number WO 93/16055 for "Hypolipidemic Benzothiepine Compounds".
Selected benzothiepines are disclosed in world patent application number ~?V093/21146 for numerous uses including fatty acid metabolism and coronary vascular diseases.
Additional benzothiegines for use as hypolipidemic agents are disclosed in W097/33882 and U.S. Patent 5,994,391.
Other selected benzothiepines are la~own for use as hypolipaemic and hypocholesterolaemic agents, especially for the treatment or prevention of atherosclerosis as disclosed by application Nos. EP 508425, FR 2661676, and WO 92!18462, each of which is limited by an amide bonded to the carbon adjacent the phenyl ring of the fused bicyclo benzothiepine sing.
W096/16051 published May 30, 1996 describes certain i,5-benzothiazepines as useful in the treatment of hyperlipidemic conditions.
W096/05188 published February 22,1996 describes certain 1,4-benzothiazepines as useful in the treatment of hyperlipidemic conditions.
Additional benzotbiazepines are discussed m the references set forth below. These references either do not disclose a specific utility or disclose a different utility than the present invention.
Orahovats et al., "A Ring Enlargement From Seven- To Ten-Membered-Ring Sulfonamide Derivatives", Helv. Chim. Acts. vol. 79, pp.
I 121-1128 (1996) describes 4,5-dihydro-7,8-dimethoxy-1,2 benzothiazepine-3-one-I,1-dioxide.
I~atrlzky et al., "Preparation Of 6-, 7- and 8-Membered Sultams By Friedel-Crafts, Cyciization Of Z~-Phenylalkanesulfamoyl Chlorides", Ors.
Prep. Proced. Int.. vol. 24(4), pp. 463-467 (1992) describes 2,3,4,5-tetrahydro-1,2-benzothiazepine-1,1-dioxide and 2,3,4,5-tetrahydro-2 butyl-1,2-benzothiazepine-l, I-dioxide for possible use as an anticonvulsant, diuretic or sedative.
AMENDED SHEET
Beckwith et al., "Iododediazoniation Of Arenediazonium Salts Accompanied By Aryl Radical Ring Closure", J. Org. Chem., vol. 52, pp.
1922-1930 (1987) describes 2,3,4,5-tetrahydro-2-allyl-1,2-benzothiazepine-1,1-dioxide.
Stassinopolou et al., "'3C NMR Spectra Of Benzothiazepine, Benzothiazone and Benzosulphonamide N-substituted Derivatives", Ors.
Magn. Reson., vol. 21(3), pp. 187-189 (1983), describes certain N-substituted 4,5-dihydro-7,8-dimethoxy-1,2-benzothiazepine-3-one-1,1-dioxides.
Tamura et al., "Novel Conversions Of Benzo[b]thiophen-3(2H)-ones Into 1,2-Benzisothiazole And Tetrahydro-1,2-benzothiazepin-5-One Systems Via Sulphimide Intermediates", J. Chem. Soc., Perkin Trans. I, vol. 12, pp.
2830-2834 (1980) describes 2,3,4,5-tetrahydro-2-tosyl-4-methyl-1,2-benzothiazepine-5-one-1,1-dioxide.
Catsoulacos et al., "Synthesis Of Some N-Substituted 4,5-Dihydro-7,8-dimethoxybenzothiazepin-3-one 1,1-Dioxides, J. Hetero. Chem., vol. 13(6), pp. 1309-1314 (1976) describes 4,5-dihydro-7,8-dimethoxy-1,2-benzothiazepine-3-one-1,1-dioxide and certain 4,5-dihydro-2-(phenyl, substituted phenyl or pyridyl)-7,8-dimethoxy-1,2-benzothiazepine-3-one-1,1-dioxides having anti-inflammatory and central nervous system activity.
Pangiotopoulos et al., "N(p-Bromophenyl)-4,5-Dihydro-7,8-Dimethoxy Benzothiazepine-3-One l,l-Dioxide C1~HI6BrNO5S", Crvst.
Struct. Comm., vol. 9, pp. 313-320 (1980) describes 4,5-dihydro-2-(4-bromo-phenyl)-7, 8-dimethoxy-1,2-b enzothi azepine-3-one-1,1-di oxide.
Catsoulacos et al., "Thiazo Compounds. Derivatives Of 4,5-Dihydro-7,8-Dimethoxybenzothiazepin-3-one 11-Dioxides", J. Chem. Eng Data, vol.
22(3), pp. 353-354 (1977) describes 4,5-dihydro-2-(ethyl, n-propyl or isopropyl)-7,8-dimethoxy-1,2-benzothiazepine-3-one-l, l-dioxide.
Camoutsis et al., "N-Substituted 4,5-Dihydro-1,2-benzothiaepin-3-one 1,1-Dioxide", J. Hetero. Chem., vol. 17(5), pp. 1135-1136 (1980) describes S
certain 4,5-dihydro-2-(3- or S-pyridyl)-7,8-dimethoxy-1,2-benzothiazepine-3-one-l, l-dioxides.
U.S. Patent No. 5,350,761 describes hydroxylamine derivatives that generically encompass certain benzothiazepine compounds. These derivatives are described as lipoxygenase inhibitors useful in the treatment of inflammatory and allergic conditions.
W098/02432 published January 22, 1998 describes certain S-(aryl-(N-containing-heterocyclyl)alkyl)benzothiazepines and aralkyl-(N-containing-heterocyclyl)alkyl)-benzothiazepines as useful for controlling micturition.
W097/03953 published February 6, 1997 describes certain sulfonylamino-substituted benzothiazepines as inhibitors of the enzyme cyclooxygenase II.
W095/21843 published August 17, 1995 describes certain benzothiazepines substituted with azacyclic condensed piperazines. These compounds are identified as kappa receptor agonists useful as analgesics and diuretics and for the treatment of cerebral ischaemia.
EP338331 published October 25, 1989 describes certain 2-benzothiazepine-S-ones useful as muscle relaxants.
Summary of the Invention A first aspect of the invention comprises novel 1,2- benzothiazepines that are effective agents for the prophylaxis and/or treatment of hyperlipidemic diseases, conditions and/or disorders.
A second aspect of the invention comprises pharmaceutical compositions comprising the novel 1,2- benzothiazepines that are suitable for the prophylaxis and/or treatment of hyperlipidemic diseases, conditions and/or disorders.
A third aspect of the invention comprises methods for the prophylaxis and/or treatment of hyperlipidemic diseases, conditions and/or disorders SUBSTITUTE SHEET (RULE 26) comprising administering to a subject a prophylactically or therapeutically effective amount of one of the novel 1,2- benzothiazepines.
A fourth aspect of the invention comprises methods of making the novel 1,2-benzothiazepines of the present invention.
Additional aspects of the invention are discussed throughout the specification of this application.
Detailed Description of the Invention The following detailed description is provided to aid those skilled in the art in practicing the present invention. This detailed description, however, should not be construed to unduly limit the present invention as modifications and variations in the embodiments discussed herein can be made by those of ordinary skill in the art without departing from the spirit or scope of the present inventive discovery. The contents of each of the references cited herein, including the contents of the references cited within these primary references, are herein incorporated by reference in their entirety.
Accordingly, the present invention provides compounds corresponding to the structure of Formula (I):

~RN
S _N
s t : R' Rx ~a 4 wR:
s R' R~, I
R, Rs (I) wherein:

q is an integer from 1 to 4;
R1 and R2 are independently selected from the group consisting of hydrogen and hydrocarbyl, wherein said hydrocarbyl may be optionally substituted with one or more groups comprising one or more heteroatoms, and wherein said hydrocarbyl optionally may have one or more carbon atoms replaced by one or more heteroatoms independently selected from the group consisting of oxygen, nitrogen, sulfur and phosphorus;
R3 and R4 are independently selected from the group consisting of hydrogen; hydrocarbyl; -OR9; -NR9R10; -SR9; _S(O)R9; -S02R9; and -S03R9; or R3 and R4 together form =O; =NOR9; =S; =NNR9R10; -NR9; or =CR11R12;
wherein R9 and R10 are independently selected from the group consisting of hydrogen; hydrocarbyl; amino; and hydrocarbylamino; wherein said hydrocarbyl moieties may be optionally substituted with one or more groups comprising one or more heteroatoms, and wherein said hydrocarbyl moieties optionally may have one or more carbon atoms replaced by one or more heteroatoms independently selected from the group consisting of oxygen, nitrogen, sulfur and phosphorus; and wherein R11 and R12 are independently selected from the group consisting of hydrogen; -CN; halogen; oxo; hydrocarbyl; -OR9; -NR9R10; -SR9; -S(O)R9; -S02R9; and -S03R9; wherein said hydrocarbyl may be optionally substituted with one or more groups comprising one or more heteroatoms, and wherein said hydrocarbyl optionally may have one or more carbon atoms replaced by one or more heteroatoms independently selected from the group consisting of oxygen, nitrogen, sulfur and phosphorus; or R11 and R12 together with the carbon atom to which they are attached form a cyclic ring; and RS and R6 are independently selected from the group consisting of hydrogen; alkyl; cycloalkyl; alkenyl; alkynyl; aryl; heterocyclyl; quaternary heterocyclyl; -OR9; -SR9; -S(O)R9; -S02R9; and -S03R9;
wherein the RS and R6 radicals optionally may be substituted with one or more radicals independently selected from the group consisting of halogen; -N02; -CN; oxo; hydrocarbyl; -OR13; -~13R14; -SR13~ -S(O)R13; -S02R13; -S03R13~ -~130R14; _~13~14R15; -C02R13~ _ OM; -S020M; -S02NR13R14~ -C(O)~13R14; -C(O)OM; -COR13; -~13C(O)R14; -~13C(O)~14R15; -~13COZRi4~ -OC(O)R13; _ OC(O)NR'3R14~ -~13SOR14; -NR'3SOZR'4; -NR13SONR'4RI5; _ lO NR13SOZNR14R1s; -pR13R14; -p(O)R13R14; -p+R13R14R15A ; -P(OR13)OR14; -S+R13R14A-~ and -N+R13R14R15A-; wherein said hydrocarbyl may be optionally substituted with one or more groups comprising one or more heteroatoms, and wherein said hydrocarbyl optionally may have one or more carbon atoms replaced by one or more heteroatoms independently selected from the group consisting of oxygen, nitrogen, sulfur and phosphorus; and wherein R13, R14, and R'S are independently selected from hydrogen and hydrocarbyl, wherein said hydrocarbyl may be optionally substituted with one or more groups comprising one or more heteroatoms, and wherein said hydrocarbyl optionally may have one or more carbon atoms replaced by one or more heteroatoms independently selected from the group consisting of oxygen, nitrogen, sulfur and phosphorus; or wherein R'3 and R'4 together with the nitrogen atom to which they are attached form a mono- or polycyclic heterocyclyl that is optionally substituted with one or more radicals selected from the group consisting of oxo, carboxy, and quaternary salts; or wherein R14 and R15 together with the nitrogen atom to which they are attached form a cyclic ring; and wherein A- is a pharmaceutically acceptable anion, and M is a pharmaceutically acceptable cation; and wherein R9 is as defined above; or R4 and R6 together represent a bond; and RN is selected from the group consisting of hydrogen and hydrocarbyl, wherein said hydrocarbyl may be optionally substituted with one or more groups comprising one or more heteroatoms, and wherein said hydrocarbyl optionally may have one or more carbon atoms replaced by one or more heteroatoms independently selected from the group consisting of oxygen, nitrogen, sulfur and phosphorus;
one or more Rx radicals are independently selected from the group consisting of hydrogen; halogen; -CN; -N02; hydrocarbyl; -OR13; -~13R14; -SR13; -S(O)R13; _S(O)2R13; -S03R13; -S+R13R14A_; _ ~130R14; -~13~14R15; -C02R13; _OM; -S020M; -S02NR13R14; -~14C(O)R13; _C(O)~13R14; -C(O)OM; -COR13; -S(O)n~l3Ria~ _ N+R13R14R15A-; -PR13R14; -P(O)R13R14; -P+R13R14R15A-; amino acid residue; peptide residue; polypeptide residue; and carbohydrate residue, wherein said hydrocarbyl may be optionally substituted with one or more groups comprising one or more heteroatoms, and wherein said hydrocarbyl optionally may have one or more carbon atoms replaced by one or more heteroatoms independently selected from the group consisting of oxygen, nitrogen, sulfur and phosphorus; and wherein n is 0, 1 or 2; and wherein R'3, R'4, R's, A-, and M are as defined above; or a pharmaceutically acceptable salt, solvate, or prodrug thereof; and provided that at least one of R1, R2, R3, R4, R5, and R6 is a radical other than hydrogen or alkyl; and provided that when RS or R6 is aryl, the other of RS and R6 is a radical other than heterocycylalkyl.

A preferred class of compounds comprises those compounds of Formula I wherein:
q is an integer from 1 to 4;
R1 and R2 are independently selected from the group consisting of 5 hydrogen; alkyl; cycloalkyl; alkenyl; cycloalkenyl; alkynyl; aryl;
heterocyclyl; arylalkyl; heterocyclylalkyl; alkoxyalkyl; alkoxyalkenyl;
alkoxyalkynyl; aryloxyalkyl; aryloxyalkenyl; aryloxyalkynyl;
heterocylcyloxyalkyl; heterocycloxyalkenyl; heterocyclyloxyalkynyl;
alkylaryl; and (polyalkyl)aryl; or 10 R1 and R2 taken together with the carbon to which they are attached form C3-Coo cycloalkyl or C3-C,o cycloalkenyl;
wherein the R1 and R2 alkyl; cycloalkyl; alkenyl; cycloalkenyl;
alkynyl; aryl; heterocyclyl; arylalkyl; heterocyclylalkyl; alkoxyalkyl;
alkoxyalkenyl; alkoxyalkynyl; aryloxyalkyl; aryloxyalkenyl;
aryloxyalkynyl; heterocylcyloxyalkyl; heterocycloxyalkenyl;
heterocyclyloxyalkynyl; alkylaryl; and (polyalkyl)aryl radicals optionally may be substituted with one or more radicals selected from the group consisting of -CN; halogen; oxo; -OR9; -NR9R10; -N+R9R10RwA ; -SR9;
-S+R9R~oA-; -pR9R10; -p+R9R10RwA ; -S(O)R9; _S02R9; -S03R9; -C02R9; and -CONR9R10; and wherein the R1 and R2 alkyl; cycloalkyl; alkenyl; cycloalkenyl;
alkynyl; aryl; heterocyclyl; arylalkyl; heterocyclylalkyl; alkoxyalkyl;
alkoxyalkenyl; alkoxyalkynyl; aryloxyalkyl; aryloxyalkenyl;
aryloxyalkynyl; heterocylcyloxyalkyl; heterocycloxyalkenyl;
heterocyclyloxyalkynyl; alkylaryl; and (polyalkyl)aryl radicals optionally may have one or more carbons replaced by -O-; -NR9-; -N+R9R10A--; -S-; -SO-; -S02-; -S+R9A--; -PR9-; -P(O)R9-; -P+R9R10A--; or phenylene; and wherein R9, R10, and Rw are independently selected from the group consisting of hydrogen; alkyl; cycloalkyl; alkenyl; alkynyl; aryl;

heterocyclyl; alkylammoniumalkyl; arylalkyl; heterocyclylalkyl;
carboxyalkyl; alkoxyalkyl; carboalkoxyalkyl; carboxyaryl;
carboxyheterocyclyl; amino; alkylamino; carboxyalkylamino;
alkoxyalkylamino; and acyl; or wherein A- is a pharmaceutically acceptable anion; and R3 and R4 are independently selected from the group consisting of hydrogen; alkyl; alkenyl; alkynyl; aryl; heterocyclyl; -OR9; -NR9R10; -SR9; -S(O)R9; -S02R9; and -S03R9; or R3 and R4 together form =O; =NOR9; =S; =NNR9R1.0; =~9; or =CR11R12.
wherein R11 and R12 are independently selected from the group consisting of hydrogen; -CN; halogen; oxo; alkyl; alkenyl; alkynyl; aryl;
heterocyclyl; arylalkyl; heterocyclylalkyl; carboxyalkyl; alkoxyalkyl;
carboalkoxyalkyl; cycloalkyl; cycloalkenyl; haloalkyl; hydroxyalkyl;
cyanoalkyl; -OR9; -NR9R10; -SR9; _S(O)R9; -S02R9; -S03R9; -C02R9;
and -CONR9R10; or R11 and R12 together with the carbon atom to which they are attached form a cyclic ring; and wherein R9 and R'° are as defined above; and RS and R6 are independently selected from the group consisting of hydrogen; alkyl; cycloalkyl; alkenyl; alkynyl; aryl; heterocyclyl; quaternary heterocyclyl; -OR9; -SR9; -S(O)R9; -S02R9; and -S03R9;
wherein the RS and R6 alkyl; cycloalkyl; alkenyl; alkynyl; aryl;
heterocyclyl; and quaternary heterocyclyl radicals optionally may be substituted with one or more radicals independently selected from the group consisting of halogen; -CN; -N02; oxo; alkyl; polyalkyl; haloalkyl;
hydroxyalkyl; cycloalkyl; alkenyl; alkynyl; aryl; heterocyclyl; quaternary heterocyclyl; arylalkyl; heterocyclylalkyl; polyether; -OR13; -~13R14; -SR13; -S(O)R13; -S02R13; -S03R13; -~130R14; -~13~14R15; _ C02R13; -OM; -S020M; -S02NR13R14~ -C(O)~13R14; -C(O)OM; _ COR13; -NR13C(O)R14; -~13C(O)~14R15; -~13COZR14; -OC(O)R13; _ OC(O)NR'3R14~ -~13SOR14; -NR'3SOzR14; -NR13SONR14Rls; _ ~13SO2~14R15; -pR13R14~ -p(O)R13R14; -p+R13R14R15A ; -P(OR13)OR14; -S+R13R14A-~ ~d -N+R13R14R15A-; and wherein the alkyl, polyalkyl, haloalkyl, hydroxyalkyl, cycloalkyl, alkenyl, alkynyl, aryl, heterocyclyl, quaternary heterocyclyl, arylalkyl, heterocyclylalkyl, and polyether substituents of the RS and R6 radicals optionally may be further substituted with one or more radicals selected from the group consisting of -CN; halogen; hydroxy; oxo; alkyl; cycloalkyl;
alkenyl; alkynyl; aryl; heterocyclyl; arylalkyl; heterocyclylalkyl; quaternary heterocyclyl; -ORS; -NR~Rg; -SRS; -S(O)RB; -S02R~; -S03R~;- C02R~; -CONR~Rg; -N+R~RgR9A-; -P(O)R~R8; -PR~Rg; -P+R~R8R9A ; and -P(O)(OR~)ORg; and wherein the alkyl, polyalkyl, haloalkyl, hydroxyalkyl, cycloalkyl, alkenyl, alkynyl, aryl, heterocyclyl, quaternary heterocyclyl, arylalkyl, heterocyclylalkyl, and polyether substituents of the RS and R6 radicals optionally may have one or more carbons replaced by -O-; -NR~-; -N+R~R8A--; -S-; -SO-; -S02-; -S+R~A--; -PRA-; -P(O)RE-; -P+R~RgA--; or phenylene; and wherein R~ and R8 are independently selected from the group consisting of hydrogen; alkyl, alkenyl; alkynyl; aryl; and heterocyclyl; and wherein R13, R14, and R15 are independently selected from the group consisting of hydrogen; alkyl; haloalkyl; cycloalkyl; polyalkyl;
alkenyl; alkynyl; aryl; heterocyclyl; quaternary heterocyclyl; arylalkyl;
heterocyclylalkyl; quaternary heterocyclylalkyl; alkylarylalkyl;
alkylheterocyclylalkyl; alkylammoniumalkyl; aminoalkyl;
aminocarbonylalkyl; alkylaminocarbonylalkyl;
carboxyalkylaminocarbonylalkyl; and polyether; or wherein R'3 and R'4 together with the nitrogen atom to which they are attached form a mono- or polycyclic heterocyclyl that is optionally substituted with one or more radicals selected from the group consisting of oxo, carboxy, and quaternary salts; or wherein R14 and R15 together with the nitrogen atom to which they are attached form a cyclic ring; and wherein the R13, R14, and R15 alkyl; haloalkyl; cycloalkyl;
polyalkyl; alkenyl; alkynyl; aryl; heterocyclyl; quaternary heterocyclyl;
arylalkyl; heterocyclylalkyl; quaternary heterocyclylalkyl; alkylarylalkyl;
alkylheterocyclylalkyl; alkylammoniumalkyl; aminoalkyl;
aminocarbonylalkyl; alkylaminocarbonylalkyl;
carboxyalkylaminocarbonylalkyl; and polyether radicals optionally may be substituted with one or more radicals selected from the group consisting of halogen; -CN; sulfo; oxo; alkyl; haloalkyl; hydroxyalkyl; sulfoalkyl;
1 S alkenyl; alkynyl; aryl; heterocyclyl; quaternary heterocyclyl; quaternary heterocyclylalkyl; carboxy; carboxyalkyl; guanidinyl; -OR16; -~9R10; -N+R9R10R~'A-; -SR16; -S(O)R9; -S02R9; -S03R16; -C02R16; _ CONR9R10; -S02NR9R10; -PO(OR16)ORl~; -p9R10; -p+R9RlOR1IA-~ _ S+R9R10A-; and carbohydrate residue; and wherein the R13, R14~ ~d R15 amyl; haloalkyl; cycloalkyl;
polyalkyl; alkenyl; alkynyl; aryl; heterocyclyl; quaternary heterocyclyl;
arylalkyl; heterocyclylalkyl; quaternary heterocyclylalkyl; alkylarylalkyl;
alkylheterocyclylalkyl; alkylammoniumalkyl; aminoalkyl;
aminocarbonylalkyl; alkylaminocarbonylalkyl;
carboxyalkylaminocarbonylalkyl; and polyether radicals optionally may have one or more carbons replaced by -O-; -NR9-; -N+R9R10A--; -S-; -SO-;
-SOZ-; -S+R9A'-; -PR9-; -P+R9R10A--; -P(O)R9-; phenylene; carbohydrate residue; amino acid residue; peptide residue; or polypeptide residue; and wherein R16 and R1~ are independently selected from the group consisting of R9 and M; and wherein M is a pharmaceutically acceptable canon; and wherein R9, R'°, R", R'2, RW, and A- are as defined above; and RN is selected from the group consisting of hydrogen; alkyl; alkenyl;
alkynyl; aralkyl; and heterocyclylalkyl; and one or more Rx radicals are independently selected from the group consisting of hydrogen; halogen; -CN; -N02; alkyl; cycloalkyl; polyalkyl;
haloalkyl; hydroxyalkyl; alkenyl; alkynyl; aryl; heterocyclyl; quaternary heterocyclyl; arylalkyl; heterocyclylalkyl; polyether; acyloxy; -OR13; -~13R14; -SR13; -S(O)R13~ -S(p)2R13; -S03R13; -S+R13R14A_; -~130R14; -~13~14R15; -C02R13; _OM; -S020M; -S02NR13R14, ~14C(O)R13; _C(O)~13R14; -C(O)OM; -COR13; -OR18; _ S(O)nNR13R14; _~13R18; -~180R14; -N+R13R14R15A-~ -PR13R14;
-P(O)R13R14~ -P+R13R14R15A-; wino acid residue; peptide residue;
polypeptide residue; and carbohydrate residue;
wherein the R" alkyl; cycloalkyl; polyalkyl; haloalkyl; hydroxyalkyl;
alkenyl; alkynyl; aryl; heterocyclyl; arylalkyl; heterocyclylalkyl; polyether;
acyloxy radicals optionally may be further substituted with one or more radicals selected from the group consisting of halogen; -CN; oxo; -OR16; -NR9R10; -N+R9RlORwA-; -SR16; -S(O)R9; -S02R9; _S03R16; _ C02R16; -CONR9R10; -S02NR9R10; -PO(OR'6)OR"; -P9R10; _ P+R9R11R12A-; -S+R9R10A ; ~d carbohydrate residue; and wherein the R" quaternary heterocyclyl radical optionally may be substituted with one or more radicals selected from the group consisting of halogen; -CN; -N02; oxo; alkyl; cycloalkyl; polyalkyl; haloalkyl;
hydroxyalkyl; alkenyl; alkynyl; aryl; heterocyclyl; arylalkyl;
heterocyclylalkyl; polyether; -OR13; -NR13R14; -SR13; -S(O)R13; -S02R13; -S03R13; -NR130R14; -NR13NR14R15; -C02R13; OM; _ S020M; -S02NR13R14; -C(O)~13R14; -C(O)OM; -COR13; -p(O)R13R14; -p13R14; -p+R13R14R15A ; -p(OR13)OR14; -S+R13R14A
-N+R13R14R15A-; and carbohydrate residue; and wherein the Rx radicals comprising carbon optionally may have one or more carbons replaced by -O-; -NR13-; -N+R13R14A_-; _S-; -SO-; -S02-;
-S+R13A -; -pRl3-; _P O R13 ~ -PR13R14, -p+R13R14A_ ( ) -, , -; phenylene;
amino acid residue; peptide residue; polypeptide residue; carbohydrate residue; polyether; or polyalkyl; wherein said phenylene; amino acid residue; peptide residue; polypeptide residue; carbohydrate residue; and polyalkyl optionally may have one or more carbons replaced by -O-; -NR9-;
10 -N+R9R10A -; -S-; -SO-; -S02_; -S+R9A--; -PR9-; -P+R9R10A_-~ or -P(O)R9-; and wherein R1$ is selected from the group consisting of alkyl; alkenyl;
alkyriyl; aryl; heterocyclyl; quaternary heterocyclyl; arylalkyl;
heterocyclylalkyl; acyl; alkoxycarbonyl; arylalkoxycarbonyl; and 15 heterocyclylalkoxycarbonyl; and wherein the R'g alkyl; alkenyl; alkynyl; aryl; heterocyclyl; quaternary heterocyclyl; arylalkyl; heterocyclylalkyl; acyl; alkoxycarbonyl;
arylalkoxycarbonyl; and heterocyclylalkoxycarbonyl radicals optionally may be substituted with one or more radicals selected from the group consisting of halogen; -CN ; NO2; oxo; -OR9; -NR9R10; -N+R9R11R12A-;
-SR9; -S(O)R9; -S02R9; -S03R9; -C02R9; -CONR9R10; -S020M; _ S02NR9R10; -PR9R10; -P(OR13)OR14; -PO(OR16)OR1~; and -C(O)OM;
and wherein R9, R'°, R", R'2, R'3, R'4, R'S, R'6, R", RW, A-, and M are as defined above; or a pharmaceutically acceptable salt, solvate, or prodrug thereof.
In the various embodiments of the invention, RS and R6 preferably are independently selected from the group consisting of H; aryl;

heterocyclyl; and quaternary heterocyclyl;
wherein the RS and R6 aryl; heterocyclyl; and quaternary heterocyclyl; radicals optionally may be substituted with one or more radicals independently selected from the group consisting of halogen; -CN;
-N02; oxo; alkyl; polyalkyl; haloalkyl; hydroxyalkyl; cycloalkyl; alkenyl;
alkynyl; aryl; heterocyclyl; quaternary heterocyclyl; arylalkyl;
heterocyclylalkyl; polyether; -OR13; -NR13R14; _SR13; -S(O)R13; -S02R13; -S03R13; _~130R14; -~13~14R15; -C02R13; _OM; _ S020M; -S02NR13R14~ -C(O)~13R14; -C(O)OM; -COR13; -1 O NR13C(Q)Ri4; -~13C(O)~14R15; _~13COZR14; _OC(O)R13; _ OC(O)NR13R14; -~13SOR14; -~13SOZR14; -~13SONR'4R15; -~13SO2~14R15; -pR13R14; -p(O)R13R14; -pR13R14; -p+R13R14R15A
-P(OR13)OR14; -S+R13R14A ; ~d -N+R13R14R15A-; and wherein the alkyl, polyalkyl, haloalkyl, hydroxyalkyl, cycloalkyl, 15 alkenyl, alkynyl, aryl, heterocyclyl, quaternary heterocyclyl, arylalkyl, heterocyclylalkyl, and polyether substituents of the RS and R6 radicals optionally may be further substituted with one or more radicals selected from the group consisting of -CN; halogen; hydroxy; oxo; alkyl; cycloalkyl;
alkenyl; alkynyl; aryl; heterocyclyl; arylalkyl; heterocyclylalkyl; quaternary 20 heterocyclyl; -ORS; -NR~Rg; -SRS; -S(O)RB; -S02R~; -S03R~;- C02R~; -CONR~R8; -N+R~R$R9A-; -P(O)R~Rg; -PR~R8; -P+R~RgR9A ; and -P(O)(OR~)OR8; and wherein the alkyl, polyalkyl, haloalkyl, hydroxyalkyl, cycloalkyl, alkenyl, alkynyl, aryl, heterocyclyl, quaternary heterocyclyl, arylalkyl, 25 heterocyclylalkyl, and polyether substituents of the RS and R6 radicals optionally may have one or more carbons replaced by -O-; -NR~-; -N+R~R8A--; -S-; -SO-; -S02-; -S+R~A~-; -PRA-; -P(O)RE-; -P+R~RgA--; or phenylene; and wherein R~ and R8 are independently selected from the group consisting of hydrogen; alkyl, alkenyl; alkynyl; aryl; and heterocyclyl; and wherein R13, R14, and R1 S are independently selected from the group consisting of hydrogen; alkyl; haloalkyl; cycloalkyl; polyalkyl;
alkenyl; alkynyl; aryl; heterocyclyl; quaternary heterocyclyl; arylalkyl;
S heterocyclylalkyl; quaternary heterocyclylalkyl; alkylarylalkyl;
alkylheterocyclylalkyl; alkylammoniumalkyl; aminocarbonylalkyl;
alkylaminocarbonylalkyl; carboxyalkylaminocarbonylalkyl; and polyether;
or wherein R'3 and R'4 together with the nitrogen atom to which they are attached form a mono- or polycyclic heterocyclyl that is optionally substituted with one or more radicals selected from the group consisting of oxo, carboxy, and quaternary salts; or wherein R14 and R15 together with the nitrogen atom to which they are attached form a cyclic ring; and wherein the R13, R14, and Rls alkyl; haloalkyl; cycloalkyl;
polyalkyl; alkenyl; alkynyl; aryl; heterocyclyl; quaternary heterocyclyl;
arylalkyl; heterocyclylalkyl; quaternary heterocyclylalkyl; alkylarylalkyl;
alkylheterocyclylalkyl; alkylammoniumalkyl; aminocarbonylalkyl;
alkylaminocarbonylalkyl; carboxyalkylaminocarbonylalkyl; and polyether radicals optionally may be substituted with one or more radicals selected from the group consisting of halogen; -CN; sulfo; oxo; alkyl; haloalkyl;
hydroxyalkyl; sulfoalkyl; alkenyl; alkynyl; aryl; heterocyclyl; quaternary heterocyclyl; quaternary heterocyclylalkyl; carboxy; carboxyalkyl;
guanidinyl; -OR16; -NR9R10; -N+R9R10RwA-; -SR16; -S(O)R9; -S02R9~
-S03R16; -C02R16; -CONR9R10; -S02NR9R10; -PO(OR16)OR17; _ PR9R10; -P+R9R10R1 lA-; -S+R9R10A-; and carbohydrate residue; and wherein the R13, R14, and R15 alkyl; haloalkyl; cycloalkyl;
polyalkyl; alkenyl; alkynyl; aryl; heterocyclyl; quaternary heterocyclyl;
arylalkyl; heterocyclylalkyl; quaternary heterocyclylalkyl; alkylarylalkyl;

alkylheterocyclylalkyl; alkylammoniumalkyl; aminocarbonylalkyl;
alkylaminocarbonylalkyl; carboxyalkylaminocarbonylalkyl; and polyether radicals optionally may have one or more carbons replaced by -O-; -NR9-; -N+R9R10A--; -S-; -SO-; -SOZ-; -S+R9A--; -PR9-; -P+R9R10A_-; -P(O)R9-;
phenylene; carbohydrate residue; amino acid residue; peptide residue; or polypeptide residue; and wherein R16 and R1~ are independently selected from the group consisting of R9 and M; and wherein M is a pharmaceutically acceptable canon; and wherein R9, R'°, R", R'2, R"', and A- are as previously set forth above for the compounds of Formula I.
More preferably, RS or R6 has the formula -Ar-(RY)~
wherein:
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 benzoisothiazolyl; and one or more Ry are independently selected from the group consisting of halogen; -CN; -N02; oxo; alkyl; polyalkyl; haloalkyl; hydroxyalkyl;
cycloalkyl; alkenyl; alkynyl; aryl; heterocyclyl; quaternary heterocyclyl;
arylalkyl; heterocyclylalkyl; polyether; -OR13; -~13R14; -SR13; -S(O)R13; -S02R13; -S03R13; -~130R14; -~13~14R15; -C02R13; _ OM; -S020M; -S02NR13R14; -C(O)~13R14; -C(O)OM; -COR13; -~13C(O)R14; -~13C(O)~14R15; -~13COZR14; -OC(O)Ri3; -OC(O)NR'3R'4; -y3SOR'4; -NR'3SOzR'4; -NR13SONR'4R'S; -~13SO2~14R15; -p(O)R13R14; -pR13R14; -p+R13R14R15A ;

P(OR13)OR14; -S+R13R14A ; ~d -N+R13R14R15A-~ and wherein the alkyl, polyalkyl, haloalkyl, hydroxyalkyl, cycloalkyl, alkenyl, alkynyl, aryl, heterocyclyl, quaternary heterocyclyl, arylalkyl, heterocyclylalkyl, and polyether substituents of the Ry radicals optionally may be further substituted with one or more radicals selected from the group consisting of -CN; halogen; hydroxy; oxo; alkyl; cycloalkyl; alkenyl;
alkynyl; aryl; heterocyclyl; arylalkyl; heterocyclylalkyl; quaternary heterocyclyl; -ORS; -NR~Rg; -SRS; -S(O)RB; -S02R~; -S03R~;- C02R~; -CONR~Rg; -N+R~RgR9A-; -P(O)R~Rg; -PR~Rg; -P+R~RgR9A ; and -P(O)(OR~)ORg; and wherein the alkyl, polyalkyl, haloalkyl, hydroxyalkyl, cycloalkyl, alkenyl, alkynyl, aryl, heterocyclyl, quaternary heterocyclyl, arylalkyl, heterocyclylalkyl, and polyether substituents of the Ry radicals optionally may have one or more carbons replaced by -O-; -NR~-; -N+R~RgA--; -S-; -1 S SO-; -S02-; -S+R~A--; -PRA-; -P(O)RE-; -P+R~RgA--; or phenylene; and wherein R~ and Rg are independently selected from the group consisting of hydrogen; alkyl, alkenyl; alkynyl; aryl; and heterocyclyl; and wherein R13, R14, and R15 are independently selected from the group consisting of hydrogen; alkyl; haloalkyl; cycloalkyl; polyalkyl;
alkenyl; alkynyl; aryl; heterocyclyl; quaternary heterocyclyl; arylalkyl;
heterocyclylalkyl; quaternary heterocyclylalkyl; alkylarylalkyl;
alkylheterocyclylalkyl; alkylammoniumalkyl; aminocarbonylalkyl;
alkylaminocarbonylalkyl; carboxyalkylaminocarbonylalkyl; and polyether;
or wherein R'3 and R'4 together with the nitrogen atom to which they are attached form a mono- or polycyclic heterocyclyl that is optionally substituted with one or more radicals selected from the group consisting of oxo, carboxy, and quaternary salts; or wherein R14 and R15 together with the nitrogen atom to which they are attached form a cyclic ring; and wherein the R13, R14, and R15 alkyl; haloalkyl; cycloalkyl;
polyalkyl; alkenyl; alkynyl; aryl; heterocyclyl; quaternary heterocyclyl;
arylalkyl; heterocyclylalkyl; quaternary heterocyclylalkyl; alkylarylalkyl;
S alkylheterocyclylalkyl; alkylammoniumalkyl; aminocarbonylalkyl;
alkylaminocarbonylalkyl; carboxyalkylaminocarbonylalkyl; and polyether radicals optionally may be substituted with one or more radicals selected from the group consisting of halogen; -CN; sulfo; oxo; alkyl; haloalkyl;
hydroxyalkyl; sulfoalkyl; alkenyl; alkynyl; aryl; heterocyclyl; quaternary 10 heterocyclyl; quaternary heterocyclylalkyl; carboxy; carboxyalkyl;
guanidinyl; -OR16; -NR9R10; -N+R9R10RwA-; -SR16; -S(O)R9; -S02R9;
-S03R16; -C02R16; -CONR9R10; -S02NR9R10; -PO(OR16)OR1~; _ PR9R10; -P+R9R10R1 lA-; -S+R9R10A-; ~d carbohydrate residue; and wherein the R13, R14, and R15 alkyl; haloalkyl; cycloalkyl;
15 polyalkyl; alkenyl; alkynyl; aryl; heterocyclyl; quaternary heterocyclyl;
arylalkyl; heterocyclylalkyl; quaternary heterocyclylalkyl; alkylarylalkyl;
alkylheterocyclylalkyl; alkylammoniumalkyl; aminocarbonylalkyl;
alkylaminocarbonylalkyl; carboxyalkylaminocarbonylalkyl; and polyether radicals optionally may have one or more carbons replaced by -O-; -NR9-; -20 N+R9R10A--; -S-; -SO-; -SOZ-; -S+R9A~-; -PR9-; -P+R9R10A_-; -P(O)R9-;
phenylene; carbohydrate residue; amino acid residue; peptide residue; or polypeptide residue; and wherein R16 and R1~ are independently selected from the group consisting of R9 and M; and wherein M is a pharmaceutically acceptable cation; and wherein R9, R'°, R", R'2, R"', and A- are as previously set forth above for the compounds of Formula I.
Still more preferably, at least one of RS or R6 has the formula (II) i ~Ry~t (II) wherein RY and t are defined as above.
In the various embodiments of the invention, the compounds of Formula I preferably satisfy at least one or more of the following additional conditions:
(1) R' and Rz are independently selected from the group consisting of hydrogen, alkyl and (C3_,o)cycloalkyl. Preferably, R' and RZ are independently selected from the group consisting of hydrogen and (C~_ ,o)alkyl. More preferably, R' and RZ are independently selected from the group consisting of (C~_~o)alkyl. Still more preferably, R' and RZ are independently selected from the group consisting of (CI_~)alkyl. Still more preferably, R' and Rz are independently selected from the group consisting of (CZ_4)alkyl. Still more preferably, R' and Rz are the same (CZ_4)alkyl.
Still more preferably, R' and Rz are each n-butyl; and/or (2) R3 and R4 are independently selected from the group consisting of hydrogen and -OR9 wherein R9 is defined as previously set forth above for the compounds of Formula I. Preferably, R3 is hydrogen and R4 is -OR9 Still more preferably, R3 is hydrogen and R4 is hydroxy. Still more preferably, the hydroxy group is in a syn relationship to the structure of Formula II; and/or (3) RS is phenyl substituted with a radical selected from the group consisting Of -OR'3, -I~R13R14~ -~13C(O)R14, -~ 13C(O)~14R15~ -~l3COzR14~ -OC(O)R13~ -OC(O)~13R14 ~ -~13SOR14, -NR13SOZR14, _ NR'3SONR'4R'S, and -NR'3SOZNR'4R'S wherein R'3, R'4 and R'S are as previously set forth above for the compounds of Formula I. Still more preferably, RS is phenyl substituted with -OR'3 or -NR'3C(O)R'4. Still more preferably, RS is phenyl substituted at the para or meta position with -OR'3 wherein R'3 comprises a quaternary heterocyclyl, quaternary heterocyclylalkyl or alkylammoniumalkyl, or RS is phenyl substituted at the para or meta position with -NR'3C(O)R'4 wherein R'3 is hydrogen and R'4 comprises a quaternary heterocyclyl, quaternary heterocyclylalkyl or alkylammoniumalkyl; and/or (4) R6 is hydrogen; and/or (5) RN is selected from the group consisting of hydrogen, alkyl and aralkyl. Preferably, RN is selected from the group consisting of hydrogen, (C,_,o)alkyl and aryl(C,_,o)alkyl. More preferably, RN is selected from the group consisting of hydrogen, methyl, ethyl and benzyl. Still more preferably, RN is hydrogen; and/or (6) R" is independently selected from the group consisting of -OR'3, -~13R14~ -N+R13R1aR1sA-~ ~d polyether. More preferably, R" is selected from the group consisting of -OR'3 and -NR'3R'4. Still more preferably, RX
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; and/or (7) One or more R" are present at the 7-, 8- or 9-position of the benzo ring of the structure of Formula I. Preferably, said R" are present at the l-and 9-positions of the benzo ring of the structure of Formula I. More preferably, RX is present at the 7-position of the benzo ring of the structure of Formula I; and/or (8) q is 1, 2 or 3. Preferably, q is 1 or 2, and more preferably q is 1;

and/or (9) t is 1 or 2.
In still another embodiment of the invention, the compounds of Formula I satisfy at least one or more of the above-described conditions and S RS comprises a carbohydrate residue.
A more preferred class of compounds comprises those compounds of Formula I wherein:
q is an integer from 1 to 4;
R1 and R2 are independently selected from the group consisting of hydrogen; alkyl; cycloalkyl; alkenyl; alkynyl; arylalkyl; alkoxyalkyl;
alkoxyalkenyl; alkoxyalkynyl; alkylaryl; and (polyalkyl)aryl; or R1 and R2 taken together with the carbon to which they are attached form C3-C,° cycloalkyl or C3-C,° cycloalkenyl; and wherein the R1 and R2 alkyl; cycloalkyl; alkenyl; alkynyl; arylalkyl;
alkoxyalkyl; alkoxyalkenyl; alkoxyalkynyl; alkylaryl; and (polyalkyl)aryl radicals optionally may be substituted with one or more radicals selected from the group consisting of -CN; halogen; oxo; -OR9; -NR9R10; -N+R9R10Rw A ; -SR9; -S+R9R'oA-; -pR9R10; -P+R9R10RwA ; -S(O)R9~ -S02R9; -S03R9; -C02R9; and -CONR9R10; and wherein the R1 and R2 alkyl; cycloalkyl; alkenyl; alkynyl; arylalkyl;
alkoxyalkyl; alkoxyalkenyl; alkoxyalkynyl; alkylaryl; and (polyalkyl)aryl radicals optionally may have one or more carbons replaced by -O-; -NR9-; -N+R9R10A-; -S-; -SO-; -S02-; -S+R9A--; -PR9-; -P(O)R9-; -P+R9R10A--;
or phenylene; and wherein R9, R10, and Rw are independently selected from the group consisting of hydrogen; alkyl; cycloalkyl; alkenyl; alkynyl; aryl;
heterocyclyl; alkylammoniumalkyl; arylalkyl; heterocyclylalkyl;

carboxyalkyl; carboalkoxyalkyl; carboxyheterocyclyl; carboxyalkylamino;
and acyl; and wherein A- is a pharmaceutically acceptable anion; and R3 and R4 are independently selected from the group consisting of hydrogen; alkyl; alkenyl; alkynyl; aryl; heterocyclyl; -OR9; -NR9R10; -SR9; -S(O)R9; -S02R9; and -S03R9; or R3 and R4 together form =O; =NOR9; =S; =NNR9R10; =NR9; or =CR11R12;
wherein R11 and R12 are independently selected from the group consisting of hydrogen; -CN; halogen; oxo; alkyl; alkenyl; alkynyl; aryl;
heterocyclyl; arylalkyl; carboxyalkyl; carboalkoxyalkyl; cycloalkyl;
cyanoalkyl; -OR9; -NR9R10; -SR9; -S(O)R9; -S02R9; -S03R9; -C02R9;
and -CONR9R10; or R11 and R12 together with the carbon atom to which they are attached form a cyclic ring; and wherein R9 and R'° are as defined above; and RS and R6 are independently selected from the group consisting of hydrogen; alkyl; cycloalkyl; alkenyl; alkynyl; aryl; heterocyclyl; quaternary heterocyclyl; -OR9; -SR9; -S(O)R9; -S02R9; and -S03R9;
wherein the RS and R6 alkyl; cycloalkyl; alkenyl; alkynyl; aryl;
heterocyclyl; and quaternary heterocyclyl radicals optionally may be substituted with one or more radicals independently selected from the group consisting of halogen; -CN; -N02; oxo; alkyl; polyalkyl; haloalkyl;
cycloalkyl; alkenyl; alkynyl; aryl; heterocyclyl; quaternary heterocyclyl;
arylalkyl; heterocyclylalkyl; polyether; -OR13; -NR13R14; -SR13; -S(O)R13; -S02R13; -S03R13; -~130R14; -~13~14R15; -C02R13; _ OM; -S020M; -S02NR13R14; -C(O)NR13R14; -C(O)OM; -COR13; -~13C(O)R14; -~13C(O)~14RI5; -ysCO2Ria; -OC(O)Ri3; _ OC(O)NR'3R14~ -y3SOR'4; -NR'3SOZR'4; -NR13SONR'4R15; _ ~13SO2~14R15~ -pR13R14; -p(O)R13R14; -p+R13R14R15A ; -P(OR13)OR14; -S+R13R14A ; ~d -N+R13R14R15A-~ and wherein the alkyl, polyalkyl, haloalkyl, hydroxyalkyl, cycloalkyl, alkenyl, alkynyl, aryl, heterocyclyl, quaternary heterocyclyl, arylalkyl, heterocyclylalkyl, and polyether substituents of the RS and R6 radicals optionally may be further substituted with one or more radicals selected from the group consisting of -CN; halogen; hydroxy; oxo; alkyl; cycloalkyl;
alkenyl; alkynyl; aryl; heterocyclyl; arylalkyl; heterocyclylalkyl; quaternary heterocyclyl; -ORS; -NR~RB; -SRS; -S(O)RB; -S02R~; -S03R~;- C02R~; -10 CONR~R8; -N+R~RgR9A-; -P(O)R~R8; -PR~Rg; -P+R~RgR9A ; and -P(O)(OR~)OR8; and wherein the alkyl, polyalkyl, haloalkyl, hydroxyalkyl, cycloalkyl, alkenyl, alkynyl, aryl, heterocyclyl, quaternary heterocyclyl, arylalkyl, heterocyclylalkyl, and polyether substituents of the RS and R6 radicals 15 optionally may have one or more carbons replaced by -O-; -NR~-; -N+R~R8A--; -S-; -SO-; -S02-; -S+R~A--; -PRA-; -P(O)RE-; -P+R~R8A~-; or phenylene; and wherein R~ and Rg are independently selected from the group consisting of hydrogen and alkyl; and 20 wherein R13, R14, and R15 are independently selected from the group consisting of hydrogen; alkyl; haloalkyl; cycloalkyl; polyalkyl;
alkenyl; alkynyl; aryl; heterocyclyl; quaternary heterocyclyl; arylalkyl;
heterocyclylalkyl; quaternary heterocyclylalkyl; alkylarylalkyl;
alkylheterocyclylalkyl; alkylammoniumalkyl;
25 carboxyalkylaminocarbonylalkyl; and polyether; or wherein R'3 and R'4 together with the nitrogen atom to which they are attached form a mono- or polycyclic heterocyclyl that is optionally substituted with one or more radicals selected from the group consisting of oxo, carboxy, and quaternary salts; or wherein R14 and R15 together with the nitrogen atom to which they are attached form a cyclic ring; and wherein the R13, R14, and R15 alkyl; haloalkyl; cycloalkyl;
polyalkyl; alkenyl; alkynyl; aryl; heterocyclyl; quaternary heterocyclyl;
arylalkyl; heterocyclylalkyl; quaternary heterocyclylalkyl; alkylarylalkyl;
alkylheterocyclylalkyl; alkylammoniumalkyl; aminocarbonylalkyl;
alkylaminocarbonylalkyl; carboxyalkylaminocarbonylalkyl; and polyether radicals optionally may be substituted with one or more radicals selected from the group consisting of halogen; -CN; sulfo; oxo; alkyl; sulfoalkyl;
heterocyclyl; quaternary heterocyclyl; quaternary heterocyclylalkyl;
carboxy; carboxyalkyl; guanidinyl; -OR16; -~9R10; -N+R9R10RwA-; -SR16; -S(O)R9; -S02R9; -S03R16; -C02R16; -CONR9R10; _ S02NR9R10; -PO(OR16)OR1~; -PR9R10; -P+R9R10R11A_; -S+R9R10A_ and carbohydrate residue; and wherein the R13, R14, and R15 alkyl; haloalkyl; cycloalkyl;
polyalkyl; alkenyl; alkynyl; aryl; heterocyclyl; quaternary heterocyclyl;
arylalkyl; heterocyclylalkyl; quaternary heterocyclylalkyl; alkylarylalkyl;
alkylheterocyclylalkyl; alkylammoniumalkyl; aminocarbonylalkyl;
alkylaminocarbonylalkyl; carboxyalkylaminocarbonylalkyl; and polyether radicals optionally may have one or more carbons replaced by -O-; -NR9-; -N+R9R10A--; -S-; -SO-; -SOZ-; -S+R9A--; -PR9-; -P+R9Rl0A_-~ -P(O)R9-;
phenylene; carbohydrate residue; amino acid residue; peptide residue; or polypeptide residue; and wherein R16 and R1~ are independently selected from the group consisting of R9 and M; and wherein M is a pharmaceutically acceptable cation; and wherein R9, R'°, R", R'2, R"', and A- are as defined above; and RN is selected from the group consisting of hydrogen; alkyl; alkenyl;
alkynyl; and aralkyl; and one or more Rx radicals are independently selected from the group consisting of hydrogen; halogen; -CN; -N02; alkyl; cycloalkyl; polyalkyl;
haloalkyl; alkenyl; alkynyl; aryl; heterocyclyl; quaternary heterocyclyl;
arylalkyl; po~yether; acyloxy; -OR13; _~13R14; _SR13; _S(O)R13; _ S(O)2R13; _S03R13; -S+R13R14A_~ -~130R14; -~13~14R15; _ C02R13; -OM; -S020M; -S02NR13R14; _NRI4C(O)R13; -C(O)~13R14;
-C(O)OM; -COR13; -OR18; -S(O)nNR13R14; -~13R18; -~180R14; _ N+R13R14R15A-; -pR13R14; -p(O)R13R14; -p+R13R14R15A-; amino acid residue; peptide acid residue; polypeptide acid residue; and carbohydrate acid residue;
wherein the R" alkyl; cycloalkyl; polyalkyl; haloalkyl; hydroxyalkyl;
alkenyl; alkynyl; aryl; heterocyclyl; arylalkyl; heterocyclylalkyl; polyether;
acyloxy radicals optionally may be further substituted with one or more radicals selected from the group consisting of halogen; -CN; oxo; -OR16; -NR9R10; -N+R9R10RwA-; -SR16; -S(O)R9; -S02R9; _S03R16; _ C02R16; -CONR9R10; -S02NR9R10; -PO(OR'6)OR"; -PR9R10; _ p+R9R11R12A-; -S+R9R10A ; ~d carbohydrate acid residue; and wherein the RX quaternary heterocyclyl radical optionally may be substituted with one or more radicals selected from the group consisting of halogen; -CN; -N02; oxo; alkyl; cycloalkyl; polyalkyl; haloalkyl;
hydroxyalkyl; alkenyl; alkynyl; aryl; heterocyclyl; arylalkyl;
heterocyclylalkyl; polyether; -OR13; -~13R14; -SR13; -S(O)R13; _ S02R13; -S03R13; -NR13OR14; -~13~14R15; -C02R13; OM; _ S020M; -S02NR13R14; _C(O)~13R14; -C(O)OM; -COR13; -p(O)R13R14; _pR13R14; _p+R13R14R15A ; _p(OR13)OR14; _ S+R13R14A ; -N+R13R14R15A-; ~d carbohydrate acid residue; and wherein the Rx radicals comprising carbon optionally may have one or more carbons replaced by -O-; -NR13-; -N+R13R14A__; _S-; -SO-; -S02-;
-S+R13A -, -pRl3 . -p O R13 ~ -PR13 ~ _p+R13R14A_ -, ( ) -, -, -; phenylene; amino acid; peptide; polypeptide; carbohydrate; polyether; or polyalkyl; wherein said phenylene; amino acid; peptide; polypeptide; carbohydrate; and polyalkyl optionally may have one or more carbons replaced by -O-; -NR9-;
~N+R9R10A -; -S-; _SO_; _SOz-; -S+R9A~-; -PR9-; -P+R9R10A_-~ or -P(O)R9-; and wherein R18 is selected from the group consisting of alkyl; alkenyl;
alkynyl; aryl; heterocyclyl; quaternary heterocyclyl; arylalkyl;
heterocyclylalkyl; acyl; alkoxycarbonyl; arylalkoxycarbonyl; and heterocyclylalkoxycarbonyl; and wherein the R' 8 alkyl; alkenyl; alkynyl; aryl; heterocyclyl; quaternary heterocyclyl; arylalkyl; heterocyclylalkyl; acyl; alkoxycarbonyl;
arylalkoxycarbonyl; and heterocyclylalkoxycarbonyl radicals optionally may be substituted with one or more radicals selected from the group consisting of halogen; -CN ; oxo; -OR9; -NR9R10; -N+R9R11R12A-; -SR9;
-S(O)R9; -S02R9; -S03R9; -C02R9; -CONR9R10; -S020M; -S02NR9R10; -PR9R10; -P(OR13)OR14; -PO(OR16)OR1~; and -C(O)OM;
and wherein R9, R'°, R", R'2, R'3, R'4, R'S, R'6, R", R'", A-, and M are as defined above; or a pharmaceutically acceptable salt, solvate, or prodrug thereof.
A class of compounds of interest comprises those compounds of Formula I wherein:
q is an integer from 1 to 4;
R1 and R2 are independently selected from the group consisting of hydrogen; (C~-C1°)alkyl; (C3-C~o)cycloalkyl; (Cz-CI°)alkenyl;
(CZ-C,°)alkynyl; aryl(C1-C1°)alkyl; (CnC,o)alkoxy(C1-CIO)alkyl;
(C1-CIO)alkoxy(CZ-C,°)alkenyl; (C,-CI°)alkoxy(CZ-C,°)alkynyl; (CI-C,°)alkylaryl;
and (polyalkyl)aryl; or R1 and R2 taken together with the carbon to which they are attached form (C3-C,°)cycloalkyl; and wherein the R1 and R2 (C,-C,°)alkyl; (C3-C,°)cycloalkyl; (CZ-C,°)alkenyl; (Cz-C,°)alkynyl; aryl(C,-C,°)alkyl; (C,-C,°)alkoxy(C,-C,°)alkyl;
(C,-C,°)alkoxy(CZ-C1°)alkenyl; (C,-C,°)alkoxy(CZ-C,°)alkynyl; (C,-C,°)alkylaryl; and (polyalkyl)aryl radicals optionally may be substituted with one or more radicals selected from the group consisting of -CN; halogen;
oxo; -OR9; -NR9R10; -N+R9R10RwA ; _SR9; -S+R9R'°A~; -PR9R10; _ P+R9R10R~'A ; -S(O)R9; -S02R9; -S03R9; -C02R9; and -CONR9R10;
and wherein the R1 and R2 (C,-C,°)alkyl; (C3-C,°)cycloalkyl; (CZ-C,°)alkenyl; (CZ-C,°)alkynyl; aryl(C,-C,°)alkyl; (C,-C,°)alkoxy(C,-C,°)alkyl;
(C,-C,°)alkoxy(CZ-C1°)alkenyl; (C,-C,°)alkoxy(CZ-C,°)alkynyl; (C,-C,°)alkylaryl; and (polyalkyl)aryl radicals optionally may have one or more carbons replaced by -O-; -NR9-; -N+R9R10A--; -S-; -SO-; -S02-; -S+R9A---PR9; -P(O)R9-; -P+R9R10A--; or phenylene; and wherein R9, R10, and Rw are independently selected from the group consisting of hydrogen; (C1-C,°)alkyl; (C3-C,°)cycloalkyl; (Cz-C,°)alkenyl;
(Cz-C,°)alkynyl; aryl; heterocyclyl; ammonium(C,-C1°)alkyl; (C,-C,°)alkylammonium(C,-C,°)alkyl; aryl(C,-C,°)alkyl;
heterocyclyl(C,-C1°)alkyl; carboxy(C,-C,°)alkyl; carbo(C,-C,°)alkoxy(C,-C1°)alkyl;
carboxyheterocyclyl; carboxy(C,-C1°)alkylamino; and acyl; and wherein A- is a pharmaceutically acceptable anion; and R3 and R4 are independently selected from the group consisting of hydrogen; (C,-C,°)alkyl; (CZ-C,°)alkenyl; (CZ-C,°)alkynyl; aryl; heterocyclyl;
-OR9; -NR9R10; -SR9; -S(O)R9; -S02R9; and -S03R9; or R3 and R4 together form =O; =NOR9; =S; =NNR9R10; =NR9; or =CR11R12;
wherein R11 and R12 are independently selected from the group consisting of hydrogen; -CN; halogen; oxo; (C1-C1°)alkyl; (CZ-C1°)alkenyl;
(CZ-C1°)alkynyl; aryl; heterocyclyl; aryl(C,-C1°)alkyl;
carboxy(C,-C1°)alkyl;
carbo(C1-C1°)alkoxy(C1-C1°)alkyl; (C3-C1°)cycloalkyl;
cyano(C1-C,°)alkyl; -OR9; -NR9R10; -SR9; -S(O)R9; -S02R9; -S03R9; -C02R9; and -CONR9R10; or R11 and R12 together with the carbon atom to which they are attached form a cyclic ring; and wherein R9 and R'° are as defined above; and RS and R6 are independently selected from the group consisting of 10 hydrogen; (C1-C1°)alkyl; (C3-C1°)cycloalkyl; (CZ-C1°)alkenyl; (CZ-C1°)alkynyl; aryl; heterocyclyl; quaternary heterocyclyl; -OR9; -SR9;
S(O)R9; -S02R9; and -S03R9;
wherein the RS and R6 (C1-C1°)alkyl; (C3-C1°)cycloalkyl; (Cz-C,°)alkenyl; (CZ-C1°)alkynyl; aryl; heterocyclyl; and quaternary heterocyclyl 15 radicals optionally may be substituted with one or more radicals independently selected from the group consisting of halogen; -CN; -N02;
oxo; (C1-C1°)alkyl; polyalkyl; halo(C1-C1°)alkyl; (C3-C1°)cycloalkyl; (CZ-C1°)alkenyl; (CZ-C1°)alkynyl; aryl; heterocyclyl; quaternary heterocyclyl;
aryl(C1-C1°)alkyl; heterocyclyl(C1-C1°)alkyl; polyether; -OR13; -~13R14~
20 -SR13; -S(O)R13; -S02R13; -S03R13; -~130R14; -~13~14R15; _ C02R13; -OM; -S020M; -S02NR13R14; -C(O)~13R14; -C(O)OM; _ COR13; -NR13C(O)R14; -~13C(O)~14R15; -~13COZR14; -OC(O)R13; -OC O)NR13R14; -~13SOR14; -NR13SOZR14; -NR13SONR14R15;
~13SO2~14R15~ -p(O)R13R14; -pR13R14; -p+R13R14R15A ; -25 P(OR13)OR14; _S+R13R14A ; ~d -N+R13R14R15A-; and wherein the (C,-C,°)alkyl, polyalkyl, halo(C1-C1°)alkyl, hydroxy(C1-C1°)alkyl, (C3-C1°)cycloalkyl, (CZ-C1°)alkenyl, (Cz-C,°)alkynyl, aryl, heterocyclyl, quaternary heterocyclyl, aryl(C1-C1°)alkyl, heterocyclyl(C1-C1°)alkyl, and polyether substituents of the RS and R6 radicals optionally may be further substituted with one or more radicals selected from the group consisting of -CN; halogen; hydroxy; oxo; (C,-Clo)alkyl; (C3-C~o)cycloalkyl;
(Cz-C,o)alkenyl; (CZ-C,o)alkynyl; aryl; heterocyclyl; aryl(C,-C,o)alkyl;
heterocyclyl(C,-C,o)alkyl; quaternary heterocyclyl; -ORS; -NR~R8; -SRS; -S(O)RB; -S02R~; -S03R~;- C02R~; -CONR~R8; -N+R~RgR9A-; -P(O)R~Rg; -PR~R8; -P+R~RgR9A ; and -P(O)(OR~)ORg; and wherein the (C,-C~o)alkyl, polyalkyl, halo(C,-C~o)alkyl, hydroxy(C,-C,o)alkyl, (C3-Clo)cycloalkyl, (CZ-Clo)alkenyl, (CZ-C~o)alkynyl, aryl, heterocyclyl, quaternary heterocyclyl, aryl(CI-C~o)alkyl, heterocyclyl(C,-Clo)alkyl, and polyether substituents of the RS and R6 radicals optionally may have one or more carbons replaced by -O-; -NR~-; -N+R~RgA--; -S-; -SO-; -S02-; -S+R~A--; -PRA-; -P(O)RE-; -P+R~RgA--; or phenylene; and wherein R~ and Rg are independently selected from the group consisting of hydrogen and (C~-C~o)alkyl; and wherein R13, 8149 and R15 are independently selected from the group consisting of hydrogen; (C~-Clo)alkyl; halo(C~-C,o)alkyl; (C3-C,o)cycloalkyl; polyalkyl; (CZ-C,o)alkenyl; (Cz-C,o)alkynyl; aryl;
heterocyclyl; quaternary heterocyclyl; aryl(C~-C~o)alkyl; heterocyclyl(C,-C,o)alkyl; quaternary heterocyclyl(C~-CIO)alkyl; (C~-C,o)alkylaryl(C1-C,o)alkyl; (C~-C,o)alkylheterocyclyl(Cl-CIO)alkyl; (C1-CIO)alkylammonium(CI-C,o)alkyl; carboxy(C,-Clo)alkylaminocarbonyl(CI-C,o)alkyl; and polyether; or wherein R'3 and R'4 together with the nitrogen atom to which they are attached form a mono- or polycyclic heterocyclyl that is optionally substituted with one or more radicals selected from the group consisting of oxo, carboxy, and quaternary salts; or wherein R14 and R15 together with the nitrogen atom to which they are attached form a cyclic ring; and wherein the R13, R14~ ~d R15 (C~-C,o)alkyl; halo(C1-C,o)alkyl; (C3-C,°)cycloalkyl; polyalkyl; (CZ-C,°)alkenyl; (CZ-C,°)alkynyl; aryl;
heterocyclyl; quaternary heterocyclyl; aryl(C,-C,°)alkyl;
heterocyclyl(C,-C,°)alkyl; quaternary heterocyclyl(C,-C,°)alkyl; (C,-C,°)alkylaryl (C,-C,°)alkyl; (C,-C,°)alkylheterocyclyl(C,-C,°)alkyl;
(C,-C,°)alkylammonium(C,-C,°)alkyl; aminocarbonyl(C,-C,°)alkyl; (C,-C,°)alkylaminocarbonyl(C,-C,°)alkyl; carboxy(C,-C,°)alkylaminocarbonyl (C,-C,°)alkyl; and polyether radicals optionally may be substituted with one or more radicals selected from the group consisting of halogen; -CN; sulfo;
oxo; (C,-C,°)alkyl; sulfo(C,-C,°)alkyl; heterocyclyl; quaternary heterocyclyl;
quaternary heterocyclyl(C,-C,°)alkyl; carboxy; carboxy(C,-C,°)alkyl;
guanidinyl; -OR16; -NR9R10; -N+R9RlORwA-; -SR16; -S(O)R9; _S02R9;
-S03R16; -C02R16; -CONR9R10; _ _Sp2~9R10; _p0(OR16)OR1~; -pR9R10; -p+R9R10R11A-;-S+R9R10A-; ~d carbohydrate residue; and wherein the R13, R14~ ~d R15 (C~-C,°)alkyl; halo(C,-C,°)alkyl;
(C3-C,°)cycloalkyl; polyalkyl; (CZ-C,°)alkenyl; (Cz-C,°)alkynyl; aryl;
heterocyclyl; quaternary heterocyclyl; aryl(C,-C,°)alkyl;
heterocyclyl(C,-C,°)alkyl; quaternary heterocyclyl(C,-C,°)alkyl; (C,-C,°)alkylaryl(C,-C,°)alkyl; (C,-C,°)alkylheterocyclyl(C,-C,°)alkyl;
(C,-C,°)alkylammonium(C,-C,°)alkyl; aminocarbonyl(C,-C,°)alkyl; (C,-C,°)alkylaminocarbonyl(C,-C,°)alkyl; carboxy(C,-C,°)alkylaminocarbonyl(C,-C,°)alkyl; and polyether radicals optionally may have one or more carbons replaced by -O-; -NR9-; -N+R9R10A'-; -S-; -SO-;
-SOz-; -S+R9A--; -PR9-; -P+R9R10A--; -P(O)R9-; phenylene; carbohydrate residue; amino acid residue; peptide residue; or polypeptide residue; and wherein R16 and R1~ are independently selected from the group consisting of R9 and M; and wherein M is a pharmaceutically acceptable cation; and wherein R9, R'°, R", R'2, R'", and A- are as defined above; and RN is selected from the group consisting of hydrogen; (C,-C,°)alkyl;

(Cz-C,o)alkenyl; (Cz-C~o)alkynyl; and aryl(C~-C,o)alkyl; and one or more Rx radicals are independently selected from the group consisting of hydrogen; halogen; -CN; -N02; (C,-C,o)alkyl; (C3-C,o)cycloalkyl; polyalkyl; halo(C~-C,o)alkyl; (Cz-C,o)alkenyl; (Cz-C,o)alkynyl; aryl; heterocyclyl; quaternary heterocyclyl; aryl(C1-C~o)alkyl;
polyether; acyloxy; -ORl3; -~13R14; -SRl3; _S(O)R13; -S(O)2R13; -S03R13; -S+R13R14A_; -~130R14; -~13~14R15; -C02R13; _OM; _ S020M; -S02NR13R14; _y4C(O)R'3; -C(O)NR13R14~ -C(O)OM; _ COR13; -OR18; -S(O)nNR13R14; -~13R18; -~180R14; _ N+R13R14R15A-; -PR13R14; -P(O)R13R14; -P+R13R14R15A-; amino acid residue; peptide acid residue; polypeptide acid residue; and carbohydrate acid residue;
wherein the R" (CI-C~o)alkyl; (C3-C,o)cycloalkyl; polyalkyl; halo(CI-C,o)alkyl; hydroxy(CI-C,o)alkyl; (Cz-C,o)alkenyl; (Cz-C,o)alkynyl; aryl;
heterocyclyl; aryl(C,-C,o)alkyl; heterocyclyl(C~-C,o)alkyl; polyether;
acyloxy radicals optionally may be further substituted with halogen; -CN;
-OR16; _~9R10; -N+R9R11R12A-; -SR16; _S(O)R9~ -S02R9; -oxo;
S03R16; -C02R16; -CONR9R10; -S02NR9R10; -PO(OR'6)OR"; _ PR9R10; -P+R9R11R12A-; or -S+R9R10A ; and wherein the R" quaternary heterocyclyl radical optionally may be substituted with one or more radicals selected from the group consisting of halogen; -CN; -N02; oxo; (C,-C,o)alkyl; (C3-C,o)cycloalkyl; polyalkyl;
halo(C,-Clo)alkyl; hydroxy(C,-Clo)alkyl; (Cz-C,o)alkenyl; (Cz-Clo)alkynyl;
aryl; heterocyclyl; aryl(C,-C,o)alkyl; heterocyclyl(C,-Clo)alkyl; polyether; -OR13; -NR13R14; -SR13; -S(O)RB; -S02R13; -S03R13; -~130R14; _ ~13~14R15; -C02R13; _OM; -S020M; -S02NR13R14; -C(O)~13R14; -C(O)OM; _COR13; -P(O)R13R14; -PR13R14; _ p+R13R14R15A-; -P(OR13)OR14; -S+R13R14A ; ~d -N+R13R14R15A-;
and wherein the Rx radicals comprising carbon optionally may have one or more carbons replaced by -O-; -NR13-; -N+R13R14A_-; _S-; -SO-; -S02-;
-S+R13A -; -PR13-; -P(O)R13-; _PR13-; -P+R13R14A_-~ phenylene; amino acid residue; peptide residue; polypeptide residue; carbohydrate residue;
polyether; or polyalkyl; wherein said phenylene; amino acid residue; peptide residue; polypeptide residue; carbohydrate residue; and polyalkyl optionally may have one or more carbons replaced by -O-; -NR9-; -N+R9R10A -; -S-; -SO-; -SOZ-~ -S+R9A--; -PR9-; -P+R9R10A_-; or -P(O)R9_; and wherein R1 g is selected from the group consisting of (C,-C,°)alkyl;
heterocyclyl; quaternary heterocyclyl; aryl(C,-C1°)alkyl; acyl; and aryl(C,-C,°)alkoxycarbonyl; and wherein the R'g (C1-C~°)alkyl; heterocyclyl; quaternary heterocyclyl;
aryl(C1-C1°)alkyl; acyl; and aryl(C1-C1°)alkoxycarbonyl radicals optionally may be substituted with one or more radicals selected from the group consisting of halogen; -CN ; oxo; -OR9; -NR9R10; -N+R9R11R12A-; _SR9;
-S(O)R9; -S02R9; -S03R9; -C02R9; -CONR9R10; -S020M; _ S02NR9R10; -PR9R10; -P(OR13)OR14; -PO(OR16)OR1~; and -C(O)OM;
and wherein R9, R'°, R", R'2, R'3, R'4, R's, R'6, R", RW, A-, and M are as defined above; or a pharmaceutically acceptable salt, solvate, or prodrug thereof; and provided that aryl is selected from the group consisting of optionally substituted phenyl, biphenyl and naphthyl; and provided that heterocyclyl is selected from the group consisting of optionally substituted heterocyclyl comprising a 5 to 10 membered ring and comprising one or more ring atoms that are heteroatoms selected from the group consisting of oxygen, nitrogen, sulfur and phosphorus.
A class of compounds of particular interest comprises those compounds of Formula I wherein:
q is an integer from 1 to 4;
R1 and R2 are independently selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, 5 tert-butyl, pentyl, hexyl, phenoxymethylene, phenoxyethylene, phenoxypropylene, pyridinyloxymethylene, pyridinyloxyethylene;
methylpyridinyloxymethylene, methylpyridinyloxyethylene, pyrimidinyloxymethylene, and pyrimidinyloxyethylene; or R1 and R2 taken together with the carbon to which they are attached 10 form cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl; and R3 and R4 are independently selected from the group consisting of hydrogen, hydroxy, methyl, ethyl, phenyl, pyridinyl, amino, methylamino, dimethylamino, ethylamino and diethylamino; and RS and R6 are independently selected from the group consisting of 15 hydrogen, phenyl, chlorophenyl, fluorophenyl, bromophenyl, iodophenyl, hydroxyphenyl, methoxyphenyl, ethoxyphenyl, methoxy(chlorophenyl), methoxy(fluorophenyl), methoxy(bromophenyl), methoxy(iodophenyl), ethoxy(chlorophenyl), ethoxy(fluorophenyl), ethoxy(bromophenyl), ethoxy(iodophenyl), nitrophenyl, aminophenyl, methylaminophenyl, 20 dimethylaminophenyl, ethylaminophenyl, diethylaminophenyl, trimethylammoniumphenyl, triethylammoniumphenyl, trimethylammoniummethylcarbonylaminophenyl, triethylammoniummethylcarbonylaminophenyl, trimethylammoniumethylcarbonylaminophenyl, 25 triethylammoniumethylcarbonylaminophenyl, trimethylammoniumpropylcarbonylaminophenyl, triethylammoniumpropylcarbonylaminophenyl, trimethylammoniumbutylcarbonylaminophenyl, triethylammoniumbutylcarbonylaminophenyl, methylcarbonylaminophenyl, chloromethylcarbonylaminophenyl, fluoromethylcarbonylaminophenyl, bromomethylcarbonylaminophenyl, iodomethylcarbonylaminophenyl, ethylcarbonylaminophenyl, chloroethylcarbonylaminophenyl, fluoroethylcarbonylaminophenyl, bromoethylcarbonylaminophenyl, iodoethylcarbonylaminophenyl, propylcarbonylaminophenyl, chloropropylcarbonylaminophenyl, fluoropropylcarbonylaminophenyl, bromopropylcarbonylaminophenyl, iodopropylcarbonylaminophenyl, butylcarbonylaminophenyl, chlorobutylcarbonylaminophenyl, fluorobutylcarbonylaminophenyl, bromobutylcarbonylaminophenyl, iodobutylcarbonylaminophenyl, 3,4-dioxymethylenephenyl, pyridinyl, methylpyridinyl, pyridinium, methylpyridinium, thienyl, chlorothienyl, fluorothienyl, bromothienyl, iodothienyl; methoxycarbonylphenyl, ethoxycarbonylphenyl, trimethylammoniumethoxyethoxyethoxyphenyl, triethylammoniumethoxyethoxyethoxyphenyl, chloroethoxyethoxyethoxyphenyl, fluoroethoxyethoxyethoxyphenyl, bromoethoxyethoxyethoxyphenyl, iodoethoxyethoxyethoxyphenyl, pyridiniumethoxyethoxyethoxyphenyl, pip erazinyloxymethoxyethoxyethoxyphenyl, methylpiperazinyloxymethoxyethoxyethoxyphenyl, dimethylpiperazinyloxymethoxyethoxyethoxyphenyl, piperidinyloxymethoxyethoxyethoxyphenyl, methylpiperidinyloxymethoxyethoxyethoxyphenyl, and dimethylpiperidinyloxymethoxyethoxyethoxyphenyl; and RN is selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl and benzyl; and one or more Rx radicals are independently selected from the group consisting of hydroxy, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, methoxy, ethoxy, n-propoxy, isopropoxy, methylthio, methylsulfinyl, methylsulfonyl, ethylthio, ethylsulfinyl, ethylsulfonyl, amino, hydroxyamino, methylamino, dimethylamino, ethylamino, diethylamino, trimethylammonium, triethylammonium, N-methyl-N-carboxymethyl-amino, N,N-dimethyl-N-carboxymethyl-ammonium, methylcarbonylamino, chloromethylcarbonylamino, fluoromethylcarbonylamino, bromomethylcarbonylamino, iodomethylcarbonylamino, ethylcarbonylamino, n-propylcarbonylamino, n-butylcarbonylamino, n-pentylcarbonylamino, n-hexylcarbonylamino, benzyloxycarbonylamino, aminoimidocarbonylamino, morpholinyl, N-methyl-morpholinium, azetidinyl, N-methyl-azetidinium, pyrrolidine, N-methyl-pyrrolidinium, piperazinyl, N-methylpiperazinyl, N,N'-dimethyl-piperazinium, piperidinyl, methylpiperidinyl, N-methyl-piperidinium, and thienyl; or a pharmaceutically acceptable salt, solvate, or prodrug thereof.
A class of compounds of specific interest comprises those compounds of Formula I wherein:
q is an integer from 1 to 4;
R1 and R2 are independently selected from the group consisting of hydrogen and (C,-C,o)alkyl; or R1 and R2 taken together with the carbon to which they are attached form (C3-C~o)cycloalkyl; and R3 and R4 are independently selected from the group consisting of hydrogen and hydroxy; and RS is phenyl, wherein said phenyl is optionally substituted with one or more radicals independently selected from the group consisting of halogen; hydroxy; -N02; (C~-C,o)alkyl; halo(C,-Clo)alkyl; aryl(C,-C,o)alkyl;
heterocyclyl(C~-C~o)alkyl; polyether; -OR13; -~13R14; and -NR'3C(O)R'4;
and wherein R13, R14, and R15 are independently selected from the group consisting of hydrogen; (C,-Clo)alkyl; halo(C,-C,o)alkyl; heterocyclyl;
quaternary heterocyclyl; aryl(C~-C,o)alkyl; heterocyclyl(C,-C,o)alkyl;
quaternary heterocyclyl(C,-C~o)alkyl; (C~-C,o)alkylheterocyclyl(C~-C,o)alkyl; (C,-C,o)alkylammonium(C,-C,o)alkyl; and polyether; or wherein the R13, R14, and R15 (C~-C,o)alkyl; halo(C,-C,o)alkyl;
heterocyclyl; quaternary heterocyclyl; aryl(C1-C,o)alkyl; heterocyclyl(C,-C,o)alkyl; quaternary heterocyclyl(C,-C,o)alkyl; (C,-C,o)alkylheterocyclyl(C~-C~o)alkyl; (C1-C,o)alkylammonium(C~-C,o)alkyl;
and polyether radicals optionally may be substituted with one or more radicals selected from the group consisting of halogen; (C~-C~o)alkyl;
heterocyclyl; quaternary heterocyclyl; quaternary heterocyclyl(C,-C~o)alkyl;
carboxy; carboxy(C,-C,o)alkyl; -OR16; -~9R10; -N+R9R10RwA-; ~d -CONR9R10; and wherein R9 and R10 are independently selected from the group consisting of hydrogen; (C,-Clo)alkyl; heterocyclyl; ammonium(C,-C,o)alkyl; (C1-C~o)alkylammonium(C,-C,o)alkyl; aryl(C,-C,o)alkyl;
heterocyclyl(C~-C~o)alkyl; carboxy(C~-C,o)alkyl; carbo(C~-C,o)alkoxy(C~-C~o)alkyl; carboxyheterocyclyl; carboxy(C1-CIO)alkylamino; and acyl; or wherein A- is a pharmaceutically acceptable anion; and wherein R~11 and R12 are independently selected from the group consisting of hydrogen; (C~-C,o)alkyl; heterocyclyl; aryl(C1-C~o)alkyl;
carboxy(C~-C,o)alkyl; and carbo(C,-C~o)alkoxy(C,-C,o)alkyl; or R11 and R12 together with the carbon atom to which they are attached form a cyclic ring; and wherein RW and R'6 are as previously set forth above for the compounds of Formula I; and R6 is hydrogen; and RN is selected from the group consisting of hydrogen; (C~-C,o)alkyl;
and aryl(CI-C,o)alkyl; and one or more Rx radicals are independently selected from the group consisting of hydrogen; -N02; (C,-Clo)alkyl; halo(C~-C,o)alkyl; -OR13; -~13R14;
wherein R'3 and R'4 are as defined above; or a pharmaceutically acceptable salt, solvate, or prodrug thereof; and provided that aryl is selected from the group consisting of optionally substituted phenyl, biphenyl and naphthyl; and provided that heterocyclyl is selected from the group consisting of optionally substituted heterocyclyl comprising a 5 to 10 membered ring and comprising one or more ring atoms that are heteroatoms selected from the group consisting of oxygen, nitrogen, sulfur and phosphorus.
A class of compounds of high interest comprises those compounds of Formula I wherein:
q is an integer from 1 to 4;
R1 and R2 are independently selected from the group consisting of ethyl and n-butyl; or R1 and R2 taken together with the carbon to which they are attached form cyclopentyl; and one of R3 and R4 is hydrogen and the other of R3 and R4 is hydroxy; and RS is selected from the group consisting of phenyl, hydroxyphenyl, methoxyphenyl, ethoxyphenyl, nitrophenyl, aminophenyl, methylaminophenyl, dimethylaminophenyl, ethylaminophenyl, diethylaminophenyl, trimethylammoniumphenyl, triethylammoniumphenyl, trimethylammoniummethylcarbonylaminophenyl, triethylammoniummethylcarbonylaminophenyl, trimethylammoniumethylcarbonylaminophenyl, triethylammoniumethylcarbonylaminophenyl, trimethylammoniumpropylcarbonylaminophenyl, triethylammoniumpropylcarbonylaminophenyl, trimethylammoniumbutylcarbonylaminophenyl, triethylammoniumbutylcarbonylaminophenyl, methylcarbonylaminophenyl, 5 chloromethylcarbonylaminophenyl, fluoromethylcarbonylaminophenyl, bromomethylcarbonylaminophenyl, iodomethylcarbonylaminophenyl, ethylcarbonylaminophenyl, chloroethylcarbonylaminophenyl, fluoroethylcarbonylaminophenyl, bromoethylcarbonylaminophenyl, iodoethylcarbonylaminophenyl, propylcarbonylaminophenyl, 10 chloropropylcarbonylaminophenyl, fluoropropylcarbonylaminophenyl, bromopropylcarbonylaminophenyl, iodopropylcarbonylaminophenyl, butylcarbonylaminophenyl, chlorobutylcarbonylaminophenyl, fluorobutylcarbonylaminophenyl, bromobutylcarbonylaminophenyl, iodobutylcarbonylaminophenyl, 15 trimethylammoniumethoxyethoxyethoxyphenyl, triethylammoniumethoxyethoxyethoxyphenyl, chloroethoxyethoxyethoxyphenyl, fluoroethoxyethoxyethoxyphenyl, bromoethoxyethoxyethoxyphenyl, iodoethoxyethoxyethoxyphenyl, and pyridiniumethoxyethoxyethoxyphenyl; and 20 R6 is hydrogen;
RN is selected from the group consisting of hydrogen, methyl, ethyl, and benzyl; and one or more Rx radicals are independently selected from the group consisting of hydroxy, methyl, ethyl, methoxy, ethoxy, amino, 25 hydroxyamino, methylamino, dimethylamino, ethylamino, diethylamino, trimethylammonium, triethylammonium, N-methyl-N-carboxymethyl-amino, N,N-dimethyl-N-carboxymethyl-ammonium, methylcarbonylamino, chloromethylcarbonylamino, fluoromethylcarbonylamino, bromomethylcarbonylamino, iodomethylcarbonylamino, ethylcarbonylamino, benzyloxycarbonylamino, and aminoimidocarbonylamino; or a pharmaceutically acceptable salt, solvate, or prodrug thereof.
A subclass of compounds of high interest comprises those compounds of Formula I wherein:
wherein:
q is 1 or 2;
R1 and R2 are each independently alkyl;
R3 is hydroxy;
R4 and R6 are hydrogen;
RS has the formula (II):
(Ry~t wherein t is an integer from 0 to 5;
one or more Ry are independently selected from the group consisting of hydrogen; halogen; -CN; -N02; oxo; alkyl; polyalkyl; haloalkyl;
hydroxyalkyl; cycloalkyl; alkenyl; alkynyl; aryl; heterocyclyl; quaternary heterocyclyl; arylalkyl; heterocyclylalkyl; polyether; -OR13; -NR13R14; -SR13; -S(O)R13; _S02R13; -S03R13; -~130R14; _~13~14R15; _ C02R13; -OM; -S020M; -S02NR13R14; _C(O)~13R14; -C(O)OM; _ COR13; -NR13C(O)R14; -~13C(O)~14R15; -~13COZR14; -OC(O)R13; -OC(O)NR'3R14; _NRI3SOR14; -NR13SOZR14; _~13SONR14R15; -~13SOZ~laRls; -p(O)R13R14; -PR13R14; -P+R13R14R15A ; -P(OR13)OR14; -S+R13R14A ; and -N+R13R14R15A-; and wherein the alkyl, polyalkyl, haloalkyl, hydroxyalkyl, cycloalkyl, alkenyl, alkynyl, aryl, heterocyclyl, quaternary heterocyclyl, arylalkyl, heterocyclylalkyl, and polyether substituents of the Ry radicals optionally may be further substituted with one or more radicals selected from the group consisting of -CN; halogen; hydroxy; oxo; alkyl; cycloalkyl; alkenyl;
alkynyl; aryl; heterocyclyl; arylalkyl; heterocyclylalkyl; quaternary heterocyclyl; -ORS; -NR~RB; -SRS; -S(O)RB; -S02R~; -S03R~;- C02R~; -CONR~R8; -N+R~RgR9A-; -P(O)R~Rg; -PR~Rg; -P+R~RgR9A ; and -P(O)(OR~)ORg; and wherein the alkyl, polyalkyl, haloalkyl, hydroxyalkyl, cycloalkyl, alkenyl, alkynyl, aryl, heterocyclyl, quaternary heterocyclyl, arylalkyl, heterocyclylalkyl, and polyether substituents of the Ry radicals optionally may have one or more carbons replaced by -O-; -NR7-; -N+R~R8A--; -S-; -SO-; -S02-; -S+R~A--; -PRA-; -P(O)RE-; -P+R~R8A--; or phenylene; and wherein R~ and Rg are independently selected from the group consisting of hydrogen; alkyl, alkenyl; alkynyl; aryl; and heterocyclyl; and wherein R13, R14, and Rl S are independently selected from the group consisting of hydrogen; alkyl; haloalkyl; cycloalkyl; polyalkyl;
alkenyl; alkynyl; aryl; heterocyclyl; quaternary heterocyclyl; arylalkyl;
heterocyclylalkyl; quaternary heterocyclylalkyl; alkylarylalkyl;
alkylheterocyclylalkyl; alkylammoniumalkyl; aminocarbonylalkyl;
alkylaminocarbonylalkyl; carboxyalkylaminocarbonylalkyl; and polyether;
or wherein R'3 and R'4 together with the nitrogen atom to which they are attached form a mono- or polycyclic heterocyclyl that is optionally substituted with one or more radicals selected from the group consisting of oxo, carboxy, and quaternary salts; or wherein R14 and Rl S together with the nitrogen atom to which they are attached form a cyclic ring; and wherein the R13, R14~ ~d Rl S alkyl; haloalkyl; cycloalkyl;
polyalkyl; alkenyl; alkynyl; aryl; heterocyclyl; quaternary heterocyclyl;
arylalkyl; heterocyclylalkyl; quaternary heterocyclylalkyl; alkylarylalkyl;
alkylheterocyclylalkyl; alkylammoniumalkyl; aminocarbonylalkyl;
alkylaminocarbonylalkyl; carboxyalkylaminocarbonylalkyl; and polyether radicals optionally may be substituted with one or more radicals selected from the group consisting of halogen; -CN; sulfo; oxo; alkyl; haloalkyl;
hydroxyalkyl; sulfoalkyl; alkenyl; alkynyl; aryl; heterocyclyl; quaternary heterocyclyl; quaternary heterocyclylalkyl; carboxy; carboxyalkyl;
guanidinyl; -OR16; -NR9R10; -N+R9RlORwA-; -SR16; -S(O)R9; -S02R9;
-S03R16; -C02R16; -CONR9R10; -S02NR9R10; -PO(OR16)ORl~; _ PR9R10; -P+R9R10R11A-~ -S+R9Rl0A-; ~d carbohydrate residue; and wherein the R13, R14, and Rls alkyl; haloalkyl; cycloalkyl;
polyalkyl; alkenyl; alkynyl; aryl; heterocyclyl; quaternary heterocyclyl;
arylalkyl; heterocyclylalkyl; quaternary heterocyclylalkyl; alkylarylalkyl;
alkylheterocyclylalkyl; alkylammoniumalkyl; aminocarbonylalkyl;
alkylaminocarbonylalkyl; carboxyalkylaminocarbonylalkyl; and polyether radicals optionally may have one or more carbons replaced by -O-; -NR9-; -N+R9R10A--; -S-; -SO-; -SOZ-; -S+R9A--; -PR9-; -P+R9R10A_-~ -P(O)R9-;
phenylene; carbohydrate residue; amino acid residue; peptide residue; or polypeptide residue; and wherein R16 and Rl~ are independently selected from the group consisting of R9 and M; and wherein M is a pharmaceutically acceptable cation; and wherein R9, R'°, R", R'Z, R'", and A- are as previously set forth above for the compounds of Formula I; and RN is selected from the group consisting of hydrogen; alkyl; and aralkyl; and one or more Rx radicals are independently selected from the group consisting of alkoxy, alkylamino and dialkylamino; or a pharmaceutically acceptable salt, solvate, or prodrug thereof.
A family of specific compounds of particular interest within Formula I consists of the following compounds:
(4R,SR)-3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-2-methyl-S-(3-nitrophenyl)-1,2-benzothiazepin-4-of 1,1-dioxide;
(4R,SR)-5-(3-aminophenyl)-3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-2-methyl-1,2-benzothiazepin-4-of 1,1-dioxide;
5-chloro-N [3-[(4R,SR)-3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-4-hydroxy-2-methyl- l , l -dioxido-1,2-benzothi azepin-5-yl]phenyl]pentanamide;
5-[[3-[(4R,SR)-3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-4-hydroxy-2-methyl-l,l-dioxido-1,2-benzothiazepin-5-yl]phenyl]amino]-N,N,N triethyl-5-oxo-pentanaminium trifluoroacetate;
2-chloro-N [3-[(4R,SR)-3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-4-hydroxy-2-methyl-1,1-dioxido-1,2-benzothiazepin-5-yl]phenyl]acetamide;
2-[[3-[(4R,SR)-3,3-dibutyl-7-(dimethylamino]-2,3,4,5-tetrahydro-4-hydroxy-2-methyl-l,l-dioxido-1,2-benzothiazepin-5-yl]phenyl]amino]-N,N,N triethyl-2-oxoethanaminium chloride;
(4R,SR)-3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-5-(4-methoxyphenyl)-2-methyl-1,2-benzothiazepin-4-of 1,1-dioxide;

(4R,5R)-3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-5-(4-hydroxyphenyl)-2-methyl-1,2-benzothiazepin-4-of 1,1-dioxide;
(4R,5R)-3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-5-(4-(((2-iodoethyoxy)ethoxy)ethoxy)phenyl)-2-methyl-1,2-benzothiazepin-4-of 1,1-dioxide;
1-[2-[2-[2-[4-[(4R,5R)-3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-4-hydroxy-2-methyl-1,1-dioxido-1,2-b enzothiazepin-5-yl]phenoxy] ethoxy] ethoxy] ethyl]pyridinium;
10 2-[2-[2-[4-[(4R,5R)-3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-4-hydroxy-2-methyl-1,1-dioxido-1,2-benzothi azepin-5-yl]phenoxy]ethoxy]ethoxy]-N,N,N triethylethanaminium iodide;
(4R,5R)-3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-5-(3-methoxyphenyl)-2-methyl-1,2-benzothi azepin-4-o 1 1,1-dioxide;
(4R,5R)-3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-5-(3-nitrophenyl)-1,2-benzothiazepin-4-of 1,1-dioxide and (4S,5R)-3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-5-(3-nitrophenyl)-1,2-benzothiazepin-4-of 1,1-dioxide;
(4R,5R)-5-(3-aminophenyl)-3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-1,2-benzothiazepin-4-of 1,1-dioxide;
5-bromo-N [3-[(4R,5R)-3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-4-hydroxy-1,1-dioxido-1,2-benzothiazepin-5-yl)phenyl]pentanamide;

5-[[3-[(4R,SR)-3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-4-hydroxy-1,1-dioxido-1,2-benzothiazepin-5-yl]phenyl]amino]-N,N,N triethyl-5-oxo-1-pentanaminium trifluoroacetate;
(4R,SR)-3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-5-phenyl-1,2-benzothiazepin-4-of 1,1-dioxide;
(4R,SR)-3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-5-(4-methoxyphenyl)-1,2-b enzothiazepin-4-of l , l -dioxide;
(4R, SR)-3, 3-dibutyl-7-(dimethylamino)-2,3,4, 5-tetrahydro-S-(4-hydroxyphenyl)-1,2-benzothiazepin-4-of 1,1-dioxide;
2-[2-[2-[4-[(4R,SR)-3,3-dibutyl-7- (dimethylamino)-2,3,4,5-tetrahydro-4-hydroxy-1,1-dioxido-1,2-b enzothiazepin-5-yl]phenoxy] ethoxy] ethoxy]-N, N, N
triethylethanaminium iodide;
(4R,SR)-3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-5-(3-nitrophenyl)-2-(phenylmethyl)-1,2-benzothiazepin-4-oll,l-dioxide;
(4R,SR)-3,3-dibutyl-7-(dimethylamino)-5-[3-(ethylamino)phenyl]-2,3,4,5-tetrahydro-2-(phenylmethyl)-1,2-benzothiazepin-4-of 1,1-dioxide;
(4R,SR)-3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-5-(4-methoxyphenyl)-2-(phenylmethyl)-1,2-benzothiazepin-4-of 1,1-dioxide; and (4R,SR)-7-dimethylamino)-2-ethyl-4,5-dihydro-5-(4-methoxyphenyl)-spiro[1,2-benzothiazepine-3(2H),1'-cyclopentan]-4-of 1,1-dioxide; and the pharmaceutically-acceptably salts thereof.
The invention further comprises a compound selected from among:
R2° R's-R2' ( F o rmu I a D I ) Rzo R~ sR21 ( F o rmu I a D 1 1 ) , and R2° R~sR2~ ( F o rmu I a D 1 1 1 ) wherein R'9 is selected from the group consisting of alkane diyl, alkene diyl, alkyne diyl, polyalkane diyl, alkoxy diyl, polyether diyl, polyalkoxy diyl, carbohydrate residue, amino acid residue, peptide residue, and polypeptide residue; and wherein alkane diyl, alkene diyl, alkyne diyl, polyalkane diyl, alkoxy diyl, polyether diyl, polyalkoxy diyl, carbohydrate residue, amino acid residue, peptide residue, and polypeptide residue optionally may have one or more carbon atoms replaced by -O-, -NR'-, -N+R'R$A--, -S-, -SO-, -SOZ-, -S+R'A--, -PR'-, -PR'R$A--, phenylene, heterocyclyl, quaternary heterocyclyl, or aryl;
wherein alkane diyl, alkene diyl, alkyne diyl, polyalkane diyl, alkoxy diyl, polyether diyl, polyalkoxy diyl, carbohydrate residue, amino acid residue, peptide residue, and polypeptide residue optimally can be substituted with one or more radicals independently selected from the group consisting of alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocyclyl, arylalkyl, halogen, oxo, -OR13; _NR13R14~ -SR13; _S~O)R13; -S02R13; -S03R13; -NR13OR14; -NR13NR14R15~ -N02; _C02R13; -CN; -OM; _ S020M; -S02NR13R14; -C~O)~13R14; _C~O)OM; -COR13; -P(O)R13R14~ _PR13R14~ -P+R13R14R~sA_~ _p~OR'3)OR'4; -S+R'3R'aA-; and -N+R13R14R15A-;
wherein R'3, R'a, R's, M and A- are as previously set forth above for the compounds of Formula I; and wherein R'9 can further comprise functional linkages by which R'9 is bonded to Rz° and/or Rz' in the compounds of Formula DI; to Rz°, Rz' and/or Rzz in the compounds of Formula DII; and to Rz°, Rz', Rzz and/or Rz3 in the compounds of Formula DIII; and wherein each of Rz°, Rz', or Rzz and Rz3 comprises a benzothiazepine 1 S moiety as described above that is therapeutically effective in inhibiting ileal bile acid transport.
Exemplary R'9 substituents include, but are not limited to, the following:
Rzs Rzs Rz~
R3o \R31 a R2$ O O~R
h O O
32 \ ~ 33 R ~ ~ S i IJ R

R3g \ ~R37 wherein:
R25 is selected from the group consisting of carbon and nitrogen; and Rzb, RZ', R28, R29, R3~, R3', R3z, R33, R34, R35, R36, and R3' are independently selected from the group consisting of:

R3e -CH2- ; - -;

O -N-s S -N - ~

--C - ;

O -NH-NH-;

O- i -N-NH

-O - s -S-O

-NHSOZ-; and -S - ;

O R4o -S - ; -S ~ ;

p R41 wherein R3g , R39, Rao and Ra' are independently selected from the group consisting of alkyl, alkenyl, alkylaryl, aryl, arylalkyl, cycloalkyl, heterocyclyl, 5 and heterocyclylalkyl;
A- is a pharmaceutically acceptable anion; and h, i, j and k are independently selected from the group consisting of integers from 1 to 10 inclusive.

The invention is also directed to a compound selected from among Formula DI, Formula DII and Formula DIII in which each of RZ°, RZ', RZZ and R23 comprises a benzothiazepine moiety corresponding to the Formula DIV or Formula DIVA:
X N
( R ) q °y ~~ /R
S~N R~
R2 (Formula DIV) Rs ~ ~ s R4 R
or:
(Rx)q o\\~~ RN
S_N/ R~
R2 (Formula DIVA) Rs ~ ~ R4 Rss wherein R', R2, R3, R4, R5, R6, RN, RX, q, and n are as previously defined above for the compounds of Formula I, and R55 is either a covalent bond or arylene.

In compounds of Formula DIV, it is particularly preferred that each of RZ°, RZ', Rz2, and Rz3 in Formulae DI, DII and DIII be bonded at its 7- or 8 position to R'9. In compounds of Formula DIVA, it is particularly preferred that R55 comprise a phenylene moiety bonded at a m- orp-carbon thereof to R'9.
Examples of Formula DI include:

R RsA
R
R3 4 4A ~ N~ ~~ ( 1 I 1 ) R R~s R. ~S~
~O
~S
v , v , i i ( RY ~ t ( RYA ~ ~ ( RxA ~ r (RX~q and YA
(R 1..
~~(RY~t ,A
Ra R2R \ R3A ( Iv) R1~' RzA
R~ _ .t N~N ~S~O ( Rx ~ q ( RxA ~ r O// \\ \ NA ~A
R O O R
and A
RN
R~ 2 R3A
R
\ R3 R~~ RZA
Q~ - _ R .t~A
Q \Q \RNA
W ~ ~ ~RxA) /J I
~Ry~t (RX~q wherein R'", RZA, R3A~ R4A' RNA' RyA~ R~~ r and a have the same definitions as stated above for R', Rz, R3, R4, RNA, Ry, RX, q and t, respectively.
In any of the compounds of the present invention, R' and RZ can be, among other combinations, ethyl/butyl or butyl/butyl.
Illustrative dimeric compounds include the following:
L RyA ) __ ~N~PE~
N
H H
O
O
O
O
O
O
/ /
/N i ,vOH - 'OOH
\ / /N /
S N \ S N
O O
O O
N~PE
\N
H H
O O
O
O
O - O
O ~ S ~~n ~ ~ O ~ ,~~i O~ \
N O
.'OOH OH

In another embodiment, a core moiety backbone, R'~, as discussed herein in Formulae DI, DII and DIII can be multiply substituted with more than four pendant active benzothiazepine units, i.e., RZ°, RZ', RZZ, and R23 as discussed above, through multiple functional groups within the core moiety 5 backbone. The core moiety backbone unit, R'9, can comprise a single core moiety unit, multimers thereof, and multimeric mixtures of the different core moiety units discussed herein, i.e., alone or in combination. The number of individual core moiety backbone units can range from about one to about 100, preferably about one to about 80, more preferably about one to about 50, and 10 even more preferably about one to about 25. The number of points of attachment of similar or different pendant active benzothiazepine units within a single core moiety backbone unit can be in the range from about one to about 100, preferably about one to about 80, more preferably about one to about 50, and even more preferably about one to about 25. Such points of attachment 15 can include bonds to C, S, O, N, or P within any of the groups encompassed by the definition of R'9.
The more preferred benzothiazepine moieties comprising RZ°, RZ', RZz and/or R23 conform to the preferred structures as outlined above for Formula I.
The 3-position carbon on each benzothiazepine moiety can be achiral, and the 20 substituents R', RZ, R3, R4, RS and RX can be selected from the preferred groups and combinations of substituents as discussed above. The core structures can comprise, for example, poly(oxyalkylene) or oligo(oxyalkylene), especially poly- or oligo(oxyethylene) or poly- or oligo(oxypropylene).
Methods of Treatment 25 In another aspect, the present invention provides a pharmaceutical composition for the prophylaxis and/or treatment of a disease, condition and/or disorder for which a bile acid transport inhibitor is indicated, such as a hyperlipidemic condition, for example, atherosclerosis. Such compositions comprise any of the compounds disclosed above, alone or in combination, in an amount effective to reduce bile acid levels in the blood, or to reduce transport thereof across digestive system membranes, alone or in a composition comprising, for example, one or more pharmaceutically acceptable Garners, excipients, and/or diluents. In any of the dimeric or multimeric structures discussed immediately above, for example, the benzothiazepine compounds of the present invention can be used alone or in various combinations.
In a further aspect, the present invention also provides a method of treating a disease, condition and/or disorder in mammals, including humans, for which a bile acid transport inhibitor is indicated, comprising administering to a patient in need thereof a compound of the present invention in an effective amount in unit dosage form or in divided doses.
In yet a further aspect, the present invention comprises the use of the compounds of Formula I and/or the dimeric or multimeric compounds of Formulae DI, DII and/or DIII in the preparation of a medicament useful for the prophylaxis and/or treatment of a disease, condition and/or disorder for which a bile acid transport inhibitor is indicated.
The compounds of Formula I are also useful for the prophylaxis and/or treatment of gallstones.
In yet a further aspect, the present invention also provides processes for the preparation of compounds of the present invention.
Further scope of the applicability of the present invention will become apparent from the detailed description provided below. However, it should be understood that the following detailed description and examples, while indicating preferred embodiments of the invention, are given by way of illustration only since various changes and modifications within the spirit and scope of the invention will beomce apparent to those skilled in the art from this detailed description.
Definitions and Abbreviations In order to aid the reader in understanding the following detailed description, the following definitions are provided:
The term "hydrocarbyl" refers to radicals consisting exclusively of the elements carbon and hydrogen. These radicals include, for example, alkyl, S cycloalkyl, alkenyl, cycloalkenyl, alkynyl, and aryl moieties. These radicals also include alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, and aryl moieties substituted with other aliphatic or cyclic hydrocarbon groups, such as alkaryl, alkenaryl and alkynaryl. Preferably, these moieties comprise 1 to 20 carbon atoms.
The term "substituted hydrocarbyl" refers to a hydrocarbyl radical that is substituted with a group comprising at least one atom other than carbon, such as but not limited to, halogen, oxygen, nitrogen, sulfur and phosphorus.
Examples of such substituted hydrocarbyl include hydrocarbyl radicals substituted with groups such as, but not limited to, lower alkoxy such as methoxy, ethoxy, and butoxy; halogen such as chloro and fluoro; ethers;
acetals; ketals; esters; heterocyclyl such as furyl and thienyl; alkanoxy;
hydroxy; protected hydroxy; acyl; acyloxy; nitro; cyano; amino; and amido.
Substituted hydrocarbyl also includes hydrocarbyl radicals in which a carbon chain atom is replaced with a heteroatom such as nitrogen, oxygen, sulfur, or a halogen.
Where the term "alkyl" is used, either alone or within other terms such as "haloalkyl", and "hydroxyalkyl", it embraces linear or branched radicals having one to about twenty carbon atoms or, preferably, one to about twelve carbon atoms. More preferred alkyl radicals are "lower alkyl" radicals having one to about six carbon atoms. Examples of such radicals include methyl, ethyl; n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tent-butyl, pentyl, iso-amyl, hexyl and the like. Even more preferred are lower alkyl radicals having one to three carbon atoms.
Where the term "alkenyl" is used, either alone or within other terms such as "arylalkenyl", it embraces linear or branched radicals having at least one carbon-carbon double bond of two to about twenty carbon atoms or, preferably, two to about twelve carbon atoms. More preferred alkenyl radicals are "lower alkenyl" radicals having two to about six carbon atoms. Examples of alkenyl radicals include ethenyl, propenyl, allyl, propenyl, butenyl and 4-methylbutenyl.
The terms "alkenyl" and "lower alkenyl", embrace radicals having "cis"
and "trans" orientations, or alternatively, "E" and "Z" orientations.
The term "alkynyl" denotes linear or branched radicals having two to about twenty carbon atoms or, preferably, two to about twelve carbon atoms.
More preferred alkynyl radicals are "lower alkynyl" radicals having two to about ten carbon atoms. Most preferred are lower alkynyl radicals having two to about six carbon atoms. Examples of such radicals include propargyl, butynyl, and the like.
The term "cycloalkyl" embraces saturated carbocyclic radicals having three to about twelve carbon atoms. More preferred cycloalkyl radicals are "lower cycloalkyl" radicals having three to about ten carbon atoms. Examples of such radicals include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
The term "cycloalkyl" additionally encompasses spiro systems wherein the cycloalkyl ring has a carbon ring atom in common with the seven-membered heterocyclic ring of the benzothiazepine.
The term "cycloalkenyl" embraces partially unsaturated carbocyclic radicals having three to twelve carbon atoms. Cycloalkenyl radicals that are partially unsaturated carbocyclic radicals that contain two double bonds (that may or may not be conjugated) can be called "cycloalkyldienyl". More preferred cycloalkenyl radicals are "lower cycloalkenyl" radicals having four to about ten carbon atoms. Examples of such radicals include cyclobutenyl, cyclopentenyl and cyclohexenyl.
The term "halo" and "halogen" means halogens such as fluorine, chlorine, bromine or iodine atoms. The term "haloalkyl" embraces radicals wherein any one or more of the alkyl carbon atoms is substituted with halo as defined above. Specifically embraced are monohaloalkyl, dihaloalkyl and polyhaloalkyl radicals. A monohaloalkyl radical, for one example, may have either an iodo, bromo, chloro or fluoro atom within the radical. Dihalo and polyhaloalkyl radicals may have two or more of the same halo atoms or a combination of different halo radicals. "Lower haloalkyl" embraces radicals having one to six carbon atoms. Examples of haloalkyl radicals include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl and dichloropropyl. "Perfluoroalkyl" means alkyl radicals having all hydrogen atoms replaced with fluoro atoms. Examples include trifluoromethyl and pentafluoroethyl.
The term "hydroxyalkyl" embraces linear or branched alkyl radicals having one to about ten carbon atoms any one of which may be substituted with one or more hydroxyl radicals. More preferred hydroxyalkyl radicals are "lower hydroxyalkyl" radicals having one to six carbon atoms and one or more hydroxyl radicals. Examples of such radicals include hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl and hydroxyhexyl. Even more preferred are lower hydroxyalkyl radicals having one to three carbon atoms.
The term "aryl", alone or in combination, means a carbocyclic aromatic system containing one or more rings wherein such rings may be attached together in a pendent manner or may be fused. The term "aryl" embraces aromatic radicals such as phenyl, naphthyl, tetrahydronaphthyl, indane, biphenyl, and anthracenyl. More preferred aryl is phenyl. Said "aryl" group may have one to three substituents such as lower alkyl, hydroxy, halo, haloalkyl, nitro, cyano, alkoxy and lower alkylamino.
The term "heterocyclyl" embraces saturated, partially saturated and unsaturated heteroatom-containing ring-shaped radicals, where the heteroatoms may be selected from nitrogen, sulfur and oxygen. Preferred heterocyclyl are 3-10 membered ring heterocyclyl, particularly S-8 membered ring heterocyclyl.

Examples of saturated heterocyclic radicals include saturated 3 to 6-membered heteromonocyclic groups containing 1 to 4 nitrogen atoms [e.g. pyrrolidinyl, imidazolidinyl, piperidino, piperazinyl]; saturated 3 to 6-membered heteromonocyclic groups containing 1 to 2 oxygen atoms and 1 to 3 nitrogen 5 atoms [e.g. morpholinyl]; saturated 3 to 6-membered heteromonocyclic groups containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms [e.g., thiazolidinyl].
Examples of partially saturated heterocyclyl radicals include dihydrothiophene, dihydropyran, dihydrofuran and dihydrothiazole. Examples of unsaturated heterocyclic radicals, also termed "heteroaryl" radicals, include unsaturated 10 to 6 membered heteromonocyclyl groups containing 1 to 4 nitrogen atoms, for example, pyrrolinyl, imidazolyl, pyrazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazolyl [e.g., 4H-1,2,4-triazolyl, 1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl]; unsaturated condensed heterocyclic groups containing 1 to 5 nitrogen atoms, for example, indolyl, isoindolyl, indolizinyl, 15 benzimidazolyl, quinolyl, isoquinolyl, indazolyl, benzotriazolyl, tetrazolopyridazinyl [e.g., tetrazolo [1,5-b]pyridazinyl]; unsaturated 3 to 6-membered heteromonocyclic groups containing an oxygen atom, for example, pyranyl, 2-furyl, 3-furyl, etc.; unsaturated 5 to 6-membered heteromonocyclic groups containing a sulfur atom, for example, 2-thienyl, 3-thienyl, etc.;
20 unsaturated 5- to 6-membered heteromonocyclic groups containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, for example, isoxazolyl, oxadiazolyl [e.g., 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl]; unsaturated condensed heterocyclic groups containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms [e.g. benzoxazolyl, benzoxadiazolyl]; unsaturated 5 to 6-25 membered heteromonocyclic groups containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, for example, thiazolyl, thiadiazolyl [e.g., 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl]; unsaturated condensed heterocyclic groups containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms [e.g., benzothiazolyl, benzothiadiazolyl] and the like. The term also embraces 30 radicals where heterocyclic radicals are fused with aryl radicals. Examples of such fused bicyclic radicals include benzofuran, benzothiophene, and the like.
Said "heterocyclyl" group may have 1 to 3 substituents such as lower alkyl, hydroxy, oxo, amino and lower alkylamino.
Heterocyclic radicals can include fused or unfused radicals, particularly 3-10 membered fused or unfused radicals. Preferred examples of heteroaryl radicals include benzofuryl, 2,3-dihydrobenzofuryl, benzothienyl, indolyl, dihydroindolyl, chromanyl, benzopyran, thiochromanyl, benzothiopyran, benzodioxolyl, benzodioxanyl, pyridyl, thienyl, thiazolyl, furyl, and pyrazinyl.
More preferred heteroaryl radicals are 5- or 6-membered heteroaryl, containing one or two heteroatoms selected from sulfur nitrogen and oxygen, selected from thienyl, furanyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, pyridyl, piperidinyl and pyrazinyl.
The term "heteroaryl" means a fully unsaturated heterocyclyl.
In either "heterocyclyl" or "heteroaryl," the point of attachment to the molecule of interest can be at the heteroatom or elsewhere within the ring.
The term "triazolyl" includes all positional isomers. In all other heterocyclyl and heteroaryl which contain more than one ring heteroatom and for which isomers are possible, such isomers are included in the definition of said heterocyclyl and heteroaryl.
The term "quaternary heterocyclyl" means a heterocyclyl in which one or more of the heteroatoms, for example, nitrogen, sulfur, phosphorus or oxygen, has such a number of bonds that it is positively charged (and therefore the term is intended to encompass both ternary and quaternary positively charged structures). The point of attachment of the quaternary heterocyclyl to the molecule of interest can be at a heteroatom or elsewhere.
The term "quaternary heteroaryl" means a heteroaryl in which one or more of the heteroatoms, for example, nitrogen, sulfur, phosphorus or oxygen, has such a number of bonds that it is positively charged (and therefore the term is intended to encompass both ternary and quaternary positively charged structures). The point of attachment of the quaternary heteroaryl to the molecule of interest can be at a heteroatom or elsewhere.
The term "diyl" means a diradical moiety wherein said moiety has two points of attachment to molecules of interest.
The term "oxo" means a doubly bonded oxygen.
The term "polyalkyl" means a branched or straight hydrocarbon chain having a molecular weight up to about 20,000, more preferably up to about 10,000, and most preferably up to about 5,000.
The term "polyether" means a polyalkyl wherein one or more carbons are replaced by oxygen, wherein the polyether has a molecular~weight up to about 20,000, more preferably up to about 10,000, and most preferably up to about 5,000.
The term "polyalkoxy" means a polymer of alkylene oxides, wherein the polyalkoxy has a molecular weight up to about 20,000, more preferably up to about 10,000, and most preferably up to about 5,000.
The term "carbohydrate residue" encompasses residues derived from carbohydrates such as, but is not limited to, mono-, di-, tri-, tetra- and polysaccharides wherein the polysaccharides can have a molecular weight of up to about 20,000, for example, hydroxypropyl-methylcellulose or chitosan residue; compounds derived from aldoses and ketoses with 3 to 7 carbon atoms and which belong to the D- or L-series; aminosugars; sugar alcohols; and saccharic acids. Nonlimiting specific examples of such carbohydrates include glucose, mannose, fructose, galactose, ribose, erythrose, glycerinaldehyde, sedoheptulose, glucosamine, galactosamine, glucoronic acid, galacturonic acid, gluconic acid, galactonic acid, mannoic acid, glucamine, 3-amino-1,2-propanediol, glucaric acid and galactaric acid.
The term "peptide residue" means polyamino acid residue containing up to about 100 amino acid units.
The term "polypeptide residue" means a polyamino acid residue containing from about 100 amino acid units to about 1000 amino acid units, more preferably from about 100 amino acid units to about 750 amino acid untis, and most preferably from about 100 amino acid units to about 500 amino acid units.
The term "alkylammoniumalkyl" means an an -NHZ group or a mono-, di- or tri-substituted amino group, any of which is bonded to an alkyl wherein said alkyl is bonded to the molecule of interest.
The term "sulfo" means a sulfo group, -S03H, and its salts.
The term "sulfoalkyl" means an alkyl group to which a sulfonate group is bonded, wherein said alkyl is bonded to the molecule of interest.
The term "aralkyl" embraces aryl-substituted alkyl radicals. Preferable aralkyl radicals are "lower aralkyl" radicals having aryl radicals attached to alkyl radicals having one to six carbon atoms. Even more preferred are lower aralkyl radicals having phenyl attached to alkyl portions having one to three carbon atoms. Examples of such radicals include benzyl, diphenylmethyl and phenylethyl. The aryl in said aralkyl may be additionally substituted with halo, alkyl, alkoxy, halkoalkyl and haloalkoxy. The term "arylalkenyl" embraces aryl-substituted alkenyl radicals. Preferable arylalkenyl radicals are "lower arylalkenyl" radicals having aryl radicals attached to alkenyl radicals having The term "heterocyclylalkyl" means an alkyl radical that is substituted with one or more heterocyclyl groups. Preferable heterocyclylalkyl radicals are "lower heterocyclylalkyl" radicals having one or more heterocyclyl groups attached to an alkyl radical having one to ten carbon atoms.
The term "heteroarylalkyl" means an alkyl radical that is substituted with one or more heteroaryl groups. Preferable heteroarylalkyl radicals are "lower heteroarylalkyl" radicals having one or more heteroaryl groups attached to an alkyl radical having one to ten carbon atoms.
The term "quaternary heterocyclylalkyl" means an alkyl radical that is substituted with one or more quaternary heterocyclyl groups. Preferable quaternary heterocyclylalkyl radicals are "lower quaternary heterocyclylalkyl"
radicals having one or more quaternary heterocyclyl groups attached to an alkyl radical having one to ten carbon atoms.

The term "quaternary heteroarylalkyl" means an alkyl radical that is substituted with one or more quaternary heteroaryl groups. Preferable quaternary heteroarylalkyl radicals are "lower quaternary heteroarylalkyl"
radicals having one or more quaternary heteroaryl groups attached to an alkyl radical having one to ten carbon atoms.
The term "alkylheteroarylalkyl" means a heteroarylalkyl radical that is substituted with one or more alkyl groups. Preferable alkylheteroarylalkyl radicals are "lower alkylheteroarylalkyl" radicals with alkyl portions having one to ten carbon atoms.
The term "alkoxy" means an alkyl radical which is attached to the molecule of interest by oxygen, such as a methoxy radical. More preferred alkoxy radicals are "lower alkoxy" radicals having one to six carbon atoms.
Examples of such radicals include methoxy, ethoxy, propoxy, iso-propoxy, butoxy and tert-butoxy.
The term "carboxy" means the carboxy group, -COzH, or its salts.
The term "carboxyalkyl" means an alkyl radical that is substituted with one or more carboxy groups. Preferable carboxyalkyl radicals are "lower carboxyalkyl" radicals having one or more carboxy groups attached to an alkyl radical having one to six carbon atoms.
The term "carboxyheterocyclyl" means a heterocyclyl radical that is substituted with one or more carboxy groups.
The term "carboxyheteroaryl" 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. Preferable carboalkoxyalkyl radicals are "lower carboalkoxyalkyl" radicals having one or more alkoxycarbonyl groups attached to an alkyl radical having one to six carbon atoms.
The term "carboxyalkylamino" means an amino radical that is mono- or di-substituted When used in combination, for example "alkylaryl" or "arylalkyl," the individual terms listed above have the meaning indicated above.
The term "acyl" means an organic acid group in which the hydroxy of the carboxy group has been removed. Examples of acyl groups include, but are not limited to, acetyl and benzoyl.
5 The term "active compound" means a compound of the present invention that inhibits transport of bile acids.
The term "a bile acid transport inhibitor" means a compound capable of inhibiting absorption of bile acids from the intestine into the circulatory system of a mammal, such as a human. This includes increasing the fecal excretion of 10 bile acids, as well as reducing the blood plasma or serum concentrations of cholesterol and cholesterol ester, and more specifically, reducing LDL and VLDL cholesterol. Conditions and/or diseases that benefit from the prophylaxis and/or treatment by bile acid transport inhibition include, for example, a hyperlipidemic condition such as atherosclerosis.
15 The abbreviations used in this application have the following meanings:
The term "THF" means tetrahydrofuran;
The term "PTC" means phase transfer catalyst;
The term "Aliquart 336" means methyltricaprylylammonium chloride;
The term "MCPBA" means m-chloroperbenzoic acid;
20 The term "Celite" refers to a brand of diatomaceous earth filtering aid;
The term "DMF" means dimethylformamide;
The term "DME" means ethylene glycol dimethyl ether;
The term "BOC" means t-butoxycarbonyl;
The term "Me" means methyl;
25 The term "Et" means ethyl;
The term "Bu" means butyl;
The term "EtOAc" means ethyl acetate;
The term "EtzO" means diethyl ether;
The term "LAH" means lithium aluminum hydride;

The term "DMSO" means dimethylsulfoxide;
The term "KOSiMe3" means potassium trimethylsilanolate;
The term "PEG" means polyethylene glycol;
The term "MS" means mass spectrometry;
The term "HRMS" means high resolution mass spectrometry;
The term "ES" means electrospray;
The term "NMR" means nuclear magnetic resonance spectroscopy;
The term "GC" means gas chromatography;
The term "MPLC" means medium pressure liquid chromatography;
The term "HPLC" means high pressure liquid chromatography;
The term "RPHPLC" means reverse phase high pressure liquid chromatography The term "RT" means room temperature;
The terms "h" or "hr" means hour(s); and The term "min" means minute(s);
Alternate Forms of Compounds The compounds of the present invention can have at least two asymmetrical carbon atoms, and therefore include racemates and stereoisomers, such as diastereomers and enantiomers, in both pure form and in admixture.
Such stereoisomers can be prepared and separated using conventional techniques, either by reacting enantiomeric starting materials, or by separating isomers of compounds of the present invention. Isomers may include geometric isomers, for example cis isomers or trans isomers across a double bond. All such isomers are contemplated among the compounds of the present invention.
The compounds of the present invention also include tautomers, salts, solvates and prodrugs of such compounds.

Compound Syntheses The starting materials for use in the preparation of the compounds of the invention are commercially available or can be prepared by conventional methods known to a skilled person or in an analogous manner to processes described in the art.
Generally, the compounds of the present invention can be prepared by the procedures described below.

Scheme 1 PhCHO R~X/ base EtOzC~ Ntiz EtOzC~ N~ Ph X~ EtOZC~ N~ Ph R' R2 O
H~NHz.HCI .
V R~~R2 lu'FiF~
SO2CI ,~ NHZ Et3N ~ SOzNH
(~')q i / H" Ri R2 (~)a ~ / R~ ~ OH
THF

TBDMSa imidazde DMF
~ SOzNH
~ ~N~ '(R")q i / R~ ~ OT~M
(~')q i / ROT~MS base 1) rrBuLirTHF
(O~tiit if RN = H) 2) B(a)s 3) R5CH2X/Pd(PPh3)a 1 M Na2C03 tduenelEtOH
RN RN
SOZN ~ SOzN
(~)a i / R ~ OT~MS ~~ (~)q i / R ~ OH
THF
s (aC0)2 w so2N /_~o t (RK)q ~ / , R1 N
R
~OH KOf-Bu ~ ~ SAN~ CHO
RN . (R'')qT / R; \R2 ~ sa2ni 1R5 R~

OH
9b Scheme 1 illustrates the preparation of racemic benzothiazepines 9a and 9b. Reaction of benzenesulfonyl chloride 1 with aminoalcohol Z in the presence of a base, such as triethylamine, in a solvent, such as tetrahydrofuran, yields benzenesulfonamide 3 which can be converted to protected benzenesulfonamide 4. Protected benzenesulfonamide 4 optionally can be treated with an alkyl halide, such as methyl iodide, in the presence of a base such as sodium hydride, in a solvent, such as dimethylformamide, to yield N-substituted benzenesulfonamide 5. Protected benzenesulfonamide 4 or N-substituted benzenesulfonamide 5 is then successively reacted with (i) a strong base (such as n-butyllithium in hexanes) in a solvent (such as tetrahydrofuran), (ii) an electrophile (such as trimethyl borate), and (iii) a base (such as sodium carbonate), a benzyl halide (such as p-methoxybenzyl chloride), and a catalyst (such as tetrakis(triphenylphosphine)palladium(0)) to yield sulfonamide 6.
Treatment of sulfonamide 6 with a fluoride source, such as tetrabutylammonium fluoride, in a solvent, such as tetrahydrofuran, provides the deprotected sulfonamide alcohol 7. Sulfonamide alcohol 7 is successively oxidized using a method such as Swern Oxidation to yield sulfonamide aldehyde 8. Upon treatment with a base such as potassium tert-butoxide, aldehyde 8 is converted to racemic benzothiazepines 9a and 9b. R', R2, R5, RN, Rx and q are as previously defined above for compounds of Formula I.

Alternative Synthesis of sulfonamide alcohol S02CI HO~NH2 Et3N ~ S02NH
R~ R2 ~ R~~OH
L
L

Where L = F, CI, Br, N02, TsO, Tf0 R~ R OH

Scheme 2 illustrates an alternative synthetic scheme for the preparation of sulfonamide alcohol 3 used in Scheme 1. Reaction of benzenesulfonyl chloride 10 with aminoalcohol 11 in the presence of a base, such as 5 triethylamine, in a solvent, such as tetrahydrofuran, yields sulfonamide 12.
Substituent L of benzenesulfonyl chloride 10 is a suitable leaving group such as fluoro, chloro, bromo, nitro, tosyloxy or trifluoromethylsulfonyloxy.
Reaction of sulfonamide 12 with a suitable nucleophile in the presence of a base, such as triethylamine, in a solvent, such as tetrahydrofuran, yields 10 benzenesulfonamide 3 which can be further reacted in accordance with Scheme 1. R', RZ, RX and q are as previously defined above for compounds of Formula I. Substituent M is a metal, preferably an alkali metal, or a hydrogen.

) , ~ ~K 1 ~ ~ ~K 1 R (R~)q ~ R (R'')q ~ R
/ R2 - R2 - Rz OH ~ O R5 N~
1g 19 Lavues~n's ~o ~t'ra NaB(C~cy~H
RN
R1 (~)q / ~ R1 (~)q / R1 SOzN
/ R2 vR2 ~R2 N~lo ~ f~FiR9 l.~Al~'1a RN
~ (R~)9 ~ / R1 1 R9X ~ , w SOzN R1 [~ ~ S(OR9 (R")q ; / R2 Base ( ~ ~ / R2 17 RN
15 ~ S (~')q ; ~ R1 ,R2 RN ~ RN
~ so~N Msa ~ sazN KcN ~ so~v (R~)q / R1 ~S2 (Rx)q ~ / R1 (R~)4 /
O tH~ ~ O tMC~s ~ C I-~N
9 ~ ~ ~~ R9oH
KOHL
w ~ w ~
(R~c)9 ~ R1 (Rr)9 ~ R1 _ R2 ~ R2 Scheme 3 illustrates the preparation of benzothiazepines having 4-position substituents other than hydroxy.
In the preparation of 4-thioxo-, thio-, sulfinyl- or sulfonyl-benzothiazepines, benzothiazepine 9a or 9b is first oxidized to benzothiazepine-4-one 13. Conventional oxidizing agents, such as PCC, or Swern conditions can be used. Benzothiazepine-4-one 13 is then reacted with Lawesson's Reagent to produce 4-thioxo-benzothiazepine 14. 4-Thioxo-benzothiazepine 14 can be reacted with a suitable reducing agent, such as lithium aluminum hydride, in a suitable solvent, such as tetrahydrofuran, to yield 4-mercapto-benzothiazepine 15. 4-Mercapto-benzothiazepine 15 can be reacted with a suitable alkylating agent, such as an alkyl halide, in the presence of a base, such as sodium hydride, in a suitable solvent, such as dimethylformamide, to yield 4-alkylthio-benzothiazepine 16. 4-Alkylthio-benzothiazepine 16 can be reacted with a suitable oxidizing agent, such as t-butyl hydroperoxide or m-chloroperbenzoic acid, to yield, successively, 4-alkylsulfinyl-benzothiepine 17 and 4-alkylsulfonyl-benzothiazepine 18.
Alternatively, 4-amino- or imino-benzothiazepines can be prepared by reacting benzothiazepine-4-one 13 with ammonia or a primary amine in a suitable solvent, such as tetrahydrofuran, to produce 4-imino-benzothiazepine 19. 4-Imino-benzothiazepine 19 can be reacted with a suitable reducing agent, such as lithium aluminum hydride, in a suitable solvent, such as tetrahydrofuran, to yield 4-amino-benzothiazepine 20. Benzothiazepine-4-one 13 also can undergo reductive alkylation by reaction with ammonia, a primary amine or a secondary amine in the presence of an reducing agent, such as sodium triacetoxyborohydride, in a suitable solvent, such as tetrahydrofuran, to produce 4-amino-benzothiazepine Z1.
Scheme 3 also illustrates the preparation of 4-alkyl-benzothiazepine 23 and 4-alkoxycarbonyl-benzothiazepine 25. The 4-position hydroxy of benzothiazepine 9a or 9b is first converted to a suitable leaving group such as mesyloxy to form protected benzothiazepine 22. Protected benzothiazepine 22 is then reacted with a suitable nucleophile, such as butyl lithium, in a suitable solvent, such as tetrahydrofuran, to yield 4-alkyl-benzothiazepine 23.
Alternatively, protected benzothiazepine 22 can be reacted with a suitable cyanidating agent, such as an potassium cyanide, in a suitable solvent, such as dimethylformamide, to yield 4-cyano-benzothiazepine 24. 4-Cyano-benzothiazepine 24 is converted to 4-alkoxycarbonyl-benzothiazepine 25 by reaction with a suitable alcohol in the presence of a base, such as potassium hydroxide.

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Scheme 4 illustrates the preparation of benzothiazepine-4-ene 36 and benzothiazepine-4-one 33. Reaction of phenol 26 with a thiocarbamyl chloride, such as dimethylthiocarbamyl chloride, in a solvent, such as methanolaetrahydrofuran yields O-thiocarbamate 27. Heating of O-S thiocarbamate 27 in a solvent, such as tetradecane, yields S-thiocarbamate 28.
Hydrolysis of S-thiocarbamate 28 in the presence of a base, such as sodium hydroxide, in a solvent, such as methanolaetrahydrofuran, yields thiophenol 29. Thiophenol 29 can be treated with a sulfonylating agent, such as sulfonyl chloride, in the presence of a oxidant such as potassium nitrate, in a solvent, 10 such as tetrahydrofuran, to yield sulfonyl chloride 30. Sulfonyl chloride 30 is then reacted with an aminoalcohol in a solvent, such as tetrahydrofuran, to yield benzenesulfonamide 31. Benzenesulfonamide 31 optionally can be hydroxyl protected with a silylating group agent, such as tert-butyldimethylsilyl chloride, in the presence of a base, such as imidazole, in a 15 solvent, such as tetrahydrofuran, to yield protected benzenesulfonamide 32.
Protected benzenesulfonamide 32 can be treated with an alkyl halide, such as methyl iodide, in the presence of a base such as sodium hydride, in a solvent, such as dimethylformamide, to yield N-substituted benzenesulfonamide 33.
Deprotection of the protected N-substituted benzene sulfonamide 33 with a 20 fluoride source, such as tetrabutylammonium fluoride, in a solvent, such as tetrahydrofuran, yields N-substitued benzenesulfonamide 34.
Benzenesulfonamide 31 or N-substituted benzenesulfonamide 34 is then oxidized with a suitable oxidizing agent or under Swern conditions to form aldehyde 35. Upon treatment with zinc and titanium trichloride aldehyde 35 is 25 converted to a mixture of benzothiazepine-4-ene 36 and benzothiazepine-4-one 37.
The recovery, isolation and purification of the intermediates and the reaction products of this invention, and in particular the intermediates and the reaction products illustrated in Schemes 1, 2, 3 and 4, can be accomplished by 30 conventional methods well known to those skilled in the art, such as precipitation, filtration, extraction, or chromatography. Except where otherwise indicated, conditions, solvents, and reagents are either conventional, not narrowly critical, or both.
Additional Embodiments and Examples Another class of compounds of specific interest comprises those compounds of Formula I wherein R' and Rz are selected from among substituted and unsubstituted C,_,o alkyl wherein substituted C,_~o alkyl comprises one or more radicals independently selected from among, for example, alkylcarbonyl, alkoxy, hydroxy, and nitrogen-containing heterocyclyl joined to the C1_~o alkyl through an ether linkage. These R' and RZ
substituents include ethyl, n-propyl, n-butyl, n-pentyl, isobutyl, isopropyl, -CHZC(=O)CZHS, -CHZOCzHS, and -CHZ O-(4-picoline). Ethyl, n-propyl, n-butyl, and isobutyl are preferred. In certain particularly preferred compounds of the present invention, substituents R' and RZ are identical, for example n-butyl/n-butyl, so 1 S that the compound is achiral at the 3-position carbon. Eliminating optical isomerism at the 3-position carbon simplifies the selection, synthesis, separation, and quality control of the compound used as an deal bile acid transport inhibitor.
In the compounds of the present invention having a chiral 3-position carbon as well as those having an achiral 3-position carbon, substituents R"
on the benzo ring can include, for example, hydrogen, aryl, alkyl, hydroxy, halo, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, haloalkyl, haloalkoxy, (N)-hydroxy-carbonylalkylamino, haloalkylthio, haloalkylsulfmyl, haloalkylsufonyl, amino, N-alkylamino, N,N-dialkylamino, (N)-alkoxycarbamoyl, (N)-aryloxycarbamoyl, (N)-aralkyloxycarbamoyl, trialkylammonium (especially with a halide counterion), (N)-amido, (N)-alkylamido, N,N-dialkylamido, (1~-haloalkylamido, (N)-sulfonamido, (N)-alkylsulfonamido, (N)-haloalkylsulfonamido, carboxyalkylamino, trialkylammonium salt, (1~-carbamic acid, alkyl or benzyl ester, N-acylamino, hydroxylamino, haloacylamino, carbohydrate residue, thiophene, a trialkyl ammonium salt having a carboxylic acid or hydroxy substituent on one or more of the alkyl substituents, an alkylene bridge having a quaternary ammonium salt substituted thereon, -[O(CH2)d ] a X where a is 2 to 12, d is 2 or 3 and X is a halo or a quaternary ammonium salt, and (I~-nitrogen containing heterocyclyl wherein the nitrogen of said heterocyclyl is optionally quaternized.
Among the preferred species which may constitute RX are methyl, ethyl, isopropyl, t-butyl, hydroxy, methoxy, ethoxy, isopropoxy, methylthio, iodo, bromo, fluoro, methylsulfinyl, methylsulfonyl, ethylthio, amino, hydroxylamino, N-methylamino, N,N-dimethylamino, N,N-diethylamino, (N)-benzyloxycarbamoyl, trimethylammonium A-, -NHC(=O)CH3, -NHC(=O)CSH,1 , -NHC(=O)C6H13, carboxyethylamino, (I~-morpholinyl, (N)-azetidinyl, (I~-N-methylazetidinium A-, (I~-pyrrolidinyl, pyrrolyl, (N)-N-methylpyridinium A-, (I~-N-methylmorpholinium A-, and N-N'-methylpiperazinyl, (N)-bromomethylamido, (N)-N-hexylamino, thiophene, -N+(CH3)2 COZ H I-, -NCH3 CHZ COZH, -(I~-N'-dimethylpiperazinium I-, (N)-t-butyloxycarbamoyl, (N)-methylsulfonamido, (IAN'-methylpyrrolidinium, and -(OCHZCHZ)31, where A- is a pharmaceutically acceptable anion.
The benzo ring can be mono-substituted at the 6, 7 or 8 position, or disubstituted at the 7- and -8 positions. Also included are the 6,7,8-trialkoxy compounds, for example the 6,7,8-trimethoxy compounds. A variety of other substituents can be advantageously present on the 6, 7, 8, and/or 9- positions of the benzo ring including, for example, guanidinyl, cycloalkyl, carbohydrate residue (e.g., a 5 or 6 carbon monosaccharide residue), peptide residue, and quaternary ammonium salts linked to the ring via poly(oxyalkylene) linkages, e.g., -(OCHZ CH z)X -N+R'3R'4R'SA-, where x is 2 to 10.
In further compounds of the present invention, RS and R6 are independently selected from among hydrogen and ring-carbon substituted or unsubstituted aryl, thiopene, pyridine, pyrrole, thiazole, imidazole, pyrazole, pyrimidine, morpholine, N-alkylpyridinium, N-alkylpiperazinium, N-alkylmorpholinium, or furan in which the substituent(s) are selected from among, for example, halo, hydroxyl, trihaloalkyl, alkoxy, amino, N-alkylamino, N,N-dialkylamino, quaternary ammonium salts, a C, to C4 alkylene bridge having a quaternary ammonium salt substituted thereon, alkoxycarbonyl, aryloxycarbonyl, alkylcarbonyloxy and arylcarbonyloxy, (O,O)-dioxyalkylene, -[O(CHz)a]eX where a is 2 to 12, d is 2 or 3 and x comprises halo or a quaternary ammonium salt, thiophene, pyridine, pyrrole, thiazole, imidazole, pyrazole, or furan. The aryl group of RS or R6 is preferably phenyl, phenylene, or benzene triyl, i.e., may be unsubstituted, mono-substituted, or di-substituted.
Among the species that may constitute the substituents on the aryl ring of RS or R6 are fluoro, chloro, bromo, methoxy, ethoxy, isopropoxy, trimethylammonium (preferably with an iodide or chloride counterion), methoxycarbonyl, ethoxycarbonyl, formyl, acetyl, propanoyl, (N)-hexyldimethylammonium, hexylenetrimethylammonium, tri(oxyethylene)iodide, and tetra(oxyethylene)trimethyl-ammonium iodide, each substituted at the p-position, the m-position, or both of the aryl ring.
Other substituents that can be present on a phenylene, benzene triyl or other aromatic ring includes 3, 4-dioxymethylene (S-membered ring) and 3, 4-dioxyethylene (6-membered ring). One group of compounds of interest are those in which RS or R6 is selected from phenyl, p-fluorophenyl, m-fluorophenyl, p-hydroxyphenyl, m-hydroxyphenyl, p-methoxyphenyl, m-methoxyphenyl, p-N,N-dimethylaminophenyl, m-N, N-dimethylaminophenyl, I- p-(CH3)3-N+-phenyl, I- m-(CH3)3-N+-phenyl, I' m-(CH3)3-N+-CHZCH2-(OCHZCHZ)2-O-phenyl, I- p-(CH3)3-N+-CHZCHZ-(OCHZCHZ)2-O-phenyl, I- m-(N,N-dimethylpiperazinium)-(N')-CHZ-(OCHZCHz)2-O-phenyl, 3-methoxy-4-fluorophenyl, thienyl-2-yl, S-cholorothienyl-2-yl, 3, 4-difluorophenyl, I- p-(N,N-dimethylpiperazinium)-(N')-CHZ-OCHZCHZ)Z-O-phenyl, 3-fluoro-4-methoxyphenyl, 4-pyridinyl, 2-pyridinyl, 3-pyridinyl, N-methyl-4-pyridinium, I- N-methyl-3-pyridinium, 3, 4-dioxymethylenephenyl, 3, 4-dioxyethylenephenyl, and p-methoxycarbonylphenyl.
Preferred compounds include 3-ethyl-3-butyl and 3-butyl-3-butyl compounds having each of the above preferred RS substituents in combination with the RX substituents shown in Tables 1, 2 and 3 below. It is particularly preferred that one, but not both, of RS and R6 is hydrogen.
It is especially preferred that R4 and R6 be hydrogen, that R3 and RS not be hydrogen, and that R3 and RS be oriented in the same direction relative to the plane of the molecule, i.e., both in a- or both in ~3-configuration. It is further preferred that, where RZ is butyl and R' is ethyl, then R' has the same orientation relative to the plane of the molecule as R3 and R5.
A class of compounds of particular interest comprises those 1,2-benzothiazepines wherein the R', R2, R3, R4 and RS radicals are as set forth in Table 1 below; the R6 radical is hydrogen; the RN radical is selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl and benzyl; and the RX radical or radicals are independently selected from the group of R" radicals disclosed in Table 1 below. The first part of Table 1 identifies the R', R2, R3, R4 and RS radicals for each compound and the second part of Table 1 identifies the Rx radical or radicals for those compounds.

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Another class of compounds of particular interest comprises those 1,2-benzothiazepines wherein the R', R2, R3, R4, R5, R6, RN and RX radicals are selected from among the radicals disclosed in Table 2 below. Preferably, R6 is hydrogen and Rs is other than hydrogen; and/or R3 is hydroxy and R4 is S hydrogen; and/or R' and Rz are alkyl. More preferably, R' and RZ are the same.
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R1/R2 R3/R R5/R6 (Rx)q RN

ethyl HO- H 7-methyl H-n-propyl H- Ph- 7-ethyl methyl n-butyl p-F-Ph- 7-iso-propyl ethyl n-pentyl m-F-Ph- 7-tert-butyl n-propyl n-hexyl p-CH30-Ph- 7-OH n-butyl iso-propyl p-HO-Ph- 7-OCH3 n-pentyl iso-butyl m-CH30-Ph- 7-O(iso-propyl) n-hexyl iso-pentyl m-HO-Ph- 7-SCH3 benzyl CH20C2H5 p-(CH3)2N-Ph- 7-SOCH3 CH20-(4- m-(CH3)2N-Ph- 7-S02CH3 picoline) p-H2N-Ph- 7-SCH2CH3 CHZCHZCHZ m-H2N-Ph- 7-NH2 CF3 I-, p-(CH3)3-N+-Ph-7-NHOH

I-, m-(CH3)3-N+-Ph-7-NHCH3 I-~ P-(CH3)3-~- 7-N(CH3)2 CH2CH2- 7-N+(CH3)3, I_ (OCH2CH2)2-O- 7-NHC(O)CH3 Ph- 7-N(CH2CH3)2 I-, m-(CH3)3-N+-7-NMeCH2C02H

CH2CH2- 7-N+(Me)2CH2C02H, (OCH2CH2)2-O- I-Ph- 7-(N)-morpholine I-, p-(N,N-dimethyl-7-(N)-azetidine piperazine)-(N')-7-(I~-N-CHZ- methylazetidinium, (OCH2CH2)2-O- (N)-pyrrolidine Ph- 7-(N)-N-methyl-I-, m-(N,N-dimethyl-pyrrolidinium, I- 7-(N)-piperazine)-(N')-N-methyl-CH2- morpholinium, I-(OCH2CH2)2-O- 7-(N)-N'_ Ph- methylpiperazine m-F, p-CH30-Ph- 7-(N)-N'-3,4,dioxymethylene-Phdimethylpiperazinium, I-m-CH30-, p-F-Ph-7-NH-CBZ

4-pyridine 7-NHC(O)CSH 11 N-methyl-4-pyridinium,7-NHC(O)CH2Br I 7-NH-C(NH)NH2 3-pyridine 7-(2)-thiophene N-methyl-3-pyridinium,8-methyl I- 8-ethyl 2-pyridine 8-iso-propyl p-CH302C-Ph- 8-tent-butyl thienyl-2-yl 8-OH

5-Cl-thienyl-2-yl8-OCH3 R1/R2 R3/R R5/R6 (Rx)q Rrv 8-O(iso-propyl) 8-N(CH3)2 8-N+(CH3)3~ I_ 8-NHC(O)CH3 8-N(CH2CH3)2 8-NMeCH2C02H

8-N+(Me)2CH2C02H, I-8-(N)-morpholine 8-(N)-azetidine 8_~_N_ methylazetidinium, I-8-(N)-pyrrolidine 8-(N)-N-methyl-pyrrolidinium, I- 8-(N)-N-methyl-morpholinium, I-g_(N)_N~_ methylpiperazine g_(N)_~r~_ dimethylpiperazinium, I-8-NHC(O)CgHl l 8-NHC(O)CH2Br 8-NH-C(NH)NH2 8-(2)-thiophene 9-methyl 9-ethyl 9-iso-propyl 9-tert-butyl 9-O(iso-propyl) 9-N+(Me)2CH2C02H, I' R1/R2 R3/R RS/R6 (RR)9 9-N(CH3)2 9-N+(CH3)3~
I_ 9-NHC(O)CH3 9-N(CH2CH3)2 9-NMeCH2C02H

9-(N)-morpholine 9-(N)-azetidine 9-(N)-N-methylazetidinium, I-9-(N)-pyrrolidine 9-(N)-N-methyl-pyrrolidinium, I- 9-(N)-N-methyl-morpholinium, I' 9-(N)-N'-methylpiperazine 9-(N)-N'-dimethyl-piperazinium, I' 9-NHC(O)CSH11 9-NHC(O)CH2Br 9-NH_C(NH)NH2 9-(2)-thiophene 7-OCH3, 8-OCH3 7-SCH3, 8-OCH3 7-SCH3, 8-SCH3 6-OCH3, 7-OCH3, Another class of compounds of particular interest comprises those 1,2-benzothiazepines wherein the R', Rz, R3, R4 and RS radicals are as set forth in Table 3 below; R6 is hydrogen; the RN radical is selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl and benzyl; and the R" radical or radicals are independently selected from the group of RX radicals disclosed in Table 2 above. In one embodiment of the compounds of Table 3, for example, q is 1 and RX is 7-dimethylamino.

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x x x x zx o x x x Zx zx x x zx zx zx x x x .~ ~ D
x x x x x x x x x zx o zx ~ zx ~
x x x zx zx zx x x x x x x x x x zx ' x zx x x N
~rll Another group of compounds of interest consists of those compounds of Formula I wherein R' and RZ are alkyl, preferably n-butyl; R3 is hydroxy;
R4 and R6 are hydrogen; RN is hydrogen; Rx radicals are selected from the group consisting of amino, dimethylamino and methoxy; and RS is phenyl substituted at the para or meta position with one of the following groups:
~O
Cl- N+
'C02H
/O N ~C02H
~C02H .
/0~0~ N ~C02H ' H
N
O NH
N~ ;
O
O ~ -O-S-Me O

N
\O / \N ;
HN-N
\O

+NEt3 O ;
\O -O-S-Me O
\O~R~O~ R= 1000 MW PEG
2Q ;
~N~
O
-S
-p o O ~ O ~ / Me .N

° ~ ~
N ~C02H ' \O ~ O
N+ -O"CF3 / \
O
\ P~\ H
O OH
\O~O~O~+NEt3 H
N ~C02H
O
IO
N_-N
\O S N, N
~C02H

\O N~ N~C02H
/

\O N+ \
O
-O-S-Me ~ /
O
OH
H
/N / 'O
1 _O ~~ ~
N+ O~Me \O

/ /
~N
O
() \N~ ~~\N~C02H
O

O
c~-\ ~N+ v H
and O ~NH NH
w0~ N ~~~ H
H N ~ M\
NH NH
wherein M is selected from the group consisting of CoII, Conl, Mnn, ~III~ FeII, FeIIh Nlll, NllIh Ct II, Cll~, ZnII, CdII, GaIIh III' VIVA RuII, PtIV, RhIII
and Irlu Dosages. Formulations, and Routes of Administration The deal bile acid transport inhibitor compounds of the present invention can be administered for the prophylaxis andlor treatment of hyperlipidemic diseases, conditions and/or disorders by any means, preferably oral, that contacts these compounds with their site of action in the body, for example in the ileum of a mammal such as a human.
For the prophylaxis and/or treatment of the diseases, conditions and/or disorders referred to above, the compounds of the present invention can be used as the compound per se. Pharmaceutically acceptable salts are particularly suitable for medical applications because of their greater aqueous solubility relative to the parent compound. Such salts comprise a pharmaceutically acceptable anion or canon. Suitable pharmaceutically acceptable acid addition salts of the compounds of the present invention where appropriate include those salts derived from inorganic acids, such as hydrochloric, hydrobromic, phosphoric, metaphosphoric, nitric, sulfonic, and sulfuric acids, and organic acids such as acetic, benzenesulfonic, benzoic, citric, ethanesulfonic, fumaric, gluconic, glycolic, isothionic, lactic, lactobionic, malefic, malic, methanesulfonic, succinic, toluenesulfonic, tartaric, and trifluoroacetic acids. The chloride salt is particularly preferred for medical purposes. Suitable pharmaceutically acceptable base salts where appropriate 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 pharmaceutically acceptable anions such as those anions selected, for example, from the above list.
The compounds of the present invention also can be administered in the form of a pharmaceutical composition comprising additional ingredients such as acceptable Garners, diluents, excipients, adjuvants and the like (collectively referred to herein as "carrier materials"). Acceptable Garner materials are compatible with the other ingredients of the composition and are not deleterious to the recipient. A carrier material 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 or capsule, which can contain from 0.05%
to 95% by weight of the active compound. Other pharmacologically active substances can also be present, including other compounds of the present invention. The pharmaceutical compositions of the invention can be prepared by any of the well known techniques of pharmacy, consisting essentially of admixing the components.
These compounds can be administered by any conventional means available for use in conjunction with pharmaceuticals, either as an individual therapeutic compound in a monotherapeutic regimen or as a combination of therapeutic compounds in a combination therapy regimen.
The amount of compound that is required to achieve the desired biological effect will depend on a number of factors such as the specific compound chosen, the use for which it is intended, the mode of administration, and the clinical condition of the recipient.
In general, a daily dose can be in the range of from about 0.3 to about 100 mg/kg bodyweight/day, preferably from about 1 mg to about SO mglkg bodyweight/day, and more preferably from about 3 to about 10 mg/kg bodyweight/day. This total daily dose can be administered to the patient in a single dose, or in proportionate multiple subdoses. Subdoses can be administered 2 to 6 times per day. Doses can be in sustained release form effective to obtain desired results.
Orally administrable unit dose formulations, such as tablets or capsules, can contain, for example, from about 0.1 to about 100 mg of benzothiazepine compound, preferably about 1 to about 75 mg of compound, more preferably from about 10 to about 50 mg of compound. In the case of pharmaceutically acceptable salts, the weights indicated above refer to the weight of the benzothiazepine ion derived from the salt.
Oral delivery of an ileal bile acid transport inhibitor of the present invention can include formulations, as are well known in the art, to provide prolonged or sustained delivery of the drug to the gastrointestinal tract by any number of mechanisms. These include, but are not limited to, pH sensitive release from the dosage form based on the changing pH of the small intestine, slow erosion of a tablet or capsule, retention in the stomach based on the physical properties of the formulation, bioadhesion of the dosage form to the mucosal lining of the intestinal tract, or enzymatic release of the active drug from the dosage form. The intended effect is to extend the time period over which the active drug molecule is delivered to the site of action (the ileum) by manipulation of the dosage form. Thus, enteric-coated and enteric-coated controlled release formulations are within 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 can, for example, be in the range of from about 0.1 mg/kg body weight to about 1.0 mg/kg body weight, preferably from about 0.25 mg/kg body weight to about 0.75 mg/kg body weight, and more preferably from about 0.4 mg/kg body weight to about 0.6 mg/kg body weight. This dose can be conveniently administered as an infusion of from about 10 ng/kg body weight to about 100 ng/kg body weight per minute. Infusion fluids suitable for this purpose can contain, for example, from about 0.1 ng to about 10 mg, and preferably from about 1 ng to about 10 mg per milliliter. Unit doses can contain, for example, from about 1 mg to about 10 g of the compound of the present invention. Thus, ampoules for injection can 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., sublingual), and parenteral (e.g., subcutaneous, intramuscular, intradermal, or intravenous) administration, although the most suitable route in any given case will depend on the nature and severity of the condition being treated and on the nature of the particular compound which is being used. In most cases, the preferred route of administration is oral.
Pharmaceutical compositions suitable for oral administration can be presented in discrete units, such as capsules, cachets, 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 a suspension in an aqueous or non-aqueous liquid; or as an oil-in-water or water-in-oil emulsion. As indicated, such compositions can be prepared by any suitable method of pharmacy which includes the step of bringing into association the active compounds) and the Garner material (which can constitute one or more accessory ingredients). In general, the compositions are prepared by uniformly and intimately admixing the active compound with a liquid or finely divided solid Garner material, or both, and then, if necessary, shaping the product. For example, a tablet can be prepared by compressing or molding a powder or granules of the compound, optionally with one or more assessory ingredients. Compressed tablets can be prepared by compressing, in a suitable machine, the compound in a free-flowing form, such as a powder or granules optionally mixed with a binder, lubricant, inert diluent and/or surface active/dispersing agent(s). Molded tablets can be made by molding, in a suitable machine, the powdered compound moistened with an inert liquid diluent.
Pharmaceutical compositions suitable for buccal (sub-lingual) administration include lozenges comprising a compound of the present invention in a flavored base, usually sucrose, and acacia or tragacanth, and pastilles comprising 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 admixing the compound with water and rendering the resulting solution sterile and isotonic with the blood. Injectable compositions according to the invention will generally contain from 0.1 to 5%
w/w of a compound disclosed herein.
Pharmaceutical compositions suitable for rectal administration are preferably presented as unit-dose suppositories. These can be prepared by admixing a compound of the present invention with one or more conventional solid Garner materials, for example, cocoa butter, and then shaping the resulting mixture.
Pharmaceutical compositions suitable for topical application to the skin preferably take the form of an ointment, cream, lotion, paste, gel, spray;
aerosol, or oil. Carner materials that can be used include vaseline, lanoline, polyethylene glycols, alcohols, and combinations of two or more thereof. The active compound is generally present at a concentration of from 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 can be presented as discrete patches adapted to remain in intimate contact with the epidermis of the recipient for a prolonged period of time. Such patches suitably contain a compound of the present invention in an optionally buffered, 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%. As one particular possibility, the compound can be delivered from the patch by electrotransport or iontophoresis, for example, as described in Pharmaceutical Research, 3(6), 318 (1986).
In any case, the amount of active ingredient that can be combined with the carrier materials to produce a single dosage form to be administered will vary depending upon the host treated and the particular mode of administration.
The solid dosage forms for oral administration including capsules, tablets, pills, powders, and granules noted above comprise one or more compounds of the present invention admixed with at least one inert diluent such as sucrose, lactose, or starch. Such dosage forms may also comprise, as in normal practice, additional substances other than inert diluents, e.g., lubricating agents such as magnesium stearate. In the case of capsules, tablets, and pills, the dosage forms may also comprise buffering agents. Tablets and pills can additionally be prepared with enteric coatings.
Liquid dosage forms for oral administration can 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 wetting agents, emulsifying and suspending agents, and sweetening, flavoring, and perfuming agents.
Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing or setting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables.
Pharmaceutically acceptable Garner materials encompass all the foregoing and the like.
Treatment Re ig'men The dosage regimen to prevent, give relief from, or ameliorate a disease, condition and/or disorder relating to hyperlipemia, e.g., atherosclerosis, or to protect against or treat further high cholesterol plasma or blood levels with the compounds and/or compositions of the present invention is selected in accordance with 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 employed, whether a drug delivery system is utilized, and whether the compound is administered as part of a drug combination.
Thus, the dosage regimen actually employed may vary widely and therefore deviate from the preferred dosage regimen set forth above.
Initial treatment of a patient suffering from a hyperlipidemic condition can begin with the dosages indicated above. Treatment should generally be continued as necessary over a period of several weeks to several months or years until the hyperlipidemic disease condition has been controlled or eliminated. Patients undergoing treatment with the compounds or compositions disclosed 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 therapy. Continuous analysis of such data permits modification of the treatment regimen during therapy so that optimal effective amounts of compounds of the present invention are administered at any point in time, and so that the duration of treatment can be determined as well. In this way, the treatment regimen/dosing schedule can be rationally modified over the course of therapy so that the lowest amount of ileal bile acid transport inhibitor of the present invention which exhibits satisfactory effectiveness is administered, and so that administration is continued only so long as is necessary to successfully treat the hyperlipidemic condition.
The following non-limiting examples serve to illustrate various aspects of the present invention.
Examples of Synthetic Procedures The starting materials used in the preparation of the compounds of the following examples, as well as other compounds of the present invention, are commercially available or can be prepared by conventional methods known to one of ordinary skill in the art or in an analogous manner to conventional methods described in the art. The starting materials of the following examples were obtained from commercial sources unless otherwise noted. The ethyl 2-amino-2-butylhexanoate hydrochloride used below was prepared in an analogous manner to the literature method of Stork (J. Org. Chem. 41, 3491 (1976)).
Example 1 (4R,SR)-3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-2-methyl-S-(3-nitrophenyl)-1,2-benzothiazepin-4-of 1,1-dioxide O O
S _N
~ /
N
OH
N~ O
\ O
Step 1. 2-Amino-2-butylhexanol NHZ
H O ~/~~
Bu Bu To a solution of 29.75 g (0.12 mol) of ethyl 2-amino-2-butylhexanoate hydrochloride in 100 mL of tetrahydrofuran cooled to -20 °C was added 148.8 mL of a 1.0 M solution of lithium aluminum hydride in tetrahydrofuran while maintaining a temperature below -15 °C. The reaction mixture was stirred for one hour at -20 °C, warmed to room temperature and stirred for 16 hours. The reaction mixture was then cooled to -20 °C and 6 mL of water was added, followed by 5.6 mL of 3.75 M aqueous sodium hydroxide and 16 mL of water.
The reaction mixture was stirred for one hour and warmed to room temperature. The resulting slurry was filtered and washed with 100 mL ethyl acetate. The ethyl acetate solution was washed with water (2x200 mL) and then brine (300 mL). The ethyl acetate layer was dried over magnesium sulfate and concentrated. The resulting yellow oil was dissolved in 300 mL of tetrahydrofuran and concentrated to give 20.61 g of 2-amino-2-butylhexanol as an oil.
Step 2. N [1-Butyl-1-(hydroxymethyl)pentyl]-4-fluorobenzenesulfonamide B° Bu SOZNH
OH
F
To a solution of 16.95 g (0.09 mol) of 4-fluorobenzene sulfonyl chloride in 150 mL of tetrahydrofuran was added 36.4 mL of triethylamine.
The reaction mixture was cooled to 0 °C and a solution of 19.61 g of 2-amino-2-butylhexanol (prepared in step 1 above) in 70 mL of tetrahydrofuran was added. The reaction mixture was stirred 30 minutes at 0 °C and then 16 hours at room temperature. The reaction mixture was concentrated and then the residue was dissolved in 250 mL of ethyl acetate. This ethyl acetate solution was washed with water (2 x 200 mL) and brine (300 mL). The ethyl acetate layer was dried over magnesium sulfate and concentrated to give 29.47 g of N
[1-butyl-1-(hydroxymethyl)pentyl]-4-fluorobenzenesulfonamide as an oil.

Step 3. N (1-Butyl-1-(hydroxymethyl)pentyl]-4-(dimethylamino) benzenesulfonamide Bu gu S OZN li ON
~N
A solution containing 28.89 g (0.09 mol) of the oil prepared in Step 2 above, 872 mL of 2.0 M dimethylamine in tetrahydrofuran and 100 mL of neat dimethylamine was prepared and placed in a bomb. The reaction mixture was heated to 110 °C for 16 hours, cooled, and then concentrated to give 25.46 g of N [1-butyl-1-(hydroxymethyl)pentyl]-4-(dimethylamino)benzenesulfonamide as an solid.
Step 4. N [1-Butyl-1-[[[(1,1-dimethylethyl)dimethylsilyl]oxy]methyl]pentyl]-4-(dimetliylamino)benzenesulfonamide Bu gu S OZN N
OTBDMS
~N
To a solution of 15.51 g (0.10 mol) of t-butyldimethylsilyl chloride in 158 mL of dimethylformamide was added 24.46 g (0.07 mol) of the solid prepared in Step 3 and then 14.01 g of imidazole. The reaction mixture was stirred 3 days and then diluted with 1 L of ethyl acetate and 500 mL of water.
The ethyl acetate solution was washed with 5% hydrochloric acid solution (2 x 200 mL), water (200 mL) and then brine (200 mL). The ethyl acetate layer was dried with magnesium sulfate and concentrated to an oil. The oil was stirred with hexane and the resulting solid was filtered to give 25.31 g of N
[ 1-butyl-1-[[[( 1,1-dimethylethyl)dimethylsilyl]oxy]methyl]pentyl]-4-(dimethylamino)benzenesulfonamide as a white solid.
Step 5. N [1-Butyl-1-[[[(l,ldimethylethyl)dimethylsilyl]oxy]methyl]pentyl]-4-(dimethylamino)-N methylbenzenesulfonamide Bu Bu OTBDMS
'N
To a solution of 0.476 g (11.90 mmol) of 60% sodium hydride dispersion in mineral oil in 43 mL of tetrahydrofuran was added 4.0 g (8.50 mmol) of the solid prepared in Step 4 above and then 1.6 mL of dimethyl sulfate dropwise. The reaction mixture was heated at reflux for one hour, cooled to 0 °C, and then water was added. The reaction mixture was concentrated and 250 mL ethyl acetate and 250 mL water added. The layers were separated and the ethyl acetate solution was washed with 1 M
hydrochloric acid (2 x 200 mL), saturated sodium bicarbonate (2 x 200 mL), water (200 mL) and then brine (200 mL). The ethyl acetate layer was dried over magnesium sulfate and concentrated to give 4.63 g of a residue. The residue was purified by flash chromatography with 15% ethyl acetate/hexane as eluent to give 3.35 g ofN [1-butyl-1-[[[(l,ldimethylethyl) dimethylsilyl]
oxy]methyl]pentyl]-4-(dimethylamino)-N methylbenzenesulfonamide as an oil.

Step 6.
Bu Bu OTBDMS
1N B(OH)2 To a solution of 3.35 g (6.90 mmol) of the oil prepared in Step 5 above in 35 mL of tetrahydrofuran cooled to 0 °C was added dropwise 9.66 mL
of 1.6 M n-butyllithium in hexanes. The reaction mixture was stirred 30 minutes at 0 °C, warmed to room temperature, and stirred one hour. To the reaction mixture was added 6.5 mL of 5% hydrochloric acid and then the Tetrahydrofuran was evaporated. To the residue was added 200 mL
dichloromethane and 200 mL water and the layers separated. The dichloromethane layer was washed with brine (200 mL), dried over magnesium sulfate and concentrated to give 3.12 g of a yellow solid.
Step 7. N [1-Butyl-1-[[[(1-dimethylethyl)dimethylsilyl]oxy]methyl]pentyl]-4-(dimethylamino)-2-[(3-nitrophenyl)methyl]-N methylbenzenesulfonamide I B° Bu OTBDMS
~N
NOZ
To a solution of 130 mg (0.11 mmol) of tetrakis(triphenylphosphine) palladium(0) in 10 mL of toluene was added 825 mg of 3-nitrobenzyl bromide. After the toluene solution was stirred 10 minutes, a degassed solution of 2.02 g (3.82 mmol) of the solid prepared in Step 6 above in 8 mL
ethanol was added followed by 10 mL of 1 M sodium carbonate. The reaction mixture was heated at reflux 45 minutes and then cooled and concentrated. To S the residue was added 250 mL of ethyl acetate. The ethyl acetate mixture was washed with brine (2 x 200 mL), dried over magnesium sulfate and concentrated to give 2.76 g of a residue. To the residue was added 200 mL of 30% ethyl acetate in hexane, and the mixture was stirred 1.5 hours and then filtered through silica. The ethyl acetate solution was concentrated to give 2.30 g ofN [1-butyl-1-[[[(1-dimethylethyl)dimethylsilyl]oxy]methyl]pentyl]-4-(dimethylamino)-2-[(3-nitrophenyl)methyl]-N methylbenzenesulfonamide as a yellow solid.
Step 8. N [1-Butyl-1-(hydroxymethyl)pentyl]-4-(dimethylamino)-2-[(3-nitrophenyl)methyl]-N methylbenzenesulfonamide Bu gu SOZN
OH
~N

To a solution of 2.16 g (3.48 mmol) of the solid prepared in Step 7 above in 10 mL of tetrahydrofuran cooled to 0 °C was added 4.4 mL of 1 M
tetrabutylammonium fluoride in tetrahydrofuran. The reaction mixture was stirred 15 minutes at 0 °C and then 12 hours at room temperature. To the reaction mixture was added 250 mL of ethyl acetate. The ethyl acetate solution was washed with water (200 mL) and brine (200 mL). The ethyl acetate layer was dried over magnesium sulfate and concentrated to give 1.88 g of a brown oil residue. The residue was purified by flash chromatography with 30% ethyl acetate in hexane as eluent to give 1.49 g of N [1-butyl-1-(hydroxymethyl)pentyl]-4-(dimethylamino)-2-[(3-nitrophenyl)methyl]-N
S methylbenzenesulfonamide as a yellow oil.
Step 9. N [1-Butyl-1-formylpentyl]-4-(dimethylamino)-2-[(3-nitrophenyl) methyl]-N methylbenzenesulfonamide.
Bu Bu S02N -~
CHO
~N
NOZ
To a solution of 1.49 g (2.95 mmol) of the oil prepared in Step 8 above in 10 mL of dimethylsulfoxide was added 1.23 mL of triethylamine and then 1.41 g of sulfur trioxide pyridine complex. The reaction mixture was stirred one hour and then diluted with 200 mL water. The aqueous mixture was washed with ethyl acetate (3 x 100 mL). The combined organic layers were washed with 5% hydrochloric acid (100 mL) and brine (100 mL). The ethyl acetate layer was dried over magnesium sulfate and concentrated. The residue was purified by flash chromatography with 25% ethyl acetate in hexane as eluent to give 1.31 g ofN [1-butyl-1-formylpentyl]-4-(dimethylamino)-2-[(3-nitrophenyl)methyl]-N methylbenzenesulfonamide as a yellow oil.
Step 10. (4R,SR)-3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-2-methyl-5-(3-nitrophenyl)-1,2-benzothiazepin-4-of 1,1-dioxide To a solution of 504 mg (2.60 mmol) of the oil prepared in Step 9 above in 50 mL of tetrahydrofuran cooled to 0 °C was added 2.80 mL of 1 M
potassium t-butoxide in tetrahydrofuran. The reaction mixture was stirred for 1 S minutes, water was added, and then the mixture was concentrated to yield a residue. The residue was dissolved in 100 mL ethyl acetate. The ethyl acetate solution was washed with water (100 mL) and brine (100 mL). The ethyl acetate layer was dried over magnesium sulfate and concentrated to give 1.25 g of a semi-solid. The residue was purified by crystallization with ethyl acetate and hexane to give 737.5 mg of (4R,SR)-3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-2-methyl-5-(3-nitrophenyl)-1,2-benzothiazepin-4-of 1,1-dioxide as a yellow crystalline solid.'H NMR
(CDCl3) b 0.90-1.00 (m, 6H), 1.05-1.80 (m, 12H), 2.50-2.60 (m, 1H), 2.79 (s, 6H), 2.85 (s, 3H), 4.09 (d, J= 9.0 Hz, 1H), 5.76 (d, J= 2.0 Hz, 1H), 5.88 (s, 1H), 6.53 (dd, J= 2.4, 8.9 Hz, 1H), 7.59 (t, J= 7.9 Hz, 1H), 7.84-7.88 (m, 2H), 8.22 (dd, J= 1.0, 8.1 Hz, 1H), 8.47 (s, 1H). MS (M+H+) 504.
Example 2 (4R,SR)-5-(3-aminophenyl)-3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-2-methyl-1,2-benzothiazepin-4-of 1,1-dioxide O
S'N
N
OH

A solution of 737 mg (1.46 mmol) of the solid prepared in Step 10 of Example 1 was dissolved in 110 mL of ethanol in a 3 oz. Fisher/Porter vessel, and about 1 SO mg of 10% PdIC catalyst was added. This mixture was hydrogenated at 40 psi HZ for 20 hours and then filtered. The filtrate was concentrated to give 0.82 g of a semi-solid material. The semi-solid material was crystallized from ethyl acetate and hexane to give 0.51 g of (4R,SR)-5-(3-aminophenyl)-3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-2-methyl-1,2-benzothiazepin-4-of 1,1-dioxide as colorless crystals.'H NMR (CDCl3) 8 0.89 (t, J= 6.6 Hz, 3H), 0.92 (t, J= 7.2 Hz, 3H), 1.10-1.45 (m, 8H), 1.60-1.75 (m, 3H), 1.98-2.10 (m, 1H), 2.48-2.58 (m, 1H), 2.79 (s, 6H), 2.81 (s, 3H), 3.69 (s, 2H), 4.12 (d, J = 7. 8 Hz, 1 H), 5 :62 (s, 1 H), 6.07 (d, J = 2.1 Hz, 1 H), 6.46 (dd, J = 2.4, 8. 7 Hz, 1 H), 6. 61 (br d, J = 7. 8 Hz, 1 H), 6. 8 0 (br s, 1 H), 6.
8 9 (br d, J
= 2.1 Hz, 1 H), 7.1 S (t, J = 7. 8 Hz, 1 H), 7.79 (d, J = 8.7 Hz, 1 H). MS
(M+H+) 474.
Example 3 5-bromo-N [3-[(4R,SR)-3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-4-hydroxy-2-methyl-1,1-dioxido-1,2-benzothiazepin-S-yl]phenyl]pentanamide O~~ i O
S'N
~N
\ OH
O
N Br H
To a solution of 0.25 g (0.53 mmol) of the solid prepared in Example 2 above in 3 mL of tetrahydrofuran was added 153 pL of triethylamine followed by 86 pL of 5-bromovaleryl chloride. The reaction mixture was stirred one hour and then concentrated to form a residue. Water (50 mL) was added to the residue. The aqueous solution was extracted with ethyl acetate (2 x 50 mL).
The combined ethyl acetate layers were washed with 5% hydrochloric acid (2 x 25 mL), saturated sodium bicarbonate solution (2 x 25 mL) and brine (25 mL). The ethyl acetate layer was dried over magnesium sulfate and concentrated to give 0.29 g of a solid. The solid was purified by crystallization with ethyl acetate and hexane to give 202.3 mg of 5-bromo-N
[3-[(4R,SR)-3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-4-hydroxy-2-methyl-1,1-dioxido-1,2-benzothiazepin-5-yl]phenyl]pentanamide as a tan solid. 'H NMR (CDC13) b 0.88 (t, J= 7.2 Hz, 3H), 0.92 (t, J= 6.9 Hz, 3H), 1.20-1.42 (m, 8H), 1.57-2.10 (m, 8H), 2.37 (t, J= 6.9 Hz, 2H), 2.46-2.57 (m, 1H), 2.78 (s, 6H), 2.81 (m, 3H), 3.41 (t, J= 6.3 Hz, 2H), 4.10 (d, J= 8.5 Hz, 1 H), 5.69 (s, 1 H), 5.97 (s, 1 H), 6.47 (dd, J = 2.4, 8.9 Hz, 1 H), 7.24-7.40 (m, 4H), 7.76 (br s, 1H), 7.80 (d, J= 8.7 Hz, 1H). MS (M+H+) 636, 638.
Example 4 5-[[3-[(4R,SR)-3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-4-hydroxy-2-methyl-1,1-dioxido-1,2-benzothiazepin-5-yl]phenyl]amino]-N,N,N triethyl-5-oxo-pentanaminium trifluoroacetate O
O
S'N
N
OH
O
N N
H

To a solution of 100 mg (0.16 mmol) of the solid prepared in Example 3 above in 1 mL of acetonitrile was added 87 ~L of triethylamine. The reaction mixture was heated at 55 °C for 28 hours and then at 75 °C for 16 hours. The reaction mixture was concentrated to form a residue. The residue was purified by reverse phase high pressure liquid chromatography to give 16.2 mg of 5-[[3-[(4R,SR)-3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-4-hydroxy-2-methyl-1,1-dioxido-1,2-benzothiazepin-5-yl]phenyl]amino]-N,N,N triethyl-5-oxo-pentanaminium trifluoroacetate as a white solid. 'H NMR was consistent with the product. MS (M+) 657:
Example 5 2-chloro-N [3-[(4R,SR)-3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-4-hydroxy-2-methyl-l,1-dioxido-1,2-benzothiazepin-5-yl]phenyl]acetamide Ov i O
S'N
N .,, OH
O
~CI
N
H
To a solution of 100 mg (0.21 mmol) of the solid prepared in Example 4 above in 2 mL of tetrahydrofuran was added 29 mg of bromoacetic acid, 29 ~L of triethylamine, and then 40 mg of ethyldimethylaminopropylcarbodiimide hydrochloride. The reaction mixture was stirred 16 hours and then 50 mL ethyl acetate was added. The ethyl acetate solution was washed with water, 5% hydrochloric acid (2 x 25 mL), saturated sodium bicarbonate solution (2 x 25 mL), and then brine (25 mL).
The ethyl acetate layer was dried over magnesium sulfate and then concentrated to give 88 mg of an oil. The oil was purified by flash chromatography with 50% ethyl acetate in hexane as eluent to give 72.0 mg of cis-3,3-dibutyl-2,3,4,5-tetrahydro-4-hydroxy-2-methyl-7-dimethylamino-5-(3-(2-chloroaceamido)phenyl)-1,2-benzothiazepine with a trace of 2-chloro-N [3-((4R,5R)-3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-4-hydroxy-2-methyl-1,1-dioxido-1,2-benzothiazepin-5-yl]phenyl]acetamide present.'H
NMR was consistent with the product. MS (M+H+) 550.

Example 6 2-[[3-[(4R,SR)-3,3-dibutyl-7-(dimethylamino]-2,3,4,5-tetrahydro-4-hydroxy-2-methyl-1,1-dioxido-1,2-benzothiazepin-5-yl]phenyl]amino]-N,N,N triethyl-2-oxoethanaminium chloride Ov i O
S -N
.,, ~N
\ OH
O
+~
N N
H
c ~' To a mixture of 63 mg (0.12 mmol) of the material prepared in Example 5 above in 1 mL of tetrahydrofuran was added 64 pL of triethylamine. The reaction mixture was heated to reflux for three days and then concentrated. The residue was triturated with ether to give 66.5 mg of 2-[[3-[(4R,SR)-3,3-dibutyl-7-(dimethylamino]-2,3,4,5-tetrahydro-4-hydroxy-2-methyl-1,1-dioxido-1,2-benzothiazepin-5-yl]phenyl]amino]-N,N,N triethyl-2-oxoethanaminium chloride as a tan solid. 'H NMR was consistent with the product. MS (M+) 61 S.
Example 7 (4R,SR)-3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-5-(4-methoxyphenyl)-2-methyl-1,2-benzothiazepin-4-oll,l-dioxide Ov ii S _ N
y _ N
\ OH
O
Step 1. N [1-Butyl-1-[[[(1-dimethylethyl)dimethylsilyl]oxy]methyl]pentyl]-4-(dimethylamino)-2-[(4-methoxyphenyl)methyl]-N methylbenzenesulfonamide Bu Bu \ S02N
OTBDMS
~N U
O
To a solution of 1.00 g (2.06 mmol) of the material from Step S of Example 1 above in 10 mL of tetrahydrofuran cooled to 0 °C was added 2 mL
of 1.6 M n-butyllithium in hexanes. The reaction mixture was stirred one hour at 0 °C. To the reaction mixture was added 480 uL of trimethyl borate and the mixture stirred 15 minutes at 0 °C and then one hour at room temperature.
The reaction mixture was concentrated to form a residue. The residue was dissolved in 20 mL of toluene and 2.1 mL of 2 M aqueous sodium carbonate.

To the mixture was added 300 pL ofp-methoxybenzyl chloride and then 71 mg of tetrakis(triphenylphosphine)palladium(0). The reaction mixture was heated at 100 °C for 16 hours, cooled, and then 50 mL of toluene added.
The reaction mixture was washed with water (50 mL) and brine (50 mL), filtered through silica, and concentrated to form a residue. The residue was purified by flash chromatography to give 0.82 g ofN [1-butyl-1-[[[(1-dimethylethyl)dimethylsilyl]oxy]methyl]pentyl]-4-(dimethylamino)-2-[(4-methoxyphenyl)methyl]-N methylbenzenesulfonamide as an oil.
Step 2. N [1-Butyl-1-(hydroxymethyl)pentyl)-4-(dimethylamino)-2-[(4-methoxyphenyl)methyl]-N methylbenzenesulfonamide Bu SOaN
OH
~' N U
O
The procedure of Step 8 of Example 1 above was followed except that N [1-butyl-1-[[[(1-dimethylethyl)dimethylsilyl]oxy]methyl]pentyl]-4-(dimethylamino)-2-[(4-methoxyphenyl)methyl]-N methylbenzenesulfonamide was used in place ofN [1-butyl-1-[[[(1-dimethylethyl)dimethylsilyl]oxy]
methyl]pentyl]-4-(dimethylamino)-2-((3-nitrophenyl)methyl]-N
methylbenzenesulfonamide.

Step 3. N [1-Butyl-1-formylpentyl]-4-(dimethylamino)-2-[(4-methoxyphenyl) methyl]-N methylbenzenesulfonamide Bu gu \ SOZN
CHO
'N
O
The procedure of Step 9 of Example l above was followed except that N [1-butyl-1-(hydroxymethyl)pentyl]-4-(dimethylamino)-2-[(4-methoxyphenyl)methyl]-N methylbenzenesulfonamide was used in place of N
[ 1-butyl-1-(hydroxymethyl)pentyl]-4-(dimethylamino)-2-[(3-nitrophenyl)methyl]-N methylbenzenesulfonamide.
Step 4. (4R,SR)-3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-5-(4-methoxyphenyl)-2-methyl-1,2-benzothiazepin-4-of 1,1-dioxide The procedure of Step 10 of Example 1 above was followed except that N [1-butyl-1-formylpentyl]-4-(dimethylamino)-2-[(4-methoxyphenyl)methyl]-N methylbenzenesulfonamide was used in place of N
[ 1-butyl-1-formylpentyl]-4-(dimethylamino)-2-[(3-nitrophenyl)methyl]-N
methylbenzenesulfonamide.
'H NMR (CDCl3) 8 0.83-0.96 (m, 6H), 1.15-1.38 (m, 6H), 1.69-1.83 (m, 4H), 2.00-2.08 (m, 1H), 2.55-2.59 (m, 1H), 2.81 (s, 6H), 2.83 (s, 3H), 3.84 (s, 3H), 4.10-41.6 (m, 1H), 5.70 (s, 1H), 5.99 (s, 1H), 6.52 (s, 1H), 6.93 (d, J= 8.6 Hz, 2H), 7.43 (d, J= 8.4 Hz, 2H), 7.83 (d, J= 8.6 Hz).
Example 8 (4R,SR)-3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-5-(4-hydroxyphenyl)-2-methyl-1,2-benzothiazepin-4-of l, l-dioxide Ov i O /
S'N
/ ~
_N
\ OH
OH
To a solution of 0.52 g (1.06 mmol) of the solid prepared in Step 4 of Example 7 above in 10 mL of dichloromethane cooled to -78 °C was added 300 ~L of boron tribromide. The reaction mixture was stirred for one hour at -78 °C and then 100 mL of water and 100 mL of dichloromethane were added.
The dichloromethane solution was washed with 10% aqueous sodium carbonate(100 mL), 10% hydrochloric acid (100 mL) and brine (100 mL).
The dichloromethane layer was dried over magnesium sulfate and concentrated to give 0.46 g of (4R,SR)-3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-5-(4-hydroxyphenyl)-2-methyl-1,2-benzothiazepin-4-oll,l-dioxide as a solid. 'H NMR (CDC13) 8 0.82-0.97 (m, 6H), 1.15-1.40 (m, 6H), 1.67-1.76 (m, 4H), 2.00-2.10 (m, 1H), 2.51-2.59 (m, 1H), 2.83 (s, 6H), 2.84 (s, 9H), 4.12 (d, J= 8.0 Hz, 1H), 4.88 (br s, 1H), 5.69 (s, 1H), 6.07 (d, J= 2.2 Hz, 1H), 6.60 (dd, J= 2.2, 8.6 Hz, 1H), 6.88 (d, J= 8.6 Hz, 2H), 7.38 (d, J= 8.3 Hz, 2H), 7.85 (d, J= 8.6 Hz). HRMS (ES) Calc'd for C26H39NzO4S: 475.2631.

Found: 475.2649.
Example 9 (4R, SR)-3,3-dibutyl-7-(dimethylamino)-2,3,4, 5-tetrahydro-5-(4-(((2-iodoethyoxy)ethoxy)ethoxy)phenyl)-2-methyl-1,2-benzothiazepin-4-of 1,1-dioxide °~~ ~i S'N
w N .,., \ OH
I w °~o~°~ ~
To a solution of 0.38 g (0.80 mmol) of the solid prepared in Example 8 in 8 mL dimethylformamide was added 44 mg of 95% sodium hydride and then 730 ~L of 1,2-bis(2-iodoethoxy)ethane. The reaction mixture was stirred one hour. To the reaction mixture was added 100 mL of water and 100 mL of ethyl acetate and the reaction mixture extracted with ethyl acetate. The ethyl acetate layer was washed with brine (100 mL), dried over magnesium sulfate and concentrated to form a residue. The residue was purified by flash chromatography with 10-25% ethyl acetate in hexane as eluent to give 0.37 g of (4R,SR)-3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-5-(4-(((2-iodoethyoxy)ethoxy)ethoxy)phenyl)-2-methyl-1,2-benzothiazepin-4-oll,l-dioxide as a solid. HRMS (ES) Calc'd for C32HSON2~6Sj 717.2434. Found:
717.2419. 'H NMR is consistent with the structure of the product.

Example 10 1-[2-[2-[2-[4-[(4R,SR)-3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-4-hydroxy-2-methyl-1,1-dioxido-1,2-benzothi azepin-5-yl]phenoxy] ethoxy] ethoxy] ethyl]pyridinium Oy ~i O
S -N
w N ,r OH
O~O~O~N ~
A solution of 75 mg of the solid prepared in Example 9 above in 5 mL
of pyridine was heated at 70 °C for 16 hours. The reaction mixture was concentrated to form a residue. The residue was triturated with ether to give 56.8 mg of 1-[2-[2-[2-[4-[(4R,SR)-3,3-dibutyl-7- (dimethylamino)-2,3,4,5-tetrahydro-4-hydroxy-2-methyl-1,1-dioxido-1,2-benzothiazepin-S
yl]phenoxy]ethoxy]ethoxy]ethyl]pyridinium as a solid. 'H NMR (CDC13) b 0.89-0.97 (m, 6H), 1.19-1.40 (m, 6H), 1.70-1.74 (m, 4H), 2.00-2.10 (m, 1H), 2.60-2.69 (m, 1H), 2.80 (s, 6H), 2.83 (s, 3H), 3.69-3.72 (m, 4H), 3.83-3.87 (m, 2H), 4.09-4.15 (m, SH), 5.23-5.27 (m, 2H), 5.70 (s, 1H), 5.97 (d, J= 2.4 Hz, 1 H), 6.5 0 (dd, J = 2.4, 8.8 Hz, 1 H), 6.93 (d, J = 8.8 Hz, 2H), 7.46 (d, J =
8.7 Hz, 2H), 7.83 (d, J= 8.7 Hz, 1H), 7.96-8.01 (m, 2H), 8.63-8.67 (m, 2H), 9.52 (d, J= 6.0 Hz, 1H). HRMS (ES) Calc'd for C3~HSqNgO6S: 668.3733. Found:
668.3762.

Example 11 2-[2-[2-[4-[(4R,SR)-3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-4-hydroxy-2-methyl-l, l-dioxido-1,2-benzothiazepin-5-yl]phenoxy]ethoxy]ethoxy]-N,N,N triethylethanaminium iodide O
~y ~i S -N
N ..,, \ _ OH
O~O~O\/~N+ 1_ The procedure of Example 10 was followed except that triethylamine was used in place of pyridine and heating was at 90 °C for 6 hours. 'H
NMR is consistent with the desired product.'H NMR (CDC13) 8 0.90-0.97 (m, 6H), 1.12-1.45 (m, 15H), 1.60-1.73 (m, 4H), 2.09-2.11 (m, 1H), 2.52-2.55 (m, 1H), 2.82 (s, 6H), 2.83 (s, 3H), 3.06-3.15 (m, 2H), 3.53 (q, J= 7.2 Hz, 6H), 3.74-3.75 (m, 4H), 3.86-3.89 (m, 2H), 4.04-4.16 (m, SH), 5.70 (s, 1H), 5.98 (m, 1 H), 6.5 0 (d, J = 3 .0 Hz, 1 H), 6.93 (d, J = 8 .7 Hz, 2H), 7.45 (d, J = 8.7 Hz, 2H), 7.83 (d, J= 8.7 Hz, 1H). HRMS (ES) Calc'd for C38H64N3O6S: 690.4516.
Found: 690.4548.
Example 12 (4R,SR)-3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-5-(3-methoxyphenyl)-2-methyl-1,2-benzothiazepin-4-of 1,1-dioxide Oy ~i S_N
w N ..,, OH
O /
The procedures set forth in Example 1 above were followed except that 3-methoxybenzyl chloride was substituted for 3-nitrobenzyl chloride. 'H NMR
was consistent with the product.'H NMR (CDCl3) 8 0.90-0.97 (m, 6H), 1.17-1.38 (m, 8H),1.69-1.73 (m, 2H), 2.04-2.08 (m, 1H), 2.55-2.62 (m, 1H), 2.81 (s, 6H), 2.84 (s, 3H), 3.82 (s, 3H), 4.15 (d, J= 7.8 Hz, 1H), 5.72 (s, 1H), 6.01 (d, J= 2.4 Hz, 1H), 6.50 (dd, J= 2.4, 8.4 Hz, 1H), 6.86-6.89 (m, 1H), 7.05 (br s, 1H), 7.13-7.16 (m, 1H), 7.32 (t, J= 8.1 Hz, 1H), 7.83 (d, J= 8.7 Hz, 1H).
MS (M+H+) 489.
O
OW ~~
S'NH
w N
OH
,O
+~
N
O

Example 13 (4R,SR)-3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-5-(3-nitrophenyl)-1,2-benzothiazepin-4-of 1,1-dioxide and (4S,SR)-3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-5-(3-nitrophenyl)-1,2-benzothiazepin-4-of 1,1-dioxide O O
S-NH
/
N
OH
N~ O
O
Step 1. N [1-Butyl-1-[[[(1-dimethylethyl)dimethylsilyl]oxy]methyl]pentyl]-4-(dimethylamino)-2-[(3-nitrophenyl)methyl]benzenesulfonamide Bu gu \ S02NH~
~~----OTBDMS
~N
NO

To a solution of 2.0 g (4.25 mmol) of the material prepared in Step 4 of Example 1 above in 10 mL of tetrahydrofuran cooled to 0 °C was added 8.0 mL of 1.6 M n-butyllithium in hexane. The reaction mixture was stirred at 0 °C for 30 minutes. To the reaction mixture was added 1.9 mL of trimethyl borate and the mixture stirred 10 minutes at 0 °C and then one hour at room temperature. To the reaction mixture was added 100 mL of water and 5%
hydrochloric acid to bring the solution to a pH of 6-7 and then the volatiles were evaporated. To the aqueous solution was added 100 mL of ethyl acetate and the solution extracted. The ethyl acetate layer was washed with water (100 mL) and brine (100 mL), dried over magnesium sulfate and concentrated to form a residue. The residue was dissolved in 7 mL of ethanol and degassed with nitrogen. In a separate flask was placed 150 mg of tetrakis(triphenylphosphine)palladium(0), 10 mL of toluene and 918 mg of 3-nitrobenzaldehyde. The ethanol solution was added to the toluene solution followed by 10 mL of 1 M aqueous sodium carbonate. The reaction mixture was heated to reflux for one hour, cooled to room temperature, and then stirred for 16 hours. The reaction mixture was concentrated and dissolved in 100 mL
of ethyl acetate. The ethyl acetate solution was washed with water (100 mL) and brine (100 mL). The ethyl acetate layer was dried over magnesium sulfate and concentrated to form a residue. The residue was purified by flash chromatography to give 1.72 g ofN [1-butyl-1-[[[(1-dimethylethyl)dimethylsilyl]oxy]methyl]pentyl]-4-(dimethylamino)-2-[(3-nitrophenyl)methyl]benzenesulfonamide.
Step 2. N [1-Butyl-1-(hydroxymethyl)pentyl]-4-(dimethylamino)-2-[(3-nitrophenyl)methyl]benzenesulfonamide Bu gu SOZNH~
CHO
~N
/.
NO

The procedure of Step 8 of Example 1 was followed except that N [1-butyl-1-[[[(1-dimethylethyl)dimethylsilyl]oxy]methyl]pentyl)-4-(dimethylamino)-2-[(3-nitrophenyl)methyl]benzenesulfonamide was used in place ofN [1-butyl-1-[[[(1-dimethylethyl)dimethylsilyl)oxy]methyl]pentyl]-4-S (dimethylamino)-2-[(3-nitrophenyl)methyl)-N methylbenzenesulfonamide.
Step 3. N [1-Butyl-1-formylpentyl]-4-(dimethylamino)-2-[(3-nitrophenyl) methyl]benzenesulfonamide Bu gu \ 502NH~
OOH
~N
NO

To a solution of 79 pL of oxalyl chloride in 2 mL of dichloromethane cooled to -78 °C was added 107 pL of dimethylsulfoxide and the mixture stirred 20 minutes. To the cooled reaction mixture was added a solution of 370 mg (0.75 mmol) of the alcohol from Step 2 above in 2 mL of dichloromethane and the mixture was stirred one hour at -78 °C. To the cooled reaction mixture was added 660 pL of diisopropylethylamine. The reaction mixture was warmed to room temperature and stirred for 30 minutes.
To the reaction mixture was added 100 mL of water and mixture was extracted with dichloromethane (2 x SO mL). The combined dichloromethane layers were washed with brine (SO mL), dried over magnesium sulfate and concentrated to give 0.47 g of a yellow oil. The residue was dissolved in 25 mL of 25% ethyl acetate in hexane and filtered through silica and concentrated. The residue was crystallized with ethyl acetate and hexane to give 301.6 mg ofN [1-butyl-1-formylpentyl]-4-(dimethylamino)-2-[(3-nitrophenyl)methyl]benzenesulfonamide as a yellow solid.
Step 4. (4R,SR)-3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-5-(3-nitrophenyl)-1,2-benzothiazepin-4-of 1,1-dioxide and (4S,SR)-3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-5-(3-nitrophenyl)-1,2-benzothiazepin-4-of 1,1-dioxide To a solution of 150 mg (0.31 mmol) of the material prepared in Step 3 above in 6 mL of tetrahydrofuran cooled to -15 °C was added 0.90 mL 1 M
of potassium t-butoxide in tetrahydrofuran. The reaction mixture was stirred for 15 minutes at -15 °C and then water was added. The organics were evaporated and 100 mL of ethyl acetate was added and then extracted. The ethyl acetate layer was washed with brine (100 mL), dried over magnesium sulfate and concentrated to form a residue. The residue was purified by flash chromatography with 30% ethyl acetate in hexane as eluent to give 61.8 mg of (4S,SR)-3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-5-(3-nitrophenyl)-1,2-benzothiazepin-4-of l,l-dioxide, and 65.7 mg of (4R,SR)-3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-5-(3-nitrophenyl)-1,2-benzothiazepin-4-of 1,1-dioxide. 'H NMR and mass spectra were consistent with the product.
Example 14 (4R,SR)-5-(3-aminophenyl)-3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-1,2-benzothiazepin-4-of 1,1-dioxide O O
v ii S'NH
w W N
OH

The procedure of Example 2 above was followed except that (4R,SR)-3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-5-(3-nitrophen~l)-1,2-benzothiazepin-4-of l,l-dioxide was used in place of (4R,5R)-3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-5-(3-nitrophenyl)-2-methyl-1,2-benzothiazepin-4-of l,l-dioxide. 'H NMR was consistent with the product.
MS (M+) 460.
Exam lp a 15 5-bromo-N [3-[(4R,5R)-3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-4-hydroxy-1,1-dioxido-1,2-benzothiazepin-S-yl)phenyl]pentanamide O
Oy S'NH
~N W
OH
O
N Br H

The procedure of Example 3 above was followed except that (4R,SR)-5-(3-aminophenyl)-3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-1,2-benzothiazepin-4-of 1,1-dioxide was used in place of (4R,SR)-5-(3-aminophenyl)-3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-2-methyl-1,2-benzothiazepin-4-of 1,1-dioxide.'H NMR was consistent with the product.
MS (M+H+) 623.
Example 16 5-[[3-[(4R,SR)-3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-4-hydroxy-1,1-dioxido-1,2-benzothiazepin-5-yl]phenyl]amino]-N,N,N triethyl-5-oxo-1-pentanaminium trifluoroacetate Ov i O
S'NH
N .,, \ OH
O
N +~ CF3CO2 N
H
To a solution of 54.1 mg (0.09 mmol) of the bromide prepared in Example 15 above in 1 mL of tetrahydrofuran was added 48 ~L of triethylamine. The reaction mixture was heated at reflux for three days. The solvent was evaporated and the residue triturated with ether. The solid was purified by reverse phase high pressure liquid chromatography to give 17.9 mg of 5-[[3-[(4R,SR)-3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-4 hydroxy-1,1-dioxido-1,2-benzothiazepin-5-yl]phenyl]amino]-N,N,N triethyl-5-oxo-1-pentanaminium trifluoroacetate as a white solid. 'H NMR was consistent with the product. MS (M+) 643.
Example 17 (4R,SR)-3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-5-phenyl-1,2-benzothiazepin-4-of 1,1-dioxide O\\ ~ O
S-NH
N ..,, \ OH
Step 1-2. N [1-Butyl-1-(hydroxymethyl)pentyl]-4-(dimethylamino)-2-(phenylmethyl)benzenesulfonamide Bu gu 502NH-'C
OOH
'N
The procedure of Steps 1-2 of Example 7 was followed except that N
[ 1-butyl-1-[[ [( 1,1 dimethylethyl)dimethylsilyl]oxy]methyl]pentyl]-4-(dimethylamino)benzenesulfonamide and benzyl chloride were used in place ofN [1-butyl-1-[[[(l,ldimethylethyl)dimethylsilyl]oxy]methyl]pentyl]-4-(dimethylamino)-N methylbenzenesulfonamide and p-methoxybenzyl chloride.
Step 3. N [1-Butyl-1-formylpentyl]-4-(dimethylamino)-2-(phenylmethyl) benzenesulfonamide Bu gu \ S02NH--CHO
~N
The procedure of Step 3 of Example 13 was followed except that N [1-butyl-1-(hydroxymethyl)pentyl]-4-(dimethylamino)-2-(phenylmethyl) benzenesulfonamide was used in place of N [1-butyl-1-(hydroxymethyl) pentyl]-4-(dimethylamino)-2-[(3-nitrophenyl)methyl]benzenesulfonamide.
Step 4. (4R,SR)-3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-5-phenyl-1,2-benzothiazepin-4-of l,l-dioxide The procedure Step 4 of Example 7 was followed except that N [1-Butyl-1-formylpentyl]-4-(dimethylamino)-2-(phenylmethyl) benzenesulfonamide was used in place of N [1-butyl-1-formylpentyl]-4-(dimethylamino)-2-[(4-methoxyphenyl)methyl]-N methylbenzene-sulfonamide. 'H NMR (CDCl3) 8 0.9 (m, 6H), 1-1.7 (m, 13H), 2.3 (m, 1H), 2.8 (s, 6H), 4.0 (s, 2H), 5.5 (s, 1 H), 5.9 (s, 1 H), 6.5 (m, 1 H), 7.4 (m, 3H), 7.5 (m, 2H), 7.8 (m, 1H). MS (M+H+) 445Ø

Example 18 (4R,SR)-3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-5-(4-methoxyphenyl)-1,2-benzothiazepin-4-of l,l-dioxide O
Ov ii S'NH
/I \
~N ', \ OH
O \
Step 1. N [1-Butyl-1-[[[(1-dimethylethyl)dimethylsilyl]oxy]methyl]pentyl]-4-(dimethylamino)-2-[(4-methoxyphenyl)methyl]benzenesulfonamide Bu gu \ S02NH-'C
~OTBDMS
~N U
O
The procedure of Step 1 of Example 7 was followed except that N [1-butyl-1-[[[( 1,1 dimethylethyl)dimethylsilyl]oxy]methyl]pentyl]-4-(dimethylamino)benzenesulfonamide was used in place ofN [1-butyl-1-[[[(1,1 dimethylethyl)dimethylsilyl]oxy]methyl]pentyl]-4-(dimethylamino)-N
methylbenzenesulfonamide.

Step 2. N [1-Butyl-1-(hydroxymethyl)pentyl]-4-(dimethylamino)-2-[(4-methoxyphenyl)methyl]benzenesulfonamide B~u ~Bu \ S02NH--'C
OOH
~N
O
The procedure of Step 8 of Example 1 was followed except that N [1-butyl-1-[[[(1-dimethylethyl)dimethylsilyl]oxy]methyl]pentyl]-4-(dimethylamino)-2-[(4-methoxyphenyl)methyl]benzenesulfonamide was used in place ofN [1-butyl-1-[[[(1-dimethylethyl)dimethylsilyl]oxy]methyl]
pentyl]-4-(dimethylamino)-2-[(3-nitrophenyl)methyl]-N methylbenzene-sulfonamide.
Step 3. N [1-Butyl-1-formylpentyl]-4-(dimethylamino)-2-[(4-methoxyphenyl) methyl]benzenesulfonamide Bu Bu \ S02NH--CHO
~N
O \

The procedure of Step 3 of Example 13 was followed except that N [1-butyl-1-(hydroxymethyl)pentyl]-4-(dimethylamino)-2-[(4-methoxyphenyl) methyl]benzenesulfonamide was used in place of N [1-butyl-1-[[[(1-dimethylethyl)dimethylsilyl]oxy]methyl]pentyl]-4-(dimethylamino)-2-[(3-nitrophenyl)methyl]-N methylbenzenesulfonamide.
Step 4. (4R,SR)-3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-S-(4-methoxyphenyl)-1,2-benzothiazepin-4-of l,l-dioxide The procedure of Step 10 of Example 1 was followed except that N [1-butyl-1-formylpentyl]-4-(dimethylamino)-2-[(4-methoxyphenyl)methyl]
benzenesulfonamide was used in place ofN [1-butyl-1-formylpentyl]-4-(dimethylamino)-2-[(3-nitrophenyl)methyl]-N methylbenzenesulfonamide. 'H
NMR (CDC13) 8 0.89-1.00 (m, 6H), 1.06-1.73 (m, 11H), 2.36 (t, J= 9.5 Hz, 1H), 2.80 (s, 6H), 2.98 (s, 1H), 3.85 (s, 3H), 3.97 (s, 1H), 4.03 (d, J= 9.0 Hz, 1H), 5.47 (s, 1H), 6.00 (d, J= 2.4 Hz, 1H), 6.50 (dd, J= 2.6, 8.9 Hz, 1H), 6.95 (d, J= 8.8 Hz, 2H), 7.44 (d, J= 8.5 Hz, 2H), 7.81 (d, J= 8.7 Hz, 1H).
Example 19 (4R,SR)-3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-5-(4-hydroxyphenyl)-1,2-benzothiazepin-4-of 1,1-dioxide O\\ ~ O
S'NH
N ,,, \ OH
OH

The procedure set forth in Example 8 above was followed except that (4R,SR)-3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-5-(4-methoxyphenyl)-1,2-benzothiazepin-4-of 1,1-dioxide was used in place of (4R,SR)-3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-S-(4-hydroxyphenyl)-2-methyl-1,2-benzothiazepin-4-of 1,1-dioxide and a reaction temperature of 0 °C was employed.'H NMR (CDC13) b 0.86-0.97 (m, 6H), 1.15-1.75 (m, 11H), 2.35 (t, J = 9.9 Hz, 1 H), 2. 80 (s, 6H), 3.98 (s, 1 H), 4.02 (d, J = 8.6 Hz, 1 H), 5.12 (s, 1H), 5.45 (s, 1H), 5.98 (d, J= 2.4 Hz, 1H), 6.48 (dd, J= 2.6, 8.6 Hz, 1H), 6.88 (d, J= 8.8 Hz, 2H), 7.38 (d, J= 8.1 Hz, 2H), 7.80 (d, J= 8.7 Hz, 1H).
Example 20 2-[2-[2-[4-[(4R,SR)-3,3-dibutyl-7- (dimethylamino)-2,3,4,5-tetrahydro-4-hydroxy-1,1-dioxido-1,2-benzothiazepin-5-yl]phenoxy]ethoxy] ethoxy]-N,N,N
triethylethanaminium iodide O\\ ~ O
S'NH
N ~,, \ OH
O~O ~O ~ i Step 1 O
O~~ ~i S-NH
--N .,,, OH
O~O~O~N+ 1_ The procedure set forth in Example 9 above was followed except that (4R,SR)-3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-S-(4-hydroxyphenyl)-1,2-benzothiazepin-4-of 1,1-dioxide was used in place of (4R,SR)-3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-5-(4-(((2-iodoethyoxy)ethoxy)ethoxy)phenyl)-2-methyl-1,2-benzothiazepin-4-of 1,1-dioxide and 3.3 equivalents of 95% sodium hydride was used instead of 2.2 equivalents. 'H NMR was consistent with the product.
Step 2. 2-[2-[2-[4-[(4R,SR)-3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-4-hydroxy- l , l -dioxido-1,2-benzothiazepin-5-yl]phenoxy]ethoxy]ethoxy]-N,N,N triethylethanaminium iodide The procedure set forth in Example 10 above was followed except that the benzothiazepine prepared in Step 1 above was used. 'H NMR (CDC13) 8 0.88-0.05 (m, 6H), 1.14-1.60 (m, 20H), 2.31-2.39 (m, 1H), 2.82 (s, 6H), 3.06-3.15 (m, 2H), 3.54 (q, J= 7.3 Hz, 6H), 3.75-3.81 (m, 4H), 3.88-4.17 (m, 7H), 5.47 (s, 1H), 5.98-6.02 (m, 1H), 6.47-6.54 (m, 1H), 6.93-6.98 (m, 2H), 7.42-7.47 (m, 2H), 7.81-7.84 (m, 1H).
Example 21 (4R,SR)-3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-5-(3-nitrophenyl)-2-(phenylmethyl)-1,2-benzothiazepin-4-of 1,1-dioxide O\~ i O I i S '_ N
w ~' N
\ OH
N+=O
O
Step 1. N [1-Butyl-1-[[[(1-dimethylethyl)dimethylsilyl]oxy]methyl]pentyl]-4-(dimethylamino)-2-[(3-nitrophenyl)methyl]-N (phenylmethyl) benzenesulfonamide Bu gu S02N-'( OH
~' N

To a solution of 4.24 g (7.0 mmol) of the sulfonamide prepared in Step 1 of Example 13 in 30 mL of acetone was added 2.90 g of potassium carbonate, 0.517 g of tetra-n-butylammonium iodide then 2.394 g of benzyl bromide. The reaction mixture was heated at reflux for five days. To the reaction mixture was added 2.394 g of benzyl bromide, 0.517 g of tetra-n-butylammonium iodide, and then 2.90 g of powdered potassium carbonate.
The reaction mixture was heated at reflux for one day. To the reaction mixture 250 mL of ethyl acetate was added. The ethyl acetate solution was washed with water (3 x 100 mL) and brine (200 mL). The ethyl acetate layer was dried over magnesium sulfate and concentrated to a residue. The residue was purified by flash chromatography to give 1.82 g ofN [1-butyl-1-[[[(1-dimethylethyl)dimethylsilyl]oxy]methyl]pentyl]-4-(dimethylamino)-2-[(3-nitrophenyl)methyl]-N (phenylmethyl)benzenesulfonamide.
Step 2. N [1-Butyl-1-(hydroxymethyl)pentyl]-4-(dimethylamino)-2-[(3-nitrophenyl)methyl]-N (phenylmethyl) benzenesulfonamide Bu gu \ SOZN--~
CliO
/ /
'N ~/.

The procedure of Step 8 of Example 1 was followed except that N [1-butyl-1-[[ [( 1-dimethylethyl)dimethylsilyl]oxy]methyl]pentyl]-4-(dimethylamino)-2-[(3-nitrophenyl)methyl]-N (phenylmethyl) benzenesulfonamide was used in place of N [1-butyl-1-[[[(1-dimethylethyl)dimethylsilyl]oxy]methyl]pentyl]-4-(dimethylamino)-2-[(3-nitrophenyl)methyl]-N methylbenzenesulfonamide.
Step 3. N [1-Butyl-1-formylpentyl)-4-(dimethylamino)-2-[(3-nitrophenyl)methyl]-N (phenylmethyl)benzenesulfonamide B~° ~Bu \ S02N
~OTBDMS
_N U
/.
NO

The procedure of Step 3 of Example 13 was followed except that N [1-Butyl-1-(hydroxymethyl)pentyl]-4-(dimethylamino)-2-[(3-nitrophenyl) methyl]-N (phenylmethyl)benzenesulfonamide was used in place ofN [1-butyl-1-[[[( 1-dimethylethyl)dimethylsilyl]oxy]methyl]pentyl]-4-(dimethylamino)-2-[(3-nitrophenyl)methyl]benzenesulfonamide.
Step 4. (4R,SR)-3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-5-(3-nitrophenyl)-2-(phenylmethyl)-1,2-benzothiazepin-4-of 1,1-dioxide The procedure of Step 10 of Example 1 was followed except that N [1-butyl-1-formylpentyl]-4-(dimethylamino)-2-[(3-nitrophenyl)methyl]-N
(phenylmethyl)benzenesulfonamide was used in place ofN [1-butyl-1-formylpentyl]-4-(dimethylamino)-2-[(3-nitrophenyl)methyl]-N
methylbenzenesulfonamide. 'H NMR was consistent with the product. MS
(M+H+) 580.

Example 22 (4R,SR)-3,3-dibutyl-7-(dimethylamino)-S-[3-(ethylamino)phenyl]-2,3,4,5-tetrahydro-2-(phenylmethyl)-1,2-benzothiazepin-4-of 1,1-dioxide w Ov i O ( i S'N
w N .., \ _ OH
w ~ N~
H
To a solution of 50 mg (0.09 mmol) of the compound prepared in Step 4 of Example 21 in 50 mL ethanol was added about 10 mg of Pearlman's Catalyst. This mixture was hydrogenated at 60 psi HZ for 20 hours. To the reaction mixture was added about 10 mg of Pearlman's Catalyst and the mixture was hydrogenated at 60 psi at 60 °C for 20 hours. The reaction mixture was filtered and washed with SO mL of ethyl acetate. The filtrate was washed with water (2 x 50 mL) and brine (50 mL). The ethyl acetate layer was dried over magnesium sulfate and concentrated to give 39.8 mg of a residue. The residue was purified by flash chromatography to give 12.6 mg of (4R,SR)-3,3-dibutyl-7-(dimethylamino)-5-[3-(ethylamino)phenyl]-2,3,4,5-tetrahydro-2-(phenylmethyl)-1,2-benzothiazepin-4-of 1,1-dioxide. 'H NMR
(CDC13) b 0.72 (t, J= 6.6, 3H), 0.90 (t, J= 7.4 Hz), 1.00-1.98 (rn, 15H), 2.81 (s, 6H), 3.17 (q, J= 7.2 Hz, 2H), 4.15 (d, J= 7.8 Hz, 1H), 4.39 (s, 2H), 5.69 (s, 1H), 6.12 (s, 1H), 6.47 (dd, J= 2.7, 9.0 Hz, 1H), 6.61-6.65 (m, 1H), 6.78-6.83 (m, 1H), 6.95-7.00 (m, 1H), 7.16-7.31 (m, SH), 7.40 (d, J= 7.2 Hz, 1H), 7.81 (d, J= 8.7 Hz, 1H). MS (M+H+) 578.

Example 23 (4R,SR)-3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-5-(4-methoxyphenyl)-2-(phenylmethyl)-1,2-benzothiazepin-4-of 1,1-dioxide /
O O
S _N
N
I OH
/
I
O
Step 1. N [1-Butyl-1-[[[(1-dimethylethyl)dirnethylsilyl]oxy]methyl]pentyl]-4-(dimethylamino)-2-[(4-methoxyphenyl)methyl]-N
(phenylmethyl)benzenesulfonamide eu gu SOZN
OOH
/ /
N
O

To a solution of 2.15 g (4.05 mmol) of the sulfonamide prepared in Step 1 of Example 7 above in 30 mL of dimethylformamide was added 123 mg of 95% sodium hydride and then 964 ~L of benzyl bromide. The reaction mixture was stirred 18 hours. To the reaction mixture was added 250 mL of ethyl acetate and the mixture was washed with saturated sodium bicarbonate solution (100 mL) and brine (150 mL). The ethyl acetate layer was dried over magnesium sulfate and concentrated to give 2.88 g ofN [1-butyl-1-[[[(1-dimethylethyl)dimethylsilyl]oxy]methyl]pentyl]-4-(dimethylamino)-2-[(4-methoxyphenyl)methyl]-N (phenylmethyl)benzenesulfonamide.
Step 2. N [1-Butyl-1-(hydroxymethyl)pentyl]-4-(dimethylamino)-2-[(4-methoxyphenyl)methyl]-N (phenylmethyl)benzenesulfonamide Bu gu ~OTBDMS
/ /
N
O
The procedure of Step 8 of Example 1 was followed except that N [1-butyl-1-[[[( 1-dimethylethyl)dimethylsilyl]oxy]methyl]pentyl]-4-(dimethylamino)-2-[(4-methoxyphenyl)methyl]-N
(phenylmethyl)benzenesulfonamide was used in place ofN [1-butyl-1-[[[(1-dimethylethyl)dimethylsilyl]oxy]methyl]pentyl]-4-(dimethylamino)-2-[(3-nitrophenyl)methyl]-N methylbenzenesulfonamide.
Step 3. N [1-Butyl-1-formylpentyl]-4-(dimethylamino)-2-[(3-nitrophenyl)methyl]-N (phenylmethyl)benzenesulfonamide Bu gu CHO
~N U
O
The procedure of Step 3 of Example 13 was followed except that N [1-butyl-1-(hydroxymethyl)pentyl]-4-(dimethylamino)-2-[(4-methoxyphenyl)methyl]-N (phenylmethyl)benzenesulfonamide was used in place ofN [1-butyl-1-[[[(1-dimethylethyl)dimethylsilyl]oxy]methyl]pentyl]-4-(dimethylamino)-2-[(3-nitrophenyl)methyl]-N methylbenzenesulfonamide.
Step 4. (4R,SR)-3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-5-(4-methoxyphenyl)-2-(phenylmethyl)-1,2-benzothiazepin-4-of 1,1-dioxide The procedure of Step 10 of Example 1 was followed except that N [1-butyl-1-formylpentyl]-4-(dimethylamino)-2-[(3-nitrophenyl)methyl)-N
(phenylmethyl)benzenesulfonamide was used in place ofN [1-butyl-1-formylpentyl]-4-(dimethylamino)-2-[(3-nitrophenyl)methyl]-N
methylbenzenesulfonamide. 'H NMR (CDC13) 8 0.7 (m, 3H), 0.9 (m, 3H), 1-1.7 (m, lOH), 1.9 (m, 1H), 2.1 (m, 1H), 2.8 (s, 6H), 3.8 (s, 3H), 4.1 (s, 1H), 4.4 (s, 2H), 5.8 (s, 1H), 6.0 (s, 1H), 6.5 (m, 1H), 7.0 (d, J= 8 Hz, 1H), 7.1-7.5 (m, 7H), 7. 8 (m, 1 H).

Example 24 (4R,SR)-7-dimethylamino)-2-ethyl-4,5-dihydro-S-(4-methoxyphenyl)-spiro[1,2-benzothiazepine-3(2H),1'-cyclopentan]-4-of 1,1-dioxide SOZN
MeZN
OH
Me0 Step 1. N [1-(hydroxymethyl)cyclopentyl]-4-fluorobenzenesulfonamide HQOH
SOZN
F
The procedure of Step 2 of Example 1 was followed except that cycloleucinol was substituted for 2-amino-2-butylhexanol.
Step 2-3. N [1-[[[(1,1-dimethylethyl)dimethylsilyl]oxy]methyl]cyclopentyl]-4-(dimethylamino)benzenesulfonamide H~OTBDMS
SOZN
N
The procedure of Steps 3 and 4 of Example 1 was followed except that N [1-(hydroxymethyl)cyclopentyl]-4-fluorobenzenesulfonamide was used in place ofN [1-butyl-1-(hydroxymethyl)pentyl]-4-fluorobenzenesulfonamide.
Step 4. N [1-[[[(1-dimethylethyl)dimethylsilyl]oxy]methyl]cyclopentyl]-4-(dimethylamino)-2-[(4-methoxyphenyl)methyl]-N methylbenzenesulfonamide H~OTBDMS
SOZN
N
O
The procedure of Step 1 of Example 7 was followed except that N [1-[[[( 1,1-dimethylethyl)dimethylsilyl]oxy]methyl]cyclopentyl]-4-(dimethylamino)benzenesulfonamide was used in place of N [1-butyl-1-[[[( 1,1 dimethylethyl)dimethylsilyl]oxy]methyl]pentyl]-4-(dimethylamino)-N
methylbenzenesulfonamide.
Step 5. N [1-(hydroxymethyl)cyclopentyl]-4-(dimethylamino)-2-[(4-methoxyphenyl)methyl]-N ethylbenzenesulfonamide ~OTBDMS

N
O

To a solution of 0.25 g (0.49 mmol) of the sulfonamide prepared in Step 4 above in 5 mL of tetrahydrofuran was added 25 mg of 95% sodium hydride. After 15 minutes, 125 ~L of ethyl iodide was added to the reaction mixture. The reaction mixture was stirred 16 hours. To the reaction mixture was added 5 mL of dimethylformamide and the mixture stirred four hours. To the reaction mixture 100 mL of water was added and the mixture extracted with 100 mL of ethyl acetate. The ethyl acetate layer was washed with brine (100 mL), dried over magnesium sulfate and concentrated to give 0.27g of an oil.
Step 6-8. (4R,SR)-7-dimethylamino)-2-ethyl-4,5-dihydro-5-(4-methoxyphenyl)-spiro[1,2-benzothiazepine-3(2H),1'-cyclopentan]-4-of 1,1-dioxide The procedure of Steps 8-10 of Example 1 was followed except that N
[ 1-(hydroxymethyl)cyclopentyl]-4-(dimethylamino)-2-[(4-methoxyphenyl)methyl]-N ethylbenzenesulfonamide was used in place of N
[ 1-butyl-1-[[[(1-dimethylethyl)dimethylsilyl]oxy]methyl]pentyl]-4-(dimethylamino)-2-[(3-nitrophenyl)methyl]-N methylbenzenesulfonamide. 'H
NMR was consistent with product. MS (M+H+) 445.
Biological Assays The utility of the compounds of the present invention is shown by the following assays. These assays are performed in vitro and in animal models essentially using a procedure recognized to show the utility of the present invention.
In Vitro Assay Of Compounds That Inhibit IBAT-Mediated Uptake Of ['4C~-Taurocholate (TCl in H14 Cells Baby hamster kidney cells (BHK) transfected with the cDNA of human IBAT (H14 cells) are seeded at 60,000 cells/well in 96 well Top-Count tissue culture plates for assays run within 24 hours of seeding; 30,000 cells/well for assays run within 48 hours; and 10,000 cells/well for assays run within 72 hours.
On the day of assay, the cell monolayer is gently washed once with 100 mL assay buffer (Dulbecco's Modified Eagle's medium with 4.5 g/L
glucose + 0.2% (w/v) fatty acid free bovine serum albumin ((FAF)BSA). To each well 50 mL of a two-fold concentrate of test compound in assay buffer is added along with 50 mL of 6 mM ['4C]-taurocholate in assay buffer (final concentration of 3 mM ['4C]-taurocholate). The cell culture plates are incubated two hours at 37° C prior to gently washing each well twice with 100 mL of 4° C Dulbecco's phosphate-buffered saline (PBS) containing 0.2%
(w/v) (FAF)BSA. The wells are then gently washed once with 100 mL of 4° C PBS
without (FAF)BSA. To each 200 mL of liquid scintillation counting fluid is added, the plates are heat sealed and shaken for 30 minutes at room temperature prior to measuring the amount of radioactivity in each well on a Packard Top-Count instrument.
In Vitro Assay Of Compounds That Inhibit Uptake Of ['4C]-Alanine The alanine uptake assay is performed in an identical fashion to the taurocholate assay, with the exception that labeled alanine is substituted for the labeled taurocholate.
Data from each of the noted compounds in this assay is as set forth in Table 4 below:

Table 4 COMPOUND HUMAN TC ICso ALANINE UPTAKE
(EXAMPLE (~M) ICSo NUMBER) 1 1.2 2 0.32 3 0.69 4 0.083 >100 5 0.97 6 0.32 7 0.57 8 0.5 8 10 0.31 11 0.20 12 1.2 13 (cis) 0.044 13 (trans) 0.21 14 0.006 15 0.022 16 0.0016 17 0.035 18 0.026 19 0.003 > 100 20 0.008 21 >1.0 22 2.5 24 13.9 In Vivo Assay Of Compounds That Inhibit Rat Ileal Uptake Of ['4C1-Taurocholate into Bile (See "Metabolism of 3a,7(3dihydroxy-7[i-methyl-S~i-cholanoic acid and 3a,7~3-dihydroxy-7a-methyl-5(3-cholanoic acid in hamsters" in Biochimica et S Biophysica Acta 833 (1985) 196-202 by Une et al.) Male wistar rats (200-300 g) are anesthetized with inactin @100 mg/kg. Bile ducts are cannulated with a 10 " length of PE10 tubing. The small intestine is exposed and laid out on a gauze pad. A canulae (1/8" luer lock, tapered female adapter) is inserted at 12 cm from the junction of the small intestine and the cecum. A slit is cut at 4 cm from this same junction (utilizing a 8 cm length of ileum). 20 mL of warm Dulbecco's phosphate buffered saline, pH
6.5 (PBS) is used to flush out the intestine segment. The distal opening is cannulated with a 20 cm length of silicone tubing (0.02" LD. x 0.037" O.D.).
The proximal cannulae is hooked up to a peristaltic pump and the intestine is washed for 20 minutes with warm PBS at 0.25 mL/minute. Temperature of the gut segment is monitored continuously. At the start of the experiment, 2.0 mL of control sample (['4C]-taurocholate @ 0.05 mi/mL with 5 mM cold taurocholate) is loaded into the gut segment with a 3 mL syringe and bile sample collection is begun. Control sample is infused at a rate of 0.25 mL/minute for 21 minutes. Bile samples fractions are collected every three minutes for the first 27 minutes of the procedure. After the 21 minutes of sample infusion, the ileal loop is washed out with 20 mL of warm PBS (using a 30 mL syringe), and then the loop is washed out for 21 minutes with warm PBS at 0.25 mL/minute. A second perfusion is initiated as described above but with the test compound being administered as well (21 minutes administration followed by 21 minutes of wash out) and bile sampled every three minutes for the first 27 minutes. If necessary, a third perfusion is performed as above that typically contains the control sample.

Measurement Of Hepatic Cholesterol Concentration (HEPATIC CHOLI
Liver tissue is weighed and homogenized in chloroform:methanol (2:1). After homogenization and centrifugation the supernatant is separated and dried under nitrogen. The residue is dissolved in isopropanol and the cholesterol content is measured enzymatically, using a combination of cholesterol oxidase and peroxidase, as described by Allain, C. A., et al. (1974) Clin. Chem. 20, 470.
Measurement Of Hepatic HMG CoA-Reductase Activity (HMG COAL
Hepatic microsomes are prepared by homogenizing liver samples in a phosphate/sucrose buffer, followed by centrifugal separation. The final pelleted material is resuspended in buffer and an aliquot is assayed for HMG
CoA reductase activity by incubating for 60 minutes at 37° C in the presence of '4C-HMG-CoA (Dupont-NEN). The reaction is stopped by adding 6N HCl followed by centrifugation. An aliquot of the supernatant is separated, by thin-layer chromatography, and the spot corresponding to the enzyme product is scraped off the plate, extracted and radioactivity is 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 + LDLI
Total serum cholesterol (SER.CHOL) is measured enzymatically using a commercial kit from Wako Fine Chemicals (Richmond, VA); Cholesterol C11, Catalog No. 276-64909. HDL cholesterol (HDL-CHOL) is assayed using this same kit after precipitation of VLDL and LDL with Sigma Chemical Co. HDL Cholesterol reagent, Catalog No. 352-3 (dextran sulfate method). Total serum triglycerides (blanked) (TGI) are assayed enzymatically with Sigma Chemical Co. GPO-Trinder, Catalog No. 337-B. VLDL and LDL

(VLDL + LDL) cholesterol concentrations are calculated as the difference between total and HDL cholesterol.
Measurement Of Hepatic Cholesterol 7-a Hydroxylase Activity~7a-OHase) Hepatic microsomes are prepared by homogenizing liver samples in a S phosphate/sucrose buffer, followed by centrifugal separation. The final pelleted material is resuspended in buffer and an aliquot is assayed for cholesterol 7-a-hydroxylase activity by incubating for 5 minutes at 37°
C in the presence of NADPH. Following extraction into petroleum ether, the organic solvent is evaporated and the residue is dissolved in acetonitrile/
methanol. The enzymatic product is separated by injecting an aliquot of the extract onto a C~$ reversed phase HPLC column and quantitating the eluted material using UV detection at 240nm. (Reference: Norton, J. D., et al. (1994) J. Clin. Invest. 93, 2084).
Rat Gava eg Assay_ Male blister rats (275-300g) are administered IBAT inhibitors using an oral gavage procedure. Drug or vehicle (0.2% Tween 80 in water) is administered once a day (9:00-10:00 a.m.) for four days at varying dosages in a final volume of 2 mL per kilogram of body weight. Total fecal samples are collected during the final 48 hours of the treatment period and analyzed for bile acid content using an enzymatic assay as described below. Compound efficacy is determined by comparison of the increase in fecal bile acid (FBA) concentration in treated rats to the mean FBA concentration of rats in the vehicle group. Table 5 describes the results of this assay when the compound of Example 4 was tested.

Table 5 COMPOUND DOSE (mg/kg/day) % INCREASE IN
(EXAMPLE FECAL BILE ACID
NUMBER) CONCENTRATION

4 S 217.2 4 0.4 157.8 4 0.04 244.0 Measurement Of Fecal Bile Acid Concentration (FBAI
Total fecal output from individually housed hamsters is collected for 24 or 48 hours, dried under a stream of nitrogen, pulverized and weighed.
Approximately 0.1 gram is weighed out and extracted into an organic solvent (butanol/water). Following separation and drying, the residue is dissolved in methanol and the amount of bile acid present is measured enzymatically using the 3a-hydroxysteroid steroid dehydrogenase reaction with bile acids to reduce NAD. (Reference: Mashige, F., et al. (1981) Clin. Chem. 27, 1352).
j3H]taurocholate Uptake in Rabbit Brush Border Membrane Vesicles (BBMV) Rabbit heal brush border membranes are prepared from frozen ileal mucosa by the calcium precipitation method described by Malathi et al.
(Reference: (1979) Biochimica Biophysica Acta, 554, 259). The method for measuring taurocholate is essentially as described by Kramer et al.
(Reference:
(1992) Biochimica Biophysica Acta, 1111, 93) except the assay volume is 200 ~L instead of 100 ~L. Briefly, at room temperature a 190 ~L solution containing 2~M [3H]-taurocholate(0.75 ~Ci), 20 mM tris, 100 mM NaCI, 100 mM mannitol pH 7.4 is incubated for 5 seconds with 10 ~L of brush border membrane vesicles (60-120 ~g protein). The incubation is initiated by the addition of the BBMV while vortexing and the reaction is stopped by the addition of 5 mL of ice cold buffer (20 mM Hepes-tris, 150 mM KCl) followed immediately by filtration through a nylon filter (0.2 ~tm pore) and an additional 5 mL wash with stop buffer.
Acyl-CoA; cholesterol Acyl Transferase (ACAT) Hamster liver and rat intestinal microsomes are prepared from tissue as described previously (Reference: (1980) J. Biol. Chem. 255, 9098) and used as a source of ACAT enzyme. The assay consists of a 2.0 mL incubation containing 24 ~M Oleoyl-CoA (0.05 ~Ci) in a 50 mM sodium phosphate, 2 mM DTT ph 7.4 buffer containing 0.25 % BSA and 200 ~g of microsomal protein. The assay is initiated by the addition of oleoyl-CoA. The reaction proceeds for five minutes at 37° C and is terminated by the addition of 8.0 mL
of chloroform/methanol (2:1). To the extraction is added 125 ~g of cholesterol oleate in chloroform methanol to act as a Garner and the organic and aqueous phases of the extraction are separated by centrifugation after thorough vortexing. The chloroform phase is taken to dryness and then spotted on a silica gel 60 TLC plate and developed in hexane/ethyl ether (9:1).
The amount of cholesterol ester formed is determined by measuring the amount of radioactivity incorporated into the cholesterol oleate spot on the TLC plate with a Packard instaimager. The examples herein can be repeated with similar success by substituting the generically or specifically described reactants and/or operating conditions of this invention for those used in the preceding examples.
The invention being thus described, it is apparent that the same can be varied in many ways. Such variations are not to be regarded as a departure from the spirit and scope of the present invention, and all such modifications and equivalents as would be obvious to one skilled in the art are intended to be included within the scope of the following claims.

Claims (166)

What is claimed is:
1. A compound of formula (I):
wherein:
q is an integer from 1 to 4;
R1 and R2 are independently selected from the group consisting of hydrogen and hydrocarbyl, wherein said hydrocarbyl may be optionally substituted with one or more groups comprising one or more heteroatoms, and wherein said hydrocarbyl optionally may have one or more carbon atoms replaced by one or more heteroatoms independently selected from the group consisting of oxygen, nitrogen, sulfur and phosphorus;
R3 and R4 are independently selected from the group consisting of hydrogen; hydrocarbyl; -OR9; -NR9R10; -SR9; -S(O)R9; -SO2R9; and -SO3R9; or R3 and R4 together form =O; =NOR9; =S; =NNR9R10; =NR9; or =CR11R12;
wherein R9 and R10 are independently selected from the group consisting of hydrogen; hydrocarbyl; amino; and hydrocarbylamino; wherein said hydrocarbyl moeities may be optionally substituted with one or more groups comprising one or more heteroatoms, and wherein said hydrocarbyl moieties optionally may have one or more carbon atoms replaced by one or more heteroatoms independently selected from the group consisting of oxygen, nitrogen, sulfur and phosphorus; and wherein R11 and R12 are independently selected from the group consisting of hydrogen; -CN; halogen; oxo; hydrocarbyl; -OR9; -NR9R10; -SR9; -S(O)R9; -SO2R9; and -SO3R9; wherein said hydrocarbyl moeities may be optionally substituted with one or more groups comprising one or more heteroatoms, and wherein said hydrocarbyl moieties optionally may have one or more carbon atoms replaced by one or more heteroatoms independently selected from the group consisting of oxygen, nitrogen, sulfur and phosphorus;
or R11 and R12 together with the carbon atom to which they are attached form a cyclic ring; and R5 and R6 are independently selected from the group consisting of hydrogen; alkyl; cycloalkyl; alkenyl; alkynyl; aryl; heterocyclyl; quaternary heterocyclyl; -OR9; -SR9; -S(O)R9; -SO2R9; and -SO3R9;
wherein the R5 and R6 radicals optionally may be substituted with one or more radicals independently selected from the group consisting of halogen;
-NO2; -CN; oxo; hydrocarbyl; -OR13; -NR13R14; -SR13; -S(O)R13; -SO2R13; -SO3R13; -NR13OR14; -NR13NR14R15; -CO2R13; -OM; -SO2OM; -SO2NR13R14; -C(O)NR13R14; -C(O)OM; -COR13; -NR13C(O)R14; -NR13C(O)NR14R15; -NR13CO2R14; -OC(O)R13; -OC(O)NR13R14;
-NR13SOR14; -NR13SO2R14; -NR13SONR14R15; -NR13SO2NR14R15; -PR13R14; -P(O)R13R14; -P+R13R14R15A-; -P(OR13)OR14; -S+R13R14A-; and -N+R13R14R15A-; wherein said hydrocarbyl may be optionally substituted with one or more groups comprising one or more heteroatoms, and wherein said hydrocarbyl optionally may have one or more carbon atoms replaced by one or more heteroatoms independently selected from the group consisting of oxygen, nitrogen, sulfur and phosphorus;
wherein R13, R14, and R15 are independently selected from the group consisting of hydrogen or hydrocarbyl, wherein said hydrocarbyl may be optionally substituted with one or more groups comprising one or more heteroatoms, and wherein said hydrocarbyl optionally may have one or more carbon atoms replaced by one or more heteroatoms independently selected from the group consisting of oxygen, nitrogen, sulfur and phosphorus; or wherein R13 and R14 together with the nitrogen atom to which they are attached form a mono- or polycyclic heterocyclyl that is optionally substituted with one or more radicals selected from the group consisting of oxo, carboxy, and quaternary salts; or wherein R14 and R15 together with the nitrogen atom to which they are attached form a cyclic ring; and wherein A- is a pharmaceutically acceptable anion, and M is a pharmaceutically acceptable cation; and wherein R9 is as defined above; or R4 and R6 together represent a bond; and R N is selected from the group consisting of hydrogen and hydrocarbyl, wherein said hydrocarbyl may be optionally substituted with one or more groups comprising one or more heteroatoms, and wherein said hydrocarbyl optionally may have one or more carbon atoms replaced by one or more heteroatoms independently selected from the group consisting of oxygen, nitrogen, sulfur and phosphorus;
one or more R x radicals are independently selected from the group consisting of hydrogen; halogen; -CN; -NO2; hydrocarbyl; -OR13; -NR13R14; -SR13; -S(O)R13; -S(O)2R13; -SO3R13; -S+R13R14A-; -NR13OR14; -NR13NR14R15; -CO2R13; -OM; -SO2OM; -SO2NR13R14; -NR14C(O)R13; -C(O)NR13R14; -C(O)OM; -COR13; -S(O)NR13R14; -N+R13R14R15A-; -PR13R14; -P(O)R13R14; -P+R13R14R15A-; amino acid residue; peptide residue; polypeptide residue; and carbohydrate residue, wherein said hydrocarbyl may be optionally substituted with one or more groups comprising one or more heteroatoms, and wherein said hydrocarbyl optionally may have one or more carbon atoms replaced by one or more heteroatoms independently selected from the group consisting of oxygen, nitrogen, sulfur and phosphorus; and wherein n is 0, 1 or 2; and wherein R13, R14, R15, A-, and M are as defined above; or a pharmaceutically acceptable salt, solvate, or prodrug thereof; and provided that at least one of R1, R2, R3, R4, R5, and R6 is a radical other than hydrogen or alkyl; and provided that when R5 or R6 is aryl, the other of R5 and R6 is a radical other than heterocycylalkyl.
2. A compound of claim 1 wherein:
q is an integer from 1 to 4;
R1 and R2 are independently selected from the group consisting of hydrogen; alkyl; cycloalkyl; alkenyl; cycloalkenyl; alkynyl; aryl;
heterocyclyl;
arylalkyl; heterocyclylalkyl; alkoxyalkyl; alkoxyalkenyl; alkoxyalkynyl;
aryloxyalkyl; aryloxyalkenyl; aryloxyalkynyl; heterocylcyloxyalkyl;
heterocycloxyalkenyl; heterocyclyloxyalkynyl; alkylaryl; and (polyalkyl)aryl;
or R1 and R2 taken together with the carbon to which they are attached form C3-C10 cycloalkyl or C3-C10 cycloalkenyl;
wherein the R1 and R2 alkyl; cycloalkyl; alkenyl; cycloalkenyl;
alkynyl; aryl; heterocyclyl; arylalkyl; heterocyclylalkyl; alkoxyalkyl;
alkoxyalkenyl; alkoxyalkynyl; aryloxyalkyl; aryloxyalkenyl; aryloxyalkynyl;
heterocylcyloxyalkyl; heterocycloxyalkenyl; heterocyclyloxyalkynyl;
alkylaryl; and (polyalkyl)aryl radicals optionally may be substituted with one or more radicals selected from the group consisting of -CN; halogen; oxo; -OR9, -NR9R10, -N+R9R10R w A-; -SR9, -S+R9R10A-; -PR9R10; -P+R9R10R w A-; -S(O)R9; -SO2R9; -SO3R9; -CO2R9; and -CONR9R10; and wherein the R1 and R2 alkyl; cycloalkyl; alkenyl; cycloalkenyl;
alkynyl; aryl; heterocyclyl; arylalkyl; heterocyclylalkyl; alkoxyalkyl;
alkoxyalkenyl; alkoxyalkynyl; aryloxyalkyl; aryloxyalkenyl; aryloxyalkynyl;
heterocylcyloxyalkyl; heterocycloxyalkenyl; heterocyclyloxyalkynyl;
alkylaryl; and (polyalkyl)aryl radicals optionally may have one or more carbons replaced by -O-; -NR9-; -N+R9R10A- -; -S-; -SO-; -SO2-; -S+R9A- -; -PR9-; -P(O)R9-; -P+R9R10A- -; or phenylene; and wherein R9, R10, and R w are independently selected from the group consisting of hydrogen; alkyl; cycloalkyl; alkenyl; alkynyl; aryl;
heterocyclyl;
alkylammoniumalkyl; arylalkyl; heterocyclylalkyl; carboxyalkyl; alkoxyalkyl;
carboalkoxyalkyl; carboxyaryl; carboxyheterocyclyl; amino; alkylamino;
carboxyalkylamino; alkoxyalkylamino; and acyl; and wherein A- is a pharmaceutically acceptable anion; and R3 and R4 are independently selected from the group consisting of hydrogen; alkyl; alkenyl; alkynyl; aryl; heterocyclyl; -OR9; -NR9R10; -SR9; -S(O)R9; -SO2R9; and -SO3R9; or R3 and R4 together form =O; =NOR9; =S; =NNR9R10; =NR9; or =CR11R12;
wherein R11 and R12 are independently selected from the group consisting of hydrogen; -CN; halogen; oxo; alkyl; alkenyl; alkynyl; aryl;
heterocyclyl; arylalkyl; heterocyclylalkyl; carboxyalkyl; alkoxyalkyl;
carboalkoxyalkyl; cycloalkyl; cycloalkenyl; haloalkyl; hydroxyalkyl;
cyanoalkyl; -OR9; -NR9R10; -SR9; -S(O)R9; -SO2R9; -SO3R9; -CO2R9;
and -CONR9R10; or R11 and R12 together with the carbon atom to which they are attached form a cyclic ring; and wherein R9 and R10 are as defined above; and R5 and R6 are independently selected from the group consisting of hydrogen; alkyl; cycloalkyl; alkenyl; alkynyl; aryl; heterocyclyl; quaternary heterocyclyl; -OR9; -SR9; -S(O)R9; -SO2R9; and -SO3R9;
wherein the R5 and R6 alkyl; cycloalkyl; alkenyl; alkynyl; aryl;
heterocyclyl; and quaternary heterocyclyl radicals optionally may be substituted with one or more radicals independently selected from the group consisting of halogen; -CN; -NO2; oxo; alkyl; polyalkyl; haloalkyl;
hydroxyalkyl; cycloalkyl; alkenyl; alkynyl; aryl; heterocyclyl; quaternary heterocyclyl; arylalkyl; heterocyclylalkyl; polyether; -OR13; -NR13R14; -SR13; -S(O)R13; -SO2R13; -SO3R13; -NR13OR14; -NR13NR14R15; -CO2R13; -OM; -SO2OM; -SO2NR13R14; -C(O)NR13R14; -C(O)OM; -COR13; -NR13C(O)R14; -NR13C(O)NR14R15; -NR13CO2R14; -OC(O)R13; -OC(O)NR13R14; -NR13SOR14; -NR13SO2R14; -NR13SONR14R15; -NR13SO2NR14R15; -PR13R14; -P(O)R13R14; -P+R13R14R15A-; -P(OR13)OR14; -S+R13R14A-; and -N+R13R14R15A-; and wherein the alkyl, polyalkyl, haloalkyl, hydroxyalkyl, cycloalkyl, alkenyl, alkynyl, aryl, heterocyclyl, quaternary heterocyclyl, arylalkyl, heterocyclylalkyl, and polyether substituents of the R5 and R6 radicals optionally may be further substituted with one or more radicals selected from the group consisting of -CN; halogen; hydroxy; oxo; alkyl; cycloalkyl;
alkenyl; alkynyl; aryl; heterocyclyl; arylalkyl; heterocyclylalkyl; quaternary heterocyclyl; -OR7; -NR7R8; -SR7; -S(O)R7; -SO2R7; -SO3R7;- CO2R7; -CONR7R8; -N+R7R8R9A-; -P(O)R7R8; -PR7R8; -P+R7R8R9A-; and -P(O)(OR7OR8; and wherein the alkyl, polyalkyl, haloalkyl, hydroxyalkyl, cycloalkyl, alkenyl, alkynyl, aryl, heterocyclyl, quaternary heterocyclyl, arylalkyl, heterocyclylalkyl, and polyether substituents of the R5 and R6 radicals optionally may have one or more carbons replaced by -O-; -NR7-; -N+R7R7A--; -S-; -SO-; -SO2-; -S+R7A- -; -PR7-; -P(O)R7-; -P+R7R8A- -; or phenylene;
and wherein R7 and R 8 are independently selected from the group consisting of hydrogen; alkyl, alkenyl; alkynyl; aryl; and heterocyclyl; and wherein R13, R14, and R15 are independently selected from the group consisting of hydrogen; alkyl; haloalkyl; cycloalkyl; polyalkyl; alkenyl;
alkynyl; aryl; heterocyclyl; quaternary heterocyclyl; arylalkyl;
heterocyclylalkyl; quaternary heterocyclylalkyl; alkylarylalkyl;
alkylheterocyclylalkyl; alkylammoniumalkyl; aminoalkyl;
aminocarbonylalkyl; alkylaminocarbonylalkyl;
carboxyalkylaminocarbonylalkyl; and polyether; or wherein R13 and R14 together with the nitrogen atom to which they are attached form a mono- or polycyclic heterocyclyl that is optionally substituted with one or more radicals selected from the group consisting of oxo, carboxy, and quaternary salts; or wherein R14 and R15 together with the nitrogen atom to which they are attached form a cyclic ring; and wherein the R13, R14, and R15 alkyl; haloalkyl; cycloalkyl; polyalkyl;
alkenyl; alkynyl; aryl; heterocyclyl; quaternary heterocyclyl; arylalkyl;
heterocyclylalkyl; quaternary heterocyclylalkyl; alkylarylalkyl;
alkylheterocyclylalkyl; alkylammoniumalkyl; aminoalkyl;
aminocarbonylalkyl; alkylaminocarbonylalkyl;
carboxyalkylaminocarbonylalkyl; and polyether radicals optionally may be substituted with one or more radicals selected from the group consisting of halogen; -CN; sulfo; oxo; alkyl; haloalkyl; hydroxyalkyl; sulfoalkyl; alkenyl;
alkynyl; aryl; heterocyclyl; quaternary heterocyclyl; quaternary heterocyclylalkyl; carboxy; carboxyalkyl; guanidinyl; -OR16; -NR9R10; -N+R9R10R w A-; -SR16; -S(O)R9; -SO2R9; -SO3R16; -CO2R16; -CONR9R10; -SO2NR9R10; -PO(OR16)OR17; -P9R10; -P+R9R10R11A-; -S+R9R10A-; and carbohydrate residue; and wherein the R13, R14, and R15 alkyl; haloalkyl; cycloalkyl; polyalkyl;
alkenyl; alkynyl; aryl; heterocyclyl; quaternary heterocyclyl; arylalkyl;
heterocyclylalkyl; quaternary heterocyclylalkyl; alkylarylalkyl;
alkylheterocyclylalkyl; alkylammoniumalkyl; aminoalkyl;
aminocarbonylalkyl; alkylaminocarbonylalkyl;
carboxyalkylaminocarbonylalkyl; and polyether radicals optionally may have one or more carbons replaced by -O-; -NR9-; -N+R9R10A- -; -S-; -SO-; -SO2-;
-S+R9A- -; -PR9-; -P+R9R10A- -; -P(O)R9-; phenylene; carbohydrate residue;
amino acid residue; peptide residue; or polypeptide residue; and wherein R16 and R17 are independently selected from the group consisting of R9 and M; and wherein M is a pharmaceutically acceptable cation; and wherein R9, R10, R11, R12, R w, and A- are as defined above; and R N is selected from the group consisting of hydrogen; alkyl; alkenyl;
alkynyl; aralkyl; and heterocyclylalkyl; and one or more R x radicals are independently selected from the group consisting of hydrogen; halogen; -CN; -NO2; alkyl; cycloalkyl; polyalkyl;
haloalkyl; hydroxyalkyl; alkenyl; alkynyl; aryl; heterocyclyl; quaternary heterocyclyl; arylalkyl; heterocyclylalkyl; polyether; acyloxy; -OR13; -NR13R14; -SR13; -S(O)R13; -S(O)2R13; -SO3R13; -S+R13R14A-; -NR13OR14; -NR13NR14R15; -CO2R13; -OM; -SO2OM; -SO2NR13R14; -NR14C(O)R13; -C(O)NR13R14; -C(O)OM; -COR13; -OR18; -S(O)n NR13R14; -NR13R18; -NR18OR14; -N+R13R14R15A-; -PR13R14, P(O)R13R14; -P+R13R14R15A-; amino acid residue; peptide residue;
polypeptide residue; and carbohydrate residue;
wherein the R x alkyl; cycloalkyl; polyalkyl; haloalkyl; hydroxyalkyl;
alkenyl; alkynyl; aryl; heterocyclyl; arylalkyl; heterocyclylalkyl; polyether;
acyloxy radicals optionally may be further substituted with one or more radicals selected from the group consisting of halogen; -CN; oxo; -OR16; -NR9R10; -N+R9R10R w A-; -SR16; -S(O)R9; -SO2R9; -SO3R16; -CO2R16; -CONR9R10; -SO2NR9R10; -PO(OR16)OR17; -P9R10; -P+R9R11R12A-; -S+R9R10A-; and carbohydrate residue; and wherein the R x quaternary heterocyclyl radical optionally may be substituted with one or more radicals selected from the group consisting of halogen; -CN; -NO2; oxo; alkyl; cycloalkyl; polyalkyl; haloalkyl;

hydroxyalkyl; alkenyl; alkynyl; aryl; heterocyclyl; arylalkyl;
heterocyclylalkyl; polyether; -OR13; -NR13R14; -SR13; -S(O)R13; -SO2R13;
-SO3R13; -NR130R14; -NR13NR14R15; -CO2R13; OM; -SO2OM; -SO2NR13R14; -C(O)NR13R14; -C(O)OM; -COR13; -P(O)R13R14; -P13R14; -P+R13R14R15A-; -P(OR13)OR14; -S+R13R14A-; -N+R13R14R15A-; and carbohydrate residue; and wherein the R x radicals comprising carbon optionally may have one or more carbons replaced by -O-; -NR13-; -N+R13R14A- -; -S-; -SO-; -SO2-; -S+R13A- -; -PR13-; -P(O)R13-; -PR13R14; -P+R13R14A- -; phenylene; amino acid residue; peptide residue; polypeptide residue; carbohydrate residue;
polyether; or polyalkyl; wherein said phenylene; amino acid residue; peptide residue; polypeptide residue; carbohydrate residue; and polyalkyl optionally may have one or more carbons replaced by -O-; -NR9-; -N+R9R10A- -; -S-; -SO-; -SO2-; -S+R9A- -; -PR9-; -P+R9R10A- -; or -P(O)R9-; and wherein R18 is selected from the group consisting of alkyl; alkenyl;
alkynyl; aryl; heterocyclyl; quaternary heterocyclyl; arylalkyl;
heterocyclylalkyl; acyl; alkoxycarbonyl; arylalkoxycarbonyl; and heterocyclylalkoxycarbonyl; and wherein the R18 alkyl; alkenyl; alkynyl; aryl; heterocyclyl; quaternary heterocyclyl; arylalkyl; heterocyclylalkyl; acyl; alkoxycarbonyl;
arylalkoxycarbonyl; and heterocyclylalkoxycarbonyl radicals optionally may be substituted with one or more radicals selected from the group consisting of halogen; -CN ; NO2; oxo; -OR9; -NR9R10; -N+R9R11R12A-; -SR9; -S(O)R9; -SO2R9; -SO3R9; -CO2R9; -CONR9R10; -SO2OM; -SO2NR9R10;
-PR9R10; -P(OR13)OR14; -PO(OR16)OR17; and -C(O)OM; and wherein R9, R10, R11, R12, R13, R14, R15, R16, R17, R w, A-, and M are as defined above; or a pharmaceutically acceptable salt, solvate, or prodrug thereof.
3. A compound of claim 1 wherein:
q is an integer from 1 to 4;
R1 and R2 are independently selected from the group consisting of hydrogen; alkyl; cycloalkyl; alkenyl; alkynyl; arylalkyl; alkoxyalkyl;
alkoxyalkenyl; alkoxyalkynyl; alkylaryl; and (polyalkyl)aryl; or R1 and R2 taken together with the carbon to which they are attached form C3-C10 cycloalkyl or C3-C10 cycloalkenyl;
wherein the R1 and R2 alkyl; cycloalkyl; alkenyl; alkynyl; arylalkyl;
alkoxyalkyl; alkoxyalkenyl; alkoxyalkynyl; alkylaryl; and (polyalkyl)aryl radicals optionally may be substituted with one or more radicals selected from the group consisting of -CN; halogen; oxo; -OR9; -NR9R10; -N+R9R10R w A-; -SR9; -S+R9R10A-; -PR9R10; -P+R9R10R w A-; -S(O)R9; -SO2R9; -SO3R9; -CO2R9; and -CONR9R10; and wherein the R1 and R2 alkyl; cycloalkyl; alkenyl; alkynyl; arylalkyl;
alkoxyalkyl; alkoxyalkenyl; alkoxyalkynyl; alkylaryl; and (polyalkyl)aryl radicals optionally may have one or more carbons replaced by -O-; -NR9-; -N+R9R10A- -, -S-; -SO-; -SO2-; -S+R9A- -, -PR9-; -P(O)R9-; -P+R9R10A- -, or phenylene; and wherein R9, R10, and R w are independently selected from the group consisting of hydrogen; alkyl; cycloalkyl; alkenyl; alkynyl; aryl;
heterocyclyl;
alkylammoniumalkyl; arylalkyl; heterocyclylalkyl; carboxyalkyl;
carboalkoxyalkyl; carboxyheterocyclyl; carboxyalkylamino; and acyl; and wherein A- is a pharmaceutically acceptable anion; and R3 and R4 are independently selected from the group consisting of hydrogen; alkyl; alkenyl; alkynyl; aryl; heterocyclyl; -OR9; -NR9R10; -SR9; -S(O)R9; -SO2R9; and -SO3R9; or R3 and R4 together form =O; =NOR9; =S; =NNR9R10; =NR9; or =CR11R12;
wherein R11 and R12 are independently selected from the group consisting of hydrogen; -CN; halogen; oxo; alkyl; alkenyl; alkynyl; aryl;
heterocyclyl; arylalkyl; carboxyalkyl; carboalkoxyalkyl; cycloalkyl;
cyanoalkyl; -OR9; -NR9R10; -SR9; -S(O)R9; -SO2R9; -SO3R9; -CO2R9;
and -CONR9R10; or R11 and R12 together with the carbon atom to which they are attached form a cyclic ring; and wherein R9 and R10 are as defined above; and R5 and R6 are independently selected from the group consisting of hydrogen; alkyl; cycloalkyl; alkenyl; alkynyl; aryl; heterocyclyl; quaternary heterocyclyl; -OR9; -SR9; -S(O)R9; -SO2R9; and -SO3R9;

wherein the R5 and R6 alkyl; cycloalkyl; alkenyl; alkynyl; aryl;
heterocyclyl; and quaternary heterocyclyl radicals optionally may be substituted with one or more radicals independently selected from the group consisting of halogen; -CN; -NO2; oxo; alkyl; polyalkyl; haloalkyl;
cycloalkyl; alkenyl; alkynyl; aryl; heterocyclyl; quaternary heterocyclyl;
arylalkyl; heterocyclylalkyl; polyether; -OR13; -NR13R14; -SR13; -S(O)R13;
-SO2R13; -SO3R13; -NR13OR14; -NR13NR14R15; -CO2R13; -OM; -SO2OM; -SO2NR13R14; -C(O)NR13R14; -C(O)OM; -COR13; -NR13C(O)R14; -NR13C(O)NR14R15; -NR13CO2R14; -OC(O)R13; -OC(O)NR13R14;
-NR13SOR14; -NR13SO2R14; -NR13SONR14R15; -NR13SO2NR14R15; -PR13R14; -P(O)R13R14; -P+R13R14R15A-; -P(OR13)OR14; -S+R13R14A-; and -N+R13R14R15A-; and wherein the alkyl, polyalkyl, haloalkyl, hydroxyalkyl, cycloalkyl, alkenyl, alkynyl, aryl, heterocyclyl, quaternary heterocyclyl, arylalkyl, heterocyclylalkyl, and polyether substituents of the R5 and R6 radicals optionally may be further substituted with one or more radicals selected from the group consisting of -CN; halogen; hydroxy; oxo; alkyl; cycloalkyl;
alkenyl; alkynyl; aryl; heterocyclyl; arylalkyl; heterocyclylalkyl; quaternary heterocyclyl; -OR7; -NR7R8; -SR7; -S(O)R7; -SO2R7; -SO3R7;- CO2R7; -CONR7R8; -N+R7R8R9A-; -P(O)R7R8; -PR7R8; -P+R7R7R9A-; and -P(O)(OR7)OR8; and wherein the alkyl, polyalkyl, haloalkyl, hydroxyalkyl, cycloalkyl, alkenyl, alkynyl, aryl, heterocyclyl, quaternary heterocyclyl, arylalkyl, heterocyclylalkyl, and polyether substituents of the R5 and R6 radicals optionally may have one or more carbons replaced by -O-; -NR7-; -N+R7R8A--; -S-; -SO-; -SO2-; -S+R7A- -; -PR7-; -P(O)R7-; -P+R7R8A- -; or phenylene;
and wherein R7 and R8 are independently selected from the group consisting of hydrogen and alkyl; and wherein R13, R14, and R15 are independently selected from the group consisting of hydrogen; alkyl; haloalkyl; cycloalkyl; polyalkyl; alkenyl;
alkynyl; aryl; heterocyclyl; quaternary heterocyclyl; arylalkyl;
heterocyclylalkyl; quaternary heterocyclylalkyl; alkylarylalkyl;
alkylheterocyclylalkyl; alkylammoniumalkyl;
carboxyalkylaminocarbonylalkyl; and polyether; or wherein R13 and R14 together with the nitrogen atom to which they are attached form a mono- or polycyclic heterocyclyl that is optionally substituted with one or more radicals selected from the group consisting of oxo, carboxy, and quaternary salts; or wherein R14 and R15 together with the nitrogen atom to which they are attached form a cyclic ring; and wherein the R13, R14, and R15 alkyl; haloalkyl; cycloalkyl; polyalkyl;
alkenyl; alkynyl; aryl; heterocyclyl; quaternary heterocyclyl; arylalkyl;
heterocyclylalkyl; quaternary heterocyclylalkyl; alkylarylalkyl;
alkylheterocyclylalkyl; alkylammoniumalkyl; aminocarbonylalkyl;
alkylaminocarbonylalkyl; carboxyalkylaminocarbonylalkyl; and polyether radicals optionally may be substituted with one or more radicals selected from the group consisting of halogen; -CN; sulfo; oxo; alkyl; sulfoalkyl;
heterocyclyl; quaternary heterocyclyl; quaternary heterocyclylalkyl; carboxy;
carboxyalkyl; guanidinyl; -OR16; -NR9R10; -N+R9R10R w A-; -SR16; -S(O)R9; -SO2R9; -SO3R16; -CO2R16; -CONR9R10; -SO2NR9R10; -PO(OR16)OR17; -PR9R10; -P+R9R10R11A-; -S+R9R10A-; and carbohydrate residue; and wherein the R13, R14, and R15 alkyl; haloalkyl; cycloalkyl; polyalkyl;
alkenyl; alkynyl; aryl; heterocyclyl; quaternary heterocyclyl; arylalkyl;
heterocyclylalkyl; quaternary heterocyclylalkyl; alkylarylalkyl;
alkylheterocyclylalkyl; alkylammoniumalkyl; aminocarbonylalkyl;
alkylaminocarbonylalkyl; carboxyalkylaminocarbonylalkyl; and polyether radicals optionally may have one or more carbons replaced by -O-; -NR9-; -N+R9R10A- -; -S-; -SO-; -SO2-; -S+R9A- -; -PR9-; -P+R9R10A- -; -P(O)R9-;
phenylene; carbohydrate residue; amino acid residue; peptide residue; or polypeptide residue; and wherein R16 and R17 are independently selected from the group consisting of R9 and M; and wherein M is a pharmaceutically acceptable cation; and wherein R9, R10, R11, R12, R w, and A- are as defined above; and R N is selected from the group consisting of hydrogen; alkyl; alkenyl;
alkynyl; and aralkyl; and one or more R x radicals are independently selected from the group consisting of hydrogen; halogen; -CN; -NO2; alkyl; cycloalkyl; polyalkyl;

haloalkyl; alkenyl; alkynyl; aryl; heterocyclyl; quaternary heterocyclyl;
arylalkyl; polyether; acyloxy; -OR13; -NR13R14; -SR13; -S(O)R13; -S(O)2R13; -SO3R13; -S+R13R14A-; -NR13OR14; -NR13NR14R15; -CO2R13; -OM; -SO2OM; -SO2NR13R14; -NR14C(O)R13; -C(O)NR13R14; -C(O)OM; -COR13; -OR18; -S(O)n NR13R14; -NR13R18; -NR18OR14; -N+R13R14R15A-; -PR13R14; -P(O)R13R14; -P+R13R14R15A-; amino acid residue; peptide acid residue; polypeptide acid residue; and carbohydrate acid residue;
wherein the R x alkyl; cycloalkyl; polyalkyl; haloalkyl; hydroxyalkyl;
alkenyl; alkynyl; aryl; heterocyclyl; arylalkyl; heterocyclylalkyl; polyether;
and acyloxy radicals optionally may be further substituted with one or more radicals selected from the group consisting of halogen; -CN; oxo; -OR16; -NR9R10; -N+R9R10R w A-; -SR16; -S(O)R9; -SO2R9; -SO3R16; -CO2R16; -CONR9R10; -SO2NR9R10; -PO(OR16)OR17; -PR9R10; -P+R9R11R12A-; -S+R9R10A-; and carbohydrate residue; and wherein the R x quaternary heterocyclyl radical optionally may be substituted with one or more radicals selected from the group consisting of halogen; -CN; -NO2; oxo; alkyl; cycloalkyl; polyalkyl; haloalkyl;
hydroxyalkyl; alkenyl; alkynyl; aryl; heterocyclyl; arylalkyl;
heterocyclylalkyl; polyether; -OR13; -NR13R14; -SR13; -S(O)R13; -SO2R13;
-SO3R13; -NR13OR14; -NR13NR14R15; -CO2R13; OM; -SO2OM; -SO2NR13R14; -C(O)NR13R14; -C(O)OM; -COR13; -P(O)R13R14; -PR13R14; -P+R13R14R15A-; -P(OR13)OR14; -S+R13R14A-; and -N+R13R14R15A-; and carbohydrate residue; and wherein the R x radicals comprising carbon optionally may have one or more carbons replaced by -O-; -NR13-; -N+R13R14A- -; -S-; -SO-; -SO2-; -S+R13A- -; -PR13-; -P(O)R13-; -PR13-; -P+R13R14A- -; phenylene; amino acid; peptide; polypeptide; carbohydrate; polyether; or polyalkyl; wherein said phenylene; amino acid; peptide; polypeptide; carbohydrate; and polyalkyl optionally may have one or more carbons replaced by -O-; -NR9-; -N+R9R10A- -; -S-; -SO-; -SO2-; -S+R9A- -; -PR9-; -P+R9R10A- -; or -P(O)R9-;
and wherein R18 is selected from the group consisting of alkyl; alkenyl;
alkynyl; aryl; heterocyclyl; quaternary heterocyclyl; arylalkyl;

heterocyclylalkyl; acyl; alkoxycarbonyl; arylalkoxycarbonyl; and heterocyclylalkoxycarbonyl; and wherein the R18 alkyl; alkenyl; alkynyl; aryl; heterocyclyl; quaternary heterocyclyl; arylalkyl; heterocyclylalkyl; acyl; alkoxycarbonyl;
arylalkoxycarbonyl; and heterocyclylalkoxycarbonyl radicals optionally may be substituted with one or more radicals selected from the group consisting of halogen; -CN ; oxo; -OR9; -NR9R10; -N+R9R11R12A-; -SR9; -S(O)R9; -SO2R9; -SO3R9; -CO2R9; -CONR9R10; -SO2OM; -SO2NR9R10; -PR9R10; -P(OR13)OR14; -PO(OR16)OR17; and -C(O)OM; and wherein R9, R10, R11, R12, R13, R14, R15, R16, R17, R w, A-, and M are as defined above; or a pharmaceutically acceptable salt, solvate, or prodrug thereof.
4. A compound of claim 1 wherein:
q is an integer from 1 to 4;
R1 and R2 are independently selected from the group consisting of hydrogen; (C1-C10)alkyl; (C3-C10)cycloalkyl; (C2-C10)alkenyl; (C2-C10)alkynyl;
aryl(C1-C10)alkyl; (C1-C10)alkoxy(C1-C10)alkyl; (C1-C10)alkoxy(C2-C10)alkenyl;
(C1-C10)alkoxy(C2-C10)alkynyl; (C1-C10)alkylaryl; and (polyalkyl)aryl; or R1 and R2 taken together with the carbon to which they are attached form (C3-C10)cycloalkyl;
wherein the R1 and R2 (C1-C10)alkyl; (C3-C10)cycloalkyl; (C2-C10)alkenyl; (C2-C10)alkynyl; aryl(C1-C10)alkyl; (C1-C10)alkoxy(C1-C10)alkyl;
(C1-C10)alkoxy(C2-C10)alkenyl; (C1-C10)alkoxy(C2-C10)alkynyl; (C1-C10)alkylaryl; and (polyalkyl)aryl radicals optionally may be substituted with one or more radicals selected from the group consisting of -CN; halogen; oxo;
-OR9; -NR9R10; -N+R9R10R w A-; -SR9; -S+R9R10A-; -PR9R10; -P+R9R10R w A-; -S(O)R9; -SO2R9; -SO3R9; -CO2R9; and -CONR9R10; and wherein the R1 and R2 (C1-C10)alkyl; (C3-C10)cycloalkyl; (C2-C10)alkenyl; (C2-C10)alkynyl; aryl(C1-C10)alkyl; (C1-C10)alkoxy(C1-C10)alkyl;
(C1-C10)alkoxy(C2-C10)alkenyl; (C1-C10)alkoxy(C2-C10)alkynyl; (C1-C10)alkylaryl; and (polyalkyl)aryl radicals optionally may have one or more carbons replaced by -O-; -NR9-; -N+R9R10A- -; -S-; -SO-; -SO2-; -S+R9A- -; -PR9; -P(O)R9-; -P+R9R10A- -; or phenylene; and wherein R9, R10, and R w are independently selected from the group consisting of hydrogen; (C1-C10)alkyl; (C3-C10)cycloalkyl; (C2-C10)alkenyl;
(C2-C10)alkynyl; aryl; heterocyclyl; ammonium(C1-C10)alkyl; (C1-C10)alkylammonium(C1-C10)alkyl; aryl(C1-C10)alkyl; heterocyclyl(C1-C10)alkyl; carboxy(C1-C10)alkyl; carbo(C1-C10)alkoxy(C1-C10)alkyl;
carboxyheterocyclyl; carboxy(C1-C10)alkylamino; and acyl; and wherein A- is a pharmaceutically acceptable anion; and R3 and R4 are independently selected from the group consisting of hydrogen; (C1-C10)alkyl; (C2-C10)alkenyl; (C2-C10)alkynyl; aryl; heterocyclyl;
-OR9; -NR9R10; -SR9; -S(O)R9; -SO2R9; and -SO3R9; or R3 and R4 together form =O; =NOR9; =S; =NNR9R10; =NR9; or =CR11R12;
wherein R11 and R12 are independently selected from the group consisting of hydrogen; -CN; halogen; oxo; (C1-C10)alkyl; (C2-C10)alkenyl;
(C2-C10)alkynyl; aryl; heterocyclyl; aryl(C1-C10)alkyl; carboxy(C1-C10)alkyl;
carbo(C1-C10)alkoxy(C1-C10)alkyl; (C3-C10)cycloalkyl; cyano(C1-C10)alkyl; -OR9; -NR9R10; -SR9; -S(O)R9; -SO2R9; -SO3R9; -CO2R9; and -CONR9R10; or R11 and R12 together with the carbon atom to which they are attached form a cyclic ring; and wherein R9 and R10 are as defined above; and R5 and R6 are independently selected from the group consisting of hydrogen; (C1-C10)alkyl; (C3-C10)cycloalkyl; (C2-C10)alkenyl; (C2-C10)alkynyl;
aryl; heterocyclyl; quaternary heterocyclyl; -OR9; -SR9; -S(O)R9; -SO2R9;
and -SO3R9;
wherein the R5 and R6 (C1-C10)alkyl; (C3-C10)cycloalkyl; (C2-C10)alkenyl; (C2-C10)alkynyl; aryl; heterocyclyl; and quaternary heterocyclyl radicals optionally may be substituted with one or more radicals independently selected from the group consisting of halogen; -CN; -NO2; oxo; (C1-C10)alkyl; polyalkyl; halo(C1-C10)alkyl; (C3-C10)cycloalkyl; (C2-C10)alkenyl;
(C2-C10)alkynyl; aryl; heterocyclyl; quaternary heterocyclyl; aryl(C1-C10)alkyl;
heterocyclyl(C1-C10)alkyl; polyether; -OR13; -NR13R14; -SR13; -S(O)R13; -SO2R13; -SO3R13; -NR13OR14; -NR13NR14R15; -CO2R13; -OM; -SO2OM; -SO2NR13R14; -C(O)NR13R14; -C(O)OM; -COR13; -NR13C(O)R14; -NR13C(O)NR14R15; -NR13CO2R14; -OC(O)R13; -OC(O)NR13R14;

-NR13SOR14; -NR13SO2R14; -NR13SONR14R15; -NR13SO2R14R15; -P(O)R13R14; -PR13R14; -P+R13R14R15A-; -P(OR13)OR14; -S+R13R14A-and -N+R13R14R15A-; and wherein the (C1-C10)alkyl, polyalkyl, halo(C1-C10)alkyl, hydroxy(C1-C10)alkyl, (C3-C10)cycloalkyl, (C2-C10)alkenyl, (C2-C10)alkynyl, aryl, heterocyclyl, quaternary heterocyclyl, aryl(C1-C10)alkyl, heterocyclyl(C1-C10)alkyl, and polyether substituents of the R5 and R6 radicals optionally may be further substituted with one or more radicals selected from the group consisting of -CN; halogen; hydroxy; oxo; (C1-C10)alkyl; (C3-C10)cycloalkyl;
(C3-C10)alkenyl; (C2-C10)alkynyl; aryl; heterocyclyl; aryl(C1-C10)alkyl;
heterocyclyl(C1-C10)alkyl; quaternary heterocyclyl; -OR7; -NR7R8; -SR7; -S(O)R7; -SO2R7; -SO3R7;- CO2R7; -CONR7R8; -N+R7R8R9A-; -P(O)R7R8; -PR7R8; -P+R7R8R9A-; and -P(O)(OR7)OR8; and wherein the (C1-C10)alkyl, polyalkyl, halo(C1-C10)alkyl, hydroxy(C1-C10)alkyl, (C3-C10)cycloalkyl, (C2-C10)alkenyl, (C2-C10)alkynyl, aryl, heterocyclyl, quaternary heterocyclyl, aryl(C1-C10)alkyl, heterocyclyl(C1-C10)alkyl, and polyether substituents of the R5 and R6 radicals optionally may have one or more carbons replaced by -O-; -NR7-; -N+R7R8A- -; -S-; -SO-; -SO2-; -S+R7A- -; -PR7-; -P(O)R7-; -P+R7R8A- -; or phenylene; and wherein R7 and R8 are independently selected from the group consisting of hydrogen and (C1-C10)alkyl; and wherein R13, R14, and R15 are independently selected from the group consisting of hydrogen; (C1-C10)alkyl; halo(C1-C10)alkyl; (C3-C10)cycloalkyl;
polyalkyl; (C2-C10)alkenyl; (C1-C10)alkynyl; aryl; heterocyclyl; quaternary heterocyclyl; aryl(C1-C10)alkyl; heterocyclyl(C1-C10)alkyl; quaternary heterocyclyl(C1-C10)alkyl; (C1-C10)alkylaryl(C1-C10)alkyl; (C1-C10)alkylheterocyclyl(C1-C10)alkyl; (C1-C10)alkylammonium(C1-C10)alkyl;
carboxylC1-C10)alkylaminocarbonyl(C1-C10)alkyl; and polyether; or wherein R13 and R14 together with the nitrogen atom to which they are attached form a mono- or polycyclic heterocyclyl that is optionally substituted with one or more radicals selected from the group consisting of oxo, carboxy, and quaternary salts; or wherein R14 and R15 together with the nitrogen atom to which they are attached form a cyclic ring; and wherein the R13, R14, and R15 (C1-C10)alkyl; halo(C1-C10)alkyl; (C3-C10)cycloalkyl; polyalkyl; (C2-C10)alkenyl; (C2-C10)alkynyl; aryl;
heterocyclyl;
quaternary heterocyclyl; aryl(C1-C10)alkyl; heterocyclyl(C1-C10)alkyl;
quaternary heterocyclyl(C1-C10)alkyl; (C1-C10)alkylaryl (C1-C10)alkyl; (C1-C10)alkylheterocyclyl(C1-C10)alkyl; (C1-C10)alkylammonium(C1-C10)alkyl;
aminocarbonyl(C1-C10)alkyl; (C1-C10)alkylaminocarbonyl(C1-C10)alkyl;
carboxy(C1-C10)alkylaminocarbonyl (C1-C10)alkyl; and polyether radicals optionally may be substituted with one or more radicals selected from the group consisting of halogen; -CN; sulfo; oxo; (C1-C10)alkyl; sulfo(C1-C10)alkyl; heterocyclyl; quaternary heterocyclyl; quaternary heterocyclyl(C1-C10)alkyl; carboxy; carboxy(C1-C10)alkyl; guanidinyl; -OR16; -NR9R10; -N+R9R10R w A-; -SR16; -S(O)R9; -SO2R9; -SO3R16; -CO2R16; -CONR9R10; - -SO2NR9R10; -PO(OR16)OR17; -PR9R10; -P+R9R10R11A--S+R9R10A-; and carbohydrate residue; and wherein the R13, R14, and R15 (C1-C10)alkyl; halo(C1-C10)alkyl; (C3-C10)cycloalkyl; polyalkyl; (C2-C10)alkenyl; (C2-C10)alkynyl; aryl;
heterocyclyl;
quaternary heterocyclyl; aryl(C1-C10)alkyl; heterocyclyl(C1-C10)alkyl;
quaternary heterocyclyl(C1-C10)alkyl; (C1-C10)alkylaryl(C1-C10)alkyl; (C1-C10)alkylheterocyclyl(C1-C10)alkyl; (C1-C10)alkylammonium(C1-C10)alkyl;
aminocarbonyl(C1-C10)alkyl; (C1-C10)alkylaminocarbonyl(C1-C10)alkyl;
carboxy(C1-C10)alkylaminocarbonyl(C1-C10)alkyl; and polyether radicals optionally may have one or more carbons replaced by -O-; -NR9-; -N+R9R10A- -; -S-; -SO-; -SO2-; -S+R9A- -; -PR9-; -P+R9R10A- -; -P(O)R9-;
phenylene; carbohydrate residue; amino acid residue; peptide residue; or polypeptide residue; and wherein R16 and R17 are independently selected from the group consisting of R9 and M; and wherein M is a pharmaceutically acceptable cation; and wherein R9, R10, R11, R12, R w, and A- are as defined above; and R N is selected from the group consisting of hydrogen; (C1-C10)alkyl;
(C2-C10)alkenyl; (C2-C10)alkynyl; and aryl(C1-C10)alkyl; and one or more R x radicals are independently selected from the group consisting of hydrogen; halogen; -CN; -NO2; (C1-C10)alkyl; (C3-C10)cycloalkyl; polyalkyl; halo(C1-C10)alkyl; (C2-C10)alkenyl; (C2-C10)alkynyl;
aryl; heterocyclyl; quaternary heterocyclyl; aryl(C1-C10)alkyl; polyether;

acyloxy; -OR13; -NR13R14; -SR13; -S(O)R13; -S(O)2R13; -SO3R13; -S+R13R14A-; -NR13OR14; -NR13NR14R15; -CO2R13; -OM; -SO2OM; -SO2NR13R14; -NR14C(O)R13; -C(O)NR13R14; -C(O)OM; -COR13; -OR18;
-S(O)n NR13R14; -NR13R18; -NR18OR14; -N+R13R14R15A-; -PR13R14; -P(O)R13R14; -P+R13R14R15A-; amino acid residue; peptide acid residue;
polypeptide acid residue; and carbohydrate acid residue;
wherein the R x (C1-C10)alkyl; (C3-C10)cycloalkyl; polyalkyl; halo(C1-C10)alkyl; hydroxy(C1-C10)alkyl; (C2-C10)alkenyl; (C2-C10)alkynyl; aryl;
heterocyclyl; aryl(C1-C10)alkyl; heterocyclyl(C1-C10)alkyl; polyether; and acyloxy radicals optionally may be further substituted with halogen; -CN; oxo;
-OR16; -NR9R10; -N+R9R11R12A-; -SR16; -S(O)R9; -SO2R9; -SO3R16; -CO2R16; -CONR9R10; -SO2NR9R10; -PO(OR16)OR17; -PR9R10; -P+R9R11R12A-; or -S+R9R10A-; and wherein the R x quaternary heterocyclyl radical optionally may be substituted with one or more radicals selected from the group consisting of halogen; -CN; -NO2; oxo; (C1-C10)alkyl; (C3-C10)cycloalkyl; polyalkyl;
halo(C1-C10)alkyl; hydroxy(C1-C10)alkyl; (C2-C10)alkenyl; (C2-C10)alkynyl;
aryl; heterocyclyl; aryl(C1-C10)alkyl; heterocyclyl(C1-C10)alkyl; polyether; -OR13; -NR13R14; -SR13; -S(O)R13; -SO2R13; -SO3R13; -NR13OR14; -NR13NR14R15; -CO2R13; -OM; -SO2OM; -SO2NR13R14; -C(O)NR13R14;
-C(O)OM; -COR13; -P(O)R13R14; -PR13R14; -P+R13R14R15A-; -P(OR13)OR14; -S+R13R14A-; and -N+R13R14R15A-; and wherein the R x radicals comprising carbon optionally may have one or more carbons replaced by -O-; -NR13-; -N+R13R14A- -; -S-; -SO-; -SO2-; -S+R13A- -; -PR13-; -P(O)R13-; -PR13-; -P+R13R14A- -; phenylene; amino acid residue; peptide residue; polypeptide residue; carbohydrate residue;
polyether; or polyalkyl; wherein said phenylene; amino acid residue; peptide residue; polypeptide residue; carbohydrate residue; and polyalkyl optionally may have one or more carbons replaced by -O-; -NR9-; -N+R9R10A- -; -S-; -SO-; -SO2-; -S+R9A- -; -PR9-; -P+R9R10A- -; or -P(O)R9-; and wherein R18 is selected from the group consisting of (C1-C10)alkyl;
heterocyclyl; quaternary heterocyclyl; aryl(C1-C10)alkyl; acyl; and aryl(C1-C10)alkoxycarbonyl; and wherein the R18 (C1-C10)alkyl; heterocyclyl; quaternary heterocyclyl;
aryl(C1-C10)alkyl; acyl; and aryl(C1-C10)alkoxycarbonyl radicals optionally may be substituted with one or more radicals selected from the group consisting of halogen; -CN ; oxo; -OR9; -NR9R10; -N+R9R11R12A-; -SR9; -S(O)R9; -SO2R9; -SO3R9; -CO2R9; -CONR9R10; -SO2OM; -SO2NR9R10;
-PR9R10; -P(OR13)OR14; -PO(OR16)OR17; and -C(O)OM; and wherein R9, R10, R11, R12, R13, R14, R15, R16, R17, R w, A-, and M are as defined above; or a pharmaceutically acceptable salt, solvate, or prodrug thereof; and provided that aryl is selected from the group consisting of optionally substituted phenyl, biphenyl and naphthyl; and provided that heterocyclyl is selected from the group consisting of optionally substituted heterocyclyl comprising a 5 to 10 membered ring and comprising one or more ring atoms that are heteroatoms selected from the group consisting of oxygen, nitrogen, sulfur and phosphorus.
5. A compound of claim 1 wherein:
q is an integer from 1 to 4;
R1 and R2 are independently selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, phenoxymethylene, phenoxyethylene, phenoxypropylene, pyridinyloxymethylene, pyridinyloxyethylene; methylpyridinyloxymethylene, methylpyridinyloxyethylene, pyrimidinyloxymethylene, and pyrimidinyloxyethylene; or R1 and R2 taken together with the carbon to which they are attached form cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl; and R3 and R4 are independently selected from the group consisting of hydrogen, hydroxy, methyl, ethyl, phenyl, pyridinyl, amino, methylamino, dimethylamino, ethylamino and diethylamino; and R5 and R6 are independently selected from the group consisting of hydrogen, phenyl, chlorophenyl, fluorophenyl, bromophenyl, iodophenyl, hydroxyphenyl, methoxyphenyl, ethoxyphenyl, methoxy(chlorophenyl), methoxy(fluorophenyl), methoxy(bromophenyl), methoxy(iodophenyl), ethoxy(chlorophenyl), ethoxy(fluorophenyl), ethoxy(bromophenyl), ethoxy(iodophenyl), nitrophenyl, aminophenyl, methylaminophenyl, dimethylaminophenyl, ethylaminophenyl, diethylaminophenyl, trimethylammoniumphenyl, triethylammoniumphenyl, trimethylammoniummethylcarbonylaminophenyl, triethylammoniummethylcarbonylaminophenyl, trimethylammoniumethylcarbonylaminophenyl, triethylammoniumethylcarbonylaminophenyl, trimethylammoniumpropylcarbonylaminophenyl, triethylammoniumpropylcarbonylaminophenyl, trimethylammoniumbutylcarbonylaminophenyl, triethylammoniumbutylcarbonylaminophenyl, methylcarbonylaminophenyl, chloromethylcarbonylaminophenyl, fluoromethylcarbonylaminophenyl, bromomethylcarbonylaminophenyl, iodomethylcarbonylaminophenyl, ethylcarbonylaminophenyl, chloroethylcarbonylaminophenyl, fluoroethylcarbonylaminophenyl, bromoethylcarbonylaminophenyl, iodoethylcarbonylaminophenyl, propylcarbonylaminophenyl, chloropropylcarbonylaminophenyl, fluoropropylcarbonylaminophenyl, bromopropylcarbonylaminophenyl, iodopropylcarbonylaminophenyl, butylcarbonylaminophenyl, chlorobutylcarbonylaminophenyl, fluorobutylcarbonylaminophenyl, bromobutylcarbonylaminophenyl, iodobutylcarbonylaminophenyl, 3,4-dioxymethylenephenyl, pyridinyl, methylpyridinyl, pyridinium, methylpyridinium, thienyl, chlorothienyl, fluorothienyl, bromothienyl, iodothienyl; methoxycarbonylphenyl, ethoxycarbonylphenyl, trimethylammoniumethoxyethoxyethoxyphenyl, triethylammoniumethoxyethoxyethoxyphenyl, chloroethoxyethoxyethoxyphenyl, fluoroethoxyethoxyethoxyphenyl, bromoethoxyethoxyethoxyphenyl, iodoethoxyethoxyethoxyphenyl, pyridiniumethoxyethoxyethoxyphenyl, piperazinyloxymethoxyethoxyethoxyphenyl, methylpiperazinyloxymethoxyethoxyethoxyphenyl, dimethylpiperazinyloxymethoxyethoxyethoxyphenyl, piperidinyloxymethoxyethoxyethoxyphenyl, methylpiperidinyloxymethoxyethoxyethoxyphenyl, and dimethylpiperidinyloxymethoxyethoxyethoxyphenyl; and R N is selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl and benzyl; and one or more R x radicals are independently selected from the group consisting of hydroxy, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, methoxy, ethoxy, n-propoxy, isopropoxy, methylthio, methylsulfinyl, methylsulfonyl, ethylthio, ethylsulfinyl, ethylsulfonyl, amino, hydroxyamino, methylamino, dimethylamino, ethylamino, diethylamino, trimethylammonium, triethylammonium, N-methyl-N-carboxymethyl-amino, N,N-dimethyl-N-carboxymethyl-ammonium, methylcarbonylamino, chloromethylcarbonylamino, fluoromethylcarbonylamino, bromomethylcarbonylamino, iodomethylcarbonylamino, ethylcarbonylamino, n-propylcarbonylamino, n-butylcarbonylamino, n-pentylcarbonylamino, n-hexylcarbonylamino, benzyloxycarbonylamino, aminoimidocarbonylamino, morpholinyl, N-methyl-morpholinium, azetidinyl, N-methyl-azetidinium, pyrrolidine, N-methyl-pyrrolidinium, piperazinyl, N-methylpiperazinyl, N,N'-dimethyl-piperazinium, piperidinyl, methylpiperidinyl, N-methyl-piperidinium, and thienyl; or a pharmaceutically acceptable salt, solvate, or prodrug thereof.
6. A compound of claim 1 wherein:
q is an integer from 1 to 4;
R1 and R2 are independently selected from the group consisting of hydrogen and (C1-C10)alkyl; or R1 and R2 taken together with the carbon to which they are attached form (C3-C10)cycloalkyl; and R3 and R4 are independently selected from the group consisting of hydrogen and hydroxy; and R5 is phenyl, wherein said phenyl is optionally substituted with one or more radicals independently selected from the group consisting of halogen;
hydroxy; -NO2; (C1-C10)alkyl; halo(C1-C10)alkyl; aryl(C1-C10)alkyl;
heterocyclyl(C1-C10)alkyl; polyether; -OR13; -NR13R14; and -NR13C(O)R14;
and wherein R13, R14, and R15 are independently selected from the group consisting of hydrogen; (C1-C10)alkyl; halo(C1-C10)alkyl; heterocyclyl;
quaternary heterocyclyl; aryl(C1-C10)alkyl; heterocyclyl(C1-C10)alkyl;
quaternary heterocyclyl(C1-C10)alkyl; (C1-C10)alkylheterocyclyl(C1-C10)alkyl;
(C1-C10)alkylammonium(C1-C10)alkyl; and polyether; or wherein the R13, R14, and R15 (C1-C10)alkyl; halo(C1-C10)alkyl;
heterocyclyl; quaternary heterocyclyl; aryl(C1-C10)alkyl; heterocyclyl(C1-C10)alkyl; quaternary heterocyclyl(C1-C10)alkyl; (C1-C10)alkylheterocyclyl(C1-C10)alkyl; (C1-C10)alkylammonium(C1-C10)alkyl; and polyether radicals optionally may be substituted with one or more radicals selected from the group consisting of halogen; (C1-C10)alkyl; heterocyclyl; quaternary heterocyclyl; quaternary heterocyclyl(C1-C10)alkyl; carboxy; carboxy(C1-C10)alkyl; -OR16; -NR9R10; -N+R9R10R w A-; and -CONR9R10; and wherein R9 and R10 are independently selected from the group consisting of hydrogen; (C1-C10)alkyl; heterocyclyl; ammonium(C1-C10)alkyl;
(C1-C10)alkylammonium(C1-C10)alkyl; aryl(C1-C10)alkyl; heterocyclyl(C1-C10)alkyl; carboxy(C1-C10)alkyl; carbo(C1-C10)alkoxy(C1-C10)alkyl;
carboxyheterocyclyl; carboxy(C1-C10)alkylamino; and acyl; and wherein A- is a pharmaceutically acceptable anion; and wherein R11 and R12 are independently selected from the group consisting of hydrogen; (C1-C10)alkyl; heterocyclyl; aryl(C1-C10)alkyl;
carboxy(C1-C10)alkyl; and carbo(C1-C10)alkoxy(C1-C10)alkyl; or R11 and R12 together with the carbon atom to which they are attached form a cyclic ring; and wherein R w and R16 are as defined in claim 2; and R6 is hydrogen; and R N is selected from the group consisting of hydrogen; (C1-C10)alkyl;
and aryl(C1-C10)alkyl; and one or more R x radicals are independently selected from the group consisting of hydrogen; -NO2; (C1-C10)alkyl; halo(C1-C10)alkyl; -OR13; -NR13R14;
wherein R13 and R14 are as defined above; or a pharmaceutically acceptable salt, solvate, or prodrug thereof; and provided that aryl is selected from the group consisting of optionally substituted phenyl, biphenyl and naphthyl; and provided that heterocyclyl is selected from the group consisting of optionally substituted heterocyclyl comprising a 5 to 10 membered ring and comprising one or more ring atoms that are heteroatoms selected from the group consisting of oxygen, nitrogen, sulfur and phosphorus.
7. A compound of claim 1 wherein:
q is an integer from 1 to 4;

R1 and R2 are independently selected from the group consisting of ethyl and n-butyl; or R1 and R2 taken together with the carbon to which they are attached form cyclopentyl; and one of R3 and R4 is hydrogen and the other of R3 and R4 is hydroxy;
and R5 is selected from the group consisting of phenyl, hydroxyphenyl, methoxyphenyl, ethoxyphenyl, nitrophenyl, aminophenyl, methylaminophenyl, dimethylaminophenyl, ethylaminophenyl, diethylaminophenyl, trimethylammoniumphenyl, triethylammoniumphenyl, trimethylammoniummethylcarbonylaminophenyl, triethylammoniummethylcarbonylaminophenyl, trimethylammoniumethylcarbonylaminophenyl, triethylammoniumethylcarbonylaminophenyl, trimethylammoniumpropylcarbonylaminophenyl, triethylammoniumpropylcarbonylaminophenyl, trimethylammoniumbutylcarbonylaminophenyl, triethylammoniumbutylcarbonylaminophenyl, methylcarbonylaminophenyl, chloromethylcarbonylaminophenyl, fluoromethylcarbonylaminophenyl, bromomethylcarbonylaminophenyl, iodomethylcarbonylaminophenyl, ethylcarbonylaminophenyl, chloroethylcarbonylaminophenyl, fluoroethylcarbonylaminophenyl, bromoethylcarbonylaminophenyl, iodoethylcarbonylaminophenyl, propylcarbonylaminophenyl, chloropropylcarbonylaminophenyl, fluoropropylcarbonylaminophenyl, bromopropylcarbonylaminophenyl, iodopropylcarbonylaminophenyl, butylcarbonylaminophenyl, chlorobutylcarbonylaminophenyl, fluorobutylcarbonylaminophenyl, bromobutylcarbonylaminophenyl, iodobutylcarbonylaminophenyl, trimethylammoniumethoxyethoxyethoxyphenyl, triethylammoniumethoxyethoxyethoxyphenyl, chloroethoxyethoxyethoxyphenyl, fluoroethoxyethoxyethoxyphenyl, bromoethoxyethoxyethoxyphenyl, iodoethoxyethoxyethoxyphenyl, and pyridiniumethoxyethoxyethoxyphenyl; and R6 is hydrogen;

R N is selected from the group consisting of hydrogen, methyl, ethyl, and benzyl; and one or more R x radicals are independently selected from the group consisting of hydroxy, methyl, ethyl, methoxy, ethoxy, amino, hydroxyamino, methylamino, dimethylamino, ethylamino, diethylamino, trimethylammonium, triethylammonium, N-methyl-N-carboxymethyl-amino, N,N-dimethyl-N-carboxymethyl-ammonium, methylcarbonylamino, chloromethylcarbonylamino, fluoromethylcarbonylamino, bromomethylcarbonylamino, iodomethylcarbonylamino, ethylcarbonylamino, benzyloxycarbonylamino, and aminoimidocarbonylamino; or a pharmaceutically acceptable salt, solvate, or prodrug thereof.
8. A compound of claim 1 selected from the compounds of the group consisting of:
(4R,5R)-3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-2-methyl-5-(3-nitrophenyl)-1,2-benzothiazepin-4-ol 1,1-dioxide;
(4R,5R)-5-(3-aminophenyl)-3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-2-methyl-1,2-benzothiazepin-4-ol 1,1-dioxide;
5-chloro-N [3-[(4R,5R)-3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-4-hydroxy-2-methyl-1,1-dioxido-1,2-benzothiazepin-5-yl]phenyl]pentanamide;
5-[[3-[(4R,5R)-3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-4-hydroxy-2-methyl-1,1-dioxido-1,2-benzothiazepin-5-yl]phenyl]amino]-N,N,N-triethyl-5-oxo-pentanaminium trifluoroacetate;
2-chloro-N-[3-[(4R,5R)-3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-4-hydroxy-2-methyl-1,1-dioxido-1,2-benzothiazepin-5-yl]phenyl]acetamide;
2-[[3-[(4R,5R)-3,3-dibutyl-7-(dimethylamino]-2,3,4,5-tetrahydro-4-hydroxy-2-methyl-1,1-dioxido-1,2-benzothiazepin-5-yl]phenyl]amino]-N,N,N-triethyl-2-oxoethanaminium chloride;

(4R,5R)-3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-5-(4-methoxyphenyl)-2-methyl-1,2-benzothiazepin-4-ol 1,1-dioxide;
(4R,5R)-3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-5-(4-hydroxyphenyl)-2-methyl-1,2-benzothiazepin-4-ol 1,1-dioxide;
(4R,5R)-3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-5-(4-(((2-iodoethyoxy)ethoxy)ethoxy)phenyl)-2-methyl-1,2-benzothiazepin-4-ol 1,1-dioxide;
1-[2-[2-[2-[4-[(4R,5R)-3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-4-hydroxy-2-methyl-1,1-dioxido-1,2-benzothiazepin-5-yl]phenoxy]ethoxy]ethoxy]ethyl]pyridinium;
2-[2-[2-[4-[(4R,5R)-3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-4-hydroxy-2-methyl-1,1-dioxido-1,2-benzothiazepin-5-yl]phenoxy]ethoxy]ethoxy]-N,N,N-triethylethanaminium iodide;
(4R,5R)-3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-5-(3-methoxyphenyl)-2-methyl-1,2-benzothiazepin-4-ol 1,1-dioxide;
(4R,5R)-3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-5-(3-nitrophenyl)-1,2-benzothiazepin-4-ol 1,1-dioxide and (4S,5R)-3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-5-(3-nitrophenyl)-1,2-benzothiazepin-4-ol 1,1-dioxide;
(4R,5R)-5-(3-aminophenyl)-3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-1,2-benzothiazepin-4-ol 1,1-dioxide;
5-bromo-N-[3-[(4R,5R)-3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-4-hydroxy-1,1-dioxido-1,2-benzothiazepin-5-yl)phenyl]pentanamide;
5-[[3-[(4R,5R)-3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-4-hydroxy-1,1-dioxido-1,2-benzothiazepin-5-yl]phenyl]amino]-N,N,N-triethyl-5-oxo-1-pentanaminium trifluoroacetate;

(4R,5R)-3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-5-phenyl-1,2-benzothiazepin-4-ol 1,1-dioxide;
(4R,5R)-3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-5-(4-methoxyphenyl)-1,2-benzothiazepin-4-ol 1,1-dioxide;
(4R,5R)-3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-5-(4-hydroxyphenyl)-1,2-benzothiazepin-4-ol 1,1-dioxide;
2-[2-[2-[4-[(4R,5R)-3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-4-hydroxy-1,1-dioxido-1,2-benzothiazepin-5-yl]phenoxy]ethoxy]ethoxy]-N,N,N-triethylethanaminium iodide;
(4R,5R)-3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-5-(3-nitrophenyl)-2-(phenylmethyl)-1,2-benzothiazepin-4-ol 1,1-dioxide;
(4R,5R)-3,3-dibutyl-7-(dimethylamino)-5-[3-(ethylamino)phenyl]-2,3,4,5-tetrahydro-2-(phenylmethyl)-1,2-benzothiazepin-4-ol 1,1-dioxide;
(4R,5R)-3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-5-(4-methoxyphenyl)-2-(phenylmethyl)-1,2-benzothiazepin-4-ol 1,1-dioxide; and (4R,5R)-7-dimethylamino)-2-ethyl-4,5-dihydro-5-(4-methoxyphenyl)-spiro[1,2-benzothiazepine-3(2H),1'-cyclopentan]-4-ol 1,1-dioxide; and their pharmaceutically acceptable salts.
9. A compound of claim 2 wherein R5 and R6 are independently selected from the group consisting of H; aryl; heterocyclyl; and quaternary heterocyclyl;
wherein the R5 and R6 aryl; heterocyclyl; and quaternary heterocyclyl radicals optionally may be substituted with one or more radicals independently selected from the group consisting of halogen; -CN; -NO2; oxo; alkyl;
polyalkyl; haloalkyl; hydroxyalkyl; cycloalkyl; alkenyl; alkynyl; aryl;
heterocyclyl; quaternary heterocyclyl; arylalkyl; heterocyclylalkyl;
polyether; -OR13; -NR13R14; -SR13; -S(O)R13; -SO2R13; -SO3R13; -NR13OR14; -NR13NR14R15; -CO2R13; -OM; -SO2OM; -SO2NR13R14; -C(O)NR13R14;
-C(O)OM; -COR13; -NR13C(O)R14; -NR13C(O)NR14R15; -NR13CO2R14; -OC(O)R13; -OC(O)NR13R14; -NR13SOR14; -NR13SO2R14; -NR13SONR14R15; -NR13SO2NR14R15; -PR13R14; -P(O)R13R14; -PR13R14; -P+R13R14R15A-; -P(OR13)OR14; -S+R13R14A-; and -N+R13R14R15A-; and wherein the alkyl, polyalkyl, haloalkyl, hydroxyalkyl, cycloalkyl, alkenyl, alkynyl, aryl, heterocyclyl, quaternary heterocyclyl, arylalkyl, heterocyclylalkyl, and polyether substituents of the R5 and R6 radicals optionally may be further substituted with one or more radicals selected from the group consisting of -CN; halogen; hydroxy; oxo; alkyl; cycloalkyl;
alkenyl;
alkynyl; aryl; heterocyclyl; arylalkyl; heterocyclylalkyl; quaternary heterocyclyl; -OR7; -NR7R8; -SR7; -S(O)R7; -SO2R7; -SO3R7;- CO2R7; -CONR7R8; -N+R7R8R9A-; -P(O)R7R8; -PR7R8; -P+R7R8R9A-; and -P(O)(OR7)OR8; and wherein the alkyl, polyalkyl, haloalkyl, hydroxyalkyl, cycloalkyl, alkenyl, alkynyl, aryl, heterocyclyl, quaternary heterocyclyl, arylalkyl, heterocyclylalkyl, and polyether substituents of the R5 and R6 radicals optionally may have one or more carbons replaced by -O-; -NR7-; -N+R7R8A--; -S-; -SO-; -SO2-; -S+R7A- -; -PR7-; -P(O)R7-; -P+R7R8A- -; or phenylene;
and wherein R7 and R8 are independently selected from the group consisting of hydrogen; alkyl, alkenyl; alkynyl; aryl; and heterocyclyl; and wherein R13, R14, and R15 are independently selected from the group consisting of hydrogen; alkyl; haloalkyl; cycloalkyl; polyalkyl; alkenyl;
alkynyl; aryl; heterocyclyl; quaternary heterocyclyl; arylalkyl;
heterocyclylalkyl; quaternary heterocyclylalkyl; alkylarylalkyl;
alkylheterocyclylalkyl; alkylammoniumalkyl; aminocarbonylalkyl;
alkylaminocarbonylalkyl; carboxyalkylaminocarbonylalkyl; and polyether; or wherein R13 and R14 together with the nitrogen atom to which they are attached form a mono- or polycyclic heterocyclyl that is optionally substituted with one or more radicals selected from the group consisting of oxo, carboxy, and quaternary salts; or wherein R14 and R15 together with the nitrogen atom to which they are attached form a cyclic ring; and wherein the R13, R14, and R15 alkyl; haloalkyl; cycloalkyl; polyalkyl;
alkenyl; alkynyl; aryl; heterocyclyl; quaternary heterocyclyl; arylalkyl;
heterocyclylalkyl; quaternary heterocyclylalkyl; alkylarylalkyl;
alkylheterocyclylalkyl; alkylammoniumalkyl; aminocarbonylalkyl;
alkylaminocarbonylalkyl; carboxyalkylaminocarbonylalkyl; and polyether radicals optionally may be substituted with one or more radicals selected from the group consisting of halogen; -CN; sulfo; oxo; alkyl; haloalkyl;
hydroxyalkyl; sulfoalkyl; alkenyl; alkynyl; aryl; heterocyclyl; quaternary heterocyclyl; quaternary heterocyclylalkyl; carboxy; carboxyalkyl; guanidinyl;
-OR16; -NR9R10; -N+R9R10R w A-; -SR16; -S(O)R9; -SO2R9; -SO3R16; -CO2R16; -CONR9R10; -SO2NR9R10; -PO(OR16)OR17; -PR9R10; -P+R9R10R11A-; -S+R9R10A-; and carbohydrate residue; and wherein the R13, R14, and R15 alkyl; haloalkyl; cycloalkyl; polyalkyl;
alkenyl; alkynyl; aryl; heterocyclyl; quaternary heterocyclyl; arylalkyl;
heterocyclylalkyl; quaternary heterocyclylalkyl; alkylarylalkyl;
alkylheterocyclylalkyl; alkylammoniumalkyl; aminocarbonylalkyl;
alkylaminocarbonylalkyl; carboxyalkylaminocarbonylalkyl; and polyether radicals optionally may have one or more carbons replaced by -O-; -NR9-; -N+R9R10A- -; -S-; -SO-; -SO2-; -S+R9A- -; -PR9-; -P+R9R10A- -; -P(O)R9-;
phenylene; carbohydrate residue; amino acid residue; peptide residue; or polypeptide residue; and wherein R16 and R17 are independently selected from the group consisting of R9 and M; and wherein M is a pharmaceutically acceptable cation; and wherein R9, R10, R11, R12, R w, and A- are as defined in claim 2.
10. A compound of claim 2 wherein R5 or R6 has the formula -Ar-(R y)t wherein:
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 benzoisothiazolyl; and one or more R y are independently selected from the group consisting of halogen; -CN; -NO2; oxo; alkyl; polyalkyl; haloalkyl; hydroxyalkyl;
cycloalkyl; alkenyl; alkynyl; aryl; heterocyclyl; quaternary heterocyclyl;
arylalkyl; heterocyclylalkyl; polyether; -OR13; -NR13R14; -SR13; -S(O)R13;
-SO2R13; -SO3R13; -NR13OR14; -NR13NR14R15; -CO2R13; -OM; -SO2OM; -SO2NR13R14; -C(O)NR13R14; -C(O)OM; -COR13; -NR13C(O)R14; -NR13C(O)NR14R15; -NR13CO2R14; -OC(O)R13; -OC(O)NR13R14;
-NR13SOR14; -NR13SO2R14; -NR13SONR14R15; -NR13SO2NR14R15; -P(O)R13R14; -PR13R14; -P+R13R14R15A-; -P(OR13)OR14; -S+R13R14A-;
and -N+R13R14R15A-; and wherein the alkyl, polyalkyl, haloalkyl, hydroxyalkyl, cycloalkyl, alkenyl, alkynyl, aryl, heterocyclyl, quaternary heterocyclyl, arylalkyl, heterocyclylalkyl, and polyether substituents of the R y radicals optionally may be further substituted with one or more radicals selected from the group consisting of -CN; halogen; hydroxy; oxo; alkyl; cycloalkyl; alkenyl; alkynyl;
aryl; heterocyclyl; arylalkyl; heterocyclylalkyl; quaternary heterocyclyl; -OR7;
-NR7R8; -SR7; -S(O)R7; -SO2R7; -SO3R7;-CO2R7; -CONR7R8; -N+R7R8R9A-; -P(O)R7R8; -PR7R8; -P+R7R8R9A-; and -P(O)(OR7)OR8;
and wherein the alkyl, polyalkyl, haloalkyl, hydroxyalkyl, cycloalkyl, alkenyl, alkynyl, aryl, heterocyclyl, quaternary heterocyclyl, arylalkyl, heterocyclylalkyl, and polyether substituents of the R y radicals optionally may have one or more carbons replaced by -O-; -NR7-; -N+R7R8A- -; -S-; -SO-; -SO2-; -S+R7A- -; -PR7-; -P(O)R7-; -P+R7R8A- -; or phenylene; and wherein R7 and R8 are independently selected from the group consisting of hydrogen; alkyl, alkenyl; alkynyl; aryl; and heterocyclyl; and wherein R13, R14, and R15 are independently selected from the group consisting of hydrogen; alkyl; haloalkyl; cycloalkyl; polyalkyl; alkenyl;
alkynyl; aryl; heterocyclyl; quaternary heterocyclyl; arylalkyl;
heterocyclylalkyl; quaternary heterocyclylalkyl; alkylarylalkyl;
alkylheterocyclylalkyl; alkylammoniumalkyl; aminocarbonylalkyl;
alkylaminocarbonylalkyl; carboxyalkylaminocarbonylalkyl; and polyether; or wherein R13 and R14 together with the nitrogen atom to which they are attached form a mono- or polycyclic heterocyclyl that is optionally substituted with one or more radicals selected from the group consisting of oxo, carboxy, and quaternary salts; or wherein R14 and R15 together with the nitrogen atom to which they are attached form a cyclic ring; and wherein the R13, R14, and R15 alkyl; haloalkyl; cycloalkyl; polyalkyl;
alkenyl; alkynyl; aryl; heterocyclyl; quaternary heterocyclyl; arylalkyl;
heterocyclylalkyl; quaternary heterocyclylalkyl; alkylarylalkyl;
alkylheterocyclylalkyl; alkylammoniumalkyl; aminocarbonylalkyl;
alkylaminocarbonylalkyl; carboxyalkylaminocarbonylalkyl; and polyether radicals optionally may be substituted with one or more radicals selected from the group consisting of halogen; -CN; sulfo; oxo; alkyl; haloalkyl;
hydroxyalkyl; sulfoalkyl; alkenyl; alkynyl; aryl; heterocyclyl; quaternary heterocyclyl; quaternary heterocyclylalkyl; carboxy; carboxyalkyl; guanidinyl;
-OR16; -NR9R10; -N+R9R10R w A-; -SR16; -S(O)R9; -SO2R9; -SO3R16; -CO2R16; -CONR9R10; -SO2NR9R10; -PO(OR16)OR17; -PR9R10; -P+R9R10R11A-; -S+R9R10A-; and carbohydrate residue; and wherein the R13, R14, andd R15 alkyl; haloalkyl; cycloalkyl; polyalkyl;
alkenyl; alkynyl; aryl; heterocyclyl; quaternary heterocyclyl; arylalkyl;
heterocyclylalkyl; quaternary heterocyclylalkyl; alkylarylalkyl;
alkylheterocyclylalkyl; alkylammoniumalkyl; aminocarbonylalkyl;
alkylaminocarbonylalkyl; carboxyalkylaminocarbonylalkyl; and polyether radicals optionally may have one or more carbons replaced by -O-; -NR9-; -N+R9R10A- -; -S-; -SO-; -SO2-; -S+R9A- -; -PR9-; -P+R9R10A- -; -P(O)R9-;
phenylene; carbohydrate residue; amino acid residue; peptide residue; or polypeptide residue; and wherein R16 and R17 are independently selected from the group consisting of R9 and M; and wherein M is a pharmaceutically acceptable cation; and wherein R9, R10, R11, R12, R w, and A- are as defined in claim 2.
11. A compound of claim 2 wherein at least one of R5 and R6 has the formula wherein R y and t are defined as in claim 10.
12. A compound of claim 11 wherein R N is selected from the group consisting of hydrogen, alkyl and aralkyl.
13. A compound of claim 11 wherein R N is selected from the group consisting of hydrogen, (C1-C10)alkyl and aryl(C1-C10)alkyl.
14. A compound of claim 11 wherein R N is selected from the group consisting of hydrogen, methyl, ethyl and benzyl.
15. A compound of claim 11 wherein R1 and R2 are independently selected from the group consisting of hydrogen, alkyl, and (C3-C10)cycloalkyl.
16. A compound of claim 11 wherein R1 and R2 are independently selected from the group consisting of hydrogen and (C1-C10)alkyl.
17. A compound of claim 11 wherein R1 and R2 are independently selected from the group consisting of (C1-C10)alkyl.
18. A compound of claim 11 wherein R1 and R2 are independently selected from the group consisting of (C1-C7)alkyl.
19. A compound of claim 11 wherein R1 and R2 are independently selected from the group consisting of (C2-C4)alkyl.
20. A compound of claim 11 wherein R1 and R2 are the same (C1-C10)alkyl.
21. A compound of claim 11 wherein R1 and R2 are independently selected from the group consisting ethyl; n-propyl; n-butyl; and isobutyl.
22. A compound of claim 11 wherein R1 and R2 are each n-butyl.
23. A compound of claim 11 wherein one of R1 and R2 is ethyl and the other of R1 and R2 is n-butyl.
24. A compound of claim 11 wherein q is 1, 2, or 3.
25. A compound of claim 11 wherein q is 1 or 2.
26. A compound of claim 11 wherein q is 1.
27. A compound of claim 11 wherein R3 and R4 are independently selected from the group consisting of hydrogen and -OR9.
28. A compound of claim 27 wherein R9 is hydrogen.
29. A compound of claim 28 wherein said hydroxy group is in a syn relationship to said structure of formula (II).
30. A compound of claim 11 wherein R X radicals are present at the 7-, 8- and 9-positions of the benzo ring of the structure of formula (I).
31. A compound of claim 11 wherein an R X radical is present at one or more of the 7-, 8-, or 9-positions of the benzo ring of the structure of formula (I).
32. A compound of claim 11 wherein R X radicals are present at the 7- and 9-positions of the benzo ring of the structure of formula (I).
33. A compound of claim 11 wherein an R x radical is present at the 7-position of the benzo ring of the structure of formula (I).
34. A compound of claim 32 wherein said one or more R x are independently selected from the group consisting of alkyl; aryl; cycloalkyl;
heterocyclyl; polyalkyl; acyloxy; polyether; halogen; -OR13; -NR13R14; -NR13NR14R15; -N+R9R11R12A-; -SR13; -S+R13R14A; -CO2R13; and -NR14C(O)R13;
wherein alkyl; aryl; cycloalkyl; heterocyclyl; polyalkyl; acyloxy; and polyether; can be further substituted with -OR16; -NR9R10; -N+R9R10R W A-;
-SR16; -S(O)R9; -SO2R9; -SO3R16; oxo; -CO2R16; -CN; halogen; -CONR9R10; -SO2NR9R10; -PO(OR16)OR17; -PR9R10; -P+R9R11R12A-; or -S+R9R10A-; and wherein in R X, one or more carbons are optionally replaced by -O-; -NR13-; -N+R13R14A--; -S-; -SO-; -SO2-; -S+R13A--; -PR13-; -P(O)R13-; -P+R13R14A--; phenylene; amino acid residue; peptide residue; polypeptide residue; carbohydrate residue; polyether; or polyalkyl; and wherein in said polyalkyl; phenylene; amino acid residue; peptide residue; polypeptide residue; and carbohydrate residue; one or more carbons are optionally replaced by -O-; -NR9-; -N+R9R10A--; -S-; -SO-; -SO2-; -S+R9A--; -PR9-; -P+R9R10A--; or -P(O)R9-.
35. A compound of claim 33 wherein said one or more R X are independently selected from the group consisting of alkyl; aryl; cycloalkyl;
heterocyclyl; polyalkyl; acyloxy; polyether; halogen; -OR13; -NR13R14; -NR13NR14R15; -N+R9R11R12A-; -SR13; -S+R13R14A-; -CO2R13; and -NR14C(O)R13;
wherein alkyl; aryl; cycloalkyl; heterocyclyl; polyalkyl; acyloxy; and polyether; can be further substituted with -OR16; -NR9R10; -N+R9R10R W A-;
-SR16; -S(O)R9; -SO2R9; -SO3R16; oxo; -CO2R16; -CN; halogen; -CONR9R10; -SO2NR9R10; -PO(OR16)OR17; -PR9R10; -P+R9R11R12A-; or -S+R9R10A-; and wherein in R X, one or more carbons are optionally replaced by -O-; -NR13-; -N+R13R14A--; -S-; -SO-; -SO2-; -S+R13A--; -PR13-; -P(O)R13-; -P+R13R14A--; phenylene; amino acid residue; peptide residue; polypeptide residue; carbohydrate residue; polyether; or polyalkyl; and wherein in said polyalkyl; phenylene; amino acid residue; peptide residue; polypeptide residue; and carbohydrate residue; one or more carbons are optionally replaced by -O-; -NR9-; -N+R9R10A--; -S-; -SO-; -SO2-; -S+R9A--; -PR9-; -P+R9R10A--; or -P(O)R9-.
36. A compound of claim 34 wherein said one or more R X are independently selected from the group consisting of polyether; -OR13; -NR13R14; and -N+R9R11R12A-.
37. A compound of the claim 35 wherein said R X is selected from the group consisting of polyether; -OR13; -NR13R14; and -N+R9R11R12A-.
38. A compound of claim 36 wherein said one or more R X are independently selected from the group consisting of -OR13 and -NR13R14
39. A compound of claim 37 wherein said R X is independently selected from the group consisting of -OR13 and -NR13R14.
40. A compound of claim 38 wherein R13 and R14 are each methyl.
41. A compound of the claim 39 wherein R13 and R14 are each methyl.
42. A compound of claim 11 wherein an R Y substituent is attached at the 3- or the 4-position of the phenyl ring of the structure of formula (II).
43. A compound of claim 11 wherein t is 1 or 2.
44. A compound of claim 42 wherein t is 1 or 2.
45. A compound of claim 11 wherein said one or more R Y are independently selected from the group consisting of hydrogen; halogen;
hydroxy; -NO2; (C1-C10)alkyl; halo(C1-C10)alkyl; aryl(C1-C10)alkyl;

heterocyclyl(C1-C10)alkyl; polyether; -OR13; -NR13R14; and -NR13C(O)R14;
and wherein R13, R14, and R15 are independently selected from the group consisting of hydrogen; (C1-C10)alkyl; halo(C1-C10)alkyl; heterocyclyl;
quaternary heterocyclyl; aryl(C1-C10)alkyl; heterocyclyl(C1-C10)alkyl;
quaternary heterocyclyl(C1-C10)alkyl; (C1-C10)alkylheterocyclyl(C1-C10)alkyl;
(C1-C10)alkylammonium(C1-C10)alkyl; and polyether; or wherein the R13, R14, and R15 (C1-C10)alkyl; heterocyclyl; quaternary heterocyclyl; aryl(C1-C10)alkyl; halo(C1-C10)alkyl; heterocyclyl(C1-C10)alkyl;
quaternary heterocyclyl(C1-C10)alkyl; (C1-C10)alkylheterocyclyl(C1-C10)alkyl;
(C1-C10)alkylammonium(C1-C10)alkyl; and polyether radicals optionally may be substituted with one or more radicals selected from the group consisting of halogen; (C1-C10)alkyl; heterocyclyl; quaternary heterocyclyl; quaternary heterocyclyl(C1-C10)alkyl; carboxy; carboxy(C1-C10)alkyl; -OR16; -NR9R10; -N+R9R10R W A-; and -CONR9R10; and wherein R9, R10, and R W are independently selected from the group consisting of hydrogen; (C1,-C10)alkyl; heterocyclyl; ammonium(C1-C10)alkyl;
(C1-C10)alkylammonium(C1-C10)alkyl; aryl(C1-C10)alkyl; heterocyclyl(C1-C10)alkyl; carboxy(C1-C10)alkyl; carbo(C1-C10)alkoxy(C1-C10)alkyl;
carboxyheterocyclyl; carboxy(C1-C10)alkylamino; and acyl; and wherein A- is a pharmaceutically acceptable anion; and wherein R11 and R12 are independently selected from the group consisting of hydrogen; (C1-C10)alkyl; heterocyclyl; aryl(C1-C10)alkyl;
carboxy(C1-C10)alkyl; and carbo(C1-C10)alkoxy(C1-C10)alkyl; or R11 and R12 together with the carbon atom to which they are attached form a cyclic ring; and wherein R16 and R17 are independently selected from the group consisting of R9 and M; and wherein M is a pharmaceutically acceptable cation.
46. A compound of claim 11 wherein said R Y is independently selected from the group consisting of hydrogen, chloro, fluoro, bromo, iodo, hydroxy, methoxy, ethoxy, nitro, amino, methylamino, dimethylamino, ethylamino, diethylamino, trimethylammonium, triethylammonium, trimethylammoniummethylcarbonylamino, triethylammoniummethylcarbonylamino, trimethylammoniumethylcarbonylamino, triethylammoniumethylcarbonylamino, trimethylammoniumpropylcarbonylamino, triethylammoniumpropylcarbonylamino, trimethylammoniumbutylcarbonylamino, triethylammoniumbutylcarbonylamino, methylcarbonylamino, chloromethylcarbonylamino, fluoromethylcarbonylamino, bromomethylcarbonylamino, iodomethylcarbonylamino, ethylcarbonylamino, chloroethylcarbonylamino, fluoroethylcarbonylamino, bromoethylcarbonylamino, iodoethylcarbonylamino, propylcarbonylamino, chloropropylcarbonylamino, fluoropropylcarbonylamino, bromopropylcarbonylamino, iodopropylcarbonylamino, butylcarbonylamino, chlorobutylcarbonylamino, fluorobutylcarbonylamino, bromobutylcarbonylamino, iodobutylcarbonylamino, methoxycarbonyl, ethoxycarbonyl, trimethylammoniumethoxyethoxyethoxy, triethylammoniumethoxyethoxyethoxy, chloroethoxyethoxyethoxy, fluoroethoxyethoxyethoxy, bromoethoxyethoxyethoxy, iodoethoxyethoxyethoxy, pyridiniumethoxyethoxyethoxy, piperazinyloxymethoxyethoxyethoxy, methylpiperazinyloxymethoxyethoxyethoxy, dimethylpiperazinyloxymethoxyethoxyethoxy, piperidinyloxymethoxyethoxyethoxy, methylpiperidinyloxymethoxyethoxyethoxy, and dimethylpiperidinyloxymethoxyethoxyethoxyphenyl.
47. A compound of claim 11 wherein said one or more R Y are independently selected from the group consisting of hydroxy, methoxy, ethoxy, nitro, amino, methylamino, dimethylamino, ethylamino, diethylamino, trimethylammonium, triethylammonium, trimethylammoniummethylcarbonylamino, triethylammoniummethylcarbonylamino, trimethylammoniumethylcarbonylamino, triethylammoniumethylcarbonylamino, trimethylammoniumpropylcarbonylamino, triethylammoniumpropylcarbonylamino, trimethylammoniumbutylcarbonylamino, triethylammoniumbutylcarbonylamino, methylcarbonylamino, chloromethylcarbonylamino, fluoromethylcarbonylamino, bromomethylcarbonylamino, iodomethylcarbonylamino, ethylcarbonylamino, chloroethylcarbonylamino, fluoroethylcarbonylamino, bromoethylcarbonylamino, iodoethylcarbonylamino, propylcarbonylamino, chloropropylcarbonylamino, fluoropropylcarbonylamino, bromopropylcarbonylamino, iodopropylcarbonylamino, butylcarbonylamino, chlorobutylcarbonylamino, fluorobutylcarbonylamino, bromobutylcarbonylamino, iodobutylcarbonylamino, trimethylammoniumethoxyethoxyethoxy, triethylammoniumethoxyethoxyethoxy, chloroethoxyethoxyethoxy, fluoroethoxyethoxyethoxy, bromoethoxyethoxyethoxy, iodoethoxyethoxyethoxy, and pyridiniumethoxyethoxyethoxy.
48. A compound of claim 11 wherein said one or more R Y are independently selected from the group consisting of trimethylammonium, triethylammonium, trimethylammoniummethylcarbonylamino, triethylammoniummethylcarbonylamino, trimethylammoniumethylcarbonylamino, triethylammoniumethylcarbonylamino, trimethylammoniumpropylcarbonylamino, triethylammoniumpropylcarbonylamino, trimethylammoniumbutylcarbonylamino, triethylammoniumbutylcarbonylamino, trimethylammoniumethoxyethoxyethoxy, and triethylammoniumethoxyethoxyethoxy.
49. A compound of claim 11 wherein:
R N is selected from the group consisting of hydrogen, alkyl and aralkyl;
and R1 and R2 are independently selected from the group consisting of hydrogen, alkyl, and (C3-C10)cycloalkyl.
50. A compound of claim 11 wherein:
R N is selected from the group consisting of hydrogen, alkyl and aralkyl;
and R3 and R4 are independently selected from the group consisting of hydrogen and hydroxy.
51. A compound of claim 50 wherein said hydroxy group is in a syn relationship to said structure of formula (II).
52. A compound of claim 11 wherein:
R N is selected from the group consisting of hydrogen, alkyl and aralkyl;
and R X is selected from the group consisting of polyether; -OR13; -NR13R14; and -N+R9R11R12A-;
wherein R9, R11, R12, R13 and R14 are as defined in claim 2.
53. A compound of claim 11 wherein:
R1 and R2 are independently selected from the group consisting of hydrogen, alkyl, and (C3-C10)cycloalkyl; and R3 and R4 are independently selected from the group consisting of hydrogen and hydroxy.
54. A compound of claim 11 wherein:
R1 and R2 are independently selected from the group consisting of hydrogen, alkyl, and (C3-C10)cycloalkyl; and R X
is selected from the group consisting of polyether; -OR13; -NR13R14; and -N+R9R11R12A-;
wherein R9, R11, R12, R13 and R14 are as defined in claim 2.
55. A compound of claim 11 wherein:
R3 and R4 are independently selected from the group consisting of hydrogen and hydroxy; and R X is selected from the group consisting of polyether; -OR13; -NR13R14; and -N+R9R11R12A-;

wherein R9, R11, R12, R13 and R14 are as defined in claim 2.
56. A compound of claim 11 wherein:
R N is selected from the group consisting of hydrogen, alkyl and aralkyl;
R1 and R2 are independently selected from the group consisting of hydrogen, alkyl, and (C3-C10)cycloalkyl; and R3 and R4 are independently selected from the group consisting of hydrogen and hydroxy.
57. A compound of claim 11 wherein:
R N is selected from the group consisting of hydrogen, alkyl and aralkyl;
R1 and R2 are independently selected from the group consisting of hydrogen, alkyl, and (C3-C10)cycloalkyl; and R X
is selected from the group consisting of polyether; -OR13; -NR13R14; and -N+R9R11R12A-;
wherein R9, R11, R12, R13 and R14 are as defined in claim 2.
58. A compound of claim 11 wherein:
R N is selected from the group consisting of hydrogen, alkyl and aralkyl;
R3 and R4 are independently selected from the group consisting of hydrogen and hydroxy; and R X is selected from the group consisting of polyether; -OR13; -NR13R14; and -N+R9R11R12A-;
wherein R9, R11, R12, R13 and R14 are as defined in claim 2.
59. A compound of claim 11 wherein:
R1 and R2 are independently selected from the group consisting of hydrogen, alkyl, and (C3-C10)cycloalkyl;
R3 and R4 are independently selected from the group consisting of hydrogen and hydroxy; and R X is selected from the group consisting of polyether; -OR13; -NR13R14; and -N+R9R11R12A-;
wherein R9, R11, R12, R13 and R14 are as defined in claim 2.
60. A compound of claim 11 wherein:

R N is selected from the group consisting of hydrogen, alkyl and aralkyl;
R1 and R2 are independently selected from the group consisting of hydrogen, alkyl, and (C3-C10)cycloalkyl; R3 and R4 are independently selected from the group consisting of hydrogen and hydroxy;
and R X is selected from the group consisting of polyether; -OR13; -NR13R14; and -N+R9R11R12A-;
wherein R9, R11, R12, R13 and R14 are as defined in claim 2.
61. A compound of claim 60 wherein R N is selected from the group consisting of hydrogen, (C1-C10)alkyl and aryl(C1-C10)alkyl.
62. A compound of claim 60 wherein R N is selected from the group consisting of hydrogen, methyl, ethyl and benzyl.
63. A compound of claim 60 wherein R1 and R2 are independently selected from the group consisting of hydrogen and (C1-C10)alkyl.
64. A compound of claim 60 wherein R1 and R2 are independently selected from the group consisting of (C1-C10)alkyl.
65. A compound of claim 60 wherein R1 and R2 are independently selected from the group consisting of (C2-C4)alkyl.
66. A compound of claim 60 wherein R1 and R2 are independently selected from the group consisting ethyl; n-propyl; n-butyl; and isobutyl.
67. A compound of claim 60 wherein R1 and R2 are each n-butyl.
68. A compound of claim 60 wherein one of R1 and R2 is ethyl and the other of R1 and R2 is n-butyl.
69. A compound of claim 60 wherein q is 1, 2, or 3.
70. A compound of claim 60 wherein q is 1 or 2.
71. A compound of claim 60 wherein q is 1.
72. A compound of claim 60 wherein R X radicals are present at the 7-, 8- and 9-positions of the benzo ring of the structure of formula (I).
73. A compound of claim 60 wherein an R X radical is present at one or more of the 7-, 8-, or 9-positions of the benzo ring of the structure of formula (I).
74. A compound of claim 60 wherein R X radicals are present at the 7- and 9-positions of the benzo ring of the structure of formula (I).
75. A compound of claim 60 wherein an R X radical is present at the 7-position of the benzo ring of the structure of formula (I).
76. A compound of claim 60 wherein said one or more R x are independently selected from the group consisting of -OR13 and -NR13R14, wherein R13 and R14 are as defined in claim 2..
77. A compound of claim 76 wherein R13 and R14 are each methyl.
78. A compound of claim 60 wherein an R Y substituent is independently attached at the 3- or the 4-position of the phenyl ring of formula (II).
79. A compound of claim 60 wherein t is 1 or 2.
80. A compound of claim 60 wherein t is 1.
81. A compound of claim 60 wherein said one or more R Y are independently selected from the group consisting of hydrogen; halogen;
hydroxy; -NO2;(C1-C10)alkyl; halo(C1-C10)alkyl; aryl(C1-C10)alkyl;
heterocyclyl(C1-C10)alkyl; polyether; -OR13; -NR13R14; and -NR13C(O)R14;
and wherein R13, R14, and R15 are independently selected from the group consisting of hydrogen; (C1-C10)alkyl; halo(C1-C10)alkyl; heterocyclyl;
quaternary heterocyclyl; aryl(C1-C10)alkyl; heterocyclyl(C1-C10)alkyl;
quaternary heterocyclyl(C1-C10)alkyl; (C1-C10)alkylheterocyclyl(C1-C10)alkyl;
(C1-C10)alkylammonium(C1-C10)alkyl; and polyether; or wherein the R13, R14, and R15(C1-C10)alkyl; halo(C1-C10)alkyl;
heterocyclyl; quaternary heterocyclyl; aryl(C1-C10)alkyl; heterocyclyl(C1-C10)alkyl; quaternary heterocyclyl(C1-C10)alkyl;(C1-C10)alkylheterocyclyl(C1-C10)alkyl;(C1-C10)alkylammonium(C1-C10)alkyl; and polyether radicals optionally may be substituted with one or more radicals selected from the group consisting of halogen; (C1-C10)alkyl; heterocyclyl; quaternary heterocyclyl; quaternary heterocyclyl(C1-C10)alkyl; carboxy; carboxy(C1-C10)alkyl; -OR16; -NR9R10; -N+R9R10R W A-; and -CONR9R10; and wherein R9, R10, and R W are independently selected from the group consisting of hydrogen; (C1-C10)alkyl; heterocyclyl; ammonium(C1-C10)alkyl;
C1-C10)alkylammonium(C1-C10)alkyl; aryl(C1-C10)alkyl; heterocyclyl(C1-C10)alkyl; carboxy(C1-C10)alkyl; carbo(C1-C10)alkoxy(C1-C10)alkyl;
carboxyheterocyclyl; carboxy(C1-C10)alkylamino; and acyl; and wherein A- is a pharmaceutically acceptable anion; and wherein R11 and R12 are independently selected from the group consisting of hydrogen; (C1-C10)alkyl; heterocyclyl; aryl(C1-C10)alkyl;
carboxy(C1-C10)alkyl; and carbo(C1-C10)alkoxy(C1-C10)alkyl; or R11 and R12 together with the carbon atom to which they are attached form a cyclic ring; and wherein R16 and R17 are independently selected from the group consisting of R9 and M; and wherein M is a pharmaceutically acceptable cation.
82. A compound of claim 60 wherein said R Y is independently selected from the group consisting of hydrogen, chloro, fluoro, bromo, iodo, hydroxy, methoxy, ethoxy, nitro, amino, methylamino, dimethylamino, ethylamino, diethylamino, trimethylammonium, triethylammonium, trimethylammoniummethylcarbonylamino, triethylammoniummethylcarbonylamino, trimethylammoniumethylcarbonylamino, triethylammoniumethylcarbonylamino, trimethylammoniumpropylcarbonylamino, triethylammoniumpropylcarbonylamino, trimethylammoniumbutylcarbonylamino, triethylammoniumbutylcarbonylamino, methylcarbonylamino, chloromethylcarbonylamino, fluoromethylcarbonylamino, bromomethylcarbonylamino, iodomethylcarbonylamino, ethylcarbonylamino, chloroethylcarbonylamino, fluoroethylcarbonylamino, bromoethylcarbonylamino, iodoethylcarbonylamino, propylcarbonylamino, chloropropylcarbonylamino, fluoropropylcarbonylamino, bromopropylcarbonylamino, iodopropylcarbonylamino, butylcarbonylamino, chlorobutylcarbonylamino, fluorobutylcarbonylamino, bromobutylcarbonylamino, iodobutylcarbonylamino, methoxycarbonyl, ethoxycarbonyl, trimethylammoniumethoxyethoxyethoxy, triethylammoniumethoxyethoxyethoxy, chloroethoxyethoxyethoxy, fluoroethoxyethoxyethoxy, bromoethoxyethoxyethoxy, iodoethoxyethoxyethoxy, pyridiniumethoxyethoxyethoxy, piperazinyloxymethoxyethoxyethoxy, methylpiperazinyloxymethoxyethoxyethoxy, dimethylpiperazinyloxymethoxyethoxyethoxy, piperidinyloxymethoxyethoxyethoxy, methylpiperidinyloxymethoxyethoxyethoxy, and dimethylpiperidinyloxymethoxyethoxyethoxyphenyl.
83. A compound of claim 60 wherein said one or more R Y are independently selected from the group consisting of hydroxy, methoxy, ethoxy, nitro, amino, methylamino, dimethylamino, ethylamino, diethylamino, trimethylammonium, triethylammonium, trimethylammoniummethylcarbonylamino, triethylammoniummethylcarbonylamino, trimethylammoniumethylcarbonylamino, triethylammoniumethylcarbonylamino, trimethylammoniumpropylcarbonylamino, triethylammoniumpropylcarbonylamino, trimethylammoniumbutylcarbonylamino, triethylammoniumbutylcarbonylamino, methylcarbonylamino, chloromethylcarbonylamino, fluoromethylcarbonylamino, bromomethylcarbonylamino, iodomethylcarbonylamino, ethylcarbonylamino, chloroethylcarbonylamino, fluoroethylcarbonylamino, bromoethylcarbonylamino, iodoethylcarbonylamino, propylcarbonylamino, chloropropylcarbonylamino, fluoropropylcarbonylamino, bromopropylcarbonylamino, iodopropylcarbonylamino, butylcarbonylamino, chlorobutylcarbonylamino, fluorobutylcarbonylamino, bromobutylcarbonylamino, iodobutylcarbonylamino, trimethylammoniumethoxyethoxyethoxy, triethylammoniumethoxyethoxyethoxy, chloroethoxyethoxyethoxy, fluoroethoxyethoxyethoxy, bromoethoxyethoxyethoxy, iodoethoxyethoxyethoxy, and pyridiniumethoxyethoxyethoxy.
84. A compound of claim 60 wherein said one or more R y are independently selected from the group consisting of trimethylammonium, triethylammonium, trimethylammoniummethylcarbonylamino, triethylammoniummethylcarbonylamino, trimethylammoniumethylcarbonylamino, triethylammoniumethylcarbonylamino, trimethylammoniumpropylcarbonylamino, triethylammoniumpropylcarbonylamino, trimethylammoniumbutylcarbonylamino, triethylammoniumbutylcarbonylamino, trimethylammoniumethoxyethoxyethoxy, and triethylammoniumethoxyethoxyethoxy.
85. A compound of claim 60 wherein said hydroxy group is in a syn relationship to said structure of formula (II).
86. A compound of formula (I):

wherein:
q is 1 or 2;
R1 and R2 are each independently alkyl;
R3 is hydroxy;
R4 and R6 are hydrogen;
R5 has the formula (II):
wherein t is an integer from 0 to 5;
one or more R y are independently selected from the group consisting of hydrogen; halogen; -CN; -NO2; oxo; alkyl; polyalkyl; haloalkyl;
hydroxyalkyl; cycloalkyl; alkenyl; alkynyl; aryl; heterocyclyl; quaternary heterocyclyl; arylalkyl; heterocyclylalkyl; polyether; -OR13; -NR13R14; -SR13; -S(O)R13; -SO2R13; -SO3R13; -NR130R14; -NR13NR14R15; -CO2R13; -OM; -SO2OM; -SO2NR13R14; -C(O)NR13R14; -C(O)OM; -COR13; -NR13C(O)R14; -NR13C(O)NR14R15; -NR13CO2R14; -OC(O)R13; -OC(O)NR13R14; -NR13SOR14; -NR13SO2R14; -NR13SONR14R15; -NR13SO2NR14R15; -P(O)R13R14; -PR13R14; -P+R13R14R15A-; -P(OR13)OR14; -S+R13R14A-; and -N+R13R14R15A-; and wherein the alkyl, polyalkyl, haloalkyl, hydroxyalkyl, cycloalkyl, alkenyl, alkynyl, aryl, heterocyclyl, quaternary heterocyclyl, arylalkyl, heterocyclylalkyl, and polyether substituents of the R y radicals optionally may be further substituted with one or more radicals selected from the group consisting of -CN; halogen; hydroxy; oxo; alkyl; cycloalkyl; alkenyl; alkynyl;
aryl; heterocyclyl; arylalkyl; heterocyclylalkyl; quaternary heterocyclyl; -OR7;
-NR7R8; -SR7; -S(O)R7; -SO2R7; -SO3R7;- CO2R7; -CONR7R8; -N+R7R8R9A-; -P(O)R7R8; -PR7R8; -P+R7R8R9A-; and -P(O)(OR7)OR8;
and wherein the alkyl, polyalkyl, haloalkyl, hydroxyalkyl, cycloalkyl, alkenyl, alkynyl, aryl, heterocyclyl, quaternary heterocyclyl, arylalkyl, heterocyclylalkyl, and polyether substituents of the R y radicals optionally may have one or more carbons replaced by -O-; -NR7-; -N+R7R8A- -; -S-; -SO-; -SO2-; -S+R7A- -; -PR7-; -P(O)R7-; -P+R7R8A- -; or phenylene; and wherein R7 and R8 are independently selected from the group consisting of hydrogen; alkyl, alkenyl; alkynyl; aryl; and heterocyclyl; and wherein R13, R14; and R15 are independently selected from the group consisting of hydrogen; alkyl; haloalkyl; cycloalkyl; polyalkyl; alkenyl;
alkynyl; aryl; heterocyclyl; quaternary heterocyclyl; arylalkyl;
heterocyclylalkyl; quaternary heterocyclylalkyl; alkylarylalkyl;
alkylheterocyclylalkyl; alkylammoniumalkyl; aminocarbonylalkyl;
alkylaminocarbonylalkyl; carboxyalkylaminocarbonylalkyl; and polyether; or wherein R13 and R14 together with the nitrogen atom to which they are attached form a mono- or polycyclic heterocyclyl that is optionally substituted with one or more radicals selected from the group consisting of oxo, carboxy, and quaternary salts; or wherein R14 and R15 together with the nitrogen atom to which they are attached form a cyclic ring; and wherein the R13, R14, and R15 alkyl; haloalkyl; cycloalkyl; polyalkyl;
alkenyl; alkynyl; aryl; heterocyclyl; quaternary heterocyclyl; arylalkyl;
heterocyclylalkyl; quaternary heterocyclylalkyl; alkylarylalkyl;
alkylheterocyclylalkyl; alkylammoniumalkyl; aminocarbonylalkyl;
alkylaminocarbonylalkyl; carboxyalkylaminocarbonylalkyl; and polyether radicals optionally may be substituted with one or more radicals selected from the group consisting of halogen; -CN; sulfo; oxo; alkyl; haloalkyl;

hydroxyalkyl; sulfoalkyl; alkenyl; alkynyl; aryl; heterocyclyl; quaternary heterocyclyl; quaternary heterocyclylalkyl; carboxy; carboxyalkyl; guanidinyl;
-OR16; -NR9R10; -N+R9R10R w A-; -SR16; -S(O)R9; -SO2R9; -SO3R16; -CO2R16; -CONR9R10; -SO2NR9R10; -PO(OR16)OR17; -PR9R10; -P+R9R10R11A-; -S+R9R10A-; and carbohydrate residue; and wherein the R13, R14, and R15 alkyl; haloalkyl; cycloalkyl; polyalkyl;
alkenyl; alkynyl; aryl; heterocyclyl; quaternary heterocyclyl; arylalkyl;
heterocyclylalkyl; quaternary heterocyclylalkyl; alkylarylalkyl;
alkylheterocyclylalkyl; alkylammoniumalkyl; aminocarbonylalkyl;
alkylaminocarbonylalkyl; carboxyalkylaminocarbonylalkyl; and polyether radicals optionally may have one or more carbons replaced by -O-; -NR9-; -N+R9R10A- -; -S-; -SO-; -SO2-; -S+R9A- -; -PR9-; -P+R9R10A- -; -P(O)R9-;
phenylene; carbohydrate residue; amino acid residue; peptide residue; or polypeptide residue; and wherein R16 and R17 are independently selected from the group consisting of R9 and M; and wherein M is a pharmaceutically acceptable cation; and wherein R9, R10, R11, R12, R w, and A- are as defined in claim 2; and R N is selected from the group consisting of hydrogen; alkyl; and aralkyl; and one or more R x radicals are independently selected from the group consisting of alkoxy, alkylamino and dialkylamino; or a pharmaceutically acceptable salt, solvate, or prodrug thereof.
87. A compound of claim 86 wherein R1 and R2 are each the same (C1-C10)alkyl.
88. A compound of claim 86 wherein R1 and R2 are each n-butyl.
89. A compound of claim 86 wherein one or more R x are independently selected from the group consisting of methoxy and dimethylamino.
90. A compound of claim 86 wherein q is 1.
91. A compound of claim 86 wherein q is 1, and R x is selected from the group consisting of methoxy and dimethylamino.
92. A compound of claim 86 wherein R N is selected from thegroup consisting of hydrogen; methyl, ethyl and benzyl.
93. A compound of claim 86 wherein said hydroxy group is in a syn relationship to said structure of formula (II).
94. A compound of claim 86 wherein t is 1.
95. A compound of claim 86 wherein t is 1 and R y is in the para position.
96. A compound of claim 86 wherein t is 1 and R y is in the meta position.
97. A compound of claim 86 wherein one or more R y are independently selected from selected from the group consisting of halogen; hydroxy; -NO2;
(C1-C10)alkyl; halo(C1-C10)alkyl; aryl(C1-C10)alkyl; heterocyclyl(C1-C10)alkyl;
polyether; -OR13; -NR13R14; and -NR13C(O)R14; and wherein R13, R14, and R15 are independently selected from the group consisting of hydrogen; (C1-C10)alkyl; halo(C1-C10)alkyl; heterocyclyl;
quaternary heterocyclyl; aryl(C1-C10)alkyl; heterocyclyl(C1-C10)alkyl;
quaternary heterocyclyl(C1-C10)alkyl; (C1-C10)alkylheterocyclyl(C1-C10)alkyl;
(C1-C10)alkylammonium(C1-C10)alkyl; and polyether; or wherein the R13, R14, and R15 (C1-C10)alkyl; halo(C1-C10)alkyl;
heterocyclyl; quaternary heterocyclyl; aryl(C1-C10)alkyl; heterocyclyl(C1-C10)alkyl; quaternary heterocyclyl(C1-C10)alkyl; (C1-C10)alkylheterocyclyl(C1-C10)alkyl; (C1-C10)alkylammonium(C1-C10)alkyl; and polyether radicals optionally may be substituted with one or more radicals selected from the group consisting of halogen; (C1-C10)alkyl; heterocyclyl; quaternary heterocyclyl; quaternary heterocyclyl(C1-C10)alkyl; carboxy; carboxy(C1-C10)alkyl; -OR16; -NR9R10; -N+R9R10R w A-; and -CONR9R10; and wherein R9, R10, and R w are independently selected from the group consisting of hydrogen; (C1-C10)alkyl; heterocyclyl; ammonium(C1-C10)alkyl;
(C1-C10)alkylammonium(C1-C10)alkyl; aryl(C1-C10)alkyl; heterocyclyl(C1-C10)alkyl; carboxy(C1-C10)alkyl; carbo(C1-C10)alkoxy(C1-C10)alkyl;
carboxyheterocyclyl; carboxy(C1-C10)alkylamino; and acyl; and wherein A- is a pharmaceutically acceptable anion; and wherein R11 and R12 are independently selected from the group consisting of hydrogen; (C1-C10)alkyl; heterocyclyl; aryl(C1-C10)alkyl;
carboxy(C1-C10)alkyl; and carbo(C1-C10)alkoxy(C1-C10)alkyl; or R11 and R12 together with the carbon atom to which they are attached form a cyclic ring; and wherein R16 and R17 are independently selected from the group consisting of R9 and M; and wherein M is a pharmaceutically acceptable cation.
98. A compound of claim 97 wherein:
R1 and R2 are each the same (C1-C10)alkyl;
one or more R x are independently selected from the group consisting of methoxy and dimethylamino;
said hydroxy group is in a syn relationship to said structure of formula (II);
t is 1; and R y is in the meta or para position.
99. A compound of claim 97 wherein R1 and R2 are each n-butyl.
100. A compound of claim 97 wherein q is 1.
101. A compound of claim 97 wherein R N is selected from the group consisting of hydrogen; methyl, ethyl and benzyl.
102. A compound of claim 97 wherein R y is in the para position.
103. A compound of claim 97 wherein R y is in the meta position.
104. A compound of the formula (III):
wherein q and r are independently integers from 0 to 4;
t and u are independently integers from 0 to 4;
R1, R2, R1A, and R2A are independently selected from the group consisting of hydrogen; alkyl; cycloalkyl; alkenyl; cycloalkenyl; alkynyl;
aryl;
heterocyclyl; arylalkyl; heterocyclylalkyl; alkoxyalkyl; alkoxyalkenyl;
alkoxyalkynyl; aryloxyalkyl; aryloxyalkenyl; aryloxyalkynyl;
heterocylcyloxyalkyl; heterocycloxyalkenyl; heterocyclyloxyalkynyl; alkylaryl;
and (polyalkyl)aryl; or R1 and R2 taken together with the carbon to which they are attached form C3-C10 cycloalkyl or C3-C10 cycloalkenyl; or R1A and R2A taken together with the carbon to which they are attached form C3-C10 cycloalkyl or C3-C10 cycloalkenyl;
wherein the R1, R2, R1A, and R2A alkyl; cycloalkyl; alkenyl;
cycloalkenyl; alkynyl; aryl; heterocyclyl; arylalkyl; heterocyclylalkyl;
alkoxyalkyl; alkoxyalkenyl; alkoxyalkynyl; aryloxyalkyl; aryloxyalkenyl;
aryloxyalkynyl; heterocylcyloxyalkyl; heterocycloxyalkenyl;
heterocyclyloxyalkynyl; alkylaryl; and (polyalkyl)aryl radicals optionally may be substituted with one or more radicals selected from the group consisting of -CN; halogen; oxo; -OR9; -NR9R10; -N+R9R10R w A-; -SR9; -S+R9R10A-; -PR9R10; -P+R9R10R w A-; -S(O)R9; -SO2R9; -SO3R9; -CO2R9; and -CONR9R10; and wherein the R1, R2, R1A, and R2A alkyl; cycloalkyl; alkenyl;
cycloalkenyl; alkynyl; aryl; heterocyclyl; arylalkyl; heterocyclylalkyl;
alkoxyalkyl; alkoxyalkenyl; alkoxyalkynyl; aryloxyalkyl; aryloxyalkenyl;
aryloxyalkynyl; heterocylcyloxyalkyl; heterocycloxyalkenyl;
heterocyclyloxyalkynyl; alkylaryl; and (polyalkyl)aryl radicals optionally may have one or more carbons replaced by -O-; -NR9-; -N+R9R10A~; -S-; -SO-; -SO2-; -S+R9A~; -PR9-; -P(O)R9-; -P+R9R10A~; or phenylene; and wherein R9, R10, and R w are independently selected from the group consisting of hydrogen; alkyl; cycloalkyl; alkenyl; alkynyl; aryl;
heterocyclyl;
alkylammoniumalkyl; arylalkyl; heterocyclylalkyl; carboxyalkyl; alkoxyalkyl;
carboalkoxyalkyl; carboxyaryl; carboxyheterocyclyl; amino; alkylamino;
carboxyalkylamino; alkoxyalkylamino; and acyl; and wherein A- is a pharmaceutically acceptable anion; and R3, R4, R3A, and R4A are independently selected from the group consisting of hydrogen; alkyl; alkenyl; alkynyl; aryl; heterocyclyl; -OR9; -NR9R10; -SR9; -S(O)R9; -SO2R9; and -SO3R9; or R3 and R4 together form =O; =NOR9; =S; =NNR9R10; =NR9; or -CR11R12; or R3A and R4A together form =O; =NOR9; =S; =NNR9R10; =NR9; or =CR11R12;
wherein R11 and R12 are independently selected from the group consisting of hydrogen; -CN; halogen; oxo; alkyl; alkenyl; alkynyl; aryl;
heterocyclyl; arylalkyl; heterocyclylalkyl; carboxyalkyl; alkoxyalkyl;
carboalkoxyalkyl; cycloalkyl; cycloalkenyl; haloalkyl; hydroxyalkyl;
cyanoalkyl; -OR9; -NR9R10; -SR9; -S(O)R9; -SO2R9; -SO3R9; -CO2R9; and -CONR9R10; or R11 and R12 together with the carbon atom to which they are attached form a cyclic ring; and wherein R9 and R10 are as defined above; and one or more R y and R yA are independently selected from the group consisting of halogen; -CN; -NO2; oxo; alkyl; polyalkyl; haloalkyl;
hydroxyalkyl; cycloalkyl; alkenyl; alkynyl; aryl; heterocyclyl; quaternary heterocyclyl; arylalkyl; heterocyclylalkyl; polyether; -OR13; -NR13R14; -SR13; -S(O)R13; -SO2R13; -SO3R13; -NR13OR14; -NR13NR14R15;-CO2R13; -OM; -SO2OM; -SO2NR13R14; -C(O)NR13R14; -C(O)OM;-COR13; -NR13C(O)R14; -NR13C(O)NR14R15; -NR13CO2R14; -OC(O)R13;-OC(O)NR13R14; -NR13SOR14; -NR13SO2R14; -NR13SONR14R15;-NR13SO2NR14R15; -P(O)R13R14; -PR13R14; -P+R13R14R15A-;-P(OR13)OR14;-S+R13R14A-; and -N+R13R14R15A-; and wherein the alkyl, polyalkyl, haloalkyl, hydroxyalkyl, cycloalkyl, alkenyl, alkynyl, aryl, heterocyclyl, quaternary heterocyclyl, arylalkyl, heterocyclylalkyl, and polyether substituents of the R y and R yA radicals optionally may be further substituted with one or more radicals selected from the group consisting of -CN; halogen; hydroxy; oxo; alkyl; cycloalkyl;
alkenyl;
alkynyl; aryl; heterocyclyl; arylalkyl; heterocyclylalkyl; quaternary heterocyclyl; -OR7; -NR7R8; -SR7; -S(O)R7; -SO2R7; -SO3R7;- CO2R7;-CONR7R8; -N+R7R8R9A-; -P(O)R7R8; -PR7R8; -P+R7R8R9A-; and -P(O)(OR7)OR8; and wherein the alkyl, polyalkyl, haloalkyl, hydroxyalkyl, cycloalkyl, alkenyl, alkynyl, aryl, heterocyclyl, quaternary heterocyclyl, arylalkyl, heterocyclylalkyl, and polyether substituents of the R y and R yA radicals optionally may have one or more carbons replaced by -O-; -NR7-; -N+R7R8A--; -S-; -SO-; -SO2-; -S+R7A- - -PR7-; -P(O)R7-; -P+R7R8A- -; or phenylene;
and wherein R7 and R8 are independently selected from the group consisting of hydrogen; alkyl, alkenyl; alkynyl; aryl; and heterocyclyl; and wherein R13, R14, and R15 are independently selected from the group consisting of hydrogen; alkyl; haloalkyl; cycloalkyl; polyalkyl; alkenyl;
alkynyl; aryl; heterocyclyl; quaternary heterocyclyl; arylalkyl;
heterocyclylalkyl; quaternary heterocyclylalkyl; alkylarylalkyl;
alkylheterocyclylalkyl; alkylammoniumalkyl; aminocarbonylalkyl;
alkylaminocarbonylalkyl; carboxyalkylaminocarbonylalkyl; and polyether; or wherein R13 and R14 together with the nitrogen atom to which they are attached form a mono- or polycyclic heterocyclyl that is optionally substituted with one or more radicals selected from the group consisting of oxo, carboxy, and quaternary salts; or wherein R14 and R15 together with the nitrogen atom to which they are attached form a cyclic ring; and wherein the R13, R14, and R15 alkyl; haloalkyl; cycloalkyl; polyalkyl;
alkenyl; alkynyl; aryl; heterocyclyl; quaternary heterocyclyl; arylalkyl;
heterocyclylalkyl; quaternary heterocyclylalkyl; alkylarylalkyl;
alkylheterocyclylalkyl; alkylammoniumalkyl; aminocarbonylalkyl;
alkylaminocarbonylalkyl; carboxyalkylaminocarbonylalkyl; and polyether radicals optionally may be substituted with one or more radicals selected from the group consisting of halogen; -CN; sulfo; oxo; alkyl; haloalkyl;
hydroxyalkyl; sulfoalkyl; alkenyl; alkynyl; aryl; heterocyclyl; quaternary heterocyclyl; quaternary heterocyclylalkyl; carboxy; carboxyalkyl; guanidinyl;
-OR16; -NR9R10; -N+R9R10R w A-; -SR16; -S(O)R9; -SO2R9; -SO3R16;-CO2R16; -CONR9R10; -SO2NR9R10; -PO(OR16)OR17; -PR9R10;-P+R9R10R11A-; -S+R9R10A-; and carbohydrate residue; and wherein the R13, R14, and R15 alkyl; haloalkyl; cycloalkyl; polyalkyl;
alkenyl; alkynyl; aryl; heterocyclyl; quaternary heterocyclyl; arylalkyl;
heterocyclylalkyl; quaternary heterocyclylalkyl; alkylarylalkyl;
alkylheterocyclylalkyl; alkylammoniumalkyl; aminocarbonylalkyl;
alkylaminocarbonylalkyl; carboxyalkylaminocarbonylalkyl; and polyether radicals optionally may have one or more carbons replaced by -O-; -NR9-; -N+R9R10A~; -S-; -SO-; -SO2-; -S+R9A~; -PR9-; -P+R9R10A~; -P(O)R9-;
phenylene; carbohydrate residue; amino acid residue; peptide residue; or polypeptide residue; and wherein R16 and R17 are independently selected from the group consisting of R9 and M; and wherein n is 0, 1 or 2; and wherein M is a pharmaceutically acceptable cation; and wherein R9, R10, R11, R12, R w, and A- are as defined above; and R N and R NA are independently selected from the group consisting of hydrogen; alkyl; alkenyl; alkynyl; aralkyl; and heterocyclylalkyl; and one or more R x and R XA radicals are independently selected from the group consisting of hydrogen; halogen; -CN; -NO2; alkyl; cycloalkyl;
polyalkyl; haloalkyl; hydroxyalkyl; alkenyl; alkynyl; aryl; heterocyclyl;
uaternary heterocyclyl; arylalkyl; heterocyclylalkyl; polyether; acyloxy;
OR13; -NR13R14; -SR13; -S(O)R13; -S(O)2R13; -SO3R13; -S+R13R14A-;-NR13OR14; -NR13NR14R15; -CO2R13; -OM; -SO2OM; -SO2NR13R14;-NR14C(O)R13; -C(O)NR13R14; -C(O)OM; -COR13; -OR18; -SO n NR13R18; -NR18OR14; -N+R13R14R15A-; -PR13R14; -P(O)R13R14; -p+R13R14R15A-; amino acid residue; peptide residue; polypeptide residue;
and carbohydrate residue;
wherein the R X and R XA alkyl; cycloalkyl; polyalkyl; haloalkyl;
hydroxyalkyl; alkenyl; alkynyl; aryl; heterocyclyl; arylalkyl;
heterocyclylalkyl;
polyether; acyloxy radicals optionally may be further substituted with one or more radicals selected from the group consisting of halogen; -CN; oxo; -OR16;
-NR9R10; -N+R9R10R w A-; -SR16; -S(O)R9; -SO2R9; -SO3R16; -CO2R16; -CONR9R10; -SO2NR9R10; -PO(OR16)OR17; -PR9R10; -P+R9R11R12A-; -S+R9R10A-; and carbohydrate residue; and wherein the R X and R XA quaternary heterocyclyl radical optionally may be substituted with one or more radicals selected from the group consisting of halogen; -CN; -NO2; oxo; alkyl; cycloalkyl; polyalkyl; haloalkyl;
hydroxyalkyl; alkenyl; alkynyl; aryl; heterocyclyl; arylalkyl;
heterocyclylalkyl;
polyether; -OR13; -NR13R14; -SR13; -S(O)R13; -SO2R13; -SO3R13; -NR13OR14; -NR13NR14R15; -CO2R13; OM; -SO2OM; -SO2NR13R14; -C(O)NR13R14; -C(O)OM; -COR13; -P(O)R13R14; -PR13R14;-P+R13R14R15A-; -P(OR13)OR14; -S+R13R14A-; -N+R13R14R15A-; and carbohydrate residue; and wherein the R X and R XA radicals comprising carbon optionally may have one or more carbons replaced by -O-; -NR13-; -N+R13R14A~; -S-; -SO-;
-SO2-; -S+R13A~; -PR13-; -P(O)R13-; -P+R13R14A~; phenylene; amino acid residue; peptide residue; polypeptide residue; carbohydrate residue;
polyether;
or polyalkyl; wherein said phenylene; amino acid residue; peptide residue;
polypeptide residue; carbohydrate residue; and polyalkyl optionally may have one or more carbons replaced by -O-; -NR9-; -N+R9R10A~; -S-; -SO-; -SO2-;
-S+R9A~; -PR9-; -P+R9R10A~; or -P(O)R9-; and wherein R18 is selected from the group consisting of alkyl; alkenyl;
alkynyl; aryl; heterocyclyl; quaternary heterocyclyl; arylalkyl;
heterocyclylalkyl; acyl; alkoxycarbonyl; arylalkoxycarbonyl; and heterocyclylalkoxycarbonyl; and heterocyclylalkoxycarbonyl; and wherein the R18 alkyl; alkenyl; alkynyl; aryl; heterocyclyl; quaternary heterocyclyl; arylalkyl; heterocyclylalkyl; acyl; alkoxycarbonyl;
arylalkoxycarbonyl; and heterocyclylalkoxycarbonyl radicals optionally may be substituted with one or more radicals selected from the group consisting of halogen; -CN ; NO2; oxo; -OR9; -NR9R10; -N+R9R11R12A-; -SR9; -S(O)R9;
-SO2R9; -SO3R9; -CO2R9; -CONR9R10; -SO2OM; -SO2NR9R10; -PR9R10;
-P(OR16)OR17; -PO(OR16)OR17; and -C(O)OM; and wherein R9, R10, R11, R12, R13, R14, R15, R16, R17, R w, A-, and M are as defined above; and R19 is selected from the group consisting of alkane diyl; alkene diyl;
alkyne diyl; polyalkane diyl; alkoxy diyl; polyether diyl; polyalkoxy diyl;
carbohydrate; amino acid; and peptide; polypeptide; wherein alkane diyl;
alkene diyl; alkyne diyl; polyalkane diyl; alkoxy diyl; polyether diyl;
polyalkoxy diyl; carbohydrate residue; amino acid residue; peptide residue;
and polypeptide residue; can optionally have one or more carbons replaced by -O-;
-NR7-; -N+R7R8A~; -S-; -SO-; -SO2-; -S+R7A~; -PR7-; -P+R7R8A~;
phenylene; heterocyclyl; quaternary heterocyclyl; or aryl;
wherein alkane diyl; alkene diyl; alkyne diyl; polyalkane diyl; alkoxy diyl; polyether diyl; polyalkoxy diyl; carbohydrate residue; amino acid residue;
peptide residue; and polypeptide residue can be substituted with one or more substituent groups independently selected from the group consisting of alkyl;
alkenyl; alkynyl; polyalkyl; polyether; aryl; haloalkyl; cycloalkyl;
heterocyclyl;
arylalkyl; halogen; oxo; -OR13; -NR13R14; -SR13; -S(O)R13; -SO2R13; -SO3R13; -NR13OR14; -NR13NR14R15; -NO2; -CO2R13; -CN; -OM; -SO2OM; -SO2NR13R14; -C(O)NR13R14; -C(O)OM; -COR13; -P(O)R13R14; -PR13R14; -P+R13R14R15A-; -P(OR13)OR14; -S+R13R14A-; and -N+R13R14R15A-;
wherein R7, R8, R11, R12, R13, R14 R15, and A- are as defined above; or a pharmaceutically acceptable salt, solvate, or prodrug thereof.
105. A compound of claim 104 wherein R1, R1A, R2, and R2A are independently selected from the group consisting of hydrogen and alkyl.
106. A compound of claim 104 wherein R1, R1A, R2, and R2A are independently selected from the group consisting of hydrogen and C1-C10 alkyl.
107. A compound of claim 104 wherein R1, R1A, R2, and R2A are independently selected from the group consisting of C2-C7 alkyl.
108. A compound of claim 104 wherein R1, R1A, R2, and R2A are independently selected from the group consisting of C2-C4 alkyl.
109. A compound of claim 104 wherein R1, R1A, R2, and R2A are independently selected from the group consisting of ethyl; n-propyl; n-butyl;
and isobutyl.
110. A compound of claim 104 wherein R3, R3A, R4, and R4A are independently selected from the group consisting of hydrogen and -OR9, wherein R9 is as defined in claim 104.
111. A compound of claim 110 wherein R9 is hydrogen.
112. A compound of claim 104 wherein R N and R NA are independently selected from the group consisting of hydrogen, alkyl and aralkyl.
113. A compound of claim 104 wherein R N and R NA are independently selected from the group consisting of hydrogen, (C1-C10)alkyl and aryl(C1-C10)alkyl.
114. A compound of claim 104 wherein R N and R NA are independently selected from the group consisting of hydrogen, methyl, ethyl and benzyl.
115. A compound of claim 104 wherein one or more R X and R XA are independently selected from the group consisting of methoxy and dimethylamino.
116. A compound of claim 104 wherein q and r are each 1.
117. A compound of claim 104 wherein one or more R y are independently selected from selected from the group consisting of halogen;
hydroxy; -NO2; (C1-C10)alkyl; halo(C1-C10)alkyl; aryl(C1-C10)alkyl;

heterocyclyl(C1-C10)alkyl; polyether; -OR13; -NR13R14; and -NR13C(O)R14;
and wherein R13, R14, and R15 are independently selected from the group consisting of hydrogen; (C1-C10)alkyl; halo(C1-C10)alkyl; heterocyclyl;
quaternary heterocyclyl; aryl(C1-C10)alkyl; heterocyclyl(C1-C10)alkyl;
quaternary heterocyclyl(C1-C10)alkyl;(C1-C10)alkylheterocyclyl(C1-C10)alkyl;
(C1-C10)alkylammonium(C1-C10)alkyl; and polyether; or wherein the R13, R14, and R15 (C1-C10)alkyl; halo(C1-C10)alkyl;
heterocyclyl; quaternary heterocyclyl; aryl(C1-C10)alkyl; heterocyclyl(C1-C10)alkyl; quaternary heterocyclyl(C1-C10)alkyl;(C1-C10)alkylheterocyclyl(C1-C10)alkyl; (C1-C10)alkylammonium(C1-C10)alkyl; and polyether radicals optionally may be substituted with one or more radicals selected from the group consisting of halogen;(C1-C10)alkyl; heterocyclyl; quaternary heterocyclyl; quaternary heterocyclyl(C1-C10)alkyl; carboxy; carboxy(C1-C10)alkyl; -OR16; -NR9R10; -N+R9R10R w A-; and -CONR9R10; and wherein R9, R10, and R w are independently selected from the group consisting of hydrogen; (C1-C10)alkyl; heterocyclyl; ammonium(C1-C10)alkyl;
(C1-C10)alkylammonium(C1-C10)alkyl; aryl(C1-C10)alkyl; heterocyclyl(C1-C10)alkyl; carboxy(C1-C10)alkyl; carbo(C1-C10)alkoxy(C1-C10)alkyl;
carboxyheterocyclyl; carboxy(C1-C10)alkylamino; and acyl; and wherein A- is a pharmaceutically acceptable anion; and wherein R11 and R12 are independently selected from the group consisting of hydrogen; (C1-C10)alkyl; heterocyclyl; aryl(C1-C10)alkyl;
carboxy(C1-C10)alkyl; and carbo(C1-C10)alkoxy(C1-C10)alkyl; or R11 and R12 together with the carbon atom to which they are attached form a cyclic ring wherein R16 and R17 are independently selected from the group consisting of R9 and M; and wherein M is a pharmaceutically acceptable cation.
118. A compound of claim 104 wherein R19 is selected from the group consisting of alkane diyl; polyalkane diyl; alkoxy diyl; and polyalkoxy diyl; wherein alkane diyl and polyalkane diyl can optionally have one or more carbons replaced by -O-; -NR7-; -N+R7R8A--; -S-; -SO-; -SO2-; -S+R7A--; -PR7-; -P(O)R7-; -P+R7R8A--; or phenylene, wherein R7 and R8 are defined as in claim 104.
119. A compound of claim 104 wherein R'9 is selected from the group consisting of alkoxy diyl and polyalkoxydiyl wherein one or more carbons are optionally replaced by -O-; -NR7-; -N+R7R8A--; -S-; -SO-; -SO2-;
-S+R7A--; -PR7-; -P(O)R7-; -P+R7R8A--; phenylene; amino acid residue;
peptide residue; polypeptide residue; carbohydrate residue; or polyalkyl, wherein R9 and R10 are defined as in claim 104.
120. A compound of claim 104 having the formula:
121. A compound of the formula (IV):

wherein:
q and r are independently integers from 0 to 3;
t and a are independently integers from 0 to 5;
R1, R2, R1A, and R2A are independently selected from the group consisting of hydrogen; alkyl; cycloalkyl; alkenyl; cycloalkenyl; alkynyl;
aryl;
heterocyclyl; arylalkyl; heterocyclylalkyl; alkoxyalkyl; alkoxyalkenyl;
alkoxyalkynyl; aryloxyalkyl; aryloxyalkenyl; aryloxyalkynyl;
heterocylcyloxyalkyl; heterocycloxyalkenyl; heterocyclyloxyalkynyl; alkylaryl;
and (polyalkyl)aryl; or R1 and R2 taken together with the carbon to which they are attached form C3-C10 cycloalkyl or C3-C10 cycloalkenyl; or R1A and R2A taken together with the carbon to which they are attached form C3-C10 cycloalkyl or C3-C10 cycloalkenyl;
wherein the R1, R2, R1A, and R2A alkyl; cycloalkyl; alkenyl;
cycloalkenyl; alkynyl; aryl; heterocyclyl; arylalkyl; heterocyclylalkyl;
alkoxyalkyl; alkoxyalkenyl; alkoxyalkynyl; aryloxyalkyl; aryloxyalkenyl;
aryloxyalkynyl; heterocylcyloxyalkyl; heterocycloxyalkenyl;
heterocyclyloxyalkynyl; alkylaryl; and (polyalkyl)aryl radicals optionally may be substituted with one or more radicals selected from the group consisting of -CN; halogen; oxo; -OR9; -NR9R10; -N+R9R10R W A-; -SR9; -S+R9R10A-; -PR9R10; -P+R9R10R W A-; -S(O)R9; -SO2R9; -SO3R9; -CO2R9; and -CONR9R10; and wherein the R1, R2, R1A, and R2A alkyl; cycloalkyl; alkenyl;
cycloalkenyl; alkynyl; aryl; heterocyclyl; arylalkyl; heterocyclylalkyl;
alkoxyalkyl; alkoxyalkenyl; alkoxyalkynyl; aryloxyalkyl; aryloxyalkenyl;
aryloxyalkynyl; heterocylcyloxyalkyl; heterocycloxyalkenyl;
heterocyclyloxyalkynyl; alkylaryl; and (polyalkyl)aryl radicals optionally may have one or more carbons replaced by -O-; -NR9-; -N+R9R10A--; -S-; -SO-; -SO2-; -S+R9A--; -PR9-; -P(O)R9-; -P+R9R10A--; or phenylene; and wherein R9, R10, and R W are independently selected from the group consisting of hydrogen; alkyl; cycloalkyl; alkenyl; alkynyl; aryl;
heterocyclyl;
alkylammoniumalkyl; arylalkyl; heterocyclylalkyl; carboxyalkyl; alkoxyalkyl;
carboalkoxyalkyl; carboxyaryl; carboxyheterocyclyl; amino; alkylamino;
carboxyalkylamino; alkoxyalkylamino; and acyl; and wherein A- is a pharmaceutically acceptable anion; and R3, R4, R3A, and R4A are independently selected from the group consisting of hydrogen; alkyl; alkenyl; alkynyl; aryl; heterocyclyl; -OR9; -NR9R10; -SR9; -S(O)R9; -SO2R9; and -SO3R9; or R3 and R4 together form =O; =NOR9; =S; =NNR9R10; =NR9; or =CR11R12;
R3A and R4A together form =O; =NOR9; =S; =NNR9R10; =NR9; or =CR11R12;
wherein R11 and R12 are independently selected from the group consisting of hydrogen; -CN; halogen; oxo; alkyl; alkenyl; alkynyl; aryl;
heterocyclyl; arylalkyl; heterocyclylalkyl; carboxyalkyl; alkoxyalkyl;
carboalkoxyalkyl; cycloalkyl; cycloalkenyl; haloalkyl; hydroxyalkyl;
cyanoalkyl; -OR9; -NR9R10; -SR9; -S(O)R9; -SO2R9; -SO3R9; -CO2R9; and -CONR9R10; or R11 and R12 together with the carbon atom to which they are attached form a cyclic ring; and wherein R9 and R10 are as defined above; and one or more R y and R yA are independently selected from the group consisting of hydrogen; halogen; -CN; -NO2; oxo; alkyl; polyalkyl; haloalkyl;
hydroxyalkyl; cycloalkyl; alkenyl; alkynyl; aryl; heterocyclyl; quaternary heterocyclyl; arylalkyl; heterocyclylalkyl; polyether; -OR13; -NR13R14; -SR13; -S(O)R13; -SO2R13; -SO3R13; -NR13OR14; -NR13NR14R15; _ CO2R13; -OM; -SO2OM; -SO2NR13R14; -C(O)NR13R14; -C(O)OM; _ COR13; -NR13C(O)R14; -NR13C(O)NR14R15; -NR13CO2R14; -OC(O)R13; _ OC(O)NR13R14; -NR13SOR14; -NR13SO2R14; -NR13SONR14R15; -NR13SO2NR14R15; -P(O)R13R14; -PR13R14; -P+R13R14R15A -P(OR13)OR14; -S+R13R14A-; and -N+R13R14R15A-; and wherein the alkyl, polyalkyl, haloalkyl, hydroxyalkyl, cycloalkyl, alkenyl, alkynyl, aryl, heterocyclyl, quaternary heterocyclyl, arylalkyl, heterocyclylalkyl, and polyether substituents of the R y and R yA radicals optionally may be further substituted with one or more radicals selected from the group consisting of -CN; halogen; hydroxy; oxo; alkyl; cycloalkyl;
alkenyl;
alkynyl; aryl; heterocyclyl; arylalkyl; heterocyclylalkyl; quaternary heterocyclyl; -OR7; -NR7R8; -SR7; -S(O)R7; -SO2R7; -SO3R7;- CO2R7; -CONR7R8; -N+R7R8R9A-; -P(O)R7R8; -PR7R8; -P+R7R8R9A ; and -P(O)(OR7)OR8; and wherein the alkyl, polyalkyl, haloalkyl, hydroxyalkyl, cycloalkyl, alkenyl, alkynyl, aryl, heterocyclyl, quaternary heterocyclyl, arylalkyl, heterocyclylalkyl, and polyether substituents of the R y and R yA radicals optionally may have one or more carbons replaced by -O-; -NR7-; -N+R7R8A--; -S-; -SO-; -SO2-; -S+R7A--; -PR7-; -P(O)R7-; -P+R7R8A--; or phenylene;
and wherein R7 and R8 are independently selected from the group consisting of hydrogen; alkyl, alkenyl; alkynyl; aryl; and heterocyclyl; and wherein R13, R14, and R15 are independently selected from the group consisting of hydrogen; alkyl; haloalkyl; cycloalkyl; polyalkyl; alkenyl;
alkynyl; aryl; heterocyclyl; quaternary heterocyclyl; arylalkyl;
heterocyclylalkyl; quaternary heterocyclylalkyl; alkylarylalkyl;
alkylheterocyclylalkyl; alkylammoniumalkyl; aminocarbonylalkyl;
alkylaminocarbonylalkyl; carboxyalkylaminocarbonylalkyl; and polyether; or wherein R13 and R14 together with the nitrogen atom to which they are attached form a mono- or polycyclic heterocyclyl that is optionally substituted with one or more radicals selected from the group consisting of oxo, carboxy, and quaternary salts; or wherein R14 and R15 together with the nitrogen atom to which they are attached form a cyclic ring; and wherein the R13, R14, and R15 alkyl; haloalkyl; cycloalkyl; polyalkyl;
alkenyl; alkynyl; aryl; heterocyclyl; quaternary heterocyclyl; arylalkyl;

heterocyclylalkyl; quaternary heterocyclylalkyl; alkylarylalkyl;
alkylheterocyclylalkyl; alkylammoniumalkyl; aminocarbonylalkyl;
alkylaminocarbonylalkyl; carboxyalkylaminocarbonylalkyl; and polyether radicals optionally may be substituted with one or more radicals selected from the group consisting of halogen; -CN; sulfo; oxo; alkyl; haloalkyl;
hydroxyalkyl; sulfoalkyl; alkenyl; alkynyl; aryl; heterocyclyl; quaternary heterocyclyl; quaternary heterocyclylalkyl; carboxy; carboxyalkyl; guanidinyl;
-OR16; -NR9R10; -N+R9R11R12A-; -SR16; -S(O)R9; -SO2R9; -SO3R16; _ CO2R16; -CONR9R10; -SO2NR9R10; -PO(OR16)OR17; -PR9R10; _ P+R9R10R11A-; -S+R9R10A-; and carbohydrate residue; and wherein the R13, R14, and R15 alkyl; haloalkyl; cycloalkyl; polyalkyl;
alkenyl; alkynyl; aryl; heterocyclyl; quaternary heterocyclyl; arylalkyl;
heterocyclylalkyl; quaternary heterocyclylalkyl; alkylarylalkyl;
alkylheterocyclylalkyl; alkylammoniumalkyl; aminocarbonylalkyl;
alkylaminocarbonylalkyl; carboxyalkylaminocarbonylalkyl; and polyether radicals optionally may have one or more carbons replaced by -O-; -NR9-; -N+R9R10A--; -S-; -SO-; -SO2-; -S+R9A--; -PR9-; -P+R9R10A--; -P(O)R9-;
phenylene; carbohydrate residue; amino acid residue; peptide residue; or polypeptide residue; and wherein R16 and R17 are independently selected from the group consisting of R9 and M; and wherein M is a pharmaceutically acceptable cation; and wherein n is 0, 1 or 2; and wherein R9, R10, R11, R12, R W, and A- are as defined above; and R N and R NA are independently selected from the group consisting of hydrogen; alkyl; alkenyl; alkynyl; aralkyl; and heterocyclylalkyl; and one or more R X and R XA radicals are independently selected from the group consisting of hydrogen; halogen; -CN; -NO2; alkyl; cycloalkyl;
polyalkyl; haloalkyl; hydroxyalkyl; alkenyl; alkynyl; aryl; heterocyclyl;
quaternary heterocyclyl; arylalkyl; heterocyclylalkyl; polyether; acyloxy; -OR13; -NR13R14; -SR13; -S(O)R13; -S(O)2R13; -SO3R13; -S+R13R14A-; -NR13OR14; -NR13NR14R15; -CO2R13; -OM; -SO2OM; -SO2NR13R14; -NR14C(O)R13; -C(O)NR13R14; -C(O)OM; -COR13; -OR18; -SOnNR13R14; _ NR18OR14; -N+R13R14R15A-; -PR13R14; -P(O)R13R14; -P+R13R14R15A-; wino acid residue; peptide residue; polypeptide residue;
and carbohydrate residue;
wherein the R X and R XA alkyl; cycloalkyl; polyalkyl; haloalkyl;
hydroxyalkyl; alkenyl; alkynyl; aryl; heterocyclyl; arylalkyl;
heterocyclylalkyl;
polyether; acyloxy radicals optionally may be further substituted with one or more radicals selected from the group consisting of halogen; -CN; oxo; -OR16;
-NR9R10; -N+R9R10R W A-; -SR16; -S(O)R9; -SO2R9; _SO3R16; -CO2R16; -CONR9R10; -SO2NR9R10; -PO(OR16)OR17; -PR9R10; -P+R9R11R12A-; -S+R9R10A-; and carbohydrate residue; and wherein the R X and R XA quaternary heterocyclyl radical optionally may be substituted with one or more radicals selected from the group consisting of halogen; -CN; -NO2; oxo; alkyl; cycloalkyl; polyalkyl; haloalkyl;
hydroxyalkyl; alkenyl; alkynyl; aryl; heterocyclyl; arylalkyl;
heterocyclylalkyl;
polyether; -OR13; -NR13R14; -SRl3; -S(O)R13; -SO2R13; -SO3R13; -NR13OR14; -NR13NR14R15; -CO2R13; OM; -SO2OM; -SO2NR13R14; -C(O)NR13R14; -C(O)OM; -COR13; -P(O)R13R14; -PR13R14; -P+R13R14R15A-; -P(OR13)OR14; -S+R13R14A-; -N+R13R14R15A-; and carbohydrate residue; and wherein the R X and R XA radicals comprising carbon optionally may have one or more carbons replaced by -O-; -NR13-; -N+R13R14A-; -S-; -SO-;
-SO2-; -S+R13A-; -PR13-; -P(O)R13-; -P+R13R14A-; phenylene; amino acid; peptide; polypeptide; carbohydrate; polyether; or polyalkyl; wherein said phenylene; amino acid residue; peptide residue; polypeptide residue;
carbohydrate residue; and polyalkyl optionally may have one or more carbons replaced by -O-; -NR9-; -N+R9R10A--; -S-; -SO-; -SO2-; -S+R9A--; -PR9-; -P+R9R10A--; or -P(O)R9-; and wherein R18 is selected from the group consisting of alkyl; alkenyl;
alkynyl; aryl; heterocyclyl; quaternary heterocyclyl; arylalkyl;
heterocyclylalkyl; acyl; alkoxycarbonyl; arylalkoxycarbonyl; and heterocyclylalkoxycarbonyl; and heterocyclylalkoxycarbonyl; and wherein the R18 alkyl; alkenyl; alkynyl; aryl; heterocyclyl; quaternary heterocyclyl; arylalkyl; heterocyclylalkyl; acyl; alkoxycarbonyl;
arylalkoxycarbonyl; and heterocyclylalkoxycarbonyl radicals optionally may be substituted with one or more radicals selected from the group consisting of halogen; -CN ; NO2; oxo; -OR9; -NR9R10; -N+R9R11R12A-; -SR9; -S(O)R9;

-SO2R9; -SO3R9; -CO2R9; -CONR9R10; -SO2OM; -SO2NR9R10; -PR9R10;
-P(OR16)OR17; -PO(OR16)OR17; and -C(O)OM; and wherein R9, R10, R11, R12, R13, R14, R15, R16, R17, R W, A-, and M are as defined above; and R19 is selected from the group consisting of alkane diyl; alkene diyl;
alkyne diyl; polyalkane diyl; alkoxy diyl; polyether diyl; polyalkoxy diyl;
carbohydrate; amino acid; and peptide; polypeptide; wherein alkane diyl;
alkene diyl; alkyne diyl; polyalkane diyl; alkoxy diyl; polyether diyl;
polyalkoxy diyl; carbohydrate residue; amino acid residue; peptide residue;
and polypeptide residue; can optionally have one or more carbons replaced by -O-;
-NR7-; -N+R7R8A--; -S-; -SO-; -SO2-; -S+R7A--; -PR7-; -P(O)R7-; -P+R7R8A--; phenylene; heterocyclyl; quaternary heterocyclyl; or aryl;
wherein alkane diyl; alkene diyl; alkyne diyl; polyalkane diyl; alkoxy diyl; polyether diyl; polyalkoxy diyl; carbohydrate residue; amino acid residue;
peptide residue; and polypeptide residue can be substituted with one or more substituent groups independently selected from the group consisting of alkyl;
alkenyl; alkynyl; polyalkyl; polyether; aryl; haloalkyl; cycloalkyl;
heterocyclyl;
arylalkyl; halogen; oxo; -OR13; -NR13R14; -SR13; -S(O)R13; -SO2R13; -SO3R13; -NR13OR14; -NR13NR14R15; -NO2; -CO2R13; -CN; -OM; -SO2OM; -SO2NR13R14; -C(O)NR13R14; -C(O)OM; -COR13; -P(O)R13R14; -PR13R14; -P+R13R14R15A-; -P(OR13)OR14; -S+R13R14A-; and -N+R9R11R12A-;
wherein R7, R8, R11, R12, R13, R14 R15, and A- are as defined above; or a pharmaceutically acceptable salt, solvate, or prodrug thereof.
122. A compound of claim 121 wherein R1, R1A, R2, and R2A are independently selected from the group consisting of hydrogen and alkyl.
123. A compound of claim 121 wherein R1, R1A, R2, and R2A are independently selected from the group consisting of hydrogen and C1-C10 alkyl.
124. A compound of claim 121 wherein R1, R1A, R2, and R2A are independently selected from the group consisting of C2-C7 alkyl.
125. A compound of claim 121 wherein R1, R1A, R2, and R2A are independently selected from the group consisting of C2-C4 alkyl.
126. A compound of claim 121 wherein R1, R1A, R2, and R2A are independently selected from the group consisting of ethyl; n-propyl; n-butyl;
and isobutyl.
127. A compound of claim 121 wherein R3, R3A, R4, and R4A are independently selected from the group consisting of hydrogen and -OR9, wherein R9 is as defined in claim 121.
128. A compound of claim 126 wherein R9 is hydrogen.
129. A compound of claim 121 wherein R N and R NA are independently selected from the group consisting of hydrogen, alkyl and aralkyl.
130. A compound of claim 121 wherein R N and R NA are independently selected from the group consisting of hydrogen, (C1-C10)alkyl and aryl(C1-C10)alkyl.
131. A compound of claim 121 wherein R N and R NA are independently selected from the group consisting of hydrogen, methyl, ethyl and benzyl.
132. A compound of claim 121 wherein one or more R X and R XA are independently selected from the group consisting of methoxy and dimethylamino.
133. A compound of claim 121 wherein q and r are each 1.
134. A compound of claim 121 wherein one or more R y are independently selected from selected from the group consisting of halogen;
hydroxy; -NO2; (C1-C10)alkyl; halo(C1-C10)alkyl; aryl(C1-C10)alkyl;

heterocyclyl(C1-C10)alkyl; polyether; -OR13; -NR13R14; and -NR13C(O)R14;
and wherein R13, R14, and R15 are independently selected from the group consisting of hydrogen; (C1-C10)alkyl; haloC1-C10)alkyl; heterocyclyl;
quaternary heterocyclyl; aryl(C1-C10)alkyl; heterocyclyl(C1-C10)alkyl;
quaternary heterocyclyl(C1-C10)alkyl; (C1-C10)alkylheterocyclyl(C1-C10)alkyl;
(C1-C10)alkylammonium(C1-C10)alkyl; and polyether; or wherein the R13, R14, and R15 (C1-C10)alkyl; halo(C1-C10)alkyl;
heterocyclyl; quaternary heterocyclyl; aryl(C1-C10)alkyl; heterocyclyl(C1-C10)alkyl; quaternary heterocyclyl(C1-C10)alkyl; (C1-C10)alkylheterocyclyl(C1-C10)alkyl; (C1-C10)alkylammonium(C1-C10)alkyl; and polyether radicals optionally may be substituted with one or more radicals selected from the group consisting of halogen; (C1-C10)alkyl; heterocyclyl; quaternary heterocyclyl; quaternary heterocyclyl(C1-C10)alkyl; carboxy; carboxy(C1-C10)alkyl; -OR16; -NR9R10; -N+R9R10R W A-; and -CONR9R10; and wherein R9, R10 and R W are independently selected from the group consisting of hydrogen; (C1-C10)alkyl; heterocyclyl; ammonium(C1-C10)alkyl;
(C1-C10)alkylammonium(C1-C10)alkyl; aryl(C1-C10)alkyl; heterocyclyl(C1-C10)alkyl; carboxy(C1-C10)alkyl; carbo(C1-C10)alkoxy(C1-C10)alkyl;
carboxyheterocyclyl; carboxy(C1-C10)alkylamino; and acyl; and wherein A- is a pharmaceutically acceptable anion; and wherein R11 and R12 are independently selected from the group consisting of hydrogen; (C1-C10)alkyl; heterocyclyl; aryl(C1-C10)alkyl;
carboxy(C1-C10)alkyl; and carbo(C1-C10)alkoxy(C1-C10)alkyl; or R11 and R12 together with the carbon atom to which they are attached form a cyclic ring;
wherein R16 and R17 are independently selected from the group consisting of R9 and M; and wherein M is a pharmaceutically acceptable cation.
135. A compound of claim 121 wherein R19 is selected from the group consisting of alkane diyl; polyalkane diyl; alkoxy diyl; and polyalkoxy diyl; wherein alkane diyl and polyalkane diyl can optionally have one or more carbons replaced by -O-; -NR7-; -N+R7R8A--; -S-; -SO-; -SO2-; -S+R7A--; -PR7-; -P(O)R7-; -P+R7R8A- -; or phenylene, wherein R7 and R8 are defined as in claim 121.
136. A compound of claim 121 wherein R19 is selected from the group consisting of alkoxy diyl and polyalkoxydiyl wherein one or more carbons are optionally replaced by -O-; -NR7-; -N+R7R8A- -; -S-; -SO-; -SO2-;
-S+R7A- -; -PR7-; -P(O)R7-; -P+R7R8A- -; phenylene; amino acid residue;
peptide residue; polypeptide residue; carbohydrate residue; or polyalkyl, wherein R9 and R10 are defined as in claim 121.
137. A compound of claim 121 having the structural formula:
138. A compound of formula (V):

wherein:
q is an integer from 0 to 4;
r is an integer from 0 to 3;
t is an integer from 0 to 4;
u is an integer from 0 to 5;
R1, R2, R1A, and R2A are independently selected from the group consisting of hydrogen; alkyl; cycloalkyl; alkenyl; cycloalkenyl; alkynyl;
aryl;
heterocyclyl; arylalkyl; heterocyclylalkyl; alkoxyalkyl; alkoxyalkenyl;
alkoxyalkynyl; aryloxyalkyl; aryloxyalkenyl; aryloxyalkynyl;
heterocylcyloxyalkyl; heterocycloxyalkenyl; heterocyclyloxyalkynyl; alkylaryl;
and (polyalkyl)aryl; or R1 and R2 taken together with the carbon to which they are attached form C3-C10 cycloalkyl or C3-C10 cycloalkenyl; or R1A and R2A taken together with the carbon to which they are attached form C3-C10 cycloalkyl or C3-C10 cycloalkenyl;
wherein the R1, R2, R1A, and R2A alkyl; cycloalkyl; alkenyl;
cycloalkenyl; alkynyl; aryl; heterocyclyl; arylalkyl; heterocyclylalkyl;
alkoxyalkyl; alkoxyalkenyl; alkoxyalkynyl; aryloxyalkyl; aryloxyalkenyl;
aryloxyalkynyl; heterocylcyloxyalkyl; heterocycloxyalkenyl;
heterocyclyloxyalkynyl; alkylaryl; and (polyalkyl)aryl radicals optionally may be substituted with one or more radicals selected from the group consisting of -CN; halogen; oxo; -OR9;-NR9R10;-N+R9R10R W A-;-SR9;-S+R9R10A-;-P+R9R10R W A-;-PR9R10;-S(O)R9;-SO2R9;-SO3R9;-CO2R9; and-CONR9R10; and wherein the R1, R2, R1A, and R2A alkyl; cycloalkyl; alkenyl;
cycloalkenyl; alkynyl; aryl; heterocyclyl; arylalkyl; heterocyclylalkyl;
alkoxyalkyl; alkoxyalkenyl; alkoxyalkynyl; aryloxyalkyl; aryloxyalkenyl;
aryloxyalkynyl; heterocylcyloxyalkyl; heterocycloxyalkenyl;
heterocyclyloxyalkynyl; alkylaryl; and (polyalkyl)aryl radicals optionally may have one or more carbons replaced by -O-;-NR9-;-N+R9R10A--;-S-;-SO-;-SO2-;-S+R9A--;-PR9-;-P(O)R9-;-P+R9R10A--; or phenylene; and wherein R9, R10, and R w are independently selected from the group consisting of hydrogen; alkyl; cycloalkyl; alkenyl; alkynyl; aryl;
heterocyclyl;
alkylammoniumalkyl; arylalkyl; heterocyclylalkyl; carboxyalkyl; alkoxyalkyl;
carboalkoxyalkyl; carboxyaryl; carboxyheterocyclyl; amino; alkylamino;
carboxyalkylamino; alkoxyalkylamino; and acyl; and wherein A- is a pharmaceutically acceptable anion; and R3,R4,R3A, and R4A are independently selected from the group consisting of hydrogen; alkyl; alkenyl; alkynyl; aryl; heterocyclyl; -OR9;-NR9R10;-SR9;-S(O)R9;-SO2R9; and -SO3R9; or R3 and R4 together form =O; =NOR9;=S;=NNR9R10;=NR9; or =CR11R12;
R3A and R4A together form =O;=NOR9;=S;=NNR9R10;=NR9; or =CR11R12;
wherein R11 and R12 are independently selected from the group consisting of hydrogen; -CN; halogen; oxo; alkyl; alkenyl; alkynyl; aryl;
heterocyclyl; arylalkyl; heterocyclylalkyl; carboxyalkyl; alkoxyalkyl;
carboalkoxyalkyl; cycloalkyl; cycloalkenyl; haloalkyl; hydroxyalkyl;
cyanoalkyl; -OR9;-NR9R10;-SR9;-S(O)R9;-SO2R9;-SO3R9;-CO2R9; and -CONR9R10; or R11 and R12 together with the carbon atom to which they are attached form a cyclic ring; and wherein R9 and R10 are as defined above; and one or more R y and R yA are independently selected from the group consisting of halogen; -CN; -NO2; oxo; alkyl; polyalkyl; haloalkyl;
hydroxyalkyl; cycloalkyl; alkenyl; alkynyl; aryl; heterocyclyl; quaternary heterocyclyl; arylalkyl; heterocyclylalkyl; polyether; -OR13;-NR13R14;-SR13;-S(O)R13;-SO2R13;-SO3R13;-NR13OR14;-NR13NR14R15;-CO2R13;-OM;-SO2OM;-SO2NR13R14;-C(O)NR13R14;-C(O)OM;-COR13;-NR13C(O)R14;-NR13C(O)NR14R15;-NR13CO2R14;-OC(O)R13;-OC(O)NR13R14;-NR13SOR14;-NR13SO2R14;-NR13SONR14R15;-NR13SO2NR14R15;-P(O)R13R14;-PR13R14;-P+R13R14R15A-;-P(OR13)OR14;-S+R13R14A-; and -N+R13R14R15A-; and wherein the alkyl, polyalkyl, haloalkyl, hydroxyalkyl, cycloalkyl, alkenyl, alkynyl, aryl, heterocyclyl, quaternary heterocyclyl, arylalkyl, heterocyclylalkyl, and polyether substituents of the R y and R yA radicals optionally may be further substituted with one or more radicals selected from the group consisting of -CN; halogen; hydroxy; oxo; alkyl; cycloalkyl;
alkenyl;
alkynyl; aryl; heterocyclyl; arylalkyl; heterocyclylalkyl; quaternary heterocyclyl; -OR7;-NR7NR8;-SR7;-S(O)R7;-SO2R7;-SO3R7;-CO2R7;-CONR7R8;-N+R7R8R9A-;-P(O)R7R8;-PR7R8; -P+R7R8R9A-; and -P(O)(OR7)OR8; and wherein the alkyl, polyalkyl, haloalkyl, hydroxyalkyl, cycloalkyl, alkenyl, alkynyl, aryl, heterocyclyl, quaternary heterocyclyl, arylalkyl, heterocyclylalkyl, and polyether substituents of the R y and R yA radicals optionally may have one or more carbons replaced by -O-;-NR7-;-N+R7R8A--;-S-;-SO-;-SO2-;-S+R7A--;-PR7-;-P(O)R7-;-P+R7R8A--; or phenylene;
and wherein R7 and R8 are independently selected from the group consisting of hydrogen; alkyl, alkenyl; alkynyl; aryl; and heterocyclyl; and wherein R13, R14, and R15 are independently selected from the group consisting of hydrogen; alkyl; haloalkyl; cycloalkyl; polyalkyl; alkenyl;
alkynyl; aryl; heterocyclyl; quaternary heterocyclyl; arylalkyl;
heterocyclylalkyl; quaternary heterocyclylalkyl; alkylarylalkyl;
alkylheterocyclylalkyl; alkylammoniumalkyl; aminocarbonylalkyl;
alkylaminocarbonylalkyl; carboxyalkylaminocarbonylalkyl; and polyether; or wherein R13 and R14 together with the nitrogen atom to which they are attached form a mono- or polycyclic heterocyclyl that is optionally substituted with one or more radicals selected from the group consisting of oxo, carboxy, and quaternary salts; or wherein R14 and R15 together with the nitrogen atom to which they are attached form a cyclic ring; and wherein the R13, R14~ ~d R15 alkyl; haloalkyl; cycloalkyl; polyalkyl;
alkenyl; alkynyl; aryl; heterocyclyl; quaternary heterocyclyl; arylalkyl;
heterocyclylalkyl; quaternary heterocyclylalkyl; alkylarylalkyl;
alkylheterocyclylalkyl; alkylammoniumalkyl; aminocarbonylalkyl;
alkylaminocarbonylalkyl; carboxyalkylaminocarbonylalkyl; and polyether radicals optionally may be substituted with one or more radicals selected from the group consisting of halogen; -CN; sulfo; oxo; alkyl; haloalkyl;
hydroxyalkyl; sulfoalkyl; alkenyl; alkynyl; aryl; heterocyclyl; quaternary heterocyclyl; quaternary heterocyclylalkyl; carboxy; carboxyalkyl; guanidinyl;
-OR16; -~9R10; -N+R9R11R12A-; -SR16; -S(O)R9; -S02R9; _S03R16; _ C02R16; -CONR9R10; -S02NR9R10; -PO(OR16)OR1~; -PR9R10; _ P+R9R10R11A-; -S+R9R10A-; ~d carbohydrate residue; and wherein the R13, R14, and R15 alkyl; haloalkyl; cycloalkyl; polyalkyl;
alkenyl; alkynyl; aryl; heterocyclyl; quaternary heterocyclyl; arylalkyl;
heterocyclylalkyl; quaternary heterocyclylalkyl; alkylarylalkyl;
alkylheterocyclylalkyl; alkylammoniumalkyl; aminocarbonylalkyl;
alkylaminocarbonylalkyl; carboxyalkylaminocarbonylalkyl; and polyether radicals optionally may have one or more carbons replaced by -O-; -NR9-; -N+R9R10A--; -S-; -SO-; -SOZ-; -S+R9A~-; -PR9-; -P+R9R10A_-; -P(O)R9-phenylene; carbohydrate residue; amino acid residue; peptide residue; or polypeptide residue; and wherein R16 and R1~ are independently selected from the group consisting of R9 and M; and wherein M is a pharmaceutically acceptable canon; and wherein n is 0, 1 or 2; and wherein R9, R'°, R", R'2, Rw and A- are as defined above; and RN and RNA are independently selected from the group consisting of hydrogen; alkyl; alkenyl; alkynyl; aralkyl; and heterocyclylalkyl; and one or more Rx and R'{A radicals are independently selected from the group consisting of hydrogen; halogen; -CN; -N02; alkyl; cycloalkyl;
polyalkyl; haloalkyl; hydroxyalkyl; alkenyl; alkynyl; aryl; heterocyclyl;
quaternary heterocyclyl; arylalkyl; heterocyclylalkyl; polyether; acyloxy; -OR13; -NR13R14; -SR13; -S(O)R13~ -S(O)2R13; -S03R13~ -S+R13R14A-; _ ~130R14; -~13~14R15; -C02R13; _OM; -S020M; -S02NR13R14, ~14C(O)R13; -C(O)~13R14; -C(O)OM; -COR13; -ORIg; -S(O)nNR13R14;

-NR13R18;-NR18OR14;-N+R13R14R15A-;-PR13R14;-P(O)R13R14;-P+R13R14R15A-; amino acid residue; peptide residue; polypeptide residue;
and carbohydrate residue;
wherein the R X and R XA alkyl; cycloalkyl; polyalkyl; haloalkyl;
hydroxyalkyl; alkenyl; alkynyl; aryl; heterocyclyl; arylalkyl;
heterocyclylalkyl;
polyether; acyloxy radicals optionally may be further substituted with one or more radicals selected from the group consisting of halogen; -CN; oxo;-OR16;
-NR9R10;-N+R9R10R W A-;-SR16;-S(O)R9;-SO2R9;-SO3R16;-CO2R16;-CONR9R10;-SO2NR9R10;-PO(OR16)OR17;-PR9R10;-P+R9R11R12A-;-S+R9R10A-; and carbohydrate residue; and wherein the R X and R XA quaternary heterocyclyl radical optionally may be substituted with one or more radicals selected from the group consisting of halogen; -CN; -NO2; oxo; alkyl; cycloalkyl; polyalkyl; haloalkyl;
hydroxyalkyl; alkenyl; alkynyl; aryl; heterocyclyl; arylalkyl;
heterocyclylalkyl;
polyether; -OR13;-NR13R14;-SR13;-S(O)R13;-SO2R13;-SO3R13;-NR13OR14;-NR13NR14R15; -CO2R13; OM; -SO2OM; -SO2NR13R14;-C(O)NR13R14;-C(O)OM;-COR13;-P(O)R13R14;-PR13R14;-P+R13R14R15A-;-P(OR13)OR14;-S+R13R14A-;-N+R13R14R15A-; and carbohydrate residue; and wherein the R X and R XA radicals comprising carbon optionally may have one or more carbons replaced by -O-;-NR13-;-N+R13R14A--;-S-;-SO-;
-SO2-;-S+R13A--;-PR13-;-P(O)R13-;-P+R13R14A--;phenylene; amino acid residue; peptide residue; polypeptide residue; carbohydrate residue;
polyether;
or polyalkyl; wherein said phenylene; amino acid residue; peptide residue;
polypeptide residue; carbohydrate residue; and polyalkyl optionally may have one or more carbons replaced by -O-; -NR9-;-N+R9R10A--;-S-;-SO-;-SO2-;
-S+R9A--;-PR9-;-P+R9R10A--; or P(O)R9-; and wherein R18 is selected from the group consisting of alkyl; alkenyl;
alkynyl; aryl; heterocyclyl; quaternary heterocyclyl; arylalkyl;
heterocyclylalkyl; acyl; alkoxycarbonyl; arylalkoxycarbonyl; and heterocyclylalkoxycarbonyl; and wherein the R18 alkyl; alkenyl; alkynyl; aryl; heterocyclyl; quaternary heterocyclyl; arylalkyl; heterocyclylalkyl; acyl; alkoxycarbonyl;
arylalkoxycarbonyl; and heterocyclylalkoxycarbonyl radicals optionally may be substituted with one or more radicals selected from the group consisting of halogen; -CN; NO2; oxo; -OR9; -NR9R10; -N+R9R11R12A-; -SR9; -S(O)R9;
-SO2R9; -SO3R9; -CO2R9; -CONR9R10; -SO2OM; -SO2NR9R10; -PR9R10;
-P(OR16)OR17; -PO(OR16)OR17; and -C(O)OM; and wherein R9, R10, R11, R12, R13, R14, R15, R16, R17, R w,A-, and M are as defined above; and R19 is selected from the group consisting of alkane diyl; alkene diyl;
alkyne diyl;polyalkane diyl; alkoxy diyl; polyether diyl; polyalkoxy diyl;
carbohydrate residue; amino acid residue; peptide residue; and polypeptide residue; wherein alkane diyl; alkene diyl; alkyne diyl; polyalkane diyl;
alkoxy diyl; polyether diyl; polyalkoxy diyl; carbohydrate residue; amino acid residue;
peptide residue; and polypeptide residue; can optionally have one or more carbons replaced by -O-; -NR7-; -N+R7R8A- -; -S-; -SO-; -SO2-; -S+R7A- -; -PR7-; -P(O)R7-; -P+R7R8A- -; phenylene; heterocyclyl; quaternary heterocyclyl; or aryl;
wherein alkane diyl; alkene diyl; alkyne diyl; polyalkane diyl; alkoxy diyl; polyether diyl; polyalkoxy diyl; carbohydrate residue; amino acid residue;
peptide; and polypeptide residue can be substituted with one or more substituent groups independently selected from the group consisting of alkyl;
alkenyl; alkynyl; polyalkyl; polyether; aryl; haloalkyl; cycloalkyl;
heterocyclyl;
arylalkyl; halogen; oxo; -OR13; -NR13R14; -SR13; -S(O)R13; -SO2R13; -SO3R13; -NR13OR14; -NR13NR14R15; -NO2; -CO2R13; -CN; -OM; -SO2OM; -SO2NR13R14; -C(O)NR13R14; -C(O)OM; -COR13; -P(O)R13R14; -PR13R14; -P+R13R14R15A-; -P(OR13)OR14; -S+R13R14A-; and -N+R13R14R15A-;
wherein R7, R8, R11, R12, R13, R14 R15, and A- are as defined above; or a pharmaceutically acceptable salt, solvate, or prodrug thereof.
139. A compound of claim 138 wherein R1, R1A, R2, and R2A are independently selected from the group consisting of hydrogen and alkyl.
140. A compound of claim 138 wherein R1, R1A, R2, and R2A are independently selected from the group consisting of hydrogen and C1-C10 alkyl.
141. A compound of claim 138 wherein R1, R1A, R2, and R2A are independently selected from the group consisting of C2-C7 alkyl.
142. A compound of claim 138 wherein R1,R1A,R2, and R2A are independently selected from the group consisting of C2-C4 alkyl.
143. A compound of claim 138 wherein R1,R1A,R2, and R2A are independently selected from the group consisting of ethyl; n-propyl; n-butyl;
and isobutyl.
144. A compound of claim 138 wherein R3,R3A,R4, and R4A are independently selected from the group consisting of hydrogen and -OR9, wherein R9 is as defined in claim 138.
145. A compound of claim 144 wherein R9 is hydrogen.
146. A compound of claim 138 wherein R N and R NA are independently selected from the group consisting of hydrogen, alkyl and aralkyl.
147 A compound of claim 138 wherein R N and R NA are independently selected from the group consisting of hydrogen, (C1-C10)alkyl and aryl(C1-C10)alkyl.
148. A compound of claim 138 wherein R N and R NA are independently selected from the group consisting of hydrogen, methyl, ethyl and benzyl.
149. A compound of claim 138 wherein one or more R X and R XA are independently selected from the group consisting of methoxy and dimethylamino.
150. A compound of claim 138 wherein q and r are each 1.
151. A compound of claim 138 wherein one or more R y are independently selected from selected from the group consisting of halogen;
hydroxy; -NO2; (C1-C10)alkyl; halo(C1-C10)alkyl; aryl(C1-C10)alkyl;

heterocyclyl(C1-C10)alkyl; polyether; -OR13;-NR13R14; and -NR13C(O)R14;
and wherein R13,R14, and R15 are independently selected from the group consisting of hydrogen;(C1-C10)alkyl; halo(C1-C10)alkyl; heterocyclyl;
quaternary heterocyclyl; aryl(C1-C10)alkyl; heterocyclyl(C1-C10)alkyl;
quaternary heterocyclyl(C1-C10)alkyl;(C1-C10)alkylheterocyclyl(C1-C10)alkyl;
(C1-C10)alkylammonium(C1-C10)alkyl; and polyether; or wherein the R13,R14,and R15 (C1-C10)alkyl;halo(C1-C10)alkyl;
heterocyclyl; quaternary heterocyclyl; aryl(C1-C10)alkyl; heterocyclyl(C1-C10)alkyl; quaternary heterocyclyl(C1-C10)alkyl;(C1-C10)alkylheterocyclyl(C1-C10)alkyl;(C1-C10)alkylammonium(C1-C10)alkyl; and polyether radicals optionally may be substituted with one or more radicals selected from the group consisting of halogen;(C1-C10)alkyl; heterocyclyl; quaternary heterocyclyl; quaternary heterocyclyl(C1-C10)alkyl; carboxy; carboxy(C1-C10)alkyl;-OR16;-NR9R10;-N+R9R10R W A-; and -CONR9R10; and wherein R9 and R10 are independently selected from the group consisting of hydrogen; (C1-C10)alkyl; heterocyclyl; ammonium(C1-C10)alkyl;
(C1-C10)alkylammonium(C1-C10)alkyl; aryl(C1-C10)alkyl; heterocyclyl(C1-C10)alkyl; carboxy(C1-C10)alkyl; carbo(C1-C10)alkoxy(C1-C10)alkyl;
carboxyheterocyclyl; carboxy(C1-C10)alkylamino; and acyl; and wherein A- is a pharmaceutically acceptable anion; and wherein R11 and R12 are independently selected from the group consisting of hydrogen; (C1-C10)alkyl; heterocyclyl; aryl(C1-C10)alkyl;
carboxy(C1-C10)alkyl; and carbo(C1-C10)alkoxy(C1-C10)alkyl; or R11 and R12 together with the carbon atom to which they are attached form a cyclic ring;

wherein R16 and R17 are independently selected from the group consisting of R9 and M; and wherein M is a pharmaceutically acceptable cation.
152. A compound of claim 138 wherein R19 is selected from the group consisting of alkane diyl; polyalkane diyl; alkoxy diyl; and polyalkoxy diyl; wherein alkane diyl and polyalkane diyl can optionally have one or more carbons replaced by -O-; -NR7-; -N+R7R8A--;-S-;-SO-;-SO2-;-S+R7A--;-PR7- ; -P(O)R7- ; -P+R7R8A- - ; or phenylene, wherein R7 and R8 are defined as in claim 138.
153. A compound of claim 138 wherein R19 is selected from the group consisting of alkoxy diyl and polyalkoxydiyl wherein one or more carbons are optionally replaced by -O- ; -NR7- ;-N+R7R8A-- ;-S- ;-SO- ;-SO2- ;
-S+R7A- -; -PR7-; -P(O)R7-; -P+R7R8A- -; phenylene; amino acid; peptide;
polypeptide; carbohydrate; or polyalkyl, wherein R9 and R10 are defined as in claim 138.
154. A compound of claim 138 having the formula:
155. A pharmaceutical composition comprising an anti-hyperlipidemic effective amount of a compound of formula (I) of claim 1; and a pharmaceutically acceptable carrier.
156. A pharmaceutical composition comprising an anti-atherosclerotic effective amount of a compound of formula (I) of claim 1; and a pharmaceutically acceptable carrier.
157. A pharmaceutical composition comprising an anti-hypercholesterolemia effective amount of a compound of formula (I) of claim 1; and a pharmaceutically acceptable carrier.
158. A pharmaceutical composition comprising an anti-hyperlipidemic effective amount of a compound of formula (I) of claim 2; and a pharmaceutically acceptable carrier.
159. A pharmaceutical composition comprising an anti-atherosclerotic effective amount of a compound of formula (I) of claim 2; and a pharmaceutically acceptable carrier.
160. A pharmaceutical composition comprising an anti-hypercholesterolemia effective amount of a compound of formula (I) of claim 2; and a pharmaceutically acceptable carrier.
161. A method for the prophylaxis or treatment of a hyperlipidemic condition comprising administering to a patient in need thereof a composition of claim 155 in unit dosage form.
162 A method for the prophylaxis or treatment of an atherosclerotic condition comprising administering to a patient in need thereof a composition of claim 156 in unit dosage form.
163. A method for the prophylaxis or treatment of hypercholesterolemia comprising administering to a patient in need thereof a composition of claim 157 in unit dosage form.
164. A method for the prophylaxis or treatment of a hyperlipidemic condition comprising administering to a patient in need thereof a composition of claim 158 in unit dosage form.
165. A method for the prophylaxis or treatment of an atherosclerotic condition comprising administering to a patient in need thereof a composition of claim 159 in unit dosage form.
166. A method for the prophylaxis or treatment of hypercholesterolemia comprising administering to a patient in need thereof a composition of claim 160 in unit dosage form.
CA002362147A 1999-02-12 2000-02-10 1,2-benzothiazepines for the treatment of hyperlipidemic diseases Abandoned CA2362147A1 (en)

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