CZ20002137A3 - Potassium channel opening agents - Google Patents

Abstract

Compounds of formula I are effective in preventing or ameliorating disease by opening potassium channels. Also provided herein are potassium channel opening compositions and methods for opening potassium channels in mammals.

Description

POTASSIUM CHANNEL OPENERS

Technical area

New dihydropyridine compounds and their derivatives can open potassium channels and are thus effective in treating various diseases.

State of the art

Potassium channels play an important role in regulating the excitability of cell membranes. When potassium channels are open, changes in electrical potential occur across the cell membrane, resulting in a more polarized state. Many diseases or conditions can be treated with therapeutic agents that are able to open these potassium channels. For review, see K. Lawon, Pharmacol. Ther., v. 70, 39-63; (1996) D.R. Gehlert et al., Prog. Neuro-Psychopharmacol & Biol. Psychiat., v. 18, 1093 - 1102 (1994); M. Gopalakrishnan et al., Drug Development Research, v. 28, 95 - 127 (1993); J.E. Freedman et al., The Neuroscientist, v. 145 - 152 (1996). Such conditions or diseases include asthma, epilepsy, hypertension, impotence, migraine, pain, urinary incontinence, stroke, Raynaud's syndrome, eating disorders, functional bowel disorders, and neurodegeneration.

Potassium channel openers also act as smooth muscle relaxants. Because urinary incontinence can arise from spontaneous, uncontrolled contractions of bladder smooth muscle, the ability of potassium channel openers to hyperpolarize bladder cells and relax bladder smooth muscle provides a way to improve or prevent urinary incontinence.

Patent applications WO 9408966 and EP 0539154 A1 disclose a group of acridinedione and quinolone compounds which are claimed to be effective in the treatment of urinary incontinence. These compounds belong to the chemical group of dihydropyridines. The compounds of the present invention are chemically different from those disclosed in patent applications WO 94/08966 and EP 0539154 A1 in that they have at least one sulfonyl group attached at the 3-position of the dihydropyridine ring.

Dihydropyridines of different chemical structures can be biologically active in different ways. For example, patent application US 4,879,384 discloses a group of thiacycloalkeno[3,2-b]pyridines, which belong to the group of dihydropyridines and are among

• · * - *· · ¹¹ ·» · ·, -s . · < - « * <. '> * t · , « « “ « '· * ·» · calcium channel antagonists. The compounds of the present invention are chemically distinct from those disclosed in patent application 4,879,384 in that they do not have carboxylic acid derivatives attached at the 3-position of the dihydropyridine ring.

Therefore, the compounds of the present invention are chemically distinct from the prior art by hyperpolarizing cell membranes, opening potassium channels, relaxing smooth muscle cells, inhibiting bladder contractions, and are effective in treating diseases that can be ameliorated by opening potassium channels.

The essence of the invention

The present invention relates to a compound having formula (I)

or pharmaceutically acceptable salts, esters, amides or prodrugs thereof, wherein the substituent R ¹ is alkyl;

the substituent R ² is selected from the group consisting of aryl and heteroaryl; the aryl or heteroaryl may be optionally substituted; the index n is 0-2;

substituent A is selected from the group consisting of hydrogen, alkyl and -X-R;

the substituent R ³ is alkyl or haloalkyl;

the substituent X is -C(O)- or -S(O) _P -, where the index p is 1-2;

R ⁴ and R ⁵ are independently selected from the group consisting of hydrogen, alkyl or haloalkyl; or R ¹ and R ⁵ together with the ring to which they are attached form a 5-, 6- or 7-membered ring containing a sulfur atom, with 1-2 double bonds and 0-2 oxo substituents; or the substituents A and R ⁴ taken together form with the ring to which they are attached a ring selected from the group consisting of a 5-membered, 6-membered or 7-membered carbocyclic ring with 1-2 double bonds and 0-1 oxo substituents and a 5-membered, 6-membered or 7-membered ring containing a sulfur atom with 1-2 double bonds and 0-2 oxo substituents, provided that at least one of the substituents R ¹ and R ⁵ or A and R ⁴ forms a ring.

Detailed description of the invention

In one embodiment, the present invention provides compounds having formula (I)

or pharmaceutically acceptable salts, esters, amides or prodrugs thereof, wherein the substituent R ¹ is alkyl;

the substituent R ² is selected from the group consisting of aryl and heteroaryl; the aryl or heteroaryl may be optionally substituted; the index n is 0-2;

substituent A is selected from the group consisting of hydrogen, alkyl and -X-R;

the substituent R ³ is alkyl or haloalkyl;

the substituent X is -C(O)- or -S(O)p-, where the index p is 1-2;

R ⁴ and R ⁵ are independently selected from the group consisting of hydrogen, alkyl or haloalkyl; or R ¹ and R ⁵ together with the ring to which they are attached form a 5-, 6- or 7-membered ring containing a sulfur atom, with 1-2 double bonds and O-2 oxo substituents; or the substituents A and R ⁴ taken together form with the ring to which they are attached a ring selected from the group consisting of a 5-membered, 6-membered or 7-membered carbocyclic ring with 1-2 double bonds and O - 1 oxo substituents and a 5-membered, 6-membered or 7-membered ring containing a sulfur atom, with 1-2 double bonds and O - 2 · · · · · · · · · · · oxo substituents, provided that at least one of the substituents R ¹ and R ⁵ or A and R ⁴ forms a ring.

In another embodiment, the present invention provides compounds of formula (II)

or pharmaceutically acceptable salts, esters, amides or prodrugs thereof, the substituent R is selected from the group consisting of aryl and heteroaryl; the aryl or heteroaryl may be optionally substituted; the index n is 1 or 2;

the substituent X is selected from the group consisting of -CH 2 -, -C(O)-, -S(O)- or -S(O) ₂ -; and an' and an are independently 1-3.

In another embodiment, the present invention provides pharmaceutical compositions comprising compounds having formula (I) and (II).

In another embodiment, the present invention provides methods of treatment comprising administering an effective amount of compounds having formulas (I) and (II).

Explanation of technical terms

The term "alkanoyl" as used herein refers to an alkyl group attached to the parent molecule through a carbonyl group (-C(O)-). Examples of alkanoyl include acetyl, propionyl, and the like.

The term "alkanoyloxy" as used herein refers to an alkanoyl group attached to the parent molecule through an oxygen atom.

• · » · » ·

The term "lower alkyl" or "alkyl" as used herein refers to branched or unbranched chain alkyl radicals having 1 to 10 carbon atoms including, but not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, t-butyl, n-pentyl, 1-methylbutyl, 2,2-dimethylbutyl, 2-methylpentyl, 2,2-dimethylpropyl, n-hexyl, and the like.

The term "alkenyl" as used herein refers to a monovalent group derived from a hydrocarbon containing at least one carbon-carbon double bond by the removal of a single hydrogen atom. Alkenyl groups include, for example, vinyl(ethenyl), allyl(propenyl), butenyl, 1-methyl-2-buten-1-yl, and the like.

The term "alkylene" refers to a divalent group obtained from a straight or indirect chain of a saturated hydrocarbon by removing two hydrogen atoms. Examples of alkylene groups include, for example, methylene, 1,2-ethylene, 1,1-ethylene, 1,3-propylene, 2,2-dimethylpropylene, etc.

The term "alkenylene" refers to a divalent group derived from a straight or indirect hydrocarbon chain containing at least one carbon-carbon double bond. Examples of alkenylene include -CIT CH-, -CH ₂ CH=CH-, -C(CH ₃ )=CH-, -CH ₂ CH=CHCH ₂ -, and the like.

The term "alkylsulfinyl" as used herein refers to an alkyl group as defined above attached to the parent molecular moiety through a sulfinyl group (-S(O)). Examples of alkylsulfinyl include methylsulfinyl, ethylsulfinyl, isopropylsulfinyl, and the like.

The term "alkylsulfonyl" as used herein refers to an alkyl group as defined above attached to the parent molecular moiety through a sulfonyl group (-S(O) ₂ ). Examples of alkylsulfonyl include methylsulfonyl, ethylsulfonyl, isopropylsulfonyl, and the like.

The term "alkynylene" as used herein refers to a divalent group obtained by removing two hydrogen atoms from a branched or unbranched chain acyclic hydrocarbon containing a carbon-carbon triple bond. Examples of alkynylene include -GC-, -C=C-CH ₂ -, -QC-CH(CHj)-, and the like.

The term "alkoxy" as used herein refers to R ⁴¹ O-, where the substituent R ⁴¹ is a lower alkyl group as defined above. Examples of alkoxy groups include, but are not limited to, ethoxy, tert-butoxy, and the like.

The term "alkoxyalkoxy" as used herein refers to an alkoxy group attached to the parent molecule through an alkoxy group. Examples of alkoxyalkoxy groups include ethoxymethoxy, propoxymethoxy, and the like.

The term "alkoxyalkyl" as used herein refers to an alkoxy group, as defined above, attached to an alkyl group, as defined above. Examples of alkoxyalkyl include, but are not limited to, methoxymethyl, methoxyethyl, isopropoxymethyl, and the like.

The term "alkoxycarbonyl" as used herein refers to an alkoxy group as defined above attached to the parent molecular moiety through a carbonyl group. Examples of alkoxycarbonyl include methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl, and the like.

The term "alkynyl" as used herein refers to a monovalent branched or unbranched group of two or more carbon atoms derived from at least one alkyne.

The term "aryl" as used herein refers to a monocyclic or bicyclic carbocyclic ring system having one or more aromatic rings. Examples of aryl include, but are not limited to, phenyl, naphthyl, tetrahydronaphthyl, naphthyridinyl, indanyl, indenyl, and the like. The aryl groups of the present invention may be optionally substituted with substituents independently selected from alkanoyl, alkenyl, alkoxy, alkoxyalkoxy, alkyl, alkylsulfinyl, alkylsulfonyl, alkoxycarbonyl, alkynyl, aryl, azido, carboxy, cyano, halogen, haloalkyl, haloalkoxy, heteroaryl, hydroxy, nitro, thioalkoxy, -C(O)NR ⁶ R ⁷ (wherein R ⁶ and R ⁷ are independently hydrogen, alkyl, or aryl), thioureido, ureido, and S(O)pNR ⁶ R ⁷ . Additionally, substituted aryl groups include tetrafluorophenyl and pentafluorophenyl.

The term "arylalkyl" as used herein refers to an aryl group as defined above attached to a lower alkyl radical, e.g., benzyl, etc.

The term "azido" as used herein refers to -N3.

The term "carboxy" as used herein refers to -CO2H.

The term "cyano" as used herein refers to -CN.

The term "cycloalkyl" as used herein refers to an aliphatic ring system having 3-10 carbon atoms and 1-3 rings including, but not limited to, cyclopropyl, cyclopentyl, cyclohexyl, norbornyl, adamantyl, and the like. Cycloalkyl groups may be unsubstituted or substituted with one, two, or three substituents independently selected from the group consisting of lower alkyl, haloalkyl, alkoxy, thioalkoxy, amino, alkylamino, dialkylamino, hydroxy, halogen, mercapto, nitro, carboxaldehyde, carboxy, alkoxycarbonyl, and carboxamide.

The term "cycloalkylalkyl" as used herein refers to a cycloalkyl group attached to a lower alkyl radical including, but not limited to, cyclohexylmethyl.

The term "halogen" or "halo" as used herein refers to I, Br, Cl, or F.

• · · · « · « • t · · « · « * · • * · ··· · « ·« ···· ···«

The term "haloalkyl" as used herein refers to a lower alkyl radical as defined above bearing at least one halogen substituent, e.g., chloromethyl, fluoroethyl, 1-chloro-2-fluoropropyl, 2,3-dichloropropyl, or trifluoroethyl, etc.

The term "haloalkoxy" as used herein refers to a lower alkoxy radical as defined above bearing at least one halogen substituent, e.g., chloromethoxy, fluoroethoxy, 1-chloro-2-fluoropropoxy, 2,3-dichloropropoxy or trifluoroethoxy, and the like.

The term "heteroaryl" as used herein refers to a 5-membered, 6-membered or 7-membered ring containing one, two or three heteroatoms independently selected from the group consisting of nitrogen, oxygen and sulfur. The 5-membered ring has two double bonds and the 6-membered and 7-membered rings have three double bonds. The term "heteroaryl" also includes bicyclic, tricyclic and tetracyclic groups in which any of the above heteroaryl rings is fused to one or two rings independently selected from the group consisting of an aryl ring, a cyclohexane ring, a cyclohexene ring, a cyclopentane ring, a cyclopentene ring and other monocyclic heterocyclic rings, such as indolyl, quinolyl, isoquinolyl, tetrahydroquinolyl, benzofuryl, benzothienyl, and the like. The heteroaryl groups of the present invention may be optionally substituted with 1-4 substituents independently selected from the group consisting of alkanoyl, alkenyl, alkoxy, alkyl, alkyl sulfinyl, alkylsulfonyl, alkoxycarbonyl, alkynyl, aryl, azido, carboxy, cyano, halogen, haloalkyl, haloalkoxy, heteroaryl, hydroxy, hydroxyalkyl, nitro, thioalkoxy groups, -C(O)NR ⁶ R ⁷ (wherein R ⁶ and R ⁷ are independently hydrogen, alkyl or aryl), thioureido groups, ureido groups and -S(O) _P NR ⁶ R ⁷ . Examples of heteroaryl include, but are not limited to, indolyl, quinolyl, isoquinolyl, tetrahydroquinolyl, benzofuryl, benzothienyl, pyrrolyl, pyrazolyl, imidazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, isoxazolyl, thiazolyl, thiazolyl, isothiazolyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, furyl, thienyl, benzoxadiazole and benzothiadiazole.

The terms “heterocyclic ring” or “heterocycle” or “heterocycle” as used herein refers to any 3-membered or 4-membered ring containing a heteroatom selected from the group consisting of oxygen, nitrogen, and sulfur; or a 5-membered, 6-membered, or 7-membered ring containing one, two, or three nitrogen atoms; one nitrogen atom and one sulfur atom; or one nitrogen atom and one oxygen atom. A 5-membered ring has 0-2 double bonds and a 6-membered and 7-membered ring has 0-3 double bonds. “Heteroaryl” as defined above falls under “heterocycle”. The nitrogen heteroatoms may optionally be quaternized. The term ••F· * v ,·*,*,'*,·· ' *** ,

I · - « · '· • · * « · ♦ «« < )r « "heterocyclic" also includes bicyclic groups in which any of the above heterocyclic rings is fused to a cyclohexane ring or other heterocyclic ring, etc. Heterocycles include: azetidinyl, pyrrolinyl, pyrrolidinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, piperidinyl, homopiperidinyl, piperazinyl, oxazolidinyl, isoxazolidinyl, morpholinyl, thiazolidinyl, isothiazolidinyl, indolyl, quinolinyl, isoquinolinyl, etc.

Heterocycles can be unsubstituted or monosubstituted, disubstituted or trisubstituted by substituents independently selected from the group consisting of hydroxy, halogen, oxo (=O), alkylimino (R*N= where R* is a lower alkyl group), amino, alkylamino, dialkylamino, alkoxy, alkoxyalkoxy, haloalkyl, cycloalkyl, aryl, arylalkyl, -COOH, -SO3H and lower alkyl. In addition, heterocycles containing a nitrogen atom can be N-protected.

The term "hydroxy" as used herein refers to -OH.

The term "hydroxyalkyl" as used herein refers to a lower alkyl radical as defined above bearing at least one hydroxy substituent, e.g., hydroxymethyl, hydroxyethyl, 1-hydroxy-2-hydroxypropyl, 2,3-dihydroxypropyl, and the like.

The term "nitro" as used herein refers to -NO2.

The term "thioalkoxy" as used herein refers to R70S-, where the R substituent is lower alkyl.

Examples of thioalkoxy groups include, but are not limited to, methylthio, ethylthio, and the like.

The term "thioureido" as used herein refers to -NH-SC-NH2.

The term "ureido" as used herein refers to -NH-CO-NH2.

The term "pharmaceutically acceptable prodrugs" as used herein refers to those prodrugs of the compounds of the present invention which are within the scope of sound medical judgment suitable for use in contact with human and lower animal tissue without causing toxicity, irritation, allergic reactions, etc., commensurate with a reasonable benefit/risk ratio, and effective for their intended use, as well as zwitterion forms of the compounds of the present invention, where possible. Prodrugs of the present invention may be readily transformable in vivo to the parent compound of the above formula, e.g., by hydrolysis in blood. Full details can be found in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 of the A.C.S. Symposium Series and in Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, both incorporated herein by reference.

• *

The compounds of the present invention may exist as stereoisomers where asymmetric or chiral centers are present. These compounds are designated by the symbols “R” and “S” according to the configuration of the substituents on the chiral carbon atom. The present invention contemplates various stereoisomers and mixtures thereof. Stereoisomers include enantiomers and diastereomers and mixtures of enantiomers or diastereomers. Individual stereoisomers of the compounds of the present invention may be prepared synthetically from commercially available starting materials containing asymmetric or chiral centers or by preparation of a racemic mixture followed by resolution into the enantiomers, techniques well known to those skilled in the art. Such methods of resolution into the enantiomers include, for example: (1) coupling a mixture of enantiomers to a chiral auxiliary group, separating the resulting mixture of diastereomers by recrystallization or chromatography and liberating the optically pure product from the auxiliary group, or (2) direct separation of the mixture of optical enantiomers on chiral chromatography columns.

Representative compounds of the present invention include, but are not limited to:

3,4,6,7,8,10-hexahydro-10-phenyl-2H-thiopyrano[3,2-b]quinolin9(5H)-one 1,1-dioxide;

3,4,6,7,8,10-hexahydro-10-(3-nitrophenyl)-2H-thiopyrano[3,2-b]quinolin-9(5H)-one 1,1-dioxide;

10-(3-cyanophenyl)-3,4,6,7,8,10-hexahydro-2H-thiopyrano[3,2-b]quinolin-9(5H)-one 1,1-dioxide;

3,4,6,7,8,10-hexahydro-10-[3-(trifluoromethyl)phenyl]-2Hthiopyrano[3,2-b]quinolin-9(5H)-one 1,1-dioxide;

10-(3-bromophenyl)-3,4,6,7,8,10-hexahydro-2H-thiopyrano[3,2-b]quinolin-9(5H)-one 1,1-dioxide;

10-(3-fluorophenyl)-3,4,6,7,8,10-hexahydro-2H-thiopyrano[3,2-b]quinolin-9(5H)-one 1,1-dioxide;

10-(3-chlorophenyl)-3,4,6,7,8,10-hexahydro-2H-thiopyrano[3,2-b]quinolin-9(5H)-one 1,1-dioxide;

3,4,6,7,8,10-hexahydro-10-[4-(trifluoromethyl)phenyl]-2Hthiopyrano[3,2-b]quinolin-9(5H)-one 1,1-dioxide;

10-(4-bromophenyl)-3,4,6,7,8,10-hexahydro-2H-thiopyrano[3,2-b]quinolin-9(5H)-one 1,1-dioxide;

10-(3,4-dichlorophenyl)-3,4,6,7,8,10-hexahydro-2H-thiopyrano[3,2-b]quinolin-9(5H)-one 1,1-dioxide;

10-(3-chloro-4-fluorophenyl)-3,4,6,7,8,10-hexahydro-2Hthiopyrano[3,2-b]quinolin-9(5H)-one 1,1-dioxide;

10-(3-bromo-4-fluorophenyl)-3,4,6,7,8,10-hexahydro-2Hthiopyrano[3,2-b]quinolin-9(5H)-one 1,1-dioxide;

10-(3,4-difluorophenyl)-3,4,6,7,8,10-hexahydro-2Hthiopyrano[3,2-b]quinolin-9(5H)-one 1,1-dioxide;

10-[3-fluoro-5-(trifluoromethyl)phenyl]-3,4,6,7,8,10-hexahydro-2Hthiopyrano[3,2-b]quinolin-9(5H)-one 1,1-dioxide;

10-[4-fluoro-3-(trifluoromethyl)phenyl]-3,4,6,7,8,10-hexahydro-2Hthiopyrano[3,2-b]quinolin-9(5H)-one 1,1-dioxide;

3,4,6,7,8,10-hexahydro-10-(4-methyl-3-nitrophenyl)2Hthiopyrano[3,2-b]quinolin-9(5H)-one 1,1-dioxide;

10-(4-chloro-3-fluorophenyl)-3,4,6,7,8,10-hexahydro-2Hthiopyrano[3,2-b]quinolin-9(5H)-one 1,1-dioxide;

10-(4-chloro-3-nitrophenyl)-3,4,6,7,8,10-hexahydro-2Hthiopyrano[3,2-b]quinolin-9(5H)-one 1,1-dioxide;

3,4,6,7,8,10-hexahydro-10-(3,4,5-trifluorophenyl)-2H-thiopyrano[3,2-b]quinolin-9(5H)-one 1,1-dioxide;

10-(3-pyridyl)-3,4,6,7,8,10-hexahydro-2H-thiopyrano[3,2-b]quinolin-9(5H)-one 1,1-dioxide;

10-(4-pyridyl)-3,4,6,7,8,10-hexahydro-2H-thiopyrano[3,2-b]quinolin-9(5H)-one 1,1-dioxide;

9-(3-cyanophenyl)-3,4,5,6,7,9-hexahydrothieno[3,2-b]quinolin-8(2H)-one 1,1-dioxide;

9-(3-nitrophenyl)-3,4,5,6,7,9-hexahydrothieno[3,2-b]quinolin-8(2H)-one 1,1-dioxide;

9-(3,4-dichlorophenyl)-3,4,5,6,7,9-hexahydrothieno[3,2-b]quinolin-8(2H)-one 1,1-dioxide;

9-[4-fluoro-3-(trifluoromethyl)phenyl]-3,4,5,6,7,9-hexahydrothieno[3,2-b]quinolin-8(2H)-one 1,1-dioxide;

3,4,5,6,7,9-hexahydro-9-(4-methyl-3-nitrophenyl)thieno[3,2-b]quinolin-8(2H)-one 1,1-dioxide;

« <1

9-(3,4-difluorophenyl)-3,4,5,6,7,9-hexahydrothieno[3,2-b]quinolin-8(2H)-one 1,1-dioxide;

9-(4-chloro-3-nitrophenyl)-3,4,5,6,7,9-hexahydrothieno[3,2-b]quinolin-8(2H)-one 1,1-dioxide;

9-(3-bromo-4-fluorophenyl)-3,4,5,6,7,9-hexahydrothieno[3,2-b]quinolin-8(2H)-one 1,1-dioxide;

4-(3-cyanophenyl)-4,6,7,8-tetrahydro-2-methyl-3-(methylsulfonyl)-5(1H)-quinolinone;

4,6,7,8-tetrahydro-2-methyl-3-(methylsulfonyl)-4-(3-nitrophenyl)-5(1H)-quinolinone;

4.6.7.8-tetrahydro-2-methyl-3-(methylsulfonyl)-4[4-(trifluoromethyl)phenyl]-5(1H)-quinolinone;

4-(3,4-dichlorophenyl)-4,6,7,8-tetrahydro-2-methyl-3-(methylsulfonyl)-5(1H)-quinolinone;

4.6.7.8- tetrahydro-2-methyl-4-(4-methyl-3-nitrophenyl)-3(methylsulfonyl)-5(1H)-quinolinone;

4-(4-chloro-3-nitrophenyl)-4,6,7,8-tetrahydro-2-methyl-3-(methylsulfonyl)-5(1H)-quinolinone;

4-(3-Bromo-4-fluorophenyl)-4,6,7,8-tetrahydro-2-methyl-3-(methylsulfonyl)-5(1H)-quinolinone;

4-(4-chloro-3-fluorophenyl)-4,6,7,8-tetrahydro-2-methyl-3-(methylsulfonyl)-5(1H)-quinolinone;

4-(3,4,5-trifluorophenyl)-4,6,7,8-tetrahydro-2-methyl-3-(methylsulfonyl)-5(1H)-quinolinone;

9-(3-cyano)-3,4,5,6,7,9-hexahydrocyclopenta[b]thiopyrano[2,3-e]pyridin-8(2H)-one 1,1-dioxide;

9-(3,4-dichlorophenyl)-3,4,5,6,7,9-hexahydrocyclopenta[b]thiopyrano[2,3-e]pyridin-8(2H)-one 1,1-dioxide;

9-(4-chloro-3-nitrophenyl)-3,4,5,6,7,9-hexahydrocyclopenta[b]thiopyrano[2,3-e]pyridin-8(2H)-one 1,1-dioxide;

9-(3-chloro-4-fluorophen1)-3,4,5,6,7,9-hexahydrocyclopenta[b]thiopyrano[2,3-e]pyridin-8(2H)-one 1,1-dioxide,

9-(3-bromo-4-fluorophenyl)-3,4,5,6,7,9-hexahydrocyclopenta[b]thiopyrano[2,3-e]pyridin-8(2H)-one 1,1-dioxide;

9-(4-fluoro-3-trifluoromethyl)-3,4,5,6,7,9-hexahydrocyclopenta[b]thiopyrano[2,3-e]pyridin-8(2H)-one 1,1-dioxide;

9-(4-methyl-3-nitro)-3,4,5,6,7,9-hexahydrocyclopenta[b]thiopyrano[2,3-e]pyridin-8(2H)-one 1,1-dioxide;

8-(4-Chloro-3-nitrophenyl)-3,5,6,8-tetrahydro-2H-cyclopenta[b]thieno[2,3-e]pyridin-7(4H)-one 1,1-dioxide;

8-(3-bromo-4-fluorophenyl)-3,5,6,8-tetrahydro-2H-cyclopenta[b]thieno[2,3-e]pyridin-7(4H)-one 1,1-dioxide;

1-[8-(3,4-dichlorophenyl)-3,4,5,8-tetrahydro-6-methyl-1,1-dioxido2H-thiopyrano[3,2-b]pyridin-7-yl]ethanone;

-[8-(4-chloro-3-nitrophenyl)-3,4,5,8-tetrahydro-6-methyl-1,1-dioxido-2Hthiopyrano[3,2-b]pyridin-7-yl]ethanone;

1,1,9,9-tetraoxide 10-(4-chloro-3-nitrophenyl)-3,4,6,7,10-hexahydro-2H,5Hbisthiopyrano[3,2-b:2',3'-e]pyridine;

3,4,6,7,8,10-hexahydro-10-phenyl-2H-thiopyrano[3,2-b]quinolin-9(5H)-one 1,1-dioxide;

3,4,6,7,8,10-hexahydro-10-(3-nitrophenyl)-2H-thiopyrano[3,2-b]quinolin-9(5H)-one 1,1-dioxide;

10-(3-cyanophenyl)-3,4,6,7,8,10-hexahydro-2H-thiopyrano[3,2-b]quinolin-9(5H)-one 1,1-dioxide;

3,4,6,7,8,10-hexahydro-10-[3-(trifluoromethyl)phenyl]-2Hthiopyrano[3,2-b]quinolin-9(5H)one 1,1-dioxide;

10-(3-bromophenyl)-3,4,6,7,8,10-hexahydro-2H-thiopyrano[3,2-b]quinolin-9(5H)-one 1,1-dioxide;

10-(3-fluorophenyl)-3,4,6,7,8,10-hexahydro-2H-thiopyrano[3,2-b]quinolin-9(5H)-one 1,1-dioxide;

10-(3-Chlorophene 1-3,4,6,7,8,10-hexahydro-2H-thiopyrano[3,2-b]quinolin-9(5H)-one 1,1-dioxide;

3,4,6,7,8,10-hexahydro-10-[4-(trifluoromethyl)phenyl]-2H-thiopyrano[3,2-b]quinolin-9(5H)-one 1,1-dioxide;

10-(4-bromophenyl)-3,4,6,7,8,10-hexahydro-2H-thiopyrano[3,2-b]quinolin-9(5H)-one 1,1-dioxide;

10-(3,4-dichlorophenyl)-3,4,6,7,8,10-hexahydro-2H-thiopyrano[3,2-b]quinolin-9(5H)-one 1,1-dioxide;

10-(3-chloro-4-fluorophenyl)-3,4,6,7,8,10-hexahydro-2Hthiopyrano[3,2-b]quinolin-9(5H)-one 1,1-dioxide;

10-(3-bromo-4-fluorophenyl)-3,4,6,7,8,10-hexahydro-2Hthiopyrano[3,2-b]quinolin-9(5H)-one 1,1-dioxide;

10-(3,4-difluorophenyl)-3,4,6,7,8,10-hexahydro-2H-thiopyrano[3,2-b]quinolin-9(5H)-one 1,1-dioxide;

10-[3-fluoro-5-(trifluoromethyl)phenyl)-3,4,6,7,8,10-hexahydro-2Hthiopyrano[3,2-b]quinolin-9(5H)-one 1,1-dioxide;

10-[4-fluoro-3-(trifluoromethyl)phenyl]-3,4,6,7,8,10-hexahydro-2Hthiopyrano[3,2-b]quinolin-9(5H)-one 1,1-dioxide;

3,4,6,7,8,10-hexahydro-10-(4-methyl-3-nitrophenyl)2Hthiopyrano[3,2-b]quinolin-9(5H)-one 1,1-dioxide;

10-(4-chloro-3-fluorophenyl)-3,4,6,7,8,10-hexahydro-2Hthiopyrano[3,2-b]quinolin-9(5H)-one 1,1-dioxide;

10-(4-chloro-3-nitrophenyl)-3,4,6,7,8,10-hexahydro-2Hthiopyrano[3,2-b]quinolin-9(5H)-one 1,1-dioxide;

3,4,6,7,8,10-hexahydro-10-(3,4,5-trifluorophenyl)-2H-thiopyrano[3,2-b]quinolin-9(5H)-one 1,1-dioxide;

10-(3-pyridyl)-3,4,6,7,8,10-hexahydro-2H-thiopyrano[3,2-b]quinolin-9(5H)-one 1,1-dioxide;

10-(4-pyridyl)-3,4,6,7,8,10-hexahydro-2H-thiopyrano[3,2-b]quinolin-9(5H)-one 1,1-dioxide;

9-(3-cyanophenyl)-3,4,5,6,7,9-hexahydrothieno[3,2-b]quinolin-8(2H)-one 1,1-dioxide;

9-(3-nitrophenyl)-3,4,5,6,7,9-hexahydrothieno[3,2-b]quinolin-8(2H)-one 1,1-dioxide;

9-(3,4-dichlorophenyl)-3,4,5,6,7,9-hexahydrothieno[3,2-b]quinolin-8(2H)-one 1,1-dioxide;

9-[4-fluoro-3-(trifluoromethyl)phenyl]-3,4,5,6,7,9-hexahydrothieno[3,2b]quinolin-8(2H)-one 1,1-dioxide;

3,4,5,6,7,9-hexahydro-9-(4-methyl-3-nitrophenyl)thieno[3,2-b]quinolin-8(2H)-one 1,1-dioxide;

9-(3,4-difluorophenyl)-3,4,5,6,7,9-hexahydrothieno 1,1-dioxide

[3,2-b]quinolin-8(2H)one;

9-(4-chloro-3-nitrophenyl)-3,4,5,6,7,9-hexahydrothieno[3,2-b]quinolin-8(2H)-one 1,1-dioxide;

9-(3-Bromo-4-fluorophenyl)-3,4,5,6,7,9-hexahydrothieno[3,2-b]quinolin-8(2H)-one 1,1-dioxide;

4-(3-cyanophenyl)-4,6,7,8-tetrahydro-2-methyl-3-(methylsulfonyl)5(1H)-quinolinone;

4.6.7.8- tetrahydro-2-methyl-3-(methylsulfonyl)-4-(3-nitrophenyl)5(1H)quinolinone;

4.6.7.8-tetrahydro-2-methyl-3-(methylsulfonyl)-4-[4-(trifluoromethyl)phenyl]5(1H)-quinolinone;

4-(3,4-dichlorophenyl)-4,6,7,8-tetrahydro-2-methyl-3-(methylsulfonyl)-5(1H)-quinolinone;

4.6.7.8-tetrahydro-2-methyl-4-(4-methyl-3-nitrophenyl)-3-(methylsulfonyl)-5(1H)-quinolinone;

4-(4-chloro-3-nitrophenyl)-4,6,7,8-tetrahydro-2-methyl-3-(methylsulfonyl)-5(1H)-quinolinone;

4-(3-bromo-4-fluorophenyl)-4,6,7,8-tetrahydro-2-methyl-3-(methylsulfonyl)-5(1H)-quinolinone;

4-(4-Chloro-3-fluorophen1)-4,6,7,8-tetrahydro-2-methyl-3-(methylsulfonyl)-5(1H)-quinolinone;

4-(3,4,5-trifluorophenyl)-4,6,7,8-tetrahydro-2-methyl-3-(methylsulfonyl)-5(1H)-quinolinone;

9-(3-cyano)-3,4,5,6,7,9-hexahydrocyclopenta[b]thiopyrano[2,3-e]pyridin-8(2H)one 1,1-dioxide;

9-(3,4-dichlorophenyl)-3,4,5,6,7,9-hexahydrocyclopenta[b]thiopyrano[2,3-e]pyridin-8(2H)-one 1,1-dioxide;

9-(4-chloro-3-nitrophenyl)-3,4,5,6,7,9-hexahydrocyclopenta[b]thiopyrano[2,3-e]pyridin-8(2H)-one 1,1-dioxide;

9-(3-chloro-4-fluorophenyl)-3,4,5,6,7,9-hexahydrocyclopenta[b]thiopyrano[2,3-e]pyridin-8(2H)-one 1,1-dioxide;

9-(3-bromo-4-fluorophenyl)-3,4,5,6,7,9-hexahydrocyclopenta[b]thiopyrano[2,3-e]pyridin-8(2H)-one 1,1-dioxide;

9-(4-fluoro-3-trifluoromethyl)-3,4,5,6,7,9-hexahydrocyclopenta[b]thiopyrano[2,3-e]pyridin-8(2H)-one;

9-(4-methyl-3-nitro)-3,4,5,6,7,9-hexahydrocyclopenta[b]thiopyrano[2,3-e]pyridin-8(2H)-one 1,1-dioxide;

8-(4-Chloro-3-nitrophenyl)-3,5,6,8-tetrahydro-2H-cyclopenta[b]thieno [2,3-e]pyridin-7(4H)-one 1,1-dioxide;

1,1-dioxide 8-(3-bromo-4-fluorophen1)-3,5,6,8-tetrahydro-2H-cyclopenta[b]thieno[2,3-e]pyridin-7(4H)-one;

1-[8-(3,4-dichlorophenyl)-3,4,5,8-tetrahydro-6-methyl-1,1-dioxido-2Hthiopyrano[3,2-b]pyridin-7-yl]ethanone;

1-[8-(4-chloro-3-nitrophenyl)-3,4,5,8-tetrahydro-6-methyl-1,1-dioxido-2Hthiopyrano[3,2-b]pyridin-7-yl)ethanone;

1,1,9,9-10-(4-Chloro-3-nitrophenyl)-3,4,6,7,10-hexahydro-2H,5H-bisthiopyrano[3,2-b:2',3'-epyridine tetraoxide;

1,1- 9-(3,4-difluorophenyl)-3,4,5,6,7,9-hexahydrocyclopenta[b]thiopyrano[2,3-e]pyridin-8(2H)-one dioxide;

8-(4-chloro-3-nitrophenyl)-2,3,4,5,6,8-hexahydrodithieno[3,2-b:2n,3n]pyridine 1,1,7,7-tetraoxide;

8-(3-cyanophenyl)-2,3,4,5,6,8-hexahydro-7H-cyclopenta[b]thieno [2,3-e]pyridin-7-one 1,1-dioxide;

8-(3-bromo-4-fluorophenyl)-2,3,4,5,6,8-hexahydrodithieno[3,2-b:2n,3n-e]pyridine 1,1,7,7-tetraoxide;

1,1,9,9-10-(3-bromo-4-fluorophenyl)-3,4,6,7,8,10-hexahydro-2H,5H-dithiopyrano[3,2-b:21,31-e]pyridine tetraoxide;

3,4,5,6,7,9-hexahydro-9-(3-nitrophenyl)cyclopenta[b]thiopyrano[2,3-e]pyridin-8(2H)-one 1,1-dioxide;

8-(3-bromo-4-fluorophenyl)-2,3,4,5,6,8-hexahydro-7H-cyclopenta[b]thieno[2,3-e]pyridin-7-one 1,1-dioxide;

8-(4-Fluoro-3-trifluoroethylphenyl)-2,3,4,5,6,8-hexahydro7H-cyclopenta[b]thieno[2,3-e]pyridin-7-one 1,1-dioxide;

2,3,4,5,6,8-hexahydro-8-(3-nitrophenyl)-7H-cyclopenta[b]thieno[2,3-e]pyridin-7-one 1,1-dioxide;

3,4,6,7,8,10-hexahydro-10-(3-nitrophenyl)-2H,5H16-dithiopyrano[3,2b:21,31-e]pyridine 1,1,9,9-tetraoxide;

8-(3,4-dichlorophenyl)-2,3,4,5,6,8-hexahydro-7H-cyclopenta[b]thieno[2,3-e]pyridin-7-one 1,1-dioxide;

8-(3-chloro-4-fluorophenyl)-2,3,4,5,6,8-hexahydro7H-cyclopenta[b]thieno[2,3-e]pyridin-7-one 1,1-dioxide;

8-(3-cyanophenyl)-2,3,4,5,6,8-hexahydrodithieno[3,2-b:2n,3n-e]pyridine 1,1,7,7-tetraoxide;

8-(2-cyano-4-pyridinyl)-2,3,4,5,6,8-hexahydro7H-cyclopenta[b]thieno[2,3-e]pyridin-7-one 1,1-dioxide;

8-(3-bromophenyl)-2,3,4,5,6,8-hexahydro-7H-cyclopenta[b]thieno[2,3-e]pyridin-7-one 1,1-dioxide;

1,1,7,7-tetraoxide 8-(4-fluoro-3-trifluoromethylphenyl)-2,3,4,5,6,8hexahy drodithieno [3,2b; 2n, 3n-e]pyridine;

8-(4-bromo-2-thienyl)-2,3,4,5,6,8-hexahydro-7H-cyclopenta[b]thieno[2,3-e]pyridin-7-one 1,1-dioxide;

8-(5-bromo-2-thienyl)-2,3,4,5,6,8-hexahydro-7H-cyclopenta[b]thieno [2,3-e]pyridin-7-one 1,1-dioxide;

2,3,4,5,6,8-hexahydro-8-(5-nitro-3-thienyl)-7H-cyclopenta[b]thieno[2,3-e]pyridin-7-one 1,1-dioxide;

2,3,4,5,6,8-hexahydro-8-(5-nitro-2-thienyl)-7H-cyclopenta[b]thieno[2,3-e]pyridin-7-one 1,1-dioxide;

2,3,4,5,6,8-hexahydro-8-(5-nitro-2-furyl)-7H-cyclopenta[b]thieno[2,3-e]pyridin-76-one 1,1-dioxide,

8-(3,4-dibromophenyl)-2,3,4,5,6,8-hexahydro-7H-cyclopenta[b]thieno[2,3-e]pyridin-7-one 1,1-dioxide;

1,1,7,7-tetraoxide 2,3,4,5,6,8-hexahydro-8-(3-nitrophenyl)dithieno [3,2-b; 2 µl, 3 µl-e]pyridine

8-(3-chloro-4-fluorophenyl)-2,3,4,5,6,8-hexahydrodithieno[3,2-b:2n,3n]pyridine 1,1,7,7-tetraoxide;

8-(3,4-chlorophenyl)-2,3,4,5,6,8-hexahydrodithieno[3,2-b:21,31-e]pyridine 1,1,7,7-tetraoxide;

8-(4-bromophenyl)-2,3,4,5,6,8-hexahydro-7H-cyclopenta[b]thieno[2,3-e]pyridin-7-one 1,1-dioxide;

8-(3,4-difluorophenyl)-2,3,4,5,6,8-hexahydro-7H-cyclopenta[b]thieno[2,3-e]pyridin-7-one 1,1-dioxide;

8-(4-Chloro-3-fluorophenyl)-2,3,4,5,6,8-hexahydro7H-cyclopenta[b]thieno[2,3-eppyridin-7-one] 1,1-dioxide;

9-(3-Chloro-4-fluorophenyl)-2,3,5,6,7,9-hexahydroquino[3,2-b]quinolin-8(4H)-one 1,1-dioxide;

8-(3-cyano-4-fluorophenyl)-2,3,4,5,6,8-hexahydrodithieno[3,2-b:2n,3n]pyridine 1,1,7,7-tetraoxide;

1,1-dioxide (+) (9R)-9-(3-bromo-4-fluorophenyl)-2,3,5,6,7,9-hexahydrothieno [3,2-b]quinolin-8(4H)-one;

1,1-Dioxide (-) (9S)-9-(3-Bromo-4-fluorophenyl)-2,3,5,6,7,9-hexahydrothieno[3,2-b]quinolin-8(4H)-one;

8-(2,1,3-benzoxadiazol-5-yl)-2,3,4,5,6,8-hexahydro7H-cyclopenta[b]thieno[2,3-e]pyridin-7-one 1,1-dioxide;

(-)(8S)-8-(3-bromo-4-fluorophenyl)-2,3,4,5,6,8-hexahydro7H-cyclopenta[b]thieno[2,3-e]pyridin-7-one 1,1-dioxide;

(+) (8R)-8-(3-bromo-4-fluorophenyl)-2,3,4,5,6,8-hexahydro-7H-cyclopenta [b]thieno[2,3-e]pyridin-7-one;

9-(2,1,3-benzoxadiazol-5-yl)-2,3,5,6,7,9-hexahydrothieno[3,2-b]quinolin-8(4H)-one 1,1-dioxide;

9-(4-fluoro-3-iodophenyl)-2,3,5,6,7,9-hexahydrothieno[3,2-b]quinolin-8(4H)-one 1,1-dioxide;

8-(4-Fluoro-3-iodophenyl)-2,3,4,5,6,8-hexahydro-7H-cyclopenta[b]thieno[2,3-e]pyridin-7-one 1,1-dioxide;

(+)9-(3-Bromo-4-fluorophenyl)-3,4,5,6,7,9-hexahydrocyclopenta [b]thiopyrano[2,3-e]pyridin-8(2H)-one;

(-)9-(3-bromo-4-fluorophenyl)-3,4,5,6,7,9-hexahydrocyclopenta [b]thiopyrano[2,3-e]pyridin-8(2H)-one;

1,1-dioxide (+) 10-(3-bromo-4-fluorophenyl)-3,4,6,7,8,10-hexahydro-2H-thiopyrano[3,2-b]quinolin-9(5H)-one;

1,1-dioxide (-) 10-(3-bromo-4-fluorophenyl)-3,4,6,7,8,10-hexahydro-2H-thiopyrano[3,2-b]quinolin-9(5H)-one;

1,1-dioxide (+)(9R)-9-(3,4-dichlorophenyl)-3,4,5,6,7,9-hexahydrothieno [3,2-b]quinolin-8(2H)-one;

1,1-dioxy d (-(9S)-9-(3,4-dichlorophenyl)-3,4,5,6,7,9-hexahydrothieno[3,2-b]quinolin-8(2H)-one;

Hexahydrothieno[3,2-b]quinolin-8(4H)-one 1,1-dioxide (+)(9R)-9-(2,1,3-benzoxadiazol-5-yl)-2,3,5,6,7,91,1-dioxide;

(-) (9S)-9-(2,1,3-Benzoxadiazol-5-yl)-2,3,5,6,7,9-hexahydrothieno [3,2-b]quinolin-8(4H)-one;

(+)(9R)-9-(4-chloro-3-nitrophenyl)-3,4,5,6,7,9-hexahydrothieno[3,2-b]quinolin-8(2H)-one 1,1-dioxide;

1,1-dioxide (-) (9S)-9-(4-Chloro-3-nitrophen1)-3,4,5,6,7,9-hexahydrothieno[3,2-b]quinolin-8(2H)-one;

11-(3-bromo-4-fluorophenyl)-2,3,4,5,7,8,9,11-octahydrothiepino[3,2-b]quinolin-10(6H)-one 1,1-dioxide; and

10-(3-bromo-4-fluorophenyl)-2,3,4,5,6,7,8,10-octahydro-9H-cyclopenta[b]thiepino[2,3-e]pyridin-9-one or pharmaceutically acceptable salts, esters, amides or prodrugs thereof.

Preparation of the compounds of the present invention

The compounds and processes of the present invention will be better understood in connection with the following synthetic schemes and methods, which illustrate the means by which the compounds of the present invention can be prepared.

The compounds of the present invention can be prepared by a variety of synthetic routes. Representative procedures are shown in Schemes 1-2.

Scheme 1

(Q)n 2 R ^, _fA —. ^rVS yt ^a * r ⁵ ^o CHO (i) (ii) (iii) I

As shown in Scheme 1, dihydropyridines of formula (I) are prepared by heating a ketone (i) with an aldehyde (ii) and an enamine (iii) in a protic solvent, such as ethyl alcohol.

• 9 • 9

In the case where the substituents R ¹ and R ⁵ form a 5-membered ring, an additional step in which the mixture is heated may be required to obtain the product.

As shown in Scheme 2, for those examples where the substituent X is S(O) _P , where the index p is 2, R ^{1 = x} R ³ and R ⁴ = R ⁵ , dihydropyridines of formula (I) are prepared by heating 2 equivalents of ketone (i) with 1 equivalent of aldehyde (ii) and concentrated ammonium hydroxide in a protic solvent such as ethyl alcohol.

The following methods are intended to be illustrative and are not intended to limit the scope of the invention, which is fully defined in the appended claims. All citations are hereby incorporated by reference.

Scheme 3

The compounds in the examples of the present invention, which have a chiral center and thus occur in racemic form, were separated into their individual enantiomers by the methods shown in Scheme 3. Racemic compounds of general formula (I) are reacted • » with potassium tert-butoxide (1 equivalent) in tetrahydrofuran and subsequently with chloroformate

8-phenylmenthyl to obtain a mixture of diastereomeric 8-phenylmenthyl carbamates (i) and (ii). The diastereomers (i) and (ii) are separated on a silica gel column and the 8-phenylmenthyl moiety is removed by reaction with sodium methoxide in methanol to obtain the single enantiomers indicated.

In addition to using the method illustrated in Scheme 3, the individual enantiomers of the compounds of the present invention were also separated by chiral chromatography.

Examples of embodiments of the invention

Example 1

1,1-Dioxide of 3,4,6,7,8,10-hexahydro-10-(3-nitrophenyl)-2H-thiopyrano[3,2-b]quinolin-9(5H)-one A solution of 3-nitrobenzaldehyde (151 mg, 1.00 mmol), tetrahydrothiopyran-3-one-1,1-dioxide (148 mg, 1.00 mmol) was prepared according to the method described in J. Heterocycl. Chem. (1990), 27, 1453 and 3-amino-2-cyclohexen-1-one (111 mg, 1.00 mmol) in ethanol (7 mL) was heated at reflux for 24 h and cooled. The solid that precipitated was washed with ethanol, dried and triturated with hot methanol to give the desired compound. MS (APCI) m/e 375 (M+H) ⁺ , ³ H NMR (DMSO-d ₆ ) 1.75 (m, 1H), 1.90 (m, 1H), 2.22 (m, 4H), 2.55 (m, 4H), 3.22 (m, 2H), 5.15 (s, 1H), 7.55 (t, 1H), 7.65 (d, 1H), 8.00 (m, 1H), 9.48 (br s, 1H), Analytical calcd for C, 57.74; H, 4.85; N, 7.48. Found: C, 57.41; H, 4.75; N, 7.39.

Example 2

10-(3,4-dichlorophenyl)-3,4,6,7,8,10-hexahydro-2H-thiopyrano[3,2-b]quinolin9(5H)-one 1,1-dioxide

3,4-Dichlorobenzaldehyde (175 mg, 1.00 mmol) was treated according to the procedure of Example 1 to give the desired compound. MS (APCI) m/e 398 (M+H) ⁺ , 400 (M+H) ⁺ ; 1H NMR (DMSO-d6) 1.75 (m, 1H), 1.90 (m, 1H), 2.22 (m, 4H), 2.55 (m, 4H), 3.20 (m, 2H), 5.01 (s, 1H), 7.06 (dd, 1H), 7.32 (d, 1H), 7.50 (d, _1H ), _9.40 (br s, 1H) _; Analytical calcd for _{C18H17C12NO3S} : C, 54.28; H, 4.30; N, 3.52. Found: C, 54.13; H, 4.18; N, 3.46.

Example 3

10-(3-chloro-4-fluorophenyl)-3,4,6,7,8,10-hexahydro-2H-thiopyrano[3,2-b]quinolin9(5H)-one 1,1-dioxide

3-Chloro-4-fluorobenzaldehyde (159 mg, 1.00 mmol)) was processed according to the procedure of Example 1 to give the desired compound. MS (APCI) m/e 382 (M+H) ⁺ , 384 (M+H) ⁺ ; 1H NMR (DMSO-d6) 1.75 (m, ÍH), 1.88 (m, ÍH), 2.20 (m, 4H), 2.50 (m, 4H), 3.20 (m, 2H), 5.01 (s, ÍH), 7.15 (ddd, ÍH), 7.26 (m, 3H), 9.38 (br s, ÍH _{); Analytical calcd for C18H17C1FNO3S : C} , 56.62; H, 4.49; N, 3.67. Found: C, 56.64; H, 4.43; N, 3.57.

Example 4

10-(3-bromo-4-fluorophenyl)-3,4,6,7,8,10-hexahydro-2H-thiopyrano[3,2-b]quinolin9(5H)-one 1,1-dioxide

3-Bromo-4-fluorobenzaldehyde (203 mg, 1.00 mmol) was treated according to the procedure of Example 1 to give the desired compound. MS (APCI) m/e 426 (M+H) ⁺ , 428 (M+H) ^{+ ;} 1 H NMR (DMSO-d6) 1.75 (m, ÍH), 1.90 (m, ÍH), 2.20 (m, 4H), 2.55 (m, 4H), 3.20 (m, 2H), 5.01 (s, ÍH), 7.20 (m, 2H), 7.40 (dd, ÍH), 9.35 (br s, ÍH); Analytical calcd for C ₈ H ₇ BrFNO ₃ S: C, 50.71; H, 4.02; N, 3.29, Found: C, 50.69; H, 3.99; N, 3.16.

Example 5

1,1-dioxide of 10-(3-cyanophenyl)-3,4,6,7,8,10-hexahydro-2H-thiopyrano[3,2-b]quinolin-9(5H)one

3-Cyanobenzaldehyde (131 mg, 1.00 mmol) was treated according to the procedure of Example 1 to give the desired compound. MS (APCI) m/e 355 (M+H) ⁺ ; *H NMR (DMSO-d6) 1.75 (m, ÍH), 1.88 (m, ÍH), 2.20 (m, 4H), 2.55 (m, 4H), 3.20 (m, 2H), 5.07 (s, ÍH), 7.45 (t, ÍH),

7.52 (s, ÍH), 7.54 (dt, ÍH), 7.60 (dt, ÍH), 9.40 (br s, ÍH); Analytical calcd for C ₁₉ H ₁₈ N ₂ O ₃ S: C, 64.39; H, 5.12; N, 7.90. Found: C, 64.18; H, 5.15; N, 7.83.

Example 6

1,1 -dioxide of 3,4,6,7,8,10-hexahydro-10-[3-(trifluoromethyl)phenyl]-2H-thiopyrano[3,2-b]quinolin9-(5H)-one • · < < I <» ., » · « ··*·'* + · • « · ♦ r.

3-Trifluoromethylbenzaldehyde (134 mL, 1.00 mmol) was treated according to the procedure of Example 1 to give the desired compound. MS (APCI) m/e 398 (M+H) ⁺ ; *H NMR (DMSOd6) 1.74 (m, 1H), 1.90 (m, 1H), 2.20 (m, 4H), 2.55 (m, 4H), 3.18 (m, 2H), 5.11 (s, 1H), 7.48 (br s, 4H), 9.40 (br s, 1H); Analytical calcd for C19H18F3NO3S: C, 57.42; H, 4.57; N, 3.52. Found: C, 57.12; H, 4.67; N, 3.39.

Example 7

10-(3,4-difluorophenyl)-3,4,6,7,8,10-hexahydro-2H-thiopyrano[3,2-b]quinolin-9(5H)one 1,1-dioxide

3,4-Difluorobenzaldehyde (110L, 1.00 mmol) was processed according to the procedure of Example 1 to give the desired compound. MS (APCI) m/e 366 (M+H) ⁺ ; 1H NMR (DMSO-d6) 1.75 (m, 1H), 1.88 (m, 1H), 2.20 (m, 4H), 2.50 (m, 4H), 3.20 (m, 2H), 5.02 (s, 1H), 7.02 (m, 1H), 7.10 (m, 1H), 7.26 (dt, 1H), 9.37 (br s, 1H); Analytical calcd for C18H17F2NO3S: C, 59.17; H, 4.69; N, 3.83. Found: C, 58.91; H, 4.70; N, 3.69.

Example 8

10-(3-Bromophenyl)-3,4,6,7,8,10-hexahydro-2H-thiopyrano[3,2-b]quinolin-9(5H)-one 3-Bromobenzaldehyde (117 mL, 1.00 mmol) was treated according to the procedure of Example 1 to give the desired compound. MS (APCI) m/e 408 (M+H) ⁺ , 410 (M+H) ⁺ ; 1H NMR (DMSO-d6) 1.75 (m, 1H), 1.90 (m, 1H), 2.20 (m, 4H), 2.55 (m, 4H), 3.20 (m, 2H), 5.01 (s, 1H), 7.20 (m, 2H), 7.30 (m, 2H), 9.40 (br s, 1H); Analytical calcd for C 18 H 18 BrNO 3 S: C, 52.95; H, 4.44; N, 3.43. Found: C, 52.91; H, 4.53; N, 3.37.

Example 9

3,4,6,7,8,10-hexahydro-10-(3,4,5-trifluorophenyl)-2H-thiopyrano[3,2-b]quinolin9(5H)-one 1,1-dioxide

3,4,5-Trifluorobenzaldehyde (160 mg, 1.00 mmol) was processed according to the procedure of Example 1 to give the desired compound. MS (APCI) m/e 384 (M+H) ⁺ ; *H NMR (DMSO-d6) 1.75 (m, 1H), 1.88 (m, 1H), 2.20 (m, 4H), 2.50 (m, 4H), 3.20 (m, 2H), 5.02 (s, 1H), 7.00 (m, 2H), 9.41 (br s, 1H); Analytical calcd for C18H16F3NO3S: C, 56.39; H, 4.21; N, 3.65. Found: C, 56.26; H, 4.27; N, 3.55.

• ·

Example 10

10-[3-fluoro-5-(trifluoromethyl)phenyl]-3,4,6,7,8,10-hexahydro-2H-thiopyrano[3,2b]quinolin-9(5H)-one 1,1-dioxide

3-Fluoro-5-trifluoromethylbenzaldehyde (192 mg, 1.00 mmol) was treated according to the procedure of Example 1 to give the desired compound. MS (APCI) m/e 416 (M+H) ⁺ ; 1H NMR (DMSO-d ₆ ) 1.75 (m, 1H), 1.90 (m, 1H), 2.20 (m, 4H), 2.55 (m, 4H), 3.20 (m, 2H), 5.14 (s, 1H), 7.23 (d, 1H), 7.36 (s, 1H), 7.44 (d, 1H), 9.45 (br s, 1H); Analytical calcd for C19H17F4NO3S: C, 54.94; H, 4.12; N, 3.37. Found: C, 54.84; H, 4.20; N, 3.26.

Example IX

1,1-dioxide of 10-(3-fluorophenyl)-3,4,6,7,8,10-hexahydro-2H-thiopyrano[3,2-b]quinolin-9(5H)-one 3-Fluorobenzaldehyde (106 mL, 1.00 mmol) was treated according to the procedure of Example 1 to give the desired compound. MS (APCI) m/e 348 (M+H) ^{+ ;} 1 H NMR (DMSO-d6) 1.75 (m, 1H), 1.88 (m, 1H), 2.20 (m, 4H), 2.55 (m, 4H), 3.20 (m, 2H), 5.05 (s, 1H), 6.93 (m, 2H), 7.04 (d, 1H), 7.25 (dt, 1H), 9.35 (br s, 1H); Analytical calcd for C16H16FNCbS: C, 62.23; H, 5.22; N, 4.03. Found: C, 61.95; H, 5.03; N, 3.89.

Example 12

3,4,6,7,8,10-hexahydro-10-phenyl-2H-thiopyrano[3,2-b]quinolin-9(5H)-one 1,1-dioxide

Benzaldehyde (102 mL, 1.00 mmol) was treated according to the procedure of Example 1 to give the desired compound. MS (APCI) m/e 330 (M+H) ⁺ ; *HNMR (DMSO-d6) 1.73 (m, 1H), 1.90 (m, 1H), 2.20 (m, 4H), 2.50 (m, 4H), 3.18 (m, 2H), 5.03 (s, 1H), 7.10 (m, 1H), 7.20 (m, 4H), 9.28 (br s, 1H); Analytical calcd for C18H19NO3S: C, 65.63; H, 5.81; N, 4.25. Found: C, 65.57; H, 5.99; N, 4.12.

Example 13

10-[4-fluoro-3-(trifluoromethyl)phenyl]-3,4,6,7,8,10-hexahydro-2H-thiopyrano[3,2b]quinolin-9(5H)-one 1,1-dioxide

4-Fluoro-3-trifluoromethylbenzaldehyde (194 mg, 1.01 mmol) was worked up according to the procedure of Example 1 to give the desired compound. MS (APCI) m/e 416 (M+H) ⁺ ; 1H NMR (DMSO-d6) 1.75 (m, 1H), 1.90 (m, 1H), 2.22 (m, 4H), 2.52 (m, 4H), 3.20 (m, 2H), 5.09 (s, 1H), 7.38 (dd, 1H), 7.50 (m, 2H), 9.42 (br s, 1H); Analytical calcd for C19H17F4NO3S: C, 54.93; H, 4.12; N, 3.37. Found: C, 54.77; H, 4.16; N, 3.26.

Example 14

3,4,6,7,8,10-hexahydro-10-(4-methyl-3-nitrophenyl)2H-thiopyrano[3,2-b]quinolin9(5H)-one 1,1-dioxide

4-Methyl-3-nitrobenzaldehyde (165 mg, 1.00 mmol) was worked up according to the procedure of Example 1 to give the desired compound. MS (APCI) m/e 389 (M+H) ⁺ ; *Η NMR (DMSOd6) 1.75 (m, 1H), 1.88 (m, 1H), 2.22 (m, 4H), 2.45 (s, 3H), 2.55 (m, 4H), 3.20 (m, 2H), 5.09 (s, 1H), 7.35 (d, 1H), 7.43 (dd, 1H), 7.72 (d, 1H), 9.42 (br s, 1H); Analytical calcd for C ₉ H 20 N _{2 O 5} S*0.25H ₂ 0: C, 58.07; H, 5.25; N, 7.12. Found: C, 58.21; H, 5.36; N, 6.95.

Example 15

10-(4-chloro-3-fluorophenyl)-3,4,6,7,8,10-hexahydro-2H-thiopyrano[3,2-b]quinolin9(5H)-one 1,1-dioxide

4-Chloro-3-fluorobenzaldehyde (159 mg, 1.00 mmol) was treated according to the procedure of Example 1 to give the desired compound. MS (APCI) m/e 382 (M+H) ⁺ , 384 (M+H) ⁺ ; *H NMR (DMSO-d6) 1.75 (m, 1H), 1.90 (m, 1H), 2.20 (m, 4H), 2.55 (m, 4H), 3.20 (m, 2H), 5.03 (s, 1H), 7.07 (m, 2H), 7.42 (t, 1H), 9.37 (br s, 1H); Analytical calcd. for

_{C18H17C1FNO3S :} C, _56.62 ; H, 4.49; N, 3.67. Found: C, 56.36; H, 4.53; N, 3.59.

Example 16

10-(3-chlorophenyl)-3,4,6,7,8,10-hexahydro-2H-thiopyrano[3,2-b]quinolin-9(5H)-one

3-Chlorobenzaldehyde (113 mL, 1.00 mmol) was treated according to the procedure of Example 1 to give the desired compound. MS (APCI) m/e 364 (M+H) ⁺ , 366 (M+H) ⁺ ; 1H NMR (DMSO-d6) 1.75 (m, 1H), 1.90 (m, 1H), 2.20 (m, 4H), 2.50 (m, 4H), 3.18 (m, 2H), 5.02 (s, 1H) I 11.» χιιWBWBWMBBWIWr

ΙΗ), 7.15 (m, 3H), 7.25 (m, 1H), 9.35 (br s, 1H); Analytical calcd for C18H18ClNCbS: C, 59.42; H, 4.99; N, 3.85. Found: C, 59.16; H, 5.13; N, 3.71.

Example 17

3,4,6,7,8,10-hexahydro-10-[4-(trifluoromethylphenyl]-2H-thiopyrano[3,2-b]quinolin9(5H)-one 1,1-dioxide

4-Trifluoromethylbenzaldehyde (137 mL, 1.00 mmol) was treated according to the procedure of Example 1 to give the desired compound. MS (APCI) m/e 398 (M+H) ⁺ ; *H NMR (DMSOd6) 1.75 (m, 1H), 1.89 (m, 1H), 2.20 (m, 4H), 2.50 (m, 4H), 3.19 (m, 2H), 5.10 (s, 1H), 7.38 (d, 2H), 7.58 (d, 2H), _9.37 (br s, 1H); Analytical calcd for _C19H18F3NO3S : C, 57.42; H, 4.56; N, 3.52. Found: C, 57.28; H, 4.58; N, 3.32.

Example 18

10-(4-bromophenyl)-3,4,6,7,8,10-hexahydro-2H-thiopyrano[3,2-b]quinolin-9(5H)one 1,1-dioxide

4-Bromobenzaldehyde (185 mg, 1.00 mmol) was treated according to the procedure of Example 1 to give the desired compound. MS (APCI) m/e 408 (M+H) ⁺ , 410 (M+H) ⁺ ; *H NMR (DMSO-d6) 1.75 (m, 1H), 1.90 (m, 1H), 2.20 (m, 4H), 2.50 (m, 4H), 3.20 (m, 2H), 5.00 (s, 1H), 7.12 (d, 2H), 7.40 (d, 2H), 9.32 (br s, 1H); Analytical calcd for C18H18BrNO3S: C, 52.95; H, 4.44; N, 3.43. Found: C, 52.76; H, 4.34; N, 3.40.

Example 19

10-(4-chloro-3-nitrophenyl)-3,4,6,7,8,10-hexahydro-2H-thiopyrano[3,2-b]quinolin9(5H)-one 1,1-dioxide

4-Chloro-3-nitrobenzaldehyde (185 mg, 1.00 mmol) was worked up according to the procedure of Example 1 to give the desired compound. MS (APCI) m/e 409 (M+H) ⁺ , 411 (M+H) ⁺ ; *H NMR (DMSO-d6) 1.75 (m, 1H), 1.90 (m, 1H), 2.21 (m, 4H), 2.55 (m, 4H), 3.20 (m, 2H), 5.10 (s, 1H), 7.50 (dd, 1H), 7.63 (d, 1H), 7.75 (d, 1H), _9.45 (br s, 1H); Analytical calcd for _C18H , _7C1N2O5S : C, 52.88; H, 4.19; N, 6.85. Found: C, 52.59; H, 4.11; N, 6.72.

Example 20

4-(3,4-Dichlorophenyl)-4,6,7,8-tetrahydro-2-methyl-3-(methylsulfonyl)-5(1H)-quinolinone

A solution of methanesulfonylacetone (135 mg, 1.00 mmol), 3,4-dichlorobenzaldehyde (175 mg, 1.00 mmol) and 3-amino-2-cyclohexen-1-one (111 mg, 1.00 mmol) in ethanol (7 mL) was heated at reflux for 24 h and cooled. The precipitated solid was collected, washed with ethanol, dried and triturated with methanol to give the desired compound. MS (APCI) m/e 386 (M+H) ⁺ , 388 (M+H) ⁺ ; ^J H NMR (DMSO-d ₆ ) 1.75 (m, 1H), 1.90 (m, 1H), 2.21 (m, 2H), 2.32 (s, 3H), 2.50 (m, 2H), 2.73 (s, 3H), 4.94 (s, 1H), 7.18 (dd, 1H), 7.34 (d, 1H), 7.53 (d, 1H),

9.48 (br s, 1H); Analytical calcd for C17H17Cl2NO3S: C, 52.86; H, 4.44; N, 3.63. Found: C, 52.91; H, 4.31; N, 3.55.

Example 21

4-(3-Cyanophenyl)-4,6,7,8-tetrahydro-2-methyl-3-(methylsulfonyl)-5(1H)-quinolinone

3-Cyanobenzaldehyde (131 mg, 1.00 mmol) was treated according to the procedure of the example to give the desired compound. MS (APCI) m/e 343 (M+H) ⁺ ; ¹ H NMR (DMSO-d6) 1.75 (m, 1H), 1.90 (m, 1H), 2.22 (m, 2H), 2.32 (s, 3H), 2.50 (m, 2H), 2.68 (s, 3H), 4.99 (s, 1H), 7.50 (m, 3H), 7.63 (dt, 1H), 9.48 (br s, 1H); Analytical calcd for C18H18N2O3S: C, 63.14; H, 5.30; N, 8.18. Found: C, 63.15; H, 5.35; N, 8.11.

Example 22

4-(3,4,5-trifluorophenyl)-4,6,7,8-tetrahydro-2-methyl-3-(methylsulfonyl)-5(1H)-quinolinone

3,4,5-Trifluoromethylbenzaldehyde (160 mg, 1.00 mmol) was treated according to the procedure of Example 20 to give the desired compound. MS (APCI) m/e 370 (M-H)', 406 (M+Cl)'; 1H NMR (DMSO-d6) 1.75 (m, 1H), 1.90 (m, 1H), 2.22 (m, 2H), 2.33 (s, 3H), 2.52 (m, 2H), 2.76 (s, 3H), 4.97 (s, 1H), 7.00 (m, 2H), 9.51 (br s, 1H); Analytical calcd for C17H16F3NO3S: C, 54.98; H, 4.34; N, 3.77. Found: C, 55.14; H, 4.16; N, 3.76.

Example 23

4,6,7,8-tetrahydro-2-methyl-4-(4-methyl-3-nitrophenyl)-3-(methylsulfonyl)-5(1H)quinolinone * *

4-Methyl-3-nitrobenzaldehyde (165 mg, 1.00 mmol) was treated according to the procedure of Example 20 to give the desired compound. MS (APCI) m/e 377 (M+H) ⁺ ; 1H NMR (DMSO-d6) 1.73 (m, 1H), 1.90 (m, 1H), 2.20 (m, 2H), 2.32 (s, 3H), 2.45 (s, 3H), 2.50 (m, 2H), 2.70 (s, 3H), 5.00 (s, 1H), 7.39 (d, 1H), 7.43 (dd, 1H), 7.75 (d, 1H), 9.48 (br s, 1H); Analytical calcd for C18H20N2O5S: C, 57.43; H, 5.36; N, 7.44. Found: C, 57.41; H, 5.28; N, 7.48.

Example 24

4-(4-Chloro-3-nitrophenyl)-4,6,7,8-tetrahydro-2-methyl-3-(methylsulfonyl)-5(1H)-quinolinone 4-Chloro-3-nitrobenzaldehyde (185 mg, 1.00 mmol) was processed according to the procedure of Example 20 to give the desired compound. MS (APCI) m/e 397 (M+H) ⁺ ; 1H NMR (DMSO-d6) 1.75 (m, 1H), 1.90 (m, 1H), 2.22 (m, 2H), 2.33 (s, 3H), 2.50 (m, 2H), 2.78 (s, 3H), 5.02 (s, 1H), 7.50 (dd, 1H), 7.67 (d, 1H), 7.76 (d, 1H), 9.51 (br s, 1H); Analytical calcd for C17H17CIN2O5S: C, 51.45; H, 4.32; N, 7.06. Found: C, 51.50; H, 4.26; N, 7.10.

Example 25

4-(3-Bromo-4-fluorophenyl)-4,6,7,8-tetrahydro-2-methyl-3-(methylsulfonyl)-5(1H)-quinolinone 3-Bromo-4-fluorobenzaldehyde (203 mg, 1.00 mmol) was worked up according to the procedure of Example 20 to give the desired compound. MS (APCI) m/e 414 (M+H) ⁺ ; ¹ H NMR (DMSO-d6) 1.75 (m, 1H), 1.90 (m, 1H), 2.22 (m, 2H), 2.31 (s, 3H), 2.50 (m, 2H), 2.70 (s, 3H), 4.94 (s, 1H), 7.25 (m, 2H), 7.40 (dd, 1H), 9.47 (br s, 1H); Analytical calcd for C ₁₇ H ₁₇ BrFNO ₃ S: C, 49.29; H, 4.14; N, 3.38. Found: C, 49.57; H, 3.93; N, 3.39.

Example 26

4,6,7,8-tetrahydro-2-methyl-3-(methylsulfonyl)-4-(3-nitrophenyl)-5(1H)-quinolinone

3-Nitrobenzaldehyde (151 mg, 1.00 mmol) was treated according to the procedure of Example 20 to give the desired compound. MS (APCI) m/e 363 (M+H) ⁺ ; 1H NMR (DMSO-d6) 1.70 (m, 1H), 1.90 (m, 1H), 2.32 (s, 3H), 2.50 (m, 2H), 2.70 (s, 3H), 5.07 (s, 1H), 7.57 (t, 1H), 7.65 (dt, 1H), 8.00 (m, 2H), 9.50 (br s, 1H); Analytical calcd for C17H18N2O5S: C, 56.34; H,

5.01; N, 7.73. Found: C, 56.39; H, 4.92; N, 7.75.

• · · fc · ·

Example 27

4-(4-Chloro-3-fluorophenyl)-4,6,7,8-tetrahydro-2-methyl-3-(methylsulfonyl)-5(1H)-quinolinone 4-Chloro-3-fluorobenzaldehyde (159 mg, 1.00 mmol) was processed according to the procedure of Example 20 to give the desired compound. MS (APCI) m/e 370 (M+H) ⁺ ; *Η NMR (DMSO-d ₆ ) 1.73 (m, 1H), 1.90 (m, 1H), 2.21 (m, 2H), 2.31 (s, 3H), 2.50 (m, 2H), 2.70 (s, 3H), 4.96 (s, 1H), 7.10 (m, 2H), 7.46 (t, 1H), 9.46 (br s, 1H); Analytical calcd for C17H17ClFNO3S: C, 55.21; H, 4.63; N, 3.79. Found: C, 55.07; H, 4.50; N, 3.67.

Example 28

4,6,7,8-tetrahydro-2-methyl-3-(methylsulfonyl)-4-[4-(trifluoromethyl)phenyl]-5(1H)-quinolinone 4-Trifluoromethylbenzaldehyde (137 mL, 1.00 mmol) was treated according to the procedure of Example 20 to give the desired compound. MS (APCI) m/e 386 (M+H) ⁺ ; 1H NMR (DMSO-d6) 1.72 (m, 1H), 1.90 (m, 1H), 2.21 (m, 1H), 2.31 (s, 3H), 2.50 (m, 3H), 2.63 (s, 3H), 5.02 (s, 1H), 7.41 (d, 2H), 7.61 (d, 2H), 9.65 (br s, 1H); _Analytical calcd for C, _8H18F3NO3S : C, 56.10; H, 4.71; N, 3.63. Found: C, 56.13; _H , 4.61; _N , 3.56.

Example 29

9-(3,4-dichloro-phenyl)-3,4,5,6,7,9-hexahydrothieno[3,2-b]quinolin-8(2H)-one 1,1-dioxide

A solution of tetrahydrothiophene-3-oxo-1,1-dioxide (144 mg, 1.07 mmol), prepared according to the method of J. Heterocycl. Chem., n. 27 , 1453 (1990), 3,4-dichlorobenzaldehyde (175 mg, 1.00 mmol) and 3-amino-2-cyclohexen-1-one (111 mg, 1.00 mmol) in ethanol (7 mL) was heated at reflux for 24 h and cooled. The precipitate was isolated and heated at reflux in toluene (5 mL) for 24 h and cooled. The precipitated solid was combined, cooled, washed with toluene and ethanol and triturated to give the desired compound. MS (APCI) m/e 384 (M+H) ⁺ ; 1H NMR (DMSO-d ₆ ) 1.75-2.0 (m, 2H), 2.23 (m, 2H), 2.57 (m, 2H), 2.85 (dt, IH), 3.03 (dt, IH), 3.38 (m, 2H), 4.84 (s, IH), 7.17 (dd, IH), 7.35 (d, IH), 7.50 (d, IH), 9.85 (br s, IH); Analytical calculated for C17H15Cl2NO3S: C, 53.14; H, 3.93; N, 3.64. Found: C, 52.97; H, 3.90; N, 3.56.

Example 30

9-(3-Cyanophenyl)-3,4,5,6,7,9-hexahydrothieno[3,2-b]quinolin-8(2H)-one 1,1-dioxide

3-Cyanobenzaldehyde (136 mg, 1.04 mmol) was treated according to the procedure of the example to give the desired compound. MS (APCI) m/e 341 (M+H) ⁺ ; ¹ H NMR (DMSO-d6) 1.88 (m, 2H), 2.22 (m, 2H), 2.56 (m, 2H), 2.85 (dtd, ÍH), 3.03 (dt, ÍH), 3.36 (m, 2H), 4.90 (s, ÍH),

7.45 (td, 1H), 7.54 (dd, 1H), 7.56 (d, 1H), 7.61 (dd, 1H), 9.81 (br s, 1H); Analytical calcd for C18H16N2O3S: C, 63.51; H, 4.73; N, 8.22. Found: C, 63.31; H, 4.61; N, 8.19.

Example 31

9-[4-fluoro-3-(trifluoromethyl)phenyl)-3,4,5,6,7,9-hexahydrothieno[3,2-b]quinolin8(2H)-one 1,1-dioxide

4-Fluoro-3-trifluoromethylbenzaldehyde (130 mL) was treated according to the procedure of Example 29 to give the desired compound. MS (APCI) m/e 402 (M+H) ⁺ ; 1H NMR (DMSO-d6) 1.88 (m, 2H), 2.23 (m, 2H), 2.55 (m, 2H), 2.85 (dtd, 1H), 3.03 (dt, 1H), 3.35 (m, 2H), 4.95 (s, 1H), 7.40 (dd, 1H), 7.52 (m, 2H), 9.60 (br s, 1H); Analytical calcd. for

_C18H15F4NO3S *0.25H2O: C, 53.27; H, 3.85; N, 3.49. Found: C, 53.29; _H , 3.74; N, 3.55.

Example 32

1,1-Dioxide of 3,4,5,6,7,9-hexahydro-9-(4-methyl-3-nitrophenyl)thieno[3,2-b]quinolin-8(2H)-one 4-Methyl-3-nitrobenzaldehyde (165 mg, 1.00 mmol) was treated according to the procedure of Example 29 to give the desired compound. MS (APCI) m/e 375 (M+H) ⁺ ; 1H NMR (DMSO-d6) 1.88 (m, 2H), 2.23 (m, 2H), 2.45 (s, 3H), 2.56 (m, 2H), 2.85 (dtd, 1H), 3.03 (dt, 1H), 3.35 (m, 2H), 4.93 (s, 1H), 7.36 (d, 1H), 7.45 (dd, 1H), 7.72 (d, 1H), 9.83 (br s, 1H); Analytical calcd for C18H18N2OsS*0.25H2O: C, 57.06; H, 4.92; N, 7.39. Found: C, 57.24; H, 4.77; N, 7.23.

Example 33

9-(3 4-difluorophenyl)-3,4,5,6,7,9-hexahydrothieno[3,2-b]quinolin-8(2H)-one 1,1-dioxide

3,4-Difluorobenzaldehyde (100 mL, 1.00 mmol) was treated according to the procedure of the example to give the desired compound. MS (APCI) m/e 352 (M+H) ⁺ ; *H NMR (DMSO-d6) 1.90

(m, 2H), 2.23 (m, 2H), 2.55 (m, 2H), 2.82 (dt, 1H), 3.02 (dt, 1H), 3.35 (m, 2H), 4.86 (s, 1H), 7.02 (m, 1H), 7.15 (ddd, 1H), 7.29 (dt, 1H), 9.79 (br s, 1H); Analytical calcd for C17H15F2NO3S: C, 58.11; H, 4.30; N, 3.99. Found: C, 57.90; H, 3.96; N, 3.88.

Example 34

9-(4-Chloro-3-nitrophenyl)-3,4,5,6,7,9-hexahydrothieno[3,2-b]quinolin-8(2H)-one 1,1-dioxide 4-Chloro-3-nitrobenzaldehyde (185 mg, 1.00 mmol) was treated according to the procedure of Example 29 to give the desired compound. MS (APCI) m/e 393 (MH)', 395 (MH)'; ^] H NMR (DMSO-d ₆ ) 1.90 (m, 2H), 2.23 (m, 2H), 2.55 (m, 2H), 2.85 (dtd, IH), 3.01 (dt, IH), 3.35 (m, 2H), 4.95 (s, IH), 7.51 (dd, IH), 7.64 (d, IH), 7.79 (d, IH), 9.88 (br s, IH); Analytical calculated for: C, 51.71; H, 3.38; N, 7.09. Found: C, 51.46; H, 3.86; N, 6.95.

Example 35

-[8-(3,4-dichlorophenyl)-3,4,5,8-tetrahydro-6-methyl-1,1-dioxido-2H-thiopyrano[3,2-b]pyridin7-yl]ethanone

A solution of tetrahydrothiopyran-3-one-1,1-dioxide (255 mg, 1.72 mmol), 3,4-dichlorobenzaldehyde (250 mg, 1.43 mmol) and 4-amino-3-penten-2-one (140 mg, 1.41 mmol) in ethanol (5 mL) was heated at reflux for 24 h and cooled. The precipitated solid was collected, washed with ethanol and dried to give the desired compound. MS (APCI) m/e 386 (M+H) ⁺ , 388 (M+H) ⁺ ; 1H NMR (DMSO-d ₆ ) 2.19 (m, 2H), 2.20 (s, 3H), 2.30 (s, 3H), 2.50 (m, 2H), 3.20 (m, 2H), 5.07 (s, 1H), 7.15 (dd, 1H), 7.34 (d, 1H), 7.51 (d, 1H), 9.15 (br s, 1H); Analytical calcd for C17H17Cl2NO3S: C, 52.86; H, 4.44; N, 3.63. Found: C, 52.74; H, 4.39; N, 3.64.

Example 36

-[8-(4-chloro-3-nitrophenyl)-3,4,5,8-tetrahydro-6-methyl-1,1-dioxido-2H-thiopyrano[3,2b]pytidin-7-yl]ethanone

4-Chloro-3-nitrobenzaldehyde (220 mg, 1.19 mmol) was treated according to the procedure of Example 35 to give the desired compound. MS (APCI) m/e 397 (M+H) ⁺ ; *H NMR (DMSO-d6) 2.19 (m, 2H), 2.23 (s, 3H), 2.31 (s, 3H), 2.4-2.6 (m, 2H), 3.1-3.3 (m, 2H), 5.15 (s, ···· · Λ · « • · * · * · f « ·»···> . « · • · · · *4 • · · · · · « « »# 31

ΙΗ), 7.49 (dd, 1H), 7.64 (d, 1H), 7.76 (d, 1H), 9.19 (br s, 1H); Analytical calcd for C17H17CIN2O5S: C, 51.45; H, 4.32; N, 7.06. Found: C, 51.18; H, 4.12; N, 7.03.

Example 37

9-(3,4-dichlorophenyl)-3,4,5,6,7,9-hexahydrocyclopenta[b]thiopyrano[2,3-e]pyridin8(2H)-one 1,1-dioxide

A solution of tetrahydrothiopyran-3-one-1,1-dioxide (175 mg, 1.20 mmol), 3,4-dichlorobenzaldehyde (175 mg, 1.00 mmol) and 3-amino-2-cyclopenten-1-one (101 mg, 1.05 mmol), prepared as described in Synthesis, p. 176 (1990), in ethanol (5 mL) was heated at reflux for 24 h and cooled. The precipitated solid was collected, washed with ethanol and dried to give the desired compound. MS (APCI) m/e 384 (M+H) ⁺ ; *H NMR (DMSO-d6) 2.25 (m, 4H), 2.60 (m, 4H), 3.20 (m, 2H), 4.82 (s, 1H), 7.20 (dd, 1H), 7.36 (d, 1H), 7.52 (d, 1H), 9.98 (br s, 1H); Analytical calcd for C17H15Cl2NO3S*0.25H2O: C, 52.52; H, 4.02; N, 3.60. Found: C, 52.36; H, 3.69; N, 3.63.

Example 38

9-(4-chloro-3-nitrophenyl)-3,4,5-6,7,9-hexahydrocyclopenta[b]thiopyrano[2,3e]pyridin-8(2H)-one 1,1-dioxide

4-Chloro-3-nitrobenzaldehyde (187 mg, 1.01 mmol) was treated according to the method described in Example 37 to give the desired compound. MS (APCI) m/e 395 (M+H) ⁺ ; NMR (DMSO-d6) 2.25 (m, 4H), 2.60 (m, 4H), 3.24 (m, 2H), 4.93 (s, 1H), 7.55 (dd, 1H), 7.67 (d, 1H), 7.80 (d, 1H), 10.03 (br s, 1H); Analytical calcd for C17H15ClN2O5S*0.2H2O: C, 51.13; H, 3.91; N, 7.01. Found: C, 50.96; H, 4.02; N, 6.79.

Example 39

9-(3-chloro-4-fluorophenyl)-3,4,5,6,7,9-hexahydrocyclopenta[b]thiopyrano[2,3e]pyridin-8(2H)-one 1,1-dioxide

3-Chloro-4-fluorobenzaldehyde (158 mg, 1.00 mmol) was worked up according to the procedure of Example 37 and recrystallized from methanol/ethanol acetate to give the desired compound. MS (APCI) m/e 368 (M+H) ⁺ , 370 (M+H) ⁺ ; Ή NMR (DMSO-d6) 2.25 (m, 4H), 2.62 (m, 4H), ¹ ·»·«»·»· • ♦ * · « ř · • · · · · ' ·. * · • ·· 4 9 9 * « * · · · · * » _t ♦ · »· ♦· 9 9

3.20 (m, 2H), 4.93 (s, 1H), 7.20 (ddd, 1H), 7.30 (m, 2H), 9.96 (br s, 1H); Analytical calcd for C17H15ClFNO3S: C, 55.51; H, 4.11; N, 3.81. Found: C, 55.24; H, 3.85; N, 3.67.

Example 40

9-(3-bromo-4-fluorophenyl)-3,4,5,6,7,9-hexahydrocyclopenta[b]thiopyrano[2,3e]pyridin-8(2H)-one 1,1-dioxide

3-Bromo-4-fluorobenzaldehyde (212 mg, 1.04 mmol) was processed according to the procedure of Example 37 to give the desired compound. MS (APCI) m/e 412 (M+H) ⁺ , 414 (M+H) ⁺ ; *H NMR (DMSO-d ₆ ) 2.25 (m, 4H), 2.60 (m, 4H), 3.20 (m, 2H), 4.83 (s, 1H), 7.25 (m, 2H), 7.41 (dd, 1H), 9.96 (br s, 1H); Analytical calcd for C 17 H ₅ BrFNO 3 S*0.25H 2 O: C, 48.99; H, 3.75; N, 3.36. Found: C, 48.98; H, 3.63; N, 3.28.

Example 41

9-(3-nitrophenyl)-3,4,5,6,7,9-hexahydrothieno[3,2-b]quinolin-8(2H)-one 1,1-dioxide

3-Nitrobenzaldehyde (153 mg, 1.01 mmol) was worked up according to the procedure of Example 29 to give the desired compound. MS (APCI) m/e 359 (MH); 1H NMR (DMSO-d6) 1.83 (m, 1H), 1.92 (m, 1H), 2.24 (m, 2H), 2.57 (m, 2H), 2.85 (dtd, 1H), 3.05 (dt, 1H), 3.35 (m, 2H), 4.99 (s, 1H), 7.55 ₍ t, 1H), 7.67 (dt, 1H), 7.98 (t, 1H), 8.03 (ddd, 1H), _{9.91 (s, 1H); Analytical calcd for C17H16N2O5S :} C, 56.65; H, 4.47; N, 7.77. Found: C, 56.67; H, 4.35; N, 7.59.

Example 42

9-(3-cyano)-3,4,5,6,7,9-hexahydrocyclopenta[b]thiopyrano[2,3-e]pyridin-8(2H)one 1,1-dioxide

3-Cyanobenzaldehyde (131 mg, 1.0 mmol) was worked up according to the procedure of Example 37 to give the desired compound. MS (APCI) m/e 339 (MH)'; ¹ H NMR (DMSO-d6) 2.25 (m, 4H), 2.60 (m, 4H), 3.21 (m, 2H), 4.89 (s, 1H), 7.47 (t, 1H), 7.57 (dd, 1H), 7.59 (d, 1H), 7.64 (dt, 1H), 9.98 (br s, 1H); Analytical calcd for C18H10N2O3S*0.25H2O: C, 62.68; H,

4.82; N, 8.12. Found: C, 62.53; H, 4.53; N, 8.08.

• · «· • · » fc • 9 * * · · - « I * · · · · »

Afc fcfc

Example 43

1,1-dioxide of 9-(3-bromo-4-fluorophenyl)-3,4,5,6,7,9-hexahydrothieno[3,2-b]quinolin-8(2H)-one 3-Bromo-4-fluorobenzaldehyde (201 mg, 0.99 mmol) was worked up according to the procedure of Example 29 and recrystallized from methanol/chloroform to give the desired compound. MS (APCI); m/e 410 (MH)', 412 (MH)'; Ή NMR (DMSO-d ₆ ) 1.88 (m, 2H), 2.23 (m, 2H), 2.56 (m, 2H), 2.83 (dtd, 1H), 3.03 (dt, 1H), 3.33 (t, 2H), 4.85 (s, 1H), 7.22 (m, 2H), 7.40 (dd, 1H), 9.78 (br s, 1H); Analytical calcd for CnHisBrFNOjS: C, 49.52; H, 3.66; N, 3.39. Found: C, 49.19; H, 3.59, N, 3.24.

Example 44

8-(4-chloro-3-nitrophenyl)-3,5,6,8-tetrahydro-2H-cyclopenta[b]thieno[2,3-e]pyridine7(4H)-one 1,1-dioxide

A solution of tetrahydrothiophene-3-oxo-1,1-dioxide (171 mg, 1.28 mmol), 4-chloro-3-nitrobenzaldehyde (210 mg, 1.13 mmol) and 3-amino-2-cyclopenten-1-one (110 mg, 1.13 mmol) in ethanol (3 mL) was heated at reflux for 24 h and cooled. The precipitate was collected, washed with ethanol, dried and recrystallized from methanol/chloroform to give the desired compound. MS (APCI); m/e 379 (MH); 1H NMR (DMSO-d6) 2.30 (t, 2H), 2.65 (m, 2H), 2.89 (dt, 1H), 3.05 (dt, 1H), 3.40 (t, 2H), 4.87 (s, 1H), 7.58 (dd, 1H), 7.68 (d, 1H), 7.88 (d, 1H), 10.4 (s, 1H); Analytical calcd for C16H13ClN2O5S* _0.25CH3OH : C, 50.19; H, 3.62; N, 7.20. Found: C, 49.87; H, 3.26; N, 7.07.

Example 45

10-(4-chloro-3-nitrophenyl)-3,4,6,7,10-hexahydro-2H,5H-bisthiopyrano[3,2b^^SteJpyridine 1,1,9,9-tetraoxide

A solution of tetrahydrothiopyran-3-one-1,1-dioxide (150 mg, 1.01 mmol), 4-chloro-3-nitrobenzaldehyde (95 mg, 0.51 mmol) and concentrated ammonium hydroxide (0.5 mL) was heated at 78°C in ethanol (1 mL) for 24 h in a sealed vessel and cooled. The precipitated solid was washed with ethanol, dried and triturated with hot acetone to give the desired compound. MS (APCI); m/e 443 (M-H)'; Ή NMR (DMSO-d6) 2.18 (m, 4H), 2.50 (m, 4H), 3.20 (m, 4H), 5.18 (s, 1H), 7.51 (dd, 1H), 7.69 (d, 1H), 7.76 (d, 1H), 9.24 (s, 1H); Analytical w wwíwhmww···· calculated for CnHnClNzC^^lSNI^OH: C, 45.36; H, 3.99; N, 6.72. Found: C, 45.71; H, 3.85; N, 7.02.

Example 46

10-(3-pyridyl)-3,4,6,7,8,10-hexahydro-2H-thiopyrano[3,2-b]quinolin-9(5H)-one 1,1-dioxide

3- Pyridinecarboxaldehyde (94 mL, 1.0 mmol) was worked up according to the procedure of Example 1 with recrystallization from methanol to give the desired compound. MS (APCI); m/e 331 (M+H) ⁺ ; 1H NMR (DMSO-d6) 1.75 (m, 1H), 1.90 (m, 1H), 2.20 (m, 4H), 2.53 (m, 4H), 3.20 (m, 2H), 5.03 (s, 1H), 7.25 (dd, 1H), 7.52 (dt, 1H), 8.31 (dd, 1H), 8.38 (d, 1H), 9.40 (br s, 1H); Analytical calcd for CnHg^OjS*!^: C, 5 8.60; H, 5.79; N, 8.04. Found: C, 58.79;

H, 5.81; N, 7.63.

Example 47

I, 10-(4-pyridyl)-3,4,6,7,8,10-hexahydro-2H-thiopyrano[3,2-b]quinolin-9(5H)-one 1-dioxide

4- Pyridinecarboxaldehyde (95 mL, 1.0 mmol) was treated as in Example 1 and recrystallized from methanol to give the title compound. MS (APCI); m/e 331 (M+H) ⁺ ; 1H NMR (DMSO-d ₆ ) 1.75 (m, 1H), 1.90 (m, 1H), 2.20 (m, 4H), 2.53 (m, 4H), 3.20 (m, 2H), 5.03 (s, 1H), 7.20 (d, 2H), 8.41 (d, 2H), 9.44 (br s, 1H); Analytical calcd for C ₇ H,8N ₂ O 3 S: C, 61.80; H, 5.49; N, 8.48. Found: C, 61.71; H, 5.40; N, 8.42.

Example 48

9-(4-fluoro-3-trifluoromethyl)-3,4,5,6,7,9-hexahydrocyclopenta[b]thiopyrano[2,3e]pyridin-8(2H)-one 1,1-dioxide

4-Fluoro-3-trifluoromethylbenzaldehyde (130 mL) was treated according to the procedure of Example 37 to give the desired compound. MS (APCI); m/e 400 (M-H)'; *11 NMR (DMSO-d6) 2.25 (m, 4H), 2.58 (m, 4H), 3.20 (m, 2H), 4.92 (s, 1H), 7.40 (dd, 1H), 7.54 (m, 2H), 9.96 (br s, 1H); Analytical calcd for C18H15F4NO3S: C, 53.86; H, 3.77; N, 3.49. Found: C, 53.60; H, 3.82; N, 3.38.

• ·

Example 49

9-(4-methyl-3-nitro)-3,4,5,6,7,9-hexahydrocyclopenta[b]thiopyrano[2,3-e]pyridine8(2H)-one 1,1-dioxide

4-Methyl-3-nitrobenzaldehyde (165 mg, 1.00 mmol) was treated according to the procedure of Example 37 to give the desired compound. MS (APCI); m/e 373 (M-H)'; 1H NMR (DMSO-d6) 2.24 (m, 4H), 2.45 (s, 3H), 2.60 (m, 4H), 3.20 (m, 2H), 4.90 (s, 1H), 7.38 (d; 1H),

7.46 (dd, 1H), 7.73 (d, 1H), 9.97 (br s, 1H); Analytical calcd. for Ci ₈ Hi ₈ N ₂ O ₅ S: C,

57.74; H, 4.85; N, 7.48. Found: C, 57.43; H, 4.72; N, 7.34.

Example 50

9-(3,4-difluorophenyl)-3,4,5,6,7,9-hexahydrocyclopenta[b]thiopyrano[2,3-e]pyridine8(2H)-one 1,1-dioxide

3,4-Difluorobenzaldehyde (110 mL) was treated according to the procedure of Example 37 to give the desired compound as a white solid. *H NMR (DMSO-d6) 2.25 (m, 4H), 2.60 (m, 4H), 3.20 (m, 2H), 4.83 (s, 1H), 7.05 (m, 1H), 7.16 (ddd, 1H), 7.30 (dt, 1H), 9.95 (br s, 1H); MS (APCI-) m/z 350 (M-H)'; Analytical calcd for C17H15F2NO3S: C, 58.11; H, 4.30; N, 3.98. Found: C, 58.10; H, 4.32; N, 3.94.

Example 51

8-(4-chloro-3-nitrophenyl)-2,3,4,5,6,8-hexahydrodithieno[3,2-b:2i,3i]pyridine 1,1,7,7-tetraoxide

4-Chloro-3-nitrobenzaldehyde (215 mg, 1.16 mmol), tetrahydrothiophene-3-oxo-1,1-dioxide (310 mg, 2.32 mmol) and 2.0 M NH3 in ethyl alcohol (0.75 mL, 1.5 mmol) were heated in ethyl alcohol (4 mL) for 3 days at 80°C in a sealed vessel, cooled, the precipitated solid was collected and washed with ethanol. The solid was then heated at reflux in toluene with a catalytic amount of para-toluenesulfonic acid, cooled, the solid was collected, washed with toluene, ethanol, methanol and dried. Trituration with hot methanol/chloroform (1:1) gave 184 mg of an off-white solid.

*H NMR (DMSO-d6) 2.85 (m, 2H), 3.00 (dt, 2H), 3.40 (m, 4H), 5.12 (s, 1H), 7.63 (dd, 1H), 7.72 (d, 1H), 7.97 (d, 1H), 10.11 (br s, 1H); MS (APCI-) m/z 415 (M-H); Analytical .»Α*Λ' *r*w* calculated for C 18 H 11 Cl 11 O 6 Si^l toluene: C, 44.26; H, 3.26; N, 6.57. Found: C, 44.63; H, 3.06; N, 6.53.

Example 52

8-(3-Cyanophenyl)-2,3,4,5,6,8-hexahydro-7H-cyclopenta[b]thieno[2,3-e]pyridin-7-one 1,1-dioxide

3-Cyanobenzaldehyde (206 mg, 1.57 mmol), tetrahydrothiophene-3-oxo-1,1-dioxide (212 mg, 1.58 mmol) and 3-amino-2-cyclopenten-1-one (150 mg, 1.55 mmol) were heated in ethanol (4 mL) at 80°C for 3 days in a sealed vessel, cooled, the precipitated solid was collected and washed with ethanol. The solid was then heated at reflux in ethanol (10 mL) with 1N HCl in ether (0.5 mL) for 2 hours, cooled and the solvent was evaporated. The crude oil was triturated with ethyl acetate and the resulting solid was collected, washed with ethyl acetate and dried to give 252 mg of a solid.

Melting point: 156-176 °C;

¹ H NMR (DMSO-do) 2.30 (t, 2H), 2.63 (m, 2H), 2.88 (dt, 1H), 3.07 (dt, 1H), 3.40 (t, 2H),

4.70 (s, IH), 7.49 (t, IH), 7.60 (d, IH), 7.64 (s, IH), 7.66 (dd, IH), 10.38 (s, IH);

MS (APCI-) m/z 325 (M-H)';

Analytical calcd for C17H14N2O3S*0.33EtOAc*0.75H2O: C, 59.64; H, 4.95; N, 7.59. Found: C, 59.32; H, 4.77; N, 7.41.

Example 53

8-(3-bromo-4-fluorophenyl)-2,3,4,5,6,8-hexahydrodithieno[3,2-b:2i,3i]pyridine 1,1,7,7-tetraoxide

3-Bromo-4-fluorobenzaldehyde (305 mg, 1.5 mmol), tetrahydrothiophene-3-oxo-1,1-dioxide (402 mg, 3.00 mmol) and 2.0 M NH ₃ in ethanol (1.1 mL, 2.2 mmol) in ethanol (3 mL) were heated at 80°C for 3 days in a sealed vessel, cooled, the precipitated solid was combined and washed with ethanol. This solid was then heated at reflux overnight in ethanol with 1.0 M HCl in ether (1 mL), cooled, the solid was combined, washed with ethanol and dried to give 185 mg of the desired compound as an off-white solid.

1H NMR (DMSO-do) 2.80 (m, 2H), 3.01 (dt, 2H), 3.35 (m, 4H), 4.97 (s, 1H), 7.30 (m, 2H),

7.53 (dd, IH), 9.19 (br s, IH);

MS (APCI-) m/ _{z 432 (MH)'; Analytical calcd for C15H13BrFNO4S2 :} C, _{41.48 ;} H, 3.01;

N, 3.22. Found: C, 41.61; H, 2.76; N, 3.14.

Example 54

10-(3-bromo-4-fluorophenyl)-3,4,6,7,8,10-hexahydro-2H,5H-dithiopyrano[3,2b:2n,3n-e]pyridine 1,1,9,9-tetraoxide

3-Bromo-4-fluorobenzaldehyde (202 mg, 1.0 mmol), tetrahydrothiopyran-3-one-1,1-dioxide (305 mg, 2.06 mmol) and 2.0 M NH ₃ in ethanol (0.70 mL, 1.4 mmol) were heated in ethanol (3 mL) at 80°C for 5 days in a sealed vessel, cooled, the precipitated solid was combined and washed with ethanol. This solid was then heated at reflux in toluene (10 mL) overnight, cooled, combined, washed with ethanol and dried to give 129 mg of the desired compound as a white solid.

*H NMR (DMSO-de) 2.17 (m, 4H), 2.50 (m, 4H), 3.18 (m, 4H), 5.09 (s, 1H), 7.2a (m, 2H),

7.38 (dd, 1H), 9.11 (s, 1H);

MS (APCI-) m/z 460 (M-H)';

Analytical calcd for C11H11BrFNO4: C, 44.16; H, 3.70; N, 3.02. Found: C, 43.97;

H, 3.80; N, 2.95.

Example 55

I, 3,4,5,6,7,9-hexahydro-9-(3-nitrophenyl)cyclopenta[b]thiopyrano[2,3-e]pyridine8(2H)-one 1-dioxide

3-Nitrobenzaldehyde (153 mg, 1.0 mmol), tetrahydrothiopyran-3-one-1,1-dioxide (148 mg, 1.00 mmol) and 3-amino-2-cyclopenten-1-one (97 mg, 1.00 mmol) were heated at 80°C for 5 days in a sealed vessel, cooled, the precipitated solid was combined and washed with ethanol and dried to give 145 mg of the desired compound as a white solid.

Melting point >260 °C;

Ή NMR (DMSO-de) 2.25 (m, 4H), 2.60 (m, 4H), 3.23 (m, 2H), 4.98 (s, 1H), 7.57 (t, 1H),

7.69 (d, ÍH), 8.00 (s, ÍH), 8.04 (d, ÍH), 10.03 (br s, ÍH);

MS (APCI-) m/z 359 (M-H)';

Analytical calcd for C17H16N2O5S: C, 56.65; H, 4.47; N, 7.77. Found: C, 56.34; H,

4.44; N, 7.50.

Example 56

8-(3-bromo-4-fluorophenyl)-2,3,4,5,6,8-hexahydro-7H-cyclopenta[b]thieno[2,3e]pyridin-7-one 1,1-dioxide

3-Bromo-4-fluorobenzaldehyde (250 mg, 1.23 mmol) was processed according to the procedure of Example 44 except that heating was for 3 days and recrystallization was not required to give 241 mg of the desired compound as an off-white solid.

Melting point >260 °C;

*H NMR (DMSO-do) 2.30 (t, 2H), 2.63 (m, 2H), 2.85 (dt, 1H), 3.06 (dt, 1H), 3.40 (t, 2H),

4.72 (s, 1H), 7.27 (m, 2H), 7.47 (d, 1H), 10.33 (br s, 1H);

MS (APCI-) m/z 396 (M-H)';

Analytical Calcd for C16H11BrFNO3S: C, 48.25; H, 3.29; N, 3.52. Found: C, 48.26; H, 3.17; N, 3.34.

Example 57

8-(4-fluoro-3-trifluoromethylphenyl)-2,3,4,5,6,8-hexahydro-7Hcyclopenta[b]thieno[2,3-e]pyridin-7-one 1,1-dioxide

4-Fluoro-3-trifluoromethylbenzaldehyde (0.20 mL), tetrahydrothiophene-3-oxo-1,1-dioxide (136 mg, 1.01 mmol) and 3-amino-2-cyclopenten-1-one (97 mg, 1.00 mmol) were heated in ethanol (4 mL) at 80°C in a sealed vessel for 3 days, cooled and the solvent evaporated. Flash chromatography on silica gel (10% methanol/chloroform) followed by trituration of the product with ethyl acetate gave the title compound as a white solid.

Melting point: 254 °C;

1H NMR (DMSO-do) 2.30 (t, 2H), 2.65 (m, 2H), 2.88 (dt, 1H), 3.06 (dt, 1H), 3.40 (t, 2H),

4.85 (s, IH), 7.41 (dd, IH), 7.58 (m, 2H), 10.38 (s, IH),

MS (APCI-) m/z 386 (M-H)';

Analytical calcd for C17H13F4NO3S* _0.25H2O : C, 52.10; H, 3.47; N, 3.57. Found: C, 52.13; H, 3.31; N, 3.47.

A A» UWAJ-WW»» »A.AA9

R*r 'Μ^ΑΛ A ^Α^'.Α,* y?

Example 58

2,3,4,5,6,8-hexahydro-8-(3-nitrophenyl)-7H-cyclopenta[b]thieno[2,3-e]pyridin-7-one 1,1-dioxide

3-Nitrobenzaldehyde (225 mg, 1.49 mmol), tetrahydrothiophene-3-oxo-1,1-dioxide (202 mg, 1.51 mmol) and 3-amino-2-cyclopenten-1-one (144 mg, 1.48 mmol) were heated in ethanol (5 mL) at 80°C in a sealed vessel for 3 days, cooled and the precipitated solid was filtered off. The filtrate was treated with 1.0 M HCl in ether (0.1 mL), heated at reflux for 1.5 hours, cooled and the solvent was evaporated. Recrystallization from ethanol gave 130 mg of the desired compound as a pale yellow solid.

^! H NMR (DMSO-do) 2.31 (t, 2H), 2.65 (m, 2H), 2.90 (dt, 1H), 3.08 (dt, 1H), 3.40 (t, 2H),

4.90 (s, 1H), 7.58 (t, 1H), 7.73 (dt, 1H), 8.05 (m, 2H), 10.41 (s, 1H);

MS (APCI-) m/z 345 (M-H)';

Analytical calcd for C16H14N2O5S: C, 55.48; H, 4.07; N, 8.08. Found: C, 55.37; H, 4.02; N, 7.88.

Example 59

3,4,6,7,8,10-hexahydro-10-(3-nitrophenyl)-2H,5H-dithiopyrano[3,2-b:2i,3i]pyridine 1,1,9,9-tetraoxide

3-Nitrobenzaldehyde (153 mg, 1.0 mmol) was treated according to the procedure of Example 54 to give 188 mg of the desired compound as a white solid.

Melting point >260 °C, *H NMR (DMSO-d6) 2.19 (m, 4H), 2.52 (m, 4H), 3.20 (m, 4H), 5.23 (s, 1H), 7.60 (t, 1H),

7.68 (d, 1H), 7.98 (s, 1H), 8.08 (d, 1H), 9.23 (br s, 1H);

MS (APCI-) m/z 409 (M-H)';

Analytical calcd for C17H18N2O6S2: C, 49.75; H, 4.42; N, 6.82. Found: C, 49.58; H, 4.34; N, 6.79.

Example 60

1,1-dioxide of 8-(3,4-dichlorophenyl)-2,3,4,5,6,8-hexahydro-7H-cyclopenta[b]thieno[2,3-e]pyridin7-one

3,4-Dichlorobenzaldehyde (175 mg, 1.0 mmol) was treated according to the procedure of Example 52 to give 204 mg of the desired compound as a white solid.

Melting point >260 °C;

1 H NMR (DMSO-d ₆ ) 2.30 (t, 2H), 2.63 (m, 2H), 2.87 (dt, 1H), 3.05 (dt, 1H), 3.40 (t, 2H),

4.72 (s, ÍH), 7.22 (dd, ÍH), 7.41 (d, ÍH), 7.52 (d, ÍH), 10.36 (br s, ÍH);

MS (APCI-) m/z 368 (M-H)'; Analytical calcd for C16H13Cl2NO3S: C, 51.90; H, 3.54; N, 3.78. Found: C, 51.93; H, 3.59; N, 3.53.

Example 61

8-(3-chloro-4-fluorophenyl)-2,3,4,5,6,8-hexahydro-7H-cyclopenta[b]thieno[2,3e]pyridin-7-one 1,1-dioxide

3-Chloro-4-fluorobenzaldehyde (0.16 mL) was treated according to the procedure of Example 56 to give 107 mg of the desired compound as a white solid.

*H NMR (DMSO-do) 2.30 (t, 2H), 2.64 (m, 2H), 2.85 (dt, 1H), 3.05 (dt, 1H), 3.39 (t, 2H),

4.72 (s, ÍH), 7.23 (m, ÍH), 7.28 (m, ÍH), 7.37 (d, ÍH), 10.31 (br s, ÍH);

MS (APCI-) m/z 352 (M-H)';

Analytical calcd for C16H13ClFNO3S: C, 54.32; H, 3.70; N, 3.96. Found: C, 54.34; H, 3.68; N, 3.85.

Example 62

8-(3-cyanophenyl)-2,3,4,5,6,8-hexahydrodithieno[3,2-b:2i,3i-e]pyridine 1,1,7,7-tetraoxide

3-Cyanobenzaldehyde (132 mg, 1.01 mmol), tetrahydrothiophene-3-oxo-1,1-dioxide (272 mg, 2.03 mmol) and 2.0 M NH3 in ethanol (0.75 mL, 1.5 mmol) were heated at 80°C in ethanol (4 mL) in a sealed vessel for 3 days, cooled, treated with 1.0 M HCl in ether (1 mL), heated at reflux for 1 hour, cooled and the solvent evaporated. The crude product was flash chromatographed on a silica gel column (15% methanol/chloroform) and the product was triturated with ethyl acetate to give 87 mg of the title compound as an off-white solid. Melting point: 248 °C;

Ή NMR (DMSO-do) 2.83 (dt, 2H), 3.02 (dt, 2H), 3.40 (m, 4H), 5.03 (s, 1H), 7.50 (t, 1H),

7.61 (d, 1.H); 7.70 (d, ÍH), 7.73 (s, ÍH), 10.07 (br s, ÍH);

MS (APCI-) m/z 361 (M-H)';

Analytical calcd for C16H14N2O4S2*0.33EtOAc*0.6H2O: C, 51.71; H, 4.47; N, 6.96.

Found: C, 51.84; H, 4.21; N, 6.61.

Example 63

8-(2-cyano-4-pyridinyl)-2,3,4,5,6,8-hexahydro-7H-cyclopenta[b]thieno[2,3e]pyridin-7-one 1,1-dioxide

2-Cyanopyridine-4-carboxaldehyde (0.20 g, 1.52 mmol), prepared according to the method of Ashimori (Chem Farm Bull 1990, 38, 2446), tetrahydrothiophene-3-oxo-1,1-dioxide (241 mg, 1.8 mmol) and 3-amino-2-cyclopenten-1-one (0.146 g, 1.5 mmol) were heated at 40-50°C in isopropanol for 3 days, cooled, the solvent evaporated and flash chromatography (10% methanol/methylene chloride) was performed. The product was dissolved in isopropanol, treated with 1.0 M HCl in ether (1.5 mL), heated at 50°C for 10 minutes, cooled and the solvent evaporated. The residue was triturated with ether, combined, washed with ether and dried to give 63.5 mg of the desired compound as a pale yellow powder.

^] H NMR (DMSO-de) 2.30 (t, 2H), 2.65 (m, 2H), 3.02 (m, 2H), 3.45 (t, 2H), 4.85 (s, 1H), 7.64 (d, 1H), 7.94 (s, 1H), 8.65 (d, 1H), 10.48 (s, 1H);

MS (APCI-) m/z 326 (M-H)';

Analytical calcd for C16H11N3O3S*0.42C2H6O*0.25H2O*0.15HCl: C, 57.31; H, 4.48;

Example 64

8-(3-Bromophenyl)-2,3,4,5,6,8-hexahydro-7H-cyclopenta[b]thieno[2,3-e]pyridin-7-one 1,1-dioxide

3-Bromobenzaldehyde (0.12 mL, 1.0 mmol), tetrahydrothiophene-3-oxo-1,1-dioxide (137 mg, 1.02 mmol) and 3-amino-2-cyclopenten-1-one (98 mg, 1.0 mmol) were heated in ethanol (4 mL) at 80°C in a sealed vessel for 3 days and then treated with 1.0 M HCl in ether (1.5 mL), heated at reflux for 3 hours, cooled and the solvent evaporated. The crude product was flash chromatographed on a silica gel column (10% methanol/chloroform) and triturated with ethyl acetate to give 147 mg of the desired compound as an off-white solid.

Melting point: 246 °C;

« ·

Ή NMR (DMSO-de) 2.32 (t, 2H), 2.65 (m, 2H), 2.85 (dt, 1H), 3.07 (dt, 1H), 3.40 (t, 2H),

4.69 (s, 1H), 7.22 (m, 2H), 7.36 (m, 2H), 10.33 (br s, 1H);

MS (APCI-) m/z 378 (M-H)';

Analytical calcd for C16H14BrNO3S: C, 50.54; H, 3.71; N, 3.68. Found: C, 50.62; H,

3.63; N, 3.54.

Example 65

8-(4-fluoro-3-trifluoromethylphenyl)-2,3,4,5,6,8-hexahydrodithieno[3,2-b:2i,3i]pyridine 1,1,7,7-tetraoxide

4-Fluoro-3-trifluoromethylbenzaldehyde (0.19 mL) was treated according to the procedure of Example 62 to give 35 mg of the desired compound as a white solid.

Melting point >260 °C;

1H NMR (DMSO-de) 2.83 (dtd, 2H), 3.02 (dt, 2H), 3.39 (m, 4H), 5.11 (s, 1H), 7.45 (dd, 1H), 7.62 (d, 1H), 7.67 (m, 1H), 10.07 (br s, 1H);

MS (APCI-) m/z 422 (M-H)';

Analytical calcd for C16H13F4NO4S2: C, 45.39; H, 3.09; N, 3.31. Found: C, 45.23; H, 2.87; N, 3.12.

Example 66

-[8-(3-bromo-4-fluorophenyl)-3,4,5,8-tetrahydro-6-methyl-1,1-dioxido-2H-thiopyrano[3,2b]pyridin-7-yl 1 )]ethan-1-one

3-Bromo-4-fluorobenzaldehyde (246 mg, 1.21 mmol) was treated according to the procedure of Example 35 to give 325 mg of the desired compound as a white solid.

Melting point >260 °C;

’H NMR (DMSO-de) 2.17 (m, 2H), 2.20 (s, 3H), 2.30 (s, 3H), 2.50 (m, 2H), 3.20 (m, 2H), 5.06 (s, 1H), 7.20 (m, 2H), 7.40 (dd, 1H), 9.11 (s, 1H);

MS (APCI-) m/z 412 (M-H)';

Analytical calcd for CnHnBrFNOsS: C, 49.28; H, 4.13; N, 3.38. Found: C, 49.06; H, 4.10; N, 3.28.

.» .<*«.W«» II » w ). _g o« »her

Example 67

8-(4-bromo-2-thienyl)-2,3,4,5,6,8-hexahydro-7H-cyclopenta[b]thieno[2,3-e]pyridin7-one 1,1-dioxide

4-Bromothiophene-2-carboxaldehyde (500 mg, 2.6 mmol), tetrahydrothiophene-3-oxo-1,1-dioxide (295 mg, 2.2 mmol) and 3-amino-2-cyclopenten-1-one (215 mg, 2.2 mmol) were heated in ethanol (5 mL) at 80°C in a sealed vessel for 2 days, cooled, the precipitated solid was combined, washed with ethanol, dissolved in a 1:3 methanol/methylene chloride solution, filtered through cotton, concentrated on a steam bath and allowed to crystallize to give 0.34 g of the desired compound as a white-brown solid.

Melting point 254-255 °C;

Ή NMR (DMSO-ds) 2.35 (t, 2H), 2.53-2.75 (m, 2H), 2.78-2.91 (m, 1H), 2.97-3.10 (m, 1H),

3.42 (t, 2H), 4.95 (s, 1H), 6.88 (d, 1H), 7.46 (d, 1H), 10.43 (bs, 1H);

MS (APCI+) m/z 386 (M+H), 403 (M+NH _4f , MS (APCI-) m/z 384 (MH)';

Analytical calcd for C1+H11NCbSiBr: C, 43.53; H, 3.13; N, 3.63. Found: C, 43.39; H, 2.84; N, 3.41.

Example 68

8-(5-bromo-2-thienyl)-2,3,4,5,6,8-hexahydro-7H-cyclopenta[b]thieno[2,3-e]pyridin7-one 1,1-dioxide

5-Bromothiophene-2-carboxaldehyde (500 mg, 2.6 mmol) was treated according to the procedure of Example 67 to give 0.297 g of the desired compound as a brown solid.

Melting point: 246-247 °C;

^] H NMR (DMSO-do) 2.35 (t, 2H), 2.52-2.73 (m, 2H), 2.78-2.90 (m, IH), 2.95-3.08 (m, IH), 3.41 (t, 2H), 4.92 (s, IH), 6.73 (d, IH), 6.97 (d, IH), 10.39 (s, IH);

MS (APCI-) m/z 384 (M-H)';

Analytical calcd for C14H12NO3S2Br: C, 43.53; H, 3.13; N, 3.63. Found: C, 43.19; H, 3.16; N, 3.31.

Example 69

2,3,4,5,6,8-hexahydro-8-(5-nitro-3-thienyl)-7H-cyclopenta[b]thieno[2,3-e]pyridin7-one 1,1-dioxide

2-Nitrothiophene-4-carboxaldehyde (0.41 g, 2.6 mmol) was treated according to the procedure of Example 67 to give 0.423 g of the desired compound as a brown powder.

^! H NMR (DMSO-d ₆ ) 2.34 (t, 2H), 2.52-2.74 (m, 2H), 2.80-2.92 (m, 1H), 2.98-3.11 (m, 1H),

3.43 (t, 2H), 4.84 (s, 1H), 7.78 (d, 1H), 7.94 (d, 1H), 10.39 (s, 1H);

MS (APCI+) m/z 353 (M+H) ⁺ , 370 (Μ+ΝΗ4Γ, MS (APCI-) m/z 351 (MH)';

Analytical calcd for C14H12N2O5S2: C, 47.72; H, 3.43; N, 7.95. Found: C, 47.43; H, 3.22; N, 7.65.

Example 70

2,3,4,5,6,8-hexahydro-8-(5-nitro-2-thienyl)-7H-cyclopenta[b]thieno[2,3-e]pyridin7-one 1,1-dioxide

5-Nitrothiophene-2-carboxaldehyde (205 mg, 1.30 mmol) was treated according to the procedure of Example 67 to give 238 mg of the desired compound as a brown solid.

Melting point 251-254 °C;

*H NMR (DMSO-do) 2.37 (t, 2H), 2.56-2.78 (m, 2H), 2.83-2.96 (m, IH), 3.01-3.14 (m, IH), 3.46 (t, 2H), 5.07 (s, IH), 7.10 (d, IH), 7.97 (d, IH), 10.59 (s, IH);

MS (APCI ⁺ ) m/z 353 (M+H) ⁺ , 370 (M+NH 4 /, (APCI-) m/z 351 (MH)';

Analytical calcd for C14H12N2O5S2: C, 47.72; H, 3.43; N, 7.95. Found: C, 47.39; H, 3.39; N, 7.67.

Example 71

2,3,4,5,6,8-hexahydro-8-(5-nitro-2-furyl)-7H-cyclopenta[b]thieno[2,3-e]pyridin-7-one 1,1-dioxide

5-Nitro-2-furaldehyde (185 mg, 1.30 mmol) was treated according to the procedure of Example 67 to give 117 mg of the desired compound as a brown solid.

Ή NMR (DMSO-d 0 ) 2.38 (t, 2H), 2.57-2.79 (m, 2H), 2.83-2.96 (m, 1H), 2.96-3.09 (m, 1H),

3.43 (t, 2H), 4.96 (s, 1H), 6.71 (d, 1H), 7.65 (d, 1H), 10.52 (s, 1H);

MS (APCI+) m/z 337 (M+H) ⁺ , 354 (Μ+ΝΗ,) ⁺ , MS (APCI-) m/z 335 (MH)';

Analytical calcd for C14H12N2O6S: C, 50.00; H, 3.60; N, 8.33. Found: C, 49.80; H, 3.42; N, 8.14.

Example 72

8-(3,4-Dibromophene 1)-2,3,4,5,6,8-hexahydro-7H-cyclopenta[b]thieno[2,3-e]pyridin7-one 1,1-dioxide

3,4-Dibromobenzaldehyde (293 mg, 1.11 mmol), tetrahydrothiophene-3-oxo-1,1-dioxide (146 mg, 1.09 mmol) and 3-amino-2-cyclopenten-1-one (107 mg, 1.10 mmol) were heated in ethanol (4 mL) at 80°C in a sealed vessel for 3 days, cooled, the precipitated solid was collected, washed with ethanol and dried to give 211 mg of the desired compound. The filtrate was treated with 1.0 M HCl in ether (1 mL), heated at reflux for 2 hours, cooled and the solvent was evaporated. The residue was treated with ethanol, heated and the resulting solid was collected, washed with ethanol and dried to give an additional 29 mg of the desired compound. The two combined portions were triturated with hot ethyl acetate, washed with ethyl acetate and dried to give 197 mg of the desired compound as a white solid.

Melting point >260 °C;

*H NMR (DMSO-do) 2.30 (t, 2H), 2.55-2.75 (m, 4H), 2.85 (dt, 1H), 3.05 (dt, 1H), 3.40 (t, 2H), 4.71 (s, 1H), 7.17 (dd, 1H), 7.54 (d, 1H), 7.65 (d, 1H), 10.36 (br s, 1H);

MS (APCI-) m/z 458 (M-H)';

Analytical Calcd for C16H11Br1NO3S: C, 41.85; H, 2.85; N, 3.05. Found: C, 41.79; H, 2.75; N, 2.78.

Example 73

2,3,4,5,6,8-hexahydro-8-(3-nitrophenyl)dithieno[3,2-b:2i,3i-e]pyridine 1,1,7,7-tetraoxide

3-Nitrobenzaldehyde (155 mg, 1.03 mmol), tetrahydrothiophene-3-oxo-1,1-dioxide (273 mg, 2.04 mmol) and 2.0 M NH3 in ethanol (0.7 mL, 1.4 mmol) were heated at 80°C in ethanol (4 mL) for 3 days in a sealed vessel, cooled, treated with 1.0 M HCl in ether (1 mL), heated at reflux for 15 min, cooled, the precipitated solid was collected, washed with ethanol and dried. The solid was triturated with hot ethyl acetate, collected, washed with ethyl acetate and dried to give 174 mg of the desired compound as an orange-yellow solid.

Melting point: 248-252°C;

’H NMR (DMSO-de) 2.85 (m, 2H), 3.05 (m, 2H), 3.40 (m, 4H), 5.15 (s, 1H), 7.61 (t, 1H),

7.77 (dt, 1H), 8.10 (m, 2H), 10.09 (br s, 1H);

MS (APCI-) m/z 381 (M-H)';

• ·

Analytical calcd for C15H14N2O6S2: C, 47.11; H, 3.68; N, 7.32. Found: C, 47.47; H,

3.68; N, 7.29.

Example 74

8-(3-chloro-4-fluorophenyl)-2,3,4,5,6,8-hexahydrodithieno[3,2-b:2',3'-e'pyridine tetraoxide

3-Chloro-4-fluorobenzaldehyde (160 mg, 1.0 mmol), tetrahydrothiophene-3-oxo-1,1-dioxide (273 mg, 2.04 mmol) and 2.0 M NH3 in ethanol (0.7 mL, 1.4 mmol) were heated at 80°C in ethanol (4 mL) for 3 days in a sealed vessel, cooled, the precipitated solid was combined, washed with ethanol and dried to give 146 mg of the desired compound as a pale yellow solid.

Melting point >260 °C;

*H NMR (DMSO-d ₆ ) 2.82 (dt, 2H), 3.02 (dt, 2H), 3.38 (m, 4H), 4.97 (s, IH), 7.24-7.38 (m, 2H), 7.43 (dd, IH), 9.35 (br s, IH);

MS (APCI-) m/z 388 (M-H)';

Analytical calcd for C15H13ClFNO4S2: C, 46.09; H, 3.61; N, 3.58. Found: C, 45.91; H, 3.40; N, 3.63.

Example 75

4-(3,4-dichlorophenyl)-1,4,6,7-tetrahydro-2-methyl-3-(methylsulfonyl)-5H-cyclopenta[b]pyridin-5-one

3,4-Dichlorobenzaldehyde (175 mg, 1.0 mmol), methanesulfonylacetone (137 mg, 1.01 mmol) and 3-aminocyclopentenone (95 mg, 0.98 mmol) were heated at 80°C in ethanol (4 mL) in a sealed vessel for 3 days, cooled and the solvent was evaporated. The crude material was flash chromatographed on a silica gel column (5% methanol/chloroform) to give 80 mg of the desired compound as a tan solid.

Melting point: 218-220 °C;

1H NMR (CDCb) 2.48-2.50 (br s, 5H), 2.59 (s, 3H), 2.63 (m, 2H), 5.01 (s, 1H), 6.53 (br s,

1H), 7.25 (m, 1H), 7.48 (m, 2H);

MS (APCI-) m/z 370 (M-H)';

Analytical calcd for C16H15Cl2NO3S: C, 51.62; H, 4.06; N, 3.76. Found: C, 51.36; H,

3.99; N, 3.83.

Example 76

4-(4-chloro-3-nitrophenyl)-1,4,6,7-tetrahydro-2-methyl-3-(methylsulfonyl)-5H-cyclopenta[b]pyridin-5-one

4-Chloro-3-nitrobenzaldehyde (186 mg, 1.0 mmol) was treated according to the procedure of Example 75 to give 105 mg of the desired compound as an off-white solid.

Melting point: 232 °C;

1H NMR (DMSO-do) 2.27 (m, 2H), 2.36 (s, 3H), 2.58 (m, 2H), 2.83 (s, 3H), 4.87 (s, 1H), 7.53 (dd, 1H), 7.70 (d, 1H), 7.80 (d, 1H), 10.10 (s, 1H);

MS (APCI-) m/z 381 (M-H)';

Analytical calcd for C16H15CIN2O5S: C, 51.62; H, 4.06; N, 3.76. Found: C, 51.36; H, 3.99; N, 3.83.

Example 77

8-(3,4-chlorophenyl-2,3,4,5,6,8-hexahydrodithieno[3,2-b:2i,3i-e]pyridine 1,1,7,7-tetraoxide

3,4-Dichlorobenzaldehyde (196 mg) was treated according to the procedure of Example 74 to give 165 mg of the desired compound as a pale yellow solid.

Melting point > 260 °C;

1H NMR (DMSO-do) 2.82 (m, 2H), 3.00 (dt, 2H), 3.39 (m, 4H), 4.97 (s, IH), 7.26 (dd, 1H), 7.49 (d, IH), 7.55 (d, IH), 9.53 (br s, IH);

MS (APCI-) m/z 404 (M-H)';

Analytical calcd for C15H13Cl2NO4S2: C, 44.34; H, 3.22; N, 3.44. Found: C, 43.99; H, 3.11; N, 3.68.

Example 78

8-(4-Bromophenyl)-2,3,4,5,6,8-hexahydro-7H-cyclopenta[b]thieno[2,3-e]pyridin-7-one 1,1-dioxide « » * · ». * » *« * * • * · » ‘ • « » : · * · • « « » « « . ® • « · » » ·

4-Bromobenzaldehyde (377 mg, 2.00 mmol), tetrahydrothiophene-3-oxo-1,1-dioxide (230 mg, 1.7 mmol) and 3-amino-2-cyclopenten-1-one (165 mg, 1.7 mmol) were heated at 80°C in a sealed vessel for 2 days, cooled, the precipitated solid was combined and washed with ethanol. The filtrate was treated with 1.0 M HCl/diethyl ether (4 mL), heated at reflux for 15 minutes, cooled, concentrated, combined with the precipitated solid and purified by flash chromatography on silica gel (5% methanol/methylene chloride). The product was crystallized from ethanol to give 218 mg of the desired compound.

Melting point: 253-256 °C;

1 H NMR (DMSO-d ₆ ) 2.30 (t, 2H), 2.51-2.72 (m, 2H), 2.79-2.91 (m, 1H), 2.97-3.09 (m, 1H),

3.34-3.42 (m, 2H), 4.66 (s, 1H), 7.17 (d, 2H), 7.43 (d, 2H), 10.27 (s, 1H);

MS (APCI+) m/z 380 (M+H) ⁺ , MS (APCI-) m/z 378 (MH)';

Analytical Calcd for C16H11NO3S: C, 50.54; H, 3.71; N, 3.68. Found: C, 50.50; H, 3.74; N, 3.52.

Example 79

1,1-dioxide of 8-(3,4-difluorophenyl)-2,3,4,5,6,8-hexahydro-7H-cyclopenta[b]thieno[2,3-e]pyridin7-one

3,4-Difluorobenzaldehyde (162 mg) was treated according to the procedure of Example 56 to obtain 169 mg of the desired compound as a white powder.

Melting point > 260 °C;

1H NMR (DMSO-do) 2.30 (t, 2H), 2.5-2.75 (m, 2H), 2.86 (dt, 1H), 3.07 (dt, 1H), 3.40 (t, 2H),

4.72 (s, 1H), 7.08 (m, 1H), 7.18-7.36 (m, 2H), 10.32 (br s, 1H);

MS (APCI-) m/z 336 (M-H)';

Analytical calcd for C16H13F2NO3S: C, 56.96; H, 3.88; N, 4.15. Found: C, 57.01; H, 3.78; N, 4.08.

Example 80

8-(4-chloro-3-fluorophenyl)-2,3,4,5,6,8-hexahydro-7H-cyclopenta[b]thieno[2,3e]pyridin-7-one 1,1-dioxide

4-Chloro-3-fluorobenzaldehyde (180 mg, 1.13 mmol) was treated according to the procedure of Example 56 to give 135 mg of the desired compound as a white solid.

.Λ.ΙΛΑΑ U.«X· «« «· ·» « * ·* ♦

Melting point >260 °C;

Ή NMR (DMSO-dó) 2.30 (t, 2H), 2.50-2.75 (m, 2H), 2.87 (dt, IH), 3.05 (dt, IH), 3.40 (t, 2H), 4.73 (s, IH), 7.10 (dd, IH), 7.21 (dd, IH), 7.45 (t, IH), 10.32 (br s, IH);

MS (APCI-) m/z 352 (M-H)';

Analytical calcd for C16H13ClFNO3S: C, 54.31; H, 3.70; N, 3.95. Found: C, 54.08; H, 3.65; N, 3.88.

Example 81

9-(3-chloro-4-fluorophenyl)-2,3,5,6,7,9-hexahydrothieno[3,2-b]quinolin-8(4H)-one 1,1-dioxide

3-Chloro-4-fluorobenzaldehyde (264 mg, 1.66 mmol) was worked up according to the procedure of Example 43 to give 317 mg of the title compound as a pale yellow solid. Melting point > 260 °C 1 H NMR (DMSO-d6) 1.73-1.96 (m, 2H), 2.23 (m, 2H), 2.55 (m, 2H), 2.82 (dt, 1H), 3.02 (dt, 1H), 3.46 (m, 2H), 4.85 (s, 1H), 7.17 (m, 1H), 7.28 (m, 2H), 9.75 (br s, 1H);

MS (APCI-) m/z 366 (M-H)';

Analytical calcd for C17H15ClFNO3S: C, 55.51; H, 4.11; N, 3.80. Found: C, 55.24; H, 3.97; N, 3.85.

Example 82

8-(3-cyano-4-fluorophenyl)-2,3,4,5,6,8-hexahydrodithieno[3,2-b:2i,3i]pyridine 1,1,7,7-tetraoxide

Example 82A

-cyano-4-fluorobenzyl bromide

A solution of 3-cyano-4-fluorotoluene (1.0 g, 7.4 mmol), N-bromosuccinimide (1.3 g, 7.4 mmol) and a catalytic amount of 2,2'-azobisisobutyronitrile (AIBN) in benzene was heated at reflux for 16 hours, evaporated to dryness and flash chromatographed on a silica gel column (10% ethyl acetate/hexane) to give 1.0 g of 3-cyano-,4-fluorobenzyl bromide.

1 H NMR (CDCl 3 ) d 4.45 (s, 2H), 7.21 (t, 1H), 7.65 (m, 2H).

Example 82B

3-cyano-4-fluorobenzyl alcohol

A solution of 85% formic acid (0.63 mL) and triethylamine (2.32 mL, 16.7 mmol) in acetonitrile at 0 °C was treated with the product of Example 82A (1.3 g, 5.6 mmol), stirred at room temperature for 3 hours, the reaction mixture was evaporated to dryness, partitioned between ethyl acetate/water, the organic layer was dried over sodium sulfate, filtered, and the solvent was evaporated to give the crude formate ester. This residue was dissolved in methanol-water (5:1), treated with a catalytic amount of concentrated hydrochloric acid, stirred at room temperature overnight, evaporated to dryness, and flash chromatographed on a silica gel column (ethyl acetate:hexane 1:1) to give 0.40 g of 3-cyano-4-fluorobenzyl alcohol.

1 H NMR (CDCl 3 ) d 1.81 (t, 1H), 4.72 (d, 2H), 7.21 (t, 1H), 7.62 (m, 2H).

Example 82C

-cyano-4-fluorobenzaldehyde

A solution of the product from Example 82B (0.40 g, 2.6 mmol) in chloroform (50 mL) was treated with manganese dioxide (0.55 g, 7.8 mmol), stirred at room temperature overnight, filtered, the solvent was evaporated, and the residue was flash chromatographed on a silica gel column (ethyl acetate:hexane 1:1) to give 0.21 g of 3-cyano-4-fluorobenzaldehyde.

1H NMR (CDCl 2 ) d 7.43 (t, 1H), 8.17 (m, 2H), 9.99 (s, 1H).

Example 82D

3-Cyano-4-fluorobenzaldehyde (0.21 g, 1.4 mmol) was treated according to the procedure of Example 62 to give 0.20 g of the desired compound as a white solid.

Melting point: 275-280 °C (decomposition);

*H NMR (DMSO-de) 2.82 (m, 2H), 3.0 (m, 2H), 3.4 (m, 4H), 5.06 (s, 1H), 7.48 (t, 1H), 7.7 (m, 1H), 7.86 (dd, 1H) 10.1 (s, 1H);

MS (ESU-) m/z 398 (M+NH ₄ ) ⁺ , MS (ESI-) m/z 379 (MH)';

Analytical calcd for C16H13FN2O4S2: C, 50.52; H, 3.44; N, 7.36. Found: C, 50.47; H,

3.52; N, 7.26.

-«W

Example 83

1,1-dioxide (+)(9R)-9-(3-bromo-4-fluorophenyl)-2,3,5,6,7,9-hexahydrothieno[3,2-b]quinolin8(4H)-one.

The product from Example 43 (0.50 g) was chromatographed on a 5x25 cm Regis WhelkO 2 chiral column with 280 g of mobile phase (hexane:methanol:methylene chloride 77.5/15/7.5) at a flow rate of 117 ml/min to give 220 mg of the desired compound in the form of the more polar enantiomers.

[] ²³ d+50.24° (CH ₃ CN);

*H NMR (DMSO-d ₆ ) 1.72-1.98 (m, 2H), 2.22 (m, 2H), 2.55 (m, 2H), 2.8 (m, 1H), 3.1 (m,

1H), 3.32 (m, 2H), 4.82 (s, 1H), 7.2 (m, 2H), 7.4 (m, 1H), 9.8 (s, 1H);

MS (APCI+) m/z 414 (M+H) ⁺ ;

Analytical calcd for _{C17H15BrFNO3S} : C, 49.52; H, 3.66; N, 3.39. Found: C, 49.56; H, 3.86; N, 3.33.

Example 84

1,1-dioxide (-)(9S)-9-(3-bromo-4-fluorophenyl)-2,3,5,6,7,9-hexahydrothieno[3,2-b]quinolin-8(4H)one

From the above chiral chromatography in Example 83, 210 mg of the desired compound was obtained in the form of the less polar enantiomer.

[] ²³ d-48.8 (CH ₃ CN);

1 H NMR (DMSO-d 0 ) 1.72-1.98 (m, 2H), 2.22 (m, 2H), 2.52 (m, 2H), 2.8 (m, 1H), 3.1 (m,

1H), 3.31 (m, 2H), 4.82 (s, 1H), 7.2 (m, 2H), 7.4 (m, 1H), 9.8 (s, 1H);

MS (APCI+) m/z 414 (M+H) ⁺ ;

Analytical calcd for _{C17H15BrFNO3S} : C, 49.52; H, 3.66; N, 3.39. Found: C, 49.54; H,

3.76; N, 3.41.

·· *·

Example 85

8-(2,1,3-Benzoxadiazol-5-yl)-2,3,4,5,6,8-hexahydro-7H-cyclopenta[b]thieno[2,3e]pyridin-7-one 1,1-dioxide

2,1,3-Benzoxadiazole-5-carboxaldehyde (0.296 g, 2.00 mmol), prepared according to Gasca (Eur. J. Med. Chem. 1996, 31, 3), tetrahydrothiophene-3-oxo-1,1-dioxide (0.27 g, 2.0 mmol) and 3-amino-2-cyclopenten-1-one (0.194 g, 2.00 mmol) were heated in ethanol (4 mL) at 80°C for 2 days in a sealed vessel, treated with 1.0 M HCl in ether (1 mL), heated at reflux for 3 hours, cooled, the precipitated solid was collected, washed with ethanol and dried to give 0.27 g of the desired compound. ^] H NMR (DMSO-d6) 2.31 (t, 2H), 2.65 (m, 2H), 2.9 (m, 1H), 3.05 (m, 1H), 3.42 (m, 2H), 4.92 (s, 1H), 7.55 (d, 1H), 7.82 (s, 1H), 7.96 (d, 1H), 10.42 (s, 1H);

MS (Cl/NH 2 ) m/z 361 (M+NR,) ⁺ ;

Analytical calcd for C10H13N3O4S: C, 55.96; H, 3.81; N, 12.23. Found: C, 55.80, H, 3.73; N, 12.18.

Example 86

(-)(8S)-8-(3-bromo-4-fluorophen1)-2,3,4,5,6,8-hexahydro-7Hcyclopenta[b]thieno[2,3-e]pyridin-7-one 1,1-dioxide

The product from Example 56 (0.80 g) was chromatographed on a 5x25 cm Regis WhelkO 2 chiral column with 280 g of mobile phase (hexane:methanol:methylene chloride 77/15/15) at a flow rate of 117 ml/min to give 250 mg of the desired compound as the less polar enantiomer.

[] ²³ d -4.5°(CH ₃ CN) *H NMR (DMSO-do) 2.3 (t, 2H), 2.63 (m, 2H), 2.85 (m, 1H), 3.06 (m, 1H), 3.4 (m, 2H), 4.71 (s, 1H), 7.25 (d, 2H), 7.47 (d, 1H) 10.35 (s, 1H);

MS (ESI+) m/z 400 (M+H) ⁺ ;

Analytical calcd for C16H11BrFNO3S: C, 48.25; H, 3.29; N, 3.52. Found: C, 48.14; H,

3.42; N, 3.42.

• · · « · * ' ' » • « · · 1 ··'··» • ·* ··« ··· *· • · ♦ · .. . . «

Example 87

(+)(8R)-8-(3-bromo-4-fluorophenyl)-2,3,4,5,6,8-hexahydro-7Hcyclopenta[b]thieno[2,3-e]pyridin-7-one 1,1-dioxide

8(4H)-one

From the above chiral chromatography in Example 86, 264 mg of the desired compound was obtained in the form of the more polar enantiomer.

[] ²³ d+4.8° (CH ₃ CN);

^] H NMR (DMSO-dé) 2.3 (m, 2H), 2.62 (m, 2H), 2.85 (m, 1H), 3.05 (m, 1H), 3.4 (m, 2H),

4.72 (s, 1H), 7.25 (m, 2H), 7.48 (d, 1H), 10.35 (s, 1H);

MS (ESI+) m/z 400 (M+H) ⁺ ;

Analytical calcd for _{C16H13BrFNO3S} : C, _48.25 ; H, 3.29; N, 3.52. Found: C, 48.14; H, 3.52; N, 3.42.

Example 88

9-(2,1,3-Benzoxadiazoyl-5-yl)-2,3,5,6,7,9-hexahydrothieno[3,2-b]quinolin-8(4H)one 1,1-dioxide

2,1,3-Benzoxadiazole-5-carboxaldehyde (0.296 g, 2.00 mmol) was treated according to the method of Example 89 to give 0.42 g of the desired compound.

^] H NMR (DMSO-do) 1.9 (m, 2H), 2.25 (m, 2H), 2.55 (m, 2H), 2.88 (m, 1H), 3.05 (m, 1H),

3.4 (m, 2H), 5.0 (s, 1H), 7.51 (d, 1H), 7.7 (s, 1H), 7.95 (d, 1H), 9.96 (s, 1H);

MS (ESI+) m/z 358 (M+H) ⁺ ;

Analytical calcd for C11H11N12S: C, 57.13; H, 4.23; N, 11.75. Found: C, 57.05; H, 4.31; N, 11.73.

Example 89

9-(4-fluoro-3-iodophenyl)-2,3,5,6,7,9-hexahydrothieno[3,2-b]quinolin-8(4H)-one 1,1-dioxide

Example 89A

-amino-4-fluorobenzyl alcohol ., · »· ·<· ·· ·· · · , < « « · · * * , ₍ .,, « '» * »' ♦ *

4 « · · »· · « ·

.. < · * · * · ' ”

............

3-Amino-4-fluorobenzoic acid (15 g, 97 mmol) in THF at 0°C was treated with 1.0 M BH3*THF (50 mL), stirred overnight at room temperature, treated with an additional 130 mL of 1.0 M BH3*THF, stirred for 10 hours, quenched by addition of methanol, stirred for 3 hours at room temperature, the solvent was evaporated, the product was partitioned between aqueous sodium bicarbonate/methylene chloride, the organic layer was dried (sodium sulfate), filtered, and the solvent was evaporated. The product was purified by flash chromatography on a silica gel column (ethyl acetate/hexane 1:1) to give 7.0 g of the desired compound.

1 H NMR (CDCl 2 ) 4.58 (s, 2H), 6.67 (br m, 1H), 6.81 (d, 1H), 6.95 (t, 1H).

Example 89B

4-fluoro-3-iodobenzyl alcohol

The product of Example 89A (7.0 g, 50 mmol) in water (100 mL) at 0°C was treated cautiously with concentrated sulfuric acid (30 mL) to maintain the temperature below 10°C, then treated dropwise with aqueous sodium nitrite (3.45 g, 50 mmol). This solution was then added to a solution of potassium iodide (8.13 g, 50 mmol) in water (15 mL), heated at 60°C for 2 hours, cooled, extracted with methylene chloride, the organic layers were washed with 10% sodium hydroxide, 1 M sodium thiosulfate, 10% hydrochloric acid, aqueous sodium bicarbonate, dried (sodium sulfate), filtered, and the solvent was evaporated. The material was purified by flash chromatography on a silica gel column (ethyl acetate/hexane 7:3) to obtain 6.4 g of the desired compound.

¹ H NMR (CDCl 3 ) 1.69 (t, 1H), 4.66 (d, 2H), 7.05 (ζ 1H), 7.60 (d, 1H), 7.78 (dd, 1H).

Example 89C

4-fluoro-3-iodobenzaldehyde

The product of Example 89B (6.4 g, 26 mmol) in chloroform (300 mL) was treated with manganese dioxide (4.5 g, 50 mmol), stirred overnight, treated with another portion of manganese dioxide (2.25 g), stirred overnight, filtered, and the solvent was evaporated. The material was purified by flash chromatography on silica gel (ethyl acetate/hexane 1:4) to give 1.9 g of the desired compound.

'HNMR (CDCb) 7.23 (t, 1H), 7.89 (m, 1H), 832 (dd, 1H), 9.91 (s, 1H).

Example 89D

9-(4-fluoro-3-iodophenyl)-2,3,5,6,7,9-hexahydrothieno[3,2-b]quinolin-8(4H)-one 1,1-dioxide

4-Fluoro-3-iodobenzaldehyde (0.25 g, 1.0 mmol), tetrahydrothiophene-3-oxo-1,1-dioxide (0.13 g, 1.0 mmol), 3-amino-2-cyclohexen-1-one (0.11 g, 1.0 mmol) and triethylamine (0.07 ml) were heated in ethanol (2 ml) at 80°C in a sealed vessel for 96 h, cooled, the solvent evaporated, flash chromatographed on a silica gel column (10% ethanol/methylene chloride), the product was dissolved in ethanol, treated with 1.0 M HCl in ether (1 ml), heated at reflux for 2 h, cooled, the precipitated solid was collected, washed with ethanol and dried to give 0.20 g of the desired compound.

Melting point > 250 °C;

1H NMR (DMSO-do) 1.88 (m, 2H), 2.22 (m, 2H), 2.62 (m, 2H), 2.7 (m, IH), 3.02 (m, IH), 3.45 (m, 2H), 4.81 (s, IH), 7.12 (m, IH), 7.18 (m, IH), 7.55 (dd, IH), 9.81 (s, 1H); MS (ESI+) m/z 460 (M+H) ⁺ ;

Analytical calcd for C17H15FINO3S: C, 44.45; H, 3.29; N, 3.04. Found: C, 44.51; H, 3.31; N, 2.97.

Example 90

8-(4-fluoro-3-iodophenyl)-2,3,4,5,6,8-hexahydro-7H-cyclopenta[b]thieno[2,3e]pyridin-7-one 1,1-dioxide

4-Fluoro-3-iodobenzaldehyde (0.25 g, 1.0 mmol), tetrahydrothiophene-3-oxo-1,1-dioxide (0.13 g, 1.0 mmol) and 3-amino-2-cyclopenten-1-one (97 mg, 1.0 mmol) were heated in ethanol (2 mL) at 80°C in a sealed vessel for 96 h, cooled, the solvent evaporated, flash chromatographed on a silica gel column (10% ethanol/methylene chloride), the product was dissolved in ethanol, treated with 1.0 M HCl in ether (1 mL), heated at reflux for 2 h, cooled, the precipitated solid was collected, washed with ethanol and dried to give 0.10 g of the desired compound.

Melting point >250 °C;

1H NMR (DMSO-do) 2.3 (t, 2H), 2.62 (m, 2H), 2.85 (m, 1H), 3.08 (m, 1H), 3.4 (m, 2H), 4.68 (s, 1H), 7.13 (t, 1H), 7.24 (m, 1H), 7.6 (dd, 1H), 10.33 (s, 1H);

MS (ESI+) m/z 446 (M+H) ⁺ ;

Analytical calcd for C16H13FINO3S: C, 43.16; H, 2.94; N, 3.14. Found: C, 42.91; H,

2.94; N; 3.00.

Example 91

1,1-dioxide (+)9-(3-bromo-4-fluorophenyl)-3,4,5,6,7,9-hexahydrocyclopenta[b]thiopyrano[2,3e]pyridin-8(2H)-one

The product of Example 40 (1.476 g, 3.58 mmol) as a slurry in THF (20 mL) under nitrogen at 5°C was treated dropwise with a solution of 1.0 M potassium tert-butoxide in THF (3.9 mL), allowed to warm to room temperature over 20 min, then treated with a solution of (-)-8-phenylmenthyl chloroformate (1.17 g, 3.97 mmol) in THF (5 mL), stirred at room temperature overnight, quenched with aqueous sodium bicarbonate, extracted with diethyl ether (2x), the organic layers were dried over sodium sulfate, filtered, and the solvent was evaporated to give a mixture of diastereomeric carbamates. This mixture was flash chromatographed on a 6x36 cm column of silica gel (ether:hexane 85/15) to give 746 mg of the less polar diastereomer. This material, as a slurry in methanol (10 mL) under nitrogen, was treated with a catalytic amount of sodium methoxide, stirred at room temperature for 24 hours, treated with glacial acetic acid (3 drops), the solid precipitate was collected, washed with ethyl alcohol and dried to give 227 mg of the desired compound as a white solid.

[] ²³ d +63.9 (MeCN);

¹ H NMR (DMSO-do) 2.15-2.35 (m, 4H), 2.46-2.70 (m, 4H), 3.23 (m, 2H), 4.83 (s, 1H), 7.25 (m, 2H), 7.42 (dd, 1H), 9.96 (br s, 1H);

MS (APCI-) m/z 410 (M-H)';

Analytical calcd for C11H12BrFNO1S: C, 49.53; H, 3.67; N, 3.40. Found: C, 49.47; H, 3.53; N, 3.37.

Example 92

1,1-dioxide (-)9-(3-bromo-4-fluorophenyl)-3,4,5,6,7,9-hexahydrocyclopenta[b]thiopyrano[2,3e]pyridin-8(2H)-one

From the above described diastereomeric chromatography in Example 91, 824 mg of the impure more polar diastereomer was obtained. This material was flash chromatographed on a 6x36 cm column of silica gel (ether:hexane 9/1) to give 695 mg of the more polar diastereomer. This diastereomer, as a slurry in methanol (10 mL) under nitrogen, was treated with a catalytic amount of sodium methoxide, stirred at room temperature for 5 days, treated with glacial acetic acid (3 drops), the solid precipitate was collected, washed with ethanol and dried to give 120 mg of the desired compound as a white solid. The filtrate was flash chromatographed on a silica gel column (5-15% ethanol/methylene chloride) and the product was triturated with ethyl acetate to give an additional 186 mg of the desired compound.

[] ²³ d -60.8 (MeCN) Η NMR (DMSO-d ₆ ) 2.15-2.30 (m, 4H), 2.47-2.70 (m, 4H), 3.20 (m, 2H), 4.83 (s, IH), 7.25 (m, 2H), 7.41 (dd, IH), 9.96 (br s, IH);

MS (APCI-) m/z 410 (M-H)'; Analytical calcd for CpHisBrFNO3S: C, 49.53; H, 3.67; N, 3.40. Found: C, 49.61; H, 3.58; N, 3.34.

Example 93

1,1-dioxide (+)10-(3-bromo-4-fluorophenyl)-3,4,6,7,8,10-hexahydro-2H-thiopyrano[3,2b]quinolin-9(5H)-one

The product of Example 4 (1.646 g, 3.86 mmol) was processed according to the method of Example 91 to obtain 223 mg of the desired compound as a white solid.

[] ²³ d +7.3 (DMSO);

1 H NMR (DMSO-d 0 ) 1.75 (m, 1H), 1.88 (m, 1H), 2.20 (m, 4H), 2.50 (m, 4H), 3.20 (m, 2H); 5.01 (s, 1H), 7.15-7.28 (m, 2H), 7.88 (dd, 1H), 9.39 (br s, 1H);

MS (APCI-) m/z 424 (M-H)';

Analytical calcd for C18H18BrFNO3S: C, 50.71; H, 4.02; N, 3.29. Found: C, 50.73; H,

4.24, N, 3.26.

Example 94

1,1-dioxide (-) 10-(3-bromo-4-fluorophenyl)-3,4,6,7,8,10-hexahydro-2H-thiopyrano[3,2-b]quinoline

9(5H)-onu ¹ i wwwwwwiwmawwwaHW·

The product of Example 4 (1.646 g, 3.86 mmol) was processed according to the method of Example 91 and Example 92 to obtain 148 mg of the desired compound as a white solid.

[] ²³ D-5.2 (DMSO);

Ή NMR (DMSO-de) 1.73 (m, 1H), 1.88 (m, 1H), 2.20 (m, 4H), 2.50 (m, 4H), 3.20 (m, 2H), 5.01 (s, 1H), 7.15-7.27 (m, 2H), 7.38 (dd, 1H), 9.40 (br s, 1H);

MS (APCI-) m/z 424 (M-H)';

Analytical calcd for C18H11BrFNO3S: C, 50.71; H, 4.02; N, 3.29. Found: C, 50.68; H, 4.17; N, 3.22.

Example 95

1,1-dioxide (+)(9R)-9-(3,4-dichlorophenyl)-3,4,5,6,7,9-hexahydrothieno[3,2-b]quinolin-8(2H)one

The title compound of Example 29 (1.65 g, 4.30 mmol) as a slurry in THF (20 mL) under nitrogen at 5°C was treated dropwise with a solution of 1.0 M potassium tert-butoxide in THF (3.9 mL), allowed to warm to room temperature over 20 min, then treated with a solution of (-)-8-phenylmenthyl chloroformate (4.3 mmol) in THF (5 mL), stirred at room temperature overnight, quenched with aqueous sodium bicarbonate, extracted with diethyl ether (3x), the organic layers were dried over sodium sulfate, filtered, and the solvent was evaporated to give a mixture of diastereomeric carbamates. This mixture was flash chromatographed on a 6x40 cm silica gel column (chloroform:hexane:ether 7:2:1) to give 664 mg of the less polar diastereomer. This material, as a slurry in methanol (10 mL) under nitrogen, was treated with a catalytic amount of sodium methoxide, stirred at room temperature overnight, treated with glacial acetic acid (2 drops), the solid precipitate was collected, washed with ethyl alcohol and dried to give 295 mg of the desired compound as a white solid.

[] ²³ d +70.9° (DMSO);

Ή NMR (DMSO-dé) 1.75-1.95 (m, 2H), 2.23 (m, 2H), 2.54 (m, 2H), 2.83 (dt, 1H), 3.02 (dt,

1H), 3.45 (m, 2H), 4.84 (s, 1H), 7.16 (dd, 1H), 7.34 (d, 1H), 7.49 (d, 1H), 9.82 (br s, 1H);

MS (APCI-) m/z 382 (M-H)';

Analytical calcd for C17H15Cl2NO3S: C, 53.14; H, 3.93; N, 3.64. Found: C, 53.38; H,

4.19; N, 3.61.

• · • «» ··♦ * · · • ·· · * ·« ·

Example 96

1,1-dioxide (-)(9S)9-(3,4-dichlorophenyl)-3,4,5,6,7,9-hexahydrothieno[3,2-b]quinolin-8(2H)-one

The above described chromatography of the diastereomers in Example 95 gave the impure more polar diastereomer. This material was flash chromatographed on a 6x40 cm silica gel column (chloroform:hexane:ether 7:2:1) to give 628 mg of the more polar diastereomer. This diastereomer, as a slurry in methanol (10 ml) under nitrogen, was treated with a catalytic amount of sodium methoxide, stirred at room temperature overnight, treated with glacial acetic acid (2 drops), the solid precipitate was collected, washed with ethyl alcohol and dried to give 228 mg of the desired compound as a white solid. [] ²³ d-68.6° (DMSO);

^! H NMR (DMSO-do) 1.75-1.95 (m, 2H), 2.23 (m, 2H), 2.55 (m, 2H), 2.73 (dt, 1H), 3.03 (dt, 1H), 3.35 (m, 2H), 4.84 (s, 1H), 7.17 (dd, 1H), 7.35 (d, 1H), 7.50 (d, ÍH), 9.85 (br s, ÍH);

MS (APCI-) m/z 382 (M-H)';

Analytical calcd for C17H15Cl2NO3S: C, 53.14; H, 3.93; N, 3.64. Found: C, 53.11; H, 4.01; N, 3.59.

Example 97

(+)(9R)-9-(2,1,3-benzoxadiazol-5-yl)-2,3,5,6,7,9-hexahydrothieno[3,2-b]quinolin8(4H)-one 1,1-dioxide

The product of Example 88 (1.34 g) was processed according to the methods of Example 95 to give 120 mg of the desired compound as a white solid.

[] ²³ d +43.3° (DMSO);

1 H NMR (DMSO-d 0 ) 1.9 (m, 2H), 2.23 (m, 2H), 2.56 (m, 2H), 2.88 (m, 1H), 3.05 (m, 1H),

3.4 (m, 2H), 5.0 (s, 1H), 7.51 (d, 1H), 7.7 (s, 1H), 7.95 (d, 1H), 9.95 (s, 1H);

MS (ESI-) m/z 356 (M-H)';

Analytical calcd for C17H15N3O4S: C, 57.13; H, 4.23; N, 11.75. Found: C, 56.98; H,

4.28; N, 11.76.

Example 98

1,1-dioxide (-)(9S)-9-(2,1,3-benzoxadiazol-5-yl)-2,3,5,6,7,9-hexahydrothieno[3,2-b]quinolin8(4H)-one

The product of Example 88 (1.34 g) was processed according to the methods of Example 95 and Example 96 to obtain 110 mg of the desired compound as a white solid.

[] ²³ d -41.7° (DMSO);

^! H NMR (DMSO-dé) 1.9 (m, 2H), 2.25 (m, 2H), 2.57 (m, 2H), 2.9 (m, IH), 3.05 (m, IH), 3.4 (m, 2H), 5.0 (s, IH), 7.51 (d, IH), 7.7 (s, IH), 7.95 (d, IH), 9.95 (s, IH);

MS (ESI-) m/z 356 (M-H)';

Analytical calcd for C17H15N3O4S: C, 57.13; H, 4.23; N, 11.75. Found: C, 56.97; H, 4.43; N, 11.71.

Example 99

(+)(9R)-9-(4-chloro-3-nitrophenyl)-3,4,5,6,7,9-hexahydrothieno[3,2-b]quinolin8(2H)-one 1,1-dioxide

The product of Example 34 (1.64 g) was processed according to the methods of Example 95 to obtain 300 mg of the desired compound.

[] ²³ d +41.04° (DMSO);

³ H NMR (DMSO-dé) 1.90 (m, 2H), 2.25 (m, 2H), 2.52 (m, 2H), 2.85 (m, IH), 3.02 (m, IH), 3.35 (m, 2H), 4.95 (s, IH), 7.54 (dd, IH, J=3), 7.65 (d, IH, J=9) Hz), 7.80 (d, IH, J=3 Hz),

9.90 (s, 1H);

MS (ESI-) m/z 393 (M-H);

Analytical calcd for C17H15CIN2O5S: C, 51.71; H, 3.83; N, 7.10. Found: C, 51.72; H, 3.85; N, 7.10.

Example 100

1,1-dioxide (9S)-9-(4-chloro-3-nitrophenyl)-3,4,5,6,7,9-hexahydrothieno[3,2-b]quinolin-8(2H)one

The product of Example 34 (1.64 g) was processed according to the methods of Example 95 and Example 96 to give 424 mg of the desired compound as a white solid. [] ²³ d -31.74°(DMSO);

Ή NMR (DMSO-do) 1.92 (m, 2H), 2.24 (m, 2H), 2.52 (m, 2H), 2.86 (m, 1H), 3.02 (m, 1H),

3.38 (m, 2H), 4.95 (s, IH), 7.54 (dd, IH, J=3 Hz), 7.66 (d, IH, J=9 Hz), 7.79 (d, IH, J=3 Hz), 9.89 (s, IH);

MS (ESI-) m/z 393 (M-H)';

Analytical calcd for C17H15CIN2O5S: C, 7.10; H, 3.83; N, 7.10. Found: C, 51.70; H, 3.83; N, 7.08.

Example 101

1 l-(3-bromo-4-fluorophenyl)-2,3,4,5,7,8,9,1 l-octahydrothiepino[3,2-b]quinolin-10(6H)-one 1,1-dioxide

A solution of 3-bromo-4-fluorobenzaldehyde (1.22 g, 6.00 mmol), 3-amino-2-cyclohexen-one (667 mg, 6.00 mmol) and 1,1-thiacycloheptan-3-one dioxide (973 mg, 6.00 mmol) (prepared according to the method described in J. Heterocycl. Chem. (1990,27,1453)) in ethanol (10 mL) with triethylamine (0.4 mL) was heated at 80°C in a sealed vessel for 3 days, cooled, the solid precipitate was collected, washed with ethanol and dried to give 1.8 g of the desired compound as a white solid.

Ή NMR (DMSO- d ) 1.65 (m, 1H), 1.75 (m, 2H), 1.90 (m, 1H), 2.02 (m, 2H), 2.52 (m, 2H), 2.75 (m, 3H), 3.15 (m, 1H), 4.95 (s, 1H), 7.20 (m, 1H), 7.25 (m, 1H). 7.40 (dd, 1 H, J=3 Hz),

9.44 (s, 1H);

MS (ESI+) m/z 441 (M+H) ⁺ ;

Analytical calcd for CuH18BrFNCbS: C, 51.83; H, 4.35; N, 3.18. Found: C, 51.59; H, 4.35; N, 3.18.

¹ U ···» · · * · * * * » - · · · · *·· * · ” ' . Λ » ··« ·* ··· ' “ »'

Example 102

10-(3-bromo-4-fluorophenyl)-2,3,4,5,6,7,8,10-octahydro-9H-cyclopenta[b]thiepino[2,3-e]pyridin9-one

A solution of 3-bromo-4-fluorobenzaldehyde (639 mg, 3.14 mmol); 3-amino-2-cyclopenten-one (305 mg, 3.14 mmol) and thiacycloheptan-3-one 1,1-dioxide (510 mg, 3.14 mmol) in ethanol (10 mL) was heated at 80°C in a sealed vessel for 3 days, cooled, the solid precipitate was collected, washed with ethanol and dried to give 700 mg of the desired compound as a white solid.

Melting point 210 °C;

'H NMR (DMSO-dó) 1.60 (m, IH), 1.82 (m, IH), 2.05 (m, 2H), 2.32 (m, 2H), 2.62 (m, 3H), 2.92 (m, 2H), 3.20 (m, IH), 4.75 (s, IH), 7.25 (dd, IH, J=3 Hz), 7.32 (m, IH), 7.45 (dd, IH, J=3 Hz), 10.02 (s, IH);

MS (ESI+) m/z 427 (M+H) ⁺ ;

Analytical calcd for _{C18H17BrFNO3S} : C, _50.71 ; H, 4.02; N, 3.29. Found: C, 50.71; H,

4.10; N, 3.20.

Determination of potassium channel opening activity

Determination of membrane hyperpolarization

Compounds were evaluated for potassium channel opening activity using rat thoracic aortic smooth muscle cell line A10 or primary cultured guinea pig urinary bladder (GPB) cells.

The A10 cell line was purchased from the American Type Culture Collection (Rockville,

MD; Cat # 30-2002). Cells were cultured in black 96-well clear-bottomed tubes (Packard) in culture medium (composition: Dulbecco's modified Eagle's medium supplemented with 20% fetal bovine serum, 100 units/ml penicillin, 100 units/ml streptomycin, and 0.25 mg/ml amphotericin B) at 37°C with 5% CO2 in a humidified chamber to form a confluent layer consisting of a single layer of cells.

To prepare bladder smooth muscle cells, the bladder was removed from a male guinea pig (Hartley, Charles River, Wilmington, MA) weighing 300 - 400 g and placed in ice-cold Ca ²⁺ -depleted Krebs solution (composition. mM: KCl, 2.7; KH2PO4, 1.5;

NaCl, 75; Na ₂ HPO ₄ , 9.6; Na ₂ HPO4*7H ₂ O, 8; MgSO ₄ , 2; glucose, 5; HEPES, 10; pH 7.4).

♦ ·

Cells were isolated by the enzymatic dissociation described above with minor modifications (Klockner, U. and Isenberg, G., Pflugers Arch. 1985, 405, 329-339). The bladder was dissected into several small portions and incubated in 5 ml of Krebs solution containing 1 mg/ml collagenase (Sigma, St. Louis, MO) and 0.2 mg/ml pronase (Calbiochem, La Jolla, CA) with constant agitation in a cell incubator for 30 minutes. The mixture was then centrifuged at 1300 xg for 5 minutes and the pellets were resuspended in Dulbecco's PBS (GIBCO, Gaithersburg, MD) and centrifuged again to remove residual enzyme. The cell pellets were resuspended in 5 ml of growth medium (composition: Dulbecco's modified Eagle's medium supplemented with 10% fetal bovine serum, 100 units/ml penicillin, 100 units/ml streptomycin, and 0.25 mg/ml amphotericin B) and further dissociated by pipetting the suspension with flame-sterilized Pasteur pipettes and passing through a polypropylene mesh membrane (Spectrum, Houston, TX). The cell density was adjusted to 100,000 cells/ml by resuspension in growth medium. For membrane potential studies, cells were plated in black 96-well clear-bottom plates (Packard) at a density of 20,000 cells/tube and maintained in a cell incubator with 90% air: 10% _CO2 until confluent. Verification of smooth muscle cell type was performed by cytoskeletal labeling using mouse-derived monoclonal anti-human smooth muscle actin (Biomeda, Foster City, CA).

Functional activity in potassium channels was measured by evaluating changes in membrane potential using the bis-oxonal dye DiBAC(4)3 (Molecular Probes) in a 96-tube Fluorescent Imaging Plate Reader (FLIPR) kinetic assay system (KS Schroeder et al., J. Biomed. Screen., v. 1, 75-81 (1996)). DIBAC(4)3 is an anionic potentiometric sensor that partitions into two phases, the cellular phase and the extracellular solution phase, depending on the membrane potential. With increasing membrane potential (e.g., depolarization of K ⁺ ), the sensor further partitions into the cellular phase; this is measured as an increase in fluorescence due to interactions of the dye with intracellular lipids and proteins. Conversely, with decreasing membrane potential (hyperpolarization by potassium channel openers) causes a decrease in fluorescence.

Confluent A10 smooth muscle cells or guinea pig bladder cells cultured in 96-well black tube plates were rinsed with 2 x 200 ml of assay buffer (composition, mM: HEPES, 20; NaCl, 120; KC1, 2; CaCl ₂ . 2; MgCl ₂ . 1; glucose,

5; pH 7.4 at 25°C) containing 5 M DIBAC(4) ₃ and incubated with 180 ml of buffer •9W ··-·*?

solution in a cell incubator for 30 minutes at 37°C to ensure distribution of the dye across the membrane. After recording the baseline fluorescence for 5 minutes, reference or test compounds prepared at tenfold concentration in assay buffer were added directly to the tubes. Changes in fluorescence were monitored for an additional 25 minutes. Hyperpolarization responses were corrected for any intrinsic noise and normalized to responses observed with 10 M of the reference compound P1075 (determined as 100%), a potent opener of _ΚΑ ·π> smooth muscle channels (Quast et al., Mol. Pharmacol., v. 43 474-481 (1993)).

Five concentrations of P1075 or test compounds (logarithmic or half-logarithmic dilutions) were calculated and the values of the maximal steady-state hyperpolarization (expressed as % relative to P1075) plotted as a function of concentration. EC50 values (the concentration that elicits 50% of the maximal response for the test sample) were calculated by nonlinear regression analysis using a four-variable sigmoidal equation. The maximal responses of each compound (expressed as % relative to P1075) are shown below.

A stock solution of compounds was prepared in 100% DMSO and further dilutions were made in assay buffer and added to 96-well plates.

Table 1

Membrane hyperpolarization (MHP) in A10 cells and guinea pig bladder (GPB) cells MHP in A10 cells MHP in GPB cells

Example number Maximum response (%P1075) EC50(M) Maximum response (%P1075) EC50(M) .—- ¹ 93 2.1 -50- 2 73 -0770- 77 2.1 3 90 -E6- 110 1J 4 ”110 030 120 038 5 78 5.5 41 18 6 ' 48 - _n - 31 17 7 94 —o- 100 2.8 8 -56- -73- —ΓΟΟ 2.5 In 39 16 67 7.2 10 61 4.0 —ioo— 15 11 42 - _n - 29 20

kA-lk-XKWIffyWW<9gWWg‘^Wi'H

12 -34 ->T0- ro- —>ro— 13 110 2.0 roo 1.6 14 83 P.2 roo 1.8 15 74 5.7 95 '2.0 16 83 6.3 47 3.5 17 79 43 73 5:1 18 64 7.6 66 1.4 -fg- —ΓΟΟ tf 039 ΓΖΟ 043 -ZO- 52 10 76 3.0 21 33 >10 15 >10 -zz- 15 >10 71 3.6 -Z3- 49 3.6 91 3.0 -- 76 3.9 roo 1.4 25 90 ' 1.8 110 0754 26 42 ' 44..... 93 372 27 40 377 75 333 -Z8- 42 3.6 78' 2.9 29 rro 034 ISO 0.46 30 91 3.8 97 2.3 - _J1 - -Γ00-- 0727 —roo 0.16 -32- -100- 0.64 —rro 044 33 —roo— 3.0 100 2.0 34 97 038 rro 033 33 93 2.4 91 1.1 36 96 1.7 110 048 -37- -IDO- 0.15 —rro -030 38 ' —roo— 0.51 140 0.44 39 ISO 0.35 rust O7T7 40 ΓΖΟ -033- 130 ' 0.15 41 -IZO- 1.0 I30~ 032 42 57 3.7 69 3.9 -43- 44 . —roo— 038 —rust O.b 45 77 3.8 -52- 2.4

-- —ΠΙΟ 0713- -49- 92...... ^. 0.56 -50- 87 1.4 51 102 0793 -- 79 4.3 53 Γ03 0740" 54 Γ07 3.2 55 103 2.6 54 133 0.11 -- Γ04 0712 -58- Γ24 0737 59 0' 0 60 117 07076 -- 101 07059 62 0 0 63 50 3.2 64 88 0739 65 96 0724 66 90 0721 67 84 0774 68 99 ' 1.9 69 99..... 0724 70 93 0.15 71 57 5.4 72 9/ 07042 73 102 2.7 74 90 0752 75 79 1.7 76 67 1.8 77 Γ09 0722 78 ΓΠ 2.7 79 116 0773 -80- -108- 0752 81 110 07078

-52- -53- 6.5 -53- 91 0353 -- 95 0.11' -55- 79~ 033 86 85 1.1 -87- 93 0344 -SB- 90 035 -59 79 0350 -90- 83 0328 -91- 44 15 -92- 93 0352 93 and 14 Γ21 -95- 86 0355 - _g? - 86 0315 -95- 96 ~ 0315 -102- 84 2.3

In vitro functional models

The compounds were evaluated for functional activity to open potassium channels using tissue sections obtained from Landrace pig bladders and human subjects.

Landrace pig bladders were obtained from female Landrace pigs weighing 9-30 kg. The subjects were sacrificed by intraperitoneal injection of pentobarbital solution, Somlethal®, JA Webster Inc., Sterling MA. The entire bladder was removed and immediately placed in Krebs's saline bicarbonate solution (composition, mM: NaCl, 120; NaHCO3, 20; dextrose, 11; KCl, 4.7; _CaCl2 , 2.5; _MgSO4 , _1.5 ; _KH2PO4 , 1.2; _K2EDTA , 0.01, equilibrated in 5% _CO2 /95% _O2 pH 7.4 at 37°C). Propranolol (0.004 mM) was included in all assays to block adrenoceptors. The trigeminal and superior portions were removed. Strips 3-5 mm wide and 20 mm long were prepared from the remaining tissue by radial incision and the mucosal layer was removed. One end was attached to a rigid glass rod and the other to a Grass FT03 transducer at a pre-basal load of 1.0 grams. The rigid glass rod contained two parallel platinum electrodes to provide field stimulation of 0.05 Hz, 0.5 milliseconds at 20 volts. This low frequency stimulation produced stable

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response of contractions of 100-500 centigrams. Tissues were allowed to equilibrate for at least 60 minutes and treated with 80 mM KCl. A control concentration (cumulative) response curve was generated for each tissue using P1075, a potassium channel opener, as a control agonist. P1075 completely eliminated stimulated contractions in a dose-dependent manner over a concentration range of 10' ⁹ - 10' ⁵ M at 1/2 log steps. After a 60 minute washout, a concentration (cumulative) response curve was generated for the test agonists in the same manner as for the control agonist P1075. The maximal potency of each compound (expressed as % relative to P1075) is shown below. The amount of agent required to produce 50% of the maximal response (ED50) for the test sample was calculated using "ALLFIT" (DeLean et al., Am. J. Physiol., 235, E97 (1980)) and the agonist potency was expressed as pD2 (negative logarithm). Agonist potency was also expressed as an index relative to P1075. The index was calculated by dividing the ED50 value for P1075 by the ED50 value of the test agonist in that tissue. Each tissue was used for only one test agonist and the data obtained from each tissue were averaged to obtain an average potency index. These data are shown in Table 2.

Human bladders were obtained from women over 45 years of age. Human tissue was provided by the Anatomy Gift Foundation, Phoenix AZ and was delivered the next day on wet ice placed in Krebs's bicarbonate saline (composition:, mM: NaCl, 120; NaHCO ₃ , 20; dextrose, 11; KC1, 4.7; CaCl ₂ , 2.5; MgSO ₄ , 1.5; KH ₂ PO ₄ , 1.2; K ₂ EDTA, 0.01; equilibrated in 5% CO 2 /95% O ₂ pH 7.4 at 37°C). Propranolol (0.004 mM) was included in all assays to block adrenoceptors. Triangular and upper portions were removed.

Strips 3-5 mm wide and 20 mm long were prepared from the remaining tissue, cut radially, and the mucosal layer was removed. For human detrusor strips, the tissues were concentrated with 25 mM KCl, which produced a steady state pressure of approximately 400 centigrams. A control concentration (cumulative) response curve was generated for each tissue using P1075, a potassium channel opener, as a control agonist. P1075 fully relaxed the stimulated contractions over a concentration range of 10' ⁹ - 10' ⁴ M at 1/2 log steps. After a 60 minute washout, a concentration (cumulative) response curve was generated for the test agonists in the same manner as for the control agonist P1075. The maximal potency of each compound (expressed as % relative to P1075) is shown below. The amount of agent required to produce 50% of the maximal response (ED50) for the test sample was calculated using "ALLFIT" (DeLean et al., Am. J. Physiol., 235, E97 (1980)) and the agonist potency was expressed as pD ₂ (negative logarithm). The agonist potency was also expressed as an index relative to P1075.

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The index was calculated by dividing the ED50 value for P1075 by the ED50 value of the test agonist in the indicated tissue. Each tissue was used for only one test agonist and the data obtained from each tissue were averaged to obtain an average potency index. These data are shown in Table 2.

Example number Landrace pig bladder Human bladder Efficiency (%P1075) ρϋ2 Index Efficiency (%Ρ1075) ρϋ2 index 19” 94 6.0 07Π ΓΟΟ 578 Ο7Τ5 2 96 537 0.15 1 Γ00 5.5 0.022"' 16 Γ00 5.0 ~(Π)Π— 11 —ιοο— 4.1 0.ΟΟ21 5 96 4.8 0.0076 3 85 6.0 0.11 8 95- 5.0 “07025” 4 93 6.2 —07Γ8— 36 97 5.5 07040 26 78 4.5 0.0099” 25 -88- 5.4 '0038 23 81 4.4 “070053” 22 ΊΊ 4.5 “00059” 34 —100— 6.8 032 38 98 6.2 0714 40 98 6.9 045 30 99 5.5 '' 0.018....... 44 99 6.2 ' 0715 43 . ' 98 6.6 041 51 99 5.4 0.023” 52 —roo— -575- ' ϋΟΙ'8”' 53 —roo— -50- —0717— 54 89 —ο— O7OT5 56 97 -77Γ- '' 0788“

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-- —roo— —ο— —032— -- -94- 5.3 0.026 — _5σ — —roo— 6.9 030 61 —roo— 7.1 —0771 65 —roo— 6.0 0348 -55- 94 6.3 07ΓΖ - 69 98 6.2 0.15 70 —roo— -53- 07Γ3 72 97 6.6 033 -73- -98 4.4 O.OÚ22 -75- —roo— 6.1 0.081 - ₇₇ - 93 5.5 0345 —you- 91 6.4 039 -- —roo— -735- 037 -84- —roo— -578- 030 -85- —roo— 6.5 0.069 -87- —ΓΟΟ— -73- “030 -- -93- -43- 0.0034” - ₉₂ - —tos— 6.5 044

As shown in Tables 1 and 2, the compounds of the present invention reduce stimulated bladder contractions by opening potassium channels and are therefore effective in the treatment of disease prevention or disease amelioration.

The present invention also provides pharmaceutical compositions comprising the compounds of the present invention formulated together with one or more non-toxic pharmaceutically acceptable carriers. The pharmaceutical compositions may be specially formulated for oral administration in solid or liquid form, for parenteral injection, or for rectal administration.

The pharmaceutical compositions of the present invention may be administered to humans or other animals orally, rectally, parenterally, intracystically, intravaginally, intraperitoneally, or topically (as dusts, ointments, drops), buccally, or as an oral or nasal spray. The term "parenteral" as used herein refers to routes of administration that include intravenous, intramuscular, intraperitoneal, intrastemal, subcutaneous, and intraarticular injection and infusion.

Pharmaceutical preparations of the present invention for parenteral injection comprise pharmaceutically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, as well as sterile powders for reconstitution into sterile injectable solutions or dispersions before use. Examples of suitable aqueous and non-aqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, etc.) and suitable mixtures thereof, vegetable oils (such as olive oil) and injectable organic esters such as ethyl oleate. Intrinsic fluidity can be maintained, for example, by the use of coating agents such as lecithin, in the case of dispersions by maintaining the desired particle size and by the use of surfactants.

These preparations may also contain adjuvants such as stabilizing agents, detergents, emulsifiers and dispersants. Prevention against the action of microorganisms may be provided by the inclusion of various antibacterial agents and fungicides, e.g., paraben, chlorobutanol, phenolsorbic acid, etc. It may also be desirable to include isotonic agents such as sugar, sodium chloride, etc. Prolonged absorption of the injectable pharmaceutical form may be caused by the admixture of agents (such as aluminum monostearate and gelatin) which delay absorption.

In some cases, in order to prolong the effects of a drug, it is desired to slow the absorption of the drug from subcutaneous or intramuscular injection, which can be achieved by using a liquid suspension of a crystalline or amorphous substance with poor water solubility. The rate of absorption of the drug is then determined by the degree of solubility of this substance, which depends on the crystal size and crystalline form.

Alternatively, delayed absorption of a parenterally administered drug can be achieved by dissolving or suspending the drug in an oil vehicle.

Injectable depot forms are made by forming microscopically encapsulated drug matrices into biodegradable polymers, such as polylactidepolyglycolide. The rate of drug release can be controlled depending on the ratio of drug to polymer and the origin of the polymer particles used. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions that are compatible with body tissues.

Injectable formulations may be sterilized, for example, by filtration through a bacterial-retaining filter or by incorporating a sterilizing agent in the form of sterile solid preparations which may be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.

Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such dosage forms, the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier, such as sodium citrate or dicalcium phosphate, and/or a) fillers or extenders such as starch, lactose, sucrose, glucose, mannitol and orthosilicic acid, b) binders such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates and calcium carbonate, e) solution inhibitors such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) detergents such as cetyl alcohol and glycerol monostearate, h) adsorbents such as for example, kaolin and bentonite kaolin, and (i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets, and pills, the dosage forms may also contain a buffering agent.

Solid preparations of a similar type can also be used as fillers in lightly filled and densely filled gelatin capsules using such excipients as lactose or milk sugar, as well as polyethylene glycols of high relative molecular weight, etc.

Solid dosage forms, such as tablets, dragees, capsules, pills and granules, can be prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical formulation art. Solid dosage forms can optionally contain opacifying agents and can also be free of such preparations that release the active ingredients only or preferentially in a certain part of the intestinal tract, optionally to some extent delayed. Examples of encapsulating preparations that can be used include polymeric substances and waxes.

The active compounds may also be in microencapsulated form with one or more of the above-mentioned excipients.

Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs. In addition to the active compounds, liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents, solubilizing agents, and emulsifiers, such as ethyl alcohol, * » isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol,

1,3-butylene glycol, dimethylformamide, oils (especially cottonseed, peanut, corn, germ, olive, castor and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and sorbitan fatty acid esters and mixtures thereof.

In comparison to inert diluents, oral preparations may also include adjuvants, such as detergents, emulsifying and suspending agents, sweeteners, flavorings, and perfuming agents.

Suspensions, in addition to the active compounds, may contain suspending agents such as ethoxylated isostearyl alcohols, polyoxyethylene sorbitols and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.

Formulations for rectal or vaginal administration are preferably suppositories, which may be prepared by mixing the compounds of the invention with suitable, non-irritating excipients or carriers, such as cocoa butter, polyethylene glycols or wax suppositories, which are solid at room temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity to release the active compound.

The compounds of the present invention can also be administered in the form of liposomes.

As is known in the art, liposomes are generally derived from phospholipids or other lipid substances. Liposomes are formed by monolamellar or multilamellar hydrated liquid crystals which are dispersed in an aqueous medium. Any non-toxic, physiologically acceptable and usable lipid capable of forming liposomes may be used. The present liposome formulations may contain, in addition to the compounds of the present invention, stabilizers, preservatives, excipients, etc. Preferred lipids are synthetic or natural phospholipids and phosphatidylcholines (lecithins) used together or separately. Methods for forming liposomes are known in the art. See, for example, Prescott, Ed., Methods in Cell Biology, Volume XIV, Academic Press, New York, N. Y., (1976), pages 33 et seq.

The compounds of the present invention may be used in the form of pharmaceutically acceptable salts derived from inorganic or organic acids. The term "pharmaceutically acceptable salt" as used herein refers to those salts which, within the scope of sound medical judgment, are suitable for use in contact with human or lower animal tissues without toxicity, irritation, allergic reactions, etc., and which are proportionate to a reasonable benefit/risk ratio. Pharmaceutically acceptable salts are well known in the art, e.g., S. M. Berge, et al., describes pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 66: 1-19 (1977), incorporated herein by reference. The salts may be prepared in situ during the final isolation and purification of the compounds of the invention or separately by reacting the free base with a suitable organic acid. Examples of pharmaceutically acceptable, non-toxic acid addition salts include, but are not limited to, adipate, alginate, citrate, aspartate, benzenesulfonate, benzoate, bisulfate, butyrate, camphor, camphorsulfonate, digluconate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrogen chloride, hydrogen bromide, hydrogen iodide, 2-hydroxyethanesulfonate (isethionate), lactate, maleate, methanesulfonate,

2-naphthalenesulfonate, nicotinate, oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, glutamate, bicarbonate, p-toluenesulfonate and undecanoate. Also, basic nitrogen-containing groups can be quaternized with such agents as lower alkyl halides, such as methyl, ethyl, propyl and butyl chlorides, bromides and iodides; dialkyl sulfates such as dimethyl, diethyl, dibutyl and diamyl sulfates; long-chain halides, such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides; arylalkyl halides such as benzyl and phenethyl bromides and others. In this way, water- or oil-soluble or dispersible products are obtained. Examples of acids that can be used to form pharmaceutically acceptable acid addition salts include such inorganic acids as hydrochloric acid, hydrobromic acid, sulfuric acid and orthophosphoric acid, and such organic acids as oxalic acid, maleic acid, succinic acid and citric acid.

Base addition salts can be prepared in situ during the final isolation and purification of the compounds of the present invention by reacting the carboxylic acid-containing moiety with a suitable base, such as, for example, the hydroxide, carbonate, bicarbonate of a pharmaceutically acceptable metal cation or with ammonia or an organic primary, secondary or tertiary amine. Pharmaceutically acceptable salts include, but are not limited to, alkali metal or alkaline earth metal cations, such as lithium, sodium, potassium, calcium, magnesium or aluminum salts, and the like, and non-toxic quaternary ammonium salts and amine cations including ammonia, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, diethylamine, ethylamine, and the like. Other representative organic amines useful for forming base addition salts include ethylenediamine, ethanolamine, diethanolamine, piperidine, piperazine, and the like. Preferred salts of the compounds of the present invention include phosphate, tris-, and acetate salts.

Dosage forms for topical administration of the compounds of this invention include dusts, sprays, inhalants, and creams. The active compound is admixed under sterile conditions with a pharmaceutically acceptable carrier and any necessary preservatives, buffers, or propellants as desired. Ophthalmic formulations, eye ointments, dusts, and solutions are also contemplated within the scope of the present invention.

The actual dosage level of the active compound component in the pharmaceutical compositions of the present invention may thus vary to provide an amount of the active compound(s) effective to achieve the desired therapeutic response for the individual patient, composition, and route of administration. The dosage level selected will depend on the activity of the individual compound, the route of administration, the severity of the condition being treated, and the prior medical history of the patient being treated. However, to achieve the desired therapeutic effect, it is known from experience that the dosage of the compound is started at lower levels than desired and gradually increased until the desired effect is achieved.

The compounds of the present invention, including but not limited to those specified in the Examples, have potassium channel opening activity in mammals (especially humans). As potassium channel openers, the compounds of the present invention are useful for the treatment and prevention of diseases such as asthma, epilepsy, hypertension, Raynaud's syndrome, impotence, migraine, pain, eating disorders, urinary incontinence, functional bowel disorders, neurodegeneration and stroke.

The ability of the compounds of the present invention to treat asthma, epilepsy, hypertension, Raynaud's syndrome, impotence, migraine, pain, eating disorders, urinary incontinence, functional bowel disorders, neurodegeneration and stroke can be demonstrated according to the methods described (D.E. Nurse et al., Br. J. Urol., v. 68, 27-31 (1991); B.B. Howe et al.,J.

Pharmacol. Exp. Ther., v. 274 884-890 (1995); K. Lawson, Pharmacol. Ther., V. 70 39-63 (1996); D.R. Gehlert et al., Neuro-Psychopharmacol & Biol.Psychiat., v. 18 1093-1102 (1994); M. Gopalakrishnan et al., Drug Development Research, v. 28 95-127 (1993); J.E. Freedman et al., The Neuroscientist, v. 2 145-152 (1996); D. Spanswick et al., Nature, v. 390 521 -25 (December 4, 1997)).

The aqueous liquid preparations of the present invention are particularly effective for the treatment and prevention of diseases such as asthma, epilepsy, hypertension, Raynaud's syndrome, impotence, migraine, pain, eating disorders, urinary incontinence, functional bowel disorders, neurodegeneration and stroke.

When the compounds of the present invention are used for the treatment of the above-mentioned diseases or for the treatment of other diseases, a therapeutically effective amount of one of the compounds of the present invention may be used in pure form or in the form of a pharmaceutically acceptable salt, ester or prodrug. Alternatively, the compound may be administered as a pharmaceutical composition comprising the desired compound in combination with one or more pharmaceutically acceptable excipients. By the term "therapeutically effective amount" of a compound of the invention is meant a sufficient amount of a compound of the invention to treat the disease at a reasonable benefit/risk ratio applicable to any medical treatment. However, it is understood that the total daily use of the compounds and compositions of the present invention is at the discretion of the attending physician, using sound medical judgment. The specific, therapeutically effective dosage level for any individual patient will depend on a variety of factors including the disease being treated and the severity of that disease; the activity of the specific compound being used; the use of the specific composition; the age, body weight, general health, sex and lifestyle of the patient; the time of administration, the route of administration, and the rate of excretion of the specific compound used; the duration of treatment; the drugs used in combination or in concert with the specific compound used; and similar factors well known in the art of medicine. For example, to achieve the desired therapeutic effect, it is known from experience to start with doses of the compound at lower levels than desired and gradually increase the doses until the desired effect is achieved.

The total daily dose of the compounds of this invention administered to humans or lower mammals may range from about 0.003 to 10 mg/kg/day. For oral administration, doses in the range of about 0.01 to about 5 mg/kg/day are more preferred. If desired, the effective daily dose for administration may be divided into several doses; consequently, a single dose may contain such amounts or fractions thereof as to constitute the daily dose.

Claims (40)

A compound of formula (I) or pharmaceutically acceptable salts, esters, amides, or prodrugs thereof, wherein R ¹ is alkyl; R ² is selected from the group consisting of aryl and heteroaryl; aryl or heteroaryl may be optionally substituted; index n is 0-2; A is selected from the group consisting of hydrogen, alkyl and -X-R; R ³ is alkyl or haloalkyl; X is -C (O) - or -S (O) _P -, wherein the index p is 1-2; R ⁴ and R ⁵ are independently selected from the group consisting of hydrogen, alkyl or haloalkyl; or R ¹ and R ⁵ joined together form to the ring to which they are attached, A 5-membered, 6-membered or 7-membered one containing a sulfur atom with 1-2 double bonds and 0 2 oxo substituents; or the substituents A and R ⁴ taken together form to the ring to which they are attached a ring selected from the group consisting of a 5-membered, 6-membered or 7-membered carbocyclic ring with 1-2 double bonds and 0-1 oxo substituents az A 5-membered, 6-membered or 7-membered sulfur-containing ring with 1-2 double bonds and 0-2 oxo substituents, provided that at least one of R ¹ and R ⁵ or A and R ⁴ forms a ring. A compound according to claim 1, wherein the substituents A and R ⁴ together with the ring to which they are attached form a 6-membered carbocyclic ring with one double bond and one oxo substituent. V · ',: / T ... The compound of claim 2, wherein R ¹ and R ⁵ together with the ring to which they are attached form a 6-membered ring containing a sulfur atom with one double bond and two oxo substituents. The compound of claim 3, wherein R ² is optionally substituted aryl. A compound according to claim 4 selected from the group consisting of: 3,4,6,7,8,10-Hexahydro-10-phenyl-2H-thiopyrano [3,2-b] quinolin-9- (5H) -one, 1,1-dioxide; 3,4,6,7,8,10-Hexahydro-10- (3-nitrophenyl) -2H-thiopyrano [3,2-b] quinolin-9 (5H) -one, 1,1-dioxide; 10- (3-cyanophenyl) -3,4,6,7,8,10-hexahydro-2H-thiopyrano [3,2-b] quinolin-9 (5H) -one, 1,1-dioxide; 3,4,6,7,8,10-Hexahydro-10- [3- (trifluoromethyl) phenyl] -2H-thiopyrano [3,2-b] quinolin-9 (5H) -one, 1,1-dioxide; 10- (3-bromophenyl) -3,4,6,7,8,10-hexahydro-2H-thiopyrano [3,2-b] quinolin-9 (5H) -one, 1,1-dioxide; 10- (3-Fluorophenyl) -3,4,6,7,8,10-hexahydro-2H-thiopyrano [3,2-b] quinolin-9 (5H) -one, 1,1-dioxide; 10- (3-chlorophenyl) -3,4,6,7,8,10-hexahydro-2H-thiopyrano [3,2-b] quinolin-9 (5H) -one, 1,1-dioxide; 3,4,6,7,8,10-Hexahydro-10- [4- (trifluoromethyl) phenyl] -2H-thiopyrano [3,2-b] quinolin-9 (5H) -one, 1,1-dioxide; 10- (4-bromophenyl) -3,4,6,7,8,10-hexahydro-2H-thiopyrano [3,2-b] quinolin-9 (5H) -one, 1,1-dioxide; 10- (3,4-dichlorophenyl) -3,4,6,7,8,10-hexahydro-2H-thiopyrano [3,2-b] quinolin-9 (5H) -one, 1,1-dioxide; 10- (3-chloro-4-fluorophenyl) -3,4,6,7,8,10-hexahydro-2H-thiopyrano [3,2-b] quinolin-9 (5H) -one, 1,1-dioxide; 10- (3-bromo-4-fluorophenyl) -3,4,6,7,8,10-hexahydro-2H-thiopyrano [3,2-b] quinolin-9 (5H) -one, 1,1-dioxide; 10- (3,4-difluorophenyl) -3,4,6,7,8,10-hexahydro-2H-thiopyrano [3,2-b] quinolin-9 (5H) -one, 1,1-dioxide; 10- [3-fluoro-5- (trifluoromethyl) phenyl] -3,4,6,7,8,10-hexahydro-2H79-thiopyrano [3,2-b] quinolin-9 (5H) - 1,1-dioxide onu; 10- [4-fluoro-3- (trifluoromethyl) phenyl] -3,4,6,7,8,10-hexahydro-2H-thiopyrano [3,2-b] quinolin-9 (5H) -one, 1,1-dioxide ; 3,4,6,7,8,10-Hexahydro-10- (4-methyl-3-nitrophenyl) 2H-thiopyrano [3,2-b] quinolin-9 (5H) -one, 1,1-dioxide; 10- (4-chloro-3-fluorophenyl) -3,4,6,7,8,10-hexahydro-2H-thiopyrano [3,2-b] quinolin-9 (5H) -one, 1,1-dioxide; 10- (4-chloro-3-nitrophenyl) -3,4,6,7,8,10-hexahydro-2H-thiopyrano [3,2-b] quinolin-9 (5H) -one, 1,1-dioxide; 3,4,6,7,8,10-Hexahydro-10- (3,4,5-trifluorophenyl) -2H-thiopyrano [3,2-b] quinolin-9 (5H) -one, 1,1-dioxide. The compound of claim 3, wherein R ² is optionally substituted heteroaryl. A compound according to claim 6 selected from the group consisting of. 10- (3-pyridyl) -3,4,6,7,8,10-hexahydro-2H-thiopyrano [3,2-b] quinolin-9 (5H) -one, 1,1-dioxide; 10- (4-Pyridyl) -3,4,6,7,8,10-hexahydro-2H-thiopyrano [3,2-b] quinolin-9 (5H) -one, 1,1-dioxide. The compound of claim 2, wherein R ¹ and R ⁵ together with the ring to which they are attached form a 5-membered ring containing a sulfur atom with one double bond and two oxo substituents. The compound of claim 8, wherein R ² is optionally substituted aryl. The compound of claim 9 selected from the group consisting of. 9- (3-cyanophenyl) -3,4,5,6,7,9-hexahydrothieno [3,2-b] quinolin-8 (2H) -one, 1,1-dioxide; 9- (3-nitrophenyl) -3,4,5,6,7,9-hexahydrothieno [3,2-b] quinolin-8 (2H) -one, 1,1-dioxide; 9- (3,4-dichlorophenyl) -3,4,5,6,7,9-hexahydrothieno [3,2-b] quinolin-8 (2H) -one, 1,1-dioxide; 9- [4-fluoro-3- (trifluoromethyl) phenyl] -3,4,5,6,7,9-hexahydrothieno [3,2-b] quinolin-8 (2H) -one, 1,1-dioxide; 3,4,5,6,7,9-hexahydro-9- (4-methyl-3-nitrophenyl) thieno [3,2-b] quinolin-8 (2H) -one, 1,1-dioxide; 9- (3,4-difluorophenyl) -3,4,5,6,7,9-hexahydrothieno [3,2-b] quinolin-8 (2H) -one, 1,1-dioxide; 9- (4-chloro-3-nitrophenyl) -3,4,5,6,7,9-hexahydrothieno [3,2-b] quinolin-8 (2H) -one, 1,1-dioxide; and 9- (3-bromo-4-fluorophenyl) -3,4,5,6,7,9-hexahydrothieno [3,2-b] quinolin-8 (2H) -one, 1,1-dioxide. The compound of claim 2, wherein R ¹ and R ⁵ are alkyl. The compound of claim 11, wherein R ² is optionally substituted aryl. A compound according to claim 12 selected from the group consisting of: 4- (3-cyanophenyl) -4,6,7,8-tetrahydro-2-methyl-3 (methylsulfonyl) -5 (1H) -quinolinone; 4,6,7,8-tetrahydro-2-methyl-3- (methylsulfonyl) -4 (3-nitrophenyl) -5 (1H) -quinolinone; 4.6.7.8-tetrahydro-2-methyl-3- (methylsulfonyl) -4- [4- (trifluoromethyl) phenyl] -5 (1H) -quinolinone; 4- (3,4-dichlorophenyl) -4,6,7,8-tetrahydro-2-methyl-3- (methylsulfonyl) -5 (1H) -quinolinone; 4.6.7.8-tetrahydro-2-methyl-4- (4-methyl-3-nitrophenyl) -3 (methylsulfonyl) -5 (1H) -quinolinone; 4- (4-chloro-3-nitrophenyl) -4,6,7,8-tetrahydro-2-methyl-3 (methylsulfonyl) -5 (1H) -quinolinone; 4- (3-bromo-4-fluorophenyl) -4,6,7,8-tetrahydro-2-methyl-3- (methylsulfonyl) -5 (1H) -quinolinone; 4- (4-chloro-3-fluorophenyl) -4,6,7,8-tetrahydro-2-methyl-3- (methylsulfonyl) -5 (1H) -quinolinone; and 4- (3,4,5-trifluorophenyl) -4,6,7,8-tetrahydro-2-methyl-3- (methylsulfonyl) -5 (1H) -quinolinone; The compound of claim 1, wherein the substituents A and R ⁴ together with the ring to which they are attached form a 5-membered carbocyclic ring with one double bond and one oxo substituent. The compound of claim 14, wherein R ¹ and R ⁵ together with the ring to which they are attached form a 6-membered ring containing a sulfur atom with one double bond and two oxo substituents. The compound of claim 15, wherein R ² is optionally substituted aryl. A compound according to claim 16 selected from the group consisting of: 9- (3-cyano) -3,4,5,6,7,9-hexahydrocyclopenta [b] thiopyrano [2,3-e] pyridin-8 (2H) -one, 1,1-dioxide; 9- (3,4-dichlorophenyl) -3,4,5,6,7,9-hexahydrocyclopenta [b] thiopyrano [2,3-e] pyridin-8 (2H) -one, 1,1-dioxide; 9- (4-chloro-3-nitrophenyl) -3,4,5,6,7,9-hexahydrocyclopenta [b] thiopyrano [2,3-e] pyridin-8 (2H) -one, 1,1-dioxide; 9- (3-chloro-4-fluorophenyl) -3,4,5,6,7,9-hexahydrocyclopenta [b] thiopyrano [2,3-e] pyridin-8 (2H) -one, 1,1-dioxide; 9- (3-bromo-4-fluorophenyl) -3,4,5,6,7,9-hexahydrocyclopenta [b] thiopyrano [2,3-e] pyridin-8 (2H) -one, 1,1-dioxide; 9- (4-fluoro-3-trifluoromethyl) -3,4,5,6,7,9-hexahydrocyclopenta [b] thiopyrano [2,3-e] pyridin-8 (2H) -one, 1,1-dioxide; and 9- (4-Methyl-3-nitro) -3,4,5,6,7,9-hexahydrocyclopenta [b] thiopyrano [2,3-e] pyridin-8 (2H) -one, 1,1-dioxide. The compound of claim 14, wherein R ¹ and R ⁵ together with the ring to which they are attached form a 5-membered ring containing a sulfur atom with one double bond and two oxo substituents. The compound of claim 18, wherein R ² is optionally substituted aryl. A compound according to claim 19 selected from the group consisting of: • · · 8- (4-Chloro-3-nitrophenyl) -3,5,6,8-tetrahydro-2H-cyclopenta [b] thieno [2,3-e] pyridin-7 (4H) -one, 1,1-dioxide; and 8- (3-Bromo-4-fluorophenyl) 3,5,6,8-tetrahydro-2H-cyclopenta [b] thieno [2,3-e] pyridin-7 (4H) -one, 1,1-dioxide. The compound of claim 1, wherein A is -XR, X is -C (O) -, and R ³ and R ⁴ are alkyl. The compound of claim 21, wherein R ¹ and R ⁵ together with the ring to which they are attached form a 6-membered ring containing a sulfur atom, with one double bond and two oxo substituents. The compound of claim 22, wherein R ² is optionally substituted aryl. The compound of claim 23 selected from the group consisting of: 1- [8- (3,4-Dichlorophenyl) -3,4,5,8-tetrahydro-6-methyl-1,1-dioxido-2H-thiopyrano [3,2-b] pyridin-7-yl] ethanone; 1- [8- (4-Chloro-3-nitrophenyl) -3,4,5,8-tetrahydro-6-methyl-1,1-dioxido-2H-thiopyrano [3,2-b] pyridin-7-yl] ethanone . The compound of claim 1, wherein the substituents A and R ⁴ together with the ring to which they are attached form a 6-membered carbocyclic ring containing a sulfur atom with one double bond and 0-2 oxo substituents. The compound of claim 25, wherein R ¹ and R ⁵ together with the ring to which they are attached form a 6-membered ring containing a sulfur atom with one double bond and 0-2 oxo substituents. The compound of claim 26, wherein R ² is optionally substituted aryl. A compound according to claim 27 which is 10,9- (4-chloro-3-nitrophenyl) -3,4,6,7,10-hexahydro-2H, 5H-bisthiopyrano [3,2- b: 2 ', 3'-e] pyridine; • A ¹ '* ...... ^{1 Ι} '. ··! .Φ · ¹ II I ', H'. 29. A compound selected from the group consisting of. 3,4,6,7,8,10-Hexahydro-10-phenyl-2H-thiopyrano [3,2-b] quinolin-9- (5H) -one, 1,1-dioxide; 3,4,6,7,8,10-Hexahydro-10- (3-nitrophenyl) -2H-thiopyrano [3,2-b] quinolin-9 (5H) -one, 1,1-dioxide; 10- (3-cyanophenyl) -3,4,6,7,8,10-hexahydro-2H-thiopyrano [3,2-b] quinolin-9 (5H) -one, 1,1-dioxide; 3,4,6,7,8,10-Hexahydro-10- [3- (trifluoromethyl) phenyl] -2H-thiopyrano [3,2-b] quinolin-9 (5H) -one, 1,1-dioxide; 10- (3-bromophenyl) -3,4,6,7,8,10-hexahydro-2H-thiopyrano [3,2-b] quinolin-9 (5H) -one, 1,1-dioxide; 10- (3-Fluorophenyl) -3,4,6,7,8,10-hexahydro-2H-thiopyrano [3,2-b] quinolin-9 (5H) -one, 1,1-dioxide; 10- (3-chlorophenyl) -3,4,6,7,8,10-hexahydro-2H-thiopyrano [3,2-b] quinolin-9 (5H) -one, 1,1-dioxide; 3,4,6,7,8,10-Hexahydro-10- [4- (trifluoromethyl) phenyl] -2H-thiopyrano [3,2-b] quinolin-9 (5H) -one, 1,1-dioxide; 10- (4-bromophenyl) -3,4,6,7,8,10-hexahydro-2H-thiopyrano [3,2-b] quinolin-9 (5H) -one, 1,1-dioxide; 10- (3,4-dichlorophenyl) -3,4,6,7,8,10-hexahydro-2H-thiopyrano [3,2-b] quinolin-9 (5H) -one, 1,1-dioxide; 10- (3-chloro-4-fluorophenyl) -3,4,6,7,8,10-hexahydro-2H-thiopyrano [3,2-b] quinolin-9 (5H) -one, 1,1-dioxide; 10- (3-bromo-4-fluorophenyl) -3,4,6,7,8,10-hexahydro-2H-thiopyrano [3,2-b] quinolin-9 (5H) -one, 1,1-dioxide; 10- (3,4-difluorophenyl) -3,4,6,7,8,14-hexahydro-2H-thiopyrano [3,2-b] quinolin-9 (5H) -one, 1,1-dioxide; 10- [3-Fluoro-5- (trifluoromethyl) phenyl] -3,4,6,7,8,10-hexahydro-2H-thiopyrano [3,2-b] quinolin-9 (5H) -one, 1,1-dioxide ; 10- [4-fluoro-3- (trifluoromethyl) phenyl] -3,4,6,7,8,10-hexahydro-2H-thiopyrano [3,2-b] quinolin-9 (5H) -one, 1,1-dioxide ; 3,4,6,7,8,10-hexahydro-10- (4-methyl-3-nitrophenyl) 2H-thiopyrano [3,2-b] quinolin-9 (5H) -one, 1,1-dioxide; 10- (4-chloro-3-fluorophenyl) -3,4,6,7,8,10-hexahydro-2H-thiopyrano [3,2-b] quinolin-9 (5H) -one, 1,1-dioxide; 10- (4-chloro-3-nitrophenyl) -3,4,6,7,8,10-hexahydro-2H-thiopyrano [3,2-b] quinolin-9 (5H) -one, 1,1-dioxide; 3,4,6,7,8,10-Hexahydro-10- (3,4,5-trifluorophenyl) -2H-thiopyrano [3,2-b] quinolin-9 (5H) -one, 1,1-dioxide; 10- (3-pyridyl) -3,4,6,7,8,10-hexahydro-2H-thiopyrano [3,2-b] quinolin-9 (5H) -one, 1,1-dioxide; 10- (4-pyridyl) -3,4,6,7,8,10-hexahydro-2H-thiopyrano [3,2-b] quinolin-9 (5H) -one, 1,1-dioxide; 9- (3-cyanophenyl) -3,4,5,6,7,9-hexahydrothieno [3,2-b] quinolin-8 (2H) -one, 1,1-dioxide; 9- (3-nitrophenyl) -3,4,5,6,7,9-hexahydrothieno [3,2-b] quinolin-8 (2H) -one, 1,1-dioxide; 9- (3,4-dichlorophenyl) -3,4,5,6,7,9-hexahydrothieno [3,2-b] quinolin-8 (2H) -one, 1,1-dioxide; 9- [4-fluoro-3- (trifluoromethyl) phenyl] -3,4,5,6,7,9-hexahydrothieno [3,2-b] quinolin-8 (2H) -one, 1,1-dioxide; 3,4,5,6,7,9-hexahydro-9- (4-methyl-3-nitrophenyl) thieno [3,2-b] quinolin-8 (2H) -one, 1,1-dioxide; 9- (3,4-difluorophenyl) -3,4,5,6,7,9-hexahydrothieno [3,2-b] quinolin-8 (2H) -one, 1,1-dioxide; 9- (4-chloro-3-nitrophenyl) -3,4,5,6,7,9-hexahydrothieno [3,2-b] quinolin-8 (2H) -one 1,1-dioxide; 9- (3-bromo-4-fluorophenyl) -3,4,5,6,7,9-hexahydrothieno [3,2-e] quinolin-8 (2H) -one 1,1-dioxide; 4- (3-cyanophenyl) -4,6,7,8-tetrahydro-2-methyl-3 (methylsulfonyl) -5 (1H) -quinolinone; 4,6,7,8-tetrahydro-2-methyl-3- (methylsulfonyl) -4 (3-nitrophenyl) -5 (1H) -quinolinone; 4,6,7,8-tetrahydro-2-methyl-3- (methylsulfonyl) -4- [4- (trifluoromethyl) phenyl] -5 (1H) -quinolinone; 4- (3,4-dichlorophenyl) -4,6,7,8-tetrahydro-2-methyl-3- (methylsulfonyl) -5 (1H) -quinolinone; .. .... »• .... .... .... .... .... .... .... .... .... 4,6,7,8-tetrahydro-2-methyl-4- (4-methyl-3-nitrophenyl) -3 (methylsulfonyl) -5 (1H) -quinolinone 1,1-dioxide; 4- (4-chloro-3-nitrophenyl) -4,6,7,8-tetrahydro-2-methyl-3 (methylsulfonyl) -5 (1H) -quinolinone; 4- (3-bromo-4-fluorophenyl) -4,6,7,8-tetrahydro-2-methyl-3- (methylsulfonyl) -5 (1H) -quinolinone; 4- (4-chloro-3-fluorophenyl) -4,6,7,8-tetrahydro-2-methyl-3- (methylsulfonyl) -5 (1H) -quinolinone; 4- (3,4,5-trifluorophenyl) -4,6,7,8-tetrahydro-2-methyl-3- (methylsulfonyl) -5 (1H) -quinolinone; 9- (3-cyano) -3,4,5,6,7,9-hexahydrocyclopenta [b] thiopyrano [2,3-e] pyridin-8 (2H) -one, 1,1-dioxide; 9- (3,4-dichlorophenyl) -3,4,5,6,7,9-hexahydrocyclopenta [b] thiopyrano [2,3-e] pyridin-8 (2H) -one, 1,1-dioxide; 9- (4-chloro-3-nitrophenyl) -3,4,5,6,7,9-hexahydrocyclopenta [b] thiopyrano [2,3-e] pyridin-8 (2H) -one, 1,1-dioxide; 9- (3-chloro-4-fluorophenyl) -3,4,5,6,7,9-hexahydrocyclopenta [b] thiopyrano [2,3-e] pyridin-8 (2H) -one, 1,1-dioxide; 9- (3-bromo-4-fluorophenyl) -3,4,5,6,7,9-hexahydrocyclopenta [b] thiopyrano [2,3-e] pyridin-8 (2H) -one, 1,1-dioxide; 9- (4-fluoro-3-trifluoromethyl) -3,4,5,6,7,9-hexahydrocyclopenta [b] thiopyrano [2,3-e] pyridin-8 (2H) -one, 1,1-dioxide; 9- (4-methyl-3-nitro) -3,4,5,6,7,9-hexahydrocyclopenta [b] thiopyrano [2,3-e] pyridin-8 (2H) -one, 1,1-dioxide; 8- (4-Chloro-3-nitrophenyl) -3,5,6,8-tetrahydro-2H-cyclopenta [b] thieno [2,3-e] pyridin-7- (4H) -one, 1,1-dioxide; 8- (3-bromo-4-fluorophenyl) -3,5,6,8-tetrahydro-2H-cyclopenta [b] thieno [2,3-e] pyridin-7 (4H) -one, 1,1-dioxide; 1- [8- (3,4-dichlorophenyl) -3,4,5,8-tetrahydro-6-methyl-1,1-dioxido-2H-thiopyrano [3,2-b] pyridin-7-yl] ethanone; 1- [8- (4-Chloro-3-nitrophenyl) -3,4,5,8-tetrahydro-6-methyl-1,1-dioxido-2H-thiopyrano [3,2-b] pyridin-7-yl] ethanone ; 10- (4-chloro-3-nitrophenyl) -3,4,6,7,10-hexahydro-2H, 5H-bis-thiopyrano [3,2-b: 2 ', 3 ^, -e] 1,1,9,9-tetraoxide ] pyridine; Or pharmaceutically acceptable salts, esters, amides or prodrugs thereof. 30. A method of treating a disease comprising administering an effective amount of a compound of claim 1. The method of claim 30, wherein the disease is selected from the group consisting of asthma, epilepsy, hypertension, Raynaud's syndrome, impotence, migraine, pain, eating disorders, urinary incontinence, bowel functional disorders, neurodegeneration and stroke. or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof, wherein R ² is selected from the group consisting of aryl and heteroaryl; aryl or heteroaryl may be optionally substituted; n is 1 or 2; X is selected from the group consisting of -CH 2 -, -C (O) -, -S (O) -, or -S (O) ₂ -; and n and n are independently 1-3. The compound of claim 32, wherein R ² is optionally substituted aryl. The compound of claim 33, wherein said substituted aryl is substituted with substituents selected from the group consisting of halogen, nitro, cyano, and haloalkyl. The compound of claim 32, wherein R is optionally substituted heteroaryl. The compound of claim 35, wherein said substituted heteroaryl is substituted with substituents selected from the group consisting of halogen, nitro, cyano, and haloalkyl. A compound according to claim 32 selected from the group consisting of: 9- (3,4-difluorophenyl) -3,4,5,6,7,9-hexahydrocyclopenta [b] thiopyrano [2,3-e] pyridin-8 (2H) -one, 1,1-dioxide; 8- (4-Chloro-3-nitrophenyl) -2,3,4,5,6,8-hexahydrodithieno [3,2-b: 2H, 3i-e] pyridine, 1,1,7,7-tetraoxide; 8- (3-Cyanophenyl) -2,3,4,5,6,8-hexahydro-7H-cyclopenta [b] thieno [2,3-e] pyridin-7-one, 1,1-dioxide; 8- (3-bromo-4-fluorophenyl) -2,3,4,5,6,8-hexahydrodithieno [3,2-b: 2H, 3H-e] pyridine, 1,1,7,7-tetraoxide; 10- (3-bromo-4-fluorophenyl) -3,4,6,7,8,10-hexahydro-2H, 5H-dithiopyrano [3,2-b: 2H, 3i-e] 1,1,9,9-tetraoxide ] pyridine; 3,4,5,6,7,9-hexahydro-9- (3-nitrophenyl) cyclopenta [b] thiopyrano [2,3-e] pyridin-8 (2H) -one, 1,1-dioxide; 8- (3-bromo-4-fluorophenyl) -2,3,4,5,6,8-hexahydro-7H-cyclopenta [b] thieno [2,3-e] pyridin-7-one, 1,1-dioxide; 8- (4-fluoro-3-trifluoromethylphenyl) -2,3,4,5,6,8-hexahydro-7H-cyclopenta [b] thieno [2,3-e] pyridin-7-one, 1,1-dioxide; 2,3,4,5,6,8-hexahydro-8- (3-nitrophenyl) -7H-cyclopenta [b] thieno [2,3-e] pyridin-7-one, 1,1-dioxide; 3,4,6,7,8,10-hexahydro-10- (3-nitrophenyl) -2H, 5H-dithiopyrano [3,2b: 2H, 3i-e] pyridine 1,1,9,9-tetraoxide; 8- (3,4-dichlorophenyl) -2,3,4,5,6,8-hexahydro-7H-cyclopenta [b] thieno [2,3-e] pyridin-7-one, 1,1-dioxide; 8- (3-Chloro-4-fluorophenyl) -2,3,4,5,6,8-hexahydro-7H-cyclopenta [b] thieno [2,3-e] pyridin-7-one, 1,1-dioxide; 8- (3-Cyanophenyl) -2,3,4,5,6,8-hexahydrodithieno [3,2-b: 2H, 3H-e] pyridine 1,1,7,7-tetraoxide; 8- (2-Cyano-4-pyridinyl) -2,3,4,5,6,8-hexahydro-88-dioxide 7H-cyclopenta [b] thieno [2,3-e] pyridin-7-one; 8- (3-Bromo-phenyl) -2,3,4,5,6,8-hexahydro-7H-cyclopenta [b] thieno [2,3-e] pyridin-7-one, 1,1-dioxide; 8- (4-fluoro-3-trifluoromethylphenyl) -2,3,4,5,6,8-hexahydrodithieno [3,2b: 2H, 3i-e] pyridine, 1,1,7,7-tetraoxide; 8- (4-bromo-2-thienyl) -2,3,4,5,6,8-hexahydro-7H-cyclopenta [b] thieno [2,3-e] pyridin-7-one 1,1-dioxide; 8- (5-bromo-2-thienyl) -2,3,4,5,6,8-hexahydro-7H-cyclopenta [b] thieno [2,3-e] pyridin-7-one 1,1-dioxide ; 2,3,4,5,6,8-Hexahydro-8- (5-nitro-3-thienyl) -7H-cyclopenta [b] thieno [2,3-e] pyridin-7-one, 1,1-dioxide; 2,3,4,5,6,8-Hexahydro-8- (5-nitro-2-thienyl) -7H-cyclopenta [b] thieno [2,3-e] pyridin-7-one 1,1-dioxide ; 2,3,4,5,6,8-Hexahydro-8- (5-nitro-2-furyl) -7H-cyclopenta [b] thieno [2,3-e] pyridin-7-one, 1,1-dioxide; 8- (3,4-Dibromophenyl) -2,3,4,5,6,8-hexahydro-7H-cyclopenta [b] thieno [2,3-e] pyridin-7-one, 1,1-dioxide; 2,3,4,5,6,8-Hexahydro-8- (3-nitrophenyl) dithieno [3,2-b: 2H, 3H-e] pyridine 1,1,7,7-tetraoxide 8- (3-Chloro-4-fluorophenyl) -2,3,4,5,6,8-hexahydrodithieno [3,2-b: 2,1-e] pyridine 1,1,7,7-tetraoxide ; 8- (3,4-Chloro-phenyl) -2,3,4,5,6,8-hexahydrodithieno [3,2-b: 2H, 3H-pyridine] 1,1,7,7-tetraoxide; 8- (4-Bromo-phenyl) -2,3,4,5,6,8-hexahydro-7H-cyclopenta [b] thieno [2,3-e] pyridin-7-one, 1,1-dioxide; 8- (3,4-Difluorophenyl) -2,3,4,5,6,8-hexahydro-7H-cyclopenta [b] thieno [2,3-e] pyridin-7-one, 1,1-dioxide; 8- (4-Chloro-3-fluorophenyl) -2,3,4,5,6,8-hexahydro-7H-cyclopenta [b] thieno [2,3-e] pyridin-7-one, 1,1-dioxide; 9- (3-chloro-4-fluorophenyl) -2,3,5,6,7,9-hexahydrothieno [3,2-b] quinolin-8 (4H) -one, 1,1-dioxide; 8- (3-Cyano-4-fluorophenyl) -2,3,4,5,6,8-hexahydrodithieno [3,2-b: 2H, 3e] pyridine, 1,1,7,7-tetraoxide; - * · (► (+) (9R) -9- (3-bromo-4-fluorophenyl) -2,3,5,6,7,9-hexahydrothieno [3,2-b] quinolin-8 (4H) 1,1-dioxide -one; (-) (9S) -9- (3-Bromo-4-fluorophenyl) -2,3,5,6,7,9-hexahydrothieno [3,2-b] quinolin-8 (4H) 1,1-dioxide -one; 8- (2,1,3-Benzoxadiazol-5-yl) -2,3,4,5,6,8-hexahydro-7H-cyclopenta [b] thieno [2,3-e] pyridin-7-1,1-dioxide -one; (-) (8S) -8- (3-bromo-4-fluorophenyl) -2,3,4,5,6,8-hexahydro-7H-cyclopenta [b] thieno [2,3-e] 1,1-dioxide pyridin-7-one; (+) (8R) -8- (3-Bromo-4-fluorophenyl) -2,3,4,5,6,8-hexahydro-7H-cyclopenta [b] thieno [2,3-e] pyridine-7 -one; 9- (2,1,3-Benzoxadiazol-5-yl) -2,3,5,6,7,9-hexahydrothieno [3,2-b] quinolin-8 (4H) -one, 1,1-dioxide; 9- (4-fluoro-3-iodophenyl) -2,3,5,6,7,9-hexahydrothieno [3,2-b] quinolin-8 (4H) -one, 1,1-dioxide; 8- (4-fluoro-3-iodophenyl) -2,3,4,5,6,8-hexahydro-7H-cyclopenta [b] thieno [2,3-e] pyridin-7-one, 1,1-dioxide; (+) 9- (3-Bromo-4-fluorophenyl) -3,4,5,6,7,9-hexahydrocyclopenta [b] thiopyrano [2,3-e] pyridin-8 (2H) -one; (-) 9- (3-bromo-4-fluorophenyl) -3,4,5,6,7,9-hexahydrocyclopenta [b] thiopyrano [2,3-e] pyridin-8 (2H) -one; (+) 10- (3-Bromo-4-fluorophenyl) -3,4,6,7,8,10-hexahydro-2H-thiopyrano [3,2-b] quinolin-9 (5H) 1,1-dioxide -one; (-) 10- (3-Bromo-4-fluorophenyl) -3,4,6,7,8,10-hexahydro-2H-thiopyrano [3,2-b] quinolin-9 (5H) 1,1-dioxide -one; (+) (9R) -9- (3,4-Dichlorophenyl) -3,4,5,6,7,9-hexahydrothieno [3,2-b] quinolin-8 (2H) -one, 1,1-dioxide ; (-) (9S) -9- (3,4-dichlorophenyl) -3,4,5,6,7,9-hexahydrothieno [3,2-b] quinolin-8 (2H) -one, 1,1-dioxide ; (+) (9R) -9- (2,1,3-Benzoxadiazol-5-yl) -2,3,5,6,7,9-hexahydrothieno [3,2-b] quinolin-8 1,1-dioxide ( 4H) -one; (-) (9S) -9- (2,1,3-benzoxadiazol-5-yl) -2,3,5,6,7,9-hexahydrothieno [3,2-b] quinolin-8 (4H) - he; (+) (9R) -9- (4-Chloro-3-nitrophenyl) -3,4,5,6,7,990 hexahydrothieno [3,2-b] quinolin-8 (2H) -one, 1,1-dioxide; (-) (9S) -9- (4-Chloro-3-nitrophenyl) -3,4,5,6,7,9-hexahydrothieno [3,2-b] quinolin-8 (2H) -one, 1,1-dioxide ; 11- (3-bromo-4-fluorophenyl) -2,3,4,5,7,8,9,11-octahydrothiepino [3,2-b] quinolin-10 (6H) -one, 1,1-dioxide; and 10- (3-bromo-4-fluorophenyl) -2,3,4,5,6,7,8,10-octahydro-9H-cyclopenta [b] thiepino [2,3-e] pyridin-9-one or their pharmaceutically acceptable salts, esters, amides or prodrugs. 38. A method of treating a disease comprising administering an effective amount of a compound of claim 32. 39. The method of claim 38, wherein the disease is selected from the group consisting of asthma, epilepsy, hypertension, Raynaud's syndrome, impotence, migraine, pain, eating disorders, urinary incontinence, bowel functional disorders, neurodegeneration and stroke. 40. A method of treating a disease comprising administering an effective amount of a compound of claim 37. 41. The method of claim 40, wherein the disease is selected from the group consisting of asthma, epilepsy, hypertension, Raynaud's syndrome, impotence, migraine, pain, eating disorders, urinary incontinence, functional bowel disorders, neurodegeneration and stroke.