MXPA01004246A

MXPA01004246A - Dihydropyridine compounds and methods of use

Info

Publication number: MXPA01004246A
Application number: MXPA/A/2001/004246A
Authority: MX
Inventors: Michael E Kort; Philip R Kym; William A Carroll; Konstantinos A Agrios; Fatima Z Basha; Yiyuan Chen; Rui Tang; Sean C Turner; Lin Yi
Original assignee: Abbott Laboratories
Priority date: 1998-10-28
Filing date: 2001-04-27
Publication date: 2002-03-05

Abstract

Compounds having formula (I) are useful in treating diseases prevented by or ameliorated with potassium channel openers. Also disclosed are potassium channel opening compositions and a method of opening potassium channels in a mammal.

Description

COMPOUNDS OF DIHID OPIRIDINE AND METHODS OF USE This application is a partial continuation of the Application of the United States of America Serial Number 09 / 181,239, filed on October 28, 1998, and incorporated herein by reference.

TECHNICAL FIELD The novel dihydropyridine compounds and their derivatives can open potassium channels, and are useful for the treatment of a variety of medical conditions.

BACKGROUND OF THE INVENTION Potassium channels have an important role in regulating the excitability of the cell membrane. When the potassium channels are opened, changes in electrical potential occur through the cell membrane, and result in a more polarized state. A number of diseases or conditions can be treated with therapeutic agents that open the potassium channels; see (K. Lawson, Pharmacol. Ther., volume 70, pages 39-63 (1996)); (.D.R. Gehlert et al., Prog. Neuro-Psychopharmacol &Biol. Psychiat., Volume 18, pages 1093-1102 (1994)); (M. Gopala-krishnan et al., Drug Development Research, volume 28, pages 95-127 (1993)); (J.E. Freedman et al. The Neuroscientist, volume 2, pages 145-152 (1996)); (D.E. Nurse et al., Br. J. Urol., Volume 68, pages 27-31 (1991)); (B.B. Howe et al., J. Pharmacol. Exp. Ther., Volume 274 pages 884-890 (1995)); and (D. Spanswick et al., Nature, volume 390, pages 521-25 (December 4, 1997)). These diseases or conditions include asthma, epilepsy, hypertension, male sexual dysfunction, female sexual dysfunction, migraine, pain, urinary incontinence, embolism, Raynaud's syndrome, co-mer disorders, functional bowel disorders, and neurodegeneration. The potassium channel openers also act as smooth muscle relaxants. Because urinary incontinence can result from spontaneous uncontrolled contractions of the smooth muscle of the bladder, the ability of the potassium channel openers to hyperpolarize the bladder cells and relax the smooth muscle of the bladder provides a method to reduce or prevent urinary incontinence. Patent Numbers WO 9408966, EP 0539153 Al and EP 0539154 Al discloses a group of acridine dione and quinolone compounds that belong to the larger general chemical class of dihydropyridines. Dihydropyridines of different chemical structure may possess a variety of biological activities. Patents Nos. 3605742 Al and US 4,284,634 disclose compounds that are calcium channel antagonists. U.S. Patent No. 5,025,011 discloses pyridine compounds that possess both calcium channel and β-receptor blocking activity, while European Patent Number EP 299727 discloses compounds that act as a factor antagonist. platelet activator (PAF). The compounds of the present invention are novel, hyperpolarize cell membranes, open potassium channels, relax smooth muscle cells, inhibit bladder contractions, and are useful for the treatment of diseases that can be ameliorated by opening of potassium channels.

COMPENDIUM OF THE INVENTION In its main embodiment, the present invention provides compounds having the formula I: I, or a pharmaceutically acceptable salt, amide, ester, or prodrug thereof, wherein: n and n 'are independently from 1 to 3; A is selected from O, -NR2, and S; A 'is selected from O, -NR2', S, and CR4-R5; D is selected from CH2 and C (0); D 'is selected from CH2, C (0), S (0), and S (0) 2; Ri is selected from aryl and heterocycle; R2 and R2- are independently selected from hydrogen, alkoxyalkyl, alkyl, arylalkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, heterocycloalkyl, hydroxyl, hydroxyalkyl, -NZ? Z2, and (NZXZ2) alkyl, wherein Zi and Z2 are independently selected from from hydrogen, alkyl, alkylcarbonyl, aryl, arylalkyl, and formyl; R4- and R5- are independently selected from hydrogen and alkyl; Re. And R7. they are independently selected from hydrogen and alkyl; with the proviso that, when D is CH2, then D 'is different from CH2; with the proviso that when D 'is S (O) or S (0) 2, then A' is CR4-R5.; and with the proviso that the following compounds are excluded: 8- [2- (difluoromethoxy) phenyl] -1,7-dioxo-2,3,4,5,6,8-hexahydrodipyrrolo [3,4-b; 3, 4-e] pyridin-2,6-dipropanoic, (8- [2- (difluoromethoxy) phenyl] -1,7-dioxo-2, 3,4,5,6,8-hexahydrodipyrrolo dipropanate [3, 4-b; 3, 4-e] pyridin-2,6-ethyl, 8- [2- (difluoromethoxy) phenyl] -6-methyl-4,5,6,8-tetrahydro-lH-furo [3, 4 -b] pyrrolo [3, 4-e] pyridin-1, 7 (3H) -dione; 8- [2- (difluoromethoxy) phenyl] -2,6-dimethyl-2,3,4,5,6,8 hexahydrodipyrrolo [3, 4-b; 3,4-e] pyridin-1,7-dione; 2,6-dimethyl-8-phenyl-2, 3,4,5,6,8-hexahydrodipyrrolo [3, 4 -b; 3, 4-e] pyridin-1, 7-dione, 8- (3-nitrophenyl) -5,8-dihydro-lH, 3H-difuro [3,4- b; 3,4-e] pyridine - 1, 7 (4H) -dione, 8 - (2,4-dichlorophenyl) -5,8-dihydro-1H, 3H-difuro [3,4-b; 3, 4-e] pyridin-1, 7 ( 4H) -dione, 8- (4-methoxyphenyl) -5,8-dihydro-lH, 3H-difuro [3,4-b; 3,4-e] iridin-1,7 (4H) -dione, 8- (4-iodophenyl) -5,8-dihydro-lH, 3H-difuro [3,4- b; 3,4-e] pyridin-1,7 (4H) -dione, 8- (4-bromo-phenyl) -5 , 8-dihydro-lH, 3H-difuro [3,4-b; 3,4-e] pyridin-l, 7 (4H) -dione, 8- (3-bromo-phenyl) -5,8-di hydro-lH, 3H-difuro [3,4-b; 3,4-e] pyridin-1,7 (4H) -dione, 8- (2- (fluorophenyl) -5,8-dihydro-1H, 3H- difuro [3,4-b; 3,4-e] pyridin-l, 7 (4H) -dione, 8-phenyl-5,8-dihydro-lH, 3H-difuro [3,4-b; 3,4 -e] pyridin-1, 7 (4H) -dione, 8- (2-aminophenyl) -5,8-dihydro-lH, 3H-difuro [3,4-b; 3,4-e] pyridin-1, 7 (4H) -dione, 8- [2- (difluoromethoxy) phenyl] -5,8-dihydro-1H, 3H-difure [3, 4-b; 3, 4-e] pyridine-1,7 (4H) -dione, 8- (2-chlorophenyl) -5,8-dihydro-H, 3 H-dif [3, 4-b; 3,4-e] pyridin-1, 7 (4H) -dione, 8- (2, 3, 4-trimethoxyphenyl) -5,8-dihydro-1H, 3H-difure [3, 4-b; 3, 4-e] pyridine-1,7 (4H) -dione, 8- [2- (trifluoromethyl) phenyl] -5,8-dihydro-lH, 3H-difure [3, 4-b; 3, 4-e] pyridin-1, 7 (4H) -dione, 8- (2-chloro-3-nitrophenyl) -5,8-dihydro-1H, 3H-difure [3, 4-b; 3, 4-e] pyridine-1,7 (4H) -dione, 8- (4-nitrophenyl) -5,8-dihydro-lH, 3H-difuro [3,4-b; 3,4-e] pyridine - 1, 7 (4H) -dione, 8- (4-chlorophenyl) -5,8-dihydro-1H, 3H-difure [3, 4-b; 3, 4-e] pyridin-1, 7 (4H) -dione, 8- (3-chlorophenyl) -5,8-dihydro-1H, 3H-difuso [3, 4-b; 3, 4-e] pyridine - 1, 7 (4H) -dione, 8- (2-nitrophenyl) -5,8-dihydro-1H, 3H-difuro [3,4- b; 3, 4-e] iridin-1, 7 (4H) -dione, 3,7-dimethyl-10-phenyl-3,4,5,6,7,10-hexahydro-1H, 9H-dipyran [4, 3-b; 3, 4-e] pyridin-1,9-dione, 6,6-dimethyl-9-phenyl-5,6,7,9-tetrahydrofuro [3,4-b] quinolin-1, 8 (3H, 4H) -dione, 9- (1, 3-benzodioxol-5-yl) -5,6,7,9-tetrahydrofuro [3,4-b] quinolin-1, 8 (3H, 4H) -dione, 9- (3 -methoxyphenyl) -5,6,7,9-tetrahydrofuro [3,4-b] quinolin-1, 8 (3H, 4H) -dione, 9- (2-methoxyphenyl) -6,6-dimethyl-5,6 , 7,9-tetrahydrofuro [3,4-b] quinolin-1, 8 (3H, 4H) -dione, 6,6-dimethyl-9- (2-nitrophenyl) -5,6,7,9-tetrahydrofuro [ 3, 4-b] quinolin-1, 8 (3H, 4H) -dione, 6,6-dimethyl-9- [2- (trifluoromethyl) phenyl] -5,6,7,9-tetrahydrofuro [3, 4- b] quinolin-1, 8 [3H, 4H] -dione, and 9- [3- (benzyloxy) phenyl] -6,6-dimethyl-5,6,7,9-tetrahydrofuro [3,4-b] quinolin -1, 8 (3H, 4H) -dione.

DETAILED DESCRIPTION OF THE INVENTION All patents, patent applications, and literature references cited in the specification are hereby incorporated by reference in their entirety. In the case of inconsistencies, the present disclosure will prevail, including definitions. It is understood that the above detailed description and the accompanying examples are merely illustrative, and should not be construed as limitations on the scope of the invention, which is defined exclusively by the appended claims and their equivalents. Different changes and modifications to the modalities disclosed will be apparent to those skilled in the art. These changes and modifications, including, without limitation, those related to the chemical structures, substituents, derivatives, intermediates, syntheses, formulations, and / or methods of use of the invention, can be made without departing from their spirit and scope. In its main embodiment, the present invention provides compounds having the formula I: I, or a pharmaceutically acceptable salt, amide, ester, or prodrug thereof, wherein: n and n 'are independently from 1 to 3; A is selected from O, -NR2, and S; A 'is selected from 0, -NR2-, S, and CR4'R5', - D is selected from CH2 and C (0); D 'is selected from CH2, C (0), S (O), and S (0) 2; Ri is selected from aryl and heterocycle; R2 and R2- are independently selected from hydrogen, alkoxyalkyl, alkyl, arylalkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, heterocycloalkyl, hydroxyl, hydroxyalkyl, -NZ.Z2 / and (NZ? Z2) alkyl, wherein Zi and Z2 are independently selected from, hydrogen, alkyl, alkylcarbonyl, aryl, arylalkyl, and formyl; R4- and R5- are independently selected from hydrogen and alkyl; R6- and R7 'are independently selected from hydrogen and alkyl; with the proviso that, when D is CH2, then D 'is different from CH2; with the proviso that when D 'is S (O) or S (0) 2, then A' is CR4'R5 '; and with the proviso that the following compounds are excluded: 8- [2- (difluoromethoxy) phenyl] -1,7-dioxo-2,3,4,5,6,8-hexahydrodipyrrolo [3,4-b; 3, 4-e] pyridin-2,6-dipropanoic, (8- [2- (difluoromethoxy) phenyl] -1,7-dioxo-2, 3,4,5,6,8-hexahydrodipyrrolo dipropanate [3, 4-b; 3, 4-e] pyridin-2,6-ethyl, 8- [2- (difluoromethoxy) phenyl] -6-methyl-4,5,6,8-tetrahydro-lH-furo [3, 4 -b] pyrrolo [3, 4-e] pyridin-1, 7 (3H) -dione; 8- [2- (difluoromethoxy) phenyl] -2,6-dimethyl-2,3,4,5,6,8 hexahydrodipyrrolo [3, 4-b; 3,4-e] pyridin-1,7-dione; 2,6-dimethyl-8-phenyl-2,3,3,5,6,8-hexahydrodipyrrolo [3, 4] -b; 3,4-e] pyridin-1,7-dione, 8- (3-nitrophenyl) -5,8-dihydro-lH, 3H-difuro [3,4-b; 3,4-e] pyridine -1,7 (4H) -dione, 8- (2,4-dichlorophenyl) -5,8-dihydro-lH, 3H-difuro [3,4-b; 3,4-e] pyridin-1, 7 ( 4H) -dione, 8- (4-methoxyphenyl) -5,8-dihydro-lH, 3H-difuro [3,4- b; 3,4-e] pyridin-1, 7 (4H) -dione, 8- (4-iodophenyl) -5,8-dihydro-1H, 3H-difure [3, 4-b; 3,4-pyridin-1, 7 (4H) -dione, 8- (4-bromo-phenyl) -5 , 8-dihydro-lH, 3H-difuro [3,4-b; 3,4-e] pyridin-l, 7 (4H) -dione, 8- (3-bromophenyl) -5, 8- dihydro-lH, 3H-difuro [3,4- b; 3,4-e] pyridin-1, 7 (4H) -dione, 8- (2- (fluorophenyl) -5,8-dihydro-1H, 3H- difuro [3, 4-b; 3, 4-e] pyridin-1, 7 (4H) -dione, 8-phenyl-5,8-dihydro-lH, 3H-difuro [3,4-b; 3,4-e] pyridin-1, 7 (4H) -dione, 8- (2-aminophenyl) -5,8-dihydro-lH, 3H-difuro [3,4-b; 3, 4-e] pyridin-1, 7 (4H) -dione, 8- [2- (difluoromethoxy) phenyl] -5,8-dihydro-lH, 3H-difuro [3,4-b; 3, 4-e] pyridin-1, 7 (4H) -dione, 8- (2-chlorophenyl) -5,8-dihydro-lH, 3H-difuro [3,4-b; 3, 4-e] pyridin-1, 7 (4H) -dione, 8- (2, 3, 4-trimethoxyphenyl) -5,8-dihydro-1H, 3H-difure [3, 4-b; 3, 4-e] pyridin-1, 7 (4H) -dione, 8- [2- (trifluoromethyl) phenyl] -5,8-dihydro-lH, 3H-difuro [3,4- b; 3, 4-e] pyridin-1, 7 (4H) -dione, 8- (2-chloro-3-nitrophenyl) -5,8-dihydro-lH, 3H-difuro [3,4-b3,4-e! Pyridin-l, 7 (4H) -dione, 8- (4-nitrophenyl) -5,8-dihydro-lH, 3H-difuro [3,4- b; 3,4-e] pyridin-1, 7 (4H) -dione, 8- (4-chlorophenyl) -5,8-dihydro-1H, 3H-difuro [3,4-b; 3, 4-e] pyridin-1, 7 (4H) -dione, 8- (3-chlorophenyl) -5,8-dihydro-lH, 3H-difuro [3,4-b; 3,4-e] pyridine - 1, 7 (4H) -dione, 8- (2-nitrophenyl) -5,8-dihydro-lH, 3H-difure [3, 4-b; 3, 4-e] pyridin-1, 7 (4H) -dione, 3,7-dimethyl-10-phenyl-3, 4, 5, 6, 7, 10-hexahydro-1H, 9H-dipyran [4, 3 -b; 3, 4-e] pyridin-1,9-dione, 6,6-dimethyl-9-phenyl-5,6,7,9-tetrahydrofuro [3,4-b] quinolin-1, 8 (3H, 4H) -dione, 9 - (1,3-benzodioxol-5-yl) -5,6,7,9-tetrahydrofuro [3,4-b] quinolin-1, 8 (3H, 4H) -dione, 9- (3 -methoxyphenyl) -5,6,7,9-tetrahydrofuro [3,4-b] quinolin-1,8 (3H, 4H) -dione, 9- (2-methoxyphenyl) -6,6-dimethyl-5,6 , 7,9-tetrahydrofuro [3,4-b] quinolin-1, 8 (3H, 4H) -dione, 6,6-dimethyl-9- (2-nitrophenyl) -5,6,7,9-tetrahydrofuro [ 3, 4-b] quinolin-1, 8 (3H, 4H) -dione, 6,6-dimethyl-9- [2- (trifluoromethyl) phenyl] -5,6,7,9-tetrahydrofuro [3, 4- b] quinolin-1, 8 [3H, 4H] -dione, and 9- [3- (benzyloxy) phenyl] -6,6-dimethyl-5,6,7,9-tetrahydrofuro [3,4-b] quinolin -1, 8 (3H, 4H) -dione.

In another embodiment, the present invention provides compounds having the formula II: II, Or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof, wherein n, n ', A, AA Ri / Re-, and v are as defined in formula I. In another embodiment of the present invention, the compounds have the formula II, wherein A is NR2; A 'is NR2-; n 'is 1; and n, R1 # R2, R2-, R6A and v are as defined in formula I. In another embodiment of the present invention, the compounds have the formula II, wherein A is NR2; A 'is O; 1 is 1; and n is Ri, R2, R6-, and R7- are as defined in formula I. In another embodiment of the present invention, the compounds have the formula II, wherein A is NR2, A 'is S; n 'is 1; and n, Rx, R2, R6-, and R7 'are as defined in form-mule I. In another embodiment of the present invention, the compounds have the formula II, wherein A is NR2; A 'is CR4R5', - n 'is 1; and n, Rx, R2, -, s-, Re- / and R7 'are as defined in formula I. In another embodiment of the present invention, the compounds have the formula II, wherein A is O; A 'is NR2 *; n 'is 1; and n, Rlf R2 > , Rß > , and R - are as defined in formula I. In another embodiment of the present invention, the compounds have the formula II, wherein A is O; A 'is O; n 'is 1; and n, Ri, R6-, and R7- are as defined in formula I. In another embodiment of the present invention, the compounds have the formula II, wherein A is O; A 'is S; n 'is 1; and n, Ri, R6-, and R7- are as defined in formula I. In another embodiment of the present invention, the compounds have the formula II, wherein A is O; A 'is CR4'R5', - n 'is 1; and n, Ri, R4-, R5-, R6 < , and R7 < they are as defined in formula I. In another embodiment of the present invention, the compounds have the formula II, wherein A is S; A 'is NR2-; n 'is 1; and n, Rl t R2. , R6. , and R7. they are as defined in formula I. In another embodiment of the present invention, the compounds have the formula II, wherein A is S; A 'is O; n 'is 1; and n, Ri, R6-, and R7- are as defined in formula I. In another embodiment of the present invention, the compounds have the formula II, wherein A is S; A 'is S; n 'is 1; and n, Rl f R6 < , and R7- are as defined in formula I. In another embodiment of the present invention, the compounds have the formula II, wherein A is S; A 'is CR4'R5', - n 'is 1; and n, Ri, R 4 -, R 5 -, R 6 > , and R7 < they are as defined in formula I. In another embodiment of the present invention, the compounds have the formula II, wherein A is NR2; A 'is NR2'; n 'is 2; and n, Ri, R2, R2-, R6-, and R7- are as defined in formula I. In another embodiment of the present invention, the compounds have the formula II, wherein A is NR2; A 'is O; n 'is 2; and n, R ±, R2, R6-, and R7- are as defined in formula I. In another embodiment of the present invention, the compounds have the formula II, wherein A is NR2; A 'is S; n 'is 2; and n, R? , R2, Re-, and 7- are as defined in the form-mule I. In another embodiment of the present invention, the compounds have the formula II, wherein A is NR2; A 'is CR4'R5', - n 'is 2; and n, R. ,, R4-, R5-, R6-, and R7. they are as defined in formula I.

In another embodiment of the present invention, the compounds have the formula II, wherein A is O; A 'is NR2-; n 'is 2; and n, Rlf R2 < , R6-, and R7- are as defined in formula I. In another embodiment of the present invention, the compounds have the formula II, wherein A is 0; A 'is 0; n 'is 2; and n, Ri, Re-, and R7- are as defined in formula I. In another embodiment of the present invention, the compounds have the formula II, wherein A is O; A 'is S; n 'is 2; and n, R1 # R6-, and R7- are as defined in formula I. In another embodiment of the present invention, the compounds have the formula II, wherein A is 0; A 'is CR4'R5', - n 'is 2; and n, Ri # R4-, R5-, R6-, and R7- are as defined in formula I. In another embodiment of the present invention, the compounds have the formula II, wherein A is S; A 'is NR2.; n 'is 2; and n, Ri, R2 < , R6-, and R- are as defined in formula I. In another embodiment of the present invention, the compounds have the formula II, wherein A is S; A 'is O; n 'is 2; and n, Ri, R6-, and R7- are as defined in formula I. In another embodiment of the present invention, the compounds have the formula II, wherein A is S; A 'is S; n 'is 2; and n, Rl7 R6 < , and R7- are as defined in formula I.

In another embodiment of the present invention, the compounds have the formula II, wherein A is S; A 'is CR4.R5-; n 'is 2; and n, Ri, R4-, R5 < , R6-, and R7- are as defined in formula I.

In another embodiment, the present invention provides compounds having the formula III: III, or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof, wherein n, n ', A, AA Ri, Re- and R7' are as defined in formula I. In another embodiment of this invention, the compounds have the formula III, wherein A is NR2; A 'is NR2-; n 'is 1; and n, R1 t R2, R2-, Rg-, and R7- are as defined in formula I. In another embodiment of the present invention, the compounds have the formula III, wherein A is NR2; A 'is NR2-; n 'is 1; R6- is hydrogen; R7 < it is hydrogen; and Rlf R2, and R2. they are as defined in formula I. In another embodiment of the present invention, the compounds have the formula III, wherein A is NR2; A 'is O; n 'is 1; and n, Ri # R2, R6-, and R7- are as defined in formula I. In another embodiment of the present invention, the compounds have the formula III, wherein A is NR2; A 'is O; n 'is 1; n is 1; R6- is hydrogen; R7 it is hydrogen; and Ri and R2 are as defined in formula I. In another embodiment of the present invention, the compounds have the formula III, wherein A is NR2; A 'is S; n 'is 1; and n, Ri # R2, R6 < , and R7- are as defined in the form-mule I. In another embodiment of the present invention, the compounds have the formula III, wherein A is NR2; A 'is CR4.R5; n 'is 1; and n, Ri, R2, R4 < , R5-, R6 < , and R7- are as defined in formula I. In another embodiment of the present invention, the compounds have the formula III, wherein A is NR2; A '-is CR4-R5; n 'is 1; n is 1; R6- is hydrogen; R? - is hydrogen; and Ri, R2, R < , and R5- are as defined in formula I. In another embodiment of the present invention, the compounds have the formula III, wherein A is NR2; A 'is CR4.R5-; n 'is 1; n is 2; R6- is hydrogen; R7- is hydrogen; and Ri, R, R4-, and R5- are as defined in formula I. In another embodiment of the present invention, the compounds have the formula III, wherein A is O; A 'is NR2.; n 'is 1; and n, Rlf R2-, R6-, and R7- are as defined in formula I. In another embodiment of the present invention, the compounds have the formula III, wherein A is O; A 'is 0; n 'is 1; and n, Rl t R6. , and R7. they are as defined in formula I. In another embodiment of the present invention, the compounds have the formula III, wherein A is 0; A 'is 0; n 'is 1; n is 1; R6 it is hydrogen; R7 it is hydrogen; and Ri is as defined in formula I. In another embodiment of the present invention, the compounds have the formula III, wherein A is 0; A 'is S; n 'is 1; and n, R1 # R6-, and R7- are as defined in formula I. In another embodiment of the present invention, the compounds have the formula III, wherein A is O; A 'is CR4'R5', - n 'is 1; and n, Ri, R4. , R5. , R6-, and R7- are as defined in formula I. In another embodiment of the present invention, the compounds have the formula III, wherein A is O; A 'is CR4.R5 <; n 'is 1; n is 1; R6- is hydrogen; R- is hydrogen; and i / R 'and Rs- are as defined in formula I. In another embodiment of the present invention, the compounds have the formula III, wherein A is 0; A 'is CR4.R5-; n 'is 1; n is 2; R6 < it is hydrogen; R7- is hydrogen; and Ri R4- / and Rs' are as defined in formula I. In another embodiment of the present invention, the compounds have the formula III, wherein A is S; A 'is NR2-; n 'is 1; and n, Ri, R2-, R6-, and R7- are as defined in formula I. In another embodiment of the present invention, the compounds have the formula III, wherein A is S; A 'is O; n 'is 1; and n, Ri7 R6-, and R7- are as defined in formula I. In another embodiment of the present invention, the compounds have the formula III, wherein A is S; A 'is S; n 'is 1; and n, R, R6 <; , and R7- are as defined in formula I. In another embodiment of the present invention, the compounds have the formula III, wherein A is S; A 'is CR4-R5'; n 'is 1; and n, Rlf R4. , R5. , R6. , and R7. they are as defined in formula I. In another embodiment of the present invention, the compounds have the formula III, wherein A is NR2; A 'is NR2-; n 'is 2; and n, R, R2, R2. , Re-, and R7- are as defined in formula I. In another embodiment of the present invention, the compounds have the formula III, wherein A is NR2; A 'is NR2-; n 'is 2; n is 2; R6- is hydrogen; R7 it is hydrogen; and Ri, R2 and R2- are as defined in formula I. In another embodiment of the present invention, the compounds have the formula III, wherein A is NR2; A 'is O; n 'is 2; and n, Ri, R2, R6-, and R- are as defined in formula I. In another embodiment of the present invention, the compounds have the formula III, wherein A is NR2; A 'is S; n 'is 2; and n, Ri, R2, R6-, and R7 * are as defined in form-mule I. In another embodiment of the present invention, the compounds have the formula III, wherein A is NR2; A 'is CR4 < R5 <; n 'is 2; and n, Ri, R2, R4-, R5-, Rβ > , and R7- are as defined in formula I. In another embodiment of the present invention, the compounds have the formula III, wherein A is NR2; A 'is CR4.R5-; n 'is 2; n is 1; R6- is hydrogen; R7- is hydrogen; and Ri, R2-, R4., and R5? they are as defined in formula I. In another embodiment of the present invention, the compounds have the formula III, wherein A is NR2; A 'is CR4'R5'; n 'is 2; n is 2; R6- is hydrogen; R7 < it is hydrogen; and Ri, R2, R4 ', and R5- are as defined in formula I. In another embodiment of the present invention, the compounds have the formula III, wherein A is O; A 'is NR2.; n 'is 2; and n, R1 # R2 < , Rß-, and R7- are as defined in formula I. In another embodiment of the present invention, the compounds have the formula III, wherein A is 0; A 'is 0; n 'is 2; and n, Rlf Re., and R7 < they are as defined in formula I. In another embodiment of the present invention, the compounds have the formula III, wherein A is O; A 'is S; n 'is 2; and n, R1 # R6-, and R7 > they are as defined in formula I. In another embodiment of the present invention, the compounds have the formula III, wherein A is 0; A 'is CR4'R5 <; n 'is 2; and n, Rlf R4-, R5. , R6. , and R7. they are as defined in formula I. In another embodiment of the present invention, the compounds have the formula III, wherein A is O; A 'is CR4'R5-; n 'is 2; n is 1; R6 'is hydrogen; R7 * is hydrogen; and Ri / R4- / and Rs' are as defined in formula I. In another embodiment of the present invention, the compounds have the formula III, wherein A is O; A 'is CR4'R5', - n 'is 2; n is 1; R4 is hydrogen, R5. is hydrogen, R6- is hydrogen; R7 it is hydrogen; and Rx is as defined in formula I. In another embodiment of the present invention, the compounds have the formula III, wherein A is O; A 'is CR4 < R5 '; n # is 2; n is 1; R4- is methyl; R5 is methyl; R6- is hydrogen; R7 it is hydrogen; and R is as defined in formula I. In another embodiment of the present invention, the compounds have the formula III, wherein A is 0; A 'is CR4'R5', - n 'is 2; n is 2; R6 < it is hydrogen; R7 it is hydrogen; and Ri / 4- / and Rs- are as defined in formula I. In another embodiment of the present invention, the compounds have the formula III, wherein A is S; A 'is NR2; n 'is 2; and n, Rl7 R2. , R6 < , and R7. they are as defined in formula I. In another embodiment of the present invention, the compounds have the formula III, wherein A is S; A 'is O; n 'is 2; and n, Rx, R6 < , and R7- are as defined in formula I. In another embodiment of the present invention, the compounds have the formula III, wherein A is S; A 'is S; n 'is 2; and n, Ri # R6-, and R7- are as defined in formula I. In another embodiment of the present invention, the compounds have the formula III, wherein A is S; A 'is CR4.R5 <; n 'is 2; and n, Rlf R4-, R5-, Re-, and R7 < they are as defined in formula I.

In another embodiment, the present invention discloses compounds having the formula IV: IV, or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof, wherein n, n ', A, Ri, R4-, and Rs' / e- / and R7' are as defined in formula I. In another embodiment of the present invention, the compounds have the formula IV, wherein A is NR2; n 'is 1; and n, Ri, R2 / R4-, R5-, RG < , and R7- are as defined in formula I. In another embodiment of the present invention, the compounds have the formula IV, wherein A is NR2; n 'is 1; n is 1; Re- is hydrogen; R7- is hydrogen; and Ri, R2 -, R4-, and Rs-are as defined in formula I. In another embodiment of the present invention, the compounds have the formula IV, wherein A is NR2; n 'is 1; n is 2; Re. Is hydrogen; R7 < it is hydrogen; R1 t R2, R4-, and R5-are as defined in formula I. In another embodiment of the present invention, the compounds have the formula IV, wherein A is O; n 'is 1; and n, Ri, R4-, R5 < , R6-, and R7- are as defined in formula I. In another embodiment of the present invention, the compounds have the formula IV, wherein A is S; n 'is 1; and n, Ri, R4-, R5-, R6-, and R7- are as defined in formula I. In another embodiment of the present invention, the compounds have the formula IV, wherein A is NR2; n 'is 2; and n, Ri, R2, R4, R5-, R6-, and R7- are as defined in formula I. In another embodiment of the present invention, the compounds have the formula IV, wherein A is NR2; n 'is 2; n is 1; R6- is hydrogen; R7 < it is hydrogen; and R, R2, R < , and R5. they are as defined in formula I. In another embodiment of the present invention, the compounds have the formula IV, wherein A is 0; n 'is 2; and n, Ri, R < , R5 < , R6-, and R7- are as defined in formula I. In another embodiment of the present invention, the compounds have the formula IV, wherein A is O; n 'is 2; n is 1; R6 < it is hydrogen; R7 > it is hydrogen; and Ri # R4. , and R5- are as defined in formula I. In another embodiment of the present invention, the compounds have the formula IV, wherein A is S; n 'is 2; and n, Ri, R4-, R5-, R6-, and R7- are as defined in formula I. In another embodiment, the present invention provides compounds having the formula V: V, or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof, wherein n, n ', A, AA Ri / R-β, and R7 are as defined in formula I. In another embodiment of the present invention, the compounds have the formula V, wherein A is NR2; A 'is NR2.; n 'is 1; and n, Rl t R2, R2 -, R6 < , and R7- are as defined in formula I. In another embodiment of the present invention, the compounds have the formula V, wherein A is NR2; A 'is 0; n 'is 1; and n, Rx, R2, R6-, and R7. they are as defined in formula I. In another embodiment of the present invention, the compounds have the formula V, wherein A is NR2; A 'is S; n 'is 1; and n, Ri, R2, R6-, and R7- are as defined in form-mule I. In another embodiment of the present invention, the compounds have the formula V, wherein A is NR2; A 'is CR4 < R5; n 'is 1; and n, R1 t R2, R4-, R5-, R6-, and R7- are as defined in formula I. In another embodiment of the present invention, the compounds have the formula V, wherein A is 0; A 'is NR2 <; n 'is 1; and n, R1 t R2, e-, and R7- are as defined in formula I. In another embodiment of the present invention, the compounds have the formula V, wherein A is O; A 'is O; n 'is 1; and n, Rx, R6-, and R7- are as defined in formula I. In another embodiment of the present invention, the compounds have the formula V, wherein A is 0; A 'is S; n 'is 1; and n, Rx, R6-, and R7 < they are as defined in formula I. In another embodiment of the present invention, the compounds have the formula V, wherein A is 0; A 'is CR4'R5; n 'is 1; and n, Rl t R-, R5 < , Re-, and R7- are as defined in formula I. In another embodiment of the present invention, the compounds have the formula V, wherein A is S; A 'is NR2.; n 'is 1; and n, Ri, R2, R6-, and R7- are as defined in formula I. In another embodiment of the present invention, the compounds have the formula V, wherein A is S; A 'is 0; n 'is 1; and n, R1 f R6-, and R7- are as defined in formula I. In another embodiment of the present invention, the compounds have the formula V, wherein A is S; A 'is S; n 'is 1; and n # R1 # R6-, and R7- are as defined in formula I. In another embodiment of the present invention, the compounds have the formula V, wherein A is S; A 'is CR4.R5; n 'is 1; and n, Ri7 R4-, RB-, R6-, and R7- are as defined in formula I. In another embodiment of the present invention, the compounds have the formula V, wherein A is NR2; A 'is NR2-; n 'is 2; and n, Rt, R2, R2-, R6-, and R- are as defined in formula I. In another embodiment of the present invention, the compounds have the formula V, wherein A is NR2; A 'is O; n 'is 2; and n7 Rl R2, R6-, and R7- are as defined in form-mule I. In another embodiment of the present invention, the compounds have the formula V, wherein A is NR2; A 'is S; n 'is 2; and n, Rl t R2, R6 < , and R7- are as defined in formula I. In another embodiment of the present invention, the compounds have the formula V, wherein A is NR2; A 'is CR4'R5-; n 'is 2; and n, Rif R2, R4-, Rs- / ß 'and R7' are as defined in formula I. In another embodiment of the present invention, the compounds have the formula V, wherein A is O; A 'is NR2-; n 'is 2; and n, Rl f R2. , R6-, and R7 'are as defined in formula I. In another embodiment of the present invention, the compounds have the formula V, wherein A is O; A 'is O; n 'is 2; and n, Rl t Re-, and R7- are as defined in formula I. In another embodiment of the present invention, the compounds have the formula V, wherein A is O; A 'is S; n is 2; and n, R1 # R6-, and R7 'are as defined in formula I. In another embodiment of the present invention, the compounds have the formula V, wherein A is O; A 'is CR4-R5 <; n 'is 2; and n, Rx, R4. , R5. , R6-, and R7- are as defined in formula I. In another embodiment of the present invention, the compounds have the formula V, wherein A is S; A 'is NR2 *; n 'is 2; and n, Ri, R2-, R6-, and R7- are as defined in formula I. In another embodiment of the present invention, the compounds have the formula V, wherein A is S; A 'is 0; n 'is 2; and n, Rx, R6. , and R7- are as defined in formula I. In another embodiment of the present invention, the compounds have the formula V, wherein A is S; A 'is S; n 'is 2; and n, R1 # Re-, and R7. they are as defined in formula I. In another embodiment of the present invention, the compounds have the formula V, wherein A is S; A 'is CR4.R5; n 'is 2; and n, Ri, R4 < , R5-, R6-, and R7 < they are as defined in formula I.

In another embodiment, the present invention provides compounds having the formula VI: VI, or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof, wherein n, n ', A, R1 t R4-, s' / Re- / and R7' are as defined in the formula I. In another embodiment of the present invention, the compounds have the formula VI, wherein A is NR2; n 'is 1; and 11, Ri, R2, R4. , R5-, R-, and R-T are as defined in the form-mule I. In another embodiment of the present invention, the compounds have the formula VI, wherein A is O; n 'is 1; and n, R1 # R4., R5. , R6 < , and R7- are as defined in formula I. In another embodiment of the present invention, the compounds have the formula VI, wherein A is S; n 'is 1; and n, Ri, R4-, R5 < , R6-, and R7 'are as defined in formula I. In another embodiment of the present invention, the compounds have the formula VI, wherein A is NR2; n 'is 2; and n, Ri, R2, R4. , R5-, R6-, and R7- are as defined in the form-mule I. In another embodiment of the present invention, the compounds have the formula VI, wherein A is O; n 'is 2; and n, Ri, R4. , R5. , R6. , and R7. they are as defined in formula I. In another embodiment of the present invention, the compounds have the formula VI, wherein A is S; n 'is 2; and n, Rlf R4-, R5-, R6-, and R7 'are as defined in formula I.

Another embodiment of the present invention relates to pharmaceutical compositions comprising a therapeutically effective amount of a compound of the formulas I-VI, or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof, in combination with a pharmaceutically carrier. acceptable. Yet another embodiment of the invention relates to a method for the treatment of hypertension, w comprises administering a therapeutically effective amount of a compound of the formulas I-VI, or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof. Still another embodiment of the invention relates to a method for the treatment of asthma, epilepsy, hypertension, Raynaud's syndrome, migraine, pain, eating disorders, urinary incontinence, functional bowel disorders, neurodegeneration, embolism, female sexual dysfunction, including, but not limited to, female anorgasmia, clitoral erectile insufficiency, vaginal congestion, dyspareunia, and vaginismus, and male sexual dysfunction, including, but not limited to, male erectile dysfunction and premature ejaculation, w comprises administering a therapeutically amount effective of a compound of formulas I-VI, including 8- [2- (difluoromethoxy) phenyl] -1,7-dioxo-2,3,4,5,6,8-hexahydrodipyrrolo [3,4-b; 3, 4-e] pyridin-2,6-dipropanoic; dipropanate of (8- [2- (difluoromethoxy) phenyl] -1,7-dioxo-2, 3,4,5,6,8-hexahydrodipyrrolo [3,4- b; 3,4-e] pyridin-2, 6-ethyl, 8- [2- (difluoromethoxy) phenyl] -6-methyl-4,5,6,8-tetrahydro-lH-furo [3,4-b] pyrrolo [3,4-e] pyridin-1 , 7 (3H) -dione; 8- [2- (difluoromethoxy) phenyl] -2,6-dimethyl-2, 3,4,5,6,8-hexahydrodipyrrolo [3,4-b; 3, 4-e] pyridin-1,7-dione; 2,6-dimethyl-d-phenyl-2, 3,4,5,6,8-hexahydrodipyrrolo [3, 4-b; 3,4-e] pyridin-1, 7-dione, 8- (3-nitrophenyl) -5,8-dihydro-lH, 3H-difuro [3,4-b; 3,4-e] pyridin-1, 7 (4H) -dione, 8- (2,4-dichlorophenyl) -5,8-dihydro-1H, 3H-difure [3, 4-b; 3, 4-e] pyridin-1, 7 (4H) -dione, 8- (4-methoxyphenyl) -5,8-dihydro-lH, 3H-difuro [3,4-b; 3, 4-e] pyridin-1, 7 (4H) -dione, 8- (4-iodophenyl) -5,8-dihydro-lH, 3H-difure [3, 4-b, -3, 4-e] iridin-1,7 (4H) -dione, 8- (4-bromo-phenyl) -5,8-dihydro-lH, 3H-difuro [3,4-b; 3, 4-e] pyridin-l, 7 (4H) -dione, 8- (3-bromo-phenyl) -5,8-dihydro-lH, 3H-difuro [3,4-b; 3,4-e] pyridine -l, 7 (4H) -dione, 8- (2- (fluorophenyl) -5,8-dihydro-lH, 3H-difuro [3,4-b; 3,4-e] pyridine-1,7 (4H ) -dione, 8-phenyl-5, 8-dihydro-1H, 3H-difuso [3, 4-b; 3, 4-e] pyridin-1, 7 (4H) -dione, 8- (2-aminophenyl) -5,8-dihydro-lH, 3H-difuro [3,4-b; 3,4-e] pyridin-1,7 (4H) -dione, 8- [2- (difluoromethoxy) phenyl] -5,8 -dihydro-lH, 3H-difuro [3, 4-b; 3, 4-e] pyridin-1, 7 (4H) -dione, 8- (2-chlorophenyl) -5,8-dihydro-1H, 3H-difure [3, 4-b; 3, 4-e] pyridin-1, 7 (4H) -dione, 8- (2, 3, 4-trimethoxyphenyl) -5,8-dihydro-lH, 3H-difuro [3,4-b; 3,4 -e] pyridin-l, 7 (4H) -dione, 8- [2- (trifluoromethyl) phenyl] -5,8-dihydro-lH, 3H-difure [3, 4-b; 3,4-e] pyridin-1, 7 (4H) -dione, 8- (2-chloro-3-nitrophenyl) -5,8-dihydro-lH, 3H-difuro [3,4-b; 3,4 -e] pyridin-1, 7 (4H) -dione, 8- (4-nitrophenyl) -5,8-dihydro-1H, 3H-difure [3, 4-b, -3, 4-e] pyridin-1 , 7 (4H) '-dione, 8- (4-chlorophenyl) -5,8-dihydro-lH, 3H-difuro [3,4- b, • 3,4-e] pyridin-1,7 (4H) -dione, 8- (3-chlorophenyl) -5,8-dihydro-lH, 3H-difuro [3,4-b; 3,4-e] pyridin-l, 7 (4H) -dione, 8- (2 -nitrophenyl) -5,8-dihydro-1H, 3H-difure [3, 4-b; 3, 4-e] pyridin-1, 7 (4H) -dione, 3,7-dimethyl-10-phenyl-3, 4, 5,6,7, 10-hexahydro-1H, 9H-dipyran [4, 3 -b; 3, 4-e] pyridin-1, 9-dione, 6,6-dimethyl-9-phenyl-5,6,7,9-tetrahydrofuro [3,4-b] quinolin-1, 8 (3H, 4H) -dione, 9- (1, 3-benzodioxol-5-yl) -5,6,7,9-tetrahydrofuro [3,4-b] quinolin-1, 8 (3H, 4H) -dione, 9- (3 -methoxyphenyl) -5,6,7,9-tetrahydrofuro [3,4-b] quinolin-1,8 (3H, 4H) -dione, 9- (2-methoxyphenyl) -6,6-dimethyl-5,6 , 7, 9-tetrahydrofuro [3,4-b] quinolin-1,8 (3H, 4H) -dione, 6,6-dimethyl-9- (2-nitrophenyl) -5,6,7, -tetrahydrofuro [3 , 4-b] quinolin-1, 8 (3H, 4H) -dione, 6,6-dimethyl-9- [2- (trifluoromethyl) phenyl] -5,6,7,9-tetrahydrofuro [3, 4-b] ] quinolin-1, 8 [3H, 4H] -dione, and 9- [3- (benzyloxy) phenyl] -6,6-dimethyl-5,6,7,9-tetrahydrofuro [3,4-b] quinoline- 1, 8 (3H, 4H) -dione, or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof.

Definition of Terms The term "alkenyl", as used herein, refers to a straight or branched chain hydrocarbon containing from 2 to 10 carbon atoms, and containing at least one carbon-carbon double bond formed by the removal of two hydrogens. Representative examples of alkenyl include, but are not limited to, ethenyl, 2-propenyl, 2-methyl-2-propenyl, 3-butenyl, 4-pentenyl, 5-hexenyl, 2-heptenyl, 2-methyl-1 heptenyl, 3-decenyl, and the like. • The term "alkoxy", as used in the pre- sentate, refers to an alkyl group, as defined herein, attached to the parent molecular moiety through an oxy moiety, as defined herein. . Representative examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tert-butoxy, pentyloxy, hexyloxy, and the like. The term "alkoxyalkoxy", as used herein, refers to an alkoxy group, as defined herein, attached to the parent molecular moiety through another alkoxy group, as defined herein.

Representative examples of alkoxyalkoxy include, but are not limited to, terbutoxymethoxy, 2-ethoxyethoxy, 2-methoxyethoxy, methoxymethoxy, and the like. The term "alkoxyalkoxyalkyl", as used herein, refers to an alkoxyalkoxy group, as defines herein, attached to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of alkoxyalkoxyalkyl include, but are not limited to, terbutoxymethoxymethyl, ethoxymethoxymethyl, (2-methoxyethoxy) methyl, 2- (2-methoxyethoxy) ethyl, and similar.

The term "alkoxyalkyl", as used herein, refers to an alkoxy group, as defined herein, attached to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of alkoxyalkyl include, but are not limited to, terbutoxymethyl, 2-ethoxyethyl, 2-methoxyethyl, methoxymethyl, and the like. The term "alkoxycarbonyl", as used herein, refers to an alkoxy group, as defined herein, attached to the parent molecular moiety through a carbonyl group, as defined herein. Representative examples of alkoxycarbonyl include, but are not limited to, methoxycarbonyl, ethoxycarbonyl, terbutoxycarbonyl, and the like. The term "alkoxycarbonylalkyl", as used herein, refers to an alkoxycarbonyl group, as defined herein, attached to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of alkoxycarbonylalkyl include, but are not limited to, 3-methoxycarbonylpropyl, 4-ethoxycarbonylbutyl, 2-terbutoxycarbonylethyl, and the like. The term "alkyl", as used herein, refers to a straight or branched chain hydrocarbon containing from 1 to 10 carbon atoms. Representative examples of alkyl include, but are not limited to, methyl, ethyl, normal propyl, isopropyl, normal butyl, secondary butyl, isobutyl, tertiary butyl, normal pentyl, isopentyl, neopentyl, normal hexyl, 3-methylhexyl, , 2-dimethylpentyl, 2,3-dimethylpentyl, normal heptyl, normal octyl, normal nonyl, normal decyl, and the like. The term "alkylcarbonyl", as used herein, refers to an alkyl group, as defined herein, attached to the parent molecular moiety through a carbonyl group, as defined herein. Representative examples of alkylcarbonyl include, but are not limited to, acetyl, 1-oxopropyl, 2,2-dimethyl-1-oxopropyl, 1-oxobutyl, 1-oxopentyl, and the like. The term "alkylcarbonylalkyl", as used herein, refers to an alkylcarbonyl group, as defined herein, attached to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of alkylcarbonylalkyl include, but are not limited to, 2-oxopropyl, 3,3-dimethyl-2-oxopropyl, 3-oxobutyl, 3-oxopentyl, and the like. The term "alkylcarbonyloxy", as used herein, refers to an alkylcarbonyl group, as defined herein, attached to the parent molecular moiety through an oxy moiety, as defined herein. Representative examples of alkylcarbonyloxy include, but are not limited to, acetyloxy, ethylcarbonyloxy, tert-butylcarbonyloxy, and the like. The term "alkylsulfinyl," as used herein, refers to an alkyl group, as defined herein, attached to the parent molecular moiety through a sulfinyl group, as defined herein. Representative examples of alkynylsulfinyl include, but are not limited to, methylsulfinyl, ethylsulfinyl, and the like. The term "alkylsulfonyl", as used herein, refers to an alkyl group, as defined herein, attached to the parent molecular moiety through a sulfonyl group, as defined herein. Representative examples of alkylsulfonyl include, but are not limited to, methylsulfonyl, ethylsulfonyl, and the like. The term "thioalkyl", as used herein, refers to an alkyl group, as defined herein, attached to the parent molecular moiety through a thio moiety, as defined herein. Representative examples of thioalkyl include, but are not limited to, methylsulfanyl, ethylsulfanyl, tertbutylsulfanyl, hexylsulfañyl, and the like. The term "alkynyl", as used herein, refers to a straight or branched chain hydrocarbon group containing from 2 to 10 carbon atoms, and containing at least one carbon-carbon triple bond.

Representative examples of alkynyl include, but are not limited to, acetylenyl, 1-propynyl, 2-propynyl, 3-butynyl, 2-pentynyl, 1-butynyl, and the like. The term "aryl", as used herein, refers to a monocyclic carbocyclic ring system, or a bicyclic carbocyclic fused ring system having one or more aromatic rings. Representative examples of aryl include azulenyl, indanyl, indenyl, naphthyl, phenyl, tetrahydronaphthyl, and the like. The aryl group of this invention may be substituted with 1, 2, 3, 4, or 5 substituents independently selected from alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl, alkylcarbonyloxy, alkylsulfinyl, alkylsulfonyl, thioalkyl, alkynyl, aryl, azido, arylalkoxy, arylalkyl, aryloxy, carboxyl, cyano, formyl, halogen, haloalkyl, haloalkoxy, hydroxyl, hydroxyalkyl, mercapto, nitro, sulfo, sulfonate, R8uR8? (wherein R8o and Rsi are independently selected from hydrogen, alkyl, alkylcarbo-nyl, aryl, arylalkyl, and formyl), and -C (0) NR82R83 (wherein β2 and R3 are independently selected from hydrogen, alkyl , aryl, and arylalkyl). The term "arylalkoxy", as used herein, refers to an aryl group, as defined herein, attached to the parent molecular moiety through an alkoxy group, as defined herein. Representative examples of arylalkoxy include, but are not limited to, 2-phenylethoxy, 3-naphth-2-ylpropoxyl, 5-phenylpentyloxy, and the like. The term "arylalkoxycarbonyl", as used herein, refers to an arylalkoxy group, as defined herein, attached to the parent molecular moiety through a carbonyl group, as defined herein. Representative examples of arylalkoxycarbonyl include, but are not limited to, benzyloxycarbonyl, naphth-2-ylmethoxycarbonyl, and the like. The term "arylalkyl", as used herein, refers to an aryl group, as defined herein, attached to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of arylalkyl include, but are not limited to, benzyl, 2-phenylethyl, 3-phenylpropyl, 2-naphth-2-ylethyl, and the like. The term "arylcarbonyl", as used herein, refers to an aryl group, as defined herein, attached to the parent molecular moiety through a carbonyl group, as defined herein. Representative examples of arylcarbonyl include, but are not limited to, benzoyl, naphthoyl, and the like. The term "aryloxy", as used in the pre- sentate, refers to an aryl group, as defined herein, attached to the parent molecular moiety through an oxy moiety, as defined herein. Representative examples of aryloxy include, but are not limited to, phenoxy, naphthyloxy, 3-bromophenoxyl, 4-chlorophenoxy, 4-methylphenoxy, 3,5-dimethoxyphenoxy, and the like. The term "aryloxyalkyl", as used herein, refers to an aryloxy group, as defined herein, attached to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of aryloxyalkyl include, but are not limited to, 2-phenoxyethyl, 3-naphth-2-yloxypropyl, 3-bromophenoxymethyl, and the like. The term "azido", as used herein, refers to a group -N3. The term "carbonyl", as used herein, refers to a -C (O) - group. The term "carboxyl", as used herein, refers to a -C02H group. The term "carboxyalkyl", as used herein, refers to a carboxyl group, as defined herein, attached to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of carboxyalkyl include, but are not limited to, carboxymethyl, 2-carboxyethyl, 3-carboxypropyl, and the like. The term "cyano", as used herein, refers to a -CN group. ~ "The term" cyanoalkyl ", as used herein, refers to a cyano group, as defined herein, attached to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of cyanoalkyl include, but are not limited to, cyanomethyl, 2-cyanoethyl, 3-cyanopropyl, and the like. The term "cycloalkyl," as used herein, refers to a saturated cyclic hydrocarbon group containing from 3 to 8 carbon atoms Representative examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and the like The term "cycloalkylalkyl," as used herein , refers to a cycloalkyl group, as defined herein, linked to the moiety progenitor-ra through an alkyl group, as defined herein.Regional examples of cycloalkylalkyl include, but are not limited to, or are limited to, cyclopropylmethyl, 2-cyclobutylethyl, cyclopentylmethyl, cyclohexylmethyl, and 4-cycloheptylbutyl, and the like. The term "formyl," as used herein, refers to a -C (0) H group. The term "halo" or "halogen", as used herein, refers to -Cl, -Br, -I, or -F. The term "haloalkoxy", as used herein, refers to at least one halogen, as defined herein, attached to the parent molecular moiety through an alkoxy group, as defined herein. Representative examples of haloalkoxy include, but are not limited to, chloromethoxy, 2,2,2-trifluoroethoxy, trifluoromethoxy, pentafluoroethoxy, and the like. The term "haloalkyl", as used herein, refers to at least one halogen, as defined herein, attached to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of haloalkyl include, but are not limited to, chloromethyl, 2-fluoroethyl, trifluoromethyl, pentafluoroethyl, 2-chloro-3-fluoropentyl, and the like. The term "heterocycle", as used herein, refers to a monocyclic or bi-cyclic ring system. Monocyclic ring systems are exemplified by any 5 or 6 membered ring containing 1, 2, 3, or 4 heteroatoms independently selected from oxygen, nitrogen, and sulfur. The 5-membered ring has 0 to 2 double bonds, and the 6-membered ring has 0 to 3 double bonds. Representative examples of monocyclic ring systems include, but are not limited to, azetidine, azepine, aziridine, diazepine, 1,3-dioxolane, dioxane, dithiane, furan, imidazole, imidazoline, imidazolidine, isothiazole, isothiazoline, isothiazolidine, iso -xazole, isoxazoline, isoxazolidine, morpholine, oxadiazole, oxa-diazoline, oxadiazolidine, oxazole, oxazoline, oxazolidine, piperazine, piperidine, pyran, pyrazine, pyrazole, pyrazolone, pyrazolidine, pyridine, pyrimidine, pyridazine, pyrrole, pyrroline, pyrrolidine , tetrahydrofuran, tetrahydrothiophene, tetrazine, tetrazole, thiadiazole, thiadiazoline, thiadiazolidine, thiazole, thiazoline, thiazolidine, thiophene, thiomorpholine, thio-morpholine-sulfone, thiopyran, triazine, triazole, tritium, and the like. The bicyclic ring systems are exemplified by any of the above monocyclic ring systems fused with an aryl group as defined herein, a cycloalkyl group as defined herein, or another monocyclic ring system as defined herein . Representative examples of the bicyclic ring systems include, but are not limited to, for example, benzimidazole, benzothiazole, benzothiadiazole, benzothiophene, benzoxadiazole, benzoxazole, benzofuran, benzopyran., benzo-thiopyran, benzodioxine, 1,3-benzodioxole, cinoline, indazole, indoline, indolicin, naphthyridine, isobenzofuran, isobenzo-thiophene, isoindol, isoindoline, isoquinoline, phthalazine, pi-ranopyridine, quinoline, quinolizine, quinoxaline, quinazoli-na , tetrahydroisoquinoline, tetrahydroquinoline, thiopyranopyridine, and the like. The heterocycle groups of this invention can be substituted with 1, 2, or 3 substituents independently selected from alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl, alkylcarbonyloxy, alkylsulfinyl, alkylsulfonyl, thioalkyl, alkynyl, aryl, azido, arkoxyl, arylalkoxycarbonyl, arylalkyl, aryloxy, carboxyl, cyano, formyl, halogen, haloalkyl, haloalkoxy, hydroxyl, hydroxyalkyl, mercapto, nitro, sulfo, sulfonate, -NR8? R8? (wherein R8? and R8? are independently selected from hydrogen, alkyl, alkylcarbonyl, aryl, arylalkyl, and formyl), and -C (0) NR82R83 (wherein R82 and R83 are independently selected from hydrogen , alkyl, aryl, and arylalkyl). The term "heterocycloalkyl", as used herein, refers to a heterocycle, as defined herein, attached to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of heterocycloalkyl include, but are not limited to, pyrid-3-ylmethyl, 2-pyrimidin-2-ylpropyl, and the like. The term "hydroxyl", as used in the pre-sité, refers to an -OH group.

The term "hydroxyalkyl", as used herein, refers to a hydroxyl group, as defined herein, attached to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of hydroxyalkyl include, but are not limited to, .hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl, 2-ethyl-4-hydroxyheptyl, and the like. The term "lower alkyl", as used herein, refers to a straight or branched chain hydrocarbon group containing from 1 to 4 carbon atoms. Representative examples of lower alkyl include, but are not limited to, methyl, ethyl, normal propyl, isopropyl, normal butyl, isobutyl, tertiary butyl, and the like. The term "mercapto", as used herein, refers to a -SH group. The term "nitro", as used herein, refers to a group -N02. The term "protecting group of N" or "nitrogen protecting group", as used herein, refers to the groups intended to protect an amino group from undesirable reactions during synthetic procedures. Protecting groups of N include carbamates, amides including those containing heteroa-ryl groups, N-alkyl derivatives, aminoacetal derivatives, N-benzyl derivatives, imine derivatives, enamine derivatives, and N-heteroatom derivatives. . Preferred N-protecting groups are formyl, acetyl, benzoyl, pivaloyl, phenylsulfonyl, benzyl, triphenylmethyl (trityl), t-butyloxycarbonyl (Boc), benzyloxycarbonyl (Cbz), and the like. The commonly used N-protecting groups are disclosed in T.H. Greene and P.G.M. Wuts, Protective Groups in Organic Synthesis, Second Edition, John Wiley & Sons, New York (1991), which is incorporated herein by reference. The term "NZ? Z2 #", as used herein, refers to two groups Zx and Z2, which bind to the parent molecular moiety through a nitrogen atom. Zx and Z2 are independently selected from hydrogen, alkyl, alkylcarbonyl, aryl, arylalkyl, and formyl. Representative examples of -ZZZ2 include, but are not limited to, amino, benzylamino, methylamino, acetylamino, acetylmethylamino, and the like. The term "oxo", as used herein, refers to a fraction = 0. The term "oxy", as used herein, refers to a fraction -0-. The term "sulfinyl", as used herein, refers to a group -S (O). The term "sulfo", as used herein, refers to a -S03H group.

The term "sulfonate", as used herein, refers to a group -S (0) 2OR9e, wherein R96 is selected from alkyl, aryl, and arylalkyl, as defined herein. The term "sulfonyl", as used herein, refers to a -S02- group. The term "thio", as used herein, refers to a -S- fraction. The term "pharmaceutically acceptable prodrugs", as used herein, represents the prodrugs of the compounds of the present invention which are, within the scope of a conscious medical judgment, suitable for use in contact with the tissues of humans and animals. inferiors without an undue toxicity, irritation, allergic, and the like response, commensurate with a reasonable benefit / risk ratio, and effective for their intended use, as well as the zwitterionic forms, where possible, of the compounds of the invention . The prodrugs of the present invention can be rapidly transformed in vivo to the parent compound of the above formula, for example by hydrolysis in the blood. A full discussion is provided in (T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Volume 14 of the ACS Symposium Series, and in Edward B. Roche, editor, Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Perga-mon Press (1987)). The present invention contemplates pharmaceutically active metabolites formed by the biotransformation in vivo of the compounds of the formulas I-VI. The term "pharmaceutically active metabolite", as used herein, refers to a compound formed by the biotransformation in vivo of the compounds of the formulas I-VI. A full discussion of biotransformation is provided in Goodman and Gilman's, The Pharmacological Basis of Therapeutics, seventh edition. The compounds of the present invention can exist as stereoisomers, wherein asymmetric or chiral centers are present. These stereoisomers are "R" or "S". depending on the configuration of the substituents around the chiral carbon atom. The present invention contemplates different stereoisomers and their mixtures. Stereoisomers include enantiomers and diastereomers, and mixtures of enantiomers or diastereomers. Individual stereoisomers of the compounds of the present invention can be prepared synthetically from commercially available starting materials containing asymmetric or chiral centers, or by the preparation of racemic mixtures, followed by resolution well known to those of ordinary skill in the art. These resolution methods are exemplified by (1) the binding of a mixture of enantiomers to a chiral auxiliary, the separation of the resulting mixture from diastereomers by recrystallization or chromatography, and the release of the optically pure product from the auxiliary, or (2) ) the direct separation of the mixture of optical enantiomers on chiral chromatographic columns. Preferred compounds of the formula I include, but are not limited to: 9- (4-chloro-3-methylphenyl) -5,6,7,9-tetrahydrofuro [3,4-b] quinolin-1,3 (3H , 4H) -dione, 9- (3-methyl-4-nitrophenyl) -5,6,7,9-tetrahydrofuro [3,4-b] quinolin-1, 8 (3H, 4H) -dione, 9- [ 4-fluoro-3- (2-furyl) phenyl] -5,6,7,9-tetrahydrofuro (3,4-b) quinolin-1, 8 (3H, 4H) -dione, 9- (3-bromo- 4-methylphenyl) -5,6,7,9-tetrahydrofuro [3,4-b] quinolin-1,8 (3H, 4H) -dione, 9- (2,1, 3-benzoxadiazol-5-yl) - 5,6,7,9-tetrahydrofuro [3,4-b] quinolin-1, 8 (3H, 4H) -dione, 9- (3-bromo-4-chlorophenyl) -5,6,7,9-tetrahydrofuro [3, 4-b] quinolin-1, 8 (3H, 4H) -dione, 9- [3-bromo-4- (trifluoromethyl) phenyl] -5,6,7,9-tetrahydrofuro [3, 4-b] ] quinolin-1, 8 (3H, 4H) -dione, 9- [4-chloro-3- (trifluoromethyl) phenyl] -5,6,7,9-tetrahydrofuro [3,4-b] quinolin-1, 8 (3H, 4H) -dione, 9- (4-bromo-3-chlorophenyl) -5,6,7,9-tetrahydrofuro [3,4-b] quinolin-1, 8 (3H, 4H) -dione, - (4-bromo-3-methylphenyl) -5,6,7,9-tetrahydrofuro [ 3, 4-b] quinolin-1, 8 (3H, 4H) -dione, 9- (3-iodo-4-methylphenyl) -5,6,7,9-tetrahydrofuro [3,4-b] quinolin-1 8 (3H, 4H) -dione, 9- [3-nitro-4- (trifluoromethyl) phenyl] -5,6,7,9-tetrahydrofuro [3,4-b] quinolin-1, 8 (3H, 4H ) -dione, 9- (5-bromo-4-fluoro-2-hydroxyphenyl) -5,6,7,9-tetrahydrofuro [3,4-b] quinolin-1,8 (3H, 4H) -dione, 9 - [3-chloro-4- (trifluoromethyl) phenyl] -5,6,7,9-tetrahydrofuro [3,4-b] quinolin-1, 8 (3H, 4H) -dione, 9- [3-iodo- 4- (trifluoromethyl) phenyl] -5,6,7,9-tetrahydrofuro [3,4-b] quinolin-1,8 (3H, 4H) -dione, 9- (2, 1, 3-benzothiadiazol-5-) il) -5,6,7,9-tetrahydrofuro [3,4-b] quinolin-18 (3H, 4H) -dione, 8- (3,4-dibromophenyl) -4,5,6,8-tetrahydro- 1H-cyclopenta [b] furo [3,4-e] pyridin-1, 7 (3H) -dione, 8- (4-chloro-3-nitrophenyl) -4,5,6,8-tetrahydro-1H-cyclopenta [b] furo [3, 4-b] pyridin-1, 7 (3H) -dione, 8- (4-fluoro-3-iodophenyl) -4,5,6, 8-tetrahydro-lH-cyclopenta [b] furo [3, 4-e] pyridin-1, 7 (3H) -dione, 8- (3-chloro-4-fluorofen) nil) -4.5.6, 8 -tetrahydro-1H-cyclopenta [b] furo [3,4-e] pyridin-1, 7 (3H) -dione, 8- (3,4-difluorophenyl) -4, 5, 6, 8 -tetrahydro-1H-cyclopenta [b] furo [3,4-e] pyridin-1,7 (3H) -dione, 8- (4-chloro-3-methylphenyl) -4,5,6 , 8-tetrahydro-lH-cyclopenta [b furo [3,4-e] iridin-1, 7 (3H) -dione, 8- 3 -methyl-4-nitrophenyl) -4,5,6, 8 -tetrahydro- 1H-cyclopenta [b furo [3,4-e] pyridin-l, 7 (3H) -dione, 8- 3 -bromo-4-methylphenyl) -4,5,6,8-tetrahydro-1H-cyclopenta [b furo [3,4-e] pyridin-1, 7 (3H) -dione, 8-2.1, 3-benzoxadiazol-5-yl) -4, 5,6,8 -tetrahydro-1H-cyclopenta [b furo [3,4-e] pyridin-1,7 (3H) -dione, 8- 3 -bromo-4-chlorophenyl) -4,5,6, 8 -tetrahydro-1H-cyclopenta [b furo [3,4-e] pyridin-1,7 (3H) -dione, 8- 3-bromo-4- (trifluoromethyl) phenyl] -4,5,6,8- tetrahydro-lH-cyclopenta [b] furo [3,4-e] pyridin-1, 7 (3H) -dione, 8- 4 -chloro-3- (trifluoromethyl) phenyl] -4,5,6,8-tetrahydro-lH-cyclopenta [b] furo [3,4- e] pyridin-1,7 (3H) -dione, 8- 4-bromo-3-chlorophenyl) -4,5,6,8-tetrahydro-1H-cyclopenta [b furo [3,4-e] pyridin-1,7 (3H) -dione, 8- 4 -bromo -3-methylphenyl) -4,5,6,8-tetrahydro-1H-cyclopenta [b furo [3,4-e] pyridin-1,7 (3H) -dione, 8- 3 -iodo-4-methylphenyl) -4.5.6, 8 -tetrahydro-1H-cyclopenta [b furo [3,4-e] pyridin-1, 7 (3H) -dione, 8- 3-nitro-4- (trifluoromethyl) phenyl] -4 , 5,6,8-tetrahydro-lH-cyclopenta [b] furo [3,4-e] pyridin-1, 7 (3H) -dione 8- 5-bromo-4-fluoro-2-hydroxyphenyl) -4, 5,6,8-tetrahydro-lH-cyclopenta [b] furo [3,4-e] pyridin-1, 7 (3H) -dione, 8- 3 -chloro-4- (trifluoromethyl) phenyl] -4,5,6,8-tetrahydro-lH-cyclopenta [b] furo [3,4-e] pyridin-1,7 (3H) -dione, - (3-bromo-4-fluorophenyl) -3,4,5,6,7, 10-hexahydro-1H, 9H-dipyran [4, 3-b; 3, 4-e] pyridin-1, -dione, 9- (3-bromo-4-fluorophenyl) -4,5,6,9-tetrahydro-lH-furo [3,4-b] pyran [3, 4 -e] pyridin-1, 8 (3H) -dione, 8- [3-iodo-4- (trifluoromethyl) phenyl] -4,5,6,8-tetrahydro-lH-cyclopenta [b] furo [3, 4 -e] pyridin-1, 7 (3H) -dione, and 8- (2,1, 3-benzothiadiazol-5-yl) -4,5,6,8-tetrahydro-lH-cyclopenta [b] furo [3,4-e] pyridin-1,7 (3H) - dione, or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof. More preferred compounds of the formula I include, but are not limited to: 8- (3-bromo-4-fluorophenyl) -2,3,4,5,6,8-hexahydrodipyrrolo [3,4-b; 3, 4-e] pyridin-1, 7 -dione, 8- (3-bromo-4-fluorophenyl) -2,6-dimethyl-2, 3,4,5,6,8-hexahydrodipyrrolo [3, 4- b; 3, 4-e] pyridin-1,7-dione, 8- (3-bromo-4-fluorophenyl) -2-methyl-2, 3,4,5,6,8-hexahydrocyclopenta [b] pyrrolo [3, 4-e] pyridin-1, 7-dione, 8- (3-bromo-4-fluorophenyl) -2-ethyl-2, 3, 4, 5,6,8-hexahydrocyclopenta [b] pyrrolo [3, 4- e] pyridine-1, 7-dione, 8- (3-bromo-4-fluorophenyl) -5,8-dihydro-lH, 3H-difure [3, 4-b; 3, 4-e] pyridin-1, 7 (4H) -dione, 8- (3-bromo-4-fluorophenyl) -4,5,6,8-tetrahydro-1H-cyclopenta [b] furo [3, 4 -e] pyridin-1, 7 (3H) -dione, 8- (3-bromo-4-fluorophenyl) -2- (2-methoxyethyl) -2,3,4,5,6,8-hexahydrocyclopenta [b] pyrrolo [3, 4-e] pyridin-1, 7-dione, 9- (3-bromo-4-fluorophenyl) -2-methyl-2, 3, 5,6,7,9-hexahydro-lH-pyrrolo [ 3, 4-b] quinolin-1, 8 (4H) -dione, 9- (3-bromo-4-fluorophenyl) -2-yl -2, 3,5,6, 7, 9-hexahydro-1H- pyrrolo [3, 4-b] quinolin-1, 8 (4H) -dione, 9- (3-bromo-4-fluorophenyl) -5,6,7,9-tetrahydrofuro [3,4-b] quinolin-1 , 8 (3H, 4H) -dione, 9- (3-bromo-4-fluorophenyl) -2,3,5,6,7,9-hexahydro-lH-pyrrolo [3,4-b] quinolin-1, 8 (4H) -dione, 8- (3-bromo-4-fluorophenyl) -2- [2- (4-morpholinyl) ethyl] -2,3,4,5,6,8-hexahydrocyclopenta hydrochloride [b] irrolo [3, 4-e] pyridin-1, 7-dione, 8- (3-bromo-4-fluorophenyl) -2- [2- (dimethylamino) ethyl] -2,3,4,5,6-hydrochloride , 8-hexahydrocyclopenta [b] pyrrolo [3,4-e] pyridin-1,7-dione, 9- (3-bromo-4-fluorophenyl) -2- (2-methoxyethyl) -2,3,5,6,7,9-hexahydro-lH-pyrrolo [3,4-b] quinolin-1, 8 (4H) -dione, (9R) -9- (3-bromo-4-fluorophenyl) -2-methyl-2, 3,5,6,7,9-hexahydro-lH-pyrrolo [3, 4-b] quinolin-1 , 8 (4H) -dione, (9R) -9- (3-bromo-4-fluorophenyl) -5,6,7,9-tetrahydrofuro [3,4-b] quinolin-1, 8 (3H, 4H) -dione, (9R) -9- (3-bromo-4-fluorophenyl) -2,3,5,6,7,9-hexahydro-lH-pyrrolo [3, 4-b] quinolin-1, 8 (4H ) -dione, (9S) -9- (3-bromo-4-fluorophenyl) -5,6,7,9-tetrahydrofuro [3,4-b] quinolin-1, 8 (3H, 4H) -dione, ( 9S) -9- (3-bromo-4-fluorophenyl) -2-methyl-2, 3, 5,6,7,9-hexahydro-lH-pyrrolo [3,4-b] quinolin-1, 8 (4H ) -dione, (9S) -9- (3-bromo-4-fluorophenyl) -2,3,5,6,7,9-hexahydro-lH-pyrrolo [3,4-b] quinolin-1, 8 ( 4H) -dione, 9- (3-cyanophenyl) -2-methyl-2, 3,5,6,7,9-hexahydro-lH-pyrrolo [3,4-b] quinolin-1, 8 (4H) - dione, 8- (3-bromo-4-fluorophenyl) -6-methyl-2,3,4,5,6, 8-hexahydro-7H-pyrrolo [3,4-b] thieno 1,1-dioxide 2, 3-e] pyridin-7-one, 9- (3-bromo) -4-fluorophenyl) -3,4,5,6,7,9-hexahydro-lH-cyclopenta [b] [1, 6] naphthyridin-1, 8 (2H) -dione, 10- (3-bromo-4-fluorophenyl) -3, 4, 6, 7,8, 10-hexahydrobenzo [b] [1, 6] naphthyridin-1 , 9 (2H, 5H) -dione, (9S) -9- (4-fluoro-3-iodophenyl) -5,6,7,9-tetrahydrofuro [3,4-b] quinolin-1, 8 (3H, 4H) -dione, 10- (3-bromo-4-fluorophenyl) -3, 4, 6, 7,8, 10-hexahydropyrido [4, 3-b] [1,6] naphthyridin-1, 9 (2H, 5H) -dione, 9- (3-bromo-4-fluorophenyl) -7-methyl-3,4,5,6,7,19-hexahydropyrrolo [3,4-b] thiopyran 1,1-dioxide [2] , 3-e] pyridin-8 (2H) -one, 9- (3-bromo-4-fluorophenyl) -3,4,6,9-tetrahydro-2H-furo [3-4] b] thiopyrano [2,3-e] pyridin-8 (5H) -one, (8R) -8- (3-bromo-4-fluorophenyl) -2-methyl -2, 3,4,5,6,8 -hexahydrocyclopenta [b] pyrrolo [3, 4-e] pyridine-1,7-dione, (9S) -9- (3-bromo-4-fluorophenyl) 3,4,6, 9- 1,1-dioxide tetrahydro-2H-furo [3,4-b] thiopyrano [2,3-e] pyridin-8 (5H) -one, (8S) -8- (3-bromo-4-fluorophenyl) -2-methyl -2 , 3, 4, 5,6,8-hexahydrocyclopenta [b] pyrrolo [3, 4-e] pyridin-1,7-dione, 1,1-di (9R) -9- (3-bromo-4-fluorophenyl) 3,4,6,9-tetrahydro-2H-furo [3,4-b] thiopyrano [2,3-e] pyridin-8 (5H) oxide ) -one, 9- (3-bromo-4-fluorophenyl) -2- (2-ethoxyethyl) -2,3,5,6,7,9-hexahydro-lH-pyrrolo [3,4-b] quinoline- 1, 8 (4H) -dione, (9R) -9- (3-bromo-4-fluorophenyl) -2- (2-ethoxyethyl) -2,3,5,6,7, 9-hexahydro-lH-pyrrolo [3, 4-b] quinolin-1,8 (4H) -dione, (9S) -9- (3-bromo-4-fluorophenyl) -2- (2-ethoxyethyl) -2,3,5,6, 7, 9-hexahydro-lH-pyrrolo [3,4-b] quinoline-1,8 (4H) -dione,, (9S) -9- (3-bromo-4-fluorophenyl) -2-cyclopropyl-2, 3,5,6,7,9-hexahydro-lH-pyrrolo [3,4-b] quinolin-1,8 (4H) -dione, 9- (3-bromo-4-fluorophenyl) 1,1-dioxide) -2,3,5,6,7, 9-hexahydrothieno [3,2-b] [1,6] naphthyridin-8 (4H) -one, (9R) -9- (4-fluoro-3-iodophenyl) -5,6,7,9-tetrahydrofuro [3,4-b] quinolin-1, 8 (3H, 4H) -dione, (9R) -9- (3-chloro-4-fluorophenyl) -5,6, 7, 9-tetrahydrofuro [3,4-b] quinolin-1, 8 (3H, 4H) -dione, (3-chloro-4-fluorophenyl) -3,4,5,6,7,9-hexahydro-lH -cyclopenta [b] [1, 6] na ftiridin-1, 8 (2H) -dione, 9- [4-fluoro-3- (trifluoromethyl) phenyl] -3,4,5,6,7,9-hexahydro-1H-cyclopenta [b] [1, 6] ] naf iridin-1, 8 (2H) -dione, 9- (4-chloro-3-fluorophenyl) -3,4,5,6,7,9-hexahydro-lH-cyclopenta [b] [1, 6] naphthyridin-1, 8 (2H) -dione, 9- (3,4-dichlorophenyl) -3,4,5,6,7,9-hexahydro-lH-cyclopenta [b] [1,6] naphthyridin-1, 8 (2H) -dione, 9- [4-chloro-3- (trifluoromethyl) phenyl] -3,4,5,6,7,9-hexahydro-lH-cyclopenta [b] [1,6] naphthyridin-1 , 8 (2H) -dione, 9- (3,4-dibromophenyl) -3,4,5,6,7,9-hexahydro-lH-cyclopenta [b] [1,6] naphthyridin-1,8 (2H) ) -dione, 9 (3-cyanophenyl) -3,4,5,6,7, 9-hexahydro-lH-cyclopenta [b] [1,6] naphthyridin-1,8 (2H) -dione, 9- ( 5-chloro-2-thienyl) -3,4,5,6,7,9-hexahydro-lH-cyclopenta [b] [1,6] naphthyridin-1,8 (2H) -dione, 9- (3 - nitrophenyl) -3,4,5,6,7,9-hexahydro-lH-cyclopenta [b] [1,6] naphthyridin-l, 8 (2H) -dione, 9 (5-nitro-2-thienyl) - 3,4,5,6,7, 9-hexahydro-lH-cyclopenta [b] [1,6] naphthyridin-1,8 (2H) -dione, 9- (5-nitro-3 -thienyl) -3,4,5,6,7, 9-hexahydro-lH-cyclopenta [b] [1,6] naphthyridin-1,8 (2H) -dione, 9- [4-fluoro-3- ( trifluoromethyl) phenyl] -5,6,7,9-tetrahydrofuro [3,4-b] quinolin-1, 8 (3H, 4H) -dione, 9- (4-chloro-3-nitrophenyl) -5,6, 7,9-tetrahydrofuro [3,4-b] quinolin-1, 8 (3H, 4H) -dione, 8- [4-fluoro-3- (2-furyl) phenyl] -5,8-dihydro-1H, 3H-difure [3, 4-b; 3, 4-e] pyridin-1, 7 (4H) -dione, (8S) -8- (3-bromo-4-fluorophenyl) -4,5,6, 8-tetrahydro-lH-cyclopenta [b] furo [3, 4-e] pyridin-1, 7 (3H) -dione, (8R) -8- (3-bromo-4-fluorophenyl) -4,5,6, 8-tetrahydro-lH-cyclopenta [b] furo [3, 4-e] iridin-1, 7 (3H) -dione, 8- [4-fluoro-3- (trifluoromethyl) phenyl] -5,8-dihydro-1H, 3H-difure [3, 4 b; 3, 4-e] pyridin-1, 7 (4H) -dione, (9S) -9- [4-fluoro-3- (trifluoromethyl) -5,6,7,9-tetrahydrofuro [3, 4-b] quinolin-1, 8 (3H, 4H) -dione, (9R) -9- [4-fluoro-3- (trifluoromethyl) phenyl] -5,6,7,9-tetrahydrofuro [3,4-b] quinoline- 1, 8 (3H, 4H) -dione, 8- (3,4-dichlorophenyl) -5,8-dihydro-1H, 3H-difuro [3,4-b; 3, 4-e] pyridin-1, 7 (4H) -dione, 8- (4-methyl-3-nitrophenyl) -5,8-dihydro-lH, 3H-difuro [3,4-b; 3, 4-e] pyridin-1, 7 (4H) -dione, (9S) -9- (3,4-dibromophenyl) -5,6,7,9-tetrahydrofuro [3,4-b] quinolin-1 , 8 (3H, 4H) -dione, (9R) -9- (3,4-dibromophenyl) -5,6,7,9-tetrahydrofuro [3,4-b] quinolin-1, 8 (3H, 4H) -dione, (9S) -9- (4-methyl-3-nitrophenyl) -5,6,7,9-tetrahydrofuro [3,4-b] quinolin-1, 8 (3H, 4H) -dione, (9R ) -9- (4-methyl-3-nitrophenyl) -5,6,7,9-tetrahydrofuro [3,4-b] quinolin-1, 8 (3H, 4H) -dione, (9S) -9- ( 3,4-dichlorophenyl) -5,6,7,9-tetrahydrofuro [3,4-b] quinolin-1, 8 (3H, 4H) -dione, (9R) -9- (3,4-dichlorophenyl) - 5,6,7,9-tetrahydrofuro [3,4-b] quinolin-1, 8 (3H, 4H) -dione, (9S) -9- (4-chloro-3-nitrophenyl) -5,6,7 , 9-tetrahydrofuro [3, 4-b] quinolin-1, 8 (3H, 4H) -dione, (9R) -9- (4-chloro-3-nitrophenyl) -5,6,7,9-tetrahydrofuro [ 3, 4-b] quinolin-1, 8 (3H, 4H) -dione, (9S) -9- (3,4-difluorophenyl) -5,6,7,9-tetrahydrofuro [3,4-b] quinolin -1, 8 (3H, 4H) -dione, (9R) -9- (3,4-difluorophenyl) -5,6,7,9-tetrahydrofuro [3,4-b] quinolin-1, 8 (3H, 4H) -d ione, (8S) -8- (4-methyl-3-nitrophenyl) -4,5,6, 8-tetrahydro-lH-cyclopenta [b] furo [3,4-e] pyridin-1, 7 (3H) -dione, (8R) -8- (4-methyl-3-nitrophenyl) -4,5,6, 8-tetrahydro-lH-cyclopenta [b] furo [3,4-e] pyridin-1, 7 (3H ) -dione, (8S) -8- (3,4-dichlorophenyl) -4,5,6,8-tetrahydro-lH-cyclopenta [b] furo [3,4-e] pyridin-1, 7 (3H) -dione, (8R) -8- (3,4-dichlorophenyl) -4,5,6,8-tetrahydro-1H-cyclopenta [b] furo [3,4-e] pyridin-1,7 (3H) - dione, (8S) -8- [4-fluoro-3- (trifluoromethyl) phenyl] -4,5,6,8-tetrahydro-l-cyclopenta [b] furo [3,4-e] pyridin-1, 7 (3 H) -dione, (8R) -8- [4-fluoro-3- (trifluoromethyl) phenyl] -4,5,6,8-tetrahydro-lH-cyclopenta [b] furo [3,4-e] pyridine -1, 7 (3H) -dione, (9S) -9- (3-Bromo-4-methylphenyl) -5,6,7,9-tetrahydrofuro [3,4-b] quinolin-1, 8 (3H, 4H) -dione, (9R) -9 - (3-bromo-4-methylphenyl) -5,6,7,9-tetrahydrofuro [3,4-b] quinolin-1, 8 (3H, 4H) -dione, 8- (3-chloro-4-fluorophenyl) ) -5, 8-dihydro-lH, 3H-difuro [3,4-b, -3, 4-e) pyridin-1,7 (4H) -dione, 8- (3,4-dibromophenyl) -5, 8-dihydro-lH, 3H-difuro [3,4-b; 3, 4-e] pyridin-1, 7 (4H) -dione, 8- (3-bromo-4-methylphenyl) -5,8-dihydro-lH, 3H-difuro [3,4- b; 3, 4-e] pyridin-1, 7 (4H) -dione, 8- [4-chloro-3- (trifluoromethyl) phenyl] -5,8-dihydro-1H, 3H-difuro [3,4-b; 3, 4-e] pyridin-1, 7 (4H) -dione, 8- (3-bromo-4-fluorophenyl) -4,5,6,8-tetrahydro-1H-furo [3, 4-b] pyrrolo [3, 4-e] -1.7 (3H) -dione, 2- (2-aminoethyl) -9- (3-bromo-4-fluorophenyl) -2,3,5,6,7, 9-hexahydro -lH-pyrrolo [3,4-b] quinolin-1,8 (4H) -dione, 8- (4-bromo-3-methylphenyl) -5,8-dihydro-1H, 3H-difure [3, 4 b; 3, 4-e] pyridin-1, 7 (4H) -dione, 8- (4-fluoro-3-isopropenylphenyl) -5,8-dihydro-1H, 3H-difure [3, 4-b, -3, 4-e] pyridin-1, 7 (4H) -dione, (9S) -2- (2-aminoethyl) -9- (3-bromo-4-fluorophenyl) -2,3,5,6,7, 9 -hexahydro-lH-pyrrolo [3,4-b] quinolin-1,8 (4H) -dione, 8- (3-iodo-4-methylphenyl) -5,8-dihydro-1H, 3H-difure [3, 4 -b; 3, 4-e] pyridin-1, 7 (4H) -dione, (-) -9- (3-bromo-4-fluorophenyl) -7,7-dimethyl-5,6,7,9-tetrahydrofuro [3 , 4-b] quinolin-1, 8 (3H, 4H) -dione, (+) - 9- (3-bromo-4-fluorophenyl) -7,7-dimethyl-5,6,7,9-tetrahydrofuro [ 3, 4-b] quinolin-1, 8 (3H, 4H) -dione, 8- [3- (2-furyl) -4-methylphenyl] -5,8-dihydro-lH, 3H-difure [3, 4 -b; 3, 4-e] pyridin-1, 7 (4H) -dione, 9- (3-bromo-4-fluorophenyl) -3,4,5,6,7,9-hexahydrocyclopenta [b] pyran [3, 4 -e] pyridine-1, 8-dione, 10- (3-bromo-4-fluorophenyl) -3,4,6,7,8, 10-hexahydro-1H-pyran [4, 3-b] quinolin-1 , 9 (5H) -dione, 10- [4-fluoro-3-trifluoromethyl] phenyl] -3,4,6,7,8,10-hexahydro-1H-pyran [4, 3-b] quinolin-1, 9 (5H) -dione, and 9- [4-fluoro-3- (trifluoromethyl) phenyl] -3,4,5,6,7,9-hexahydrocyclopenta [b] pyrano [3,4-e] pyridin-1 , 8-dione, or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof.

Preparation of the Compounds of the Invention The compounds and processes of the present invention will be better understood in connection with the following synthetic schemes and methods illustrating a means by which the compounds of the invention can be prepared.

The compounds of this invention can be prepared by a variety of synthetic routes. The representative procedures are shown in Schemes 1-41.

Scheme 1 Dihydropyridines of the general formula (4) can be prepared, wherein R2 = R2-, and R? and R 2 are as defined in formula I, as described in Scheme 1. Diester (1), prepared by the reaction of Hantzsch (Singer, A. and McElvain, SM, Org. Synth., Coll. Volume II (1943) 214), can be treated with N-bromosuccinimide (NBS), to provide the dibrominated dihydropyridine (2). Dibrominated dihydropyridine (2) can be treated with a primary amine (R2NH2), or with ammonia in a protic solvent, such as ethyl or methyl alcohol, to provide dihydropyridines of the general formula (4). The dihydropyridines of the general formula (5), wherein Rx is as defined in formula I, can be prepared by heating the clean dibromide (2) at 180 ° C.

Scheme 2 The dihydropyridines of the general formula (13), wherein Ri, R2, and n 'are as defined in formula I, can be prepared as described in Scheme 2. The β-keto-esters of the general formula (6) ), wherein R is lower alkyl, the aldehydes of the general formula (7), and the cyclic enami-nones of the general formula (8), can be combined in ethanol with heat to provide the dihydropyridines of the general formula (9). ). The dihydropyridines of the general formula (9) can be prepared using an alternative method. The 3-aminocrotonates of the general formula (10), wherein R is lower alkyl, the aldehydes of the general formula (7), and the cyclic dicarbonyls of the general formula (11), can be combined and heated in ethanol to provide the dihydropyridines of the general formula (9). The dihydropyridines of the general formula (9) can be treated with a brominating agent, such as pyridinium tribromide in pyrethrin / chloroform or NBS, in a solvent such as methanol, ethanol, isopropanol, or chloroform, to provide the bromomethyl- dihydropyridines of the general formula (12). The bromo-methyl dihydropyridines of the general formula (12) can be treated with a primary amine of the general formula (3) in an alcohol solvent, to provide the dihydropyridines of the general formula (13). The dihydropyridines of the general formula (14), wherein R x and n 'are as defined in formula I, can be prepared by heating the bromomethyl-dihydropyridines of the general formula (12) cleaned at 180 ° C.

Scheme 3 The dihydropyridines of the general formula (16), wherein A = A ', and A is as defined in formula I, can be prepared as described in Scheme 3. The dicarbonyl compounds of the general formula (15) they can be treated with the aldehydes of the general formula (7) in ammonia and ethanol, to provide the dihydropyridines of the general formula (16). Some dicarbonyl compounds of the general formula (15) can be prepared as described in (Nakagawa, S., Heterocycles 13 (1979) 477; D'Angelo, J., Tetrahedron Letters 32 (1991) 3063).

Scheme 4 The dihydropyridines of the general formula (17), wherein A, Rl7 and n 'are as defined in formula I, can be prepared as described in Scheme 4. The dicarbonyl compounds of the general formula (15), the aldehydes of the general formula (7), and the cyclic enaminones of the general formula (8), can be combined in ethanol, and can be heated to provide the dihydropyridines of the general formula (17). Scheme 5 O) (18) The dihydropyridines of the general formula (22-25), wherein Rl t R2, and n 'are as defined in formula I, can be prepared as described in Scheme 5. The dihydropyridines of the general formula (9), from Scheme 2, they can be treated with boron trichloride in methylene chloride to provide the dihydropyridines of the general formula (18). The dihydropyridines of the general formula (18) can be treated with thionyl chloride, and then with mandelic acid (+) or (-), to provide the diastereomers of the general formulas (19) and (20). The diastereomers of the general formulas (19) and (20) can be separated by column chromatography on silica gel. Each separated diastereomeric ester can then be processed as described in Scheme 2, to provide the enantiomeric dihydropyridines of the general formulas (22-25). The enantiomeric dihydropyridines of the general formulas (22-25) can be prepared using an alternative method. The diastereomers of the general formulas (19) and (20) can be treated with MeOH / NaOMe to provide the transesterified compounds. The methyl esters can then be treated as described in Scheme 2, to provide the enantiomeric dihydropyridines of the general formulas (22-25). In addition to the use of the method illustrated in Scheme 5, the individual enantiomers of the compounds of the present invention can also be separated by chiral chromatography. Both of the aforementioned methods for obtaining the individual enantiomers of the invention can also be applied to the preparation of other compounds, which methods for the preparation appear in Schemes 6-41. Scheme 6 The dihydropyridines of the general formulas (29) and (30), wherein Ri # R2, and n 'are as defined in formula I, can be prepared as described in Scheme 6. The 3-aminoprotonates of the general formula (10), wherein R is lower alkyl, the aldehydes of the general formula (7), and the cyclic β-keto-sulfones of the general formula (26), can be combined and heated in a solvent such as ethanol, methanol , acetonitrile, or toluene, to provide the dihydropyridines of the general formula (27), in the case where n '= 1, an additional heating step may be necessary at an elevated temperature in the presence or absence of an acid, such as hydrochloric acid or para-toluenesulfonic acid, to drive the reaction to completion. The dihydropyridines of the general formula (27) can be processed as described in Scheme 2, using reagents such as NBS, pyridinium tribromide, or a similar brominating agent, to provide the dihydropyridines of the general formula (28). The dihydropyridines of the general formula (28) can be processed as described in Scheme 2, to provide the dihydropyridines of the general formulas (29) and (30). The dihydropyridines of the general formula (27) can also be treated with gilding reagents such as S02C12, PC15 or NCS, to provide the analogous chloromethyl derivatives, which can also be processed as described in Scheme 2, to provide the dihydropyridines of the general formulas (29) and (30). Scheme 7 The dihydropyridines of the general formula (31), wherein A, Rx, and n 'are as defined in formula I, can be prepared as described in Scheme 7. The dicarbonyl compounds of the general formula (15) are they can be treated with a suitable ammonia source, such as NH 3, NH 4 OH, or NH 4 OAc, then the aldehydes of the general formula (7) and the cyclic β-keto-sulfones of the general formula (26) can be added, and heated the reaction mixture to provide the dihydropyridines of the general formula (31). In the case where n '= 1, an additional heating step at elevated temperature may be necessary in the presence or absence of an acid, such as hydrochloric acid or para-toluenesulfonic acid, to drive the reaction to completion. Scheme 8 The dihydropyridines of the general formulas (35) and (36), wherein Ri, R2, and A 'are as defined in formula I, can be prepared as described in Scheme 8. The 3-aminocrotonates of the formula (10), wherein R is lower alkyl, the aldehydes of the general formula (7), and the cyclic dicarbonyls of the general formula (32), the preparation of some dicarbonyls being described in (Naka-gawa, S., Heterocycles 13 (1979) 477; D'Angelo, J., Tetrahedron Letters 32 (1991) 3063), can be combined and heated in a solvent such as ethanol, methanol, acetonitrile, or toluene, to provide the dihydropyridines of the general formula ( 33). The dihydropyridines of the general formula (33) can be processed as described in Scheme 2 with NBS, pyridinium tribromide, or similar brominating agents, to provide the dihydropyridines of the general formula (34). The dihydropyridines of the general formula (34) can be processed as described in Scheme 2, to provide the dihydropyridines of the general formulas (35) and (36). The preparation of the compounds of the general formulas (35) and (36) can also be carried out by means of the chlorine analog of (34).

Scheme 9 The dihydropyridines of the general formulas (42) and (43), wherein Ri, R2 < , A, and n are as defined in formula I, can be prepared as described in Scheme 9. The condensation of the carbonyl compounds of the general formula (38) with the aldehydes of the general formula (7) using the Aldol reaction, provides the α, β-unsaturated ketones of the general formula (39). The preferred reaction is performed by first forming an enamine derivative of (38) with a secondary amine, such as morpholine, pyrrolidine, or piperidine. Then the enamine obtained is treated directly with the (7) under thermal conditions to form the (39). The α, β-unsaturated ketones of the general formula (39) can be treated with the 3-aminocrotonates of the general formula (10), wherein R is lower alkyl, such as methyl 3-aminocrotonate, to provide the dihydropyridines of the general formula (40). An alternative method can be performed for the preparation of (40) with (39), methyl acetoacetate, and ammonia with heating. The dihydropyridines of the general formula (40) can be processed as described in Scheme 2, to provide the bromomethyl-dihydropyridines of the general formula (41). The dihydro-pyridines of the general formula (41) can also be processed as described in Scheme 2, to provide the dihydropyridines of the general formulas (42) and (43).

The dihydropyridines of the general formula (45), wherein R 1 t A, n, and n 'are as defined in formula I, can be prepared as described in Scheme 10. The α, β-unsaturated keto the general formula (39), of Scheme 9, can be treated with the cyclic enaminones of the general formula (8) with heating, to provide the dihydropyridines of the general formula (45). An alternative method uses (39), ammonia, and dicarbonyl compounds of the general formula (11), with heating, to provide (45).

Scheme 11 The dihydropyridines of the general formula (46), wherein Rl t A, n, and n 'are as defined in formula I, can be prepared as described in Scheme 11. The α, β-unsaturated keto-ies of the general formula (39), of Scheme 9, can be treated with the cyclic ß-keto-sulfones of the general formula (26), and a suitable source of ammonia (see Scheme 7), with heating, to produce the dihydropyridines of the general formula (46).

Scheme 12 The dihydropyridines of the general formula (48), wherein Ri, A, A ', and n are as defined in formula I, can be prepared as described in Scheme 12. The α, β-unsaturated ketones of the formula General (39), of Scheme 9, can be treated with dicarbonyl compounds of the general formula (32) and ammonia or a suitable source of ammonia (see Scheme 7), with heating, to provide the dihydropyridines of the general formula ( 48).

Scheme 13 An alternative method for the preparation of the dihydropyridines of the general formula (45), wherein A is NR2, and R2 and n 'are as defined in formula I, can be performed as described in Scheme 13. The dihydropyridines of the general formula (13), of Scheme 2, can be reduced to provide the dihydropyridines of the general formula (45). Preferably, this transformation can be carried out by converting the (13) to the imino ether with trimethyl- or triethyl-oxonium tetrafluoroborate, and the reduction with sodium borohydride. Alternatively, the amide can be converted to the thioamide using a Lawesson reagent. The desulfurization of thioamide can be carried out with Raney nickel under a hydrogen atmosphere, desulfurization can also be carried out by conversion to the sulfonium species by the addition of an alkyl halide, such as iodomethane, and then reduction with sodium borohydride.

Scheme 14 An alternative method for the preparation of the dihydropyridines of the general formula (46), wherein A is NR2, and R2 and n 'are as defined in the formula I, can be performed as described in Scheme 14. The dihydropyridines of the general formula (30), of Scheme 6, can be reduced to provide the dihydropyridines of the general formula (46) as described in Scheme 13. Preferably, this transformation can be carried out by converting the (30) to the iminoether with trimethyl- or triethyl-oxonium tetrafluoroborate, and reduction with sodium borohydride.

Scheme 15 The dihydropyridines of the general formula (53), wherein Ri and R2 are as defined in formula I, can be prepared as described in Scheme 15. The dihydropyridine (1), of Scheme 1, can be mono-brominated to provide (50), and then heated to 180 ° C to provide the dihydropyridine (51). The dihydropyridine (51) can be brominated to provide the dihydropyridine (52). The dihydropyridine (52) can then be treated with primary amines of the general formula (3), as described in Scheme 2, to provide the dihydropyridines of the general formula (53). Alternatively, the sequence of reactions can be reconfigured, because the dihydropyridine (50) can be treated with a primary amine of the general formula (3), followed by a brominating agent as described in Scheme 2, and then it is heated to provide the dihydropyridines of the general formula (53).

Scheme 16 (55) The dihydropyridines of the general formula (55), wherein R 1 t A, and A 'are as defined in formula I, can be prepared as described in Scheme 16. The dicarbonyl compounds of the general formula (15) they can be treated with ammonia, and then they can be treated with the aldehydes of the general formula (7) and the dicarbonyl compounds of the general formula (32), with heating, to provide the dihydropyridines of the general formula (55) .

Scheme 17 The dihydropyridines of the general formula (62), wherein R1 # A, and n 'are as defined in formula I, can be prepared as described in Scheme 17. The carbonyl compounds of the general formula (58) are they can treat with secondary amines, such as morpholine, pi-rrolidine, or piperidine, to provide the enamines (59). The enamines (59) can be treated with the aldehydes of the general formula (7) in an appropriate organic solvent, to provide sulfides of the general formula (60). Oxidation of the sulfide with an oxidant, such as meta-chloroperoxybenzoic acid, provides the sulfoxides of the general formula (61), which can then be treated with dicarbonyl compounds of the general formula (15) and a source of ammonia, such as ammonia, ammonium acetate, or ammonium hydroxide, with heating, in a solvent such as ethyl alcohol or a similar alcohol solvent, acetonitrile, or dimethylformamide, to provide the dihydropyridines of the general formula (62).

Scheme 18 The dihydropyridines of the general formula (65), wherein Ri, A, and n 'are as defined in formula I, can be prepared as described in Scheme 18. The 3-aminocrotonates of the general formula (10) are can be treated with sulfoxides of the general formula (61), of Scheme 17, with heating, in a solvent such as ethyl alcohol or a similar alcohol solvent, acetonitrile, or dimethylformamide, to provide the bicyclic dihydropyridine sulfoxides of the general formula (64 ). Then the dihydropyridine sulfoxides of the general formula (64) can be processed as described in Scheme 2, to provide the dihydropyridines of the general formula (65).

Scheme 19 MeONa THF The dihydropyridines of the general formulas (70) and (71), wherein Rlf A, n, and n 'are as defined in formula I, can be prepared as described in Scheme 19. The racemic sulfones of the general formula (67) can be treated with potassium p-butoxide (one equivalent) in tetrahydrofuran, followed by 8-phenylmentyl (+) chloroformate or (-), to generate a mixture of diastereomeric 8-phenylmethyl carbamates (68) and ( 69). The diastereomers (68) and (69) can be separated by column chromatography on silica gel, and the 8-phenylmentol fraction is removed by a reaction with sodium methoxide in methanol, to provide the individual enantiomers of the general formulas ( 70) and (71).

Scheme 20 The dihydropyridines of the general formulas (77) and (78), wherein Ri, R4 < , R5 < , and A are as defined in formula I, can be prepared as described in Scheme 20. The 3-aminocrotonates of the general formula (10) can be treated with the aldehydes of the general formula (7) and the cycloalkanediones substituted by alkyl of the general formula (73), as described in Scheme 8, to provide the dihydropyridines of the general formula (74). The dihydropyridines of the general formula (74) can be separated into the individual (75) and (76) enantiomers using chiral chromatography or the method of Scheme 5. The enantiomers (75) and (76) can be processed as described in Scheme 2, to provide the enantiomeric dihydropyridines of the general formulas (77) and (78).

Scheme 21 The dihydropyridines of the general formula (81), wherein Ri # R4-, R5-, A, and n 'are as defined in formula I, can be prepared as described in Scheme 21. The dicarbonyl compounds of the general formula (15) can be treated with the aldehydes of the general formula (7) and the alkyl-substituted cyclic enaminones of the general formula (80) with heating in a solvent, such as ethyl alcohol or another similar alcohol solvent, acetonitrile, or dimethylformamide, to provide the dihydropyridines of the general formula (81).

Scheme 22 An alternative method can be used for the preparation of the dihydropyridines of the general formula (81), wherein R1 # R4-, R5-, A, and n 'are as defined in formula I, as described in Scheme 22. The heterocyclic enamines of the general formula (82) can be treated with the aldehydes of the general formula (7) and alkyl-substituted cyclic diones of the general formula (83) with heating, in a solvent, such as ethyl alcohol or other similar alcohol solvent, acetonitrile, or dimethylformamide, to provide the dihydropyridines of the general formula ( 81).

Scheme 23 The dihydropyridines of the general formula (86), wherein Rl t Re-, R7 < A, and n 'are as defined in formula I, can be prepared as described in Scheme 23. The heterocyclic dicarbonyl compounds of the general formula (82), can be treated with the aldehydes of the general formula (7) and alkyl substituted cyclic enaminones of the general formula (85), with heating, in a solvent, such as ethyl alcohol or other similar alcohol solvent, acetonitrile, or dimethylformamide, to provide the dihydropyridines of the general formula (86).

Scheme 24 Alternative methods can be used for the preparation of the dihydropyridines of the general formula (53) and (4), wherein Rlf R2, and R2- are as defined in formula I, as described in Scheme 24. The 2,4-pyrrolidinedione derivatives of the general formula (88), the aldehydes of the general formula (7), and the 3-aminocrotonates of the general formula (10), wherein R is lower alkyl, can be condensed to provide the dihydropyridines of the general formula (89). The dihydropyridines of the general formula (89) can be treated with a suitable brominating agent, such as pyridinium bromide perbromide or N-bromosuccinimide in a solvent, such as chloroform or methanol, to provide the dihydropyridines of the general formula (90) . The dihydropyridines of the general formula (90) can be heated to 70 ° C to provide the dihydropyridines of the general formula (53). The dihydropyridines of the general formula (90) can also be heated in the presence of a primary amine of the general formula (91), to provide the dihydropyridines of the general formula (4). Many of the starting materials needed to perform the methods described in the above schemes can be purchased from commercial sources, while others are known in the chemical literature. Appropriate literature references can be found in the following section or in the examples section for these known entities. For the starting materials not previously described in the literature, it is intended that the following schemes illustrate their preparation through a general method.

Scheme 25 The enamines of the general formula (94), where n 'is an integer of 1 to 3, and R3 is absent or can be one or two substituents independently selected from alkyl, can be prepared according to the general method shown in Scheme 25. This method involves reacting an appropriate cycloalkanedione of the general formula (92) with an alcohol, such as ethanol or methanol, with catalysis by an acid, such as sulfuric acid or acid. hydrochloric, or other similar acid, to form an enol ether intermediary of the general formula (93), wherein R is lower alkyl, such as ethyl or methyl. The enol ether (93) can be converted to an enamine of the general formula (94) by its reaction with ammonia, usually in a solvent such as methanol, ethanol, or tetrahydrofuran. This method is preferred for the preparation of 3-amino-4,4-dimethyl-2-cyclohexen-1-one and 3-amino-6,6-dimethyl-2-cyclohexen-1-one.

Scheme 26 As shown in Scheme 26, the enamines of the general formula (95), wherein n 'is an integer from 1 to 3, and R3 < is absent or can be one or two substituents independently selected from alkyl, they can be pre-stopped by methods directly analogous to those described in Scheme 25, wherein the carbonyl compound of the general formula (95) can be converting to an enol ether intermediate of the general formula (96), wherein R is lower alkyl, and then to the enamine (97). Many of the starting aryl and heteroaryl aldehydes required to perform the methods described in the above and following schemes can be purchased from commercial sources, or can be synthesized by known procedures found in the chemical literature. References in the literature suitable for the preparation of the aryl and heteroaryl aldehydes can be found in the following section or in the examples. For the starting materials not previously described in the literature, it is intended that the following schemes illustrate their preparation through a general method. The preparation of the aldehydes used to synthesize many preferred compounds of the invention can be found in the following literature references: Pearson, Org. Synth Coll. Volume V (1973), 117; Nwaukwa, Tetrahedron Lett. (1982), 23, 3131; Badder, J. In-dian Chem. Soc. (1976), 53, 1053; Khanna, J. Med. Chem. (1997), 40, 1634, Rinkes, Recl. Trav. Chim. The Netherlands (1945), 64, 205; van der Lee, Recl. Trav. Chim. The Netherlands (1926), 45, 687; Widman, Chem. Ber. (1882), 15, 167; Hodgson, J. Chem. Soc. (1927), 2425; Clark, J. Fluorine Chem. (1990), 50, 411; Hodgson, J. Chem. Soc. (1929), 1635; Duff, J. Chem. Soc. (1951), 1512; Crawford, J. Chem. Soc. (1956), 2155; Taneouchi, J. Med. Chem. (1981), 24, 1149; Bergmann, J. Am. Chem. Soc. (1959), 81, 5641; Others: Eistert, Chem. Ber. (1964), 97, 1470; Sekikawa, Bull. Chem. Soc. Jpn. (1959), 32, 551.

Scheme 27 The meta, para-disubstituted aldehydes of the general formula (100), wherein Ri0 is selected from haloalkyl, halogen, haloalkoxy, alkoxy, thioalkyl, -NZ? Z2, and -C (0) NZ? Z2, wherein Zx and Z2 are independently selected from hydrogen, alkyl, alkylcarbonyl, aryl, arylalkyl, and formyl, and R12 is selected from nitro, halogen, and alkylcarbonyl, they can be prepared according to the method described in Scheme 27. A para-substituted aldehyde of the general formula (99), or the corresponding acetal protected aldehyde of the general formula (101), wherein R is selected from alkyl, or together with the oxygen atoms with which they are attached they form a 5 or 6 membered ring, wherein the 1,3-dioxolanes are preferred, they can be subjected to conditions of an electrophilic aromatic substitution reaction to provide the aldehydes of the general formula (100), or the protected aldehydes of the general formula (10 2) . Preferred protecting groups for the compounds of the general formulas (101) and (102) include dimethyl or diethyl acetals or the 1,3-dioxolanes. These protecting groups can be introduced at the beginning, and can be removed at the end to provide the substituted aldehydes of the general formula (100), using methods well known to those skilled in the art of organic chemistry.

Scheme 28 105) (106) The aldehydes of the general formula (106), wherein Rio is selected from alkyl, haloalkyl, halogen, haloalkoxy, thioalkyl, -NZ? Z2, and -C (0) NZ? Z2 / wherein Zi and Z2 are independently selected from hydrogen, alkyl, alkylcarbonyl, aryl, arylalkyl, and formyl, and Ri2 is selected from nitro, halogen, and alkylcarbonyl, they can be prepared by the method described in Scheme 28. A phenol meta-substituted (104) is converted to the para-substituted salicylaldehyde (105) by its reaction with a base, such as sodium hydroxide, and a reagent such as trichloromethane or tribromomethane, known as the Reimer-Tiemann reaction. An alternative set of reaction conditions involves the reaction with magnesium methoxide and paraformaldehyde (Aldred, J. Chem. Soc. Perkin Trans. 1 (1994), 1823). The aldehyde (105) can be subjected to conditions of an electrophilic aromatic substitution reaction to provide the meta, para-disubstituted salicylaldehydes of the general formula (106).

Scheme 29 An alternative method can be used for the preparation of the meta, para-disubstituted salicylaldehydes of the general formula (106), wherein Rio is selected from alkyl, haloalkyl, halogen, haloalkoxy, alkoxy-lo, thioalkyl, -NZ? Z2, and -C (0) NZ? Z2, wherein Zi and Z2 are independently selected from hydrogen, alkyl, alkylcarbonyl, aryl, arylalkyl, and formyl, and R12 is selected from nitro, halogen, and alkylcarbonyl, as described in Scheme 29. A meta, para-disubstituted phenol of the general formula (107) can be reacted with a base, such as sodium hydroxide, and a reagent such as trichloromethane or tribromomethane, known as the reaction of Reimer-Tiemann, to provide the disubstituted salicylaldehydes of the general formula (106). An alternative set of reaction conditions involves the reaction with magnesium methoxide and paraformaldehyde (Aldred, J. Chem. Soc. Perkin Trans. 1 (1994), 1823). Scheme 30 In Scheme 30 an alternative method for the preparation of the benzaldehydes of the general formula (100) is described, wherein Ri2 is selected from alkyl, haloalkyl, chlorine, fluorine, haloalkoxy, alkoxy, thioalkyl, nitro, alkylcarbonyl, arylcarbonyl, - ZZ and -C (0) NZ? Z2, wherein Zi and Z2 are independently selected from hydrogen, > alkyl, alkylcarbonyl, aryl, arylalkyl, and formyl, and R10 is selected from alkyl, hydroxyalkyl, thioalkyl, alkylcarbonyl, and formyl. The protected benzaldehydes of the general formula (108), wherein R is selected from alkyl, or together with the oxygen atoms with which they are attached, form a 5 or 6 membered ring, where 1, 3 are preferred. -dioxolanes, can be converted to the 3,4-disubstituted benzaldehyde of the general formula (102) by converting the bromide to an intermediate lithium or magnesium derivative, followed by the reaction with a suitable electrophile, such as an aldehyde, disulfide dialkyl, a Weinreb amide, dimethylformamide, an alkyl halide, or other electrophilic, followed by deprotection of the acetal to provide the benzaldehydes of the general formula (100). Scheme 31 An alternative method can be used for the preparation of the benzaldehydes of the general formula (100), wherein Rio is selected from alkyl, haloalkyl, chloro, fluoro, haloalkoxy, alkoxy, thioalkyl, -NZ? Z2, and -C (0) NZ? Z2, wherein Z and Z2 are independently selected from hydrogen, alkyl, alkylcarbonyl, aryl, arylalkyl, and formyl, Ri2 is selected from alkyl, hydroxyalkyl, thioalkyl, alkylcarbonyl, arylcarbonyl, and formyl, as described in Scheme 31. The protected benzaldehydes of the general formula (110), wherein R is selected from alkyl, or together with the oxygen atoms with which they are attached form a 5 or 6 membered ring, wherein the 1,3-dioxolanes are preferred, they can be processed as described in Scheme 30, to provide the benzaldehydes of the general formula (100).

Scheme 32 The benzaldehydes of the general formula (113), wherein R10 is selected from hydrogen, alkyl, alkylsulfonyl, aryl, heteroaryl, cyano, haloalkyl, halogen, haloalkoxy, nitro, alkoxy, thioalkyl, -NZ? Z2, and -C (0) NZ? Z2, wherein Zx and Z2 are independently selected from hydrogen, alkyl, alkylcarbonyl, aryl, arylalkyl, and formyl, and Ri3 is selected from hydrogen, alkyl, arylalkyl, and haloalkyl , wherein the preferred haloalkyl groups are selected from difluoromethyl, 2,2,2-trifluoroethyl, and bromodifluoromethyl, can be prepared as described in Scheme 32. The 3-hydroxybenzaldehyde of the general formula (112) can be treated with suitable alkylating reagents, such as benzyl bromide, iodomethane, 2-iodo-1,1,1-trifluoroethane, chlorodi-fluoromethane, or dibromodifluoromethane, in the presence of a base, such as potassium carbonate, potassium terbutoxide, or sodium terbutoxide, to provide r the benzaldehydes of the general formula (113). The synthesis of the useful 3-hydroxybenzaldehydes of the general formula (112) can be found in the following literature references: J. Chem. Soc. (1923), 2820; J. Med. Chem. (1986), 29, 1982; Monatsh Chem. (1963), 94, 1262; Justus Leibigs Ann. Chem. (1897), 294, 381; J. Chem. Soc. Perkin Trans. 1 (1990), 315; Tetrahedron Lett. (1990), 5495; J. Chem. Soc. Perkin Trans. 1 (1981), 2677.

Scheme 33 The benzaldehydes of the general formula (115), wherein R12 is selected from hydrogen, alkyl, alkylsulfonyl, aryl, heteroaryl, cyano, haloalkyl, halogen, haloalkoxy, nitro, alkoxy, thioalkyl, -NZXZ2, and -C (0) ) NZ? Z2, wherein Zi and Z2 are independently selected from hydrogen, alkyl, alkylcarbonyl, aryl, arylalkyl, and formyl, and Ri3 is selected from hydrogen, alkyl, arylalkyl, and haloalkyl, wherein the haloalkyl groups Preferred are selected from difluoromethyl, 2,2,2-trifluoroethyl, and bromodifluoromethyl, they can be prepared as described in Scheme 33. The 4-hydroxybenzaldehydes of the general formula (114) can be treated with suitable alkylating reagents, such as such as benzyl bromide, iodomethane, 2-iodo-l, 1,1-trifluoroethane, clo-rhodifluoromethane, or dibromodifluoromethane, in the presence of a base, such as potassium carbonate, potassium terbutoxide, or sodium terbutoxide, to provide the benzaldehydes of the general formula (115). The synthesis of the useful 4-hydroxybenzaldehydes of the general formula (114) can be found in the following literature references: Angyal, J. Chem. Soc. (1950), 2141; Ginsburg, J. Am. Chem. Soc. (1951), 73, 702; Claisen, Justus Liebigs Ann. Chem. (1913), 401, 107; Nagao, Tetrahedron Lett. (1980), 21, 4931; Ferguson, J. Am. Chem. Soc. (1950), 72, 4324; Barnes, J. Chem. Soc. (1950), 2824; Villagomez-Ibarra, Tetrahedron (1995), 51, 9285; Komiyama, J. Am. Chem. Soc. (1983), 105, 2018; DE 87255; Hodgson, J. Chem. Soc. (1929), 469; Hodgson, J. Chem. Soc. (1929), 1641.

Scheme 34 An alternative method for introducing the substituents at the 3-position of the benzaldehydes of the general formula (100), wherein R x x is selected from hydrogen, alkyl, alkylsulfonyl, aryl, heteroaryl, cyano, haloalkyl, halogen, can be used. , haloalkoxy, ni-tro, alkoxy, thioalkyl, and -C (0) NZ? Z2, wherein Zi and Z2 are independently selected from hydrogen, alkyl, alkylcarbonyl, aryl, arylalkyl, and formyl, as described in Scheme 34. This method, also known as the Sandmeyer reaction, involves converting the 3-aminobenzaldehydes of the general formula (116) to an intermediate diazonium salt with sodium nitrite. The diazonium salts can be treated with a source of bromine or iodine to provide the bromide or iodide. The Sandmeyer reaction and the conditions for effecting the transformation are well known to those skilled in the art of organic chemistry. The types of R12 substituents that may be introduced in this form include cyano, hydroxyl, or halogen. In order to carry out this transformation successfully, in certain circumstances it may be convenient to carry out the Sandmeyer reaction on a protected aldehyde. The resulting iodide or bromide can be treated with unsaturated halides, boronic acids, or tin reagents in the presence of a palladium catalyst, such as tetrakis (triphenylphosphine) pala-dio (0), to provide the benzaldehydes of the general formula neral (100). The diazonium salts can also be treated directly with unsaturated halides, boronic acids, or tin reagents in the presence of a palladium catalyst, such as tetrakis (triphenylphosphine) palladium (0), to provide the benzaldehydes of the general formula (100 ).

Scheme 35 An alternative method for the introduction of the substituents at the 4-position of the benzaldehydes of the general formula (100), wherein R12 is selected from hydrogen, alkyl, alkylsulfonyl, aryl, heteroaryl, cyano, haloalkyl, can be used. , halogen, haloalkoxy, nitro, alkoxy, thioalkyl, and -C (0) NZ? Z2, wherein Zi and Z2 are independently selected from hydrogen, alkyl, alkylcarbonyl, aryl, arylalkyl, and formyl, as described in Scheme 35. This method, also known as the Sandmeyer reaction, involves converting the 4-aminobenzaldehydes of the general formula (117) to an intermediate diazonium salt with sodium nitrite, and then treating the diazonium salts in a manner similar to that described in Scheme 34. The types of Ri0 substituents that may be introduced in this form include cyano, hydroxyl, or halogen. The Sandmeyer reaction and the conditions for effecting the transformation are well known to those skilled in the art of organic chemistry. In order to carry out this transformation successfully, in certain circumstances it may be convenient to carry out the Sandmeyer reaction on a protected aldehyde.

Scheme 36 The 4-bromo-3- (trifluoromethoxy) benzaldehyde or the 4-chloro-3- (trifluoromethoxy) benzaldehyde can be prepared as described in Scheme 36. Commercially available 4-bromo-2- (trifluoromethoxy) aniline can be prepared. protect on the amino group with a suitable N-protecting group, well known to those skilled in the art of organic chemistry, such as acetyl or terbutoxycarbonyl. The bromine can then be converted to the lithium or magnesium derivative and reacted directly with dimethylformamide to give the 4-amino-protected 3- (trifluoromethoxy) benzaldehyde derivative. Removal of the N-protecting group, followed by conversion of the amine to a bromide or chloride by the Sandmeyer method of Scheme 35, provides 4-bromo-3- (trifluoromethoxy) benzaldehyde, or 4-chloro-4- (trifluoromethoxy) benzaldehyde.

Scheme 37 The 4-trifluoromethylbenzaldehydes of the general formula (119), wherein X is selected from cyano, nitro, and halogen, can be prepared according to the method of Scheme 37. First, 4-trifluoromethylbenzoic acid is nitrated, using suitable conditions well known in the literature, such as nitric acid with sulfuric acid, and the carboxylic acid group it is reduced with borane to provide the 3-nitro-4-trifluoromethylbenzyl alcohol. From this benzyl alcohol, 3-nitro-4-trifluoromethylbenzaldehyde can be obtained by oxidation with typical reagents, such as manganese dioxide. The nitrobenzyl alcohol can be reduced to the aniline using any of a number of different conditions to effect this transformation, among which a preferred method is hydrogenation over a palladium catalyst. The aniline can be converted to a halogen or cyano substituent using the Sandmeyer reaction described in Scheme 34. The benzylic alcohols of the general formula (118) can be oxidized using conditions well known to those skilled in the art, such as dioxide of manganese, or Swern conditions, to provide the benzaldehydes of the general formula (119). For certain Ri ring aromatic substitutions for the compounds of the present invention, it is preferable to effect the transformations of the aromatic ring substitutions after the aldehyde has been incorporated into the nuclear structure of the present invention. As such, the compounds of the present invention can be further transformed to other compounds than the present invention. These transformations involve coupling reactions of Stille, Suzuki, and Heck, all of which are well known to those skilled in the art of organic chemistry. Some representative methods of these transformations of compounds of the present invention to other compounds of the present invention are shown below.

Scheme 38 The dihydropyridines of the general formula (121), wherein A, AD, DA n and n 'are as defined in formula I, R 3 - is 1 or 2 substituents independently selected from hydrogen or alkyl, Rio is selected from hydrogen, alkyl, alkylcarbonyl, alkylsulfonyl, aryl, heteroaryl, cyano, haloalkyl, chloro, fluoro, haloalkoxy, nitro, alkoxy, and thioalkyl, and -C (0) NZ! Z2, wherein Zx and Z2 are independently selected from hydrogen, alkyl, alkylcarbonyl, aryl, arylalkyl, and formyl, Rn is selected from hydrogen, hydroxyl, alkoxy, haloalkoxy, and arylalkoxy, Ri2 is selected from alkyl, vinyl, aryl, heteroaryl, cyano, and the like , can be prepared as described in Scheme 38. Compounds of the general formula (120), wherein X is selected from bromine, iodine, and triflate, are protected with a terbuto-xicarbonyl (Boc) group, using conventional procedures. The bromide, iodide, or aromatic triflate can be treated with a suitable reagent of tin, boronic acid, or unsaturated halide in the presence of a palladium catalyst with heating in a solvent, such as dimethylformamide, to effect a coupling reaction which provides the dihydropyridines of the general formula (121). The conditions for this transformation also effect the removal of the Boc protecting group.

Scheme 39 (122) (123) The dihydropyridines of the general formula (123), wherein A, AA D, DA n and n 'are as defined in formula I, R 3 - is 1 or 2 substituents independently selected from hydrogen or alkyl , R12 is selected from hydrogen, alkyl, alkylcarbonyl, alkylsulfonyl, aryl, heteroaryl, cyano, haloalkyl, chlorine, fluorine, haloalkoxy, nitro, alkoxy, thioalkyl, and -C (0) NZ? Z2, in where Zi and Z2 are independently selected from hydrogen, alkyl, alkylcarbonyl, aryl, arylalkyl, and formyl, Rii is selected from hydrogen, hydroxyl, alkoxy, haloalkoxy, and arylalkoxy, Rio is selected from alkyl, vinyl, aryl, heteroaryl, cyano, and the like, can be prepared as described in Scheme 39. The dihydropyridines of the general formula (122), wherein X is selected from bromine, iodine, and triflate, can be protected with a Terbutoxycarbonyl group (Boc) using conventional procedures is. The aromatic bromide, iodine, or triflate, can be reacted with a suitable reagent of tin, boronic acid, or unsaturated halide, in the presence of a palladium catalyst with heating in a solvent, such as dimethylformamide, to effect a reaction of coupling that provides the dihydropyridines of the general formula (123). The conditions for this transformation also effect the removal of the Boc protecting group. Scheme 40 (126) The dihydropyridines of the general formula (126), wherein A, A ', D, D', n, and n 'are as defined in formula I, R3. is 1 or 2 substituents independently selected from hydrogen or alkyl, R10 is selected from hydrogen, alkyl, alkylcarbonyl, alkylsulfonyl, aryl, heteroaryl, cyano, haloalkyl, chloro, fluoro, haloalkoxy, nitro, alkoxy, thioalkyl, and - C (0) NZ? Z2, where Z? and Z2 are independently selected from hydrogen, alkyl, alkylcarbonyl, aryl, arylalkyl, and formyl, and Rn is selected from hydrogen, hydroxyl, alkoxy, haloalkoxy, and arylalkoxy, can be prepared as described in Scheme 40. The dihydropyridines of the general formula (125), wherein X is selected from bromine, iodine, and triflate, can be protected with a terbutoxycarbonyl (Boc) using conventional procedures. The bromide, iodide, or aromatic triflate can be treated with a suitable halozinc reagent in the presence of a palladium catalyst with heating, in a solvent, such as dimethylformamide, to effect a coupling reaction that provides the dihydropyridines of the general formula (126). The conditions for this transformation also effect the removal of the Boc protecting group. The types of meta substituents that may be introduced in this form include trihalopropenyl, and more specifically the trifluoropropenyl group.

Scheme 41 The dihydropyridines of the general formula (128), wherein A, A ', O, O', n, and n 'are as defined in formula I, R3- is 1 or 2 substituents independently selected from hydrogen or alkyl , Rx0 is selected from hydrogen, alkyl, alkylcarbonyl, alkylsulfonyl, aryl, heteroaryl, cyano, haloalkyl, chlorine, fluorine, haloalkoxy, nitro, alkoxy, thioalkyl, -C (0) NZ? Z, wherein Zi and Z2 are independently selected from hydrogen, alkyl, alkylcarbonyl, aryl, arylalkyl, and formyl, Rn is selected from hydrogen, hydroxyl, alkoxy, haloalkoxy, and arylalkoxy, they can be prepared as described in Scheme 41. Dihydropyridines of the general formula (127), wherein X is selected from bromine, iodine, and triflate, can be protected with a terbutoxy-carbonyl group (Boc) using conventional procedures. The bromide, iodide, or aromatic triflate can be treated with a suitable halozinc reagent in the presence of a palladium catalyst with heating in a solvent, such as dimethylformamide, to effect a coupling reaction that provides the dihydropyridines of the general formula ( 128). The conditions for this transformation also effect the removal of the Boc protecting group. The types of substituents that can be introduced in this form include trihalopropenyl, and more specifically the trifluoropropenyl group. The following methods are intended as an illustration and not a limitation of the scope of the invention as defined in the appended claims. In addition, all citations herein are incorporated by reference.

Example 1 8- (3-bromo-4-fluorophenyl) -2.3.4.5.6.8-hexahydrodipirrolo 3.4- b; 3.4-pyridine-1.7-dione The use of 4- 4-bromo-4-fluorophenyl) -1,4-dihydro-2,6-dimethyl-3,5-pyridine-diethyl dicarboxylate A solution of 3-bromo-4-fluorobenzaldehyde (6.00 grams, 29.6 millimoles) and ethyl acetoacetate (7.81 grams, 60 millimoles) in ethyl alcohol (15 milliliters) and methylene chloride (15 milliliters) was treated with concentrated ammonium hydroxide (6.2 milliliters) in two portions over a period of 2 days with heating under reflux. The reaction was allowed to cool to room temperature. The solvent was evaporated, and the crude material was purified by evaporation chromatography (1: 3 -ethyl acetate: hexane), to give 11.3 grams of the title compound as a light yellow solid. XH NMR (300 MHz, CDCl 3) d 1.22 (t, 6H), 2.35 (s, 6H), 4.10 (m, 4H), 4.94 (s, ÍH), 5.56 (s, ÍH), 6.95 (t, ÍH) , 7.18 (m, ÍH), 7.42 (dd, ÍH). MS (DCI / NH3) m / z 443 (M + NH4) +.

Example IB 2 .6-bis- (bromomethyl) -4- (3-bromo-4-fluorophenyl) -1,4-dihydro-3,5-pyridine-dicarboxylate diethyl A solution of the product of Example IA (1.27 grams, 3.00 mmol) in Methyl alcohol (60 milliliters), treated with N-bromosuccinimide (1.068 grams, 6.00 mmol), and stirred for 1.5 hours at room temperature. The reaction was poured into water, and the resulting precipitate was collected. The precipitate was crystallized from acetone-na / hexane to give 685 milligrams of the title compound as a yellow solid. XH NMR (300 MHz, CDC13) d 1.25 (t, 6H), 4.15 (m, 4H), 4.76 (AB qu, .4H), 4.96 (s, ÍH), 6.48 (s, ÍH), 6.99 (t, ÍH), 7.18 (m, ÍH), 7.43 (dd, ÍH); MS (APCI +) m / z 584 (M + H) +.

Example 1C 8- (3-bromo-4-fluorophenyl) -2.3.4.5.6.8-hexahydrodipyrrolo 3 .4-b; 3.4-iridin-1.7-dione The product of Example IB (0.29 grams, 0.50 milli-moles) was treated with liquid ammonia (25 milliliters) in ethyl alcohol (25 milliliters) in a high-pressure pump for 2 days at room temperature. The solvent was evaporated, and the resulting solid was triturated with hot ethyl alcohol / ethyl acetate. This solid was washed with water, then with diethyl ether, and dried to provide 26 milligrams of the title compound as a yellow solid. XH NMR (300 MHz, DMS0-dβ) d 3.95 (q, 4H), 4.58 (s, ÍH), 7.25 (d, 2H), 7.42 (s, 2H), 7.46 (s, ÍH), 9.83 (s, ÍH); MS (APCI +) m / z 364 (M + H) +. MS (APCI-) m / z 362 (MH) "; Analysis calculated for C? 5HnBrFN3O2" 0.3 H2O "0.5 C2H60: C, 48.95; H, 3.75; N, 10.70. Found: C, 48.64; H, 3.96; N , 10.33.

Example 2 8- (3-bromo-4-fluorophenyl) -2,6-dimethyl-2.3.4.5.6.8- hexahydrodipyrrolo T3.4 -b: 3.4 - pyridine-1.7-dione The product of Example IB (0.812 grams, 1.4 milli -moles) was treated with methylamine / 2.0 M methyl alcohol (7.0 milliliters) for 3 hours. The reaction mixture was concentrated, and the resulting white precipitate was triturated with diethyl ether / methylene chloride / methyl alcohol. The solid was washed with water and dried to give 183 milligrams of the title compound. XH NMR (300 MHz, DMSO-d6) d 2.80 (s, 6H), 4.05 (q, 4H), 4.59 (s, ÍH), 7.22 (d, 2H), 7.45 (d, ÍH), 9.88 (s, ÍH); MS (APCI +) m / z 392 (M + H) A MS (APCI-) m / z 390 (MH) "; Analysis calculated for C? 7H? 5BrFN3O2 * 0.25 H20: C, 51.47; H, 3.94; N, 10.59, Found: C, 51.13; H, 4.19; N, 10.36.

Example 3 8- (3-bromo-4-fluorophenyl) -2-methyl-2.3.4.5.6.8- hexahydrocyclopenta Tbl pyrrolo T3.4-pyridine-1.7-dione Example 3A 4- (3-bromo-4-fluorophenyl) -4.5.6.7- ehydro-2-methyl-5-oxo-lH-cyclopentyl methyl 3-pyridine-3-carboxylate 3-bromo-4-fluorobenzaldehyde (3.045) grams, 15 millimoles), methyl acetoacetate (2.09 grams, 18 mmol), and 3-aminocyclopent-2-enone (1.45 grams, 15 mmol) at 65 ° C in methyl alcohol for 5 days. The reaction was allowed to cool to room temperature, and the white precipitate was collected, washed with methyl alcohol, and dried, to provide 2.29 grams of the title compound. Evaporation chromatography (5 percent methyl alcohol / methylene chloride) of the filtrate gave an additional 1.46 grams of the title compound. XH NMR (300 MHz, CDC13) d 2.45 (s, 3H), 3.60 (s, 3H), 4.90 (s, ÍH), 6.33 (s, ÍH), 6.98 (t, ÍH), 7.23 (m, ÍH) 7.37 (d, ÍH); MS (APCI +) m / z 380 (M + H) +; Analysis calculated for C? 7H? 5BrFN03: C, 53.70; H, 3.98; N, 3.68. Found: C, 53.57; H, 3.91; N, 3.48.

Example 3B 4- (3-Bromo-4-fluorophenyl) -2- (bromomethyl) -4.5.6.7-tetrahydro-5-oxo-lH-cyclopentarb1pyridine-3-carboxylic acid methyl ester A solution of the product of Example 3A (1.9 grams, 5.0 mmol) in isopropyl alcohol (30 milliliters) was treated with N-bromosuccinimide (890 milligrams, 5.0 mmol), and stirred at room temperature for 45 minutes. The solvent was evaporated, and the crude evaporated was passed through chromatography to provide 1.19 grams of the title compound. XH NMR (300 MHz, CDCl 3) d 2.47 (m, 2H), 2.65 (m, 2H), 3.63 (s, 3H), 4.83 (AB q, 2H), 4.90 (s, ÍH), 6.80 (br s, ÍH), 7.00 (t, ÍH), 7.23 (m, ÍH), 7.40 (dd, ÍH).

Example 3C 8- (3-bromo-4-fluorophenyl) -2-methyl-2.3.4.5.6.8- hexahydrocyclopenta Tbl pyrrone T3.4-pyridine-1.7-dione The product of Example 3B (0.110 grams, 0.24 ml-limes) ) in methyl alcohol (1.5 milliliters), treated with methylamine / 2M methyl alcohol (1 milliliter), and stirred overnight at room temperature. The reaction mixture was concentrated, and the crude evaporated was passed through chromatography (10 percent methyl alcohol / methylene chloride). The product was triturated with diethylether to provide 51.6 milligrams of the title compound as a white powder. XH NMR (DMSO-de) d 2.30 (d, 2H), 2.65 (m, 2H), 4.08 (q, 2H), 4.55 (s, ÍH), 7.22 (m, 2H), 7.45 (d, ÍH), 10.32 (s, ÍH); MS (APCI +) m / z 377 (M + H) +; MS (APCI-) m / z 375 (M-H) "- Calculated Analysis for C? 7H? 4BrFN202; C, 54.13; H, 3.74; N, 7.43. Found: C, 53.76; H, 3.94; N, 7.34.

Example 4 8- 3-bromo-4-fluorophenyl) -2-ethyl-2.3.4.5.6.8- hexahydrocyclopenta Tbl pyrrone T3.4-pyridine-1.7-dione The product of Example 3B (0.30 grams, 0.52 milli-moles ) in methyl alcohol (2 milliliters), treated with ethylamine / 2M methyl alcohol (2.5 milliliters), and stirred for 1 hour at room temperature. The reaction mixture was concentrated, and the crude evaporated was passed through chromatography (7.5 percent methyl alcohol / methylene chloride), to provide 100 milligrams of the title compound as a tan solid. H NMR (300 MHz, DMSO-dg) d 1.04 (t, 3H), 2.30 (t, 2H), 2.62 (t, 2H), 3.26 (q, 2H), 4.08 (q, 2H), 4.53 (s) , HH), 7.22 (m, 2H), 7.43 (d, HH), 10.35 (s, HH); MS (APCI +) m / z 391 (M + H) +; MS (APCI-) m / z 389 (M-H) "; Analysis calculated for C? 8H16BrFN202: C, 55.26; H, 4.12; N, 7.16, Found: C, 54.92; H, 4.16; N, 6.99.

Example 5 8- (3-bromo-4-fluorophenyl) -5,8-dihydro-H 3 H-difure T3.4-b; 3.4- pyridine-1.7 (4H) -dione The product of Example IB (90 milligrams) was heated in an oil bath at 180 ° C for 1 hour, and then allowed to cool to room temperature. The residue was triturated with acetone, and the solid was collected, washed with acetone, and dried, to provide 32 milligrams of the title compound as a light yellow solid. P.f. > 260 ° C? H NMR (300 MHz, DMSO-d6) d 4.69 (s, ÍH), 4.98 (q, 4H), 7.32 (m, 2H), 7.57 (d, ÍH), 10.73 (s, ÍH); MS (ESI-) m / z 364 (M-H) "; Analysis calculated for C? 5H9BrFN04: C, 49.21; H, 2.48; N, 3.83. Found: C, 49.23; H, 2.61; N, 3.69.

Example 6 8- (3-bromo-4-fluorophenyl) -4.5.6.8-tetrahydro-1H-cyclopenta Tbl furo T.4-e1 iridin-1.7 (3H) -dione The product of Example 3B (85 milligrams, 0.19 mmol) it was heated in an oil bath at 180 ° C for 1 hour, and then allowed to cool to room temperature. The residue was triturated with acetone, and the solid was collected, washed with acetone, and dried, to provide 30 milligrams of the title compound as an orange solid. P.f. > 260 ° C XH NMR (300 MHz, DMS0-d6) d 2.35 (t, 2H), 2.70 (m, 2H), 4.60 (s, ÍH), 4.98 (q, 2H), 7.26 (m, 2H), 7.50 (d, 1H =), 10.71 (s, ÍH); MS (ESI-) m / z 362 (M-H) "; Analysis calculated for C? 6HnBrFNO3 * 0.2 H20: C, 51.91; H, 2.97; N, 3.77. Found: C, 52.25; H, 3.12; N, 3.81.

Example 7 8- (3-bromo-4-fluorophenyl) -2- (2-methoxyethyl) -2.3.4.5.6.8- hexahydrocyclopenta Tbl pyrrolo T3.4-pyridine-1.7-dione The product of Example 3B (300 milligrams, 0.65 mmol) in methanol was treated with 2-methoxyethylamine (488 milligrams, 6.5 mmol) at room temperature overnight. The solvent was evaporated, and the residue was passed through chromatography by evaporation on silica gel (10 percent methanol / methylene chloride). The product was triturated with ether, collected, and dried to provide 93 milligrams of the title compound as a yellow solid. P.f. 100 ° C (decomposition); XH NMR (300 MHz, DMSO-dg) d 2.32 (t, 2H), 2.67 (m, 2H), 3.24 (s, 3H), 3.42 (m, 4H), 4.13 (q, 2H), 4.57 (s, ÍH), 7.22 (m, 2H), 7.44 (d, ÍH), 10.63 (s, ÍH); MS (ESI +) m / z 421 (M + H) +; MS (ESI-) m / z 419 (MH) "Analysis calculated for C? 9H? 8BrFN2O3 * 0.2 H20: C, 53.71; H, 4.37; N, 6.59. Found: C, 53.29; H, 4.59; N, 6.27.

Example 8 9 - (3-bromo-4-fluorophenyl) -2-methyl-2.3.5.6.7.9-hexahydro-1H-pyrrolor3.4-b1 quinolin-1.8 (4H) -dione Example 8A 4- (3-Bromo-4-fluorophenyl) -2-methyl-5-oxo-l .4.5.6.7.8-methyl-hexahydroquinoline-3-carboxylate 3-Bromo-4-fluorobenzaldehyde (3.05 grams, 15 mmol), methyl 3-aminocrotonate (1.73 grams, 15 mmol), and 1,3-cyclohexanedione (1.68 grams, 15 mmol) in refluxing methanol for 2 hours, and then allowed to cool to room temperature. The precipitate was collected and dried to provide 4.89 grams of the title compound. E NMR (300 MHz, CDC13) d 1.8-2.1 (m, 2H), 2.25-2.50 (m, 4H), 2.42 (s, 3H), 3.62 (s, 3H), 5.07 (s, ÍH), 5.86 ( br s, ÍH), 6.95 (t, ÍH), 7.23 (m, ÍH), 7.39 (dd, ÍH); MS (ESI +) m / z 394 (M + H) +.

Example 8B 4- (3-bromo-4-fluorophenyl) -2- (bromomethyl) -5-oxo-l.4.5.6.7.8- methyl hexahydroquinoline-3-carboxylate The product of Example 8A (3.94 grams, 10 mmol ) in chloroform (25 milliliters) and pyridine (0.97 milliliters, 12 millimoles) was treated with 90 percent pyridinium tribromide (4.26 grams, 12 millimoles) at -10 ° C. The reaction mixture was stirred for 3.5 hours, quenched on water, and extracted with chloroform (3 times). The organic phases were dried (MgSO 4), filtered, and the solvent was evaporated to provide 5.5 grams of the title compound as a yellow foam. XH NMR (300 MHz, CDC13) d 1.80-2.15 (m, 2H), 2.30-2.62 (m, 4H), 3.66 (s, 3H), 4.80 (s, 2H), 5.08 (s, ÍH), 6.32 ( br s, ÍH), 6.97 (t, ÍH), 7.23 (m, ÍH), 7.42 (dd, ÍH).

Example 8C 9- (3-bromo-4-fluorophenyl) -2-methyl-2.3.5.6.7.9-hexahydro-lH-pyrrolo T3.4-bl? N? Inolin-1.8 (4H) -dione The product of Example 8B (100 milligrams) in methanol (2 milliliters) was treated with 2.0 M methylamine in methanol (0.75 milliliters), and stirred during the night. The solvent was evaporated, and the crude was purified by chromatography by evaporation on silica gel (10 percent methanol / methylene chloride), to provide 41 milligrams of the title compound as a white solid. P.f. >260 ° C; XH NMR (300 MHz, DMS0-de) d 1.91 (m, 2H), 2.23 (t, 2H), 2.55 (m, 2H), 2.80 (s, 3H), 4.00 (q, 2H), 4.70 (s, ÍH), 7.19 (m, 2H), 7.44 (d, 2H), 9.83 (s, ÍH); MS (ESI +) m / z 391 (M + H) +; MS (ESI-) m / z 389 (M-H) "; Analysis calculated for d8H? 6BrFN202: C, 55.26; H, 4.12; N, 7.16, Found: C, 54.97; H, 4.15; N, 6.90.

Ex ml 9 9- (3-bromo-4-fluorophenyl) -2-ethyl-2.3.5.6.7.9-hexahydro-lH-pyrrolo T3.4-bl quinolin-1.8 (4H) -dione The product of Example 8B (0.35 grams) in methanol (2 milliliters) was treated with 2.0 M ethylamine in methanol (2.35 milliliters), and stirred overnight. The solvents were evaporated, and the crude was purified by chromatography by evaporation on silica gel (10 percent methanol / methylene chloride). The product was triturated with ether / methanol / methylene chloride, to provide 138 milli-grams of the title compound as a white solid. P.f. 241-247 ° C XH NMR (300 MHz, DMS0-d6) d 1.02 (t, 3H), 1.91 (m, 2H), 2.23 (m, 2H), 2.56 (m, 2H), 3.21 (q, 2H) , 4.00 (q, 2H), 4.70 (s, ÍH), 7.19 (m, 2H), 7.42 (d, ÍH), 9.83 (s, ÍH); MS (ESI +) m / z 405 (M + H) +; MS (ESI-) m / z 403 (M-H) "Analysis calculated for C? 9H18BrFN202: C, 56.31; H, 4.48; N, 6.91, Found: C, 55.95; H, 4.44; N, 6.84.

Example 10 9- (3-bromo-4-fluorophenyl) -5.6.7.9-tetrahydrofide T3.4- bl quinolin-1.8 (3H.4H) -dione The product of Example 8B (100 milligrams) was heated to 180 ° C in an oil bath for 1 hour, and then allowed to cool to room temperature. The residue was triturated with acetone, collected, washed with acetone, and dried to give 40 milligrams of the title compound as a pink solid. P.f. > 260 ° C; XH NMR (300 MHz, DMS0-de) d 1.91 (m, 2H), 2.25 (m, 2H), 2.58 (m, 2H), 4.68 (s, ÍH), 4.90 (q, 2H), 7.23 (m, 2H), 7.44 (d, ÍH), 10.19 (s, ÍH); MS (ESI +) m / z 378 (M + H) +; MS (ESI-) m / z 376 (M-H) "; Analysis calculated for C? 7H? 3BrFN03; C, 53.99; H, 3.46; N, 3.70. Found: C, 53.91; H, 3.46; N, 3.58.

EXAMPLE 11 9- (3-Bromo-4-fluorophenyl) -2.3.5.6.7.9-hexahydro-lH-pyrrolo T3.4-bl quinolin-1.8 (4H) -dione The product of Example 8B (0.40 grams) in methanol ( 35 milliliters) was treated with ammonia (35 milliliters) at room temperature for 20 hours in a high pressure pump. The solvent was evaporated, and the precipitate was collected, washed with 10 percent methanol / methylene chloride, water, and dried under vacuum at 90 ° C overnight, to provide 93 milligrams of the title compound as a powder Gray . P.f. > 260 ° C; XH NMR (300 MHz, DMS0-dg) d 1.90 (m, 2H), 2.25 (m, 2H), 2.55 (m, 2H), 3.92 (q, 2H), 4.70 (s, ÍH), 7.19 (m, 2H), 7.44 (m, 2H), 9.78 (s, ÍH); MS (ESI +) m / z 377 (M + H) +; MS (ESI-) m / z 375 (MH) "; Analysis calculated for C? 7H? 4BrFN2O2 * 0.6 H20: C, 52.62; H, 3.95; N, 7.22. Found: C, 52.29; H, 3.76; N, 7.38.

Example 12 8- (3-bromo-4-fluorophenyl) -2- T2- (4-morpholinyl) ethyl ester -2.3.4.5.6.8-hexahydrocyclopenta Tbl irritated T3.4-pyridine-1.7-dione La 2- ( 4-morpholino) ethylamine was replaced by methylamine, and processed as described in Example 3C, to provide the title compound as a white solid. The free amine (80 milligrams) was dissolved in methyl alcohol, and treated with hydrochloric acid (1M in diethyl ether, 10 equivalents). The reaction mixture was stirred at room temperature for 30 minutes. After removing the volatiles, the residue was triturated with diethyl ether to provide the title compound (82 milligrams) as a tan solid. MS (ESI (+)) m / z 476 (M + H) +; MS (ESI (-)) m / z 474 (MH) "; XH NMR (300 MHz, DMSO-d6) d 2.32 (t, 2H), 2.68 (m, 2H), 3.0-4.0 (m, 8H), 4.22 (q, 2H), 4.59 (s, ÍH), 7.25 (m, 2H), 7.51 (d, ÍH), 10.28 (br s, ÍH), 10.61 (s, ÍH); Analysis calculated for C22H24BrClFN3O3 * 0.65 CH2C12 * 2.5 H20: C, 44.38; H, 4.98; N, 6.85; Cl, 13.32, Found: C, 44.01; H, 5.04; N, 7.02; Cl, 13.57.

Example 13 8-3-bromo-4-fluorophenyl hydrochloride) -2- T2- (dimethylamino) ethyl -2.3.4.5.6.8-hexahydrocyclopenta Tbl irritated T3.4-bl pyridine-1.7-dione The 2-dimethylaminoethylamine was substituted per methylamine, and processed as described in Example 3C, to provide the title compound as a white solid. The free amine was dissolved in methyl alcohol, and treated with hydrochloric acid (1 M in diethylether, 10 equivalents). The reaction mixture was stirred at room temperature for 30 minutes. After removing the volatiles, the residue was triturated with diethyl ether, to give the title compound (75 milligrams) as a tan solid. MS (ESK +)) m / z 434 (M + H) +; MS (ESI (-)) m / z 432 (MH) "); XH NMR (300 MHz, DMSO-d6) d 2.32 (t, 2H), 2.49 (s, 6H), 2.55-2.80 (m, 4H) , 3.48 (m, 2H), 4.17 (s, 2H), 4.59 (s, ÍH), 7.23 (d, 2H), 7.48 (d, ÍH), 9.43 (br s, ÍH), 10.53 (s, ÍH) Analysis calculated for C20H22BrClFN3O2 * 0.2 CH2C12 * 1.8 H20: C, 46.64; H, 5.04; N, 8.08; Cl, 10.09, Found: C, 46.26; H, 5.21; N, 7.74; Cl, 9.88.

Example 14 9- (3-bromo-4-fluorophenyl) -2- (2-methoxyethyl) -2.3.5.6.7.9- hexahydro-lH-pyrrolo T3.4-bl quinolin- 1.8 (4H) -dione 2-methoxyethylamine was replaced by methylamine, and processed as described in Example 8C, to provide the title compound as a white solid. P.f. 206-208 ° C; MS (ESI (-)) m / z 433 (MH) ";? E NMR (300 MHz, DMSO-d6) d 1.92 (m, 2H), 2.23 (t, 2H), 2.55 (m, 2H), 3.22 (s, 3H), 3.32 (t, 2H), 3.39 (m, 2H), 4.05 (q, 2H), 4.70 (s, ÍH), 7.20 (m, 2H), 7.42 (d, ÍH), 9.83 ( s, H), Analysis calculated for C20H20BrFN2O3; C, 55.19; H, 4.63; N, 6.44, Found: C, 54.86; H, 4.44; N, 6.06.

Example 15 (9R) -9- (3-bromo-4-fluorophenyl) -2-methyl-2.3.5.6.7.9-hexahydro-lH-pyrrolo T3.4-bl quinolin-1.8 (4H) -dione Example 15A 4- (3-Bromo-4-fluorophenyl) -2-methyl-5-oxo-l .4.5.6.7.8-hexahydro-3-quinolinecarboxylic acid boron trichloride (1 M in methylene chloride) , 200 milliliters) to a solution of the product of Example 8A (19.7 grams, 50 mmol) in 50 milliliters of methylene chloride cooled in an ice bath. The reaction mixture was stirred overnight at room temperature, and then diluted with 1,000 milliliters of ice water and 750 milliliters of ethyl acetate. After the addition of ethyl acetate, a fine solid formed, was collected, washed with additional ethyl acetate, and dried under vacuum at 90 ° C to provide the title compound (16.9 grams, 89 percent). ) as a white powder. P.f. 225-228 ° C; MS (ESI (+)) m / z 380 (M + H) +; MS (ESI (-)) m / z 378 (MH) "; XH NMR (300 MHz, DMSO-d6) d 1.70-1.95 (m, 2H), 2.20 (t, 2H), 2.30 (s, 3H), 2.45 (m, 2H), 4.87 (s, ÍH), 7.13 (m, ÍH), 7.20 (t, ÍH), 7.36 (d, ÍH), 9.14 (s, ÍH), 11.8 (br s, ÍH); Analysis calculated for C? 7H15BrFN03: C, 53.70; H, 3.98; N, 3.68. Found: C, 53.43; H, 3.92; N, 3.56.

Example 15B Acid (2R) - ( {T4- (3-bromo-4-fluorophenyl) -2-methyl-5-oxo- 1.4.5.6.7.8-hexahydro-3-quinolinip carbonyl} oxy) (phenyl) ) ethanoic To a solution of Example 15A (16.9 grams, 44.5 mmol) in N, N-dimethylformamide (150 milliliters) at -10 ° C, thionyl chloride (5.29 grams, 44.5 mmol) was added. The reaction mixture was stirred at -10 ° C for 1.5 hours. (R) -mandelic acid (6.77 grams, 44.5 millimoles) was added, followed by the addition of triethylamine (4.5 grams, 44.5 millimoles). The reaction mixture was maintained at -10 ° C for another 2 hours, and at room temperature for 1 hour, before quenching with ethyl acetate: diethylether (1: 2) and water. The organic layer was dried, filtered, and concentrated to provide the crude diastereomeric mixture (20 grams). The title compound was isolated as the most polar diastereomer after chromatography by evaporation (silica, methyl alcohol: methylene chloride: acetic acid, 10: 90: 0.5) as a yellow solid. MS (ESK +)) m / z 514 (M + H) +; MS (ESI (-)) m / z 512 (MH) "; XH NMR (300 MHz, DMSO-d6) d 1.70-1.81 (m, HH), 1.85-1.94 (m, HH), 2.20 (m, 2H ), 2.34 (s, 3H), 2.48 (m, 2H), 4.87 (s, ÍH), 7.13-7.28 (m, 3H), 7.38-7.45 (m, 5H), 9.37 (s, ÍH); Calculated Analysis for C25H21BrFN05: C, 58.38; H, 4.12; N, 2.72, Found: C, 57.93; H, 4.47; N, 2.33.

Example 15C (4R) -4- (3-bromo-4-fluorophenyl) -2-methyl-5-oxo-l.4.5.6.7.8-methyl hexahydro-3-quinolinecarboxylate The product of Example 15B (257 milligrams, 0.5 mmol) was dissolved in methyl alcohol (50 milliliters). Metal sodium (0.58 grams, 25 mmol) was added, and the reaction mixture was refluxed overnight. After concentration, the residue was treated with hydrochloric acid (2M) at a pH of 7, and diluted with water (50 milli-liters). After being allowed to cool, the mixture was extracted several times with methylene chloride. The combined organic layers were dried over magnesium sulfate, filtered, and concentrated to provide the title compound as a white foamy solid (153 milligrams, 84 percent).

Example 15D (9R) -9- (3-bromo-4-fluorophenyl) -2-methyl-2.3.5.6.7.9-hexahydro-lH-pyrrolo T3.4-bl quinolin-1.8 (4H) -dione The product of Example 15C was processed as described in Example 8C to provide the title compound as a white powder. MS (ESK +)) m / z 391 (M + H) +; MS (ESI (-)) m / z 389 (MH) ";? H NMR (300 MHz, DMSO-dg) d 1.91 (m, 2H), 2.23 (m, 2H), 2.55 (m, 2H), 2.79 (s, 3H), 4.02 (q, 2H), 4.70 (s, ÍH), 7.19 (m, 2H), 7.42 (d, ÍH), 9.82 (s, ÍH); Analysis calculated for C? 8H? 6BrFN202 0.4 CH2C12: C, 51.97; H, 3.98; N, 6.59. Found: C, 51.95; H, 3.89; N, 6.60.

Example 16 (9R) -9- (3-bromo-4-fluorophenyl) -5.6.7.9-etrahydrofide T3.4-b1fAIPPlin, -l, 8 (3R.4H) -dione The product of Example 15C was processed as described in Example 10 to provide the title compound as a chestnut solid.

MS (APCI-) m / z 376 (MH) ";? U NMR (300 MHz, DMSO-dg) d 1.92 (m, 2H), 2.25 (m, 2H), 2.57 (m, 2H), 4.68 (s) , ÍH), 4.88 (q, 2H), 7.23 (m, 2H), 7.44 (d, ÍH), 10.18 (S, ÍH), Analysis calculated for C? 7H? 3BrFN03: C, 53.99; H, 3.46; N 3.70, Found: C, 54.10, H, 3.69, N, 3.88.

Example 17 (9R) -9- (3-bromo-4-fluorophenyl) -2.3.5.6.7.9-hexahydro-lH-pyrrolo 13 .4-b-quinoline-1.8 4H) -dione The product of Example 15C was processed as described in Example 11 to provide the title compound as a yellow powder. MS (APCI-) m / z 375 (MH) "; 411 (M + Cl") "; XH NMR (300 MHz, DMSO-dg) d 1.90 (m, 2H), 2.23 (m, 2H), 2.55 ( m, 2H), 3.93 (q, 2H), 4.70 (s, ÍH), 7.20 (m, 2H), 7.42 (d, ÍH), 7.47 (s, ÍH), 9.80 (s, ÍH); Analysis calculated for C? 7H14BrFN2O2 * 0.5 H20: C, 52.87; H, 3.91; N, 7.25, Found: C, 52.87; H, 3.80; N, 7.21.

Example 18 (9S) -9- (3-bromo-4-fluorophenyl) -5.6.7.9-tetrahydrofuro T3.4- bl quinolin-1.8 (3H.4H) -dione Example 18A Acid 4- (3-bromo-4- fluorophenyl) -2-methyl-5-oxo-1.4.5.6.7.8-hexahydro-3-quinolinecarboxylic boron trichloride (1 M in methylene chloride, 200 milliliters) was added to a solution of the product of Example 8A (19.7 grams, 50 millimoles) in 50 milliliters of methylene chloride cooled in an ice bath. The reaction mixture is stirred overnight at room temperature, and then diluted with 1,000 milliliters of ice water and 750 milliliters of ethyl acetate. After the addition of the ethyl acetate, a fine solid formed, was collected, washed with additional ethyl acetate, and dried under vacuum at 90 ° C, to provide the title compound (16.9 grams, 89 percent) like a white powder. P.f. 225-228 ° C; MS (ESI (+)) m / z 380 (M + H) +; MS (ESI (-)) m / z 378 (M-H) "; XU NMR (300 MHz, DMSO-dg) d 1.70-1.95 (m, 2H), 2.20 (t, 2H), 2. 30 (s, 3H), 2.45 (m, 2H), 4.87 (s, ÍH), 7.13 (m, ÍH), 7.20 (t, ÍH), 7.36 (d, ÍH), 9.14 (s, ÍH), 11.8 (br s, ÍH); Analysis calculated for C? 7H? 5BrFN03: C, 53.70; H, 3.98; N, 3.68. Found: C, 53.43; H, 3.92; N, 3.56.

Example 18B Acid (2R) - ( {T4- (3-bromo-4-fluorophenyl) -2-methyl-5-oxo-1.4.5.6.7.8-hexahydro-3-quinolinyl carbonyl} oxy) (phenyl) Ethanoic To a solution of the product of Example 18A (16.9 grams, 44.5 mmol) in N, N-dimethylformamide (150 milliliters) at -10 ° C, thionyl chloride (5.29 grams, 44.5 mmol) was added. The reaction mixture was stirred at -10 ° C, for 1.5 hours. (R) -mandelic acid (6.77 grams, 44.5 millimoles) was added, followed by the addition of triethylamine (4.5 grams, 44.5 millimoles). The reaction mixture was kept at -10 ° C for another 2 hours, and at room temperature for 1 hour, before quenching with ethyl acetate: diethylether (1: 2), and water. The organic layer was dried, filtered, and concentrated to provide the crude diastereomeric mixture (20 grams). The title compound was isolated as the less polar diastereomer after chromatography by evaporation (silica, methyl alcohol: methylene chloride: acetic acid, 10: 90: 0.5) as a yellow solid. MS (ESI (+)) m / z 514 (M + H) +; MS (ESI (-)) m / z 512 (MH) "; XH NMR (300 MHz, DMSO-d6) d 1.70-1.81 (m, HH), 1.85-1.94 (m, HH), 2.20 (m, 2H ), 2.34 (s, 3H), 2.48 (m, 2H), 4.87 (s, ÍH), 7.13-7.28 (m, 3H), 7.38-7.45 (m, 5H), 9.37 (s, ÍH); Calculated Analysis for C25H2? BrFN05 0.2 C7H8: C, 59.52; H, 4.28; N, 2.63, Found: C, 59.90; H, 4.57; N, 2.35.

Example 18C (4S) -4- (3-bromo-4-fluorophenyl) -2-methyl-5-oxo-1.4.5.6.7.8-methyl hexahydro-3-quinolinecarboxylate The product of Example 18B (257 milligrams, 0.5 mmol. ) was dissolved in methyl alcohol (50 milliliters). Metal sodium (0.58 grams, 25 mmol) was added, and the reaction mixture was refluxed overnight. After the concentration, the residue was treated with hydrochloric acid (2 M) at a pH of 7, and diluted with water (50 ml-liliters). After being allowed to cool, the mixture was extracted several times with methylene chloride. The combined organic layers were dried over magnesium sulfate, filtered, and concentrated to provide the title compound as a white foamy solid (153 milligrams, 84 percent). Absolute stereochemistry was determined by X-ray crystallographic analysis.

Example 18D (9S) -9- (3-bromo-4-fluorophenyl) -5.6.7.9- etrahydrofide T3.4- bl quinolin-1.8 (3H.4H) -dione The product of Example 18C was processed as described in Example 10 to provide the title compound as a light pink powder. MS (ESI (-)) m / z 376 (MH) "; XH NMR (300 MHz, DMSO-dg) d 1.91 (m, 2H), 2.26 (m, 2H), 2.58 (m, 2H), 4.68 ( s, ÍH), 4.89 (q, 2H), 7.23 (m, 2H), 7.4 * 4 (d, ÍH), 10.17 (s, ÍH); Analysis calculated for CX7H13BrFN03 • 0.2 H20: C, 53.48; H, 3.54; N, 3.67, Found:, C, 53.18; H, 3.92; N, 3.46.

Example 19 (9S) -9- (3-bromo-4-fluorophenyl) -2-methyl-2.3.5.6.7.9-hexahydro-lH-pyrrolo T3.4-bl quinolin-1.8 (4H) -dione The product of Example 18 C was processed as described in Example 8C to provide the title compound as a pale yellow solid. MS (ESK +)) m / z 391 (M + H) +; MS (ESI (-)) m / z 389 (MH) "; XH NMR (300 MHz, DMSO-dg) d 1.90 (m, 2H), 2.24 (m, 2H), 2.55 (m, 2H), 2.78 ( s, 3H), 4.02 (q, 2H), 4.69 (s, ÍH), 7.18 (m, 2H), 7.43 (d, ÍH), 9.80 (s, ÍH); Analysis calculated for C? 8H? 6BrFN202: C, 55.26; H, 4.12; N, 7. 16. Found: C, 54.99; H, 4.08; N, 7.03.

Example 20 (9S) -9- (3-bromo-4-fluorophenyl) -2.3.5.6.7.9-hexahydro-lH-pyrrolo T3.4-bl quinolin-1.8 (4H) -dione The product of Example 18C was processed as is described in Example 11 to provide the title compound as a beige solid.

MS (ESI (+)) m / z 377 (M + H) +; MS (ESI (-)) m / z 375 (MH) "; XH NMR (300 MHz, DMSO-dg) d 1.90 (m, 2H), 2.23 (m, 2H), 2.55 (m, 2H), 3.93 ( q, 2H), 4.69 (s, ÍH), 7.19 (, 2H), 7.42 (d, ÍH), 7.48 (s, ÍH), 9.80 (s, ÍH); Analysis calculated for C1H14BrFN2O2 »0.4 CH2C12: C, 50.83; H, 3.63; N, 6.81, Found: C, 50.67; H, 3.80; N, 6.75.

Example 21 9- (3-cyanophenyl) -2-methyl-2.3.5.6.7.9-hexahydro-lH-pyrrolo T3.4-bl quinoline-1.8 4H) -dione The 3-cyanobenzaldehyde was replaced by 3-bromo-4- fluorobenzaldehyde, and processed as described in Example 8C, to provide the title compound as a yellow solid. MS (ESI (+)) m / z 320 (M + H) +; MS (ESI (-)) m / z 318 (M-H) ";? U NMR (300 MHz, DMSO-dg) d 1.88-1.94 (m, 2H), 2.21-2.26 (m, 2H), 2.54-2.57 (m, 2H), 2.78 (s, 3H), 4.00 (q, 2H), 4.74 (s, ÍH), 7.42 (t, ÍH), 7.52-7.58 (m, 3H), 9.83 (Yes H); Analysis calculated for C19H17N3O2 »0.6 H20: C, 69.33; H, 5.27; N, 12.77. Found: C, 68.87; H, 5.71; N, 12.42.

Example 22 l. 8- (3-bromo-4-f luorofenyl) -6-methyl-2-l-dioxide. 3 . Four . 5. 6. 8- hexahydro-7H-pyrrolo T3.4-bl thieno 12.3-pyridin-7-one Example 22A 1.1-dioxide of 7- (3-bromo-4-4-fluorophenyl) -5-methyl-2.3.4.7- tetrahydrotienor3 .2-bl methyl pyridine-6-carboxylate 3-bromo-4-fluorobenzaldehyde (2.03 grams, 10 mmol), 3-aminocrotonate (1.15 grams, 10 mmol), and tetrahydrothiophene-3-oxo-l, 1-dioxide prepared as described in (J. Heterocycl, Chem., volume 27, pages 1453 (1990)), (1.29 grams, 9.6 mmol) were suspended in methyl alcohol (30 milliliters). The reaction mixture was stirred in a sealed tube at 65 ° C overnight. The formed white precipitate (hemiaminal intermediate) was filtered and washed with acetone. This intermediate was again suspended in methyl alcohol, and treated with hydrochloric acid (1 M in diethylether, 10 milliliters). The reaction mixture was refluxed for 2 hours. After concentration, the white residue was triturated with diethyl ether, and filtered to provide the title compound (2.88 grams, 72 percent) as a white solid. P.f. 232-234 ° C; MS (ESI (-)) m / z 416 (MH) "; XH NMR (300 MHz, DMSO-dg) d 2.28 (s, 3H), 2.75-3.05 (m, 2H), 3.28-3.35 (m, 2H ), 3.52 (s, 3H), 4.87 (s, ÍH), 7.19 (m, ÍH), 7.26 (t, ÍH), 7.48 (d, ÍH), 9.50 (s, ÍH); Analysis calculated for C? EH 5BrFN04S: C, 46.17; H, 3.63; N, 3.36, Found: C, 46.13; H, 3.78; N, 3.27, Example 22B 1.1-8- (3-bromo-4-fluorophenyl) -6-methyl dioxide -2.3.4.5.6.8- hexahydro-7H-pyrrolo T3.4-bl thieno \ 2.3 -pyridin-7-one The product of Example 22A (104 milligrams, 0.25 mmol) was dissolved in chloroform (2 milliliters), and treated with pyridinium tribromide (58 milligrams, 0.275 milli-moles) at -10 ° C. The reaction mixture was gradually warmed to room temperature and stirred for 2 hours. Methylamine (2.0 M in methyl alcohol, 1.4 milliliters) was added to the reaction mixture. After stirring at room temperature overnight, the reaction mixture was concentrated, and the residue was purified by column chromatography by evaporation (silica, 7.5 percent methyl alcohol-methylene chloride), to provide the title compound ( 26 milligrams, 25 percent) as a white yellow powder. MS (ESK +)) m / z 413 (M + H) +; MS (ESI (-)) m / z 411 (MH) "; XH NMR (300 MHz, DMSO-dg) d 2.78 (s, 3H), 2.82-3.10 (m, 2H), 3.36 (t, 2H), 4.04 (q, 2H), 4.78 (s, ÍH), 7.27 (m, 2H), 7.48 (d, ÍH), 9.96 (s, ÍH); Example 23 9- (3-bromo-4-fluorophenyl) -3.4.5.6.7.9-hexahydro-lH-cyclopenta Tbl TI. β-naphthyridine-1.8 (2H) -dione The 3-bromo-4-fluorobenzaldehyde (1 millimole, 203 milligrams), piperidin-2,4-dione, prepared using a procedure similar to that described in (Lowe, G. and Yeung, HW, J. Chem. Soc. Perkin I, (1973) 2907-2910, from ß-alanine ethyl ether hydrochloride and ethylmalonyl chloride), (1 millimole, 113 milligrams), and 3-amino-2-cyclopenten-1 -one (1 millimole, 97 milligrams), were suspended in ethyl alcohol (5 milliliters). The reaction mixture was heated in a sealed tube at 80 ° C for a period of 48 hours. The formed precipitate was collected by filtration, washed with cold ethyl alcohol, and dried under vacuum to provide the title compound (122 milligrams, 32 percent). MS (APCI +) m / z 377 (M + H) +; 2H NMR (DMSO-dg) d 2.25 (t, 2H), 2.40-2.70 (m, 4H), 3.15-3.35 (m, 2H), 4.70 (s, ÍH), 7.07 (bs, ÍH), 7.17-7.22 (m, 2H), 7.42 (dd, ÍH), 9.83 (S, ÍH); Analysis calculated for d7H? 4N202FBr: C, 54.13; H, 3.74; N, 7.43. Found: C, 53.91; H, 3.82; N, 7.42.

Example 24 10- (3-bromo-4-fluorophenyl) -3.4.6.7.8.10-hexahydrobenzo Tbl fl .61 naphthyridine-1.9 (2H.5H) -dione The 3-bromo-4-fluorobenzaldehyde (1 millimole, 203 ml) ligramos, piperidin-2, 4-dione (1 millimole, 113 milligrams), and 3-amino-2-cyclohexen-l-one (1 millimole, 111 milligrams) were suspended in ethyl alcohol (5 milliliters). was heated in a sealed tube at 50 ° C for a period of 72 hours.The precipitate formed was collected by filtration, washed with cold ethyl alcohol, and dried under vacuum to provide the title compound (218 milligrams, 56 percent) MS (ESI +) m / z 391 (M + H) +; XH NMR (DMSO-dg) d 1.70-1.97 (m, 2H), 2.15-2.25 (m, 2H), 2.36-2.59 (m , 4H), 3.13-3.23 (m, 2H), 4.90 (s, ÍH), 7.00 (bs, ÍH), 7.15-7.20 (m, 2H), 7.39 (dd, ÍH), 9.28 (s, ÍH); Analysis calculated for C? 8H? EN202FBr: C, 55.26; H, 4.12; N, 7.16, Found: C, 55.06; H, 4.32; N, 7.14.

Example 25 (9S) -9- (4-fluoro-3-iodophenyl) -5.6.7.9- etrahydrofuro f3.4- bl uinolin-1.8 (3H.4H) -dione Example 25A (3-amino-4-fluorophenyl) methanol 3-Amino-4-fluorobenzoic acid (15 grams, 97 mmol) in tetrahydrofuran, at 0 ° C, was treated with a borane 1.0 M-tetrahydrofuran complex (50 milliliters ), was stirred overnight at room temperature, treated with an additional 130 milliliters of a 1.0 M-tetrahydrofuran borane complex, stirred for 10 hours, quenched by the addition of methanol, stirred for 3 hours at room temperature, concentrated, and partitioned between aqueous sodium bicarbonate / methylene chloride. The methylene chloride layer was dried (sodium sulfate), filtered, and concentrated. The residue was purified by flash chromatography on silica gel (ethyl acetate / hexane, 1: 1) to provide 7.0 grams of the title compound. XH NMR (300 MHz, CDC13) d 4.58 (s, 2H), 6.67 (br m, ÍH), 6.81 (d, ÍH), 6.95 (t, ÍH).

Example 25B (4-fluoro-3-iodophenyl) methanol The product of Example 25A (7.0 grams, 50 millimoles) in water (100 milliliters) at 0 ° C, was slowly treated with concentrated sulfuric acid (30 milliliters), a speed to keep the temperature below 10 ° C, and then treated by dripping with an aqueous solution of sodium nitrite (3.45 grams, 50 mmol). This solution was then added to a solution of potassium iodide (8.13 grams, 50 mmol) in water (15 milliliters), heated at 60 ° C for 2 hours, cooled, and extracted with methylene chloride. The methylene chloride layer was washed with 10 percent sodium hydroxide, washed with 1 M sodium thiosulfate, washed with 10 percent hydrochloric acid, washed with aqueous sodium bicarbonate, dried (sulfate sodium), filtered, and concentrated. The residue was purified by chromatography by evaporation on silica gel (ethyl acetate / hexane, 7: 3), to provide 6.4 grams of the title compound. NMR (300 MHz, CDCl 3) d 1.69 (t, ÍH), 4.66 (d, 2H), 7.05 (t, ÍH), 7.60 (d, ÍH), 7.78 (dd, ÍH).

Example 25C 4-Fluoro-3-iodobenzaldeh The product of Example 25B (6.4 grams, 26 mmol) in chloroform (300 milliliters) was treated with manganese dioxide (4.5 grams, 50 mmol), stirred overnight, treated with an additional portion of manganese dioxide (2.25 grams), it was stirred overnight, filtered, and concentrated. The residue was purified by chromatography by evaporation on silica gel (ethyl acetate / hexane, 1: 4), to give 1.9 grams of the title compound. H NMR (300 MHz, CDCl 3) d 7.23 (t, ÍH), 7.89 (m, ÍH), 8.32 (dd, ÍH), 9.91 (s, ÍH).

Example 25D (9S) -9- (4-fluoro-3-? Odofenil) -5.6.7.9- etrahydrofuro T3.4- blquinolin-1.8 (3H.4H) -dione The 4-fluoro-3-iodobenzaldehyde was replaced by 3 -bromo-4-fluorobenzaldehyde, and processed as described in Example 18C, to provide the title compound as a white pr. MS (ESI (+)) m / z 426 (M + H) +; MS (ESI (-)) m / z 424 (M-H) "; rl NMR (300 MHz, DMSO-dg) d 1.85-1.95 (m, 2H), 2.22-2.27 (m, 2H), 2.56-2.59 (m, 2H), 4.63 (s, ÍH), 4.89 (q, 2H), 7.12 (t, ÍH), 7.20 (dt, ÍH), 7.60 (dd, ÍH), 10.18 (br s, ÍH); Analysis calculated for C? 7H? 3FIN03: C, 48.02; H, 3.08; N, 3. 29. Found: C, 47.86; H, 3.35; N, 3.22.

Example 26 10- (3-bromo-4-fluorophenyl) -3.4.6.7.8.10-hexahydropyride T4.3- bl n.61naf iridin-1.9 2H.5H) -dione A mixture of 3-bromo-4-fluorobenzaldehyde (1 milli-mol, 203 milligrams), and piperidin-2,4-dione (2 millimoles, 226 milligrams) in ethyl alcohol (5 milliliters), was treated with ammonia (2 M in ethyl alcohol, 1 millimole, 0.5 milliliters).

The reaction mixture was heated in a sealed tube at 70 ° C for a period of 48 hours. The formed precipitate was re-collected by filtration, washed with cold ethyl alcohol, and dried under vacuum to provide the title compound (150 milligrams, 38 percent). MS (APCI +) m / z 392 (M + H) +; XU NMR (DMSO-dg) d 2.32-2.56 (m, 4H), 3.12-3.22 (m, 4H), 4.93 (s, ÍH), 6.94 (bs, 2H), 7.18-7.22 (m, 2H), 7.42 (dd, ÍH), 8. 98 (s, ÍH); Analysis calculated for C? 7H15N302FBr: C, 52. 06; H, 3. 85; N, . 71. Found: C, 52.09; H, 4.11; N, 10.36.

EXAMPLE 27 9- (3-bromo-4-fluorophenyl) -7-methyl-3.4.5.6.7.9-hexahydropyrrolo T3.4-bl-iopyran (2,3-pyridin-8 (2H) -one Example 27A 8- (3-bromo-4-fluorophenyl) -6-methyl-3,4,5,8-tetrahydro-2H-thiopyran methyl 3-bipyridin-7-carboxylate 3-bromo-4-fluorobenzaldehyde (2.03 grams, 10 millimoles), 3-aminocrotonate (1.15 grams, 10 millimoles), and tetrahydropyran-3 -one-1,1-dioxide, prepared as described in J. Heterocycl. Chem. (1990), 27, 1453) (1.48 grams, 10 mmol), were suspended in methyl alcohol (30 milliliters). The reaction mixture was stirred in a sealed tube at 65 ° C overnight. The formed precipitate was collected and washed with acetone to provide the desired product (3.11 grams, 72 percent) as a white pr. P.f. 255 ° C; MS (ESI (-)) m / z 430 (MH) "; XH NMR (300 MHz, DMSO-dg) d 2.18 (m, 2H), 2.27 (s, 3H), 2.43-2.55 (m, 2H), 3.14-3.22 (m, 2H), 3.58 (s, 3H), 4.97 (s, ÍH), 7.19 (m, ÍH), 7.25 (t, ÍH), 7.36 (d, ÍH), 9.12 (s, ÍH); Analysis calculated for C? 7H17BrFN04S: C, 47. Four. Five; H, 3. 98; N, 3 26 Found: C, 47. 40; H, 4 eleven; N, 3 twenty-one .

Example 27P ll-dioxide 9- (3-bromo-4-fluorophenyl) -7-methyl-3.4.5.6.7.9- hexahydropyrrolo T3.4-bl iopyran 2.3-pyridine-8 (2H) -one The product of the Example 27A (107.5 milligrams, 0.25 millimoles) was dissolved in chloroform (2 milliliters), and treated with pyridine (0.30 millimoles). The reaction mixture was cooled to -10 ° C, and then pyridinium tribromide (98 milligrams, 0.275 mmol) was added. After stirring at -10 ° C for 1 hour, and at room temperature for another hour, the reaction mixture was treated with hydrochloric acid (1 M, 2 milliliters), and extracted with chloroform (3 milliliters, 3 ve-ees) . The organic layer was dried over magnesium sulfate, filtered, and concentrated to give a white foamy solid. This solid was dissolved in methyl alcohol (2 milliliters), and treated with methylamine (2 M in methyl alcohol, 1.25 milliliters). The reaction mixture was stirred at ambient temperature overnight. Following the concentration, the residue was passed through chromatography by evaporation (silica gel, 10 percent methyl alcohol-methylene chloride), to give the title compound (49 milligrams, 46 percent) as a light yellow powder . MS (ESK +)) m / z 427 (M + H) +; MS (ESI (-)) m / z 425 (MH) "; XH NMR (300 MHz, DMSO-dg) d 2.18-2.24 (m, 2H), 2.58 (m, 2H), 2.78 (s, 3H), 3.16-3.22 (m, 2H), 3.98 (q, 2H), 4.86 (s, ÍH), 7.26 (m, 2H), 7.43 (d, ÍH), 9.60 (s, ÍH); Analysis calculated for C17H16BrFN203S: C , 49.79; H, 3.77; N, 6.56. Found: C, 47.31; H, 4.03; N, 6.31.

Example 28 9- (3-bromo-4-fluorophenyl) -3.4.6.9-tetrahydro-2H-furo T3.4-bl thiopyran-2.3-iridin-8 (5H) -one The product of Example 27A (860 milligrams, 2 millimoles) was dissolved in chloroform (15 milliliters), and treated with pyridine (2.4 millimoles). The reaction mixture was cooled to -10 ° C, and then pyridinium tribromide (782 milligrams, 2.2 mmol) was added. After stirring at -10 ° C for 1 hour, and at room temperature for another hour, the reaction mixture was treated with hydrochloric acid (1 M, 15 milliliters), and extracted with chloroform (15 milliliters, 3 times). The organic layer was dried over magnesium sulfate, filtered, and concentrated to give a white foamy solid. This solid was heated at 140 ° C for 1 hour. Evaporation chromatography (silica gel, 10 percent methyl alcohol-methylene chloride) provided the title compound (345 milligrams, 63 percent) as a white solid. MS (ESI (-)) m / z 412 (M-H) "; XH NMR (300 MHz, DMSO-dg) d 2.18-2.22 (m, 2H), 2.56-2.61 (m, 2H), 3.18-3.23 (m, 2H), 4.86 (s, ÍH), 4.87 (q, 2H) ), 7.28 (m, 2H), 7.47 (d, ÍH), 10.03 (br S, ÍH); Analysis calculated for C? 6H13BrFN02S: C, 46.39; H, 3.16; N, 3.38. Found: C, 46.65; H, 3.46; N, 3.31.

Example 29 (8R) -8- (3-bromo-4-fluorophenyl) -2-methyl-2.3.4.5.6.8- hexahydrocyclopenta Tbl pyrrolo T3.4-pyridine-1.7-dione The enantiomerically pure title compound was obtained after of the resolution with chiral HPLC (Chiralcel OD, 4.6 x 250 millimeters, hexane ethanol, 90:10) of the corresponding racemate prepared as described in Example 3C. Light yellow crystalline solid; MS (ESI (+)) m / z 377 (M + H) +; MS (ESI (-)) m / z 375 (MH) "; XH NMR (300 MHz, DMSO-dg) d 2.30 (t, 2H), 2.55-2.67 (m, 2H), 2.80 (s, 3H), 4.08 (q, 2H), 4.56 (s, ÍH), 7.21 (m, 2H), 7.44 (d, ÍH); Analysis calculated for C17H14BrFN202: C, 54.13; H, 3.74; N, 7.43. Found: C, 53.96; H, 3.89; N, 7.17.

Example 30 9-dioxide 9- (3-bromo-4-f luorofenyl) -3.4.6.9-tetrahydro-2H-f uro T3.4-bl iopyran T2.3-pyridin-8 (5H) -one Example 30A 11-dioxide 9- (3-bromo-4-fluorophenyl) -8-oxo-2.3.4.6.8.9- hexahydro-5H-furo T3.4-bl iopyrano T2.3-the pyridine-5-carboxylate of ( 1R.2S.5R) -5-methyl-2- (1-methyl-1-phenylethyl) cyclohexyl To a suspension of the product of Example 28 (1.02 grams, 2.46 mmol) in tetrahydrofuran (10 milliliters) maintained at 0 ° C under nitrogen, potassium t-butoxide (1 M in tetrahydrofuran, 2.46 milliliters) was added slowly. The reaction mixture was allowed to warm to room temperature over a period of 10 minutes, and then cooled back to 0 ° C. Then a solution of 8-phenylmentol chloroformate prepared from (-) - 8-phenylmentol was added as described in (Reference: Yamamoto, Y., J. Amer. Chem. Soc. (1992), 114, 121- 125) (0.727 grams, 2.46 millimoles) in tetrahydrofuran (25 milliliters). The reaction mixture was allowed to warm to room temperature again, and stirred for another 2 hours. It was then poured into a saturated aqueous solution of sodium bicarbonate, and extracted with a mixture of diethyl ether and ethyl acetate (4: 1, 25 milliliters 3 times). The layers were separated, and the organic layer was dried over magnesium sulfate, filtered, and concentrated. Column chromatography (silica, diethyl ether: hexane, 85:15) of the residue gave the least polar diastereomer (750 milligrams) and the most polar diastereomer (655 milligrams).

Example 3QB 9- (3-bromo-4-fluorophenyl) -3.4.6.9-tetrahydro-2H-furo T3.4-bl thiopyran 11-dioxide-pyridin-8 (5H) -one A solution of the diastereomer less polar of Example 30A (639 milligrams) in methyl alcohol (10 milliliters) was treated with a 25 percent sodium methoxide solution in methyl alcohol (3 drops) under nitrogen. The solution slowly became a suspension. After the reaction is finished (evidenced by thin-layer chromatography), a few drops of acetic acid were added, resulting in the formation of a precipitate, which was isolated by filtration and air dried to provide the title compound (210 milligrams, 53 percent yield) as a white solid . MS (ESI (-)) m / z 412 (M-H) "; XH NMR (300 MHz, DMSO-dg) d 2.18-2.22 (m, 2H), 2.56-2.61 (, 2H), 3.18-3.23 (m, 2H), 4.86 (s, ÍH), 4.87 (q, 2H) , 7.28 (m, 2H), 7.47 (d, ÍH), 10.03 (br s, ÍH); Analysis calculated for C? 6H13BrFN04S: C, 46.39; H, 3.16; N, 3.38. Found: C, 46.55; H, .3.16; N, 3.23.

Example 31 (8S) -8- (3-bromo-4-fluorophenyl) -2-methyl-2.3.4.5.6.8- hexahydrocyclopenta Tbl pyrrolo T3.4-pyridine-1.7-dione The enantiomerically pure title compound was obtained after of the resolution with chiral HPLC (Chiralcel OD, 4.6 x 250 millimeters, hexane: ethanol, 90:10) of the corresponding racemate prepared as described in Example 3C. The absolute stereochemistry was determined by X-ray crystallographic analysis. Light yellow crystalline solid: MS (ESI (+)) m / z 377 (M + H) +; MS (ESI (-)) m / z 375 (MH) "; XH NMR (300 MHz, DMSO-d6) d 2.30 (t, 2H), 2.55-2.67 (m, 2H), 2.80 (s, 3H), 4.08 (q, 2H), 4.56 (s, ÍH), 7.21 (m, 2H), 7.44 (d, ÍH); Analysis calculated for C? 7H? 4BrFN2O2 * 0 .5 H20: C, 52.87; H, 3. 91; N, 7. 25 Found: C, 53.16; H, 4.13; N, 6.78.

For example 32 ll-dioxide 9- (3-bromo-4-fluorophenyl) -3.4.6.9-tetrahydro-2H-furo T3.4-bl thiopyran T2.3 -pyridin-8 (5H) -one The diastereomer more polar of Example 30A (655 milligrams) was processed as described in Example 30B, to provide the title compound as a white solid (290 milligrams, 72 percent). MS (ESI (-)) m / z 412 (MH) ";? U NMR (300 MHz, DMSO-dg) d 2.18-2.22 (m, 2H), 2.56-2.61 (m, 2H), 3.18-3.23 ( m, 2H), 4.86 (s, ÍH), 4.87 (q, 2H), 7.28 (m, 2H), 7.47 (d, ÍH), 10.03 (br s, ÍH); Analysis calculated for C? 6H13BrFN04S: C, 46.39; H, 3.16; N, 3.38. Found: C, 46.39; H, 3.24; N, 3.33.

Example 33 9- (3-bromo-4-fluorophenyl) -2- (2-ethoxyethyl) -2.3.5.6.7.9- hexahydro-lH-pyrrolof3.4-blsuinolin-1.8 (4H) -dione The 2-ethoxyethylamine was substituted per methylamine, and processed as described in Example 8C, to provide the title compound. MS (APCK +)) m / z 451 (M + H) +; XH NMR (300 MHz, DMSO-dg) d 1.15 (t, 3H), 1.82-1.97 (m, 2H), 2.20-2.30 (m, 2H), 2.50-2.65 (m, 2H), 3.35-3.45 (m , 6H), 4.08 (q, 2H), 4.72 (s, ÍH), 7.15-7.25 (m, 2H), 7.45 (m, ÍH), 9.80 (s, ÍH).

Example 34 (9R) -9- (3-bromo-4-fluorophenyl) -2- (2-ethoxyethyl) -2.3.5.6.7.9- hexahydro-lH-pyrrolo T3.4-bl quinolin-1.8 (4H) -dione The enantiomerically pure title compound was obtained as described in Example 8C, using the product of Example 18C, and substituting 2-ethoxyethylamine for methylamine. MS (APCK +)) m / z 451 (M + H) +; XH NMR (300 MHz, DMSO-dg) d 1.08 (t, 3H), 1.82-1.98 (m, 2H), 2.20-2.30 (m, 2H), 2.50-2.65 (m, 2H), 3.35-3.50 (m , 6H), 4.06 (q, 2H), 4.70 (s, ÍH), 7.15-7.25 (m, 2H), 7.45 (m, ÍH), 9.79 (s, ÍH).

Example 35 (9S) -9- (3-bromo-4-fluorophenyl) -2- (2-ethoxyethyl) -2.3.5.6.7.9- hexahydro-lH-pyrrolo T3.4-bl uinolin-1.8 4H) -dione The Compound of the enantiomerically pure title was obtained as described in Example 8C, using the product of Example 15C and substituting 2-ethoxyethylamine for methylamine. Solid yellow: MS (ESK +)) m / z 449 (M + H) +; MS (ESI (-)) m / z 447 (MH) "; XH NMR (300 MHz, DMSO-dg) d 1.6 (t, 3H), 1.85-1.94 (m, 2H), 2.22-2.28 (m, 2H ), 2.53-2.58 (m, 2H), 3.34-3.45 (m, 6H), 4.18 (q, 2H), 4.70 (s, ÍH), 7.17-7.22 (m, 2H), 7.42 (d, ÍH), 9.82 (s, ÍH): Analysis calculated for C2? H22BrFN203: C, 56.14; H, 4.94; N, 6.23, Found: C, 56.43; H, 4.99; N, 5.98.

Example 36 (9S) -9- (3-bromo-4-fluorophenyl) -2-cyclopropyl-2.3.5.6.7.9- hexahydro-lH-pyrrolo T3.4-bl quinolin-1.8 (4H) -dione The title compound enantiomerically pure was obtained as described in Example 8C, using the product of Example 15C and substituting cyclopropylamine for methylamine. MS (APCK +)) m / z 419 (M + H) +; XH NMR (300 MHz, DMSO-dg) d 0.58-0.65 (m, 4H), 1.80-1.98 (m, 2H), 2.05 (s, ÍH), 2.20-2.28 (m, 2H), 2.55-2.65 (m , 2H), 3.90 (q, 2H), 4.65 (s, ÍH), 7.15-7.22 (m, 2H), 7.45 (m, ÍH), 9.80 (s, ÍH).

Example 37 9- (3-bromo-4-fluorophenyl) -2.3.5.6.7.9- hexahydrothienor3.2-bl TI.61 naphthyridin-8 (4H) -one A suspension of 3-bromo-4-fluorobenzaldehyde (2.19 millimoles, 444 milligrams), piperidin-2, 4-dione (2.19 millimoles), 247 milligrams), and tetrahydrothiophene-3-oxo-l, 1- dioxide (2.19 millimoles, 293 milligrams) in ethyl alcohol (10 milliliters), was treated with ammonium acetate (1.5 equivalents, 3.29 millimoles), and heated in a sealed tube at 80 ° C for a period of 72 hours. The white precipitate formed was collected by filtration. Column chromatography (silica gel, methylene chloride: methyl alcohol, 10: 1 to 5: 1) of that precipitate gave the title compound (80 milligrams, yield 9 percent). MS (APCK +)) m / z 413 (M + H) +; XH NMR (DMS0-d6) d 2.33-2.53 (m, 2H), 2.73-2.86 (m, 2H), 2.94-3.07 (m, 2H), 3.13-3.22 (m, 2H), 4.90 (s, ÍH) , 7.08 (bs, ÍH), 7. 19-7. 27 (m, 2H), 7. 41 (dd, ÍH), 9. 50 (s, ÍH); Analysis calculated for C16H? 4N203SFBr: C, 46. fifty; H, 3. 41; N, 6. 78. Found: C, 46.24; H, 3.55; N, 6.72.

Example 38 (9R) -9- (4-fluoro-3-iodophenyl) -5.6.7.9-tetrahydrofuro? 3.4- bl quinolin-1.8 (3H.4H) -dione The product of Example 15C and 4-fluoro-3-iodobenzaldehyde of Example 25C, were processed as described in Example 16, to provide the title compound as a pink powder. MS (ESI (+)) m / z 426 (M + H) +; MS (ESI (-)) m / z 424 (MH) ";? U NMR (300 MHz, DMSO-dg) d 1.85-1.95 (m, 2H), 2.22-2.27 (m, 2H), 2.56-2.59 ( m, 2H), 4.63 (s, ÍH), 4.89 (q, 2H), 7.12 (t, ÍH), 7.20 (dt, ÍH), 7.60 (dd, ÍH), 10.18 (br s, ÍH); • Analysis calculated for C? 7H13FIN03: C, 48.02; H, 3.08; N, 3. 29. Found: C, 47.92; H, 3.06; N, 3.10.

Example 39 (9R) -9- (3-chloro-4-fluorophenyl) -5.6.7.9-tetrahydrofide T3.4-bl uinolin-1.8 (3H.4H) -dione The product of Example 15C and 3-chloro-4- Fluorobenzaldehyde, were processed as described in Example 16, to provide the title compound as a tan solid. MS (ESK +)) m / z 334 (M + H) +; MS (ESI (-)) m / z 332 (MH) "; XH NMR (300 MHz, DMSO-dg) d 1.85-1.95 (m, 2H), 2.23-2.29 (m, 2H), 2.55-2.60 (m , 2H), 4.69 (s, ÍH), 4.90 (q, 2H), 7.19 (m, ÍH), 7.28 (t, ÍH), 7.32 (d, ÍH), 10.20 (s, ÍH); Analysis calculated for C17H13ClFNO3 »0.2 H20: C, 60.53; H, 4.00; N, 4.15, Found: C, 60.29; H, 3.97; N, 4.15.

Example 40 9- (3-chloro-4-fluorophenyl) -3.4.5.6.7.9-hexahydro-lH-cyclopenta fb1? L .61 naf iridin-1.8 (2H) -dione The 3-chloro-4-fluorobenzaldehyde was replaced by 3-bromo-4-fluorobenzaldehyde, and processed as described in Example 23, to provide the title compound. MS (APCK +)) m / z 333 (M + H) +; XH NMR (300 MHz, DMSO-dg) d 2.15 (m, 2H), 2.45-2.63 (m, 4H), 3.15-3.34 (m, 2H), 4.85 (s, ÍH), 7.05 (s, ÍH), 7.13-7.35 (m, 3H), 9.95 (s, ÍH).

Example 41 9-r4-fluoro-3- (trifluoromethyl) phenyl -3.4.5.6.7.9-hexahydro-lH-cyclopentarbyl TI .61 naf iridin-1.8 (2H) -dione 4-Fluoro-3-trifluoromethylbenzaldehyde was substituted by 3-bromo-4-fluorobenzaldehyde, and processed as described in Example 23, to provide the title compound. MS (APCK +)) m / z 367 (M + H) +; XH NMR (300 MHz, DMSO-dg) d 2.15 (m, 2H), 2.35-2.65 (m, 4H), 3.26-3.40 (m, 2H), 4.90 (s, ÍH), 7.07 (s, ÍH), 7.26-7.43 (m, 3H), 9.80 (s, ÍH).

Example 42 9- (4-chloro-3-fluorophenyl) -3.4.5.6.7.9-hexahydro-lH-cyclopentyl Tbl TI.61 naphidin-1.8 (2H) -dione The 4-chloro-3-fluorobenzaldehyde was replaced by 3-chlorobenzaldehyde. -bromo-fluorobenzaldehyde, and processed as described in Example 23, to provide the title compound. MS (APCK +)) m / z 333 (M + H) +; XH NMR (300 MHz, DMSO-ds) d 2.10 (m, 2H), 2.25-2.70 (m, 4H), 3.10-3.35 (m, 2H), 4.80 (s, ÍH), 6.95-7.65 (m, 4H ), 959 (s, ÍH).

Example 43 9- (3,4-dichlorophenyl) -3.4.5.6.7.9-hexahydro-lH-cyclopentyl Tbl TI .61 naphthyridine-1.8 2H) -dione The 3,4-dichlorobenzaldehyde was replaced by 3-bromo-4-fluorobenzaldehyde, and was processed as described in Example 23, to provide the title compound. MS (APCK +)) m / z 349 (M + H) +; XH NMR (300 MHz, DMSO-dg) d 2.20 (m, 2H), 2.25-2.80 (m, 4H), 3.25-3.45 (m, 2H), 4.90 (s, ÍH), 7.05-7.58 (, 4H) 9.90 (s, ÍH).

Example 44 9-r4-chloro-3- (trifluoromethyl) phenyl -3.4.5.6.7.9-hexahydro-lH-cyclopenta Tbl n.61 naphthyridine-1.8 (2H) -dione The 4-chloro-3-trifluoromethylbenzaldehyde was replaced by 3 -bromo-4-fluorobenzaldehyde, and processed as described in Example 23, to provide the title compound. MS (APCK +)) m / z 383 (M + H) +; XH NMR (300 MHz, DMSO-de) d 2.15 (m, 2H), 2.20-2.70 (m, 4H), 3.10-3.40 (m, 2H), 4.80 (s, ÍH), 7.10 (s, ÍH), 7.40-7.70 (m, 3H), 9.85 (s, ÍH).

Example 45 9- (3,4-dibromophenyl) -3.4.5.6.7.9-hexahydro-lH-cyclopenta Tbl n.61 naphthyridine-1.8 (2H) -dione The 3,4-dibromobenzaldehyde was replaced by 3-bromo-4-fluorobenzaldehyde, and processed as described in Example 23, to provide the title compound. MS (APCK +)) m / z 439 (M + H) +; XH NMR (300 MHz, DMSO-dg) d 2.14 (m, 2H), 2.19-2.75 (m, 4H), 3.15-3.45 (m, 4H), 4.70 (s, ÍH), 7.00-7.63 (m, 4H) ), 9.85 (s, ÍH).

Example 46 9- (3-cyanophenyl) -3.4.5.6.7.9-hexahydro-lH-cyclopenta Tbl TI.61 naf iridin-1.8 (2H) -dione The 3-cyanobenzaldehyde was replaced by 3-bromo-4-fluorobenzaldehyde, and was processed as described in Example 23, to provide the title compound. MS (APCK +)) m / z 306 (M + H) +; XH NMR (300 MHz, DMSO-dg) d 2.15 (m, 2H), 2.20-2.70 (, 4H), 3.15-3.40 (m, 2H), 4.79 (s, ÍH), 7.05 (s, ÍH), 7.40 -7.60 (m, 3H), 9.90 (s, ÍH).

Example 47 9- (5-chloro-2-thienyl) -3.4.5.6.7.9-hexahydro-lH-cyclopenta Tbl TI .61 naphthyridine-1.8 (2H) -dione The 5-chloro-2-thiophenecarboxaldehyde was replaced by 3 - bromo-4-fluorobenzaldehyde, and processed as described in Example 23, to provide the title compound. MS (APCK +)) m / z 321 (M + H) +; XH NMR (300 MHz, DMSO-dg) d 2.20-2.75 (m, 6H), 3.15-3.40 (m, 2H), 4.85 (s, ÍH), 6.50 (d, ÍH), 6.80 (d, ÍH), 7.20 (s, ÍH), 9.90 (s, ÍH).

Example 48 9- (3-nitrophenyl) -3.4.5.6.7.9-hexahydro-lH-cyclopenta Tbl TI.61 naphthyridine-1.8 (2H) -dione The 3-nitrobenzaldehyde was replaced by 3-bromo-4-fluorobenzaldehyde, and processed as described in Example 23, to provide the title compound. MS (APCK +)) m / z 326 (M + H) +; U NMR (300 MHz, DMSO-dg) d 2.25 (m, 2H), 2.40-2.70 (m, 4H), 3.15-3.40 (m, 2H), 4.85 (s, ÍH), 7.05 (s, ÍH) , 7.50-8.00 (m, 3H), 9.90 (s, ÍH).

Example 49 9- (5-nitro-2-thienyl) -3.4.5.6.7.9-hexahydro-lH-cyclopenta Tbl ri.61 naphthyridine-1.8 (2H) -dione The 5-nitro-2-thiophenecarboxaldehyde was replaced by 3 - Bromo-4-fluorobenzaldehyde, and processed as described in Example 23 to provide the title compound. MS (APCK +)) m / z 332 (M + H) +; XH NMR (300 MHz, DMSO-dg) d 2.25-2.80 (m, 6H), 3.20-3.45 (m, 2H), 5.00 (s, ÍH), 6.90 (d, ÍH), 7.25 (s, ÍH), 7.90 (d, ÍH), 10.05 (s, ÍH).

Example 50 9 - (5-nitro-3-thienyl) -3. Four . 5 . 6 7 9-hexahydro-lH-cyclopenta Tbl TI .61 naphthyridine-1.8 (2H) -dione The 5-nitro-3-thiophenecarboxaldehyde was replaced by 3-bromo-4-fluorobenzaldehyde, and processed as described in Example 23, provide the title compound. MS (APCK +)) m / z 332 (M + H) +; XH NMR (300 MHz, DMSO-dg) d 2.25 (m, 2H), 2.39-2.80 (m, 4H), 3.20-3.40 (m, 2H), 4.80 (s, ÍH), 7.18 (s, ÍH), 7.59 (s, ÍH), 7.85 (s, ÍH), 9.90 (s, ÍH).

Example 51 9-r4-Fluoro-3- (trifluoromethyl) phenyl -5.6.7.9-tetrahydro T3.4-b1quinolin-1.8 (3H.4H) -dione The 4-fluoro-3-trifluoromethylbenzaldehyde was replaced by 3-bromine -4-fluorobenzaldehyde, and processed as described in Example 10, to provide the title compound as a white solid. MS (ESI (+)) m / z 368 (M + H) +; MS (ESI (-)) m / z 366 (M-H) "; XH NMR (300 MHz, DMSO-dg) d 1.88-1.95 (m, 2H), 2.24-2.28 (m, 2H), 2.55-2.61 (m, 2H), 4.78 (s, ÍH), 4.90 (q, 2H), 7Í49 (t, ÍH), 7.52 (m, 2H), 10.21 (s, ÍH); Analysis calculated for C18H13F4N03: C, 58.86; H, 3.57; N, 3. 81. Found: C, 58.71; H, 3.60; N, 3.80.

Example 52 9 - (4-chloro-3-nitrophenyl) -5. 6. 7. 9- tetrahydro Í3. 4-br auinolin- 1. 8 (3H. 4H) -dione The 4-chloro-3-nitrobenzaldehyde was replaced by 3-bromo-4-fluorobenzaldehyde, and processed as described in Example 10, to provide the title as a yellow solid. MS (ESI (-)) m / z 359 (MH) "; XH NMR (300 MHz, DMSO-dg) d 1.88-1.96 (m, 2H), 2.25-2.60 (m, 2H), 2.56-2.61 (m , 2H), 4.79 (s, ÍH), 4.90 (q, 2H), 7.55 (d, ÍH), 7.65 (d, ÍH), 7.81 (s, ÍH), 10.27 (s, ÍH); Analysis calculated for C17H 3ClN2O5 * 0.1 CH2C12: C, 55.62; H, 3.60; N, 7.59. Found: C, 55.71; H, 3.75; N, 7.40.

Example 53 8-r4-Fluoro-3- (2-furyl) phenyl-5,8-dihydro-lH.3H-difure T3.4- b; 3.4-elpyridin-1.7 (4H) -dione The title compound of Example 5 processed as described in Example 91, to provide the title compound. MS (ESI (-)) m / z 352 (MH) "; XH NMR (300 MHz, DMSO-dg) d 4.71 (s, ÍH), 4.91-5.07 (m, 4H), 6.67 (m, ÍH), 6.85 (t, J = 3.4 Hz, HH), 7.22 (m, HH), 7.27 (m, HH), 7.66 (d, J = 7.3, 2.2 Hz, HH), 7.85 (d, J = 2.2 Hz, HH ), 10.71 (s, ÍH); Analysis calculated for C? 9H12FNO5 * 0.3 H20: C, 63.62; H, 3.54; N, 3.90. Found: C, 63.53; H, 3.93; N, 3.96.

Example 54 8- (3-bromo-4-fluorophenyl) -4.5.6.8-tetrahydro-1H-cyclopenta Tblfuro-3.4-pyridine-1.7 (3H) -dione The enantiomerically pure e compound was obtained as the least polar enantiomer , retention time = 22.5 minutes, after resolution with chiral HPLC (Gilson 215 automated liquid handler / HPLC, column (R, R) -Whelk-01 (2.1 centimeters x 25 centimeters) flow rate = 10 milliliters / minute , hexane: methyl alcohol: methylene chloride (50:33:17) of the corresponding racemate prepared as described in Example 6. Yellow solid: MS (ESI (+)) m / z 364 (M + H) +; MS (ESI (-)) m / z 362 (MH) "; XH NMR (300 MHz, DMSO-dg) d 2.35 (t, 2H), 2.70 (m, 2H), 4.60 (s, ÍH), 4.98 (q , 2H), 7.26 (m, 2H), 7.50 (d, ÍH), 10.71 (s, "ÍH); Analysis calculated for C? 6HnBrFN03: C, 52.77; H, 3.04; N, 3.85. Found: C, 52.39; H, 3.18; N, 3.75.

Example 55 8- (3-bromo-4-f luorofenyl) -4.5.6.8- etrahydro-H-cyclopenta Tbl furo T3.4-pyridine-1.7 (3H) -dione The enantiomerically pure e compound was obtained as the more polar enantiomer, retention time = 28 minutes, after resolution with chiral HPLC (automated liquid handler Gilson 215 / HPLC, column (R, R) -Whelk 01 (2.1 centimeters x 25 centimeters), flow rate = 10 milliliters / minute, hexane: methylene alcohol: methylene chloride (50:33:17)) of the corresponding racemate prepared as described in Example 6. Yellow solid: MS (ESI (+)) m / z 364 (M + H) +; MS (ESI (-)) m / z 362 (M-H) "; XH NMR (300 MHz, DMSO-dg) d 2.35 (t, 2H), 2.70 (m, 2H), 4.60 (s, ÍH), 4.98 (q, 2H), 7.26 (m, 2H), 7.50 (d, ÍH), 10.71 (s, ÍH); Analysis calculated for C? GHnBrFN03: C, 52.77; H, 3.04; N, 3.85. Found: C, 52.54; H, 3.18; N, 3.75.

Example 56 8-r4-fluoro-3- (trifluoromethyl) phenyl-5,8-dihydro-lH.3H-difuror3.4-b: 3.4-elpyridin-1.7 (4H) -dione 4-Fluoro-3-trifluoromethylbenzaldehyde was substed by 3-bromo-4-fluorobenzaldehyde, and processed as in Example 5, to provide the e compound as a white solid.

MS (DCI / NH3) m / z 373 (100%) (M + NH4); XH NMR (300 MHz, DMSO-dg) d 4.82 (s, ÍH), 4.98 (q, 4H), 7.44 (t, ÍH), 7.63 (m, 2H), 10.78 (s, ÍH); Analysis calculated for C? GH9F4N0: C, 54.10; H, 2.55; N, 3.94. Found: C, 53.81; H, 2.65; N, 3.86.

Example 57 9-r4-lw? Ro-3- (trifluoromethyl) phenyl -5.6.7.9- tetrahydrofide T3.4-bl quinolin-1.8 (3H.4H) -dione The enantiomerically pure e compound was obtained as the least polar enantiomer , retention time = 65 minutes, after resolution with chiral HPLC (automated liquid manipulator Gilson 215 / HPLC, column (R, R) -Whelk-01 (2.1 centimeters x 25 centimeters), flow rate = 10 milliliters / minute, hexane: methyl alcohol: methylene chloride (75: 16.5: 8.5)) of the corresponding racemate prepared as described in Example 10, substing 3-bromo-4-fluorobenzaldehyde with 4-fluoro-3-trifluoromethylbenzaldehyde. MS (ESK +)) m / z 368 (M + H) +; MS (ESI (-)) m / z 366 (MH) "; XH NMR (300 MHz, DMSO-dg) d 1.82-1.98 (m, 2H), 2.23-2.28 (m, 2H), 2.54-2.60 (m , 2H), 4.77 (s, ÍH), 4.89 (q, 2H), 7.38 (t, ÍH), 7.53 (m, 2H), 10.21 (s, ÍH); Analysis calculated for C? 8H? 3F4N03: C, 58.86; H, 3.57; N, 3.81, Found: C, 58.75; H, 3.84; N, 3.62.

Example 58 9-r4-Fluoro-3- (trifluoromethyl) phenyl -5.6.7.9-tetrahydrofide? .4-bl uinolin-1.8 (3H.4H) -dione The enantiomerically pure e compound was obtained as the most polar enantiomer, retention time = 77 minutes, after resolution with chiral HPLC (Gilson 215 automated liquid manipulator / HPLC, column (R, R) -Whelk-01 (2.1 centimeters x 25 centimeters), flow rate = 10 milliliters / minute, hexane: methyl alcohol, methylene chloride (75: 16.5: 8.5)) of the corresponding racemate prepared as is described in Example 10, substing 3-bromo-4-fluorobenzaldehyde with 4-fluoro-3-trifluoromethylbenzaldehyde. MS (ESI (+)) m / z 368 (M + H) +; MS (ESI (-)) m / z 366 (MH) "; XH NMR (300 MHz, DMSO-dg) d 1.82-1.98 (m, 2H), 2.23-2.28 (m, -2H), 2.54-2.60 ( m, 2H), 4.77 (s, ÍH), 4.89 (q, 2H), 7.38 (t, ÍH), 7.53 (m, 2H), 10.21 (s, ÍH); Analysis calculated for C18H13F4N03: C, 58.86; 3.57, N, 3.81, Found: C, 58.70, H, 3.83, N, 3.67.

Example 59 8- (3,4-dichlorophenyl) -5,8-dihydro-lH.3H-difure T3.4-b.3.4- e) pyridyl-l-7 (4B) -dione The 3,4-dichlorobenzaldehyde was replaced by 3- Bromo-4-fluorobenzaldehyde, and processed as in Example 5, to provide the title compound as a white solid. MS (DCI / NH3) m / z 346 (100%) (M + NH4); 1H NMR (300 MHz, DMSO-dg) d 4.78 (s, ÍH), 4.98 (q, 4H), 7.42 (d, ÍH), 7.55 (d, ÍH), 7.82 (s, ÍH), 10.74 (s, ÍH); Analysis calculated for C? 5H9Cl2NO4 »0.25 H20: C, 52.58; H, 2.79; N, 4.09. Found: C, 52.64; H, 2.60; N, 4.04.

Example 60 8- (4-methyl-3-nitrophenyl) -5,8-dihydro-lH.3H-difure T3.4-b; 3.4- -1.7 (4H) -dione 4-, Methyl-3-nitrobenzaldehyde was substituted by 3-bromo-4-fluorobenzaldehyde, and processed as in Example , to provide the title compound as a yellow solid. MS (DCI / NH3) m / z 355 (100%) (M + NH4); XH NMR (300 MHz, DMSO-dg) d 3.37 (s, 3H), 4.68 (s, ÍH), 4.97 (q, 4H), 7.29 (d, ÍH), 7.50 (s, ÍH), 7.52 (d, ÍH), 10.70 (s, ÍH); Analysis calculated for C? 6H12N204: C, 58.54; H, 3.68; N, 8.53.

Found: C, 58.20; H, 3.72; N, 8.47.

Example $ 9- (3,4-dibromophenyl -5.6.7.9-tetrahydrofuro 13 .4-bl quinolin-1.8 (3H.4H) -dÍPna The enantiomerically pure title compound was obtained as the less polar enantiomer, retention time = 23.5 minutes, after resolution with chiral HPLC (Gilson 215 automated liquid handler / HPLC, column (R, R) -Whelk-01 (2.1 centimeters x 25 centimeters), flow rate = 10 milliliters / minute, hexane: methyl alcohol Methylene chloride (60:26:13)) of the corresponding racemate prepared as described in Example 10, substituting 3-bromo-4-fluorobenzaldehyde with 3,4-dibromobenzaldehyde MS (ESI (+)) m / z 440 (M + H) +; MS (ESI (-)) m / z 438 (MH) "; XH NMR (300 MHz, DMSO-dg) d 1.87-1.96 (m, 2H), 2.22-2.28 (m, 2H), 2.55-2.60 (m, 2H), 4.64 (s, ÍH), 4.90 (q, 2H), 7.13 (d, ÍH), 7.52 (s, ÍH), 7.62 (d, ÍH), 10.18 (br s, ÍH); Analysis calculated for C? 7H? 3Br2NO3 «0.1 C6H14: C, 47.22; H, 3.24; N, 3.13, Found: C, 47.16; H, 3.39; N, 2.93 .

Example 62 9- (3,4-dibromophenyl -5.6.7.9-tetrahydrofuro \ 3 .4-bl quinolin-1.8 (3H.4H) -dione The enantiomerically pure title compound was obtained as the most polar enantiomer, retention time = 32.5 minutes , after resolution with chiral HPLC (Gilson 215 / HPLC automated liquid manipulator, column (R, R) -Whelk-01 (2.1 centimeters x 25 centimeters), flow rate = 10 milliliters / minute, hexane: methyl alcohol co: methylene chloride (60:26:13)) of the corresponding racemate prepared as described in Example 10, substituting 3-bromo-4-fluorobenzaldehyde with 3,4-dibromobenzaldehyde MS (ESI (+)) m / z 440 (M + H) +; MS (ESI (-)) m / z 438 (MH) "; 2H NMR (300 MHz, DMSO-dg) d 1.87-1.96 (m, 2H), 2.22-2.28 (m , 2H), 2.55-2.60 (m, 2H), 4.64 (s, ÍH), 4.90 (q, 2H), 7.13 (d, ÍH), 7.52 (s, ÍH), 7.62 (d, ÍH), 10.18 ( br s, ÍH); Analysis calculated for C17H? 3Br2N03: C, 46.50; H, 2.98; N, 3.19. Found: C, 46.68; H, 3.13; N, 3.03.

Example 63 9 - (4-methyl-3-nitrophenyl) -5.6.7.9-tetrahydrofuro-3,4-blquinolin-1.8 (3H.4H) -dione The enantiomerically pure title compound was obtained as the less polar enantiomer, retention time = 32 minutes, after resolution with chiral HPLC (Gilson 215 / HPLC automated liquid manipulator, column (R, R) -Whelk-01 (2.1 centimeters x 25 centimeters), flow rate = 10 milliliters / minute, hexane: alcohol methylene chloride: methylene chloride (60:26:13)) of the corresponding racemate prepared as described in Example 10, substituting 3-bromo-4-fluorobenzaldehyde with 4-methyl-3-nitrobenzaldehyde. MS (ESK +)) m / z 341 (M + H) +; MS (ESI (-)) m / z 339 (MH) "; XH NMR (300 MHz, DMSO-dg) d 1.86-1.97 (m, 2H), 2.22-2.29 (m, 2H), 2.44 (s, 3H ), 2.55-2.62 (m, 2H), 4.75 (s, ÍH), 4.90 (q, 2H), 7.37 (d, ÍH), 7.48 (d, ÍH), 7.73 (s, ÍH), 10.20 (br s) , ÍH); Analysis calculated for C? 8H? 6N205: C, 63.52; H, 4.74; N, 8.23, Found: C, 63.27; H, 4.83; N, 8.01.

Example 64 9- (4-methyl-3-nitrophenyl) -5.6.7.9-tetrahydrofide T3.4- bl quinolin-1.8 (3H.4H) -dione The enantiomerically pure title compound was obtained as the more polar enantiomer, time of retention = 37 minutes, after resolution with HPLC quira? (Automated liquid handler Gilson 215 / HPLC, column (R, R) -Whelk-01 (2.1 centimeters x 25 centimeters), flow rate = 10 milliliters / minute, hexane: methylene alcohol: methylene chloride ( 60:26:13)) of the corresponding racemate prepared as described in Example 10, substituting the 3-bromo-4-fluorobenzaldehyde with 4-methyl-3-nitrobenzaldehyde. MS (ESK +)) m / z 341 (M + H) +; MS (ESI (-)) m / z 339 (M-H) "; E NMR (300 MHz, DMSO-dg) d 1.86-1.97 (m, 2H), 2.22-2.29 (m, 2H), 2.44 (s, 3H), 2.55-2.62 (m, 2H), 4.75 (s, ÍH), 4.90 (q, 2H), 7.37 (d, ÍH), 7.48 (d, ÍH), 7.73 (s, ÍH), 10.20 (br, ÍH); Analysis calculated for C? 8H? GN205: C, 63.52; H, 4.74; N, 8.23.

Found: C, 63.36; H, 4.85; N, 8.17.

Example 65 9- (3,4-dichlorophenyl) -5.6.7.9-tetrahydrofide 13.4-bl quinolin-1.8 (3H.4H) -dione The enantiomerically pure title compound was obtained as the less polar enantiomer, retention time = 28.5 minutes, then of resolution with chiral HPLC (Gilson 215 / HPLC automated liquid manipulator, column (R, R) -Whelk-01 (2.1 centimeters x 25 centimeters), flow rate = 10 milliliters / minute, hexane: methyl alcohol: methylene chloride (60:26:13)) of the corresponding racemate prepared as described in Example 10, substituting 3-bromo-4-fluorobenzaldehyde with 3,4-dichlorobenzaldehyde. MS (ESI (+)) m / z 350 (M + H) +; MS (ESI (-)) m / z 348 (M-H) "; E NMR (300 MHz, DMSO-dg) d 1.87-1.96 (m, 2H), 2.24-2.29 (m, 2H), 2.55-2.61 (m, 2H), 4.68 (s, ÍH), 4.88 (q, 2H ), 7.18 (d, ÍH), 7.37 (s, ÍH), 7.49 (d, ÍH), 10.19 (br s, ÍH); Analysis calculated for C 7 H 3 Cl 2 N 0 3: C, 58.31; H, 3.74; N, 4.00. Found: C, 58.12; H, 3.85; N, 3.89.

Example 66 9- (3,4-dichlorophenyl) -5.6.7.9-tetrahydrofuran T3.4-bl quinolin- 1.8 3H.4H) -dione The enantiomerically pure title compound was obtained as the most polar enantiomer, retention time = 39 minutes , after resolution with chiral HPLC (Gilson 215 / HPLC automated liquid manipulator, column (R, R) -Whelk-01 (2.1 centimeters x 25 centimeters), flow rate = 10 milliliters / minute, hexane: methyl alcohol co: methylene chloride (60:26:13)) of the corresponding racemate prepared as described in Example 10, substituting 3-bromo-4-fluorobenzaldehyde with 3,4-dichlorobenzaldehyde. MS (ESK +)) m / z 350 (M + H) +; MS (ESI (-)) m / z 348 (MH) "; E NMR (300 MHz, DMSO-dg) d 1.87-1.96 (, 2H), 2.24-2.29 (m, 2H), 2.55-2.61 (m, 2H), 4.68 (s, ÍH), 4.88 (q, 2H), 7.18 (d, ÍH), 7.37 (s, ÍH), 7.49 (d, ÍH), 10.19 (br s, ÍH); Analysis calculated for C ? 7H? 3Cl2N03: C, 58.31; H, 3.74; N, 4.00, Found: C, 58.01; H, 3.82; N, 3.87.

Example 67 9- (4-Chloro-3-nitrophenyl) -5.6.7.9-tetrahydrofuro-4-quinolin-1.8 (3H-4H) -dione The enantiomerically pure title compound was obtained as the less polar enantiomer, retention = 33 minutes, after resolution with chiral HPLC (automated liquid manipulator Gilson 215 / HPLC, column (R, R) -Whelk-01 (2.1 centimeters x 25 centimeters), flow rate = 10 milliliters / minute, hexane methylene alcohol: methylene chloride (60:26:13)) of the corresponding racemate of Example 52. White solid: MS (ESI (+)) m / z 361 (M + H) +; MS (ESI (-)) m / z 359 (MH) "; XE NMR (300 MHz, DMSO-dg) d 1.88-1.96 (m, 2H), 2.25-2.60 (m, 2H), 2.56-2.61 (m , 2H), 4.79 (s, ÍH), 4.90 (q, 2H), 7.55 (d, ÍH), 7.65 (d, ÍH), 7.81 (s, ÍH), 10.27 (s, ÍH); Analysis calculated for C ? 7H? 3ClN205: C, 56.60; H, 3.63; N, 7.70. Found: C, 56.36; H, 4.02; N, 7.29.

Example 68 9 - (4-chloro-3-nitrophenyl) -5.6.7.9- tetrahydrofide T3.4 - blquinolin-1.8 (3H.4H) -dione The enantiomerically pure title compound was obtained as the most polar enantiomer, retention time = 45 minutes, after resolution with chiral HPLC (Gilson 215 / HPLC automated liquid manipulator, column (R, R) -Whelk-01 (2.1 centimeters x 25 centimeters), flow rate = 10 milliliters / minute, hexane: methylene alcohol: methylene chloride (60:26:13)) of the corresponding racemate of Example 52. White solid: MS (ESI (+)) m / z 361 (M + H) +; MS (ESI (-)) m / z 359 (MH) "; NMR (300 MHz, DMSO-dg) d 1.88-1.96 (m, 2H), 2.25-2.60 (m, 2H), 2.56-2.61 (m, 2H), 4.79 (s, ÍH), 4.90 (q, 2H), 7.55 (d, ÍH), 7.65 (d, ÍH), 7.81 (s, ÍH), 10.27 (s, ÍH); Analysis calculated for C17H13C1N205: C, 56.60; H, 3.63; N, 7. 70. Found: C, 56.37; H, 3.90; N, 7. 53.

Example 69 9 - (3,4-di-luo-phenyl) -5.6.7.9- etrahydrofide T3.4-b-quinoline-1.8 (3 H 4 H) -dione The enantiomerically pure title compound was obtained as the less polar enantiomer, retention time = 22.5 minutes, after resolution with chiral HPLC (automated liquid manipulator Gilson 215 / HPLC, column (R, R) -Whelk-01 (2.1 centimeters x 25 centimeters), flow rate = 10 milliliters / minute, hexane alcohol methyll -co: methylene chloride (60:26:13)) of the corresponding racemate prepared as described in Example 10, substituting 3-bromo-4-fluorobenzaldehyde with 3,4-difluorobenzaldehyde. White solid: MS (ESK +)) m / z 318 (M + H) +; MS (ESI (-)) m / z 316 (MH) "; E NMR (300 MHz, DMSO-dg) d 1.88-1.98 (m, 2H), 2.22-2.30 (m, 2H), 2.55-2.64 (m , 2H), 4.68 (s, ÍH), 4.89 (q, 2H), 7.05 (br s, ÍH), 7.17 (t, ÍH), 7.28 (q, ÍH), 10.16 (s, ÍH); Analysis calculated for C? 7H13F2N03: C, 64.35; H, 4.13; N, 4.30, Found: C, 64.20; H, 4.37; N, 3.96.

Example 70 9- (3,4-difluorophenyl) -5.6.7.9-tetrahydrofuro T3.4-bl uinolin-1.8 (3H.4H) -dione The enantiomerically pure title compound was obtained as the more polar enantiomer, retention time = 27 minutes , after resolution with chiral HPLC (Gilson 215 / HPLC automated liquid manipulator, column (R, R) -Whelk-01 (2.1 centimeters x 25 centimeters), flow rate = 10 milliliters / minute, hexane: methyl alcohol co: methylene chloride (60:26:13)) of the corresponding racemate prepared as described in Example 10, substituting the 3-bromo-4-fluorobenzaldehyde with 3,4-difluorobenzaldehyde. White solid: MS (ESK +)) m / z 318 (M + H) +; MS (ESI (-)) m / z 316 (MH) "; E NMR (300 MHz, DMSO-dg) d 1.88-1.98 (m, 2H), 2.22-2.30 (m, 2H), 2.55-2.64 (m , 2H), 4.68 (s, ÍH), 4.89 (q, 2H), 7.05 (br s, ÍH), 7.17 (t, ÍH), 7.28 (q, ÍH), 10.16 (s, ÍH); Analysis calculated for C? 7H? 3F2N03: C, 64.35; H, 4.13; N, 4.30, Found: C, 63.97; H, 4.22; N, 4.07.

Example 1 8- (4-methyl-3-nitrophenyl) -4.5.6.8-tetrahydro-1H-cyclopenta Tbl furo T3.4-pyridine-1.7 (3H) -dione The enantiomerically pure title compound was obtained as the less enantiomer polar, retention time = 30 minutes, after resolution with chiral HPLC (Gilson 215 / HPLC automated liquid manipulator, column (R, R) -Whelk-01 (2.1 centimeters x 25 centimeters), flow rate = 10 milliliters / minute, hexane: methylene alcohol: methylene chloride (50:33:17)) of the corresponding racemate prepared as described in Example 6, substituting 3-bromo-4-fluorobenzaldehyde with 4-methyl-3-nitrobenzaldehyde . White solid: MS (ESI (+)) m / z 327 (M + H) +; MS (ESI (-)) m / z 325 (MH) "; XH NMR (300 MHz, DMSO-dg) d 2.34 (t, 2H), 2.46 (s, 3H), 2.62-2.74 (m, 2H), 4.67 (s, ÍH), 4.98 (q, 2H), 7.40 (d, ÍH), 7.50 (d, ÍH), 7.78 (s, ÍH), 10.67 (br s, ÍH); Analysis calculated for C17H? 4N2O5 « 0.4 H20: C, 61.22; H, 4.47; N, 8.40, Found: C, 61.27; H, 4.48; N, 7.94.

Example 72 8- (4-methyl-3-nitrophenyl) -4.5.6.8-tetrahydro-1H-cyclopenta Tbl furo T3.4-pyridine-1.7 (3H) -dione The enantiomerically pure title compound was obtained as the enantiomer polar, retention time = 36 minutes, after resolution with chiral HPLC (automated liquid handler Gilson 215 / HPLC, column (R, R) -Whelk-01 (2.1 centimeters x 25 centimeters), flow rate = 10 milliliters / minute, hexane: methylene alcohol: methylene chloride (50:33:17)) of the corresponding racemate prepared as described in Example 6, substituting 3-bromo-4-fluorobenzaldehyde with 4-methyl. -3-nitrobenzaldehyde. Solid yellow: MS (ESI (+)) m / z 327 (M + H) +; MS (ESI (-)) m / z 325 (MH) "; XH NMR (300 MHz, DMSO-dg) d 2.34 (t, 2H), 2.46 (s, 3H), 2.62- 2.74 (m, 2H), 4.67 (s, ÍH), 4.98 (q, 2H), 7.40 (d, ÍH), 7.50 (d, ÍH), 7.78 (s, ÍH), 10.67 (br s, ÍH); Analysis calculated for C? 7H? 4N2O5 * 0.25 H20: C, 61.72; H, 4.42; N, 8.47. Found: C, 62.08; H, 4.66; N, 7.99.

Example 8- (3,4-dichlorophenyl) -4.5.6.8- etrahydro-1H-cyclopenta Tbl furo T3.4-pyridine-1.7 (3H) -dione The enantiomerically pure title compound was obtained as the less polar enantiomer, retention time = 23 minutes, after resolution with chiral HPLC (Gilson 215 / HPLC automated liquid manipulator, column (R, R) -Whelk-01 (2.1 centimeters x 25 centimeters), flow rate = 10 milliliters / minute, hexane: methylene alcohol: methylene chloride (50:33:17)) of the corresponding racemate prepared as described in Example 6, substituting 3-bromo-4-fluorobenzaldehyde with 3,4-dichlorobenzaldehyde. MS (ESK +)) m / z 336 (M + H) +; MS (ESI (-)) m / z 334 (MH) "; * H NMR (300 MHz, DMSO-dg) d 2.34 (t, 2H), 2.59-2.78 (m, 2H), 4.60 (s, ÍH) , 4.96 (q, 2H), 7.22 (d, ÍH), 7.43 (s, ÍH), 7.52 (d, ÍH), 10.59 (s, ÍH); Analysis calculated for C? 6HnCl2NO3 * 0.1 C6H? 4 * 0.4 H20 : C, 56.64; H, 3.78; N, 3.98, Found: C, 56.73; H, 3.58; N, 3.55.

Example 74 8- (3,4-dichlorophenyl) -4.5.6.8-tetrahydro-lH-cyclopenta Tbl furo T3.4-elpyridin-l.7 (3H) -dione The enantiomerically pure title compound was obtained as the more polar enantiomer, time retention = 30.5 minutes, after resolution with chiral HPLC (Gilson 215 / HPLC automated liquid manipulator, column (R, R) -Whelk-01 (2.1 centimeters x 25 centimeters), flow rate = 10 milliliters / minute, hexane methylene alcohol: methylene chloride (50:33:17)) of the corresponding racemate prepared as described in Example 6, substituting 3-bromo-4-fluorobenzaldehyde with 3,4-dichlorobenzaldehyde. MS (ESI (+)) m / z 336 (M + H) +; MS (ESI (-)) m / z 334 (MH) "; E NMR (300 MHz, DMSO-dg) d 2.34 (t, 2H), 2.59-2.78 (m, 2H), 4.60 (s, ÍH) , 4.96 (q, 2H), 7.22 (d, ÍH), 7.43 (s, ÍH), 7.52 (d, ÍH), 10.59 (s, ÍH); Analysis calculated for C? 6H11Cl2NO3 * 0.15 C6H? 4 * 0.3 H20 : C, 57.26; H, 3.9; N, 3.95, Found: C, 57.46; H, 3.62; N, 3.48, Example 75 8-r4-fluoro-3- (tri luoromethyl) fenip -4,5,6,9 -tgtrahydro-H-cyclopentarbl furo 3.4-elpyridin-l.7 (3H) -dione The enantiomerically pure title compound was obtained as the less polar enantiomer, retention time = 62.5 minutes, after resolution with chiral HPLC ( automated liquid manipulator Gilson 215 / HPLC, column (R, R) -Whelk-01 (2.1 centimeters x 25 centimeters), flow rate = 10 milliliters / minute, hexane, methyl alcohol, methylene chloride (75: 16.5: 8.5 )) of the corresponding racemate prepared as described in Example 6, substituting 3-bromo-4-fluorobenzaldehyde with 4-fluoro-3-trifluoromethylbenzaldehyde Yellow solid: MS (ESK +)) m / z 354 (M + H) +; MS (ESI (-)) m / z 352 (M-H) "; XH NMR (300 MHz, DMSO-dg) d 2.29 (t, 2H), 2.55-2.74 (m, 2H), 4. 70 (s, ÍH), 4.88 (q, 2H), 7.39 (t, ÍH), 7.52-7.60 (m, 2H), 10.70 (br s, ÍH); Analysis calculated for C? 7HnF4N03: C, 57.80; H, 3.14; N, 3.96. Found: C, 57.82; H, 3.18; N, 3.60.

Example 76 8-r4-fluoro-3- (trifluoromethyl) phenyl -4.5.6.8-tetrahydro-1H-cyclopenta Tbl furo T3.4-pyridine-1.7 (3H) -dione The enantiomerically pure title compound was obtained as the enantiomer more polar, retention time = 71 minutes, after resolution with chiral HPLC (automated Gilson 215 / HPLC liquid handler, column (R, R) -Whelk-01 (2.1 centimeters x 25 centimeters), flow rate = 10 milliliters / minute, hexane Methyl alcohol: methylene chloride (75: 16.5: 8.5)) of the corresponding racemate prepared as described in Example 6, substituting 3-bromo-4-fluorobenzaldehyde with 4-fluoro-3-trifluoromethylbenzaldehyde. MS (ESK +)) m / z 354 (M + H) +; MS (ESI (-)) m / z 352 (MH) "; XH NMR (300 MHz, DMSO-dg) d 2.29 (t, 2H), 2.55-2.74 (m, 2H), 4.70 (s, ÍH), 4.88 (q, 2H), 7.39 (t, ÍH), 7.52-7.60 (m, 2H), 10.70 (br s, ÍH); Analysis calculated for C17H ?: LF4N03 ¡C, 57.80; H, 3.14; N, 3. 96. Found: C, 57.53; H, 3. 06; N, 3. 59.

Example 77 9- (3-bromo-4-methylphenyl) -5.6.7.9-tetrahydrofuro T3.4- bl uinolin-1.8 (3H.4H) -dione The enantiomerically pure title compound was obtained as the least polar enantiomer, retention time = 23 minutes, after resolution with chiral HPLC (Gilson 215 / HPLC automated liquid manipulator, column (R, R) -Whelk-01 (2.1 centimeters x 25 centimeters), flow rate = 10 milliliters / minute, hexane: methylene alcohol: methylene chloride (60: 26.5: 13.5)) of the corresponding racemate prepared as described in Example 10, substituting 3-bromo-4-fluorobenzaldehyde with 3-bromo- 4-methylbenzaldehyde (Reference: Pearson et al., J. Org. Chem. (1958), 23, 1412-1416). MS (ESI (-)) m / z 373 (M-H) "; XH NMR (300 MHz, DMSO-dg) d 1.91 (m, 2H), 2.23 (s, 3H), 2.26 (m, 2H), 2.58 (m, 2H), 4.68 (s, ÍH), 4.89 (q, 2H), 7.07 (dd, J = 8.0, 1.5 Hz, ÍH), 7.19 (d, J = 8.0 Hz, HH), 7.30 (d, J = 1.5 Hz, HH), 10.17 (s, HH); Analysis calculated for C? 8H16BrN03: C, 57.77; H, 4.31; N, 3.74. Found: C, 57.61; H, 4.51; N, 3.80.

Example 78 9- (3-bromo-4-methylphenyl) -5.6.7.9-tetrahydrofuro 1,4-bl qv-iflplin-, 8 (3H, 4H) -dione The enantiomerically pure title compound was obtained as the most polar enantiomer , retention time = 28 minutes, after resolution with chiral HPLC (Gilson 215 / HPLC automated liquid manipulator, column (R, R) -Whelk-01 (2.1 centimeters x 25 centimeters), flow rate = 10 milliliters / minute, hexane: methyl alcohol: methylene chloride (60: 26.5: 13.5)) of the corresponding racemate prepared as described in Example 10, substituting 3-bromo-4-fluorobenzaldehyde with 3-bromo-4-methylbenzaldehyde. MS (ESI (-)) m / z 373 (M-H) "; E NMR (300 MHz, DMSO-dg) d 1.91 (m, 2H), 2.23 (s, 3H), 2.26 (m, 2H), 2.58 (m, 2H), 4.68 (s, ÍH), 4.89 (q, 2H), 7.07 (dd, J = 8.0, 1.5 Hz, HH), 7.19 (d, J = 8.0 Hz, HH), 7.30 (d, J = 1.5 Hz, HH), 10.17 (s, HH); Analysis calculated for C? 8H? 6BrN03: C, 57.77; H, 4.31; N, 3.74. Found: C, 57.61; H, 4.51; N, 3.80.

Example 79 8- (3-Chloro-4-fluorophenyl) -5,8-dihydro-H 3 H-difure T 3,4-b: 3.4- pyridine-1.7 (4 H) -dione The 3 Lchloro-4-fluorobenzaldehyde was replaced by 3 - . 3-bromo-4-fluorobenzaldehyde, and processed as in Example , to provide the title compound as a white solid. MS (DCI / NH3) m / z 339 (100%) (M + NH4); ? E NMR (300 MHz, DMSO-dg) d 4.68 (s, ÍH), 4.98 (q, 4H), 7.28 (m, 2H), 7.33 (d, ÍH), 10.70 (s, ÍH); Analysis calculated for C? 5H9NFCl04 ¡C, 56.01; H, 2.82; N, 4. 35. Found: C, 55.99; H, 2.77; N, 4.19.

Example 80 8- (3,4-dibromofenyl) -5,8-dihydro-lH.3H-difure 13.4-b: 3.4- iridin-1 > 7 (4H) -dione The 3,4-dibromobenzaldehyde was replaced by 3-bromo-4-fluorobenzaldehyde and processed as in Example 5 to provide the title compound as a white solid. MS (DCI / NH3) m / z 445 (100%) (M + NH4); H NMR (300 MHz, DMSO-dg) d 4.64 (s, ÍH), 4.98 (q, 4H), 7.21 (d, ÍH), 7.61 (s, ÍH), 7.68 (d, ÍH), 10.72 (s, ÍH); Analysis calculated for C15H9NBr2O4 * 0.25C3H60: C, 42.84; H, 2.40; N, 3.17. Found: C, 42.82; H, 2.24; N, 3.07.

Example 81 8- (3-bromo-4-methylphenyl) -5,8-dihydro-lH.3H-difuror3.4-b: 3.4- pyridine-1.7 (4H) -dione 3-bromo-4-methylbenzaldehyde (Reference: Pearson et al., J. Org. Chem. (1958), 23, 1412-1416) was replaced by 3-bromo-4-fluorobenzaldehyde, and processed as described in Example 5, to provide the title compound . MS (ESI (-)) m / z 361.01 (MH) "; E NMR (300 MHz, DMS0-d6) d 4.60 (s, ÍH), 4.88-5.05 (m, 4H), 7.17 (dd, J = 7.7 , 1.8 Hz, HH), 7.28 (d, J = 7.7 Hz, ÍH), 7.42 (d, J = 1.8 Hz, HH), 10.68 (s, HH); Analysis calculated for C 6 6H 2 2BrN04: C, 53.06; H, 3.34; N, 3.87, Found: C, 52.77; H, 3.44; N, 3.68, Example 82 8-r4-chloro-3- (trifluoromethyl) phenyl, 5,8-dihydro-lH.3H-difure T3.4- b: 3.4-pyridine-1.7 (4H) -dione The 4-chloro-3-trifluoromethylbenzaldehyde was replaced by 3-bromo-4-fluorobenzaldehyde, and processed as in Example 5, to provide the title compound as a solid white MS (DCI / NH3) m / z 389 (100%) (M + NH4); E NMR (300 MHz, DMSO-dg) d 4.82 (s, ÍH), 4.99 (q, 4H), 7.59 (d , ÍH), 7.66 (d, ÍH), 7.74 (s, ÍH), 10.78 (s, ÍH); Analysis calculated for C? 6H9ClFN04: C, 51.70; H, 2.44; N, 3.77. Found: C, 50.86; H, 2.22; N, 3.59.

E p 83 83- (3-bromo-4-fluorophenyl) -4.5.6.8-tetrahydro-1H-furo T3.4- bl pyrrolo T3.4-pyridine-1.7 (3H) -dione Example 83A 4- (3-bromo-4-fluorophenyl) -2-methyl. -5-oxo-4.5.6.7-tetrahydro-l-pyrrolor3.4-bl iridin3-methylcarboxylate A mixture of pyrrolidin-2,4-dione (Reference: G. Lowe, HW Yeung, J. Chem. Soc. Perkin Trans. I, (1973), 2907-2910) (2 millimoles, 198 milligrams), 3-bromo-4-fluorobenzaldehyde (2 millimoles, 406 milligrams), and methyl 3-aminocrotonate (2 millimoles) in ethyl alcohol (7 milliliters), was heated in a sealed tube at 80 ° C for a period of 48 hours. The reaction mixture was concentrated, and the residue was passed by evaporation chromatography (silica gel, methylene chloride, ethyl acetate, methyl alcohol, 4: 2: 0.5), to afford the title compound as a solid. yellow (165 milligrams, 22 percent yield).

Example 83B 8- (3-bromo-4-fluorophenyl) -4.5.6.8-tetrahydro-1H-furo 13 .4-pyrrolo 13-4-pyridine-1.7 (3H) -dione A suspension of the product of Example 83A ( 0.42 mmol, 159 milligrams) in chloroform (4 milliliters) was treated at 0 ° C with pyridine (1.2 equivalents, 0.04 milliliters) and pyridinium tribromide (1.1 equivalents, 147 milligrams). The reaction mixture was allowed to warm to room temperature over a period of 1 hour, and was stirred at that temperature for another hour. The homogeneous solution was poured into a dilute aqueous solution of hydrochloric acid, and the layers were separated. The organic phase was dried over magnesium sulfate, filtered, and concentrated. The solid residue was dissolved in chloroform (2 milliliters), and heated at 75 ° C overnight. Following the concentration, evaporation chromatography (silica gel, methylene chloride: ethyl acetate: methyl alcohol, 4: 2: 0.7 to 4: 2: 1.7) of the residue afforded the title compound (42 milligrams, yield 28 percent). MS (APCI +) m / z 365 (M + H) +; XH NMR (DMSO-dg) d 4.00 (ABq, 2H), 4.61 (s, ÍH), 4.91 (ABq, 2H), 7.24-7.30 (m, 2H), 7.50 (d, ÍH), 7.58 (s, ÍH) ); Analysis calculated for C? 5H? 0N2O3FBr * l .0 H20: C, 47.02; H, 3.16; N, 7.31. Found: C, 47.00; H, 2.81; N, 7.07.

Example 84 2- (2-aminoethyl) -9- (3-bromo-4-fluorophenyl) -2.3.5.6.7.9- hexahydro-lH-pyrrolo 13.4-bl quinolin-1.8 (4H) -dione Ethylenediamine was replaced by methylamine , and processed as described in Example 8C, to provide the title compound as a yellow solid. MS (APCI +) m / z 420 (M + H) +; XE NMR (DMSO-dg) d 1.82-1.97 (m, 2H), 2.19-2.29 (m, 2H), 2.47-2.65 (m, 2H), 2.60 (t, 2H), 3.07-3.20 (m, 2H) , 4.08 (ABq, 2H), 4.71 (s, ÍH), 7.16-7.23 (m, 2H), 7.40-7.45 (m, ÍH); Analysis calculated for C? 9H? 9N302FBr * l .0 H20: C, 52.07; H, 4.83; N, 9.59. Found: C, 51.61; H, 5.01; N, 11.36.

Example 85 8- (4-bromo-3-methylphenyl) -5,8-dihydro-lH.3H-difuror3.4-b: 3.4- elpyridin-1.7 4H) -dione Example 85a 4-bromo-3-methylbenzaldehyde A solution of 2,5-dibromotoluene (5.00 grams, 2.75 milliliters, 20.0 mmol) in diethyl ether (50 milliliters) was stirred under nitrogen at -78 ° C. N-butyl lithium (10 milliliters, 2.0 M, 20.0 mmol) was added dropwise over 10 minutes, and stirring was continued for an additional 1 hour. Anhydrous N, N-dimethylformamide (2.19 grams, 2.32 milliliters, 30.0 mmol) was added dropwise over 15 minutes, and the solution was allowed to reach -40 ° C for 4 hours. The reaction mixture was quenched by the addition of saturated aqueous sodium bicarbonate. The solvent was removed in vacuo, and the residue was partitioned between ethyl acetate (100 milliliters) and water (100 milliliters). The organic phase was washed with water (50 milliliters, 2 times), brine, dried over sodium sulfate, filtered, and concentrated to give a colorless oil (55 percent yield) as a 7: 3 mixture of 4-bromo-3-methylbenzaldehyde to 4-bromo-2-methylbenzaldehyde.

Example 85b 8- (4-bromo-3-methylphenyl) -5.8-dihydro-IIIH-difure T3.4-b: 3.4- iridin-1.7 (4H) -dione 4-Bromo-3-methylbenzaldehyde (1.43) equivalents) was processed as described in Example 5, to provide the title compound as a white solid. MS (DCI / NH3) m / z 381 (100%) (M + NH4); E NMR (300 MHz, DMSO-dg) d 2.30 (s, 3H), 4.58 (s, ÍH), 4.97 (q, 4H), 7.01 (d, ÍH), 7.22 (s, ÍH), 7.48 (d, ÍH), 10.70 (s, ÍH); Analysis calculated for C? GH12BrN04: C, 53. 06; H, 3. 3. 4; N, 3. 87. Found: C, 52.67; H, 3.23; N, 3.60.

Example 86 8- (4-fluoro-3-isopropenylphenyl) -5,8-dihydro-lH.3H-difure T3.4- b: 3.4-elpyridin-1.7 (4H) -dione Example 86a tributyl (isopropenyl) stannane Tributyltin chloride (5.00 grams, 4.17 milliliters, 15.3 millimoles) was dissolved in dry tetrahydrofuran (30 milliliters), and isopro-penylmagnesium bromide (30.7 milliliters, 0.5M, 15.3 millimoles) was added dropwise. ) in he-xano for 10 minutes. The solution was heated to 50 ° C, allowed to cool to room temperature, and stirred for 18 hours. The solution was poured into hexane (200 milliliters), filtered, and the filtrate was concentrated in vacuo to provide a colorless oil (4.44 grams, 87 percent yield). XH NMR (300 MHz, CDC13) d 0.88 (m, 15H), 1.30 (m, 6H), 1.48 (m, 6H), 4.58 (s, ÍH), 1.96 (s, 3H), 5.04 (s, ÍH) , 5.68 (s, ÍH).

Example 86b 8- (4-f luoro-3-isopropenylphenyl) -5,8-dihydro-lH.3H-difure 13.4-b: 3.4-elpyridine-1.7 (4H) -dione The product of Example 5 was processed as described. Test in Example 91, substituting tributyl (2-furyl) stannane with the product of Example 86A, to provide the title compound as a white solid. MS (DCI / H3) m / z 345 (100%) (M + NH4); E NMR (300 MHz, DMSO-dg) d 2.07 (s, 3H), 4.63 (s, ÍH), 4.97 (q, 4H), 5.20 (s, ÍH), 5.25 (s, ÍH), 7.16 (m, 2H), 7.24 (d, ÍH), 10.70 (s, ÍH); Analysis calculated for C? 8H? 4FNO4 * 0.25 H20: C, 65.16; H, 4.40; N, 4.22. Found: C, 65.40; H, 4.17; N, 3.89.

Example 87 (9S) -2- (2-aminoethyl) -9- (3-bromo-4-fluorophenyl) -2.3.5.6.7.9- hexahydro-lH-pyrrolo 13.4-bl quinolin-1.8 (4H) -dione The product of Example 18C was treated with ethylenediamine, and processed as described in Example 8C, to provide the title compound as a yellow powder. MS (ESI (+)) m / z 420 (M + H) +; MS (ESI (-)) m / z 418 (MH) "; XH NMR (300 MHz, DMSO-dg) d 1.85-1.97 (m, 2H), 2.15-2.30 (m, 4H), 2.52-2.58 (m , 2H), 3.18-3.30 (m, 2H), 4.07 (m, 2H), 7.18 (m, 2H), 7.41 (d, ÍH), 9.79 (s, ÍH); Analysis calculated for C? 9H? 9BrFN3O2 * 0.4 C6H1: C, 56.52; H, 5.05; N, 9.24. Found: C, 56.79; H, 5.06; N, 9.00 Example 88 8- (3-Iodo-4-methylphenyl) -5,8-dihydro-lH.3H-difure 13.4-b: 3.4- elpyridin-1.7 (4H) -dione Example 88a 3-Iodo-4-methylbenzaldehyde To a paste of 3-iodo-4-methylbenzoic acid (5.0 grams, 19.1 mmol) in 100 milliliters of dry tetrahydrofuran was added a complex of borane-methyl sulfide (2.3 milliliters, 22.9 millimoles). This mixture was refluxed for 60 minutes, and then cooled to room temperature. After concentration, a dark brown oil was obtained. This oil was dissolved in 32 milliliters of methylene chloride, and the solution was treated with pyridinium chlorochromate (4.55 grams, 21 mmol). This mixture was refluxed for 60 minutes, cooled to room temperature, and concentrated. The dark red oil obtained was diluted with ethyl acetate, and washed successively with water, 1N aqueous hydrochloric acid, saturated aqueous sodium bicarbonate, and brine, dried over sodium sulfate, filtered, and concentrated. The residue was purified by chromatography by evaporation on silica gel, using hexane-ethyl acetate (20: 1) as eluent, to afford the title aldehyde as a pale yellow solid (1.7 grams, 36 percent yield).

Example 88b 8- (3-iodo-4-methylphenyl) -5,8-dihydro-lH.3H-difure 13.4-b: 3.4- pyridine-1.7 (4H) -dione The 3-iodo-4-methylbenzaldehyde was replaced by 3-iodo-4-methylbenzaldehyde. -bromo-4-fluorobenzaldehyde, and processed as described in Example 5, to provide the title compound as a white solid. MS (ESI (-)) m / z 408 (M-H) "; E NMR (300 MHz, DMSO-dg) d 2.32 (s, 3H), 4.57 (s, ÍH), 4.98 (q, J = 12.54 Hz, 4H), 7.19 (dd, J = 8.07, 1.11 Hz, ÍH), 7.26 (d, J = 8.07 Hz, ÍH), 7.66 (d, J = l.ll Hz, ÍH); Analysis calculated for C? GH? 2IN04: C, 46.97; H, 2.96; N, 3.42.

Found: C, 46.65; H, 2.80; N, 3.26.

Example 89 (-) 9- 3-bromo-4-fluorophenyl) -7,7-dimethyl-5.6.7.9- tetrahydrofide 13.4-bl quinolin- 1. (3H.4H) -dione Example 89A 4- (3-bromo-4-fluorophenyl) -2.6.6-trimethyl-5 -oxo- 1.4.5.6.7.8- methyl hexahydro-3'-n-methylcarboxylate A stirred solution of 3-bromo-4- Fluorobenzaldehyde (1.80 grams, 8.87 millimoles), 4,4-dimethyl-1,3-cyclohexanedione (1.24 grams, 8.87 millimoles), and methyl 3-aminocrotonate (1.02 grams, 8.87 millimoles) in methanol (50 milliliters), was treated with anhydrous ammonium acetate (957 milligrams, 12.4 millimoles), and the mixture was heated to reflux for 36 hours. The reaction mixture was cooled to room temperature, and the white solid that precipitated was isolated by filtration. The solid was triturated in sequence with cold methanol, followed by diethyl ether, to give the title compound as a white solid 1.54 grams (3.64 mmol, 41 percent). The enantiomers were resolved by chiral HPLC, using a column (R, R) -Whelk-01 (2.1 centimeters x 25 centimeters), 25% EtOH / hexanes, flow rate = 10 milliliters / minute. Less polar isomer, retention time = 29 minutes: MS (DCI / NH3) m / z 422 (M + H) +; E NMR (300 MHz, DMSO-dg) d 0.91 (s, 3H), 1.02 (s, 3H), 1.64-1.78 (m, 2H), 2.31 (s, 3H), 3.31-3.39 (m, 2H), 3.57 (s, 3H), 4.86 (s, ÍH), 7.12-7.23 (m, 2H), 7.36 (dd, J = 6.6, 2.1 Hz, ÍH), 9.20 (br S, ÍH); Analysis calculated for C20H? BrFNO3: C, 56.88; H, 5.01; N, 3.32. Found: C, 56.69; H, 5.16; N, 3.34. More polar isomer, retention time = 36 minutes: MS (DCI / NH3) m / z 422 (M + H) +; XH NMR (300 MHz, DMSO-dg) d 0.91 (s, 3H), 1.02 (s, 3H), 1.64-1.78 (m, 2H), 2.31 (s, 3H), 3.31-3.39 (m, 2H), 3.57 (s, 3H), 4.86 (s, ÍH), 7.12-7.23 (m, 2H), 7.36 (dd, J = 6.6, 2.1 Hz, ÍH), 9.20 (br s, ÍH); Analysis calculated for C2oH2? BrFN03 ¡C, 56.88; H, 5.01; N, 3.32. Found: C, 56.74; H, 5.07; N, 3.40.

Example 89B (-) 9- (3-bromo-4- fluorophenyl) -7.7-dimethyl-5.6.7.9- tetrahydrofide 13.4-bl quinolin-1.8 (3H.4H) -dione The more polar enantiomer (272 milligrams, 0.644 mmol) of Example 89A, was dissolved in chloroform (6 milliliters), and N-bromosuccinimide (115 milligrams, 0.644 mmol) was added at 23 ° C. After 3 hours of stirring at 23 ° C, the reaction mixture was partitioned between ethyl acetate (20 milliliters) and water (8 milliliters). The organic portion was washed with brine (5 milliliters), and then dried (sodium sulfate), filtered, and concentrated to give a yellow solid. The crude solid was placed in a 25 milliliter round bottom flask, and immersed in an oil bath previously heated (130 ° C) under a stream of nitrogen for 1.5 hours. The resulting residue was dissolved in a minimum volume of methylene chloride, and purified by evaporation chromatography (silica, elution with 10 percent ethyl acetate / methylene chloride), to provide the title compound as a solid. white (194 milligrams, 0.478 millimoles, 74 percent). [a] D23 -109 ° (c 0.3, CHC13); P.f. 197-198 ° CE NMR (300 MHz, DMS0-de) d 0.87 (s, 3H), 0.94 (s, 3H), 1.75 (t, J = 6.3 Hz, 2H), 2.48-2.69 (m, 2H), 4.61 (s, ÍH), 4.83 (ABq, JAB = 16.5 HZ,? VAB = 29.7 HZ, 2H), 7.13-7.24 (m, 2H), 7.38 (dd, J = 6.7, 2.0 Hz, ÍH), 10.11 ( br s, ÍH); 13 C NMR (DMSO-dg) d 23.6, 24.1, 24.8, 33.7, 33.9, 65.2, 101.3, 107.2, 109.0, 116.1, 128.5, 132.0, 143.4, 151.2, 156.3, 171.3, 199.5; MS (DCI / NH3) m / z 423 (M + NH4) +; Analysis calculated for C? 9H17BrFN03: C, 56.17; H, 4.22; N, 3.45. Found: C, 56.09; H, 4.16; N, 3.44.

Example 90 (+) 9- (3-bromo-4-fluorophenyl) -7,7-dimethyl-5.6.7.9-tetrahydrofide T3.4-bl quinolin-1.8 (3H.4H) -dione The less polar isomer of Example 89A was subjected to the bromination / lactonization process described in Example 89B, to provide the title compound. [a] D23 -114 ° (c 0.3, CHC13); P.f. 197-198 ° C; MS (DCI / NH3) m / z 423 (M + NH4) +; X H NMR (300 MHz, DMSO-d 6) d 0.87 (s, 3 H), 0.94 (s, 3 H), 1.75 (t, J = 6.3 Hz, 2 H), 2.48-2.69 (m, 2 H), 4.61 (s, ÍH), 4.83 (ABq, JAB = 16.5 Hz,? VM = 29.7 Hz, 2H), 7.13-7.24 (m, 2H), 7.38 (dd, J = 6.7, 2.0 Hz, ÍH), 10.11 (br s, ÍH ); 13C NMR (DMSO-dg) d 23.6, 24.1, 24.8, 33.7, 33.9, 65.2, 101.3, 107.2, 109.0, 116.1, 128.5, 132.0, 143.4, 151.2, 156.3, 171. 3, 199.5; Analysis calculated for C? 9H? 7BrFN03: C, 56.17; H, 4.22; N, 3. 45. Found C, 56.10; H, 4.26; N, 3.51.

EXAMPLE 91 8- 13- (2-furyl) -4-methylphenyl-5,8-dihydro-3H-dihydrate r3.4-b: 3.4-elpyridine-1.7t / 4H) -dione To a paste of the product of Example 81 (130 milligrams, 0.36 millimoles) in 5 milliliters of N, N-dimethylformamide, was added tributyl (2-furyl) stannane (0.14 milliliters, 0.43 millimoles), diterbutyl dicarbonate (75 milligrams, 0.36 millimoles), and tetrakis (triphenylphosphine) ) palladium (0) (46 milligrams, 0.04 millimoles). The reaction mixture was heated to 120 ° C in a sealed high pressure tube overnight. It was then cooled to room temperature, and diluted with ethyl acetate. The solution was washed successively with brine, IN hydrochloric acid, saturated aqueous sodium bicarbonate and brine, dried over sodium sulfate, filtered, and concentrated. The residue was purified by chromatography by evaporation on silica gel using methylene chloride-methyl alcohol (20 + 1) as eluent, to give the title compound as a pale yellow solid. The title compound was recrystallized from methylene chloride-methylene-ethyl diethylether (1: 1: 20) (62 milligrams, 49 percent). MS (ESI (-)) m / z 348 (MH) "; XH NMR (300 MHz, DMSO-dg) d 2.40 (s, 3H), 4.62 (s, ÍH), 4.98 (q, J = 12.54 Hz, 4H), 6.63 (q, J = 1.04 Hz, HH), 6.70 (d, J = 3.31 Hz, HH), 7.10 (d, J = 7.72, 1.84 Hz, HH), 7.22 (d, J = 8.09 Hz, HH), 7.53 (d, J = 1.84 Hz, HH), 7.79 (d, J = 1.11 Hz, HH), Analysis calculated for C20H15NO5 * 0.2 H20: C, 68.76; H, 4.33; N, 4.01. : C, 67.82; H, 4.23; N, 3.63.

Example 92 9- (3-bromo-4-fluorophenyl) -3.4.5.6.7.9- hexahydrocyclopenta Tb pyran 13.4-pyridine-1,8-dione Example 92A 4- (1-ethoxyethoxy) -1-butyne 3-butyn-1-ol (46.33 grams, 0.661 moles) was dissolved in methylene chloride (700 milliliters), and treated with ethylvinyl ether (0.661 moles, 63.2 milliliters) ) and pyridinium p-toluenesulfonate (0.033 moles, 8.31 grams) (note: after the addition of the pyridinium p-toluenesulfonate, an exothermic reaction takes place). After stirring for a period of 2 hours, the reaction mixture was concentrated and filtered through a pad of silica gel (ethyl acetate / hexane, 1-1), to give the title compound as a colorless liquid (80.29 grams, yield of 85.5 percent).

Example 92B 5- (l-ethoxyethoxy) -2-benzyl pentynoate A solution of the product of Example 92A (79.99 grams, 0.563 mol) in tetrahydrofuran (1 liter) was treated dropwise at -78 ° C with N-butyl lithium (2.5 M in hexane, 0.563 moles, 225 milliliters). The reaction mixture was stirred at -78 ° C for half an hour, and then chlorine-benzyl formate (0.563 moles, 80.4 milliliters) was added dropwise. The reaction mixture was stirred at -78 ° C for 2 hours, allowed to warm to room temperature, and stirred overnight. After quenching with water, ethyl acetate was added, and the layers were separated. The organic layer was dried over magnesium sulfate, filtered, and concentrated. Chromatography by evaporation of the residue (silica, hexane to hexane ethyl acetate, 30% 1 to 4%) afforded the title compound as a colorless oil (155.5 grams, 78 percent yield).

Example 92C 5-benzyl 5-hydroxy-2-pentynoate A solution of the product of Example 92B (122.1 grams, 0.442 mole) in acetone (400 N, 200 milliliters) was treated at room temperature with an aqueous solution of hydrochloric acid (0.5 N, 200 milliliters). The reaction mixture was stirred for 6 hours, and then diluted with water and ethyl acetate. The layers were separated, and the organic layer was dried over magnesium sulfate, filtered, and concentrated to give the title compound as a colorless oil (90.17 grams, 100 percent yield). X H NMR (300 MHz, CDCl 3) d 2.61 (t, 2 H), 3.79 (t, 2 H), 5.19 (s, 2 H), 7.32-7.40 (m, 5 H).

Example 92D 4- (benzyloxy) -5,6-dihydro-2H-pyran-2-one A heterogeneous mixture of benzyl alcohol (2.65 moles, 274.4 milliliters), red mercury (II) oxide (13.26 millimoles), 2.87 grams), and boron trifluoride diethyl ether (0.133 moles, 16.3 milliliters), heated at 60 ° C for 3 hours (eventually became homogeneous). Then a solution of the product of Example 92C (90.17 grams, 0.442 mole) in benzyl alcohol (91.5 milliliters) was added at room temperature, and the reaction mixture was stirred at 70 ° C for 4 hours, and again at room temperature. overnight. It was poured into a saturated aqueous solution of sodium bicarbonate, and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, filtered, and concentrated. Evaporation chromatography (silica, hexane to hexane ethyl acetate, 30% 1 to 1.2) gave the title compound as a white solid (49.6 grams, 55 percent yield). XH NMR (300 MHz, CDC13) d 2.60 (t, 2H), 4.38 (t, 2H), 4.95 (s, 2H), 5.28 (s, ÍH), 7.32-7.46 (m, 5H).

Example 92E Dihydro-2H-pyran-2.4 (3H) -dione The product of Example 92D (9.17 grams, 0.045 moles) was dissolved in isopropanol (500 milliliters), and treated with palladium hydroxide (20 weight percent palladium). , dry base, on carbon) (4 grams) under a nitrogen atmosphere. The reaction mixture was stirred under an atmosphere of hydrogen at atmospheric pressure overnight. It was filtered through a pad of silica gel (elution with ethyl acetate). The filtrate was concentrated to provide the title compound as a white solid (4.28 grams, 84 percent). E NMR (300 MHz, CDCl 3) d 2.73 (t, 2H), 3.57 (s, 2H), 4.61 (t, 2H).

Example 92F 9- (3-bromo-4-fluorophenyl) -3.4.5.6.7.9- hexahydrocyclopenta Tbl irano T3.4-iridin-1,8-dione A mixture of the product of Example 92E (1.5 milli-moles, 171 milligrams), 3-bromo-4-fluorobenzaldehyde (1.5 millimoles, 305 milligrams), and 3-amino-2-cyclopenten-1-one (1.5 millimoles, 146 milligrams) was suspended in ethyl alcohol (5 milliliters). The reaction mixture was heated in a sealed tube at 80 ° C for a period of 72 hours. The formed precipitate was collected by filtration, and dried to provide the title compound (246 milligrams, 43 percent yield). MS (APCI +) m / z 378 (M + H) +; E NMR (DMSO-dg) d 2.28 (t, 2H), 2.52-2.86 (m, 4H), 4.20-4.38 (m, 2H), 4.63 (s, ÍH), 7.20-7.27 (m, 2H), 7.45 (d, ÍH), 10.27 (bs, ÍH); Analysis calculated for C? 7H13N03FBr C, 53.99; H, 3.46; N, 3.70. Found: C, 53.38; H, 3.76; N, 3.49.

Example 93 10- (3-bromo-4-fluorophenyl) -3.4.6.7.8.10-hexahydro-1H-pyran 14.3-bl uinolin-1.9 (5H) -dione A mixture of the product of Example 92E (1.5 milli-moles, 171 milligrams), 3-bromo-4-fluorobenzaldehyde (1.5 millimoles, 305 milligrams) and 3-amino-2-cyclohexen-1-one (1.5 millimoles, 167 milligrams) was suspended in ethyl alcohol (5 milliliters). The reaction mixture was heated in a sealed tube at 80 ° C for a period of 72 hours. The formed precipitate was collected by filtration, and dried to provide the title compound (265 milligrams, 45 percent yield). MS (APCI-) m / z 378 (MH) "; XH NMR (DMSO-dg) d 1.73-2.00 (m, 2H), 2.19-2.29 (m, 2H), 2.54-2.80 (m, 4H), 4.10 -4.35 (m, 2H), 4.80 (s, ÍH), 7.18-7.23 (m, 2H), 7.39 (dd, ÍH), 9.72 (bs, ÍH); Analysis calculated for C? 8H? 5N03FBr: C, 55 12; H, 3.85; N, 3. 57. Found: C, 55.00; H, 3.79; N, 3. 54.

Example 94 10-r4-Fluoro-3- (trifluoromethyl) phenyl -3.4.6.7.8.10-hexahydro-l-pyran 14. 3-bl quinolin-1.9 (5H) -dione The 4-fluoro-3-trifluoromethylbenzaldehyde was replaced by 3-bromo-4-fluorobenzaldehyde, and processed as described in Example 93, to provide the title compound. MS (APCI +) m / z 382 (M + H) +; E NMR (DMSO-dg) d 1.74 * 2.00 (m, 2H), 2.19-2.29 (m, 2H), 2.54-2.80 (m, 4H), 4.12-4.35 (m, 2H), 4.87 (s, ÍH) , 7.35 (dd, ÍH), 7.47-7.56 (m, 2H), 9.77 (bs, ÍH); Analysis calculated for C? 9H15N03F4 ¡C, 59.85; H, 3.96; N, 3.67. Found: C, 59.66; H, 3.88; N, 3.60.

Example 95 9- f4-fluoro-3- (trifluoromethyl) phenyl -3.4.5.6.7.9- hexahydrocyclopenta Tbran 13.4 -pyridine-1,8-dione 4-Fluoro-3-trifluoromethylbenzaldehyde was replaced by 3-bromo-4-fluorobenzaldehyde , and processed as described in Example 92, to provide the title compound. MS (APCI +) m / z 368 (M + H) +; NMR (DMSO-dg) d 2.28 (t, 2H), 2.52-2.86 (m, 4H), 4.21-4.38 (m, 2H), 4.72 (s, ÍH), 7.38 (dd, ÍH), 7.50-7.59 ( m, 2H), 10.31 (bs, ÍH); Analysis calculated for C? 8H? 3N03F4 ¡C, 58.86; H, 3.57; N, 3.81. Found C, 58.55; H, 3.82; N, 3.63.

Determination of the Opening Activity of the Potassium Channel Membrane Hyperpolarization Assays The compounds were evaluated for their potassium channel opener activity, using guinea pig urinary bladder cells (GPB). For the preparation of urinary bladder smooth muscle cells, the urinary bladders of male guinea pigs (Hartley, Charles River, Wilmington, MA) weighing 300 to 400 grams (g) were removed and placed in a solution of Krebs free of Ca2 + freeze (Composition, millimolar (mM) KCl, 2.7; KH2P04, 1.5: NaCl, 75; Na2HP04, 9.6; Na2HP04 «7H20, 8; MgSO4, 2; glucose, 5; HEPES, 10; pH 7.4 ). The cells were isolated by enzymatic dissociation (Klockner, U. and Isenberg, G., Pflugers Arch. (1985), 405, 329-339). The bladder was cut into small secti and incubated in 5 milliliters (mL) of the Kreb solution containing 1 milligram per milliliter (mg / ml) of collagenase (Sigma, St. Louis, MO) and 0.2 milligram / milliliter of pronase (Calbiochem, La Jolla, CA) with continuous agitation in a cell incubator for 30 minutes. The mixture was then centrifuged at 1,300 x g for 5 minutes, and the pellet was resuspended in Dulbecco's phosphate buffered serum (PBS) (GIBCO, Gaithersburg, MD), and recentrifuged to remove the residual enzyme. The cell pellet was resuspended in 5 milliliters of the growth medium (composition: Dulbecco's modified Eagle's medium supplemented with 10 percent fetal bovine serum, 100 units / milliliter of penicillin, 100 units / milliliter of streptomycin, and 0.25 milligrams / milliliter of amphotericin B), and also the suspension was dissociated by pipetting the suspension through a Pasteur pipette polished with flame, and passing it through a polypropylene mesh membrane (Spectrum, Houston, TX). The cell density was adjusted to 100,000 cells / milliliter by resuspension in the growth medium. The cells were applied to 96-well black bottom-transparent plates (Packard) for membrane potential studies, at a density of 20,000 cells / well, and were maintained in a cell incubator with 90 percent air: C02 al 10 percent, until confluence. It was confirmed that the cells were of the smooth muscle type by cytoskeletal staining using a muscle-to-human mouse actin (Biomeda, Foster City, CA). Functional activity in the potassium channels was measured by evaluating the changes in membrane potential using the bis-oxonol dye (DiBAC (4) 3 (Molecular Probes) in a kinetic assay system based on 96-well cells, using a Fluorescent Imaging Plate Reader (FLIPR) (KS Schroeder et al, J. Biomed.Screen, volume 1, pages 75-81 (1996)) DiBAC (4) 3 is an anionic po-titiometric probe that is divided between cells and the extracellular solution in a manner dependent on the membrane potential.With a growing membrane potential (eg depolarization of K +), the probe is further divided into the cell; this is measured as an increase in fluorescence due to the interaction of the dye with the lipids and intracellular proteins. Conversely, the reduction of the membrane potential (hyperpolarization by the potassium channel openers) causes a reduction in fluorescence. The confluent guinea pig urinary bladder cells cultured in 96-well black plates with a clear bottom were rinsed twice with 200 milliliters of assay buffer (composition, mM: HEPES, 20, NaCl, 120, KCl, 2).; CaCl2, 2; MgCl2, 2; MgCl2, 1; glucose, 5; pH 7.4 at 25 ° C) containing DiBAC (4) 3 5 μM, and incubated with 180 milliliters of the regulator in a cell incubator for 30 minutes at 37 ° C to ensure the distribution of the dye through the membrane. After recording the fluorescence of the baseline for 5 minutes, reference or test compounds, prepared at 10 times the concentration in the assay regulator, were added directly to the wells. Changes in fluorescence were monitored for an additional 25 minutes. The hyper-polarization responses were corrected for any background noise, and normalized to the response observed with 10 μM of the reference compound P1075 (assigned as 100 percent), a potent opener of smooth muscle KATP channels ( Quast et al., Mol.Pharmacol., Volume 43, pages 474-481 (1993)). Routinely, five concentrations of P1075 or test compounds (log or half-log dilutions) were evaluated, and the maximum continuous state hyperpolarization values (expressed as% relative to P1075) were plotted as a function of the concentration. The EC50 values (concentration that causes 50 percent of the maximum response for the test sample) were calculated by non-linear regression analysis using a sigmoidal equation of four parameters. The maximum micromolar EC50 response of each compound (expressed as% in relation to P1075) is reported. Compound delivery solutions were prepared in 100 percent dimethyl sulfoxide, and additional dilutions were made in the assay regulator, and added to a 96-well plate.

Table 1 Membrane Hyperpolarization (MHP) in Guinea Pig Bladder Cells (GPM) Functional Models In Vi tro Compounds were evaluated to determine the opening activity of the functional potassium channel using tissue strips obtained from Landrace pig bladders. Landrace pig bladders were obtained from female Landrace pigs from 9 to 30 kilograms. The Landrace pigs are euthanized with an intraperitoneal injection of pentobarbital soon, Somlethal®, J.A. Webster Inc., Sterling MA. The entire bladder was removed, immediately placed in a soon of Krebs Ringer bicarbonate (composition, mM: NaCl, 120, NaHCO3, 20, dextrose, 11, KCl, 4.7, CaCl2, 2.5, MgSO4, 1.5, KH2P04, 1.2; K2EDTA, 0.01, equilibrated with C02 at 5 percent / 02 at 95 percent, pH 7.4, at 37 ° C). Propanolol (0.004 mM) was included in all trials to block β-adrenoceptor. The trigonal and dome portions were discarded. Strips 3 to 5 millimeters (mm) wide and 20 millimeters long were prepared from the remaining tissue cut into a circular shape. The mucous layer was removed. One end was fixed to a stationary glass rod, the other to a Grass FT03 transducer at a basal preload of 1.0 gram. Two parallel platinum electrodes were included in the stationary glass rod to provide a field stimulus of 0.05 Hz, 0.5 millisecond, at 20 volts. This low frequency stimulus produced a stable torsion response of 100 to 500 centigrams. The tissues were allowed to equilibrate for at least 60 minutes, and were prepared with 80 mM KCl. A response curve to the control concentration (cumulative) was generated for each tissue, using the potassium channel opener P1075 as the control agonist. P1075 completely eliminated stimulated twisting in a dose-dependent manner over a concentration range of 10"9 to 10" 5M, using 1/2 log increments. After a 60 minute rinsing period, a concentration response curve (cumulative) was generated for the test agonist in the same manner as was used for the P1075 control agonist. The maximum efficiency of each of the compounds is reported (expressed as% in relation to P1075). The amount of agent necessary to cause 50 percent of the agent's maximum response (ED50) was calculated using "ALLFIT" (DeLean et al., Am. J. Physiol., 235, E97 (1980)), and the potency of the agonist were expressed as PD (the negative logarithm). The agonist powers were also expressed as an index in relation to P1075. The index was calculated by dividing the ED50 for P1075 between the ED50 for the test agonist in a given tissue. Each tissue was used for only one test agonist, and the indices obtained for each tissue were averaged to provide an average power index. These data are shown in Table 2.

Table 2 Functional Potassium Channel Opener Activity in Isolated Bladder Strips As shown by the data in Tables 1 and 2, the compounds of this invention reduce the stimulated contractions of the bladder by opening the potassium channels, and consequently, may have utility in the treatment of diseases prevented by, or ameliorated by, the , the potassium channel openers. The term "pharmaceutically acceptable carrier", as used herein, means a non-toxic solid, semi-solid, or liquid inert filler, a diluent, an encapsulating material, or a formulation aid of any type. Some examples of materials that can serve as pharmaceutically acceptable carriers are sugars, such as lactose, glucose, and sucrose; starches, such as corn starch and potato starch; cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose, and cellulose acetate; powdered tragacanth; malt; jelly; talcum powder; excipients, such as cocoa butter and suppository waxes; oils, such as peanut oil, cottonseed oil, saffron oil, sesame oil, olive oil, corn oil, and soybean oil; glycols; such as propylene glycol; esters, such as ethyl oleate and ethyl laurate; agar; regulating agents, such as magnesium hydroxide and aluminum hydroxide; alginic acid; water free of pyrogen; isotonic-co serum; Ringer's solution; ethyl alcohol, and phosphate buffer solutions, as well as other non-toxic compatible lubricants, such as sodium laurisulfate and magnesium stearate, as well as coloring agents, release agents, coating agents, sweeteners, flavorings, and perfuming agents, preservatives and antioxidants, which may also be present in the composition, according to the formulator's judgment. The present invention provides pharmaceutical compositions comprising compounds of the present invention formulated together with one or more non-toxic pharmaceutically acceptable carriers. The pharmaceutical compositions can be formulated for oral administration in solid or liquid form, for parenteral injection, or for rectal administration. Also included within the scope of the present invention are pharmaceutical compositions comprising one or more of the compounds of the formulas I-VI prepared and formulated in combination with one or more pharmaceutically acceptable non-toxic compositions. The pharmaceutical compositions can be formulated for oral administration in solid or liquid form, for parenteral injection, or for rectal administration. The pharmaceutical compositions of this invention can be administered to humans and other mammals orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, topically (as by powders, ointments, or drops), buccally, or as an oral or nasal spray. The term "parenterally", as used herein, refers to modes of administration that include intravenous, intramuscular, intraperitoneal, intrasternal, subcutaneous, intraarticular injection and infusion. The pharmaceutical compositions of this invention for parenteral injection comprise sterile aqueous or non-aqueous, pharmaceutically acceptable solutions, dispersions, suspensions, or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Examples of suitable carriers, diluents, solvents, or aqueous and non-aqueous vehicles include water, ethanol, polyols (propylene glycol, polyethylene glycol, glycerol, and the like), suitable mixtures thereof, vegetable oils (such as olive oil), and injectable organic esters, such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of a coating, such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants. These compositions may also contain adjuvants, such as preservatives, wetting agents, emulsifying agents, and dispersing agents. The prevention of the action of the microorganisms can be ensured by different antibacterial and antifungal agents, for example parabens, chlorobutanol, phenol, sorbic acid, and the like. It may also be desirable to include isotonic agents, for example, sugars, sodium chloride, and the like. Prolonged absorption of the injectable pharmaceutical form can be caused by the use of agents delaying absorption, for example aluminum monostearate and gelatin. In some cases, in order to prolong the effect of a drug, it is often desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This can be done by using a liquid suspension of a crystalline or amorphous material with poor solubility in water. The rate of absorption of the drug then depends on its rate of dissolution, which in turn may depend on the size of the crystal and the crystalline form. In an alternative manner, a delayed absorption of a parenterally administered drug form is performed by dissolving or suspending the drug in an oil vehicle. The suspensions, in addition to the active compounds, may contain suspending agents, such as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol, and sorbitan esters, microcrystalline cellulose, aluminum methohydroxide, bentonite, agar-agar, tragacanth, and mixtures thereof. If desired, and for a more effective distribution, the compounds of the present invention can be incorporated into slow delivery or targeted delivery systems, such as polymer matrices, liposomes, and microspheres. They can be sterilized, for example, by filtration through a bacteria retention filter, or by the incorporation of sterilizing agents in the form of sterile solid compositions, which can be dissolved in sterile water or in some other sterile injectable medium. immediately before use. The active compounds may also be in a microencapsulated form, if appropriate, with one or more excipients, as noted above. The solid dosage forms of tablets, dragees, capsules, pills, and granules, can be prepared with coatings and shells, such as enteric coatings, release control coatings, and other coatings well known in the pharmaceutical formulating art. . In these solid dosage forms, the active compound can be mixed with at least one inert diluent, such as sucrose, lactose, or starch. These dosage forms may also comprise, as in normal practice, additional substances other than inert diluents, for example, lubricants for the formation of tablets and other tableting aids, such as magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets, and pills, the dosage forms may also comprise regulatory agents. They may optionally contain opacifying agents, and may also be of such composition that they release the active ingredients only, or preferably, in a certain part of the intestinal tract in a delayed manner. Examples of the embedment compositions that can be used include polymeric substances and waxes. Injectable depot forms are made by forming microencapsulated matrices of the drug in biodegradable polymers, such as polylactide-polyglycolide. Depending on the ratio of the drug to the polymer, and the nature of the particular polymer employed, the rate of release of the drug can be controlled. Examples of other biodegradable polymers include poly (orthoesters) and po-li (anhydrides). Depot injectable formulations can also be prepared by trapping the drug in liposomes or in microemulsions that are compatible with body tissues. The injectable formulations can be sterilized, for example, by filtration through a bacteria retention filter, or by the incorporation of sterilizing agents in the form of sterile solid compositions, which can be dissolved or dispersed in sterile water or in another sterile injectable medium just before use.

Injectable preparations, for example injectable sterile aqueous or oleaginous suspensions, can be formulated according to the known art, using suitable dispersing agents or humectants and suspending agents. The sterile injectable preparation can also be a sterile injectable solution, suspension, or emulsion in a non-toxic, parenterally-acceptable diluent or solvent, such as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, U.S.P. and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any soft fixed oil may be employed, including synthetic mono- or diglycerides. In addition, fatty acids, such as oleic acid, are used in the preparation of injectables. Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In these solid dosage forms, the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier, such as sodium citrate or calcium diphosphate, and / or) fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and silicic acid; b) binders, such as carboxymethyl cellulose, alginates, gelatin, polyvinyl pyrrolidinone, 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 sodium carbonate; e) solution retarding agents, such as paraffin; f) absorption accelerators, such as quaternary ammonium compounds; g) wetting agents, such as cetyl alcohol and glycerol monostearate; h) absorbers, such as kaolin and bentonite clay; 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 form may also comprise regulatory agents. Solid compositions of a similar type can also be employed as fillings in soft and hard filled gelatin capsules, using excipients such as lactose or milk sugar, as well as high molecular weight polyethylene glycols, and the like. The solid dosage forms of 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 formulating art. They may optionally contain opacifying agents, and may also be of a composition that they release the active ingredients only, or preferably, in a certain part of the intestinal tract, in a delayed manner. Examples of the embedment compositions that can be used include polymeric substances and waxes. Compositions for rectal or vaginal administration are preferably suppositories, which can be prepared by mixing the compounds of this invention with suitable non-irritating excipients or vehicles, such as cocoa butter, polyethylene glycol, or a suppository wax that is solid at room temperature , but liquid at body temperature, and therefore, which melts in the rectum or vaginal cavity, and releases the active compound. Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art, such as, for example, water or other solvents, solubilizing and emulsifying agents, such as ethyl alcohol, isopropyl alcohol, carbonate ethyl, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (in particular cottonseed, peanut, corn, germ, olive, castor, and sesame oils) ), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and sorbitan fatty acid esters, and mixtures thereof. In addition to the inert diluents, the oral compositions also include adjuvants, such as wetting agents, emulsifying and suspending agents, sweeteners, flavorings, and perfuming agents. Dosage forms for topical or transdermal administration of a compound of this invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants, or patches. The active component is mixed under sterile conditions with a pharmaceutically acceptable carrier, and with any necessary preservatives or regulators that may be required. Ophthalmic formulations, eye drops, eye ointments, powders and solutions are also contemplated as being within the scope of this invention. Ointments, pastes, creams, and gels may contain, in addition to an active compound of this invention, excipients, such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates, and polyamide powder, or mixtures thereof. these substances. Sprays may additionally contain customary propellants, such as chloro-fluorohydrocarbons. Transdermal patches have the additional advantage of providing a controlled supply of a compound to the body. These dosage forms can be made by dissolving or dispersing the compound in the appropriate medium. Absorption enhancers can also be used to increase the flow of the compound through the skin. The speed can be controlled by providing a speed control membrane, or by dispersing the compound in a polymer matrix or gel. 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 mono- or mul-ti-lamellar hydrated liquid crystals that are dispersed in an aqueous medium. Any non-toxic, physiologically acceptable and metabolizable lipid capable of forming liposomes can be used. The present compositions in the form of liposomes may contain, in addition to the compounds of the present invention, stabilizers, preservatives, excipients, and the like.The preferred lipids are the natural and synthetic phospholipids, and the phosphatidylcholines (lecithins) used separately or methods of forming liposomes are known in the art, see, for example, Prescott, Editor, Methods in Cell Biology, Volume XIV, Academic Press, New York, NY, (1976), pages 33 et seq. The term "pharmaceutically acceptable cation", as used herein, refers to a positively charged inorganic or organic ion which is generally considered suitable for human consumption Examples of pharmaceutically acceptable cations are hydrogen, alkali metal ( lithium, sodium, and potassium), magnesium, calcium, ferrous, ferric, ammonium, alkylammonium, dialkylammonium, trialkylammonium, tetraalkylammonium, diethanolammonium, and choline. The cations can be exchanged by methods known in the art, such as ion exchange. The terms "pharmaceutically acceptable salts, esters, and amides", as used herein, refer to carboxylate salts, amino acid addition salts, zwitterions, esters, and amides of the compounds of formulas I-VI which , within the scope of a conscious medical judgment, are suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, and are commensurate with a reasonable benefit / risk ratio, and are effective for their intended use. The term "pharmaceutically acceptable salt", as used herein, refers to salts that are well known in the art. For example, S.M. Berge et al. Describe pharmaceutically acceptable salts in detail in (J. Pharmaceutical Sciences, 66: 1-19 (1977)). Examples of the non-toxic, pharmaceutically acceptable acid addition salts are salts of an amino group formed with inorganic acids, such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid, or with organic acids , such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid, or using other methods employed in the art, such as ion exchange. Other pharmaceutically acceptable salts include nitrate, bisulfate, borate, formate, butyrate, valerate, 3-phenylpropionate, camphorrate, adipate, benzoate, oleate, palmitate, stearate, laurate, lactate, fumarate, ascorbate, aspartate, nicotinate, p-toluenesulfonate, camphorsulfonate. , methanesulfonate, 2-hydroxyethanesulfonate, gluconate, glucoheptonate, lactobionate, glycerophosphate, laurisulfate, and the like; metal salts, such as sodium, potassium, magnesium, or calcium salts, or amino salts, such as ammonium, triethylamine salts, and the like, all of which can be prepared according to conventional methods. The term "pharmaceutically acceptable ester", as used herein, refers to esters of compounds of the present invention that are hydrolyzed in vivo, and include those that decompose rapidly in the human body to leave the parent compound or a salt of it. Examples of the non-toxic pharmaceutically acceptable esters of the present invention include alkyl esters of 1 to 6 carbon atoms and cycloalkyl esters of 5 to 7 carbon atoms, although alkyl esters of 1 to 4 carbon atoms are preferred. The esters of the compounds of the formulas I-VI can be prepared according to conventional methods. The term "pharmaceutically acceptable amide", as used herein, refers to non-toxic amides of the present invention derived from ammonia, primary alkylamines of 1 to 6 carbon atoms, and secondary dialkylamines of 1 to 6. carbon atoms. In the case of the secondary amines, the amine can also be in the form of a 5- or 6-membered heterocycle containing a nitrogen atom. Amides derived from ammonia, primary alkylamides of 1 to 3 carbon atoms, and secondary dialkylamides of 1 to 2 carbon atoms are preferred. The amides of the compounds of the formulas I-VI can be prepared according to conventional methods. It is intended that the amides of the present invention include amino acid and peptide derivatives of the compounds of the formulas I-VI as well. The term "pharmaceutically acceptable prodrug" or "prodrug", as used herein, represents the prodrugs of the compounds of the present invention which, within the scope of a conscious medical judgment, are suitable for use in contact with the tissues of a patient. - human and lower animals without undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable proportion of benefit / risk, and effective for their intended use. The prodrugs of the present invention can be rapidly transformed in vivo to the parent compound of the above formula, for example by hydrolysis in the blood. A full discussion is provided in (T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, volume 14 of the A. C.S. Symposium Series, and in Ed-ward D. Roche, editor, Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press (1987)). The term "prodrug ester group", as used herein, refers to any of the ester forming groups that are hydrolysed under physio-logical conditions. Examples of the prodrug ester groups include pivayloxymethyl, acetoxymethyl, phthalidyl, indanyl, and methoxymethyl, as well as other groups known in the art. Other examples of prodrug ester groups can be found in the book ("Pro-drugs as Novel Delivery Systems" by Higuchi and Stella) cited above. Dosage forms for topical administration of a compound of this invention include powders, sprays, ointments, and inhalants. The active compound is mixed under sterile conditions with a pharmaceutically acceptable carrier and any necessary preservatives, regulators, or propellants that may be required. Ophthalmic formulations, eye ointments, powders and solutions are also contemplated within the scope of this invention. The actual dosage levels of the active ingredients in the pharmaceutical compositions of this invention can be varied to obtain an amount of the active compounds that is effective to achieve the desired therapeutic response for a particular patient, the compositions, and the mode of administration. The level of dosage selected will depend on the activity of the particular compound, the route of administration, the severity of the condition being treated, and the condition and prior medical history of the patient being treated. However, it is within the skill of the art to start with doses of the compound at levels lower than those required to achieve the desired therapeutic effect, and gradually increase the dosage until the desired effect is achieved. The present invention contemplates pharmaceutically active metabolites formed by the biotransformation in vivo of the compounds of the formulas I-VI. The term "pharmaceutically active metabolite", as used herein, refers to a compound formed by the biotransformation in vivo of the compounds of the formulas I-VI. The present invention contemplates the compounds of the formulas I-VI and its metabolites. A full discussion of biotransformation is provided in Goodman and Gilman's, The Pharmacological Basis of Therapeutics, seventh edition, incorporated herein by reference. The compounds of the invention, including, but not limited to, those specified in the examples, possess an opener activity of the potassium channel 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, disorders in eating, urinary incontinence. , functional bowel disorders, neurodegeneration, and embolism. The ability of the compounds of the invention to treat asthma, epilepsy, hypertension, Raynaud's syndrome, male sexual dysfunction, female sexual dysfunction, migraine, pain, eating disorders, urinary incontinence, functional bowel disorders, neurodegeneration, and embolism, it can be demonstrated according to the methods described (DE Nurse et al., Br. J. Urol volume 68, pages 27-31 (1991); BB Howe et al., J. Pharmacol. Exp. Ther. volume 274, pages 884-890 (1995), K. Lawson, Pharmacol. Ther., volume 70, pages 39-63 (1996), DR Gehlert et al., Neuro-Psychopharmacol &Biol. Psychiat., volume 18, pages 1093-1102. (1994), M. Gopala-krishnan et al, Drug Development Research, volume 28, pages 95-127 (1993), JE Freedman et al, The Neuroscientist, volume 2, pages 145-152 (1996), D. Spans- Wick et al., Nature, volume 390, pages 521-25 (December 4, 1997)). The aqueous liquid compositions of the present invention are particularly useful for the treatment and prevention of asthma, epilepsy, hypertension, Raynaud syndrome, male sexual dysfunction, female sexual dysfunction, migraine, pain, eating disorders, urinary incontinence, functional bowel disorders, neurodegeneration, and embolism. When used in the above and other treatments, a therapeutically effective amount of one of the compounds of the present invention may be employed in pure form, or where such forms exist, in a salt, ester, amide, or prodrug form. pharmaceutically acceptable. Alternatively, the compound can be administered as a pharmaceutical composition containing the compound of interest in combination with one or more pharmaceutically acceptable excipients. The phrase "therapeutically effective amount" of the compound of the invention means a sufficient amount of the compound to treat disorders, at a reasonable rate of benefit / risk applicable to any medical treatment. However, it will be understood that the total daily use of the compounds and compositions of the present invention will be decided by the attending physician within the scope of a conscious medical judgment. The specific therapeutically effective dose level for any particular patient will depend on a variety of factors, including the disorder being treated and the severity of the disorder; the activity of the specific compound employed; the specific composition employed; age, body weight, general health, sex and the patient's diet; the time of administration, the route of administration, and the rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincident with the specific compound used; and similar factors well known in the medical art. For example, it is well within the skill of the art to start with doses of the compound at levels lower than those required to achieve the desired therapeutic effect, and gradually increase the dosage until the desired effect is achieved. The total daily dose of the compounds of this invention administered to a human or a lower animal may be from about 0.003 to about 10 milligrams / kilogram / day. For purposes of oral administration, the most preferable doses may be in the range of about 0.01 to about 5 milligrams / kilogram / day. If desired, the effective daily dose can be divided into multiple doses for administration purposes; consequently, the individual dose compositions may contain these amounts or their multiples thereof to form the daily dose.

Claims

1. A compound that has the formula I D n N 'ffi RD'6-W H. n ' I, or a pharmaceutically acceptable salt, amide, ester, or prodrug thereof, wherein: n and n 'are independently from 1 to 3; A is selected from the group consisting of O, -NR2, and S; A 'is selected from the group consisting of O, -NR2. , S, and CR4.R5-; abis D is selected from the group consisting of CH2 and C (O); D 'is selected from the group consisting of CH2, C (O), S (O), and S (0) 2; Ri is selected from the group consisting of aryl and heterocycle; R2 and R2- are independently selected from the group consisting of hydrogen, alkoxyalkyl, alkyl, arylalkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, heterocycloalkyl, hydroxyl, hydroxyalkyl, -NZ? Z2, and (NZXZ2) alkyl, wherein Zx and Z2 are independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, aryl, arylalkyl, and formyl; R4- and R5 'are independently selected from the group consisting of hydrogen and alkyl; R6 and R7- are independently selected from the group consisting of hydrogen and alkyl; with the proviso that, when D is CH2, then D 'is different from CH2; with the proviso that when D 'is S (0) or S (0) 2, then A' is CR 'R5-; and with the proviso that the following compounds are excluded: 8- [2- (difluoromethoxy) phenyl] -1,7-dioxo-2,3,4,5,6,8-hexahydrodipyrrolo [3, 4-b; 3, 4-e] pyridin-2,6-dipropanoic, (8- [2- (difluoromethoxy) phenyl] -1,7-dioxo-2, 3,4,5,6,8-hexahydrodipyrrolo dipropanate [3, 4-b; 3, 4-e] pyridin-2,6-ethyl, 8- [2- (difluoromethoxy) phenyl] -6-methyl-4,5,6,8-tetrahydro-lH-furo [3, 4 -b] pyrrolo [3, 4-e] pyridin-1, 7 (3H) -dione; 8- [2- (difluoromethoxy) phenyl] -2,6-dimethyl-2,3,4,5,6,8 hexahydrodipyrrolo [3, 4-b; 3,4-e] pyridin-1,7-dione; 2,6-dimethyl-8-phenyl-2, 3,4,5,6,8-hexahydrodipyrrolo [3, 4 -b; 3, 4-e] pyridin-1, 7-dione, 8- (3-nitrophenyl) -5,8-dihydro-lH, 3H-difuro [3,4-b; 3,4-e] pyridine -l, 7 (4H) -dione, 8- (2,4-dichlorophenyl) -5,8-dihydro-lH, 3H-difuro [3,4- b; 3,4-e] pyridin-1, 7 ( 4H) -dione, 8- (4-methoxy-enyl) -5,8-dihydro-1H, 3H-difuro [3,4-b, • 3, 4-e] iridin-1,7 (4H) -dione, 8- (4-iodophenyl) -5,8-dihydro-lH, 3H-difuro [3,4- b; 3,4-e] pyridin-1,7 (4H) -dione, 8- (4-bromo-enyl) ) -5,8-dihydro-lH, 3H-difuro [3,4-b; 3,4-e] pyridin-l, 7 (4H) -dione, 8- (3-bromophenyl) -5,8-dihi dro-lH, 3H-difure [3, 4-b; 3, 4-e] pyridin-1, 7 (4H) -dione, 8- (2- (fluorophenyl) -5,8-dihydro-lH, 3H-difuro [3,4- b; 3,4-e] pyridin-l, 7 (4H) -dione, 8-phenyl-5,8-dihydro-lH, 3H-difuro [3,4-b; 3,4-e] pyridin-1,7 (4H) -dione, 8- (2-Aminophenyl) -5,8-dihydro-H, 3 H -duburo [3,4-b; 3,4 -e] pyridin-1,7 (4H) -dione, 8- [2- (difluoromethoxy ) phenyl] -5,8-dihydro-lH, 3H-difuro [3,4-b; 3,4-e] pyridin-1,7 (4H) -dione, 8- (2-chlorophenyl) -5,8 -dihydro-lH, 3H-difuro [3,4-b; 3,4-e] pyridin-1, 7 (4H) -dione, 8- (2, 3, 4-trimethoxyphenyl) -5,8-dihydro- lH, 3H-difure [3,4-b; 3,4-e] pyridin-l, 7 (4H) -dione, 8- [2- (trifluoromethyl) phenyl] -5,8-dihydro-1H, 3H- difuro [3, 4-b; 3, 4-e] pyridin-1, 7 (4H) -dione, 8- (2-chloro-3-nitrophenyl) -5,8-dihydro-lH, 3H-difure [3 , 4-b, 3,4-e] pyridin-l, 7 (4H) -dione, 8- (4-nitrophenyl) -5,8-dihydro-lH, 3H-difuro [3, 4-b; 3, 4-e] pyridin-l, 7 (4H) -dione, 8- (4-chlorophenyl) -5,8-dihydro-lH, 3H-difuro [3,4- b; 3,4-e] pyridin-1 , 7 (4H) -dione, 8- (3-chlorophenyl) -5,8-dihydro-1H, 3 H-difuso [3,4-b; 3,4-e] pyridin-l, 7 (4H) -dione, 8- (2-nitrophenyl) -5,8-dihydro-lH, 3H-difure [3, 4 -b; 3, 4-e] pyridin-1, 7 (4H) -dione, 3,7-dimethyl-10-phenyl-3,4,5,6,7,10-hexahydro-lH, 9H-dipyran [4, 3 -b; 3,4 -e] pyridin-1,9-dione, 6,6-dimethyl-9-phenyl-5,6,7,9-tetrahydrofuro [3,4-b] quinolin-1,8 (3H, 4H) -dione, 9- (1, 3-benzodioxol-5-yl) -5,6,7,9-tetrahydrofuro [3,4-b] quinolin-1, 8 (3H, 4H) -dione, 9- (3 -methoxyphenyl) -5, 6,7, 9-tetrahydrofuro [3,4-b] quinolin-1, 8 (3H, 4H) -dione, 9- (2-methoxyphenyl) -6,6-dimethyl-5,6,7,9- tetrahydrofuro [3,4-b] quinolin-1,8 (3H, 4H) -dione, 6,6-dimethyl-9- (2-nitrophenyl) -5,6,7,9-tetrahydrofuro [3, 4-b] ] quinolin-1, 8 (3H, 4H) -dione, 6,6-dimethyl-9- [2- (trifluoromethyl) phenyl] -5,6,7,9-tetrahydrofuro [3,4-b] quinolin-1 , 8 [3 H, 4 H] -dione, and 9- [3- (benzyloxy) phenyl] -6,6-dimethyl-5,6,7,9-tetrahydrofuro [3,4-b] quinolin-1, 8 ( 3H.4H) -dione.

2. A compound according to claim 1, of formula II: II, or a pharmaceutically acceptable salt, amide, ester, or prodrug thereof, wherein: n and n 'are independently from 1 to 3; A is selected from the group consisting of O, -NR2, and S; A 'is selected from the group consisting of 0, -NR2', S, and CR4.R5; Ri is selected from the group consisting of aryl and heterocycle; R2 and R2- are independently selected from the group consisting of hydrogen, alkoxyalkyl, alkyl, arylalkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, heterocycloalkyl, hydroxyl, hydroxyalkyl, -NZ? Z2, and (NZi-Z2) alkyl, wherein Z and Z2 are independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, aryl, arylalkyl, and formyl; R4 < and R5 < they are independently selected from the group consisting of hydrogen and alkyl; and R6- and R7 'are independently selected from the group consisting of hydrogen and alkyl.

3. A compound according to claim 2, wherein: A is NR2; A 'is NR2.; and n 'is 1.

4. A compound according to claim 2, wherein: A is NR2; A 'is O; and n 'is 1.

5. A compound according to claim 2, wherein: A is NR2; A 'is S; and n 'is 1.

6. A compound according to claim 2, wherein: A is NR2; A 'is CR4.R5; and n 'is 1.

7. A compound according to claim 2, wherein: A is O; A 'is NR2 <; and n 'is 1.

8. A compound according to claim 2, wherein: A is O; A 'is O; and n 'is 1.

9. A compound according to claim 2, wherein: A is O; A 'is S; and n 'is 1.

10. A compound according to claim 2, wherein: A is O; A 'is CR4'R5', - and n 'is 1.

11. A compound according to claim, wherein: A is S; A 'is NR2-; and n 'is 1.

12. A compound according to claim, wherein: A is S; A 'is O; and n 'is 1.

13. A compound according to claim, wherein: A is S; A 'is S; and n 'is 1.

14. A compound according to claim, wherein: A is S; A 'is CR4-R5; and n is 1.

15. A compound according to claim 2, wherein: A is NR2; A 'is NR2'; and n 'is 2.

16. A compound according to the claim 2, where: A is NR2; A 'is 0; and n 'is 2.

17. A compound according to claim, wherein: A is NR2; A 'is S; and n 'is 2.

18. A compound according to claim, wherein: A is NR2; A 'is CR4.R5-; and n 'is 2.

19. A compound according to claim 2, wherein: A is O; A 'is NR2-; and n 'is 2.

20. A compound according to claim 2, wherein: A is O; A 'is O; and n 'is 2.

21. A compound according to claim, wherein: A is O; A 'is S; and n 'is 2.

22. A compound according to claim, wherein: A is O; A 'is CR4-R5; and n 'is 2.

23. A compound according to claim 2, wherein: A is S; A 'is NR2; and n 'is 2.

24. A compound according to claim 2, wherein: A is S; A 'is O; and n 'is 2.

25. A compound according to claim 2, wherein: A is S; A 'is S; and n 'is 2.

26. A compound according to claim 2, wherein: A is S; A 'is CR.R5; and n 'is 2.

27. A compound according to claim 1 of formula III III, or a pharmaceutically acceptable salt, amide, ester, or prodrug thereof, wherein: n and n 'are independently from 1 to 3; A is selected from the group consisting of O, -NR2, and S; A 'is selected from the group consisting of O, -NR2. , S, and CR4-R5 '; R. is selected from the group consisting of aryl and heterocycle; R2 and R2- are independently selected from the group consisting of hydrogen, alkoxyalkyl, alkyl, arylalkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, heterocycloalkyl, hydroxyl, hydroxyalkyl, -NZ? Z2, and (NZ? Z2) alkyl, wherein Zx and Z2 are independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, aryl, arylalkyl, and formyl; R4 and R5. they are independently selected from the group consisting of hydrogen and alkyl; and Rg- and R7 'are independently selected from the group consisting of hydrogen and alkyl.

28. A compound according to claim 27, wherein: A is NR2; A 'is NR2; and n 'is 1.

29. A compound according to claim 27, wherein: A is NR2; A 'is NR2-; R6 'is hydrogen; R7- is hydrogen; n is 1; and n 'is 1.

30. A compound according to claim 29, selected from the group consisting of: 8- (3-bromo-4-fluorophenyl) -2, 3,4,5,6,8-hexahydrodipirrolo [3, 4-b; 3, 4-e] pyridin-1,7-dione; and 8- (3-bromo-4-fluorophenyl) -2,6-dimethyl-2, 3,4,5,6,8-hexahydrodipyrrolo [3,4- b; 3,4-e] pyridin-1, 7 -Diona.

31. A compound according to claim 27, wherein: A is NR2; A 'is O; and n 'is 1.

32. A compound according to the claim 27, where: A is NR2; A 'is O; R6 it is hydrogen; R7- is hydrogen; n is 1; and n 'is 1.

33. A compound according to claim 32, which is 8- (3-bromo-4-fluorophenyl) -4,5,6,8-tetrahydro-lH-furo [3,4-b] pyrrolo [3, 4-e ] pyridin-1, 7 (3H) -dione.

34. A compound according to claim 27, wherein: A is NR2; A 'is S; and n 'is 1.

35. A compound according to claim 27, wherein: A is NR2; A 'is CR.R5-; and n 'is 1.

36. A compound according to claim 27, wherein: A is NR2; A 'is CR4.R5', - Rg 'is hydrogen; R7- is hydrogen; n is 1; and n 'is 1.

37. A compound according to claim 36, selected from the group consisting of: 8- (3-bromo-4-fluorophenyl) -2-methyl-2, 3,4,5,6,8-hexahydrocyclopenta [b] pyrrolo [3, 4-e] pyridin-1, 7-dione, 8- (3-bromo-4-fluorophenyl) -2-ethyl-2, 3,4,5, 6, 8-hexahydrocyclopenta [b] pyrrolo [ 3, 4-e] pyridin-1, 7-dione, 8- (3-bromo-4-fluorophenyl) -2- (2-methoxyethyl) -2,3,4,5,6,8-hexahydrocyclopenta [b] pyrrolo [3, 4-e] pyridin-1, 7-dione, 8- (3-bromo-4-fluorophenyl) -2- [2- (4-morpholinyl) ethyl] -2,3,4,5 hydrochloride , 6, 8-hexahydrocyclopenta [b] pyrrolo [3,4-e] pyridin-1,7-dione, hydrochloride 8- (3-bromo-4-fluorophenyl) -2- [2- (dimethylamino) ethyl] -2 , 3,4,5,6,8-hexahydrocyclopenta [b] pyrrolo [3,4-e] pyridin-1,7-dione, (8R) -8- (3-bromo-4-fluorophenyl) -2-methyl -2, 3, 4, 5, 6,8-hexahydrocyclopenta [b] pyrrolo [3,4-e] pyridin-1,7-dione, and (8S) -8- (3-bromo-4-fluorophenyl) - 2-methyl-2, 3, 4, 5,6,8-hexahydrocyclopenta [b] pyrrolo [3, 4-e] pyridin-1, 7-diona.

38. A compound according to claim 27, wherein: A is NR2; A 'is CR4'R5', - R - is hydrogen; R7 'is hydrogen; n is 2; and n 'is 1.

39. A compound according to claim 38, selected from the group consisting of: 9- (3-bromo-4-fluorophenyl) -3,4,5,6,7,9-hexahydro-lH-cyclopenta [b] [1, 6] naphthyridin-1, 8 (2H) -dione, 9- (3-chloro-4-fluorophenyl) -3,4,5,6,7,9-hexahydro-1H-cyclopenta [b] [1 , 6] naphthyridin-1, 8 (2H) -dione, 9- [4-fluoro-3- (trifluoromethyl) phenyl] -3,4,5,6,7,9-hexahydro-lH-cyclopenta [b] [ 1,6] naphthyridin-1, 8 (2H) -dione, 9- (4-chloro-3-fluorophenyl) -3,4,5,6,7,9-hexahydro-1H-cyclopenta [b] [1, 6] naphthyridin-1, 8 (2H) -dione, 3,4-dichlorophenyl) -3,4,5,6,7,9-hexahydro-lH-cyclopenta [b [1,6] naphthyridin-l, 8 ( 2H) -dione, 9- 4-chloro-3- (trifluoromethyl) phenyl] -3,4,5,6,7,9-hexahydro-lH • cyclopenta [b] [1,6] naphthyridin-1, 8 ( 2H) -dione, 9- 3, 4 -dibromophenyl) -3,4,5,6,7,9-hexahydro-lH-cyclopenta [b [1, 6] naphthyridin-1,8 (2H) -dione, 9 - 3-cyanophenyl) -3,4,5,6,7,9-hexahydro-lH-cyclopenta [b [1, 6] naphthyridin-l, 8 (2H) -dione, 9- 5-chloro-2-thienyl ) -3,4,5,6, 7, 9-hexahydro- lH-cyclopenta [b [1, 6] naphthyridin-1, 8 (2H) -dione, 9-3-nitrophenyl) -3,4,5,6,7,9-hexahydro-1H-cyclopenta [b [1, 6] naphthyridin-1, 8 (2H) -dione, 9-5-nitro-2-thienyl) -3,4,5,6,7,9-hexahydro-1H-cyclopenta [b [1,6] naphthyridine- 1, 8 (2H) -dione; and 9-5-nitro-3-thienyl) -3,4,5,6,7,9-hexahydro-1H-cyclopenta [b [1, 6] naphthyridin-1, 8 (2H) -dione.

40 A compound according to the claim 27, where A is O; A 'is NR2.; and n 'is 1.

41. A compound according to claim 27, wherein: A is O; A 'is O; and n 'is 1.

42. A compound according to claim 27, wherein: A is 0; A 'is O; Rg. it is hydrogen; R7- is hydrogen; n is 1; and n 'is 1.

43. A compound according to claim 42, selected from the group consisting of: 8- (3-bromo-4-fluorophenyl) -5,8-dihydro-lH, 3H-difuro [3,4-b; 3, 4-e] pyridin-l, 7 (4H) -dione, 8- [4-fluoro-3- (2-furyl) phenyl] -5,8-dihydro-lH, 3H-difuro [3,4- b; 3, 4-e] pyridin-1, 7 (4H) -dione, 8- [4-fluoro-3- (trifluoromethyl) phenyl] -5,8-dihydro-lH, 3H-difuro [3,4-b; 3,4-e] pyridin-l, 7 (4H) -dione, 8- (3,4-dichlorophenyl) -5,8-dihydro-lH, 3H-difuro [3,4-b; 3,4-e ] pyridin-l, 7 (4H) -dione, 8- (4-methyl-3-nitrophenyl) -5,8-dihydro-lH, 3H-difuro [3,4-b; 3, 4-e] pyridin-1, 7 (4H) -dione, 8- (3-chloro-4-fluorophenyl) -5,8-dihydro-1H, 3H-difure [3, 4-b; 3, 4-e] pyridin-1, 7 (4H) -dione; 8- (3, 4 -dibromophenyl) -5,8-dihydro-1H, 3H-difure [3,4-b; 3,4-e] pyridin-l, 7 (4H) -dione, 8- (3- bromo-4-methylphenyl) -5,8-dihydro-lH, 3H-difuro [3,4-b; 3,4-e] pyridin-l, 7 (4H) -dione, 8- [4-chloro-3 - (trifluoromethyl) phenyl] -5,8-dihydro-1H, 3H-difure [3, 4-b; 3, 4-e] pyridin-1, 7 (4H) -dione, 8- (4-bromo-3-methylphenyl) -5,8-dihydro-1H, 3H-difure [3, 4-b; 3, 4 -e] pyridin-1, 7 (4H) -dione, 8- (4-fluoro-3-isopropenylphenyl) -5,8-dihydro-1H, 3H-difure [3, 4-b; 3, 4-e] pyridin-1, 7 (4H) -dione, 8- (3-iodo-4-methylphenyl) -5,8-dihydro-1H, 3H-difure [3, 4-b; 3, 4 -e] pyridin-1, 7 (4H) -dione; and 8- [3- (2-furyl) -4-methylphenyl] -5,8-dihydro-lH, 3H-difuro [3,4- b, -3,4-e] pyridin-1, 7 (4H) -Diona.

44. A compound according to claim 27, wherein: A is O; A 'is S; and n 'is 1.

45. A compound according to claim 27, wherein: A is O; A 'is CR4.R5', - and n 'is 1.

46. A compound according to claim 27, wherein: A is O; A 'is CR'R5-; R6 it is hydrogen; R7 < it is hydrogen; n is 1; and n 'is 1.

47. A compound according to the claim 46, selected from the group consisting of: 8- (3-bromo-4-fluorophenyl) -4,5,6, 8-tetrahydro-lH-cyclopenta [b] furo [3,4-e] pyridin-1 , 7 (3H) -dione, (8S) -8- (3-bromo-4-fluorophenyl) -4,5,6, 8-tetrahydro-lH-cyclopenta [b] furo [3,4-e] pyridin- 1, 7 (3H) -dione; (8R) -8- (3-Bromo-4-fluorophenyl) -4,5,6,8-tetrahydro-1H-cyclopenta [b] furo [3,4-e] pyridin-1,7 (3H) -dione , (8S) -8- (4-methyl-3-nitrophenyl) -4,5,6,8-tetrahydro-lH-cyclopenta [b] furo [3,4-e] pyridin-1,7 (3H) - dione, (8R) -8- (4-methyl-3-nitrophenyl) -4,5,6, 8-tetrahydro-lH-cyclopenta [b] furo [3,4-e] pyridin-1, 7 (3H) -dione, (8S) -8- (3,4-dichlorophenyl) -4, 5, 6, 8-tetrahydro-lH-cyclopenta [b] furo [3,4-e] pyridin-1, 7 (3H) - dione, (8R) -8- (3,4-dichlorophenyl) -4,5,6, 8-tetrahydro-lH-cyclopenta [b] furo [3,4-e] pyridin-1,7 (3H) -dione , (8S) -8- [4-Fluoro-3 - (trifluoromethyl) phenyl] -4,5,6,8-tetrahydro-lH-cyclopenta [b] furo [3,4-e] pyridin-1, 7 ( 3H) -dione, and (8R) -8- [4-fluoro3- (t'-trifluoromethyl) phenyl] -4,5,6,8-tetrahydro-1H-cyclopenta [b] furo [3, 4-e] pyridine -1, 7 (3H) -dione.

48. A compound according to claim 27, wherein A is 0; A 'is CR4.R5'; Rg. it is hydrogen; R7- is hydrogen; n is 2; and n 'is 1.

49. A compound according to the claim 48, which is selected from the group consisting of: 8- (3-bromo-4-fluorophenyl) -3,4,5,6,7,9-hexahydrocyclopenta [b] pyrano [3,4-e] pyridine -1, 8 -diona; and 9- [4-fluoro-3- (trifluoromethyl) phenyl] -3,4,5,6,7,9-hexahydrocyclopenta [b] pyrano [3,4-e] pyridin-1,8-dione.

50. A compound according to claim 27, wherein A is S; . A 'is NR2-; and n 'is 1.

51. A compound according to claim 27, wherein A is S; A 'is O; and n 'is 1.

52. A compound according to claim 27, wherein A is S; A 'is S; and n 'is 1.

53. A compound according to claim 27, wherein A is S; A 'is CR4.R5', - and n 'is 1.

54. A compound according to the claim 27, where A is NR2; A 'is NR2.; and n 'is 2.

55. A compound according to claim 27, wherein A is NR2; A 'is NR2-; Rg. it is hydrogen; R7- is hydrogen; n is 2; and n 'is 2.

56. A compound according to the claim 55, which is 10- (3-bromo-4-fluorophenyl) -3, 4, 6, 7, 8, 10-hexahydropyrido [4, 3-b] [1,6] naphthyridin-1, 9 (2H, 5H ) -diona.

57. A compound according to claim 27, wherein: A is NR2; A 'is 0; and n 'is 2.

58. A compound according to claim 27, wherein: A is NR2; A 'is S; and n 'is 2.

59. A compound according to claim 27, wherein: A is NR2; A 'is CR4.R5; and n 'is 2. 5

60. A compound according to claim 27, wherein: A is NR2; A 'is CR4.R5', -! > . 10 Rg. it is hydrogen; R7 'is hydrogen; n is 1; and n 'is 2. 15

61. A compound according to the claim 60, which is selected from the group consisting of: 9- (3-bromo-4-fluorophenyl) -2-methyl-2, 3,5,6,7,9-hexahydro-lH-pyrrolo [3, 4 -b] quinolin-1, 8 (4H) -dione, 9- (3-bromo-4-fluorophenyl) -2-ethyl-2, 3, 5,6,7,9- 20 hexahydro-lH-pyrrolo [3 , 4-b] quinolin-1, 8 (4H) -dione, 9- (3-bromo-4-fluorophenyl) -2,3,5,6,7, 9-hexahydro-lH-pyrrolo [3, 4- b] quinolin-1, 8 (4H) -dione, 9- (3-bromo-4-fluorophenyl) -2- (2-methoxyethyl) -2,3,5,6,7,9-hexahydro-lH-pyrrolo [3, 4-b] quinolin-1, 8 (4H) -25-dione, (9R) -9- (3-bromo-4-fluorophenyl) -2-methyl -2, 3, 5,6,7,9 hexahydro-lH-pyrrolo [3,4-b] uinolin-1, 8 (4H) -dione, (9R) -9- (3-bromo-4-fluoro-phenyl) -2,3,5,6,7, 9-hexahydro-lH-pyrrolo [3,4-b] quinolin-1, 8 (4H) -dione, (9S) -9- (3-bromo-4-fluorophenyl) -2-methyl -2, 3.5 , 6,7,9-hexahydro-lH-pyrrolo [3,4-b] quinolin-1, 8 (4H) -dione, (9S) -9- (3-bromo-4-fluorophenyl) -2,3, 5,6,7,9-hexahydro-lH-pyrrolo [3,4-b] quinolin-1, 8 (4H) -dione, 9- (3-cyanophenyl) -2-methyl -2, 3, 5,6 , 7 9-hexahydro-lH-pyrrolo [3, 4-b] quinolin-1, 8 (4H) -dione, 9- (3-bromo-4-fluoro-phenyl) -2- (2-ethoxyethyl) -2,3,5 , 6,7, 9-hexahydro-lH-pyrrolo [3,4-b] quinolin-1, 8 (4H) -dione, (9R) -9- (3-bromo-4-fluorophenyl) -2- (2 ethoxyethyl) -2,3,5,6,7,9-hexahydro-lH-pyrrolo [3,4-b] quinolin-1,8 (4H) -dione, (9S) -9- (3-bromo- 4-fluorophenyl) -2- (2-ethoxyethyl) -2,3,5,6,7,9-hexahydro-lH-pyrrolo [3,4-b] quinolin-1,8 (4H) -dione (9S ) -9- (3-bromo-4-fluorophenyl) -2-cyclopropyl-2,3,5,6,7,9-hexahydro-lH-pyrrolo [3,4-b] quinolin-1, 8 (4H) -dione, 2- (2-aminoethyl) -9- (3-bromo-4-fluorophenyl) -2,3,5,6,7,9-hexahydro-lH-pyrrolo [3,4-b] quinolin-l , 8 (4H) -dione, and (9S) -2- (2-aminoethyl) -9- (3-bromo-4-fluorophenyl) -2,3,5,6,7, 9-hexahydro-lH-pyrrolo [3,4-b] quinolin-1, 8 (4H) -dione.

62. A compound according to claim 27, wherein: A is NR2; A 'is CR4-R5; Rg- is hydrogen; R 'is hydrogen; n is 2; and n 'is 2.

63. A compound according to claim 62, which is 10- (3-bromo-4-fluorophenyl) -3, 4, 6, 7, 8, 10-hexahydrobenzo [b] [1,6] naphthyridin-1, 9 ( 2H, 5H) -dione.

64. A compound according to claim 27, wherein: A is O; A 'is NR2; and n # is 2.

65. A compound according to claim 27, wherein: A is O; A 'is O; and n 'is 2.

66. A compound according to claim 27, wherein: A is 0; A 'is S; and n 'is 2.

67. A compound according to claim 27, wherein: A is O; A 'is CR4.R5-; and n 'is 2.

68. A compound according to the claim 27, where: A is O; A 'is CR4.R5-; Rg- is hydrogen; R7 it is hydrogen; n is 1; and n 'is 2.

69. A compound according to claim 27, wherein: A is O; A 'is CR4'R5', - R4 < it is hydrogen; R5 it is hydrogen; R6 it is hydrogen; R7 'is hydrogen; n is l; and n 'is 2.

70. A compound according to the claim 69, selected from the group consisting of: 9- (3-bromo-4-fluorophenyl) -5,6,7,9-tetrahydrofuro [3,4-b] quinolin-1, 8 (3H, 4H) - dione, (9R) -9- (3-bromo-4-fluorophenyl) -5,6,7,9-tetrahydrofuro [3,4-b] quinolin-1, 8 (3H, 4H) -dione, (9S) -9- (3-bromo-4-fluorophenyl) -5,6,7,9-tetrahydrofuro [3,4-b] quinolin-1, 8 (3H, 4H) -dione, (9S) -9- (4 -fluoro-3-iodophenyl) -5,6,7,9-tetrahydrofuro [3, 4-b] quinolin-1, 8 (3H, 4H) -dione, (9R) -9- (4-fluoro-3-iodophenyl) -5,6,7,9-tetrahydrofuro [3, 4-b] quinolin-1, 8 (3H, 4H) -dione, (9R) -9- (3-chloro-4-fluorophenyl) -5,6,7,9-tetrahydrofuro [3,4-b] quinolin-1, 8 (3H, 4H) -dione, 9- [4-fluoro-3- (trifluoromethyl) phenyl] -5,6,7,9-tetrahydrofuro [3,4-b] quinolin-1, 8 (3H, 4H) - dione, 9- (4-chloro-3-nitrophenyl) -5,6,7,9-tetrahydrofuro [3,4-b] quinolin-1, 8 (3H, 4H) -dione, (9S) -9- [ 4-fluoro-3- (trifluoromethyl) phenyl] -5,6,7,9-tetrahydrofuro [3,4-b] quinolin-1, 8 (3H, 4H) -dione, (9R) -9- [4- fluoro-3- (trifluoromethyl) phenyl] -5,6,7,9-tetrahydrofuro [3,4-b] quinolin-1, 8 (3H, 4H) -dione, (9S) -9- (3, 4 - dibromophenyl) -5,6,7,9-tetrahydrofuro [3,4-b] quinolin-1, 8 (3H, 4H) -dione, (9R) -9- (3,4-dibromophenyl) -5,6, 7,9-tetrahydrofuro [3,4-b] quinolin-1, 8 (3H, 4H) -dione, (9S) -9- (4-methyl-3-nitrophenyl) -5,6,7,9-tetrahydrofuro [3, 4-b] quinolin-1, 8 (3H, 4H) -dione, (9R) -9- (4-methyl-3-nitrophenyl) -5,6,7,9-tetrahydrofur or [3, 4-b] quinolin-1, 8 (3H, 4H) -dione, (9S) -9- (3,4-dichlorophenyl) -5,6,7,9-tetrahydrofuro [3,4-b] ] quinolin-1, 8 (3H, 4H) -dione, (9R) -9- (3,4-dichlorophenyl) -5,6,7,9-tetrahydrofuro [3,4-b] quinolin-1, 8 ( 3H, 4H) -dione, (9S) -9- (4-chloro-3-nitrophenyl) -5,6,7,9-tetrahydrofuro [3,4-b] quinolin-1, 8 (3H, 4H) - dione, (9R) -9- (4-chloro-3-nitrophenyl) -5,6,7,9-tetrahydrofuro [3,4-b] quinolin-1, 8 (3H, 4H) -dione, (9S) -9- (3,4-difluorophenyl) -5,6,7,9-tetrahydrofuro [3,4-b] quinolin-1, 8 (3H, 4H) -dione, (9R) -9- (3, 4 -difluorophenyl) -5,6,7,9-tetrahydrofuro [3, 4-b] quinolin-1, 8 (3H, 4H) -dione, (9S) -9- (3-bromo-4-methylphenyl) -5 , 6,7,9-tetrahydrofuro [3,4-b] quinolin-1, 8 (3H, 4H) -dione; and (9R) -9- (3-bromo-4-methylphenyl) -5,6,7,9-tetrahydrofuro [3,4-b] quinolin-1,8 (3H, 4H) -dione.

71. A compound according to claim 27, wherein A is O; A 'is CR4'R5.; R < it's methyl; R5 it's methyl; R6 it is hydrogen; R7 it is hydrogen; n is 1; and n 'is 2.

72. A compound according to claim 71, selected from the group consisting of: (-) -9- (3-bromo-4-fluorophenyl) -7,7-dimethyl-5,6,7,9-tetrahydrofuro [ 3, 4-b] quinolin-1, 8 (3H, 4H) -dione; and (+) -9- (3-bromo-4-fluorophenyl) -7, 7-dimethyl-5, 6,7,9-tetrahydrofuro [3, 4-b] quinolin-1, 8 (3H, 4H) - diona; and

73. A compound according to claim 27, wherein: A is O; A 'is CR4.R5'; Rg- is hydrogen; R7- is hydrogen; is 2; and n 'is 2.

74. A compound according to claim 73, selected from the group consisting of: 10- (3-bromo-4-fluorophenyl) -3,4,6,7,8, 10-hexahydro-1H-pyran [4, 3-b] quinolin-1, 9 (5H) -dione, and 10- [4-fluoro-3- (trifluoromethyl) phenyl] -3, 4, 6, 7,8, 10-hexahydro-lH-pyrano [4 , 3-b] quinolin-1, 9 (5H) -dione.

75. A compound according to claim 27, wherein: A is S; A 'is NR2-; and n 'is 2.

76. A compound according to claim 27, wherein: A is S; A 'is O; and n 'is 2.

77. A compound according to claim 27, wherein: A is S; A 'is S; and n 'is 2.

78. A compound according to claim 27, wherein: A is S; A 'is CR4-R5.; and n 'is 2.

79. A compound according to claim 1 of formula VI: IV, or a pharmaceutically acceptable salt, amide, ester, or prodrug thereof, wherein: n and n 'are independently from 1 to 3; A is selected from the group consisting of O, -NR2, and S; Rx is selected from the group consisting of aryl and heterocycle; R is selected from the group consisting of hydrogen, alkoxyalkyl, alkyl, arylalkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, heterocyclealkyl, hydroxy-lo hydroxyalkyl, -NZ? Z2, and (NZXZ2) alkyl wherein Zx and Z2 are selected independently from the group consisting of hydrogen, alkyl, alkylcarbonyl, aryl, arylalkyl, and formyl; R4- and R5. they are independently selected from the group consisting of hydrogen and alkyl; and Re. and R7. they are independently selected from the group consisting of hydrogen and alkyl.

80. A compound according to claim 79, wherein: A is NR2; and n 'is 1.

81. A compound according to claim 79, wherein: A is NR2; R6 it is hydrogen; R7 it is hydrogen; n is 1; and n 'is 1.

82. A compound according to claim 81, which is 1,1-dioxide of 8- (3-bromo-4-fluorophenyl) -6-methyl-2,3,4,5,6,8-hexahydro-7H-pyrrolo [3, 4-b] thieno [2, 3-e] pyridin-7-one.

83. A compound according to the claim 79, where: A is NR2; Rg- is hydrogen; R7- is hydrogen; n is 2; and n 'is 1.

84. A compound according to claim 83, which is 9- (3-bromo-4-fluorophenyl) -2, 3, 5, 6, 7, 9-hexahydrothieno [3,2-b] 1,1-dioxide [ 1, 6] naphthyridin-8 (4H) -one.

85. A compound according to claim 79, wherein: A is O; and n 'is 1.

86. A compound according to claim 79, wherein: A is S; and n 'is 1.

87. A compound according to claim 79, wherein: A is NR2; and n 'is 2.

88. A compound according to the claim 79, where: A is NR2; Rg- is hydrogen; R7 it is hydrogen; n is l; and n 'is 2.

89. A compound according to claim 88, which is 9- (3-bromo-4-fluorophenyl) -7-methyl-3,4,5,6,7,9-hexahydropyrrolo 1,1-dioxide [3, 4 -b] thiopyrano [2, 3-e] pyridin-8 (2H) -one.

90. A compound according to claim 79, wherein: A is O; and n 'is 2.

91. A compound according to claim 79, wherein: A is O; Re. Is hydrogen; R7 it is hydrogen; n is 1; and n 'is 2.

92. A compound according to the claim 91, which is selected from the group consisting of: 9- (3-bromo-4-fluorophenyl) -3,4,6,9-tetrahydro-2H-furo 1,1-dioxide [3, 4-b ] thiopyrano [2, 3-e] pyridin-8 (5H) -one, 1,1-dioxide (9S) - 9- (3-bromo-4-fluorophenyl) -3,4,6, 9-tetrahydro- 2H-furo [3, 4-b] thiopyrano [2,3-e] pyridin-8 (5H) -one; and (9R) -9- (3-bromo-4-fluorophenyl) -3,4,6,9-tetrahydro-2H-furo [3,4-b] thiopyran 1,1-dioxide [2, 3-e] ] pyridin-8 (5H) -one.

93. A compound according to the claim 79, where: A is S; and n 'is 2.

94. A compound according to the claim 1, of the formula V: V. or a pharmaceutically acceptable salt, amide, ester, or prodrug thereof, wherein: n and n 'are independently from 1 to 3; A is selected from the group consisting of 0, -NR2, and S; A 'is selected from the group consisting of O, -NR2-, S, and CR4.R5-; Ri is selected from the group consisting of aryl and heterocycle; R2 and R2. are independently selected from the group consisting of hydrogen, alkoxyalkyl, alkyl, arylalkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, heterocycloalkyl, hydroxyl, hydroxyalkyl, -NZ? Z2, and (NZiZ2) alkyl, wherein Z? and Z2 are independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, aryl, arylalkyl, and formyl; R4- and R5- are independently selected from the group consisting of hydrogen and alkyl; R6 'and R7- are independently selected from the group consisting of hydrogen and alkyl.

95. A compound according to claim 94, wherein: A is NR2; A 'is NR2.; and n 'is 1.

96. A compound according to claim 94, wherein: A is NR2; A 'is 0; and n 'is 1.

97. A compound according to claim 94, wherein: A is NR2; A 'is S; and n 'is 1.

98. A compound according to claim 94, wherein: A is NR2; A 'is CR4.R5; and n 'is 1.

99. A compound according to claim 94, wherein: A is O; A 'is NR2; and n 'is 1.

100. A compound according to claim 94, wherein: A is 0; A 'is 0; and n 'is 1.

101. A compound according to claim 94, wherein: A is 0; A 'is S; and n 'is 1.

102. A compound according to claim 94, wherein: A is 0; A 'is CR4.R5-; and n 'is 1.

103. A compound according to claim 94, wherein: A is S; A 'is NR2-; and n 'is 1.

104. A compound according to claim 94, wherein: A is S; A 'is O; and n 'is 1.

105. A compound according to claim, wherein: A is S; A 'is S; and n 'is 1.

106. A compound according to claim, wherein: A is S; A 'is CR.R5-; and n 'is 1.

107. A compound according to claim, wherein: A is NR2; A 'is NR2; and n 'is 2.

108. A compound according to claim, wherein: A is NR2; A 'is O; and n 'is 2.

109. A compound according to claim, wherein: A is NR2; A 'is S; and n 'is 2.

110. A compound according to claim, wherein: A is NR2; A 'is CR4-R5; and n 'is 2.

111. A compound according to claim, wherein: A is O; A 'is NR2.; and n 'is 2.

112. A compound according to claim, wherein: A is O; A 'is O; and n 'is 2.

113. A compound according to claim 94, wherein: A is O; A 'is S; and n 'is 2.

114. A compound according to claim 94, wherein: A is O; A 'is CR4.R5; and n 'is 2.

115. A compound according to the claim 94, where: A is S; A 'is NR2.; and n 'is 2.

116. A compound according to claim 4, wherein: A is S; A 'is O; and - n 'is 2.

117. A compound according to claim 94, wherein: A is S; A 'is S; and n 'is 2.

118. A compound according to claim 94, wherein: A is S; A 'is CR4.R5 <; and n 'is 2.

119. A compound according to claim 1, of formula VI: SAW, or a pharmaceutically acceptable salt, amide, ester, or prodrug thereof, wherein: n and n are independently from 1 to 3; A is selected from the group consisting of O, -NR2, and S; Ri is selected from the group consisting of aryl and heterocycle; R2 is selected from the group consisting of hydrogen, alkoxyalkyl, alkyl, arylalkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, heterocycloalkyl, hydroxyl, hydroxyalkyl, -NZ? Z2, and (NZ? Z2) alkyl, wherein Z and Z2 are selected independently from the group consisting of hydrogen, alkyl, alkylcarbonyl, aryl, arylalkyl, and formyl; R. and R5. they are independently selected from the group consisting of hydrogen and alkyl; and Re. and R7. they are independently selected from the group consisting of hydrogen and alkyl.

120. A compound according to claim 119, wherein: A is NR2; and n 'is 1.

121. A compound according to claim 119, wherein: A is O; and n 'is 1.

122. A compound according to claim 119, wherein: A is S; and n 'is 1.

123. A compound according to claim 119, wherein: A is NR2; and n 'is 2.

124. A compound according to claim 119, wherein: A is O; and n 'is 2.

125. A compound according to claim 119, wherein: A is S; and n 'is 2.

126. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1, in combination with a pharmaceutically acceptable carrier.

127. A method for the treatment of asthma, epilepsy, Raynaud's syndrome, migraine, pain, eating disorders, functional bowel disorders, neurodegeneration, and embolism, by administering a compound of claim 1, including a compound selected from the group consisting of 8- [2- (difluoromethoxy) phenyl] -1,7-dioxo-2, 3, 4, 5,6,8-hexahydrodipirrolo [3, 4-b; 3, 4-e] pyridin-2,6-dipropanoic, (8- [2- (difluoromethoxy) phenyl] -1,7-dioxo-2, 3,4,5,6,8-hexahydrodipyrrolo dipropanate [3, 4-b; 3, 4-e] pyridin-2,6-ethyl, 8- [2- (difluoromethoxy) phenyl] -6-methyl-4,5,6,8-tetrahydro-lH-furo [3, 4 -b] pyrrolo [3, 4-e] pyridin-1, 7 (3H) -dione, 8- [2- (difluoromethoxy) phenyl] -2,6-dimethyl-2,3,4,5,6,8 hexahydrodipyrrolo [3, 4-b; 3, 4-e] pyridin-1,7 -dione, 2,6-dimethyl-8-phenyl-2,3,4,5,6,8-hexahydrodipyrrolo [3,4-b; 3, 4-e] pyridin-1, 7-dione, 8- (3-nitrophenyl) -5,8-dihydro-lH, 3H-difuro [3,4- b; 3,4-e] pyridin-1, 7 (4H) -dione, 8- (2,4-dichlorophenyl) -5,8-dihydro-1H, 3H-difuro [3,4-b; 3,4-e] pyridin-1, 7 (4H) - dione, 8- (4-methoxyphenyl) -5,8-dihydro-lH, 3H-difuro [3,4-b; 3,4-e] pyridin-1,7 (4H) -dione, 8- (4- iodophenyl) -5,8-dihydro-1H, 3H-difure [3, 4-b; 3, 4-e] pyridin-1, 7 (4H) -dione, 8- (4-bromo-phenyl) -5,8-dihydro-lH, 3H-difuro [3,4- b; 3,4-e] pyridine -1, 7 (4H) -dione, 8- (3-bromo-phenyl) -5,8-dihydro-lH, 3H-difuro [3,4-b; 3,4-e] pyridin-l, 7 (4H) -dione, 8- (2- (fluorophenyl) -5,8-dihydro-lH, 3H-difuro [3,4- b; 3,4-e] pyridin-l, 7 (4H) -dione, 8-f enyl -5,8-dihydro-H, 3 H-difuro [3,4-b; 3,4-e] pyridin-1,7 (4 H) -dione, 8- (2-aminophenyl) -5,8-dihydro -lH, 3H-difure [3,4-b; 3,4-e] pyridin-l, 7 (4H) -dione, 8- [2- (difluoromet oxy) phenyl] -5,8-dihydro-lH , 3H-difure [3,4-b; 3,4-e] pyridin-l, 7 (4H) -dione, 8- (2-chlorophenyl) -5,8-dihydro-1H, 3H-difure [3, 4-b; 3, 4-e] pyridin-1, 7 (4H) -dione, 8- (2,3,4-trimethoxyphenyl) -5,8-dihydro-lH, 3H-difuro [3,4-b 3,4-e! Pyridin-l, 7 (4H) -dione, 8- [2- (trifluoromethyl) phenyl] -5,8-dihydro-lH, 3H-difuro [3,4- b; 3, 4 -e] pyridin-1, 7 (4H) -dione, 8- (2-chloro-3-nitrophenyl) -5,8-dihydro-lH, 3H-difure [3, 4-b; 3, 4-e] pyridin-1, 7 (4H) -dione, 8- (4-nitrophenyl) -5,8-dihyd ro-lH, 3H-difuro [3,4-b; 3, 4-e] pyridin-1, 7 (4H) -dione, 8- (4-chlorophenyl) -5,8-dihydro-lH, 3H-difuro [3,4- b; 3,4-e] pyridine -l, 7 (4H) -dione,. 8- (3-chlorophenyl) -5,8-dihydro-lH, 3H-difuro [3,4- b; 3,4-e] pyridin-1, 7 (4H) -dione, 8- (2-nitrophenyl) -5,8-dihydro-lH, 3H-difuro [3,4-b; 3, 4-e] pyridin-1, 7 (4H) -dione, 3,7-dimethyl-10-phenyl-3,4,5,6,7,1-hexahydro-1H, 9H-dipyran [4, 3 -b; 3, 4-e] pyridin-1, 9-dione, 6,6-dimethyl-9-phenyl-5,6,7,9-tetrahydrofuro [3,4-b] quinolin-1, 8 (3H, 4H) -dione, 9- (1, 3-benzodioxol-5-yl) -5,6,7,9-tetrahydrofuro [3,4-b] quinolin-1, 8 (3H, 4H) -dione, 9- (3 -methoxyphenyl) -5,6,7,9-tetrahydrofuro [3,4-b] quinolin-1, 8 (3H, 4H) -dione, 9- (2-methoxyphenyl) -6,6-dimethyl-5,6 , 7,9-tetrahydrofuro [3,4-b] quinolin-1, 8 (3H, 4H) -dione, 6,6-dimethyl-9- (2-nitrophenyl) -5,6,7,9-tetrahydrofuro [ 3, 4-b] quinolin-1, 8 (3H, 4H) -dione, 6,6-dimethyl-9- [2- (trifluoromethyl) phenyl] -5,6,7,9-tetrahydrofuro [3, 4- b] quinolin-1, 8 [3H, 4H] -dione, and 9- [3- (benzyloxy) phenyl] -6,6-dimethyl-5,6,7,9-tetrahydrofuro [3,4-b] quinolin -1, 8 (3H, 4H) -dione.

128. The method of claim 128 for the treatment of urinary incontinence.

129. The method of claim 128 for the treatment of male erectile dysfunction and premature ejaculation.

130. The method of claim 128, for the treatment of female anorgasmia, erectile clitoral insufficiency, vaginal congestion, dyspareunia, and vaginismus.