MXPA02005016A - Tricyclic dihydropyrimidine potassium channel openers. - Google Patents

Abstract

Compounds of 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

POTASSIUM CHANNEL OPENERS OF TRICYCLIC DIHYDROPYR1MIDINE Technical Field New tricyclic dihydropyrimidine compounds and their derivatives can open potassium channels and are useful for treating a variety of medical conditions.

BACKGROUND OF THE INVENTION Potassium channels play an important role in regulating the excitability of the cell membrane. When the potassium channels open, changes in electrical power along the cell membrane occur and result in a more polarized state. A number of diseases or conditions can be treated with therapeutic agents that open the potassium channels; for example, see K. Lawson, Pharmacol. Ther., V. 70, pp. 39-63 (1996); D.R. Géhlert ef al., Prog. Neuro-Psychopharmacol & Bíol. Psychiat., V. 18, pp. 1093-1102 (1994); . Gopalakrishman ef al. , Drug Development Research, v. 28, PP-95-127 (1993); J.E. Freedman et al., The Neuroscientist, v. 2, pp. 145-152 (1996); FROM. Nurse et al. , Br. J. Urol., V. 68 pp. 27-31 (1991); B. B. Howe et al. , J. Pharmacol. Exp. Ther., V. 274 pp. 884-890 (1995); D. Spanswick ef al., Nature, v. 390 pp. 521-25 (December 4, 1997); Dompeling Vasa. Supplementum (1992) 3434; WO9932495; Grover, J Mol Cell Cardiol. (2000) 32, 677; and Buchheit, Pulmonary Pharmacology & Therapeutics (1999) 12, 103. Such diseases or conditions include asthma, hypertension, epilepsy, male sexual dysfunction, female sexual dysfunction, pain, vesicle hyperactivity, infarction, diseases associated with reduced skeletal blood flow such as Raynaud's phenomenon and claudication. intermittent, eating disorders, disorders of the functional bowel, neurodegeneracíót, benign prostatic hyperplasia (BPH), dysmenorrhea, premature labor, alopecia, cardioprotection, coronary artery disease, angina and ischemia. Vesicle overactivity is a condition associated with uncontrolled, spontaneous contractions of the smooth muscle of the gallbladder. Vesicle hyperactivity in this manner is associated with or can cause diseases and / or conditions such as feelings of urgency, urinary incontinence, polakiuria, vesicle instability, nocturia, vesicle hyperreflexia, and enuresis (Resnick, The Lancet (1995) 346 , 94-99; Hampel, Urology (1997) 50 (Compl.6A), 4-14; Bosch, BJU International (1999) 83 (Compl.2), 7-9. Potassium channel openers (KCOs) act As smooth muscle relaxants, Because gallbladder overactivity and urinary incontinence can occur as a result of uncontrolled, spontaneous contractions of the smooth muscle of the gallbladder, the ability of potassium channel openers to hyperpolarize vesicle cells and relaxing the smooth muscle of the gallbladder may provide a method to lessen or prevent vesicle hyperactivity, polakiuria, vesicle instability, nocturia, vesicle hyperreflexia, urinary incontinence, and enuresis (An dersson, Urology (1997) 50 (Compl. 5A), 74-84; Lawson, Pharmacol. Ther., (1996) 70, 39-63; Nurse., Br. J. Urol., (1991) 68, 27-31; Howe, J. Pharmacol. Exp. Ther., (1995) 274, 884-890; Gopalakrishnan, Drug Development Research, (1993) 28, 95-127). The irritating symptoms of BPH (urgency, frequency, nocturia, and force incontinence) have been shown to correlate with vesicle instability (Pandita, The J. of Urology (1999) 162, 943). Therefore, the ability of potassium channel openers to hyperpolarize vesicle cells and relax smooth muscle of the gallbladder may provide a method to lessen or prevent the symptoms of BPH. (Andersson, Prostate (1997) 30: 202-215). The excitability of smooth muscle cells of the corpus cavernosum is important in the male erectile process. The relaxation of the corporal smooth muscle cells allows the arterial blood to be built under pressure in the erectile tissue of the penis leading to the erection (Andersson, Pharmacological Reviews (1993) 45, 253), Potassium channels play a significant role in the modulation of the body smooth muscle tone hum no, and in this way, the erectile capacity. Using the patch fastening technique, potassium channels have been characterized in human body smooth muscle cells (Lee, Int. J. Impot. Res. (1999) 11 (4), 179-188). Potassium channel openers are smooth muscle relaxants and have been shown to relax smooth muscle of cavernous crow and induce erections (Andersson, Pharmacological Reviews (1993) 45, 253; Lawson, Pharmacol. Ther., (1996) 70, 39-63, Vick, J. Urol (2000) 163: 202. Therefore, potassium channel openers may have utility in the treatment of male sexual dysfunctions such as male erectile dysfunction, impotence and premature mutation. The sexual response in women is classified in four stages: excitement, leveling, orgasm and resolution. Sexual onset and arousal increase blood flow in the genital area, and lubrication of the vagina as a result of plasma transudation. Local application of KCOs such as minoxidil and nicroandil have been shown to increase clitoral blood flow (JJ Kim, J.-Yu, JG Lee, DG Moon, "Effects of topical K-ATP channel opener solution on clitorideal blood flow", J. Urol (2000) 163 (4): 240). KCOs may be effective for the treatment of female sexual dysfunction including clitoral erectile insufficiency, vaginal obstruction and vaginismus (I. Goldstein and JR Berman., "Vasculogenic female sexual dysfunction: vaginal engorgement and clitorical erectile insufficiency syndromes.", Int. J. Impotence Res. (1998) 10: S84-S90), as KCOs can increase blood flow to the female sex organs. Potassium channel openers may have utility as tocolytic agents to inhibit uterine contractions in order to suppress or prevent preterm birth in individuals or to decrease or retain supply for brief periods to undertake other therapeutic measures (1993) 169 (5 ), 1277-85). Potassium channel openers also inhibit the contractile responses of human uterus and intrauterine vasculature. This combined effect could suggest the potential use of KCOs for dysmenorrhoea (Kostrzewska, Acta Obstet, Gynecol, Scand. (1996) 75 (10), 886-91). Potassium channel openers relax uterine smooth muscle and intrauterine vasculature and therefore can have utility in the treatment of premature labor and dysmenorrhea. (Lawson, Pharmacol. Ther., (1996) 70, 39-63). Potassium channel openers relax gastrointestinal uniform tissues and therefore, may be useful in the treatment of functional bowel disorders such as irritable bowel syndrome. (Lawson, Pharmacol. Ther., (1996) 70, 39-63). Potassium channel openers retain the smooth muscle of the respiratory tract and induce bronchodilation. Therefore, potassium channel openers may be useful in the treatment of asthma and hyperactivity of the respiratory tract (Lawson, Pharmacol. Ther., (1996) 70, 39-63; Bucheit, Pulmonary Pharmacology &Therapeutics (1999). ) 12, 103; Gopalakrsihnan, Drug Development Research, (1993) 28, 95-127). Neuronal hyperpolarization can produce analgesic effects. The opening of the potassium channels through the potassium channel openers and the resulting hyperpolarization in the membrane of target neurons is a key mechanism in the effect of opioids. The contraceptive effect of morphine occurs as a result of the activation of primary afferents, leading to a reduction in the generation of action potency (Rodríguez, Br J Pharmacol (2000) 129 (1), 1 10-4). The opening of KATP channels by potassium channel openers plays an important role in contraception mediated by alpha 2 adrenoceptors and mu opioid receptors. The KCOs can enhance the analgesic action of both the morphine and the dexmedetomidine by means of an activation of KATP channels at the level of the spinal cord (Vergoni, Life Scí. (1992) 50 (16), PL135-8; Asano, Anesth, Analg. (2000) 90 (5), 1146-51). In this way, potassium channel openers can hyperpolarize neuron cells and have shown analgesic effects. Therefore, potassium channel openers may be useful as analgesics in the treatment of various pain states including but not limited to migraine and dyspareunia (Lawson, Pharmacol. Ther., (1996) 70, 39-63; Gopalakrishnan , Drug Development Research, (1993) 28, 95-127; Gehlert, Prog. Neuro-Psychopharmacol. &Bio .. Psychiat., (1994) 18, 1093-1102). Epilepsy occurs as a result of the propagation of non-physiological electrical impulses. Potassium channel openers hyperpolarize neuronal cells and lead to a reduction in cell excitability and have demonstrated antiepileptic effects. Therefore, potassium channel openers may be useful in the treatment of epilepsy (Lawson, Pharmacol. Ther., (1996) 70, 39-63.; Gopalakrishnan, Drug Development Research, (1993) 28, 95-127; Gehiert, Prog. Neuro- Psychopharmacol. & Biol. Psychiat. , (1994) 18, 1093-1102). Neuronal cell depolarization can lead to excitotoxicity and neuronal cell death. When this occurs as a result of acute ischemic conditions, it can lead to infarction. Long-term neurodegeneration can cause conditions such as Alzheimer's and Parkinson's diseases. Potassium channel openers can hyperpolarize neuronal cells and lead to a reduction in cell excitability. Activation of potassium channels has been shown to improve neuronal survival. Therefore, potassium channel openers can have utility as neuroprotectors in the treatment of neurodegenerative conditions and diseases such as Cerebral ischemia, infarction, Alzheimer's disease and Parkinson's disease (Lawson, Pharmacol, Ther., (1996) 70, 39-63; Gopalakrishnan, Drug Development Research, (1993) ) 28, 95-127, Gehlert, Prog. Neuro-Psycopharmacol &Biol. Psychiat., (1994) 18, 1093-1102; Freedman, The Neuroscientist (1996) 2, 145). Potassium channel openers may have utility in the treatment of diseases or conditions associated with reduced skeletal muscle blood flow such as Raynaud syndrome and intermittent claudication (Lawson, Pharmacol. Ther., (1996) 70, 39-63. Gopalakrishnan, Drug Development Research, (1993) 28, 95-127; Dompeling Vasa, Supplementum (1992) 3434; and WO9932495). Potassium channel openers can be useful in the treatment of eating disorders such as obesity (Spanswick, Nature, (1997) 390, 521-25; Freedman, The Neuroscientist (1996) 2, 145). Potassium channel openers have been shown to promote hair growth therefore, potassium channel openers have utility in the treatment of hair loss and baldness also known as alopecia (Lawson, Pharmacol. Ther, (1996) 70, 39-63; Gopalákrishnan, Drug Development Research, (1993) 28, 95-127). Potassium channel openers have cardioprotective effects against myocardial injury during ischemia and feperfusion. (Garlid, Circ. Res. (1997) 81 (6), 1072-82). Therefore, potassium channel openers can be useful in the treatment of j ^ t "* Ato - ^ ** -t ^ -nl» -. - ^ im-heart diseases (Lawson, Pharrnacol, Ther, (1996) 70, 39-63, Grover, J. Mol. Cell Cardiol. (2000) 32, 677. Potassium channel openers, by hyperpolarization of smooth muscle membranes, can exert vasodilation of the collateral circulation of the coronary vasculature leading to an increase in blood flow in ischemic areas and could be useful for coronary artery disease (Lawson, Pharmacol. Ther., (1996) 70, 39-63, Gopalakrishnan, Drug Development ResearGh, (1993) 28, 95-127), US 4918074, EP 183848 B1, EP 217142, EP 328700, JP 10 68060985, JP 63243029, JP 61227584, and AtwaI, KS, Bioorg, Med. Chem. Lett (1991) 1, 291-294 disclose bioclical 4,7-dihydropyrazot [1,5-aJpyrimidines. of the present invention are new and hyperpolarize cell membranes, open potassium channels and relax smooth muscle cells.

BRIEF DESCRIPTION OF THE INVENTION In its main embodiment, the present invention describes the compounds of the formula (I): (, Or a pharmaceutically acceptable salt, ester, amide, or prodrug of the where n is an integer of 0-1; m is an integer of 1 -2; with the proviso that when m is 2, n is 0; R1 is selected from aryl and heterocycle; Q is selected from C (O), S (O), and S (O) 2; V is selected from C (R6) (R7), O, S, and NR2, wherein R2 is selected from hydrogen, alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkyl, alkynyl, aryl, arylalkoxy, arylalkenyl, arylalkyl, cyano, cycloalkyl , cycloalkylalkyl, haloalkoxy, haloalkyl, heterocycle, heterocyclealkynyl, hydroxy, hydroxyalkyl, -NR R5, and (NR4R5) alkyl wherein R4 and R5 are independently selected from hydrogen and lower alkyl; R6 and R7 are independently selected from hydrogen, alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkyl, alkylthio, alkynyl, aryl, arylalkoxy, arylalkenyl, arylalkyl, carboxy, cyano, cycloalkyl, cycloalkylalkyl, haloalkoxy, haloalkyl, halogen, heterocycle, heterocyclealkyl, hydroxy , hydroxyalkyl, oxo, -NR R5, and (NR R5) alkyl wherein R4 and R5 are as defined above; R8 and R9 are independently selected from hydrogen, alkenyl, alkoxy, alkoxyalkyl, alkoxyalkyl, alkyl, alkylthio, alkynyl, aryl, arylalkoxy, arylalkenyl, arylalkyl, carboxy, cyano, cycloalkyl, cycloalkylalkyl, haloalkoxy, haloalkyl, halogen, heterocycle, heterocyclealkyl, hydroxy , hydroxyalkyl, -NR R5, and (NR4R5) alkyl wherein R4 and R5 are as defined above; .SS? - X is selected from N and CRS wherein R3 is selected from hydrogen, alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkyl, alkylthio, juyl, aryl, arylalkoxy, arylalkenyl, arylalkyl, carboxy, cyano, cycloalkyl, cycloalkylalkyl, haloalkoxy, haloalkyl, halogen, heterocyclic, heterocycloalkyl, hydroxy, hydroxyalkyl, -NR R5, and (MR4R5) alkyl wherein R4 and R5 are as defined above; and D and E are independently selected from hydrogen, alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkyl, alkylthio, alkynyl, aryl, arylalkoxy, arylalkenyl, arylalkyl, carboxy, cyan, cycloatyl, cycloalkylalkyl, haloalkoxy, haloalkyl, halogen, heterocycle, heterocyclic, hydroxy, hydroxyalkyl, -NR4R5, and (NR4R5) alkyl wherein R4 and R5 are as defined above.

DETAILED DESCRIPTION OF THE INVENTION All patents, patent applications, and literature references cited in the specification are incorporated herein by reference in their entirety. In the case of inconsistencies, the present description, including definitions, shall prevail. It is understood that the foregoing detailed description and the accompanying examples are merely illustrative and are not taken as limitations on the scope of the invention. Various changes and modifications to the modalities described will be apparent to those experts in the field. Such changes and modifications, including without limitation those that relate to chemical structures, substituents, derivatives, intermediates, tape, formulations and / or methods of the invention, can be elaborated without departing from the spirit and scope thereof. In its main embodiment, the present invention describes the compounds of the formula (I): (I), or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof wherein, n is an integer of 0-1; m is an integer of 1 -2, with the proviso that when m is 2, n is 0; R1 is selected from aryl and heterocycle; Q is selected from C (O), S (O), and S (O) 2; V is selected from C (R6) (R7), O, S, and NR2, wherein R2 is selected from hydrogen, alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkyl, alkynyl, aryl, arylalkoxy, arylalkenyl, arylalkyl, cyano, cycloalkyl , cycloalkylalkyl, haloalkoxy, haloalkyl, heterocycle, heterocyclealkyl, hydroxy, hydroxyalkyl, -R4R5, and (NR4R5) alkyl wherein R4 and R5 are independently selected from hydrogen and lower alkyl; R6 and R7 are independently selected from hydrogen, alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkyl, alkylthio, alkynyl, aryl, arylalkoxy, arylalkenium, arylalkyl, carboxy, cyano »cycloalkyl, cycloalkylalkyl, haloalkoxy, haloalkyl, halogen, heterocycle, heterocyclealkyl, hydroxy, hydroxyalkyl, oxo, -NR4R5, and (NR R5) alkyl wherein R4 and R5 are as defined previously; R8 and R9 are independently selected from hydrogen, alkenyl, alkoxy, alkoxyalkyl, alkoxyalkyl, alkyl, alkylthio, alkynyl, aryl, arylalkoxy, arylalkenyl, arylalkyl, carboxy, eianb, cycloalkyl, cycloalkylalkyl, haloalkoxy, haloalkyl, halogen, heterocycle, heterocycloalkyl, hydroxy , hydroxyalkyl, -NR4R5, and (NR4R5) alkyl wherein R4 and R5 are as defined above; X is selected from N and CR3 wherein R3 is selected from hydrogen, alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkyl, alkylthio, alkynyl, aryl, arylalkoxy, arylalkenyl, arylalkyl, carboxy, cyano, cycloalkyl, cycloalkylalkyl, haloalkoxy, haloalkyl, halogen , heterocycle, heterocyclealkyl, hydroxy, hydroxyalkyl, -NR4R5, and (NR4R5) alkyl wherein R4 and R5 are as defined above; and D and E are independently selected from hydrogen, alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkyl, alkylthio, alkynyl, aryl, arylalkoxy, arylalkenyl, arylalkyl, carboxy, cyano, cycloalkyl, cycloalkylalkyl, haloalkoxy, haloalkyl, halogen, heterocycle, heterocyclealkyl, hydroxy, hydroxyalkyl, -NR4R5, and (NR4R5) alkyl wherein R4 and R5 are as defined above. In another embodiment of the present invention, the compounds have the formula (I) wherein, R1 is aryl; X is CR3; R3 is hydrogen, and R8, R9, D, E, Q, V, m, and n are as defined in formula (I).

In another embodiment of the present invention, the compounds have the formula (I) wherein, R 1 is heterocyclic; X is CR3; R3 is hydrogen; and R8, R9, D, E, Q, V, m, and n are as defined in the formula (I) In a preferred embodiment, the compounds of the present invention have the formula (II): (11), or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof, wherein R 1 is selected from aryl and heterocycle; Q is selected from C (O), S (O), and S (O) 2; V is selected from C (R6) (R7), O, S, and NR2, wherein R2 is selected from hydrogen, alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkyl, alkynyl, aryl, arylalkoxy, arylalkenyl, arylalkyl, cyano, cycloalkyl , cycloalkylalkyl, haloalkoxy, haloalkyl, heterocycle, heterocyclealkyl, hydroxy, hydroxyalkyl, -NR4R5, and (NR4R5) alkyl wherein R4 and R5 are independently selected from hydrogen and lower alkyl; R6 and R7 are independently selected from hydrogen, alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkyl, alkylthio, alkynyl, aryl, arylalkoxy, arylalkenyl, arylalkyl, carboxy, cyano, cycloalkyl, cycloalkylalkyl, haloalkoxy, haloalkyl, halogen, heterocycle, cycloalkyl, hydroxy , hydroxyalkyl, oxo, -NR R5, and (NR R5) alkyl wherein R4 and R5 are as defined above; R8 and R9 are independently selected from hydrogen, alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkyl, alkylthio, alkynyl, aryl, arylalkoxy, arylalkenyl, arylalkyl, carboxy, cyano, cycloalkyl, cycloalkylalkyl, haloalkoxy, haloalkyl, halogen, heterocycle, heterocyclealkyl, hydroxy , hydroxyalkyl, -NR4R °, and (NR4R5) alkyl wherein R4 and R5 are as defined above; and D and E are independently selected from hydrogen, alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkyl, alkylthio, alkynyl, aryl, arylalkoxy, arylalkenyl, arylalkyl, carboxy, cyano, cycloalkyl, cycloalkylalkyl, haloalkoxy, haloalkyl, halogen, heterocycle, heterocyclealkyl, hydroxy, hydroxyalkyl, -NR4R5, and (NR4R5) alkyl wherein R4 and R5 are as defined above. In another preferred embodiment of the present invention, the compounds have the formula (II) wherein, R 1 is heterocycle; Q is C (O); and Rβ, R9, D, E, and V are as defined in formula (I). In another preferred embodiment of the present invention, the compounds have the formula (II) wherein, R 1 is heterocycle; Q is S (O); and R8, R9, D, E, and V are as defined in formula (I). In another preferred embodiment of the present invention, the compounds have the formula (II) wherein, R is heterocycle; Q is S (O) 2; and R8, R9, D, E, and V are as defined in formula (I). In another preferred embodiment of the present invention, the compounds have the formula (II) wherein, R 1 is heterocycle; Q is C (O); V is S; and R8, R9, D, and E are as defined in formula (I). In another preferred embodiment of the present invention, the compounds have the formula (II) wherein, R 1 is heterocycle; Q is C (O); V is S; and R8, R9, D, and E are hydrogen. In another preferred embodiment of the present invention, the compounds have the formula (II) wherein, R 1 is heterocycle; Q is C (O); V is CH2; and R8, R9, D, and E are as defined in formula (I). In another preferred embodiment of the present invention, the compounds have the formula (II) wherein, R 1 is heterocycle; Q is C (O); V is CH2; E is alkyl; D is alkyl; and R8 and R9 are as defined in formula (I). In another preferred embodiment of the present invention, the compounds have the formula (II) wherein, R 1 is heterocycle; Q is C (O); V is CH2; E is alkyl; D is alkyl; and R8, R9 are hydrogen. In another preferred embodiment of the present invention, the compounds have the formula (I I) wherein R 1 is heterocycle; Q is C (O); V is CH2; and R8, R9, D, and E are hydrogen. In another preferred embodiment of the present invention, the compounds have the formula (II) wherein, R 1 is heterocycle; Q is S (O) 2; V is CH2; and R8, R9, D, and E are as defined in formula (I). In another preferred embodiment of the present invention, the compounds have the formula (II) wherein, R 1 is heterocycle; Q is S (O) 2; V is CH2; and R8, R9, D, and E are hydrogen. In another preferred embodiment of the present invention, the f || 111 or II IIIII or T? NiMmtrt * ^ wt compounds have the formula (II) wherein, R1 is aryl; Q is C (O); and R8, R9, D, E and V are as defined in formula (I). In another preferred embodiment of the present invention, the compounds have the formula (II) wherein, R1 is aryl; Q is C (O); V is S; and R8, R9, D, and E are as defined in formula (I). In another preferred embodiment of the present invention, the compounds have the formula (II) wherein, R1 is aryl; Q is C (O); V is S; and R8, R9, D, and E are hydrogen. In another preferred embodiment of the present invention, the compounds have the formula (II) wherein, R1 is aryl; Q is C (O); V is CH2; and R8, R9, D, and E are as defined in formula (I). In another preferred embodiment of the present invention, the compounds have the formula (II) wherein, R1 is aryl; Q is C (O); V is CH2; D is alkyl; E is alkyl; and R8 and R9 as defined in formula (I). In another preferred embodiment of the present invention, the compounds have the formula (II) wherein, R1 is aryl; Q is C (O); V is CH2; D is alkyl; E is alkyl; and R8, R9 are hydrogen. In another preferred embodiment of the present invention, the compounds have the formula (II) wherein, R1 is aryl; Q is C (O); V is CH2; R9 is aryl; and R8, D and E are as defined in formula (I). In another preferred embodiment of the present invention, the compounds have the formula (II) wherein, R1 is aryl; Q < is C (O); V is CH¿; R9 is aryl; and R8, D and E are hydrogen. In another preferred embodiment of the present invention, the compounds have the formula (II) wherein, R1 is aryl; Q is C (OV is CH2; R9 is heterocycle; and R8, D and E are as defined in formula * I. In another preferred embodiment of the present invention, the compounds have the formula (II) in wherein, R1 is aryl, Q is C (O), V is CH2, R9 is heterocycle, and R8, D and E are hydrogen, In another preferred embodiment of the present invention, the compounds have the formula (II) wherein, R1 is aryl, Q is C (O), V is CH2, R9 is halogen, and R8, D and E are as defined in formula (I) In another preferred embodiment of the present invention, the compounds have the formula (II) wherein, R1 is aryl, Q is C (O), V is CH2, R9 is halogen, and R8, D and E are hydrogen, In another preferred embodiment of the present invention, the compounds have the formula (II) ) wherein, R1 is aryl, Q is C (O), V is CH2, and R8, R9, D and E are hydrogen.In another preferred embodiment of the present invention, the compounds have the formula (II) wherein, R1 is aryl, Q is S (O), and R8, R9, D, E, and V are are defined in formula (I). In another preferred embodiment of the present invention, the compounds have the formula (II) wherein, R1 is aryl; Q is S (O); and R8, R9 D, E and V are as defined in formula (I). In another preferred embodiment of the present invention, the compounds have the formula (II) wherein, R1 is aryl; Q is S (O) 2; V is CH =; and R8, R9, D and E are as defined in formula (I). In another preferred embodiment of the present invention, the compounds have the formula (II) wherein, R1 is aryl; Q is S (O) 2; V is | and R8, R9, D and E are hydrogen. In another preferred embodiment, the compounds of the present invention have the formula (III): (III), or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof, wherein R1 is selected from aryl and heterocycle; Q is selected from C (O), S (O), and S (O) 2; V is selected from C (R6) (R7), O, S and NR2, wherein R2 is selected from hydrogen, alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkyl, alkynyl, aryl, arylalkoxy, arylalkenyl, arylalkyl, cyano, cycloalkyl, cycloalkylalkyl, haloalkoxy, haloalkyl, heterocycle, heterocyclealkyl, hydroxy, hydroxyalkyl, -NR R5, and (NR R5) alkyl wherein R4 and R5 are independently selected from hydrogen and lower alkyl; R6 and R7 are independently selected from hydrogen, alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkyl, alkylthio, alkynyl, aryl, arylalkoxy, arylalkenyl, arylalkyl, carboxy, cyano, cycloalkyl, cycloalkylalkyl, haloalkoxy, haloalkyl, halogen, heterocycle, heterocyclealkyl, hydroxy , hydroxyalkyl, oxo, -NR4RS, and (NR4R5) alkyl wherein R4 and R5 are as defined above; R8 and R9 are independently selected from hydrogen, alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkyl, alkylthio, alkynyl, aryl, arylalkoxy, arylalkenyl, arylalkyl, carboxy, cyano, cycloalkyl, cycloalkylalkyl, haloalkoxy, haloalkyl, halogen, heterocycle, heterocyclealkyl, hydroxy, hydroxyalkyl, -NR4R5, and (NR4R5 ) alkyl wherein R4 and Rs are as defined above; and D and E are independently selected from hydrogen, alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkyl, alkylthio, alkynyl, aryl, arylalkoxy, arylalkenyl, arylalkyl, carboxy, cyano, cycloalkyl, cycloalkylalkyl, haloalkoxy, haloalkyl, halogen, heterocycle, heterocyclealkyl, hydroxy, hydroxyalkyl, oxo, -NR4R5, and (NR R5) alkyl wherein R4 and R5 are as defined above. In another preferred embodiment of the present invention, the compounds have the formula (III) wherein, R1 is heterocycle; Q is C (O); and R8, R9, D, E, and V are as defined in formula (I). In another preferred embodiment of the present invention, the compounds have the formula (III) wherein, R1 is heterocycle; Q is S (O); and R8, R9, D, E, and V are as defined in formula (I). In another preferred embodiment of the present invention, the compounds have the formula (III) wherein, R1 is heterocycle; Q is S (O) 2; and R8, R9, D, E, and V are as defined in formula (I). In another preferred embodiment of the present invention, the compounds have the formula (III) wherein, R1 is aryl; Q is C (O); and R8, R9, D, E, and V are as defined in formula (I). In another preferred embodiment of the present invention, the ^ ^ - ^ - S ^ -Á liliM c üipuestos have the formula (lll) where, R1 is arílo; Q is C (O); V is O; and R8, R9, P, and E are as defined in formula (I). In another preferred embodiment of the present invention, compounds Ips have the formula (III) wherein, R1 is aryl; Q is C (O); V is O; and R8, R9, D, and E are hydrogen. In another preferred embodiment of the present invention, the compounds have the formula (III) wherein, R1 is aryl; Q is S (O); and R8, R9, D, E, and V are as defined in formula (I). In another preferred embodiment of the present invention, the compounds have the formula (III) wherein, R1 is aryl; Q is S (O) 2; and R8, R9, D, E, and V are as defined in formula (I). In another preferred embodiment, the compounds of the present invention have the formula (IV): (IV), or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof, wherein R1 is selected from aryl and heterocycle, Q is selected from C (O), S (O), and S (O) 2; V is selected from C (R6) (R7), O, S. and NR2, wherein Ra is selected from hydrogen, alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkyl, alkynyl, aryl, arylalkoxy, arylalkenyl, arylalkyl, cyano, cycloalkyl, cycloalkylalkyl, haloalkoxy, haloalkyl, heterocycle, rocycloalkyl, hydroxy, hydroxyalkyl, -MR4R5, and (NR R5) alkyl wherein R4 and R5 are independently selected from hydrogen and lower alkyl; R6 and R7 are independently selected from hydrogen, alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkyl, alkylthio, alkynyl, aryl, arylalkoxy, arylalkenyl, arylalkyl, carboxy, cyano, cycloalkyl, cycloalkylalkyl, haloalkoxy, haloalkyl, halogen, heterocycle, heterocyclealkyl, hydroxy , hydroxyalkyl, oxo, -NR4R5, and (NR4R5) alkyl wherein R4 and R5 are as defined above; R8 and R9 are independently selected from hydrogen, alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkyl, alkylthio, alkynyl, aryl, arylalkoxy, arylalkenyl, arylalkyl, carboxy, cyano, cycloalkyl, cycloalkylalkyl, haloalkoxy, haloalkyl, halogen, heterocycle, heterocycloalkyl, hydroxy , hydroxyalkyl, -NR4R5, and (NR4R5) alkyl wherein R4 and R5 are as defined above; and D and E are independently selected from hydrogen, alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkyl, alkylthio, alkynyl, aryl, arylalkoxy, arylalkenyl, arylalkyl, carboxy, cyano, cycloalkyl, cycloalkylalkyl, haloalkoxy, haloalkyl, halogen, heterocycle, heterocyclealkyl, hydroxy, hydroxyalkyl, oxo, -NR R5, and (NR4R5) alkyl wherein R4 and R5 are as defined above. In a preferred embodiment of the present invention, the compounds have the formula (IV) wherein, R 1 is heterocycle; Q is C (O); R8, R9, D, and E are as defined in formula (I); and V is as defined in formula (IV). In a preferred embodiment of the present invention, the compounds have the formula (IV) wherein, R 1 is heterocycle; Q is S (O); R8, R9, D, and E are as defined in formula (I); and V is as defined in formula (IV), In a preferred embodiment of the present invention, the compounds have the formula (IV) wherein, R 1 is heterocycle; Q is S (O) 2; R8, R9, D, and E are as defined in formula (I); and V is as defined in formula (IV). In a preferred embodiment of the present invention, the compounds have the formula (IV) wherein, R1 is aryl; Q is C (O); R8, R9, D, and E are as defined in formula (I); and V is as defined in formula (IV). In a preferred embodiment of the present invention, the compounds have the formula (IV) wherein, R1 is aryl; Q is S (O); R8, R9, D, and E are as defined in formula (I); and V is as defined in formula (IV). In a preferred embodiment of the present invention, the compounds have the formula (IV) wherein, R1 is aryl; Q is S (O) 2; R8, R &, D, and E are as defined in formula (I); and V is as defined in formula (IV). Another embodiment of the present invention relates to pharmaceutical compositions comprising a therapeutically effective amount of a compound of the formula (1-4) or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof in a carrier with a carrier. pharmaceutically acceptable. Another embodiment of the invention relates to a method for treating male sexual dysfunction including, but not limited to, male erectile dysfunction and premature ejaculation, which comprises administering a therapeutically effective amount of a compound of formula (I-IV) or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof. Another embodiment of the invention relates to a method of treating female sexual dysfunction including, but not limited to, female anorgasmia, clitoral erectile insufficiency, vaginal obstruction, dyspareunia, and vaginismus which comprises administering a therapeutically effective amount of a compound of the formula (1-4), or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof. Still another embodiment of the invention relates to a method for treating asthma, epilepsy, Raynaud's syndrome, intermittent claudication, migraine, pain, gall bladder overactivity, polakiuria, vesicle instability, nocturia, gall bladder hyperreflexia, eating disorders, urinary incontinence. , enuresis, functional bowel disorders, neurodegeneration, benign prostatic hyperplasia (BPH), dysmenorrhea, premature labor, alopecia, cardioprotection, and ischemia which comprises administering a therapeutically effective amount of a compound of the formula (I-IV) or a pharmaceutically salt accept, ester, amide, or prodrug thereof. DEFINITION OF TERMS As used throughout this specification and the The following terms have the following meanings: 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 for 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-pentanyl, 5-hexenyl, 2-heptenyl, 2-methyl-1-heptenyl, 3-decentyl and the like The term "alkenyloxy", as used herein, refers to an alkenyl group , as defined above, appended to the parent molecular moiety through an oxy group, as defined herein, Representative examples of alkenyloxy include, but are not limited to, propen-3-yloxy (allyloxy), buten- 4-yloxy, and the like The term "alkoxy", as used in the prese This refers to an alkyl group, as defined herein, appended to the parent molecular moiety through an oxygen group, 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, appended to the parent molecular moiety through another alkoxy group, as defined herein. Representative examples of alkoxyalkoxy include, but are not limited to, tert-butoxymethoxy, 2-ethoxyethoxy, 2-methoxyethoxy, methoxymethoxy, and the like. The term "alkoxyalkyl", as used herein, refers to an alkoxy group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of alkoxyalkyl include, but are not limited to, tert-butoxymethyl, 2-ethoxyethyl, 2-methoxyethyl, methoxymethyl, and the like. The term "alkoxycarbonyl", as used herein, refers to an alkoxy group, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein. Representative examples of alkoxycarbonyl include, but are not limited to, methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, and the like. The term "alkyl", as used herein, refers to a straight or branched chain hydrocarbon of 1 to 10 carbon atoms. Representative examples of alkylo include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n -hexyl, 3-methylhexyl, 2,2-dimethylpentyl, 2,3-dimethylpentyl, n-heptyl, n-octyl, n-nonyl, n-decyl, and the like. The term "alkylcarbonyl", as used herein, refers to an alkyl group, as defined herein, appended 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-o-xopentyl, and the like. The term "alkylcarbonyloxy," as used herein, refers to an alkylcarbonyl group, as defined herein, appended to the parent molecular moiety through an oxy group, as defined herein. Representative examples of alkylcarbonyloxy include, but are not limited to, acetyloxy, ethycarbonyloxy, tert-butylcarbonyloxy, and the like. The term "alkylsulfinyl", as used herein, refers to an alkyl group, as defined herein, appended to the parent molecular moiety through a sulfinyl group, as defined herein. Representative examples of alkylsulfinyl 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, appended 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 "alkylthio", as used herein, refers to an alkyl group, as defined herein, appended to the parent molecular moiety through a thio moiety, as defined herein. Representative examples of alkylthio include, but are not limited to, methylthio, ethylthio, tert-butylthio, hexylthio, 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 triple bond of. ono-carbo? o. 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. Representative examples of aryl include, but are not limited to, azulenyl, indanyl, indenyl, naphthyl, phenyl, tetrahydronaphthyl, and the like. The aryl groups of this invention can be substituted with 1, 2, 3, 4 or 5 substituents independently selected from alkenyl, alkenyloxy, alkoxy, alkoxyalkoxy, alkoxycarbonyl, alkyl, alkylcarbonyl, alkylcarbonyloxy, alkylsulfinyl, alkylsulfonyl, alkylthio, alkynyl, aryl, aryloxy, azido, arylalkoxy, arylalkyl, aryloxy, carboxy, cyano, formyl, halogen, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, mercapto, nitro, sulfamyl, sulfo, sulfonate, -NR80R81 (wherein, R80 and R81 are independently selected from hydrogen, alkyl , alkylcarbonyl, aryl, arylalkyl and formyl), and -C (O) NR82R83 (wherein, R82 and R83 are independently selected from hydrogen, alkyl, alkylcarbonyl, aryl, arylalkyl, and formyl). The term "arylalkenyl", as used herein, refers to an aryclo group, as defined herein, appended to the parent molecular moiety through an alkenyl group, as defined herein. Representative examples of arylalkenyl include, but are not limited to, 2-phenylethenyl, 3-phenylpropene-2-yl, 2-naphth-2-yletenyl, and the like. & J £ L. ^ J $ 3 £ - IHB -------- I The term "arylalkoxy", as used herein, refers to an aryl group, as defined herein, appended to the major molecular moiety through an alkoxy group, as defined herein. Representative examples of arylalkoxy include, but are not limited to, 2-phenylethoxy, 3-naphth-2-ylpropoxy, 5-phenylpentyloxy, and the like. The term "arylalkoxycarbonyl", as used herein, refers to an arylalkoxy group, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein. Representative examples of arylalkoxy 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, appended 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 "aryloxy," as used herein, refers to an aryl group, as defined herein, appended to the parent molecular moiety through an oxy group, as defined herein. Representative examples of aryloxy include, but are not limited to, phenoxy, naphthyloxy, 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. ..4. *.! **. *. * - ~. ~ ** ii * The term "carboxy", as used herein, refers to a group -CO2H. The term "carboxy protecting group", as used herein, refers to the carboxylic acid protecting ester group employed to block or protect the functionality of the carboxylic acid while carrying out reactions that include other functional sites of the compound. The Carboxi protecting groups are described in T.H. Greene and P.G.M. Wuts, Protective Groups in Organic Synthesis, 2nd edition, John Wiley & Sons, New York (1991), which is incorporated herein by reference. In addition, a carboxy protecting group can be used as a prodrug by which the carboxy protecting group can be easily opened in vivo, for example, by enzymatic hydrolysis, to release the biologically active principal. T. Higuchi and V, Stella provide a full discussion of the prodrug concept in "Pro-drugs as Novel Delivery Systems," Vol. 14 of the ACS Symposium Series, American Chemical Society (1975), which is incorporated herein. Reference, such carboxy protecting groups are well known to those skilled in the art, having been widely used in the protection of carboxyl groups in the cephalosporin and penicillin fields, as described in Pat. of E.U. No. 3,840,556 and 3,719,667, the descriptions of which are incorporated herein by reference. Examples of esters useful as prodrugs for compounds containing carboxyl groups can be found on pages 14-21 of "Bioreversible Carriers in Drug Design: Theory and Application", edited by E.B. Roche, Pergamon Press, New York (1987), which is incorporated herein by reference. Representative carboxy protecting groups are lower alkyl (eg, methyl, ethyl or tertiary butyl and the like); benzyl (phenylmethyl) and substituted benzyl derivatives thereof substituents are selected from alkoxy, alkyl, halogen, and nitro groups and the like. The term "cyano", as used herein, refers to a -CN group. The term "cycloalkyl", as used herein, refers to a saturated cyclic hydrocarbon group containing from 3 to 8 carbons. Representative examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. The term "cycloalkylalkyl", as used herein, refers to a cycloalkyl group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of cycloalkylalkyl include, but are not limited to, cyclopropylmethyl, 2-cyclobutylethyl, cyclopentylmethyl, cyclohexylmethyl and 4-cycloheptylbutyl, and the like. The term "formyl", as used herein, refers to a group -C (O) H The term "halo" or "halogen", as used herein, refers to -Cl, -Br, -I or -F. The term "haloalkyl", as used herein, refers to at least one halogen, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined I presented. Representative examples of hafoalkyl include, but are not limited to, chloromethyl, 2-fluoroethyl, trifluoromethyl, pentafluoroetyl, 2-chloro-3-fluoropentyl ?, and the like. The term "haloalkoxy", as used herein, refers to at least one halogen, as defined herein, appended to the parent molecular moiety through an alkoxy group, as defined herein. Representative examples of haloalkoxy include, but are not limited to, 2-chloroethoxy, difluoromethoxy, 1,2-difluoroethoxy, 2,2,2-trifluoroethoxy, trifluoromethoxy, and the like. The term "heterocycle", as used herein, refers to a bicyclic ring system or a monocyclic 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 0-2 double bonds and the 6-membered ring has 0-3 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, isotiazola, isothiazoline, isothiazolidine, isoxazoia , Isoxazoline, Isoxazolidine, Morpholine, Oxadiazole, Oxadiazoline, Oxadiazolidine, Oxazole, Oxazoline, Oxazolidine, Piperazine, Piperidine, Piera, Pyrrazine, Pyrazole, Pyrazoline, Pyrazolidine, Pyridine, Pyrimidine, Pyridazine, Pyrrole, Pyrroline, Pyrrolidine, Tetrahydrofuran, Tetrahydrofothiophene, tetrazine, tetrazole, thiadiazole, thiadiazoline, thiadiazolidine, thiazole, thiazoline, thiazolidine, thiophene, tiomorfina, thiomorpholine sulfone, thiopyran, triazine, triazole, trithiane, and the like. The bicyclic ring systems are exemplified by any of the systems above monocyclic ring fused to an aryl group as defined herein, a cycloalkyl group as defined herein, or another monocyclic ring system as defined herein . Representative examples of bicyclic ring systems include, but are not limited to, for example, benzimidazole, benzothiazole, benzotiadiazola, benzothiophene, benzoxadiazola, benzoxaz? The, benzofuran, benzopyran, benzothiopyran, benzodioxine, 1, 3-benzodioxoia, cinnoline, indazola , indole, indoline, indolizine, naphthyridine, isobenzofuran, isobenzothiophene, isoindola, isoindoline, isoquinoline, phthalazine, pyranopyridine, quinoline, quinolizine, quinoxaline, quinazoline, tetrahydroisoquinoline, tetrahydroquinoline, tipiranopiridina, and the like.

The heterocycle groups of this invention can be substituted with 1, 2, or 3 substituents independently selected from. alkenyl, alkenyloxy, akoxy, alkoxylaxy, alkoxycarbonyl, alkyl, alkylcarbonyl, alkylcarbonyloxy, alkylsulfinyl, alkylsulfonyl, alkylthio, alkynyl, aryl, azido, arylalkoxy, arylalkoxycarbonyl, arylalkyl, aryloxy, carboxy, cyano, formyl, halogen, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, mercapto, nitro, sulfamyl, sulfo, sulfonate, -NR80R81 (wherein, R80 and R81 are independently selected from hydrogen, alkyl, alkylcarbonyl, aryl, arylalkyl and formyl), and -C (O) NR83R83 (wherein, R82 and R83 are independently selected from hydrogen, alkyl, aryl, and annihil). The term "heterocycloalkyl," as used herein, refers to a heterocycle, as defined herein, appended 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 "hydroxy", as used herein, refers to an -OH group. The term "hydroxyalkyl," as used herein, refers to a hydroxy group, as defined herein, appended 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, and the like. The term "lower alkyl", as used herein, is a subset of alkyl as defined herein and 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, n-propyl, iso-propyl, n-butyl, iso-butyl, tert-butyl, and the like. The term "mercapto", as used herein, refers to a -SH group. The term "(NR R5) alkyl", as used herein, refers to a group -NR4R5, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined in I presented. Representative examples of (NR R5) alkyl include, but are not limited to, aminomethyl, dimethylaminomethyl, 2- (amino) ethyl, 2- (dimethylamino) ethyl, and the like.

The term "nitro", as used herein, refers to a group -NO2. The term "oxo", as used herein, refers to a portion = O. The term "oxy", as used herein, refers to a -O- portion. The term "sulfamyl", as used herein, refers to a group -SO2NR94R95, wherein, R94 and R95 are independently selected from hydrogen, alkyl, aryl, and arylalkyl, as defined herein. The term "sulfinyl", as used herein, refers to a group -S (O) -. The term "sulfo", as used herein, refers to a group -SO3H. The term "sulfonate", as used herein, refers to a group -S (O) 2OR96, wherein, R96 is selected from alkyl, aryl, and arylalkyl, as defined herein. The term "sulfonyl", as used herein, refers to a group -SO2-. The term "thio", as used herein, refers to a -S- portion. Preferred compounds of the formula (I) include, but are not limited to: 9- (3-bromo-4-flurophenyl) -5,6,7,9-tetrahydropyrazolo [5-1-bJquinazolin-8 (4H) - ona, | ^ |? a | ^^ gjtí 9- (3-bromo-4-flurofenil) -5,9-dihydro-4H-pírazolo. { t, 5- altiopyrano [3,4-d] pyrimidin-8 (7H) -one; 9- (1-naphthyl) -5,6,7I9-tetrahydropyrazole) or [5t 1-bJquinazolin-8 (4H) -one; 9- (2-naphthi.o) -5,6,7,9-tetrahydropyrazolo [5-1-b] quinazolin-8 (4H) -one; 9- (3,4-dibromophenyl) -5,6,7,9-tetrahydropyrazolo [5-1-b} quinazolin-8 (4H) -one; 9- (3,4-dichlorophenyl) -5,6,7,9-tetrahydropyrazole [5-1-bJquinazolin-8 (4H) -one; 9- (3-bromophenyl) -5,6,7,9-tetrahydropyrazolo [5-1-bJquinazolin-8 (4H) -one; 9- (3-chlorophenyl) -5,6,7,9-tetrahydropyrazolo [5-1-bJquinazolin-8 (4H) -one; 9- [4-chloro-3- (trifluoromethyl) phenyl] -5,6,7,9-tetrahydropyrazolo [5-1-b] quinazolin-8 (4H) -one; 9- [4-fluoro-3- (trifluoromethyl) phenyl] -5,6,7,9-tetrahydropyrazolo [5-1-b] quinazolin-8 (4H) -one; 9- [3- (trifluoromethoxy) phenylJ-5,6,7,9-tetrahydropyrazolo [5-1-bJquinazolin-8 (4H) -one; 9- (3-cyanophenyl) -5,6,7,9-tetrahydropyrazolo [5- \ 1-b] quinazolin-8 (4H) -one; 9- (3-methylphenyl) -5,6,7,9-tetrahydropyrazolo [5-1-b] quinazolin-8 (4H) -one; 9- (3-bromo-4-flurophenyl) -5,8-dihydro-4H, 7H-furot3,4- dlfwrazolo [1, 5-a] pyrimidin-7-one; (-) 9 ~ (3-bromo-4-flurophenyl) -5,6,7,9-tetrahydropyrazole [5-1- b-JN-nazolin-8 (4H) -one; (+) 9- (3-bromo-4-flurofenyl) -5,6,7,9-tetrahydropyrazole (5-1-bJquinazolin-8 (4H) -one;? -IS-bromo ^ -flurofeni -d.ßJ .T-tetrahydro-H-pyrazolofl. S -thiopyrano [3,2-d] pyrimidine 8,8-dioxide, 9- (3-chloro-4-hydroxyphenyl) -5,6,7,9-tetrahydropyrazolo [5- 1-b -quinazolin-8 (4H) -one; 3-bromo-9- (3-bromo-4-flurophenyl) -5,6,7,9-tetrahydropyrazolo [5-1-bJquinazolin-8 (4H) -one; 9- (3-chloro-4-flurophenyl) -5,6,7,9-tetrahydropyrazolo [5-1-b] quinazolin-8 (4H) -one; 9- (3,4-difluorophenyl) -5,6 , 7,9-tetrahydropyrazolo [5-1-bJquinazolin-8 (4 ') -one; 9- (4-flurophenyl) -5,6,7,9-tetrahydropyrazolo [5-1-b] quinazolin-8 (4H > -one; 9- [4-trifluoromethyl] phenyl] -5,6,7,9-tetrahydropyrazolol-5-b -quinazolin-8 (4H) -one; 9- (4-cyanophenyl) -5,6,7, 9-tetrahydropyrazolo [5-1-bJquinazolin-8 (4H) -one; 9r (4-chloro-3-nitropheni) -5,6,7,9-tetrahydropyrazo [5-1-bJquinazolin-8 (4H) -one; 9- (4-chloro-3-fluorophenyl) -7,7-dimethyl-5,6,7,9-tetrahydropyrazolo [5-1-b] quinazolin-8 (4H) -one; 9- (3-bromo-4-flurophenyl) -7,7-dimethyl-5,6,7,9-tetrahydropyrazolo [5-1-b] quinazolin-8 (4H) -one; 9- [4-fluoro-3- (trifluoromethyl) phenyl] -7,7-dimethyl-5,6,7,9-tetrahydropyrazolo [5-1-b] qu? Nazolin-8 (4H) -one, 9- (3,4-dichlorophenyl) -7,7-dimethyl-5,6,7,9-tetrahydropyrazolo [5-1-b} quinazolin-8 (4H) -one; 9- (4-chloro-3-nitrophenyl) -7,7-dimethyl-5,6,7,9-tetrahydropyrazolo [5-1-b] quinazolin-8 (4H) -one; 9- (3,4-dibromophenyl) -7,7-dimethyl-5,6,7,9-tetrahydropyrazolo [5-1-b] quinazolin-8 (4H) -one; 9- [3-fluoro-4- (trifluoromethyl) phenyl] -7,7-dimethyl-5,6,7,9-tetrahydropyrazolo [5-1-b] quinazolin-8 (4H) -one; 9- (3-nitrophenyl) -7,7-dimethyl-5,6,7,9-tetrahydropyrazolo [5-1-b] quinazolin-8 (4H) -one; 9- (3-cyanophenyl) -7,7-dimethyl-5,6,7,9-tetrahydropyrazolo [5-1-b] quinazolin-8 (4H) -one, 7,7-dimethyl-9- (5- nitro-3-thienyl) -5,6,7,9-tetrahydropyrazolo [5-1-b] quinazolin-8 (4H) -one; 9- (5-Bromo-2-hydroxyphenyl) -7,7-dimethyl-5,6,7,9-tetrahydropyrazolo [5-1-b] quinazolin-8 (4H) -one; 9- (5-chloro-2-hydroxyphenyl) -7,7-dimethyl-5,6,7,9-tetrahydropyrazone [5-1-b] quinazolin-8 (4H) -one; 9- (2-hydroxy-5-nitrophenyl) -7,7-dimethyl-5,6,7,9-tetrahydropyrazolo [5-1-b] quinazolin-8 (4H) -one; 9- (3,5-dibromo-2-hydroxyphenyl) -7,7-dimethyl-5,6,7,9-Úáíáí'kliiÉ "i - - ^ í. ^ * * ^ ** - ^^^.-.- ^. * ^^» - ^^ «gfJ tetrahydropyrazolo [5-1-b] quinazolin-8 (4H) -one; 9- (3-bromo-5-chloro-2-hydroxyphenyl) -7,7-dimethyl-5,6,7,9-tetrahydropyrazolo [5-1-b] quinazolin-8 (4H) -one; 9- (3,5-dichloro-2-hydroxyphenyl) -7,7-dimethyl-5,6,7,9-tetrahydropyrazolo [5-1-b] quinazolin-8 (4H) -one; 9- (3, 4,5-trifluorophenyl) -7,7-dimethyl-5,6) 7,9-tetrahydropyrazolo [5-1-b] quinazolin-8 (4H) -one; 9- (3,4-dichlorophenyl) -3- (3-fluorophenyl) -5,6,7,9-tetrahydropyrazolo [5-1-b] quinazolin-8 (4H) -one; 9- (3,4-dichlorophenyl) -3- (3-chlorophenyl) -5 6,7,9-tetrahydropyrazolo [5- 1-bJquinazolin-8 (4H) -one; 9- (3,4-dichlorophenyl) -3- (4-carboxyphenyl) -5,6,7,9-tetrahydropyrazolo [ 5-1-b] quinazolin-8 (4H) -one; 9- (3,4-dichlorophenyl) -3- (2-thienyl) -5,6,7,9-tetrahydropyrazolol-5-b] quinazolin- € (4H) -one; 9- (3,4-dichlorophenyl) -3- [2- (trifluoromethyl) phenyl] -5,6,7,9-tetrahydropyrazolo [5-1-b] quinazolin-8 (4H) - ona, 3-bromo-9- (3,4-dichlorophenyl) -5,6,7,9-tetrahydropyrazolo [5-1-bJquinazolin-8 (4H) -one, (+) 3-bromo-9- ( 3,4-dichlorophenyl) -5,6,7,9-tetrahydropyrazolo [5-1-b] quinazolin-8 (4H) -one; (-) 3-Bromo-9- (3,4-dichlorophenyl)) - 5,6,7,9-tetrahydropyrazolo [5-1-b] < _Juinazolin-8 (4H) -one; (+) 9- (3,4-dichlorophenyl) -3- (2-thienyl) -5,6,7,9-tetrahydropyrazolo [5-1-bJquinazolin-8 (4H) -one; .-- ----- t_i_A ^ _ < ___ ^ _ a ^ J .. »^ (-) 9- (3,4-dichlorophenyl) -3- (2-thienyl) -5,6,7,9-tetrahydropyrazolo [5-1-b] quinazole- 8 (4H) -one; 9- (3,4-dichlorophenyl) -3- (2-furyl) -5,6,7,9-tetrahydropyrazolo [5-1-bJquinazolin-8 (4H) -one and pharmaceutically acceptable salts, esters, amides, or prodrugs of it.

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 that illustrate 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 1-20. Scheme 1 The fused pyrimidines of the general formula (4), wherein R \ X, Q, R8 and R9, D and E are as defined in the formula (I) and m is an integer 1-2, can be prepared according to the method of Scheme 1. A carbonyl component of the general formula (1) can be treated with an aldehyde of the general formula (2) and an amino heterocycle of the general formula (3) in a solvent such as ethanol, acetonitrile or dimethylformamide. ijTtiU with heating to provide the fused pyrimidines of the general formula (4). Scheme 2 The fused pyrimidines of the general formula (6), wherein R \ X, Q, V, R8 and R9, D and E are as defined in the formula (I), can be prepared according to the method of Scheme 2. A The carbonyl component of the general formula (5) can be treated with an aldehyde of the general formula (2) and an amino heterocycle of the general formula (3) in a solvent such as ethanol, acetonitrile or dimethylformamide with heating to provide the pyrimidines. fused of the general formula (6). The carbonyl components of the general formula (5) can be prepared using the methods described in (Dood, J.H., Journal of Heterocyclic Chemistry 27 (1990) 1453; Terasawa, T., Journal of Organic Chemistry 42 (1997) 1 163). Scheme 3 The fused pyrimidines of the general formula (3), wherein R \ X, Q, V, R8 and R9, D and E are as defined in the formula (I), can be prepared according to the method of Scheme 3. A The carbonyl component of the general formula (7) can be treated with an aldehyde of the general formula (2) and an amino heterocycle of the general formula (3) in a solvent such as ethanol, acetonitrile or dimethylformamide with heating to provide the pyrimidines. fused of the general formula (8). The carbonyl components of the general formula (7) can be prepared as described in) Nakagawa, S., Heterocycles 13 (1979) 477; D'Angelo, J., Tetrahedron Letters 32 (1991) 3063). Scheme 4 , - The fused pyrimidines of the general formula (10), wherein R 1, X, Q, V, R 8 and R 9, D and E are as defined in the formula (I), can be prepared according to the Scheme method 4. A carbonyl component of the general formula (9) can be treated with an aldehyde of the general formula (2) and an amino heterocycle of the general formula (3) in Or a solvent such as ethanol, acetonitrile or dimethylformamide with heating to provide the fused pyrimidines of the general formula (10). 5 Scheme 5 (13) The fused pyrimidines of the general formula (13), wherein R 1, X, R 8 and R 9, and D are as defined in the formula (I), can be prepared according to the method of Scheme 5. A dicarbonyl component of the general formula (11), wherein R 'is selected from Cl, and Oac and R is selected from the group protecting lower alkyl, cyanoalkyl, and carboxy, can be treated with an aldehyde of the general formula (2) and an amino heterocycle of the general formula (3) in a solvent such as ethanol, acetonitrile or dimethylformamide with heating to provide the fused pyrimidines of the general formula (12). In the case where R 'is OAc, the division of the acetyl group may be required to induce cyclization to provide the fused pyrimidines of the formula (13). In the case where R 'is Cl, the cyclization can proceed directly without the isolation of (12) to provide the fused pyrimidines of the general formula (13). Many of the heteroaryl and aryl aldehydes of raw material necessary to carry out the methods described in the preceding and following Schemes can be purchased from commercial sources or can be synthesized by methods known in the chemical literature. Suitable literature references for the preparation of heteroaryl and aryl aldehydes can be found in the following section or in the Examples. For raw materials not previously described in the literature, the following Schemes are intended to illustrate their preparation through a general method. The preparation of aldehydes used to synthesize several of the preferred compounds of the invention can be found in the following literature references: Pearson, Org. Synth Col. Vol (1973), 117; Nwaukwa, Tetrahedron Lett. (1982), 23, 3131; Badder, J. Indian Chem. Soc. (1976), 53, 1053; Khanna, J. Med. Chem. (1997), 40, 1634; Rinkes, Red. Trav. Chim. Pays-Bas (1945), 64, 205; van der Lee, Red. Trav. Chim. Páys-Bas (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; Tanouchi, J. Med. Qhem. (1981), 24, 1 149; Bergmann, J. Am. Chem. Soc. (1959), 81, 5641; Others: Eister, Chem. Ber. (1964), 97, 1740; Sekikawa, Bull. Chem. Soc. Jpn. (1959), 32, 551.

Scheme 6 The para-disubstituted, meta-aldehydes of the general formula (21), wherein R10 is selected from alkyl, haloalkyl, halo, haloalkoxy, alkoxy, alkylthio, -NR82R83, and -C (O) NR82R83 wherein R82 and R83 are independently selected from hydrogen, alkyl, alkylcarbonyl, aryl, arylalkyl, and formyl and R12 is selected from nitro, halo, and alkylcarbonyl, can be prepared according to the method described in Scheme 6. An aldehyde for substituted of the general formula (20) or the corresponding acetal protected aldehyde of the general formula (22), wherein R is selected from alkyl or together with the oxygen atoms to which they are bound they form a 5- or 6-membered ring wherein 1,3-dioxolanes are preferred , can be subjected to conditions of an electrophilic aromatic substitution reaction to provide aldehydes of the general formula (21) or the protected aldehydes of the general formula (23). Preferred protecting groups for the compounds of the general formula (22) and (23) include diethyl or dimethyl acetals or the 1, 3-These protecting groups can be introduced at the beginning, and removed at the end to provide substituted aldehydes of the general formula (21) using methods well known to those skilled in the art of organic chemistry. Scheme 7 The aldehydes of the general formula (27), wherein R10 is selected from alkyl, haloalkyl, halo, haloalkoxy, alkoxy, alkylthio, -NRß2R83, and -C (O) NR82R83 wherein R82 and R83 are independently selected from hydrogen, alkyl, alkylcarbonyl, aryl, arylalkyl, and formyl and R12 is selected from nitro, halo , and alkylcarbonyl, can be prepared by the method described in Scheme 7. A substituted meta phenol (25) is converted to salicylaldehyde for substituted (26) by reaction with a base such as sodium hydroxide and a reagent such as trichloromethane or tribromomethane , known as the Reimer-Tiemann reaction. An alternative group of reaction conditions includes the reaction with magnesium methoxide and paraformaldehyde (Aldred, J. Chem. Soo, Perkin Trans. 1 (1994), 1823). The aldehyde (26) can be subjected to conditions of an electrophilic aromatic substitution reaction to provide meta, disubstituted salicylaldehydes of the general formula (27).

Scheme 8 An alternative method for preparing meta, for disubstituted salicylaldehydes of the general formula (27), wherein R1? is selected from alkyl, haloalkyl, halo, haloalkoxy, alkoxy, alkylthio, -NR82R83, and -C (O) NR82R83r wherein R82 and R83 are independently selected from hydrogen, alkyl, alkylcarbonyl, aryl, arylalkyl, and formyl and R12 is selected of nitro, halo, and alkylcarbonyl, can be used as described in Scheme 8. A disubstituted meta phenol of the general formula (28) can be reacted with a base such as sodium hydroxide and a reagent such as trichloromethane or tribromomethane, known as the Reimer-Tiemann reaction, to provide disubstituted salicylaldehydes of the general formula (27). An alternative group of reaction conditions includes the reaction with magnesium methoxide and paraformaldehyde (Aldred, J. Chem. Soc. Perkin Trans. 1 (1994), 1823). Scheme 9 An alternative method for preparing benzaldehydes of the general formula (21), wherein R12 is selected from alkyl, haloalkyl, chloro, fluoro, haloalkoxy, alkoxy, alkylthio, nitro, alkylcarbonyl, arylcarbonyl, ~ NR82R83, and -C (O) NR82R83 wherein R82 and R83 are independently selected from hydrogen, alkyl, alkylcarbonyl, aryl, arylalkyl, and formyl, and R10 is selected from alkyl, hydroxyalkyl, alkylthio, alkylcarbonyl, and formyl, is described in Scheme 9. The protected benzaldehydes of the general formula (29), wherein R is selected from alkyl or together with the oxygen atoms to which they are bound, form a 5- or 6-membered ring where 1, 3 are preferred. dioxolanes, can be converted to the 3,4-disubstituted benzaidehyde of the general formula (23) by means of the conversion of the bromide to an intermediate magnesium or lithium derivative, followed by the reaction with a suitable electrophilic such as an aldehyde, dialkyldisulfide, a Weinreb amide, dimethylformamide, an alkyl halide or other electrophilic followed by deprotection of the acetal to provide benzaldehydes of the general formula (21). Scheme 10 An alternative method for preparing benzaldehydes of the general formula (21), in dort R10 is selected from alkyl, haloalkyl, doro, fluorine, haloalkoxy, alkoxy, alkylthio, -NR8 R83, and -C (O) NR82R83 wherein R 2 and 83 are independently selected from hydrogen, alkyl, alkylcarbonyl, aryl, arylalkyl, and formyl, and R 12 is selected from alkyl, hydroxyalkyl, alkylthio, alkylcarbonyl, and formyl, can be used as described in Scheme 10. protected benzaldehydes of the general formula (31), wherein R is selected from alkyl or together with the oxygen atoms to which they are attached form a 5- or 6-membered ring wherein 1,3-dioxolanes are preferred, they can be processed according to is described in Scheme 9 to provide benzaldehydes of the general formula (21). Scheme 1 1 The benzaldehydes of the general formula (33), wherein R10 is selected from hydrogen, alkyl, alkylsulfonyl, aryl, heteroaryl, cyano, haloalkyl, halo, haloalkoxy, nitro, alkoxy, alkylthio, -NR8 R83, and -C (O) NR82R83 wherein R82 and R83 are independently selected from hydrogen, alkyl, alkylcarbonyl, aryl, arylalkyl, and formyl, and R13 is selected from hydrogen, alkyl, arylalkyl, and haloalkyl wherein the preferred haloalkyl groups are selected from difluromethyl, 2.2 , 2-trifluoroethyl and bromodifluoromethyl, can be prepared as described in Scheme 1 1. 3-Hydroxybenzaldehyde of the general formula (32) can be treated with suitable alkylating reagents such as benzyl bromide, iodomethane, 2-iodo-1,1,1- trifluoroethane) chlorodifluoromethane, or dibromodifluoromethane in the presence of base such as potassium carbonate, potassium tert-butoxide or sodium tert-butoxide, to provide the benzaldehydes of the general formula (33). The synthesis of useful 3-hydroxybenzaldehydes of the general formula (32) 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 Liebigs 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 12 The benzaldehydes of the general formula (35), wherein R12 is selected from hydrogen, alkyl, alkylsulfonyl, aryl, heteroaryl, cyano, haloalkyl, halo, haloalkoxy, nitro, alkoxy, alkylthio, -NR82R83, and -C (O) NR82R83 wherein R82 and R83 are independently selected from hydrogen, alkyl, alkylcarbonyl, aryl, arylalkyl, and formyl, and R13 is selected from hydrogen, alkyl, arylalkyl, and haloalkyl wherein the preferred haloalkyl groups are selected from difluromethyl, 2.2, 2-trifluoroethyl and bromodifluoromethyl, can be prepared as described in Scheme 12. 4-Hydroxybenzaldehydes of the general formula (34) treated with suitable alkylating reagents such as benzyl bromide, iodomethane, 2-iodo-1,1,1trif luoroethane, chlorodifluoromethane, or dibromodiftuoromethane in the presence of base such as potassium carbonate, potassium tert-butoxide or sodium tert-butoxide, to provide the benzaldehydes of the general formula (35). The synthesis of useful 4-hydroxybenzaldehydes of the general formula (34) can be found in the following literature references: Anguilla, 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-lbarra, 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 13 An alternative method for the introduction of substituents at the 3-position of benzaldehydes of the general formula (21), wherein R10 is selected from hydrogen, alkyl, alkylsulfonyl, aryl, hfteroalkyl, cyano, haloalkyl, halo, haloalkoxy, nitro, alkoxy, alkylthio, and -C (O) NR82R83, wherein R82 and R83 are independently selected from hydrogen, alkyl, alkylcarbonyl, aryl, arylalkyl, and formyl can be used according to t e. { described in Scheme 13. This method, also known as the Sandmeyer reaction, includes converting 3-amino benzaldehydes of the general formula (36) 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 can be introduced in this form include cyano, hydroxy, or halo. In order to carry out this transformation successfully, it may be advantageous under certain circumstances to carry out the Sandmeyer reaction in a protected aldehyde. The resulting iodide or bromide can be treated with unsaturated halides, boronic acids or tin reagents in the presence of a patadium catalyst such as tetrakis (triphenylphosphine) palladium (0) to provide benzaldehydes of the general formula (21). 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 benzaldehydes of the formula (21).

Scheme 14 An alternative method for introducing substituents at the 4-position of benzaldehydes of the general formula (21), wherein R12 is selected from hydrogen, alkyl, alkylsulfonyl, aryl, heteroalkyl, cyano, haloalkylol, halo, haloalkoxy, nitro, alkoxy, alkylthio, and -C (O) NR82R83, in doh of R82 and R83 are independently selected from hydrogen, alkyl, alkylcarbonyl, aryl, arylalkyl, and formyl can be used as described in Scheme 14. This method, also known as the Sandmeyer reaction , includes converting 4-amino benzaldehydes of the general formula (37) to an intermediate diazonium salt with sodium nitrite and then treating the diazonium salts in a similar manner as that described in Scheme 13. The types of substituents of R 0 which can be introduced in this form include cyano, hydroxy, or halo. 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, it may be advantageous under certain circumstances to carry out the Sandmeyer reaction on a protected aldehyde. t? f¡-¿L * k,,? . to. j ,, áfc S __. i Scheme 15 4-Bromo-3- (trifluoromethox?) Benzaldehyde or 4-chloro-3- (triftuoromethoxy) benzaldehyde can be prepared as described in Scheme 15. Commercially available 4-bromo-2- (tr? Fluoromethoxy) aniline can be protected on et amino group co? an appropriate N-protecting group well known to those skilled in the art of organic chemistry such as acetyl or tert-butoxycarbonyl. Bromine can thus be converted to the lithium or magnesium derivative and reacted directly with dimethylformamide to provide the 4-aminoprotected derivative 3- (triftuoromethoxy) bertzaldehyde. Removal of the protecting group N followed by conversion of the amine to a bromine or chlorine by means of the Sandmeyer method of Scheme 14 provides 4-bromo-3- (trifluoromethoxy) benzaldehyde or 4-chloro-3- (trifluoromethoxy) benzaldehyde. Scheme 16 4-Trifluoromethylbenzaldehydes of the general formula (39), wherein Y is selected from cyano, nitro, and halo can be prepared according to the method of Scheme 16. The 4-trifluoromethylbenzoic acid is first nitrated, using suitable conditions well known in the art such as with sulfuric acid, and the carboxylic acid group reduced with borane to provide 3-nitro-4-trifluoromethylbenzyl alcohol. From this benzyl alcohol, 3- nitride-4-trifluoromethylbenzaldehyde can be obtained by oxidation with typical reagents such as manganese dioxide. The benzyl alcohol nitro can be reduced in the aniline using any of a number of different conditions to effect this transformation among which the preferred method is hydrogenation over a palladium catalyst. The aniline can be converted to either a cyano or halo substituent using the Sandmeyer reaction described in Scheme 13. The benzylic alcohols of the general formula (38) can be oxidized using conditions well known to those skilled in the art such as manganese dioxide or sworn conditions to provide benzaldehydes of the general formula (39). For certain Ri ring aromatic substitutions for the compounds of the present invention, it is preferable to effect transformations of the aromatic ring substitutions after the aldehyde has been incorporated into the core structure of the present invention. As such, the compounds of the present invention can be further transformed into various other compounds of the present invention. These transformations include coupling reactions t, Suzuki and Heck, all of which are well known by those experts in organic chemistry. The ones shown below are some representative methods of such transformations of compounds of the present invention to other compounds of the present invention. Scheme 17 The dihydropyridines of the general formula (42), wherein R8, R9, D, E, Q, V, X, m, and n are as defined in the formula (I), R10 is selected from hydrogen, alkyl, alkylcarbonyl, alkylsulfonyl, aryl, heteroaryl, damage, haloalkyl, chloro, fluoro, haloalkoxy, nitro, alkoxy, and alkylthio, and -C (O) NR82R83 wherein R82 and R83 are independently selected from hydrogen, alkyl, alkylcarbonyl, aryl, arylalkyl, and formyl, R11 is selected from hydrogen, hydroxy, alkoxy, haloalkoxy, and arylalkoxy, R12 is selected from alkyl, vinyl, aryl, heteroaryl, cyano, and the like, can be prepared as described in Scheme 17. Compounds of the general formula (41), wherein Y is selected from bromine, iodine, and triflate, are protected with a tert-butoxycarbonyl (Boc) group using standard procedures. The aromatic bromine, iodine, or triflate can be treated with a suitable tin, boronic acid, or unsaturated haiuro reagent in the presence of a palladium catalyst with heating in a solvent such as dimethylformamide to effect a coupling reaction that provides dihydropyridines of the general formula (42). The conditions for this transformation also effect the removal of the Boc protecting group. Scheme 18 The dihydropyridines of the general formula (44), wherein R8, R9, D, E, Q, V, X, m, and n are as defined in the tormula (I), R12 is selected from hydrogen, alkyl, alkylcarbonyl, alkylsulfonyl, aryl, heteroaryl, cyano, haloalkyl, chloro, fluoro, haloalkoxy, nitro, alkoxy, and alkylthio, and -C (O) NRB¿RβJ wherein R, 82 R 83 are independently selected from hydrogen, alkyl, alkylcarbonyl, aryl , arylalkyl, and formyl, R11 is selected from hydrogen, hydroxy, alkoxy, haloalkoxy, and arylalkoxy, R10 is selected from alkyl, vinyl, aryl, heteroaryl, < iano and the like, can be prepared as described in Scheme 18. The dihydropyridines of the general formula (43), wherein Y is selected from bromine, iodine, and triflate, can be protected with a tert-butoxycarbonyl (Boc) group using standard procedures. The aromatic bromine, iodine, or triflate can be reacted with a suitable tin, boronic acid, or unsaturated halide reagent in the presence of a palladium catalyst with heating in a solvent such as dimethylformamide to effect a coupling reaction that provides dihydropyridines. of the general formula (44). The conditions for this transformation also effect the removal of the Boc protecting group. Scheme 19 The dihydropyridines of the general formula (47), wherein R8, R9, D, E, Q, V, X, m, and n are as defined in the formula (I), R10 is selected from hydrogen, alkyl, alkylcarbonyl, alkylsulfonyl, aryl, heteroaryl, cyano, haloalkyl, chloro, fluoro, haloalkoxy, nitro, alkoxy, and alkylthio, and -C (O) NR82R83 wherein R82 and R83 are independently selected from hydrogen, alkyl, alkylcarbonyl, aryl, arylalkyl, and formyl, R11 is selected from hydrogen, hydroxy, alkoxy, haloalkoxy, and arylalkoxy, can be prepared as described in Scheme 19. The dihydripyridines of the general formula (41), wherein Y is selected from bromine, iodine, and triflate, can be protected with a tertiary group . ^ .. ^^ t. ^^ e ^^^^^^? ^^. ^^ -W ». Bitumencarbonyl (Boc) using standard procedures. The aromatic bromine, iodine, or triflate can be treated with a suitable halogen reagent in the presence of a palladium catalyst with heating in a solvent such as dimethylformamide to effect a coupling reaction that provides dihydropyridines of the general formula (47). The conditions for this transformation also effect the removal of the Boc protecting group. The types of meta substituents that can be introduced in this form include trihalopropenyl and more specifically the trifluoropropenyl group. 0 Scheme 20 The dihydropyridines of the general formula (48), wherein R8, R9, D, E, Q, V, X, m, and n are as defined in formula (I), R10 is selected from hydrogen, alkyl, alkylcarbonyl, alkylsulfonyl, aryloyl, heteroaryl, cyano, haloalkyl, chloro, fluoro, haloalkoxy, nitro, alkoxy, and alkylthio, and -C (O) NR82R83 wherein R82 and R83 are independently selected from hydrogen, alkyl, alkylcarbonyl, aryl, arylalkyl , 5 and formyl, R 11 is selected from hydrogen, hydroxy, alkoxy, haloalkoxy, and * yes-r.

* WNftlcFxt-t can be prepared as described in Scheme 2Q. The dihydropyridines of the general formula (43), wherein Y is selected from bromine, iodine, and triflate, can be protected with a tert-butoxycarbonyl (Boc) group using standard procedures. The aromatic bromine, iodine, or triflate can be treated with a suitable halogen reagent in the presence of a palladium catalyst with heating in a solvent such as dimethylformamide to effect a coupling reaction that provides dihydropyridines of the general formula (48). The conditions for this transformation also effect the removal of the Boc protecting group. The types of substituents for which they can be introduced in this form include trihalopropenyl and more specifically the trifluoropropenyl group. Scheme 21 R = alkyl or phenyl X I or BR The fused pyrimidines of the general formula (52), wherein R1, X < Q, V, R8, D, E, m and n are as defined in formula (I) and Fr is selected from alkenyl, alkynyl, aryl and heterocyc, and can be prepared according to the method of Scheme 21. The fused pyrimidines of the General formula (50) can be treated with N-bromosuccinimide (NBS) in a solvent such as methylene chloride to provide bromides of the general formula (51). The bromides of the general formula (51) can be treated with a palladium (O) catalyst such as tetrakis (triphenylphosphine) palladium (0), an organoborane reagent and a hase such as cesium fluoride or potassium carbonate ba} or Suzuki conditions that are known to those skilled in the art (Syn.Comm. 11, 1981, 51 a; JOG 49; 1984, 5237; Tet.Lett.:26, 1985, 5997; Tet.Lett.:28, 1987, 5093 and Tet., Lett., 28, 1987, 5097) to provide fused pyrimidines of the general formula (52). The bromides of the general formula (51) can also be treated with a palladium (O) catalyst such as tetrakis (triphenylphosphine) palladium (0) and a tin reagent under Stille conditions which are known to those skilled in the art (JACS 101 , 1979, 4992) to provide fused pyrimidines of the general formula (52). The bromides of the general formula (51) can also be treated with a palladium (O) catalyst, an aryl halide (Br or I), or a heterocyclic halide (Br or I) and a base such as triethylamine under coupling conditions of biaryl or Heck conditions which are known to those skilled in the art to provide fused pyrimidines of the general formula (52). The compounds and processes of the present invention will be better understood by reference to the following examples, which are intended as an illustration of and not a limitation on the scope of the invention. - l ^ l ^ - ^ --- ^., .. ^^. ^ J ^^ ». * ^ ** ¿t2U A? Jp invention. In addition, all the credits herein are incorporated for reference.

Example 1 9- (4-bromo-3-fluorophenyl) -5.6.7.9-tetrahydr? Pyrazolof5.1-b1ainazolin-8 (4H > -one A solution of 1,3-cyclohexanedione (0.56 g, 5 mmol), 3 -bromo-4-fluorobenzaldehyde (1.01 g, 5 mmol), and 3-aminopyrazol (0.41 g, 5 mmol) in ethanol (5 mL) was heated to reflux for 24 hours after the reaction mixture was allowed to cool to room temperature, the volatiles were evaporated under reduced pressure and the resulting residue was chromatographed on silica gel, eluting with 5% ethanol / methylene chloride to give 0.9 g (49%) of the title compound.1H NMR (DMSO -d6) d 1.94 (m, 2H), 2.25 (m, 2H), 2.63 (m, 2H), 5.72 (d, 1 H), 6.19 (s, 1 H), 7.1 (m, 1 H), 7.23 (t, 1 H), 7.31 (d, 1 H), 7.4 (dd, 1 H), 10.55 (s, 1H); MS (ESI-) m / z: 362 (MH) "; Calculated Analysis for C1ßHi3FBrN3O: C, 53.06; H, 3.62; N, 1 1.60, Found: C, 52.92; H, 4.02; N, 11.48, Example 2 9- (3-bromo-4-fluorophenyl) -5,9-dihydro-4H-pyrazolofl .5-altiopiranof3.4- dlpírimÍdin-8 (7H) -one A solution of 3,5-thiopyradione (0.13 g, 1 mmol), prepared as described in (Fehnel, E.A., J. Amer. Chem. Soo, (1955), 77, 4241-4244), 3-bromo-4-fluorobenzaldehyde (0.203 g, 1 mmol), and 3- .- *, ...- ^ -.- -lAj ^ __ ^. ^. * »_ fc | to inopirazole < 0.O82 g, 1 mmol) were heated to reflux for 24 hours. After the reaction mixture was allowed to cool to room temperature, the volatiles were evaporated under reduced pressure and the resulting residue was chromatographed on silica gel, eluting with 5% ethanol / methylene chloride to provide 0.045 g (12 g). %) of the titular compound. mp 160-163 ° C; 1 H NMR (DMSO-d 6) d 3.1 ß (d, 1 H), 3.5 (d, 1 H), 3.6 (d, 1 H), 3.9 (d, 1 H), 5.8 (d, 1 H), 6.26 (s, 1 H), 7.13 (m, 1 H), 7.29 (t, 1 H), 7.38 (d, 1 H), 7.42 (dd, 1 H), 10.86 (s, 1 H); MS (ESI-) m / z: 380 (MH) "; Calculated Analysis for CsHuBrFNaOS ^ O ^ dCzHeO: C, 47.52; H, 3.22; N, 10.73 Found: C, 47.67; H, 2.89; N, 10.29. Example 3 9- (1-naphthyl) -5.6.7.9-tetrahydropyrazolof5.1 -blquinalozin-8 (4H) -one A solution of 1, 3-cyclohexanedione (0.1 1 g, 1 mmol), 1-naphthaldehyde (0.16 g, 1 mmol), and 3-aminopyrazol (0.11 g, 1.27 mmol) in ethanol (10 mL) were heated to 80 ° C in a flask of 20 mL sealed for 3 days. After the reaction mixture was allowed to cool to room temperature, the solvent was evaporated under reduced pressure and the resulting residue was chromatographed on silica gel, eluting with 5% ethanol / methylene chloride to give 0.14 g (44%) ) of the titular compound. 1 H NMR (DMSO-de) d 1.95 (m, 2 H), 2.21 (m, 2 H), 2.72 (m, 2 H), 5.62 (s, 1 H), 7.00 (d, 1 H), 7.15-7.95 (m, 7H), 8.61 (d, 1 H), 10.45 (s, 1 H); MS (APCI +) m / z: 316 (M + H) +; Analysis Calculated for C20H17N3O: C, 76.17; H, 5. 43; N, 13.32. Found: C, 75.99; H, 5.48; N, 13.27. j: Example 4 9- (2-naphthyl) -5,6,7,9-tetrahydropyrazolof5-1 blquinazolin-8 (4H) -one 2-Naphtaldehyde (0.16 g, 1 mmol) was treated according to the procedure described in Example 3 to provide 0.16 g (51%) of the title compound. 1 H NMR (DMSO-de) d 1.91 (m, 2 H), 2.25 (m, 2 H), 2.68 (m, 2 H), 5.74 (d, 1 H), 6.37 (s, 1 H), 7.20-7.90 (m , 8H), 10.50 (s, 1 H); MS (APCI +) m / z: 316 (M + H) +; Analysis Calculated for C20H17N3O: C, 76.17; H, 5.43; N, 13.32. Found: C, 75.97; H, 5.50; N, 13.35. Example 5 9- (3,4-dibromophenyl) -5,6,7,9-tetrahydropyrazolof5.1-blq? Inazolin-8 (4H) -one A solution of 1,3-cyclohexanedione (0.1 1 g, 1 mmol), 3.4 -dibromobenzaldehyde (0.26 g, 1 mmol) and 3-aminopyrazol (0.1 1 g, 1.27 mmol) in ethanol (10 mL) was heated at 80 ° C in a sealed 20 mL flask for 3 days. After the reaction mixture was allowed to cool to room temperature, the resulting solid was isolated by filtration and recrystallization of acetone to provide 0.23 g (56%) of the title compound. 1 H NMR (DMSO-de) d 1.91 (m, 2 H), 2.25 (m, 2 H), 2.64 (m, 2 H), 5.78 (d, 1 H), 6.19 (s, 1 H), 6.95-7.65 (m, 4H), 10.59 (s, 1 H); MS (APCI +) m / z: 423 (M + H) +; Analysis Calculated for Ci6H? 3Br2N3O: C, 45.42; H, 3.10; N, 9.93; Br, 37.77. Found: C, 45.17; H, 3.22; N, 9.88J Br, 37.59. Example 6 9- (3,4-dichlorophenyl) -5,6,7,9-tetrahydropyrazolof5,1-bilquinazolin-8 (4H) -one -, .A - ^., _. Ij_i ^ -a- l ^ - »Ai ---- i- 3,4-Dichlorobenzaldehyde (0.18 g, 1 mmol) was treated according to the procedure described in Example 3 to provide 0.18 g (55%) of the title compound. 1 H NMR (DMSO-de) d 1.95 (m, 2 H), 2.25 (m, 2 H), 2.64 (m, 2 H), 5.78 (d, 1 H), 6.20 (s, 1 H), 7.00-7.58 (m, 4H), 10.50 (s, 1 H); MS (APCI +) m / z: 334 (M + H) +; Analysis Calculated for C 16 H 13 Cl 2 N 3 O: C, 57.50; H, 3.92; N, 12.57; Cl, 21.22. Found: C, 57.29; H, 4.06; N, 12.53; Cl, 21.45. Example 7 9- (3-bromophenyl) -5,6,7,9-tetrahydropyrolof5-1 blquinazolin-8 (4H) -one 3-Bromobenzaldehyde (0.19 g, 1 mmol) was treated according to the procedure described in Example 3 to provide 0.21 g (60%) of the title compound. 1 H NMR (DMSO-de) d 1.93 (m, 2 H), 2.25 (m, 2 H), 2 65 (m, 2 H), 5.78 (d, 1 H), 6.20 (s, 1 H), 7.05-7.40 ( m, 5H), 10.55 (s, 1 H); MS (APCI +) m / z: 344 (M + H) +; Analysis Calculated for C 16 H 4BrN 3 O: C, 55.83; H, 4.10; N, 12.21; Br, 23.21. Found: C, 55.95; H, 4.30 N, 12.14; Br, 23.30. Example 8 9- (3-chlorophenyl) -5.6.7.9-tetrahydropyrazoloyl-5-blquinazolin-8 (4H) -one 3-Chlorobenzaldehyde (0.14 g, 1 mmol) was treated according to the procedure described in Example 3 to give 0.17 g (49%) of the titular compound. 1 H NMR (DMSO-d 6) d 1.95 (m, 2 H), 2.25 (m, 2 H), 2.65 (m, 2 H), 5.75 (d, 1 H), 6.20 (s, 1 H), 7.02-7.38 (m , 5H), 10.55 (s, 1 H); MS (APCI +) m / z: 300 (M + H) +; Analysis Calculated for C 16 H 14 CIN 3 O: C, 64.1 1; H, 4.71; N, 14.02; Cl, 1 1.83 Found: C, 63.81; H, 4.82; N, 14.30; Cl, 11.96.

, .. ^ -. ^ --- EiM- -fa -.- a - ^^^ - ^ Example 9 9-í4-chloro-3-trifluoromethyl) phenyl-5,6,7,9-tetrahydropyrazolof5.1-bladylzolin-8 ( 4H) -one 4-Chloro-3-trifluoromethylbenzaldehyde (0.21 g, 1 mmol) was treated according to the procedure described in Example 3 to provide 0.17 g (45%) of the title compound. 1 H NMR (DMSO-de) d 1.95 (m, 2 H), 2.25 (m, 2 H), 2.65 (m, 2 H), 5.78 (d, 1 H), 6.30 (S, 1 H), 7.30-7.61 (m, 4H), 10.59 (s, 1 H); MS (APCI +) m / z: 368 (M + H) +; Anal. Calc'd for C? 7H13CIF3N3O: C, 55.52; H, 3.56; Nr 11.43; Cl, 9.64; F, 15.50. Found: C, 55.50; H, 3.67; N, 1 1 .59; Cl, 9.68; F, 15.15. Example 10 9-l4-fluoro-3- (trifluoromethyl) phenyl-5,6,7,9-tetrahydropyrazoloyl-1, -blq? Inazotin-8 (4H) -one 3-Fluoro-3-trifluoromethylbenzaldehyde (0.19 g, 1 mmol) was treated with according to the procedure described in Example 3 to provide 0.16 g (46%) of the title compound. 1 H NMR (DMSO-dβ) d 1.95 (m, 2 H), 2.25 (m, 2 H), 2.65 (m, 2 H), 5.79 (d, 1 H), 6.29 (s, 1 H), 7.35-7.48 (m, 4H), 10.60 (s, 1 H); MS (APCI +) m / z: 352 (M + H) +; Analysis Calculated for C 17 H 13 F 4 N 3 O: C, 58.12; H, 3.73; N, 1 1 .96; F, 21 .63. Found: C, 54.49; H, 3.90; N, 1 1 .07; F, 22.79. Example 1 1 9-f3- (trifluoromethoxy enyl-5,6,7,9-tetrahydropyrazolof5-1blq? Inazolin-8 (4H-one 3-Trifluoromethoxybenzaldehyde (0.19 g, 1 mmol) was treated with -tM ** L.? kéit * éÁ-z-. - India tOiiuMiAil? iatM? ja? ** *** "dÜtr-do to the procedure described in Example 3 to provide 0.17 g (50%) of the title compound. 1 H NMR (DMSO-dβ) d 1.95 (m, 2 H), 2.25 (m, 2 H), 2.65 (m, 2 H), 5.78 (d, 1 H), 6.25 (s, 1 H), 7.05-7.40 (m, 5H), 10.05 (s, 1 H); MS (APCI +) m / z: 350 (M + H) +; Analysis Calculated for C 17 H 13 F 3 N 3 O: C, 58.45; H, 4.04; N, 12.03; F, 16.32. Found: C, 58.43; H, 3.93; N, 1 1 .90; F, 15.92. Example 12 9- (3-cyanophenyl) -5,6,7,9-tetrahydropyrazoloyl-5,1-bilquinazolin-8 (4H) -one 3-Cyanobenzaldehyde (0.13 g, 1 mmol) was treated according to the procedure described in Example 3 to provide 0.16. g (55%) of the title compound. 'H NMR (DMSO-de) d 1.95 (m, 2H), 2.25 (m, 2H), 2.65 (m, 2H), 5.78 (d, 1 H), 6.25 (s, 1 H), 7.30- 7.66 (m, 5H), 10.60 (s, 1 H); MS (APCI +) m / z: 291 (M + H) +; Analysis Calculated for C? 7H? 4N4O: C, 70.33; H, 4.86; N, 19.30. Found: C, 70.31; H, 4.95; N, 19.36. Example 1 3 9- (3-methylphenyl) -5.6.7.9-tetrahydropyrazolof5.1-bladzolin-8 (4H) -one 3-Methylbenzaldehyde (0.12 g, 1 mmol) was treated according to the procedure described in Example 3 to provide 0.17 g (60%) of the title compound. H NMR (DMSO-de) d 1.90 (m, 2H), 2.21 (s, 3H), 2.24 (, 2H), 2.61 (m, 2H), 5.70 (d, 1 H), 6.19 (s, 1 H), 6.85-7.30 (m, 5H), 10.40 (s, 1 H); μs (APCI +) m / z: 280 (M + H) +; Analysis Calculated for C? 7H.7N3O: C, 73.10; H, 6.13; N, 15.04. Found: C, 72.92; H, 6.17; N, 15.35. or 14 8- (3-bromo-4-fluorophenyl) -5,8-dihydro-4H. 7H-furo, 3,4 ~ dlpirazolof1.5- alpirimidin-7-one A solution of methyl 4-chloroacetate (0.108 g, 1 mmol), 3-bromo-4-fluorobenzaldehyde (0.203 g, 1 mmol) and 3- aminopyrazol (0.082 g, 1 mmol) in ethanol (2 mL) was heated to reflux for 24 hours. After the reaction mixture was allowed to cool to room temperature, the volatiles were evaporated under reduced pressure and the resulting residue was chromatographed on silica gel, eluting with 5% ethanol / methylene chloride to provide 0.045 g (12%) ) of the titular compound. 1 H NMR (DMSO-de) d 5. 02 (q, 2 H), 5.85 (d, 1 H), 6.3 (s, 1 H), 7.25 (m, 1 H), 7.31 (t, 1 H), 7.39 (d, 1 H), 7.52 (dd, 1 H), 11.08 (s, 1 H); MS (ESI +) m / z: 352 (M + H) +; Analysis Calculated for C14H9BrFN3O2: C, 48.02; H, 2.59; N, 12.00 Found: C, 48.40; H, 2.87; N, 1 1.65. Example 15 (-) 9- (3-bromo-4-fluorophenyl) -5.6.7.9-tetrahydropyrazolof5.1-blquinazolin-8 (4H.-one The product of Example 1 (0.6 g) was chromatographed on a Prep Model column. Chiracel OD 4.6 x 250, eluting with 10% ethanol / hexane to provide 0.259 g of the title compound (retention time 12.0 min). [Al23D-35.85 ° (DMSO); 1H NMR (DMSO-d6) d 1.93 (m , 2H), 2.25 (m, 2H), 2. 62 (m, 2H), 5.72 (d, 1 H), 6.19 (s, 1H), 7.1 (m, 1H), 7.22 (t, 1 H), 7.31 (d, 1 H), 7.4 (dd, 1 H), 10.55 (s, 1 H); MS (ESI +) m / z: 362 (M + H) +; Analysis Calculated for C16H13N3BrFO: C, 53.06; H, 3.62; N, 1 1 .60. Found: C, 52.82; H, 3.77; N, 11.28. Example 16 (+) 9- (3-bromo-4-fluorophenin-5,6,7,9-tetrahydropyrazolof5.1-bladylzolin-8 (4H) -one The product of Example 1 (0.6 g) was chromatographed on a Model Prep column. Chiracel OD 4.6 x 250, eluting with 10% ethanol / hexane to provide 0.252 g of the title compound (retention time 14.639 min.) [AJ230 + 35.88 ° (DMSO); 1 H NMR (DMSO-de) d 1.92 (m, 2H), 2.25 (m, 2 H), 22.5 (m, 2H), 5.72 (d, 1 H), 6.19 (s, 1 H), 7.1 (m, 1 H), 7.23 (t, 1) H), 7.32 (d, 1 H), 7.4 (dd, 1 H), 10.55 (s, 1 H), MS (ESI +) m / z: 362 (M + H) +, Analysis Calculated for C? 6H? 3N3BrFO: C, 53.06; H, 3.62; N, 1 1, 60. Found: C, 52.81; H, 3.72, N, 1, .54, Example 17, 9- (3-bromo-4-fluorophenyl) -5, 6.7.9-tetrahydro-4H-pyrazolofl, 5-a-thiopyran, 3,2-dlpyrimidine 8.8-dioxide A solution of tetrahydrothiopyran-3-one-1,1-dioxide (0.74 g, 5 mmol), 3-bromo-4- Fluorobenzaldehyde (1.01 g, 5 mmol), and 3-aminopyrazol (0.41 g, 5 mmol) in ethanol (5 mL) was heated to reflux for 24 hours.

After the reaction mixture was allowed to cool to room temperature, the solid that precipitated was filtered, washed with ethanol, and dried to provide the title compound. 1 H NMR (DMSO-d 6) d 2.23 (m, 2 H), 2.63 (m, 2 H), 3.26 (m, 1 H), 3.42 (m, 1 H), 5.63 (d, 1 H), 6.32 (s, 1 H), 7.22 (m, 1 H), 7.3 (d, 1 H), 7.31 (t, 1 H), 7.48 (dd, 1H), 10.17 (s, 1H); MS (ESlf) m / z: 400 (M + H) +; Calculated Analysis »for C15H13N3BrFO2S: C, 45.11; H, 3.26; N, 10.53. Found: C, 45.13; H, 3-50; N, 10.40. Examples 18-53 were prepared according to General Procedure A General Procedure A 1, 3-Cyclohexanedione or 4,4-dimethyl-1,3-cyclohexanedione (0.2-0.5 mmol), an aldehyde (0.2-0.5 mmol) and Amine-pyrozole (0.2-0.5 mmol) in absolute ethanol (2 mL) were combined in a 1: 1: 1 molar ratio and heated at 80 ° C for 3 days. The mixture was allowed to cool to room temperature and the solvent was removed by evaporation under reduced pressure. The crude products were purified by any flash column chromatography (5% MeOH in methylene chloride as eluent), recrystallization from ethanol or prepared TLC (5% MeOH in methylene chloride as solvent) Example 18 0"f3- chloro-4-hydroxyphenyl) -5.6.7.9-tetráhidropirazoloí5.1-biququiñazolin-8 (4H) -one 1,3-Cyclohexanedione, 3-chloro-4-hydroxybenzaldehyde and 3-aminopyrazol were processed as described in General Procedure A to give the title compound: 1 H NMR (DMSO-de) d 1 95 (m, 2 H), 2.25 (m, 2 H), 2.65 (m, 2 H), 5.70 (s, 1 H), 6.07 (s, 1 H ), 6.80-6.90 (m, 2H), 7.00 (s, 1 H), 7.24 (s, 1 H), MS (APCI +) m / z: 316 (M + H) +, Example 19 3-bromo-9 - (3-bromo-4-fluorophenyl) -5,6,7,9-tetrahydropylaZloI5,1-b.-aminotin-8 (4H) -one The product of Exercise 1 and N-bromosuccinimide were procured as described in Example 48 to give the title compound: 1H-MR (DMSO-d6) d 1.94 (m, 2H), 2.25 (m, 2H), 2.70 (m, 2H), 6.19 (s, 2H), 7.12 ( m, 1 H), 7.25 (m, 1 H), 7.44 (s, 1 H), 7.46 (m, 1 H); MS (APCI +) m / z: 439 (M + H) +. Example 20 9t (3-Chloro-4-fluorophenyl) -5,6,7,9-tetrahydropyrazole? F5.1-bilazolin-8 (4H) -one 1,3-Cyclohexanedione, 3-chloro-4-fluorobenzatdehyde and 3-aminopiperazole were processed as described in General Procedure A to provide the title compound. ^ NMR (DMSO-de) d 10.54 (s, 1 H), 7.24-7.33 (m, 3H), 7.04-7.10 (m, 1 H), 6.19 (S, 1 H), 5.73 (d, 1 H) , 2.55-2.71 (m, 2H), 2.18-2.33 (m, 2H), 1.82-2.01 (, 2H); MS (APCI +) m / z: 318 (M + H) +. Example 21 9- (3,4-difluorophenit) -5.6.7.9-tetrahydropyrazolo 5, 1-b1quinazotin-8 (4H) -one 1,3-Cyclohexanedione, 3,4-difluorobenzaldehyde and 3-aminopyrazol were processed as described in General Procedure A to provide the title compound. 1 H NMR (DMSO-de) d 10.53 (s, 1 H), 7.25-7.33 (m, H), 7.08-7.17 (m, 1 H), 6.19 (s, 1 H), 5.72 (d, 1 H ), 2.55-2.71 (m, 2H), 2.18-2.2.34 (m, 2H), 1.82-2.01 (m, 2H); MS (APCI +) m / z: 302 (M + H) *. Example 22 9- (4-fluorophenyl, 5,6,7,9-tetrahydropyrazolof5.1-bladzolin-8 (4H) -one 1,3-C.). Clohexanodtonai-fluorobenzaldehyde and 3-amynopyrazol were processed as described in the General Procedure A to provide the title compound. 'H NMR (DMSO-d6) d 10.46 (s, 1 H), 7.39 (d, 1 H), 7.1 1 -7.16 (m, 2H), 7.01 t 7.08 (m, 2H) , 6.19 (s, 1 H), 5.70 (d, 1 H), 2.60-2.69 (m, 2H), 2.18-2.34 (m, 2H), 1 .82-2.01 (m, 2H); MS (APCI +) m / z: 284 (M + H) +. Example 23 9-r4- (trifluoromethyl) phenin-5,6,7,9-tetrahydropyrazolof 5,1-bladzolin-8 (4H) -one 1,3-Cyclohexanedione, 4-trifluoromethylbenzaldehyde and 3-aminopyrazol were processed as described in General Procedure A to provide the title compound.1H NMR (DMSO-de) d 10.56 (s, 1 H), 7.61 (d, 2H), 7.32 (d, 2H), 6.26 (s, 1 H), 5.73 (d, 1 H), 2.58-2.69 (m, 2H), 2.19-2.32 (m, 2H); MS (APCI +) m / z: 334 (M + H) +. Example 24 9- (4-cyanophenyl) -5,6,7,9-tetrahydropyrazolof5, 1 -b] quinazolin-8 (4H) -one 1,3-Cyclohexanod ione, 4-cyanobenzaldehyde and 3-aminopyrazol were processed as described in General Procedure A to provide the title compound. 1 H NMR (DMSO-d 6) d 10.60 (s, 1 H), 7.71 (d, 2 H), 7.23 (d, 2 H), 6.25 (S, H), 5.74 (D, 1 H), 2.55-2.69 ( M, 2H), 2.18-2.30 (M, 2H), 1.80-2.00 (M, 2H); MS (APCI +) m / z: 291 (M + H) +. Example 25 > 9- (4-Chloro-3-nitrophenyl) -5,6,7,9-tetrahydropyrazolof5.1-β -quinazolin-8 (4H) - Figure US0720000003121-C 1-4-Cyclohexanedione, 4-chloro-3-nitrobenzatdehyde and 3-aminopyrazole were processed as described in General Procedure A to provide the title compound. 1 H NMR (DMSO-de) d 1.95 (m, 2 H), 2.25 (m, 2 H), 2 62 (m, 2 H), 5.79 (d, 1 H), 6.25 (s, 1 H), 7.20 (m, 2H), 7.6 (m, 1 H), 7.8 (m, 1 H), 10.6 (s, 1 H). Example 26 9- (4-chloro-3-fluorophenyl) -7,7-dimethyl-5,6,7,9-tetrahydropyrazole-5,1-blquinazolin-8 (4H) -one 4,4-Dimetiyl-1,3-cyclohexanedione, 4-chloro- 3-Fluorobenzaldehyde and 3-aminopyrazol were processed as described in General Procedure A to provide the title compound. 1 H NMR (DMSO-de) d 10.45 (s, 1 H), 7.45 (t, 1 H), 7.31 (d, 1 H), 7.1 1 (dd, 1 H), 9.95 (dd, 1 H), 6.15 (s, 1 H), 5.71 (d, 1 H), 2.61 -2.70 (m, 2H), 1.80 (t, 2H), 1.02 (s, 3H), 0.94 (s, 3H); MS (APCI +) m / z: 346 (M + H) +. Example 27 9- (3-bromo-4-fluorophenyl) -7,7-dimethyl-5,6,7,9-tetrahydropyrazolor-5,1-blquinazolin-8 (4H) -one 4,4-Dimethyl-1,3-cyclohexanedione, 3- Bromo-4-fluojobenzaldehyde and 3-aminopyrazol were processed as described in General Procedure A to provide the title compound. 1 H NMR (DMSO-de) d 10.48 (s, 1 H), 7.40 (dd, 1 H), 7.30 (d, 1 H), 7.24 (t, 1 H), 7.10-7.16 (m, 1 H), 6.14 (s, 1 H), 5.70 (d, 1 H), 2.62-2.71 (m, 2H) 1, 80 (t, 2H), 1.02 (s, 3H), 0.94 (s, 3H); MS (APCI +) m / z: 391 (M + H) +.

It eluted 28 9-f4-fluoro-3-trifluoromethyl) p6nip-7.7-dimet8l-5,6,7,9-tetrahydropyrazolof5-blquinazolin-8 (4H) -one 4,4-Dimethyl-1,3-cyclohexanedione, 4-fluoro-3- trifluoromethylbenzaldehyde and 3-aminopyrazol were processed as described in General Procedure A to provide the title compound. 1 H NMR (DMSO-de) d 10.53 (s, 1 H), 7.35-7.52 (m, 3 H), 7.32 (d, 1 H), 6.24 (S, 1 H), 5.72 (d, 1 H), 2.63 -2.71 (m, 2H), 1.81 (t, 2H), 1.02 (ß, 1H), 0.93 (s, 1 H). Example 29 9- (3,4-dichlorophenyl) -7,7-dimethyl-5,6,7,9-tetrahydropyrazolof5.1-blquinazolin-8 (4H) -one 4,4-Dimethyl-1,3-cyclohexanedione, 3,4-dichlorobenzaldehyde and 3- aminopyrazol were processed as described in General Procedure A to provide the title compound. 1 H NMR (DMSO-de) d 10.49 (s, 1 H), 7.50 (d, 1 H), 7.31 -7.35 (m, 2H), 7.07 (dd, 1 H), 6.14 (s, 1H), 5.71 ( d, 1 H), 2.62-2.75 (m, 2H), 1.80 (t, 2H), 1.02 (s, 3H), 0.94 (s, 3H); MS (APCI +) m / z 363 (M + H) +. EXAMPLE 30 9 4-Chloro-3-nStrQfenin-7.7-dimethyl-5,6,7,9-tetrahydropyrazolor-5-blquinazolin-8 (4H) -one 4,4-Dimethyl-1,3-cyclohexanedinone, 4-chloro 3-Nitrobenzaldehyde and 3-aminopyrazol were processed as described in General Procedure A to provide the title compound. 1W NMR (DMSO-de) d 10.55 (s, 1 H), 7.81 (d, 1H), 7.65 (d, 1 H), 7.45 (dd, 1H), 7.33 (d, 1H), 6.24 (s, 1 H), 5.73 (d, 1 H), 2.61-2.73 (m, 2H), 1 P82 (t, 2H >, 1.02 (s, 3H), 0.94 (s, 3H); (APCI +) m / z: 373 (M + H) +. Example 31 9 ^ 3,4-dibromophenyl) -7,7-dimethyl-5,6,7,9-tetrahydropyrazolof 5,1-blcazolin-8 (4H) -one 4,4-Dimethyl-1,3-cyclohexanedione, 3 , 4-dibromobenzaldehyde and 3-aminopyrazol were processed as described in General Procedure A to provide the title compound. 1 H NMR (DMSO-de) d 10.51 (s, 1 H), 7.62 (d, 1 H). 7.47 (d, 1 H), 7.31 (d, 1 H), 7.02 (dd, 1 H), 6.12 (s, 1 H), 5.71 (d, 1 H), 2.59-2.74 (m, 2H), 1.80 (t, 2H), 1.02 (s, 3H), 0.94 (s, 3H); MS (APCI +) m / z: 452 (M + H) +. Example 32 9-f3-fluoro-4- (trifl? Orometnfenill-7.7-dimethyl-5.6.7.9-tetrahydropyrazolof5.1-blquinazolin-8 (4H) -one 4,4-Dimethyl-1,3-cyclohexanedione, 3 Fluoro-4-trifluoromethylbenzaldehyde and 3-aminopyrazol were processed as described in General Procedure A to provide the title compound. * H NMR (DMSO-de) d 10.54 (s, 1 H), 7.66 (t, 1 H) , 7.33 (d, 1 H), 7.22 (d, 1 H), 7.13 (d, 1 H), 6.23 (s, 1 H), 5.74 (d, 1 H), 2.62-2.72 (m, 2H), 1.81 (t, 2H), 1.03 (s, 3H), 0.94 (s, 3H); MS (APCI +) m / z: 380 (M + H) +. Example 33 7.7-dimethyl-9- (3-nitrophenyl) -5.6.7.9-tetrahydropyrazolor5.1-bilquinazolin-8 (4H) -one 4,4-Dimethyl-1,3-cyclohexanedione, 3-nitrobenzaldehyde and 3-aminopyrazol were processed as described in General Procedure A to provide the title compound. 1 H NMR (DMSO-de) d 10.44 (s, 1 H), 8.03-8.08 (m, 1 H), 7.91-7.94 (m, 1 H), 7.57-7.59 (m, 2H), 7.33 (d, 1 H), 6.30 (s, 1 H), 5.74 (d, 1 H), 2.62-2.72 (m, 2H), 1.75-1.84 (m, 2H), 1.03 (s, 3H), 0.93 (s, 3H); MS (APCI +) m / z: 339 (M + H)? Example 34 9- (3-cyanophenyl) -7,7-dimethyl-5,6,7,9-tetrahydropyrazolof5.1-blquinazolin-8 (4H) -one 4,4-Dimethyl -1,3-cyclohexanedione, 3-cyanobenzathdehyde and 3-aminopyrazol were processed as described in General Procedure A to provide the title compound. 'H NMR (DMSO-de) d 10.47 (s, 1 H), 7.64-7.69 (m, 1 H), 7.54-7.57 (m, 1 H), 7.44-7.48 (m, 2H), 7.31 (d, 1 H), 6.20 (s, 1 H), 5.72 (d, 1 H), 2.59-2.76 (m, 2 H), 1.81 (t, 2 H), 1.02 (s, 3 H), 0.92 (s, 3 H); MS (APCI +) m / z: 319 (M + H)? Example 35 7.7-dimethy-9- (5-nitro-3-thienyl) -5.6.7.9-tetrahydropyrazolof5.1-blq? Inazolin-8 (4H) - 4,4-Dimethyl-1,3-cyclohexanedione, 4-formyl-2-nitrothiophene and 3-aminopyrazole were processed as described in General Procedure A to provide the title compound. 1 H NMR (DMSO-de) d 10.55 (s, 1 H), 7.68 (d, 1 H), 7.62 (d, 1 H), 6.24 (s, 1 H), 5.72 (d, 1 H), 2.62- 2.70 (m, 2H), 1.79-1.87 (m, 2H), 1.04 (s, 3H), 1.01 (s, 3H); MS (APCI +) m / z: 345 (M + H) +.

Example 36 9- (5-bromo-2-hydroxyphenyl) -7,7-dimethyl-5,6,7,9-tetrahydropyrazolof5.1-blquinazolin-8 (4H) -one 4,4-Dimethyl-1,3-cyclohexanedione, 5-Bromo-2-hydroxybenzaldehyde and 3-aminopyrazol were processed as described in General Procedure A to provide the title compound. 1 H NMR (DMSO-de) d 10.44 (s, 1 H), 9.86 (s, 1 H), 7.26 (d, 1 H), 7.1 3 (dd, 1 H), 6.93 (d, 1 H), 6.66 (d, 1 H), 6.30 (s, 1 H), 5.66 (d, 1 H) (2.60-2.69 (m, 2H), 1 .78-1.85 (m, 2H), 1 .02 (s) , 3H), 0.95 (s, 3H), MS (APCI +) m / ¿: 389 (M + H) +, Example 37 9- (5-chloro-2-hydroxyphenyl) -7,7-dimethyl-5,6.7 .9-tetrahydropyrazolof5.1-blq-inazolin-8 (4H) -one 4,4-Dimethyl-1,3-cyclohexanedione, 5-chloro-2-hydroxybenzaldehyde and 3-aminopyrazol were processed as described in General Procedure A to give the title compound: 1 H NMR (DMSO-dβ) d 10.45 (s, 1 H), 9.84 (s, 1 H), 7.26 (d, 1 H), 7.02 (dd, 1 H), 6.79 (d, 1 H), 6-.71 (d, 1 H), 6.31 (s, 1 H), 5.66 (d, 1 H), 2.60-2.70 (m, 2H), 1 .76-1 .84 (m, 2H), 1 .02 (s, 3H), 0.95 (s, 3H); MS (APCI +) m / z: 344 (M + H) +. Example 38 9- (2-hydroxy-5-nitrophenyl) -7.7 -dimethyl-5.6.7.9-tetrahydropyrazolof5.1-blquinazolin-8 (4H) -one 4,4-Dimethyl-1,3-cyclohexanedione, 2-hydroxy-5-nitrobenzaldehyde and 3-aminopyrazol were processed as described e in General Procedure A to provide the titular compound. 1H NMR (DMSO-de)? 1 1 .13 (s, 1 H), 10.46 (s, 1 H), 7.95 (dd, 1 H), 7.87 (d, 1 H), 7.25 (d, 1 H), 6.86 (d, 1 H) , 6.38 (s, 1 H), 5.66 (d, 1 H), 2.64-2.68 (m, 2H> »1.77-1.84 (m, 2H), 1.02 (s, 3H), 0.91 (s, 3H); MS (APCI +) m / z: 355 (M + H) + Example 39 9- (3,5-dibromo-2-hydroxyphenyl) -7,7-dithmet-5,6,7,9-tetrahydropyrazotol 5,1-blquinazolin-8 (4H) 4,4-Dimethyl-1, 3-cyclohexanedione, 3,5-dibromo-2-hydroxybenzaldehyde and 3-aminopyrazol were processed as described in General Procedure A to provide the title compound.1H NMR (DMSO-de) d 10.79 (s, 1 H), 7.59 (d, 1 H), 7.42 (d, 1 H), 6.65 (d, 1 H), 6.42 (s, 1 H), 5.81 (d, 1 H), 2.60 -2.76 (m, 2H), 1.82 (t, 2H), 1.06 (s, 3H), 1.02 (s, 3H), MS (APCI +) m / z: 468 (M + H) +, Example 40 9- ( 3-bromo-5-chloro-2-hydroxyphenyl) -7,7-dimethyl-5,6,7,9-tetrahydropyrazolor-5-blquinazolin-8 (4H) rna-4,4-dimethyl-1,3-cyclohexanedione, 3-bromo- 5-chloro > -2-hydroxybenzaldehyde and 3-aminopyrazol were processed as described in the Gen Process A to provide the title compound. 'H NMR (DMSO-d6) d 1.02 (s, 3H), 1.06 (s, 3H), 1.84 (t, 2H), 2.62-2.75 (m, 2H), 5.79 (d, 1H), 6.43 (s, 1 H), 6.54 (d, 1 H), 7.40 (d, 1 H), 7.48 (d, 1 H), 10 8 (s, 1 H); MS (APCI +) m / z: 423 (M + H) +. Example 41 9- (3,5-dichloro-2-hydraxyphenyl) -7,7-dimethyl-5,6,7,9-tetrahydropyrazolof 5J-ichlquinazolin-8 (4H) -one 4,4-Dimethyl-1,3-cyclohexanedione, 3,5-dichloro-2-hydroxybenzaldehyde and 3-aminopyrazol were processed as described in General Procedure A to provide the title compound. 1 H NMR (DMSO-d €) d 7.34-7.38 (m, 1 H), 6.58 (d, 1 H), 6.43 (s, 1 H), 5.77 (d, 1 O), 2.62-2.81 (m, 2 H) , 1.83 (t, 2H), 1, 05 (s, 3H), 1.00 (s, 3H); MS (APCI +) m / z: 379 (M + H) +. Example 42 7.7-dimethyl-9- (3,4,5-triftuorophenyl) -5.6.7.9-tetrahydropyrazoloyl-5-blquinazolin-8 (4H) -one 4,4-Dimethyl-1,3-cyclohexanedione, 3,4,5- trifluorobenzaldehyde and 3-amynopyrazol were processed as described in General Procedure A to provide the title compound. 1 H NMR (DMS0-d6) d 10.51 (s, 1 H), 7.33 (d, 1 H), 7.00-7.07 (m, 2 H), 6.15 (S, 1 H), 5.71 (d, 1 H), 2.58 -2.77 (m, 2H), 1.82 (t, 2H), 1.02 (s, 3H), 0.96 (s, 3H); MS (APCI +) m / z: 347 (M + H) +. Example 43 9- (3,4-dictorophen?) -3- (3-fluoropheni0-5.6,7,9-tetrahydropyrazolo, 5.1-blq? Inazolin-8 (4H) -one The product of Example 48 (0.041 g, 0.1 mmol ) in dimethoxyethane / methanol (1.5 mL) was treated with 3-fluorophenylboronic acid (0.13 mmol), cesium fluoride (0.2 mmol) and tetrakis (triphenylfine) palladium (0) (0.008 g, 0.006 mmol). 100 ° C for 48 hours and then allowed to cool to room temperature.The reaction mixture was filtered through Celite and The ether was concentrated under reduced pressure. The residue was purified by HPLC chromatography. 1 H NMR (DMSO-d 6) d 1.95 (m, 2 H), 2.28 (m, 2 H), 2.75 (m, 2 H), 6.2 (s, 1 H), 7.10 (m, 2 H), 7.3 (m, 1 H ), 7.4 (m, 3H), 7.65 (s, 1 H), 10.5 (s, 1 H). Example 44 3- (3-chlorophenone) -9- (3,4-dichlorophenyl) -5,6,7,9-tetrahydropyrazole-5,1-blquinazolin-8 (4H) -one The product of Example 48 and 3-chlorophenylboronic acid were processed as described in Example 43 to provide the title compound. * H NMR (DMSO-de) d 1.95 (m, 2H), 2.25 (m, 2H), 2.74 (m, 2H), 6.20 (s, 1 H), 7.10 (m, 1 H), 7.30 (m, 1 H), 7.45-7.55 (m, 4H), 7.65 (s, 1 H); MS (APCI +) m / z: 444 (M + H) +. Example 45 3- (4-carb? Xyphenyl) -9- (3,4-dichlorophenyl) -5? 6,7,9-tetrahydropyrazolof5.1-b1q? -nazolin-8 (4H) -one The product of Example 48 and acid 4 -carboxifeni | boronic were processed as described in Example 43 to provide the title compound. 1 H NMR (DMSO-de) d 1.95 (m, 2 H), 2.25 (m, 2 H), 2.74 (m, 2 H), 6.22 (s, 1 H), 7.12 (m, 1 H), 7.44 (s, 1 H ), 7.54 (m, 1 H), 7.62 (d, J = 8, 2H), 7.77 (m, 1H), 7.98 (d, J = 8, 2H); MS (APCI +) m / z: 454 (M + H) +. Example 46 9- (3,4-dichlorophenyl) -3- (2-thienyl) -5,6,7,9-tetrahydropyrazolo-1,5-blquinazolin-8 (4H) -one The product of Example 48 and 2-tributylstannylthiophene were processed as described in Example 51 to provide the title compound as a light yellow solid. HH NMR (DMSO-de) d 1.95 (m, 2H), 2.27 (m, 2H), 2.75 (m, 2H), 6.22 (s, 1 H), 7.1 1 (d, 1 H), 7.14 (dd, 1 H), 7.22 (d, 1 H), 7-45 (s, 1 H), 7.48 (d, 1 H), 7.52 (s, 1 H), 7.53 (d, 1 H), 10.30 (s, 1 HOUR); MS (ES | +) m / z: 416 (M + H); MS (ESI-) m / z 414 (M-H) 'Anal. Caled, for C20H15C12N3OS: C, 57.70; H, 3.63; N, 10.09. Found: 0.57.53; H, 3.46; N, 9.76. Example 47 9- (3,4-dichlorophenyl) -3-l2-arifluoromethyl) phenyl-5,6,7,9-tetrahydropyrazolof5.1- blquinazolin-8 (4H) -one The product of Example 48 and 2- (trifluoromethyl) phenylboronic acid were processed as is described in Example 43 to provide the title compound. 1 H NMR (DMSO-de) d 1.95 (m, 2 H), 2.25 (m, 2 H), 2.74 (m, 2 H), 6.28 (s, 1 H), 7.10 (m, 1 H), 7.30 (m, 1 H), 7.40-7.95 (m, 5H), 10.22 (s, 1 H); MS (APC1 +) m / z: 478 (M + H) +. Example 48 3-bromo-9- (3,4-dichlorophenyl) -5,6,7,9-tetrahydropyrazolof5.1-blq? Inazolin-8 (4H) -one The product of Example 6 (0.52 g, 1.56 mmol) in dichloromethane was treated with N-bromosuccinimide (0.28 mg, 1.56 mmol) and allowed to stir at room temperature overnight. The mixture was filtered and the filter bark was washed with CH2Cl1 to give the title compound (0.54 g) as a solid. - ^ - ....- ^ -.-. s? -á- ^ 1 H NMR (DMSO-d6) d 1.94 (m * 9 &), 2.24 < m, 2H), 2.77 (m, 2H), 6.20 (s, 1 H), 7.06 (d, J = * 8, 1 H), 7.40 (s,, 7.44 (s, 1 H), 7.55 (d, J = 8, 1 H); MS (APCI +) m / z: 411 (M + H) +. Example 49 3-bromo-9- (3,4-dichlorophenit) -5.6.7.9 ^ ahydropyrazolof5.1-blquinazolin-8 (4H) -one The product of Example 48 was subjected to chiral column chromatography (Wheiko column, 2.11 cm x 25 cm, eluying cop 80:20 hexane: (CH 3 OH: CH 2 Cl22: 1)) to provide two enantiomers. Faster movement, retention time 25 minutes, was isolated as an off white solid.1H NMR (DMSO-de) d 1.94 (m, 2H), 2.26 (m, 2H), 2.72 (m, 2H), 6.18 (s) , ÍH.}., 7.07 (d, 1H), 7.42 (s, 1 H), 7.48 (s, 1 H), 7.52 (d, 1 H), 10.57 (s, 1 H); MS (ESI +) m / z: 412 (M + H); MS (ESI-) m / z 410 (MH) "Anal Caled, for C1eH .2BrC.2N3O: C, 46.52; H, 2.93; N, 10.17. Found: C, 46.49; H, 3.11; N, 9.92, Example 50 3> -bromo-9- (3,4-dichlorophenyl) -5,6,7,9-tetrahydropyrazolor-5,1-b -quinazolin-8 (4H) -one The product of Example 48 submitted to chiral column chromatography (Wheiko column, 2.1 1 cm x 25 cm, eluting with 80:20 hexane: (CH3OH: CH2Cl22: 1)) to provide two enantiomers. The fastest moving enantiomer, retention time 31.2 minutes, was isolated as an off white solid. 1 H NMR (DMSO-de) d 1.94 (m, 2H), 2.26 (m, 2H), 2.72 (m, 2H), 6.18 (s, - hí. 7.07 (d, 1 H), 7.42 (s, 1H), 7.48 (s, 1 H), 7.52 (d, 1 H), 10.57 (s, 1 || MS (ESI +) m / z: 412 (M + H); MS (ESI-) m / z 410 (MH) "Anal.Called, for CteH12BrCl2N3O: C, 46.52; H, 2.93; N, 10.17. Found: C, 46.78; H, 2.92; N, 10.02.Example 51 9- (3,4-dichlorophenyl) -3-2-thienin- ^. 6.7.9-tetrahydropyrazolor-5-blquinazolin-8 (4H) -one The product of Example 49 (0.2 g, 0.5 mmot) in DMF (4 mL) was treated with tetrakis (triphenylphosphine) palladium (0) (0.11 g) and 2-tributylstannylthiophene (0.41 g, 1.1 mmol) The resulting mixture was heated at 110 ° C for 20 hours.

After cooling to room temperature, the mixture was filtered through Celite and the filtrate was diluted with ethyl acetate. The diluted filtrate was washed with a salt water solution, dried over MgSO 4 and concentrated under reduced pressure. The residue was chromatographed on silica gel eluting with hexane: ethyl acetate (1: 1) to yield 0.14 g of the Titrant compound as a light yellow solid. 1 H NMR (DMSO-de) d 1.95 (m, 2 H), 2.27 (m, 2 H), 2.75 (m, 2 H), 6.22 (s, 1 H), 7.11 (d, 1 H), 7.14 (dd, 1 H) ), 7.22 (d, 1 H), 7.45 (s, 1 H), 7.48 (d, 1 H), 7.52 (s, 1 H), 7.53 (d, 1 H), 10.30 (s, 1 H); MS (ESI +) m / z: 416 (M + H); MS (ESJ-) m / z 414 (MH) "Anal.Called, for C20H1.5CI2N3OS: C, 57.70; H, 3.63; N, 10.09.Found: C, 57.80; H, 3.70; N, 9.86.Emple 52 QO ^ -D-Dichloropheni-S-thienyl-4-tetrahydropyrazole.l-blquinazolin-8 (4H) -one The product of Example 50 is processed as described in iplo 51 to give the title compound as a solid light yellow. 'H NMR (DMSO-de) d 1.95 (m, 2H), 2.27 (m, 2H), 2.75 (m, 2H), 6.22 (s, 1 H), 7.11 (d, 1 H), 7.14 (dd, 1 H), 7.22 (d, 1 H), 7.45 (s, 1 H), 7.48 (d, 1 H), 7.52 (s, 1 H), 7.53 (d, 1 H), 10.30 (s) , 1 H); MS (ESI +) m / z: 416 (M + H); MS (ESI-) m / Z 414 (MH) - Anal. Caled, for C20H? 5C (2N3OS: C, 57.70; H, 3.63; N, 10.09, Found: C, 57.78; H, 3.60; N, 9.85, Example 53, 9- (3,4-dichlorophenyl) -3- (2-furyl) -5.6.7.9-tetrahydropyrazotof5.1-blquinazotin-8 ( 4H) -one The product of Example 6, tetrakis (triphenylphosphite) palladium (0) (0.11 g) and 2-tributylstanilfuran were processed as described in Example 51 to provide the this holder. 1 H NMR (DMSO-dβ) d 1.95 (m, 2 H), 2.28 (m, 2 H), 2.78 (m, 2 H), 6.22 (s, 1 H), 6.57 (dd, 1 H), 6.64 (d, 1 H), 7.09 (d, 1 H), 7.42 (s, 1 H), 7.53 (d, 1 H), 7.64 (s, 1 H), 7.65 (d, 1 H), 9.97 (s, 1 H); MS (ESI +) m / z: 400 (M + H); MS (ESI-) m / z 398 (MH) "Anal.Called, for C2oH15CI2N3? 2: C, 60.02, H, 3.78; N, 10.50. Found: C, 60.06; H, 3.76; N, 10.33. Potassium Channel Opener Activity Membrane Hyperpolarization Assays Compounds were evaluated for potassium channel opener activity using guinea pig urinary vesicle cells (GPB). urinary vesicle, the urinary vesicles were removed from male guinea pigs (Hartley, Charles River, Witmington, MA) weighing 300-400 g and placed in a Krebs Ca2 + -free cold solution (Composition, mM: KCl, 2.7; KH2PO4, 1.5; NaCl, 75; Na2HPO4-7H2O, 8; MgSO, 2; glucose, 5; HEPES, 10; pH 7.4) Cells were isolated by automatic disassociation as described above with minor modifications in (Klockner, U. and Isenberg G., Pflugers Arch. 1985, 405, 329-339), incorporated herein by reference. The particle was cut into small pieces and incubated in 5 mL of the Kreb solution containing 1 mg / mL of collagenase (Sigma, St. Louis, MO) and 0.2 mg / mL of pronase (Calbiochem, La Jolla, CA) with shaking Continue in a cell incubator for 30 minutes. The mixture was centrifuged thus at 1300 x g for 5 minutes, and the pellets were resuspended in Dulbecco's PBS (GIBCO, Gaithersburg, MD) and re-centrifuged to remove the residual enzyme. The cell pellet was resuspended in 5 mL of growth medium (composition: Dulbecco's modified Eagle's medium supplemented with 10% fetal bovine serum, 100 units / mL of penicillin, 100 units / mL of streptomycin and 0.25 mg / mL of amphotericin B) and is further dissociated by pipetting the suspension through a flame-washed Pasteur pipette and passing it through a polypropylene mesh membrane (Spectrum, Houston, TX). The cell density was adjusted to 100,000 cells / mL by resuspension in growth medium. The cells were laminated in 96-well clear-bottom black sheets (Packard) for potential membrane studies at a density of 20,000 cells / well and maintained in a cell incubator with 90% air: 10% CO2 to the confluent . The cells were confirmed to be smooth muscle type by cytoskeletal staining using a smooth muscle actin to anti-human monoclonal mouse (Biomeda, Foster City, CA). Functional activity in the potassium channels was measured by evaluating changes in membrane potential using the bis-oxonol D¡BAC (4) 3 dye (Molecular Probes) in a 96-cell cell-based kinetic assay system, Fluorescent Image Sheet Reader (FLIPR) (KS Schroeder et al., J. Biomed. Screen, v. 1 pp. 75-81 (1996)), incorporated herein by reference. DiBAC (4) 3 is an anionic potentiometric test piece which is divided between cells and extracellular solution in a manner dependent on the membrane potential. With the increase of the membrane potential (for example, depolarization K +), the specimen is further divided into the cell; this is measured as an increase in fluorescence due to the interaction of the dye with lipids and intracellular proteins. Conversely, the reduction membrane potential (hyperpolarization by potassium channel openers) induces a reduction in fluorescence. The urinary guinea pig vesicle cells Confluent in 96-well light black cavity sheets were rinsed twice with 200 mL of assay buffer (composition, mM: HEPES, 20, NaCl, 120, KCl, 2, CaCl2, 2 MgCl2, 1, glucose, 5, pH 7.4 at 25 ° C) containing 5 μM of DiBAC (4) 3 and incubated with 180 mL of the regulator in a cell incubator for 30 minutes at 370C to ensure the distribution of red to along the membrane. After recording the baseline fluorescence for 5 minutes, the reference or the pru a compounds, prepared at 10 times the concentration in the assay regulator, were added directly to the cavities. Changes in fluorescence were monitored for an additional 25 minutes. The hyperpolarization responses were corrected for any background noise and normalized to the response observed with 10 μM of the reference compound P1075, N ^ cyano-N-ítert-penti - '- ^ pyridinium guanidine, which was assigned as 100% . P1075 is a potent opener of smooth muscle KATP channels (Quast ef al., Mol.Pharmacol., V. 43 pp. 474-481 (1993)) and was prepared using the procedures described in (Manley, J. Med. Chem. (1992) 35, 2327-2340), incorporated herein by reference. Routinely, five concentrations of P1075 or test compounds (logarithm or half logarithm dilutions) were evaluated and maximum permanent regime hyperpolarization values (expressed as% relative to P1075) are marked as a concentration function. The EC5o values (concentration that produces 50% of the maximum response for the test sample) were calculated by regression analysis using a sigmoidal equation of four parameters. The maximum response of each compound (expressed as% in relation to P1075) is reported. The concentrated solutions of the compounds were prepared in 100% DMSO and further dilutions were carried out in the assay regulator and added to a 96-well sheet. The hyperpolarization values of the maximum permanent regime (expressed as% in relation to P1075) and the EC5o values for the representative compounds of the present invention are shown in Table 1. Table 1 of Membrane (MHP) in Guinea Pig Vesicle Cells (GPB). »^ ..» ... and J- ^ M «ifii --_- Ji- < ... l..fete ilfe ^ ii Functional In Vitro Models The compounds of the present invention were evaluated for functional potassium channel opener activity using tissue bands obtained from Landrape pig vesicles. The Landrace pig vesicles were obtained from Landraoe female pigs of 9-30 kg. Landrace pigs were euthanized with an intraperitoneal injection of pentobarbital solution, Somlethal®, J.A .: Webster Inc., Sterling M.A. The whole vesicle was removed and placed immediately in Krebs Ringer's bicarbonate solution (composition, M: NaCl, 120, NaHCO3, 20, dextrose, 1.1, KCl, 4.7, CaCl2, 2.5, MgSO4, 1.5, KH2PO4) 1.2; K2EDTA, 0.01, was equilibrated with 5% CO2 / 95% O2pH 7.4 at 37 ° C). Propanolol (0.004 mM) was included in all trials to block β-adrenoceptors. The convex or trigonal parts were rejected. Bands of 3-5 ram of amplitude and 20 mm in length were prepared from the remaining tissue in a circular form. The mucosal layer was removed. One end was fixed to a stationary glass cylinder and the other to a Grass FT03 transducer at a basic preload of 1.0 gram. Two parallel plation electrodes were included in the stationary glass cylinder to provide field stimulation of 0.05 Hz, 0.5 thousandths of seconds at 20 volts. This low frequency stimulation produced a stable crisp response of 100-500 centigrams. The tissues were allowed to equilibrate for at least 60 minutes and primed with 80 mM KCl. A Control Concentration response curve (cumulative) was generated for each tissue using the P1075 potassium channel opener as the control fighter. P1075 stimulated crispation was completely eliminated in a dose-dependent manner over a concentration range of 10 9 to 10 ° M dissolved in DMSO using 1/2 increments of logarithm. After a 60 minute rinsing period, a concentration response curve (cumulative) was generated for the test fighter in the same way as that used for the control fighter P1075. The maximum efficacy of each of the compounds (expressed as% relative to P1075) is reported. The amount of agent necessary to originate 50% of the agent's maximum response (ED50) was calculated using "ALLFIT" (DeLean et al., Am. J. Physiol., 235, E97 (1980)), incorporated herein by reference. reference, and combatant powers were expressed as pD2 (the negative logarithm). The powers of Caliente were also expressed as an index in relation to PtOfd. The index was calculated by dividing the ED5o for P1075 by the ED50 for the test fighter in a given fabric. Each fabric was used only for one test fighter, and the indices obtained from each fabric were averaged to provide an average power index. These data are shown in Table 2. Table 2 Functional Potassium Channel Opener Activity in Isolated Vesicle Bands As shown by the data in Tables 1 and 2, the compounds of this invention reduce the stimulated contractions of the vesicle and therefore, may have utility in the treatment of diseases prevented by or ameliorated with potassium channel openers. The compounds of the present invention can exist as stereoisomers wherein chiral or asymmetric centers occur. These stereoisomers are "R" or "S" depending on the configuration of the substituents around the chiral carbon atom. The terms "R" and "S" as used herein, are configurations as defined in IPUAC 1974 Recommendations for Section E, Fundamental Stereochemistry, Pure Appl. Chem., 1976, 45: 13-30. In particular, the stereochemistry at the point of attachment of R \ as shown in formula (I) - (IV), can independently be either (R) or (S), unless specifically stated otherwise. The present invention contemplates various stereoisomers and mixtures thereof and are specifically included within the scope of this invention. Stereoisomers include enantiomers and diastereomers, and mixtures of enantiomers or diastereomers. The individual stereoisomers of compounds of the present invention can be prepared synthetically from commercially available raw materials containing chiral or asymmetric centers or by preparation of racemic mixtures followed by the resolution well known to those skilled in the art. These resolution methods are exemplified by (1) the binding of a mixture of enantiomers to a chiral auxiliary, separation of the resulting mixture of diastereomers by recrystallization or chromatography and release of the optically pure product from the auxiliary or (2) direct separation of the mixture of optical enantiomers in chiral chromatographic columns. The term "pharmaceutically acceptable carrier", as used herein, means a liquid, semi-solid, inert solid, non-toxic reagent material, diluent, encapsulating material or formulation aid of any kind. Some examples of materials that can serve as pharmaceutically acceptable carriers are sugars such as lactose, glucose and sucrose; starches such as starch corn 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, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols, such as a propylene glycol; esters such as ethyl oleate and ethyl laurate; agar; pyrogen-free water, isotonic saline; Ringer solution; ethyl alcohol, and phosphate buffer solutions, as well as other compatible non-toxic lubricants such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, coating agents, flavoring agents, flavorings , and sweeteners, preservatives and antioxidants can 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 compounds of the formula (I) - (tV) prepared and formulated in combination with one or more non-toxic pharmaceutically acceptable 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, locally (as by powders, ointments or drops), buccally or as a nasal or oral sprayer. 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 pharmaceutically acceptable aqueous or non-aqueous solutions, dispersions, suspensions or emulsions and sterile powders for reconstitution into sterile injectable solutions or dispersions. Examples of suitable vehicles, diluents, solvents or aqueous and non-aqueous vehicles include water, ethane, polyols (polypropylene glycol, polyethylene glycol, glycerol, and the like), suitable mixtures thereof, vegetable oils (such as olive) 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 * i! Microorganisms can be ensured by various antibacterial antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, and the like. It is also 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 that suppress the absorption, for example, of aluminum monostearate and gelatin. In some chaos, in order to prolong the effect of a drug, it is often desirable to decrease the absorption of the drug from intramuscular or subcutaneous injection. This can be achieved by the use of a liquid suspension of amorphous or crystalline material with poor water solubility. The rate of absorption of the drug thus depends on its rate of dissolution, which, in turn, may depend on the crystal size and crystal shape. Alternatively, suppressed absorption of a parenterally administered drug form is achieved 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 metahydroxide, benthic acid, agar-agar, tragacanth, and mixtures thereof. the same. If desired, and for the most efficient distribution, the compounds of the present invention can be incorporated into target delivery or slow release systems such as polymer matrices, liposomes, and microspheres. They can be sterilized, for example, by filtration through iiMM-¿i¿-- ¿> --- ^ - «a« ~. »-.- ^ .- a bacterial filter retainer or by incorporation of sterilization agents in the form of sterile solid compositions, which can be dissolved in sterile water or some other injectable medium immediately before use. The active compounds may also be in the microencapsulated form, if appropriate, with one or more excipients as noted above. The solid dosage forms of pills, pills, 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 formulation art. In such solid dosage forms, the active compound can be mixed with at least one inert diluent such as sucrose, lactose, or starch. Such dosage forms may also comprise, as is normal practice, additional substances other than inert diluents, for example, tabletting lubricants and other tabletting media such as magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, the dosage forms may also comprise regulating agents. They may optionally contain opacifying agents and may also be of such a composition that they release the active ingredient (s) only, or preferentially, in a certain part of the intestinal tract in a suppressed manner. Examples of the incorporation compositions that can be used include polymeric substances and waxes. Injectable warehouse forms are made by forming microencapsulated matrices of the drug in biodegradable polymers tai such as polylactide-polyglycotide. Depending on the ratio of the drug to the polymer and the nature of the particular polymer employed, the drug release scale can be controlled. Examples of other biodegradable polymers include poly (orthoesters) and poly (anhydrides). Injectable depot formulations can also be prepared by enclosing the drug in liposomes or microemulsions that are compatible with body tissues. The injectable formulations can be sterilized, for example, by filtration through a bacteria-retaining filter or by incorporating the sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium, just before be used. Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions can be formulated according to known matter using wetting or dispersing agents 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 vehicles and acceptable solvents that may be employed are water, Ringer's solution, U.S.P. and isotonic sodium chloride solution. In addition, sterile, sterile oils are conventionally employed as a solvent or suspending medium. For this purpose, any soft fixed oil can be threaded, including mono- or diglyceric oils. In addition, such fatty acids ran acid Oleic acid are used in the preparation of injectables. Solid dosage forms for oral administration include capsules, tablets, lozenges, powders, and granules. In such solid dosage forms, the active compound is mixed with at least one pharmaceutically acceptable excipient or carrier, inert such as sodium citrate or dicalcium phosphate and / or a) fillers or extenders such as starches, lactose, sucrose, glucose , mannitol, and silicic acid; b) binders such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and acacia; c) humectants such as glycerol; d) disintegrating agents such as agar-agar, calcium carbonate, tapioca or potato starch, alginic acid, certain silicates, and sodium carbonate; e) solution delay agents such as paraffin; f) paraffin accelerators such as quaternary ammonium compounds; g) wetting agents such as cetiio alcohol and glycerol monostearate); 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 regulating agents. Solid compositions of a similar type can also be used as filling materials in soft and hard filled gelatin capsules using such excipients as lactose or bed sugar as well as polyethylene glycols of high molecular weight and the like. The solid dosage forms of tablets, pills, m -t áfc-t- ^ rí f -U ^ * ^ ~~ L > í -eilL.

Caules, pellets, and granules can be prepared with coatings or shells such as enteric coatings and other coatings known in the pharmaceutical formulation art. Optionally, they may contain opacifying agents and may also be of a composition that they release the active ingredient (s) only, or preferentially, in a certain part of the intestinal tract in a manner suppressed. Examples of incorporation 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 as cocoa butter, polyethylene glycol or a suppository wax which are solid at room temperature but liquid at body temperature and therefore fuse in the vaginal or rectal cavity and release the active compound. Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to compounds cough active, the liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzoate behcilo, propylene glycol, glycol 1, 3-butylene, dimethylformamide, oils (in particular oils and sesame, castor, olive seed, corn, peanut, cottonseed), glycerol, JJA ^ l ^^ jH jtf -¿a ^ jj -.j ^ ^ t ^ la-¿ '-..? ^^^ ^ üai__á á__i --- -i * il ol tetrahydrofurfuryl polyethylene glycols esters of fatty fish sorbitan, and mixtures thereof. In addition to the inert diluents, the oral compositions may also include adjuvants such as wetting agents, suspending agents and emulsifiers, sweeteners, flavorings, and flavoring agents. Dosage forms for transdermal or local 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 any of the necessary preservatives as may be required. Ophthalmic formulation, ear drops, ointments for ears, powders and solutions are also contemplated to be 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 animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, zinc oxide and talc, or mixtures thereof. The powders and sprays may contain, in addition to the compounds of this invention, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances. The sprinklers may additionally contain normal impellants such as chlorofluorohydrocarbons. - ---- 4 .- ^ a - ^ .--- ^ .-! ^^ The compounds of the present invention can also be administered in the form of lipesomes. As is known in the art, liposomes are generally derived from phospholipids or other lipid substances. The liposomes are formed by mono-9 multilamellar hydrated liquid crystals that are dispersed in an aqueous medium. Any metabolizable, physiologically acceptable lipid capable of forming liposomes can be used. The present compositions in the liposome form may contain, in addition to the compounds of the present invention, stabilizers, preservatives, excipients, and the similar. The preferred lipids are synthetic and natural phospholipids and phosphatidylcholines (lecithins) used separately or together. Methods for forming liposomes are known in the art. See, for example, Prescott, Ed., Methods in Cell Biology, Volume XIV, Academic Press, New York, N.Y., (1976), p 33 ef seq. The terms "pharmaceutically acceptable salts, esters and amides", as used herein, refer to carboxylate salts, amino acid addition salts, amphoteric ions, esters and amides of compounds of the formula (I) - (IV) which, are within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, are commensurate with a reasonable benefit / risk ratio , and they are effective for their intended use. The compounds of the present invention can be used in the form of pharmaceutically acceptable salts derived from acids ül l organic or inorganic. "Pharmaceutically acceptable salts" means those which are within the scope of sounding medical judgment, 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. Pharmaceutically acceptable salts are well known in the art. For example, S.M. Berge ef alr, describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66: 1 et seq. The salts can be prepared in situ during the final isolation and purification of the compounds of the invention or separately by reacting a function of free base with a suitable organic acid. Representative acid addition salts include, but are not limited to, acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesutphonate, bisulfate, butyrate, camphorrate, camphorsulfonate, glucogonate, glycerophosphate, hemisuthate, heptanoate, hexanoate, fumarate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate (isethionate), lactate, maleate, methanesulfonate, nicotinate, 2-naphthalene sulfonate, oxalate, parmoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, sucinate, tartrate, thiocyanate, phosphate , glutamate, bicarbonate, p-toluenesulfonate and undecanoate. Also, groups containing basic nitrogen can be quaternized with such agents as lower alkyl, halides such as methyl, ethyl, propyl, and butyl chlorides, bromides and iodide; dialkyl sulfates such as dimethyl, diethyl, dibutyl and diamyl sulfates; long-chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and Íl M. ^ .. ^ - Lé.i fe ^.

! * I f. iodides; arylalkyl halides such as bei > Do you have phenethyl bromides and #t? »J f l In such a way that the dispersible or oil soluble products are obtained. Examples of acids that can be used to form pharmaceutically acceptable acid addition salts include inorganic acids such as hydrochloric acid, hydrolytic acid, sulfuric acid and phosphoric acid and such organic acids such as oxalic acid, maleic acid, succinic acid and citric acid. The basic addition salts can be prepared in situ during the final isolation and purification of compounds of this invention a) reacting a carboxylic acid-containing portion with a suitable base such as the hydroxide, carbonate or bicarbonate of a pharmaceutically acceptable metal cation or with Ammonium or a tertiary amine, Secondary or primary, organic. Pharmaceutically acceptable salts include, but are not limited to, cations based on alkali metals or alkaline earth metals such as lithium, sodium, potassium, calcium, magnesium and aluminum salts and the like and non-toxic quaternary ammonium and ammonium cations. including ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, diethylamine, ethylamine and the like. Other representative organic amines useful for the formation of base addition salts include ethylenediamine, ethanolamine, diethanolamine, piperidine, piperazine and the like. Preferred salts of the compounds of the invention include phosphate, tris and acetate. 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 burst in the human body to leave the original compound or a salt thereof. Examples of nontoxic, pharmaceutically acceptable esters of the present invention include C to C6 alkyl esters and C5 to C7 cycloalkyl esters, although Ci to C4 alkyl esters are preferred. The esters of the compounds of the formulas (I) - (IV) can be prepared according to conventional methods. For example, 9- (3,4-dichlorophenyl) -3- (4-carboxyphenyl) -5, 6,7,9-tetrahydropyrazolo [5,1-bJquinazolin-8 (4) -one can be treated with an acid, such as HCl, in an alcohol solvent, such as methanol, to provide the ester 9- (3,4 - dicloforenyl) -3- (4-methoxycarbonylphenyl) -5,6,7,9-tetrahydro-tetrazololo [5, 1-b -quinazolin-8 (4H) -one. The term "pharmaceutically acceptable amide", as used herein, refers to non-toxic amides of the present invention derived from ammonia, primary Ci to C6 alkyl amines and secondary Ct to C6 dialkyl amines. In the case of secondary amines, the amine may also be in the form of a 5- or 6-membered heterocycle containing a nitrogen atom. Amide-derived amides, primary C1 to C3 primary alkyl amides and secondary C to C2 dialkyl amines are preferred. The amides of the compounds of the formulas (I) - (IV) can be prepared according to conventional methods. For example, 9- (3,4-doorophenyl) -3- (4-carboxyphenyl) -5,6,7,9-tetrahydropyrazolo [5,1-bjquinazolin-8 (4H) -one can be treated with a chloroformate, such as isobutylchloroformate, in an organic solvent, such as methylene chloride or tetrahydrofuran at a temperature of about 0 ° C at room temperature, to * Jktt * Ít *? ** k ?. ^ ¿Üm z & providing an intermediate anhydride which can then be treated with an amine, such as dimethylamine, to provide 9- (3,4-dichlorophenol) -3- (4-dimetitaminocarbonylphenyl) -5,6,7, tetrahydropyrazolo [5,1-b -quinazolin] -8 (4H) -one. It is further attempted that the amides of the present invention include peptide and amino acid derivatives of the compounds of the formula (I), as well. The term "pharmaceutically acceptable prodrug" or "prodrug", as used herein, represents those prodrugs of the compounds of the present invention that are, within the scope of sound medical judgment, suitable for use in contact with human tissues. and lower animals without undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit / risk ratio, and effective for their proposed use. The prodrugs of the present invention can be rapidly transformed in vivo into the parent compound of the above formula, for example, by hydrolysis in blood. A direct discussion is provided in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, V. 14 of the ACS Symposium Series, and in Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press (1987), incorporated herein by reference. 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. # II Ophthalmic formulations, eye ointments, powders and solutions are also contemplated as being within the scope of this invention. The current dose levels of active ingredients in the pharmaceutical compositions of this invention can be varied to obtain an amount of the active compound (s) that is effective to achieve the desired therapeutic response for a particular patient, compositions and mode of administration. The level of dose 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 experience of the subject to initiate dose of the compound at levels lower than those required to achieve the desired therapeutic effect and to gradually increase the dose until the desired effect is achieved. The present invention contemplates pharmaceutically active compounds either chemically synthesized or formed by biotransformation in vivo to compounds of the formulas (1-4). The compounds of the invention, include but are not limited to those specified in the examples, possess activity that opens the potassium channel in mammals (especially humans). As potassium channel openers, the compounds of the present invention can be useful for the treatment and prevention of diseases such as asthma, epilepsy, male sexual dysfunction, female sexual dysfunction, pain, bladder overactivity, attack, diseases associated with flow. reduced skeletal blood loss such as Raynatlu's phenomenon? M intermittent claudication, eating disorders, functional bowel disorders, neurodegeneration, benign prostatic hyperplasia (BPH), dysmenorrhea, premature labor, alopecia, ardioprotection, coronary artery disease, angina and ischemia . The ability of the compounds of the present invention, including but not limited to those specified in the examples, to treat overactivity of the bladder, urgency of incontinence, urinary incontinence, polakiuria, bladder instability, nocturia, bladder hyperreflexia, and enuresis can be demonstrated by (Resnick, The Lancet (1995) 346, 94-99; Hampel, Urology (1997) 50 (Suppl 6a), 4-14; Bosch, BJU International (1999) 83 (Suppl 2), 7-9; Anderson, Urology (1997) 50 (adj 6A); 74-84; Lawson, Pharmacol, Ther., (1996) 70, 39-63; Nurse, Br. J. Urol., (1991) 68, 27-31; Howe, J. Pharmacol. Exp. Ther., (1995) 274, 84-890; Gopalakrishnan, Drug Development Research, (1993) 28, 95-127). The ability of the compounds of the present invention, including but not limited to those specified in the examples, to treat male sexual dysfunction such as male erectile dysfunction, impotence and premature ejaculation can be demonstrated by (Andersson, Pharmacological Reviews (1993) 45, 253; Lee, Int. J. Impot. Res. (1999) 11 (4), 179-188; Andersson, Pharmacologipal Reviews (1993) 45, 253; Lawson, Pharmaool. Ther., (1996) 70, 39-63 , Viok, J. Urol. (2000) 163: 202). The ability of the compounds of the present invention, but not limited to those specified in the examples, to treat female sexual dysfunction such as clitoral erectile insufficiency, vaginismus and vaginal obstruction can be demonstrated by (JJ Kim, JW Yu, JG Lee, DG Moon , "Effects of topical K-ATP channel oppose solutíon on clitoral blood flow", J. Urol. (2000) 163 (4): 240, 1. Goldstein and JR Berman., "Vasculogenic female sexual dysfunction: vaginal engorgement and clitoral erectile insufficiency syndromes "., Int. J. Impotence Res. (1998) 10: S84-S90). The ability of the compounds of the present invention, including but not limited to those specified in the examples, to treat benign prostatic hyperplasia (BPH) can be demonstrated by (Pandita, The J. of Urology (1999) 162, 943, Andersson, Prostate (1997) 30; 202-215). The ability of the compounds of the present invention, including but not limited to those specified in the examples, to treat premature labor and dysmenorrhoea can be demonstrated by (Sanborn, Semin. Perinatol. (1995) 19, 31-40; Morrison, Am. J. Obstet, Gynecol. (1993) 169 (5), 1277-85, Kostrzewska, Obstet Acta, Gynecol, Scand. (1996) 75 (10), 886-91, Lawson, Pharmacol. Ther., (1996). , 39-63). The ability of the compounds of the present invention, including but not limited to those specified in the examples, to treat functional bowel disorders such as irritable bowel syndrome can be demonstrated by (Lawson, Pharmacol. Ther., (1996) 70, 39 -63). f. The ability of the compounds of this invention, including but not limited to those specified in the examples, to treat asthma and hyperreactivities of the Respiratory tract can be demonstrated by (Lawson, Pharmacol. Ther., (1996) 70, 39-63; Buchheit, Pulmonary Pharmacology &Therapeutics (1999) 12, 103; Gopalakrishnan, Drug Development Research, (1993) 28, 95-127 ). The ability of the compounds of the present invention, including but not limited to those specified in the examples, to treat various pain states including but not limited to migraine and dyspareunia can be demonstrated by (Rodriguez, Br. J. Rharmacol. (2000) 129 (1), 1 10-4, Vßrgoni, Life Sci. (1992) 50 (16), PL135-8, Asano, Anesth, Analg. (2000) 90 (5), 1 146-51, Lawson, Pharmacol. Ther., (1996) 70, 39-63, Gopalakrishnan, Drug Development Research, (1993) 28, 95-127, Gehlert, Prog. Neuro-Psychopharmacol. &Biol. Psychiat., (1994) 18, 1093-1. 102). The ability of the compounds of the present invention, including but not limited to those specified in the examples, to treat epilepsy can be demonstrated by (Lawson, Pharmacol. Ther., (1996) 70, 39-63; Gopalakrishnan, Drug Development Research, (1993) 28, 95-127; Gehlert, Prog. Neuro-Psuchopharmacol &Biol. Psychiat., (1994) 18, 1093-1 102). The ability of the compounds of the present invention, including but not limited to those specified in the examples, to treat diseases and neurodegenerative conditions such as cerebral ischemia, stroke, Alzheimer's disease and MttÉ ^ gütt Parkinson can be demonstrated by (La son, Pharmacol. Ther., (19 ®]. F • H 39-63; Gopalakrishnan, Drug Devetopment Researoh, (1993) 28, 95-127; Gehlert, Prog. N? Uro-Psychoí > harmacol. & Biol, Psychiat., (1994) 18, 1093-1 tu2; Freedman, The Neuroscientist (1996) 2, 145). The ability of the compounds of the present invention, including but not limited to those specified in the examples, to treat diseases or conditions associated with reduced skeletal muscle blood flow such as Raynaud's syndrome and intermittent claudication can be demonstrated by (Lawson, Pharmacol. ., (1996) 70, 39-63; Gopalakrishnan, Drug Development ResearCh, (1993) 28, 95-127; Dompelin Vasa, Supplementum (1992) 3434; WO 9932495). The ability of the compounds of the present invention, including but not limited to those specified in the examples, to treat eating disorders such as obesity can be demonstrated by (Spanswick, Nature, (1997) 390, 521-25; Freedman, The Neuroscientist (1996) 2, 145). The ability of the compounds of the present invention, including but not limited to those specified in the examples, to treat aplopecia can be demonstrated by (Lawson, Pharmacol. Ther., (1996) 70, 39-63; Gopalakrishnan, Drug Development Research, (1993) 28, 95-127). The ability of the compounds of the present invention, including but not limited to those specified in the examples, to treat myocardial injury during ischemia and reperfusion can by (Garlid, Circ Res (1997) 81 (6), 1072-82; Lawson, Pharmacol, Ther., (1996) 70, 39-63; Grover, J. Mol. Cell Cardiol. (2000) 32, 677) . The ability of the compounds of the present invention, including but not limited to those specified in the examples, to treat coronary artery disease can be demonstrated by Lawson, Pharmacol. Ther., (1996) 70, 39-63; Gopalakrishnan, Drug Development Research, (1993) 28, 95-127). The liquid compositions of the present invention are particularly useful for the treatment and prevention of asthma, epilepsy, hypertension, Raynaud's syndrome, male sexual dysfunction, female sexual dysfunction, migraine, pain, eating disorders, urinary incontinence, functional disorders of the intestine, neurodegeneration and attack. 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 pharmaceutically acceptable salt, ester, amide or prodrug thereof. Alternatively, the compound can be administered co or 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 benefit / risk ratio 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 sound 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; activity of the specific compound employed; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of treatment; medications used in combination or that match the specific compound used; and similar factors well known in medical matters. For example, it is well within the skill of the art to start dose of the compound at levels lower than those required to achieve the desired therapeutic effect and to gradually increase the dose until the desired effect is achieved. The total daily dose of the compounds of this invention administered to a lower or human animal can vary from about 0.003 to about 10 mg / kg / day. For purposes of oral administration, the most preferred doses may be in the range of from about 0.01 to about 5 mg / kg / day. If desired, the effective daily dose can be divided into multiple doses for administration purposes; consequently, the single dose compositions may contain such amounts or submultiples thereof to make the daily dose.

Claims (11)

1. CLAIMS A compound having the formula (I):
2. (I), or a pharmaceutically acceptable salt, wherein n is an integer of 0-1; m is an integer of 1 -2; with the statement that when m is 2, n is 0; R1 is selected from the group consisting of aryl and heterocycle; Q is selected from the group consisting of C (O), S (O), and S (O) 2; V is selected from the group consisting of C (R6) (R7), O, S, and NR2, wherein R2 is selected from the group consisting of hydrogen, alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkyloxy, alkynyl, aryl, arylalkoxy , arylalkenyl, arylalkyl, cyano, cycloalkyl, cycloalkylalkyl, haloalkoxy, haloalkyl, heterocycle, heterocyclealkyl, hydroxy, hydroxyalkyl, -NR4R6, and (NR4R5) alkyl wherein R4 and R5 are independently selected from the group consisting of hydrogen and lower alkyl; R6 and R7 are independently selected from the group consisting of hydrogen, alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkyl, alkylthio, alkynyl, aryl, arylalkoxy, arylalkenyl, arylalkyl, carboxy, cyano, cycloalkyl, cycloalkylalkyl, haloalkoxy, haloalkyl, halogen, heterocycle , heterocycloalkyl, hydroxy, hydroxyalkyl, oxo, -NR4R5, and (NR4R5) alkyl; R8 and R9 are independently selected from the group consisting of hydrogen, alkenyl, alkoxy, alkoxyalkyl, alkoxyalkyl, alkyl, alkylthio, alkynyl, aryl, arylalkoxy, arylalkenyl, arylalkyl, carboxy, cyano, cycloalkyl, cycloalkylalkyl, haloalkoxy, haloatquiio, halogen, heterocycle , heterocycloalkyl, hydroxy, hydroxyacyl, -NR R5, and (NR4R5) alkyl; X is selected from the group consisting of N and CR3, wherein R3 is selected from the group consisting of hydrogen, alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkyl, alkylthio, alkynyl, aryl, arylalkoxy, arylalkenyl, arylalkyl, carboxy, cyano, cycloalkyl, cycloalkylalkyl, haloalkoxy, haloalkyl, halogen, heterocycle, heterocyclealkyl, hydroxy, hydroxyalkyl, -NR4R5, and (NR4R5) alkyl; D and E are independently selected from the group consisting of hydrogen, alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkyl, alkylthio, alkynyl, aryl, arylalkoxy, arylalkenyl, arylalkyl, carboxy, cyano, cycloalkyl, cycloalkylalkyl, hatoalkoxy, haloalkyl, halogen, heterocycle , heterocycloalkyl, hydroxy, hydroxyalkyl, oxo, -NR4R5, and (NR4R5) alkenyl; with the proviso that when Q is S (O) or S (O) 2, then V is C (R6) (R7). 2. A compound according to claim 1, characterized in that R1 is aryl; X is CR3; Y
3. 3. A compound according to claim 1, characterized in that R1 is heterocycle; X is CR3; and R3 is hydrogen. 4. A compound according to claim 1 of the formula
4. (II): ("), or a pharmaceutically acceptable salt thereof
5. 5. A compound according to claim 4, characterized in that R1 is heterocycle, and Q is C (O)
6. 6. A compound according to claim 4, characterized in that R1 is heterocycle and Q is S (O)
7. 7. A compound according to claim 4, characterized in that R1 is heterocycle, and Q is S (O) 2. *. i
8. 8. A compound according to claim 4, characterized in that R1 is heterocycle; and Q is C (O); and V is S.
9. 9. A compound according to claim 4, characterized in that R is heterocycle; and Q is C (O); V is S; R8 is hydrogen; R9 is hydrogen; D is hydrogen; and E is hydrogen.
10. 10. A compound according to claim 4, characterized in that R1 is heterocycle; and Q is C (O); and V is CH2. 1 1. A compound according to claim 4, characterized in that R1 is heterocycle; and Q is C (O); V is CH2; D is alkyl; Y ^^ | g ^^ ^ j | j H ^ | ^ Éi &auy ^ ¡E is alkyl. 12. A compound according to claim 4, characterized in that R1 is heterocycle; and Q is C (O); V is CH2; D is alkyl; E is alkyl, R8 is hydrogen; and R9 is hydrogen. 13. A compound according to claim 12, ie, 7,7-dimethyl-9- (5-nitro-3-thienyl) -5,6,7,9-tetrahydropyrazolo [5,1-b] quinazolin-8 ( 4H) -one. 14. A compound according to claim 4, characterized in that R1 is heterocycle; and Q is C (O); V is CH2; R8 is hydrogen; R9 is hydrogen; D is hydrogen; and E is hydrogen. 15. A compound according to claim 4, characterized in that R1 is heterocycle; Y ¡,,, ^ ^ 0 ^. ^ Q is S (O) 2; V is CH2. 16. A compound according to claim 4, characterized in that R1 is heterocycle; and Q is S (O) 2; V is CH2; R8 is hydrogen; R9 is hydrogen; D is hydrogen; and E is hydrogen. 17. A compound according to claim 4, characterized in that R1 is aryl; and Q is C (O). 18. A compound according to claim 4, characterized in that R1 is aryl; Q is C (O); and V is S. 19. A compound according to claim 4, characterized in that R1 is aryl; and Q is C (O); V is S; R8 is hydrogen; R9 is hydrogen; D is hydrogen; and E is hydrogen. 20. A compound according to claim 18, ie 9- (3-bromo-4-fluorophenyl) -5,9-dihydro-4H-pyrazolo [1,5-a] thopyran [3,4-d] pyrimidin-8 (7H) -one. 21. A compound according to claim 4, characterized in that R1 is aryl; and Q is C (O); V is CH2. 22. A compound according to claim 4, characterized in that R1 is aryl; and Q is C (O); V is CH2; D is alkyl; and E is alkyl. 23. A compound according to claim 4, characterized in that R1 is aryl; and is C (O); V is CH2; D is alkyl; E is alkyl; R8 is hydrogen; and R9 is hydrogen. 24. A compound according to claim 23, selected from the group consisting of: 9- (4-chloro-3-fluorophenyl) -7,7-dimethyl-5,6,7,9-tetrahydropyrazolo [5-1-b] quinazolin-8 (4H) -one; 9- (3-bromo-4-flutophenyl) -7,7-dimethyl-5,6,7,9-tetrahydropyrazolo [5-1-b] quinazolin-8 (4H) -one; 9- [4-fluoro-3- (trifluoromethyl) phenyl] -7,7-dimethyl-5,6,7,9-tetrahydropyrazolo [5-1-b] quinazolin-8 (4H) -one; 0- (3,4-dichlorophenyl) -7,7-dimethyl-5,6,7,9-tetrahydropyrazolot-5-1-bJquinazolin-8 (4H) -one; 9- (4-Doro-3-nitrophenyl) -7,7-dimethyl-5,6,7,9-tetrahydropyrazolo [5-1-b} quinazolin-8 (4H) -one; 9- (3,4-dibromophenyl) -7,7-dimethyl-5,6,7,9-tetrahydropyrazolo [5-1-bJquinazolin-8 (4H) -one; 9- (3-fluoro-4- (trifluoromethyl) phenyl) -7,7-dimethyl-5,6,7,9-tetrahydropyridolo [5-1-b] quinazolin-8 (4H) -one; 7,7-dimethyl-9- (3-nitrophenyl) -5,6,7,9-tetrahydropyrazolol-5,1-b -quinazolin-8 (4H) -one; 9- (3-cyanophenyl) -7,7-dimethyl-5,6,7,9-tetrahydropyrazolo [5-1-blquinazoHn-8 (4H) -one; 9- (5-Bromo-2-hydroxyphenyl) -7,7-dimethyl-5,6,7,9-tetrahydropyrazolo [5-1-b] quinazolin-8 (4H) -one; 9- (5-Cl? Fo-2-hydroxyphenyl) -7,7-d -imethoxy
11. ll.-5- -, ft6, 77, O9.- *! tetrahydropyrazolole { 5-1-b] quinazolin-8 (4H) -one; 9- (2-hydroxy-5-nitrophenyl) -7,7-dimethyl-5,6,7,9-tetrahydropyrazolole. { 5-1 -b] quinazolin-8 (4H) - # anger; 9- (3,5-dibromo-2-hydroxyphenyl) -7,7-dime «*» 5,, 7,9-tetrahydropyrazolo [5-1-bJquinazolin-8 (4H) -one; 9- (3-bromo-5-chloro-2-hydroxyphenyl) -7,7-dimethyl-5,6,7,9-tetrahydropyrazolo [5-1-b] quinazolin-8 (4H) -one; 9- (3,5-dichloro-2-hydroxyphenyl) -7,7-dimethyl-5,6,7,9-tetrahydropyrazolol-5-1-b] qUinazolin-8 (4H) -one; 7,7-dimethyl-9- (3,4,5-trifluorophenyl) -5,6,7,9-tetrahydropyrazolo [5-1-bJquinazolin-8 (4H) -one; 25. A compound according to claim 4, characterized in that R1 is aryl; Q is C (O); V is CH2; and R9 is aryl. 26. A compound according to claim 4, characterized in that R1 is aryl; Q is C (O); V is CH2; and R9 is aryl; R8 is hydrogen; * if - D is hydrogen; and E is hydrogen. 27. A compound according to claim 26, selected from the group consisting of: 9- (3,4-dichlorophenyl) -3- (3-fluorophenyl) -5,6,7,9-tetrahydropyrazot [5,1-b] quinazolin-8 (4H) -one; 3- (3-Chlorophenyl) -9- (3,4-dichlorophenyl) -5,6,7,9-tetrahydropyrazolo [5,1-b] quinazolin-8 (4H) -one; 3- (4-carbo ifenyl) -9- (3,4-dichlorophenyl) -5,6,7,9-tetrahydropyrazolo [5,1-b] quinazolin-8 (4H) -one; 9- (3,4-Dichlorophenyl) -3- [2- (trifluoromethyl) phenyl] -5,6,7,9-tetrahydropyrazolo [5,1-b] quinazolin-8 (4H) -one; 28. A compound according to claim 4, characterized in that R1 is aryl; Q is C (O); V is CH2; and R9 is heterocycle. 29. A compound according to claim 4, characterized in that R1 is aryl; Q is C (O); V is CH2; R9 is heterocycle; R8 is hydrogen; D is hydrogen; ? E is hydrogen. 30. A compound according to claim 29, selected from the group consisting of: 9- (3,4-dichlorophenyl) -3- (2-thienyl) -5,6,7,9-tetrahydropyrazolo [5,1-bJquinazolin- 8 (4H) -one; (+) 9- (3,4-dichlorophenyl) -3- (2-thienyl) -5,6,7,9-tetrahydropyrazolo-5,1-b] quinazolin-8 (4H) -one; (-) 9- (3,4-Dichlorophenyl) -3- (2-thienyl) -5,6,7,9-tetrahydropyrazolo [5,1-bJquinazo | in-8 (4H) -one; 9- (3,4-dichlorophenyl) -3- (2-furyl) -5,6,7,9-tetrahydropyrazolo [5,1-b] quinazolin-8 (4H) -one, 31. A compound according to claim 4, characterized in that R1 is aryl; Q is C (O); V is CH2; and R9 is halogen. 32. A compound according to claim 4, characterized in that R1 is aryl; Q is C (O); V is CH2; R9 is halogen; R8 is hydrogen; D is hydrogen; and t E is < hydrogen. 33. A compound according to claim 32, selected from the group consisting of. 3-bromo-9- (3-bromo-4-fluorophenyl) -5,6,7,9-tetrahydropyrazolo (5,1-b] quinazolin-8 (4H) -one; 3-bromo-9- (3, 4-dichlorophen? L) -5,6,7,9-tetrahydropyrazolo [5,1-bJquinazolin-8 (4H) -one, (+) 3-bromo-9- (3,4-dichlorophenyl) -5,6 , 7,9-tetrahydropyrolo [5,1-bJqiinazolin-8 (4H) -one; (-) 3-bromo-9- (3,4-dichlorophenyl) -5,6,7,9-tetrahydropyrazolo [5, 1-h.) Quinazolin-8 (4H) -one, 34. A compound according to claim 4, characterized in that R1 is aryl, Q is C (O), V is CH2, R8 is hydrogen, R9 is hydrogen; is hydrogen, and E is hydrogen 35. A compound according to claim 34, which is selected from the group consisting of 9- (3-bromo-4-fluorophenyl) -5,6,7,9-tetrahydropyrazole? 5,1- b] quinazolin-8 (4H) -one, 9- (1-naphthyl) -5,6,7,9-t # i tidropyrazolot-5,1-b] quinazolin-8 (4H) -one; 9- (2- naphthyl) -5,6,7,9-tetrahydropyrazoloth-5,1-b -quinazolin-8 (4H) -one; 9- (3,4-dibromophenyl) -5,6,7,9-tetrahydropyrazolo [5,1-b -quinazolin- 8 (4H) -one; 9- (3,4-dichlorophenyl) -5,6,7,9-tetrahydropyrazolol-5,1-b] quinazolin-8 (4H) - ona; 9- (3-bromophenyl) -5,6,7,9-tetrahydropyrazolo [5,1-bjquinazolin-8 (4H) -one; 9- (3-chlorophenyl) -5,6,7,9-tetrahydropyrazolo [5, 1-b] quinazolin-8 (4H) -one; 9- [4-chloro-3- (trifluoromethyl) phenyl] -5,6,7,9-tetrahydropyrazoloyl-5,1-bJquinazolin-8 (4H) -one; 9- [4-fluoro-3- (trifluoromethyl) phenyl] -5,6,7,9-tetrahydropyrazolo]; 5,1-b] quinazolin-8 (4H) -one; 9- [3- (trifluoromethoxy) phenyl] -5,6,7,9-tetrahydropyrazolo [5, 1-bJquinazolin-8 (4H) -one; 9- (3-cyanophenyl) -5,6,7,9-tetrahydropyrazolo [5,1-b] quinazolin-8 (4H) -one; 9- (3-methylphenyl) -5,6,7,9-tetrahydropyrazolo [5,1-b] quinazolin-8 (4H) -one; (-) 9- (3-Bromo-4-fluorophenyl) -5,6,7,9-tetrahydropyrazolo [5,1-bJquinazolin-8 (4H) -one; (+) 9- (3-bromo-4-fluorophenyl) -5,6,7,9-tetrahydropyrazolo | 5,1-blquinazolin-8 (4H) -one; 9- (3-chloro-4-hydroxyphenyl) -5,6,7,9-tetrahydropyrazolo [5,1-bJquinazolin-8j (4H) -one; 9- (3-chloro-4-fluorophenyl) -5,6,7,9-tetrahydropyrazolo [5,1-b -quinazolin-8 (4H) -one; 9- (3,4-difluorophenyl) -5,6,7,9-tetrahydropyrazolo [5,1-b) quinazolin-8 (4H) -one; 9- (4-fluorophenyl) -5,6,7,9-tetrahydropyrazolo [5,1-hekquinazolin-8 (4H) -one; 9- [4- (trifluoromethyl) phenyl] -5,6,7,9-tetrahydropyrazolo [5, 1-b -quinazolin-8 (4H) -one; 9- (4-cyanophenyl) -5,6,7,9-tetrahydropyrazolo [5,1-bJquinazolin-8 (4H) -one; 9- (4-chloro-3-nitrophenyl) -5,6,7,9-tetrahydropyrazopho [5,1-bJquinazolin-3 (4H) -one; 36. A compound according to claim 4, characterized in that R1 is aryl; and Q is S (O). 37. A compound according to claim 4, characterized in that R is aryl; and Q is S (O) 2. 38. A compound according to claim 4, characterized in that V is CH2. 39. A compound according to claim 4, characterized in that R1 is aryl; Q is S (O) 2; V is CH2; R8 is hydrogen; R9 is hydrogen; D is hydrogen; and E is hydrogen. 40. A compound according to claim 39 which is 9- (3-bromo-4-fluorophenyl) -5,6,7,9-tetrahydro-4H-pyrazolo [1,5-a] thiopyrano [3,2-dyrimidine]. , 8-dioxide. 41. A compound according to claim 1 of the formula (neither); (III), or a pharmaceutically acceptable salt thereof. 42. A compound according to claim 41, characterized in that R1 is heterocycle; Y Q is C (C-). 43. A compound according to claim 41, characterized in that R is heterocycle; and Q is S (O). 44. A compound according to claim 41, characterized in that R is heterocycle; and Q is S (O) 2. 45. A compound according to claim 41, characterized in that R1 is aryl; and Q is C (O). 46. A compound according to claim 41, characterized in that R1 is aryl; Q is C (O); and V is O. 47. A compound according to claim 41, characterized in that R1 is aryl; and Q is C (O); V is O; R8 is hydrogen; R9 is hydrogen; D is hydrogen; and E is hydrogen. 48. A compound according to claim 47 which is 8- (3-bromo-4-fluorophenyl) -5,8-dihydro-4H, 7H-furo [3,4-d] pyrazolo [1,5-a] pyrimidin-7-one. 49. A compound according to claim 41, characterized in that R1 is aryl; and Q is S (O). 50. A compound according to claim 41, characterized in that R1 is aryl; and Q is S (O) 2. 51. A compound according to claim 1 of the formula (IV): (IV), or a pharmaceutically acceptable salt thereof. 52. A compound according to claim 51, characterized in that R1 is heterocycle; and Q is C (O). 53. A compound according to claim 51, characterized ..... - .. 3ttM - ^, .. ¿^^ a, .- ^^ ríl [fflma¡ | f | ||, | 1 because R1 is heterocycle; and Q is S (O). 54. A compound according to claim 51, characterized in that R1 is heterocycle; and Q is S (O) 2. 55. A compound according to claim 51, characterized in that R1 is aryl; and Q is C (O). 56. A compound according to claim 51, characterized in that R1 is aryl; and Q is S (O). 57. A compound according to claim 51, characterized in that R1 is aryl; and Q is S (O) 2. 58. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1 in combination with a pharmaceutically acceptable carrier. 59. A method of treating a disorder in a mammalian host in need of such treatment comprising administering to the mammal a therapeutically effective amount of a compound of the claim 1. 60. The method seg | n claim 29, characterized in that the disorder is selected from the group consisting of asthma, epilepsy, Raynaud syndrome, intermittent claudication, migraine, pain, polakiuria, vesicle instability, nocturia, vesicle hyperrefiexia, enuresis, alopecia, cardioprotection, ischemia, eating disorders, functional bowel disorders, and neurodegeneration. 61. The method according to claim 59, characterized in that the disorder is vesicle hyperactivity. 62. The method according to claim 59, characterized in that the disorder is benign prostatic hyperplasia. 63. The method according to claim 59, characterized in that the disorder is dysmenorrhea. 64. The method according to claim 59, characterized in that the disorder is premature labqr. 65. The method according to claim 59, characterized in that the disorder is urinary incontinence. 66. The method according to claim 59, characterized in that the disorder is selected from the group consisting of male erectile dysfunction and premature ejaculation. 67. The method according to claim 59, characterized in that the disorder is female sexual dysfunction. íM ------------ - * --- t? t > ? lttm¡ > The compounds of the formula (I) are useful in the treatment of diseases prevented by or ameliorated with potassium channel openers. Also disclosed are potassium channel opener compositions and a method for opening potassium channels in a mammal. 0 2. Jo I