KR20020066832A - Fused pyrazolyl compounds - Google Patents

Abstract

PURPOSE: Provided are a novel fused pyrazolyl compound represented by the formula(1) and a pharmaceutical composition containing an effective amount of the compound. The fused pyrazolyl compound increases cGMP level in a cell by activating sGC or inhibiting PDEs, and is thus useful for diseases related to platelets-aggregation. CONSTITUTION: The novel fused pyrazolyl compound represented by the formula(1), wherein Ar1, Ar2 and Ar3 are individually phenyl, thienyl, pyrrolyl or furyl selectively substituted with halo, alkyl, carboxyl, alkoxycarbonyl, thiocarbonyl, aminocarbonyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, thioalkyl; X and Y are individually an oxygen atom, a sulfur atom or NH; m is 1,2 or 3; and n is 0,1,2,3 or 4.

Description

Fused pyrazolyl compounds

CGMP, an intracellular messenger, plays an important role in regulating various cellular activities. It is converted from GTP by soluble guanylate cyclase (“sGC”) and degraded by phosphodiesterases (“PDEs”). Thus, an increase in cGMP levels can be achieved by increasing the activity of sGC or decreasing the activity of PDEs.

Platelet aggregation contributes to the development of various cardiovascular diseases such as arteriosclerosis, myocardial infarction, unstable angina, thrombosis, and hypertension. Since low intracellular levels of cGMP result in increased platelet aggregation, an increase in cGMP levels in platelets provides a method of treating these diseases. Intracellular cGMP levels are also known to affect other physiological functions, such as erection of the penis.

Compounds that increase intracellular cGMP levels by activating sGC or inhibiting PDEs have clinical effects on diseases associated with low intracellular cGMP levels. Certain pyrazolyl compounds have been found to activate sGC and are potential cardiovascular drugs.

One aspect of the invention relates to a novel fused pyrazolyl compound of formula

Where

Ar ₁ , Ar ₂ , and Ar ₃ are each independently substituted with halo, alkyl, carboxyl, alkoxycarbonyl, thiocarbonyl, aminocarbonyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, or thioalkyl Phenyl, thienyl, pyrrolyl, or furyl;

X and Y are each independently an oxygen atom, a sulfur atom, or NH;

m is 1, 2, or 3; And,

n is 0, 1, 2, 3, or 4.

The term "alkyl", the prefix "alk" (as in alkoxyalkyl), or the suffix "-alkyl" (as in hydroxyalkyl) is C _{1. -6} .

With reference to Formula 1, a subset of the compounds of the present invention is characterized by X being an oxygen atom, Y being an oxygen atom, and m being one. In these compounds, Ar ₂ is preferably phenyl or furyl, or Ar ₃ is thienyl or phenyl. Another subset of the compounds of the invention is characterized in that Ar ₂ is phenyl or furyl. In these compounds, Ar ₁ is phenyl or Ar ₃ is thienyl or phenyl. Another subset of the compounds of the invention is characterized by Ar ₃ being thienyl or phenyl. In these compounds, Ar ₁ is phenyl and Ar ₂ is furyl; Or Ar ₂ is phenyl.

Four exemplary compounds of the invention are 1-benzyl-3- (5'-methoxycarbonyl-2'-furyl) -5,6-methylenedioxoindazole, 1-benzyl-3- (5'- Hydroxycarbonyl-2'-furyl) -5,6-methylenedioxoindazole, 1-benzyl-3- (5'-methoxymethyl-2'-furyl) -5,6-methylenedioxoindazole And 1-benzyl-3- (5'-hydroxymethyl-2'-furyl) -5,6-methylenedioxoindazole. The structure of 1-benzyl-3- (5'-hydroxycarbonyl-2'-furyl) -5,6-methylenedioxindazole is shown below, with the atoms in the aryl ring numbered.

The fused pyrazolyl compounds described above include their salts, if applicable. Such salts may be formed between anions and positively charged substituents such as, for example, amino. Suitable anions include, but are not limited to, chloride ions, bromide ions, iodide ions, sulfates, nitrates, phosphates, or acetates. Likewise, negatively charged substituents (eg, carboxylates) can form salts with cations. Suitable cations include, but are not limited to, ammonium cations such as sodium ions, potassium ions, magnesium ions, calcium ions, and tetramethylammonium ions. Two examples of salts of the invention are the hydrochloride salts of 1-benzyl-3- (5'-aminomethyl-2'-furyl) -5,6-methylenedioxoindazole and 1-benzyl-3- (5 ' Sodium salt of -carboxy-2'-furyl) -5,6-methylenedioxoindazole.

Compounds of the present invention may activate sGC or inhibit PDEs.

Accordingly, another aspect of the present invention relates to a pharmaceutical composition for the treatment of a disease associated with low activity of sGC, high activity of PDE, or platelet aggregation, comprising an effective amount of a compound of Formula 1 and a pharmaceutically acceptable carrier. will be.

Detailed descriptions of some embodiments of the invention are given below. Other features, objects, and advantages of the invention will be apparent from the following description and claims.

The fused pyrazolyl compound of the present invention can be synthesized by the following method. The alkylenedioxoarylacyl chloride is reacted with an aryl compound to produce an alkylenedioxoarylaryl aryl ketone. The ketone is then reacted with hydrazine to produce a hydrazone, which is then converted into an intermediate in the presence of the first catalyst Pb (OAc) ₄ . Without purification, the intermediate is converted to a fused pyrazolyl compound in the presence of the second catalyst BF ₃ .Et ₂ O. By further modification, the desired functional groups, such as hydroxy carbonyl or hydroxyalkyl, can be introduced into the fused pyrazolyl compound thus obtained.

A schematic depicting the synthesis of the four fused pyrazolyl compounds 1 , 2 , 3 and 4 of the present invention is shown in Scheme 1 below.

Details of the synthesis of compounds 1 , 2 , 3 and 4 are described in Examples 1, 2, 3 and 4, respectively.

Compounds of the invention can be used to increase intracellular levels of cGMP by activating sGC or inhibiting PDEs. Accordingly, another aspect of the invention relates to diseases associated with low intracellular cGMP levels, including erectile dysfunction, comprising an effective amount of at least one fused pyrazolyl compound (or salt thereof) of formula (1) and a pharmaceutically acceptable carrier. Or to a pharmaceutical composition for treating platelet aggregation-related diseases. By "effective dose" is meant the amount of compound required to confer a therapeutic effect on the treated subject. Correlation of doses to animals and humans (based on mg per m ² body surface area) is described by Freireich et al., Cancer Chemother. Rep. , 1966, 50, 219. Body surface area can be approximately estimated from the height and weight of the patient. See, eg, Scientific Tables, Geigy Pharmaceuticals, Ardley, NY, 1970, 537. Effective amounts are also appreciated by those of ordinary skill in the art, and therefore the possibility of simultaneous use with other therapeutic regimens, including routes of administration, excipient regimens, and the use of other anti-platelet aggregation agents. Depends on. Examples of such carriers include colloidal silicon dioxide, magnesium stearate, cellulose, sodium lauryl sulfate, and D & C Yellow # 10.

The pharmaceutical compositions can be administered by parenteral routes, for example topically, subcutaneously, intraperitoneally, intramuscularly, and intravenously. Examples of parenteral dosage forms include aqueous solutions of the active compounds in isotonic saline, 5% glucose, or other known pharmaceutically acceptable carriers. Solubles such as cyclodextrins, or other soluble agents known to those of ordinary skill in the art, may also be included in the pharmaceutical compositions.

The fused pyrazolyl compounds of the present invention can be formulated in dosage forms for other routes of administration (eg, orally, mucosally, or transdermally) using known methods. The pharmaceutical composition may be formulated, for example, in oral administration in a capsule, gel seal, or tablet. The capsule may comprise any known pharmaceutically acceptable substance such as gelatin or cellulose derivative. Tablets can be prepared by compressing a mixture of the active compound, solid carrier, and lubricant according to known methods. Examples of solid carriers include starch and sugar bentonite. The compounds may also be administered in the form of hard shell tablets, or capsules, including, for example, lactose or mannitol as binder, known fillers, and tableting agents.

The use of the fused pyrazolyl compound of formula 1 for the preparation of a medicament for the aforementioned uses is also within the scope of the present invention.

Compounds of the present invention can be prescreened for their efficacy in treating the aforementioned diseases by using one or more of the following assays:

The efficacy of a compound in the activation of sGC can be assessed in vitro by the following assay. Washed platelets are suspended in buffer and disrupted by sonication. The lysate is then centrifuged to obtain a supernatant to be used as the source of sGC. An aliquot of the supernatant and the compound to be tested are added to a buffer containing GTP, the substrate of sGC. The activity of sGC is described in Cerzer et al., J. Pharmacol. Exp. Ther. 1983, 226: 180.

The efficacy of compounds in the inhibition of PDEs can be assessed in vitro by the following assays. Washed platelets are suspended in Tris-HCl buffer and disrupted by sonication. The lysate is then centrifuged to obtain a supernatant containing PDEs. An aliquot of the supernatant is taken to make a PDE-containing solution. The compound to be tested and cGMP (substrate of PDE) are added to the solution. Then, the addition of Hanna operational OPA Goose (Ophiophagus hannah) baemdok to produce shoes guanosine 5'-GMP are uncharged by removing the phosphate in the (converted from cGMP by PDEs year). Anion-exchange resin is used to remove residual cGMP. After centrifuging the cGMP-removed solution, an aliquot of the supernatant is taken to quantify uncharged guanosine with a liquid scintillation counter (LSC). The activity of PDEs is assessed based on the amount of uncharged guanosine.

In vitro assays can be used to assess the efficacy of the fused pyrazolyl compounds of the invention in inhibiting platelet aggregation due to low intracellular cGMP levels. For example, the compounds are incubated in platelet suspensions containing platelet aggregation factors, and then the degree of aggregation is measured as turbidity with a dual-channel lumiaggregometer to determine Teng et al., Biochem. Biophys Acta. 1987, 924: 375-382 according to the method described in percent.

Screening in vivo (in vivo) can be carried out according to methods known to the art.

Without further effort, it is believed that one of ordinary skill in the art can, based on the description herein, utilize the present invention to its fullest extent. All publications cited herein are hereby incorporated by reference in their entirety. Accordingly, the following specific examples describing the synthesis and biological testing of the various compounds of the present invention should be understood to be illustrative only and in no way limit the remainder of the disclosure.

Example 1:

1-benzyl-3- (5'-methoxycarbonyl-2'-furyl) -5,6-methylenedioxoindazole

(compound One ) Synthesis

First 5-methoxycarbonyl-2-furyl-3 ', 4'-methylenedioxophenylphenyl was synthesized as follows: anhydrous iron chloride (0.42 g, 2.6 mmol) and 3,4-methylenedioxobenzoyl chloride ( 52.4 g, 0.3 mmol) was dissolved in CCl ₄ (40 ml). Methyl-2-furoate (25.2 g, 0.20 mmol) was then added dropwise into the solution over 10 minutes. The solution was heated at reflux for 36 hours and then cooled to room temperature. Water (120 ml) was added to the solution to give a mixture. The mixture was stirred for 1 hour and then left until it was separated into two layers (ie water layer and CCl ₄ layer). The precipitate was recovered and dissolved in chloroform. The water layer (top) was extracted with chloroform. The extract was combined with the precipitate solution, dried over anhydrous magnesium sulfate and filtered. The solvent of the filtrate was removed under reduced pressure to yield a residue. The residue was recrystallized from isopropanol to give 57.1 g of 5-methoxycarbonyl-2-furyl-3 ', 4'-methylenedioxophenyl ketone in a yield of 56.0%.

mp: 81-82 ° C

MS (%), m / z: 274 (M ⁺ )

IR (KBr) γ _max : 1716, 1635cm ^-1 (C = O)

¹ H-NMR (CDCl ₃ ) δ: 3.95 (3H, s, —OCH ₃ ); 6.08 (3H, s, -OCH ₂ 0-); 7.00 (2H, doublet, J = 10.2 Hz, H-5); 7.27 (2H, S, H-3 ', 4'); 7.56 (1H, doublet, J = 1.7 Hz, C2-H); And (2H, doublet of doublets, J = 10.2, 1.7 Hz, H-6)

Elemental Analysis C, H (%): Calculated: 61.32, 3.68; Measured value: 61.32, 3.70

6.6 g (0.024 mol) of 5-methoxycarbonyl-2-furyl-3 ', 4'-methylenedioxophenyl ketone thus obtained was first dissolved in methanol (60 ml). Benzylhydrazine (9.0 g, 0.070 mol) and acetic acid (0.5 ml) were added to the ketone solution. The solution was then heated to reflux until the reaction was complete. After cooling the solution to room temperature, the solvent was removed in vacuo to give a residue. The residue was extracted with chloroform. The extract was washed sequentially with diluted HCl solution and water and then dried over anhydrous magnesium sulfate. The dried solution was then filtered and the solvent of the filtrate was removed to afford 5-methoxycarbonylfuryl methylenedioxophenyl ketone benzylhydrazone.

The benzylhydrazone thus obtained was first dissolved in dichloromethane (100 ml). The solution thus obtained was added dropwise to Pb (OAc) ₄ (28.2 g, 0.06 mol) dichloromethane solution (400 ml). The mixture was then heated at 30 ± 2 ° C. for 30 minutes and then BF ₃ · Et ₂ O (containing 47% BF ₃ , 122 ml) was added. The mixture was heated at reflux for 30 minutes and then poured into ice water (1000 ml) to complete the reaction. The organic layer was separated, washed sequentially with water and 10% sodium carbonate solution, neutralized by water washing, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to give an oily crude product. Obtained. Ethanol was then added to the crude product, and then the mixture was left overnight in the refrigerator to produce a precipitate. The precipitate was recovered and recrystallized from ethanol to give 5.7 g of compound 1 in a yield of 63.8%.

mp: 190 ~ 192 ℃

MS (%), m / z: 376 (M ⁺ )

IR (KBr) γ _max : 1724cm ^-1 (C = O)

¹ H-NMR (CDCl ₃ ) δ: 3.93 (3H, s, —OCH ₃ ); 5.51 (2H, s, = NCH _2- ); 5.98 (2H, s, -OCH ₂ 0-); 6.62 (1H, s, H-7); 6.91 (1H, doublet, J = 3.8 Hz, H-3 '); 7.18-7.32 (6H, m, H-4 ', phenyl); And 7.52 (1H, s, H-4)

Elemental Analysis C, H, N (%): Calculated: 67.02, 4.29, 7.44; Measured value: 67.12, 4.31, 7.47

Example 2:

1-benzyl-3- (5'-hydroxycarbonyl-2'-furyl) -5,6-methylenedioxoindazole

(compound 2 ) Synthesis

Compound 1 (120 mg, 0.32 mmol) was dissolved in a mixture of methanol (8 ml) and sodium hydroxide solution (75 mg in 3 ml of water). The solution was heated to reflux. After cooling, the solvent was removed to give a residue. The residue was dissolved in water (1.5 ml) and acidified with diluted HCl solution to give a precipitate. The precipitate was recovered and then recrystallized from acetone to give 87.5 mg of compound 2 in 75.5% yield.

mp: 291-292 ° C

MS (%), m / z: 362 (M ⁺ )

IR (KBr) γ _max : 3479cm ^-1 (-OH), 1720cm ^-1 (C = O)

¹ H-NMR (DMSO-d ₆ ) δ: 5.62 (2H, s, = NCH _2- ); 6.11 (2H, s, -OCH ₂ 0-); 7.09 (1H, doublet, J = 3.6 Hz, H-3 '); 7.20-7.36 (7H, m, H-7, 4 ', phenyl); And 7.43 (1 H, s, H-4)

Elemental Analysis C, H, N (%): Calculated: 66.30, 3.89, 7.73; Found: 66.35, 3.92, 7.78

Example 3:

1-benzyl-3- (5'-hydroxymethyl-2'-furyl) -5,6-methylenedioxoindazole

(compound 3 ) Synthesis

Anhydrous calcium chloride (88.8 mg, 0.8 mmol) was stirred with anhydrous THF (20 ml) with sodium borohydride (60 mg, 1.6 mmol) for 4 hours to prepare a calcium borohydride solution. Then 30 ml of a THF solution containing 101 mg of compound 1 (0.27 mmol) was added dropwise to the calcium borohydride solution at 30 ± 2 ° C. The mixture was heated at reflux for 6 hours, cooled and then quenched with ice. The solvent was then removed to give a solid product which was dissolved in 50 ml of dichloromethane. Petroleum ether was added to the dichloromethane solution to obtain a precipitate. The precipitate was recovered and purified by column chromatography (silica gel-benzene) to give 84.5 mg of compound 3 in a yield of 90%.

mp: 122-123 degreeC

MS (%), m / z: 348 (M ⁺ )

IR (KBr) γ _max : 3387cm ^-1 (-OH)

¹ H-NMR (CDCl ₃ ) δ: 2.05 (1H, br, -OH); 4.71 (2H, s, -CH ₂ O); 5.53 (2H, s, = NCH _2- ); 5.99 (2H, s, -OCH ₂ 0-); 6.43 (1H, doublet, J = 3.3 Hz, H-4 '); 6.61 (1 H, s, H-7); 6.76 (1H, doublet, J = 3.3 Hz, H-3 '); And 7.20-7.31 (6H, m, H-4, phenyl)

Elemental Analysis C, H, N (%): Calculated: 68.96, 4.63, 8.04; Measured value: 68.92, 4.61, 8.01

Example 4:

1-benzyl-3- (5'-methoxymethyl-2'-furyl) -5,6-methylenedioxoindazole

(compound 4 ) Synthesis

0.23 g (0.66 mmol) of Compound 1 were dissolved in 5 ml of THF. 0.8 g (3.3 mmol) of NaH was added to the solution at 0 ± 2 ° C. to obtain a mixture, and the mixture was reacted at the same temperature for 0.5 hours. Subsequently, 0.1 g (0.66 mmol) of methyl iodide was added to the reaction mixture. The mixture was stirred for 1 hour and then quenched with ice water. The mixture thus obtained was extracted with CH ₂ Cl ₂ , the extract was neutralized with water, washed and dried over anhydrous magnesium sulfate. The solvent was dried under vacuum to give a residue which was then purified by column chromatography (silica gel-benzene) to give 0.24 g of compound 4 in 80% yield.

mp: 99-101 ° C.

MS (%), m / z: 362 (M ⁺ )

IR (KBr) γ _max : 1635cm ^-1 (C = -O)

¹ H-NMR (CDCl ₃ ) δ: 3.42 (3H, S, -OCH ₃ ); 4.52 (2H, s, -CH ₂ 0); 5.52 (2H, s, = NCH _2- ); 5.98 (2H, s, -OCH ₂ 0-); 6.48 (1H, doublet, J = 3.3 Hz, H-4 '); 6.61 (1 H, s, H-7); 6.79 (1H, doublet, J = 3.3 Hz, H-3 '); 7.15-7.30 (5H, m, H-4, phenyl); And 7.38 (1 H, S, H-4)

Elemental Analysis C, H, N (%): Calculated: 68.60, 5.01, 7.73; Measured value: 69.58, 5.03, 7.71

Example 5:

sGC activation

Teng et al., Thromb. Haemost. Washed rabbit platelets were prepared according to the method described in 1988, 59: 304. The platelets were suspended in 50 mM pH 7.4 Tris-HCl buffer and then disrupted by sonication. The lysate thus obtained was centrifuged at 39,000 × g at 4 ° C. for 20 minutes, and the supernatant was used as the sGC source. Two 50 μl aliquots of the supernatant were respectively GTP (0.2 mM, containing 1 × 10 ⁶ cpm [α- ³² P] GTP), MgCl ₂ (5 mM), cGMP (2.5 mM), creatine phosphate (15 mM) and 150 μl of pH 7.4 Tris-HCl (50 mM) buffer containing creatine phosphokinase (30 μg) was added. One of the two solutions also contains 100 μM of compound 3 . After 10 minutes of incubation at 30 ° C., the conversion of GTP to cGMP by sGC was terminated with HCl (200 μl, 0.5N). The reaction solution was then heated at 100 ° C. for 6 minutes and then cooled in an ice bath. Imidazole (200 μl, 1 mM) was added to each mixture, followed by GTP and cGMP by White et al., Anal. Biochem. Separation was carried out on neutral alumina as described in 1971, 41: 372. Radioactivity ([ ³² P] cGTP) was measured with a liquid scintillation counter (LSC) to determine the amount of GTP. As a result, Compound 3 was found to be an effective activator of sGC.

Example 6:

Inhibition of PDE

Teng et al., Biochem. Biophys. Acta. Washed human platelets were prepared according to the method described in 1989, 990: 315-320. The platelets were suspended in 50 mM pH 7.4 Tris-HCl buffer (containing 5 mM MgCl ₂ ) and then disrupted by sonication at 4 ° C. The lysate thus obtained was centrifuged at 39,000 × g for 20 minutes at 4 ° C. to obtain a supernatant containing PDEs. An aliquot of the supernatant was taken to prepare two PDE solutions (in Tris-HCl buffer). One of the two PDE solutions contains 10 μM of compound 3 . Both solutions were first incubated at 37 ° C. for 5 minutes, then 10 μM cGMP (containing 0.1 μCi [ ³ H] cGMP) was added. After further incubation at 37 ° C. for 30 minutes to convert cGMP to 5′-GMP by PDEs, both solutions were heated at 100 ° C. for 1 minute and then cooled to room temperature. Then, the operational OPA Goose Hannah (Ophiophagus hannah) baemdok was added (0.1ml, 1mg / ml), and converted into guanosine 5'-GMP are ttiji to the charge at 25 ℃ by incubation for 30 min. Ion-exchange resin slurry (1.0 ml; Dowex-1, Sigma Chemical Co., St. Louis, Mo.) was added to each solution to remove residual cGMP by binding. Each of the cGMP-removed solutions thus obtained was centrifuged, an aliquot (0.5 ml) of the supernatant was taken, and uncharged guanosine was quantified by a liquid scintillation counter (LSC). As a result, Compound 3 was found to be a potent inhibitor of PDEs.

Example 7:

Inhibition of Platelet Aggregation

Blood from rabbit ear peripheral blood vessels was added with EDTA to a final concentration of 6 mM. The EDTA-containing blood was then centrifuged at 90 × g at room temperature for 10 minutes. The platelet-rich plasma supernatant was further centrifuged at 500 × g for 10 minutes. The platelet precipitate thus obtained was washed with a solution containing EDTA (2 mM) and serum albumin (3.5 mg / ml), and then centrifuged at 500 x g for 10 minutes. The precipitate was washed with Tyrode's solution without EDTA having the following composition: NaCl (136.8), KCl (2.8), NaHCO ₃ (11.9), MgCl ₂ (1.1), NaH ₂ PO ₄ (0.33), CaCl ₂ (1.0 ), And glucose (11.2). After centrifugation under the same conditions, platelet precipitates were suspended in Tyrode's solution without the EDTA described above. Platelets were counted by Coulter Counter (model ZM) and adjusted to 4.5 × 10 ⁸ platelets / ml.

The compound to be tested was added to four platelet suspensions and incubated at 37 ° C. for 3 minutes under stirring conditions (900 rpm). After 1 minute of stirring, four aggregation inducers, thrombin, collagen, arachidonic acid (AA), and platelet aggregation factor (PAF), respectively, were added to the four suspensions to allow platelets to aggregate. Platelet aggregation in each suspension is described by Born et al., J. Physiol. It was measured using a dual-channel lumiaggregometer (model 1020, Payton, Canada) according to the turbidimetric method disclosed in 1963, 168: 178-195. Percent platelet aggregation values measured 5 minutes after each aggregation inducer were added to Teng et al., Biochem. Biophys Acta. It was calculated according to the method described in 1987, 924: 375-382.

Compounds 1 , 2 , 3 and 4 were tested and they all showed inhibitory effects on platelet aggregation induced by different inducers. Among them, compound 3 was most effective in inhibiting platelet aggregation induced by thrombin, AA, collagen, and PAF.

Other embodiments

A number of embodiments of the invention have been described. Nevertheless, it will be understood that various modifications may be made without departing from the spirit and scope of the invention. For example, the alkylenedioxo groups in 1-benzyl-3- (5'-methoxycarbonyl-2'-furyl) -5,6-methylenedioxoindazole may be selected from one or two lower alkylene groups (i.e., C _1-2 ) may be attached to the fused phenyl group. Accordingly, other embodiments are also within the scope of the following claims.

As described in detail above, the fused pyrazolyl compounds of the present invention can increase intracellular cGMP levels by activating sGCs or inhibiting PDEs, which is associated with low activity of sGCs, high activity of PDEs, or platelet aggregation. It is useful for the treatment of diseases.

Claims (36)

Fused pyrazolyl compounds having the structure of Formula 1: [Formula 1] Where Ar ₁ , Ar ₂ , and Ar ₃ are each independently substituted with halo, alkyl, carboxyl, alkoxycarbonyl, thiocarbonyl, aminocarbonyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, or thioalkyl Phenyl, thienyl, pyrrolyl, or furyl; X and Y are each independently an oxygen atom, a sulfur atom, or NH; m is 1, 2, or 3; And, n is 0, 1, 2, 3, or 4. The method of claim 1, X is an oxygen atom, Y is an oxygen atom, and m is 1, fused pyrazolyl compound. The method of claim 2, Ar ₂ is a fusion characterized in that it is phenyl or furyl, optionally substituted with halo, alkyl, carboxyl, alkoxycarbonyl, thiocarbonyl, aminocarbonyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, or thioalkyl Pyrazolyl compounds. The method of claim 3, wherein Ar ₁ is phenyl pyrazolyl, characterized in that it is phenyl, optionally substituted with halo, alkyl, carboxyl, alkoxycarbonyl, thiocarbonyl, aminocarbonyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, or thioalkyl compound. The method of claim 3, wherein Ar ₃ is a fused pyrazolyl compound, characterized in that thienyl or phenyl. The method of claim 5, Ar ₁ is phenyl pyrazolyl, characterized in that it is phenyl, optionally substituted with halo, alkyl, carboxyl, alkoxycarbonyl, thiocarbonyl, aminocarbonyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, or thioalkyl compound. The method of claim 5, Ar ₃ is thienyl, fused pyrazolyl compound. The method of claim 7, wherein Ar ₁ is phenyl pyrazolyl, characterized in that it is phenyl, optionally substituted with halo, alkyl, carboxyl, alkoxycarbonyl, thiocarbonyl, aminocarbonyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, or thioalkyl compound. The method of claim 5, Ar ₃ is phenyl, wherein the fused pyrazolyl compound. The method of claim 9, Ar ₁ is phenyl pyrazolyl, characterized in that it is phenyl, optionally substituted with halo, alkyl, carboxyl, alkoxycarbonyl, thiocarbonyl, aminocarbonyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, or thioalkyl compound. The method of claim 2, Ar ₃ is a fused pyrazolyl compound, characterized in that thienyl or phenyl. The method of claim 11, Ar ₁ is phenyl pyrazolyl, characterized in that it is phenyl, optionally substituted with halo, alkyl, carboxyl, alkoxycarbonyl, thiocarbonyl, aminocarbonyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, or thioalkyl compound. The method of claim 11, Ar ₂ is fused pyrazolyl, characterized in that it is furyl, optionally substituted with halo, alkyl, carboxyl, alkoxycarbonyl, thiocarbonyl, aminocarbonyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, or thioalkyl compound. The method of claim 13, Ar ₁ is phenyl pyrazolyl, characterized in that it is phenyl, optionally substituted with halo, alkyl, carboxyl, alkoxycarbonyl, thiocarbonyl, aminocarbonyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, or thioalkyl compound. The method of claim 11, Ar ₂ is fused pyrazolyl, characterized in that it is phenyl optionally substituted with halo, alkyl, carboxyl, alkoxycarbonyl, thiocarbonyl, aminocarbonyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, or thioalkyl compound. The method of claim 15, Ar ₁ is phenyl pyrazolyl, characterized in that it is phenyl, optionally substituted with halo, alkyl, carboxyl, alkoxycarbonyl, thiocarbonyl, aminocarbonyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, or thioalkyl compound. The method of claim 1, Ar ₂ is a fusion characterized in that it is phenyl or furyl, optionally substituted with halo, alkyl, carboxyl, alkoxycarbonyl, thiocarbonyl, aminocarbonyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, or thioalkyl Pyrazolyl compounds. The method of claim 17, Ar ₁ is phenyl pyrazolyl, characterized in that it is phenyl, optionally substituted with halo, alkyl, carboxyl, alkoxycarbonyl, thiocarbonyl, aminocarbonyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, or thioalkyl compound. The method of claim 17, Ar ₃ is a fused pyrazolyl compound, characterized in that thienyl or phenyl. The method of claim 19, Ar ₁ is phenyl pyrazolyl, characterized in that it is phenyl, optionally substituted with halo, alkyl, carboxyl, alkoxycarbonyl, thiocarbonyl, aminocarbonyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, or thioalkyl compound. The method of claim 19, Ar ₃ is thienyl, fused pyrazolyl compound. The method of claim 21, Ar ₁ is phenyl pyrazolyl, characterized in that it is phenyl, optionally substituted with halo, alkyl, carboxyl, alkoxycarbonyl, thiocarbonyl, aminocarbonyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, or thioalkyl compound. The method of claim 19, Ar ₃ is phenyl, wherein the fused pyrazolyl compound. The method of claim 23, wherein Ar ₁ is phenyl pyrazolyl, characterized in that it is phenyl, optionally substituted with halo, alkyl, carboxyl, alkoxycarbonyl, thiocarbonyl, aminocarbonyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, or thioalkyl compound. The method of claim 1, Ar ₃ is a fused pyrazolyl compound, characterized in that thienyl or phenyl. The method of claim 25, Ar ₁ is phenyl pyrazolyl, characterized in that it is phenyl, optionally substituted with halo, alkyl, carboxyl, alkoxycarbonyl, thiocarbonyl, aminocarbonyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, or thioalkyl compound. The method of claim 25, Ar ₂ is fused pyrazolyl, characterized in that it is furyl, optionally substituted with halo, alkyl, carboxyl, alkoxycarbonyl, thiocarbonyl, aminocarbonyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, or thioalkyl compound. The method of claim 27, Ar ₁ is phenyl pyrazolyl, characterized in that it is phenyl, optionally substituted with halo, alkyl, carboxyl, alkoxycarbonyl, thiocarbonyl, aminocarbonyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, or thioalkyl compound. The method of claim 25, Ar ₂ is fused pyrazolyl, characterized in that it is phenyl, optionally substituted with halo, alkyl, carboxyl, alkoxycarbonyl, thiocarbonyl, aminocarbonyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, or thioalkyl compound. The method of claim 29, Ar ₁ is phenyl pyrazolyl, characterized in that it is phenyl, optionally substituted with halo, alkyl, carboxyl, alkoxycarbonyl, thiocarbonyl, aminocarbonyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, or thioalkyl compound. The method of claim 1, Ar ₁ is phenyl; Ar ₂ is furyl, which is linked to the pyrazolyl ring at 2-C and is substituted at 5-C with methoxymethyl, hydroxymethyl, methoxycarbonyl, or hydroxycarbonyl; Ar ₃ is phenyl which is phenyl fused to said pyrazolyl ring at 1-C and 2-C and substituted with X and Y at 4-C and 5-C, respectively; X and Y are each an oxygen atom; And, m and n are each 1, fused pyrazolyl compound. A pharmaceutical composition comprising a compound having the structure of Formula 1 [Formula 1] Where Ar ₁ , Ar ₂ , and Ar ₃ are each independently substituted with halo, alkyl, carboxyl, alkoxycarbonyl, thiocarbonyl, aminocarbonyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, or thioalkyl Phenyl, thienyl, pyrrolyl, or furyl; X and Y are each independently an oxygen atom, a sulfur atom, or NH; m is 1, 2, or 3; And, n is 0, 1, 2, 3, or 4. The method of claim 32, X is an oxygen atom, Y is an oxygen atom, and m is 1, the pharmaceutical composition. The method of claim 33, Ar ₂ is phenyl or furyl pharmaceutical composition, characterized in that. The method of claim 33, Ar ₃ is thienyl or phenyl. The method of claim 33, The compound has a structure of formula 2, 3, 4, or 5, characterized in that: