TWI293027B - - Google Patents

Description

1293027 V. INSTRUCTIONS (2) Alkoxy groups [Example: -(^ = (^-0-C5HU], thiophene Weigi [eg: -( C = 0)-S-C4H9], aminocarbonyl) [Example: -(c = 〇)-N(C3H7)2], hydroxyalkyl (for example: -C6H120H), alkoxyalkyl (for example: -C3H6-0"C4H9), amine group, aminoalkyl group [Example: -C3H6N(C3H7)2], thioalkyl (for example: -C4H8SC4H9) or oxyalkoxy (for example, ·CH2CH20- is a disubstituted group). This compound is administered by an individual in an effective amount. To treat the disease. The following is a structural formula containing many of the aforementioned condensed D ratios.

The structural formula (I) comprises a pyrazole core and three aryl groups, i.e., Aq, Αιν and Ars represent the three aryl groups described in the foregoing. Each of, Ar 2 and Ar^ may be independently identified as a phenyl group, a thienyl group, a furyl group or a pyrrolyl group; each of h, R2, Rs, &, & and the heart may be individually and independently One hydrogen, one dentine-R, one c(=〇)〇H, -C(=0)0R, -C(=0)SH, -C(=〇) SR, -C( = 〇)NRR, A R0H — R 〇 R, — — RSH, —〇R, 〇H, _sr, —SH, —NRR′, —NHR, —RNR'R", —RNHR′ or —RSR, or heart and R2 ", R3 and 匕 together or R5 and r6 together are a 〇R 〇; wherein R and Rn may independently be alkyl of Ci $; and η is 1 or 2 or 3. Compound of formula (I) The characteristics of a group of compounds in

Page 5 1293027 V. Description of Invention (3): η is 1, Ar3 is phenyl, and each of R5 and R6, independently hydrogen, halogen, -R, -C(=〇)〇H,- C( = 0)0R, -C( = 0)SH, -C( = 0)SR, -C(=0)NRR', -R〇H, -R〇R', -RSH -NRR', - NHR—RNR'R ", -RNHR, or -RSR,; or R5 and Ruler 6 — are both -0R0-. Another group of compounds of the formula (I) are characterized by the fact that η is 1, Ar3 is a furyl group, and each of R5 and hydrazine is independently hydrogen, halogen, -R, -C( = 0 )0H, -C(=0)0R, -C( = 0)SH, -C(=〇) SR, -c(=0)NRR', -R0H, -R0R', -RSH, -NRR, -NHR, -R ΝΠ, -RNHR' or -RSR'; or R5 and R6 - are both -〇R〇-. The following are specific examples of such compounds that can be used to carry out the invention: 1-indolyl-3-(4'-ethoxycarbonyl)phenyl-B-primed, 1-mercapto-3-( 3'-Methyl)phenyl-D-n-n, 1-indolyl-3-(5'-dimethylaminoindolyl)furanyl-carbazole, 1-benzyl-3-(5,- Methoxymethyl)furanyl-carbazole, 1-T-yl-3-(5'-hydroxymethyl)furanyl-6-methyl-oxazole, benzyl-tris(5'-hydroxymethyl) Furanyl-carbazole, 1-benzyl-1,3-(5-hydroxymethyl)furanyl-6-fluoro-indenyl, 1-benzyl-3-(5,-hydroxymethyl)furanyl-6 -Methoxy-D- 丨 丨 以及 and 〒 -3--3-(5'-hydroxymethyl)furanyl-5,6-fluorenylenedioxy-D The structure of the (4,-ethoxycarbonyl)phenyl-oxazole and the benzyl-3-n-(5-methylaminomethyl)pyranyl-D-doprene compound is as follows: 'The aryl group is also indicated. Number of each atom:

1293027 —1-—.— V. Description of invention (4)

For the sake of simplicity, the fused D to 0-supplement compounds described above are those which comprise a pharmaceutically acceptable salt and a precursor thereof, which may be a ratio of a condensed D to a positively charged substituent on the compound. (eg, an amine group) is similar to I formed by a negatively charged relative ion (eg, a gas ion, a bromide ion, a moth ion, a sulfate ion, a nitrate ion, a phosphate ion, or an acetate ion) A negatively charged substituent on a pyrazole compound (eg, a slow group) can be associated with a positively charged ion (eg, sodium ion, potassium ion magnesium ion, dance ion, or class cation (eg, tetramethine ion) ) Formation of salts. Salts which can be used in the present invention, for example, 1-hydroxyl 3-(5'-aminomethyl)furanyl-oxazole hydrochloride and benzyl-3-yl-amp; 'carboxy-phenyl) phenyl - sodium salt of carbazole. Examples of prodrugs include esters and other pharmaceutically acceptable derivatives which, upon administration, produce the fused pyrazole compounds described above. This thickening must be done before a person in need takes a fused pyrazole compound to treat a disease associated with PAR-induced cell activation (eg, arteriosclerosis, myocardial infarction, unstable angina, thrombosis, etc.) Oh, the saliva compound is formulated into a pharmaceutical composition. Therefore, the scope of the present invention is a kind of inclusion or treatment for treating the diseases or symptoms described in the foregoing.

1293027 V. INSTRUCTIONS (5) A pharmaceutical composition of a viscous fused pyrazole compound (or a salt thereof) and an acceptable carrier. Examples of the carrier include colloidal cerium oxide, stearic acid hydride, cellulose, sodium lauryl sulfate, and MC YeU〇w #1〇. The present invention also relates to the use of such a pharmaceutical composition for the manufacture of a medicament for the treatment of the diseases or conditions described hereinbefore. In the present invention, it is surprisingly capable of specifically inhibiting cell activation induced by PAR (e.g., coagulase), such as platelet aggregation, which has little or no inhibitory effect on other platelet activating factors. Other advantages and features of the invention will be apparent from the following detailed description of the embodiments of the invention. DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a pharmaceutical composition comprising a fused pyrazole compound for use in the treatment of diseases caused by protease-activated receptor (pARs)-induced cell activation, and these fused pyrazole compounds . The method for synthesizing the fused pyrazole compound is as follows: first, an aryl aryl ketone is prepared by bonding an aryl carbene gas with another aryl compound, and each aryl compound can be selectively provided. There are single- or multiple-substituents. The ketone compound and the monoarylalkyl group, the aryl group referred to herein may also optionally have a mono- or poly-substituent reaction to form a ruthenium compound containing three aryl groups, which are further converted. A fused pyrazole compound is prepared. In the fused pyrazole compound, one aryl group is bonded to the position of the pyrazole core at the N position using an olefinic linker, and the other aryl group is fused to the 4-C and 5-C positions of the pyrazole core and The third aryl group is directly bonded to the 3-C position of the pyrazole core. Various derivatives of the fused ruthenium compound can be repaired

Hi 9006068.ptd Page 8 1293027 V. INSTRUCTIONS (6) Prepared by changing the substituent on any aryl group. Three types of fused pyrazole compounds were synthesized, that is, 1-benzyl-3-mouth fumarate "snoring, 1-mercapto-3-phenyl-D-inducing saliva and saliva sit. The following Scheme 1 shows the synthesis of five benzylfuranyl-carbazoles (designated as (1)-(5), respectively), which are useful in the practice of the invention.

Flow chart 1

9006068.ptd Page 9 1293027 V. INSTRUCTIONS (7) - As shown in Scheme 1, (5~methoxycarbonyl-2-furfuryl)phenyl ketone is composed of methyl 2-furanoate and benzamidine After the gas bonding, the benzyl hydrazine compound obtained by mixing the E- and Z-form isomers is formed after the reaction with the benzyl hydrazine. The isomer mixture is then converted to the compound d) via a comparable azo intermediate after treatment with lead tetraacetate and a boron difluoride-ether complex in dichloromethane at room temperature. The methoxycarbonyl group of the compound can be hydrolyzed to a carboxylic acid group by sodium hydroxide to form a compound (2). On the other hand, the use of 'methoxycarbonyl group' can be reduced to a methylol group by using boron argon calcium hydride in tetrahydro D-propanol to form compound (3). The compound (3) is sequentially subjected to the action of boron trioxide and diethylamine to obtain an N,n-diethylaminoindenyl derivative, that is, the compound (4). Alternatively, the compound (3) may be used in the order of using boron trioxide and methanol in order to obtain a methoxymethyl derivative, that is, a compound (5). Although not shown in the scheme 1, the derivative of the compound (!)-(5) may be an aryl group which is a mono- or poly-substituted group of other methyl phthalate, benzamidine. Or a benzyl hydrazine starting material is prepared. The 1-benzyl-4-phenyl-oxazole compound can be equipped according to the reaction sequence shown in Scheme 1 '" ί 疋, which must be selectively provided with a soap- or poly-substituted group A ketone is substituted for 2-nonyl phenyl. The oxidation of benzophenone to benzoylbenzoic acid using chromium trioxide is the first step of the reaction. The benzamidine benzoic acid is then reacted with ethanol to form benzamidine benzoic acid, which is then converted to 1-mercapto-4-phenyl-rhodium. If desired, the benzyl-4-phenyl-Q-oxazole can be further converted to other derivatives by modifying the substituents on the three aryl groups. A fused pyrazole compound containing a thienylpyrazole structure can also be based on a stream

9006068.ptd Page 10 1293027 V. INSTRUCTION DESCRIPTION (8) The synthesis method shown in Scheme 1 was prepared, but in this case 2-thienylphenyl ketone must be used instead of 2-furyl phenyl ketone. Any mono- or poly-substituted thiophene B prepared using this method may be further modified to form an additional thienylpyrazole compound than the salic compound.

An effective amount of a fused pyrrole compound or a salt thereof and a pharmaceutically acceptable carrier must be formulated into a pharmaceutical preparation for the individual in need thereof to take the fused and azole compound to treat a disease associated with PAR-induced platelet aggregation. Composition. "Effective amount" means the amount of the compound used to treat a therapeutically effective subject, and the relationship between the animal and the human dose (based on milligrams per square meter of body surface area). See Freireich et al., Cancer Chemother. Rep., 1 966, 50, 219 states that the body surface area can be approximated from the patient's height and weight. See, eg, Scientific Tables, Geigy Pharmaceuticals, Ardley, New York, 1 970, 537. As recognized by those skilled in the art, the difference in effective dose may result from the route of administration, the excipient, and the co-use of other therapeutic agents (including the use of other anti-platelet aggregation drugs) η ^ The pharmaceutical composition may be passed through the skin Examples of topical, subcutaneous, intraperitoneal, and gastrointestinal dosage forms include activated isotonic saline, 5% glucose solubilized carrier. The agent may also contain other solubilizing agents known to the dissolving agent. The gastrointestinal route is administered, for example, intramuscularly and intravenously. An aqueous solution of the compound, the solvent may be a liquid or any known agent such as a cyclodextrin or a technique for practicing the present invention. The fused pyrrole compound can be used in the practice of the present invention.

1293027 V. INSTRUCTIONS (9) The method of formulating the drug for use in the skin, the use of soft capsules or ingots may be based on the compression of the mountain clay. The appropriate amount of the agent and the tableting agent 0 can be used to evaluate the platelets in the cell activation of the fused pyrrole and trigger the degree of platelet coagulation. The steps of the known process can be used in the synthesis according to the specific implementations listed here, and the organism can not be used as the hair:: way=(?, · oral 'mucosal administration or oral administration etc.~ The pharmaceutical composition can be formulated into, for example, a capsule = Γ =; the dosage form 1 capsule may contain any mature active compound, solid carrier and lubrication = Gu Zhao carrier examples such as temple powder, sugar and fire = have ': lactose or mannitol for bonding Agent, traditional filling, etc., into a hard shell or capsule form of the knife to take the compound = (in vitro) inhibition activity can be inhibited by the PARs (pre-activated by thrombin): for example, can be prepared to suspend in Tyr 〇de solution 欲:: The compound is cultured together 'Add thrombin to collect, and then measure the turbidity using a translucent coagulometer to determine the in vivo test can be carried out according to this. π T _ One step detail ώ In this regard, it is believed that the descriptions set forth herein are intended to be exhaustive of the application of the invention. All publications are hereby incorporated by reference. The method of testing, exemplified by way of illustration only therefore, whether such; = clear limit scope.

1293027 V. INSTRUCTIONS (10) Dimethyl-3-(5'-methoxycarbonyl-2'-furanyl)-introduction, synthesis of (a) (5-methoxyhistyl-2-? Synthesis of phenyl ketone

Anhydrous ferric chloride (〇·42 g, 2.6 mmol) and gasified benzamidine (29.6 g, 〇·21 mmol) were dissolved in four carbonized carbon (40 ml). Methyl furan-2-carboxylate (25. 2 g, 0.20 mmol) was added dropwise over 10 minutes. The reaction mixture was then heated to reflux for 3 6 h then added to water (120 mL). The mixture was stirred for 1 hour and then allowed to stand to separate into two layers. The water layer and the sedimentation are extracted by gas imitation. The chloroform extraction layer was dried over anhydrous magnesium sulfate and filtered. The solvent of the filtrate was removed under reduced pressure, and the residue was recrystallized from isopropyl alcohol to give a yield of 64.0% of (5- methoxymethyl-2- fluorenyl) phenyl phthalate. Mp: 70-73 0 C. MS (%), m/z: 230 (M+). IR (KBr) max: 1720,1 650 cm-i (〇〇)· , Η-NMR (CDCls, 200 MHz) : 3.86 (3H, s, -CH3), 7. 26-7.32 (2H, m, H 3 , 5 ), 7.40-7.65 (3H, m, H-3, 4,4V) , &8·05- 8·10(2Η, ηι, Η-2', 6,)

(b) Synthesis of benzyl-3-(5'-fluorenyloxycarbonyl-2,-furanyl)carbazole (5-methoxycarbonyl-2-furyl)phenyl ketone (5 5 g, () () 24 Mool) was dissolved in methanol (60 ml), and benzyl hydrazine (9 g, 〇〇7 mol) and acetic acid (〇·5 ml) were added and heated to reflux until the reaction was completed. The solvent is evaporated to dryness. The obtained product is washed with dilute hydrochloric acid, followed by washing with water, and the residue is extracted with a gas mixture and finally with anhydrous acid and acid.

1293027

5. Description of the invention (11) to dry and filter. After removing the solvent of the filtrate, (5-methyl group 2 - Dfu) phenyl hydrazine can be obtained. The prepared solution of benzamidine in di-hydrogen methane (100 ml) was added dropwise to a solution of lead tetraacetate (28·2 g, 〇·06 mmol) dissolved in di-methane (4 〇〇 ml). . After the dropwise addition, the mixture was allowed to stand at 3 〇 ± 2. The reaction was carried out for 30 minutes under c. The addition of boron difluoride-B-form (containing ο% of monofluorinated 126 2 ml) was carried out. The reaction mixture was then heated to reflux for 3 hrs, then poured into ice water (100 mL) to terminate the reaction. After the organic layer was separated, it was washed with water and a 10% sodium carbonate solution in that order, and then washed with water until neutral. The organic layer was dried with anhydrous magnesium sulfate and evaporated Ethanol was added to the crude product, and the mixture was ice-cold overnight to effect precipitation. 0%。 The solid precipitate was collected and then recrystallized with ethanol to obtain 3.7 g of 1-benzyl-3-(5,-methoxycarbonyl-2,-furanyl)-oxazole, the yield was 47.0%. 〇mp: 117- 118oC. MS (%), m/z: 332 (M+). IR (KBr )max : 1 72 0 cm.! (C = 0). J-NMR (CDC13): 3·95 ( 3H, s, CH3), 5.66 (2H, s, = NCH2-), 7· 02 (1H, d, J = 3· 5 Hz, H-3,), 7· 20-7· 40 (9Η m, H-δ, 6, 7, 4', phenyl), and 8·26 (1H, dd, J=8·1, 1·5 Hz, H-4)· Example 2: 1-〒 Synthesis of 3-(5,-methoxycarbonyl-2'-furanyl)-6-fluorocarbazole

9006068.ptd Page 14 1293027 V. INSTRUCTION DESCRIPTION (12) 4,~-based (5-methoxybenzyl-2-decyl) ketone (5. 96 g) was prepared according to the method of Example 1 (a). , '24 used as a primer and according to the gram in the example 1 (b), the yield of 48.8% of the methoxyl methoxyl-2, _ 咲: yl) _; fluorocarbazole . Mp: 108-109° C. MS (%), m/z: 350 (M+). IR (KBr)nax: 1710 ciilJC:. iH-NMR (DMSO-d6, 200 MHz): 3·87 (3H, s, a Ch3), 5 73 (211, 3, 4 (: 112-), 7.18-7.37 (711, 1 „,! 1-5, 3,, 3 stupid ^), 7·45 (1H, d, J = 3.5 Hz, H-4), 7·77 (1H, dd, J = l〇0,1·5 Hz, C7-H), and 8.17 (1H· dd, J = 8.0, 6.3 Hz · C4-H)·, Example 3: T-based-3-(5'-methoxycarbonyl-2'-furanyl Synthesis of _6-methylcarbazole (5-methoxycarbonyl-2-furanyl) 4,-tolyl ketone (5.85 g, 〇·〇24 Mohr) was prepared by a similar method, using it as a The yield was 3.7 g, and the yield was 45.1% of benzyl-3-(5,-oxacarbonyl-2,-furanyl)-6-mercaptocarbazole. mp: 102-104 ° C. MS (%), m/z: 346 (M+) IR (KBr)max: 1 720 cm'1 (C = 〇). ^-NMRCDMSO-de): 2.46 (3H, s, ~CH3), 3.87 (3H, s,

9006068.ptd Page 15 1293027 V. Description of invention (13) -0CH2-), 5· 71 (2H, s, =NCH2-), , 7·14-7·36 (7H, m, Η-5, 3 ',, phenyl), 7·45 (1H, d, J = 3.4 Hz, H-4); 7·59 (1H, s, H-7); and 8·10 (1H, d·J=8.0 Hz, H-4). Example 4: Synthesis of 1-benzyl-3-(5'-methoxycarbonyl-2'-furanyl)-6-methoxycarbazole (5-methoxycarbonyl-2 4克克,收率为。 4 - methoxyphenyl ketone (6. 50. 2% of benzyl-3-(5'-methoxycarbonyl-2'-furanyl)-6-methoxy D. Mp: 108-109 ° C MS (°/〇), m/z: 362 (M+). IR (KBr)max: 1710 cm'1 (C = 0). ^-NMR (DMSO-d6, 20 0 MHz ): 3.85 (3H, s, -OCH3), 3.88 (3H, s, -COOCH3), 5.71 (2H, s, =NCH2-), 6· 95 (1H, d, J=8.5 Hz, H-5) , 7.16 (1H, d. J=3.5 Hz, H-3,), 7·24-7·36 (6H, m, H-7, phenyl), 7.40 (1H, d, J = 3.5 Hz, H -4), and 7.98 (1H, d, J = 8.5 Hz, H-4) · Example 5: 1-benzyl-3-(5'-methoxycarbonyl-2'-furanyl)-5, 6 - Synthesis of methylenedioxycarbazole

9006068.ptd Page 16 1293027

(5-methoxycarbonyl-2-furanyl) (3,4,-,y-dimethoxyphenyl)_ (6·24 g, 0·024 moir) was prepared by a similar method, using 6-亚甲甲。 The benzylic acid can be produced in a yield of 5·7 grams, 63.8% yield of 1-benzyl-3-(5,-methoxyweiyl-2'- sinyl)-5. 6 - Dioxy D is astringent. Mp: 1 90-1 92 0 C MS (%), m/z·· 376 (r)· IR (KBr) fflax: 1 724 cm-1 (C = 〇). ^-NMR (CDCI3, 200 MHz) : 3.93 (3H, s, -OCH3), 5.51 (2H, s, =NCH2~), 5. 98 (2H, s, -0CH20-), 6· 62 (1H, s, H-7), 6· 91 (1H,d,J = 3.8 Hz, H-3,), 7·18-7·32 (6H, m, H-4,, phenyl), and 7.52 (1H, s, H-4). Example 6: Synthesis of benzyl-3-(5'-carboxy-2'-furanyl)carbazole 1 -Mercapto-3-(5-indoleoxy- 2'-indolyl)d The mixture was dissolved in decyl alcohol (8 ml) and a solution of sodium hydroxide (75 mg in 3 ml of water) and heated to reflux. After cooling, the solvent was removed under reduced pressure. The residue was bathed in water (1.5 ml). The aqueous solution was then acidified with dilute hydrochloric acid to give crystals. After crystallization, it was recrystallized from acetone to give 73 mg of benzyl-3-(5,-carboxy-2,-furanyl)carbazole in a yield of 71.7%. Mp: 202-203 0 C. MS (%), m/z: 318 (M+). W (KBr)nax: 3450 cmUH) and 1 700 ciitKOO)·

9006068.ptd Page 17 1293027 V. INSTRUCTIONS (15) UMR (DMS0-d6, 200 ΜΗζ): 5·76 (2H,,s,=NCH2-), 7· 20 (1H,d,J = 3- 5 Hz, H-3,), 7·26-7·35 (6H, m, H-5, phenyl), 7·38 (1H, d, J = 3.5 Hz, H-4'), 7· 49 (1H, t, J = 8.2 Hz, H-6), 7.80 (1H, dd, J = 8. 2, 1.5 Hz, H-7), and 8·15 (1H,d,J = 8· 1 ,1·5 Hz, H-4)· Example 7 · Synthesis of benzyl-3-( 5'-carboxy-2'-furanyl)-6-fluorocarbazole using benzyl-3-(5'-A Oxycarbonyl-2'-furanyl-6-fluorocarbazole (11 2 mg, 0.32 mmol) is the starting material and can be treated according to the procedure described in Example 6 to give 70 mg of benzyl-3- (5'-Carboxy-2'-furanyl)-6-fluorocarbazole, yield 65%, mp: 252-253 ° C. MS (%), m/z·· 336 (M+)· IR (KBr )max·· 3450 cur1(-OH) and 1 690 cm-KOO)· UMR (DMSO-d6, 20 0 MHz): 5·72 (2H, s, =NCH2-), 7· 21 (1H, d, J = 3.5 Hz, H-3), 7.2 3-7.33 (6H, m, H-5, phenyl), 7·39 (1H, d, J = 3.5 Hz, H-4), 7·79 (1H ,dd, J = 9.8,1·8 Hz, H-7), and 8.17 (1H, dd, J = 8.5, 5·3 Hz, H-4) · Example 8: Synthesis of benzyl-3-(5,-carboxy-2'-furanyl)-6-methylcarbazole Mercapto-3-(5'-methoxycarbonyl-2'-furanyl)-6-methyloxime

9006068.ptd Page 18 1293027

V. Description of invention (16)

The azole (112 mg, 0·32 mmol) was the starting material, and according to the procedure described in Example 6, 9 5 mg of benzyl-3-(5, _carboxy~2, -furan was obtained. Base) - 6-methyl B guanidine, yield § 9 %. Mp: 201-202 0 C MS (°/〇), m/z: 332 (M+). IR (KBr)max: 3450 co^C-OH), 1 700 cm-KOO)· 4-NMR (DMSO- D6,200 MHz): 2·46 (3H, s, -CH3), 5·70 (2H, s, =NCH2-), 7·16 (1Η, d, J = 3.5 Hz, H-3'), 7·23-7·33 (6H, m, H-5, phenyl), 7·38 (1H, d, J = 3.5 Hz, H-4), 7.61 (1H, d, J = 1.4 Hz , H-7), and 8·0〇 (1H, d, J = 8.2 Hz, H-4)· Example 9: 1-T-based-3-(5'-rebel-2'-anthraquinone ) - 6 - methoxy D bow 丨. The synthesis of sitting was carried out using 1-T-based 3-(5,-methoxycarbonyl-2'-furanyl)-6-methoxycarbazole (116 mg, 0·32 mmol) as the starting material. 88.1 mg of 1-benzyl-3-(5'-carboxy-2'-furanyl)-6-methoxycarbazole was recovered in the same manner as described in Example 6, yield 77. 3 %. Mp: 222-223 ° C. MS (%), m/z: 348 (M+) ϊΚ (KBr)max: 3450 cmK-OH) and 1710 cm'HC^O) UMR (DMS0-d6, 200 MHz): 3.84 (3H, s, -〇CH3); 5.70 (2H, s, =NCH2-), 6.95 (1H, dd, J = 8. 3, 1.8 Hz, H-3,), 7.12 (1H, d , J = 3. 4 Hz, H-3), 7.25-7.38 (7H,

9006068.ptd Page 19 1293027 V. Description of the invention (17) m, H-7, 4, stupid), and 7.98 (1H, d, J? 8.3 Hz, H-4) · Example 10: Synthesis of 1-benzyl-3-(5-carboxy-2'-Df-based)-5,6-methylenedioxy π-induced saliva using 1-benzyl-3-(5,-methoxycarbonyl -2'-furyl)-5,6-methylenedioxycarbazole (120 mg, 0.32 mmol) as a starting material, which was treated according to the procedure described in Example 6 to obtain 88·1 mg. 1-Benzyl-3-(5,-carboxy-2'-furazyl)-5,6-methylenedioxypropazole, yield 75.5% 〇mp: 291-292 0 C. MS (%), m/z: 362 (M+) IR (KBr)max: 3479 cnr1 (-OH) and 1 720 cnr1 (OO) I-NMR (DMSO-d6, 200 MHz): 5·62 (2H, s ,=NCH2-),6· II (2H,s,-0CH20-), 7.09 (1H,d,J:3,6,H-3,),7·20-7·36 (7H,m,H -7, 4', phenyl), and 7.43 (1H, s H - 4) · Example 11 ·············· The synthesis of oxazole firstly burned anhydrous gas (88·8 mg '〇·8 mM) and sodium hydride (60 mg, 1.6 mmol) It was stirred in dry tetrahydro taste Misaki (2 milliliters) for 4 hours to prepare a Mi calcium hydride. Next, 88.0 mg of benzylamino-3-(5'-methoxycarbonyl-2'-furanyl)carbazole (〇27 mmol) was dissolved in 3 ml.

1293027 V. INSTRUCTIONS (18) The solution formed by tetrahydrofuran is at 30 ± 2. Under the C, it was added to a good solution of borohydride, and the mixture was heated and refluxed for 6 hours to be cooled, and the mixture was quenched by crushing ice. The tetrahydrofuran was removed under reduced pressure, and the solid product was obtained by filtration. The solid was extracted using digas methane. The extract was concentrated to 5 mL, followed by the addition of petroleum ether as a solid precipitate appeared. After the precipitate was collected and purified by column chromatography (yellow-benzene), 70 mg of benzyl-3-(5'-hydroxymethyl-2'-furanyl)carbazole was obtained in a yield of 87%. Mp: 108-109 ° C. MS (%), m/z: 304 (M+). IR (KBr)nax: 33 50 cm-i (-oh)· LH-NMR (DMSO-d6, 2 0 0 MHz ): 4.51 (2H, d, J = 5. 5 Hz, a CH20-), 5·31 (1H, t, J = 5.5 Hz, -OH), 5·70 (2H, s, = NCH2-), 6.48 (1H,d,J = 3.4 Hz, H-4,), 6.97 (1H, d, J = 3. 4 Hz, H-3'), 7· 2 Bu 7· 31 (6H, m, H-5, stupid), 7.4 5 (1H, t, J = 8. 2 Hz, H-6), 7. 7& (1H, dd, -8. 2, 1.8 Hz, H-7), and 8.12 (1H· dd, J = 8. 2· 1·〇Hz· C4-H Example 1 2 : 1-T-based-3-(5'-hydroxymethyl-2'-furanyl)-6-fluoro The synthesis of carbazole was carried out using 1-benzyl-3-(5'-methoxycarbonyl-2,-furanyl)-6-fluorocarbazole (93 mg '〇·27 mmol) as a starting material. The procedure described in Example 11 was carried out to give 75.0 mg of benzyl-3-(5,-hydroxymethyl-2'-furanyl)-6-fluorocarbazole in a yield of 88.%.

9006068.ptd Page 21 1293027 V. Description of invention (19) mp: 110-112 0 C. , MS (%), m/z; 322 (M+). IR (KBr)max·· 3450 cm, (-OH 1H-NMR (DMSO-d6, 2 0 0 MHz): 4·49 (2H, br, -CH20-), 5.45 (1H, br, -OH), 5.88 (1H, s, =NCH2-), 6.48 (1H, d, J = 3.2 Hz, H-4,), 6.98 (1H, d, J = 3. 2 Hz, H-3,), 7.10-7·18 (1H, m, H-7) , 7.24-7·36 (5H, m, phenyl-H), 7.70 (1H, dd, J = 10.0, 2·0 Hz, C5-H), and 8·15 (1H, dd, J = 8· 5,5·1 Hz, H-4)· Example 1 3: Synthesis of 1-benzyl-3-(5'-hydroxymethyl-2'-furanyl)-6-methylcarbazole using benzyl- 3-( 5'-methoxycarbonyl-2'-furanyl)-6-methylcarbazole (92 mg, 0.227 mmol) was taken as a material, which was taken according to the procedure described in Example 11. 70.4 mg of 1-mercapto-3-(5'-hydroxymethyl- 2,-pyranyl)- 6-methyl-bone bow can be obtained, with a yield of 88%. Mp: 112-114° C. MS (°/〇), m/z: 318 (M+). IR (KBr)max: 3400 cm-1 (-OH)· 4-NMR (DMSO-d6,200 MHz) : 2·44 (3H, s, -CH3), 4·50 (2H, d. J = 5· 2 Ήζ, -CH20-), 5· 30 (1H, br, -0Ή), 5.64 (2H, s , =NCH2->, 6. 45 (1H, d, J = 3. 3 Hz, 6.07 (1H, d, J = 3.3 Hz, H-3, ), 7.08 (1H, dd, J = 8.3, 1 · 0 Hz, H-5), 7.19-7·36 (5H, m, phenyl-H), 7.57 (1H,

9006068.ptd Page 22 1293027 V. Description of invention (20) d, J = 1.0 Hz, H-7), and 7·98 (1H, dd, J = 8.3, 1·〇Hz, H-4). '·' Example 1 4: 1 -T-based 3-(5'-methyl-2'-indolyl)- 6-methoxy D-xanthene was synthesized using 1-benzyl-3- (5'-Methoxycarbonyl-2'-furanyl)-6-methoxycarbazole (96 mg, 0.27 mmol) as a starting material, which can be obtained according to the procedure described in Example 11. 80 mg of benzyl-3-(5'-hydroxyindolyl-2'-furanyl)-6-methoxycarbazole in a yield of 90.%. Mp: 109-110 ° C MS (%), m/z: 334 (M+). IR (KBr)nax: 3300-3400 cnr1 (-OH)· 4-NMR (CDC13,200 MHz): 1·90 ( 1H, br, -〇H), 3·80 (3H, s, -CH3), 4·74 (2H, d, J = 4.9 Hz, -CH20-), 5.59 (2H, s, =NCH2-), 6·47 (1H,d, J = 3.2 Hz, H-4,), 6·59 (1H,d,J = 2.0 Hz, H-7), 6.84 (1H,d,J = 3.2, 1.0 Hz, H-3,), 6·88 (ΪΗ, dd, J = 8.5, 1·5 Hz, H-5), 7·17-7·31 (5H, m, phenyl-H), and 7 91 (1H, d·J = 8.5 Hz, H-4)· Example 15: 1-Benzyl-3-(5,-hydroxymethyl-2'-furanyl)-5,6-methylene Synthesis of Dioxy D-Thrazole Using 1-Benzyl-3-(5'-methoxycarbonyl-2'-furanyl)-5,6-Methylene

9006068.ptd Page 23 1293027 V. INSTRUCTIONS (21) Dioxycarbazole (1 〇 1 mg, 〇 · 27 mM) is a primer which can be obtained according to the procedure described in Example 11. 84·5 mg of benzylidene-3-(5'-hydroxymethyl-2'-furyl)-5,6-methylenedioxycarbazole, yield 90% 〇mp: 122-123 C· (%), m/z: , a CH20-), 5.53 (2H, s, =NCH2-), 5·99 (2H, s, —〇CH2 0-), 6·43 (1H,d,J = 3.3 Hz, H:4,) , 6.61 (1H, s, H-7), 6.76 (1H, d, J = 3.3 Hz, H-3,), and 7.20-7·31 (6Η, m, Η-4, phenyl). Example 1 6 : 1 - mercapto-3-(5'-methoxymethyl-2'-decyl) D-pin 丨cr sitting synthesized under -10 ± 2 ° C, in 1-section Base 3-(5'-methyl- 2,-decyl) carbazole (0.2 g, 〇·66 mM) dissolved in dioxane (5 ml) 0 Μ three gasified boron / two gas combustion solution (Im 5 ml), let the solution continue to stir at this temperature 4 small hire . Methanol (5 ml) was then added and stirring was continued for 1 hour, after which the reaction solution was poured into ice water to quench the reaction. The gram is obtained by the column chromatography (pluton-benzene) to obtain 0. 1 gram. 〇%。 The liquid is obtained in a yield of 50% by weight.

9006068.ptd Page 24 1293027 V. INSTRUCTIONS (22) MS (%), m/z: 318 (Mf)., IR (KBr)nax: 1610 cm-1 (C-0)· HMR (CDC13,200 MHz): 3·45 (3H, s, -CH2OCH3), 4·56 (3H, s, -£U2OCH3), 5·29 (2H, s, =NCH2-), 6.52 (1H, d, J = 3.3 Hz, H-4'), 6.91 (1H, d, J = 3.3 Hz, H-3'), 7·18-7·36 (8H, m, H-5, 6, 7, phenyl) , and 8·ΐ2 (1H, dd, J=8·1, 1·1 Hz, H-4)· Example 17: 1-mercapto-3-(5-^-methylaminomethyl-2 &quot ; 咲 基 base) - tt bow 丨嗤 synthesis at -10 ± 2. Under C, in 1-benzyl-3-(5,-hydroxymethyl-2,monofuryl)carbazole (1.0 g, 3.4 mmol) dissolved in dioxane (5 mL) To the solution was added 1.00 Torr of a boron trioxide/di-methane solution (2 〇 ml), and the mixed solution was allowed to continue to react at this temperature for 4 Torr. Then, dimethylamine (30 ml) was added. The mixed solution was heated to reflux for 4 hours, and then the reaction liquid was poured into ice water to quench the reaction. The mixed solution was extracted using digas methane. The organic extract layer is neutralized by washing with water, dried over anhydrous magnesium sulfate, and the solvent is evaporated to give a residue, which is purified by column chromatography (yellow-benzene) to obtain 0·16 g of 1-benzyl group- 0%。 3-(5,-dimethylaminomethyl-2,-furoyl) oxazole, a yield of 39.0%. MS (%), m/z: 359 (M+). IR (KBr)Bax: 1 350 cnr1 (CN)· ^-NMR (CDC 13, 2 0 0 MHz): 1.16 (6H, t, J = 7. 1 Hz, -N(CH2CH3)2), 2.63 (4H, q, J = 7e ! Hz> -N(CH2CH3)2),

1293027

V. INSTRUCTIONS (23) 3·86 (2H, s, -CH2N-), 5·64 (2H, s, =NCH2-), 6.37 (1Η, d, J = 3.3 flz, Η -4' ),6·87 (1Η,d,J=3.3 Ηζ, H-3'),7·10,7·40 (8H,m,H-5,6,7,phenyl), and 8·/〇 (1Η, d, J = 8.2 Ηζ, Η-4). Example 1 8 : Synthesis of 1-mercapto-3-(4'-ethoxycarbonylphenyl)carbazole (a) In anhydrous aluminum ( In a solution of 85 g, 0.64 mol) in dry toluene (90 ml), a gasified stupid (50 ml, 0.43 mol) was added dropwise at 10^2 °C. The mixed solution was warmed to 30 ± 2. After C, the reaction was continued for 12 hours, then heated to 100 ± 5 ^ C and stirred for 2 hours.

The reaction was cooled and added to ice water (200 mL) to complete the reaction. The organic layer was separated, washed sequentially with water and a 5% sodium carbonate solution, and then washed with water until neutral. The organic layer was dried over anhydrous magnesium sulfate and the solution was removed. The residue was recrystallized using n-hexane to obtain 6 2 · 1 g of 4-methylbenzophenone in a yield of 73.5%. Mp: 55-57 ° C (b) In a mixture of 4-methylbenzophenone (25 g, 0.127 mol) and acetic acid (130 ml), chromium trioxide (35 g) and water (8 ml) were added in that order. ) and concentrated sulfuric acid (25 ml). The reaction mixture was heated to 1 q alumina 5 C and maintained for 3 hours 'pour into ice water (500 ml) to quench the reaction to give a crude 4-benzylidene benzoic acid solid which was dissolved in 1 〇. The potassium hydroxide solution was filtered again. The filtrate was acidified to pH 2·0 with dilute hydrochloric acid, then placed on ice

9006068.ptd Page 26 1293027 V. INSTRUCTIONS (24) The product is precipitated in the bath. 1%。 The precipitate was collected to obtain 2 丨··g of 4-benzylidene benzoic acid in a yield of 74.1%. ^ (C) Mixture of 4-phenylphenylbenzoic acid (20 g, 88.4 mmol), methyl (5 ml), p-toluenesulfonic acid (1 g) and ethanol (20 ml) It was heated to reflux for 12 hours, allowed to cool, washed with 5% sodium carbonate solution and then washed with water until neutral. The organic layer was dried over anhydrous magnesium sulfate and then concentrated to give 22 g of 4-phenylbenzhydrylbenzene. The yield was 90.5% 〇 (hearts, 4-benzylidene benzoic acid acetamidine 3. a mixture of gram, μmmol, 卞肼 (8 gram, 65 mM), ethanol (5 mM) and acetic acid liters was heated to reflux for 2 hours, and then the steps were treated. The crude product can be produced, / the gelatin-benzene of Example 1 can be purified to obtain 48 g of b? Base - 3 s chromatography (phenyl) D-bendazole, yield 5.2 %. Ethoxycarbonyl mp: 95-96 〇C· IR (KBr) fflax: 1710, 1 620cm'1 (C = 0). MS (%), m/z: 356 (M+). 4-NMR (CDC13,200 MHz): 1.35 (3H,t, -CH2 escape), 4·35 (2H,q,j= 8.0 Hz,~qCh ·〇Hz, (2H,s,=NCH2-), and 7·40 — 8· 40 (13H 2 5.78 • 'Fangxiang protons) Example 19: Synthesis of benzyl-3-(3'-ethoxycarbonylphenyl)carbazole

1293027

The 3-methylbenzophenone can be treated in the order of (a), (b), (c) and (4) in Example 18 to obtain 3 - 25.5 / fluorene 1-mercapto- 3-(3). ,-Ethoxycarbonylphenyl) 11-oxazole. Mp: 85-86 0 C. MS (%), m/z: 356 (M+). IR (KBr) Stuff: 1 720,1610cm] (C = 0)· ^-NMR (CDC 13, 20 0 MHz) : 1.43 (3H, t, J = 7 〇Hz -CH2CH3), 4.44 (2H, q, J = 7.〇Hz, ^CH.CHa)', 5.68 (2H, s,=NCH2-)' and 7.20- 8.20 (13H, m, aromatic proton) Example 20: Synthesis of benzyl-3-(4'-carboxyphenyl)carbazole

To a solution of dibufen-3-(4'-ethoxycarbonylphenyl)carbazole dissolved in 1 ml of methanol was added a sodium hydroxide solution (〇·56 g dissolved in 2 ml of water). After heating under reflux for 6 hours, the methanol was removed by evaporation. The resulting residue was acidified using dilute hydrochloric acid. After cooling in an ice bath, solids were allowed to dry, and 0.87 g of benzyl-3-(4,-indenyl)carbazole was obtained in a yield of 94.5%. I mp: 20 5-207 0 C. MS (%), m/z: 328 (Mf). IR (KBr)nax: 3500-3300 cnrKOH) and 1 700 cm-1 (C = 〇) 4-NMR ( DMSO-d6, 200 MHz): 5·77 (2H, s, = NCH2-), 7

1293027 V. INSTRUCTIONS (26) 20-8·20 (13H, m, aromatic protons), and 13.0 (1H, br, -0H Example 21 · · benzyl-3-(3'-hydroxycarbonyl) Synthesis of carbazole 1-benzylindole-3-(3'-ethoxycarbonylphenyl)carbazole (0·49 g, 〇11 mmol) was treated according to the procedure described in Example 20 to obtain hydrazine· 83 g of indolin-3-(3'-hydroxycarbonylphenyl)-terazole, yield 90.2% 〇mp: 190-192 ° C. MS (%), m/z: 328 (M+). IR ( KBr)max: 3500-3300 cnr1 (-OH) and 1 700 cnr1 (C = 0)· 4-NMR (DMSO-d6, 200 MHz): 5·76 (2H, s, =NCH2-), and 7· 20-8·20 (13H, m, aromatic proton). Example 2 2: Synthesis of benzyl-3-( 4'-hydroxydecylphenyl)carbazole 1-mercapto-3-(4-ethoxyl) The carbonyl phenyl) oxazole (〇·4 g, 2 mmol) was treated according to the procedure described in Example 12 to obtain 苄·24 g of 1-benzyl-3-(4'-oxindole). Phenyl) carbazole, yield 67.

1293027 V. Description of invention (27)

- CH2o-), =NCH2-), 5.31 (1H, t, J = 5. 2 Hz and 7·20-8· 20 (13H, m, :0H),, 5.73 (2H, aromatic protons). s , Example 23 · Synthesis of benzyl-3-(3,-hydroxymethylphenyl)carbazole, benzyl-3-(3'-ethoxycarbonylphenyl) oxime, oxazolidine according to Example 12 The procedure described in the case of Moke I2聋乡 can be difficult to be ^ gram of 1-pyramid-3 - (3' - via methyl phytoa, κ 丨 . τ 本 base) 吲 saliva, yield 64 1%. Mp: 98-99. C· ^ 0

MS (%), m/z: 314 (M+). IR (KBr)max: 3300-2500 cm·1 (〇H) s, -CH20-), 5· 1 -NMR (DMS0-(16,200 MHz ): 4·78 (2H 65 (2H, s, =NCH2-), and 7.20-8.20 (13H, m, aromatic proton). Example 2 4 ··1卞yl-3-(5~methoxycarbonyl) Synthesis of a 2'-furanyl)thienyl[3,2_c]carbazole (a) (5-methoxyl-yl-2-yl-d-sulfenyl) Synthesis of 2'-propenyl oxime using 2-thiophene carbonyl ( 30·5 g, 0.21 mol), 2-furanoic acid methyl vinegar (24 g, 〇·19 moire) and anhydrous tri-iron (〇·42 g, 2.6 mmol) according to Example 1 The above procedure can be carried out to obtain 28.7 g of (5-methoxycarbonyl-2-furanyl) 2,-thienyl ketone in a yield of 63.8% 〇9006068.ptd Page 30 1293027 V. Description of the invention (28) mp : 103- 1 0 6 0 C. , MS (%), m/z: 236 (M+). IR (KBr)max: 1 720,1 620cm-1 (C = 0)· 1 -NMR (CDC13,200 MHz): 3·98 (3H, s, -CH3), 7.22-7.31 (2H, m, H-3, 4), 7.41 (1H, d, J = 3. 5 Hz, H-4,), 7 ·76 (IH,d,J = 3.5 Hz, H-3,), and 8.36 (1H, d, J=4.5 Hz, H- 5). (b) Synthesis of 1-T-based 3-(5'-methoxycarbonyl-2'-furyl)thienyl [3,2 - c ] D ruthenium (5-methoxycarbonyl-2) -furanyl) 2'-thenyl ketone (5.7 g, 0. 0 24 mol) as a starting material, treated according to the same procedure as described in Example 1 to obtain 1.2 g of 1-benzyl group -3-(5'-methoxycarbonyl-2'-furanyl)thienyl[3,2-c]carbazole, yield 14·8°/〇. mp: 142-143 ° C. MS (%) , m/z: 338 (M+)· IR (KBr)max: 1 72 0 cm-1 (C = 0). UMR (DMSO-d6, 200 MHz): 3·85 (3H, s, -CH3), 5·62 (2H, s, = NCH2-), 6.92 (1H, d, J = 3.5 Hz, H-3,), 7·24 (1H, d, J = 4·8 Hz, H-6 ), 7·26-7·35 (5H, m, phenyl-H), 7.43 (1H, d, J = 3.5 Hz, H-4'), and 7.77 (1H, dd, J=4· 8, 1·5 Hz, H-5)· Example 25:

9006068.ptd Page 31 1293027 V. INSTRUCTIONS (29) Synthesis of benzyl-3-(5,-hydroxycarbonyl-2,-furyl)thiophene[3,2-c]carbazole 1-Benzyl-3 -(5'-methoxycarbonyl-2'-furanyl)thienyl[3,2-c]carbazole (108 mg, 〇32 mmol) can be obtained by treating according to the procedure described in Example 6. 83.3 g of 1-benzyl-3-(5'-hydroxycarbonyl 2'-furyl)thienyl [3,2-c]carbazole in a yield of 80.3%.瓜ρ : 221 - 224 〇C· MS (%), m/z: 324 (M+). IR (KBr)max: 3500 cm'1 (-OH), 1 720 cm^1 (C = 0). 4 NMR (DMSO-d6, 200 MHz): 5·62 (2H, s, =NCH2 -), 6·90 (1H, d, J = 3.5 Hz, H-3,), 7.26 (1H, d, J = 4. 8 Hz, H-6), 7·25-7·35 (6H, m, H_4', phenyl), and 7.78 (1H, d, J=4·8 Hz, C5-H). Example 2 6 : 1-pyringyl-3-(5'-methyl-2'-indolyl)thienyl [3,2-0][1 丨 丨 的 l l l l -3 - -3 -Methoxy-yl-2'-indenyl)thienyl [3 2 -c]carbazole (90 mg, 0 · 27 mmol) can be obtained according to the step described in Example 11. 4 g of benzyl-3-(5,-hydroxymethyl-2,-n-fluoromethyl)thienyl[3,2-c]carbazole, yield 69.3%. ^ mp: 103-104 ° C. MS (%), m/z: 310 (M+). IR (KBr)max: 3360 cnr1 (-OH)·

1293027 V. INSTRUCTIONS (30) ^-NMR (DMS0-d6, 200 MHz): 4.46 (2H, ,d, 1 = 5.3 Hz, a CH20-), 5·27 (1H,t, J = 5.3 Hz, -OH), 5·55 (2H, s, = NCH2-), 6.43 (1H, d, J = 3.2 Hz, H-4,), 6·64 (1H, d, J = 3.2 Hz, H-3 '), 7· 20 (1H, d, J = 4· 8 Hz, H-6), 7·27-7·35 (5H, m, phenyl-H), and 7.72 (1H·d, J = 4.8 Hz, H-5)· Example 2 7 : Screening of Compounds with Inhibition of PARs-Induced Platelet Aggregation The in vitro inhibitory activity of fused pyrazole compounds was initially evaluated by the following method: suspension in Ty r〇de solution The platelets were prepared according to the method described by Wu et al., Br. J. Pharm., 1 995, 1 6 6: 1 973-1 978. The composition of the Tyrode solution is as follows (mM): sodium carbonate (136·8), potassium carbonate KC1 (2.8), sodium hydrogencarbonate (ιι 9), magnesium vapor (i.m.), sodium dihydrogen phosphate (sodium dihydrogen phosphate) 〇·33), gasified calcium (l〇) and glucose (η·2). The number of platelets in the platelet suspension was adjusted to 4·5χ1〇8 platelets per ml with the aid of c〇ulter c〇unter (M〇ciel ΖΜ I. Each compound to be tested was first added to a certain amount of platelet suspension. In the solution, the cells were incubated for 3 minutes under agitation (1,200 rpm), and then thrombin was added to activate PARs. The agglutination of platelets was measured by a light-transmitting blood coagulator to measure the turbidity of the test solution. And find the degree of agglutination of platelets by adding coagulation. Using Teng et al. at Bileffl.

The method described in Bl〇 PhyS· Acta·, 1 987, 924·· 375-382 accounts for the percentage of agglutination. <

1293027 Case No. 90119408 Λ_Ά 修正 Revision Year

翁五、发明说明(31) The compounds prepared in Example 26 showed that they inhibited platelet aggregation activity at different concentrations after being tested. For example, 1-benzyl-3-(5'-diethylaminomethyl)furanyl-oxazole unexpectedly shows some compounds (eg, 1-mercapto-3-(5'- Methyl-2'-oxime)-carbazole) is still better. Further, 1-mercapto-3-(3'-ethoxycarbonylphenyl)carbazole unexpectedly shows some other compounds (for example: 1-benzyl-3-(4'-hydroxydecylphenyl) ) oxazole) is also ten times more active. Another unexpected result is that these compounds have no effect on other platelet activating factors that are not via PARs. Other Embodiments Those skilled in the art can easily devise the necessary features of the present invention from the above description, and make appropriate modifications and modifications to the present invention without departing from the spirit and scope of the invention. Meet specific uses and conditions. Accordingly, other specific embodiments are also included in the scope of the application of this patent.

900606803.ptc Page 34 1293027 Schematic description 9006068.ptd Page 35

Claims (1)

1293027 _ Case No. 90119408_年月日日__ VI. Patent application scope 1. A pharmaceutical composition for treating a disease associated with activation of a cell induced by a protease-activated receptor, comprising a compound having the following structural formula : Wherein ^ is phenyl, Ar2 is phenyl, Ar3 is fluorenyl or phenyl; each core, R2, R3, R4, R5 and hydrazine can be independently hydrogen, halogen, -OR, -OH , -SR , -SH , -R , -C(=0)0H , -C(=0)0R , -C(two 0)SH , -C(=0)SR , -C(=0)NRR, -R0R, , -RS R9, -RSH, -NRR', -NHR, -NH2, -RNR' R, ', -RNH2, -RNH R, or -RSR, or & and 匕, R3 and ratio Together or R5 and & together are -0R0-; wherein R, R' and R" may independently be independently (: alkyl of 4; and η is 0 or 1; and a pharmaceutically acceptable carrier. The composition of claim 1, wherein Ar3 is a furyl group, and each of R5 and R6 is independently hydrogen, -halogen, -R, -C(=0)0 Η, -C(:0 ) 0R, -C(=0)SH, -C(=0)SR, -C( = 0)NRR, -R0 Η, -ROR' > -RSH, -NRR', -NHR, -NH2 — RNR' Rn, -RNH R,, -RNH24-RSR'; or R5&R6 - same as -0R0-. 900606803.ptc Page 36 1293027 _ Case No. 90119408_年月日日__ VI. Patent application scope 3. For the composition of claim 1, the Ar3 is a phenyl group, each of which is individually and independently Is nitrogen, - 13⁄4, -R, -C( = 0)0H, -C (= 0)0R, -C( = 0)SH, -C( = 0)SR, -C(two 0)NRR, , -ROH, -R OR', -RSH, -NRR', -NHR, -NH2, -RNR' Rf, -RNHR', -R NH2 or -RSR'; or R5 and 匕 together are -0R0-. 4. The composition of claim 3, wherein Ar3 is phenyl, R5 is deuterium, and R6 is at 4'-C. 5. The composition of claim 3, wherein Ar3 is a phenyl group, the R5 position is at a 3'-C position, and the R6 position is at a 5'-C position. 6. For the composition of claim 4, R6 is 11, -C(=0)0H, -C(=0)0R, -C(=0)SH, -C(=0)SR Or -C(=0)NRR' and R5 is H. 7. For the composition of claim 6 of the patent scope, wherein R6 is -C(=0)0R 〇8. As in the composition of claim 7, the R6 is -0: (=〇) ( ^1 〇9. The composition of claim 8 wherein Ar2 is a phenyl group, each of which is independently chlorine, - _, -R '-CC^COOH, -C (= 0) 0R , -C(=0)SH , -C(=0)SR , -C(=0)NRR, , -ROH , -R OR' > -RSH, -NRR' ^ -NHR, -NH2 , -RNR' Rfl ... RNHR', -R NH2 or -RSR, or R3 and R4 - are the same as -0R0-. 1 0- The composition of claim 9 wherein Aq is phenyl, each A 1^ and a ruler 2 are independently hydrogen, -_素, -R, _C(=0)0H, -C(=0)0R, -C(=0)SH, -C(=0)SR, -C(:0)NRR' , -ROH , -R 900606803.ptc Page 37 1293027 _ Case No. 90119408_年月日日_ί±^_ VI. Patent application scope OR' > -RSH-NRR', -NHR, -RNR' R丨,, -RNHR', or -RSR' ; or & and 1^2 - same as -0R0-. 11. If the composition of claim 10 of the scope of patent application, the heart and the sputum are all Η , 12, such as the composition of the scope of claim 1 of the patent, wherein the position is in the 5-C position and the R4 position 6-C position. 13. If the composition of claim 12, the 匕 and 1^4 are both Η 〇 14. As in the scope of claim 2, R5 is 11 and R6 is at 5 ' C position. 15. The composition of claim 14 wherein R6 is -R, -R OH, -R0R', -RSH, -NH2, -NRR', -NHR, -RNR' R1 丨, -RN HR', -RNH2 or -RSR' 〇1 6. The composition of claim 15 wherein Aq is a phenyl group, and each of R1 and R2 is independently hydrogen, -halogen, -R, -R0H, -R0R'-NH2 ... NRR', -RSR', -OR, -OH, -SR or -SH ° 1 7. The composition of claim 15 wherein A 2 is a phenyl group , R3 is in the 5 - C position and R 4 is in the 6 - C position. 18. The composition of claim 17 wherein Aq is a phenyl group, each of which is independently hydrogen, halogen, -R, -R0H, -R0R, -NH2, -NRR , -RSR, -OR - OH, -SR or -SH ° 19. The composition of claim 18, wherein both 匕 and 匕 are Η 20. For example, claim 19 Composition, wherein R6 is -CH20H 900606803.ptc Page 38 1293027 Case No. 90119408 修正 Amendment VI. Patent application scope R3 is 11. Wherein R4 is -CH3. Wherein R4 is -OCH3. Wherein R6 is -cioc, wherein R3 and 1?4 are both Η 2 1, as in the scope of claim 20 of the patent application. 22. The composition of claim 2, item 23. Composition of item 1 1 24. The composition H3 of claim 19 of the patent application. 25. The composition of claim 24 of the patent application. 26. The composition of claim 19, wherein R6 is -CH9NEts 27. The composition of claim 26, wherein 匕And 1?4 are all Η 900606803.ptc第39页