TWI373468B - Method for preparation of amido pyrazole - Google Patents

Description

1373468 t, DISCLOSURE OF THE INVENTION: FIELD OF THE INVENTION The present invention relates to a process for preparing a guanamine-based pyrazole derivative, and more particularly to the preparation of a guanamine-based pyrazole derivative in a one-pot process. [Prior Art] Glutamate is an excitatory neurotransmitter in the central nervous system of mammals, and metabotropic glutamate receptors in the central nervous system of mammalian brains. , mGluRs), plays a role in the binding and transport of glutamate in nerve cells by controlling the nerve impulses of nerve cells by transporting glutamate into the cells. Therefore, metabotropic glutamate receptors are involved in many physiological mechanisms of the brain or nerves, such as memory, learning, and pain, which are also related to emotional feelings such as anxiety or depression. Therefore, many clinical and neurological and spiritual effects. The study or treatment of sexually transmitted diseases is carried out against metabotropic glutamate receptors. It has been pointed out that guanamine pyrazole derivatives can be combined with metabotropic glutamate receptor 5 (mGluRs) to achieve the effect of treating schizophrenia. See Lindsley α/., J. Med. Chem., 2004, 47, 5825 A Paulis et al., Med. Chem., 2006, 49, 3332, the entire disclosure of which is hereby incorporated by reference. To date, derivatives of guanidine (1,3-diphenyl-1//-pyrazol-5-yl)benzamide have been developed as positive ectopics of the fifth type of metabotropic glutamate receptor. Activating substances that are regulated as drugs for the treatment of schizophrenia. There are two main methods for preparing guanamine-based pyrazole derivatives. The first system 5 1373468 is prepared by the following reaction process (see, for example, Chen ei α/_, Tetrahedron Lett., 1998, 39, 8229, the entire disclosure of which is hereby incorporated by reference):

In this conventional method, 2'-Bromoacetophenone (Compound 2) is substituted with potassium phthalimide to obtain Compound 3, followed by Compound 3 and 'Benzene Phenylhydrazine is subjected to a cyclization reaction to give a compound 4. Then, Compound 4 is further subjected to a ring opening reaction with a hydrazine hydrate to obtain Compound 5. Finally, the amine oximation reaction is carried out to obtain the final product compound 6. The procedure of this synthetic method is cumbersome and the reagents used are expensive, and the yield of the final product is only about 11 to 17%, which is completely uneconomical. 6 1373468 The second synthetic method is the reaction process shown below (see Paulis β/., Med. C/zew., 2006, 49, 3332, the entire disclosure of which is hereby incorporated by reference):

Total yield: 2 to 38%

In this conventional method, benzonitrile (Compound 7) is reacted with acetonitrile to give Compound 8. Next, the compound 8 is subjected to a cyclization reaction with phenylhydrazine hydrochloride to obtain a compound 9. Finally, an amine oximation reaction is carried out to obtain a final product compound 10 in a yield of about 2 to 38%. The above two methods for preparing the guanamine-based pyrazole derivative have to undergo at least three to four steps, and after completion of each step, a complicated purification procedure such as extraction and chromatography is required, so that the process of the pharmaceutical factory is enlarged. In the process, it is quite labor-intensive, material and financial. Therefore, there is a need in the art for a synthetic method which can reduce the manufacturing cost, and to prepare a guanamine-based ratio σ sitting derivative in a convenient, rapid and large-scale manner. 1373468 The present invention is directed to the research results of the above requirements, and the guanamine group can be synthesized quickly and conveniently by using a compound of acy 丨 oni oni oni oni ( ( ( ( ( ( ( 丨 丨 丨 丨 丨 丨 丨 丨 丨 丨 丨 丨 丨 丨 丨 丨 丨 丨 丨 丨 丨 丨 丨 丨 丨 丨 丨 丨 丨[Description of the Invention] The present invention has an object to provide a method for preparing an amine group of the following formula (1), which is a compound of a salino derivative, and a ruthenium compound, a ruthenium compound, and a ruthenium compound, to carry out a condensation ring. The reaction is carried out to obtain a _th reaction product; and a brewing agent is added to the first reaction product to carry out an amine oximation reaction to obtain an amine group α-β-supplement derivative of the formula (1): X1-Ν

(1). DETAILED DESCRIPTION OF THE INVENTION The present invention will be described in the following description of the present invention in order to provide a description of the present invention. In particular, the use of "-", "the" and similar terms in the scope of the patent application 40 will be understood to include the singular and plural forms. According to the World Health Organization's 2001 Mental Health Report, there are one in every four people in the world. May be suffering from mental illness or neurological disease in one lifetime. As mentioned above, the neurological or psychiatric diseases of the central nervous system in the brain are related to the metabotropic partial receptors of 1373,468 and can be derived from amidinopyrazole. The obligate binding properties of the substance to the first-generation 6-shot type of alanine receptor, making it a fifth-generation 'item 2 glutamate agonist l ag〇mst) to treat neuropathic or Mental illness. The present invention provides a preparation of the amine group of the following formula (1). ratio. How to sit on a derivative 0 X1

R-N

, X3 X2 (I), which comprises the following steps: (1) mixing a compound of formula (II) with a compound of formula (ΠΙ) acetonitrile (acylacetonitrile) to carry out a condensation cyclization reaction to obtain a first a reaction product; and X1-NHNH2(II)0(III) (2) at least one of the σ (IV) and formula (v) deuteration reagents are added to the first reaction product to carry out an amine hydrazine The reaction gives the guanamine pyrazole derivative of formula (I): 1373468

Where: ο ο R is Η, -ί-Χ3 or -&Χ3,; χ and χ2 are independently: 3⁄4 base, dentate, cyano, schlossylthio, alkoxy groups, alkylene groups, • alkoxy, aryl, heteroaryl, or heterocyclic; X3 and χ3, different and independently fluorenyl, aryl, fluorenyl, cyclohetero, heteroaryl, or fluorenyl; And L is the leaving group. Specifically, in the process of the present invention, a sulfonium compound of the formula (8) and a ruthenium cyanide compound of the formula (III) are first subjected to a condensation cyclization reaction to obtain a first reaction product. After the completion of the cyclization reaction, at least one of the formula () and the deuteration reagent of the formula (V) is added to the first reaction product to carry out an amine oximation reaction, thereby preparing a ratio of the amine group to the α. Saliva derivatives. In the step (1) of the process of the present invention, a desired compound of the formula (II) and a compound of the formula (ΠΙ) can be selected according to the desired formula (τ). Preferably, in the step (1), a compound of the formula (II) and a compound of the formula (ΙΠ) are used to prepare a corresponding amide-based pyrazole derivative of the formula (I): oxime and X2 are independently Halogen, cyano, nitro, thio, C3 to Qo cycloalkyl, C5 to (: 2 aryl, or, if desired, a C or a C dentate substituent or C to C2 oxime alkoxy, one or more carbon atoms in the ring of the cycloalkyl or aryl group may be independently replaced by N, 〇 or S by 1373468, more preferably, the compound of formula (8) and formula (5) are used. The compound is consistent with the following t-forms and X2 are independently ...-aryl groups, and the carbon atoms in the ring of the aryl group may be independently replaced by hydrazine, hydrazine or s.

For the eight methods of the present invention, the compounding ratio of the compound of the formula (8) in the step (1) and the formula (1) is not the focus of the invention. However, based on economic considerations, the formula (η) in the step (1) The molar amount of the compound and the compound of the formula (5)), the formula (111). S (II) is usually at least about 9: i, preferably at least about ^: ^. In the method t of the present invention, it can be used without The condensation cyclization reaction of the compound of the formula (II) and the compound of the formula (III) is carried out in the presence of a solvent to provide a first reaction product in a high yield. Therefore, after the completion of the step (1), the step (7) can be directly carried out without intermediate purification of v V It is confirmed by analysis that the first reaction product has the following formula (v):

The operating temperature of the step (1) is not critical to the method of the present invention, depending on the selected formula (1 〇 compound and formula (ΙΠ) compound. For example, when χι and X2 are used as the stupid formula (II) In the case of the compound and the compound of the formula (in), the condensation cyclization reaction of the step (1) can be carried out at a temperature of about 215 to 220 ° C without using a solvent to provide #-(1,3-diphenyl-1). //-吼. Sodium 5-amino)amine (ie, the first reaction product). In the step (2) of the method of the present invention, the species of the formula (I) can be used as the amine species. Preferably, the deuteration reagent is preferably used in step (2) using at least one of formula (IV) and formula (V) & reagent: X3 and X3' are independent of 1373468. Or a plurality of substituents c2. an alkyl group, [to c2. a renewed group, a C3 to c20 cycloalkyl group, or a C"c2 aryl group, which is independently a dentate, a cyano group, Nitro, c2i C, cycloacyl, €5 to C2a aryl, or optionally C, or a plurality of dentate substituents, to C4 alkyl or C| to q alkoxy, and the naphthenic Ring of aryl or aryl One or more carbon atoms may be independently replaced by N 〇 or S. More preferably, the formula (IV) and/or formula (V) oximation reagent used is in accordance with the following conditions: X and X3 are independent. A Cl to Go alkyl group having one or more substituents, a core to (:|()sulfonyl group, a q to C|G cycloalkyl group, or a fluorene to a C|indenyl group, wherein the substituent is independent Is i, methyl, trifluoromethyl, methoxy, cyano, nitro, C 2 % anhydride, phenyl, or quinolyl, and - or more in the ring of the cycloalkyl or aryl The carbon atoms may be independently replaced by N, 〇 or s. The formula (IV) and/or the formula (v) used in the step (2) may contain any suitable leaving group L. In general, L may be selected from the group consisting of _ 素, & to oxy, or C | to C 2 oxime ester group. Preferably, L is selected from halogen, C | to alkoxy, or ( ^ to the leaving group of the C|() ester group, such as c ethoxy group, and ethyl acetate. For the method of the present invention, the amount of the hydrazine reagent of step (2) is not critical. Knowing that S, the number of moles of the deuteration reagent used in step (2) is at least equal to 11) The molar number of the compound, preferably about 15 times or more the molar number of the compound of the formula (II) (e.g., about 1.5 times to about 3 times), so that the formula (VI) is first At least one of the hydrogen on the amine group of the reaction product is substituted with a mercapto group to obtain the desired mercaptopyrazole derivative. Similarly, depending on the selected deuteration reagent species, the present invention can be carried out at different temperatures. Method / method step (2). For example, when the step (2) is used as the chlorine chlorination type chlorinating agent of chlorine, the amine group can be carried out at a low temperature (for example, about 〇 to 1 〇. The reaction can be 12 1373468 . As an example of the method (2) helium gas deuteration reagent of the method of the present invention, including: gasification, 2, furan, helium, 2-thiophene oxime, isoxazole -5- gasified carbon helium, 2-p-furan oxime • helium, trimellitic chloride, quinoline-8-sulfonium, and combinations thereof. In contrast, when an ester or acid anhydride deuteration reagent is used in the step (2), the amine group deuteration reaction is carried out at a relatively high temperature. It is known that a derivative of W-(l,3-diphenyl-1//-pyrazol-5-phenyl)benzamine can be used as a drug for treating neurological and psychiatric diseases. Therefore, in one embodiment of the method of the present invention, a compound of the formula (11) wherein χ| is a phenyl group (ie, ruthenium) and a compound of the formula (HI) wherein X2 is a phenyl group are used in the step (1) ( That is, benzoyl acetonitrile is subjected to a condensation cyclization reaction. Thereafter, in the step (7), at least the oxime agent of the formula (IV) is used to carry out an amine-based brewing reaction, wherein X3 is a stupid group having one or more substituents as necessary, and a substituent on the phenyl group Is independently halogen, cyano, nitro, C2 to C10 cyclic anhydride, C5 to C2 aryl, or, if desired, one or more halogen substituents (^ to C4 alkyl or (:! to C4 alkane) An oxy group, and one or more carbon atoms in the ring of the cycloalkyl or aryl group may be independently substituted by N, hydrazine or s; preferably, the substituent on the ^ 6 X X-based group is independently halogen a methyl group, a trifluoromethyl group, a methoxy group, a cyano group, a nitro group, a C2 cyclic anhydride group, a stupid group, or a quinolyl group, and one or more carbon atoms in the ring of the cycloalkyl group or the aryl group It can be replaced by N, 〇 or s as needed. • Another document is privately available, 7V~(1,3-diphenyl-1-//-. Indoleamine derivatives also have positive ectopic regulation of the fifth type of metabotropic glutamate receptor (see Paulis ei from, j. 2006, 49, 3332, the entire disclosure of which is hereby incorporated by reference. ). These have the fifth type A derivative of the forward ectopically regulated activity of a metabotropic glutamate receptor can be obtained by using a compound of the formula (H) and a formula (ΙΠ) wherein X and X are a phenyl group in the step (〖) of the method of the present invention. And using X3/X3: is a heterocyclic ring of formula (IV) and/or formula (V) deuteration reagent in step (2) 13 1373468. By the method of the invention, the following compounds can be obtained:

14 1373468

In the method of the present invention, since the purification operation between the steps (1) and (2) is not essential, it can be carried out by one-pot synthesis, that is, in a single reactor. The condensation cyclization reaction is carried out with an amine oximation reaction. Therefore, compared with the conventional method for preparing a guanamine-based pyrazole derivative, the method of the invention has not only fewer steps, simple process, but also can eliminate the complicated purification steps in the reaction process, so that the method can be carried out in a relatively low cost and relatively simple manner. To obtain the desired guanamine pyrazole derivative. As shown in the following examples, the preparation of the amide-based pyrazole derivative by the method of the present invention has a yield of usually 70% or more. In summary, the present invention provides a low-cost and simple method for preparing a guanamine-based pyrazole derivative, which can be used in a pharmaceutical factory: v is prepared in a large amount and economically for the treatment of psychotic 15 1373468 disease or neurological disease. drug. The present invention is further illustrated by the following specific embodiments to further illustrate the preparation of the guanamine group. A method of thiazole derivatives. The embodiments are provided by way of illustration only and are not intended to limit the scope of the invention. [Example 1] Synthesis of 5-amino-1,3-diphenylpyrazole Directly mixing phenylhydrazine with benzamidine cyanide (Compound 11), and heating the mixture to 215 to 220 ° C for condensation cyclization For 2 hours, to prepare 5-amino-1,3-diphenylpyrazole for subsequent amine oximation reaction, the reaction scheme is shown in the following figure. After that, it was monitored by thin layer chromatography, and it was found that the reaction was completed, and without extraction, drying, filtration and concentration, a yield of 94% of 5-amino-1,3-diphenyl was obtained. base. Than 化合物 (Compound 5). Analytical data: 5-Amino-1,3-diphenylpyrazole (Compound 5): Melting point: 129 to 131 ° C; W NMR (CDC13, 200 MHz) δ 3.82 (s, 2 H, NH2), 5.88 (s, 1 H, Py-H), 7.32-7.49 (m, 10 H, ArH), 7.58 (dd, 2 H, J = 6.6, 1.2 Hz, ArH), 7.80 (dd, 2 H, J= 6.6 , 1.2 Hz, ArH); l3CNMR (50MHz, CDC13) 8 88.1, 124.2, 125.6, 127.5, 127.8, 128.5, 129.5, 133.5, 138.7, 145.8, 151.5 ; IR (KBr) 3427 (brs, NH), 3337 (brs , NH), 3059, 1616, 1598, 1558, 1505, 1456, 1375, 1070, 952, 758, 698 cm-1 ; MS m/z (relative intensity) 235 (M+, 100), 207 (20), 192 (3), 180 (3), 131 (7), 117 (4), 104 (11), 102 (10), 92 (7), 77 (17), 65 (3), 51 (8). C丨5H13N3 Analytical calculations: C· 76.57; Η: 5.57; Ν: 17.86 ; Actual value: C: 76.14; Η: 5·81; Ν: 18.05. 16 1373468

11

PhNHNH2 ------ reflux for 2 to 3 hours, 94 〇 / 〇 [Examples 2 to 4] [Example 2] gasification of acetamidine as an amine sulfonating reagent under a nitrogen system, in a reaction In the bottle, the 5-amino-1,3-1,3-diphenylpyrazole (Compound 5) prepared in Example 1 was dissolved in anhydrous tetrahydrofuran, and then cooled to 0 to 10 ° C in an ice bath. Ethyl chloride was slowly added dropwise to the reaction flask. Wait for gasification of acetonitrile - after the addition is completed, remove the ice bath, warm it to room temperature, stir for about 2 hours, and monitor the reaction by thin layer chromatography. After the reaction is terminated, the tetrahydrofuran is removed by concentration and drying, and the reaction mixture is dissolved by adding dioxane. After washing with water, the organic layer is collected, washed with saturated brine, filtered and concentrated, and finally purified by chromatography. That is, a 7V-(1,3-diphenyl-1//-pyrazol-5-yl)acetamide (Compound 12) product was obtained in a yield of 85%, as shown in Table 1.

® Analytical data: 7V-(1,3-diphenyl-1//-pyrazol-5-yl)acetamide (Compound I2): melting point (purified by ruthenium column chromatography, yellow solid) 148 to 150 °C; WNMROCDCbJOOMHzM 2.06 (s, 3 H, Me), 6.95 (s, 1 Hs Py-H), 7.32-7.84 (m, 8 H, ArH), 7.81 (dd, 2 H, J 4 =6.6, 1.7 Hz, ArH) ; , 3C NMR (50 MHz, CDC13) δ 23.7, 96.4, 124.2, 125.0, 125.7, 128.1, 129.8, 133.0, 136.5, 137.9, 151.8, 167.0 ; IR (KBr) 3230 (brs, NH), 3061, 1681, 1595, 1560, 1505, 1496, 1468, 1367, 1267, 1072, 954, 763, 692 cnT1 ; MS m/z (relative intensity) 277 (M+, 14), 235 (24), 207 (6 ), 180 (2), 131 (5), 102 (23), 77 (45), 65 (5), 51 (34), 43 (100). Cl7Hl5N30 Analytical calculated value: C: 73.63; H: 17 1373468 5.45; N: 15.15 'Period value · C: 73.52; Η: 5.64; N: 15.49. [Example 3] 5-amino-indole, 3-diphenylphosphonium obtained in Example 1 was prepared under the nitrogen system using acetic anhydride as an amine sulfonating reagent. The solution (Compound 5) was dissolved in anhydrous tetrahydrofuran and directly mixed with acetic anhydride, followed by heating under reflux and monitoring by thin layer chromatography. After the reaction is completed (about 2 hours), the tetrahydrogenate is removed by concentration and drying, and then the dioxane is added to dissolve the reaction mixture, and the organic layer is collected by water extraction, and then washed with saturated brine, filtered and concentrated. The layer was finally subjected to chromatographic purification to obtain a product of 83% yield of diphenyl_1//-pyrazol-5-yl)acetamide (Compound 12) as shown in Table 。. [Example 4] 5-Amino-indole, 3-diphenylpyrazole (Compound 5) obtained in Example 1 was dissolved in anhydrous tetrahydrofuran using ethyl acetate as an amine sulfonating reagent under a nitrogen gas system. Then, ethyl acetate was directly added and mixed, and after heating under reflux for 12 hours, it was monitored by thin layer chromatography. After the reaction is terminated, the tetrahydrofuran is removed by concentration and drying, and the reaction mixture is dissolved in dioxane, and extracted with water. The organic layer is collected, washed with saturated brine, filtered and concentrated, and then purified. The product of #_(1,3-diphenyl-17/ppyridin-5-yl)ethinamine (Compound 12) having a yield of less than 1% by weight can be obtained as shown in Table 1. In the amine oximation reaction of the above Examples 2 to 4, 5-amino-1,3-diphenylpyridinium. The reaction (supplement 5) is reacted with three kinds of glycerin and acid anhydride esters, respectively, and the reaction scheme is as shown in the following figure. Since acid needles and ester derivatives must be able to react under the conditions of recirculation of the south dish, it is relatively energy-consuming in the process, and the helium-based reagent can be reacted in the reaction conditions of 〇 to l〇〇c. Go on. 1373468

Table 1, 5-amino-1,3-diphenylpyrazole (Compound 5) was subjected to various nucleophilic reactions to obtain #-(1,3-diphenyl-1//-pyrazole-5-yl)B. Guanamine. Deuterated reagent ΑΜ,3-diphenyl-I//-»Bis-5-yl-ethyl amide yield (%) gasified acetonitrile 12 85 acetic anhydride 12 83 ethyl acetate 12 <10

[Examples 5 to 21] Examples 5 to 21 were combined with a condensation cyclization reaction and an amine oximation reaction to prepare a series of jin~( 1,3 -diphenyl-1 //-11 ratio by a steel synthesis method. The α-spin-5-yl) amidocarboxamide derivative is shown in the following figure. 19 1373468

ΟkA^CN

PhNHNH 2 reflux hour: 94%

NH, Ph-N

5

X A W Cl

W NH 11 CH2CI2 or THF W = methyl, alum, or unsubstituted phenyl

Ph-N

12-28 12. W = Me, 77%, 13. W = CH2Ph, 90% 14. W = Ar, R1, R2, R3 = H, 78% 15. W = Ar, R1, R2 = F, R3 = H, 77% 16. W = Ar, R1, R2 = H, R3 = F, 70%

17. W = Ar, R1 = Cl, R2, R3 = H: 85% 18. W= Ar, R1, R3 = H. R2 = Cl, 71% 19. W = Ar, R1 = Me, R2, R3 = H, 84% 20. W = Ar, R1, R2 = H, R3 = Me, 76% 21. W = Ar, R1, R2 = H, R3 = CF3, 78% 22. W = Ar, R1 = OMe, R2, R3 = H, 90% 23. W = Ar, R1, R3 = H, R2 = OMe, 72% 24. W = Ar, R1, R3 = F, R2 = H, 88% 25. W = Ar, R1, R3 = H R2 = CN, 90% 26. W = Ar, R1, R2 = H R3 = CN, 78% 27. W = Ar, R1 = N02, R2, R3 = H, 76% 28. W = Ar, R1, R2 = H R3 = N02, 89% [Example 5] Synthesis of 3-diphenyl-1//-pyrazol-5-yl) acetamidine under nitrous oxide system (Compound 11) and an equivalent amount of phenylhydrazine, reacted under solvent-free conditions (neat) for 2 hours, then cooled in an ice bath and stirred to react the mixture, and slowly added dropwise vaporized acetamidine to be gasified. After the addition of acetamidine was completed, the ice bath was removed, warmed to room temperature, stirred for about 2 hours, and the reaction was monitored by thin layer chromatography. When the reaction was terminated, the tetrahydrogen bite was removed by concentration and drying. In the south, the reaction mixture is dissolved in dioxane, washed with water, and the organic layer is collected, washed with saturated brine, filtered and concentrated, and finally purified by chromatography to obtain a yield of 77%. 7V-(1,3-Diphenyl-1//-pyrazol-5-yl)acetamide (Compound 12). [Example 6] Synthesis of 2-phenyldiphenyl-1//-pyrazol-5-yl)acetamidine Under a nitrogen system, benzamidine cyanide (compound 11) and an equivalent amount of phenylhydrazine were obtained. After reacting for 2 hours under the conditions of the unreacting agent, the temperature was lowered in an ice bath and the reaction mixture was stirred, and 20 1373468 was slowly added dropwise to the phenylacetonitrile gas. After the addition of the phenethyl hydrazine gas was completed, the ice bath was removed, and the temperature was returned to the room. The temperature was further stirred for about 2 hours to monitor the progress by thin layer chromatography. After the reaction is terminated, the concentrated tetrahydrofuran is added to dryness, and the reaction mixture is further dissolved by washing with water. The organic layer is collected, washed with saturated brine, and concentrated and finally purified by chromatography. A yield of 90% 2-phenyl-#-(1,3-diphenylidene.sodium-5-yl)acetamide (compound 丨3) was obtained. Analytical data: 2-phenyl#(1,;3-diphenyl-1/^pyrazole-5-yl)acetamide (Compound 13): (purified by Shixi gum column chromatography, yellow solid) 132 To 134 ° C; iHNMRfDCl^OOMHzy 3 69 (s, 2 H, CH2), 7.05 (s, 1 H, Py-H), 7.09-7.43 (m, 13 H, ArH), 7.83 (d, 2 H, 6.6 Hz, ArH) ; , 3C NMR (50 MHz, CDC13) δ 29.7, 94.9, 123.66 (2 χ CH), 124.2, 125.7 (2 x CH), 128.1 (2 x CH), 128.6, 129.5 (4 x CH ), 129.6, 129.8 (2 x CH), 132.9, 133.5, 136.5, 137.4, 151.8, 167.3; IR (KBr) 3268 (brs, NH), 3064, 2924, 1700, 1559, I486, 1458, 1368, 1158, 1073,954 cm^MSm/z (relative intensity) 353 (M+, 8), 269 (1), 235 (18), 207 (3), 180 (1), 167 (1), 131 (3), 102 (17), 91 (100), 77 (40), 65 (29), 51 (18). C23H19N30 Analytical calculated value: C: 78.16; H: 5.42; N: 11.89; Actual value: C: 78.01; H: 5.34; N: 11.69. [Example 7] Synthesis of AT-(l,3-diphenyl-1//-pyrazol-5-yl)benzamide under the nitrogen system, taking benzamidine cyanide (compound 11) and an equivalent amount Awkward, after reacting for 2 hours under solvent-free conditions, the temperature is lowered in an ice bath and the reaction mixture is stirred, and then the gasified phenylhydrazine is slowly added dropwise. After the chlorinated phenylhydrazine is added, the ice bath is removed and the temperature is returned. After stirring to room temperature for about 2 hours, the reaction was monitored by thin layer chromatography. After the reaction is terminated, the tetrahydrofuran is removed by concentration and drying, and the reaction mixture is dissolved in dioxane, washed with water, and the organic layer is collected, washed with saturated brine, filtered and concentrated, and finally purified by chromatography. A yield of 78% of 21 1373468 diphenyl-I//- was obtained. More than 嗤-5-yl) phenylamine (Compound 14), as shown in Table 2. Analytical data: 7V-(1,3-diphenyl-1//-pyrazol-5-yl)phenylguanamine (Compound 14): melting point (purified by hydrazine column chromatography, white solid) 171 to 173° C; iHNMR^CDCbJOOMHzMTJO (s, 1 Η, Py-H), 7.30-7.64 (m, 9 H, ArH), 7.88 (dd, 2 H, J= 6.6, 1.6 Hz, ArH), 7.87 (dd, 2 H, 7= 6.6, 1.6 Hz, ArH), 8.06 (dd, 2 H, /= 6.6, 1.6 Hz, ArH) ; l3C NMR (50 MHz, CDC13) δ 95.9, 124.9 (2 χ CH), 125.8 (2 χ CH), 127.1 (2 χ CH), 128.2, 128.5 (2 χ CH), 129.0 (2 x CH), 129.3, 130.1 (2 x CH), 130.2, 132.5, 133.0, 133.7, 136.7, 137.9, 171.1; IR (KBr) 3275 (brs} NH), 3062, 1645, 1558, 1365, 1258, 1072,954,763,711,698 〇 11-1 ; MSm/z (relative intensity) 339 (M+,74), 234 (2), 206 ( 2), 105 (100), 77 (45), 51 (5). C22Hl7N30 Analytical calculated value: C: 77.86; H: 5.05; N: 12.38; actual value: C: 77.56; H: 5.24; N: 12.47. [Example 8] Synthesis of 3-fluoro-7V-(1,3-diphenyl-1//-pyrazol-5-yl) acesulfame under nitrogen system, abbreviated acetonitrile (Compound 11) After reacting with an equivalent amount of benzoquinone in a solvent-free condition for 2 hours, the temperature is lowered in an ice bath and the reaction mixture is stirred, and then the inter-fluorinated alum gas is slowly added dropwise, after the addition of the fluorophenyl hydrazine gas is completed. The ice bath was removed, warmed to room temperature, stirred for additional 2 hours, and the reaction was monitored by thin layer chromatography. When the reaction is terminated, the tetrahydrofuran is removed by concentration and drying, and then the reaction mixture is dissolved by water extraction. The organic layer is collected and washed with saturated brine. After filtration and concentration, the chromatographic purification is carried out. That is, a product of 3-fluoro-; V-(1,3-diphenylpyrazole-5-yl)benzamide (Compound 15) having a yield of 77% was obtained, as shown in Table 2. Analytical data: 3-H(l,3-diphenyl-indene//-pyrazole-5-phenyl)benzamide (Compound 15): melting point (recrystallized from CH2Cl2 / MeOH, white solid) 175 to 177 〇c; iH nmr (CDq3, 2〇〇MHz) 1373468 δ 7.18 (s, 1 Η, Py-H), 7.31-7.41 (m, 8 Η, ArH), 7.57 (dd, 4 H, J = 4.2, 1.4 Hz, • ArH), 7.88 (dd, 2 H, J= 6.6, 1.4 Hz, ArH), 8.21 (b, 1 Η, NH) ; , 3C NMR (50 • MHz, CDC13) 8 96.4, 114.5, 114.9 , 119.4, 119.8, 122.4 (2 χ CH), 124.7 (2 x CH), 125.8, 128.6, 128.7 (2 x CH), 130.1 (2 χ CH), 130.6, 130.8, 132.9, 135.3, 135.4, 136.3.137.8 , 152.0, 160.4, 162.6, 165.3; IR (KBr) 3269 (brs, NH), 3064, 1684, 1589, 1458, 1365, 1290, 1072, 956,692 cm_l; MSm/z (relative intensity) 357 (ivf, 15) , 356 (15), 206 (2), 123 (100), 101 (18), 95 (35), 77 (17), 51 (10). C22Hl6FN30 Analytical calculated value: C: 73.94; H: 4.51; N : 11.76 ; Actual values: C: 73.66; H: 4.46; N: 11.41. • [Example 9] Synthesis of 4-fluoro-7V-(1,3-diphenyl-1//-pyrazol-5-yl)benzamide as a benzoic acid cyanide under a nitrogen system (Compound 11) After reacting with an equivalent amount of benzoquinone in a solvent-free condition for 2 hours, the temperature is lowered in an ice bath and the reaction mixture is stirred, and then p-fluorobenzoquinone gas is slowly added dropwise, after the addition of the fluorobenzoquinone gas is completed. The ice bath was removed, warmed to room temperature, stirred for about 2 hours, and the reaction was monitored by thin layer chromatography. After the reaction is terminated, the tetrahydrofuran is removed by concentration and drying, and the reaction mixture is dissolved by adding methane. After washing with water, the organic layer is collected, washed with saturated brine, water, filtered and concentrated, and finally purified by chromatography. That is, 4-fluoro-indole, 3-diphenyl-177-pyrazol-5-ylbenzoguanamine (Compound 16) having a yield of 70% was obtained, as shown in Table 2. Analytical data: 4-Fluoro-iV-(l,3-diphenyl-1//-pyrazol-5-yl)benzamide (Compound 16): m.p. (yield from CH2Cl2/MeOH, white solid) 187 to 189 ° C; WNMRiCDCb, 200 MHz) δ 7.12 (t, 1 Η, J = 8.7 Hz, ArH), 7.18 (s, 1H, Py-H), 7.32-7.48 (m, 4 H, ArH), 7.55-7.58 (m, 4 H, ArH), 7.70-7.77 (m, 2 H, ArH), 7.88 (dd, 4 H, J = 7.9, 1.3 Hz, ArH), 8.12 (b, 1H, NH); l3C NMR (50 MHz, CDC13) δ 96.0, Π6.0, 116.4, 124.8 (2 x CH), 125.8 (2 χ CH), 128.2, 128.6 (2 x CH), 128.7, 129.4, 1373468 129_6, 130.1 (2 xCH), 132.9, 136.5, 137.9, 146.2, 152.1, 162.6; IR(KBr) 3217 (brs, NH), 3045, 1685, 1529, 1504, 1460, 1367, 1286, 1234, 1072, 918, 760, 694 cm —1; MS m/2 (relative intensity) 357 (M+, 15), 234 (1), 206 (1), 123 (100), 102 (24), 95 (46), 77 (24), 51 ( 12). Calculated for C22Hl6FN30: c: 73.94; H: 4.51; N: 11.76; Actual: C: 73.87; H: 4.67; N: 11.35. [Example 10] Synthesis of 2-gas-"-(1,3-diphenyl-1//-pyrazol-5-yl)benzamide as a benzoic acid cyanide under a nitrogen system (Compound 11) After reacting with an equivalent amount of benzoquinone in a solvent-free condition for 2 hours, the temperature is lowered in an ice bath and the reaction mixture is mixed. Then, the adjacent gas is slowly added dropwise, and the addition of the adjacent gas is completed. The ice bath was removed and warmed to room temperature, stirred for about 2 hours, and the reaction was monitored by thin layer chromatography. After the reaction is terminated, the tetrahydrofuran is removed by concentration and drying, and the reaction mixture is dissolved in dioxane, and the mixture is extracted with water. The organic layer is collected and washed with saturated brine. After filtration and concentration, the chromatographic purification is carried out. That is, 2-gas-AM,3-diphenyl-1//-pyrazole-5-yl acinoxalide (Compound 17) was obtained in a yield of 85%, as shown in Table 2. Analytical data: 2-gas-7V-(1,3-diphenyl-1//-pyrazol-5-yl)phenylguanamine (Compound 17): melting point (purified by hydrazine column chromatography, yellow solid 147 to 149 ° C; WNMR^CDCb, 200 ΜΗζ) δ 7.14 (s, 1 H, Py-H), 7.22-7.68 (m, 11 H, ArH), 7.70-7.94 (m, 3 H, ArH), 8.64 (b, 1 Η, NH) ; l3C NMR (50 MHz, CDC13) δ 96.2, 125.5 (2 χ CH), 125.8 (2 x CH), 127.5, 128.2, 128.6 (2 χ CH), 128.9, 129.5 ( 2 x CH), 130.5, 131.2, 132.0, 132.5, 132.9, 136.6, 137.6, 151.9, 162.7, 168.9; IR (KBr) 3256 (brs, NH), 3066, 1666, 1566, 1502, 1460, 1369, 1263, 1117, 1051, 765, 696 cm"' ; MS m/z (relative intensity) 373 〇Vf,10),338(18),234(1),206 (2), 141 (44),139(100) , 111 (36), 102 (34), 77 (36), 51 (16). C22H16C1N30 Analytical calculated value: C: 70.68; H: 4.31; N: 24 Ϊ 373468 1 1·24 ; Actual value: c: 70.29; Η: 4.51; N: 丨丨.丨4. • [ κ she example 1 合成] synthesis of 3 · gas - 々 - (1,3-diphenyl _] / / _ pyrazole _5 yl) benzoguanamine under a nitrogen system, take a clunk acetonitrile ( The compound 丨丨) is reacted with an equivalent amount of phenylhydrazine in a solvent-free condition for 2 hours, then the temperature is lowered in an ice bath and the reaction mixture is stirred, and then the mixture is added dropwise to the gas, and the gas is added to the gas. After the gas addition was completed, the ice was removed, and the mixture was warmed to room temperature, stirred for about 2 hours, and the reaction was monitored by thin layer chromatography. After the reaction is terminated, the tetrahydrofuran is removed by concentration and drying, and the reaction mixture is dissolved by dioxane, washed with water, and the organic layer is collected, washed with saturated brine, filtered and concentrated, and finally purified by chromatography. That is, 3-gas-#-1,3-diphenyl_1//-pyrazole-5-yl azelaamine (Compound 18) having a yield of 71% was obtained, as shown in Table 2. Analytical data: 3-gas-AL(i,3_diphenylpyrazole-5-phenyl)benzamide (Compound 丨8): melting point (purified by Shixi rubber column chromatography, yellow solid) 168 to 17 〇 〇c ; iHNMR(CDC13, 200 ΜΗζ) δ 7.14 (s, 1 Η, Py-H), 7.22-7.61 (m, 10 H, ArH), 7.65-7.94 (m, 3 H, ArH), 8.04 (b , 1 H, NH); l3CNMR (50MHz, CDC13) 8 96.4, 124.8 (2 x CH), 124.9, 125.8 (2 x CH), 127.7, 128.2, 128.6 (2 x CH), 128.8, 130.1 (2 x CH ), 130.3, 132.6, 133.7, φ 134.9, 136.2, 137.8, 152.1, 162.6, 169.6; IR (KBr) 3248 (brs, NH), 3052, 1675, 1573, 1498, 1455, 1431, 1358, 1292, 1252, 1061,758, 692 cm-1 ; MS m/z (relative intensity) 373 (M+, 15), 343 (1), 234 (2), 206(3), 141 (33), 139(100), 111 (46), l〇2 (32), 77 (33), 75 (27), 51 (19). C22HI6C1N30 Analytical calculations: C: 70.68; HM.31; • N: 11.24; Actual: C: 70.29 ; H: 4.51; N: 11.14. [Example 12] Synthesis of 2-mercapto 3-diphenyl-1//-pyrazol-5-yl)benzamide Under a nitrogen system, benzoquinone (Compound 11) and equivalent benzene were taken.肼, after reacting for 2 hours without solvent, the temperature was lowered in an ice bath and the reaction mixture was stirred, and then o-methylbenzonitrile was slowly added dropwise, after the addition of m-o-methyl sulphonium was completed 25 1373468. The ice bath was removed, warmed to room temperature, stirred for additional 2 hours, and the reaction was monitored by thin layer chromatography. After the reaction is terminated, the tetrahydrofuran is removed by concentration and drying, and the reaction mixture is dissolved by adding dioxane, washed with water, and the organic layer is collected, washed with saturated brine, and then subjected to chromatography and purification. That is, 2-mercapto-W-(l,3-diphenyl-1//-pyrazol-5-yl)benzamide (Compound 19) was obtained in a yield of 84%, as shown in Table 2. Analytical data: 2-methyl-AK1,3-diphenyl-1//-pyrazol-5-ylphenylamine (Compound 19): melting point (recrystallized from CH2C12 / hexanes, white solid) 187 To lSVC^HNMR^CDCbJOO MHz) δ 2.17 (s, 3 H, CH3), 6.82 (s, 1 H, Py-H), 6.91-7.56 (m, 12 H, ArH), 7.86 (dd, 2H, J =7.1, 1.0 Hz, ArH) ; l3C NMR (50 MHz, CDC13) δ 19.7, 102.8, 125.2, 125.7, 125.9, 127.3, 128.2, 128.6, 129.1, 129.4, 131.3 (5 χ CH), 132.8, 134.3 (2 x C), 137.6, 138.3 (2 χ C), 151.8, 172.1 ; IR (KBr) 3064 (brs, NH), 1718, 1683, 1599, 1549, 1501, 1458, 1383, 1319, 1233, 1140, 1108, 1078, 953, 901, 841 cm-1 ; MS m々 (relative intensity) 354 (M+, 14), 336 (13), 307 (11), 289 (11), 262 (8), 235 (9), 219 (12), 178 (9), 154 (68), 136 (65), 119 (100), 107 (36), 91 (79), 77 (50), 69 (43), 55 (50). Analysis calculated for C23Hl9N30: C: 78.16; Η: 5.42; N: 11.89; actual value: 78.19; Η: 5.47; N: 11.69. [Example 13] Synthesis of 4-mercapto-A41,3-diphenyl-1//-pyrazol-5-yl)benzamide under a nitrogen system, taking benzoquinone (Compound 11) and the like Equivalent phenylhydrazine, after reacting for 2 hours without solvent, the temperature is lowered in an ice bath and the reaction mixture is stirred, and then o-mercaptobenzyl hydrazine chloride is slowly added dropwise, after the addition of m-toluene gas is completed. The ice bath was removed, warmed to room temperature, stirred for about 2 hours, and the reaction was monitored by thin layer chromatography. After the reaction is terminated, the tetrahydrofuran is removed by concentration in a dry state, and the reaction mixture is dissolved by adding methane, washed with water, and the organic layer is collected, washed with 1373468 and brine, filtered and concentrated, and finally layered. Purification and purification, that is, the yield of 76% 4-methyl-; V-(1,3-diphenyl-1//-pyrazol-5-yl)benzamide (Compound 20), as shown in the table 2 is shown. Analytical data: 4-mercaptodiphenyl-1//-pyrazol-5-yl)benzamide (Compound 20): m.p. (recrystallized from CH2C12/hexanes, white solid) 181 to 183 °C; 'HNMR^CDCbJOO MHz) δ 2.39 (s, 3 H, CH3), 7.19 (s, 1 H, Py-H), 7.24-7.65 (m, 12 H, ArH), 7.89 (dd, 2 H, 7.3, 1.4 Hz, ArH), 8.12 (b, 1 H, NH); 13C NMR (50 MHz, CDC13) δ 21.5, 95.7, 124.8 (2 x CH), 125.8 (2 x CH), 127.1 (2 x CH), 128.1,128.6 (2 x CH), 129.6, 129.7 (2 χ CH), 130.0 (2 χ CH), 130.3, 133.0, 136.8, 137.9, 143.3, 152.0, 163.6 ; IR (KBr) 3277 (brs, NH), 1654, 1558, 1505, 1459, 1387, 1282, 1074, 1018, 953, 915, 834 cm_1 ; MS m/z (relative intensity) 354 (M+, 6), 233 (2), 205 (2), 177 ( 1), 167(1), 130 (3), 119(100), 102 (19), 91 (56), 77(19), 65 (8), 51 (5). C23H19N30 Analytical calculation: C: 78.16; H: 5.42; N: 11.89; actual values: C: 78.05; H: 5.34; N: 11.71. [Example 14] Synthesis of 3-tri-It-methyl-A/~ (l,3-diphenyl ratio. Sodium _5-yl) phenyl-ternamine was taken under a nitrogen system to obtain benzamidine cyanide (Compound 11) After reacting with an equivalent amount of benzoquinone in the absence of solvent for 2 hours, the temperature was lowered in an ice bath and the reaction mixture was stirred, and then p-trifluorodecyl phenyl hydrazine was slowly added dropwise to the trifluoromethyl benzophenone. After the addition of helium gas was completed, the ice bath was removed, warmed to room temperature, and stirred for about 2 hours, and the reaction was monitored by thin layer chromatography. When the reaction is terminated, the tetrahydrogenate is removed by concentration and drying, and then the reaction mixture is dissolved by adding methylene chloride, and the organic layer is collected by water extraction, and then washed with de and brine, filtered and concentrated, and finally Chromatographic purification gave a yield of 78% of 3-trifluoromethyl-iV-(l,3-diphenyl)benzoic acid amine (Compound 21) as shown in Table 2. 27 1373468 • $7 analysis data. 3-Dimethylmethyl-/V-(l,3-one-based-1//-α ratio 〇--5-yl) phenylamine (Compound 2 I): melting point ( Recrystallization of 'yellow solids' from CH2C12/hexanes I% to 198 °C; iHNMR (CDC13, 200 MHz) δ 7.19 (s, 1 H, Py-H), 7.29-7.49 (m, 4 H, ArH) , 7.56-7.58 (m, 4 H, ArH), 7.71 (d, 2W, J = 8.7 Hz, ArH), 7.82-7.91 (m, 4 H, ArH), 8.21 (b, 1 H, NH) ; l3C NMR (50 _z, CDC13) δ 96.4, 124.0, 124.7 (2 x CH), 125.8 (2 x CH), 126.1, 127.6 (2 x CH), 128.3, 128.6 (2 x CH), 128.6, 128.8, 129.4, 130.1 (2 x CH), 130.5, 131.1, 133.8, 136.1, 1 137.8, 152.1, 162.6 ; IR (KBr) 3205 (brs, NH), 3051, 1658, 1593, 1556, 1537, 1498, 1460, 1367, 1303 , 1168. 1066, 854, 758, 688 cm-1; MS m/z (relative intensity) 407 (M+, 30), 377 (2), 234 (4), 206 (4), 173 (100), 145 (54), 131 (6), 102 (38), 77 (38), 51 (15). C23H16F3N30 Analytical calculated value: C: 67.81; H: 3.96; N: 10.31 ; Actual value: C: 68.12; H: 4.10; N: 10.21. [Example 15] Synthesis of 2-decyloxy-7V-(1,3-diphenyl-1//-pyrazole-5-yl)benzamide Under the nitrogen system, benzamidine cyanide (compound) 11) After reacting with an equivalent amount of benzoquinone in the absence of solvent for 2 hours, the temperature is lowered in an ice bath and the reaction mixture is stirred, and then o-methoxybenzoquinone gas is slowly added dropwise to the o-methoxybenzoquinone. After the completion of the addition of helium, the 'ice bath was removed' and the temperature was warmed to room temperature, and the mixture was further stirred for about 2 hours, and the reaction was monitored by thin layer chromatography. When the reaction is terminated, the mixture is concentrated and dried to remove the tetrahydrogenate. Then, the reaction mixture is dissolved by adding a nitrogen nitrite. The extract is washed with water, and the organic layer is collected, washed with saturated brine, filtered and concentrated, and finally layered. Purification and purification, that is, the yield of 90% of 2-nonyloxy good (1,3-diphenyl-1 / / -. azole 3-5 group) benzoguanamine (Compound 22), as shown in Table 2 Shown. Analytical data: 2-methoxy-AKU-diphenyl-purine from pyrazole-5-yl) acesulfame (Compound 22): melting point (purified by hydrazine column chromatography, white solid) 196 to 198. (:; 4νΜΚ(ΟΧ:13,200 MHz) δ 3i2 (s, 3 H, Me), 6.91 (d, 1 H, J= 6.9 Hz, ArH), 7.10 (t, 1 H, J = 4.6 1373468

Hz, ArH), 7.13 (s, 1 H, Py-H), 7.33-7.89 (m, 8 H, ArH), 7.91 (dd, 2 H, 7= 6.7, • 1.3 Hz, ArH), 8.43 (dd , 1 H, J = 6.7, 1.3 Hz, ArH) ; , 3C NMR (50 MHz, CDC13) δ 55.6, 94.6, 111.4, 120.1, 121.8, 125.8 (2 χ CH), 125.9 (2 x CH), 128.0, 129.8 (2 x CH), 132.7 (2 χ CH), 133.1, 133.9, 135.1, 136.7, 138.1, 152.1, 157.2, 161.2; IR (KBr) 3306 (brs, NH), 3062, 2924, 1674, 1598, 1570 , 1496, 1483, 1371, 1296, 1244, 1163. 1018, 759, 694 cm_l; MS w/z (relative strength) 369 (M+, 2), 206 (1), 135 (100), 120 (3), 102 (15),92 (25), 77 (49),63 (7),51 (11). C23Hl9N30 Analytical calculated value: C: 74.78; H: 5.18; N: 11.37 ; Actual value: C: 74_98; H : 5.43; N: 11_48. ® [Example 16] Synthesis of 3-methoxy-7V-(1,3-diphenyl-1//-pyrazol-5-yl)benzamide under nitrous acid system Compound 11) is reacted with an equivalent amount of phenylhydrazine in a solvent-free condition for 2 hours, then the temperature is lowered in an ice bath and the reaction mixture is stirred, and then m-decyloxybenzonitrile is slowly added dropwise, to be m-methoxybenzene. After the addition of formazan gas was completed, the ice bath was removed, warmed to room temperature, and stirred for about 2 hours, and the reaction was monitored by thin layer chromatography. After the reaction is terminated, the tetrahydrofuran is removed by concentration and drying, and then the reaction mixture is dissolved by adding methane, washed with water, and the organic layer is collected, washed with φ saturated brine, filtered and concentrated, and finally purified by chromatography. A yield of 72% of 3-decyloxy-7V-(1,3-diphenyl-1//-pyrazol-5-yl)benzamide (Compound 23) can be obtained as shown in Table 2. Show. Analytical data: 3-decyloxy-AKU-diphenyl-1//-pyrazol-5-yl)benzamide (Compound 23): melting point (purified by hydrazine column chromatography, yellow solid) 175 to 177 °C; WNMI^CDCl^OO MHz) δ 3.84 (s, 3 Η, Me), 7.19 (s, 1 H, Py-H), 7.28-7.72 (m, 12 H, ArH), 7.88 (d, 2 H, J = 8.0 Hz, ArH), 8.21 (b, 1 H, NH); , 3C NMR (50 MHz, CDC13) δ 55.5, 96.1, 112.6, 118.6, 118.7, 124.4 (2 χ CH), 124.8, 125.9 (2.x CH), 128.2, 128.6 (2 x CH), 129.6, 130.0 (2 x CH), 133.0, 134.6, 136.6, 137.9, 152.0, 160.1, 29 1373468 163.7 ; IR (KBr) 3257 (brs, NH ), 3066, 2843, 1667, 1597, 1560, 1502, 1460, 1369, 1284, 1230, 1041, 769, 702 cm_l; MSm/Z (relative strength) 369 (M+, 1), 234 (2), 206 (2) , 135 (100), 107 (27), 92 (25), 77 (52), 64 (13), 51 (12). C23H丨9N30 Analytical calculated value: C: 74.78; Η: 5.18; N: 11.37; Actual value: C: 74.55; Η: 5.64; N: 11.72. [Example 17] Synthesis of 2,4-difluoro 3-diphenyl-1//-pyrazol-5-yl)benzamine under the nitrogen system, taking benzamidine cyanide (compound 11) and the like The equivalent of awkward, after reacting for 2 hours without solvent, the temperature is lowered in an ice bath and the reaction mixture is stirred, and o-p-difluorobenzoquinone gas is slowly added dropwise, to the adjacent p-difluorobenzophenone gas. After the addition was completed, the ice bath was removed, warmed to room temperature, and stirred for about 2 hours, and the reaction was monitored by thin layer chromatography. After the reaction is terminated, the tetrahydrofuran is removed by concentration and drying, and the reaction mixture is dissolved by adding methane, washed with water, and the organic layer is collected, washed with saturated brine, filtered, concentrated, and finally purified by chromatography. That is, a yield of 88% of 2,4-difluoro-7V-(1,3-diphenyl-1//-pyrazol-5-yl)benzamide (Compound 24) was obtained, as shown in Table 2 Shown. Analytical data: 2,4-difluoro-ethyl (1,3-diphenyl-1//-pyrazol-5-yl)benzamide (Compound 24): melting point (recrystallized from CH2C12/hexane) , yellow solid) 162 to 164 °C; W NMR (CDC13, 200 MHz) δ 6.74-6.89 (m, 1 Η, ArH), 7.92-7.10 (m, 1 H, ArH), 7.26 (s, 1 H, Py-H), 7.31-7.51 (m, 4 H, ArH), 7.55-7.59 (m, 4 H, ArH), 7.88 (dd, 2 H, J = 6.7, 1.4 Hz, ArH), 8.14-8.39 ( m, 1 H, ArH), 8.74 (b, 1 Η, NH) ; , 3C NMR (50 MHz, CDC13) δ 95.5, 104.0, 104.5, 105.0, 112.9, 113.3, 116.7, 116.9, 117.0, 125.1 (2 x CH), 125.8 (2 χ CH), 128.2, 128.6 (2 χ CH), 128.8, 130.0 (2 χ CH), 132.9, 134.2, 134.4, 136.7, 152.0, 158.2, 164.3 ; IR (KBr) 3423 (brs, NH), 3061, 1693, 1614, 1570, 1494, 1289, 1111,970, 766, 694 cm-1; MS w/z (relative strength) 376 (W,100),358 (3),336 (3) ,304 (3),282 (5),262 (3),234 (6),219 (4)::207 30 1373468 ' (5),154 (5),141 (98),113 (7),92 (4),77 (12), 57 (4)· C22H|5f2N3〇 Analytical calculation • Value: C: 70.39; H: 4.03; N: 11.19 ; Actual value: C: 70·81; H: 4.19 ; N: 11.54. • [Example 18] Synthesis of 3-cyano-#-(l,3-diphenyl·indol//·pyrazole-5-yl)benzamide as a benzoic acid cyanide (nitrogen compound) 11) After reacting with an equivalent amount of benzoquinone in a bathless condition for 2 hours, the temperature is lowered in an ice bath and the reaction mixture is stirred, and then o-cyanobenzoquinone chloride 'o-cyanobenzamide is slowly added dropwise. After the gas addition was completed, the ice bath was removed, warmed to room temperature, and further mixed for about 2 hours, and the reaction was monitored by thin layer chromatography. After the reaction is terminated, the tetrahydrofuran is removed by concentration and drying, and then the mixture is extracted by water extraction, and the organic layer is collected, washed with saturated brine, filtered and concentrated, and finally layered. The purification was carried out to obtain 3-cyano-indole 1,3-diphenyl-1//-carbazole-5-phenyl)benzamide (Compound 25) in a yield of 90%, as shown in Table 2. Analytical data: Cyanamide (1,3-diphenyl-1//-.biazole-5) phenylamine (Compound 25): Hyun point (purified by Shixi rubber column chromatography, brown solid) 207 To 208 4 NMR €CDC1:3, 200 δ 6.90 (s, 1 Η, Py-H), 7.26-7.45 (m, 11 H, ArH), 7.79-7.92 (m, 3 H, ArH) ; l3C φ NMR (50 MHz, CDC13) δ 100.5, 112.7, 117.1, 124.3 (2 χ CH), 125.3 (2 χ CH), 128.3 (2 x CH), 128.7, 129.5 (2 χ CH), 129.6, 131.2, 131.8, 134.4 , 135.3, 135.7, 138.6, 151.7, 164.3; IR (KBr) 3309 (brs, NH), 3068, 2922, 2852, 2232, 1689, 1654, 1560, 1498, 1458, 1363, 1292, 1190, 1072, 916cnTi; MSm/z (relative intensity), 364 (M+, 59), 234 (11), 207 (6), 147 (8), 130 (100), 102 (49), 91 (2), 77 (15), Anal. Calcd.: C: 75.81; [Example 19] Synthesis of 4-cyano-indenyl-(1,3-diphenyl-1//-pyrazol-5-yl)benzoguanamine under a nitrogen system, and taking benzamidine cyanide 11) reacted with an equivalent amount of benzoquinone at 31 1373468 under solvent-free conditions for 2 hours, then cooled in an ice bath and stirred the reaction mixture, and slowly added p-cyanobenzoquinone gas slowly, to p-cyanobenzene After the addition of formazan chlorine was completed, the temperature was removed to room temperature and stirred for about 2 hours, and the reaction was monitored by thin layer chromatography. After the reaction is terminated, the tetrahydrofuran is removed by concentration and drying, and the reaction mixture is dissolved by adding methane, washed with water, and the organic layer is collected and washed with saturated brine. After filtration and concentration, the chromatographic purification is carried out. A yield of 78% of 4-cyano-7V-(1,3-diphenyl-1//-pyrazol-5-yl)benzamide (Compound 26) was obtained as shown in Table 2. Analytical data: 4-cyano-r7V-(i,3-diphenyl-1//-pyrazol-5-yl) acesulfame (Compound 26): m.p. (m.p. 2〇7 to 209 °C; it NMR (CDC13, 200 MHz) δ 7_02 (s, 1 H, Py-H), 7.35-7.49 (m, 6 H, ArH), 7.66-7.72 (m, 3 H, ArH), 7.90-7.95 (m, 3 H, ArH), 8.12-8.20 (m, 2 H, ArH), 8.27 (b, 1 Η, NH) ; , 3C NMR (50 MHz, CDC13) δ 99.7, 112.7 , 117.7, 124.0 (2 χ CH), 125.3 (2 χ CH), 127.7, 127.9, 128.6 (2 χ CH), 129.9 (2 χ CH), 129.9, 131.3, 132.1, 133.4, 134.9, 135.3, 136.8, 139.2 , 150.7, 163.8 ; IR (KBr) 3250 (brs, NH), 3087, 1686, 1578, 1501, 1296, 769, 699 cm_l ; MS m/z (relative intensity) 364 (M+, 100), 335 (6) ,262 (3),234 (12),206 (7),130 (98),102 (44),77 (16),51 (5). C23H|6N40 Analytical calculated value: C: 75.81; Η: 4 · 43; N: 15.38 ; Actual value: C: 76.12; Η: 4·42; N: 15.14. [Example 20] Synthesis of 2-nitro-iV-(l,3-diphenyl-1//-~bazol-5-yl)benzamide Under the nitrogen system, benzoic acid acetonitrile was taken ( Compound 11) is reacted with an equivalent amount of phenylhydrazine in a solvent-free condition for 2 hours, then 'decreasing the temperature in ice and dialing off the reaction mixture'. Then slowly adding o-nitrobenzidine to the o-nitrobenzoquinone After the addition of the brewing gas was completed, the ice bath was removed and returned to room temperature for further 2 hours, and the reaction was monitored by thin layer chromatography. When the reaction is terminated, the tetrahydrofuran is removed by concentration and drying, and then the reaction mixture is dissolved in -1373468 dichloromethane, washed with water, and the organic layer is collected, washed with saturated brine, filtered and concentrated, and finally chromatographed. Purification, i.e., yield of 76% 2-nitro-3-diphenyl-1//-pyrazol-5-yl)benzamide (Compound 27), as shown in Table 2. Analytical data: 2-nitro-#-(1,3-diphenyl-1//-pyrazol-5-yl)phenylguanamine (Compound 27): melting point (recrystallized from CH2C12/hexanes, white Solid) 229 to 231 ° C; iHNMR^CDCbJOO MHz) δ 7.00 (s, 1 Η, Py-H), 7.36-7.89 (m, 12 H, ArH), 8.08-8.26 (m, 3 H, ArH + NH ; ; 3C NMR (50 MHz, CDC13) δ 100.1, 124.4 (2 x CH), 124.8, 125.7 (2 x CH), 128.3, 128.6, 129.2 (2 χ CH), 129.7, 130.2 (2 χ CH), 132.0, 133.1, 134.6, 135.6, 137.0, 138.9, 144.4, 147.0, 150.8, 167.8; IR (KBr) 3261 (brs, NH), 3061, 1718, 1533, 1502, 1354, 1249, 7574, 690 cm-1; MS m/z (relative intensity) 385 (M+, 66), 370 (27), 339 (22), 323 (10), 307 (45), 289 (39), 285 (18), 262 (15), 234 (32), 206 (22), 178 (31), 165 (48), 154 (100). C22H, 6N403 Analytical calculated values: C: 68.74; H: 4.20; N: 14.58 ; Actual value: C: 68.81 ; H: 4.15; N: 14.81. [Example 21] Synthesis of 4-nitro-indole 1,3-diphenyl-1//-pyrazol-5-yl) acesulfame under nitrogen system 'take benzoquinone cyanide (compound 11) and the like Equivalent phenylhydrazine, after reacting for 2 hours without solvent, 'cool down in an ice bath and stir the reaction mixture, then slowly add p-nitrophenyl hydrazine gas after the addition of p-nitrophenyl hydrazine gas is completed. The ice bath was removed, warmed to room temperature, stirred for additional 2 hours, and the reaction was monitored by thin layer chromatography. After the reaction is terminated, the tetrahydrofuran is removed by concentration and drying, and the reaction mixture is dissolved by adding dioxane. The organic layer is collected, washed with saturated brine, filtered and concentrated, and finally purified by chromatography. That is, a yield of 89% of 4-mercapto-iV-(l,3-diphenyl-1//-. than σ--5-yl) abbreviated amine (compound 28) was obtained, as shown in Table 2. Show. 33 1373468 Analytical data: 4-nitro-W-(l,3-diphenyl-1//-pyrazol-5-yl) acesulfame (Compound 28): melting point (recrystallization from CH2C12/hexane) , yellow solid) 221 to 223 °C; iHNMRfDCbJOO MHz) δ 7.23 (s, 1 Η, Py-H), 7.37 (t, 1 Η), 7.43 (t, 1 Η), 7.51 (q, 1 Η), 7.60 (d, 2 H, J = 4.5 Hz, ArH), 7.36-7.89 (m, 12 H, ArH), 8.08-8.26 (m, 3 H, ArH + NH), 7.92 (m, 4H), 8.09 ( b, 1 Η, NH), 8.32 (d, 2 H, 8.7 Hz, ArH) ; l3C NMR (50 MHz, CDC13) δ 100.1, 122.9 (2 x CH), 123.0 (2 χ CH), 124.7 (2 χ CH), 126.9, 127.5, 128.1 (2 x CH), 128.6 (2 χ CH), 128.8 (2 χ CH), 132.3, 136.1, 138.3,

138.5, 150.8, 162.0, 163.5 ; IR (KBr) 3250 (brs, NH), 3087, 1686, 1578, 1501, 1296, 769, 699 cnT1 ; MS (relative intensity) 364 (IVT, 100), 335 (6) , 262 (3), 234 (12), 206 (7), 130 (98), 102 (44), 77 (16), 51 (5). C23Hl6N4 〇 analytical calculated value: c: 75.81; H: 4.43; N: 15.38 ; Actual value: C: 76.12; H: 4.42; N: 15.14.

Table 2. Preparation of #-(1,3-diphenyl-1//-°°-s--5-yl)benzamide derivatives by one-pot synthesis Product yield (%) Example R1 R2 R3 7V-(1,3-Diphenyl-1//-pyrazol-5-yl) stupid γ" decylamine derivative 7 Η Η Η 14 78 8 Η F Η 15 77 9 Η Η F 16 70 10 Cl Η Η 17 85 11 Η C1 Η 18 71 12 Me Η Η 19 84 13 Η Η Me 20 76 14 Η Η cf3 21 78 15 OMe Η Η 22 90 16 Η OMe Η 23 72 17 F Η F 24 88 18 Η CN Η 25 90 19 Η Η CN 26 78 20 Ν〇2 Η Η 27 76 21 Η Η Ν〇 2 28 89 34 1373468 [Examples 22 to 27] Examples 22 to 27 were prepared by one-pot synthesis using a series of heterocyclic substitutions. The reaction process of the W-(l,3-diphenyl-1-//-pyrazol-5-yl) decylamine derivative is as follows:

PhNHNH2 back to 3 hours, 94%

NH, Ph-N

Ο 'People Cl

CH2Cl2orTHF

29-34 W=heteroaryl or heteroaryl substituted sulfonyl

, 73%, 84%, 90% [Example 22] Synthesis of iV-2-furan-1,3-diphenyl-5-amino-1//-pyrazole under a nitrogen system, taking benzoquinone B Cyanide (Compound 11) and an equivalent amount of phenylhydrazine, reacted for 2 hours without solvent, then cooled in an ice bath and stirred the reaction mixture, and then slowly added 2-furanium to 2-furan After the gas addition was completed, the ice bath was removed, warmed to room temperature, stirred for about 2 hours, and the reaction was monitored by thin layer chromatography. When the reaction is terminated, the tetrahydrofuran is removed by concentration and drying, and then the reaction mixture is dissolved in a gas mixture, and the mixture is washed with water, and the organic layer is collected, washed with saturated brine, filtered, concentrated, and finally purified by chromatography. That is, #-2-furan-1,3-diphenyl-5-amino-1//-pyrazole (Compound 29) having a yield of 70% was obtained, as shown in Table 3. 35 1373468 Analytical data: Λ,-2-furan-1,3-diphenyl-5-amino-1//-pyrazole (Compound 29): melting point (purified by hexane column chromatography, brown solid) 143 To 1450C; iHNMRiCDCbJOOMHzMe.SA (dd, 1 H, "/= 3.6, 1.7 Hz, furan-H), 7.18 (s, 1 H, Py-H), 7.25 (d, 1 H, J = 3.6 Hz, furan -H), 7.32 - 7.51 (m, 6 H), 7.56-7.60 (m, 3 Η), 7·89 (dd, 2 H, "/= 8.0, 1.3 Hz, ArH), 8.34 (b5 1 Η, NH) ; , 3C NMR (50 MHz, CDC13) δ 95.4, 112.8, 116.4, 124.7 (2 x CH), 125.8 (2 χ CH), 128.1, 128.6 (3 χ CH), 130.0 (2 χ CH), 133.0 , 136.0, 137.9, 144.8, 146.8, 152.0, 154.2; IR (KBr) 3400 (brs, NH), 3277, 3138, 3061, 1672, 1587, 1556, 1537, 1500, 1471, 1415, 1365, 1288, 1228, 1157, 1074, 1012, 954, 883, 763, 692 cnT1 ; MS w/z (relative intensity) 330 (M+, 100), 315 (9), 262 (11), 236 (14), 221 (16), 207 (12), 154 (28), 121 (42), 119 (58), 95 (95), 79 (57), 69 (100), 55 (99). C2〇H|5N302HRMS Calculated value: 329.1164; Actual value: 329.1241. [Example 23] Synthesis of W-2-thiophenecarbenyl-1,3-diphenyl-5-amino-1//-pyrazole in the presence of a nitrogen system to extract benzamidine cyanide (compound 11) and Equivalent phenylhydrazine, after reacting for 2 hours without solvent, the temperature was lowered in an ice bath and the reaction mixture was stirred, and then 2-thiophenemethyl hydrazine was slowly added dropwise, after the addition of 2-» s. The ice bath was removed and returned to room temperature for a further 2 hours, and the reaction was monitored by thin layer chromatography. When the reaction is terminated, the tetrahydrofuran is removed by concentration and drying, and then the reaction mixture is dissolved by adding methane, washed with water, and the organic layer is collected, washed with saturated brine, filtered and concentrated, and finally purified by chromatography. A porphin-yttrium-1,3-hexyl-5-amino-1 was obtained in a yield of 77%. Sit (Compound 30) as shown in Table 3.

Analytical data: #-2-thiophenecarbenyl-1,3-diphenyl-5-amino-1//-pyrazole (Compound 30): orange-red colloid; 1H NMR (CDC13): 7.04 (dd, 1 11, /= 4.9, 3.8 out of the order, 7.13 (s, 1 H, Py-H), 7.36-7.66 (m, 10 H, ArH), 7.86-7.90 (m, 2 H, thiophene-Η) , 7.90 (b, 1H 1373468 NH) ; , 3C NMR (CDC13): 96.0, 124.7 (2 χ CH), 125.8 (2 χ CH), 128.1, 128.2, • 128.6 (2 χ CH + CH), 129.2, 1.30 .1 (2 χ CH), 131.8, 132.9, 136.2, 137.4, 137.8, m , 152.0, 158.1 ; IR (KBr) 3061 (brs, NH), 2922, 2851, 1654, 1554, 1537, 1504, 1365, 1283 , 1214, 1171, 1065, 1038, 888 cnT'MSw/z (relative intensity) 345 (M+, 42), 236 (4), 207 (3), 111 (100), 102 (11), 83 (2) , 77 (10), 51 (3). C2〇H, 5N3OS HRMS calcd.: 345.0936; actual value: 345.0939. [EXAMPLE 24] Synthesis of iV-isoxazole-5-carbon fluorenyl-1,3-di Phenyl-5-amino-1//-pyrazole in a nitrogen system, taking phenylhydrazine cyanide (compound 11) and an equivalent of phenylhydrazine, reacting in a solvent-free condition for 2 hours, in an ice bath Decrease the temperature and stir the reaction mixture, then add the isoxazole slowly and dropwise. -5-carbonate helium gas, after the addition of isoxazole-5-gasified carbonium chloride, remove the ice bath, warm to room temperature, stir for about 2 hours, and monitor the reaction by thin layer chromatography. After the reaction is terminated, the tetrahydrogen is removed by concentration and drying, and the reaction mixture is dissolved in dioxane, washed with water, and the organic layer is collected, washed with saturated brine, filtered and concentrated, and finally. Purification by chromatography, i.e., 71% yield of isoxazol-5-carbenyl-1,3-diphenyl-5-amino-1//-pyridin. Sit (Compound 3 1 ), As shown in Table 3. Analytical data: dioxazole-5-carbonindolyl-1,3-diphenyl-5-amino-1//-pyrazole (Compound 31): melting point Purification by chromatography, orange solid) 153 to 155 ° C; 4 NMR (CDC13): 7.04 • (d, 1 H,*/= 1.8 Hz, isoxazole-H), 7.19 (s, 1 H, Py- H), 7, 35 - 7.58 (m, 8 H, ArH), 7.87 (dd, 2 H, /= 6.6, 1.4 Hz, ArH), 8.35 (d, 1 H, / = 1.8 8.51 (b5 1HNH); I3CNMR (CDC13): 96.2, 107.9, 124.7 (2 χ CH), 125.8 (2 χ CH), 128.3, 128.6 (2 x CH), 128.9, 130.2 (2 χ CH), 132.7, 135.0, 137.5, 151.4, 151.7, 152.0, 161.5; IR (KBr) 3399 (brs, NH), 3306, 3151, 3085, 1700, 1559, 1498, 1457, 1418, 1364, 1330, 1270, 1204, 1162, 1073, 1018, 825 cm- 1; MS m/z (relative intensity) 37 1373468 331 (M+, 62), 262 (15), 236 (11), 203 (11), 169 (12), 154 (22), 121 (21), 119 (41), 95 (74), 79 (53), 69 (96), 55 (100). Cl9Hl4N402 HRMS calc.: 330.1117; calc.::::::::::::::::::::::::::::::::::::: : 16.96 ; Actual value: c: 69.91; H: 4.54; N: 17.21. [Example 25] Synthesis of #-2-benzenefurancarbenyl-1,3-diphenyl-5-amino-1//-pyrazole under a nitrogen system, taking phenylhydrazine cyanide (Compound 11) After reacting with an equivalent amount of benzoquinone in a solvent-free condition for 2 hours, the temperature was lowered in an ice bath and the reaction mixture was stirred, and 2-benzofuranium oxime was slowly added dropwise, and the addition of 2-benzaldehyde methyl hydrazine was completed. Thereafter, the ice bath was removed, warmed to room temperature, and stirred for about 2 hours, and the reaction was monitored by thin layer chromatography. After the reaction is terminated, the tetrahydrofuran is removed by concentration and drying, and the reaction mixture is dissolved by adding methane, washed with water, and the organic layer is collected, washed with saturated brine, filtered and concentrated, and finally purified by chromatography. 7V-2-benzofurancarbenyl-1,3-diphenyl-5-amino-1//-pyrazole (compound 3 2) having a yield of 73% was obtained as shown in Table 3.

Analytical data: TV-2-phenylfurancarbenyl-l,3-diphenyl-5-amino-1//-pyrazole (Compound 32): melting point (purified by hydrazine column chromatography, dark red solid 164 to 166 ° C; NMR (CDC13): 7.24-7.72 (m, 14 H, ArH), 7.90 (dd, 2 U, J = 8.1, 1.6 Hz, ArH), 8.62 (b, 1H)

I NH) ; l3C NMR (CDC13): 95.8, 111.9, 112.5, 123.0, 124.2, 124.7 (2 χ CH), 125.8 (2 x CH), 127.3, 127.5, 127.7 (2 x CH + CH), 128.2, 128.6 (2 χ CH), 130.1, 132.9, 135.8, 137.8, 147.2, 152.1, 154.8; IR (KBr) 3061 (brs, NH), 2922, 2850, 1554, 1504, 1365, 1282, 1170, 1142 crtT1 ;MSm/ z (relative intensity) 379 (1^,47),351 (16), 246 (4), 233 (2), 206 (3), 180 (1), 145 (100), 131 (4), 102 ( 15), 89 (33), 77 (14), 63 (5), 51 (4). C24Hl7N302 HRMS calculated: 379.1321; actual value: 379.1315. [Example 26] Synthesis #-5-p-trimellimidyl-1,3-diphenyl-5-amino-1//-pyrazole! 38 1373468 Under the nitrogen system, take the benzamidine B Cyanide (Compound 11) and an equivalent of phenylhydrazine, reacted for 2 hours under solvent-free conditions, then cool the reaction mixture in an ice bath and stir the reaction mixture. • Slowly add benzotriazole gas dropwise, to be trimellitic. After the addition of helium gas was completed, the ice bath was removed, warmed to room temperature, and stirred for about 2 hours, and the reaction was monitored by thin layer chromatography. After the reaction is terminated, the tetrahydrofuran is concentrated and dried, and the reaction mixture is dissolved in dichloromethane, washed with water, and the organic layer is collected, washed with saturated brine, filtered and concentrated, and then purified by chromatography to yield. The rate of 84% ΑΓ-5-p-trimellimidyl-1,3-diphenyl-5-amino-1//-pyrazole (Compound 33) is shown in Table 3. Analytical data: W-5-p-trimethylene-yl-1,3-diphenyl-5-amino-1//-pyrazole (compound 33): yellow colloid; 111 grab 411 〇: 0 (: 丨 3 ): 6.78 (3,1 乂?乂-印, 6.95 (5,11^, isobenzofuran-1^(isobenzofuran-oxime), 7.27-7.50 (m,8 Η,ArH),7.72- 7.89 (m,3 H, ArH), 8.06 (d,1 Η, «/= 6.4 Hz, isobenzofuran-H), 8.5 (b, 1H NH) ; l3C NMR (CDC13): 97.6, 104.1, 122.7 , 124.4 (2 χ CH), 124.8, 125.7 (2 χ CH), 128.5, 128.7, 129.4 (2 χ CH + CH), 129.8, 130.0, 131.8, 132.4, 133.9, 135.7, 137.9, 139.4, 151.9, 152.1 φ 165.0 ; IR (KBr) 3062 (brs, NH), 2924, 1735, 1674, 1558, 1497, 1458, 1367, 1087 cnT1 ; MS m/z (relative intensity) 409 (M+, 4), 364 (100), 336 (5), 313 (6), 262 (4), 234 (12), 206 (12), 180 (5), 131 (4), 103 (10), 91 (9), 77 (27), 55 (6). • C24H15N304 Analytical calculated value; C: 70.41; Η: 3·ό9; N: 10.26; Actual value: C: 70.27; Η: 3.78; N: 11.22. [Comprehensive Example 27] Synthesis of TV·喧琳-8-Exactly kiln-1,3-diphenyl-5-amino-1//- ratio. Sitting under a nitrogen system, taking benzoquinone cyanide 11) and an equivalent of phenylhydrazine, reacted in the absence of solvent for 2 hours, then cooled in an ice bath and stirred the reaction mixture, and slowly added a drop of lag-8 - continued brewing gas 'waiting to say -8 - After the completion of the addition of chlorine, the ice bath was removed from 39 1373468, warmed to room temperature, stirred for about 2 hours, and the reaction was monitored by thin layer chromatography. When the reaction was terminated, the tetrahydrofuran was removed by concentration and then added. The reaction mixture is dissolved in dioxane, washed with water, and the organic layer is collected, washed with saturated brine, filtered and concentrated, and then purified by chromatography to give a yield of 90% of 7V-quinoline- 8-sulfonyl-1,3-diphenyl-5-amino-1//-pyrazole (Compound 34), as shown in Table 3, Analytical data: quinoline-8-sulfonyl-1, 3-diphenyl-5-amino-1//-pyrazole (Compound 34): dark red colloid; 1H NMR (CDC13, 200 ΜΗζ) δ 6.38 (s, 1 H, Py-H), 7.25-7.68 (m, 12 H, ArH + quinoline-H), 8_01 (dd, 1 H, «/ 8.4, 1.4 Hz, quinoline-H), 8.20 (dd, 1 H, "/2:8,4,1· 7Ηζ,啥琳-H), 8.35(dd,lH,J=7.3,1.4Hz, 啥啦-H), 8.47(dd,lH,J = 4 .3, 1.7 Hz, 啥. Lin-H); I3C NMR (50 MHz, CDC13) δ 96.4, 122.3, 123.7, 125.2 (2 x CH), 125.5 (2 χ CH), 125.7, 127.4, 128.1, 128.3, 128.5 (2 χ CH), 129.3 (2 x CH), 131.5, 132.6, 134.0, 135.0, 136.4, 137.1, 137.8, 151.0, 151.4; IR (KBr) 3450 (brs, NH), 3061, 1597, 1544, 1502, 1460, 1379, 1173, 1146 , 766, 696 cm -1 ; MS m/z (relative intensity) 427 (IVT, 86), 395 (59), 337 (13), 289 (13), 281 (20), 235 (59), 221 ( 23), 207 (28), 194 (15), 185 (46), 176 (38), 165 (32), 154 (80), 109 (86), 83 (100), 71 (100), 57 ( 100). Calculated for C24H18N402S HRMS: 427.1150; actual value: 427.1123; C24H|8N402S analytical value; C: 67.59; H: 4.25; N: 13.14; actual value: C: 67_25; Η: 4_56; N: 12.97. 1373468 Table 3, 1 Preparation of a heterocyclic substituent-containing #_(1,3 diphenyl phenanthrene) decylamine derivative 'Biological sitting-5-----~~_ 醯化试剂Yield of diphenyl----pyrazol-5-yl)guanamine derivatives of s heterocyclic substituents (%) 29 30 31 70 77 71 2-furanyl fluorene 2-thiophene oxime.恶°坐-5 - gasification · ε charcoal

As can be seen from the above examples, the process of the present invention provides a simple and convenient process for preparing a desired amine group. ratio. Sitting on the derivative. 2_ 呋 呋 醯 偏 偏 偏 上述 上述 上述 上述 上述 上述 上述 上述 上述 上述 上述 上述 上述 上述 上述 上述 上述 上述 上述 上述 上述 上述 上述 上述 上述 上述 上述 上述 上述Modifications and variations of the above-described embodiments can be made by those skilled in the art without departing from the spirit and scope of the invention. Therefore, the scope of protection of the present invention should be as set forth in the appended claims.

[Simple description of the diagram] .fe. 〇 [Main component symbol description] None 0 41

Claims (1)

1373468 Port, the scope of patent application: 1. A method for preparing the guanamine-based pyrazole derivative of the following formula (1), (I) 099102990 No. Zhu Yushen _竿 The application for the scope of patent replacement (丨01 July) The method comprises the following steps: (1) mixing a hydrazine compound with a acylacetonitdle compound to carry out a condensation cyclization reaction to obtain a first reaction product. χ 2 (VI); and X1-NHNH2 (II) 0 /CN X, (III) (2) adding at least one of the deuteration reagents of the formula (IV) and the formula (V) to the first reaction product to carry out an amine oximation reaction, Known to the formula (I) guanamine-based ratio 〇 sitting derivative: 1373468 099102990 _ fecal application Chinese patent application scope replacement (丨 0丨 July) 0 II 0 II II II into L X3 (IV L' V ( V ) where: 〇〇R is Η, -(^Χ3 or _fc_x3'; X1 and X2 are independently Ci to C20 alkyl, halogen, cyano, nitro, thio, halo (C To c20) alkyl, C, to c20 alkoxy, c3 to c20 cycloalkyl, halo (C丨 to c20) alkoxy, aryl, heteroaryl, or heterocyclic; X3 and X3' Is different and independent (: 丨 to c2 alkyl, aryl, sulfonyl, c3 to C2 fluorenyl, heteroaryl, or heterocyclic; and L is a leaving group. The method of claim 1, wherein the rule of the formula (I) is in the form of a hydrazine. 3. The method of claim ,, wherein the step (1) is carried out using the formula (II) Compounds and compounds of formula (III): hydrazine and X2 are independently halogen , cyano, nitro, thio, C3 to Cm cycloalkyl, Cs to Cm aryl, or optionally C to CM alkyl or C 丨 to C 2 decyloxy having one or more functional group substituents One or more carbon atoms in the ring of the cycloalkyl or aryl group may be independently replaced by N ' 〇 or s. The method of claim 3, wherein the following conditions are used in the step (1) The compound of the formula (11) and the compound of the formula (HI): X1 and X2 are independently C5 to & aryl, and one or more carbon atoms in the ring of the aryl group may be independently substituted by N, hydrazine or S as needed. 1373468 Patent No. 099丨02990, the scope of the Chinese patent application is replaced by this (July 1st). 5. The method of claim 4, wherein in the step (1), the formula (II) is used as the phenyl group (II) The compound of the formula (III), wherein the method of any one of claims 1 to 5, wherein at least the brewing agent of the formula (IV) and the formula (V) satisfying the following conditions is used. One: X3 and X3' are independently required to have one or more substituents, c丨 to C2 alkyl, C丨 to C, s, C:3 to 〇2〇, Os to C 2 〇 aryl, wherein the substituent is independently halogen, cyano, nitro, C 2 to c quinone anhydride, C 5 to c 20 aryl, or optionally one or more halogen substituents One or more carbon atoms of the C|SQ alkyl or C4 alkoxy group and the ring of the t-thyl ring or aryl group may be independently replaced by N, 0 or s. Wherein at least step (IV) is used in the step (2) Replaced by N, 〇 or S. 7. The method of claim 6, wherein the step (2) is performed using a condition that satisfies the following conditions (d) base, and - or a plurality of carbon atoms in the ring of the ring or aryl group may be independently replaced by N, 〇 or s as needed. 8. The method of claim 6 which utilizes the formula (IV) to degenerate 'wherein the substituent C anthraquinone anhydride group, C5 to c20 aryl group, to C4 thiol group or C, to c4 alkoxylate Or a plurality of carbon atoms may be independently required. 9. The method of claim 7, wherein the step (2) is at least using the formula (Iy) 3 1373468 No. 099102990, the application of the patent scope is replaced by July 01) Reagents and X3 is a phenyl group optionally having one or more substituents, wherein the substituent is independently halogen, fluorenyl, trifluoromethyl, methoxy, cyano, nitro, a cyclic anhydride group, a phenyl group, or a quinolyl group, and one or more carbon atoms in the ring of the cycloalkyl or aryl group may be independently substituted by N, hydrazine or S as needed. The method according to any one of the preceding claims, wherein in the formula (IV) and/or the formula (v) deuteration reagent used in the step (2), the L system is selected from the group consisting of Leaving group: dentate, C 丨 to (: 2 decyloxy, and c 丨 to c20 ester group. 1. The method of claim 1 wherein L is selected from the group of leaving groups: Halogen, hydrazine|to C1Q alkoxy, and (^ to C|Q ester group. 12. Method of π to item i to 5) wherein the formula (IV) and / used in the step (7) Or the formula (V) of the brewing agent, wherein L is a method of C12, wherein the formula (IV) and the formula are independently selected from the group consisting of acetyl chloride and 2, furan. Chlorine, thiophene guanidine, chlorine, isoform, sputum, sulphur, sulphur, sulphur, sulphur, sulphur, sulphur, sulphur, sulphur, sulphur, sulphur, sulphur, sulphur, sulphur The method of any one of items 1 to 5, wherein in the step (1), the molar ratio of the compound of the formula (m) to the compound of the formula (II) is at least: a method according to claim 14, wherein the mo The ear ratio is at least i. Widely, the method of any one of items 1 to 5, wherein the amount of the compound of the formula (1) is (8) For reference, the total number of moles of the step-test sample is at least 1.5 times the number of moles of the compound of formula (8). 17. The method of claim 6, the step of the towel (the number of moles of the test compound is doubled to 3 The number of the ear is the formula (8) A. The method of any one of claims 1 to 5, which is prepared by the following group: 1373468 No. 099102990 No. 099102990 July of the following year) (i) Amidoxime pyrazole derivatives: 5 0 0 1373468 Patent Application No. 099102990 Replacement of Chinese Patent Application (July July) Ph-N Ph-N