TW202110847A - 6-aminopyrazolo[3,4-d]pyrimidines and processes for their preparation - Google Patents

Abstract

The present invention describes 6-aminopyrazolo[3,4-d]pyrimidines and a novel process for prepaation. The convenient one-pot acid catalytic synthesis of 6-aminopyrazolo[3,4-d]pyrimidine was developed by the reaction of 1H-pyrazol-5-yl-N,N-dimethylformamidines, 5-amino-1H-pyrazole-4-carbaldehydes, and/or N-[(5-amino-1,3-diphenyl-1H-pyrazol-4-yl)methylene]-cyanamide with cyanamide analogues under acid mediated solution.

Description

6-aminopyrazolo[3,4-d]pyrimidine and preparation method

The present invention relates to a novel method for preparing 6-aminopyrazolo[3,4- d ]pyrimidine and the use of these for preparing pharmaceutically active compounds.

Pyrazolo[3,4- d ]pyrimidine derivatives are biologically active heterocyclic molecules of medically active compounds, which have many pharmacological effects, such as being a variety of mitotic kinase (MMK) inhibitors ( Bioorg.Med.Chem.Lett. 2011 , 21 , 5633-5637), human epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor ( Bioorg.Med.Chem. Lett. 2015, 25 , 3382-3389), phosphodiesterase inhibitor ( Org. Biomol. Chem. , 2007 , 5 , 3034-3045), and as an anti-inflammatory drug ( Eur. J. Pharm. Sci. 2014 , 62 , 197-211). In recent years, 6-aminopyrazolopyrimidine has been reported in the literature as an anti-tumor target drug that inhibits Aurora kinase ( Bioorg.Med.Chem.Lett. 2012 , 22 , 2070-2074, Bioorg.Med.Chem.Lett . 2012 , 22 , 4033-4037 and patent application WO 2004/080466).

The synthesis method of the 6-aminopyrazolo[3,4- d ]pyrimidine is described in the patent case WO 2011/156698. The synthesis method is shown as the path of the compound shown in Figure 1 below. The synthesis method is regioselective formylation of 5-bromo-2,4-dichloropyrimidine and morpholine-4-carbaldehyde, and after extraction and purification, 2,4-Dichloropyrimidine-5-carbaldehyde was synthesized with a yield of 71%. Subsequently, hydrazine was added for cyclization reaction, and after extraction and purification, 6-chloro-1 H -pyrazolo[3,4- d ]pyrimidine was synthesized with a yield of 34%. Finally, the mixture of 6-chloro-1 H -pyrazolo[3,4- d ]pyrimidine, 10% palladium/carbon, and ammonium formate was dissolved in methanol and heated to reflux for about 4 hours, and then filtered with diatomaceous earth to obtain The final product, 6-aminopyrazolo[3,4- d ]pyrimidine, has a yield of 31%. From an economic point of view, the method requires three steps. The precious metals must be used in the method, which will increase the production cost. In addition, the total yield is less than 8%, which may not be allowed to be used in industrial synthesis in the future.

According to the above-mentioned prior art, the object of the present invention is to provide 6-aminopyrazolo[3,4- d ]pyrimidine (I) with high yield through a convenient one-pot method without the disadvantageous complicated steps mentioned above.

The first figure is the patent case WO 2011/156698, the method of synthesizing 6-amino-1 H -pyrazolo[3,4- d ]pyrimidine.

Figure 2 is the general formula for the synthesis of 6-amino- 1H -pyrazolo[3,4- d]pyrimidine in the present invention.

Figure 3 shows the optimum conditions for the synthesis method of the present invention. 1 H -pyrazol-5-yl- N , N -dialkylformamidine was used as the starting material to synthesize 6-amino-1,3-di Phenyl- 1H -pyrazolo[3,4- d ]pyrimidine.

Figure 4 shows the synthesis of 6-amino-1 H -pyrazolo ^{substituted with different R 1} and R ² by using 1 H -pyrazol-5-yl- N , N -dialkyl formamidine as the starting material of the present invention [3,4- d ] Pyrimidine compound.

Figure 5 shows the synthesis of 6-amino-1 H -pyrazolo with ^{different R 1} and R ² substitutions using 5-amino-1 H -pyrazole-4-carbaldehyde as the starting material in the present invention. 3,4- d ]pyrimidine compounds.

Figure 6 shows the synthesis of the present invention using N -[(5-amino-1,3-diphenyl-1 H -pyrazol-4-yl)methylene]cyanamide as the starting material. Different R ¹ and R ² substituted 6-amino-1 H -pyrazolo [3,4- d ] pyrimidine compounds.

The objective of the present invention consists of the following: To provide a synthetic method for preparing substituted 6-aminopyrazolo[3,4-d ]pyrimidines (ie compounds of formula (I)), wherein the synthetic method is intended to achieve high purity and high yield. Rate of the target compound.

式I或其醫藥學上可接受之鹽。 The present invention provides compounds of formula I:

Formula I or a pharmaceutically acceptable salt thereof.

The definitions of substituents, symbols and indices are as follows: R ¹ is independently an alkyl, aryl, heteroaryl or heterocyclic group, and R ² is independently an alkyl, aryl, heteroaryl or heterocyclic group .

According to the present invention, a general formula for preparation is provided. The synthesis method is shown as the path of the compound shown in the following reaction diagram (2), including heating in a microwave, acid medium solution, and the presence of cyanamide derivatives (III), and 1 H -pyrazol-5-yl- N , N -dimethylformamidine (IIa) or 5-amino-1 H -pyrazole-4-carbaldehyde (IIb) or N -[(5-amino-1,3 -Diphenyl- 1H -pyrazol-4-yl)methylene]cyanamide (IIc) reaction.

Wherein the definitions of substituents, symbols and indices are as follows: R ^{1 is} independently hydrogen, aryl, arylalkyl, heteroaryl; R ^{2 is} independently hydrogen, aryl, heteroaryl; and wherein, said Hydrogen, aryl, arylalkyl, heteroaryl; Y is NR ³ R ⁴ , R ³ is hydrogen, R ⁴ is hydrogen, or R ³ and R ⁴ together form CHNR ⁶ R ⁷ , R ⁶ is hydrogen or alkane Group (-C _n H _2n+1 , n=1~6), R ⁷ alkyl group (-C _n H _2n+1 , n=1~6), Z series aldehyde group, imino group or -CH(= NCN); R ^{9 is} independently nitrile, thioamide, amide, N-(aminocarboximidodisulfanyl)formamidine, iminomethanesulfinate, azomethine, methyl .

A suitable acid medium solution system, for example, acetic acid, trifluoroacetic acid, p-toluenesulfonyl chloride, methanesulfonic acid, methylsulfonyl chloride, preferably methylsulfonyl chloride. The conventional amount of acid catalyst is 0.03 to 0.5M, preferably 0.1 to 0.5M, more preferably 0.04 to 0.08M, based on compound (II).

The customary amount of the cyanamide derivatives of formula (III) is 2 to 4 mol ratio, based on compound (II).

The preparation method of the present invention is conventionally carried out under room pressure and microwave heating up to the boiling point of the solvent used. It is preferably in the range from 50 to 60°C.

The following examples illustrate the invention.

The following description only illustrates specific embodiments of the present invention. Therefore, the specific embodiments or improvements discussed herein should not be construed as limiting the scope of the present invention. Those skilled in the art can clearly see that the various changes or equivalents made do not depart from the scope of the present invention.

In order to make the present invention clearer and easier to understand, specific terms must be defined first. Additional definition series are included in the full text of the embodiment. Unless otherwise defined, the technical and scientific terms used herein have meanings that can be conventionally understood by those skilled in the art of the present invention.

The articles "one" and "one" as used herein refer to one or more than one (ie, at least one) of the article's grammatical object. For example, "a component" refers to one component or more than one component.

1. Implementation cases 1 to 16

Embodiments 1 to 8 of the present invention are an acidic catalytic solvent system that seeks to optimize one-step amination and cyclization reactions. The reaction steps are as shown in the reaction diagram (3), with 1 H -pyrazol-5-yl- N , N -dialkyl formamidine (IIa-a) as the starting material, and 3 equivalents of cyanamide , In 35% hydrochloric acid aqueous solution, 35% hydrochloric acid/acetic acid (2:8), 35% hydrochloric acid/acetic acid (1:9), acetic acid, trifluoroacetic acid, p-toluenesulfonic acid chloride, methanesulfonic acid and methylsulfonic acid chloride The temperature is raised to the boiling point of the solvent used for the reaction. Then the reaction progress was monitored by thin layer chromatography. When the reaction was terminated, it was extracted with dichloromethane, the organic layer was collected, washed with saturated aqueous sodium bicarbonate solution, filtered and concentrated, and finally purified by chromatography to obtain no yield. 51% of the 6-amino-1,3-diphenyl-1-hydro-pyrazolo[3,4- d ]pyrimidine, Ia) product was detected, as shown in Table 1.

Implementation cases twelve to sixteen are to find the optimal heating method, reaction temperature and time for the one-step amination and cyclization reaction. The reaction steps are shown in Figure 3, with 1 H -pyrazol-5-yl- N , N -Dialkyl formamidine (IIa-a) is the starting material, and 3 equivalents of cyanamide, in methylsulfonyl chloride as the acidic catalytic solvent, reacted at 85-95℃ for 6 hours, 65-75℃ The reaction was carried out for 8 hours, 50-60°C for 10 hours, and the temperature was raised to 65-75°C in a microwave manner to react for 50 minutes, and the temperature was raised to 50-60°C in a microwave manner to react for 2 hours, and the reaction was carried out. Then the reaction progress was monitored by thin layer chromatography. When the reaction was terminated, the organic layer was extracted with dichloromethane, washed with saturated sodium bicarbonate aqueous solution, filtered and concentrated, and finally purified by chromatography to obtain the yield 52%, 57%, 63%, 71% and 83% of 6-amino-1,3-diphenyl-1 H -pyrazolo[3,4- d ]pyrimidine (Ia) products, as shown in Table 1 Show.

Through implementation cases 1 to 16 of the present invention, 1 H -pyrazol-5-yl- N , N -dimethylformamidine (II-a) with different equivalents of cyanamide and eight different acidic catalytic solvents Carry out a one-step amination and cyclization reaction. According to the results of the invention shown in Table 1, with 3 equivalents of cyanamide as the best amination and cyclization reagent, and methylsulfonate chloride as the solvent system, it can be The best yield of 6-amino-1,3-diphenyl-1 H -pyrazolo[3,4- d ]pyrimidine (Ia) was obtained.

Table 1. Taking 1 H -pyrazol-5-yl- N , N -dialkyl formamidine (II-a) as the optimal conditions for one-step amination and cyclization.

2. Implementation cases 17-30

The seventeenth to thirty-thirty examples of the present invention are the one-pot amination and cyclization reaction of 1 H -pyrazol-5-yl- N , N -dimethylformamidine (IIa) and 3 equivalents of cyanamide , Methanesulfonyl chloride is used as the acidic catalyst solvent, and the temperature is raised to 50-60°C by microwave, and the reaction time is 2 hours to carry out the reaction. Then the progress of the reaction was monitored by thin layer chromatography. When the reaction was terminated, the organic layer was extracted with dichloromethane, dried, washed with saturated sodium bicarbonate aqueous solution, filtered and concentrated, and finally layered. Analytical purification yields 63 to 83% of different R ¹ and R ² substituted 6-amino-1 H -pyrazolo [3,4- d ] pyrimidine (Ia to In) products, as shown in the table and the research results map 4 and Table 2. Synthesis example, example seventeen 6-amino-1,3-diphenyl-1 H -pyrazolo[3,4- d ]pyrimidine, ¹ H NMR (CDCl ₃ , 400MHz): δ 5.36(br, NH ₂ ), 7.29(1H,t, J =7.40Hz,Ar H ),7.45-7.54(5H,m,Ar H ),7.98(2H,d, J =7.24Hz,Ar H ),8.24(2H,d, J = 7.88 Hz, Ar H ), 9.06 (1H, s); Example eighteen 6-amino-1-(2-methylphenyl)-3-phenyl-1 H -pyrazolo[3,4- d ] Pyrimidine, ¹ H NMR (CDCl ₃ , 400MHz): δ 2.22 (3H, s, CH ₃ ), 5.43 (2H, br, NH ₂ ), 7.33-7.40 (3H, m, Ar H ), 7.42-7.46 (2H,m,Ar H ), 7.50 (2H, t, J = 7.36 Hz, Ar H ), 7.96 (2H, d, J = 7.08 Hz, Ar H ), 9.08 (1H, s); Example 19: 6 -Amino-1-(3-methylphenyl)-3-phenyl-1 H -pyrazolo[3,4- d ]pyrimidine, ¹ H NMR (CDCl ₃ , 400MHz): δ 2.44(3H, s ,CH ₃ ), 5.45 (2H, br, NH ₂ ), 7.11 (1H, d, J = 7.48 Hz, Ar H ), 7.37 (1H, t, J = 7.83 Hz, Ar H ), 7.44 (1H, t , J =7.32Hz,Ar H ),7.51(2H,t, J =7.42Hz,Ar H ),7.97(1H,d, J =0.48Hz,Ar H ),7.98(2H,s,Ar H ), 8.01 (1H, d, J = 8.12 Hz, Ar H ), 9.03 (1H, s); Example 20 6-amino-1-(4-methylphenyl)-3-phenyl-1 H -pyrazole And [3,4- d ] pyrimidine, ¹ H NMR (CDCl ₃ , 400MHz): δ 2.39 (3H, s, CH ₃ ), 5.33 (2H, br, NH ₂ ), 7.29 (2H, d, J = 8.40 Hz,Ar H ),7.44-7.46(1H,m,Ar H ),7.51(2H,dd, J =14.80,7.60Hz,Ar H ),7.98(2H,d, J =7.60,Ar H ),8.06 (2H, d, J = 8.40, Ar H ), 9.04 (1H, s).; Example 21 6-amino-1-(2-chlorophenyl)-3- Phenyl-1 H -pyrazolo [3,4- d ] pyrimidine, ¹ H NMR (CDCl ₃ , 400MHz): δ 7.48-7.51 (3H, m, Ar H ), 7.55 (2H, t, J =7.40 Hz, Ar H ), 7.60-7.65 (2H, m, Ar H ), 8.05 (2H, d, J = 7.56 Hz, Ar H ), 9.08 (1H, s); Example 22 6-amino-1- (3-Chlorophenyl)-3-phenyl-1 H -pyrazolo[3,4- d ]pyrimidine, ¹ H NMR (CDCl ₃ ,400MHz): δ 5.36(2H,br,NH ₂ ), 7.23 -7.26 (1H, m, Ar H ), 7.41 (1H, t, J = 8.13 Hz, Ar H ), 7.44-7.48 (1H, m, Ar H ), 7.50-7.54 (2H, m, Ar H ), 7.97 (2H, dt, J = 6.48, 1.52 Hz, Ar H ), 8.24 (1H, dq, J = 8.24, 0.98 Hz, Ar H ), 8.37 (1H, t, J = 2.02 Hz, Ar H ), 9.04 (1H,s); Example Twenty-three 6-amino-1-(4-chlorophenyl)-3-phenyl-1 H -pyrazolo[3,4- d ]pyrimidine, ¹ H NMR(CDCl ₃ ,400MHz): δ 5.36 (2H, br, NH ₂ ), 7.46 (3H, t, J = 7.48 Hz, Ar H ), 7.52 (2H, t, J = 7.40 Hz, Ar H ), 7.96 (2H, d , J = 7.20 Hz, Ar H ), 8.25 (2H, d, J = 8.84 Hz, Ar H ), 9.04 (1H, s); example twenty-four 6-amino-1-(4-bromophenyl)- 3-Phenyl-1 H -pyrazolo[3,4- d ]pyrimidine, ¹ H NMR (CDCl ₃ ,400MHz): δ 5.32(2H,br,NH ₂ ),7.47(1H,d, J =7.22 Hz,Ar H ), 7.52 (2H, t, J = 7.29 Hz, Ar H ), 7.60 (2H, d, J = 8.83 Hz, Ar H ), 7.97 (2H, d, J = 6.93 Hz, Ar H ) , 8.20 (2H, dd, J = 6.97, 1.93 Hz, Ar H ), 9.05 (1H, s); Example 25 6-amino-1-(4-methoxyphenyl)-3-phenyl- 1 H -pyrazolo[3,4- d ]pyrimidine, ¹ H NMR (CDCl ₃ ,400MHz): δ 3.85(3H,s,OCH ₃ ), 5.29 (2H, br, NH ₂ ), 7.02 (2H, dd, J = 6.98, 2.11 Hz, Ar H ), 7.45 (1H, d, J = 7.61 Hz, ArH), 7.51 (2H, t, J =7.45Hz,Ar H ),7.97(2H,d, J =7.10Hz,Ar H ), 8.05(2H,dd, J =6.92,2.18Hz,Ar H ),9.04(1H,s); example two Hexadecan 6-amino-1-(3-nitrophenyl)-3-phenyl-1 H -pyrazolo[3,4- d ]pyrimidine, ¹ H NMR (CDCl ₃ , 400MHz): δ 5.41( 2H,br,NH ₂ ),7.49-7.56(3H,m,Ar H ),7.64-7.68(1H,m,Ar H ),7.99(2H,d, J =8.00Hz,Ar H ),8.11(1H ,d, J =8.00Hz,Ar H ), 8.73(1H,d, J =8.00Hz,Ar H ), 9.08(1H,s,ArH),9.33(1H,s); Example 27 6-amino -3-tert-butyl-1-phenyl-1 H -pyrazolo[3,4- d ]pyrimidine, ¹ H NMR (CDCl ₃ , 500MHz): δ 1.50 (9H, s, t -Bu), 5.20 (2H,br,NH ₂ ),7.21-7.25(1H,m,Ar H ),7.44-7.47(2H,m,Ar H ),8.16(2H,dd, J =8.60, 1.1Hz,Ar H ), 8.88(1H,s,Ar H ); Example 28 Example 29 6-amino-3-(4-chlorophenyl)-1-phenyl-1 H -pyrazolo[3,4- d ] Pyrimidine, ¹ H NMR (CDCl ₃ , 500MHz): δ 5.33 (2H, br, NH ₂ ), 7.30 (1H, t, J =7.42 Hz, Ar H ), 7.48-7.51 (m, 4 H, Ar H ) ,7.92 (2H, d, J = 8.15 Hz, Ar H ), 8.21 (2H, d, J = 8.02 Hz, Ar H ), 9.02 (1H, s); Example 29 6-amino-3-(4 -Methoxyphenyl)-1-phenyl-1 H -pyrazolo[3,4- d ]pyrimidine, ¹ H NMR (CDCl ₃ , 500MHz): δ 3.87 (3H, s, OCH ₃ ), 5.28 (2H, br, NH ₂ ), 7.04 (2H, dd, J = 6.85, 1.95 Hz, Ar H ), 7.28 (1H, t, J = 7. 43Hz,Ar H ),7.49(2H,t, J =7.98Hz,Ar H ),7.92(2H,dd, J =6.80,2.02Hz,Ar H ),8.23(2H,d, J =7.60Hz,Ar H ), 9.01(1H,s); Example thirty 6-amino-3-(4-methylphenyl)-1-phenyl-1 H -pyrazolo[3,4- d ]pyrimidine, ¹ H NMR (CDCl ₃ , 400MHz): δ 2.42 (3H, s, CH ₃ ), 5.29 (2H, br, NH ₂ ), 7.29-7.33 (2H, m, Ar H ), 7.49 (2H, t, J =7.88 Hz,Ar H ), 7.56 (2H, t, J = 8.58 Hz, Ar H ), 7.88 (2H, d, J = 8.04 Hz, Ar H ), 8.23 (2H, d, J = 8.04 Hz, Ar H ) ,9.03(1H,s).

3. Implementation cases 31 to 38

The thirty-first to thirty-eight embodiments of the present invention are 5-amino-1 H -pyrazole-4-carbaldehyde (IIb) and 3 equivalents of cyanamide in one-pot amination and cyclization. Methanesulfonate As an acidic catalytic solvent, chlorin was heated to 50-60° C. in a microwave and reacted for 50 minutes. Then the progress of the reaction was monitored by thin layer chromatography. When the reaction was terminated, the organic layer was extracted with dichloromethane, dried, washed with saturated sodium bicarbonate aqueous solution, filtered and concentrated, and finally layered. Analytical purification yields 77 to 89% of different R ¹ and R ² substituted 6-amino-1 H -pyrazolo [3,4- d ]pyrimidine, Ia to Ii) products, as shown in the table and the research results map 5 and Table 3.

Fourth, implementation case thirty-two

Thirty-two implementation cases of the present invention are N -[(5-amino-1,3-diphenyl-1 H -pyrazol-4-yl)methylene]cyanamide (IIc-a) and 3 equivalents The cyanamide undergoes a one-pot amination and cyclization reaction. Methanesulfonyl chloride is used as an acidic catalyst solvent. The temperature is raised to 50-60°C by microwave, and the reaction is carried out for 50 minutes. Then the progress of the reaction was monitored by thin layer chromatography. When the reaction was terminated, the organic layer was extracted with dichloromethane, dried, washed with saturated sodium bicarbonate aqueous solution, filtered and concentrated, and finally layered. Analytical purification yielded 84% yield of 6-amino-1,3-diphenyl- 1H -pyrazolo[3,4- d ]pyrimidine (Ia) product.

Claims (10)

A method for preparing compound of formula (I)

, The method uses the compound of formula (II)

The compound reacts with NH ₂ R ^{9 of} formula (III) in an acidic catalytic solution, and the reaction is heated up. The definitions of substituents, symbols and indices are as follows: R ^{1 is} independently hydrogen, alkyl (-C _n H _2n+1 , N=1~6), alkenyl, alkynyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkane Group or alkoxycarbonyl; R ^{2 is} independently hydrogen, alkyl (-C _n H _2n+1 , n=1~6), cycloalkyl, aryl, heteroaryl, heterocyclyl, heterocyclyl alkane Group or alkoxycarbonyl; and wherein said hydrogen, alkyl, alkenyl, alkynyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl , Heterocyclyl, heterocyclylalkyl or alkoxycarbonyl can be optionally substituted by fluorine, chlorine, bromine, iodine, alkoxy, cyano, hydroxyl, nitro, alkylamino, amino, trifluoromethyl, trifluoromethyl Fluoromethoxy, haloalkyl substituted aryl, halogen substituted aryl or trifluoromethanesulfonyl mono-substituted or same or different multi-substitution; Y is NR ³ R ⁴ , R ³ is hydrogen or COR ⁵ , R ⁴ is hydrogen or COR ⁵ , or R ³ and R ⁴ together form COCH ₂ CH ₂ CO or CHNR ⁶ R ⁷ or CO-phenylene-CO, R ⁵ is (C ₁ -C ₆ )-alkyl or phenyl , R ⁶ is hydrogen or alkyl (-C _n H _2n+1 , n=1~6), R ^{7 is} alkyl (-C _n H _2n+1 , n=1~6), Z is hydrogen, aldehyde group , Thioaldehyde, -CH(=NR ⁸ ), R ⁸ is alcohol group, amine group, alkyl group (-C _n H _2n+1 , n=1~6), -CH(=NCN); R ^{9 is} independently It is nitrile, thioamide, amide, N- (carbamidodisulfanyl) formamidine, iminomethanesulfinic acid group, azomethine group, and methyl group. For example, the method of item 1 to 2 of the scope of patent application, wherein the acidic catalytic solution is any organic Acids, including Lewis Acids and Brønsted-Lowry acids. For example, in the method of items 1 to 3 in the scope of patent application, the more suitable acidic catalytic solutions are acetic acid, trifluoroacetic acid, p-toluenesulfonic acid, methanesulfonic acid and methylsulfonic acid. Such as the method of any one of items 1 to 5 in the scope of the patent application, wherein the formula (III) NH ₂ R ^{9 is} preferably used in an amount of 1 to 5 equivalents, based on the compound (II). For example, the method of any one of items 1 to 7 in the scope of the patent application is characterized in that the heating method can be any method that can increase the temperature, including heat conduction, heat convection, heat radiation, or microwave. For example, the method according to any one of the first to tenth patents is characterized in that the reaction temperature is 40C up to the boiling point of the solvent used. For example, the method according to any one of the first to 13th patents is characterized in that the more suitable reaction time is 50 minutes to 10 hours. A compound represented by formula (I),

Or its enantiomers, diastereomers, tautomers, hydrates, solvates or pharmaceutically acceptable salts, wherein the substituents, symbols and indices are defined as follows: R ^{1 is} independently hydrogen , Alkyl (-C _n H _2n+1 , n=1~6), alkenyl, alkynyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, cycloalkyl Alkyl, heterocyclyl, heterocyclylalkyl or alkoxycarbonyl; R ^{2 is} independently hydrogen, alkyl (-C _n H _2n+1 , n=1~6), cycloalkyl, aryl, hetero Aryl, heterocyclyl, heterocyclylalkyl or alkoxycarbonyl; and wherein said hydrogen, alkyl, alkenyl, alkynyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl Group, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl or alkoxycarbonyl can be optionally substituted by fluorine, chlorine, bromine, iodine, alkoxy, cyano, hydroxy, nitro, Alkylamino, amino, trifluoromethyl, trifluoromethoxy, haloalkyl substituted aryl, halogen substituted aryl, or trifluoromethanesulfonyl are mono-substituted or the same or different multi-substituted. A precursor is the compound represented by formula (II),

Or its enantiomers, diastereomers, tautomers, hydrates, solvates or pharmaceutically acceptable salts, wherein the substituents, symbols and indices are defined as follows: R ^{1 is} independently hydrogen , Alkyl (-C _n H _2n+1 , n=1~6), alkenyl, alkynyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, cycloalkyl Alkyl, heterocyclyl, heterocyclylalkyl or alkoxycarbonyl; R ^{2 is} independently hydrogen, alkyl (-C _n H _2n+1 , n=1~6), cycloalkyl, aryl, hetero Aryl, heterocyclyl, heterocyclylalkyl or alkoxycarbonyl; and wherein said hydrogen, alkyl, alkenyl, alkynyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl Group, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl or alkoxycarbonyl can be optionally substituted by fluorine, chlorine, bromine, iodine, alkoxy, cyano, hydroxy, nitro, Alkylamino, amino, trifluoromethyl, trifluoromethoxy, haloalkyl substituted aryl, halogen substituted aryl, or trifluoromethanesulfonyl mono-substituted or the same or different multi-substitution; Y is NR ³ R ⁴ , R ³ is hydrogen or COR ⁵ , R ⁴ is hydrogen or COR ⁵ , or R ³ and R ⁴ together form COCH ₂ CH ₂ CO or CHNR ⁶ R ⁷ or CO-phenylene-CO, R ⁵ series (C ₁ -C ₆ )-alkyl or phenyl, R ⁶ is hydrogen or alkyl (-C _n H _2n+1 , n=1~6), R ^{7 is} alkyl (-C _n H _2n+1 , n= 1~6), Z is hydrogen, aldehyde group, thioaldehyde, -CH(=NR ⁸ ), R ⁸ is alcohol group, amine group, alkyl (-C _n H _2n+1 , n=1~6), -CH(=NCN). A reaction reagent such as formula (III) NH ₂ R ⁹ diastereomers, tautomers, hydrates, solvates or pharmaceutically acceptable salts, wherein the definitions of substituents, symbols and indices are as follows: R ⁹ Independently nitrile, thioamide, amide, N-(carbamidodisulfanyl)formamidine, iminomethanesulfinyl group, azomethine group, methyl group.

Images