Small molecule heparin reversal agent with triazine skeleton, and preparation method therefor and use thereof

Abstract

The present invention belongs to the field of medical chemistry. Disclosed is a triazine compound as represented by formula (I) or a pharmaceutically acceptable salt, a stereoisomer or a solvate thereof. Also disclosed in the present invention is the use of the triazine compound or the pharmaceutically acceptable salt, the stereoisomer or the solvate thereof in the preparation of an anticoagulant reversal agent. Further disclosed in the present invention is the use of the triazine compound or the pharmaceutically acceptable salt, the stereoisomer or the solvate thereof in the preparation of a drug for treating the side effects of excessive anticoagulation caused by using heparin to treat diseases, and in the preparation of a drug for reversing the anticoagulant activity of heparin during surgical operations. The triazine compound of the present invention has the advantages of a simple preparation method, low costs, low toxicity and a strong binding ability to heparin, and can reverse the anticoagulant effect of heparin.

Description

Triazine skeleton small molecule heparin reversal agent and its preparation method and use Technical Field

[0001] The present invention belongs to the field of medicine and relates to a triazine skeleton small molecule heparin reversal agent and a preparation method and use thereof, and in particular to a triazine skeleton small molecule compound capable of reversing the anticoagulant activity of heparin and a preparation method and use thereof, as well as a pharmaceutical composition comprising the triazine skeleton small molecule compound. Background Art

[0002] Heparin is widely used clinically as an intravenous anticoagulant to prevent excessive coagulation during cardiac surgery, extracorporeal circulation, or dialysis. Heparin anticoagulation primarily forms an antithrombin-heparin-coagulation factor complex, which inactivates thrombin through an antithrombin-dependent mechanism. Upon completion of extracorporeal circulation or during invasive procedures requiring heparin anticoagulation, timely quantification of heparin levels in the blood is essential to neutralize the anticoagulant effect of heparin and initiate coagulation.

[0003] Protamine, currently the only approved heparin reversal agent in China, is a highly positively charged, polycationic, strongly basic peptide mixture with a relative molecular mass of 5 to 10 kDa. Protamine binds to heparin through anionic and cationic interactions, forming a stable, neutrally charged salt complex. This competitively separates heparin from antithrombin, restoring the blood's original flow properties. The heparin-protamine complex is then immediately cleared by the reticuloendothelial system. Heparin is a mixture of linear, helical polysaccharides with varying chain lengths. Urotic acid and glucosamine are primarily linked by 1→4 bonds. Sulfur-containing and carboxyl groups extend along the flexible polysaccharide backbone at defined intervals and directions, providing the highest negative charge density of any known biomacromolecule. Therefore, the key features to consider in heparin neutralization are anionic and cationic interactions and conformational flexibility.

[0004] Protamine can rapidly reverse the effects of heparin, but its use may be associated with adverse reactions, including allergic reactions, respiratory problems, and severe cardiovascular effects such as hypotension and bradycardia, which can, in severe cases, lead to coronary thrombosis and myocardial infarction. Protamine has been reported to only partially reverse the anticoagulant effects of low-molecular-weight heparin. Furthermore, its metabolite, propylamine, is highly toxic. Environmental pollution and seasonal shortages further limit the availability and application of protamine.

[0005] In the early 1950s, the macromolecular cationic hexadimethrine bromide was investigated as a protamine alternative. In vitro and in vivo studies demonstrated that hexadimethrine bromide could neutralize the anticoagulant effects of heparin, but it also presented challenges such as hypotension and nephrotoxicity. Currently reported macromolecular cationic compounds or cationic modifications can enhance heparin binding specificity and biocompatibility, but challenges remain, such as insufficient in vivo efficacy or toxicity at doses sufficient to achieve efficacy.

[0006] Compared to large molecule drugs, small molecule drugs have good spatial dispersion, predictable drugability, and pharmacokinetic properties. Small molecule heparin reversal drugs entering clinical trials include Delparantag and Ciraparantag. Delparantag is a small molecule salicylic acid derivative that has good neutralizing effects both in vivo and in vitro, but its development was terminated due to cases of hypotension in Phase II clinical trials. Ciraparantag binds to heparin through hydrogen bonds and charge interactions, and the reversal effect is measured using whole blood clotting time. The measuring equipment has not yet been approved by the FDA and is currently in Phase II clinical trials.

[0007] There is still a need in the art to develop compounds with heparin anticoagulation reversal activity or better pharmacodynamic properties.

[0008] Summary of the Invention

[0009] The purpose of the present invention is to provide a novel triazine compound or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof having heparin anticoagulant reversal activity, better pharmacodynamics, and low blood and cell toxicity.

[0010] The technical solution adopted in the present invention is as follows:

[0011] The triazine skeleton small molecule heparin reversal agent is selected from the triazine compound shown in the structure of formula I or its pharmaceutically acceptable salt, stereoisomer, solvate:

[0012] in:

[0013] X1, X2, X3 are the same as or different from each other and are independently selected from N or phenyl;

[0014] L1, L2, L3 are the same or different from each other, unsubstituted or independently selected from H, alkyl;

[0015] R1, R2, and R3 are independently optionally substituted alkyl, optionally substituted alkylamino, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heterocyclic aryl, optionally substituted halogenated aryl, or optionally substituted heterochain alkyl; the nitrogen atom is optionally quaternized and may be optionally oxidized;

[0016] The alkyl group is C1-C 10 Straight-chain or branched alkyl group;

[0017] The alkylamino group refers to an alkyl group containing 1 to 3 carbon atoms connected to the rest of the molecule through an amino group, wherein the nitrogen atom of the amino group is optionally quaternized;

[0018] The cycloalkyl group is a C3-C6 cycloalkyl group, and optionally, the cycloalkyl group is selected from cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl;

[0019] The heterocycloalkyl group is a 3-6 membered monocyclic or polycyclic non-aromatic ring structure, including but not limited to piperazinyl, morpholinyl, piperidinyl, pyrrolidinyl, hexahydropyridinyl, tetrahydrofuranyl, tetrahydropyranyl, etc.; the 3-6 membered heterocycloalkyl group may be connected to the rest of the molecule through a heteroatom, carbon atom or alkyl group, including but not limited to 1-(2-piperazin-1-ylacetyl)pyrrolidine;

[0020] The aryl group includes but is not limited to phenyl;

[0021] The heterocyclic aromatic group is a saturated or unsaturated 5-6 membered monocyclic or polycyclic aromatic ring structure containing 1-3 heteroatoms selected from N, O, and S, including but not limited to thienyl, furyl, pyranyl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, etc.; the 5-6 membered heterocyclic aromatic group can be connected to the rest of the molecule through a heteroatom, carbon atom, or alkyl group, including but not limited to 4-(4-morpholinyl)aniline, 4-amino-1-benzylpiperidine, 1-(4-fluorobenzyl)piperazine, N-benzylpiperazine, etc.;

[0022] The heterochain hydrocarbon structure of the heterochain hydrocarbon group is C1-C 20 Saturated or unsaturated, straight or branched chain structure containing 1-3 heteroatoms selected from N, O, and S;

[0023] The heteroatom may occupy the connecting position between molecules, and the heteroatom is selected from nitrogen, oxygen or sulfur;

[0024] In the optional substitution, substitution refers to substitution by one or more of the following substituents, and the substituents are selected from: halogen, C1-C5 alkyl, hydroxyl, cycloalkyl, heterocycloalkyl, alkoxy, carbonyl, heterocyclic aromatic, aryl, etc.

[0025] The halogen is selected from fluorine, chlorine, bromine or iodine.

[0026] Preferably, the R1-X1-L1 group is selected from:

[0027] The R2-X2-L2 group is selected from:

[0028] The R3-X3-R3 group is selected from:

[0029] Further preferably, the R1-X1-L1 group is selected from:

[0030] The R2-X2-L2 group is selected from:

[0031] The R3-X3-R3 group is selected from:

[0032] More preferably, the R1-X1-L1 group is selected from The R2-X2-L2 group is selected from The R3-X3-R3 group is selected from The R1-X1-L1 group is selected from The R2-X2-L2 group is selected from The R3-X3-R3 group is selected from The R1-X1-L1 group is selected from The R2-X2-L2 group is selected from The R3-X3-R3 group is selected from The R1-X1-L1 group is selected from The R2-X2-L2 group is selected from The R3-X3-R3 group is selected from The R1-X1-L1 group is selected from The R2-X2-L2 group is selected from The R3-X3-R3 group is selected from The R1-X1-L1 group is selected from The R2-X2-L2 group is selected from The R3-X3-R3 group is selected from The R1-X1-L1 group is selected from The R2-X2-L2 group is selected from The R3-X3-R3 group is selected from The R1-X1-L1 group is selected from The R2-X2-L2 group is selected from The R3-X3-R3 group is selected from The R1-X1-L1 group is selected from The R2-X2-L2 group is selected from The R3-X3-R3 group is selected from

[0033] Specifically, the triazine compound of the present invention is selected from the following compounds:

[0034] Table 1. Structural formula of triazine compounds of the present invention

[0035] The chemical names of the above triazine compounds are as follows:

[0036] Most preferably, the triazine skeleton small molecule heparin reversal agent is selected from the triazine compound or its pharmaceutically acceptable salt, stereoisomer, or solvate thereof, which has passed the anti-Xa enzyme activity test and the acute toxicity and heparin reversal experiments in mice:

[0037] The solvate of the triazine compound is a hydrate of the triazine compound.

[0038] Another object of the present invention is to provide a method for preparing the triazine compound, the synthesis route of which is as follows:

[0039] Wherein, when the R1-X1-L1 group is selected from When A n for When the R1-X1-L1 group is selected from the group consisting of When other than the above groups, A n is selected from R1-X1H-L1, that is, X1 is selected from N, R1-X1-L1 is as described above, A n Specific selection

[0040] B m Selected from R2-X2H-L2, R2-X2-L2 is as described above, B m Specific selection

[0041] C z Selected from R3-X3 H-R3, R3-X3-L3 as described above, C z Specific selection

[0042] include:

[0043] Step (1), using tetrahydrofuran (THF) as a reaction solvent and N,N-diisopropylethylamine (DIPEA) as an acid-binding agent, cyanuric chloride and An are reacted at a temperature of -20°C to obtain intermediate III; wherein the molar ratio of cyanuric chloride to An is 1:1 to 1:2; the molar ratio of cyanuric chloride to N,N-diisopropylethylamine is 1:1 to 1:2.5;

[0044] Step (2), using tetrahydrofuran as a reaction solvent and N,N-diisopropylethylamine as an acid-binding agent, the intermediate III and Bm are reacted at a temperature of 25° C. to obtain the intermediate II; the molar ratio of the intermediate III to Bm is 1:1 to 1:2; the molar ratio of the intermediate III to N,N-diisopropylethylamine is 1:1 to 1:2.5;

[0045] Step (3): using tetrahydrofuran as the reaction solvent and N,N-diisopropylethylamine as the acid-binding agent, the intermediate II and Cz react under reflux conditions to obtain a triazine compound with a structure as shown in Formula I; the molar ratio of the intermediate II and Cz is 1:1 to 1:2.5; and the molar ratio of the intermediate II and N,N-diisopropylethylamine is 1:1 to 1:4.

[0046] Another object of the present invention is to provide a pharmaceutical composition comprising the triazine compound or its pharmaceutically acceptable salt, stereoisomer, or solvate as an active ingredient or main active ingredient, and a pharmaceutically acceptable carrier to prepare a preparation.

[0047] Another object of the present invention is to provide use of the triazine compound or its pharmaceutically acceptable salt, stereoisomer, or solvate in the preparation of an anticoagulant reversal agent.

[0048] Another object of the present invention is to provide the use of the triazine compound or its pharmaceutically acceptable salt, stereoisomer, or solvate in the preparation of a drug for treating excessive anticoagulation side effects caused by the use of heparin to treat diseases, and in the preparation of a drug for treating surgical operations requiring reversal of heparin's anticoagulant activity.

[0049] The diseases treated with heparin are thromboembolic diseases; the embolic diseases are myocardial infarction, thrombophlebitis, and pulmonary embolism; the surgical operations are hemodialysis, extracorporeal circulation, catheterization, and microvascular surgery.

[0050] Beneficial effects of the present invention:

[0051] The triazine skeleton small molecule heparin reversal agent of the present invention has a simple preparation method, low cost, low toxicity, strong binding ability with heparin, and has been proven through in vitro and in vivo tests to be able to reverse the anticoagulant effect of heparin. It can be used to prepare drugs for treating and / or preventing adverse reactions and diseases caused by excessive heparin anticoagulation in subjects. DETAILED DESCRIPTION

[0052] The following examples are provided to help those skilled in the art better understand the technical solutions of the present invention. The examples are merely intended to illustrate the present invention rather than to limit the scope of the present invention.

[0053] The structures of the compounds were determined by mass spectrometry (MS) and / or nuclear magnetic resonance ( 1 confirmed by H NMR) data.

[0054] Synthesis method

[0055] The compounds of this invention can be prepared according to conventional methods in the art and using suitable reagents, raw materials and purification methods known to those skilled in the art. The preparation methods of the compounds of this invention are described in more detail below, but these specific methods do not constitute any limitation to the present invention. The compounds of this invention can also be conveniently prepared by optionally combining various synthetic methods described in this specification or known in the art, and such combinations can be easily carried out by those skilled in the art.

[0056] Example 1: N 2 -(2-(4-methylpiperazin-1-yl)ethyl)-N 4 -phenyl-N 6 Preparation of -(pyridin-3-ylmethyl)-1,3,5-triazine-2,4,6-triamine (Compound 61)

[0057] Step 1: Synthesis of 4,6-dichloro-N-phenyl-1,3,5-triazine-2-amine

[0058] At -20°C, cyanuric chloride (10.00 g, 54.2 mmol) was added to an eggplant-shaped flask. After precooling, aniline (5.05 g, 54.2 mmol), N,N-diisopropylethylamine (DIPEA, 18.29 mL, 108.4 mmol), and 200 mL of tetrahydrofuran were added. The reaction was allowed to react at 0°C for 2 hours. The reaction was monitored for completion by thin-layer chromatography (TLC). 100 mL of water was added to the reaction system, and the mixture was extracted with dichloromethane (150 mL x 2). The combined dichloromethane layers were washed with saturated sodium chloride solution (100 mL x 3), dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 20:1, by volume) to yield 8.85 g of a white solid, 4,6-dichloro-N-phenyl-1,3,5-triazin-2-amine. mp 184-186°C. 1H NMR(300MHz,Chloroform-d)δppm7.98(s,1H),7.60–7.51(m,2H),7.48–7.36(m,2H),7.28–7.20(m,1H); LC-MS(ESI):m / z=241.06[M+H] + .

[0059] Step 2: 6-chloro-N 2 -phenyl-N 4 Synthesis of -(pyridin-3-ylmethyl)-1,3,5-triazine-2,4-diamine

[0060] At 25°C, 4,6-dichloro-N-phenyl-1,3,5-triazine-2-amine (1.00 g, 4.15 mmol), pyridin-3-ylmethylamine (0.45 g, 4.15 mmol), DIPEA (1.39 mL, 8.30 mmol) and 5 mL of tetrahydrofuran were added to an eggplant-shaped flask in sequence. The mixture was reacted at 25°C for 2 hours. The reaction was monitored by TLC to determine if the reaction was complete. 30 mL of water was added to the reaction system, and the mixture was extracted with dichloromethane (50 mL x 2). The dichloromethane layers were combined and washed with saturated sodium chloride solution (30 mL x 3). The mixture was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The mixture was purified by silica gel column chromatography (volume ratio of dichloromethane to methanol = 20:1) to obtain 280 mg of a red solid, which was 6-chloro-N-phenyl-1,3,5-triazine-2-amine. 2 -phenyl-N 4 -(pyridin-3-ylmethyl)-1,3,5-triazine-2,4-diamine. 1 H NMR(400MHz,DMSO-d6)δppm 10.08(s,1H),8.76(s,1H),8.55(s,1H),8.46(t,J=8.0Hz,1H),7.79-7.47(m,3H),7.40- 7.19(m,3H),7.03(t,J=6.8Hz,1H),4.52(d,J=6.0Hz,2H).LC-MS(ESI):m / z=314.26[M+H] + .

[0061] Step 3: N 2 -(2-(4-methylpiperazin-1-yl)ethyl)-N 4 -phenyl-N 6 Synthesis of -(pyridin-3-ylmethyl)-1,3,5-triazine-2,4,6-triamine

[0062] Add 6-chloro-N 2 -phenyl-N 42-(Pyridin-3-ylmethyl)-1,3,5-triazine-2,4-diamine (280 mg, 0.895 mmol), 2-(4-methylpiperazin-1-yl)ethan-1-amine (257 mg, 1.791 mmol), DIPEA (405 mg, 3.133 mmol), and 3 mL of tetrahydrofuran were refluxed at 80°C for 2 hours. 30 mL of water was added to the reaction system, and the mixture was extracted with dichloromethane (50 mL × 2). The combined dichloromethane layers were washed with saturated sodium chloride solution (30 mL × 3), dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The mixture was purified by reverse-phase silica gel column chromatography to obtain 210 mg of compound 61 as a white solid. 1 H NMR(400MHz,Chloroform-d)δppm 8.62(s,1H),8.53(d,J=4.9Hz,1H),7.68(d,J=7.8Hz,1H),7.54(s,2H),7.33-7.22(m,2H),7.25(d,J=5.1Hz,1H),7.03(t,J=7.4Hz,1H),6.91( s,1H),5.49(s,1H),5.35(s,1H),4.64(d,J=6.1Hz,2H),3.49(q,J=9.7Hz,2H),2.69-2.36(m,9H),2.31(s,3H).LC-MS(ESI):m / z=420.12[M+H] + .

[0063] Example 2: Preparation of (4-((2-(4-methylpiperazin-1-yl)ethyl)amino)-6-phenyl-1,3,5-triazin-2-yl)-L-histidine methyl ester (1)

[0064] Step 1: Synthesis of 2,4-dichloro-6-phenyl-1,3,5-triazine

[0065] To an eggplant-shaped flask at -20°C were added cyanuric chloride (10.00 g, 54.2 mmol), phenylmagnesium bromide (54.2 mL, 1 M phenylmagnesium bromide in THF, 54.2 mmol), DIPEA (10.98 mL, 65.1 mmol), and 200 mL of tetrahydrofuran. The mixture was allowed to react at 0°C for 1 hour. TLC monitored the reaction for completion. Water (100 mL) was added to the reaction system, and the mixture was extracted with ethyl acetate (150 mL x 2). The ethyl acetate layers were combined, washed with saturated sodium chloride (100 mL x 3), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The mixture was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 20:1) to afford 9.81 g of 2,4-dichloro-6-phenyl-1,3,5-triazine as a white solid.

[0066] Step 2, Step 3: Replace pyridin-3-ylmethylamine in Step 2 of Example 1 with L-histidine methyl ester, and the rest is the same as in Example 1 to obtain Compound 1. LC-MS (ESI): m / z = 466.27 [M+H] + .

[0067] Example 3: N 2 -(2-(1H-benzimidazol-2-yl)ethyl)-N 4 Preparation of -(2-(dimethylamino)ethyl)-6-phenyl-1,3,5-triazine-2,4-diamine (2)

[0068] Referring to the method of Example 2, L-histidine methyl ester was replaced with 1H-benzimidazole-2-ethylamine and 4-methyl-1-piperazineethylamine was replaced with N,N-dimethylethylenediamine to obtain compound 2. LC-MS (ESI): m / z = 403.23 [M+H] + .

[0069] Example 4: N 2 -(2-Benzimidazole-2-ethyl)-N 4 Preparation of -(3-dimethylamino)propyl-6-phenyl-1,3,5-triazine-2,4-diamine (3)

[0070] Following the method of Example 2, L-histidine methyl ester was replaced with 1H-benzimidazole-2-ethylamine and 4-methyl-1-piperazineethylamine was replaced with 1-(2-aminoethyl)pyrrolidine to obtain compound 3. LC-MS (ESI): m / z = 429.25 [M+H] + .

[0071] Example 5: N 2 -(2-(1H-benzimidazol-2-yl)ethyl)-N 4 Preparation of -(2-(4-methylpiperazin-1-yl)ethyl)-6-phenyl-1,3,5-triazine-2,4-diamine (4)

[0072] Referring to the method of Example 2, L-histidine methyl ester was replaced with 1H-benzimidazole-2-ethylamine to obtain compound 4. LC-MS (ESI): m / z = 458.28 [M+H] + .

[0073] Example 6: N 2 -(2-(dimethylamino)ethyl)-6-phenyl-N 4 Preparation of -(pyridin-3-ylmethyl)-1,3,5-triazine-2,4-diamine (Compound 5)

[0074] Referring to the method of Example 3, L-histidine methyl ester was replaced with 3-aminomethylpyridine and 4-methyl-1-piperazineethylamine was replaced with N,N-dimethylethylenediamine to obtain compound 5. LC-MS (ESI): m / z = 350.21 [M+H] + .

[0075] Example 7: 6-phenyl-N 2 -(pyridin-3-ylmethyl)-N 4 Preparation of 1,3,5-triazine-2,4-diamine (6)

[0076] Referring to the method of Example 2, L-histidine methyl ester was replaced with 3-aminomethylpyridine, and 4-methyl-1-piperazineethylamine was replaced with 1-(2-aminoethyl)pyrrolidine to obtain compound 6. LC-MS (ESI): m / z = 376.24 [M+H] + .

[0077] Example 8: N 2 -(2-(4-methylpiperazin-1-yl)ethyl)-6-phenyl-N 4 - Preparation of pyridin-3-ylmethyl-1,3,5-triazine-2,4-diamine (7)

[0078] Following the method of Example 2, L-histidine methyl ester was replaced with 3-aminomethylpyridine to obtain compound 7. LC-MS (ESI): m / z = 405.25 [M+H] + .

[0079] Example 9: N 2 -(2-(1H-imidazol-5-yl)ethyl)-6-phenyl-N 4 Preparation of -(2-(pyrrolidin-1-yl)ethyl)-1,3,5-triazine-2,4-diamine (8)

[0080] Following the method of Example 2, L-histidine methyl ester was replaced with histamine, and 4-methyl-1-piperazineethylamine was replaced with 1-(2-aminoethyl)pyrrolidine to obtain compound 8. LC-MS (ESI): m / z = 379.25 [M+H] + .

[0081] Example 10: N 2 -(2-(4-methylpiperazin-1-yl)ethyl)-6-phenyl-N 4 - Preparation of pyridin-4-yl-1,3,5-triazine-2,4-diamine (9)

[0082] Following the method of Example 2, L-histidine methyl ester was replaced with 4-aminopyridine to obtain compound 9. LC-MS (ESI): m / z = 391.23 [M+H] + .

[0083] Example 11: Preparation of N-(2-(4-methylpiperazin-1-yl)ethyl)-4-phenyl-6-(3,4,6,7-tetrahydroimidazo[4,5-c]pyridin-5-yl)-1,3,5-triazin-2-amine (10)

[0084] Following the method of Example 2, L-histidine methyl ester was replaced with 4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridine to obtain compound 10. LC-MS (ESI): m / z = 420.29 [M+H] + .

[0085] Example 12: N 2 -(2-(4-methylpiperazin-1-yl)ethyl)-6-phenyl-N 4 - Preparation of pyridin-4-ylmethyl-1,3,5-triazine-2,4-diamine (11)

[0086] Following the method of Example 2, L-histidine methyl ester was replaced with 4-methylaminopyridine to obtain compound 11. LC-MS (ESI): m / z = 405.25 [M+H] + .

[0087] Example 13: N 2 -(2-(4-methylpiperazin-1-yl)ethyl)-6-phenyl-N 4 - Preparation of pyridin-2-yl-1,3,5-triazine-2,4-diamine (12)

[0088] Following the method of Example 2, L-histidine methyl ester was replaced with 2-aminopyridine to obtain compound 12. LC-MS (ESI): m / z = 391.23 [M+H] + .

[0089] Example 14: N 2 -(2-(1H-benzimidazol-2-yl)ethyl)-N 4 Preparation of 6-(4-fluorobenzyl)piperazin-1-yl)-1,3,5-triazine-2,4-diamine (13)

[0090] Referring to the method of Example 1, aniline was replaced by ethylamine, 3-aminomethylpyridine was replaced by 1H-benzimidazole-2-ethylamine, and 4-methyl-1-piperazineethylamine was replaced by 1-(4-fluorobenzyl)piperazine to obtain compound 13. LC-MS (ESI): m / z = 476.27 [M+H]+ .

[0091] Example 15: N 2 -(3-dimethylamino)propyl-N 4 -ethyl-N 6 - Preparation of pyridin-3-ylmethyl-1,3,5-triazine-2,4,6-triamine (14)

[0092] The method of Example 1 was followed, except that aniline was replaced by ethylamine and 4-methyl-1-piperazineethylamine was replaced by N,N-dimethyl-1,3-diaminopropane. LC-MS (ESI): m / z = 331.23 [M+H] + .

[0093] Example 16: N 2 -ethyl-N 4 -(3-(4-methylpiperazin-1-yl)propyl)-N 6 - Preparation of pyridin-3-ylmethyl-1,3,5-triazine-2,4,6-triamine (15)

[0094] Following the method of Example 1, aniline was replaced by ethylamine and 4-methyl-1-piperazineethylamine was replaced by 1-(3-aminopropyl)-4-methylpiperazine to obtain Compound 15. LC-MS (ESI): m / z = 386.28 [M+H] + .

[0095] Example 17: Preparation of 2-(4-(4-ethylamino)-6-(pyridin-3-ylmethyl)amino)-1,3,5-triazin-2-yl)piperazin-1-yl)ethyl-1-ol (16)

[0096] Referring to the method of Example 1, aniline was replaced by ethylamine and 4-methyl-1-piperazineethylamine was replaced by N-hydroxyethylpiperazine to obtain compound 16. LC-MS (ESI): m / z=359.23 [M+H] + .

[0097] Example 18: N 2 -(2-(1H-imidazol-5-yl)ethyl)-N 4 -ethyl-N 6 Preparation of -(3-(4-methylpiperazine-1-propyl)-1,3,5-triazine-2,4,6-triamine (17)

[0098] Following the method of Example 1, aniline was replaced with ethylamine, 3-aminomethylpyridine was replaced with histamine, and 4-methyl-1-piperazineethylamine was replaced with 1-(3-aminopropyl)-4-methylpiperazine to obtain compound 17. LC-MS (ESI): m / z = 389.29 [M+H] + .

[0099] Example 19: N 2 -(2-(1H-imidazol-5-yl)ethyl)-6-(4-benzylpiperazin-1-yl)-N 4 Preparation of ethyl-1,3,5-triazine-2,4-diamine (18)

[0100] Following the method of Example 1, aniline was replaced by ethylamine, 3-aminomethylpyridine was replaced by histamine, and 4-methyl-1-piperazineethylamine was replaced by N-benzylpiperazine to obtain compound 18. LC-MS (ESI): m / z = 408.26 [M+H] + .

[0101] Example 20: N 2 -(2-(1H-imidazol-5-yl)ethyl)-N 4 -(4-aminophenethyl)-N 6 Preparation of ethyl-1,3,5-triazine-2,4,6-triamine (19)

[0102] Following the method of Example 1, aniline was replaced by ethylamine, 3-aminomethylpyridine was replaced by histamine, and 4-methyl-1-piperazineethylamine was replaced by 4-aminophenethylamine to obtain compound 19. LC-MS (ESI): m / z = 368.23 [M+H] + .

[0103] Example 21: N 2 -ethyl-N 4 -(2-(4-methylpiperazin-1-yl)ethyl)-N 6 Preparation of -pyridin-4-ylmethyl-1,3,5-triazine-2,4,6-triamine (20)

[0104] Following the method of Example 1, aniline was replaced by ethylamine and 3-aminomethylpyridine was replaced by 4-methylaminopyridine to obtain compound 20. LC-MS (ESI): m / z=372.26 [M+H] + .

[0105] Example 22: N 2 -(2-(1H-benzimidazol-2-yl)ethyl)-N 4 -cyclopropyl-N 6 Preparation of -(2-(4-methylpiperazin-1-yl)ethyl)-1,3,5-triazine-2,4,6-triamine (21)

[0106] Referring to the method of Example 1, aniline was replaced by cyclopropylamine and 3-aminomethylpyridine was replaced by 1H-benzimidazole-2-ethylamine to obtain compound 21. LC-MS (ESI): m / z = 437.29 [M+H]+ .

[0107] Example 23: N 2 -(2-(1H-benzimidazol-2-yl)ethyl)-N 4 Preparation of cyclopropyl-6-(4-fluorobenzyl)piperazin-1-yl)-1,3,5-triazine-2,4-diamine (22)

[0108] Following the method of Example 1, aniline was replaced by cyclopropylamine, 3-aminomethylpyridine was replaced by 1H-benzimidazole-2-ethylamine, and 4-methyl-1-piperazineethylamine was replaced by 1-(4-fluorobenzyl)piperazine to obtain compound 22. LC-MS (ESI): m / z = 488.27 [M+H] + .

[0109] Example 24: N 2 -cyclopropyl-N 4 -pyridin-3-ylmethyl-N 6 Preparation of 2-(2-pyrrolidin-1-yl)ethyl)-1,3,5-triazine-2,4,6-triamine (23)

[0110] Following the method of Example 1, aniline was replaced by cyclopropylamine and 4-methyl-1-piperazineethylamine was replaced by 1-(2-aminoethyl)pyrrolidine to obtain compound 23. LC-MS (ESI): m / z = 355.23 [M+H] + .

[0111] Example 25: N 2 -cyclopropyl-6-(4-fluorobenzyl)piperazin-1-yl)-N 4 Preparation of pyridin-3-ylmethyl-1,3,5-triazine-2,4-diamine (24)

[0112] Following the method of Example 1, aniline was replaced by cyclopropylamine and 4-methyl-1-piperazineethylamine was replaced by 1-(4-fluorobenzyl)piperazine to obtain compound 24. LC-MS (ESI): m / z = 435.24 [M+H] + .

[0113] Example 26: Preparation of 2-(4-(4-cyclopropylamino)-6-(pyridin-3-ylmethyl)amino)-1,3,5-triazin-2-yl)piperazin-1-yl)ethyl-1-ol (25)

[0114] Referring to the method of Example 1, aniline was replaced by cyclopropylamine and 4-methyl-1-piperazineethylamine was replaced by N-hydroxyethylpiperazine to obtain compound 25. LC-MS (ESI): m / z = 371.23 [M+H] + .

[0115] Example 27: N 2 -(1H-imidazol-2-yl)ethyl)-N 4 -cyclopropyl-N 6 Preparation of -(2-(4-methylpiperazin-1-yl)ethyl)-1,3,5-triazine-2,4,6-triamine (26)

[0116] Following the method of Example 1, aniline was replaced by cyclopropylamine and 3-aminomethylpyridine was replaced by histamine to obtain compound 26. LC-MS (ESI): m / z = 387.27 [M+H] + .

[0117] Example 28: N 2 -(2-(1H-imidazol-2-yl)ethyl)-N 4 Preparation of cyclopropyl-6-(4-fluorobenzyl)piperazin-1-yl)-1,3,5-triazine-2,4-diamine (27)

[0118] Following the method of Example 1, aniline was replaced by cyclopropylamine, 3-aminomethylpyridine was replaced by histamine, and 4-methyl-1-piperazineethylamine was replaced by 1-(4-fluorobenzyl)piperazine to obtain compound 27. LC-MS (ESI): m / z = 438.25 [M+H] + .

[0119] Example 29: N 2 -cyclopropyl-N 4 -(2-(4-methylpiperazin-1-yl)ethyl)-N 6 Preparation of -pyridin-4-ylmethyl-1,3,5-triazine-2,4,6-triamine (28)

[0120] Referring to the method of Example 1, aniline was replaced by cyclopropylamine and 3-aminomethylpyridine was replaced by 4-methylaminopyridine to obtain compound 28. LC-MS (ESI): m / z=384.29 [M+H] + .

[0121] Example 30: N 2 -cyclopropyl-N 4 -pyridin-2-yl-N 6 Preparation of -(2-pyrrolidine-1-ethyl)-1,3,5-triazine-2,4,6-triamine (29)

[0122] Following the method of Example 1, aniline was replaced by cyclopropylamine, 3-aminomethylpyridine was replaced by 2-aminopyridine, and 4-methyl-1-piperazineethylamine was replaced by 1-(2-aminoethyl)pyrrolidine to obtain compound 29. LC-MS (ESI): m / z = 341.31 [M+H] + .

[0123] Example 31: Preparation of (4-(cyclohexylamino)-6-((2-(4-methylpiperazin-1-yl)ethyl)amino)-1,3,5-triazin-2-yl)-L-histidine methyl ester (30)

[0124] Following the method of Example 1, aniline was replaced by cyclohexylamine and 3-aminomethylpyridine was replaced by L-histidine methyl ester to obtain compound 30. LC-MS (ESI): m / z = 487.31 [M+H] + .

[0125] Example 32: N 2 -(2-(1H-benzimidazol-2-yl)ethyl)-N 4 Preparation of cyclohexyl-6-(4-fluorobenzyl)piperazin-1-yl)-1,3,5-triazine-2,4-diamine (31)

[0126] Following the method of Example 1, aniline was replaced with cyclohexylamine, 3-aminomethylpyridine was replaced with 1H-benzimidazole-2-ethylamine, and 4-methyl-1-piperazineethylamine was replaced with 1-(4-fluorobenzyl)piperazine to obtain compound 31. LC-MS (ESI): m / z = 529.31 [M+H] + .

[0127] Example 33: N 2 -cyclohexyl-N 4 -(2-(4-methylpiperazin-1-yl)ethyl)-N 6 Preparation of -pyridin-3-ylmethyl-1,3,5-triazine-2,4,6-triamine (32)

[0128] Following the method of Example 1, aniline was replaced by cyclohexylamine to obtain compound 32. LC-MS (ESI): m / z = 426.31 [M+H] + .

[0129] Example 34: N 2 -cyclohexyl-6-(4-fluorobenzyl)piperazin-1-yl)-N 4 Preparation of pyridin-3-ylmethyl-1,3,5-triazine-2,4-diamine (33)

[0130] Referring to the method of Example 1, aniline was replaced by cyclohexylamine, and 4-methyl-1-piperazineethylamine was replaced by 1-(4-fluorobenzyl)piperazine to obtain compound 33. LC-MS (ESI): m / z=477.29 [M+H] + .

[0131] Example 35: N 2 -(1H-imidazol-2-yl)ethyl)-N 4-cyclohexyl-N 6 Preparation of -(2-(dimethylamino)ethyl)-1,3,5-triazine-2,4,6-triamine (34)

[0132] Following the method of Example 1, aniline was replaced by cyclohexylamine, 3-aminomethylpyridine was replaced by histamine, and 4-methyl-1-piperazineethylamine was replaced by N,N-dimethylethylenediamine to obtain compound 34. LC-MS (ESI): m / z = 374.28 [M+H] + .

[0133] Example 36: N 2 -(1H-imidazol-2-yl)ethyl)-N 4 -cyclohexyl-N 6 Preparation of -(2-(dimethylamino)ethyl)-1,3,5-triazine-2,4,6-triamine (35)

[0134] Following the method of Example 1, aniline was replaced by cyclohexylamine, and 3-aminomethylpyridine was replaced by 4-aminopyridine to obtain compound 35. LC-MS (ESI): m / z = 412.29 [M+H] + .

[0135] Example 37: N 2 -(1H-imidazol-2-yl)ethyl)-N 4 -cyclohexyl-N 6 Preparation of -(2-(dimethylamino)ethyl)-1,3,5-triazine-2,4,6-triamine (36)

[0136] Referring to the method of Example 1, aniline was replaced by cyclohexylamine, and 3-aminomethylpyridine was replaced by 4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridine to obtain compound 36. LC-MS (ESI): m / z=441.32 [M+H] + .

[0137] Example 38: N 2 -cyclohexyl-N 4 -(pyridin-2-ylmethyl)-N 6 Preparation of 2-(2-pyrrolidin-1-yl)ethyl)-1,3,5-triazine-2,4,6-triamine (37)

[0138] Following the method of Example 1, aniline was replaced by cyclohexylamine, 3-aminomethylpyridine was replaced by 2-aminomethylpyridine, and 4-methyl-1-piperazineethylamine was replaced by 1-(2-aminoethyl)pyrrolidine to obtain compound 37. LC-MS (ESI): m / z = 397.28 [M+H] + .

[0139] Example 39: N2 -cyclohexyl-N 4 -(2-(4-methylpiperazin-1-yl)ethyl)-N 6 Preparation of -pyridin-2-ylmethyl-1,3,5-triazine-2,4,6-triamine (38)

[0140] Following the method of Example 1, aniline was replaced by cyclohexylamine and 3-aminomethylpyridine was replaced by 2-aminomethylpyridine to obtain compound 38. LC-MS (ESI): m / z = 426.31 [M+H] + .

[0141] Example 40: N 2 -cyclohexyl-N 4 -(2-(4-methylpiperazin-1-yl)ethyl)-N 6 Preparation of -pyridin-2-ylmethyl-1,3,5-triazine-2,4,6-triamine (39)

[0142] Following the method of Example 1, aniline was replaced by cyclohexylamine, 3-aminomethylpyridine was replaced by 4-methylaminopyridine, and 4-methyl-1-piperazineethylamine was replaced by 1-(2-aminoethyl)pyrrolidine to obtain compound 39. LC-MS (ESI): m / z = 397.28 [M+H] + .

[0143] Example 41: N 2 -cyclohexyl-N 4 -(2-(dimethylamino)ethyl)-N 6 Preparation of -pyridin-2-yl-1,3,5-triazine-2,4,6-triamine (40)

[0144] Following the method of Example 1, aniline was replaced by cyclohexylamine, 3-aminomethylpyridine was replaced by 4-methylaminopyridine, and 4-methyl-1-piperazineethylamine was replaced by 1-(2-aminoethyl)pyrrolidine to obtain compound 40. LC-MS (ESI): m / z = 357.25 [M+H] + .

[0145] Example 42: N 2 -cyclohexyl-N 4 -(2-(4-methylpiperazin-1-yl)ethyl)-N 6 Preparation of pyridin-2-yl-1,3,5-triazine-2,4,6-triamine (41)

[0146] Following the method of Example 1, aniline was replaced by cyclohexylamine and 3-aminomethylpyridine was replaced by 2-aminopyridine to obtain compound 41. LC-MS (ESI): m / z = 412.29 [M+H] + .

[0147] Example 43: Preparation of (4-((2-(1H-benzo[d]imidazol-2-yl)ethyl)amino)-6-(4-(4-fluorobenzyl)piperazin-1-yl)-1,3,5-triazin-2-yl)-L-lysine methyl ester (42)

[0148] Following the method of Example 1, aniline was replaced with L-lysine methyl ester, 3-aminomethylpyridine was replaced with 1H-benzimidazole-2-ethylamine, and 4-methyl-1-piperazineethylamine was replaced with 1-(4-fluorobenzyl)piperazine to obtain compound 42. LC-MS (ESI): m / z = 591.38 [M+H] + .

[0149] Example 44: Preparation of (4-((pyridin-3-yl)methylamino)-6-((2-(pyrrolidin-1-yl)ethyl)amino)-1,3,5-triazin-2-yl)-L-lysine methyl ester (43)

[0150] Following the method of Example 1, aniline was replaced by L-lysine methyl ester and 4-methyl-1-piperazineethylamine was replaced by 1-(2-aminoethyl)pyrrolidine to obtain compound 43. LC-MS (ESI): m / z = 458.37 [M+H] + .

[0151] Example 45: Preparation of (4-((2-(4-methylpiperazin-1-yl)ethyl)amino)-6-((pyridin-3-ylmethyl)amino)-1,3,5-triazin-2-yl)-L-lysine methyl ester (44)

[0152] Following the method of Example 1, aniline was replaced with L-lysine methyl ester to obtain compound 44. LC-MS (ESI): m / z = 487.38 [M+H] + .

[0153] Example 46: Preparation of (4-((2-(1H-imidazol-2-yl)ethyl)amino)-6-(4-(4-fluorobenzyl)piperazin-1-yl)-1,3,5-triazin-2-yl)-L-lysine methyl ester (45)

[0154] Following the method of Example 1, aniline was replaced with L-lysine methyl ester, histamine was replaced with 3-aminomethylpyridine, and 1-(4-fluorobenzyl)piperazine was replaced with 4-methyl-1-piperazineethylamine to obtain compound 45. LC-MS (ESI): m / z = 541.32 [M+H] + .

[0155] Example 47: Preparation of (4-((2-(dimethylamino)ethyl)amino)-6-(pyridin-4-ylamino)-1,3,5-triazin-2-yl)-L-lysine methyl ester (46)

[0156] Following the method of Example 1, aniline was replaced with L-lysine methyl ester, 3-aminomethylpyridine was replaced with 4-aminopyridine, and 4-methyl-1-piperazineethylamine was replaced with N,N-dimethylethylenediamine to obtain compound 46. LC-MS (ESI): m / z = 418.31 [M+H] + .

[0157] Example 48: Preparation of (4-((2-(4-methylpiperazin-1-yl)ethyl)amino)-6-((pyridin-4-ylmethyl)amino)-1,3,5-triazin-2-yl)-L-lysine methyl ester (47)

[0158] Following the method of Example 1, aniline was replaced by L-lysine methyl ester and 3-aminomethylpyridine was replaced by 4-methylaminopyridine to obtain compound 47. LC-MS (ESI): m / z = 487.38 [M+H] + .

[0159] Example 49: Preparation of (S)-methyl 2-((4-((cyclohexylmethyl)amino)-6-((2-(4-methylpiperazin-1-yl)ethyl)amino)-1,3,5-triazin-2-yl)amino)-2-(1H-imidazol-5-yl)acetate (48)

[0160] Referring to the method of Example 1, aniline was replaced by cyclohexylmethylamine and 3-aminomethylpyridine was replaced by L-histidine methyl ester to obtain compound 48. LC-MS (ESI): m / z = 487.32 [M+H] + .

[0161] Example 50: Preparation of methyl 2-(4-(cyclohexylmethyl)amino)-6-(2-(4-methylpiperazin-1-yl)ethyl)amino)-1,3,5-triazin-2-yl)amino)-2-(1H-imidazol-5-yl)acetate (49)

[0162] Following the method of Example 1, aniline was replaced with cyclohexylmethylamine, 3-aminomethylpyridine was replaced with 1H-benzimidazole-2-ethylamine, and 4-methyl-1-piperazineethylamine was replaced with N,N-dimethylethylenediamine to obtain compound 49. LC-MS (ESI): m / z = 438.31 [M+H] + .

[0163] Example 51: Preparation of methyl 2-(4-(cyclohexylmethyl)amino)-6-(2-(4-methylpiperazin-1-yl)ethyl)amino)-1,3,5-triazin-2-yl)amino)-2-(1H-imidazol-5-yl)acetate (50)

[0164] Following the method of Example 1, aniline was replaced by cyclohexylmethylamine and 4-methyl-1-piperazineethylamine was replaced by 1-(2-aminoethyl)pyrrolidine to obtain compound 50. LC-MS (ESI): m / z=411.30 [M+H] + .

[0165] Example 52: Preparation of methyl 2-(4-(cyclohexylmethyl)amino)-6-(2-(4-methylpiperazin-1-yl)ethyl)amino)-1,3,5-triazin-2-yl)amino)-2-(1H-imidazol-5-yl)acetate (51)

[0166] Following the method of Example 1, aniline was replaced with cyclohexylmethylamine to obtain compound 51. LC-MS (ESI): m / z = 440.32 [M+H] + .

[0167] Example 53: 6-(4-Benzylpiperazin-1-yl)-N 2 -cyclohexylmethyl-N 4 Preparation of pyridin-3-ylmethyl-1,3,5-triazine-2,4-diamine (52)

[0168] Following the method of Example 1, aniline was replaced by cyclohexylmethylamine and 4-methyl-1-piperazineethylamine was replaced by N-benzylpiperazine to obtain compound 52. LC-MS (ESI): m / z = 473.31 [M+H] + .

[0169] Example 54: N 2 -(1H-imidazol-2-yl)ethyl)-N 4 -cyclohexylmethyl-N 6 Preparation of -(2-(dimethylamino)ethyl)-1,3,5-triazine-2,4,6-triamine (53)

[0170] Following the method of Example 1, aniline was replaced by cyclohexylmethylamine, 3-aminomethylpyridine was replaced by histamine, and 4-methyl-1-piperazineethylamine was replaced by N,N-dimethylethylenediamine to obtain compound 53. LC-MS (ESI): m / z = 473.31 [M+H] + .

[0171] Example 55: Preparation of 2-(4-(2-(1H-imidazole-2-ethyl)amino)-6-(cyclohexylmethyl)amino)-1,3,5-triazin-2-yl)piperazin-1-yl)ethyl-1-ol (54)

[0172] Following the method of Example 1, aniline was replaced by cyclohexylmethylamine, 3-aminomethylpyridine was replaced by histamine, and 4-methyl-1-piperazineethylamine was replaced by N-hydroxyethylpiperazine to obtain compound 54. LC-MS (ESI): m / z = 430.30 [M+H] + .

[0173] Example 56: N 2 -cyclohexylmethyl-N 4 -(2-(4-methylpiperazin-1-yl)ethyl)-N 6 Preparation of pyridin-4-yl-1,3,5-triazine-2,4,6-triamine (55)

[0174] Referring to the method of Example 1, aniline was replaced by cyclohexylmethylamine and 3-aminomethylpyridine was replaced by 4-aminopyridine to obtain compound 55. LC-MS (ESI): m / z = 426.21 [M+H] + .

[0175] Example 57: Preparation of 4-(4-benzylpiperazin-1-yl)-N-cyclohexylmethyl-6-(3,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridin-5-yl)-1,3,5-triazin-2-amine (56)

[0176] Following the method of Example 1, aniline was replaced by cyclohexylmethylamine, 3-aminomethylpyridine was replaced by 4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridine, and 4-methyl-1-piperazineethylamine was replaced by N-benzylpiperazine to obtain Compound 56. LC-MS (ESI): m / z = 488.32 [M+H] + .

[0177] Example 58: Preparation of 2-(4-(4-(cyclohexylmethyl)amino)-6-((pyridin-4-ylmethyl)amino)-1,3,5-triazin-2-yl)piperazin-1-yl)ethyl-1-ol (57)

[0178] Referring to the method of Example 1, aniline was replaced by cyclohexylmethylamine, 3-aminomethylpyridine was replaced by 4-methylaminopyridine, and 4-methyl-1-piperazineethylamine was replaced by N-hydroxyethylpiperazine to obtain compound 57. LC-MS (ESI): m / z = 427.29 [M+H] + .

[0179] Example 59: Preparation of 2-(4-(4-(cyclohexylmethyl)amino)-6-((pyridin-4-ylmethyl)amino)-1,3,5-triazin-2-yl)piperazin-1-yl)ethyl-1-ol (58)

[0180] Following the method of Example 1, 3-aminomethylpyridine was replaced with 1H-benzimidazole-2-ethylamine and 4-methyl-1-piperazineethylamine was replaced with 1-(4-fluorobenzyl)piperazine to obtain Compound 58. LC-MS (ESI): m / z = 524.31 [M+H] + .

[0181] Example 60: N 2 -(2-(1H-benzimidazol-2-yl)ethyl)-6-(4-benzylpiperazin-1-yl)-N 4 Preparation of phenyl-1,3,5-triazine-2,4-diamine (59)

[0182] Referring to the method of Example 1, 3-aminomethylpyridine was replaced with 1H-benzimidazole-2-ethylamine and 4-methyl-1-piperazineethylamine was replaced with N-benzylpiperazine to obtain compound 59. LC-MS (ESI): m / z = 506.27 [M+H] + .

[0183] Example 61: N 2 -(3-dimethylamino)propyl-N 4 -phenyl-N 6 Preparation of -(pyridin-4-yl)-1,3,5-triazine-2,4,6-triamine (60)

[0184] Referring to the method of Example 1, 4-methyl-1-piperazineethylamine was replaced with N,N-dimethylethylenediamine to obtain compound 60. LC-MS (ESI): m / z=365.22 [M+H] + .

[0185] Example 62: N 2 -(3-dimethylamino)propyl-N 4 -phenyl-N 6 Preparation of -(pyridin-4-yl)-1,3,5-triazine-2,4,6-triamine (62)

[0186] Following the method of Example 1, 3-aminomethylpyridine was replaced with 4-aminopyridine and 4-methyl-1-piperazineethylamine was replaced with N,N-dimethyl-1,3-diaminopropane to obtain compound 62. LC-MS (ESI): m / z = 365.21 [M+H] + .

[0187] Example 63: N 2 -(2-(1H-benzimidazol-2-yl)ethyl)-6-(4-benzylpiperazin-1-yl)-N 4 Preparation of phenyl-1,3,5-triazine-2,4-diamine (63)

[0188] Referring to the method of Example 1, 3-aminomethylpyridine was replaced by 4-aminopyridine, and 4-methyl-1-piperazineethylamine was replaced by 4-dimethylaminopiperidine to obtain compound 63. LC-MS (ESI): m / z=391.23 [M+H] + .

[0189] Example 64: 6-(4-Fluorobenzyl)piperazin-1-yl)-N 2 -phenyl-N 4 Preparation of pyridin-2-ylmethyl-1,3,5-triazine-2,4-diamine (64)

[0190] Referring to the method of Example 1, 3-aminomethylpyridine was replaced with 2-aminomethylpyridine and 4-methyl-1-piperazineethylamine was replaced with 1-(4-fluorobenzyl)piperazine to obtain compound 64. LC-MS (ESI): m / z = 471.23 [M+H] + .

[0191] Example 65: Preparation of 2-(4-(4-phenylamino)-6-(pyridin-2-ylmethyl)amino)-1,3,5-triazin-2-yl)piperazin-1-yl)ethyl-1-ol (65)

[0192] Referring to the method of Example 1, 3-aminomethylpyridine was replaced with 2-aminomethylpyridine and 4-methyl-1-piperazineethylamine was replaced with N-hydroxyethylpiperazine to obtain compound 65. LC-MS (ESI): m / z = 407.34 [M+H] + .

[0193] Example 66: N 2 -(2-(1H-benzimidazol-2-yl)ethyl)-N 4 -Benzyl-N 6 Preparation of -(2-(4-methylpiperazin-1-yl)ethyl)-1,3,5-triazine-2,4,6-triamine (66)

[0194] Following the method of Example 1, aniline was replaced by benzylamine and 3-aminomethylpyridine was replaced by 1H-benzimidazole-2-ethylamine to obtain compound 66. LC-MS (ESI): m / z = 487.30 [M+H] + .

[0195] Example 67: N 2 -Benzyl-N 4 -(2-(piperidin-1-yl)ethyl)-N 6 - Preparation of pyridin-3-ylmethyl-1,3,5-triazine-2,4,6-triamine (67)

[0196] Following the method of Example 1, aniline was replaced by benzylamine, and 4-methyl-1-piperazineethylamine was replaced by 1-(2-aminoethyl)piperidine to obtain compound 67. LC-MS (ESI): m / z = 419.26 [M+H] + .

[0197] Example 68: N 2 -Benzyl-N 4 -(2-morpholinoethyl)-N 6 - Preparation of pyridin-3-ylmethyl-1,3,5-triazine-2,4,6-triamine (68)

[0198] Following the method of Example 1, aniline was replaced by benzylamine and 4-methyl-1-piperazineethylamine was replaced by N-(2-aminoethyl)morpholine to obtain Compound 68. LC-MS (ESI): m / z = 421.24 [M+H] + .

[0199] Example 69: N 2 -Benzyl-N 4 -(2-morpholinoethyl)-N 6 Preparation of pyridin-3-ylmethyl-1,3,5-triazine-2,4,6-triamine (69)

[0200] Following the method of Example 1, aniline was replaced by benzylamine and 4-methyl-1-piperazineethylamine was replaced by 1-(4-fluorobenzyl)piperazine to obtain compound 69. LC-MS (ESI): m / z = 485.25 [M+H] + .

[0201] Example 70: N 2 -Benzyl-N 4 -(2-morpholinoethyl)-N 6 Preparation of pyridin-3-ylmethyl-1,3,5-triazine-2,4,6-triamine (70)

[0202] Following the method of Example 1, aniline was replaced by benzylamine, 3-aminomethylpyridine was replaced by histamine, and 4-methyl-1-piperazineethylamine was replaced by N-methylpiperazine to obtain compound 70. LC-MS (ESI): m / z = 394.23 [M+H] + .

[0203] Example 71: Preparation of 2-(4-(2-(1H-imidazole-2-ethyl)amino)-6-benzylamino-1,3,5-triazin-2-yl)piperazin-1-yl)-1-pyrrolidin-1-ylethyl (71)

[0204] Following the method of Example 1, aniline was replaced by benzylamine, 3-aminomethylpyridine was replaced by histamine, and 4-methyl-1-piperazineethylamine was replaced by 1-(2-piperazin-1-ylacetyl)pyrrolidine to obtain Compound 71. LC-MS (ESI): m / z = 491.30 [M+H] + .

[0205] Example 72: N 2 -Benzyl-N 4 Preparation of -(2-(pyrrolidin-1-yl)ethyl)-6-(3,4,6,7-tetrahydroimidazo[4,5-c]pyridin-5-yl)-1,3,5-triazine-2,4-diamine (72)

[0206] Following the method of Example 1, aniline was replaced with benzylamine, 3-aminomethylpyridine was replaced with 4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridine, and 4-methyl-1-piperazineethylamine was replaced with 1-(2-aminoethyl)pyrrolidine to obtain Compound 72. LC-MS (ESI): m / z = 420.26 [M+H] + .

[0207] Example 73: N 2 -Benzyl-N 4 Preparation of -(2-(pyrrolidin-1-yl)ethyl)-6-(3,4,6,7-tetrahydroimidazo[4,5-c]pyridin-5-yl)-1,3,5-triazine-2,4-diamine (73)

[0208] Following the method of Example 1, aniline was replaced by benzylamine, 3-aminomethylpyridine was replaced by 4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridine, and 4-methyl-1-piperazineethylamine was replaced by N-benzylpiperazine to obtain compound 73. LC-MS (ESI): m / z = 482.28 [M+H] + .

[0209] Example 74: N 2 -Benzyl-N 4 Preparation of -(2-(pyrrolidin-1-yl)ethyl)-6-(3,4,6,7-tetrahydroimidazo[4,5-c]pyridin-5-yl)-1,3,5-triazine-2,4-diamine (74)

[0210] Following the method of Example 1, aniline was replaced by benzylamine and 3-aminomethylpyridine was replaced by 4-methylaminopyridine to obtain compound 74. LC-MS (ESI): m / z = 434.28 [M+H] + .

[0211] Example 75: N 2 -Benzyl-N 4Preparation of -(2-(pyrrolidin-1-yl)ethyl)-6-(3,4,6,7-tetrahydroimidazo[4,5-c]pyridin-5-yl)-1,3,5-triazine-2,4-diamine (75)

[0212] Following the method of Example 1, aniline was replaced by 2-thiophenemethylamine and 3-aminomethylpyridine was replaced by 1H-benzimidazole-2-ethylamine to obtain compound 75. LC-MS (ESI): m / z = 493.26 [M+H] + .

[0213] Example 76: N 2 -pyridin-3-ylmethyl-N 4 -(2-pyrrolidin-1-yl)ethyl)-N 6 Preparation of thiophen-2-ylmethyl-1,3,5-triazine-2,4,6-triamine (76)

[0214] Following the method of Example 1, aniline was replaced by 2-thiophenemethylamine and 4-methyl-1-piperazineethylamine was replaced by 1-(2-aminoethyl)pyrrolidine to obtain compound 76. LC-MS (ESI): m / z = 411.21 [M+H] + .

[0215] Example 77: N 2 -(1-Benzylpiperidin-4-yl)-N 4 -pyridin-3-ylmethyl-N 6 Preparation of -thiophen-2-ylmethyl-1,3,5-triazine-2,4,6-triamine (77)

[0216] Following the method of Example 1, aniline was replaced by 2-thiophenemethylamine and 4-methyl-1-piperazineethylamine was replaced by 4-amino-1-benzylpiperidine to obtain compound 77. LC-MS (ESI): m / z = 487.24 [M+H] + .

[0217] Example 78: N 2 -(1-Benzylpiperidin-4-yl)-N 4 -pyridin-3-ylmethyl-N 6 Preparation of -thiophen-2-ylmethyl-1,3,5-triazine-2,4,6-triamine (78)

[0218] Following the method of Example 1, aniline was replaced by 2-thiophenemethylamine and 4-methyl-1-piperazineethylamine was replaced by 1-(4-fluorobenzyl)piperazine to obtain Compound 78. LC-MS (ESI): m / z = 491.21 [M+H] + .

[0219] Example 79: N2 -(1-Benzylpiperidin-4-yl)-N 4 -pyridin-3-ylmethyl-N 6 Preparation of thiophen-2-ylmethyl-1,3,5-triazine-2,4,6-triamine (79)

[0220] Following the method of Example 1, aniline was replaced by 2-thiophenemethylamine and 4-methyl-1-piperazineethylamine was replaced by N-hydroxyethylpiperazine to obtain compound 79. LC-MS (ESI): m / z = 427.20 [M+H] + .

[0221] Example 80: N 2 -(2-(4-methylpiperazin-1-yl)ethyl)-N 4 -pyridin-4-yl-N 6 Preparation of thiophen-2-ylmethyl-1,3,5-triazine-2,4,6-triamine (80)

[0222] Following the method of Example 1, aniline was replaced by 2-thiophenemethylamine and 3-aminomethylpyridine was replaced by 4-aminopyridine to obtain compound 80. LC-MS (ESI): m / z = 426.21 [M+H] + .

[0223] Example 81: N 2 -(1-Benzylpiperidin-4-yl)-N 4 -pyridin-4-yl-N 6 Preparation of thiophen-2-ylmethyl-1,3,5-triazine-2,4,6-triamine (81)

[0224] Following the method of Example 1, aniline was replaced by 2-thienylmethylamine, 3-aminomethylpyridine was replaced by 4-aminopyridine, and 4-methyl-1-piperazineethylamine was replaced by 4-amino-1-benzylpiperidine to obtain Compound 81. LC-MS (ESI): m / z = 473.22 [M+H] + .

[0225] Example 82: N 2 -(2-(4-methylpiperazin-1-yl)ethyl)-6-(3,4,6,7-tetrahydroimidazo[4,5-c]pyridin-5-yl)-N 4 Preparation of -thiophen-2-ylmethyl-1,3,5-triazine-2,4-diamine (82)

[0226] Following the method of Example 1, aniline was replaced by 2-thiophenemethylamine and 3-aminomethylpyridine was replaced by 4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridine to obtain compound 82. LC-MS (ESI): m / z = 455.24 [M+H]+ .

[0227] Example 83: N 2 -(2-(4-methylpiperazin-1-yl)ethyl)-6-(3,4,6,7-tetrahydroimidazo[4,5-c]pyridin-5-yl)-N 4 Preparation of thiophene-2-ylmethyl-1,3,5-triazine-2,4-diamine (83)

[0228] Following the method of Example 1, aniline was replaced with 2-thiophenemethylamine, 3-aminomethylpyridine was replaced with 4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridine, and 4-methyl-1-piperazineethylamine was replaced with N-hydroxyethylpiperazine to obtain Compound 83. LC-MS (ESI): m / z = 442.21 [M+H] + .

[0229] Example 84: 6-(4-Benzylpiperazin-1-yl)-N 2 -pyridin-2-ylmethyl-N 4 Preparation of thiophene-2-ylmethyl-1,3,5-triazine-2,4-diamine (84)

[0230] Following the method of Example 1, aniline was replaced by 2-thienylmethylamine, 3-aminomethylpyridine was replaced by 2-aminomethylpyridine, and 4-methyl-1-piperazineethylamine was replaced by N-benzylpiperazine to obtain compound 84. LC-MS (ESI): m / z = 473.22 [M+H] + .

[0231] Example 85: 6-(4-Benzylpiperazin-1-yl)-N 2 -pyridin-2-ylmethyl-N 4 Preparation of thiophen-2-ylmethyl-1,3,5-triazine-2,4-diamine (85)

[0232] Following the method of Example 1, aniline was replaced by 2-thiophenemethylamine and 3-aminomethylpyridine was replaced by 4-methylaminopyridine to obtain compound 85. LC-MS (ESI): m / z = 440.24 [M+H] + .

[0233] Example 86: N 2 -(2-(dimethylamino)ethyl)-N 4 -pyridin-2-yl-N 6 Preparation of thiophen-2-ylmethyl-1,3,5-triazine-2,4,6-triamine (86)

[0234] Following the method of Example 1, aniline was replaced by 2-thienylmethylamine, 3-aminomethylpyridine was replaced by 2-aminopyridine, and 4-methyl-1-piperazineethylamine was replaced by N,N-dimethylethylenediamine to obtain compound 86. LC-MS (ESI): m / z = 371.17 [M+H] + .

[0235] Example 87: N 2 -(2-(dimethylamino)ethyl)-N 4 -pyridin-2-yl-N 6 Preparation of thiophen-2-ylmethyl-1,3,5-triazine-2,4,6-triamine (87)

[0236] Following the method of Example 1, aniline was replaced by 2-thiophenemethylamine and 3-aminomethylpyridine was replaced by 2-aminopyridine to obtain compound 87. LC-MS (ESI): m / z = 426.22 [M+H] + .

[0237] Example 88: Preparation of (S)-methyl 2-((4-((2-(1H-indol-3-yl)ethyl)amino)-6-((2-(4-methylpiperazin-1-yl)ethyl)amino)-1,3,5-triazin-2-yl)amino)-2-(1H-imidazol-5-yl)acetate (88)

[0238] Following the method of Example 1, aniline was replaced by tryptamine and 3-aminomethylpyridine was replaced by L-histidine methyl ester to obtain compound 88. LC-MS (ESI): m / z = 534.30 [M+H] + .

[0239] Example 89: Preparation of (S)-methyl 2-((4-((2-(1H-indol-3-yl)ethyl)amino)-6-(4-(2-hydroxyethyl)piperazin-1-yl)-1,3,5-triazin-2-yl)amino)-2-(1H-imidazol-5-yl)acetate (89)

[0240] Following the method of Example 1, aniline was replaced by tryptamine, 3-aminomethylpyridine was replaced by L-histidine methyl ester, and 4-methyl-1-piperazineethylamine was replaced by N-hydroxyethylpiperazine to obtain compound 89. LC-MS (ESI): m / z = 521.27 [M+H] + .

[0241] Example 90: Preparation of methyl 2-(4-(2-(1H-indole-3-ethyl)ethylamino)-6-(4-(2-hydroxyethyl)piperazin-1-yl)-1,3,5-triazin-2-yl)amino)-2-(1H-imidazol-5-yl)acetate (90)

[0242] Following the method of Example 1, aniline was replaced with tryptamine, 3-aminomethylpyridine was replaced with 1H-benzimidazole-2-ethylamine, and 4-methyl-1-piperazineethylamine was replaced with N,N-dimethylethylenediamine to obtain compound 90. LC-MS (ESI): m / z = 521.27 [M+H] + .

[0243] Example 91: N 2 -(2-benzimidazol-2-yl)ethyl)-N 4 -(2-(1H-indol-3-yl)ethyl)-N 6 Preparation of -(3-(4-methylpiperazin-1-yl)propyl)-1,3,5-triazine-2,4,6-triamine (91)

[0244] Following the method of Example 1, aniline was replaced with tryptamine, 3-aminomethylpyridine was replaced with 1H-benzimidazole-2-ethylamine, and 4-methyl-1-piperazineethylamine was replaced with 1-(3-aminopropyl)-4-methylpiperazine to obtain Compound 91. LC-MS (ESI): m / z = 554.34 [M+H] + .

[0245] Example 92: N 2 -(2-(1H-benzimidazol-2-yl)ethyl)-N 4 Preparation of -(2-(1H-indol-3-yl)ethyl)-6-(4-methylpiperazin-1-yl)-1,3,5-triazine-2,4-diamine (92)

[0246] Following the method of Example 1, aniline was replaced by tryptamine, 3-aminomethylpyridine was replaced by 1H-benzimidazole-2-ethylamine, and 4-methyl-1-piperazineethylamine was replaced by N-methylpiperazine to obtain compound 92. LC-MS (ESI): m / z = 497.29 [M+H] + .

[0247] Example 93: N 2 -(2-(1H-benzimidazol-2-yl)ethyl)-N 4 Preparation of -(2-(1H-indol-3-yl)ethyl)-6-(4-methylpiperazin-1-yl)-1,3,5-triazine-2,4-diamine (93)

[0248] Following the method of Example 1, compound 93 was obtained by replacing aniline with tryptamine, 3-aminomethylpyridine with 1H-benzimidazole-2-ethylamine, and 4-methyl-1-piperazineethylamine with 1-(2-piperazin-1-ylacetyl)pyrrolidine. LC-MS (ESI): m / z = 594.34 [M+H] + .

[0249] Example 94: Preparation of 2-(4-(2-(2-(1H-benzimidazole-2-ethyl)amino)-6-(2-(1H-indol-3-yl)ethyl)amino)-1,3,5-triazin-2-yl)piperazin-1-yl)ethyl-1-ol (94)

[0250] Following the method of Example 1, aniline was replaced by tryptamine, 3-aminomethylpyridine was replaced by 1H-benzimidazole-2-ethylamine, and 4-methyl-1-piperazineethylamine was replaced by N-hydroxyethylpiperazine to obtain compound 94. LC-MS (ESI): m / z = 527.30 [M+H] + .

[0251] Example 95: Preparation of 2-(4-(2-(2-(1H-benzimidazole-2-ethyl)amino)-6-(2-(1H-indol-3-yl)ethyl)amino)-1,3,5-triazin-2-yl)piperazin-1-yl)ethyl-1-ol (95)

[0252] Following the method of Example 1, aniline was replaced by tryptamine and 4-methyl-1-piperazineethylamine was replaced by 1-(2-aminoethyl)pyrrolidine to obtain compound 95. LC-MS (ESI): m / z = 458.28 [M+H] + .

[0253] Example 96: N 2 -(2-(1H-indol-3-yl)ethyl)-N 4 -(3-(4-methylpiperazin-1-yl)propyl)-N 6 Preparation of -(pyridin-3-ylmethyl)-1,3,5-triazine-2,4,6-triamine (96)

[0254] Following the method of Example 1, aniline was replaced by tryptamine and 4-methyl-1-piperazineethylamine was replaced by 1-(3-aminopropyl)-4-methylpiperazine to obtain compound 96. LC-MS (ESI): m / z = 501.32 [M+H] + .

[0255] Example 97: N 2 -(2-(1H-indol-3-yl)ethyl)-N 4 -(3-(4-methylpiperazin-1-yl)propyl)-N 6 Preparation of -(pyridin-3-ylmethyl)-1,3,5-triazine-2,4,6-triamine (97)

[0256] Following the method of Example 1, aniline was replaced by tryptamine and 4-methyl-1-piperazineethylamine was replaced by N-methylpiperazine to obtain compound 97. LC-MS (ESI): m / z = 444.26 [M+H] +.

[0257] Example 98: N 2 -(2-(1H-indol-3-yl)ethyl)-N 4 -(3-(4-methylpiperazin-1-yl)propyl)-N 6 Preparation of -(pyridin-3-ylmethyl)-1,3,5-triazine-2,4,6-triamine (98)

[0258] Following the method of Example 1, aniline was replaced by tryptamine and 4-methyl-1-piperazineethylamine was replaced by 1-(4-fluorobenzyl)piperazine to obtain compound 98. LC-MS (ESI): m / z = 538.28 [M+H] + .

[0259] Example 99: N 2 -(2-(1H-indol-3-yl)ethyl)-N 4 -(3-(4-methylpiperazin-1-yl)propyl)-N 6 Preparation of -(pyridin-3-ylmethyl)-1,3,5-triazine-2,4,6-triamine (99)

[0260] Following the method of Example 1, aniline was replaced by tryptamine and 4-methyl-1-piperazineethylamine was replaced by 1-(2-piperazin-1-ylacetyl)pyrrolidine to obtain Compound 99. LC-MS (ESI): m / z = 538.28 [M+H] + .

[0261] Example 100: Preparation of 2-(4-(2-(1H-indole-3-ethyl)ethylamino)-6-(pyridin-3-ylmethyl)amino)-1,3,5-triazin-2-yl)piperazin-1-yl)ethyl-1-ol (100)

[0262] Following the method of Example 1, aniline was replaced by tryptamine and 4-methyl-1-piperazineethylamine was replaced by N-hydroxyethylpiperazine to obtain compound 100. LC-MS (ESI): m / z=474.27 [M+H] + .

[0263] Example 101: N 2 -(1H-imidazol-2-yl)ethyl)-N 4 -(2-(1H-indol-3-yl)ethyl)-N 6 Preparation of -(2-(pyrrolidin-1-yl)ethyl)-1,3,5-triazine-2,4,6-triamine (101)

[0264] Following the method of Example 1, aniline was replaced by tryptamine, 3-aminomethylpyridine was replaced by histamine, and 4-methyl-1-piperazineethylamine was replaced by 1-(2-aminoethyl)pyrrolidine to obtain Compound 101. LC-MS (ESI): m / z = 461.29 [M+H] + .

[0265] Example 102: N 2 -(1H-imidazol-2-yl)ethyl)-N 4 -(2-(1H-indol-3-yl)ethyl)-N 6 Preparation of -(3-(4-methylpiperazin-1-yl)propyl)-1,3,5-triazine-2,4,6-triamine (102)

[0266] Following the method of Example 1, aniline was replaced by tryptamine, 3-aminomethylpyridine was replaced by histamine, and 4-methyl-1-piperazineethylamine was replaced by 1-(3-aminopropyl)-4-methylpiperazine to obtain compound 102. LC-MS (ESI): m / z = 504.33 [M+H] + .

[0267] Example 103: N 2 -(2-(1H-indol-3-yl)ethyl)-N 4 Preparation of -(2-(4-methylpiperazin-1-yl)ethyl)-6-(3,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridin-5-yl)-1,3,5-triazine-2,4-diamine (103)

[0268] Following the method of Example 1, aniline was replaced by tryptamine and 3-aminomethylpyridine was replaced by 4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridine to obtain compound 103. LC-MS (ESI): m / z = 502.31 [M+H] + .

[0269] Example 104: Preparation of N-(2-(1H-indol-3-yl)ethyl)-4-(4-methylpiperazin-1-yl)-6-(3,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridin-5-yl)-1,3,5-triazin-2-amine (104)

[0270] Following the method of Example 1, aniline was replaced with tryptamine, 3-aminomethylpyridine was replaced with 4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridine, and 4-methyl-1-piperazineethylamine was replaced with N-methylpiperazine to obtain Compound 104. LC-MS (ESI): m / z = 459.27 [M+H] + .

[0271] Example 105: Preparation of 2-(4-(2-(1H-indole-3-ethyl)ethylamino)-6-(3,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridin-5-yl)-1,3,5-triazin-2-yl)piperazin-1-yl)-1-(pyrrolidin-1-yl)ethan-1-one (105)

[0272] Following the method of Example 1, compound 105 was obtained by replacing aniline with tryptamine, 3-aminomethylpyridine with 4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridine, and 4-methyl-1-piperazineethylamine with 1-(2-piperazin-1-ylacetyl)pyrrolidine. LC-MS (ESI): m / z = 556.32 [M+H] + .

[0273] Example 106: Preparation of 2-(4-(4-(2-(1H-indole-3-ethyl)ethylamino)-6-(3,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridin-5-yl)-1,3,5-triazin-2-yl)piperazin-1-yl)ethyl-1-ol (106)

[0274] Following the method of Example 1, aniline was replaced with tryptamine, 3-aminomethylpyridine was replaced with 4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridine, and 4-methyl-1-piperazineethylamine was replaced with N-hydroxyethylpiperazine to obtain Compound 106. LC-MS (ESI): m / z = 489.28 [M+H] + .

[0275] Example 107: N 2 -(2-(1H-indol-3-yl)ethyl)-6-(4-methylpiperazin-1-yl)-N 4 Preparation of -(2-methylpyridine)-1,3,5-triazine-2,4-diamine (107)

[0276] Following the method of Example 1, aniline was replaced by tryptamine, 3-aminomethylpyridine was replaced by 2-aminoethylpyridine, and 4-methyl-1-piperazineethylamine was replaced by 1-(3-aminopropyl)-4-methylpiperazine to obtain compound 107. LC-MS (ESI): m / z = 501.32 [M+H] + .

[0277] Example 108: N 2 -(2-(1H-indol-3-yl)ethyl)-6-(4-methylpiperazin-1-yl)-N 4 Preparation of -(2-methylpyridine)-1,3,5-triazine-2,4-diamine (108)

[0278] Following the method of Example 1, aniline was replaced by tryptamine, 3-aminomethylpyridine was replaced by 2-aminoethylpyridine, and 4-methyl-1-piperazineethylamine was replaced by N-methylpiperazine to obtain compound 108. LC-MS (ESI): m / z = 444.26 [M+H] + .

[0279] Example 109: N 2 -(2-(1H-indol-3-yl)ethyl)-6-(4-fluorobenzyl)piperazin-1-yl)-N 4 Preparation of -pyridin-2-ylmethyl-1,3,5-triazine-2,4-diamine (109)

[0280] Following the method of Example 1, aniline was replaced by tryptamine, 3-aminomethylpyridine was replaced by 2-aminoethylpyridine, and 4-methyl-1-piperazineethylamine was replaced by 1-(4-fluorobenzyl)piperazine to obtain Compound 109. LC-MS (ESI): m / z = 538.28 [M+H] + .

[0281] Example 110: Preparation of 2-(4-(2-(1H-indole-3-ethyl)amino)-6-(pyridin-2-ylmethyl)amino)-1,3,5-triazin-2-yl)piperazin-1-yl)ethyl-1-ol (110)

[0282] Following the method of Example 1, aniline was replaced by tryptamine, 3-aminomethylpyridine was replaced by 2-aminoethylpyridine, and 4-methyl-1-piperazineethylamine was replaced by N-hydroxyethylpiperazine to obtain compound 110. LC-MS (ESI): m / z = 474.27 [M+H] + .

[0283] Example 111: N 2 -(2-(1H-indol-3-yl)ethyl)-N 4 -(2-(4-methylpiperazin-1-yl)ethyl)-N 6 Preparation of pyridin-4-ylmethyl-1,3,5-triazine-2,4,6-triamine (111)

[0284] Following the method of Example 1, aniline was replaced by tryptamine and 3-aminomethylpyridine was replaced by 4-methylaminopyridine to obtain compound 111. LC-MS (ESI): m / z = 487.30 [M+H] + .

[0285] Example 112: Preparation of N-(2-benzimidazol-2-yl)ethyl)-4-(4-(4-fluorobenzylpiperazin-1-yl)-6-piperidin-1,3,5-triazin-2-amine (112)

[0286] Following the method of Example 1, aniline was replaced with hexahydropyridine, 3-aminomethylpyridine was replaced with 1H-benzimidazole-2-ethylamine, and 4-methyl-1-piperazineethylamine was replaced with 1-(4-fluorobenzyl)piperazine to obtain compound 112. LC-MS (ESI): m / z = 516.30 [M+H] + .

[0287] Example 113: N 2 -(2-(4-methylpiperazin-1-yl)ethyl)-6-(piperidin-1-yl)-N 4 Preparation of -(pyridin-3-ylmethyl)-1,3,5-triazine-2,4-diamine (113)

[0288] Following the method of Example 1, aniline was replaced with hexahydropyridine to obtain compound 113. LC-MS (ESI): m / z = 412.29 [M+H] + .

[0289] Example 114: N 2 -(2-(1H-imidazol-2-yl)ethyl)-N 4 Preparation of -(2-(4-methylpiperazin-1-yl)ethyl)-6-(piperidin-1-yl)-1,3,5-triazine-2,4-diamine (114)

[0290] Following the method of Example 1, aniline was replaced by hexahydropyridine and 3-aminomethylpyridine was replaced by histamine to obtain compound 114. LC-MS (ESI): m / z = 415.30 [M+H] + .

[0291] Example 115: Preparation of N-(2-(4-methylpiperazin-1-yl)ethyl)-4-(piperidin-1-yl)-6-(3,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridin-5-yl)-1,3,5-triazin-2-amine (115)

[0292] Following the method of Example 1, aniline was replaced with hexahydropyridine and 3-aminomethylpyridine was replaced with 4,5,6,7-tetrahydro-3H-imidazole-[4,5-c]pyridine to obtain compound 115. LC-MS (ESI): m / z = 427.30 [M+H] + .

[0293] Example 116: N 2 -(2-(4-methylpiperazin-1-yl)ethyl)-6-piperidin-1-yl)-N 4 Preparation of -(pyridin-4-ylmethyl)-1,3,5-triazine-2,4-diamine (116)

[0294] Following the method of Example 1, aniline was replaced by hexahydropyridine and 3-aminomethylpyridine was replaced by 1-(3-aminopropyl)-4-methylpiperazine to obtain Compound 116. LC-MS (ESI): m / z = 412.29 [M+H] + .

[0295] Example 117: N 2 -(2-Benzimidazole-2-ethyl)-N 4 -(3,4-dimethoxyphenyl)-N 6 Preparation of -(2-(4-methylpiperazin-1-yl)ethyl)-1,3,5-triazine-2,4,6-triamine (117)

[0296] Following the method of Example 1, aniline was replaced by 3,4-dimethoxyaniline and 3-aminomethylpyridine was replaced by 1H-benzimidazole-2-ethylamine to obtain compound 117. LC-MS (ESI): m / z = 533.31 [M+H] + .

[0297] Example 118: N 2 -(2-Benzimidazole-2-ethyl)-N 4 Preparation of -(3,4-dimethoxyphenyl)-6-(4-fluorobenzyl)piperazin-1-yl)-1,3,5-triazine-2,4-diamine (118)

[0298] Following the method of Example 1, aniline was replaced with 3,4-dimethoxyaniline, 3-aminomethylpyridine was replaced with 1H-benzimidazole-2-ethylamine, and 4-methyl-1-piperazineethylamine was replaced with 1-(4-fluorobenzyl)piperazine to obtain Compound 118. LC-MS (ESI): m / z = 584.29 [M+H] + .

[0299] Example 119: N 2 -(3,4-dimethoxyphenyl)-6-(4-methylpiperazin-1-yl)-N 4 Preparation of pyridin-3-ylmethyl-1,3,5-triazine-2,4-diamine (119)

[0300] Following the method of Example 1, aniline was replaced by 3,4-dimethoxyaniline and 4-methyl-1-piperazineethylamine was replaced by N-methylpiperazine to obtain Compound 119. LC-MS (ESI): m / z = 437.24 [M+H] + .

[0301] Example 120: N 2 -(3,4-dimethoxyphenyl)-6-(4-fluorobenzyl)piperazin-1-yl)-N 4Preparation of -(pyridin-3-ylmethyl)-1,3,5-triazine-2,4-diamine (120)

[0302] Following the method of Example 1, aniline was replaced by 3,4-dimethoxyaniline and 4-methyl-1-piperazineethylamine was replaced by 1-(4-fluorobenzyl)piperazine to obtain Compound 120. LC-MS (ESI): m / z = 531.26 [M+H] + .

[0303] Example 121: N 2 -(2-(1H-imidazol-2-yl)ethyl)-N 4 Preparation of -(3,4-dimethoxyphenyl)-6-(4-methylpiperazin-1-yl)-1,3,5-triazine-2,4-diamine (121)

[0304] Following the method of Example 1, aniline was replaced by 3,4-dimethoxyaniline, 3-aminomethylpyridine was replaced by histamine, and 4-methyl-1-piperazineethylamine was replaced by N-methylpiperazine to obtain compound 121. LC-MS (ESI): m / z = 440.25 [M+H] + .

[0305] Example 122: N 2 -(3,4-dimethoxyphenyl)-6-(4-(dimethylamino)piperidin-1-yl)-N 4 Preparation of pyridin-4-yl-1,3,5-triazine-2,4-diamine (122)

[0306] Following the method of Example 1, aniline was replaced by 3,4-dimethoxyaniline, 3-aminomethylpyridine was replaced by 4-aminopyridine, and 4-methyl-1-piperazineethylamine was replaced by 4-dimethylaminopiperidine to obtain Compound 122. LC-MS (ESI): m / z = 451.25 [M+H] + .

[0307] Example 123: Preparation of N-(3,4-dimethoxyphenyl)-4-(4-methylpiperazin-1-yl)-6-(3,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridin-5-yl)-1,3,5-triazin-2-amine (123)

[0308] Following the method of Example 1, aniline was replaced with 3,4-dimethoxyaniline, 3-aminomethylpyridine was replaced with 4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridine, and 4-methyl-1-piperazineethylamine was replaced with N-methylpiperazine to obtain Compound 123. LC-MS (ESI): m / z = 452.25 [M+H] + .

[0309] Example 124: Preparation of N-(3,4-dimethoxyphenyl)-4-(4-fluorobenzyl)piperazin-1-yl)-6-3,4,6,7-tetrahydroimidazo[4,5-c]pyridin-5-yl)-1,3,5-triazin-2-amine (124)

[0310] Following the method of Example 1, compound 124 was obtained by replacing aniline with 3,4-dimethoxyaniline, 3-aminomethylpyridine with 4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridine, and 4-methyl-1-piperazineethylamine with 1-(4-fluorobenzyl)piperazine. LC-MS (ESI): m / z = 546.27 [M+H] + .

[0311] Example 125: N 2 -(3,4-dimethoxyphenyl)-N 4 -pyridin-4-ylmethyl-N 6 Preparation of -(2-(pyrrolidin-1-yl)ethyl)-1,3,5-triazine-2,4,6-triamine (125)

[0312] Following the method of Example 1, aniline was replaced by 3,4-dimethoxyaniline, 3-aminomethylpyridine was replaced by 4-methylaminopyridine, and 4-methyl-1-piperazineethylamine was replaced by 1-(2-aminoethyl)pyrrolidine to obtain Compound 125. LC-MS (ESI): m / z = 452.25 [M+H] + .

[0313] Example 126: N 2 -(3,4-dimethoxyphenyl)-N 4 -(2-(4-methylpiperazin-1-yl)ethyl)-N 6 Preparation of -(pyridin-4-ylmethyl)-1,3,5-triazine-2,4,6-triamine (126)

[0314] Following the method of Example 1, aniline was replaced by 3,4-dimethoxyaniline and 3-aminomethylpyridine was replaced by 4-methylaminopyridine to obtain compound 126. LC-MS (ESI): m / z = 480.28 [M+H] + .

[0315] Example 127: N 2 -(2-(1H-benzimidazol-2-yl)ethyl)-N 4 Preparation of -(3,4-dimethoxyphenethyl)-6-(4-(dimethylamino)piperidin-1-yl)-1,3,5-triazine-2,4-diamine (127)

[0316] Following the method of Example 1, aniline was replaced with 3,4-dimethoxyphenethylamine, 3-aminomethylpyridine was replaced with 1H-benzimidazole-2-ethylamine, and 4-methyl-1-piperazineethylamine was replaced with 4-dimethylaminopiperidine to obtain Compound 127. LC-MS (ESI): m / z = 546.33 [M+H] + .

[0317] Example 128: N 2 -(3,4-dimethoxyphenethyl)-N 4 -(2-(4-methylpiperazin-1-yl)ethyl)-N 6 Preparation of -(pyridin-3-ylmethyl)-1,3,5-triazine-2,4,6-triamine (128)

[0318] Following the method of Example 1, aniline was replaced with 3,4-dimethoxyaniline to obtain compound 128. LC-MS (ESI): m / z = 508.31 [M+H] + .

[0319] Example 129: N 2 -(3,4-dimethoxyphenethyl)-6-(4-fluorobenzyl)piperazin-1-yl)-N 4 Preparation of -(pyridin-3-ylmethyl)-1,3,5-triazine-2,4-diamine (129)

[0320] Following the method of Example 1, aniline was replaced with 3,4-dimethoxyphenethylamine, 3-aminomethylpyridine was replaced with 1H-benzimidazole-2-ethylamine, and 4-methyl-1-piperazineethylamine was replaced with 1-(4-fluorobenzyl)piperazine to obtain Compound 129. LC-MS (ESI): m / z = 559.29 [M+H] + .

[0321] Example 130: N 2 -(3,4-dimethoxyphenethyl)-N 4 -(2-(4-methylpiperazin-1-yl)ethyl)-N 6 Preparation of -(4-pyridine)-1,3,5-triazine-2,4,6-triamine (130)

[0322] Following the method of Example 1, aniline was replaced by 3,4-dimethoxyphenethylamine and 3-aminomethylpyridine was replaced by 4-aminopyridine to obtain compound 130. LC-MS (ESI): m / z=494.40 [M+H] + .

[0323] Example 131: N 2 -(3,4-dimethoxyphenethyl)-N 4Preparation of -(2-(4-methylpiperazin-1-yl)ethyl)-6-(3,4,6,7-tetrahydroimidazo[4,5-c]pyridin-5-yl)-1,3,5-triazine-2,4-diamine (131)

[0324] Following the method of Example 1, aniline was replaced by 3,4-dimethoxyphenethylamine and 3-aminomethylpyridine was replaced by 4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridine to obtain compound 131. LC-MS (ESI): m / z = 523.32 [M+H] + .

[0325] Example 132: Preparation of N-(3,4-dimethoxyphenethyl)-4-(4-fluorobenzyl)piperazin-1-yl-6-(3,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridin-5-yl)-1,3,5-triazin-2-amine (132)

[0326] Following the method of Example 1, aniline was replaced with 3,4-dimethoxyphenethylamine, 3-aminomethylpyridine was replaced with 4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridine, and 4-methyl-1-piperazineethylamine was replaced with 1-(4-fluorobenzyl)piperazine to obtain Compound 132. LC-MS (ESI): m / z = 574.30 [M+H] + .

[0327] Example 133: N 2 -(3,4-dimethoxyphenethyl)-N 4 -(2-(dimethylamino)ethyl)-N 6 Preparation of -pyridin-4-ylmethyl-1,3,5-triazine-2,4,6-triamine (133)

[0328] Following the method of Example 1, aniline was replaced by 3,4-dimethoxyphenylethylamine, 3-aminomethylpyridine was replaced by 4-methylaminopyridine, and 4-methyl-1-piperazineethylamine was replaced by N,N-dimethylethylenediamine to obtain compound 133. LC-MS (ESI): m / z = 453.27 [M+H] + .

[0329] Example 134: N 2 -(3,4-dimethoxyphenethyl)-N 4 -(2-(4-methylpiperazin-1-yl)ethyl)-N 6 Preparation of -(4-methylpyridine)-1,3,5-triazine-2,4,6-triamine (134)

[0330] Following the method of Example 1, aniline was replaced by 3,4-dimethoxyphenethylamine and 3-aminomethylpyridine was replaced by 4-methylaminopyridine to obtain compound 134. LC-MS (ESI): m / z = 508.31 [M+H] + .

[0331] Example 135: N 2 -(2-(1H-benzimidazol-2-yl)ethyl)-6-(4-fluorobenzyl)piperazin-1-yl)-N 4 Preparation of 4-tetrahydropyran-1,3,5-triazine-2,4-diamine (135)

[0332] Following the method of Example 1, aniline was replaced by 4-aminotetrahydropyran, 3-aminomethylpyridine was replaced by 4-methylaminopyridine, and 4-methyl-1-piperazineethylamine was replaced by 1-(4-fluorobenzyl)piperazine to obtain Compound 135. LC-MS (ESI): m / z = 532.29 [M+H] + .

[0333] Example 136: N 2 -(pyridin-3-ylmethyl)-N 4 -(2-pyrrolidin-1-yl)ethyl)-N 6 Preparation of -tetrahydropyran-4-yl)-1,3,5-triazine-2,4,6-triamine (136)

[0334] Following the method of Example 1, aniline was replaced by 4-aminotetrahydropyran and 4-methyl-1-piperazineethylamine was replaced by 1-(2-aminoethyl)pyrrolidine to obtain Compound 136. LC-MS (ESI): m / z = 399.26 [M+H] + .

[0335] Example 137: 6-(4-Fluorobenzyl)piperazin-1-yl)-N 2 -(pyridin-3-ylmethyl)-N 4 - Preparation of tetrahydropyran-4-yl-1,3,5-triazine-2,4-diamine (137)

[0336] Following the method of Example 1, aniline was replaced by 4-aminotetrahydropyran and 4-methyl-1-piperazineethylamine was replaced by 1-(4-fluorobenzyl)piperazine to obtain Compound 137. LC-MS (ESI): m / z = 479.27 [M+H] + .

[0337] Example 138: N 2 -(1H-imidazol-2-yl)ethyl)-6-(4-benzylpiperazin-1-yl)-N 4- Preparation of tetrahydropyran-4-yl-1,3,5-triazine-2,4-diamine (138)

[0338] Following the method of Example 1, aniline was replaced by 4-aminotetrahydropyran, 3-aminomethylpyridine was replaced by histamine, and 4-methyl-1-piperazineethylamine was replaced by N-benzylpiperazine to obtain compound 138. LC-MS (ESI): m / z = 464.29 [M+H] + .

[0339] Example 139: N 2 -(1-Benzylpiperidin-4-yl)-N 4 -pyridin-4-yl-N 6 Preparation of 4-tetrahydropyran-1,3,5-triazine-2,4,6-triamine (139)

[0340] Following the method of Example 1, aniline was replaced by 4-aminotetrahydropyran, 3-aminomethylpyridine was replaced by 4-aminopyridine, and 4-methyl-1-piperazineethylamine was replaced by 4-amino-1-benzylpiperidine to obtain Compound 139. LC-MS (ESI): m / z = 461.27 [M+H] + .

[0341] Example 140: N 2 -(2-(4-methylpiperazin-1-yl)ethyl)-N 4 Preparation of 1,3,5-triazine-2,4-diamine (140)

[0342] Following the method of Example 1, aniline was replaced by 4-aminotetrahydropyran and 3-aminomethylpyridine was replaced by 4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridine to obtain compound 140. LC-MS (ESI): m / z = 443.30 [M+H] + .

[0343] Example 141: N 2 -pyridin-2-ylmethyl-N 4 -(2-pyrrolidin-1-yl)ethyl)-N 6 Preparation of 4-tetrahydropyran-1,3,5-triazine-2,4,6-triamine (141)

[0344] Following the method of Example 1, aniline was replaced by 4-aminotetrahydropyran, 3-aminomethylpyridine was replaced by 2-aminomethylpyridine, and 4-methyl-1-piperazineethylamine was replaced by 1-(2-aminoethyl)pyrrolidine to obtain Compound 141. LC-MS (ESI): m / z = 399.26 [M+H]+ .

[0345] Example 142: N 2 -(4-methylpyridine)-N 4 -(2-pyrrolidin-1-yl)ethyl)-N 6 Preparation of -tetrahydropyran-4-yl)-1,3,5-triazine-2,4,6-triamine (142)

[0346] Following the method of Example 1, aniline was replaced by 4-aminotetrahydropyran, 3-aminomethylpyridine was replaced by 4-aminomethylpyridine, and 4-methyl-1-piperazineethylamine was replaced by 1-(2-aminoethyl)pyrrolidine to obtain Compound 141. LC-MS (ESI): m / z = 399.26 [M+H] + .

[0347] Example 143: N 2 -(2-(4-methylpiperazin-1-yl)ethyl)-N 4 -pyridin-4-ylmethyl-N 6 Preparation of tetrahydropyran-4-yl-1,3,5-triazine-2,4,6-triamine (143)

[0348] Following the method of Example 1, aniline was replaced by 4-aminotetrahydropyran and 3-aminomethylpyridine was replaced by 4-aminomethylpyridine to obtain compound 143. LC-MS (ESI): m / z = 428.29 [M+H] + .

[0349] Example 144: N 2 -(2-methylpiperazin-1-yl)ethyl)-N 4 -pyridin-2-yl-N 6 Preparation of tetrahydropyran-4-yl-1,3,5-triazine-2,4,6-triamine (144)

[0350] Following the method of Example 1, aniline was replaced by 4-aminotetrahydropyran and 3-aminomethylpyridine was replaced by 2-aminopyridine to obtain compound 144. LC-MS (ESI): m / z = 414.27 [M+H] + .

[0351] Example 145: N 2 -(2-(1H-benzimidazol-2-yl)ethyl)-N 4 -(2-(4-methylpiperazin-1-yl)ethyl)-N 6 Preparation of -(tetrahydrofuran-3-yl)methyl)-1,3,5-triazine-2,4,6-triamine (145)

[0352] Following the method of Example 1, aniline was replaced by 3-methylamine tetrahydrofuran and 3-aminomethylpyridine was replaced by 1H-benzimidazole-2-ethylamine to obtain compound 145. LC-MS (ESI): m / z = 481.31 [M+H] + .

[0353] Example 146: N 2 -(2-(1H-benzimidazol-2-yl)ethyl)-6-(4-fluorobenzyl)piperazin-1-yl)-N 4 Preparation of -(tetrahydrofuran-3-yl)methyl)-1,3,5-triazine-2,4-diamine (146)

[0354] Following the method of Example 1, aniline was replaced with 3-methylamine tetrahydrofuran, 3-aminomethylpyridine was replaced with 1H-benzimidazole-2-ethylamine, and 4-methyl-1-piperazineethylamine was replaced with 1-(4-fluorobenzyl)piperazine to obtain Compound 146. LC-MS (ESI): m / z = 532.29 [M+H] + .

[0355] Example 147: N 2 -(pyridin-3-ylmethyl)-N 4 -(2-pyrrolidin-1-yl)ethyl)-N 6 Preparation of -(tetrahydrofuran-3-yl)methyl)-1,3,5-triazine-2,4,6-triamine (147)

[0356] Following the method of Example 1, aniline was replaced with 3-methylamine tetrahydrofuran, 3-aminomethylpyridine was replaced with 1H-benzimidazole-2-ethylamine, and 4-methyl-1-piperazineethylamine was replaced with 1-(4-fluorobenzyl)piperazine to obtain Compound 147. LC-MS (ESI): m / z = 399.26 [M+H] + .

[0357] Example 148: N 2 -(2-(4-methylpiperazin-1-yl)ethyl)-N 4 -pyridin-3-ylmethyl-N 6 Preparation of -(tetrahydrofuran-3-yl)methyl)-1,3,5-triazine-2,4,6-triamine (148)

[0358] Following the method of Example 1, aniline was replaced with 3-methylamine tetrahydrofuran to obtain compound 148. LC-MS (ESI): m / z = 428.29 [M+H] + .

[0359] Example 149: N 2 -(1H-imidazol-2-yl)ethyl)-N 4-(2-(dimethylamino)ethyl)-N 6 Preparation of -(tetrahydrofuran-3-yl)methyl)-1,3,5-triazine-2,4,6-triamine (149)

[0360] Following the method of Example 1, aniline was replaced with 3-methylamine tetrahydrofuran, 3-aminomethylpyridine was replaced with histamine, and 4-methyl-1-piperazineethylamine was replaced with N,N-dimethylethylenediamine to obtain Compound 149. LC-MS (ESI): m / z = 376.25 [M+H] + .

[0361] Example 150: N 2 -(1H-imidazol-2-yl)ethyl)-N 4 -(2-(4-methylpiperazin-1-yl)ethyl)-N 6 Preparation of -(tetrahydrofuran-3-yl)methyl)-1,3,5-triazine-2,4,6-triamine (150)

[0362] Following the method of Example 1, aniline was replaced by 3-methylaminetetrahydrofuran and 3-aminomethylpyridine was replaced by histamine to obtain compound 150. LC-MS (ESI): m / z = 431.30 [M+H] + .

[0363] Example 151: N 2 -(2-(4-methylpiperazin-1-yl)ethyl)-N 4 -pyridin-4-yl-N 6 Preparation of -(tetrahydrofuran-3-yl)methyl)-1,3,5-triazine-2,4,6-triamine (151)

[0364] Following the method of Example 1, aniline was replaced by 3-methylamine tetrahydrofuran and 3-aminomethylpyridine was replaced by 4-aminopyridine to obtain compound 151. LC-MS (ESI): m / z = 414.27 [M+H] + .

[0365] Example 152: Preparation of 4-(4-benzylpiperazin-1-yl)-6-(3,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridin-5-yl)-N-(tetrahydrofuran-3-yl)methyl)-1,3,5-triazin-2-amine (152)

[0366] Following the method of Example 1, aniline was replaced with 3-methylamine tetrahydrofuran, 3-aminomethylpyridine was replaced with 4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridine, and 4-methyl-1-piperazineethylamine was replaced with N-benzylpiperazine to obtain Compound 152. LC-MS (ESI): m / z = 476.29 [M+H]+ .

[0367] Example 153: N 2 -(pyridin-2-ylmethyl)-N 4 -(2-pyrrolidin-1-yl)ethyl)-N 6 Preparation of -(tetrahydrofuran-3-yl)methyl)-1,3,5-triazine-2,4,6-triamine (153)

[0368] Following the method of Example 1, aniline was replaced with 3-methylamine tetrahydrofuran, 3-aminomethylpyridine was replaced with 2-aminomethylpyridine, and 4-methyl-1-piperazineethylamine was replaced with 1H-benzimidazole-2-ethylamine to obtain compound 153. LC-MS (ESI): m / z = 399.26 [M+H] + .

[0369] Example 154: N 2 -(2-(1H-benzimidazol-2-yl)ethyl)-N 4 -(2-(4-methylpiperazin-1-yl)ethyl)-N 6 Preparation of -(tetrahydro-2H-pyran-4-yl)methyl)-1,3,5-triazine-2,4,6-triamine (154)

[0370] Following the method of Example 1, aniline was replaced by 4-aminomethyltetrahydropyran and 3-aminomethylpyridine was replaced by 1H-benzimidazole-2-ethylamine to obtain compound 154. LC-MS (ESI): m / z = 495.33 [M+H] + .

[0371] Example 155: N 2 -(2-methylpiperazin-1-yl)ethyl)-N 4 -(pyridin-3-ylmethyl)-N 6 Preparation of -(tetrahydro-2H-pyran-4-yl)methyl)-1,3,5-triazine-2,4,6-triamine (155)

[0372] Following the method of Example 1, aniline was replaced with 3-methylamine tetrahydrofuran to obtain compound 155. LC-MS (ESI): m / z = 442.30 [M+H] + .

[0373] Example 156: N 2 -(1H-imidazol-2-yl)ethyl)-N 4 -(2-(dimethylamino)ethyl)-N 6 Preparation of -(tetrahydro-2H-pyran-4-yl)methyl)-1,3,5-triazine-2,4,6-triamine (156)

[0374] Following the method of Example 1, aniline was replaced by 4-aminomethyltetrahydropyran, 3-aminomethylpyridine was replaced by histamine, and 4-methyl-1-piperazineethylamine was replaced by N,N-dimethylethylenediamine to obtain compound 156. LC-MS (ESI): m / z = 390.27 [M+H] + .

[0375] Example 157: N 2 -(3-(4-methylpiperazin-1-yl)propyl)-N 4 -pyridin-4-yl-N 6 Preparation of -(tetrahydro-2H-pyran-4-yl)methyl)-1,3,5-triazine-2,4,6-triamine (157)

[0376] Following the method of Example 1, aniline was replaced by 4-aminomethyltetrahydropyran, 3-aminomethylpyridine was replaced by 4-aminopyridine, and 4-methyl-1-piperazineethylamine was replaced by 4-methylaminopyridine to obtain Compound 157. LC-MS (ESI): m / z = 442.30 [M+H] + .

[0377] Example 158: N 2 -(2-dimethylamino)ethyl-N 4 Preparation of 6-(tetrahydro-2H-pyran-4-yl)methyl)-6-3,4,6,7-tetrahydroimidazo[4,5-c]pyridin-5-yl)-1,3,5-triazine-2,4-diamine (158)

[0378] Following the method of Example 1, aniline was replaced by 4-aminomethyltetrahydropyran, 3-aminomethylpyridine was replaced by 4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridine, and 4-methyl-1-piperazineethylamine was replaced by N,N-dimethylethylenediamine to obtain Compound 158. LC-MS (ESI): m / z = 402.27 [M+H] + .

[0379] Example 159: N 2 -pyridin-2-ylmethyl-N 4 -(2-pyrrolidin-1-yl)ethyl)-N 6 Preparation of -(tetrahydro-2H-pyran-4-yl)methyl)-1,3,5-triazine-2,4,6-triamine (159)

[0380] Following the method of Example 1, aniline was replaced by 4-aminomethyltetrahydropyran, 3-aminomethylpyridine was replaced by 2-aminomethylpyridine, and 4-methyl-1-piperazineethylamine was replaced by 1H-benzimidazole-2-ethylamine to obtain compound 159. LC-MS (ESI): m / z = 413.27 [M+H]+ .

[0381] Example 160: N 2 -(2-methylpiperazin-1-yl)ethyl)-N 4 -pyridin-2-yl-N 6 Preparation of -(tetrahydro-2H-pyran-4-yl)methyl)-1,3,5-triazine-2,4,6-triamine (160)

[0382] Following the method of Example 1, aniline was replaced by 4-aminomethyltetrahydropyran and 3-aminomethylpyridine was replaced by 2-aminopyridine to obtain compound 160. LC-MS (ESI): m / z = 428.29 [M+H] + .

[0383] Example 161: Preparation of (S)-methyl 2-((4-(4-(4-fluorobenzyl)piperazin-1-yl)-6-morpholin-1,3,5-triazin-2-yl)amino)-2-(1H-imidazol-5-yl)acetate (161)

[0384] Following the method of Example 1, aniline was replaced by morpholine, 3-aminomethylpyridine was replaced by L-histidine methyl ester, and 4-methyl-1-piperazineethylamine was replaced by 1-(4-fluorobenzyl)piperazine to obtain Compound 161. LC-MS (ESI): m / z = 512.25 [M+H] + .

[0385] Example 162: N 2 -(2-(1H-benzimidazol-2-yl)ethyl)-N 4 Preparation of -(2-(4-methylpiperazin-1-yl)ethyl)-6-morpholino-1,3,5-triazine-2,4-diamine (162)

[0386] Following the method of Example 1, aniline was replaced by morpholine and 3-aminomethylpyridine was replaced by 1H-benzimidazole-2-ethylamine to obtain compound 162. LC-MS (ESI): m / z = 467.30 [M+H] + .

[0387] Example 163: 6-morpholinyl-N 2 -(pyridin-3-ylmethyl)-N 4 Preparation of 1,3,5-triazine-2,4-diamine (163)

[0388] Following the method of Example 1, morpholine was substituted for aniline and 1-(2-aminoethyl)pyrrolidine was substituted for 4-methyl-1-piperazineethylamine to obtain Compound 163. LC-MS (ESI): m / z = 385.25 [M+H]+ .

[0389] Example 164: N 2 -(2-(4-methylpiperazin-1-yl)ethyl)-6-morpholinyl-N 4 Preparation of -(pyridin-3-ylmethyl)-1,3,5-triazine-2,4-diamine (164)

[0390] Following the method of Example 1, aniline was replaced with morpholine to obtain compound 164. LC-MS (ESI): m / z = 414.27 [M+H] + .

[0391] Example 165: Preparation of N-(2-(1H-imidazol-2-yl)ethyl)-4-(4-fluorobenzyl)piperazin-1-yl)-6-morpholinyl-1,3,5-triazin-2-amine (165)

[0392] Following the method of Example 1, Compound 165 was obtained by replacing aniline with morpholine, 3-aminomethylpyridine with histamine, and 4-methyl-1-piperazineethylamine with 1-(4-fluorobenzyl)piperazine. LC-MS (ESI): m / z = 428.26 [M+H] + .

[0393] Example 166: N 2 -(2-(dimethylamino)ethyl)-6-morpholinyl-N 4 Preparation of -(pyridin-4-yl)-1,3,5-triazine-2,4-diamine (166)

[0394] Following the method of Example 1, aniline was replaced by morpholine, 3-aminomethylpyridine was replaced by 4-aminopyridine, and 4-methyl-1-piperazineethylamine was replaced by N,N-dimethylethylenediamine to obtain Compound 166. LC-MS (ESI): m / z = 345.21 [M+H] + .

[0395] Example 167: N-(2-(4-methylpiperazin-1-yl)ethyl)-5-morpholinyl-N 3 Preparation of 4-pyridin-1,3-diamine (167)

[0396] Following the method of Example 1, aniline was replaced by morpholine and 3-aminomethylpyridine was replaced by 4-aminopyridine to obtain Compound 166. LC-MS (ESI): m / z = 397.27 [M+H] + .

[0397] Example 168: Preparation of N-(2-(4-methylpiperazin-1-yl)ethyl)-4-morpholinyl-6-(3,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridin-5-yl)-1,3,5-triazin-2-amine (168)

[0398] Following the method of Example 1, aniline was replaced by morpholine and 3-aminomethylpyridine was replaced by 4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridine to obtain compound 168. LC-MS (ESI): m / z = 429.28 [M+H] + .

[0399] Example 169: 6-morpholinyl-N 2 -(pyridin-2-ylmethyl)-N 4 Preparation of 1,3,5-triazine-2,4-diamine (169)

[0400] Following the method of Example 1, morpholine was substituted for aniline, 2-aminomethylpyridine for 3-aminomethylpyridine, and 1H-benzimidazole-2-ethylamine for 4-methyl-1-piperazineethylamine to obtain Compound 169. LC-MS (ESI): m / z = 385.24 [M+H] + .

[0401] Example 170: N 2 -(2-(dimethylamino)ethyl)-6-morpholinyl-N 4 Preparation of -(pyridin-4-ylmethyl)-1,3,5-triazine-2,4-diamine (170)

[0402] Following the method of Example 1, aniline was replaced by morpholine, 3-aminomethylpyridine was replaced by 4-methylaminopyridine, and 4-methyl-1-piperazineethylamine was replaced by N,N-dimethylethylenediamine to obtain Compound 170. LC-MS (ESI): m / z = 359.22 [M+H] + .

[0403] Example 171: N 2 -(2-(4-methylpiperazin-1-yl)ethyl)-6-morpholinyl-N 4 - Preparation of pyridin-4-ylmethyl-1,3,5-triazine-2,4-diamine (171)

[0404] Following the method of Example 1, aniline was replaced by morpholine and 3-aminomethylpyridine was replaced by 4-methylaminopyridine to obtain compound 171. LC-MS (ESI): m / z = 414.27 [M+H] + .

[0405] Example 172: N2 -(2-(4-methylpiperazin-1-yl)ethyl)-6-morpholinyl-N 4 Preparation of pyridin-2-yl-1,3,5-triazine-2,4-diamine (172)

[0406] Following the method of Example 1, aniline was replaced by morpholine and 3-aminomethylpyridine was replaced by 2-aminopyridine to obtain compound 172. LC-MS (ESI): m / z = 400.50 [M+H] + .

[0407] Example 173: Preparation of (S)-methyl 2-((4-(bis(2-methoxyethyl)amino)-6-(4-(4-fluorobenzyl)piperazin-1-yl)-1,3,5-triazin-2-yl)amino)-2-(1H-imidazol-5-yl)acetate (173)

[0408] Following the procedure of Example 1, compound 173 was obtained by replacing aniline with bis(2-methoxyethyl)amine, 3-aminomethylpyridine with L-histidine methyl ester, and 4-methyl-1-piperazineethylamine with 1-(4-fluorobenzyl)piperazine. LC-MS (ESI): m / z = 558.29 [M+H] + .

[0409] Example 174: N 2 -(2-(1H-benzimidazol-2-yl)ethyl)-6-(4-fluorobenzyl)piperazin-1-yl)-N 4 ,N 4 Preparation of bis(2-methoxyethyl)-1,3,5-triazine-2,4-diamine (174)

[0410] Following the method of Example 1, aniline was replaced with bis(2-methoxyethyl)amine, 3-aminomethylpyridine was replaced with 1H-benzimidazole-2-ethylamine, and 4-methyl-1-piperazineethylamine was replaced with 1-(4-fluorobenzyl)piperazine to obtain Compound 174. LC-MS (ESI): m / z = 564.31 [M+H] + .

[0411] Example 175: N 2 ,N 2 -bis(2-methoxyethyl)-N 4 -pyridin-3-ylmethyl-N 6 Preparation of -(2-(pyrrolidin-1-yl)ethyl)-1,3,5-triazine-2,4,6-triamine (175)

[0412] Following the method of Example 1, aniline was replaced by bis(2-methoxyethyl)amine and 4-methyl-1-piperazineethylamine was replaced by 1H-benzimidazole-2-ethylamine to obtain Compound 175. LC-MS (ESI): m / z = 431.28 [M+H] + .

[0413] Example 176: N 2 ,N 2 -bis(2-methoxyethyl)-N 4 -(2-(4-methylpiperazin-1-yl)ethyl)-N 6 Preparation of -(pyridin-3-ylmethyl)-1,3,5-triazine-2,4,6-triamine (176)

[0414] Following the method of Example 1, aniline was replaced with bis(2-methoxyethyl)amine to obtain Compound 176. LC-MS (ESI): m / z = 460.31 [M+H] + .

[0415] Example 177: N 2 -(2-(1H-imidazol-2-yl)ethyl)-6-(4-fluorobenzyl)piperazin-1-yl)-N 4 ,N 4 Preparation of bis(2-methoxyethyl)-1,3,5-triazine-2,4-diamine (177)

[0416] Following the method of Example 1, aniline was replaced by bis(2-methoxyethyl)amine, 3-aminomethylpyridine was replaced by histamine, and 4-methyl-1-piperazineethylamine was replaced by 1-(4-fluorobenzyl)piperazine to obtain Compound 177. LC-MS (ESI): m / z = 514.30 [M+H] + .

[0417] Example 178: N 2 ,N 2 -bis(2-methoxyethyl)-N 4 -(3-(4-methylpiperazin-1-yl)propyl)-N 6 Preparation of pyridin-4-yl-1,3,5-triazine-2,4,6-triamine (178)

[0418] Following the procedure of Example 1, compound 178 was obtained by replacing aniline with bis(2-methoxyethyl)amine, 3-aminomethylpyridine with 4-aminopyridine, and 4-methyl-1-piperazineethylamine with 1-(3-aminopropyl)-4-methylpiperazine. LC-MS (ESI): m / z = 460.31 [M+H] + .

[0419] Example 179: 6-(4-(dimethylamino)piperidin-1-yl)-N 2 ,N 2 -bis(2-methoxyethyl)-N 4 Preparation of -(4-pyridyl)-1,3,5-triazine-2,4-diamine (179)

[0420] Following the method of Example 1, aniline was replaced by bis(2-methoxyethyl)amine, 3-aminomethylpyridine was replaced by 4-aminopyridine, and 4-methyl-1-piperazineethylamine was replaced by 4-dimethylaminopiperidine to obtain Compound 179. LC-MS (ESI): m / z = 431.28 [M+H] + .

[0421] Example 180: Preparation of 4-(4-fluorobenzyl)piperazin-1-yl)-N,N-bis(2-methoxyethyl)-6-3,4,6,7-tetrahydroimidazo[4,5-c]pyridin-5-yl)-1,3,5-triazin-2-amine (180)

[0422] Following the method of Example 1, aniline was replaced with bis(2-methoxyethyl)amine, 3-aminomethylpyridine was replaced with 4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridine, and 4-methyl-1-piperazineethylamine was replaced with 1-(4-fluorobenzyl)piperazine to obtain Compound 180. LC-MS (ESI): m / z = 526.30 [M+H] + .

[0423] Example 181: N 2 ,N 2 -bis(2-methoxyethyl)-N 4 -pyridin-2-ylmethyl-N 6 Preparation of -(2-(pyrrolidin-1-yl)ethyl)-1,3,5-triazine-2,4,6-triamine (181)

[0424] Following the method of Example 1, aniline was replaced with bis(2-methoxyethyl)amine, 3-aminomethylpyridine was replaced with 2-aminomethylpyridine, and 4-methyl-1-piperazineethylamine was replaced with 1H-benzimidazole-2-ethylamine to obtain Compound 181. LC-MS (ESI): m / z = 431.28 [M+H] + .

[0425] Example 182: N 2 ,N 2 -bis(2-methoxyethyl)-N 4 -(2-(4-methylpiperazin-1-yl)ethyl)-N 6 Preparation of -(4-methylpyridine)-1,3,5-triazine-2,4,6-triamine (182)

[0426] Following the method of Example 1, aniline was replaced by bis(2-methoxyethyl)amine and 3-aminomethylpyridine was replaced by 4-methylaminopyridine to obtain compound 182. LC-MS (ESI): m / z = 460.30 [M+H] + .

[0427] Example 183: N 2 ,N 2 -bis(2-methoxyethyl)-N 4 -pyridin-2-yl-N 6 Preparation of 1,3,5-triazine-2,4,6-triamine (183)

[0428] Following the method of Example 1, aniline was replaced with bis(2-methoxyethyl)amine, 3-aminomethylpyridine was replaced with 2-aminopyridine, and 4-methyl-1-piperazineethylamine was replaced with 1H-benzimidazole-2-ethylamine to obtain Compound 183. LC-MS (ESI): m / z = 417.29 [M+H] + .

[0429] Example 184: N 2 ,N 2 -bis(2-methoxyethyl)-N 4 -(2-(4-methylpiperazin-1-yl)ethyl)-N 6 - Preparation of pyridin-2-yl-1,3,5-triazine-2,4,6-triamine (184)

[0430] Following the method of Example 1, aniline was replaced by bis(2-methoxyethyl)amine and 3-aminomethylpyridine was replaced by 2-aminopyridine to obtain compound 184. LC-MS (ESI): m / z = 446.29 [M+H] + .

[0431] Example 185: Preparation of (S)-methyl 2-((4-(4-benzylpiperazin-1-yl)-6-((4-morpholinophenyl)amino)-1,3,5-triazin-2-yl)amino)-2-(1H-imidazol-5-yl)acetate (185)

[0432] Following the method of Example 1, compound 185 was obtained by replacing aniline with 4-(4-morpholinyl)aniline, 3-aminomethylpyridine with L-histidine methyl ester, and 4-methyl-1-piperazineethylamine with N-benzylpiperazine. LC-MS (ESI): m / z = 585.30 [M+H] + .

[0433] Example 186: N 2-(2-(1H-benzimidazol-2-yl)ethyl)-6-(4-fluorobenzyl)piperazin-1-yl)-N 4 Preparation of -(4-morpholinylphenyl)-1,3,5-triazine-2,4-diamine (186)

[0434] Following the procedure of Example 1, Compound 186 was obtained by replacing aniline with 4-(4-morpholinyl)aniline, 3-aminomethylpyridine with 1H-benzimidazole-2-ethylamine, and 4-methyl-1-piperazineethylamine with 1-(4-fluorobenzyl)piperazine. LC-MS (ESI): m / z = 609.32 [M+H] + .

[0435] Example 187: 6-(4-Fluorobenzyl)piperazin-1-yl)-N 2 -(4-morpholinylphenyl)-N 4 Preparation of pyridin-3-ylmethyl-1,3,5-triazine-2,4-diamine (187)

[0436] Following the method of Example 1, aniline was replaced by 4-(4-morpholinyl)aniline and 4-methyl-1-piperazineethylamine was replaced by 1-(4-fluorobenzyl)piperazine to obtain Compound 187. LC-MS (ESI): m / z = 556.29 [M+H] + .

[0437] Example 188: Preparation of 2-(4-(4-(2-(1H-imidazole-2-ethyl)amino)-6-(4-morpholinylphenyl)amino)-1,3,5-triazin-2-yl)piperazin-1-yl)ethyl-1-ol (188)

[0438] Following the method of Example 1, aniline was replaced by 4-(4-morpholinyl)aniline, 3-aminomethylpyridine was replaced by histamine, and 4-methyl-1-piperazineethylamine was replaced by N-hydroxyethylpiperazine to obtain Compound 188. LC-MS (ESI): m / z = 495.29 [M+H] + .

[0439] Example 189: N 2 -(2-(4-methylpiperazin-1-yl)ethyl)-N 4 -(4-morpholinylphenyl)N 6 Preparation of -(4-pyridyl)-1,3,5-triazine-2,4,6-triamine (189)

[0440] Following the method of Example 1, aniline was replaced by 4-(4-morpholinyl)aniline and 3-aminomethylpyridine was replaced by 4-aminopyridine to obtain Compound 189. LC-MS (ESI): m / z = 491.29 [M+H] + .

[0441] Example 190: 6-(4-Methylpiperazin-1-yl)-N 2 -(4-morpholinylphenyl)-N 4 Preparation of pyridin-4-yl-1,3,5-triazine-2,4-diamine (190)

[0442] Following the method of Example 1, aniline was replaced by 4-(4-morpholinyl)aniline, 3-aminomethylpyridine was replaced by 4-aminopyridine, and 4-methyl-1-piperazineethylamine was replaced by N-methylpiperazine to obtain Compound 190. LC-MS (ESI): m / z = 448.25 [M+H] + .

[0443] Example 191: Preparation of 4-(4-methylpiperazin-1-yl)-N-(4-morpholinylphenyl)-6-(3,4,6,7-tetrahydro)-5H-imidazo[4,5-c]pyridin-5-yl)-1,3,5-triazin-2-amine (191)

[0444] Following the method of Example 1, compound 191 was obtained by replacing aniline with 4-(4-morpholinyl)aniline, 3-aminomethylpyridine with 4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridine, and 4-methyl-1-piperazineethylamine with N-methylpiperazine. LC-MS (ESI): m / z = 477.28 [M+H] + .

[0445] Example 192: N 2 -(2-(4-methylpiperazin-1-yl)ethyl)-N 4 -(4-morpholinylphenyl)-N 6 Preparation of -pyridin-2-ylmethyl-1,3,5-triazine-2,4,6-triamine (192)

[0446] Following the method of Example 1, aniline was replaced by 4-(4-morpholinyl)aniline and 3-aminomethylpyridine was replaced by 2-aminomethylpyridine to obtain Compound 192. LC-MS (ESI): m / z = 505.31 [M+H] + .

[0447] Example 193: 6-(4-Fluorobenzyl)piperazin-1-yl)-N 2 -(4-morpholinylphenyl)-N 4 Preparation of pyridin-2-ylmethyl-1,3,5-triazine-2,4-diamine (193)

[0448] Following the method of Example 1, compound 193 was obtained by replacing aniline with 4-(4-morpholinyl)aniline, 3-aminomethylpyridine with 2-aminomethylpyridine, and 4-methyl-1-piperazineethylamine with 1-(4-fluorobenzyl)piperazine. LC-MS (ESI): m / z = 556.29 [M+H] + .

[0449] Example 194: N 2 -(4-morpholinylphenyl)-N 4 -pyridin-4-ylmethyl-N 6 Preparation of 1,3,5-triazine-2,4,6-triamine (194)

[0450] Following the method of Example 1, compound 194 was obtained by replacing aniline with 4-(4-morpholinyl)aniline, 3-aminomethylpyridine with 4-methylaminopyridine, and 4-methyl-1-piperazineethylamine with 1-(2-aminoethyl)pyrrolidine. LC-MS (ESI): m / z = 476.28 [M+H] + .

[0451] Example 195: N 2 -(2-(4-methylpiperazin-1-yl)ethyl)-N 4 -(4-morpholinylphenyl)-N 6 Preparation of -pyridin-2-ylpyridine-1,3,5-triazine-2,4,6-triamine (195)

[0452] Following the method of Example 1, aniline was replaced by 4-(4-morpholinyl)aniline and 3-aminomethylpyridine was replaced by 2-aminopyridine to obtain Compound 195. LC-MS (ESI): m / z = 491.30 [M+H] + .

[0453] Example 196: 6-(4-Fluorobenzyl)piperazin-1-yl)-N 2 -(4-morpholinylphenyl)-N 4 Preparation of pyridin-2-yl-1,3,5-triazine-2,4-diamine (196)

[0454] Following the method of Example 1, compound 196 was obtained by replacing aniline with 4-(4-morpholinyl)aniline, 3-aminomethylpyridine with 2-aminopyridine, and 4-methyl-1-piperazineethylamine with 1-(4-fluorobenzyl)piperazine. LC-MS (ESI): m / z = 542.28 [M+H] + .

[0455] Example 197 Qualitative Test of In Vitro Binding Ability of Small Molecule Reversal Agents to Heparin Sodium

[0456] DLS (dynamic light scattering) was used to qualitatively evaluate the binding ability of small molecule reversal agents to heparin sodium in water.

[0457] Experimental principle: The particle size of the compound is 1-10nm, and the particle size of heparin sodium is 1-10nm. 化合物 :m 肝素 =1:1 mixing, if polymer is formed, the particle size increases to about 100nm.

[0458] Experimental instruments: Zetasizer Nano ZS nanoparticle size potentiometer (Malvern Instruments Ltd., UK); particle size sample cell (from Malvern Instruments Ltd., UK, model: DTS0012); potentiometric sample cell (Malvern Instruments Ltd., UK, model: DTS1070).

[0459] Experimental materials: Low molecular weight heparin (LMWH) selected from enoxaparin sodium injection (hereinafter referred to as enoxaparin solution), from Sanofi-Aventis (40 mg: 4000AXa IU, product number CS543A); tris (hydroxymethylaminomethane) (Tris), from GBCBIO (product number G3470); compounds 1-196.

[0460] Experimental Procedure: Before each use, rinse the particle size or potentiometric cell three times with distilled water and rinse the cell with the sample to be tested. To determine the particle size of the complex, dilute a 100 mg / mL enoxaparin solution to 0.1 mg / mL with distilled water. Prepare the test compound with distilled water to concentrations of 0.1, 1, and 10 mg / mL. Mix the diluted enoxaparin solution with the test compound or reference in Tris-HCl buffer (pH 7.4) to prepare the sample for size measurement. After each preparation, allow the sample to equilibrate for 2 minutes. Perform each measurement in triplicate, and measure all titration points in duplicate.

[0461] The experimental results are shown in Table 2. The triazine compounds of the present invention have binding activity with heparin sodium in vitro.

[0462] Table 2. Evaluation of compound DLS's ability to bind to heparin sodium in vitro

[0463] Note: √ indicates that the compound forms a polymer with heparin sodium, * indicates that the compound forms a polymer with heparin sodium and the instrument analysis report result is excellent.

[0464] Example 198 Quantitative Competitive Binding Test of Small Molecule Triazine Compounds and Azure A to Heparin Sodium

[0465] The cationic dye Azure A colorimetric method was used to quantitatively assess the ability of small molecule heparin reversal agents to bind to enoxaparin.

[0466] Experimental Principle: Azure A (absorption peaks at 590nm / 630nm) is a cationic dye, and heparin sodium is a strongly negatively charged polysaccharide. Heparin sodium and Azure A reversibly bind through electrostatic neutralization to form a complex (absorption peak at 520nm). Small molecule reversal agents compete with heparin sodium for Azure A, restoring the Azure A absorption peak to varying degrees while reducing the absorption peak of the complex.

[0467] Experimental instrument: SpectraMax iD3 microplate reader.

[0468] Experimental materials: protamine sulfate, from TCI (product number P0675); Ciraparantag, from Peptidejia Biopharmaceuticals; low molecular weight heparin selected from enoxaparin sodium injection, from Sanofi-Aventis (40 mg: 4000AXa IU, product number CS543A); Azure A, from Shanghai MacLean Biochemical Technology Co., Ltd. (product number C14252971); triazine compounds synthesized by the present invention.

[0469] Experimental Procedure: Resuspend the enoxaparin solution and Azure A in distilled water at a mass ratio of 1:2, then vortex in a centrifuge tube to prepare an enoxaparin-Azure A mixed solution. The ability of triazine compounds to reverse the competitive binding of Azure A to enoxaparin sodium was evaluated by the absorbance ratio at λ (630 nm) / λ (520 nm) at 20°C. Each compound was assayed in triplicate.

[0470] Experimental results: Table 3 shows the reversal percentage of competitive binding of triazine compounds to heparin sodium. As shown in Table 3, all the tested triazine compounds can reverse the binding of Azure A to heparin to varying degrees in vitro, and have the ability to reverse the activity of heparin.

[0471] Table 3. Quantitative test results of competitive binding of triazine compounds and Azure A to heparin sodium

[0472] Example 199 In vitro cytotoxicity test of triazine compounds (HUVEC)

[0473] When cells are stimulated, their potential may change based on their resting potential. The metabolic transport of cationic compounds in the body needs to take into account changes in the surface potential of human cells and cytotoxicity. In addition, the anti-angiogenic activity of heparin may have different effects on the structure and mechanical properties of fibrin, and cationic compounds targeting heparin may have the same effect. The experimental steps for testing cytotoxicity are as follows:

[0474] Experimental instruments: clean bench (THermo); electronic balance (METTLER TOLEDO AL104); centrifuge (Dalong Xingchuang Laboratory Instrument DM0412); cell counter (THermo Countess3 automatic cell counter); CO2 incubator (THermo); microplate reader (SpectraMax iD3).

[0475] Experimental materials: human umbilical vein endothelial cells (HUVEC, from the American Type Culture Collection); DMEM medium, fetal bovine serum (Gibco); trypsin (Amresco); DMSO (Sigma product number D1435)

[0476] 1. HUVECs were seeded in DMEM + 10% FBS complete medium and cultured at 37°C, 5% CO2, and 95% humidity to allow them to adhere to the wall.

[0477] 2. Experimental Methods: HUVEC in logarithmic growth were trypsinized and centrifuged to obtain a cell pellet. Fresh medium was added to resuspend the pellet, and the cells were counted by trypan blue staining. The cells were diluted to the appropriate concentration and 50 μL of the cell suspension was seeded into a 96-well plate at 4000 cells / well. The 96-well plate was placed in a CO2 incubator and incubated overnight. The stock solutions of the test compounds were prepared. All compounds (triazine compounds, Ciraparantag, protamine sulfate) were prepared with ultrapure water to a concentration of 5 mg / mL. 5% DMSO was used as a solubilizer, stored at -80°C, and aliquoted for use. According to the required working concentration, the compound stock solution was diluted with culture medium to the appropriate concentration, so that the final test concentration was 50 μg / mL. 50 μL of the test compound solution was added to a 96-well plate, and triplicate wells were set for each test compound. The 96-well plate was placed in a CO2 incubator and incubated for 1 day to allow the cells to adhere and grow. 20 μL of 5 mg / mL MTT reagent was added to each well. After incubation for 4 hours, 150 μL of DMSO was added to each well and mixed and shaken for 5 minutes. The absorbance was read at 580 nm using a microplate reader, and the cell growth inhibition efficiency was calculated.

[0478] Cell viability (%) = (OD 待测药 -OD 培养液对照 ) / (OD 细胞对照 -OD 培养液对照 )×100%

[0479] OD 待测药 : absorbance of triazine compound, Ciraparantag or protamine sulfate at 580 nm;

[0480] OD 培养液对照 : Absorbance of blank control group with only culture medium added at 580 nm;

[0481] OD 细胞对照 : Absorbance at 580 nm of the control group supplemented with culture medium and cells.

[0482] Experimental results: As shown in Table 4, the triazine compounds have no HUVEC toxicity (inhibition rate ≤ 30%), indicating that the triazine compounds of the present invention are good heparin reversal agents and have certain safety.

[0483] Table 4. In vitro toxicity test results of triazine compounds on HUVEC

[0484] Example 200 Hemolytic Toxicity Test of Triazine Compounds

[0485] After intravenous injection, the drug comes into direct contact with blood tissue, and cationic compounds have the potential to directly induce erythrocyte rupture (i.e., hemolysis). The ability of cationic compounds to induce erythrocyte hemolysis is one of the most important and frequently studied biocompatibility tests.

[0486] Experimental instruments: electronic balance (METTLER TOLEDO AL104); centrifuge (Titan DMC-12K); microplate reader (SpectraMax iD3).

[0487] Experimental Materials: PBS buffer (Biyuntian Biotechnology Co., Ltd., product number C0221A). Fresh blood was collected from human volunteers and immediately placed in a blue sodium citrate coagulation test tube after venous blood collection and stored at 4°C.

[0488] Experimental Method: Based on the desired working concentration, the compound was prepared into a 2.5 mg / mL solution using PBS buffer. The compound solution or control (the absorbance of a 100% hemolyzed sample in ultrapure water was used as a positive control, and the absorbance in PBS was used as a negative control) and fresh blood sample were added to a centrifuge tube at a volume ratio of 9:1. The tubes were inverted to mix thoroughly. Three replicates were performed for each test compound. The mixed samples were incubated at 37°C for 1 hour, then centrifuged at 3500 rpm for 15 minutes. The supernatant was aspirated and the absorbance at 575 nm was measured using a microplate reader to calculate the hemolysis rate.

[0489] Hemolysis rate (%) = (OD 待测药 -OD PBS对照 ) / (OD 超纯水对照 -OD PBS对照 )×100%

[0490] OD 待测药 : The absorbance value of the sample to be tested at 575nm.

[0491] OD PBS对照: Absorbance value of negative control well at 575 nm.

[0492] OD 超纯水对照 : Absorbance value of positive control well at 575 nm.

[0493] Experimental Results: Table 5 presents the hemolytic toxicity data of triazine compounds. The results demonstrate that the triazine compounds of the present invention exhibit no hemolytic toxicity (hemolysis rate ≤ 5%) at an extremely high concentration of 2.5 mg / mL, demonstrating a good safety profile. In contrast, the positive control, protamine, exhibited significant hemotoxicity at high concentrations. Protamine's hemolytic toxicity is one of its key toxicity characteristics. These experimental data are consistent with literature reports and clinical data. The triazine compounds of the present invention exhibit no hemolytic toxicity and meet the requirements for intravenous injection materials.

[0494] Table 5. Hemolytic toxicity test results of triazine compounds

[0495] Example 201 Coagulation Factor Activity Test (Anti-Xa Factor Test)

[0496] Enoxaparin primarily produces its anticoagulant effect through an antithrombin-heparin-coagulation factor Xa ternary complex, formed through an antithrombin-heparin-coagulation factor Xa mechanism. The anti-Xa assay is an enzymatic activity test used in clinical and scientific research to assess a compound's ability to reverse heparin.

[0497] Experimental instruments: electronic balance (METTLER TOLEDO AL104); microplate reader (SpectraMax iD3).

[0498] Experimental materials: BiopHen Heparin Anti-Xa kit (HYPHEN BioMed); Tris (Beyond the Sky Biotechnology Co., Ltd., product number ST761); citric acid (Anaiji Anhui Zesheng Technology Co., Ltd., product number E011084); protamine sulfate (TCI, product number P0675); enoxaparin (Sanofi, product number CS543A).

[0499] Experimental methods:

[0500] Reconstitute the kit: Dilute the sample to be tested and reconstitute the kit according to the instructions of the BiopHen Heparin Anti-Xa kit. Remove the freeze-dried antithrombin, coagulation factor Xa, and coagulation factor Xa specific chromogenic substrate from the kit and add Tris-NaCl Reconstitution was performed at pH 7.4. The compound was incubated with enoxaparin in ultrapure water at a mass ratio of 2:1 at 37°C for 10 minutes. Samples were then diluted to the appropriate concentration. Ultrapure water served as the heparin-free control sample, and an enoxaparin solution of appropriate concentration diluted with ultrapure water served as the heparin control. 40 μL of each reconstituted sample was added to a 96-well plate, with triplicate wells set up for each test compound. First, 40 μL of antithrombin was added to each well, mixed by vortexing, and incubated at 37°C for 2 minutes. Then, 40 μL of coagulation factor Xa was added to each well, mixed by vortexing, and incubated at 37°C for 2 minutes. Then, 40 μL of a specific chromogenic substrate for coagulation factor Xa was added to each well, mixed by vortexing, and incubated at 37°C for exactly 2 minutes. Finally, 80 μL of 2% citric acid solution was added to each well, mixed by vortexing, and the absorbance at 405 nm was immediately read using a microplate reader. The neutralization activity of triazine compounds against enoxaparin was expressed as the neutralization rate.

[0501] Neutralization rate (%) = (OD 待测药 -OD 肝素对照 ) / (OD 无肝素对照 -OD 肝素对照 )×100%

[0502] OD 待测药 : Absorbance value of the sample to be tested at 405nm.

[0503] OD 肝素对照 : Absorbance of heparin control wells at 405 nm.

[0504] OD 无肝素对照 : Absorbance of heparin control wells at 405 nm.

[0505] Experimental Results: As shown in Table 6, all triazine compounds of the present invention exhibit anti-Xa activity and can reverse the anticoagulant activity of enoxaparin. Literature reports indicate that the positive control, protamine, can only partially reverse Factor Xa activity in response to low molecular weight heparin, a factor that limits its clinical application. Ciraparantag's inherent chelation with buffer salts in solutions makes it unsuitable for anti-Xa testing. However, the anti-Xa activity of the 22 triazine compounds of the present invention was superior to that of protamine sulfate. Compounds 194, 131, 195, 61, and 145 exhibited anti-Xa neutralization activity exceeding 70%, demonstrating potent heparin reversal activity.

[0506] Table 6. Coagulation factor activity test results of triazine compounds

[0507] Example 202 Mouse tail docking experiment

[0508] Tail docking in mice after high-dose heparin injection can prolong bleeding time and increase blood loss. After intravenous heparin injection, the use of a heparin reversal agent can restore bleeding time and blood loss. The specific experimental steps are as follows:

[0509] C57 female mice weighing 18-20 g were randomly divided into two groups: blank control group (NS): normal saline was injected into the tail vein, and normal saline was injected into the tail vein 5 minutes later, and the mice were immediately anesthetized with 2.5% avertin by intraperitoneal injection; enoxaparin group (LMWH): 3 mg / kg enoxaparin (prepared in normal saline) was injected into the tail vein, and normal saline was injected into the tail vein 5 minutes later, and the mice were immediately anesthetized with 2.5% avertin by intraperitoneal injection; experimental group: 3 mg / kg enoxaparin (prepared in normal saline) was injected into the tail vein, and 4.5 mg / kg reversal agent (compounds 61, 131, 145, 154, 194, 195, Ciraparantag, all prepared in normal saline) was injected into the tail vein 5 minutes later, and the mice were immediately anesthetized with 2.5% avertin by intraperitoneal injection. Ten minutes after the reversal agent was injected into the tail vein, the mouse tail was transected at a diameter of 2.5 mm. The tail was immediately immersed in a centrifuge tube containing 15 mL of 37°C saline to collect blood from the wound. The blood loss observation window was 20 minutes. At the end of the experiment, the tail was cauterized to stop bleeding.

[0510] The results of the in vivo heparin reversal experiment of the triazine compounds of the present invention in mice are shown in Table 7. The tested triazine compounds and Ciraparantag significantly reversed the bleeding time and blood loss caused by heparin to the baseline.

[0511] Table 7. Results of the mouse tail-cutting test on triazine compounds

[0512] Acute toxicity test of compound in Example 203 in female mice

[0513] C57 female mice weighing 18-20 g were randomly divided into groups and each group received a tail vein injection of the corresponding compound (prepared in saline) or saline. The mice's activity status and other parameters were regularly observed after injection. Twenty-four hours after tail vein injection, the mice were dissected and the status of various organs (lungs and kidneys) was observed and recorded. The results of in vivo acute toxicity studies for some compounds (Compounds 61, 145, and 154) are shown in Table 8. Tail vein injection of the triazine compounds of the present invention had no effect on the normal activity of mice 24 hours after injection. Following tail vein injection of triazine compounds, a few mice developed lung symptoms such as edema, discoloration, and dark plaques. Following tail vein injection of Ciraparantag, a few mice developed lung symptoms. Twenty-four hours after tail vein injection of protamine, most mice developed significant kidney discoloration and yellowing.

[0514] It can be seen that the triazine compound of the present invention has good safety.

[0515] Table 8. Acute toxicity test of some compounds in mice

[0516] Note: - / - indicates the number of mouse lesions / total number of mice; - indicates observation was not performed.

[0517] In summary, the small molecule triazine compounds of the present invention showed potent and low-toxic heparin reversal activity through in vitro dynamic photobinding ability qualitative test of sodium heparin, quantitative test of competitive binding of azure A to sodium heparin, in vitro cytotoxicity test and hemolytic toxicity test, anti-Xa factor test, acute toxicity test, and in vivo heparin reversal test in mice. Compounds 61, 131, 145, 154, 156, 194, and 195 were superior to or comparable to the positive control protamine or ciraparantag in reversing heparin anticoagulation activity in vitro and in vivo and had good biocompatibility.

Claims

1. A triazine compound having a structure as shown in Formula I or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof: in: X1, X2, X3 are the same as or different from each other and are independently selected from N or phenyl; L1, L2, L3 are the same or different from each other, unsubstituted or independently selected from H, alkyl; R1, R2, R3 are the same as or different from each other, and are each independently an optionally substituted alkyl, an optionally substituted alkylamino, an optionally substituted cycloalkyl, an optionally substituted heterocycloalkyl, an optionally substituted aryl, an optionally substituted heterocyclic aryl, an optionally substituted halogenated aryl, or an optionally substituted heterochain alkyl; the nitrogen atom is optionally quaternized, and the nitrogen atom may be optionally oxidized; The alkyl group is C1-C 10 Straight or branched chain alkyl; The alkylamino group refers to an alkyl group containing 1 to 3 carbon atoms which is attached to the rest of the molecule via an amino group, wherein the nitrogen atom of the amino group is optionally quaternized; The cycloalkyl group is a C3-C6 cycloalkyl group; The heterocycloalkyl group is a 3-6 membered monocyclic or polycyclic non-aromatic ring structure, and the 3-6 membered heterocycloalkyl group may be connected to the rest of the molecule through a heteroatom, a carbon atom or an alkyl group; The heterocyclic aromatic group is a saturated or unsaturated 5-6-membered monocyclic or polycyclic aromatic ring structure containing 1-3 heteroatoms selected from N, O, and S on the ring; the 5-6-membered heterocyclic aromatic group can be connected to the rest of the molecule through a heteroatom or a carbon atom or an alkyl group; The heterochain hydrocarbon structure of the heterochain hydrocarbon group is C1-C 20 Saturated or unsaturated, straight or branched chain structure containing 1 to 3 heteroatoms selected from N, O, and S; The heteroatom may occupy the connecting position between molecules, and the heteroatom is selected from nitrogen, oxygen or sulfur; In the optional substitution, substitution refers to substitution by one or more of the following substituents, and the substituents are selected from: halogen, C1-C5 alkyl, hydroxyl, cycloalkyl, heterocycloalkyl, alkoxy, carbonyl, heterocyclic aromatic, and aromatic.

2. The triazine compound according to claim 1, characterized in that: The R1-X1-L1 group is selected from: The R2-X2-L2 group is selected from: The R3-X3-R3 group is selected from:

3. The triazine compound according to claim 2, characterized in that: The R1-X1-L1 group is selected from: The R2-X2-L2 group is selected from: The R3-X3-R3 group is selected from:

4. The triazine compound according to claim 3, characterized in that: The R1-X1-L1 group is selected from The R2-X2-L2 group is selected from The R3-X3-R3 group is selected from The R1-X1-L1 group is selected from The R2-X2-L2 group is selected from The R3-X3-R3 group is selected from The R1-X1-L1 group is selected from The R2-X2-L2 group is selected from The R3-X3-R3 group is selected from The R1-X1-L1 group is selected from The R2-X2-L2 group is selected from The R3-X3-R3 group is selected from The R1-X1-L1 group is selected from The R2-X2-L2 group is selected from The R3-X3-R3 group is selected from The R1-X1-L1 group is selected from The R2-X2-L2 group is selected from The R3-X3-R3 group is selected from The R1-X1-L1 group is selected from The R2-X2-L2 group is selected from The R3-X3-R3 group is selected from The R1-X1-L1 group is selected from The R2-X2-L2 group is selected from The R3-X3-R3 group is selected from The R1-X1-L1 group is selected from The R2-X2-L2 group is selected from The R3-X3-R3 group is selected from 5. A triazine compound or a pharmaceutically acceptable salt, stereoisomer or solvate thereof, characterized in that: The triazine compound is selected from the following compounds:

6. A triazine compound or a pharmaceutically acceptable salt, stereoisomer or solvate thereof, characterized in that: The triazine compound is selected from the following compounds:

7. A method for preparing the triazine compound according to claim 1, characterized in that: The synthetic route is as follows: Among them, when the R1-X1-L1 group is selected from When A n for When the R1-X1-L1 group is selected from When other than the above groups, A n Selected from R1-X1H-L1, R1, X1, L1 as described in claim 1; B m Selected from R2-X2H-L2, R2, X2, L2 as described in claim 1; C z Selected from R3-X3H-R3, R3, X3, L3 as described in claim 1; include: Step (1), using tetrahydrofuran as a reaction solvent and N,N-diisopropylethylamine as an acid-binding agent, cyanuric chloride and An are reacted at a temperature of -20°C to obtain intermediate III; wherein the molar ratio of cyanuric chloride to An is 1:1 to 1:2; and the molar ratio of cyanuric chloride to N,N-diisopropylethylamine is 1:1 to 1:2.5; Step (2), using tetrahydrofuran as a reaction solvent and N,N-diisopropylethylamine as an acid-binding agent, the intermediate III and Bm are reacted at a temperature of 25° C. to obtain the intermediate II; the molar ratio of the intermediate III to Bm is 1:1 to 1:2; the molar ratio of the intermediate III to N,N-diisopropylethylamine is 1:1 to 1:2.5; Step (3), using tetrahydrofuran as a reaction solvent and N,N-diisopropylethylamine as an acid-binding agent, the intermediate II and Cz react under reflux conditions to obtain a triazine compound with a structure as shown in formula I; the molar ratio of the intermediate II and Cz is 1:1 to 1:2.5; the molar ratio of the intermediate II and N,N-diisopropylethylamine is 1:1 to 1:

4.

8. A pharmaceutical composition, characterized in that: The pharmaceutical composition is prepared by using the triazine compound or its pharmaceutically acceptable salt, stereoisomer, solvate as the active ingredient or the main active ingredient and a pharmaceutically acceptable carrier.

9. Use of the triazine compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt, stereoisomer or solvate thereof in the preparation of an anticoagulant reversal agent.

10. Use of the triazine compound according to any one of claims 1 to 6 or its pharmaceutically acceptable salt, stereoisomer, solvate in the preparation of a drug for treating the side effect of excessive anticoagulation caused by the use of heparin to treat diseases, and in the preparation of a drug for treating surgical operations requiring reversal of the anticoagulant activity of heparin; the disease treated with heparin is a thromboembolic disease; the embolic disease is myocardial infarction, thrombophlebitis, pulmonary embolism; the surgical operation is hemodialysis, extracorporeal circulation, catheterization, microvascular surgery.

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