Chiral or racemic tetrahydropteridine compound, preparation method thereof and application of chiral or racemic tetrahydropteridine compound in antitumor drugs and lead compounds thereof

Abstract

The invention belongs to the technical field of organic synthesis and medicinal chemistry, and discloses a chiral or racemic tetrahydropteridine compound, a preparation method thereof and application of the chiral or racemic tetrahydropteridine compound in preparation of antitumor drugs and lead compounds thereof. The novel tetrahydropteridine compound is synthesized with high efficiency, high regioselectivity and high enantioselectivity. A CCK-8 method is used for carrying out preliminary in-vitro tumor inhibition activity evaluation on the synthesized compound, and the result shows that the tetrahydropteridine compound or the pharmaceutically acceptable salt thereof has good in-vitro tumor inhibition activity on various tumor cells such as colon cancer cells, liver cancer cells and cervical cancer cells; the compound has broad-spectrum activity on tumor tissue specific expression targets, and can be applied to preparation of anti-tumor drugs and lead compounds thereof. According to the invention, the application range of allylation reaction substrates is widened, and a novel heterocyclic structure and a novel method for efficiently constructing chiral heterocyclic molecules are provided for research and development of new drugs.

Description

Technical Field

[0001] This invention belongs to the field of organic synthesis and medicinal chemistry, and relates to a class of chiral or racemic tetrahydropteridine compounds, their preparation methods, and their applications in the preparation of antitumor drugs and their lead compounds. Background Technology

[0002] In 2020, the FDA approved 18 new anti-tumor drugs, accounting for 34% of all approved new drugs. While many new biological therapy strategies for cancer have emerged, such as RNA interference, activation of natural killer (NK) cells, and CAR-T therapy, these methods have made some progress in clinical applications and show promising prospects. However, they also have significant limitations and uncertainties in efficacy. Therefore, chemotherapy remains the most widely used treatment method in clinical practice. However, chemotherapy also has many toxic side effects. These chemotherapeutic drugs can also kill the proliferation of normal cells such as bone marrow hematopoietic cells and gastric mucosal epithelial cells. Meanwhile, small molecule drugs targeting tumor tissue have developed rapidly in recent years. Their mechanism of action mainly involves selective pharmacological action on targets with different expression levels in cancer cells and normal cells, thereby enhancing the drug's selectivity for tumor cells and reducing the toxic side effects of chemotherapy drugs on normal cells. However, long-term use of targeted small molecule drugs may induce gene mutations in cancer cells, leading to drug resistance and multidrug resistance. Therefore, developing highly effective, low-toxicity, and less likely to induce drug resistance novel chemotherapy drugs remains a key focus of current cancer treatment drug research and development.

[0003] Carbon-heteroatom bonding reactions and their molecular skeleton construction strategies are among the main research areas in organic synthetic chemistry, playing a crucial role in the rapid and efficient synthesis of complex natural product molecules or the establishment of libraries of bioactive compounds. Among these, the study of asymmetric allylation reactions has seen rapid development in recent years, with chiral monophosphine, bisphosphine, phosphonium, phosphonoxy, dinitrogen, and nitrogen-sulfur ligands being applied to these reactions. With further research, chemists have discovered that chiral phosphoramide ligands are relatively good ligands for asymmetric allylation reactions, forming catalysts with the central active metal Ir, effectively catalyzing these reactions. Currently, transition metal-catalyzed asymmetric allylation reactions, including amination, etherification, and dearomatization, can effectively construct CX (X = S, O, N, etc.) bonds, synthesizing many chiral polycyclic compounds widely found in natural products and pharmaceutical active molecules with high regioselectivity and enantioselectivity. This has become an emerging environmentally friendly and atom-economical synthetic strategy for constructing new compounds. However, the types of effective chiral ligands and catalysts are still relatively limited, and the catalytic activity needs further improvement. Furthermore, the reported pathways and successful examples for constructing chiral heterocyclic compounds are also limited, and the types of substrates for the reaction and the synthesis of novel chiral compounds need further expansion. Therefore, in-depth research on the construction of chiral heterocyclic compounds based on this reaction has significant theoretical importance and broad application value.

[0004] Pyrimidine-chiral heterocyclic compounds are important structural units in drug molecules and natural products, and also crucial pharmacophores in drug development. Drugs containing these structures exhibit diverse combinatorial biological activities and possess significant medicinal value in areas such as antihistamine, anti-inflammatory, anti-Alzheimer's disease, anti-schizophrenia, and anticancer activities. Given the unique structural characteristics, pharmacological activities, and wide range of applications of pyrimidine-chiral heterocyclic compounds, their synthesis and applications in chemistry and medicine have attracted increasing attention. However, to date, there are few reports on the efficient synthesis of pyrimidine-chiral heterocyclic compounds, and reports on the synthesis of pyrimidine-chiral heterocyclic compounds using asymmetric catalysis are extremely limited. There are no precedents for directly synthesizing chiral tetrahydropteridine compounds and introducing chiral centers through asymmetric catalytic reactions. Summary of the Invention

[0005] To overcome the shortcomings and deficiencies of the prior art, the primary objective of this invention is to provide a class of chiral or racemic tetrahydropteridine compounds or pharmaceutically acceptable salts thereof. The tetrahydropteridine compounds of this invention are levorotatory, dextrorotatory, or racemic. The levorotatory is a pure levorotatory product or a mixture of enantiomers in excess of levorotatory. The dextrorotatory is a pure dextrorotatory product or a mixture of enantiomers in excess of dextrorotatory. The racemic is an enantiomer mixture with an ee value of 0.

[0006] Another object of the present invention is to provide a method for preparing the above-mentioned chiral or racemic tetrahydropteridine compounds. The method of the present invention enables the efficient and highly enantioselective synthesis of optically active centrally chiral or racemic tetrahydropteridine compounds.

[0007] One method of this invention involves synthesizing chiral tetrahydropteridine compounds and their enantiomers or racemates via intramolecular allyl-catalyzed amination reaction using allyl compounds as substrates. Specifically, this method uses an iridium-phosphoramide ligand complex as a catalyst and a specially designed allyl compound as a substrate to efficiently and with high enantioselectivity synthesize chiral tetrahydropteridine compounds via intramolecular allyl amination reaction. The enantiomers are obtained by preparing corresponding catalysts from ligands with opposite configurations and undergoing similar intramolecular allyl amination catalytic reactions. The racemates are obtained by preparing corresponding catalysts from racemic ligands and undergoing similar intramolecular allyl amination catalytic reactions. This invention also provides another method for synthesizing racemates of tetrahydropteridine compounds using pyrimidinylamines and allylamine compounds as substrates in a two-step, one-pot process under alkaline conditions without metal catalysis, involving intermolecular nucleophilic substitution and allyl amination. Specifically, racemic tetrahydropteridine compounds are synthesized efficiently in a two-step, one-pot method using a base as an additive and pyrimidineamines and allylamines as substrates, without the need for metal catalysis, via intermolecular nucleophilic substitution and allyl amination reactions in an air atmosphere.

[0008] Another object of the present invention is to provide the use of the above-mentioned tetrahydropteridine compounds or pharmaceutically acceptable salts thereof in the preparation of antitumor drugs and their lead compounds.

[0009] The objective of this invention is achieved through the following solution:

[0010] A class of chiral or racemic tetrahydropteridine compounds or pharmaceutically acceptable salts thereof, having the structural formula shown in Formula I; wherein, the carbon atom marked with * is a chiral carbon atom with a configuration of R, S or R / S; the tetrahydropteridine compound is a levorotatory, dextrorotatory or racemic form;

[0011]

[0012] Among them, R 1 R 2Individually selected from hydrogen, deuterium, halogen atom, hydroxyl, cyano, nitro, amino, mercapto, substituted or unsubstituted C1-C20 straight-chain or branched alkyl, substituted or unsubstituted C3-C20 cycloalkyl, C1-C20 haloalkyl, substituted or unsubstituted C1-C20 alkyloxy, substituted or unsubstituted C1-C20 alkylthio, substituted or unsubstituted C1-C20 alkylsulfonyl, substituted or unsubstituted C1-C20 alkylsulfoxide, substituted or unsubstituted C1-C20 N-alkyl-substituted amino, substituted or unsubstituted C1-C20 N,N-dialkyl-substituted amino, substituted or unsubstituted C1-C20 acyl, substituted or unsubstituted C1-C20 amide. The following groups are included: alkyl, substituted or unsubstituted C1-C20 carboxyl groups and their corresponding esters, sulfonic acid groups, substituted or unsubstituted C1-C20 sulfonate groups, substituted or unsubstituted C1-C20 aminosulfonyl groups, substituted or unsubstituted C1-C20 sulfonamide groups, substituted or unsubstituted aryl groups, substituted or unsubstituted arylmethylene groups, substituted or unsubstituted arylmethoxy groups, substituted or unsubstituted C2-C20 heterocyclic groups or heterocyclic aryl groups containing one or more of N, O and S, substituted or unsubstituted C2-C20 heterocyclic methylene groups or heterocyclic arylmethylene groups containing one or more of N, O and S, substituted or unsubstituted C1-C9 alkylsilyl groups, and substituted or unsubstituted phenylsilyl groups.

[0013] R 3 R 4 The groups are individually selected from hydrogen, deuterium, substituted or unsubstituted C1-C20 straight-chain or branched alkyl groups, substituted or unsubstituted C3-C20 cycloalkyl groups, substituted or unsubstituted C3-C20 cycloalkylmethylene groups, substituted or unsubstituted C2-C20 alkenyl groups, substituted or unsubstituted C2-C20 alkynyl groups, substituted or unsubstituted C1-C20 carboxyl groups and corresponding ester groups, substituted or unsubstituted C1-C20 acyl groups, substituted or unsubstituted C1-C20 amide groups, and sulfonic acid groups. Substituted or unsubstituted C1-C20 aminosulfonyl group, substituted or unsubstituted C1-C20 sulfonamide group, substituted or unsubstituted C1-C20 sulfonyl group, substituted or unsubstituted aryl acyl group, substituted or unsubstituted C1-C20 alkyloxycarbonyl group, substituted or unsubstituted aryl group, substituted or unsubstituted arylmethylene group, substituted or unsubstituted benzyl group, substituted or unsubstituted C2-C20 heterocyclic methylene group or heterocyclic arylmethylene group containing one or more of N, O and S;

[0014] R 5 R 6 R 7 R 8 R 9Individually selected from hydrogen, deuterium, halogen, hydroxyl, cyano, nitro, amino, C1-C20 straight-chain or branched alkyl, C3-C20 cycloalkyl, C1-C20 haloalkyl, C1-C20 carboxyl and its corresponding ester or amide, C2-C20 alkenyl, C2-C20 alkynyl, C1-C20 hydroxyloxy, C1-C20 hydroxythio, substituted or unsubstituted aryl, substituted or unsubstituted arylmethylene, C1-C20 N-alkyl-substituted amino, C1-C20 N,N-dialkyl-substituted amino, or a combination of one or more combinations thereof, substituted or unsubstituted C2-C20 heterocyclic or heterocyclic aryl groups containing N, O, and S, substituted or unsubstituted C2-C20 heterocyclic methylene or heterocyclic arylmethylene groups containing N, O, and S, or R 7 R 8 A heterocyclic group or heterocyclic aryl group containing one or more of N, O and S, connected to form a substituted or unsubstituted C2-C20.

[0015] Furthermore, the substituents are independently selected from one or more combinations of hydrogen, deuterium, halogen, hydroxyl, cyano, nitro, amino, C1-C20 straight-chain or branched alkyl, C3-C20 cycloalkyl, C1-C20 haloalkyl, C1-C20 carboxyl and corresponding ester group, sulfonic acid group, C1-C20 sulfonic acid group, C2-C20 alkenyl, C2-C20 alkynyl, C1-C20 hydroxyloxy, C1-C20 hydroxythio, aryl, C1-C20 N-alkyl-substituted amino, and C1-C20 N,N-dialkyl-substituted amino.

[0016] Furthermore, R 1 R 2 R 3 R 4 R 5 R 6 R 7 R 8 R 9 One or more hydrogen atoms are replaced by a deuterium atom, halogen atom, oxygen atom, sulfur atom, C1-C20 straight-chain or branched alkyl group, C3-C20 cycloalkyl group, C1-C20 haloalkyl group, alkenyl group, alkynyl group, aryl group, hydroxyl group, amino group, carbonyl group, carboxyl group, ester group, sulfonic acid group, sulfonate group, cyano group, nitro group, C1-C20 alkyloxy group, C1-C20 alkylthio group, or substituted or unsubstituted C2-C20 heterocyclic methylene or heterocyclic aryl methylene group containing N, O and S.

[0017] Furthermore, the structural formula of the tetrahydropteridine compound of the present invention is shown in Formula I, wherein R 1 R 2Individually selected from hydrogen, deuterium, halogen atom, hydroxyl, cyano, nitro, amino, mercapto, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, substituted or unsubstituted C5-C20 straight-chain or branched alkyl, cyclopropane, substituted or unsubstituted C4-C20 cycloalkyl, trifluoromethyl, C2-C20 haloalkyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, substituted or unsubstituted C5-C20 alkyloxy, methylthio, substituted or unsubstituted C2-C20 alkylthio, methyl sulfone, substituted or unsubstituted C2-C20 alkyl sulfone, substituted or unsubstituted C1-C20 N-alkyl-substituted amino, substituted or unsubstituted C1-C20 N,N-dialkyl-substituted amino, substituted or unsubstituted C1- Acyl group of C20, substituted or unsubstituted amide group of C1-C20, substituted or unsubstituted carboxyl group of C1-C20 and its corresponding ester group, sulfonic acid group, substituted or unsubstituted sulfonate group of C1-C20, substituted or unsubstituted sulfonamide group of C1-C20, substituted or unsubstituted sulfonyl group of C1-C20, substituted or unsubstituted aryl group, substituted or unsubstituted arylmethylene group, substituted or unsubstituted arylmethoxy group, substituted or unsubstituted heterocyclic group or heterocyclic aryl group of C2-C20 containing one or more of N, O and S, substituted or unsubstituted heterocyclic methylene group or heterocyclic arylmethylene group of C2-C20 containing one or more of N, O and S, trimethylsilyl group, triethylsilyl group, substituted or unsubstituted alkylsilyl group of C7-C9, substituted or unsubstituted triphenylsilyl group;

[0018] R 3 R 4 Individually selected from hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, substituted or unsubstituted C5-C20 straight-chain or branched alkyl, cyclopropane, substituted or unsubstituted C4-C20 cycloalkyl, substituted or unsubstituted C4-C20 cycloalkylmethylene, allyl, substituted or unsubstituted C4-C20 alkenyl, propargyl, substituted or unsubstituted C4-C20 alkynyl, substituted or unsubstituted C1-C20 carboxyl and its corresponding ester group, substituted or unsubstituted C1-C20 amide, formyl, acetyl, etc. Substituted or unsubstituted C3-C20 acyl group, sulfonic acid group, substituted or unsubstituted C1-C20 sulfonamide group, substituted or unsubstituted C1-C20 sulfonyl group, benzoyl group, substituted or unsubstituted aryl acyl group, tert-butoxycarbonyl group, fluorenylmethoxycarbonyl group, 2,2,2-trichloroethoxycarbonyl group, substituted or unsubstituted C5-C20 hydroxyoxycarbonyl group, substituted or unsubstituted aryl group, substituted or unsubstituted arylmethylene group, substituted or unsubstituted benzyl group, substituted or unsubstituted C2-C20 heterocyclic methylene group or heterocyclic arylmethylene group containing one or more of N, O and S;

[0019] R 5 R 6 R 7 R 8 R 9 Each group is independently selected from hydrogen, deuterium, halogen, hydroxyl, cyano, nitro, amino, C1-C20 straight-chain or branched alkyl, C3-C20 cycloalkyl, C1-C20 haloalkyl, C1-C20 carboxyl and its corresponding ester group, C1-C20 amide, C2-C20 alkenyl, C2-C20 alkynyl, C1-C20 hydroxyloxy, C1-C20 hydroxythio, substituted or unsubstituted aryl, etc. One or more of the following: substituted or unsubstituted arylmethylene, C1-C20 N-alkyl-substituted amino group, C1-C20 N,N-dialkyl-substituted amino group; substituted or unsubstituted C2-C20 heterocyclic group or heterocyclic aryl group containing N, O and S; substituted or unsubstituted C2-C20 heterocyclic methylene or heterocyclic arylmethylene group containing N, O and S; or R 7 R 8 A heterocyclic group or heterocyclic aryl group containing one or more of N, O and S, connected to form a substituted or unsubstituted C2-C20.

[0020] The substituents are independently selected from one or more combinations of hydrogen, deuterium, halogen, hydroxyl, cyano, nitro, amino, C1-C20 straight-chain or branched alkyl, C3-C20 cycloalkyl, C1-C20 haloalkyl, C1-C20 carboxyl and corresponding ester group, sulfonic acid group, C1-C20 sulfonic acid group, C2-C20 alkenyl, C2-C20 alkynyl, C1-C20 hydroxyloxy, C1-C20 hydroxythiol, aryl, C1-C20 N-alkyl-substituted amino, and C1-C20 N,N-dialkyl-substituted amino.

[0021] Furthermore, R 1 R 2 R 3 R 4 R 5 R 6 R 7 R 8 R 9One or more hydrogen atoms are replaced by a deuterium atom, halogen atom, oxygen atom, sulfur atom, C1-C20 straight-chain or branched alkyl group, C3-C20 cycloalkyl group, C1-C20 haloalkyl group, alkenyl group, alkynyl group, aryl group, hydroxyl group, amino group, carbonyl group, carboxyl group, ester group, sulfonic acid group, sulfonate group, cyano group, nitro group, C1-C20 alkyloxy group, C1-C20 alkylthio group, or substituted or unsubstituted C2-C20 heterocyclic methylene or heterocyclic aryl methylene group containing N, O and S.

[0022] Furthermore, the structural formula of the tetrahydropteridine compound is shown in Formula I, wherein R 1 R 2 Each group is independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, carboxyl, cyano, nitro, amino, mercapto, methylthio, methyl sulfone, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, substituted or unsubstituted C5-C20 straight-chain or branched alkyl groups, cyclopropane, substituted or unsubstituted C4-C20 cycloalkyl groups, trifluoromethyl, C2-C20 haloalkyl groups, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, and substituted or unsubstituted C5-C20 alkyloxy groups. , tert-butoxyamide, acetyl, acetamido, aminosulfonyl, methylaminosulfonyl, anilinesulfonyl, benzylaminosulfonyl, phenylsulfonamide, substituted or unsubstituted phenyl, substituted or unsubstituted aryl, benzyl, benzyloxy, morpholinyl, piperidinyl, piperazine, pyrrole, tetrahydropyrrole, substituted or unsubstituted C2-C20 heterocyclic groups or heterocyclic aryl groups containing one or more of N, O and S, trimethylsilyl, triethylsilyl, substituted or unsubstituted C7-C9 alkylsilyl, substituted or unsubstituted triphenylsilyl;

[0023] R 3 R 4 Each of the following is independently selected from hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, substituted or unsubstituted C5-C20 straight-chain or branched alkyl, cyclopropane, cyclohexane, substituted or unsubstituted C4-C20 cycloalkyl, formyl, acetyl, aminosulfonyl, methylaminosulfonyl, anilinesulfonyl, benzylaminosulfonyl, phenylsulfonamide, benzyl, 4-methylbenzyl, 4-methoxybenzyl, 4-fluorobenzyl, benzoyl, p-toluenesulfonyl, tert-butoxycarbonyl, fluorenemethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, 2-thiazolylmethylene, 2-thiophenemethylene, 2-furanmethylene or 2-pyridinylmethylene;

[0024] R 5 R 6 R 7 R 8 R 9Each group is independently selected from one or more combinations of hydrogen, deuterium, halogen, hydroxyl, cyano, nitro, amino, C1-C20 straight-chain or branched alkyl, C3-C20 cycloalkyl, C1-C20 haloalkyl, C1-C20 carboxyl and its corresponding ester group, C1-C20 amide, C2-C20 alkenyl, C2-C20 alkynyl, C1-C20 hydroxyloxy, C1-C20 hydroxythio, aryl, C1-C20 N-alkyl-substituted amino, and C1-C20 N,N-dialkyl-substituted amino, or R. 7 R 8 Connected to form oxygen-containing rings of C2-C20.

[0025] Furthermore, R 1 R 2 R 3 R 4 R 5 R 6 R 7 R 8 R 9 One or more hydrogen atoms are substituted by deuterium, fluorine, chlorine, bromine, iodine, oxygen, alkenyl, alkynyl, aryl, hydroxyl, amino, carbonyl, carboxyl, ester, cyano, methyl, ethyl, methoxy, methylthio, or nitro.

[0026] The aryl groups mentioned above are C6-C20 aryl groups.

[0027] The present invention also provides a method for preparing the above-mentioned chiral or racemic tetrahydropteridine compounds.

[0028] One specific preparation method of the present invention involves using an allyl compound intermediate as a raw material, and using an iridium complex generated by the reaction of an iridium compound with a phosphoramidite ligand as a catalyst, reacting under the action of an alkali to obtain the product.

[0029] Another preparation method of the present invention is to use a base as an additive and pyrimidine amine compounds and allyl amine compounds as substrates to efficiently synthesize racemic tetrahydropteridine compounds in air via a two-step one-pot method involving intermolecular nucleophilic substitution and allyl amination reactions without metal catalysis.

[0030] The reaction equations for the preparation method of the present invention are shown below:

[0031]

[0032] Where L is a chiral or achiral ligand, Base is a combination of various bases and additives, T is the reaction temperature, and Solvent is a combination of various organic solvents.

[0033] Furthermore, the target compounds derived from its structure can be obtained by conventional reactions such as hydrogenation reduction, oxidation, olefin metathesis, substitution, and addition of its vinyl groups.

[0034] In the preparation method of the present invention, the molar ratio of the allyl compound intermediate, the iridium atom of the iridium compound, the ligand, and the base is 1:(0.005-0.2):(0.005-0.4):(0.05-8).

[0035] The molar ratio of the pyrimidine amine compound, allyl amine compound, and base is 1:(0.05-20):(0.05-8).

[0036] In the method of the present invention, the iridium compound may be at least one of [Ir(COD)Cl]2, [Ir(dncot)Cl]2, [Ir(OMe)(COD)]2, [Ir(COD)2]BArF4, Ir(COD)2BF4, [Ir(OH)(COD)]2, Ir(ppy)3, [Ir(COD)2]SbF6, etc.

[0037] In the method of this invention, the ligand L refers to the phosphoramidite ligand in CN109336887A, as detailed in paragraphs

[0076] -

[0085] of the specification. The base can be an organic base or an inorganic base, and can refer to the base in CN109336887A, as detailed in paragraph

[0086] of the specification.

[0038] In the method of this invention, the reaction can be carried out at 0-200°C. The reaction time can be 20 min-48 h.

[0039] In the method of this invention, the allyl compound intermediate (S) a ), pyrimidine amine compounds (S b ), allylamine compounds (S c The structural formula is shown below:

[0040]

[0041] Wherein, LG is the leaving group, which can be hydroxyl, chlorine, bromine, etc. Where M is NH or O; R 10 It is at least one of a halogen-substituted or unsubstituted C1-C20 alkyl group or a halogen-substituted or unsubstituted C1-C20 alkyl group; R 11 It is a C1-C20 alkyl group, or a substituted or unsubstituted C6-C20 aryl group.

[0042] Preferred, formula (S) a R 10In this formula, the halogen can be fluorine, chlorine, bromine, or iodine, each independently. Furthermore, the halogen-substituted C1-C20 alkyl group includes trichloromethyl. (S) a R 11 In this context, the substituents can be one or more of C1-C20 alkyl groups, halogens, or C1-C20 hydroxyl groups. The aryl group is a C6-C20 aryl group.

[0043] Preferred, formula (S) a R 10 and R 11 In this context, the alkyl groups of C1-C20 can be independently selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, or tert-butyl.

[0044] Preferably, the hydrocarbon oxygen groups of the above C1-C20 are independently selected from methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, or benzyloxy.

[0045] Preferably, the aryl group is a C6-C20 aryl group, including phenyl and C7-C20 aryl groups.

[0046] The substituents may be one or more, and when there are multiple substituents, the substituents may be the same or different.

[0047] In the method of this invention, the allyl compound intermediate (S) a It can be prepared by a method including the following steps: a 4-halo-2,6-disubstituted pyrimidine-5-amine compound (compound 1) reacts with a halogenated compound 2 via a substitution reaction to generate a 4-halo-2,6-disubstituted pyrimidine-5-amine compound (pyrimidineamine compound S). b (or this substitution reaction may not occur), then with (Allylamine compounds S) c The reaction yields compound S. a .

[0048]

[0049] Furthermore, the substitution reaction can be carried out in the presence of sodium hydride; the molar ratio of compound 1 to sodium hydride can be 1:1 to 1:10; the reaction temperature can be -10℃ to 100℃; and the reaction time can be 1 to 10 h.

[0050] Furthermore, compound S b With compound S c In the presence of a base and a phase transfer catalyst, an intermolecular nucleophilic substitution reaction occurs to give compound S. a A base can be an organic base or an inorganic base; compound S b Compound Sc The molar ratio of base to alkali can be 1:1:1 to 1:10:10; the reaction temperature can be 20℃ to 140℃; and the reaction time can be 30 min to 2 h.

[0051] The substituent R in the 4-halo-2,6-disubstituted pyrimidine-5-amino compound (compound 1) 1 R 2 It can be obtained directly from commercially available products or introduced from 2,4,6-trihalo-pyrimidin-5-amines via conventional nucleophilic substitution reactions, Suzuki coupling reactions, or Grignard reactions. Compound S a S b S c The target compound I was obtained by catalytic reaction using it as a substrate.

[0052] In the method of this invention, the reaction is carried out in an organic solvent system. The organic solvent can be a polar solvent or a non-polar solvent. Preferably, the organic solvent can be one or a combination of more than one of the following: aromatic solvents or substituted aromatic solvents, halogenated hydrocarbon solvents, ether solvents, amide solvents, alkane solvents, cycloalkane solvents, nitrile solvents, dimethyl sulfoxide, alcohol solvents, and pyrrolidone solvents. Further, the aromatic solvents or substituted aromatic solvents preferably include at least one of toluene, xylene, ethylbenzene, cumene, chlorobenzene, and nitrobenzene; the halogenated hydrocarbon solvents preferably include at least one of dichloromethane, 1,2-dichloroethane, and trichloromethane; the ether solvents preferably include at least one of tetrahydrofuran, methyltetrahydrofuran, diethyl ether, ethylene glycol dimethyl ether, methyl tert-butyl ether, 1,4-dioxane, diphenyl ether, and dibenzyl ether; and the amide solvents preferably include N,N-dimethylformyl... The solvent comprises at least one of amine, N,N-dimethylacetamide, and N,N-dimethylpropionamide; the alkane solvent preferably comprises at least one of n-hexane, n-pentane, and n-heptane; the cycloalkane solvent preferably comprises at least one of cyclopentane, cyclohexane, and cycloheptane; the nitrile solvent preferably comprises acetonitrile; the pyrrolidone solvent preferably comprises at least one of α-pyrrolidone and N-methylpyrrolidone; and the alcohol solvent preferably comprises at least one of methanol, ethanol, isopropanol, n-propanol, and tert-butanol.

[0053] This invention utilizes iridium complexes formed from metallic iridium compounds and phosphoramidite ligands as catalysts to achieve intramolecular allyl amination reactions with allyl substrates, resulting in the highly efficient and enantioselective synthesis of tetrahydropteridine compounds. The enantiomers are obtained by preparing corresponding catalysts from ligands with opposite configurations, followed by similar intramolecular allyl amination catalytic reactions. The racemic compounds are obtained by preparing corresponding catalysts from racemic ligands, followed by similar intramolecular allyl amination catalytic reactions. Another preparation method uses a base as an additive, with pyrimidine amines and allyl amine compounds as substrates. Without metal catalysis in air, racemic tetrahydropteridine compounds are synthesized efficiently in a two-step, one-pot process via intermolecular nucleophilic substitution and allyl amination reactions.

[0054] The first preparation method of this invention has advantages such as high catalytic activity, good enantioselectivity, wide substrate applicability, mild reaction conditions, and environmental friendliness. It can synthesize the target product with high efficiency, high regioselectivity, and high enantioselectivity, and can be used to prepare various tetrahydropteridine compounds. The other preparation method of this invention has advantages such as no metal catalysis required, no inert gas protection required, one-pot process, and wide substrate applicability. It can synthesize racemic tetrahydropteridine target products with high efficiency.

[0055] The chiral or racemic tetrahydropteridine compounds of the present invention or their pharmaceutically acceptable salts exhibit good in vitro tumor inhibitory activity against various tumor cells such as colon cancer cells, liver cancer cells, and cervical cancer cells. They also have broad-spectrum activity against targets specifically expressed in tumor tissues and can be used to prepare anti-tumor drugs and their lead compounds.

[0056] Furthermore, the tumors include colon cancer, liver cancer, cervical cancer, ovarian cancer, breast cancer, skin cancer, kidney cancer, lung cancer, esophageal adenocarcinoma, bile duct cancer, pancreatic cancer, prostate cancer, pancreatic cancer, and melanoma, etc.

[0057] Furthermore, the same or different drugs respectively include therapeutically effective amounts of chiral or racemic tetrahydropteridine compounds or pharmaceutically acceptable salts thereof.

[0058] Furthermore, the drug can be prepared into various pharmaceutical dosage forms using conventional methods.

[0059] Furthermore, the drug may also contain one or more pharmaceutically acceptable carriers or excipients.

[0060] Furthermore, the carrier or excipient may include diluents, adhesives, surfactants, humectants, adsorbents, lubricants, fillers, disintegrants, preservatives, etc.

[0061] The present invention also provides a pharmaceutical composition for the prevention and / or treatment of tumors, comprising the above-described chiral or racemic tetrahydropteridine compounds or pharmaceutically acceptable salts thereof.

[0062] Compared with the prior art, the present invention has the following advantages and beneficial effects:

[0063] This invention provides an efficient strategy and method for synthesizing novel tetrahydropteridine compounds using an iridium-phosphoramide ligand complex as a catalyst, via intramolecular allyl-catalyzed amination of specially designed allyl substrates. This method achieves high efficiency, high regioselectivity, and high enantioselectivity, and can be used to prepare various tetrahydropteridine compounds. In addition, this invention provides another efficient strategy and method for synthesizing racemic tetrahydropteridine compounds in an air atmosphere without metal catalysis, using a base as an additive and pyrimidineamines and allylamines as substrates. This involves intermolecular nucleophilic substitution and allyl amination. Furthermore, this invention utilizes the CCK-8 assay to conduct preliminary in vitro tumor-suppressive activity evaluations of the constructed compounds, obtaining good experimental results.

[0064] Compared with existing methods, the method of this invention is applicable to the catalytic reactions of various types of pyrimidine allyl compounds. It features milder reaction conditions, a wide range of applicable substrates, simple operation, and good reaction yields (up to 99%) with high enantioselectivity (up to 95% ee). This method for efficiently constructing tetrahydropteridine compounds using catalytic asymmetric intramolecular allyl amination and the resulting compounds are currently unreported in the literature, both domestically and internationally. Furthermore, another method of this invention is applicable to the reactions of various types of pyrimidine amines and allyl amines. It requires no metal catalysis, no inert gas protection, is a one-pot process, has a wide range of applicable substrates, is simple to operate, and also yields good results. This method for efficiently constructing racemic tetrahydropteridine compounds using a one-pot reaction of base-catalyzed intermolecular nucleophilic substitution and allyl amination, and the resulting compounds are also currently unreported in the literature, both domestically and internationally.

[0065] This invention not only enriches the application of bridged phosphoramidite ligands and other types of phosphoramidite ligands, but also broadens the applicable range of substrates for allylation reactions, providing novel heterocyclic structures and efficient methods for constructing chiral heterocyclic molecules for new drug development. Detailed Implementation

[0066] The present invention will be further described in detail below with reference to embodiments, but the implementation of the present invention is not limited thereto. Unless otherwise specified, the materials involved in the following embodiments are all commercially available. Unless otherwise specified, the methods described are conventional methods. The amounts of each component are expressed in molar parts and volume parts, mol / L.

[0067] Example 1: Allyl compound intermediate (S) a Preparation of )

[0068]

[0069] Starting with compound 1, it was dissolved in a dry tetrahydrofuran solution and the system was kept at 0°C. Then, compound 2 (1.2 equiv) and sodium hydride (1.2 equiv) were slowly added. After the addition was complete, the system was kept at room temperature and stirred for 1 hour. TLC was monitored until the reaction was complete. Water was added to quench the reaction, followed by extraction with ethyl acetate. The organic phase was concentrated under reduced pressure, and the crude product was separated by stirred column chromatography to obtain compound S. b Using triethylamine (2.0 equiv) as a base and ethanol as a solvent, compound S... b (1.0 equiv) and the corresponding compound S c (1.2 equiv) was used as the reactant, and the mixture was stirred at 120 °C until the reactants reacted completely. The ethanol was then evaporated, and the mixture was extracted with ethyl acetate. The organic phase was washed with a saturated NaCl aqueous solution and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the crude product was purified by column chromatography to give the target compound S. a .

[0070] S a -1a: (E)-4-((5-amino-6-chloropyrimidin-4-yl)(benzyl)amino)but-2-ene-1-yl tert-butyl carbonate. Pale yellow viscous liquid, yield: 90%. 1 H NMR(600MHz,Chloroform-d)δ8.12(s,1H),7.35(t,J=7.5Hz,2H),7.30(s,3H),5.96–5.88(m,1H),5.79(dt ,J=15.5,6.0Hz,1H),4.61(s,2H),4.57(d,J=6.0Hz,2H),3.99(d,J=5.7Hz,2H),3.87(s,2H),1.50(s,9H). 13 C NMR(151MHz,Chloroform-d)δ155.48,153.24,147.11,143.97,137.60,130.77,12 8.71,127.54,127.51,127.41,82.29,66.58,51.58,49.88,27.76.HRMS(ESI)calcd for C 20 H 26 ClN4O3[M+H] + :405.1688,Found:405.1688.

[0071] S a-1b: (E)-4-(benzyl(5-(benzylamino)-6-chloropyrimidin-4-yl)amino)but-2-ene-1-yl tert-butyl carbonate. Pale yellow viscous liquid, yield: 90%. 1 H NMR(600MHz,Chloroform-d)δ8.19(s,1H),7.34–7.29(m,5H),7.27–7.18(m,5H),5.77(dt,J=15.7,5.8Hz,1H),5.71(dt,J=15.6, 5.7Hz,1H),4.93(s,2H),4.53(d,J=5.7Hz,2H),4.30(d,J=5.8Hz,2H),4.13(d,J=6.9Hz,2H),4.00(t,J=6.9Hz,1H),1.50(s,9H). 13 C NMR(151MHz,Chloroform-d)δ157.81,153.24,151.88,150.08,138.36,137.76,130.55,128.74,128.62,128.57,128.1 8,128.10,127.96,127.91,127.66,127.62,127.30,126.41,82.24,66.60,50.81,49.44,48.37,27.76.HRMS(ESI)calcd for C 27 H 32 ClN4O3[M+H] + :495.2158,Found:495.2150.

[0072] S a -1c: (E)-4-(benzyl(6-chloro-5-((4-methylbenzyl)amino)pyrimidin-4-yl)amino)but-2-en-1-yl tert-butyl carbonate. Yellow viscous liquid, yield: 92%. 1 H NMR(600MHz,Chloroform-d)δ8.18(s,1H),7.33–7.30(m,2H),7.29–7.26(m,1 H),7.21(d,J=7.5Hz,2H),7.16–7.10(m,4H),5.77(dt,J=15.8,5.9Hz,1H),5.7 1(dt,J=15.6,5.8Hz,1H),4.93(s,2H),4.54(d,J=5.8Hz,2H),4.30(d,J=5.8H z, 2H), 4.09 (d, J = 6.3Hz, 2H), 3.98 (t, J = 7.0Hz, 1H), 2.35 (s, 3H), 1.51 (s, 9H). 13C NMR(151MHz,Chloroform-d)δ157.78,153.25,151.80,150.00,137.80,137.35,135.38,130.59,129.39,128.5 6,128.21,127.89,127.60,127.28,126.51,82.22,66.61,50.79,49.18,48.32,27.77,21.10.HRMS(ESI)calcd for C 28 H 34 ClN4O3[M+H] + :509.2314,Found:509.2312.

[0073] S a -1f: (E)-4-(benzyl(6-chloro-5-((4-chlorobenzyl)amino)pyrimidin-4-yl)amino)but-2-en-1-yl tert-butyl carbonate. Pale yellow viscous liquid, yield: 89%. 1 H NMR(600MHz,Chloroform-d)δ8.19(s,1H),7.31(t,J=7.3Hz,2H),7.29–7.26(m,3H),7.21–7.18(m,2H),7.11(d,J=8.1Hz,2H),5.78(dt,J=15.7,5.8Hz, 1H),5.72(dt,J=15.6,5.7Hz,1H),4.91(s,2H),4.54(d,J=5.7Hz,2H),4.28 (d,J=5.8Hz,2H),4.09(d,J=7.0Hz,2H),3.97(t,J=7.0Hz,1H),1.50(s,9H). 13 CNMR(151MHz,Chloroform-d)δ157.87,153.23,152.10,150.28,137.67,136.80,133.50,130.42,129.25,1 28.86,128.60,128.14,127.73,127.36,126.01,82.27,66.56,50.86,48.69,48.54,27.77.HRMS(ESI)calcd for C 27 H 31 Cl2N4O3[M+H] + :529.1768,Found:529.1763.

[0074]

[0075]

[0076] S a -1g: (E)-4-((5-(allylamino)-6-chloropyrimidin-4-yl)(benzyl)amino)but-2-en-1-yl tert-butyl carbonate. Yellow viscous liquid, yield: 89%. 1 H NMR(600MHz,Chloroform-d)δ8.16(d,J=1.3Hz,1H),7.29(t,J=7.3Hz,2H),7.24(dd,J=8.4,6.6H z,1H),7.16(d,J=7.4Hz,2H),5.85(ddt,J=16.4,10.9,5.9Hz,1H),5.74(dt,J=15.7,5.8Hz,1H), 5.68(dt,J=15.6,5.7Hz,1H),5.18(d,J=17.1Hz,1H),5.12(d,J=10.4Hz,1H),4.86(s,2H),4.52( d,J=5.7Hz,2H),4.22(d,J=5.8Hz,2H),3.77(t,J=7.2Hz,1H),3.58(d,J=6.0Hz,2H),1.49(s,9H). 13 C NMR(151MHz,Chloroform-d)δ157.65,153.23,151.73,150.01,137.81,134.82,130.57,128.51,12 8.10,127.48,127.23,126.21,117.08,82.19,66.59,50.67,48.23,47.54,27.76.HRMS(ESI)calcd for C 23 H 30 ClN4O3[M+H] + :445.2001,Found:445.1998.

[0077] S a -1h: (E)-4-((5-(benzylamino)-6-chloropyrimidin-4-yl)(4-methoxybenzyl)amino)but-2-en-1-yl tert-butyl carbonate. Yellow viscous liquid, yield: 89%. 1H NMR(600MHz,Chloroform-d)δ8.16(d,J=1.6Hz,1H),7.32–7.20(m,5H),7.15–7.09(m,2H),6.85–6.79(m,2H),5.79–5.68(m,2H), 4.84(s,2H),4.53(d,J=4.8Hz,2H),4.27(d,J=5.5Hz,2H),4.12(d,J=4.7Hz,2H),4.05(d,J=7.1Hz,1H),3.77(s,3H),1.49(s,9H). 13 C NMR(151MHz,Chloroform-d)δ158.91,157.76,153.24,151.59,149.94,138.45,130.67,129.62,129.56,128.71 ,127.92,127.62,127.58,126.51,113.98,82.13,66.60,55.20,50.18,49.23,48.10,27.77.HRMS(ESI)calcdfor C 28 H 34 ClN4O4[M+H] + :525.2263,Found:525.2260.

[0078] Example 2: Phosphoramide ligands L1-L25 refer to the phosphoramide ligands in CN109336887A, and see the detailed implementation instructions in paragraphs

[0117] -

[0133] .

[0079] Example 3: Allyl intermediate S a Research on ligands for intramolecular allyl amination of iridium-phosphoramide complexes as substrates

[0080]

[0081] Table 1

[0082] Serial Number ligands Yield (%) ee value (%) 1 L4 92 -80 2 L9 95 86 3 L11 95 82

[0083] Example 4: Allyl intermediate S a Study on the base and solvent of intramolecular allyl amination reaction of -1a as a substrate under the catalysis of iridium-phosphoramide complex.

[0084]

[0085] Table 2

[0086]

[0087] In this context, THF stands for tetrahydrofuran, DCM for dichloromethane, DCE for 1,2-dichloroethane, DME for ethylene glycol dimethyl ether, PhMe for toluene, CH3CH2OH for ethanol, and MeCN for acetonitrile.

[0088] Example 5: Allyl intermediate S a -1a and S a Study on the temperature of intramolecular allyl amination reaction of -1b as a substrate catalyzed by iridium-phosphamide complex

[0089]

[0090] Table 3

[0091]

[0092]

[0093] Example 6: Preparation of iridium-catalyzed tetrahydropteridine compounds (compound I)

[0094]

[0095] Under argon protection, iridium compound (0.04 mol), chiral phosphoramide ligand (0.08 mol), base (5 parts by volume), and tetrahydrofuran (5 parts by volume) were added sequentially. The reaction was carried out at 50°C for 30 minutes, then allowed to cool naturally to room temperature, and the solvent was removed under reduced pressure. Substrate S was then added sequentially to the reaction tube. a The reaction mixture (1 molar), base (2 molar), and organic solvent (20 parts by volume) was carried out at -10 to 100 °C. After the reaction was completed by TLC monitoring, the solvent was removed under reduced pressure, and the crude product obtained after concentration was separated by column chromatography to obtain product I (petroleum ether:ethyl acetate = 5:1-10:1, v / v). The preparation methods and specific reaction conditions of compounds I-1 to I-11 are shown in Table 4. The molar ratios in Table 4 refer to the substrate S. a The molar ratio of iridium, ligand, and base.

[0096] Table 4

[0097]

[0098] Wherein, Boc is tert-butyloxycarbonyl, PhMe is toluene, DCM is dichloromethane, DCE is 1,2-dichloroethane, DME is ethylene glycol dimethyl ether, and THF is tetrahydrofuran.

[0099]

[0100] I-1: (R)-8-benzyl-4-chloro-6-vinyl-5,6,7,8-tetrahydropteridine.f =0.50 (petroleum ether:ethyl acetate = 2:1, v / v); yellow oily liquid; 93% yield; 88% ee [Daicel Chiralcel IA-3 (0.46cm x 25cm), n-hexane / 2-propanol = 95 / 5, v = 1.0 mL·min] -1 T = 25℃, λ = 254nm, t R (minor) = 15.177min,t R (major) = 16.220 min];[α] D 25 = -23.5° (c = 0.60, CHCl3). 1 H NMR(400MHz,Chloroform-d)δ7.98(s,1H),7.39–7.27(m,5H),5.77(ddd,J=17.0,10.3,6.6Hz,1H),5.35(dt,J=17.1,1.1Hz,1H),5.27(dt ,J=10.3,1.0Hz,1H),4.96–4.84(m,2H),4.18(s,1H),3.95–3.88(m,1H),3.43(ddd,J=12.0,3.5,1.6Hz,1H),3.28(dd,J=11.9,7.5Hz,1H). 13 CNMR(151MHz,Chloroform-d)δ151.06,147.57,138.47,136.75,135.72,128.78,128 .69,127.91,127.85,127.58,122.11,118.30,51.07,50.63,50.47.HRMS(ESI)calcd forC 15 H 16 ClN4[M+H] + :287.1058,Found:287.1057.

[0101] I-2: (R)-5,8-Dibenzyl-4-chloro-6-vinyl-5,6,7,8-tetrahydropteridine. f =0.50 (petroleum ether:ethyl acetate = 2:1, v / v); yellow oily liquid; 97% yield; 91% ee [Daicel Chiralcel IA-3 (0.46cm x 25cm), n-hexane / 2-propanol = 95 / 5, v = 1.0 mL·min] -1 T = 25℃, λ = 254nm, t R(major) = 33.774 min, t R (minor) = 42.844min];[α] D 25 = -88.7° (c = 0.38, CHCl3). 1 H NMR(600MHz,Chloroform-d)δ8.21(s,1H),7.53(d,J=7.6Hz,2H),7.34(dq,J=24.0,7.6 Hz,6H),7.27(d,J=7.5Hz,2H),5.40(ddd,J=17.3,10.5,3.3Hz,1H),5.21(dd,J=17.2,1 .9Hz,1H),5.05(dd,J=10.6,1.9Hz,1H),4.96(s,2H),4.61(d,J=14.8Hz,1H),3.79(d,J =14.8Hz,1H),3.58–3.52(m,1H),3.48(dd,J=12.3,4.0Hz,1H),3.24(d,J=12.2Hz,1H). 13 C NMR(151MHz,Chloroform-d)δ155.59,151.52,151.25,137.57,136.81,135.79,128.64,128.58 ,128.11,127.98,127.68,127.65,122.12,117.38,58.62,52.02,51.64,44.02.HRMS(ESI)calcd for C 22 H 22 ClN4[M+H] + :377.1528,Found:377.1530.

[0102] I-3: (R)-8-benzyl-4-chloro-5-(4-methylbenzyl)-6-vinyl-5,6,7,8-tetrahydropteridine. f =0.50 (petroleum ether:ethyl acetate = 2:1, v / v); pale yellow oily liquid; 98% yield; 91% ee [Daicel Chiralcel IF-3 (0.46cm x 25cm), n-hexane / 2-propanol = 85 / 15, v = 1.0 mL·min] -1 T = 25℃, λ = 254nm, t R (major) = 11.590 min, t R (minor) = 13.763min];[α] D 25= -103.5° (c = 0.60, CHCl3). 1 H NMR(600MHz,Chloroform-d)δ8.21(s,1H),7.40(d,J=7.8Hz,2H),7.37–7.29(m,3H),7.28–7.24(m ,2H),7.17(d,J=7.8Hz,2H),5.40(ddd,J=17.2,10.5,3.3Hz,1H),5.20(dt,J=17.1,1.8Hz,1H),5. 05(dt,J=10.6,1.8Hz,1H),5.00–4.91(m,2H),4.56(d,J=14.7Hz,1H),3.77(d,J=14.7Hz,1H),3.5 5(dh,J=4.1,2.1Hz,1H),3.46(dd,J=12.3,4.0Hz,1H),3.23(dd,J=12.2,1.7Hz,1H),2.37(s,3H). 13 C NMR(151MHz,Chloroform-d)δ155.59,151.45,151.21,137.35,136.84,135.89,134.48,129.26,12 8.61,128.10,127.96,127.62,122.17,117.33,58.33,51.88,51.64,44.06,21.14.HRMS(ESI)calcd forC 23 H 24 ClN4[M+H] + :391.1684,Found:391.1684.

[0103] I-5: (R)-8-benzyl-5-(4-(tert-butyl)benzyl)-4-chloro-6-vinyl-5,6,7,8-tetrahydropteridine. f =0.50 (petroleum ether:ethyl acetate = 2:1, v / v); yellow oily liquid; 98% yield; 92% ee [Daicel Chiralcel IA-3 (0.46cm x 25cm), n-hexane / 2-propanol = 90 / 10, v = 1.0 mL·min] -1 T = 25℃, λ = 254nm, t R (minor) = 10.034min,t R [(major) = 25.117 min]; [α] D 25 = -103.4° (c = 1.01, CHCl3). 1H NMR(600MHz,Chloroform-d)δ8.21(d,J=1.0Hz,1H),7.46(d,J=8.0Hz,2H),7.39(d,J=8.0Hz,2H) ,7.37–7.30(m,3H),7.28(d,J=7.2Hz,2H),5.41(ddd,J=17.3,10.5,3.3Hz,1H),5.22(dd,J=17.1 ,1.9Hz,1H),5.06(dd,J=10.4,2.0Hz,1H),4.97(s,2H),4.58(d,J=14.8Hz,1H),3.76(d,J=14.8H z,1H),3.57(dt,J=4.4,2.0Hz,1H),3.49(dd,J=12.3,3.9Hz,1H),3.28–3.20(m,1H),1.35(s,9H). 13 CNMR(151MHz,Chloroform-d)δ155.60,151.47,151.29,150.63,136.87,135.93,134.47,128.63,127.9 6,127.73,127.64,125.46,122.27,117.33,58.32,51.85,51.66,43.95,34.54,31.39.HRMS(ESI)calcd forC 26 H 30 ClN4[M+H] + :433.2154,Found:433.2158.

[0104] I-6: (R)-8-benzyl-4-chloro-5-(4-chlorobenzyl)-6-vinyl-5,6,7,8-tetrahydropteridine. f =0.50 (petroleum ether:ethyl acetate = 2:1, v / v); yellow oily liquid; 99% yield; 92% ee [Daicel Chiralcel IF-3 (0.46cm x 25cm), n-hexane / 2-propanol = 85 / 15, v = 1.0 mL·min] -1 T = 25℃, λ = 254nm, t R (major) = 12.965 min, t R (minor) = 13.963min];[α] D 25 = -112.1° (c = 0.32, CHCl3). 1HNMR(600MHz,Chloroform-d)δ8.21(s,1H),7.47(d,J=8.1Hz,2H),7.37–7.28 (m,5H),7.28–7.23(m,2H),5.39(ddd,J=17.1,10.5,3.1Hz,1H),5.18(dt,J=1 7.2,1.7Hz,1H),5.05(dt,J=10.6,1.7Hz,1H),4.96(d,J=3.2Hz,2H),4.54(d, J=15.0Hz,1H),3.75(d,J=15.0Hz,1H),3.52–3.41(m,2H),3.30–3.21(m,1H). 13 C NMR(151MHz,Chloroform-d)δ155.51,151.64,151.28,136.71,136.09,135.56,133.42,129.37 ,128.75,128.65,127.99,127.71,121.85,117.51,58.01,52.16,51.64,43.98.HRMS(ESI)calcd for C 22 H 21 Cl2N4[M+H] + :411.1138,Found:411.1140.

[0105] I-7: (R)-5-allyl-8-benzyl-4-chloro-6-vinyl-5,6,7,8-tetrahydropteridine. f =0.50 (petroleum ether:ethyl acetate = 2:1, v / v); yellow oily liquid; 95% yield; 89% ee [Daicel Chiralcel IF-3 (0.46cm x 25cm), n-hexane / 2-propanol = 85 / 15, v = 1.0 mL·min] -1 T = 25℃, λ = 254nm, t R (minor) = 8.747min,t R [(major) = 9.374 min]; [α] D 25 = -59.8° (c = 0.50, CHCl3). 1H NMR(600MHz,Chloroform-d)δ8.15(s,1H),7.36–7.26(m,5H),6.01–5.93(m,1H),5.48–5.40(m,1H),5.33(d,J=17.2Hz,1H),5.22(d,J=10.2Hz,1H),5. 16(d,J=17.2Hz,1H),5.05(d,J=10.5Hz,1H),5.01–4.89(m,2H),3.96–3.89 (m,1H),3.70–3.66(m,1H),3.45(dd,J=12.3,4.0Hz,1H),3.32–3.22(m,2H). 13 CNMR(151MHz,Chloroform-d)δ155.20,151.11,150.67,136.86,135.83,134.60,128.61 ,127.99,127.63,122.29,117.90,117.33,57.92,52.32,51.58,44.56.HRMS(ESI)calcd for C 18 H 20 ClN4[M+H] + :327.1371,Found:327.1372.

[0106] I-8: (R)-5-benzyl-4-chloro-8-(4-methoxybenzyl)-6-vinyl-5,6,7,8-tetrahydropteridine. f =0.50 (petroleum ether:ethyl acetate = 2:1, v / v); yellow oily liquid; 98% yield; 91% ee [Daicel Chiralcel IF-3 (0.46cm x 25cm), n-hexane / 2-propanol = 85 / 15, v = 1.0 mL·min] -1 T = 25℃, λ = 254nm, t R (minor) = 19.807min,t R [(major) = 27.408 min]; [α] D 25 = -111.3° (c = 0.34, CHCl3). 1H NMR(600MHz,Chloroform-d)δ8.21(s,1H),7.52(d,J=7.5Hz,2H),7.38–7.28(m,3H),7. 21(d,J=8.5Hz,2H),6.88(d,J=8.5Hz,2H),5.41–5.34(m,1H),5.19(d,J=17.2Hz,1H),5 .03(d,J=10.6Hz,1H),4.94–4.83(m,2H),4.59(d,J=14.8Hz,1H),3.83(s,3H),3.77(d, J=14.9Hz,1H),3.52(s,1H),3.44(dd,J=12.4,3.6Hz,1H),3.23(dd,J=12.4,2.6Hz,1H). 13 C NMR(151MHz,Chloroform-d)δ159.19,155.52,151.50,151.21,137.59,135.79,129.38,128.83,12 8.56,128.10,127.65,122.09,117.33,114.01,58.61,55.28,51.96,50.96,43.66.HRMS(ESI)calcd for C 23 H 24 ClN4O[M+H] + :407.1633,Found:407.1635.

[0107] I-9: (R)-5-benzyl-8-(4-(tert-butyl)benzyl)-4-chloro-6-vinyl-5,6,7,8-tetrahydropteridine. f =0.50 (petroleum ether:ethyl acetate = 2:1, v / v); yellow oily liquid; 97% yield; 98% ee [Daicel Chiralcel IF-3 (0.46cm x 25cm), n-hexane / 2-propanol = 85 / 15, v = 1.0 mL·min] -1 T = 25℃, λ = 254nm, t R (major) = 8.806 min, t R (minor) = 12.799min];[α] D 25 = -75.4° (c = 0.41, CHCl3). 1H NMR (600MHz, Chloroform-d) δ8.21 (s, 1H), 7.53 (d, J = 7.5Hz, 2H), 7.40–7.34 (m, 4H), 7.33–7. 29(m,1H),7.20(d,J=7.4Hz,2H),5.46–5.40(m,1H),5.22(d,J=17.3Hz,1H),5.06(d,J=10.5Hz ,1H),5.00(d,J=15.1Hz,1H),4.87(d,J=15.0Hz,1H),4.61(d,J=14.8Hz,1H),3.80(d,J=14.8 Hz,1H),3.56–3.53(m,1H),3.49(dd,J=12.3,4.0Hz,1H),3.26(d,J=12.4Hz,1H),1.35(s,9H). 13 C NMR(151MHz,Chloroform-d)δ155.61,151.54,151.17,150.60,137.62,135.86,133.67,128.57,128.1 2,127.65,127.61,125.53,122.10,117.34,58.63,52.05,51.40,44.08,34.54,31.37.HRMS(ESI)calcd for C 26 H 30 ClN4[M+H] + :433.2154,Found:433.2157.

[0108] I-10: (R)-5-benzyl-8-(4-bromobenzyl)-4-chloro-6-vinyl-5,6,7,8-tetrahydropteridine. f =0.50 (petroleum ether:ethyl acetate = 2:1, v / v); yellow oily liquid; 97% yield; 95% ee [Daicel Chiralcel IF-3 (0.46cm x 25cm), n-hexane / 2-propanol = 85 / 15, v = 1.0 mL·min] -1 T = 25℃, λ = 254nm, t R (major) = 12.363 min, t R (minor) = 15.415min];[α] D 25 = -92.4° (c = 0.49, CHCl3). 1H NMR(600MHz,Chloroform-d)δ8.19(s,1H),7.51(d,J=7.6Hz,2H),7.46(d,J=8.2Hz,2H), 7.35(d,J=7.8Hz,2H),7.32(d,J=7.5Hz,1H),7.14(d,J=8.1Hz,2H),5.44–5.35(m,1H),5. 21(d,J=17.2Hz,1H),5.06(d,J=10.5Hz,1H),4.89(q,J=15.2Hz,2H),4.60(d,J=14.6Hz, 1H), 3.80 (d, J = 14.7Hz, 1H), 3.55 (s, 1H), 3.46 (d, J = 12.6Hz, 1H), 3.20 (d, J = 12.4Hz, 1H). 13 C NMR(151MHz,Chloroform-d)δ155.43,151.44,151.32,137.45,135.92,135.69,131.75,129.68 ,128.61,128.10,127.73,122.18,121.57,117.53,58.61,52.10,51.09,44.26.HRMS(ESI)calcd for C 22 H 21 BrClN4[M+H] + :455.0633,Found:455.0635.

[0109] I-11: (R)-5,8-Dibenzyl-4-chloro-2-methyl-6-vinyl-5,6,7,8-tetrahydropteridine. f =0.50 (petroleum ether:ethyl acetate = 2:1, v / v); yellow oily liquid; 97% yield; 87% ee [Daicel Chiralcel IF-3 (0.46cm x 25cm), n-hexane / 2-propanol = 92 / 8, v = 1.0 mL·min] -1 T = 25℃, λ = 254nm, t R (major) = 7.989 min, t R (minor) = 8.382min];[α] D 25 = -110.4° (c = 0.38, CHCl3). 1H NMR(600MHz,Chloroform-d)δ7.53(d,J=7.5Hz,2H),7.37–7.27(m,8H),5.43–5.36(m,1H),5.21(d,J=17.2Hz,1H),5.04(d,J=10.5 Hz,1H),5.00–4.93(m,2H),4.56(d,J=14.8Hz,1H),3.74(d,J=14.8Hz,1H),3.54–3.45(m,2H),3.20(d,J=11.6Hz,1H),2.52(s,3H). 13 CNMR(151MHz,Chloroform-d)δ161.01,155.43,151.28,137.80,137.17,135.96,128.57,128.52,12 8.15,128.13,127.59,127.56,119.28,117.25,58.75,52.03,51.42,43.71,25.50.HRMS(ESI)calcd for C 23 H 24 ClN4[M+H] + :391.1684,Found:391.1687.

[0110] Example 7: I-12 to I-28 were prepared according to the method of Example 6, and the results are shown in Table 5.

[0111] Table 5

[0112]

[0113] Note: Solvent: THF, Temperature: 25℃, Base: DBU, Reaction Time: 2h

[0114] Example 8: When the R of the tetrahydropteridine compound of the present invention 1 Or R 2 When the halogen is present, R can be prepared by coupling reaction with boric acid compounds. 1 Or R 2 Tetrahydropteridine compounds with different substituents.

[0115] Using 4-chlorotetrahydropteridine compounds I-1–I-17, I-22–I-28, or 2-chlorotetrahydropteridine compounds I-18–I-21 as substrates, tetrahydropteridine compounds I-29–I-52 can be prepared by coupling reactions with various borate compounds under palladium catalyst catalysis. Under argon protection, 0.1 mol of 2-chlorotetrahydropteridine compound I-8 or I-22 or 0.1 mol of 2-chlorotetrahydropteridine compound I-19 and 0.20 mol of boric acid such as alkylboronic acid, arylboronic acid, various borate esters such as trimethyl borate, triethyl borate, tri-n-propyl borate, triisopropyl borate, tri-n-butyl borate, triisobutyl borate, tri-tert-butyl borate, triaryl borate, or various potassium borates such as alkylpotassium borate, arylpotassium borate were added sequentially. Then, 0.005 mol of palladium compound, 0.01 mol of ligand, 0.20 mol of base, and 2 parts by volume of organic solvent were added sequentially, and the reaction was carried out at 0-180 °C. After the reaction was monitored by TLC, the solvent was removed under reduced pressure, and the concentrated crude product was separated by column chromatography to obtain the product (petroleum ether:ethyl acetate = 5:1, v / v). The preparation of other compounds was carried out in the same manner, and the results are shown in Table 6.

[0116]

[0117] Table 6

[0118]

[0119]

[0120] I-29:(R)-4-(benzofuran-2-yl)-5-benzyl-8-(4-methoxybenzyl)-6-vinyl-5,6,7,8-tetrahydropteridine. f =0.20 (petroleum ether / ethyl acetate = 2:1, v / v); yellow oil, 89% yield; 84% ee [Daicel Chiralcel IA-3 (0.46cm x 25cm), n-hexane / 2-propanol = 85 / 15, v = 1.0 mL·min] -1 T = 25℃, λ = 254nm, t R (major) = 22.211 min,t R (minor) = 26.042min];[α] D 25 = -74.2° (c = 0.25, CHCl3). 1H NMR(600MHz,Chloroform-d)δ8.53(s,1H),7.83(s,1H),7.63(d,J=7.9Hz,1H),7.49(d,J=8.4Hz ,1H),7.40–7.29(m,7H),7.21(d,J=8.9Hz,2H),6.87(d,J=9.1Hz,2H),5.64–5.56(m,1H),5.31( d,J=17.2Hz,1H),5.10(d,J=10.8Hz,1H),4.97–4.84(m,2H),4.36(d,J=15.1Hz,1H),4.06(d,J= 15.1Hz,1H),3.83(d,J=2.5Hz,3H),3.79(s,1H),3.36(d,J=12.4Hz,1H),3.20(d,J=12.3Hz,1H). 13 C NMR(151MHz,Chloroform-d)δ159.07,155.66,155.08,152.95,152.35,137.36,136.59,129.31,128.62,128.04,12 7.53,125.47,123.05,121.62,117.16,113.96,111.82,109.55,58.98,55.28,52.34,50.81,43.92.HRMS(ESI)calcd for C 31 H 29 N4O2[M+H] + :489.2285,Found:489.2286.

[0121] I-30:(R)-5-benzyl-4-cyclopropyl-8-(2,4-dimethoxybenzyl)-6-vinyl-5,6,7,8-tetrahydropteridine. f =0.20 (petroleum ether / ethyl acetate = 2:1, v / v); yellow oil, 84% yield; 95% ee [Daicel Chiralcel IA-3 (0.46cm x 25cm), n-hexane / 2-propanol = 85 / 15, v = 1.0 mL·min] -1 T = 25℃, λ = 254nm, t R (minor) = 10.267min,t R (major) = 14.400 min; [α] D 25 = -77.5° (c = 0.32, CHCl3). 1H NMR(600MHz,Chloroform-d)δ8.30(s,1H),7.51–7.45(m,2H),7.39–7.35(m,2H),7.32–7 .28(m,1H),7.18–7.13(m,1H),6.52–6.42(m,2H),5.59–5.50(m,1H),5.22(d,J=16.9Hz, 1H),5.06(d,J=11.0Hz,1H),4.87(s,2H),4.50(d,J=15.5Hz,1H),3.87(d,J=15.4Hz,1H) ,3.82(s,6H),3.54(s,2H),3.25(d,J=9.6Hz,1H),2.56–2.48(m,1H),0.99–0.85(m,4H). 13 C NMR(151MHz,Chloroform-d)δ160.19,158.63,154.04,152.50,138.19,136.95,129.99,128.69,127.59,127.55,127.41 ,123.15,117.89,116.50,104.08,98.40,59.92,55.36,55.29,52.29,45.53,43.35,11.28,9.57,8.37.HRMS(ESI)calcd forC 27 H 31 N4O2[M+H] + :443.2442,Found:443.2443.

[0122] I-31:(R)-5-benzyl-8-(2,4-dimethoxybenzyl)-4-phenyl-6-vinyl-5,6,7,8-tetrahydropteridine. f =0.20 (petroleum ether / ethyl acetate = 2:1, v / v); yellow oil, 92% yield; 96% ee [Daicel Chiralcel IA-3 (0.46cm x 25cm), n-hexane / 2-propanol = 85 / 15, v = 1.0 mL·min] -1 T = 25℃, λ = 254nm, t R (major) = 12.708 min,t R (minor) = 14.558min];[α] D 25 = -46.2° (c = 0.41, CHCl3). 1H NMR(600MHz,Chloroform-d)δ8.48(s,1H),7.97(d,J=7.6Hz,2H),7.44(t,J=7.6Hz,2H),7.36(t,J=7.4H z,1H),7.24–7.17(m,4H),7.07–7.00(m,2H),6.51–6.43(m,2H),5.73(ddd,J=16.6,10.6,5.3Hz,1H),5.2 2–5.09(m,2H),4.97(d,J=15.1Hz,1H),4.84(d,J=15.0Hz,1H),3.90(d,J=14.4Hz,1H),3.83(s,3H),3.81 (s,3H),3.67(d,J=14.4Hz,1H),3.58–3.53(m,1H),3.40(dd,J=12.5,4.0Hz,1H),3.30(d,J=12.4Hz,1H). 13 C NMR(151MHz,Chloroform-d)δ160.28,158.68,155.59,154.41,152.26,138.57,137.42,136.97,130.30,128.77,128.59,128.3 9,128.30,128.20,127.33,123.56,117.62,116.45,104.14,98.43,58.99,55.38,55.30,52.50,45.95,44.16.HRMS(ESI)calcd for C 30 H 31 N4O2[M+H] + :479.2442,Found:479.2443.

[0123] I-32:(R)-5-benzyl-8-(2,4-dimethoxybenzyl)-4-(6-methoxypyridin-3-yl)-6-vinyl-5,6,7,8-tetrahydropteridine. f =0.20 (petroleum ether / ethyl acetate = 2:1, v / v); yellow oil, 90% yield; 95% ee [Daicel Chiralcel IA-3 (0.46cm x 25cm), n-hexane / 2-propanol = 85 / 15, v = 1.0 mL·min] -1 T = 25℃, λ = 254nm, t R (major) = 16.181 min, t R (minor) = 17.360 min];[α] D25 = -43.1° (c = 0.26, CHCl3). 1 H NMR(600MHz,Chloroform-d)δ8.93(s,1H),8.46(s,1H),8.22(dd,J=8.6,2.5Hz,1H),7.26–7.20(m,3H), 7.19–7.15(m,1H),7.10–7.06(m,2H),6.82–6.77(m,1H),6.50–6.43(m,2H),5.76–5.69(m,1H),5.17–5. 08(m,2H),4.95(d,J=15.0Hz,1H),4.84(d,J=14.9Hz,1H),3.98(s,3H),3.93(d,J=14.4Hz,1H),3.82(d, J=9.9Hz,6H),3.73–3.68(m,1H),3.59(d,J=5.2Hz,1H),3.41(d,J=12.4Hz,1H),3.30(d,J=12.7Hz,1H). 13 C NMR(151MHz,Chloroform-d)δ164.12,160.34,158.68,155.70,152.67,151.89,147.63,139.16,137.02,136.70,130.34,128.46,128. 33,127.50,127.34,123.43,117.44,116.65,110.31,104.16,98.43,59.00,55.38,55.30,53.60,52.53,45.93,44.00.HRMS(ESI)calcd for C 30 H 32 N5O3[M+H] + :510.2500,Found:510.2503.

[0124] I-33:(R)-5-benzyl-8-(2,4-dimethoxybenzyl)-4-(thiophen-3-yl)-6-vinyl-5,6,7,8-tetrahydropteridine. f =0.20 (petroleum ether / ethyl acetate = 2:1, v / v); yellow oil, 87% yield; 96% ee [Daicel Chiralcel IA-3 (0.46cm x 25cm), n-hexane / 2-propanol = 85 / 15, v = 1.0 mL·min] -1 T = 25℃, λ = 254nm, t R(minor) = 13.974min,t R (major) = 20.113 min];[α] D 25 = -38.2° (c = 0.29, CHCl3). 1 H NMR(600MHz,Chloroform-d)δ8.44(d,J=1.4Hz,1H),8.28(s,1H),7.96(d,J=3.8Hz,1H),7.37–7.35(m,1H),7.30– 7.26(m,3H),7.16(d,J=7.3Hz,2H),7.12(d,J=8.3Hz,1H),6.49–6.42(m,2H),5.68(ddd,J=16.3,10.6,4.9Hz,1H), 5.19(d,J=17.3Hz,1H),5.09(d,J=10.7Hz,1H),4.92(d,J=15.2Hz,1H),4.82(d,J=15.1Hz,1H),4.04(d,J=14.5Hz ,1H),3.82(s,3H),3.80(s,3H),3.68(dq,J=4.5,2.3Hz,1H),3.35(dd,J=12.5,4.2Hz,1H),3.25(d,J=12.4Hz,1H). 13 C NMR(151MHz,Chloroform-d)δ160.26,158.64,155.87,152.38,137.19,137.05,130.10,128.51,128.46,128.42,127.46,1 26.73,124.83,122.82,117.53,116.44,104.11,98.46,98.41,58.71,55.38,55.28,52.53,45.93,44.24.HRMS(ESI)calcd for C 28 H 29 N4O2S[M+H] + :485.2006,Found:485.2008.

[0125] I-34:(R)-5-benzyl-2-cyclopropyl-8-(2,4-dimethoxybenzyl)-6-vinyl-5,6,7,8-tetrahydropteridine. f=0.20 (petroleum ether / ethyl acetate = 2:1, v / v); yellow oil, 87% yield; 94% ee [Daicel Chiralcel IA-3 (0.46cm x 25cm), n-hexane / 2-propanol = 85 / 15, v = 1.0 mL·min] -1 T = 25℃, λ = 254nm, t R (minor) = 11.245min,t R (major) = 15.890 min];[α] D 25 = -88.5° (c = 0.32, CHCl3). 1 H NMR(600MHz,Chloroform-d)δ8.30(s,1H),7.51–7.45(m,2H),7.39–7.35(m,2H),7.30–7 .27(m,1H),7.18–7.13(m,1H),6.52–6.42(m,2H),5.69–5.40(m,1H),5.21(d,J=16.9Hz, 1H),5.06(d,J=11.0Hz,1H),4.87(s,2H),4.50(d,J=15.5Hz,1H),3.87(d,J=15.4Hz,1H) ,3.82(s,6H),3.54(s,2H),3.25(d,J=9.6Hz,1H),2.56–2.48(m,1H),0.99–0.85(m,4H). 13 C NMR(151MHz,Chloroform-d)δ160.19,158.63,154.04,152.50,138.19,136.95,129.99,128.69,127.59,127.55,127.41 ,123.15,117.89,116.50,104.08,98.40,59.92,55.36,55.29,52.29,45.53,43.36,11.28,9.57,9.37.HRMS(ESI)calcd forC 27 H 31 N4O2[M+H] + :443.2442,Found:443.2440.

[0126] I-35:(R)-5-benzyl-8-(2,4-dimethoxybenzyl)-2-phenyl-6-vinyl-5,6,7,8-tetrahydropteridine. f= 0.20 (petroleum ether / ethyl acetate = 2:1, v / v); yellow oil, 91% yield; 95% ee [Daicel Chiralcel IA-3 (0.46 cm x 25 cm), n-hexane / 2-propanol = 85 / 15, v = 1.0 mL·min -1 , T = 25 °C, λ = 254 nm, t R (major) = 13.256 min, t R (minor) = 16.012 min]; [α] D 25 = -47.4° (c = 0.41, CHCl3). 1 H NMR (600 MHz, Chloroform-d) δ 8.48 (s, 1H), 7.96 (d, J = 7.6 Hz, 2H), 7.40 (t, J = 7.6 Hz, 2H), 7.36 (t, J = 7.4 Hz, 1H), 7.24–7.17 (m, 4H), 7.079–7.01 (m, 2H), 6.51–6.43 (m, 2H), 5.73 (ddd, J = 16.6, 10.6, 5.3 Hz, 1H), 5.22–5.09 (m, 2H), 4.97 (d, J = 15.1 Hz, 1H), 4.84 (d, J = 15.0 Hz, 1H), 3.90 (d, J = 14.4 Hz, 1H), 3.83 (s, 3H), 3.81 (s, 3H), 3.67 (d, J = 14.4 Hz, 1H), 3.54–3.50 (m, 1H), 3.40 (dd, J = 12.5, 4.0 Hz, 1H), 3.27 (d, J = 12.4 Hz, 1H). 13 C NMR (151 MHz, Chloroform-d) δ 160.28, 158.68, 155.59, 154.41, 152.26, 138.57, 137.42, 136.97, 130.30, 128.77, 128.59, 128.39, 128.30, 128.20, 127.33, 123.56, 117.62, 116.45, 104.14, 98.43, 58.99, 55.38, 55.32, 52.50, 44.95, 43.16. HRMS (ESI) calcd for C 30 H 31 N4O2 [M + H] + : 479.2442, Found: **479.2440**.

[0127] I-36:(R)-5,8-Dibenzyl-4-methyl-2-(naphth-1-yl)-6-vinyl-5,6,7,8-tetrahydropteridine. f =0.15 (petroleum ether / ethyl acetate = 10:1, v / v); Yellow oil, 44.8 mg, 93% yield; 1H NMR (600 MHz, Chloroform-d) δ 8.75 (d, J = 8.6 Hz, 1H), 8.06 (dd, J = 7.1, 1.4 Hz, 1H), 7.93–7.86 (m, 2H), 7.58–7.53 (m, 3H), 7.49–7.32 (m, 10H), 5.61 (ddd, J = 17.3, 10.6, 3.9 Hz, 1H), 5.24 (dt, J = 17.3, 1.7 Hz) ,1H),5.13(dt,J=10.6,1.8Hz,1H),5.04(s,2H),4.37(d,J=15.2Hz,1H),3.93(d,J=15.4Hz,1H),3.6 5(dd,J=12.1,4.0Hz,1H),3.59(dh,J=4.1,2.0Hz,1H),3.27(dd,J=12.1,1.7Hz,1H),2.70(s,3H).13C NMR(151MHz,Chloroform-d)δ159.91,157.57,154.19,137.97,137.86,137.22,136.87,134.11,131.32,129.22,128.75,128.52,128.42,12 8.15,127.98,127.68,127.57,127.29,126.75,125.93,125.39,125.20,121.89,116.74,59.73,52.62,51.29,43.67,20.23.HRMS(ESI)calcd for C33H31N4[M+H]+:483.2543,Found:483.2538.

[0128] I-37:(R)-5,8-Dibenzyl-2-(6-methoxypyridin-3-yl)-4-methyl-6-vinyl-5,6,7,8-tetrahydropteridine. f =0.10 (petroleum / EtOAc=10:1, v / v); Yellow oil, 42.2 mg, 91% yield; 1H NMR(600MHz,Chloroform-d)δ9.22(d,J=2.5Hz,1H),8.56(dd,J=8.7,2.2Hz,1H),7.50(d,J= 7.6Hz,2H),7.40(q,J=8.3,7.5Hz,3H),7.36–7.32(m,5H),6.79(d,J=8.8Hz,1H),5.52(ddd,J =15.9,10.8,2.8Hz,1H),5.15(d,J=17.2Hz,1H),5.11–5.00(m,3H),4.27(d,J=15.5Hz,1H), 4.01(s,3H),3.85(d,J=15.5Hz,1H),3.61–3.52(m,2H),3.23(d,J=12.0Hz,1H),2.61(s,3H). 13 C NMR(151MHz,Chloroform-d)δ164.84,157.64,155.82,154.18,147.30,138.10,137.92,137.78,136.76,128.72,128.5 4,128.06,127.65,127.55,127.38,122.19,116.63,110.00,59.55,53.58,52.52,51.22,43.49,20.21.HRMS(ESI)calcd forC 29 H 30 N5O[M+H] + :464.2445,Found:464.2441.

[0129] I-38:(R)-5,8-Dibenzyl-4-methyl-2-(thiophen-2-yl)-6-vinyl-5,6,7,8-tetrahydropteridine. f =0.30 (petroleum / EtOAc=10:1, v / v); Yellow oil, 42.5 mg, 97% yield; 1 H NMR(600MHz,Chloroform-d)δ7.92–7.87(m,1H),7.48(d,J=7.6Hz,2H),7.42–7.30(m,9H),7.13–7.08(m,1H),5.54–5.46(m,1 H),5.16–4.96(m,4H),4.24(d,J=15.4Hz,1H),3.82(d,J=15.5Hz,1H),3.59–3.49(m,2H),3.22(d,J=12.0Hz,1H),2.59(s,3H). 13C NMR(151MHz,Chloroform-d)δ157.62,154.49,153.95,144.96,137.91,137.83,136.69,128.71,128.52,128.39,12 7.79,127.76,127.65,127.53,127.42,126.94,121.97,116.61,59.51,52.50,51.29,43.40,20.12.HRMS(ESI)calcd for C 27 H 27 N4S[M+H] + :439.1951,Found:439.1945.

[0130] I-39:(R)-2-(benzofuran-2-yl)-5,8-dibenzyl-4-methyl-6-vinyl-5,6,7,8-tetrahydropteridine. f =0.15 (petroleum / EtOAc=10:1, v / v); Yellow oil, 45.3 mg, 96% yield; 1 H NMR(600MHz,Chloroform-d)δ7.65(dd,J=17.0,8.0Hz,2H),7.54(s,1H),7.48(d,J=7.6Hz,2H),7.40–7.31(m,9H),7.27(q,J=7.7Hz,1H),5.52(ddd, J=17.2,10.7,3.7Hz,1H),5.18–5.03(m,4H),4.29(d,J=15.5Hz,1H),3.87 (d,J=15.5Hz,1H),3.60–3.52(m,2H),3.24(d,J=11.0Hz,1H),2.69(s,3H). 13 C NMR(151MHz,Chloroform-d)δ157.43,155.64,154.83,154.20,151.08,137.72,137.63,136.57,128.75,128.59,128.30,12 7.61,127.50,125.06,123.02,122.94,121.51,116.76,112.12,107.17,59.48,52.58,51.30,43.54,20.37.HRMS(ESI)calcd for C 31 H 29 N4O[M+H] + :464.2445,Found:464.2441.

[0131] I-40:(R)-5,8-Dibenzyl-4-methyl-2-phenyl-6-vinyl-5,6,7,8-tetrahydropteridine. f =0.30 (petroleum / EtOAc=10:1, v / v); Yellow oil, 41.1 mg, 95% yield; 1 H NMR(600MHz,Chloroform-d)δ8.47–8.42(m,2H),7.51(d,J=7.6Hz,2H),7.47–7.33(m,11H),5.54(ddd,J=17.2,10.5,3.6Hz,1H), 5.19–5.04(m,4H),4.29(d,J=15.5Hz,1H),3.86(d,J=15.5Hz,1H),3.61–3.53(m,2H),3.23(dd,J=11.8,1.4Hz,1H),2.66(s,3H). 13 C NMR(151MHz,Chloroform-d)δ129.15–128.81(m),128.40(d,J=8.5Hz).HRMS(ESI)calcd for C 29 H 29 N4[M+H] + :433.2387,Found:433.2383.

[0132] Example 9: Pyrimidine S b -1 and allylamine S c Study on the base and temperature for the two-step one-pot synthesis of racemic tetrahydropteridine compounds via intermolecular nucleophilic substitution and allyl amination reactions using -1 as a substrate.

[0133]

[0134] Table 7

[0135]

[0136] Example 10: Preparation of tetrahydropteridine compounds by a two-step one-pot method of base-catalyzed intermolecular nucleophilic substitution and allyl amination.

[0137] Add pyrimidine amine compound S sequentially b (1 molar), allylamine compounds S c(2 molar parts) of base, (2 molar parts) of organic solvent, and reaction at 20-200℃. After the reaction was monitored by TLC, the solvent was removed under reduced pressure, and the crude product was concentrated and separated by column chromatography to obtain product I (petroleum ether:ethyl acetate = 10:1-20:1, v / v). The preparation methods and specific reaction conditions of compounds I-53 to I-56 are shown in Table 8. The molar ratios in Table 8 refer to the substrate S. b :S c Molar ratio of bases.

[0138] Table 8

[0139]

[0140] I-53: 5,8-Dibenzyl-2-chloro-4-methyl-6-vinyl-5,6,7,8-tetrahydropteridine. f =0.30 (petroleum ether / ethyl acetate = 10:1, v / v); yellow oil, 83% yield; 1 H NMR(600MHz,Chloroform-d)δ7.46–7.41(m,2H),7.40–7.27(m,8H),5.42(ddt,J=17.1,10.6,3.0Hz,1H),5.12–5.02(m,2H),4.90(t ,J=3.0Hz,2H),4.18(d,J=15.2Hz,1H),3.79(dd,J=15.4,2.1Hz,1H),3.53–3.44(m,2H),3.18(dt,J=12.3,1.9Hz,1H),2.50(s,3H).

[0141] I-54: 5-Benzyl-2-chloro-8-(4-chlorobenzyl)-4-methyl-6-vinyl-5,6,7,8-tetrahydropteridine. f =0.35 (petroleum ether / ethyl acetate = 10:1, v / v); yellow oil, 81% yield; 1H NMR(600MHz,Chloroform-d)δ7.42(d,J=7.6Hz,2H),7.36(td,J=7.6,7.0,4.1Hz,2H),7.31( dt,J=8.5,2.4Hz,3H),7.24–7.20(m,2H),5.46–5.37(m,1H),5.12–5.03(m,2H),4.89(d,J=1 5.0Hz,1H),4.81(dd,J=15.1,1.7Hz,1H),4.18(d,J=15.3Hz,1H),3.80(d,J=15.3Hz,1H),3. 53(dp,J=4.1,2.0Hz,1H),3.46(dd,J=12.4,4.0Hz,1H),3.15(d,J=12.3Hz,1H),2.50(s,3H).

[0142] I-55: 5-Benzyl-8-(4-(tert-butyl)benzyl)-2-chloro-4-methyl-6-vinyl-5,6,7,8-tetrahydropteridine. f =0.40 (petroleum ether / ethyl acetate = 10:1, v / v); yellow oil, 82% yield; 1 H NMR(600MHz,Chloroform-d)δ7.44(d,J=7.5Hz,2H),7.36(dd,J=8.0,5.9Hz,4H),7.31(t ,J=7.4Hz,1H),7.22(d,J=8.0Hz,2H),5.45(ddd,J=17.3,10.6,3.7Hz,1H),5.12–5.01(m ,2H),4.93(d,J=14.9Hz,1H),4.81(d,J=14.9Hz,1H),4.18(d,J=15.3Hz,1H),3.80(d,J= 15.3Hz,1H),3.54–3.44(m,2H),3.20(dd,J=12.4,1.5Hz,1H),2.50(s,3H),1.34(s,9H).

[0143] I-56: 5-Benzyl-2-chloro-8-cyclopropyl-4-methyl-6-vinyl-5,6,7,8-tetrahydropteridine. f =0.20 (petroleum ether / ethyl acetate = 10:1, v / v); yellow oil, 73% yield; 1H NMR(600MHz,Chloroform-d)δ7.45(d,J=7.6Hz,2H),7.39(t,J=7.5Hz,2H),7.33(d,J=7.3Hz,1H),5.48(ddd,J=17 .2,10.5,4.0Hz,1H),5.19–5.10(m,1H),5.06(ddt,J=10.6,2.1,1.1Hz,1H),4.18(d,J=15.4Hz,1H),3.78(d,J=15 .5Hz,1H),3.54(dp,J=3.9,2.0Hz,1H),3.47(dd,J=12.4,3.7Hz,1H),3.30(dd,J=12.4,1.9Hz,1H),2.90(tt,J=7. 5,4.0Hz,1H),2.48(d,J=1.0Hz,3H),1.04–0.97(m,1H),0.92–0.88(m,1H),0.79–0.72(m,1H),0.59–0.51(m,1H).

[0144] Example 11: Racemic tetrahydropteridine compounds I-36 to I-40 and I-57 to I-80 were prepared according to the method of Example 10. Tetrahydropteridine compounds (S)-I-53 to (S)-I-80 with chiral center configuration S were prepared according to the method of Example 6. The results are shown in Table 9.

[0145] Table 9

[0146] compound I-57 I-58 I-59 I-60 I-61 I-62 I-63 I-64 I-65 Yield (%) 70 77 83 66 69 71 80 77 79 compound I-66 I-67 I-68 I-69 I-70 I-71 I-72 I-73 I-74 Yield (%) 82 81 68 83 78 70 72 80 74 compound I-75 (S)-I-53 (S)-I-54 (S)-I-55 (S)-I-56 (S)-I-57 (S)-I-58 (S)-I-59 (S)-I-60 Yield (%) 71 98 92 90 93 93 92 91 90 ee(%) / 90 91 92 92 98 93 93 94 compound (S)-I-61 (S)-I-62 (S)-I-63 (S)-I-64 (S)-I-65 (S)-I-66 (S)-I-67 (S)-I-68 (S)-I-69 Yield (%) 96 96 90 91 98 97 93 93 93 ee(%) 90 90 90 90 93 92 92 90 92 compound (S)-I-70 (S)-I-71 (S)-I-72 (S)-I-73 (S)-I-74 (S)-I-75 I-76 (S)-I-76 I-77 Yield (%) 94 95 95 90 93 94 80 98 78 ee(%) 93 97 93 96 96 98 / 98 / compound (S)-I-77 I-78 (S)-I-78 I-79 (S)-I-79 I-80 (S)-I-80 Yield (%) 95 70 90 72 89 68 94 ee(%) 97 / 97 / 93 / 90

[0147]

[0148]

[0149] I-57: 8-Benzyl-2-chloro-4-methyl-5-(naphth-2-ylmethyl)-6-vinyl-5,6,7,8-tetrahydropteridine. f =0.30 (petroleum / EtOAc=10:1, v / v); Yellow oil, 59.9 mg, 68% yield; 1H NMR(600MHz,Chloroform-d)δ7.88–7.84(m,3H),7.84–7.81(m,1H),7.57(dd,J=8.6,1.5Hz,1H),7.51 (hept,J=5.1Hz,2H),7.33(ddd,J=11.4,7.6,5.8Hz,3H),7.30–7.28(m,2H),5.44(ddd,J=17.2,10.6, 3.7Hz,1H),5.14–5.04(m,2H),4.92(d,J=2.1Hz,2H),4.33(d,J=15.3Hz,1H),3.94(d,J=15.3Hz,1H), 3.56(dh,J=3.9,1.8Hz,1H), 3.52(dd,J=12.3,4.1Hz,1H), 3.19(dd,J=12.3,1.6Hz,1H), 2.56(s,3H). 13 C NMR(151MHz,Chloroform-d)δ159.61,155.75,153.38,136.67,136.16,134.85,133.38,133.02,128.65,128.60,128.28 ,127.73,127.68,126.53,126.36,126.01,125.53,122.45,116.96,59.58,52.09,51.46,43.30,19.92.HRMS(ESI)calcd for C 27 H 26 ClN4[M+H] + :441.1841,Found:441.1837.

[0150] I-58: 5-Allyl-8-benzyl-2-chloro-4-methyl-6-vinyl-5,6,7,8-tetrahydropteridine. f =0.35 (petroleum / EtOAc=10:1, v / v); Yellow oil, 42.9 mg, 63% yield; 1H NMR(600MHz,Chloroform-d)δ7.36–7.27(m,5H),5.89(dddd,J=17.2,10.6,7.0,4. 0Hz,1H),5.43(ddd,J=17.1,10.6,3.7Hz,1H),5.36(dd,J=17.1,2.1Hz,1H),5.25–5 .19(m,1H),5.07–5.00(m,2H),4.94–4.84(m,2H),3.64–3.60(m,1H),3.52(ddt,J=1 5.9, 4.0, 2.0Hz, 1H), 3.44 (dd, J=12.4, 4.0Hz, 1H), 3.26–3.19 (m, 2H), 2.41 (s, 3H). 13 C NMR(151MHz,Chloroform-d)δ159.27,155.41,152.93,136.72,136.17,134.31,128.57,12 8.29,127.66,122.61,117.62,116.87,58.55,52.28,51.38,43.57,19.70.HRMS(ESI)calcd for C 19 H 22 ClN4[M+H] + :341.1528,Found:341.1525.

[0151] I-59: 8-Benzyl-2-chloro-4-methyl-5-(4-(trifluoromethyl)benzyl)-6-vinyl-5,6,7,8-tetrahydropteridine. f =0.20 (petroleum / EtOAc=10:1, v / v); Yellow oil, 55.0mg, 60% yield; 1 H NMR(600MHz,Chloroform-d)δ7.63(d,J=8.0Hz,2H),7.57(d,J=8.1Hz,2H),7. 37–7.28(m,5H),5.43(ddd,J=17.2,10.5,3.8Hz,1H),5.13–5.04(m,2H),4.91( s,2H),4.20(d,J=16.0Hz,1H),3.87(d,J=16.0Hz,1H),3.49(dd,J=12.5,4.0H z,1H),3.44(dq,J=4.2,2.1Hz,1H),3.21(dd,J=12.5,1.6Hz,1H),2.47(s,3H). 13C NMR(151MHz,Chloroform-d)δ159.50,155.61,153.51,141.62,136.52,135.70,130.38,130.17,129.95,129.74,128.64 ,128.30,127.77,127.61,125.81,125.78,125.76,125.73,123.12,122.14,117.25,59.08,52.55,51.46,43.21,19.76. 19 F NMR(565MHz,Chloroform-d)δ-62.55.HRMS(ESI)calcd forC 24 H 23 ClF3N4[M+H] + :459.1558,Found:459.1553.

[0152] I-60: 5-Benzyl-2-chloro-4-methyl-8-(thiophen-2-ylmethyl)-6-vinyl-5,6,7,8-tetrahydropteridine. f =0.30 (petroleum / EtOAc=10:1, v / v); Yellow oil, 60.7 mg, 81% yield; 1 H NMR(600MHz,Chloroform-d)δ7.43(d,J=7.6Hz,2H),7.37(t,J=7.5Hz,2H),7.31(t,J=7.3Hz,1 H),7.25(dd,J=5.1,1.2Hz,1H),7.06–7.03(m,1H),6.98(dd,J=5.1,3.5Hz,1H),5.45(ddd,J=1 7.2,10.6,3.4Hz,1H),5.14(d,J=15.2Hz,1H),5.09–5.01(m,2H),4.90(d,J=15.3Hz,1H),4.16 (d,J=15.3Hz,1H),3.76(d,J=15.3Hz,1H),3.59–3.52(m,2H),3.32–3.25(m,1H),2.48(s,3H). 13CNMR(151MHz,Chloroform-d)δ159.66,155.20,153.16,138.78,137.34,136.01,128.77,127.69,12 7.59,127.06,126.60,125.60,122.76,116.93,59.40,52.17,46.41,43.22,19.79.HRMS(ESI)calcd for C 21 H 22 ClN4S[M+H] + :397.1248,Found:397.1243.

[0153] I-61: 5-Benzyl-2-chloro-8-cyclopropyl-4-methyl-6-vinyl-5,6,7,8-tetrahydropteridine. f =0.35 (petroleum / EtOAc=10:1, v / v); Yellow oil, 54.4 mg, 80% yield; 1 H NMR(600MHz,Chloroform-d)δ7.45(d,J=7.5Hz,2H),7.39(t,J=7.5Hz,2H),7.33(d,J=7.3Hz,1H),5.52–5.44(m ,1H),5.13(ddt,J=17.2,2.0,1.0Hz,1H),5.06(dp,J=10.6,1.1Hz,1H),4.18(d,J=15.4Hz,1H),3.78(d,J=15.5H z,1H),3.54(dh,J=3.8,2.0Hz,1H),3.47(dd,J=12.4,3.7Hz,1H),3.30(dt,J=12.4,1.3Hz,1H),2.90(tt,J=7.5 ,4.0Hz,1H),2.48(d,J=1.0Hz,3H),1.04–0.97(m,1H),0.91–0.87(m,1H),0.79–0.71(m,1H),0.59–0.51(m,1H). 13 CNMR(151MHz,Chloroform-d)δ158.92,156.89,153.10,137.44,135.96,128.76,127.68,1 27.52,123.21,116.85,59.56,52.64,43.80,30.88,19.97,8.32,7.21.HRMS(ESI)calcdfor C 19 H 22 ClN4[M+H] +:341.1528,Found:341.1524.

[0154] I-62: 5,8-Dibenzyl-4-methyl-2-(pyrrolidone-1-yl)-6-vinyl-5,6,7,8-tetrahydropteridine. f =0.10 (petroleum / EtOAc=4:1, v / v); Yellow oil, 42.1 mg, 99% yield; 1 H NMR(600MHz,Chloroform-d)δ7.49(d,J=7.5Hz,2H),7.36(dt,J=8.3,6.0Hz,6H),7.31–7.27(m,2H),5 .52(ddd,J=17.3,10.6,3.8Hz,1H),5.10(dt,J=17.2,1.8Hz,1H),5.00(dt,J=10.6,1.8Hz,1H),4.93( d,J=2.2Hz,2H),4.11(d,J=15.0Hz,1H),3.75(d,J=15.1Hz,1H),3.63(dd,J=12.1,4.1Hz,1H),3.59–3 .53(m,4H),3.42(dh,J=4.0,1.9Hz,1H),3.10(dd,J=12.2,1.7Hz,1H),2.46(s,3H),1.96–1.92(m,4H). 13 C NMR(151MHz,Chloroform-d)δ158.96,156.63,154.76,138.68,138.59,137.51,128.54,128.36,128.18,127.8 9,127.26,127.10,116.08,65.58,59.95,52.40,50.92,46.62,42.99,29.72,25.68,19.81.HRMS(ESI)calcdfor C 27 H 32 N5[M+H] + :426.2652,Found:426.2646.

[0155] I-63:2-(4-(benzo[d][1,3]dihydroxy-5-ylmethyl)piperazin-1-yl)-5,8-dibenzyl-4-methyl-6-vinyl-5,6,7,8-tetrahydropteridine. R f =0.15 (petroleum / EtOAc=4:1, v / v); Yellow oil, 56.9 mg, 99% yield; 1H NMR(600MHz,Chloroform-d)δ7.49(d,J=7.6Hz,2H),7.39–7.29(m,8H),6.93(d,J=1.5Hz,1H),6.82–6.77(m,2H) ,5.96(s,2H),5.51(ddd,J=17.2,10.6,3.7Hz,1H),5.11(dt,J=17.2,1.8Hz,1H),5.01(dt,J=10.6,1.8Hz,1H),4 .93–4.85(m,2H),4.12(d,J=15.2Hz,1H),3.77(dd,J=8.7,3.8Hz,5H),3.61(dd,J=12.2,4.0Hz,1H),3.48(s,2H) ,3.43(dp,J=4.2,2.0Hz,1H),3.11(dd,J=12.2,1.7Hz,1H),2.50(t,J=5.1Hz,4H),2.45(s,3H).HRMS(ESI)calcd for C 35 H 39 N6O2[M+H] + :575.3129,Found:575.3120.

[0156] Example 12: Using chiral or racemic tetrahydropteridine compound I-11 as a substrate, a reduction reaction was carried out with hydrogen in the presence of palladium on carbon to prepare chiral or racemic tetrahydropteridine compound I-81.

[0157]

[0158] A chiral or racemic tetrahydropteridine compound I-11 (10 mol) and palladium on carbon reagent (0.1 mol) were added sequentially. Then, 200 parts by volume of organic solvent were added to the reaction tube. The system was purged with a hydrogen balloon to create a hydrogen atmosphere, and the reaction was carried out at 0-80°C until the reactants were completely reacted. After the reaction, the solvent was removed under reduced pressure. The concentrated crude product was separated by column chromatography to obtain the chiral or racemic product I-81 (petroleum ether:ethyl acetate = 5:1, v / v): (R)-5,8-dibenzyl-4-chloro-6-ethyl-2-methyl-5,6,7,8-tetrahydropteridine. f =0.60 (petroleum ether:ethyl acetate = 2:1, v / v); yellow oily liquid; 91% yield; 87% ee [Daicel Chiralcel IF-3 (0.46cm x 25cm), n-hexane / 2-propanol = 92 / 8, v = 1.0 mL·min] -1 T = 25℃, λ = 254nm, t R(major) = 8.139 min, t R (minor) = 9.432 min];[α] D 25 = -118.4° (c = 0.38, CHCl3). 1 HNMR(600MHz,Chloroform-d)δ7.43(d,J=7.5Hz,2H),7.33–7.25(m,8H),5.13(d,J=17.2Hz,1H),4.91(d,J=10.5Hz,1H),4.43(d,J= 14.8Hz,1H),3.67(d,J=14.8Hz,1H),3.44–3.31(m,2H),3.08(d,J=11.6Hz,1H),2.48(s,3H),1.48–1.40(m,2H),0.90–0.85(m,3H).

[0159] Example 13: Using chiral or racemic tetrahydropteridine compound I-11 as a substrate, a double bond epoxidation reaction was carried out in the presence of m-chloroperoxybenzoic acid to prepare chiral or racemic tetrahydropteridine compound I-82.

[0160]

[0161] A chiral or racemic tetrahydropteridine compound, I-11 (10 mol) and m-chloroperoxybenzoic acid (20 mol), were added sequentially. Then, an organic solvent (200 parts by volume) was added to the reaction tube, and the reaction was carried out at 0-120°C until the reactants were completely reacted. After the reaction, the system was washed sequentially with saturated sodium thiosulfate solution and saturated sodium sulfite solution. The mixture was extracted three times with ethyl acetate, and the combined organic layers were removed under reduced pressure. The concentrated crude product was separated by column chromatography to obtain the chiral or racemic product I-82 (petroleum ether:ethyl acetate = 2:1, v / v): (S)-5,8-dibenzyl-4-chloro-2-methyl-6-((R)-ethylene oxide-2-yl)-5,6,7,8-tetrahydropteridine. f =0.20 (petroleum ether:ethyl acetate = 2:1, v / v); yellow oily liquid; 85% yield; 87% ee [Daicel Chiralcel IF-3 (0.46cm x 25cm), n-hexane / 2-propanol = 70 / 30, v = 1.0 mL·min] -1 T = 25℃, λ = 254nm, t R (major) = 10.157 min, t R (minor) = 12.566min];[α] D 25= -98.2° (c = 0.36, CHCl3). 1 HNMR(600MHz,Chloroform-d)δ7.77–7.64(m,2H),7.56–7.35(m,8H),4.56–4.42(m,2H),4.13–4.07(m,2H),3.42–3.36(m,2H),2.61–2.40(m,6H).

[0162] Example 14: Using chiral or racemic tetrahydropteridine compound I-11 as a substrate, a double bond oxidation reaction was carried out in the presence of osmium tetroxide to prepare chiral or racemic tetrahydropteridine compound I-83.

[0163]

[0164] Quinine (0.5 mol), K3Fe(CN)6 (30 mol), K2CO3 (30 mol), OsO4 (0.05 mol), and organic solvent (200 parts by volume) were added sequentially to the reaction tube at room temperature. The system was then cooled to 0°C, and a chiral or racemic tetrahydropteridine compound, I-11 (10 mol), was added. The reaction was carried out at 0-120°C until the reactants were completely reacted. After the reaction was completed, a saturated sodium sulfite solution was added to quench the reaction. The mixture was extracted three times with ethyl acetate, and the organic layers were combined to remove the solvent under reduced pressure. The crude product was concentrated and separated by column chromatography to obtain the chiral or racemic product I-83 (petroleum ether: ethyl acetate = 1:2, v / v): (R)-1-((S)-5,8-dibenzyl-4-chloro-2-methyl-5,6,7,8-tetrahydropteridine-6-yl)ethane-1,2-diol.

[0165] R f =0.10 (petroleum ether:ethyl acetate = 1:2, v / v); yellow oily liquid; 98% yield; 87% ee [Daicel Chiralcel IF-3 (0.46cm x 25cm), n-hexane / 2-propanol = 50 / 50, v = 1.0 mL·min] -1 T = 25℃, λ = 254nm, t R (major) = 21.237 min, t R (minor) = 28.654min];[α] D 25 = -79.2° (c = 0.46, CHCl3). 1HNMR(600MHz,Chloroform-d)δ7.87–7.73(m,2H),7.67–7.45(m,8H),4.66–4.48(m,2H),4.23–4.16(m,2H),3.65–3.36(m,6H),2.51–2.45(m,3H).

[0166] Example 15: Using chiral or racemic tetrahydropteridine compound I-11 as a substrate, a double bond olefin metathesis reaction was carried out under the action of Grubbs catalyst to prepare chiral or racemic tetrahydropteridine compound I-84.

[0167]

[0168] Under nitrogen atmosphere, chiral or racemic tetrahydropteridine compound I-11 (10 mol), ethyl acrylate (100 mol), and Grubbs catalyst (1 mol) were added sequentially to a reaction tube. Then, 200 parts by volume of organic solvent were added, and the reaction was carried out at 0-120°C until the reactants were completely reacted. After the reaction, the solvent was removed under reduced pressure, and the concentrated crude product was separated by column chromatography to obtain the chiral or racemic product I-84 (petroleum ether:ethyl acetate = 3:1, v / v):(R,E)-3-(5,8-dibenzyl-4-chloro-2-methyl-5,6,7,8-tetrahydropteridine-6-yl)ethyl acrylate. f =0.30 (petroleum ether:ethyl acetate = 1:3, v / v); yellow oily liquid; 88% yield; 87% ee [Daicel Chiralcel IF-3 (0.46cm x 25cm), n-hexane / 2-propanol = 50 / 50, v = 1.0 mL·min] -1 T = 25℃, λ = 254nm, t R (major) = 17.256 min, t R (minor) = 19,987 min];[α] D 25 = -84.2° (c = 0.45, CHCl3). 1 H NMR(600MHz,Chloroform-d)δ7.65–7.57(m,2H),7.43–7.17(m,8H),4.52–4.38(m,2H),4.3 2–4.18(m,4H),4.11–4.02(m,2H),3.62–3.36(m,3H),2.51–2.45(m,3H),1.31–1.17(m,3H).

[0169] Example 16: Antitumor activity of tetrahydropteridine compounds

[0170] (1) Cell type and culture: Human colon cancer cells (HCT-116), human liver cancer cells (Hep G2), and human cervical cancer cells (Hela) were all purchased from iCell. All cell culture reagents were purchased from Life Technologies (Grand Island, Nebraska, USA). HCT-116, Hep G2, and Hela were cultured in Dulbecco's modified Eagle's medium (Gibco, USA) containing 10% fetal bovine serum (Gibco, USA) and in an incubator at 37°C with 5% CO2.

[0171] (2) Cell inhibition rate assay: The inhibitory rates of tetrahydropteridine compounds on tumor cells HCT-116, Hep G2, and HeLa were detected using the CCK-8 assay. Specific steps: 1×10⁻⁶ 5 Cells were seeded into each well of a 96-well plate and cultured for 24 hours to allow cell adhesion and stability. The target compound was then added for 48 hours, followed by CCK-8 reagent and incubation for another 1-4 hours. After treatment, the OD value was measured at 450 nm using a microplate reader, and absorbance was analyzed to determine cell viability and inhibition rate at a specific concentration (20 μM), compared with the positive control drug camptothecin (CPT). The results are shown in Table 10-12: Inhibition rate = (Control - Experimental) / (Control - Blank) * 100%.

[0172] Table 10. Inhibitory effects of tetrahydropteridine compounds on human colon cancer cells (HCT-116).

[0173]

[0174]

[0175] Table 11 Inhibitory effects of tetrahydropteridine compounds on human hepatocellular carcinoma cells (Hep G2).

[0176] compound Inhibition rate (% ± SD) compound Inhibition rate (% ± SD) compound Inhibition rate (% ± SD) CPT 78.33±5.15 (±)-I-58 79.24±7.82 (S)-I-69 82.51±2.34 (±)-I-1 87.18±0.34 (S)-I-58 82.26±4.81 (±)-I-70 90.49±0.07 (R)-I-1 84.26±0.90 (±)-I-59 76.51±2.44 (S)-I-70 92.33±0.45 (±)-I-2 90.23±0.76 (S)-I-59 78.61±2.37 (±)-I-71 83.48±0.11 (R)-I-2 88.82±1.97 (±)-I-60 84.48±1.39 (S)-I-71 87.34±0.65 (±)-I-6 96.23±1.33 (S)-I-60 86.37±1.27 (±)-I-72 86.90±0.24 (R)-I-6 63.01±3.25 (±)-I-61 66.41±2.01 (S)-I-72 90.90±0.65 (±)-I-7 86.07±4.17 (S)-I-61 69.43±2.23 (±)-I-73 87.46±6.35 (R)-I-7 75.26±0.99 (±)-I-62 96.23±6.50 (S)-I-73 91.43±6.45 (±)-I-9 85.57±2.97 (S)-I-62 97.22±6.43 (±)-I-74 95.55±3.39 (R)-I-9 83.90±4.78 (±)-I-63 34.26±5.53 (S)-I-74 97.54±3.23 (±)-I-11 89.35±0.67 (S)-I-63 41.25±5.03 (±)-I-75 96.29±4.39 (R)-I-11 79.43±3.30 (±)-I-64 57.58±3.77 (S)-I-75 97.23±4.44 (S)-I-11 93.99±0.57 (S)-I-64 59.34±3.54 (±)-I-81 80.92±0.63 (±)-I-24 93.52±1.42 (±)-I-65 55.97±2.59 (R)-I-81 70.67±1.33 (R)-I-24 91.43±2.52 (S)-I-65 59.23±2.34 (±)-I-82 77.62±0.62 (S)-I-24 95.24±0.43 (±)-I-66 29.25±2.87 (R)-I-82 68.54±0.43 (±)-I-30 88.23±0.21 (S)-I-66 31.24±3.07 (±)-I-83 75.63±0.96 (R)-I-30 61.10±1.45 (±)-I-67 47.97±6.34 (R)-I-83 71.67±0.45 (S)-I-30 93.21±0.56 (S)-I-67 53.23±5.31 (±)-I-84 87.33±0.66 (±)-I-34 72.84±0.28 (±)-I-68 89.80±5.49 (R)-I-84 77.29±3.30 (R)-I-34 64.37±3.65 (S)-I-68 92.45±5.76 (S)-I-34 80.56±0.22 (±)-I-69 79.57±3.14

[0177] Table 12 Inhibitory effects of tetrahydropteridine compounds on human cervical cancer cells (HeLa).

[0178]

[0179]

[0180] Experimental results showed that: (1) at a concentration of 20 μM, the tetrahydropteridine compounds of the present invention exhibited significant inhibitory effects on human colon cancer cells HCT-116, human liver cancer cells Hep G2, and human cervical cancer cells Hela; (2) the series of compounds showed excellent inhibitory activity against human colon cancer cells HCT-116, with most single-concentration inhibition rates exceeding 90%; compounds (±)-I-6, (±)-I-62, (S)-I-62, (±)-I-74, (S)-I-74, (±)-I-75 and compound (S)-I-75 showed inhibition rates exceeding 95% against human liver cancer cells Hep G2, demonstrating excellent inhibitory activity; compounds (S)-I-24, (±)-I-67, (S)-I-67, (±)-I-75 and compound (S)-I-75 showed inhibition rates exceeding 99% against human cervical cancer cells Hela, demonstrating excellent inhibitory activity. (3) Comparing the inhibition rate data of the same compound with different configurations in the table above, it can be concluded that when the chiral center configuration of the compound is S, it exhibits better inhibitory activity. (4) Comparing the inhibition rate data of (±)-I-1 and (±)-I-2 (or (R)-I-1 and (R)-I-2) in the table above, it can be concluded that the presence of benzyl in the compound has an auxiliary effect on improving its inhibitory activity. (5) Comparing the inhibition rate data of (±)-I-11 and its double bond reduction product (±)-I-81 (or (R)-I-11 and its double bond reduction product (R)-I-81) in the table above, it can be concluded that the presence of vinyl groups on the chiral center of this type of compound has an auxiliary effect on improving its inhibitory activity. (6) Comparing the inhibition rate data of (±)-I-11 and its double bond oxidation products (±)-I-82, (±)-I-83 or its olefin metathesis product (±)-I-84 (or (R)-I-11 and its double bond oxidation products (R)-I-82, (R)-I-83 or its olefin metathesis product (R)-I-84) in the table above, it can be concluded that the presence of vinyl groups on the chiral centers of these compounds has an auxiliary effect in enhancing their inhibitory activity. (7) In summary, the test results show that the tetrahydropteridine compounds with significant structural features provided by this invention have significant in vitro antitumor activity and can be further developed as potential antitumor drugs.

[0181] The above embodiments are preferred embodiments of the present invention, but the embodiments of the present invention are not limited to the above embodiments. Any changes, modifications, substitutions, combinations, or simplifications made without departing from the spirit and principle of the present invention shall be considered equivalent substitutions and shall be included within the protection scope of the present invention.

Claims

1. A class of chiral or racemic tetrahydropteridine compounds or pharmaceutically acceptable salts thereof, characterized in that... Its structural formula is shown in Formula I; wherein, the carbon atom marked with * is a chiral carbon atom with a configuration of R, S or R / S; the tetrahydropteridine compound is a levorotatory, dextrorotatory or racemic form; Among them, R 1 R 2 Individually selected from hydrogen, deuterium, halogen atom, hydroxyl, cyano, nitro, amino, mercapto, substituted or unsubstituted C1-C20 straight-chain or branched alkyl, substituted or unsubstituted C3-C20 cycloalkyl, C1-C20 haloalkyl, substituted or unsubstituted C1-C20 alkyloxy, substituted or unsubstituted C1-C20 alkylthio, substituted or unsubstituted C1-C20 alkylsulfonyl, substituted or unsubstituted C1-C20 alkylsulfoxide, substituted or unsubstituted C1-C20 N-alkyl-substituted amino, substituted or unsubstituted C1-C20 N,N-dialkyl-substituted amino, substituted or unsubstituted C1-C20 acyl, substituted or unsubstituted C1-C20 amide. The following groups are included: alkyl, substituted or unsubstituted C1-C20 carboxyl groups and their corresponding esters, sulfonic acid groups, substituted or unsubstituted C1-C20 sulfonate groups, substituted or unsubstituted C1-C20 aminosulfonyl groups, substituted or unsubstituted C1-C20 sulfonamide groups, substituted or unsubstituted aryl groups, substituted or unsubstituted arylmethylene groups, substituted or unsubstituted arylmethoxy groups, substituted or unsubstituted C2-C20 heterocyclic groups or heterocyclic aryl groups containing one or more of N, O and S, substituted or unsubstituted C2-C20 heterocyclic methylene groups or heterocyclic arylmethylene groups containing one or more of N, O and S, substituted or unsubstituted C1-C9 alkylsilyl groups, and substituted or unsubstituted phenylsilyl groups. R 3 R 4 The groups are individually selected from hydrogen, deuterium, substituted or unsubstituted C1-C20 straight-chain or branched alkyl groups, substituted or unsubstituted C3-C20 cycloalkyl groups, substituted or unsubstituted C3-C20 cycloalkylmethylene groups, substituted or unsubstituted C2-C20 alkenyl groups, substituted or unsubstituted C2-C20 alkynyl groups, substituted or unsubstituted C1-C20 carboxyl groups and corresponding ester groups, substituted or unsubstituted C1-C20 acyl groups, substituted or unsubstituted C1-C20 amide groups, and sulfonic acid groups. Substituted or unsubstituted C1-C20 aminosulfonyl group, substituted or unsubstituted C1-C20 sulfonamide group, substituted or unsubstituted C1-C20 sulfonyl group, substituted or unsubstituted aryl acyl group, substituted or unsubstituted C1-C20 alkyloxycarbonyl group, substituted or unsubstituted aryl group, substituted or unsubstituted arylmethylene group, substituted or unsubstituted benzyl group, substituted or unsubstituted C2-C20 heterocyclic methylene group or heterocyclic arylmethylene group containing one or more of N, O and S; R 5 R 6 R 7 R 8 R 9 Individually selected from hydrogen, deuterium, halogen, hydroxyl, cyano, nitro, amino, C1-C20 straight-chain or branched alkyl, C3-C20 cycloalkyl, C1-C20 haloalkyl, C1-C20 carboxyl and its corresponding ester or amide, C2-C20 alkenyl, C2-C20 alkynyl, C1-C20 hydroxyloxy, C1-C20 hydroxythio, substituted or unsubstituted aryl, substituted or unsubstituted arylmethylene, C1-C20 N-alkyl-substituted amino, C1-C20 N,N-dialkyl-substituted amino, or a combination of one or more combinations thereof, substituted or unsubstituted C2-C20 heterocyclic or heterocyclic aryl groups containing N, O, and S, substituted or unsubstituted C2-C20 heterocyclic methylene or heterocyclic arylmethylene groups containing N, O, and S, or R 7 R 8 A heterocyclic group or heterocyclic aryl group containing one or more of N, O and S, connected to form a substituted or unsubstituted C2-C20.

2. The chiral or racemic tetrahydropteridine compound or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that: The structural formula of the tetrahydropteridine compound is shown in Formula I, wherein R 1 R 2 Individually selected from hydrogen, deuterium, halogen atom, hydroxyl, cyano, nitro, amino, mercapto, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, substituted or unsubstituted C5-C20 straight-chain or branched alkyl, cyclopropane, substituted or unsubstituted C4-C20 cycloalkyl, trifluoromethyl, C2-C20 haloalkyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, substituted or unsubstituted C5-C20 alkyloxy, methylthio, substituted or unsubstituted C2-C20 alkylthio, methyl sulfone, substituted or unsubstituted C2-C20 alkyl sulfone, substituted or unsubstituted C1-C20 N-alkyl-substituted amino, substituted or unsubstituted C1-C20 N,N-dialkyl-substituted amino, substituted or unsubstituted C1- Acyl group of C20, substituted or unsubstituted amide group of C1-C20, substituted or unsubstituted carboxyl group of C1-C20 and its corresponding ester group, sulfonic acid group, substituted or unsubstituted sulfonate group of C1-C20, substituted or unsubstituted sulfonamide group of C1-C20, substituted or unsubstituted sulfonyl group of C1-C20, substituted or unsubstituted aryl group, substituted or unsubstituted arylmethylene group, substituted or unsubstituted arylmethoxy group, substituted or unsubstituted heterocyclic group or heterocyclic aryl group of C2-C20 containing one or more of N, O and S, substituted or unsubstituted heterocyclic methylene group or heterocyclic arylmethylene group of C2-C20 containing one or more of N, O and S, trimethylsilyl group, triethylsilyl group, substituted or unsubstituted alkylsilyl group of C7-C9, substituted or unsubstituted triphenylsilyl group; R 3 R 4 Individually selected from hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, substituted or unsubstituted C5-C20 straight-chain or branched alkyl, cyclopropane, substituted or unsubstituted C4-C20 cycloalkyl, substituted or unsubstituted C4-C20 cycloalkylmethylene, allyl, substituted or unsubstituted C4-C20 alkenyl, propargyl, substituted or unsubstituted C4-C20 alkynyl, substituted or unsubstituted C1-C20 carboxyl and its corresponding ester group, substituted or unsubstituted C1-C20 amide, formyl, acetyl, etc. Substituted or unsubstituted C3-C20 acyl group, sulfonic acid group, substituted or unsubstituted C1-C20 sulfonamide group, substituted or unsubstituted C1-C20 sulfonyl group, benzoyl group, substituted or unsubstituted aryl acyl group, tert-butoxycarbonyl group, fluorenylmethoxycarbonyl group, 2,2,2-trichloroethoxycarbonyl group, substituted or unsubstituted C5-C20 hydroxyoxycarbonyl group, substituted or unsubstituted aryl group, substituted or unsubstituted arylmethylene group, substituted or unsubstituted benzyl group, substituted or unsubstituted C2-C20 heterocyclic methylene group or heterocyclic arylmethylene group containing one or more of N, O and S; R 5 R 6 R 7 R 8 R 9 Each group is independently selected from hydrogen, deuterium, halogen, hydroxyl, cyano, nitro, amino, C1-C20 straight-chain or branched alkyl, C3-C20 cycloalkyl, C1-C20 haloalkyl, C1-C20 carboxyl and its corresponding ester group, C1-C20 amide, C2-C20 alkenyl, C2-C20 alkynyl, C1-C20 hydroxyloxy, C1-C20 hydroxythio, substituted or unsubstituted aryl, etc. One or more of the following: substituted or unsubstituted arylmethylene, C1-C20 N-alkyl-substituted amino group, C1-C20 N,N-dialkyl-substituted amino group; substituted or unsubstituted C2-C20 heterocyclic group or heterocyclic aryl group containing N, O and S; substituted or unsubstituted C2-C20 heterocyclic methylene or heterocyclic arylmethylene group containing N, O and S; or R 7 R 8 A heterocyclic group or heterocyclic aryl group containing one or more of N, O and S, connected to form a substituted or unsubstituted C2-C20.

3. The chiral or racemic tetrahydropteridine compound or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that: The structural formula of the tetrahydropteridine compound is shown in Formula I, wherein R 1 R 2 Each group is independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, carboxyl, cyano, nitro, amino, mercapto, methylthio, methyl sulfone, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, substituted or unsubstituted C5-C20 straight-chain or branched alkyl groups, cyclopropane, substituted or unsubstituted C4-C20 cycloalkyl groups, trifluoromethyl, C2-C20 haloalkyl groups, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, and substituted or unsubstituted C5-C20 alkyloxy groups. , tert-butoxyamide, acetyl, acetamido, aminosulfonyl, methylaminosulfonyl, anilinesulfonyl, benzylaminosulfonyl, phenylsulfonamide, substituted or unsubstituted phenyl, substituted or unsubstituted aryl, benzyl, benzyloxy, morpholinyl, piperidinyl, piperazine, pyrrole, tetrahydropyrrole, substituted or unsubstituted C2-C20 heterocyclic groups or heterocyclic aryl groups containing one or more of N, O and S, trimethylsilyl, triethylsilyl, substituted or unsubstituted C7-C9 alkylsilyl, substituted or unsubstituted triphenylsilyl; R 3 R 4 Each of the following is independently selected from hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, substituted or unsubstituted C5-C20 straight-chain or branched alkyl, cyclopropane, cyclohexane, substituted or unsubstituted C4-C20 cycloalkyl, formyl, acetyl, aminosulfonyl, methylaminosulfonyl, anilinesulfonyl, benzylaminosulfonyl, phenylsulfonamide, benzyl, 4-methylbenzyl, 4-methoxybenzyl, 4-fluorobenzyl, benzoyl, p-toluenesulfonyl, tert-butoxycarbonyl, fluorenemethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, 2-thiazolylmethylene, 2-thiophenemethylene, 2-furanmethylene or 2-pyridinylmethylene; R 5 R 6 R 7 R 8 R 9 Each group is independently selected from one or more combinations of hydrogen, deuterium, halogen, hydroxyl, cyano, nitro, amino, C1-C20 straight-chain or branched alkyl, C3-C20 cycloalkyl, C1-C20 haloalkyl, C1-C20 carboxyl and its corresponding ester group, C1-C20 amide, C2-C20 alkenyl, C2-C20 alkynyl, C1-C20 hydroxyloxy, C1-C20 hydroxythio, aryl, C1-C20 N-alkyl-substituted amino, and C1-C20 N,N-dialkyl-substituted amino, or R. 7 R 8 Connected to form oxygen-containing rings of C2-C20.

4. The chiral or racemic tetrahydropteridine compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-3, characterized in that: The substituents are independently selected from one or more combinations of hydrogen, deuterium, halogen, hydroxyl, cyano, nitro, amino, C1-C20 straight-chain or branched alkyl, C3-C20 cycloalkyl, C1-C20 haloalkyl, C1-C20 carboxyl and corresponding ester group, sulfonic acid group, C1-C20 sulfonic acid group, C2-C20 alkenyl, C2-C20 alkynyl, C1-C20 hydroxyloxy, C1-C20 hydroxythiol, aryl, C1-C20 N-alkyl-substituted amino, and C1-C20 N,N-dialkyl-substituted amino.

5. The chiral or racemic tetrahydropteridine compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-3, characterized in that: R 1 R 2 R 3 R 4 R 5 R 6 R 7 R 8 R 9 One or more hydrogen atoms are replaced by a deuterium atom, halogen atom, oxygen atom, sulfur atom, C1-C20 straight-chain or branched alkyl group, C3-C20 cycloalkyl group, C1-C20 haloalkyl group, alkenyl group, alkynyl group, aryl group, hydroxyl group, amino group, carbonyl group, carboxyl group, ester group, sulfonic acid group, sulfonate group, cyano group, nitro group, C1-C20 alkyloxy group, C1-C20 alkylthio group, or substituted or unsubstituted C2-C20 heterocyclic methylene or heterocyclic aryl methylene group containing N, O and S.

6. The chiral or racemic tetrahydropteridine compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-3, characterized in that: R 1 R 2 R 3 R 4 R 5 R 6 R 7 R 8 R 9 One or more hydrogen atoms are substituted by deuterium, fluorine, chlorine, bromine, iodine, oxygen, alkenyl, alkynyl, aryl, hydroxyl, amino, carbonyl, carboxyl, ester, cyano, methyl, ethyl, methoxy, methylthio, or nitro.

7. A method for preparing a chiral or racemic tetrahydropteridine compound or a pharmaceutically acceptable salt thereof as described in any one of claims 1-6, characterized in that: Specifically, it is obtained by reacting an allyl compound intermediate as a raw material with an iridium complex generated by the interaction of an iridium compound and a phosphoramidite ligand under the action of an alkali. Alternatively, using a base as an additive, and pyrimidine amines and allyl amines as substrates, racemic tetrahydropteridine compounds can be synthesized efficiently in air via a two-step, one-pot method involving intermolecular nucleophilic substitution and allyl amination reactions without the need for metal catalysis.

8. The preparation method according to claim 7, characterized in that: The structural formulas of the allyl compound intermediates, pyrimidine amine compounds, and allyl amine compounds are shown below: Wherein, LG is the leaving group, which can be hydroxyl, chlorine, bromine, etc. Where M is NH or O; R 10 It is at least one of a halogen-substituted or unsubstituted C1-C20 alkyl group or a halogen-substituted or unsubstituted C1-C20 alkyl group; R 11 It is a C1-C20 alkyl group, or a substituted or unsubstituted C6-C20 aryl group.

9. The use of the chiral or racemic tetrahydropteridine compound or a pharmaceutically acceptable salt thereof as described in any one of claims 1-6 in the preparation of an antitumor medicament and its lead compound.

10. A pharmaceutical composition for the prevention and / or treatment of tumors, characterized in that... The components contain a chiral or racemic tetrahydropteridine compound or a pharmaceutically acceptable salt thereof as described in any one of claims 1-6.

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