TWI690529B - Hydroxyl purine compound and application thereof - Google Patents

Abstract

The present invention provides a series of hydroxyl purine compounds and their applications as a PDE2 inhibitor or a TNF-α inhibitor, specifically a compound having a chemical structure as shown in the following formula (I), tautomers, and pharmaceutically acceptable salts thereof.

Description

Hydroxypurine compounds and their applications

The present invention relates to a series of hydroxypurine compounds and their application as PDE2 or TNF-α inhibitors, in particular to compounds represented by formula (I), tautomers thereof or pharmaceutically acceptable salts thereof.

Phosphodiesterase (PDE) catalyzes the hydrolysis of cyclic nucleotides cGMP and cAMP, and controls various physiological reactions by controlling the intramolecular concentration of these two important secondary signaling factors. The abnormal regulation of cyclic nucleotides cGMP and cAMP molecules is the cause of many diseases. There are many drugs to improve and treat diseases by inhibiting PDE activity, such as PDE5 inhibitors for pulmonary hypertension, PDE4 inhibitors for Arthritis caused by psoriasis. There are eleven major classes of phosphodiesterase genes currently known, and each class can express several subtypes, with a total of more than 100 PDE subtypes. Different subtypes have different structures, different tissue distributions, and also have very different activities on the cyclic nucleotides cGMP and cAMP, and the physiological functions of regulation are also very different.

PDE2 phosphodiesterase can catalyze the hydrolysis of cyclic nucleotides cGMP and cAMP, while cAMP activity is regulated by cGMP, which plays a key role in the balance of cGMP and cAMP functions in cells. PDE2 is widely expressed in human tissues, mainly distributed in the heart, central nervous system, liver, adrenal glands, endothelial cells and platelets. PDE2 participates in the regulation of various physiological activities, such as central learning, memory, and cognition, and maintains the basic rhythm of the heart, smooth muscle, and endothelial cells. Cell permeability and regulate inflammation. PDE2 gene knockout mice directly cause embryo death. By inhibiting PDE2 activity, it may be used for various central and cardiovascular diseases, and to control inflammation.

The non-selective PDE inhibitory activity of various natural and synthetic purine compounds has been discovered for a long time, such as caffeine, theophylline, pentoxifylline and so on. Pentoxifylline (PDE2 activity) is clinically approved for the claudication of the lower extremities caused by peripheral vascular occlusion. Its main functions are to reduce blood viscosity, improve red blood cell deformation, and inhibit platelet aggregation. New highly selective PDE2 inhibitors have also been reported to control endothelial cell division and vascular regeneration, and to improve central cognitive impairment. However, the overall development and application of new selective PDE2 inhibitors is still very limited, and the discovery and application of new PDE2 inhibitors has broad prospects.

Tumor necrosis factor alpha (TNF-α) is a cytokine with multiple biological activities, which has an important influence on the occurrence, development and outcome of various diseases. TNF-α is mainly produced by monocytes and macrophages, and participates in the body's immune regulation and cytokine network coordination. Under normal circumstances, TNF-α plays an important role in immune defense and immune supervision, but in some cases it has an adverse effect. Studies have shown that overexpression of TNF-α can induce the expression of proinflammatory cytokines such as interleukin-1 (IL-1), IL-6, etc., increase the permeability of endothelial cells, up-regulate the expression of adhesion molecules, and activate Leukocytes and eosinophils, and induce bone synoviocytes and chondrocytes to secrete acute-phase substances and tissue-degrading enzymes to promote inflammation. These pathological reactions play a very important role in the occurrence and development of many immune-mediated inflammatory diseases (IMID), such as rheumatoid arthritis (RA), psoriatic arthritis (psoriatic arthritis) , PsA), ankylosing spondylitis (AS), inflammatory bowel disease (IBD), juvenile chronic arthritis (JCA), vasculitis, etc. Studies have shown that TNF-α is an ideal target for the above multiple IMIDs. Using TNF-α antagonists (TNF-α inhibitors) to neutralize excess TNF-α is effective in preventing and treating TNF-α -An ideal pathway for chronic inflammatory diseases caused by over-expression of α. The mechanism of PDE2 can regulate the expression of TNF-α, so the level of TNF-α can be controlled by regulating the activity of PDE2, so that the inflammation can be controlled.

其中，環B為任選被1~3個R取代的4~6元環醚或烷氧基-環烷基；L為任選被1~2個R取代的C_1-3烷基；環A選自任選被1或2個R₁取代的5~6元芳基或雜芳基；R₁選自鹵素、OH、NH₂、任選被1~3個R₂取代的：C_1-6烷基或雜烷基、3~6元環烷基或雜環烷基、被3~6元環烷基或雜環烷基取代的C_1-6烷基或雜烷基；R₂選自鹵素、OH、NH₂、Me、CF₃、OMe、OCF₃；所述雜代表雜原子，選自O、S、N，每個雜烷基或雜環烷基上的雜原子數目分別獨立地選自1、2或3；R選自鹵素、N(R’)(R’)、任選被1~3個R’取代的C_1-3烷基或雜烷基；R’選自H、鹵素、NH₂、Me、CF₃、OMe、OCF₃。 The present invention provides a compound represented by formula (I), its tautomer or a pharmaceutically acceptable salt thereof,

Among them, ring B is a 4- to 6-membered cyclic ether or alkoxy-cycloalkyl optionally substituted by 1 to 3 R; L is a C _1-3 alkyl optionally substituted by 1 to 2 R; A is selected from 5-6 membered aryl or heteroaryl optionally substituted with 1 or 2 R ₁ ; R _{1 is} selected from halogen, OH, NH ₂ , optionally substituted with 1 to 3 R ₂ : C _{1 -6} alkyl or heteroalkyl, 3-6 membered cycloalkyl or heterocycloalkyl, C _1-6 alkyl or heteroalkyl substituted with 3-6 membered cycloalkyl or heterocycloalkyl; R ₂ Selected from halogen, OH, NH ₂ , Me, CF ₃ , OMe, OCF ₃ ; the hetero represents hetero atoms, selected from O, S, N, the number of hetero atoms on each heteroalkyl or heterocycloalkyl group is Independently selected from 1, 2 or 3; R is selected from halogen, N(R')(R'), C _1-3 alkyl or heteroalkyl optionally substituted with 1 to 3 R's;R'is selected From H, halogen, NH ₂ , Me, CF ₃ , OMe, OCF ₃ .

In one embodiment of the present invention, the above R _{1 is} selected from halogen, OH, NH ₂ , optionally substituted by 1 to 3 R ₂ : C _1-4 alkyl or heteroalkyl, and substituted by 3 to 5 membered cycloalkyl Or heterocycloalkyl substituted C _1-3 alkyl or heteroalkyl.

In one aspect of the present invention, the above R _{1 is} selected from: Me, CF ₃ , Et, CH ₂ CF ₃ ,

In one aspect of the present invention, the above, R is selected from the group consisting of: F, Cl, Br, I, Me,

In one embodiment of the present invention, the above-mentioned ring B is selected from those optionally substituted with 1 to 3 R:

In one embodiment of the present invention, the above-mentioned ring B is selected from those optionally substituted with 1 to 3 R:

In one embodiment of the present invention, the ring B is selected from:

In one aspect of the present invention, the above L is selected from those optionally substituted by 1 to 2 R: methylene,

In one aspect of the present invention, the above L is selected from the group consisting of methylene,

In one aspect of the present invention, the above-mentioned ring A is selected from those optionally substituted with 1 or 2 R ₁ : imidazolyl, pyrazolyl, pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl, phenyl.

In one embodiment of the present invention, the above ring A is optionally substituted with 1 or 2 R ₁ :

In one embodiment of the present invention, the ring A is selected from:

選自：

In one aspect of the present invention, the above structural unit

From:

In one embodiment of the present invention, the above compound is selected from:

The present invention also provides the use of the above compound, its tautomer or its chemically acceptable salt in the preparation of PDE2 inhibitors and TNF-a inhibitors.

Related definitions.

Unless otherwise stated, the following terms and phrases used herein are intended to have the following meanings. A specific term or phrase should not be considered uncertain or unclear unless specifically defined, but should be understood in its ordinary meaning. When a trade name appears in this article, it is intended to refer to its corresponding trade product or its active ingredient.

C _{1-12 is} selected from C ₁ , C ₂ , C ₃ , C ₄ , C ₅ , C ₆ , C ₇ , C ₈ , C ₉ , C ₁₀ , C ₁₁ and C ₁₂ ; C _{3-12 is} selected from C ₃ , C ₄ , C ₅ , C ₆ , C ₇ , C ₈ , C ₉ , C ₁₀ , C ₁₁ and C ₁₂ .

The term "pharmaceutically acceptable" as used herein refers to those compounds, materials, compositions and/or dosage forms, which are within the scope of reliable medical judgment and are suitable for use in contact with human and animal tissues Without excessive toxicity, irritation, allergic reactions or other problems or complications, commensurate with a reasonable benefit/risk ratio.

The term "pharmaceutically acceptable salt" refers to a salt of a compound of the present invention, prepared from a compound having a specific substituent and a relatively non-toxic acid or base found in the present invention. When the compounds of the present invention contain relatively acidic functional groups, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of base in a pure solution or a suitable inert solvent. Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amine or magnesium salts or similar salts. When the compounds of the present invention contain relatively basic functional groups, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of acid in a pure solution or a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include inorganic acid salts including, for example, hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, Bisulfate, hydroiodic acid, phosphorous acid, etc.; and organic acid salts, such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, Fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, methanesulfonic acid and other similar acids; also includes amino acids (such as arginine, etc.) Salt, as well as Portuguese Salts of organic acids such as uronic acids (see Berge et al., "Pharmaceutical Salts", Journal of Pharmaceutical Science 66: 1-19 (1977)). Certain compounds of the present invention contain basic and acidic functional groups and can be converted to any base or acid addition salt.

Preferably, the salt is contacted with a base or an acid in a conventional manner, and then the parent compound is separated, thereby regenerating the neutral form of the compound. The parent form of the compound differs from its various salt forms in certain physical properties, such as solubility in polar solvents.

As used herein, a "pharmaceutically acceptable salt" belongs to a derivative of the compound of the present invention, wherein the parent compound is modified by forming a salt with an acid or a salt with a base. Examples of pharmaceutically acceptable salts include, but are not limited to, inorganic acids or organic acid salts of bases such as amines, alkali metal or organic salts of acid radicals such as carboxylic acids, and the like. Pharmaceutically acceptable salts include conventional non-toxic salts or quaternary ammonium salts of the parent compound, such as salts formed from non-toxic inorganic or organic acids. Conventional non-toxic salts include, but are not limited to, those derived from inorganic and organic acids selected from 2-ethoxybenzoic acid, 2-hydroxyethanesulfonic acid, acetic acid, ascorbic acid , Benzenesulfonic acid, benzoic acid, bicarbonate, carbonic acid, citric acid, edetic acid, ethanedisulfonic acid, ethanesulfonic acid, fumaric acid, glucoheptose, gluconic acid, glutamic acid, glycolic acid , Hydrobromic acid, hydrochloric acid, hydroiodide, hydroxyl, hydroxynaphthalene, isethionic acid, lactic acid, lactose, dodecylsulfonic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, nitric acid, oxalic acid , Pamoic acid, pantothenic acid, phenylacetic acid, phosphoric acid, polygalacturaldehyde, propionic acid, salicylic acid, stearic acid, acetic acid, succinic acid, aminosulfonic acid, p-aminobenzenesulfonic acid, sulfuric acid, Tannin, tartaric acid and p-toluenesulfonic acid.

The pharmaceutically acceptable salts of the present invention can be synthesized from parent compounds containing acid or base groups via conventional chemical methods. Generally, such salts are prepared by reacting these compounds in free acid or base form with a stoichiometric amount of the appropriate base or acid in water or an organic solvent or a mixture of both. Generally, non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred.

In addition to salt forms, the compounds provided by the invention also exist in prodrug forms. The prodrugs of the compounds described herein easily undergo chemical changes under physiological conditions to transform the compounds of the invention. In addition, prodrugs can be converted to the compounds of the invention via chemical or biochemical methods in the in vivo environment.

Certain compounds of the invention may exist in unsolvated or solvated forms, including hydrated forms. Generally speaking, the solvated form is equivalent to the unsolvated form, and is included in the scope of the present invention.

Certain compounds of the invention may have asymmetric carbon atoms (optical centers) or double bonds. Racemates, diastereomers, geometric isomers and individual isomers are included within the scope of the present invention.

The graphical representation of racemic, ambiscalemic and scalemic or enantiomerically pure compounds in this article is from Maehr, J. Chem. Ed. 1985, 62: 114-120. In 1985, 62: 114-120. Unless otherwise stated, the absolute configuration of a three-dimensional center is indicated by a wedge-shaped key and a dotted key. When the compounds described herein contain olefinic double bonds or other geometrically asymmetric centers, unless otherwise specified, they include E and Z geometric isomers. Likewise, all tautomeric forms are included within the scope of the present invention.

The compounds of the present invention may exist in specific geometric or stereoisomeric forms. The present invention contemplates all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, ( R )- and ( S )-enantiomers, diastereomers Isomers, ( D )-isomers, ( L )-isomers, and their racemic mixtures and other mixtures, such as enantiomerically or diastereomerically enriched mixtures, all of which belong to Within the scope of the invention. Additional asymmetric carbon atoms may be present in the substituents such as alkyl. All these isomers and mixtures thereof are included in the scope of the present invention.

The optically active ( R )- and ( S )-isomers and D and L isomers can be prepared via chiral synthesis or chiral reagents or other conventional techniques. If an enantiomer of a compound of the present invention is desired, it can be prepared via asymmetric synthesis or derivatization with a chiral auxiliary, where the resulting mixture of diastereomers is separated and the auxiliary group is cleaved to provide pure Enantiomers are required. Alternatively, when the molecule contains a basic functional group (such as an amine group) or an acidic functional group (such as a carboxyl group), a salt of a diastereomer is formed with an appropriate optically active acid or base, which is then dissociated by a well-known method in the art. The diastereoisomers are resolved by the separation method, and then the pure enantiomers are recovered. In addition, the separation of enantiomers and diastereomers is usually accomplished through the use of chromatography, which uses a chiral stationary phase and is optionally combined with chemical derivatization methods (eg, from amines to amines) Carboxylate).

The compound of the present invention may contain unnatural proportions of atomic isotopes in one or more atoms constituting the compound. For example, compounds can be labeled with radioisotopes, such as tritium ( ³ H), iodine-125 ( ¹²⁵ I) or C-14 ( ¹⁴ C). The conversion of all isotopic compositions of the compounds of the present invention, whether radioactive or not, is included in the scope of the present invention.

The term "pharmaceutically acceptable carrier" refers to any preparation or carrier medium capable of delivering an effective amount of the active substance of the present invention without interfering with the biological activity of the active substance and having no toxic side effects to the host or patient. Representative carriers include water, oil, and vegetables And minerals, paste base, lotion base, ointment base, etc. These bases include suspending agents, tackifiers, penetration enhancers and the like. Their formulation is well known to those skilled in the cosmetics field or topical pharmaceutical field. For other information about the carrier, reference can be made to Remington: The Science and Practice of Pharmacy, 21st Ed., Lippincott, Williams & Wilkins (2005), the contents of which are incorporated herein by reference.

The term "excipient" generally refers to the carrier, diluent and/or medium required to formulate an effective pharmaceutical composition.

For drugs or pharmacologically active agents, the term "effective amount" or "therapeutically effective amount" refers to a sufficient amount of a drug or medicament that is non-toxic but achieves the desired effect. For the present invention For oral dosage forms, the "effective amount" of one active substance in the composition refers to the amount required to achieve the desired effect when used in combination with another active substance in the composition. The determination of the effective amount varies from person to person, depending on the age and general condition of the recipient, and also on the specific active substance. The appropriate effective amount in a case can be determined by those skilled in the art based on routine experiments.

The terms "active ingredient", "therapeutic agent", "active substance" or "active agent" refer to a chemical entity that can effectively treat a target disorder, disease or condition.

The term "substituted" means that any one or more hydrogen atoms on a particular atom are replaced by a substituent, including heavy hydrogen and hydrogen variants, as long as the valence state of the particular atom is normal and the compound after substitution is stable . When the substituent is a keto group (ie = O), it means that two hydrogen atoms are substituted. Ketone substitution does not occur on aromatic groups. The term "optionally substituted" means that it may or may not be substituted. Unless otherwise specified, the type and number of substituents may be arbitrary on the basis of chemical realization.

When any variable (such as R) appears more than once in the composition or structure of a compound, its definition in each case is independent. Thus, for example, if a group is substituted with 0-2 Rs, the group can optionally be substituted with up to two Rs, and R in each case has independent options. In addition, combinations of substituents and/or variants thereof are only allowed if such combinations will produce stable compounds.

When one of the variables is selected from a single bond, it means that the two groups to which it is connected are directly connected. For example, when L represents a single bond in A-L-Z, it means that the structure is actually A-Z.

或

表示其可在環己基或者環基二烯上的任意一個位置發生取代。 When the bond of a substituent can be cross-linked to two atoms on a ring, the substituent can be bonded to any atom on the ring. When the substituents listed do not indicate via which atom they are connected to a compound included in the chemical structure formula but not specifically mentioned, such substituents may be bonded via any of their atoms. Combinations of substituents and/or variants thereof are only allowed if such combinations will produce stable compounds. For example, structural unit

or

It means that it can be substituted at any position on the cyclohexyl group or the cyclodiene.

The substituents of the alkyl and heteroalkyl radicals are generally referred to as "alkyl substituents", which can be selected from but not limited to one or more of the following groups: -R', -OR', =O, = NR', =N-OR', -NR'R", -SR', halogen, -SiR'R"R"', OC(O)R', -C(O)R', -CO ₂ R ', -CONR'R", -OC(O)NR'R", -NR"C(O)R', NR'C(O)NR"R'", -NR"C(O) ₂ R '、-NR'''''-C(NR'R”R''')=NR'''', NR''''C(NR'R'')=NR''', -S(O ) R', -S(O) ₂ R', -S(O) ₂ NR'R", NR"SO ₂ R', -CN, -NO ₂ , -N ₃ , -CH(Ph) ₂ and fluorine Substitute (C ₁ -C ₄ )alkyl, the number of substituents is 0~(2m'+1), where m'is the total number of carbon atoms in this type of atomic group. R', R", R'", R ``'' and R''''' are each independently preferably hydrogen, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl (for example, aryl substituted with 1 to 3 halogens), Substituted or unsubstituted alkyl, alkoxy, thioalkoxy or aralkyl groups. When the compound of the present invention includes more than one R group, for example, each R group is independently selected, as when there is more than one R', R", R'", R"" Each of these groups is the same as R'"" groups. When R'and R" are attached to the same nitrogen atom, they can combine with the nitrogen atom to form a 5-, 6-, or 7-membered ring. For example, -NR'R" is intended to include, but is not limited to, 1-pyrrolidinyl and 4-morpholinyl. Based on the above discussion of substituents, those skilled in the art can understand that the term "alkyl" is intended to include carbon Groups composed of atoms bonded to non-hydrogen groups, such as haloalkyl (eg -CF ₃ , -CH ₂ CF ₃ ) and acetyl groups (eg -C(O)CH ₃ , -C(O)CF ₃ , -C(O)CH ₂ OCH ₃ etc.).

Similar to the substituents described for alkyl radicals, aryl and heteroaryl substituents are generally collectively referred to as "aryl substituents" and are selected from, for example, -R', -OR', -NR'R", -SR',- Halogen, -SiR'R"R"', OC(O)R', -C(O)R', -CO ₂ R', -CONR'R", -OC(O)NR'R",- NR"C(O)R', NR'C(O)NR"R"', -NR"C(O) ₂ R', -NR"'"-C(NR'R"R''')=NR'''',NR''''C(NR'R")=NR''',-S(O)R', -S(O) ₂ R', -S(O) ₂ NR'R", NR"SO ₂ R', -CN, -NO ₂ , -N ₃ , -CH(Ph) ₂ , fluorine (C ₁ -C ₄ ) alkoxy and fluorine (C ₁ -C ₄ ) Alkyl groups, etc., the number of substituents is between 0 and the total number of open valences on the aromatic ring; where R', R", R"', R"" and R'"" are independently preferably hydrogen , Substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl. When the compound of the present invention includes more than one R group, for example, each R group is independently selected, as when there is more than one R', R", R'", R"" and R''''' groups are each of these groups.

The two substituents on adjacent atoms of the aryl or heteroaryl ring may be optionally substituted with a substituent of the formula -TC(O)-(CRR')qU-, where T and U are independently selected From -NR-, -O-, CRR'- or single bond, q is an integer from 0 to 3. As an alternative, the two substituents on adjacent atoms of the aryl or heteroaryl ring may be optionally substituted with a substituent of the formula -A(CH ₂ )rB-, where A and B are independently selected From -CRR'-, -O-, -NR-, -S-, -S(O)-, S(O) ₂ -, -S(O) ₂ NR'- or single bond, r is 1~4 Integer. Optionally, a single bond on the new ring thus formed can be replaced with a double bond. As an alternative, the two substituents on adjacent atoms of the aryl or heteroaryl ring may be optionally substituted with substituents of the formula -A(CH ₂ )rB-, where s and d are independently An integer selected from 0 to 3, X is -O-, -NR', -S-, -S(O)-, -S(O) ₂ -or -S(O) ₂ NR'-. The substituents R, R′, R″ and R″′ are independently preferably from hydrogen and substituted or unsubstituted (C ₁ -C ₆ ) alkyl.

Unless otherwise specified, the term "halogen" or "halogen" itself or as part of another substituent means a fluorine, chlorine, bromine or iodine atom. In addition, the term "haloalkyl" is intended to include monohaloalkyl and polyhaloalkyl. For example, the term "halo(C ₁ -C ₄ )alkyl" is intended to include but is not limited to trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, etc. Wait.

Examples of haloalkyl include, but are not limited to: trifluoromethyl, trichloromethyl, pentafluoroethyl, and pentachloroethyl. "Alkoxy" represents the above alkyl group having a specific number of carbon atoms connected via an oxygen bridge. C _1-6 alkoxy groups include C ₁ , C ₂ , C ₃ , C ₄ , C ₅ and C ₆ alkoxy groups. Examples of alkoxy groups include, but are not limited to: methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, secondary butoxy, tertiary butoxy, n-pentyloxy and S -pentyloxy. "Cycloalkyl" includes saturated cyclic groups such as cyclopropyl, cyclobutyl or cyclopentyl. The 3-7 cycloalkyl group includes C ₃ , C ₄ , C ₅ , C ₆ and C ₇ cycloalkyl groups. "Alkenyl" includes straight or branched chain hydrocarbon chains in which one or more carbon-carbon double bonds are present at any stable site on the chain, such as vinyl and propenyl.

The term "halogen" or "halogen" refers to fluorine, chlorine, bromine and iodine.

Unless otherwise specified, the term "hetero" means heteroatoms or heteroatom groups (ie, atomic groups containing heteroatoms), including atoms other than carbon (C) and hydrogen (H) and atomic groups containing these heteroatoms, including, for example, oxygen (O ), nitrogen (N), sulfur (S), silicon (Si), germanium (Ge), aluminum (Al), boron (B), -O-, -S-, =O, =S, -C (= O)O-, -C(=O)-, -C(=S)-S(=O), -S(=O) ₂ -, and optionally substituted -C(=O)N(H )-, -N(H)-, -C(=NH)-, -S(=O) ₂ N(H)- or -S(=O)N(H)-.

Unless otherwise specified, "ring" means a substituted or unsubstituted cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, cycloalkynyl, heterocycloalkynyl, aryl or heteroaryl group. The so-called ring includes a single ring, a bicyclic ring, a spiro ring, a parallel ring or a bridge ring. The number of atoms on a ring is usually defined as the number of ring members. For example, "5-7 member ring" refers to 5-7 atoms arranged around. Unless otherwise specified, the ring optionally contains 1 to 3 heteroatoms. Therefore, "5-7 membered ring" includes, for example, phenyl, pyridine, and pyridyl; on the other hand, the term "5-7 membered heterocyclic alkyl ring" includes pyridyl and pyridyl, but does not include phenyl. The term "ring" also includes ring systems containing at least one ring, each of which "ring" independently conforms to the above definition.

Unless otherwise specified, the term "heterocycle" or "heterocyclyl" means a stable heteroatom or heteroatom-containing monocyclic, bicyclic or tricyclic ring, which may be saturated, partially unsaturated or unsaturated ( Aromatic), they contain carbon atoms and 1, 2, 3 or 4 ring heteroatoms independently selected from N, O and S, wherein any of the above heterocycles can be fused to a benzene ring to form a bicyclic ring. Nitrogen and sulfur Heteroatoms can be optionally oxidized (ie NO and S(O)p). The nitrogen atom may be substituted or unsubstituted (ie, N or NR, where R is H or other substituents that have been defined herein). The heterocyclic ring can be attached to any heteroatom or carbon atom side group to form a stable structure. If the resulting compound is stable, the heterocycle described herein may be substituted at the carbon or nitrogen position. The nitrogen atom in the heterocycle is optionally quaternized. A preferred solution is that when the total number of S and O atoms in the heterocycle exceeds 1, these heteroatoms are not adjacent to each other. Another preferred solution is that the total number of S and O atoms in the heterocycle does not exceed 1. As used herein, the term "aromatic heterocyclic group" or "heteroaryl" means a stable 5, 6, 7 membered monocyclic or bicyclic or 7, 8, 9, or 10 membered bicyclic heterocyclic aromatic ring, It contains carbon atoms and 1, 2, 3 or 4 ring heteroatoms independently selected from N, O and S. The nitrogen atom may be substituted or unsubstituted (ie, N or NR, where R is H or other substituents that have been defined herein). Nitrogen and sulfur heteroatoms can be optionally oxidized (ie NO and S(O)p). It is worth noting that the total number of S and O atoms on the aromatic heterocycle does not exceed 1. Bridged rings are also included in the definition of heterocycles. When one or more atoms (ie, C, O, N, or S) connect two non-adjacent carbon or nitrogen atoms, a bridge ring is formed. Preferred bridge rings include, but are not limited to: one carbon atom, two carbon atoms, one nitrogen atom, two nitrogen atoms, and one carbon-nitrogen group. It is worth noting that a bridge always converts a single ring into a triple ring. In the bridge ring, the substituents on the ring may also appear on the bridge.

Examples of heterocyclic compounds include, but are not limited to: acridinyl, azeinyl, benzimidazolyl, benzofuranyl, benzomercaptofuranyl, benzomercaptophenyl, benzoxazolyl, benzoxanyl Oxazolinyl, benzothiazolyl, benzotriazolyl, benzotetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, oxazolyl, 4a H -oxazolyl , Porphyrinyl, benzodihydropiperanyl, chromene, cinnolinyl decahydroquinolinyl, 2 H ,6 H -1,5,2-dithiazinyl, dihydrofuro[2,3 -b ] Tetrahydrofuranyl, furanyl, furazyl, imidazolidinyl, imidazolinyl, imidazolyl, 1 H -indazolyl, indolenyl, dihydroindolyl, indolizinyl, indolyl , 3 H -indolyl, isatinoyl, isobenzofuranyl, piperan, isoindolyl, isoindoline, isoindolyl, indolyl, isoquinolinyl, isothiazolyl, Isoxazolyl, methylenedioxyphenyl, morpholinyl, naphthyridyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4- Oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, isoxazolyl, oxindoleyl, pyrimidinyl, phenanthrene Pyridinyl, phenanthrolinyl, phenazine, phenothiazine, benzoxanthinyl, phenoxazinyl, phthalazinyl, pyrazinyl, pyridinyl, pyridinone, 4-pyridinone, Piperonyl, pteridyl, purinyl, piperanyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridoxazole, pyridoimidazole, pyridothiazole, pyridine , Pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2 H -pyrrolyl, pyrrolyl, pyrazolyl, quinazolinyl, quinolinyl, 4 H -quinazinyl, quinoxalinyl, quinine ring , Tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, tetrazolyl, 6 H -1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2 ,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthryl, thiazolyl, isothiazolylthienyl, thienyl, thienoxazole Group, thienothiazolyl, thienoimidazolyl, thienyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1 , 3,4-triazolyl and xanthene. Also includes fused ring and spiro compounds.

Unless otherwise specified, the term "hydrocarbyl" or its subordinate concepts (such as alkyl, alkenyl, alkynyl, phenyl, etc.) itself or as part of another substituent means linear, branched or cyclic Hydrocarbon radicals or combinations thereof may be fully saturated, unit or polyunsaturated, may be mono-substituted, di-substituted or poly-substituted, may be monovalent (such as methyl), divalent (such as methylene) or Multivalent (such as methine), which may include divalent or multivalent atomic groups, with a specified number of carbon atoms (such as C ₁ -C ₁₀ represents 1 to 10 carbons). "Hydrocarbyl" includes but is not limited to aliphatic hydrocarbon groups and aromatic hydrocarbon groups, the aliphatic hydrocarbon groups include chain and cyclic, specifically including but not limited to alkyl, alkenyl, alkynyl groups, the aromatic hydrocarbon groups include but are not limited to 6-12 members Aromatic hydrocarbon groups such as benzene, naphthalene, etc. In some embodiments, the term "hydrocarbyl" refers to a linear or branched radical or a combination thereof, which may be fully saturated, mono- or polyunsaturated, and may include divalent and polyvalent radicals. Examples of saturated hydrocarbon radicals include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, tertiary butyl, isobutyl, secondary butyl, isobutyl, cyclohexyl, (cyclo (Hexyl) methyl, cyclopropylmethyl, and homologues or isomers of atomic groups such as n-pentyl, n-hexyl, n-heptyl, n-octyl and the like. The unsaturated alkyl group has one or more double bonds or triple bonds, and examples thereof include, but are not limited to, vinyl, 2-propenyl, butenyl, crotonyl, 2-isopentenyl, 2-(butadienyl ), 2,4-pentadienyl, 3-(1,4-pentadienyl), ethynyl, 1- and 3-propynyl, 3-butynyl, and higher homologs and iso Constructor.

Unless otherwise specified, the term "heterohydrocarbyl" or its underlying concepts (such as heteroalkyl, heteroalkenyl, heteroalkynyl, heteroaryl, etc.) by itself or in combination with another term means a stable linear, branched chain The cyclic or cyclic hydrocarbon atom group or a combination thereof has a certain number of carbon atoms and at least one heteroatom. In some embodiments, the term "heteroalkyl" by itself or in combination with another term means a stable linear, branched hydrocarbon radical or combination thereof, consisting of a certain number of carbon atoms and at least one heteroatom. In a typical embodiment, the heteroatom is selected from B, O, N, and S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen heteroatom is optionally quaternized. The heteroatom or heteroatom group may be located at any internal position of the heterohydrocarbyl group (including the position where the hydrocarbyl group is attached to the rest of the molecule). Examples include but are not limited to -CH ₂ -CH ₂ -O-CH ₃ , -CH ₂ -CH ₂ -NH-CH ₃ , -CH ₂ -CH ₂ -N(CH ₃ )-CH ₃ , -CH ₂ -S -CH ₂ -CH ₃ , -CH ₂ -CH ₂ , -S(O)-CH ₃ , -CH ₂ -CH ₂ -S(O) ₂ -CH ₃ , -CH=CH-O-CH ₃ ,- CH ₂ -CH=N-OCH ₃ and -CH=CH-N(CH ₃ )-CH ₃ . Up to two heteroatoms may be consecutive, for example, -CH ₂ -NH-OCH _3.

The terms "alkoxy", "alkylamino" and "alkylthio" (or thioalkoxy) are conventional expressions and refer to those connected to the rest of the molecule via an oxygen atom, amine group or sulfur atom, respectively Those alkyl groups.

Unless otherwise specified, the term "cyclohydrocarbyl", "heterocyclic hydrocarbyl" or its subordinate concepts (such as aryl, heteroaryl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, cycloalkynyl) , Heterocycloalkynyl, etc.) by itself or in combination with other terms mean cyclized "hydrocarbyl" and "heterohydrocarbyl." In addition, in the case of heterohydrocarbon groups or heterocyclic hydrocarbon groups (such as heteroalkyl, heterocycloalkyl), heteroatoms may occupy the position where the heterocycle is attached to the rest of the molecule. Examples of cycloalkyl include, but are not limited to, cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl, and the like. Non-limiting examples of heterocyclic groups include 1-(1,2,5,6-tetrahydropyridyl), 1-pyridyl, 2-pyridyl, 3-pyridyl, 4-morpholinyl, 3-morpholinyl, tetrahydrofuran-2-yl, tetrahydrofuran indol-3-yl, tetrahydrothiophen-2-yl, tetrahydrothiophen-3-yl, 1-pyrazinyl and 2-pyrazinyl.

Unless otherwise specified, the term "aryl" means a polyunsaturated aromatic hydrocarbon substituent, which may be mono-, di- or poly-substituted, may be monovalent, divalent or polyvalent, it may be monocyclic or Polycyclic rings (such as 1 to 3 rings; at least one of which is aromatic), which are fused together or covalently linked. The term "heteroaryl" refers to an aryl group (or ring) containing one to four heteroatoms. In an exemplary example, the heteroatom is selected from B, N, O, and S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atoms are optionally quaternized. Heteroaryl groups can be attached to the rest of the molecule via heteroatoms. Non-limiting examples of aryl or heteroaryl include phenyl, 1-naphthyl, 2-naphthyl, 4-biphenyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 3-pyryl Oxazolyl, 2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl, 2-phenyl-4-oxazolyl, 5-oxazolyl, 3-isoxyl Oxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furanyl, 3-furanyl, 2-thienyl, 3-thiophene Group, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-benzothiazolyl, purinyl, 2-benzimidazolyl, 5-indolyl, 1-isoquinolinyl, 5-isoquinolinyl, 2-quinoxalinyl, 5-quinoxalinyl, 3-quinolinyl and 6-quinolinyl. The substituents of any one of the above aryl and heteroaryl ring systems are selected from acceptable substituents described below.

For simplicity, aryl when used in combination with other terms (eg aryloxy, arylthio, aralkyl) includes aryl and heteroaryl rings as defined above. Therefore, the term "aralkyl" is intended to include those radicals where the aryl group is attached to the alkyl group (eg, benzyl, phenethyl, pyridylmethyl, etc.), These include those alkyl groups in which carbon atoms (such as methylene) have been replaced by, for example, oxygen atoms, such as phenoxymethyl, 2-pyridyloxymethyl 3-(1-naphthyloxy)propyl, and the like.

The term "leaving group" refers to a functional group or atom that can be replaced by another functional group or atom via a substitution reaction (eg, an affinity substitution reaction). For example, representative leaving groups include triflate; chlorine, bromine, and iodine; sulfonate groups such as mesylate, tosylate, p-bromobenzenesulfonate, and p-toluenesulfonate Ester, etc.; Acyloxy, such as acetoxy, trifluoroethoxy, etc.

The term "protecting group" includes but is not limited to "amine protecting group", "hydroxy protecting group" or "mercapto protecting group". The term "amine protecting group" refers to a protecting group suitable for preventing side reactions at the nitrogen position of the amine group. Representative amine protecting groups include, but are not limited to: methyl acetyl; acetyl, such as alkanoyl (such as acetyl, trichloroacetyl, or trifluoroacetyl); alkoxycarbonyl, such as tri Butoxycarbonyl (Boc); arylmethoxycarbonyl, such as benzyloxycarbonyl (Cbz) and 9-fluorene methoxycarbonyl (Fmoc); arylmethyl, such as benzyl (Bn), trityl ( Tr), 1,1-bis-(4'-methoxyphenyl)methyl; silyl, such as trimethylsilyl (TMS) and tertiary butyldimethylsilyl (TBS) and many more. The term "hydroxyl protecting group" refers to a protecting group suitable for preventing side reactions of hydroxyl groups. Representative hydroxy protecting groups include, but are not limited to: alkyl groups, such as methyl, ethyl, and tertiary butyl; acyl groups, such as alkanoyl groups (such as acetyl); arylmethyl groups, such as benzyl (Bn ), p-methoxybenzyl (PMB), 9-fluorenylmethyl (Fm) and diphenylmethyl (diphenylmethyl, DPM); silyl, such as trimethylsilyl (TMS) And tertiary butyldimethylsilyl (TBS) and so on.

The compounds of the present invention can be prepared by various synthetic methods well known to those skilled in the art, including the specific embodiments listed below, the embodiments formed by the combination with other chemical synthetic methods, and equivalents well known to those skilled in the art Alternatively, preferred embodiments include but are not limited to the embodiments of the present invention.

All solvents used in the present invention are commercially available and can be used without further purification. The present invention uses the following abbreviations: aq stands for water; HATU stands for O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethylurea hexafluorophosphate ; EDC stands for N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride; m-CPBA stands for 3-chloroperoxybenzoic acid; eq stands for equivalent and equivalent; CDI Stands for carbonyldiimidazole; DCM stands for dichloromethane; PE stands for petroleum ether; DIAD stands for diisopropyl azodicarboxylate; DME stands for N,N-dimethylformamide; DMSO stands for dimethylsulfoxide; EtOAc stands for Ethyl acetate; EtOH stands for ethanol; MeOH stands for methanol; CBz stands for benzyloxycarbonyl, which is an amine protecting group; BOC stands for tertiary butylcarbonyl, which is an amine protecting group; HOAc stands for acetic acid; NaCNBH ₃ stands for boron cyano Sodium hydride; rt represents room temperature; O/N represents overnight; THF represents tetrahydrofuran; Boc ₂ O represents di-tertiary butyl dicarbonate; TFA represents trifluoroacetic acid; DIPEA represents diisopropylethylamine; SOCl ₂ Represents sulfony chloride; CS ₂ stands for carbon disulfide; TsOH stands for p-toluenesulfonic acid; NFSI stands for N-fluoro-N-(benzenesulfonyl)benzenesulfonamide; NCS stands for 1-chloropyrrolidine-2,5-di Ketone; n -Bu ₄ NF stands for tetrabutylammonium fluoride; iPrOH stands for 2-propanol; mp stands for melting point; LDA stands for lithium diisopropylamide; TMSCF ₃ stands for trifluoromethyltrimethylsilane; Ti( Oi-Pr) ₄ represents tetraisopropyl titanate; MSCl represents methanesulfonyl chloride; DMAP represents N,N-dimethyl-4-aminopyridine; TEA represents triethylamine; BnBr represents benzyl bromide; DIEA represents di Isopropylethylamine; BH ₃ DMS stands for borane dimethyl sulfide; DMP stands for Dess Martin iodide; TBAF stands for tetrabutylamine fluoride; HOBT stands for 1-hydroxybenzotriazole; AIBN stands for azobis Isobutyronitrile; NBS stands for N-bromobutanediimide.

Compounds are named by hand or ChemDraw® software, and commercially available compounds use the supplier catalog name.

detailed description.

The following describes the present invention in detail through examples, but it does not mean any adverse limitation of the present invention.

Example 1.

3,7-dimethyl-1-(oxetan-3-ylmethyl)purine-2,6-dione.

first step.

Oxetane-3-ylmethyl methanesulfonate.

Dissolve oxetane-3-yl-methanol (150 mg, 1.70 mmol) and triethylamine (344 mg, 3.40 mmol) in dichloromethane (5 mL), add methanesulfonyl chloride (390 mg, 3.40) at 0°C mmol). The reaction solution was slowly raised to room temperature and stirred for 2 hours. Saturated aqueous sodium bicarbonate solution (10 mL) was added to quench the reaction. Extract with dichloromethane (10 mL x 3). The organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain oxetane-3-ylmethyl methanesulfonate (200 mg, yellow oil), yield : 70%. MS-ESI calculation [M+H] ⁺ 167, found 167.

The second step.

3,7-dimethyl-1-(oxetan-3-ylmethyl)purine-2,6-dione.

The oxetane-3-ylmethyl methanesulfonate (200 mg, 1.20 mmol), 3,7-dimethyl-1 H -purine-2,6(3 H ,7 H )-dione ( 216 mg, 1.20 mmol), potassium iodide (20.0 mg, 0.120 mmol) and potassium carbonate (250 mg, 1.81 mmol) were dissolved in N , N -dimethylformamide (10 mL). The reaction liquid was heated to 120°C and stirred for 3 hours. Cooled to room temperature, filtered, the filtrate was concentrated under reduced pressure and purified by preparative high performance liquid chromatography to obtain 3,7-dimethyl-1-(oxetane-3-ylmethyl)purine-2,6- Dione (100 mg), yield: 33%.

¹ H NMR: (400 MHz, Methonal- d ₄ ) δ = 7.87 (s, 1H), 4.74 (t, J = 6.8 Hz, 2H), 4.61 (t, J = 6.8 Hz, 2H), 4.30 (d, J = 6.8 Hz, 2H), 3.96 (s, 3H), 3.51 (s, 3H), 3.42-3.35 (m, 1H). MS-ESI calculated value [M+H] ⁺ 251, found value 251.

Example 2.

1-(3-fluoro-oxetane-3-ylmethyl)-3,7-dimethyl-3,7-dihydro-purine-2,6-dione.

first step.

2-((benzyloxy)methyl)prop-2-enyl-1-ol.

To a solution of sodium hydride (3.63 g, 90.8 mmol) in tetrahydrofuran (180 mL) was added dropwise 2-methenylpropane-1,3-diol (8.00 g, 90.8 mmol) in tetrahydrofuran (20 mL) at 0°C. Solution. The reaction solution was stirred at 0°C for 1 hour. Add tetrabutylammonium iodide (33.5g, 90.8mmol) And benzyl bromide (15.5 g, 90.8 mmol). The reaction mixture was reacted at room temperature for 3 hours. The reaction solution was cooled to 0°C, and quenched by adding water (200 mL). Extract with ethyl acetate (100 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether/ethyl acetate 3:1) to give 2-((benzyloxy)methyl) Prop-2-enyl-1-ol (7.00, colorless liquid), yield: 43%.

¹ H NMR: (400 MHz, CDCl ₃ ) δ = 7.38-7.30 (m, 5H), 5.22 (s, 1H), 5.16 (s, 1H), 4.53 (s, 2H), 4.20 (s, 2H), 4.10 (s, 2H).

The second step.

3-(benzyloxy)-2-(bromomethyl)-2-fluoropropan-1-ol.

To a solution of 2-((benzyloxy)methyl)prop-2-enyl-1-ol (2.00 g, 11.2 mmol) in methylene chloride (30 mL) was added triethylamine hydrofluoride at 0°C Salt (4.50 g, 27.9 mmol) and bromobutadiene imide (3.00 g, 16.8 mmol). The reaction solution was stirred at room temperature for 3 hours. Water (30 mL) was added to quench the reaction. Extract with dichloromethane (30 mL x 2). The combined organic phases were washed successively with saturated aqueous sodium bicarbonate solution and saturated brine. It was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. It was separated and purified by silica gel column chromatography (5:1 petroleum ether/ethyl acetate) to obtain 3-(benzyloxy)-2-(bromomethyl)- 2-fluoropropane-1-ol (1.40 g, colorless oil), yield: 45%.

¹ H NMR: (400 MHz, CDCl ₃ ) δ = 7.38-7.31 (m, 5H), 4.60 (s, 2H), 3.89 (d, J =16.0 Hz, 2H), 3.77 (d, J =16.0 Hz, 2H ), 3.70-3.65 (m, 2H).

third step.

3-((benzyloxy)methyl)-3-fluoropropylene oxide.

To a solution of 3-(benzyloxy)-2-(bromomethyl)-2-fluoropropan-1-ol (200mg, 0.721mmol) in anhydrous tetrahydrofuran (2mL) at 0°C was added sodium hydride (75.0 mg, 1.88 mmol). The reaction solution was stirred at room temperature overnight. The reaction was quenched by adding ice water (20 mL), extracted with ethyl acetate (10 mL x 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and purified by silica gel column chromatography (3:1 Petroleum ether/ethyl acetate) to give 3-((benzyloxy)methyl)-3-fluoropropylene oxide (42.0 mg, colorless liquid), yield: 30%.

¹ H NMR: (400 MHz, CDCl ₃ ) δ = 7.40-7.32 (m, 5H), 4.79 (dd, J = 20.0, 8.0 Hz, 2H), 4.64 (s, 2H), 4.60 (dd, J = 20.0, 8.0 Hz, 2H), 3.82 (d, J = 20.0 Hz, 2H).

the fourth step.

(3-fluoro-oxetane-3-yl) methanol.

Dissolve 3-benzyloxymethyl-3-fluoro-oxetane (190 mg, 0.968 mmol) in tetrahydrofuran (10 mL), add acetic acid (0.25 mL), dry palladium on carbon (palladium 10%, water 1%, 20 mg) at room temperature, the reaction solution was reacted under hydrogen (30 psi) for 5 hours. The reaction solution was filtered to obtain a solution of (3-fluoro-oxetane-3-yl)methanol in tetrahydrofuran, which was directly used in the next reaction.

the fifth step.

Methanesulfonic acid-3-fluoro-oxetane-3-yl methyl ester.

Under the protection of nitrogen, add triethylamine (298mg, 2.94mmol) and methanesulfonyl chloride to the (3-fluoro-oxetane-3-yl) methanol (104mg, 0.980mmol) and tetrahydrofuran solution obtained in the previous step. 225mg, 1.96mmol), the reaction solution was reacted at room temperature for 3 hours. Dichloromethane (30 mL) was added, and the reaction solution was washed successively with 0.5N aqueous hydrochloric acid solution (15 mL) and saturated sodium bicarbonate solution (15 mL), and the organic phase was washed with saturated brine organic phase (10 mL), dried over anhydrous sodium sulfate, and reduced pressure Concentrate to obtain 3-fluoro-oxetane-3-yl methyl methanesulfonate (102 mg, yellow oil), yield: 57%.

¹ H NMR: (400 MHz, CDCl ₃ ) δ=4.84 (dd, J =18.4, 8.4 Hz, 2H), 4.67-4.51 (m, 4H), 3.09 (s, 3H). MS-ESI calculated value [M+H] ⁺ 185, found value 185.

The sixth step.

1-(3-fluoro-oxetane-3-ylmethyl)-3,7-dimethyl-3,7-dihydro-purine-2,6-dione.

Dissolve 3-fluoro-oxetane-3-yl methyl methanesulfonate (100 mg, 0.543 mmol) in N , N -dimethylformamide (2 mL), and add 3,7-dimethyl- 1 H -purine-2,6(3H,7H)-dione (97.8 mg, 0.543 mmol), potassium carbonate (150 mg, 1.09 mmol) and potassium iodide (9.0 mg, 0.054 mmol). The reaction solution was heated to 120°C and stirred for 3 hours. After concentration under reduced pressure, the residue was purified by high-performance liquid chromatography to obtain 1-(3-fluoro-oxetane-3-ylmethyl)-3,7-dimethyl-3,7-dihydro- Purine-2,6-dione (28.0mg), yield: 19%.

¹ H NMR: (400 MHz, CDCl ₃ ) δ = 7.54 (s, 1 H), 4.92 (d, J = 9.2 Hz, 1 H), 4.86 (d, J = 9.2 Hz, 1 H), 4.80 (d, J = 8.8 Hz, 1H), 4.74 (d, J = 8.8 Hz, 1H), 4.54 (d, J =10.0 Hz, 2H), 3.99 (s, 3H), 3.59 (s, 3H). MS-ESI calculated [M+H] ⁺ 269, found 269.

Example 3.

3,7-dimethyl-1-((3-methyloxetan-3-yl)methyl)-1 H -purine-2,6(3 H ,7 H )-dione.

The mixture 3,7-dimethyl-1 H -purine-2,6(3 H ,7 H )-dione (200 mg, 1.10 mmol), 3-(chloromethyl)-3-methyloxane Butane (198mg, 1.65mmol), potassium carbonate (304mg, 2.20mmol) and methyl iodide (18.0mg, 0.109mmol) were dissolved in N , N -dimethylformamide (2mL), the reaction solution was in a microwave reactor The reaction was carried out at 130°C for 15 minutes. The reaction solution was concentrated under reduced pressure and purified by preparative high performance liquid chromatography to obtain 3,7-dimethyl-1-((3-methyloxetan-3-yl)methyl)-1 H -purine- 2,6(3 H ,7 H )-dione.

¹ H NMR: (400 MHz, Methonal- d ₄ ) δ = 7.91 (s, 1H), 4.78 (d, J = 6.4 Hz, 2H), 4.23 (d, J = 6.4 Hz, 2H), 4.13 (s, 2H ), 3.99 (s, 3H), 3.54 (s, 3H), 1.36 (s, 3H). MS-ESI calculated value [M+H] ⁺ 265, found value 265.

Example 4.

first step.

(3-ethyloxetan-3-yl) methyl methanesulfonate.

Dissolve (3-ethyloxetane-3-yl)methanol (64.0 mg, 0.552 mmol) and triethylamine (111 mg, 1.10 mmol) in methylene chloride (20 mL), add methane at 0°C Sulfonyl chloride (94.9 mg, 0.829 mmol). After the reaction solution was stirred at room temperature for 2 hours, it was diluted with dichloromethane (20 mL), washed with saturated sodium bicarbonate solution (20 mL x 2), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, using a silica gel column layer Separation and purification (4:1 Petroleum ether/ethyl acetate, Rf=0.5) gave (3-ethyloxetan-3-yl) methyl methanesulfonate (100 mg, colorless oil), yield: 93%.

MS-ESI calculated value [M+H] ⁺ 195, found value 195.

The second step.

L - ((3-ethyl-oxetan-3-yl) methyl) -3,7-dimethyl -1 H - purine -2,6 (3 H, 7 H) - dione.

(3-ethyloxetane-3-yl)methyl methanesulfonate (100 mg, 0.520 mmol) was dissolved in N , N -dimethylformamide (20 mL), and the reaction solution was at room temperature was added 3,7-dimethyl -1 H under conditions - purin -2,6 (3 H, 7 H) - dione (92.7mg, 0.520mmol), potassium carbonate (107mg, 0.780mmol) and potassium iodide (86.3 mg , 0.520 mmol). The reaction solution was heated to 100°C, reacted for 2 hours, diluted with ethyl acetate (20 mL), and the organic phase was washed with saturated sodium bicarbonate solution (20 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure using high-efficiency solution Purified by phase chromatography to obtain 1-((3-ethyloxetan-3-yl)methyl)-3,7-dimethyl-1 H -purine-2,6(3 H ,7 H )- Dione (80.0 mg), yield: 56%.

¹ H NMR: (400 MHz, CDCl ₃ ) δ = 7.53 (s, 1H), 4.62 (d, J = 6.4 Hz, 2H), 4.28 (d, J = 6.4 Hz, 2H), 4.06 (s, 2H), 3.98 (s, 3H), 3.58 (s, 3H), 1.82 (q, J = 7.2 Hz, 2H), 1.06 (t, J = 7.2 Hz, 3H). MS-ESI calculated value [M+H] ⁺ 279, found value 279.

Example 5.

1-(2-(2-ethyloxetan-3-yl)ethyl)-3,7-dimethyl-1 H -purine-2,6(3 H ,7 H )-dione .

first step.

Methyl 2-(2-(benzyloxy)ethyl)-3-oxopentanoate.

At 0°C, sodium hydride (842 mg, 35.1 mmol) was added to a solution of methyl 3-oxopentanoate (3.04 g, 23.4 mmol) in tetrahydrofuran (100 mL). The reaction solution was stirred at 0°C for 1 hour. A solution of ((2-bromoethoxy)-methyl)-benzene (10.0 g, 46.7 mmol) in tetrahydrofuran (10 mL) was added dropwise to the reaction solution at 0°C. The reaction solution was stirred at 70°C for 24 hours and then cooled to 0°C. Saturated ammonium chloride solution (20 mL) was added to quench the reaction and extracted with ethyl acetate (20 mL x 3). The organic phase was washed with saturated brine (100 mL x 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Separated and purified by silica gel column chromatography (20:1 petroleum ether/ethyl acetate, Rf=0.3) to obtain methyl 2-(2-(benzyloxy)ethyl)-3-oxopentanoate (3.01g, Colorless oil), yield: 49%.

The second step.

Methyl 2-(2-(benzyloxy)ethyl)-3-hydroxyvalerate.

Dissolve methyl 2-(2-(benzyloxy)ethyl)-3-oxopentanoate (2.50g, 9.47mmol) in methanol (30mL) and add lithium borohydride (208mg, 9.47) at 0°C mmol), and the reaction solution was stirred at 25°C for 1 hour. Water (10 mL) was added to quench the reaction, and ethyl acetate (30 mL) was used x 3) Extraction. The organic phase was washed with saturated sodium chloride solution (20 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether/ethyl acetate 3:1, Rf=0.5 ) To give methyl 2-(2-(benzyloxy)ethyl)-3-hydroxyvalerate (2.01 g, colorless oil), yield: 80%.

¹ H NMR: (400 MHz, Methonal- d ₄ ) δ=7.35-7.33 (m, 5H), 4.47 (s, 2H), 3.63-3.61 (m, 3H), 3.52-3.49 (m, 1H), 2.62- 2.45 (m, 2H), 2.15-1.85 (m, 2H), 1.57-1.25 (m, 3H), 1.00-0.98 (m, 3H).

third step.

2-(2-(benzyloxy)ethyl)pentane-1,3-diol.

Under nitrogen protection, lithium aluminum hydride (323 mg, 8.27 mmol) was slowly added to methyl 2-(2-(benzyloxy)ethyl)-3-hydroxyvalerate (2.00 g, 7.52 mmol) in tetrahydrofuran (100 mL) at 0°C. ) In solution. The reaction solution was stirred at 0°C for 1 hour. The reaction solution was cooled to 0°C, and water (0.33 mL), 15% sodium hydroxide solution (0.33 mL) and water (0.99 mL) were slowly added in sequence. After filtration, the filtrate was concentrated under reduced pressure to obtain the product 2-(2-(benzyloxy)ethyl)pentane-1,3-diol (1.50 g, yellow oil), yield: 76%.

¹ H NMR: (400 MHz, Methonal- d ₄ ) δ=7.36-7.28 (m, 5H), 4.52 (s, 2H), 3.66-3.57 (m, 5H), 1.73-1.69 (m, 5H), 1.00- 0.95 (m, 3H).

the fourth step.

2-(2-(benzyloxy)ethyl)-3-hydroxypentyl methanesulfonate.

Dissolve 2-(2-(benzyloxy)ethyl)pentane-1,3-diol (1.50 g, 6.30 mmol) and triethylamine (1.91 g, 18.9 mmol) in dichloromethane (20 mL) At 0°C, methanesulfonyl chloride (846 mg, 7.56 mmol) was slowly added. The reaction solution was slowly raised to 25°C and stirred for 0.5 hour. Water (20 mL) was added to quench the reaction and extracted with dichloromethane (30 mL x 3). merge The organic phase was washed with saturated sodium chloride solution (20 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and purified by silica gel column chromatography (10:1 petroleum ether/ethyl acetate, Rf = 0.4) to give the product 2-(2-(benzyloxy)ethyl)-3-hydroxypentyl methanesulfonate (1.50 g, yellow oil), yield: 74%.

¹ H NMR: (400 MHz, Methonal- d ₄ ) δ=7.34-7.27 (m, 5H), 4.50 (s, 2H), 4.32-4.26 (m, 2H), 3.60-3.50 (m, 3H), 3.00 ( s, 3H), 1.96-1.70 (m, 5H), 0.98-0.94 (m, 3H).

the fifth step.

3-(2-(benzyloxy)ethyl)-2-ethyloxetane.

At 0°C, sodium hydride (228 mg, 9.49 mmol) was added to 2-(2-(benzyloxy)ethyl)-3-hydroxypentyl methanesulfonate (1.50 g, 4.75 mmol) in tetrahydrofuran (10 mL) In solution. The reaction solution was slowly raised to 25°C and stirred for 12 hours. Saturated ammonium chloride solution (5 mL) was added to quench the reaction and extracted with ethyl acetate (20 mL x 3). The organic phase was washed with saturated brine (20 mL x 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Separated and purified by silica gel column chromatography (15:1 petroleum ether/ethyl acetate, Rf=0.5) to obtain 3-(2-(benzyloxy)ethyl)-2-ethyloxetane (800 mg, Colorless oil), yield: 77%.

¹ H NMR: (400 MHz, Methonal- d ₄ ) δ = 7.37-7.28 (m, 5H), 4.60-4.58 (m, 1H), 4.57-4.56 (m, 1H), 4.48 (s, 2H), 4.44- 4.25 (m, 1H), 3.49-3.44 (m, 2H), 2.77-2.75 (m, 1H), 1.98-1.94 (m, 2H), 1.74-1.63 (m, 2H), 0.92-0.88 (m, 3H) ).

The sixth step.

2-(2-ethyloxetan-3-yl)ethanol.

3-(2-(Benzyloxy)ethyl)-2-ethyloxetane (800 mg, 3.64 mmol) was dissolved in dichloromethane (10 mL) solution, and ferric chloride (1.17 g, 7.27 mmol). The reaction solution was stirred at 25°C under nitrogen for 0.5 hour. The reaction solution was filtered, the filtrate was concentrated under reduced pressure, and was separated and purified by silica gel column chromatography (3:1 petroleum ether/ethyl acetate, Rf=0.5) to obtain 2-(2-ethyloxetan-3-yl)ethanol (60.0 mg, colorless oil), yield: 13%.

¹ H NMR: (400 MHz, Methonal- d ₄ ) δ=3.85-3.82 (m, 3H), 3.77-3.75 (m, 2H), 2.08-2.03 (m, 2H), 1.61-1.52 (m, 3H), 1.05-0.96 (m, 3H).

The seventh step.

2-(2-ethyloxetan-3-yl) ethyl methanesulfonate.

Dissolve 2-(2-ethyloxetane-3-yl)ethanol (60.0 mg, 0.463 mmol) and triethylamine (93.0 mg, 0.923 mmol) in dichloromethane (2 mL) at 0°C Methanesulfonyl chloride (62.2 mg, 0.556 mmol) was added slowly. The reaction solution was slowly raised to 25°C and stirred for 0.5 hour. Water (5 mL) was added to quench the reaction and extracted with dichloromethane (10 mL x 3). The organic phases were combined, the organic phase was washed with a saturated sodium chloride solution (10 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the product 2-(2-ethyloxetan-3-yl ) Ethyl methanesulfonate (40.0 mg, yellow oil), yield: 42%.

Step 8.

1-(2-(2-ethyloxetan-3-yl)ethyl)-3,7-dimethyl-1 H -purine-2,6(3 H ,7 H )-dione .

Combine 2-(2-ethyloxetan-3-yl)ethyl methanesulfonate (40.0 mg, 0.192 mmol), 3,7-dimethyl-1 H -purine-2,6(3 H, 7 H) - dione (34.6mg, 0.192mmol), potassium iodide (3.5mg, 0.019mmol) and potassium carbonate (53.0mg, 0.384mmol) was dissolved in anhydrous N, N - dimethylformamide (2mL) in. The reaction solution was heated to 120°C and reacted for 3 hours. The reaction solution was cooled to 20°C, filtered, and purified by preparative high performance liquid chromatography to obtain 1-(2-(2-ethyloxetan-3-yl)ethyl)-3,7-dimethyl- 1 H -purine-2,6(3 H ,7 H )-dione (3.0 mg), yield: 5%.

¹ H NMR: (400 MHz, Methonal- d ₄ ) δ = 7.52 (s, 1H), 4.17-4.14 (m, 1H), 4.00 (s, 3H), 3.98-3.96 (m, 1H), 3.86-3.85 ( m, 2H), 3.59 (s, 3H), 3.58-3.57 (m, 1H), 2.41-2.39 (m, 1H), 1.95-1.94 (m, 1H), 1.85-1.81 (m, 1H), 1.60- 1.55 (m, 2H), 1.00-0.96 (m, 3H).

MS-ESI calculated value [M+H] ⁺ 293, found value 293.

Example 6.

3,7-dimethyl-1-[3-(3-methyloxetan-3-yl)propyl]purine-2,6-dione.

first step.

3-(3-Methyloxetan-3-yl)prop-2-enoic acid ethyl ester.

Ethyl-2-ethoxyethyl phosphate (4.03g, 17.9mmol) was dissolved in tetrahydrofuran (20mL), sodium hydrogen (719mg, 17.9mmol) was added at 0°C, and 3-methyl was added after 0.5 hours of reaction Oxetane-3-carbaldehyde (900 mg, 8.99 mmol), and react at room temperature for 2 hours. Saturated ammonium chloride solution (10 mL) was added to quench the reaction. Extracted with ethyl acetate (20mL x 3), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and purified by silica gel column chromatography (10:1 petroleum ether/ethyl acetate, Rf value = 0.2) to give 3- (3-Methyloxetane-3-yl)prop-2-enoic acid ethyl ester (800 mg, yellow oil), yield: 52%.

¹ H NMR: (400 MHz, Methonal- d ₄ ) δ = 7.27 (d, J =16.0 Hz, 1H), 5.93 (d, J =16.0 Hz, 1H), 4.67 (d, J = 6.0 Hz, 2H), 4.48 (d, J = 6.0 Hz, 2H), 4.20 (q, J = 7.2 Hz, 2H), 1.53 (s, 3H), 1.29 (t, J = 7.2 Hz, 3H). MS-ESI calculated value [M+H] ⁺ 171, found value 171.

The second step.

Ethyl-3-(3-methyloxetane-3-yl)propanoate.

Mix 3-(3-methyloxetan-3-yl)prop-2-enoic acid ethyl ester (550 mg, 3.23 mmol) and wet palladium on carbon (100 mg, 3.23 mmol) in tetrahydrofuran (30 mL) , 12 hours under hydrogen (15psi) atmosphere. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain ethyl-3-(3-methyloxetane-3-yl)propanoate (500 mg, yellow oil), yield: 90%.

¹ H NMR: (400 MHz, Methonal- d ₄ ) δ = 4.45 (d, J = 6.0 Hz, 2H), 4.33 (d, J = 6.0 Hz, 2H), 4.14 (q, J = 7.2 Hz, 2H), 2.35 (t, J = 4.8 Hz, 2H), 1.98 (t, J = 4.8 Hz, 2H), 1.31 (s, 3H), 1.25 (t, J = 7.2 Hz, 3H). MS-ESI calculated value [M+H] ⁺ 173, found value 173.

third step.

3-(3-methyloxetan-3-yl)propan-1-ol.

Dissolve ethyl-3-(3-methyloxetane-3-yl)propanoate (550mg, 3.19mmol) in tetrahydrofuran (10mL), add lithium aluminum tetrahydrogen (242mg) at 0°C , 6.38mmol), react for 1 hour. Water (10 mL) was added to quench the reaction. Extract with ethyl acetate (10mL x 3), It was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 3-(3-methyloxetan-3-yl)propan-1-ol (250 mg, colorless oil), yield: 60%.

MS-ESI calculated value [M+H] ⁺ 131, found value 131.

the fourth step.

3-(3-methyloxetan-3-yl)propyl methanesulfonate.

Dissolve 3-(3-methyloxetane-3-yl)propan-1-ol (250 mg, 1.92 mmol) and triethylamine (583 mg, 5.76 mmol) in dichloromethane (5 mL), 0 Methanesulfonyl chloride (659 mg, 5.76 mmol) was added at ℃. The reaction solution was slowly raised to room temperature and stirred for 2 hours. Aqueous sodium bicarbonate (10 mL) was added to quench the reaction. Extract with dichloromethane (10 mL x 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give 3-(3-methyloxetan-3-yl)propyl methanesulfonate (200 mg, yellow oil Condition), yield: 50%.

¹ H NMR: (400 MHz, Methonal- d ₄ ) δ = 4.47 (d, J = 6.0 Hz, 2H), 4.37 (d, J = 6.0 Hz, 2H), 4.28 (t, J = 6.4 Hz, 2H), 3.09 (s, 3H), 1.71-1.50 (m, 4H), 1.31 (s, 3H). MS-ESI calculated value [M+H] ⁺ 209, found value 209.

the fifth step.

3,7-dimethyl-1-[3-(3-methyloxetan-3-yl)propyl]purine-2,6-dione.

3-(3-Methyloxetane-3-yl)propyl methanesulfonate (200mg, 0.960mmol), 3,7-dimethyl- 1H -purine-2,6( 3H ,7 H )-diketone (173 mg, 0.960 mmol), potassium iodide (15.9 mg, 0.0960 mmol) and potassium carbonate (265 mg, 1.92 mmol) were dissolved in N , N -dimethylformamide (10 mL). The reaction liquid was heated to 120°C and stirred for 3 hours. Cooled to room temperature, filtered, the filtrate was concentrated under reduced pressure and purified by preparative high performance liquid chromatography to obtain 3,7-dimethyl-1-[3-(3-methyloxetan-3-yl)propan Base] purine-2,6-dione (50.0 mg), yield: 18%.

¹ H NMR: (400 MHz, Methonal- d ₄ ) δ = 7.89 (s, 1H), 4.46 (d, J = 6.0 Hz, 2H), 4.36 (d, J = 6.0 Hz, 2H), 4.03-3.95 (m , 5H), 3.55 (s, 3H), 1.74-1.61 (m, 4H), 1.31 (s, 3H). MS-ESI calculated value [M+H] ⁺ 293, found value 293.

Example 7.

3,7-dimethyl-1-((tetrahydrofuran-2-yl)methyl)-1 H -purine-2,6(3 H ,7 H )-dione.

The mixture 3,7-dimethyl-1 H -purine-2,6 (3 H ,7 H )-dione (538 mg, 2.99 mmol), 2-(chloromethyl)tetrahydrofuran (300 mg, 2.49 mmol), Potassium carbonate (688 mg, 4.98 mmol) and iodomethane (41.0 mg, 0.25 mmol) were dissolved in N , N -dimethylformamide (3 mL), and the reaction solution was heated to 130° C. for 3 hours. The reaction solution was concentrated under reduced pressure and purified by preparative high performance liquid chromatography to obtain 3,7-dimethyl-1-((tetrahydrofuran-2-yl)methyl)-1 H -purine-2,6(3 H ,7 H )-diketone (50.0 mg), yield: 8%.

¹ H NMR: (400 MHz, Methonal- d ₄ ) δ = 7.87 (s, 1H), 4.36-4.28 (m, 1H), 4.23-4.16 (m, 1H), 3.97 (s, 3H), 3.93-3.83 ( m, 2H), 3.76-3.69 (m, 1H), 3.53 (s, 3H), 2.07-1.86 (m, 3H), 1.79-1.69 (m, 1H). MS-ESI calculated value [M+H] ⁺ 265, found value 265.

Example 8.

first step.

(Tetrahydrofuran-3-yl) methyl methanesulfonate.

(Tetrahydrofuran-3-yl)methanol (56.0 mg, 0.552 mmol) and triethylamine (111 mg, 1.10 mmol) were dissolved in dichloromethane (20 mL), and methanesulfonyl chloride (94.9 mg, 0.829) was added at 0°C. mmol). After the reaction solution was stirred at room temperature for 2 hours, it was diluted with dichloromethane (20 mL), washed with saturated sodium bicarbonate solution (20 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure using silica gel column chromatography Separation and purification (4:1 petroleum ether/ethyl acetate, Rf=0.5) gave (tetrahydrofuran-3-yl) methyl methanesulfonate (90.0 mg, colorless oil), yield: 90%.

MS-ESI calculated value [M+H] ⁺ 181, found value 181.

The second step.

3,7-dimethyl-1-((tetrahydrofuran-3-yl)methyl)-1 H -purine-2,6(3 H ,7 H )-dione.

(Tetrahydrofuran-3-yl) methyl methanesulfonate (90.0 mg, 0.510 mmol) was dissolved in N , N -dimethylformamide (20 mL), and 3,7- Dimethyl-1 H -purine-2,6 (3 H ,7 H )-dione (92.7 mg, 0.520 mmol), potassium carbonate (107 mg, 0.780 mmol) and potassium iodide (86.3 mg, 0.520 mmol). The reaction solution was heated to 100°C, reacted for 2 hours, diluted with ethyl acetate (20 mL), the organic phase was washed with saturated sodium bicarbonate (20 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, using a high-performance liquid phase Chromatographic purification gave 3,7-dimethyl-1-((tetrahydrofuran-3-yl)methyl)-1 H -purine-2,6(3 H ,7 H )-dione (80.0 mg), yield : 60%.

¹ H NMR: (400 MHz, CDCl ₃ ) δ = 7.49 (s, 1H), 3.95-3.93 (m, 1H), 3.88 (s, 3H), 3.86 (m, 2H), 3.66-3.60 (m, 2H) , 3.46-3.45 (m, 1H), 3.42 (s, 3H), 2.62-2.57 (m, 1H), 1.86-1.82 (m, 1H), 1.63-1.58 (m, 1H). MS-ESI calculated value [M+H] ⁺ 265, found value 265.

Example 9.

3,7-dimethyl-1-[2-(2-methyltetrahydrofuran-3-yl)ethyl]purine-2,6-dione.

first step.

2-(2-methyl-3-ylidene) ethyl acetate.

Ethyl-2-ethoxyethyl phosphate (2.24g, 9.98mmol) was dissolved in tetrahydrofuran (20mL), sodium hydrogen (399mg, 9.98mmol) was added at 0°C, and 2-methyltetrahydrofuran was added after 0.5 hours of reaction -3-one (500mg, 4.99mmol), react at room temperature for 2 hours. Saturated ammonium chloride solution (10 mL) was added to quench the reaction. Extracted with ethyl acetate (30mL x 3), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and purified by silica gel column chromatography (10:1 petroleum ether/ Ethyl acetate, Rf value = 0.6) to give 2-(2-methyl-3-ylidene) ethyl acetate (400 mg, yellow oil), yield: 47%.

¹ H NMR: (400 MHz, Methonal- d ₄ ) δ = 5.76 (s, 1H), 4.45-4.42 (m, 1H), 4.19 (q, J = 7.2 Hz, 2H), 4.12-4.09 (m, 1H) , 3.80-3.76 (m, 1H), 3.17-3.11 (m, 1H), 2.98-2.92 (m, 1H), 1.34 (d, J = 6.0Hz, 3H), 1.28 (t, J = 7.2Hz, 3H) ). MS-ESI calculated value [M+H] ⁺ 171, found value 171.

The second step.

2-(2-methyltetrahydrofuran-3-yl) ethyl acetate.

Mix ethyl 2-(2-methyl-3-ylidene)acetate (1.70 g, 9.99 mmol) and wet palladium on carbon (100 mg, 3.23 mmol) in tetrahydrofuran (30 mL) and react under hydrogen (15 psi) atmosphere 12 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain ethyl-2-(2-methyltetrahydrofuran-3-yl)ethyl acetate (1.50 g, yellow oil). Yield: 87%.

¹ H NMR: (400 MHz, Methonal- d ₄ ) δ = 4.17 (q, J = 7.2 Hz, 2H), 3.92-3.55 (m, 3H), 2.62-2.10 (m, 4H), 1.72-1.64 (m, 1H), 1.32-1.22 (m, 6H). MS-ESI calculated value [M+H] ⁺ 173, found value 173.

third step.

2-(2-methyltetrahydrofuran-3-yl)ethanol.

Dissolve ethyl 2-(2-methyltetrahydrofuran-3-yl)acetate (250 mg, 1.45 mmol) in tetrahydrofuran (10 mL), add lithium aluminum hydride (61.0 mg, 1.61 mmol) at 0°C, reaction 1 hour. Water (10 mL) was added to quench the reaction. Extracted with ethyl acetate (10mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give 2-(2-methyltetrahydrofuran-3-yl)ethanol (180mg, colorless oil), yield: 95% .

¹ H NMR: (400 MHz, Methonal- d ₄ ) δ=3.96-3.51 (m, 5H), 2.26-2.08 (m, 2H), 1.77-1.62 (m, 2H), 1.48-1.35 (m, 1H), 1.31-1.13 (m, 3H). MS-ESI calculated value [M+H] ⁺ 131, found value 131.

the fourth step.

2-(2-methyltetrahydrofuran-3-yl) ethyl methanesulfonate.

Dissolve 2-(2-methyltetrahydrofuran-3-yl)ethanol (180 mg, 1.38 mmol) and triethylamine (280 mg, 2.77 mmol) in dichloromethane (5 mL), add methanesulfonyl chloride (0 mL) 310 mg, 2.71 mmol). The reaction solution was slowly raised to room temperature and stirred for 2 hours. Aqueous sodium bicarbonate (10 mL) was added to quench the reaction. Extract with dichloromethane (10 mL x 3). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give 2-(2-methyltetrahydrofuran-3-yl)ethyl methanesulfonate (200 mg, yellow oil) ), yield: 69%.

MS-ESI calculated value [M+H] ⁺ 209, found value 209.

the fifth step.

3,7-dimethyl-1-[2-(2-methyltetrahydrofuran-3-yl)ethyl]purine-2,6-dione.

Combine 2-(2-methyltetrahydrofuran-3-yl)ethyl methanesulfonate (200 mg, 0.960 mmol), 3,7-dimethyl-1 H -purine-2,6(3 H ,7 H ) -Diketone (173 mg, 0.960 mmol), potassium iodide (16.0 mg, 0.0960 mmol) and potassium carbonate (200 mg, 1.45 mmol) were dissolved in N , N -dimethylformamide (10 mL). The reaction liquid was heated to 120°C and stirred for 3 hours. Cooled to room temperature, filtered, the filtrate was concentrated under reduced pressure, and purified by preparative high performance liquid chromatography to obtain 3,7-dimethyl-1-[2-(2-methyltetrahydrofuran-3-yl)ethyl]purine -2,6-Dione (20.0mg), yield: 7%.

¹ H NMR: (400 MHz, Methonal- d ₄ ) δ=7.86 (s, 1H), 4.13-4.03 (m, 3H), 3.99 (s, 3H), 3.95-3.44 (m, 2H), 3.52 (s, 3H), 2.22-1.65 (m, 4H), 1.60-1.53 (m, 1H), 1.25-1.02 (m, 3H). MS-ESI calculated value [M+H] ⁺ 293, found value 293.

Example 10.

3,7-dimethyl-1 - ((tetrahydro -2 H - pyran-4-yl) methyl) -1 H - purine -2,6- (3 H, 7 H) - dione.

first step.

(Tetrahydro- 2H -piperan-4-yl) methyl methanesulfonate.

Tetrahydropyran-4-ylmethanol (500 mg, 4.30 mmol) and triethylamine (870 mg, 8.60 mmol) were dissolved in dichloromethane (10 mL), and methanesulfonyl chloride (985 mg, 8.60 mmol) was added at 0°C. . Reaction at 25°C for 1 hour. Water (10 mL) was added to quench the reaction. Extracted with dichloromethane (10 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give (tetrahydro-2H-piperan-4-yl) methyl methanesulfonate (700 mg, yellow oil) , Yield: 84%.

¹ H NMR: (400 MHz, Methonal- d ₄ ) δ = 4.10 (d, J = 6.4 Hz, 2H), 3.99-3.96 (m, 2H), 3.48-3.42 (m, 2H), 3.09 (s, 3H) , 2.05-2.03 (m, 1H), 1.72-1.67 (m, 2H), 1.43-1.39 (m, 2H). MS-ESI calculated value [M+H] ⁺ 195, found value 195.

The second step.

3,7-dimethyl-1 - ((tetrahydro -2 H - pyran-4-yl) methyl) -1 H - purine -2,6- (3 H, 7 H) - dione.

(Tetrahydro- 2H -piperan-4-yl)methyl methanesulfonate (700mg, 3.60mmol), 3,7-dimethyl- 1H -purine-2,6-( 3H ,7 H )-diketone (649 mg, 3.60 mmol), potassium iodide (119 mg, 0.720 mmol) and potassium carbonate (995 mg, 7.20 mmol) were dissolved in N , N -dimethylformamide (20 mL). The reaction liquid was heated to 120°C and stirred for 3 hours. Cool to room temperature, filter, and concentrate the filtrate under reduced pressure. The residue (10 mL) to give 3,7-dimethyl-1 was washed with methanol - ((tetrahydro -2 H - pyran-4-yl) methyl) -1 H - purine -2,6- (3 H , 7 H )-diketone (200 mg), yield: 20%.

¹ H NMR: (400 MHz, Methonal- d ₄ ) δ = 7.88 (s, 1H), 3.99 (s, 3H), 3.96-3.91 (m, 4H), 3.54 (s, 3H), 3.40-3.36 (m, 2H), 2.10-2.07 (m, 1H), 1.60-1.56 (m, 2H), 1.46-1.40 (m, 2H). MS-ESI calculated value [M+H] ⁺ 279, found value 279.

Example 11.

3,7-dimethyl-1 - ((4-methyl-tetrahydro -2 H - pyran-4-yl) methyl) -1 H - purine -2,6- (3 H, 7 H) - Dione.

3,7-Dimethyl-1-(2-(3-methyltetrahydrofuran-3-yl)ethyl)-1 H -purine-2,6-(3 H ,7 H )-dione.

first step.

4-Methyltetrahydro- 2H -piperan-4-carboxylic acid methyl ester.

Dissolve methyl tetrahydro- 2H -piran-4-carboxylate (2.50g, 17.3mmol) in anhydrous tetrahydrofuran (50mL), under nitrogen protection, and slowly add lithium diisopropylamide dropwise at -78°C The solution (2M n-hexane solution, 10.4 mL, 20.8 mmol), and the reaction solution was stirred at -78°C for 1 hour. Iodomethane (4.92 g, 34.7 mmol) was slowly added, and stirring was continued for 1 hour. Water (20 mL) was added to quench the reaction. The reaction solution was extracted with ethyl acetate (50 mL x 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and purified by silica gel column chromatography (10:1 petroleum ether/ethyl acetate, Rf= 0.4) 4-methyltetrahydro- 2H -piper-4-carboxylic acid methyl ester (1.20 g, yellow oil) was obtained, yield: 44%.

¹ H NMR: (400 MHz, Methonal- d ₄ ) δ = 3.79-3.75 (m, 2H), 3.71 (s, 3H), 3.48-3.42 (m, 2H), 2.06-2.02 (m, 2H), 1.51- 1.44 (m, 2H), 1.20 (s, 3H).

The second step.

(4-methyltetrahydro- 2H -piperan-4-yl) methanol.

Dissolve 4-methyltetrahydro- 2H -piperan-4-carboxylic acid methyl ester (1.20g, 7.59mmol) in anhydrous tetrahydrofuran (10mL), and add lithium aluminum tetrahydrogen (576mg, 15.2mmol) at 0°C . The reaction liquid was heated to 25°C and stirred for 1 hour. It was quenched by adding water (20 mL), extracted with ethyl acetate (50 mL x 3), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and purified by silica gel column chromatography (1:1 petroleum ether/ethyl acetate, Rf= 0.2) to give (4-methyltetrahydro- 2H -piperan-4-yl)methanol (700 mg, yellow oil), yield: 71%.

¹ H NMR: (400 MHz, Methonal- d ₄ ) δ=3.75-3.71 (m, 2H), 3.68-3.66 (m, 2H), 3.33 (s, 2H), 1.62-1.55 (m, 2H), 1.31- 1.26 (m, 2H), 1.03 (s, 3H).

third step.

(4-methyltetrahydro- 2H -piperan-4-yl) methyl methanesulfonate.

(4-Methyltetrahydro- 2H -piperan-4-yl)methanol (700 mg, 5.38 mmol) was dissolved in dichloromethane (10 mL), and triethylamine (1.09 g, 10.8 mmol) was added at 0°C. ) And methanesulfonyl chloride (739 mg, 6.46 mmol). The reaction solution was reacted at 0°C for 2 hours. Saturated aqueous sodium bicarbonate solution (10 mL) was added to quench, extracted with dichloromethane (50 mL x 3), the organic phases were combined, washed with saturated sodium chloride solution (50 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was depressurized Concentrate to give (4-methyltetrahydro- 2H -piperan-4-yl) methyl methanesulfonate (700 mg, yellow oil), yield: 63%.

¹ H NMR: (400 MHz, Methonal- d ₄ ) δ=4.08 (s, 2H), 3.73-3.71 (m, 2H), 3.68-3.65 (m, 2H), 3.08 (s, 3H), 1.66-1.59 ( m, 2H), 1.39-1.35 (m, 2H), 1.12 (s, 3H).

the fourth step.

3,7-dimethyl-1 - ((4-methyl-tetrahydro -2 H - pyran-4-yl) methyl) -1 H - purine -2,6- (3 H, 7 H) - Dione.

3,-Dimethyl-1-(2-(3-methyltetrahydrofuran-3-yl)ethyl)-1 H -purine-2,6-(3 H ,7 H )-dione.

(4-methyltetrahydro- 2H -piperan-4-yl) methyl methanesulfonate (300mg, 1.44mmol), 3,7-dimethyl- 1H -purine-2,6-(3 H, 7 H) - dione (259mg, 1.44mmol), potassium iodide (23.9mg, 0.144mmol) and potassium carbonate (239mg, 1.73mmol) was dissolved in anhydrous N, N - dimethylformamide (10 mL) in. The reaction solution was heated to 130°C and reacted in a microwave for 2 hours. The reaction liquid was cooled to 20°C, filtered, and purified by preparative high performance liquid chromatography to obtain 3,7-dimethyl-1-((4-methyltetrahydro- 2H -piperan-4-yl)methyl) -1 H -purine-2,6-(3 H ,7 H )-dione (isomer 1) (80.0 mg), yield: 19%, and 3,7-dimethyl-1-(2 -(3-methyltetrahydrofuran-3-yl)ethyl)-1 H -purine-2,6-(3 H ,7 H )-dione (isomer 2) (90.0 mg), yield: 24 %.

3,7-dimethyl-1 - ((4-methyl-tetrahydro -2 H - pyran-4-yl) methyl) -1 H - purine -2,6- (3 H, 7 H) - Dione. ¹ H NMR: (400 MHz, Methonal- d ₄ ) δ = 7.87 (s, 1H), 3.97 (s, 3H), 3.96 (s, 2H), 3.78-3.74 (m, 2H), 3.66-3.64 (m, 2H), 3.33 (s, 3H), 1.68-1.62 (m, 2H), 1.35-1.31 (m, 2H), 1.02 (s, 3H). MS-ESI calculated value [M+H] ⁺ 293, found value 293.

3,7-Dimethyl-1-(2-(3-methyltetrahydrofuran-3-yl)ethyl)-1 H -purine-2,6-(3 H ,7 H )-dione. ¹ H NMR: (400 MHz, Methonal- d ₄ ) δ = 7.87 (s, 1H), 4.04-3.99 (m, 2H), 3.92 (s, 3H), 3.90-3.89 (m, 2H), 3.61-3.33 ( m, 5H), 1.97-1.93 (m, 1H), 1.77-1.70 (m, 3H), 1.02 (s, 3H). MS-ESI calculated value [M+H] ⁺ 293, found value 293.

Example 12.

1-((4-ethyltetrahydro- 2H -piperan-4-yl)methyl)-3,7-dimethyl- 1H -purine-2,6-( 3H , 7H )- Dione.

1-(2-(3-ethyltetrahydro-furan-3-yl)ethyl)-3,7-dimethyl-1 H -purine-2,6-(3 H ,7 H )-dione .

first step.

4-ethyltetrahydro- 2H -piran-4-carboxylic acid methyl ester.

Dissolve methyl tetrahydro- 2H -piran-4-carboxylate (2.50g, 17.3mmol) in anhydrous tetrahydrofuran (50mL), under nitrogen protection, and slowly add lithium diisopropylamide dropwise at -78°C The solution (2M n-hexane solution, 10.4 mL, 20.8 mmol), and the reaction solution was stirred at -78°C for 1 hour. Iodoethane (5.41 g, 34.7 mmol) was slowly added, and stirring was continued for 1 hour. Water (20 mL) was added to quench the reaction. The reaction solution was extracted with ethyl acetate (50 mL x 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and purified by silica gel column chromatography (10:1 petroleum ether/ethyl acetate, Rf= 0.4) Methyl 4-ethyltetrahydro- 2H -piper-4-carboxylate (1.00 g, yellow oil) was obtained, yield: 33%.

¹ H NMR: (400 MHz, Methonal- d ₄ ) δ=3.84-3.81 (m, 2H), 3.73 (s, 3H), 3.47-3.40 (m, 2H), 2.10-2.06 (m, 2H), 1.53- 1.28 (m, 2H), 0.85-0.81 (m, 2H), 1.20 (t, J = 7.2 Hz, 3H).

The second step.

(4-ethyltetrahydro- 2H -piperan-4-yl) methanol.

Dissolve 4-ethyltetrahydro- 2H -piperan-4-carboxylic acid methyl ester (1.00g, 5.81mmol) in anhydrous tetrahydrofuran (10mL), and add lithium aluminum tetrahydrogen (220mg, 5.81mmol) at 0°C. . The reaction liquid was heated to 25°C and stirred for 1 hour. It was quenched by adding water (20 mL), extracted with ethyl acetate (50 mL x 3), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and purified by silica gel column chromatography (1:1 petroleum ether/ethyl acetate, Rf= 0.2) to give (4-ethyltetrahydro- 2H -piperan-4-yl) methanol (600 mg, yellow oil), yield: 72%.

¹ H NMR: (400 MHz, Methonal- d ₄ ) δ=3.75-3.66 (m, 4H), 3.45 (s, 2H), 1.54-1.50 (m, 4H), 1.42-1.38 (m, 2H), 0.88- 0.84 (m, 3H).

third step.

(4-ethyltetrahydro- 2H -piperan-4-yl) methyl methanesulfonate.

(4-ethyl-tetrahydro -2 H - pyran-4-yl) methanol (600mg, 4.16mmol) was dissolved in dichloromethane (10mL), was added triethylamine (843mg, 8.32mmol) at 0 ℃ And methanesulfonyl chloride (572mg, 4.99mmol). The reaction solution was reacted at 0°C for 2 hours. Saturated aqueous sodium bicarbonate solution (10 mL) was added to quench, extracted with dichloromethane (50 mL x 3), the organic phases were combined, washed with saturated sodium chloride solution (50 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was depressurized Concentrate to give (4-ethyltetrahydro- 2H -piperan-4-yl) methyl methanesulfonate (600 mg, yellow oil), yield: 65%.

¹ H NMR: (400 MHz, Methonal- d ₄ ) δ = 4.12 (s, 2H), 3.71-3.69 (m, 4H), 3.11 (s, 3H), 1.61-1.52 (m, 4H), 1.28-1.24( m, 2H), 0.93-0.89 (m, 3H).

the fourth step.

1-((4-ethyltetrahydro- 2H -piperan-4-yl)methyl)-3,7-dimethyl- 1H -purine-2,6-( 3H , 7H )- Dione.

1-(2-(3-ethyltetrahydro-furan-3-yl)ethyl)-3,7-dimethyl-1 H -purine-2,6-(3 H ,7 H )-dione .

(4-ethyltetrahydro- 2H -piperan-4-yl) methyl methanesulfonate (300mg, 1.35mmol), 3,7-dimethyl- 1H -purine-2,6-(3 H, 7 H) - dione (243mg, 1.35mmol), potassium iodide (22.4mg, 0.135mmol) and potassium carbonate (224mg, 1.62mmol) was dissolved in anhydrous N, N - dimethylformamide (10 mL) in. The reaction solution was heated to 130°C and reacted in a microwave for 2 hours. The reaction solution was cooled to 20°C, filtered, and purified by preparative high performance liquid chromatography to obtain 1-((4-ethyltetrahydro- 2H -piperan-4-yl)methyl)-3,7-dimethyl -1 H -purine-2,6-(3 H ,7 H )-diketone (isomer 1) (120 mg), yield: 29%, and 1-(2-(3-ethyltetrahydro- Furan-3-yl)ethyl)-3,7-dimethyl-1 H -purine-2,6-(3 H ,7 H )-dione (isomer 2) (80.0 mg), yield : 19%.

1-((4-ethyltetrahydro- 2H -piperan-4-yl)methyl)-3,7-dimethyl- 1H -purine-2,6-( 3H , 7H )- Dione. ¹ H NMR: (400 MHz, Methonal- d ₄ ) δ = 7.88 (s, 1H), 4.03 (s, 2H), 3.98 (s, 3H), 3.73-3.72 (m, 2H), 3.65-3.63 (m, 2H), 3.53 (s, 3H), 1.62-1.52 (m, 4H), 1.52-1.43 (m, 2H), 0.98-0.94 (m, 3H). MS-ESI calculated value [M+H] ⁺ 307, found value 307.

1-(2-(3-ethyltetrahydro-furan-3-yl)ethyl)-3,7-dimethyl-1 H -purine-2,6-(3 H ,7 H )-dione . ¹ H NMR: (400 MHz, Methonal- d ₄ ) δ = 7.87 (s, 1H), 4.00-3.98 (m, 5H), 3.87-3.86 (m, 2H), 3.63-3.61 (m, 2H), 3.56 ( s, 3H), 1.90-1.80 (m, 1H), 1.75-1.72 (m, 3H), 1.58-1.54 (m, 2H), 1.05-1.01 (m, 3H). MS-ESI calculated value [M+H] ⁺ 307, found value 307.

Example 13.

3,7-dimethyl-1- (2- (tetrahydro -2 H - pyran-4-yl) ethyl) -1 H - purine -2,6 (3 H, 7 H) - dione.

4- (2-bromoethyl) tetrahydro -2 H - pyran (200mg, 1.00mmol), 3,7- dimethyl -1 H - purine -2,6 (3 H, 7 H) - two Ketone (186mg, 1.00mmol), potassium iodide (17.0mg, 0.100mmol) and potassium carbonate (414mg, 3.00mmol) were dissolved in N , N -dimethylformamide (4mL), the reaction solution was heated to 130 ℃ reaction 3 hour. The reaction solution was cooled to 25°C, saturated brine was added to quench the reaction, and extracted with ethyl acetate (50 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and purified with an efficient preparation plate (ethyl acetate , Rf = 0.5) to give the product 3,7-dimethyl-1- (2- (tetrahydro -2 H - pyran-4-yl) ethyl) -1 H - purine -2,6 (3 H, 7 H )-diketone (224 mg), yield: 77%.

¹ H NMR: (400 MHz, Methonal- d ₄ ) δ = 7.86 (s, 1H), 4.06-4.01 (m, 2H), 3.97 (s, 3H), 3.92 (dd, J = 12, 3.2 Hz, 2H) , 3.53 (s, 3H), 3.44-3.38 (m, 2H), 1.73 (d, J =12.8 Hz, 2H), 1.61-1.55 (m, 3H), 1.38-1.24 (m, 2H). MS-ESI calculated value [M+H] ⁺ 293, found value 293.

Example 14.

1-[2-((2S,6S)-2,6-dimethyltetrahydro- 2H -piperan-4-yl)-ethyl]-3,7-dimethyl- 1H -2, 6(3 H ,7 H )-dione.

first step.

2-methyl- 2H -piperan-4( 3H )-one.

( E )-((4-methoxy-1,3-dien-2-yl)oxy)trimethylsilane (5.00 g, 29.0 mmol) and acetaldehyde (55.0 g, 58.0 mmol) are dissolved in anhydrous To ether (50 mL), boron trifluoride etherate (4.33 g, 30.5 mmol) was added at -78°C, and the reaction was stirred at -78°C for 2.5 hours. A saturated solution of ammonium chloride (40 mL) was added to quench, extracted with ethyl acetate (20 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. Separated and purified by silica gel column chromatography (10:1 petroleum ether/ethyl acetate, Rf=0.6) to obtain 2-methyl- 2H -piperan-4( 3H )-one (1.25g, yellow oil) Material), yield: 38%.

¹ H NMR: (400 MHz, Methonal- d ₄ ) δ = 7.75 (d, J = 6.4 Hz, 1H), 5.65 (d, J = 6.4 Hz, 1H), 4.63-4.58 (m, 1H), 2.59-2.45 (m, 2H), 1.46 (d, J = 3.2 Hz, 3H).

The second step.

(2 S ,6 S )-2,6-dimethyl-tetrahydro-piperan-4-one.

Methyl lithium (1.6M ether solution, 20.9mL, 33.4mmol) was dissolved in anhydrous ether (30mL) solution at 0°C, and cuprous iodide (4.25g, 22.3mmol) was added under nitrogen protection. The reaction solution was reacted at 0°C for 0.5 hour. A solution of 2-methyl- 2H -piperan-4( 3H )-one (1.25g, 11.2mmol) in ether (5mL) was slowly added. The reaction liquid was heated to 20°C and stirred for 3 hours. Saturated ammonium chloride solution (20 mL) was added to quench, extracted with ethyl acetate (20 mL x 3), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and purified by silica gel column chromatography (10:1 petroleum ether/ Ethyl acetate, Rf=0.3) to give (2 S ,6 S )-2,6-dimethyl-tetrahydro-piperan-4-one (400 mg, yellow solid), yield: 29%.

¹ H NMR: (400 MHz, Methonal- d ₄ ) δ=4.36-4.31 (m, 2H), 2.58-2.53 (m, 2H), 2.28-2.25 (m, 2H), 1.25 (d, J =6.0 Hz, 6H).

third step.

(2,6-dimethyl-tetrahydro-piperan-4-ylidene)-ethyl acetate.

The ethyl triphenyl phosphine (3.26g, 9.37mmol) was dissolved in dry toluene (10 mL) was added ((2 S, 6 S) -2,6- dimethyl - tetrahydro --pyran-4 Ketone (400mg, 3.13mmol). The reaction solution was heated to 110°C for 72 hours. Cooled to 20°C, quenched with water (50mL), extracted with ethyl acetate (20mL x 3), dried over anhydrous sodium sulfate, filtered, and filtrate Concentrate under reduced pressure and purify by silica gel column chromatography (10:1 petroleum ether/ethyl acetate, Rf=0.7) to obtain (2,6-dimethyl-tetrahydro-piperan-4-ylidene)-acetic acid Ethyl ester (200 mg, yellow oil), yield: 32%.

¹ H NMR: (400 MHz, Methonal- d ₄ ) δ=5.77 (s, 1H), 4.14-4.07 (m, 4H), 2.98-2.97 (m, 1H), 2.84-2.82 (m, 1H), 2.44- 2.40 (m, 1H), 2.11-2.09 (m, 1H), 1.28-1.25 (m, 3H), 1.18-1.16 (m, 6H).

the fourth step.

(2,6-Dimethyl-tetrahydro-piperan-4-yl)-ethyl acetate.

(2,6-Dimethyl-tetrahydro-piperan-4-ylidene)-ethyl acetate (200 mg, 1.01 mmol) was dissolved in ethyl acetate (20 mL) solution, and wet palladium carbon (10%, 20.0mg). The reaction solution was stirred at 25°C under hydrogen balloon pressure for 2 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain (2,6-dimethyl-tetrahydro-piperan-4-yl)-ethyl acetate (150 mg, yellow oil), yield: 75%.

¹ H NMR: (400 MHz, Methonal- d ₄ ) δ = 4.20-4.10 (m, 3H), 3.83-3.82 (m, 1H), 2.28-2.21 (m, 3H), 1.72-1.69 (m, 1H), 1.58-1.55 (m, 1H), 1.31-1.30 (m, 1H), 1.28-1.26 (m, 6H), 1.12-1.11 (m, 1H), 1.02-1.01 (m, 3H).

the fifth step.

2-(2,6-dimethyl-tetrahydro-piperan-4-yl)-ethanol.

(2,6-Dimethyl-tetrahydro-piperan-4-yl)-ethyl acetate (150 mg, 0.750 mmol) was dissolved in anhydrous tetrahydrofuran (2 mL), and lithium aluminum tetrahydrogen (57.0 mg) was added at 0°C. , 1.50mmol). The reaction liquid was heated to 25°C and stirred for 1 hour. It was quenched with water (10 mL), extracted with ethyl acetate (10 mL x 3), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and purified by preparative TLC plate (3:1 petroleum ether/ethyl acetate, Rf= 0.5) to give 2-(2,6-dimethyl-tetrahydro-piperan-4-yl)-ethanol (70.0 mg, yellow oil), yield: 86%.

¹ H NMR: (400 MHz, Methonal- d ₄ ) δ = 4.20-4.18 (m, 1H), 3.83-3.81 (m, 1H), 3.64-3.61 (m, 2H), 1.99-1.98 (m, 1H), 1.70-1.68 (m, 1H), 1.55-1.53 (m, 1H), 1.47-1.42 (m, 3H), 1.31-1.29 (m, 3H), 1.13-1.11 (m, 3H), 0.85-0.82 (m , 1H).

The sixth step.

2-((2 S ,6 S )-2,6-dimethyltetrahydro-2 H -piperan-4-yl)ethyl methanesulfonate.

2-(2,6-Dimethyl-tetrahydro-piperan-4-yl)-ethanol (150 mg, 0.949 mmol) was dissolved in dichloromethane (5 mL), and triethylamine (287 mg) was added at 0°C. , 2.85mmol) and methanesulfonyl chloride (213mg, 1.90mmol). The reaction solution was reacted at 25°C for 2 hours. Saturated aqueous sodium bicarbonate solution (10 mL) was added to quench, extracted with dichloromethane (10 mL x 3), the organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give 2- ((2 S ,6 S )-2,6-dimethyltetrahydro-2 H -piperan-4-yl)ethyl methanesulfonate (200 mg, yellow oil), yield: 90%.

¹ H NMR: (400 MHz, Methonal- d ₄ ) δ = 4.33-4.30 (m, 2H), 4.23-4.20 (m, 1H), 3.85-3.82 (m, 1H), 3.08 (s, 3H), 2.03- 2.14 (m, 1H), 1.68-1.67 (m, 1H), 1.65-1.63 (m, 2H), 1.58-1.56 (m, 1H), 1.41-1.39 (m, 1H), 1.31-1.29 (m, 3H) ), 1.14-1.12 (m, 3H), 0.89-0.86 (m, 1H).

The seventh step.

1-[2-((2S,6S)-2,6-dimethyltetrahydro- 2H -piperan-4-yl)-ethyl]-3,7-dimethyl- 1H -2, 6(3 H ,7 H )-dione.

2-((2 S ,6 S )-2,6-dimethyltetrahydro-2H-piperan-4-yl)ethyl methanesulfonate (100 mg, 0.424 mmol), 3,7-dimethyl -3,7-dihydro-purine-2,6-dione (83.9mg, 0.466mmol), potassium iodide (7.4mg, 0.047mmol) and potassium carbonate (109mg, 0.790mmol) dissolved in N , N -dimethyl In carboxamide (3 mL), the reaction solution was heated to 120°C and reacted for 3 hours. The reaction was cooled to 20°C, filtered, and the filtrate was separated and purified by preparative high performance liquid chromatography to obtain 1-[2-((2S,6S)-2,6-dimethyltetrahydro- 2H -piperan-4-yl ) - ethyl] -3,7-dimethyl -1 H -2,6 (3 H, 7 H) - dione (40.0mg), yield: 30%.

¹ H NMR: (400 MHz, Methonal- d ₄ ) δ = 8.14 (s, 1H), 4.21-4.18 (m, 1H), 4.07-4.05 (m, 2H), 4.01 (s, 3H), 3.82-3.81 ( m, 1H), 3.54 (s, 3H), 1.85-1.66 (m, 1H), 1.55-1.51 (m, 2H), 1.40-1.39 (m, 2H), 1.29-1.28 (m, 1H), 1.27- 1.26 (m, 3H), 1.12-1.11 (m, 3H), 0.89-0.86 (m, 1H). MS-ESI calculated value [M+H] ⁺ 321, found value 321.

Example 15.

1-(2-(3-ethyltetrahydro- 2H -piperan-4-yl)ethyl)-3,7-dimethyl- 1H -purine-2,6-( 3H , 7H )-Diketone.

first step.

3-ethyldihydro- 2H -piperan-4-( 3H )-one.

Dihydro- 2H -piperan-4-( 3H )-one (5.00g, 50.0mmol) and hexamethylphosphoramide (8.95g, 50.0mmol) were dissolved in tetrahydrofuran (50mL) at -78°C Under conditions, lithium diisopropylamide (50 mL, 2.0 M tetrahydrofuran solution, 100 mmol) was slowly added dropwise, and stirred at -78°C for 30 minutes. The reaction solution was added ethyl iodide (16.2 g, 75.0 mmol) at 0°C and stirred for 2 hours. The reaction solution was added with water (15 mL) and ethyl acetate (40 mL x 3) for extraction. The organic phases were combined and washed with saturated sodium chloride (20 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure using a silica gel column layer Separation and purification (10:1 petroleum ether/ethyl acetate, Rf=0.5) gave 3-ethyldihydro- 2H -piperan-4-( 3H )-one (1.20g, colorless oil) ), yield: 19%.

¹ H NMR: (400 MHz, CDCl ₃ ) δ=4.15-4.11 (m, 2H), 3.77-3.76 (m, 1H), 3.47-3.42 (m, 1H), 2.45-2.40 (m, 3H), 1.80- 1.78 (m, 2H), 0.91 (t, J = 7.2 Hz, 3H). MS-ESI calculated value [M+H] ⁺ 129, found value 129.

The second step.

Ethyl-2-(3-ethyldihydro- 2H -piran-4( 3H )-ylidene) ethyl acetate.

Combine 3-ethyldihydro- 2H -piperan-4( 3H )-one (600mg, 4.68mmol) and ethyl-2-(diethoxyphosphonoyl)acetate (1.15g, 5.15 mmol) was dissolved in tetrahydrofuran (30 mL), and sodium hydride (224 mg, 9.36 mmol) was added to the reaction solution at 0°C. After stirring at room temperature for 30 minutes, water (10 mL) was added to the reaction solution at 0°C. The reaction solution was diluted with ethyl acetate (30 mL), the organic phase was washed with water (20 mL x 2), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and purified by silica gel column chromatography (10:1 petroleum ether/ Ethyl acetate, Rf=0.7) to give ethyl-2-(3-ethyldihydro- 2H -piran-4( 3H )-subunit) ethyl acetate (800mg, yellow oil), produced Rate: 86%. MS-ESI calculated value [M+H] ⁺ 199, found value 199.

third step.

2-(3-ethyltetrahydro- 2H -piperan-4-yl) ethyl acetate.

Dissolve ethyl-2-(3-ethyldihydro- 2H -piran-4( 3H )-subunit) ethyl acetate (800mg, 4.04mmol) in methanol (40mL) at room temperature Wet palladium on carbon (10%, 0.02g) was added. The reaction system was replaced with a hydrogen balloon three times, and then reacted at room temperature for 2 hours. The reaction solution was filtered and concentrated to obtain ethyl 2-(3-ethyltetrahydro- 2H -piperan-4-yl)acetate (600 mg, yellow oil Material), yield: 74%. MS-ESI calculated value [M+H] ⁺ 201, found value 201.

the fourth step.

2-(3-ethyltetrahydro- 2H -piperan-4-yl)ethanol.

Ethyl 2-(3-ethyltetrahydro- 2H -piperan-4-yl) ethyl acetate (600mg, 3.00mmol) was dissolved in tetrahydrofuran (30mL), and lithium aluminum hydride (170mg, 4.50 mmol), after stirring at room temperature for 2 hours, water (0.2 mL), 15% sodium hydroxide (0.2 mL) and water (0.6 mL) were added to the reaction solution, stirred for 20 minutes, and ethyl acetate ( 30mL) diluted, the organic phase was washed with water (20mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give 2-(3-ethyltetrahydro- 2H -piperan-4-yl)ethanol (400mg, Yellow oil), yield: 84%.

MS-ESI calculated value [M+H] ⁺ 159, found value 159.

the fifth step.

2-(3-ethyltetrahydro- 2H -piperan-4-yl)ethyl methanesulfonate.

2- (3-ethyl-tetrahydro -2 H - pyran-4-yl) ethanol (474mg, 3.00mmol) and triethylamine (455mg, 4.50mmol) was dissolved in dichloromethane (30mL), the reaction solution Methanesulfonyl chloride (412 mg, 3.60 mmol) was added at 0°C. Stir at 0°C for 2 hours, dilute dichloromethane (30 mL) to the reaction solution, wash the organic phase with water (20 mL x 2), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to give 2-(3-ethyltetrazol Hydrogen- 2H -piperan-4-yl)ethyl methanesulfonate (600 mg, yellow oil) Yield: 85%.

MS-ESI calculated value [M+H] ⁺ 237, found value 237.

The sixth step.

1-(2-(3-ethyltetrahydro- 2H -piperan-4-yl)ethyl)-3,7-dimethyl- 1H -purine-2,6-( 3H , 7H )-Diketone.

Combine 2-(3-ethyltetrahydro- 2H -piperan-4-yl)ethyl methanesulfonate (400mg, 1.69mmol) and 3,7-dimethyl- 1H -purine-2,6 -(3 H ,7 H )-dione (305 mg, 1.69 mmol) was dissolved in N,N -dimethylformamide (20 mL), and potassium carbonate (467 mg, 3.38 mmol) and potassium iodide were added at room temperature ( 28.0 mg, 0.169 mmol). The reaction solution was stirred at 100°C for 2 hours. The reaction solution was cooled to room temperature and concentrated, diluted with ethyl acetate (30 mL), the organic phase was washed with water (20 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. Purified by high performance liquid chromatography to obtain 1-(2-(3-ethyltetrahydro- 2H -piperan-4-yl)ethyl)-3,7-dimethyl- 1H -purine-2,6 -(3 H ,7 H )-dione (200 mg), yield: 37%.

¹ H NMR: (400 MHz, CDCl ₃ ) δ=7.49 (s, 1H), 3.97-3.95 (m, 5H), 3.83-3.77 (m, 2H), 3.43 (s, 3H), 3.42-3.35 (m, 2H), 1.79-1.41 (m, 8H), 0.91-0.82 (m, 3H). MS-ESI calculated value [M+H] ⁺ 321, found value 321.

Example 16.

1- (2- (2-ethyl-tetrahydro -2 H - pyran-4-yl) ethyl) -3,7-dimethyl -1 H - purine -2,6 (3 H, 7 H) -Diketones.

first step.

2-(2-ethyltetrahydro- 2H -piperan-4-yl) ethyl methanesulfonate.

2- (2-ethyl-tetrahydro -2 H - pyran-4-yl) ethanol (100mg, 0.630mmol) and N, N - diisopropylethylamine (122mg, 0.940mmol) was dissolved in dichloromethane (20 mL), methanesulfonyl chloride (86.9 mg, 0.750 mmol) was added at 0°C. After the reaction solution was stirred at 25°C for 0.5 hours, it was diluted with dichloromethane (20 mL), washed with saturated sodium bicarbonate (30 mL x 2), the organic phase was dried over anhydrous sodium sulfate, and concentrated to give 2-(2-ethyltetrahydrogen -2 H - pyran-4-yl) ethyl methanesulfonate (180 mg of, yellow oil), yield: 100%.

The second step.

1- (2- (2-ethyl-tetrahydro -2 H - pyran-4-yl) ethyl) -3,7-dimethyl -1 H - purine -2,6 (3 H, 7 H) -Diketones.

2- (2-ethyl-tetrahydro -2 H - pyran-4-yl) ethyl methanesulfonate (180mg, 0.760mmol) was dissolved in N, N - dimethylformamide (10 mL), the At 25°C, 3,7-dimethyl-1 H -purine-2,6(3 H ,7 H )-dione (146 mg, 0.800 mmol), potassium iodide (13.0 mg, 0.0800 mmol) and Potassium carbonate (211 mg, 1.60 mmol). The reaction solution was heated to 120°C for 2 hours, diluted with ethyl acetate (30 mL), washed with saturated sodium bicarbonate (20 mL x 2), the organic phase was dried over anhydrous sodium sulfate, and concentrated to give a yellow oil. Chromatographic separation and purification gave 1-(2-(2-ethyltetrahydro- 2H -piperan-4-yl)ethyl)-3,7-dimethyl- 1H -purine-2,6(3 H, 7 H) - dione (50.0mg), yield: 20%.

¹ H NMR: (400MHz, Methanol- d ₄ ) δ = 7.87 (s, 1H), 4.05-3.96 (m, 6H), 3.54-3.19 (m, 5H), 1.80-1.45 (m, 8H), 0.98- 0.92 (m, 4H). MS-ESI calculated value [M+H] ⁺ 321, found value 321.

Example 17.

3,7-dimethyl-1-(2-morpholinoethyl)-purine-2,6-dione.

At room temperature, to the mixture 1-(3-chloropropyl)-3,7-dimethyl-purine-2,6(3 H ,7 H )-dione (71.9 mg, 0.826 mmol) and morpholine (50.0 mg, 0.207 mmol) in acetonitrile (2 mL) was added potassium carbonate (138 mg, 1.03 mmol) and potassium iodide (86.3 mg, 0.517 mmol). The reaction solution was stirred at 90°C for 4 hours. Water (5 mL) was added to quench the reaction and extracted with ethyl acetate (5 mL x 3). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Separated and purified by preparative high performance liquid chromatography to obtain 3,7-dimethyl-1-(2-morpholinoethyl)-purine-2,6-dione (15.0 mg), yield: 25%. ¹ H NMR: (400 MHz, Methonal- d ₄ ) δ = 7.86 (s, 1H), 4.16 (t, J = 6.4 Hz, 2H), 3.97 (s, 3H), 3.68-3.65 (m, 4H), 3.52 (s, 3H), 2.65-2.57 (m, 6H). MS-ESI calculated value [M+H] ⁺ 294, found value 294.

Example 18.

1((4-methoxycyclohexyl)methyl)-3,7-dimethyl- 1H -purine-2,6-( 3H , 7H )-dione.

first step.

Methyl 4-methoxycyclohexanecarboxylate.

4-Methoxycyclohexanecarboxylic acid (300 mg, 1.90 mmol) was dissolved in methanol (7 mL), dichlorosulfite (1.13 g, 9.50 mmol) was slowly added at 0°C, and the reaction solution was stirred at room temperature for 12 hours. The reaction solution was concentrated under reduced pressure to obtain crude methyl 4-methoxycyclohexanecarboxylate (283 mg, yellow oil), yield: 86%.

¹ H NMR: (400 MHz, Methonal- d ₄ ) δ = 3.65 (s, 3H), 3.41-3.35 (m, 1H), 3.30 (s, 3H), 2.44-2.38 (m, 1H), 1.84-1.75 ( m, 4H), 1.67-1.54 (m, 4H).

The second step.

(4-methoxycyclohexyl) methanol.

At 0°C, lithium tetrahydroaluminum (92.8 mg, 2.45 mmol) was slowly added to tetrahydrofuran (7 mL) in which methyl-4-methoxycyclohexanecarboxylic acid (280 mg, 1.63 mmol) was dissolved under the protection of nitrogen. The reaction was stirred at room temperature for 4 hours, the reaction solution was cooled to 0°C in an ice water bath, and water (0.1 mL), 15% sodium hydroxide (0.1 mL) and water (0.3 mL) were slowly added in sequence. The reaction solution was warmed to room temperature and stirred for half an hour, filtered, the filter cake was washed with tetrahydrofuran (8mL x 2), and the filtrate was concentrated under reduced pressure to give (4-methoxycyclohexyl) methanol (213mg, yellow oil), yield: 91%. ¹ H NMR: (400 MHz, Methonal- d ₄ ) δ = 3.49-3.45 (m, 1H), 3.39-3.37 (m, 2H), 3.32 (s, 3H), 1.95-1.80 (m, 3H), 1.56- 1.48 (m, 4H), 1.36-1.27 (m, 2H).

third step.

(4-methoxycyclohexyl) methyl methanesulfonate.

(4-Methoxycyclohexyl) methanol (210 mg, 1.46 mmol) and triethylamine (443 mg, 4.38 mmol) were dissolved in dichloromethane (7 mL), and methanesulfonyl chloride (250 mg, 2.19 mmol). The reaction solution was stirred overnight at room temperature, water was added, extracted with dichloromethane (50 mL x 3), the organic phase was washed with saturated brine (25 mL x 2) and dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the product Silica gel column chromatography (5:1 petroleum ether/ethyl acetate, Rf=0.4) gave the product (4-methoxycyclohexyl) methyl methanesulfonate (240 mg, yellow oil), yield: 74 %. ¹ H NMR: (400 MHz, Methonal- d ₄ ) δ=4.07 (d, J =6.4 Hz, 2H), 3.51-3.47 (m, 1H), 3.32 (s, 3H), 3.07 (s, 3H), 1.98 -1.92 (m, 2H), 1.85-1.78 (m, 1H), 1.63-1.36 (m, 6H).

the fourth step.

1-((4-methoxycyclohexyl)methyl)-3,7-dimethyl- 1H -purine-2,6-( 3H , 7H )-dione.

(4-Methoxycyclohexyl) methyl methanesulfonate (240mg, 1.08mmol), 3,7-dimethyl- 1H -purine-2,6-( 3H , 7H )-dione (233 mg, 1.30 mmol) and potassium iodide (17.9 mg, 0.108 mmol) were dissolved in N,N -dimethylformamide (5 mL), potassium carbonate (298 mg, 2.16 mmol) was added, and the reaction was heated to reflux at 130°C for 4 hours. The reaction solution was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure. The obtained product was purified by preparative high performance liquid chromatography to obtain the product 1-((4-methoxycyclohexyl)methyl)-3,7-dimethyl- 1 H -purine-2,6-(3 H ,7 H )-dione (67.0 mg), yield: 20%. ¹ H NMR: (400 MHz, Methonal- d ₄ ) δ = 7.88 (s, 1H), 3.99 (s, 3H), 3.89 (d, J = 7.2 Hz, 2H), 3.54 (s, 3H), 3.47-3.42 (m, 1H), 3.32 (s, 3H), 1.94-1.87 (m, 3H), 1.47-1.39 (m, 6H). MS-ESI calculated value [M+H] ⁺ 307, found value 307.

Example 19.

3-methyl-1-((3-methyloxetan-3-yl)methyl)-7-(2,2,2-trifluoroethyl)-1 H -purine-2,6 (3 H ,7 H )-Diketone.

first step.

3-methyl-1-((3-methyloxetan-3-yl)methyl)-7-(2,2,2-trifluoroethyl)-1 H -purine-2,6 (3 H ,7 H )-Diketone.

3-methyl-7-(2,2,2-trifluoroethyl)-1 H -purine-2,6(3 H ,7 H )-dione (200 mg, 0.806 mmol), 3-(chloro Methyl)-3-methyloxetane (97.2mg, 0.806mmol) and potassium iodide (13.4mg, 0.0806mmol) were dissolved in N , N -dimethylformamide (5mL), potassium carbonate ( 223mg, 1.61mmol), the reaction was heated to reflux at 130 ℃ for 2.5 hours. The reaction solution was cooled to 25°C, filtered, and the filtrate was concentrated under reduced pressure. The obtained product was purified by preparative high performance liquid chromatography to obtain the product 3-methyl-1-((3-methyloxetane-3-yl)methyl Radical)-7-(2,2,2-trifluoroethyl)-1 H -purine-2,6(3 H ,7 H )-dione (48.0 mg), yield: 18%. ¹ H NMR: (400 MHz, Methonal- d ₄ ) δ = 8.09 (s, 1H), 5.25-5.18 (m, 2H), 4.75 (d, J = 6.4 Hz, 2H), 4.23 (d, J = 6.4 Hz , 2H), 4.15 (s, 2H), 3.56 (s, 3H), 1.35 (s, 3H). MS-ESI calculated value [M+H] ⁺ 333, found value 333.

Example 20.

1-(2-((2 R ,6 R )-2,6-dimethyltetrahydro-2 H -piperan-4-yl)ethyl)-3-methyl-7-(2,2, 2-trifluoroethyl)-1 H -purine 2,6(3 H ,7 H )-dione.

Combine 3-methyl-7-(2,2,2-trifluoroethyl)-1 H -purine-2,6(3 H ,7 H )-dione (100 mg, 0.4 mmol) and potassium iodide (7.0 mg , 0.040mmol) and potassium carbonate (165mg, 1.20mmol) were dissolved in N , N -dimethylformamide (3mL), the reaction was heated to 130 ℃ for 1 hour, 2-(( 2S , 6S ) was added -2,6-dimethyltetrahydro- 2H -piperan-4-yl)ethyl methanesulfonate (50.0 mg, 0.200 mmol), and the reaction was continued at 130° C. for 2.5 hours. The reaction solution was directly filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product and purified by preparative high performance liquid chromatography to obtain the product 1-(2-((2 R ,6 R )-2,6-dimethyltetrahydro-2 H -piper Furan-4-yl)ethyl)-3-methyl-7-(2,2,2-trifluoroethyl)-1 H -purine 2,6(3 H ,7 H )-dione (68.0mg ), yield: 87%. ¹ H NMR: (400 MHz, Methonal- d ₄ ) δ = 8.08 (s, 1H), 5.27-5.21 (m, 2H), 4.22-4.15 (m, 1H), 4.10-4.03 (m, 2H), 3.80- 3.75 (m, 1H), 3.57 (s, 3H), 1.95-1.30 (m, 7H), 1.28 (d, J = 6.8 Hz, 3H), 1.12 (d, J = 6.8 Hz, 3H). MS-ESI calculated value [M+H] ⁺ 389, found value 389.

Example 21.

1-(2-((2 R ,6 R )-2,6-dimethyltetrahydro-2 H -piperan-4-yl)ethyl)yl-7-isopropyl-3-methyl- 1 H -purine-2,6(3 H ,7 H )-dione.

2-((2 S ,6 S )-2,6-dimethyltetrahydro-2 H -piperan-4-yl)ethyl methanesulfonate (100 mg, 0.424 mmol), 7-isopropyl -3-Methyl-1 H -purine-2,6(3 H ,7 H )-dione (100 mg, 0.466 mmol), potassium iodide (7.4 mg, 0.047 mmol) and potassium carbonate (109 mg, 0.790 mmol) were dissolved In anhydrous N , N -dimethylformamide (3 mL), the reaction solution was heated to 120°C and stirred for 3 hours. The reaction was cooled to 20°C, filtered, and the filtrate was separated and purified by preparative high performance liquid chromatography to obtain 1-(2-((2 R ,6 R )-2,6-dimethyltetrahydro-2 H -piran-4 -Yl)ethyl)yl-7-isopropyl-3-methyl-1 H -purine-2,6(3 H ,7 H )-dione (70.0 mg), yield: 46%.

¹ H NMR: (400 MHz, Methonal- d ₄ ) δ = 8.92 (s, 1H), 5.21-5.15 (m, 1H), 4.21-4.09 (m, 1H), 4.08-4.06 (m, 2H), 4.05- 4.04 (m, 1H), 3.58 (s, 3H), 1.86-1.80 (m, 1H), 1.68-1.66 (m, 2H), 1.65-1.64 (m, 6H), 1.57-1.55 (m, 2H), 1.54-1.52 (m, 1H), 1.30-1.28 (m, 3H), 1.13-1.12 (m, 3H), 0.90-0.87 (m, 1H). MS-ESI calculated value [M+H] ⁺ 349, found value 349.

Example 22.

7-(cyclopropylmethyl)-3-methyl-1-((3-methyloxetan-3-yl)methyl)-1 H -purine-2,6(3 H ,7 H )-Diketone.

first step.

7-(cyclopropylmethyl)-3-methyl-1-((3-methyloxetan-3-yl)methyl)-1 H -purine-2,6(3 H ,7 H )-Diketone.

7-(cyclopropylmethyl)-3-methyl-1 H -purine-2,6(3 H ,7 H )-dione (250 mg, 1.14 mmol), 3-(chloromethyl)-3 -Methyloxetane (137mg, 1.14mmol) and potassium iodide (18.9mg, 0.114mmol) were dissolved in N , N- dimethylformamide (5mL), potassium carbonate (315mg, 2.28mmol) was added, The reaction was heated to reflux at 130°C for 2.5 hours. The reaction solution was cooled to 25°C, filtered, and the filtrate was concentrated under reduced pressure. The obtained product was purified by preparative high performance liquid chromatography to obtain the product 7-(cyclopropylmethyl)-3-methyl-1-((3-methyloxygen Heterocyclobutan-3-yl)methyl)-1 H -purine-2,6(3 H ,7 H )-dione (55.0 mg), yield: 16%. ¹ H NMR: (400M Hz, Methonal- d ₄ ) δ = 8.01 (s, 1H), 4.76 (d, J = 6.4 Hz, 2H), 4.24-4.18 (m, 4H), 4.14 (s, 2H), 3.55 (s, 3H), 1.39-1.33 (m, 4H), 0.62-0.56 (m, 2H), 0.48-0.43 (m, 2H). MS-ESI calculated value [M+H] ⁺ 305, found value 305.

Example 23.

7-(cyclopropylmethyl-1-(2-((2 R ,6 R )-2,6-dimethyltetrahydro-2 H -piperan-4-yl)ethyl-3-methyl -1 H -purine-2,6(3 H ,7 H )-dione.

((2 S ,6 S )-2,6-dimethyltetrahydro-2 H -piperan-4-yl)ethyl methanesulfonate (100 mg, 0.424 mmol) and 7-(cyclopropylmethyl Yl)-3-methyl-1 H -purine-2,6(3 H ,7 H )-dione (102 mg, 0.466 mmol) dissolved in N , N -dimethylformamide (3 mL), under nitrogen Potassium carbonate (109 mg, 0.790 mmol) and potassium iodide (7.4 mg, 0.047 mmol) were added under protection. The reaction solution was heated to 120°C and stirred for 3 hours. After cooling to 20°C, the mixture was filtered, and the filtrate was separated and purified by preparative high performance liquid chromatography to obtain 7-(cyclopropylmethyl)-1-(2-((2 R ,6 R )-2,6-di methyl-tetrahydro -2 H - pyran-4-yl) ethyl) -3-methyl -1 H - purine -2,6 (3 H, 7 H) - dione (70.0mg), yield: 46%.

¹ H NMR: (400 MHz, Methonal-d ₄ ) δ = 8.02 (s, 1H), 4.25-4.21 (m, 3H), 4.20-4.19 (m, 2H), 4.08-4.02 (m, 1H), 3.55 ( s, 3H), 1.87-1.80 (m, 1H), 1.66-1.56 (m, 2H), 1.54-1.50 (m, 2H), 1.42-1.40 (m, 2H), 1.29-1.27 (m, 3H), 1.13-1.12 (m, 3H), 0.89-0.86 (m, 1H), 0.63-0.60 (m, 2H), 0.49-0.47 (m, 2H). MS-ESI calculated value [M+H] ⁺ 361, found value 361.

Example 24.

7-(cyclopropylmethyl)-1-((4-methoxycyclohexyl)methyl)-3-methyl-purine-2,6-dione.

first step.

7-(cyclopropylmethyl)-1-((4-methoxycyclohexyl)methyl)-3-methyl-purine-2,6-dione.

(4-Methoxycyclohexyl) methyl methanesulfonate (30.0 mg, 0.135 mmol), 7-(cyclopropylmethyl)-3-methyl-purine-2,6-dione (26.8 mg , 0.121mmol), potassium iodide (2.2mg, 0.014mmol) and potassium carbonate (37.3mg, 0.269mmol) were dissolved in N , N- dimethylformamide (5mL). The reaction liquid was heated to 120°C and stirred for 3 hours. Cooled to room temperature, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by preparative high performance liquid chromatography to obtain 7-(cyclopropylmethyl)-1-((4-methoxycyclohexyl)methyl)-3 -Methyl-purine-2,6-dione (20.0 mg), yield: 43%. ¹ H NMR: (400 MHz, Methonal- d ₄ ) δ = 8.01 (s, 1H), 4.20 (d, J = 7.2 Hz, 2H), 3.88 (d, J =16.0 Hz, 2H), 3.56 (s, 3H ), 3.34 (s, 3H), 3.17-3.14 (m, 1H), 2.09-2.06 (m, 2H), 1.75-1.73 (m, 3H), 1.41-1.39 (m, 1H), 1.34-1.10 (m , 4H), 0.63-0.61 (m, 2H), 0.48-0.47 (m, 2H). MS-ESI calculated value [M+H] ⁺ 347, found value 347.

Example 25.

7-isobutyl-3-methyl-1-((3-methyloxetan-3-yl)methyl)-1 H -purine-2,6(3 H ,7 H )-di ketone.

first step.

7-isobutyl-3-methyl-1-((3-methyloxetan-3-yl)methyl)-1 H -purine-2,6(3 H ,7 H )-di ketone.

7-isobutyl-3-methyl-1 H -purine-2,6(3 H ,7 H )-dione (200 mg, 0.900 mmol), 3-(chloromethyl)-3-methyloxygen Heterocyclobutane (109mg, 0.900mmol) and potassium iodide (14.9mg, 0.0900mmol) were dissolved in N , N -dimethylformamide (5mL), potassium carbonate (249mg, 1.80mmol) was added, and the reaction was heated at 130°C Reflux for 2.5 hours. The reaction solution was cooled to 25°C, filtered, and the filtrate was concentrated under reduced pressure. The obtained product was purified by preparative high performance liquid chromatography to obtain the product 7-isobutyl-3-methyl-1-((3-methyloxetane -3-yl)methyl)-1 H -purine-2,6(3 H ,7 H )-dione (34.0 mg), yield: 12%. ¹ H NMR: (400M Hz, Methonal- d ₄ ) δ = 7.95 (s, 1H), 4.75 (d, J = 1.2 Hz, 2H), 4.22 (d, J = 6.4 Hz, 2H), 4.15-4.12 ( m, 4H), 3.55 (s, 3H), 2.23-2.12 (m, 1H), 1.35 (s, 3H), 0.92 (d, J = 6.8 Hz, 6H). MS-ESI calculated value [M+H] ⁺ 307, found value 307.

Example 26.

1-(2-((2 R ,6 R )-2,6-dimethyltetrahydro-2 H -piperan-4-yl)ethyl)-7-isobutyl-3-methyl-1 H -purine-2,6(3 H ,7 H )-dione.

Combine 7-isobutyl-3-methyl-1 H -purine-2,6(3 H ,7 H )-dione (90.0 mg, 0.400 mmol), potassium iodide (7.0 mg, 0.040 mmol) and potassium carbonate ( 165mg, 1.20mmol) was dissolved in N , N -dimethylformamide (3mL), the reaction was heated to 130°C for 1 hour, 2-(( 2S , 6S )-2,6-dimethyl was added Tetrahydro- 2H -piperan-4-yl)ethyl methanesulfonate (50.0 mg, 0.200 mmol), the reaction was continued at 130°C for 2.5 hours. The reaction solution was directly filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product and purified by preparative high performance liquid chromatography to obtain the product 1-(2-((2 R ,6 R )-2,6-dimethyltetrahydro-2 H -piper thiopyran-4-yl) ethyl) -7-isobutyl-3-methyl -1 H - purine -2,6 (3 H, 7 H) - dione (71.0mg), yield: 97%.

¹ H NMR: (400 MHz, Methonal- d ₄ ) δ = 7.93 (s, 1H), 4.24-3.98 (m, 5H), 3.86-3.78 (m, 1H), 3.55 (s, 3H), 2.26-2.16 ( m, 1H), 1.79-1.77 (m, 1H), 1.72-1.65 (m, 1H), 1.60-1.47 (m, 2H), 1.45-1.38 (m, 1H), 1.28 (d, J = 6.8Hz, 3H), 1.12 (d, J = 6.8 Hz, 3H), 0.94-0.88 (m, 8H). MS-ESI calculated value [M+H] ⁺ 363, found value 363.

Example 27.

4-methyl-6-((3-methyloxetan-3-yl)methyl)-1-(2,2,2-trifluoroethyl)-pyrazolo[4,3- d] Pyrimidine-5,7-dione.

first step.

4-Nitro-pyrazole-5-carboxylic acid methyl ester.

4-Nitro-pyrazole-5-carboxylic acid (45.0 g, 286 mmol) was dissolved in methanol (700 mL), and sulfoxide (102 g, 859 mmol) was added dropwise at 0°C. The reaction solution was stirred at 25°C for 18 hours. The reaction solution was concentrated under reduced pressure to obtain methyl 4-nitro-pyrazole-5-carboxylate (49.0 g, white solid), yield: 100%. ¹ H NMR: (400 MHz, CDCl ₃ ) δ=8.53 (s, 1H), 4.06 (s, 3H). MS-ESI calculated value [M+H] ⁺ 172, found value 172.

The second step.

4-Nitro-1-(2,2,2-trifluoroethyl)-pyrazole-5-carboxylic acid methyl ester.

Dissolve methyl 4-nitro-pyrazole-5-carboxylate (25.0g, 146mmol) in N , N -dimethylformamide (350mL) and add sodium hydride (6.43g, 161mmol) in portions at 0°C . The reaction was stirred at 0°C for 1 hour, and 2,2,2-trifluoroethyl trifluoromethanesulfonate (33.9 g, 146 mmol) was added dropwise. The reaction solution was stirred at 25°C for 18 hours. Water (1.2 L) was added to the reaction liquid, and extracted with ethyl acetate (300 mL x 2). The organic phases were combined, washed with saturated brine (500 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (5:1 petroleum ether/ethyl acetate, Rf=0.3) to obtain 4-Nitro-1-(2,2,2-trifluoroethyl)-pyrazole-5-carboxylic acid methyl ester (8.00 g, colorless oil), yield: 22%. ¹ H NMR: (400 MHz, CDCl ₃ ) δ=8.13 (s, 1H), 5.06 (q, J =8.0 Hz, 2H), 4.04 (s, 3H). MS-ESI calculated value [M+H] ⁺ 254, found value 254.

third step.

4-Amino-1-(2,2,2-trifluoroethyl)-pyrazole-5-carboxylic acid methyl ester.

Dissolve 4-nitro-1-(2,2,2-trifluoroethyl)-pyrazole-5-carboxylic acid methyl ester (7.50 g, 29.6 mmol) in methanol (100 mL) and add dry palladium on carbon (palladium 10 %, water 1%, 750 mg), at room temperature, the reaction solution was reacted under 40 psi hydrogen pressure for 3 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain methyl 4-amino-1-(2,2,2-trifluoroethyl)-pyrazole-5-carboxylate (6.30 g, off-white solid), yield: 95 %. ¹ H NMR: (400 MHz, CDCl ₃ ) δ = 7.25 (s, 1H), 5.10 (q, J = 8.4 Hz, 2H), 4.21 (s, 2H), 3.94 (s, 3H). MS-ESI calculated value [M+H] ⁺ 224, found value 224.

the fourth step.

4-(2,2,2-Trifluoroacetamide)-1-(2,2,2-trifluoroethyl)-pyrazole-5-carboxylic acid methyl ester.

Dissolve 4-amino-1-(2,2,2-trifluoroethyl)-pyrazole-5-carboxylic acid methyl ester (6.30g, 28.2mmol) in dichloromethane (100mL) and add dropwise under nitrogen protection Trifluoroacetic anhydride (8.89g, 42.4mmol), the reaction solution was stirred at room temperature for 2 hours, quenched with saturated sodium bicarbonate solution (100mL), extracted with dichloromethane (100mL), washed with saturated brine (50mL) organic Phase, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 4-(2,2,2-trifluoroacetamide)-1-(2,2,2-trifluoroethyl)-pyrazole-5-carboxylic acid methyl Ester (9.20 g crude product, yellow oil). ¹ H NMR: (400 MHz, CDCl ₃ ) δ=9.66 (s, 1H), 8.45 (s, 1H), 5.18 (q, J =8.0 Hz, 2H), 4.06 (s, 3H). MS-ESI calculated value [M+H] ⁺ 320, measured value 320.

the fifth step.

4-(2,2,2-Trifluoro- N -methylacetamide)-1-(2,2,2-trifluoroethyl)-pyrazole-5-carboxylic acid methyl ester.

Dissolve methyl 4-(2,2,2-trifluoroacetamide)-1-(2,2,2-trifluoroethyl)-pyrazole-5-carboxylate (9.20 g, 28.8 mmol) in N , N -dimethylformamide (50mL), and potassium carbonate (5.98g, 43.3mmol) was added. The reaction solution was heated to 80°C and reacted for 1 hour. Cool to room temperature and add methyl iodide (6.14 g, 43.2 mmol). The reaction solution was stirred at room temperature for 18 hours, and then water (300 mL) was added to the reaction solution and extracted with ethyl acetate (100 mL x 3). The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 4-(2,2,2-trifluoro- N -methylacetamide)-1-(2, 2,2-trifluoroethyl)-pyrazole-5-carboxylic acid methyl ester (9.80 g crude product, yellow oil). ¹ H NMR: (400 MHz, CDCl ₃ ) δ = 7.65 (s, 1H), 5.45-5.15 (m, 2H), 3.93 (s, 3H), 3.29 (s, 3H). MS-ESI calculated value [M+H] ⁺ 334, found value 334.

The sixth step.

4-[(tertiary butoxycarbonyl)(methyl)amino]-1-(2,2,2-trifluoroethyl)-pyrazole-5-carboxylic acid.

Methyl 4-(2,2,2-trifluoro- N -methylacetamide)-1-(2,2,2-trifluoroethyl)-pyrazole-5-carboxylic acid methyl ester (9.90g, 29.7 mmol) was dissolved in tetrahydrofuran (40 mL) and water (40 mL), lithium hydroxide monohydrate (6.23 g, 0.149 mol) was added, and the reaction was stirred at room temperature for 18 hours. Di-tertiary butyl dicarbonate (13.0g, 59.4mmol) was added, and the reaction was continued at room temperature for 6 hours. The reaction was concentrated under reduced pressure, adjusted to pH=4 with 2N hydrochloric acid aqueous solution, filtered, and the filter cake was dried to obtain 4- [(Tertiary butoxycarbonyl)(methyl)amino]-1-(2,2,2-trifluoroethyl)-pyrazole-5-carboxylic acid (8.00 g, white solid), yield: 83 %. ¹ H NMR: (400 MHz, CDCl ₃ ) δ=7.58 (s, 1H), 5.25 (q, J =8.0 Hz, 2H), 3.27 (s, 3H), 1.42 (s, 9H). MS-ESI calculated value [M+H] ⁺ 324, found value 324.

The seventh step.

4-[(tertiary butoxycarbonyl)(methyl)amino]-1-(2,2,2-trifluoroethyl)-pyrazole-5-carboxamide.

4-[tertiary butoxycarbonyl (methyl)amino]-2-(2,2,2-trifluoroethyl)pyrazole-5-carboxylic acid, 2-(7-azobenzotri Nitrozole)-tetramethylurea hexafluorophosphate (13.8g, 36.2mmol) and ammonium chloride (2.98g, 55.7mmol) were dissolved in dichloromethane (120mL), triethylamine (4.23g) was added dropwise at room temperature , 41.8 mmol). The reaction solution was stirred at room temperature for 18 hours. Water (100 mL) was added to the reaction solution, extracted with dichloromethane (100 mL x 2), the organic phases were combined, and washed sequentially with saturated sodium bicarbonate (50 mL) and saturated brine (50 mL). , Dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was ethanol (20mL) to give 4-[(tertiary butoxycarbonyl)(methyl)amino]-1-(2,2,2-tri Fluoroethyl)-pyrazole-5-carboxamide (6.00 g, white solid), yield: 67%. ¹ H NMR: (400 MHz, CDCl ₃ ) δ = 7.54 (s, 1H), 5.25 (q, J = 8.0 Hz, 2H), 3.22 (s, 3H), 1.48 (s, 9H). MS-ESI calculated value [M+H] ⁺ 323, found value 323.

Step 8.

4-(methylamino)-2-(2,2,2-trifluoroethyl)pyrazole-5-carboxamide.

4-[(tertiary butoxycarbonyl)(methyl)amino]-1-(2,2,2-trifluoroethyl)-pyrazole-5-carboxamide (5.00 g, 15.51 mmol) Dissolved in ethyl acetate hydrochloride (50mL). The reaction was stirred at room temperature for 18 hours and concentrated under reduced pressure. The residue was dissolved with methanol (50 mL), potassium carbonate (5.36 g, 38.8 mmol) was added, and stirred at room temperature for 2 hours. Concentrate under reduced pressure, extract the residue with dichloromethane (100 mL), filter, and spin-dry the filtrate to give 4-(methylamino)-2-(2,2,2-trifluoroethyl)pyrazole-5- Formamide (2.90 g, white solid), yield: 84%. ¹ H NMR: (400 MHz, Methanol- d ₄ ) δ = 7.93 (s, 1H), 5.26 (q, J = 8.4 Hz, 2H), 3.13 (s, 3H). MS-ESI calculated value [M+H] ⁺ 223, found value 223.

Step nine.

4-methyl-1-(2,2,2-trifluoroethyl)-pyrazolo[4,3-d]pyrimidine-5,7-dione.

Combine 4-(methylamino)-2-(2,2,2-trifluoroethyl)pyrazole-5-carboxamide (2.70g, 12.2mmol) and 1,1-carbonyldiimidazole (3.94g , 24.3mmol) was dissolved in N , N -dimethylformamide (20mL), the reaction solution was heated to 140 ℃ for 1 hour. After cooling to room temperature, water (100 mL) was added to the reaction liquid, the solid precipitated, collected by filtration, and the filter cake was dried to obtain 4-methyl-1-(2,2,2-trifluoroethyl)-pyrazolo [4,3-d]pyrimidine-5,7-dione (1.80 g, white solid), yield: 60%. ¹ H NMR: (400 MHz, DMSO- d ₆ ) δ=11.56 (s, 1H), 7.95 (s, 1H), 5.35 (q, J =8.8 Hz, 2H), 3.33 (s, 3H). MS-ESI calculated value [M+H] ⁺ 249, found value 249.

Step ten.

4-methyl-6-((3-methyloxetan-3-yl)methyl)-1-(2,2,2-trifluoroethyl)-pyrazolo[4,3- d] Pyrimidine-5,7-dione.

Dissolve 4-methyl-1-(2,2,2-trifluoroethyl)pyrazolo[4,3-d]pyrimidine-5,7-dione (70.0 mg, 0.282 mmol) in N , N -Dimethylformamide (2mL), add 3-(chloromethyl)-3-methyl-oxetane (40.8mg, 0.338mmol), potassium carbonate (78.0mg, 0.564mmol) and potassium iodide ( 56.2 mg, 0.338 mmol). The reaction solution was heated to 120°C and stirred for 1 hour. The reaction solution was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by high-performance liquid chromatography to obtain 4-methyl-6-[(3-methyloxetan-3-yl)methyl ]-1-(2,2,2-trifluoroethyl)pyrazolo[4,3-d]pyrimidine-5,7-dione (30.0 mg), yield: 32%. ¹ H NMR: (400 MHz, CDCl ₃ ) δ = 7.57 (s, 1H), 5.21 (q, J = 8.0 Hz, 2H), 4.72 (d, J = 6.0 Hz, 2H), 4.26 (d, J = 6.0 Hz, 2H), 4.16 (s, 2H), 3.52 (s, 3H), 1.40 (s, 3H). MS-ESI calculated value [M+H] ⁺ 333, found value 333.

Example 28.

6-((3-ethyloxetan-3-yl)methyl)-4-methyl-1-(2,2,2-trifluoroethyl)-pyrazolo[4,3- d] Pyrimidine-5,7-dione.

first step.

(3-ethyloxetan-3-yl) methyl methanesulfonate.

(3-ethyloxetane-3-yl)methanol (1.00g, 8.61mmol) and triethylamine (1.74g, 17.2mmol) were dissolved in anhydrous dichloromethane (15mL), nitrogen protection, 0 Methanesulfonyl chloride (1.28 g, 11.2 mmol) was slowly added at ℃. The reaction solution was stirred at 0°C for 1 hour. Saturated sodium bicarbonate solution (50 mL) was added to quench the reaction and extracted with dichloromethane (20 mL x 2). The organic phases were combined, washed with saturated sodium chloride solution (50 mL x 2), dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give (3-ethyloxetan-3-yl)methyl methanesulfonate (1.30g, yellow oil), yield: 78%. MS-ESI calculated value [M+H] ⁺ 195, found value 195.

The second step.

6-((3-ethyloxetan-3-yl)methyl)-4-methyl-1-(2,2,2-trifluoroethyl)-pyrazolo[4,3- d] Pyrimidine-5,7-dione.

4-methyl-1-(2,2,2-trifluoroethyl)pyrazolo[4,3-d]pyrimidine-5,7-dione (30.0 mg, 0.121 mmol), (3-ethyl Oxetan-3-yl)methyl methanesulfonate (35.2 mg, 0.181 mmol), potassium carbonate (33.2 mg, 0.242 mmol) and potassium iodide (4.0 mg, 0.024 mmol) were dissolved in N , N -di Methylformamide (10mL). The reaction solution was heated to 120°C and stirred for 3 hours. The reaction solution was cooled to room temperature, poured into water (30 mL), and extracted with ethyl acetate (20 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was separated and purified by preparative high performance liquid chromatography to obtain 6-((3-ethyloxetan-3-yl)methyl)-4-methyl-1-(2,2,2-trifluoroethyl )-Pyrazolo[4,3-d]pyrimidine-5,7-dione (10 mg), yield: 24%. ¹ H NMR: (400 MHz, Methonal- d ₄ ) δ = 7.86 (s, 1H), 5.37-5.31 (m, 2H), 4.64 (d, J = 6.4 Hz, 2H), 4.30 (d, J = 6.4 Hz , 2H), 4.14 (s, 2H), 3.54 (s, 3H), 1.84-1.79 (m, 2H), 1.07 (t, J = 7.2 Hz, 3H). MS-ESI calculated value [M+H] ⁺ 347, found value 347.

Example 29.

4-methyl-6-((tetrahydrofuran-3-yl)methyl)-1-(2,2,2-trifluoroethyl)-pyrazolo[4,3-d]pyrimidine-5,7- Dione.

first step.

4-methyl-6-((tetrahydrofuran-3-yl)methyl)-1-(2,2,2-trifluoroethyl)-pyrazolo[4,3-d]pyrimidine-5,7- Dione.

Tetrahydrofuran-3-ylmethyl methanesulfonate (30.0 mg, 0.166 mmol), 4-methyl-1-(2,2,2-trifluoroethyl)pyrazolo[4,3-d]pyrimidine -5,7-Dione (41.3 mg, 0.166 mmol), potassium carbonate (46.0 mg, 0.333 mmol) and potassium iodide (5.5 mg, 0.033 mmol) were dissolved in N , N -dimethylformamide (5 mL). The reaction solution was heated to 120°C and stirred for 3 hours. The reaction solution was cooled to room temperature, poured into water (20 mL), and extracted with ethyl acetate (20 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated, and purified by preparative high performance liquid chromatography to obtain 4-methyl-6-((tetrahydrofuran-3-yl)methyl)-1-(2,2, 2-trifluoroethyl)-pyrazolo[4,3-d]pyrimidine-5,7-dione (10.0 mg), yield: 18%. ¹ H NMR: (400 MHz, Methonal- d ₄ ) δ = 7.83 (s, 1H), 5.38-5.30 (m, 2H), 4.10-4.04 (m, 2H), 3.92-3.87 (m, 1H), 3.78- 3.75 (m, 2H), 3.64-3.62 (m, 1H), 3.52 (s, 3H), 2.76-2.72 (m, 1H), 2.04-2.01 (m, 1H), 1.79-1.72 (m, 1H). MS-ESI calculated value [M+H] ⁺ 333, found value 333.

Example 30.

6-((tetrahydro-piperan-4-yl)methyl)-4-methyl-1-(2,2,2-trifluoroethyl)-pyrazolo[4,3-d]pyrimidine- 5,7-dione.

first step.

(Tetrahydropyran-4-yl) methyl methanesulfonate.

Dissolve tetrahydropiperan-4-ylmethanol (1.00 g, 8.61 mmol) and triethylamine (1.74 g, 17.2 mmol) in anhydrous dichloromethane (20 mL), protect with nitrogen, and slowly add methanesulfonyl chloride at 0°C (1.28 g, 11.2 mmol). The reaction solution was stirred at 0°C for 1 hour. Saturated sodium bicarbonate solution (50 mL) was added to quench the reaction and extracted with dichloromethane (20 mL x 2). The organic phases were combined, washed with saturated sodium chloride solution (50 mL x 2), dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give (tetrahydropiperan-4-yl) methyl methanesulfonate (1.30 g, yellow Oily), yield: 78%. MS-ESI calculated value [M+H] ⁺ 195, found value 195.

The second step.

4-methyl-6-((tetrahydropiperan-4-yl)methyl)-1-(2,2,2-trifluoroethyl)-pyrazolo[4,3-d]pyrimidine-5 , 7-diketone.

4-methyl-1-(2,2,2-trifluoroethyl)pyrazolo[4,3-d]pyrimidine-5,7-dione (30.0 mg, 0.121 mmol), (tetrahydropiper (Fan-4-yl) methyl methanesulfonate (35.2 mg, 0.181 mmol), potassium carbonate (33.2 mg, 0.242 mmol) and potassium iodide (4.0 mg, 0.024 mmol) were dissolved in N , N -dimethylformamide (10mL). The reaction solution was heated to 120°C and stirred for 3 hours. The reaction solution was cooled to room temperature, poured into water (30 mL), and extracted with ethyl acetate (20 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. Separated and purified by preparative high performance liquid chromatography to obtain 4-methyl-6-((tetrahydropiperan-4-yl)methyl)-1-(2,2,2-trifluoroethyl)-pyrazolo[ 4,3-d]pyrimidine-5,7-dione (10.0 mg), yield: 24%. ¹ H NMR: (400 MHz, Methonal- d ₄ ) δ = 7.80 (s, 1H), 5.33-5.27 (m, 2H), 3.93-3.89 (m, 4H), 3.49 (s, 3H), 3.36-3.34 ( m, 2H), 2.08-2.05 (m, 1H), 1.57-1.53 (m, 2H), 1.44-1.37 (m, 2H). MS-ESI calculated value [M+H] ⁺ 347, found value 347.

Example 31.

4-methyl-6-(2-(tetrahydropiperan-4-yl)ethyl)-1-(2,2,2-trifluoroethyl)-pyrazolo[4,3-d]pyrimidine -5,7-dione.

first step.

4-methyl-6-(2-(tetrahydropiperan-4-yl)ethyl)-1-(2,2,2-trifluoroethyl)-pyrazolo[4,3-d]pyrimidine -5,7-dione.

The 2-tetrahydropiperan-4-ylethyl methanesulfonate (50.0 mg, 0.240 mmol), 4-methyl-1-(2,2,2-trifluoroethyl)pyrazolo[4, 3-d]pyrimidine-5,7-dione (59.6 mg, 0.240 mmol), potassium carbonate (66.4 mg, 0.480 mmol) and potassium iodide (7.9 mg, 0.048 mmol) were dissolved in N , N -dimethylformamide (5mL). The reaction solution was heated to 120°C and stirred for 3 hours. The reaction solution was cooled to room temperature, poured into water (20 mL), and extracted with ethyl acetate (20 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was separated and purified by preparative high performance liquid chromatography to obtain 4-methyl-6-(2-(tetrahydropiperan-4-yl)ethyl)-1-(2,2,2-trifluoroethyl)-pyridine Zazolo[4,3-d]pyrimidine-5,7-dione (20.0 mg), yield: 23%. ¹ H NMR: (400 MHz, Methonal- d ₄ ) δ = 7.82 (s, 1H), 5.36-5.27 (m, 2H), 4.08-4.05 (m, 2H), 3.95-3.91 (m, 2H), 3.51 ( s, 3H), 3.44-3.41 (m, 2H), 1.76-1.73 (m, 2H), 1.60-1.58 (m, 3H), 1.37-1.30 (m, 2H). MS-ESI calculated value [M+H] ⁺ 361, found value 361.

Example 32.

6-((4-methoxycyclohexyl)methyl)-4-methyl-1-(2,2,2-trifluoroethyl)-pyrazolo[4,3-d]pyrimidine-5, 7-diketone.

first step.

6-((4-methoxycyclohexyl)methyl)-4-methyl-1-(2,2,2-trifluoroethyl)-pyrazolo[4,3-d]pyrimidine-5, 7-diketone.

4-methyl-1-(2,2,2-trifluoroethyl)pyrazolo[4,3-d]pyrimidine-5,7-dione (50.0 mg, 0.201 mmol), ((4- Methoxycyclohexyl) methyl methanesulfonate (44.8 mg, 0.201 mmol), potassium carbonate (55.7 mg, 0.403 mmol) and potassium iodide (6.7 mg, 0.040 mmol,) were dissolved in N , N -dimethylformamide Amine (5mL). The reaction solution was heated to 120°C and stirred for 3 hours. The reaction solution was cooled to room temperature, poured into water (20mL), and extracted with ethyl acetate (20mL x 3). The organic phases were combined and dried over anhydrous sulfuric acid Sodium was dried, filtered, and the filtrate was concentrated, and purified by preparative high performance liquid chromatography to obtain 6-((4-methoxycyclohexyl)methyl)-4-methyl-1-(2,2,2-trifluoroethane Group)-pyrazolo[4,3-d]pyrimidine-5,7-dione (20.0 mg), yield: 26%. ¹ H NMR: (400 MHz, Methonal- d ₄ ) δ=7.82(s, 1H), 5.36-5.30 (m, 2H), 3.89 (d, J = 6.8Hz, 2H), 3.51 (s, 3H), 3.39 (s, 3H), 3.21-3.15 (m, 1H), 2.09-2.08 (m, 2H), 1.81-1.73 (m, 3H), 1.16-1.10 (m, 4H). MS-ESI calculated value [M+H] ⁺ 375, measured value 375.

Example 33.

1-(cyclopropylmethyl)-4-methyl-6-((3-methyloxetan-3-yl)methyl)-pyrazolo[4,3-d]pyrimidine-5 , 7-diketone.

first step.

1-(Cyclopropylmethyl)-4-nitro-pyrazole-5-carboxylic acid methyl ester.

Dissolve methyl 4-nitro-pyrazole-5-carboxylate (22.0 g, 129 mmol) in N,N-dimethylformamide (350 mL) and add sodium hydride (5.66 g, 141 mmol) in portions at 0°C . The reaction was stirred at 0°C for 1 hour, sodium iodide (21.2 g, 141 mmol) was added, and bromomethylcyclopropane (19.1 g, 141 mmol) was added dropwise. The reaction solution was stirred at 25°C for 18 hours. Water (1.2 L) was added to the reaction liquid, and extracted with ethyl acetate (300 mL x 2). The organic phases were combined, washed with saturated brine (500 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (5:1 petroleum ether/ethyl acetate, Rf=0.3), 1-(Cyclopropylmethyl)-4-nitro-pyrazole-5-carboxylic acid methyl ester (5.00 g, colorless oil) was obtained, yield: 17%. ¹ H NMR: (400 MHz, CDCl ₃ ) δ = 8.04 (s, 1H), 4.14 (d, J = 7.6 Hz, 2H), 4.03 (s, 3H), 1.40-1.23 (m, 1H), 0.75-0.55 (m, 2H), 0.47-0.34 (m, 2H). MS-ESI calculated value [M+H] ⁺ 226, found value 226.

The second step.

4-Amino-1-(cyclopropylmethyl)-pyrazole-5-carboxylic acid methyl ester.

Dissolve methyl 1-(cyclopropylmethyl)-4-nitro-pyrazole-5-carboxylate (5.00 g, 22.2 mmol) in methanol (70 mL) and add dry palladium on carbon (palladium 10%, water 1%) , 500mg), at room temperature, the reaction under 40psi hydrogen pressure for 3 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain methyl 4-amino-1-(cyclopropylmethyl)-pyrazole-5-carboxylate (4.30 g, off-white solid), yield: 99%. ¹ H NMR: (400 MHz, CDCl ₃ ) δ = 7.11 (s, 1H), 4.27 (d, J = 7.6 Hz, 2H), 4.11 (s, 2H), 3.91 (s, 3H), 1.46-1.21 (m , 1H), 0.53-0.43 (m, 2H), 0.41-0.32 (m, 2H). MS-ESI calculated value [M+H] ⁺ 196, found value 196.

third step.

1-(Cyclopropylmethyl)-4-(2,2,2-trifluoroacetamido)-pyrazole-5-carboxylic acid methyl ester.

Dissolve 4-amino-1-(cyclopropylmethyl)-pyrazole-5-carboxylic acid methyl ester (4.30g, 22.0mmol) in dichloromethane (40mL), and add trifluoroacetic anhydride dropwise under nitrogen protection ( 6.94g, 33.1mmol), the reaction solution was stirred at room temperature for 2 hours, quenched with saturated sodium bicarbonate solution (50mL), extracted with dichloromethane (40mL), washed the organic phase with saturated brine (50mL), anhydrous sodium sulfate Dry and concentrate under reduced pressure to give 1-(cyclopropylmethyl)-4-(2,2,2-trifluoroacetamido)-pyrazole-5-carboxylic acid methyl ester (6.30g, colorless oil) ), yield: 98%. ¹ H NMR: (400 MHz, CDCl ₃ ) δ = 9.72 (s, 1H), 8.28 (s, 1H), 4.37 (d, J = 7.2 Hz, 2H), 4.09 (s, 3H), 1.39-1.23 (m , 1H), 0.60-0.48 (m, 2H), 0.45-0.37 (m, 2H). MS-ESI calculated value [M+H] ⁺ 292, found value 292.

the fourth step.

1-(Cyclopropylmethyl)-4-(2,2,2-trifluoro- N -methylacetamido)-pyrazole-5-carboxylic acid methyl ester.

Dissolve 1-(cyclopropylmethyl)-4-(2,2,2-trifluoroethylamido)-pyrazole-5-carboxylic acid methyl ester (6.20g, 21.3mmol) in N , N -di Methylformamide (50 mL) was added potassium carbonate (4.41 g, 31.9 mmol). The reaction solution was heated to 80°C and reacted for 1 hour. Cool to room temperature and add iodomethane (4.53 g, 31.9 mmol). The reaction solution was stirred at room temperature for 18 hours. Water (300 mL) was added to the reaction liquid, and extracted with ethyl acetate (100 mL x 3). The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 1-(cyclopropylmethyl)-4-(2,2,2-trifluoro- N -methyl Acetylamino)-pyrazole-5-carboxylic acid methyl ester (6.44 g, yellow oil), yield: 99%. ¹ H NMR: (400 MHz, CDCl ₃ ) δ = 7.50 (s, 1H), 4.43 (d, J = 7.2 Hz, 2H), 3.90 (s, 3H), 3.28 (s, 3H), 1.43-1.27 (m , 1H), 0.60-0.47 (m, 2H), 0.45-0.33 (m, 2H). MS-ESI calculated value [M+H] ⁺ 306, found value 306.

the fifth step.

4-[(tertiary butoxycarbonyl)(methyl)amino]-1-(cyclopropylmethyl)-pyrazole-5-carboxylic acid.

Dissolve 1-(cyclopropylmethyl)-4-(2,2,2-trifluoro-N-methylacetamido)-pyrazole-5-carboxylic acid methyl ester (6.40 g, 21.0 mmol) Tetrahydrofuran (30 mL) and water (30 mL) were added lithium hydroxide monohydrate (4.40 g, 105 mmol), and the reaction was stirred at room temperature for 18 hours. Di-tertiary butyl dicarbonate (9.15g, 41.9mmol) was added, and the reaction was continued at room temperature for 16 hours. The reaction was concentrated under reduced pressure, adjusted to pH=4 with 2N hydrochloric acid aqueous solution, filtered, and the filter cake was dried to obtain 4- ((Tertiary butoxycarbonyl)(methyl)amino)-1-(cyclopropylmethyl)-pyrazole-5-carboxylic acid (4.50 g, white solid), yield: 73%. ¹ H NMR: (400 MHz, CDCl ₃ ) δ = 7.46 (s, 1H), 4.38 (d, J = 6.8 Hz, 2H), 3.21 (s, 3H), 1.58-1.25 (m, 10H), 0.60-0.47 (m, 2H), 0.45-0.37 (m, 2H). MS-ESI calculated value [M+H] ⁺ 296, found value 296.

The sixth step.

(5-Aminomethylamido-1-(cyclopropylmethyl)-pyrazol-4-yl)(methyl)aminocarboxylic acid tertiary butyl ester.

Combine 4-[(tertiary butoxycarbonyl)(methyl)amino]-1-(cyclopropylmethyl)-pyrazole-5-carboxylic acid (3.40 g, 11.5 mmol), 2-(7-couple Nitrobenzotriazole)-tetramethylurea hexafluorophosphate (5.69g, 15.0mmol) and ammonium chloride (1.23g, 23.0mmol) were dissolved in dichloromethane (120mL), triethyl ether was added dropwise at room temperature Amine (1.75 g, 17.3 mmol). The reaction solution was stirred at room temperature for 18 hours. Water (50 mL) was added to the reaction solution and extracted with dichloromethane (500 mL x 2). The organic phases were combined and washed with saturated sodium bicarbonate (50 mL) and saturated brine (50 mL) in this order. , Dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the residue was ethanol (20mL) to give (5-aminomethylamino-1-(cyclopropylmethyl)-pyrazol-4-yl) (methyl ) Tertiary butyl carbamate (3.00g, crude product, yellow oil). MS-ESI calculated value [M+H] ⁺ 295, found value 295.

The seventh step.

1-(cyclopropylmethyl)-4-(methylamino)-pyrazole-5-carboxamide.

Dissolve (5-aminomethylamido-1-(cyclopropylmethyl)-pyrazol-4-yl)(methyl)aminocarboxylic acid tertiary butyl ester (3.30 g, 11.2 mmol) in ethyl acetate hydrochloride Ester (25mL). The reaction was stirred at room temperature for 18 hours, concentrated under reduced pressure, the residue was dissolved with methanol (40 mL), potassium carbonate (3.10 g, 22.4 mmol) was added, and stirred at room temperature for 2 hours. The reaction solution was filtered, concentrated under reduced pressure, the residue was extracted with dichloromethane (60 mL), filtered, the filtrate was spin-dried, the residue was slurried with dichloromethane (15 mL), and filtered to obtain 1-(cyclopropylmethyl)-4 -(Methylamino)-pyrazole-5-carboxamide (1.45 g, white solid), yield: 67%. ¹ H NMR: (400 MHz, CDCl ₃ ) δ = 7.34 (s, 2H), 7.17 (s, 1H), 4.62-4.47 (m, 1H), 4.21 (d, J = 6.8 Hz, 2H), 2.65 (d , J = 5.6 Hz, 3H), 1.22-1.10 (m, 1H), 0.43-0.34 (m, 2H), 0.31-0.23 (m, 2H). MS-ESI calculated value [M+H] ⁺ 195, found value 195.

Step 8.

1-(cyclopropylmethyl)-4-methyl-pyrazolo[4,3-d]pyrimidine-5,7-dione.

Dissolve 1-(cyclopropylmethyl)-4-(methylamino)-pyrazole-5-carboxamide (1.45g, 7.47mmol) in N , N -dimethylformamide (10mL) At 0°C, sodium hydride (627 mg, 15.7 mmol) was added in portions. Under nitrogen, the reaction solution was stirred at 0°C for 1 hour. 1,1-Carbondiimidazole (1.82g, 11.2mmol) was added, and the reaction solution was heated to 75°C and reacted for 2 hours. The reaction solution was cooled to room temperature, water (80 mL) was added to quench the reaction, filtered, and the filter cake was dried to obtain 1-(cyclopropylmethyl)-4-methyl-pyrazolo[4,3-d]pyrimidine -5,7-dione (1.60 g, white solid), yield: 97%. ¹ H NMR: (400MHz, DMSO- d ₆ ) δ=11.35(s, 1H), 7.72(s, 1H), 4.29(d, J =6.8Hz, 2H), 3.32(s, 3H), 1.17-1.07 (m, 1H), 0.54-0.32 (m, 4H). MS-ESI calculated value [M+H] ⁺ 221, found value 221.

Step nine.

1-(cyclopropylmethyl)-4-methyl-6-((3-methyloxetan-3-yl)methyl)-pyrazolo[4,3-d]pyrimidine-5 , 7-diketone.

Dissolve 1-(cyclopropylmethyl)-4-methyl-pyrazolo[4,3-d]pyrimidine-5,7-dione (62.1mg, 0.282mmol) in N , N -dimethyl Formamide (2mL), add 3-(chloromethyl)-3-methyl-oxetane (40.8mg, 0.338mmol), potassium carbonate (78.0mg, 0.564mmol) and potassium iodide (56.2mg, 0.338 mmol). The reaction solution was heated to 120°C and stirred for 1 hour. The reaction solution was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by high-performance liquid chromatography to obtain 1-(cyclopropylmethyl)-4-methyl-6-((3-methyloxetan-3-yl)methyl Group)-pyrazolo[4,3-d]pyrimidine-5,7-dione (46.0 mg), yield: 54%. ¹ H NMR: (400 MHz, CDCl ₃ ) δ = 7.42 (s, 1H), 4.73 (d, J = 6.4 Hz, 2H), 4.43 (d, J = 6.8 Hz, 2H), 4.26 (d, J = 6.4 Hz, 2H), 4.14 (s, 2H), 3.50 (s, 3H), 1.41 (s, 3H), 1.40-1.28 (m, 1H), 0.60-0.52 (m, 2H), 0.51-0.38 (m, 2H). MS-ESI calculated value [M+H] ⁺ 305, found value 305.

Example 34.

1-(cyclopropylmethyl)-6-((3-ethyloxetan-3-yl)methyl)-4-methyl-pyrazolo[4,3-d]pyrimidine-5 , 7-diketone.

first step.

1-(cyclopropylmethyl)-6-((3-ethyloxetan-3-yl)methyl)-4-methyl-pyrazolo[4,3-d]pyrimidine-5 , 7-diketone.

(3-ethyloxetane-3-yl)methyl methanesulfonate (34.4 mg, 0.177 mmol), 1-(cyclopropylmethyl)-4-methyl-pyrazolo[4 ,3-d]pyrimidine-5,7-dione (30.0 mg, 0.136 mmol), potassium iodide (2.3 mg, 0.014 mmol) and potassium carbonate (56.5 mg, 0.408 mmol) dissolved in N , N -dimethylformamide Amine (3mL). The reaction liquid was heated to 120°C and stirred for 3 hours. Cooled to room temperature, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by preparative high performance liquid chromatography to obtain 1-(cyclopropylmethyl)-6-((3-ethyloxetan-3-yl ) Methyl)-4-methyl-pyrazolo[4,3-d]pyrimidine-5,7-dione (21.0 mg), yield: 48%. ¹ H NMR: (400 MHz, CDCl ₃ ) δ-7.44 (s, 1H), 4.62 (d, J = 6.4 Hz, 2H), 4.44 (d, J = 7.6 Hz, 2H), 4.30 (d, J = 6.8 Hz, 2H), 4.10 (s, 2H), 3.52 (s, 3H), 1.88-1.83 (m, 2H), 1.37-1.36 (m, 1H), 1.11-1.07 (m, 3H), 0.56-0.46 ( m, 4H). MS-ESI calculated value [M+H] ⁺ 319, found value 319.

Example 35.

1-(cyclopropylmethyl)-4-methyl-6-((tetrahydrofuran-3-yl)methyl)-pyrazolo[4,3-d]pyrimidine-5,7-dione.

first step.

1-(cyclopropylmethyl)-4-methyl-6-((tetrahydrofuran-3-yl)methyl)-pyrazolo[4,3-d]pyrimidine-5,7-dione.

(Tetrahydrofuran-3-yl)methyl methanesulfonate (53.1 mg, 0.295 mmol), 1-(cyclopropylmethyl)-4-methyl-pyrazolo[4,3-d]pyrimidine-5 , 7-dione (50.0mg, 0.227mmol) and potassium carbonate (94.1mg, 0.681mmol) dissolved in N , N- dimethylformamide (5mL), added potassium iodide (3.8mg, 0.023mmol), the reaction The liquid was stirred at 120°C for 3 hours. The reaction solution was directly filtered, the filtrate was concentrated under reduced pressure, and the crude product was purified by preparative high performance liquid chromatography to obtain the product 1-(cyclopropylmethyl)-4-methyl-6-((tetrahydrofuran-3-yl)methyl)- Pyrazolo[4,3-d]pyrimidine-5,7-dione (36.0 mg), yield: 52%. ¹ H NMR: (400 MHz, Methonal- d ₄ ) δ = 7.63 (s, 1H), 4.41 (d, J = 7.2 Hz, 2H), 3.95-3.90 (m, 1H), 3.87-3.82 (m, 1H) , 3.77-3.72 (m, 1H), 3.61-3.54 (m, 2H), 3.45-3.42 (m, 1H), 3.14 (s, 3H), 2.59-2.52 (m, 1H), 1.87-1.79 (m, 1H), 1.62-1.53 (m, 1H), 1.22-1.12 (m, 1H), 0.36-0.25 (m, 4H). MS-ESI calculated value [M+H] ⁺ 305, found value 305.

Example 36.

1-(cyclopropylmethyl)-4-methyl-6-((tetrahydropyran-4-yl)methyl)-pyrazolo[4,3-d]pyrimidine-5,7-dione .

first step.

1-(cyclopropylmethyl)-4-methyl-6-((tetrahydropiperan-4-yl)methyl)-pyrazolo[4,3-d]pyrimidine-5,7-dione .

(Tetrahydropyran-4-yl)methyl methanesulfonate (34.4 mg, 0.177 mmol), 1-(cyclopropylmethyl)-4-methyl-pyrazolo[4,3-d] Pyrimidine-5,7-dione (30.0mg, 0.136mmol), potassium iodide (2.3mg, 0.014mmol) and potassium carbonate (56.5mg, 0.408mmol) were dissolved in N , N -dimethylformamide (3mL) . The reaction liquid was heated to 120°C and stirred for 3 hours. Cooled to room temperature, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by preparative high performance liquid chromatography to obtain 1-(cyclopropylmethyl)-4-methyl-6-((tetrahydropiperan-4-yl ) Methyl)-pyrazolo[4,3-d]pyrimidine-5,7-dione (30.0 mg), yield: 69%. ¹ H NMR: (400 MHz, CDCl ₃ ) δ = 7.42 (s, 1H), 4.45 (d, J = 7.6 Hz, 2H), 4.00-3.95 (m, 4H), 3.49 (s, 3H), 3.39-3.33 (m, 2H), 2.10-2.06 (m, 1H), 1.48-1.40 (m, 5H), 0.57-0.48 (m, 4H). MS-ESI calculated value [M+H] ⁺ 319, found value 319.

Example 37.

1-(cyclopropylmethyl)-4-methyl-6-(2-(tetrahydropiperan-4-yl)ethyl)-pyrazolo[4,3-d]pyrimidine-5,7- Dione.

first step.

1-(cyclopropylmethyl)-4-methyl-6-(2-(tetrahydropiperan-4-yl)ethyl)-pyrazolo[4,3-d]pyrimidine-5,7- Dione.

Combine 2-(tetrahydropiperan-4-yl)ethyl methanesulfonate (50.0 mg, 0.227 mmol), 1-(cyclopropylmethyl)-4-methyl-pyrazolo[4,3- d) Pyrimidine-5,7-dione (47.3mg, 0.227mmol), potassium iodide (3.8mg, 0.023mmol) and potassium carbonate (62.3mg, 0.454mmol) were dissolved in N , N -dimethylformamide (3mL) )in. The reaction liquid was heated to 120°C and stirred for 3 hours. Cooled to room temperature, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by preparative high performance liquid chromatography to obtain 1-(cyclopropylmethyl)-4-methyl-6-(2-(tetrahydropiperan-4 -Yl)ethyl)-pyrazolo[4,3-d]pyrimidine-5,7-dione (20.0 mg), yield: 27%. ¹ H NMR: (400 MHz, CDCl ₃ ) δ = 7.40 (s, 1H), 4.43 (d, J = 7.2 Hz, 2H), 4.08-4.05 (m, 2H), 3.98-3.94 (m, 2H), 3.49 (s, 3H), 3.38 (t, J = 1.6 Hz, 2H), 1.73-1.69 (m, 2H), 1.62-1.59 (m, 4H), 1.39-1.36 (m, 2H), 0.55-0.46 (m , 4H). MS-ESI calculated value [M+H] ⁺ 333, found value 333.

Example 38.

1-(cyclopropylmethyl)-6-((4-methoxycyclohexyl)methyl)-4-methyl-pyrazolo[4,3-d]pyrimidine-5,7-dione.

first step.

1-(cyclopropylmethyl)-6-((4-methoxycyclohexyl)methyl)-4-methyl-pyrazolo[4,3-d]pyrimidine-5,7-dione.

(4-Methoxycyclohexyl) methyl methanesulfonate (30.0 mg, 0.135 mmol), 1-(cyclopropylmethyl)-4-methyl-pyrazolo[4,3-d]pyrimidine -5,7-Dione (26.8 mg, 0.121 mmol), potassium iodide (2.2 mg, 0.014 mmol) and potassium carbonate (37.3 mg, 0.269 mmol) were dissolved in N , N -dimethylformamide (5 mL). The reaction liquid was heated to 120°C and stirred for 3 hours. Cooled to room temperature, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by preparative high performance liquid chromatography to obtain 1-(cyclopropylmethyl)-6-((4-methoxycyclohexyl)methyl)-4 -Methyl-pyrazolo[4,3-d]pyrimidine-5,7-dione (16.0 mg), yield: 34%. ¹ H NMR: (400 MHz, Methonal- d ₄ ) δ = 7.64 (s, 1H), 4.42 (d, J = 6.8 Hz, 2H), 3.89 (d, J = 6.8 Hz, 2H), 3.50 (s, 3H ), 3.35 (s, 3H), 3.20-3.15 (m, 1H), 2.10-2.06 (m, 2H), 1.76-1.73 (m, 3H), 1.38-1.36 (m, 1H), 1.16-1.12 (m , 4H), 0.55-0.46 (m, 4H). MS-ESI calculated value [M+H] ⁺ 347, found value 347.

Example 39.

1-methyl-3-((3-methyloxetan-3-yl)methyl)pyrido[2,3-d]pyrimidine-2,4-dione.

first step.

2-(methylamino) nicotinitrile.

2-chloro-3-cyanopyridine (30.0 g, 216 mmol) was added to a 40% methylamine aqueous solution (300 mL), heated to 80° C. and stirred for 2 hours. The reaction solution was concentrated by distillation under reduced pressure, and the solid obtained by filtration was washed with water (30 mL x 3) and dried to give 2-(methylamino)nicotinonitrile (22.3 g, light yellow solid), yield: 76%. ¹ H NMR: (400 MHz, Methonal- d ₄ ) δ=8.25-8.22 (m, 1H), 7.79-7.74 (m, 1H), 6.65-6.59 (m, 1H), 2.96 (s, 3H).

The second step.

2-(methylamino)pyridine-3-carboxamide.

Dissolve 2-(methylamino)nicotinonitrile (600mg, 4.51mmol), potassium carbonate (1.87mg, 0.130mmol), hydrogen peroxide (0.1mL) in dimethyl sulfoxide (10mL), and react at room temperature for 1 hour , Water (10 mL) was added to quench the reaction. It was extracted with ethyl acetate (10 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. Preparation of silica gel plate for purification (1:1 petroleum ether/ethyl acetate, Rf value = 0.2) to give 2-(methylamino)pyridine-3-carboxamide (500 mg, white solid), yield: 73% . ¹ H NMR: (400 MHz, DMSO- d ₆ ) δ = 8.45-8.40 (br, 1H), 8.28 (d, J = 2.0 Hz, 1H), 7.95-7.93 (m, 2H), 7.35-7.30 (br, 1H), 6.53 (dd, J = 7.6, 2.0 Hz, 1H), 3.03 (d, J = 4.8 Hz, 3H). MS-ESI calculated value [M+H] ⁺ 152, found value 152.

third step.

1-methylpyrido[2,3-d]pyrimidine-2,4(1 H ,3 H )-dione.

2-(Methylamino)pyridine-3-carboxamide (100 mg, 0.661 mmol) and phenyl isocyanate (157 mg, 1.32 mmol) were dissolved in toluene (10 mL) and stirred at 110°C for 12 hours. Water (10 mL) was added to quench the reaction. Filtration gave 1-methylpyrido[2,3-d]pyrimidine-2,4(1 H ,3 H )-dione (20.0 mg, yellow solid), yield: 17%. ¹ H NMR: (400MHz, DMSO- d ₆ ) δ=11.72(s, 1H), 8.72(d, J =2.0Hz, 1H), 8.31(d, J =7.6Hz, 1H), 7.29(dd, J = 7.6, 2.0 Hz, 1H), 3.48 (s, 3H). MS-ESI calculated [M+H] ⁺ 178, found 178.

the fourth step.

Dissolve 1-methylpyrido[2,3-d]pyrimidine-2,4-dione (70.0mg, 0.395mmol) in N , N -dimethylformamide (2mL), add 3-(chloro Methyl)-3-methyl-oxetane (52.4 mg, 0.435 mmol), potassium carbonate (109 mg, 0.790 mmol) and potassium iodide (78.7 mg, 0.474 mmol). The reaction solution was heated to 120°C and stirred for 1 hour. The reaction solution was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by high-performance liquid chromatography to obtain 1-methyl-3-((3-methyloxetan-3-yl)methyl)pyrido[2,3-d ] Pyrimidine-2,4-dione (44.0 mg), yield: 43%. ¹ H NMR: (400 MHz, CDCl ₃ ) δ = 8.69 (d, J = 2.0 Hz, 1H), 8.46 (d, J = 5.6 Hz, 1H), 7.27-7.18 (m, 1H), 4.76 (d, J = 6.8 Hz, 2H), 4.28 (d, J = 6.8 Hz, 2H), 4.23 (s, 2H), 3.73 (s, 3H), 1.41 (s, 3H). MS-ESI calculated value [M+H] ⁺ 262, found value 262.

Example 40.

3-((3-ethyloxetan-3-yl)methyl)-1-methylpyrido[2,3-d]pyrimidine-2,4-dione.

first step.

3-((3-ethyloxetan-3-yl)methyl)-1-methylpyrido[2,3-d]pyrimidine-2,4-dione.

1-Methylpyrido[2,3-d]pyrimidine-2,4-dione (30.0 mg, 0.169 mmol), (3-ethyloxetan-3-yl)methyl methanesulfonic acid The ester (49.3 mg, 0.254 mmol), potassium carbonate (46.8 mg, 0.338 mmol) and potassium iodide (5.6 mg, 0.034 mmol) were dissolved in N , N -dimethylformamide (10 mL). The reaction solution was heated to 120°C and stirred for 3 hours. The reaction solution was cooled to room temperature, poured into water (30 mL), and extracted with ethyl acetate (20 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. Separation and purification by preparative high performance liquid chromatography yielded 3-((3-ethyloxetan-3-yl)methyl)-1-methylpyrido[2,3-d]pyrimidine-2,4- Dione (10.0 mg), yield: 21%. ¹ H NMR: (400 MHz, Methonal- d ₄ ) δ = 8.74-8.73 (m, 1H), 8.48-8.46 (m, 1H), 7.35-7.32 (m, 1H), 4.67 (d, J = 6.8 Hz, 2H), 4.32 (d, J = 6.8 Hz, 2H), 4.20 (s, 2H), 3.72 (s, 3H), 1.84-1.79 (m, 2H), 1.08 (t, J = 7.2 Hz, 3H). MS-ESI calculated value [M+H] ⁺ 276, found value 276.

Example 41.

1-methyl-3-(tetrahydrofuran-3-ylmethyl)pyrido[2,3-d]pyrimidine-2,4-dione.

first step.

1-methyl-3-(tetrahydrofuran-3-ylmethyl)pyrido[2,3-d]pyrimidine-2,4-dione.

Tetrahydrofuran-3-ylmethyl methanesulfonate (30.0 mg, 0.166 mmol), 1-methylpyrido[2,3-d]pyrimidine-2,4-dione (29.5 mg, 0.166 mmol), carbonic acid Potassium (46.0 mg, 0.333 mmol) and potassium iodide (5.5 mg, 0.033 mmol) were dissolved in N , N -dimethylformamide (5 mL). The reaction solution was heated to 120°C and stirred for 3 hours. The reaction solution was cooled to room temperature, poured into water (20 mL), and extracted with ethyl acetate (20 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated, and purified by preparative high performance liquid chromatography to obtain 1-methyl-3-(tetrahydrofuran-3-ylmethyl)pyrido[2,3-d]pyrimidine- 2,4-Dione (10.0 mg), yield: 23%. ¹ H NMR: (400 MHz, Methonal- d ₄ ) δ = 8.65-8.63 (m, 1H), 8.46-8.41 (m, 1H), 7.33-7.30 (m, 1H), 4.14-4.12 (m, 2H), 4.09-4.07 (m, 1H), 3.79-3.75 (m, 2H), 3.69 (s, 3H), 3.65-3.62 (m, 1H), 2.79-2.75 (m, 1H), 2.06-2.01 (m, 1H) ), 1.78-1.75 (m, 1H). MS-ESI calculated value [M+H] ⁺ 262, found value 262.

Example 42.

1-methyl-3-((tetrahydropiperan-4-yl)methyl)pyrido[2,3-d]pyrimidine-2,4-dione.

first step.

1-methyl-3-((tetrahydropiperan-4-yl)methyl)pyrido[2,3-d]pyrimidine-2,4-dione.

1-Methylpyrido[2,3-d]pyrimidine-2,4-dione (30.0 mg, 0.169 mmol), tetrahydropiperan-4-ylmethyl methanesulfonate (49.4 mg, 0.254 mmol ), potassium carbonate (46.8 mg, 0.338 mmol) and potassium iodide (5.6 mg, 0.034 mmol) were dissolved in N , N -dimethylformamide (10 mL). The reaction solution was heated to 120°C and stirred for 3 hours. The reaction solution was cooled to room temperature, poured into water (30 mL), and extracted with ethyl acetate (20 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. Separation and purification by preparative high performance liquid chromatography yielded 1-methyl-3-((tetrahydropiperan-4-yl)methyl)pyrido[2,3-d]pyrimidine-2,4-dione (10.0mg , Yellow oil), yield: 21%. ¹ H NMR: (400 MHz, Methonal- d ₄ ) δ=8.71-8.69 (m, 1H), 8.48-8.40 (m, 1H), 7.33-7.30 (m, 1H), 3.99-3.91 (m, 4H), 3.69 (s, 3H), 3.39-3.33 (m, 2H), 2.13-2.10 (m, 1H), 1.62-1.58 (m, 2H), 1.44-1.40 (m, 2H). MS-ESI calculated value [M+H] ⁺ 276, found value 276.

Example 43.

1-methyl-3-(2-(tetrahydropiperan-4-yl)ethyl)pyrido[2,3-d]pyrimidine-2,4-dione.

first step.

1-methyl-3-(2-(tetrahydropiperan-4-yl)ethyl)pyrido[2,3-d]pyrimidine-2,4-dione.

Combine 2-tetrahydropiperan-4-ylethyl methanesulfonate (50.0 mg, 0.240 mmol), 1-methylpyrido[2,3-d]pyrimidine-2,4-dione (42.5 mg, 0.240 mmol), potassium carbonate (66.4 mg, 0.480 mmol) and potassium iodide (7.9 mg, 0.048 mmol) were dissolved in N , N -dimethylformamide (5 mL). The reaction solution was heated to 120°C and stirred for 3 hours. The reaction solution was cooled to room temperature, poured into water (20 mL), and extracted with ethyl acetate (20 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated, and purified by preparative high performance liquid chromatography to obtain 1-methyl-3-(2-(tetrahydropiperan-4-yl)ethyl)pyrido[ 2,3-d]pyrimidine-2,4-dione (20.0 mg), yield: 29%. ¹ H NMR: (400 MHz, Methonal- d ₄ ) δ=8.72-8.71 (m, 1H), 8.47-8.45 (m, 1H), 7.34-7.31 (m, 1H), 4.14-4.10 (m, 2H), 3.96-3.93(m, 2H), 3.70(s, 3H), 3.43-3.40(m, 2H), 1.78-1.75(m, 2H), 1.66-1.62(m, 3H), 1.38-1.32(m, 2H) ). MS-ESI calculated value [M+H] ⁺ 290, found value 290.

Example 44.

3-((4-methoxycyclohexyl)methyl)-1-methylpyrido[2,3-d]pyrimidine-2,4-dione.

first step.

3-((4-methoxycyclohexyl)methyl)-1-methylpyrido[2,3-d]pyrimidine-2,4-dione.

1-methylpyrido[2,3-d]pyrimidine-2,4-dione (50.0 mg, 0.282 mmol), (4-methoxycyclohexyl) methyl methanesulfonate (62.7 mg, 0.282 mmol), potassium carbonate (78.0 mg, 0.564 mmol) and potassium iodide (9.4 mg, 0.056 mmol) were dissolved in N , N -dimethylformamide (5 mL). The reaction solution was heated to 120°C and stirred for 3 hours. The reaction solution was cooled to room temperature, poured into water (20 mL), and extracted with ethyl acetate (20 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated, and purified by preparative high performance liquid chromatography to obtain 3-((4-methoxycyclohexyl)methyl)-1-methylpyrido[2,3 -d] Pyrimidine-2,4-dione (20.0 mg), yield: 23%. ¹ H NMR: (400 MHz, Methonal- d ₄ ) δ=8.73-8.71 (m, 1H), 8.47-8.45 (m, 1H), 7.34-7.31 (m, 1H), 3.95 (d, J = 6.8 Hz, 2H), 3.71 (s, 3H), 3.36 (s, 3H), 3.20-3.16 (m, 1H), 2.10-2.08 (m, 2H), 1.84-1.76 (m, 3H), 1.21-1.08 (m, 4H). MS-ESI calculated value [M+H] ⁺ 304, found value 304.

Example 45.

1-methyl-3-((3-methyl-oxetan-3-yl)methyl)pyrido[3,4-d]pyrimidine-2,4-dione.

first step.

3-(methylamino) isonicotinic acid.

3-Fluoroisonicotinic acid (3.00 g, 21.3 mmol) was dissolved in dioxane (6 mL), and 30% aqueous methylamine solution (22.0 g, 213 mmol) was added. The reaction liquid was heated to 140°C and stirred for 14 hours. Concentrated hydrochloric acid (12N, 3 mL) was added to adjust the pH to 3, filtered, and the filter cake was dried to obtain 3-(methylamino) isonicotinic acid (3.00 g, yellow solid), yield: 93%. ¹ H NMR: (400 MHz, DMSO- d ₆ ) δ = 8.46 (s, 1H), 7.89 (s, 1H), 7.69 (d, J = 4.8 Hz, 1H), 7.50 (d, J = 4.8 Hz, 1H) ), 2.80 (s, 3H).

The second step.

3-(Methylamino) isonicotinamide.

3-(Methylamino) isonicotinic acid (4.00 g, 26.3 mmol), 1-hydroxybenzotriazole (10.7 g, 78.9 mmol), 1-(3-dimethylaminopropyl)-3- Ethylcarbodiimide (15.1g, 78.9mmol) and ammonium chloride (5.63g, 105mmol) were dissolved in N , N -dimethylformamide (5mL). The reaction solution was stirred at 25°C for 24 hours. Water (100 mL) was added to quench the reaction. The mixture was extracted with isopropanol/chloroform (1:3) (50 mL x 2). The organic phases were combined and concentrated under reduced pressure. Dichloromethane/methanol (10:1, 30 mL) was added to the residue, stirred for 10 minutes, filtered, and the filter cake was dried to obtain 3-(methylamino)isonicotinamide (3.50 g, yellow solid), yield: 88%. ¹ H NMR: (400 MHz, DMSO- d ₆ ) δ = 8.09 (s, 2H), 7.80 (d, J = 5.2 Hz, 1H), 7.62-7.61 (m, 1H), 7.52-7.48 (m, 1H) , 7.43 (d, J = 5.2 Hz, 1H), 2.84 (d, J = 5.2 Hz, 3H).

third step.

1-methylpyrido[3,4-d]pyrimidine-2,4-dione.

To a solution of 3-(methylamino)isonicotinamide (3.40g, 22.5mmol) in N , N -dimethylformamide (50mL) was added sodium hydride (1.80g, 45.0) at 0°C. mmol). The reaction solution was stirred at 0°C for 1 hour. Carbonyldiimidazole (5.47 g, 33.7 mmol) was added. The reaction mixture was reacted at room temperature for 1 hour. The reaction solution was cooled to 0°C, and quenched by adding water (20 mL). A white solid was precipitated, filtered, and the filter cake was dried to obtain 1-methylpyrido[3,4-d]pyrimidine-2,4-dione (3.50 g, yellow solid), yield: 95%. ¹ H NMR: (400MHz, DMSO- d ₆ ) δ=11.83(s, 1H), 8.86(s, 1H), 8.48(d, J =4.8Hz, 1H), 7.82(d, J =4.8Hz, 1H) ), 3.49 (s, 3H).

the fourth step.

1-methyl-3-((3-methyl-oxetan-3-yl)methyl)pyrido[3,4-d]pyrimidine-2,4-dione.

3-(chloromethyl)-3-methyl-oxetane (22.5 mg, 0.186 mmol), 1-methylpyrido[3,4-d]pyrimidine-2,4-dione (30.0 mg, 0.169 mmol), potassium iodide (2.8 mg, 0.017 mmol) and potassium carbonate (46.8 mg, 0.338 mmol) were dissolved in N , N -dimethylformamide (5 mL). The reaction liquid was heated to 120°C and stirred for 3 hours. Cooled to room temperature, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by preparative high performance liquid chromatography to obtain 1-methyl-3-((3-methyl-oxetane-3-yl)methyl) Pyrido[3,4-d]pyrimidine-2,4-dione (10.0 mg), yield: 19%. ¹ H NMR: (400 MHz, Methonal- d ₄ ) δ = 8.88 (s, 1H), 8.53 (d, J = 5.2 Hz, 1H), 8.03 (d, J = 5.2 Hz, 1H), 4.78 (d, J = 6.4 Hz, 2H), 4.28-4.26 (m, 4H), 3.69 (s, 3H), 1.38 (s, 3H). MS-ESI calculated value [M+H] ⁺ 262, found value 262.

Example 46.

3-((3-ethyloxetan-3-yl)methyl)-1-methylpyrido[3,4-d]pyrimidine-2,4-dione.

first step.

3-((3-ethyloxetan-3-yl)methyl)-1-methylpyrido[3,4-d]pyrimidine-2,4-dione.

(3-ethyloxetane-3-yl) methyl methanesulfonate (36.2 mg, 0.186 mmol), 1-methylpyrido[3,4-d]pyrimidine-2,4-di Ketone (30.0 mg, 0.169 mmol), potassium iodide (2.8 mg, 0.017 mmol), and potassium carbonate (46.8 mg, 0.338 mmol) were dissolved in N , N -dimethylformamide (5 mL). The reaction liquid was heated to 120°C and stirred for 3 hours. Cooled to room temperature, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by preparative high performance liquid chromatography to obtain 3-((3-ethyloxetan-3-yl)methyl)-1-methylpyridine And [3,4-d]pyrimidine-2,4-dione (11.0mg), yield: 22%. ¹ H NMR: (400 MHz, CDCl ₃ ) δ = 8.79 (s, 1 H), 8.60 (d, J = 4.8 Hz, 1 H), 8.01 (d, J = 4.8 Hz, 1 H), 4.62 (d, J = 6.8 Hz, 2H), 4.32 (d, J = 6.4 Hz, 2H), 4.20 (s, 2H), 3.71 (s, 3H), 1.85-1.79 (m, 2H), 1.10-1.07 (m, 3H). MS-ESI calculated value [M+H] ⁺ 276, found value 276.

Example 47.

1-methyl-3-((tetrahydrofuran-3-yl)methyl)pyrido[3,4-d]pyrimidine-2,4-dione.

first step.

1-methyl-3-((tetrahydrofuran-3-yl)methyl)pyrido[3,4-d]pyrimidine-2,4-dione.

3-(Tetrahydrofuran-3-yl)methyl methanesulfonate (33.6 mg, 0.186 mmol), 1-methylpyrido[3,4-d]pyrimidine-2,4-dione (30.0 mg, 0.169 mmol), potassium iodide (2.8 mg, 0.017 mmol) and potassium carbonate (46.8 mg, 0.338 mmol) were dissolved in N , N -dimethylformamide (5 mL). The reaction liquid was heated to 120°C and stirred for 3 hours. Cooled to room temperature, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by preparative high performance liquid chromatography to obtain 1-methyl-3-((tetrahydrofuran-3-yl)methyl)pyrido[3,4-d] Pyrimidine-2,4-dione (21.0 mg), yield: 45%. ¹ H NMR: (400 MHz, CDCl ₃ ) δ = 8.78 (s, 1H), 8.60 (d, J = 4.8 Hz, 1H), 8.03 (d, J = 4.8 Hz, 1H), 4.23-4.21 (m, 2H ), 3.85-3.81 (m, 3H), 3.71 (s, 3H), 3.66-3.65 (m, 1H), 2.81-2.77 (m, 1H), 2.05-2.00 (m, 1H), 1.81-1.77 (m , 1H). MS-ESI calculated value [M+H] ⁺ 262, found value 262.

Example 48.

1-methyl-3-((tetrahydropiperan-4-yl)methyl)pyrido[3,4-d]pyrimidine-2,4-dione.

first step.

1-methyl-3-((tetrahydropiperan-4-yl)methyl)pyrido[3,4-d]pyrimidine-2,4-dione.

(Tetrahydropiperan-4-yl) methyl methanesulfonate (36.2 mg, 0.186 mmol), 1-methylpyrido[3,4-d]pyrimidine-2,4-dione (30.0 mg, 0.169 mmol), potassium iodide (2.8 mg, 0.017 mmol) and potassium carbonate (46.8 mg, 0.338 mmol) were dissolved in N , N -dimethylformamide (5 mL). The reaction liquid was heated to 120°C and stirred for 3 hours. Cooled to room temperature, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by preparative high performance liquid chromatography to obtain 1-methyl-3-((tetrahydropiperan-4-yl)methyl)pyrido[3,4 -d] Pyrimidine-2,4-dione (10.0 mg), yield: 21%. ¹ H NMR: (400 MHz, CDCl ₃ ) δ = 8.76 (s, 1 H), 8.58 (d, J = 4.8 Hz, 1 H), 8.01 (d, J = 4.8 Hz, 1 H), 4.03 (d, J = 7.2 Hz, 2H), 3.99-3.95 (m, 2H), 3.70 (s, 3H), 3.37-3.18 (m, 2H), 2.13-2.09 (m, 1H), 1.57-1.48 (m, 4H). MS-ESI calculated value [M+H] ⁺ 276, found value 276.

Example 49.

1-methyl-3-(2-(tetrahydropiperan-4-yl)ethyl)pyrido[3,4-d]pyrimidine-2,4-dione.

first step.

1-methyl-3-(2-(tetrahydropiperan-4-yl)ethyl)pyrido[3,4-d]pyrimidine-2,4-dione.

Combine 2-(tetrahydropiperan-4-yl)ethyl methanesulfonate (38.8 mg, 0.186 mmol), 1-methylpyrido[3,4-d]pyrimidine-2,4-dione (30.0 mg, 0.169 mmol), potassium iodide (2.8 mg, 0.017 mmol) and potassium carbonate (46.8 mg, 0.338 mmol) were dissolved in N , N -dimethylformamide (5 mL). The reaction liquid was heated to 120°C and stirred for 3 hours. Cooled to room temperature, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by preparative high performance liquid chromatography to obtain 1-methyl-3-(2-(tetrahydropiperan-4-yl)ethyl)pyrido[3 ,4-d]pyrimidine-2,4-dione (10.0 mg), yield: 20%. ¹ H NMR: (400 MHz, CDCl ₃ ) δ = 9.17 (s, 1H), 8.62-8.60 (m, 1H), 8.43-8.41 (m, 1H), 4.16-4.13 (m, 2H), 3.99-3.95 ( m, 2H), 3.77 (s, 3H), 3.42-3.36 (m, 2H), 1.72-1.64 (m, 5H), 1.43-1.34 (m, 2H). MS-ESI calculated value [M+H] ⁺ 290, found value 290.

Example 50.

3-((4-methoxycyclohexyl)methyl)-1-methylpyrido[3,4-d]pyrimidine-2,4-dione.

first step.

3-((4-methoxycyclohexyl)methyl)-1-methylpyrido[3,4-d]pyrimidine-2,4-dione.

(4-Methoxycyclohexyl) methyl methanesulfonate (41.4 mg, 0.186 mmol), 1-methylpyrido[3,4-d]pyrimidine-2,4-dione (30.0 mg, 0.169 mmol), potassium iodide (2.8 mg, 0.017 mmol) and potassium carbonate (46.8 mg, 0.338 mmol) were dissolved in N , N -dimethylformamide (5 mL). The reaction liquid was heated to 120°C and stirred for 3 hours. Cooled to room temperature, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by preparative high-performance liquid chromatography to obtain 3-((4-methoxycyclohexyl)methyl)-1-methylpyrido[3,4- d] Pyrimidine-2,4-dione (10.0 mg), yield: 19%. ¹ H NMR: (400 MHz, CDCl ₃ ) δ = 8.76 (s, 1 H), 8.58 (d, J = 4.8 Hz, 1 H), 8.01 (d, J = 4.8 Hz, 1 H), 3.99 (d, J = 7.2 Hz, 2H), 3.69 (s, 3H), 3.35 (s, 3H), 3.15-3.11 (m, 1H), 2.08-1.97 (m, 2H), 1.86-1.82 (m, 3H), 1.23-1.10 ( m, 4H). MS-ESI calculated value [M+H] ⁺ 304, found value 304.

Example 51.

1-methyl-3-((3-methyl-oxetan-3-yl)methyl)pyrido[4,3-d]pyrimidine-2,4-dione.

first step.

4-(methylamino) nicotinic acid.

Dissolve 4-chloronicotinic acid (7.00 g, 44.3 mmol) in dioxane (14 mL) and add 30% aqueous methylamine solution (55.2 g, 444 mmol). The reaction solution was heated to 100°C in the microwave and stirred for 50 minutes. Aqueous hydrochloric acid (4N, 5 mL) was added to adjust the pH to 3, filtered, and the filter cake was dried to obtain 4-(methylamino)nicotinic acid (5.00 g, white solid), yield: 74%. ¹ H NMR: (400 MHz, DMSO- d ₆ ) δ = 8.52 (s, 1H), 8.13 (d, J = 6.8 Hz, 1H), 6.78 (d, J = 6.8 Hz, 1H), 2.95 (d, J =4.4Hz, 3H).

The second step.

4-(Methylamino) nicotinamide.

Combine 4-(methylamino)nicotinic acid (5.20g, 34.2mmol), 1-hydroxybenzotriazole (27.7g, 205mmol), 1-ethyl-(3-dimethylaminopropyl) carbon Acetylenediimide hydrochloride (39.3 g, 205 mmol) and ammonium chloride (14.6 g, 273 mmol) were dissolved in N , N -dimethylformamide (50 mL). The reaction solution was stirred at 25°C for 8 hours. Water (100 mL) was added to quench the reaction. The mixture was extracted with isopropanol/chloroform (1:3) (30 mL x 5). The organic phases were combined and concentrated under reduced pressure. Dichloromethane/methanol (10:1, 50 mL) was added to the residue, stirred for 10 minutes, filtered, and the filter cake was dried to obtain 4-(methylamino) nicotinamide (4.70 g, white solid), yield: 91 %. ¹ H NMR: (400 MHz, DMSO- d ₆ ) δ = 9.67 (d, J = 7.6 Hz, 1H), 8.77 (s, 1H), 8.52 (s, 1H), 8.30-8.28 (m, 1H), 7.87 (s, 1H), 7.01 (d, J = 7.6 Hz, 1H), 3.01 (s, 3H).

third step.

1-methylpyrido[4,3-d]pyrimidine-2,4-dione.

To a solution of 4-(methylamino) nicotinamide (4.80g, 31.8mmol) in N , N -dimethylformamide (50mL) was added sodium hydride (1.52g, 63.5mmol) at 0°C. ). The reaction solution was stirred at 0°C for 1 hour. Carbonyldiimidazole (7.72 g, 47.6 mmol) was added. The reaction mixture was reacted at 75°C for 2 hours. The reaction solution was cooled to room temperature, and quenched by adding water (50 mL). Hydrochloric acid aqueous solution (12N, 5mL) was added to adjust the pH value to 3, a white solid precipitated, and the filter cake was dried to obtain 1-methylpyrido[4,3-d]pyrimidine-2,4-dione ( 3.50g, yellow solid), yield: 95%. ¹ H NMR: (400MHz, DMSO- d ₆ ) δ=11.76(s, 1H), 8.97(s, 1H), 8.69(d, J =6.0Hz, 1H), 7.38(d, J =6.0Hz, 1H ), 3.39 (s, 3H).

the fourth step.

1-methyl-3-((3-methyl-oxetan-3-yl)methyl)pyrido[4,3-d]pyrimidine-2,4-dione.

3-(chloromethyl)-3-methyloxetane (26.5 mg, 0.220 mmol), 1-methylpyrido[4,3-d]pyrimidine-2,4-dione (30.0 mg , 0.169 mmol) and potassium carbonate (70.2 mg, 0.508 mmol) were dissolved in N , N -dimethylformamide (3 mL), potassium iodide (2.8 mg, 0.017 mmol) was added, and the reaction solution was stirred at 120° C. for 3 hours. The reaction solution was directly filtered, the filtrate was concentrated under reduced pressure, and the crude product was purified by preparative high performance liquid chromatography to obtain the product 1-methyl-3-((3-methyl-oxetan-3-yl)methyl)pyrido [4,3-d]pyrimidine-2,4-dione (22.0 mg), yield: 48%. ¹ H NMR: (400 MHz, Methonal- d ₄ ) δ = 9.14 (s, 1H), 8.71 (d, J = 6.4 Hz, 1H), 7.44 (d, J = 6.4 Hz, 1H), 4.79 (d, J = 6.0 Hz, 2H), 4.27 (d, J = 6.0 Hz, 2H), 4.25 (s, 2H), 3.61 (s, 3H), 1.38 (s, 3H). MS-ESI calculated value [M+H] ⁺ 262, found value 262.

Example 52.

3-((3-ethyloxetan-3-yl)methyl)-1-methylpyrido[4,3-d]pyrimidine-2,4-dione.

first step.

3-((3-ethyloxetan-3-yl)methyl)-1-methylpyrido[4,3-d]pyrimidine-2,4-dione.

(3-ethyloxetan-3-yl) methyl methanesulfonate (42.7mg, 0.220mmol), 1-methylpyrido[4,3-d]pyrimidine-2,4-di Ketone (30.0mg, 0.169mmol) and potassium carbonate (70.2mg, 0.508mmol) were dissolved in N , N -dimethylformamide (3mL), potassium iodide (2.8mg, 0.017mmol) was added, and the reaction solution was at 120°C Stir for 3 hours. The reaction solution was directly filtered, the filtrate was concentrated under reduced pressure, and the crude product was purified by preparative high performance liquid chromatography to obtain the product 3-((3-ethyloxetan-3-yl)methyl)-1-methylpyrido[ 4,3-d]pyrimidine-2,4-dione (20.0 mg), yield: 42%. ¹ H NMR: (400 MHz, CDCl ₃ ) δ = 9.29 (s, 1H), 8.75 (d, J = 6.0 Hz, 1H), 7.09 (d, J = 6.0 Hz, 1H), 4.61 (d, J = 6.4 Hz, 2H), 4.31 (d, J = 6.4Hz, 2H), 4.17 (s, 2H), 3.59 (s, 3H), 1.83-1.78 (q, J = 7.6Hz, 2H), 1.07 (t, J = 7.6 Hz, 3H). MS-ESI calculated value [M+H] ⁺ 276, found value 276.

Example 53.

1-methyl-3-((tetrahydrofuran-3-yl)methyl)pyrido[4,3-d]pyrimidine-2,4-dione.

first step.

1-methyl-3-((tetrahydrofuran-3-yl)methyl)pyrido[4,3-d]pyrimidine-2,4-dione.

(Tetrahydrofuran-3-yl) methyl methanesulfonate (39.6 mg, 0.220 mmol), 1-methylpyrido[4,3-d]pyrimidine-2,4-dione (30.0 mg, 0.169 mmol) And potassium carbonate (70.2 mg, 0.508 mmol) was dissolved in N , N -dimethylformamide (3 mL), potassium iodide (2.8 mg, 0.017 mmol) was added, and the reaction solution was stirred at 120° C. for 3 hours. The reaction solution was directly filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by preparative high performance liquid chromatography to obtain the product 1-methyl-3-((tetrahydrofuran-3-yl)methyl)pyrido[4,3-d]pyrimidine- 2,4-Dione (20.0mg), yield: 43%. ¹ H NMR: (400 MHz, Methonal- d ₄ ) δ = 9.11 (s, 1H), 8.68 (d, J = 6.0 Hz, 1H), 7.42 (d, J = 6.0 Hz, 1H), 4.17-4.04 (m , 2H), 3.96-3.91 (m, 1H), 3.81-3.73 (m, 2H), 3.65-3.61 (m, 1H), 3.60 (s, 3H), 2.81-2.71 (m, 1H), 2.08-2.00 (m, 1H), 1.81-1.73 (m, 1H). MS-ESI calculated value [M+H] ⁺ 262, found value 262.

Example 54.

1-methyl-3-((tetrahydropiperan-4-yl)methyl)pyrido[4,3-d]pyrimidine-2,4-dione.

first step.

1-methyl-3-((tetrahydropiperan-4-yl)methyl)pyrido[4,3-d]pyrimidine-2,4-dione.

(Tetrahydropyran-4-yl) methyl methanesulfonate (42.7 mg, 0.220 mmol), 1-methylpyrido[4,3-d]pyrimidine-2,4-dione (30.0 mg, 0.169 mmol) and potassium carbonate (70.2 mg, 0.508 mmol) were dissolved in N , N -dimethylformamide (3 mL), potassium iodide (2.8 mg, 0.017 mmol) was added, and the reaction solution was stirred at 120°C for 3 hours. The reaction solution was directly filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by preparative high performance liquid chromatography to obtain the product 1-methyl-3-((tetrahydropiperan-4-yl)methyl)pyrido[4,3-d ] Pyrimidine-2,4-dione (19.0 mg), yield: 40%. ¹ H NMR: (400 MHz, Methonal- d ₄ ) δ = 9.12 (s, 1H), 8.69 (d, J = 6.0 Hz, 1H), 7.42 (d, J = 6.0 Hz, 1H), 3.99 (d, J =7.2Hz, 2H), 3.96-3.92(m, 2H), 3.60(s, 3H), 3.37-3.33(m, 2H), 2.13-2.11(m, 1H), 1.63-1.59(m, 2H), 1.47-1.37 (m, 2H). MS-ESI calculated value [M+H] ⁺ 276, found value 276.

Example 55.

1-methyl-3-(2-(tetrahydropiperan-4-yl)ethyl)pyrido[4,3-d]pyrimidine-2,4-dione.

first step.

1-methyl-3-(2-(tetrahydropiperan-4-yl)ethyl)pyrido[4,3-d]pyrimidine-2,4-dione.

Combine 2-(tetrahydropiperan-4-yl)ethyl methanesulfonate (35.2 mg, 0.169 mmol), 1-methylpyrido[4,3-d]pyrimidine-2,4-dione (30.0 mg, 0.169 mmol) and potassium carbonate (70.2 mg, 0.508 mmol) were dissolved in N , N -dimethylformamide (3 mL), potassium iodide (2.8 mg, 0.017 mmol) was added, and the reaction solution was stirred at 120° C. for 3 hours . The reaction solution was directly filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by preparative high performance liquid chromatography to obtain the product 1-methyl-3-(2-(tetrahydropiperan-4-yl)ethyl)pyrido[4,3 -d] Pyrimidine-2,4-dione (25.0 mg), yield: 51%. ¹ H NMR: (400 MHz, Methonal- d ₄ ) δ = 9.12 (s, 1H), 8.69 (d, J = 6.4 Hz, 1H), 7.43 (d, J = 6.4 Hz, 1H), 4.10 (t, J =7.4Hz, 2H), 3.96-3.92(m, 2H), 3.60(s, 3H), 3.46-3.39(m, 2H), 1.75(d, J =12.8Hz, 2H), 1.66-1.61(m, 3H), 1.37-1.31 (m, 2H). MS-ESI calculated value [M+H] ⁺ 290, found value 290.

Example 56.

3-((4-methoxycyclohexyl)methyl)-1-methylpyrido[4,3-d]pyrimidine-2,4-dione.

first step.

3-((4-methoxycyclohexyl)methyl)-1-methylpyrido[4,3-d]pyrimidine-2,4-dione.

(4-Methoxycyclohexyl) methyl methanesulfonate (37.6 mg, 0.169 mmol), 1-methylpyrido[4,3-d]pyrimidine-2,4-dione (30.0 mg, 0.169 mmol) and potassium carbonate (70.2 mg, 0.508 mmol) were dissolved in N , N -dimethylformamide (3 mL), potassium iodide (2.8 mg, 0.017 mmol) was added, and the reaction solution was stirred at 120° C. for 3 hours. The reaction solution was directly filtered, the filtrate was concentrated under reduced pressure, and the crude product was purified by preparative high performance liquid chromatography to obtain the product 3-((4-methoxycyclohexyl)methyl)-1-methylpyrido[4,3-d] Pyrimidine-2,4-dione (20.0 mg), yield: 37%. ¹ H NMR: (400 MHz, Methonal- d ₄ ) δ = 9.14 (s, 1H), 8.69 (d, J = 6.0 Hz, 1H), 7.43 (d, J = 6.0 Hz, 1H), 3.95 (d, J =6.8Hz, 2H), 3.64(s, 3H), 3.35(s, 3H), 3.22-3.16(m, 1H), 2.09(d, J =8.8Hz, 2H), 1.85-1.77(m, 3H) , 1.18-1.12 (m, 4H). MS-ESI calculated value [M+H] ⁺ 304, found value 304.

Example 57.

1-methyl-3-[(3-methyl-oxetan-3-yl)methyl]pyrido[3,2- d ]pyrimidine-2,4-dione.

first step.

N- (2-chloro-3-pyridyl) carbamic acid tertiary butyl ester.

2-chloropyridine-3-amine (30.0 g, 233 mmol) was dissolved in dichloromethane (250 mL) and triethylamine (47.2 g, 467 mmol) was added. Di-tert-butyl dicarbonate (102 g, 467 mmol) was added dropwise at 0°C. The reaction solution was stirred at 25°C for 18 hours. Water (100 mL) was added to quench the reaction. The reaction solution was extracted with ethyl acetate (100 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (15:1 petroleum ether/ethyl acetate, Rf=0.6) to obtain N- (2-chloro- 3-pyridyl)carbamic acid tertiary butyl ester (11.0 g, white solid), yield: 21%. ¹ H NMR: (400 MHz, DMSO- d ₆ ) δ = 8.89 (s, 1H), 8.17-8.16 (m, 1H), 8.03-8.01 (m, 1H), 7.43-7.39 (m, 1H), 1.47 ( s, 9H).

The second step.

(2-chloropyridin-3-yl) (methyl) carbamic acid tertiary butyl ester.

Dissolve N- (2-chloro-3-pyridyl)carbamic acid tertiary butyl ester (11.0g, 48.1mmol) in anhydrous tetrahydrofuran (150mL), under nitrogen protection, slowly add sodium hydrogen (1.39g) at 0°C , 57.7mmol), the reaction solution was stirred at 0 ℃ for half an hour. Iodomethane (10.2 g, 72.2 mmol) was slowly added and stirred at room temperature for 12 hours. Water (50 mL) was added to quench the reaction. The reaction solution was extracted with ethyl acetate (80 mL x 3), the organic phases were combined, washed with saturated brine (150 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give (2-chloropyridin-3-yl) (methyl Group) tertiary butyl carbamate (11.0 g, colorless oil), yield: 94%. ¹ H NMR: (400 Hz, DMSO- d ₆ ) δ = 8.33 (d, J = 4.8 Hz, 1H), 7.92-7.90 (m, 1H), 7.48 (d, J = 8.0 Hz, 1H), 3.06 (s , 3H), 1.45-1.14 (m, 9H). MS-ESI calculated value [M+H] ⁺ 243, found value 243.

third step.

2-chloro- N -picoline-3-amine.

Dissolve (2-chloropyridin-3-yl)(methyl)carbamic acid tert-butyl ester (11.0g, 45.3mmol) in ethyl acetate (50mL), and add 4M ethyl acetate hydrochloride (150mL) at 0°C dropwise ) And then stirred at 25°C for 15 hours. The reaction solution was concentrated under reduced pressure. Purified by silica gel column chromatography (10:1 petroleum ether/ethyl acetate, Rf=0.3) to give 2-chloro- N -methylpyridin-3-amine (5.50 g, colorless oil), yield: 85 %. ¹ H NMR: (400 Hz, DMSO- d ₆ ) δ = 7.56 (d, J = 4.8 Hz, 1H), 7.20-7.17 (m, 1H), 6.95 (d, J = 8.0 Hz, 1H), 5.76-5.73 (m, 1H), 2.73 (d, J = 4.8 Hz, 3H). MS-ESI calculated value [M+H] ⁺ 143, found value 143.

the fourth step.

3-(Methylamino) methyl picolinate.

Dissolve 2-chloro- N -methylpyridin-3-amine (5.50g, 38.6mmol) in methanol (100mL), and add 1,1'-bis(diphenylphosphine) dichloride at 25℃ Ferrocene palladium chloride (2.82g, 3.86mmol). At 50°C, the reaction liquid was reacted for 56 hours in a carbon monoxide atmosphere (50 psi). The reaction liquid was cooled to 25°C, concentrated under reduced pressure, and separated and purified by silica gel column chromatography (5:1 petroleum ether/ethyl acetate, Rf=0.5) to give methyl 3-(methylamino)picolinate (6.00 g, colorless oil), yield: 94%. ¹ H NMR: (400 MHz, Methonal- d ₄ ) δ = 7.84 (d, J = 4.8 Hz, 1H), 7.45-7.42 (m, 1H), 7.29 (d, J = 8.0 Hz, 1H), 3.93 (s , 3H), 2.94 (s, 3H). MS-ESI calculation [M+H] ⁺ 167, found 167.

the fifth step.

3-(methylamino)pyridine-2-carboxamide.

3-(Methylamino)pyridine-2-carboxylic acid methyl ester (6.00 g, 36.1 mmol) was dissolved in methanol (100 mL), and ammonia water (1.27 g, 36.1 mmol) was added. The reaction solution was stirred at 40°C for 18 hours. The reaction solution was added with water (200 mL), and extracted with ethyl acetate (100 mL x 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 3-(methylamino)pyridine-2-carboxamide (3.50 g, yellow solid), yield: 64%. ¹ H NMR: (400 MHz, DMSO- d ₆ ) δ = 8.27-8.23 (br, 1H), 7.80-7.95 (br, 1H), 7.76 (d, J = 4.0 Hz, 1H), 7.37-7.32 (m, 2H), 7.11 (d, J = 8.0 Hz, 1H), 2.79 (d, J = 4.8 Hz, 3H).

The sixth step.

N -[(2-Methamido-3-pyridyl) -N -methyl]-carbamic acid ethyl ester.

3-(Methylamino)pyridine-2-carboxamide (1.70 g, 10.9 mmol) was dissolved in ethyl chloroformate (35.3 g, 326 mmol), and the reaction solution was stirred at 90°C for 1 hour. The reaction solution was quenched with saturated aqueous sodium bicarbonate solution (20 mL) and extracted with ethyl acetate (20 mL x 2). The organic phase was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (1:1 petroleum ether/ethyl acetate, Rf=0.2) to give N -[(2-methylamido-3-pyridyl)- N -methyl]-carbamic acid ethyl ester (2.00 g, white solid), yield: 83%. ¹ H NMR: (400 MHz, DMSO- d ₆ ) δ = 8.48 (d, J = 4.0 Hz, 1H), 7.90 (br, 1H), 7.82 (d, J = 8.0 Hz, 1H), 7.60-7.56 (m , 1H), 7.50 (br, 1H), 3.88 (q, J = 7.2 Hz, 2H), 3.12 (s, 3H), 1.00 (t, J = 7.2 Hz, 3H).

The seventh step.

1-methylpyrido[3,2- d ]pyrimidine-2,4-dione.

N -[(2-Carboxamido-3-pyridyl) -N -methyl]-carbamic acid ethyl ester (2.00 g, 8.96 mmol) and sodium hydroxide (717 mg, 17.9 mmol) were dissolved in toluene ( 25mL), the reaction solution was stirred at 110 ℃ for 0.5h. The reaction solution was diluted with water (15 mL) and adjusted to pH=7 with 1N hydrochloric acid aqueous solution. After filtration, the filter cake was diluted with methanol (15 mL) and concentrated under reduced pressure to obtain 1-methylpyrido[3,2- d ]pyrimidine-2,4-dione (1.09 g, white solid), yield: 69%. ¹ H NMR: (400 MHz, DMSO- d ₆ ) δ=11.72 (s, 1H), 8.50 (d, J = 4.8 Hz, 1H), 7.89 (dd, J = 8.0, 4.8 Hz, 1H), 7.74-7.71 (m, 1H), 3.41 (s, 3H).

Step 8.

1-methyl-3-[(3-methyl-oxetan-3-yl)methyl]pyrido[3,2- d ]pyrimidine-2,4-dione.

1-methylpyrido[3,2- d ]pyrimidine-2,4-dione (30.0mg, 0.169mmol), 3-(chloromethyl)-3-methyloxetane (26.5mg , 0.220 mmol) and potassium carbonate (58.5 mg, 0.424 mmol) were dissolved in N , N -dimethylformamide (4mL), potassium iodide (2.8mg, 0.017mmmol) was added, and the reaction was heated to reflux at 120°C for 3 hours. The reaction solution was directly filtered, the filtrate was concentrated under reduced pressure, and the crude product was purified by preparative high performance liquid chromatography to obtain the product 1-methyl-3-[(3-methyl-oxetan-3-yl)methyl]pyrido [3,2- d ] Pyrimidine-2,4-dione (12.0 mg), yield: 27%. ¹ H NMR: (400 MHz, Methonal- d ₄ ) δ = 8.57 (d, J = 4.8 Hz, 1H), 8.00 (d, J = 8.0 Hz, 1H), 7.82-7.77 (m, 1H), 4.80 (d , J = 6.0 Hz, 2H), 4.31-4.25 (m, 4H), 3.64 (s, 3H), 1.40 (s, 3H). MS-ESI calculated value [M+H] ⁺ 262, found value 262.

Example 58.

3-[(3-ethyloxetan-3-yl)methyl]-1-methylpyrido[3,2- d ]pyrimidine-2,4-dione.

first step.

3-[(3-ethyloxetan-3-yl)methyl]-1-methylpyrido[3,2- d ]pyrimidine-2,4-dione.

1-Methylpyrido[3,2- d ]pyrimidine-2,4-dione (30.0mg, 169mmol), (3-ethyloxetan-3-yl) methyl methanesulfonate (42.8 mg, 220 mmol) and potassium carbonate (70.2 mg, 508 mmol) were dissolved in N , N -dimethylformamide (4 mL), potassium iodide (2.80 mg, 0.017 mmol) was added, and the reaction was heated to reflux at 120°C for 3 hours. The reaction solution was directly filtered, the filtrate was concentrated under reduced pressure, and the crude product was purified by preparative high performance liquid chromatography to obtain the product 3-[(3-ethyloxetan-3-yl)methyl]-1-methylpyrido[ 3,2- d ]pyrimidine-2,4-dione (16.0 mg), yield: 34%. ¹ H NMR: (400 MHz, Methonal- d ₄ ) δ = 8.57 (d, J = 4.4 Hz, 1H), 8.00 (d, J = 4.4 Hz, 1H), 7.83-7.79 (m, 1H), 4.69 (d , J = 6.8Hz, 2H), 4.33 (d, J = 6.8Hz, 2H), 4.25 (s, 2H), 3.65 (s, 3H), 1.86-1.80 (m, 2H), 1.09 (t, J = 7.4Hz, 3H). MS-ESI calculated value [M+H] ⁺ 276, found value 276.

Example 59.

1-methyl-3-((tetrahydrofuran-3-yl)methyl)pyrido[3,2-d]pyrimidine-2,4-dione.

first step.

1-methyl-3-((tetrahydrofuran-3-yl)methyl)pyrido[3,2-d]pyrimidine-2,4-dione.

(Tetrahydrofuran-3-yl) methyl methanesulfonate (30.5 mg, 0.169 mmol), 1-methylpyrido[3,2-d]pyrimidine-2,4-dione (25.0 mg, 0.141 mmol) , Potassium iodide (2.3 mg, 0.014 mmol) and potassium carbonate (39.0 mg, 0.282 mmol) were dissolved in N , N -dimethylformamide (3 mL). The reaction liquid was heated to 120°C and stirred for 3 hours. Cooled to room temperature, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by preparative high performance liquid chromatography to obtain 1-methyl-3-((tetrahydrofuran-3-yl)methyl)pyrido[3,2-d] Pyrimidine-2,4-dione (20.0 mg), yield: 54%. ¹ H NMR: (400 MHz, Methonal- d ₄ ) δ = 8.56 (d, J = 4.4 Hz, 1H), 7.98 (d, J = 8.0 Hz, 1H), 7.81-7.77 (m, 1H), 4.21-4.14 (m, 2H), 3.96-3.90 (m, 1H), 3.81-3.78 (m, 2H), 3.67-3.63 (m, 4H), 2.82-2.79 (m, 1H), 2.06-2.03 (m, 1H) , 1.83-1.79 (m, 1H). MS-ESI calculated value [M+H] ⁺ 262, found value 262.

Example 60.

1-methyl-3-((tetrahydropiperan-4-yl)methyl)pyrido[3,2-d]pyrimidine-2,4-dione.

first step.

1-methyl-3-((tetrahydropiperan-4-yl)methyl)pyrido[3,2-d]pyrimidine-2,4-dione.

(Tetrahydropyran-4-yl) methyl methanesulfonate (39.5 mg, 0.203 mmol), 1-methylpyrido[3,2-d]pyrimidine-2,4-dione (30.0 mg, 0.169 mmol), potassium iodide (2.8 mg, 0.017 mmol) and potassium carbonate (46.8 mg, 0.339 mmol) were dissolved in N , N -dimethylformamide (3 mL). The reaction liquid was heated to 120°C and stirred for 3 hours. Cooled to room temperature, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by preparative high performance liquid chromatography to obtain 1-methyl-3-((tetrahydropiperan-4-yl)methyl)pyrido[3,2 -d] Pyrimidine-2,4-dione (20.0 mg), yield: 43%. ¹ H NMR: (400 MHz, Methonal- d ₄ ) δ = 8.56 (d, J = 3.6 Hz, 1H), 7.98 (d, J = 8.0 Hz, 1H), 7.81-7.77 (m, 1H), 4.06-4.04 (m, 2H), 3.96-3.93 (m, 2H), 3.63 (s, 3H), 3.38-3.33 (m, 2H), 2.17-2.14 (m, 1H), 1.64-1.61 (m, 2H), 1.49 -1.44(m, 2H). MS-ESI calculated value [M+H] ⁺ 276, found value 276.

Example 61.

1-methyl-3-(2-(tetrahydropiperan-4-yl)ethyl)pyrido[3,2-d]pyrimidine-2,4-dione.

first step.

1-methyl-3-(2-(tetrahydropiperan-4-yl)ethyl)pyrido[3,2-d]pyrimidine-2,4-dione.

2-(tetrahydropiperan-4-yl)ethyl methanesulfonate (35.3 mg, 0.169 mmol), 1-methylpyrido[3,2-d]pyrimidine-2,4-dione (25.0 mg, 0.141 mmol), potassium iodide (2.3 mg, 0.014 mmol) and potassium carbonate (39.0 mg, 0.282 mmol) were dissolved in N , N -dimethylformamide (3 mL). The reaction liquid was heated to 120°C and stirred for 3 hours. Cooled to room temperature, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by preparative high performance liquid chromatography to obtain 1-methyl-3-(2-(tetrahydropiperan-4-yl)ethyl)pyrido[3 ,2-d]pyrimidine-2,4-dione (20.0 mg), yield: 49%. ¹ H NMR: (400 MHz, Methonal- d ₄ ) δ = 8.55 (d, J = 4.0 Hz, 1H), 7.99 (d, J = 8.0 Hz, 1H), 7.78 (d, J = 8.0, 4.0 Hz, 1H) ), 4.19-4.15(m, 2H), 3.95-3.93(m, 2H), 3.63(s, 3H), 3.47-3.40(m, 2H), 1.79-1.76(m, 2H), 1.68-1.64(m , 3H), 1.37-1.33 (m, 2H). MS-ESI calculated value [M+H] ⁺ 290, found value 290.

Example 62.

3-((4-methoxycyclohexyl)methyl)-1-methylpyrido[3,2-d]pyrimidine-2,4-dione.

first step.

3-((4-methoxycyclohexyl)methyl)-1-methylpyrido[3,2-d]pyrimidine-2,4-dione.

(4-Methoxycyclohexyl) methyl methanesulfonate (37.7 mg, 0.169 mmol), 1-methylpyrido[3,2-d]pyrimidine-2,4-dione (25.0 mg, 0.141 mmol), potassium iodide (2.3 mg, 0.014 mmol) and potassium carbonate (39.0 mg, 0.282 mmol) were dissolved in N , N -dimethylformamide (3 mL). The reaction liquid was heated to 120°C and stirred for 3 hours. Cooled to room temperature, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by preparative high-performance liquid chromatography to obtain 3-((4-methoxycyclohexyl)methyl)-1-methylpyrido[3,2- d] Pyrimidine-2,4-dione (20.0 mg), yield: 47%. ¹ H NMR: (400 MHz, Methonal- d ₄ ) δ = 8.55 (d, J = 4.0 Hz, 1H), 7.97 (d, J = 8.4 Hz, 1H), 7.80-7.77 (m, 1H), 3.99-3.97 (m, 2H), 3.62 (s, 3H), 3.33 (s, 3H), 3.18-3.15 (m, 1H), 2.09-2.06 (m, 2H), 1.86-1.76 (m, 3H), 1.19-1.10 (m, 4H). MS-ESI calculated value [M+H] ⁺ 304, found value 304.

Example 63.

1-methyl-3-((3-methyloxetan-3-yl)methyl) pteridine-2,4-dione.

first step.

6-amino-1-methylpyrimidine-2,4-dione.

At 25°C, sodium metal (7.80 g, 340 mmol) was added portionwise to stirred anhydrous ethanol (180 mL) and heated to 80°C under reflux for 0.5 hour. Then methylurea (12.6 g, 170 mmol) was added in portions, and reflux was continued for 0.5 hour. Ethyl cyanoacetate (19.0g, 170mmol) was added dropwise to the reaction, and a large amount of precipitation occurred. Continue to reflux for 3 hours, and recover ethanol under reduced pressure. The residue was dissolved in water (50 mL), adjusted to pH=7 with dilute hydrochloric acid (1N), and filtered to obtain the product 6-amino-1-methylpyrimidine-2,4-dione (7.60 g, white solid), yield: 32%. ¹ H NMR: (400 MHz, DMSO- d ₆ ) δ = 10.39 (s, 1H), 6.79 (s, 2H), 4.54 (s, 1H), 3.14 (s, 3H). MS-ESI calculated value [M+H] ⁺ 142, measured value 142.

The second step.

5,6-Diamino-1-methylpyrimidine-2,4-dione.

6-Amino-1-methylpyrimidine-2,4-dione (10.0 g, 70.1 mmol) was dissolved in water (100 mL), and hydrochloric acid (7 mL, 84.0 mmol, 12N) was added dropwise with stirring at 0°C. Then sodium nitrite (5.80 g, 84.2 mmol) was dissolved in water (50 mL) and added dropwise to the reaction, and a purple precipitate appeared. The reaction solution was stirred at 25°C for 2 hours, filtered, and washed with cold water to obtain a purple solid. The solid was dissolved in water (100 mL), sodium hyposulfite (18.7 g, 118 mmol) was added in portions with stirring, heated to 60°C and stirred for 0.5 hours, and the temperature was lowered to 25°C and stirred for 16 hours. Filter and wash with cold water (50 mL), ethanol (50 mL), and acetone (50 mL), respectively. After drying, the product 5,6-diamino-1-methylpyrimidine-2,4-dione (8.60 g, light yellow solid) was obtained with a yield of 93%. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ=10.49 (s, 1H), 6.15 (s, 2H), 3.25 (s, 3H), 2.95 (s, 2H). MS-ESI calculated value [M+H] ⁺ 157, found value 157.

third step.

1-methylpteridine-2,4-dione.

Dissolve 5,6-diamino-1-methylpyrimidine-2,4-dione (4.00g, 25.6mmol) in water (150mL) and add glyoxal (5.58g) at 25°C in one portion , 38.4mmol, 40% aqueous solution). Heat to 60°C and stir for 16 hours. After filtration, the resulting solid was washed with water (50 mL) to obtain the product 1-methylpteridine-2,4-dione (3.60 g, yellow solid), yield: 79%.

the fourth step.

1-methyl-3-((3-methyloxetan-3-yl)methyl) pteridine-2,4-dione.

Dissolve 1-methylpteridine-2,4-dione (299mg, 1.68mmol) in N , N -dimethylformamide (8mL) and add 3-(chloromethyl)-3 at 25°C -Methyl-oxetane (222 mg, 1.85 mmol), potassium iodide (334 mg, 2.02 mmol) and potassium carbonate (464 mg, 3.36 mmol), the reaction solution was heated to 120° C. and stirred for 17 hours. The reaction solution was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by high-performance liquid chromatography to obtain 1-methyl-3-((3-methyloxetan-3-yl)methyl) pteridine-2,4-di Ketone (40.0 mg), yield: 9%. ¹ H NMR: (400 MHz, CDCl ₃ ) δ = 8.68 (d, J = 4.0 Hz, 1H), 8.62 (d, J = 4.0 Hz, 1H), 4.78 (d, J = 8.0 Hz, 2H), 4.32- 4.29 (m, 4H), 3.73 (s, 3H), 1.42 (s, 3H). Calculated value [M+H] ⁺ 263, measured value 263.

Example 64.

3-((3-ethyloxetan-3-yl)methyl)-1-methylpteridine-2,4-dione.

first step.

3-((3-ethyloxetan-3-yl)methyl)-1-methylpteridine-2,4-dione.

Dissolve 1-methylpteridine-2,4-dione (100mg, 0.560mmol) in N , N -dimethylformamide (4mL) and add (3-ethyloxetane) at 25°C Alkan-3-yl)methyl methanesulfonate (119 mg, 0.620 mmol), potassium iodide (19.0 mg, 0.110 mmol) and potassium carbonate (155 mg, 1.12 mmol). The reaction solution was heated to 120° C. and stirred for 16 hours. The reaction solution was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by preparative high performance liquid chromatography to obtain the product 3-((3-ethyloxetan-3-yl)methyl)-1-methylpteridine-2,4-di Ketone (18.0 mg), yield: 12%. ¹ H NMR: (400 MHz, CDCl ₃ ) δ = 8.68 (d, J = 2.0 Hz, 1H), 8.62 (d, J = 2.0 Hz, 1H), 4.66 (d, J = 6.4 Hz, 2H), 4.35 ( d, J = 6.8 Hz, 2H), 4.26 (s, 2H), 3.73 (s, 3H), 1.86-1.80 (m, 2H), 1.09 (t, J = 7.2 Hz, 3H). MS-ESI calculated value [M+H] ⁺ 277, found value 277.

Example 65.

1-methyl-3-((tetrahydrofuran-3-yl)methyl) pteridine-2,4-dione.

first step.

1-methyl-3-((tetrahydrofuran-3-yl)methyl) pteridine-2,4-dione.

Dissolve 1-methylpteridine-2,4-dione (60.0mg, 0.337mmol) in N , N -dimethylformamide (4mL) and add (tetrahydrofuran-3-yl)methyl at 25°C Methanesulfonate (61.0 mg, 0.337 mmol), potassium iodide (11.0 mg, 0.0670 mmol) and potassium carbonate (93.0 mg, 0.674 mmol). The reaction solution was heated to 120° C. and stirred for 16 hours. The reaction solution was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by preparative high performance liquid chromatography to obtain the product 1-methyl-3-((tetrahydrofuran-3-yl)methyl) pteridine-2,4-dione (6.0 mg), yield : 7%. ¹ H NMR: (400 MHz, CDCl ₃ ) δ = 8.66 (d, J = 2.4 Hz, 1H), 8.61 (d, J = 2.4 Hz, 1H), 4.31-4.25 (m, 1H), 4.18-4.12 (m , 1H), 3.98-3.94 (m, 1H), 3.87-3.78 (m, 2H), 3.73 (s, 3H), 3.67-3.63 (m, 1H), 2.84-2.78 (m, 1H), 2.04-1.98 (m, 1H), 1.83-1.75 (m, 1H). MS-ESI calculated value [M+H] ⁺ 263, found value 263.

Example 66.

1-methyl-3-((tetrahydropiperan-4-yl)methyl) pteridine-2,4-dione.

first step.

1-methyl-3-((tetrahydropiperan-4-yl)methyl) pteridine-2,4-dione.

Dissolve 1-methylpteridine-2,4-dione (100mg, 0.560mmol) in N , N -dimethylformamide (4mL) and add (tetrahydropyran-4-yl) at 25°C ) Methane methanesulfonate (119 mg, 0.622 mmol), potassium iodide (19.0 mg, 0.112 mmol) and potassium carbonate (155 mg, 1.12 mmol). The reaction solution was heated to 120° C. and stirred for 16 hours. The reaction solution was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by preparative high performance liquid chromatography to obtain the product 1-methyl-3-((tetrahydropiperan-4-yl)methyl) pteridine-2,4-dione (14.0mg) , Yield: 9%. ¹ H NMR: (400 MHz, CDCl ₃ ) δ = 8.65 (d, J = 2.0 Hz, 1H), 8.60 (d, J = 2.0 Hz, 1H), 4.08 (d, J = 7.2 Hz, 2H), 3.98- 3.95 (m, 2H), 3.72 (s, 3H), 3.37-3.31 (m, 2H), 2.19-2.09 (m, 1H), 1.61-1.49 (m, 4H). MS-ESI calculated value [M+H] ⁺ 277, found value 277.

Example 67.

1-methyl-3-(2-(tetrahydropiperan-4-yl)ethyl) pteridine-2,4-dione.

first step.

1-methyl-3-(2-(tetrahydropiperan-4-yl)ethyl) pteridine-2,4-dione.

Combine 2-(tetrahydropiperan-4-yl)ethyl methanesulfonate (117 mg, 0.561 mmol), 1-methylpteridine-2,4-dione (100 mg, 0.561 mmol) and potassium carbonate (233 mg , 1.68 mmol) was dissolved in N , N -dimethylformamide (5 mL), potassium iodide (9.3 mg, 0.0561 mmol) was added, and the reaction solution was stirred at 120° C. for 3 hours. The reaction solution was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure, and the crude product was purified by preparative high performance liquid chromatography to obtain the product 1-methyl-3-(2-(tetrahydropiperan-4-yl)ethyl) pteridine-2,4-dione (12.0 mg), yield: 7.4%. ¹ H NMR: (400 MHz, CDCl ₃ ) δ = 8.65 (d, J = 2.4 Hz, 1H), 8.60 (d, J = 2.4 Hz, 1H), 4.18 (t, J = 7.2 Hz, 2H), 3.98- 3.95 (m, 2H), 3.72 (s, 3H), 3.42-3.37 (m, 2H), 1.73 (d, J = 12.8 Hz, 2H), 1.67 (t, J = 7.2 Hz, 2H), 1.58 (s , 1H), 1.43-1.33 (m, 2H). MS-ESI calculated value [M+H] ⁺ 291, found value 291.

Example 68.

3-((4-methoxycyclohexyl)methyl)-1-methylpteridine-2,4-dione.

first step.

3-((4-methoxycyclohexyl)methyl)-1-methylpteridine-2,4-dione.

Combine (4-methoxycyclohexyl) methyl methanesulfonate (162 mg, 0.729 mmol), 1-methylpteridine-2,4-dione (100 mg, 0.561 mmol) and potassium carbonate (233 mg, 1.68 mmol) ) Was dissolved in N , N -dimethylformamide (5mL), potassium iodide (9.3mg, 0.056mmol) was added, and the reaction solution was stirred at 120°C for 3 hours. The reaction solution was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure, and the crude product was purified by preparative high performance liquid chromatography to obtain the product 3-((4-methoxycyclohexyl)methyl)-1-methylpteridine-2,4-dione (19.0mg), Yield: 11%. ¹ H NMR: (400 MHz, CDCl ₃ ) δ = 8.64 (d, J = 2.0 Hz, 1H), 8.59 (d, J = 2.0 Hz, 1H), 4.03 (d, J = 7.2 Hz, 2H), 3.72 ( s, 3H), 3.34 (s, 3H), 3.15-3.09 (m, 1H), 2.08-2.06 (m, 2H), 1.90-1.84 (m, 1H), 1.77 (d, J =10.0Hz, 2H) , 1.20-1.13 (m, 4H). MS-ESI calculated value [M+H] ⁺ 305, found value 305.

Example 69.

1-methyl-3-((3-methylpyridin-3-yl)methyl)pyrimido[4,5-d]pyrimidine-2,4-dione.

first step.

1-methylpyrimido[4,5-d]pyrimidine-2,4-dione.

6-Amino-1-methylpyrimidine-2,4-dione (3.50g, 24.8mmol) was added to formamide (5.00g, 111mmol), and the reaction solution was heated to 180°C and stirred for 3 hours. Filter to room temperature, add water (10 mL) to the filtrate and stir, and filter again to obtain 1-methylpyrimido[4,5-d]pyrimidine-2,4-dione (1.60 g, light yellow solid), producing The rate is 36%. ¹ H NMR: (400 MHz, DMSO- d ₆ ) δ=9.16 (s, 1H), 9.08 (s, 1H), 3.43 (s, 3H).

The second step.

1-methyl-3-((3-methylpyridin-3-yl)methyl)pyrimido[4,5-d]pyrimidine-2,4-dione.

Dissolve 1-methylpyrimido[4,5-d]pyrimidine-2,4-dione (300mg, 1.68mmol) in N , N -dimethylformamide (8mL) and add 3 at 25°C. -(Chloromethyl)-3-methyloxetane (403 mg, 1.85 mmol), potassium carbonate (465 mg, 3.37 mmol) and potassium iodide (335 mg, 2.02 mmol). The reaction solution was heated to 120°C and stirred for 16 hours. The reaction solution was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by high-performance liquid chromatography to obtain 1-methyl-3-((3-methylpyridin-3-yl)methyl)pyrimido[4,5-d]pyrimidine-2 , 4-diketone (135 mg), yield: 31%. ¹ H NMR: (400 MHz, CDCl ₃ ) δ = 9.29 (s, 1H), 9.16 (s, 1H), 4.73 (d, J = 6.4 Hz, 2H), 4.29 (d, J = 6.4 Hz, 2H), 4.22 (s, 2H), 3.69 (s, 3H), 1.39 (s, 3H). MS-ESI calculated value [M+H] ⁺ 263, found value 263.

Example 70.

3-((3-ethyloxetan-3-yl)methyl)-1-methylpyrimido[4,5-d]pyrimidine-2,4-dione.

first step.

3-((3-ethyloxetan-3-yl)methyl)-1-methylpyrimido[4,5-d]pyrimidine-2,4-dione.

1-Methylpyrimido[4,5-d]pyrimidine-2,4-dione (60mg, 0.337mmol) was dissolved in N , N -dimethylformamide (4mL) and added at 25°C ( 3-ethyloxetane-3-yl)methyl methanesulfonate (71.0 mg, 0.370 mmol), potassium iodide (11.0 mg, 0.0674 mmol) and potassium carbonate (93.0 mg, 0.673 mmol), the reaction solution is heated At 120°C, stir for 16 hours. The reaction solution was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by preparative high performance liquid chromatography to obtain the product 3-((3-ethyloxetan-3-yl)methyl)-1-methylpyrimido[4,5-d ] Pyrimidine-2,4-dione (43.0 mg), yield: 46%. ¹ H NMR: (400 MHz, CDCl ₃ ) δ = 9.31 (s, 1H), 9.17 (s, 1H), 4.61 (d, J = 6.4 Hz, 2H), 4.34 (d, J = 6.4 Hz, 2H), 4.18 (s, 2H), 3.71 (s, 3H), 1.81 (q, J = 7.2 Hz, 2H), 1.08 (t, J = 7.2 Hz, 3H). MS-ESI calculated value [M+H] ⁺ 277, found value 277.

Example 71.

1-methyl-3-((tetrahydrofuran-3-yl)methyl)pyrimido[4,5-d]pyrimidine-2,4-dione.

first step.

1-methyl-3-((tetrahydrofuran-3-yl)methyl)pyrimido[4,5-d]pyrimidine-2,4-dione.

Dissolve 1-methylpyrimido[4,5-d]pyrimidine-2,4-dione (50.0mg, 0.281mmol) in N , N -dimethylformamide (4mL) and add at 25°C (Tetrahydrofuran-3-yl) methyl methanesulfonate (56.0 mg, 0.308 mmol), potassium iodide (9.0 mg, 0.056 mmol) and potassium carbonate (78.0 mg, 0.561 mmol), the reaction solution was heated to 120° C. and stirred for 16 hours . The reaction solution was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by preparative high performance liquid chromatography to obtain the product 1-methyl-3-((tetrahydrofuran-3-yl)methyl)pyrimido[4,5-d]pyrimidine-2,4-di Ketone (45.0 mg), yield: 61%. ¹ H NMR: (400 MHz, CDCl ₃ ) δ = 9.30 (s, 1H), 9.15 (s, 1H), 4.23-4.14 (m, 1H), 4.11-4.03 (m, 1H), 3.99-3.92 (m, 1H), 3.85-3.75 (m, 2H), 3.69 (s, 3H), 3.64-3.59 (m, 1H), 2.82-2.70 (m, 1H), 2.06-1.96 (m, 1H), 1.80-1.64 ( m, 1H). MS-ESI calculated value [M+H] ⁺ 263, found value 263.

Example 72.

1-methyl-3-((tetrahydropiperan-4-yl)methyl)pyrimido[4,5-d]pyrimidine-2,4-dione.

first step.

1-methyl-3-((tetrahydropiperan-4-yl)methyl)pyrimido[4,5-d]pyrimidine-2,4-dione.

Dissolve 1-methylpteridine-2,4-dione (60.0 mg, 0.337 mmol) in N , N -dimethylformamide (4 mL) and add (tetrahydropyran-4- Methyl) methanesulfonate (72.0 mg, 0.370 mmol), potassium iodide (11.0 mg, 0.674 mmol) and potassium carbonate (93.0 mg, 0.674 mmol). The reaction solution was heated to 120° C. and stirred for 16 hours. The reaction solution was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by preparative high performance liquid chromatography to obtain the product 1-methyl-3-((tetrahydropiperan-4-yl)methyl)pyrimido[4,5-d]pyrimidine-2,4-dione ( 43.0 mg), yield: 46%. ¹ H NMR: (400 MHz, CDCl ₃ ) δ = 9.30 (s, 1H), 9.15 (s, 1H), 4.02-3.94 (m, 4H), 3.69 (s, 3H), 3.38-3.30 (m, 2H) , 2.15-2.03 (m, 1H), 1.67-1.58 (m, 2H), 1.54-1.44 (m, 2H). MS-ESI calculated value [M+H] ⁺ 277, found value 277.

Example 73.

1-methyl-3-(2-(tetrahydropiperan-4-yl)ethyl)pyrimido[4,5-d]pyrimidine-2,4-dione.

first step.

1-methyl-3-(2-(tetrahydropiperan-4-yl)ethyl)pyrimido[4,5-d]pyrimidine-2,4-dione.

Combine 2-(tetrahydropiperan-4-yl)ethyl methanesulfonate (117 mg, 0.561 mmol), 1-methylpyrimido[4,5-d]pyrimidine-2,4-dione (100.0 mg , 0.561 mmol) and potassium carbonate (233 mg, 1.68 mmol) were dissolved in N , N -dimethylformamide (5 mL), potassium iodide (4.7 mg, 0.028 mmol) was added, and the reaction solution was stirred at 120°C for 3 hours. The reaction solution was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure, and the crude product was purified by preparative high performance liquid chromatography to obtain the product 1-methyl-3-(2-(tetrahydropiperan-4-yl)ethyl)pyrimido[4,5-d]pyrimidine- 2,4-Dione (49.0mg), yield: 30%. ¹ H NMR: (400 MHz, CDCl ₃ ) δ = 9.32 (s, 1H), 9.17 (s, 1H), 4.13 (t, J = 7.2 Hz, 2H), 4.01-3.97 (m, 2H), 3.71 (s , 3H), 3.41 (t, J =10.8 Hz, 2H), 1.75-1.69 (m, 2H), 1.67-1.63 (m, 2H), 1.60 (s, 1H), 1.42-1.36 (m, 2H). MS-ESI calculated value [M+H] ⁺ 291, found value 291.

Example 74.

3-((4-methoxycyclohexyl)methyl)-1-methylpyrimido[4,5-d]pyrimidine-2,4-dione.

first step.

3-((4-methoxycyclohexyl)methyl)-1-methylpyrimido[4,5-d]pyrimidine-2,4-dione.

(4-Methoxycyclohexyl) methyl methanesulfonate (81.1 mg, 0.364 mmol), 1-methylpyrimido[4,5-d]pyrimidine-2,4-dione (50.0 mg, 0.280 mmol) and potassium carbonate (38.7 mg, 0.280 mmol) were dissolved in N , N -dimethylformamide (5 mL), potassium iodide (46.5 mg, 0.280 mmol) was added, and the reaction solution was stirred at 120° C. for 3 hours. The reaction solution was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure, and the crude product was purified by preparative high performance liquid chromatography to obtain the product 3-((4-methoxycyclohexyl)methyl)-1-methylpyrimido[4,5-d]pyrimidine-2,4 -Diketone (53.0 mg), yield: 62%. ¹ H NMR: (400 MHz, Methonal- d ₄ ) δ = 9.20 (s, 1H), 9.13 (s, 1H), 3.93 (d, J = 7.2 Hz, 2H), 3.67 (s, 3H), 3.35 (s , 3H), 3.22-3.16 (m, 1H), 2.10-2.07 (m, 2H), 1.84-1.78 (m, 3H), 1.21-1.08 (m, 4H). MS-ESI calculated value [M+H] ⁺ 305, found value 305.

Experimental Example 1: Evaluation of PDE2 phosphodiesterase inhibitory activity in vitro.

Purpose: to detect the AMP / GMP concentration in the reaction system is generated, calculating PDE2 phosphodiesterase inhibition test compounds IC ₅₀ value of the detection antibody substituted AMP / GMP AlexaFluor 633 fluorescent dye via fluorescent polarization assay.

Experimental material: Assay buffer solution: 10 mM Tris-HCl, pH 7.5, 5 mM MgCl ₂ , 0.01% Brij 35, 1 mM DTT and 1% DMSO.

Enzymes: The recombinant full-length human PDE2A protein was expressed in insect Sf9 cells with baculovirus using the N-terminal GST tag.

Substrate: 1 μM cGMP.

Detection methods: Transcreener ^® AMP ² /GMP ² antibody, AMP ² /GMP ² AlexaFluor 633 fluorescent dye.

Experimental operation: Dispense the freshly prepared buffer solution into the enzyme solution, and then add it to the reaction well. Add the DMSO solution of the test compound via the Echo550 non-contact nano-upgrade sonic pipetting system, and then pre-incubate at room temperature for 10 minutes. The substrate (1 μM cGMP) initiates the reaction and reacts at room temperature for one hour. Then add a detection system (Transcreener® AMP ² /GMP ² antibody, AMP ² /GMP ² AlexaFluor 633 fluorescent dye), react at room temperature for 90 minutes, and then use Ex/Em 620/688 to detect the fluorescence polarization.

Via a polarized fluorescence intensity in terms of AMP / GMP nM concentration to a standard curve, and then to calculate the relative activity of inhibition relative to DMSO blank, and the value of IC _{50 was} calculated using Prism Curve software package (GraphPad Software, San Diego California, USA).

Experimental results:

Conclusion: The compounds of the present invention have significant or unexpected PDE2A protease inhibitory activity.

Experimental Example 2: In vitro evaluation of the effect of compounds on TNF-α in the blood of rats induced by LPS.

Experimental purpose: To detect the effect of compounds on LPS-induced TNF-α in rat blood in vitro and to evaluate the inhibitory effect of compounds on LPS-induced TNF-α in rat blood.

Experimental materials: Sprague Dawley rats (male, 210~260g, 8~10 weeks old, Shanghai Slake); and Rat TNF-alpha Quantikine ELISA Kit (R&D, #SRTA00).

Experimental operation: Prepare a test compound solution with a concentration of 1 mM, and add 40 ul (final compound concentration of 100 uM) to 48-well cell culture plates. After the rats were anesthetized with isoflurane, blood was collected from the heart (heparin anticoagulation). Add blood to the 48-well plate to which the test compound has been added, 320ul per well. Place the 48-well plate in the cell incubator, remove after 30 minutes of incubation, add 40ul LPS The solution (100ug/ml) was mixed and placed in an incubator to continue incubation. After 5 hours, the 48-well plate was taken out, and the blood sample was transferred to a 1.5ml centrifuge tube, placed in a centrifuge and centrifuged (4,500rpm, 4°C, 5minutes). The upper layer was separated to obtain plasma. The next day, according to the kit instructions, the R&D ELISA kit was used to detect TNF-α levels in plasma samples.

Experimental results:

Conclusion: The compounds of the present invention have significant or unexpected TNF-α inhibitory activity.

Claims (14)

A compound represented by formula (I), its tautomer or a pharmaceutically acceptable salt thereof,

Among them, ring B is optionally substituted with 1 to 3 R

L is C _1-3 alkyl optionally substituted with 1 to 2 R; ring A is selected from 5 to 6 membered aryl or heteroaryl optionally substituted with 1 or 2 R ₁ ; R _{1 is} selected from halogen , OH, NH ₂ , optionally substituted with 1 to 3 R ₂ : C _1-6 alkyl or heteroalkyl, 3 to 6 membered cycloalkyl or heterocycloalkyl, substituted by 3 to 6 membered cycloalkyl Or heterocycloalkyl substituted C _1-6 alkyl or heteroalkyl; R _{2 is} selected from halogen, OH, NH ₂ , Me, CF ₃ , OMe, OCF ₃ ; the hetero represents a heteroatom, selected from O, S , N, the number of heteroatoms on each heteroalkyl or heterocycloalkyl group is independently selected from 1, 2, or 3; R is selected from halogen, N(R')(R'), optionally 1~3 C _1-3 alkyl or heteroalkyl substituted with R′; and R′ is selected from H, halogen, NH ₂ , Me, CF ₃ , OMe, OCF ₃ . The compound according to claim 1, its tautomer or a pharmaceutically acceptable salt thereof, wherein R _{1 is} selected from halogen, OH, NH ₂ , optionally substituted with 1 to 3 R ₂ : C _1-4 alkyl or heteroalkyl, C _1-3 alkyl or heteroalkyl substituted with 3 to 5 membered cycloalkyl or heterocycloalkyl. The compound according to claim 2, its tautomer or a pharmaceutically acceptable salt thereof, wherein R _{1 is} selected from the group consisting of: Me, CF ₃ , Et, CH ₂ CF ₃ ,

The compound according to claim 1, its tautomer or a pharmaceutically acceptable salt thereof, wherein R is selected from the group consisting of: F, Cl, Br, I, Me,

The compound according to claim 1, a tautomer thereof or a pharmaceutically acceptable salt thereof, wherein the ring B is selected from optionally substituted with 1 to 3 R:

The compound according to claim 4, its tautomer or a pharmaceutically acceptable salt thereof, wherein B is selected from:

The compound according to claim 1, its tautomer or a pharmaceutically acceptable salt thereof, wherein the L is selected from the group optionally substituted by 1 to 2 R: methylene,

The compound according to claim 7, its tautomer or a pharmaceutically acceptable salt thereof, wherein L is selected from methylene,

The compound according to claim 1, its tautomer or a pharmaceutically acceptable salt thereof, ring A is selected from those optionally substituted by 1 or 2 R ₁ : imidazolyl, pyrazolyl, pyridyl, pyridine Azinyl, pyridazinyl, pyrimidinyl, phenyl. The compound according to claim 9, its tautomer or a pharmaceutically acceptable salt thereof, wherein Ring A is optionally substituted with 1 or 2 R ₁ :

The compound according to claim 10, its tautomer or a pharmaceutically acceptable salt thereof, ring A is selected from:

The compound according to claim 9, its tautomer or a pharmaceutically acceptable salt thereof, structural unit

From:

The compound according to claim 1, its tautomer or a pharmaceutically acceptable salt thereof, wherein the compound is selected from:

. Use of a compound according to any one of claims 1 to 13, a tautomer thereof, or a chemically acceptable salt thereof in the preparation of PDE2 inhibitors and TNF-α inhibitors.