TW201706268A - 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-[alpha] inhibitor, and specifically a compound as shown in the following formula (I), tautomers, and pharmaceutically acceptable salts thereof. (I).

Description

Hydroxyl steroids and their applications

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

Phosphodiesterase (PDE) catalyzes the hydrolysis of the cyclized nucleotides cGMP and cAMP, regulating various physiological responses via intramolecular concentrations that control these two important secondary signal factors. The abnormal regulation of cyclized nucleotides cGMP and cAMP molecules is the cause of many diseases. Several drugs have been used to improve and treat diseases by inhibiting PDE activity, such as PDE5 inhibitors for pulmonary hypertension and PDE4 inhibitors. Arthritis caused by psoriasis. There are currently eleven major classes of phosphodiesterase genes known, each of which can express several subtypes, for a total of more than 100 PDE subtypes. Different subtypes have different structures and different tissue distributions, and the activities of cyclized nucleotides cGMP and cAMP are also very different, and the physiological functions of regulation are also very different.

PDE2 phosphodiesterase can catalyze the hydrolysis of cyclized 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 and is mainly distributed in the heart, central nervous system, liver, adrenal gland, endothelial cells and platelets. PDE2 is involved in the regulation of various physiological activities, such as central learning, memory and cognition; maintaining the basic rhythm of the heart, smooth muscle and endothelial cells; permeability of endothelial cells, regulating inflammation. PDE2 knockout mice directly cause embryonic death. It may be used in various central and cardiovascular diseases and to control inflammatory responses by inhibiting PDE2 activity.

Non-selective PDE inhibitory activities of a variety of natural and synthetic terpenoids have long been discovered, such as caffeine, theophylline, ketoconazole, and the like. Hexaconcone (PDE2 activity) is clinically approved for lower limb paralysis caused by peripheral vascular occlusion. The main role is to reduce blood viscosity, increase red blood cell deformation, and inhibit platelet aggregation. Novel highly selective PDE2 inhibitors have also been reported to control endothelial cell division and angiogenesis, and to improve central cognitive impairment. However, the development and application of the new novel selective PDE2 inhibitors are still very limited, and the discovery and application of new PDE2 inhibitors have broad prospects.

Tumor necrosis factor alpha (TNF-α) is a cytokine with many biological activities, which has an important impact on the occurrence, development and outcome of many diseases. TNF-α is mainly produced by monocytes and macrophage cell lines 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 surveillance, 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, increase endothelial cell permeability, up-regulate adhesion molecule expression, and initiate White blood cells and eosinophils, and induce the secretion of acute phase substances and tissue degrading enzymes by bone synovial cells and chondrocytes to promote inflammation. These pathological reactions play a very important role in the 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), and vasculitis. Studies have shown that TNF-α is an ideal target for many of the above IMIDs. The use of TNF-α inhibitors (TNF-α inhibitors) to neutralize excess TNF-α is effective in preventing and treating chronic inflammatory diseases caused by overexpression of TNF-α. The ideal way. PDE2 can regulate the expression of TNF-α in a mechanism, so that the level of TNF-α can be controlled by regulating PDE2 activity, thereby controlling the inflammatory response.

The present invention provides a compound of the formula (I), a tautomer thereof or a pharmaceutically acceptable salt thereof, (I) where the structural unit Can be replaced by Ring A is selected from a 5-6-membered aryl or heteroaryl group optionally substituted by 1 or 2 R ₁ ; G is selected from 5 to 9-membered aromatic or heteroaryl optionally substituted by 1 to 3 R ring, , , Or optionally substituted by 1 to 3 R One of X is selected from C(R) ₂ or a single bond, and the remaining X is selected from C(R) ₂ , N(R), O, S, C(=O), S(=O), S(=O ₂ , -C(=O)N(R)-; one of Y is selected from C(R) ₂ or a single bond, and at least two of the other four Y are independently selected from heteroatoms or heteroatoms, and the remaining Y Is C(R) ₂ ; the hetero atom represents a hetero atom or a hetero atom, and is independently selected from N(R), O, S, C(=O), S(=O), S(=O) ₂ , -C(=O)N(R)-, the number of heteroatoms on each of the defined groups is independently selected from 1, 2 or 3; , , , And R ₁ are each independently selected from H, halogen, OH, NH ₂ , optionally substituted by 1 to 3 R ₂ : C _1-6 alkyl or heteroalkyl, 3 to 6-membered cycloalkyl or heterocyclic ring; alkyl, 3-6 membered cycloalkyl or heterocycloalkyl C _1-6 alkyl, or substituted heteroalkyl, substituted cycloalkyl of 5 to 6-membered aryl or heteroaryl group or C _1-6 alkyl Heteroalkyl; R _{2 is} selected from the group consisting of halogen, OH, NH ₂ , Me, CF ₃ , OMe, OCF ₃ ; When optionally, R _{1 is} bonded to G to form a spiro ring; R is selected from H, halogen, N(R')(R'), C _1-3 alkane optionally substituted by 1 to 3 R' Or a heteroalkyl group; R' is selected from the group consisting of H, halogen, NH ₂ , Me, CF ₃ , OMe, OCF ₃ .

In one embodiment of the invention, the above R ₁ are each independently selected from the group consisting of H, halogen, OH, NH ₂ , optionally substituted by 1 to 3 R ₂ : C _1-4 alkyl or heteroalkyl, 3 to 5 a cycloalkyl or heterocycloalkyl group, a C _1-3 alkyl or heteroalkyl group substituted by a 3- to 6-membered cycloalkyl or heterocycloalkyl group, substituted by a 5- to 6-membered cycloaryl or heteroaryl group; C _1-3 alkyl or heteroalkyl.

In one aspect of the invention, the above R ₁ are each independently selected from the group consisting of H, halogen, OH, NH ₂ , optionally substituted with 1 to 3 R ₂ : Me, , , , , , , , , , , .

In one aspect of the invention, the above R _{1 is} selected from the group consisting of: H, halogen, OH, NH ₂ , Me, , , , , , , , , , , , , .

In one aspect of the invention, the above L is selected from , , , , CH ₂ , , , .

In one embodiment of the invention, the ring A is selected from the group consisting of, preferably, substituted by 1 or 2 R ₁ : pyrrolyl, pyrazolyl, imidazolyl, pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl, Phenyl.

In one embodiment of the invention, the ring A is selected from the group consisting of optionally substituted by 1 or 2 R ₁ : , , , , , , , , , , .

In one aspect of the invention, the ring A is selected from the group consisting of: , , , , , , , , , , , , , , , , , , , , , , , , , , .

In one aspect of the invention, the structural unit From: , , , , , , , , , , , , , , , , , , , , , , , , , , .

In one aspect of the invention, the above R _{1 is} bonded to G to form a spiro ring selected from the group consisting of , .

In one aspect of the invention, the above R is selected from the group consisting of: H, Me, , , , .

In one aspect of the invention, the G is selected from the group consisting of , , , Or optionally substituted by 1 to 3 R: imidazolyl, pyrazolyl, thiazolyl, isoxazolyl, oxazolyl, 1,3,4-oxadiazolyl, 2H-1, 2,3- Triazolyl, 1H-1,2,3-triazolyl, 2H-tetrazolyl, 1H-tetrazolyl, pyridyl, benzofuranyl, fluorenyl, benzothiazolyl, 4,5,6 , 7-tetrahydro-2H-carbazolyl.

In one aspect of the invention, the G is selected from the group consisting of: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , .

a compound of the invention selected from the group consisting of

The invention also provides the use of the above compounds, their tautomers or chemically acceptable salts thereof for the preparation of PDE2 inhibitors and TNF-α inhibitors.

Related definitions.

Unless otherwise stated, the following terms and phrases as used herein are intended to have the following meanings. A particular term or phrase should not be considered undefined or unclear without a particular definition, but should be understood in the ordinary sense. When a trade name appears in this document, it is intended to refer to its corresponding commodity 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 is intended to mean that the compounds, materials, compositions and/or dosage forms are within the scope of sound 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 invention prepared from a compound having a particular substituent found in the present invention and a relatively non-toxic acid or base. When a relatively acidic functional group is contained in the compound of the present invention, a base addition salt can be obtained by contacting a neutral form of such a compound with a sufficient amount of a base in a neat solution or a suitable inert solvent. Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic ammonia or magnesium salts or similar salts. When a relatively basic functional group is contained in the compound of the present invention, an acid addition salt can be obtained by contacting a neutral form of such a compound with a sufficient amount of an acid in a neat 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, hydrogencarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, Hydrogen sulfate, hydroiodic acid, phosphorous acid, etc.; and an organic acid salt, such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, Similar acids such as fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, and methanesulfonic acid; and salts of amino acids (such as arginine, etc.) And salts of organic acids such as glucuronic acid (see Berge et al., "Pharmaceutical Salts", Journal of Pharmaceutical Science 66: 1-19 (1977)). Certain specific compounds of the invention contain both basic and acidic functional groups which can be converted to any base or acid addition salt.

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

As used herein, "pharmaceutically acceptable salts" are derivatives of the compounds of the invention wherein the parent compound is modified by salt formation with an acid or with a base. Examples of pharmaceutically acceptable salts include, but are not limited to, inorganic or organic acid salts of bases such as amines, alkali metal or organic salts of acid groups such as carboxylic acids, and the like. Pharmaceutically acceptable salts include the conventional non-toxic salts or quaternary ammonium salts of the parent compound, for example salts formed from non-toxic inorganic or organic acids. Conventional non-toxic salts include, but are not limited to, those derived from inorganic acids and organic acids selected from the group consisting of 2-ethyloxybenzoic acid, 2-hydroxyethanesulfonic acid, acetic acid, ascorbic acid. , benzenesulfonic acid, benzoic acid, hydrogencarbonate, carbonic acid, citric acid, edetic acid, ethane disulfonic acid, ethanesulfonic acid, fumaric acid, glucoheptose, gluconic acid, glutamic acid, glycolic acid , hydrobromic acid, hydrochloric acid, hydroiodide, hydroxyl, hydroxynaphthalene, isethionethane, lactic acid, lactose, dodecyl sulfonic acid, maleic acid, malic acid, mandelic acid, methane sulfonic acid, nitric acid, oxalic acid , pamoic acid, pantothenic acid, phenylacetic acid, phosphoric acid, polygalacturaldehyde, propionic acid, salicylic acid, stearic acid, acetic acid, succinic acid, sulfamic 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 the parent compound containing an acid group or a base via conventional chemical methods. In general, such salts are prepared by reacting these compounds in water or an organic solvent or a mixture of the two via a free acid or base form with a stoichiometric amount of a suitable base or acid. Generally, a nonaqueous medium such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile is preferred.

In addition to the form of the salt, the compounds provided herein also exist in the form of prodrugs. Prodrugs of the compounds described herein are readily chemically altered under physiological conditions to convert to the compounds of the invention. Furthermore, prodrugs can be converted to the compounds of the invention via chemical or biochemical methods in an in vivo setting.

Certain compounds of the invention may exist in unsolvated or solvated forms, including hydrated forms. In general, the solvated forms are equivalent to the unsolvated forms and are included within the scope of the 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 invention.

Graphical representations of racemates, ambiscalemic and scalemic or enantiomerically pure compounds herein are from Maehr, J. Chem. Ed. 1985, 62: 114-120. 1985, 62: 114-120. The absolute configuration of a stereocenter is indicated by a wedge key and a dashed key unless otherwise stated. When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, they include the E , Z geometric isomers unless otherwise specified. Likewise, all tautomeric forms are included within the scope of the invention.

The compounds of the invention may exist in specific geometric or stereoisomeric forms. The present invention contemplates all such compounds, including the cis and trans isomers, the (-)- and (+)-p-enantiomers, the ( R )- and ( S )-enantiomers, diastereomeric a conformation, a ( D )-isomer, a ( L )-isomer, and a racemic mixture thereof, and other mixtures, such as enantiomerically or diastereomeric enriched mixtures, all of which belong to It is within the scope of the invention. Additional asymmetric carbon atoms may be present in the substituents such as alkyl groups. All such isomers, as well as mixtures thereof, are included within the scope of the invention.

The optically active ( R )- and ( S )-isomers as well as the 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 invention is desired, it can be prepared via asymmetric synthesis or by derivatization with a chiral auxiliary wherein the resulting mixture of diastereomers is separated and the auxiliary group cleaved to provide a pure Enantiomers are required. Alternatively, when a molecule contains a basic functional group (e.g., an amino group) or an acidic functional group (e.g., a carboxyl group), a diastereomeric salt is formed with a suitable optically active acid or base, and then resolved by art. Method The diastereomer is resolved and the pure enantiomer is recovered. Furthermore, the separation of enantiomers and diastereomers is usually carried out via the use of chromatography using a chiral stationary phase and optionally in combination with chemical derivatization (for example an amino group from an amine) Formate).

The compounds of the present invention may contain unnatural proportions of atomic isotopes on one or more of the atoms that make up the compound. For example, radiolabeled compounds can be used, such as tritium ⁽³ H), iodine -125 ⁽¹²⁵ I) or ^C-14 (14 C). Alterations of all isotopic compositions of the compounds of the invention, whether radioactive or not, are included within the scope of the invention.

The term "pharmaceutically acceptable carrier" refers to any formulation or carrier medium that is capable of delivering an effective amount of the active substance of the present invention, does not interfere with the biological activity of the active substance, and has no toxic side effects to the host or patient, including water, oil, vegetables. And minerals, cream bases, lotion bases, ointment bases, and the like. These bases include suspending agents, tackifiers, transdermal enhancers, and the like. Their formulations are well known to those skilled in the cosmetic or topical pharmaceutical arts. For additional information on vectors, reference is 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 vehicle required to formulate an effective pharmaceutical composition.

For a pharmaceutical or pharmacologically active agent, the term "effective amount" or "therapeutically effective amount" means a sufficient amount of a drug or agent that is non-toxic but achieves the desired effect. For the oral dosage form of the present invention, the "effective amount" of an active substance in the composition means 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 will vary from person to person, depending on the age and general condition of the recipient, and also on the particular active substance, and a suitable effective amount in a case can be determined by one skilled in the art based on routine experimentation.

The term "active ingredient", "therapeutic agent", "active substance" or "active agent" refers to a chemical entity that is effective in treating 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 variants of heavy hydrogen and hydrogen, as long as the valence of the particular atom is normal and the substituted compound is stable. . When the substituent is a keto group (ie, =0), it means that two hydrogen atoms are substituted. Ketone substitution does not occur on the aryl group. The term "optionally substituted" means that it may or may not be substituted, and unless otherwise specified, the kind and number of substituents may be arbitrary on the basis of chemically achievable.

When any variable (e.g., R) occurs more than once in the composition or structure of the compound, its definition in each case is independent. Thus, for example, if a group is substituted with 0-2 R, the group may optionally be substituted with at most two R, and each case has an independent option. Furthermore, combinations of substituents and/or variants thereof are permissible only if such combinations result in stable compounds.

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

When a 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 recited substituents are not indicated by which atom is attached to a compound included in the chemical structural formula, but not specifically mentioned, such a substituent may be bonded via any atomic phase thereof. Combinations of substituents and/or variants thereof are permissible only if such combinations result in stable compounds. For example, a structural unit or It is indicated that it can be substituted at any position on the cyclohexyl or cyclodiene.

The substituents of the alkyl and heteroalkyl radicals are generally referred to as "alkyl substituents" and may be selected from 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 fluoro(C ₁ -C ₄ )alkyl The number of substituents is 0 to (2m'+1), where m' is the total number of carbon atoms in such an atomic group. R', R", R"', R'''', and R''''' Each independently preferably hydrogen, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl (eg substituted by 1 to 3 halogen aryl), substituted or unsubstituted alkyl, alkane An oxy group, a thioalkoxy group or an aralkyl group. When the compound of the present invention includes more than one R group, for example, each R group is independently selected as if present Each of these groups of R', R", R"', R'''' and R'''' groups. When R' and R" are attached to the same nitrogen atom, they It can be combined 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. In light of the above discussion of substituents, those skilled in the art will appreciate that the term "alkyl" is intended to include carbon. a group bonded to a non-hydrogen group such as a haloalkyl group (e.g., -CF ₃ , -CH ₂ CF ₃ ) and a mercapto group (e.g., -C(O)CH ₃ , -C(O)CF ₃ , -C(O)CH ₂ OCH _{3 ,} etc.).

Similar to the substituents of the alkyl group, the aryl and heteroaryl substituents are generally collectively referred to as "aryl substituents" 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, etc., the number of substituents is 0 To the total number of open valencies on the aromatic ring; wherein R', R", R"', R"" and R""' are independently preferred from hydrogen, substituted or unsubstituted alkyl, substituted or not a substituted heteroalkyl group, a substituted or unsubstituted aryl group, and a substituted or unsubstituted heteroaryl group. When the compound of the present invention includes more than one R group, for example, each R group is Each of these groups is selected independently as when more than one R', R", R"', R"" and R"" group are present.

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-, wherein T and U are independently selected From -NR-, -O-, CRR'- or a single bond, q is an integer from 0 to 3. Alternatively, 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-, wherein A and B are independently selected From -CRR'-, -O-, -NR-, -S-, -S(O)-, S(O) ₂ -, -S(O) ₂ NR'- or a single bond, r is 1 to 4 The integer. Optionally, a single bond on the new ring thus formed can be replaced with a double bond. Alternatively, 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-, wherein s and d are each 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 each independently preferably selected from hydrogen and substituted or unsubstituted (C ₁ -C ₆ )alkyl.

Unless otherwise specified, the term "halo" or "halogen" by itself or as part of another substituent denotes a fluorine, chlorine, bromine or iodine atom. Further, 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, and the like. Wait.

Examples of haloalkyl groups include, but are not limited to, trifluoromethyl, trichloromethyl, pentafluoroethyl, and pentachloroethyl. "Alkoxy" represents the above alkyl group having a specified number of carbon atoms attached via an oxygen bridge. The C _1-6 alkoxy group includes a 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, bis-butoxy, tert-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 hydrocarbon chains in a straight or branched configuration wherein one or more carbon-carbon double bonds, such as vinyl and propylene groups, are present at any stable site on the chain.

The term "halo" or "halogen" means fluoro, chloro, bromo and iodo.

Unless otherwise specified, the term "hetero" means a hetero atom or a hetero atomic group (ie, a radical containing a hetero atom), including atoms other than carbon (C) and hydrogen (H), and atomic groups containing such heteroatoms, including, for example, oxygen (O). ), nitrogen (N), sulfur (S), antimony (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 substituted or unsubstituted cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, cycloalkynyl, heterocycloalkynyl, aryl or heteroaryl. So-called rings include single rings, interlocking rings, spiral rings, parallel rings or bridge rings. The number of atoms on the ring is usually defined as the number of elements of the ring. For example, "5 to 7-membered ring" means that 5 to 7 atoms are arranged in a circle. Unless otherwise specified, the ring optionally contains from 1 to 3 heteroatoms. Therefore, the "5- to 7-membered ring" includes, for example, a phenyl group, a pyridine group and an acridinyl group; on the other hand, the term "5- to 7-membered heterocycloalkyl ring" includes a pyridyl group and an acridinyl group, but does not include a phenyl group. 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 monocyclic, bicyclic or tricyclic ring containing a hetero atom or a heteroatom group which may be saturated, partially unsaturated or unsaturated ( Aromatic) which comprise a carbon atom and 1, 2, 3 or 4 ring heteroatoms independently selected from N, O and S, wherein any of the above heterocycles may be fused to a phenyl ring to form a bicyclic ring. The nitrogen and sulfur heteroatoms can be optionally oxidized (i.e., NO and S(O)p). The nitrogen atom can be substituted or unsubstituted (i.e., N or NR, wherein R is H or other substituents as already defined herein). The heterocyclic ring can be attached to the side groups of any hetero atom or carbon atom to form a stable structure. If the resulting compound is stable, the heterocycles described herein can undergo substitutions at the carbon or nitrogen sites. The nitrogen atom in the heterocycle is optionally quaternized. A preferred embodiment 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 embodiment is that the total number of S and O atoms in the heterocycle does not exceed one. The term "aromatic heterocyclic group" or "heteroaryl" as used herein means a stable 5, 6, or 7 membered monocyclic or bicyclic or aromatic ring of a 7, 8, 9 or 10 membered bicyclic heterocyclic group. It contains carbon atoms and 1, 2, 3 or 4 ring heteroatoms independently selected from N, O and S. The nitrogen atom can be substituted or unsubstituted (i.e., N or NR, wherein R is H or other substituents as already defined herein). The nitrogen and sulfur heteroatoms can be optionally oxidized (i.e., 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 one. Bridged rings are also included in the definition of heterocycles. A bridged ring is formed when one or more atoms (ie, C, O, N, or S) join two non-adjacent carbon or nitrogen atoms. Preferred bridged 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 three ring. In the bridged ring, a substituent on the ring can also be present on the bridge.

Examples of heterocyclic compounds include, but are not limited to, acridinyl, octanoyl, benzimidazolyl, benzofuranyl, benzofuranylfuranyl, benzindenylphenyl, benzoxazolyl, benzimidin Oxazolinyl, benzothiazolyl, benzotriazolyl, benzotetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolyl, oxazolyl, 4a H -carbazolyl , porphyrin, chroman, chromene, porphyrin-decahydroquinolinyl, 2 H , 6 H -1,5,2-dithiazinyl, dihydrofuran [2,3 - b ] tetrahydrofuranyl, furyl, furfuryl, imidazolidinyl, imidazolinyl, imidazolyl, 1 H -carbazolyl, nonenyl, indanyl, mesoindolyl, fluorenyl , 3 H -fluorenyl, isatin, isobenzofuranyl, pyran, isodecyl, isoindoline, isodecyl, fluorenyl, isoquinolyl, isothiazolyl, Isoxazolyl, methylenedioxyphenyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4- Oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, isoxazole , hydroxydecyl, pyrimidinyl, phenanthryl, phenanthroline, phenazine, phenothiazine, benzoxanthyl, phenoloxazinyl, pyridazinyl, pyridazinyl, acridinyl, acridine Keto, 4-acridone, piperonyl, pteridinyl, fluorenyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole , pyridoimidazole, pyridylthiazole, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2 H -pyrrolyl, pyrrolyl, pyrazolyl, quinazolinyl, quinolinyl, 4 H -quinolizine , quinoxalinyl, quinuclidinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolyl, tetrazolyl, 6 H -1,2,5-thiadiazinyl, 1,2, 3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thioxyl, thiazolyl, isothiazolyl Thienyl, thienyl, thienooxazolyl, thienothiazolyl, thienoimidazolyl, thienyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1 , 2,5-triazolyl, 1,3,4-triazolyl and xanthene. Also included are fused ring and spiro compounds.

Unless otherwise specified, the term "hydrocarbyl" or its subordinate concept (such as alkyl, alkenyl, alkynyl, phenyl, etc.), by itself or as part of another substituent, is meant to be straight-chain, branched or cyclic. The hydrocarbon radical or a combination thereof may be fully saturated, mono- or polyunsaturated, may be monosubstituted, disubstituted or polysubstituted, and may be monovalent (such as methyl), divalent (such as methylene) or polyvalent (methine), may include a divalent or polyvalent radical having the specified number of carbon atoms (e.g., C ₁ -C ₁₀ represents 1 to 10 carbons). "Hydrohydrocarbyl" includes, but is not limited to, aliphatic hydrocarbyl groups including chain and cyclic, including but not limited to alkyl, alkenyl, alkynyl groups including, but not limited to, 6-12 members. An aromatic hydrocarbon group such as benzene, naphthalene or the like. In some embodiments, the term "hydrocarbyl" means a straight or branched chain radical or a combination thereof, which may be fully saturated, unitary or polyunsaturated, and may include divalent and multivalent radicals. Examples of saturated hydrocarbon radicals include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, secondary butyl, isobutyl, cyclohexyl, (ring Hexyl) methyl, cyclopropylmethyl, and homologs or isomers of radicals such as n-pentyl, n-hexyl, n-heptyl, n-octyl. The unsaturated alkyl group has one or more double or triple bonds, and examples thereof include, but are not limited to, a vinyl group, a 2-propenyl group, a butenyl group, a crotyl group, a 2-isopentenyl group, and a 2-(butadienyl group). ), 2,4-pentadienyl, 3-(1,4-pentadienyl), ethynyl, 1- and 3-propynyl, 3-butynyl, and higher homologs and Structure.

Unless otherwise specified, the term "heterohydrocarbyl" or its subordinate concept (such as heteroalkyl, heteroalkenyl, heteroalkynyl, heteroaryl, etc.), by itself or in combination with another term, means a stable straight chain, branched chain. Or a cyclic hydrocarbon radical or a combination thereof having a number of carbon atoms and at least one heteroatom. In some embodiments, the term "heteroalkyl", by itself or in conjunction with another term, refers to a stable linear, branched hydrocarbon radical or combination thereof, having a number of carbon atoms and at least one heteroatom. In a typical embodiment, the heteroatoms are selected from the group consisting of B, O, N, and S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen heteroatoms are optionally quaternized. The heteroatom or heteroatom group can be located at any internal position of the heterohydrocarbyl group (including 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 customary expressions and are those which are attached to the remainder of the molecule via an oxygen atom, an amino group or a sulfur atom, respectively. Base group.

Unless otherwise specified, the term "cycloalkyl", "heterocycloalkyl" or its subordinate concept (such as aryl, heteroaryl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, cycloalkynyl) The heterocyclic alkynyl group, etc., by itself or in combination with other terms, respectively represent a cyclized "hydrocarbyl group" or "heterohydrocarbyl group". Further, in the case of a heterohydrocarbyl group or a heterocycloalkyl group (such as a heteroalkyl group or a heterocycloalkyl group), a hetero atom may occupy a position at which the hetero ring is attached to the rest of the molecule. Examples of cycloalkyl groups 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-acridinyl, 2-acridinyl, 3-acridinyl, 4-morpholinyl, 3-morpholinyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrothiophen-2-yl, tetrahydrothiophen-3-yl, 1-pyridazinyl and 2-pyridazinyl.

Unless otherwise specified, the term "aryl" denotes a polyunsaturated, aromatic hydrocarbon substituent which may be monosubstituted, disubstituted or polysubstituted, may be monovalent, divalent or polyvalent, it may be monocyclic or Polycyclic (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 (or ring) containing one to four heteroatoms. In an illustrative example, the heteroatoms are selected from the group consisting of B, N, O, and S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom is optionally quaternized. A heteroaryl group can be attached to the remainder of the molecule via a heteroatom. Non-limiting examples of aryl or heteroaryl groups include phenyl, 1-naphthyl, 2-naphthyl, 4-biphenyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 3-pyridyl Azyl, 2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl, 2-phenyl-4-oxazolyl, 5-oxazolyl, 3-isoxan Azyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thiophene , 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-benzothiazolyl, indolyl, 2-benzimidazolyl, 5-indenyl, 1-isoquinolyl, 5-isoquinolinyl, 2-quinoxalinyl, 5-quinoxalinyl, 3-quinolyl and 6-quinolinyl. The substituents of any of the above aryl and heteroaryl ring systems are selected from the group of acceptable substituents described below.

For simplicity, aryl groups, when used in conjunction with other terms (eg, aryloxy, arylthio, aralkyl), include aryl and heteroaryl rings as defined above. Thus, the term "aralkyl" is intended to include those radicals to which an aryl group is attached to an alkyl group (eg, benzyl, phenethyl, pyridylmethyl, and the like), including wherein the carbon atom (eg, methylene) has been, for example, oxygen. Those alkyl groups substituted by an atom, 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 substituted by another functional group or atom via a substitution reaction (eg, an affinity substitution reaction). For example, representative leaving groups include triflate; chlorine, bromine, iodine; sulfonate groups such as mesylate, tosylate, p-bromobenzenesulfonate, p-toluenesulfonic acid Ester and the like; an oxime group such as an ethoxy group, a trifluoroacetoxy group or the like.

The term "protecting group" includes, but is not limited to, "amino protecting group", "hydroxy protecting group" or "thiol protecting group". The term "amino protecting group" refers to a protecting group suitable for preventing side reactions at the amino nitrogen position. Representative amino protecting groups include, but are not limited to, indolyl; fluorenyl, such as alkane fluorenyl (e.g., ethoxymethyl, trichloroethyl or trifluoroethyl); alkoxycarbonyl, such as tertiary Butoxycarbonyl (Boc); arylmethoxycarbonyl, such as benzyloxycarbonyl (Cbz) and 9-fluorenylmethoxycarbonyl (Fmoc); arylmethyl, such as benzyl (Bn), trityl (Tr , 1,1-di-(4'-methoxyphenyl)methyl; methoxyalkyl, such as trimethylmethanyl (TMS) and tertiary butyl dimethyl methacrylate (TBS), etc. Wait. The term "hydroxy protecting group" refers to a protecting group suitable for preventing the side reaction of a hydroxyl group. Representative hydroxy protecting groups include, but are not limited to, alkyl groups such as methyl, ethyl and tertiary butyl groups; fluorenyl groups such as alkane fluorenyl groups (e.g., ethenyl); arylmethyl groups such as benzyl (Bn) , p-methoxybenzyl (PMB), 9-fluorenylmethyl (Fm) and diphenylmethyl (diphenylmethyl, DPM); formyl, such as trimethylmethanyl (TMS) And tertiary butyl dimethylformamidine (TBS) and the like.

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

All solvents used in the present invention are commercially available and can be used without further purification. The present invention employs the following abbreviations: aq for water; HATU for O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate ; EDC stands for N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride; m-CPBA stands for 3-chloroperoxybenzoic acid; eq stands for equivalent, equivalent; CDI stands for Carbonyldiimidazole; DCM stands for dichloromethane; PE stands for petroleum ether; DIAD stands for diisopropyl azodicarboxylate; DMF stands for N,N-dimethylformamide; DMSO stands for dimethyl hydrazine; EtOAc stands for acetic acid Ethyl ester; EtOH for ethanol; MeOH for methanol; CBz for benzyloxycarbonyl, an amine protecting group; BOC for tertiary carbonyl is an amine protecting group; HOAc for acetic acid; NaCNBH ₃ for sodium cyanoborohydride ; rt stands for room temperature; O/N stands for overnight; THF stands for tetrahydrofuran; Boc ₂ O stands for di-tertiary butyl dicarbonate; TFA stands for trifluoroacetic acid; DIPEA stands for diisopropylethylamine; SOCl ₂ stands for chlorine CS ₂ represents carbon disulfide; TsOH represents p-toluenesulfonic acid; NFSI stands for N-fluoro-N-(phenylsulfonyl)benzenesulfonamide; NCS stands for 1-chloropyrrolidine-2,5-dione; 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 trifluoromethyltrimethylnonane; Ti(Oi-Pr) ₄ represents tetraisopropyl titanate; MSCl represents methanesulfonyl chloride; DMAP stands for N,N-dimethyl-4-aminopyridine; TEA stands for triethylamine; BnBr stands for benzyl bromide; DIEA stands for diisopropylethylamine BH ₃ DMS stands for borane dimethyl sulfide; DMP stands for Des Martin Sodium Periodane; TBAF stands for tetrabutyl fluorinated amine; HOBT stands for 1-hydroxybenzotriazole; AIBN stands for azobisisobutyronitrile; NBS Represents N-bromosuccinimide.

Compounds are named by hand or by ChemDraw® software, and commercial compounds are listed under the supplier's catalogue.

Example 1.

5-(3,7-Dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1 H -indol-1-yl)pentanylamine.

Dissolve 5-(3,7-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1 H -indol-1-yl)valeronitrile (300 mg, 1.03 mmol) Potassium carbonate (272 mg, 1.97 mmol) and hydrogen peroxide (0.5 mL) were added to dimethyl hydrazide (5 mL), and the mixture was stirred at 20 ° C for 12 hours. The reaction was quenched with EtOAc EtOAc (EtOAc (EtOAc) 5-(3,7-Dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1 H -indol-1-yl)pentanylamine (150 mg), yield : 52%.

¹ H NMR: (400 MHz, Methonal- d ₄ ) δ = 8.76 (s, 1H), 4.13 (s, 3H), 4.05-4.04 (m, 2H), 3.58 (s, 3H), 2.54-2.52 (m) , 2H), 1.75-1.73 (m, 4H). MS-ESI calcd [M+H] ⁺ 280.

Example 2.

5-(3,7-Dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1 H -indol-1-yl)- N , N -dimethylammonium .

5-(3,7-Dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1 H -indol-1-yl) -N -methylpentamidine.

5-(3,7-Dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1 H -indol-1-yl)pentanylamine (200 mg, 0.717 mmol) Dissolved in N , N -dimethylformamide (5 mL), sodium hydrogen (86.0 mg, 2.15 mmol) was added at 0 ° C, and the mixture was stirred at 0 ° C for 0.5 h. Methyl iodide (305 mg, 2.15 mmol) was added, and the mixture was stirred at 25 ° C for 12 hours. The reaction was quenched with EtOAc (EtOAc) (EtOAc (EtOAc) 7-Dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-indol-1-yl) -N , N -dimethylvaleramide (product 1) (50.0 Mg), yield: 24%.

¹ H NMR: (400 MHz, Methonal- d ₄ ) δ = 8.35 (s, 1H), 4.06 (s, 3H), 4.04-4.03 (m, 2H), 3.56 (s, 3H), 3.15 (s, 3H) ), 3.00 (s, 3H), 2.55-2.51 (m, 2H), 1.76-1.67 (m, 4H). MS-ESI calcd [M+H] ⁺ 308.

5-(3,7-Dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1 H -indol-1-yl) -N -methylpentamidine (product 2 (50.0 mg), yield: 23%.

¹ H NMR: (400 MHz, Methonal- d ₄ ) δ = 8.54 (s, 1H), 4.09 (s, 3H), 4.05-4.03 (m, 2H), 3.57 (s, 3H), 2.82 (s, 3H) ), 2.39-2.37 (m, 2H), 1.71-1.68 (m, 4H). MS-ESI calcd [M + H] ⁺ 294.

Example 3.

3,7-dimethyl-1- (3- (2-oxo-l-pyrrolidinyl) propyl) -1 H - purine -2,6 (3 H, 7 H) - dione.

first step.

3-(2-Oxopyrrolidin-1-yl)propyl methanesulfonic acid.

1-(3-Hydroxypropyl)pyrrolidin-2-one (200 mg, 1.40 mmol) was dissolved in anhydrous dichloromethane (5 mL). Under nitrogen, triethylamine (282 mg, 2.80 mmol), methanesulfonium chloride (192 mg, 1.68 mmol) was added at 0 °C. The reaction solution was slowly warmed to room temperature and stirred for 2 hours. The reaction was quenched by the addition of water (40 mL). The reaction mixture was extracted with ethyl acetate (30 mL EtOAc). Oxopyrrolidin-1-yl)propyl methanesulfonic acid (164 mg, yellow oil), yield: 53%. MS-ESI calcd for [M + H] ⁺ 222.

The second step.

3,7-dimethyl-1- (3- (2-oxo-l-pyrrolidinyl) propyl) -1 H - purine -2,6 (3 H, 7 H) - dione.

3-(2-Oxopyrrolidin-1-yl)propyl methanesulfonic acid (164 mg, 0.740 mmol) was dissolved in anhydrous N , N -methylcarbamide (5 mL). Under nitrogen, potassium carbonate (205 mg, 1.48 mmol), potassium iodide (13.0 mg, 0.0740 mmol), 2,6-hydroxy-3,7-dimethylindole (160 mg, 0.888 mmol) was added at room temperature. The reaction solution was heated to 130 ° C and stirred for 3 hours. The reaction was quenched by the addition of water (40 mL). The reaction mixture was extracted with ethyl acetate (30 mL×2). EtOAc (EtOAc m. The resulting product is 3,7-dimethyl-1-(3-(2-oxopyrrolidin-1-yl)propyl)-1 H -indole-2,6(3 H ,7 H )-dione (20.0 mg), yield: 10%. MS-ESI calcd [M+H] ⁺ 306, Found 306.

Example 4.

3,7-Dimethyl-1-(3-(2-oxooxazolidin-3-yl)propyl)-1 H -indole-2,6(3 H ,7 H )-dione.

Sodium hydrogen (27.6 mg, 0.690 mmol) was added to a solution of oxazolidin-2-one (68.3 mg, 0.690 mmol) in N , N -dimethylformamide (1 mL). The reaction solution was stirred at 20 ° C for 1 hour. N , N -dimethylformamide of 1-(3-iodopropyl)-3,7-dimethyl-1 H -indole-2,6(3 H ,7 H )-dione (1 The mL) solution was added dropwise to the reaction solution at 0 °C. The reaction mixture was stirred at 20 ° C for 12 hr then cooled to EtOAc (EtOAc) The combined organic layers were washed with brine (10 mL EtOAc) Separation and purification by preparative high performance liquid chromatography gave 3,7-dimethyl-1-(3-(2-oxooxazolidin-3-yl)propyl)-1 H -嘌呤-2,6 (3 H , 7 H )-dione (50.0 mg), Yield: 27%.

¹ H NMR: (400 MHz, Methonal- d ₄ ) δ = 7.85 (s, 1H), 3.95 (s, 3H), 3.92 (s, 3H), 3.61-3.57 (m, 2H), 3.09-3.08 (m, 2H), 2.40-2.34 (m, 2H), 2.28-2.25 (m, 2H), 1.87-1.78 (m, 2H), 1.63-1.60 (m, 1H), 1.24-1.23 (m, 3H). MS-ESI calcd for [M+H] ⁺ 320, found 320.

Example 5.

3,7-Dimethyl-1-(3-(2-oxooxazolidin-3-yl)propyl)-1 H -indole-2,6(3 H ,7 H )-dione.

At 0 ° C, sodium hydroxide (27.6 mg, 0.690 mmol) was added to a oxazolidin-2-one (60.0 mg, 0.690 mmol) in N, N - dimethylformamide (1 mL) solution. The reaction solution was stirred at 20 ° C for 1 hour. N , N -dimethylformamide of 1-(3-iodopropyl)-3,7-dimethyl-1 H -indole-2,6(3 H ,7 H )-dione (1 The mL) solution was added dropwise to the reaction solution at 0 °C. The reaction mixture was stirred at 20 ° C for 12 hr then cooled to EtOAc (EtOAc)EtOAc. The combined organic layers were washed with brine (30 mL EtOAc) Separation and purification by preparative high performance liquid chromatography gave 3,7-dimethyl-1-(3-(2-oxooxazolidin-3-yl)propyl)-1 H -嘌呤-2,6 (3 H , 7 H )-dione (50.0 mg), yield: 28%.

¹ H NMR: (400 MHz, Methonal- d ₄ ) δ = 7.85 (s, 1H), 4.38-4.34 (m, 2H), 3.99-3.97 (m, 2H), 3.95 (s, 3H), 3.69-3.65 ( m, 2H), 3.49 (s, 3H), 3.32-3.29 (m, 2H), 2.21-1.88 (m, 2H). MS-ESI calcd [M+H] ⁺ 308.

Example 6.

1-(2-(1,1-Dioxidemorpholinyl)ethyl)-3,7-dimethyl-1 H -indole-2,6(3 H ,7 H )-dione.

first step.

2-(1,1-Dioxide morpholinyl)ethyl methanesulfonate.

4-(2-Hydroxyethyl)thiomorpholine 1,1-dioxide (300 mg, 1.67 mmol) was dissolved in anhydrous dichloromethane (5 mL). Under nitrogen, triethylamine (423 mg, 4.17 mmol), methanesulfonium chloride (228 mg, 2.01 mmol) was added at 0 °C. The reaction solution was slowly warmed to room temperature and stirred for 2 hours. The reaction was quenched by the addition of water (40 mL). The reaction mixture was extracted with EtOAc. EtOAc (EtOAc m. Methanesulfonate (230 mg, yellow oil), yield: 53%. MS-ESI calcd for [M + H] ⁺ 258.

The second step.

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

2-(1,1-Dioxidemorpholinyl)ethyl methanesulfonate (200 mg, 0.780 mmol) was dissolved in anhydrous N , N -methylcarbamide (5 mL). Nitrogen, room temperature was added potassium carbonate (215 mg, 1.56 mmol), potassium iodide (13.0 mg, 0.0780 mmol), 3,7- dimethyl -1 H - purine -2,6 (3 H, 7 H) - Diketone (168 mg, 0.936 mmol). The reaction solution was heated to 130 ° C and stirred for 3 hours. The reaction was quenched by the addition of water (40 mL ). The reaction mixture was extracted with ethyl acetate (30 mL EtOAc). The resultant was purified by chromatography 1- (2- (1,1-morpholinyl) ethyl) -3,7-dimethyl -1 H - purine -2,6 (3 H, 7 H) - two Ketone (23.0 mg), yield: 10%.

¹ H NMR: (400 MHz, Methonal- d ₄ ) δ = 7.86 (s, 1H), 3.97 (s, 3H), 3.53-3.35 (m, 4H), 3.34 (s, 3H), 2.40-2.36 (m) , 2H), 2.11-2.04 (m, 4H), 1.92-1.88 (m, 2H). MS-ESI calcd for [M + H] ⁺ 342.

Example 7.

3,7-Dimethyl-1-((2-oxo-1-oxa-3-azaspiro[4.5]decane-8-yl)methyl)-1 H -嘌呤-2,6( 3 H , 7 H )-dione.

first step.

Ethyl 4-(2-(tertiary butoxy)-2-oxoethyl)-4-hydroxycyclohexylcarboxylate.

Lithium diisopropylamide (1.6 mL, 2M solution in n-hexane, 3.2 mmol) was added to anhydrous tetrahydrofuran (5 mL) under stirring at -65 ° C, and then tributyl acetate (0.360) was added dropwise. g, 3.08 mmol), after the dropwise addition, the reaction solution was added dropwise to a solution of p-cyclohexanonecarboxylate (0.500 g, 2.93 mmol) in tetrahydrofuran (5 mL), and the mixture was stirred at -65 °C. 1 hour. Diluted with 20 mL of ethyl acetate, and washed with saturated aqueous ammonium chloride (20 mL) and brine (30 mL×2). (5:1 petroleum ether / ethyl acetate, Rf = 0.5) to give ethyl 4-(2-(tert-butoxy)-2-oxoethyl)-4-hydroxycyclohexylcarboxylate (0.650 g, Yellow oil), yield: 78%.

^{1 H NMR: (400MHz, CDCl} 3) δ = 4.15-4.09 (m, 2H), 2.46-2.03 (m, 3H), 2.00-1.54 (m, 8H), 1.50 (s, 9H), 1.26-1.23 ( m, 3H).

The second step.

Ethyl 2-(4-(ethoxycarbonyl)-1-hydroxycyclohexyl)carboxylate.

Ethyl 4-(2-(tertiary butoxy)-2-oxoethyl)-4-hydroxycyclohexylcarboxylate (25.2 g, 0.0880 mol) was dissolved in anhydrous dichloromethane (200 mL). Trifluoroacetic acid (100 g, 0.880 mol) was added dropwise at 0 ° C, and the reaction mixture was stirred at 0 ° C for 1 hour and then allowed to react at room temperature for 4 hours. The reaction mixture was added with sodium carbonate solid until the excess trifluoroacetic acid was consumed, washed with anhydrous dichloromethane (50 mL×3), and the organic phase was dried over anhydrous sodium sulfate, concentrated, and purified by gel column chromatography (1:1 petroleum ether) Ethyl acetate (Rf = 0.2) gave ethyl 2-(4-(ethoxycarbonyl)-1-hydroxycyclohexyl)carboxylate (11.5 g, brown oil).

^{1 H NMR: (400MHz, DMSO-} d 6) δ = 4.06-3.97 (m, 2H), 2.39-2.25 (m, 3H), 1.78-1.35 (m, 8H), 1.13 (t, J = 7.0 Hz, 3H).

third step.

Ethyl ethyl 2-oxo-1-oxa-3-azaspiro[4.5]decane-8-carboxylate.

Ethyl 2-(4-(ethoxycarbonyl)-1-hydroxycyclohexyl)carboxylate (500 mg, 2.17 mmol) was dissolved in toluene (30 mL). N , N -diisopropyl Ethylamine (560 mg, 4.34 mmol) and diphenylphosphoryl azide (718 mg, 2.60 mmol), and the mixture was stirred under nitrogen and heated to reflux overnight. The reaction mixture was concentrated and purified by column chromatography (3:1 petroleum ether / ethyl acetate, Rf = 0.6) to give ethyl-2-oxo-1-oxa-3-azaspiro[4.5] decane-8 Ethyl carboxylate (380 mg, white solid), yield: 77%.

the fourth step.

8-(Hydroxymethyl)-1-oxa-3-azaspiro[4.5]nonan-2-one.

Lithium tetrahydroaluminum (1.6 g, 4.62 mmol) was added to anhydrous tetrahydrofuran (20 mL) at 0 ° C, and ethyl-2-oxo-1-oxa-3-azaspiro was slowly added dropwise [4.5 a solution of decane-8-carboxylic acid ethyl ester (1.00 g, 4.40 mmol in 5 mL of tetrahydrofuran), the reaction mixture was stirred at 0 ° C for 1 hour, then water (1 mL) was added, and a 15% aqueous sodium hydroxide solution ( 3 mL) and water (1 mL) were quenched. The mixture was stirred at 0<0>C for 0.5 h, filtered, and the filtrate was evaporated.jjjjjjjjjjjjjjjjjjjjjjjjjjjjjj 3-Azaspiro[4.5]nonan-2-one (550 mg, white solid), yield: 67%.

¹ H NMR: (400 MHz, DMSO- d ₆ ) δ = 7.41 (br, 1H), 4.46 - 4.42 (m, 1H), 3.25 - 3.14 (m, 4H), 1.91 - 0.96 (m, 9H).

the fifth step.

(2-Oxo-1-oxa-3-azaspiro[4.5]decane-8-yl)methylmethanesulfonate.

8-(Hydroxymethyl)-1-oxa-3-azaspiro[4.5]nonan-2-one (200 mg, 1.08 mmol) was dissolved in anhydrous dichloromethane (20 mL) and N was added. N -Diisopropylethylamine (0.81 mL, 1.62 mmol) was slowly added dropwise with methylsulfonium chloride (148 mg, 1.30 mmol) at 0 ° C, and the mixture was stirred at 0 ° C for 0.5 hour. The reaction mixture was quenched with EtOAc (EtOAc)EtOAc. = 0.5) (2-Oxo-1-oxa-3-azaspiro[4.5]decane-8-yl)methylmethanesulfonate (285 mg, white solid). Yield: 100%. MS-ESI calcd [M + H] ⁺ 264.

The sixth step.

3,7-Dimethyl-1-((2-oxo-1-oxa-3-azaspiro[4.5]decane-8-yl)methyl)-1 H -嘌呤-2,6( 3 H , 7 H )-dione.

(2-Oxo-1-oxa-3-azaspiro[4.5]decane-8-yl)methyl methanesulfonate (285 mg, 1.08 mmol) was dissolved in N , N -dimethylmethyl Indoleamine (5 mL), then potassium carbonate (300 mg, 2.16 mmol), potassium iodide (18.0 mg, 0.100 mmol) and 3,7-dimethyl- 1H -indole-2,6 ( 3H ,7) H )-dione (205 mg, 1.13 mmol). The reaction solution was heated to 120 ° C for 2 hours. The reaction mixture was diluted with ethyl acetate (20 mL), washed with brine (20 mL EtOAc) ((2-oxo-1-oxa-3-azaspiro[4.5]decane-8-yl)methyl)-1 H -indole-2,6(3 H ,7 H )-dione ( 50.0 mg), yield: 13%.

¹ H NMR: (400 MHz, Methonal- d ₄ ) δ = 7.85 (s, 1H), 4.10-3.87 (m, 5H), 3.52-3.04 (m, 5H), 2.00-1.19 (m, 9H). MS-ESI calcd for [M ⁺ H] + 348, found 348.

Example 8.

1-((2,4-dioxo-1,3-diazaspiro[4,5]decane-8-yl)methyl)-3,7-dimethyl-1 H -indole-2 , 6(3 H , 7 H )-dione.

3,7-Dimethyl-1-((4-oxocyclohexyl)methyl)-1 H -indole-2,6(3 H ,7 H )-dione (100 mg, 0.340 mmol), carbonic acid Ammonium (80.0 mg, 0.750 mmol) was dissolved in ethanol / water (1 mL / 1 mL), and aqueous sodium chloride (35.0 mg, 0.720 mmol) (0.4 mL) was slowly added at room temperature. The reaction solution was heated to 50 ° C for 16 hours, cooled to room temperature and then quenched with saturated sodium carbonate (20 mL). It was extracted with ethyl acetate (30 mL×2), and the organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by preparative HPLC to give the product 1-((2,4-dioxo-1, 3-diazaspiro[4,5]decane-8-yl)methyl)-3,7-dimethyl-1 H -indole-2,6(3 H ,7 H )-dione (12.0 Mg), yield: 10%.

¹ H NMR: (400 MHz, Methonal- d ₄ ) δ = 7.87 (s, 1H), 3.98 (s, 3H), 3.92 (d, J = 7.0 Hz, 2H), 3.54 (s, 3H), 2.01 1.95 (m, 1H), 1.90 - 1.86 (m, 2H), 1.79-1.64 (m, 6H). MS-ESI calcd for [M ⁺ H] + 361, found 361.

Example 9.

first step.

(4,4-Difluoro-cyclohexyl)methanol.

Methyl 4,4-difluoro-cyclohexanecarboxylate (500 mg, 2.60 mmol) was dissolved in tetrahydrofuran (15 mL). EtOAc (1. <RTI ID=0.0> The reaction was stirred for 18 hours under protection. The reaction solution was cooled to 0 ° C, and water (1.50 mL), 15% sodium hydroxide (1.50 mL) and water (4.50 mL) were added slowly. Filtration and concentration of the filtrate under reduced pressure gave the product (4,4-difluoro-cyclohexyl)methanol (300 mg, colorless liquid), yield: 77%.

¹ H NMR: (400 MHz, CDCl ₃ ) δ = 3.58-3.44 (m, 2H), 2.20-2.05 (m, 2H), 1.93-1.42 (m, 6H), 1.40-1.20 (m, 2H). MS-ESI calcd for [M + H] ⁺ 151.

The second step.

4,4-Difluorocyclohexylmethyl methanesulfonate.

(4,4-Difluoro-cyclohexyl)methanol (300 mg, 2.00 mmol) and triethylamine (303 mg, 3.00 mmol) were dissolved in dichloromethane (10 mL). Sulfonium chloride (458 mg, 4.00 mmol). The reaction solution was stirred at 0 ° C for 4 hours. The reaction was quenched with water (10 mL)EtOAcEtOAc The organic phase was combined, washed with aq. NaHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH , Yield: 77%. MS-ESI calcd for [M + H] ⁺ 229.

third step.

1-(4,4-Difluoro-cyclohexylmethyl)-3,7-dimethyl-3,7-dihydro-indole-2,6-dione.

Dissolve 3,7-dimethyl-1 H -indole-2,6(3 H ,7 H )-dione (78.9 mg, 0.438 mmol) in N , N -dimethylformamide (100 mL) 4,4-Difluorocyclohexylmethyl methanesulfonate (78.9 mg, 0.438 mmol), potassium carbonate (121 mg, 0.876 mmol) and potassium iodide (87.3 mg, 0.526 mmol) were added. The reaction solution was heated to 120 ° C and stirred for 3 hours. The organic layer was concentrated under reduced pressure. Base-3,7-dihydro-indole-2,6-dione (30.0 mg), yield: 22%.

¹ H NMR: (400 MHz, CDCl ₃ ) δ = 7.53 (s, 1H), 4.00 (s, 3H), 3.95 (d, J = 6.8 Hz, 2H), 3.59 (s, 3H), 2.18-2.05 ( m, 2H), 2.02-1.87 (m, 1H), 1.82-1.62 (m, 4H), 1.60-1.40 (m, 2H). MS-ESI calcd for [M ⁺ H] + 313, found 313.

Example 10.

1- (3- (1 H - imidazol-1-yl) propyl) -3,7-dimethyl -1 H - purine -2,6 (3 H, 7 H) - dione.

first step.

1-(3-Chloropropyl)-3,7-dimethyl-1 H -indole-2,6(3 H ,7 H )-dione.

3,7-Dimethyl-1 H -indole-2,6(3H,7H)-dione (9.00 g, 49.9 mmol) was dissolved in methanol (12 mL), and freshly prepared sodium methoxide (9.64 g, 49.9 mmol) and 1-bromo-3-chloropropane (47.2 g, 299 mmol). The reaction was carried out under nitrogen at 80 ° C for 12 hours. After concentration under reduced pressure was dissolved in dichloromethane (50 mL), filtered, and the filtrate was concentrated and dried in vacuo to give 1- (3-chloropropyl) -3,7-dimethyl -1 H - purin-2,6 (3 H , 7 H )-dione (10.0 g, white solid), yield: 78%.

¹ H NMR: (400 MHz, CDCl ₃ ) δ = 7.49 (s, 1H), 4.16-4.13 (m, 2H), 3.96 (s, 3H), 3.69-3.66 (m, 2H), 3.58 (s, 3H) ), 2.25-2.24 (m, 1H), 2.14 - 2.12 (m, 1H). MS-ESI calcd [M + H] ⁺ 257.

The second step.

1-(3-Iodopropyl)-3,7-dimethyl-1 H -indole-2,6(3H,7H)-dione.

1-(3-Chloropropyl)-3,7-dimethyl-1 H -indole-2,6(3 H ,7 H )-dione (12.8 g, 49.9 mmol) was dissolved in acetone (250 mL) ), sodium iodide (9.36 g, 62.4 mmol) was added. The reaction solution was stirred at 70 ° C for 48 hours and then concentrated. Purification by gel column chromatography (5:1 petroleum ether/ethyl acetate, Rf = 0.4) affords 1-(3-iodopropyl)-3,7-dimethyl- 1H -indole-2,6 (3H, 7H)-Dione (10.0 g, pale yellow solid), yield: 58%.

¹ H NMR: (400 MHz, CDCl ₃ ) δ = 7.50 (s, 1H), 4.09-4.05 (m, 2H), 3.97 (s, 3H), 3.56 (s, 3H), 3.20-3.17 (m, 2H) ), 2.23-2.20 (m, 2H). MS-ESI calculated [M + H] ⁺ 349 found 349.

third step.

1- (3- (1 H - imidazol-1-yl) propyl) -3,7-dimethyl -1 H - purine -2,6 (3 H, 7 H) - dione.

To sodium hydrogen (28.0 mg, 0.690 mmol) was added to a solution of the imidazole (46.9 mg, 0.690 mmol) in N , N -dimethylformamide (1 mL) at 0 °C. The reaction solution was stirred at 20 ° C for 1 hour. 1-(3-Iodopropyl)-3,7-dimethyl-1 H -indole-2,6(3 H ,7 H )-dione (200 mg, 0.570 mmol) of N , N - A solution of methylformamide (1 mL) was added dropwise to the reaction solution at 0 °C. The reaction mixture was slowly warmed to 20 ° C. After stirring for 12 hours, the mixture was cooled to 0 ° C, and then the mixture was evaporated to ethyl acetate (10 mL). The combined organic layers were washed with brine (10 mL EtOAc) To give 1- (3- (1 H - imidazol-1-yl) propyl) isolating purified by preparative HPLC using 3,7-dimethyl -1 H - purine -2,6 (3 H, 7 H )-dione (50.0 mg), yield: 30%.

¹ H NMR: (400 MHz, Methonal- d ₄ ) δ = 7.86 (s, 1H), 7.79 (s, 1H), 7.21 (s, 1H), 6.96 (s, 1H), 4.13-4.09 (m, 2H) , 4.06-4.03 (m, 2H), 3.96 (s, 3H), 3.51 (s, 3H), 2.21-2.16 (m, 2H). MS-ESI calcd for [M + H] ⁺ 289.

Example 11.

1-(2-(3-ethyl-1-methyl-1 H -pyrazol-5-yl)ethyl)-3,7-dimethyl-1 H -indole-2,6(3 H , 7 H )-dione.

1-(2-(5-Ethyl-1-methyl-1 H -pyrazol-3-yl)ethyl)-3,7-dimethyl-1 H -indole-2,6(3 H , 7 H )-dione.

first step.

Ethyl 5-(benzyloxy)-3-oxopentanoate.

Under a nitrogen atmosphere, sodium hydride (3.38 g, 84.6 mmol, 60%) was added to tetrahydrofuran (300 mL). Then, ethyl acetate (10.0 g, 76.9 mmol) was slowly added, and the reaction mixture was slowly warmed to -10 ° C and stirred for 10 minutes. Then, n-butyllithium (0.3 mL, 2.5 M n-hexane solution, 0.75 mmol) was slowly added at this temperature, and stirring was continued for 10 minutes. To the reaction liquid, ((2-chloroethoxy)methyl)benzene (12.6 g, 80.7 mmol) was slowly added dropwise, and the mixture was reacted for 30 minutes. The reaction was quenched with EtOAc (EtOAc) (EtOAc) The organic phase was combined, washed with brine (50 mL), dried over anhydrous sodium sulfatessssssssssssssssssssssssss Ethyl (benzyloxy)-3-oxopentanoate (9.02 g, yellow oil), yield: 47%.

¹ H NMR: (400 MHz, Methonal- d ₄ ) δ = 7.35-7.27 (m, 5H), 4.50 (s, 2H), 4.20-4.15 (m, 2H), 3.76-3.73 (m, 2H), 3.47 (s, 2H), 2.82 (t, J = 6.0 Hz, 2H), 1.26 (t, J = 6.0 Hz, 3H).

The second step.

Ethyl 5-(benzyloxy)-3-hydroxyvalerate.

Add sodium borohydride (864 mg, 24.0 mmol) to a solution of ethyl 5-(benzyloxy)-3-oxopentanoate (6.00 g, 24.0 mmol) in methanol (50.0 mL). The solution was stirred at this temperature for 2.5 hours. After completion of the reaction, the reaction was quenched with EtOAc (EtOAc) The organic phase was combined, washed with EtOAc (EtOAc) Ethyl (benzyloxy)-3-hydroxyvalerate (3.40 g, yellow oil), yield: 56%.

¹ H NMR: (400 MHz, CDCl ₃ ) δ = 7.37-7.29 (m, 5H), 4.53 (s, 2H), 4.28-4.20 (m, 1H), 4.18-4.14 (m, 2H), 3.72-3.66 (m, 2H), 2.51-2.49 (m, 2H), 1.85-1.78 (m, 2H), 1.29-1.26 (m, 3H).

third step.

5-(Benzyloxy)-3-hydroxy- N -methoxy- N -methylpentanamine.

Under nitrogen, slowly add 5-(benzyloxy)-3-hydroxypentanoate (3.20 g, 12.7 mmol) to isopropylmagnesium chloride (2M in tetrahydrofuran, 44.0 mL, 57.2 mmol). And a solution of N , O -dimethylhydroxylamine hydrochloride (3.02 g, 31.8 mmol) in tetrahydrofuran (50 mL). The reaction solution was slowly warmed to 0 ° C and stirred for 3 hours. The reaction was quenched with EtOAc (EtOAc)EtOAcEtOAc The combined organic phases were washed with EtOAc (EtOAc) (EtOAcjjjHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH Oxy)-3-hydroxy- N -methoxy- N -methylpentamidine (2.50 g, yellow oil), yield: 74%. MS-ESI calcd [M + H] ⁺ 266.

the fourth step.

7-(Benzyloxy)-5-hydroxyheptan-3-one.

Under nitrogen, slowly to a solution of 5-(benzyloxy)-3-hydroxy-N-methoxy-N-methylpentamidine (380 mg, 1.42 mmol) in tetrahydrofuran (10.0 mL) at -5 °C Ethyl magnesium bromide (1.2 mL, 3 M in diethyl ether, 3.5 mmol) was added. The reaction solution was slowly warmed to 0 ° C and stirred for 3 hours. The reaction was quenched with EtOAc (EtOAc)EtOAcEtOAc The organic phase was combined, washed with EtOAc EtOAc EtOAc EtOAcjHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH ), yield: 74%. MS-ESI calcd for [M + H] ^{+ s} .

the fifth step.

1-(Benzyloxy)heptane-3,5-dione.

To a solution of dimethyl hydrazide (1.50 g, 19.1 mmol) in dichloromethane (50 mL), EtOAc (EtOAc) The reaction solution was stirred at this temperature for 20 minutes, and then 7-(benzyloxy)-5-hydroxyheptane-3-one (750 mg, 3.18 mmol) was added and stirring was continued for 2 hr. Triethylamine (3.30 g, 32.5 mmol) was added and stirring was continued at -65 °C for 1 hour and slowly to 25 °C. Saline solution (5 mL) was added and extracted with dichloromethane (10 mL×2). The organic phase was combined, dried over anhydrous sodium sulfate, filtered, evaporated, evaporated,jjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj , 5-dione (220 mg, yellow oil), yield: 30%.

¹ H NMR: (400 MHz, CDCl ₃ ) δ = 7.37-7.29 (m, 5H), 5.56 (s, 2H), 4.54-4.50 (m, 2H), 3.77-3.74 (m, 2H), 2.60 (t) , J = 8.0 Hz, 2H), 2.36-2.30 (m, 2H), 1.14 (t, J = 8.0 Hz, 3H).

The sixth step.

5-(2-(Benzyloxy)ethyl)-3-ethyl-1-methyl-1 H -pyrazole.

3-(2-(Benzyloxy)ethyl)-5-ethyl-1-methyl-1 H -pyrazole.

1-(Benzyloxy)heptane-3,5-dione (120 mg, 0.513 mmol) and methyl hydrazine hydrochloride (423 mg, 5.13 mmol) were dissolved in ethanol (10 mL). The reaction solution was refluxed for 1.5 hours. Concentration under reduced pressure gave 5-(2-(benzyloxy)ethyl)-3-ethyl-1-methyl- 1H -pyrazole and 3-(2-(benzyloxy)ethyl)-5 a mixture of ethyl-1-methyl-1 H -pyrazole (100 mg, yellow oil), yield: 80%. MS-ESI calcd for [M + H] ⁺ 245.

The seventh step.

2-(3-Ethyl-1-methyl-1 H -pyrazol-5-yl)ethanol.

2-(5-Ethyl-1-methyl-1 H -pyrazol-3-yl)ethanol.

Add 5-(2-(benzyloxy)ethyl)-3-ethyl-1-methyl to a solution of ferric chloride (665 mg, 4.09 mmol) in dichloromethane (3 mL) at 25 °C a mixture of benzyl- 1H -pyrazole and 3-(2-(benzyloxy)ethyl)-5-ethyl-1-methyl-1 H -pyrazole (100 mg, 0.409 mmol) in dichloromethane (20 mL) solution was stirred at 25 ° C for 20 minutes. The reaction was quenched by the addition of water (5 mL), EtOAc (EtOAc) The organic phase was combined, washed with EtOAc EtOAc EtOAc (HHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH a mixture of 3-ethyl-1-methyl-1 H -pyrazol-5-yl)ethanol and 2-(5-ethyl-1-methyl-1 H -pyrazol-3-yl)ethanol (52.0 Mg, yellow oil), yield: 88%. MS-ESI calcd for [M + H] ⁺ 155.

The eighth step.

2-(3-Ethyl-1-methyl-1 H -pyrazol-5-yl)ethyl methanesulfonate.

2-(5-Ethyl-1-methyl-1 H -pyrazol-3-yl)ethyl methanesulfonate.

2-(3-Ethyl-1-methyl-1 H -pyrazol-5-yl)ethanol and 2-(5-ethyl-1-methyl-1 H -pyrazol-3-yl)ethanol The mixture (56.0 mg, 0.364 mmol) was dissolved in dichloromethane (5 mL) and N , N -diisopropylethylamine (186 mg, 1.44 mmol). The reaction solution was cooled to 0 ° C, and methanesulfonium chloride (46.1 mg, 0.404 mmol) was added dropwise, and the mixture was slowly warmed to 25 ° C and stirred for 3.5 hours. The reaction was quenched with water and extracted with EtOAc EtOAc. The combined organic phases were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 2- (3-ethyl-1-methyl -1 H - pyrazol-5-yl) ethyl A mixture of mesylate and 2-(5-ethyl-1-methyl-1 H -pyrazol-3-yl)ethyl methanesulfonate (102 mg, yellow oil). MS-ESI calcd for [M + H] ⁺ 233.

The ninth step.

1-(2-(3-ethyl-1-methyl-1 H -pyrazol-5-yl)ethyl)-3,7-dimethyl-1 H -indole-2,6(3 H , 7 H )-dione.

1-(2-(5-Ethyl-1-methyl-1 H -pyrazol-3-yl)ethyl)-3,7-dimethyl-1 H -indole-2,6(3 H , 7 H )-dione.

2-(3-Ethyl-1-methyl-1 H -pyrazol-5-yl)ethyl methanesulfonate and 2-(5-ethyl-1-methyl-1 H -pyrazole- 3- yl) ethyl methanesulfonate ester mixture (100 mg, 0.431 mmol), 3- methyl -1 H - purine -2,6 (3 H, 7 H) - dione (116 mg, 0.646 mmol) Potassium carbonate (178 mg, 1.29 mmol) and potassium iodide (10.7 mg, 0.0650 mmol) were dissolved in N , N -dimethylformamide (8 mL), and the mixture was heated to 130 ° C and stirred for 2.5 hours. Concentration under reduced pressure and purification by preparative high-performance liquid chromatography to give the compound 1-(2-(3-ethyl-1-methyl-1 H -pyrazol-5-yl)ethyl)-3,7-dimethyl Base-1 H -嘌呤-2,6(3 H ,7 H )-dione (product 1) (15.0 mg) and 1-(2-(5-ethyl-1-methyl-1 H -pyrazole) 3- yl) ethyl) -3,7-dimethyl -1 H - purine -2,6 (3 H, 7 H) - dione (product 2) (16.0 mg), yield: 29%.

1-(2-(3-ethyl-1-methyl-1 H -pyrazol-5-yl)ethyl)-3,7-dimethyl-1 H -indole-2,6(3 H , 7 H )-dione.

¹ H NMR: (400 MHz, Methonal- d ₄ ) δ = 7.87 (s, 1H), 5.88 (s, 1H), 4.19 (t, J = 8.0 Hz, 2H), 3.96 (s, 3H), 3.81 ( s, 3H), 3.52 (s, 3H), 2.96 (t, J = 8.0 Hz, 2H). 2.54-2.48 (q, J = 7.6 Hz, 2H), 1.14 (t, J = 7.6 Hz, 3H). MS-ESI calcd [M + H] ⁺ 303.

1-(2-(5-Ethyl-1-methyl-1 H -pyrazol-3-yl)ethyl)-3,7-dimethyl-1 H -indole-2,6(3 H , 7 H )-dione.

¹ H NMR: (400 MHz, Methonal- d ₄ ) δ = 7.86 (s, 1H), 5.96 (s, 1H), 4.20 (t, J = 8.0 Hz, 2H), 3.96 (s, 3H), 3.68 ( s, 3H), 3.52 (s, 3H), 2.86 (t, J = 8.0 Hz, 2H), 2.64 - 2.58 (q, J = 7.6 Hz, 2H), 1.23 (t, J = 7.6 Hz, 3H). MS-ESI calcd [M + H] ⁺ 303.

Example 12.

3,7-Dimethyl-1-(4-(3-methyl-1 H -pyrazol-5-yl)butyl)-1 H -嘌呤-2,6(3 H ,7 H )- ketone.

first step.

8-chlorooctane-2,4-dione.

Pentane-2,4-dione (1.00 g, 10.0 mmol) was dissolved in tetrahydrofuran (20 mL). Under nitrogen, 60% sodium hydride (440 mg, 11.0 mmol) was added at 0 °C. The reaction solution was stirred at 0 ° C for 40 minutes, cooled to -78 ° C, and then n-butyl lithium (4.2 mL, 2.5 M hexane solution, 10.5 mmol) was added dropwise and stirred at -78 ° C for 40 min. 1-Bromo-3-chloropropane (1.65 g, 10.5 mmol) was added and stirred for 3 hours. The reaction solution was warmed to 0 ° C and then quenched with saturated ammonium chloride (30 mL). The reaction mixture was extracted with ethyl acetate (30 mL x 2). The combined organic layers were dried with anhydrous sodium s Separation and purification by gel column chromatography (10:1 petroleum ether / ethyl acetate, Rf = 0.7) afforded 8-chlorooctane-2,4-dione (1.30 g, yellow oil). Yield: 74 %.

¹ H NMR: (400 MHz, CDCl ₃ ) δ = 5.50 (s, 2H), 3.55 (t, J = 6.0 Hz, 2H), 2.31 (t, J = 7.2 Hz, 2H), 2.05 (s, 3H) , 1.86-1.63 (m, 4H). MS-ESI calcd for [M + H] ⁺ 177.

The second step.

5-(4-Chlorobutyl)-3-methyl-1 H -pyrazole.

8-Chlorooctane-2,4-dione (500 mg, 2.83 mmol) was dissolved in ethanol (10 mL), and 85% hydrazine hydrate (160 mg, 4.25 mmol) was added. The reaction mixture was concentrated under reduced pressure, the residue was purified by silica gel column chromatography separation (1: 1 petroleum ether / ethyl acetate, Rf = 0.5), to give 5- (4-chlorobutyl) -3-methyl -1 H - Pyrazole (100 mg, colorless oil), yield: 20%.

¹ H NMR: (400 MHz, CDCl ₃ ) δ = 8.07 (brs, 1H), 5.83 (s, 1H), 3.54 (t, J = 6.0 Hz, 2H), 2.65 (t, J = 7.2 Hz, 2H) , 2.28 (s, 3H), 1.88-1.73 (m, 4H). MS-ESI calcd for [M + H] ⁺ 173.

third step.

3,7-Dimethyl-1-(4-(3-methyl-1 H -pyrazol-5-yl)butyl)-1 H -嘌呤-2,6(3 H ,7 H )- ketone.

5-(4-Chlorobutyl)-3-methyl-1 H -pyrazole (100 mg, 0.580 mmol) was dissolved in N , N -dimethylformamide (3 mL), and 3,7- Dimethyl-1 H -indole-2,6(3 H ,7 H )-dione (104 mg, 0.580 mmol), potassium carbonate (120 mg, 0.870 mmol) and potassium iodide (115 mg, 0.700 mmol). The reaction was heated to 120 ⁰ C, stirred for 16 hours. Concentrated under reduced pressure, and purified by preparative high performance liquid chromatography to give 3,7-dimethyl-1-(4-(3-methyl-1 H -pyrazol-5-yl)butyl)-1 H - purine -2,6 (3 H, 7 H) - dione (25.0 mg), yield: 14%.

¹ H NMR: (400 MHz, Methonal- d ₄ ) δ = 7.99 (s, 1H), 6.46 (s, 1H), 4.06-3.90 (m, 5H), 3.52 (s, 3H), 2.88-2.77 (m) , 2H), 2.44 (s, 3H), 1.84-1.62 (m, 4H). MS-ESI calcd [M + H] ⁺ 303.

Example 13.

3,7-Dimethyl-1-[3-(1-methyl-4-pyrazolyl)-propyl]-3,7-dihydro-indole-2,6-dione.

first step.

3-(1-Methyl-4-pyrazolyl)-propionic acid methyl ester.

3-(1-Methyl-4-pyrazolyl)-propionic acid (150 mg, 0.974 mmol) was dissolved in methanol (3 mL). EtOAc (229 mg, 1. , the reaction was 0.5 hours. The reaction was quenched by the addition of water (10 mL). It was extracted with ethyl acetate (10 mL×3), dried over anhydrous sodium sulfate, filtered, evaporated, evaporated, evaporated. Methyl 1-methyl-4-pyrazolyl)-propanoate (140 mg, yellow oil), yield: 83%. MS-ESI calcd for [M+H] ⁺ 169.

The second step.

3-(1-Methyl-4-pyrazolyl)-1-propanol.

3-(1-Methyl-4-pyrazolyl)-propionic acid methyl ester (140 mg, 0.833 mmol) was dissolved in tetrahydrofuran (10 mL). At 0 ° C, lithium tetrahydrogen aluminum (67.0 mg, 1.70 mmol), react for 1 hour. The reaction was quenched by the addition of water (10 mL). It was extracted with ethyl acetate (10 mL×3), dried over anhydrous sodium sulfate, filtered, evaporated, evaporated, evaporated. 1-Methyl-4-pyrazolyl)-1-propanol (90.0 mg, yellow oil). Yield: 77%. MS-ESI calcd for [M ⁺ H] + 141, found 141.

third step.

3-(1-Methyl-4-pyrazolyl)-propyl methanesulfonate.

3-(1-Methyl-4-pyrazolyl)-1-propanol (90.0 mg, 0.642 mmol) and triethylamine (173 mg, 1.71 mmol) were dissolved in dichloromethane (5 mL) Methanesulfonium chloride (128 mg, 1.14 mmol) was added at °C. The reaction solution was slowly warmed to room temperature and stirred for 2 hours. The reaction was quenched by the addition of aqueous sodium bicarbonate (10 mL). Extracted with dichloromethane (30 mL x 3), EtOAc (EtOAc m. 4-pyrazolyl)-propyl methanesulfonate (90.0 mg, yellow oil), yield: 69%. MS-ESI calcd for [M + H] ⁺ 219.

the fourth step.

3,7-Dimethyl-1-[3-(1-methyl-4-pyrazolyl)-propyl]-3,7-dihydro-indole-2,6-dione.

3-(1-Methyl-4-pyrazolyl)-propyl methanesulfonate (90.0 mg, 0.413 mmol), 3,7-dimethyl- 1H -indole-2,6 ( 3H , 7 H )-Diketone (74.3 mg, 0.413 mmol) and potassium carbonate (114 mg, 0.826 mmol) were dissolved in N , N -dimethylformamide (3 mL). The reaction solution was warmed to 120 ° C and stirred for 3 hours. After cooling to room temperature, filtration, the filtrate was concentrated under reduced pressure and purified by preparative high-purity liquid chromatography to give 3,7-dimethyl-1-[3-(1-methyl-4-pyrazolyl)-propyl] -3,7-Dihydro-indole-2,6-dione (25.0 mg), Yield: 30%.

¹ H NMR: (400 MHz, Methonal- d ₄ ) δ = 7.87 (s, 1H), 7.42 (s, 1H), 7.32 (s, 1H), 4.06-4.02 (m, 2H), 3.98 (s, 3H) ), 3.80 (s, 3H), 3.52 (s, 3H), 2.57-2.53 (m, 2H), 1.97-1.89 (m, 2H).

MS-ESI calcd [M + H] ⁺ 303, Found 303.

Example 14.

1-(4-(1,3-Dimethyl-1 H -pyrazol-5-yl)butyl)-3,7-dimethyl-1 H -indole-2,6(3 H ,7 H )-dione.

1-(4-(1,5-Dimethyl-1 H -pyrazol-3-yl)butyl)-3,7-dimethyl-1 H -indole-2,6(3 H ,7H) - Diketone.

first step.

3-(4-Chlorobutyl)-1,5-dimethyl-1 H -pyrazole.

5-(4-Chlorobutyl)-1,3-dimethyl-1 H -pyrazole.

8-Chlorooctane-2,4-dione (500 mg, 2.83 mmol) was dissolved in ethanol (10 mL). The reaction mixture was concentrated under reduced pressure. EtOAc mjjjjjjjjjjjjjjj Mixture of 1 H -pyrazole and 5-(4-chlorobutyl)-1,3-dimethyl-1 H -pyrazole (100 mg, colorless oil), yield: 20%.

¹ H NMR: (400 MHz, CDCl ₃ ) δ = 5.80 (s, 1H), 3.73-3.65 (m, 3H), 3.60-3.49 (m, 2H), 2.61-2.51 (m, 2H), 2.25-2.15 (m, 3H), 1.90-1.68 (m, 4H). MS-ESI calcd for [M + H] ⁺ 187.

The second step.

1-(4-(1,3-Dimethyl-1 H -pyrazol-5-yl)butyl)-3,7-dimethyl-1 H -indole-2,6(3 H ,7 H )-dione.

1-(4-(1,5-Dimethyl-1 H -pyrazol-3-yl)butyl)-3,7-dimethyl-1 H -indole-2,6(3 H ,7H) - Diketone.

a mixture of 3-(4-chlorobutyl)-1,5-dimethyl-1 H -pyrazole and 5-(4-chlorobutyl)-1,3-dimethyl-1 H -pyrazole (330 mg, 1.76 mmol) dissolved in N , N -dimethylformamide (10 mL), added potassium carbonate (364 mg, 2.64 mmol), 3,7-dimethyl- 1H -indole-2 , 6(3 H , 7 H )-dione (315 mg, 1.76 mmol) and potassium iodide (350 mg, 2.11 mmol). The reaction solution was heated to 120 ° C and stirred for 16 hours. The reaction was cooled to room temperature and then quenched with water (30 mL). The reaction mixture was extracted with ethyl acetate (30 mL x 2). The organic phase was combined, washed with brine (20 mL) The filtrate was concentrated under reduced pressure and purified with EtOAc EtOAc (EtOAc:EtOAc: This isomer mixture was separated and purified by preparative SFC to obtain substituted isomeric products, respectively. Separation method: Separation column: Chiralpak AD 250×30 mm ID, 10 um Mobile phase: supercritical carbon dioxide/methanol (0.1%) ammonia water = 60/40 at 80 mL/min Wavelength: 220 nm.

1-(4-(1,3-Dimethyl-1 H -pyrazol-5-yl)butyl)-3,7-dimethyl-1 H -indole-2,6(3 H ,7 H )-Dione (40.0 mg) (isomer 1, first peak).

¹ H NMR: (400 MHz, CDCl ₃ ) δ = 7.50 (s, 1H), 5.79 (s, 1H), 4.04 (t, J = 7.2 Hz, 2H), 3.98 (s, 3H), 3.70 (s, 3H), 3.57 (s, 3H), 2.58 (t, J = 7.2 Hz, 2H), 2.19 (s, 3H), 1.80-1.60 (m, 4H). MS-ESI calcd for [M ⁺ H] + 331, found 331.

1-(4-(1,5-Dimethyl-1 H -pyrazol-3-yl)butyl)-3,7-dimethyl-1 H -indole-2,6(3 H ,7H) - Diketone (200 mg) (isomer 2, second peak).

¹ H NMR: (400 MHz, CDCl ₃ ) δ = 7.49 (s, 1H), 5.81 (s, 1H), 4.04 (t, J = 7.2 Hz, 2H), 3.98 (s, 3H), 3.69 (s, 3H), 3.57 (s, 3H), 2.59 (t, J = 7.2 Hz, 2H), 2.21 (s, 3H), 1.78-1.60 (m, 4H). MS-ESI calcd for [M ⁺ H] + 331, found 331.

Example 15.

1-((3-Isopropyloxazol-5-yl)methyl)-3,7-dimethyl- 1H -indole-2,6(3H,7H)-dione.

first step.

(3-Isopropyloxazol-5-yl)methanol.

(3-Isopropyloxazolyl-5-yl)carboxaldehyde (200 mg, 1.44 mmol) was dissolved in anhydrous methanol (5 mL) and sodium borohydride (109 mg, 2.88 mmol). Reaction for 1 hour. Quenched with water (10 mL). The reaction mixture was extracted with EtOAc (EtOAc (EtOAc) (EtOAc) (3-Isopropyloxazole-5-yl)methanol (150 mg, yellow oil), yield: 74%.

¹ H NMR: (400 MHz, Methonal- d ₄ ) δ = 6.27 (s, 1H), 4.63 (s, 2H), 3.06 - 2.99 (m, 1H), 1.22 (d, J = 3.4 Hz, 6H).

The second step.

5-(Chloromethyl)-3-isopropylisoxazole.

(3-Isopropyloxazol-5-yl)methanol (150 mg, 1.06 mmol) and triethylamine (322 mg, 3.16 mmol) were dissolved in anhydrous dichloromethane (5 mL). Methanesulfonium chloride (237 mg, 2.12 mmol) was added at 0 °C. The reaction solution was slowly warmed to 25 ° C and stirred for 2 hours. The reaction was quenched with aq. EtOAc (EtOAc) The organic phase was combined, washed with EtOAc EtOAc EtOAcjHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH Yield: 43%.

¹ H NMR: (400 MHz, Methonal- d ₄ ) δ = 6.44 (s, 1H), 4.74 (s, 2H), 3.27 - 3.25 (m, 1H), 1.35 (d, J = 3.4 Hz, 6H).

third step.

L - ((3-isopropyl-5-yl) methyl) -3,7-dimethyl -1 H - purine -2,6 (3 H, 7 H) - dione.

5-(Chloromethyl)-3-isopropylisoxazole (72.5 mg, 0.457 mmol), 3,7-dimethyl-1 H -indole-2,6(3 H ,7 H )- Ketone (85.5 mg, 0.457 mmol), potassium iodide (7.2 mg, 0.0457 mmol) and potassium carbonate (126 mg, 0.913 mmol) were dissolved in anhydrous N , N -dimethylformamide (3 mL). The reaction solution was heated to 120 ° C and allowed to react for 3 hours. The reaction solution was cooled to 20 ° C, filtered, and purified by preparative high-performance liquid chromatography to give 1-((3-isopropylisooxa-5-yl)methyl)-3,7-dimethyl-1 H -嘌呤-2,6(3 H ,7 H )-dione (20.0 mg), yield: 14%.

¹ H NMR: (400 MHz, Methonal- d ₄ ) δ = 7.88 (s, 1H), 6.24 (s, 1H), 5.23 (s, 2H), 3.96 (s, 3H), 3.52 (s, 3H), 3.01-2.93 (m, 1H), 1.22 (d, J = 3.4 Hz, 6H). MS-ESI calcd for [M + H] ⁺ 303.

Example 16.

3,7-Dimethyl-1-(2-(3-methylisoxazol-5-yl)ethyl)-1 H -indole-2,6(3 H ,7 H )-dione.

first step.

2-(3-methylisoxazol-5-yl)acetic acid.

3,5-Dimethylisoxazole (5.00 g, 51.5 mmol) was dissolved in tetrahydrofuran (50 mL). Under nitrogen atmosphere, n-butyllithium (23 mL, 2.5 M-hexane solution, 57 mmol) was added at -78 ° C and stirred for 1 hour. The reaction solution was passed through carbon dioxide, and stirring was continued for 1 hour under one atmosphere. Quenched by the addition of saturated ammonium chloride (30 mL), concentrated under reduced pressure, the aqueous phase was adjusted to pH 3, extracted with ethyl acetate (30 mL x 3), combined organic phase, saturated sodium chloride solution (30 mL x 2) Washing, drying over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give 2-(3-methylisoxazole-5-yl)acetic acid (2.40 g, white solid).

¹ H NMR: (400 MHz, CDCl ₃ ) δ = 6.14 (s, 1H), 3.85 (s, 2H), 2.30 (s, 3H). MS-ESI calcd for [M + H] ⁺ 422.

The second step.

Methyl 2-(3-methylisoxazol-5-yl)acetate.

2-(3-Methylisoxazol-5-yl)acetic acid (2.40 g, 17.0 mmol) was dissolved in methanol (30 mL), and concentrated sulfuric acid (8.34 g, 85.0 mmol). The reaction mixture was concentrated with EtOAc EtOAc (EtOAc)EtOAc. The organic phase was combined, washed with a saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered and evaporated. Methyl 2-(3-methylisoxazol-5-yl)acetate (2.00 g, yellow oil) was obtained.

¹ H NMR: (400 MHz, CDCl ₃ ) δ = 6.10 (s, 1H), 3.79 (s, 2H), 3.75 (s, 3H), 2.29 (s, 3H). MS-ESI calcd for [M + H] ⁺ 156.

third step.

2-(3-methylisoxazol-5-yl)ethanol.

Methyl methyl 2-(3-methylisoxazol-5-yl)acetate (2.00 g, 12.9 mmol) was dissolved in tetrahydrofuran (30 mL). Under nitrogen atmosphere, lithium tetrahydroaluminum (725 mg, 19.4 mmol) was added portionwise at 0 ° C, and the mixture was stirred at 0 ° C for 1 hour. Water (0.7 mL) and 15% sodium hydroxide solution (0.7 mL) were added to the reaction mixture, and water (2.1 mL) was added to the mixture. After filtration, the filtrate was dried (MgSO4jjjjj:

¹ H NMR: (400 MHz, CDCl ₃ ) δ = 5.94 (s, 1H), 3.93 (t, J = 6.0 Hz, 2H), 2.98 (t, J = 6.0 Hz, 2H), 2.69 (br, 1H) , 2.26 (s, 3H). MS-ESI calcd [M + H] ⁺ 128, Found.

the fourth step.

2-(3-Methylisoxazol-5-yl)ethyl methanesulfonate.

2-(3-Methylisoxazol-5-yl)ethanol (1.00 g, 7.87 mmol) was dissolved in dichloromethane (15 mL), cooled to 0 ° C, and triethylamine (1.19 g, 11.8 mmol) And methane sulfonium chloride (1.35 g, 11.8 mmol). The reaction solution was slowly warmed to room temperature and stirred for 1 hour. The reaction solution was diluted with methylene chloride (30 mL), and then 1N hydrochloric acid (20 mL) was added, and the mixture was stirred and then stratified, and the organic layer was separated, and then saturated sodium bicarbonate (30 mL) and saturated brine (20) Wash with mL), dry over anhydrous sodium sulfate and filter. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (5:1 petroleum ether / ethyl acetate, Rf = 0.5) to give 2-(3-methylisoxazole-5-yl)ethyl methanesulfonate (350 mg, yellow oil), yield: 22%.

¹ H NMR: (400 MHz, CDCl ₃ ) δ = 6.01 (s, 1H), 4.50 (t, J = 6.0 Hz, 2H), 3.19 (t, J = 6.0 Hz, 2H), 2.99 (s, 3H) , 2.28 (s, 3H). MS-ESI calcd for [M + H] &^lt;

the fifth step.

3,7-Dimethyl-1-(2-(3-methylisoxazol-5-yl)ethyl)-1 H -indole-2,6(3 H ,7 H )-dione.

2-(3-Methylisoxazole-5-yl)ethyl methanesulfonate (150 mg, 0.730 mmol), 3,7-dimethyl- 1H -indole-2,6 ( 3H , 7 H )-Dione (132 mg, 0.730 mmol) and cesium carbonate (357 mg, 1.10 mmol) were dissolved in N , N -dimethylformamide (3 mL). The reaction solution was heated to 100 ° C and stirred overnight. The reaction mixture was cooled to room temperature, and the mixture was evaporated, evaporated, evaporated, evaporated, evaporated, evaporated 3,7-Dimethyl-1-(2-(3-methylisoxazol-5-yl)ethyl)-1 H -嘌呤-2 was isolated and purified by preparative high performance liquid chromatography under reduced pressure. 6( 3H , 7H )-dione (20.0 mg), yield: 10%.

¹ H NMR: (400 MHz, Methonal- d ₄ ) δ = 8.38 (s, 1H), 6.13 (s, 1H), 4.30 (t, J = 7.2 Hz, 2H), 4.04 (s, 3H), 3.54 ( s, 3H), 3.10 (t, J = 7.2 Hz, 2H), 2.24 (s, 3H). MS-ESI calcd for [M + H] ⁺ 290.

Example 17.

1-(2-(3-ethylisoxazol-5-yl)ethyl)-3,7-dimethyl-1 H -indole-2,6(3 H ,7 H )-dione; - (2- (5-ethyl-isoxazol-3-yl) ethyl) -3,7-dimethyl -1 H - purine -2,6 (3 H, 7 H) - dione.

first step.

5-(2-(Benzyloxy)ethyl)-3-ethylisoxazole.

3-(2-(Benzyloxy)ethyl)-5-ethylisoxazole.

1-(Benzyloxy)heptane-3,5-dione (100 mg, 0.427 mmol) and hydroxylamine hydrochloride (299 mg, 4.27 mmol) were dissolved in ethanol (2 mL). The reaction solution was refluxed for 1.5 hours. Concentration under reduced pressure gave a mixture of 5-(2-(benzyloxy)ethyl)-3-ethylisoxazole and 3-(2-(benzyloxy)ethyl)-5-ethylisoxazole (81.0 mg, yellow oil), yield: 82%. MS-ESI calcd [M+H] ⁺ 232.

The second step.

2-(3-Ethylisoxazole-5-yl)ethanol.

2-(5-ethylisoxazol-3-yl)ethanol.

Add 5-(2-(benzyloxy)ethyl)-3-ethylisoxazole and a solution of ferric chloride (562 mg, 3.46 mmol) in dichloromethane (3 mL) at 25 °C A solution of a mixture of 3-(2-(benzyloxy)ethyl)-5-ethylisoxazole (80.0 mg, 0.346 mmol) in dichloromethane (20 mL) The reaction was quenched with water (5 mL). The organic phase was combined, washed with EtOAc EtOAc EtOAcjjjjjjjjjj Mixture of isoxazol-3-yl)ethanol (52.0 mg, yellow oil). MS-ESI calcd for [M + H] ⁺ 422.

third step.

2-(3-Ethylisoxazole-5-yl)ethyl methanesulfonate.

2-(5-Ethylisoxazol-3-yl)ethyl methanesulfonate.

A mixture of 2-(3-ethylisoxazol-5-yl)ethanol and 2-(5-ethylisoxazol-3-yl)ethanol (36.0 mg, 0.255 mmol) was dissolved in dichloromethane (5 mL), N , N -diisopropylethylamine (98.7 mg, 0.765 mmol) was added. The reaction solution was lowered to 0 ° C, methanesulfonium chloride (630 mg, 5.53 mmol) was added dropwise, and the mixture was slowly warmed to 25 ° C and stirred for 3.5 hours. The reaction was quenched with water and extracted with EtOAc EtOAc. The organic phase was combined, washed with EtOAc EtOAc EtOAc m. Mixture of 5-ethylisoxazol-3-yl)ethyl methanesulfonate (60.0 mg, yellow oil). MS-ESI calcd for [M + H] ⁺ 220.

the fourth step.

1- (2- (3-ethyl-5-yl) ethyl) -3,7-dimethyl -1 H - purine -2,6 (3 H, 7 H) - dione.

1- (2- (5-ethyl-isoxazol-3-yl) ethyl) -3,7-dimethyl -1 H - purine -2,6 (3 H, 7 H) - dione.

a mixture of 2-(3-ethylisoxazol-5-yl)ethyl methanesulfonate and 2-(5-ethylisoxazol-3-yl)ethyl methanesulfonate (60.0 mg, 0.274 Methyl), 3-methyl- 1H -indole-2,6( 3H ,7H)-dione (74.0 mg, 0.411 mmol), potassium carbonate (113 mg, 0.822 mmol) and potassium iodide (5.0 mg, 0.027 mmol) Dissolved in N , N -dimethylformamide (8.0 mL), and the mixture was heated to 130 ° C and stirred for 2.5 hours. The organic layer was concentrated under reduced pressure and purified by preparative high-purity chromatography to give the compound 1-(2-(3-ethylisooxazol-5-yl)ethyl)-3,7-dimethyl- 1H -indole-2, 6(3 H , 7 H )-dione (isomer 1) (13.0 mg). ¹ H NMR: (400 MHz, Methonal- d ₄ ) δ = 7.88 (s, 1H), 6.15 (s, 1H), 4.30 (t, J = 7.6 Hz, 2H), 3.96 (s, 3H), 3.52 ( s, 3H), 3.10 (t, J = 7.2 Hz, 2H), 2.66-2.63 (m, 2H), 1.23 (t, J = 7.6 Hz, 3H). MS-ESI calcd for [M + H] ⁺ 303.

1-(2-(5-ethylisoxazol-3-yl)ethyl)-3,7-dimethyl-1 H -indole-2,6(3 H ,7 H )-dione (iso) Construct 2) (13.0 mg), yield: 30%. ¹ H NMR: (400 MHz, Methonal- d ₄ ) δ = 7.87 (s, 1H), 6.13 (s, 1H), 4.28 (t, J = 7.2 Hz, 2H), 3.96 (s, 3H), 3.52 ( s, 3H), 2.97 (t, J = 7.6 Hz, 2H), 2.78-2.72 (m, 2H), 1.27 (t, J = 7.6 Hz, 3H). MS-ESI calcd for [M + H] ⁺ 303.

Example 18.

3,7-Dimethyl-1-(3-(3-methylisoxazole-5-yl)propyl)-1 H -indole-2,6(3 H ,7 H )-dione.

first step.

3-(3-Methylisoxazole-5-yl)-1-propanol.

3,5-Dimethyl-isoxazole (1.90 g, 19.6 mmol) was dissolved in anhydrous tetrahydrofuran (20 mL), and a solution of n-butyllithium (2.5 M was slowly added dropwise at -68 ° C under nitrogen atmosphere. Alkane solution, 8 mL, 19.6 mmol), and the mixture was stirred at -68 ° C for 2 hr. Ethylene oxide (862 mg, 19.6 mmol) was slowly added and stirring was continued for 1 hour. The reaction was quenched by the addition of water (100 mL). The reaction mixture was extracted with ethyl acetate (30 mL EtOAc)EtOAc. Purification (3:1 petroleum ether/ethyl acetate, Rf = 0.6) afforded 3-(3-methylisoxazol-5-yl)-1-propanol (1.10 g, yellow oil). 40%. MS-ESI calcd for [M + H] ⁺ 422.

The second step.

3-(3-Methylisoxazol-5-yl)propyl methanesulfonate.

3-(3-Methylisoxazol-5-yl)-1-propanol (260 mg, 1.84 mmol) was dissolved in anhydrous dichloromethane (5 mL). Under nitrogen, triethylamine (465 mg, 4.60 mmol), methanesulfonium chloride (252 mg, 2.20 mmol) was added at 0 °C. The reaction solution was slowly warmed to room temperature and stirred for 2 hours. The reaction was quenched by the addition of water (60 mL). The reaction mixture was extracted with ethyl acetate (30 mL EtOAc)EtOAc. Purification (2:1 petroleum ether / ethyl acetate, Rf = 0.3) afforded 3-(3-methylisoxazol-5-yl)propyl methanesulfonate ( 215 mg, yellow oil) : 53%. MS-ESI calcd for [M + H] ⁺ 220.

third step.

3,7-Dimethyl-1-(3-(3-methylisoxazole-5-yl)propyl)-1 H -indole-2,6(3 H ,7 H )-dione.

3-(3-Methylisoxazol-5-yl)propyl methanesulfonate (100 mg, 0.450 mmol) was dissolved in anhydrous N , N -methylcarbamide (5 mL). Under nitrogen, potassium carbonate (126 mg, 0.900 mmol), potassium iodide (8.0 mg, 0.045 mmol), 2,6-hydroxy-3,7-dimethylindole (98.0 mg, 0.550 mmol) was added at room temperature. The reaction solution was heated to 130 ° C and stirred for 3 hours. The reaction was quenched by the addition of water (40 mL). The reaction mixture was extracted with ethyl acetate (30 mL×3), EtOAc (EtOAc m. The product 3,7-dimethyl-1-(3-(3-methylisoxazole-5-yl)propyl)-1 H -indole-2,6(3 H ,7 H )-dione (23.0 mg), yield: 16%.

¹ H NMR: (400 MHz, CDCl ₃ ) δ = 7.52 (s, 1H), 5.93 (s, 1H), 4.11 (t, J = 7.2 Hz, 2H), 3.99 (s, 3H), 3.58 (s, 3H), 2.80 (t, J = 8.0 Hz, 2H), 2.24 (s, 3H), 2.11-2.03 (m, 2H). MS-ESI calcd for [M + H] ⁺ 303.

Example 19.

5-(4-Bromobutyl)-3-methylisoxazole.

first step.

3,5-Dimethylisoxazole (2.00 g, 20.6 mmol), 1,3 dibromopropane (25.0 g, 124 mmol) was dissolved in tetrahydrofuran (100 mL) and added dropwise at -60 ° C under nitrogen Lithium diisopropylamide (10.3 mL, 2 M tetrahydrofuran solution, 20.6 mmol) was stirred at -60 ° C for 1 hour, then slowly warmed to 20 ° C and stirring was continued for 2 hours. The reaction solution was quenched by the addition of saturated aqueous ammonium chloride (100 mL). The mixture was extracted with ethyl acetate (100 mL x 3). The organic layer was washed with brine (100 mL EtOAc) Separation and purification by gel column chromatography (5:1 petroleum ether / ethyl acetate, Rf = 0.6) to give 5-(4-bromobutyl)-3-methylisoxazole (2.00 g, white solid) : 50%.

^{1 H NMR: (400MHz, CDCl} 3) δ = 5.81 (s, 1H), 3.41-3.34 (m, 2H), 2.79-2.70 (m, 2H), 2.24 (s, 3H), 1.89-1.82 (m, 4H).

MS-ESI calculated [M + H] ⁺ 218 and 220, found 218 and 220.

The second step.

3,7-Dimethyl-1-(4-(3-methylisoxazol-5-yl)butyl)-1 H -indole-2,6(3 H ,7 H )-dione.

Dissolve 3,7-dimethyl-1 H -indole-2,6(3 H ,7 H )-dione (150 mg, 0.833 mmol) in N , N -dimethylformamide (5 mL) Add 5-(4-bromobutyl)-3-methylisoxazole (272 mg, 1.25 mmol), potassium carbonate (345 mg, 2.50 mmol). The reaction solution was stirred at 80 ° C for 12 hours. Water (30 mL) was added and extracted with ethyl acetate (100 mL×3). The organic layer was washed with brine (100 mL EtOAc) Separation and purification by gel column chromatography (5:1 petroleum ether / ethyl acetate, Rf = 0.6) to give 3,7-dimethyl-1-(4-(3-methylisoxazole-5-yl) yl) -1 H - purine -2,6 (3 H, 7 H) - dione (50.0 mg), yield: 19%.

¹ H NMR: (400 MHz, Methonal- d ₄ ) δ = 7.85 (s, 1H), 6.03 (s, 1H), 4.02-3.99 (m, 2H), 3.96 (s, 3H), 3.51 (s, 3H) ), 2.79-2.76 (m, 2H), 2.22 (s, 3H), 1.72-1.70 (m, 4H). MS-ESI calcd [M + H] ⁺ 318. Found 318.

Example 20.

3,7-Dimethyl-1-(4-(5-methylisoxazol-3-yl)butyl)-1 H -indole-2,6(3 H ,7 H )-dione.

first step.

5-(4-Chlorobutyl)-3-methylisoxazole.

3-(4-Chlorobutyl)-5-methylisoxazole.

8-Chlorooctane-2,4-dione (1.00 g, 5.70 mmol) was dissolved in dry ethanol (5 mL). EtOAc (EtOAc) The reaction solution was heated to 100 ° C and stirred for 3 hours. The reaction was quenched by the addition of water (60 mL). The reaction solution was extracted with ethyl acetate (30 mL×3). The organic phase was combined, washed with aq. EtOAc EtOAc (EtOAc (EtOAc) = 0.3) a mixture of 5-(4-chlorobutyl)-3-methylisoxazole and 3-(4-chlorobutyl)-5-methylisoxazole (900 mg, yellow oil), Yield: 92%. MS-ESI calcd for [M + H] ⁺ 174.

The second step.

3,7-Dimethyl-1-(4-(5-methylisoxazol-3-yl)butyl)-1 H -indole-2,6(3 H ,7 H )-dione.

A mixture of 5-(4-chlorobutyl)-3-methylisoxazole and 3-(4-chlorobutyl)-5-methylisoxazole (400 mg, 2.32 mmol) was dissolved in N , N - in dimethylformamide (10 mL). Under nitrogen, potassium carbonate (638 mg, 4.64 mmol), potassium iodide (38.0 mg, 0.230 mmol), 2,6-hydroxy-3,7-dimethylindole (502 mg, 2.80 mmol) was added at room temperature. The reaction solution was heated to 130 ° C and stirred for 3 hours. The reaction was quenched by the addition of water (60 mL). The reaction mixture was extracted with ethyl acetate (30 mL×3) Washed with a saturated sodium chloride solution (30 mL×3), dried over anhydrous magnesium sulfate, filtered, and evaporated. : 68%. The mixture was chromatographed to give 3,7-dimethyl-1-(4-(3-methylisoxazol-3-yl)butyl)-1 H -indole-2,6 ( 3H , 7 H )-dione (Example 19, first peak) (40.0 mg) and 3,7-dimethyl-1-(4-(5-methylisoxazol-3-yl)butyl) -1H-indole-2,6(3H,7H)-dione (Example 20, second peak) (50.0 mg).

3,7-Dimethyl-1-(4-(5-methylisoxazol-3-yl)butyl)-1 H -indole-2,6(3 H ,7 H )-dione: ¹ H NMR: (400 MHz, CDCl 3) δ = 7.50 (s, 1H), 5.81 (s, 1H), 4.03-3.99 (m, 2H), 3.96 (s, 3H), 3.54 (s, 3H), 2.66 - 2.62 (m, 2H), 2.34 (s, 3H), 1.70-1.69 (m, 4H). MS-ESI calcd [M + H] ⁺ 318. Found 318.

Example 21.

1-(2-(3,5-Dimethylisoxazol-4-yl)ethyl)-3,7-dimethyl-1 H -indole-2,6(3 H ,7 H )- ketone.

first step.

2-(3,5-Dimethylisoxazole-4-yl)acetonitrile.

4-Chloromethyl-3,5-dimethylisoxazole (300 mg, 2.07 mmol) was dissolved in dimethyl hydrazine (3 mL) and sodium cyanide (121 mg, 2.48 mmol). The reaction was warmed to 60 ° C and allowed to react for 3 hours. The reaction was cooled to 25 ° C, and water (10 mL) was evaporated. Isooxazol-4-yl)acetonitrile (200 mg, yellow oil), yield: 71%. ¹ H NMR: (400 MHz, Methonal- d ₄ ) δ = 3.67 (s, 2H), 2.30 (s, 3H), 2.28 (s, 3H).

The second step.

Methyl 2-(3,5-dimethylisoxazol-4-yl)acetate.

2-(3,5-Dimethylisoxazol-4-yl)acetonitrile (200 mg, 1.08 mmol) was dissolved in MeOH (5 mL). The reaction was warmed to 60 ° C and allowed to react for 3 hours. The reaction was cooled to 25 ° C, water (10 mL) was added, and the mixture was adjusted to pH 7 with a saturated sodium hydrogen carbonate solution (10 mL), and the mixture was extracted with ethyl acetate (10 mL x 3). Drying and concentrating under reduced pressure gave methyl 2-(3,5-dimethylisoxazol-4-yl)acetate (200 mg,yield of yellow oil).

¹ H NMR: (400 MHz, Methonal- d ₄ ) δ = 3.72 (s, 3H), 3.46 (s, 2H), 2.35 (s, 3H), 2.20 (s, 3H).

third step.

2-(3,5-Dimethylisoxazole-4-yl)ethanol.

Methyl 2-(3,5-dimethylisoxazol-4-yl)acetate (180 mg, 1.06 mmol) was dissolved in anhydrous tetrahydrofuran (2 mL). Mg, 2.12 mmol). The reaction solution was warmed to 25 ° C and stirred for 1 hour. It was quenched with water (2 mL), EtOAc (EtOAc (EtOAc)EtOAc. = 0.2), 2-(3,5-dimethylisoxazol-4-yl)ethanol (100.0 mg, yellow oil) was obtained.

¹ H NMR: (400 MHz, Methonal- d ₄ ) δ = 3.65-3.62 (m, 2H), 2.59-2.55 (m, 2H), 2.38 (s, 3H), 2.25 (s, 3H).

the fourth step.

2-(3,5-Dimethylisoxazol-4-yl)ethyl methanesulfonate.

Dissolve 2-(3,5-dimethylisoxazol-4-yl)ethanol (100 mg, 0.708 mmol) in dichloromethane (3 mL) and add triethylamine (143 mg) at 0 °. , 1.42 mmol) and methanesulfonyl chloride (79.3 mg, 0.708 mmol). The reaction solution was reacted at 25 ° C for 2 hours. The organic layer was extracted with aq. EtOAc (EtOAc) The filtrate was concentrated under reduced pressure to give 2-(3,5-dimethylisoxazol-4-yl)ethyl methanesulfonate (100 mg,yield of yellow oil).

the fifth step.

1-(2-(3,5-Dimethylisoxazol-4-yl)ethyl)-3,7-dimethyl-1 H -indole-2,6(3 H ,7 H )- ketone.

2-(3,5-Dimethylisoxazol-4-yl)ethyl methanesulfonate (100 mg, 0.457 mmol), 3,7-dimethyl- 1H -indole-2,6 ( 3 H ,7 H )-dione (82.2 mg, 0.457 mmol), potassium iodide (7.2 mg, 0.046 mmol) and potassium carbonate (126 mg, 0.914 mmol) dissolved in anhydrous N , N -dimethylformamide (3 In mL). The reaction solution was heated to 120 ° C and allowed to react for 3 hours. The reaction solution was cooled to 20 ° C, filtered, and purified by preparative HPLC to give 1-(2-(3,5-dimethylisoxazol-4-yl)ethyl)-3,7-dimethyl yl -1 H - purine -2,6 (3 H, 7 H) - dione (50.0 mg), yield: 36%.

¹ H NMR: (400 MHz, Methonal- d ₄ ) δ = 7.88 (s, 1H), 4.11-4.07 (m, 2H), 3.97 (s, 3H), 3.54 (s, 3H), 2.74-2.71 (m) , 2H), 2.30 (s, 3H), 2.29 (s, 3H). MS-ESI calcd for [M + H] ⁺ 303.

Example 22.

1-((5-Isopropyloxazol-4-yl)methyl)-3,7-dimethyl-1 H -indole-2,6(3 H ,7 H )-dione.

first step.

Methyl 5-isopropylisoxazole-4-carboxylate.

5-Isoisoxazole-4-carboxylic acid (1.00 g, 6.45 mmol) was dissolved in methanol (2 mL), and then dichloromethane (1.51 g, 12.9 mmol) was slowly added at 0 ° C. The solution was slowly warmed to 25 ° C and stirred for 12 hours. The reaction was quenched with EtOAc (EtOAc)EtOAc. Methyl carboxylate (800 mg, yellow oil), yield: 73%.

¹ H NMR: (400 MHz, Methonal- d ₄ ) δ = 6.55 (s, 1H), 3.95 (s, 3H), 3.20-3.17 (m, 1H), 1.35 (d, J = 3.4 Hz, 6H).

The second step.

(5-Isopropyloxazol-4-yl)methanol.

Nitrogen-protected, lithium aluminum hydride (231 mg, 5.92 mmol) was slowly dissolved in tetrahydrofuran (60 mL) at 0 ° C, and methyl 5-isopropylisoxazole-4-carboxylate (500 mg, 2.96) was slowly added. A solution of mmol) in tetrahydrofuran (10 mL). The reaction solution was slowly warmed to 25 ° C and stirred for 1.5 hours. The reaction solution was cooled to 0 ° C, and water (2.3 mL), 15% sodium hydroxide solution (2.3 mL) and water (9.9 mL) were added slowly. The reaction solution was warmed to 25 ° C, stirred for half an hour, filtered, and the filter cake was washed with tetrahydrofuran (10 mL x 3). The filtrate was concentrated under reduced pressure to give (5-isopropylisoxazole-4-yl)methanol (250 mg,yield of yellow oil).

¹ H NMR: (400 MHz, Methonal- d ₄ ) δ = 6.18 (s, 1H), 4.62 (s, 2H), 3.12-3.08 (m, 1H), 1.32 (d, J = 3.4 Hz, 6H).

third step.

(5-Isoisoxazole-4-yl)methyl methanesulfonate.

(5-Isopropyloxazol-4-yl)methanol (250 mg, 1.77 mmol) and triethylamine (358 mg, 3.55 mmol) were dissolved in dichloromethane (5 mL) at 0 ° C Methane sulfonium chloride (238 mg, 2.12 mmol) was added slowly. The reaction solution was slowly warmed to 25 ° C and stirred overnight. The reaction was quenched by the addition of water (30 mL). Extracted with dichloromethane (10 mL x 3), EtOAc (EtOAc m. 200 mg, yellow oil), yield: 52%.

¹ H NMR: (400 MHz, Methonal- d ₄ ) δ = 6.38 (s, 1H), 5.29 (s, 2H), 3.28 (s, 3H), 3.11-3.06 (m, 1H), 1.24 (d, J) = 3.4 Hz, 6H).

the fourth step.

1-((5-Isopropyloxazol-4-yl)methyl)-3,7-dimethyl-1 H -indole-2,6(3 H ,7 H )-dione.

(5-Isopropyloxazol-4-yl)methyl methanesulfonate (219 mg, 1.00 mmol), 3,7-dimethyl- 1H -indole-2,6 ( 3H ,7 H )-dione (180 mg, 1.00 mmol) and potassium carbonate (414 mg, 3.00 mmol) were dissolved in N , N -dimethylformamide (4 mL), and potassium iodide (17.0 mg, 0.100 mmol) was added. The reaction was heated to 120 ° C and stirred for 3 hours. The reaction solution was cooled to 25 ° C, and brine (30 mL) was evaporated. The organic phase was combined, dried over anhydrous sodium sulfate, filtered, evaporated, evaporated, , 7-Dimethyl-1 H -indole-2,6(3 H ,7 H )-dione (50.0 mg), Yield: 17%.

¹ H NMR: (400 MHz, Methonal- d ₄ ) δ = 7.92 (s, 1H), 6.27 (s, 1H), 5.27 (s, 2H), 4.00 (s, 3H), 3.56 (s, 3H), 3.03-2.97 (m, 1H), 1.26 (d, J = 3.4 Hz, 6H). MS-ESI calcd for [M + H] ⁺ 303.

Example 23.

1-((5-Isoisoxazol-3-yl)methyl)-3,7-dimethyl-1 H -indole-2,6(3 H ,7 H )-dione.

first step.

Methyl 5-isopropylisoxazole-3-carboxylate.

5-Isoisoxazole-3-carboxylic acid (1.00 g, 6.45 mmol) was dissolved in methanol (20 mL), and then dichlorothylene (1.51 g, 12.9 mmol) was slowly added at 0 ° C. The solution was slowly warmed to 25 ° C and stirred for 12 hours. The reaction was quenched with EtOAc (EtOAc (EtOAc)EtOAc. Methyl carboxylate (800 mg, yellow oil), yield: 73%.

¹ H NMR: (400 MHz, Methonal- d ₄ ) δ = 7.05 (s, 1H), 3.93 (s, 3H), 3.12-3.08 (m, 1H), 1.30 (d, J = 3.6 Hz, 6H).

The second step.

(5-Isoisoxazole-3-yl)methanol.

Nitrogen-protected, lithium aluminum hydride (231 mg, 5.92 mmol) was slowly dissolved in tetrahydrofuran (60 mL) at 0 ° C, and methyl 5-isopropylisoxazole-3-carboxylate (500 mg, 2.96) was slowly added. A solution of mmol) in tetrahydrofuran (10 mL). The reaction solution was slowly warmed to 25 ° C and stirred for 1.5 hours. The reaction solution was cooled to 0 ° C, and water (0.2 mL), 15% sodium hydroxide (0.2 mL) and water (0.7 mL). The reaction solution was warmed to 25 ° C, stirred for half an hour, filtered, and the filter cake was washed with tetrahydrofuran (10 mL x 3). The filtrate was concentrated under reduced pressure to give (5-isopropylisooxazol-3-yl)methanol (250 mg,yield of yellow oil).

¹ H NMR: (400 MHz, Methonal- d ₄ ) δ = 6.29 (s, 1H), 4.64 (s, 2H), 3.08-3.01 (m, 1H), 1.29 (d, J = 3.4 Hz, 6H).

third step.

(5-Isoisoxazol-3-yl)methyl methanesulfonate.

(5-Isoisoxazole-3-yl)methanol (250 mg, 1.77 mmol) and triethylamine (358 mg, 3.55 mmol) were dissolved in dichloromethane (5 mL) at 0 ° C Methane sulfonium chloride (238 mg, 2.12 mmol) was added slowly. The reaction solution was slowly warmed to 25 ° C and stirred overnight. The reaction was quenched by the addition of water (20 mL). Extracted with methylene chloride (10 mL x 3), EtOAcjjjjjjjjjjjjjj (200 mg, yellow oil), yield: 52%.

¹ H NMR: (400 MHz, Methonal- d ₄ ) δ = 6.67 (s, 1H), 5.37 (s, 2H), 3.27 (s, 3H), 3.02-2.99 (m, 1H), 1.20 (d, J = 3.4 Hz, 6H).

the fourth step.

1-((5-Isoisoxazol-3-yl)methyl)-3,7-dimethyl-1 H -indole-2,6(3 H ,7 H )-dione.

(5-Isoisoxazol-3-yl)methyl methanesulfonate (219 mg, 1.00 mmol), 3,7-dimethyl- 1H -indole-2,6( 3H ,7 H )-dione (180 mg, 1.00 mmol) and potassium carbonate (414 mg, 3.00 mmol) were dissolved in N , N -dimethylformamide (4 mL), and potassium iodide (17.0 mg, 0.100 mmol) was added. The reaction was heated to 120 ° C and stirred for 3 hours. The reaction solution was cooled to 25 ° C, then brine (20 mL) The organic phase was combined, dried over anhydrous sodium sulfate, filtered, evaporated, evaporated, , 7-Dimethyl-1 H -indole-2,6(3 H ,7 H )-dione (50.0 mg), Yield: 17%.

¹ H NMR: (400 MHz, Methonal- d ₄ ) δ = 7.91 (s, 1H), 6.13 (s, 1H), 5.22 (s, 2H), 4.00 (s, 3H), 3.56 (s, 3H), 3.09-3.03 (m, 1H), 1.29 (d, J = 3.4 Hz, 6H).

MS-ESI calcd for [M + H] ⁺ 303.

Example 24.

1-(5-Ethyl-isoxazol-3-ylmethyl)-3,7-dimethyl-3,7-dihydro-indole-2,6-dione.

first step.

Methyl 5-ethylisoxazole-3-carboxylate.

5-Ethylisoxazole-3-carboxylic acid (500 mg, 3.54 mmol) was dissolved in methanol (4 mL). The reaction was quenched by the addition of saturated sodium bicarbonate (20 mL). Extracted with ethyl acetate (10 mL×3), dried over anhydrous NaHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH 89%. MS-ESI calcd for [M + H] ⁺ 156.

The second step.

(5-Ethyl-isoxazol-3-yl)methanol.

Methyl 5-ethylisoxazole-3-carboxylate (100 mg, 0.645 mmol) was dissolved in tetrahydrofuran (5 mL), and lithium aluminum hydride (36.7 mg, 0.967 mmol) was added portionwise at 0 ° C, nitrogen The reaction was stirred for 1 hour under protection. The reaction solution was cooled to 0 ° C, and water (0.04 mL), 15% sodium hydroxide (0.04 mL) and water (0.12 mL). Filtration and concentration of the filtrate under reduced pressure gave (5-ethyl-isoxazol-3-yl)methanol (70.0 mg,yield of yellow oil).

¹ H NMR: (400 MHz, CDCl ₃ ) δ = 6.04 (s, 1H), 4.71 (s, 2H), 2.76 (q, J = 7.6 Hz, 2H), 2.57 (br, 1H), 1.29 (t, J = 7.6 Hz, 3H).

third step.

5-ethyl-isoxazol-3-ylmethyl methanesulfonate.

(4,4-Difluoro-cyclohexyl)methanol (70.0 mg, 0.551 mmol) and triethylamine (167 mg, 1.65 mmol) were dissolved in dichloromethane (10 mL). Sulfonium chloride (126 mg, 1.10 mmol). The reaction solution was stirred at 0 ° C for 4 hours. The reaction was quenched with water (10 mL)EtOAcEtOAc The combined organic layers were washed with aq. EtOAc EtOAc (EtOAc) 3-methylmethyl ester (90.0 mg, yellow oil), yield: 80%.

¹ H NMR: (400 MHz, CDCl ₃ ) δ = 6.17 (s, 1H), 5.28 (s, 2H), 3.08 (s, 3H), 2.82 (q, J = 7.6 Hz, 2H), 1.33 (t, J = 7.6 Hz, 3H). MS-ESI calcd for [M + H] &^lt;

the fourth step.

1-(5-Ethyl-isoxazol-3-ylmethyl)-3,7-dimethyl-3,7-dihydro-indole-2,6-dione.

Dissolve 3,7-dimethyl-1 H -indole-2,6(3 H ,7 H )-dione (79.0 mg, 0.439 mmol) in N , N -dimethylformamide (100 mL) 5-Methyl-isoxazol-3-ylmethyl methanesulfonate (90.0 mg, 0.439 mmol), potassium carbonate (121 mg, 0.876 mmol) and potassium iodide (87.3 mg, 0.526 mmol) were added. The reaction solution was heated to 120 ° C and stirred for 3 hours. The organic layer was concentrated under reduced pressure. EtOAc mjjjjjjjjjjj -Dimethyl-3,7-dihydro-indole-2,6-dione (48.0 mg), Yield: 38%.

¹ H NMR: (400 MHz, CDCl ₃ ) δ = 7.53 (s, 1H), 6.00 (s, 1H), 5.26 (s, 2H), 4.00 (s, 3H), 3.60 (s, 3H), 2.72 ( q, J = 7.6 Hz, 2H), 1.26 (t, J = 7.6 Hz, 3H). MS-ESI calcd for [M + H] ⁺ 290.

Example 25.

L - ((3,5-dimethyl-4-yl) methyl) -3,7-dimethyl -1 H - purine -2,6 (3 H, 7 H) - dione.

first step.

L - ((3,5-dimethyl-4-yl) methyl) -3,7-dimethyl -1 H - purine -2,6 (3 H, 7 H) - dione.

4-Chloro-3,5-dimethyl-isoxazole (100 mg, 0.689 mmol), 3,7- dimethyl -1 H - purine -2,6 (3 H, 7 H) - two Ketone (124 mg, 0.689 mmol), potassium iodide (10.9 mg, 0.0689 mmol) and potassium carbonate (190 mg, 1.38 mmol) were dissolved in anhydrous N , N -dimethylformamide (3 mL). The reaction solution was heated to 120 ° C and allowed to react for 3 hours. The reaction solution was cooled to 20 ° C, filtered, and purified by preparative HPLC to give 1-((3,5-dimethylisoxazol-4-yl)methyl)-3,7-dimethyl- 1 H - purine -2,6 (3 H, 7 H) - dione (30.0 mg), yield: 15%.

¹ H NMR: (400 MHz, Methonal- d ₄ ) δ = 7.73 (s, 1H), 4.94 (s, 2H), 4.03 (s, 3H), 3.60 (s, 3H), 2.50 (s, 3H), 2.32 (s, 3H). MS-ESI calcd for [M + H] ⁺ 290.

Example 26.

3,7-Dimethyl-1-((5-methyl-1,3,4-oxadiazol-2-yl)methyl)-1 H -indole-2,6(3 H ,7 H ) - Diketone.

first step.

3,7-Dimethyl-1-((5-methyl-1,3,4-oxadiazol-2-yl)methyl)-1 H -indole-2,6(3 H ,7 H ) - Diketone.

2-Chloromethyl-5-methyl-1,3,4-oxadiazole (100 mg, 0.758 mmol), 3,7-dimethyl- 1H -indole-2,6( 3H ,7 H )-Dione (136 mg, 0.758 mmol), potassium iodide (12.0 mg, 0.0758 mmol) and potassium carbonate (209 mg, 1.52 mmol) were dissolved in anhydrous N , N -dimethylformamide (3 mL). The reaction solution was heated to 120 ° C and allowed to react for 3 hours. The reaction solution was cooled to 20 ° C, filtered, and purified by preparative high-performance liquid chromatography to give 3,7-dimethyl-1-((5-methyl-1,3,4-oxadiazol-2-yl). Methyl)-1 H -嘌呤-2,6(3 H ,7 H )-dione (30.0 mg), Yield: 34%.

^{1 H NMR: (400 MHz,} Methonal- d 4) δ = 7.94 (s, 1H), 5.39 (s, 2H), 4.00 (s, 3H), 3.57 (s, 3H), 2.54 (s, 3H). MS-ESI calcd for [M + H] ⁺ 277.

Example 27.

3,7-Dimethyl-1-(4-(3-methylisoxazole-5-yl)cyclohexyl)-1 H -indole-2,6(3 H ,7 H )-dione.

first step.

3-methyl-5-(tributylstannyl)isoxazole.

Nitroethane (1.65 g, 22.0 mmol) and phenyl isocyanate (10.4 g, 87.7 mmol) were dissolved in dry toluene (20 mL), heated to 50 ° C and stirred for 5 minutes, then tributyl acetylene was added. Alkane (6.30 g, 20.0 mmol) and triethylamine (3.7 mg, 0.0364 mmol). The reaction solution was further stirred at 50 ° C for 14 hours. Add ethyl acetate (70 mL), dilute with EtOAc (EtOAc) (EtOAc)EtOAc. = 0.5) 3-methyl-5-(tributylstannyl)isoxazole (6.35 g, yellow oil) was obtained. Yield: 85%.

¹ H NMR: (400 MHz, CDCl ₃ ) δ = 6.19 (s, 1H), 2.31 (s, 3H), 1.55-1.53 (m, 5H), 1.35-1.29 (m, 7H), 1.15-1.11 (m , 5H), 0.90-0.87 (m, 10H). MS-ESI calcd [M + H] ⁺ 374.

The second step.

3-methyl-5-(1,4-dioxaspiro[4.5]indole-7-en-8-yl)isoxazole.

3-methyl-5-(tributylstannyl)isoxazole (4.00 g, 10.7 mmol) was dissolved in 1,4-dioxane (30 mL), and the reaction mixture was added at 25 ° C. 4-Dioxaspiro[4.5]dec-7-en-8-yl trifluoromethanesulfonate (2.57 g, 8.93 mmol) and tetrakistriphenylphosphine palladium (1.02 g, 0.883 mmol). The reaction mixture was heated to 120 ° C and stirred for 2 hours. The reaction mixture was cooled to 25 ° C, diluted with ethyl acetate (70 mL), washed with saturated sodium bicarbonate (30 mL EtOAc) Separation and purification by gel column chromatography (5:1 petroleum ether / ethyl acetate, Rf = 0.3) to give 3-methyl-5-(1,4-dioxaspiro[4.5]indole-7-ene- 8-yl)isoxazole (1.21 g, yellow oil), yield: 62%. MS-ESI calcd for [M + H] ⁺ 222.

third step.

3-methyl-5-(1,4-dioxaspiro[4.5]decane-8-yl)isoxazole.

3-Methyl-5-(1,4-dioxaspiro[4.5]indole-7-en-8-yl)isoxazole (800 mg, 3.62 mmol) was dissolved in methanol (30 mL), 25 Pd/C (10%, 20.0 mg, 0.171 mmol) was added under the conditions of ° C. The reaction mixture was stirred under a hydrogen balloon for 2 hours, filtered, and the filter cake was washed with methanol, and the filtrate was concentrated to give 3-methyl-5. -(1,4-Dioxaspiro[4.5]decane-8-yl)isoxazole (500 mg, colorless oil), yield: 62%. MS-ESI calcd for [M + H] ⁺ 224.

the fourth step.

4-(3-Methylisoxazole-5-yl)cyclohexanone.

3-methyl-5-(1,4-dioxaspiro[4.5]decane-8-yl)isoxazole (500 mg, 2.24 mmol) was dissolved in tetrahydrofuran (15 mL) at 25 °C 10% hydrochloric acid (5 mL) was added, and the mixture was stirred at 50 ° C for 1 hour, cooled to 25 ° C, diluted with ethyl acetate (20 mL), washed with saturated sodium hydrogen carbonate (20 mL×2) Dryed over sodium sulfate, filtered, and then evaporated, mjjjjjjjjjjjj MS-ESI calc. [M+H] ⁺ 180, Found.

the fifth step.

4-(3-Methylisoxazol-5-yl)cyclohexanol.

4-(3-Methylisoxazol-5-yl)cyclohexanone (400 mg, 2.23 mmol) was dissolved in methanol (30 mL). EtOAc EtOAc The reaction solution was stirred at 25 ° C for 4 hours. The reaction was quenched with EtOAc (EtOAc)EtOAc. The organic phase was washed with saturated sodium bicarbonate (20 mL EtOAc) (EtOAc m. 4-(3-Methylisoxazole-5-yl)cyclohexanol (200 mg, colorless oil) was obtained, yield: 50%. MS-ESI calcd for [M + H] ⁺ 182.

The sixth step.

4-(3-Methylisoxazol-5-yl)cyclohexyl methanesulfonate.

4-(3-Methylisoxazol-5-yl)cyclohexanol (100 mg, 0.552 mmol) and triethylamine (111 mg, 1.10 mmol) in dichloromethane (20 mL) Methanesulfonium chloride (94.9 mg, 0.829 mmol) was added under C conditions. After the reaction mixture was stirred at 25 ° C for 2 hours, it was diluted with methylene chloride (20 mL), washed with saturated sodium hydrogen sulfate (30 mL), dried over anhydrous sodium sulfate and filtered. Separation and purification (4:1 petroleum ether / ethyl acetate, Rf = 0.5) gave 4-(3-methylisoxazol-5-yl)cyclohexyl methanesulfonate (100 mg, colorless oil) , yield: 50%. MS-ESI calcd [M+H] ⁺ 262.

The seventh step.

3,7-Dimethyl-1-(4-(3-methylisoxazole-5-yl)cyclohexyl)-1 H -indole-2,6(3 H ,7 H )-dione.

4-(3-Methylisoxazole-5-yl)cyclohexyl methanesulfonate (40.0 mg, 0.154 mmol) was dissolved in N , N -dimethylformamide (10 mL). 3,7-Dimethyl-1 H -indole-2,6(3 H ,7 H )-dione (55.6 mg, 0.309 mmol) and cesium carbonate (110 mg, 0.309 mmol) were added at 25 °C. The reaction mixture was heated to 100 ° C, and the mixture was stirred for 2 hr. EtOAc (EtOAc) Purification by high performance liquid chromatography gave 3,7-dimethyl-1-(4-(3-methylisoxazole-5-yl)cyclohexyl)-1 H -indole-2,6(3 H ,7 H )-dione (4.0 mg), yield: 9%.

^{1 H NMR: (400MHz, Methonal-} d 4) δ = 7.84 (s, 1H), 6.32 (s, 1H), 3.96 (s, 3H), 3.51 (s, 3H), 3.21 (m, 1H), 2.91 -2.72 (m, 1H), 2.68-2.63 (m, 2H), 2.33 (s, 3H), 2.27 (m, 1H), 1.95-1.88 (m, 2H), 1.55-1.56 (m, 3H). MS-ESI calcd [M+H] ⁺ 344.

Example 28.

first step.

3-((3-Methylisoxazol-5-yl)methyl)cyclohex-2-enone.

3,5-Dimethylisoxazole (5.00 g, 51.5 mmol) was dissolved in anhydrous tetrahydrofuran (100 mL), and n-butyllithium solution (62 mL, 3M) was slowly added dropwise at -78 °C under nitrogen. A solution of n-hexane (155 mmol) was stirred at -78 °C for 2 hr. 3-Ethoxy-2cyclohexen-1-one (7.22 g, 51.5 mmol) was added slowly and stirring was continued for 1 hour. The reaction was quenched by the addition of water (100 mL). The reaction mixture was extracted with EtOAc EtOAc (EtOAc)EtOAc. Purification by gel column chromatography (5:1 petroleum ether / ethyl acetate, Rf = 0.4) to give 3-((3-methylisoxazol-5-yl)methyl)cyclohex-2-enone (5.10 g) , yellow oil), yield: 52%.

MS-ESI calcd [M + H] ⁺ 192.

The second step.

3-((3-Methylisoxazol-5-yl)methyl)cyclohexanone.

3-((3-Methylisoxazol-5-yl)methyl)cyclohex-2-enone (1.50 g, 7.84 mmol) was dissolved in methanol (30 mL), 10% at room temperature Pd/C (20.0 mg, 0.171 mmol), and the mixture was stirred for 1 hour under a hydrogen balloon (15 psi), filtered, and the filter cake was washed with methanol (10 mL). Methyl isoxazole-5-yl)methyl)cyclohexanone (1.20 g, colorless oil), yield: 80%.

MS-ESI calcd for [M ⁺ H] + 194, found 194.

third step.

3-((3-Methylisoxazol-5-yl)methyl)cyclohexanol.

3-((3-Methylisoxazol-5-yl)methyl)cyclohexanone (2.00 g, 10.4 mmol) was dissolved in methanol (30 mL) and sodium borohydride (0.790 g , 20.8 mmol), and the reaction solution was stirred at room temperature for 4 hours. The reaction was quenched with water (20 mL)EtOAc. The organic phase was washed with saturated sodium bicarbonate (20 mL EtOAc) (EtOAc m. 3-((3-Methylisoxazol-5-yl)methyl)cyclohexanol (1.21 g, colorless oil) was obtained.

MS-ESI calcd for [M + H] ⁺ 196.

the fourth step.

3-((3-Methylisoxazol-5-yl)methyl)cyclohexylmethyl methanesulfonate.

3-((3-Methylisoxazol-5-yl)methyl)cyclohexanol (300 mg, 1.54 mmol) and triethylamine (311 mg, 3.08 mmol) dissolved in dichloromethane (20 mL) Methionine chloride (264 mg, 2.31 mmol) was added at 0 °C. After the reaction mixture was stirred at room temperature for 2 hr, EtOAc EtOAc (EtOAc m. Separation and purification (4:1 petroleum ether / ethyl acetate, Rf = 0.5) gave 3-((3-methylisoxazol-5-yl)methyl)cyclohexylmethyl methanesulfonate (400 mg, Colorless oil), Yield: 96%.

MS-ESI calcd for [M + H] ⁺ 274.

the fifth step.

3,7-Dimethyl-1-(3-((3-methylisoxazole-5-yl)methyl)cyclohexyl)-1 H -indole-2,6(3 H ,7 H )- Dione.

3-((3-Methylisoxazol-5-yl)methyl)cyclohexylmethyl methanesulfonate (100 mg, 0.366 mmol) dissolved in N , N -dimethylformamide (15 mL) In the reaction solution, 3,7-dimethyl-1 H -indole-2,6(3 H ,7 H )-dione (66.0 mg, 0.366 mmol), potassium iodide (6.1 mg, 0.037 mmol) and potassium carbonate (758 mg, 0.549 mmol). The reaction mixture was heated to 100 ° C, and the mixture was stirred for 2 hr. EtOAc (EtOAc) Purification by high performance liquid chromatography gave 3,7-dimethyl-1-(3-((3-methylisoxazole-5-yl)methyl)cyclohexyl)-1 H -嘌呤-2,6 (3) H ,7 H )-dione (20.0 mg), yield: 15%.

¹ H NMR: (400 MHz, CDCl ₃ ) δ = 7.48 (s, 1H), 5.89 (s, 1H), 5.19-5.12 (m, 1H), 3.97 (s, 3H), 3.54 (s, 3H), 2.94 (d, J = 8.0 Hz, 2H), 2.77-2.75 (m, 1H), 2.73-2.70 (m, 2H), 2.25 (s, 3H), 1.70-1.68 (m, 3H), 1.58-1.51 ( m, 3H). MS-ESI calcd for [M + H] ⁺ 358.

Example 29.

L - ((2,4-dimethyl-thiazol-5- yl) methyl) -3,7-dimethyl -1 H - purine -2,6 (3 H, 7 H) - dione.

first step.

(2,4-Dimethylthiazol-5-yl)methanol.

Ethyl (2,4-dimethylthiazol-5-yl)carboxylate (500 mg, 2.70 mmol) was dissolved in anhydrous tetrahydrofuran (10 mL), and lithium tetrahydroaluminum (205 mg, 5.40) was added at 0 °C. Methyl), reaction for 1 hour. The mixture was extracted with EtOAc (EtOAc (EtOAc) 0.4), (2,4-dimethylthiazol-5-yl)methanol (300 mg, yellow solid).

¹ H NMR: (400 MHz, Methonal- d ₄ ) δ = 4.68 (s, 2H), 2.64 (s, 3H), 2.33 (s, 3H).

The second step.

5-(Chloromethyl)-2,4-dimethylthiazole.

(2,4-Dimethylthiazol-5-yl)methanol (300 mg, 2.09 mmol) and triethylamine (635 mg, 6.29 mmol) were dissolved in anhydrous dichloromethane (10 mL). Methanesulfonium chloride (468 mg, 4.18 mmol) was added at 0 °C. The reaction solution was slowly warmed to 25 ° C and stirred for 2 hours. The reaction was quenched with EtOAc (EtOAc)EtOAc The organic phase was combined, washed with EtOAc EtOAc EtOAcjHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH : 54%.

¹ H NMR: (400 MHz, Methonal- d ₄ ) δ = 4.86 (s, 2H), 2.65 (s, 3H), 2.73 (s, 3H).

third step.

L - ((2,4-dimethyl-thiazol-5- yl) methyl) -3,7-dimethyl -1 H - purine -2,6 (3 H, 7 H) - dione.

5-(Chloromethyl)-2,4-dimethylthiazole (182 mg, 1.13 mmol), 3,7-dimethyl-1 H -indole-2,6(3 H ,7 H )- Ketone (203 mg, 1.13 mmol), potassium iodide (17.9 mg, 0.113 mmol) and potassium carbonate (312 mg, 2.26 mmol) were dissolved in anhydrous N , N -dimethylformamide (5 mL). The reaction solution was heated to 120 ° C and allowed to react for 3 hours. The reaction solution was cooled to 20 ° C, filtered, and purified by preparative HPLC to give 1-((2,4-dimethylthiazol-5-yl)methyl)-3,7-dimethyl- 1H - purine -2,6 (3 H, 7 H) - dione (130 mg), yield: 38%.

¹ H NMR: (400 MHz, Methonal- d ₄ ) δ = 7.88 (s, 1H), 5.23 (s, 2H), 3.99 (s, 3H), 3.54 (s, 3H), 2.58 (s, 3H), 2.52 (s, 3H). MS-ESI calcd [M+H] ⁺ 306, Found 306.

Example 30.

3,7-Dimethyl-1-2-(2-methylthiazol-4-yl)ethyl)-1 H -indole-2,6(3 H ,7 H )-dione.

first step.

Methyl 2-(2-methylthiazol-4-yl)acetate.

2-(2-Methylthiazol-4-yl)acetic acid (50.0 mg, 0.270 mmol) was dissolved in methanol (2 mL), and dichlorothylene (0.1 mL) was slowly added at 0 ° C. Slowly warm to room temperature and stir for 2.5 hours. The reaction was quenched with EtOAc (EtOAc) (EtOAc (EtOAc) Petroleum ether / ethyl acetate, Rf = 0.4) gave the product, m.p., 2-(2-methylthiazol-4-yl)acetate (40.0 mg, yellow liquid), yield: 87%.

¹ H NMR: (400 MHz, Methonal- d ₄ ) δ = 7.21 (s, 1H), 3.78 (s, 2H), 3.70 (s, 3H), 2.67 (s, 3H).

The second step.

2-(2-methylthiazol-4-yl)ethanol.

Lithium aluminum hydride (34.0 mg, 0.890 mmol) was slowly dissolved in tetrahydrofuran (20 mL) at 0 ° C under nitrogen, and methyl 2-(2-methylthiazol-4-yl)acetate was slowly added. 40.0 mg, 0.230 mmol) in tetrahydrofuran (3 mL). The reaction solution was slowly warmed to room temperature and stirred for 1.5 hours. The reaction solution was cooled to 0 ° C, and water (0.1 mL), 15% sodium hydroxide (0.1 mL) and water (0.3 mL) were added slowly. The reaction solution was warmed to room temperature, stirred for half an hour, filtered, and the filter cake was washed with tetrahydrofuran (10 mL x 3). The filtrate was concentrated under reduced pressure and purified (1:3 petroleum ether/ethyl acetate, Rf = 0.5) to afford product 2-(2-methylthiazol-4-yl)ethanol (22.0 mg, yellow liquid). Yield: 67%.

¹ H NMR: (400 MHz, Methonal- d ₄ ) δ = 7.04 (s, 1H), 3.83 (t, J = 6.8 Hz, 2H), 2.92 (t, J = 6.8 Hz, 2H), 2.67 (s, 3H).

third step.

2-(2-Methylthiazol-4-yl)ethyl methanesulfonate.

2-(2-Methylthiazol-4-yl)ethanol (22.0 mg, 0.150 mmol) and diisopropylethylamine (40.0 mg, 0.310 mmol) were dissolved in dichloromethane (5 mL) Methanesulfonyl chloride (50.0 mg, 0.440 mmol) was slowly added at °C. The reaction solution was slowly warmed to room temperature and stirred overnight. The reaction was quenched by the addition of water (20 mL). Extracted with ethyl acetate (30 mL×3), EtOAcjjjjjjjjj 26.0 mg, yellow liquid), yield: 79%.

the fourth step.

3,7-Dimethyl-1-2-(2-methylthiazol-4-yl)ethyl)-1 H -indole-2,6(3 H ,7 H )-dione.

2- (2-methyl-thiazol-4-yl) ethyl methanesulfonate (218 mg, 1.00 mmol), 3,7- dimethyl -1 H - purine -2,6 (3 H, 7 H )-dione (180 mg, 1.00 mmol) and potassium carbonate (414 mg, 3.00 mmol) were dissolved in N , N -dimethylformamide (3.3 mL), and potassium iodide (17.0 mg, 0.100 mmol) was added. Heat to 130 ° C and stir for 3 hours. The reaction solution was cooled to room temperature and brine (20 mL) The organic phase was combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by preparative high-performance liquid chromatography to give 3,7-dimethyl-1-2-(2-methylthiazol-4-yl) Base)-1 H -嘌呤-2,6(3 H ,7 H )-dione (44.0 mg), yield: 15%.

¹ H NMR: (400 MHz, Methonal- d ₄ ) δ = 7.86 (s, 1H), 7.04 (s, 1H), 4.29 (t, J = 7.2 Hz, 2H), 3.95 (s, 3H), 3.51 ( s, 3H), 3.04 (t, J = 7.2 Hz, 2H), 2.65 (s, 3H). MS-ESI calcd [M+H] ⁺ 306, Found 306.

Example 31.

1- (2- (2,4-dimethyl-thiazol-5-yl) ethyl) -3,7-dimethyl -1 H - purine -2,6 (3 H, 7 H) - dione.

first step.

Methyl 2-(2,4-dimethylthiazol-5-yl)acetate.

2-(2,4-Dimethylthiazol-5-yl)acetic acid (50.0 mg, 0.250 mmol) was dissolved in methanol (2 mL). The reaction solution was slowly warmed to room temperature and stirred for 2.5 hours. The reaction was quenched with water (20 mL)EtOAc. The organic phase was combined, dried over anhydrous sodium sulfate, filtered, evaporated, evaporated, evaporated, evaporated, Methyl thiazol-5-yl)acetate (32.0 mg, yellow liquid), yield: 70%.

¹ H NMR: (400 MHz, Methonal- d ₄ ) δ = 3.79 (s, 2H), 3.71 (s, 3H), 2.61 (s, 3H), 2.27 (s, 3H).

The second step.

2-(2,4-Dimethylthiazol-5-yl)ethanol.

Lithium aluminum hydride (47.0 mg, 1.20 mmol) was slowly dissolved in tetrahydrofuran (60 mL) at 0 ° C under nitrogen, and methyl 2-(2,4-dimethylthiazol-5-yl)acetate was slowly added. (159 mg, 0.820 mmol) in tetrahydrofuran (4 mL). The reaction was slowly warmed to room temperature and stirred for 1.5 hours. The reaction solution was cooled to 0 ° C, and water (0.1 mL), 15% sodium hydroxide solution (0.1 mL) and water (0.3 mL) were added slowly. The reaction mixture was warmed to room temperature, stirred for half an hour, filtered, and the filter cake was washed with tetrahydrofuran (10 mL x 3), and the filtrate was concentrated under reduced pressure and purified by high-purity TLC (1:3 petroleum ether / ethyl acetate, Rf = 0.5) The product 2-(2,4-dimethylthiazol-5-yl)ethanol (61.0 mg, yellow liquid) was obtained.

¹ H NMR: (400 MHz, Methonal- d ₄ ) δ = 3.69 (t, J = 6.4 Hz, 2H), 2.90 (t, J = 6.4 Hz, 2H), 2.59 (s, 3H), 2.28 (s, 3H).

third step.

2-(2,4-Dimethylthiazol-5-yl)ethyl methanesulfonate.

2-(2,4-Dimethylthiazol-5-yl)ethanol (61.0 mg, 0.400 mmol) and diisopropylethylamine (103 mg, 0.800 mmol) were dissolved in dichloromethane (1.8 mL) Methanesulfonium chloride (124 mg, 1.10 mmol) was slowly added at 0 °C. The reaction solution was slowly warmed to room temperature and stirred overnight. The reaction was quenched with water (10 mL)EtOAcEtOAc The organic phase was combined, dried over anhydrous sodium sulfate, filtered and evaporated. : 75%.

the fourth step.

1- (2- (2,4-dimethyl-thiazol-5-yl) ethyl) -3,7-dimethyl -1 H - purine -2,6 (3 H, 7 H) - dione.

2-(2,4-Dimethylthiazol-5-yl)ethyl methanesulfonate (70.0 mg, 0.300 mmol), 3,7-dimethyl- 1H -indole-2,6 ( 3H , 7 H )-dione (60.0 mg, 0.330 mmol) and potassium carbonate (124 mg, 0.900 mmol) dissolved in N , N -dimethylformamide (3 mL), and added potassium iodide (5.0 mg, 0.0300 mmol) ). The reaction solution was heated to 130 ° C and stirred for 3 hours. The reaction mixture was cooled to room temperature and brine (30 mL) The organic phase was combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated. 3,7-Dimethyl-1 H -indole-2,6(3 H ,7 H )-dione (20.0 mg), Yield: 21%.

¹ H NMR: (400 MHz, Methoanl- d ₄ ) δ = 7.87 (s, 1H), 4.17-4.12 (m, 2H), 3.96 (s, 3H), 3.52 (s, 3H), 3.08-3.03 (m) , 2H), 2.59 (s, 3H), 2.29 (s, 3H). MS-ESI calcd for [M+H] ⁺ 320, found 320.

Example 32.

1-[2-(2,4-Dimethylthiazol-5-yl)ethyl]-3,7-dimethylindole-2,6-dione.

first step.

4-bromo-5-oxohexanoic acid.

5-oxohexanoic acid (2.00 g, 15.4 mmol) was dissolved in concentrated hydrochloric acid (20 mL) and EtOAc (EtOAc) The reaction was carried out for 2 hours at room temperature. The reaction was quenched by the addition of water (10 mL). It was extracted with ethyl acetate (10 mL×3), dried over anhydrous sodium sulfate, filtered, evaporated, evaporated, evaporated, evaporated. Bromo-5-oxohexanoic acid (2.50 g, yellow oil), yield: 76%. MS-ESI calculated [M + H] ⁺ 209 and 211, found 209 and 211.

The second step.

Ethyl ethyl 3-(2,4-dimethylthiazol-5-yl)propanoate.

4-Bromo-5-oxohexanoic acid (2.50 g, 11.9 mmol), thioacetamide (1.00 g, 13.3 mmol) was dissolved in ethanol (30 mL). The reaction was quenched by the addition of water (10 mL). It was extracted with ethyl acetate (10 mL×3), dried over anhydrous sodium sulfate, filtered, evaporated, evaporated, evaporated. Ethyl (2,4-dimethylthiazol-5-yl)propanoate (120 mg, yellow oil). Yield: 6%.

MS-ESI calcd for [M ⁺ H] + 214, found 214.

third step.

2-(2,4-Dimethylthiazol-5-yl)ethanol.

Ethyl ethyl 3-(2,4-dimethylthiazol-5-yl)propanoate (150 mg, 0.703 mmol) was dissolved in tetrahydrofuran (10 mL). 40.0 mg, 1.05 mmol), reacted for 1 hour. The reaction was quenched by the addition of water (10 mL). It was extracted with ethyl acetate (10 mL×3), dried over anhydrous sodium sulfate, filtered, evaporated, evaporated, evaporated. 2,4-Dimethylthiazol-5-yl)ethanol (100 mg, colorless oil), yield: 83%.

MS-ESI calcd for [M + H] ⁺ 172.

the fourth step.

2-(2,4-Dimethylthiazol-5-yl)ethyl methanesulfonate.

2-(2,4-Dimethylthiazol-5-yl)ethanol (75.0 mg, 0.477 mmol) and triethylamine (96.0 mg, 0.949 mmol) in dichloromethane (5 mL) Methane sulfonium chloride (54.6 mg, 0.477 mmol) was added. The reaction solution was slowly warmed to room temperature and stirred for 2 hours. The reaction was quenched by the addition of aqueous sodium bicarbonate (10 mL). Extract with dichloromethane (10 mL x 3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate Shape), yield: 89%. MS-ESI calculated [M+H] ⁺ 250, found 250.

the fifth step.

1-[2-(2,4-Dimethylthiazol-5-yl)ethyl]-3,7-dimethylindole-2,6-dione.

2-(2,4-Dimethylthiazol-5-yl)ethyl methanesulfonate (100 mg, 0.425 mmol), 3,7-dimethyl- 1H -indole-2,6 ( 3H , 7 H )-dione (76.5 mg, 0.425 mmol), potassium iodide (7.0 mg, 0.042 mmol) and potassium carbonate (117 mg, 0.846 mmol) dissolved in N , N -dimethylformamide (10 mL) . The reaction solution was warmed to 120 ° C and stirred for 3 hours. It was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure and purified by preparative high-purity liquid chromatography to give 1-[2-(2,4-dimethylthiazol-5-yl)ethyl]-3,7-dimethyl Base-2,6-dione (22.0 mg), yield: 16%.

¹ H NMR: (400 MHz, Methonal- d ₄ ) δ = 7.86 (s, 1H), 4.06 (t, J = 7.6 Hz, 2H), 3.96 (s, 3H), 3.51 (s, 3H), 2.80 ( t, J = 7.6 Hz, 2H), 2.53 (s, 3H), 2.26 (s, 3H), 2.00-1.91 (m, 2H). MS-ESI calcd for [M ⁺ H] + 334, found 334.

Example 33.

3,7-Dimethyl-1-((5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl)methyl)-1 H -indole-2,6(3 H , 7 H )-dione.

first step.

3,7-Dimethyl-1-((5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl)methyl)-1 H -indole-2,6(3 H , 7 H )-dione.

2-Chloromethyl-5-trifluoromethyl-1,3,4-oxadiazole (100 mg, 0.541 mmol), 3,7-dimethyl-1 H -indole-2,6 (3 H ,7 H )-dione (97.3 mg, 0.541 mmol), potassium iodide (8.5 mg, 0.0541 mmol) and potassium carbonate (143 mg, 1.08 mmol) dissolved in anhydrous N , N -dimethylformamide (3 mL) in. The reaction solution was heated to 120 ° C and allowed to react for 3 hours. The reaction solution was cooled to 20 ° C, filtered, and purified by preparative high-performance liquid chromatography to give 3,7-dimethyl-1-((5-(trifluoromethyl)-1,3,4-oxadiazole- 2- yl) methyl) -1 H - purine -2,6 (3 H, 7 H) - dione (60.0 mg), yield: 34%.

¹ H NMR: (400 MHz, Methonal- d ₄ ) δ = 7.95 (s, 1H), 5.53 (s, 2H), 4.40 (s, 3H), 3.57 (s, 3H). MS-ESI calcd for [M ⁺ H] + 331, found 331.

Example 34.

1-(4-(2 H -1,2,3-triazol-4-yl)butyl)-3,7-dimethyl-1 H -indole-2,6(3 H ,7 H )- Dione.

first step.

1-(Hex-5-yn-1-yl)-3,7-dimethyl-1 H -indole-2,6(3 H ,7 H )-dione.

Dissolve 3,7-dimethyl-1 H -indole-2,6(3 H ,7 H )-dione (773 mg, 4.15 mmol) in N , N -dimethylformamide (20 mL) 6-Chlorohex-1-yne (500 mg, 4.15 mmol), potassium carbonate (859 mg, 6.23 mmol) and potassium iodide (103 mg, 0.623 mmol) were added at room temperature. The reaction solution was heated to 100 ° C and stirred for 2 hours. The reaction solution was cooled to room temperature and diluted with ethyl acetate (30 mL). The organic phase was washed with saturated sodium bicarbonate solution (20 mL x 2), dried over anhydrous sodium sulfate, to give 1- (hex-5-yn-1-yl) -3,7-dimethyl -1 H concentrated under reduced pressure - purine -2,6 (3 H, 7 H) - dione (1.15 g, yellow oil) yield: 95%. MS-ESI calculated [M + H] ⁺ 261, found 261.

The second step.

1-(4-(2 H -1,2,3-triazol-4-yl)butyl)-3,7-dimethyl-1 H -indole-2,6(3 H ,7 H )- Dione.

Dissolving 1-(hex-5-yn-1-yl)-3,7-dimethyl-1 H -indole-2,6(3 H ,7 H )-dione (1.00 g, 3.85 mmol) Tertiary butanol (15 mL) and water (15 mL). Sodium azide (375 mg, 5.77 mmol), sodium anti-sodium citrate (305 mg, 1.54 mmol) and copper sulfate pentahydrate (96.3 mg, 0.385 mmol) were added at room temperature. The reaction solution was heated to 60 ° C and stirred for 24 hours. It was cooled to room temperature and diluted with ethyl acetate (30 mL). The organic phase was washed with saturated sodium bicarbonate solution (20 mL x 2), dried over anhydrous sodium sulfate, and evaporated under reduced pressure and concentrated to give 1- (4- (2 H -1,2,3- triazol-4-yl) butyl ) -3,7-dimethyl -1 H - purine -2,6 (3 H, 7 H) - dione (300 mg), yield: 19%).

¹ H NMR: (400MHz, Methanol- d ₄ ) δ = 7.88 (s, 1H), 7.61 (s, 1H), 4.04 (t, J = 7.2 Hz, 2H), 3.98 (s, 3H), 3.54 (s) , 3H), 2.80 (t, J = 7.2 Hz, 2H), 1.71-1.73 (m, 4H). MS-ESI calcd for [M + H] ⁺ 303.

Example 35.

3,7-Dimethyl-1-(4-(2-methyl-2 H -1,2,3-triazol-4-yl)butyl)-1 H -嘌呤-2,6(3 H , 7 H )-dione.

1-(4-(2 H -1,2,3-triazol-4-yl)butyl)-3,7-dimethyl-1 H -indole-2,6(3 H ,7 H ) The diketone (300 mg, 0.990 mmol) was dissolved in N , N -dimethylformamide (20 mL). Methyl iodide (281 mg, 2.00 mmol) and potassium carbonate (276 mg, 2.00 mmol) were added at room temperature. The reaction was stirred at room temperature for 2 hours. It was diluted with ethyl acetate (40 mL), and the organic phase was washed with saturated sodium hydrogen sulfate (20 mL EtOAc). 1-(4-(2-methyl-2 H -1,2,3-triazol-4-yl)butyl)-1 H -indole-2,6(3 H ,7 H )-di Ketone (15.0 mg) Yield: 10%.

¹ H NMR: (400MHz, Methanol- d ₄ ) δ = 7.88 (s, 1H), 7.46 (s, 1H), 4.10 (s, 3H), 4.02 (t, J = 7.2 Hz, 2H), 3.98 (s , 3H), 3.53 (s, 3H), 2.72 (t, J = 7.2 Hz, 2H), 1.69-1.71 (m, 4H). MS-ESI calcd [M + H] ⁺ 318. Found 318.

Example 36.

3,7-Dimethyl-1-(3-(2-methyl-2 H -1,2,3-triazol-4-yl)propyl)-1 H -嘌呤-2,6(3 H , 7 H )-dione.

3,7-Dimethyl-1-(3-(1-methyl-1 H -1,2,3-triazol-4-yl)propyl)-1 H -嘌呤-2,6(3 H , 7 H )-dione.

3,7,9-trimethyl-1-(3-(2-methyl-1 H -1,2,3-triazol-4-yl)propyl)-2,6-dioxo-2, 3,6,7-tetrahydro-1 H -indole-2,6(3 H ,7 H )-dione.

first step.

3,7-Dimethyl-1-(pent-4-yn-1-yl)-1 H -indole-2,6(3 H ,7 H )-dione

Dissolve 3,7-dimethyl-1 H -indole-2,6(3 H ,7 H )-dione (965 mg, 5.37 mmol) in N , N -dimethylformamide (20 mL) in. 5-Chloropent-1-yne (500 mg, 4.88 mmol), potassium carbonate (1.35 g, 9.76 mmol) and potassium iodide (162 mg, 0.976 mmol) were added at room temperature. The reaction solution was heated to 100 ° C and stirred for 2 hours. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (30 mL), EtOAc (EtOAc) 7-Dimethyl-1-(pent-4-yn-1-yl)-1 H -indole-2,6(3 H ,7 H )-dione (1.02 g, yellow oil), yield : 94%. MS-ESI calcd for [M + H] ⁺ 247.

The second step.

1-(3-(1 H -1,2,3-triazol-4-yl)propyl)-3,7-dimethyl-1 H -indole-2,6(3 H ,7 H )- Dione.

1-(3-(1 H -1,2,3-triazol-5-yl)propyl)-3,7-dimethyl-1 H -indole-2,6(3 H ,7 H )- Dione.

Dissolve 3,7-dimethyl-1-(pent-4-yn-1-yl)-1 H -indole-2,6(3 H ,7 H )-dione (1.40 g, 5.69 mmol) In a tertiary butanol (20 mL) and water (20 mL). Sodium azide (444 mg, 6.83 mmol), sodium anti-sodium sulphate (450 mg, 2.28 mmol) and copper sulfate pentahydrate (142 mg, 0.569 mmol) were added at room temperature. The reaction solution was heated to 60 ° C and stirred for 24 hours. It was cooled to room temperature and diluted with ethyl acetate (30 mL). The organic phase was washed with saturated sodium bicarbonate solution (20 mL x 2). The organic phases were combined, dried over anhydrous sodium sulfate and evaporated to dryness to afford 1-(3-( 1H -1,2,3-triazol-4-yl)propyl)-3,7-dimethyl- 1H -嘌呤-2,6(3 H ,7 H )-dione and 1-(3-(1 H -1,2,3-triazol-5-yl)propyl)-3,7-dimethyl -1 H - purine -2,6 (3 H, 7 H) - dione mixture (300 mg, yellow oil). yield: 19%. MS-ESI calcd for [M + H] ⁺ 290.

third step.

3,7-Dimethyl-1-(3-(2-methyl-2 H -1,2,3-triazol-4-yl)propyl)-1 H -嘌呤-2,6(3 H , 7 H )-dione.

3,7-Dimethyl-1-(3-(1-methyl-1 H -1,2,3-triazol-4-yl)propyl)-1 H -嘌呤-2,6(3 H , 7 H )-dione.

3,7,9-trimethyl-1-(3-(2-methyl-1 H -1,2,3-triazol-4-yl)propyl)-2,6-dioxo-2, 3,6,7-tetrahydro-1 H -indole-2,6(3 H ,7 H )-dione.

1-(3-(1 H -1,2,3-triazol-4-yl)propyl)-3,7-dimethyl-1 H -indole-2,6(3 H ,7 H ) -dione and 1-(3-(1 H -1,2,3-triazol-5-yl)propyl)-3,7-dimethyl-1 H -indole-2,6(3 H , A mixture of 7 H )-diketone (300 mg, 1.04 mmol) was dissolved in N , N -dimethylformamide (20 mL). Methyl iodide (295 mg, 2.08 mmol) and potassium carbonate were added at room temperature. (287 mg, 2.08 mmol). The reaction solution was stirred at room temperature for 2 hr and then diluted with ethyl acetate (40 mL). The organic phase was washed with saturated sodium bicarbonate solution (20 mL x 2). The combined organic phases are dried over anhydrous sodium sulfate, concentrated and evaporated to dryness, and purified by high-purity liquid chromatography to give two substituted isomers and a tri-substituted quaternary ammonium salt: 3,7-dimethyl-1-(3-( 2-methyl-2 H -1,2,3-triazol-4-yl)propyl)-1 H -indole-2,6(3 H ,7 H )-dione (20.0 mg) (isomeric Body 1, first peak), yield: 10%; 3,7-dimethyl-1-(3-(1-methyl-1 H -1,2,3-triazol-4-yl) Propyl)-1 H -嘌呤-2,6(3 H ,7 H )-dione (8.0 mg) (isomer 2, second peak), yield: 3%; 3,7,9- Trimethyl-1-(3-(2-methyl-1 H -1,2,3-triazol-4-yl)propyl)-2,6-dioxo-2,3,6,7- Tetrahydro-1 H -indole-2,6(3 H ,7 H )-dione (10.0 mg) (isomer 3, third peak), yield: 6%.

3,7-Dimethyl-1-(3-(2-methyl-2 H -1,2,3-triazol-4-yl)propyl)-1 H -嘌呤-2,6(3 H , 7 H )-dione: ¹ H NMR: (400 MHz, Methanol- d ₄ ) δ = 7.87 (s, 1H), 7.48 (s, 1H), 4.07 (t, J = 7.2 Hz, 2H), 4.04 (s, 3H), 3.98 (s, 3H), 3.52 (s, 3H), 2.74 (t, J = 7.2 Hz, 2H), 2.02-2.07 (m, 2H). MS-ESI calcd for [M + H] ⁺ 303.

3,7-Dimethyl-1-(3-(1-methyl-1 H -1,2,3-triazol-4-yl)propyl)-1 H -嘌呤-2,6(3 H , 7 H )-dione: ¹ H NMR: (400MHz, Methanol- d ₄ ) δ = 7.90 (s, 1H), 7.76 (s, 1H), 4.09 (t, J = 7.2 Hz, 2H), 4.05 ( s, 3H), 3.99 (s, 3H), 3.53 (s, 3H), 2.77 (t, J = 7.2 Hz, 2H), 2.03 (m, 2H). MS-ESI calcd for [M + H] ⁺ 303.

3,7,9-trimethyl-1-(3-(2-methyl-1 H -1,2,3-triazol-4-yl)propyl)-2,6-dioxo-2, 3,6,7-tetrahydro-1 H -indole-2,6(3 H ,7 H )-dione: ¹ H NMR: (400 MHz, Methanol- d ₄ ) δ = 8.64 (s, 1H), 7.91 (s, 1H), 4.33 (s, 3H), 4.24 (s, 3H), 4.10 (t, J = 7.2 Hz, 2H), 4.00 (s, 3H), 3.56 (s, 3H), 2.96 (t, J = 7.2 Hz, 2H), 2.13-2.19 (m, 2H). MS-ESI calcd for [M ⁺ H] + 319, found 319.

Example 37.

1- (4- (2 H - tetrazol-5-yl) butyl) -3,7-dimethyl -1 H - purine -2,6 (3 H, 7 H) - dione.

first step.

5-(3,7-Dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1 H -indol-1-yl)pentanenitrile.

6-chlorovaleronitrile (1.00 g, 8.56 mmol) was dissolved in anhydrous N , N -dimethylformamide (15 mL). Potassium iodide (142 mg, 0.850 mmol), 2,6-hydroxy-3,7-dimethylhydrazine (1.85 g, 10.3 mmol). The reaction solution was heated to 130 ° C and stirred for 3 hours. The reaction solution was cooled to room temperature and quenched by water (100 mL). The reaction mixture was extracted with ethyl acetate (30 mL×3). The combined organic layers were washed with aq. EtOAc (EtOAc (EtOAc) 2,3,6,7-tetrahydro-1 H -indol-1-yl)pentanenitrile (2.30 g, yellow oil), yield: 100%. MS-ESI calcd [M+H] ⁺ 262.

The second step.

1- (4- (2 H - tetrazol-5-yl) butyl) -3,7-dimethyl -1 H - purine -2,6 (3 H, 7 H) - dione.

Dissolve 5-(3,7-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1 H -indol-1-yl)valeronitrile (400 mg, 1.53 mmol) Sodium azide (299 mg, 4.60 mmol) and ammonium chloride (244 mg, 0.740 mmol) were added to N , N -dimethylformamide (5 mL). The reaction solution was heated to 130 ° C and stirred for 80 hours. The reaction mixture was cooled to rt. EtOAc (3 mL) The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and purified by preparative high-performance liquid chromatography to give 1-(4-( 2H -tetrazol-5-yl)butyl)-3,7-dimethyl- 1H -indole-2,6 ( 3 H , 7 H )-dione (250 mg), yield: 54%.

¹ H NMR: (400 MHz, Methonal- d ₄ ) δ = 7.88 (s, 1H), 4.07-4.04 (m, 2H), 3.98 (s, 3H), 3.54 (s, 3H), 3.05-3.01 (m) , 2H), 1.87-1.81 (m, 2H), 1.77-1.71 (m, 2H). MS-ESI calcd [M + H] ⁺ 303.

Example 38.

3,7-Dimethyl-1-(4-(2-methyl-2 H -tetrazol-5-yl)butyl)-1 H -indole-2,6(3 H ,7 H )- ketone.

3,7-Dimethyl-1-(4-(1-methyl-1H-tetrazol-5-yl)butyl)-1 H -indole-2,6(3H,7H)-dione.

1-(4-( 2H -tetrazol-5-yl)butyl)-3,7-dimethyl-1 H -indole-2,6(3 H ,7 H )-dione (200 mg , 0.658 mmol) was dissolved in N , N -dimethylformamide (5 mL), iodomethane (280 mg, 1.97 mmol) and potassium carbonate (272 mg, 1.97 mmol) were added, and the mixture was stirred at 20 ° C 12 hour. Water (30 mL) was added to the mixture and the mixture was evaporated. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by preparative high-performance liquid chromatography to give two substituted isomeric products: 3,7-dimethyl-1-(4-(2-methyl) -2 H -tetrazol-5-yl)butyl)-1 H -indole-2,6(3 H ,7 H )-dione (70.0 mg) (isomer 1, first peak), Rate: 33%. And 3,7-dimethyl-1-(4-(1-methyl-1H-tetrazol-5-yl)butyl)-1H-indole-2,6(3H,7H)-dione (70.0 Mg) (isomer 2, second peak), yield: 33%.

3,7-Dimethyl-1-(4-(2-methyl-2 H -tetrazol-5-yl)butyl)-1 H -indole-2,6(3 H ,7 H )- Ketone: ¹ H NMR: (400 MHz, Methonal- d ₄ ) δ = 7.88 (s, 1H), 4.32 (s, 3H), 4.04-4.02 (m, 2H), 3.99 (s, 3H), 3.54 (s , 3H), 2.93-2.91 (m, 2H), 1.82-1.73 (m, 4H). MS-ESI calcd for [M ⁺ H] + 319, found 319.

3,7-Dimethyl-1-(4-(1-methyl-1H-tetrazol-5-yl)butyl)-1H-indole-2,6(3H,7H)-dione: ¹ H NMR: (400 MHz, Methonal- d ₄ ) δ = 7.88 (s, 1H), 4.08 (s, 3H), 4.06-4.04 (m, 2H), 3.98 (s, 3H), 3.53 (s, 3H), 3.03-2.99 (m, 2H), 1.88-1.76 (m, 4H). MS-ESI calcd for [M ⁺ H] + 319, found 319.

Example 39.

1- (5- (2 H - tetrazol-5-yl) pentyl) -3,7-dimethyl -1 H - purine -2,6 (3 H, 7 H) - dione.

first step.

6-(3,7-Dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1 H -indol-1-yl)capronitrile.

6-Bromohexronitrile (1.00 g, 5.70 mmol) was dissolved in anhydrous N , N -dimethylformamide (15 mL), and then added with potassium carbonate (1.60 g, 11.7 mmol). Potassium iodide (94.0 mg, 0.570 mmol), 2,6-hydroxy-3,7-dimethylindole (1.20 g, 6.80 mmol). The reaction solution was heated to 130 ° C and stirred for 3 hours. The reaction mixture was slowly lowered to room temperature and quenched by water (60 mL). The mixture was extracted with ethyl acetate. The combined organic layers were washed with water and aq. The filtrate was concentrated under reduced pressure to give 6-(3,7-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1 H -indol-1-yl)hexanenitrile (1.80). g, yellow oil). MS-ESI calcd for [M + H] ⁺ 276.

The second step.

1- (5- (2 H - tetrazol-5-yl) pentyl) -3,7-dimethyl -1 H - purine -2,6 (3 H, 7 H) - dione.

Dissolve 6-(3,7-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1 H -indol-1-yl)capronitrile (300 mg, 1.09 mmol) Add sodium azide (355 mg, 5.45 mmol), ammonium chloride (300 mg, 5.45 mmol) in anhydrous N , N -dimethylformamide (10 mL) under nitrogen. The reaction solution was heated to 130 ° C and stirred for 10 hours. The reaction mixture was slowly lowered to room temperature and quenched by water (60 mL). The mixture was extracted with ethyl acetate (30 mL x 2). The combined organic phases were washed with saturated sodium chloride solution (30 mL x 2), dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the product 1- (5- (2 H purified by preparative high performance liquid chromatography - tetrazole 5-yl) pentyl) -3,7-dimethyl -1 H - purine -2,6 (3 H, 7 H) - dione (80.0 mg), yield: 23%.

¹ H NMR: (400 MHz, CDCl ₃ ) δ = 7.60 (s, 1H), 4.17 (t, J = 6.0 Hz, 2H), 4.12 (s, 3H), 3.67 (s, 3H), 3.13 (t, J = 6.0 Hz, 2H), 2.11-2.07 (m, 2H), 1.87-1.82 (m, 2H), 1.33-1.29 (m, 2H). MS-ESI calcd for [M ⁺ H] + 319, found 319.

Example 40.

3,7-Dimethyl-1-(5-(1-methyl-1 H -tetrazol-5-yl)pentyl)-1 H -indole-2,6(3 H ,7 H )- ketone.

3,7-Dimethyl-1-(5-(1-methyl-2 H -tetrazol-5-yl)pentyl)-1 H -indole-2,6(3H,7H)-dione.

1-(5-( 2H -tetrazol-5-yl)pentyl)-3,7-dimethyl-1 H -indole-2,6(3 H ,7 H )-dione (80.0 mg , 0.250 mmol) was dissolved in anhydrous N , N -dimethylformamide (3 mL). N.sub.2. The reaction solution was stirred at room temperature for 3 hours. The reaction was quenched with water (40 mL)EtOAcEtOAc The combined organic layers were washed with aq. EtOAc (EtOAc) The filtrate was concentrated under reduced pressure and purified by preparative high-performance liquid chromatography to give two substituted isomeric products: 3,7-dimethyl-1-(5-(1-methyl-1H-tetrazol-5-yl)pentyl -1 H -嘌呤-2,6(3 H ,7 H )-dione (10.0 mg) (isomer 1, first peak). ¹ H NMR: (400 MHz, Methonal- d ₄ ) δ = 7.87 (s, 1H), 4.06 (s, 3H), 4.02-4.00 (m, 2H), 3.97 (s, 3H), 3.52 (s, 3H) ), 2.94 (t, J = 7.6 Hz, 2H), 1.89-1.85 (m, 2H), 1.74-1.70 (m, 2H), 1.47-1.42 (m, 2H). MS-ESI calcd [M + H] ⁺ 333.

3,7-Dimethyl-1-(5-(1-methyl-2 H -tetrazol-5-yl)pentyl)-1 H -indole-2,6(3H,7H)-dione ( 10.0 mg) (isomer 2, second peak), yield: 23%. ¹ H NMR: (400 MHz, Methonal- d ₄ ) δ = 7.88 (s, 1H), 4.32 (s, 3H), 4.02-3.99 (m, 2H), 3.98 (s, 3H), 3.54 (s, 3H) ), 2.89 (t, J = 7.6 Hz, 2H), 1.85-1.82 (m, 2H), 1.72-1.68 (m, 2H), 1.48-1.42 (m, 2H). MS-ESI calcd [M + H] ⁺ 333.

Example 41.

1-(3-(1 H -indol-3-)propyl-3,7-dimethyl-1 H -indole-2,6(3 H ,7 H )-dione.

first step.

3-(1 H -indol-3-)-propionic acid methyl ester.

3-( 1H -indol-3-yl)-propionic acid (200 mg, 1.06 mmol) was dissolved in anhydrous methanol (3 mL). ), the reaction was carried out for 0.5 hours. Quenched with water (10 mL). The reaction mixture was extracted with EtOAc (EtOAc (EtOAc)EtOAc. 3-( 1H -indol-3-yl)-propionic acid methyl ester (180 mg, green solid), yield: 85%. MS-ESI calcd for [M + H] ⁺ 204, found 204.

The second step.

3-(1 H -indol-3-)propan-1-ol.

Methyl 3-( 1H -indole-3-)-propanoate (180 mg, 0.890 mmol) was dissolved in anhydrous tetrahydrofuran (10 mL), and lithium tetrahydroaluminum (67.0 mg, 1.70. Methyl), reaction for 1 hour. Quenched with water (10 mL). The reaction mixture was extracted with ethyl acetate (10 mL EtOAc) (EtOAcjjHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH H -indole-3-)propan-1-ol (100 mg, green solid), yield: 65%. MS-ESI calcd for [M + H] ⁺ 176.

third step.

3-(1 H -indol-3-)propyl methanesulfonic acid.

3-( 1H -Indol-3-)propan-1-ol (100 mg, 0.570 mmol) and triethylamine (173 mg, 1.71 mmol) were dissolved in anhydrous dichloromethane (5 mL). Methanesulfonium chloride (128 mg, 1.14 mmol) was added at 0 °C. The reaction solution was slowly warmed to room temperature and stirred for 2 hours. The reaction was quenched with aq. EtOAc (EtOAc) Concentration under reduced pressure gave 3-( 1H -indole-3-)propyl methanesulfonic acid (100 mg, m. MS-ESI calcd for [M+H] ⁺ 254.

the fourth step.

1-(3-(1 H -indol-3-)propyl-3,7-dimethyl-1 H -indole-2,6(3 H ,7 H )-dione.

The 3- (1 H - indol-3-) propyl methanesulfonate (100 mg, 0.395 mmol), 3,7- dimethyl -1 H - purine -2,6 (3 H, 7 H) - Diketone (71.1 mg, 0.395 mmol), potassium iodide (7.1 mg, 0.039 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 allowed to react for 3 hours. The reaction solution was cooled to 20 ° C, filtered, and purified by preparative high-performance liquid chromatography to give 1-(3-( 1H -indol-3-)propyl-3,7-dimethyl- 1H -indole- 2,6( 3H , 7H )-dione (40.0 mg), yield: 30%.

¹ H NMR: (400 MHz, Methonal- d ₄ ) δ = 8.05 (s, 1H), 7.50 (d, J = 3.8 Hz, 1H), 7.01 (d, J = 4.0 Hz, 1H), 7.01-6.97 ( m, 3H), 4.17-4.13 (m, 2H), 3.92 (s, 3H), 3.40 (s, 3H), 2.88-2.84 (m, 2H), 2.19-2.16 (m, 2H). MS-ESI calcd for [M + H] ⁺ 338.

Example 42.

1-(4-(benzofuran-2-yl)butyl)-3,7-dimethyl-1 H -indole-2,6(3 H ,7 H )-dione.

first step.

2-(4-Chlorobutyl)benzofuran.

2-Methylbenzofuran (400 mg, 3.03 mmol) was dissolved in tetrahydrofuran (15 mL), cooled to -78 ° C, and diisopropylaminosamine (2 M tetrahydrofuran solution, 1.7 mL, 3.33 mmol) The reaction liquid was stirred at -78 ° C for 1 hour, 1-bromo-3-chloropropane (525 mg, 3.33 mmol) was added, and the mixture was further stirred at -78 ° C for 2 hours. The reaction was quenched by the addition of saturated aqueous ammonium chloride (30 mL). The mixture was extracted with ethyl acetate (30 mL x 2). The organic phase was combined, washed with EtOAc EtOAc m. MS-ESI calcd for [M + H] ⁺

The second step.

1-(4-(benzofuran-2-yl)butyl)-3,7-dimethyl-1 H -indole-2,6(3 H ,7 H )-dione.

2-(4-Chlorobutyl)benzofuran (500 mg, 2.40 mmol) was dissolved in N , N -dimethylformamide (10 mL), and potassium carbonate (662 mg, 4.80 mmol), 7-Dimethyl-1 H -indole-2,6(3 H ,7 H )-dione (432 mg, 2.40 mmol) and potassium iodide (478 mg, 2.88 mmol). The reaction solution was heated to 120 ° C and stirred for 16 hours. Cool to room temperature and quench the reaction by adding water (30 mL). The reaction mixture was extracted with ethyl acetate (30 mL×2). The organic phase was combined, dried over anhydrous sodium sulfate, filtered and evaporated, evaporated, evaporated, furan-2-yl) butyl) -3,7-dimethyl -1 H - purine -2,6 (3 H, 7 H) - dione (200 mg), yield: 24%.

¹ H NMR: (400 MHz, CDCl ₃ ) δ = 7.50 (m, 1H), 7.47 (d, J = 7.2 Hz, 1H), 7.38 (d, J = 7.2 Hz, 1H), 7.23-7.12 (m, 2H), 6.39 (s, 1H), 4.07 (t, J = 7.2 Hz, 2H), 3.98 (s, 3H), 3.57 (s, 3H), 2.83 (t, J = 7.2 Hz, 2H), 1.88- 1.71 (m, 4H). MS-ESI calcd for [M + H] ⁺ 353.

Example 43.

1-(3-(Benzo[d]thiazol-2-yl)propyl)-3,7-dimethyl-1 H -indole 2,6(3 H ,7 H )-dione.

first step.

Methyl 3-benzothiazol-2-propionate.

3-(Benzo[d]thiazol-2-)propanoic acid (200 mg, 0.970 mmol) was dissolved in methanol (3 mL). EtOAc (229 mg, 1. The reaction was carried out for 0.5 hours under protection. The reaction was quenched with EtOAc (EtOAc)EtOAc. Methyl 3-benzothiazol-2-propanoate (150 mg, yellow solid). Yield: 70%. MS-ESI calcd for [M + H] ⁺ 222.

The second step.

3-(Benzo[d]thiazole-2-)propan-1-ol.

Methyl 3-benzothiazol-2-propanoate (150 mg, 0.680 mmol) was dissolved in tetrahydrofuran (10 mL), and lithium tetrahydroaluminum (52.0 mg, 1.36 mmol) was added at 0 ° C for 1 hour. The reaction was quenched with EtOAc (EtOAc) (EtOAc (EtOAc) 3-(Benzo[d]thiazol-2-)propan-1-ol (100 mg, yellow solid) was obtained, yield: 52%. MS-ESI calcd for [M ⁺ H] + 194, found 194.

third step.

3-(Benzo[d]thiazole-2-)propyl methanesulfonate.

Dissolve 3-(benzo[d]thiazol-2-)propan-1-ol (100 mg, 0.520 mmol) and triethylamine (173 mg, 1.71 mmol) in dichloromethane (5 mL). Methanesulfonium chloride (128 mg, 1.14 mmol) was added at °C. The reaction solution was slowly warmed to room temperature and stirred for 2 hours. The reaction was quenched with aqueous sodium hydrogen sulfate (10 mL) andEtOAcEtOAc The organic phase was combined, washed with EtOAc EtOAc EtOAcjHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH , Yield: 71%. MS-ESI calcd for [M + H] ⁺ 272.

the fourth step.

1-(3-(Benzo[d]thiazol-2-yl)propyl)-3,7-dimethyl-1 H -indole 2,6(3 H ,7 H )-dione.

3- (benzo [d] thiazol-2) propyl methanesulfonate (100 mg, 0.370 mmol), 3,7- dimethyl -1 H - purine -2,6 (3 H, 7 H )-Dione (66.4 mg, 0.370 mmol), potassium iodide (7.1 mg, 0.037 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 solution was cooled to 20 ° C, filtered, and purified by high performance liquid chromatography to give 1-(3-(benzo[d]thiazol-2-yl)propyl)-3,7-dimethyl-1 H - 2,6( 3H , 7H )-dione (40.0 mg), yield: 30%.

¹ H NMR: (400 MHz, Methonal- d ₄ ) δ = 8.15 (d, J = 4.0 Hz, 1H), 8.06 (s, 1H), 7.98 (d, J = 4.0 Hz, 1H), 7.75-7.72 ( m, 1H), 7.67-7.65 (m, 1H), 4.23-4.20 (m, 2H), 3.99 (s, 3H), 3.50 (s, 3H), 3.48-3.46 (m, 2H), 2.40-2.37 ( m, 2H). MS-ESI calcd for [M+H] ⁺ 356.

Example 44.

3,7-Dimethyl-1-(3-(4,5,6,7-tetrahydro-2 H -indol-3-yl)propyl)-1 H -嘌呤-2,6(3 H , 7 H )-dione.

first step.

3-(4,5,6,7-Tetrahydro- 2H -indol-3-yl)-propionic acid methyl ester.

3-(4,5,6,7-Tetrahydro- 2H -indol-3-yl)-propionic acid (150 mg, 0.770 mmol) was dissolved in anhydrous methanol (7 mL). The hydrazine chloride (0.1 mL) was stirred at room temperature for 4 hours. Quenched with water (10 mL). The reaction solution was extracted with ethyl acetate (10 mL x 3), the organic phases were combined, dried over anhydrous sodium sulfate, to give 3- (4,5,6,7-tetrahydro-concentrated under reduced pressure -2 H - indol-3-yl -Methyl propionate (150 mg, white solid), yield: 94%. MS-ESI calcd for [M + H] ⁺

The second step.

3-(4,5,6,7-tetrahydro- 2H -indol-3-yl)-propanol.

3-(4,5,6,7-Tetrahydro- 2H -indol-3-yl)-propionic acid methyl ester (150 mg, 0.720 mmol) was dissolved in anhydrous tetrahydrofuran (5 mL) at 0 ° Lithium tetrahydroaluminum (41.0 mg, 1.08 mmol) was added under C. The reaction mixture was slowly warmed to room temperature and stirred for 3 hr. Water (0.04 mL), 15% sodium hydroxide solution (0.04 mL) and water (0.12 mL) were added sequentially. Filtration and concentration of the filtrate under reduced pressure gave 3-(4,5,6,7-tetrahydro- 2H -indol-3-yl)-propanol (110 mg, yellow liquid), yield: 85%. MS-ESI calcd for [M + H] ⁺ 181.

third step.

3-(2-(Methanesulfonyl)-4,5,6,7-tetrahydro- 2H -indol-3-yl)-propyl methanesulfonic acid.

3-(4,5,6,7-Tetrahydro- 2H -indol-3-yl)-propanol (110 mg, 0.610 mmol) and diisopropylethylamine (236 mg, 1.83 mmol) Dissolved in anhydrous dichloromethane (3 mL). Methanesulfonium chloride (139 mg, 1.22 mmol) was added at 0 °C. The reaction solution was slowly warmed to room temperature and stirred for 0.5 hours. The reaction was quenched with EtOAc (EtOAc)EtOAc. , 3-(2-(methylsulfonyl)-4,5,6,7-tetrahydro- 2H -indol-3-yl)-propylmethanesulfonic acid (50.0 mg, yellow oil) , Yield: 25%. MS-ESI calcd for [M ⁺ H] + 337, found 337.

the fourth step.

3,7-Dimethyl-1-(3-(4,5,6,7-tetrahydro-2 H -indol-3-yl)propyl)-1 H -嘌呤-2,6(3 H , 7 H )-dione.

3-(2-(Methanesulfonyl)-4,5,6,7-tetrahydro- 2H -indol-3-yl)-propylmethanesulfonic acid (50.0 mg, 0.150 mmol), 3, 7-Dimethyl-1 H -indole-2,6(3 H ,7 H )-dione (32.0 mg, 0.180 mmol), potassium iodide (2.5 mg, 0.015 mmol) and potassium carbonate (41.0 mg, 0.300 mmol) Dissolved in anhydrous N , N -dimethylformamide (2 mL). The reaction solution was heated to 130 ° C and allowed to react for 3 hours. The reaction solution was cooled to 20 ° C, filtered, and purified by preparative high-performance liquid chromatography to give 3,7-dimethyl-1-(3-(4,5,6,7-tetrahydro- 2H -indole- 3- yl) propyl) -1 H - purine -2,6 (3 H, 7 H) - dione (40.0 mg), yield: 32%.

¹ H NMR: (400 MHz, Methonal- d ₄ ) δ = 7.84 (s, 1H), 4.02 (t, J = 7.2 Hz, 2H), 3.96 (s, 3H), 3.49 (s, 3H), 2.66- 2.59 (m, 2H), 2.52 (t, J = 5.4 Hz, 2H), 2.43 (t, J = 5.4 Hz, 2H), 2.02-1.95 (m, 2H), 1.78-1.66 (m, 4H). MS-ESI calcd for [M + H] ⁺ 343.

Example 45.

3,7-Dimethyl-1-[4-(3-methylisoxazol-5-yl)-benzyl]-3,7-dihydro-indole-2,6-dione.

first step.

4-(3-Methylisoxazol-5-)-benzoic acid ethyl ester.

3-Methyl-5-(tri-n-butylstannyl)isoxazole (200 mg, 0.540 mmol) and ethyl 4-bromo-benzoate (122 mg, 0.540 mmol) were dissolved in anhydrous dioxane (3) In mL), tetrakistriphenylphosphine palladium (15.0 mg, 0.0141 mmol) was added under a nitrogen atmosphere, and the reaction mixture was heated to 100 ° C and stirred for 2 hours. The reaction was cooled to 20 ° C, EtOAc (EtOAc)EtOAc. Ethyl acetate (Rf = 0.5) gave 4-(3-methylisoxazole-5-)-benzoic acid ethyl ester (100 mg, yellow solid). MS-ESI calcd [M+H] ⁺ 232.

The second step.

[4-(3-Methylisoxazole-5-)-phenyl]-methanol.

Ethyl 4-(3-methylisoxazol-5-yl)-benzoate (100 mg, 0.430 mmol) was dissolved in anhydrous tetrahydrofuran (2 mL). , 0.860 mmol), warmed to 25 ° C, and stirred for 1 hour. The reaction was quenched with EtOAc (EtOAc)EtOAc. Rf = 0.4) gave [4-(3-methylisoxazol-5-)-phenyl]-methanol (70.0 mg,yiel. MS-ESI calcd for [M + H] ⁺ 190.

third step.

4-(3-Methylisoxazol-5-yl)benzyl methanesulfonate.

[4-(3-Methylisoxazol-5-yl)-phenyl]-methanol (70.0 mg, 0.370 mmol) and triethylamine (112 mg, 1.11 mmol) were dissolved in anhydrous dichloromethane (5 mL) Into the methanesulfonium chloride (83.0 mg, 0.740 mmol) was added at 0 °C. The reaction solution was slowly warmed to 25 ° C and stirred for 2 hours. The mixture was quenched with EtOAc EtOAc (EtOAc (EtOAcMeOHMeOHMeOH 3-Methylisoxazole-5-yl)benzyl methanesulfonate (80.0 mg, yellow oil), yield: 82%. MS-ESI calcd [M + H] ⁺ 266.

the fourth step.

3,7-Dimethyl-1-[4-(3-methylisoxazol-5-yl)-benzyl]-3,7-dihydro-indole-2,6-dione.

4-(3-Methylisoxazol-5-yl)benzyl methanesulfonate (80.0 mg, 0.300 mmol), 3,7-dimethyl-3,7-dihydro-indole-2,6 -dione (55.0 mg, 0.300 mmol), potassium iodide (7.0 mg, 0.0300 mmol) and potassium carbonate (109 mg, 0.790 mmol) dissolved in anhydrous N , N -dimethylformamide (3 mL). The temperature was raised to 120 ° C and stirred for 3 hours. Cool to 20 ° C, filter, and purify by preparative high performance liquid chromatography to give 3,7-dimethyl-1-[4-(3-methylisoxazole-5-yl)-benzyl]-3,7 -Dihydro-indole-2,6-dione (40.0 mg), yield: 30%.

¹ H NMR: (400 MHz, Methonal- d ₄ ) δ = 8.04 (s, 1H), 7.73 (d, J = 8.4 Hz, 2H), 7.41 (d, J = 8.4 Hz, 2H), 6.81 (s, 1H), 5.07 (s, 2H), 3.87 (s, 3H), 3.41 (s, 3H), 2.25 (s, 3H). MS-ESI calcd for [M + H] ⁺ 352.

Example 46.

3,7-Dimethyl-1-(3-(pyridin-4-yl)propyl)-1 H -indole-2,6(3 H ,7 H )-dione.

first step.

Methyl 3-(pyridin-4-yl)propanoate.

3-(Pyridin-4-yl)propanoic acid (200 mg, 1.32 mmol) was dissolved in methanol (5 mL), and then dichloro-hydrazide (471 mg, 3.96 mmol) was slowly added at 0 ° C. Stir at °C for 3 hours. The reaction mixture was concentrated under reduced vacuoielielielielieliel ¹ H NMR: (400 M Hz, Methonal- d ₄ ) δ = 8.75 (d, J = 6.4 Hz, 2H), 8.02 (d, J = 6.4 Hz, 2H), 3.66 (s, 3H), 3.26 (t) , J = 7.2 Hz, 2H), 2.89 (t, J = 7.2 Hz, 2H).

The second step.

3-(pyridin-4-yl)propan-1-ol.

Lithium tetrahydroaluminum (107 mg, 2.82 mmol) was slowly added to tetrahydrofuran (10 mg, 1.88 mmol) dissolved in methyl 3-(pyridin-4-yl)propanoate (10 mL) at 0 ° C. In the reaction, the reaction was stirred at 25 ° C for 4 hours, and the reaction solution was cooled to 0 ° C in an ice water bath, and water (107 mg, 5.94 mmol), 15% sodium hydroxide (107 mg, 2.68 mmol) and water ( 321 mg, 17.8 mmol). The reaction solution was heated to 25 ° C, stirred for half an hour, filtered, and the filter cake was washed with tetrahydrofuran (8 mL x 3), and the filtrate was concentrated under reduced pressure to give 3-(pyridin-4-yl)propan-1-ol (182 mg, Yellow solid), Yield: 71%. ¹ H NMR: (400 M Hz, Methonal- d ₄ ) δ = 8.44-8.41 (m, 2H), 7.33 (d, J = 6.0 Hz, 2H), 3.60 (t, J = 6.4 Hz, 2H), 2.79 -2.74 (m, 2H), 1.92-1.85 (m, 2H).

third step.

3-(pyridin-4-yl)propyl methanesulfonate.

3-(Pyridin-4-yl)propan-1-ol (180 mg, 1.31 mmol), triethylamine (398 mg, 3.93 mmol) dissolved in dichloromethane (8 mL) Methane sulfonium chloride (300 mg, 2.62 mmol) was added. The reaction mixture was stirred at 25 ° C, EtOAc (EtOAc m. Methanesulfonate (741 mg, red solid).

the fourth step.

3,7-Dimethyl-1-(3-(pyridin-4-yl)propyl)-1 H -indole-2,6(3 H ,7 H )-dione.

3-(Pyridin-4-yl)propyl methanesulfonate (1.20 g, 5.57 mmol), 3,7-dimethyl-1 H -indole-2,6(3 H ,7 H )-dione (502 mg, 2.79 mmol) and potassium iodide (92.5 mg, 0.557 mmol) dissolved in N , N -dimethylformamide (20 mL), added potassium carbonate (847 mg, 6.13 mmol), heated at 130 °C Reflux for 3 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 HPLC to give the product 3,7-dimethyl-1-(3-(pyridin-4-yl)propyl) -1 H - purine -2,6 (3 H, 7 H) - dione (163 mg), yield: 10%. ¹ H NMR: (400 M Hz, Methonal- d ₄ ) δ = 8.36 (d, J = 6.0 Hz, 2H), 7.85 (s, 1H), 7.32 (d, J = 6.0 Hz, 2H), 4.05 (t , J = 7.2 Hz, 2H), 3.96 (s, 3H), 3.50 (s, 3H), 2.76 (t, J = 7.2 Hz, 2H), 2.09-2.00 (m, 2H). MS-ESI calculated [M+H] ⁺ 300, found 300.

Example 47.

first step.

Methyl 2-(4,6-dimethylpyridin-2-yl)acetate.

2,4,6-trimethylpyridine (1.00 g, 8.25 mmol) was dissolved in tetrahydrofuran (30 mL), and lithium diisopropylamide (8.2 mL, 2 M tetrahydrofuran solution) was added dropwise at 0 ° C under nitrogen. 16.5 mmol), the reaction solution was stirred at 0 ° C for 0.5 hour, and dimethyl carbonate (743 mg, 8.25 mmol) was added to the reaction mixture, then slowly warmed to 20 ° C and stirring was continued for 2 hours. The reaction solution was quenched by the addition of saturated aqueous ammonium chloride (100 mL). The mixture was extracted with ethyl acetate (20 mL x 3). The organic layer was washed with brine (20 mL EtOAc) Separation and purification by gel column chromatography (2:1 petroleum ether / ethyl acetate, Rf = 0.5) to give methyl 2-(4,6-dimethylpyridin-2-yl)acetate (1.20 g, yellow oil ), yield: 81%.

¹ H NMR: (400 MHz, CDCl ₃ ) δ = 6.91 (s, 1H), 6.87 (s, 1H), 3.77 (s, 2H), 3.70 (s, 3H), 2.48 (s, 3H), 2.28 ( s, 3H). MS-ESI calc. [M+H] ⁺ 180, Found.

The second step.

2-(4,6-Dimethylpyridin-2-yl)ethanol.

Methyl 2-(4,6-dimethylpyridin-2-yl)acetate (500 mg, 2.79 mmol) was dissolved in tetrahydrofuran (20 mL). 5.58 mmol), react for 1 hour. The reaction was quenched by the addition of water (10 mL). It was extracted with ethyl acetate (20 mL×3), dried over anhydrous sodium sulfate, filtered, evaporated, evaporated, evaporated. (4,6-Dimethylpyridin-2-yl)ethanol (410 mg, yellow oil), yield: 92%.

MS-ESI calcd for [M + H] ⁺ 152.

third step.

2-(4,6-Dimethylpyridin-2-yl)ethyl methanesulfonate.

2-(4,6-Dimethylpyridin-2-yl)ethanol (421 mg, 3.07 mmol) and triethylamine (1.18 g, 11.6 mmol) were dissolved in dichloromethane (20 mL) Methanesulfonate chloride (794 mg, 6.94 mmol) was added under the conditions. After the reaction mixture was stirred at room temperature for 2 hr, EtOAc EtOAc (EtOAc m. Separation and purification (4:1 petroleum ether / ethyl acetate, Rf = 0.5) gave 2-(4,6-dimethylpyridin-2-yl)ethyl methanesulfonate (400 mg, colorless oil) , Yield: 61%.

MS-ESI calcd [M+H] ⁺ 230, found 230.

the fourth step.

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

2-(4,6-Dimethylpyridin-2-yl)ethyl methanesulfonate (200 mg, 0.929 mmol) was dissolved in N , N -dimethylformamide (15 mL). Add 3,7-dimethyl-1 H -indole-2,6(3 H ,7 H )-dione (167 mg, 0.929 mmol), potassium carbonate (192 mg, 1.39 mmol) and at room temperature Potassium iodide (184 mg, 1.11 mmol). The reaction mixture was heated to 100 ° C, and the mixture was stirred for 2 hr. EtOAc (EtOAc) Purification by high performance liquid chromatography gave 1-(2-(4,6-dimethylpyridin-2-yl)ethyl)-3,7-dimethyl-1 H -indole-2,6( 3H ,7 H )-dione (120 mg), yield: 43%.

¹ H NMR: (400 MHz, CDCl ₃ ) δ = 7.53 (s, 1H), 6.99 (s, 1H), 6.91 (s, 1H), 4.33 (t, J = 7.6 Hz, 2H), 3.97 (s, 3H), 3.56 (s, 3H), 3.13 (t, J = 7.6 Hz, 2H), 2.52 (s, 3H), 2.32 (s, 3H). MS-ESI calcd for [M + H] ⁺ 314.

Example 48.

1-((6-Methoxypyridin-3-yl)methyl)-3,7-dimethyl-1 H -indole-2,6(3 H ,7 H )-dione.

first step.

1-((6-Methoxypyridin-3-yl)methyl)-3,7-dimethyl-1 H -indole-2,6(3 H ,7 H )-dione.

Dissolve 3,7-dimethyl-1 H -indole-2,6(3 H ,7 H )-dione (300 mg, 1.67 mmol) in N , N -dimethylformamide (10 mL) 5-(Chloromethyl)-2-methoxypyridine (263 mg, 1.67 mmol), potassium iodide (332 mg, 2.00 mmol) and potassium carbonate (461 mg, 3.34 mmol). The reaction solution was heated to 120 ° C, stirred for 3 hours, concentrated under reduced pressure, and the residue was purified eluting with EtOAc EtOAc EtOAc EtOAc pyridin-3-yl) methyl) -3,7-dimethyl -1 H - purine -2,6 (3 H, 7 H) - dione (20.0 mg), yield: 4%.

¹ H NMR: (400 MHz, CDCl ₃ ) δ = 8.28 (s, 1H) 7.78 (d, J = 8.0 Hz, 1H), 7.51 (s, 1H), 6.67 (d, J = 8.0 Hz, 1H), 5.12 (s, 2H), 3.99 (s, 3H), 3.91 (s, 3H), 3.57 (s, 3H). MS-ESI calcd for [M + H] ⁺ 302, found 302.

Example 49.

7-(Difluoromethyl)-3-methyl-1(4-(3-methylisoxazol-5-yl)butyl)-1 H -indole-2,6(3 H ,7 H ) - Diketone.

9-(Difluoromethyl)-3-methyl-1(4-(3-methylisoxazole-5-yl)butyl)-1 H -indole-2,6(3 H ,7 H ) - Diketone.

first step.

7-(Difluoromethyl)-3-methyl-1 H -indole-2,6(3 H ,7 H )-dione.

9-(Difluoromethyl)-3-methyl-1 H -indole-2,6(3 H ,7 H )-dione.

3-Methyl-1 H -indole-2,6(3 H ,7 H )-dione (1.00 g, 6.02 mmol) was dissolved in N , N -dimethylformamide (40 mL). Sodium 2-chloro-2,2-difluoroacetate (1.84 g, 12.0 mmol), potassium carbonate (1.66 g, 12.0 mmol). The reaction mixture was heated to 95 ° C. After 8 hours, the reaction mixture was cooled to room temperature. The reaction mixture was evaporated to dryness. Drying with anhydrous sodium sulfate, filtering, and concentrating the filtrate under reduced pressure, and separating and purifying by gel column chromatography (1: 1 petroleum ether / ethyl acetate, Rf = 0.3) to give 7-(difluoromethyl)-3-methyl -1 H -嘌呤-2,6(3 H ,7 H )-dione and 9-(difluoromethyl)-3-methyl-1 H -indole-2,6(3 H ,7 H )- Diketone mixture (300 mg, yellow solid), yield: 23%.

MS-ESI calcd for [M + H] ⁺ 217.

The second step.

7-(Difluoromethyl)-3-methyl-1(4-(3-methylisoxazol-5-yl)butyl)-1 H -indole-2,6(3 H ,7 H ) - Diketone.

9-(Difluoromethyl)-3-methyl-1(4-(3-methylisoxazole-5-yl)butyl)-1 H -indole-2,6(3 H ,7 H ) - Diketone.

7-(Difluoromethyl)-3-methyl-1 H -indole-2,6(3 H ,7 H )-dione and 9-(difluoromethyl)-3-methyl-1 H-嘌呤-2,6(3 H ,7 H )-dione mixture (200 mg, 0.917 mmol) was dissolved in N , N -dimethylformamide (20 mL) at room temperature 5-(4-Bromobutyl)-3-methylisoxazole (200 mg, 0.917 mmol), potassium carbonate (190 mg, 1.38 mmol) and potassium iodide (86.3 mg, 0.520 mmol). The reaction mixture was heated to 100 ° C, and the mixture was stirred for 2 hr. EtOAc (EtOAc) Purification by high performance liquid chromatography gave 7-(difluoromethyl)-3-methyl-1(4-(3-methylisoxazol-5-yl)butyl)-1 H -嘌呤-2,6 ( 3 H ,7 H )-dione (isomer 1) (50.0 mg), yield: 15%, ¹ H NMR: (400 MHz, CDCl ₃ ) δ = 8.07 (s, 1H), 7.93-7.63 ( m, 1H), 5.83 (s, 1H), 4.02 (m, 2H), 3.58 (s, 3H), 2.73 (m, 2H), 2.23 (s, 3H), 1.71 (m, 4H). MS-ESI calcd for [M + H] ⁺ 352.

9-(Difluoromethyl)-3-methyl-1(4-(3-methylisoxazole-5-yl)butyl)-1 H -indole-2,6(3 H ,7 H ) -dione (isomer 2) (20.0 mg), yield: 6%, ¹ H NMR: (400 MHz, CDCl ₃ ) δ = 7.86 (s, 1H), 7.73-7.43 (m, 1H), 5.84 (s, 1H), 4.06 (m, 2H), 3.75 (s, 3H), 2.74 (m, 2H), 2.24 (s, 3H), 1.72 (m, 4H). MS-ESI calcd for [M + H] ⁺ 352.

Example 50.

7-Ethyl-3-methyl-1-(4-(3-methylisoxazol-5-yl)butyl)-1 H -indole-2,6(3 H ,7 H )-dione .

7-Ethyl-3-methyl-1 H -indole-2,6(3 H ,7 H )-dione (50.0 mg, 0.260 mmol), 5-(4-bromobutyl)-3-methyl Isoxazole (60.0 mg, 0.335 mmol), potassium carbonate (70.0 mg, 0.520 mmol) and potassium iodide (4.0 mg, 0.0260 mmol) dissolved in N , N -dimethylformamide (10 mL). Heat to 110 ° C and react for two hours. The reaction solution was poured into water and extracted with ethyl acetate (20 mL x 3). The organic phases were combined, dried over anhydrous MgSO~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ -1 H - purine -2,6 (3 H, 7 H) - dione (30.0 mg), yield: 39%.

^{1 H NMR: (400MHz, CDCl} 3): δ = 7.94 (s, 1H), 6.03 (s, 1H), 4.39-4.33 (m, 2H), 4.04-4.02 (m, 2H), 3.53 (s, 3H ), 2.81-2.78 (m, 2H), 2.23 (s, 3H), 1.73-1.71 (m, 4H), 1.48 (t, J = 7.0 Hz, 3H). MS-ESI calcd for [M + H] ⁺ 332.

Example 51.

3-methyl-1-(4-(3-methylisoxazol-5-yl)butyl)-7-(2,2,2-trifluoroethyl)-1 H -嘌呤-2,6 (3 H , 7 H )-dione.

first step.

3-Methyl-7-(2,2,2-trifluoroethyl)-1 H -indole-2,6(3 H ,7 H )-dione.

3-Methyl-1 H -indole-2,6(3 H ,7 H )-dione (3.00 g, 1.81 mmol) was dissolved in methanol (50 mL) and sodium hydrogen (760) Mg, 19.0 mmol). The reaction solution was heated to 40 ° C and stirred for 1.5 hours. 2,2,2-Trifluoroethyl trifluoromethanesulfonate (5.45 g, 23.5 mmol), and the reaction mixture was stirred at 40 ° C for 16 hours. It was cooled to room temperature, filtered, and the filter cake was washed with water (30 mL) and methanol (20 mL). And dried to give 3-methyl-7- (2,2,2-trifluoroethyl) -1 H - purine -2,6 (3 H, 7 H) - dione (1.90 g, white solid), producing Rate: 42%.

^{1 H NMR: (400 Hz,} DMSO- d 6) δ = 11.32 (s, 1H), 8.19 (s, 1H), 5.23 (q, J = 4.2 Hz, 2H), 3.36 (s, 3H). MS-ESI calcd [M + H] ⁺ 495.

The second step.

3-methyl-1-(4-(3-methylisoxazol-5-yl)butyl)-7-(2,2,2-trifluoroethyl)-1 H -嘌呤-2,6 (3 H , 7 H )-dione.

5-(4-Bromobutyl)-3-methylisoxazole (130 mg, 0.600 mmol) was dissolved in N , N -dimethylformamide (10 mL) and potassium carbonate (166 mg, 1.20 mmol), 3- methyl-7-propyl -1 H - purine -2,6 (3 H, 7 H) - dione (150 mg, 0.60 mmol) and potassium iodide (119 mg, 0.720 mmol). The reaction solution was heated to 120 ° C and stirred for 16 hours. The reaction solution is concentrated under reduced pressure and purified by preparative high-performance liquid chromatography to give 3-methyl-1-(4-(3-methylisoxazol-5-yl)butyl)-7-(2,2, 2-Trifluoroethyl)-1 H -indole-2,6(3 H ,7 H )-dione (60.0 mg), yield: 26%.

¹ H NMR: (400 MHz, CDCl ₃ ) δ = 7.70 (s, 1H), 5.83 (s, 1H), 5.05 (q, J = 8.4 Hz, 2H), 4.12-3.98 (m, 2H), 3.60 ( s, 3H), 2.77-2.70 (m, 2H), 2.25 (s, 3H), 1.80-1.66 (m, 4H). MS-ESI calculated [M+H] ⁺ 386. Found 386.

Example 52.

3-methyl-1-(4-(3-methylisoxazole-5-yl)butyl)-7-propyl-1 H -indole-2,6(3 H ,7 H )-dione .

first step.

3-methyl-7-propyl-1 H -indole-2,6(3 H ,7 H )-dione.

3-Methyl-1 H -indole-2,6(3 H ,7 H )-dione (4.00 g, 24.1 mmol) was dissolved in methanol (30 mL), and potassium hydroxide (1.48 g, 26.5 mmol) of aqueous solution (15 mL), the mixture was heated to 80 ° C and stirred for 1.5 hours. The temperature was lowered to 50 ° C, 1-iodopropane (5.33 g, 31.3 mmol) was added, and the reaction mixture was further stirred at 50 ° C for 24 hours. After cooling to room temperature, filtration, the cake was washed with water (30 mL) and methanol (30 mL). And dried to give 3-methyl-7-propyl--1 H - purine -2,6 (3 H, 7 H) - dione (2.30 g, white solid), yield: 46%.

¹ H NMR: (400 Hz, DMSO- d ₆ ) δ = 11.12 (s, 1H), 8.05 (s, 1H), 4.16 (t, J = 7.2 Hz, 2H), 3.34 (s, 3H), 1.68 (m, 2H), 0.81 (t, J = 7.2 Hz, 3H). MS-ESI calcd for [M + H] ⁺

The second step.

3-methyl-1-(4-(3-methylisoxazole-5-yl)butyl)-7-propyl-1 H -indole-2,6(3 H ,7 H )-dione .

5-(4-Bromobutyl)-3-methylisoxazole (218 mg, 1.00 mmol) was dissolved in N , N -dimethylformamide (10 mL) and potassium carbonate (276 mg, 2.00 mmol), 3- methyl-7-propyl -1 H - purine -2,6 (3 H, 7 H) - dione (208 mg, 1.00 mmol) and potassium iodide (199 mg, 1.20 mmol). The reaction solution was heated to 120 ° C and stirred for 16 hours. The reaction solution was concentrated under reduced pressure and purified by preparative high-performance liquid chromatography to give 3-methyl-1-(4-(3-methylisoxazol-5-yl)butyl)-7-propyl- 1H. - purine -2,6 (3 H, 7 H) - dione (60.0 mg), yield: 17%.

¹ H NMR: (400 MHz, CDCl ₃ ) δ = 7.54 (s, 1H), 5.82 (s, 1H), 4.24 (t, J = 7.2 Hz, 2H), 4.10-3.97 (m, 2H), 3.58 ( s, 3H), 2.82-2.70 (m, 2H), 2.25 (s, 3H), 1.97-1.84 (m, 2H), 1.81-1.65 (m, 4H), 0.95 (t, J = 7.2 Hz, 3H) . MS-ESI calcd [M+H] ⁺ 346.

Example 53.

7-Cyclopropyl-3-methyl-1-(4-(5-methylisoxazol-3-yl)butyl)-1 H -indole-2,6(3 H ,7 H )-di ketone.

first step.

6-Amino-5-bromo-1-methylpyrimidine-2,4(1 H ,3 H )-dione.

Mixture 6-Amino-1-methylpyrimidine-2,4(1 H ,3 H )-dione (5.46 g, 40.0 mmol) and bromobutaneimide (7.56 g, 42.0 mmol) in acetonitrile (100) The mL) solution was heated to reflux under nitrogen for 1.5 hours. The reaction solution was cooled to room temperature, filtered, and the solvent was evaporated, and the obtained solid was washed with water (20 mL) and dried to give 6-amino-5-bromo-1-methylpyrimidine-2,4( 1H , 3H )-dione (8.6 g, white solid), Yield: 98%. ¹ H NMR: (400 MHz, DMSO- d6 ) δ = 10.90 (s, 1H), 7.04 (s, 2H), 3.28 (s, 3H).

The second step.

6-Amino-5-(cyclopropylamine)-1-methylpyrimidine-2,4(1 H ,3 H )-dione.

6-Amino-5-bromo-1-methylpyrimidine-2,4(1 H ,3 H )-dione (2.19 g, 10.0 mmol) dissolved in a mixture of cyclopropylamine (20 mL) and water (5 mL) In the solvent. The reaction solution was heated to reflux for 5 hours. The reaction solution was filtered to remove the solvent to give the crude product 6-amino-5-(cyclopropylamine)-1-methylpyrimidine-2,4( 1H , 3H )-dione.

third step.

7-Cyclopropyl-3-methyl-1 H -indole-2,6(3 H ,7 H )-dione.

6-Amino-5-(cyclopropylamine)-1-methylpyrimidine-2,4(1 H ,3 H )-dione (1.96 g, 10.0 mmol), trimethyl orthoformate under N2 (2.12 g, 20.0 mmol) and p-toluenesulfonic acid (86.0 mg, 0.500 mmol) were dissolved in anhydrous N , N -dimethylformamide (20 mL). The reaction solution was heated to 100 ° C overnight. The reaction was filtered, the solvent was removed to give crude product 7-cyclopropyl-3-methyl -1 H - purine -2,6 (3 H, 7 H) - dione was used directly in the next reaction.

the fourth step.

7-Cyclopropyl-3-methyl-1-(4-(5-methylisoxazol-3-yl)butyl)-1 H -indole-2,6(3 H ,7 H )-di ketone.

7-Cyclopropyl-3-methyl-1 H -indole-2,6(3 H ,7 H )-dione (96.0 mg, 0.470 mmol), 3-(4-bromobutyl) under N2 -5-Methylisoxazole (152 mg, 0.700 mmol) and potassium carbonate (130 mg, 0.940 mmol) were dissolved in N , N -dimethylformamide (5 mL). The reaction solution was heated to 120 ° C and allowed to react for 3 hours. After cooling to room temperature, it was diluted with water (20 mL), ethyl acetate (30 mL×2), and the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by high-performance liquid chromatography to give 7-cyclopropyl- 3-methyl-1-(4-(5-methylisoxazol-3-yl)butyl)-1 H -indole-2,6(3 H ,7 H )-dione (100 mg, produced Rate: 63%).

¹ H NMR: (400 MHz, Methonal- d ₄ ) δ = 7.95 (s, 1H), 6.05 (s, 1H), 4.04 (t, J = 6.8 Hz, 2H), 3.75-3.69 (m, 1H), 3.53 (s, 3H), 2.81 (t, J = 6.8 Hz, 2H), 2.25 (s, 3H), 1.75-1.34 (m, 4H), 1.19-1.10 (m, 4H). MS-ESI calcd [M+H] ⁺ 344.

Example 54.

7-Isopropyl-3-methyl-1-(4-(3-methylisoxazole-5-yl)butyl)-1 H -indole-2,6(3 H ,7 H )- ketone.

first step.

7-Isopropyl-3-methyl-1 H -indole-2,6(3 H ,7 H )-dione.

3-Methyl-1 H -indole-2,6(3 H ,7 H )-dione (3.00 g, 1.81 mmol) was dissolved in dimethyl hydrazine (50 mL) and added portionwise at room temperature Sodium hydrogen (760 mg, 19.0 mmol). The reaction solution was heated to 40 ° C and stirred for 1.5 hours. 2-Iodopropane (4.00 g, 23.5 mmol) was added. The reaction solution was further stirred at 40 ° C for 16 hours. After cooling to room temperature, filtration, the cake was washed with water (30 mL) and methanol (30 mL). And dried to give 7-isopropyl-3-methyl -1 H - purine -2,6 (3 H, 7 H) - dione (2.20 g, white solid), yield: 59%.

¹ H NMR: (400 Hz, DMSO- d ₆ ) δ = 11.11 (s, 1H), 8.15 (s, 1H), 4.90-4.75 (m, 1H), 3.35 (s, 3H), 1.48 (d, J = 6.8 Hz, 6H). MS-ESI calcd for [M + H] ⁺

The second step.

7-Isopropyl-3-methyl-1-(4-(3-methylisoxazole-5-yl)butyl)-1 H -indole-2,6(3 H ,7 H )- ketone.

4-bromo-3-methyl isoxazole (91.1 mg, 0.424 mmol), 7- isopropyl-3-methyl -1 H - purine -2,6 (3 H, 7 H) - two Ketone (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 give 7-isopropyl-3-methyl-1-(4-(3-methylisoxazole-5-yl). Butyl)-1 H -嘌呤-2,6(3 H ,7 H )-dione (80.0 mg), yield: 55%.

¹ H NMR: (400 MHz, Methonal- d ₄ ) δ = 8.89 (s, 1H), 6.06 (s, 1H), 5.21-5.16 (m, 1H), 4.08-4.04 (m, 2H), 3.58 (s) , 3H), 2.83-2.79 (m, 2H), 2.24 (s, 3H), 1.75-1.72 (m, 4H), 1.65 (d, J = 3.4 Hz, 6H). MS-ESI calcd [M+H] ⁺ 346.

Example 55.

7-Butyl-3-methyl-1-(4-(3-methylisoxazole-5-yl)butyl)-1 H -indole-2,6(3 H ,7 H )-dione .

first step.

7-Butyl-3-methyl-1 H -indole-2,6(3 H ,7 H )-dione.

3-Methyl-1 H -indole-2,6(3 H ,7 H )-dione (4.00 g, 24.1 mmol) was dissolved in methanol (30 mL), and potassium hydroxide (1.48 g, 26.5 mmol) of aqueous solution (15 mL), the mixture was heated to 80 ° C and stirred for 1.5 hours. The temperature was lowered to 50 ° C, 1-iodobutane (5.76 g, 31.3 mmol) was added, and the reaction mixture was stirred at 50 ° C for 24 hours. After cooling to room temperature, filtration, the cake was washed with water (30 mL) and methanol (30 mL). And dried to give 7-butyl-3-methyl -1 H - purine -2,6 (3 H, 7 H) - dione (2.80 g, white solid), yield: 52%.

^{1 H NMR: (400 Hz,} DMSO- d 6) δ = 11.11 (s, 1H), 8.05 (s, 1H), 4.20 (t, J = 6.8 Hz, 2H), 3.37 (s, 3H), 1.81- 1.67 (m, 2H), 1.30-1.12 (m, 2H), 0.87 (t, J = 7.2 Hz, 3H). MS-ESI calcd for [M ⁺ H] + 223, found 223.

The second step.

7-Butyl-3-methyl-1-(4-(3-methylisoxazole-5-yl)butyl)-1 H -indole-2,6(3 H ,7 H )-dione .

5-(4-Bromobutyl)-3-methylisoxazole (218 mg, 1.00 mmol) was dissolved in N , N -dimethylformamide (10 mL) and potassium carbonate (276 mg, 2.00 mmol), 7- butyl-3-methyl -1 H - purine -2,6 (3 H, 7 H) - dione (222 mg, 1.00 mmol) and potassium iodide (199 mg, 1.20 mmol). The reaction solution was heated to 120 ° C and stirred for 16 hours. The reaction solution was concentrated under reduced pressure and purified by preparative high-performance liquid chromatography to give 7-butyl-3-methyl-1-(4-(3-methylisoxazol-5-yl)butyl)-1 H - purine -2,6 (3 H, 7 H) - dione (60.0 mg), yield: 17%.

¹ H NMR: (400 MHz, CDCl ₃ ) δ = 7.53 (s, 1H), 5.82 (s, 1H), 4.28 (t, J = 7.2 Hz, 2H), 4.10-3.99 (m, 2H), 3.58 ( s, 3H), 2.81-2.70 (m, 2H), 2.25 (s, 3H), 1.91-1.80 (m, 2H), 1.79-1.67 (m, 4H), 1.42-1.28 (m, 2H), 0.96 ( t, J = 7.2 Hz, 3H). MS-ESI calculated [M + H] ⁺ 360, found 360.

Example 56.

7-(cyclopropylmethyl)-3-methyl-1-(4-(3-methylisoxazol-5-yl)butyl)-1 H -嘌呤-2,6(3 H ,7 H )-dione.

first step.

7-(Cyclopropylmethyl)-3-methyl-1 H -indole-2,6(3 H ,7 H )-dione.

3-Methyl-1 H -indole-2,6(3 H ,7 H )-dione (3.00 g, 1.81 mmol) was dissolved in dimethyl hydrazine (50 mL) and added portionwise at room temperature Sodium hydrogen (760 mg, 19.0 mmol). The reaction solution was heated to 40 ° C and stirred for 1.5 hours. Bromomethylcyclopropane (3.17 g, 23.5 mmol) and potassium iodide (3.60 g, 2.17 mmol) were added, and the mixture was stirred at 40 ° C for 16 hours. After cooling to room temperature, filtration, the cake was washed with water (30 mL) and methanol (30 mL). And dried to give 7- (cyclopropylmethyl) -3-methyl -1 H - purine -2,6 (3 H, 7 H) - dione (1.70 g, white solid), yield: 43%.

¹ H NMR: (400 Hz, DMSO- d ₆ ) δ = 11.14 (s, 1H), 8.08 (s, 1H), 4.06 (d, J = 7.2 Hz, 2H), 3.35 (s, 3H), 1.37- 1.20 (m, 1H), 0.55-0.34 (m, 4H). MS-ESI calcd for [M ⁺ H] + 221, found 221.

The second step.

7-(cyclopropylmethyl)-3-methyl-1-(4-(3-methylisoxazol-5-yl)butyl)-1 H -嘌呤-2,6(3 H ,7 H )-dione.

5- (4-bromobutyl) -3-methylisoxazole (91.1 mg, 0.424 mmol), 7- ( cyclopropylmethyl) -3-methyl -1 H - purin-2,6 ( 3 H ,7 H )-dione (102 mg, 0.466 mmol), potassium iodide (7.4 mg, 0.047 mmol) and potassium carbonate (109 mg, 0.790 mmol) dissolved in anhydrous N , N -dimethylformamide (3 In 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 purified by preparative high-purity liquid chromatography to give 7-(cyclopropylmethyl)-3-methyl-1-(4-(3-methylisoxazole-5) - yl) butyl) -1 H - purine -2,6 (3 H, 7 H) - dione (80.0 mg), yield: 53%.

¹ H NMR: (400 MHz, Methonal- d ₄ ) δ = 8.56 (s, 1H), 6.05 (s, 1H), 4.30-4.29 (m, 2H), 4.07-4.04 (m, 2H), 3.57 (s) , 3H), 2.83-2.79 (m, 2H), 2.24 (s, 3H), 1.75-1.72 (m, 4H), 1.47-1.44 (m, 1H), 0.67 - 0.65 (m, 2H), 0.54-0.51 (m, 2H). MS-ESI calcd for [M + H] ⁺ 358.

Example 57.

7-(Cyclopropylmethyl)-1-((3,5-dimethylisoxazol-4-yl)methyl)-3-methyl-1 H -indole-2,6-(3 H , 7 H )-dione.

first step.

7-(Cyclopropylmethyl)-1-((3,5-dimethylisoxazol-4-yl)methyl)-3-methyl-1 H -indole-2,6-(3 H , 7 H )-dione.

4-Chloromethyl-3,5-dimethylisoxazole (200 mg, 1.37 mmol), 7-(cyclopropylmethyl)-3-methyl-1 H -indole-2,6-( 3 H ,7 H )-dione (332 mg, 1.51 mmol), potassium iodide (22.7 mg, 0.137 mmol) and potassium carbonate (568 mg, 4.11 mmol) dissolved in anhydrous N , N -dimethylformamide (5 In mL). The reaction solution was heated to 120 ° C and allowed to react for 3 hours. The reaction solution was cooled to 20 ° C, filtered, and purified by preparative HPLC to give 7-(cyclopropylmethyl)-1-((3,5-dimethylisoxazol-4-yl)methyl -3-methyl-1 H -indole-2,6-(3 H ,7 H )-dione (200 mg), Yield: 44%.

¹ H NMR: (400 MHz, Methonal- d ₄ ) δ = 8.01 (s, 1H), 4.98 (s, 2H), 4.22 (d, J = 3.2 Hz, 2H), 3.54 (s, 3H), 2.47 ( s, 3H), 2.29 (s, 3H), 1.44-1.39 (m, 1H), 0.64-0.60 (m, 2H), 0.50-0.47 (m, 2H). MS-ESI calcd for [M + H] ⁺ 330, found 330.

Example 58.

7-(Cyclopropylmethyl)-1-((5-isopropylisoxazol-4-yl)methyl)-3-methyl-1 H -indole-2,6-(3 H ,7 H )-dione.

first step.

7-(Cyclopropylmethyl)-1-((5-isopropylisoxazol-4-yl)methyl)-3-methyl-1 H -indole-2,6-(3 H ,7 H )-dione.

4-(Chloromethyl)-5-isopropylisoxazole (100 mg, 0.627 mmol), 7-(cyclopropylmethyl)-3-methyl-1 H -indole-2,6-( 3 H ,7 H )-dione (138 mg, 0.627 mmol), potassium iodide (10.4 mg, 0.0627 mmol) and potassium carbonate (260 mg, 1.88 mmol) dissolved in anhydrous N , N -dimethylformamide (5 In mL). The reaction solution was heated to 120 ° C and allowed to react for 3 hours. The reaction solution was cooled to 20 ° C, filtered, and purified by preparative HPLC to give 7-(cyclopropylmethyl)-1-((5-isopropylisooxazol-4-yl)methyl)- 3-Methyl-1 H -indole-2,6-(3 H ,7 H )-dione (80.0 mg), Yield: 37%.

¹ H NMR: (400 MHz, Methonal- d ₄ ) δ = 8.34 (s, 1H), 8.08 (s, 1H), 5.00 (s, 2H), 4.23 (d, J = 3.6 Hz, 2H), 3.68- 3.65 (m, 1H), 3.56 (s, 3H), 1.44-1.41 (m, 1H), 1.32 (d, J = 3.4 Hz, 6H), 0.63-0.61 (m, 2H), 0.49-0.48 (m, 2H).

MS-ESI calcd [M+H] ⁺ 344.

Example 59.

7-(Cyclopropylmethyl)-1-((3-isopropylisoxazol-5-yl)methyl)-3-methyl-1 H -indole-2,6-(3 H ,7 H )-dione.

first step.

7-(Cyclopropylmethyl)-1-((3-isopropylisoxazol-5-yl)methyl)-3-methyl-1 H -indole-2,6-(3 H ,7 H )-dione.

5-(Chloromethyl)-3-isopropylisoxazole (72.5 mg, 0.456 mmol), 7-(cyclopropylmethyl)-3-methyl-1 H -indole-2,6-( 3 H ,7 H )-dione (94.0 mg, 0.456 mmol), potassium iodide (7.5 mg, 0.046 mmol) and potassium carbonate (189 mg, 1.37 mmol) dissolved in anhydrous N , N -dimethylformamide (5 In mL). The reaction solution was heated to 120 ° C and allowed to react for 3 hours. The reaction solution was cooled to 20 ° C, filtered, and purified by preparative HPLC to give 7-(cyclopropylmethyl)-1-((3-isopropylisoxazole-5-yl)methyl)- 3-Methyl-1 H -indole-2,6-(3 H ,7 H )-dione (50.0 mg), yield: 31%.

¹ H NMR: (400 MHz, Methonal- d ₄ ) δ = 8.04 (s, 1H), 6.27 (s, 1H), 5.27 (s, 2H), 4.21 (d, J = 3.6 Hz, 2H), 3.57 ( s, 3H), 3.03-2.96 (m, 1H), 1.44-1.41 (m, 1H), 1.25 (d, J = 3.4 Hz, 6H), 0.64-0.59 (m, 2H), 0.50-0.47 (m, 2H). MS-ESI calcd [M+H] ⁺ 344.

Example 60.

7-Isobutyl-3-methyl-1-(4-(3-methylisoxazole-5-yl)butyl)-1 H -indole-2,6(3 H ,7 H )- ketone.

first step.

7-Isobutyl-3-methyl-1 H -indole-2,6(3 H ,7 H )-dione.

3-Methyl-1 H -indole-2,6(3 H ,7 H )-dione (3.00 g, 1.81 mmol) was dissolved in dimethyl hydrazine (50 mL) and added portionwise at room temperature Sodium hydrogen (760 mg, 19.0 mmol). The reaction solution was heated to 40 ° C and stirred for 1.5 hours. 1-Bromo-2-methylpropane (3.22 g, 23.5 mmol) was added, and the mixture was stirred at 40 ° C for 16 hours. After cooling to room temperature, filtration, the cake was washed with water (30 mL) and methanol (30 mL). And dried to give 7-isobutyl-3-methyl -1 H - purine -2,6 (3 H, 7 H) - dione (1.80 g, white solid), yield: 45%. MS-ESI calcd for [M ⁺ H] + 223, found 223.

The second step.

7-Isobutyl-3-methyl-1-(4-(3-methylisoxazole-5-yl)butyl)-1 H -indole-2,6(3 H ,7 H )- ketone.

Dissolve 5-(4-bromobutyl)-3-methylisoxazole (196 mg, 0.900 mmol) in N , N -dimethylformamide (10 mL), add potassium carbonate (248 mg) , 1.80 mmol), 7-isobutyl-3-methyl-1 H -indole-2,6(3 H ,7 H )-dione (200 mg, 0.90 mmol) and potassium iodide (179 mg, 1.08 mmol) . The reaction solution was heated to 120 ° C and stirred for 16 hours. The reaction solution was concentrated under reduced pressure and purified by preparative high-performance liquid chromatography to give 7-isobutyl-3-methyl-1-(4-(3-methylisooxazol-5-yl)butyl)-1H. - 嘌呤-2,6(3H,7H)-dione (70.0 mg), yield: 33%.

¹ H NMR: (400 MHz, CDCl ₃ ) δ = 7.50 (s, 1H), 5.81 (s, 1H), 4.12-3.95 (m, 4H), 3.57 (s, 3H), 2.80-2.67 (m, 2H) ), 2.28-2.12 (m, 4H), 1.80-1.65 (m, 4H), 0.92 (d, J = 6.8 Hz, 6H). MS-ESI calculated [M + H] ⁺ 360, found 360.

Example 61.

3-methyl-1-(4-(3-methylisoxazol-5-yl)butyl)-7-((3-methyloxetan-3-yl)methyl)-1 H -嘌呤-2,6(3 H ,7 H )-dione.

first step.

3-Methyl-7-((3-methyloxetan-3-yl)methyl)-1 H -indole-2,6(3 H ,7 H )-dione.

3-Methyl-1 H -indole-2,6(3 H ,7 H )-dione (4.00 g, 24.1 mmol) was dissolved in methanol (30 mL), and potassium hydroxide (1.48 g, 26.5 mmol) of aqueous solution (15 mL), the mixture was heated to 80 ° C and stirred for 1.5 hours. The temperature was lowered to 50 ° C, 3-(chloromethyl)-3-methyloxetane (3.77 g, 31.3 mmol) and potassium iodide (4.80 g, 28.9 mmol) were added, and the reaction mixture was stirred at 50 ° C. 24 hours. After cooling to room temperature, filtration, the cake was washed with water (30 mL) and methanol (30 mL). After drying, 3-methyl-7-((3-methyloxetan-3-yl)methyl)-1 H -indole-2,6(3 H ,7 H )-dione (2.40) g, white solid), yield: 40%.

¹ H NMR: (400 Hz, DMSO- d ₆ ) δ = 11.18 (s, 1H), 8.14 (s, 1H), 4.58-4.40 (m, 4H), 4.19 (d, J = 6.0 Hz, 2H), 3.36 (s, 3H), 1.20 (s, 3H). Calcd MS-ESI [M ⁺ H] + 251, found 251.

The second step.

3-methyl-1-(4-(3-methylisoxazol-5-yl)butyl)-7-((3-methyloxetan-3-yl)methyl)-1 H -嘌呤-2,6(3 H ,7 H )-dione.

5-(4-Bromobutyl)-3-methylisoxazole (174 mg, 0.80 mmol) was dissolved in N , N -dimethyl decylamine (10 mL) and potassium carbonate (220 mg, 1.60) mmol), 3- methyl-7-propyl -1 H - purine -2,6 (3 H, 7 H) - dione (200 mg, 0.80 mmol) and potassium iodide (159 mg, 0.96 mmol). The reaction solution was heated to 120 ° C and stirred for 16 hours. The reaction solution is concentrated under reduced pressure and purified by preparative high-performance liquid chromatography to give 3-methyl-1-(4-(3-methylisoxazol-5-yl)butyl)-7-((3- oxetane-3-yl) methyl) -1 H - purine -2,6 (3 H, 7 H) - dione (40.0 mg), yield: 13%.

¹ H NMR: (400 MHz, CDCl ₃ ) δ = 7.57 (s, 1H), 5.82 (s, 1H), 4.64 - 4.52 (m, 4H), 4.39 (d, J = 6.0 Hz, 2H), 4.12 3.97 (m, 2H), 3.59 (s, 3H), 2.82-2.68 (m, 2H), 2.25 (s, 3H), 1.80-1.65 (m, 4H), 1.35 (s, 3H). MS-ESI calcd [M + H] ⁺ 388.

Example 62.

7-(Cyclobutylmethyl)-3-methyl-1-(4-(3-methylisoxazole-5-yl)butyl)-1 H -indole-2,6(3 H ,7 H ) - Diketone.

first step.

7-(Cyclobutylmethyl)-3-methyl-1 H -indole-2,6(3 H ,7 H )-dione.

3-Methyl-1 H -嘌呤-2,6(3 H ,7 H )-dione (2.00 g, 12.0 mmol) was dissolved in dimethyl hydrazine (15 mL), slowly at 0 ° C Sodium hydrogen (530 mg, 13.2 mmol, 60%) was added. The reaction solution was warmed to 80 ° C and stirred for 30 minutes, then (bromomethyl)cyclobutane (1.97 g, 13.2 mmol) was slowly added under nitrogen. The reaction solution was stirred at 80 ° C for 12 hours. The reaction solution was cooled to 25 ° C, water (150 mL) was added and filtered and the filter cake was rinsed with water (10 mL x 2). The solid was dried under reduced pressure to give product 7 with an oil pump (cyclobutylmethyl) -3-methyl -1 H - purine -2,6 (3 H, 7 H) - dione (1.29 g, yellow solid), yield: 46%. ¹ H NMR: (400 Hz, DMSO- d ₆ ) δ = 11.10 (s, 1H), 8.05 (s, 1H), 4.22 (d, J = 7.2 Hz, 2H), 3.32 (s, 3H), 2.79- 2.70 (m, 1H), 1.97-1.61 (m, 6H). MS-ESI calcd for [M + H] ⁺

The second step.

7-(Cyclobutylmethyl)-3-methyl-1-(4-(3-methylisoxazole-5-yl)butyl)-1 H -indole-2,6(3 H ,7 H ) - Diketone.

7-(Cyclobutylmethyl)-3-methyl-1 H -indole-2,6(3 H ,7 H )-dione (100 mg, 0.427 mmol), 5-(4-bromobutyl)- 3-Methylisoxazole (93.1 mg, 0.427 mmol) and potassium iodide (7.1 mg, 0.043 mmol) were dissolved in N , N -dimethylformamide (5 mL), and potassium carbonate (118 mg) was added at 25 °C. , 0.854 mmol). The reaction was heated to reflux at 130 ° C for 3 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 HPLC to give the product 7-(cyclobutylmethyl)-3-methyl-1-(4-(3-methyl) isoxazol-5-yl) butyl) -1 H - purine -2,6 (3 H, 7 H) - dione (64.0 mg), yield: 40%. ¹ H NMR: (400 M Hz, Methonal- d ₄ ) δ = 7.94 (s, 1H), 6.02 (s, 1H), 4.34 (d, J = 7.6 Hz, 2H), 4.02 (t, J = 6.0 Hz) , 2H), 3.52 (s, 3H), 2.90-2.77 (m, 3H), 2.22 (s, 3H), 2.04-1.98 (m, 2H), 1.95-1.77 (m, 4H), 1.76-1.73 (m , 4H). MS-ESI calcd [M+H] ⁺ 372.

Example 63.

7-(Cyclopentylmethyl)-3-methyl-1-(4-(3-methylisoxazol-5-yl)butyl)-1 H -嘌呤-2,6(3 H ,7 H )-dione.

first step.

7-(Cyclopentylmethyl)-3-methyl-1 H -indole-2,6(3 H ,7 H )-dione.

3-Methyl-1 H -嘌呤-2,6(3 H ,7 H )-dione (350 mg, 2.11 mmol) was dissolved in dimethyl hydrazide (5 mL), slowly at 0 ° C Sodium hydrogen (92.7 mg, 2.32 mmol, 60%) was added. The reaction solution was warmed to 80 ° C and stirred for 30 minutes, then (iodomethyl)cyclopentane (487 mg, 2.32 mmol) was slowly added under nitrogen. The reaction solution was stirred at 80 ° C for 12 hours. The reaction solution was cooled to 25 ° C, water (50 mL) was added and filtered and the filter cake was rinsed with water (5 mL x 2). The solid was dried under reduced pressure to give the product 7- oil pump (cyclopentylmethyl) -3-methyl -1 H - purine -2,6 (3 H, 7 H) - dione (125 mg, yellow solid), producing Rate: 24%. ¹ H NMR: (400 M Hz, DMSO- d ₆ ) δ = 11.11 (s, 1H), 8.07 (s, 1H), 4.11 (d, J = 7.6 Hz, 2H), 3.33 (s, 3H), 2.43 -2.31 (m, 1H), 1.60-1.46 (m, 6H), 1.24-1.18 (m, 2H). MS-ESI calcd [M+H] ⁺ 495.

The second step.

7-(Cyclopentylmethyl)-3-methyl-1-(4-(3-methylisoxazol-5-yl)butyl)-1 H -嘌呤-2,6(3 H ,7 H )-dione.

7-(Cyclopentylmethyl)-3-methyl-1 H -indole-2,6(3 H ,7 H )-dione (100 mg, 0.403 mmol), 5-(4-bromobutyl) 3-methylisoxazole (87.8 mg, 0.403 mmol) and potassium iodide (6.7 mg, 0.40 mmol) were dissolved in N , N -dimethylformamide (5 mL), and potassium carbonate was added at 25 °C ( 111 mg, 0.806 mmol). The reaction was heated to reflux at 130 ° C for 3 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 HPLC to give the product 7-(cyclopentylmethyl)-3-methyl-1-(4-(3- methyl-isoxazol-5-yl) butyl) -1 H - purine -2,6 (3 H, 7 H) - dione (41.0 mg), yield: 26%. ¹ H NMR: (400 M Hz, Methonal- d ₄ ) δ = 7.98 (s, 1H), 6.05 (s, 1H), 4.27 (d, J = 7.6 Hz, 2H), 4.05 (t, J = 6.4 Hz) , 2H), 3.55 (s, 3H), 2.83-2.79 (m, 2H), 2.54-2.44 (m, 1H), 2.25 (s, 3H), 1.76-1.68 (m, 8H), 1.37-1.31 (m , 4H). MS-ESI calculated [M+H] ⁺ 386. Found 386.

Example 64.

7-(Cyclohexylmethyl)-3-methyl-1-(4-(3-methylisoxazol-5-yl)butyl)-1 H -嘌呤-2,6(3 H ,7 H )-dione.

first step.

7-(Cyclohexylmethyl)-3-methyl-1 H -indole-2,6(3 H ,7 H )-dione.

3-Methyl-1 H -嘌呤-2,6(3 H ,7 H )-dione (2.00 g, 12.0 mmol) was dissolved in dimethyl hydrazine (15 mL), slowly at 0 ° C Sodium hydrogen (530 mg, 13.2 mmol, 60%) was added. The reaction solution was warmed to 80 ° C and stirred for 30 min, then (bromomethyl) cyclohexane (2.34 g, 13.2 mmol) was slowly added under nitrogen. The reaction solution was stirred at 80 ° C for 12 hours. The reaction solution was cooled to 25 ° C, water (150 mL) was added and filtered and the filter cake was rinsed with water (10 mL x 2). The solid was dried under reduced pressure to give the product 7- oil pump (cyclohexylmethyl) -3-methyl -1 H - purine -2,6 (3 H, 7 H) - dione (2.80 g, yellow solid), yield : 89%. ^{1 H NMR: (400 M Hz} , DMSO- d 6) δ = 11.09 (s, 1H), 8.00 (s, 1H), 4.04 (d, J = 7.2 Hz, 2H), 3.33 (s, 3H), 1.67 -1.55 (m, 4H), 1.18-1.09 (m, 4H), 0.95 - 0.79 (m, 3H). MS-ESI calcd [M+H] ⁺ 262.

The second step.

7-(Cyclohexylmethyl)-3-methyl-1-(4-(3-methylisoxazol-5-yl)butyl)-1 H -嘌呤-2,6(3 H ,7 H )-dione.

7-(Cyclohexylmethyl)-3-methyl-1 H -indole-2,6(3 H ,7 H )-dione (100 mg, 0.381 mmol), 5-(4-bromobutyl) 3-methylisoxazole (83.0 mg, 0.381 mmol) and potassium iodide (6.3 mg, 0.038 mmol) were dissolved in N , N -dimethylformamide (5 mL), and potassium carbonate (105) was added at 25 °C. Mg, 0.763 mmol). The reaction was heated to reflux at 130 ° C for 3 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 HPLC to give the product 7-(cyclohexylmethyl)-3-methyl-1-(4-(3-) yl isoxazol-5-yl) butyl) -1 H - purine -2,6 (3 H, 7 H) - dione (75.0 mg), yield: 49%. ¹ H NMR: (400 M Hz, Methonal- d ₄ ) δ = 7.90 (s, 1H), 6.03 (s, 1H), 4.15 (d, J = 7.2 Hz, 2H), 4.09-4.01 (m, 2H) , 3.53(s,3H),2.82-2.76(m,2H), 2.23(s,3H),1.92-1.80(m,1H),1.72-1.61(m,7H),1.59(d, J = 12.8 Hz , 2H), 1.26-1.16 (m, 3H), 1.08-0.96 (m, 2H). MS-ESI calcd [M+H] ⁺ 400, found 400.

Example 65.

7-Benzyl-3-methyl-1-(4-(3-methylisoxazol-5-yl)butyl)-1 H -indole-2,6(3 H ,7 H )-dione .

first step.

7-Benzyl-3-methyl-1 H -indole-2,6(3 H ,7 H )-dione.

3-Methyl-1 H -嘌呤-2,6(3 H ,7 H )-dione (200 mg, 1.20 mmol), benzyl bromide (153 mg, 1.20 mmol) and potassium iodide (19.9 mg, 0.120 mmol) It was dissolved in N , N -dimethylformamide (10 mL), and potassium carbonate (182 mg, 1.32 mmol) was added, and the mixture was heated to reflux at 60 ° C for 12 hours. The reaction solution was cooled to 25 ° C, water (50 mL) was added and filtered and the filter cake was rinsed with water (5 mL x 2). The solid was dried under reduced pressure to give the product oil pump 7-Benzyl-3-methyl -1 H - purine -2,6 (3 H, 7 H) - dione (271 mg, yellow solid), yield: 88%. ¹ H NMR: (400 M Hz, DMSO- d ₆ ) δ = 8.22 (s, 1H), 7.95 (s, 1H), 7.37-7.27 (m, 5H), 5.45 (s, 2H), 3.34 (s, 3H).

The second step.

7-Benzyl-3-methyl-1-(4-(3-methylisoxazol-5-yl)butyl)-1 H -indole-2,6(3 H ,7 H )-dione .

7-Benzyl-3-methyl-1 H -indole-2,6(3 H ,7 H )-dione (270 mg, 1.05 mmol), 5-(4-bromobutyl)-3-methyl Isoxazole (230 mg, 1.05 mmol) and potassium iodide (17.4 mg, 0.105 mmol) were dissolved in N , N -dimethylformamide (8 mL), and potassium carbonate (290 mg, 2.10 mmol) ). The reaction was heated to reflux at 130 ° C for 3 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 HPLC to give the product 7-benzyl-3-methyl-1-(4-(3-methylisoxazole). 5-yl) butyl) -1 H - purine -2,6 (3 H, 7 H) - dione (92.0 mg), yield: 22%. ¹ H NMR: (400 M Hz, Methonal- d ₄ ) δ = 8.05 (s, 1H), 7.38-7.27 (m, 5H), 6.02 (s, 1H), 5.54 (s, 2H), 4.04-3.08 ( m, 2H), 3.53 (s, 3H), 2.79-2.75 (m, 2H), 2.23 (s, 3H), 1.73-1.67 (m, 4H). MS-ESI calcd for [M + H] ⁺ 394.

Example 66.

1-methyl-3- (4- (3-methyl-5-yl) butyl) -1 H - pyrrolo [2,3-d] pyrimidine -2,4 (3 H, 7 H )-dione.

first step.

1-Methyl-1 H -pyrrole [2,3-d]pyrimidine-2,4(3 H ,7 H )-dione.

The mixture was 6-amino-1-methylpyrimidine-2,4(1 H ,3 H )-dione (2.00 g, 15.7 mmol), sodium acetate (1.30 g, 15.7 mmol) and 2-chloroacetaldehyde (3.70) g, 47.2 mmol) water (7 mL) solution was heated to 70 ° C, the reaction was stirred for 2 hours, cooled to room temperature, filtered, and the filter cake was dried to give 1-methyl- 1H -pyrrole [2,3- d] pyrimidine -2,4 (3 H, 7 H) - dione (400 mg, light brown solid), yield: 15%. ¹ H NMR: (400 MHz, DMSO- d ₆ ) δ = 11.66 (s, 1H), 10.70 (s, 1H), 6.74 (d, J = 3.2 Hz, 1H), 6.30 (d, J = 3.2 Hz, 1H), 3.34 (s, 3H). MS-ESI calcd for [M + H] ⁺ 166.

The second step.

Tert-butyl-1-methyl-2,4-dioxo-3,4-dihydro-1 H -pyrrole[2,3-d]pyrimidin-7( 2H )-carboxylate.

Add 1-methyl-1 H -pyrrole [2,3-d]pyrimidine-2 in a suspension of sodium hydride (96.0 mg, 2.40 mmol) in dimethyl hydrazine (10 mL) at 15 °C. 4( 3H , 7H )-dione (396 mg, 2.40 mmol) and di-tert-butyl butyl carbonate (785 mg, 3.60 mmol). The reaction solution was heated to 30 ° C and stirred overnight. The reaction solution was poured into ice water (20 mL) and then evaporated. Filtration, filter cake dried to give tertiary butyl-1-methyl-2,4-dioxo-3,4-dihydro-1 H -pyrrole [2,3-d]pyrimidin-7(2 H ) - Carboxylic ester (400 mg, light brown solid), yield: 62%. ¹ H NMR: (400 MHz, DMSO- d ₆ ) δ = 11.29 (s, 1H), 7.10 (d, J = 3.2 Hz, 1H), 6.50 (d, J = 3.2 Hz, 1H), 3.32 (s, 3H), 1.57 (s, 9H). MS-ESI calcd [M + H] ⁺ 266, Found 266.

third step.

Tert-butyl-1-methyl-3-(4-(3-methylisoxazol-5-yl)butyl)-2,4-dioxo-3,4-dihydro-1 H - Pyrrolo[2,3-d]pyrimidin-7( 2H )-carboxylic acid tert-butyl ester.

Tertiary butyl-1-methyl-2,4-dioxo-3,4-dihydro-1 H -pyrrolo[2,3-d]pyrimidin-7(2 H )-carboxylic acid tert-butyl The ester (196 mg, 0.734 mmol) was dissolved in N , N -dimethylformamide (5 mL). 5-(4-bromobutyl)-3-methylisoxazole (200 mg, 0.917 mmol) , potassium iodide (15.0 mg, 0.0917 mmol) and potassium carbonate (253 mg, 1.83 mmol). The reaction solution was stirred at 20 ° C for 72 hours. The reaction was quenched with water (30 mL) EtOAc (EtOAc)EtOAc. Ethyl ester, Rf = 0.4) gives tert-butyl-1-methyl-3-(4-(3-methylisoxazol-5-yl)butyl)-2,4-dioxo-3, 4-Dihydro-1 H -pyrrolo[2,3-d]pyrimidin-7( 2H )-carboxylic acid tert-butyl ester (200 mg, yellow solid), yield: 54%. MS-ESI calcd [M + H] ⁺ 403.

the fourth step.

1-methyl-3-(4-(3-methylisoxazol-5-yl)butyl)-1 H -pyrrolo[2,3-d]pyrimidine-2,4(3 H ,7 H )-dione.

Tert-butyl-1-methyl-3-(4-(3-methylisoxazol-5-yl)butyl)-2,4-dioxo-3,4- at 0 °C Dihydro-1 H -pyrrolo[2,3-d]pyrimidin-7( 2H )-carboxylic acid tert-butyl butyl ester (200 mg, 0.497 mmol) was dissolved in ethyl acetate (2 mL). The ester solution (5 mL) was stirred at 0 ° C for 5 hours. The reaction solution was directly concentrated under reduced pressure and purified by preparative high-purity liquid chromatography to give 1-methyl-3-(4-(3-methylisoxazole-5-yl)butyl)-1 H -pyrrolo[2, 3-d]pyrimidine-2,4(3 H ,7 H )-dione (60.0 mg), yield: 40%. ¹ H NMR: (400 MHz, Methonal- d ₄ ) δ = 6.75 (d, J = 3.2 Hz, 1H), 6.49 (d, J = 3.2 Hz, 1H), 6.05 (s, 1H), 4.07-4.03 ( m, 2H), 3.54 (s, 3H), 2.82-2.79 (m, 2H), 2.24 (s, 3H), 1.74-1.72 (m, 4H). MS-ESI calcd [M + H] ⁺ 303, Found 303.

Example 67.

1,7-Dimethyl-3-(4-(3-methylisoxazole-5-yl)butyl)-1 H -pyrrolo[2,3-d]pyrimidine-2,4(3 H , 7 H )-dione.

first step.

1,7-Dimethyl-3-(4-(3-methylisoxazole-5-yl)butyl)-1 H -pyrrolo[2,3-d]pyrimidine-2,4(3 H , 7 H )-dione.

1-methyl-3-(4-(3-methylisoxazol-5-yl)butyl)-1 H -pyrrolo[2,3-d]pyrimidine-2,4(3 H ,7 H )-dione (60.0 mg, 0.199 mmol) was dissolved in N , N -dimethylformamide (3 mL), and sodium hydrogen (24.0 mg, 0.596 mmol) was added at 0 ° C, stirred for 30 minutes and then added Methyl iodide (85.0 mg, 0.596 mmol). The reaction solution was stirred at 25 ° C for 12 hours. The reaction mixture was quenched with water (30 mL).EtOAc. Methyl-3-(4-(3-methylisoxazol-5-yl)butyl)-1 H -pyrrolo[2,3-d]pyrimidine-2,4(3 H ,7 H )- Diketone (20.0 mg), yield: 32%. ¹ H NMR: (400 MHz, Methonal- d ₄ ) δ = 6.59 (d, J = 3.2 Hz, 1H), 6.41 (d, J = 3.2 Hz, 1H), 6.02 (s, 1H), 4.03-4.00 ( m, 2H), 3.94 (s, 3H), 3.79 (s, 3H), 2.79-2.76 (m, 2H), 2.21 (s, 3H), 1.70-1.68 (m, 4H). MS-ESI calcd [M + H] ⁺ 303.

Example 68.

1,4-Dimethyl-6-[4-(3-methylisoxazol-5-yl)-butyl]-1,4-dihydro-pyrazolo[4,3-d]pyrimidine- 5,7-dione.

first step.

Methyl 4-amino-2-methyl- 2H -pyrazole-3-carboxylate.

Methyl 2-methyl-4-nitro- 2H -pyrazole-3-carboxylate (4.00 g, 21.6 mmol) was dissolved in methanol (120 mL), dry palladium carbon (palladium 10%, water 1%) , 400 mg), the reaction solution was reacted at 30 psi hydrogen pressure for 5 hours at room temperature. The reaction mixture was filtered, the filtrate was concentrated under reduced pressure to give 4-amino-2-methyl -2 H - pyrazole-3-carboxylate (3.00 g, white solid), yield: 90%. ¹ H NMR: (400 MHz, CDCl ₃ ) δ = 7.10 (s, 1H), 4.09 (s, 2H), 4.02 (s, 3H), 3.90 (s, 3H). MS-ESI calcd for [M + H] ⁺ 156.

The second step.

Methyl 2-methyl-4-(2,2,2-trifluoro-ethylamido)-2 H -pyrazole-3-carboxylate.

Methyl 4-amino-2-methyl- 2H -pyrazole-3-carboxylate (3.00 g, 19.3 mmol) was dissolved in dichloromethane (50 mL) and trifluoroacetic anhydride (4.47) g, 21.3 mmol), the reaction mixture was stirred at room temperature for 20 min, then quenched with saturated sodium hydrogen carbonate (30 mL), dichloromethane (50 mL×2) ), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 2-methyl-4- (2,2,2-trifluoro - acetylamino) -2 H - pyrazole-3-carboxylate (4.20 g , yellow oil), Yield: 86%.

MS-ESI calcd for [M + H] ⁺ 252.

third step.

Methyl 2-methyl-4-[methyl-(2,2,2-trifluoro-ethinyl)-amino]-2 H -pyrazole-3-carboxylate.

2-Methyl-4- (2,2,2-trifluoro - acetylamino) -2 H - pyrazole-3-carboxylate (4.20 g, 16.7 mmol) was dissolved in tetrahydrofuran (50 mL), Sodium hydride (736 mg, 18.4 mmol) was added portionwise at 0 ° C, and the mixture was stirred under nitrogen. The mixture was stirred at 0 ° C for 40 min. 18 hours. Water (50 mL), and ethyl acetate (100 mL×2) was evaporated. -4- [methyl - (2,2,2-trifluoro - acetylglucosamine-yl) - amino] -2 H - pyrazole-3-carboxylate (3.60 g, yellow oil), yield : 85%. ¹ H NMR: (400 MHz, CDCl ₃ ) δ = 7.49 (s, 1H), 4.20 (s, 3H), 3.90 (s, 3H), 3.27 (s, 3H). MS-ESI calcd [M + H] ⁺ 266, Found 266.

the fourth step.

4-(tertiary butoxycarbonyl-methyl-amino)-2-methyl- 2H -pyrazole-3-carboxylic acid.

Methyl 2-methyl-4-[methyl-(2,2,2-trifluoro-ethinyl)-amino]-2 H -pyrazole-3-carboxylate (2.90 g, 10.9 mmol) To a solution of lithium hydroxide monohydrate (1.84 g, 43.8 mmol), triethylamine (2.21 g, 21.9 mmol) and dibutyl succinate (7.16 g) in tetrahydrofuran (30 mL) and water (30 mL). 32.8 mmol), the reaction solution was reacted at room temperature for 24 hours, and the reaction mixture was concentrated under reduced pressure. The mixture was adjusted to pH 4 with 2N aqueous hydrochloric acid (20 mL), ethyl acetate (50 mL x 2) Washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered, evaporated, evaporated, evaporated. Butoxycarbonyl-methyl-amino)-2-methyl- 2H -pyrazole-3-carboxylic acid (2.20 g, yellow oil), yield: 79%. ¹ H NMR: (400 MHz, CDCl ₃ ) δ = 7.47 (s, 1H), 4.15 (s, 3H), 3.20 (s, 3H), 1.46 (s, 9H). MS-ESI calculated [M + H] ⁺ 256, found 256.

the fifth step.

(5-Carbamino-1-yl-1 H -pyrazol-4-yl)-methyl-carbamic acid tert-butyl ester.

4-(tertiary butoxycarbonyl-methyl-amino)-2-methyl- 2H -pyrazole-3-carboxylic acid (1.60 g, 6.27 mmol), 2-(7-azobenzotriene) Azole)-tetramethylurea hexafluorophosphate (7.15 g, 18.8 mmol) and ammonium chloride (671 mg, 12.5 mmol) were dissolved in dichloromethane (100 mL) and triethylamine (952) was added dropwise at room temperature. Mg, 9.40 mmol). The reaction mixture was stirred at room temperature for 18 hr, and water (200 mL) was evaporated. Concentration under reduced pressure, and the residue was purified by silica gel column chromatography (1:1 petroleum ether / ethyl acetate, Rf = 0.6) to give (5-aminocarbazin-1-methyl-1 H -pyrazole-4 -yl)-methyl-carbamic acid tert-butyl ester (600 mg, yellow oil), yield: 38%. ¹ H NMR: (400 MHz, CDCl ₃ ) δ = 7.38 (s, 1H), 4.10 (s, 3H) 3.19 (s, 3H), 1.47 (s, 9H). MS-ESI calcd [M + H] ⁺ 255.

The sixth step.

2-Methyl-4-methylamino- 2H -pyrazole-3-carboxylic acid decylamine hydrochloride.

(5-Carbamino-1-methyl-1 H -pyrazol-4-yl)-methyl-carbamic acid tert-butyl ester (550 mg, 2.16 mmol) dissolved in 4 N ethyl acetate The solution (15 mL) was stirred at room temperature for 18 h. Concentration under reduced pressure gave 2-methyl-4-methylamino- 2H -pyrazole-3-carboxylic acid decylamine hydrochloride (300 mg, white solid). ^{1 H NMR: (400 MHz,} DMSO- d 6) δ = 8.19 (br, 2H), 7.67 (s, 1H), 3.96 (s, 3H), 2.88 (s, 3H). MS-ESI calcd for [M + H] ⁺ 155.

The seventh step.

1,4-Dimethylpyrazolo[4,3-d]pyrimidine-5,7-dione.

2-Methyl-4-methylamino- 2H -pyrazole-3-carboxylic acid decylamine hydrochloride (300 mg, 1.57 mmol) was dissolved in N,N-dimethylformamide (10 mL) Sodium hydride (378 mg, 9.44 mmol) was added portionwise at 0 °C. The reaction solution was stirred at 0 ° C for 0.5 hour under a nitrogen atmosphere. 1,1-Carbonyldiimidazole (766 mg, 4.72 mmol) was added, and the reaction solution was heated to 75 ° C for 3 hours. The reaction was quenched by the addition of water (30 mL), filtered, and then filtered and washed with Et. Et. 5,7-Dione (210 mg, off-white solid), yield: 74%. ¹ H NMR: (400 MHz, DMSO- d ₆ ) δ = 11.35 (s, 1H), 7.69 (s, 1H), 4.07 (s, 3H), 3.30 (s, 3H). MS-ESI calcd for [M + H] ⁺ 181.

The eighth step.

1,4-Dimethyl-6-[4-(3-methylisoxazol-5-yl)-butyl]-pyrazolo[4,3-d]pyrimidine-5,7-dione.

1,4-Dimethylpyrazolo[4,3-d]pyrimidine-5,7-dione (50.0 mg, 0.278 mmol) was dissolved in N , N -dimethylformamide (2 mL). 5-(4-Bromobutyl)-3-methylisoxazole (60.5 mg, 0.278 mmol), potassium carbonate (76.7 mg, 0.555 mmol) and potassium iodide (55.3 mg, 0.333 mmol). The reaction solution was heated to 120 ° C and stirred for 3 hours. Concentrated under reduced pressure, and the residue was purified by high-purity liquid chromatography to give 1,4-dimethyl-6-[4-(3-methylisoxazole-5-yl)-butyl]-pyrazole. [4,3-d]pyrimidine-5,7-dione (30.0 mg), Yield: 34%. ¹ H NMR: (400 MHz, CDCl ₃ ) δ = 7.36 (s, 1H), 5.82 (s, 1H), 4.22 (s, 3H), 4.12-3.97 (m, 2H), 3.47 (s, 3H), 2.82-2.70 (m, 2H), 2.25 (s, 3H), 1.85-1.60 (m, 4H). MS-ESI calcd [M + H] ⁺ 318. Found 318.

Example 69.

2,4-Dimethyl-6-[4-(3-methylisoxazol-5-yl)-butyl]-2,4-dihydro-pyrazolo[4,3-d]pyrimidine- 5,7-dione.

first step.

Methyl 1-methyl-4-nitro-pyrazole-3-carboxylate.

4-Nitro-pyrazole-3-carboxylic acid (27.5 g, 175 mmol) was dissolved in N, N - dimethylformamide (800 mL), at room temperature was added _{K 2 CO 3 (53.2 g,} 385 mmol ). The reaction solution was heated to 80 ° C and stirred for 3 hours. After cooling to room temperature, methyl iodide (74.6 g, 525 mmol) was added, and the mixture was reacted at room temperature for 15 hours. The reaction mixture was diluted with water (2.5 L) and evaporated withEtOAc. The combined organic phases were washed with saturated aqueous sodium chloride (800 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, the residue was purified by silica gel column chromatography (1: 1 petroleum ether / ethyl acetate, Rf ₁ = 0.5, Rf ₂ = 0.3) gave 2-methyl-4-nitro- 2H -pyrazole-3-carboxylic acid methyl ester (6.00 g, yellow liquid), yield: 19%, 1-methyl-4 Methyl-nitro-pyrazole-3-carboxylate (11.0 g, white solid), yield: 34%.

¹ H NMR: (400 MHz, CDCl ₃ ) δ = 8.15 (s, 1H), 4.01 (s, 3H), 4.40 (s, 3H). MS-ESI calcd [M + H] ⁺ 186.

The second step.

1-Methyl-4-nitro-pyrazole-3-carboxylic acid decylamine.

Methyl 1-methyl-4-nitro-pyrazole-3-carboxylate (5.00 g, 27.0 mmol) was dissolved in aqueous ammonia (30 mL), and the reaction mixture was heated to 80 ° C, and the reaction was stirred for 18 hours. The reaction mixture was cooled to EtOAc EtOAc. , yield: 50%. MS-ESI calcd for [M + H] ⁺ 171.

third step.

4-Amino-1-methyl-pyrazole-3-carboxylic acid decylamine.

1-Methyl-4-nitro-pyrazole-3-carboxylic acid decylamine (2.30 g, 13.5 mmol) was dissolved in methanol (50 mL), dry palladium carbon (palladium 10%, water 1%, 230 mg) The reaction solution was reacted under a hydrogen pressure of 30 psi for 18 hours at room temperature. The reaction mixture was filtered, and the filtrate was evaporated evaporated evaporated. MS-ESI calcd for [M ⁺ H] + 141, found 141.

the fourth step.

4-(2,4-Dinitro-benzenesulfonylamino)-1-methyl-pyrazole-3-carboxylic acid decylamine.

4-Amino-1-methyl-pyrazole-3-carboxylic acid decylamine (140 mg, 0.999 mmol) was dissolved in tetrahydrofuran (15 mL), triethylamine (152 mg, 1.50 mmol) and 2 , 4-dinitro-benzenesulfonium chloride (200 mg, 1.05 mmol). The reaction solution was stirred at room temperature for 1.5 hours. The reaction solution was filtered, and the filter cake was washed with water (5 mL) and filtered to give 4-(2,4-dinitro-phenylsulfonylamino)-1-methyl-pyrazole-3-carboxylic acid decylamine (200) Mg, yellow solid) Yield: 54%. MS-ESI calcd for [M + H] ⁺ 372.

the fifth step.

4-[(2,4-Dinitro-benzenesulfonyl)-methyl-amino]-1-methyl-pyrazole-3-carboxylic acid decylamine.

Dissolving 4-(2,4-dinitro-benzenesulfonylamino)-1-methyl-pyrazole-3-carboxylic acid decylamine (100 mg, 0.270 mmol) in N , N -dimethylmethyl The guanamine (5 mL) was added with potassium carbonate (56.0 mg, 0.405 mmol), and the mixture was heated to 80 ° C and stirred for 2 hours. The reaction solution was cooled to room temperature, then dichloromethane (57.5 mg, 0.405 mmol) was added, and the mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with water (15 mL), filtered, and then filtered and washed with Et. Methyl-pyrazole-3-carboxylic acid decylamine (90.0 mg, yellow oil), yield: 87%. ¹ H NMR: (400 MHz, DMSO- d ₆ ) δ = 8.93 (d, J = 2.4 Hz, 1H), 8.49 (dd, J = 8.8, 2.4 Hz, 1H), 8.03 (d, J = 8.8 Hz, 1H), 7.97 (s, 1H), 7.35-7.30 (br, 1H), 7.15-7.10 (br, 1H), 3.88 (s, 3H), 3.33 (s, 3H). MS-ESI calcd for [M+H] ⁺ 385.

The sixth step.

1-Methyl-4-methylamino-pyrazole-3-carboxylic acid decylamine.

4-[(2,4-Dinitro-benzenesulfonyl)-methyl-amino]-1-methyl-pyrazole-3-carboxylic acid decylamine (110 mg, 0.286 mmol) was dissolved in acetonitrile ( 10 mL), cesium carbonate (280 mg, 0.859 mmol) and thiophenol (34.7 mg, 0.315 mmol) were added. The reaction solution was stirred at room temperature for 3 hours. The reaction mixture was diluted with methylene chloride (20 mL), filtered, evaporated, evaporated, evaporated. Methylamino-pyrazole-3-carboxylic acid decylamine (42.0 mg, yellow solid), yield: 95%. MS-ESI calcd for [M + H] ⁺ 155.

The seventh step.

2,4-Dimethyl-pyrazolo[4,3-d]pyrimidine-5,7-dione.

1-Methyl-4-methylamino-pyrazole-3-carboxylic acid decylamine (670 mg, 4.35 mmol) was dissolved in N,N-dimethylformamide (15 mL) at 0 °C. Sodium hydride (365 mg, 9.14 mmol) was added portionwise. The reaction solution was stirred at 0 ° C for 0.5 hour under a nitrogen atmosphere. 1,1-Carbonyldiimidazole (1.41 g, 8.70 mmol) was added, and the reaction mixture was heated to 75 ° C for 3 hours. The reaction was quenched by the addition of water (45 mL), filtered, and then filtered and washed with with with with with with with with with with with with with with with with with with with with with with with with with with with with 640 mg, off-white solid), yield: 82%. ¹ H NMR: (400 MHz, DMSO- d ₆ ) δ = 11.01 (s, 1H), 7.93 (s, 1H), 3.97 (s, 3H), 3.25 (s, 3H). MS-ESI calcd for [M + H] ⁺ 181.

The eighth step.

2,4-Dimethyl-6-[4-(3-methylisoxazol-5-yl)-butyl]-pyrazolo[4,3-d]pyrimidine-5,7-dione.

2,4-Dimethyl-pyrazolo[4,3-d]pyrimidine-5,7-dione (100 mg, 0.555 mmol) was dissolved in N , N -dimethylformamide (2 mL) 5-(4-Bromobutyl)-3-methylisoxazole (133 mg, 0.611 mmol), potassium carbonate (153 mg, 1.11 mmol) and potassium iodide (111 mg, 0.611 mmol). The reaction solution was heated to 120 ° C and stirred for 3 hours. Concentrated under reduced pressure, and the residue was purified by high-purity chromatography to give 2,4-dimethyl-6-[4-(3-methylisoxazol-5-yl)-butyl]-pyrazolo[ 4,3-d]pyrimidine-5,7-dione (40.0 mg), yield: 23%. ¹ H NMR: (400 MHz, DMSO- d ₆ ) δ = 7.26 (s, 1H), 5.84 (s, 1H), 4.15 - 4.00 (m, 5H), 3.42 (s, 3H), 2.82-2.69 (m) , 2H), 2.25 (s, 3H), 1.83-1.60 (m, 4H). MS-ESI calcd [M + H] ⁺ 318. Found 318.

Example 70.

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

first step.

Methyl 4-nitro-pyrazole-5-carboxylate.

4-Nitro-pyrazole-5-carboxylic acid (45.0 g, 286 mmol) was dissolved in methanol (700 mL) and EtOAc (EtOAc) The reaction solution was stirred at 25 ° C for 18 hours. The reaction mixture was concentrated under reduced pressure to give ethyl 4-nitro-pyrazole-5-carboxylate (49.0 g, white solid). ¹ H NMR: (400 MHz, CDCl ₃ ) δ = 8.53 (s, 1H), 4.06 (s, 3H). MS-ESI calcd for [M + H] ⁺ 172.

The second step.

Methyl 4-nitro-1-(2,2,2-trifluoroethyl)-pyrazole-5-carboxylate.

Methyl 4-nitro-pyrazole-5-carboxylate (25.0 g, 146 mmol) was dissolved in N , N -dimethylformamide (350 mL), and sodium hydride (6.43 g) , 161 mmol). 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 mixture, which was extracted with ethyl acetate (300 mL). The organic phase was combined, washed with EtOAc EtOAc EtOAc EtOAcjHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH Methyl 4-nitro-1-(2,2,2-trifluoroethyl)-pyrazole-5-carboxylate (8.00 g, mp. 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 calcd for [M+H] ⁺ 254.

third step.

Methyl 4-amino-1-(2,2,2-trifluoroethyl)-pyrazole-5-carboxylate.

Methyl 4-nitro-1-(2,2,2-trifluoroethyl)-pyrazole-5-carboxylate (7.50 g, 29.6 mmol) was dissolved in methanol (100 mL). 10%, water 1%, 750 mg), the reaction was reacted at 40 psi hydrogen pressure for 3 hours at room temperature. The reaction solution was filtered, and the filtrate was evaporated tolululululululululululululululululululu . 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 calcd for [M + H] ⁺ 224.

the fourth step.

Methyl 4-(2,2,2-trifluoroacetamide)-1-(2,2,2-trifluoroethyl)-pyrazole-5-carboxylate.

Methyl 4-amino-1-(2,2,2-trifluoroethyl)-pyrazole-5-carboxylate (6.30 g, 28.2 mmol) was dissolved in dichloromethane (100 mL). Trifluoroacetic acid anhydride (8.89 g, 42.4 mmol), the reaction mixture was stirred at room temperature for 2 hr, then quenched with saturated sodium bicarbonate (100 mL), dichloromethane (100 mL) The organic phase is washed with anhydrous sodium sulfate and concentrated under reduced pressure to give 4-(2,2,2-trifluoroacetamide)-1-(2,2,2-trifluoroethyl)-pyrazole-5 Methyl formate (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 calcd for [M+H] ⁺ 320, found 320.

the fifth step.

Methyl 4-(2,2,2-trifluoro- N -methylacetamide)-1-(2,2,2-trifluoroethyl)-pyrazole-5-carboxylate.

Methyl 4-(2,2,2-trifluoroacetamide)-1-(2,2,2-trifluoroethyl)-pyrazole-5-carboxylate (9.20 g, 28.8 mmol) was dissolved in N , N -dimethylformamide (50 mL), added potassium carbonate (5.98 g, 43.3 mmol). The reaction solution was heated to 80 ° C 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. Water (300 mL) was added to the reaction mixture, and ethyl acetate (100 mL x 3). The combined organic phases were 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 - methyl amine acetyl) -1- ( Methyl 2,2,2-trifluoroethyl)-pyrazole-5-carboxylate (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 calcd for [M ⁺ H] + 334, found 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-carboxylate (9.90 g, 29.7 Methyl acetate was dissolved in tetrahydrofuran (40 mL) and water (40 mL). Di-tertiary butyl dicarbonate (13.0 g, 59.4 mmol) was added, and the reaction was continued at room temperature for 6 hours. The reaction mixture was concentrated under reduced pressure. pH was adjusted with 4 N aqueous hydrochloric acid, filtered, and dried. 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 calcd for [M + H] ⁺ 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-azobenzotriazine) Oxyl)-tetramethylurea hexafluorophosphate (13.8 g, 36.2 mmol) and ammonium chloride (2.98 g, 55.7 mmol) were dissolved in dichloromethane (120 mL) and triethylamine (4.23 g) was added dropwise at room temperature. , 41.8 mmol). The reaction mixture was stirred at room temperature for 18 hr, and water (100 mL) was added to the mixture, and the mixture was extracted with methylene chloride (100 mL x 2), and the organic phase was combined with saturated sodium bicarbonate (50 mL) and brine. After washing with 50 mL), dried over anhydrous sodium sulfate, filtered, evaporated, evaporated. , 2-trifluoroethyl)-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 calcd [M + H] ⁺ 323.

The eighth step.

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

Dissolving 4-[(tertiary butoxycarbonyl)(methyl)amino]-1-(2,2,2-trifluoroethyl)-pyrazole-5-carboxamide (5.00 g, 15.51 mmol) To ethyl acetate (50 mL). The reaction was stirred at room temperature for 18 hours and concentrated under reduced pressure. The residue was dissolved in MeOH (50 mL). EtOAc. Concentrated under reduced pressure, the~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ 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 calcd for [M ⁺ H] + 223, found 223.

The ninth step.

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

4-(Methylamino)-2-(2,2,2-trifluoroethyl)pyrazole-5-formamide (2.70 g, 12.2 mmol) and 1,1-carbonyldiimidazole (3.94 g, 24.3 mmol) was dissolved in N , N -dimethylformamide (20 mL), and the reaction was heated to 140 ° C for 1 hour. After cooling to room temperature, water (100 mL) was added to the reaction mixture, and the solid was precipitated, collected by filtration, and dried to give 4-methyl-1-(2,2,2-trifluoroethyl)-pyrazole. And [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 calcd [M + H] ⁺ 495.

The tenth step.

6-((3-Isopropyloxazol-5-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, 0.120 mmol), (3-iso Propyl isoxazole-5-yl)methyl methanesulfonate (39.7 mg, 0.181 mmol), potassium carbonate (33.4 mg, 0.242 mmol) and potassium iodide (4.0 mg, 0.024 mmol) dissolved in N , N -dimethyl Carbenamide (10 mL). The reaction solution was heated to 120 ° C and stirred for 3 hours. The reaction was cooled to room temperature, poured into water (30 mL) The combined organic layers were dried with anhydrous sodium Separation and purification by preparative high performance liquid chromatography gave 6-((3-isopropylisoxazol-5-yl)methyl)-4-methyl-1-(2,2,2-trifluoroethyl)- Pyrazolo[4,3-d]pyrimidine-5,7-dione (10.0 mg), yield: 22%. ¹ H NMR: (400 MHz, Methonal- d ₄ ) δ = 7.83 (s, 1H), 6.26 (s, 1H), 5.33-5.27 (m, 4H), 3.50 (s, 3H), 3.00-2.92 (m) , 1H), 1.22 (d, J = 7.2 Hz, 6H). MS-ESI calcd [M + H] ⁺ 372.

Example 71.

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

first step.

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

2-(2,4-Dimethylthiazol-5-yl)ethyl methanesulfonate (30.0 mg, 0.127 mmol), 4-methyl-1-(2,2,2-trifluoroethyl) Pyrazolo[4,3-d]pyrimidine-5,7-dione (31.6 mg, 0.127 mmol), potassium carbonate (35.2 mg, 0.255 mmol) and potassium iodide (4.2 mg, 0.026 mmol) dissolved in N , N - In 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) The organic phase was combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by preparative HPLC to give 6-(2-(2,4-dimethylthiazol-5-yl)ethyl)-4- 1-(2,2,2-trifluoroethyl)-pyrazolo[4,3-d]pyrimidine-5,7-dione (10.0 mg), Yield: 20%. ¹ H NMR: (400 MHz, Methonal- d ₄ ) δ = 7.86 (s, 1H), 5.34-5.25 (m, 2H), 4.29 (t, J = 6.8 Hz, 2H), 3.51 (s, 3H), 3.26 (t, J = 6.8 Hz, 2H), 2.90 (s, 3H), 2.31 (s, 3H). MS-ESI calcd [M + H] ⁺ 388.

Example 72.

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

first step.

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

2-(4-Chlorobutyl)benzofuran (30.0 mg, 0.143 mmol), 4-methyl-1-(2,2,2-trifluoroethyl)pyrazolo[4,3-d] Pyrimidine-5,7-dione (35.7 mg, 0.143 mmol), potassium carbonate (39.7 mg, 0.287 mmol) and potassium iodide (4.7 mg, 0.029 mmol) dissolved in N , N -dimethylformamide (5 mL) in. 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) The organic phase was combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by preparative high-performance liquid chromatography to give 6-(4-(benzofuran-2-yl)butyl)-4-methyl-1-( 2,2,2-Trifluoroethyl)-pyrazolo[4,3-d]pyrimidine-5,7-dione (10.0 mg), Yield: 17%. ¹ H NMR: (400 MHz, Methonal- d ₄ ) δ = 7.79 (s, 1H), 7.34 (d, J = 7.6 Hz, 1H), 7.18 (d, J = 6.8 Hz, 1H), 7.16-7.12 ( m, 2H), 6.46 (s, 1H), 5.34 - 5.28 (m, 2H), 4.07 (t, J = 6.8 Hz, 2H), 3.47 (s, 3H), 2.84 (t, J = 6.8 Hz, 2H ), 1.83-1.75 (m, 4H). MS-ESI calcd [M + H] ⁺ 422.

Example 73.

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

first step.

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

3-( 1H -indol-3-yl)propyl methanesulfonate (30.0 mg, 0.118 mmol), 4-methyl-1-(2,2,2-trifluoroethyl)pyrazole [4,3-d]pyrimidine-5,7-dione (29.4 mg, 0.118 mmol,), potassium carbonate (32.7 mg, 0.236 mmol) and potassium iodide (3.9 mg, 0.024 mmol) dissolved in N , N -dimethyl Carbenamide (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) The organic phase was combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by preparative HPLC to give 6-(3-( 1H -indol-3-yl)propyl)-4-methyl-1 -(2,2,2-Trifluoroethyl)-pyrazolo[4,3-d]pyrimidine-5,7-dione (15.0 mg), Yield: 31%. ¹ H NMR: (400 MHz, Methonal- d ₄ ) δ = 7.70 (s, 1H), 7.50 (d, J = 7.6 Hz, 1H), 7.23 (d, J = 7.6 Hz, 1H), 7.05-6.97 ( m,3H), 5.22 (q, J = 8.4 Hz, 2H), 4.16 (t, J = 7.2 Hz, 2H), 3.39 (s, 3H), 2.86 (t, J = 7.2 Hz, 2H), 2.19- 2.12 (m, 2H). MS-ESI calcd [M + H] ⁺ 406.

Example 74.

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

first step.

3-(3-Methylisoxazol-5-yl)propan-1-ol.

3,5-Dimethylisoxazole (4.00 g, 41.2 mmol) was dissolved in anhydrous tetrahydrofuran (50 mL). N.sub.2. Solution, 41.2 mmol). The reaction solution was stirred at -78 ° C for 2 hours, then ethylene oxide (1.81 g, 41.2 mmol) was added and the reaction was continued for 1 hour. The reaction was quenched with EtOAc (EtOAc)EtOAc The organic phase was combined, washed with a saturated aqueous sodium chloride solution (50 mL EtOAc) (5.00 g, yellow oil), yield: 86%. ¹ H NMR: (400 MHz, Methonal- d ₄ ) δ = 6.05 (s, 1H), 3.63-3.55 (m, 2H), 2.85-2.81 (m, 2H), 2.27 (s, 3H), 1.95-1.87 (m, 2H). MS-ESI calcd for [M + H] ⁺ 422.

The second step.

3-(3-Methylisoxazol-5-yl)propyl methanesulfonate.

3-(3-Methylisoxazole-5-yl)propan-1-ol (5.00 g, 35.4 mmol) and triethylamine (7.17 g, 70.8 mmol) were dissolved in anhydrous dichloromethane (20 mL) Nitrogen-protected, methanesulfonyl chloride (6.09 g, 53.1 mmol) was slowly added at 0 °C. The reaction solution was stirred at 0 ° C for 1 hour. The reaction was quenched with EtOAc (EtOAc)EtOAcEtOAc The organic phase was combined, washed with aq. EtOAc (EtOAc (EtOAc) Ester (6.50 g, yellow oil), yield: 84%. MS-ESI calcd for [M + H] ⁺ 220.

third step.

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

3-(3-Methylisoxazole-5-yl)propyl methanesulfonate (30.0 mg, 0.136 mmol), 4-methyl-1-(2,2,2-trifluoroethyl)pyridin Zoxao[4,3-d]pyrimidine-5,7-dione (33.9 mg, 0.136 mmol), potassium carbonate (37.8 mg, 0.273 mmol) and potassium iodide (4.5 mg, 0.027 mmol) dissolved in N , N - II Methylformamide (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) The organic phase was combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by preparative high-performance liquid chromatography to give 4-methyl-6-(3-(3-methylisoxazole-5-yl)propyl)- 1-(2,2,2-Trifluoroethyl)-pyrazolo[4,3-d]pyrimidine-5,7-dione (20.0 mg), Yield: 39%. ¹ H NMR: (400 MHz, Methonal- d ₄ ) δ = 7.81 (s, 1H), 6.06 (s, 1H), 5.35-5.29 (m, 2H), 4.13-4.07 (m, 2H), 3.50 (s) , 3H), 2.82 (t, J = 7.4 Hz, 2H), 2.18 (s, 3H), 2.12-2.05 (m, 2H). MS-ESI calcd [M + H] ⁺ 372.

Example 75.

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

first step.

4-methyl-6-(4-(3-methylisoxazol-5-yl)butyl)-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 (70.0 mg, 0.282 mmol) was dissolved in N , N - dimethylformamide (2 mL), 5-(4-bromobutyl)-3-methylisoxazole (73.8 mg, 0.338 mmol), potassium carbonate (78.0 mg, 0.564 mmol) 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 and filtered. The filtrate was concentrated under reduced pressure. 2-Trifluoroethyl)-pyrazolo[4,3-d]pyrimidine-5,7-dione (44.0 mg), Yield: 40%. ¹ H NMR: (400 MHz, CDCl ₃ ) δ = 7.55 (s, 1H), 5.83 (s, 1H), 5.22 (q, J = 8.0 Hz, 2H), 4.14 - 4.00 (m, 2H), 3.51 ( s, 3H), 2.83-2.70 (m, 2H), 2.26 (s, 3H), 1.83-1.67 (m, 4H). MS-ESI calculated [M+H] ⁺ 386. Found 386.

Example 76.

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

first step.

Methyl 1-(cyclopropylmethyl)-4-nitro-pyrazole-5-carboxylate.

Methyl 4-nitro-pyrazole-5-carboxylate (22.0 g, 129 mmol) was dissolved in N , N -dimethylformamide (350 mL), and sodium hydride (5.66 g) , 141 mmol). 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 mixture, which was extracted with ethyl acetate (300 mL). The organic phase was combined, washed with EtOAc EtOAc EtOAc EtOAcjHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH Methyl 1-(cyclopropylmethyl)-4-nitro-pyrazole-5-carboxylate (5.00 g, colorless oil). 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 calcd [M+H] ⁺ 262.

The second step.

Methyl 4-amino-1-(cyclopropylmethyl)-pyrazole-5-carboxylate.

Methyl 1-(cyclopropylmethyl)-4-nitro-pyrazole-5-carboxylate (5.00 g, 22.2 mmol) was dissolved in methanol (70 mL), dry palladium carbon (palladium 10%, water 1) %, 500 mg), the reaction was allowed to react at 40 psi hydrogen pressure for 3 hours at room temperature. The reaction mixture was filtered, and the~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ 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 calcd for [M + H] ⁺ 196.

third step.

Methyl 1-(cyclopropylmethyl)-4-(2,2,2-trifluoroethylamino)-pyrazole-5-carboxylate.

Methyl 4-amino-1-(cyclopropylmethyl)-pyrazole-5-carboxylate (4.30 g, 22.0 mmol) was dissolved in dichloromethane (40 mL). 6.94 g, 33.1 mmol), the reaction mixture was stirred at room temperature for 2 hr, and then the mixture was diluted with EtOAc EtOAc (EtOAc) Drying over anhydrous sodium sulfate and concentrating under reduced pressure afforded 1-(cyclopropylmethyl)-4-(2,2,2-trifluoroethylamino)-pyrazole-5-carboxylic acid methyl ester (6.30 g, colorless oil (form), yield: 98%. ¹ H NMR: (400 MHz, CDCl ₃ ) δ = 9.72 (s, 1H), 8.28 (s, 1H), 4.37 (d, J = 7.6 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 calcd [M + H] ⁺ 292.

the fourth step.

Methyl 1-(cyclopropylmethyl)-4-(2,2,2-trifluoro- N -methylethylamino)-pyrazole-5-carboxylate.

Methyl 1-(cyclopropylmethyl)-4-(2,2,2-trifluoroethylamino)-pyrazole-5-carboxylate (6.20 g, 21.3 mmol) was dissolved in N , N -dimethyl Methylguanamine (50 mL) was added potassium carbonate (4.41 g, 31.9 mmol). The reaction solution was heated to 80 ° C for 1 hour. Cool to room temperature and add methyl iodide (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 mixture, and ethyl acetate (100 mL x 3). The combined organic phases were 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 acetamidine amino)-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 = 7.6 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 calcd [M+H] ⁺ 306, Found 306.

the fifth step.

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

Methyl 1-(cyclopropylmethyl)-4-(2,2,2-trifluoro-N-methylethylamino)-pyrazole-5-carboxylate (6.40 g, 21.0 mmol) was dissolved in tetrahydrofuran (30 mL) and water (30 mL) were added lithium hydroxide monohydrate (4.40 g, 105 mmol), and the mixture was stirred at room temperature for 18 hours. Di-tertiary butyl dicarbonate (9.15 g, 41.9 mmol) was added, and the reaction solution was continued at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure. pH was adjusted with 4 N aqueous hydrochloric acid, filtered, and dried. 4-((tertiary butoxycarbonyl)(methyl)amino)-1-(cyclopropylmethyl)-pyrazole-5-carboxylic acid (4.50 g, white solid). ¹ H NMR: (400 MHz, CDCl ₃ ) δ = 7.46 (s, 1H), 4.38 (d, J = 7.6 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 calcd for [M + H] ⁺ 296.

The sixth step.

(5-Carbamino-1-(cyclopropylmethyl)-pyrazol-4-yl) (methyl)carbamic acid tert-butyl ester.

4-[Tertiary butoxycarbonyl)(methyl)amino]1-(cyclopropylmethyl)-pyrazole-5-carboxylic acid (3.40 g, 11.5 mmol), 2-(7-azobenzophenone Triazole)-tetramethylurea hexafluorophosphate (5.69 g, 15.0 mmol) and ammonium chloride (1.23 g, 23.0 mmol) were dissolved in dichloromethane (120 mL) and triethylamine was added dropwise at room temperature ( 1.75 g, 17.3 mmol). The reaction mixture was stirred at room temperature for 18 hr, then water (50 mL) was added to the mixture, and the mixture was extracted with dichloromethane (500 mL×2), and the organic phase was combined with saturated sodium bicarbonate (50 mL) and brine. After washing with 50 mL), dried over anhydrous sodium sulfate, filtered, evaporated. (Methyl)carbamic acid tert-butyl butyl ester (3.00 g, crude product, yellow oil). MS-ESI calcd for [M + H] ⁺ 295.

The seventh step.

1-(Cyclopropylmethyl)-4-(methylamino)-pyrazole-5-formamide.

(5-Carbamino-1-(cyclopropylmethyl)-pyrazol-4-yl)(methyl)carbamic acid tert-butyl butyl ester (3.30 g, 11.2 mmol) was dissolved in ethyl acetate ( 25 mL). The reaction was stirred at room temperature for 18 hr, then evaporated, evaporated, evaporated. The reaction mixture was filtered, evaporated, evaporated,jjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj 4-(Methylamino)-pyrazole-5-carboxamide (1.45 g, white solid), yield: 67%. ¹ H NMR: (400 MHz, CDCl ₃ ) δ = 7.34 (br, 2H), 7.17 (s, 1H), 4.62-4.47 (q, J = 5.6 Hz, 1H), 4.21. (d, J = 7.6 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 calcd for [M + H] ⁺ 195.

The eighth step.

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

1-(Cyclopropylmethyl)-4-(methylamino)-pyrazole-5-carboxamide (1.45 g, 7.47 mmol) was dissolved in N , N -dimethylformamide (10 mL) Sodium hydride (627 mg, 15.7 mmol) was added portionwise at 0 °C. The reaction solution was stirred at 0 ° C for 1 hour under a nitrogen atmosphere. 1,1-Carbonyldiimidazole (1.82 g, 11.2 mmol) was added, and the reaction mixture was heated to 75 ° C for 2 hours. The reaction solution was cooled to room temperature, quenched by the addition of water (80 mL), filtered and dried to give 1-(cyclopropylmethyl)-4-methyl-pyrazolo[4,3-d] Pyrimidine-5,7-dione (1.60 g, white solid), yield: 97%. ¹ H NMR: (400 MHz, DMSO- d ₆ ) δ = 11.35 (s, 1H), 7.72 (s, 1H), 4.29 (d, J = 7.6 Hz, 2H), 3.32 (s, 3H), 1.17- 1.07 (m, 1H), 0.54-0.32 (m, 4H). MS-ESI calcd for [M ⁺ H] + 221, found 221.

The ninth step.

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

3-Isoisoxazole-5-methyl methanesulfonate (29.9 mg, 0.136 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 (3 mL) )in. The reaction solution was warmed to 120 ° C and stirred for 3 hours. After cooling to room temperature, filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by preparative HPLC to give 1-(cyclopropylmethyl)-6-((3-isopropylisoxazole-5-yl) Methyl)-4-methyl-pyrazolo[4,3-d]pyrimidine-5,7-dione (8.0 mg), Yield: 17%. ¹ H NMR: (400 MHz, CDCl ₃ ) δ = 7.43 (s, 1H), 6.14 (s, 1H), 5.32 (s, 2H), 4.44 (d, J = 7.6 Hz, 2H), 3.52 (s, 3H), 3.07-3.00 (m, 1H), 1.43-1.40 (m, 1H), 1.26 (d, J = 7.2 Hz, 6H), 0.56-0.47 (m, 4H). MS-ESI calcd [M+H] ⁺ 344.

Example 77.

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

first step.

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

2-(2,4-Dimethylthiazol-5-yl)ethyl methanesulfonate (80.1 mg, 0.340 mmol), 1-(cyclopropylmethyl)-4-methyl-pyrazolo[ 4,3-d]pyrimidine-5,7-dione (50.0 mg, 0.227 mmol), potassium iodide (3.8 mg, 0.0227 mmol) and potassium carbonate (94.1 mg, 0.681 mmol) dissolved in N , N -dimethyl In the guanamine (5 mL). The reaction solution was warmed to 120 ° C and stirred for 3 hours. After cooling to room temperature, filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by preparative high-performance liquid chromatography to give 1-(cyclopropylmethyl)-6-(2-(2,4-dimethylthiazole-5-) Ethyl)-4-methyl-pyrazolo[4,3-d]pyrimidine-5,7-dione (20.0 mg), yield: 25%. ¹ H NMR: (400 MHz, Methonal- d ₄ ) δ = 7.68 (s, 1H), 4.39 (d, J = 7.6 Hz, 2H), 4.26 (t, J = 6.8 Hz, 2H), 3.50 (s, 3H), 3.33 (t, J = 6.8 Hz, 2H), 2.95 (s, 3H), 2.46 (s, 3H), 1.36-1.31 (m, 1H), 0.55-0.42 (m, 4H). MS-ESI calculated [M + H] ⁺ 360, found 360.

Example 78.

6-(3-(1 H -indol-3-yl)propyl)-1-(cyclopropylmethyl)-4-methyl-pyrazolo[4,3-d]pyrimidine-5,7 - Diketone.

first step.

6-(3-(1 H -indol-3-yl)propyl)-1-(cyclopropylmethyl)-4-methyl-pyrazolo[4,3-d]pyrimidine-5,7 - Diketone.

3-( 1H -indol-3-yl)propyl methanesulfonate (80.6 mg, 0.318 mmol), 1-(cyclopropylmethyl)-4-methyl-pyrazolo[4,3 -d]pyrimidine-5,7-dione (50.0 mg, 0.227 mmol), potassium iodide (3.8 mg, 0.0227 mmol) and potassium carbonate (88.0 mg, 0.636 mmol) dissolved in N , N -dimethylformamide ( 5 mL). The reaction solution was warmed to 120 ° C and stirred for 3 hours. After cooling to room temperature, filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by preparative HPLC to give 6-(3-( 1H -indol-3-yl)propyl)-1-(cyclopropyl) 4-methyl-pyrazolo[4,3-d]pyrimidine-5,7-dione (20.0 mg), yield: 25%. ¹ H NMR: (400 MHz, Methonal- d ₄ ) δ = 7.54-7.50 (m, 2H), 7.24 (d, J = 8.4 Hz, 1H), 7.05-6.96 (m, 3H), 4.35 (d, J = 7.6 Hz, 2H), 4.15 (t, J = 7.2 Hz, 2H), 3.40 (s, 3H), 2.85 (t, J = 7.2 Hz, 2H), 2.17-2.10 (m, 2H), 1.35-1.31 (m, 1H), 0.55-0.45 (m, 4H). MS-ESI calcd for [M + H] ⁺ 378.

Example 79.

6-(4-(benzofuran-2-yl)butyl)-1-(cyclopropylmethyl)-4-methyl-pyrazolo[4,3-d]pyrimidine-5,7-di ketone.

first step.

6-(4-(benzofuran-2-yl)butyl)-1-(cyclopropylmethyl)-4-methyl-pyrazolo[4,3-d]pyrimidine-5,7-di ketone.

2-(4-Chlorobutyl)benzofuran (37.0 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, 0.0136 mmol) and potassium carbonate (24.5 mg, 0.177 mmol) were dissolved in N , N -dimethylformamide (5 mL). The reaction solution was warmed to 120 ° C and stirred for 3 hours. After cooling to room temperature, filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by preparative high-purity liquid chromatography to give 6-(4-(benzofuran-2-yl)butyl)-1-(cyclopropylmethyl). 4-Methyl-pyrazolo[4,3-d]pyrimidine-5,7-dione (20.0 mg), Yield: 37%. ¹ H NMR: (400 MHz, Methonal- d ₄ ) δ = 7.59 (s, 1H), 7.44 (d, J = 7.6 Hz, 1H), 7.33 (d, J = 7.6 Hz, 1H), 7.16-7.12 ( m, 2H), 6.44 (m, 1H), 4.38 (d, J = 7.6 Hz, 2H), 4.04 (t, J = 6.8 Hz, 2H), 3.44 (s, 3H), 2.82 (t, J = 6.8) Hz, 2H), 1.81-1.73 (m, 4H), 1.34-1.31 (m, 1H), 0.50-0.44 (m, 4H). MS-ESI calcd for [M ⁺ H] + 393, found 393.

Example 80.

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

first step.

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

3-(3-Methylisoxazole-5-yl)propyl methanesulfonate (50.0 mg, 0.228 mmol), 1-(cyclopropylmethyl)-4-methyl-pyrazolo[4 , 3-d]pyrimidine-5,7-dione (38.6 mg, 0.175 mmol) and potassium carbonate (72.7 mg, 0.526 mmol) dissolved in N , N -dimethylformamide (5 mL), added potassium iodide (3.8 mg, 0.023 mmol), and the reaction mixture 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 HPLC to give 1-(cyclopropylmethyl)-4-methyl-6-(3-(3-methylisoxazole)- 5-yl)propyl)-pyrazolo[4,3-d]pyrimidine-5,7-dione (26.0 mg), yield: 43%. ¹ H NMR: (400 MHz, Methonal- d ₄ ) δ = 7.63 (s, 1H), 6.07 (s, 1H), 4.41 (d, J = 7.6 Hz, 2H), 4.12 (t, J = 7.2 Hz, 2H), 3.48 (s, 3H), 2.83 (t, J = 7.2 Hz, 2H), 2.18 (s, 3H), 2.12-2.05 (m, 2H), 1.40-1.35 (m, 1H), 0.55-0.47 (m, 4H). MS-ESI calcd [M+H] ⁺ 344.

Example 81.

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

first step.

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

Dissolving 1-(cyclopropylmethyl)-4-methyl-pyrazolo[4,3-d]pyrimidine-5,7-dione (62.1 mg, 0.282 mmol) in N , N -dimethyl Methionamine (2 mL), 5-(4-bromobutyl)-3-methylisoxazole (73.8 mg, 0.338 mmol), potassium carbonate (78.0 mg, 0.564 mmol) and potassium iodide (56.2 mg, 0.338) Mm). 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-purpur, to give 1-(cyclopropylmethyl)-4-methyl-6-(4-(3-methylisoxazole-5-yl) Base)-pyrazolo[4,3-d]pyrimidine-5,7-dione (24.0 mg), yield: 24%. ¹ H NMR: (400 MHz, CDCl ₃ ) δ = 7.40 (s, 1H), 5.83 (s, 1H), 4.43 (d, J = 7.6 Hz, 2H), 4.13-3.98 (m, 2H), 3.49 ( s, 3H), 2.83-2.75 (m, 2H), 2.25 (s, 3H), 1.82-1.67 (m, 4H), 1.44-1.31 (m, 1H), 0.60-0.50 (m, 2H), 0.49- 0.40 (m, 2H). MS-ESI calcd for [M + H] ⁺ 358.

Example 82.

5-Isobutyl-3-(4-(3-methylisoxazol-5-yl)butyl)imidazo[5,1- F ][1,2,4]triazin-4-one.

first step.

Ethyl 5-isobutyloxazole-4-carboxylate.

Isovaleric acid anhydride (4.50 g, 24.1 mmol) and ethyl 2-isocyanoacetate (2.73 g, 24.1 mmol) were dissolved in tetrahydrofuran (50 mL), and 1,8-diazabicyclohexane was added at room temperature. Undec-7-ene (3.68 g, 24.1 mmol) was stirred for 12 hours. The reaction mixture was diluted with water (20 mL), EtOAc (EtOAc m. Separation and purification by gel column chromatography (30:1 petroleum ether / ethyl acetate, Rf = 0.6) afforded ethyl 5-isobutyloxazole-4-carboxylate (2.50 g, yellow oil). 57%. ¹ H NMR: (400 MHz, CDCl ₃ ) δ = 7.76 (s, 1H), 4.36 (q, J = 7.2 Hz, 2H), 2.93 (d, J = 7.6 Hz, 2H), 2.11-2.03 (m, 1H), 1.39 (t, J = 7.2 Hz, 3H), 0.94 (d, J = 6.4 Hz, 6H). MS-ESI calcd for [M + H] ⁺ 198.

The second step.

Ethyl 5-isobutyl-1 H -imidazole-4-carboxylate.

After the 5-isobutyl-4-carboxylic acid ethyl ester (1.50 g, 7.61 mmol) was dissolved in methyl Amides (15 mL) was heated 150 ^o C for 12 hours, the reaction was cooled to room temperature, water was added (20 mL) was diluted with EtOAc (EtOAc (EtOAc)EtOAc. The product was isolated and purified (20:1 petroleum ether / ethyl acetate, Rf = 0.2) to give ethyl 5-isobutyl- 1H -imidazole-4-carboxylate (1.20 g, yellow solid), yield: 80%. MS-ESI calcd for [M + H] ⁺ 197.

third step.

Ethyl 1-amino-4-isobutyl-1 H -imidazole-5-carboxylate.

Ethyl 5-isobutyl-1 H -imidazole-4-carboxylate (1.00 g, 5.10 mmol) and diphenylphosphonium hydroxylamine (1.43 g, 6.12 mmol) were dissolved in N , N -dimethylformamidine. amine (60 mL), the reaction solution was added lithium hexamethyldisilazide silicon based group under the conditions of -10 ^o C (6.12 mL, 1 M n-hexane solution, 6.12 mmol), the reaction at room temperature for 12 hours. The reaction mixture was concentrated, diluted with EtOAc EtOAc EtOAc. Ethyl 1-amino-4-isobutyl- 1H -imidazol-5-carboxylate (800 mg, yellow oil), yield: 74%. MS-ESI calcd for [M ⁺ H] + 212, found 212.

the fourth step.

5-Isobutylimidazo[5,1-f][1,2,4]triazin-4-one.

The 1-amino-4-isobutyl -1 H - imidazole-5-carboxylate (1.00 g, 4.73 mmol) was dissolved in methyl Amides (10 mL) was heated 150 ^o C after 4 hours, The reaction solution was cooled to room temperature and purified by high performance liquid chromatography to give 5-isobutylimidazo[5,1-f][1,2,4]triazin-4-one (500 mg, yellow oil). Yield: 55%. ¹ H NMR: (400 MHz, Methonal- d ₄ ) δ = 8.23 (s, 1H), 7.68 (s, 1H), 2.85 (d, J = 7.2 Hz, 2H), 2.15-2.05 (m, 1H), 0.95 (d, J = 6.8 Hz, 6H). MS-ESI calcd for [M + H] ⁺ 193.

the fifth step.

5-Isobutyl-3-(4-(3-methylisoxazol-5-yl)butyl)imidazo[5,1- F ][1,2,4]triazin-4-one.

5-isobutyllithium imidazo[5,1- F ][1,2,4]triazin-4-one (50.0 mg, 0.260 mmol), 5-(4-bromobutyl)-3-methyl Isooxazolyl (85.1 mg, 0.390 mmol) and potassium iodide (12.9 mg, 0.0780 mmol) were dissolved in N , N -dimethylformamide (8 mL) and potassium carbonate (71.9 mg, 0.520 mmol), 120 The reaction was carried out at ° C for 2 hours. The reaction solution was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure, and the obtained product was purified by preparative high-purity liquid chromatography to give the product 5-isobutyl-3-(4-(3-methylisoxazole-5-yl). Butyl)imidazo[5,1- F ][1,2,4]triazin-4-one (24.0 mg), Yield: 28%. ¹ H NMR: (400 MHz, CDCl ₃ ) δ = 8.00 (s, 1H), 7.38 (s, 1H), 5.83 (s, 1H), 3.87 (t, J = 6.8 Hz, 2H), 2.90 (d, J = 7.2 Hz, 2H), 2.79 (t, J = 6.8 Hz, 2H), 2.28 (s, 3H), 2.20-2.13 (m, 1H), 1.83-1.74 (m, 4H), 0.98-0.94 (m , 6H). MS-ESI calcd for [M + H] ⁺ 330, found 330.

Example 83.

1-Methyl-3-(4-(3-methylisoxazol-5-yl)butyl)quinazoline-2,4(1 H ,3 H )-dione.

first step.

1-methylquinazoline-2,4-dione.

2-(Methylamino)benzoic acid (4.50 g, 0.0300 mol) and glacial acetic acid (0.3 mL) were dissolved in water (158 mL), and sodium isocyanate (2.76 g, 42.0 mmol) was slowly added at room temperature. Water (54 mL) solution. The reaction solution was heated to 40 ° C, and sodium hydroxide (34.8 g, 0.870 mol) was added. After the addition was completed, the temperature was further raised to 75 ° C and stirred for 4 hours. Cool to room temperature, filter, and dissolve the filter cake in boiling water (10 mL). The system was adjusted to pH 1-2 with 50% sulfuric acid solution (15 mL), filtered, and the filter cake was washed with a small amount of water (3 mL) and dried under reduced pressure to give the product 1-methylquinazoline-2,4-dione. (3.64 g, yellow solid), yield: 69%. ¹ H NMR: (400 MHz, DMSO- d ₆ ) δ = 11.55 (s, 1H), 8.00 (d, J = 8.0 Hz, 1H), 7.78 (t, J = 8.0 Hz, 1H), 7.42 (d, J = 8.0 Hz, 1H), 7.28 (t, J = 8.0 Hz, 1H), 3.44 (s, 3H). MS-ESI calcd for [M + H] ⁺ 177.

The second step.

1-Methyl-3-(4-(3-methylisoxazol-5-yl)butyl)quinazoline-2,4-dione.

1-Methylquinazoline-2,4-dione (50.0 mg, 0.280 mmol), 5-(4-bromobutyl)-3-methylisoxazole (98.0 mg, 0.420 mmol), potassium iodide ( 5.0 mg, 0.030 mmol) and potassium carbonate (83.0 mg, 0.600 mmol) were dissolved in N , N -dimethylformamide (1 mL). The reaction solution was heated to 130 ° C and allowed to react for 2.5 hours. The reaction mixture was cooled to room temperature and brine (50 mL) Purification afforded the product 1-methyl-3-(4-(3-methylisoxazol-5-yl)butyl)quinazoline-2,4-dione (41.0 mg). ¹ H NMR: (400 MHz, Methonal- d ₄ ) δ = 8.16-8.13 (m, 1H), 7.77-7.75 (m, 1H), 7.44 (d, J = 8.0 Hz, 1H), 7.31 (t, J = 8.0 Hz, 1H), 6.04 (s, 1H), 4.13-4.08 (m, 2H), 3.61 (s, 3H), 2.80 (t, J = 6.8 Hz, 2H), 2.23 (s, 3H), 1.77 -1.73 (m, 4H). MS-ESI calcd for [M + H] ⁺ 314.

Example 84.

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

first step.

2-(Methylamino)nicotinonitrile.

2-Chloro-3-cyanopyridine (30.0 g, 216 mmol) was added to a 40% aqueous solution of methylamine (300 mL), and the mixture was stirred at 80 ° C for 2 hours. The reaction mixture was concentrated under reduced pressure. EtOAc (EtOAc m.) 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.

2-(Methylamino)nicotinonitrile (600 mg, 4.51 mmol), potassium carbonate (1.87 mg, 0.130 mmol), hydrogen peroxide (0.1 mL) dissolved in dimethyl hydrazine (10 mL), and reacted at room temperature 1 The reaction was quenched by the addition of water (10 mL). It was extracted with ethyl acetate (10 mL×3). Preparation of silica gel plate (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 calcd for [M + H] ⁺ 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 phenylisocyanate (157 mg, 1.32 mmol) were dissolved in toluene (10 mL) and stirred at 110 ° C for 12 hours. The reaction was quenched by the addition of water (10 mL). Filtration gave 1-methylpyrido[2,3-d]pyrimidine-2,4( 1H , 3H )-dione (20.0 mg, yellow solid), yield: 17%. ¹ H NMR: (400 MHz, DMSO- d ₆ ) δ = 11.72 (s, 1H), 8.72 (d, J = 2.0 Hz, 1H), 8.31 (d, J = 7.6 Hz, 1H), 7.29 (dd, J = 7.6, 2.0 Hz, 1H), 3.48 (s, 3H). MS-ESI calcd for [M + H] ⁺ 178.

the fourth step.

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

5(Chloromethyl)-3-isopropylisoxazole (25.0 mg, 0.157 mmol), 1-methylpyrido[2,3-d]pyrimidine-2,4-dione (30.5 mg, 0.172 Methyl acetate and potassium iodide (7.8 mg, 0.055 mmol) were dissolved in N , N -dimethylformamide (5 mL). Potassium carbonate (64.9 mg, 0.470 mmol) was added, and the mixture was heated to reflux at 120 ° C for 2 hours. The reaction solution was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure, and the obtained crude product was purified by preparative high-performance liquid chromatography to give 3-((3-isopropylisoxazole-5-yl)methyl)-1- Methylpyrido[2,3-d]pyrimidine-2,4-dione (8.0 mg), yield: 17%. ¹ H NMR: (400 MHz, Methonal- d ₄ ) δ = 8.74 (d, J = 2.0 Hz, 1H), 8.47 (d, J = 7.6 Hz, 1H), 7.36-7.31 (m, 1H), 6.32 ( s, 1H), 5.33 (s, 2H), 3.71 (s, 3H), 3.04 - 2.93 (m, 1H), 1.24 (d, J = 8.0 Hz, 6H). MS-ESI calcd [M + H] ⁺ 303, found 301.

Example 85.

3-(2-(2,4-Dimethyl-5-yl)ethyl)-1-methylpyrido[2,3-d]pyrimidine-2,4-dione.

first step.

3-(2-(2,4-Dimethyl-5-yl)ethyl)-1-methylpyrido[2,3-d]pyrimidine-2,4-dione.

2-(2,4-Dimethylthiazol-5-yl)ethyl methanesulfonate (30.0 mg, 0.127 mmol), 1-methylpyrido[2,3-d]pyrimidine-2,4- Diketone (22.6 mg, 0.127 mmol), potassium carbonate (35.2 mg, 0.255 mmol) and potassium iodide (4.2 mg, 0.026 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) The organic phase was combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by preparative HPLC to give 3-(2-(2,4-dimethyl-5-yl)ethyl)-1-methyl Pyrido[2,3-d]pyrimidine-2,4-dione (10.0 mg), yield: 25%. ¹ H NMR: (400 MHz, Methonal- d ₄ ) δ = 8.76-8.74 (m, 1H), 8.52-8.45 (m, 1H), 7.37-7.34 (m, 1H), 4.34-4.30 (m, 2H) , 3.71 (s, 3H), 3.26 (t, J = 6.8 Hz, 2H), 2.93 (s, 3H), 2.49 (s, 3H). MS-ESI calcd [M + H] ⁺ 303.

Example 86.

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

first step.

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

3-( 1H -indol-3-yl)propyl methanesulfonate (30.0 mg, 0.118 mmol), 1-methylpyrido[2,3-d]pyrimidine-2,4-dione ( 21.0 mg, 0.118 mmol), potassium carbonate (32.7 mg, 0.237 mmol) and potassium iodide (3.9 mg, 0.024 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) The organic phase was combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by preparative high-performance liquid chromatography to give 3-[3-( 1H -indol-3-yl)propyl]-1-methylpyridine. [2,3-d]pyrimidine-2,4-dione (10.0 mg), Yield: 25%. ¹ H NMR: (400 MHz, Methonal- d ₄ ) δ = 8.65-8.63 (m, 1H), 8.37-8.35 (m, 1H), 7.50 (d, J = 7.6 Hz, 1H), 7.28-7.26 (m) , 1H), 7.19 (d, J = 7.6 Hz, 1H), 7.04 (s, 1H), 7.00-6.95 (m, 2H), 4.23-4.19 (m, 2H), 3.60 (s, 3H), 2.88 ( t, J = 7.2 Hz, 2H), 2.22 - 2.15 (m, 2H). MS-ESI calcd for [M + H] ⁺ 335.

Example 87.

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

first step.

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

2-(4-Chlorobutyl)benzofuran (30.0 mg, 0.143 mmol), 1-methylpyrido[2,3-d]pyrimidine-2,4-dione (35.7 mg, 0.143 mmol), Potassium carbonate (39.7 mg, 0.287 mmol) and potassium iodide (4.8 mg, 0.029 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) The organic phase was combined, dried over anhydrous sodium sulfate, filtered, and then filtered, and then purified by preparative high-purity chromatography to give 3-(4-(benzofuran-2-yl)butyl)-1-methylpyridine [2] , 3-d]pyrimidine-2,4-dione (10.0 mg), Yield: 17%. ¹ H NMR: (400 MHz, Methonal- d ₄ ) δ = 8.72-8.71 (m, 1H), 8.37-8.35 (m, 1H), 7.49 (d, J = 6.8 Hz, 1H), 7.44 (d, J = 7.6 Hz, 1H), 7.34-7.32 (m, 1H), 7.19-7.15 (m, 2H), 6.56 (s, 1H), 3.97 (t, J = 6.8 Hz, 2H), 3.54 (s, 3H) , 2.80 (t, J = 6.8 Hz, 2H), 1.71-1.66 (m, 4H). MS-ESI calculated [M + H] ⁺ 350, found 350.

Example 88.

1-Methyl-3-(3-(3-methylisoxazol-5-yl)propyl)pyrido[2,3-d]pyrimidine-2,4-dione.

first step.

1-Methyl-3-(3-(3-methylisoxazol-5-yl)propyl)pyrido[2,3-d]pyrimidine-2,4-dione.

3-(3-Methylisoxazole-5-yl)propyl methanesulfonate (30.0 mg, 0.136 mmol), 1-methylpyrido[2,3-d]pyrimidine-2,4-di Ketone (24.2 mg, 0.136 mmol), potassium carbonate (37.8 mg, 0.273 mmol) and potassium iodide (4.5 mg, 0.027 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) The organic phase was combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by preparative HPLC to give 1-methyl-3-(3-(3-methylisoxazole-5-yl)propyl) Pyrido[2,3-d]pyrimidine-2,4-dione (20.0 mg), yield: 49%. ¹ H NMR: (400 MHz, Methonal- d ₄ ) δ = 8.72-8.69 (m, 1H), 8.44 - 8.41 (m, 1H), 7.37-7.29 (m, 1H), 6.07 (s, 1H), 4.19 -4.11 (m, 2H), 3.70 (s, 3H), 2.84 (t, J = 7.2 Hz, 2H), 2.15 (s, 3H), 2.13 - 2.07 (m, 2H). MS-ESI calcd [M + H] ⁺ 303, found 301.

Example 89.

1-Methyl-3-[4-(3-methylisoxazol-5-yl)butyl]pyrido[2,3-d]pyrimidine-2,4-dione.

first step.

1-Methyl-3-[4-(3-methylisoxazol-5-yl)butyl]pyrido[2,3-d]pyrimidine-2,4-dione.

1-Methylpyrido[2,3-d]pyrimidine-2,4(1 H ,3 H )-dione (20.0 mg, 0.112 mmol), 5-(4-bromobutyl)-3-methyl Base-isoxazole (30.5 mg, 0.139 mmol), potassium iodide (2.1 mg, 0.124 mmol) and potassium carbonate (31.5 mg, 0.228 mmol) were dissolved in N , N -dimethylformamide (10 mL). The reaction solution was warmed to 120 ° C and stirred for 3 hours. After cooling to room temperature, filtration, and concentration of the filtrate under reduced pressure and purified by preparative high-performance liquid chromatography to give 1-methyl-3-[4-(3-methylisoxazole-5-yl)butyl]pyridine [ 2,3-d]pyrimidine-2,4-dione (10.0 mg), yield: 28%. ¹ H NMR: (400 MHz, Methonal- d ₄ ) δ = 8.69 (d, J = 2.0 Hz, 1H), 8.42 (d, J = 7.6 Hz, 1H), 7.29 (dd, J = 7.6, 2.0 Hz, 1H), 6.04 (s, 1H), 4.08 (t, J = 6.8 Hz, 2H), 3.67 (s, 3H), 2.80 (t, J = 6.8 Hz, 2H), 2.23 (s, 3H), 1.79- 1.72 (m, 4H). MS-ESI calcd for [M + H] ⁺ 315.

Example 90.

1-Methyl-3-(3-(3-methylisoxazol-5-yl)propyl)pyrido[3,4-d]pyrimidine-2,4-dione.

first step.

3-(methylamino)isonicotinic acid.

3-Fluoro-isonicotinic acid (3.00 g, 21.3 mmol) was dissolved in dioxane (6 mL) and 30% aqueous methylamine (22.0 g, 213 mmol). The reaction solution was warmed to 140 ° C and stirred for 14 hours. Concentrated hydrochloric acid (12 N, 3 mL) was added, the pH was adjusted to 3, filtered, and then filtered to give 3-(methylamino)isonicosonic acid (3.00 g, yellow solid), yield: 93%. ¹ H NMR: (400 MHz, DMSO- d ₆ ) δ = 8.46 (br, 1H), 7.89 (s, 1H), 7.69 (d, J = 5.2 Hz, 1H), 7.50 (d, J = 5.2 Hz, 1H), 2.80 (s, 3H).

The second step.

3-(methylamino) isoniazid.

3-(Methylamino)isonicotinic acid (4.00 g, 26.3 mmol), 1-hydroxybenzotriazole (10.7 g, 78.9 mmol), 1-(3-dimethylaminopropyl)-3-ethyl The carbodiimide (15.1 g, 78.9 mmol) and ammonium chloride (5.63 g, 105 mmol) were dissolved in N , N -dimethylformamide (5 mL). The reaction solution was stirred at 25 ° C for 24 hours. The reaction was quenched by the addition of water (100 mL). The mixture was extracted with isopropyl alcohol / chloroform (1:3) (50 mL x 2). The organic phases were combined and concentrated under reduced pressure. The residue was added to dichloromethane/methanol (10:1, 30 mL), stirred for 10 min, filtered, and filtered to give 3-(methylamino) isoniasamine (3.50 g, yellow solid). 88%. ¹ H NMR: (400 MHz, DMSO- d ₆ ) δ = 8.12-8.06 (m, 2H), 7.80 (d, J = 5.2 Hz, 1H), 7.62-7.61 (br, 1H), 7.52-7.48 (br , 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)isonicolide (3.40 g, 22.5 mmol) in N , N -dimethylformamide (50 mL) 45.0 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 was cooled to 0 ° C and quenched with water (20 mL). A white solid was precipitated, filtered, and dried to give 1-methylpyrido[3,4-d]pyrimidine-2,4-dione (3.50 g, yellow solid). Yield: 95%. ¹ H NMR: (400 MHz, DMSO- d ₆ ) δ 11.83 (s, 1H), 8.86 (s, 1H), 8.48 (d, J = 4.8 Hz, 1H), 7.82 (d, J = 4.8 Hz, 1H), 3.49 (s, 3H).

the fourth step.

1-Methyl-3-(3-(3-methylisoxazol-5-yl)propyl)pyrido[3,4-d]pyrimidine-2,4-dione.

3-(3-Methylisoxazole-5-yl)propyl methanesulfonate (48.4 mg, 0.221 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 solution was warmed to 120 ° C and stirred for 3 hours. After cooling to room temperature, filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by preparative HPLC to give 1-methyl-3-(3-(3-methylisoxazole-5-yl)propyl)pyridine. And [3,4-d]pyrimidine-2,4-dione (10.0 mg), yield: 18%. ¹ H NMR: (400 MHz, Methonal- d ₄ ) δ = 8.85 (s, 1H), 8.51 (d, J = 4.8 Hz, 1H), 8.01 (d, J = 4.8 Hz, 1H), 6.08 (s, 1H), 4.18 (t, J = 7.0 Hz, 2H), 3.67 (s, 3H), 2.83 (t, J = 7.2 Hz, 2H), 2.16-2.11 (m, 5H). MS-ESI calcd [M + H] ⁺ 303, found 301.

Example 91.

3-(2-(2,4-Dimethylthiazol-5-yl)ethyl)-1-methylpyrido[3,4-d]pyrimidine-2,4-dione.

first step.

3-(2-(2,4-Dimethyl-5-yl)ethyl)-1-methylpyrido[3,4-d]pyrimidine-2,4-dione.

2-(2,4-Dimethylthiazol-5-yl)ethyl methanesulfonate (43.8 mg, 0.186 mmol), 1-methylpyrido[3,4-d]pyrimidine-2,4- Diketone (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 solution was warmed to 120 ° C and stirred for 3 hours. After cooling to room temperature, filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by preparative HPLC to give 3-(2-(2,4-dimethylthiazol-5-yl)ethyl)-1-methyl Pyrido[3,4-d]pyrimidine-2,4-dione (21.0 mg), yield: 38%. ¹ H NMR: (400 MHz, Methonal- d ₄ ) δ = 8.87 (s, 1H), 8.52 (d, J = 4.8 Hz, 1H), 8.01 (d, J = 4.8 Hz, 1H), 4.24 (t, J = 6.8 Hz, 2H), 3.69 (s, 3H), 3.11 (t, J = 6.8 Hz, 2H), 2.60 (s, 3H), 2.31 (s, 3H). MS-ESI calcd [M + H] ⁺ 303.

Example 92.

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

first step.

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

3-( 1H -indol-3-yl)propyl methanesulfonate (47.2 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 solution was warmed to 120 ° C and stirred for 3 hours. After cooling to room temperature, filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by preparative HPLC to give 3-(3-( 1H -indol-3-yl)propyl)-1-methylpyridine [ 3,4-d]pyrimidine-2,4-dione (10.0 mg), yield: 18%. ¹ H NMR: (400 MHz, CDCl ₃ ) δ = 8.70 (s, 1H), 8.57 (d, J = 5.2 Hz, 1H), 7.99 (d, J = 5.2 Hz, 1H), 7.73 (br, 1H) , 7.62 (d, J = 7.6 Hz, 1H), 7.32-7.28 (m, 1H), 7.19-7.11 (m, 3H), 4.28-4.24 (m, 2H), 3.63 (s, 3H), 2.93-2.89 (m, 2H), 2.24 - 2.17 (m, 2H). MS-ESI calcd for [M + H] ⁺ 335.

Example 93.

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

first step.

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

3-(4-Chlorobutyl)benzofuran (38.9 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 solution was warmed to 120 ° C and stirred for 3 hours. After cooling to room temperature, filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by preparative HPLC to give 3-(4-(benzofuran-3-yl)butyl)-1-methylpyridine [3, 4-d]pyrimidine-2,4-dione (11.0 mg), Yield: 17%. ¹ H NMR: (400 MHz, Methonal- d ₄ ) δ = 8.87 (s, 1H), 8.50 (d, J = 4.8 Hz, 1H), 8.01 (d, J = 4.8 Hz, 1H), 7.45 (d, J = 8.0 Hz, 1H), 7.34 (d, J = 8.0 Hz, 1H), 7.18-7.15 (m, 2H), 6.48 (s, 1H), 4.16-4.12 (m, 2H), 3.65 (s, 3H) ), 2.88-2.85 (m, 2H), 1.86-1.80 (m, 4H). MS-ESI calculated [M + H] ⁺ 350, found 350.

Example 94.

1-Methyl-3-(4-(3-methylisoxazol-5-yl)butyl)pyrido[3,4-d]pyrimidine-2,4-dione.

first step.

1-Methyl-3-(4-(3-methylisoxazol-5-yl)butyl)pyrido[3,4-d]pyrimidine-2,4-dione.

5-(4-Bromobutyl)-3-methylisoxazole (40.6 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 solution was warmed to 120 ° C and stirred for 3 hours. After cooling to room temperature, filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by preparative high-performance liquid chromatography to give 1-methyl-3-(4-(3-methylisooxazol-5-yl)butyl)pyridine. And [3,4-d]pyrimidine-2,4-dione (10.0 mg), yield: 19%. ¹ H NMR: (400 MHz, Methonal- d ₄ ) δ = 8.84 (s, 1H), 8.50 (d, J = 5.2 Hz, 1H), 8.00 (d, J = 5.2 Hz, 1H), 6.05 (s, 1H), 4.1-4.08 (m, 2H), 3.67 (s, 3H), 2.81 (t, J = 6.8 Hz, 2H), 2.23 (s, 3H), 1.77-1.74 (m, 4H). MS-ESI calcd for [M + H] ⁺ 315.

Example 95.

1-Methyl-3-(4-(3-methylisoxazol-5-yl)butyl)pyrido[4,3-d]pyrimidine-2,4-dione.

first step.

4-(methylamino) nicotinic acid.

4-Chloronicotinic acid (7.00 g, 44.3 mmol) was dissolved in dioxane (14 mL) and aq. 30% ethylamine (55.2 g, 444 mmol). The reaction solution was heated to 100 ° C in a microwave and stirred for 50 minutes. Aqueous hydrochloric acid (4 N, 5 mL) was added, the pH was adjusted to 3, filtered, and filtered to give 4-(methylamino)nicotinic acid (5.00 g, white solid). 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 = 4.4 Hz, 3H).

The second step.

4-(Methylamino)nicotamine.

4-(Methylamino)nicotinic acid (5.20 g, 34.2 mmol), 1-hydroxybenzotriazole (27.7 g, 205 mmol), 1-ethyl-(3-dimethylaminopropyl)carbazide Diimine 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. The reaction was quenched by the addition of water (100 mL). The mixture was extracted with isopropyl alcohol / chloroform (1:3) (30 mL x 5). The organic phases were combined and concentrated under reduced pressure. The residue was added to dichloromethane / methanol (10:1, 50 mL), and stirred for 10 min, filtered, and filtered to give 4-(methylamino)salamine (4.70 g, white solid). %. ¹ H NMR: (400 MHz, DMSO- d ₆ ) δ = 9.67 (br, 1H), 8.77 (s, 1H), 8.52 (br, 1H), 8.29 (d, J = 7.6 Hz, 1H), 7.87 ( Br, 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)nicotinamine (4.80 g, 31.8 mmol) in N , N -dimethylformamide (50 mL) was added sodium hydride (1.52 g, 63.5) Mm). 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 was cooled to room temperature and quenched with water (50 mL). Add hydrochloric acid aqueous solution (12 N, 5 mL), adjust the pH to 3, precipitate a white solid, filter, and dry the filter cake to obtain 1-methylpyrido[4,3-d]pyrimidine-2,4-di Ketone (3.50 g, yellow solid), yield: 95%. ¹ H NMR: (400 MHz, DMSO- d ₆ ) δ = 11.76 (s, 1H), 8.97 (s, 1H), 8.69 (d, J = 6.0 Hz, 1H), 7.38 (d, J = 6.0 Hz, 1H), 3.39 (s, 3H).

the fourth step.

1-Methyl-3-(4-(3-methylisoxazol-5-yl)butyl)pyrido[4,3-d]pyrimidine-2,4-dione.

5-(4-Bromobutyl)-3-methylisoxazole (48.0 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 mixture was stirred at 120 °C. hour. The reaction solution was directly filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by preparative HPLC to give 1-methyl-3-(4-(3-methylisooxazol-5-yl)butyl)pyridine [ 4,3-d]pyrimidine-2,4-dione (21.0 mg), yield: 39%. ¹ H NMR: (400 MHz, Methonal- d ₄ ) δ = 9.10 (s, 1H), 8.68 (d, J = 6.0 Hz, 1H), 7.41 (d, J = 6.0 Hz, 1H), 6.05 (s, 1H), 4.08 (t, J = 6.6 Hz, 2H), 3.59 (s, 3H), 2.80 (t, J = 6.6 Hz, 2H), 2.23 (s, 3H), 1.77-1.74 (m, 4H). MS-ESI calcd for [M + H] ⁺ 315.

Example 96.

3-(2-(2,4-Dimethyl-5-yl)ethyl)-1-methylpyrido[4,3-d]pyrimidine-2,4-dione.

first step.

3-(2-(2,4-Dimethyl-5-yl)ethyl)-1-methylpyrido[4,3-d]pyrimidine-2,4-dione.

2-(2,4-Dimethylthiazol-5-yl)ethyl methanesulfonate (51.8 mg, 0.220 mmol), 1-methylpyrido[4,3-d]pyrimidine-2,4- Diketone (30.0 mg, 0.169 mmol) and potassium carbonate (70.2 mg, 0.508 mmol) were dissolved in N , N -dimethylformamide (3 mL), and potassium iodide (2.8 mg, 0.0169 mmol) was added. Stir 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 HPLC to give the product 3-(2-(2,4-dimethyl-5-yl)ethyl)-1-methylpyridine [ 4,3-d]pyrimidine-2,4-dione (8.0 mg), yield: 15%. ¹ H NMR: (400 MHz, CDCl ₃ ) δ = 9.31 (s, 1H), 8.76 (d, J = 6.0 Hz, 1H), 7.08 (d, J = 6.0 Hz, 1H), 4.24 (t, J = 7.8 Hz, 2H), 3.59 (s, 3H), 3.08 (t, J = 7.8 Hz, 2H), 2.63 (s, 3H), 2.36 (s, 3H). MS-ESI calcd [M + H] ⁺ 303.

Example 97.

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

first step.

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

2-(4-Chlorobutyl)benzofuran (42.9 mg, 0.169 mmol), 1-methylpyrido[4,3-d]pyrimidine-2,4-dione (30.0 mg, 0.169 mmol) 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 mixture 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 HPLC to give the product 3-(3-( 1H -indol-2-yl)propyl)-1-methylpyridine [4, 3-d]pyrimidine-2,4-dione (37.0 mg), yield: 65%. ¹ H NMR: (400 MHz, Methonal- d ₄ ) δ = 8.99 (s, 1H), 8.60 (d, J = 6.0 Hz, 1H), 8.26 (br, 1H), 7.50 (d, J = 7.6 Hz, 1H), 7.26 (d, J = 6.0 Hz, 1H), 7.16 (d, J = 7.6 Hz, 1H), 7.02 (s, 1H), 6.99-6.92 (m, 2H), 4.20 (d, J = 7.2) Hz, 2H), 3.44 (s, 3H), 2.89 (d, J = 6.8 Hz, 2H), 2.24 - 2.17 (m, 2H). MS-ESI calcd for [M + H] ⁺ 335.

Example 98.

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

first step.

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

2-(4-Chlorobutyl)benzofuran (45.9 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 mixture 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 HPLC to give the product 3-(4-(benzofuran-2-yl)butyl)-1-methylpyrido[4,3- d] Pyrimidine-2,4-dione (25.0 mg), yield: 42%. ¹ H NMR: (400 MHz, Methonal- d ₄ ) δ = 9.11 (s, 1H), 8.66 (d, J = 6.0 Hz, 1H), 7.46-7.44 (m, 1H), 7.37 (d, J = 6.0) Hz, 1H), 7.33 (d, J = 7.2 Hz, 1H), 7.17-7.13 (m, 2H), 6.46 (s, 1H), 4.10 (t, J = 7.0 Hz, 2H), 3.55 (s, 3H) ), 2.85 (t, J = 6.8 Hz, 2H), 1.83-1.79 (m, 4H). MS-ESI calculated [M + H] ⁺ 350, found 350.

Example 99.

1-Methyl-3-(3-(3-methylisoxazol-5-yl)propyl)pyrido[4,3-d]pyrimidine-2,4-dione.

first step.

1-Methyl-3-(3-(3-methylisoxazol-5-yl)propyl)pyrido[4,3-d]pyrimidine-2,4-dione.

3-(3-Methylisoxazole-5-yl)propyl methanesulfonate (51.3 mg, 0.220 mmol), 1-methylpyrido[4,3-d]pyrimidine-2,4-di The ketone (30.0 mg, 0.169 mmol) and potassium carbonate (70.2 mg, 0.508 mmol) were dissolved in N , N -dimethylformamide (3 mL), and potassium iodide (2.8 mg, 0.017 mmol) was added. Stir at °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 HPLC to give 1-methyl-3-(3-(3-methylisooxazol-5-yl)propyl)pyridine [ 4,3-d]pyrimidine-2,4-dione (38.0 mg), yield: 69%. ¹ H NMR: (400 MHz, Methonal- d ₄ ) δ = 9.09 (s, 1H), 8.68 (d, J = 6.0 Hz, 1H), 7.40 (d, J = 6.0 Hz, 1H), 6.07 (s, 1H), 4.14 (t, J = 7.0 Hz, 2H), 3.58 (s, 3H), 2.83 (t, J = 7.2 Hz, 2H), 2.16 (s, 3H), 2.14 - 2.07 (m, 2H). MS-ESI calcd [M + H] ⁺ 303, found 301.

Example 100.

1-Methyl-3-[3-(3-methylisoxazol-5-yl)propyl]pyrido[3,2- d ]pyrimidine-2,4-dione.

first step.

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

2-Chloropyridin-3-amine (30.0 g, 233 mmol) was dissolved in dichloromethane (250 mL) and triethylamine (47.2 g, 467 mmol). Dibutyl dimethyl dicarbonate (102 g, 467 mmol) was added dropwise at 0 °C. The reaction solution was stirred at 25 ° C for 18 hours. The reaction was quenched by the addition of water (100 mL). The reaction solution was extracted with ethyl acetate (100 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, the residue was purified by silica gel column chromatography separation (15: 1 petroleum ether / ethyl acetate, Rf = 0.6), to give N - (2- chloro-3 -pyridyl)carbamic acid tert-butyl 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 tert-butyl butyl ester.

N- (2-Chloro-3-pyridinyl)carbamic acid tert-butyl butyl ester (11.0 g, 48.1 mmol) was dissolved in anhydrous tetrahydrofuran (150 mL). N.sub.2. g, 57.7 mmol), and the reaction solution was stirred at 0 ° C for half an hour. Methyl iodide (10.2 g, 72.2 mmol) was slowly added and stirred at room temperature for 12 hours. The reaction was quenched by the addition of water (50 mL). The reaction mixture was extracted with EtOAc (EtOAc (EtOAc)EtOAc. (Methyl)carbamic acid tert-butyl butyl ester (11.0 g, colorless oil), yield: 94%. ¹ H NMR: (400 Hz, DMSO- d ₆ ) δ = 8.33 (d, J = 6.0 Hz, 1H), 7.92-7.90 (m, 1H), 7.48 (d, J = 6.0 Hz, 1H), 3.06 ( s, 3H), 1.45-1.14 (m, 9H). MS-ESI calcd for [M + H] ⁺ 243.

third step.

2-Chloro- N -methylpyridin-3-amine.

(2-Chloropyridin-3-yl)(methyl)carbamic acid tert-butyl butyl ester (11.0 g, 45.3 mmol) was dissolved in ethyl acetate (50 mL), and 4 M ethyl acetate ethyl acetate was added dropwise at 0 ° C (150 mL) was stirred at 25 ° C for 15 hours. The reaction solution was concentrated under reduced pressure. Purification by 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 = 6.0 Hz, 1H), 7.20-7.17 (m, 1H), 6.95 (d, J = 6.0 Hz, 1H), 5.74 ( Br, 1H), 2.73 (s, 3H). MS-ESI calcd for [M ⁺ H] + 143, found 143.

the fourth step.

Methyl 3-(methylamino)picolinate.

2-Chloro- N -methylpyridin-3-amine (5.50 g, 38.6 mmol) was dissolved in methanol (100 mL), and the reaction solution was added to 1,1'-bis(diphenylphosphine) at 25 °C. Ferrocene palladium chloride (2.82 g, 3.86 mmol). The reaction liquid was reacted in a carbon monoxide atmosphere (50 psi) at 50 ° C for 56 hours, and 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 / acetic acid Methyl 3-(methylamino)picolinate (6.00 g, colorless oil), yield: 94%. ¹ H NMR: (400 MHz, Methonal- d ₄ ) δ = 7.84 (d, J = 6.0 Hz, 1H), 7.45-7.42 (m, 1H), 7.29 (d, J = 6.0 Hz, 1H), 3.93 ( s, 3H), 2.94 (s, 3H). MS-ESI calcd for [M + H] ⁺ 167.

the fifth step.

3-(Methylamino)pyridine-2-carboxamide.

Methyl 3-(methylamino)pyridine-2-carboxylate (6.00 g, 36.1 mmol) was dissolved in methanol (100 mL) and aqueous ammonia (1.27 g, 36.1 mmol). The reaction solution was stirred at 40 ° C for 18 hours. The reaction mixture was poured into water (200 mL) The organic extracts were combined, dried over anhydrous NaHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH ¹ H NMR: (400 MHz, DMSO- d ₆ ) δ = 8.25 (d, J = 4.8 Hz, 1H), 8.02-7.98 (br, 1H), 7.76 (d, J = 4.8 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-Methylamino-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 mixture was stirred at 90 ° C for one hour. The reaction mixture was quenched with EtOAc EtOAc m. The organic phase was concentrated under reduced pressure, the residue was purified by silica gel column chromatography separation (1: 1 petroleum ether / ethyl acetate, Rf = 0.2), to give N - [(2- methyl acyl-amino-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 = 4.8 Hz, 1H), 7.92-7.88 (br, 1H), 7.82 (d, J = 8.0 Hz, 1H), 7.60- 7.56 (m, 1H), 7.52-7.48 (br, 1H), 3.09 (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-Methylamino-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 (25) (mL), the reaction solution was stirred at 110 ° C for 0.5 h. The reaction mixture was diluted with water (15 mL) and pH = 7 was adjusted with 1 N aqueous hydrochloric acid. The filter cake was diluted with methanol (15 mL), concentrated under reduced pressure to give 1-methyl-pyrido [3,2- d] pyrimidine-2,4-dione (1.09 g, white solid), yield: 69% . ¹ H NMR: (400 MHz, DMSO- d ₆ ) δ = 12.72 (s, 1H), 8.50 (d, J = 8.8 Hz, 1H), 7.89 (d, J = 8.8 Hz, 1H), 7.74-7.71 ( m, 1H), 3.41 (s, 3H).

The eighth step.

1-Methyl-3-[3-(3-methylisoxazol-5-yl)propyl]pyrido[3,2- d ]pyrimidine-2,4-dione.

1-Methylpyrido[3,2- d ]pyrimidine-2,4-dione (30.0 mg, 169 mmol), 3-(3-methylisoxazole-5-yl)propyl methanesulfonic acid The ester (48.3 mg, 220 mmol) and potassium carbonate (70.2 mg, 508 mmol) were dissolved in N , N -dimethylformamide (4 mL), and potassium iodide (2.8 mg, 16.9 ummol) was added at 120 °C. Heat to reflux for 3 hours. The reaction solution was directly filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by preparative HPLC to give 1-methyl-3-[3-(3-methylisoxazol-5-yl)propyl]pyridine [ 3,2- d ]pyrimidine-2,4-dione (10.0 mg), yield: 20%. ¹ H NMR: (400 MHz, Methonal- d ₄ ) δ = 8.58-8.53 (m, 1H), 7.99-7.97 (m, 1H), 7.83-7.77 (m, 1H), 6.09 (s, 1H), 4.22 (t, J = 7.2 Hz, 2H), 3.62 (s, 3H), 2.86 (t, J = 7.2 Hz, 2H), 2.18-2.11 (m, 5H). MS-ESI calcd [M + H] ⁺ 303, found 301.

Example 101.

3-(2-(2,4-Dimethyl-5-yl)ethyl)-1-methylpyrido[3,2-d]pyrimidine-2,4-dione.

first step.

3-(2-(2,4-Dimethyl-5-yl)ethyl)-1-methylpyrido[3,2-d]pyrimidine-2,4-dione.

2-(2,4-Dimethylthiazol-5-yl)ethyl methanesulfonate (40.0 mg, 0.169 mmol), 1-methylpyrido[3,2-d]pyrimidine-2,4- Diketone (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 solution was warmed to 120 ° C and stirred for 3 hours. After cooling to room temperature, filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by preparative high-purity liquid chromatography to give 3-(2-(2,4-dimethyl-5-yl)ethyl)-1-methylpyridine. And [3,2-d]pyrimidine-2,4-dione (10.0 mg), yield: 22%. ¹ H NMR: (400 MHz, Methonal- d ₄ ) δ = 8.56-8.50 (m, 1H), 7.99 (d, J = 8.4 Hz, 1H), 7.82-7.80 (m, 1H), 4.26 (t, J = 7.6 Hz, 2H), 3.63 (s, 3H), 3.11 (t, J = 7.6 Hz, 2H), 2.60 (s, 3H), 2.32 (s, 3H). MS-ESI calcd [M + H] ⁺ 303.

Example 102.

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

first step.

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

3-( 1H -indol-3-yl)propyl methanesulfonate (40.5 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 solution was warmed to 120 ° C and stirred for 3 hours. After cooling to room temperature, filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by preparative HPLC to give 3-(3-( 1H -indol-3-yl)propyl)-1-methylpyridine [ 3,2-d]pyrimidine-2,4-dione (20.0 mg), yield: 42%. ¹ H NMR: (400 MHz, CDCl ₃ ) δ = 8.64 (d, J = 4.0 Hz, 1H), 7.88 (br, 1H), 7.62-7.52 (m, 3H), 7.28-7.26 (m, 1H), 7.10-7.08 (m, 3H), 4.32-4.28 (m, 2H), 3.52 (s, 3H), 2.92-2.88 (m, 2H), 2.24-2.20 (m, 2H). MS-ESI calcd for [M + H] ⁺ 335.

Example 103.

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

first step.

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

2-(2,4-Dimethylthiazol-5-yl)ethyl methanesulfonate (35.3 mg, 0.186 mmol), 1-methylpyrido[3,2-d]pyrimidine-2,4- Diketone (25.0 mg, 0.141 mmol), potassium iodide (2.3 mg, 0.014 mmol) and potassium carbonate (58.5 mg, 0.423 mmol) were dissolved in N , N -dimethylformamide (5 mL). The reaction solution was warmed to 120 ° C and stirred for 3 hours. After cooling to room temperature, filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by preparative HPLC to give 3-(4-(benzofuran-3-yl)butyl)-1-methylpyridine [3, 2-d]pyrimidine-2,4-dione (20.0 mg), yield: 40%. ¹ H NMR: (400 MHz, Methonal- d ₄ ) δ = 8.53-8.52 (m, 1H), 7.91 (d, J = 8.4 Hz, 1H), 7.78-7.74 (m, 1H), 7.44-7.43 (m) , 1H), 7.32 (d, J = 8.0 Hz, 1H), 7.16-7.13 (m, 2H), 6.46 (s, 1H), 4.15 (t, J = 6.8 Hz, 2H), 3.57 (s, 3H) , 2.85 (t, J = 6.4 Hz, 2H), 1.84-1.82 (m, 4H). MS-ESI calculated [M + H] ⁺ 350, found 350.

Example 104.

1-Methyl-3-[4-(3-methylisoxazol-5-yl)butyl]pyrido[3,2- d ]pyrimidine-2,4-dione.

first step.

1-Methyl-3-[4-(3-methylisoxazol-5-yl)butyl]pyrido[3,2- d ]pyrimidine-2,4-dione.

1-Methylpyrido[3,2- d ]pyrimidine-2,4-dione (30.0 mg, 169 mmol), 5-(4-bromobutyl)-3-methyl-isoxazole (40.6 Mg, 186 mmol) and potassium carbonate (58.5 mg, 423 mmol) were dissolved in N , N -dimethylformamide (4 mL), potassium iodide (2.8 mg, 0.017 mmol) was added, and the reaction was heated to reflux at 120 °C. hour. The reaction solution was directly filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by preparative HPLC to give 1-methyl-3-[4-(3-methylisoxazol-5-yl)butyl]pyridine [ 3,2- d ]pyrimidine-2,4-dione (7.2 mg), yield: 13%. ¹ H NMR: (400 MHz, Methonal- d ₄ ) δ = 8.56 (d, J = 4.0 Hz, 1H), 7.98 (d, J = 8.8 Hz, 1H), 7.79 (dd, J = 8.8, 4.0 Hz, 1H), 6.07(s,1H), 4.16(t, J = 6.4 Hz, 2H), 3.61(s,3H), 2.83(t, J = 6.4 Hz, 2H), 2.24(s,3H),1.83- 1.76 (m, 4H). MS-ESI calcd for [M + H] ⁺ 315.

Example 105.

3-(2-(2,4-Dimethyl-5-yl)ethyl)-1-methylpteridin-2,4-dione.

first step.

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

Sodium metal (7.80 g, 340 mmol) was added portionwise to stirred absolute ethanol (180 mL) at 25 ° C and heated to 80 ° C to reflux for 0.5 h. Methylurea (12.6 g, 170 mmol) was then added in portions and reflux was continued for 0.5 h. The reaction solution was added with ethyl cyanoacetate (19.0 g, 170 mmol). The reflux was continued for 3 hours, and ethanol was recovered under reduced pressure. The residue was dissolved in water (50 mL). EtOAc (EtOAc) (EtOAc) : 32%. ¹ H NMR: (400 MHz, DMSO- d ₆ ) δ = 10.39 (br, 1H), 6.79 (br, 2H), 4.54 (s, 1H), 3.14 (s, 3H). MS-ESI calcd for [M + H] ⁺ 422.

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, 12 N). Sodium nitrite (5.80 g, 84.2 mmol) was dissolved in water (50 mL) and added dropwise to a mixture. The reaction solution was stirred at 25 ° C for 2 hours, filtered and washed with cold water to give a purple solid. The solid was dissolved in water (100 mL), and sodium hyposulfite (18.7 g, 118 mmol) was added portionwise with stirring, heated to 60 ° C for 0.5 hour, and cooled to 25 ° C for 16 hours. Filter and wash with cold water (50 mL), ethanol (50 mL), acetone (50 mL). The product was dried to give the product 5,6-diamino-1-methylpyrimidine-2,4-dione (8.60 g, pale yellow solid). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 10.49 (br, 1H), 6.15 (br, 2H), 3.25 (s, 3H), 2.95 (br, 2H). MS-ESI calcd [M + H] ⁺ 157.

third step.

1-methylpteridin-2,4-dione.

5,6-Diamino-1-methylpyrimidine-2,4-dione (4.00 g, 25.6 mmol) was dissolved in water (150 mL), and glyoxal (5.58 g) was added in one portion at 25 °C. , 38.4 mmol, 40% aqueous solution). Heat to 60 ° C and stir for 16 hours. Filtration and the obtained solid were washed with water (50 mL) to give the product 1-methyl- </RTI> <RTIgt; </RTI> <RTIgt;

the fourth step.

3-(2-(2,4-Dimethyl-5-yl)ethyl)-1-methylpteridin-2,4-dione.

2-(2,4-Dimethylthiazol-5-yl)ethyl methanesulfonate (172 mg, 0.729 mmol), 1-methylpteridin-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, 0.056 mmol) was added, and the mixture 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 HPLC to give 3-(2-(2,4-dimethyl-5-yl)ethyl)-1-methylpteridin-2,4-di Ketone (9.0 mg), yield: 5%. ¹ H NMR: (400 MHz, CDCl ₃ ) δ = 8.66 (d, J = 2.0 Hz, 1H), 8.61 (d, J = 2.0 Hz, 1H), 4.30 (t, J = 8.0 Hz, 2H), 3.72 (s, 3H), 3.11 (t, J = 8.0 Hz, 2H), 2.62 (s, 3H), 2.36 (s, 3H). MS-ESI calcd [M + H] ⁺ 318. Found 318.

Example 106.

3-(3-( 1H -indol-3-yl)propyl)-1-methylpteridin-2,4-dione.

first step.

3-(3-( 1H -indol-3-yl)propyl)-1-methylpteridin-2,4-dione.

3-( 1H -indol-3-yl)propyl methanesulfonate (185 mg, 0.729 mmol), 1-methylpteridine-2,4-dione (100 mg, 0.561 mmol) and carbonic acid Potassium (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 mixture 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-purity liquid chromatography to give 3-(3-( 1H -indol-3-yl)propyl)-1-methylpteridin-2,4-dione ( 10.0 mg), yield: 5%. ¹ H NMR: (400 MHz, CDCl ₃ ) δ = 8.60 (d, J = 2.0 Hz, 1H), 8.56 (d, J = 2.0 Hz, 1H), 7.90-7.85 (br, 1H), 7.61-7.59 ( m,1H), 7.26(s,1H), 7.15-7.06(m,3H), 4.29(t, J = 7.2 Hz, 2H), 3.63(s,3H), 2.91(t, J = 7.2 Hz, 2H ), 2.27-2.20 (m, 2H). MS-ESI calcd for [M ⁺ Na] + 358, found 358.

Example 107.

3-(4-(benzofuran-2-yl)butyl)-1-methylpteridin-2,4-dione.

first step.

3-(4-(benzofuran-2-yl)butyl)-1-methylpteridin-2,4-dione.

1-methylpteridin-2,4-dione (60.0 mg, 0.342 mmol) was dissolved in N , N -dimethylformamide (4 mL). Butyl)benzofuran (84.0 mg, 0.401 mmol), potassium iodide (67.0 mg, 0.401 mmol) and potassium carbonate (93.0 mg, 0.670 mmol). The reaction mixture 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-purity chromatography to give 3-(4-(benzofuran-2-yl)butyl)-1-methylpteridin-2,4-dione (11.0 mg ), yield: 9%. ¹ H NMR: (400 MHz, CDCl ₃ ) δ = 8.64 (d, J = 2.0 Hz, 1H), 8.59 (d, J = 2.0 Hz, 1H), 7.49-7.44 (m, 1H), 7.38 (d, J = 7.6 Hz, 1H), 7.21-7.14 (m, 2H), 6.41 (s, 1H), 4.20 (t, J = 6.8 Hz, 2H), 3.70 (s, 3H), 2.85 (t, J = 6.4) Hz, 2H), 1.88-1.83 (m, 4H). MS-ESI calcd for [M + H] ⁺ 351.

Example 108.

1-Methyl-3-(3-(3-methylisoxazol-5-yl)propyl)pteridin-2,4-dione.

first step.

1-Methyl-3-(3-(3-methylisoxazol-5-yl)propyl)pteridin-2,4-dione.

3-(3-Methylisoxazole-5-yl)propyl methanesulfonate (160 mg, 0.729 mmol), 1-methylpteridine-2,4-dione (100 mg, 0.561 mmol) Potassium carbonate (233 mg, 1.68 mmol) was dissolved in N , N -dimethylformamide (5 mL). Potassium iodide (9.3 mg, 0.056 mmol) was added and the mixture was stirred at 120 ° C for 15 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 give 1-methyl-3-(3-(3-methylisoxazol-5-yl)propyl)pteridine-2,4-di. Ketone (6.0 mg), yield: 3.6%. ¹ H NMR: (400 MHz, Methonal- d ₄ ) δ = 8.76 (d, J = 2.0 Hz, 1H), 8.56 (d, J = 2.0 Hz, 1H), 6.10 (s, 1H), 4.21 (t, J = 7.2 Hz, 2H), 3.70 (s, 3H), 2.87 (t, J = 7.2 Hz, 2H), 2.18 (s, 3H), 2.17-2.12 (m, 2H). MS-ESI calcd for [M + H] ⁺ 302, found 302.

Example 109.

1-Methyl-3-(4-(3-methylisoxazol-5-yl)butyl)pteridin-2,4-dione.

first step.

1-Methyl-3-(4-(3-methylisoxazol-5-yl)butyl)pteridin-2,4-dione.

1-Methylpteridine-2,4-dione (300 mg, 1.68 mmol) was dissolved in N , N -dimethylformamide (8 mL). Add 5-(4-bromobutyl)-3-methylisoxazole (366 mg, 1.68 mmol), potassium carbonate (465 mg, 3.37 mmol) and potassium iodide (335 mg, 2.02 mmol) at 25 °C. . 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. Ketone (13.00 mg), yield: 3%. ¹ H NMR: (400 MHz, CDCl ₃ ) δ = 8.64 (d, J = 4.0 Hz, 1H), 8.58 (d, J = 4.0 Hz, 1H), 5.83 (s, 1H), 4.15 (t, J = 4.0 Hz, 2H), 3.70 (s, 3H), 2.76 (t, J = 4.0 Hz, 2H), 2.23 (s, 3H), 1.82-1.74 (m, 4H). MS-ESI calcd for [M + H] ⁺ 316.

Example 110.

3-((3-Isoisopropyloxazole-5-yl)methyl)-1-methylpyrimido[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 (3.50 g, 24.8 mmol) was added to formamide (5.00 g, 111 mmol), and the mixture was heated to 180 ° C and stirred for 3 hours. Filtration to room temperature, water (10 mL) was added to the filtrate and stirred, and filtered again to give 1-methylpyrimido[4,5-d]pyrimidine-2,4-dione (1.60 g, pale yellow solid) The yield was 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.

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

1-Methylpyrimido[4,5-d]pyrimidine-2,4-dione (20.0 mg, 0.112 mmol) was dissolved in N , N -dimethylformamide (2 mL) at 25° C was added (3-isopropylisoxazol-5-yl)methyl methanesulfonate (27.0 mg, 0.123 mmol), potassium iodide (4.0 mg, 0.0225 mmol) and potassium carbonate (31.0 mg, 0.225 mmol). The 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 give the product 3-((3-isopropylisoxazol-5-yl)methyl)-1-methylpyrimido[4,5-d]pyrimidine-2,4 -Dione (5.0 mg), yield: 15%. ¹ H NMR: (400 MHz, CDCl ₃ ) δ = 9.33 (s, 1H), 9.17 (s, 1H), 6.18 (s, 1H), 5.35 (s, 2H), 3.71 (s, 3H), 3.07- 3.00 (m, 1H), 1.26 (d, J = 6.8 Hz, 6H). MS-ESI calcd for [M + H] ⁺ 302, found 302.

Example 111.

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

first step.

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

1-Methylpyrimido[4,5-d]pyrimidine-2,4-dione (50.0 mg, 0.281 mmol) was dissolved in N , N -dimethylformamide (4 mL) at 25° C Add 2-(2,4-dimethylthiazol-5-yl)ethyl methanesulfonate (73.0 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. The residue was purified by preparative high performance liquid chromatography to give the product 3-(2-(2,4-dimethyl-5-yl)ethyl)-1-methylpyrimido[4,5-d]pyrimidine-2, 4-Dione (43.0 mg), Yield: 48%. ¹ H NMR: (400 MHz, CDCl ₃ ) δ = 9.30 (s, 1H), 9.16 (s, 1H), 4.25-4.21 (m, 2H), 3.70 (s, 3H), 3.10-3.06 (m, 2H) ), 2.62 (s, 3H), 2.36 (s, 3H). MS-ESI calcd [M + H] ⁺ 318. Found 318.

Example 112.

3-(3-( 1H -indol-3-yl)propyl)-1-methylpyrimido[4,5-d]pyrimidine-2,4-dione.

first step.

3-(3-( 1H -indol-3-yl)propyl)-1-methylpyrimido[4,5-d]pyrimidine-2,4-dione.

1-Methylpyrimido[4,5-d]pyrimidine-2,4-dione (50.0 mg, 0.281 mmol) was dissolved in N , N -dimethylformamide (4 mL) at 25° C was added 3-( 1H -indol-3-yl)propyl methanesulfonate (78.0 mg, 0.308 mmol), potassium iodide (9.0 mg, 0.056 mmol) and potassium carbonate (76.0 mg, 0.561 mmol). Heat to 120 ° C and stir 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 give the product 3-(3-( 1H -indol-3-yl)propyl)-1-methylpyrimido[4,5-d]pyrimidine-2,4- Diketone (12.0 mg), yield: 13%. ¹ H NMR: (400 MHz, CDCl ₃ ) δ = 9.22 (s, 1H), 9.09 (s, 1H), 7.95-7.90 (br, 1H), 7.59 (d, J = 7.6 Hz, 1H), 7.28- 7.26(m,1H), 7.16-7.07(m,3H), 4.21(t, J = 7.2 Hz, 2H), 3.60(s,3H), 2.89(t, J = 7.2 Hz, 2H), 2.21-2.17 (m, 2H). MS-ESI calculated [M + H] ⁺ 356 found 336.

Example 113.

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

first step.

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

1-Methylpyrimido[4,5-d]pyrimidine-2,4-dione (50.0 mg, 0.281 mmol) was dissolved in N , N -dimethylformamide (4 mL) at 25° C Add 2-(4-chlorobutyl)benzofuran (64.0 mg, 0.308 mmol), potassium iodide (56.0 mg, 0.337 mmol) and potassium carbonate (78.0 mg, 0.561 mmol). The reaction mixture was heated to 120 ° C and stirred. 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-purity chromatography to give the product 3-(4-(benzofuran-2-yl)butyl)-1-methylpyrimido[4,5-d]pyrimidine-2 , 4-dione (53.0 mg), yield: 54%. ¹ H NMR: (400 MHz, CDCl ₃ ) δ = 9.27 (s, 1H), 9.13 (s, 1H), 7.48-7.44 (m, 1H), 7.37 (d, J = 7.6 Hz, 1H), 7.20- 7.13 (m, 2H), 6.39 (s, 1H), 4.12 (m, 2H), 3.66 (s, 3H), 2.88-2.78 (m, 2H), 1.86-1.79 (m, 4H). MS-ESI calcd for [M + H] ⁺ 351.

Example 114.

1-Methyl-3-(3-(3-methylisoxazol-5-yl)propyl)pyrimido[4,5-d]pyrimidine-2,4-dione.

first step.

1-Methyl-3-(3-(3-methylisoxazol-5-yl)propyl)pyrimido[4,5-d]pyrimidine-2,4-dione.

3-(3-Methylisoxazole-5-yl)propyl methanesulfonate (80.0 mg, 0.364 mmol), 1-methylpyrimido[4,5-d]pyrimidine-2,4-di Ketone (50.0 mg, 0.280 mmol) and potassium carbonate (116 mg, 0.842 mmol) were dissolved in N , N -dimethylformamide (5 mL). Potassium iodide (4.7 mg, 0.028 mmol) was added. Stir at °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 HPLC to give 1-methyl-3-(3-(3-methylisoxazol-5-yl)propyl)pyrimidine [4,5-d Pyrimidine-2,4-dione (55.0 mg), yield: 65%. ¹ H NMR: (400 MHz, CDCl ₃ ) δ = 9.30 (s, 1H), 9.16 (s, 1H), 5.93 (s, 1H), 4.17 (t, J = 7.2 Hz, 2H), 3.69 (s, 3H), 2.83 (t, J = 7.2 Hz, 2H), 2.23 (s, 3H), 2.14 - 2.08 (m, 2H). MS-ESI calcd for [M ⁺ Na] + 324, found 324.

Example 115.

1-Methyl-3-(4-(3-methylisoxazol-5-yl)butyl)pyrimido[4,5-d]pyrimidine-2,4-dione.

first step.

1-Methyl-3-(4-(3-methylisoxazol-5-yl)butyl)pyrimido[4,5-d]pyrimidine-2,4-dione.

1-Methylpyrimido[4,5-d]pyrimidine-2,4-dione (300 mg, 1.68 mmol) was dissolved in N , N -dimethylformamide (8 mL) at 25° C was added 5-(4-bromobutyl)-3-methylisoxazole (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-purpur chromatography to give 1-methyl-3-(4-(3-methylisoxazole-5-yl)butyl)pyrimidine [4,5-d Pyrimidine-2,4-dione (11.0 mg), yield: 2%. ¹ H NMR: (400 MHz, CDCl ₃ ) δ = 9.28 (s, 1H), 9.14 (s, 1H), 5.83 (s, 1H), 4.09 (t, J = 7.2 Hz, 2H), 3.68 (s, 3H), 2.77 (t, J = 7.2 Hz, 2H), 2.25 (s, 3H), 1.78-1.75 (m, 4H). MS-ESI calcd for [M + H] ⁺ 316.

Experimental Example 1: PDE2 phosphodiesterase inhibitory activity was evaluated 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: Buffer solution was determined: 10 mM Tris-HCl, pH 7.5, 5 mM MgCl ₂ , 0.01% Brij 35, 1 mM DTT and 1% DMSO. Enzyme: Recombinant full length human PDE2A protein was expressed in insect Sf9 cells using a baculovirus using an N-terminal GST tag. Substrate: 1 μM Cgmp.

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

Experimental operation:

The freshly prepared buffer solution was prepared into an enzyme solution, and then added to the reaction well, and the DMSO solution of the test compound was added via an Echo 550 non-contact nano-sound sonic pipetting system, and then pre-incubated for 10 minutes at room temperature to add the substrate ( The reaction was initiated by 1 mM cGMP) and allowed to react at room temperature for one hour. Then, a detection system (Transcreener® AMP ² / GMP ² antibody, AMP ² / GMP ² AlexaFluor 633 fluorescent dye) was added, and reacted at room temperature for 90 minutes, and then fluorescence polarization was detected using Ex/Em 620/688.

Fluorescence polarization intensity was converted to nM concentration via the AMP/GMP standard curve, then relative enzyme activity inhibition relative to the DMSO blank was calculated, and IC50 values and curves were calculated using Prism set software (GraphPad Software, San Diego California, USA).

Experimental results: Table 1 PDE2 phosphodiesterase inhibitory activity test results Note: 10 mM ≤ + < 50 mM; 1 mM ≤ ++ < 10 mM; +++ < 1 mM; - N/A Conclusion: The compounds of the present invention have significant and unexpected PDE2A protease inhibitory activity.

Experimental Example 2: The effect of compounds on the TNF-a in the blood of rats induced by LPS was evaluated in vitro.

EXPERIMENTAL OBJECTIVE: To examine the effects of compounds on the TNF-a in rat blood induced by LPS in vitro, and to evaluate the inhibitory effect of the compounds on LPS-induced TNF-a in rat blood.

Experimental material: Sprague Dawley rats (male, 210-260 g, 8-10 weeks old, Shanghai Slack) Rat TNF-alpha Quantikine ELISA Kit (R&D, #SRTA00)

Experimental operation:

A test solution of the test compound at a concentration of 1 mM was prepared, and 40 ul (the final concentration of the compound was 100 uM) was added to a 48-well cell culture plate. After the rats were anesthetized with isoflurane, blood was collected from the heart (heparin anticoagulation). Blood was added to a 48-well plate to which the test compound had been added, 320 ul per well. The 48-well plate was placed in a cell culture incubator, and after 30 minutes of incubation, it was taken out, and 40 ul of LPS solution (100 ug/ml) was added, mixed, and placed in an incubator to continue incubation. After 5 hours, remove the 48-well plate, transfer the blood sample to a 1.5 ml centrifuge tube, centrifuge in a centrifuge (4,500 rpm, 4 ° C, 5 minutes), separate the upper layer of plasma, and then freeze it after storage. Store at -80 °C. refrigerator. The next day, according to the kit instructions, the R&D ELISA kit was used to perform TNF-a level detection in plasma samples.

Experimental results: Table 2 TNFa inhibitory activity test results Note: 80% ≥ + >60%; ++ >80%; - N/A Conclusion: The compounds of the invention have significant and unexpected TNFa inhibitory activity.

no.

no

Claims (10)

a compound of the formula (I), a tautomer thereof or a pharmaceutically acceptable salt thereof, (I) where structural unit Can be replaced by Ring A is selected from a 5-6-membered aryl or heteroaryl group optionally substituted by 1 or 2 R ₁ ; G is selected from 5 to 9-membered aromatic or heteroaryl optionally substituted by 1 to 3 R ring, , , Or optionally substituted by 1 to 3 R One of X is selected from C(R) ₂ or a single bond, and the remaining X is selected from C(R) ₂ , N(R), O, S, C(=O), S(=O), S(=O ₂ , -C(=O)N(R)-; wherein one Y is selected from C(R) ₂ or a single bond, and at least two of the other four Y are independently selected from heteroatoms or heteroatoms, and the remaining Y Is C(R) ₂ ; the hetero atom represents a hetero atom or a hetero atom, independently selected from N(R), O, S, C(=O), S(=O), S(=O) ₂ , - C(=O)N(R)-, the number of heteroatoms on each of the defined groups is independently selected from 1, 2 or 3; , , , And R ₁ are each independently selected from H, halogen, OH, NH ₂ , optionally substituted by 1 to 3 R ₂ : C _1-6 alkyl or heteroalkyl, 3 to 6-membered cycloalkyl or heterocyclic ring; alkyl, 3-6 membered cycloalkyl or heterocycloalkyl C _1-6 alkyl, or substituted heteroalkyl, substituted cycloalkyl of 5 to 6-membered aryl or heteroaryl group or C _1-6 alkyl Heteroalkyl; R _{2 is} selected from the group consisting of halogen, OH, NH ₂ , Me, CF ₃ , OMe, OCF ₃ ; When optionally, R _{1 is} bonded to G to form a spiro ring; R is selected from H, halogen, N(R') (R'), C _1-3 alkane optionally substituted by 1 to 3 R' Or a heteroalkyl group; and R' is selected from the group consisting of H, halogen, NH ₂ , Me, CF ₃ , OMe, OCF ₃ . The compound according to claim 1, wherein the R _{1 is} independently selected from the group consisting of H, halogen, OH, NH ₂ , optionally 1 to 3, or a pharmaceutically acceptable salt thereof. R ₂ substituted: C _1-4 alkyl or heteroalkyl, 3 to 5 membered cycloalkyl or heterocycloalkyl, C _1-3 alkane substituted by 3 to 6 membered cycloalkyl or heterocycloalkyl a C _1-3 alkyl or heteroalkyl group substituted by a 5- to 6-membered cyclic aryl or heteroaryl; specifically, R _{1 is} independently selected from H, halogen, OH, NH ₂ , Optionally substituted with 1 to 3 R ₂ : Me, , , , , , , , , , , And more specifically, R _{1 is} selected from the group consisting of: H, halogen, OH, NH ₂ , Me, , , , , , , , , , , , , . The compound according to claim 1, wherein the t isomer or a pharmaceutically acceptable salt thereof, wherein L is selected from the group consisting of , , , , CH ₂ , , , . The compound according to claim 1, wherein the ring A is selected from the group consisting of pyridyl and pyridyl, optionally substituted by 1 or 2 R ₁ , and the pharmaceutically acceptable salt thereof. Azolyl, imidazolyl, pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl, phenyl; in particular, ring A is selected from the group consisting of optionally substituted by 1 or 2 R ₁ : , , , , , , , , , , And more specifically, ring A is selected from: , , , , , , , , , , , , , , , , , , , , , , , , , , . The compound according to claim 4, the tautomer thereof or a pharmaceutically acceptable salt thereof, wherein the structural unit From: , , , , , , , , , , , , , , , , , , , , , , , , , , . The compound according to claim 1, wherein the R _{1 is} bonded to G to form a spiro ring selected from the group consisting of , . The compound according to claim 1, wherein the R is selected from the group consisting of H, Me, or a pharmaceutically acceptable salt thereof. , , , . The compound according to claim 1, wherein the t isomer or a pharmaceutically acceptable salt thereof, wherein G is selected from the group consisting of , , , Or optionally substituted by 1 to 3 R: imidazolyl, pyrazolyl, thiazolyl, isoxazolyl, oxazolyl, 1,3,4-oxadiazolyl, 2H-1, 2,3- Triazolyl, 1H-1,2,3-triazolyl, 2H-tetrazolyl, 1H-tetrazolyl, pyridyl, benzofuranyl, fluorenyl, benzothiazolyl, 4,5,6 , 7-tetrahydro-2H-carbazolyl; and specifically, G is selected from: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , . A compound, a tautomer thereof, or a pharmaceutically acceptable salt thereof, according to claim 1, wherein the compound is selected from the group consisting of: . The use of a compound, a tautomer thereof or a chemically acceptable salt thereof according to any one of claims 1 to 9 for the preparation of a PDE2 inhibitor and a TNF-α inhibitor.