CN118206553A

CN118206553A - Ternary parallel ring compound and application thereof

Info

Publication number: CN118206553A
Application number: CN202211615637.2A
Authority: CN
Inventors: 燕立波; 胡诗合; 刘宇; 马继业
Original assignee: Skyrun Pharma Co ltd
Current assignee: Skyrun Pharma Co ltd
Priority date: 2022-12-15
Filing date: 2022-12-15
Publication date: 2024-06-18

Abstract

The invention discloses a ternary parallel-ring compound shown in a formula I and application thereof:

Description

Ternary parallel ring compound and application thereof

Technical Field

The invention belongs to the technical field of medicines, and in particular relates to a ternary fused ring compound and application thereof in preparing medicines for preventing and/or treating diseases related to DNA-dependent protein kinase (DNA-PK) mediated or dependent diseases or cancer metastasis in organisms.

Background

Cell proliferation is achieved by the cell cycle (CELL CYCLE), and orderly operation of the cell cycle is ensured by strict monitoring and regulation of the relevant genes. This highly regulated process of cell cycle enables cell growth, genetic material replication and cell division. After the tumor cells are damaged by chemotherapy or radiotherapy DNA, a series of cell reactions such as damaged DNA repair and the like can be initiated, and the repair result is that the survival of cancer cells is improved, so that the resistance of radiotherapy and chemotherapy is caused. DNA double strand breaks, if not timely and intact repaired, can lead to cell death through apoptosis or mitotic disorders. Therefore, the DNA damage repair of tumor cells is inhibited, the sensitivity of cancer cells to radiotherapy and chemotherapy can be improved, and the proliferation of the cancer cells is inhibited. In human higher eukaryotic cells, repair of DNA double strand breaks (DNA double strand break, DSB) is mainly performed by DNA non-homologous end joining (nonhomologous end joining, NHEJ) dominated by DNA dependent protein kinases (DNA-DEPENDENT PROTEIN KINASE, DNA-PK), thereby repairing damaged DNA, maintaining cell activity and genomic stability. NHEJ repair is mainly involved in G1/S phase DNA damage repair and does not require DNA end ligation templates.

DNA-dependent protein kinases (DNA-PKcs) are a class of serine/threonine protein kinases that belong to the phosphatidylinositol 3-kinase related kinase protein family. DNA-PKcs are catalytic subunits of nuclear DNA-dependent serine/threonine protein kinases, called DNA-PKs. The second component is autoimmune antigen Ku. By itself, DNA-PK is inactive, relying on Ku to direct it to the DNA ends and trigger its kinase activity. DNA-PK is required for the non-homologous end joining (NHEJ) pathway of DNA repair, which re-joins double strand breaks. Autophosphorylation of DNA-PK plays a key role in NHEJ and is thought to induce conformational changes that allow end processing enzymes to enter the ends of double strand breaks. DNA-PK also coordinates with the DNA damage checkpoints of proteins involved in ATR and ATM to phosphorylation. Therefore, when DNA is damaged, DNA-PK is inhibited to prevent the self-repair of tumor cells and improve the sensitivity of cancer cells to radiotherapy and chemotherapy, so that the aim of enhancing and killing the tumor cells is fulfilled.

To date, a variety of DNA-PK inhibitors have been put into clinical studies such as AZD-7648 (stage II), CC-115 (stage II), BR2002 (stage I) and BR101801 (stage I), etc., but there are no DNA-PK inhibitors available in the market. Recent researches indicate that the novel DNA-PK inhibitor has a certain curative effect in cancer treatment, but more novel DNA-PK inhibitors capable of being orally taken are still required to be developed, so that candidate medicaments have more excellent characteristics, such as better curative effect, lower side effect, better drug generation characteristics, longer administration interval and the like, and are better used for preventing or treating novel DNA-PK kinase related diseases. Therefore, the development of novel DNA-PK inhibitors with high selectivity and excellent pharmacokinetic properties has become key to the development of novel antitumor drugs.

Disclosure of Invention

In view of the above-described deficiencies of the prior art, it is an object of the present invention to provide a class of pyrimidine bicyclic compounds which are selective inhibitors of DNA-dependent protein kinase (DNA-PK), providing the possibility for the treatment of diseases mediated by DNA-dependent protein kinase (DNA-PK).

In order to achieve the above object, the present invention adopts the following technical means:

The present invention provides a compound of formula I, or a pharmaceutically acceptable salt, prodrug, crystal form, stereoisomer, tautomer, hydrate, or solvate thereof:

in the formula I, the compound (I),

X is selected from-CR ³R⁴-、-NR³ -, O, or S, wherein R ³、R⁴ each independently represents hydrogen, deuterium, halogen, alkyl, aryl, or Het;

y is selected from O or S;

n=1, 2 or 3;

R ¹ is selected from hydrogen, halogen, hydroxy, alkoxy, alkyl, aryl, or Het;

R ² is selected from hydrogen, hydroxy, alkoxy, alkyl, aryl,

Wherein n=1, 2,3 or 4, m=0, 1,2 or 3, r ⁵、R⁶ each independently represents hydrogen, deuterium, halogen, alkyl, aryl or Het;

In the above groups, the alkyl group is a linear or branched saturated hydrocarbon group of 1 to 6 carbon atoms, a cyclic saturated hydrocarbon group of 3 to 6 carbon atoms, or a cyclic saturated hydrocarbon group of 3 to 6 carbon atoms to which a linear or branched saturated hydrocarbon group of 1 to 6 carbon atoms is attached;

In the above groups, the aryl group is a monocyclic aromatic hydrocarbon group of 6 to 10 ring atoms or a polycyclic aromatic hydrocarbon, for example, a carbocyclic ring selected from phenyl, naphthyl, acenaphthylenyl or tetrahydronaphthyl, each of which is optionally substituted with 1,2 or 3 substituents, each substituent being independently selected from hydrogen, alkyl, cyano, halogen, nitro, haloalkyl, hydroxy, mercapto, alkoxy, haloalkoxy, alkylthio, alkoxyalkyl, aralkyl, diarylalkyl, aryl or Het;

Of the above groups, het is a saturated or partially unsaturated cyclic group of 3 to 8 ring atoms, wherein at least one ring atom is a heteroatom selected from N, O and S, and the remaining ring atoms are C, for example a monocyclic heterocycle selected from piperidinyl, pyrrolyl, pyrazolyl, imidazolyl, furanyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridinyl, pyrimidinyl, pyrazinyl or pyridazinyl; het also includes groups in which the heterocyclic group is fused to an aromatic or heteroaromatic ring, for example a bicyclic heterocycle selected from quinolinyl, quinoxalinyl, indolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzofuranyl, benzothienyl, 2, 3-dihydrobenzo [1,4] dioxanyl or benzo [1,3] dioxolyl; each monocyclic or bicyclic heterocycle is optionally substituted with 1,2 or 3 substituents, each substituent being independently selected from halogen, haloalkyl, hydroxy, alkyl or alkoxy;

In the above groups, the alkoxy group is a linear or branched saturated alkoxy group selected from 1 to 6 carbon atoms, a cyclic saturated alkoxy group of 3 to 6 carbon atoms, or a cyclic saturated alkoxy group of 3 to 6 carbon atoms to which a linear or branched saturated hydrocarbon group of 1 to 6 carbon atoms is attached; the alkylthio is a linear or branched saturated alkylthio group with 1-6 carbon atoms, a cyclic saturated alkylthio group with 3-6 carbon atoms or a cyclic saturated alkylthio group with 3-6 carbon atoms connected with a linear or branched saturated hydrocarbon group with 1-6 carbon atoms;

in the above groups, halogen is selected from fluorine, chlorine, bromine or iodine.

Further, in the formula I,

X is selected from-CR ³R⁴ -or-NR ³ -, wherein R ³、R⁴ each independently represents hydrogen, deuterium, halogen, alkyl, aryl or Het;

y is selected from O or S;

n=1 or 2;

r ¹ is selected from hydrogen, alkoxy, alkyl, aryl, or Het;

R ² is selected from hydrogen, hydroxy, alkoxy, alkyl,

further, in the formula I,

X is selected from-NR ³ -, wherein R ³ each independently represents hydrogen, deuterium, halogen, alkyl, aryl or Het;

y is selected from O or S;

n=1 or 2;

R ¹ is selected from alkyl, aryl or Het;

R ² is selected from alkyl, Wherein n=1, 2,3 or 4, m=0, 1,2 or 3, r ⁵、R⁶ each independently represents hydrogen, deuterium, halogen, alkyl, aryl or Het;

further, in the formula I,

Y is selected from O;

n＝2；

R ¹ is selected from aryl or Het;

R ² is selected from

further, the compound of formula I is one of the following compounds:

Pharmaceutically acceptable salts of the compounds of the invention include acid addition salts of the compounds with: hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid, citric acid, tartaric acid, lactic acid, pyruvic acid, acetic acid, maleic acid or succinic acid, fumaric acid, salicylic acid, phenylacetic acid, mandelic acid; also included are the acid salts of the compounds of formula I with inorganic bases. The pharmaceutically acceptable salts also include basic metal cation salts, alkaline earth metal cation salts, and ammonium cation salts.

It is another object of the present invention to provide a pharmaceutical composition comprising the above compound or a pharmaceutically acceptable salt, prodrug, crystal form, stereoisomer, tautomer, hydrate, or solvate thereof, and a pharmaceutically acceptable carrier or excipient.

It is a further object of the present invention to provide the use of the above compound or a pharmaceutically acceptable salt, prodrug, crystal form, stereoisomer, tautomer, hydrate or solvate thereof for the preparation of a medicament for use in a DNA-dependent protein kinase (DNA-PK) mediated disease.

Further, the DNA-dependent protein kinase (DNA-PK) mediated related diseases include, but are not limited to, hyperlipidemia or cancer.

Such cancers include lung cancer, squamous cell carcinoma, bladder cancer, gastric cancer, ovarian cancer, peritoneal cancer, breast cancer, ductal breast cancer, head and neck cancer, endometrial cancer, uterine cancer, rectal cancer, liver cancer, renal pelvis cancer, esophageal adenocarcinoma, glioma, prostate cancer, thyroid cancer, cancer of the female reproductive system, carcinoma in situ, lymphoma, neurofibromatosis, bone cancer, skin cancer, brain cancer, colon cancer, testicular cancer, gastrointestinal stromal tumor, oral cancer, pharyngeal cancer, multiple myeloma, leukemia, non-hodgkin's lymphoma, large intestine villous adenoma, melanoma, cytoma and sarcoma, and myelodysplastic syndrome.

Compared with the prior art, the invention has the following beneficial effects:

the compounds of formula I and pharmaceutically acceptable salts, prodrugs, crystal forms, stereoisomers, tautomers, hydrates or solvates thereof provided herein are useful as selective DNA-dependent protein kinases (DNA-PKs).

Thus, the above compounds may be used in the preparation of a medicament for the treatment of a clinical condition associated with DNA-dependent protein kinase (DNA-PK) mediated conditions, such as: the application of the composition in preparing medicines for preventing and/or treating diseases related to abnormal proliferation, morphological change, hyperkinesia and the like of cells mediated by DNA-dependent protein kinase (DNA-PK) in organisms and diseases related to angiogenesis or cancer metastasis.

Detailed Description

The following terms used herein have the definitions given below, unless otherwise indicated.

As used herein, "cancer" refers to diseases, disorders, and conditions that include abnormal cell growth that may invade or spread to other parts of the body. Exemplary cancers include, but are not limited to, breast cancer, lung cancer, ovarian cancer, endometrial cancer, prostate cancer, and esophageal cancer.

As used herein, "treatment" refers to the amelioration of a disease or disorder or at least one identifiable symptom thereof. In another embodiment, "treatment" refers to an improvement in at least one measurable physical parameter, not necessarily discernable by the patient. In yet another embodiment, "treating" refers to inhibiting or slowing the progression of a disease or disorder. In yet another embodiment, "treating" refers to delaying the onset of a disease or disorder.

As used herein, "preventing" refers to reducing the risk of acquiring a given disease or disorder.

Dash ("-") indicates that the points of attachment for substituents, e.g., "-NH-", are attached through a nitrogen atom.

The term "pharmaceutically acceptable carrier or excipient" as used herein refers to any and all solvents, dispersion media, coating materials, isotonic and absorption delaying agents, and the like, which are compatible with the administration of the drug. The use of such media and agents for pharmaceutically active substances is well known in the art.

The term "pharmaceutically acceptable salt" as used herein refers to salts of acidic or basic groups which may be present in the compounds of the present invention. Acids useful in preparing such pharmaceutically acceptable acid addition salts are those that form non-toxic acid addition salts, i.e., salts containing pharmacologically acceptable anions, including, but not limited to, hydrochloride, hydrobromide, sulfate, phosphate, methanesulfonate, benzenesulfonate, p-toluenesulfonate, naphthalenesulfonate, citrate, tartrate, lactate, pyruvate, acetate, maleic acid or succinate, fumarate, salicylate, phenylacetate, mandelate; in addition to the acids described above, pharmaceutically acceptable salts of the invention also include the acid salts of the compounds of formula I with inorganic bases. Further, alkaline metal cation salts, alkaline earth metal cation salts, and ammonium cation salts are included, including but not limited to calcium salts, magnesium salts, sodium salts, lithium salts, zinc salts, potassium salts, and iron salts.

The pharmaceutically acceptable salts of the present invention can be synthesized from the compounds of the present invention by conventional chemical methods by those skilled in the art. Typically, salts of basic compounds are prepared by ion exchange chromatography or by reacting the free base with a stoichiometric or excess of an inorganic or organic acid in the form of the desired salt in a suitable solvent or combination of solvents. Similarly, salts of acidic compounds are formed by reaction with suitable inorganic or organic bases.

The term "prodrug" as used herein refers to any covalently bound carrier that releases the active parent drug when administered to a mammalian patient. Prodrugs can be prepared by conventional procedures or in vivo by modifying functional groups present in the compound in a manner that they decompose to the parent compound. Prodrugs include those which, when administered to a mammalian patient, wherein, for example: and (3) decomposing the hydroxyl, amino, mercapto or carboxyl groups to form free hydroxyl, amino, mercapto or carboxyl groups, respectively. Examples of prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of alcohols in the compounds of the present invention, or amine functional methyl amine, ethyl amine derivatives.

The term "stereoisomers" as used herein includes all geometric isomers, enantiomers or diastereomers. The individual stereoisomers of the compounds of the invention may be prepared synthetically from commercially available starting materials containing asymmetric or stereocenters or by preparing racemic mixtures followed by resolution procedures well known to those of ordinary skill in the art. These splitting methods are exemplified by: (1) Attaching the mixture of enantiomers to a chiral auxiliary, separating the resulting mixture of diastereomers by recrystallization or chromatography, and releasing the optically pure product from the auxiliary; (2) forming a salt using an optically active resolving agent; or (3) directly separating the mixture of optical enantiomers on a chiral chromatographic column. The stereoisomeric mixtures may also be resolved into their stereoisomeric components by well known methods, such as chiral phase gas chromatography, chiral phase high performance liquid chromatography, crystallizing a compound as a chiral salt complex, or crystallizing a compound in a chiral solvent. Stereoisomers may also be obtained from stereoisomerically pure intermediates, reagents and catalysts by well known asymmetric synthetic methods.

The compounds disclosed herein may exist as tautomers and both tautomeric forms are intended to be included within the scope of the disclosure, even though only one tautomeric structure is described.

The term "crystalline form" as used herein refers to the different crystal structures of a crystalline compound. Different crystal forms may be caused by different crystal stacks (stacking polymorphisms) or by different stacks between different conformational isomers of the same molecule (conformational polymorphisms).

The compounds of the present invention may exist in polycrystalline or amorphous form.

The term "solvate" as used herein refers to a complex formed by the combination of a compound and a solvent.

The term "hydrate" as used herein refers to a complex formed by the combination of a compound and water.

The pharmaceutical compositions of the present invention may be administered in a variety of known ways, such as orally, parenterally, by inhalation spray, or via an implanted reservoir. The pharmaceutical composition of the invention can be administered alone or in combination with other antitumor drugs. The oral composition may be any orally acceptable dosage form including, but not limited to, tablets, capsules, emulsions, suspensions, dispersions, and solutions. Common pharmaceutically acceptable carriers or excipients include stabilizers, diluents, surfactants, lubricants, antioxidants, binders, colorants, fillers, emulsifiers, and the like.

Sterile injectable compositions can be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents. Pharmaceutically acceptable carriers and solvents that can be used include water, mannitol, sodium chloride solution, and the like.

Topical compositions may be formulated as oils, lotions, creams and the like. Carriers for the compositions include vegetable or mineral oils, animal fats, and high molecular weight alcohols, among others. A pharmaceutically acceptable carrier is a carrier in which the active ingredient is soluble.

The actual dosage level of the active ingredient in the pharmaceutical compositions of the present invention may be varied to obtain an amount of active ingredient that is effective to achieve the desired therapeutic response for the particular patient, composition and mode of administration, and that is non-toxic to the patient. The dosage level selected will depend on a variety of factors including the activity of the particular compound of the invention or salt thereof employed, the route of administration, the time of administration, the rate of excretion of the particular composition employed, the duration of the treatment, other drugs, compounds and/or materials used in combination with the particular composition employed, the age, sex, weight, general health and past medical history of the patient being treated, and like factors well known in the medical arts.

The process for the preparation of the compounds of the general formula I according to the invention or their salts is described below in connection with specific examples, which, however, do not constitute any limitation on the invention. The compounds of the present invention may also be conveniently prepared by optionally combining the various synthetic methods described in this specification or known in the art, such combinations being readily apparent to those skilled in the art to which the present invention pertains.

The starting materials, reagents, etc. used in the examples of the present invention are all commercially available. The present invention may be prepared in salt form using salt forming methods commonly used in the art.

Example 1

2- ((7-Methyl- [1,2,4] triazolo [1,5-a ] pyridin-6-yl) amino) -4- (tetrahydro-2H-pyran-4-yl) -8, 9-dihydro-7H-pyrido [1,2,3-gh ] purin-5 (4H) -one (I-1)

The synthetic route is as follows:

Synthesis of Compound I-1-1:

SM-1 (14.00 g,101.36 mmol), urea (42.60 g,709.29 mmol) was added to a 500mL single-necked flask, the temperature was raised to 190℃for 3h, the temperature was raised to 100℃and the solid started to dissolve, the temperature was raised to 190℃and the solid started to form again. LCMS detects no starting material remaining, yielding the product. Water (200 mL) was added and the temperature was raised to 100deg.C for 3h, the reaction mixture was directly filtered, the filter cake was rinsed twice with ethanol, and the filter cake was dried to give 14.00g of an off-white solid with a yield of 85% and MS m/z of 164.1[ M+H ] ⁺.

Synthesis of Compound I-1-2:

to a 100mL single-necked flask was added I-1-1 (3.00 g,18.39 mmol), N, N-diisopropylethylamine (2 mL), phosphorus oxychloride (40 mL), and the mixture was reacted at 130℃for 4 hours. TLC detects no starting material remaining, yielding the product. Directly concentrating toluene for three times to obtain crude product, dissolving with ethyl acetate, filtering, leaching filter cake with ethyl acetate twice, adding active carbon into filtrate, decolorizing for 1 hr, filtering, leaching filter cake with ethyl acetate twice, concentrating filtrate to obtain crude product, yellow solid 3.60g, yield 98%, MS m/z 201.0[ M+H ] ⁺.

Synthesis of Compound I-1-3:

to a 100mL single-necked flask was added I-1-2 (3.60 g,18.00 mmol), tetrahydro-2H-pyran-4-amine hydrochloride (2.48 g,18.02 mmol), N, N-diisopropylethylamine (6.98 g,54.01 mmol), N-butanol (50 mL), and the mixture was reacted at 90℃for 2 hours. TLC (PE: ea=1:1) examined no starting material remained, yielding the product. The reaction solution was poured into saturated ammonium chloride solution, extracted with ethyl acetate (30 ml x 3), the organic phases were combined, washed twice with saturated sodium chloride solution, dried over anhydrous sodium sulfate, concentrated to give crude product, purified by column chromatography (PE: ea=1:1) to give 0.76g of white solid with a yield of 16%, MS m/z:265.7[ m+h ] ⁺.

Synthesis of Compound I-1-4:

To a 50mL single-necked flask, I-1-3 (0.65 g,2.46 mmol), trifluoroacetic acid (0.28 g,2.46 mmol), ethanol (20 mL), were added, stirring was performed at room temperature for 5min, platinum dioxide (0.10 g) was added, hydrogen was replaced three times, and the reaction was performed at room temperature until LCMS detects no material remained, yielding the product. The reaction solution was directly filtered, the filter cake was rinsed twice with ethanol and methanol, and the filtrate was concentrated to give 0.59g of crude product as an off-white solid with a yield of 89% and MS m/z of 269.8[ M+H ] ⁺.

Synthesis of Compound I-1-5:

To a 50mL three-necked flask was added I-1-4 (0.80 g,2.98 mmol), N, N-diisopropylethylamine (1.15 g,8.90 mmol), methylene chloride (15 mL), cooled to 0℃and triphosgene (0.89 g,3.00 mmol) was added in portions and the mixture was allowed to react at room temperature for 1h. LCMS detects no starting material remaining, yielding the product. The reaction mixture was poured into ice water, extracted with dichloromethane (20 ml. Times.3), the organic phases combined, dried over anhydrous sodium sulfate and concentrated to give crude product as a pale yellow solid 0.80g, yield 91%, MS m/z 295.7[ M+H ] ⁺.

Synthesis of Compound I-1-6:

To a 100mL single flask was added SM-2 (5.00 g,32.65 mmol), N, N-dimethylformamide dimethyl acetal (11.67 g,97.94 mmol), toluene (50 mL), and the mixture was allowed to react at 90℃for 2 hours. LCMS detects no starting material remaining, yielding the product. Direct concentration gave crude, 6.80g of yellow solid in 100% yield, MS m/z 209.2[ M+H ] ⁺.

Synthesis of Compound I-1-7:

To a 250mL single-necked flask was added I-1-6 (6.80 g,32.66 mmol), hydroxylamine hydrochloride (4.54 g,65.33 mmol), methanol (80 mL), and the mixture was reacted at 78℃for 3 hours. LCMS detects no starting material remaining, yielding the product. The reaction mixture was poured into ice water, extracted with ethyl acetate (30 ml. Times.3), the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to give crude product as a yellowish green solid (6.00 g), yield 94%, MS m/z:197.2[ M+H ] ⁺.

Synthesis of Compound I-1-8:

To a 50mL three-necked flask, I-1-7 (1.00 g,5.10 mmol) was added, tetrahydrofuran (15 mL) was cooled to 0℃and trifluoroacetic anhydride (1.28 g,6.09 mmol) was added dropwise thereto and reacted at room temperature for 18 hours. LCMS detects no starting material remaining, yielding the product. The reaction mixture was poured into saturated sodium bicarbonate solution, extracted with ethyl acetate (15 ml. Times.3), the organic phases were combined, dried over anhydrous sodium sulfate and concentrated to give crude product as a yellow solid 1.00g with a yield of 100%, MS m/z:179.2[ M+H ] ⁺.

Synthesis of Compound I-1-9:

To a 50mL single-necked flask was added I-1-8 (0.82 g,4.60 mmol), ammonium formate (1.46 g,23.15 mmol), palladium on carbon (0.20 g), ethanol (30 mL), and the mixture was reacted at room temperature for 18h. LCMS detects no starting material remaining, yielding the product. The reaction solution was directly filtered, the filter cake was rinsed twice with ethanol and methanol, the filtrate was concentrated to give crude product, slurried (DCM: meoh=10:1), filtered, and the filtrate was concentrated to give 0.68g of red solid with a yield of 100%, MS m/z:149.2[ m+h ] ⁺.

Synthesis of Compound I-1:

To a 50mL single-necked flask, I-1-5 (0.40G, 1.36 mmol), I-1-9 (0.20G, 1.35 mmol), cesium carbonate (0.88G, 2.70 mmol), brettPhos Pd G3 (0.08G, 0.09 mmol), 1, 4-dioxane (20 mL), nitrogen substitution three times, and the temperature was raised to 100℃for 3h. LCMS detects no starting material remaining, yielding the product. The reaction solution was poured into ice water, extracted with ethyl acetate (10 ml. Times.3), the organic phases were combined, dried over anhydrous sodium sulfate, concentrated to give crude product, purified by column chromatography (DCM: meOH=40:1-25:1), and purified by climbing a large plate (DCM: meOH=15:1) to give the product as a white solid 0.08g in 14% yield, MS m/z:407.5[ M+H ] ⁺.

¹H NMR(400MHz,CDCl₃)δ9.84(s,1H),8.26(s,1H),7.58(s,1H),6.75(s,1H),4.49(ddd,J＝12.1,8.1,3.9Hz,1H),4.16(dd,J＝11.6,4.1Hz,2H),3.89(t,J＝5.7Hz,2H),3.56(t,J＝11.8Hz,2H),2.89(t,J＝6.0Hz,2H),2.72(dd,J＝12.5,4.5Hz,2H),2.55(s,3H),2.30–2.22(m,2H),1.83–1.76(m,2H).

Example 2

2- ((7-Methyl- [1,2,4] triazolo [1,5-a ] pyridin-6-yl) amino) -4- (tetrahydro-2H-pyran-4-yl) -8, 9-dihydro-7H-pyrido [1,2,3-gh ] purin-5 (4H) -thione (I-2)

Preparation method referring to example 1, starting with 3-aminopyridine-2-carboxylic acid, a yellow solid was obtained in an amount of 10mg in 19% yield, MS m/z:423.5[ M ⁺H]⁺ ].

¹H NMR(400MHz,CDCl₃)δ9.79(s,1H),8.32(s,1H),7.68(s,1H),6.95(s,1H),5.25(ddd,J＝16.4,8.2,4.2Hz,1H),4.18(dd,J＝11.7,4.4Hz,2H),4.14–4.10(m,2H),3.61(t,J＝11.3Hz,2H),2.97(t,J＝6.1Hz,2H),2.80(dd,J＝12.5,7.9Hz,2H),2.57(s,3H),2.36(dd,J＝11.7,6.0Hz,2H),1.86(d,J＝9.8Hz,2H).

Example 3

2- ((2-Methyl-4-methoxyphenyl) amino) -4- (tetrahydro-2H-pyran-4-yl) -8, 9-dihydro-7H-pyrido [1,2,3-gh ] purin-5 (4H) -one (I-3)

Preparation method referring to example 1, starting with 3-aminopyridine-2-carboxylic acid, a yellow solid was obtained in 20mg, 15% yield, MS m/z 396.5[ M ⁺H]⁺ ].

¹H NMR(400MHz,CDCl₃)δ7.81(d,J＝9.6Hz,1H),6.81–6.78(m,2H),6.71(s,1H),4.43(ddd,J＝16.2,8.1,4.1Hz,1H),4.11(dd,J＝11.5,4.3Hz,2H),3.87–3.83(m,2H),3.82(s,3H),3.56–3.49(m,2H),2.79(t,J＝6.1Hz,2H),2.67(tt,J＝12.5,6.2Hz,2H),2.32(s,3H),2.20(dd,J＝11.8,6.0Hz,2H),1.75(dd,J＝12.5,2.4Hz,2H).

Example 4

2- ((7-Methyl- [1,2,4] triazolo [1,5-a ] pyridin-6-yl) amino) -4-cyclohexyl-8, 9-dihydro-7H-pyrido [1,2,3-gh ] purin-5 (4H) -one (I-4)

Preparation method referring to example 1, starting with 3-aminopyridine-2-carboxylic acid, 80mg of yellow solid was obtained in 29% yield, MS m/z:405.5[ M ⁺H]⁺ ].

¹H NMR(400MHz,CDCl₃)δ9.81(s,1H),8.27(s,1H),7.58(s,1H),6.91(s,1H),4.27(tt,J＝12.2,3.7Hz,1H),3.89(t,J＝5.7Hz,2H),2.88(t,J＝6.1Hz,2H),2.54(s,3H),2.38–2.23(m,5H),1.92(dd,J＝24.2,10.1Hz,4H),1.78(s,1H),1.44(t,J＝10.1Hz,3H).

Example 5

2- ((7-Methyl- [1,2,4] triazolo [1,5-a ] pyridin-6-yl) amino) -4-cyclopentyl-8, 9-dihydro-7H-pyrido [1,2,3-gh ] purin-5 (4H) -one (I-5)

Preparation method referring to example 1, starting with 3-aminopyridine-2-carboxylic acid, a yellow solid was obtained in 20mg, yield 14%, MS m/z 391.5[ M ⁺H]⁺ ].

¹H NMR(400MHz,CDCl₃)δ9.74(s,1H),8.26(s,1H),7.57(s,1H),6.73(s,1H),4.82–4.73(m,1H),3.90–3.84(m,2H),2.86(t,J＝6.1Hz,2H),2.52(s,3H),2.26(dd,J＝11.8,5.8Hz,4H),2.05(dd,J＝6.0,3.5Hz,4H),1.74–1.66(m,2H).

Example 6

2- ((7-Methyl-quinolin-6-yl) amino) -4- ((1 r,4 r) -4-hydroxycyclohexyl) -8, 9-dihydro-7H-pyrido [1,2,3-gh ] purin-5 (4H) -one (I-6)

Preparation method referring to example 1, starting with 3-aminopyridine-2-carboxylic acid, 35mg of yellow solid was obtained in 25% yield, MS m/z 431.5[ M ⁺H]⁺ ].

¹H NMR(400MHz,DMSO-d₆)δ8.71(d,J＝4.1Hz,1H),8.44(s,1H),8.35(s,1H),8.09(d,J＝8.2Hz,1H),7.83(s,1H),7.41(dd,J＝8.3,4.2Hz,1H),4.73(s,1H),4.06(tt,J＝12.3,4.0Hz,1H),3.74(t,J＝5.6Hz,2H),2.71(t,J＝6.0Hz,2H),2.50(s,4H),2.36–2.22(m,2H),2.11(p,J＝5.9Hz,2H),1.97–1.89(m,2H),1.80–1.70(m,2H),1.35–1.24(m,2H).

Example 7

2- ((7-Methyl-quinolin-6-yl) amino) -4- (4, 4-difluorocyclohexyl) -8, 9-dihydro-7H-pyrido [1,2,3-gh ] purin-5 (4H) -one (I-7)

Preparation method referring to example 1, starting with 3-aminopyridine-2-carboxylic acid, 35mg of yellow solid was obtained in 26% yield, MS m/z 451.5[ M ⁺H]⁺ ].

¹H NMR(400MHz,DMSO-d₆)δ8.72–8.67(m,1H),8.37(d,J＝12.3Hz,2H),8.12(d,J＝8.2Hz,1H),7.82(s,1H),7.38(dd,J＝8.2,4.2Hz,1H),4.34(t,J＝12.3Hz,1H),3.75(t,J＝5.5Hz,2H),2.72(t,J＝5.9Hz,2H),2.50(s,5H),2.07(dd,J＝33.1,9.8Hz,6H),1.86(d,J＝12.0Hz,2H).

Example 8

2- ((7-Methyl-quinolin-6-yl) amino) -4- (piperidin-4-yl) -8, 9-dihydro-7H-pyrido [1,2,3-gh ] purin-5 (4H) -one (I-8)

Preparation method referring to example 1, starting with 3-aminopyridine-2-carboxylic acid, a yellow solid was obtained at 32mg in 40% yield, MS m/z:416.5[ M ⁺H]⁺ ].

¹H NMR(400MHz,DMSO-d₆)δ8.79–8.66(m,1H),8.44(s,1H),8.33(s,1H),8.22(d,J＝8.2Hz,1H),7.82(s,1H),7.38(dd,J＝8.7,4.2Hz,1H),4.30(s,1H),3.74(d,J＝6.7Hz,2H),3.24(d,J＝12.4Hz,2H),2.85(t,J＝12.6Hz,2H),2.73(t,J＝6.0Hz,2H),2.50(s,5H),2.18–2.04(m,2H),1.89(d,J＝12.6Hz,2H).

Example 9

2- ((7-Methyl-quinolin-6-yl) amino) -4- (1-methylpiperidin-4-yl) -8, 9-dihydro-7H-pyrido [1,2,3-gh ] purin-5 (4H) -one (I-9)

Preparation method referring to example 1, starting with 3-aminopyridine-2-carboxylic acid, a yellow solid was obtained in an yield of 7% and 10mg, MS m/z 430.5[ M ⁺H]⁺ ].

¹H NMR(400MHz,DMSO-d₆)δ8.70(d,J＝4.1Hz,1H),8.58(s,1H),8.39(s,1H),8.23(d,J＝8.2Hz,1H),7.82(s,1H),7.39(dd,J＝8.3,4.2Hz,1H),4.10(dd,J＝10.8,6.2Hz,1H),3.75(d,J＝5.7Hz,2H),2.94(d,J＝11.5Hz,2H),2.72(d,J＝6.1Hz,2H),2.61(qd,J＝12.7,3.7Hz,2H),2.51(d,J＝4.5Hz,3H),2.27(s,3H),2.11(q,J＝12.4,9.0Hz,4H),1.79–1.67(m,2H).

Example 10

(R) -2- ((7-methyl-quinolin-6-yl) amino) -4- (1-methyltetrahydrophole-3-yl) -8, 9-dihydro-7H-pyrido [1,2,3-gh ] purin-5 (4H) -one (I-10)

Preparation method referring to example 1, starting with 3-aminopyridine-2-carboxylic acid, 22mg of yellow solid was obtained in 16% yield, MS m/z:416.5[ M ⁺H]⁺ ].

¹H NMR(400MHz,MeOD)δ8.69(d,J＝4.2Hz,1H),8.41(s,1H),8.23(d,J＝8.2Hz,1H),7.87(s,1H),7.44(dd,J＝8.3,4.3Hz,1H),5.00(dd,J＝15.2,8.0Hz,1H),3.83(t,J＝5.7Hz,2H),3.19–3.12(m,1H),3.03–2.97(m,1H),2.90(t,J＝7.0Hz,2H),2.83(t,J＝6.0Hz,2H),2.54(d,J＝7.2Hz,3H),2.42(dd,J＝12.0,5.9Hz,1H),2.38(s,3H),2.23(dd,J＝11.5,5.7Hz,2H).

Example 11

(S) -2- ((7-methyl-quinolin-6-yl) amino) -4- (1-methyltetrahydrophole-3-yl) -8, 9-dihydro-7H-pyrido [1,2,3-gh ] purin-5 (4H) -one (I-11)

Preparation method referring to example 1, starting with 3-aminopyridine-2-carboxylic acid, 25mg of yellow solid was obtained in 18% yield, MS m/z:416.5[ M ⁺H]⁺ ].

¹H NMR(400MHz,MeOD)δ8.70(d,J＝4.2Hz,1H),8.38(s,1H),8.24(d,J＝8.2Hz,1H),7.87(s,1H),7.44(dd,J＝8.3,4.3Hz,1H),5.13–5.08(m,1H),3.83(t,J＝5.6Hz,2H),3.37(d,J＝8.2Hz,1H),3.23(t,J＝8.8Hz,1H),3.12–3.05(m,1H),2.82(t,J＝6.0Hz,2H),2.53(d,J＝13.1Hz,7H),2.47(dd,J＝13.6,6.6Hz,2H),2.24(dd,J＝11.4,5.7Hz,2H).

Example 12

(S) -2- ((7-methyl-quinolin-6-yl) amino) -4- (1-hydroxyethyl tetrahydropyran-3-yl) -8, 9-dihydro-7H-pyrido [1,2,3-gh ] purin-5 (4H) -one (I-12)

Preparation method referring to example 1, starting with 3-aminopyridine-2-carboxylic acid, a yellow solid was obtained in an amount of 10mg in 13% yield, MS m/z 446.5[ M ⁺H]⁺ ].

¹H NMR(400MHz,MeOD)δ8.72(d,J＝3.9Hz,1H),8.44(s,1H),8.28(d,J＝8.3Hz,1H),7.90(s,1H),7.48–7.45(m,1H),5.16(s,1H),3.87(t,J＝5.7Hz,2H),3.71(s,2H),3.53(s,2H),3.21(s,1H),3.03(s,2H),2.87(t,J＝6.0Hz,2H),2.58(d,J＝10.9Hz,4H),2.41(d,J＝4.5Hz,2H),2.31–2.19(m,3H).

Example 13

2- ((7-Methyl-quinolin-6-yl) amino) -4- (1-methoxyethyltetrahydropyrrolidin-3-yl) -8, 9-dihydro-7H-pyrido [1,2,3-gh ] purin-5 (4H) -one (I-13)

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Preparation method referring to example 1, starting with 3-aminopyridine-2-carboxylic acid, 27mg of yellow solid was obtained in 20% yield, MS m/z:460.6[ M ⁺H]⁺ ].

¹H NMR(400MHz,DMSO-d₆)δ8.74(dt,J＝6.6,3.3Hz,2H),8.30–8.12(m,2H),7.85(s,1H),7.41(dd,J＝8.3,4.2Hz,1H),4.93(s,1H),3.75(t,J＝5.7Hz,2H),3.37(s,5H),3.17(s,4H),2.73(t,J＝6.0Hz,2H),2.49(s,5H),2.39–2.31(m,2H),2.12(t,J＝5.8Hz,2H).

Example 14

2- ((7-Methyl-quinolin-6-yl) amino) -4- (1- (epoxypropane-3-yl) tetrahydropyrrolidin-3-yl) -8, 9-dihydro-7H-pyrido [1,2,3-gh ] purin-5 (4H) -one (I-14)

Preparation method referring to example 1, starting with 3-aminopyridine-2-carboxylic acid, 33mg of a yellow solid was obtained in 24% yield, MS m/z 458.5[ M ⁺H]⁺ ].

¹H NMR(400MHz,DMSO-d₆)δ8.73(dd,J＝4.2,1.7Hz,1H),8.57(s,1H),8.18(dd,J＝8.4,1.7Hz,1H),8.15(s,1H),7.84(s,1H),7.41(dd,J＝8.2,4.2Hz,1H),4.77(dtd,J＝10.1,8.1,5.6Hz,1H),4.38–4.25(m,4H),3.78–3.69(m,2H),2.97(t,J＝8.5Hz,1H),2.77–2.56(m,4H),2.46(s,3H),2.41(t,J＝8.3Hz,1H),2.26–2.06(m,4H),1.66(s,1H).

Example 15

2- ((7-Methyl- [1,2,4] triazolo [1,5-a ] pyridin-6-yl) amino) -4- ((1 r,4 r) -4-hydroxycyclohexyl) -8, 9-dihydro-7H-pyrido [1,2,3-gh ] purin-5 (4H) -one (I-15)

Preparation method referring to example 1, starting with 3-aminopyridine-2-carboxylic acid, 90mg of a white solid was obtained in 33% yield, MS m/z 421.5[ M ⁺H]⁺ ].

¹H NMR(400MHz,DMSO-d₆)δ9.20(s,1H),8.51(s,1H),8.35(s,1H),7.68(s,1H),4.63(s,1H),3.72(t,J＝5.6Hz,2H),3.17(s,2H),2.68(t,J＝6.0Hz,2H),2.41(s,3H),2.32–2.17(m,2H),2.10(p,J＝5.8Hz,2H),1.97–1.86(m,2H),1.72(d,J＝11.6Hz,2H),1.34–1.21(m,2H).

Example 16

2- ((7-Methyl- [1,2,4] triazolo [1,5-a ] pyridin-6-yl) amino) -4- (4, 4-difluorocyclohexyl) -8, 9-dihydro-7H-pyrido [1,2,3-gh ] purin-5 (4H) -one (I-16)

Preparation method referring to example 1, starting from 3-aminopyridine-2-carboxylic acid, 54mg of a white solid was obtained in 40% yield in MS m/z 441.5[ M ⁺H]⁺ ].

¹H NMR(400MHz,DMSO-d6)δ9.02(s,1H),8.56(s,1H),8.36(s,1H),7.68(s,1H),4.29(s,1H),3.73(s,2H),2.67(s,2H),2.38(s,3H),2.19–1.93(m,7H),1.82(d,J＝12.1Hz,3H).

Example 17

2- ((7-Methyl- [1,2,4] triazolo [1,5-a ] pyridin-6-yl) amino) -4- (piperidin-4-yl) -8, 9-dihydro-7H-pyrido [1,2,3-gh ] purin-5 (4H) -one (I-17)

Preparation method referring to example 1, starting with 3-aminopyridine-2-carboxylic acid, 54mg of yellow solid was obtained in 34% yield, MS m/z 406.5[ M ⁺H]⁺ ].

¹H NMR(400MHz,DMSO-d₆)δ9.14(s,1H),8.69(s,1H),8.42(s,1H),8.36(s,1H),7.70(s,1H),4.40(ddd,J＝12.0,8.1,3.8Hz,1H),3.74(t,J＝5.6Hz,2H),3.40(d,J＝12.6Hz,2H),3.14–3.02(m,2H),2.70(t,J＝6.0Hz,2H),2.56(dd,J＝12.8,3.9Hz,2H),2.39(s,3H),2.10(p,J＝6.0Hz,2H),2.05–1.94(m,2H).

Example 18

2- ((7-Methyl- [1,2,4] triazolo [1,5-a ] pyridin-6-yl) amino) -4- (1-methylpiperidin-4-yl) -8, 9-dihydro-7H-pyrido [1,2,3-gh ] purin-5 (4H) -one (I-18)

Preparation method referring to example 1, starting with 3-aminopyridine-2-carboxylic acid, 54mg of yellow solid was obtained in 40% yield, MS m/z:420.5[ M ⁺H]⁺ ].

¹H NMR(400MHz,DMSO-d₆)δ9.11(s,1H),8.53(s,1H),8.35(s,1H),7.69(s,1H),4.17–4.05(m,1H),3.72(t,J＝5.7Hz,2H),2.97(d,J＝11.5Hz,2H),2.67(t,J＝6.0Hz,2H),2.53(d,J＝3.7Hz,1H),2.39(s,3H),2.26(d,J＝14.7Hz,5H),2.09(t,J＝5.9Hz,2H),1.90(s,1H),1.73(d,J＝12.3Hz,2H).

Example 19

(R) -2- ((7-methyl- [1,2,4] triazolo [1,5-a ] pyridin-6-yl) amino) -4- (1-methyltetrahydrophyrrol-3-yl) -8, 9-dihydro-7H-pyrido [1,2,3-gh ] purin-5 (4H) -one (I-19)

Preparation method referring to example 1, starting with 3-aminopyridine-2-carboxylic acid, a yellow solid was obtained in 20mg, yield 14%, MS m/z 406.5[ M ⁺H]⁺ ].

¹H NMR(400MHz,MeOD)δ9.37(s,1H),8.32(s,1H),7.64(s,1H),5.07–

5.00(m,1H),3.84(t,J＝5.7Hz,2H),3.18(t,J＝9.2Hz,1H),3.11–3.05(m,1H),2.98(t,J＝8.3Hz,1H),2.94–2.89(m,1H),2.83(t,J＝6.0Hz,2H),2.50(s,3H),2.48(s,3H),2.42–2.35(m,2H),2.23(dd,J＝11.5,5.8Hz,2H).

Example 20

(S) -2- ((7-methyl- [1,2,4] triazolo [1,5-a ] pyridin-6-yl) amino) -4- (1-methyltetrahydrophyrrol-3-yl) -8, 9-dihydro-7H-pyrido [1,2,3-gh ] purin-5 (4H) -one (I-20)

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Preparation method referring to example 1, starting with 3-aminopyridine-2-carboxylic acid, a yellow solid was obtained in 15mg, 11% yield, MS m/z 406.5[ M ⁺H]⁺ ].

¹H NMR(400MHz,MeOD)δ9.36(s,1H),8.32(s,1H),7.65(s,1H),5.02(dd,J＝15.7,7.7Hz,1H),3.85(t,J＝5.7Hz,2H),3.15(t,J＝9.1Hz,1H),3.06–3.00(m,1H),2.95–2.87(m,2H),2.83(d,J＝6.1Hz,2H),2.50(s,3H),2.44(s,3H),2.41–

2.34(m,2H),2.27–2.21(m,2H).

Example 21

(S) -2- ((7-methyl- [1,2,4] triazolo [1,5-a ] pyridin-6-yl) amino) -4- (1-hydroxyethyl tetrahydropyran-3-yl) -8, 9-dihydro-7H-pyrido [1,2,3-gh ] purin-5 (4H) -one (I-21)

Preparation method referring to example 1, starting with 3-aminopyridine-2-carboxylic acid, 21mg of a yellow solid was obtained in 27% yield at MS m/z 436.5[ M ⁺H]⁺ ].

¹H NMR(400MHz,MeOD)δ9.38(s,1H),8.29(s,1H),7.62(s,1H),5.06(s,1H),3.83(t,J＝5.6Hz,2H),3.70(t,J＝5.6Hz,2H),3.27–3.24(m,1H),3.19(s,1H),3.03(d,J＝5.8Hz,1H),2.92(s,1H),2.82(t,J＝5.9Hz,3H),2.49(s,3H),2.43–2.32(m,2H),2.22(dd,J＝11.6,5.9Hz,2H).

Example 22

2- ((7-Methyl- [1,2,4] triazolo [1,5-a ] pyridin-6-yl) amino) -4- (1-methoxyethyltetrahydropyran-3-yl) -8, 9-dihydro-7H-pyrido [1,2,3-gh ] purin-5 (4H) -one (I-22)

Preparation method referring to example 1, starting with 3-aminopyridine-2-carboxylic acid, a yellow solid was obtained in 20mg, 17% yield, MS m/z 450.5[ M ⁺H]⁺ ].

¹H NMR(400MHz,MeOD)δ9.29(s,1H),8.29(s,1H),7.61(s,1H),5.04–

4.97(m,1H),4.62(s,1H),3.82(t,J＝5.7Hz,2H),3.49(t,J＝5.3Hz,2H),3.29(s,3H),3.11(s,1H),3.02(s,2H),2.88(s,1H),2.79(dd,J＝12.4,6.5Hz,3H),2.46(s,3H),2.38–2.30(m,2H),2.21(dd,J＝11.6,5.8Hz,2H).

Example 23

2- ((7-Methyl- [1,2,4] triazolo [1,5-a ] pyridin-6-yl) amino) -4- (1- (epoxypropane-3-yl) tetrahydropyrrolidin-3-yl) -8, 9-dihydro-7H-pyrido [1,2,3-gh ] purin-5 (4H) -one (I-23)

Preparation method referring to example 1, starting with 3-aminopyridine-2-carboxylic acid, a yellow solid was obtained in 20mg, yield 14%, MS m/z 448.5[ M ⁺H]⁺ ].

¹H NMR(400MHz,MeOD)δ9.31(s,1H),8.34(s,1H),7.64(s,1H),5.03–

4.95(m,1H),4.65(t,J＝6.7Hz,2H),4.56(dd,J＝12.6,6.4Hz,2H),3.84(t,J＝5.7Hz,2H),3.72–3.66(m,1H),3.14(t,J＝8.8Hz,1H),2.88–2.80(m,4H),2.75–

2.68(m,1H),2.49(s,3H),2.36(dd,J＝15.7,7.7Hz,2H),2.26–2.21(m,2H).

Example 24

2- (2-Methylphenylamino) -4-cyclohexyl-8, 9-dihydro-7H-pyrido [1,2,3-gh ] purin-5 (4H) -one (I-24)

Preparation method referring to example 1, starting with 3-aminopyridine-2-carboxylic acid, 16mg of yellow solid was obtained in 13% yield, MS m/z 364.5[ M ⁺H]⁺ ].

¹H NMR(400MHz,Chloroform-d)δ8.25–8.19(m,1H),7.25–7.16(m,2H),6.96(td,J＝7.4,1.2Hz,1H),6.84(s,1H),4.21(tt,J＝12.1,3.9Hz,1H),3.87–3.80(m,2H),2.79(t,J＝6.1Hz,2H),2.34(s,4H),2.28(dd,J＝12.6,3.6Hz,1H),2.20(p,J＝6.0Hz,2H),1.86(tt,J＝12.6,2.9Hz,4H),1.77–1.69(m,1H),1.44–1.37(m,2H),1.27(d,J＝11.6Hz,3H).

Example 25

2- (4-Chlorophenylamino) -4-cyclohexyl-8, 9-dihydro-7H-pyrido [1,2,3-gh ] purin-5 (4H) -one (I-25)

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Preparation method referring to example 1, starting with 3-aminopyridine-2-carboxylic acid, a yellow solid was obtained in 20mg, 15% yield, MS m/z 384.9[ M ⁺H]⁺ ].

¹H NMR(400MHz,Chloroform-d)δ7.61(d,J＝2.1Hz,1H),7.59(d,J＝2.1Hz,1H),7.27(d,J＝2.2Hz,1H),7.25(d,J＝2.1Hz,1H),7.17(s,1H),4.22(tt,J＝12.2,3.9Hz,1H),3.88–3.81(m,2H),2.80(t,J＝6.1Hz,2H),2.31(qd,J＝12.6,12.1,3.0Hz,2H),2.21(p,J＝6.0Hz,2H),1.95–1.82(m,4H),1.80–1.73(m,1H),1.50–1.36(m,2H),1.36–1.21(m,3H).

Example 26

2-Phenylamino-4-cyclohexyl-8, 9-dihydro-7H-pyrido [1,2,3-gh ] purin-5 (4H) -one (I-26)

Preparation method referring to example 1, starting with 3-aminopyridine-2-carboxylic acid, 17mg of a white solid was obtained in a yield of 14%, MS m/z 350.4[ M ⁺H]⁺ ].

¹H NMR(400MHz,Chloroform-d)δ7.69–7.62(m,2H),7.35–7.28(m,2H),7.17(s,1H),7.03–6.96(m,1H),4.23(tt,J＝12.1,3.9Hz,1H),3.84(t,J＝5.8Hz,2H),2.80(t,J＝6.1Hz,2H),2.40–2.29(m,2H),2.20(p,J＝6.0Hz,2H),1.88(tt,J＝13.0,3.4Hz,4H),1.80–1.72(m,1H),1.51–1.21(m,5H).

Example 27

2- (4-Methoxyphenylamino) -4-cyclohexyl-8, 9-dihydro-7H-pyrido [1,2,3-gh ] purin-5 (4H) -one (I-27)

Preparation method referring to example 1, starting with 3-aminopyridine-2-carboxylic acid, 9mg of a white solid was obtained in a yield of 7% and MS m/z 380.5[ M ⁺H]⁺ ].

¹H NMR(400MHz,Chloroform-d)δ7.54(d,J＝2.3Hz,1H),7.53(d,J＝2.2Hz,1H),7.04(s,1H),6.88(d,J＝2.3Hz,1H),6.87(d,J＝2.2Hz,1H),4.21(tt,J＝12.2,3.9Hz,1H),3.86–3.80(m,5H),2.78(t,J＝6.1Hz,2H),2.39–2.25(m,2H),2.19(p,J＝6.0Hz,2H),1.86(ddd,J＝18.8,14.7,3.9Hz,4H),1.75(d,J＝12.7Hz,1H),1.48–1.35(m,2H),1.34–1.21(m,3H).

Example 28

2- (2-Methyl-4-methoxyphenylamino) -4-cyclohexyl-8, 9-dihydro-7H-pyrido [1,2,3-gh ] purin-5 (4H) -one (I-28)

Preparation method referring to example 1, starting with 3-aminopyridine-2-carboxylic acid, 24mg of yellow solid was obtained in 18% yield, MS m/z 394.5[ M ⁺H]⁺ ].

¹H NMR(400MHz,Chloroform-d)δ7.86–7.80(m,1H),6.78–6.74(m,2H),6.60(s,1H),4.17(tt,J＝12.1,3.9Hz,1H),3.83–3.78(m,5H),2.75(t,J＝6.1Hz,2H),2.29(s,3H),2.25(d,J＝3.6Hz,1H),2.17(p,J＝6.0Hz,2H),1.90–1.76(m,4H),1.75–1.67(m,1H),1.46–1.16(m,4H).

Example 29

2- (2-Methyl-5-methoxyphenylamino) -4-cyclohexyl-8, 9-dihydro-7H-pyrido [1,2,3-gh ] purine (I-29)

Preparation method referring to example 1, starting with 3-aminopyridine-2-carboxylic acid, 66mg of yellow solid was obtained in 49% yield, MS m/z 394.5[ M ⁺H]⁺ ].

¹H NMR(400MHz,Chloroform-d)δ8.00(d,J＝2.6Hz,1H),7.05(dd,J＝8.3,0.8Hz,1H),6.83(s,1H),6.50(dd,J＝8.2,2.6Hz,1H),4.22(tt,J＝12.2,3.8Hz,1H),3.85–3.79(m,5H),2.79(t,J＝6.1Hz,2H),2.39–2.28(m,2H),2.27(s,3H),2.20(p,J＝6.0Hz,2H),1.92–1.79(m,4H),1.74–1.67(m,1H),1.47–1.29(m,3H).

Example 30

2- ((7-Methyl- [1,2,4] triazolo [1,5-a ] pyridin-6-yl) amino) -8- (tetrahydro-2H-pyran-4-yl) -4, 5-dihydropyrrolo [1,2,3-gh ] purin-7 (8H) -one (I-30)

Preparation method referring to example 1, starting with 3-aminopyridine-2-carboxylic acid, a yellow solid was obtained at 15mg in 24% yield in MS m/z 393.5[ M ⁺H]⁺ ].

¹H NMR(400MHz,CDCl₃)δ9.76(s,1H),8.31(s,1H),7.65(s,1H),6.96(s,1H),5.21(ddd,J＝16.4,8.0,4.2Hz,1H),4.16(dd,J＝11.7,4.4Hz,2H),4.14–4.12(m,2H),3.60(t,J＝11.3Hz,2H),2.86(t,J＝6.1Hz,2H),2.57(s,3H),2.36(dd,J＝11.7,6.0Hz,2H),1.84(d,J＝9.8Hz,2H).

Example 31: biological Activity

1. Determination of DNA-PK inhibitory Activity of Compounds of interest

The inhibitory activity of the synthesized compounds against DNA-PK was determined by Fluorescence Resonance Energy Transfer (FRET) method (specific embodiment reference ：Lebakken CS,Kang HC,Vogel KW,A fluorescence lifetime-based binding assay to characterize kinase inhibitors.J Biomol Screen.2007.12(6):828–841.), and compared with positive control, the compounds with better activity were screened out DNA-PK was obtained by direct purchase of the kit.

2. Determination of MV-4-11 cytostatic Activity of target Compounds

A. Cell resuscitating, culturing the cells to logarithmic growth phase; b. preparing a compound: the test sample is dissolved in DMSO at a concentration of 30uM, and diluted in a gradient ratio of 1:3 for 10 gradients; c. cells with the density of 4-6 x 10 ⁴/ml are inoculated into 384-well plates, 25 mu L of each well is inoculated, and a compound is added, wherein the final concentration of the compound is 30, 10,3.33,1.11,0.37,0.123,0.041,0.014,0.005 and 0.002uM; d. the compounds were incubated with the cells for 72h and cell activity was detected by CTG method.

The following table shows the results of in vitro DNA-PK inhibition activity and in vitro cancer cell activity assays for some of the compounds:

From the above table, it can be seen that: the compound and the pharmaceutically acceptable salt thereof have the inhibition effect of DNA-dependent protein kinase (DNA-PK), and can provide basis for preparing medicines for treating/preventing diseases related to the mediation of DNA-PK.

Pharmacological test results show that the ternary fused ring compound has better DNA-PK inhibition effect and MV-4-11 cell inhibition activity, and partial compound IC ₅₀ value is equivalent to or better than that of AZD7648, and can be used for preventing or treating clinical diseases related to DNA-PK mediation.

The above-mentioned compounds and pharmaceutically acceptable salts thereof of the present invention have DNA-PK inhibitory action and are useful as active ingredients in pharmaceuticals. Therefore, the medicine containing the compound as an active ingredient can be used for preparing medicines for treating clinical symptoms related to DNA-PK mediation, such as: the application of the composition in preparing medicines for preventing and/or treating diseases related to abnormal cell proliferation, morphological change, hyperkinesia and the like related to DNA-PK mediation and diseases related to angiogenesis or cancer metastasis in organisms.

Finally, it should be noted that the above description is only for illustrating the technical solution of the present invention, and not for limiting the scope of the present invention, and that the simple modification and equivalent substitution of the technical solution of the present invention can be made by those skilled in the art without departing from the spirit and scope of the technical solution of the present invention.

Claims

1. A compound of formula I or a pharmaceutically acceptable salt, prodrug, crystal form, stereoisomer, tautomer, hydrate, or solvate thereof:

in the formula I, the compound (I),

y is selected from O or S;

n=1, 2 or 3;

R ¹ is selected from hydrogen, halogen, hydroxy, alkoxy, alkyl, aryl, or Het;

R ² is selected from hydrogen, hydroxy, alkoxy, alkyl, aryl, het, Wherein n=1, 2,3 or 4, m=0, 1,2 or 3, r ⁵、R⁶ each independently represents hydrogen, deuterium, halogen, alkyl, aryl or Het;

And Het is a heterocyclic group.

2. The compound of claim 1, or a pharmaceutically acceptable salt, prodrug, crystal form, stereoisomer, tautomer, hydrate, or solvate thereof, wherein:

The alkyl is a straight-chain or branched-chain saturated hydrocarbon group with 1 to 6 carbon atoms, a cyclic saturated hydrocarbon group with 3 to 6 carbon atoms or a cyclic saturated hydrocarbon group with 3 to 6 carbon atoms, which is connected with a straight-chain or branched-chain saturated hydrocarbon group with 1 to 6 carbon atoms;

the aryl is aromatic hydrocarbon monocyclic group or polycyclic aromatic hydrocarbon with 6-10 ring atoms;

The Het is a saturated or partially unsaturated cyclic group of 3 to 8 ring atoms, or a group in which a heterocyclic group is fused to an aromatic or heteroaromatic ring, wherein at least one ring atom is a heteroatom selected from N, O and S, the remaining ring atoms being C;

The alkoxy is selected from straight-chain or branched-chain saturated alkoxy with 1-6 carbon atoms, cyclic saturated alkoxy with 3-6 carbon atoms or cyclic saturated alkoxy with 3-6 carbon atoms connected with straight-chain or branched-chain saturated alkyl with 1-6 carbon atoms; the alkylthio group is a linear or branched saturated alkylthio group of 1-6 carbon atoms, a cyclic saturated alkylthio group of 3-6 carbon atoms or a cyclic saturated alkylthio group of 3-6 carbon atoms with a linear or branched saturated hydrocarbon group of 1-6 carbon atoms attached.

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

3. A compound according to claim 1 or 2, or a pharmaceutically acceptable salt, prodrug, crystal form, stereoisomer, tautomer, hydrate, or solvate thereof, characterized in that:

y is selected from O or S;

n=1 or 2;

r ¹ is selected from hydrogen, alkoxy, alkyl, aryl, or Het;

R ² is selected from hydrogen, hydroxy, alkoxy, alkyl, Wherein n=1, 2,3 or 4, m=0, 1,2 or 3, r ⁵、R⁶ each independently represents hydrogen, deuterium, halogen, alkyl, aryl or Het;

And Het is a heterocyclic group.

4. A compound according to claim 1 or 2, or a pharmaceutically acceptable salt, prodrug, crystal form, stereoisomer, tautomer, hydrate, or solvate thereof, characterized in that:

y is selected from O or S;

n=1 or 2;

R ¹ is selected from alkyl, aryl or Het;

And Het is a heterocyclic group.

5. A compound according to claim 1 or 2, or a pharmaceutically acceptable salt, prodrug, crystal form, stereoisomer, tautomer, hydrate, or solvate thereof, characterized in that:

Y is selected from O;

n＝2；

R ¹ is selected from aryl or Het;

R ² is selected from

And Het is a heterocyclic group.

6. The compound of claim 1, or a pharmaceutically acceptable salt, prodrug, crystal form, stereoisomer, tautomer, hydrate, or solvate thereof, wherein: the compound of formula I is one of the following compounds:

7. The compound of any one of claims 1-6, or a pharmaceutically acceptable salt, prodrug, crystal form, stereoisomer, tautomer, hydrate, or solvate thereof, wherein: the pharmaceutically acceptable salts include acid addition salts of the compounds with: hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid, citric acid, tartaric acid, lactic acid, pyruvic acid, acetic acid, maleic acid or succinic acid, fumaric acid, salicylic acid, phenylacetic acid, mandelic acid; also included are the acid salts of the compounds of formula I with inorganic bases.

8. The compound of claim 7, or a pharmaceutically acceptable salt, prodrug, crystal form, stereoisomer, tautomer, hydrate, or solvate thereof, wherein: the pharmaceutically acceptable salts include basic metal cation salts, alkaline earth metal cation salts, and ammonium cation salts.

9. A pharmaceutical composition characterized by: a compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt, prodrug, crystal form, stereoisomer, tautomer, hydrate, or solvate thereof, and a pharmaceutically acceptable carrier or excipient.

10. Use of a compound according to any one of claims 1-6, or a pharmaceutically acceptable salt, prodrug, crystal form, stereoisomer, tautomer, hydrate, or solvate thereof, for the manufacture of a medicament for the prevention and/or treatment of a disease associated with DNA-dependent protein kinase (DNA-PK) mediation; preferably, the disease mediated by DNA-dependent protein kinase (DNA-PK) is selected from hyperlipidemia or cancer; the cancers include lung cancer, squamous cell carcinoma, bladder cancer, gastric cancer, ovarian cancer, peritoneal cancer, breast cancer, ductal carcinoma of the breast, head and neck cancer, endometrial cancer, uterine cancer, rectal cancer, liver cancer, renal pelvis cancer, esophageal adenocarcinoma, glioma, prostate cancer, thyroid cancer, cancer of the female reproductive system, carcinoma in situ, lymphoma, neurofibromatosis, bone cancer, skin cancer, brain cancer, colon cancer, testicular cancer, gastrointestinal stromal tumor, oral cancer, pharyngeal cancer, multiple myeloma, leukemia, non-hodgkin's lymphoma, large intestine villous adenoma, melanoma, cytoma and sarcoma, and myelodysplastic syndrome.