CN114195805A

CN114195805A - DNA-PK selective inhibitor and preparation method and application thereof

Info

Publication number: CN114195805A
Application number: CN202010998179.XA
Authority: CN
Inventors: 陈曦; 侯登; 陈坤成; 雷永珂; 任仁; 闵汪洋; 刘志华; 刘希杰; 张凯; 孙永亮; 路畅; 张苗; 孙颖慧
Original assignee: Capital Pharmaceutical Holdings Beijing Co ltd
Current assignee: Capital Pharmaceutical Holdings Beijing Co ltd
Priority date: 2020-09-18
Filing date: 2020-09-18
Publication date: 2022-03-18

Abstract

The application relates to a DNA-PK selective inhibitor shown as a formula (I) and a preparation method and application thereof. The application comprises the application of the compound shown in the formula (I) in the preparation of medicaments for treating diseases related to DNA-PKA series of reactions, such as cyclization and alkylation, to give the compounds of the invention.

Description

DNA-PK selective inhibitor and preparation method and application thereof

Technical Field

The present invention relates to compounds that selectively inhibit the activity of DNA-PK proteins, to methods of making these compounds and salts thereof, and to methods of using such compounds and salts for the treatment of DNA-PK mediated diseases, including cancer.

Background

DNA-PK is a trimer consisting of a catalytic subunit DNA-PKcs (size 470kD) and 2 heterodimers composed of regulatory subunits Ku70 and Ku80, which polymerize upon contact with fragmented DNA. Wherein the DNA-PKcs is one of phosphatidylinositol-3 kinase family members, and participates in various biochemical reaction processes: repair of double-stranded DNA breaks (DSBs), signaling of programmed death, gene surveillance, maintenance of telomere structure, etc. (FASEB J, 2005, 19 (7): 704-715.). Radiation and a great deal of anticancer drugs can directly or indirectly act on DNA or DNA metabolic processes, so that DNA damage is caused, and a series of cellular reactions such as damaged DNA repair and the like are initiated, and the repair results in the improvement of cell survival, which is also one of the mechanisms of tumor cells for resisting radiotherapy and chemotherapy. Cell Res, 2008, 18 (1): 114-:

1) v (D) J chain rearrangements of immunoglobulin and T cell receptors, such as deletion of DNA-PKcs or Ku protein, Severe Combined Immunodeficiency (SCID) occurs in mammalian cells

2) The telomere structure is maintained to be stable, and the lack of Ku or DNA-PKcs can cause unstable genome, cell growth retardation and premature senility;

3) DNA-PKcs is a serine/threonine kinase, a member of PI-3-K (phosphine tip in to 1-3-kinase) kinase family (including A TM, A TR, etc.), and plays a role in the functions of cell signal transduction and cell cycle after DNA damage. (Int J radial Oncol Biol Phys, 2005, 61 (3): 915-.

A range of factors can induce DNA double strand breaks, including chemotherapy, radiation therapy, and PARP inhibitors such as olaparib. DNA-PK inhibitors have the potential to sensitize these therapies. A plurality of DNA-PK selective inhibitors enter a clinical stage at present all over the world, wherein two medicaments enter a clinical second stage, but no related medicament is on the market so far, and the requirements of the related medicament are not met. The DNA-PK selective inhibitor provided by the invention has high activity, strong drug resistance and small clinical side effect, can effectively enhance the sensitivity of radiotherapy and chemotherapy in tumor treatment, and has better economic value and application prospect.

Disclosure of Invention

The invention provides a DNA-PK selective inhibitor which is a compound shown as a general formula (I) or pharmaceutically acceptable salt, solvate, polymorph or isomer thereof, and also provides a series of compounds shown as the general formula (I) and pharmaceutically acceptable salt, solvate, polymorph or isomer thereof, a pharmaceutical composition containing the compounds, and a method for treating diseases by using the compounds.

In one aspect, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt, solvate, polymorph or isomer thereof

Wherein the content of the first and second substances,

ring A is 6-10 membered aryl or 5-12 membered heteroaryl,

ring B is a 4-12 membered heterocyclic ring, S on ring B may be optionally oxidized,

z is O or S, and the compound is,

X₂is CR₂Or the number of N is greater than the number of N,

X₁is CRR₄O, S, or NR₆，

R₁Is H, C_1-6Alkyl, or C_3-8Cycloalkyl, said alkyl and cycloalkyl being optionally substituted by halogen, -CN, -OH, -NH₂、-O-C_1-6Alkyl, or-NR-C_1-6Alkyl substitution;

R₇and R₈Each independently selected from halogen, CN, C_1-6Alkyl, -O-C_1-6Alkyl and-NR-C_1-6Alkyl, which may optionally be substituted by halogen, -CN, -OH, -NH₂、-O-C_1-6Alkyl, or-NR-C_1-6The substitution of the alkyl group is carried out,

m and n are each independently 0, 1, 2, or 3,

R₃is R₅or-X₃-R₅，

R₄Is R₆or-X₃-R₆，

X₃Each independently is-O-, -S-, or-NR-,

R₅and R₆Each independently selected from H and C_1-6Alkyl, or R₅And R₆Taken together to form- (CH)₂)_p-X-(CH₂)_q-, wherein X is a bond, -O-, -S, -N (R) -, -CO-, -C (O) NR-, -C (O) O-, 6-10 membered arylene, 5-12 membered heteroarylene, or 3-12 membered heterocycle, and- (CH)₂)_p-X-(CH₂)_qCH in (E)₂Optionally substituted by a halogen, and optionally substituted by a halogen,

p and q are each independently 0, 1, 2, 3, or 4, and p + q is 1, 2, 3, 4, 5, or 6,

R₂selected from H, halogen, CHF₂、CF₃、-OH、-NH₂、CN、C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, -O-C_1-6Alkyl, - (CH)₂)_1-6-CN、-(CH₂)_1-6-O-C_1-6Alkyl, - (CH)₂)_1-3-OH、-CHO、-(CO)NH₂- (CO) NHR, - (CO) OR and-NR-C_1-6An alkyl group.

Each R is independently H or C_1-6An alkyl group;

in certain embodiments, R₅And R₆Each independently selected from H and C_1-6Alkyl, or R₅And R₆Taken together to form- (CH)₂)_p-X-(CH₂)_q-, wherein X is a bond, -O-, -S, -N (R) -, -CO-, -C (O) NR-, -C (O) O-, a 6-to 10-membered arylene, a 5-to 12-membered heteroarylene, or a 3-to 12-membered heterocycle;

in certain embodiments, when R₅And R₆Each independently selected from H or C_1-6When alkyl, R₂Selected from halogen, CH₂F、CHF₂、CF₃、-OH、-NH₂、CN、C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, -O-C_1-6Alkyl, - (CH)₂)_1-6-CN、-(CH₂)_1-6-O-C_1-6Alkyl, or-NR-C_1-6An alkyl group, a carboxyl group,

when R is₅And R₆Taken together to form- (CH)₂)_p-X-(CH₂)_qWhen is，R₂Selected from H, halogen, CHF₂、CF₃、-OH、-NH₂、CN、C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, -O-C_1-6Alkyl, - (CH)₂)_1-6-CN、-(CH₂)_1-6-O-C_1-6Alkyl and-NR-C_1-6An alkyl group, a carboxyl group,

r is H or C_1-6An alkyl group;

in certain embodiments, R₂Selected from H, halogen, CHF₂、CF₃、-OH、-NH₂、CN、C_1-6Alkyl, -O-C_1-6Alkyl, - (CH)₂)_1-3-CN、-(CH₂)_1-3-O-C_1-6Alkyl, - (CH)₂)_1-3-OH、-CHO、-(CO)NH₂- (CO) OR and-NR-C_1-6Alkyl, R is H or C_1-6An alkyl group; preferably, R₂Selected from H, halogen, CHF₂、CF₃、CN、C_1-6Alkyl and- (CO) NH₂(ii) a More preferably, R₂Selected from halogen, CHF₂、CF₃、CN、C_1-6Alkyl and- (CO) NH₂；

In certain embodiments, when

Is composed of

Or

When R is₂Selected from halogen, CH₂F、CHF₂、CF₃、-OH、-NH₂、CN、C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, -O-C_1-6Alkyl, - (CH)₂)_1-6-CN、-(CH₂)_1-6-O-C_1-6Alkyl and-NR-C_1-6An alkyl group, a carboxyl group,

r is H or C_1-6An alkyl group;

in certain embodiments, R₁Is C_1-6Alkyl or C_3-8Cycloalkyl, said alkyl and cycloalkyl being optionally substituted by halogen, -CN, -OH, -NH₂、-O-C_1-6Alkyl, or-NR-C_1-6Alkyl substituted, R is H or C_1-6Alkyl, preferably said alkyl and cycloalkyl groups may be optionally substituted by halogen or-CN;

in certain embodiments, R₁Is C_1-6An alkyl group;

in some embodiments of the invention, the compounds of the invention are selected from:

or a pharmaceutically acceptable salt, solvate, polymorph or isomer thereof.

It is noted that the compounds and salts described in this specification can exist in solvated as well as unsolvated forms; the atoms of these compounds and salts described in this specification may exist as their isotopes; furthermore, the compounds and salts described in this specification may exist in optically active or racemic forms via one or more asymmetric carbon atoms.

In another aspect, the present invention provides a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt, solvate, polymorph, or tautomer thereof. In some embodiments, the pharmaceutical compositions of the present invention further comprise a pharmaceutically acceptable excipient.

In another aspect, the present invention provides a method of treating a DNA-PK related disease, said method comprising administering to a subject an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, solvate, polymorph or isomer thereof, or a pharmaceutical composition thereof;

in another aspect, the present invention provides the use of a compound of the present invention, or a pharmaceutically acceptable salt, solvate, polymorph or tautomer thereof, or a pharmaceutical composition thereof, for the manufacture of a medicament for the treatment of a DNA-PK related disease.

In some embodiments of the invention, the DNA-PK related disease is cancer; preferably, the cancer is colorectal cancer, glioblastoma, gastric cancer, ovarian cancer, diffuse large B-cell lymphoma, chronic lymphocytic leukemia, acute myelogenous leukemia, head and neck squamous cell carcinoma, breast cancer, prostate cancer, bladder cancer, hepatocellular carcinoma, small cell lung cancer, or non-small cell lung cancer.

Detailed Description

Exemplary embodiments utilizing the principles of the present invention are set forth in the following detailed description of the invention. The features and advantages of the present invention may be better understood by reference to the following summary.

It should be understood that the scope of the various aspects of the invention is defined by the claims and that methods and structures within the scope of these claims and their equivalents are intended to be covered thereby.

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the claimed subject matter belongs. All patents, patent applications, and publications cited herein are incorporated by reference in their entirety unless otherwise indicated.

It is to be understood that both the foregoing general description and the following detailed description are exemplary, explanatory and are not restrictive of any inventive subject matter. Unless otherwise indicated, the use of "or", "or" means "and/or" and, in addition, the use of the term "including" as well as other forms, such as "includes", "including", and "including", is not limiting.

Certain chemical terms

The terms "optionally," "optionally," or "optionally" mean that the subsequently described event or circumstance may or may not occur, and that the description includes instances where said event or circumstance occurs and instances where it does not. And, optionally substituted groups may be unsubstituted (e.g.: CH)₂CH₃) Fully substituted (e.g.: -CF₂CF₃) Monosubstituted (e.g.: -CH₂CH₂F) Or any level between mono-and fully substituted (e.g.: -CH₂CHF₂、-CF₂CH₃、-CFHCHF₂Etc.). It will be appreciated by those skilled in the art that any group containing one or more substituents will not incorporate any substitution or substitution pattern which is sterically impossible and/or cannot be synthesized.

Unless otherwise indicated, conventional methods within the skill of the art are employed, such as mass spectrometry, nuclear magnetism, high performance liquid chromatography, infrared and ultraviolet/visible spectroscopy, and pharmacological methods unless a specific definition is set forth, the nomenclature and experimental procedures and techniques described herein relating to analytical chemistry, organic synthetic chemistry, and pharmaceutical and medicinal chemistry are known in the art. For example, the reaction and purification can be carried out using the instructions of the kit from the manufacturer, or according to the methods known in the art or the instructions of the present invention. In this specification, groups and substituents thereof may be selected by one of ordinary skill in the art to provide stable moieties and compounds.

When a substituent is described by a general formula written from left to right, the substituent also includes chemically equivalent substituents obtained when the formula is written from right to left. For example, -CH₂O-is equivalent to-OCH₂-.

As used herein, the terms "group", "chemical group" or "chemical group" refer to a particular portion or functional group of a molecule. Chemical groups are often considered as chemical entities embedded in or attached to a molecule.

Some of the chemical groups named herein may be referred to by a shorthand notation for the total number of carbon atoms. E.g. C_1-6Alkyl describes an alkyl group, as defined below, having a total of 1 to 6 carbon atoms. The total number of carbon atoms indicated by shorthand notation does not include carbon atoms on possible substituents.

The terms "halogen", "halo" or "halide" refer to bromine, chlorine, fluorine or iodine.

The compounds of the invention may contain one or more (e.g. one, two, three or four) isotopic substitutions. For example, in the compounds, H may be in any isotopic form, including¹H、²H (D or deuterium) and³h (T or tritium); c may be in any isotopic form, including¹²C、¹³C and¹⁴c; o may be in any isotopic form, including¹⁶O and¹⁸o, and the like.

As used herein, the terms "aromatic", "aromatic ring", "aromatic" and "aromatic-cyclic" refer to a planar ring portion of one or more rings having a delocalized electron-conjugated system of 4n +2 electrons, where n is an integer. The aromatic compound may be optionally substituted and may be monocyclic or fused-ring polycyclic. The term aromatic compound includes all carbocyclic rings (e.g., benzene rings) and rings containing one or more heteroatoms (e.g., pyridine).

The terms "heteroatom" or "hetero", as used herein alone or as part of another ingredient, refer to atoms other than carbon and hydrogen, heteroatoms are independently selected from, but not limited to, oxygen, nitrogen, sulfur, phosphorus, silicon, selenium, and tin.

The terms "fused" or "fused ring" as used herein, alone or in combination, refer to a cyclic structure in which two or more rings share one or more bonds.

The term "spiro" or "spirocyclic" as used herein, alone or in combination, refers to a cyclic structure in which two or more rings share one or more atoms.

The term "alkyl" as used herein, alone or in combination, refers to an optionally substituted straight or optionally substituted branched chain monovalent saturated hydrocarbon having 1 to 12 carbon atoms, preferably 1 to 8 carbon atoms, more preferably 1 to 6 carbon atoms, attached to the rest of the molecule by a single bond, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, n-heptyl, 2-methylhexyl, 3 methylhexyl, n-octyl, n-nonyl, n-decyl, and the like.

The term "alkenyl" as used herein, alone or in combination, refers to an optionally substituted straight or optionally substituted branched chain monovalent hydrocarbon radical having one or more C ═ C double bonds and having from 2 to about 10 carbon atoms, more preferably from 2 to about 6 carbon atoms₂) 1-propenyl (CH)₂CH＝CH₂) Isopropenyl (C (CH)₃)＝CH₂) Butenyl, 1, 3-butadienyl and the like. When a numerical range is present for alkenyl as defined herein, e.g. "C₂-C₆Alkenyl "or" C_2-6The "alkenyl group" means an alkenyl group which may be composed of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, and the alkenyl group herein also covers the case where no numerical range is specified.

The term "alkynyl", as used herein, alone or in combination, refers to an optionally substituted straight or branched chain monovalent hydrocarbon radical having one or more C ≡ C triple bonds and having 2 to about 10 carbon atoms, more preferably 2 to about 6 carbon atoms. Examples include, but are not limited to, ethynyl, 2-propynyl, 2-butynyl, 1, 3-butadiynyl, and the like₂-C₆Alkynyl "or" C_2-6Alkynyl "meansAlkynyl groups that can be composed of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms, and alkynyl groups herein also encompass instances where no numerical range is specified.

The term "aryl" refers to an all-carbon monocyclic or fused ring having a fully conjugated pi-electron system, having 6 to 14 carbon atoms, preferably 6 to 12 carbon atoms, most preferably 6 carbon atoms. Aryl groups may be unsubstituted or substituted with one or more substituents, examples of which include, but are not limited to, alkyl, alkyloxy, aryl, aralkyl, amino, halo, hydroxy, sulfonyl, sulfinyl, phosphoryl, and heteroalicyclic. Non-limiting examples of unsubstituted aryl groups include, but are not limited to, phenyl, naphthyl, and anthracenyl.

The term "arylene" as used herein, alone or in combination, refers to a divalent group derived from a monovalent aryl group as defined above.

The term "heteroaryl" refers to a monocyclic or fused ring of 5 to 12 ring atoms, having 5, 6, 7, 8, 9, 10, 11 or 12 ring atoms, containing 1, 2, 3 or 4 ring atoms selected from N, O, S, the remaining ring atoms being C, and having a fully conjugated pi-electron system. Heteroaryl groups may be unsubstituted or substituted, and the substituents include, but are not limited to, alkyl, alkyloxy, aryl, aralkyl, amino, halo, hydroxy, cyano, nitro, carbonyl, and heteroalicyclic. Non-limiting examples of unsubstituted heteroaryl groups include, but are not limited to, pyrrolyl, furanyl, thienyl, imidazolyl, oxazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, quinolinyl, isoquinolinyl, tetrazolyl, triazinyl.

The term "heteroarylene" as used herein, alone or in combination, refers to a divalent radical derived from a monovalent heteroaryl group as defined above.

The term "heterocycle" refers to an aliphatic heterocycle. When the number of carbon atoms of the heterocyclic ring is indicated herein (e.g. C)_3-6Heterocyclic ring), at least one non-carbon atom (heteroatom) necessarily being present in the ring. E.g. "C_3-6The designation "heterocyclic" relates only to the number of carbon atoms in the ring and not to the total number of atoms in the ring. For example, the designation "4-to 6-membered heterocycle" refers to the ringThe total number of atoms contained in (i.e., a four, five or six membered ring in which at least one atom is a carbon atom, at least one atom is a heteroatom, and the remaining 2 to 4 atoms are carbon atoms or heteroatoms.) for a heterocyclic ring having two or more heteroatoms, the two or more heteroatoms may be the same as or different from each other. The heterocyclic ring may be optionally substituted. As used herein, a "heterocycle" preferably contains from about 5 to about 20 or 5 to 10 or 5-8 or 5-6 backbone ring-forming atoms.

The term "polymorph" or "polymorph" as used herein means that the compounds of the present invention have multiple lattice morphologies. Some of the compounds of the present invention may have more than one crystal form, and the present invention encompasses all polymorphic forms or mixtures thereof.

Intermediate compounds of the present invention and polymorphs thereof are also within the scope of the present invention.

Unless otherwise specified, the compounds of the present invention contain olefinic double bonds including E and Z isomers.

It is understood that the compounds of the present invention may contain asymmetric centers which may independently be in the R or S configuration. It will be apparent to those skilled in the art that some of the compounds of the present invention may also exhibit cis-trans isomerism. The present invention also relates to pharmaceutical compositions comprising a compound of the invention and a pharmaceutical composition comprising a compound of the invention, as well as to pharmaceutical compositions comprising a compound of the invention and a pharmaceutically acceptable carrier.

The term "pharmaceutically acceptable salts" as used herein includes both acid and base salts.

"pharmaceutically acceptable acid addition salts" refers to those salts formed with inorganic acids such as, but not limited to, acetic acid, 2-dichloroacetic acid, adipic acid, alginic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid, capric acid, caproic acid, carbonic acid, cinnamic acid, citric acid, and the like, that retain the biological potency and properties of the free acid of the compound, are not biologically or otherwise undesirable. Salts formed by reaction with an inorganic base include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like.

Salt-forming organic bases include, but are not limited to, primary, secondary, tertiary, cyclic amines, and the like, such as ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, ethanolamine, dicyclohexylamine, ethylenediamine, purine, piperazine, piperidine, choline, caffeine, and the like. Particularly preferred organic bases are isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline, and caffeine.

Crystallization often produces solvates of the compounds of the present invention. The term "solvate" as used herein refers to a combination of one or more molecules of the compound of the present invention and one or more molecules of a solvent.

The solvent may be water, in which case the solvate is a hydrate. Thus, the compounds of the present invention may exist as hydrates, including monohydrate, dihydrate, hemihydrate, trihydrate, tetrahydrate and the like, as well as the corresponding solvated forms. The compounds of the present invention may be true solvates, but in other cases, the compounds of the present invention may also retain water only by chance or a mixture of water and some other solvent. The compounds of the invention may be reacted in a solvent or precipitated or crystallized in a solvent. Solvates of the compounds of the invention are also included within the scope of the invention.

The term "pharmaceutical composition" as used herein refers to a formulation mixed with a compound of the present invention and a vehicle generally accepted in the art for delivering biologically active compounds to a mammal, such as a human. Such media comprise all pharmaceutically acceptable carriers.

As used herein, the term "acceptable" in reference to a formulation, composition or ingredient means that there is no lasting deleterious effect on the overall health of the subject being treated.

The term "pharmaceutically acceptable" as used herein refers to a substance (e.g., carrier or diluent) that does not affect the biological activity or properties of the compounds of the present invention and is relatively non-toxic, i.e., the substance can be administered to an individual without causing an adverse biological response or interacting in an adverse manner with any of the components contained in the composition.

"pharmaceutically acceptable carriers" include, but are not limited to, adjuvants, carriers, excipients, adjuvants, deodorants, diluents, preservatives, dyes/colorants, flavor enhancers, surfactants and wetting agents, dispersants, suspending agents, stabilizers, isotonic agents, solvents, or emulsifiers that have been approved by the relevant governmental authorities for use in humans and domestic animals.

The term "subject," "patient," "subject" or "individual" as used herein refers to an individual, including mammals and non-mammals, suffering from a disease, disorder or condition, among others. Humans, non-human primates (e.g., chimpanzees and other apes and monkeys); livestock, such as cattle, horses, sheep, goats, pigs; domestic animals such as rabbits, dogs, and cats; examples of non-human mammals include, but are not limited to, birds and fish, among others. In one embodiment related to the methods and compositions provided herein, the mammal is a human.

The term "treatment" as used herein refers to the treatment of a disease or condition associated with a mammal, particularly a human, and includes

(i) Preventing the development of a disease or condition in a mammal, particularly a mammal that has previously been exposed to the disease or condition but has not been diagnosed as having the disease or condition;

(ii) inhibiting the disease or disorder, i.e., controlling its development;

(iii) alleviating the disease or condition, i.e., causing regression of the disease or condition;

(iv) relieving symptoms caused by the disease or disorder.

The terms "disease" and "condition" as used herein may be used interchangeably and may have different meanings, as certain specific diseases or conditions have no known causative agent (and therefore the cause of the disease is not yet clear) and therefore are not considered as a disease but can be considered as an unwanted condition or syndrome, with more or less specific symptoms being confirmed by clinical researchers.

The term "effective amount," "therapeutically effective amount," or "pharmaceutically effective amount" as used herein refers to an amount of at least one agent or compound that is sufficient to alleviate, to some extent, one or more of the symptoms of the disease or disorder being treated, after administration. For example, an "effective amount" for treatment is the amount of a composition comprising a compound disclosed herein that is required to provide clinically significant relief from a condition.

The terms "administration," "administering," "administration," and the like, as used herein, refer to methods capable of delivering a compound or composition to a desired site for biological action. In preferred embodiments, the compounds and compositions discussed herein are administered orally.

The anti-cancer treatments described herein may be useful as monotherapy or may include conventional surgery, radiotherapy or chemotherapy in addition to the administration of a compound having formula (I); such conventional surgery, radiation therapy or chemotherapy may be administered simultaneously, sequentially or separately with a compound of formula (I) for treatment.

Preparation of the Compounds of the invention

The following reaction scheme illustrates the process for preparing the compounds of the present invention.

It will be appreciated that in the following description, combinations of substituents and/or variables of the formula are permitted only in the context of forming stable compounds.

It will also be appreciated by those skilled in the art that in the schemes described below, the functional groups of the intermediate compounds may need to be protected by suitable protecting groups. Suitable hydroxyl protecting groups include trialkylsilyl or diarylalkylsilyl groups (e.g., tert-butylmethylsilyl, tert-butyldiphenylsilyl, or trimethylsilyl), tetrahydropyranyl, benzyl, and the like. Suitable amino, amidino and guanidine protecting groups include t-butyloxycarbonyl, benzyloxycarbonyl and the like suitable protecting groups for mercapto include-C (O) -R '(R' represents alkyl, aryl or arylalkyl), p-methoxybenzyl, trityl and the like. Suitable carboxyl protecting groups include alkyl, aryl or arylalkyl esters. Protecting groups may be added or removed by standard techniques known to those skilled in the art.

Examples

The following non-limiting examples are illustrative only and do not limit the invention in any way.

Reagents are commercially available from national pharmaceutical group chemical reagents, Beijing, Inc., Afa Aesar, or Beijing Bailingwei technologies Inc., and these reagents can be used directly without further purification unless otherwise indicated.

Unless otherwise stated, the following reactions are carried out at room temperature, in anhydrous solvents, under positive pressure of nitrogen or argon, or using a drying tube; the reaction bottle is provided with a rubber diaphragm so as to add the substrate and the reagent through an injector; glassware was dried and/or heat dried.

Unless otherwise stated, column chromatography purification was performed using 200-300 mesh silica gel from Qingdao oceanic plants; preparation of thin-layer chromatography silica gel precast slab (HSGF254) produced by Nicoti chemical industry research institute was used; MS is measured by a Thermo LCQ fly model (ESI) liquid chromatography-mass spectrometer; the optical rotation was measured by using an SGW-3 automatic polarimeter, Shanghai Spanish Meter, Ltd.

Nuclear magnetic data (¹H NMR) was run at 400MHz using a Varian instrument. The solvent used for nuclear magnetic data is CDCl₃、CD₃OD、D₂O, DMSO-d6, based on tetramethylsilane (0.00ppm) or based on residual solvent (CDCl)₃：7.26ppm；CD₃OD：3.31ppm；D₂O: 4.79 ppm; d 6-DMSO: 2.50 ppm). When indicating the diversity of the peak shapes, the following abbreviations represent the different peak shapes: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), br (broad), dd (doublet of doublets), dt (doublet of triplets). If the coupling constant is given, it is given in Hertz (Hz).

Abbreviations:

intermediate 1: 4- (2-chloro-7-methyl-8-oxo-7, 8-dihydro-9H-purin-9-yl) tetrahydro-2H-pyran-4-carbonitrile

Step 1: 4- ((2-chloro-5-nitropyrimidin-4-yl) amino) tetrahydro-2H-pyran-4-carbonitrile

2, 4-dichloro-5-nitropyrimidine (1.94g) and triethylamine (1.01g) were dissolved in tetrahydrofuran (50mL), and 4-aminotetrahydro-2H-pyran-4-carbonitrile (1.26g) was slowly added under ice bath. The reaction was warmed to room temperature and stirred overnight. The reaction solution was poured into saturated aqueous ammonium chloride (200mL), extracted with ethyl acetate (100mL), the extracts were concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate 3: 1 (V: V)) to give a white solid (1.9 g).

Step 2: 4- ((5-amino-2-chloropyrimidin-4-yl) amino) tetrahydro-2H-pyran-4-carbonitrile

Reduced iron powder (1.5g) was added to a solution of 4- ((2-chloro-5-nitropyrimidin-4-yl) amino) tetrahydro-2H-pyran-4-carbonitrile (1.9g) in acetic acid (30mL) at room temperature, then the reaction was raised to 45 ℃ and stirred for 2 hours, cooled to room temperature, poured into ice water, and extracted with ethyl acetate (100 mL); the extract was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: dichloromethane: methanol ═ 20: 1 (V: V)) to give a white solid (1.3 g).

And step 3: 4- (2-chloro-8-oxo-7, 8-dihydro-9H-purin-9-yl) tetrahydro-2H-pyran-4-carbonitrile

The 4- ((5-amino-2-chloropyrimidin-4-yl) amino) tetrahydro-2H-pyran-4-carbonitrile (1.3g) and CDI (1.3g) in step 2 were dissolved in tetrahydrofuran (50mL), heated to 65 ℃ under nitrogen protection and stirred for 2 hours, cooled to room temperature, the reaction mixture was poured into water (150mL), the reaction mixture was extracted with dichloromethane, the extract was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate ═ 3: 1 (V: V)) to give a pale yellow solid (1g).

And 4, step 4: 4- (2-chloro-7-methyl-8-oxo-7, 8-dihydro-9H-purin-9-yl) tetrahydro-2H-pyran-4-carbonitrile

60% (mineral oil) of sodium hydride (200mg) was slowly added to a DMF (20mL) solution of 4- (2-chloro-8-oxo-7, 8-dihydro-9H-purin-9-yl) tetrahydro-2H-pyran-4-carbonitrile (1g) obtained in step 3 at 0 ℃ and after the addition was completed, stirring was continued at 0 ℃ for 0.5 hour, iodomethane (1.41g) was then slowly added to the reaction solution, and after the reaction was completed, the reaction solution was poured into a saturated aqueous ammonium chloride solution and stirred continuously, a yellow precipitate was generated, and was filtered and dried to obtain a yellow solid (900 mg).

Intermediate 2: 2-chloro-7-methyl-9- (tetrahydro-2H-pyran-4-yl) -7, 9-dihydro-8H-purin-8-one (synthesized according to the method described in patent CN110177791A 1)

Intermediate 4: 7-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-amine (synthesized according to the procedure described in patent CN110177791A 1)

Intermediate 6: 2-chloro-7-methyl-9- (piperidin-4-yl) -7, 9-dihydro-8H-purin-8-one (synthesized according to the method described in patent WO2019/238929A 1)

Example 29: 2- (2- ((7-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) amino) -8-oxo-9- (tetrahydro-2H-pyran-4-yl) -8, 9-dihydro-7H-purin-7-yl) acetonitrile

Step 1: 2- (2-chloro-8-oxo-9- (tetrahydro-2H-pyran-4-yl) -8, 9-dihydro-7H-purin-7-yl) acetonitrile

To a solution of 2-chloro-9- (tetrahydro-2H-pyran-4-yl) -7, 9-dihydro-8H-purin-8-one (254mg) in DMF (10mL) at 0 deg.C was slowly added 60% (mineral oil) sodium hydride (80mg) and stirring continued at 0 deg.C for 0.5H. Then, bromoacetonitrile (150mg) is slowly added into the reaction solution, and after the reaction is finished, the reaction solution is poured into saturated ammonium chloride aqueous solution and extracted by ethyl acetate; the extract was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: dichloromethane: methanol ═ 20: 1 (V: V)) to give the title compound (77 mg).

Step 2: 2- (2- ((7-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) amino) -8-oxo-9- (tetrahydro-2H-pyran-4-yl) -8, 9-dihydro-7H-purin-7-yl) acetonitrile

The above-described 2- (2-chloro-8-oxo-9- (tetrahydro-2H-pyran-4-yl) -8, 9-dihydro-7H-purin-7-yl) acetonitrile (58mg), intermediate 47-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-amine (30mg), RuPhos Pd G3(20mg) and cesium carbonate (160mg) were dissolved in dioxane (10mL) under nitrogen, and the reaction flask was replaced with nitrogen three times and heated to 100 ℃ for 3 hours with stirring. Cooled to room temperature, filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by thin layer chromatography (developing solvent: dichloromethane: methanol ═ 20: 1 (V: V)) to give the objective compound (45 mg).

¹H NMR(400MHz，DMSO-d₆)δ9.05(s，1H)，8.82(s，1H)，8.36(s，1H)，8.20(s，1H)，7.69(s，1H)，5.06(s，2H)，4.34-4.43(m，1H)，3.92(dd，J＝11.6Hz，4.0Hz，2H)，3.37(t，J＝11.6Hz，2H)，2.40-2.50(m，2H)，2.35(s，3H)，1.64-1.72(m，2H)。

Example 30: 7-methyl-2- ((7-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) amino) -9- (1-oxidotrih-2H-thiophen-4-yl) -7, 9-dihydro-8H-purin-8-one

2-chloro-7-methyl-9- (1-oxotetrahydro-2H-thiopyran-4-yl) -7, 9-dihydro-8H-purin-8-one (obtained following the synthesis of intermediate 1 using 4-aminotetrahydro-2H-thiopyran 1-oxide as the starting material) (60mg), intermediate 47-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-amine (30mg), RuPhos Pd G3(9mg) and cesium carbonate (130mg) were dissolved in dioxane (20mL) under nitrogen, heated to 100 ℃ and stirred for 2 hours. Cooled to room temperature, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by thin layer chromatography (developing solvent: dichloromethane: methanol ═ 15: 1 (V: V)) to give the objective compound (43mg).

¹H NMR(400MHz，DMSO-d₆)δ9.03(s，0.5H)，9.01(s，0.5H)，8.65(s，0.5H)，8.60(s，0.5H)，8.35(s，0.5H)，8.33(s，0.5H)，8.05(s，0.5H)，8.03(s，0.5H)，7.68(s，0.5H)，7.65(s，0.5H)，4.32-4.47(m，1H)，3.30-3.36(m，1H)，3.26(s，1.5H)，3.25(s，1.5H)，2.94-3.14(m，2H)，2.76-2.86(m，2H)，2.48-2.60(m，1H)，2.34(s，3H)，1.95-2.04(m，1H)，1.69-1.77(m，1H)。

Example 31: 4- (7-methyl-2- ((7-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) amino) -8-oxo-7, 8-dihydro-9H-purin-9-yl) piperidine-1-carbonitrile

Intermediate 62-chloro-7-methyl-9- (piperidin-4-yl) -7, 9-dihydro-8H-purin-8-one (268mg), cyanogen bromide (110mg) were dissolved in THF (20mL) at room temperature, triethylamine (200mg) was slowly added and stirring continued for 2 hours. The reaction solution was poured into water and extracted with ethyl acetate, and the organic phase was washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by column chromatography on silica gel (eluent: petroleum ether: ethyl acetate 1: 1 (V: V)) to give 4- (2-chloro-7-methyl-8-oxo-7, 8-dihydro-9H-purin-9-yl) piperidine-1-carbonitrile (120 mg). The above 4- (2-chloro-7-methyl-8-oxo-7, 8-dihydro-9H-purin-9-yl) piperidine-1-carbonitrile (59mg), intermediate 47-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-amine (30mg), RuPhos Pd G3(9mg) and cesium carbonate (130mg) were dissolved in dioxane (20mL) under nitrogen, heated to 100 ℃ and stirred for 2 hours. Cooled to room temperature, filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by thin layer chromatography (developing solvent: dichloromethane: methanol ═ 20: 1 (V: V)) to give the objective compound (36mg).

¹H NMR(400MHz，DMSO-d₆)δ9.04(s，1H)，8.67(s，1H)，8.33(s，1H)，8.05(s，1H)，7.67(s，1H)，4.22-4.35(m，1H)，3.42-3.50(m，2H)，3.26(s，3H)，3.10-3.22(m，2H)，2.44-2.56(m，2H)，2.35(s，3H)，1.69-1.79(m，2H)。

Example 32: 2⁷，4²-dimethyl-2⁸，2⁹-dihydro-2⁷H-5-oxa-3-aza-2 (9, 2) -purine-1 (4, 1) -piperidine-4 (1, 4) -phencynonane-2⁸-ketones

This compound was synthesized according to the synthesis method of example 7 using alternative phenols as starting materials.

¹H NMR(400MHz，DMSO-d₆)δ8.46(s，1H)，7.98(s，1H)，6.96(d，J＝8.4Hz，1H)，6.85(s，1H)，6.78(d，J＝7.6Hz，1H)，4.04-4.20(m，2H)，3.77-4.03(m，1H)，3.22(s，3H)，2.52-2.79(m，2H)，2.04-2.30(m，4H)，2.01(s，3H)，1.58-1.78(m，4H)，1.28-1.56(m，4H)。

Example 33: 9- (1, 3-Dimethoxypropan-2-yl) -7-methyl-2- ((7-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) amino) -7, 9-dihydro-8H-purin-8-one

2-chloro-9- (1, 3-dimethoxypropan-2-yl) -7-methyl-7, 9-dihydro-8H-purin-8-one (obtained following the synthesis of intermediate 1) (58mg), intermediate 47-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-amine (30mg), RuPhos Pd G3(9mg) and cesium carbonate (130mg) were dissolved in dioxane (20mL) under nitrogen, heated to 100 ℃ and stirred for 2 hours. Cooled to room temperature, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by thin layer chromatography (developing solvent: dichloromethane: methanol ═ 15: 1 (V: V)) to give the objective compound (43mg).

¹H NMR(400MHz，DMSO-d₆)δ9.08(s，1H)，8.63(s，1H)，8.34(s，1H)，8.08(s，1H)，7.68(s，1H)，4.63-4.70(m，1H)，3.87(t，J＝9.6Hz，2H)，3.56(dd，J＝10.4Hz，5.6Hz，2H)，3.28(s，3H)，3.16(s，6H)，2.35(s，3H)。

Example 34: 7-methyl-2- ((3-methyl-3H-imidazo [4, 5-c ] pyridin-2-yl) amino) -9- (tetrahydro-2H-pyran-4-yl) -7, 9-dihydro-8H-purin-8-one

Under the protection of nitrogen, the intermediate 2: 2-chloro-7-methyl-9- (tetrahydro-2H-pyran-4-yl) -7, 9-dihydro-8H-purin-8-one (54mg), 3-methyl-3H-imidazo [4, 5-c ] pyridin-2-amine (30mg), RuPhos Pd G3(9mg), and cesium carbonate (130mg) were dissolved in dioxane (20mL), heated to 100 ℃ and stirred for 2 hours. Cooled to room temperature, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by thin layer chromatography (developing solvent: dichloromethane: methanol ═ 15: 1 (V: V)) to give the objective compound (13mg).

¹H NMR(400MHz，DMSO-d₆)δ8.50-8.66(m，1H)，8.23(d，J＝4.8Hz，1H)，8.13(s，1H)，7.37(d，J＝4.8Hz，1H)，4.37-4.52(m，1H)，3.89-4.02(m，2H)，3.60(s，3H)，3.37-3.52(m，5H)，2.47-2.59(m，2H)，1.57-1.70(m，2H)。

Example 35: 7-cyclopropyl-2- ((7-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) amino) -9- (tetrahydro-2H-pyran-4-yl) -7, 9-dihydro-8H-purin-8-one

Step 1: 2-chloro-7-cyclopropyl-9- (tetrahydro-2H-pyran-4-yl) -7, 9-dihydro-8H-purin-8-one

To a solution of 2-chloro-9- (tetrahydro-2H-pyran-4-yl) -7, 9-dihydro-8H-purin-8-one (254mg) in 1, 2-dichloroethane (10mL) was added cyclopropylboronic acid (100mg), copper acetate (20mg) and pyridine (160mg) in that order at room temperature, and after the addition was complete, stirring was continued for 12 hours with open mouth. After the reaction is finished, pouring the reaction solution into a saturated ammonium chloride aqueous solution, and extracting with ethyl acetate; the extract was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: dichloromethane: methanol ═ 20: 1 (V: V)) to give the title compound (150 mg).

Step 2: 7-cyclopropyl-2- ((7-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) amino) -9- (tetrahydro-2H-pyran-4-yl) -7, 9-dihydro-8H-purin-8-one

The above-mentioned 2-chloro-7-cyclopropyl-9- (tetrahydro-2H-pyran-4-yl) -7, 9-dihydro-8H-purin-8-one (60mg), intermediate 47-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-amine (30mg), RuPhos Pd G3(9mg) and cesium carbonate (160mg) were dissolved in dioxane (10mL) under nitrogen, the reaction flask was replaced with nitrogen three times and heated to 100 ℃ with stirring for 2 hours, cooled to room temperature, filtered, the filtrate was concentrated under reduced pressure, and the resultant residue was purified by thin layer chromatography (developing solvent: dichloromethane: methanol 20: 1 (V: V)) to obtain the objective compound (45 mg).

¹H NMR(400MHz，DMSO-d₆)δ9.05(s，1H)，8.66(s，1H)，8.33(s，1H)，8.02(s，1H)，7.67(s，1H)，4.28-4.40(m，1H)，3.86-3.97(m，2H)，3.34-3.42(m，2H)，2.83-2.91(m，1H)，2.39-2.52(m，2H)，2.35(s，3H)，1.56-1.68(m，2H)，0.80-0.99(m，4H)。

Example 36: 2- ((1, 4-dimethyl-6-oxo-1, 6-dihydropyridin-3-yl) amino) -7-methyl-9- (tetrahydro-2H-pyran-4-yl) -7, 9-dihydro-8H-purin-8-one

Under the protection of nitrogen, the intermediate 2: 2-chloro-7-methyl-9- (tetrahydro-2H-pyran-4-yl) -7, 9-dihydro-8H-purin-8-one (54mg), 5-amino-1, 4-dimethylpyridin-2 (1H) -one (28mg), RuPhos Pd G3(9mg), and cesium carbonate (130mg) were dissolved in dioxane (20mL), heated to 100 ℃ and stirred for 2 hours. Cooled to room temperature, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by thin layer chromatography (developing solvent: dichloromethane: methanol 15: 1 (V: V)) to give the objective compound (15 mg).

¹H NMR(400MHz，DMSO-d₆)δ8.21(s，1H)，7.94(s，1H)，7.62(s，1H)，6.23(s，1H)，4.29-4.38(m，1H)，3.92(dd，J＝11.6Hz，4.4Hz，2H)，3.37(t，J＝11.6Hz，2H)，3.35(s，3H)，3.23(s，3H)，2.41-2.51(m，2H)，1.98(s，3H)，1.60(dd，J＝12.4Hz，2.4Hz，2H)。

Example 37: 13, 20-dimethyl-1, 5, 10, 15, 17, 20, 23-heptaazapentacyclic [14.5.2.2 ]^2，5.1^10， ¹⁴.0^19，22]Six carbon-12, 14(24), 16, 18, 22-pentene-11, 21-dione

This compound was synthesized according to the synthesis procedure of example 7 using the alternative nitropyridinones as starting materials.

¹H NMR(400MHz，DMSO-d₆)δ8.49(s，1H)，8.16(s，1H)，7.86(s，1H)，6.24(s，1H)，4.21-4.30(m，1H)，3.80-3.86(m，2H)，3.26-3.32(m，5H)，2.82-2.88(m，2H)，2.62-2.73(m，2H)，2.17-2.28(m，5H)，1.49-1.69(m，6H)。

Example 38: 4- (7-methyl-2- ((6-methylimidazo [1, 2-a ] pyridin-7-yl) amino) -8-oxo-7, 8-dihydro-9H-purin-9-yl) tetrahydro-2H-pyran-4-carbonitrile

Intermediate 14- (2-chloro-7-methyl-8-oxo-7, 8-dihydro-9H-purin-9-yl) tetrahydro-2H-pyran-4-carbonitrile (59mg), 6-methylimidazo [1, 2-a ] pyridin-7-amine (30mg), RuPhos Pd G3(9mg), and cesium carbonate (130mg) were dissolved in dioxane (20mL) under nitrogen, heated to 100 ℃ and stirred for 2 hours. Cooled to room temperature, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by thin layer chromatography (developing solvent: dichloromethane: methanol ═ 20: 1 (V: V)) to give the objective compound (41 mg).

¹H NMR(400MHz，DMSO)δ8.59-8.71(m，2H)，8.14(s，1H)，7.76-7.92(m，1H)，7.36-7.55(m，1H)，6.68-6.82(m，1H)，3.81-3.92(m，2H)，3.46-3.60(m，2H)，3.27(s，3H)，2.65-2.78(m，2H)，2.52-2.61(m，2H)，2.24(s，3H)。

Example 39: 4- (2- ((4-chloro-7-methylquinolin-6-yl) amino) -7-methyl-8-oxo-7, 8-dihydro-9H-purin-9-yl) tetrahydro-2H-pyran-4-carbonitrile

The intermediates 14- (2-chloro-7-methyl-8-oxo-7, 8-dihydro-9H-purin-9-yl) tetrahydro-2H-pyran-4-carbonitrile (59mg), 4-chloro-7-methylquinolin-6-amine (synthesized according to the method described in patent WO2019/238929a 1) (38mg), RuPhos Pd G3(9mg), and cesium carbonate (130mg) were dissolved in dioxane (20mL) under nitrogen, heated to 100 ℃ and stirred for 2 hours. Cooled to room temperature, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by thin layer chromatography (developing solvent: dichloromethane: methanol ═ 20: 1 (V: V)) to give the objective compound (31mg).

¹H NMR(400MHz，DMSO)δ8.80(s，1H)，8.63(d，J＝4.4Hz，1H)，8.43(s，1H)，8.27(s，1H)，7.91(s，1H)，7.60(d，J＝4.4Hz，1H)，3.84-3.92(m，2H)，3.51-3.60(m，2H[)，3.31(s，3H)，2.62-2.80(m，4H)，2.50(s，3H)。

Example 40: 4- (2- ((4-methoxy-7-methylquinolin-6-yl) amino) -7-methyl-8-oxo-7, 8-dihydro-9H-purin-9-yl) tetrahydro-2H-pyran-4-carbonitrile

Intermediate 14- (2-chloro-7-methyl-8-oxo-7, 8-dihydro-9H-purin-9-yl) tetrahydro-2H-pyran-4-carbonitrile (59mg), 4-methoxy-7-methylquinolin-6-amine (synthesized according to the method described in patent WO2019/238929a 1) (38mg), RuPhos Pd G3(9mg), and cesium carbonate (130mg) were dissolved in dioxane (20mL), heated to 100 ℃ and stirred for 2 hours, cooled to room temperature, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by thin layer chromatography (developing solvent: dichloromethane: methanol ═ 20: 1 (V: V)) to give the title compound (45 mg).

¹H NMR(400MHz，DMSO)δ8.67(s，1H)，8.55(d，J＝4.8Hz，1H)，8.34(s，1H)，8.23(s，1H)，7.74(s，1H)，6.88(d，J＝5.2Hz，1H)，3.97(s，3H)，3.81-3.88(m，2H)，3.52-3.60(m，2H)，3.30(s，3H)，2.62-2.77(m，4H)，2.44(s，3H).

Example 41: 4- (7-methyl-2- ((7-methyl- [1, 2, 4] triazolo [4, 3-a ] pyridin-6-yl) amino) -8-oxo-7, 8-dihydro-9H-purin-9-yl) tetrahydro-2H-pyran-4-carbonitrile

Step 1: 7-methyl- [1, 2, 4] triazolo [4, 3-a ] pyridin-6-amine

6-bromo-7-methyl- [1, 2, 4] triazolo [4, 3-a ] pyridine (212mg), RuPhos Pd G3(84mg), benzophenone imine (182mg) and cesium carbonate (650mg) were dissolved in toluene (15mL) under nitrogen, heated to 100 ℃ and stirred for 12 hours, cooled to room temperature, filtered, the solid was washed with dichloromethane, the filtrate was concentrated under reduced pressure, the residue was dissolved in tetrahydrofuran (30mL) and 1M dilute hydrochloric acid (10mL) was slowly added, after stirring for 1 hour, a saturated aqueous sodium bicarbonate solution was added to the system until the pH was neutral, then ethyl acetate was added for extraction, the residue was purified by column chromatography (eluent: dichloromethane: methanol ═ 20: 1 (V: V)) after the organic phase was evaporated to dryness to obtain 7-methyl- [1, 2, 4] triazolo [ 4], 3-a ] pyridin-6-amine (103 mg).

Step 2: 4- (7-methyl-2- ((7-methyl- [1, 2, 4] triazolo [4, 3-a ] pyridin-6-yl) amino) -8-oxo-7, 8-dihydro-9H-purin-9-yl) tetrahydro-2H-pyran-4-carbonitrile

Intermediate 14- (2-chloro-7-methyl-8-oxo-7, 8-dihydro-9H-purin-9-yl) tetrahydro-2H-pyran-4-carbonitrile (59mg), 7-methyl- [1, 2, 4] triazolo [4, 3-a ] pyridin-6-amine (30mg), RuPhos Pd G3(9mg), and cesium carbonate (130mg) were dissolved in dioxane (20mL) under nitrogen, heated to 100 ℃ and stirred for 2 hours. Cooled to room temperature, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by thin layer chromatography (developing solvent: dichloromethane: methanol ═ 10: 1 (V: V)) to give the objective compound (44mg).

¹H NMR(400MHz，DMSO)δ9.07(s，1H)，8.77(s，1H)，8.35(s，1H)，8.18(s，1H)，7.68(s，1H)，3.87-3.94(m，2H)，3.52-3.60(m，2H)，3.28(s，3H)，2.68-2.76(m，2H)，2.58-2.64(m，2H)，2.35(s，3H)。

Example 42: 4⁴-chloro-6, 6-difluoro-2⁷，4⁶-dimethyl-2⁸，2⁹-dihydro-2⁷H-5-oxa-3-aza-2 (9, 2) -purine-1 (4, 1) -piperidine-4 (1, 3) -benzocycloheptane-2⁸7-diketones

This compound was synthesized according to the synthesis of example 7 using the alternative phenols and ethyl difluorobromoacetate as starting materials.

¹H NMR(400MHz，DMSO-d₆)δ8.34(s，1H)，8.20(s，1H)，7.96-7.98(m，1H)，7.33(s，1H)，4.68-4.77(m，1H)，4.11-4.22(m，2H)，3.41-3.48(m，1H)，3.30(s，3H)，2.96-3.04(m，1H)，2.50-2.68(m，1H)，2.46-2.53(m，1H)，2.26(s，3H)，1.94-2.02(m，1H)，1.68-1.75(m，1H)。

Example 43: 4- (7-methyl-2- ((2-methyl-1, 8-naphthyridin-3-yl) amino) -8-oxo-7, 8-dihydro-9H-purin-9-yl) tetrahydro-2H-pyran-4-carbonitrile

Step 1: 2-methyl-1, 8-naphthyridin-3-amine

2-methyl-1, 8-naphthyridine-3-carboxylic acid (188mg) and DPPA (300mg) were dissolved in toluene (20mL), and triethylamine (0.5mL) was added slowly at room temperature and stirred for 1 hour. To the system was added 0.5mL of water, followed by heating to 80 ℃ under nitrogen atmosphere and stirring for 2 hours, cooling to room temperature, pouring the reaction solution into water (150mL), extracting the reaction solution with ethyl acetate, washing the extract with saturated brine, drying over anhydrous sodium sulfate, filtering, concentrating the filtrate under reduced pressure, and purifying the residue by silica gel column chromatography (eluent: petroleum ether: ethyl acetate ═ 2: 1 (V: V)) to obtain a pale yellow solid (60 mg).

Step 2: 4- (7-methyl-2- ((2-methyl-1, 8-naphthyridin-3-yl) amino) -8-oxo-7, 8-dihydro-9H-purin-9-yl) tetrahydro-2H-pyran-4-carbonitrile

Intermediate 14- (2-chloro-7-methyl-8-oxo-7, 8-dihydro-9H-purin-9-yl) tetrahydro-2H-pyran-4-carbonitrile (59mg), 2-methyl-1, 8-naphthyridin-3-amine (32mg), RuPhos Pd G3(9mg), and cesium carbonate (130mg) were dissolved in dioxane (20mL) under nitrogen, heated to 100 ℃ and stirred for 2 hours. Cooled to room temperature, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by thin layer chromatography (developing solvent: dichloromethane: methanol ═ 20: 1 (V: V)) to give the objective compound (41 mg).

¹H NMR(400MHz，DMSO)δ8.99(s，1H)，8.86(dd，J＝4.4Hz，2.0Hz，1H)，8.64(s，1H)，8.25-8.27(m，2H)，7.50(dd，J＝8-7.6Hz，4.4Hz，1H)，3.86-3.93(m，2H)，3.53-3.61(m，2H)，3.31(s，3H)，2.68-2.78(m，5H)，2.58-2.65(m，2H).

Example 44: 4- (7-methyl-2- ((7-methylquinazolin-6-yl) amino) -8-oxo-7, 8-dihydro-9H-purin-9-yl) tetrahydro-2H-pyran-4-carbonitrile

The intermediates 14- (2-chloro-7-methyl-8-oxo-7, 8-dihydro-9H-purin-9-yl) tetrahydro-2H-pyran-4-carbonitrile (59mg), 7-methyl quinazolin-6-amine (synthesized according to the method described in patent WO2019/238929a 1) (32mg), RuPhos Pd G3(9mg), and cesium carbonate (130mg) were dissolved in dioxane (20mL) under nitrogen, heated to 100 ℃ and stirred for 2 hours. Cooled to room temperature, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by thin layer chromatography (developing solvent: dichloromethane: methanol ═ 20: 1 (V: V)) to give the objective compound (39 mg).

¹H NMR(400MHz，DMSO)δ9.36(s，1H)，9.09(s，1H)，8.84(s，1H)，8.45(s，1H)，8.28(s，1H)，7.83(s，1H)，3.88-3.94(m，2H)，3.54-3.62(m，2H)，3.31(s，3H)，2.74-2.82(m，2H)，2.58-2.64(m，2H)，2.53(s，3H)。

Example 45: 2- ((7-chloro- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) amino) -7-methyl-9- (tetrahydro-2H-pyran-4-yl) -7, 9-dihydro-8H-purin-8-one

The intermediates 22-chloro-7-methyl-9- (tetrahydro-2H-pyran-4-yl) -7, 9-dihydro-8H-purin-8-one (54mg), 7-chloro- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-amine (synthesized following the procedure described for intermediate 4 in patent WO2019/238929a 1) (34mg), RuPhos Pd G3(9mg) and cesium carbonate (130mg) were dissolved in dioxane (20mL) under nitrogen, heated to 100 ℃ and stirred for 2 hours. Cooled to room temperature, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by thin layer chromatography (developing solvent: dichloromethane: methanol ═ 20: 1 (V: V)) to give the objective compound (18 mg).

¹H NMR(400MHz，DMSO)δ10.19(s，1H)，8.29(s，1H)，7.95(s，1H)，7.85(s，1H)，7.37(s，1H)，4.52-4.61(m，1H)，4.15(dd，J＝11.6Hz，4.4Hz，2H)，3.51-3.59(m，2H)，3.43(s，3H)，2.72-2.82(m，2H)，1.71-1.77(m，2H)。

Example 46: 4- (2- ((7-chloro- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) amino) -7-methyl-8-oxo-7, 8-dihydro-9H-purin-9-yl) tetrahydro-2H-pyran-4-carbonitrile

Intermediate 14- (2-chloro-7-methyl-8-oxo-7, 8-dihydro-9H-purin-9-yl) tetrahydro-2H-pyran-4-carbonitrile (59mg), 7-chloro- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-amine (34mg), RuPhos Pd G3(9mg), and cesium carbonate (130mg) were dissolved in dioxane (20mL) under nitrogen, heated to 100 ℃ and stirred for 2 hours, cooled to room temperature, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by thin layer chromatography (developing solvent: dichloromethane: methanol ═ 20: 1 (V: V)) to give the objective compound (39 mg).

¹H NMR(400MHz，DMSO)δ10.04(s，1H)，8.30(s，1H)，8.03(s，1H)，7.86(s，1H)，7.37(s，1H)，4.10-4.17(m，2H)，3.89-3.95(m，2H)，3.43(s，3H)，2.77-2.87(m，4H)。

Example 47: 4- (7-methyl-2- ((7-methylbenzothiazol-6-yl) amino) -8-oxo-7, 8-dihydro-9H-purin-9-yl) tetrahydro-2H-pyran-4-carbonitrile

Step 1: 7-methylbenzothiazol-6-amine

6-bromo-7-methylbenzo [ d ] thiazole (228mg), RuPhos Pd G3(80mg), benzophenone imine (182mg) and cesium carbonate (650mg) were dissolved in toluene (10mL) under nitrogen, heated to 100 ℃ and stirred for 5 hours, cooled to room temperature, filtered, the solid washed with dichloromethane then the filtrate was concentrated under reduced pressure, the residue was dissolved in tetrahydrofuran (30mL) and 1M dilute hydrochloric acid (10mL) was slowly added, stirring was continued for 1 hour and then saturated aqueous sodium bicarbonate was added to the system until the pH was neutral. Extraction was performed with ethyl acetate and the organic phase was evaporated to dryness and the residue was purified by column chromatography (developing solvent: dichloromethane: methanol 20: 1 (V: V)) to give 7-methylbenzothiazol-6-amine (73 mg).

Step 2: 4- (7-methyl-2- ((7-methylbenzothiazol-6-yl) amino) -8-oxo-7, 8-dihydro-9H-purin-9-yl) tetrahydro-2H-pyran-4-carbonitrile

Intermediate 14- (2-chloro-7-methyl-8-oxo-7, 8-dihydro-9H-purin-9-yl) tetrahydro-2H-pyran-4-carbonitrile (59mg), 7-methylbenzothiazol-6-amine (33mg), RuPhos Pd G3(9mg), and cesium carbonate (130mg) were dissolved in dioxane (20mL) under nitrogen, heated to 100 ℃ and stirred for 2 hours. Cooled to room temperature, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by thin layer chromatography (developing solvent: dichloromethane: methanol ═ 20: 1 (V: V)) to give the objective compound (37mg).

¹H NMR(400MHz，DMSO)δ9.25(s，1H)，8.93(s，1H)，8.12(s，1H)，7.84(d，J＝8.4Hz，1H)，7.61(d，J＝8.4Hz，1H)，3.82-3.92(m，2H)，3.46-3.60(m，2H)，3.33(s，3H)，2.65-2.76(m，2H)，2.50-2.59(m，2H)，2.41(s，3H)。

Example 48: 4- (7-methyl-2- ((6-methylbenzo [ d ] [1, 3] dioxin-5-yl) amino) -8-oxo-7, 8-dihydro-9H-purin-9-yl) tetrahydro-2H-pyran-4-carbonitrile

Intermediate 14- (2-chloro-7-methyl-8-oxo-7, 8-dihydro-9H-purin-9-yl) tetrahydro-2H-pyran-4-carbonitrile (59mg), 6-methylbenzo [ d ] [1, 3] dioxan-5-amine (30mg), RuPhos Pd G3(9mg), and cesium carbonate (130mg) were dissolved in dioxane (20mL) under nitrogen, heated to 100 ℃ and stirred for 2 hours. Cooled to room temperature, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by thin layer chromatography (developing solvent: dichloromethane: methanol ═ 20: 1 (V: V)) to give the objective compound (45 mg).

¹H NMR(400MHz，DMSO)δ8.40(s，1H)，8.07(s，1H)，6.95(s，1H)，6.74(s，1H)，5.92(s，2H)，3.86-3.92(m，2H)，3.53-3.61(m，2H)，3.25(s，3H)，2.68-2.77(m，2H)，2.54-2.61(m，2H)，2.07(s，3H)。

Example 49: 4- (7-methyl-2- ((7-methylbenzothiazol-6-yl) amino) -8-oxo-7, 8-dihydro-9H-purin-9-yl) tetrahydro-2H-pyran-4-carbonitrile

Step 1: 7-methylbenzothiazol-6-amine

6-bromo-7-methylbenzo [ d ] thiazole (228mg), RuPhos Pd G3(80mg), benzophenone imine (182mg) and cesium carbonate (650mg) were dissolved in toluene (10mL) under nitrogen, heated to 100 ℃ and stirred for 5 hours, cooled to room temperature, filtered, the solid washed with dichloromethane then the filtrate was concentrated under reduced pressure, the residue was dissolved in tetrahydrofuran (30mL) and 1M dilute hydrochloric acid (10mL) was slowly added, stirring was continued for 1 hour and then saturated aqueous sodium bicarbonate was added to the system until the pH was neutral. Extraction was performed with ethyl acetate, and the organic phase was evaporated to dryness and the residue was purified by column chromatography (developing solvent: dichloromethane: methanol 20: 1 (V: V)) to give 5-methylbenzothiazol-6-amine (40 mg).

Intermediate 14- (2-chloro-7-methyl-8-oxo-7, 8-dihydro-9H-purin-9-yl) tetrahydro-2H-pyran-4-carbonitrile (59mg), 7-methylbenzothiazol-6-amine (33mg), RuPhos Pd G3(9mg), and cesium carbonate (130mg) were dissolved in dioxane (20mL) under nitrogen, heated to 100 ℃ and stirred for 2 hours. Cooled to room temperature, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by thin layer chromatography (developing solvent: dichloromethane: methanol ═ 20: 1 (V: V)) to give the objective compound (31mg).

Example 50: 4- (7-methyl-2- ((6-methylpyrazolo [1, 5-a ] pyrimidin-5-yl) amino) -8-oxo-7, 8-dihydro-9H-purin-9-yl) tetrahydro-2H-pyran-4-carbonitrile

Intermediate 14- (2-chloro-7-methyl-8-oxo-7, 8-dihydro-9H-purin-9-yl) tetrahydro-2H-pyran-4-carbonitrile (59mg), 6-methylpyrazol [1, 5-a ] pyrimidin-5-amine (32mg), RuPhos Pd G3(9mg), and cesium carbonate (130mg) were dissolved in dioxane (20mL) under nitrogen, heated to 100 ℃ and stirred for 2 hours. Cooled to room temperature, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by thin layer chromatography (developing solvent: dichloromethane: methanol ═ 20: 1 (V: V)) to give the objective compound (22 mg).

¹H NMR(400MHz，DMSO)δ9.39(s，1H)，8.75(s，1H)，8.33(s，1H)，7.90(d，J＝2.0Hz，1H)，6.15(d，J＝2.0Hz，1H)，3.89-3.95(m，2H)，3.54-3.62(m，2H)，3.33(s，3H)，2.82-2.91(m，2H)，2.61-2.67(m，2H)，2.34(s，3H)。

Example 51: 4- (7-methyl-2- ((3-methyl-1, 5-naphthyridin-2-yl) amino) -8-oxo-7, 8-dihydro-9H-purin-9-yl) tetrahydro-2H-pyran-4-carbonitrile

Step 1: 3-methyl-1, 5-naphthyridin-2-amine

Under the protection of nitrogen, 3-bromo-1, 5-naphthyridin-2-amine (224mg) and PdCl are added₂(dppf) (90mg), trimethylcyclotriboroxane (250mg) and potassium carbonate (278mg) were dissolved in dioxane (20mL) and water (5mL), heated to 100 ℃ and stirred for 2 hours. After cooling to room temperature, the reaction mixture was poured into water (100mL) and extracted with ethyl acetate, and the organic phase was evaporated to dryness, and the residue was purified by column chromatography (eluent: dichloromethane: methanol ═ 20: 1 (V: V)) to give 3-methyl-1, 5-naphthyridin-2-amine (90 mg).

Step 2: 4- (7-methyl-2- ((3-methyl-1, 5-naphthyridin-2-yl) amino) -8-oxo-7, 8-dihydro-9H-purin-9-yl) tetrahydro-2H-pyran-4-carbonitrile

Intermediate 14- (2-chloro-7-methyl-8-oxo-7, 8-dihydro-9H-purin-9-yl) tetrahydro-2H-pyran-4-carbonitrile (59mg), 3-methyl-1, 5-naphthyridin-2-amine (32mg), RuPhos Pd G3(9mg), and cesium carbonate (130mg) were dissolved in dioxane (10mL) under nitrogen, heated to 100 ℃ and stirred for 3 hours. Cooled to room temperature, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by thin layer chromatography (developing solvent: dichloromethane: methanol ═ 20: 1 (V: V)) to give the objective compound (49 mg).

¹H NMR(400MHz，DMSO)δ9.42(s，1H)，8.73(d，J＝3.2Hz，1H)，8.30(s，1H)，8.11(s，1H)，8.01(d，J＝8.8Hz，1H)，7.58(dd，J＝8.8Hz，4.0Hz，1H)，3.82-3.89(m，2H)，349-3.57(m，2H)，3.32(s，3H)，2.79-2.88(m，2H)，2.58-2.65(m，2H)，2.45(s，3H)。

Example 52: 4- (7-methyl-2- ((7-methylpyridine [2, 3-b ] pyrazin-6-yl) amino) -8-oxo-7, 8-dihydro-9H-purin-9-yl) tetrahydro-2H-pyran-4-carbonitrile

Intermediate 14- (2-chloro-7-methyl-8-oxo-7, 8-dihydro-9H-purin-9-yl) tetrahydro-2H-pyran-4-carbonitrile (59mg), 7-methylpyridine [2, 3-b ] pyrazin-6-amine (32mg), RuPhos Pd G3(9mg), and cesium carbonate (130mg) were dissolved in dioxane (20mL) under nitrogen, heated to 100 ℃ and stirred for 2 hours. Cooled to room temperature, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by thin layer chromatography (developing solvent: dichloromethane: methanol ═ 20: 1 (V: V)) to give the objective compound (14 mg).

¹H NMR(400MHz，DMSO)δ9.64(s，1H)，8.85(s，1H)，8.72(s，1H)，8.36(s，1H)，8.18(s，1H)，3.86-3.96(m，2H)，3.50-3.61(m，2H)，3.34(s，3H)，2.70-2.90(m，4H)，2.47(s，3H)。

Example 53: 4- (2- ((4, 7-dimethylquinolin-6-yl) amino) -7-methyl-8-oxo-7, 8-dihydro-9H-purin-9-yl) tetrahydro-2H-pyran-4-carbonitrile

Step 1: 4, 7-dimethylquinolin-6-amines

Under the protection of nitrogen, 4-chloro-7-methylquinolin-6-amine (192mg), PdCl₂(dppf) (90mg), trimethylcyclotriboroxane (250mg) and potassium carbonate (278mg) were dissolved in dioxane (20mL) and water (5mL), heated to 100 ℃ and stirred for 4 hours, cooled to room temperature, the reaction solution was poured into water (100mL), ethyl acetate was added and extracted, the organic phase was dried and evaporated to dryness, and the residue was purified by column chromatography (developing solvent: dichloromethane: methanol ═ 20: 1 (V: V)) to give 3-methyl-1, 5-naphthyridin-2-amine (100mg).

Step 2: 4- (2- ((4, 7-dimethylquinolin-6-yl) amino) -7-methyl-8-oxo-7, 8-dihydro-9H-purin-9-yl) tetrahydro-2H-pyran-4-carbonitrile

Intermediate 14- (2-chloro-7-methyl-8-oxo-7, 8-dihydro-9H-purin-9-yl) tetrahydro-2H-pyran-4-carbonitrile (59mg), 4, 7-dimethylquinolin-6-amine (34mg), RuPhos Pd G3(9mg), and cesium carbonate (130mg) were dissolved in dioxane (10mL) under nitrogen, heated to 100 ℃ and stirred for 3 hours. Cooled to room temperature, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by thin layer chromatography (developing solvent: dichloromethane: methanol ═ 20: 1 (V: V)) to give the objective compound (37mg).

¹H NMR(400MHz，DMSO)δ8.74(s，1H)，8.57(d，J＝4.4Hz，1H)，8.20(s，1H)，8.16(s，1H)，7.81(s，1H)，7.23(d，J＝4.4Hz，1H)，3.81-3.88(m，2H)，3.50-3.57(m，2H)，3.29(s，3H)，2.70-2.79(m，2H)，2.54-2.61(m，5H)，2.43(s，3H)。

Example 54: 2⁷，4⁷-dimethyl-2⁸，2⁹-dihydro-2⁷H-5-oxa-3-aza-4 (6, 4) -quinoline-2 (9, 2) -purine-1 (4, 1) -piperidinepepane-2⁸-ketones

This compound was synthesized according to the synthesis method of example 7 using 7-methyl-6-nitroquinolin-4-ol as the starting material.

¹H NMR(400MHz，DMSO)δ8.96(s，1H)，8.49(d，J＝4.8Hz，1H)，8.20(s，1H)，8.05(s，1H)，7.71(s，1H)，6.93(d，J＝5.2Hz，1H)，4.31-4.40(m，2H)，4.18-4.30(m，1H)，3.32(s，3H)，2.90-3.03(m，4H)，2.76-2.89(m，2H)，2.52(s，3H)，2.38-2.50(m，2H)，1.56-1.66(m，2H)。

Example 55: 4⁴-fluoro-2⁷，4⁶-dimethyl-2⁸，2⁹-dihydro-2⁷H-5-oxa-3-aza-2 (9, 2) -purine-1 (4, 1) -piperidine-4 (1, 3) -benzocycloheptane-2⁸-ketones

¹H NMR(400MHz，DMSO)δ8.25(s，1H)，8.17(s，1H)，8.03(d，J＝8.0Hz，1H)，7.02(d，J＝12.4Hz，1H)，4.26-4.51(m，3H)，3.31(s，3H)，3.12-3.30(m，2H)，2.81-3.11(m，4H)，2.67-2.81(m，2H)，2.21(s，3H)，1.49-1.69(m，2H)。

Example 56: 4- (2- ((4-methoxy-7-methylquinazolin-6-yl) amino) -7-methyl-8-oxo-7, 8-dihydro-9H-purin-9-yl) tetrahydro-2H-pyran-4-carbonitrile

Intermediate 14- (2-chloro-7-methyl-8-oxo-7, 8-dihydro-9H-purin-9-yl) tetrahydro-2H-pyran-4-carbonitrile (59mg), 4-methoxy-7-methyl-quinazolin-6-amine (38mg), RuPhos Pd G3(9mg), and cesium carbonate (130mg) were dissolved in dioxane (20mL) under nitrogen, heated to 100 ℃ and stirred for 2 hours, cooled to room temperature, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by thin layer chromatography (developing solvent: dichloromethane: methanol ═ 20: 1 (V: V)) to give the objective compound (48 mg).

¹H NMR(400MHz，DMSO)δ8.76(s，1H)，8.63(s，1H)，8.42(s，1H)，8.27(s，1H)，7.74(s，1H)，4.07(s，3H)，3.84-3.92(m，2H)，3.54-3.61(m，2H)，3.31(s，3H)，2.62-2.79(m，4H)，2.48(s，3H).

Example 57: 4- (7-methyl-2- ((6-methyl- [1, 2, 5] thiadiazole [3, 4-b ] pyridin-5-yl) amino) -8-oxo-7, 8-dihydro-9H-purin-9-yl) tetrahydro-2H-pyran-4-carbonitrile

Intermediate 14- (2-chloro-7-methyl-8-oxo-7, 8-dihydro-9H-purin-9-yl) tetrahydro-2H-pyran-4-carbonitrile (59mg), 6-methyl- [1, 2, 5] thiadiazolo [3, 4-b ] pyridin-5-amine (33mg), RuPhos Pd G3(9mg), and cesium carbonate (130mg) were dissolved in dioxane (20mL) under nitrogen, heated to 100 ℃ and stirred for 2 hours. Cooled to room temperature, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by thin layer chromatography (developing solvent: dichloromethane: methanol ═ 20: 1 (V: V)) to give the objective compound (17 mg).

¹H NMR(400MHz，DMSO)δ9.62(s，1H)，8.41(s，1H)，8.16(s，1H)，3.90-3.98(m，2H)，3.56-3.63(m，2H)，3.35(s，3H)，2.85-2.94(m，2H)，2.68-2.76(m，2H)，2.47(s，3H)。

Example 58: 4⁴-fluoro-2⁷，4⁶-dimethyl-2⁸，2⁹-dihydro-2⁷H-3, 5-diaza-2 (9, 2) -purine-1 (4, 1) -piperidine-4 (1, 3) -benzocycloheptane-2⁸-ketones

This compound was synthesized by following the synthesis procedure of example 7 using 2-fluoro-4-methyl-5-nitroaniline as the starting material.

¹H NMR(400MHz，DMSO)δ8.19(s，1H)，8.02(s，1H)，7.56(d，J＝8.4Hz，1H)，6.86(d，J＝12.0Hz，1H)，5.63-5.70(br，1H)，4.52-4.65(m，1H)，3.20-3.53(m，11H)，2.72-2.86(m，2H)，2.16(s，3H)，1.74-1.86(m，2H)。

Example 59: 2⁷，4⁵-dimethyl-2⁸，2⁹-dihydro-2⁷H-5-oxa-3-aza-2 (9, 2) -purine-4 (4, 2) -pyrimidine-1 (4, 1) -piperidinepepane-2⁸-ketones

This compound was synthesized following the synthesis procedure of example 7 using 5-methylcytosine as starting material.

¹H NMR(400MHz，DMSO)δ8.73(s，1H)，8.34(s，1H)，8.09(s，1H)，4.51-4.63(m，1H)，4.40-4.47(m，2H)，3.74-3.88(m，2H)，3.35(s，3H)，3.13-3.22(m，4H)，2.78-2.95(m，2H)，2.18(s，3H)，1.67-1.82(m，2H)。

Example 60: 4- (7-methyl-2- ((5-methylbenzothiazol-6-yl) amino) -8-oxo-7, 8-dihydro-9H-purin-9-yl) tetrahydro-2H-pyran-4-carbonitrile

Intermediate 14- (2-chloro-7-methyl-8-oxo-7, 8-dihydro-9H-purin-9-yl) tetrahydro-2H-pyran-4-carbonitrile (59mg), 5-methylbenzothiazol-6-amine (33mg), RuPhos Pd G3(9mg), and cesium carbonate (130mg) were dissolved in dioxane (20mL) under nitrogen, heated to 100 ℃ and stirred for 2 hours. Cooled to room temperature, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by thin layer chromatography (developing solvent: dichloromethane: methanol ═ 20: 1 (V: V)) to give the objective compound (34 mg).

¹H NMR(400MHz，DMSO)δ9.19(s，1H)，8.70(s，1H)，8.36(s，1H)，8.19(s，1H)，7.89(s，1H)，3.86-3.92(m，2H)，3.52-3.59(m，2H)，3.28(s，3H)，2.67-2.75(m，2H)，2.56-2.63(m，2H)，2.37(s，3H)。

Example 61: 4- (2- ((5, 7-Dimethylquinolin-6-yl) amino) -7-methyl-8-oxo-7, 8-dihydro-9H-purin-9-yl) tetrahydro-2H-pyran-4-carbonitrile

Intermediate 14- (2-chloro-7-methyl-8-oxo-7, 8-dihydro-9H-purin-9-yl) tetrahydro-2H-pyran-4-carbonitrile (59mg), 5, 7-dimethylquinolin-6-amine (34mg), RuPhos Pd G3(9mg), and cesium carbonate (130mg) were dissolved in dioxane (20mL) under nitrogen, heated to 100 ℃ and stirred for 2 hours. Cooled to room temperature, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by thin layer chromatography (developing solvent: dichloromethane: methanol ═ 20: 1 (V: V)) to give the objective compound (25mg).

¹H NMR(400MHz，DMSO)δ8.80(s，1H)，8.76(s，1H)，8.40(d，J＝7.6Hz，1H)，8.03(s，1H)，7.74(s，1H)，7.41-7.48(m，1H)，3.56-3.90(m，2H)，3.32-3.52(m，2H)，3.23(s，3H)，2.50-2.74(m，2H)，2.44(s，3H)，2.31(s，3H)，1.35-1.64(m，2H)。

Example 62: 4- (7-methyl-2- ((8-methylquinolin-7-yl) amino) -8-oxo-7, 8-dihydro-9H-purin-9-yl) tetrahydro-2H-pyran-4-carbonitrile

Intermediate 14- (2-chloro-7-methyl-8-oxo-7, 8-dihydro-9H-purin-9-yl) tetrahydro-2H-pyran-4-carbonitrile (59mg), 8-methylquinolin-7-amine (32mg), RuPhos Pd G3(9mg), and cesium carbonate (130mg) were dissolved in dioxane (20mL) under nitrogen, heated to 100 ℃ and stirred for 2 hours. Cooled to room temperature, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by thin layer chromatography (developing solvent: dichloromethane: methanol ═ 20: 1 (V: V)) to give the objective compound (26 mg).

¹H NMR(400MHz，DMSO)δ8.97(s，1H)，8.84(dd，J＝4.0Hz，1.6Hz，1H)，8.24(dd，J＝8.4Hz，1.6Hz，1H)，8.17(s，1H)，7.81(d，J＝8.8Hz，1H)，7.71(d，J＝9.2Hz，1H)，7.40(dd，J＝8.4Hz，4.0Hz，1H)，3.83-3.91(m，2H)，3.50-3.58(m，2H)，3.28(s，3H)，2.68-2.76(m，2H)，2.62(s，3H)，2.54-2.61(m，2H)。

Example 63: 4- (2- ((7-fluoro-5-methylquinolin-6-yl) amino) -7-methyl-8-oxo-7, 8-dihydro-9H-purin-9-yl) tetrahydro-2H-pyran-4-carbonitrile

Step 1: 6-bromo-7-fluoro-5-methylquinoline

Adding concentrated H₂SO₄(13.7g) was slowly added to glycerol (8.63g) maintaining the temperature below 70 ℃ followed by the addition of 4-bromo-3-fluoro-5-methylaniline (6.1g) which was then warmed to 85 ℃ and stirred for 40 minutes. Potassium iodide (0.30g), iodine (0.34g) and water (1.50mL) were added, and the mixture was stirred at 135 ℃ for 4 hours. Cooling to room temperature, pouring into ice to quench the reaction, and filtering with diatomaceous earth. The filtrate was adjusted to pH 7 with ammonia and extracted thoroughly with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and concentrated, and the residue was subjected to column chromatography to give 6-bromo-7-fluoro-5-methylquinoline (1.5g) and the isomer 6-bromo-5-fluoro-7-methylquinoline (1.1g), respectively.

Step 2: 7-fluoro-5-methylquinolin-6-amine

6-bromo-7-fluoro-5-methylquinoline (240mg), RuPhos Pd G3(80mg), benzophenone imine (182mg) and cesium carbonate (650mg) were dissolved in toluene (10mL) under nitrogen, heated to 100 ℃ and stirred for 5 hours, cooled to room temperature, filtered, the solid was washed with dichloromethane, the filtrate was concentrated under reduced pressure, the residue was dissolved in tetrahydrofuran (30mL), 1M dilute hydrochloric acid (10mL) was slowly added, stirring was continued for 1 hour, a saturated aqueous sodium bicarbonate solution was added to the system until the pH was neutral, ethyl acetate was added for extraction, and the organic phase was evaporated to dryness and the residue was purified by column chromatography (eluent: dichloromethane: methanol ═ 20: 1 (V: V)) to give 7-fluoro-5-methylquinolin-6-amine (120 mg).

And step 3: 4- (2- ((7-fluoro-5-methylquinolin-6-yl) amino) -7-methyl-8-oxo-7, 8-dihydro-9H-purin-9-yl) tetrahydro-2H-pyran-4-carbonitrile

Intermediate 14- (2-chloro-7-methyl-8-oxo-7, 8-dihydro-9H-purin-9-yl) tetrahydro-2H-pyran-4-carbonitrile (59mg), 7-fluoro-5-methylquinolin-6-amine (35mg), RuPhos Pd G3(9mg), and cesium carbonate (130mg) were dissolved in dioxane (20mL) under nitrogen, heated to 100 ℃ and stirred for 2 hours. Cooled to room temperature, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by thin layer chromatography (developing solvent: dichloromethane: methanol ═ 20: 1 (V: V)) to give the objective compound (42 mg).

¹H NMR(400MHz，DMSO)δ9.01(s，1H)，8.85(d，J＝2.8Hz，1H)，8.47(d，J＝8.4Hz，1H)，8.07(s，1H)，7.63(d，J＝10.8Hz，1H)，7.51(dd，J＝8.8Hz，4.4Hz，1H)，3.74-3.83(m，2H)，3.43-3.53(m，2H)，3.25(s，3H)，2.61-2.71(m，2H)，2.53(s，3H)，2.46-2.52(m，2H)。

Example 64: 4- (2- ((5-fluoro-7-methylquinolin-6-yl) amino) -7-methyl-8-oxo-7, 8-dihydro-9H-purin-9-yl) tetrahydro-2H-pyran-4-carbonitrile

The target compound (30mg) was synthesized in two steps using 6-bromo-5-fluoro-7-methylquinoline obtained in step one of example 63 as a starting material.

¹H NMR(400MHz，DMSO)δ8.92(s，1H)，8.86(dd，J＝4.0Hz，1.2Hz，1H)，8.36(d，J＝8.4Hz，1H)，8.10(s，1H)，7.76(s，1H)，7.51(dd，J＝8.4Hz，4.0Hz，1H)，3.70-3.78(m，2H)，3.41-3.48(m，2H)，3.26(s，3H)，2.59-2.68(m，2H)，2.44-2.50(m，2H)，2.41(s，3H)。

Example 65: 4- (2- ((2, 2-difluoro-6-methylbenzo [ d ] [1, 3] dioxol-5-yl) amino) -7-methyl-8-oxo-7, 8-dihydro-9H-purin-9-yl) tetrahydro-2H-pyran-4-carbonitrile

Step 1: 2, 2-difluoro-6-methylbenzo [ d ] [1, 3] dioxin-5-amine

5-bromo-2, 2-difluoro-6-methylbenzo [ d ] [1, 3] dioxine (250mg), RuPhos Pd G3(80mg), benzophenone imine (182mg) and cesium carbonate (650mg) were dissolved in toluene (10mL) under nitrogen, heated to 100 ℃ and stirred for 5 hours. Cooled to room temperature, filtered, the solid washed with dichloromethane then the filtrate was concentrated under reduced pressure, the residue was dissolved in tetrahydrofuran (30mL) and 1M dilute hydrochloric acid (10mL) was added slowly, stirring was continued for 1 hour, and saturated aqueous sodium bicarbonate was added to the system until the pH was neutral. Extraction was performed with ethyl acetate, and the organic phase was evaporated to dryness and the residue was purified by column chromatography (eluent: dichloromethane: methanol ═ 20: 1 (V: V)) to give 2, 2-difluoro-6-methylbenzo [ d ] [1, 3] dioxin-5-amine (95 mg).

Step 2: 4- (2- ((2, 2-difluoro-6-methylbenzo [ d ] [1, 3] dioxol-5-yl) amino) -7-methyl-8-oxo-7, 8-dihydro-9H-purin-9-yl) tetrahydro-2H-pyran-4-carbonitrile

Intermediate 14- (2-chloro-7-methyl-8-oxo-7, 8-dihydro-9H-purin-9-yl) tetrahydro-2H-pyran-4-carbonitrile (59mg), 2-difluoro-6-methylbenzo [ d ] [1, 3] dioxin-5-amine (38mg), RuPhos Pd G3(9mg), and cesium carbonate (130mg) were dissolved in dioxane (20mL) under nitrogen, heated to 100 ℃ and stirred for 2 hours, cooled to room temperature, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by thin layer chromatography (developing solvent: dichloromethane: methanol ═ 20: 1 (V: V)) to give the objective compound (36mg).

¹H NMR(400MHz，DMSO)δ7.90(s，1H)，7.69(s，1H)，6.90(s，1H)，6.58(s，1H)，4.03-4.10(m，2H)，3.82-3.90(m，2H)，3.37(s，3H)，2.72-2.82(m，4H)，2.29(s，3H).

Example 66: 4- (7-methyl-2- ((7-methyl-2, 3-dihydrobenzo [ b ] [1, 4] dioxin-6-yl) amino) -8-oxo-7, 8-dihydro-9H-purin-9-yl) tetrahydro-2H-pyran-4-carbonitrile

Intermediate 14- (2-chloro-7-methyl-8-oxo-7, 8-dihydro-9H-purin-9-yl) tetrahydro-2H-pyran-4-carbonitrile (59mg), 7-methyl-2, 3-dihydrobenzo [ b ] [1, 4] dioxin-6-amine (31mg), RuPhos Pd G3(9mg), and cesium carbonate (130mg) were dissolved in dioxane (20mL) under nitrogen, heated to 100 ℃ and stirred for 2 hours, cooled to room temperature, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by thin layer chromatography (developing solvent: dichloromethane: methanol ═ 20: 1 (V: V)) to give the objective compound (43mg).

¹H NMR(400MHz，DMSO)δ8.34(s，1H)，8.07(s，1H)，6.91(s，1H)，6.64(s，1H)，4.16(s，4H)，3.87-3.93(m，2H)，3.54-3.62(m，2H)，3.25(s，3H)，2.69-2.77(m，2H)，2.56-2.63(m，2H)，2.05(s，3H)。

Example 67: 4- (7-methyl-2- ((7-methylbenzo [ b ] [1, 4] dioxin-6-yl) amino) -8-oxo-7, 8-dihydro-9H-purin-9-yl) tetrahydro-2H-pyran-4-carbonitrile

Intermediate 14- (2-chloro-7-methyl-8-oxo-7, 8-dihydro-9H-purin-9-yl) tetrahydro-2H-pyran-4-carbonitrile (59mg), 7-methylbenzo [ b ] [1, 4] dioxin-6-amine (33mg), RuPhos Pd G3(9mg), and cesium carbonate (130mg) were dissolved in dioxane (20mL) under nitrogen, heated to 100 ℃ and stirred for 2 hours, cooled to room temperature, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by thin layer chromatography (developing solvent: dichloromethane: methanol ═ 20: 1 (V: V)) to give the objective compound (27 mg).

¹H NMR(400MHz，DMSO)δ8.41(s，1H)，8.11(s，1H)，6.87(s，1H)，6.53(s，1H)，6.13(s，2H)，3.89-3.96(m，2H)，3.55-3.63(m，2H)，3.26(s，3H)，2.69-2.77(m，2H)，2.57-2.63(m，2H)，2.03(s，3H)。

Example 68: 4- (2- ((8-fluoro-7-methylquinolin-6-yl) amino) -7-methyl-8-oxo-7, 8-dihydro-9H-purin-9-yl) tetrahydro-2H-pyran-4-carbonitrile

The title compound (20mg) was synthesized in 3 steps using 4-bromo-2-fluoro-3-methylaniline as the starting material in analogy to example 63.

¹H NMR(400MHz，DMSO)δ8.93(s，1H)，8.76(dd，J＝4.4Hz，1.6Hz，1H)，8.25(s，1H)，8.22(d，J＝8.4Hz，1H)，8.08(s，1H)，7.49(dd，J＝8.4Hz，4.4Hz，1H)，3.85-3.92(m，2H)，3.52-3.60(m，2H)，3.30(s，3H)，2.70-2.79(m，2H)，2.58-2.64(m，2H)，2.36(d，J＝2.4Hz，3H)。

Example 69: 4- (2- ((7- (difluoromethyl) quinolin-6-yl) amino) -7-methyl-8-oxo-7, 8-dihydro-9H-purin-9-yl) tetrahydro-2H-pyran-4-carbonitrile

The title compound (22mg) was synthesized in 3 steps using 4-bromo-3- (difluoromethyl) aniline as the starting material in analogy to example 63.

¹H NMR(400MHz，DMSO)δ8.95(s，1H)，8.86(d，J＝2.8Hz，1H)，8.34(s，1H)，8.29(d，J＝8.4Hz，1H)，8.24(s，1H)，8.18(s，1H)，7.57(dd，J＝8.4Hz，4.4Hz，1H)，7.45(t，J＝54.2Hz，1H)，3.84-3.91(m，2H)，3.52-3.59(m，2H)，3.31(s，3H)，2.68-2.77(m，2H)，2.56-2.62(m，2H)。

Example 70: 2⁷，4⁵-dimethyl-2⁸，2⁹-dihydro-2⁷H-5-oxa-3-aza-2 (9, 2) -purine-4 (4, 2) -pyridine-1 (4, 1) -piperidinepepane-2⁸-ketones

This compound was synthesized by following the synthesis procedure of example 7 using 2-bromo-5-methyl-4-nitropyridine as starting material.

¹H NMR(400MHz，DMSO)δ8.45(s，1H)，8.26(s，1H)，8.02(s，1H)，7.80(s，1H)，4.35-4.45(m，1H)，4.26-4.32(m，2H)，3.32(s，3H)，3.07-3.15(m，2H)，2.62-2.88(m，6H)，2.18(s，3H)，1.37-1.45(m，2H)。

Example 71: 4- (7- (methyl-d 3) -2- ((7-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) amino) -8-oxo-7, 8-dihydro-9H-purin-9-yl) tetrahydro-2H-pyran-4-carbonitrile

Analogously to example 1, CD was used in the synthesis of intermediate 1₃I (deuterated iodomethane) instead of CH₃The target compound (33mg) is synthesized by 2 steps by taking the I as a substitute raw material.

¹H NMR(400MHz，DMSO)δ9.06(s，1H)，8.76(s，1H)，8.35(s，1H)，8.18(s，1H)，7.67(s，1H)，3.87-3.93(m，2H)，3.52-3.60(m，2H)，2.68-2.76(m，2H)，2.58-2.64(m，2H)，2.35(s，3H)。

Example 72: 4- (7- (methyl-d 3) -2- ((7-methylquinolin-6-yl) amino) -8-oxo-7, 8-dihydro-9H-purin-9-yl) tetrahydro-2H-pyran-4-carbonitrile

Using the same procedure as in example 71, 7-methylquinolin-6-amine as a surrogate amine was subjected to a catalytic coupling reaction to give the title compound (34 mg).

¹H NMR(400MHz，DMSO)δ8.69-8.71(m，2H)，8.26(s，1H)，8.25(s，1H)，8.14-8.17(m，1H)，7.81(s，1H)，7.39(dd，J＝8.4Hz，4.0Hz，1H)，3.85-3.92(m，2H)，3.53-3.60(m，2H)，2.72-2.79(m，2H)，2.59-2.65(m，2H)，2.47(s，3H)。

Example 73: 4⁴-chloro-2⁷，4⁶-dimethyl-2⁸，2⁹-dihydro-2⁷H-5-thia-3-aza-2 (9, 2) -purine-1 (4, 1) -piperidine-4 (1, 3) -benzocycloheptane-2⁸-ketones

This compound was synthesized by following the synthesis procedure of example 7 using 2-chloro-4-methyl-5-nitrobenzenethiol as starting material.

¹H NMR(400MHz，DMSO)δ8.23(s，1H)，7.88(s，1H)，7.20(s，1H)，6.86(s，1H)，4.47-4.58(m，1H)，3.41(s，3H)，3.21(t，J＝7.2Hz，2H)，3.12-3.19(m，2H)，3.09(t，J＝7.2Hz，2H)，2.82-2.97(m，4H)，2.29(s，3H)，1.47-1.55(m，2H)。

Example 74: 5⁴-chloro-3⁷，5⁶-dimethyl-3⁸，3⁹-dihydro-3⁷H-6-oxo-4-aza-3 (9, 2) -purine-2 (1, 4) -piperidine-1, 5(1, 3) -dibenzosuberane-3⁸-ketones

This compound was synthesized by following the synthesis procedure of example 7 using 2-chloro-4-methyl-5-nitrophenol and 3-bromobenzyl bromide as starting materials.

¹H NMR(400MHz，DMSO)δ7.79(s，1H)，7.43(s，1H)，7.31(s，1H)，7.12(s，1H)，7.09(t，J＝8.0Hz，1H)，6.86-6.90(m，1H)，6.50(d，J＝7.6Hz，1H)，5.27(s，1H)，5.24(s，2H)，4.64-4.74(m，1H)，4.05-4.13(m，2H)，3.39(s，3H)，3.27(t，J＝13.6Hz，2H)，2.59-2.72(m，2H)，2.22(s，3H)，1.61-1.69(m，2H)。

Example 75: 4- (7-methyl-2- ((6-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-7-yl) amino) -8-oxo-7, 8-dihydro-9H-purin-9-yl) tetrahydro-2H-pyran-4-carbonitrile

Step 1: (E) -N' - (4-iodo-5-methylpyridin-2-yl) -N, N-dimethylformamide

4-iodo-5-methylpyridin-2-amine (2.34g) was dissolved in toluene (50mL) at room temperature, 1-dimethoxy-N, N-dimethylmethylamine (4.0mL) was added thereto, and the reaction mixture was stirred at reflux for 3 hours. Cooled to room temperature and concentrated under reduced pressure to give the title compound (2.5g) as a yellow solid.

Step 2: (E) -N-hydroxy-N' - (4-iodo-5-methylpyridin-2-yl) carboxamide

Hydroxylamine hydrochloride (1.4g) was added to (E) -N' - (4-iodo-5-methylpyridin-2-yl) -N, N-dimethylformamide (2.5g) in MeOH (50mL) at room temperature. The reaction mixture was stirred at reflux for 2h, cooled to room temperature, poured into water and extracted with EtOAc (100 mL). The extract was washed with saturated brine (50mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the title compound (2g) as a yellow solid.

And step 3: 7-iodo-6-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridines

2, 2, 2-trifluoroacetic anhydride (2.1g) was added to (E) -N-hydroxy-N' - (4-iodo-5-methylpyridin-2-yl) formamide (2g) in THF (50mL) at 0 deg.C. The reaction mixture was stirred at room temperature for 18 hours and then concentrated. The reaction solution was poured into water, extracted with ethyl acetate, and the organic phase was evaporated to dryness and the residue was purified by column chromatography (eluent: dichloromethane: methanol 50: 1 (V: V)) to give the title compound (1.2g).

And 4, step 4: 6-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-7-amine

7-iodo-6-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridine (259mg), RuPhos Pd G3(80mg), benzophenone imine (182mg), and cesium carbonate (650mg) were dissolved in toluene (10mL) under nitrogen, heated to 100 ℃ and stirred for 7 hours. Cooled to room temperature, filtered, the solid was washed with dichloromethane, the filtrate was concentrated under reduced pressure, the residue was dissolved in tetrahydrofuran (30mL), 1M dilute hydrochloric acid (10mL) was slowly added, stirring was continued for 1 hour, and a saturated aqueous sodium bicarbonate solution was added to the system until the pH was neutral. Extraction was performed with ethyl acetate, and the organic phase was evaporated to dryness and the residue was purified by column chromatography (eluent: dichloromethane: methanol ═ 10: 1 (V: V)) to give 6-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-7-amine (90 mg).

And 5: 4- (7-methyl-2- ((6-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-7-yl) amino) -8-oxo-7, 8-dihydro-9H-purin-9-yl) tetrahydro-2H-pyran-4-carbonitrile

Intermediate 14- (2-chloro-7-methyl-8-oxo-7, 8-dihydro-9H-purin-9-yl) tetrahydro-2H-pyran-4-carbonitrile (59mg), 6-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-7-amine (30mg), RuPhos Pd G3(9mg), and cesium carbonate (130mg) were dissolved in dioxane (20mL) under nitrogen, heated to 100 ℃ and stirred for 2 hours. Cooled to room temperature, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by thin layer chromatography (developing solvent: dichloromethane: methanol ═ 10: 1 (V: V)) to give the objective compound (56 mg).

¹H NMR(400MHz，DMSO)δ8.71(s，1H)，8.68(s，1H)，8.33(s，1H)，8.27(s，1H)，8.24(s，1H)，3.95-4.01(m，2H)，3.58-3.67(m，2H)，3.32(s，3H)，2.75-2.84(m，2H)，2.67-2.73(m，2H)，2.34(s，3H).

Example 76: 7-methyl-2- ((6-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-7-yl) amino) -9- (tetrahydro-2H-pyran-4-yl) -7, 9-dihydro-8H-purin-8-one

Under the protection of nitrogen, the intermediate 2: 2-chloro-7-methyl-9- (tetrahydro-2H-pyran-4-yl) -7, 9-dihydro-8H-purin-8-one (54mg), 6-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-7-amine (30mg), RuPhos Pd G3(9mg), and cesium carbonate (130mg) were dissolved in dioxane (20mL), heated to 100 ℃ and stirred for 2 hours, cooled to room temperature, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by thin layer chromatography (developing solvent: dichloromethane: methanol ═ 15: 1 (V: V)) to give the objective compound (43mg).

¹H NMR(400MHz，DMSO)δ8.70(s，1H)，8.53(s，1H)，8.39(s，1H)，8.23(s，2H)，4.38-4.50(m，1H)，3.90-4.01(m，2H)，3.40(t，J＝11.2Hz，2H)，3.32(s，3H)，2.44-2.58(m，2H)，2.36(s，3H)，1.62-1.72(m，2H).

Example 77: 4- (7- (methyl-d 3) -2- ((6-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-7-yl) amino) -8-oxo-7, 8-dihydro-9H-purin-9-yl) tetrahydro-2H-pyran-4-carbonitrile

Following example 71, 6-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-7-amine was used as a surrogate amine to undergo a catalytic coupling reaction to give the title compound (44mg).

¹H NMR(400MHz，DMSO)δ8.71(s，1H)，8.68(s，1H)，8.33(s，1H)，8.27(s，1H)，8.24(s，1H)，3.94-4.02(m，2H)，3.58-3.67(m，2H)，2.74-2.84(m，2H)，2.66-2.74(m，2H)，2.34(s，3H)。

Example 78: 4- (7-methyl-2- ((7-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) amino) -8-oxo-7, 8-dihydro-9H-purin-9-yl) tetrahydro-2H-pyran-4-carboxamide

At room temperature, 4- (7-methyl-2- ((7-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) amino) -8-oxo-7, 8-dihydro-9H-purin-9-yl) tetrahydro-2H-pyran-4-carbonitrile (30mg) was dissolved in THF (10mL), 1M NaOH (1mL) was added and heated to 50 ℃ and stirred for 2 hours, the filtrate was cooled to room temperature, the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (eluent: dichloromethane: methanol ═ 10: 1 (V: V)) to give the objective compound (17 mg).

¹H NMR(400MHz，DMSO)δ8.93(s，1H)，8.55(s，1H)，8.33(s，1H)，8.10(s，1H)，7.66(s，1H)，7.33(s，1H)，7.13(s，1H)，3.62-3.70(m，2H)，3.38-3.48(m，2H)，3.25(s，3H)，2.97-3.06(m，2H)，2.32(s，3H)，2.01-2.11(m，2H).

Example 79: 4- (7-methyl-2- ((5-methylbenzo [ d ] oxazol-6-yl) amino) -8-oxo-7, 8-dihydro-9H-purin-9-yl) tetrahydro-2H-pyran-4-carbonitrile

Step 1: 5-methylbenzo [ d ] oxazol-6-amines

6-bromo-5-methylbenzo [ d ] oxazole (212mg), RuPhos Pd G3(80mg), benzophenone imine (182mg) and cesium carbonate (650mg) were dissolved in toluene (10mL) under nitrogen, heated to 100 ℃ and stirred for 5 hours, cooled to room temperature, filtered, the solid washed with dichloromethane then the filtrate was concentrated under reduced pressure, the residue was dissolved in tetrahydrofuran (30mL) and 1M dilute hydrochloric acid (10mL) was slowly added, stirring was continued for 1 hour and then saturated aqueous sodium bicarbonate was added to the system until the pH was neutral. Ethyl acetate was added for extraction, and the organic phase was evaporated to dryness and the residue was purified by column chromatography (developing solvent: dichloromethane: methanol 20: 1 (V: V)) to give 5-methylbenzo [ d ] oxazol-6-amine (50 mg).

Step 2: 4- (7-methyl-2- ((5-methylbenzo [ d ] oxazol-6-yl) amino) -8-oxo-7, 8-dihydro-9H-purin-9-yl) tetrahydro-2H-pyran-4-carbonitrile

Intermediate 14- (2-chloro-7-methyl-8-oxo-7, 8-dihydro-9H-purin-9-yl) tetrahydro-2H-pyran-4-carbonitrile (59mg), 5-methylbenzo [ d ] oxazol-6-amine (30mg), RuPhos Pd G3(9mg), and cesium carbonate (130mg) were dissolved in dioxane (20mL) under nitrogen, heated to 100 ℃ and stirred for 3 hours. Cooled to room temperature, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by thin layer chromatography (developing solvent: dichloromethane: methanol 15: 1 (V: V)) to give the objective compound (33 mg).

¹H NMR(400MHz，DMSO)δ8.62(s，1H)，8.57(s，1H)，8.17(s，1H)，7.95(s，1H)，7.58(s，1H)，3.86-3.92(m，2H)，3.52-3.60(m，2H)，3.28(s，3H)，2.69-2.79(m，2H)，2.56-2.63(m，2H)，2.32(s，3H).

Example 80: (E) -2⁷，4⁷-dimethyl-2⁸，2⁹-dihydro-2⁷H-5-thia-3-aza-2 (9, 2) -purine-4 (6, 3) - [1, 2, 4]]Triazole [4, 3-a ]]Pyridine-1 (4, 1) -piperidine cycloheptane-2⁸-ketones

This compound was synthesized by following the synthesis procedure of example 7 using 7-methyl-6-nitro- [1, 2, 4] triazolo [4, 3-a ] pyridine-3-thiol as the starting material.

¹H NMR(400MHz，DMSO)δ8.83(s，1H)，8.70(s，1H)，8.01(s，1H)，7.49(s，1H)，3.72-3.83(m，1H)，3.21(s，3H)，3.08-3.14(m，2H)，2.59-2.72(m，4H)，2.25(s，3H)，1.72-1.87(m，2H)，1.63-1.71(m，2H)，1.24-1.33(m，2H)。

Example 81: 4- (7-methyl-2- ((6-methylbenzothiazol-5-yl) amino) -8-oxo-7, 8-dihydro-9H-purin-9-yl) tetrahydro-2H-pyran-4-carbonitrile

Intermediate 14- (2-chloro-7-methyl-8-oxo-7, 8-dihydro-9H-purin-9-yl) tetrahydro-2H-pyran-4-carbonitrile (59mg), 6-methylbenzothiazol-5-amine (33mg), RuPhos Pd G3(9mg), and cesium carbonate (130mg) were dissolved in dioxane (20mL) under nitrogen, heated to 100 ℃ and stirred for 2 hours, cooled to room temperature, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by thin layer chromatography (developing solvent: dichloromethane: methanol ═ 20: 1 (V: V)) to give the objective compound (47 mg).

¹H NMR(400MHz，DMSO)δ9.24(s，1H)，8.67(s，1H)，8.25(s，1H)，8.17(s，1H)，7.92(s，1H)，3.85-3.92(m，2H)，3.52-3.60(m，2H)，3.28(s，3H)，2.70-2.79(m，2H)，2.58-2.65(m，2H)，2.35(s，3H)。

Example 82: 4- (7- (fluoromethyl) -2- ((7-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) amino) -8-oxo-7, 8-dihydro-9H-purin-9-yl) tetrahydro-2H-pyran-4-carbonitrile

Analogously to example 1, the intermediate 1 was synthesized by fluorinationIodomethane instead of CH₃I. Cesium carbonate is used as a substitute for sodium hydride as an alkali to obtain a target compound (13mg) through 2 steps of synthesis.

¹H NMR(400MHz，DMSO)δ9.50(s，1H)，8.26(s，1H)，8.14(s，1H)，7.58(s，1H)，6.82(s，1H)，5.90(d，J＝53.6Hz，2H)，4.07-4.14(m，2H)，3.84-3.92(m，2H)，2.73-2.83(m，4H)，2.49(s，3H)。

Example 83: 4- (7- (fluoromethyl) -2- ((7-methylquinolin-6-yl) amino) -8-oxo-7, 8-dihydro-9H-purin-9-yl) tetrahydro-2H-pyran-4-carbonitrile

The reaction was performed in analogy to example 75, using 7-methylquinolin-6-amine as the substituting amine for the catalytic coupling reaction to give the title compound (16mg).

¹H NMR(400MHz，DMSO)δ8.75(dd，J＝4.0Hz，1.6Hz，1H)，8.63(s，1H)，8.14-8.19(m，2H)，7.93(s，1H)，7.34(dd，J＝8.0Hz，4.0Hz，1H)，7.14(s，1H)，5.89(d，J＝53.6Hz，2H)，4.04-4.10(m，2H)，3.84-3.91(m，2H)，2.76-2.86(m，4H)，2.57(s，3H)。

Example 84: 7-methyl-2- ((7-methyl- [1, 2, 4] triazolo [4, 3-a ] pyridin-6-yl) amino) -9- (tetrahydro-2H-pyran-4-yl) -7, 9-dihydro-8H-purin-8-one

Under the protection of nitrogen, the intermediate 2: 2-chloro-7-methyl-9- (tetrahydro-2H-pyran-4-yl) -7, 9-dihydro-8H-purin-8-one (54mg), 7-methyl- [1, 2, 4] triazolo [4, 3-a ] pyridin-6-amine (30mg), RuPhos Pd G3(9mg), and cesium carbonate (130mg) were dissolved in dioxane (20mL), heated to 100 ℃ and stirred for 2 hours. Cooled to room temperature, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by thin layer chromatography (developing solvent: dichloromethane: methanol ═ 15: 1 (V: V)) to give the objective compound (34 mg).

¹H NMR(400MHz，DMSO)δ9.08(s，1H)，8.65(s，1H)，8.34(s，1H)，8.05(s，1H)，7.67(s，1H)，4.33-4.43(m，1H)，3.92(dd，J＝11.2Hz，4.0Hz，2H)，3.33-3.42(m，2H)，3.27(s，3H)，2.41-2.54(m，2H)，2.36(s，3H)，1.60-1.68(m，2H)。

Example 85: 4- (7- (methyl-d 3) -2- ((7-methyl- [1, 2, 4] triazolo [4, 3-a ] pyridin-6-yl) amino) -8-oxo-7, 8-dihydro-9H-purin-9-yl) tetrahydro-2H-pyran-4-carbonitrile

The procedure was followed as in example 71, and 7-methyl- [1, 2, 4] triazolo [4, 3-a ] pyridin-6-amine was used as a substitute amine to conduct a catalytic coupling reaction to give the title compound (24 mg).

¹H NMR(400MHz，DMSO)δ9.58(s，1H)，8.26(s，1H)，7.97(s，1H)，7.57(s，1H)，6.68(s，1H)，4.08-4.13(m，2H)，3.86-3.92(m，2H)，2.75-2.85(m，4H)，2.49(s，3H).

Biological Activity assay

DNA-PK compound bioactivity test method

1. Determination of proliferative Activity of Compounds in MDA-MB-468 cells

The patent relates to a detection method for cell proliferation inhibition, which is established under the condition of combination of a DNA-PK inhibitor established in human breast cancer cells MDA-MB-468 and a chemotherapeutic drug Doxorubicin. The specific method comprises the following steps: human breast cancer cells MDA-MB-468 cells were cultured in RPMI-1640 medium (purchased from Biological Industries, BI) supplemented with 10% fetal bovine serum (FBS, purchased from Hyclone) and 1% penicillin/streptomycin double antibody (P/S, purchased from Life Techology) under the conditions of (37 ℃, 5% CO 2). The day before compound detection, MDA-MB-468 cells were plated in 96-well plates (#3917, purchased from Corning) at a concentration of 1000 cells/190. mu.L/well. After 24 hours Doxorubicin was added to a final concentration of 10nM (DMSO final concentration 0.1%), the test compound was diluted 3-fold in 100% DMSO starting at 10mM (10 concentrations in total), then 2. mu.L of each concentration was added to 48. mu.L of RPMI-1640 medium, and 5. mu.L of each diluted test compound was added to the plated cell suspension. After incubation of the compounds with cells in a Cell incubator for 120h (5 days), the medium was aspirated and incubated again for 5-10 min with 25. mu.L of Cell-Titer Glo (G7570, purchased from Promega) reagent. Fluorescence values were then read on a CLARIO starPlus (purchased from BMG) plate reader and the data were calculated using GraphPad Prism software to obtain IC50 values for inhibition of cell proliferation by this compound.

Partial examples cellular Activity data

Compound numbering	Active IC in MDA-MB-468 cells₅₀(nM)
		Example 39	116
Example 40	29
		EXAMPLE 41	74
Example 42	80
		Example 43	161
Example 44	28
		Example 48	23
Example 53	59
		Example 54	58
Example 56	27
		Example 60	23
Example 67	98
		Example 71	114
Example 72	34

2. Pharmacokinetic data for compounds:

male SD rats are from Beijing Wittingle laboratory animal technology, Inc., the rats are divided into groups of 3 rats, and suspension of samples to be tested (5mg/kg, suspension is 0.5% HPMC, 0.1% Tween 80in H) is orally administrated₂O). Animals were fasted overnight prior to the experiment, with the fasting time ranging from 10 hours prior to dosing to 4 hours post-dosing. Blood was collected at 0.25, 0.5, 1, 2, 4, 6, 8, and 24 hours post-dose, respectively. After isoflurane anesthesia by using a small animal anesthesia machine, 0.3mL of whole blood is collected through an eyeground venous plexus, the whole blood is placed in a heparin anticoagulation tube, a sample is centrifuged at 4000rpm and 4 ℃ for 5 minutes, and the plasma is transferred to a centrifuge tube and stored at-80 ℃ until analysis. Sample use in plasmaProtein precipitation extraction and the extract was analyzed by LC/MS.

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt, solvate, polymorph or isomer thereof,

wherein the content of the first and second substances,

ring A is 6-10 membered aryl or 5-12 membered heteroaryl,

z is O or S, and the compound is,

X₂is CR₂Or the number of N is greater than the number of N,

X₁is CRR₄O, S, or NR₆，

R₁Is H, C_1-6Alkyl, or C_3-8Cycloalkyl, said alkyl and cycloalkyl being optionally substituted by halogen, -CN, -OH, -NH₂、-O-C_1-6Alkyl, or-NR-C_1-6The substitution of the alkyl group is carried out,

m and n are each independently 0, 1, 2, or 3,

R₃is R₅or-X₃-R₅，

R₄Is R₆or-X₃-R₆，

X₃Each independently is-O-, -S-, or-NR-,

R is H or C_1-6An alkyl group.

2. A compound according to claim 1 or a pharmaceutically acceptable salt, solvate, polymorph or isomer thereof, wherein

When R is₅And R₆Each independently selected from H or C_1-6When alkyl, R₂Selected from halogen, CH₂F、CHF₂、CF₃、-OH、-NH₂、CN、C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, -O-C_1-6Alkyl, - (CH)₂)_1-6-CN、-(CH₂)_1-6-O-C_1-6Alkyl, or-NR-C_1-6An alkyl group, a carboxyl group,

when R is₅And R₆Taken together to form- (CH)₂)_p-X-(CH₂)_qWhen is, R₂Selected from H, halogen, CHF₂、CF₃、-OH、-NH₂、CN、C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, -O-C_1-6Alkyl, - (CH)₂)_1-6-CN、-(CH₂)_1-6-O-C_1-6Alkyl and-NR-C_1-6An alkyl group, a carboxyl group,

r is H or C_1-6An alkyl group.

3. A compound according to claim 1, or a pharmaceutically acceptable salt, solvate, polymorph or isomer thereof, wherein

Is composed of

Or

r is H or C_1-6An alkyl group.

4. The compound according to claim 1, or a pharmaceutically acceptable salt, solvate, polymorph or isomer thereof, wherein R₁Is C_1-6Alkyl, which may optionally be substituted by halogen, -CN, -OH, -NH₂、-O-C_1-6Alkyl, or-NR-C_1-6Alkyl substituted, R is H or C_1-6An alkyl group.

5. The following compounds:

or a pharmaceutically acceptable salt, solvate, polymorph or isomer thereof.

6. A pharmaceutical composition comprising a compound according to any one of claims 1-5, or a pharmaceutically acceptable salt, solvate, polymorph, or isomer thereof.

7. Use of a compound according to any one of claims 1 to 5 or a pharmaceutically acceptable salt, solvate, polymorph or isomer thereof or a pharmaceutical composition according to claim 6 for the manufacture of a medicament for the treatment of DNA-PK related diseases.

8. The use of claim 7, wherein the DNA-PK related disease is cancer.

9. The use of claim 7, wherein the DNA-PK associated disease is colorectal cancer, glioblastoma, gastric cancer, ovarian cancer, diffuse large B-cell lymphoma, chronic lymphocytic leukemia, acute myelogenous leukemia, squamous cell carcinoma of the head and neck, breast cancer, prostate cancer, bladder cancer, hepatocellular carcinoma, small cell lung cancer, or non-small cell lung cancer.