A pyridinone compound derivative and use thereof

Abstract

This invention provides a pyridone derivative and its application. The pyridone derivative has the following general chemical structure (I). The pyridone derivative provided by this invention serves as a novel adenosine A derivative. 2A R inhibitors, containing adenosine A 2A R inhibitory activity, which can be used to prepare preparations for prevention or treatment of A 2A Medications for diseases related to R.

Description

Technical Field

[0001] This invention belongs to the field of medicinal chemistry, specifically relating to a pyridone derivative and its role as adenosine A. 2A Receptor (A) 2A The use of R) inhibitors, these compounds contain adenosine A 2A R-inhibitory activity, promising applications in the preparation of drugs for the prevention or treatment of A 2A Medications for diseases related to R. Background Technology

[0002] Adenosine, as an endogenous purine nucleoside, participates in numerous physiological and pathological processes: it is an essential precursor for the synthesis of adenosine triphosphate (ATP), a major molecule for storing cellular energy, and an important metabolic intermediate for the synthesis of nucleotides. Since 1983, four subtypes of adenosine receptors (A1R, A2R, A3R, A4R, A5R, A6R, A7R, A8R, A9 ... 2A R, A 2B The R and A3R receptors were cloned, and extracellular adenosine exerts its effects by regulating these four types of receptors. Adenosine receptors (ARs) belong to a class of G protein-coupled receptors (GPCRs), widely distributed in the body and playing various roles, including vasodilation and ischemia-reperfusion, angiogenesis, cardiac rhythm and circulation, sleep and wakefulness, neurodegenerative diseases, and inflammation. Targeting adenosine receptors to achieve clinical efficacy has a long history and is evident. Adenosine itself, as a generic drug (brand names Adenocard or Adenoscan), is used clinically to treat supraventricular tachycardia; caffeine is used in some clinical situations for apnea in premature infants; and many clinical drugs (dipyridamole, methotrexate) may also exert their effects through adenosine receptors. Regadesone (brand name Lexiscan) was approved by the US FDA as a myocardial perfusion contrast agent for diagnosing coronary artery disease, and itratheline (brand name Nouriast) was marketed in Japan for treating early symptoms of Parkinson's syndrome. These further confirm the role of Adenosine receptors in achieving clinical efficacy. 2A The potential of R as a drug development target.

[0003] In the central nervous system (CNS), adenosine is a potent endogenous neuromodulator that controls the release of many neurotransmitters, thus affecting motor function, sleep, anxiety, pain, and psychomotor activity. The main adenosine receptor subtypes in the brain are A1R and A1R. 2A R. Adenosine A1 receptors (A1Rs) are distributed in high density throughout the brain. A1 receptor inhibitors can lower the seizure threshold and have potential proconvulsant effects (e.g., Cotter G, et al., 2008, J. Card. Fail. 14:631-640). 2A Receptor (A) 2AR) is relatively localized, with high density distribution in the striatum of the basal ganglia (caudate putamen, nucleus accumbens, olfactory tubercle), and is located on striatal output neurons along with dopamine D2 receptors. A 2A The discrete distribution of receptors in the striatum and their inhibitory effect on dopamine D2 receptors cause A 2A Receptor inhibitors have shown improvement in motor disorders caused by neurodegenerative diseases such as Parkinson's disease, Alzheimer's disease, Huntington's disease, and psychosis (e.g., Rodrigo C, et al., Curr. Pharm. Des. 2008, 14: 1512-24; Tuite P, et al., Expert Opin. Investig. Drugs 2003, 12: 1335-52; Popoli P. et al., J. Neurosci. 2002, 22: 1967-75).

[0004] These movement disorders are often the result of brain lesions. Diseases involving the basal ganglia that cause movement disorders include Parkinson's disease, Huntington's disease, and Wilson's disease. Parkinson's disease is characterized by the progressive degeneration of the substantia nigra-striatal dopaminergic pathway. Decreased striatal dopamine levels are the cause of movement disorder symptoms. Tremor, rigidity, movement disorders, and postural changes are the four classic symptoms of Parkinson's disease, but the disease is also associated with sleep disorders, depression, anxiety, psychosis, dementia, and overall cognitive decline (e.g., Jankovic J, et al., J. Neural. Neurosurg. Psychiatry 2008, 79:368-376). Although medications can be used to alleviate symptoms and / or slow the progression of the disease, Parkinson's disease remains a progressive and currently incurable disease, and there are no definitive preventative treatments. Current therapies are based on presynaptic dopamine replacement therapy, such as directly stimulating postsynaptic D2 receptors using the dopamine precursor levodopa (L-DOPA) or inhibiting dopamine metabolism using monoamine oxidase type B (MAO-B) or catechol-O-methyltransferase (COMT). Although L-DOPA is a primary treatment for Parkinson's disease, the need for new therapies remains high due to tolerability issues and numerous adverse reactions, including involuntary movements and vomiting, which tend to worsen with continued treatment. Therefore, highly selective A... 2A Receptor inhibitors have been shown to be effective in reducing motor symptoms associated with neurodegenerative diseases such as Parkinson's disease (e.g., Shook and Jackson, ACS Chem. Neurosci. 2011, 2:555-567).

[0005] A 2AReceptor inhibitors may also be a potentially useful therapy for addiction treatment. Major addictive drugs (opioids, cocaine, ethanol, etc.) directly or indirectly regulate dopamine signaling in neurons, particularly in the nucleus accumbens. The nucleus accumbens contains high levels of dopamine. 2A Activation of receptors and the adenosine signaling pathway showed increased drug dependence, A 2A Receptor inhibitors can reduce cravings for addictive substances (e.g., Stephen H, Macdonald C, Crit. Rev. Neurobiol. 2003, 15: 235-274).

[0006] In recent years, cancer immunotherapy has gained favor from academia and industry, attracting investment from major commercial capital. Immunotherapy drugs targeting toxic T-lymphocyte-associated antigen 4 (CTLA-4) and programmed cell death protein 1 (PD-1) have been successively launched on the market. Immunotherapy is poised to become another revolution following radiotherapy, chemotherapy, and targeted therapy, ushering in a new era in cancer treatment. Despite the success of immunotherapy in various types of cancer, the tumor microenvironment (TME) exhibits multiple compensatory immunosuppressive mechanisms, leading to a low response rate. The adenosine signaling pathway plays a crucial role in the immune-inflammatory regulation of the TME, becoming a key negative feedback loop for downregulating anti-tumor immunity. High concentrations of adenosine are an important marker of the TME, activating Adenosine expression on immune cells such as T lymphocytes, NK cells, monocytes, and dendritic cells. 2A R, thereby suppressing the innate and adaptive immune functions of immune cells. A 2A R inhibitors can block the interaction between adenosine and A. 2A R binds to adenosine, thereby reversing its immunosuppressive effects. As a small molecule immune microenvironment modulator (current cancer immunotherapy almost entirely consists of peptides, antibodies, and cell-based drugs), A 2A R inhibitors can activate anti-tumor immunity, and their potential and market value as cancer immunotherapy drugs are enormous. Summary of the Invention

[0007] The purpose of this invention is to provide a class of compounds as novel adenosine A. 2A Receptor (A) 2A R) inhibitors, containing adenosine A 2A R-inhibitory activity, promising applications in the preparation of drugs for the prevention or treatment of A 2A Medications for diseases related to R.

[0008] In a first aspect, the present invention provides compounds of general chemical formula (I) or pharmaceutically acceptable salts thereof:

[0009]

[0010] X1 is selected from N or C-R1, preferably X1 is N or C-R1, and R1 is selected from hydrogen, halogen, C 1-3 Alkyl, halogen-substituted C 1-3 Alkyl, aryl or heteroaryl, more preferably, R1 is selected from hydrogen, fluorine or chlorine.

[0011] X2 is selected from N or C-R2, where R2 is selected from hydrogen, halogen, C 1-3 Alkyl, halogen-substituted C 1-3 Alkyl group, preferably, R2 is hydrogen, Cl or F.

[0012] Y is selected from O or S.

[0013] Ar is selected from unsubstituted or substituted aryl or heteroaryl groups, wherein the substituents are selected from halogens, C 1-3 Alkyl, C 1-3 alkoxy- or halogen-substituted C 1-3 Alkyl, halogen-substituted C 1-3 At least one of alkoxy and cyano groups; preferably, Ar is an unsubstituted aryl or heteroaryl group having 1-2 substituents, for example... R3, R4, and R5 are independently selected from hydrogen, halogens, and C. 1-3 Alkyl, C 1-3 alkoxy- or halogen-substituted C 1-3 Alkyl, halogen-substituted C 1-3 At least one of alkoxy and cyano groups, where X3 is O, S, or NH, for example, Ar is selected from...

[0014] More preferably, the Ar ring is unsubstituted, or substituted with F at any position, or has a meta-substituent and the other positions on the aromatic ring are unsubstituted, or has a meta-substituent and a small-volume substituent at the ortho position of the adjacent aromatic ring; the meta-substituent is preferably from cyano, methyl, F, Cl, methoxy; the small-volume substituent is preferably from methyl or F, for example, Ar is selected from... Most preferably, Ar has a cyano substitution at the meta position and is not substituted at other positions, or the aromatic ring adjacent to the cyano group has a methyl or F substitution at the ortho position. For example, Ar is selected from...

[0015] R a Selected from unsubstituted or substituted aryl or heteroaryl groups, wherein the substituents are selected from halogens, cyano groups, hydroxyl groups, C6 groups, etc. 1-6 Alkoxyalkylene, C 1-6 Alkyl, halogen-substituted C 1-6 Alkyl, hydroxyl substituted C 1-6 C-substituted with alkyl, halogen and hydroxyl groups 1-6 Alkyl, C3-6 Cycloalkyl, hydroxyl-substituted C 3-6 cycloalkyl, C 1-6 alkoxy- or halogen-substituted C 1-6 alkoxy and carboxyl substituted C 1-6 alkoxy and ester substituted C 1-6 Alkoxy, aminosulfonyl, C 1-6 At least one of alkyl sulfone and ester groups; preferably, R a It is an unsubstituted aryl or heteroaryl group or having 1-2 substituents, for example R6, R7, and R8 are independently selected from hydrogen, halogen, cyano, hydroxyl, and C. 1-6 Alkoxyalkylene, C 1-6 Alkyl, halogen-substituted C 1-6 Alkyl, hydroxyl substituted C 1-6 C-substituted with alkyl, halogen and hydroxyl groups 1-6 Alkyl, C 3-6 Cycloalkyl, hydroxyl-substituted C 3-6 cycloalkyl, C 1-6 alkoxy- or halogen-substituted C 1-6 alkoxy and carboxyl substituted C 1-6 alkoxy and ester substituted C 1-6 Alkoxy, aminosulfonyl, C 1-6 At least one of alkyl sulfone and ester groups, where X4 is CH or N; for example, R a Selected from More preferably, R6, R7, and R8 are independently selected from hydrogen and C. 1-6 Alkyl, halogen-substituted C 1-6 Alkyl, hydroxyl substituted C 1-6 C-substituted with alkyl, halogen and hydroxyl groups 1-6 Alkyl, C 3-6 C substituted with cycloalkyl, hydroxyl and / or halogen 3-6 Cycloalkyl groups. Most preferably, R6, R7, and R8 are independently preferred from hydrogen and C. 1-4 Alkyl, halogen-substituted C 1-4 Alkyl, hydroxyl substituted C 1-4 C-substituted with alkyl, halogen and hydroxyl groups 1-4 Alkyl, C 3-4 C substituted with cycloalkyl, hydroxyl and / or halogen 3-4 Cycloalkyl.

[0016] R b It is selected from hydrogen or halogen, preferably hydrogen, fluorine or chlorine.

[0017] L is selected from C1-6 Alkylene, preferably methylene or ethylene.

[0018] Preferably, X2 is N or C-R2, and R2 is selected from hydrogen, fluorine or chlorine.

[0019] Preferably, the compound is selected from the following compounds:

[0020]

[0021]

[0022]

[0023]

[0024]

[0025]

[0026] Secondly, the present invention provides a method for preparing the compound as described above or a pharmaceutically acceptable salt thereof, comprising the following four synthetic schemes:

[0027] First synthetic method (applicable to compounds where X2 is N and Y is O):

[0028]

[0029] Reagents and conditions: (a) 4,6-dichloropyrimidine-2-amine derivative, potassium bicarbonate, bis(triphenylphosphine)palladium(II) dichloride, ethanol, 78°C, 4 hours, 57-67%; (b) tetra(triphenylphosphine)palladium, cesium carbonate, 1,4-dioxane, 100°C, 12 hours, 73-79%; (c) 48% aqueous hydrogen bromide solution, ethanol, reflux at 100°C, 6 hours, 95%-100%; (d) corresponding brominated derivative (R a -L-Br), N,N-dimethylformamide, 50℃, 16 hours, 62-79%;

[0030] Scheme 1 represents a general synthetic route for some compounds having the general chemical formula (I). Starting material 1.1 is coupled with a 4,6-dichloropyrimidine-2-amine derivative to give a monosubstituted intermediate 1.2, which is then coupled with pinacol ester of 2-methoxy-4-pyridineboronic acid to give intermediate 1.3. Next, the intermediate is refluxed in 48% aqueous hydrobromic acid for 6 hours to remove the methyl group, yielding intermediate 1.4. Finally, it is nucleophilically reacted with the corresponding brominated derivative to give the final product 1.5.

[0031] The second synthetic method (applicable to compounds where X1 is C-R1, X2 is N, and Y is O):

[0032]

[0033] Reagents and conditions: (a) Potassium bicarbonate, bis(triphenylphosphine)palladium(II) chloride, ethanol, 78°C, 4 hours, 57%; (b) N-iodosuccinimide, glacial acetic acid, 25°C, 12 hours, 35%; (c) Potassium bicarbonate, bis(triphenylphosphine)palladium(II) chloride, 1,4-dioxane / water, 95°C, 12 hours, 60%; (d) Tetra(triphenylphosphine)palladium, cesium carbonate, 1,4-dioxane, 100°C, 12 hours, 70-75%; (e) 48% aqueous hydrogen bromide solution, ethanol, reflux, 6 hours, 95%-100%; (f) Corresponding bromide (R) a -L-Br), N,N-dimethylformamide, 50℃, 16 hours, 53-63%;

[0034] Scheme 2 represents a general synthetic route for some compounds having general chemical formula (I). Starting material 1.1 is coupled with 4,6-dichloropyrimidin-2-amine to give a monosubstituted intermediate 1.2, which is then iodinated at the 5-position of the pyrimidine ring by N-iodosuccinimide (NIS) to give intermediate 2.1; coupled with arylboronic acid pinacol ester to give intermediate 2.2; coupled with 2-methoxy-4-pyridinium borate pinacol ester to give intermediate 2.3; then refluxed in 48 wt.% aqueous hydrobromic acid for 6 hours to remove the methyl group, giving intermediate 2.4; finally, it is nucleophilically substituted with the corresponding bromide to give the final product 2.5.

[0035] The third synthetic method (applicable to compounds where X1 is N, X2 is CF, and Y is O):

[0036]

[0037] Reagents and conditions: (a) Ammonia (80%), ethanol, room temperature, 48 hours, 75%; (b) Potassium bicarbonate, bis(triphenylphosphine)palladium(II) chloride, acetonitrile, 90°C, 4 hours, 75-80%; (c) Tetra(triphenylphosphine)palladium, cesium carbonate, 1,4-dioxane, 100°C, 12 hours, 70-75%; (d) 48% aqueous hydrogen bromide solution, ethanol, reflux, 6 hours, 95%-100%; (e) Corresponding brominated product (R) a -L-Br), N,N-dimethylformamide, potassium carbonate, 50℃, 16 hours, 52%;

[0038] Scheme 3 represents a general synthetic route for some compounds having general chemical formula (I). Starting material 3.1 reacts with an ethanolic solution of ammonia to give intermediate 3.2; 3.2 is coupled with pinacol arylboronic acid to give intermediate 3.3; 3.3 is coupled with pinacol 2-methoxy-4-pyridineboronic acid to give intermediate 3.4, which is then refluxed in 48 wt.% aqueous hydrobromic acid for 6 hours to remove the methyl group, giving intermediate 3.5; finally, it is reacted with the corresponding brominated product via nucleophilic substitution to give the final product 3.6.

[0039] The fourth synthetic method (applicable to compounds where Y is S):

[0040]

[0041] Reagents and conditions: Lawson's reagent, toluene, reflux, 0.5 h, 50-55%;

[0042] Scheme 4 represents a general synthetic route for some compounds having the general chemical formula (I); intermediate 4.1 was refluxed with Lawson's reagent in toluene for 0.5 hours to give the target product 4.2.

[0043] Unless otherwise stated, the groups and terms used in the above synthetic schemes have the same meanings as those used in compounds of general formula I.

[0044] Thirdly, the present invention provides a pharmaceutical composition comprising the compound as described above or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0045] Fourthly, the present invention provides a pyridone compound derivative or a pharmaceutically acceptable salt thereof, as described above, for the preparation of a treatment or prevention of A 2A Application in drugs for diseases related to R.

[0046] Preferably, the disease is selected from at least one of cancer, Parkinson's disease, amyotrophic lateral sclerosis, coronary artery disease, mild cognitive impairment, multiple sclerosis, pericardial pseudocirrhosis, rheumatoid arthritis, bipolar disorder, experimental endotoxemia, and schizophrenia.

[0047] Fifthly, the present invention provides an adenosine A 2A R inhibitors, including compounds as described above or pharmaceutically acceptable salts thereof.

[0048] This invention provides a pyridone derivative as a novel adenosine A. 2A R inhibitors, containing adenosine A 2A R inhibitory activity, which can be used to prepare preparations for prevention or treatment of A 2A Medications for diseases related to R. Attached Figure Description

[0049] Figure 1-3 The in vivo efficacy of compound 38 of the present invention in a mouse MC38 xenograft model is shown; wherein, Figure 1 The trend of tumor volume change in the model group and the treatment group (compound 38, 100 mg / kg, po, once a day) in the MC38 colon cancer model; Figure 2 Changes in mouse body weight during drug administration; Figure 3 The outline of the tumor after sampling is displayed. Detailed Implementation

[0050] The present invention will be further described below with reference to the accompanying drawings and the following embodiments. It should be understood that the drawings and the following embodiments are for illustrative purposes only and are not intended to limit the present invention. The same or corresponding reference numerals in the drawings denote the same parts, and repeated descriptions are omitted.

[0051] The above synthesis schemes only illustrate some of the preparation methods of the compounds in this invention. Based on the above synthesis schemes, those skilled in the art can use similar methods to synthesize the compounds of this invention, referring to commonly used techniques and existing technologies in the field.

[0052] The "compounds" described in this invention include all stereoisomers, geometric isomers, tautomers, and isotopes.

[0053] The "compound" described in this invention may be asymmetric, for example, having one or more stereoisomers. Unless otherwise stated, all stereoisomers include, for example, enantiomers and diastereomers. Compounds containing asymmetric carbon atoms in this invention may be isolated in optically active pure form or in racemic form; the optically active pure form may be resolved from racemic mixtures or synthesized using chiral starting materials or chiral reagents.

[0054] The "compound" described in this invention also includes a tautomer form; the tautomer form is derived from the exchange of a single bond with an adjacent double bond and the migration of a proton.

[0055] This invention also includes atoms of all isotopes, whether in intermediates or the final compound; isotopic atoms include those having the same number of atoms but different mass numbers, for example, hydrogen isotopes include deuterium and tritium. Furthermore, if desired, for example for specific therapeutic or diagnostic purposes, the compounds of this invention may incorporate isotopes or radioactive isotopes known in the art, such as… 3 H, 15 O、 13 C or 13 Nitrogen isotopes.

[0056] "Pharmaceutically acceptable salts" refer to salts that are pharmaceutically acceptable in maintaining the pharmacological activity of their parent compounds while improving their physicochemical or metabolic properties. These salts include acid addition salts and base addition salts, or mixtures thereof, prepared from pharmaceutically acceptable acids or bases (including organic acids, inorganic acids, organic bases, and inorganic bases). In this invention, suitable inorganic acids include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, or similar acids; suitable organic acids include acetic acid, propionic acid, hexanoic acid, cyclopentylpropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, mandelic acid, methanesulfonic acid, trifluoromethanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, salicylic acid, stearic acid, mucoconic acid, or their analogues.

[0057] The compounds according to the present invention can also exist in their solvated forms, such as hydrates (hemihydrates, monohydrates, dihydrates, trihydrates, etc.).

[0058] In this invention, unless otherwise specified, the terms used have the following meanings.

[0059] The term "halogen" refers to fluorine, chlorine, bromine or iodine, preferably fluorine or chlorine.

[0060] The term "cyano" refers to -CN.

[0061] The term "hydroxyl group" refers to -OH.

[0062] The term "hydroxymethyl" refers to -CH2OH.

[0063] The term "trifluoromethyl" refers to -CF3.

[0064] The term "alkoxy" refers to -O-alkyl.

[0065] The term "trifluoromethoxy" refers to -OCF3.

[0066] The term "alkoxyalkylene", commonly known as "ether", refers to -alkylene-O-alkyl.

[0067] The term "carboxyl group" refers to -COOH.

[0068] The term "ester group" refers to -COO-alkyl.

[0069] The term "aminosulfonyl" refers to -SO2NH2.

[0070] The term "alkyl sulfone" refers to -SO2-alkyl.

[0071] The term "alkyl" refers to a straight-chain or branched saturated hydrocarbon group consisting of carbon and hydrogen atoms, such as C1-C2. 20Alkyl groups, preferably C1-C6 alkyl groups, such as methyl, ethyl, propyl (including n-propyl and isopropyl), butyl (including n-butyl, isobutyl, sec-butyl, or tert-butyl), pentyl (including n-pentyl, isopentyl, and neopentyl), n-hexyl, 2-methylhexyl, etc. The alkyl group may be unsubstituted or substituted with one or more substituents, including but not limited to alkyl, alkoxy, cyano, hydroxyl, carbonyl, carboxyl, aryl, heteroaryl, amino, halogen, sulfonyl, sulfinyl, and phosphoryl groups.

[0072] The term "cycloalkyl" refers to a cyclic hydrocarbon substituent of a saturated or partially unsaturated monocyclic or polycyclic (fused, spiro, or bridged) ring containing 3 to 8 carbon atoms, preferably 3 to 6 carbon atoms. Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, spiro[3.4]octyl, bicyclo[3.1.1]hexyl, etc. The cycloalkyl group may be unsubstituted or substituted with one or more substituents, including but not limited to alkyl, halogen, sulfonyl, sulfinyl, for example, forming a halocycloalkyl group, preferably a C3-C8 halocycloalkyl group, more preferably a C3-C6 halocycloalkyl group.

[0073] The term "aryl" refers to a fully carbon monocyclic or fused ring with a fully conjugated π-electron system, typically having 6-14 carbon atoms, preferably 6-12 carbon atoms, and most preferably 6 carbon atoms. The aryl group can be unsubstituted or substituted with one or more substituents, including but not limited to alkyl, halogen-substituted alkyl, alkoxy, halogen-substituted alkoxy, cyano, hydroxy, carbonyl, carboxyl, aryl, aralkyl, amino, halogen, sulfonyl, sulfinyl, and phosphoryl. Examples of unsubstituted aryl groups include, but are not limited to, phenyl, naphthyl, and anthracene.

[0074] The term "heteroaryl" refers to a monocyclic or fused ring of 5-12 ring atoms, containing 1-4 ring atoms selected from N, O, and S, with the remaining ring atoms being C, and possessing a fully conjugated π-electron system. Heteroaryl groups include, but are not limited to, pyrroloyl, furanyl, thiophene, imidazolyl, oxazolyl, isoxazolyl, pyrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, quinolinyl, isoquinolinyl, triazolyl, and tetrahydropyrroloyl. Heteroaryl groups can be unsubstituted or substituted, and the substituents include, but are not limited to, alkyl, halogen-substituted alkyl, alkoxy, halogen-substituted alkoxy, aryl, aralkyl, amino, halogen, hydroxyl, cyano, nitro, carbonyl, and heterocyclic alkyl.

[0075] The term "heterocyclic alkyl" refers to a monocyclic or polycyclic (fused, spiro, or bridged) cyclic hydrocarbon substituent that is saturated or partially unsaturated and contains one or more heteroatoms of N, O, or S. Heterocyclic alkyl groups contain 3 to 8 ring atoms, of which 1 to 3 are heteroatoms; preferably, they contain 3 to 6 ring atoms, of which 1 to 2 are heteroatoms. Typically, they are 3- to 6-membered heterocyclic groups containing one or more heteroatoms of N, O, or S, such as azirropropane-1-yl, oxacyclobutane-3-yl, azirrobutane-3-yl, azirrobutane-1-yl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazineyl, tetrahydropyranyl, tetrahydrothiopyranyl, dioxotetrahydrothiopyranyl, morpholinyl, and their derivatives. The heterocyclic alkyl group may be unsubstituted or substituted with one or more substituents, including but not limited to alkyl, halogen, sulfonyl, sulfinyl, and oxo groups, for example forming a haloheterocyclic alkyl group, preferably a haloheterocyclic alkyl group containing 3-8 ring atoms.

[0076] The term "alkylene" refers to a divalent group formed by the loss of a hydrogen atom from an alkyl group, wherein the alkyl group is as defined above. Alkylenes contain 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms. Examples include methylene, ethylene, propylene, and butylene.

[0077] “Treatment” means any treatment of disease in a mammal, including: (1) preventing disease, i.e. causing the symptoms of clinical disease to not develop; (2) suppressing disease, i.e. preventing the development of clinical symptoms; and (3) alleviating disease, i.e. causing the disappearance of clinical symptoms.

[0078] The present invention also provides a pharmaceutical composition comprising, as an active ingredient, a compound as described above or a pharmaceutically acceptable salt or solvate thereof, and one or more pharmaceutically acceptable carriers.

[0079] The term "pharmaceutical composition" as used in this invention refers to a formulation comprising one or more compounds of the invention or salts thereof, and a carrier commonly accepted in the art for delivering a bioactive compound to an organism (e.g., a human). The purpose of the pharmaceutical composition is to facilitate drug delivery to the organism.

[0080] The term "pharmaceutically acceptable carrier" refers to a substance that is co-administered with the active ingredient and facilitates the administration of the active ingredient. This includes, but is not limited to, any flow aids, sweeteners, diluents, preservatives, dyes / colorants, flavor enhancers, surfactants, wetting agents, dispersants, disintegrants, suspending agents, stabilizers, isotonic agents, solvents, or emulsifiers approved by the National Medical Products Administration for use in humans or animals (e.g., livestock). Examples include, but are not limited to, calcium carbonate, calcium phosphate, various sugars and starches, cellulose derivatives, gelatin, vegetable oils, and polyethylene glycol.

[0081] The pharmaceutical compositions described in this invention can be formulated into solid, semi-solid, liquid, or gaseous preparations, such as tablets, pills, capsules, powders, granules, ointments, emulsions, suspensions, solutions, suppositories, injections, inhalers, gels, microspheres, and aerosols, etc.

[0082] The pharmaceutical composition described in this invention can be manufactured using methods well known in the art, such as conventional mixing, dissolving, granulation, sugar-coated pill making, grinding, emulsification, freeze drying, etc.

[0083] The routes of administration for the compounds or pharmaceutically acceptable salts thereof or pharmaceutical compositions described in this invention include, but are not limited to, oral, rectal, transmucosal, enteral, or local, transdermal, inhalation, parenteral, sublingual, intravaginal, intranasal, intraocular, intraperitoneal, intramuscular, subcutaneous, and intravenous administration. The preferred route of administration is oral administration.

[0084] For oral administration, the pharmaceutical composition can be formulated by mixing the active compound with a pharmaceutically acceptable carrier well known in the art. These carriers enable the compounds of the present invention to be formulated into tablets, pills, lozenges, sugar-coated tablets, capsules, liquids, gels, pastes, suspensions, etc., for oral administration to patients. For example, a pharmaceutical composition for oral administration can be obtained as a tablet by combining the active ingredient with one or more solid carriers, granulating the resulting mixture if necessary, and adding a small amount of excipients to process it into a mixture or granules to form a tablet or tablet core. The tablet core can be combined with a coating material optionally suitable for enteric coating to process it into a coated formulation more favorable for absorption by the organism (e.g., human).

[0085] Pharmaceutically acceptable salts of the compounds of this invention include conventional non-toxic salts formed by the reaction of a base with an inorganic or organic acid. Specifically, the reaction is carried out using the free base of the compound, reacting with an inorganic or organic acid to form a salt. The inorganic or organic acid may be selected from hydrochloric acid, sulfuric acid, nitric acid, hydrofluoric acid, hydrobromic acid, formic acid, acetic acid, picric acid, citric acid, maleic acid, methanesulfonic acid, trifluoromethanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, etc.

[0086] If the inventive compound is acidic, then a suitable "pharmaceutically acceptable salt" refers to a salt prepared from a pharmaceutically acceptable non-toxic alkali, including inorganic and organic bases. Options include aluminum salts, ammonium salts, lithium salts, magnesium salts, sodium salts, etc. Particularly preferred are ammonium salts, calcium salts, magnesium salts, potassium salts, and sodium salts. Salts derived from pharmaceutically acceptable non-toxic organic alkalis, including salts of primary, secondary, and tertiary amines, with substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins such as arginine, betaine, and caffeine, are also acceptable.

[0087] The present invention also provides a compound as described above or a pharmaceutically acceptable salt or solvate thereof, or the aforementioned pharmaceutical composition in the preparation of adenosine A. 2A Applications of R inhibitors.

[0088] The present invention also provides a compound as described above, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition thereof, as adenosine A. 2A R inhibitors are used in the preparation of drugs for the treatment or prevention of A. 2A Use in drugs for diseases related to R.

[0089] The aforementioned and A 2A The diseases associated with R are selected from cancer, Parkinson's disease, amyotrophic lateral sclerosis (ALS), coronary artery disease, mild cognitive impairment, multiple sclerosis, Pick's disease, rheumatoid arthritis, bipolar disorder, experimental endotoxemia, and schizophrenia, or a combination of the aforementioned diseases.

[0090] In summary, this invention provides a class of compounds with the general formula (I). Studies have shown that these compounds can effectively inhibit adenosine A. 2A Receptors regulate the level of intracellular cyclic adenosine monophosphate (cAMP) in the immune microenvironment, thereby modulating the body's immune physiological responses and potentially serving as a treatment or preventative measure against A. 2A Drugs related to R-related diseases.

[0091] In addition to standard methods known in the literature or illustrated in experimental procedures, the compounds of the present invention can be prepared by reactions shown in the following schemes. Therefore, the following illustrative schemes are for illustrative purposes and not limited to the listed compounds or any particular substituents. The number of substituents shown in the schemes does not necessarily need to conform to the number used in the claims, and for clarity, the definition of showing a single substituent connected to the structure of this patent allows for compounds with multiple substituents.

[0092] The present invention will be further described in detail below with reference to specific embodiments. It should also be understood that the following embodiments are only for further illustration of the present invention and should not be construed as limiting the scope of protection of the present invention. Any non-essential improvements and adjustments made by those skilled in the art based on the above description of the present invention are within the scope of protection of the present invention. The specific process parameters, etc., in the following examples are merely examples within a suitable range; that is, those skilled in the art can make appropriate selections within the appropriate range based on the description herein, and are not intended to be limited to the specific values ​​in the examples below.

[0093] In the method for preparing the target compound provided by this invention, column chromatography uses silica gel (300-400 mesh) produced by Rushan Taiyang Desiccant Co., Ltd.; thin-layer chromatography uses GF254 (0.25 mm); nuclear magnetic resonance chromatography (NMR) is performed using a Varian-400 NMR spectrometer; and liquid chromatography-mass spectrometry (LC / MS) is performed using an Agilent Technologies 6120 LC / MS system.

[0094] Furthermore, all operations involving easily oxidized or hydrolyzed raw materials are performed under nitrogen protection. Unless otherwise stated, the raw materials used in this invention are commercially available and can be used directly without further purification, although it should be understood that purification may be necessary before use.

[0095] PE: Petroleum ether;

[0096] EA: Ethyl acetate;

[0097] DCM: Dichloromethane;

[0098] CH3CN: Acetonitrile;

[0099] MeOH: Methanol;

[0100] EtOH: Ethanol;

[0101] DMF: N,N'-dimethylformamide;

[0102] HOAc: Glacial acetic acid;

[0103] KHCO3: Potassium bicarbonate;

[0104] K2CO3: Potassium carbonate;

[0105] Cs2CO3: Cesium carbonate;

[0106] Pd(PPh3)4: Tetra(triphenylphosphine)palladium;

[0107] PdCl2(PPh3)2: Bis(triphenylphosphine)palladium(II) dichloride;

[0108] NIS: N-iodosuccinimide;

[0109] TLC: Thin-layer silicone plate (G254) analysis;

[0110] P-TLC: Preparation of thin-layer silicone plates.

[0111] Example 1: Preparation of Compound 1

[0112] Preparation of 4-(2-amino-6-(5-methylfuran-2-yl)pyrimidin-4-yl)-1-benzylpyridin-2(1H)-one

[0113]

[0114] Step 1: Preparation of 4-chloro-6-(5-methylfuran-2-yl)pyrimidin-2-amine

[0115] 4,4,5,5-Tetramethyl-2-(5-methylfuran-2-yl)-1,3,2-dioxoborane (1.04 g, 5 mmol), 4,6-dichloropyrimidin-2-amine (820 mg, 5 mmol), potassium bicarbonate (1 g, 10 mmol), and bis(triphenylphosphine)palladium dichloride (702 mg, 1 mmol) were placed in a 100 mL flask, and 20 mL of ethanol was added, followed by complete nitrogen purging. The flask was then placed in an oil bath at 78 °C and reacted for 4 h. The reaction was monitored by TLC. After the reaction was complete, the mixture was cooled to room temperature. The solution was diluted with ethyl acetate and then washed successively with water and saturated brine. The organic phase was dried over anhydrous sodium sulfate. After concentration, the solution was separated by column chromatography (dichloromethane / ethyl acetate = 100 / 1 to 40 / 1) to give a white solid product (576 mg, 55%).

[0116] Step 2: Preparation of 4-(2-methoxypyridin-4-yl)-6-(5-methylfuran-2-yl)pyrimidine-2-amine

[0117] The products from step 1, 4-chloro-6-(5-methylfuran-2-yl)pyrimidin-2-amine (576 mg, 2.75 mmol), 2-methoxypyridine-4-pentanoylboronic acid (775.5 mg, 3.3 mmol), cesium carbonate (1.8 g, 5.5 mmol), and tetraphenylphosphine palladium (635 mg, 0.55 mmol), were placed in a 100 mL flask, and 15 mL of dioxane and 3 mL of water were added, followed by complete nitrogen purging. The flask was then placed in an oil bath at 100 °C and reacted for 12 h. The reaction was monitored by TLC. After the reaction was complete, the mixture was cooled to room temperature. It was diluted with dichloromethane and then washed successively with water and saturated brine. The organic phase was dried over anhydrous sodium sulfate. After concentration, the product was separated by column chromatography (dichloromethane / ethyl acetate = 10 / 1 to 3 / 1) to obtain a white solid product (605 mg, 78%).

[0118] Step 3: Preparation of 4-(2-amino-6-(5-methylfuran-2-yl)pyrimidin-4-yl)pyridin-2(1H)-one

[0119] The product from step 2, 4-(2-methoxypyridin-4-yl)-6-(5-methylfuran-2-yl)pyrimidin-2-amine (605 mg, 2.1 mmol), was placed in a 50 mL flask, 2 mL of ethanol was added, followed by 4 mL of 48 wt.% aqueous hydrobromic acid solution. The flask was then placed in an oil bath at 100 °C and reacted for 6 h. The reaction was monitored by TLC. After the reaction was complete, the mixture was cooled to room temperature. Neutralization was performed using 8 mmol / mL sodium hydroxide solution until the pH reached 8-9. At this point, the product precipitated as a solid. After filtration and drying, the excess product (610 mg, containing some salt) was obtained and, based on 100% conversion, could be used in the next step without further purification.

[0120] Step 4: Preparation of 4-(2-amino-6-(5-methylfuran-2-yl)pyrimidin-4-yl)-1-benzylpyridin-2(1H)-one

[0121] Take 300 mg of the product from step 3, 4-(2-amino-6-(5-methylfuran-2-yl)pyrimidin-4-yl)pyridin-2(1H)-one, 205 mg (1.2 mmol), and 276 mg (2 mmol) of potassium carbonate, and place them in a 50 mL flask. Add 5 mL of N,N-dimethylformamide. Then place the flask in an oil bath at 50 °C and react for 12 h. Monitor the reaction by TLC. After the reaction is complete, cool to room temperature. Dilute with dichloromethane, and then wash successively with water and saturated brine. Take the organic phase and dry it with anhydrous sodium sulfate. After concentration, separate by column chromatography (dichloromethane / methanol = 300 / 3 to 300 / 6) to obtain a white solid product (143 mg, 40%).

[0122] 1 H NMR(400MHz, DMSO-d6)δ7.93(d,J=7.1Hz,1H),7.42(s,1H),7.39–7.26(m,6H),7.19(d, J=1.8Hz,1H),6.96–6.83(m,3H),6.34(dd,J=3.3,0.8Hz,1H),5.16(s,2H),2.39(s,3H). 13C NMR(101MHz,DMSO-d6)δ163.79,161.60,161.48,156.98,154.92,150.05,148.02,139.27,137.29 ,128.59,127.64,127.54,117.14,113.90,108.96,103.28,100.40,51.05,13.60.ESI(m / z):[M+H] + 358.9.

[0123] Example 2: Preparation of Compound 2

[0124] Preparation of 4-(2-amino-6-phenylpyrimidin-4-yl)-1-benzylpyridin-2(1H)-one

[0125]

[0126] The synthetic route was followed as described in Example 1. The starting material was 4,4,5,5-tetramethyl-2-phenyl-1,3,2-dioxoborane. The product was separated by column chromatography (dichloromethane / methanol = 300 / 3 to 300 / 6) to obtain a white solid product (180 mg, 19%).

[0127] 1 H NMR (400MHz, DMSO-d6) δ8.25 (dd, J=6.7, 3.0Hz, 2H), 7.96 (d, J=7.1Hz, 1H), 7.76 (s, 1H), 7. 56–7.50(m,3H),7.39–7.28(m,6H),7.03(dd,J=7.1,1.9Hz,1H),6.91(s,2H),5.18(s,2H). 13 C NMR(101MHz,DMSO-d6)δ165.47,163.94,162.12,161.66,148.14,139.18,137.29,136.91,130 .69,128.62,128.57,127.65,127.52,127.10,117.48,103.46,102.60,51.07.ESI(m / z):[M+H] + 354.9.

[0128] Example 3: Preparation of Compound 3

[0129] Preparation of 4-(2-amino-6-(o-tolyl)pyrimidin-4-yl)-1-benzylpyridin-2(1H)-one

[0130]

[0131] The synthetic route was followed as described in Example 1. The starting material was 4,4,5,5-tetramethyl-2-(o-tolyl)-1,3,2-dioxoborane. The product was separated by column chromatography (dichloromethane / methanol = 300 / 3 to 300 / 6) to obtain a white solid product (90 mg, 8%).

[0132] 1 H NMR(400MHz,DMSO-d6)δ7.92(d,J=7.1Hz,1H),7.47(d,J=7.6Hz,1H),7.38–7.26(m,9H),7 .20(d,J=1.7Hz,1H),6.94(dd,J=7.1,1.9Hz,1H),6.89(s,2H),5.16(s,2H),2.40(s,3H). 13 C NMR(101MHz,DMSO-d6)δ169.07,163.59,161.57,161.23,148.04,139.23,138.50,137.27,135.53,130.69 ,129.16,128.97,128.57,127.68,127.53,125.79,117.32,106.42,103.37,51.04,20.10.ESI(m / z):[M+H] + 368.9.

[0133] Example 4: Preparation of Compound 4

[0134] Preparation of 4-(2-amino-6-(m-tolyl)pyrimidin-4-yl)-1-benzylpyridin-2(1H)-one

[0135]

[0136] The synthetic route was followed as described in Example 1. The starting material was 4,4,5,5-tetramethyl-2-(m-tolyl)-1,3,2-dioxoborane. The product was separated by column chromatography (dichloromethane / methanol = 300 / 3 to 300 / 6) to obtain a white solid product (105 mg, 15%).

[0137] 1 H NMR (400MHz, DMSO-d6) δ8.09(s,1H),8.04(d,J=7.7Hz,1H),7.95(d,J=7.1Hz,1H),7.73(s, 1H),7.42–7.28(m,8H),7.02(dd,J=7.1,1.6Hz,1H),6.89(s,2H),5.18(s,2H),2.41(s,3H). 13C NMR(101MHz,DMSO-d6)δ165.55,163.92,162.03,161.66,148.17,139.16,137.83,137.31,136.85,131 .31,128.58,128.50,127.64,127.52,124.27,117.45,103.46,102.59,51.05,21.02.ESI(m / z):[M+H] + 368.9.

[0138] Example 5: Preparation of Compound 5

[0139] Preparation of 4-(2-amino-6-(p-tolyl)pyrimidin-4-yl)-1-benzylpyridin-2(1H)-one

[0140]

[0141] The synthetic route was followed as described in Example 1. The starting material was 4,4,5,5-tetramethyl-2-(p-tolyl)-1,3,2-dioxoborane. The product was separated by column chromatography (dichloromethane / methanol = 300 / 3 to 300 / 6) to give a white solid product (125 mg, 16%).

[0142] 1 H NMR (400MHz, DMSO-d6) δ8.16(d,J=8.2Hz,2H),7.95(d,J=7.1Hz,1H),7.72(s,1H),7.34(d t,J=7.9,4.6Hz,8H),7.02(dd,J=7.1,1.9Hz,1H),6.85(s,2H),5.18(s,2H),2.39(s,3H). 13 C NMR(101MHz,DMSO-d6)δ165.35,163.88,161.94,161.64,148.20,140.56,139.13,137.30,134.12 ,129.21,128.57,127.64,127.51,127.03,117.39,103.45,102.25,51.03,20.95.ESI(m / z):[M+H] + 368.9.

[0143] Example 6: Preparation of Compound 6

[0144] Preparation of 4-(2-amino-6-(3-methoxyphenyl)pyrimidin-4-yl)-1-benzylpyridin-2(1H)-one

[0145]

[0146] The synthetic route was followed as described in Example 1. The starting material was 2-(3-methoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxoborane. The product was separated by column chromatography (dichloromethane / methanol = 300 / 3 to 300 / 6) to obtain a white solid product (110 mg, 15%).

[0147] 1 H NMR (400MHz, DMSO-d6) δ7.96(d,J=7.2Hz,1H),7.85(d,J=7.9Hz,1H),7.80(d,J=2.1Hz,1H),7.76(s,1H),7.44(t,J=8.0Hz ,1H),7.40–7.27(m,6H),7.11(dd,J=8.1,2.2Hz,1H),7.04(dd,J=7.1,1.9Hz,1H),6.93(s,2H),5.19(s,2H),3.86(s,3H). 13 C NMR (101MHz, DMSO-d6) δ165.29,163.89,162.30,162.17,161.68,159.61,148.14,139.15,138.44,137.31,129 .70,128.58,127.66,127.53,119.53,117.56,116.48,112.24,103.51,102.79,55.29,51.08.ESI(m / z):[M+H] + 384.9.

[0148] Example 7: Preparation of Compound 7

[0149] Preparation of 4-(2-amino-6-(3-(trifluoromethoxy)phenyl)pyrimidin-4-yl)-1-benzylpyridin-2(1H)-one

[0150]

[0151] The synthetic route was followed as described in Example 1. The starting material was 4,4,5,5-tetramethyl-2-(3-(trifluoromethoxy)phenyl)-1,3,2-dioxoborane. The product was separated by column chromatography (dichloromethane / methanol = 300 / 3 to 300 / 6) to obtain a white solid product (87 mg, 10%).

[0152] 1H NMR (400MHz, DMSO-d6) δ8.32(d,J=8.0Hz,1H),8.25(s,1H),7.96(d,J=7.1Hz,1H),7.85(s,1H), 7.67(t,J=8.0Hz,1H),7.54(d,J=8.2Hz,1H),7.39–7.28(m,6H),7.05–6.96(m,3H),5.18(s,2H). 13 C NMR(101MHz,DMSO-d6)δ163.90,163.57,162.62,161.66,148.85,147.90,139.32,139.21,137.29,130.70,128 .58,127.63,127.52,126.18,123.11,121.40,119.52,118.85,117.69,103.39,102.75,51.07.ESI(m / z):[M+H] + 438.9.

[0153] Example 8: Preparation of Compound 8

[0154] Preparation of 4-(2-amino-6-(3-(trifluoromethyl)phenyl)pyrimidin-4-yl)-1-benzylpyridin-2(1H)-one

[0155]

[0156] The synthetic route was followed as described in Example 1. The starting material was 4,4,5,5-tetramethyl-2-(3-(trifluoromethyl)phenyl)-1,3,2-dioxoborane. The product was separated by column chromatography (dichloromethane / methanol = 300 / 3 to 300 / 6) to obtain a white solid product (90 mg, 11%).

[0157] 1 H NMR (400MHz, DMSO-d6) δ8.62–8.56(m,2H),7.96(d,J=7.1Hz,1H),7.90(d,J=6.9H z,2H),7.79(d,J=7.8Hz,1H),7.40–7.27(m,6H),7.08–6.96(m,3H),5.18(s,2H). 13CNMR(101MHz,DMSO-d6)δ163.93,163.64,162.70,161.65,147.90,139.19,137.93,137.28,131.07,129.81,129.73,129.41 ,128.56,127.62,127.51,127.12,127.08,125.53,123.53,123.49,122.82,117.72,103.40,102.74,51.07.ESI(m / z):[M+H] + 422.9.

[0158] Example 9: Preparation of Compound 9

[0159] Preparation of 4-(2-amino-6-(3-fluorophenyl)pyrimidin-4-yl)-1-benzylpyridin-2(1H)-one

[0160]

[0161] The synthetic route was followed as described in Example 1. The starting material was 2-(3-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxoborane. The product was separated by column chromatography (dichloromethane / methanol = 300 / 3 to 300 / 6) to obtain a white solid product (75 mg, 8%).

[0162] 1 H NMR(400MHz,DMSO-d6)δ8.75(s,1H),8.58(d,J=8.1Hz,1H),7.99(dd,J=12.3,7.4Hz,2H) ,7.92(s,1H),7.75(t,J=7.9Hz,1H),7.41–7.32(m,6H),7.07–7.01(m,3H),5.19(s,2H). 13 C NMR(101MHz,DMSO-d6)δ163.96(t,J=9.9Hz),162.56(s),161.74(s),161.43(s), 148.03(s),139.55(d,J=7.7Hz),139.28(s),137.37(s),130.72(d,J=8.1Hz),12 8.66(s),127.67(d,J=11.7Hz),123.22(s),117.68(d,J=8.5Hz),117.42(s),113 .89(s),113.66(s),103.48(s),102.82(s),54.98(s),51.16(s).ESI(m / z):[M+H] + 372.9.

[0163] Example 10: Preparation of Compound 10

[0164] Preparation of 3-(2-amino-6-(1-benzyl-2-oxo-1,2-dihydropyridin-4-yl)pyrimidin-4-yl)benzonitrile

[0165]

[0166] The synthetic route was followed as described in Example 1. The starting material was 3-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)benzonitrile. The product was separated by column chromatography (dichloromethane / methanol = 300 / 3 to 300 / 6) to obtain a white solid product (120 mg, 14%).

[0167] 1 H NMR(400MHz,DMSO-d6)δ8.75(s,1H),8.58(d,J=8.1Hz,1H),7.99(dd,J=12.3,7.4Hz,2H) ,7.92(s,1H),7.75(t,J=7.9Hz,1H),7.41–7.32(m,6H),7.07–7.01(m,3H),5.19(s,2H). 13 C NMR(101MHz,DMSO-d6)δ163.93,163.19,162.69,161.66,147.83,139.22,137.99,137.27,134.00,131.47, 130.81,129.96,128.57,127.63,127.52,118.59,117.72,111.93,103.33,102.73,51.10.ESI(m / z):[M+H] + 379.9.

[0168] Example 11: Preparation of Compound 11

[0169] Preparation of 3-(2-amino-6-(1-benzyl-2-oxo-1,2-dihydropyridin-4-yl)pyrimidin-4-yl)-2-methylbenzonitrile

[0170]

[0171] The synthetic route was followed as described in Example 1. The starting material was 22-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)benzonitrile. The product was separated by column chromatography (dichloromethane / methanol = 300 / 3 to 300 / 6) to give a white solid product (160 mg, 16%).

[0172] 1 H NMR (400MHz, DMSO-d6) δ7.97–7.87(m,2H),7.82–7.76(m,1H),7.52(t,J=7.7Hz,1H),7.40–7.26(m,6H ),7.22(d,J=1.8Hz,1H),7.01(s,2H),6.94(dd,J=7.1,1.9Hz,1H),5.15(s,2H),2.55(d,J=4.5Hz,3H). 13 C NMR(101MHz,DMSO-d6)δ167.30,163.61,161.75,161.54,147.74,139.85,139.31,139.27,137.24,133.93,133 .32,128.56,127.66,127.53,126.86,117.97,117.51,113.16,106.53,103.26,51.06,18.33.ESI(m / z):[M+H] + 393.9.

[0173] Example 12: Preparation of Compound 12

[0174] Preparation of 5-(2-amino-6-(1-benzyl-2-oxo-1,2-dihydropyridin-4-yl)pyrimidin-4-yl)-2-methylbenzonitrile

[0175]

[0176] The synthetic route was followed as described in Example 1. The starting material was 2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)benzonitrile. The product was separated by column chromatography (dichloromethane / methanol = 300 / 3 to 300 / 6) to give a white solid product (80 mg, 9%).

[0177] 1 H NMR (400MHz, DMSO-d6) δ8.68(d,J=1.7Hz,1H),8.47(dd,J=8.2,1.8Hz,1H),7.96(d,J=7.1Hz,1H),7.88(s,1H) ,7.63(d,J=8.3Hz,1H),7.39–7.28(m,6H),7.03(dd,J=7.1,1.9Hz,1H),6.97(s,2H),5.17(s,2H),2.56(s,3H). 13C NMR(101MHz,DMSO-d6)δ163.88,163.13,162.54,161.66,147.88,143.94,139.20,137.28,135.32,131.26,131 .06,130.85,128.58,127.63,127.52,117.75,117.65,112.35,103.33,102.40,51.07,19.89.ESI(m / z):[M+H] + 393.9.

[0178] Example 13: Preparation of Compound 13

[0179] Preparation of 3-(2-amino-6-(1-benzyl-2-oxo-1,2-dihydropyridin-4-yl)pyrimidin-4-yl)-5-methylbenzonitrile

[0180]

[0181] The synthetic route was followed as described in Example 1. The starting material was 3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)benzonitrile. The product was separated by column chromatography (dichloromethane / methanol = 300 / 3 to 300 / 6) to give a white solid product (78 mg, 8%).

[0182] 1 H NMR (400MHz, DMSO-d6) δ8.53 (s, 1H), 8.42 (s, 1H), 7.97 (d, J = 7.1Hz, 1H), 7.88 (s, 1H),7.82(s,1H),7.39–7.30(m,6H),7.05–6.98(m,3H),5.18(s,2H),2.46(s,3H). 13 CNMR(101MHz,DMSO-d6)δ163.91,163.26,162.62,161.67,147.85,139.87,139.22,137.89,137.28,134.15,13 2.16,128.58,128.03,127.63,127.53,118.69,117.69,111.75,103.33,102.70,51.09,20.62.ESI(m / z):[M+H] + 393.9.

[0183] Example 14: Preparation of Compound 14

[0184] Preparation of 3-(2-amino-6-(1-benzyl-2-oxo-1,2-dihydropyridin-4-yl)pyrimidin-4-yl)-4-methylbenzonitrile

[0185]

[0186] The synthetic route was followed as described in Example 1. The starting material was 4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)benzonitrile. The product was separated by column chromatography (dichloromethane / methanol = 300 / 3 to 300 / 6) to obtain a white solid product (85 mg, 9%).

[0187] 1 H NMR (400MHz, DMSO-d6) δ7.99(d,J=1.0Hz,1H),7.96(d,J=7.1Hz,1H),7.83(dd,J=7.9,1.3Hz,1H),7.54(d,J=8.0Hz,1H ),7.41(s,1H),7.32(ddd,J=18.5,9.3,4.1Hz,6H),7.02(s,2H),6.98(dd,J=7.1,1.6Hz,1H),5.17(s,2H),2.51(s,3H). 13 C NMR(101MHz,DMSO-d6)δ166.94,163.56,161.87,161.61,147.85,142.11,139.38,139.31,137.27,132.95,132 .39,132.01,128.59,127.68,127.56,118.67,117.57,108.93,106.46,103.35,51.10,20.53.ESI(m / z):[M+H] + 393.9.

[0188] Example 15: Preparation of Compound 15

[0189] Preparation of 3-(2-amino-6-(2-oxo-1-phenethyl-1,2-dihydropyridin-4-yl)pyrimidin-4-yl)-2-methylbenzonitrile

[0190]

[0191] Following the synthetic route of Example 11, bromophenylethane was selected for the substitution reaction in step 4. The product was separated by column chromatography (dichloromethane / methanol = 300 / 3 to 300 / 6) to give a white solid product (76 mg, 8%).

[0192] 1H NMR (400MHz, DMSO-d6) δ7.90(dd,J=7.7,0.9Hz,1H),7.78(d,J=7.7Hz,1H),7.63(d,J=7.1Hz,1H),7.52(t,J=7.7Hz,1H),7.34–7. 27(m,3H),7.26–7.18(m,4H),7.01(s,2H),6.82(dd,J=7.1,1.9Hz,1H),4.15(t,J=7.4Hz,2H),2.98(t,J=7.4Hz,2H),2.56(s,3H). 13 C NMR(101MHz,DMSO-d6)δ167.30,163.60,161.78,161.49,147.49,139.86,139.28,138.08,133.94,133.31,128.8 0,128.43,126.87,126.45,117.99,117.15,113.15,106.47,102.59,54.90,50.00,34.28,18.34.ESI(m / z):[M+H] + 407.9.

[0193] Example 16: Preparation of Compound 16

[0194] Preparation of 3-(2-amino-6-(1-(4-(2-hydroxypropane-2-yl)benzyl)-2-oxo-1,2-dihydropyridin-4-yl)pyrimidin-4-yl)-2-methylbenzonitrile

[0195]

[0196] Referring to the synthetic route in Example 11, 2-(4-(bromomethyl)phenyl)prop-2-ol was selected for substitution reaction in step 4.

[0197] 1 H NMR (400MHz, DMSO) δ7.95–7.89(m,2H),7.81–7.77(m,1H),7.53(t,J=7.7Hz,1H),7.44(d,J=8.3Hz,2H),7.34(s,1H),7.26(d,J= 8.3Hz,2H),7.21(d,J=1.8Hz,1H),7.00(s,2H),6.93(dd,J=7.1,1.9Hz,1H),5.12(s,2H),4.99(s,1H),2.56(s,3H),1.40(s,6H).

[0198] Example 17: Preparation of Compound 17

[0199] Preparation of 3-(2-amino-6-(1-(4-(2-fluoropropane-2-yl)benzyl)-2-oxo-1,2-dihydropyridin-4-yl)pyrimidin-4-yl)-2-methylbenzonitrile

[0200]

[0201] Referring to the synthetic route in Example 11, 1-(bromomethyl)-4-(2-fluoroprop-2-yl)benzene was selected for substitution reaction in step 4.

[0202] 1 H NMR (400MHz, DMSO) δ7.96(d,J=7.2Hz,1H),7.91(dd,J=7.7,0.9Hz,1H),7.79(d,J=6.9Hz,1H),7.52(dd,J=13.6,5.8Hz,1H),7.40(d,J=8.3Hz,2 H),7.33(d,J=7.6Hz,3H),7.22(d,J=1.8Hz,1H),7.01(s,2H),6.95(dd,J=7.1,1.9Hz,1H),5.16(s,2H),2.56(s,3H),1.66(s,3H),1.60(s,3H).

[0203] Example 18: Preparation of Compound 18

[0204] Preparation of 3-(2-amino-6-(1-(2,4-difluorobenzyl)-2-oxo-1,2-dihydropyridin-4-yl)pyrimidin-4-yl)-2-methylbenzonitrile

[0205]

[0206] Referring to the synthetic route in Example 11, 1-(bromomethyl)-2,4-difluorobenzene was selected for substitution reaction in step 4.

[0207] 1 H NMR (400MHz, DMSO) δ7.91(dd,J=10.4,3.9Hz,2H),7.79(d,J=7.8Hz,1H),7.53(t,J=7.8Hz,1H),7.35(s,1H),7.31(dd,J=8.7,1.7Hz,1H), 7.29–7.26(m,1H),7.21(d,J=1.8Hz,1H),7.09(td,J=8.5,2.1Hz,1H),7.01(s,2H),6.97(dd,J=7.2,1.9Hz,1H),5.16(s,2H),2.57(s,3H).

[0208] Example 19: Preparation of Compound 19

[0209] Preparation of 3-(2-amino-6-(1-((6-(1,1,1,3,3,3-hexafluoro-2-hydroxypropyl-2-yl)pyridin-2-yl)methyl)-2-oxo-1,2-dihydropyridin-4-yl)pyrimidin-4-yl)-2-methylbenzonitrile

[0210]

[0211] Referring to the synthetic route in Example 11, the final step involved a substitution reaction with 2-(6-(bromomethyl)pyridin-2-yl)-1,1,1,3,3,3-hexafluoropropane-2-ol. The product was separated by column chromatography (dichloromethane / methanol = 300 / 3 to 300 / 6) to obtain a white solid product (20 mg, 19%).

[0212] 1 H NMR(400MHz, DMSO-d6)δ8.22(dd,J=6.7,3.0Hz,2H),7.92(d,J=7.1Hz,1H),7.74(s,1H),7.58–7.52 (m,3H),7.36–7.25(m,6H),7.02(dd,J=7.1,1.9Hz,1H),6.93(s,2H),5.19(s,2H).ESI(m / z):[M+H] + 561.0

[0213] Example 20: Preparation of Compound 20

[0214] Preparation of 3-(2-amino-6-(1-(2-methylbenzyl)-2-oxo-1,2-dihydropyridin-4-yl)pyrimidin-4-yl)-2-methylbenzonitrile

[0215]

[0216] Following the synthetic route of Example 11, 1-(bromomethyl)-2-toluene was selected for substitution in step 4. The product was separated by column chromatography (dichloromethane / methanol = 300 / 3 to 300 / 6) to give a white solid product (50 mg, 7%).

[0217] 1H NMR (400MHz, DMSO-d6) δ7.90(d,J=7.6Hz,1H),7.78(dd,J=15.6,7.4Hz,2H),7.52(t,J=7.7Hz,1H),7.37(s,1H), 7.29–7.12(m,4H),6.99(dd,J=15.0,13.6Hz,3H),6.84(d,J=7.3Hz,1H),5.15(s,2H),2.57(s,3H),2.32(s,3H). 13 C NMR(101MHz,DMSO-d6)δ167.35,163.64,161.77,161.62,147.75,139.88,139.30,139.25,135.68,134.97,133.96,133.35,130.2 1,127.33,126.89,126.44,126.07,118.01,117.42,113.18,106.56,103.36,48.92,35.78,30.77,18.74,18.37.ESI(m / z):[M+H] + 407.9.

[0218] Example 21: Preparation of Compound 21

[0219] Preparation of 3-(2-amino-6-(1-(3-methylbenzyl)-2-oxo-1,2-dihydropyridin-4-yl)pyrimidin-4-yl)-2-methylbenzonitrile

[0220]

[0221] Following the synthetic route of Example 11, 1-(bromomethyl)-3-toluene was selected for substitution in step 4. The product was separated by column chromatography (dichloromethane / methanol = 300 / 3 to 300 / 6) to give a white solid product (75 mg, 8%).

[0222] 1 H NMR(400MHz, DMSO-d6)δ7.94–7.88(m,2H),7.80–7.76(m,1H),7.52(t,J=7.8Hz,1H),7.34(s,1H),7.26–7.20 (m,2H),7.15–7.08(m,3H),7.02(s,2H),6.93(dd,J=7.1,1.9Hz,1H),5.11(s,2H),2.55(s,3H),2.28(s,3H). 13C NMR(101MHz,DMSO-d6)δ167.32,163.63,161.76,161.55,147.72,139.87,139.34,137.75,137.20,133.97,133.36,12 8.52,128.24,128.21,126.91,124.80,118.01,117.51,113.17,106.55,103.25,50.98,21.01,18.36.ESI(m / z):[M+H] + 407.9.

[0223] Example 22: Preparation of Compound 22

[0224] Preparation of 3-(2-amino-6-(1-(4-methylbenzyl)-2-oxo-1,2-dihydropyridin-4-yl)pyrimidin-4-yl)-2-methylbenzonitrile

[0225]

[0226] Following the synthetic route of Example 11, 1-(bromomethyl)-4-toluene was selected for substitution in step 4. The product was separated by column chromatography (dichloromethane / methanol = 300 / 3 to 300 / 6) to give a white solid product (55 mg, 7%).

[0227] 1 H NMR (400MHz, DMSO-d6) δ7.92–7.88(m,2H),7.80–7.76(m,1H),7.51(t,J=7.7Hz,1H),7.33(s,1H),7.21(dd,J=9.9, 4.9Hz,3H),7.15(d,J=8.0Hz,2H),7.00(s,2H),6.92(dd,J=7.1,1.9Hz,1H),5.10(s,2H),2.55(s,3H),2.27(s,3H). 13 C NMR(101MHz,DMSO-d6)δ167.29,163.60,161.76,161.51,147.65,139.85,139.27,139.20,136.79,134.24,133.93 ,133.31,129.10,127.77,126.86,117.97,117.47,113.15,106.51,103.19,50.76,20.65,18.33.ESI(m / z):[M+H] + 407.9.

[0228] Example 23: Preparation of Compound 23

[0229] Preparation of methyl 2-(4-(2-amino-6-(3-cyano-2-methylphenyl)pyrimidin-4-yl)-2-oxopyridin-1(2H)-yl)methyl)benzoate

[0230]

[0231] Following the synthetic route of Example 11, methyl 2-(bromomethyl)benzoate was selected for substitution in step 4. The product was separated by column chromatography (dichloromethane / methanol = 300 / 3 to 300 / 6) to give a white solid product (80 mg, 7%).

[0232] 1 H NMR(400MHz,DMSO-d6)δ7.96(dd,J=7.7,0.9Hz,1H),7.93–7.89(m,1H),7.88 (d,J=7.2Hz,1H),7.80(d,J=7.6Hz,1H),7.55(dt,J=15.1,4.4Hz,2H),7.43(t ,J=7.5Hz,1H),7.38(s,1H),7.26(d,J=1.7Hz,1H),7.04(s,2H),7.00(dd,J=7 .1,1.9Hz,1H),6.89(d,J=7.8Hz,1H),5.49(s,2H),3.89(s,3H),2.57(s,3H). 13 C NMR(101MHz,DMSO-d6)δ167.37,166.87,163.65,161.72,148.01,139.88,139.70,139.30,138.14,133.98,133.37,132.83,13 0.52,128.49,127.40,126.90,126.70,118.02,117.52,113.19,106.59,103.46,54.93,52.29,50.11,18.38.ESI(m / z):[M+H] + 451.9.

[0233] Example 24: Preparation of Compound 24

[0234] Preparation of methyl 3-(4-(2-amino-6-(3-cyano-2-methylphenyl)pyrimidin-4-yl)-2-oxopyridin-1(2H)-yl)methyl)benzoate

[0235]

[0236] Following the synthetic route of Example 11, methyl 3-(bromomethyl)benzoate was selected for substitution in step 4. The product was separated by column chromatography (dichloromethane / methanol = 300 / 3 to 300 / 6) to give a white solid product (98 mg, 8%).

[0237] 1 H NMR (400MHz, DMSO-d6) δ8.01(d,J=7.2Hz,1H),7.94(s,1H),7.93–7.86(m,2H),7.82–7.76(m,1H),7.63(d,J=7.8Hz,1H),7.52(t,J =7.7Hz,2H),7.35(s,1H),7.23(d,J=1.8Hz,1H),7.01(s,2H),6.97(dd,J=7.2,1.9Hz,1H),5.23(s,2H),3.85(s,3H),2.56(s,3H). 13 C NMR(101MHz,DMSO-d6)δ167.33,165.98,163.61,161.68,161.54,147.90,139.84,139.33,139.27,137.95,133.93,133.32 ,132.70,129.89,129.09,128.36,126.86,117.97,117.53,113.16,106.56,103.44,52.20,50.91,18.33.ESI(m / z):[M+H] + 451.9.

[0238] Example 25: Preparation of Compound 25

[0239] Preparation of methyl 4-((4-(2-amino-6-(3-cyano-2-methylphenyl)pyrimidin-4-yl)-2-oxopyridin-1(2H)-yl)methyl)benzoate

[0240]

[0241] Following the synthetic route of Example 11, methyl 4-(bromomethyl)benzoate was selected for substitution in step 4. The product was separated by column chromatography (dichloromethane / methanol = 300 / 3 to 300 / 6) to give a white solid product (68 mg, 6%).

[0242] 1H NMR (400MHz, DMSO-d6) δ7.96(dd,J=9.5,7.8Hz,3H),7.90(dd,J=7.7,0.9Hz,1H),7.81–7.76(m,1H),7.52(t,J=7.8Hz,1H),7.42(d, J=8.3Hz,2H),7.36(s,1H),7.24(d,J=1.7Hz,1H),7.02(s,2H),6.97(dd,J=7.1,1.9Hz,1H),5.24(s,2H),3.84(s,3H),2.56(s,3H). 13 C NMR(101MHz,DMSO-d6)δ167.34,165.94,163.62,161.66,161.54,147.95,142.63,139.85,139.44,139.28,133.94 ,133.34,129.46,128.76,127.72,126.88,117.98,117.55,106.56,103.44,52.13,51.03,18.35.ESI(m / z):[M+H] + 451.9.

[0243] Example 26: Preparation of Compound 26

[0244] Preparation of 3-(2-amino-6-(1-(3-fluorobenzyl)-2-oxo-1,2-dihydropyridin-4-yl)pyrimidin-4-yl)-2-methylbenzonitrile

[0245]

[0246] Following the synthetic route of Example 11, 1-(bromomethyl)-3-fluorobenzene was selected for substitution in step 4. The product was separated by column chromatography (dichloromethane / methanol = 300 / 3 to 300 / 6) to give a white solid product (58 mg, 5%).

[0247] 1 H NMR (400MHz, DMSO-d6) δ7.97(d,J=7.2Hz,1H),7.93–7.89(m,1H),7.79(d,J=6.9Hz,1H),7.52(t,J=7.8Hz,1H),7.41(td,J=8.0,6.5 Hz,1H),7.35(s,1H),7.23(d,J=1.7Hz,1H),7.19–7.11(m,3H),7.03(s,2H),6.96(dd,J=7.1,1.9Hz,1H),5.16(s,2H),2.56(s,3H). 13C NMR(101MHz,DMSO-d6)δ167.34,163.63,161.69,161.54,147.91,140.07,139.99,139.86,139.35,139.30,133.97,133.36,130.68,130 .60,126.90,123.74,123.71,118.01,117.54,114.66,114.52,114.44,114.32,113.17,106.58,103.43,50.71,18.36.ESI(m / z):[M+H] + 411.9.

[0248] Example 27: Preparation of Compound 27

[0249] Preparation of 3-(2-amino-6-(1-(3-chlorobenzyl)-2-oxo-1,2-dihydropyridin-4-yl)pyrimidin-4-yl)-2-methylbenzonitrile

[0250]

[0251] Following the synthetic route of Example 11, 1-(bromomethyl)-3-chlorobenzene was selected for substitution in step 4. The product was separated by column chromatography (dichloromethane / methanol = 300 / 3 to 300 / 6) to give a white solid product (70 mg, 6%).

[0252] 1 H NMR (400MHz, DMSO-d6) δ7.98(d,J=7.2Hz,1H),7.90(dd,J=7.7,0.8Hz,1H),7.78(d,J=7.7Hz,1H),7.51(t,J=7.8Hz,1H),7.41–7.36( m,3H),7.35(s,1H),7.29(d,J=6.9Hz,1H),7.22(d,J=1.7Hz,1H),7.02(s,2H),6.96(dd,J=7.2,1.9Hz,1H),5.15(s,2H),2.55(s,3H). 13 C NMR(101MHz,DMSO-d6)δ167.34,163.63,161.68,161.54,147.94,139.85,139.68,139.33,133.95,133.35,133.14 ,130.51,127.60,127.57,126.89,126.43,118.00,117.54,113.18,106.59,103.48,50.70,18.36.ESI(m / z):[M+H]+ 427.9.

[0253] Example 28: Preparation of Compound 28

[0254] Preparation of 3-(2-amino-6-(1-(3-bromobenzyl)-2-oxo-1,2-dihydropyridin-4-yl)pyrimidin-4-yl)-2-methylbenzonitrile

[0255]

[0256] Following the synthetic route of Example 11, 1-bromo-3-(bromomethyl)benzene was selected for substitution in step 4. The product was separated by column chromatography (dichloromethane / methanol = 300 / 3 to 300 / 6) to give a white solid product (90 mg, 8%).

[0257] 1 H NMR(400MHz, DMSO-d6)δ7.98(d,J=7.2Hz,1H),7.90(dd,J=7.7,1.0Hz,1H),7.81–7.76(m,1H),7.56–7.48(m,3H ),7.37–7.32(m,3H),7.22(d,J=1.8Hz,1H),7.01(s,2H),6.96(dd,J=7.2,1.9Hz,1H),5.15(s,2H),2.56(s,3H). 13 C NMR(101MHz,DMSO-d6)δ167.32,163.60,161.66,161.51,147.93,139.92,139.84,139.31,139.27,133.93,133.33 ,130.78,130.46,126.87,126.80,121.72,117.97,117.52,113.16,106.57,103.46,50.63,18.34.ESI(m / z):[M+H] + 471.9.

[0258] Example 29: Preparation of Compound 29

[0259] Preparation of 3-(2-amino-6-(1-(3-cyanobenzyl)-2-oxo-1,2-dihydropyridin-4-yl)pyrimidin-4-yl)-2-methylbenzonitrile

[0260]

[0261] Following the synthetic route of Example 11, 3-(bromomethyl)benzonitrile was selected for substitution reaction in step 4. The product was separated by column chromatography (dichloromethane / methanol = 300 / 3 to 300 / 6) to give a white solid product (90 mg, 8%).

[0262] 1 H NMR (400MHz, DMSO-d6) δ8.01(d,J=7.2Hz,1H),7.92–7.88(m,1H),7.80(d,J=4.7Hz,2H),7.77(s,1H),7.66(d,J=7.9Hz,1H),7.58(t,J=7 .7Hz,1H),7.52(t,J=7.8Hz,1H),7.35(s,1H),7.22(d,J=1.7Hz,1H),7.02(s,2H),6.97(dd,J=7.2,1.9Hz,1H),5.19(s,2H),2.55(s,3H). 13 C NMR(101MHz,DMSO-d6)δ167.34,163.62,161.64,161.55,148.00,139.85,139.34,138.76,133.95,133.35,132.70 ,131.42,129.90,126.89,118.59,117.99,117.54,113.16,111.47,106.58,103.55,50.73,18.34.ESI(m / z):[M+H] + 418.9.

[0263] Example 30: Preparation of Compound 30

[0264] Preparation of 3-((4-(2-amino-6-(3-cyano-2-methylphenyl)pyrimidin-4-yl)-2-oxopyridin-1(2H)-yl)methyl)benzenesulfonamide

[0265]

[0266] Following the synthetic route of Example 11, 3-(bromomethyl)benzenesulfonamide was selected for substitution reaction in step 4. The product was separated by column chromatography (dichloromethane / methanol = 300 / 3 to 300 / 6) to give a white solid product (69 mg, 5%).

[0267] 1H NMR(400MHz, DMSO-d6)δ8.00(d,J=7.2Hz,1H),7.90(dd,J=7.7,0.9Hz,1H),7.80–7.75(m,3H),7.58–7.49(m,3H),7 .40(s,2H),7.36(s,1H),7.24(d,J=1.7Hz,1H),7.02(s,2H),6.98(dd,J=7.2,1.9Hz,1H),5.24(s,2H),2.56(s,3H). 13 C NMR(101MHz,DMSO-d6)δ167.37,163.63,161.68,161.54,147.94,144.48,139.87,139.38,139.30,138.20,133.96,133 .36,131.11,129.30,126.91,124.94,124.51,118.01,117.59,113.18,106.58,103.49,50.93,18.36.ESI(m / z):[M+H] + 472.9.

[0268] Example 31: Preparation of Compound 31

[0269] Preparation of 3-(2-amino-6-(1-(3-(methanesulfonyl)benzyl)-2-oxo-1,2-dihydropyridin-4-yl)pyrimidin-4-yl)-2-methylbenzonitrile

[0270]

[0271] Following the synthetic route of Example 11, 1-(bromomethyl)-3-(methanesulfonyl)benzene was selected for substitution in step 4. The product was separated by column chromatography (dichloromethane / methanol = 300 / 3 to 300 / 6) to give a white solid product (85 mg, 8%).

[0272] 1 H NMR (400MHz, DMSO-d6) δ8.03(d,J=7.2Hz,1H),7.94–7.86(m,3H),7.81–7.77(m,1H),7.66(d,J=6.0Hz,2H),7.52(t,J=7.8H z,1H),7.36(s,1H),7.24(d,J=1.7Hz,1H),7.02(s,2H),6.98(dd,J=7.2,1.9Hz,1H),5.27(s,2H),3.22(s,3H),2.56(s,3H). 13CNMR(101MHz,DMSO-d6)δ167.36,163.62,161.64,161.56,147.99,141.14,139.85,139.37,139.29,138.72,133.95,133.3 5,132.82,129.82,126.89,126.24,125.92,117.99,117.56,113.17,106.58,103.54,50.87,43.46,18.35.ESI(m / z):[M+H] + 471.9.

[0273] Example 32: Preparation of Compound 32

[0274] Preparation of 3-(2-amino-6-(1-(3-hydroxybenzyl)-2-oxo-1,2-dihydropyridin-4-yl)pyrimidin-4-yl)-2-methylbenzonitrile

[0275]

[0276] Following the synthetic route of Example 11, 3-(bromomethyl)phenol was selected for substitution reaction in step 4. The product was separated by column chromatography (dichloromethane / methanol = 300 / 3 to 300 / 6) to obtain a white solid product (30 mg, 4%).

[0277] 1 H NMR (400MHz, DMSO-d6) δ9.45(s,1H),7.90(dd,J=11.4,4.0Hz,2H),7.79(d,J=7.7Hz,1H),7.52(t,J=7.7Hz,1H),7.34(s,1H),7.22(d, J=1.7Hz,1H),7.13(t,J=7.7Hz,1H),7.02(s,2H),6.94(dd,J=7.1,1.9Hz,1H),6.70(dd,J=24.2,7.8Hz,3H),5.07(s,2H),2.56(s,3H). 13 C NMR(101MHz,DMSO-d6)δ167.32,163.63,161.77,161.55,157.55,147.73,139.87,139.38,139.30,138.64,133.96,133 .35,129.59,126.90,118.11,118.00,117.49,114.47,114.30,113.17,106.54,103.22,50.87,18.36.ESI(m / z):[M+H] + 409.9.

[0278] Example 33: Preparation of Compound 33

[0279] Preparation of 3-(2-amino-6-(1-(3-methoxybenzyl)-2-oxy-1,2-dihydropyridin-4-yl)pyrimidin-4-yl)-2-methylbenzonitrile

[0280]

[0281] Following the synthetic route of Example 11, 1-(bromomethyl)-3-methoxybenzene was selected for substitution in step 4. The product was separated by column chromatography (dichloromethane / methanol = 300 / 3 to 300 / 6) to give a white solid product (65 mg, 6%).

[0282] 1 H NMR (400MHz, DMSO-d6) δ7.91(dd,J=11.3,4.1Hz,2H),7.80–7.76(m,1H),7.52(t,J=7.7Hz,1H),7.34(s,1H),7.26(t,J=7.9Hz, 1H),7.21(d,J=1.8Hz,1H),7.01(s,2H),6.93(dd,J=7.2,1.9Hz,1H),6.91–6.84(m,3H),5.11(s,2H),3.73(s,3H),2.55(s,3H). 13 CNMR(101MHz,DMSO-d6)δ167.31,163.62,161.74,161.54,159.38,147.75,139.87,139.31,139.28,138.79,133.96,133.3 5,129.74,126.89,119.73,118.00,117.49,113.61,113.16,112.78,106.55,103.25,55.04,50.90,18.35.ESI(m / z):[M+H] + 423.9.

[0283] Example 34: Preparation of Compound 34

[0284] Preparation of 3-(2-amino-6-(1-(3-(hydroxymethyl)benzyl)-2-oxo-1,2-dihydropyridin-4-yl)pyrimidin-4-yl)-2-methylbenzonitrile

[0285]

[0286] Following the synthetic route of Example 11, in step 4, (3-(bromomethyl)phenyl)methanol was selected for the substitution reaction. The product was separated by column chromatography (dichloromethane / methanol = 300 / 3 to 300 / 6) to give a white solid product (20 mg, 2%).

[0287] 1 H NMR (400MHz, DMSO-d6) δ7.96–7.88(m,2H),7.78(d,J=7.7Hz,1H),7.52(t,J=7.7Hz,1H),7.34(s,1H),7.29(d,J=7.7Hz,2H),7.2 5–7.17(m,3H),7.01(s,2H),6.94(dd,J=7.1,1.9Hz,1H),5.21(t,J=5.7Hz,1H),5.15(s,2H),4.47(d,J=5.7Hz,2H),2.56(s,3H). 13 CNMR(101MHz,DMSO-d6)δ167.31,163.62,161.76,161.54,147.71,139.86,139.33,139.28,137.06,133.94,133.33,128.30,1 26.88,126.08,125.67,125.60,124.74,117.99,117.52,113.17,106.54,103.25,62.95,62.72,51.06,13.85.ESI(m / z):[M+H] + 423.9.

[0288] Example 35: Preparation of Compound 35

[0289] Preparation of 3-(2-amino-6-(1-(3-(methoxymethylene)benzyl)-2-oxo-1,2-dihydropyridin-4-yl)pyrimidin-4-yl)-2-methylbenzonitrile

[0290]

[0291] Following the synthetic route of Example 11, 1-(bromomethyl)-3-(methoxymethylene)benzene was selected for substitution in step 4. The product was separated by column chromatography (dichloromethane / methanol = 300 / 3 to 300 / 6) to give a white solid product (50 mg, 4%).

[0292] 1H NMR(400MHz, DMSO-d6)δ7.97–7.88(m,2H),7.80–7.76(m,1H),7.52(t,J=7.7Hz,1H),7.36–7.20(m, 6H),7.01(s,2H),6.94(dd,J=7.1,1.9Hz,1H),5.15(s,2H),4.38(s,2H),3.28(s,3H),2.56(s,3H). 13 C NMR(101MHz,DMSO-d6)δ167.31,163.61,161.73,161.53,147.74,139.86,139.32,139.27,138.71,137.30,133.94,133.33,12 8.51,126.88,126.82,126.69,126.66,117.98,117.51,113.16,106.54,103.28,73.44,57.58,51.00,18.34.ESI(m / z):[M+H] + 437.9.

[0293] Example 36: Preparation of Compound 36

[0294] Preparation of 2-(3-((4-(2-amino-6-(3-cyano-2-methylphenyl)pyrimidin-4-yl)-2-oxopyridin-1(2H)-yl)methyl)phenoxy)acetic acid

[0295]

[0296] Compound 37 (120 mg, 0.25 mmol) and lithium hydroxide monohydrate (10 mg, 0.25 mmol) were placed in a 50 mL flask, and 5 mL of EtOH and 0.5 mL of water were added. The mixture was stirred at room temperature for 6 h. The reaction was monitored by TLC. After the reaction was complete, the mixture was diluted with dichloromethane and then washed successively with water and saturated brine. The organic phase was dried over anhydrous sodium sulfate. After concentration, the product was separated by column chromatography (dichloromethane / methanol = 300 / 3 to 300 / 6) to give a white solid product (18 mg, 28%).

[0297] 1H NMR (400MHz, DMSO-d6) δ7.98–7.87(m,2H),7.79(d,J=7.0Hz,1H),7.52(t,J=7.7Hz,1H),7.34(s,1H),7.28–7.18(m,2H),7.02( s,2H),6.93(dd,J=7.1,1.8Hz,1H),6.91–6.84(m,2H),6.83–6.78(m,1H),5.11(s,2H),4.56(s,2H),4.03(s,1H),2.56(s,3H). 13 C NMR(101MHz,DMSO-d6)δ170.29,167.32,163.63,161.79,161.57,158.15,147.78,139.87,139.33,138.72,133.98,133.35,12 9.64,126.90,120.01,118.02,117.50,114.33,113.18,113.04,106.59,103.32,65.04,50.86,34.01,18.37.ESI(m / z):[M+H] + 467.9.

[0298] Example 37: Preparation of Compound 37

[0299] Preparation of methyl 2-(3-((4-(2-amino-6-(3-cyano-2-methylphenyl)pyrimidin-4-yl)-2-oxopyridin-1(2H)-yl)methyl)phenoxy)acetate

[0300]

[0301] Following the synthetic route of Example 11, methyl 2-(3-(bromomethyl)phenoxy)acetate was selected for substitution in step 4. The product was separated by column chromatography (dichloromethane / methanol = 300 / 3 to 300 / 6) to give a white solid product (136 mg, 12%).

[0302] 1H NMR (400MHz, DMSO-d6) δ7.91(dd,J=12.8,4.2Hz,2H),7.81–7.76(m,1H),7.52(t,J=7.7Hz,1H),7.34(s,1H),7.27(t,J=7.9Hz,1H),7.22(d, J=1.7Hz,1H),7.01(s,2H),6.96–6.90(m,2H),6.88(s,1H),6.85(dd,J=8.2,2.4Hz,1H),5.11(s,2H),4.77(s,2H),3.68(s,3H),2.56(s,3H). 13 C NMR(101MHz,DMSO-d6)δ169.11,167.31,163.62,161.74,161.53,157.71,147.77,139.86,139.31,139.28,138.88,133.95,13 3.34,129.75,126.89,120.49,117.99,117.49,114.19,113.17,106.55,103.27,64.52,51.80,50.83,18.35.ESI(m / z):[M+H] + 481.9.

[0303] Example 38: Preparation of Compound 38

[0304] Preparation of 3-(2-amino-6-(1-(3-(2-hydroxypropane-2-yl)benzyl)-2-oxo-1,2-dihydropyridin-4-yl)pyrimidin-4-yl)-2-methylbenzonitrile

[0305]

[0306] Following the synthetic route of Example 11, 2-(3-(bromomethyl)phenyl)propane-2-ol was selected for substitution in step 4. The product was separated by column chromatography (dichloromethane / methanol = 300 / 3 to 300 / 6) to give a white solid product (170 mg, 15%).

[0307] 1H NMR (400MHz, DMSO-d6) δ7.95–7.88(m,2H),7.78(d,J=7.0Hz,1H),7.51(dd,J=13.8,5.8Hz,2H),7.39–7.33(m,2H),7.26(t,J=7.7Hz,1H),7 .22(d,J=1.7Hz,1H),7.10(d,J=7.6Hz,1H),7.02(s,2H),6.94(dd,J=7.1,1.9Hz,1H),5.15(s,2H),5.03(s,1H),2.56(s,3H),1.40(s,6H). 13 C NMR(101MHz,DMSO-d6)δ167.33,163.63,161.77,161.56,150.98,147.69,139.87,139.37,139.30,136.64,133.98,133.36,12 8.01,126.90,125.17,123.94,123.90,118.02,117.51,113.17,106.55,103.23,70.54,51.23,31.96,18.37.ESI(m / z):[M+H] + 451.9.

[0308] Example 39: Preparation of Compound 39

[0309] Preparation of 3-(2-amino-6-(1-(3-(2-fluoropropane-2-yl)benzyl)-2-oxo-1,2-dihydropyridin-4-yl)pyrimidin-4-yl)-2-methylbenzonitrile

[0310]

[0311] Compound 38 (112 mg, 0.25 mmol) and DAST (40 mg, 0.25 mmol) were placed in a 50 mL flask, and 5 mL of dichloromethane was added. Nitrogen gas was completely purged, and the reaction was carried out at room temperature for 4 h. After the reaction was complete, the mixture was diluted with dichloromethane and then washed successively with water and saturated brine. The organic phase was dried over anhydrous sodium sulfate. After concentration, the product was separated by column chromatography (dichloromethane / methanol = 300 / 3 to 300 / 6) to obtain a white solid product (25 mg, 22%).

[0312] 1H NMR(400MHz, DMSO-d6)δ7.96(d,J=7.2Hz,1H),7.90(dd,J=7.7,1.0Hz,1H),7.81–7.76(m,1H),7.52(t,J=7.7Hz,1H),7.43(s,1H),7 .38–7.31(m,3H),7.21(t,J=4.4Hz,2H),7.01(s,2H),6.95(dd,J=7.1,1.9Hz,1H),5.17(s,2H),2.56(s,3H),1.63(d,J=22.2Hz,6H). 13 C NMR (101MHz, DMSO-d6) δ167.33,163.62,161.73,161.56,147.78,146.00,145.79,139.87,139.36,137.31,133.96,133.35,128.59,126. 89,126.50,123.16,123.07,122.97,118.00,117.51,113.16,106.56,103.31,96.54,94.87,51.13,29.13,28.88,18.35.ESI(m / z):[M+H] + 453.9.

[0313] Example 40: Preparation of Compound 40

[0314] Preparation of 3-(2-amino-6-(1-((6-(2-hydroxypropane-2-yl)pyridin-2-yl)methyl)-2-oxo-1,2-dihydropyridin-4-yl)pyrimidin-4-yl)-2-methylbenzonitrile

[0315]

[0316] Following the synthetic route of Example 11, 2-(6-(bromomethyl)pyridin-2-yl)propane-2-ol was selected for substitution in step 4. The product was separated by column chromatography (dichloromethane / methanol = 300 / 3 to 300 / 6) to give a white solid product (146 mg, 13%).

[0317] 1 H NMR(400MHz,DMSO-d6)δ7.97–7.87(m,2H),7.82–7.70(m,2H),7.57–7.48(m,2H),7.36(s,1H) ,7.21(d,J=1.7Hz,1H),7.06–6.95(m,4H),5.20(d,J=17.8Hz,3H),2.57(s,3H),1.36(s,6H). 13C NMR(101MHz,DMSO-d6)δ167.72,167.34,163.62,161.80,161.58,154.06,147.86,140.24,139.86,139.29,137.30,133.9 6,133.32,126.87,118.94,117.99,117.22,117.18,113.16,106.51,102.64,72.26,52.86,30.58,18.34.ESI(m / z):[M+H] + 452.9.

[0318] Example 41: Preparation of Compound 41

[0319] Preparation of 3-(2-amino-6-(1-((6-(2-fluoropropane-2-yl)pyridin-2-yl)methyl)-2-oxo-1,2-dihydropyridin-4-yl)pyrimidin-4-yl)-2-methylbenzonitrile

[0320]

[0321] Following the synthetic route of Example 39, the reaction was carried out using Example 40 and DAST. The product was separated by column chromatography (dichloromethane / methanol = 300 / 3 to 300 / 6) to give a white solid product (23 mg, 20%).

[0322] 1 H NMR (400MHz, DMSO-d6) δ7.97–7.89(m,2H),7.86–7.78(m,2H),7.52(t,J=7.8Hz,1H),7.44(d,J=7.8Hz,1H),7.37(s,1H),7.22(d, J=1.7Hz,1H),7.14(d,J=7.7Hz,1H),7.03(s,2H),6.99(dd,J=7.1,1.9Hz,1H),5.25(s,2H),2.57(s,3H),1.58(d,J=22.1Hz,6H). 13CNMR(101MHz,DMSO-d6)δ167.37,163.64,162.69,162.42,161.79,161.61,155.07,147.96,140.26,139.87,139.31,138.01,133.99,133. 36,126.90,120.21,118.02,117.22,116.61,116.52,113.17,106.54,102.77,97.47,95.80,52.87,27.70,27.46,18.36.ESI(m / z):[M+H] + 454.9.

[0323] Example 42: Preparation of Compound 42

[0324] Preparation of 3-(2-amino-5-fluoro-6-(1-(3-(2-hydroxypropane-2-yl)benzyl)-2-oxo-1,2-dihydropyridin-4-yl)pyrimidin-4-yl)-2-methylbenzonitrile

[0325]

[0326] Following the synthetic route of Example 38, 4,6-dichloro-5-fluoropyrimidine-2-amine was selected for coupling reaction in step 1. The product was separated by column chromatography (dichloromethane / methanol = 300 / 3 to 300 / 6) to give a white solid product (116 mg, 15%).

[0327] 1 H NMR (400MHz, DMSO-d6) δ7.95(d,J=6.9Hz,2H),7.76(d,J=7.6Hz,1H),7.54(t,J=7.8Hz,1H),7.49(s,1H),7.37(d,J=7.8Hz,1H),7.27(t, J=7.6Hz,1H),7.10(d,J=7.5Hz,1H),6.99(d,J=13.4Hz,3H),6.73(d,J=7.2Hz,1H),5.16(s,2H),5.03(s,1H),2.44(s,3H),1.40(s,6H). 13C NMR(101MHz,DMSO-d6)δ161.09,159.85,159.81,155.07,154.90,151.01,149 .71,149.60,148.09,145.59,144.37,144.33,139.64,139.35,136.48,134.7 7,134.14,133.93,128.03,126.91,125.18,123.96,120.10,120.03,117.70, 113.05,104.55,104.50,70.54,51.33,31.95,17.86,17.84.ESI(m / z):[M+H] + 469.9.

[0328] Example 43: Preparation of Compound 43

[0329] Preparation of 3-(2-amino-6-(1-(3-(2-hydroxypropane-2-yl)benzyl)-2-oxo-1,2-dihydropyridin-4-yl)-5-methylpyrimidin-4-yl)-2-methylbenzonitrile

[0330]

[0331] Following the synthetic route of Example 38, 4,6-dichloro-5-methylpyrimidin-2-amine was selected for coupling reaction in step 1. The product was separated by column chromatography (dichloromethane / methanol = 300 / 3 to 300 / 6) to give a white solid product (96 mg, 12%).

[0332] 1 H NMR(400MHz, DMSO-d6)δ7.90–7.86(m,2H),7.57(dd,J=7.7,1.1Hz,1H),7.53–7.46(m,2H),7.37(d,J=7.9Hz,1H),7.28(t,J=7.7Hz,1H),7.09(d, J=7.6Hz,1H),6.75(s,2H),6.57(d,J=1.7Hz,1H),6.42(dd,J=7.0,1.8H z,1H),5.15(s,2H),5.03(s,1H),2.30(s,3H),1.79(s,3H),1.40(s,6H). 13C NMR(101MHz,DMSO-d6)δ166.80,164.18,161.38,161.08,150.97,149.82,139.95,139.04,138.46,136.65,132.85,132.71,1 28.02,126.89,125.07,123.86,119.02,117.91,113.25,112.70,105.86,70.52,51.21,31.94,17.59,14.38.ESI(m / z):[M+H] + 465.9.

[0333] Example 44: Preparation of Compound 44

[0334] Preparation of 3-(2-amino-6-(1-(3-(2-hydroxypropane-2-yl)benzyl)-2-oxo-1,2-dihydropyridin-4-yl)-5-(pyridin-4-yl)pyrimidin-4-yl)-2-methylbenzonitrile

[0335]

[0336] Step 1: Preparation of 3-(2-amino-6-chloro-5-iodopyrimidin-4-yl)-2-toluenenitrile

[0337] 2.44 g (10 mmol) of 3-(2-amino-6-chloropyrimidin-4-yl)-2-toluenenitrile (2.24 g, 10 mmol) and NIS (2.24 g, 10 mmol) from step 1 of Synthetic Example 11 were placed in a 50 mL flask, and 10 mL of acetic acid was added. The reaction was carried out at room temperature for 12 h. The reaction was monitored by TLC. After the reaction was complete, the product was diluted with dichloromethane and then washed successively with water and saturated brine. The organic phase was dried over anhydrous sodium sulfate. After concentration, the product was separated by column chromatography (dichloromethane / ethyl acetate = 100 / 1 to 30 / 1) to obtain a brown solid product (2.59 g, 70%).

[0338] Step 2: Preparation of 3-(2-amino-6-chloro-5-(pyridin-4-yl)pyrimidin-4-yl)-2-toluenenitrile

[0339] The product from step 1, 3-(2-amino-6-chloro-5-iodopyrimidin-4-yl)-2-toluenenitrile (2.59 g, 7 mmol), pinacol ester of 4-pyridineboronic acid (1.43 g, 7 mmol), potassium bicarbonate (1.4 g, 14 mmol), and palladium dichloride bis(triphenylphosphine) (982 mg, 1.4 mmol) were placed in a 100 mL flask, and 20 mL of dioxane and 2 mL of water were added, followed by complete nitrogen purging. The mixture was then placed in an oil bath at 95 °C and reacted for 12 h. The reaction was monitored by TLC. After the reaction was complete, the mixture was cooled to room temperature. It was diluted with ethyl acetate and then washed successively with water and saturated brine. The organic phase was dried over anhydrous sodium sulfate. After concentration, the product was separated by column chromatography (dichloromethane / ethyl acetate = 100 / 1 to 40 / 1) to obtain a brown solid product (1.36 g, 60%).

[0340] The subsequent steps were the same as in Example 38. The product was separated by column chromatography (dichloromethane / methanol = 300 / 3 to 300 / 6) to obtain a white solid product (80 mg, 8%).

[0341] 1 H NMR (400MHz, DMSO-d6) δ8.28(d,J=5.9Hz,2H),7.73–7.69(m,1H),7.66(d,J=7.0Hz,1H),7.41(d,J=7.0Hz,1H),7.35(d,J=6.5Hz,2H),7.30–7. 22(m,4H),7.02–6.97(m,2H),6.89(d,J=7.6Hz,1H),6.29(d,J=1.7Hz,1 H), 6.11 (dd, J = 7.0, 1.8Hz, 1H), 5.03 (s, 3H), 2.26 (s, 3H), 1.38 (s, 6H). 13 C NMR(101MHz,DMSO-d6)δ165.65,163.36,162.28,160.72,150.92,149.34,148.98,143.92,139.19,138.69,138.50,136.52,133.60,132.67,1 27.94,126.24,125.70,124.60,123.76,123.51,119.89,118.61,117.7 1,112.33,105.93,70.49,59.74,51.03,31.92,17.88.ESI(m / z):[M+H] + 528.9.

[0342] Example 45: Preparation of Compound 45

[0343] Preparation of 4-(2-amino-6-(2-fluorophenyl)pyrimidin-4-yl)-1-benzylpyridin-2(1H)-one

[0344]

[0345] The synthetic route was followed as described in Example 1. The starting material was 2-(2-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxoborane. The product was separated by column chromatography (dichloromethane / methanol = 300 / 3 to 300 / 6) to obtain a white solid product (75 mg, 9%).

[0346] 1 H NMR(400MHz, DMSO-d6)δ7.96(dd,J=11.3,4.4Hz,2H),7.61–7.54(m,1H),7.45(d,J=1.8Hz,1H),7.41–7.38(m,1H),7.37(d,J=3.8Hz,2H),7 .35(d,J=3.2Hz,3H),7.33(d,J=1.2Hz,1H),7.15(d,J=1.7Hz,1H),6.99(s,2H),6.89(dd,J=7.1,1.9Hz,1H),5.17(s,2H).ESI(m / z):[M+H] + 372.9

[0347] Example 46: Preparation of Compound 46

[0348] Preparation of 4-(2-amino-6-(4-fluorophenyl)pyrimidin-4-yl)-1-benzylpyridin-2(1H)-one

[0349]

[0350] The synthetic route was followed as described in Example 1. The starting material was 2-(4-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxoborane. The product was separated by column chromatography (dichloromethane / methanol = 300 / 3 to 300 / 6) to obtain a white solid product (87 mg, 12%).

[0351] 1 H NMR (400MHz, DMSO-d6) δ8.37–8.28(m,2H),7.95(d,J=7.1Hz,1H),7.76(s,1H),7.39(s,1H),7.37(d,J=2.2Hz,2H),7 .35(d,J=3.2Hz,3H),7.32(d,J=1.6Hz,2H),7.02(dd,J=7.1,1.9Hz,1H),6.90(s,2H),5.18(s,2H).ESI(m / z):[M+H]+ 372.9

[0352] Example 47: Preparation of Compound 47

[0353] Preparation of 3-(2-amino-6-(1-(naphth-2-ylmethyl)-2-oxo-1,2-dihydropyridin-4-yl)pyrimidin-4-yl)-2-methylbenzonitrile

[0354]

[0355] Following the synthetic route of Example 11, 2-(bromomethyl)naphthalene was selected for substitution in step 4. The product was separated by column chromatography (dichloromethane / methanol = 300 / 3 to 300 / 6) to give a white solid product (90 mg, 11%).

[0356] 1 H NMR (400MHz, DMSO-d6) δ8.01(d,J=7.2Hz,1H),7.91(dt,J=13.4,5.4Hz,4H),7.80(dd,J=6.7,5.8Hz,2H),7.52(ddd,J=8.3,6.8,3.6Hz, 4H),7.36(s,1H),7.26(d,J=1.8Hz,1H),7.01(s,2H),6.97(dd,J=7.2,1.9Hz,1H),5.32(d,J=9.3Hz,2H),2.57(s,3H).ESI(m / z):[M+H] + 444.1

[0357] Example 48: Preparation of Compound 48

[0358] Preparation of 3-(2-amino-6-(1-(naphth-1-ylmethyl)-2-oxo-1,2-dihydropyridin-4-yl)pyrimidin-4-yl)-2-methylbenzonitrile

[0359]

[0360] Following the synthetic route of Example 11, 1-(bromomethyl)naphthalene was selected for substitution in step 4. The product was separated by column chromatography (dichloromethane / methanol = 300 / 3 to 300 / 6) to give a white solid product (95 mg, 13%).

[0361] 1H NMR(400MHz,DMSO-d6)δ8.18(d,J=7.8Hz,1H),8.03–7.98(m,1H),7.91(dd,J =10.6,4.2Hz,2H),7.82–7.77(m,2H),7.61(qd,J=6.8,3.6Hz,2H),7.56–7.4 7(m,2H),7.36(s,1H),7.31(d,J=1.8Hz,1H),7.21(d,J=7.0Hz,1H),7.01(s, 2H),6.95(dd,J=7.2,1.9Hz,1H),5.67(s,2H),2.57(s,3H).ESI(m / z):[M+H] + 444.1

[0362] Example 49: Preparation of Compound 49

[0363] Preparation of 3-(2-amino-6-(1-(4-isopropylbenzyl)-2-oxo-1,2-dihydropyridin-4-yl)pyrimidin-4-yl)-2-methylbenzonitrile

[0364]

[0365] Following the synthetic route of Example 11, 1-(bromomethyl)-4-isopropylbenzene was selected for substitution in step 4. The product was separated by column chromatography (dichloromethane / methanol = 300 / 3 to 300 / 6) to give a white solid product (35 mg, 24%).

[0366] 1 H NMR (400MHz, DMSO-d6) δ7.91(dd,J=12.7,4.3Hz,2H),7.81–7.77(m,1H),7.53(t,J=7.8Hz,1H),7.34(s,1H),7.28–7.20(m,5H),7.00( s,2H),6.93(dd,J=7.1,1.9Hz,1H),5.11(s,2H),2.87(dt,J=13.8,6.9Hz,1H),2.56(s,3H),1.19(s,3H),1.18(s,3H).ESI(m / z):[M+H] + 435.9

[0367] Example 50: Preparation of Compound 50

[0368] Preparation of 3-(4-amino-5-fluoro-6-(1-((6-(2-hydroxypropane-2-yl)pyridin-2-yl)methyl)-2-oxo-1,2-dihydropyridin-4-yl)pyrimidin-2-yl)-2-methylbenzonitrile

[0369]

[0370] Step 1: Preparation of 2,6-dichloro-5-fluoropyrimidine-4-amine

[0371] Take 10 mL of 2,4,6-trichloro-5-fluoropyrimidine (664.6 mg, 3.3 mmol) and 2 mol / L 80% ammonia in ethanol, and stir at room temperature for 6–7 hours. Monitor the reaction by TLC. After the reaction is complete, dilute with ethyl acetate, and then wash successively with water and saturated brine. Take the organic phase and dry it with anhydrous sodium sulfate. After concentration, separate by column chromatography (petroleum ether / ethyl acetate = 10 / 1–3 / 1) to obtain a white solid product (447.9 mg, 75%).

[0372] Step 2: Preparation of 3-(4-amino-6-chloro-5-fluoropyrimidin-2-yl)-2-methylbenzonitrile

[0373] 2,6-Dichloro-5-fluoropyrimidin-4-amine (400 mg, 2.2 mmol), 2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)benzonitrile (850.5 mg, 3.5 mmol), potassium bicarbonate (600 mg, 6.0 mmol), and bis(triphenylphosphine)palladium dichloride (193 mg, 0.28 mmol) were placed in a 100 mL flask, and 10 mL of acetonitrile was added. The mixture was then purged with nitrogen. The flask was then placed in an oil bath at 90 °C and reacted for 4 h. The reaction was monitored by TLC. After the reaction was complete, the reaction mixture was added to 100 mL of water, extracted with ethyl acetate, and then washed with saturated brine. The organic phase was dried over anhydrous sodium sulfate. After concentration, the product was separated by column chromatography (dichloromethane / ethyl acetate = 40 / 1 to 20 / 1) to obtain a white solid product (449.5 mg, 78%).

[0374] Step 3: Preparation of 3-(6-amino-5-fluoro-2-(2-methoxypyridin-4-yl)pyrimidin-4-yl)-2-methylbenzonitrile

[0375] 3-(4-amino-6-chloro-5-fluoropyrimidin-2-yl)-2-methylbenzonitrile (400 mg, 1.5 mmol), pinacol ester of 2-methoxy-4-pyridineboronic acid (423.0 mg, 1.8 mmol), cesium carbonate (975.0 mg, 3.0 mmol), and tetrakis(triphenylphosphine)palladium (77 mg, 0.067 mmol) were placed in a 100 mL flask, and 15 mL of dioxane and 3 mL of water were added, followed by complete nitrogen purging. The flask was then placed in an oil bath at 100 °C and reacted for 12 h. The reaction was monitored by TLC. After the reaction was complete, the mixture was cooled to room temperature. The product was diluted with ethyl acetate and then washed successively with water and saturated brine. The organic phase was dried over anhydrous sodium sulfate. After concentration, the product was separated by column chromatography (dichloromethane / ethyl acetate = 100 / 1 to 40 / 1) to obtain a white solid product (351.7 mg, 70%).

[0376] The subsequent steps were the same as in Example 38. The product was separated by column chromatography (dichloromethane / methanol = 300 / 3 to 300 / 6) to obtain a white solid product (15 mg, 50%).

[0377] 1 H NMR (400MHz, DMSO-d6) δ7.99–7.83(m,2H),7.73(t,J=7.8Hz,2H),7.59–7.42(m,2H),7.04(d,J=7.4Hz,2H),6.88(d,J=19.4 Hz,1H),6.71(d,J=25.6Hz,1H),5.21(s,2H),5.16(s,1H),4.24(d,J=7.1Hz,1H),1.35(s,6H),1.23(s,3H).ESI(m / z):[M+H] + 471.1

[0378] Example 51: Preparation of Compound 51

[0379] Preparation of 3-(4-amino-5-chloro-6-(1-((6-(2-hydroxypropane-2-yl)pyridin-2-yl)methyl)-2-oxo-1,2-dihydropyridin-4-yl)pyrimidin-2-yl)-2-methylbenzonitrile

[0380]

[0381] The synthetic route was followed as described in Example 50. Perchloropyrimidine was selected for subsequent reactions in step 1. The product was separated by column chromatography (dichloromethane / methanol = 300 / 3 to 300 / 6) to obtain a white solid product (45 mg, 15%).

[0382] 1H NMR(400MHz, DMSO-d6)δ7.92(d,J=6.9Hz,2H),7.86(d,J=6.9Hz,1H),7.79–7.59(m,3H),7.53(t,J=7.5Hz, 2H),7.21(s,1H),7.04–6.93(m,2H),5.19(s,2H),5.15(s,1H),2.34(s,3H),1.34(s,6H).ESI(m / z):[M+H] + 487.1

[0383] Example 52: Preparation of Compound 52

[0384] Preparation of 3-(2-amino-6-(1-((6-(2-hydroxypropane-2-yl)pyridin-2-yl)methyl)-2-thiooxy-1,2-dihydropyridin-4-yl)pyrimidin-4-yl)-2-methylbenzonitrile

[0385]

[0386] Compound 38 (100 mg, 0.2 mmol), Lawson's reagent (202.2 mg, 0.5 mmol), and 5 mL of toluene were placed in a 25 mL flask and refluxed for 0.5 h. The reaction was monitored by TLC. After the reaction was complete, the mixture was cooled to room temperature. The solution was diluted with dichloromethane and then washed successively with water and saturated brine. The organic phase was dried over anhydrous sodium sulfate. After concentration, the solution was separated by column chromatography (dichloromethane / ethyl acetate = 10 / 1 to 3 / 1) to obtain a colorless oily product (46.8 mg, 50%).

[0387] 1 H NMR (400MHz, DMSO-d6) δ8.30(s,1H),8.25(s,1H),7.89(d,J=8.0Hz,1H),7.75(d,J=7.0Hz,1H),7.64(s,1H),7.44(dd,J=31.7,6.1 Hz,3H),7.15–7.03(m,3H),6.99(s,1H),5.78(d,J=20.8Hz,2H),3.77(s,1H),1.26(d,J=25.1Hz,6H),1.08(s,3H).ESI(m / z):[M+H] + 469.2

[0388] Example 53: Preparation of Compound 53

[0389] Preparation of 3-(2-amino-6-(1-(1-methyl-1H-pyrazol-3-yl)methyl)-2-oxo-1,2-dihydropyridin-4-yl)pyrimidin-4-yl)-2-methylbenzonitrile

[0390]

[0391] Following the synthetic route of Example 11, 3-(bromomethyl)-1-methyl-1H-pyrazole was selected for substitution reaction in step 4. The product was separated by column chromatography (dichloromethane / methanol = 300 / 3 to 300 / 6) to give a white solid product (32 mg, 12%).

[0392] 1 H NMR (400MHz, DMSO-d6) δ7.89(d,J=7.1Hz,1H),7.83–7.73(m,2H),7.60(s,1H),7.51(t,J=7.8Hz,1H),7.30(s,1H),7.15( s,1H),6.98(s,2H),6.88(d,J=6.7Hz,1H),6.13(s,1H),5.05(s,2H),3.77(d,J=7.4Hz,3H),2.54(s,3H).ESI(m / z):[M+H] + 398.1

[0393] Example 54: Preparation of Compound 54

[0394] Preparation of 3-(2-amino-6-(1-(1-isopropyl-1H-pyrazol-3-yl)methyl)-2-oxo-1,2-dihydropyridin-4-yl)pyrimidin-4-yl)-2-methylbenzonitrile

[0395]

[0396] Following the synthetic route of Example 11, 3-(bromomethyl)-1-isopropyl-1H-pyrazole was selected for substitution in step 4. The product was separated by column chromatography (dichloromethane / methanol = 300 / 3 to 300 / 6) to obtain a white solid product (25 mg, 15%).

[0397] 1 H NMR (400MHz, DMSO-d6) δ7.89(d,J=7.5Hz,1H),7.84–7.74(m,2H),7.69(s,1H),7.51(t,J=7.5Hz,1H),7.31(s,1H),7.17(s,1H),6.89 (d,J=7.1Hz,1H),6.10(s,1H),5.07(s,2H),4.49–4.39(m,1H),3.33(s,2H),2.54(s,3H),1.38(s,3H),1.37(s,3H).ESI(m / z):[M+H] + 426.1

[0398] Example 55: Preparation of Compound 55

[0399] Preparation of 3-(4-amino-5-fluoro-6-(1-(1-isopropyl-1H-pyrazol-3-yl)methyl)-2-oxo-1,2-dihydropyridin-4-yl)pyrimidin-2-yl)-2-methylbenzonitrile

[0400]

[0401] Following the synthetic route of Example 50, the final step involved a substitution reaction using 3-(bromomethyl)-1-isopropyl-1H-pyrazole. The product was separated by column chromatography (dichloromethane / methanol = 300 / 3 to 300 / 6) to give a white solid product (25 mg, 16%).

[0402] 1 H NMR (400MHz, DMSO-d6) δ7.94(d,J=7.2Hz,1H),7.75(dd,J=15.2,7.2Hz,2H),7.68(s,2H),7.54(t,J=8.0Hz,1H),7.17(s,1H),6.93( d,J=7.0Hz,1H),6.08(s,1H),5.75(s,1H),5.05(s,2H),4.48–4.39(m,1H),2.43(s,3H),1.38(s,3H),1.36(s,3H).ESI(m / z):[M+H] + 444.1

[0403] Example 56: Preparation of Compound 56

[0404] Preparation of 3-(2-amino-6-(1-(2-methylphenethyl)-2-oxo-1,2-dihydropyridin-4-yl)pyrimidin-4-yl)-2-methylbenzonitrile

[0405]

[0406] Following the synthetic route of Example 11, the final step involved a substitution reaction with 1-(2-bromoethyl)-2-methylbenzene. The product was separated by column chromatography (dichloromethane / methanol = 300 / 3 to 300 / 6) to obtain a white solid product (20 mg, 13%).

[0407] 1H NMR (400MHz, DMSO) δ7.91(dd,J=7.7,1.1Hz,1H),7.83–7.74(m,1H),7.64(d,J=7.1Hz,1H),7.52(t,J=7.7Hz,1H),7.39–7.25(m,2H),7.21–7. 07(m,6H),6.83(dd,J=7.1,1.9Hz,1H),4.08(dd,J=17.6,9.9Hz,2H),3.03–2.91(m,2H),2.55(d,J=6.7Hz,3H),2.32(s,3H).ESI(m / z):[M+H] + 422.2

[0408] Example 57: Preparation of Compound 57

[0409] Preparation of 3-(2-amino-6-(1-(3-methylphenethyl)-2-oxo-1,2-dihydropyridin-4-yl)pyrimidin-4-yl)-2-methylbenzonitrile

[0410]

[0411] Referring to the synthetic route in Example 11, the final step involved a substitution reaction with 1-(2-bromoethyl)-3-methylbenzene. The product was separated by column chromatography (dichloromethane / methanol = 300 / 3 to 300 / 6) to obtain a white solid product (26 mg, 20%).

[0412] 1 H NMR (400MHz, DMSO) δ7.97–7.86(m,1H),7.79(d,J=7.8Hz,1H),7.63(d,J=7.1Hz, 1H),7.51(dd,J=15.1,7.3Hz,1H),7.32(s,1H),7.17(t,J=5.3Hz,1H),7.11(s,4H ),6.99(s,1H),6.82(dd,J=7.1,1.9Hz,1H),4.12(t,J=7.4Hz,2H),2.92(dd,J=14 .2,7.0Hz,2H),2.73(d,J=7.6Hz,1H),2.56(s,3H),2.27(s,3H).ESI(m / z):[M+H] + 422.2

[0413] Example 58: Preparation of Compound 58

[0414] Preparation of 3-(2-amino-6-(1-(4-methylphenethyl)-2-oxo-1,2-dihydropyridin-4-yl)pyrimidin-4-yl)-2-methylbenzonitrile

[0415]

[0416] Referring to the synthetic route in Example 11, the final step involved a substitution reaction with 1-(2-bromoethyl)-4-methylbenzene. The product was separated by column chromatography (dichloromethane / methanol = 300 / 3 to 300 / 6) to obtain a white solid product (25 mg, 18%).

[0417] 1 H NMR (400MHz, DMSO) δ7.90(d,J=7.7Hz,1H),7.79(d,J=6.8Hz,1H),7.67(d,J=7.1Hz ,1H),7.52(t,J=7.8Hz,1H),7.33(s,1H),7.22–7.15(m,2H),7.04(dd,J=17.5,8.5H z,3H),6.83(dd,J=7.1,1.9Hz,1H),4.16–4.09(m,2H),2.92(dd,J=14.3,7.2Hz,2H ),2.70–2.65(m,1H),2.56(s,3H),2.36–2.31(m,1H),2.28(s,3H).ESI(m / z):[M+H] + 422.2

[0418] Example 59: Preparation of Compound 59 Preparation of 3-(2-amino-6-(1-(3-methoxyphenethyl)-2-oxo-1,2-dihydropyridin-4-yl)pyrimidin-4-yl)-2-methylbenzonitrile

[0419]

[0420] Referring to the synthetic route in Example 11, the final step involved a substitution reaction with 1-(2-bromoethyl)-3-methoxybenzene. The product was separated by column chromatography (dichloromethane / methanol = 300 / 3 to 300 / 6) to obtain a white solid product (19 mg, 17%).

[0421] 1H NMR (400MHz, DMSO) δ7.90 (dd, J=7.7, 1.1Hz, 1H), 7.79 (d, J=6.8Hz, 1H), 7.64 (d, J=7.2Hz, 1H), 7.52(t,J=7.7Hz,1H),7.32(s,1H),7.22–7.16(m,2H),6.92–6.86(m,1H),6.71(dd,J=7.1,1.9H z,1H),6.55(d,J=14.3Hz,1H),4.47(t,J=7.0Hz,1H),4.14(dd,J=16.8,9.2Hz,3H),3.72(d,J=2 .5Hz,3H),3.01(d,J=7.0Hz,1H),2.94(d,J=7.2Hz,2H),2.55(d,J=7.0Hz,3H).ESI(m / z):[M+H] + 438.1

[0422] Example 60: Preparation of Compound 60

[0423] Preparation of 3-(2-amino-6-(1-(4-methoxyphenethyl)-2-oxo-1,2-dihydropyridin-4-yl)pyrimidin-4-yl)-2-methylbenzonitrile

[0424]

[0425] Referring to the synthetic route in Example 11, the final step involved a substitution reaction with 1-(2-bromoethyl)-4-methoxybenzene. The product was separated by column chromatography (dichloromethane / methanol = 300 / 3 to 300 / 6) to obtain a white solid product (27 mg, 10%).

[0426] 1 H NMR (400MHz, DMSO) δ7.90 (dd, J=7.7, 1.1Hz, 1H), 7.78 (d, J=6.8Hz, 1H), 7.62 (d,J=7.1Hz,1H),7.52(t,J=7.8Hz,1H),7.32(s,1H),7.16(dd,J=15.9,5.2Hz ,3H),6.86(d,J=8.6Hz,2H),6.82(dd,J=7.1,1.9Hz,1H),4.11(t,J=7.4Hz,3H ),3.72(s,3H),2.91(t,J=7.3Hz,3H),2.55(d,J=8.7Hz,3H).ESI(m / z):[M+H] + 438.1

[0427] Example 61: Preparation of Compound 61

[0428] Preparation of 3-(2-amino-6-(1-((1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-3-yl)methyl)-2-oxo-1,2-dihydropyridin-4-yl)pyrimidin-4-yl)-2-methylbenzonitrile

[0429]

[0430] Referring to the synthetic route in Example 11, the final step involved a substitution reaction with 1-(3-(bromomethyl)-1H-pyrazol-1-yl)-2-methylprop-2-ol. The product was separated by column chromatography (dichloromethane / methanol = 300 / 3 to 300 / 6) to obtain a white solid product (15 mg, 16%).

[0431] 1 H NMR (400MHz, DMSO) δ7.90(d,J=7.2Hz,1H),7.78(dd,J=7.4,2.8Hz,2H),7.61(d,J=2.1Hz,1H),7.52(t,J=7.7Hz,2H),7.31(d,J=7.3Hz,2H),7.18(d ,J=1.7Hz,1H),6.92–6.82(m,2H),6.16(d,J=2.2Hz,1H),5.08(s,2H),3.9 6(d,J=10.4Hz,2H),2.56(s,3H),1.05(d,J=11.2Hz,6H).ESI(m / z):[M+H] + 456.2

[0432] Example 62: Preparation of Compound 62

[0433] Preparation of 3-(2-amino-6-(1-((6-(1-hydroxycyclobutyl)pyridin-2-yl)methyl)-2-oxo-1,2-dihydropyridin-4-yl)pyrimidin-4-yl)-2-methylbenzonitrile

[0434]

[0435] Following the synthetic route of Example 11, the final step involved a substitution reaction with 1-(6-(bromomethyl)pyridin-2-yl)cyclobutane-1-ol. The product was separated by column chromatography (dichloromethane / methanol = 300 / 3 to 300 / 6) to obtain a white solid product (29 mg, 20%).

[0436] 1H NMR (400MHz, DMSO) δ7.95(t,J=5.8Hz,1H),7.91(d,J=7.5Hz,1H),7.79(t,J=8.0Hz,1H),7.74(t,J= 7.8Hz,1H),7.52(t,J=7.8Hz,1H),7.44(t,J=7.8Hz,1H),7.38–7.30(m,1H),7.20(dd,J=6.6,1.8Hz, 1H),7.12(d,J=7.6Hz,1H),7.03–6.93(m,1H),5.25(d,J=10.9Hz,2H),4.57(s,1H),2.56(d,J=8.5H z,3H),2.45–2.37(m,2H),2.21–2.09(m,2H),1.81–1.63(m,2H),1.28–1.20(m,2H).ESI(m / z):[M+H] + 465.2

[0437] Example 63: Preparation of Compound 63

[0438] Preparation of 3-(2-amino-6-(1-((6-(2-hydroxypropyl-2-yl)pyridin-2-yl)methyl)-2-oxo-1,2-dihydropyridin-4-yl)pyrimidin-4-yl)-2-fluorobenzonitrile

[0439]

[0440] Step 1: Preparation of 3-(2-amino-6-chloropyrimidin-4-yl)-2-fluorobenzonitrile

[0441] 2-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)benzonitrile (1.45 g, 6 mmol), 4,6-dichloropyrimidin-2-amine (800 mg, 5 mmol), potassium bicarbonate (1 g, 10 mmol), and bis(triphenylphosphine)palladium dichloride (702 mg, 1 mmol) were placed in 100 mL flasks, and 20 mL of ethanol was added, followed by complete nitrogen purging. The mixture was then placed in an oil bath at 78 °C and reacted for 4 h. The reaction was monitored by TLC. After the reaction was complete, the mixture was cooled to room temperature. The solution was diluted with ethyl acetate and then washed successively with water and saturated brine. The organic phase was dried over anhydrous sodium sulfate. After concentration, the solution was separated by column chromatography (dichloromethane / ethyl acetate = 100 / 1 to 40 / 1) to obtain a white solid product (730 mg, 60%).

[0442] Step 2: Preparation of 3-(2-amino-6-(2-methoxypyridin-4-yl)pyrimidin-4-yl)-2-fluorobenzonitrile

[0443] The products from step 1, 3-(2-amino-6-chloropyrimidin-4-yl)-2-fluorobenzonitrile (730 mg, 3.0 mmol), 2-methoxypyridin-4-pentanoylboronic acid (775.5 mg, 3.3 mmol), cesium carbonate (1.8 g, 5.5 mmol), and tetraphenylphosphine palladium (635 mg, 0.55 mmol), were placed in 100 mL flasks, and 15 mL of dioxane and 3 mL of water were added, followed by complete nitrogen purging. The mixture was then placed in an oil bath at 100 °C and reacted for 12 h. The reaction was monitored by TLC. After the reaction was complete, the mixture was cooled to room temperature. It was diluted with dichloromethane and then washed successively with water and saturated brine. The organic phase was dried over anhydrous sodium sulfate. After concentration, the product was separated by column chromatography (dichloromethane / ethyl acetate = 10 / 1 to 3 / 1) to obtain a white solid product (660 mg, 70%).

[0444] Step 3: Preparation of 3-(2-amino-6-(2-oxo-1,2-dihydropyridin-4-yl)pyrimidin-4-yl)-2-fluorobenzonitrile

[0445] The product from step 2, 3-(2-amino-6-(2-methoxypyridin-4-yl)pyrimidin-4-yl)-2-fluorobenzonitrile (660 mg, 2.0 mmol), was placed in a 50 mL flask, 2 mL of ethanol was added, followed by 4 mL of 48 wt.% aqueous hydrobromic acid solution. The flask was then placed in an oil bath at 100 °C and reacted for 6 h. The reaction was monitored by TLC. After the reaction was complete, the mixture was cooled to room temperature. Neutralization was performed using 8 mmol / mL sodium hydroxide solution until the pH reached 8-9. At this point, the product precipitated as a solid. After filtration and drying, the crude product (710 mg, containing some salt) was obtained and, based on 100% conversion, could be used in the next step without further purification.

[0446] Step 4: Preparation of 3-(2-amino-6-(1-((6-(2-hydroxypropyl-2-yl)pyridin-2-yl)methyl)-2-oxo-1,2-dihydropyridin-4-yl)pyrimidin-4-yl)-2-fluorobenzonitrile

[0447] Take 100 mg of the product from step 3, 3-(2-amino-6-(1-((6-(2-hydroxypropyl-2-yl)pyridin-2-yl)methyl)-2-oxo-1,2-dihydropyridin-4-yl)pyrimidin-4-yl)-2-fluorobenzonitrile, 90 mg (0.40 mmol) of 2-(6-(bromomethyl)pyridin-2-yl)propane-2-ol, and 90 mg (0.65 mmol) of potassium carbonate, and add 5 mL of N,N-dimethylformamide. Then place the mixture in an oil bath at 50 °C and react for 12 h. Monitor the reaction by TLC. After the reaction is complete, cool to room temperature. Dilute with dichloromethane, then wash successively with water and saturated brine. Dry the organic phase over anhydrous sodium sulfate. After concentration, the product was separated by column chromatography (dichloromethane / methanol = 300 / 3 to 300 / 6) to obtain a white solid product (74 mg, 50%).

[0448] 1 H NMR (400MHz, DMSO) δ8.25(td,J=7.7,1.6Hz,1H),8.14–8.05(m,1H),7.96(d,J=7.1Hz,1H),7.75(t,J=7.8Hz,1H),7.63–7.51(m,3H),7.17(d,J= 1.8Hz,1H),7.10(s,1H),7.05(d,J=7.6Hz,1H),6.94(dd,J=7.1,1.9Hz,1H),5.76(s,1H),5.23(s,3H),1.35(d,J=10.1Hz,6H).ESI(m / z):[M+H] + 457.2

[0449] Example 64: Preparation of Compound 64

[0450] Preparation of 3-(2-amino-6-(1-(3-(2-hydroxypropyl-2-yl)benzyl)-2-oxo-1,2-dihydropyridin-4-yl)pyrimidin-4-yl)-2-fluorobenzonitrile

[0451]

[0452] Referring to the synthetic route in Example 63, the final step was a substitution reaction using 2-(3-(bromomethyl)phenyl)propane-2-ol. The product was separated by column chromatography (dichloromethane / methanol = 300 / 3 to 300 / 6) to give a white solid product (20 mg, 18%).

[0453] 1H NMR (600MHz, DMSO) δ8.28–8.22(m,1H),8.12–8.05(m,1H),7.94(d,J=7.1Hz,1H),7.58(t,J=7.8 Hz,1H),7.54(d,J=1.4Hz,1H),7.49(s,1H),7.36(t,J=10.0Hz,1H),7.27(t,J=7.7Hz,1H),7.18( d,J=1.8Hz,1H),7.13–7.06(m,1H),6.91(dd,J=7.0,1.9Hz,1H),5.16(s,2H),2.61(dd,J=10.6, 8.9Hz,1H),2.42–2.35(m,1H),2.19(t,J=7.4Hz,1H),1.40(s,3H),1.24(s,3H).ESI(m / z):[M+H] + 456.1

[0454] Example 65: Preparation of Compound 65

[0455] Preparation of 3-(2-amino-6-(1-(((1-isopropyl-1H-pyrazol-3-yl)methyl)-2-oxo-1,2-dihydropyridin-4-yl)pyrimidin-4-yl)-2-fluorobenzonitrile

[0456]

[0457] Referring to the synthetic route in Example 63, the final step was a substitution reaction using 3-(bromomethyl)-1-isopropyl-1H-pyrazole. The product was separated by column chromatography (dichloromethane / methanol = 300 / 3 to 300 / 6) to give a white solid product (12 mg, 13%).

[0458] 1 H NMR(600MHz,DMSO)δ8.25(td,J=7.7,1.6Hz,1H),8.12–8.06(m,1H),7.83(d,J=7.2Hz,1 H),7.70(d,J=2.2Hz,1H),7.58(t,J=7.8Hz,1H),7.53(d,J=1.7Hz,1H),7.15(d,J=1.9Hz ,1H),6.91–6.85(m,1H),6.13(d,J=2.2Hz,1H),5.09(s,2H),4.47–4.42(m,1H),2.64–2. 60(m,1H),2.41–2.37(m,1H),1.39(d,J=6.7Hz,3H),1.24–1.23(m,3H).ESI(m / z):[M+H] + 430.0

[0459] Example 66: Compound A 2A Assay for the inhibitory activity of the R-cAMP signaling pathway

[0460] HEK293 cells in a 10 cm culture dish were inoculated with 3.0 μg of human amino acids using polyethyleneimine (PEI) (18 μL, Yeasen, China). 2A R plasmid and 3.0 μg pGloSensor-22F cAMP plasmid (Promega, USA) were co-transfected for 24 hours. Cells were harvested and reseeded into 384-well white plates (2 × 10⁶ cells / wells). 4 Cells were equilibrated in CO2-independent medium (Gibco, USA) containing 1% GloSensorcAMP reagent (Promega, USA) in Costar (cells / well) wells. After incubation at room temperature for 1.5 hours, cells were pretreated for 30 minutes with different concentrations of the compound, followed by stimulation with 5'-N-ethylformamide adenosine (NECA) (MCE, USA). The luminescence signal was continuously measured using a Cytation5 imaging reader (BioTek, USA). The results are shown in Tables 1 and 2.

[0461] Table 1. A of compounds in some examples 2A R cAMP inhibitory activity (inhibition rate, @1μM, @10μM)

[0462]

[0463] In Table 1: ++++ indicates an inhibition rate greater than or equal to 90%; +++ indicates an inhibition rate greater than or equal to 50% and less than 90%; ++ indicates an inhibition rate greater than or equal to 10% and less than 50%; + indicates an inhibition rate less than 10%; measured at a concentration of 20 nM NECA.

[0464] Table 2. A of compounds in some examples 2A R cAMP inhibitory activity (IC) 50 (nM)

[0465]

[0466]

[0467] In Table 2: +++ indicates IC 50 Less than 10nM; ++++ indicates IC 50 Greater than or equal to 10 nM and less than 60 nM; +++ indicates IC 50 Greater than or equal to 60 nM and less than 300 nM; ++ indicates IC 50Greater than or equal to 300 nM and less than 1000 nM; + indicates IC 50 Measured at a concentration of ≥1000 nM; 20 nM NECA.

[0468] From Table 1 and Table 2, A 2A Experimental results of the R-cAMP signaling pathway indicate that the compound of this invention affects A... 2A R exhibits good inhibitory activity. It can be seen that for compounds of formula (I), when Ar on the left-hand side is an aromatic ring, it is preferable that the aromatic ring has no substituents or has 1-2 sterically hindered substituents, such as CN, methyl, F, Cl, or methoxy; in monosubstituted cases, the meta position is preferred; in disubstituted cases, the positions of the substituents are preferably two adjacent ortho and meta positions; when the substituent is F, the activity is comparable at the ortho, meta, and para positions; especially when the meta substituent is a cyano group and there are no other substituents or only a small-volume substituent, such as methyl or F, at the adjacent ortho position, its activity against A is... 2A The inhibitory activity of R is particularly excellent. For the aromatic amine ring in the middle of formula (I), it is preferred that one of X1 and X2 is N, especially that X2 is N and X1 is CH. For Ra (aryl or heteroaryl) on the right side of formula (I), it is preferred that Ra ring has no substituents or has substituents at the meta position. The activity is better when the meta position contains a sterically hindered branched alkyl or cycloalkyl group, especially when the meta position contains a hydroxyl group and / or an F-substituted branched alkyl or cycloalkyl group.

[0469] Example 67: Pharmacokinetic Study of Compound 38 in Mice

[0470] Male C57BL / 6 mice were selected as test mice. Compound 38 was administered intravenously at 2 mg / kg (5% DMSO + 10% Solutol + 85% saline) and orally by gavage at 10 mg / kg (5% DMSO + 10% Solutol + 85% saline). Blood samples were collected within 24 hours after administration and centrifuged to obtain plasma. The obtained plasma samples were precipitated with acetonitrile and analyzed for compounds using an LC-MS / MS system. A non-compartmental model was used to analyze the pharmacokinetic parameters from the plasma concentration-time curves. The results are detailed in Table 3.

[0471] Table 3. Pharmacokinetic parameters of compound 38 in mice

[0472]

[0473] The pharmacokinetic results in mice shown in Table 3 indicate that compound 38 has good oral bioavailability and high in vivo exposure.

[0474] Example 68: Pharmacodynamic Study of Compound 38 in Mice

[0475] Female C57BL / 6 mice (6 to 8 weeks old) were purchased from National Rodent Laboratory Animal Resources (China). To establish a xenograft model, 8 × 10⁸ mice were used. 5 MC38 cells were subcutaneously injected into the right back of C57BL / 6 mice. When the average tumor volume reached approximately 100 mm... 3 Mice were randomly divided into a model group and a compound 38 treatment group. The compound 38 treatment group received oral administration once daily at a dose of 100 mg / kg. Tumor volume and mouse body weight were measured, and the tumor inhibition rate was calculated. Results are as follows: Figure 1-3 As shown.

[0476] Figure 1-3 The pharmacodynamic studies in mice showed that compound 38 achieved a tumor inhibition rate of 56% at a dose of 100 mg / kg in a mouse MC38 xenograft model, and exhibited good safety.

[0477] The above detailed embodiments further illustrate the purpose, technical solution, and beneficial effects of the present invention. It should be understood that the above are merely one specific embodiment of the present invention and are not limited to the scope of protection of the present invention. The present invention can be embodied in various forms without departing from its essential characteristics. Therefore, the embodiments described herein are for illustrative purposes only and not for limitation. Since the scope of the present invention is defined by the claims rather than the specification, all changes falling within the scope defined by the claims, or their equivalents, should be understood to be included in the claims. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the scope of protection of the present invention.

Claims

1. Compounds of the following general chemical formula (I) or pharmaceutically acceptable salts thereof: ； in, X1is selected from N or C-R1, R1is selected from hydrogen, halogen, C 1-3 alkyl, halogen-substituted C 1-3 alkyl, aryl or heteroaryl; X2 is selected from N or C-R2, and R2 is selected from hydrogen, halogen, or C. 1-3 Alkyl, halogen-substituted C 1-3 alkyl; Y is selected from O or S; Ar is selected from unsubstituted or substituted aryl or heteroaryl groups, wherein the substituents are selected from halogens, C 1-3 Alkyl, C 1-3 alkoxy- or halogen-substituted C 1-3 Alkyl, halogen-substituted C 1-3 At least one of alkoxy and cyano groups; R a Selected from unsubstituted or substituted aryl or heteroaryl groups, wherein the substituents are selected from halogens, cyano groups, hydroxyl groups, C6 groups, etc. 1-6 Alkoxyalkylene, C 1-6 Alkyl, halogen-substituted C 1-6 Alkyl, hydroxyl substituted C 1-6 C-substituted with alkyl, halogen and hydroxyl groups 1-6 Alkyl, C 3-6 Cycloalkyl, hydroxyl-substituted C 3-6 cycloalkyl, C 1-6 alkoxy- or halogen-substituted C 1-6 alkoxy and carboxyl substituted C 1-6 alkoxy and ester substituted C 1-6 Alkoxy, aminosulfonyl, C 1-6 At least one of alkyl sulfone and ester groups; R b Selected from hydrogen or halogen; L is selected from C 1-6 Alkylene; The aryl group has 6-12 carbon atoms; the heteroaryl group has 5-12 ring atoms, including 1-4 ring atoms selected from N, O, and S, and the remaining ring atoms are C; the ester group is -COO-C1-C6 alkyl.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that, X1 is N or C-R1, and R1 is selected from hydrogen, fluorine or chlorine.

3. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that, X2 is N or C-R2, and R2 is selected from hydrogen, fluorine or chlorine.

4. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that, R b Selected from hydrogen, fluorine, or chlorine.

5. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that, R a Selected from: 。 6. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that, Ar is selected from: 。 7. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that, L is selected from methylene or ethylene.

8. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-7, characterized in that, The compound is selected from the following compounds: 。 9. A pharmaceutical composition, characterized in that, It includes the compound as described in any one of claims 1-8 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

10. The compound of any one of claims 1-8, or a pharmaceutically acceptable salt thereof, in the preparation of a treatment or preventative measure for use with A 2A Application in drugs for diseases related to R.

11. The application according to claim 10, characterized in that, The disease is selected from at least one of the following: cancer, Parkinson's disease, amyotrophic lateral sclerosis, coronary artery disease, mild cognitive impairment, multiple sclerosis, pericardial pseudocirrhosis, rheumatoid arthritis, bipolar disorder, experimental endotoxemia, and schizophrenia.

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