WO2022177302A1 - Composé cyclique fusionné à la pyrimidine avec une activité d'inhibition de l'adn-pk et son utilisation - Google Patents

Composé cyclique fusionné à la pyrimidine avec une activité d'inhibition de l'adn-pk et son utilisation Download PDF

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WO2022177302A1
WO2022177302A1 PCT/KR2022/002310 KR2022002310W WO2022177302A1 WO 2022177302 A1 WO2022177302 A1 WO 2022177302A1 KR 2022002310 W KR2022002310 W KR 2022002310W WO 2022177302 A1 WO2022177302 A1 WO 2022177302A1
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methyl
amino
tetrahydro
pyran
alkyl
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PCT/KR2022/002310
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English (en)
Korean (ko)
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이희진
박진영
이혜미
양덕모
남은혜
김학도
정희진
정원근
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보령제약 주식회사
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Publication of WO2022177302A1 publication Critical patent/WO2022177302A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A61K31/52—Purines, e.g. adenine
    • A61K31/522—Purines, e.g. adenine having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/26—Heterocyclic compounds containing purine ring systems with an oxygen, sulphur, or nitrogen atom directly attached in position 2 or 6, but not in both
    • C07D473/32—Nitrogen atom

Definitions

  • the present invention relates to pyrimidine-fused ring compounds having DNA-PK inhibitory activity and uses thereof.
  • DNA is constantly damaged by metabolic or environmental factors. In this case, the normal state can be restored through the DNA repair mechanism in most cases, but otherwise, mutations may occur, resulting in cell death or cancer.
  • the main causes of DNA damage include reactive oxygen species formed as a by-product of oxidative metabolism, ionizing radiation for anticancer treatment, and use of anticancer drugs such as bleomycin.
  • DSB DNA double strand break
  • NHEJ non-homologous end-joining
  • HR homologous recombination
  • NHEJ is a mechanism that directly connects the ends of cleaved DNA double-stranded, and occurs at all stages of the cell cycle, where DNA-dependent protein kinase (DNA-PK) plays a key role.
  • DNA-PK is a nuclear serine/threonine protein kinase complex consisting of the catalytic subunit DNA-PKcs and a heterodimer of Ku protein (Ku70/Ku80). After the Ku70/Ku80 heterodimer recognizes and binds to the cleaved DNA end, DNA-PKcs are recruited to form an activated complex (Yoo S et al., Nucleic Acids Res 1999; 27: 4679-4686).
  • DNA-PK inhibitors can induce cell death without repairing DNA-damaged cells by interfering with NHEJ, various therapeutic effects related to DNA damage can be expected.
  • the DNA-PK inhibitors NU7026 and KU-0060648 have been reported to be able to potentiate the cytotoxicity of topoisomerase II inhibitors (Willmore et al., Blood 2004; 103: 4659-4665, Munck et al. ., Mol Cancer Ther 2012; 11: 1789-1798), NU7441 potentiated the effect of ionizing radiation in a breast cancer model (Ciszewski et al., Breast Cancer Res Treat 2014; 143: 47-55).
  • DNA-PK inhibitors have been shown to be effective as single agents against tumors with high levels of replication stress, such as ATM-deficient lymphoma (Riabinska et al., Science Translational Medicine 2013; 189: 189ra78).
  • An object of the present invention is to provide a pyrimidine-fused ring compound having a novel structure, an optical isomer thereof, or a pharmaceutically acceptable salt thereof.
  • Another object of the present invention is to provide a method for preparing the pyrimidine-fused ring compound.
  • Another object of the present invention is to provide a pharmaceutical use of the pyrimidine-fused ring compound, specifically, a pharmaceutical composition for treating or preventing a DNA-PK-related disease comprising the pyrimidine-fused ring compound as an active ingredient, To provide a method for treating or preventing a DNA-PK-related disease using the compound, or a method for treating or preventing a DNA-PK-related disease, comprising administering the compound.
  • the present invention was completed by confirming that the pyrimidine-fused ring compounds represented by Chemical Formula 1 mentioned below inhibit DNA-PK activity.
  • the present invention provides a compound represented by the following formula (1), an optical isomer thereof, or a pharmaceutically acceptable salt thereof:
  • n 0, 1 or 2;
  • X 1 is NR 1 or CR 2 R 3 ⁇ wherein is a double bond, then R 1 or R 3 is nothing (null) ⁇ ;
  • L 1 is -(C 1-4 alkyl)- or nothing (null);
  • W 1 is -CH 2 -, -NH-, -O-, or -S-;
  • W 2 is -CH- or -N-;
  • a to d are each independently 0, 1, 2, or 3;
  • L 2 is -(C 1-4 alkyl)- or nothing (null);
  • Z is -Z 1 -L 3 -Z 2 ;
  • the heteroaryl n is non-zero if ⁇ ;
  • R is -H or -C 1-4 alkyl
  • R 1 to R 3 are each independently —H or —C 1-4 alkyl
  • R 4 to R 6 are each independently —C 1-4 alkyl.
  • n 0 or 1
  • X 1 is NR 1 or CR 2 R 3 ⁇ wherein is a double bond, then R 1 or R 3 is nothing (null) ⁇ ;
  • L 1 is -(C 1-4 alkyl)- or nothing (null);
  • W 1 is —CH 2 —, —O—, or —S—;
  • W 2 is -CH- or -N-;
  • a to d are each independently 0, 1, or 2;
  • L 2 is -(C 1-4 alkyl)- or nothing (null);
  • Z is -Z 1 -L 3 -Z 2 ;
  • the heteroaryl n is non-zero if ⁇ ;
  • R is -H
  • R 1 to R 3 are each independently —H or —C 1-4 alkyl
  • R 4 to R 6 are each independently —C 1-4 alkyl.
  • the compound represented by Formula 1 may include a compound represented by Formula 2 below.
  • X 1 is NR 1 or CR 2 R 3 ;
  • L 1 is -(C 1-4 alkyl)- or nothing (null);
  • W 1 is -CH 2 -, -NH-, -O-, or -S-;
  • W 2 is -CH- or -N-;
  • a to d are each independently 0, 1, 2, or 3;
  • L 2 is -(C 1-4 alkyl)- or nothing (null);
  • Z is -Z 1 -L 3 -Z 2 ;
  • R is -H or -C 1-4 alkyl
  • R 1 to R 3 are each independently —H or —C 1-4 alkyl
  • R 4 to R 6 are each independently —C 1-4 alkyl.
  • the compound represented by Formula 2 may include a compound represented by Formula 2-1 below.
  • L 1 is -(C 1-4 alkyl)- or nothing (null);
  • W 1 is —CH 2 —, —O—, or —S—;
  • W 2 is -CH- or -N-;
  • a to d are each independently 0, 1, or 2;
  • L 2 is null
  • Z is -Z 1 -L 3 -Z 2 ,
  • R is -H
  • R 1 to R 3 are each independently —H or —C 1-4 alkyl
  • R 4 to R 6 are each independently —C 1-4 alkyl.
  • the compound represented by Formula 1 may include a compound represented by Formula 3 below.
  • X 1 is NR 1 or CR 2 R 3 ⁇ wherein is a double bond, then R 1 or R 3 is nothing (null) ⁇ ;
  • L 1 is -(C 1-4 alkyl)- or nothing (null);
  • W 1 is -CH 2 -, -NH-, -O-, or -S-;
  • W 2 is -CH- or -N-;
  • a to d are each independently 0, 1, 2, or 3;
  • L 2 is -(C 1-4 alkyl)- or nothing (null);
  • Z is -Z 1 -L 3 -Z 2 ;
  • R is -H or -C 1-4 alkyl
  • R 1 to R 3 are each independently —H or —C 1-4 alkyl
  • R 4 to R 6 are each independently —C 1-4 alkyl.
  • the compound represented by Formula 3 may include a compound represented by Formula 3-1 below.
  • L 1 is -(C 1-4 alkyl)- or nothing (null);
  • W 1 is —CH 2 — or —O—
  • W 2 is —CH—
  • a to d are each independently 1 or 2;
  • L 2 is -(C 1-4 alkyl)- or nothing (null);
  • Z is -Z 1 -L 3 -Z 2 ,
  • Z 2 is —H, heteroaryl, or null ⁇ wherein one or more H of the heteroaryl may be substituted with —C 1-4 alkyl ⁇ ;
  • R is -H or -C 1-4 alkyl
  • R 1 to R 3 are each independently —H or —C 1-4 alkyl.
  • the compound represented by Formula 1 may be selected from the group consisting of the compounds described below.
  • alkyl may mean a straight or branched acyclic, cyclic, or saturated hydrocarbon to which they are bonded.
  • C 1-4 alkyl can mean an alkyl containing 1 to 4 carbon atoms.
  • Acyclic alkyl may include, as an example, methyl, ethyl, n -propyl, n -butyl, isopropyl, sec -butyl, isobutyl, or tert -butyl, etc., It is not limited thereto.
  • Cyclic alkyl may be used interchangeably with “cycloalkyl” herein, and may include, as an example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl, but is limited thereto. doesn't happen
  • alkoxy may mean -(O-alkyl) as an alkyl ether group, wherein alkyl is as defined above.
  • C 1-4 alkoxy may mean alkoxy containing C 1-4 alkyl, that is, -(OC 1-4 alkyl), for example, alkoxy is methoxy ), ethoxy, n -propoxy, isopropoxy, n - butoxy , isobutoxy , sec - butoxy ), or tert - butoxy , etc., but is not limited thereto.
  • halo may be F, Cl, Br, or I.
  • haloalkyl may mean a straight or branched chain alkyl (hydrocarbon) having one or more halo substituted carbon atoms as defined herein.
  • haloalkyl include, but are not limited to, methyl, ethyl, propyl, isopropyl, isobutyl or n -butyl independently substituted with one or more halogens, such as F, Cl, Br, or I. .
  • hydroxyalkyl may mean a straight or branched chain alkyl (hydrocarbon) having a carbon atom substituted with hydroxy (OH).
  • aminoalkyl may mean a straight or branched chain alkyl (hydrocarbon) having a carbon atom substituted with amino (NR'R"), wherein R' and R" are each independently hydrogen , and may be selected from the group consisting of C 1-4 alkyl, wherein the selected R' and R" may be each independently substituted or unsubstituted.
  • cyanoalkyl may mean a straight or branched chain alkyl (hydrocarbon) having a carbon atom substituted with cyano (CN).
  • heterocycloalkyl may mean a ring containing 1 to 5 heteroatoms selected from N, O and S as atoms forming the ring, and may be saturated or partially unsaturated.
  • unsaturated it may be referred to as a heterocycloalkene.
  • a heterocycloalkyl may be a single ring or multiple rings such as a spiro ring, a bridged ring or a fused ring.
  • heterocycloalkyl may mean a heterocycloalkyl containing 3 to 12 atoms forming a ring
  • heterocycloalkyl is pyrrolidine, piperidine, imi Dazolidine, pyrazolidine, butyrolactam, valerolactam, imidazolidinone, hydantoin, dioxolane, phthalimide, piperidine, pyrimidine-2,4( 1H , 3H )- Dione, 1,4-dioxane, morpholine, thiomorpholine, thiomorpholine- S -oxide, thiomorpholine- S , S -oxide, piperazine, pyran, pyridone, 3-pyrroline, thiopyran, pyrone, tetrahydrofuran, tetrahydrothiophene, quinuclidine, tropane, 2-azaspiro[3.3]heptan
  • arene may mean an aromatic hydrocarbon ring.
  • the arene may be a monocyclic arene or a polycyclic arene.
  • the ring carbon number of arene may be 5 or more and 30 or less, 5 or more and 20 or less, or 5 or more and 15 or less.
  • examples of arenes include benzene, naphthalene, fluorene, anthracene, phenanthrene, terbenzene, quaterbenzene, quinkbenzene, sexbenzene, triphenylene, pyrene, benzofluoranthene, chrysene, etc. not limited In the present specification, the residue in which one hydrogen atom is removed from the "arene" is referred to as "aryl".
  • heteroene may be an aromatic ring containing at least one of O, N, P, Si, and S as a heterogeneous element.
  • the number of ring carbon atoms of heteroarene may be 2 or more and 30 or less, or 2 or more and 20 or less.
  • the heteroarene may be a monocyclic heteroarene or a polycyclic heteroarene.
  • the polycyclic heteroarene may have, for example, a two- or three-ring structure.
  • heteroarenes include thiophene, purine, pyrrole, pyrazole, imidazole, thiazole, oxazole, isothiazole, oxadiazole, triazole, pyridine, triazine, acridyl, pyridazine, pyrazine, quinoline , quinazoline, quinoxaline, phenoxazine, phthalazine, pyrimidine, pyridopyrimidine, pyridopyrazine, pyrazinopyrazine, isoquinoline, indole, carbazole, imidazopyridazine, imidazopyridine, imidazopyr Limidine, pyrazolopyrimidine, imidazopyrazine, pyrazolopyridine, N -arylcarbazole, N -heteroarylcarbazole, N -alkylcarbazole, benzoxazole, benzoimid
  • enantiomer means a compound of the present invention or a salt thereof having the same chemical formula or molecular formula but sterically different. Each of these optical isomers and mixtures thereof are also included within the scope of the present invention.
  • a solid line bond (-) connecting an asymmetric carbon atom is a wedge-shaped solid line bond indicating the absolute configuration of the stereocenter. or wedge-dotted join may include.
  • the compound of formula 1 of the present invention may exist in the form of a "pharmaceutically acceptable salt".
  • a pharmaceutically acceptable salt As the salt, an acid addition salt formed with a pharmaceutically acceptable free acid is useful.
  • pharmaceutically acceptable salt refers to a concentration of a compound having an effective action relatively non-toxic and harmless to a patient, and any side effects resulting from the salt do not reduce the beneficial efficacy of the compound represented by the formula (1). Any organic or inorganic acid addition salt of
  • Acid addition salts are prepared by conventional methods, for example by dissolving the compound in an aqueous solution of an excess of acid and precipitating the salt using a water-miscible organic solvent such as methanol, ethanol, acetone or acetonitrile. Equal molar amounts of the compound and the acid or alcohol in water may be heated, and then the mixture may be evaporated to dryness, or the precipitated salt may be filtered off with suction.
  • a water-miscible organic solvent such as methanol, ethanol, acetone or acetonitrile.
  • an organic acid and an inorganic acid may be used as the free acid, and hydrochloric acid, phosphoric acid, sulfuric acid, or nitric acid may be used as the inorganic acid, and the organic acid may be methanesulfonic acid, p -toluenesulfonic acid, acetic acid, trifluoroacetic acid, Maleic acid, succinic acid, oxalic acid, benzoic acid, tartaric acid, fumaric acid, manderic acid, propionic acid, citric acid, lactic acid, glycolic acid, glycolic acid, glue Conic acid, galacturonic acid, glutamic acid, glutaric acid, glucuronic acid, aspartic acid, ascorbic acid, carbonic acid, vanillic acid, or hydroiodic acid, etc. can be used However, the present invention is not limited thereto.
  • bases can be used to prepare pharmaceutically acceptable metal salts.
  • the alkali metal salt or alkaline earth metal salt is obtained, for example, by dissolving the compound in an excess alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering the undissolved compound salt, and then evaporating and drying the filtrate.
  • it is pharmaceutically suitable to prepare a sodium, potassium, or calcium salt as the metal salt, but is not limited thereto.
  • the corresponding silver salt can be obtained by reacting an alkali metal or alkaline earth metal salt with a suitable silver salt (eg, silver nitrate).
  • the pharmaceutically acceptable salts of the present invention include salts of acidic or basic groups that may be present in the compound of Formula 1, unless otherwise indicated.
  • pharmaceutically acceptable salts may include sodium, calcium and potassium salts of a hydroxyl group
  • other pharmaceutically acceptable salts of an amino group include hydrobromide, sulfate, hydrogen sulfate, phosphate, hydrogen phosphate, dihydrogen phosphate, acetate, succinate, citrate, tartrate, lactate, mandelate, methanesulfonate (mesylate), and p -toluenesulfonate (tosylate) salts; It can be prepared through a method for preparing a known salt.
  • the present invention provides the use of a compound represented by the following formula (1), an optical isomer thereof, or a pharmaceutically acceptable salt thereof.
  • the compound represented by Formula 1 of the present invention since the compound represented by Formula 1 of the present invention, its optical isomer, or a pharmaceutically acceptable salt thereof exhibits inhibitory activity against DNK-PK, it is suitable for treatment or prevention of DNA-PK-related diseases, particularly cancer. It can be useful. Since DNA-PK plays a key role in the repair process of dsDNA cleavage, inhibiting DNA-PK activity can induce cancer cell death by interfering with DNA repair in cancer cells whose cell cycle is promoted compared to normal cells. In particular, the cancer may mean a cancer having a high level of replication stress, but is not limited thereto.
  • the cancer includes all cancers capable of exhibiting therapeutic or prophylactic efficacy due to inhibition of DNA-PK activity, and may be solid cancer or blood cancer.
  • pseudomyxoma intrahepatic biliary tract cancer, hepatoblastoma, liver cancer, thyroid cancer, colon cancer, testicular cancer, myelodysplastic syndrome, glioblastoma, oral cancer, labial cancer, mycosis fungoides, acute myeloid leukemia, acute lymphoblastic leukemia, basal cell cancer, ovarian cancer Epithelial cancer, ovarian germ cell cancer, male breast cancer, brain cancer, pituitary adenoma, multiple myeloma, gallbladder cancer, biliary tract cancer, colorectal cancer, chronic myelogenous leukemia, chronic lymphocytic leukemia, retinoblastoma, choroidal melanoma, ampulla Barter cancer, bladder cancer, peritoneal cancer, Para
  • the present invention provides a pharmaceutical composition for the treatment or prevention of cancer containing the compound represented by Formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient, DNA damage It may be to further enhance the anticancer effect by being administered together in an anticancer treatment regimen that causes
  • the anti-cancer therapy may be radiation therapy or chemotherapy, but is not limited thereto.
  • the radiation therapy includes any form of treatment that can break the DNA double helix structure by causing damage to the DNA of cancer cells.
  • it may be photon irradiation (classical, electromagnetic X-ray/gamma irradiation), proton irradiation, heavy ion irradiation (ionized carbon) or neutron irradiation, but is not limited thereto.
  • the anti-tumor substance used in the chemotherapy which can be administered together with the pharmaceutical composition for the treatment or prevention of cancer of the present invention, damages the DNA of cancer cells, such as DNA replication, DNA transcription or gene expression involved in it could be
  • the anti-tumor substance may be an alkylating agent, a platinum compound, a topoisomerase inhibitor, a DNA modifier, an anticancer antibiotic, or an alpha emitter, specifically altretamine, bendamustine, busulfan, carmustine, chloroambucil, Chloromethine, cyclophosphamide, dacarbazine, ifosfamide, improsulfan tosylate, lomustine, melphalan, mitobronitol, mitolactol, nimustine, ranimustine, temozolomide, thiotepa, threosulfan , mechloroethamine, carboquinone, apaziquin, fotemustine, gluphosp
  • the pharmaceutical composition of the present invention may further include one or more active ingredients exhibiting the same or similar efficacy in addition to the compound represented by Formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof.
  • the step of administering to a subject in need thereof a therapeutically effective amount of the compound represented by Formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof provides a method for treating or preventing a DNA-PK-related disease, particularly cancer, comprising:
  • the subject may be a mammal including a human.
  • the term "therapeutically effective amount” refers to an amount of the compound represented by Formula 1 effective for treatment or prevention of a DNA-PK-related disease.
  • “therapeutically effective amount” means an amount sufficient to treat a disease at a reasonable benefit/risk ratio applicable to medical treatment, and effective dose level includes the subject type and severity, age, sex, type of disease, The activity of the drug, the sensitivity to the drug, the time of administration, the route of administration and the rate of excretion, the duration of treatment, factors including concurrently used drugs, and other factors well known in the medical field may be determined.
  • the pharmaceutical composition of the present invention may be administered as an individual therapeutic agent or may be administered in combination with other therapeutic agents, and may be administered sequentially or simultaneously with commercially available therapeutic agents.
  • the dosage of the pharmaceutical composition of the present invention may be determined by an expert according to various factors such as the patient's condition, age, sex, and complications. Since the active ingredient of the pharmaceutical composition of the present invention is excellent in safety, it can be used at a dose higher than the determined dosage.
  • the present invention provides a compound represented by Formula 1, an optical isomer thereof, or A use of a pharmaceutically acceptable salt thereof is provided.
  • the compound represented by Formula 1 for the manufacture of a drug may be mixed with an acceptable adjuvant, diluent, carrier, etc., and may have a synergistic action of the active ingredients by being prepared as a complex formulation together with other active agents.
  • Embodiments of the present invention may be modified in various other forms, and the scope of the present invention is not limited to the embodiments described below.
  • the embodiment of the present invention is provided in order to more completely explain the present invention to those of ordinary skill in the art.
  • "including" a certain element throughout the specification means that other elements may be further included, rather than excluding other elements, unless otherwise stated.
  • the pyrimidine-fused cyclic compound of the present invention exhibits excellent inhibitory activity against DNA-PK, it can be usefully used for the treatment or prevention of the DNA-PK-related disease.
  • Step 1 2-chloro-4- (tetrahydro-2H-pyran-4-yl) pyrimidine-4,5-diamine ⁇ 2-chloro-4- (tetrahydro-2H-pyran-4-yl) pyrimidine-4 Preparation of ,5-diamine ⁇
  • Step 2 2-chloro-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purin-8-one ⁇ 2-chloro-9-(tetrahydro-2H-pyran- Preparation of 4-yl)-7,9-dihydro-8H-purin-8-one ⁇
  • Step 3 2-Chloro-7-methyl-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purin-8-one ⁇ 2-chloro-7-methyl-9 Preparation of -(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purin-8-one ⁇
  • Step 1 Preparation of 2-chloro-N4-phenylpyrimidine-4,5-diamine ⁇ 2-chloro-N4-phenylpyrimidine-4,5-diamine ⁇
  • Step 2 Preparation of 2-chloro-9-phenyl-7,9-dihydro-8H-purin-8-one ⁇ 2-chloro-9-phenyl-7,9-dihydro-8H-purin-8-one ⁇
  • Step 3 2-chloro-7-methyl-9-phenyl-7,9-dihydro-8H-purin-8-one ⁇ 2-chloro-7-methyl-9-phenyl-7,9-dihydro-8H- purin-8-one ⁇ production
  • Step 1 2-chloro-9-tetrahydro-2H-pyran-4-yl-7,9-dihydro-8H-purine-8-thione ⁇ 2-chloro-9-tetrahydro-2H-pyran-4-yl Preparation of -7,9-dihydro-8H-purine-8-thione ⁇
  • Step 2 2-chloro-7-methyl-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purine-8-thione ⁇ 2-chloro-7-methyl-9 -(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purine-8-thione ⁇ production
  • Step 1 2-chloro-8-(tetrahydro-2H-pyran-4-yl)-5,8-dihydropteridine-6,7-dione ⁇ 2-chloro-8-(tetrahydro-2H-pyran) Preparation of -4-yl)-5,8-dihydropteridine-6,7-dione ⁇
  • Step 2 2-chloro-5-methyl-8-(tetrahydro-2H-pyran-4-yl)-5,8-dihydropteridine-6,7-dione ⁇ 2-chloro-5-methyl- Preparation of 8-(tetrahydro-2H-pyran-4-yl)-5,8-dihydropteridine-6,7-dione ⁇
  • Preparation 18 Preparation of 2-chloro-8-cyclopentyl-5-methyl-pteridine-6,7-dione ⁇ 2-chloro-8-cyclopentyl-5-methyl-pteridine-6,7-dione ⁇
  • Step 1 Preparation of ethyl (tetrahydro-2H-pyran-4-yl)glycinate ⁇ ethyl (tetrahydro-2H-pyran-4-yl)glycinate ⁇
  • Step 2 Ethyl N-(2-chloro-5-nitropyrimidin-4-yl)-N-(tetrahydro-2H-pyran-4-yl)glycinate ⁇ ethyl N-(2-chloro-5 Preparation of -nitropyrimidin-4-yl)-N-(tetrahydro-2H-pyran-4-yl)glycinate ⁇
  • Step 3 2-chloro-8-(tetrahydro-2H-pyran-4-yl)-7,8-dihydropteridin-6(5H)-one ⁇ 2-chloro-8-(tetrahydro-2H- Preparation of pyran-4-yl)-7,8-dihydropteridin-6(5H)-one ⁇
  • Step 4 2-Chloro-5-methyl-8-(tetrahydro-2H-pyran-4-yl)-7,8-dihydropteridin-6(5H)-one ⁇ 2-chloro-5-methyl Preparation of -8-(tetrahydro-2H-pyran-4-yl)-7,8-dihydropteridin-6(5H)-one ⁇
  • Step 1 5-bromo-2-chloro-N- (tetrahydro-2H-pyran-4-yl) pyrimidin-4-amine ⁇ 5-bromo-2-chloro-N- (tetrahydro-2H-pyran- Preparation of 4-yl)pyrimidin-4-amine ⁇
  • Step 2 2-Chloro-5-methyl-8-(tetrahydro-2H-pyran-4-yl)pyrido[2,3-d]pyrimidin-7(8H)-one ⁇ 2-chloro-5- Preparation of methyl-8-(tetrahydro-2H-pyran-4-yl)pyrido[2,3-d]pyrimidin-7(8H)-one ⁇
  • Example 1 2-((2,5-dimethylbenzo[d]thiazol-6-yl)amino)-7-methyl-9-(tetrahydro-2H-pyran-4-yl)-7,9- Dihydro-8H-purin-8-one ⁇ 2-((2,5-dimethylbenzo[d]thiazol-6-yl)amino)-7-methyl-9-(tetrahydro-2H-pyran-4-yl)- Preparation of 7,9-dihydro-8H-purin-8-one ⁇
  • Examples 2 to 31 were prepared in substantially the same manner as in Example 1, using appropriate intermediates and amines.
  • Example 2 7-methyl-2-((6-methylquinolin-7-yl)amino)-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purine- 8-one ⁇ 7-methyl-2-((6-methylquinolin-7-yl)amino)-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purin-8-one ⁇ manufacturing
  • Example 3 2-(benzo[d]thiazol-6-ylamino)-7-methyl-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purine- 8-one ⁇ 2-(benzo[d]thiazol-6-ylamino)-7-methyl-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purin-8-one ⁇ manufacture of
  • Example 4 2-((5-hydroxynaphthalen-2-yl)amino)-7-methyl-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purine -8-one ⁇ 2-((5-hydroxynaphthalen-2-yl)amino)-7-methyl-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purin-8- manufacture of one ⁇
  • Example 5 7-methyl-2-((5-methyl-1H-indol-6-yl)amino)-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H -Purin-8-one ⁇ 7-methyl-2-((5-methyl-1H-indol-6-yl)amino)-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro- Preparation of 8H-purin-8-one ⁇
  • Example 6 2-((5-chlorobenzo[d]oxazol-6-yl)amino)-7-methyl-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro -8H-purin-8-one ⁇ 2-((5-chlorobenzo[d]oxazol-6-yl)amino)-7-methyl-9-(tetrahydro-2H-pyran-4-yl)-7,9- Preparation of dihydro-8H-purin-8-one ⁇
  • Example 7 2-((2,6-dimethylbenzo[d]thiazol-5-yl)amino)-7-methyl-9-(tetrahydro-2H-pyran-4-yl)-7,9- Dihydro-8H-purin-8-one ⁇ 2-((2,6-dimethylbenzo[d]thiazol-5-yl)amino)-7-methyl-9-(tetrahydro-2H-pyran-4-yl)- Preparation of 7,9-dihydro-8H-purin-8-one ⁇
  • Example 8 2,2-dimethyl-7-((7-methyl-8-oxo-9-(tetrahydro-2H-pyran-4-yl)-8,9-dihydro-7H-purine-2- yl)amino)-2H-benzo[b][1,4]oxazin-3(4H)-one ⁇ 2,2-dimethyl-7-((7-methyl-8-oxo-9-(tetrahydro-2H) Preparation of -pyran-4-yl)-8,9-dihydro-7H-purin-2-yl)amino)-2H-benzo[b][1,4]oxazin-3(4H)-one ⁇
  • Example 9 7-methyl-2-((6-methylbenzo[d][1,3]dioxol-5-yl)amino)-9-(tetrahydro-2H-pyran-4-yl)-7 ,9-dihydro-8H-purin-8-one ⁇ 7-methyl-2-((6-methylbenzo[d][1,3]dioxol-5-yl)amino)-9-(tetrahydro-2H-pyran Preparation of -4-yl)-7,9-dihydro-8H-purin-8-one ⁇
  • Example 10 7-methyl-2-((6-methylbenzo[c][1,2,5]thiadiazol-5-yl)amino)-9-(tetrahydro-2H-pyran-4-yl )-7,9-dihydro-8H-purin-8-one ⁇ 7-methyl-2-((6-methylbenzo[c][1,2,5]thiadiazol-5-yl)amino)-9-( Preparation of tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purin-8-one ⁇
  • Example 11 2-((4,7-dimethyl-2-oxo-2H-chromen-6-yl)amino)-7-methyl-9-(tetrahydro-2H-pyran-4-yl)-7 ,9-dihydro-8H-purin-8-one ⁇ 2-((4,7-dimethyl-2-oxo-2H-chromen-6-yl)amino)-7-methyl-9-(tetrahydro-2H- Preparation of pyran-4-yl)-7,9-dihydro-8H-purin-8-one ⁇
  • Example 12 7-methyl-2-((4-methyl-6-(4-methyl-1H-imidazol-1-yl)pyridin-3-yl)amino)-9-(tetrahydro-2H-pyran -4-yl)-7,9-dihydro-8H-purin-8-one ⁇ 7-methyl-2-((4-methyl-6-(4-methyl-1H-imidazol-1-yl)pyridin- Preparation of 3-yl)amino)-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purin-8-one ⁇
  • Example 13 4-methyl-5-((7-methyl-8-oxo-9-(tetrahydro-2H-pyran-4-yl)-8,9-dihydro-7H-purin-2-yl) Amino) picolinonitrile ⁇ 4-methyl-5-((7-methyl-8-oxo-9-(tetrahydro-2H-pyran-4-yl)-8,9-dihydro-7H-purin-2-yl) Preparation of amino) picolinonitrile ⁇
  • Example 14 4-methyl-5-((7-methyl-8-oxo-9-(tetrahydro-2H-pyran-4-yl)-8,9-dihydro-7H-purin-2-yl) Amino)picolinamide ⁇ 4-methyl-5-((7-methyl-8-oxo-9-(tetrahydro-2H-pyran-4-yl)-8,9-dihydro-7H-purin-2-yl) Preparation of amino)picolinamide ⁇
  • Step 2 4-Methyl-5-((7-methyl-8-oxo-9-(tetrahydro-2H-pyran-4-yl)-8,9-dihydro-7H-purin-2-yl)amino )picolinamide ⁇ 4-methyl-5-((7-methyl-8-oxo-9-(tetrahydro-2H-pyran-4-yl)-8,9-dihydro-7H-purin-2-yl)amino ) Preparation of picolinamide ⁇
  • a target compound was prepared in substantially the same manner as in Example 1 using 5-amino-4-methyl-picolinamide obtained in Step 1 (yield: 11%).
  • 1 H-NMR 400 MHz, CDCl 3 ) ⁇ 1.74 (2H, d), 2.43 (3H, s), 2.76 (2H, m), 3.43 (3H, s), 3.55 (2H, t), 4.15 (3H, dd), 4.53-4.59 (1H, m), 5.52 (1H, s), 6.83-9.51 (5H, m)
  • Example 15 Methyl 5-((7-methyl-8-oxo-9-(tetrahydro-2H-pyran-4-yl)-8,9-dihydro-7H-purin-2-yl)amino)thi Offene-2-carboxylate ⁇ methyl 5-((7-methyl-8-oxo-9-(tetrahydro-2H-pyran-4-yl)-8,9-dihydro-7H-purin-2-yl)amino ) Preparation of thiophene-2-carboxylate ⁇
  • Example 16 Methyl 4-methyl-5-((7-methyl-8-oxo-9-(tetrahydro-2H-pyran-4-yl)-8,9-dihydro-7H-purin-2-yl )amino)picolinate ⁇ methyl 4-methyl-5-((7-methyl-8-oxo-9-(tetrahydro-2H-pyran-4-yl)-8,9-dihydro-7H-purin-2- Preparation of yl)amino)picolinate ⁇
  • Example 17 N,4-dimethyl-5-((7-methyl-8-oxo-9-(tetrahydro-2H-pyran-4-yl)-8,9-dihydro-7H-purine-2- yl)amino)picolinamide ⁇ N,4-dimethyl-5-((7-methyl-8-oxo-9-(tetrahydro-2H-pyran-4-yl)-8,9-dihydro-7H-purin- Preparation of 2-yl)amino)picolinamide ⁇
  • the compound of Example 17 was obtained by performing the following scheme using the compound of Example 16.
  • Example 18 7-methyl-2-((4-methyl-6-(methylthio)pyridin-3-yl)amino)-9-(tetrahydro-2H-pyran-4-yl)-7,9- Dihydro-8H-purin-8-one ⁇ 7-methyl-2-((4-methyl-6-(methylthio)pyridin-3-yl)amino)-9-(tetrahydro-2H-pyran-4-yl) Preparation of -7,9-dihydro-8H-purin-8-one ⁇
  • Example 19 7-methyl-2-((4-methyl-6-(trifluoromethyl)pyridin-3-yl)amino)-9-(tetrahydro-2H-pyran-4-yl)-7, 9-dihydro-8H-purin-8-one ⁇ 7-methyl-2-((4-methyl-6-(trifluoromethyl)pyridin-3-yl)amino)-9-(tetrahydro-2H-pyran-4- Preparation of yl)-7,9-dihydro-8H-purin-8-one ⁇
  • Example 20 7-methyl-2-((6-methylbenzo[d][1,3]dioxol-5-yl)amino)-9-phenyl-7,9-dihydro-8H-purin-8 -one ⁇ 7-methyl-2-((6-methylbenzo[d][1,3]dioxol-5-yl)amino)-9-phenyl-7,9-dihydro-8H-purin-8-one ⁇ Produce
  • Example 21 7-methyl-2-((6-methylbenzo[c][1,2,5]thiadiazol-5-yl)amino)-9-phenyl-7,9-dihydro-8H- Purin-8-one ⁇ 7-methyl-2-((6-methylbenzo[c][1,2,5]thiadiazol-5-yl)amino)-9-phenyl-7,9-dihydro-8H-purin- Preparation of 8-one ⁇
  • Example 22 2-((4,7-dimethyl-2-oxo-2H-chromen-6-yl)amino)-7-methyl-9-phenyl-7,9-dihydro-8H-purine-8 -one ⁇ 2-((4,7-dimethyl-2-oxo-2H-chromen-6-yl)amino)-7-methyl-9-phenyl-7,9-dihydro-8H-purin-8-one ⁇ manufacture of
  • Example 23 7-methyl-2-((4-methyl-6-(trifluoromethyl)pyridin-3-yl)amino)-9-phenyl-7,9-dihydro-8H-purine-8- Preparation of one ⁇ 7-methyl-2-((4-methyl-6-(trifluoromethyl)pyridin-3-yl)amino)-9-phenyl-7,9-dihydro-8H-purin-8-one ⁇
  • Example 24 7-methyl-2-((4-methyl-6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)amino)-9-(tetrahydro-2H-thio Pyran-4-yl)-7,9-dihydro-8H-purin-8-one ⁇ 7-methyl-2-((4-methyl-6-(1-methyl-1H-pyrazol-4-yl)pyridin) Preparation of -3-yl)amino)-9-(tetrahydro-2H-thiopyran-4-yl)-7,9-dihydro-8H-purin-8-one ⁇
  • Example 25 2-((2,5-dimethylbenzo[d]thiazol-6-yl)amino)-7-methyl-9-(spiro[3.3]heptan-2-yl)-7,9-di Hydro-8H-purin-8-one ⁇ 2-((2,5-dimethylbenzo[d]thiazol-6-yl)amino)-7-methyl-9-(spiro[3.3]heptan-2-yl)-7 Preparation of ,9-dihydro-8H-purin-8-one ⁇
  • Example 26 7-methyl-2-((6-methylbenzo[c][1,2,5]thiadiazol-5-yl)amino)-9-(spiro[3.3]heptan-2-yl) -7,9-dihydro-8H-purin-8-one ⁇ 7-methyl-2-((6-methylbenzo[c][1,2,5]thiadiazol-5-yl)amino)-9-(spiro [3.3] Preparation of heptan-2-yl)-7,9-dihydro-8H-purin-8-one ⁇
  • Example 27 2-((2,5-dimethylbenzo[d]thiazol-6-yl)amino)-9-(3-methoxycyclobutyl)-7-methyl-7,9-dihydro-8H -Purin-8-one ⁇ 2-((2,5-dimethylbenzo[d]thiazol-6-yl)amino)-9-(3-methoxycyclobutyl)-7-methyl-7,9-dihydro-8H-purin- Preparation of 8-one ⁇
  • Example 28 2-((2,5-dimethylbenzo[d]thiazol-6-yl)amino)-7-methyl-9-(2-oxaspiro[3.3]heptan-6-yl)-7, 9-dihydro-8H-purin-8-one ⁇ 2-((2,5-dimethylbenzo[d]thiazol-6-yl)amino)-7-methyl-9-(2-oxaspiro[3.3]heptan-6 Preparation of -yl)-7,9-dihydro-8H-purin-8-one ⁇
  • Example 29 7-methyl-2-((4-methyl-6-(1-methyl-1H-imidazol-4-yl)pyridin-3-yl)amino)-9-(2-oxaspiro[3.5 ] Nonan-7-yl)-7,9-dihydro-8H-purin-8-one ⁇ 7-methyl-2-((4-methyl-6-(1-methyl-1H-imidazol-4-yl) Preparation of pyridin-3-yl)amino)-9-(2-oxaspiro[3.5]nonan-7-yl)-7,9-dihydro-8H-purin-8-one ⁇
  • Example 30 7-methyl-2-((6-methylbenzo[c][1,2,5]thiadiazol-5-yl)amino)-9-(tetrahydro-2H-pyran-4-yl )-7,9-dihydro-8H-purine-8-thione ⁇ 7-methyl-2-((6-methylbenzo[c][1,2,5]thiadiazol-5-yl)amino)-9-( Preparation of tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purine-8-thione ⁇
  • Example 31 4-methyl-5-((7-methyl-9-(tetrahydro-2H-pyran-4-yl)-8-thioxo-8,9-dihydro-7H-purin-2-yl )amino)picolinamide ⁇ 4-methyl-5-((7-methyl-9-(tetrahydro-2H-pyran-4-yl)-8-thioxo-8,9-dihydro-7H-purin-2-yl Preparation of )amino)picolinamide ⁇
  • Example 32 7-methyl-2-((4-methyl-6-((1-methyl-1H-pyrazol-4-yl)amino)pyridin-3-yl)amino)-9-(tetrahydro- 2H-pyran-4-yl)-7,9-dihydro-8H-purin-8-one ⁇ 7-methyl-2-((4-methyl-6-((1-methyl-1H-pyrazol-4- Preparation of yl)amino)pyridin-3-yl)amino)-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purin-8-one ⁇
  • Step 1 4-methyl-N-(1-methyl-1H-pyrazol-4-yl)-5-nitropyridin-2-amine ⁇ 4-methyl-N-(1-methyl-1H-pyrazol-4- Preparation of yl)-5-nitropyridin-2-amine ⁇
  • Step 2 4-methyl-N-(1-methyl-1H-pyrazol-4-yl)pyridine-2,5-diamine ⁇ 4-methyl-N-(1-methyl-1H-pyrazol-4-yl) Preparation of pyridin-2,5-diamine ⁇
  • Step 3 7-methyl-2-((4-methyl-6-((1-methyl-1H-pyrazol-4-yl)amino)pyridin-3-yl)amino)-9-(tetrahydro-2H -Pyran-4-yl)-7,9-dihydro-8H-purin-8-one ⁇ 7-methyl-2-((4-methyl-6-((1-methyl-1H-pyrazol-4-yl) Preparation of )amino)pyridin-3-yl)amino)-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purin-8-one ⁇
  • Example 33 4-methyl-5-((7-methyl-8-oxo-9-(tetrahydro-2H-pyran-4-yl)-8,9-dihydro-7H-purin-2-yl) Amino)pyridin-2-yl methanesulfonate ⁇ 4-methyl-5-((7-methyl-8-oxo-9-(tetrahydro-2H-pyran-4-yl)-8,9-dihydro-7H-purin) Preparation of -2-yl)amino)pyridin-2-yl methanesulfonate ⁇
  • Step 1 Preparation of 4-methyl-5-nitropyridin-2-yl methanesulfonate (4-methyl-5-nitropyridin-2-yl methanesulfonate)
  • Step 2 Preparation of 5-amino-4-methylpyridin-2-yl methanesulfonate (5-amino-4-methylpyridin-2-yl methanesulfonate)
  • Step 3 4-Methyl-5-((7-methyl-8-oxo-9-(tetrahydro-2H-pyran-4-yl)-8,9-dihydro-7H-purin-2-yl)amino )pyridin-2-yl methanesulfonate ⁇ 4-methyl-5-((7-methyl-8-oxo-9-(tetrahydro-2H-pyran-4-yl)-8,9-dihydro-7H-purin- Preparation of 2-yl)amino)pyridin-2-yl methanesulfonate ⁇
  • Example 34 2-((6-(furan-3-yl)-4-methylpyridin-3-yl)amino)-7-methyl-9-(tetrahydro-2H-pyran-4-yl)-7 ,9-dihydro-8H-purin-8-one ⁇ 2-((6-(furan-3-yl)-4-methylpyridin-3-yl)amino)-7-methyl-9-(tetrahydro-2H- Preparation of pyran-4-yl)-7,9-dihydro-8H-purin-8-one ⁇
  • Step 1 Preparation of 6-(furan-3-yl)-4-methylpyridin-3-amine ⁇ 6-(furan-3-yl)-4-methylpyridin-3-amine ⁇
  • Step 2 2-((6-(furan-3-yl)-4-methylpyridin-3-yl)amino)-7-methyl-9-(tetrahydro-2H-pyran-4-yl)-7, 9-dihydro-8H-purin-8-one ⁇ 2-((6-(furan-3-yl)-4-methylpyridin-3-yl)amino)-7-methyl-9-(tetrahydro-2H-pyran Preparation of -4-yl)-7,9-dihydro-8H-purin-8-one ⁇
  • Examples 35 to 59 were prepared in substantially the same manner as in Example 34, using appropriate intermediates, amine derivatives and boronic acid derivatives.
  • Example 35 7-methyl-2-((4-methyl-6-(3-methylthiophen-2-yl)pyridin-3-yl)amino)-9-(tetrahydro-2H-pyran-4- yl)-7,9-dihydro-8H-purin-8-one ⁇ 7-methyl-2-((4-methyl-6-(3-methylthiophen-2-yl)pyridin-3-yl)amino)- Preparation of 9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purin-8-one ⁇
  • Example 36 7-methyl-2-((4-methyl-6-(5-methylthiophen-2-yl)pyridin-3-yl)amino)-9-(tetrahydro-2H-pyran-4- yl)-7,9-dihydro-8H-purin-8-one ⁇ 7-methyl-2-((4-methyl-6-(5-methylthiophen-2-yl)pyridin-3-yl)amino)- Preparation of 9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purin-8-one ⁇
  • Example 37 7-methyl-2-((4-methyl-6-(thiophen-2-yl)pyridin-3-yl)amino)-9-(tetrahydro-2H-pyran-4-yl)- 7,9-dihydro-8H-purin-8-one ⁇ 7-methyl-2-((4-methyl-6-(thiophen-2-yl)pyridin-3-yl)amino)-9-(tetrahydro- Preparation of 2H-pyran-4-yl)-7,9-dihydro-8H-purin-8-one ⁇
  • Example 38 2-((6-(furan-3-yl)-2-methylpyridin-3-yl)amino)-7-methyl-9-(tetrahydro-2H-pyran-4-yl)-7 ,9-dihydro-8H-purin-8-one ⁇ 2-((6-(furan-3-yl)-2-methylpyridin-3-yl)amino)-7-methyl-9-(tetrahydro-2H- Preparation of pyran-4-yl)-7,9-dihydro-8H-purin-8-one ⁇
  • Example 39 7-methyl-2-((4-methyl-6-(thiophen-3-yl)pyridin-3-yl)amino)-9-(tetrahydro-2H-pyran-4-yl)- 7,9-dihydro-8H-purin-8-one ⁇ 7-methyl-2-((4-methyl-6-(thiophen-3-yl)pyridin-3-yl)amino)-9-(tetrahydro- Preparation of 2H-pyran-4-yl)-7,9-dihydro-8H-purin-8-one ⁇
  • Example 40 7-methyl-2-((4-methyl-6-(5-methylfuran-2-yl)pyridin-3-yl)amino)-9-(tetrahydro-2H-pyran-4-yl )-7,9-dihydro-8H-purin-8-one ⁇ 7-methyl-2-((4-methyl-6-(5-methylfuran-2-yl)pyridin-3-yl)amino)-9 Preparation of -(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purin-8-one ⁇
  • Example 41 2-((6-(furan-2-yl)-4-methylpyridin-3-yl)amino)-7-methyl-9-(tetrahydro-2H-pyran-4-yl)-7 ,9-dihydro-8H-purin-8-one ⁇ 2-((6-(furan-2-yl)-4-methylpyridin-3-yl)amino)-7-methyl-9-(tetrahydro-2H- Preparation of pyran-4-yl)-7,9-dihydro-8H-purin-8-one ⁇
  • Example 42 7-methyl-2-((4-methyl-6-(2-methyloxazol-5-yl)pyridin-3-yl)amino)-9-(tetrahydro-2H-pyran-4- yl)-7,9-dihydro-8H-purin-8-one ⁇ 7-methyl-2-((4-methyl-6-(2-methyloxazol-5-yl)pyridin-3-yl)amino)- Preparation of 9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purin-8-one ⁇
  • Example 43 7-methyl-2-((4-methyl-6-(2-methylthiazol-5-yl)pyridin-3-yl)amino)-9-(tetrahydro-2H-pyran-4- yl)-7,9-dihydro-8H-purin-8-one ⁇ 7-methyl-2-((4-methyl-6-(2-methylthiazol-5-yl)pyridin-3-yl)amino)- Preparation of 9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purin-8-one ⁇
  • Example 44 7-methyl-2-((4-methyl-6-(3-methylisothiazol-5-yl)pyridin-3-yl)amino)-9-(tetrahydro-2H-pyran-4 -yl)-7,9-dihydro-8H-purin-8-one ⁇ 7-methyl-2-((4-methyl-6-(3-methylisothiazol-5-yl)pyridin-3-yl)amino) Preparation of -9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purin-8-one ⁇
  • Example 45 7-methyl-2-((4-methyl-6-(oxazol-5-yl)pyridin-3-yl)amino)-9-(tetrahydro-2H-pyran-4-yl)- 7,9-dihydro-8H-purin-8-one ⁇ 7-methyl-2-((4-methyl-6-(oxazol-5-yl)pyridin-3-yl)amino)-9-(tetrahydro- Preparation of 2H-pyran-4-yl)-7,9-dihydro-8H-purin-8-one ⁇
  • Example 46 7-methyl-2-((4-methyl-6-(oxazol-2-yl)pyridin-3-yl)amino)-9-(tetrahydro-2H-pyran-4-yl)- 7,9-dihydro-8H-purin-8-one ⁇ 7-methyl-2-((4-methyl-6-(oxazol-2-yl)pyridin-3-yl)amino)-9-(tetrahydro- Preparation of 2H-pyran-4-yl)-7,9-dihydro-8H-purin-8-one ⁇
  • Example 47 2-((6-(benzo[d][1,3]dioxol-5-yl)-4-methylpyridin-3-yl)amino)-7-methyl-9-(tetrahydro- 2H-pyran-4-yl)-7,9-dihydro-8H-purin-8-one ⁇ 2-((6-(benzo[d][1,3]dioxol-5-yl)-4-methylpyridin Preparation of -3-yl)amino)-7-methyl-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purin-8-one ⁇
  • Example 48 7-methyl-2-((4-methyl-6-(5-methylisoxazol-4-yl)pyridin-3-yl)amino)-9-(tetrahydro-2H-pyran-4- yl)-7,9-dihydro-8H-purin-8-one ⁇ 7-methyl-2-((4-methyl-6-(5-methylisoxazol-4-yl)pyridin-3-yl)amino)- Preparation of 9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purin-8-one ⁇
  • Example 49 7-methyl-2-((4-methyl-6-(1-methyl-1H-imidazol-4-yl)pyridin-3-yl)amino)-9-(tetrahydro-2H-pyran -4-yl)-7,9-dihydro-8H-purin-8-one ⁇ 7-methyl-2-((4-methyl-6-(1-methyl-1H-imidazol-4-yl)pyridin- Preparation of 3-yl)amino)-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purin-8-one ⁇
  • Example 50 7-methyl-2-((4-methyl-6-(1-methyl-1H-pyrrol-2-yl)pyridin-3-yl)amino)-9-(tetrahydro-2H-pyran- 4-yl)-7,9-dihydro-8H-purin-8-one ⁇ 7-methyl-2-((4-methyl-6-(1-methyl-1H-pyrrol-2-yl)pyridin-3 Preparation of -yl)amino)-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purin-8-one ⁇
  • Example 51 2-((6-(2,5-dihydrofuran-3-yl)-4-methylpyridin-3-yl)amino)-7-methyl-9-(tetrahydro-2H-pyran- 4-yl)-7,9-dihydro-8H-purin-8-one ⁇ 2-((6-(2,5-dihydrofuran-3-yl)-4-methylpyridin-3-yl)amino)-7 Preparation of -methyl-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purin-8-one ⁇
  • Example 52 2-((6-(4,5-dihydrofuran-3-yl)-4-methylpyridin-3-yl)amino)-7-methyl-9-(tetrahydro-2H-pyran- 4-yl)-7,9-dihydro-8H-purin-8-one ⁇ 2-((6-(4,5-dihydrofuran-3-yl)-4-methylpyridin-3-yl)amino)-7 Preparation of -methyl-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purin-8-one ⁇
  • Example 53 7-methyl-2-((4-methyl-6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)amino)-9-(2-oxaspiro[3.5 ] Nonan-7-yl)-7,9-dihydro-8H-purin-8-one ⁇ 7-methyl-2-((4-methyl-6-(1-methyl-1H-pyrazol-4-yl) Preparation of pyridin-3-yl)amino)-9-(2-oxaspiro[3.5]nonan-7-yl)-7,9-dihydro-8H-purin-8-one ⁇
  • Example 54 7-methyl-2-((4-methyl-6-(thiophen-2-yl)pyridin-3-yl)amino)-9-(2-morpholinoethyl)-7,9- Dihydro-8H-purin-8-one ⁇ 7-methyl-2-((4-methyl-6-(thiophen-2-yl)pyridin-3-yl)amino)-9-(2-morpholinoethyl)-7 Preparation of ,9-dihydro-8H-purin-8-one ⁇
  • Example 55 7-methyl-2-((4-methyl-6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)amino)-9-morpholino-7,9 -dihydro-8H-purin-8-one ⁇ 7-methyl-2-((4-methyl-6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)amino)-9- Preparation of morpholino-7,9-dihydro-8H-purin-8-one ⁇
  • Example 56 7-methyl-2-((4-methyl-6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)amino)-9-(spiro[2.5]octane- 6-yl)-7,9-dihydro-8H-purin-8-one ⁇ 7-methyl-2-((4-methyl-6-(1-methyl-1H-pyrazol-4-yl)pyridin-3) Preparation of -yl)amino)-9-(spiro[2.5]octan-6-yl)-7,9-dihydro-8H-purin-8-one ⁇
  • Example 57 7-ethyl-2-((4-methyl-6-(1-methyl-1H-imidazol-4-yl)pyridin-3-yl)amino)-9-(tetrahydro-2H-pyran -4-yl)-7,9-dihydro-8H-purin-8-one ⁇ 7-ethyl-2-((4-methyl-6-(1-methyl-1H-imidazol-4-yl)pyridin- Preparation of 3-yl)amino)-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purin-8-one ⁇
  • Example 58 7-ethyl-2-((4-methyl-6-(oxazol-2-yl)pyridin-3-yl)amino)-9-(tetrahydro-2H-pyran-4-yl)- 7,9-dihydro-8H-purin-8-one ⁇ 7-ethyl-2-((4-methyl-6-(oxazol-2-yl)pyridin-3-yl)amino)-9-(tetrahydro- Preparation of 2H-pyran-4-yl)-7,9-dihydro-8H-purin-8-one ⁇
  • Example 59 7-methyl-2-((4-methyl-6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)amino)-9-(tetrahydro-2H-pyran -4-yl)-7,9-dihydro-8H-purin-8-one ⁇ 7-methyl-2-((4-methyl-6-(1-methyl-1H-pyrazol-4-yl)pyridin- Preparation of 3-yl)amino)-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purin-8-one ⁇
  • Example 60 2-((5-Fluoro-2-methyl-4-(1-methyl-1H-imidazol-4-yl)phenyl)amino)-7-methyl-9-(tetrahydro-2H- Pyran-4-yl)-7,9-dihydro-8H-purin-8-one ⁇ 2-((5-fluoro-2-methyl-4-(1-methyl-1H-imidazol-4-yl)phenyl) Preparation of )amino)-7-methyl-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purin-8-one ⁇
  • Step 1 5-fluoro-2-methyl-4-(1-methyl-1H-imidazol-4-yl)aniline ⁇ 5-fluoro-2-methyl-4-(1-methyl-1H-imidazol-4) Preparation of -yl)aniline ⁇
  • Step 2 2-((5-Fluoro-2-methyl-4-(1-methyl-1H-imidazol-4-yl)phenyl)amino)-7-methyl-9-(tetrahydro-2H-pyran -4-yl)-7,9-dihydro-8H-purin-8-one ⁇ 2-((5-fluoro-2-methyl-4-(1-methyl-1H-imidazol-4-yl)phenyl) Preparation of amino)-7-methyl-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purin-8-one ⁇
  • Example 61 2-((5-fluoro-2-methyl-4-(2-methyloxazol-5-yl)phenyl)amino)-7-methyl-9-(tetrahydro-2H-pyran-4 -yl)-7,9-dihydro-8H-purin-8-one ⁇ 2-((5-fluoro-2-methyl-4-(2-methyloxazol-5-yl)phenyl)amino)-7-methyl Preparation of -9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purin-8-one ⁇
  • Example 62 7-methyl-2-((4-methyl-6-(methylsulfonyl)pyridin-3-yl)amino)-9-(tetrahydro-2H-pyran-4-yl)-7,9 -dihydro-8H-purin-8-one ⁇ 7-methyl-2-((4-methyl-6-(methylsulfonyl)pyridin-3-yl)amino)-9-(tetrahydro-2H-pyran-4-yl Preparation of )-7,9-dihydro-8H-purin-8-one ⁇
  • Example 63 7-methyl-2-((4-methyl-6-(methylsulfinyl)pyridin-3-yl)amino)-9-(tetrahydro-2H-pyran-4-yl)-7,9 -dihydro-8H-purin-8-one ⁇ 7-methyl-2-((4-methyl-6-(methylsulfinyl)pyridin-3-yl)amino)-9-(tetrahydro-2H-pyran-4-yl Preparation of )-7,9-dihydro-8H-purin-8-one ⁇
  • Example 64 N-(2-Methoxyethyl)-4-methyl-5-((7-methyl-8-oxo-9-(tetrahydro-2H-pyran-4-yl)-8,9-di Hydro-7H-purin-2-yl)amino)picolinamide ⁇ N-(2-methoxyethyl)-4-methyl-5-((7-methyl-8-oxo-9-(tetrahydro-2H-pyran-4) Preparation of -yl)-8,9-dihydro-7H-purin-2-yl)amino)picolinamide ⁇
  • Examples 65 to 67 were prepared in substantially the same manner as in Example 64 using appropriate amine derivatives.
  • Example 65 4-methyl-5-((7-methyl-8-oxo-9-(tetrahydro-2H-pyran-4-yl)-8,9-dihydro-7H-purin-2-yl) amino)-N-((tetrahydrofuran-2-yl)methyl)picolinamide ⁇ 4-methyl-5-((7-methyl-8-oxo-9-(tetrahydro-2H-pyran-4-yl) Preparation of -8,9-dihydro-7H-purin-2-yl)amino)-N-((tetrahydrofuran-2-yl)methyl)picolinamide ⁇
  • Example 66 N-(2-hydroxyethyl)-4-methyl-5-((7-methyl-8-oxo-9-(tetrahydro-2H-pyran-4-yl)-8,9-di Hydro-7H-purin-2-yl)amino)picolinamide ⁇ N-(2-hydroxyethyl)-4-methyl-5-((7-methyl-8-oxo-9-(tetrahydro-2H-pyran-4) Preparation of -yl)-8,9-dihydro-7H-purin-2-yl)amino)picolinamide ⁇
  • Example 68 4-methyl-N-(1-methyl-1H-pyrazol-4-yl)-5-((7-methyl-8-oxo-9-(tetrahydro-2H-pyran-4-yl) )-8,9-dihydro-7H-purin-2-yl)amino)picolinamide ⁇ 4-methyl-N-(1-methyl-1H-pyrazol-4-yl)-5-((7-methyl Preparation of -8-oxo-9-(tetrahydro-2H-pyran-4-yl)-8,9-dihydro-7H-purin-2-yl)amino)picolinamide ⁇
  • Example 69 4-methyl-5-((7-methyl-8-oxo-9-(tetrahydro-2H-pyran-4-yl)-8,9-dihydro-7H-purin-2-yl) Amino)-N-(oxetan-3-yl)picolinamide ⁇ 4-methyl-5-((7-methyl-8-oxo-9-(tetrahydro-2H-pyran-4-yl)-8,9 Preparation of -dihydro-7H-purin-2-yl)amino)-N-(oxetan-3-yl)picolinamide ⁇
  • Example 70 5-methyl-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-8-(tetrahydro-2H- Pyran-4-yl)pyrido[2,3-d]pyrimidin-7(8H)-one ⁇ 5-methyl-2-((7-methyl-[1,2,4]triazolo[1,5- Preparation of a]pyridin-6-yl)amino)-8-(tetrahydro-2H-pyran-4-yl)pyrido[2,3-d]pyrimidin-7(8H)-one ⁇
  • Examples 71 to 101 were prepared in substantially the same manner as in Example 70, using the appropriate compounds and amine derivatives.
  • Example 71 7-methyl-2-((6-methylbenzo[c][1,2,5]thiadiazol-5-yl)amino)-9-(tetrahydro-2H-thiopyran-4- yl)-7,9-dihydro-8H-purin-8-one ⁇ 7-methyl-2-((6-methylbenzo[c][1,2,5]thiadiazol-5-yl)amino)-9- Preparation of (tetrahydro-2H-thiopyran-4-yl)-7,9-dihydro-8H-purin-8-one ⁇
  • Example 72 2-((2,5-dimethylbenzo[d]thiazol-6-yl)amino)-7-methyl-9-(tetrahydro-2H-thiopyran-4-yl)-7,9 -dihydro-8H-purin-8-one ⁇ 2-((2,5-dimethylbenzo[d]thiazol-6-yl)amino)-7-methyl-9-(tetrahydro-2H-thiopyran-4-yl) Preparation of -7,9-dihydro-8H-purin-8-one ⁇
  • Example 73 7-methyl-2-((7-methylquinolin-6-yl)amino)-9-(tetrahydro-2H-thiopyran-4-yl)-7,9-dihydro-8H-purine -8-one ⁇ 7-methyl-2-((7-methylquinolin-6-yl)amino)-9-(tetrahydro-2H-thiopyran-4-yl)-7,9-dihydro-8H-purin-8- manufacture of one ⁇
  • Example 74 7-methyl-2-((6-methylbenzo[d][1,3]dioxol-5-yl)amino)-9-(2-oxaspiro[3.5]nonan-7-yl) -7,9-dihydro-8H-purin-8-one ⁇ 7-methyl-2-((6-methylbenzo[d][1,3]dioxol-5-yl)amino)-9-(2-oxaspiro [3.5] Preparation of nonan-7-yl)-7,9-dihydro-8H-purin-8-one ⁇
  • Example 75 2-((2,5-dimethylbenzo[d]thiazol-6-yl)amino)-7-methyl-9-(2-oxaspiro[3.5]nonan-7-yl)-7, 9-dihydro-8H-purin-8-one ⁇ 2-((2,5-dimethylbenzo[d]thiazol-6-yl)amino)-7-methyl-9-(2-oxaspiro[3.5]nonan-7 Preparation of -yl)-7,9-dihydro-8H-purin-8-one ⁇
  • Example 76 7-methyl-2-((6-methylbenzo[c][1,2,5]thiadiazol-5-yl)amino)-9-(2-oxaspiro[3.5]nonane-7 -yl)-7,9-dihydro-8H-purin-8-one ⁇ 7-methyl-2-((6-methylbenzo[c][1,2,5]thiadiazol-5-yl)amino)-9 Preparation of -(2-oxaspiro[3.5]nonan-7-yl)-7,9-dihydro-8H-purin-8-one ⁇
  • Example 77 2-((2,5-dimethylbenzo[d]thiazol-6-yl)amino)-7-methyl-9-(2-morpholinoethyl)-7,9-dihydro-8H -Purin-8-one ⁇ 2-((2,5-dimethylbenzo[d]thiazol-6-yl)amino)-7-methyl-9-(2-morpholinoethyl)-7,9-dihydro-8H-purin- Preparation of 8-one ⁇
  • Example 78 7-methyl-2-((6-methylbenzo[d][1,3]dioxol-5-yl)amino)-9-(2-morpholinoethyl)-7,9-di Hydro-8H-purin-8-one ⁇ 7-methyl-2-((6-methylbenzo[d][1,3]dioxol-5-yl)amino)-9-(2-morpholinoethyl)-7,9- Preparation of dihydro-8H-purin-8-one ⁇
  • Example 79 7-methyl-2-((6-methylbenzo[d][1,3]dioxol-5-yl)amino)-9-morpholino-7,9-dihydro-8H-purine -8-one ⁇ 7-methyl-2-((6-methylbenzo[d][1,3]dioxol-5-yl)amino)-9-morpholino-7,9-dihydro-8H-purin-8-one ⁇ manufacturing
  • Example 80 2-((2,5-dimethylbenzo[d]thiazol-6-yl)amino)-7-methyl-9-morpholino-7,9-dihydro-8H-purine-8- Preparation of one ⁇ 2-((2,5-dimethylbenzo[d]thiazol-6-yl)amino)-7-methyl-9-morpholino-7,9-dihydro-8H-purin-8-one ⁇
  • Example 81 7-methyl-2-((6-methylbenzo[c][1,2,5]thiadiazol-5-yl)amino)-9-(spiro[2.5]octan-6-yl) -7,9-dihydro-8H-purin-8-one ⁇ 7-methyl-2-((6-methylbenzo[c][1,2,5]thiadiazol-5-yl)amino)-9-(spiro Preparation of [2.5]octan-6-yl)-7,9-dihydro-8H-purin-8-one ⁇
  • Example 82 7-methyl-2-((6-methylbenzo[d][1,3]dioxol-5-yl)amino)-9-(spiro[2.5]octan-6-yl)-7, 9-dihydro-8H-purin-8-one ⁇ 7-methyl-2-((6-methylbenzo[d][1,3]dioxol-5-yl)amino)-9-(spiro[2.5]octan- Preparation of 6-yl)-7,9-dihydro-8H-purin-8-one ⁇
  • Example 83 2-((2,5-dimethylbenzo[d]thiazol-6-yl)amino)-7-methyl-9-((tetrahydro-2H-pyran-4-yl)methyl)-7 ,9-dihydro-8H-purin-8-one ⁇ 2-((2,5-dimethylbenzo[d]thiazol-6-yl)amino)-7-methyl-9-((tetrahydro-2H-pyran-4 Preparation of -yl)methyl)-7,9-dihydro-8H-purin-8-one ⁇
  • Example 84 7-methyl-2-((6-methylbenzo[d][1,3]dioxol-5-yl)amino)-9-((tetrahydro-2H-pyran-4-yl)methyl )-7,9-dihydro-8H-purin-8-one ⁇ 7-methyl-2-((6-methylbenzo[d][1,3]dioxol-5-yl)amino)-9-((tetrahydro Preparation of -2H-pyran-4-yl)methyl)-7,9-dihydro-8H-purin-8-one ⁇
  • Example 85 7-methyl-2-((6-methylbenzo[c][1,2,5]thiadiazol-5-yl)amino)-9-((tetrahydro-2H-pyran-4- yl)methyl)-7,9-dihydro-8H-purin-8-one ⁇ 7-methyl-2-((6-methylbenzo[c][1,2,5]thiadiazol-5-yl)amino)- Preparation of 9-((tetrahydro-2H-pyran-4-yl)methyl)-7,9-dihydro-8H-purin-8-one ⁇
  • Example 86 7-methyl-2-((7-methylquinolin-6-yl)amino)-9-((tetrahydro-2H-pyran-4-yl)methyl)-7,9-dihydro-8H -Purin-8-one ⁇ 7-methyl-2-((7-methylquinolin-6-yl)amino)-9-((tetrahydro-2H-pyran-4-yl)methyl)-7,9-dihydro-8H Preparation of -purin-8-one ⁇
  • Example 87 7-methyl-2-((7-methyl-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)amino)-9-((tetrahydro-2H- Pyran-4-yl)methyl)-7,9-dihydro-8H-purin-8-one ⁇ 7-methyl-2-((7-methyl-2,3-dihydrobenzo[b][1,4]dioxin) Preparation of -6-yl)amino)-9-((tetrahydro-2H-pyran-4-yl)methyl)-7,9-dihydro-8H-purin-8-one ⁇
  • Example 88 9-(2-methoxyethyl)-7-methyl-2-((6-methylbenzo[c][1,2,5]thiadiazol-5-yl)amino)-7,9 -dihydro-8H-purin-8-one ⁇ 9-(2-methoxyethyl)-7-methyl-2-((6-methylbenzo[c][1,2,5]thiadiazol-5-yl)amino)- Preparation of 7,9-dihydro-8H-purin-8-one ⁇
  • Example 89 7-methyl-2-((6-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)amino)-9-(tetrahydro-2H -pyran-4-yl)-7,9-dihydro-8H-purin-8-one ⁇ 7-methyl-2-((6-methyl-2-oxo-2,3-dihydro-1H-benzo[d Preparation of ]imidazol-5-yl)amino)-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purin-8-one ⁇
  • Example 90 6-methyl-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-8-(tetrahydro-2H- Pyran-4-yl)pyrido[2,3-d]pyrimidin-7(8H)-one ⁇ 6-methyl-2-((7-methyl-[1,2,4]triazolo[1,5- Preparation of a]pyridin-6-yl)amino)-8-(tetrahydro-2H-pyran-4-yl)pyrido[2,3-d]pyrimidin-7(8H)-one ⁇
  • Example 91 2-((2,5-dimethylbenzo[d]thiazol-6-yl)amino)-5-methyl-8-(tetrahydro-2H-pyran-4-yl)pyrido[2, 3-d]pyrimidin-7(8H)-one ⁇ 2-((2,5-dimethylbenzo[d]thiazol-6-yl)amino)-5-methyl-8-(tetrahydro-2H-pyran-4- Preparation of yl)pyrido[2,3-d]pyrimidin-7(8H)-one ⁇
  • Example 92 2-((2,6-dimethylbenzo[d]thiazol-5-yl)amino)-5-methyl-8-(tetrahydro-2H-pyran-4-yl)pyrido[2, 3-d]pyrimidin-7(8H)-one ⁇ 2-((2,6-dimethylbenzo[d]thiazol-5-yl)amino)-5-methyl-8-(tetrahydro-2H-pyran-4- Preparation of yl)pyrido[2,3-d]pyrimidin-7(8H)-one ⁇
  • Example 93 5-methyl-2-((6-methylbenzo[c][1,2,5]thiadiazol-5-yl)amino)-8-(tetrahydro-2H-pyran-4-yl )pyrido[2,3-d]pyrimidin-7(8H)-one ⁇ 5-methyl-2-((6-methylbenzo[c][1,2,5]thiadiazol-5-yl)amino)- Preparation of 8-(tetrahydro-2H-pyran-4-yl)pyrido[2,3-d]pyrimidin-7(8H)-one ⁇
  • Example 94 5-methyl-2-((6-methylbenzo[d][1,3]dioxol-5-yl)amino)-8-(tetrahydro-2H-pyran-4-yl)pyrido [2,3-d]pyrimidin-7(8H)-one ⁇ 5-methyl-2-((6-methylbenzo[d][1,3]dioxol-5-yl)amino)-8-(tetrahydro- Preparation of 2H-pyran-4-yl)pyrido[2,3-d]pyrimidin-7(8H)-one ⁇
  • Example 96 5-ethyl-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-8-(tetrahydro-2H- Pyran-4-yl)pyrido[2,3-d]pyrimidin-7(8H)-one ⁇ 5-ethyl-2-((7-methyl-[1,2,4]triazolo[1,5- Preparation of a]pyridin-6-yl)amino)-8-(tetrahydro-2H-pyran-4-yl)pyrido[2,3-d]pyrimidin-7(8H)-one ⁇
  • Example 97 2-((6-bromo-4-methylpyridin-3-yl)amino)-5-ethyl-8-(tetrahydro-2H-pyran-4-yl)pyrido[2,3- d]pyrimidin-7(8H)-one ⁇ 2-((6-bromo-4-methylpyridin-3-yl)amino)-5-ethyl-8-(tetrahydro-2H-pyran-4-yl)pyrido[ Preparation of 2,3-d]pyrimidin-7(8H)-one ⁇
  • Example 98 8-(4,4-difluorocyclohexyl)-5-methyl-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridine-6- yl)amino)pyrido[2,3-d]pyrimidin-7(8H)-one ⁇ 8-(4,4-difluorocyclohexyl)-5-methyl-2-((7-methyl-[1,2, Preparation of 4]triazolo[1,5-a]pyridin-6-yl)amino)pyrido[2,3-d]pyrimidin-7(8H)-one ⁇
  • Example 99 5-methyl-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-8-((tetrahydro-2H) -pyran-4-yl)methyl)pyrido[2,3-d]pyrimidin-7(8H)-one ⁇ 5-methyl-2-((7-methyl-[1,2,4]triazolo[1 Preparation of ,5-a]pyridin-6-yl)amino)-8-((tetrahydro-2H-pyran-4-yl)methyl)pyrido[2,3-d]pyrimidin-7(8H)-one ⁇
  • Example 100 8-cyclohexyl-5-methyl-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)pyrido[2, 3-d]pyrimidin-7(8H)-one ⁇ 8-cyclohexyl-5-methyl-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl Preparation of )amino)pyrido[2,3-d]pyrimidin-7(8H)-one ⁇
  • Example 101 (1R,4R)-4-(5-methyl-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)- 7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)cyclohexylacetate ⁇ (1R,4R)-4-(5-methyl-2-((7-methyl-[1, Preparation of 2,4]triazolo[1,5-a]pyridin-6-yl)amino)-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)cyclohexylacetate ⁇
  • Example 102 2-((2,5-dimethylbenzo[d]thiazol-6-yl)amino)-5-methyl-8-(tetrahydro-2H-pyran-4-yl)-5,8- Dihydropyrido[2,3-d]pyrimidin-7(6H)-one ⁇ 2-((2,5-dimethylbenzo[d]thiazol-6-yl)amino)-5-methyl-8-(tetrahydro Preparation of -2H-pyran-4-yl)-5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one ⁇
  • Example 103 5-methyl-2-((6-methylbenzo[c][1,2,5]thiadiazol-5-yl)amino)-8-(tetrahydro-2H-pyran-4-yl )-5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one ⁇ 5-methyl-2-((6-methylbenzo[c][1,2,5]thiadiazol- Preparation of 5-yl)amino)-8-(tetrahydro-2H-pyran-4-yl)-5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one ⁇
  • Example 93 5-methyl-2-((6-methylbenzo[c][1,2,5]thiadiazol-5-yl)amino)-8- prepared in Example 93 in substantially the same manner as in Example 102
  • the title compound was prepared using (tetrahydro-2H-pyran-4-yl)pyrido[2,3-d]pyrimidin-7(8H)-one (yield: 44%).
  • Example 104 2-((6-bromo-4-methylpyridin-3-yl)amino)-5-ethyl-8-(tetrahydro-2H-pyran-4-yl)-5,8-dihydro pyrido[2,3-d]pyrimidin-7(6H)-one ⁇ 2-((6-bromo-4-methylpyridin-3-yl)amino)-5-ethyl-8-(tetrahydro-2H-pyran Preparation of -4-yl)-5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one ⁇
  • Example 97 2-((6-bromo-4-methylpyridin-3-yl)amino)-5-ethyl-8-(tetrahydro-2H-pyran-) prepared in Example 97 in substantially the same manner as in Example 102
  • the title compound was prepared using 4-yl)pyrido[2,3-d]pyrimidin-7(8H)-one (yield: 45%).
  • Example 105 4-methyl-5-((5-methyl-7-oxo-8-(tetrahydro-2H-pyran-4-yl)-7,8-dihydropyrido[2,3-d] Pyrimidin-2-yl)amino)picolinamide ⁇ 4-methyl-5-((5-methyl-7-oxo-8-(tetrahydro-2H-pyran-4-yl)-7,8-dihydropyrido[2] Preparation of ,3-d]pyrimidin-2-yl)amino)picolinamide ⁇
  • Example 106 4-methyl-5-((6-methyl-7-oxo-8-(tetrahydro-2H-pyran-4-yl)-7,8-dihydropyrido[2,3-d] Pyrimidin-2-yl)amino)picolinamide ⁇ 4-methyl-5-((6-methyl-7-oxo-8-(tetrahydro-2H-pyran-4-yl)-7,8-dihydropyrido[2] Preparation of ,3-d]pyrimidin-2-yl)amino)picolinamide ⁇
  • Example 107 8-((1R,4R)-4-hydroxycyclohexyl)-5-methyl-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridine -6-yl)amino)pyrido[2,3-d]pyrimidin-7(8H)-one ⁇ 8-((1R,4R)-4-hydroxycyclohexyl)-5-methyl-2-((7- Preparation of methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)pyrido[2,3-d]pyrimidin-7(8H)-one ⁇
  • Example 108 2-((3,4-dimethoxyphenethyl)amino)-5-methyl-8-(tetrahydro-2H-pyran-4-yl)pyrido[2,3-d]pyrimidine- 7(8H)-one ⁇ 2-((3,4-dimethoxyphenethyl)amino)-5-methyl-8-(tetrahydro-2H-pyran-4-yl)pyrido[2,3-d]pyrimidin-7(8H )-one ⁇ preparation
  • Examples 109 and 110 were prepared in substantially the same manner as in Example 108, using the appropriate compounds and appropriate amine derivatives.
  • Example 109 2-((2-(6-methoxypyridin-3-yl)ethyl)amino)-7-methyl-9-(tetrahydro-2H-pyran-4-yl)-7,9-di hydro-8H-purin-8-one ⁇ 2-((2-(6-methoxypyridin-3-yl)ethyl)amino)-7-methyl-9-(tetrahydro-2H-pyran-4-yl)-7, Preparation of 9-dihydro-8H-purin-8-one ⁇
  • Example 110 2-((2-(3,4-dimethoxyphenyl)propyl)amino)-5-methyl-8-(tetrahydro-2H-pyran-4-yl)pyrido[2,3-d ]pyrimidin-7(8H)-one ⁇ 2-((2-(3,4-dimethoxyphenyl)propyl)amino)-5-methyl-8-(tetrahydro-2H-pyran-4-yl)pyrido[2, Preparation of 3-d]pyrimidin-7(8H)-one ⁇
  • Example 111 2-((3,4-dimethoxyphenethyl)amino)-5-methyl-8-(tetrahydro-2H-pyran-4-yl)-5,8-dihydropyrido[2, 3-d]pyrimidin-7(6H)-one ⁇ 2-((3,4-dimethoxyphenethyl)amino)-5-methyl-8-(tetrahydro-2H-pyran-4-yl)-5,8-dihydropyrido Preparation of [2,3-d]pyrimidin-7(6H)-one ⁇
  • Example 108 2-((3,4-dimethoxyphenethyl)amino)-5-methyl-8-(tetrahydro-2H-pyran-4-yl)pyrido[2,3-d]pyrimidine obtained in Example 108
  • the title compound was prepared in substantially the same manner as in Example 102 using -7(8H)-one (yield: 42%).
  • Example 112 2-((2-(3,4-dimethoxyphenyl)propyl)amino)-5-methyl-8-(tetrahydro-2H-pyran-4-yl)-5,8-dihydropyri Do[2,3-d]pyrimidin-7(6H)-one ⁇ 2-((2-(3,4-dimethoxyphenyl)propyl)amino)-5-methyl-8-(tetrahydro-2H-pyran-4 Preparation of -yl)-5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one ⁇
  • the title compound was prepared in substantially the same manner as in Example 102 using pyrimidin-7(8H)-one (yield: 36%).
  • Example 113 5-methyl-2-((4-methyl-6-(3-methylisothiazol-5-yl)pyridin-3-yl)amino)-8-(tetrahydro-2H-pyran-4 -yl)pyrido[2,3-d]pyrimidin-7(8H)-one ⁇ 5-methyl-2-((4-methyl-6-(3-methylisothiazol-5-yl)pyridin-3-yl Preparation of )amino)-8-(tetrahydro-2H-pyran-4-yl)pyrido[2,3-d]pyrimidin-7(8H)-one ⁇
  • Step 1 Preparation of 4-methyl-6-(3-methylisothiazol-5-yl)pyridin-3-amine ⁇ 4-methyl-6-(3-methylisothiazol-5-yl)pyridin-3-amine ⁇
  • Example 34 and substantially same in a way The title compound was prepared.
  • Step 2 5-methyl-2-((4-methyl-6-(3-methylisothiazol-5-yl)pyridin-3-yl)amino)-8-(tetrahydro-2H-pyran-4- yl)pyrido[2,3-d]pyrimidin-7(8H)-one ⁇ 5-methyl-2-((4-methyl-6-(3-methylisothiazol-5-yl)pyridin-3-yl) Preparation of amino)-8-(tetrahydro-2H-pyran-4-yl)pyrido[2,3-d]pyrimidin-7(8H)-one ⁇
  • 4-methyl-6-(3-methylisothiazol-5-yl)pyridin-3-amine 40 prepared in step 1 mg and 2M isopropyl magnesium chloride (in THF) 0.1 mL tetrahydrofuran 2 into mL, at room temperature for 40 minutes agitation after 2-Chloro-5-methyl-8-(tetrahydro-2H-pyran-4-yl)pyrido[2,3-d]pyrimidin-7(8H)-one 50 mg and 2M Isopropyl Magnesium Chloride (in THF) 0.1 mL add more, at 60 °C for 16 hours stirred.
  • Example 114 5-methyl-2-((2-methyl-4-(1-methyl-1H-pyrazol-4-yl)phenyl)amino)-8-(tetrahydro-2H-pyran-4-yl ) pyrido [2,3-d] pyrimidin-7 (8H) -one ⁇ 5-methyl-2-((2-methyl-4- (1-methyl-1H-pyrazol-4-yl) phenyl) amino Preparation of )-8-(tetrahydro-2H-pyran-4-yl)pyrido[2,3-d]pyrimidin-7(8H)-one ⁇
  • Example 113 and practically The title compound was prepared in the same manner using appropriate aniline derivatives and boronic acid derivatives (yield: 22%).
  • 1 H-NMR 400 MHz, CDCl 3 ) ⁇ 1.51 (2H, d), 2.37 (6H, s), 3.07 (2H, qd), 3.49 (2H, t), 3.95 (3H, s), 4.07 (2H, dd), 5.58 (1H, tt), 6.26 (1H, s), 7.04 (1H, s), 7.37 (1H, s), 7.61 (1H, s), 7.75 (1H, s), 7.92 (1H, d), 8.61 (1H, s)
  • Example 115 2-((6-(furan-3-yl)-4-methylpyridin-3-yl)amino)-5-methyl-8-(tetrahydro-2H-pyran-4-yl)-5 ,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one ⁇ 2-((6-(furan-3-yl)-4-methylpyridin-3-yl)amino)-5 Preparation of -methyl-8-(tetrahydro-2H-pyran-4-yl)-5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one ⁇
  • Step 1 Preparation of 6-(furan-3-yl)-4-methylpyridin-3-amine ⁇ 6-(furan-3-yl)-4-methylpyridin-3-amine ⁇
  • Step 2 2-((6-(furan-3-yl)-4-methylpyridin-3-yl)amino)-5-methyl-8-(tetrahydro-2H-pyran-4-yl)pyrido[ 2,3-d]pyrimidin-7(8H)-one ⁇ 2-((6-(furan-3-yl)-4-methylpyridin-3-yl)amino)-5-methyl-8-(tetrahydro- Preparation of 2H-pyran-4-yl)pyrido[2,3-d]pyrimidin-7(8H)-one ⁇
  • Example Step 2 of 113 and substantially The title compound was prepared in the same manner.
  • Step 3 2-((6-(furan-3-yl)-4-methylpyridin-3-yl)amino)-5-methyl-8-(tetrahydro-2H-pyran-4-yl)-5, 8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one ⁇ 2-((6-(furan-3-yl)-4-methylpyridin-3-yl)amino)-5- Preparation of methyl-8-(tetrahydro-2H-pyran-4-yl)-5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one ⁇
  • Example Step 2 of 102 and substantially The title compound was prepared in the same manner (yield: 11%).
  • 1 H-NMR 400 MHz, CDCl 3 ) ⁇ 1.93 (3H, s), 2.38 (3H, s), 3.10 (2H, m), 3.48 (2H, m), 4.02 (2H, dd), 4.35 (2H, s), 5.57 (1H, m), 5.93 (1H, s), 6.34 (1H, s), 6.87 (1H, s), 7.40 (1H, s), 7.51 (1H, s), 8.02 (1H, s), 8.46 (1H, s)
  • Examples 116 and 117 were prepared in substantially the same manner as in Example 115 using appropriate intermediates, amine derivatives and boronic acid derivatives.
  • Example 116 2-((6-(furan-2-yl)-4-methylpyridin-3-yl)amino)-5-methyl-8-(tetrahydro-2H-pyran-4-yl)-5 ,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one ⁇ 2-((6-(furan-2-yl)-4-methylpyridin-3-yl)amino)-5 Preparation of -methyl-8-(tetrahydro-2H-pyran-4-yl)-5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one ⁇
  • Example 117 5-ethyl-2-((4-methyl-6-(thiophen-3-yl)pyridin-3-yl)amino)-8-(tetrahydro-2H-pyran-4-yl)- 5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one ⁇ 5-ethyl-2-((4-methyl-6-(thiophen-3-yl)pyridin-3- Preparation of yl)amino)-8-(tetrahydro-2H-pyran-4-yl)-5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one ⁇
  • Example 118 2-((2,5-dimethylbenzo[d]thiazol-6-yl)amino)-5-methyl-8-(tetrahydro-2H-pyran-4-yl)-5,8- Dihydropteridine-6,7-dione ⁇ 2-((2,5-dimethylbenzo[d]thiazol-6-yl)amino)-5-methyl-8-(tetrahydro-2H-pyran-4-yl) Preparation of -5,8-dihydropteridine-6,7-dione ⁇
  • Examples 119 to 148 were prepared in substantially the same manner as in Example 118, using appropriate intermediates and amine derivatives.
  • Example 119 5-methyl-2-((6-methylbenzo[c][1,2,5]thiadiazol-5-yl)amino)-8-(tetrahydro-2H-pyran-4-yl )-5,8-dihydropteridine-6,7-dione ⁇ 5-methyl-2-((6-methylbenzo[c][1,2,5]thiadiazol-5-yl)amino)-8- Preparation of (tetrahydro-2H-pyran-4-yl)-5,8-dihydropteridine-6,7-dione ⁇
  • Example 120 5-methyl-2-((6-methylbenzo[d][1,3]dioxol-5-yl)amino)-8-(tetrahydro-2H-pyran-4-yl)-5 ,8-dihydropteridine-6,7-dione ⁇ 5-methyl-2-((6-methylbenzo[d][1,3]dioxol-5-yl)amino)-8-(tetrahydro-2H- Preparation of pyran-4-yl)-5,8-dihydropteridine-6,7-dione ⁇
  • Example 121 5-methyl-2-((7-methyl-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)amino)-8-(tetrahydro-2H-pyran -4-yl)-5,8-dihydropteridine-6,7-dione ⁇ 5-methyl-2-((7-methyl-2,3-dihydrobenzo[b][1,4]dioxin-6) Preparation of -yl)amino)-8-(tetrahydro-2H-pyran-4-yl)-5,8-dihydropteridine-6,7-dione ⁇
  • Example 122 5-methyl-2-((2-methyl-4-(1-methyl-1H-imidazol-4-yl)phenyl)amino)-8-(tetrahydro-2H-pyran-4-yl )-5,8-dihydropteridine-6,7-dione ⁇ 5-methyl-2-((2-methyl-4-(1-methyl-1H-imidazol-4-yl)phenyl)amino)- Preparation of 8-(tetrahydro-2H-pyran-4-yl)-5,8-dihydropteridine-6,7-dione ⁇
  • Example 123 5-methyl-2-((2-methyl-4-(1-methyl-1H-pyrazol-4-yl)phenyl)amino)-8-(tetrahydro-2H-pyran-4-yl )-5,8-dihydropteridine-6,7-dione ⁇ 5-methyl-2-((2-methyl-4-(1-methyl-1H-pyrazol-4-yl)phenyl)amino)- Preparation of 8-(tetrahydro-2H-pyran-4-yl)-5,8-dihydropteridine-6,7-dione ⁇
  • Example 124 5-methyl-2-((7-methylquinolin-6-yl)amino)-8-(tetrahydro-2H-pyran-4-yl)-5,8-dihydropteridine-6 ,7-dione ⁇ 5-methyl-2-((7-methylquinolin-6-yl)amino)-8-(tetrahydro-2H-pyran-4-yl)-5,8-dihydropteridine-6,7-dione ⁇ manufacture of
  • Example 125 5-methyl-2-((7-methyl-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)amino)-8-((tetrahydro-2H- Pyran-4-yl)methyl)-5,8-dihydropteridin-6,7-dione ⁇ 5-methyl-2-((7-methyl-2,3-dihydrobenzo[b][1,4] Preparation of dioxin-6-yl)amino)-8-((tetrahydro-2H-pyran-4-yl)methyl)-5,8-dihydropteridine-6,7-dione ⁇
  • Example 126 5-methyl-2-((6-methylbenzo[d][1,3]dioxol-5-yl)amino)-8-((tetrahydro-2H-pyran-4-yl)methyl )-5,8-dihydropteridine-6,7-dione ⁇ 5-methyl-2-((6-methylbenzo[d][1,3]dioxol-5-yl)amino)-8-(( Preparation of tetrahydro-2H-pyran-4-yl)methyl)-5,8-dihydropteridine-6,7-dione ⁇
  • Example 127 5-methyl-2-((6-methylbenzo[c][1,2,5]thiadiazol-5-yl)amino)-8-((tetrahydro-2H-pyran-4- yl)methyl)-5,8-dihydropteridine-6,7-dione ⁇ 5-methyl-2-((6-methylbenzo[c][1,2,5]thiadiazol-5-yl)amino) Preparation of -8-((tetrahydro-2H-pyran-4-yl)methyl)-5,8-dihydropteridine-6,7-dione ⁇
  • Example 128 2-((2,5-dimethylbenzo[d]thiazol-6-yl)amino)-5-methyl-8-((tetrahydro-2H-pyran-4-yl)methyl)-5 ,8-dihydropteridine-6,7-dione ⁇ 2-((2,5-dimethylbenzo[d]thiazol-6-yl)amino)-5-methyl-8-((tetrahydro-2H-pyran- Preparation of 4-yl)methyl)-5,8-dihydropteridine-6,7-dione ⁇
  • Example 129 5-methyl-2-((7-methylquinolin-6-yl)amino)-8-((tetrahydro-2H-pyran-4-yl)methyl)-5,8-dihydropteri Din-6,7-dione ⁇ 5-methyl-2-((7-methylquinolin-6-yl)amino)-8-((tetrahydro-2H-pyran-4-yl)methyl)-5,8-dihydropteridine- Preparation of 6,7-dione ⁇
  • Example 130 8-(4,4-difluorocyclohexyl)-5-methyl-2-((6-methylbenzo[d][1,3]dioxol-5-yl)amino)-5, 8-dihydropteridine-6,7-dione ⁇ 8-(4,4-difluorocyclohexyl)-5-methyl-2-((6-methylbenzo[d][1,3]dioxol-5-yl)amino Preparation of )-5,8-dihydropteridine-6,7-dione ⁇
  • Example 131 8-(4,4-difluorocyclohexyl)-5-methyl-2-((7-methyl-2,3-dihydrobenzo[b][1,4]dioxine-6- yl)amino)-5,8-dihydropteridine-6,7-dione ⁇ 8-(4,4-difluorocyclohexyl)-5-methyl-2-((7-methyl-2,3-dihydrobenzo[b Preparation of ][1,4]dioxin-6-yl)amino)-5,8-dihydropteridine-6,7-dione ⁇
  • Example 132 2-((2,5-dimethylbenzo[d]thiazol-6-yl)amino)-5-methyl-8-(tetrahydro-2H-pyran-4-yl)-7,8- Dihydropteridin-6(5H)-one ⁇ 2-((2,5-dimethylbenzo[d]thiazol-6-yl)amino)-5-methyl-8-(tetrahydro-2H-pyran-4-yl Preparation of )-7,8-dihydropteridin-6(5H)-one ⁇
  • Example 133 5-methyl-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-8-(tetrahydro-2H- Pyran-4-yl)-7,8-dihydropteridin-6(5H)-one ⁇ 5-methyl-2-((7-methyl-[1,2,4]triazolo[1,5-a Preparation of ]pyridin-6-yl)amino)-8-(tetrahydro-2H-pyran-4-yl)-7,8-dihydropteridin-6(5H)-one ⁇
  • Example 134 2-((2,6-dimethylbenzo[d]thiazol-5-yl)amino)-5-methyl-8-(tetrahydro-2H-pyran-4-yl)-7,8- Dihydropteridin-6(5H)-one ⁇ 2-((2,6-dimethylbenzo[d]thiazol-5-yl)amino)-5-methyl-8-(tetrahydro-2H-pyran-4-yl Preparation of )-7,8-dihydropteridin-6(5H)-one ⁇
  • Example 135 5-methyl-2-((6-methylbenzo[c][1,2,5]thiadiazol-5-yl)amino)-8-(tetrahydro-2H-pyran-4-yl )-7,8-dihydropteridin-6(5H)-one ⁇ 5-methyl-2-((6-methylbenzo[c][1,2,5]thiadiazol-5-yl)amino)-8 Preparation of -(tetrahydro-2H-pyran-4-yl)-7,8-dihydropteridin-6(5H)-one ⁇
  • Example 136 2-((5-hydroxynaphthalen-2-yl)amino)-5-methyl-8-(tetrahydro-2H-pyran-4-yl)-7,8-dihydropteridine- 6(5H)-one ⁇ 2-((5-hydroxynaphthalen-2-yl)amino)-5-methyl-8-(tetrahydro-2H-pyran-4-yl)-7,8-dihydropteridin-6(5H) manufacture of -one ⁇
  • Example 137 5-methyl-2-((6-methylbenzo[d][1,3]dioxol-5-yl)amino)-8-(tetrahydro-2H-pyran-4-yl)-7 ,8-dihydropteridin-6(5H)-one ⁇ 5-methyl-2-((6-methylbenzo[d][1,3]dioxol-5-yl)amino)-8-(tetrahydro-2H Preparation of -pyran-4-yl)-7,8-dihydropteridin-6(5H)-one ⁇
  • Example 138 5-methyl-2-((4-methyl-6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)amino)-8-(tetrahydro-2H-pyran -4-yl)-7,8-dihydropteridin-6(5H)-one ⁇ 5-methyl-2-((4-methyl-6-(1-methyl-1H-pyrazol-4-yl) Preparation of pyridin-3-yl)amino)-8-(tetrahydro-2H-pyran-4-yl)-7,8-dihydropteridin-6(5H)-one ⁇
  • Example 139 5-methyl-2-((7-methyl-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)amino)-8-(tetrahydro-2H-pyran -4-yl)-7,8-dihydropteridin-6(5H)-one ⁇ 5-methyl-2-((7-methyl-2,3-dihydrobenzo[b][1,4]dioxin- Preparation of 6-yl)amino)-8-(tetrahydro-2H-pyran-4-yl)-7,8-dihydropteridin-6(5H)-one ⁇
  • Example 140 5-methyl-2-((7-methylquinolin-6-yl)amino)-8-(tetrahydro-2H-pyran-4-yl)-7,8-dihydropteridine-6 (5H)-one ⁇ 5-methyl-2-((7-methylquinolin-6-yl)amino)-8-(tetrahydro-2H-pyran-4-yl)-7,8-dihydropteridin-6(5H)- manufacture of one ⁇
  • Example 141 2-((2,5-dimethylbenzo[d]thiazol-6-yl)amino)-5-methyl-8-((tetrahydro-2H-pyran-4-yl)methyl)-7 ,8-dihydropteridin-6(5H)-one ⁇ 2-((2,5-dimethylbenzo[d]thiazol-6-yl)amino)-5-methyl-8-((tetrahydro-2H-pyran) Preparation of -4-yl)methyl)-7,8-dihydropteridin-6(5H)-one ⁇
  • Example 142 5-methyl-2-((7-methylquinolin-6-yl)amino)-8-((tetrahydro-2H-pyran-4-yl)methyl)-7,8-dihydropteri Din-6(5H)-one ⁇ 5-methyl-2-((7-methylquinolin-6-yl)amino)-8-((tetrahydro-2H-pyran-4-yl)methyl)-7,8-dihydropteridin Preparation of -6(5H)-one ⁇
  • Example 143 2-((2,5-dimethylbenzo[d]thiazol-6-yl)amino)-5,7-dimethyl-8-(tetrahydro-2H-pyran-4-yl)-7, 8-dihydropteridin-6(5H)-one ⁇ 2-((2,5-dimethylbenzo[d]thiazol-6-yl)amino)-5,7-dimethyl-8-(tetrahydro-2H-pyran Preparation of -4-yl)-7,8-dihydropteridin-6(5H)-one ⁇
  • Example 144 8-cyclohexyl-5-methyl-2-((6-methylbenzo[d][1,3]dioxol-5-yl)amino)-5,8-dihydropteridin-6 ,7-dione ⁇ 8-cyclohexyl-5-methyl-2-((6-methylbenzo[d][1,3]dioxol-5-yl)amino)-5,8-dihydropteridine-6,7-dione ⁇ Produce
  • Examples 145 to 154 were prepared in substantially the same manner as in Example 144, using the appropriate compounds and appropriate amine derivatives.
  • Example 145 8-cyclohexyl-5-methyl-2-((6-methylbenzo[c][1,2,5]thiadiazol-5-yl)amino)-5,8-dihydropteri din-6,7-dione ⁇ 8-cyclohexyl-5-methyl-2-((6-methylbenzo[c][1,2,5]thiadiazol-5-yl)amino)-5,8-dihydropteridine-6, Preparation of 7-dione ⁇
  • Example 146 8-cyclohexyl-2-((2,5-dimethylbenzo[d]thiazol-6-yl)amino)-5-methyl-5,8-dihydropteridin-6,7- Preparation of dione ⁇ 8-cyclohexyl-2-((2,5-dimethylbenzo[d]thiazol-6-yl)amino)-5-methyl-5,8-dihydropteridine-6,7-dione ⁇
  • Example 147 8-cyclohexyl-5-methyl-2-((7-methyl-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)amino)-5,8- Dihydropteridine-6,7-dione ⁇ 8-cyclohexyl-5-methyl-2-((7-methyl-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)amino)- Preparation of 5,8-dihydropteridine-6,7-dione ⁇
  • Example 148 8-cyclohexyl-5-methyl-2-((7-methylquinolin-6-yl)amino)-5,8-dihydropteridine-6,7-dione ⁇ 8-cyclohexyl-5 Preparation of -methyl-2-((7-methylquinolin-6-yl)amino)-5,8-dihydropteridine-6,7-dione ⁇
  • Example 149 8-cyclopentyl-5-methyl-2-((6-methylbenzo[d][1,3]dioxol-5-yl)amino)-5,8-dihydropteridine-6 ,7-dione ⁇ 8-cyclopentyl-5-methyl-2-((6-methylbenzo[d][1,3]dioxol-5-yl)amino)-5,8-dihydropteridine-6,7-dione ⁇ Produce
  • Example 150 8-cyclopentyl-5-methyl-2-((6-methylbenzo[c][1,2,5]thiadiazol-5-yl)amino)-5,8-dihydropteri din-6,7-dione ⁇ 8-cyclopentyl-5-methyl-2-((6-methylbenzo[c][1,2,5]thiadiazol-5-yl)amino)-5,8-dihydropteridine-6, Preparation of 7-dione ⁇
  • Example 151 8-cyclopentyl-2-((2,5-dimethylbenzo[d]thiazol-6-yl)amino)-5-methyl-5,8-dihydropteridin-6,7- Preparation of dione ⁇ 8-cyclopentyl-2-((2,5-dimethylbenzo[d]thiazol-6-yl)amino)-5-methyl-5,8-dihydropteridine-6,7-dione ⁇

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Abstract

La présente invention concerne un composé cyclique fusionné à la pyrimidine et son utilisation. Le composé cyclique fusionné à la pyrimidine de la présente invention présente une excellente activité inhibitrice vis-à-vis de l'ADN-PK et peut donc être avantageusement utilisé en tant qu'agent thérapeutique contre des maladies associées à l'ADN-PK.
PCT/KR2022/002310 2021-02-17 2022-02-16 Composé cyclique fusionné à la pyrimidine avec une activité d'inhibition de l'adn-pk et son utilisation WO2022177302A1 (fr)

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WO2023036156A1 (fr) * 2021-09-07 2023-03-16 首药控股(北京)股份有限公司 Inhibiteur sélectif de l'adn-pk, son procédé de préparation et son utilisation

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FOK JACQUELINE H. L., RAMOS-MONTOYA ANTONIO, VAZQUEZ-CHANTADA MERCEDES, WIJNHOVEN PAUL W. G., FOLLIA VALERIA, JAMES NEIL, FARRINGT: "AZD7648 is a potent and selective DNA-PK inhibitor that enhances radiation, chemotherapy and olaparib activity", NATURE COMMUNICATIONS, vol. 10, no. 1, 1 December 2019 (2019-12-01), XP055826432, DOI: 10.1038/s41467-019-12836-9 *
GOLDBERG FREDERICK W., FINLAY M. RAYMOND V., TING ATTILLA K. T., BEATTIE DAVID, LAMONT GILLIAN M., FALLAN CHARLENE, WRIGLEY GAIL L: "The Discovery of 7-Methyl-2-[(7-methyl[1,2,4]triazolo[1,5- a ]pyridin-6-yl)amino]-9-(tetrahydro-2 H -pyran-4-yl)-7,9-dihydro-8 H -purin-8-one (AZD7648), a Potent and Selective DNA-Dependent Protein Kinase (DNA-PK) Inhibitor", JOURNAL OF MEDICINAL CHEMISTRY, AMERICAN CHEMICAL SOCIETY, US, vol. 63, no. 7, 9 April 2020 (2020-04-09), US , pages 3461 - 3471, XP055826430, ISSN: 0022-2623, DOI: 10.1021/acs.jmedchem.9b01684 *

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WO2023036156A1 (fr) * 2021-09-07 2023-03-16 首药控股(北京)股份有限公司 Inhibiteur sélectif de l'adn-pk, son procédé de préparation et son utilisation

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