WO2021136461A1 - Purine derivative and medical use thereof - Google Patents

Purine derivative and medical use thereof Download PDF

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Publication number
WO2021136461A1
WO2021136461A1 PCT/CN2020/141859 CN2020141859W WO2021136461A1 WO 2021136461 A1 WO2021136461 A1 WO 2021136461A1 CN 2020141859 W CN2020141859 W CN 2020141859W WO 2021136461 A1 WO2021136461 A1 WO 2021136461A1
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Prior art keywords
methyl
chloro
amino
dihydro
alkyl
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PCT/CN2020/141859
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French (fr)
Chinese (zh)
Inventor
魏用刚
许学珍
楚洪柱
何吕学
雷飞全
何阳
苏桂转
王美微
刘兵
孙毅
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成都百裕制药股份有限公司
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Publication of WO2021136461A1 publication Critical patent/WO2021136461A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
    • 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
    • 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
    • C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
    • C07D473/18—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 one oxygen and one nitrogen atom, e.g. guanine
    • 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

  • This application relates to purine derivatives represented by general formula (I), or their stereoisomers, solvates, prodrugs, deuterated products, metabolites, pharmaceutically acceptable salts or co-crystals, their pharmaceutical compositions and Preparation of DNA-PK inhibitors.
  • DNA-dependent protein kinase is a DNA-PK enzyme complex composed of Ku70/Ku80 heterodimer and DNA-dependent protein kinase catalytic subunit (DNA-PKcs). The enzyme complex needs to be activated with the participation of DNA to perform its corresponding functions (George et al., 2019). As a serine/threonine protein kinase, DNA-PK belongs to the PIKK (phosphatidylinositol 3-kinase-related kinase) family.
  • PIKK phosphatidylinositol 3-kinase-related kinase
  • DSBs In the normal physiological process, a variety of factors may lead to the occurrence of DSBs in DNA: For example, DSBs often appear as intermediate products in the process of somatic DNA recombination. This physiological process is very important for the formation of the functional immune system of all vertebrates; DNA replication is in progress. When the replication fork encounters damaged bases, it may also cause single-strand or double-strand breaks; DNA may also generate DSBs due to the attack of reactive oxygen species (ROS) during normal metabolism (Cannan & Pederson, 2016).
  • ROS reactive oxygen species
  • DSBs ionizing radiation (IR) and chemotherapeutic agents (such as topoisomerase II inhibitors)
  • IR ionizing radiation
  • chemotherapeutic agents such as topoisomerase II inhibitors
  • NHEJ non-homologous end-joining
  • NHEJ is a dynamic process mediated by DNA-PK that requires the participation of multiple proteins and signaling pathways.
  • the basic process is as follows: (1) Ku70/Ku80 heterodimer recognizes and binds to the ends of double-stranded DNA breaks; (2) Recruitment DNA-PKcs, XRCC4-DNA ligase IV complex and other proteins to both sides of the DNA break double-strand; (3) DNA-PKcs autophosphorylate and activate its own kinase activity; (4) DNA-PKcs as an adhesive to connect Break both ends of the DNA to prevent exonuclease from degrading the DNA; (5) Process the DNA to remove unlinkable ends or other forms of damage at the break; (6) XRCC4-DNA ligase IV complex repair DNA ends (in some cases, DNA polymerase may be required to synthesize new ends before ligation).
  • DNA-PKcs When DNA-PKcs is phosphorylated, it can induce protein conformation to change and regulate the activity of various proteins in the NHEJ process (such as Artemis, Ku70, Ku80, DNA ligase), which is essential for the DNA repair process. Therefore, phosphorylated DNA-PKcs (pDNA-PKcs) is often used as a marker of cellular DSBs.
  • DNA-PK activity is related to the occurrence and development of a variety of tumors: for example, DNA-PKcs in melanoma can promote angiogenesis and tumor metastasis; DNA-PKcs expression in multiple myeloma is significantly up-regulated; radiotherapy The content of Ku protein in tolerant thyroid tumors is significantly increased (Ihara, Ashizawa, Shichijo, & Kudo, 2019). Therefore, it can be considered to combine DNA-PK inhibitors with anti-tumor therapies that cause DNA damage (such as IR, chemotherapeutic agents, etc.) to improve the effect.
  • the use of DNA-PK inhibitors can interfere with the DNA repair function of normal cells to a certain extent. However, there are many DNA repair pathways in normal cells as a supplement, and tumor cells face strong DNA replication pressure and lack effective DNA repair methods. . By inhibiting the activity of tumor cell DNA-PK, the killing effect of other anti-tumor drugs on tumor cells can be improved.
  • DNA-PK inhibitors After years of research, several DNA-PK inhibitors have been discovered.
  • the first compound found to have DNA-PK kinase inhibitory activity is a fungal metabolite—Wortmannin, with an IC 50 (DNA-PK) of about 15 nM.
  • DNA-PK fungal metabolite
  • This compound also plays an important role in the acetylation and phosphorylation of p53 protein.
  • the quercetin derivative LY294002 later reported that the quercetin derivative LY294002 also has DNA-PK inhibitory activity (Maira, Stauffer, Schnell, & Garcia-Echeverria, 2009); later based on the structure of LY294002 and developed NU7026, NU7441, etc.
  • a new generation of DNA-PK inhibitors A new generation of DNA-PK inhibitors.
  • DNA-PK inhibitors have also been reported, such as OK1035, SU11752, PP121, KU-0060648 and other small molecule compounds, but these compounds also have defects such as low specificity for DNA-PK (George et al., 2019). Therefore, there is still a need to develop DNA-PK inhibitors with high activity, high specificity, and low toxicity to better meet clinical needs.
  • One or more embodiments of the present application provide purine derivatives, or their stereoisomers, solvates, prodrugs, deuterated products, metabolites, pharmaceutically acceptable salts or co-crystals, their pharmaceutical compositions and their Use in the preparation of DNA-PK inhibitors.
  • the compound has high inhibitory activity and/or high selectivity for DNA-PK, and can be used as a chemotherapy and radiotherapy sensitizer to effectively treat cancer, improve the curative effect of the prior art, and reduce toxic side effect.
  • One or more embodiments of the present invention provide a compound represented by general formula (I), or its stereoisomers, solvates, prodrugs, deuterated products, metabolites, pharmaceutically acceptable salts or co-crystals :
  • R 1 is selected from H, -OH, cyano, halogen, -NH 2 , C 1-6 alkyl or C 1-6 alkoxy, and the C 1-6 alkyl is optionally further grouped by 1-3 Substituted by a substituent selected from D or halogen;
  • R 2 is selected from H or C 1-6 alkyl
  • R 3 is selected from C 1-6 alkyl, C 3-12 carbocyclic group, C 3 heterocyclic group, C 4-12 heterocyclic group, -C 1-6 alkylene-C 3-12 carbocyclic group, -C 1-6 alkylene-C 3 heterocyclic group or -C 1-6 alkylene-C 4-12 heterocyclic group, said C 3 heterocyclic group and C 4-12 heterocyclic group include 1 Up to 3 heteroatoms selected from N, O or S, the C 1-6 alkyl group, C 3-12 carbocyclic group, C 3 heterocyclic group and C 4-12 heterocyclic group, C 1-6
  • the condition is: when R 3 is cyclohexyl, the cyclohexyl group is substituted by at least one cyano group; and R 3 is not tetrahydrofuranyl or oxanyl; or, the condition is: R 3 is not cyclohexyl or tetrahydrofuranyl Or oxacyclohexyl;
  • R a3 is selected from C 1-6 alkyl, C 1-6 alkoxy or C 6-12 aryl;
  • R a4 and R a5 are each independently selected from H or C 1-6 alkyl; or R a4 and R a5 and N atoms form a 3- to 8-membered heterocyclic ring, and the 3- to 8-membered heterocyclic ring includes 1 to 4 One heteroatom selected from N, O or S;
  • p is selected from 0, 1, 2 or 3;
  • the general formula (I) may be optionally substituted with one or more D atoms.
  • One or more embodiments of the present application provide a compound, or its stereoisomer, solvate, prodrug, deuterated product, metabolite, pharmaceutically acceptable salt or co-crystal, wherein the compound is selected from the general formula ( II) The compound shown:
  • R 1 is selected from halogen or C 1-6 alkyl, and said C 1-6 alkyl is optionally further substituted with 1-3 substituents selected from D or halogen;
  • R 3 is selected from C 1-6 alkyl, C 3-12 carbocyclic group, C 3 heterocyclic group, C 4-12 heterocyclic group, -C 1-6 alkylene-C 3-12 carbocyclic group, -C 1-6 alkylene-C 3 heterocyclic group or -C 1-6 alkylene-C 4-12 heterocyclic group, said C 3 heterocyclic group and C 4-12 heterocyclic group include 1 Up to 3 heteroatoms selected from N, O or S, the C 1-6 alkyl group, C 3-12 carbocyclic group, C 3 heterocyclic group and C 4-12 heterocyclic group, C 1-6
  • the condition is: when R 3 is cyclohexyl, the cyclohexyl group is substituted by at least one cyano group; and R 3 is not tetrahydrofuranyl or oxanyl; or, the condition is: R 3 is not cyclohexyl or tetrahydrofuranyl Or oxacyclohexyl;
  • R a3 is selected from C 1-6 alkyl, C 1-6 alkoxy or C 6-12 aryl;
  • R a4 and R a5 are each independently selected from H or C 1-6 alkyl; or R a4 and R a5 and N atoms form a 3- to 8-membered heterocyclic ring, and the 3- to 8-membered heterocyclic ring includes 1 to 4 One heteroatom selected from N, O or S;
  • p is selected from 0, 1, 2 or 3.
  • One or more embodiments of the application provide (I) or (II) compounds, or stereoisomers, solvates, prodrugs, deuterated products, metabolites, pharmaceutically acceptable salts or co-crystals thereof, wherein :
  • R 1 is selected from halogen or C 1-4 alkyl, and said C 1-6 alkyl is optionally further substituted with 1-3 substituents selected from D or halogen;
  • R 3 is selected from C 1-4 alkyl, C 3-8 carbocyclic group, C 4-8 heterocyclic group, -C 1-2 alkylene-C 3-8 carbocyclic group or -C 1-2 alkylene Alkyl-C 4-8 heterocyclic group, said C 4-8 heterocyclic group contains 1 to 3 heteroatoms selected from N or O, said C 1-4 alkyl group, C 3-8 carbon
  • the C 1-4 alkyl in the substituent is optionally further substituted by one or more substituents selected from -OH, cyano or halogen; provided that: when R 3 is a ring In the case of hexyl, the cyclohexyl group is substituted by at least one cyano group; and R 3 is not tetrahydrofuranyl or oxanyl; or, provided that R 3 is not cyclohexyl, tetrahydrofuranyl or oxanyl;
  • p is selected from 1.
  • One or more embodiments of the application provide a compound, or its stereoisomer, solvate, prodrug, deuterated product, metabolite, pharmaceutically acceptable salt or co-crystal, wherein the compound is selected from but not limited to The following structure:
  • One or more embodiments of the present application provide intermediates for preparing the compounds of the present invention, and the intermediates include but are not limited to:
  • composition comprising:
  • One or more embodiments of the application provide the above-mentioned pharmaceutical composition or the above-mentioned compound of the present invention or its stereoisomers, solvates, prodrugs, deuterated products, metabolites, pharmaceutically acceptable salts or co- The use of crystals in the preparation of medicines for the treatment of cancer.
  • One or more embodiments of the application provide the above-mentioned pharmaceutical composition or the above-mentioned compound of the present invention or its stereoisomers, solvates, prodrugs, deuterated products, metabolites, pharmaceutically acceptable salts or co- The use of crystals in the preparation of DNA-PK inhibitors.
  • One or more embodiments of the present application provide the compound of the present application for use as a medicine.
  • One or more embodiments of the present application provide the compound of the present application for use as a DNA-PK inhibitor.
  • One or more embodiments of the present application provide a compound of the present application for use in a method of treating, preventing, or inhibiting cancer.
  • One or more embodiments of the present application provide the compound of the present application for use in a method of inhibiting DNA-PK.
  • One or more embodiments of the present application provide a method of treating, preventing or inhibiting cancer, which comprises administering the compound of the present application to a subject in need.
  • One or more embodiments of the present application provide a method for inhibiting DNA-PK, which includes administering the compound of the present application to a subject in need.
  • the carbon, hydrogen, oxygen, sulfur, nitrogen or F, Cl, Br, and I involved in the groups and compounds of the present invention include their isotopes, and the carbon involved in the groups and compounds of the present invention , Hydrogen, oxygen, sulfur or nitrogen are optionally further replaced by one or more of their corresponding isotopes, wherein carbon isotopes include 12 C, 13 C and 14 C, and hydrogen isotopes include protium (H), deuterium (D, Also called heavy hydrogen), tritium (T, also called super heavy hydrogen), oxygen isotopes include 16 O, 17 O and 18 O, sulfur isotopes include 32 S, 33 S, 34 S and 36 S, and nitrogen isotopes include 14 N and 15 N, fluorine isotopes include 17 F and 19 F, chlorine isotopes include 35 Cl and 37 Cl, and bromine isotopes include 79 Br and 81 Br.
  • carbon isotopes include 12 C, 13 C and 14 C
  • hydrogen isotopes include
  • Alkyl refers to a linear or branched saturated aliphatic hydrocarbon group of 1 to 20 carbon atoms, preferably 1 to 8 (for example, 1, 2, 3, 4, 5, 6, 7, 8) carbon atoms
  • the alkyl group of is more preferably an alkyl group of 1 to 6 carbon atoms, and still more preferably an alkyl group of 1 to 4 carbon atoms.
  • Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, neobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl And its various branched isomers; when the alkyl group is substituted, it may be optionally further substituted with one or more substituents.
  • Alkoxy refers to a group formed by replacing at least one carbon atom in an alkyl group with an oxygen atom.
  • Non-limiting examples include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy, n-hexoxy, cyclopropyl Oxy and cyclobutoxy.
  • the definition of the alkyl group is the same as the definition of "alkyl" mentioned above.
  • Alkenyl refers to a straight line consisting of 1 to 10 (for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10) carbon-carbon double bonds consisting of 2 to 20 carbon atoms. Chain or branched unsaturated aliphatic hydrocarbon group, preferably 2 to 12 (for example, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12) carbon atoms alkenyl group, more preferably 2 to The alkenyl group of 8 carbon atoms is more preferably the alkenyl group of 2 to 6 carbon atoms.
  • Non-limiting examples include vinyl, propen-2-yl, buten-2-yl, buten-2-yl, penten-2-yl, penten-4-yl, hexen-2-yl, Hexen-3-yl, hepten-2-yl, hepten-3-yl, hepten-4-yl, octen-3-yl, nonen-3-yl, decen-4-yl and undecenyl En-3-yl.
  • the alkenyl group may be further substituted with one or more substituents.
  • Alkynyl refers to those containing 1 to 10 (for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) carbon-carbon triple bonds, consisting of 2 to 20 carbon atoms Straight or branched chain unsaturated aliphatic hydrocarbon group, preferably 2 to 12 (for example, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12) carbon atom alkynyl group, more preferably 2 An alkynyl group having to 8 carbon atoms, and an alkynyl group having 2 to 6 carbon atoms is more preferable.
  • Non-limiting examples include ethynyl, propyn-1-yl, propyn-2-yl, butyn-1-yl, butyn-2-yl, butyn-3-yl, 3,3-dimethyl Butyn-2-yl, pentyn-1-yl, pentyn-2-yl, hexyn-1-yl, 1-heptyn-1-yl, heptyn-3-yl, heptyn-4- Base, octyn-3-yl, nonyn-3-yl, decyn-4-yl, undecyn-3-yl, dodecyn-4-yl.
  • the alkynyl group may be optionally further substituted with 1 to more substituents.
  • Aryl refers to a substituted or unsubstituted aromatic ring, which can be a 5- to 8-membered (e.g., 5, 6, 7, 8-membered) monocyclic ring, 5 to 12-membered (e.g., 5, 6, 7 , 8, 9, 10, 11, 12 membered) bicyclic or 10 to 15 membered (for example, 10, 11, 12, 13, 14, 15 membered) tricyclic ring system, which can be bridged or spiro ring, non-limiting implementation Examples include phenyl and naphthyl. The aryl group may be further substituted with one or more substituents.
  • Heteroaryl refers to a substituted or unsubstituted aromatic ring, which can be 3 to 8 membered (e.g. 3, 4, 5, 6, 7, 8 membered) monocyclic, 5 to 12 membered (e.g. 5, 6, 7, 8, 9, 10, 11, 12 membered) bicyclic or 10 to 15 membered (e.g. 10, 11, 12, 13, 14, 15 membered) tricyclic ring system, and contains 1 to 6 (e.g. 1, 2, 3, 4, 5, 6) heteroatoms selected from N, O or S, preferably 5 to 8 membered heteroaryl groups, and 1 to 4 (e.g. 1, 2 , 3, 4) N and S can be oxidized into various oxidation states.
  • 3 to 8 membered e.g. 3, 4, 5, 6, 7, 8 membered
  • monocyclic e.g. 5, 6, 7, 8, 9, 10, 11, 12 membered
  • 10 to 15 membered e.g. 10, 11, 12, 13, 14, 15 membered
  • tricyclic ring system contains 1 to
  • the heterocyclic group can be attached to a hetero atom or a carbon atom, and the heteroaryl group can be a bridged ring or a spiro ring.
  • Non-limiting examples include cyclopyridyl, furyl, thienyl, pyranyl, pyrrolyl, pyrimidinyl, Pyrazinyl, pyridazinyl, imidazolyl, piperidinyl benzimidazolyl, benzopyridyl, pyrrolopyridyl.
  • the heteroaryl group is optionally further substituted with one or more substituents.
  • Carbocyclic group or “carbocyclic ring” refers to a saturated or unsaturated aromatic ring or a non-aromatic ring.
  • aromatic ring When it is an aromatic ring, its definition is the same as the definition of "aryl”above; when it is a non-aromatic ring, it can be 3 to 10 members (for example, 3, 4, 5, 6, 7, 8, 9, 10 Yuan), 4 to 12 yuan (e.g. 4, 5, 6, 7, 8, 9, 10, 11, 12 yuan) bicyclic ring or 10 to 15 yuan (e.g.
  • tricyclic ring system which can be bridged or spiro ring
  • non-limiting examples include cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopentyl-1-enyl, 1-cyclopentyl-2 -Alkenyl, 1-cyclopentyl-3-alkenyl, cyclohexyl, 1-cyclohexyl-2-alkenyl, 1-cyclohexyl-3-alkenyl, cyclohexenyl, cyclohexadienyl, cyclo Heptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl,
  • the "carbocyclic group” or "carbocyclic ring” is optionally further substituted with one or more substituents.
  • Heterocyclic group or “heterocyclic ring” refers to a saturated or unsaturated aromatic heterocyclic ring or non-aromatic heterocyclic ring. When it is an aromatic heterocyclic ring, its definition is the same as the definition of "heteroaryl” above; when When it is a non-aromatic heterocyclic ring, it can be a 3- to 10-membered (e.g. 3, 4, 5, 6, 7, 8, 9, 10-membered) monocyclic ring, 4 to 12-membered (e.g. 4, 5, 6, 7, 8, 9, 10, 11, 12 membered) bicyclic or 10 to 15 membered (e.g. 10, 11, 12, 13, 14, 15 membered) tricyclic ring system, and contains 1 to 4 (e.g.
  • heteroatoms selected from N, O or S preferably 3 to 8 membered heterocyclic groups.
  • One to four (for example, 1, 2, 3, 4) N and S optionally substituted in the "heterocyclic group” or “heterocyclic ring” can be oxidized to various oxidation states;
  • heterocyclic group” or “Heterocycle” can be attached to a heteroatom or carbon atom;
  • heterocyclic group” or “heterocycle” can be a bridged ring or a spiro ring.
  • heterocyclic group or “heterocyclic ring” include oxirane, glycidyl, aziridinyl, oxetanyl, azetidinyl, thietanyl , 1,3-dioxolane, 1,4-dioxolane, 1,3-dioxanyl, azepanyl, oxepanyl, thiepanyl, oxygen Azepine, diazepine, thiazepine, pyridinyl, piperidinyl, homopiperidinyl, furyl, thienyl, pyranyl, N-alkylpyrrolyl, pyrimidinyl, pyridine Azinyl, pyridazinyl, piperazinyl, homopiperazinyl, imidazolyl, piperidinyl, morpholinyl, thiomorpholinyl, thiazinyl, 1,3-
  • Cycloalkyl refers to a saturated cyclic hydrocarbon group whose ring can be 3 to 10 membered (e.g. 3, 4, 5, 6, 7, 8, 9, 10 membered) monocyclic, 4 to 12 membered (e.g. 4 , 5, 6, 7, 8, 9, 10, 11, 12-membered) bicyclic or 10- to 20-membered (for example, 4, 5, 6, 7, 8, 9, 10, 11, 12-membered) polycyclic ring system, ring
  • the carbon atom is preferably 3 to 10 carbon atoms, more preferably 3 to 8 carbon atoms.
  • Non-limiting examples of "cycloalkyl” include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexyl Alkenyl, cycloheptenyl, 1,5-cyclooctadienyl, 1,4-cyclohexadienyl and cycloheptatrienyl, etc. When the cycloalkyl group is substituted, it may be further substituted with one or more substituents.
  • Heterocycloalkyl refers to a substituted or unsubstituted saturated non-aromatic ring group, which can be 3 to 8 membered (for example, 3, 4, 5, 6, 7, 8 membered) monocyclic, 4 to 12 membered (E.g. 4, 5, 6, 7, 8, 9, 10, 11, 12-membered) bicyclic or 10 to 15-membered (e.g. 10, 11, 12, 13, 14, 15-membered) tricyclic ring system, including 1, 2 or 3 heteroatoms selected from N, O or S, preferably 3 to 8 membered heterocyclic group.
  • the selectively substituted N and S in the "heterocycloalkyl" ring can be oxidized to various oxidation states; the "heterocycloalkyl” can be connected to a heteroatom or a carbon atom; the “heterocycloalkyl” can be a bridge Ring or spiro ring.
  • heterocycloalkyl include oxirane ethyl, aziridinyl, oxetanyl, azetidinyl, 1,3-dioxolane, 1,4-dioxolane, Oxolane, 1,3-dioxanyl, azepanyl, piperidinyl, piperidinyl, morpholinyl, thiomorpholinyl, 1,3-dithianyl, tetrahydrofuranyl , Tetrahydropyrrolyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydropyranyl, azabicyclo[3.2.1]octyl, azabicyclo[5.2.0]nonyl, oxa Tricyclic[5.3.1.1]dodecyl, azaadamantyl and oxaspiro[3.3]heptyl.
  • “Pharmaceutically acceptable salt” or “pharmaceutically acceptable salt thereof” means that the compound of the present invention maintains the biological effectiveness and characteristics of the free acid or free base, and the free acid is combined with a non-toxic inorganic base or An organic base is a salt obtained by reacting the free base with a non-toxic inorganic acid or organic acid.
  • “Pharmaceutical composition” refers to a mixture of one or more compounds of the present invention, their pharmaceutically acceptable salts or prodrugs, and other chemical components, where "other chemical components” refer to pharmaceutically acceptable compounds. Accepted carriers, excipients and/or one or more other therapeutic agents.
  • Carrier refers to a material that does not cause significant irritation to the organism and does not eliminate the biological activity and characteristics of the administered compound.
  • Excipient refers to an inert substance added to a pharmaceutical composition to facilitate the administration of a compound.
  • Non-limiting examples include calcium carbonate, calcium phosphate, sugar, starch, cellulose derivatives (including microcrystalline cellulose), gelatin, vegetable oils, polyethylene glycols, diluents, granulating agents, lubricants, adhesives Agent and disintegrant.
  • a “prodrug” refers to a compound of the present invention that can be converted into a biologically active compound by metabolism in the body.
  • the prodrug of the present invention is prepared by modifying the amino or carboxyl group in the compound of the present invention, and this modification can be removed by conventional operations or in vivo to obtain the parent compound.
  • the prodrug of the present invention is administered to a mammalian individual, the prodrug is split to form free amino or carboxyl groups.
  • Co-crystal refers to the crystal formed by the combination of active pharmaceutical ingredient (API) and co-crystal former (CCF) under the action of hydrogen bonds or other non-covalent bonds.
  • API active pharmaceutical ingredient
  • CCF co-crystal former
  • the pure state of API and CCF are both at room temperature. Solid, and there is a fixed stoichiometric ratio between the components.
  • a eutectic is a multi-component crystal, which contains both a binary eutectic formed between two neutral solids and a multi-element eutectic formed between a neutral solid and a salt or solvate.
  • Stepoisomers refer to isomers produced by the different arrangements of atoms in a molecule in space, including cis-trans isomers, enantiomers and conformational isomers.
  • Optional or “optionally” or “selective” or “selectively” means that the event or condition described later can but does not necessarily occur, and the description includes the situation in which the event or condition occurs and its failures. What happened.
  • heterocyclic group optionally substituted by an alkyl group means that the alkyl group may but does not necessarily exist, and the description includes the case where the heterocyclic group is substituted by an alkyl group and the case where the heterocyclic group is not substituted by an alkyl group.
  • the structure of the compound is determined by nuclear magnetic resonance (NMR) or (and) mass spectrometry (MS).
  • NMR shift ( ⁇ ) is given in units of 10 -6 (ppm).
  • NMR is measured with (Bruker Avance III 400 and Bruker Avance 300) nuclear magnetic instrument, the solvent is deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated chloroform (CDCl 3 ), deuterated methanol (CD 3 OD) ), the internal standard is tetramethylsilane (TMS);
  • HPLC determination uses Agilent 1260DAD high pressure liquid chromatograph (Zorbax SB-C18 100 ⁇ 4.6mm, 3.5 ⁇ M);
  • the thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate.
  • the size of the silica gel plate used for thin layer chromatography (TLC) is 0.15mm-0.20mm, and the size used for thin layer chromatography separation and purification products is 0.4mm. -0.5mm;
  • the known starting materials of the present invention can be synthesized by or according to methods known in the art, or can be purchased from Titan Technology, Anaiji Chemical, Shanghai Demo, Chengdu Kelon Chemical, Shaoyuan Chemical Technology, Bailingwei Technology, etc. the company;
  • Nitrogen atmosphere means that the reaction flask is connected to a nitrogen balloon with a volume of about 1L;
  • the hydrogen atmosphere refers to the reaction flask connected to a hydrogen balloon with a volume of about 1L;
  • the hydrogenation reaction is usually evacuated and filled with hydrogen, and the operation is repeated 3 times;
  • the reaction temperature is room temperature, and the most suitable reaction temperature for room temperature is 20°C-30°C;
  • THF Tetrahydrofuran
  • PE petroleum ether
  • NCS N-chlorosuccinimide
  • Pd(dppf)Cl 2 [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride;
  • DMSO dimethyl sulfoxide
  • DNA Deoxyribonucleotide
  • IC 50 refers to a DNA-PK kinase activity by 50% inhibitory concentration of the compounds.
  • the 2-chloro-7-methyl-9-(((3-methyloxetan-3-yl)methyl)-7,9-dihydro-8H-purin-8-one 2d (0.6g , 2.23mmol), 7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-ylamine (297mg, 2.01mmol), cesium carbonate (1.45g, 4.46mmol), Tris(dibenzylideneacetone)dipalladium (204mg, 0.2mmol) and 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (277mg, 0.4mmol) are dissolved in dioxane , Nitrogen protection and ventilation, stirring at 100 °C for 1 h.
  • tert-butyl (3-oxocyclopentyl) carbamate 6a (10 g, 50.19 mmol) in 60 mL of THF, and slowly add sodium borohydride (2.85 g, 75.28 mmol) in an ice bath. After 3h, TLC monitored the end of the reaction. Slowly add saturated NaCl solution until no bubbles appear, add EA for extraction, collect the organic phase, and rotate to remove the organic solvent to obtain the title compound, tert-butyl (3-hydroxycyclopentyl) carbamate 6b (yellow oily liquid, 10.10g) , Yield 99%).
  • the seventh step is a first step.
  • the 2-chloro-9-(3-hydroxycyclopentyl)-7-methyl-7,9-dihydro-8H-purin-8-one 6g (300mg, 1.12mmol), 7-methyl-[1 ,2,4]triazolo[1,5-a]pyridine-6-amine (165mg, 1.12mmol), cesium carbonate (727mg, 2.23mmol), methanesulfonic acid (2-dicyclohexylphosphine-3,6 -Dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II ) (101 mg, 0.11 mmol) was dissolved in 1,4-dioxane (5 mL), protected by nitrogen and ventilated, stirred at 110° C.
  • TLC monitors to the end of the reaction, extracts twice with saturated ammonium chloride solution, bromine water and ethyl acetate, dried over anhydrous magnesium sulfate, filtered and concentrated the organic layer to obtain the intermediate 8-methyl-1,4-dioxaspiro [ 4.5] Decane-8-carbonitrile, then add THF (60mL) to dissolve, add 3M HCl (60mL) to the reaction solution, heat to 50°C for 5h. TLC monitors to the end of the reaction.
  • Ethyl 2,4-dichloro-5-pyrimidinecarboxylate 1a (6.72g, 30.39mmol) was dissolved in acetonitrile (30mL), potassium carbonate (8.40g, 60.78mmol) was added while stirring at 0°C, and then 4 was slowly added dropwise.
  • the seventh step is a first step.
  • TLC monitors to the end of the reaction add 10 mL of water to the reaction solution, separate the organic phase, wash with saturated brine once, dry with anhydrous sodium sulfate and mix the sample with silica gel, pass the product with a normal phase column passer, and concentrate to obtain the title compound tert-butyl Group (trans-4-carbamoylcyclohexyl) carbamate 8b (white solid, 4.4 g, yield 83%).
  • Tert-butyl (trans-4-carbamoylcyclohexyl) carbamate 8b (4.4g, 18.0mmol) was dissolved in 70mL of pyridine, cooled in an ice bath, and then phosphorus oxychloride (7.7mL) was added dropwise to the reaction In the solution, stir in an ice bath for 1 hour. TLC monitors the completion of the reaction, adds 20 mL of water in an ice bath, extracts 4 times with ethyl acetate, then washes the organic phase 7 times with acid water, and finally washes twice with saturated brine, dried with anhydrous sodium sulfate, filtered and concentrated to dryness. Compound tert-butyl (trans-4-cyanocyclohexyl) carbamate 8c (yellow solid, 1.2 g, yield 30%).
  • the seventh step is a first step.
  • Cis-4-((tert-butoxycarbonyl)amino)cyclohexane-1-carboxylic acid 9a (5.0g, 20.5mmol)
  • O-(7-azabenzotriazole)-N,N,N ',N'-Tetramethyluronium hexafluorophosphate (9.4g, 24.7mmol) was dissolved in dichloromethane (15mL), stirred at 0°C for 20min, and N,N diisopropylethylamine (10.5g , 82mmol) and ammonium chloride (3.3g, 61.5mmol), stirred at room temperature for 4h.
  • TLC monitors to the end of the reaction add 10 mL of water to the reaction solution, separate the organic phase, wash with saturated brine once, dry with anhydrous sodium sulfate and mix the sample with silica gel, pass the product with a normal phase column passer, and concentrate to obtain the title compound tert-butyl Benzyl (cis-4-carbamoylcyclohexyl) carbamate 9b (white solid, 3.5 g, yield 71%).
  • Tert-butyl (cis-4-carbamoylcyclohexyl) carbamate 9b (3.5g, 14.4mmol) was dissolved in 70mL of pyridine, cooled in an ice bath, and then phosphorus oxychloride (7.7mL) was added dropwise to the reaction In the solution, stir in an ice bath for 1 hour. TLC monitors the completion of the reaction, adds 20 mL of water in an ice bath, extracts 4 times with ethyl acetate, then washes the organic phase 7 times with acid water, and finally washes twice with saturated brine, dried with anhydrous sodium sulfate, filtered and concentrated to dryness. The compound tert-butyl (cis-4-cyanocyclohexyl) carbamate 9c (yellow solid, 1.5 g, yield 36%).
  • the seventh step is a first step.
  • Cis-4-(2-chloro-7-methyl-8-oxo-7,8-dihydro-9H-purin-9-yl)cyclohexane-1-carbonitrile 9h (200mg, 0.68mmol), 7-Methyl-[1,2,4]triazolo[1,5-a]pyridine-6-amine (101mg, 0.68mmol), cesium carbonate (391mg, 1.2mmol), methanesulfonic acid (2-di Cyclohexylphosphine-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl- 2-yl)palladium (II) (62 mg, 0.068 mmol) was dissolved in 3 mL of dioxane, protected with nitrogen and ventilated, and stirred at 110° C.
  • the seventh step is a first step.
  • the seventh step is a first step.
  • the seventh step is a first step.
  • the tert-butyl (3-hydroxy-3-methylcyclohexyl) carbamate 15b (2.07 g, 9.03 mmol) was dissolved in 4M hydrogen chloride-1,4-dioxane (10 mL), and the reaction was stirred at room temperature. TLC monitoring until the end of the reaction, concentrated and evaporated the 1,4-dioxane solution to obtain the title compound 3-amino-1-methylcyclohexane-1-ol hydrochloride 15c (light yellow solid, crude product, 1.49g, Yield 99.60%).
  • the seventh step is a first step.
  • reaction solution was quenched by adding water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered and concentrated to obtain the title compound, 2-oxaspiro[3.5]non-7-amine 19c (light yellow oil) ,481mg, yield 37.6%).
  • the seventh step is a first step.
  • the 2-chloro-9-(3-(hydroxymethyl)bicyclo[1.1.1]pent-1-yl)-7-methyl-7,9-dihydro-8H-purin-8-one 21f (80mg ,0.28mmol) was dissolved in 1,4-dioxane (6mL), and 7-methyl-[1,2,4]triazolo[1,5-a]pyridine-6-amine ( 63mg, 0.43mmol), cesium carbonate (139mg, 0.43mmol), BrettPhos-G3-Pd (26mg, 0.028mmol), protected by nitrogen and ventilated, then heated to 110°C and refluxed for 4h. The reaction was monitored by TLC until the reaction was over. The reaction solution was concentrated.

Abstract

The present invention relates to a triazole derivative and medical use thereof. Specifically, the present invention relates to a pyrimidine derivative represented by the general formula (I), or a stereoisomer thereof, a solvate thereof, a prodrug thereof, a deutero compound thereof, a metabolite thereof, a pharmaceutically acceptable salt or an eutectic thereof, a pharmaceutical composition comprising same, and use of the compound or the composition in the field of preparing DNA-PK inhibitors, wherein the definitions of the substituents in the general formula (I) are the same as the definitions in the description.

Description

嘌呤衍生物及其在医药上的应用Purine derivatives and their applications in medicine 技术领域Technical field
本申请涉及通式(I)所示的嘌呤衍生物，或者其立体异构体、溶剂化物、前药、氘代物、代谢产物、药学上可接受的盐或共晶，其药物组合物以及在制备DNA-PK抑制剂的用途。This application relates to purine derivatives represented by general formula (I), or their stereoisomers, solvates, prodrugs, deuterated products, metabolites, pharmaceutically acceptable salts or co-crystals, their pharmaceutical compositions and Preparation of DNA-PK inhibitors.
背景技术Background technique
DNA依赖的蛋白激酶(DNA-dependent protein kinase，DNA-PK)是由Ku70/Ku80异二聚体和DNA依赖的蛋白激酶催化亚基(DNA-PKcs)构成的DNA-PK酶复合物。该酶复合物需要在DNA参与下才能被激活发挥出相应的功能(George et al.,2019)。作为一种丝氨酸/苏氨酸蛋白激酶，DNA-PK属于PIKK(phosphatidylinositol 3-kinase-related kinase)家族成员，它不仅在修复细胞内DNA双链断裂(double-strand breaks；DSBs)和细胞DNA重组或抗体DNA重排(V(D)J重组)过程中具有重要作用，还参与染色体修饰、转录调节、端粒维持等生理过程。DNA-dependent protein kinase (DNA-PK) is a DNA-PK enzyme complex composed of Ku70/Ku80 heterodimer and DNA-dependent protein kinase catalytic subunit (DNA-PKcs). The enzyme complex needs to be activated with the participation of DNA to perform its corresponding functions (George et al., 2019). As a serine/threonine protein kinase, DNA-PK belongs to the PIKK (phosphatidylinositol 3-kinase-related kinase) family. It not only repairs intracellular DNA double-strand breaks (DSBs) and cell DNA recombination Or it plays an important role in the process of antibody DNA rearrangement (V(D)J recombination), and also participates in physiological processes such as chromosome modification, transcription regulation, and telomere maintenance.
在正常生理过程中，多种因素可能导致DNA发生DSBs：如体细胞DNA重组过程中DSBs常常作为中间产物出现，这一生理过程对所有脊椎动物的功能性免疫***的形成十分重要；DNA复制中复制叉遇到受损的碱基，也可能造成单链或双链断裂；DNA也可能因为正常代谢过程中活性氧(reactive oxygen species；ROS)的攻击而产生DSBs(Cannan&Pederson,2016)。此外，还有多种外源性因素也可能导致DSBs，如电离辐射(Ionizing radiation，IR)和化疗试剂(如拓扑异构酶II抑制剂)等(George et al.,2019)。如果DSBs未被修复或者错误地修复，将会产生突变和/或染色体畸变，最终导致细胞死亡。为了应对DSBs带来的危害，真核细胞已进化出多种机制来修复受损的DNA以维持细胞的活力和基因组的稳定性。在真核细胞中，最主要的DNA修复方式是非同源末端连接(non-homologous end-joining，NHEJ)。这种直接将断裂DNA连接起来的方式并不需要有同源DNA片段参与，可以发生在细胞周期的任何阶段。NHEJ是由DNA-PK介导的需要多种蛋白与信号通路共同参与的动态过程，基本过程如下：(1)Ku70/Ku80异二聚体识别并结合至双链DNA断裂末端；(2)募集DNA-PKcs、XRCC4-DNA连接酶IV复合体等蛋白至DNA断裂双链的两侧；(3)DNA-PKcs自身磷酸化，激活自身的激酶活性；(4)DNA-PKcs作为粘合剂连接断裂DNA的两端，防止核酸外切酶对DNA的降解作用；(5)对DNA进行加工以移除断裂处的不可连接末端或其他损伤形式；(6)XRCC4-DNA连接酶IV复合体修复DNA末端(某些情况下，在连接之前可能还需要DNA聚合酶来合成新的末端)。当DNA-PKcs发生磷酸化后，可诱导蛋白构象发生改变，调节NHEJ过程中多种蛋白的活性(如Artemis、Ku70、Ku80、DNA ligase)，这对DNA修复过程至关重要。因此，磷酸化的DNA-PKcs(pDNA-PKcs)常常作为细胞DSBs的标志物。In the normal physiological process, a variety of factors may lead to the occurrence of DSBs in DNA: For example, DSBs often appear as intermediate products in the process of somatic DNA recombination. This physiological process is very important for the formation of the functional immune system of all vertebrates; DNA replication is in progress. When the replication fork encounters damaged bases, it may also cause single-strand or double-strand breaks; DNA may also generate DSBs due to the attack of reactive oxygen species (ROS) during normal metabolism (Cannan & Pederson, 2016). In addition, there are a variety of exogenous factors that may also cause DSBs, such as ionizing radiation (IR) and chemotherapeutic agents (such as topoisomerase II inhibitors) (George et al., 2019). If DSBs are not repaired or repaired incorrectly, mutations and/or chromosomal aberrations will occur, eventually leading to cell death. In order to cope with the harm caused by DSBs, eukaryotic cells have evolved a variety of mechanisms to repair damaged DNA to maintain cell viability and genome stability. In eukaryotic cells, the most important way of DNA repair is non-homologous end-joining (NHEJ). This method of directly connecting broken DNA does not require the participation of homologous DNA fragments, and can occur at any stage of the cell cycle. NHEJ is a dynamic process mediated by DNA-PK that requires the participation of multiple proteins and signaling pathways. The basic process is as follows: (1) Ku70/Ku80 heterodimer recognizes and binds to the ends of double-stranded DNA breaks; (2) Recruitment DNA-PKcs, XRCC4-DNA ligase IV complex and other proteins to both sides of the DNA break double-strand; (3) DNA-PKcs autophosphorylate and activate its own kinase activity; (4) DNA-PKcs as an adhesive to connect Break both ends of the DNA to prevent exonuclease from degrading the DNA; (5) Process the DNA to remove unlinkable ends or other forms of damage at the break; (6) XRCC4-DNA ligase IV complex repair DNA ends (in some cases, DNA polymerase may be required to synthesize new ends before ligation). When DNA-PKcs is phosphorylated, it can induce protein conformation to change and regulate the activity of various proteins in the NHEJ process (such as Artemis, Ku70, Ku80, DNA ligase), which is essential for the DNA repair process. Therefore, phosphorylated DNA-PKcs (pDNA-PKcs) is often used as a marker of cellular DSBs.
已有研究表明，DNA-PK活性与多种肿瘤的发生发展有关：如黑色素瘤中的DNA-PKcs可以促进血管再生和肿瘤的转移；多发性骨髓瘤中的DNA-PKcs表达量显著上调；放疗耐受的甲状腺肿瘤中的Ku蛋白的含量明显增加(Ihara,Ashizawa,Shichijo,&Kudo,2019)。因此，可以考虑将DNA-PK抑制剂与引起DNA损伤的抗肿瘤疗法(如IR、化疗试剂等)联用来提高效果。DNA-PK抑制剂的使用在一定程度上会干扰正常细胞的DNA修复功能，然而正常细胞体内还存在多种DNA修复途径作为补充，而肿瘤细胞面临强大的DNA复制压力且缺乏有效的DNA修复方式。通过抑制肿瘤细胞DNA-PK的活性能够提高其他抗肿瘤药物对肿瘤细胞的杀伤效果。Studies have shown that DNA-PK activity is related to the occurrence and development of a variety of tumors: for example, DNA-PKcs in melanoma can promote angiogenesis and tumor metastasis; DNA-PKcs expression in multiple myeloma is significantly up-regulated; radiotherapy The content of Ku protein in tolerant thyroid tumors is significantly increased (Ihara, Ashizawa, Shichijo, & Kudo, 2019). Therefore, it can be considered to combine DNA-PK inhibitors with anti-tumor therapies that cause DNA damage (such as IR, chemotherapeutic agents, etc.) to improve the effect. The use of DNA-PK inhibitors can interfere with the DNA repair function of normal cells to a certain extent. However, there are many DNA repair pathways in normal cells as a supplement, and tumor cells face strong DNA replication pressure and lack effective DNA repair methods. . By inhibiting the activity of tumor cell DNA-PK, the killing effect of other anti-tumor drugs on tumor cells can be improved.
经多年研究，目前已经发现了多个DNA-PK抑制剂。最早发现具有DNA-PK激酶抑制活性的化合物是一种真菌代谢产物——Wortmannin，IC 50(DNA-PK)约15nM，该 化合物同时在p53蛋白的乙酰化和磷酸化过程中也发挥着重要作用(Sarkaria et al.,1998)；之后报道的槲皮素衍生物LY294002也具有DNA-PK抑制活性(Maira,Stauffer,Schnell,&Garcia-Echeverria,2009)；后来基于LY294002结构又研发了NU7026、NU7441等新一代DNA-PK抑制剂。虽然已经证实了这些化合物对肿瘤细胞有着良好的杀伤效果，但它们存在高毒性、选择性差等问题而无法进入临床开发(Maira et al.,2009)。还曾报道过其他DNA-PK抑制剂，如OK1035、SU11752、PP121、KU-0060648等小分子化合物，但这些化合物同样存在对DNA-PK特异性较低等缺陷(George et al.,2019)。所以，目前仍然需要开发高活性、高特异性、低毒性的DNA-PK抑制剂，以更好满足临床需求。 After years of research, several DNA-PK inhibitors have been discovered. The first compound found to have DNA-PK kinase inhibitory activity is a fungal metabolite—Wortmannin, with an IC 50 (DNA-PK) of about 15 nM. This compound also plays an important role in the acetylation and phosphorylation of p53 protein. (Sarkaria et al., 1998); later reported that the quercetin derivative LY294002 also has DNA-PK inhibitory activity (Maira, Stauffer, Schnell, & Garcia-Echeverria, 2009); later based on the structure of LY294002 and developed NU7026, NU7441, etc. A new generation of DNA-PK inhibitors. Although these compounds have been proven to have a good killing effect on tumor cells, they have problems such as high toxicity and poor selectivity and cannot enter clinical development (Maira et al., 2009). Other DNA-PK inhibitors have also been reported, such as OK1035, SU11752, PP121, KU-0060648 and other small molecule compounds, but these compounds also have defects such as low specificity for DNA-PK (George et al., 2019). Therefore, there is still a need to develop DNA-PK inhibitors with high activity, high specificity, and low toxicity to better meet clinical needs.
发明内容Summary of the invention
本申请的一个或多个实施方式提供了嘌呤衍生物，或者其立体异构体、溶剂化物、前药、氘代物、代谢产物、药学上可接受的盐或共晶，其药物组合物以及其在制备DNA-PK抑制剂中的用途。One or more embodiments of the present application provide purine derivatives, or their stereoisomers, solvates, prodrugs, deuterated products, metabolites, pharmaceutically acceptable salts or co-crystals, their pharmaceutical compositions and their Use in the preparation of DNA-PK inhibitors.
在本申请的一个或多个实施方式中，化合物对DNA-PK具有高抑制活性和/或高选择性，且能够作为化疗和放疗增敏剂有效治疗癌症，改善现有技术的疗效，同时降低毒副作用。In one or more embodiments of the present application, the compound has high inhibitory activity and/or high selectivity for DNA-PK, and can be used as a chemotherapy and radiotherapy sensitizer to effectively treat cancer, improve the curative effect of the prior art, and reduce toxic side effect.
本发明的一个或多个实施方式提供给了通式(I)所示的化合物，或者其立体异构体、溶剂化物、前药、氘代物、代谢产物、药学上可接受的盐或共晶：One or more embodiments of the present invention provide a compound represented by general formula (I), or its stereoisomers, solvates, prodrugs, deuterated products, metabolites, pharmaceutically acceptable salts or co-crystals :
Figure PCTCN2020141859-appb-000001
Figure PCTCN2020141859-appb-000001
其中：among them:
R 1选自H、-OH、氰基、卤素、-NH 2、C 1-6烷基或者C 1-6烷氧基，所述的C 1-6烷基任选进一步被1-3个选自D或者卤素的取代基所取代； R 1 is selected from H, -OH, cyano, halogen, -NH 2 , C 1-6 alkyl or C 1-6 alkoxy, and the C 1-6 alkyl is optionally further grouped by 1-3 Substituted by a substituent selected from D or halogen;
R 2选自H或者C 1-6烷基； R 2 is selected from H or C 1-6 alkyl;
R 3选自C 1-6烷基、C 3-12碳环基、C 3杂环基、C 4-12杂环基、-C 1-6亚烷基-C 3-12碳环基、-C 1-6亚烷基-C 3杂环基或者-C 1-6亚烷基-C 4-12杂环基，所述的C 3杂环基和C 4-12杂环基包含1至3个选自N、O或者S的杂原子，所述的C 1-6烷基、C 3-12碳环基、C 3杂环基和C 4-12杂环基、C 1-6亚烷基任选进一步被1个或者多个选自-OH、羧基、卤素、氰基、＝O、C 1-6烷基、C 1-6杂烷基、C 2-6烯基、C 2-6炔基、-NR a1R a2、-C(＝O)OC 1-6烷基、-C(＝O)NR a1R a2、C 3-12环烷基、C 3杂环烷基、C 4-12杂环烷基、C 6-12芳基或者C 5-12杂芳基的取代基所取代；且所述取代基中的所述的C 1-6烷基、C 1-6杂烷基、C 2-6烯基或者C 2-6炔基任选进一步被1个或者多个选自-OH、羧基、氰基、卤素、-O-R a1、-NR a1R a2、C 3- 12环烷基、C 3杂环烷基、C 4-12杂环烷基、C 6-12芳基或者C 5-12杂芳基的取代基所取代； R 3 is selected from C 1-6 alkyl, C 3-12 carbocyclic group, C 3 heterocyclic group, C 4-12 heterocyclic group, -C 1-6 alkylene-C 3-12 carbocyclic group, -C 1-6 alkylene-C 3 heterocyclic group or -C 1-6 alkylene-C 4-12 heterocyclic group, said C 3 heterocyclic group and C 4-12 heterocyclic group include 1 Up to 3 heteroatoms selected from N, O or S, the C 1-6 alkyl group, C 3-12 carbocyclic group, C 3 heterocyclic group and C 4-12 heterocyclic group, C 1-6 The alkylene group is optionally further selected by one or more selected from -OH, carboxyl, halogen, cyano, =0, C 1-6 alkyl, C 1-6 heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl, -NR a1 R a2 , -C(=O)OC 1-6 alkyl, -C(=O)NR a1 R a2 , C 3-12 cycloalkyl, C 3 heterocycloalkyl , C 4-12 heterocycloalkyl, C 6-12 aryl or C 5-12 heteroaryl substituents; and the C 1-6 alkyl, C 1- 6 heteroalkyl, C 2-6 alkenyl or C 2-6 alkynyl is optionally further selected by one or more selected from -OH, carboxyl, cyano, halogen, -OR a1 , -NR a1 R a2 , C 3-12 cycloalkyl, C 3 heterocycloalkyl, C 4-12 heterocycloalkyl, C 6-12 aryl or C 5-12 heteroaryl group substituents;
条件是：当R 3为环己基时，所述的环己基至少被一个氰基取代；且R 3不为四氢呋喃基或者氧杂环己基；或者，条件是：R 3不为环己基、四氢呋喃基或者氧杂环己基； The condition is: when R 3 is cyclohexyl, the cyclohexyl group is substituted by at least one cyano group; and R 3 is not tetrahydrofuranyl or oxanyl; or, the condition is: R 3 is not cyclohexyl or tetrahydrofuranyl Or oxacyclohexyl;
R a1、R a2各自独立地选自H、C 1-6烷基、-C(＝O)R a3或者-C(＝O)NR a4R a5，其中所述的C 1-6烷基任选进一步被1个或者多个选自OH、卤素、C 1-6烷基、C 1-6烷氧基、C 6-12芳基、C 5-12杂芳基、C 3-12环烷基、C 3杂环烷基或者C 4-12杂环烷基的取代基所取代； R a1 and R a2 are each independently selected from H, C 1-6 alkyl, -C(=O)R a3 or -C(=O)NR a4 R a5 , wherein the C 1-6 alkyl is any Optionally, one or more selected from OH, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 6-12 aryl, C 5-12 heteroaryl, C 3-12 cycloalkane Substituted by the substituents of C 3 heterocycloalkyl or C 4-12 heterocycloalkyl;
R a3选自C 1-6烷基、C 1-6烷氧基或者C 6-12芳基； R a3 is selected from C 1-6 alkyl, C 1-6 alkoxy or C 6-12 aryl;
R a4、R a5各自独立地选自H或者C 1-6烷基；或者R a4与R a5及N原子形成3至8元杂环，所述的3至8元杂环包含1个至4个选自N、O或者S的杂原子； R a4 and R a5 are each independently selected from H or C 1-6 alkyl; or R a4 and R a5 and N atoms form a 3- to 8-membered heterocyclic ring, and the 3- to 8-membered heterocyclic ring includes 1 to 4 One heteroatom selected from N, O or S;
p选自0、1、2或者3；p is selected from 0, 1, 2 or 3;
任选地，通式(I)可以任选被1个或者多个D原子取代。Optionally, the general formula (I) may be optionally substituted with one or more D atoms.
本申请的一个或多个实施方式提供了化合物，或者其立体异构体、溶剂化物、前药、氘代物、代谢产物、药学上可接受的盐或共晶，其中该化合物选自通式(II)所示的化合物：One or more embodiments of the present application provide a compound, or its stereoisomer, solvate, prodrug, deuterated product, metabolite, pharmaceutically acceptable salt or co-crystal, wherein the compound is selected from the general formula ( II) The compound shown:
Figure PCTCN2020141859-appb-000002
Figure PCTCN2020141859-appb-000002
其中：among them:
R 1选自卤素或者C 1-6烷基，所述的C 1-6烷基任选进一步被1-3个选自D或者卤素的取代基所取代； R 1 is selected from halogen or C 1-6 alkyl, and said C 1-6 alkyl is optionally further substituted with 1-3 substituents selected from D or halogen;
R 3选自C 1-6烷基、C 3-12碳环基、C 3杂环基、C 4-12杂环基、-C 1-6亚烷基-C 3-12碳环基、-C 1-6亚烷基-C 3杂环基或者-C 1-6亚烷基-C 4-12杂环基，所述的C 3杂环基和C 4-12杂环基包含1至3个选自N、O或者S的杂原子，所述的C 1-6烷基、C 3-12碳环基、C 3杂环基和C 4-12杂环基、C 1-6亚烷基任选进一步被1个或者多个选自-OH、羧基、卤素、氰基、＝O、C 1-6烷基、C 1-6杂烷基、C 2-6烯基、C 2-6炔基、-NR a1R a2、-C(＝O)OC 1-6烷基、-C(＝O)NR a1R a2、C 3-12环烷基、C 3杂环烷基、C 4-12杂环烷基、C 6-12芳基或者C 5-12杂芳基的取代基所取代；且所述取代基中的所述的C 1-6烷基、C 1-6杂烷基、C 2-6烯基或者C 2-6炔基任选进一步被1个或者多个选自-OH、羧基、氰基、卤素、-O-R a1、-NR a1R a2、C 3- 12环烷基、C 3杂环烷基、C 4-12杂环烷基、C 6-12芳基或者C 5-12杂芳基的取代基所取代； R 3 is selected from C 1-6 alkyl, C 3-12 carbocyclic group, C 3 heterocyclic group, C 4-12 heterocyclic group, -C 1-6 alkylene-C 3-12 carbocyclic group, -C 1-6 alkylene-C 3 heterocyclic group or -C 1-6 alkylene-C 4-12 heterocyclic group, said C 3 heterocyclic group and C 4-12 heterocyclic group include 1 Up to 3 heteroatoms selected from N, O or S, the C 1-6 alkyl group, C 3-12 carbocyclic group, C 3 heterocyclic group and C 4-12 heterocyclic group, C 1-6 The alkylene group is optionally further selected by one or more selected from -OH, carboxyl, halogen, cyano, =0, C 1-6 alkyl, C 1-6 heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl, -NR a1 R a2 , -C(=O)OC 1-6 alkyl, -C(=O)NR a1 R a2 , C 3-12 cycloalkyl, C 3 heterocycloalkyl , C 4-12 heterocycloalkyl, C 6-12 aryl or C 5-12 heteroaryl substituents; and the C 1-6 alkyl, C 1- 6 heteroalkyl, C 2-6 alkenyl or C 2-6 alkynyl is optionally further selected by one or more selected from -OH, carboxyl, cyano, halogen, -OR a1 , -NR a1 R a2 , C 3-12 cycloalkyl, C 3 heterocycloalkyl, C 4-12 heterocycloalkyl, C 6-12 aryl or C 5-12 heteroaryl group substituents;
条件是：当R 3为环己基时，所述的环己基至少被一个氰基取代；且R 3不为四氢呋喃基或者氧杂环己基；或者，条件是：R 3不为环己基、四氢呋喃基或者氧杂环己基； The condition is: when R 3 is cyclohexyl, the cyclohexyl group is substituted by at least one cyano group; and R 3 is not tetrahydrofuranyl or oxanyl; or, the condition is: R 3 is not cyclohexyl or tetrahydrofuranyl Or oxacyclohexyl;
R a1、R a2各自独立地选自H、C 1-6烷基、-C(＝O)R a3或者-C(＝O)NR a4R a5，其中所述的C 1-6烷基任选进一步被1个或者多个选自OH、卤素、C 1-6烷基、C 1-6烷氧基、C 6-12芳基、C 5-12杂芳基、C 3-12环烷基、C 3杂环烷基或者C 4-12杂环烷基的取代基所取代； R a1 and R a2 are each independently selected from H, C 1-6 alkyl, -C(=O)R a3 or -C(=O)NR a4 R a5 , wherein the C 1-6 alkyl is any Optionally, one or more selected from OH, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 6-12 aryl, C 5-12 heteroaryl, C 3-12 cycloalkane Substituted by the substituents of the group, C 3 heterocycloalkyl or C 4-12 heterocycloalkyl;
R a3选自C 1-6烷基、C 1-6烷氧基或者C 6-12芳基； R a3 is selected from C 1-6 alkyl, C 1-6 alkoxy or C 6-12 aryl;
R a4、R a5各自独立地选自H或者C 1-6烷基；或者R a4与R a5及N原子形成3至8元杂环，所述的3至8元杂环包含1个至4个选自N、O或者S的杂原子； R a4 and R a5 are each independently selected from H or C 1-6 alkyl; or R a4 and R a5 and N atoms form a 3- to 8-membered heterocyclic ring, and the 3- to 8-membered heterocyclic ring includes 1 to 4 One heteroatom selected from N, O or S;
p选自0、1、2或者3。p is selected from 0, 1, 2 or 3.
本申请的一个或多个实施方式提供了(I)或者(II)化合物，或者其立体异构体、溶剂化物、前药、氘代物、代谢产物、药学上可接受的盐或共晶，其中：One or more embodiments of the application provide (I) or (II) compounds, or stereoisomers, solvates, prodrugs, deuterated products, metabolites, pharmaceutically acceptable salts or co-crystals thereof, wherein :
R 1选自卤素或者C 1-4烷基，所述的C 1-6烷基任选进一步被1-3个选自D或者卤素的取代基所取代； R 1 is selected from halogen or C 1-4 alkyl, and said C 1-6 alkyl is optionally further substituted with 1-3 substituents selected from D or halogen;
R 3选自C 1-4烷基、C 3-8碳环基、C 4-8杂环基、-C 1-2亚烷基-C 3-8碳环基或者-C 1-2亚烷基-C 4-8杂环基，所述的C 4-8杂环基包含1至3个选自N或者O的杂原子，所述的C 1-4烷基、C 3-8碳环基和C 4-8杂环基、C 1-2亚烷基任选进一步被1个或者多个选自-OH、卤素、＝O、氰基或者C 1-4烷基的取代基所取代；且所述取代基中的所述的C 1-4烷基任选进一步被1个或者多个选自-OH、氰基或者卤素的取代基所取代；条件是：当R 3为环己基时，所述的环己基至少被一个氰基取代；且R 3不为四氢呋喃基或者氧杂环己基；或者，条件是：R 3不为环己基、四氢呋喃基或者氧杂环己基； R 3 is selected from C 1-4 alkyl, C 3-8 carbocyclic group, C 4-8 heterocyclic group, -C 1-2 alkylene-C 3-8 carbocyclic group or -C 1-2 alkylene Alkyl-C 4-8 heterocyclic group, said C 4-8 heterocyclic group contains 1 to 3 heteroatoms selected from N or O, said C 1-4 alkyl group, C 3-8 carbon The cyclic group, C 4-8 heterocyclic group, and C 1-2 alkylene group are optionally further substituted by one or more substituents selected from -OH, halogen, =0, cyano or C 1-4 alkyl. Substituted; and the C 1-4 alkyl in the substituent is optionally further substituted by one or more substituents selected from -OH, cyano or halogen; provided that: when R 3 is a ring In the case of hexyl, the cyclohexyl group is substituted by at least one cyano group; and R 3 is not tetrahydrofuranyl or oxanyl; or, provided that R 3 is not cyclohexyl, tetrahydrofuranyl or oxanyl;
p选自1。p is selected from 1.
本申请的一个或多个实施方式提供了化合物，或者其立体异构体、溶剂化物、前药、氘代物、代谢产物、药学上可接受的盐或共晶，其中该化合物选自但不限于以下结构：One or more embodiments of the application provide a compound, or its stereoisomer, solvate, prodrug, deuterated product, metabolite, pharmaceutically acceptable salt or co-crystal, wherein the compound is selected from but not limited to The following structure:
Figure PCTCN2020141859-appb-000003
Figure PCTCN2020141859-appb-000004
Figure PCTCN2020141859-appb-000005
或者
Figure PCTCN2020141859-appb-000006
Figure PCTCN2020141859-appb-000003
Figure PCTCN2020141859-appb-000004
Figure PCTCN2020141859-appb-000005
or
Figure PCTCN2020141859-appb-000006
本申请的一个或多个实施方式提供制备本发明所述化合物中间体，所述的中间体包括但不限于：One or more embodiments of the present application provide intermediates for preparing the compounds of the present invention, and the intermediates include but are not limited to:
Figure PCTCN2020141859-appb-000007
Figure PCTCN2020141859-appb-000008
或者
Figure PCTCN2020141859-appb-000009
Figure PCTCN2020141859-appb-000007
Figure PCTCN2020141859-appb-000008
or
Figure PCTCN2020141859-appb-000009
本申请的一个或多个实施方式提供药物组合物，所述药物组合物包括：One or more embodiments of the present application provide a pharmaceutical composition, the pharmaceutical composition comprising:
(1)所述的本发明化合物或者其立体异构体、溶剂化物、前药、氘代物、代谢产物、药学上可接受的盐或共晶；(1) The compound of the present invention or its stereoisomers, solvates, prodrugs, deuterated products, metabolites, pharmaceutically acceptable salts or co-crystals;
(2)任选的一种或者多种其他活性成分；以及(2) Optional one or more other active ingredients; and
(3)药学上可接受的载体和/或赋形剂。(3) A pharmaceutically acceptable carrier and/or excipient.
本申请的一个或多个实施方式提供上文所述的药物组合物或者上述本发明化合物或者其立体异构体、溶剂化物、前药、氘代物、代谢产物、药学上可接受的盐或共晶在制备用于治疗癌症的药物中的用途。One or more embodiments of the application provide the above-mentioned pharmaceutical composition or the above-mentioned compound of the present invention or its stereoisomers, solvates, prodrugs, deuterated products, metabolites, pharmaceutically acceptable salts or co- The use of crystals in the preparation of medicines for the treatment of cancer.
本申请的一个或多个实施方式提供上文所述的药物组合物或者上述本发明化合物或者其立体异构体、溶剂化物、前药、氘代物、代谢产物、药学上可接受的盐或共晶在制备DNA-PK抑制剂中的用途。One or more embodiments of the application provide the above-mentioned pharmaceutical composition or the above-mentioned compound of the present invention or its stereoisomers, solvates, prodrugs, deuterated products, metabolites, pharmaceutically acceptable salts or co- The use of crystals in the preparation of DNA-PK inhibitors.
本申请一个或多个实施方式提供了作为药物使用的本申请的化合物。One or more embodiments of the present application provide the compound of the present application for use as a medicine.
本申请一个或多个实施方式提供了作为DNA-PK抑制剂使用的本申请的化合物。One or more embodiments of the present application provide the compound of the present application for use as a DNA-PK inhibitor.
本申请一个或多个实施方式提供了在治疗、预防或抑制癌症的方法中使用的本申请的化合物。One or more embodiments of the present application provide a compound of the present application for use in a method of treating, preventing, or inhibiting cancer.
本申请一个或多个实施方式提供了在抑制DNA-PK的方法中使用的本申请的化合 物。One or more embodiments of the present application provide the compound of the present application for use in a method of inhibiting DNA-PK.
本申请一个或多个实施方式提供了治疗、预防或抑制癌症的方法，其包括向有需要的对象施用本申请的化合物。One or more embodiments of the present application provide a method of treating, preventing or inhibiting cancer, which comprises administering the compound of the present application to a subject in need.
本申请一个或多个实施方式提供了抑制DNA-PK的方法，其包括向有需要的对象施用本申请的化合物。One or more embodiments of the present application provide a method for inhibiting DNA-PK, which includes administering the compound of the present application to a subject in need.
除非有相反的陈述，在说明书和权利要求书中使用的术语具有下述含义。Unless stated to the contrary, the terms used in the specification and claims have the following meanings.
本发明所述基团和化合物中所涉及的碳、氢、氧、硫、氮或F、Cl、Br、I均包括它们的同位素情况，及本发明所述基团和化合物中所涉及的碳、氢、氧、硫或氮任选进一步被一个或多个它们对应的同位素所替代，其中碳的同位素包括 12C、 13C和 14C，氢的同位素包括氕(H)、氘(D，又叫重氢)、氚(T，又叫超重氢)，氧的同位素包括 16O、 17O和 18O，硫的同位素包括 32S、 33S、 34S和 36S，氮的同位素包括 14N和 15N，氟的同位素包括 17F和 19F，氯的同位素包括 35Cl和 37Cl，溴的同位素包括 79Br和 81Br。 The carbon, hydrogen, oxygen, sulfur, nitrogen or F, Cl, Br, and I involved in the groups and compounds of the present invention include their isotopes, and the carbon involved in the groups and compounds of the present invention , Hydrogen, oxygen, sulfur or nitrogen are optionally further replaced by one or more of their corresponding isotopes, wherein carbon isotopes include 12 C, 13 C and 14 C, and hydrogen isotopes include protium (H), deuterium (D, Also called heavy hydrogen), tritium (T, also called super heavy hydrogen), oxygen isotopes include 16 O, 17 O and 18 O, sulfur isotopes include 32 S, 33 S, 34 S and 36 S, and nitrogen isotopes include 14 N and 15 N, fluorine isotopes include 17 F and 19 F, chlorine isotopes include 35 Cl and 37 Cl, and bromine isotopes include 79 Br and 81 Br.
“烷基”是指1至20个碳原子的直链或支链饱和脂肪族烃基，优选为1至8个(例如1、2、3、4、5、6、7、8个)碳原子的烷基，更优选为1至6个碳原子的烷基，进一步优选为1至4个碳原子的烷基。非限制性实施例包括甲基、乙基、正丙基、异丙基、正丁基、仲丁基、新丁基、叔丁基、正戊基、异戊基、新戊基、正己基及其各种支链异构体；当烷基被取代基时，可以任选进一步被1个或者多个取代基所取代。"Alkyl" refers to a linear or branched saturated aliphatic hydrocarbon group of 1 to 20 carbon atoms, preferably 1 to 8 (for example, 1, 2, 3, 4, 5, 6, 7, 8) carbon atoms The alkyl group of is more preferably an alkyl group of 1 to 6 carbon atoms, and still more preferably an alkyl group of 1 to 4 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, neobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl And its various branched isomers; when the alkyl group is substituted, it may be optionally further substituted with one or more substituents.
“烷氧基”是指烷基中至少1个碳原子被氧原子取代所形成的基团。非限制性实施例包括甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、仲丁氧基、叔丁氧基、正戊氧基、正己氧基、环丙氧基和环丁氧基。所述的烷基定义与上文所述的“烷基”定义相同。"Alkoxy" refers to a group formed by replacing at least one carbon atom in an alkyl group with an oxygen atom. Non-limiting examples include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy, n-hexoxy, cyclopropyl Oxy and cyclobutoxy. The definition of the alkyl group is the same as the definition of "alkyl" mentioned above.
“烯基”是指包含1至10个(例如1、2、3、4、5、6、7、8、9、10个)碳-碳双键，由2至20个碳原子组成的直链或者支链不饱和脂肪族烃基，优选2至12个(例如2、3、4、5、6、7、8、9、10、11、12个)碳原子的烯基，更优选2至8个碳原子的烯基，进一步优选2至6个碳原子的烯基。非限制性实施例包括乙烯基、丙烯-2-基、丁烯-2-基、丁烯-2-基、戊烯-2-基、戊烯-4-基、己烯-2-基、己烯-3基、庚烯-2-基、庚烯-3-基、庚烯-4-基、辛烯-3-基、壬烯-3-基、癸烯-4-基和十一烯-3-基。所述的烯基可以任选进一步被1个或者多个取代基所取代。"Alkenyl" refers to a straight line consisting of 1 to 10 (for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10) carbon-carbon double bonds consisting of 2 to 20 carbon atoms. Chain or branched unsaturated aliphatic hydrocarbon group, preferably 2 to 12 (for example, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12) carbon atoms alkenyl group, more preferably 2 to The alkenyl group of 8 carbon atoms is more preferably the alkenyl group of 2 to 6 carbon atoms. Non-limiting examples include vinyl, propen-2-yl, buten-2-yl, buten-2-yl, penten-2-yl, penten-4-yl, hexen-2-yl, Hexen-3-yl, hepten-2-yl, hepten-3-yl, hepten-4-yl, octen-3-yl, nonen-3-yl, decen-4-yl and undecenyl En-3-yl. The alkenyl group may be further substituted with one or more substituents.
“炔基”是指包含1至10个(例如1、2、3、4、5、6、7、8、9、或10个)碳-碳叁键，由2至20个碳原子组成的直链或者支链不饱和脂肪族烃基，优选2至12个(例如2、3、4、5、6、7、8、9、10、11或12个)碳原子的炔基，更优选2至8个碳原子的炔基，进一步优选2至6个碳原子的炔基。非限制性实施例包括乙炔基、丙炔-1-基、丙炔-2-基、丁炔-1-基、丁炔-2-基、丁炔-3-基、3,3-二甲基丁炔-2-基、戊炔-1-基、戊炔-2-基、己炔-1-基、1-庚炔-1-基、庚炔-3-基、庚炔-4-基、辛炔-3-基、壬炔-3-基、癸炔-4-基、十一炔-3-基、十二炔-4-基。所述的炔基可以任选进一步被1至多个取代基所取代。"Alkynyl" refers to those containing 1 to 10 (for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) carbon-carbon triple bonds, consisting of 2 to 20 carbon atoms Straight or branched chain unsaturated aliphatic hydrocarbon group, preferably 2 to 12 (for example, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12) carbon atom alkynyl group, more preferably 2 An alkynyl group having to 8 carbon atoms, and an alkynyl group having 2 to 6 carbon atoms is more preferable. Non-limiting examples include ethynyl, propyn-1-yl, propyn-2-yl, butyn-1-yl, butyn-2-yl, butyn-3-yl, 3,3-dimethyl Butyn-2-yl, pentyn-1-yl, pentyn-2-yl, hexyn-1-yl, 1-heptyn-1-yl, heptyn-3-yl, heptyn-4- Base, octyn-3-yl, nonyn-3-yl, decyn-4-yl, undecyn-3-yl, dodecyn-4-yl. The alkynyl group may be optionally further substituted with 1 to more substituents.
“芳基”是指是指取代的或未取代的芳香环，其可以是5至8元(例如5、6、7、8元)的单环、5至12元(例如5、6、7、8、9、10、11、12元)双环或者10至15元(例如10、11、12、13、14、15元)三环体系，其可以是桥环或者螺环，非限制性实施例包括苯基、萘基。所述的芳基可以任选进一步被1个或者多个取代基所取代。"Aryl" refers to a substituted or unsubstituted aromatic ring, which can be a 5- to 8-membered (e.g., 5, 6, 7, 8-membered) monocyclic ring, 5 to 12-membered (e.g., 5, 6, 7 , 8, 9, 10, 11, 12 membered) bicyclic or 10 to 15 membered (for example, 10, 11, 12, 13, 14, 15 membered) tricyclic ring system, which can be bridged or spiro ring, non-limiting implementation Examples include phenyl and naphthyl. The aryl group may be further substituted with one or more substituents.
“杂芳基”是指取代的或未取代的芳香环，其可以是3至8元(例如3、4、5、6、7、8元)的单环、5至12元(例如5、6、7、8、9、10、11、12元)双环或者10至15元(例如10、11、12、13、14、15元)三环体系，且包含1至6个(例如1、2、3、4、5、6个)选自N、O或S的杂原子，优选5至8元杂芳基，杂芳基的环中选择性取代的1至4个(例如1、2、3、4个)N、S可被氧化成各种氧化态。杂环基可以连接在杂原子或者碳原子上，杂芳基可以是桥环或者螺环，非限制性实施例包括环吡啶基、呋喃基、噻吩 基、吡喃基、吡咯基、嘧啶基、吡嗪基、哒嗪基、咪唑基、哌啶基苯并咪唑基、苯并吡啶基、吡咯并吡啶基。杂芳基任选进一步被1个或多个取代基所取代。"Heteroaryl" refers to a substituted or unsubstituted aromatic ring, which can be 3 to 8 membered (e.g. 3, 4, 5, 6, 7, 8 membered) monocyclic, 5 to 12 membered (e.g. 5, 6, 7, 8, 9, 10, 11, 12 membered) bicyclic or 10 to 15 membered (e.g. 10, 11, 12, 13, 14, 15 membered) tricyclic ring system, and contains 1 to 6 (e.g. 1, 2, 3, 4, 5, 6) heteroatoms selected from N, O or S, preferably 5 to 8 membered heteroaryl groups, and 1 to 4 (e.g. 1, 2 , 3, 4) N and S can be oxidized into various oxidation states. The heterocyclic group can be attached to a hetero atom or a carbon atom, and the heteroaryl group can be a bridged ring or a spiro ring. Non-limiting examples include cyclopyridyl, furyl, thienyl, pyranyl, pyrrolyl, pyrimidinyl, Pyrazinyl, pyridazinyl, imidazolyl, piperidinyl benzimidazolyl, benzopyridyl, pyrrolopyridyl. The heteroaryl group is optionally further substituted with one or more substituents.
“碳环基”或“碳环”是指饱和或者不饱和的芳香环或者非芳香环。当为芳香环时，其定义与上文“芳基”的定义相同；当为非芳香环时，其可以是3至10元(例如3、4、5、6、7、8、9、10元)的单环、4至12元(例如4、5、6、7、8、9、10、11、12元)双环或者10至15元(例如10、11、12、13、14、15元)三环体系，可以是桥环或者螺环，非限制性实施例包括环丙基、环丁基、环戊基、1-环戊基-1-烯基、1-环戊基-2-烯基、1-环戊基-3-烯基、环己基、1-环己基-2-烯基、1-环己基-3-烯基、环己烯基、环己二烯基、环庚基、环辛基、环壬基、环癸基、环十一烷基、环十二烷基、
Figure PCTCN2020141859-appb-000010
Figure PCTCN2020141859-appb-000011
所述的“碳环基”或“碳环”任选进一步被1个或者多个取代基所取代。 "Carbocyclic group" or "carbocyclic ring" refers to a saturated or unsaturated aromatic ring or a non-aromatic ring. When it is an aromatic ring, its definition is the same as the definition of "aryl"above; when it is a non-aromatic ring, it can be 3 to 10 members (for example, 3, 4, 5, 6, 7, 8, 9, 10 Yuan), 4 to 12 yuan (e.g. 4, 5, 6, 7, 8, 9, 10, 11, 12 yuan) bicyclic ring or 10 to 15 yuan (e.g. 10, 11, 12, 13, 14, 15 Member) tricyclic ring system, which can be bridged or spiro ring, non-limiting examples include cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopentyl-1-enyl, 1-cyclopentyl-2 -Alkenyl, 1-cyclopentyl-3-alkenyl, cyclohexyl, 1-cyclohexyl-2-alkenyl, 1-cyclohexyl-3-alkenyl, cyclohexenyl, cyclohexadienyl, cyclo Heptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl,
Figure PCTCN2020141859-appb-000010
Figure PCTCN2020141859-appb-000011
The "carbocyclic group" or "carbocyclic ring" is optionally further substituted with one or more substituents.
“杂环基”或“杂环”是指饱和或不饱和的芳香性杂环或者非芳香性杂环，当为芳香性杂环时，其定义与上文“杂芳基”定义相同；当为非芳香性杂环时，其可以是3至10元(例如3、4、5、6、7、8、9、10元)的单环、4至12元(例如4、5、6、7、8、9、10、11、12元)双环或者10至15元(例如10、11、12、13、14、15元)三环体系，且包含1至4个(例如1、2、3、4个)选自N、O或S的杂原子，优选3至8元杂环基。“杂环基”或“杂环”的环中选择性取代的1至4个(例如1、2、3、4个)N、S可被氧化成各种氧化态；“杂环基”或“杂环”可以连接在杂原子或者碳原子上；“杂环基”或“杂环”可以为桥环或者螺环。“杂环基”或“杂环”的非限制性实施例包括环氧乙基、环氧丙基、氮杂环丙基、氧杂环丁基、氮杂环丁基、硫杂环丁基、1,3-二氧戊环基、1,4-二氧戊环基、1,3-二氧六环基、氮杂环庚基、氧杂环庚基、硫杂环庚基、氧氮杂卓基、二氮杂卓基、硫氮杂卓基、吡啶基、哌啶基、高哌啶基、呋喃基、噻吩基、吡喃基、N-烷基吡咯基、嘧啶基、吡嗪基、哒嗪基、哌嗪基、高哌嗪基、咪唑基、哌啶基、吗啉基、硫代吗啉基、噻噁烷基、1,3-二噻烷基、二氢呋喃基、二噻戊环基、四氢呋喃基、四氢噻吩基、四氢吡喃基、四氢噻喃基、四氢吡咯基、四氢咪唑基、四氢噻唑基、四氢吡喃基、苯并咪唑基、苯并吡啶基、吡咯并吡啶基、苯并二氢呋喃基、2-吡咯啉基、3-吡咯啉基、二氢吲哚基、2H-吡喃基、4H-吡喃基、二氧杂环己基、1,3-二氧戊基、吡唑啉基、二噻烷基、二噻茂烷基、二氢噻吩基、吡唑烷基、咪唑啉基、咪唑烷基、1,2,3,4-四氢异喹啉基、3-氮杂双环[3.1.0]己基、3-氮杂双环[4.1.0]庚基、氮杂双环[2.2.2]己基、3H-吲哚基喹嗪基、N-吡啶基尿素、1,1-二氧硫代吗啉基、氮杂二环[3.2.1]辛烷基、氮杂二环[5.2.0]壬烷基、氧杂三环[5.3.1.1]十二烷基、氮杂金刚烷基和氧杂螺[3.3]庚烷基。所述的“杂环基”或“杂环”可以任选进一步被1个或者多个取代基所取代。"Heterocyclic group" or "heterocyclic ring" refers to a saturated or unsaturated aromatic heterocyclic ring or non-aromatic heterocyclic ring. When it is an aromatic heterocyclic ring, its definition is the same as the definition of "heteroaryl" above; when When it is a non-aromatic heterocyclic ring, it can be a 3- to 10-membered (e.g. 3, 4, 5, 6, 7, 8, 9, 10-membered) monocyclic ring, 4 to 12-membered (e.g. 4, 5, 6, 7, 8, 9, 10, 11, 12 membered) bicyclic or 10 to 15 membered (e.g. 10, 11, 12, 13, 14, 15 membered) tricyclic ring system, and contains 1 to 4 (e.g. 1, 2, 3, 4) heteroatoms selected from N, O or S, preferably 3 to 8 membered heterocyclic groups. One to four (for example, 1, 2, 3, 4) N and S optionally substituted in the "heterocyclic group" or "heterocyclic ring" can be oxidized to various oxidation states; "heterocyclic group" or "Heterocycle" can be attached to a heteroatom or carbon atom; "heterocyclic group" or "heterocycle" can be a bridged ring or a spiro ring. Non-limiting examples of "heterocyclic group" or "heterocyclic ring" include oxirane, glycidyl, aziridinyl, oxetanyl, azetidinyl, thietanyl , 1,3-dioxolane, 1,4-dioxolane, 1,3-dioxanyl, azepanyl, oxepanyl, thiepanyl, oxygen Azepine, diazepine, thiazepine, pyridinyl, piperidinyl, homopiperidinyl, furyl, thienyl, pyranyl, N-alkylpyrrolyl, pyrimidinyl, pyridine Azinyl, pyridazinyl, piperazinyl, homopiperazinyl, imidazolyl, piperidinyl, morpholinyl, thiomorpholinyl, thiazinyl, 1,3-dithiazinyl, dihydrofuran Group, dithiopentyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydropyrrolyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydropyranyl, benzene Bisimidazolyl, benzopyridyl, pyrrolopyridyl, chromanyl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl , Dioxanyl, 1,3-dioxolyl, pyrazolinyl, dithianyl, dithiazolinyl, dihydrothienyl, pyrazolidinyl, imidazolinyl, imidazolinyl, 1,2,3,4-Tetrahydroisoquinolinyl, 3-azabicyclo[3.1.0]hexyl, 3-azabicyclo[4.1.0]heptyl, azabicyclo[2.2.2]hexyl, 3H-indolylquinazinyl, N-pyridylurea, 1,1-dioxothiomorpholinyl, azabicyclo[3.2.1]octyl, azabicyclo[5.2.0]non Alkyl, oxatricyclo[5.3.1.1]dodecyl, azaadamantyl and oxaspiro[3.3]heptyl. The "heterocyclic group" or "heterocyclic ring" may be optionally further substituted with one or more substituents.
“环烷基”是指饱和的环烃基，其环可以为3至10元(例如3、4、5、6、7、8、9、10元)的单环、4至12元(例如4、5、6、7、8、9、10、11、12元)双环或者10至20元(例如4、5、6、7、8、9、10、11、12元)多环体系，环碳原子优选3至10个碳原子，进一步优选3至8个碳原子。“环烷基”非限制性实施例包括环丙基、环丁基、环戊基、环己基、环庚基、环辛基、环丙烯基、环丁烯基、环戊烯基、环己烯基、环庚烯基、1,5-环辛二烯基、1,4-环己二烯基和环庚三烯基等。当环烷基被取代时，可以任选进一步被1个或者多个取代基所取代。"Cycloalkyl" refers to a saturated cyclic hydrocarbon group whose ring can be 3 to 10 membered (e.g. 3, 4, 5, 6, 7, 8, 9, 10 membered) monocyclic, 4 to 12 membered (e.g. 4 , 5, 6, 7, 8, 9, 10, 11, 12-membered) bicyclic or 10- to 20-membered (for example, 4, 5, 6, 7, 8, 9, 10, 11, 12-membered) polycyclic ring system, ring The carbon atom is preferably 3 to 10 carbon atoms, more preferably 3 to 8 carbon atoms. Non-limiting examples of "cycloalkyl" include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexyl Alkenyl, cycloheptenyl, 1,5-cyclooctadienyl, 1,4-cyclohexadienyl and cycloheptatrienyl, etc. When the cycloalkyl group is substituted, it may be further substituted with one or more substituents.
“杂环烷基”是指取代的或未取代的饱和非芳香环基，其可以是3至8元(例如3、4、5、6、7、8元)的单环、4至12元(例如4、5、6、7、8、9、10、11、12元)双环或者10至15元(例如10、11、12、13、14、15元)三环体系，且包含1、2或3个选自N、O或S的杂原子，优选3至8元杂环基。“杂环烷基”的环中选择性取代的N、S可被氧 化成各种氧化态；“杂环烷基”可以连接在杂原子或者碳原子上；“杂环烷基”可以为桥环或者螺环。“杂环烷基”非限制性实施例包括环氧乙基、氮杂环丙基、氧杂环丁基、氮杂环丁基、1,3-二氧戊环基、1,4-二氧戊环基、1,3-二氧六环基、氮杂环庚基、哌啶基、哌叮基、吗啉基、硫代吗啉基、1,3-二噻烷基、四氢呋喃基、四氢吡咯基、四氢咪唑基、四氢噻唑基、四氢吡喃基、氮杂二环[3.2.1]辛烷基、氮杂二环[5.2.0]壬烷基、氧杂三环[5.3.1.1]十二烷基、氮杂金刚烷基和氧杂螺[3.3]庚烷基。"Heterocycloalkyl" refers to a substituted or unsubstituted saturated non-aromatic ring group, which can be 3 to 8 membered (for example, 3, 4, 5, 6, 7, 8 membered) monocyclic, 4 to 12 membered (E.g. 4, 5, 6, 7, 8, 9, 10, 11, 12-membered) bicyclic or 10 to 15-membered (e.g. 10, 11, 12, 13, 14, 15-membered) tricyclic ring system, including 1, 2 or 3 heteroatoms selected from N, O or S, preferably 3 to 8 membered heterocyclic group. The selectively substituted N and S in the "heterocycloalkyl" ring can be oxidized to various oxidation states; the "heterocycloalkyl" can be connected to a heteroatom or a carbon atom; the "heterocycloalkyl" can be a bridge Ring or spiro ring. Non-limiting examples of "heterocycloalkyl" include oxirane ethyl, aziridinyl, oxetanyl, azetidinyl, 1,3-dioxolane, 1,4-dioxolane, Oxolane, 1,3-dioxanyl, azepanyl, piperidinyl, piperidinyl, morpholinyl, thiomorpholinyl, 1,3-dithianyl, tetrahydrofuranyl , Tetrahydropyrrolyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydropyranyl, azabicyclo[3.2.1]octyl, azabicyclo[5.2.0]nonyl, oxa Tricyclic[5.3.1.1]dodecyl, azaadamantyl and oxaspiro[3.3]heptyl.
当上文所述的“烷基”、“烷氧基”、“烯基”、“炔基”、“芳基”、“杂芳基”、“碳环基”、“碳环”、“杂环基”、“杂环”、“环烷基”、“杂环烷基”或者“杂环基”被取代时，可以任选进一步被0、1、2、3、4、5、6、7、8、9或者10个选自F、Cl、Br、I、羟基、巯基、硝基、氰基、氨基、C 1-6烷基氨基、＝O、C 1-6烷基、C 1-6烷氧基、C 2-6烯基、C 2-6炔基、-NR q4R q5、＝NR q6、-C(＝O)OC 1-6烷基、-OC(＝O)C 1-6烷基、-C(＝O)NR q4R q5、C 3-12环烷基、C 3杂环烷基C 4-12杂环烷基、C 6-12芳基、C 5-12杂芳基、-C(＝O)OC 6-12芳基、-OC(＝O)C 6- 12芳基、-OC(＝O)C 5-12杂芳基、-C(＝O)OC 5-12杂芳基、-OC(＝O)C 3杂环烷基、-OC(＝O)C 4-12杂环烷基、-C(＝O)OC 3杂环烷基、-C(＝O)OC 4-12杂环烷基、-OC(＝O)C 3-12环烷基、-C(＝O)OC 3-12环烷基、-NHC(＝O)C 3杂环烷基、-NHC(＝O)C 4-12杂环烷基、-NHC(＝O)C 6-12芳基、-NHC(＝O)C 5-12杂芳基、-NHC(＝O)C 3-12环烷基、-NHC(＝O)C 2-6烯基或者-NHC(＝O)C 2-6炔基的取代基所取代，且其中所述的取代基C 1-6烷基、C 1-6烷氧基、C 2-6烯基、C 2-6炔基、C 3-12环烷基、C 3杂环烷基、C 4-12杂环烷基、C 6-12芳基、C 5-12杂芳基、-NHC(＝O)C 6-12芳基、-NHC(＝O)C 5-12杂芳基、-NHC(＝O)C 3杂环烷基、-NHC(＝O)C 4-12杂环烷基或者-NHC(＝O)C 3-12环烷基任选进一步被1至3个选自OH、F、Cl、Br、I、C 1-6烷基、C 1-6烷氧基、-NR q4R q5或者＝O的取代基所取代；R q1选自C 1-6烷基、C 1-6烷氧基或者C 6-12芳基；R q2、R q3选自H或者C 1-6烷基；其中，R q4、R q5选自H、C 1-6烷基、-NH(C＝NR q1)NR q2R q3、-S(＝O) 2NR q2R q3、-C(＝O)R q1或者-C(＝O)NR q2R q3，其中所述的C 1-6烷基任选进一步被1个或者多个选自OH、F、Cl、Br、I、C 1-6烷基、C 1-6烷氧基、C 6-12芳基、C 5-12杂芳基、C 3-12环烷基、C 3杂环烷基或者C 4-12杂环烷基的取代基所取代；或者R q4与R q5及N原子形成一个3至8元杂环，所述的杂环可以包含1个或者多个选自N、O或者S的杂原子。 When the above-mentioned "alkyl", "alkoxy", "alkenyl", "alkynyl", "aryl", "heteroaryl", "carbocyclyl", "carbocyclic", " When "heterocyclyl", "heterocycle", "cycloalkyl", "heterocycloalkyl" or "heterocyclyl" are substituted, they may optionally be further substituted with 0, 1, 2, 3, 4, 5, 6 , 7, 8, 9 or 10 selected from F, Cl, Br, I, hydroxyl, mercapto, nitro, cyano, amino, C 1-6 alkylamino, =0, C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, -NR q4 R q5 , =NR q6 , -C(=O)OC 1-6 alkyl, -OC(=O) C 1-6 alkyl, -C(=O)NR q4 R q5 , C 3-12 cycloalkyl, C 3 heterocycloalkyl, C 4-12 heterocycloalkyl, C 6-12 aryl, C 5 -12 heteroaryl, -C (= O) OC 6-12 aryl group, -OC (= O) C 6- 12 aryl group, -OC (= O) C 5-12 heteroaryl, -C (= O)OC 5-12 heteroaryl, -OC(=O)C 3 heterocycloalkyl, -OC(=O)C 4-12 heterocycloalkyl, -C(=O)OC 3 heterocycloalkyl , -C(=O)OC 4-12 heterocycloalkyl, -OC(=O)C 3-12 cycloalkyl, -C(=O)OC 3-12 cycloalkyl, -NHC(=O) C 3 heterocycloalkyl, -NHC(=O)C 4-12 heterocycloalkyl, -NHC(=O)C 6-12 aryl, -NHC(=O)C 5-12 heteroaryl,- NHC(=O)C 3-12 cycloalkyl, -NHC(=O)C 2-6 alkenyl or -NHC(=O)C 2-6 alkynyl substituents are substituted, and the substituents mentioned therein C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl, C 3 heterocycloalkyl, C 4-12 hetero Cycloalkyl, C 6-12 aryl, C 5-12 heteroaryl, -NHC(=O)C 6-12 aryl, -NHC(=O)C 5-12 heteroaryl, -NHC(= O) C 3 heterocycloalkyl, -NHC(=O)C 4-12 heterocycloalkyl or -NHC(=O)C 3-12 cycloalkyl is optionally further selected from OH, F , Cl, Br, I, C 1-6 alkyl, C 1-6 alkoxy, -NR q4 R q5 or =0 substituent; R q1 is selected from C 1-6 alkyl, C 1- 6 alkoxy or C 6-12 aryl; R q2 and R q3 are selected from H or C 1-6 alkyl; wherein R q4 and R q5 are selected from H, C 1-6 alkyl, -NH(C =NR q1 )NR q2 R q3 , -S(=O) 2 NR q2 R q3 , -C(=O)R q1 or -C(=O)NR q2 R q3 , Wherein, the C 1-6 alkyl group is optionally further substituted by one or more selected from OH, F, Cl, Br, I, C 1-6 alkyl, C 1-6 alkoxy, C 6-12 Substituted by aryl, C 5-12 heteroaryl, C 3-12 cycloalkyl, C 3 heterocycloalkyl or C 4-12 heterocycloalkyl substituent; or R q4 is formed with R q5 and N atom A 3- to 8-membered heterocyclic ring, said heterocyclic ring may contain one or more heteroatoms selected from N, O or S.
“药学上可接受的盐”或者“其药学上可接受的盐”是指本发明化合物保持游离酸或者游离碱的生物有效性和特性，且所述的游离酸通过与无毒的无机碱或者有机碱，所述的游离碱通过与无毒的无机酸或者有机酸反应获得的盐。"Pharmaceutically acceptable salt" or "pharmaceutically acceptable salt thereof" means that the compound of the present invention maintains the biological effectiveness and characteristics of the free acid or free base, and the free acid is combined with a non-toxic inorganic base or An organic base is a salt obtained by reacting the free base with a non-toxic inorganic acid or organic acid.
“药物组合物”是指一种或多种本发明所述化合物、其药学上可接受的盐或前药和其它化学组分形成的混合物，其中，“其它化学组分”是指药学上可接受的载体、赋形剂和/或一种或多种其它治疗剂。"Pharmaceutical composition" refers to a mixture of one or more compounds of the present invention, their pharmaceutically acceptable salts or prodrugs, and other chemical components, where "other chemical components" refer to pharmaceutically acceptable compounds. Accepted carriers, excipients and/or one or more other therapeutic agents.
“载体”是指不会对生物体产生明显刺激且不会消除所给予化合物的生物活性和特性的材料。"Carrier" refers to a material that does not cause significant irritation to the organism and does not eliminate the biological activity and characteristics of the administered compound.
“赋形剂”是指加入到药物组合物中以促进化合物给药的惰性物质。非限制性实施例包括碳酸钙、磷酸钙、糖、淀粉、纤维素衍生物(包括微晶纤维素)、明胶、植物油、聚乙二醇类、稀释剂、成粒剂、润滑剂、粘合剂和崩解剂。"Excipient" refers to an inert substance added to a pharmaceutical composition to facilitate the administration of a compound. Non-limiting examples include calcium carbonate, calcium phosphate, sugar, starch, cellulose derivatives (including microcrystalline cellulose), gelatin, vegetable oils, polyethylene glycols, diluents, granulating agents, lubricants, adhesives Agent and disintegrant.
“前药”是指可经体内代谢转化为具有生物活性的本发明化合物。本发明的前药通过修饰本发明化合物中的氨基或者羧基来制备，该修饰可以通过常规的操作或者在体内被除去，而得到母体化合物。当本发明的前药被施予哺乳动物个体时，前药被割裂形成游离的氨基或者羧基。A "prodrug" refers to a compound of the present invention that can be converted into a biologically active compound by metabolism in the body. The prodrug of the present invention is prepared by modifying the amino or carboxyl group in the compound of the present invention, and this modification can be removed by conventional operations or in vivo to obtain the parent compound. When the prodrug of the present invention is administered to a mammalian individual, the prodrug is split to form free amino or carboxyl groups.
“共晶”是指活性药物成分(API)和共晶形成物(CCF)在氢键或其他非共价键的作用下结合而成的晶体，其中API和CCF的纯态在室温下均为固体，并且各组分间存在固定的化学计量比。共晶是一种多组分晶体，既包含两种中性固体之间形成的二元共晶， 也包含中性固体与盐或溶剂化物形成的多元共晶。"Co-crystal" refers to the crystal formed by the combination of active pharmaceutical ingredient (API) and co-crystal former (CCF) under the action of hydrogen bonds or other non-covalent bonds. The pure state of API and CCF are both at room temperature. Solid, and there is a fixed stoichiometric ratio between the components. A eutectic is a multi-component crystal, which contains both a binary eutectic formed between two neutral solids and a multi-element eutectic formed between a neutral solid and a salt or solvate.
“立体异构体”是指由分子中原子在空间上排列方式不同所产生的异构体，包括顺反异构体、对映异构体和构象异构体。"Stereoisomers" refer to isomers produced by the different arrangements of atoms in a molecule in space, including cis-trans isomers, enantiomers and conformational isomers.
“任选”或“任选地”或“选择性的”或“选择性地”是指随后所述的事件或状况可以但未必发生，该描述包括其中发生该事件或状况的情况及其中未发生的情况。例如，“任选地被烷基取代的杂环基”是指该烷基可以但未必存在，该描述包括其中杂环基被烷基取代的情况，及其中杂环基未被烷基取代的情况。"Optional" or "optionally" or "selective" or "selectively" means that the event or condition described later can but does not necessarily occur, and the description includes the situation in which the event or condition occurs and its failures. What happened. For example, "heterocyclic group optionally substituted by an alkyl group" means that the alkyl group may but does not necessarily exist, and the description includes the case where the heterocyclic group is substituted by an alkyl group and the case where the heterocyclic group is not substituted by an alkyl group. Happening.
具体实施方式Detailed ways
以下实施例详细说明本发明的技术方案，但本发明的保护范围包括但是不限于此。The following embodiments illustrate the technical solutions of the present invention in detail, but the protection scope of the present invention includes but is not limited thereto.
化合物的结构是通过核磁共振(NMR)或(和)质谱(MS)来确定的。NMR位移(δ)以10 -6(ppm)的单位给出。NMR的测定是用(Bruker Avance III 400和Bruker Avance 300)核磁仪，测定溶剂为氘代二甲基亚砜(DMSO-d 6)，氘代氯仿(CDCl 3)，氘代甲醇(CD 3OD)，内标为四甲基硅烷(TMS)； The structure of the compound is determined by nuclear magnetic resonance (NMR) or (and) mass spectrometry (MS). The NMR shift (δ) is given in units of 10 -6 (ppm). NMR is measured with (Bruker Avance III 400 and Bruker Avance 300) nuclear magnetic instrument, the solvent is deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated chloroform (CDCl 3 ), deuterated methanol (CD 3 OD) ), the internal standard is tetramethylsilane (TMS);
MS的测定用(Agilent 6120B(ESI)和Agilent 6120B(APCI))；For MS measurement (Agilent 6120B (ESI) and Agilent 6120B (APCI));
HPLC的测定使用Agilent 1260DAD高压液相色谱仪(Zorbax SB-C18 100×4.6mm,3.5μM)；HPLC determination uses Agilent 1260DAD high pressure liquid chromatograph (Zorbax SB-C18 100×4.6mm, 3.5μM);
薄层层析硅胶板使用烟台黄海HSGF254或青岛GF254硅胶板，薄层色谱法(TLC)使用的硅胶板采用的规格是0.15mm-0.20mm，薄层层析分离纯化产品采用的规格是0.4mm-0.5mm；The thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate. The size of the silica gel plate used for thin layer chromatography (TLC) is 0.15mm-0.20mm, and the size used for thin layer chromatography separation and purification products is 0.4mm. -0.5mm;
柱层析一般使用烟台黄海硅胶200-300目硅胶为载体；Column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh silica gel as the carrier;
本发明的己知起始原料可以采用或按照本领域已知的方法来合成，或可购买于泰坦科技、安耐吉化学、上海德默、成都科龙化工、韶远化学科技、百灵威科技等公司；The known starting materials of the present invention can be synthesized by or according to methods known in the art, or can be purchased from Titan Technology, Anaiji Chemical, Shanghai Demo, Chengdu Kelon Chemical, Shaoyuan Chemical Technology, Bailingwei Technology, etc. the company;
氮气氛是指反应瓶连接约1L容积的氮气气球；Nitrogen atmosphere means that the reaction flask is connected to a nitrogen balloon with a volume of about 1L;
氢气氛是指反应瓶连接约1L容积的氢气气球；The hydrogen atmosphere refers to the reaction flask connected to a hydrogen balloon with a volume of about 1L;
氢化反应通常抽真空，充入氢气，反复操作3次；The hydrogenation reaction is usually evacuated and filled with hydrogen, and the operation is repeated 3 times;
实施例中无特殊说明，反应在氮气氛下进行；There are no special instructions in the examples, and the reaction is carried out under a nitrogen atmosphere;
实施例中无特殊说明，溶液是指水溶液；There is no special description in the examples, and the solution refers to an aqueous solution;
实施例中无特殊说明，反应的温度为室温，室温最适宜的反应温度，为20℃-30℃；No special instructions in the examples, the reaction temperature is room temperature, and the most suitable reaction temperature for room temperature is 20°C-30°C;
DCM：二氯甲烷；DCM: dichloromethane;
EA：乙酸乙酯；EA: ethyl acetate;
HCl：盐酸；HCl: hydrochloric acid;
THF：四氢呋喃；THF: Tetrahydrofuran;
DMF：N,N-二甲基甲酰胺；DMF: N,N-dimethylformamide;
PE:石油醚；PE: petroleum ether;
TLC:薄层色谱；TLC: thin layer chromatography;
SFC：超临界流体色谱法；SFC: Supercritical fluid chromatography;
NCS：N-氯代丁二酰亚胺；NCS: N-chlorosuccinimide;
Pd(dppf)Cl 2：[1,1'-双(二苯基膦)二茂铁]二氯化钯； Pd(dppf)Cl 2 : [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride;
DMSO：二甲基亚砜；DMSO: dimethyl sulfoxide;
DTT：二硫苏糖醇；DTT: Dithiothreitol;
ATP：三磷酸腺苷；ATP: Adenosine triphosphate;
DNA：脱氧核糖核苷酸；DNA: Deoxyribonucleotide;
IC 50：是指DNA-PK激酶的活性受到50％抑制时化合物的浓度。 IC 50: refers to a DNA-PK kinase activity by 50% inhibitory concentration of the compounds.
实施例Example
实施例1Example 1
7-甲基-2-((7-甲基-[1,2,4]***并[1,5-a]吡啶-6-基)氨基)-9-(氧杂环丁-3-基甲基)-7,9-二氢-8H-嘌呤-8-酮(化合物1)7-methyl-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-9-(oxetan-3- Methyl)-7,9-dihydro-8H-purin-8-one (compound 1)
7-methyl-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-9-(oxetan-3-ylmethyl)-7,9-dihydro-8H-purin-8-one7-methyl-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-9-(oxetan-3-ylmethyl)-7,9- dihydro-8H-purin-8-one
Figure PCTCN2020141859-appb-000012
Figure PCTCN2020141859-appb-000012
第一步：first step:
2-氯-4-((氧杂环丁-3-基甲基)氨基)嘧啶-5-羧酸乙酯(1b)Ethyl 2-chloro-4-((oxetan-3-ylmethyl)amino)pyrimidine-5-carboxylate (1b)
ethyl 2-chloro-4-((oxetan-3-ylmethyl)amino)pyrimidine-5-carboxylateethyl 2-chloro-4-((oxetan-3-ylmethyl)amino)pyrimidine-5-carboxylate
将2,4-二氯嘧啶-5-羧酸乙酯1a(5g,22.6mmol)、碳酸钾(6.2g,44.8mmol)溶解于乙腈(20mL)，在0℃下加入3-氨甲基氧杂环丁烷(1.9g，22.6mmol)，在室温搅拌20h。TLC监测至反应完全，加水30mL，用乙酸乙酯60mL萃取三次，饱和盐水洗一次，浓缩有机相，残留物用硅胶柱色谱分离提纯(石油醚:乙酸乙酯(v/v)＝10:1～1:10)，得到标题化合物，2-氯-4-((氧杂环丁-3-基甲基)氨基)嘧啶-5-羧酸乙酯1b(白色固体，3.3g，产率63％)。Dissolve 2,4-dichloropyrimidine-5-carboxylic acid ethyl ester 1a (5g, 22.6mmol), potassium carbonate (6.2g, 44.8mmol) in acetonitrile (20mL), add 3-aminomethyloxy at 0℃ Etidine (1.9 g, 22.6 mmol) was stirred at room temperature for 20 h. TLC monitors until the reaction is complete, add 30 mL of water, extract three times with 60 mL of ethyl acetate, wash with saturated brine once, concentrate the organic phase, and separate and purify the residue by silica gel column chromatography (petroleum ether: ethyl acetate (v/v) = 10:1 ~1:10) to obtain the title compound, ethyl 2-chloro-4-((oxetan-3-ylmethyl)amino)pyrimidine-5-carboxylate 1b (white solid, 3.3g, yield 63 %).
1H NMR(400MHz DMSO)δ8.66(t,1H),8.60(s,1H),4.62(q,2H),4.37-4.27(m,4H),3.75(d,2H),3.26-3.19(m,1H),1.30(t,3H)。 1 H NMR(400MHz DMSO)δ8.66(t,1H), 8.60(s,1H), 4.62(q,2H), 4.37-4.27(m,4H), 3.75(d,2H), 3.26-3.19( m, 1H), 1.30 (t, 3H).
第二步：The second step:
2-氯-4-((氧杂环丁-3-基甲基)氨基)嘧啶-5-羧酸(1c)2-chloro-4-((oxetan-3-ylmethyl)amino)pyrimidine-5-carboxylic acid (1c)
2-chloro-4-((oxetan-3-ylmethyl)amino)pyrimidine-5-carboxylic acid2-chloro-4-((oxetan-3-ylmethyl)amino)pyrimidine-5-carboxylic acid
2-氯-4-((氧杂环丁-3-基甲基)氨基)嘧啶-5-羧酸乙酯1b(3.3g,12.1mmol)溶解于四氢呋喃10mL，水5mL中，加入氢氧化锂(582mg,24.2mmol)，室温搅拌1h。TLC监测至反应完全，旋干四氢呋喃，调pH为4-5，有白色固体析出，过滤，滤饼用石油醚/乙酸乙酯(v/v＝10/1)洗两次，过滤、干燥得到标题化合物，2-氯-4-((氧杂环丁-3-基甲基)氨基)嘧啶-5-羧酸1c(白色固体，2.4g，产率82％)，直接进行下一步实验。Ethyl 2-chloro-4-((oxetan-3-ylmethyl)amino)pyrimidine-5-carboxylate 1b (3.3g, 12.1mmol) was dissolved in 10mL of tetrahydrofuran, 5mL of water, and lithium hydroxide was added (582mg, 24.2mmol), stirred at room temperature for 1h. TLC monitors until the reaction is complete, spin-dry the tetrahydrofuran, adjust the pH to 4-5, a white solid precipitates out, filter, wash the filter cake twice with petroleum ether/ethyl acetate (v/v=10/1), filter and dry to obtain The title compound, 2-chloro-4-((oxetan-3-ylmethyl)amino)pyrimidine-5-carboxylic acid 1c (white solid, 2.4g, yield 82%), proceed directly to the next experiment.
第三步：third step:
2-氯-9-(氧杂环丁-3-基甲基)-7,9-二氢-8H-嘌呤-8-酮(1d)2-chloro-9-(oxetan-3-ylmethyl)-7,9-dihydro-8H-purin-8-one (1d)
2-chloro-9-(oxetan-3-ylmethyl)-7,9-dihydro-8H-purin-8-one2-chloro-9-(oxetan-3-ylmethyl)-7,9-dihydro-8H-purin-8-one
将2-氯-4-((氧杂环丁-3-基甲基)氨基)嘧啶-5-羧酸1c(1.3g,5.3mmol)溶解于二甲基乙酰胺(20mL)，加入三乙胺(585mg,5.8mmol)、叠氮磷酸二苯酯(1.6g,5.8mmol)，室温搅拌1h，随后逐步升温至120℃,搅拌1.5h。TLC监测至反应完全，浓缩反 应液，残留物用硅胶柱色谱分离提纯(石油醚:乙酸乙酯(v/v)＝5:1～1:10)，得到标题化合物，2-氯-9-(氧杂环丁-3-基甲基)-7,9-二氢-8H-嘌呤-8-酮1d(白色固体，780mg，产率35％)。Dissolve 2-chloro-4-((oxetan-3-ylmethyl)amino)pyrimidine-5-carboxylic acid 1c (1.3g, 5.3mmol) in dimethylacetamide (20mL) and add triethyl Amine (585 mg, 5.8 mmol) and diphenyl azide phosphate (1.6 g, 5.8 mmol) were stirred at room temperature for 1 h, then gradually heated to 120° C. and stirred for 1.5 h. The reaction was monitored by TLC until the reaction was complete, the reaction solution was concentrated, and the residue was separated and purified by silica gel column chromatography (petroleum ether: ethyl acetate (v/v) = 5:1 to 1:10) to obtain the title compound, 2-chloro-9- (Oxetan-3-ylmethyl)-7,9-dihydro-8H-purin-8-one 1d (white solid, 780 mg, yield 35%).
1H NMR(400MHz DMSO)δ8.13(s,1H),4.63(q,2H),4.39(t,2H),4.08(d,2H),3.46-3.15(m,3H)。 1 H NMR (400MHz DMSO) δ 8.13 (s, 1H), 4.63 (q, 2H), 4.39 (t, 2H), 4.08 (d, 2H), 3.46 to 3.15 (m, 3H).
第四步：the fourth step:
2-氯-7-甲基-9-(氧杂环丁-3-基甲基)-7,9-二氢-8H-嘌呤-8-酮(1e)2-chloro-7-methyl-9-(oxetan-3-ylmethyl)-7,9-dihydro-8H-purin-8-one (1e)
2-chloro-7-methyl-9-(oxetan-3-ylmethyl)-7,9-dihydro-8H-purin-8-one2-chloro-7-methyl-9-(oxetan-3-ylmethyl)-7,9-dihydro-8H-purin-8-one
将2-氯-9-(氧杂环丁-3-基甲基)-7,9-二氢-8H-嘌呤-8-酮1d(800mg，3.3mmol)溶解于二甲基甲酰胺(10mL)，在0℃下加入硫酸二甲酯(420mg，3.3mmol)和碳酸铯(1.5g,4.8mmol)，0℃搅拌1h。TLC监测至反应完全，随后加10mL水，用乙酸乙酯萃取3次，有机相用无水硫酸钠干燥，浓缩，有固体析出，过滤得到标题化合物,2-氯-7-甲基-9-(氧杂环丁-3-基甲基)-7,9-二氢-8H-嘌呤-8-酮1e(白色固体，423mg，产率63％)。Dissolve 2-chloro-9-(oxetan-3-ylmethyl)-7,9-dihydro-8H-purin-8-one 1d (800mg, 3.3mmol) in dimethylformamide (10mL ), add dimethyl sulfate (420 mg, 3.3 mmol) and cesium carbonate (1.5 g, 4.8 mmol) at 0°C, and stir at 0°C for 1 h. TLC monitored until the reaction was complete, then added 10 mL of water, extracted 3 times with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, concentrated, a solid precipitated out, filtered to obtain the title compound, 2-chloro-7-methyl-9- (Oxetan-3-ylmethyl)-7,9-dihydro-8H-purin-8-one 1e (white solid, 423 mg, yield 63%).
1H NMR(400MHz DMSO)δ8.33(s,1H),4.62(t,2H),4.40(t,2H),4.12(d,2H),3.36(s,3H),2.25(d,1H)。 1 H NMR(400MHz DMSO)δ8.33(s,1H), 4.62(t,2H), 4.40(t,2H), 4.12(d,2H), 3.36(s,3H), 2.25(d,1H) .
第五步：the fifth step:
7-甲基-2-((7-甲基-[1,2,4]***并[1,5-a]吡啶-6-基)氨基)-9-(氧杂环丁-3-基甲基)-7,9-二氢-8H-嘌呤-8-酮(化合物1)7-methyl-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-9-(oxetan-3- Methyl)-7,9-dihydro-8H-purin-8-one (compound 1)
7-methyl-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-9-(oxetan-3-ylmethyl)-7,9-dihydro-8H-purin-8-one7-methyl-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-9-(oxetan-3-ylmethyl)-7,9- dihydro-8H-purin-8-one
将2-氯-9-(3-氨甲基氧杂环丁烷)-7-甲基-7,9-二氢-8H-嘌呤-8-酮1e(423mg，1.6mmol)、7-甲基-[1,2,4]***并[1,5-a]吡啶-6-基胺(132mg，0.3mmol)、碳酸铯(1g,1.2mmol)、三(二亚苄基丙酮)二钯(146mg，0.16mmol),2,2'-双(二苯基膦基)-1,1'-联萘(200mg，0.32mmol)溶解于二氧六环，氮气保护并换气，在100℃搅拌4h。TLC监测至反应完全，浓缩反应液，残留物用硅胶柱色谱分离提纯(二氯甲烷:甲醇(v/v)＝30/1)，得到标题化合物，7-甲基-2-((7-甲基-[1,2,4]***并[1,5-a]吡啶-6-基)氨基)-9-(氧杂环丁-3-基甲基)-7,9-二氢-8H-嘌呤-8-酮化合物1(白色固体，12.6mg，产率3.2％)。The 2-chloro-9-(3-aminomethyloxetane)-7-methyl-7,9-dihydro-8H-purin-8-one 1e (423mg, 1.6mmol), 7-methyl -[1,2,4]triazolo[1,5-a]pyridin-6-ylamine (132mg, 0.3mmol), cesium carbonate (1g, 1.2mmol), three (dibenzylidene acetone) two Palladium (146mg, 0.16mmol), 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (200mg, 0.32mmol) was dissolved in dioxane, protected with nitrogen and ventilated, at 100 Stir at ℃ for 4h. TLC monitored until the reaction was complete, the reaction solution was concentrated, and the residue was separated and purified by silica gel column chromatography (dichloromethane:methanol (v/v)=30/1) to obtain the title compound, 7-methyl-2-((7- Methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-9-(oxetan-3-ylmethyl)-7,9-dihydro -8H-purine-8-one compound 1 (white solid, 12.6 mg, yield 3.2%).
1H NMR(400MHz DMSO)δ9.13(s,1H),8.70(s,1H),8.38(s,1H),8.08(s,1H),7.71(s,1H),4.62(q,2H),4.41(t,2H),4.05(d,2H),3.35-3.30(m,4H),2.38(s,3H)。 1 H NMR(400MHz DMSO)δ9.13(s,1H), 8.70(s,1H), 8.38(s,1H), 8.08(s,1H), 7.71(s,1H), 4.62(q,2H) , 4.41 (t, 2H), 4.05 (d, 2H), 3.35-3.30 (m, 4H), 2.38 (s, 3H).
LC-MS m/z(ESI)＝367.10[M+1]。LC-MS m/z(ESI)=367.10[M+1].
实施例2Example 2
7-甲基-2-((7-甲基-[1,2,4]***并[1,5-a]吡啶-6-基)氨基)-9-((3-甲基氧杂环丁-3-基)甲基)-7,9-二氢-8H-嘌呤-8-酮(化合物2)7-methyl-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-9-((3-methyloxa Cyclobut-3-yl)methyl)-7,9-dihydro-8H-purin-8-one (compound 2)
7-methyl-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-9-((3-methyloxetan-3-yl)methyl)-7,9-dihydro-8H-purin-8-one7-methyl-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-9-((3-methyloxetan-3-yl)methyl) -7,9-dihydro-8H-purin-8-one
Figure PCTCN2020141859-appb-000013
Figure PCTCN2020141859-appb-000013
Figure PCTCN2020141859-appb-000014
Figure PCTCN2020141859-appb-000014
第一步：first step:
2-氯-4-((3-甲基-氧杂-3-基甲基)-氨基)-嘧啶-5-羧酸乙酯(2a)2-Chloro-4-((3-Methyl-oxa-3-ylmethyl)-amino)-pyrimidine-5-carboxylic acid ethyl ester (2a)
ethyl 2-chloro-4-[(3-methyl-oxetan-3-ylmethyl)-amino]-pyrimidine-5-carboxylicethyl 2-chloro-4-[(3-methyl-oxetan-3-ylmethyl)-amino]-pyrimidine-5-carboxylic
将2,4-二氯嘧啶-5-羧酸乙酯1a(5.0g,22.62mmol)、(碳-3-甲基氧杂环丁-3-基)甲胺(2.29g,22.62mmol)溶解于乙腈(600mL)，搅拌,分多次加入碳酸钾(4.69g,33.93mmol)，在室温搅拌4h。TLC监测至反应完毕后过滤，滤渣用乙酸乙酯(300mL)清洗，将滤液浓缩得粗品，粗品通过柱分离提纯(正己烷:乙酸乙酯(v/v)＝5:1)，得到标题化合物,2-氯-4-((3-甲基-氧杂-3-基甲基)-氨基)-嘧啶-5-羧酸乙酯2a(白色固体，3.8g，产率77.4％)。Dissolve 2,4-dichloropyrimidine-5-carboxylic acid ethyl ester 1a (5.0g, 22.62mmol), (carbon-3-methyloxetan-3-yl) methylamine (2.29g, 22.62mmol) Stir in acetonitrile (600 mL), add potassium carbonate (4.69 g, 33.93 mmol) in multiple portions, and stir at room temperature for 4 h. After the reaction was monitored by TLC, it was filtered. The residue was washed with ethyl acetate (300 mL). The filtrate was concentrated to obtain a crude product. The crude product was separated and purified by column (n-hexane: ethyl acetate (v/v) = 5:1) to obtain the title compound , 2-Chloro-4-((3-methyl-oxa-3-ylmethyl)-amino)-pyrimidine-5-carboxylic acid ethyl ester 2a (white solid, 3.8 g, yield 77.4%).
1H NMR(400MHz DMSO)δ8.68(d,1H),8.63(s,1H),4.44(d,2H),4.33-4.29(m,2H),4.23(d,2H),3.69(d,2H),1.31(t,3H),1.26(s,3H)。 1 H NMR(400MHz DMSO)δ8.68(d,1H), 8.63(s,1H), 4.44(d,2H), 4.33-4.29(m,2H), 4.23(d,2H), 3.69(d, 2H), 1.31 (t, 3H), 1.26 (s, 3H).
第二步：The second step:
2-氯-4-(((3-甲基-氧杂-3-基甲基)-氨基)-嘧啶-5-羧酸(2b)2-Chloro-4-(((3-Methyl-oxa-3-ylmethyl)-amino)-pyrimidine-5-carboxylic acid (2b)
2-chloro-4-(((3-methyloxetan-3-yl)methyl)amino)pyrimidine-5-carboxylic acid2-chloro-4-(((3-methyloxetan-3-yl)methyl)amino)pyrimidine-5-carboxylic acid
将2-氯-4-((3-甲基-氧杂-3-基甲基)-氨基)-嘧啶-5-羧酸乙酯2a(3.8g，13.30mmol)溶解于四氢呋喃(20mL)，水(20mL)中，加入氢氧化锂(636.9mg,20.60mmol)，室温搅拌1h。TLC监测至反应完全，浓缩除去四氢呋喃，用6N盐酸调pH为5，有白色固体析出，过滤，滤饼用石油醚洗两次，收集固体得到标题化合物，2-氯-4-[((3-甲基-氧杂-3-基甲基)-氨基]-嘧啶-5-羧酸2b(白色固体，3.0g,产率87.54％)，直接进行下一步实验。2-Chloro-4-((3-methyl-oxa-3-ylmethyl)-amino)-pyrimidine-5-carboxylic acid ethyl ester 2a (3.8g, 13.30mmol) was dissolved in tetrahydrofuran (20mL), Lithium hydroxide (636.9 mg, 20.60 mmol) was added to water (20 mL), and the mixture was stirred at room temperature for 1 h. TLC monitored until the reaction was complete, concentrated to remove tetrahydrofuran, adjusted the pH to 5 with 6N hydrochloric acid, a white solid precipitated out, filtered, the filter cake was washed twice with petroleum ether, the solid was collected to obtain the title compound, 2-chloro-4-[((3 -Methyl-oxa-3-ylmethyl)-amino]-pyrimidine-5-carboxylic acid 2b (white solid, 3.0g, yield 87.54%), proceed directly to the next experiment.
1H NMR(400MHz DMSO)δ8.87(t,1H),8.59(s,1H),4.43(d,2H),4.23(d,2H),3.68(d,2H),1.26(s,3H)。 1 H NMR (400MHz DMSO) δ 8.87 (t, 1H), 8.59 (s, 1H), 4.43 (d, 2H), 4.23 (d, 2H), 3.68 (d, 2H), 1.26 (s, 3H) .
第三步：third step:
2-氯-9-(3-甲基-氧杂环丁-3-基甲基)-7,9-二氢嘌呤-8-酮(2c)2-chloro-9-(3-methyl-oxetan-3-ylmethyl)-7,9-dihydropurin-8-one (2c)
2-chloro-9-(3-methyl-oxetan-3-ylmethyl)-7,9-dihydro-purin-8-one2-chloro-9-(3-methyl-oxetan-3-ylmethyl)-7,9-dihydro-purin-8-one
将2-氯-4-((3-甲基-氧杂-3-基甲基)-氨基)-嘧啶-5-羧酸2b(3.0g，58.21mmol)溶解于二甲基乙酰胺(40mL)，加入三乙胺(1.18g,11.64mmol)、叠氮磷酸二苯酯(3.2g,11.64mmol)，随后逐步升温至120℃搅拌1h。TLC监测至反应完全，将反应液倒入冰水中，过滤收集固体，用水洗3次，真空浓缩干燥得标题化合物，2-氯-9-(3-甲基-氧杂环丁-3-基甲基)-7,9-二氢嘌呤-8-酮2c(白色固体，2.0g，产率67.45％)。Dissolve 2-chloro-4-((3-methyl-oxa-3-ylmethyl)-amino)-pyrimidine-5-carboxylic acid 2b (3.0g, 58.21mmol) in dimethylacetamide (40mL ), add triethylamine (1.18g, 11.64mmol) and diphenyl azide phosphate (3.2g, 11.64mmol), and then gradually increase the temperature to 120°C and stir for 1h. TLC monitors until the reaction is complete, the reaction solution is poured into ice water, the solid is collected by filtration, washed with water 3 times, concentrated and dried in vacuo to obtain the title compound, 2-chloro-9-(3-methyl-oxetan-3-yl Methyl)-7,9-dihydropurin-8-one 2c (white solid, 2.0 g, yield 67.45%).
1H NMR(400MHz DMSO)δ11.70(s,1H),8.15(s,1H),4.62(d,2H),4.22(d,2H),3.99(s,2H),1.23(s,3H)。 1 H NMR (400MHz DMSO) δ 11.70 (s, 1H), 8.15 (s, 1H), 4.62 (d, 2H), 4.22 (d, 2H), 3.99 (s, 2H), 1.23 (s, 3H) .
第四步：the fourth step:
2-氯-7-甲基-9-((3-甲基氧杂环丁-3-基)甲基)-7,9-二氢-8H-嘌呤-8-酮(2d)2-chloro-7-methyl-9-((3-methyloxetan-3-yl)methyl)-7,9-dihydro-8H-purin-8-one (2d)
2-chloro-7-methyl-9-((3-methyloxetan-3-yl)methyl)-7,9-dihydro-8H-purin-8-one2-chloro-7-methyl-9-((3-methyloxetan-3-yl)methyl)-7,9-dihydro-8H-purin-8-one
将2-氯-9-(3-甲基-氧杂环丁-3-基甲基)-7,9-二氢嘌呤-8-酮2c(1g，3.93mmol)溶解于二甲基甲酰胺(20mL)，在0℃下加入硫酸二甲酯(495mg，3.93mmol)和碳酸铯(1.92g,5.89mmol)，0℃搅拌1h。TLC监测至反应结束，将反应液倒入冰水中，有固体析出，过滤、收集固体得到标题化合物，2-氯-7-甲基-9-((3-甲基氧杂环丁-3-基)甲基)-7,9-二氢-8H-嘌呤-8-酮2d(白色固体，0.6g，产率56.87％)。Dissolve 2-chloro-9-(3-methyl-oxetan-3-ylmethyl)-7,9-dihydropurin-8-one 2c (1g, 3.93mmol) in dimethylformamide (20 mL), add dimethyl sulfate (495 mg, 3.93 mmol) and cesium carbonate (1.92 g, 5.89 mmol) at 0°C, and stir at 0°C for 1 h. The reaction was monitored by TLC until the reaction was over. The reaction solution was poured into ice water. A solid precipitated out. The solid was filtered and collected to obtain the title compound, 2-chloro-7-methyl-9-((3-methyloxetan-3- (Yl)methyl)-7,9-dihydro-8H-purin-8-one 2d (white solid, 0.6g, yield 56.87%).
1H NMR(400MHz DMSO)δ8.40(d,1H),4.65(d,2H),4.25(d,2H),4.06(s,2H),3.41(s,3H),1.27(s,3H)。 1 H NMR (400MHz DMSO) δ 8.40 (d, 1H), 4.65 (d, 2H), 4.25 (d, 2H), 4.06 (s, 2H), 3.41 (s, 3H), 1.27 (s, 3H) .
第五步：the fifth step:
7-甲基-2-((7-甲基-[1,2,4]***并[1,5-a]吡啶-6-基)氨基)-9-((3-甲基氧杂环丁-3-基)甲基)-7,9-二氢-8H-嘌呤-8-酮(化合物2)7-methyl-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-9-((3-methyloxa Cyclobut-3-yl)methyl)-7,9-dihydro-8H-purin-8-one (compound 2)
7-methyl-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-9-((3-methyloxetan-3-yl)methyl)-7,9-dihydro-8H-purin-8-one7-methyl-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-9-((3-methyloxetan-3-yl)methyl) -7,9-dihydro-8H-purin-8-one
将2-氯-7-甲基-9-(((3-甲基氧杂环丁-3-基)甲基)-7,9-二氢-8H-嘌呤-8-酮2d(0.6g，2.23mmol)、7-甲基-[1,2,4]***并[1,5-a]吡啶-6-基胺(297mg，2.01mmol)、碳酸铯(1.45g,4.46mmol)、三(二亚苄基丙酮)二钯(204mg，0.2mmol)和2,2'-双(二苯基膦基)-1,1'-联萘(277mg，0.4mmol)溶解于二氧六环，氮气保护并换气，在100℃搅拌1h。TLC监测至反应结束，将反应液倒入冰水中，收集固体，将固体用硅胶柱色谱分离提纯(二氯甲烷:甲醇(v/v)＝30/1)，得到标题化合物，7-甲基-2-((7-甲基-[1,2,4]***并[1,5-a]吡啶-6-基)氨基)-9-((3-甲基氧杂环丁-3-基)甲基)-7,9-二氢-8H-嘌呤-8-酮化合物2(白色固体，0.15g，产率17.66％)。The 2-chloro-7-methyl-9-(((3-methyloxetan-3-yl)methyl)-7,9-dihydro-8H-purin-8-one 2d (0.6g , 2.23mmol), 7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-ylamine (297mg, 2.01mmol), cesium carbonate (1.45g, 4.46mmol), Tris(dibenzylideneacetone)dipalladium (204mg, 0.2mmol) and 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (277mg, 0.4mmol) are dissolved in dioxane , Nitrogen protection and ventilation, stirring at 100 ℃ for 1 h. TLC monitoring until the end of the reaction, the reaction solution was poured into ice water, the solid was collected, and the solid was separated and purified by silica gel column chromatography (dichloromethane: methanol (v/v) = 30/1) to obtain the title compound, 7-methyl-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-9 -((3-Methyloxetan-3-yl)methyl)-7,9-dihydro-8H-purin-8-one compound 2 (white solid, 0.15g, yield 17.66%).
1H NMR(400MHz DMSO)δ9.08(s,1H),8.66(s,1H),8.37(s,1H),8.11(s,1H),7.70(s,1H),4.61(d,2H),4.17(d,2H),3.93(s,2H),3.35(s,2H),2.36(s,3H),1.22(s,3H)。 1 H NMR(400MHz DMSO)δ9.08(s,1H),8.66(s,1H),8.37(s,1H),8.11(s,1H),7.70(s,1H), 4.61(d,2H) , 4.17(d, 2H), 3.93(s, 2H), 3.35(s, 2H), 2.36(s, 3H), 1.22(s, 3H).
LC-MS m/z(ESI)＝381.10[M+1]。LC-MS m/z(ESI)=381.10[M+1].
实施例3Example 3
7-甲基-2-((7-甲基-[1,2,4]***并[1,5-a]吡啶-6-基)氨基)-9-((四氢呋喃-2-基)甲基)-7,9-二氢-8H-嘌呤-8-酮(化合物3)7-methyl-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-9-((tetrahydrofuran-2-yl) Methyl)-7,9-dihydro-8H-purin-8-one (compound 3)
7-methyl-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-9-((tetrahydrofuran-2-yl)methyl)-7,9-dihydro-8H-purin-8-one7-methyl-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-9-((tetrahydrofuran-2-yl)methyl)-7 ,9-dihydro-8H-purin-8-one
Figure PCTCN2020141859-appb-000015
Figure PCTCN2020141859-appb-000015
第一步：first step:
2-氯-4-(((四氢呋喃-2-基)甲基)氨基)嘧啶-5-羧酸乙酯(3a)Ethyl 2-chloro-4-(((tetrahydrofuran-2-yl)methyl)amino)pyrimidine-5-carboxylate (3a)
ethyl 2-chloro-4-(((tetrahydrofuran-2-yl)methyl)amino)pyrimidine-5-carboxylateethyl 2-chloro-4-(((tetrahydrofuran-2-yl)methyl)amino)pyrimidine-5-carboxylate
将2,4-二氯嘧啶-5-羧酸乙酯1a(5g,22.6mmol)、碳酸钾(6.2g,44.8mmol)溶解于乙腈(20mL)，在0℃下加入碳-(四氢呋喃-2-基)甲胺(2.3g，22.6mmol)，在室温搅拌20h。TLC监测至反应结束，加水30mL，用乙酸乙酯60mL萃取三次，有机层用饱和食盐水洗一次，用无水硫酸钠干燥，浓缩后残留物用硅胶柱色谱分离提纯，(石油醚/乙酸乙酯(v/v)＝10:1)，得到标题化合物，2-氯-4-(((四氢呋喃-2-基)甲基)氨基)嘧啶-5-羧酸乙酯3a(白色固体，4.7g，产率87％)。Dissolve 2,4-dichloropyrimidine-5-carboxylic acid ethyl ester 1a (5g, 22.6mmol), potassium carbonate (6.2g, 44.8mmol) in acetonitrile (20mL), add carbon-(tetrahydrofuran-2) at 0℃ -Yl)methylamine (2.3g, 22.6mmol), stirred at room temperature for 20h. TLC monitors until the reaction is complete, add 30 mL of water, extract three times with 60 mL of ethyl acetate, wash the organic layer with saturated brine once, and dry over anhydrous sodium sulfate. After concentration, the residue is separated and purified by silica gel column chromatography, (petroleum ether/ethyl acetate) (v/v)=10:1) to obtain the title compound, 2-chloro-4-(((tetrahydrofuran-2-yl)methyl)amino)pyrimidine-5-carboxylic acid ethyl ester 3a (white solid, 4.7g , The yield is 87%).
1H NMR(400MHz DMSO)δ8.62(s,1H),8.57(s,1H),4.33-4.28(m,2H),4.04-4.01(m,1H),3.82-3.77(m,1H),3.68-3.58(m,1H),3.47-3.42(m,1H),1.96-1.81(m,2H),1.59-1.54(m,1H),1.32-1.29(m,3H)。 1 H NMR(400MHz DMSO)δ8.62(s,1H),8.57(s,1H),4.33-4.28(m,2H),4.04-4.01(m,1H),3.82-3.77(m,1H), 3.68-3.58 (m, 1H), 3.47-3.42 (m, 1H), 1.96-1.81 (m, 2H), 1.59-1.54 (m, 1H), 1.32-1.29 (m, 3H).
LC-MS m/z(ESI)＝286.20[M+1]。LC-MS m/z(ESI)=286.20[M+1].
第二步：The second step:
2-氯-4-(((四氢呋喃-2-基)甲基)氨基)嘧啶-5-羧酸(3b)2-chloro-4-(((tetrahydrofuran-2-yl)methyl)amino)pyrimidine-5-carboxylic acid (3b)
2-chloro-4-(((tetrahydrofuran-2-yl)methyl)amino)pyrimidine-5-carboxylic acid2-chloro-4-(((tetrahydrofuran-2-yl)methyl)amino)pyrimidine-5-carboxylic acid
将2-氯-4-(((四氢呋喃-2-基)甲基)氨基)嘧啶-5-羧酸乙酯3a(4.7g,16.4mmol)溶解于四氢呋喃10mL，水5mL中，加入氢氧化锂(788mg,32.8mmol)，室温搅拌1h。TLC监测至反应结束，四氢呋喃旋干，调pH为4-5，有白色固体析出，过滤，滤饼用石油醚/乙酸乙酯(v/v＝10/1)洗两次，浓缩得到标题化合物，2-氯-4-(((四氢呋喃-2-基)甲基)氨基)嘧啶-5-羧酸3b(白色固体，3.8g,产率83％)。Dissolve 2-chloro-4-(((tetrahydrofuran-2-yl)methyl)amino)pyrimidine-5-carboxylic acid ethyl ester 3a (4.7g, 16.4mmol) in 10mL of tetrahydrofuran, 5mL of water, and add lithium hydroxide (788mg, 32.8mmol), stirred at room temperature for 1h. TLC monitors to the end of the reaction. The tetrahydrofuran is spin-dried and the pH is adjusted to 4-5. A white solid precipitates out. It is filtered. The filter cake is washed twice with petroleum ether/ethyl acetate (v/v=10/1) and concentrated to obtain the title compound. , 2-Chloro-4-(((tetrahydrofuran-2-yl)methyl)amino)pyrimidine-5-carboxylic acid 3b (white solid, 3.8 g, yield 83%).
1H NMR(400MHz DMSO)δ13.75(s,1H),8.74(t,1H),8.58(s,1H),4.40-4.01(m,1H),3.82-3.76(m,1H),3.69-3.58(m,2H),3.46-3.40(m,1H),1.95-1.90(m,1H),1.86-1.81(m,1H),1.58-1.53(m,1H)。 1 H NMR (400MHz DMSO) δ 13.75 (s, 1H), 8.74 (t, 1H), 8.58 (s, 1H), 4.40-4.01 (m, 1H), 3.82-3.76 (m, 1H), 3.69- 3.58 (m, 2H), 3.46-3.40 (m, 1H), 1.95-1.90 (m, 1H), 1.86-1.81 (m, 1H), 1.58-1.53 (m, 1H).
LC-MS m/z(ESI)＝259.20[M+1]。LC-MS m/z(ESI)=259.20[M+1].
第三步：third step:
2-氯-9-((四氢呋喃-2-基)甲基)-7,9-二氢-8H-嘌呤-8-酮(3c)2-chloro-9-((tetrahydrofuran-2-yl)methyl)-7,9-dihydro-8H-purin-8-one (3c)
2-chloro-9-((tetrahydrofuran-2-yl)methyl)-7,9-dihydro-8H-purin-8-one2-chloro-9-((tetrahydrofuran-2-yl)methyl)-7,9-dihydro-8H-purin-8-one
将2-氯-4-(((四氢呋喃-2-基)甲基)氨基)嘧啶-5-羧酸3b(3.8g，14.7mmol)溶解于二甲基乙酰胺(20mL)，加入三乙胺(1.8g，17.6mmol)、叠氮磷酸二苯酯(4.4g，16.2mmol)，随后逐步升温至120℃，搅拌1.5h。浓缩反应液，残留物用硅胶柱色谱分离提纯，(石油醚/乙酸乙酯(v/v)＝5:1～1:10)，得到标题化合物，2-氯-9-((四氢呋喃-2-基)甲基)-7,9-二氢-8H-嘌呤-8-酮3c(白色固体，1.3g，产率46％)。Dissolve 2-chloro-4-(((tetrahydrofuran-2-yl)methyl)amino)pyrimidine-5-carboxylic acid 3b (3.8g, 14.7mmol) in dimethylacetamide (20mL) and add triethylamine (1.8g, 17.6mmol), diphenyl azide phosphate (4.4g, 16.2mmol), then gradually increase the temperature to 120°C and stir for 1.5h. The reaction solution was concentrated, and the residue was separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v)=5:1～1:10) to obtain the title compound, 2-chloro-9-((tetrahydrofuran-2 -Yl)methyl)-7,9-dihydro-8H-purin-8-one 3c (white solid, 1.3 g, yield 46%).
LC-MS m/z(ESI)＝255.20[M+1]。LC-MS m/z(ESI)=255.20[M+1].
第四步：the fourth step:
2-氯-7-甲基-9-((四氢呋喃-2-基)甲基)-7,9-二氢-8H-嘌呤-8-酮(3d)2-chloro-7-methyl-9-((tetrahydrofuran-2-yl)methyl)-7,9-dihydro-8H-purin-8-one (3d)
2-chloro-7-methyl-9-((tetrahydrofuran-2-yl)methyl)-7,9-dihydro-8H-purin-8-one2-chloro-7-methyl-9-((tetrahydrofuran-2-yl)methyl)-7,9-dihydro-8H-purin-8-one
将2-氯-9-((四氢呋喃-2-基)甲基)-7,9-二氢-8H-嘌呤-8-酮3c(1.3g，5.1mmol)溶解于二甲基甲酰胺(10mL)，在0℃下加入硫酸二甲酯(644mg，5.1mmol)和碳酸铯(2.5g,7.6mmol)，0℃搅拌1h。TLC监测至反应结束，随后加入10mL水，有固体析出，过滤得到标题化合物，2-氯-7-甲基-9-((四氢呋喃-2-基)甲基)-7,9-二氢-8H-嘌呤-8-酮3d(白色固体，600mg，产率45％)。Dissolve 2-chloro-9-((tetrahydrofuran-2-yl)methyl)-7,9-dihydro-8H-purin-8-one 3c (1.3g, 5.1mmol) in dimethylformamide (10mL ), add dimethyl sulfate (644 mg, 5.1 mmol) and cesium carbonate (2.5 g, 7.6 mmol) at 0°C, and stir at 0°C for 1 h. TLC monitored to the end of the reaction, and then added 10mL of water, a solid precipitated out, filtered to obtain the title compound, 2-chloro-7-methyl-9-((tetrahydrofuran-2-yl)methyl)-7,9-dihydro- 8H-purin-8-one 3d (white solid, 600 mg, yield 45%).
1H NMR(400MHz DMSO)δ8.35(s,1H),4.24-4.20(m,1H),3.90-3.85(m,1H),3.79-3.73(m,2H),3.60(q,1H),3.37(s,3H),1.95-1.77(m,3H),1.70-1.63(m,1H)。 1 H NMR (400MHz DMSO) δ 8.35 (s, 1H), 4.24-4.20 (m, 1H), 3.90-3.85 (m, 1H), 3.79-3.73 (m, 2H), 3.60 (q, 1H), 3.37 (s, 3H), 1.95-1.77 (m, 3H), 1.70-1.63 (m, 1H).
LC-MS m/z(ESI)＝268.20[M+1]。LC-MS m/z(ESI)=268.20[M+1].
第五步：the fifth step:
7-甲基-2-((7-甲基-[1,2,4]***并[1,5-a]吡啶-6-基)氨基)-9-((四氢呋喃-2-基)甲基)-7,9- 二氢-8H-嘌呤-8-酮(化合物3)7-methyl-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-9-((tetrahydrofuran-2-yl) Methyl)-7,9-dihydro-8H-purin-8-one (compound 3)
7-methyl-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-9-((tetrahydrofuran-2-yl)methyl)-7,9-dihydro-8H-purin-8-one7-methyl-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-9-((tetrahydrofuran-2-yl)methyl)-7 ,9-dihydro-8H-purin-8-one
将2-氯-7-甲基-9-((四氢呋喃-2-基)甲基)-7,9-二氢-8H-嘌呤-8-酮3d(200mg，0.7mmol)、7-甲基-[1,2,4]***并[1,5-a]吡啶-6-基胺(105mg，0.7mmol)、碳酸铯(456mg,1.4mmol)、甲磺酸(2-二环己基膦-3,6-二甲氧基-2’,4’,6'-三异丙基-1,1'-联苯)(2'-氨基-1,1'-联苯基-2-基)钯(II)(63.4mg，0.07mmol)溶解于二氧六环(3mL)，氮气保护并换气，在100℃搅拌4h。TLC监测至反应结束，浓缩反应液，残留物用硅胶柱色谱分离提纯(二氯甲烷/甲醇(v/v)＝30/1)，得到标题化合物，7-甲基-2-((7-甲基-[1,2,4]***并[1,5-a]吡啶-6-基)氨基)-9-((四氢呋喃-2-基)甲基)-7,9-二氢-8H-嘌呤-8-酮化合物3(白色固体，30mg，产率31％)。The 2-chloro-7-methyl-9-((tetrahydrofuran-2-yl)methyl)-7,9-dihydro-8H-purin-8-one 3d (200mg, 0.7mmol), 7-methyl -[1,2,4]triazolo[1,5-a]pyridin-6-ylamine (105mg, 0.7mmol), cesium carbonate (456mg, 1.4mmol), methanesulfonic acid (2-dicyclohexylphosphine) -3,6-Dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl ) Palladium(II) (63.4mg, 0.07mmol) was dissolved in dioxane (3mL), protected with nitrogen and ventilated, and stirred at 100°C for 4h. The reaction was monitored by TLC until the end of the reaction. The reaction solution was concentrated. The residue was separated and purified by silica gel column chromatography (dichloromethane/methanol (v/v)=30/1) to obtain the title compound, 7-methyl-2-((7- Methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-9-((tetrahydrofuran-2-yl)methyl)-7,9-dihydro- 8H-purine-8-one compound 3 (white solid, 30 mg, yield 31%).
1H NMR(400MHz DMSO)δ9.15(s,1H),8.67(s,1H),8.36(s,1H),8.09(s,1H),7.69(s,1H),4.27-4.22(m,3H),3.84-3.67(m,3H),3.62-3.57(m,1H),2.38(s,3H),1.94-1.77(m,3H),1.69-1.62(m,1H)。 1 H NMR (400MHz DMSO) δ 9.15 (s, 1H), 8.67 (s, 1H), 8.36 (s, 1H), 8.09 (s, 1H), 7.69 (s, 1H), 4.27-4.22 (m, 3H), 3.84-3.67 (m, 3H), 3.62-3.57 (m, 1H), 2.38 (s, 3H), 1.94-1.77 (m, 3H), 1.69-1.62 (m, 1H).
LC-MS m/z(ESI)＝381.20[M+1]。LC-MS m/z(ESI)=381.20[M+1].
实施例4Example 4
7-甲基-2-((7-甲基-[1,2,4]***并[1,5-a]吡啶-6-基)氨基)-9-((四氢呋喃-3-基)甲基)-7,9-二氢-8H-嘌呤-8-酮(化合物4)7-methyl-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-9-((tetrahydrofuran-3-yl) Methyl)-7,9-dihydro-8H-purin-8-one (Compound 4)
7-methyl-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-9-((tetrahydrofuran-3-yl)methyl)-7,9-dihydro-8H-purin-8-one7-methyl-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-9-((tetrahydrofuran-3-yl)methyl)-7 ,9-dihydro-8H-purin-8-one
Figure PCTCN2020141859-appb-000016
Figure PCTCN2020141859-appb-000016
第一步：first step:
2-氯-4-(((四氢呋喃-3-基)甲基)氨基)嘧啶-5-羧酸乙酯(4a)Ethyl 2-chloro-4-(((tetrahydrofuran-3-yl)methyl)amino)pyrimidine-5-carboxylate (4a)
ethyl 2-chloro-4-(((tetrahydrofuran-3-yl)methyl)amino)pyrimidine-5-carboxylateethyl 2-chloro-4-(((tetrahydrofuran-3-yl)methyl)amino)pyrimidine-5-carboxylate
将2,4-二氯嘧啶-5-羧酸乙酯1a(5g,22.6mmol)、碳酸钾(6.2g,44.8mmol)溶解于乙腈(20mL)，在0℃下加入(四氢呋喃-3-基)甲胺(2.3g,22.6mmol)，在室温搅拌20h。TLC监测至反应结束，加水30mL，用乙酸乙酯60mL萃取三次，有机层用饱和食盐水洗一次，用无水硫酸钠干燥，浓缩后残留物用硅胶柱色谱分离提纯，(石油醚/乙酸乙酯(v/v)＝10:1)，得到标题化合物，2-氯-4-(((四氢呋喃-3-基)甲基)氨基)嘧啶-5-羧酸乙酯4a(白色固体，4.4g,产率85％)。Dissolve 2,4-dichloropyrimidine-5-carboxylic acid ethyl ester 1a (5g, 22.6mmol), potassium carbonate (6.2g, 44.8mmol) in acetonitrile (20mL), add (tetrahydrofuran-3-yl ) Methylamine (2.3g, 22.6mmol), stirred at room temperature for 20h. TLC monitors until the reaction is complete, add 30 mL of water, extract three times with 60 mL of ethyl acetate, wash the organic layer with saturated brine once, and dry over anhydrous sodium sulfate. After concentration, the residue is separated and purified by silica gel column chromatography, (petroleum ether/ethyl acetate) (v/v)=10:1) to obtain the title compound, 2-chloro-4-(((tetrahydrofuran-3-yl)methyl)amino)pyrimidine-5-carboxylic acid ethyl ester 4a (white solid, 4.4g , The yield is 85%).
1H NMR(400MHz DMSO)δ8.61-8.58(m,2H),4.31(q,2H),3.78-3.73(m,1H),3.69-3.58(m,2H),3.48-3.44(m,3H),2.57-2.53(m,1H),1.98-1.91(m,1H),1.62-1.58(m,1H),1.31(t,3H)。 1 H NMR (400MHz DMSO) δ8.61-8.58 (m, 2H), 4.31 (q, 2H), 3.78-3.73 (m, 1H), 3.69-3.58 (m, 2H), 3.48-3.44 (m, 3H) ), 2.57-2.53 (m, 1H), 1.98-1.91 (m, 1H), 1.62-1.58 (m, 1H), 1.31 (t, 3H).
LC-MS m/z(ESI)＝286.20[M+1]。LC-MS m/z(ESI)=286.20[M+1].
第二步：The second step:
2-氯-4-(((四氢呋喃-3-基)甲基)氨基)嘧啶-5-羧酸(4b)2-chloro-4-(((tetrahydrofuran-3-yl)methyl)amino)pyrimidine-5-carboxylic acid (4b)
2-chloro-4-(((tetrahydrofuran-3-yl)methyl)amino)pyrimidine-5-carboxylic acid2-chloro-4-(((tetrahydrofuran-3-yl)methyl)amino)pyrimidine-5-carboxylic acid
将2-氯-4-(((四氢呋喃-3-基)甲基)氨基)嘧啶-5-羧酸乙酯4a(4.4g,15.3mmol)溶解于四氢呋喃10mL，水5mL中，加入氢氧化锂(736mg,30.6mmol)，室温搅拌1h。TLC监测至反应结束，四氢呋喃旋干，调pH为4-5，有白色固体析出，过滤，滤饼用石油醚/乙酸乙酯(v/v＝10/1)洗两次，浓缩得到标题化合物，2-氯-4-(((四氢呋喃-3-基)甲基)氨基)嘧啶-5-羧酸4b(白色固体，3.4g,产率80％)。Dissolve 2-chloro-4-(((tetrahydrofuran-3-yl)methyl)amino)pyrimidine-5-carboxylic acid ethyl ester 4a (4.4g, 15.3mmol) in 10mL of tetrahydrofuran, 5mL of water, and add lithium hydroxide (736mg, 30.6mmol), stirred at room temperature for 1h. TLC monitors to the end of the reaction. The tetrahydrofuran is spin-dried and the pH is adjusted to 4-5. A white solid precipitates out. It is filtered. The filter cake is washed twice with petroleum ether/ethyl acetate (v/v=10/1) and concentrated to obtain the title compound. , 2-Chloro-4-(((tetrahydrofuran-3-yl)methyl)amino)pyrimidine-5-carboxylic acid 4b (white solid, 3.4 g, yield 80%).
1H NMR(400MHz DMSO)δ13.75(s,1H),8.75(s,1H),8.57(s,1H),3.78-3.73(m,3H),3.47-3.43(m,3H),2.58-2.52(m,1H),1.98-1.89(m,3H),1.63-1.55(m,1H)。 1 H NMR (400MHz DMSO) δ 13.75 (s, 1H), 8.75 (s, 1H), 8.57 (s, 1H), 3.78-3.73 (m, 3H), 3.47-3.43 (m, 3H), 2.58- 2.52 (m, 1H), 1.98-1.89 (m, 3H), 1.63-1.55 (m, 1H).
LC-MS m/z(ESI)＝259.20[M+1]。LC-MS m/z(ESI)=259.20[M+1].
第三步：third step:
2-氯-9-((四氢呋喃-3-基)甲基)-7,9-二氢-8H-嘌呤-8-酮(4c)2-chloro-9-((tetrahydrofuran-3-yl)methyl)-7,9-dihydro-8H-purin-8-one (4c)
2-chloro-9-((tetrahydrofuran-3-yl)methyl)-7,9-dihydro-8H-purin-8-one2-chloro-9-((tetrahydrofuran-3-yl)methyl)-7,9-dihydro-8H-purin-8-one
将2-氯-4-((四氢呋喃-3-基)甲基)氨基)嘧啶-5-羧酸4b(3.4g，13.0mmol)溶解于二甲基乙酰胺(20mL)，加入三乙胺(1.58g,13mmol)、叠氮磷酸二苯酯(3.6g,13mmol)，随后逐步升温至120℃，搅拌1.5h。TLC监测至反应结束，浓缩反应液，残留物用硅胶柱色谱分离提纯，(石油醚/乙酸乙酯(v/v)＝5:1～1:10)，得到标题化合物，2-氯-9-((四氢呋喃-3-基)甲基)-7,9-二氢-8H-嘌呤-8-酮4c(白色固体，1.46g，产率50％)。2-Chloro-4-((tetrahydrofuran-3-yl)methyl)amino)pyrimidine-5-carboxylic acid 4b (3.4g, 13.0mmol) was dissolved in dimethylacetamide (20mL), and triethylamine ( 1.58g, 13mmol), diphenyl azide phosphate (3.6g, 13mmol), then gradually increase the temperature to 120°C and stir for 1.5h. The reaction was monitored by TLC until the end of the reaction. The reaction solution was concentrated. The residue was separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v)=5:1～1:10) to obtain the title compound, 2-chloro-9 -((Tetrahydrofuran-3-yl)methyl)-7,9-dihydro-8H-purin-8-one 4c (white solid, 1.46 g, yield 50%).
1H NMR(400MHz DMSO)δ11.65(s,1H),8.14(s,1H),3.80-3.74(m,3H),3.66-3.57(m,2H),3.52-3.49(m,1H),2.73-2.69(m,1H),1.98-1.89(m,1H),1.67-1.60(m,1H)。 1 H NMR (400MHz DMSO) δ 11.65 (s, 1H), 8.14 (s, 1H), 3.80-3.74 (m, 3H), 3.66-3.57 (m, 2H), 3.52-3.49 (m, 1H), 2.73-2.69 (m, 1H), 1.98-1.89 (m, 1H), 1.67-1.60 (m, 1H).
LC-MS m/z(ESI)＝255.20[M+1]。LC-MS m/z(ESI)=255.20[M+1].
第四步：the fourth step:
2-氯-7-甲基-9-((四氢呋喃-3-基)甲基)-7,9-二氢-8H-嘌呤-8-酮(4d)2-chloro-7-methyl-9-((tetrahydrofuran-3-yl)methyl)-7,9-dihydro-8H-purin-8-one (4d)
2-chloro-7-methyl-9-((tetrahydrofuran-3-yl)methyl)-7,9-dihydro-8H-purin-8-one2-chloro-7-methyl-9-((tetrahydrofuran-3-yl)methyl)-7,9-dihydro-8H-purin-8-one
将2-氯-9-((四氢呋喃-3-基)甲基)-7,9-二氢-8H-嘌呤-8-酮4c(1.6g，5.2mmol)溶解于二甲基甲酰胺(10mL)，在0℃下加入硫酸二甲酯(663mg，5.2mmol)和碳酸铯(2.4g,7.7mmol)，0℃搅拌1h。TLC监测至反应结束，随后加入10mL水，有固体析出，过滤得到标题化合物，2-氯-7-甲基-9-((四氢呋喃-3-基)甲基)-7,9-二氢-8H-嘌呤-8-酮4d(白色固体，1.2g，产率80％)。Dissolve 2-chloro-9-((tetrahydrofuran-3-yl)methyl)-7,9-dihydro-8H-purin-8-one 4c (1.6g, 5.2mmol) in dimethylformamide (10mL ), add dimethyl sulfate (663 mg, 5.2 mmol) and cesium carbonate (2.4 g, 7.7 mmol) at 0°C, and stir at 0°C for 1 h. TLC monitored to the end of the reaction, and then added 10mL of water, a solid precipitated out, filtered to obtain the title compound, 2-chloro-7-methyl-9-((tetrahydrofuran-3-yl)methyl)-7,9-dihydro- 8H-purin-8-one 4d (white solid, 1.2 g, yield 80%).
1H NMR(400MHz DMSO)δ8.35(s,1H),3.81-3.75(m,3H),3.65-3.57(m,2H),3.52-3.49(m,1H),3.37(s,3H),2.73-2.70(m,1H),1.96-1.91(m,1H),1.67-1.61(m,1H)。 1 H NMR (400MHz DMSO) δ 8.35 (s, 1H), 3.81-3.75 (m, 3H), 3.65-3.57 (m, 2H), 3.52-3.49 (m, 1H), 3.37 (s, 3H), 2.73-2.70 (m, 1H), 1.96-1.91 (m, 1H), 1.67-1.61 (m, 1H).
LC-MS m/z(ESI)＝268.20[M+1]。LC-MS m/z(ESI)=268.20[M+1].
第五步：the fifth step:
7-甲基-2-((7-甲基-[1,2,4]***并[1,5-a]吡啶-6-基)氨基)-9-((四氢呋喃-3-基)甲基)-7,9-二氢-8H-嘌呤-8-酮(化合物4)7-methyl-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-9-((tetrahydrofuran-3-yl) Methyl)-7,9-dihydro-8H-purin-8-one (Compound 4)
7-methyl-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-9-((tetrahydrofuran-3-yl)methyl)-7,9-dihydro-8H-purin-8-one7-methyl-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-9-((tetrahydrofuran-3-yl)methyl)-7 ,9-dihydro-8H-purin-8-one
将2-氯-9-((四氢呋喃-3-基)甲基)-7,9-二氢-8H-嘌呤-8-酮4d(200mg，0.7mmol)、7-甲基-[1,2,4]***并[1,5-a]吡啶-6-基胺(105mg，0.7mmol)、碳酸铯(456mg，1.4mmol)、甲磺酸(2-二环己基膦-3,6-二甲氧基-2’,4’,6'-三异丙基-1,1'-联苯)(2'-氨基-1,1'-联苯基-2-基)钯(II)(CAS：1470372-59-8)(63.4mg，0.07mmol)溶解于二氧六环(3mL)，氮气保护并换气，在100℃搅拌4h。TLC监测至反应结束，浓缩反应液，残留物用硅胶柱色 谱分离提纯(二氯甲烷/甲醇(v/v)＝30/1)，得到标题化合物7-甲基-2-((7-甲基-[1,2,4]***并[1,5-a]吡啶-6-基)氨基)-9-((四氢呋喃-3-基)甲基)-7,9-二氢-8H-嘌呤-8-酮化合物4(白色固体，30mg，产率31％)。The 2-chloro-9-((tetrahydrofuran-3-yl)methyl)-7,9-dihydro-8H-purin-8-one 4d (200mg, 0.7mmol), 7-methyl-[1,2 ,4]Triazolo[1,5-a]pyridine-6-ylamine (105mg, 0.7mmol), cesium carbonate (456mg, 1.4mmol), methanesulfonic acid (2-dicyclohexylphosphine-3,6- Dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (CAS:1470372-59-8) (63.4mg, 0.07mmol) was dissolved in dioxane (3mL), protected with nitrogen and ventilated, and stirred at 100°C for 4h. The reaction was monitored by TLC until the end of the reaction, the reaction solution was concentrated, and the residue was separated and purified by silica gel column chromatography (dichloromethane/methanol (v/v)=30/1) to obtain the title compound 7-methyl-2-((7-form -[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-9-((tetrahydrofuran-3-yl)methyl)-7,9-dihydro-8H -Purine-8-one compound 4 (white solid, 30 mg, yield 31%).
1H NMR(400MHz DMSO)δ9.14(s,1H),8.69(s,1H),8.37(s,1H),8.09(s,1H),7.70(s,1H),3.78-3.72(m,3H),3.66-3.57(m,2H),3.53-3.50(m,1H),3.32(s,3H),2.79-2.72(m,1H),2.38(s,3H),1.96-1.87(m,1H),1.69-1.60(m,1H)。 1 H NMR (400MHz DMSO) δ 9.14 (s, 1H), 8.69 (s, 1H), 8.37 (s, 1H), 8.09 (s, 1H), 7.70 (s, 1H), 3.78-3.72 (m, 3H), 3.66-3.57 (m, 2H), 3.53-3.50 (m, 1H), 3.32 (s, 3H), 2.79-2.72 (m, 1H), 2.38 (s, 3H), 1.96-1.87 (m, 1H), 1.69-1.60 (m, 1H).
LC-MS m/z(ESI)＝381.20[M+1]。LC-MS m/z(ESI)=381.20[M+1].
实施例5Example 5
7-甲基-2-((7-甲基-[1,2,4]***并[1,5-a]吡啶-6-基)氨基)-9-((四氢-2H-吡喃-4-基)甲基)-7,9-二氢-8H-嘌呤-8-酮(化合物5)7-methyl-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-9-((tetrahydro-2H-pyridine (Pyran-4-yl)methyl)-7,9-dihydro-8H-purin-8-one (compound 5)
7-methyl-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-9-((tetrahydro-2H-pyran-4-yl)methyl)-7,9-dihydro-8H-purin-8-one7-methyl-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-9-((tetrahydro-2H-pyran-4-yl) methyl)-7,9-dihydro-8H-purin-8-one
Figure PCTCN2020141859-appb-000017
Figure PCTCN2020141859-appb-000017
第一步：first step:
2-氯-4-(((四氢-2H-吡喃-4-基)甲基)氨基)氨基]嘧啶-5-羧酸乙酯(5a)2-chloro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)amino)pyrimidine-5-carboxylic acid ethyl ester (5a)
ethyl 2-chloro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)pyrimidine-5-carboxylateethyl 2-chloro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)pyrimidine-5-carboxylate
将2,4-二氯嘧啶-5-羧酸乙酯1a(5g,22.6mmol)、碳酸钾(6.2g,44.8mmol)溶解于乙腈(20mL)，在0℃下加入碳-(四氢吡喃-4-基)-甲胺(2.6g,22.6mmol)，在室温搅拌20h。TLC监测至反应结束，加水30mL，用乙酸乙酯60mL萃取三次，有机层用饱和食盐水洗一次，用无水硫酸钠干燥，浓缩后残留物用硅胶柱色谱分离提纯，(石油醚/乙酸乙酯(v/v)＝10:1)，得到标题化合物，2-氯-4-(((四氢-2H-吡喃-4-基)甲基)氨基)氨基]嘧啶-5-羧酸乙酯5a(白色固体，3.6g,产率70％)。Dissolve 2,4-dichloropyrimidine-5-carboxylic acid ethyl ester 1a (5g, 22.6mmol), potassium carbonate (6.2g, 44.8mmol) in acetonitrile (20mL), add carbon-(tetrahydropyridine) at 0℃ Pyran-4-yl)-methylamine (2.6g, 22.6mmol), stirred at room temperature for 20h. TLC monitors until the reaction is complete, add 30 mL of water, extract three times with 60 mL of ethyl acetate, wash the organic layer with saturated brine once, and dry over anhydrous sodium sulfate. After concentration, the residue is separated and purified by silica gel column chromatography, (petroleum ether/ethyl acetate) (v/v)=10:1) to obtain the title compound, 2-chloro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)amino)pyrimidine-5-carboxylic acid ethyl Ester 5a (white solid, 3.6 g, yield 70%).
1H NMR(400MHz DMSO)δ8.60(s,1H),8.54(t,1H),4.31(q,2H),3.84(dd,2H),3.38(t,2H),3.29-3.23(m,2H),1.87-1.82(m,1H),1.55(dd,2H),1.30(t,3H),1.25-1.17(m,2H)。 1 H NMR(400MHz DMSO)δ8.60(s,1H),8.54(t,1H),4.31(q,2H), 3.84(dd,2H), 3.38(t,2H), 3.29-3.23(m, 2H), 1.87-1.82 (m, 1H), 1.55 (dd, 2H), 1.30 (t, 3H), 1.25-1.17 (m, 2H).
LC-MS m/z(ESI)＝301.20[M+1]。LC-MS m/z(ESI)=301.20[M+1].
第二步：The second step:
2-氯-4-(((四氢-2H-吡喃-4-基)甲基)氨基)嘧啶-5-羧酸(5b)2-chloro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)pyrimidine-5-carboxylic acid (5b)
2-chloro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)pyrimidine-5-carboxylic acid将2-氯-4-(((四氢-2H-吡喃-4-基)甲基)氨基)氨基]嘧啶-5-羧酸乙酯5a(4.6g,15.3mmol)溶解于四氢呋喃10mL，水5mL中，加入氢氧化锂(736mg,30.6mmol)，室温搅拌1 h。TLC监测至反应结束，四氢呋喃旋干，调PH为4-5，有白色固体析出，过滤，滤饼用石油醚/乙酸乙酯(v/v＝10/1)洗两次，浓缩得到标题化合物，2-氯-4-(((四氢-2H-吡喃-4-基)甲基)氨基)嘧啶-5-羧酸5b(白色固体，4.0g，产率83％)。2-chloro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)pyrimidine-5-carboxylic acid )Methyl)amino)amino)pyrimidine-5-carboxylic acid ethyl ester 5a (4.6g, 15.3mmol) was dissolved in 10mL of tetrahydrofuran and 5mL of water. Lithium hydroxide (736mg, 30.6mmol) was added and stirred at room temperature for 1 h. TLC monitors to the end of the reaction. The tetrahydrofuran is spin-dried and the pH is adjusted to 4-5. A white solid precipitates out. It is filtered. The filter cake is washed twice with petroleum ether/ethyl acetate (v/v=10/1) and concentrated to obtain the title compound. , 2-Chloro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)pyrimidine-5-carboxylic acid 5b (white solid, 4.0 g, yield 83%).
1H NMR(400MHz DMSO)δ13.72(s,1H),8.71(s,1H),8.56(s,1H),3.84(dd,2H),3.37(t,2H),3.29-3.23(m,2H),1.87-1.80(m,1H),1.54(dd,2H),1.26-1.17(m,2H)。 1 H NMR (400MHz DMSO) δ 13.72 (s, 1H), 8.71 (s, 1H), 8.56 (s, 1H), 3.84 (dd, 2H), 3.37 (t, 2H), 3.29-3.23 (m, 2H), 1.87-1.80 (m, 1H), 1.54 (dd, 2H), 1.26-1.17 (m, 2H).
LC-MS m/z(ESI)＝273.20[M+1]。LC-MS m/z(ESI)=273.20[M+1].
第三步：third step:
2-氯-9-((四氢-2H-吡喃-4-基)甲基)-7,9-二氢-8H-嘌呤-8-酮(5c)2-chloro-9-((tetrahydro-2H-pyran-4-yl)methyl)-7,9-dihydro-8H-purin-8-one (5c)
2-chloro-9-((tetrahydro-2H-pyran-4-yl)methyl)-7,9-dihydro-8H-purin-8-one2-chloro-9-((tetrahydro-2H-pyran-4-yl)methyl)-7,9-dihydro-8H-purin-8-one
将2-氯-4-(((四氢-2H-吡喃-4-基)甲基)氨基)嘧啶-5-羧酸5b(4g，14.6mmol)溶解于二甲基乙酰胺(20mL)，加入三乙胺(2.9g,29mmol)、叠氮磷酸二苯酯(5.2g,19mmol)，随后逐步升温至120℃，搅拌1.5h。TLC监测至反应结束，浓缩反应液，残留物用硅胶柱色谱分离提纯，(石油醚/乙酸乙酯(v/v)＝5:1～1:10)，得到标题化合物，2-氯-9-((四氢-2H-吡喃-4-基)甲基)-7,9-二氢-8H-嘌呤-8-酮5c(白色固体，1.46g，产率50％)。Dissolve 2-chloro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)pyrimidine-5-carboxylic acid 5b (4g, 14.6mmol) in dimethylacetamide (20mL) , Add triethylamine (2.9g, 29mmol) and diphenyl azide phosphate (5.2g, 19mmol), then gradually increase the temperature to 120°C and stir for 1.5h. The reaction was monitored by TLC until the end of the reaction. The reaction solution was concentrated. The residue was separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v)=5:1～1:10) to obtain the title compound, 2-chloro-9 -((Tetrahydro-2H-pyran-4-yl)methyl)-7,9-dihydro-8H-purin-8-one 5c (white solid, 1.46 g, yield 50%).
1H NMR(400MHz DMSO)δ11.63(s,1H),8.13(s,1H),3.81(dd,2H),3.66(d,2H),3.25-3.15(m,2H),2.07-2.00(m,1H),1.50(dd,2H),1.29-1.21(m,2H)。 1 H NMR (400MHz DMSO) δ 11.63 (s, 1H), 8.13 (s, 1H), 3.81 (dd, 2H), 3.66 (d, 2H), 3.25-3.15 (m, 2H), 2.07-2.00 ( m, 1H), 1.50 (dd, 2H), 1.29-1.21 (m, 2H).
LC-MS m/z(ESI)＝269.20[M+1]。LC-MS m/z(ESI)=269.20[M+1].
第四步：the fourth step:
2-氯-7-甲基-9-((四氢-2H-吡喃-4-基)甲基)-7,9-二氢-8H-嘌呤-8-酮(5d)2-chloro-7-methyl-9-((tetrahydro-2H-pyran-4-yl)methyl)-7,9-dihydro-8H-purin-8-one (5d)
2-chloro-7-methyl-9-((tetrahydro-2H-pyran-4-yl)methyl)-7,9-dihydro-8H-purin-8-one2-chloro-7-methyl-9-((tetrahydro-2H-pyran-4-yl)methyl)-7,9-dihydro-8H-purin-8-one
将2-氯-9-((四氢-2H-吡喃-4-基)甲基)-7,9-二氢-8H-嘌呤-8-酮5c(1.4g，5.4mmol)溶解于二甲基甲酰胺(10mL)，在0℃下加入硫酸二甲酯(688mg，5.4mmol)和碳酸铯(2.6g,8.0mmol)，0℃搅拌1h。TLC监测至反应结束，随后加入10mL水，有固体析出，过滤得到标题化合物，2-氯-7-甲基-9-((四氢-2H-吡喃-4-基)甲基)-7,9-二氢-8H-嘌呤-8-酮5d(白色固体，1.2g，产率80％)。The 2-chloro-9-((tetrahydro-2H-pyran-4-yl)methyl)-7,9-dihydro-8H-purin-8-one 5c (1.4g, 5.4mmol) was dissolved in two Methylformamide (10 mL), dimethyl sulfate (688 mg, 5.4 mmol) and cesium carbonate (2.6 g, 8.0 mmol) were added at 0°C, and stirred at 0°C for 1 h. TLC monitored to the end of the reaction, and then added 10 mL of water, a solid precipitated out, filtered to obtain the title compound, 2-chloro-7-methyl-9-((tetrahydro-2H-pyran-4-yl)methyl)-7 , 9-Dihydro-8H-purin-8-one 5d (white solid, 1.2g, yield 80%).
1H NMR(400MHz DMSO)δ8.34(s,1H),3.81(dd,2H),3.70(d,2H),3.36(s,3H),3.25-3.19(m,2H),2.07-2.00(m,1H),1.51(dd,2H),1.29-1.19(m,2H)。 1 H NMR(400MHz DMSO)δ8.34(s,1H), 3.81(dd,2H), 3.70(d,2H), 3.36(s,3H), 3.25-3.19(m,2H), 2.07-2.00( m, 1H), 1.51 (dd, 2H), 1.29-1.19 (m, 2H).
LC-MS m/z(ESI)＝283.20[M+1]。LC-MS m/z(ESI)=283.20[M+1].
第五步：the fifth step:
7-甲基-2-((7-甲基-[1,2,4]***并[1,5-a]吡啶-6-基)氨基)-9-((四氢-2H-吡喃-4-基)甲基)-7,9-二氢-8H-嘌呤-8-酮(化合物5)7-methyl-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-9-((tetrahydro-2H-pyridine (Pyran-4-yl)methyl)-7,9-dihydro-8H-purin-8-one (compound 5)
7-methyl-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-9-((tetrahydro-2H-7-methyl-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-9-((tetrahydro-2H-
pyran-4-yl)methyl)-7,9-dihydro-8H-purin-8-onepyran-4-yl)methyl)-7,9-dihydro-8H-purin-8-one
将2-氯-7-甲基-9-((四氢-2H-吡喃-4-基)甲基)-7,9-二氢-8H-嘌呤-8-酮5d(200mg，0.7mmol)、7-甲基-[1,2,4]***并[1,5-a]吡啶-6-基胺(105mg，0.7mmol)、碳酸铯(456mg,1.4mmol)、甲磺酸(2-二环己基膦-3,6-二甲氧基-2’,4’,6'-三异丙基-1,1'-联苯)(2'-氨基-1,1'-联苯基-2-基)钯(II)(63.4mg，0.07mmol)溶解于二氧六环(3mL)，氮气保护并换气，在100℃搅拌4h。TLC监测至反应结束，浓缩反应液，残留物用硅胶柱色谱分离提纯(二氯甲烷/甲醇(v/v)＝30/1)，得到标题化合物，7-甲基-2-((7-甲基-[1,2,4]***并[1,5-a]吡啶-6-基)氨基)-9-((四氢-2H-吡喃-4-基)甲基)-7,9-二氢-8H-嘌呤-8-酮化合物5(白色固体，12.6mg，产率3.2％)。The 2-chloro-7-methyl-9-((tetrahydro-2H-pyran-4-yl)methyl)-7,9-dihydro-8H-purin-8-one 5d (200mg, 0.7mmol ), 7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-ylamine (105mg, 0.7mmol), cesium carbonate (456mg, 1.4mmol), methanesulfonic acid ( 2-Dicyclohexylphosphine-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl) Phenyl-2-yl)palladium (II) (63.4 mg, 0.07 mmol) was dissolved in dioxane (3 mL), protected with nitrogen and ventilated, and stirred at 100° C. for 4 h. The reaction was monitored by TLC until the end of the reaction. The reaction solution was concentrated. The residue was separated and purified by silica gel column chromatography (dichloromethane/methanol (v/v)=30/1) to obtain the title compound, 7-methyl-2-((7- Methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-9-((tetrahydro-2H-pyran-4-yl)methyl)-7 , 9-Dihydro-8H-purin-8-one compound 5 (white solid, 12.6 mg, yield 3.2%).
1H NMR(400MHz DMSO)δ9.23(s,1H),9.21(s,1H),8.51(s,1H),8.12(s,1H),7.79(s,1H),3.84-3.81(m,2H),3.65(d,2H),3.32(s,3H),3.26-3.20(m,2H),2.40(s,3H),2.10-2.04(m,1H),1.50(d,2H),1.28-1.17(m,2H)。 1 H NMR(400MHz DMSO)δ9.23(s,1H), 9.21(s,1H), 8.51(s,1H), 8.12(s,1H), 7.79(s,1H), 3.84-3.81(m, 2H), 3.65(d, 2H), 3.32(s, 3H), 3.26-3.20(m, 2H), 2.40(s, 3H), 2.10-2.04(m, 1H), 1.50(d, 2H), 1.28 -1.17 (m, 2H).
LC-MS m/z(ESI)＝395.20[M+1]。LC-MS m/z(ESI)=395.20[M+1].
实施例6Example 6
9-(3-羟基环戊基)-7-甲基-2-((7-甲基-[1,2,4]***并[1,5-a]吡啶-6-基)氨基)-7,9-二氢-8H-嘌呤-8-酮(化合物6)9-(3-hydroxycyclopentyl)-7-methyl-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino) -7,9-dihydro-8H-purin-8-one (compound 6)
9-(3-hydroxycyclopentyl)-7-methyl-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-7,9-dihydro-8H-purin-8-one9-(3-hydroxycyclopentyl)-7-methyl-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-7,9-dihydro- 8H-purin-8-one
Figure PCTCN2020141859-appb-000018
Figure PCTCN2020141859-appb-000018
第一步：first step:
(3-羟基环戊基)氨基甲酸叔丁酯(6b)(3-Hydroxycyclopentyl) tert-butyl carbamate (6b)
tert-butyl(3-oxocyclopentyl)carbamatetert-butyl(3-oxocyclopentyl)carbamate
将(3-氧代环戊基)氨基甲酸叔丁酯6a(10g，50.19mmol)溶解于60mL THF中，冰浴下缓慢加入硼氢化钠(2.85g，75.28mmol)。3h后，TLC监测到反应结束。缓慢加入饱和NaCl溶液至没有气泡出现，加入EA进行萃取，收集有机相，旋蒸除去有机溶剂，得到标题化合物，(3-羟基环戊基)氨基甲酸叔丁酯6b(黄色油状液体，10.10g，产率99％)。Dissolve tert-butyl (3-oxocyclopentyl) carbamate 6a (10 g, 50.19 mmol) in 60 mL of THF, and slowly add sodium borohydride (2.85 g, 75.28 mmol) in an ice bath. After 3h, TLC monitored the end of the reaction. Slowly add saturated NaCl solution until no bubbles appear, add EA for extraction, collect the organic phase, and rotate to remove the organic solvent to obtain the title compound, tert-butyl (3-hydroxycyclopentyl) carbamate 6b (yellow oily liquid, 10.10g) , Yield 99%).
LC-MS m/z(ESI)＝202.20[M+1]。LC-MS m/z(ESI)=202.20[M+1].
第二步：The second step:
3-氨基环戊烷-1-醇盐酸盐(6c)3-Aminocyclopentane-1-ol hydrochloride (6c)
3-aminocyclopentan-1-ol hydrochloride3-aminocyclopentan-1-ol hydrochloride
将(3-羟基环戊基)氨基甲酸叔丁酯6b(10.10g，50.18mmol)加入于20mL 1,4-二氧六环溶液中，常温搅拌至完全溶解，将反应液置于冰浴下，缓慢加入4M的盐酸-1,4二氧六环溶液(8.75g，239.87mmol)，继续搅拌，出现少量固体，2h后，TLC监测反应结束，过滤并浓缩得到标题化合物，3-氨基环戊烷-1-醇盐酸盐6c(黑色油状液体，6.91g，产率100％)。Add tert-butyl (3-hydroxycyclopentyl) carbamate 6b (10.10g, 50.18mmol) to 20mL 1,4-dioxane solution, stir at room temperature until completely dissolved, and place the reaction solution in an ice bath , Slowly add 4M hydrochloric acid-1,4 dioxane solution (8.75g, 239.87mmol), continue to stir, a small amount of solid appears, after 2h, TLC monitors the completion of the reaction, filtered and concentrated to obtain the title compound, 3-aminocyclopentan Alkan-1-ol hydrochloride 6c (black oily liquid, 6.91 g, yield 100%).
LC-MS m/z(ESI)＝138.10[M+1]。LC-MS m/z(ESI)=138.10[M+1].
第三步：third step:
2-氯-4-((3-羟基环戊基)氨基)嘧啶-5-羧酸乙酯(6d)Ethyl 2-chloro-4-((3-hydroxycyclopentyl)amino)pyrimidine-5-carboxylate (6d)
ethyl 2-chloro-4-((3-hydroxycyclopentyl)amino)pyrimidine-5-carboxylateethyl 2-chloro-4-((3-hydroxycyclopentyl)amino)pyrimidine-5-carboxylate
将3-氨基环戊烷-1-醇盐酸盐6c(6.91g，50.22mmol)和2,4-二氯嘧啶-5-羧酸乙酯(13.32g，60.26mmol)加入75mL ACN中，常温搅拌至2,4-二氯嘧啶-5-羧酸乙酯溶解后，冰浴下，缓慢加入碳酸钾(17.35g，125.54mmol)。常温搅拌10h后，反应完全，过滤反应液，收集有机相，用EA(3*100mL)萃取，收集并浓缩有机相，残留物用硅胶柱色谱分离提纯(石油醚/乙酸乙酯(v/v)＝1/1)。得到标题化合物，2-氯-4-((3-羟基环戊基)氨基)嘧啶-5-羧酸乙酯6d(黄色油状液体，7.78g，产率54.2％)。Add 3-aminocyclopentane-1-ol hydrochloride 6c (6.91g, 50.22mmol) and 2,4-dichloropyrimidine-5-carboxylic acid ethyl ester (13.32g, 60.26mmol) into 75mL ACN at room temperature After stirring until the ethyl 2,4-dichloropyrimidine-5-carboxylate was dissolved, potassium carbonate (17.35 g, 125.54 mmol) was slowly added in an ice bath. After stirring at room temperature for 10 hours, the reaction was complete, the reaction solution was filtered, the organic phase was collected, extracted with EA (3*100mL), the organic phase was collected and concentrated, and the residue was separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) )=1/1). The title compound, ethyl 2-chloro-4-((3-hydroxycyclopentyl)amino)pyrimidine-5-carboxylate 6d (yellow oily liquid, 7.78 g, yield 54.2%) was obtained.
LC-MS m/z(ESI)＝286.10[M+1]。LC-MS m/z(ESI)=286.10[M+1].
第四步：the fourth step:
2-氯-4-((3-羟基环戊基)氨基)嘧啶-5-羧酸(6e)2-chloro-4-((3-hydroxycyclopentyl)amino)pyrimidine-5-carboxylic acid (6e)
2-chloro-4-((3-hydroxycyclopentyl)amino)pyrimidine-5-carboxylic acid2-chloro-4-((3-hydroxycyclopentyl)amino)pyrimidine-5-carboxylic acid
将2-氯-4-((3-羟基环戊基)氨基)嘧啶-5-羧酸乙酯6d(7.78g，27.23mmol)溶于50mL THF中，将氢氧化锂(1.3g，54.46mmol)溶于50mL水中，冰浴下，将氢氧化锂水溶液缓慢加入THF溶液中，出现浑浊，2h后，TLC监测反应结束，THF旋干，加入盐酸溶液调节pH至4，过滤收集固体，滤液加入EA(3*50mL)萃取。将有机相于滤渣混合浓缩，得到标题化合物，2-氯-4-((3-羟基环戊基)氨基)嘧啶-5-羧酸6e(淡黄色固体，6.78g，产率96％)。Dissolve 2-chloro-4-((3-hydroxycyclopentyl)amino)pyrimidine-5-carboxylic acid ethyl ester 6d (7.78g, 27.23mmol) in 50mL THF, and mix lithium hydroxide (1.3g, 54.46mmol) ) Dissolve in 50 mL of water, slowly add lithium hydroxide aqueous solution to the THF solution under an ice bath, and it will appear turbid. After 2 hours, the reaction is monitored by TLC, the THF is spin-dried, hydrochloric acid solution is added to adjust the pH to 4, the solid is filtered and the filtrate is added EA (3*50mL) extraction. The organic phase was mixed and concentrated with the filter residue to obtain the title compound, 2-chloro-4-((3-hydroxycyclopentyl)amino)pyrimidine-5-carboxylic acid 6e (light yellow solid, 6.78 g, yield 96%).
LC-MS m/z(ESI)＝258.10[M+1]。LC-MS m/z(ESI)=258.10[M+1].
第五步：the fifth step:
2-氯-9-(3-羟基环戊基)-7,9-二氢-8H-嘌呤-8-酮(6f)2-chloro-9-(3-hydroxycyclopentyl)-7,9-dihydro-8H-purin-8-one (6f)
2-chloro-9-(3-hydroxycyclopentyl)-7,9-dihydro-8H-purin-8-one2-chloro-9-(3-hydroxycyclopentyl)-7,9-dihydro-8H-purin-8-one
冰浴下，将2-氯-4-((3-羟基环戊基)氨基)嘧啶-5-羧酸6e(6.0g，23.29mmol)溶解于60mL DMAc中，缓慢加入叠氮磷酸二苯酯(6.41g，23.29mmol),然后缓慢加入三乙胺(2.36g，23.29mmol)。常温搅拌1h后，90℃油浴加热5h，TLC监测反应结束，将反应液滴入200mL水中，析出固体，加入EA(3*100mL)萃取，收集有机相，用饱和氯化铵溶液洗涤，无水硫酸钠干燥，浓缩后得到标题化合物，2-氯-9-(3-羟基环戊基)-7,9-二氢-8H-嘌呤-8-酮6f(黄色油状液体，5.47g，产率92％)，。Under ice bath, dissolve 2-chloro-4-((3-hydroxycyclopentyl)amino)pyrimidine-5-carboxylic acid 6e (6.0g, 23.29mmol) in 60mL DMAc, and slowly add diphenyl azide phosphate (6.41g, 23.29mmol), then triethylamine (2.36g, 23.29mmol) was slowly added. After stirring for 1 hour at room temperature, heating in an oil bath at 90°C for 5 hours, the reaction was monitored by TLC. The reaction solution was dropped into 200 mL of water to precipitate a solid, and EA (3*100 mL) was added for extraction. The organic phase was collected and washed with saturated ammonium chloride solution. After drying with sodium sulfate and concentration, the title compound was obtained, 2-chloro-9-(3-hydroxycyclopentyl)-7,9-dihydro-8H-purin-8-one 6f (yellow oily liquid, 5.47g, product 92%),.
LC-MS m/z(ESI)＝255.10[M+1]。LC-MS m/z(ESI)=255.10[M+1].
第六步：The sixth step:
2-氯-9-(3-羟基环戊基)-7-甲基-7,9-二氢-8H-嘌呤-8-酮(6g)2-chloro-9-(3-hydroxycyclopentyl)-7-methyl-7,9-dihydro-8H-purin-8-one (6g)
2-chloro-9-(3-hydroxycyclopentyl)-7-methyl-7,9-dihydro-8H-purin-8-one2-chloro-9-(3-hydroxycyclopentyl)-7-methyl-7,9-dihydro-8H-purin-8-one
将2-氯-9-(3-羟基环戊基)-7,9-二氢-8H-嘌呤-8-酮6f(2.5g，9.82mmol)和碳酸铯(4.16g，12.76mmol)溶于40mL DMF中，冰浴搅拌10min后，缓慢加入硫酸二甲酯(1.24g，9.82mmol)，1h后，TLC监测反应完全。向反应液中加入100mL水，析出固体，加入EA(3*50mL)进行萃取，用饱和食盐水洗涤有机相，收集有机相并浓缩，将残留物进行柱层析纯化，得到标题化合物，2-氯-9-(3-羟基环戊基)-7-甲基-7,9-二氢-8H-嘌呤-8-酮6g(橙色固体，900mg，产率34％)。Dissolve 2-chloro-9-(3-hydroxycyclopentyl)-7,9-dihydro-8H-purin-8-one 6f (2.5g, 9.82mmol) and cesium carbonate (4.16g, 12.76mmol) After stirring in 40 mL DMF for 10 min in an ice bath, dimethyl sulfate (1.24 g, 9.82 mmol) was slowly added. After 1 h, TLC monitored the reaction to be complete. 100mL of water was added to the reaction solution to precipitate a solid, and EA (3*50mL) was added for extraction, the organic phase was washed with saturated brine, the organic phase was collected and concentrated, and the residue was purified by column chromatography to obtain the title compound, 2- Chloro-9-(3-hydroxycyclopentyl)-7-methyl-7,9-dihydro-8H-purin-8-one 6g (orange solid, 900mg, yield 34%).
1H NMR(400MHz,DMSO-d 6)δ8.35(s,1H),4.90(d,1H),4.71–4.62(m,1H),4.16–4.08(m,1H),3.35(s,3H),2.29–2.23(m,1H),2.17–2.10(m,2H),1.92–1.77(m,3H)。 1 H NMR(400MHz,DMSO-d 6 )δ8.35(s,1H), 4.90(d,1H), 4.71-4.62(m,1H), 4.16-4.08(m,1H), 3.35(s,3H) ), 2.29–2.23(m,1H), 2.17–2.10(m,2H), 1.92–1.77(m,3H).
LC-MS m/z(ESI)＝269.10[M+1]。LC-MS m/z(ESI)=269.10[M+1].
第七步：The seventh step:
9-(3-羟基环戊基)-7-甲基-2-((7-甲基-[1,2,4]***并[1,5-a]吡啶-6-基)氨基)-7,9-二氢-8H-嘌呤-8-酮(化合物6)9-(3-hydroxycyclopentyl)-7-methyl-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino) -7,9-dihydro-8H-purin-8-one (compound 6)
9-(3-hydroxycyclopentyl)-7-methyl-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)7,9-dihydro-8H-purin-8-one9-(3-hydroxycyclopentyl)-7-methyl-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)7,9-dihydro-8H -purin-8-one
将2-氯-9-(3-羟基环戊基)-7-甲基-7,9-二氢-8H-嘌呤-8-酮6g(300mg，1.12mmol)、7-甲基-[1,2,4]***并[1,5-a]吡啶-6-胺(165mg，1.12mmol)、碳酸铯(727mg，2.23mmol)、甲磺酸(2-二环己基膦-3,6-二甲氧基-2’,4’,6'-三异丙基-1,1'-联苯)(2'-氨基-1,1'-联苯基-2-基)钯(II)(101mg，0.11mmol)溶解于1,4-二氧六环(5mL)，氮气保护换气，在110℃搅拌4.5h，TLC监测至反应结束。浓缩反应液，残留物用硅胶柱色谱分离提纯(二氯甲烷/甲醇(v/v)＝20/1)，并经过Pre-HPLC得到标题化合物，9-(3-羟基环戊基)-7-甲基-2-((7-甲基-[1,2,4]***并[1,5-a]吡啶-6-基)氨基)-7,9-二氢-8H-嘌呤-8-酮(化合物6，即化合物6-1和化合物6-2)，两个白色固体，化合物6-1(69mg，产率16％，RT＝5.15min，dr＝99.11％)，化合物6-2(48mg，产率11％，RT＝5.53min，dr＝99.04％)，Pre-HPLC(OZ),流动相:CO 2/异丙醇＝70/30；柱温:35℃；柱压:80bar；流速:1mL/min；检测器信号通道:220nm@4nm；二极管阵列检测器波长:200～400nm。 The 2-chloro-9-(3-hydroxycyclopentyl)-7-methyl-7,9-dihydro-8H-purin-8-one 6g (300mg, 1.12mmol), 7-methyl-[1 ,2,4]triazolo[1,5-a]pyridine-6-amine (165mg, 1.12mmol), cesium carbonate (727mg, 2.23mmol), methanesulfonic acid (2-dicyclohexylphosphine-3,6 -Dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II ) (101 mg, 0.11 mmol) was dissolved in 1,4-dioxane (5 mL), protected by nitrogen and ventilated, stirred at 110° C. for 4.5 h, monitored by TLC until the reaction was completed. The reaction solution was concentrated, and the residue was separated and purified by silica gel column chromatography (dichloromethane/methanol (v/v)=20/1), and the title compound, 9-(3-hydroxycyclopentyl)-7 was obtained through Pre-HPLC -Methyl-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-7,9-dihydro-8H-purine- 8-ketone (compound 6, namely compound 6-1 and compound 6-2), two white solids, compound 6-1 (69 mg, yield 16%, RT=5.15 min, dr=99.11%), compound 6 2 (48mg, yield 11%, RT=5.53min, dr=99.04%), Pre-HPLC (OZ), mobile phase: CO 2 /isopropanol=70/30; column temperature: 35°C; column pressure: 80bar; flow rate: 1mL/min; detector signal channel: 220nm@4nm; diode array detector wavelength: 200～400nm.
化合物6-1：Compound 6-1:
1H NMR(400MHz,DMSO-d 6)δ9.10(s,1H),8.64(s,1H),8.38(s,1H),8.10(s,1H),7.70(s,1H),4.97–4.89(m,1H),4.58(d,1H),4.23(s,1H),3.29(s,3H),2.38(s,3H),2.33–2.31(m,1H),2.14–2.06(m,2H),1.81–1.76(m,1H),1.49–1.46(m,1H),0.86–0.82(m,1H)。 1 H NMR(400MHz,DMSO-d 6 )δ9.10(s,1H),8.64(s,1H),8.38(s,1H),8.10(s,1H),7.70(s,1H),4.97-- 4.89 (m, 1H), 4.58 (d, 1H), 4.23 (s, 1H), 3.29 (s, 3H), 2.38 (s, 3H), 2.33-2.31 (m, 1H), 2.14-2.06 (m, 2H), 1.81–1.76(m,1H), 1.49–1.46(m,1H), 0.86–0.82(m,1H).
化合物6-2：Compound 6-2:
1H NMR(400MHz,DMSO-d 6)δ9.10(s,1H),8.64(s,1H),8.38(s,1H),8.10(s,1H),7.70(s,1H),4.97–4.89(m,1H),4.58(d,1H),4.24(s,1H),3.29(s,3H),2.38(s,3H),2.31–2.24(m,1H),2.05–1.99(m,2H),1.81–1.76(m,1H),1.50–1.44(m,1H),0.86–0.82(m,1H)。 1 H NMR(400MHz,DMSO-d 6 )δ9.10(s,1H),8.64(s,1H),8.38(s,1H),8.10(s,1H),7.70(s,1H),4.97-- 4.89 (m, 1H), 4.58 (d, 1H), 4.24 (s, 1H), 3.29 (s, 3H), 2.38 (s, 3H), 2.31-2.24 (m, 1H), 2.05-1.99 (m, 2H), 1.81–1.76(m,1H), 1.50–1.44(m,1H), 0.86–0.82(m,1H).
LC-MS m/z(ESI)＝383.40[M+1]。LC-MS m/z(ESI)=383.40[M+1].
实施例7Example 7
1-甲基-4-(7-甲基-2-((7-甲基-[1,2,4]***[1,5-a]吡啶-6-基)氨基)-8-氧代-7,8-二氢-9H-嘌呤-9-基)环己烷-1-碳腈(化合物7)1-methyl-4-(7-methyl-2-((7-methyl-[1,2,4]triazole[1,5-a]pyridin-6-yl)amino)-8-oxy (7,8-dihydro-9H-purin-9-yl)cyclohexane-1-carbonitrile (compound 7)
1-methyl-4-(7-methyl-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-8-oxo-7,8-dihydro-9H-purin-9-yl)cyclohexane-1-carbonitrile1-methyl-4-(7-methyl-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-8-oxo-7,8 -dihydro-9H-purin-9-yl)cyclohexane-1-carbonitrile
Figure PCTCN2020141859-appb-000019
Figure PCTCN2020141859-appb-000019
Figure PCTCN2020141859-appb-000020
Figure PCTCN2020141859-appb-000020
第一步：first step:
1-甲基-4-氧代环己烷-1-碳腈(7b)1-Methyl-4-oxocyclohexane-1-carbonitrile (7b)
2-1-methyl-4-oxocyclohexane-1-carbonitrile2-1-methyl-4-oxocyclohexane-1-carbonitrile
将1,4-二氧杂螺[4.5]癸烷-8-碳腈7a(5.00g,29.9mmol)溶于THF(60mL)中，0℃下缓慢滴加双三氟甲烷磺酰亚胺锂(9.87mL,34.38mmol)搅拌反应，1h后缓慢加入碘甲烷(4.24g,29.9mmol)再搅拌反应1h。TLC监测至反应结束，用饱和氯化铵溶液以及溴水和乙酸乙酯萃取2次，无水硫酸镁干燥，过滤浓缩有机层得中间体8-甲基-1,4-二氧杂螺[4.5]癸烷-8-碳腈，再加入THF(60mL)溶解，反应液中加入3M HCl(60mL)，加热至50℃反应5h。TLC监测至反应结束，冷却至室温后用3M NaOH调节pH值至7-8，加入二氯甲烷萃取3次，无水硫酸钠干燥，浓缩有机相得标题化合物，1-甲基-4-氧代环己烷-1-碳腈7b(黄色液体，3.48g，产率84.84％)。Dissolve 1,4-dioxaspiro[4.5]decane-8-carbonitrile 7a (5.00g, 29.9mmol) in THF (60mL), slowly add lithium bistrifluoromethanesulfonimide dropwise at 0℃ (9.87mL, 34.38mmol) and the reaction was stirred. After 1h, methyl iodide (4.24g, 29.9mmol) was slowly added and the reaction was stirred for another 1h. TLC monitors to the end of the reaction, extracts twice with saturated ammonium chloride solution, bromine water and ethyl acetate, dried over anhydrous magnesium sulfate, filtered and concentrated the organic layer to obtain the intermediate 8-methyl-1,4-dioxaspiro [ 4.5] Decane-8-carbonitrile, then add THF (60mL) to dissolve, add 3M HCl (60mL) to the reaction solution, heat to 50°C for 5h. TLC monitors to the end of the reaction. After cooling to room temperature, adjust the pH to 7-8 with 3M NaOH, add dichloromethane to extract 3 times, dry with anhydrous sodium sulfate, concentrate the organic phase to obtain the title compound, 1-methyl-4-oxygen Cyclohexane-1-carbonitrile 7b (yellow liquid, 3.48 g, yield 84.84%).
LC-MS m/z(ESI)＝138.10[M+1]。LC-MS m/z(ESI)=138.10[M+1].
第二步：The second step:
4-氨基-1-甲基环己烷-1-碳腈(7c)4-amino-1-methylcyclohexane-1-carbonitrile (7c)
4-amino-1-methylcyclohexane-1-carbonitrile4-amino-1-methylcyclohexane-1-carbonitrile
将1-甲基-4-氧代环己烷-1-碳腈7b(3.48g，25.37mmol)溶于无水甲醇(50mL)中，常温搅拌下加入甲酸铵(16.00g,253.70mmol)反应4h，再加入氰基硼氢化钠(1.88g,30.44mmol)搅拌反应3h，TLC监测至反应结束，加入2N HCl调节pH值至1-2搅拌反应0.5小时后加入乙酸乙酯萃取2次，再用2N NaOH溶液调节pH值至10左右，二氯甲烷萃取3次，无水硫酸镁干燥，浓缩有机相得标题化合物，4-氨基-1-甲基环己烷-1-碳腈7c(淡黄色液体，2.80g，产率79.85％)。Dissolve 1-methyl-4-oxocyclohexane-1-carbonitrile 7b (3.48g, 25.37mmol) in anhydrous methanol (50mL), add ammonium formate (16.00g, 253.70mmol) under stirring at room temperature for reaction 4h, then add sodium cyanoborohydride (1.88g, 30.44mmol) and stir the reaction for 3h, monitor by TLC until the reaction is over, add 2N HCl to adjust the pH to 1-2, stir the reaction for 0.5 hours, add ethyl acetate for extraction twice, and then Adjust the pH to about 10 with 2N NaOH solution, extract 3 times with dichloromethane, dry with anhydrous magnesium sulfate, and concentrate the organic phase to obtain the title compound, 4-amino-1-methylcyclohexane-1-carbonitrile 7c (light Yellow liquid, 2.80 g, yield 79.85%).
LC-MS m/z(ESI)＝139.10[M+1]。LC-MS m/z(ESI)=139.10[M+1].
第三步：third step:
2-氯-4-((4-氰基-4-甲基环己基)氨基)嘧啶-5-羧酸乙酯(7d)Ethyl 2-chloro-4-((4-cyano-4-methylcyclohexyl)amino)pyrimidine-5-carboxylate (7d)
ethyl 2-chloro-4-((4-cyano-4-methylcyclohexyl)amino)pyrimidine-5-carboxylateethyl 2-chloro-4-((4-cyano-4-methylcyclohexyl)amino)pyrimidine-5-carboxylate
将2,4-二氯-5-嘧啶甲酸乙酯1a(6.72g,30.39mmol)溶于乙腈(30mL)中，0℃搅拌下加入碳酸钾(8.40g，60.78mmol)，再缓慢滴加4-氨基-1-甲基环己烷-1-碳腈7c (2.80g，20.26mmol)的乙腈溶液(10mL)搅拌反应1h，TLC监测至反应结束，硅藻土过滤后用硅胶柱色谱分离提纯(石油醚/乙酸乙酯(v/v)＝20:1)纯化得标题化合物，2-氯-4-((4-氰基-4-甲基环己基)氨基)嘧啶-5-羧酸乙酯7d(白色固体，2.63g，产率40.22％)。Ethyl 2,4-dichloro-5-pyrimidinecarboxylate 1a (6.72g, 30.39mmol) was dissolved in acetonitrile (30mL), potassium carbonate (8.40g, 60.78mmol) was added while stirring at 0°C, and then 4 was slowly added dropwise. -Amino-1-methylcyclohexane-1-carbonitrile 7c (2.80g, 20.26mmol) in acetonitrile (10mL) was stirred and reacted for 1h, monitored by TLC until the reaction was over, filtered through diatomaceous earth and purified by silica gel column chromatography (Petroleum ether/ethyl acetate (v/v)=20:1) purified to obtain the title compound, 2-chloro-4-((4-cyano-4-methylcyclohexyl)amino)pyrimidine-5-carboxylic acid Ethyl ester 7d (white solid, 2.63 g, yield 40.22%).
1H NMR(400MHz,Chloroform-d)δ8.68(d,1H),4.38(p,2H),2.23–1.82(m,4H),1.79–1.49(m,6H),1.46–1.36(m,6H)。 1 H NMR(400MHz, Chloroform-d)δ8.68(d,1H), 4.38(p,2H), 2.23-1.82(m,4H), 1.79-1.49(m,6H), 1.46-1.36(m, 6H).
LC-MS m/z(ESI)＝323.10[M+1]。LC-MS m/z(ESI)=323.10[M+1].
第四步：the fourth step:
2-氯-4-((4-氰基-4-甲基环己基)氨基)嘧啶-5-羧酸(7e)2-chloro-4-((4-cyano-4-methylcyclohexyl)amino)pyrimidine-5-carboxylic acid (7e)
2-chloro-4-((4-cyano-4-methylcyclohexyl)amino)pyrimidine-5-carboxylic acid2-chloro-4-((4-cyano-4-methylcyclohexyl)amino)pyrimidine-5-carboxylic acid
将2-氯-4-((4-氰基-4-甲基环己基)氨基)嘧啶-5-羧酸乙酯7d(2.63g，8.15mmol)溶解于四氢呋喃/水(20mL/10mL)中，加入氢氧化锂一水合物(1.00g，24.45mmol)，常温搅拌反应2h，TLC监测至反应结束，浓缩蒸发掉四氢呋喃后加入2N HCl调节pH至3-4左右，有白色固体析出，过滤，滤饼用水以及石油醚/乙酸乙酯(v/v＝10/1)洗两次得标题化合物，2-氯-4-((4-氰基-4-甲基环己基)氨基)嘧啶-5-羧酸7e(白色固体，2.20g，产率91.59％)。Dissolve 2-chloro-4-((4-cyano-4-methylcyclohexyl)amino)pyrimidine-5-carboxylic acid ethyl ester 7d (2.63g, 8.15mmol) in tetrahydrofuran/water (20mL/10mL) , Add lithium hydroxide monohydrate (1.00g, 24.45mmol), stir the reaction at room temperature for 2h, monitor by TLC until the reaction is over, concentrate and evaporate the tetrahydrofuran, add 2N HCl to adjust the pH to about 3-4, a white solid precipitates, filter, The filter cake was washed twice with water and petroleum ether/ethyl acetate (v/v=10/1) to obtain the title compound, 2-chloro-4-((4-cyano-4-methylcyclohexyl)amino)pyrimidine- 5-carboxylic acid 7e (white solid, 2.20 g, yield 91.59%).
1H NMR(400MHz,DMSO-d6)δ13.75(s,1H),8.59(s,1H),8.52(d,1H),3.97(m,1H),2.06–1.92(m,4H),1.63–1.47(m,4H),1.35(s,3H)。 1 H NMR (400MHz, DMSO-d6) δ 13.75 (s, 1H), 8.59 (s, 1H), 8.52 (d, 1H), 3.97 (m, 1H), 2.06-1.92 (m, 4H), 1.63 –1.47(m,4H),1.35(s,3H).
LC-MS m/z(ESI)＝295.10[M+1]。LC-MS m/z(ESI)=295.10[M+1].
第五步：the fifth step:
4-(2-氯-8-氧代-7,8-二氢-9H-嘌呤-9-基)-1-甲基环己烷-1-碳腈(7f)4-(2-Chloro-8-oxo-7,8-dihydro-9H-purin-9-yl)-1-methylcyclohexane-1-carbonitrile (7f)
4-(2-chloro-8-oxo-7,8-dihydro-9H-purin-9-yl)-1-methylcyclohexane-1-carbonitrile4-(2-chloro-8-oxo-7,8-dihydro-9H-purin-9-yl)-1-methylcyclohexane-1-carbonitrile
将2-氯-4-((4-氰基-4-甲基环己基)氨基)嘧啶-5-羧酸7e(2.20g，7.46mmol)用N,N-二甲基乙酰胺(15mL)溶解，常温搅拌下加入三乙胺(1.04mL,7.46mmol)和叠氮磷酸二苯酯(1.61mL,7.46mmol)反应2h后，升温至110℃回流反应2.5h。TLC监测至反应结束，加入水和乙酸乙酯萃取3次，浓缩有机层硅胶柱色谱分离提纯(二氯甲烷/甲醇(v/v)＝80/1)，得到标题化合物，4-(2-氯-8-氧代-8,9-二氢-7h-嘌呤-9-基)-1-甲基环己烷-1-碳腈7f(白色固体，0.9g，产率41.35％)。Use 2-chloro-4-((4-cyano-4-methylcyclohexyl)amino)pyrimidine-5-carboxylic acid 7e (2.20g, 7.46mmol) with N,N-dimethylacetamide (15mL) Dissolve, add triethylamine (1.04 mL, 7.46 mmol) and diphenyl azide phosphate (1.61 mL, 7.46 mmol) under stirring at room temperature, and react for 2 h, then heat to 110° C. and reflux for 2.5 h. TLC monitored until the reaction was over, water and ethyl acetate were added for extraction 3 times, the organic layer was concentrated and the organic layer was separated and purified by silica gel column chromatography (dichloromethane/methanol (v/v)=80/1) to obtain the title compound, 4-(2- Chloro-8-oxo-8,9-dihydro-7h-purin-9-yl)-1-methylcyclohexane-1-carbonitrile 7f (white solid, 0.9g, yield 41.35%).
1H NMR(400MHz,DMSO-d6)δ11.64(s,1H),8.13(s,1H),4.31–4.20(m,1H),2.45–2.33(m,2H),2.01–1.94(m,4H),1.71–1.64(m,2H),1.49(s,3H)。 1 H NMR(400MHz,DMSO-d6)δ11.64(s,1H),8.13(s,1H),4.31-4.20(m,1H),2.45-2.33(m,2H),2.01-1.94(m, 4H), 1.71–1.64 (m, 2H), 1.49 (s, 3H).
LC-MS m/z(ESI)＝292.10[M+1]。LC-MS m/z(ESI)=292.10[M+1].
第六步：The sixth step:
4-(2-氯-7-甲基-8-氧代-7,8-二氢-9H-嘌呤-9-基)-1-甲基环己烷-1-碳腈(7g)4-(2-Chloro-7-methyl-8-oxo-7,8-dihydro-9H-purin-9-yl)-1-methylcyclohexane-1-carbonitrile (7g)
4-(2-chloro-7-methyl-8-oxo-7,8-dihydro-9H-purin-9-yl)-1-methylcyclohexane-1-carbonitrile4-(2-chloro-7-methyl-8-oxo-7,8-dihydro-9H-purin-9-yl)-1-methylcyclohexane-1-carbonitrile
将4-(2-氯-8-氧代-8,9-二氢-7h-嘌呤-9-基)-1-甲基环己烷-1-碳腈7f(0.90g,3.08mmol)用N,N-二甲基甲酰胺(10mL)溶解，0℃搅拌下加入硫酸二甲酯(0.29mL,3.08mmol)和碳酸铯(1.51g,4.62mmol)反应2h。TLC监测至反应结束，把反应液缓慢滴加到冰水中搅拌，析出白色固体，用水和石油醚洗3次过滤得到标题化合物4-(2-氯-7-甲基-8-氧代-8,9-二氢-7h-嘌呤-9-基)-1-甲基环己烷-1-碳腈7g(白色固体，0.85g，产率90.26％)。Use 4-(2-chloro-8-oxo-8,9-dihydro-7h-purin-9-yl)-1-methylcyclohexane-1-carbonitrile 7f (0.90g, 3.08mmol) N,N-dimethylformamide (10 mL) was dissolved, and dimethyl sulfate (0.29 mL, 3.08 mmol) and cesium carbonate (1.51 g, 4.62 mmol) were added under stirring at 0° C. and reacted for 2 h. TLC monitors to the end of the reaction, the reaction solution is slowly added dropwise to ice water and stirred, a white solid precipitates out, washed with water and petroleum ether three times and filtered to obtain the title compound 4-(2-chloro-7-methyl-8-oxo-8 , 9-dihydro-7h-purin-9-yl)-1-methylcyclohexane-1-carbonitrile 7g (white solid, 0.85g, yield 90.26%).
1H NMR(400MHz,DMSO-d6)δ8.35(s,1H),4.35–4.20(m,1H),3.36(s,3H),2.48–2.31(m,2H),2.06–1.95(m,3H),1.83–1.76(m,1H),1.71–1.57(m,2H),1.48(s,1H),1.36(s,2H)。 1 H NMR(400MHz,DMSO-d6)δ8.35(s,1H), 4.35-4.20(m,1H), 3.36(s,3H), 2.48-2.31(m,2H), 2.06-1.95(m, 3H), 1.83–1.76(m,1H), 1.71–1.57(m,2H), 1.48(s,1H), 1.36(s,2H).
LC-MS m/z(ESI)＝306.10[M+1]。LC-MS m/z(ESI)=306.10[M+1].
第七步：The seventh step:
1-甲基-4-(7-甲基-2-((7-甲基-[1,2,4]***[1,5-a]吡啶-6-基)氨基)-8-氧代-7,8-二氢-9H- 嘌呤-9-基)环己烷-1-碳腈(化合物7-1和化合物7-2)1-methyl-4-(7-methyl-2-((7-methyl-[1,2,4]triazole[1,5-a]pyridin-6-yl)amino)-8-oxy -7,8-dihydro-9H-purin-9-yl)cyclohexane-1-carbonitrile (compound 7-1 and compound 7-2)
1-methyl-4-(7-methyl-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-8-oxo-7,8-dihydro-9H-purin-9-yl)cyclohexane-1-carbonitrile1-methyl-4-(7-methyl-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-8-oxo-7,8 -dihydro-9H-purin-9-yl)cyclohexane-1-carbonitrile
将4-(2-氯-7-甲基-8-氧代-8,9-二氢-7h-嘌呤-9-基)-1-甲基环己烷-1-碳腈7g(0.15g,0.49mmol)用1,4-二氧六环(12mL)溶解，常温搅拌下加入7-甲基-[1,2,4]***并[1,5-a]吡啶-6-胺(0.11g,0.73mmol)、碳酸铯(0.24g,0.73mmol)、BrettPhos-G3-Pd(0.05g,0.04mmol)，氮气保护并换气，升温至110℃回流反应4h。TLC监测至反应结束，浓缩反应液，残留物用硅胶柱色谱分离提纯(二氯甲烷/甲醇(v/v)＝30/1)，得标题化合物7(即化合物7-1和化合物7-2)，两个白色固体，化合物7-1(19mg，产率9.26％(结构猜测)RT＝5.068min，dr％:99.85％)、化合物7-2(28mg，产率13.64％(结构猜测)RT＝5.900min，DR％:dr％：99.38％)。Pre-HPLC(OZ),流动相:CO 2/(50％异丙醇/乙腈溶液中加入0.3％二乙胺)＝60/40；柱温:35℃；柱压:80bar；流速:1mL/min；检测器信号通道:[email protected]；二极管阵列检测器波长:200～400nm。 Combine 4-(2-chloro-7-methyl-8-oxo-8,9-dihydro-7h-purin-9-yl)-1-methylcyclohexane-1-carbonitrile 7g (0.15g ,0.49mmol) was dissolved in 1,4-dioxane (12mL), and 7-methyl-[1,2,4]triazolo[1,5-a]pyridine-6-amine ( 0.11g, 0.73mmol), cesium carbonate (0.24g, 0.73mmol), BrettPhos-G3-Pd (0.05g, 0.04mmol), protected by nitrogen and ventilated, heated to 110°C and refluxed for 4h. The reaction was monitored by TLC until the end of the reaction. The reaction solution was concentrated. The residue was separated and purified by silica gel column chromatography (dichloromethane/methanol (v/v)=30/1) to obtain the title compound 7 (namely compound 7-1 and compound 7-2). ), two white solids, compound 7-1 (19mg, yield 9.26% (structure guessed) RT=5.068min, dr%: 99.85%), compound 7-2 (28mg, yield 13.64% (structure guessed) RT =5.900min, DR%: dr%: 99.38%). Pre-HPLC (OZ), mobile phase: CO 2 /(50% isopropanol/acetonitrile solution with 0.3% diethylamine added) = 60/40; column temperature: 35℃; column pressure: 80bar; flow rate: 1mL/ min; detector signal channel: [email protected]; diode array detector wavelength: 200～400nm.
化合物7-1 1H NMR(400MHz,DMSO-d6)δ8.97(s,1H),8.73(s,1H),8.40(s,1H),8.11(s,1H),7.73(s,1H),4.19–4.10(m,1H),3.29(s,3H),2.32(s,3H),2.29–2.20(m,2H),1.90–1.75(m,4H),1.58–1.50(m,2H),0.84(s,3H)。 Compound 7-1 1 H NMR (400MHz, DMSO-d6) δ 8.97 (s, 1H), 8.73 (s, 1H), 8.40 (s, 1H), 8.11 (s, 1H), 7.73 (s, 1H) ,4.19–4.10(m,1H), 3.29(s,3H), 2.32(s,3H), 2.29–2.20(m,2H), 1.90–1.75(m,4H), 1.58–1.50(m,2H) ,0.84(s,3H).
LC-MS m/z(ESI)＝418.20[M+1]。LC-MS m/z(ESI)=418.20[M+1].
化合物7-2 1H NMR(400MHz,DMSO-d6)δ9.06(s,1H),8.54(s,1H),8.34(s,1H),8.09(s,1H),7.67(s,1H),4.22–4.13(m,1H),3.30(s,3H),2.47–2.41(m,2H),2.36(s,3H),2.03–1.95(m,2H),1.80–1.73(m,2H),1.55–1.45(m,2H),1.33(s,3H)。 Compound 7-2 1 H NMR (400MHz, DMSO-d6) δ 9.06 (s, 1H), 8.54 (s, 1H), 8.34 (s, 1H), 8.09 (s, 1H), 7.67 (s, 1H) ,4.22–4.13(m,1H), 3.30(s,3H), 2.47–2.41(m,2H), 2.36(s,3H), 2.03–1.95(m,2H), 1.80–1.73(m,2H) ,1.55–1.45(m,2H),1.33(s,3H).
LC-MS m/z(ESI)＝418.20[M+1]。LC-MS m/z(ESI)=418.20[M+1].
实施例8Example 8
反-4-(7-甲基-2-((7-甲基-[1,2,4]***并[1,5-a]吡啶-6-6基)氨基)-8-氧代-7,8-二氢-9H-嘌呤-9-基)环己烷-1-腈(化合物8)Trans-4-(7-methyl-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-6 yl)amino)-8-oxo -7,8-dihydro-9H-purin-9-yl)cyclohexane-1-carbonitrile (compound 8)
trans-4-(7-methyl-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-8-oxo-7,8-dihydro-9H-purin-9-yl)cyclohexane-1-carbonitriletrans-4-(7-methyl-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-8-oxo-7,8-dihydro -9H-purin-9-yl)cyclohexane-1-carbonitrile
Figure PCTCN2020141859-appb-000021
Figure PCTCN2020141859-appb-000021
Figure PCTCN2020141859-appb-000022
Figure PCTCN2020141859-appb-000022
第一步：first step:
叔丁基(反-4-氨甲酰环己基)氨基甲酸酯(8b)Tert-Butyl (trans-4-carbamoylcyclohexyl) carbamate (8b)
tert-butyl(trans-4-carbamoylcyclohexyl)carbamatetert-butyl(trans-4-carbamoylcyclohexyl)carbamate
反-4-((叔丁氧羰基)氨基)环己烷-1-羧酸8a(5.0g,20.5mmol)、O-(7-氮杂苯并三氮唑基)-N,N,N',N'-四甲基脲鎓六氟磷酸盐(9.4g,24.7mmol)溶解于二氯甲烷(15mL)，在0℃下搅拌20min，加入N,N二异丙基乙胺(10.5g,82mmol)及氯化铵(3.3g,61.5mmol)，在室温搅拌4h。TLC监测至反应结束，向反应液中加入水10mL，分离有机相，饱和盐水洗一次，用无水硫酸钠干燥并用硅胶拌样，用正相过柱仪过出产物，浓缩得到标题化合物叔丁基(反-4-氨甲酰环己基)氨基甲酸酯8b(白色固体，4.4g,产率83％)。Trans-4-((tert-butoxycarbonyl)amino)cyclohexane-1-carboxylic acid 8a (5.0g, 20.5mmol), O-(7-azabenzotriazole)-N,N,N ',N'-Tetramethyluronium hexafluorophosphate (9.4g, 24.7mmol) was dissolved in dichloromethane (15mL), stirred at 0℃ for 20min, and N,N diisopropylethylamine (10.5g , 82mmol) and ammonium chloride (3.3g, 61.5mmol), stirred at room temperature for 4h. TLC monitors to the end of the reaction, add 10 mL of water to the reaction solution, separate the organic phase, wash with saturated brine once, dry with anhydrous sodium sulfate and mix the sample with silica gel, pass the product with a normal phase column passer, and concentrate to obtain the title compound tert-butyl Group (trans-4-carbamoylcyclohexyl) carbamate 8b (white solid, 4.4 g, yield 83%).
LC-MS m/z(ESI)＝243.30[M+1]。LC-MS m/z(ESI)=243.30[M+1].
第二步：The second step:
叔丁基(反-4-氰基环己基)氨基甲酸酯(8c)Tert-butyl (trans-4-cyanocyclohexyl) carbamate (8c)
tert-butyl(trans-4-cyanocyclohexyl)carbamatetert-butyl(trans-4-cyanocyclohexyl)carbamate
叔丁基(反-4-氨甲酰环己基)氨基甲酸酯8b(4.4g,18.0mmol)溶解于70mL吡啶中，冰浴降温，然后将三氯氧磷(7.7mL)滴加进反应液中，冰浴搅拌1h。TLC监测反应完全，在冰浴下加入水20mL，用乙酸乙酯萃取4次，然后用酸水洗有机相7次，最后用饱和盐水洗两次，无水硫酸钠干燥，过滤并浓缩至干得到化合物叔丁基(反-4-氰基环己基)氨基甲酸酯8c(黄色固体，1.2g,产率30％)。Tert-butyl (trans-4-carbamoylcyclohexyl) carbamate 8b (4.4g, 18.0mmol) was dissolved in 70mL of pyridine, cooled in an ice bath, and then phosphorus oxychloride (7.7mL) was added dropwise to the reaction In the solution, stir in an ice bath for 1 hour. TLC monitors the completion of the reaction, adds 20 mL of water in an ice bath, extracts 4 times with ethyl acetate, then washes the organic phase 7 times with acid water, and finally washes twice with saturated brine, dried with anhydrous sodium sulfate, filtered and concentrated to dryness. Compound tert-butyl (trans-4-cyanocyclohexyl) carbamate 8c (yellow solid, 1.2 g, yield 30%).
1H NMR(400MHz DMSO)δ6.80(m,1H),3.24-3.22(m,1H),2.63-2.55(m,1H),1.99-1.95(m,2H),1.77-1.73(m,2H),1.56-1.46(m,2H),1.36(s,9H),1.21-1.11(m,2H)。 1 H NMR (400MHz DMSO) δ 6.80 (m, 1H), 3.24-3.22 (m, 1H), 2.63-2.55 (m, 1H), 1.99-1.95 (m, 2H), 1.77-1.73 (m, 2H) ), 1.56-1.46 (m, 2H), 1.36 (s, 9H), 1.21-1.11 (m, 2H).
LC-MS m/z(ESI)＝225.30[M+1]。LC-MS m/z(ESI)=225.30[M+1].
第三步：third step:
反-4-氨基环己烷-1-碳腈(8d)Trans-4-aminocyclohexane-1-carbonitrile (8d)
trans-4-aminocyclohexane-1-carbonitriletrans-4-aminocyclohexane-1-carbonitrile
将叔丁基(反-4-氰基环己基)氨基甲酸酯8c(1.2g，9.6mmol)溶解于盐酸乙酸乙酯溶液中(20mL)，加热至45℃，搅拌2h。TLC监测至反应结束，有白色固体析出，浓 缩干燥得到标题化合物反-4-氨基环己烷-1-碳腈8d(白色固体，660mg，产率60％)。Dissolve tert-butyl (trans-4-cyanocyclohexyl) carbamate 8c (1.2 g, 9.6 mmol) in hydrochloric acid ethyl acetate solution (20 mL), heat to 45° C., and stir for 2 h. TLC monitored to the end of the reaction, a white solid precipitated, and concentrated and dried to obtain the title compound trans-4-aminocyclohexane-1-carbonitrile 8d (white solid, 660 mg, yield 60%).
LC-MS m/z(ESI)＝125.30[M+1]。LC-MS m/z(ESI)=125.30[M+1].
第四步：the fourth step:
2-氯-4-(反-4-氰基环己基)氨基)嘧啶-5-羧酸乙酯(8e)2-chloro-4-(trans-4-cyanocyclohexyl)amino)pyrimidine-5-carboxylic acid ethyl ester (8e)
ethyl 2-chloro-4-(trans-4-cyanocyclohexyl)amino)pyrimidine-5-carboxylateethyl 2-chloro-4-(trans-4-cyanocyclohexyl)amino)pyrimidine-5-carboxylate
将2,4-二氯嘧啶-5-羧酸乙酯1a(1.4g,5.35mmol)、碳酸钾(1.4g,10.7mmol)溶解于乙腈(10mL)，在0℃下加入反-4-氨基环己烷-1-碳腈8d(660mg,5.35mmol)，在室温搅拌20h。TLC监测至反应结束，向反应液中加入水和乙酸乙酯萃取三次，饱和盐水洗一次，用无水硫酸钠干燥并用硅胶柱色谱分离(正己烷/乙酸乙酯(v/v)＝10:1)纯化，得到标题化合物2-氯-4-(反-4-氰基环己基)氨基)嘧啶-5-羧酸乙酯8e(白色固体，810mg，产率62％)。Dissolve 2,4-dichloropyrimidine-5-carboxylic acid ethyl ester 1a (1.4g, 5.35mmol) and potassium carbonate (1.4g, 10.7mmol) in acetonitrile (10mL), add trans-4-amino at 0℃ Cyclohexane-1-carbonitrile 8d (660 mg, 5.35 mmol) was stirred at room temperature for 20 h. TLC monitors until the reaction is complete, the reaction solution is added with water and ethyl acetate for extraction three times, washed with saturated brine once, dried with anhydrous sodium sulfate and separated by silica gel column chromatography (n-hexane/ethyl acetate (v/v)=10: 1) Purification to obtain the title compound 2-chloro-4-(trans-4-cyanocyclohexyl)amino)pyrimidine-5-carboxylic acid ethyl ester 8e (white solid, 810 mg, yield 62%).
1H NMR(400MHz DMSO)δ8.62(s,1H),8.27(d,1H),4.30(q,2H),4.04-3.96(m,1H),4.04-3.67(m,1H),2.76-2.70(m,1H),2.04-2.00(m,2H),1.96-1.92(m,2H),1.72-1.62(m,2H),1.47-1.37(m,2H),1.30(t,3H)。 1 H NMR(400MHz DMSO)δ8.62(s,1H), 8.27(d,1H), 4.30(q,2H), 4.04-3.96(m,1H), 4.04-3.67(m,1H), 2.76 2.70 (m, 1H), 2.04-2.00 (m, 2H), 1.96-1.92 (m, 2H), 1.72-1.62 (m, 2H), 1.47-1.37 (m, 2H), 1.30 (t, 3H).
LC-MS m/z(ESI)＝310.20[M+1]。LC-MS m/z(ESI)=310.20[M+1].
第五步：the fifth step:
2-氯-4-((反-4-氰基环己基)氨基)嘧啶-5-羧酸(8f)2-chloro-4-((trans-4-cyanocyclohexyl)amino)pyrimidine-5-carboxylic acid (8f)
2-chloro-4-((trans-4-cyanocyclohexyl)amino)pyrimidine-5-carboxylic acide2-chloro-4-((trans-4-cyanocyclohexyl)amino)pyrimidine-5-carboxylic acid
将2-氯-4-((反-4-氰基环己基)氨基)嘧啶-5-羧酸乙酯8e(810mg,2.6mmol)溶解于四氢呋喃/水(4mL/4mL)中，加入氢氧化锂(247mg,5.2mmol)，室温搅拌1h。TLC监测至反应结束，旋干四氢呋喃，调pH至4-5，有白色固体析出，过滤，滤饼用石油醚/乙酸乙酯(v/v＝10/1)洗两次，浓缩得到标题化合物2-氯-4-((反-4-氰基环己基)氨基)嘧啶-5-羧酸8f(白色固体，790mg，产率86％)Dissolve 2-chloro-4-((trans-4-cyanocyclohexyl)amino)pyrimidine-5-carboxylic acid ethyl ester 8e (810mg, 2.6mmol) in tetrahydrofuran/water (4mL/4mL) and add hydroxide Lithium (247mg, 5.2mmol), stirred at room temperature for 1h. TLC monitors to the end of the reaction, spin-dry the tetrahydrofuran, adjust the pH to 4-5, a white solid is precipitated, filtered, the filter cake is washed twice with petroleum ether/ethyl acetate (v/v=10/1), and concentrated to obtain the title compound 2-Chloro-4-((trans-4-cyanocyclohexyl)amino)pyrimidine-5-carboxylic acid 8f (white solid, 790mg, yield 86%)
1H NMR(400MHz DMSO)δ8.58(s,1H),8.49(d,1H),4.01-3.87(m,1H),2.76-2.71(m,1H),2.03-1.93(m,4H),1.72-1.63(m,2H),1.44-1.35(m,2H)。 1 H NMR (400MHz DMSO) δ 8.58 (s, 1H), 8.49 (d, 1H), 4.01-3.87 (m, 1H), 2.76-2.71 (m, 1H), 2.03-1.93 (m, 4H), 1.72-1.63 (m, 2H), 1.44-1.35 (m, 2H).
LC-MS m/z(ESI)＝282.30[M+1]。LC-MS m/z(ESI)=282.30[M+1].
第六步：The sixth step:
反-4-(2-氯-8-氧代-7,8-二氢-9H-嘌呤-9-基)环己烷-1-碳腈(8g)Trans-4-(2-chloro-8-oxo-7,8-dihydro-9H-purin-9-yl)cyclohexane-1-carbonitrile (8g)
trans-4-(2-chloro-8-oxo-7,8-dihydro-9H-purin-9-yl)cyclohexane-1-carbonitriletrans-4-(2-chloro-8-oxo-7,8-dihydro-9H-purin-9-yl)cyclohexane-1-carbonitrile
将2-氯-4-(反-4-氰基环己基)氨基)嘧啶-5-羧酸8f(730mg，2.6mmol)溶解于二甲基乙酰胺(10mL)，加入三乙胺(263mg,2.6mmol)、叠氮磷酸二苯酯(715mg,2.6mmol)，随后逐步升温至110℃,搅拌1.5h。TLC监测至反应结束，浓缩反应液，残留物用硅胶柱色谱分离(石油醚/乙酸乙酯(v/v)＝1:10)，得到标题化合物反-4-(2-氯-8-氧代-7,8-二氢-9H-嘌呤-9-基)环己烷-1-碳腈8g(白色固体，553mg，产率68％)。2-Chloro-4-(trans-4-cyanocyclohexyl)amino)pyrimidine-5-carboxylic acid 8f (730mg, 2.6mmol) was dissolved in dimethylacetamide (10mL), and triethylamine (263mg, 2.6mmol), diphenyl azide phosphate (715mg, 2.6mmol), then gradually heated to 110°C and stirred for 1.5h. The reaction was monitored by TLC until the end of the reaction. The reaction solution was concentrated. The residue was separated by silica gel column chromatography (petroleum ether/ethyl acetate (v/v)=1:10) to obtain the title compound trans-4-(2-chloro-8-oxygen 8 g (white solid, 553 mg, 68% yield) of chloro-7,8-dihydro-9H-purin-9-yl)cyclohexane-1-carbonitrile.
1H NMR(400MHz DMSO)δ11.63(s,1H),8.12(s,1H),4.23-4.16(m,1H),2.78-2.72(m,1H),2.25-2.12(m,4H),1.82-1.68(m,4H)。 1 H NMR(400MHz DMSO)δ11.63(s,1H), 8.12(s,1H), 4.23-4.16(m,1H), 2.78-2.72(m,1H), 2.25-2.12(m,4H), 1.82-1.68 (m, 4H).
LC-MS m/z(ESI)＝278.30[M+1]。LC-MS m/z(ESI)=278.30[M+1].
第七步：The seventh step:
反-4-(2-氯-7-甲基-8-氧代-7,8-二氢-9H-嘌呤-9-基)环己烷-1-碳腈(8h)Trans-4-(2-chloro-7-methyl-8-oxo-7,8-dihydro-9H-purin-9-yl)cyclohexane-1-carbonitrile (8h)
trans-4-(2-chloro-7-methyl-8-oxo-7,8-dihydro-9H-purin-9-yl)cyclohexane-1-carbonitriletrans-4-(2-chloro-7-methyl-8-oxo-7,8-dihydro-9H-purin-9-yl)cyclohexane-1-carbonitrile
将反-4-(2-氯-8-氧代-7,8-二氢-9H-嘌呤-9-基)环己烷-1-碳腈8g(553mg，2mmol)溶解于二甲基甲酰胺(5mL)，在0℃下加入硫酸二甲酯(252mg，2mmol)和碳酸铯(977mg,3mmol)，0℃搅拌30min。TLC监测至反应结束，向反应液中加入水10mL，有固体析出，过滤得到标题化合物反-4-(2-氯-7-甲基-8-氧代-7,8-二氢-9H-嘌呤-9-基)环己烷-1-碳腈8h(黄色固体，420mg，产率72％)。Dissolve 8g (553mg, 2mmol) of trans-4-(2-chloro-8-oxo-7,8-dihydro-9H-purin-9-yl)cyclohexane-1-carbonitrile in dimethylform Amide (5 mL), dimethyl sulfate (252 mg, 2 mmol) and cesium carbonate (977 mg, 3 mmol) were added at 0°C, and stirred at 0°C for 30 min. TLC monitored to the end of the reaction, 10mL of water was added to the reaction solution, a solid precipitated out, filtered to obtain the title compound trans-4-(2-chloro-7-methyl-8-oxo-7,8-dihydro-9H- Purin-9-yl)cyclohexane-1-carbonitrile 8h (yellow solid, 420 mg, yield 72%).
1H NMR(400MHz DMSO)δ8.34(s,1H),4.28-4.21(m,1H),2.79-2.72(m,1H),2.22- 2.13(m,4H),1.82-1.70(m,4H)。1H NMR(400MHz DMSO)δ8.34(s,1H), 4.28-4.21(m,1H), 2.79-2.72(m,1H), 2.22-2.13(m,4H), 1.82-1.70(m,4H) .
LC-MS m/z(ESI)＝292.30[M+1]。LC-MS m/z(ESI)=292.30[M+1].
第八步：The eighth step:
反-4-(7-甲基-2-((7-甲基-[1,2,4]***并[1,5-a]吡啶-6-6基)氨基)-8-氧代-7,8-二氢-9H-嘌呤-9-基)环己烷-1-腈(化合物8)Trans-4-(7-methyl-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-6 yl)amino)-8-oxo -7,8-dihydro-9H-purin-9-yl)cyclohexane-1-carbonitrile (compound 8)
trans-4-(7-methyl-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-8-oxo-7,8-trans-4-(7-methyl-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-8-oxo-7,8-
dihydro-9H-purin-9-yl)cyclohexane-1-carbonitriledihydro-9H-purin-9-yl)cyclohexane-1-carbonitrile
将反-4-(2-氯-7-甲基-8-氧代-7,8-二氢-9H-嘌呤-9-基)环己烷-1-腈8h(200mg，0.68mmol)、7-甲基-[1,2,4]***并[1,5-a]吡啶-6-胺(101mg，0.68mmol)、碳酸铯(391mg,1.2mmol)、甲磺酸(2-二环己基膦-3,6-二甲氧基-2’,4’,6'-三异丙基-1,1'-联苯)(2'-氨基-1,1'-联苯基-2-基)钯(II)(62mg，0.068mmol)溶解于二氧六环3mL中，氮气保护并换气，在110℃搅拌4h，经TLC监测反应完全，浓缩反应液，残留物用硅胶柱色谱分离提纯(二氯甲烷/甲醇(v/v)＝60/1)，并通过Pre-HPLC得到标题化合物，反-4-(7-甲基-2-((7-甲基-[1,2,4]***并[1,5-a]吡啶-6-6基)氨基)-8-氧代-7,8-二氢-9H-嘌呤-9-基)环己烷-1-腈化合物8(白色固体，57mg，产率20.2％)。Trans-4-(2-chloro-7-methyl-8-oxo-7,8-dihydro-9H-purin-9-yl)cyclohexane-1-carbonitrile 8h (200mg, 0.68mmol), 7-Methyl-[1,2,4]triazolo[1,5-a]pyridine-6-amine (101mg, 0.68mmol), cesium carbonate (391mg, 1.2mmol), methanesulfonic acid (2-di Cyclohexylphosphine-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl- 2-base) palladium(II) (62mg, 0.068mmol) was dissolved in 3mL of dioxane, protected by nitrogen and ventilated, stirred at 110°C for 4h, monitored by TLC, the reaction was complete, concentrated the reaction solution, and used silica gel column for the residue Chromatographic separation and purification (dichloromethane/methanol (v/v)=60/1), and pre-HPLC to obtain the title compound, trans-4-(7-methyl-2-((7-methyl-[1 ,2,4]Triazolo[1,5-a]pyridine-6-6yl)amino)-8-oxo-7,8-dihydro-9H-purin-9-yl)cyclohexane-1 -Nitrile compound 8 (white solid, 57 mg, yield 20.2%).
1H NMR(400MHz DMSO)δ9.22(s,1H),8.65(s,1H),8.38(s,1H),8.11(s,1H),7.72(s,1H),4.25-4.19(m,1H),3.30(s,3H),2.67-2.61(m,1H),2.41(s,3H),2.32-2.24(m,2H),2.15-2.12(m,2H),1.82-1.79(m,2H),1.73-1.64(m,2H)。 1 H NMR(400MHz DMSO)δ9.22(s,1H),8.65(s,1H),8.38(s,1H),8.11(s,1H),7.72(s,1H),4.25-4.19(m, 1H), 3.30(s, 3H), 2.67-2.61(m, 1H), 2.41(s, 3H), 2.32-2.24(m, 2H), 2.15-2.12(m, 2H), 1.82-1.79(m, 2H), 1.73-1.64 (m, 2H).
LC-MS m/z(ESI)＝404.20[M+1]。LC-MS m/z(ESI)=404.20[M+1].
实施例9Example 9
顺-4-(7-甲基-2-((7-甲基-[1,2,4]***并[1,5-a]吡啶-6-6基)氨基)-8-氧代-7,8-二氢-9H-嘌呤-9-基)环己烷-1-腈(化合物9)Cis-4-(7-methyl-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-6 yl)amino)-8-oxo -7,8-dihydro-9H-purin-9-yl)cyclohexane-1-carbonitrile (compound 9)
cis-4-(7-methyl-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-8-oxo-7,8-dihydro-9H-purin-9-yl)cyclohexane-1-carbonitrilecis-4-(7-methyl-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-8-oxo-7,8-dihydro -9H-purin-9-yl)cyclohexane-1-carbonitrile
Figure PCTCN2020141859-appb-000023
Figure PCTCN2020141859-appb-000023
Figure PCTCN2020141859-appb-000024
Figure PCTCN2020141859-appb-000024
第一步：first step:
叔丁基(顺-4-氨甲酰环己基)氨基甲酸酯(9b)Tert-Butyl (cis-4-carbamoylcyclohexyl) carbamate (9b)
tert-butyl(cis-4-carbamoylcyclohexyl)carbamatetert-butyl(cis-4-carbamoylcyclohexyl)carbamate
顺-4-((叔丁氧羰基)氨基)环己烷-1-羧酸9a(5.0g,20.5mmol)、O-(7-氮杂苯并三氮唑基)-N,N,N',N'-四甲基脲鎓六氟磷酸盐(9.4g,24.7mmol)溶解于二氯甲烷(15mL)，在0℃下搅拌20min，加入N,N二异丙基乙胺(10.5g,82mmol)及氯化铵(3.3g,61.5mmol)，在室温搅拌4h。TLC监测至反应结束，向反应液中加入水10mL，分离有机相，饱和盐水洗一次，用无水硫酸钠干燥并用硅胶拌样，用正相过柱仪过出产物，浓缩得到标题化合物叔丁基(顺-4-氨甲酰环己基)氨基甲酸酯9b(白色固体，3.5g,产率71％)。Cis-4-((tert-butoxycarbonyl)amino)cyclohexane-1-carboxylic acid 9a (5.0g, 20.5mmol), O-(7-azabenzotriazole)-N,N,N ',N'-Tetramethyluronium hexafluorophosphate (9.4g, 24.7mmol) was dissolved in dichloromethane (15mL), stirred at 0℃ for 20min, and N,N diisopropylethylamine (10.5g , 82mmol) and ammonium chloride (3.3g, 61.5mmol), stirred at room temperature for 4h. TLC monitors to the end of the reaction, add 10 mL of water to the reaction solution, separate the organic phase, wash with saturated brine once, dry with anhydrous sodium sulfate and mix the sample with silica gel, pass the product with a normal phase column passer, and concentrate to obtain the title compound tert-butyl Benzyl (cis-4-carbamoylcyclohexyl) carbamate 9b (white solid, 3.5 g, yield 71%).
LC-MS m/z(ESI)＝243.30[M+1]。LC-MS m/z(ESI)=243.30[M+1].
第二步：The second step:
叔丁基(顺-4-氰基环己基)氨基甲酸酯(9c)Tert-butyl (cis-4-cyanocyclohexyl) carbamate (9c)
tert-butyl(cis-4-cyanocyclohexyl)carbamatetert-butyl(cis-4-cyanocyclohexyl)carbamate
叔丁基(顺-4-氨甲酰环己基)氨基甲酸酯9b(3.5g,14.4mmol)溶解于70mL吡啶中，冰浴降温，然后将三氯氧磷(7.7mL)滴加进反应液中，冰浴搅拌1h。TLC监测反应完全，在冰浴下加入水20mL，用乙酸乙酯萃取4次，然后用酸水洗有机相7次，最后用饱和盐水洗两次，无水硫酸钠干燥，过滤并浓缩至干得到化合物叔丁基(顺-4-氰基环己基)氨基甲酸酯9c(黄色固体，1.5g,产率36％)。Tert-butyl (cis-4-carbamoylcyclohexyl) carbamate 9b (3.5g, 14.4mmol) was dissolved in 70mL of pyridine, cooled in an ice bath, and then phosphorus oxychloride (7.7mL) was added dropwise to the reaction In the solution, stir in an ice bath for 1 hour. TLC monitors the completion of the reaction, adds 20 mL of water in an ice bath, extracts 4 times with ethyl acetate, then washes the organic phase 7 times with acid water, and finally washes twice with saturated brine, dried with anhydrous sodium sulfate, filtered and concentrated to dryness. The compound tert-butyl (cis-4-cyanocyclohexyl) carbamate 9c (yellow solid, 1.5 g, yield 36%).
1H NMR(400MHz DMSO)δ6.90(d,1H),3.27-3.25(m,1H),3.01-2.99(m,1H),1.86-1.81(m,2H),1.71-1.67(m,2H),1.62-1.54(m,2H),1.43-1.40(m,1H),1.37(s,3H),1.34-1.32(m,1H)。 1 H NMR (400MHz DMSO) δ 6.90 (d, 1H), 3.27-3.25 (m, 1H), 3.01-2.99 (m, 1H), 1.86-1.81 (m, 2H), 1.71-1.67 (m, 2H) ), 1.62-1.54 (m, 2H), 1.43-1.40 (m, 1H), 1.37 (s, 3H), 1.34-1.32 (m, 1H).
LC-MS m/z(ESI)＝225.30[M+1]。LC-MS m/z(ESI)=225.30[M+1].
第三步：third step:
顺-4-氨基环己烷-1-碳腈(9d)Cis-4-aminocyclohexane-1-carbonitrile (9d)
cis-4-aminocyclohexane-1-carbonitrilecis-4-aminocyclohexane-1-carbonitrile
将叔丁基(反-4-氰基环己基)氨基甲酸酯9c(1.5g，6.7mmol)溶解于盐酸乙酸乙酯 溶液中(20mL)，加热至45℃，搅拌2h。TLC监测至反应结束，有白色固体析出，浓缩干燥得到标题化合物顺-4-氨基环己烷-1-碳腈9d(白色固体，1g，产率90％)。Dissolve tert-butyl (trans-4-cyanocyclohexyl) carbamate 9c (1.5 g, 6.7 mmol) in a hydrochloric acid ethyl acetate solution (20 mL), heat to 45°C, and stir for 2 h. TLC monitored to the end of the reaction, a white solid precipitated, concentrated and dried to obtain the title compound cis-4-aminocyclohexane-1-carbonitrile 9d (white solid, 1 g, yield 90%).
LC-MS m/z(ESI)＝125.30[M+1]。LC-MS m/z(ESI)=125.30[M+1].
第四步：the fourth step:
2-氯-4-(顺-4-氰基环己基)氨基)嘧啶-5-羧酸乙酯(9e)2-Chloro-4-(cis-4-cyanocyclohexyl)amino)pyrimidine-5-carboxylic acid ethyl ester (9e)
ethyl 2-chloro-4-(cis-4-cyanocyclohexyl)amino)pyrimidine-5-carboxylateethyl 2-chloro-4-(cis-4-cyanocyclohexyl)amino)pyrimidine-5-carboxylate
将2,4-二氯嘧啶-5-羧酸乙酯1a(1.48g,6.7mmol)、碳酸钾(1.38g,10mmol)溶解于乙腈(10mL)，在0℃下加入顺-4-氨基环己烷-1-碳腈9d(1g,6.7mmol)，在室温搅拌20h。TLC监测至反应结束，向反应液中加入水和乙酸乙酯萃取三次，饱和盐水洗一次，用无水硫酸钠干燥并用硅胶柱色谱分离(正己烷/乙酸乙酯(v/v)＝10:1)纯化，得到标题化合物2-氯-4-(顺-4-氰基环己基)氨基)嘧啶-5-羧酸乙酯9e(白色固体，589mg，产率60％)。Dissolve 2,4-dichloropyrimidine-5-carboxylic acid ethyl ester 1a (1.48g, 6.7mmol), potassium carbonate (1.38g, 10mmol) in acetonitrile (10mL), add cis-4-amino ring at 0℃ Hexane-1-carbonitrile 9d (1 g, 6.7 mmol) was stirred at room temperature for 20 h. TLC monitors until the reaction is complete, the reaction solution is added with water and ethyl acetate for extraction three times, washed with saturated brine once, dried with anhydrous sodium sulfate and separated by silica gel column chromatography (n-hexane/ethyl acetate (v/v)=10: 1) Purification to obtain the title compound 2-chloro-4-(cis-4-cyanocyclohexyl)amino)pyrimidine-5-carboxylic acid ethyl ester 9e (white solid, 589 mg, yield 60%).
1H NMR(400MHz DMSO)δ8.63(s,1H),8.38(d,1H),4.35-4.29(m,2H),4.07-3.99(m,1H),3.11-3.09(m,1H),1.92-1.73(m,6H),1,63-1.54(m,2H),1.47(t,3H)。 1 H NMR(400MHz DMSO)δ8.63(s,1H), 8.38(d,1H), 4.35-4.29(m,2H), 4.07-3.99(m,1H), 3.11-3.09(m,1H), 1.92-1.73 (m, 6H), 1,63-1.54 (m, 2H), 1.47 (t, 3H).
LC-MS m/z(ESI)＝310.20[M+1]。LC-MS m/z(ESI)=310.20[M+1].
第五步：the fifth step:
2-氯-4-((顺-4-氰基环己基)氨基)嘧啶-5-羧酸(9f)2-Chloro-4-((cis-4-cyanocyclohexyl)amino)pyrimidine-5-carboxylic acid (9f)
2-chloro-4-((cis-4-cyanocyclohexyl)amino)pyrimidine-5-carboxylic acide2-chloro-4-((cis-4-cyanocyclohexyl)amino)pyrimidine-5-carboxylic acid
将2-氯-4-((顺-4-氰基环己基)氨基)嘧啶-5-羧酸乙酯9e(589mg,1.9mmol)溶解于四氢呋喃/水(4mL/4mL)中，加入氢氧化锂(160mg,3.8mmol)，室温搅拌1h。TLC监测至反应结束，旋干四氢呋喃，调pH至4-5，有白色固体析出，过滤，滤饼用石油醚/乙酸乙酯(v/v＝10/1)洗两次，浓缩得到标题化合物2-氯-4-((顺-4-氰基环己基)氨基)嘧啶-5-羧酸9f(白色固体，490mg，产率86％)。Dissolve 2-chloro-4-((cis-4-cyanocyclohexyl)amino)pyrimidine-5-carboxylic acid ethyl ester 9e (589mg, 1.9mmol) in tetrahydrofuran/water (4mL/4mL) and add hydroxide Lithium (160 mg, 3.8 mmol) was stirred at room temperature for 1 h. TLC monitors to the end of the reaction, spin-dry the tetrahydrofuran, adjust the pH to 4-5, a white solid is precipitated, filtered, the filter cake is washed twice with petroleum ether/ethyl acetate (v/v=10/1), and concentrated to obtain the title compound 2-Chloro-4-((cis-4-cyanocyclohexyl)amino)pyrimidine-5-carboxylic acid 9f (white solid, 490 mg, yield 86%).
1H NMR(400MHz DMSO)δ13.83(s,1H),8.62-8.60(d,2H),4.05-3.98(m,1H),3.10(t,1H),1.94-1.73(m,6H),1.60-1.56(m,2H)。 1 H NMR (400MHz DMSO) δ 13.83 (s, 1H), 8.62-8.60 (d, 2H), 4.05-3.98 (m, 1H), 3.10 (t, 1H), 1.94-1.73 (m, 6H), 1.60-1.56 (m, 2H).
LC-MS m/z(ESI)＝282.30[M+1]。LC-MS m/z(ESI)=282.30[M+1].
第六步：The sixth step:
顺-4-(2-氯-8-氧代-7,8-二氢-9H-嘌呤-9-基)环己烷-1-碳腈(9g)Cis-4-(2-chloro-8-oxo-7,8-dihydro-9H-purin-9-yl)cyclohexane-1-carbonitrile (9g)
cis-4-(2-chloro-8-oxo-7,8-dihydro-9H-purin-9-yl)cyclohexane-1-carbonitrilecis-4-(2-chloro-8-oxo-7,8-dihydro-9H-purin-9-yl)cyclohexane-1-carbonitrile
将2-氯-4-(顺-4-氰基环己基)氨基)嘧啶-5-羧酸9f(490mg，1.75mmol)溶解于二甲基乙酰胺(10mL)，加入三乙胺(176mg,1.75mmol)、叠氮磷酸二苯酯(481mg,1.75mmol)，随后逐步升温至110℃,搅拌1.5h。TLC监测至反应结束，浓缩反应液，残留物用硅胶柱色谱分离(石油醚/乙酸乙酯(v/v)＝1:10)，得到标题化合物顺-4-(2-氯-8-氧代-7,8-二氢-9H-嘌呤-9-基)环己烷-1-碳腈9g(白色固体，436mg，产率68％)。2-Chloro-4-(cis-4-cyanocyclohexyl)amino)pyrimidine-5-carboxylic acid 9f (490mg, 1.75mmol) was dissolved in dimethylacetamide (10mL), and triethylamine (176mg, 1.75mmol), diphenyl azide phosphate (481mg, 1.75mmol), then gradually increase the temperature to 110°C and stir for 1.5h. The reaction was monitored by TLC until the end of the reaction. The reaction solution was concentrated. The residue was separated by silica gel column chromatography (petroleum ether/ethyl acetate (v/v)=1:10) to obtain the title compound cis-4-(2-chloro-8-oxy 9 g (white solid, 436 mg, 68% yield) of (dihydro-7,8-dihydro-9H-purin-9-yl)cyclohexane-1-carbonitrile.
1H NMR(400MHz DMSO)δ11.64(s,1H),8.13(s,1H),4.23-4.16(m,1H),3.22-3.16(m,1H),2.44-2.39(m,2H),2.00(d,2H),1.79-1.72(m,4H)。 1 H NMR (400MHz DMSO) δ 11.64 (s, 1H), 8.13 (s, 1H), 4.23-4.16 (m, 1H), 3.22-3.16 (m, 1H), 2.44-2.39 (m, 2H), 2.00 (d, 2H), 1.79-1.72 (m, 4H).
LC-MS m/z(ESI)＝278.30[M+1]。LC-MS m/z(ESI)=278.30[M+1].
第七步：The seventh step:
顺-4-(2-氯-7-甲基-8-氧代-7,8-二氢-9H-嘌呤-9-基)环己烷-1-碳腈(9h)Cis-4-(2-chloro-7-methyl-8-oxo-7,8-dihydro-9H-purin-9-yl)cyclohexane-1-carbonitrile (9h)
cis-4-(2-chloro-7-methyl-8-oxo-7,8-dihydro-9H-purin-9-yl)cyclohexane-1-carbonitrilecis-4-(2-chloro-7-methyl-8-oxo-7,8-dihydro-9H-purin-9-yl)cyclohexane-1-carbonitrile
将顺-4-(2-氯-8-氧代-7,8-二氢-9H-嘌呤-9-基)环己烷-1-碳腈9g(1.6g，5.77mmol)溶解于二甲基甲酰胺(10mL)，在0℃下加入硫酸二甲酯(728mg，5.77mmol)和碳酸铯(2.8g,8.65mmol)，0℃搅拌30min。TLC监测至反应结束，向反应液中加入水10mL，有固体析出，过滤得到标题化合物顺-4-(2-氯-7-甲基-8-氧代-7,8-二氢-9H-嘌呤-9-基)环己烷-1-碳腈9h(黄色固体，1.25g，产率75％)。Dissolve 9g (1.6g, 5.77mmol) of cis-4-(2-chloro-8-oxo-7,8-dihydro-9H-purin-9-yl)cyclohexane-1-carbonitrile in dimethyl Methyl formamide (10 mL), dimethyl sulfate (728 mg, 5.77 mmol) and cesium carbonate (2.8 g, 8.65 mmol) were added at 0°C, and stirred at 0°C for 30 min. TLC monitored to the end of the reaction, 10mL of water was added to the reaction solution, a solid precipitated out, filtered to obtain the title compound cis-4-(2-chloro-7-methyl-8-oxo-7,8-dihydro-9H- Purin-9-yl)cyclohexane-1-carbonitrile 9h (yellow solid, 1.25 g, yield 75%).
1H NMR(400MHz DMSO)δ8.35(s,1H),4.28-4.19(m,1H),3.34(s,3H),3.23-3.17(m,1H),2.46-2.39(m,2H),2.00(d,2H),1.80-1.73(m,4H)。 1 H NMR (400MHz DMSO) δ 8.35 (s, 1H), 4.28-4.19 (m, 1H), 3.34 (s, 3H), 3.23 3.17 (m, 1H), 2.46-2.39 (m, 2H), 2.00 (d, 2H), 1.80-1.73 (m, 4H).
LC-MS m/z(ESI)＝292.30[M+1]第七步：LC-MS m/z(ESI)=292.30[M+1] Step 7:
顺-4-(7-甲基-2-((7-甲基-[1,2,4]***并[1,5-a]吡啶-6-6基)氨基)-8-氧代-7,8-二氢-9H-嘌呤-9-基)环己烷-1-腈(化合物9)Cis-4-(7-methyl-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-6 yl)amino)-8-oxo -7,8-dihydro-9H-purin-9-yl)cyclohexane-1-carbonitrile (compound 9)
cis-4-(7-methyl-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-8-oxo-7,8-dihydro-9H-purin-9-yl)cyclohexane-1-carbonitrilecis-4-(7-methyl-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-8-oxo-7,8-dihydro -9H-purin-9-yl)cyclohexane-1-carbonitrile
将顺-4-(2-氯-7-甲基-8-氧代-7,8-二氢-9H-嘌呤-9-基)环己烷-1-腈9h(200mg，0.68mmol)、7-甲基-[1,2,4]***并[1,5-a]吡啶-6-胺(101mg，0.68mmol)、碳酸铯(391mg,1.2mmol)、甲磺酸(2-二环己基膦-3,6-二甲氧基-2’,4’,6'-三异丙基-1,1'-联苯)(2'-氨基-1,1'-联苯基-2-基)钯(II)(62mg，0.068mmol)溶解于二氧六环3mL中，氮气保护并换气，在110℃搅拌4h。浓缩反应液，残留物用硅胶柱色谱分离提纯(二氯甲烷/甲醇(v/v)＝60/1)，并通过Pre-HPLC得到标题化合物顺-4-(7-甲基-2-((7-甲基-[1,2,4]***并[1,5-a]吡啶-6-6基)氨基)-8-氧代-7,8-二氢-9H-嘌呤-9-基)环己烷-1-腈化合物9(白色固体,131mg，产率41.2％)。Cis-4-(2-chloro-7-methyl-8-oxo-7,8-dihydro-9H-purin-9-yl)cyclohexane-1-carbonitrile 9h (200mg, 0.68mmol), 7-Methyl-[1,2,4]triazolo[1,5-a]pyridine-6-amine (101mg, 0.68mmol), cesium carbonate (391mg, 1.2mmol), methanesulfonic acid (2-di Cyclohexylphosphine-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl- 2-yl)palladium (II) (62 mg, 0.068 mmol) was dissolved in 3 mL of dioxane, protected with nitrogen and ventilated, and stirred at 110° C. for 4 h. The reaction solution was concentrated, and the residue was separated and purified by silica gel column chromatography (dichloromethane/methanol (v/v)=60/1), and the title compound cis-4-(7-methyl-2-( (7-Methyl-[1,2,4]triazolo[1,5-a]pyridin-6-6 yl)amino)-8-oxo-7,8-dihydro-9H-purine-9 -Yl)cyclohexane-1-nitrile compound 9 (white solid, 131 mg, yield 41.2%).
1H NMR(400MHz DMSO)δ9.08(s,1H),8.57(s,1H),8.34(s,1H),8.09(s,1H),7.67(s,1H),4.23-4.15(m,1H),3.30(s,3H),3.14(s,1H),2.51-2.49(m,2H),2.36(s,3H),1.98(d,2H),1.76(d,2H),1.71-1.66(m,2H)。 1 H NMR(400MHz DMSO)δ9.08(s,1H), 8.57(s,1H), 8.34(s,1H), 8.09(s,1H), 7.67(s,1H), 4.23-4.15(m, 1H), 3.30 (s, 3H), 3.14 (s, 1H), 2.51-2.49 (m, 2H), 2.36 (s, 3H), 1.98 (d, 2H), 1.76 (d, 2H), 1.71-1.66 (m, 2H).
LC-MS m/z(ESI)＝404.20[M+1]。LC-MS m/z(ESI)=404.20[M+1].
实施例10Example 10
7-甲基-2-((7-甲基-[1,2,4]***并[1,5-a]吡啶-6-基)氨基)-9-(1-甲基哌啶-4-基)-7,9-二氢-8H-嘌呤-8-酮(化合物10)7-methyl-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-9-(1-methylpiperidine- 4-yl)-7,9-dihydro-8H-purin-8-one (compound 10)
7-methyl-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-9-(1-methylpiperidin-4-yl)-7,9-dihydro-8H-purin-8-one7-methyl-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-9-(1-methylpiperidin-4-yl)-7, 9-dihydro-8H-purin-8-one
Figure PCTCN2020141859-appb-000025
Figure PCTCN2020141859-appb-000025
第一步：first step:
4-((1-(叔丁氧基羰基)哌啶-4-基)氨基)-2-氯嘧啶-5-羧酸乙酯(10b)4-((1-(tert-butoxycarbonyl)piperidin-4-yl)amino)-2-chloropyrimidine-5-carboxylic acid ethyl ester (10b)
ethyl 4-((1-(tert-butoxycarbonyl)piperidin-4-yl)amino)-2-chloropyrimidine-5-carboxylateethyl 4-((1-(tert-butoxycarbonyl)piperidin-4-yl)amino)-2-chloropyrimidine-5-carboxylate
将2,4-二氯嘧啶-5-羧酸乙酯1a(5g,22.6mmol)、碳酸钾(6.2g,45.2mmol)溶解于乙 腈(20mL)，在0℃下加入(4-氨基哌啶-1-羧酸叔丁酯10a(4.5g,22.6mmol)，在室温搅拌20h,TLC监测至反应完全，加水30mL，用乙酸乙酯60mL萃取三次，饱和盐水洗一次，用无水硫酸钠干燥后，经硅胶柱色谱分离提纯(正己烷:乙酸乙酯＝10:1)，得到标题化合物，4-((1-(叔丁氧基羰基)哌啶-4-基)氨基)-2-氯嘧啶-5-羧酸乙酯10b(白色固体,8.2g,产率95％)。Dissolve 2,4-dichloropyrimidine-5-carboxylic acid ethyl ester 1a (5g, 22.6mmol), potassium carbonate (6.2g, 45.2mmol) in acetonitrile (20mL), add (4-aminopiperidine 1-tert-butyl carboxylate 10a (4.5g, 22.6mmol), stirred at room temperature for 20h, TLC monitored until the reaction was complete, added 30mL of water, extracted three times with 60mL of ethyl acetate, washed once with saturated brine, and dried with anhydrous sodium sulfate Then, it was separated and purified by silica gel column chromatography (n-hexane: ethyl acetate = 10:1) to obtain the title compound, 4-((1-(tert-butoxycarbonyl)piperidin-4-yl)amino)-2- Ethyl chloropyrimidine-5-carboxylate 10b (white solid, 8.2 g, yield 95%).
1H NMR(400MHz DMSO)δ8.63(s,1H),8.32(d,1H),4.33-4.28(m,2H),4.17-4.14(m,1H),3.85(d,2H),2.94(s,2H),1.88-1.80(m,2H),1.51-1.44(m,2H),1.41(s,9H),1.32-1.29(m,3H)。 1 H NMR(400MHz DMSO)δ8.63(s,1H), 8.32(d,1H), 4.33-4.28(m,2H), 4.17-4.14(m,1H), 3.85(d,2H), 2.94( s, 2H), 1.88-1.80 (m, 2H), 1.51-1.44 (m, 2H), 1.41 (s, 9H), 1.32-1.29 (m, 3H).
LC-MS m/z(ESI)＝385.10[M+1]。LC-MS m/z(ESI)=385.10[M+1].
第二步：The second step:
4-((1-(叔丁氧基羰基)哌啶-4-基)氨基)-2-氯嘧啶-5-羧酸(10c)4-((1-(tert-butoxycarbonyl)piperidin-4-yl)amino)-2-chloropyrimidine-5-carboxylic acid (10c)
4-((1-(tert-butoxycarbonyl)piperidin-4-yl)amino)-2-chloropyrimidine-5-carboxylic acid4-((1-(tert-butoxycarbonyl)piperidin-4-yl)amino)-2-chloropyrimidine-5-carboxylic acid
将4-((1-(叔丁氧基羰基)哌啶-4-基)氨基)-2-氯嘧啶-5-羧酸乙酯10b(8.2g，21.3mmol)溶解于四氢呋喃10mL，水5mL中，加入氢氧化锂(1.8g,42.7mmol)，室温搅拌1h,TLC监测至反应完全，四氢呋喃旋干，调pH为4-5，有白色固体析出，过滤，滤饼用石油醚/乙酸乙酯(v/v＝10/1)洗两次，浓缩得到标题化合物，4-((1-(叔丁氧基羰基)哌啶-4-基)氨基)-2-氯嘧啶-5-羧酸10c(白色固体,7g，产率86％)。Dissolve 4-((1-(tert-butoxycarbonyl)piperidin-4-yl)amino)-2-chloropyrimidine-5-carboxylic acid ethyl ester 10b (8.2g, 21.3mmol) in tetrahydrofuran 10mL, water 5mL Add lithium hydroxide (1.8g, 42.7mmol), stir at room temperature for 1h, TLC monitors until the reaction is complete, tetrahydrofuran is spin-dried, adjust the pH to 4-5, a white solid precipitates, filter, filter cake with petroleum ether/ethyl acetate The ester (v/v=10/1) was washed twice and concentrated to obtain the title compound, 4-((1-(tert-butoxycarbonyl)piperidin-4-yl)amino)-2-chloropyrimidine-5-carboxy Acid 10c (white solid, 7g, yield 86%).
1H NMR(400MHz DMSO)δ8.59(s,1H),8.54(d,1H),4.20-4.10(m,1H),3.87-3.84(m,2H),2.96(s,3H),1.91-1.73(m,3H),1.41(s,9H)。 1 H NMR (400MHz DMSO) δ 8.59 (s, 1H), 8.54 (d, 1H), 4.20-4.10 (m, 1H), 3.87-3.84 (m, 2H), 2.96 (s, 3H), 1.91 1.73 (m, 3H), 1.41 (s, 9H).
LC-MS m/z(ESI)＝357.10[M+1]。LC-MS m/z(ESI)=357.10[M+1].
第三步third step
4-(2-氯-8-氧代-7,8-二氢-9H-嘌呤-9-基)哌啶-1-甲酸叔丁酯(10d)Tert-Butyl 4-(2-chloro-8-oxo-7,8-dihydro-9H-purin-9-yl)piperidine-1-carboxylate (10d)
tert-butyl 4-(2-chloro-8-oxo-7,8-dihydro-9H-purin-9-yl)piperidine-1-carboxylatetert-butyl 4-(2-chloro-8-oxo-7,8-dihydro-9H-purin-9-yl)piperidine-1-carboxylate
将4-((1-(叔丁氧基羰基)哌啶-4-基)氨基)-2-氯嘧啶-5-羧酸10c(7g，19.6mmol)溶解于二甲基乙酰胺(10mL)，加入三乙胺(1.96g,19.6mmol)、叠氮磷酸二苯酯(5.4g,19.6mmol)，随后逐步升温至110℃，搅拌1.5h，TLC监测至反应完全，浓缩反应液，经硅胶柱色谱分离提纯(石油醚/乙酸乙酯(v/v)＝5:1～1:10)，得到标题化合物，4-(2-氯-8-氧代-7,8-二氢-9H-嘌呤-9-基)哌啶-1-甲酸叔丁酯10d(白色固体,6.4g，产率87％)。Dissolve 4-((1-(tert-butoxycarbonyl)piperidin-4-yl)amino)-2-chloropyrimidine-5-carboxylic acid 10c (7g, 19.6mmol) in dimethylacetamide (10mL) , Add triethylamine (1.96g, 19.6mmol) and diphenyl azide phosphate (5.4g, 19.6mmol), then gradually increase the temperature to 110°C, stir for 1.5h, TLC monitors until the reaction is complete, concentrate the reaction solution, and pass the silica gel Separation and purification by column chromatography (petroleum ether/ethyl acetate (v/v)=5:1～1:10), to obtain the title compound, 4-(2-chloro-8-oxo-7,8-dihydro-9H -Purin-9-yl)piperidine-1-carboxylic acid tert-butyl ester 10d (white solid, 6.4 g, yield 87%).
1H NMR(400MHz DMSO)δ8.14(s,1H),4.41-4.33(m,1H),4.06(d,2H),2.88(s,2H),2.30-2.20(m,2H),1.84-1.71(m,2H),1.43(s,9H)。 1 H NMR (400MHz DMSO) δ 8.14 (s, 1H), 4.41-4.33 (m, 1H), 4.06 (d, 2H), 2.88 (s, 2H), 2.30-2.20 (m, 2H), 1.84- 1.71 (m, 2H), 1.43 (s, 9H).
LC-MS m/z(ESI)＝354.10[M+1]。LC-MS m/z(ESI)=354.10[M+1].
第四步the fourth step
4-(2-氯-7-甲基-8-氧代-7,8-二氢-9H-嘌呤-9-基)哌啶-1-甲酸叔丁酯(10e)Tert-Butyl 4-(2-chloro-7-methyl-8-oxo-7,8-dihydro-9H-purin-9-yl)piperidine-1-carboxylate (10e)
tert-butyl4-(2-chloro-7-methyl-8-oxo-7,8-dihydro-9H-purin-9-yl)piperidine-1-carboxylatetert-butyl4-(2-chloro-7-methyl-8-oxo-7,8-dihydro-9H-purin-9-yl)piperidine-1-carboxylate
将4-(2-氯-8-氧代-7,8-二氢-9H-嘌呤-9-基)哌啶-1-甲酸叔丁酯10d(6.4g，18.1mmol)溶解于二甲基甲酰胺(10mL)，在0℃下加入硫酸二甲酯(2.28g，18.1mmol)和碳酸铯(8.5g,27.1mmol)，0℃搅拌30min，TLC监测至反应完全，随后加入30mL水，有固体析出，过滤得到标题化合物，4-(2-氯-7-甲基-8-氧代-7,8-二氢-9H-嘌呤-9-基)哌啶-1-甲酸叔丁酯10e(白色固体，5.4g，产率79％)。Dissolve tert-butyl 4-(2-chloro-8-oxo-7,8-dihydro-9H-purin-9-yl)piperidine-1-carboxylate 10d (6.4g, 18.1mmol) in dimethyl Formamide (10mL), add dimethyl sulfate (2.28g, 18.1mmol) and cesium carbonate (8.5g, 27.1mmol) at 0°C, stir at 0°C for 30min, TLC monitors until the reaction is complete, and then add 30mL of water. A solid precipitated out and filtered to obtain the title compound, tert-butyl 4-(2-chloro-7-methyl-8-oxo-7,8-dihydro-9H-purin-9-yl)piperidine-1-carboxylate 10e (White solid, 5.4g, yield 79%).
1H NMR(400MHz DMSO)δ8.36(s,1H),4.46-4.37(m,1H),4.05(d,2H),3.35(s,3H),2.87(s,2H),2.33-2.19(m,2H),1.74-1.72(m,2H),1.43(s,9H)。 1 H NMR (400MHz DMSO) δ 8.36 (s, 1H), 4.46-4.37 (m, 1H), 4.05 (d, 2H), 3.35 (s, 3H), 2.87 (s, 2H), 2.33-2.19 ( m, 2H), 1.74-1.72 (m, 2H), 1.43 (s, 9H).
LC-MS m/z(ESI)＝368.10[M+1]。LC-MS m/z(ESI)=368.10[M+1].
第五步the fifth step
2-氯-7-甲基-9-(哌啶-4-基)-7,9-二氢-8H-嘌呤-8-酮(10f)2-chloro-7-methyl-9-(piperidin-4-yl)-7,9-dihydro-8H-purin-8-one (10f)
2-chloro-7-methyl-9-(piperidin-4-yl)-7,9-dihydro-8H-purin-8-one2-chloro-7-methyl-9-(piperidin-4-yl)-7,9-dihydro-8H-purin-8-one
将4-(2-氯-8-氧代-7,8-二氢-9H-嘌呤-9-基)哌啶-1-甲酸叔丁酯10e(2g，5.4mmol)加 入到100mL单口瓶中，然后常温加入盐酸乙酸乙酯溶液2M(10mL)，常温搅拌4h，TLC监测至反应完全，浓缩反应液，得到标题化合物，2-氯-7-甲基-9-(哌啶-4-基)-7,9-二氢-8H-嘌呤-8-酮的盐酸盐10f(白色固体，1.4g，产率91％)。Add 4-(2-chloro-8-oxo-7,8-dihydro-9H-purin-9-yl)piperidine-1-carboxylic acid tert-butyl ester 10e (2g, 5.4mmol) into a 100mL single-mouth bottle Then add 2M hydrochloric acid ethyl acetate solution (10mL) at room temperature, and stir at room temperature for 4h. TLC monitors until the reaction is complete. The reaction solution is concentrated to obtain the title compound, 2-chloro-7-methyl-9-(piperidin-4-yl )-7,9-dihydro-8H-purin-8-one hydrochloride 10f (white solid, 1.4g, yield 91%).
1H NMR(400MHz DMSO)δ8.39(s,1H),6.42(s,1H),4.59-4.53(m,1H),3.39(s,2H),3.36(s,3H),3.16-3.04(m,2H),2.62-2.50(m,2H),2.07-1.93(m,2H)。 1 H NMR(400MHz DMSO)δ8.39(s,1H), 6.42(s,1H), 4.59-4.53(m,1H), 3.39(s,2H), 3.36(s,3H), 3.16-3.04( m, 2H), 2.62-2.50 (m, 2H), 2.07-1.93 (m, 2H).
LC-MS m/z(ESI)＝268.10[M+1]。LC-MS m/z(ESI)=268.10[M+1].
第六步：The sixth step:
2-氯-7-甲基-9-(1-甲基哌啶-4-基)-7,9-二氢-8H-嘌呤-8-酮(10g)2-chloro-7-methyl-9-(1-methylpiperidin-4-yl)-7,9-dihydro-8H-purin-8-one (10g)
2-chloro-7-methyl-9-(1-methylpiperidin-4-yl)-7,9-dihydro-8H-purin-8-one2-chloro-7-methyl-9-(1-methylpiperidin-4-yl)-7,9-dihydro-8H-purin-8-one
将2-氯-7-甲基-9-(哌啶-4-基)-7,9-二氢-8H-嘌呤-8-酮10f(1.4g,5.4mmol)溶解于甲醇(20mL)，加入4A分子筛100mg，然后加入多聚甲醛(783mg,27mmol)，在室温搅拌6h,然后加入氰基硼氢化钠(1g,16.2mmol)，TLC监测至反应完全，过滤并浓缩得到标题化合物，2-氯-7-甲基-9-(1-甲基哌啶-4-基)-7,9-二氢-8H-嘌呤-8-酮10g(白色固体，600mg,产率62％)。Dissolve 2-chloro-7-methyl-9-(piperidin-4-yl)-7,9-dihydro-8H-purin-8-one 10f (1.4g, 5.4mmol) in methanol (20mL), Add 100mg of 4A molecular sieve, then add paraformaldehyde (783mg, 27mmol), stir at room temperature for 6h, then add sodium cyanoborohydride (1g, 16.2mmol), TLC monitor until the reaction is complete, filter and concentrate to obtain the title compound, 2- Chloro-7-methyl-9-(1-methylpiperidin-4-yl)-7,9-dihydro-8H-purin-8-one 10g (white solid, 600mg, yield 62%).
1H NMR(400MHz DMSO)δ8.35(s,1H),4.21-4.13(m,1H),3.35(s,3H),2.92(d,2H),2.45-2.41(m,2H),2.23(s,3H),2.09-2.03(m,2H),1.70-1.67(m,2H)。 1 H NMR(400MHz DMSO)δ8.35(s,1H), 4.21-4.13(m,1H), 3.35(s,3H), 2.92(d,2H), 2.45-2.41(m,2H), 2.23( s, 3H), 2.09-2.03 (m, 2H), 1.70-1.67 (m, 2H).
LC-MS m/z(ESI)＝282.10[M+1]。LC-MS m/z(ESI)=282.10[M+1].
第七步：The seventh step:
7-甲基-2-((7-甲基-[1,2,4]***并[1,5-a]吡啶-6-基)氨基)-9-(1-甲基哌啶-4-基)-7,9-二氢-8H-嘌呤-8-酮(化合物10)7-methyl-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-9-(1-methylpiperidine- 4-yl)-7,9-dihydro-8H-purin-8-one (compound 10)
7-methyl-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-9-(1-methylpiperidin-4-yl)-7,9-dihydro-8H-purin-8-one7-methyl-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-9-(1-methylpiperidin-4-yl)-7, 9-dihydro-8H-purin-8-one
将2-氯-7-甲基-9-(1-甲基哌啶-4-基)-7,9-二氢-8H-嘌呤-8-酮10g(150mg，0.53mmol)、7-甲基-[1,2,4]***并[1,5-a]吡啶-6-胺(79mg，0.53mmol)、碳酸铯(518mg,1.59mmol)、甲磺酸(2-二环己基膦-3,6-二甲氧基-2’,4’,6'-三异丙基-1,1'-联苯))2'-氨基-1,1'-联苯基-2-基)钯(II)(48mg，0.053mmol)溶解于二氧六环(3mL)，氮气保护并换气，在100℃搅拌4h。TLC监测至反应完全，浓缩反应液，残留物用硅胶柱色谱分离提纯(二氯甲烷/甲醇(v/v)＝20/1)，并经过Pre-HPLC得到标题化合物，7-甲基-2-((7-甲基-[1,2,4]***并[1,5-a]吡啶-6-基)氨基)-9-(1-甲基哌啶-4-基)-7,9-二氢-8H-嘌呤-8-酮化合物10(白色固体，20mg,产率18％)。Combine 2-chloro-7-methyl-9-(1-methylpiperidin-4-yl)-7,9-dihydro-8H-purin-8-one 10g (150mg, 0.53mmol), 7-methyl -[1,2,4]triazolo[1,5-a]pyridine-6-amine (79mg, 0.53mmol), cesium carbonate (518mg, 1.59mmol), methanesulfonic acid (2-dicyclohexylphosphine) -3,6-Dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)) 2'-amino-1,1'-biphenyl-2-yl ) Palladium(II) (48mg, 0.053mmol) was dissolved in dioxane (3mL), protected with nitrogen and ventilated, and stirred at 100°C for 4h. The reaction was monitored by TLC until the reaction was complete. The reaction solution was concentrated. The residue was separated and purified by silica gel column chromatography (dichloromethane/methanol (v/v)=20/1), and the title compound, 7-methyl-2, was obtained by Pre-HPLC. -((7-Methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-9-(1-methylpiperidin-4-yl)-7 , 9-Dihydro-8H-purin-8-one compound 10 (white solid, 20 mg, yield 18%).
1H NMR(400MHz DMSO)δ9.23(s,1H),8.33(s,1H),8.29(s,1H),8.12(s,1H),7.69(s,1H),4.53-4.33(m,1H),3.50(d,2H),2.86-2.77(m,4H),2.43(s,3H),1.99(d,2H)。 1 H NMR(400MHz DMSO)δ9.23(s,1H), 8.33(s,1H), 8.29(s,1H), 8.12(s,1H), 7.69(s,1H), 4.53-4.33(m, 1H), 3.50 (d, 2H), 2.86-2.77 (m, 4H), 2.43 (s, 3H), 1.99 (d, 2H).
LC-MS m/z(ESI)＝394.20[M+1]。LC-MS m/z(ESI)=394.20[M+1].
实施例11Example 11
7-甲基-2-((7-甲基-[1,2,4]***并[1,5-a]吡啶-6-基)氨基)-9-(哌啶-4-基)-7,9-二氢-8H-嘌呤-8-酮(化合物11)7-methyl-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-9-(piperidin-4-yl) -7,9-dihydro-8H-purin-8-one (Compound 11)
7-methyl-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-9-(piperidin-4-yl)-7,9-dihydro-8H-purin-8-one7-methyl-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-9-(piperidin-4-yl)-7,9- dihydro-8H-purin-8-one
Figure PCTCN2020141859-appb-000026
Figure PCTCN2020141859-appb-000026
Figure PCTCN2020141859-appb-000027
Figure PCTCN2020141859-appb-000027
第一步：first step:
叔丁基4-(7-甲基-2-(((7-甲基-[1,2,4]***并[1,5-a]吡啶-6-基)氨基)-8-氧代-7,8-二氢-9H-嘌呤-9-基)哌啶-1-甲酸(11a)Tert-butyl 4-(7-methyl-2-(((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-8-oxy Substituted-7,8-dihydro-9H-purin-9-yl)piperidine-1-carboxylic acid (11a)
tert-butyl4-(7-methyl-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-8-oxo-7,8-dihydro-9H-purin-9-yl)piperidine-1-carboxylatetert-butyl4-(7-methyl-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-8-oxo-7,8-dihydro -9H-purin-9-yl)piperidine-1-carboxylate
将4-(2-氯-7-甲基-8-氧代-7,8-二氢-9H-嘌呤-9-基)哌啶-1-甲酸叔丁酯10e(200mg，0.54mmol)、7-甲基-[1,2,4]***并[1,5-a]吡啶-6-胺(148mg，0.54mmol)、碳酸铯(528mg,1.62mmol)、甲磺酸(2-二环己基膦-3,6-二甲氧基-2’,4’,6'-三异丙基-1,1'-联苯))2'-氨基-1,1'-联苯基-2-基)钯(II)(50mg，0.054mmol)溶解于二氧六环(3mL)，氮气保护并换气，在100℃搅拌4h。TLC监测至反应完全，浓缩反应液，残留物用硅胶柱色谱分离提纯)二氯甲烷/甲醇(v/v)＝60/1)，得到标题化合物，叔丁基4-(7-甲基-2-((7-甲基-[1,2,4]***并[1,5-a]吡啶-6-6基)氨基)-8-氧代-7,8-二氢-9H-嘌呤-9-基)哌啶-1-甲酸11a(白色固体，120mg,产率62％)。The 4-(2-chloro-7-methyl-8-oxo-7,8-dihydro-9H-purin-9-yl) piperidine-1-carboxylic acid tert-butyl ester 10e (200mg, 0.54mmol), 7-Methyl-[1,2,4]triazolo[1,5-a]pyridine-6-amine (148mg, 0.54mmol), cesium carbonate (528mg, 1.62mmol), methanesulfonic acid (2-di Cyclohexylphosphine-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)) 2'-amino-1,1'-biphenyl- 2-yl)palladium(II) (50mg, 0.054mmol) was dissolved in dioxane (3mL), protected with nitrogen and ventilated, and stirred at 100°C for 4h. TLC monitors until the reaction is complete, the reaction solution is concentrated, and the residue is separated and purified by silica gel column chromatography) dichloromethane/methanol (v/v)=60/1) to obtain the title compound, tert-butyl 4-(7-methyl- 2-((7-Methyl-[1,2,4]triazolo[1,5-a]pyridin-6-6yl)amino)-8-oxo-7,8-dihydro-9H- Purin-9-yl)piperidine-1-carboxylic acid 11a (white solid, 120 mg, yield 62%).
1H NMR(400MHz DMSO)δ9.08(s,1H),8.57(s,1H),8.36(s,1H),8.08(s,1H),7.69-7.68(m,1H),4.38-4.30(m,1H),4.06-4.10(m,2H),3.29(s,3H),2.81(s,2H),2.40(s,3H),2.37-2.31(m,2H),1.75-1.72(m,2H),1.39(s,9H)。 1 H NMR(400MHz DMSO)δ9.08(s,1H), 8.57(s,1H), 8.36(s,1H), 8.08(s,1H), 7.69-7.68(m,1H), 4.38-4.30( m, 1H), 4.06-4.10 (m, 2H), 3.29 (s, 3H), 2.81 (s, 2H), 2.40 (s, 3H), 2.37-2.31 (m, 2H), 1.75-1.72 (m, 2H), 1.39(s, 9H).
LC-MS m/z(ESI)＝480.20[M+1]。LC-MS m/z(ESI)=480.20[M+1].
第二步：The second step:
7-甲基-2-((7-甲基-[1,2,4]***并[1,5-a]吡啶-6-基)氨基)-9-(哌啶-4-基)-7,9-二氢-8H-嘌呤-8-酮(化合物11)7-methyl-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-9-(piperidin-4-yl) -7,9-dihydro-8H-purin-8-one (Compound 11)
7-methyl-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-9-(piperidin-4-yl)-7,9-dihydro-8H-purin-8-one7-methyl-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-9-(piperidin-4-yl)-7,9- dihydro-8H-purin-8-one
将叔丁基4-(7-甲基-2-((7-甲基-[1,2,4]***并[1,5-a]吡啶-6-6基)氨基)-8-氧代-7,8-二氢-9H-嘌呤-9-基)哌啶-1-甲酸11a(120mg，0.25mmol)加入到50mL单口瓶中，2M盐酸乙酸乙酯(10mL)加入其中，常温搅拌4h。TLC监测至反应完全，浓缩反应液，残留物经Pre-HPLC得到标题化合物，7-甲基-2-((7-甲基-[1,2,4]***并[1,5-a]吡啶-6-基)氨基)-9-(哌啶-4-基)-7,9-二氢-8H-嘌呤-8-酮化合物11(白色固体，32mg,产率23％)。The tert-butyl 4-(7-methyl-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-6 yl)amino)-8- Oxo-7,8-dihydro-9H-purin-9-yl)piperidine-1-carboxylic acid 11a (120mg, 0.25mmol) was added to a 50mL single-necked flask, 2M hydrochloric acid ethyl acetate (10mL) was added to it, at room temperature Stir for 4h. TLC monitored until the reaction was complete, the reaction solution was concentrated, and the residue was subjected to Pre-HPLC to obtain the title compound, 7-methyl-2-((7-methyl-[1,2,4]triazolo[1,5-a ]Pyridin-6-yl)amino)-9-(piperidin-4-yl)-7,9-dihydro-8H-purin-8-one compound 11 (white solid, 32 mg, yield 23%).
1H NMR(400MHz DMSO)δ9.20(s,1H),8.62(s,1H),8.37(s,1H),8.09(s,1H),7.70(s,1H),4.30-4.22(m,1H),3.30(s,3H),3.10-3.07(m,2H),2.67-2.58(m,2H),2.41(s,3H),2.38-2.32(m,2H),1.69-1.65(m,2H)。 1 H NMR(400MHz DMSO)δ9.20(s,1H), 8.62(s,1H), 8.37(s,1H), 8.09(s,1H), 7.70(s,1H), 4.30-4.22(m, 1H), 3.30(s, 3H), 3.10-3.07(m, 2H), 2.67-2.58(m, 2H), 2.41(s, 3H), 2.38-2.32(m, 2H), 1.69-1.65(m, 2H).
LC-MS m/z(ESI)＝380.20[M+1]。LC-MS m/z(ESI)=380.20[M+1].
实施例12Example 12
9-(反-3-羟基环丁基)-7-甲基-2-(((7-甲基-[1,2,4]***并[1,5-a]吡啶-6-基)氨基)-7,9-二氢-8H-嘌呤-8-酮(化合物12)9-(trans-3-hydroxycyclobutyl)-7-methyl-2-(((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl )Amino)-7,9-dihydro-8H-purin-8-one (compound 12)
9-(trans-3-hydroxycyclobutyl)-7-methyl-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-7,9-dihydro-8H-purin-8-one9-(trans-3-hydroxycyclobutyl)-7-methyl-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-7,9- dihydro-8H-purin-8-one
Figure PCTCN2020141859-appb-000028
Figure PCTCN2020141859-appb-000028
第一步：first step:
2-氯-4-((反-3-羟基环丁基)氨基)嘧啶-5-羧酸乙酯(12a)Ethyl 2-chloro-4-((trans-3-hydroxycyclobutyl)amino)pyrimidine-5-carboxylate (12a)
ethyl 2-chloro-4-((trans-3-hydroxycyclobutyl)amino)pyrimidine-5-carboxylateethyl 2-chloro-4-((trans-3-hydroxycyclobutyl)amino)pyrimidine-5-carboxylate
将(反-3-氨基环丁烷-1-醇盐酸盐(3.00g,34.48mmol)溶于乙腈(25mL)中，0℃搅拌下加入碳酸钾(14.30g,103.45mmol)、2,4-二氯-5-嘧啶甲酸乙酯1a(11.43g,51.72mmol)，升温至常温搅拌反应1h，TLC监测至反应结束，硅藻土过滤后用硅胶柱色谱分离提纯(石油醚/乙酸乙酯(v/v)＝2:1)纯化得标题化合物2-氯-4-((反-3-羟基环丁基)氨基)嘧啶-5-羧酸乙酯(12a)(白色固体，2.9g，产率30.95％)。Dissolve (trans-3-aminocyclobutane-1-ol hydrochloride (3.00g, 34.48mmol) in acetonitrile (25mL), add potassium carbonate (14.30g, 103.45mmol), 2,4 -Dichloro-5-pyrimidinecarboxylic acid ethyl ester 1a (11.43g, 51.72mmol), heated to room temperature and stirred for 1h, monitored by TLC until the reaction is over, filtered through diatomaceous earth and purified by silica gel column chromatography (petroleum ether/ethyl acetate) (v/v)=2:1) Purified to obtain the title compound 2-chloro-4-((trans-3-hydroxycyclobutyl)amino)pyrimidine-5-carboxylic acid ethyl ester (12a) (white solid, 2.9g , The yield is 30.95%).
1H NMR(400MHz,DMSO-d6)δ8.61(s,1H),8.48(d,1H),5.17-5.11(m,1H),4.61–4.51(m,1H),4.36–4.27(m,3H),2.32-2.20(m,4H),1.32(t,3H)。1H NMR(400MHz,DMSO-d6)δ8.61(s,1H), 8.48(d,1H), 5.17-5.11(m,1H), 4.61-4.51(m,1H), 4.36-4.27(m,3H) ), 2.32-2.20 (m, 4H), 1.32 (t, 3H).
LC-MS m/z(ESI)＝272.00[M+1]。LC-MS m/z(ESI)=272.00[M+1].
第二步：The second step:
4-((反-3-((叔丁基二苯基硅烷基)氧基)环丁基)氨基)-2-氯嘧啶-5-羧酸乙酯(12b)4-((trans-3-((tert-butyldiphenylsilyl)oxy)cyclobutyl)amino)-2-chloropyrimidine-5-carboxylic acid ethyl ester (12b)
ethyl 4-((trans-3-((tert-butyldiphenylsilyl)oxy)cyclobutyl)amino)-2-chloropyrimidine-5-carboxylateethyl 4-((trans-3-((tert-butyldiphenylsilyl)oxy)cyclobutyl)amino)-2-chloropyrimidine-5-carboxylate
将2-氯-4-((反-3-羟基环丁基)氨基)嘧啶-5-羧酸乙酯12a(3.10g,11.41mmol)溶解于二氯甲烷(20mL)中，加入叔丁基二苯基氯硅烷(4.45mL,17.11mmol)、咪唑(1.94g,28.52mmol)，氮气保护并换气，常温搅拌反应2h，TLC监测至反应结束，硅胶柱色谱分离提纯(石油醚/乙酸乙酯(v/v)＝10:1)纯化得标题化合物4-(反-3-((叔丁基二苯基硅烷基)氧基)环丁基)氨基)-2-氯嘧啶-5-羧酸乙酯(12b)(无色液体，4.18g，产率64.26％)。Dissolve 2-chloro-4-((trans-3-hydroxycyclobutyl)amino)pyrimidine-5-carboxylic acid ethyl ester 12a (3.10g, 11.41mmol) in dichloromethane (20mL), add tert-butyl Diphenylchlorosilane (4.45mL, 17.11mmol), imidazole (1.94g, 28.52mmol), protected by nitrogen and ventilated, stirred at room temperature for 2h, monitored by TLC until the end of the reaction, and purified by silica gel column chromatography (petroleum ether/ethyl acetate) Ester (v/v)=10:1) was purified to obtain the title compound 4-(trans-3-((tert-butyldiphenylsilyl)oxy)cyclobutyl)amino)-2-chloropyrimidine-5- Ethyl carboxylate (12b) (colorless liquid, 4.18 g, yield 64.26%).
LC-MS m/z(ESI)＝510.20[M+1]。LC-MS m/z(ESI)=510.20[M+1].
第三步：third step:
4-((反-3-((叔丁基二苯基硅烷基)氧基)环丁基)氨基)-2-氯嘧啶-5-羧酸(12c)4-((trans-3-((tert-butyldiphenylsilyl)oxy)cyclobutyl)amino)-2-chloropyrimidine-5-carboxylic acid (12c)
4-((trans-3-((tert-butyldiphenylsilyl)oxy)cyclobutyl)amino)-2-chloropyrimidine-5-carboxylic acid4-((trans-3-((tert-butyldiphenylsilyl)oxy)cyclobutyl)amino)-2-chloropyrimidine-5-carboxylic acid
将4-((反-3-((叔丁基二苯基硅烷基)氧基)环丁基)氨基)-2-氯嘧啶-5-羧酸乙酯12b(4.18g,8.19mmol)溶解于四氢呋喃/水(30mL/15mL)中，加入氢氧化锂一水合物(1.03g,24.58mmol)，常温搅拌反应2h，TLC监测至反应结束，浓缩蒸发掉四氢呋喃后加入2N HCl调节pH至3-4，加水和乙酸乙酯萃取两次，浓缩有机层用硅胶柱色谱分离提纯(二氯甲烷/甲醇(v/v)＝20:1)纯化得标题化合物4-((反-3-((叔丁基二苯基硅烷基)氧基)环丁基)氨基)-2-氯嘧啶-5-羧酸(12c)(白色固体，3.87g，产率97.97％)。Dissolve 4-((trans-3-((tert-butyldiphenylsilyl)oxy)cyclobutyl)amino)-2-chloropyrimidine-5-carboxylic acid ethyl ester 12b (4.18g, 8.19mmol) In tetrahydrofuran/water (30mL/15mL), lithium hydroxide monohydrate (1.03g, 24.58mmol) was added, the reaction was stirred at room temperature for 2h, TLC monitored until the reaction was over, concentrated and evaporated to remove the tetrahydrofuran, and then added 2N HCl to adjust the pH to 3 4. Add water and ethyl acetate to extract twice, concentrate the organic layer and use silica gel column chromatography to separate and purify (dichloromethane/methanol (v/v)=20:1) to obtain the title compound 4-((反-3-(( Tert-butyldiphenylsilyl)oxy)cyclobutyl)amino)-2-chloropyrimidine-5-carboxylic acid (12c) (white solid, 3.87 g, yield 97.97%).
LC-MS m/z(ESI)＝482.20[M+1]。LC-MS m/z(ESI)=482.20[M+1].
第四步：the fourth step:
9-(反-3-((叔丁基二苯基硅烷基)氧基)环丁基)-2-氯-7,9-二氢-8H-嘌呤-8-酮(12d)9-(trans-3-((tert-butyldiphenylsilyl)oxy)cyclobutyl)-2-chloro-7,9-dihydro-8H-purin-8-one(12d)
9-(trans-3-((tert-butyldiphenylsilyl)oxy)cyclobutyl)-2-chloro-7,9-dihydro-8H-purin-8-one9-(trans-3-((tert-butyldiphenylsilyl)oxy)cyclobutyl)-2-chloro-7,9-dihydro-8H-purin-8-one
将4-(反-3-((叔丁基二苯基硅烷基)氧基)环丁基)氨基)-2-氯嘧啶-5-羧酸12c(3.87g,8.03mmol)用N,N-二甲基乙酰胺(38mL)溶解，常温搅拌下加入三乙胺(1.11mL,8.03mmol)和叠氮磷酸二苯酯(1.73mL,8.03mmol)反应2h后，升温至110℃回流反应2.5h。TLC监测至反应结束，反应液中加水、乙酸乙酯进行萃取，浓缩有机层用硅胶柱色谱分离提纯(石油醚/乙酸乙酯(v/v)＝1:1)纯化得标题化合物9-(反-3-((叔丁基二苯基硅烷基)氧基)环丁基)-2-氯-7,9-二氢-8H-嘌呤-8-酮(12d)(白色固体，1.81g，产率47.06％)。Use 4-(trans-3-((tert-butyldiphenylsilyl)oxy)cyclobutyl)amino)-2-chloropyrimidine-5-carboxylic acid 12c (3.87g, 8.03mmol) with N, N -Dimethylacetamide (38mL) was dissolved, triethylamine (1.11mL, 8.03mmol) and diphenyl azide phosphate (1.73mL, 8.03mmol) were added under stirring at room temperature, and then reacted for 2h, then heated to 110℃ and refluxed for 2.5 h. TLC monitoring until the end of the reaction, the reaction solution was added with water and ethyl acetate for extraction, and the organic layer was concentrated and purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) = 1:1) to obtain the title compound 9-( Trans-3-((tert-butyldiphenylsilyl)oxy)cyclobutyl)-2-chloro-7,9-dihydro-8H-purin-8-one (12d) (white solid, 1.81g , The yield is 47.06%).
1H NMR(400MHz,DMSO-d6)δ11.59(s,1H),8.09(s,1H),7.65–7.62(m,2H),7.62–7.60(m,2H),7.47-7.39(m,6H),5.05–4.97(m,1H),4.96–4.89(m,1H),2.98-2.84(m,2H),2.54-2.46(m,2H),1.02(s,9H)。1H NMR (400MHz, DMSO-d6) δ 11.59 (s, 1H), 8.09 (s, 1H), 7.65-7.62 (m, 2H), 7.62-7.60 (m, 2H), 7.47-7.39 (m, 6H) ), 5.05–4.97(m,1H), 4.96–4.89(m,1H), 2.98-2.84(m,2H), 2.54-2.46(m,2H), 1.02(s,9H).
LC-MS m/z(ESI)＝479.20[M+1]。LC-MS m/z(ESI)=479.20[M+1].
第五步：the fifth step:
9-(反-3-((叔丁基二苯基硅烷基)氧基)环丁基)-2-氯-7-甲基-7,9-二氢-8H-嘌呤-8-酮(12e)9-(trans-3-((tert-butyldiphenylsilyl)oxy)cyclobutyl)-2-chloro-7-methyl-7,9-dihydro-8H-purin-8-one( 12e)
9-(trans-3-((tert-butyldiphenylsilyl)oxy)cyclobutyl)-2-chloro-7-methyl-7,9-dihydro-8H-purin-8-one9-(trans-3-((tert-butyldiphenylsilyl)oxy)cyclobutyl)-2-chloro-7-methyl-7,9-dihydro-8H-purin-8-one
将9-(反-3-((叔丁基二苯基硅烷基)氧基)环丁基)-2-氯-7,9-二氢-8H-嘌呤-8-酮12d(1.81g,3.78mmol)用N,N-二甲基甲酰胺(20mL)溶解，0℃搅拌下加入硫酸二甲酯(0.36mL,3.78mmol)和碳酸铯(2.47g,7.57mmol)反应2h。TLC监测至反应结束，把反应液缓慢滴加到冰水中搅拌，加入乙酸乙酯进行萃取，浓缩有机层经硅胶柱色谱分离提纯(石油醚/乙酸乙酯(v/v)＝3:1)纯化得标题化合物9-(反-3-((叔丁基二苯基硅烷基)氧基)环丁基)-2-氯-7-甲基-7,9-二氢-8H-嘌呤-8-酮(12e)(白色固体，1.80g，产率96.62％)。The 9-(trans-3-((tert-butyldiphenylsilyl)oxy)cyclobutyl)-2-chloro-7,9-dihydro-8H-purine-8-one 12d (1.81g, 3.78mmol) was dissolved in N,N-dimethylformamide (20mL), dimethyl sulfate (0.36mL, 3.78mmol) and cesium carbonate (2.47g, 7.57mmol) were added and reacted for 2h under stirring at 0°C. TLC monitors until the reaction is over, the reaction solution is slowly added dropwise to ice water and stirred, ethyl acetate is added for extraction, the concentrated organic layer is separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) = 3:1) Purified to obtain the title compound 9-(trans-3-((tert-butyldiphenylsilyl)oxy)cyclobutyl)-2-chloro-7-methyl-7,9-dihydro-8H-purine- 8-ketone (12e) (white solid, 1.80 g, yield 96.62%).
LC-MS m/z(ESI)＝493.20[M+1]。LC-MS m/z(ESI)=493.20[M+1].
第六步：The sixth step:
9-(反-3-((叔丁基二苯基甲硅烷基)氧基)环丁基)-7-甲基-2-((7-甲基-[1,2,4]***并[1,5-a]吡啶-6-基)氨基)-7,9-二氢-8H-嘌呤-8-酮(12f)9-(trans-3-((tert-butyldiphenylsilyl)oxy)cyclobutyl)-7-methyl-2-((7-methyl-[1,2,4]triazole And [1,5-a]pyridin-6-yl)amino)-7,9-dihydro-8H-purin-8-one (12f)
9-(trans-3-((tert-butyldiphenylsilyl)oxy)cyclobutyl)-7-methyl-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-7,9-dihydro-8H-purin-8-one9-(trans-3-((tert-butyldiphenylsilyl)oxy)cyclobutyl)-7-methyl-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl )amino)-7,9-dihydro-8H-purin-8-one
将9-(反-3-((叔丁基二苯基硅烷基)氧基)环丁基)-2-氯-7-甲基-7,9-二氢-8H-嘌呤-8-酮12e(200mg，0.41mmol)、7-甲基-[1,2,4]***并[1,5-a]吡啶-6-胺(123mg，0.82mmol)、碳酸铯(264mg，0.82mmol)和Brettphos G3Pd(37mg，0.041mmol)加入干燥的反应瓶，N 2置换三次，然加入干燥的1,4-二氧六环(1mL)，在110℃下反应5h。冷却至室温，过滤，浓缩滤液，得到粗品(12f)，未经纯化直接投下一步。 9-(trans-3-((tert-butyldiphenylsilyl)oxy)cyclobutyl)-2-chloro-7-methyl-7,9-dihydro-8H-purin-8-one 12e (200mg, 0.41mmol), 7-methyl-[1,2,4]triazolo[1,5-a]pyridine-6-amine (123mg, 0.82mmol), cesium carbonate (264mg, 0.82mmol) Add Brettphos G3Pd (37mg, 0.041mmol) into a dry reaction flask, replace with N 2 three times, then add dry 1,4-dioxane (1 mL), and react at 110°C for 5 hours. Cool to room temperature, filter, and concentrate the filtrate to obtain the crude product (12f), which is directly used for the next step without purification.
第七步：The seventh step:
9-(反-3-羟基环丁基)-7-甲基-2-((7-甲基-[1,2,4]***并[1,5-a]吡啶-6-基)氨基)-7,9-二氢-8H-嘌呤-8-酮(化合物12)9-(trans-3-hydroxycyclobutyl)-7-methyl-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl) Amino)-7,9-dihydro-8H-purin-8-one (Compound 12)
9-(trans-3-hydroxycyclobutyl)-7-methyl-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6- yl)amino)-7,9-dihydro-8H-purin-8-one9-(trans-3-hydroxycyclobutyl)-7-methyl-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6- yl)amino)-7,9- dihydro-8H-purin-8-one
将第六步所得粗品12f用1,4-二氧六环(5mL)溶解，然后滴加浓盐酸(1mL)，室温反应2小时。TLC监测至反应结束，用饱和碳酸氢钠溶液调节pH至7左右，加入二氯甲烷萃取三次，合并有机相，浓缩，使用硅胶柱色谱分离提纯(二氯甲烷/甲醇(v/v＝40:1))纯化，得到标题化合物9-((反-3-羟基环丁基)-7-甲基-2-((6-甲基-2,3-二氢苯并呋喃-5-基)氨基)-7,9-二氢-8H-嘌呤-8-酮(化合物12)(白色固体，54mg，产率36.23％)。The crude product 12f obtained in the sixth step was dissolved with 1,4-dioxane (5 mL), then concentrated hydrochloric acid (1 mL) was added dropwise, and the reaction was carried out at room temperature for 2 hours. TLC monitors to the end of the reaction, adjusts the pH to about 7 with saturated sodium bicarbonate solution, adds dichloromethane for extraction three times, combines the organic phases, concentrates, and uses silica gel column chromatography to separate and purify (dichloromethane/methanol (v/v=40: 1)) Purification to obtain the title compound 9-((trans-3-hydroxycyclobutyl)-7-methyl-2-((6-methyl-2,3-dihydrobenzofuran-5-yl) Amino)-7,9-dihydro-8H-purin-8-one (compound 12) (white solid, 54 mg, yield 36.23%).
1H NMR(400MHz,DMSO-d6)δ8.89(s,1H),8.24(s,1H),7.97(s,1H),7.22(s,1H),6.61(s,1H),,4.40–4.33(m,1H),3.25(s,3H),3.11(t,2H),3.02-2.92(m,2H),2.19-2.13(m,2H),2.12(s,3H)。1H NMR(400MHz,DMSO-d6)δ8.89(s,1H),8.24(s,1H),7.97(s,1H),7.22(s,1H),6.61(s,1H),,4.40-4.33 (m, 1H), 3.25 (s, 3H), 3.11 (t, 2H), 3.02-2.92 (m, 2H), 2.19-2.13 (m, 2H), 2.12 (s, 3H).
LC-MS m/z(ESI)＝368.10[M+1]。LC-MS m/z(ESI)=368.10[M+1].
实施例13Example 13
9-(顺-3-羟基环丁基)-7-甲基-2-((7-甲基-[1,2,4]***并[1,5-a]吡啶-6-基)氨基)-7,9-二氢-8H-嘌呤-8-酮(化合物13)9-(cis-3-hydroxycyclobutyl)-7-methyl-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl) Amino)-7,9-dihydro-8H-purin-8-one (compound 13)
9-(cis-3-hydroxycyclobutyl)-7-methyl-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-7,9-dihydro-8H-purin-8-one9-(cis-3-hydroxycyclobutyl)-7-methyl-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-7,9- dihydro-8H-purin-8-one
Figure PCTCN2020141859-appb-000029
Figure PCTCN2020141859-appb-000029
第一步：first step:
2-氯-4-((顺-3-羟基环丁基)氨基)嘧啶-5-羧酸乙酯(13a)Ethyl 2-chloro-4-((cis-3-hydroxycyclobutyl)amino)pyrimidine-5-carboxylate (13a)
ethyl 2-chloro-4-((cis-3-hydroxycyclobutyl)amino)pyrimidine-5-carboxylateethyl 2-chloro-4-((cis-3-hydroxycyclobutyl)amino)pyrimidine-5-carboxylate
将(1s,3s)-3-氨基环丁烷-1-醇盐酸盐(3.00g,34.48mmol)溶于乙腈(25mL)中，0℃搅拌下加入碳酸钾(14.30g,103.45mmol)、2,4-二氯-5-嘧啶甲酸乙酯1a(11.43g,51.72mmol)，升温至常温搅拌反应1h，TLC监测至反应结束，硅藻土过滤后用硅胶柱色谱分离提纯(石油醚/乙酸乙酯(v/v)＝2:1)纯化得标题化合物2-氯-4-((顺-3-羟基环丁基)氨基)嘧啶-5-羧酸乙酯(13a)(白色固体，3.3g，产率32.91％)。(1s, 3s)-3-aminocyclobutane-1-ol hydrochloride (3.00g, 34.48mmol) was dissolved in acetonitrile (25mL), and potassium carbonate (14.30g, 103.45mmol) was added while stirring at 0°C, Ethyl 2,4-dichloro-5-pyrimidinecarboxylate 1a (11.43g, 51.72mmol), heated to room temperature and stirred for 1h, monitored by TLC until the end of the reaction, filtered through diatomaceous earth and purified by silica gel column chromatography (petroleum ether/ Ethyl acetate (v/v)=2:1) was purified to obtain the title compound 2-chloro-4-((cis-3-hydroxycyclobutyl)amino)pyrimidine-5-carboxylic acid ethyl ester (13a) (white solid) , 3.3g, yield 32.91%).
1H NMR(400MHz,DMSO-d6)δ8.60(s,1H),8.41(d,1H),4.96(s,1H),4.31(q,2H),4.08–3.97(m,1H),3.94–3.84(m,1H),2.71-2.63(m,2H),1.88–1.80(m,2H),1.33–1.29(m,3H)。1H NMR(400MHz,DMSO-d6)δ8.60(s,1H),8.41(d,1H),4.96(s,1H),4.31(q,2H),4.08--3.97(m,1H),3.94-- 3.84 (m, 1H), 2.71-2.63 (m, 2H), 1.88-1.80 (m, 2H), 1.33-1.29 (m, 3H).
LC-MS m/z(ESI)＝272.00[M+1]。LC-MS m/z(ESI)=272.00[M+1].
第二步：The second step:
2-氯-4-((顺-3-羟基环丁基)氨基)嘧啶-5-羧酸(13b)2-Chloro-4-((cis-3-hydroxycyclobutyl)amino)pyrimidine-5-carboxylic acid (13b)
2-chloro-4-((cis-3-hydroxycyclobutyl)amino)pyrimidine-5-carboxylate2-chloro-4-((cis-3-hydroxycyclobutyl)amino)pyrimidine-5-carboxylate
将2-氯-4-((1s,3s)-3-羟基环丁基)氨基)嘧啶-5-羧酸乙酯13a(3.30g,12.14mmol)溶解于四氢呋喃/水(30mL/15mL)中，加入氢氧化锂一水合物(1.53g,36.44mmol)，常温搅拌反应2h，TLC监测至反应结束，浓缩蒸发掉四氢呋喃后加入2N HCl调节pH至3-4左右，有白色固体析出，过滤，滤饼用水以及石油醚/乙酸乙酯(v/v＝10/1)洗两次得标题化合物2-氯-4-((顺-3-羟基环丁基)氨基)嘧啶-5-羧酸(13b)(白色固体，2.44g，产率82.45％)。Dissolve 2-chloro-4-((1s,3s)-3-hydroxycyclobutyl)amino)pyrimidine-5-carboxylic acid ethyl ester 13a (3.30g, 12.14mmol) in tetrahydrofuran/water (30mL/15mL) , Add lithium hydroxide monohydrate (1.53g, 36.44mmol), stir the reaction at room temperature for 2h, monitor by TLC until the end of the reaction, concentrate and evaporate the tetrahydrofuran, add 2N HCl to adjust the pH to about 3-4, a white solid precipitates out, filter, The filter cake was washed twice with water and petroleum ether/ethyl acetate (v/v=10/1) to obtain the title compound 2-chloro-4-((cis-3-hydroxycyclobutyl)amino)pyrimidine-5-carboxylic acid (13b) (white solid, 2.44 g, yield 82.45%).
1H NMR(400MHz,DMSO-d6)δ8.61(d,1H),8.57(s,1H),4.43-4.20(m,1H),4.07–3.96(m,1H),3.93–3.83(m,1H),2.72-2.63(m,2H),1.87–1.77(m,2H)。1H NMR(400MHz,DMSO-d6)δ8.61(d,1H),8.57(s,1H),4.43-4.20(m,1H),4.07-3.96(m,1H),3.93-3.83(m,1H) ), 2.72-2.63 (m, 2H), 1.87-1.77 (m, 2H).
LC-MS m/z(ESI)＝244.00[M+1]。LC-MS m/z(ESI)=244.00[M+1].
第三步：third step:
2-氯-9-(顺-3-羟基环丁基)-7,9-二氢-8H-嘌呤-8-酮(13c)2-chloro-9-(cis-3-hydroxycyclobutyl)-7,9-dihydro-8H-purin-8-one (13c)
2-chloro-9-(cis-3-hydroxycyclobutyl)-7,9-dihydro-8H-purin-8-one2-chloro-9-(cis-3-hydroxycyclobutyl)-7,9-dihydro-8H-purin-8-one
将2-氯-4-(((1s,3s)-3-羟基环丁基)氨基)嘧啶-5-羧酸13b(2.44g,10.01mmol)用N,N-二甲基乙酰胺(20mL)溶解，常温搅拌下加入三乙胺(1.39mL,10.01mmol)和叠氮磷酸二苯酯(2.16mL,10.01mmol)反应2h，升温至110℃回流反应2.5h。TLC监测至反应结束，反应液中加水、二氯甲烷进行萃取，浓缩有机层得标题化合物2-氯-9-(顺-3-羟基环丁基)-7,9-二氢-8H-嘌呤-8-酮(13c)(白色固体，0.90g，产率37.35％)。Use 2-chloro-4-(((1s,3s)-3-hydroxycyclobutyl)amino)pyrimidine-5-carboxylic acid 13b (2.44g, 10.01mmol) with N,N-dimethylacetamide (20mL ) Was dissolved, triethylamine (1.39mL, 10.01mmol) and diphenyl azide phosphate (2.16mL, 10.01mmol) were added under stirring at room temperature and reacted for 2h, and the temperature was raised to 110°C and refluxed for 2.5h. TLC monitors to the end of the reaction, the reaction solution is extracted with water and dichloromethane, and the organic layer is concentrated to obtain the title compound 2-chloro-9-(cis-3-hydroxycyclobutyl)-7,9-dihydro-8H-purine -8-one (13c) (white solid, 0.90 g, yield 37.35%).
1H NMR(400MHz,DMSO-d6)δ11.59(s,1H),8.12(s,1H),4.31–4.20(m,1H),4.00-3.92(m,1H),3.80-3.54(m,1H),2.83–2.73(m,2H),2.58–2.51(m,2H)。1H NMR(400MHz,DMSO-d6)δ11.59(s,1H), 8.12(s,1H), 4.31-4.20(m,1H), 4.00-3.92(m,1H), 3.80-3.54(m,1H) ), 2.83–2.73(m,2H), 2.58–2.51(m,2H).
LC-MS m/z(ESI)＝241.00[M+1]。LC-MS m/z(ESI)=241.00[M+1].
第四步：the fourth step:
2-氯-9-(顺-3-羟基环丁基)-7-甲基-7,9-二氢-8H-嘌呤-8-酮(13d)2-Chloro-9-(cis-3-hydroxycyclobutyl)-7-methyl-7,9-dihydro-8H-purin-8-one (13d)
2-chloro-9-(cis-3-hydroxycyclobutyl)-7-methyl-7,9-dihydro-8H-purin-8-one2-chloro-9-(cis-3-hydroxycyclobutyl)-7-methyl-7,9-dihydro-8H-purin-8-one
将2-氯-9-((1s,3s)-3-羟基环丁基)-7,9-二氢-8H-嘌呤-8-酮13c(0.70g,1.25mmol)用N,N-二甲基甲酰胺(10mL)溶解，0℃搅拌下加入硫酸二甲酯(0.28mL,1.25mmol)和碳酸铯(1.42g,4.36mmol)反应2h。TLC监测至反应结束，把反应液缓慢滴加到冰水中搅拌，加入乙酸乙酯进行萃取，浓缩有机层经硅胶柱色谱分离提纯(石油醚/乙酸乙酯(v/v)＝1:1)纯化得标题化合物2-氯-9-(顺-3-羟基环丁基)-7-甲基-7,9-二氢-8H-嘌呤-8-酮(13d)(白色固体，0.32g，产率41.20％)。Use 2-chloro-9-((1s,3s)-3-hydroxycyclobutyl)-7,9-dihydro-8H-purin-8-one 13c (0.70g, 1.25mmol) with N,N-dihydro Methylformamide (10 mL) was dissolved, and dimethyl sulfate (0.28 mL, 1.25 mmol) and cesium carbonate (1.42 g, 4.36 mmol) were added under stirring at 0°C to react for 2 h. TLC monitors to the end of the reaction, the reaction solution is slowly added dropwise to ice water and stirred, ethyl acetate is added for extraction, the concentrated organic layer is separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) = 1:1) Purified to obtain the title compound 2-chloro-9-(cis-3-hydroxycyclobutyl)-7-methyl-7,9-dihydro-8H-purin-8-one (13d) (white solid, 0.32g, Yield 41.20%).
1H NMR(400MHz,DMSO-d6)δ8.33(s,1H),5.31(d,1H),4.34–4.23(m,1H),4.02-3.91(m,1H),3.34(s,3H),2.81-2.72(m,2H),2.58–2.51(m,2H)。1H NMR(400MHz,DMSO-d6)δ8.33(s,1H),5.31(d,1H),4.34-4.23(m,1H),4.02-3.91(m,1H),3.34(s,3H), 2.81-2.72 (m, 2H), 2.58-2.51 (m, 2H).
LC-MS m/z(ESI)＝255.00[M+1]。LC-MS m/z(ESI)=255.00[M+1].
第五步：the fifth step:
9-(顺-3-羟基环丁基)-7-甲基-2-((7-甲基-[1,2,4]***并[1,5-a]吡啶-6-基)氨基)-7,9-二氢-8H-嘌呤-8-酮(化合物13)9-(cis-3-hydroxycyclobutyl)-7-methyl-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl) Amino)-7,9-dihydro-8H-purin-8-one (compound 13)
9-(cis-3-hydroxycyclobutyl)-7-methyl-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-7,9-dihydro-8H-purin-8-one9-(cis-3-hydroxycyclobutyl)-7-methyl-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-7,9- dihydro-8H-purin-8-one
将2-氯-9-((1s,3s)-3-羟基环丁基)-7-甲基-7,9-二氢-8H-嘌呤-8-酮13d(50mg，0.20mmol)、7-甲基-[1,2,4]***并[1,5-a]吡啶-6-胺(59mg，0.40mmol)、碳酸铯(128mg,0.4mmol)和Brettphos G3Pd(19mg，0.020mmol)加入干燥的反应管，N 2置换三次，然后加入干燥的1,4-二氧六环(1mL)，在110℃下反应5h。TLC监测至反应结束，冷却至室温，使用硅胶柱色谱分离提纯(二氯甲烷/甲醇(v/v＝40:1))纯化，得到标题化合 物9-((1s，3s)-3-羟基环丁基)-7-甲基-2-((6-甲基-2,3-二氢苯并呋喃-5-基)氨基)-7,9-二氢-8H-嘌呤-8-酮(化合物13)(浅黄色固体，22mg，产率30.50％)。 The 2-chloro-9-((1s,3s)-3-hydroxycyclobutyl)-7-methyl-7,9-dihydro-8H-purin-8-one 13d (50mg, 0.20mmol), 7 -Methyl-[1,2,4]triazolo[1,5-a]pyridine-6-amine (59mg, 0.40mmol), cesium carbonate (128mg, 0.4mmol) and Brettphos G3Pd (19mg, 0.020mmol) Add a dry reaction tube, replace with N 2 three times, then add dry 1,4-dioxane (1 mL), and react at 110° C. for 5 hours. TLC monitors until the reaction is complete, cool to room temperature, use silica gel column chromatography (dichloromethane/methanol (v/v=40:1)) to separate and purify to obtain the title compound 9-((1s, 3s)-3-hydroxy ring Butyl)-7-methyl-2-((6-methyl-2,3-dihydrobenzofuran-5-yl)amino)-7,9-dihydro-8H-purin-8-one( Compound 13) (light yellow solid, 22 mg, yield 30.50%).
1H NMR(400MHz,DMSO-d6)δ8.65(s,1H),8.14(s,1H),7.95(s,1H),7.26(s,1H),3.94-3.88(m,1H),3.25(s,3H),3.13(t,2H),2.82–2.73(m,2H),2.54-2.44(m,2H),2.12(s,3H)。1H NMR(400MHz,DMSO-d6)δ8.65(s,1H), 8.14(s,1H), 7.95(s,1H), 7.26(s,1H), 3.94-3.88(m,1H), 3.25( s, 3H), 3.13 (t, 2H), 2.82–2.73 (m, 2H), 2.54-2.44 (m, 2H), 2.12 (s, 3H).
LC-MS m/z(ESI)＝368.10[M+1]。LC-MS m/z(ESI)=368.10[M+1].
实施例14Example 14
9-(3-羟基双环[3.2.1]辛基-8-基)-7-甲基-2-((7-甲基-[1,2,4]***并[1,5-a]吡啶-6-基)氨基)-7,9-二氢-8H-嘌呤-8-酮(化合物14)9-(3-Hydroxybicyclo[3.2.1]octyl-8-yl)-7-methyl-2-((7-methyl-[1,2,4]triazolo[1,5-a ]Pyridin-6-yl)amino)-7,9-dihydro-8H-purin-8-one (compound 14)
9-(3-hydroxybicyclo[3.2.1]octan-8-yl)-7-methyl-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-7,9-dihydro-8H-purin-8-one9-(3-hydroxybicyclo[3.2.1]octan-8-yl)-7-methyl-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl )amino)-7,9-dihydro-8H-purin-8-one
Figure PCTCN2020141859-appb-000030
Figure PCTCN2020141859-appb-000030
第一步：first step:
8-氨基双环[3.2.1]辛基-3-酮盐酸盐(14b)8-aminobicyclo[3.2.1]octyl-3-one hydrochloride (14b)
8-aminobicyclo[3.2.1]octan-3-one hydrochloride8-aminobicyclo[3.2.1]octan-3-one hydrochloride
将3-氧代双环[3.2.1]辛-8-基)氨基甲酸叔丁酯14a(1.0g,4.18mmol)溶于4N盐酸二氧六环(40mL)，室温反应1h。TLC监测反应结束，直接将反应液浓缩至干，得目标化合物8-氨基双环[3.2.1]octan-3-one盐酸盐14b(白色固体，730mg,产率99.42％)。Dissolve tert-butyl 3-oxobicyclo[3.2.1]oct-8-yl)carbamate 14a (1.0 g, 4.18 mmol) in 4N dioxane hydrochloride (40 mL), and react at room temperature for 1 h. TLC monitored the completion of the reaction, and the reaction solution was directly concentrated to dryness to obtain the target compound 8-aminobicyclo[3.2.1]octan-3-one hydrochloride 14b (white solid, 730 mg, yield 99.42%).
1H NMR(401MHz,DMSO-d6)δ8.77(s,2H),3.36(m,2H),2.80-2.77(m,2H),2.16-2.13(m,2H),1.87-1.85(m,2H),1.43-1.42(m,2H)。 1 H NMR (401MHz, DMSO-d6) δ8.77 (s, 2H), 3.36 (m, 2H), 2.80-2.77 (m, 2H), 2.16-2.13 (m, 2H), 1.87-1.85 (m, 2H), 1.43-1.42 (m, 2H).
LC-MS m/z(ESI)＝176.20[M+1]。LC-MS m/z(ESI)=176.20[M+1].
第二步：The second step:
2-氯-4-((3-氧双环[3.2.1]辛-8-基)氨基)嘧啶-5-羧酸乙酯(14c)Ethyl 2-chloro-4-((3-oxobicyclo[3.2.1]oct-8-yl)amino)pyrimidine-5-carboxylate (14c)
ethyl 2-chloro-4-((3-oxobicyclo[3.2.1]octan-8-yl)amino)pyrimidine-5-carboxylateethyl 2-chloro-4-((3-oxobicyclo[3.2.1]octan-8-yl)amino)pyrimidine-5-carboxylate
将2,4-二氯嘧啶-5-羧酸乙酯1a(1.38g,6.26mmol),8-氨基双环[3.2.1]辛基-3-酮盐酸盐14b(730mg,4.17mmol)，碳酸钾(1.73g,12.52mmol)溶于乙腈(20mL)，反应液在室温反应16h。TLC监测反应结束，过滤，并用少量乙腈清洗固体，将滤液合并后浓缩，粗品经柱层析分离(石油醚:乙酸乙酯＝1:1)后得标题化合物2-氯-4-((3-氧双 环[3.2.1]辛-8-基)氨基)嘧啶-5-羧酸乙酯14c(白色固体,1.0g,产率74.01％)。2,4-Dichloropyrimidine-5-carboxylic acid ethyl ester 1a (1.38g, 6.26mmol), 8-aminobicyclo[3.2.1]octyl-3-one hydrochloride 14b (730mg, 4.17mmol), Potassium carbonate (1.73g, 12.52mmol) was dissolved in acetonitrile (20mL), and the reaction solution was reacted at room temperature for 16h. The end of the reaction was monitored by TLC, filtered, and the solid was washed with a small amount of acetonitrile. The filtrate was combined and concentrated. The crude product was separated by column chromatography (petroleum ether: ethyl acetate=1:1) to obtain the title compound 2-chloro-4-((3 -Oxybicyclo[3.2.1]oct-8-yl)amino)pyrimidine-5-carboxylic acid ethyl ester 14c (white solid, 1.0 g, yield 74.01%).
1H NMR(400MHz,DMSO-d6)δ8.86(d,2H),8.68(s,1H),4.36-4.30(q,2H),4.20-4.16(m,1H),2.66-2.65(m,2H),2.56-2.55(m,2H),2.21-2.17(m,2H),1.97-1.93(m,2H),1.53-1.33(m,2H),1.31(t,3H)。 1 H NMR (400MHz, DMSO-d6) δ 8.86 (d, 2H), 8.68 (s, 1H), 4.36-4.30 (q, 2H), 4.20-4.16 (m, 1H), 2.66-2.65 (m, 2H), 2.56-2.55 (m, 2H), 2.21-2.17 (m, 2H), 1.97-1.93 (m, 2H), 1.53-1.33 (m, 2H), 1.31 (t, 3H).
LC-MS m/z(ESI)＝324.10[M+1]。LC-MS m/z(ESI)=324.10[M+1].
第三步：third step:
2-氯-4-((3--3-氧双环[3.2.1]辛-8-基)氨基]嘧啶-5-羧酸(14d)2-chloro-4-((3--3-oxobicyclo[3.2.1]oct-8-yl)amino]pyrimidine-5-carboxylic acid (14d)
2-chloro-4-((3-oxobicyclo[3.2.1]octan-8-yl)amino)pyrimidine-5-carboxylic acid2-chloro-4-((3-oxobicyclo[3.2.1]octan-8-yl)amino)pyrimidine-5-carboxylic acid
将2-氯-4-((3-氧双环[3.2.1]辛-8-基)氨基)嘧啶-5-羧酸乙酯14c(1.0g，3.09mmol)溶解于四氢呋喃20mL,水20mlL中,加入氢氧化锂(259mg,6.18mmol)，室温搅拌1h。TLC监测反应完全，浓缩除去四氢呋喃，用2N盐酸调pH为5，有白色固体析出，过滤，滤饼用石油醚洗两次，搜集固体得到标题化合物2-氯-4-((3-3-氧双环[3.2.1]octan-8-yl)氨基]嘧啶-5-羧酸14d(白色固体,800mg,产率87.59％)。Dissolve 2-chloro-4-((3-oxobicyclo[3.2.1]oct-8-yl)amino)pyrimidine-5-carboxylic acid ethyl ester 14c (1.0g, 3.09mmol) in tetrahydrofuran 20mL, water 20mlL Add lithium hydroxide (259mg, 6.18mmol) and stir at room temperature for 1h. TLC monitored the reaction to complete, concentrated to remove tetrahydrofuran, adjusted the pH to 5 with 2N hydrochloric acid, a white solid precipitated, filtered, the filter cake was washed twice with petroleum ether, and the solid was collected to obtain the title compound 2-chloro-4-((3-3- Oxybicyclo[3.2.1]octan-8-yl)amino]pyrimidine-5-carboxylic acid 14d (white solid, 800mg, yield 87.59%).
1H NMR(400MHz,DMSO-d6)δ13.93(s,1H),9.20(d,2H),8.64(s,1H),4.20-4.16(m,1H),2.66-2.64(m,2H),2.54-2.53(m,2H),2.21-2.16(m,2H),1.96-1.93(m,2H),1.53-1.47(m,2H)。 1 H NMR (400MHz, DMSO-d6) δ 13.93 (s, 1H), 9.20 (d, 2H), 8.64 (s, 1H), 4.20-4.16 (m, 1H), 2.66-2.64 (m, 2H) , 2.54-2.53 (m, 2H), 2.21-2.16 (m, 2H), 1.96-1.93 (m, 2H), 1.53-1.47 (m, 2H).
LC-MS m/z(ESI)＝296.10[M+1]。LC-MS m/z(ESI)=296.10[M+1].
第四步：the fourth step:
2-氯-9-(3-氧代双环[3.2.1]辛-8-基)-7,9-二氢-8H-嘌呤-8-酮(14e)2-chloro-9-(3-oxobicyclo[3.2.1]oct-8-yl)-7,9-dihydro-8H-purin-8-one (14e)
2-chloro-9-(3-oxobicyclo[3.2.1]octan-8-yl)-7,9-dihydro-8H-purin-8-one2-chloro-9-(3-oxobicyclo[3.2.1]octan-8-yl)-7,9-dihydro-8H-purin-8-one
将2-氯-4-((3-3-氧双环[3.2.1]辛-8-基)氨基)嘧啶-5-羧酸14d(800mg,2.71mmol)溶解于二甲基乙酰胺(20mL)，加入三乙胺(0.37mL,2.7mmol)、叠氮磷酸二苯酯(0.58mL,2.7mmol),随后逐步升温至90℃,搅拌2h。TLC监测反应完毕，将反应液倒入冰水中，过滤搜集固体，水洗3次，真空浓缩干燥得标题化合物2-氯-9-(3-氧代双环[3.2.1]辛-8-基)-7,9-二氢-8H-嘌呤-8-酮14e(白色固体,630mg,产率94.71％)。Dissolve 2-chloro-4-((3-3-oxobicyclo[3.2.1]oct-8-yl)amino)pyrimidine-5-carboxylic acid 14d (800mg, 2.71mmol) in dimethylacetamide (20mL ), add triethylamine (0.37mL, 2.7mmol) and diphenyl azide phosphate (0.58mL, 2.7mmol), then gradually increase the temperature to 90°C and stir for 2h. TLC monitors the completion of the reaction, the reaction solution is poured into ice water, the solid is collected by filtration, washed with water 3 times, and concentrated and dried in vacuo to obtain the title compound 2-chloro-9-(3-oxobicyclo[3.2.1]oct-8-yl) -7,9-dihydro-8H-purin-8-one 14e (white solid, 630 mg, yield 94.71%).
1H NMR(400MHz,DMSO-d6)δ11.66(s,1H),8.13(s,1H),4.01-3.99(m,1H),3.65-3.64(m,2H),2.66-2.61(m,2H),2.12-2.08(m,2H),1.89-1.86(m,2H),1.54-1.49(m,2H)。 1 H NMR(400MHz,DMSO-d6)δ11.66(s,1H),8.13(s,1H),4.01-3.99(m,1H),3.65-3.64(m,2H),2.66-2.61(m, 2H), 2.12-2.08 (m, 2H), 1.89-1.86 (m, 2H), 1.54-1.49 (m, 2H).
LC-MS m/z(ESI)＝293.00[M+l]。LC-MS m/z(ESI)=293.00[M+1].
第五步：the fifth step:
2-氯-7-甲基-9-(3-氧代双环[3.2.1]辛-8-基)-7,9-二氢-8H-嘌呤-8-酮(14f)2-chloro-7-methyl-9-(3-oxobicyclo[3.2.1]oct-8-yl)-7,9-dihydro-8H-purin-8-one(14f)
2-chloro-7-methyl-9-(3-oxobicyclo[3.2.1]octan-8-yl)-7,9-dihydro-8H-purin-8-one2-chloro-7-methyl-9-(3-oxobicyclo[3.2.1]octan-8-yl)-7,9-dihydro-8H-purin-8-one
将2-氯-9-(3-氧代双环[3.2.1]辛-8-基)-7,9-二氢-8H-嘌呤-8-酮14e(630mg，2.15mm ol)溶解于二甲基甲酰胺(10mL)，在0℃下加入硫酸二甲酯(0.2mL，2.15mmol)和碳酸铯(1.4g,4.3mmol)，0℃搅拌1h。TLC监测反应结束，将反应液倒入冰水中，有固体析出，过滤、搜集固体得到标题化合物2-氯-7-甲基-9-(3-氧代双环[3.2.1]辛-8-基)-7,9-二氢-8H-嘌呤-8-酮14f(白色固体，490mg，产率74.22％)。Dissolve 2-chloro-9-(3-oxobicyclo[3.2.1]oct-8-yl)-7,9-dihydro-8H-purin-8-one 14e (630mg, 2.15mm ol) in two Methylformamide (10 mL), dimethyl sulfate (0.2 mL, 2.15 mmol) and cesium carbonate (1.4 g, 4.3 mmol) were added at 0°C, and the mixture was stirred at 0°C for 1 h. TLC monitors the end of the reaction. Pour the reaction liquid into ice water. A solid precipitates out. The solid is filtered and collected to obtain the title compound 2-chloro-7-methyl-9-(3-oxobicyclo[3.2.1]oct-8- Base)-7,9-dihydro-8H-purin-8-one 14f (white solid, 490 mg, yield 74.22%).
1H NMR(400MHz,DMSO-d6)δ8.37(s,1H),4.03-4.01(m,1H),3.66-3.65(m,2H),3.36(s,3H),2.65-2.59(m,2H),2.13-2.08(m,2H),1.89-1.87(m,2H),1.55-1.50(m,2H)。 1 H NMR(400MHz,DMSO-d6)δ8.37(s,1H),4.03-4.01(m,1H),3.66-3.65(m,2H),3.36(s,3H),2.65-2.59(m, 2H), 2.13-2.08 (m, 2H), 1.89-1.87 (m, 2H), 1.55-1.50 (m, 2H).
LC-MS m/z(ESI)＝307.10[M+l]。LC-MS m/z(ESI)=307.10[M+1].
第六步：The sixth step:
2-氯-9-(3-羟基双环[3.2.1]辛-8-基)-7-甲基-7,9-二氢-8H-嘌呤-8-酮(14g)2-chloro-9-(3-hydroxybicyclo[3.2.1]oct-8-yl)-7-methyl-7,9-dihydro-8H-purin-8-one (14g)
2-chloro-9-(3-hydroxybicyclo[3.2.1]octan-8-yl)-7-methyl-7,9-dihydro-8H-purin-8-one2-chloro-9-(3-hydroxybicyclo[3.2.1]octan-8-yl)-7-methyl-7,9-dihydro-8H-purin-8-one
将2-氯-7-甲基-9-(3-氧代双环[3.2.1]辛-8-基)-7,9-二氢-8H-嘌呤-8-酮14f(490mg，1.6mmol)溶解于四氢呋喃(30mL)和甲醇(30mL)，在0℃下加入硼氢化钠(181.30mg，4.79mmol)。TLC监测反应结束，将反应液倒入冰水中，有固体析出，过滤、搜集固体 得到标题化合物2-氯-9-(3-羟基双环[3.2.1]辛-8-基)-7-甲基-7,9-二氢-8H-嘌呤-8-酮14g(白色固体，380mg，产率77.04％)。The 2-chloro-7-methyl-9-(3-oxobicyclo[3.2.1]oct-8-yl)-7,9-dihydro-8H-purin-8-one 14f (490mg, 1.6mmol ) Was dissolved in tetrahydrofuran (30 mL) and methanol (30 mL), and sodium borohydride (181.30 mg, 4.79 mmol) was added at 0°C. TLC monitors the end of the reaction. Pour the reaction solution into ice water. A solid precipitates out. The solid is filtered and collected to obtain the title compound 2-chloro-9-(3-hydroxybicyclo[3.2.1]oct-8-yl)-7-methyl Glycine-7,9-dihydro-8H-purin-8-one 14g (white solid, 380mg, yield 77.04%).
1H NMR(400MHz,DMSO-d6)δ8.37(s,1H),4.28-4.20(m,1H),3.74-3.66(m,2H),3.45-3.43(m,2H),3.37(s,3H),2.14-2.07(m,1H),1.74-1.50(m,5H),1.28-1.22(m,2H)。 1 H NMR(400MHz,DMSO-d6)δ8.37(s,1H), 4.28-4.20(m,1H), 3.74-3.66(m,2H),3.45-3.43(m,2H), 3.37(s, 3H), 2.14-2.07 (m, 1H), 1.74-1.50 (m, 5H), 1.28-1.22 (m, 2H).
LC-MS m/z(ESI)＝309.10[M+l]。LC-MS m/z(ESI)=309.10[M+1].
第七步：The seventh step:
9-(3-羟基双环[3.2.1]辛基-8-基)-7-甲基-2-((7-甲基-[1,2,4]***并[1,5-a]吡啶-6-基)氨基)-7,9-二氢-8H-嘌呤-8-酮(化合物14)9-(3-Hydroxybicyclo[3.2.1]octyl-8-yl)-7-methyl-2-((7-methyl-[1,2,4]triazolo[1,5-a ]Pyridin-6-yl)amino)-7,9-dihydro-8H-purin-8-one (compound 14)
9-(3-hydroxybicyclo[3.2.1]octan-8-yl)-7-methyl-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-7,9-dihydro-8H-purin-8-one9-(3-hydroxybicyclo[3.2.1]octan-8-yl)-7-methyl-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl )amino)-7,9-dihydro-8H-purin-8-one
将2-氯-9-(3-羟基双环[3.2.1]正辛-8-基)-7-甲基-7,9-二氢-8H-嘌呤-8-酮14g(100mg，0.32mmol)、7-甲基-[1,2,4]***并[1,5-a]吡啶-6-胺(97mg，0.64mmol)碳酸铯(228mg，0.64mmol)和Brettphos G3Pd(29mg，0.032mmol)加入干燥的反应管，氮气置换三次，然后加入1,4-二氧六环(2mL)，在110℃下反应5h。将反应液浓缩，使用硅胶柱色谱分离纯化(DCM:MeOH＝20:1)，得到标题化合物，9-(3-羟基双环[3.2.1]辛-8-基)-7-甲基-2-((7-甲基-[1,2,4]***并[1,5-a]吡啶-6-基)氨基)-7,9-二氢-8H-嘌呤-8-酮化合物14(白色固体，50mg，产率37.16％)。Add 2-chloro-9-(3-hydroxybicyclo[3.2.1]n-oct-8-yl)-7-methyl-7,9-dihydro-8H-purin-8-one 14g (100mg, 0.32mmol ), 7-methyl-[1,2,4]triazolo[1,5-a]pyridine-6-amine (97mg, 0.64mmol) cesium carbonate (228mg, 0.64mmol) and Brettphos G3Pd (29mg, 0.032 mmol) was added to a dry reaction tube, replaced with nitrogen three times, and then 1,4-dioxane (2 mL) was added, and reacted at 110° C. for 5 h. The reaction solution was concentrated and separated and purified by silica gel column chromatography (DCM:MeOH=20:1) to obtain the title compound, 9-(3-hydroxybicyclo[3.2.1]oct-8-yl)-7-methyl-2 -((7-Methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-7,9-dihydro-8H-purin-8-one compound 14 (White solid, 50 mg, yield 37.16%).
1H NMR(400MHz,DMSO-d 6)δ9.03(s,1H),8.57(d,1H),8.37(s,1H),8.09(d,1H),7.69(s,1H),4.30(d,1H),3.75–3.64(m,1H),3.54(d,2H),3.30(s,3H),2.38(s,3H),1.69–1.40(m,6H),1.30(t,2H)。 1 H NMR(400MHz,DMSO-d 6 )δ9.03(s,1H), 8.57(d,1H), 8.37(s,1H), 8.09(d,1H), 7.69(s,1H), 4.30( d, 1H), 3.75--3.64(m, 1H), 3.54(d, 2H), 3.30(s, 3H), 2.38(s, 3H), 1.69--1.40(m, 6H), 1.30(t, 2H) .
LC-MS m/z(ESI)＝421.20[M+1]。LC-MS m/z(ESI)=421.20[M+1].
实施例15Example 15
9-(3-羟基-3-甲基环己基)-7-甲基-2-((7-甲基-[1,2,4]***并[1,5-a]吡啶-6-基)氨基)-7,9-二氢-8H-嘌呤-8-酮(化合物15)9-(3-hydroxy-3-methylcyclohexyl)-7-methyl-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridine-6- (Yl)amino)-7,9-dihydro-8H-purin-8-one (compound 15)
9-(3-hydroxy-3-methylcyclohexyl)-7-methyl-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-7,9-dihydro-8H-purin-8-one9-(3-hydroxy-3-methylcyclohexyl)-7-methyl-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-7, 9-dihydro-8H-purin-8-one
Figure PCTCN2020141859-appb-000031
Figure PCTCN2020141859-appb-000031
第一步：first step:
叔丁基(3-羟基-3-甲基环己基)氨基甲酸酯(15b)Tert-Butyl (3-hydroxy-3-methylcyclohexyl) carbamate (15b)
tert-butyl(3-hydroxy-3-methylcyclohexyl)carbamatetert-butyl(3-hydroxy-3-methylcyclohexyl)carbamate
将叔丁基(3-氧代环己基)氨基甲酸酯15a(5.00g,23.4mmol)溶解于四氢呋喃(80mL)在-78℃下预冷，然后经45min缓慢滴加1.6M甲基锂-***溶液(61.5mL,98.28mmol)，反应液在-78℃下搅拌反应1h后加入剩余1.6M甲基锂-***溶液(61.5mL,98.28mmol)，再在-78℃搅拌反应1h。TLC监测至反应结束，加入饱和氯化铵溶液淬灭反应，再加入水和乙酸乙酯萃取，浓缩有机层用硅胶柱色谱分离提纯(石油醚/乙酸乙酯(v/v)＝8:1)纯化得标题化合物叔丁基(3-羟基-3-甲基环己基)氨基甲酸酯15b(白色固体，2.07g，产率38.53％)。Dissolve tert-butyl (3-oxocyclohexyl) carbamate 15a (5.00g, 23.4mmol) in tetrahydrofuran (80mL) and precool at -78℃, then slowly add 1.6M methyl lithium dropwise over 45min. Ether solution (61.5mL, 98.28mmol), the reaction solution was stirred at -78°C for 1h, then the remaining 1.6M methyl lithium-ether solution (61.5mL, 98.28mmol) was added, and the reaction was stirred at -78°C for 1h. TLC monitors until the reaction is over, add saturated ammonium chloride solution to quench the reaction, add water and ethyl acetate for extraction, concentrate the organic layer and use silica gel column chromatography to separate and purify (petroleum ether/ethyl acetate (v/v) = 8:1 ) Purified to obtain the title compound tert-butyl (3-hydroxy-3-methylcyclohexyl) carbamate 15b (white solid, 2.07 g, yield 38.53%).
1H NMR(400MHz,Chloroform-d)δ4.30(s,1H),3.68(s,1H),1.90(d,3H),1.67(q,1H),1.59–1.48(m,2H),1.37(s,9H),1.19–1.12(m,4H),1.06(t,1H),0.96–0.84(m,1H)。 1 H NMR (400MHz, Chloroform-d) δ 4.30 (s, 1H), 3.68 (s, 1H), 1.90 (d, 3H), 1.67 (q, 1H), 1.59-1.48 (m, 2H), 1.37 (s,9H), 1.19–1.12(m,4H), 1.06(t,1H), 0.96–0.84(m,1H).
LC-MS m/z(ESI)＝230.20[M+1]。LC-MS m/z(ESI)=230.20[M+1].
第二步：The second step:
3-氨基-1-甲基环己烷-1-醇盐酸盐(15c)3-amino-1-methylcyclohexane-1-ol hydrochloride (15c)
3-amino-1-methylcyclohexan-1-ol hydrochloride3-amino-1-methylcyclohexan-1-ol hydrochloride
将叔丁基(3-羟基-3-甲基环己基)氨基甲酸酯15b(2.07g,9.03mmol)用4M氯化氢-1,4-二氧六环(10mL)溶解，常温搅拌反应。TLC监测至反应结束，浓缩蒸发掉1,4-二氧六环溶液得标题化合物3-氨基-1-甲基环己烷-1-醇盐酸盐15c(淡黄色固体，粗品，1.49g,产率99.60％)。The tert-butyl (3-hydroxy-3-methylcyclohexyl) carbamate 15b (2.07 g, 9.03 mmol) was dissolved in 4M hydrogen chloride-1,4-dioxane (10 mL), and the reaction was stirred at room temperature. TLC monitoring until the end of the reaction, concentrated and evaporated the 1,4-dioxane solution to obtain the title compound 3-amino-1-methylcyclohexane-1-ol hydrochloride 15c (light yellow solid, crude product, 1.49g, Yield 99.60%).
LC-MS m/z(ESI)＝130.20[M+1]。LC-MS m/z(ESI)=130.20[M+1].
第三步：third step:
2-氯-4-((3-羟基-3-甲基环己基)氨基)嘧啶-5-羧酸乙酯(15d)Ethyl 2-chloro-4-((3-hydroxy-3-methylcyclohexyl)amino)pyrimidine-5-carboxylate (15d)
ethyl 2-chloro-4-((3-hydroxy-3-methylcyclohexyl)amino)pyrimidine-5-carboxyl-ateethyl 2-chloro-4-((3-hydroxy-3-methylcyclohexyl)amino)pyrimidine-5-carboxyl-ate
将2,4-二氯嘧啶-5-羧酸乙酯1a(2.99g,13.54mmol)、3-氨基-1-甲基环己烷-1-醇盐酸盐15c(1.49g,9.03mmol)溶解于乙腈(20mL)，搅拌加入碳酸钾(3.74g,27.08mm ol)，在室温搅拌4h。TLC监测至反应结束，浓缩通过柱分离提纯(石油醚:乙酸乙酯(v/v)＝4:1)得标题化合物2-氯-4-((3-羟基-3-甲基环己基)氨基)嘧啶-5-羧酸乙酯15d(白色固体，2.23g，产率78.74％)。2,4-Dichloropyrimidine-5-carboxylic acid ethyl ester 1a (2.99g, 13.54mmol), 3-amino-1-methylcyclohexane-1-ol hydrochloride 15c (1.49g, 9.03mmol) Dissolve in acetonitrile (20mL), add potassium carbonate (3.74g, 27.08mm ol) with stirring, and stir at room temperature for 4h. TLC monitors to the end of the reaction, concentrates and purifies by column separation (petroleum ether: ethyl acetate (v/v)=4:1) to obtain the title compound 2-chloro-4-((3-hydroxy-3-methylcyclohexyl) Amino)pyrimidine-5-carboxylic acid ethyl ester 15d (white solid, 2.23 g, yield 78.74%).
1H NMR(400MHz,Chloroform-d)δ8.57(s,1H),8.19(d,1H),4.43–4.32(m,1H),4.27(q,2H),2.07–1.95(m,2H),1.83–1.69(m,2H),1.64–1.56(m,2H),1.31(t,4H),1.26(d,1H),1.21(s,3H),1.10–1.05(m,1H)。 1 H NMR(400MHz, Chloroform-d)δ8.57(s,1H), 8.19(d,1H), 4.43-4.32(m,1H), 4.27(q,2H), 2.07-1.95(m,2H) ,1.83–1.69(m,2H),1.64–1.56(m,2H),1.31(t,4H),1.26(d,1H),1.21(s,3H),1.10–1.05(m,1H).
LC-MS m/z(ESI)＝314.10[M+1]。LC-MS m/z(ESI)=314.10[M+1].
第四步：the fourth step:
2-氯-4-((3-羟基-3-甲基环己基)氨基)嘧啶-5-羧酸(15e)2-chloro-4-((3-hydroxy-3-methylcyclohexyl)amino)pyrimidine-5-carboxylic acid (15e)
2-chloro-4-((3-hydroxy-3-methylcyclohexyl)amino)pyrimidine-5-carboxylate2-chloro-4-((3-hydroxy-3-methylcyclohexyl)amino)pyrimidine-5-carboxylate
将2-氯-4-((3-羟基-3-甲基环己基)氨基)嘧啶-5-羧酸乙酯15d(2.23g,7.11mmol)溶解于四氢呋喃/水(15mL/15mL)中，加入氢氧化锂(895mg,21.32mmol)，室温搅拌1h。TLC监测至反应结束，浓缩除去四氢呋喃，用2N盐酸调pH至3-4，有白色固体析出，过滤，滤饼用石油醚洗两次，搜集固体得到标题化合物2-氯-4-((3-羟基-3-甲基环己基)氨基)嘧啶-5-羧酸15e(白色固体，1.6g，产率78.79％)。Dissolve 2-chloro-4-((3-hydroxy-3-methylcyclohexyl)amino)pyrimidine-5-carboxylic acid ethyl ester 15d (2.23g, 7.11mmol) in tetrahydrofuran/water (15mL/15mL), Lithium hydroxide (895mg, 21.32mmol) was added and stirred at room temperature for 1h. TLC monitored until the reaction was over, concentrated to remove tetrahydrofuran, adjusted pH to 3-4 with 2N hydrochloric acid, a white solid precipitated out, filtered, the filter cake was washed twice with petroleum ether, and the solid was collected to obtain the title compound 2-chloro-4-((3 -Hydroxy-3-methylcyclohexyl)amino)pyrimidine-5-carboxylic acid 15e (white solid, 1.6g, yield 78.79%).
LC-MS m/z(ESI)＝286.10[M+1]。LC-MS m/z(ESI)=286.10[M+1].
第五步：the fifth step:
2-氯-9-(3-羟基-3-甲基环己基)-7,9-二氢-8H-嘌呤-8-酮(15f)2-chloro-9-(3-hydroxy-3-methylcyclohexyl)-7,9-dihydro-8H-purin-8-one (15f)
2-chloro-9-(3-hydroxy-3-methylcyclohexyl)-7,9-dihydro-8H-purin-8-one2-chloro-9-(3-hydroxy-3-methylcyclohexyl)-7,9-dihydro-8H-purin-8-one
将2-氯-4-((3-羟基-3-甲基环己基)氨基)嘧啶-5-羧酸29d(1.38g,4.83mmol)溶解于 二甲基乙酰胺(20mL)，加入三乙胺(0.67mL,4.83mmol)、叠氮磷酸二苯酯(1.04mL,4.83mmol),随后逐步升温至90℃搅拌2h。TLC监测至反应结束，将反应液倒入冰水中,过滤搜集固体,水洗3次,真空浓缩干燥得到目标化合物2-氯-9-(3-羟基-3-甲基环己基)-7,9-二氢-8H-嘌呤-8-酮15f(白色固体，1.35g，产率98.86％)。Dissolve 2-chloro-4-((3-hydroxy-3-methylcyclohexyl)amino)pyrimidine-5-carboxylic acid 29d (1.38g, 4.83mmol) in dimethylacetamide (20mL) and add triethyl Amine (0.67mL, 4.83mmol), diphenyl azide phosphate (1.04mL, 4.83mmol), then gradually heated to 90°C and stirred for 2h. TLC monitors to the end of the reaction, the reaction solution is poured into ice water, the solid is collected by filtration, washed with water 3 times, and concentrated and dried in vacuo to obtain the target compound 2-chloro-9-(3-hydroxy-3-methylcyclohexyl)-7,9 -Dihydro-8H-purin-8-one 15f (white solid, 1.35 g, yield 98.86%).
1H NMR(400MHz,DMSO-d6)δ11.60(s,1H),8.10(s,1H),4.62-4.54(m,1H),4.35(s,1H),2.19(t,1H),2.10-1.99(m,1H),1.70-1.53(m,5H),1.30-1.22(m,1H),1.16(s,3H)。 1 H NMR (400MHz, DMSO-d6) δ 11.60 (s, 1H), 8.10 (s, 1H), 4.62-4.54 (m, 1H), 4.35 (s, 1H), 2.19 (t, 1H), 2.10 -1.99 (m, 1H), 1.70 to 1.53 (m, 5H), 1.30 to 1.22 (m, 1H), 1.16 (s, 3H).
LC-MS m/z(ESI)＝283.10[M+1]。LC-MS m/z(ESI)=283.10[M+1].
第六步：The sixth step:
2-氯-9-(3-羟基-3-甲基环己基)-7-甲基-7,9-二氢-8H-嘌呤-8-酮(15g)2-Chloro-9-(3-hydroxy-3-methylcyclohexyl)-7-methyl-7,9-dihydro-8H-purin-8-one (15g)
2-chloro-9-(3-hydroxy-3-methylcyclohexyl)-7-methyl-7,9-dihydro-8H-purin-8-one2-chloro-9-(3-hydroxy-3-methylcyclohexyl)-7-methyl-7,9-dihydro-8H-purin-8-one
将2-氯-9-(3-羟基-3-甲基环己基)-7,9-二氢-8H-嘌呤-8-酮15f(1.35g，4.77mmol)溶解于二甲基甲酰胺(10mL)，在0℃下加入硫酸二甲酯(0.45mL，4.77mmol)和碳酸铯(1.56g,4.77mmol)，搅拌反应1h。TLC监测至反应结束，将反应液倒入冰水中，有固体析出，过滤、搜集固体得到标题化合物2-氯-9-(3-羟基-3-甲基环己基)-7-甲基-7,9-二氢-8H-嘌呤-8-酮15g(白色固体，873mg，产率61.61％)。Dissolve 2-chloro-9-(3-hydroxy-3-methylcyclohexyl)-7,9-dihydro-8H-purin-8-one 15f (1.35g, 4.77mmol) in dimethylformamide ( 10 mL), dimethyl sulfate (0.45 mL, 4.77 mmol) and cesium carbonate (1.56 g, 4.77 mmol) were added at 0°C, and the reaction was stirred for 1 h. TLC monitors to the end of the reaction, the reaction solution is poured into ice water, a solid precipitates out, filtered and collected the solid to obtain the title compound 2-chloro-9-(3-hydroxy-3-methylcyclohexyl)-7-methyl-7 , 9-dihydro-8H-purin-8-one 15g (white solid, 873mg, yield 61.61%).
1H NMR(400MHz,DMSO-d6)δ8.34(s,1H),4.66-4.58(m,1H),4.37(s,1H),3.35(s,3H),2.20(t,1H),2.11-2.00(m,1H),1.72-1.54(m,5H),1.32-1.24(m,1H),1.17(s,3H)。 1 H NMR(400MHz,DMSO-d6)δ8.34(s,1H), 4.66-4.58(m,1H), 4.37(s,1H), 3.35(s,3H), 2.20(t,1H), 2.11 -2.00 (m, 1H), 1.72-1.54 (m, 5H), 1.32-1.24 (m, 1H), 1.17 (s, 3H).
LC-MS m/z(ESI)＝297.10[M+1]。LC-MS m/z(ESI)=297.10[M+1].
第七步：The seventh step:
9-(3-羟基-3-甲基环己基)-7-甲基-2-((7-甲基-[1,2,4]***并[1,5-a]吡啶-6-基)氨基)-7,9-二氢-8H-嘌呤-8-酮(化合物15)9-(3-hydroxy-3-methylcyclohexyl)-7-methyl-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridine-6- (Yl)amino)-7,9-dihydro-8H-purin-8-one (compound 15)
9-(3-hydroxy-3-methylcyclohexyl)-7-methyl-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-7,9-dihydro-8H-purin-8-one9-(3-hydroxy-3-methylcyclohexyl)-7-methyl-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-7, 9-dihydro-8H-purin-8-one
将2-氯-9-(3-羟基-3-甲基环己基)-7-甲基-7,9-二氢-8H-嘌呤-8-酮15g(200mg，0.67mmol)、7-甲基-[1,2,4]***并[1,5-a]吡啶-6-胺(200mg，1.34mmol)碳酸铯(473mg，1.34mmol)和Brettphos G3Pd(61mg，0.067mmol)加入干燥的反应管，氮气置换三次，然后加入1,4-二氧六环(2mL)，在110℃下反应5h。将反应液浓缩，使用硅胶柱色谱分离纯化(DCM:MeOH＝20:1)，得到标题化合物，9-(3-羟基-3-甲基环己基)-7-甲基-2-((-甲基-[1,2,4]***并[1,5-a]吡啶-6-基)氨基)-7,9-二氢-8H-嘌呤-8-酮化合物15(浅黄色固体，200mg，产率73.08％)。The 2-chloro-9-(3-hydroxy-3-methylcyclohexyl)-7-methyl-7,9-dihydro-8H-purin-8-one 15g (200mg, 0.67mmol), 7-methyl -[1,2,4]triazolo[1,5-a]pyridine-6-amine (200mg, 1.34mmol) cesium carbonate (473mg, 1.34mmol) and Brettphos G3Pd (61mg, 0.067mmol) were added to the dry The reaction tube was replaced with nitrogen three times, then 1,4-dioxane (2 mL) was added, and the reaction was carried out at 110° C. for 5 h. The reaction solution was concentrated and separated and purified by silica gel column chromatography (DCM:MeOH=20:1) to obtain the title compound, 9-(3-hydroxy-3-methylcyclohexyl)-7-methyl-2-((- Methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-7,9-dihydro-8H-purin-8-one compound 15 (light yellow solid, 200mg, yield 73.08%).
1H NMR(400MHz,DMSO-d 6)δ9.15(s,1H),8.65(s,1H),8.37(s,1H),8.09(s,1H),7.70(d,1H),4.61-4.53(m,1H),4.27(s,1H),3.29(s,3H),2.39(d,3H),2.27(t,1H),2.06–1.93(m,1H),1.76–1.45(m,5H),1.23-1.15(m,1H),1.10(s,3H)。 1 H NMR(400MHz,DMSO-d 6 )δ9.15(s,1H),8.65(s,1H),8.37(s,1H),8.09(s,1H),7.70(d,1H),4.61- 4.53 (m, 1H), 4.27 (s, 1H), 3.29 (s, 3H), 2.39 (d, 3H), 2.27 (t, 1H), 2.06-1.93 (m, 1H), 1.76-1.45 (m, 5H), 1.23-1.15 (m, 1H), 1.10 (s, 3H).
LC-MS m/z(ESI)＝409.20[M+1]。LC-MS m/z(ESI)=409.20[M+1].
实施例16Example 16
7-甲基-2-((7-甲基-[1,2,4]***并[1,5-a]吡啶-6-基)氨基)-9-(2-氧螺环[3.3]庚-6-基)-7,9-二氢-8H-嘌呤-8-酮(化合物16)7-methyl-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-9-(2-oxospiro[3.3 ]Hept-6-yl)-7,9-dihydro-8H-purin-8-one (Compound 16)
7-methyl-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-9-(2-oxaspiro[3.3]heptan-6-yl)-7,9-dihydro-8H-purin-8-one7-methyl-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-9-(2-oxaspiro[3.3]heptan-6-yl )-7,9-dihydro-8H-purin-8-one
Figure PCTCN2020141859-appb-000032
Figure PCTCN2020141859-appb-000032
Figure PCTCN2020141859-appb-000033
Figure PCTCN2020141859-appb-000033
第一步：first step:
4-((2-氧杂螺[3.3]庚-6-6基)氨基)-2-氯嘧啶-5-羧酸乙酯(16a)4-((2-oxaspiro[3.3]hept-6-6 yl)amino)-2-chloropyrimidine-5-carboxylic acid ethyl ester (16a)
ethyl 4-((2-oxaspiro[3.3]heptan-6-yl)amino)-2-chloropyrimidine-5-carboxylateethyl 4-((2-oxaspiro[3.3]heptan-6-yl)amino)-2-chloropyrimidine-5-carboxylate
将2,4-二氯嘧啶-5-羧酸乙酯1a(4.43g,20.05mmol),2-氧杂螺[3.3]庚-6-胺盐酸盐(2.0g,13.37mmol),碳酸钾(5.54g，40.10mmol)溶于乙腈(60mL)，反应液在室温反应16h。TLC监测反应结束，过滤，并用少量乙腈清洗固体，将滤液合并后浓缩，粗品经柱层析分离(石油醚：乙酸乙酯＝1:1)后得目标化合4-((2-氧杂螺[3.3]庚-6-6基)氨基)-2-氯嘧啶-5-羧酸乙酯16a(白色固体,3.0g,产率75.38％)。2,4-Dichloropyrimidine-5-carboxylic acid ethyl ester 1a (4.43g, 20.05mmol), 2-oxaspiro[3.3]heptan-6-amine hydrochloride (2.0g, 13.37mmol), potassium carbonate (5.54g, 40.10mmol) was dissolved in acetonitrile (60mL), and the reaction solution was reacted at room temperature for 16h. The end of the reaction was monitored by TLC, filtered, and the solid was washed with a small amount of acetonitrile. The filtrate was combined and concentrated. The crude product was separated by column chromatography (petroleum ether: ethyl acetate = 1:1) to obtain the target compound 4-((2-oxaspiro) [3.3]Heptan-6-6yl)amino)-2-chloropyrimidine-5-carboxylic acid ethyl ester 16a (white solid, 3.0 g, yield 75.38%).
1H NMR(400MHz,DMSO-d6)δ8.60(s,1H),8.47(d,1H),4.63(s,2H),4.49(s,2H),4.39-4.33(m,1H),4.30-4.27(q,2H),2.66-2.61(m,2H),2.31-2.26(m,2H),1.30(t,3H)。 1 H NMR(400MHz,DMSO-d6)δ8.60(s,1H), 8.47(d,1H), 4.63(s,2H), 4.49(s,2H), 4.39-4.33(m,1H), 4.30 -4.27 (q, 2H), 2.66-2.61 (m, 2H), 2.31-2.26 (m, 2H), 1.30 (t, 3H).
LC-MS m/z(ESI)＝298.10[M+1]。LC-MS m/z(ESI)=298.10[M+1].
第二步：The second step:
4-((2-氧杂螺[3.3]庚-6-6基)氨基)-2-氯嘧啶-5-羧酸(16b)4-((2-oxaspiro[3.3]hept-6-6 yl)amino)-2-chloropyrimidine-5-carboxylic acid (16b)
4-((2-oxaspiro[3.3]heptan-6-yl)amino)-2-chloropyrimidine-5-carboxylic acid4-((2-oxaspiro[3.3]heptan-6-yl)amino)-2-chloropyrimidine-5-carboxylic acid
将4-((2-氧杂螺[3.3]庚-6-6基)氨基)-2-氯嘧啶-5-羧酸乙酯16a(3.0g，10.08mmol)溶解于四氢呋喃/水(30mL/30mL)中,加入氢氧化锂(845mg,20.15mmol)，室温搅拌1h。TLC监测至反应结束，浓缩除去四氢呋喃，用2N盐酸调pH为5，有白色固体析出，过滤，滤饼用石油醚洗两次，搜集固体得到标题化合物4-((2-氧杂螺[3.3]庚-6-6基)氨基)-2-氯嘧啶-5-羧酸16b(白色固体,1.8g,产率66.24％)。4-((2-oxaspiro[3.3]hept-6-6 yl)amino)-2-chloropyrimidine-5-carboxylic acid ethyl ester 16a (3.0g, 10.08mmol) was dissolved in tetrahydrofuran/water (30mL/ 30 mL), lithium hydroxide (845 mg, 20.15 mmol) was added, and the mixture was stirred at room temperature for 1 h. The reaction was monitored by TLC and the tetrahydrofuran was removed by concentration. The pH was adjusted to 5 with 2N hydrochloric acid. A white solid was precipitated. The filter cake was washed twice with petroleum ether. The solid was collected to obtain the title compound 4-((2-oxaspiro[3.3 ]Hept-6-6 yl)amino)-2-chloropyrimidine-5-carboxylic acid 16b (white solid, 1.8 g, yield 66.24%).
1H NMR(400MHz,DMSO-d6)δ13.76(s,1H),8.64(d,1H),8.57(s,1H),4.64(s,2H),4.49(s,2H),4.40-4.30(m,1H),2.67-2.61(m,2H),2.28-2.23(m,2H)。 1 H NMR (400MHz, DMSO-d6) δ 13.76 (s, 1H), 8.64 (d, 1H), 8.57 (s, 1H), 4.64 (s, 2H), 4.49 (s, 2H), 4.40-4.30 (m, 1H), 2.67-2.61 (m, 2H), 2.28-2.23 (m, 2H).
LC-MS m/z(ESI)＝270.20[M+1]。LC-MS m/z(ESI)=270.20[M+1].
第三步：third step:
2-氯-9-(2-氧杂螺[3.3]庚-6-基)-7,9-二氢-8H-嘌呤-8-酮(16c)2-Chloro-9-(2-oxaspiro[3.3]heptan-6-yl)-7,9-dihydro-8H-purin-8-one (16c)
2-chloro-9-(2-oxaspiro[3.3]heptan-6-yl)-7,9-dihydro-8H-purin-8-one2-chloro-9-(2-oxaspiro[3.3]heptan-6-yl)-7,9-dihydro-8H-purin-8-one
将4-((2-氧杂螺[3.3]庚-6-6基)氨基)-2-氯嘧啶-5-羧酸16b(1.8g,6.67mmol)溶解于二甲基乙酰胺(40mL)，加入三乙胺(0.92mL,6.67mmol)、叠氮磷酸二苯酯(1.4mL,6.67mmol),随后逐步升温至90℃搅拌反应2h。TLC监测至反应结束，将反应液倒入冰水中,过滤搜集固体,水洗3次,真空浓缩干燥得2-氯-9-(2-氧杂螺[3.3]庚-6-基)-7,9-二氢-8H-嘌呤-8-酮16c(白色固体,1.3g,产率73.03％)。Dissolve 4-((2-oxaspiro[3.3]hept-6-6 yl)amino)-2-chloropyrimidine-5-carboxylic acid 16b (1.8g, 6.67mmol) in dimethylacetamide (40mL) , Triethylamine (0.92mL, 6.67mmol) and diphenyl azide phosphate (1.4mL, 6.67mmol) were added, and then the temperature was gradually increased to 90°C and the reaction was stirred for 2h. TLC monitors to the end of the reaction, the reaction solution is poured into ice water, the solid is collected by filtration, washed 3 times with water, concentrated and dried in vacuo to obtain 2-chloro-9-(2-oxaspiro[3.3]heptan-6-yl)-7, 9-dihydro-8H-purin-8-one 16c (white solid, 1.3 g, yield 73.03%).
1H NMR(400MHz,DMSO-d6)δ11.61(s,1H),8.11(s,1H),4.71-4.63(m,5H),3.02-2.94(m,2H),2.69-2.66(m,2H)。 1 H NMR(400MHz,DMSO-d6)δ11.61(s,1H),8.11(s,1H),4.71-4.63(m,5H),3.02-2.94(m,2H),2.69-2.66(m, 2H).
LC-MS m/z(ESI)＝267.10[M+1]。LC-MS m/z(ESI)=267.10[M+1].
第四步：the fourth step:
2-氯-7-甲基-9-(2-氧杂螺[3.3]庚-6-基)-7,9-二氢-8H-嘌呤-8-酮(16d)2-Chloro-7-methyl-9-(2-oxaspiro[3.3]heptan-6-yl)-7,9-dihydro-8H-purin-8-one (16d)
2-chloro-7-methyl-9-(2-oxaspiro[3.3]heptan-6-yl)-7,9-dihydro-8H-purin-8-one2-chloro-7-methyl-9-(2-oxaspiro[3.3]heptan-6-yl)-7,9-dihydro-8H-purin-8-one
将2-氯-9-(2-氧杂螺[3.3]庚-6-基)-7,9-二氢-8H-嘌呤-8-酮16c(1.3g，4.87mmol)溶解于二甲基甲酰胺(10mL)，在0℃下加入硫酸二甲酯(0.46mL，4.87mmol)和碳酸铯(3.18g,9.75mmol)，搅拌反应1h。TLC监测至反应结束，将反应液倒入冰水中，有固体析出，过滤、搜集固体得到标题化合物2-氯-7-甲基-9-(2-氧杂螺[3.3]庚-6-基)-7,9-二氢-8H-嘌呤-8-酮16d(白色固体,875mg,产率63.94％)。Dissolve 2-chloro-9-(2-oxaspiro[3.3]hept-6-yl)-7,9-dihydro-8H-purin-8-one 16c (1.3g, 4.87mmol) in dimethyl Formamide (10 mL), dimethyl sulfate (0.46 mL, 4.87 mmol) and cesium carbonate (3.18 g, 9.75 mmol) were added at 0°C, and the reaction was stirred for 1 h. TLC monitors to the end of the reaction, the reaction solution is poured into ice water, a solid precipitates out, filtered and collected the solid to obtain the title compound 2-chloro-7-methyl-9-(2-oxaspiro[3.3]hept-6-yl )-7,9-dihydro-8H-purin-8-one 16d (white solid, 875 mg, yield 63.94%).
1H NMR(400MHz,DMSO-d6)δ8.35(s,1H),4.76-4.69(m,1H),4.66-4.63(m,4H),3.33(s,3H),3.01-2.95(m,2H),2.71-2.66(m,2H)。 1 H NMR(400MHz,DMSO-d6)δ8.35(s,1H),4.76-4.69(m,1H),4.66-4.63(m,4H),3.33(s,3H),3.01-2.95(m, 2H), 2.71-2.66 (m, 2H).
LC-MS m/z(ESI)＝281.10[M+1]。LC-MS m/z(ESI)=281.10[M+1].
第五步：the fifth step:
7-甲基-2-((7-甲基-[1,2,4]***并[1,5-a]吡啶-6-基)氨基)-9-(2-氧螺环[3.3]庚-6-基)-7,9-二氢-8H-嘌呤-8-酮(化合物16)7-methyl-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-9-(2-oxospiro[3.3 ]Hept-6-yl)-7,9-dihydro-8H-purin-8-one (Compound 16)
7-methyl-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-9-(2-oxaspiro[3.3]heptan-6-yl)-7,9-dihydro-8H-purin-8-one7-methyl-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-9-(2-oxaspiro[3.3]heptan-6-yl )-7,9-dihydro-8H-purin-8-one
将2-氯-7-甲基-9-(2-氧杂螺[3.3]庚基-6-基)-7,9-二氢-8H-嘌呤-8-酮16d(200mg，0.71mmol)、7-甲基-[1,2,4]***并[1,5-a]吡啶-6-胺(212mg，1.42mmol)碳酸铯(502mg，1.42mmol)和Brettphos G3Pd(65mg，0.071mmol)加入干燥的反应管，氮气置换三次，然后加入1,4-二氧六环(2mL)，在110℃下反应5h。将反应液浓缩，使用硅胶柱色谱分离纯化(DCM:MeOH＝20:1)，得到标题化合物，7-甲基-2-(((7-甲基-[1,2,4]***并[1,5-a]吡啶-6-基)氨基)-9-(2-氧螺环[3.3]庚-6-基)-7,9-二氢-8H-嘌呤-8-酮化合物16(白色固体，160mg，产率57.42％)。The 2-chloro-7-methyl-9-(2-oxaspiro[3.3]heptyl-6-yl)-7,9-dihydro-8H-purin-8-one 16d (200mg, 0.71mmol) , 7-Methyl-[1,2,4]triazolo[1,5-a]pyridine-6-amine (212mg, 1.42mmol) cesium carbonate (502mg, 1.42mmol) and Brettphos G3Pd (65mg, 0.071mmol) ) Add a dry reaction tube, replace with nitrogen three times, then add 1,4-dioxane (2 mL), and react at 110° C. for 5 hours. The reaction solution was concentrated and separated and purified using silica gel column chromatography (DCM:MeOH=20:1) to obtain the title compound, 7-methyl-2-(((7-methyl-[1,2,4]triazolo [1,5-a]pyridin-6-yl)amino)-9-(2-oxospiro[3.3]hept-6-yl)-7,9-dihydro-8H-purin-8-one compound 16 (White solid, 160 mg, yield 57.42%).
1H NMR(400MHz,DMSO-d 6)δ9.05(s,1H),8.65(s,1H),8.39(s,1H),8.11(s,1H),7.73(s,1H),4.60(d,3H),4.16(s,2H),3.27(s,3H),2.97–2.91(m,2H),2.56–2.51(m,2H),2.36(d,3H)。 1 H NMR(400MHz,DMSO-d 6 )δ9.05(s,1H),8.65(s,1H),8.39(s,1H),8.11(s,1H),7.73(s,1H),4.60( d, 3H), 4.16(s, 2H), 3.27(s, 3H), 2.97–2.91(m, 2H), 2.56–2.51(m, 2H), 2.36(d, 3H).
LC-MS m/z(ESI)＝393.10[M+1]。LC-MS m/z(ESI)=393.10[M+1].
实施例17Example 17
9-(6-羟基螺[3.3]庚-2-基)-7-甲基-2-((7-甲基-[1,2,4]***并[1,5-a]吡啶-6-基)氨基)-7,9-二氢-8H-嘌呤-8-酮(化合物17)9-(6-Hydroxyspiro[3.3]heptan-2-yl)-7-methyl-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridine- 6-yl)amino)-7,9-dihydro-8H-purin-8-one (compound 17)
9-(6-hydroxyspiro[3.3]heptan-2-yl)-7-methyl-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-7,9-dihydro-8H-purin-8-one9-(6-hydroxyspiro[3.3]heptan-2-yl)-7-methyl-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino )-7,9-dihydro-8H-purin-8-one
Figure PCTCN2020141859-appb-000034
Figure PCTCN2020141859-appb-000034
Figure PCTCN2020141859-appb-000035
Figure PCTCN2020141859-appb-000035
第一步：first step:
6-氨基螺[3.3]庚烷-2-醇盐酸盐(17b)6-Aminospiro[3.3]heptane-2-ol hydrochloride (17b)
6-aminospiro[3.3]heptan-2-ol hydrochloride6-aminospiro[3.3]heptan-2-ol hydrochloride
将叔丁基(6-羟基螺[3.3]庚烷-2-基)氨基甲酸酯17a(2g,8.80mmol)用4M氯化氢-1,4-二氧六环(15mL)溶解，常温搅拌反应2h。TLC监测至反应结束，浓缩蒸发掉1,4-二氧六环溶液得标题化合物6-氨基螺[3.3]庚烷-2-醇盐酸盐17b(淡黄色固体，粗品，1.44g,产率100％)。Dissolve tert-butyl (6-hydroxyspiro[3.3]heptan-2-yl) carbamate 17a (2g, 8.80mmol) with 4M hydrogen chloride-1,4-dioxane (15mL), stir and react at room temperature 2h. TLC monitors to the end of the reaction, concentrates and evaporates the 1,4-dioxane solution to obtain the title compound 6-aminospiro[3.3]heptane-2-ol hydrochloride 17b (light yellow solid, crude product, 1.44g, yield 100%).
LC-MS m/z(ESI)＝163.10[M+1]。LC-MS m/z(ESI)=163.10[M+1].
第二步：The second step:
2-氯-4-((6-羟基螺[3.3]庚-2-基)氨基)嘧啶-5-羧酸乙酯(17c)Ethyl 2-chloro-4-((6-hydroxyspiro[3.3]heptan-2-yl)amino)pyrimidine-5-carboxylate (17c)
ethyl 2-chloro-4-((3-hydroxy-3-methylcyclohexyl)amino)pyrimidine-5-carboxyl-ate将2,4-二氯嘧啶-5-羧酸乙酯1a(2.92g,13.20mmol)、6-氨基螺[3.3]庚烷-2-醇盐酸盐17b(1.44g,8.80mmol)溶解于乙腈(20mL)，搅拌加入碳酸钾(3.65g,26.40mmol)，在室温搅拌4h。TLC监测至反应结束，浓缩通过柱分离提纯(石油醚:乙酸乙酯(v/v)＝4:1)得标题化合物2-氯-4-((3-羟基-3-甲基环己基)氨基)嘧啶-5-羧酸乙酯17c(白色固体g，1.36g，产率49.57％)。ethyl 2-chloro-4-((3-hydroxy-3-methylcyclohexyl)amino)pyrimidine-5-carboxyl-ate ethyl 2,4-dichloropyrimidine-5-carboxyl-ate 1a (2.92g, 13.20mmol), 6-Aminospiro[3.3]heptane-2-ol hydrochloride 17b (1.44g, 8.80mmol) was dissolved in acetonitrile (20mL), potassium carbonate (3.65g, 26.40mmol) was added with stirring, and stirred at room temperature for 4h. TLC monitors to the end of the reaction, concentrates and purifies by column separation (petroleum ether: ethyl acetate (v/v)=4:1) to obtain the title compound 2-chloro-4-((3-hydroxy-3-methylcyclohexyl) Amino)pyrimidine-5-carboxylic acid ethyl ester 17c (white solid g, 1.36 g, yield 49.57%).
1H NMR(400MHz,DMSO-d6)δ8.59(s,1H),8.43(d,1H),4.91(s,1H),4.44–4.34(m,1H),4.31(q,2H),4.02–3.93(m,1H),2.43–2.35(m,2H),2.34–2.27(m,1H),2.23–2.16(m,1H),2.07–1.99(m,2H),1.90–1.80(m,2H),1.31(t,3H)。 1 H NMR(400MHz,DMSO-d6)δ8.59(s,1H),8.43(d,1H),4.91(s,1H),4.44-4.34(m,1H),4.31(q,2H),4.02 --3.93(m,1H),2.43–2.35(m,2H),2.34–2.27(m,1H),2.23–2.16(m,1H),2.07–1.99(m,2H),1.90–1.80(m, 2H), 1.31(t, 3H).
LC-MS m/z(ESI)＝312.10[M+1]。LC-MS m/z(ESI)=312.10[M+1].
第三步：third step:
2-氯-4-((6-羟基螺[3.3]庚-2-基)氨基)嘧啶-5-羧酸(17d)2-chloro-4-((6-hydroxyspiro[3.3]heptan-2-yl)amino)pyrimidine-5-carboxylic acid (17d)
2-chloro-4-((6-hydroxyspiro[3.3]heptan-2-yl)amino)pyrimidine-5-carboxylic acid2-chloro-4-((6-hydroxyspiro[3.3]heptan-2-yl)amino)pyrimidine-5-carboxylic acid
将2-氯-4-((6-羟基螺[3.3]庚-2-基)氨基)嘧啶-5-羧酸乙酯17c(1.0g，3.21mmol)溶解于四氢呋喃10mL，水10mL中，加入氢氧化锂(269mg,6.42mmol)，室温搅拌1个小时。TLC监测至反应完全，浓缩除去四氢呋喃，用2N盐酸调pH为5，有白色固体析出，过滤，滤饼用石油醚洗两次，搜集固体得到标题化合物2-氯-4-((6-羟基螺[3.3]庚-2-基)氨基)嘧啶-5-羧酸17d(760mg,白色固体,产率83.52％)。Dissolve 2-chloro-4-((6-hydroxyspiro[3.3]heptan-2-yl)amino)pyrimidine-5-carboxylic acid ethyl ester 17c (1.0g, 3.21mmol) in 10mL of tetrahydrofuran, 10mL of water, and add Lithium hydroxide (269mg, 6.42mmol) was stirred at room temperature for 1 hour. TLC monitored until the reaction was complete, concentrated to remove tetrahydrofuran, adjusted the pH to 5 with 2N hydrochloric acid, a white solid precipitated, filtered, the filter cake was washed twice with petroleum ether, the solid was collected to obtain the title compound 2-chloro-4-((6-hydroxyl Spiro[3.3]heptan-2-yl)amino)pyrimidine-5-carboxylic acid 17d (760 mg, white solid, yield 83.52%).
1H NMR(400MHz,DMSO-d6)δ13.75(s,1H),8.62(d,1H),8.56(s,1H),4.90(s,1H),4.42-4.32(m,1H),4.00-3.93(m,1H),2.42-2.35(m,2H),2.33-2.27(m,1H),2.22-2.16(m,1H),2.02-1.97(m,2H),1.88-1.80(m,2H)。 1 H NMR (400MHz, DMSO-d6) δ 13.75 (s, 1H), 8.62 (d, 1H), 8.56 (s, 1H), 4.90 (s, 1H), 4.42-4.32 (m, 1H), 4.00 -3.93(m,1H),2.42-2.35(m,2H),2.33-2.27(m,1H),2.22-2.16(m,1H),2.02-1.97(m,2H),1.88-1.80(m, 2H).
LC-MS m/z(ESI)＝284.10[M+1]。LC-MS m/z(ESI)=284.10[M+1].
第四步：the fourth step:
2-氯-9-(6-羟基螺[3.3]庚烷-2-基)-7,9-二氢-8H-嘌呤-8-酮(17e)2-chloro-9-(6-hydroxyspiro[3.3]heptan-2-yl)-7,9-dihydro-8H-purin-8-one (17e)
2-chloro-9-(6-hydroxyspiro[3.3]heptan-2-yl)-7,9-dihydro-8H-purin-8-one2-chloro-9-(6-hydroxyspiro[3.3]heptan-2-yl)-7,9-dihydro-8H-purin-8-one
将2-氯-4-((6-羟基螺[3.3]庚-2-基)氨基)嘧啶-5-羧酸17d(760mg,2.68mmol)溶解于二甲基乙酰胺(10mL)，加入三乙胺(0.37mL,2.68mmol)、叠氮磷酸二苯酯(0.57mL,2.68mmol)，随后逐步升温至90℃搅拌2小时。TLC监测至反应完毕，将反应液倒入冰水中，过滤搜集固体,水洗3次，真空浓缩干燥得到标题化合物2-氯-9-(6-羟基螺[3.3]庚烷-2-基)-7,9-二氢-8H-嘌呤-8-酮17e(580mg,白色固体,产率77.13％)。Dissolve 2-chloro-4-((6-hydroxyspiro[3.3]heptan-2-yl)amino)pyrimidine-5-carboxylic acid 17d (760mg, 2.68mmol) in dimethylacetamide (10mL), add three Ethylamine (0.37mL, 2.68mmol), diphenyl azide phosphate (0.57mL, 2.68mmol), then gradually heated to 90°C and stirred for 2 hours. The reaction was monitored by TLC until the reaction was completed, the reaction solution was poured into ice water, the solid was collected by filtration, washed with water 3 times, and concentrated and dried in vacuo to obtain the title compound 2-chloro-9-(6-hydroxyspiro[3.3]heptan-2-yl)- 7,9-dihydro-8H-purin-8-one 17e (580 mg, white solid, yield 77.13%).
1H NMR(400MHz,DMSO-d6)δ11.60(s,1H),8.10(s,1H),4.96(d,1H),4.70-4.60(m,1H),2.92-2.87(m,2H),2.46-2.43(m,2H),2.32-2.21(m,3H),1.92-1.87(m,2H)。 1 H NMR (400MHz, DMSO-d6) δ 11.60 (s, 1H), 8.10 (s, 1H), 4.96 (d, 1H), 4.70-4.60 (m, 1H), 2.92-2.87 (m, 2H) ,2.46-2.43(m,2H),2.32-2.21(m,3H),1.92-1.87(m,2H).
LC-MS m/z(ESI)＝281.10[M+1]。LC-MS m/z(ESI)=281.10[M+1].
第五步：the fifth step:
2-氯-9-(6-羟基螺[3.3]庚烷-2-基)-7-甲基-7,9-二氢-8H-嘌呤-8-酮(17f)2-chloro-9-(6-hydroxyspiro[3.3]heptan-2-yl)-7-methyl-7,9-dihydro-8H-purin-8-one (17f)
2-chloro-9-(6-hydroxyspiro[3.3]heptan-2-yl)-7-methyl-7,9-dihydro-8H-purin-8-one2-chloro-9-(6-hydroxyspiro[3.3]heptan-2-yl)-7-methyl-7,9-dihydro-8H-purin-8-one
将2-氯-9-(6-羟基螺[3.3]庚烷-2-基)-7,9-二氢-8H-嘌呤-8-酮17e(580mg，2.07mmol)溶解于二甲基甲酰胺(5mL)，0℃下加入硫酸二甲酯(260mg，2.07mmol)和碳酸铯(1.3g,4.13mmol)搅拌反应1小时。TLC监测至反应结束，将反应液倒入冰水中，有固体析出，过滤搜集固体得到标题化合物2-氯-9-(6-羟基螺[3.3]庚烷-2-基)-7-甲基-7,9-二氢-8H-嘌呤-8-酮17f(380mg，白色固体，产率62.40％)。Dissolve 2-chloro-9-(6-hydroxyspiro[3.3]heptan-2-yl)-7,9-dihydro-8H-purin-8-one 17e (580mg, 2.07mmol) in dimethylform Amide (5mL), dimethyl sulfate (260mg, 2.07mmol) and cesium carbonate (1.3g, 4.13mmol) were added at 0°C and stirred for 1 hour. TLC monitored to the end of the reaction, the reaction solution was poured into ice water, a solid precipitated out, the solid was collected by filtration to obtain the title compound 2-chloro-9-(6-hydroxyspiro[3.3]heptan-2-yl)-7-methyl -7,9-dihydro-8H-purin-8-one 17f (380 mg, white solid, yield 62.40%).
1H NMR(400MHz,DMSO-d6)δ8.33(s,1H),4.97(d,1H),4.70-4.66(m,1H),4.05-3.96(m,1H),3.33(s,3H),2.95-2.87(m,2H),2.51-2.43(m,1H),2.31-2.25(m,3H),1.93-1.87(m,2H)。 1 H NMR(400MHz,DMSO-d6)δ8.33(s,1H), 4.97(d,1H), 4.70-4.66(m,1H), 4.05-3.96(m,1H), 3.33(s,3H) ,2.95-2.87(m,2H),2.51-2.43(m,1H),2.31-2.25(m,3H),1.93-1.87(m,2H).
LC-MS m/z(ESI)＝295.10[M+1]。LC-MS m/z(ESI)=295.10[M+1].
第六步：The sixth step:
9-(6-羟基螺[3.3]庚-2-基)-7-甲基-2-((7-甲基-[1,2,4]***并[1,5-a]吡啶-6-基)氨基)-7,9-二氢-8H-嘌呤-8-酮(化合物17)9-(6-Hydroxyspiro[3.3]heptan-2-yl)-7-methyl-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridine- 6-yl)amino)-7,9-dihydro-8H-purin-8-one (compound 17)
9-(6-hydroxyspiro[3.3]heptan-2-yl)-7-methyl-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-7,9-dihydro-8H-purin-8-one9-(6-hydroxyspiro[3.3]heptan-2-yl)-7-methyl-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino )-7,9-dihydro-8H-purin-8-one
将2-氯-9-(6-羟基螺[3.3]庚-2-基)-7-甲基-7,9-二氢-8H-嘌呤-8-酮17f(140mg，0.47mmol)、7-甲基-[1,2,4]***并[1,5-a]吡啶-6-胺(142mg，0.94mmol)碳酸铯(335mg，0.94mmol)和Brettphos G3Pd(43mg，0.047mmol)加入干燥的反应管，氮气置换三次，然后加入1,4-二氧六环(2mL)，在110℃下反应5h。将反应液浓缩，使用硅胶柱色谱分离纯化(DCM:MeOH＝20:1)，得到标题化合物，9-(6-羟基螺[3.3]庚-2-基)-7-甲基-2-((7-甲基-[1,2,4]***并[1,5-a]吡啶-6-基)氨基)-7,9-二氢-8H-嘌呤-8-酮化合物17(白色固体，110mg，产率57.57％)。The 2-chloro-9-(6-hydroxyspiro[3.3]heptan-2-yl)-7-methyl-7,9-dihydro-8H-purin-8-one 17f (140mg, 0.47mmol), 7 -Methyl-[1,2,4]triazolo[1,5-a]pyridine-6-amine (142mg, 0.94mmol) cesium carbonate (335mg, 0.94mmol) and Brettphos G3Pd (43mg, 0.047mmol) were added The dry reaction tube was replaced with nitrogen three times, then 1,4-dioxane (2 mL) was added, and the reaction was carried out at 110° C. for 5 hours. The reaction solution was concentrated and separated and purified by silica gel column chromatography (DCM:MeOH=20:1) to obtain the title compound, 9-(6-hydroxyspiro[3.3]heptan-2-yl)-7-methyl-2-( (7-Methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-7,9-dihydro-8H-purin-8-one compound 17 (white Solid, 110 mg, yield 57.57%).
1H NMR(400MHz,DMSO-d 6)δ9.05(s,1H),8.67(s,1H),8.37(s,1H),8.09(s,1H),7.71(s,1H),4.90(d,1H),4.65-4.56(m,1H),3.93-3.84(m,1H),3.27(s,3H),2.87-2.79(m,2H),2.37(s,4H),2.20-2.05(m,2H),1.86-1.78(m,2H),1.64-1.59(m,1H)。 1 H NMR (400MHz, DMSO-d 6 ) δ 9.05 (s, 1H), 8.67 (s, 1H), 8.37 (s, 1H), 8.09 (s, 1H), 7.71 (s, 1H), 4.90 ( d, 1H), 4.65-4.56 (m, 1H), 3.93-3.84 (m, 1H), 3.27 (s, 3H), 2.87-2.79 (m, 2H), 2.37 (s, 4H), 2.20-2.05 ( m, 2H), 1.86-1.78 (m, 2H), 1.64-1.59 (m, 1H).
LC-MS m/z(ESI)＝407.20[M+1]。LC-MS m/z(ESI)=407.20[M+1].
实施例18Example 18
9-(8-氧杂双环[3.2.1]辛基-3-基)-7-甲基-2-((7-甲基-[1,2,4]***并[1,5-a]吡啶-6-基)氨基)-7,9-二氢-8H-嘌呤-8-酮(化合物18)9-(8-oxabicyclo[3.2.1]octyl-3-yl)-7-methyl-2-((7-methyl-[1,2,4]triazolo[1,5- a)pyridin-6-yl)amino)-7,9-dihydro-8H-purin-8-one (compound 18)
9-(8-oxabicyclo[3.2.1]octan-3-yl)-7-methyl-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-7,9-dihydro-8H-purin-8-one9-(8-oxabicyclo[3.2.1]octan-3-yl)-7-methyl-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl )amino)-7,9-dihydro-8H-purin-8-one
Figure PCTCN2020141859-appb-000036
Figure PCTCN2020141859-appb-000036
第一步：first step:
8-氧杂双环[3.2.1]辛-3-酮肟(18b)8-oxabicyclo[3.2.1]octan-3-one oxime (18b)
8-oxabicyclo[3.2.1]octan-3-one oxime8-oxabicyclo[3.2.1]octan-3-one oxime
将8-氧杂双环[3.2.1]辛-3-酮18a(1.4g，11.1mmol)、盐酸羟胺(925mg,13.3mmol)和碳酸钾(3.1g,22.2mmol)溶解于乙醇/水(10mL/5mL)混合溶剂中，在80℃下反应2h。TLC监测至反应结束，向反应液中加水淬灭，乙酸乙酯萃取，无水硫酸钠干燥，过滤浓缩得到标题化合物，8-氧杂双环[3.2.1]辛-3-酮肟18b(淡黄色固体,1.56g，产率100％)。Dissolve 8-oxabicyclo[3.2.1]octan-3-one 18a (1.4g, 11.1mmol), hydroxylamine hydrochloride (925mg, 13.3mmol) and potassium carbonate (3.1g, 22.2mmol) in ethanol/water (10mL) /5mL) in a mixed solvent, react at 80°C for 2h. TLC monitors until the reaction is over, the reaction solution is quenched by adding water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered and concentrated to obtain the title compound, 8-oxabicyclo[3.2.1]oct-3-one oxime 18b (light Yellow solid, 1.56g, yield 100%).
LC-MS m/z(ESI)＝142.10[M+1]。LC-MS m/z(ESI)=142.10[M+1].
第二步：The second step:
8-氧杂双环[3.2.1]辛-3-胺(18c)8-oxabicyclo[3.2.1]oct-3-amine(18c)
8-oxabicyclo[3.2.1]octan-3-amine8-oxabicyclo[3.2.1]octan-3-amine
将8-氧杂双环[3.2.1]辛-3-酮肟18b(1.5g，10.64mmol)溶解于甲醇(30mL)中，室温下加入六水氯化镍(2.53g，10.64mmol)，在室温下反应0.5h。将反应液冷却至-30℃，缓慢添加硼氢化钠(6.0g，159.6mmol)，添加完毕缓慢升至室温反应过夜；TLC监测至反应结束，向反应液中加水淬灭，乙酸乙酯萃取，无水硫酸钠干燥，过滤浓缩得到标题化合物，8-氧杂双环[3.2.1]辛-3-胺18c(淡黄色油状物,639mg，产率45％)。Dissolve 8-oxabicyclo[3.2.1]octan-3-one oxime 18b (1.5g, 10.64mmol) in methanol (30mL), add nickel chloride hexahydrate (2.53g, 10.64mmol) at room temperature, React at room temperature for 0.5h. The reaction solution was cooled to -30°C, and sodium borohydride (6.0 g, 159.6 mmol) was slowly added. After the addition, the temperature was slowly raised to room temperature and allowed to react overnight; TLC monitored until the reaction was over. The reaction solution was quenched by adding water and extracted with ethyl acetate. It was dried over anhydrous sodium sulfate, filtered and concentrated to obtain the title compound, 8-oxabicyclo[3.2.1]oct-3-amine 18c (light yellow oil, 639 mg, yield 45%).
LC-MS m/z(ESI)＝128.20[M+1]。LC-MS m/z(ESI)=128.20[M+1].
第三步：third step:
4-((8-氧杂双环[3.2.1]辛烷-3-基)氨基)-2-氯嘧啶-5-羧酸乙酯(18d)4-((8-oxabicyclo[3.2.1]octan-3-yl)amino)-2-chloropyrimidine-5-carboxylic acid ethyl ester (18d)
ethyl 4-((8-oxabicyclo[3.2.1]octan-3-yl)amino)-2-chloropyrimidine-5-carboxylateethyl 4-((8-oxabicyclo[3.2.1]octan-3-yl)amino)-2-chloropyrimidine-5-carboxylate
将2,4-二氯嘧啶-5-羧酸乙酯1a(1.1g，5.03mmol)、碳酸钾(1.74g，12.58mmol)溶解于乙腈(20mL)，在0℃下加入8-氧杂双环[3.2.1]辛-3-胺18c(639mg，5.03mmol)，在室温下搅拌20h。TLC监测至反应结束，向反应液中加水30mL，有固体析出，过滤并用水洗3次，浓缩得到标题化合物，4-((8-氧杂双环[3.2.1]辛烷-3-基)氨基)-2-氯嘧啶-5-羧酸乙酯18d(白色固体,1.01g，产率64.3％)。Dissolve 2,4-dichloropyrimidine-5-carboxylic acid ethyl ester 1a (1.1g, 5.03mmol), potassium carbonate (1.74g, 12.58mmol) in acetonitrile (20mL), add 8-oxabicyclo at 0℃ [3.2.1] Octan-3-amine 18c (639 mg, 5.03 mmol), stirred at room temperature for 20 h. TLC monitors to the end of the reaction, add 30 mL of water to the reaction solution, a solid is precipitated, filtered and washed with water 3 times, and concentrated to obtain the title compound, 4-((8-oxabicyclo[3.2.1]octan-3-yl)amino ) Ethyl-2-chloropyrimidine-5-carboxylate 18d (white solid, 1.01 g, yield 64.3%).
1H NMR(400MHz,DMSO)δ8.91(d,1H),8.64(s,1H),4.38–4.31(m,4H),4.30–4.24(m,1H),2.20–2.08(m,2H),2.02–1.90(m,4H),1.66(d,2H),1.32(t,3H)。 1 H NMR(400MHz,DMSO)δ8.91(d,1H), 8.64(s,1H), 4.38-4.31(m,4H), 4.30-4.24(m,1H), 2.20-2.08(m,2H) ,2.02–1.90(m,4H),1.66(d,2H),1.32(t,3H).
第四步：the fourth step:
4-((8-氧杂双环[3.2.1]辛-3-基)氨基)-2-氯嘧啶-5-羧酸(18e)4-((8-oxabicyclo[3.2.1]oct-3-yl)amino)-2-chloropyrimidine-5-carboxylic acid (18e)
4-((8-oxabicyclo[3.2.1]octan-3-yl)amino)-2-chloropyrimidine-5-carboxylic acid4-((8-oxabicyclo[3.2.1]octan-3-yl)amino)-2-chloropyrimidine-5-carboxylic acid
将4-((8-氧杂双环[3.2.1]辛烷-3-基)氨基)-2-氯嘧啶-5-羧酸乙酯(1.0g，3.21mmol)18d溶解于四氢呋喃10mL，水5mL中，加入氢氧化锂(308mg，12.83mmol)，室温下搅拌1h。TLC监测至反应结束，将四氢呋喃旋干，用2N HCl调pH至4-5，有白色固体析出，过滤，滤饼用石油醚/乙酸乙酯(v/v＝10/1)洗两次，浓缩得到标题化合物，4-((8-氧杂双环[3.2.1]辛-3-基)氨基)-2-氯嘧啶-5-羧酸18e(白色固体,808mg，产率87.9％)。Dissolve 4-((8-oxabicyclo[3.2.1]octan-3-yl)amino)-2-chloropyrimidine-5-carboxylic acid ethyl ester (1.0g, 3.21mmol) 18d in tetrahydrofuran 10mL, water In 5 mL, lithium hydroxide (308 mg, 12.83 mmol) was added, and the mixture was stirred at room temperature for 1 h. TLC monitors to the end of the reaction, spin the tetrahydrofuran to dryness, adjust the pH to 4-5 with 2N HCl, a white solid precipitates out, filter, and wash the filter cake twice with petroleum ether/ethyl acetate (v/v=10/1). Concentrated to obtain the title compound, 4-((8-oxabicyclo[3.2.1]oct-3-yl)amino)-2-chloropyrimidine-5-carboxylic acid 18e (white solid, 808 mg, yield 87.9%).
1H NMR(400MHz,DMSO)δ13.83(s,1H),9.17(d,1H),8.59(s,1H),4.32(s,2H),4.29–4.22(m,1H),2.17–2.07(m,2H),2.00–1.89(m,4H),1.65(d,2H)。 1 H NMR (400MHz, DMSO) δ 13.83 (s, 1H), 9.17 (d, 1H), 8.59 (s, 1H), 4.32 (s, 2H), 4.29-4.22 (m, 1H), 2.17-2.07 (m, 2H), 2.00–1.89 (m, 4H), 1.65 (d, 2H).
第五步：the fifth step:
9-(8-氧杂双环[3.2.1]辛-3-基)-2-氯-7,9-二氢-8H-嘌呤-8-酮(18f)9-(8-oxabicyclo[3.2.1]oct-3-yl)-2-chloro-7,9-dihydro-8H-purin-8-one(18f)
9-(8-oxabicyclo[3.2.1]octan-3-yl)-2-chloro-7,9-dihydro-8H-purin-8-one9-(8-oxabicyclo[3.2.1]octan-3-yl)-2-chloro-7,9-dihydro-8H-purin-8-one
将4-((8-氧杂双环[3.2.1]辛-3-基)氨基)-2-氯嘧啶-5-羧酸18e(808mg，2.85mmol)溶解于二甲基乙酰胺(20mL)中，加入三乙胺(288mg，2.85mmol)、叠氮磷酸二苯酯(784mg，2.85mmol)，随后逐步升温至120℃，搅拌1.5h。TLC监测至反应结束，浓缩反应液，残留物用硅胶柱色谱分离提纯(石油醚/乙酸乙酯(v/v)＝5:1～1:10)，得到标题化合物，9-(8-氧杂双环[3.2.1]辛-3-基)-2-氯-7,9-二氢-8H-嘌呤-8-酮18f(白色固体,653mg，产率71％)。4-((8-oxabicyclo[3.2.1]oct-3-yl)amino)-2-chloropyrimidine-5-carboxylic acid 18e (808mg, 2.85mmol) was dissolved in dimethylacetamide (20mL) Add triethylamine (288mg, 2.85mmol) and diphenyl azide phosphate (784mg, 2.85mmol), then gradually increase the temperature to 120°C and stir for 1.5h. The reaction was monitored by TLC until the end of the reaction. The reaction solution was concentrated. The residue was separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v)=5:1～1:10) to obtain the title compound, 9-(8-oxygen). Heterobicyclo[3.2.1]oct-3-yl)-2-chloro-7,9-dihydro-8H-purin-8-one 18f (white solid, 653 mg, yield 71%).
1H NMR(600MHz,DMSO)δ11.64(s,1H),8.12(s,1H),4.47–4.44(m,2H),4.42–4.40(m,1H),2.28–2.20(m,2H),2.07–2.01(m,2H),1.96–1.90(m,2H),1.81–1.75(m,2H)。 1 H NMR (600MHz, DMSO) δ 11.64 (s, 1H), 8.12 (s, 1H), 4.47 - 4.44 (m, 2H), 4.42 - 4.40 (m, 1H), 2.28 - 2.20 (m, 2H) ,2.07–2.01(m,2H),1.96–1.90(m,2H),1.81–1.75(m,2H).
第六步：The sixth step:
9-(8-氧杂双环[3.2.1]辛-3-基)-2-氯-7-甲基-7,9-二氢-8H-嘌呤-8-酮(18g)9-(8-oxabicyclo[3.2.1]oct-3-yl)-2-chloro-7-methyl-7,9-dihydro-8H-purin-8-one (18g)
9-(8-oxabicyclo[3.2.1]octan-3-yl)-2-chloro-7-methyl-7,9-dihydro-8H-purin-8-one9-(8-oxabicyclo[3.2.1]octan-3-yl)-2-chloro-7-methyl-7,9-dihydro-8H-purin-8-one
将9-(8-氧杂双环[3.2.1]辛-3-基)-2-氯-7,9-二氢-8H-嘌呤-8-酮18f(653mg，2.33mmol)溶解于二甲基甲酰胺(10mL)中，在0℃下加入硫酸二甲酯(293mg，2.33mmol)和碳酸铯(1.52g,4.65mmol)，在0℃下搅拌1h。TLC监测至反应结束，随后加入10mL水，用乙酸乙酯萃取3次，有机相用无水硫酸钠干燥，浓缩得到标题化合物，9-(8-氧杂双环[3.2.1]辛-3-基)-2-氯-7-甲基-7,9-二氢-8H-嘌呤-8-酮18g(白色固体,533mg，产率81.6％)。Dissolve 9-(8-oxabicyclo[3.2.1]oct-3-yl)-2-chloro-7,9-dihydro-8H-purin-8-one 18f (653mg, 2.33mmol) in dimethyl Add dimethyl sulfate (293 mg, 2.33 mmol) and cesium carbonate (1.52 g, 4.65 mmol) to methyl formamide (10 mL) at 0°C, and stir at 0°C for 1 h. The reaction was monitored by TLC, and then 10 mL of water was added, and the mixture was extracted 3 times with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and concentrated to obtain the title compound, 9-(8-oxabicyclo[3.2.1]oct-3- (Yl)-2-chloro-7-methyl-7,9-dihydro-8H-purin-8-one 18 g (white solid, 533 mg, yield 81.6%).
1H NMR(400MHz,DMSO)δ8.36–8.34(m,1H),4.51-4.47(m,2H),4.45–4.42(m,1H),3.34(s,3H),2.31–2.22(m,2H),2.07–1.98(m,2H),1.98–1.90(m,2H),1.79(t,2H)。第七步： 1 H NMR(400MHz,DMSO)δ8.36-8.34(m,1H), 4.51-4.47(m,2H), 4.45-4.42(m,1H), 3.34(s,3H), 2.31-2.22(m, 2H), 2.07–1.98(m,2H), 1.98–1.90(m,2H), 1.79(t,2H). The seventh step:
9-(8-氧杂双环[3.2.1]辛基-3-基)-7-甲基-2-((7-甲基-[1,2,4]***并[1,5-a]吡啶-6-基)氨基)-7,9-二氢-8H-嘌呤-8-酮(化合物18)9-(8-oxabicyclo[3.2.1]octyl-3-yl)-7-methyl-2-((7-methyl-[1,2,4]triazolo[1,5- a)pyridin-6-yl)amino)-7,9-dihydro-8H-purin-8-one (compound 18)
9-(8-oxabicyclo[3.2.1]octan-3-yl)-7-methyl-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-7,9-dihydro-8H-purin-8-one9-(8-oxabicyclo[3.2.1]octan-3-yl)-7-methyl-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl )amino)-7,9-dihydro-8H-purin-8-one
将9-(8-氧杂双环[3.2.1]辛-3-基)-2-氯-7-甲基-7,9-二氢-8H-嘌呤-8-酮18g(100mg，0.34mmol)、7-甲基-[1,2,4]***并[1,5-a]吡啶-6-胺(51mg，0.34mmol)、碳酸铯(221mg,0.68mmol)、Brettphos Pd G3(31mg，0.034mmol)溶解于二氧六环中，氮气保护并换气，在100℃下搅拌4h。TLC监测至反应结束，浓缩反应液，残留物用硅胶柱色谱分离提纯(二氯甲烷/甲醇(v/v)＝30/1)，得到标题化合物9-(8-氧杂双环[3.2.1]辛基-3-基)-7-甲基-2-((7-甲基-[1,2,4]***并[1,5-a]吡啶-6-基)氨基)-7,9-二氢-8H-嘌呤-8-酮化合物18(白色固体，41mg，产率28.9％)。Add 9-(8-oxabicyclo[3.2.1]oct-3-yl)-2-chloro-7-methyl-7,9-dihydro-8H-purin-8-one 18g (100mg, 0.34mmol ), 7-methyl-[1,2,4]triazolo[1,5-a]pyridine-6-amine (51mg, 0.34mmol), cesium carbonate (221mg, 0.68mmol), Brettphos Pd G3 (31mg , 0.034mmol) was dissolved in dioxane, protected by nitrogen and ventilated, and stirred at 100°C for 4h. The reaction was monitored by TLC until the end of the reaction, the reaction solution was concentrated, and the residue was separated and purified by silica gel column chromatography (dichloromethane/methanol (v/v)=30/1) to obtain the title compound 9-(8-oxabicyclo[3.2.1 ]Octyl-3-yl)-7-methyl-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-7 , 9-Dihydro-8H-purin-8-one compound 18 (white solid, 41 mg, yield 28.9%).
1H NMR(400MHz,DMSO-d 6)δ9.01(s,1H),8.70(s,1H),8.39(s,1H),8.11(s,1H),7.74(s,1H),4.41–4.27(m,3H),3.29(s,3H),2.34(s,3H),2.17–2.07(m,2H),1.91(t,2H),1.62(s,2H),1.28(d,2H)。 1 H NMR(400MHz,DMSO-d 6 )δ9.01(s,1H), 8.70(s,1H), 8.39(s,1H), 8.11(s,1H), 7.74(s,1H), 4.41-- 4.27(m,3H), 3.29(s,3H), 2.34(s,3H), 2.17-2.07(m,2H), 1.91(t,2H), 1.62(s,2H), 1.28(d,2H) .
实施例19Example 19
7-甲基-2-((7-甲基-[1,2,4]***并[1,5-a]吡啶-6-基)氨基)-9-(2-氧杂螺[3.5]壬基-7-基)-7,9-二氢-8H-嘌呤-8-酮(化合物19)7-methyl-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-9-(2-oxaspiro[3.5 ] Nonyl-7-yl)-7,9-dihydro-8H-purin-8-one (Compound 19)
7-methyl-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-9-(2-oxaspiro[3.5]nonan-7-yl)-7,9-dihydro-8H-purin-8-one7-methyl-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-9-(2-oxaspiro[3.5]nonan-7-yl )-7,9-dihydro-8H-purin-8-one
Figure PCTCN2020141859-appb-000037
Figure PCTCN2020141859-appb-000037
第一步：first step:
2-氧杂螺[3.5]壬-7-酮肟(19b)2-oxaspiro[3.5]non-7-one oxime (19b)
2-oxaspiro[3.5]nonan-7-one oxime2-oxaspiro[3.5]nonan-7-one oxime
将19a(1.5g,10.7mmol)、盐酸羟胺(744mg,10.7mmol)和碳酸钾(2.95g,21.4mmol)溶解于乙醇/水(10mL/5mL)混合溶剂中，在80℃下反应2小时，TLC监测至反应结束，向反应液中加水淬灭，乙酸乙酯萃取，无水硫酸钠干燥、过滤浓缩得到标题化合物，2-氧杂螺[3.5]壬-7-酮肟19b(淡黄色固体,1.45g，产率89％)。Dissolve 19a (1.5g, 10.7mmol), hydroxylamine hydrochloride (744mg, 10.7mmol) and potassium carbonate (2.95g, 21.4mmol) in a mixed solvent of ethanol/water (10mL/5mL) and react at 80°C for 2 hours. TLC monitors until the reaction is over, the reaction solution is quenched by adding water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered and concentrated to obtain the title compound, 2-oxaspiro[3.5]non-7-one oxime 19b (light yellow solid) , 1.45g, yield 89%).
第二步：The second step:
2-氧杂螺[3.5]壬-7-胺(19c)2-oxaspiro[3.5]non-7-amine (19c)
2-oxaspiro[3.5]nonan-7-amine2-oxaspiro[3.5]nonan-7-amine
将2-氧杂螺[3.5]壬-7-酮肟19b(1.45g，9.34mmol)溶解于甲醇(30mL)中，室温下加入六水氯化镍(2.22g，9.34mmol)，在室温下反应0.5h后，将反应液冷却至-30℃，缓慢添加硼氢化钠(5.3g，140.1mmol)，添加完毕缓慢升至室温反应过夜。TLC监测至反应结束，向反应液中加水淬灭，乙酸乙酯萃取，无水硫酸钠干燥、过滤浓缩得到标题化合物，2-氧杂螺[3.5]壬-7-胺19c(淡黄色油状物,481mg，产率37.6％)。Dissolve 2-oxaspiro[3.5]non-7-one oxime 19b (1.45g, 9.34mmol) in methanol (30mL) and add nickel chloride hexahydrate (2.22g, 9.34mmol) at room temperature. After reacting for 0.5 h, the reaction solution was cooled to -30° C., sodium borohydride (5.3 g, 140.1 mmol) was slowly added, and after the addition, it was slowly raised to room temperature and reacted overnight. The reaction was monitored by TLC until the reaction was over. The reaction solution was quenched by adding water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered and concentrated to obtain the title compound, 2-oxaspiro[3.5]non-7-amine 19c (light yellow oil) ,481mg, yield 37.6%).
第三步：third step:
4-((2-氧杂螺[3.5]壬-7-基)氨基)-2-氯嘧啶-5-甲酸乙酯(19d)4-((2-oxaspiro[3.5]non-7-yl)amino)-2-chloropyrimidine-5-carboxylic acid ethyl ester (19d)
ethyl 4-((2-oxaspiro[3.5]nonan-7-yl)amino)-2-chloropyrimidine-5-carboxylateethyl 4-((2-oxaspiro[3.5]nonan-7-yl)amino)-2-chloropyrimidine-5-carboxylate
将2,4-二氯嘧啶-5-羧酸乙酯1a(753mg，3.41mmol)、碳酸钾(940mg，6.81mmol)溶解于乙腈(20mL)，在0℃下加入2-氧杂螺[3.5]壬-7-胺19c(481mg，3.41mmol)，在室 温下搅拌20h。TLC监测至反应结束，向反应液中加水30mL，有固体析出，过滤并用水洗3次，浓缩得到标题化合物，4-((2-氧杂螺[3.5]壬-7-基)氨基)-2-氯嘧啶-5-甲酸乙酯19d(白色固体,640mg，产率57.6％)。Dissolve 2,4-dichloropyrimidine-5-carboxylic acid ethyl ester 1a (753mg, 3.41mmol), potassium carbonate (940mg, 6.81mmol) in acetonitrile (20mL), add 2-oxaspiro[3.5 ] Non-7-amine 19c (481 mg, 3.41 mmol), stirred at room temperature for 20 h. TLC monitors to the end of the reaction. Add 30 mL of water to the reaction solution. A solid precipitates out. It is filtered and washed with water 3 times, and concentrated to obtain the title compound, 4-((2-oxaspiro[3.5]non-7-yl)amino)-2 -Ethyl chloropyrimidine-5-carboxylate 19d (white solid, 640 mg, yield 57.6%).
1H NMR(400MHz,DMSO)δ8.61(s,1H),8.29(d,1H),4.34–4.29(m,4H),4.24(s,2H),3.98–3.89(m,1H),2.05–1.92(m,2H),1.86–1.75(m,2H),1.65–1.56(m,2H),1.45–1.35(m,2H),1.34–1.27(m,3H)。 1 H NMR (400MHz, DMSO) δ8.61 (s, 1H), 8.29 (d, 1H), 4.34-4.29 (m, 4H), 4.24 (s, 2H), 3.98-3.89 (m, 1H), 2.05 –1.92(m,2H), 1.86–1.75(m,2H), 1.65–1.56(m,2H), 1.45–1.35(m,2H), 1.34–1.27(m,3H).
第四步：the fourth step:
4-((2-氧杂螺[3.5]壬基-7-基)氨基)-2-氯嘧啶-5-羧酸(19e)4-((2-oxaspiro[3.5]nonyl-7-yl)amino)-2-chloropyrimidine-5-carboxylic acid (19e)
4-((2-oxaspiro[3.5]nonan-7-yl)amino)-2-chloropyrimidine-5-carboxylic acid4-((2-oxaspiro[3.5]nonan-7-yl)amino)-2-chloropyrimidine-5-carboxylic acid
将乙基4-((2-氧杂螺[3.5]壬-7-基)氨基)-2-氯嘧啶-5-甲酸乙酯19d(640mg，1.96mmol)溶解于四氢呋喃10mL，水5mL中，加入氢氧化锂(189mg，7.86mmol)，室温下搅拌1h。TLC监测至反应结束，将四氢呋喃旋干，调pH为4-5，有白色固体析出，过滤，滤饼用石油醚/乙酸乙酯(v/v＝10/1)洗两次，浓缩得到标题化合物，4-((2-氧杂螺[3.5]壬基-7-基)氨基)-2-氯嘧啶-5-羧酸19e(白色固体,518mg，产率88.5％)。Ethyl 4-((2-oxaspiro[3.5]non-7-yl)amino)-2-chloropyrimidine-5-carboxylic acid ethyl ester 19d (640mg, 1.96mmol) was dissolved in 10mL of tetrahydrofuran and 5mL of water. Lithium hydroxide (189 mg, 7.86 mmol) was added, and the mixture was stirred at room temperature for 1 h. TLC monitors to the end of the reaction, spins the tetrahydrofuran to dryness, adjusts the pH to 4-5, a white solid is precipitated, filtered, the filter cake is washed twice with petroleum ether/ethyl acetate (v/v=10/1), and concentrated to obtain the title Compound, 4-((2-oxaspiro[3.5]nonyl-7-yl)amino)-2-chloropyrimidine-5-carboxylic acid 19e (white solid, 518 mg, yield 88.5%).
1H NMR(400MHz,DMSO)δ13.74(s,1H),8.57(s,1H),8.48(d,1H),4.32(s,2H),4.24(s,2H),3.97–3.84(m,1H),1.99(d,2H),1.86–1.76(m,2H),1.66–1.54(m,2H),1.42–1.26(m,2H)。 1 H NMR (400MHz, DMSO) δ 13.74 (s, 1H), 8.57 (s, 1H), 8.48 (d, 1H), 4.32 (s, 2H), 4.24 (s, 2H), 3.97-3.84 (m ,1H),1.99(d,2H),1.86-1.76(m,2H),1.66-1.54(m,2H),1.42-1.26(m,2H).
第五步：the fifth step:
2-氯-9-(2-氧杂螺[3.5]壬-7-基)-7,9-二氢-8H-嘌呤-8-酮(19f)2-Chloro-9-(2-oxaspiro[3.5]non-7-yl)-7,9-dihydro-8H-purin-8-one (19f)
2-chloro-9-(2-oxaspiro[3.5]nonan-7-yl)-7,9-dihydro-8H-purin-8-one2-chloro-9-(2-oxaspiro[3.5]nonan-7-yl)-7,9-dihydro-8H-purin-8-one
将4-((2-氧杂螺[3.5]壬基-7-基)氨基)-2-氯嘧啶-5-羧酸19e(518mg，1.74mmol)溶解于二甲基乙酰胺(20mL)中，加入三乙胺(175mg，1.74mmol)、叠氮磷酸二苯酯(479mg，1.74mmol)，随后逐步升温至120℃，搅拌1.5h。TLC监测至反应结束，浓缩反应液，残留物用硅胶柱色谱分离提纯(石油醚/乙酸乙酯(v/v)＝5:1～1:10)，得到标题化合物，2-氯-9-(2-氧杂螺[3.5]壬-7-基)-7,9-二氢-8H-嘌呤-8-酮19f(白色固体,353mg，产率72.8％)。Dissolve 4-((2-oxaspiro[3.5]nonyl-7-yl)amino)-2-chloropyrimidine-5-carboxylic acid 19e (518mg, 1.74mmol) in dimethylacetamide (20mL) Add triethylamine (175 mg, 1.74 mmol) and diphenyl azide phosphate (479 mg, 1.74 mmol), then gradually increase the temperature to 120° C. and stir for 1.5 h. The reaction was monitored by TLC until the end of the reaction. The reaction solution was concentrated. The residue was separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v)=5:1～1:10) to obtain the title compound, 2-chloro-9- (2-oxaspiro[3.5]non-7-yl)-7,9-dihydro-8H-purin-8-one 19f (white solid, 353 mg, yield 72.8%).
1H NMR(600MHz,DMSO)δ11.61(s,1H),8.11(s,1H),4.41(s,2H),4.24(s,2H),4.15–4.08(m,1H),2.24–2.08(m,4H),1.69(d,2H),1.64–1.51(m,2H)。 1 H NMR (600MHz, DMSO) δ 11.61 (s, 1H), 8.11 (s, 1H), 4.41 (s, 2H), 4.24 (s, 2H), 4.15-4.08 (m, 1H), 2.24-2.08 (m, 4H), 1.69 (d, 2H), 1.64-1.51 (m, 2H).
第六步：The sixth step:
2-氯-7-甲基-9-(2-氧杂螺[3.5]壬-7-基)-7,9-二氢-8H-嘌呤-8-酮(19g)2-Chloro-7-methyl-9-(2-oxaspiro[3.5]non-7-yl)-7,9-dihydro-8H-purin-8-one (19g)
2-chloro-7-methyl-9-(2-oxaspiro[3.5]nonan-7-yl)-7,9-dihydro-8H-purin-8-one2-chloro-7-methyl-9-(2-oxaspiro[3.5]nonan-7-yl)-7,9-dihydro-8H-purin-8-one
将2-氯-9-(2-氧杂螺[3.5]壬-7-基)-7,9-二氢-8H-嘌呤-8-酮19f(353mg，1.18mmol)溶解于二甲基甲酰胺(10mL)中，在0℃下加入硫酸二甲酯(150mg，1.18mmol)和碳酸铯(464mg,3.36mmol)，在0℃下搅拌1h。TLC监测至反应结束，随后加入10mL水，用乙酸乙酯萃取3次，有机相用无水硫酸钠干燥，浓缩，有固体析出，过滤得到标题化合物，2-氯-7-甲基-9-(2-氧杂螺[3.5]壬-7-基)-7,9-二氢-8H-嘌呤-8-酮19g(白色固体,313mg，产率85.5％)。Dissolve 2-chloro-9-(2-oxaspiro[3.5]non-7-yl)-7,9-dihydro-8H-purin-8-one 19f (353mg, 1.18mmol) in dimethylform To the amide (10 mL), dimethyl sulfate (150 mg, 1.18 mmol) and cesium carbonate (464 mg, 3.36 mmol) were added at 0°C, and the mixture was stirred at 0°C for 1 h. TLC monitored until the reaction was complete, then 10 mL of water was added, and the mixture was extracted with ethyl acetate three times. The organic phase was dried over anhydrous sodium sulfate and concentrated. A solid precipitated out and filtered to obtain the title compound, 2-chloro-7-methyl-9- (2-oxaspiro[3.5]non-7-yl)-7,9-dihydro-8H-purin-8-one 19 g (white solid, 313 mg, yield 85.5%).
1H NMR(400MHz,DMSO)δ8.34(s,1H),4.41(s,2H),4.25(s,2H),4.22–4.08(m,1H),3.34(s,3H),2.22–2.05(m,4H),1.69(d,2H),1.64–1.50(m,2H)。 1 H NMR (400MHz, DMSO) δ 8.34 (s, 1H), 4.41 (s, 2H), 4.25 (s, 2H), 4.22-4.08 (m, 1H), 3.34 (s, 3H), 2.22-2.05 (m, 4H), 1.69 (d, 2H), 1.64-1.50 (m, 2H).
第七步：The seventh step:
7-甲基-2-((7-甲基-[1,2,4]***并[1,5-a]吡啶-6-基)氨基)-9-(2-氧杂螺[3.5]壬基-7-基)-7,9-二氢-8H-嘌呤-8-酮(化合物19)7-methyl-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-9-(2-oxaspiro[3.5 ] Nonyl-7-yl)-7,9-dihydro-8H-purin-8-one (Compound 19)
7-methyl-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-9-(2-oxaspiro[3.5]nonan-7-yl)-7,9-dihydro-8H-purin-8-one7-methyl-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-9-(2-oxaspiro[3.5]nonan-7-yl )-7,9-dihydro-8H-purin-8-one
将2-氯-7-甲基-9-(2-氧杂螺[3.5]壬-7-基)-7,9-二氢-8H-嘌呤-8-酮19g(60mg，0.194mmol)、7-甲基-[1,2,4]***并[1,5-a]吡啶-6-胺(29mg，0.194mmol)、碳酸铯(127mg，0.39mmol)、Brettphos Pd G3(17mg，0.019mmol)溶解于二氧六环中，氮气保护并换气， 在100℃下搅拌4h。浓缩反应液，残留物用硅胶柱色谱分离提纯(二氯甲烷/甲醇(v/v)＝30/1)，得到标题化合物9-(8-氧杂双环[3.2.1]辛基-3-基)-7-甲基-2-((7-甲基-[1,2,4]***并[1,5-a]吡啶-6-基)氨基)-7,9-二氢-8H-嘌呤-8-酮化合物19(白色固体，38mg，产率44.7％)。The 2-chloro-7-methyl-9-(2-oxaspiro[3.5]non-7-yl)-7,9-dihydro-8H-purin-8-one 19g (60mg, 0.194mmol), 7-Methyl-[1,2,4]triazolo[1,5-a]pyridine-6-amine (29mg, 0.194mmol), cesium carbonate (127mg, 0.39mmol), Brettphos Pd G3 (17mg, 0.019) mmol) was dissolved in dioxane, protected by nitrogen and ventilated, and stirred at 100° C. for 4 h. The reaction solution was concentrated, and the residue was separated and purified by silica gel column chromatography (dichloromethane/methanol (v/v)=30/1) to obtain the title compound 9-(8-oxabicyclo[3.2.1]octyl-3- Yl)-7-methyl-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-7,9-dihydro- 8H-purine-8-one compound 19 (white solid, 38 mg, yield 44.7%).
1H NMR(400MHz,DMSO-d 6)δ8.99(s,1H),8.66(s,1H),8.38(s,1H),8.10(s,1H),7.73(s,1H),4.15(s,2H),4.05(s,1H),3.92(s,2H),3.29(s,3H),2.34(s,3H),2.09–2.00(m,4H),1.63–1.56(m,2H),1.51–1.44(m,2H)。 1 H NMR(400MHz, DMSO-d 6 )δ8.99(s,1H), 8.66(s,1H), 8.38(s,1H), 8.10(s,1H), 7.73(s,1H), 4.15( s, 2H), 4.05 (s, 1H), 3.92 (s, 2H), 3.29 (s, 3H), 2.34 (s, 3H), 2.09-2.00 (m, 4H), 1.63-1.56 (m, 2H) ,1.51–1.44(m,2H).
实施例20Example 20
9-(6-(羟甲基)螺[3.3]庚-2-基)-7-甲基-2-((7-甲基-[1,2,4]***并[1,5-a]吡啶-6-基)氨基)-7,9-二氢-8H-嘌呤-8-酮(化合物20)9-(6-(Hydroxymethyl)spiro[3.3]heptan-2-yl)-7-methyl-2-((7-methyl-[1,2,4]triazolo[1,5- a)pyridin-6-yl)amino)-7,9-dihydro-8H-purin-8-one (compound 20)
9-(6-(hydroxymethyl)spiro[3.3]heptan-2-yl)-7-methyl-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-7,9-dihydro-8H-purin-8-one9-(6-(hydroxymethyl)spiro[3.3]heptan-2-yl)-7-methyl-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6- yl)amino)-7,9-dihydro-8H-purin-8-one
Figure PCTCN2020141859-appb-000038
Figure PCTCN2020141859-appb-000038
第一步：first step:
(6-氨基螺[3.3]庚烷-2-基)甲醇(20b)(6-Aminospiro[3.3]heptan-2-yl)methanol (20b)
(6-aminospiro[3.3]heptan-2-yl)methanol(6-aminospiro[3.3]heptan-2-yl)methanol
将6-氨基螺[3.3]庚烷-2-羧酸甲酯20a(2.0g,11.8mmol)溶于四氢呋喃(15mL)中，混合液降温至0℃，缓慢滴加1N的四氢铝锂溶液(23.6mL，1mol/L的四氢呋喃溶液)，滴加完成后，缓慢升温至室温搅拌2h。TLC监测至反应结束，加入甲醇淬灭反应，减压浓缩蒸发掉溶剂，加入乙腈(50mL)打浆过滤，滤液旋干得到标题化合物(6-氨基螺[3.3]庚烷-2-基)甲醇20b(白色固体,1.3g,产率77.8％)。Dissolve 6-aminospiro[3.3]heptane-2-carboxylic acid methyl ester 20a (2.0g, 11.8mmol) in tetrahydrofuran (15mL), cool the mixture to 0℃, slowly add 1N lithium aluminum tetrahydrogen solution dropwise (23.6mL, 1mol/L tetrahydrofuran solution), after the dripping is completed, slowly warm up to room temperature and stir for 2h. The reaction was monitored by TLC until the reaction was over, methanol was added to quench the reaction, concentrated under reduced pressure to evaporate the solvent, acetonitrile (50mL) was added to make slurry filtration, and the filtrate was spin-dried to obtain the title compound (6-aminospiro[3.3]heptan-2-yl)methanol 20b (White solid, 1.3g, yield 77.8%).
LC-MS m/z(ESI)＝142.10[M+1]。LC-MS m/z(ESI)=142.10[M+1].
第二步：The second step:
2-氯-4-((6-(羟甲基)螺[3.3]庚烷-2-基)氨基)嘧啶-5-羧酸乙酯(20c)Ethyl 2-chloro-4-((6-(hydroxymethyl)spiro[3.3]heptan-2-yl)amino)pyrimidine-5-carboxylate (20c)
ethyl 2-chloro-4-((6-(hydroxymethyl)spiro[3.3]heptan-2-yl)amino)pyrimidine-5-carboxylateethyl 2-chloro-4-((6-(hydroxymethyl)spiro[3.3]heptan-2-yl)amino)pyrimidine-5-carboxylate
将2,4-二氯嘧啶-5-羧酸乙酯1a(2.03g,9.19mmol)，(6-氨基螺[3.3]庚烷-2-基)甲醇20b(1.3g,9.19mmol)，碳酸钾(1.27g,9.19mmol)溶于乙腈(25mL)中，室温搅拌反应16h。TLC监测至反应结束，滤液浓缩经硅胶柱色谱分离提纯(石油醚:乙酸乙酯(v/v)＝1:1)纯化得到标题化合物2-氯-4-((6-(羟甲基)螺[3.3]庚烷-2-基)氨基)嘧啶-5-羧酸乙酯20c(白色固体，1.56g,产率52.2％)。2,4-Dichloropyrimidine-5-carboxylic acid ethyl ester 1a (2.03g, 9.19mmol), (6-aminospiro[3.3]heptan-2-yl)methanol 20b (1.3g, 9.19mmol), carbonic acid Potassium (1.27g, 9.19mmol) was dissolved in acetonitrile (25mL), and the reaction was stirred at room temperature for 16h. TLC monitoring until the end of the reaction, the filtrate was concentrated and purified by silica gel column chromatography (petroleum ether: ethyl acetate (v/v) = 1:1) to obtain the title compound 2-chloro-4-((6-(hydroxymethyl) Spiro[3.3]heptan-2-yl)amino)pyrimidine-5-carboxylic acid ethyl ester 20c (white solid, 1.56 g, yield 52.2%).
1H NMR(400MHz,Chloroform-d)δ8.65(s,1H),8.54(d,1H),4.59–4.48(m,1H),4.35(q,2H),3.59(dd,2H),2.66–2.58(m,1H),2.51–2.38(m,2H),2.27–2.19(m,1H),2.11–2.04(m,2H),2.03–1.91(m,2H),1.91–1.85(m,1H),1.84–1.76(m,1H),1.39(t,3H)。1H NMR(400MHz,Chloroform-d)δ8.65(s,1H),8.54(d,1H),4.59--4.48(m,1H),4.35(q,2H),3.59(dd,2H),2.66-- 2.58 (m, 1H), 2.51-2.38 (m, 2H), 2.27-2.19 (m, 1H), 2.11-2.04 (m, 2H), 2.03-1.91 (m, 2H), 1.91-1.85 (m, 1H) ), 1.84-1.76 (m, 1H), 1.39 (t, 3H).
LCMS m/z(ESI)＝326.10[M+1]。LCMS m/z(ESI)=326.10[M+1].
第三步：third step:
2-氯-4-((6-(羟甲基)螺[3.3]庚烷-2-基)氨基)嘧啶-5-羧酸(20d)2-chloro-4-((6-(hydroxymethyl)spiro[3.3]heptan-2-yl)amino)pyrimidine-5-carboxylic acid (20d)
2-chloro-4-((6-(hydroxymethyl)spiro[3.3]heptan-2-yl)amino)pyrimidine-5-carboxylic acid2-chloro-4-((6-(hydroxymethyl)spiro[3.3]heptan-2-yl)amino)pyrimidine-5-carboxylic acid
将2-氯-4-((6-(羟甲基)螺[3.3]庚烷-2-基)氨基)嘧啶-5-羧酸乙酯20c(1.07g,3.28mmol)溶解于四氢呋喃/水(10mL/10mL)中，加入氢氧化锂一水合物(0.41g,9.85mmol)，常温搅拌反应1h。TLC监测至反应结束，浓缩蒸发掉四氢呋喃后加入2N HCl调节pH至3-4，有白色固体析出，过滤，滤饼用水以及石油醚/乙酸乙酯(v/v＝10/1)洗两次得标题化合物2-氯-4-((6-(羟甲基)螺[3.3]庚烷-2-基)氨基)嘧啶-5-羧酸20d(白色固体，918mg，产率93.88％)。Dissolve 2-chloro-4-((6-(hydroxymethyl)spiro[3.3]heptan-2-yl)amino)pyrimidine-5-carboxylic acid ethyl ester 20c (1.07g, 3.28mmol) in tetrahydrofuran/water (10mL/10mL), lithium hydroxide monohydrate (0.41g, 9.85mmol) was added, and the reaction was stirred at room temperature for 1h. TLC monitors to the end of the reaction, concentrates and evaporates the tetrahydrofuran, adds 2N HCl to adjust the pH to 3-4, a white solid is precipitated, filtered, and the filter cake is washed twice with water and petroleum ether/ethyl acetate (v/v=10/1) The title compound 2-chloro-4-((6-(hydroxymethyl)spiro[3.3]heptan-2-yl)amino)pyrimidine-5-carboxylic acid 20d (white solid, 918 mg, yield 93.88%) was obtained.
1H NMR(400MHz,DMSO-d6)δ12.69(s,1H),9.67(d,1H),8.35(s,1H),4.42–4.31(m,1H),3.30(s,1H),2.55–2.46(m,3H),2.40–2.31(m,1H),2.28–2.19(m,1H),2.10–2.00(m,2H),2.00–1.91(m,2H),1.83–1.69(m,2H)。1H NMR(400MHz,DMSO-d6)δ12.69(s,1H),9.67(d,1H),8.35(s,1H),4.42-4.31(m,1H),3.30(s,1H),2.55-- 2.46 (m, 3H), 2.40-2.31 (m, 1H), 2.28-2.19 (m, 1H), 2.10-2.00 (m, 2H), 2.00-1.91 (m, 2H), 1.83-1.69 (m, 2H) ).
LC-MS m/z(ESI)＝298.10[M+1]。LC-MS m/z(ESI)=298.10[M+1].
第四步：the fourth step:
2-氯-9-(6-(羟甲基)螺[3.3]庚烷-2-基)-7,9-二氢-8H-嘌呤-8-酮(20e)2-chloro-9-(6-(hydroxymethyl)spiro[3.3]heptan-2-yl)-7,9-dihydro-8H-purin-8-one (20e)
2-chloro-9-(6-(hydroxymethyl)spiro[3.3]heptan-2-yl)-7,9-dihydro-8H-purin-8-one2-chloro-9-(6-(hydroxymethyl)spiro[3.3]heptan-2-yl)-7,9-dihydro-8H-purin-8-one
将2-氯-4-((6-(羟甲基)螺[3.3]庚烷-2-基)氨基)嘧啶-5-羧酸20d(0.91g,3.06mmol)用N,N-二甲基乙酰胺(12mL)溶解，常温搅拌下加入三乙胺(0.42mL,3.06mmol)和叠氮磷酸二苯酯(0.66mL,10.01mmol)反应2h，升温至110℃回流反应2.5h。TLC监测至反应结束，反应液中加水和乙酸乙酯进行萃取，浓缩有机层经硅胶柱色谱分离提纯(二氯甲烷/甲醇(v/v)＝20:1)纯化得标题化合物2-氯-9-(6-(羟甲基)螺[3.3]庚烷-2-基)-7,9-二氢-8H-嘌呤-8-酮20e(白色固体，516mg，产率57.28％)。Use 2-chloro-4-((6-(hydroxymethyl)spiro[3.3]heptan-2-yl)amino)pyrimidine-5-carboxylic acid 20d (0.91g, 3.06mmol) with N,N-dimethyl Acetamide (12 mL) was dissolved, triethylamine (0.42 mL, 3.06 mmol) and diphenyl azide phosphate (0.66 mL, 10.01 mmol) were added under stirring at room temperature for 2 hours, and the temperature was raised to 110° C. and refluxed for 2.5 hours. TLC monitors to the end of the reaction, the reaction solution is added with water and ethyl acetate for extraction, and the organic layer is concentrated and purified by silica gel column chromatography (dichloromethane/methanol (v/v)=20:1) to obtain the title compound 2-chloro- 9-(6-(hydroxymethyl)spiro[3.3]heptan-2-yl)-7,9-dihydro-8H-purin-8-one 20e (white solid, 516 mg, yield 57.28%).
1H NMR(400MHz,DMSO-d6)δ11.60(s,1H),8.11(s,1H),4.68–4.57(m,1H),4.46(t,1H),3.37–3.32(m,2H),2.95–2.81(m,2H),2.42–2.35(m,1H),2.32–2.19(m,2H),2.19–2.12(m,1H),2.06–1.98(m,1H),1.89–1.77(m,2H)。1H NMR(400MHz,DMSO-d6)δ11.60(s,1H),8.11(s,1H), 4.68-4.57(m,1H), 4.46(t,1H), 3.37-3.32(m,2H), 2.95–2.81(m,2H), 2.42–2.35(m,1H), 2.32–2.19(m,2H), 2.19–2.12(m,1H), 2.06–1.98(m,1H), 1.89–1.77(m ,2H).
LC-MS m/z(ESI)＝295.10[M+1]。LC-MS m/z(ESI)=295.10[M+1].
第五步：the fifth step:
2-氯-9-(6-(羟甲基)螺[3.3]庚烷-2-基)-7-甲基-7,9-二氢-8H-嘌呤-8-酮(20f)2-chloro-9-(6-(hydroxymethyl)spiro[3.3]heptan-2-yl)-7-methyl-7,9-dihydro-8H-purin-8-one (20f)
2-chloro-9-(6-(hydroxymethyl)spiro[3.3]heptan-2-yl)-7-methyl-7,9-dihydro-8H-purin-8-one2-chloro-9-(6-(hydroxymethyl)spiro[3.3]heptan-2-yl)-7-methyl-7,9-dihydro-8H-purin-8-one
将2-氯-9-(6-(羟甲基)螺[3.3]庚烷-2-基)-7,9-二氢-8H-嘌呤-8-酮20e(516mg,1.75mmol)用N,N-二甲基甲酰胺(6mL)溶解，0℃搅拌下加入硫酸二甲酯(0.17mL,1.75mmol)和碳酸铯(1.14g,3.50mmol)反应1h。TLC监测至反应结束，把反应液缓慢滴加到冰水中搅拌，加入乙酸乙酯进行萃取，浓缩有机层得标题化合物2-氯-9-(6-(羟甲基)螺[3.3]庚 烷-2-基)-7-甲基-7,9-二氢-8H-嘌呤-8-酮20f(白色固体，470mg，产率86.95％)。Use 2-chloro-9-(6-(hydroxymethyl)spiro[3.3]heptan-2-yl)-7,9-dihydro-8H-purin-8-one 20e (516mg, 1.75mmol) with N , N-dimethylformamide (6mL) was dissolved, and dimethyl sulfate (0.17mL, 1.75mmol) and cesium carbonate (1.14g, 3.50mmol) were added under stirring at 0°C and reacted for 1h. TLC monitors until the reaction is over, the reaction solution is slowly added dropwise to ice water and stirred, ethyl acetate is added for extraction, and the organic layer is concentrated to obtain the title compound 2-chloro-9-(6-(hydroxymethyl)spiro[3.3]heptane -2-yl)-7-methyl-7,9-dihydro-8H-purin-8-one 20f (white solid, 470 mg, yield 86.95%).
1H NMR(400MHz,DMSO-d6)δ8.33(s,1H),4.71–4.60(m,1H),4.10–3.96(m,2H),3.35(s,1H),3.33(s,3H),2.93–2.81(m,2H),2.44–2.36(m,1H),2.32–2.21(m,2H),2.20–2.13(m,1H),2.07–1.99(m,1H),1.89–1.78(m,2H)。1H NMR(400MHz,DMSO-d6)δ8.33(s,1H), 4.71-4.60(m,1H), 4.10-3.96(m,2H), 3.35(s,1H), 3.33(s,3H), 2.93–2.81(m, 2H), 2.44–2.36(m, 1H), 2.32–2.21(m, 2H), 2.20–2.13(m, 1H), 2.07–1.99(m, 1H), 1.89–1.78(m ,2H).
LC-MS m/z(ESI)＝309.10[M+1]。LC-MS m/z(ESI)=309.10[M+1].
第六步：The sixth step:
9-(6-(羟甲基)螺[3.3]庚-2-基)-7-甲基-2-((7-甲基-[1,2,4]***并[1,5-a]吡啶-6-基)氨基)-7,9-二氢-8H-嘌呤-8-酮(化合物20)9-(6-(Hydroxymethyl)spiro[3.3]heptan-2-yl)-7-methyl-2-((7-methyl-[1,2,4]triazolo[1,5- a)pyridin-6-yl)amino)-7,9-dihydro-8H-purin-8-one (compound 20)
9-(6-(hydroxymethyl)spiro[3.3]heptan-2-yl)-7-methyl-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-7,9-dihydro-8H-purin-8-one9-(6-(hydroxymethyl)spiro[3.3]heptan-2-yl)-7-methyl-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6- yl)amino)-7,9-dihydro-8H-purin-8-one
将2-氯-9-(6-(羟甲基)螺[3.3]庚烷-2-基)-7-甲基-7,9-二氢-8H-嘌呤-8-酮2 0f(100mg,0.32mmol)用1,4-二氧六环(6mL)溶解，常温搅拌下加入7-甲基-[1,2,4]***并[1,5-a]吡啶-6-胺(72mg,0.49mmol)、碳酸铯(158mg,0.49mmol)、BrettPhos-G3-Pd(29mg,0.032mmol)，氮气保护并换气，随后升温至110℃回流反应4h。TLC监测至反应结束，浓缩反应液，残留物用硅胶柱色谱分离纯化(二氯甲烷/甲醇(v/v)＝20:1)得标题化合物化合物20(白色固体，60mg，产率44.59％)。Combine 2-chloro-9-(6-(hydroxymethyl)spiro[3.3]heptan-2-yl)-7-methyl-7,9-dihydro-8H-purin-8-one 2 0f (100mg ,0.32mmol) was dissolved in 1,4-dioxane (6mL), and 7-methyl-[1,2,4]triazolo[1,5-a]pyridine-6-amine ( 72mg, 0.49mmol), cesium carbonate (158mg, 0.49mmol), BrettPhos-G3-Pd (29mg, 0.032mmol), protected by nitrogen and ventilated, and then heated to 110°C and refluxed for 4h. The reaction was monitored by TLC until the end of the reaction, the reaction solution was concentrated, and the residue was separated and purified by silica gel column chromatography (dichloromethane/methanol (v/v)=20:1) to obtain the title compound 20 (white solid, 60 mg, yield 44.59%) .
1H NMR(400MHz,DMSO-d6)δ9.05(s,1H),8.66(s,1H),8.36(s,1H),8.09(s,1H),7.71(s,1H),4.66–4.54(m,1H),4.40(t,1H),3.29–3.23(m,5H),2.85–2.77(m,2H),2.37(s,3H),2.30–2.22(m,1H),2.19–2.12(m,1H),2.12–2.04(m,2H),1.81–1.74(m,1H),1.66–1.59(m,1H),1.49–1.42(m,1H)。1H NMR(400MHz,DMSO-d6)δ9.05(s,1H),8.66(s,1H),8.36(s,1H),8.09(s,1H),7.71(s,1H),4.66-4.54( m,1H), 4.40(t,1H), 3.29–3.23(m,5H), 2.85–2.77(m,2H), 2.37(s,3H), 2.30–2.22(m,1H), 2.19–2.12( m,1H), 2.12–2.04(m,2H), 1.81–1.74(m,1H), 1.66–1.59(m,1H), 1.49–1.42(m,1H).
LC-MS m/z(ESI)＝421.20[M+1]。LC-MS m/z(ESI)=421.20[M+1].
实施例21Example 21
9-(3-(羟甲基)双环[1.1.1]戊-1-基)-7-甲基-2-((7-甲基-[1,2,4]***[1,5-a]吡啶-6-基)氨基)-7,9-二氢-8H-嘌呤-8-酮(化合物21)9-(3-(Hydroxymethyl)bicyclo[1.1.1]pent-1-yl)-7-methyl-2-((7-methyl-[1,2,4]triazole[1,5 -a)pyridin-6-yl)amino)-7,9-dihydro-8H-purin-8-one (compound 21)
9-(3-(hydroxymethyl)bicyclo[1.1.1]pentan-1-yl)-7-methyl-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-7,9-dihydro-8H-purin-8-one9-(3-(hydroxymethyl)bicyclo[1.1.1]pentan-1-yl)-7-methyl-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin- 6-yl)amino)-7,9-dihydro-8H-purin-8-one
Figure PCTCN2020141859-appb-000039
Figure PCTCN2020141859-appb-000039
第一步：first step:
(3-氨基双环[1.1.1]戊烷-1-基)甲醇(21b)(3-Aminobicyclo[1.1.1]pentane-1-yl)methanol (21b)
(3-aminobicyclo[1.1.1]pentan-1-yl)methanol(3-aminobicyclo[1.1.1]pentan-1-yl)methanol
将原料3-(叔丁氧羰基)氨基)二环[1.1.1]戊烷-1-羧酸21a(2.0g,8.80mmol)溶于二氯甲烷(10mL)中，再加入三氟甲酸(10mL)，室温搅拌2h。TLC监测至反应结束，减压旋干溶剂，将得到浅黄色固体溶于四氢呋喃(15mL)中，混合液降温至0℃，缓慢滴加1N的四氢铝锂溶液(16.6mL，1mol/L的四氢呋喃溶液)，滴加完成后，缓慢升温至室温搅拌2h，反应完成后，加入甲醇淬灭反应，减压旋干溶剂，再加入乙腈(50mL)打浆，过滤旋干滤液得到标题化合物(3-氨基双环[1.1.1]戊烷-1-基)甲醇21b(白色固体，890mg，产率89.4％)。The raw material 3-(tert-butoxycarbonyl)amino)bicyclo[1.1.1]pentane-1-carboxylic acid 21a (2.0g, 8.80mmol) was dissolved in dichloromethane (10mL), and then trifluoroformic acid ( 10mL), stirred at room temperature for 2h. TLC monitors to the end of the reaction, the solvent is spin-dried under reduced pressure, and the obtained light yellow solid is dissolved in tetrahydrofuran (15mL), the mixture is cooled to 0℃, and 1N lithium aluminum tetrahydrogen solution (16.6mL, 1mol/L) is slowly added dropwise. Tetrahydrofuran solution). After the dropwise addition is completed, slowly warm to room temperature and stir for 2h. After the reaction is complete, methanol is added to quench the reaction, the solvent is spin-dried under reduced pressure, acetonitrile (50mL) is added to make slurry, and the filtrate is filtered and spin-dried to obtain the title compound (3- Aminobicyclo[1.1.1]pentan-1-yl)methanol 21b (white solid, 890 mg, yield 89.4%).
LCMS m/z(ESI)＝114.10[M+1]。LCMS m/z(ESI)=114.10[M+1].
第二步：The second step:
2-氯-4-(3-(羟甲基)双环[1.1.1]戊-1-基)氨基嘧啶-5-羧酸乙酯(21c)Ethyl 2-chloro-4-(3-(hydroxymethyl)bicyclo[1.1.1]pent-1-yl)aminopyrimidine-5-carboxylate (21c)
ethyl 2-chloro-4-((3-(hydroxymethyl)bicyclo[1.1.1]pentan-1-yl)amino)-pyrimi-dine-5-carboxylateethyl 2-chloro-4-((3-(hydroxymethyl)bicyclo[1.1.1]pentan-1-yl)amino)-pyrimi-dine-5-carboxylate
将2,4-二氯嘧啶-5-羧酸乙酯1a(1.74g,7.86mmol),(3-氨基双环[1.1.1]戊烷-1-基)甲醇21b(890mg,7.86mmol)，碳酸钾(1.08g,7.86mmol)溶于乙腈(15mL)，反应液在室温反应16h。TLC监测反应结束，过滤，并用少量乙腈清洗固体，将滤液合并后浓缩，粗品经硅胶柱色谱分离(石油醚/乙酸乙酯(v/v)＝1:1)纯化得标题化合物2-氯-4-(3-(羟甲基)双环[1.1.1]戊-1-基)氨基嘧啶-5-羧酸乙酯21c(淡黄色固体，1.11g，产率50.0％)。2,4-Dichloropyrimidine-5-carboxylic acid ethyl ester 1a (1.74g, 7.86mmol), (3-aminobicyclo[1.1.1]pentane-1-yl)methanol 21b (890mg, 7.86mmol), Potassium carbonate (1.08 g, 7.86 mmol) was dissolved in acetonitrile (15 mL), and the reaction solution was reacted at room temperature for 16 hours. The end of the reaction was monitored by TLC, filtered, and the solid was washed with a small amount of acetonitrile. The filtrate was combined and concentrated. The crude product was separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v)=1:1) to obtain the title compound 2-chloro- 4-(3-(hydroxymethyl)bicyclo[1.1.1]pent-1-yl)aminopyrimidine-5-carboxylic acid ethyl ester 21c (light yellow solid, 1.11 g, yield 50.0%).
LCMS m/z(ESI)＝284.10[M+1]。LCMS m/z(ESI)=284.10[M+1].
第三步：third step:
2-氯-4-(3-(羟甲基)双环[1.1.1]戊-1-基)氨基嘧啶-5-羧酸(21d)2-Chloro-4-(3-(hydroxymethyl)bicyclo[1.1.1]pent-1-yl)aminopyrimidine-5-carboxylic acid (21d)
2-chloro-4-((3-(hydroxymethyl)bicyclo[1.1.1]pentan-1-yl)amino)-pyrimidine-5-carboxylate2-chloro-4-((3-(hydroxymethyl)bicyclo[1.1.1]pentan-1-yl)amino)-pyrimidine-5-carboxylate
将2-氯-4-(3-(羟甲基)双环[1.1.1]戊-1-基)氨基嘧啶-5-羧酸乙酯21c(1.11g,3.73mmol)溶解于四氢呋喃/水(10mL/10mL)中，加入氢氧化锂一水合物(0.47g,11.18mmol)，常温搅拌反应1h。TLC监测至反应结束，浓缩蒸发掉四氢呋喃后加入2N HCl调节pH至3-4左右，有白色固体析出，过滤，滤饼用水以及石油醚/乙酸乙酯(v/v＝10/1)洗两次得标题化合物2-氯-4-(3-(羟甲基)双环[1.1.1]戊-1-基)氨基嘧啶-5-羧酸21d(白色固体，534mg，产率53.11％)。Dissolve 2-chloro-4-(3-(hydroxymethyl)bicyclo[1.1.1]pent-1-yl)aminopyrimidine-5-carboxylic acid ethyl ester 21c (1.11g, 3.73mmol) in tetrahydrofuran/water ( 10mL/10mL), lithium hydroxide monohydrate (0.47g, 11.18mmol) was added, and the reaction was stirred at room temperature for 1h. TLC monitors to the end of the reaction, concentrates and evaporates the tetrahydrofuran, adds 2N HCl to adjust the pH to about 3-4, a white solid is precipitated, filtered, and the filter cake is washed twice with water and petroleum ether/ethyl acetate (v/v=10/1) The title compound 2-chloro-4-(3-(hydroxymethyl)bicyclo[1.1.1]pent-1-yl)aminopyrimidine-5-carboxylic acid 21d (white solid, 534 mg, yield 53.11%) was obtained in the second time.
LC-MS m/z(ESI)＝270.10[M+1]。LC-MS m/z(ESI)=270.10[M+1].
第四步：the fourth step:
2-氯-9-(3-(羟甲基)双环[1.1.1]戊-1-基)-7,9-二氢-8H-嘌呤-8-酮(21e)2-chloro-9-(3-(hydroxymethyl)bicyclo[1.1.1]pent-1-yl)-7,9-dihydro-8H-purin-8-one (21e)
2-chloro-9-(3-(hydroxymethyl)bicyclo[1.1.1]pentan-1-yl)-7,9-dihydro-8H-purin-8-one2-chloro-9-(3-(hydroxymethyl)bicyclo[1.1.1]pentan-1-yl)-7,9-dihydro-8H-purin-8-one
将2-氯-4-(3-(羟甲基)双环[1.1.1]戊-1-基)氨基嘧啶-5-羧酸21d(0.50g,1.85mmol)用N,N-二甲基乙酰胺(12mL)溶解，常温搅拌下加入三乙胺(0.40mL,1.85mmol)和叠氮磷酸二苯酯(0.26mL,1.85mmol)反应2h，升温至110℃回流反应2.5h。TLC监测至反应结束，反应液中加水和乙酸乙酯进行萃取，浓缩有机层经硅胶柱色谱分离提纯(二氯甲烷/甲醇(v/v)＝20:1)纯化得标题化合物2-氯-9-(3-(羟甲基)双环[1.1.1]戊-1-基)-7,9-二氢-8H-嘌呤-8-酮21e(白色固体，183mg，产率37.09％)。Use 2-chloro-4-(3-(hydroxymethyl)bicyclo[1.1.1]pent-1-yl)aminopyrimidine-5-carboxylic acid 21d (0.50g, 1.85mmol) with N,N-dimethyl Acetamide (12 mL) was dissolved, triethylamine (0.40 mL, 1.85 mmol) and diphenyl azide phosphate (0.26 mL, 1.85 mmol) were added under stirring at room temperature and reacted for 2 h, and the temperature was raised to 110° C. and refluxed for 2.5 h. TLC monitors to the end of the reaction, the reaction solution is added with water and ethyl acetate for extraction, and the organic layer is concentrated and purified by silica gel column chromatography (dichloromethane/methanol (v/v)=20:1) to obtain the title compound 2-chloro- 9-(3-(hydroxymethyl)bicyclo[1.1.1]pent-1-yl)-7,9-dihydro-8H-purin-8-one 21e (white solid, 183 mg, yield 37.09%).
1H NMR(400MHz,DMSO-d6)δ11.58(s,1H),8.10(s,1H),4.66(t,1H),3.54(d,2H),2.24(s,6H)。1H NMR (400MHz, DMSO-d6) δ 11.58 (s, 1H), 8.10 (s, 1H), 4.66 (t, 1H), 3.54 (d, 2H), 2.24 (s, 6H).
LCMS m/z(ESI)＝267.10[M+1]。LCMS m/z(ESI)=267.10[M+1].
第五步：the fifth step:
2-氯-9-(3-(羟甲基)双环[1.1.1]戊-1-基)-7-甲基-7,9-二氢-8H-嘌呤-8-酮(21f)2-chloro-9-(3-(hydroxymethyl)bicyclo[1.1.1]pent-1-yl)-7-methyl-7,9-dihydro-8H-purin-8-one (21f)
2-chloro-9-(3-(hydroxymethyl)bicyclo[1.1.1]pentan-1-yl)-7-methyl-7,9-dihydro-8H-purin-8-one2-chloro-9-(3-(hydroxymethyl)bicyclo[1.1.1]pentan-1-yl)-7-methyl-7,9-dihydro-8H-purin-8-one
将2-氯-9-(3-(羟甲基)双环[1.1.1]戊-1-基)-7,9-二氢-8H-嘌呤-8-酮21e(180mg,0.67mmol)用N,N-二甲基甲酰胺(4mL)溶解，0℃搅拌下加入硫酸二甲酯(64μL,0.67mmol)和碳酸铯(440mg,1.35mmol)反应1h。TLC监测至反应结束，把反应液缓慢滴加到冰水中搅拌，加入乙酸乙酯进行萃取，浓缩有机层经硅胶柱色谱分离提纯(二氯甲烷/甲醇(v/v)＝20:1)纯化得标题化合物2-氯-9-(3-(羟甲基)双环[1.1.1]戊-1-基)-7-甲基-7,9-二氢-8H-嘌呤-8-酮21f(白色固体，80mg，产率42.54％)。Use 2-chloro-9-(3-(hydroxymethyl)bicyclo[1.1.1]pent-1-yl)-7,9-dihydro-8H-purin-8-one 21e (180mg, 0.67mmol) N,N-dimethylformamide (4mL) was dissolved, and dimethyl sulfate (64μL, 0.67mmol) and cesium carbonate (440mg, 1.35mmol) were added under stirring at 0°C and reacted for 1h. TLC monitors to the end of the reaction, the reaction solution is slowly added dropwise to ice water and stirred, ethyl acetate is added for extraction, the concentrated organic layer is purified by silica gel column chromatography (dichloromethane/methanol (v/v)=20:1) Obtain the title compound 2-chloro-9-(3-(hydroxymethyl)bicyclo[1.1.1]pent-1-yl)-7-methyl-7,9-dihydro-8H-purin-8-one 21f (White solid, 80 mg, yield 42.54%).
LC-MS m/z(ESI)＝281.10[M+1]。LC-MS m/z(ESI)=281.10[M+1].
第六步：The sixth step:
9-(3-(羟甲基)双环[1.1.1]戊-1-基)-7-甲基-2-((7-甲基-[1,2,4]***[1,5-a]吡啶-6-基)氨基)-7,9-二氢-8H-嘌呤-8-酮(化合物21)9-(3-(Hydroxymethyl)bicyclo[1.1.1]pent-1-yl)-7-methyl-2-((7-methyl-[1,2,4]triazole[1,5 -a)pyridin-6-yl)amino)-7,9-dihydro-8H-purin-8-one (compound 21)
9-(3-(hydroxymethyl)bicyclo[1.1.1]pentan-1-yl)-7-methyl-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-7,9-dihydro-8H-purin-8-one9-(3-(hydroxymethyl)bicyclo[1.1.1]pentan-1-yl)-7-methyl-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin- 6-yl)amino)-7,9-dihydro-8H-purin-8-one
将2-氯-9-(3-(羟甲基)双环[1.1.1]戊-1-基)-7-甲基-7,9-二氢-8H-嘌呤-8-酮21f(80mg,0.28mmol)用1,4-二氧六环(6mL)溶解，常温搅拌下加入7-甲基-[1,2,4]***并[1,5-a]吡啶-6-胺(63mg,0.43mmol)、碳酸铯(139mg,0.43mmol)、BrettPhos-G3-Pd(26mg,0.028mmol)，氮气保护并换气，随后升温至110℃回流反应4h。TLC监测至反应结束，浓缩反应液，残留物用硅胶柱色谱分离纯化(二氯甲烷/甲醇(v/v)＝15:1)得标题化合物9-(3-(羟甲基)双环[1.1.1]戊-1-基)-7-甲基-2-((7-甲基-[1,2,4]***[1,5-a]吡啶-6-基)氨基)-7,9-二氢-8H-嘌呤-8-酮化合物21(白色固体，35mg，产率31.85％)。The 2-chloro-9-(3-(hydroxymethyl)bicyclo[1.1.1]pent-1-yl)-7-methyl-7,9-dihydro-8H-purin-8-one 21f (80mg ,0.28mmol) was dissolved in 1,4-dioxane (6mL), and 7-methyl-[1,2,4]triazolo[1,5-a]pyridine-6-amine ( 63mg, 0.43mmol), cesium carbonate (139mg, 0.43mmol), BrettPhos-G3-Pd (26mg, 0.028mmol), protected by nitrogen and ventilated, then heated to 110°C and refluxed for 4h. The reaction was monitored by TLC until the reaction was over. The reaction solution was concentrated. The residue was separated and purified by silica gel column chromatography (dichloromethane/methanol (v/v)=15:1) to obtain the title compound 9-(3-(hydroxymethyl)bicyclo[1.1 .1]pent-1-yl)-7-methyl-2-((7-methyl-[1,2,4]triazole[1,5-a]pyridin-6-yl)amino)-7 , 9-Dihydro-8H-purin-8-one compound 21 (white solid, 35 mg, yield 31.85%).
1H NMR(400MHz,DMSO-d6)δ9.14(s,1H),8.61(s,1H),8.37(s,1H),8.09(s,1H),7.70(s,1H),4.65(t,1H),3.50(d,2H),3.26(s,3H),2.39(s,3H),2.20(s,6H)。1H NMR(400MHz,DMSO-d6)δ9.14(s,1H),8.61(s,1H),8.37(s,1H),8.09(s,1H),7.70(s,1H),4.65(t, 1H), 3.50(d, 2H), 3.26(s, 3H), 2.39(s, 3H), 2.20(s, 6H).
LC-MS m/z(ESI)＝393.20[M+1]。LC-MS m/z(ESI)=393.20[M+1].
实施例22：Example 22:
9-(4,4-二氟环己基)-7-甲基-2-((7-甲基-[1,2,4]***[1,5-a]吡啶-6-基)氨基)-7,9-二氢-8H-嘌呤-8-酮(化合物22)9-(4,4-Difluorocyclohexyl)-7-methyl-2-((7-methyl-[1,2,4]triazole[1,5-a]pyridin-6-yl)amino )-7,9-dihydro-8H-purin-8-one (Compound 22)
9-(4,4-difluorocyclohexyl)-7-methyl-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-7,9-dihydro-8H-purin-8-one9-(4,4-difluorocyclohexyl)-7-methyl-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-7,9- dihydro-8H-purin-8-one
Figure PCTCN2020141859-appb-000040
Figure PCTCN2020141859-appb-000040
Figure PCTCN2020141859-appb-000041
Figure PCTCN2020141859-appb-000041
第一步：first step:
2-氯-4-((4,4-二氟环己基)氨基)嘧啶-5-羧酸乙酯(22a)Ethyl 2-chloro-4-((4,4-difluorocyclohexyl)amino)pyrimidine-5-carboxylate (22a)
ethyl-2-chloro-4-((4,4-difluorocyclohexyl)amino)pyrimidine-5-carboxylateethyl-2-chloro-4-((4,4-difluorocyclohexyl)amino)pyrimidine-5-carboxylate
将2,4-二氯嘧啶-5-羧酸乙酯1a(6.5g,29.41mmol)、4,4-二氟环己-1-胺盐酸盐(5.0g,29.41mmol)溶解于乙腈(100mL)，常温搅拌下加入碳酸钾(10.16g,73.52mmol)反应4h。TLC监测至反应完毕后过滤，滤渣用乙酸乙酯清洗，将滤液浓缩通过硅胶柱色谱分离提纯(正己烷/乙酸乙酯(v/v)＝1:1)得标题化合物2-氯-4-((四氢-2H-吡喃-4-基)氨基)嘧啶-5-羧酸乙酯22a(白色固体，8.0g，产率85.10％)。2,4-Dichloropyrimidine-5-carboxylic acid ethyl ester 1a (6.5g, 29.41mmol), 4,4-difluorocyclohexyl-1-amine hydrochloride (5.0g, 29.41mmol) were dissolved in acetonitrile ( 100mL), potassium carbonate (10.16g, 73.52mmol) was added under stirring at room temperature to react for 4h. After the reaction was monitored by TLC, it was filtered. The residue was washed with ethyl acetate. The filtrate was concentrated and separated and purified by silica gel column chromatography (n-hexane/ethyl acetate (v/v)=1:1) to obtain the title compound 2-chloro-4- ((Tetrahydro-2H-pyran-4-yl)amino)pyrimidine-5-carboxylic acid ethyl ester 22a (white solid, 8.0 g, yield 85.10%).
1H NMR(400MHz,DMSO-d6)δ8.85(s,1H),8.11(d,1H),4.34-4.25(m,2H),4.21-4.10(m,1H),2.11-1.91(m,6H),1.71-1.57(m,2H),1.23(t,3H)。1H NMR(400MHz,DMSO-d6)δ8.85(s,1H),8.11(d,1H),4.34-4.25(m,2H),4.21-4.10(m,1H),2.11-1.91(m,6H) ), 1.71-1.57 (m, 2H), 1.23 (t, 3H).
LC-MS m/z(ESI)＝320.10[M+l]。LC-MS m/z(ESI)=320.10[M+1].
第二步：The second step:
2-氯-4-((4,4-二氟环己基)氨基)嘧啶-5-羧酸(22b)2-chloro-4-((4,4-difluorocyclohexyl)amino)pyrimidine-5-carboxylic acid (22b)
2-chloro-4-((4,4-difluorocyclohexyl)amino)pyrimidine-5-carboxylic acid2-chloro-4-((4,4-difluorocyclohexyl)amino)pyrimidine-5-carboxylic acid
将2-氯-4-((4,4-二氟环己基)氨基)嘧啶-5-羧酸乙酯22a(4g，12.47mmol)溶解于四氢呋喃/水(50ml/50ml)中，加入氢氧化锂(597.22mg,24.94mmol)，室温搅拌1h。TLC监测至反应完全，旋干四氢呋喃，用2N盐酸调pH为5，有白色固体析出，过滤，滤饼用石油醚洗两次，搜集固体得到标题化合物2-氯-4-((4,4-二氟环己基)氨基)嘧啶-5-羧酸22b(白色固体，3.4g，产率91.53％)。Dissolve 2-chloro-4-((4,4-difluorocyclohexyl)amino)pyrimidine-5-carboxylic acid ethyl ester 22a (4g, 12.47mmol) in tetrahydrofuran/water (50ml/50ml) and add hydroxide Lithium (597.22mg, 24.94mmol), stirred at room temperature for 1h. TLC monitors until the reaction is complete, spin dry the tetrahydrofuran, adjust the pH to 5 with 2N hydrochloric acid, a white solid precipitates out, filter, wash the filter cake twice with petroleum ether, collect the solid to obtain the title compound 2-chloro-4-((4,4 -Difluorocyclohexyl)amino)pyrimidine-5-carboxylic acid 22b (white solid, 3.4g, yield 91.53%).
1H NMR(400MHz,DMSO-d6)δ13.79(s,1H),8.60(s,1H),8.55(d,1H),4.22-4.06(m,1H),2.12-1.89(m,6H),1.72-1.56(m,2H)。1H NMR(400MHz,DMSO-d6)δ13.79(s,1H),8.60(s,1H),8.55(d,1H),4.22-4.06(m,1H),2.12-1.89(m,6H), 1.72-1.56 (m, 2H).
LC-MS m/z(ESI)＝292.00[M+l]。LC-MS m/z(ESI)=292.00[M+1].
第三步：third step:
2-氯-9-(4,4-二氟环己基)-7,9-二氢-8H-嘌呤-8-酮(22c)2-chloro-9-(4,4-difluorocyclohexyl)-7,9-dihydro-8H-purin-8-one (22c)
2-chloro-9-(4,4-difluorocyclohexyl)-7,9-dihydro-8H-purin-8-one2-chloro-9-(4,4-difluorocyclohexyl)-7,9-dihydro-8H-purin-8-one
将2-氯-4-((四氢-2H-吡喃-4-基)氨基)嘧啶-5-羧酸22b(3.34g,11.45mmol)溶解于二甲基乙酰胺(50ml)，加入三乙胺(1.6mL,11.45mmol)、叠氮磷酸二苯酯(1.22mL,11.45mmol),随后逐步升温至120℃,搅拌1.5h。TLC监测反应完毕，将反应液倒入冰水中，过滤搜集固体，水洗3次，真空浓缩干燥得标题化合物2-氯-9-(4,4-二氟环己基)-7,9-二氢-8H-嘌呤-8-酮22c(白色固体，2.2g，产率78.5％)。Dissolve 2-chloro-4-((tetrahydro-2H-pyran-4-yl)amino)pyrimidine-5-carboxylic acid 22b (3.34g, 11.45mmol) in dimethylacetamide (50ml), add three Ethylamine (1.6mL, 11.45mmol), diphenyl azide phosphate (1.22mL, 11.45mmol), then gradually heated to 120°C and stirred for 1.5h. TLC monitors the completion of the reaction, the reaction solution is poured into ice water, the solid is collected by filtration, washed with water 3 times, concentrated and dried in vacuo to obtain the title compound 2-chloro-9-(4,4-difluorocyclohexyl)-7,9-dihydro -8H-purin-8-one 22c (white solid, 2.2 g, yield 78.5%).
1H NMR(400MHz,DMSO-d6)δ11.66(s,1H),8.13(s,1H),4.46-4.36(m,1H),2.17-1.94(m,6H),1.87-1.80(m,2H)。1H NMR(400MHz,DMSO-d6)δ11.66(s,1H),8.13(s,1H),4.46-4.36(m,1H),2.17-1.94(m,6H),1.87-1.80(m,2H) ).
LC-MS m/z(ESI)＝289.10[M+l]。LC-MS m/z(ESI)=289.10[M+1].
第四步：the fourth step:
2-氯-7-甲基-9-(4,4-二氟环己基)-7,9-二氢-8H-嘌呤-8-酮(22d)2-chloro-7-methyl-9-(4,4-difluorocyclohexyl)-7,9-dihydro-8H-purin-8-one (22d)
2-chloro-9-(4,4-difluorocyclohexyl)-7-methyl-7,9-dihydro-8H-purin-8-one2-chloro-9-(4,4-difluorocyclohexyl)-7-methyl-7,9-dihydro-8H-purin-8-one
将2-氯-9-(4,4-二氟环己基)-7,9-二氢-8H-嘌呤-8-酮22c(2.62g，9.08mmol)溶解于二甲基甲酰胺(50mL)，在0℃下加入硫酸二甲酯(1.14g，9.08mmol)和碳酸铯(4.44g,13.61mmol)，0℃搅拌1h。TLC监测反应结束，将反应液倒入冰水中，有固体析出，过滤、搜集固体得到标题化合物2-氯-7-甲基-9-(4,4-二氟环己基)-7,9-二氢-8H-嘌呤-8-酮22d(白色固体，2.2g，产率80％)。Dissolve 2-chloro-9-(4,4-difluorocyclohexyl)-7,9-dihydro-8H-purin-8-one 22c (2.62g, 9.08mmol) in dimethylformamide (50mL) Add dimethyl sulfate (1.14g, 9.08mmol) and cesium carbonate (4.44g, 13.61mmol) at 0°C, and stir at 0°C for 1h. TLC monitors the end of the reaction. Pour the reaction solution into ice water. A solid precipitates out. The solid is filtered and collected to obtain the title compound 2-chloro-7-methyl-9-(4,4-difluorocyclohexyl)-7,9- Dihydro-8H-purin-8-one 22d (white solid, 2.2 g, yield 80%).
1H NMR(400MHz,DMSO-d6)δ8.37(s,1H),4.55-4.39(m,1H),3.33(s,3H),2.21-2.01(m,6H),1.90-1.79(m,2H)。1H NMR(400MHz,DMSO-d6)δ8.37(s,1H),4.55-4.39(m,1H),3.33(s,3H),2.21-2.01(m,6H),1.90-1.79(m,2H) ).
LC-MS m/z(ESI)＝303.10[M+l]。LC-MS m/z(ESI)=303.10[M+1].
第五步：the fifth step:
9-(4,4-二氟环己基)-7-甲基-2-((7-甲基-[1,2,4]***[1,5-a]吡啶-6-基)氨基)-7,9-二氢-8H-嘌呤-8-酮9-(4,4-Difluorocyclohexyl)-7-methyl-2-((7-methyl-[1,2,4]triazole[1,5-a]pyridin-6-yl)amino )-7,9-dihydro-8H-purin-8-one
9-(4,4-difluorocyclohexyl)-7-methyl-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)ami no)-7,9-dihydro-8H-purin-8-one9-(4,4-difluorocyclohexyl)-7-methyl-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)ami no)-7,9 -dihydro-8H-purin-8-one
将2-氯-7-甲基-9-(4,4-二氟环己基)-7,9-二氢-8H-嘌呤-8-酮22d(150mg,0.50mmol)用1,4-二氧六环(6mL)溶解，常温搅拌下加入7-甲基-[1,2,4]***并[1,5-a]吡啶-6-胺(73mg,0.50mmol)、碳酸铯(323mg,0.99mmol)、甲烷磺酸(2-二环己基膦)-3,6-二甲氧基-2',4',6'-三异丙基-1,1'-联苯)(2'-氨基-1,1'-联苯-2-基)钯(II)(45mg，0.05mmol)，氮气保护并换气，随后升温至110℃回流反应4h。TLC监测至反应结束，浓缩反应液，残留物用硅胶柱色谱分离纯化(二氯甲烷/甲醇(v/v)＝20:1)得标题化合物化合物22(白色固体，30mg，产率15％)。Use 2-chloro-7-methyl-9-(4,4-difluorocyclohexyl)-7,9-dihydro-8H-purin-8-one 22d (150mg, 0.50mmol) with 1,4-bis The oxane (6mL) was dissolved, and 7-methyl-[1,2,4]triazolo[1,5-a]pyridine-6-amine (73mg, 0.50mmol) and cesium carbonate (323mg) were added under stirring at room temperature. , 0.99mmol), methanesulfonic acid (2-dicyclohexylphosphine)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl) (2 '-Amino-1,1'-biphenyl-2-yl)palladium(II) (45mg, 0.05mmol), protected by nitrogen and ventilated, then heated to 110°C and refluxed for 4h. The reaction was monitored by TLC until the reaction was over, the reaction solution was concentrated, and the residue was separated and purified by silica gel column chromatography (dichloromethane/methanol (v/v)=20:1) to obtain the title compound 22 (white solid, 30 mg, yield 15%) .
1H NMR(600MHz,DMSO-d6)δ9.02(s,1H),8.65(s,1H),8.37(s,1H),8.08(s,1H),7.69(s,1H),4.40–4.32(m,1H),3.30(s,3H),2.36(s,3H),2.11–1.93(m,6H),1.82–1.77(m,2H)。1H NMR(600MHz,DMSO-d6)δ9.02(s,1H),8.65(s,1H),8.37(s,1H),8.08(s,1H),7.69(s,1H),4.40-4.32( m,1H), 3.30(s,3H), 2.36(s,3H), 2.11–1.93(m,6H), 1.82–1.77(m,2H).
LC-MS m/z(ESI)＝415.20[M+l]。LC-MS m/z(ESI)=415.20[M+1].
实施例23：Example 23:
4-(7-甲基-2-((7-甲基-[1,2,4]***[1,5-a]吡啶-6-基)氨基)-8-氧代7,8-二氢-9H-嘌呤-9-基双环[2.2.2]辛烷-1-腈(化合物23)4-(7-methyl-2-((7-methyl-[1,2,4]triazole[1,5-a]pyridin-6-yl)amino)-8-oxo7,8- Dihydro-9H-purin-9-ylbicyclo[2.2.2]octane-1-carbonitrile (Compound 23)
4-(7-methyl-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-8-oxo-7,8-dihydro-9H-purin-9-yl)bicyclo[2.2.2]octane-1-carbonitrile4-(7-methyl-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-8-oxo-7,8-dihydro-9H -purin-9-yl)bicyclo[2.2.2]octane-1-carbonitrile
Figure PCTCN2020141859-appb-000042
Figure PCTCN2020141859-appb-000042
Figure PCTCN2020141859-appb-000043
Figure PCTCN2020141859-appb-000043
第一步：first step:
4-氨基甲酰基双环[2.2.2]辛烷-1-甲酸甲酯(23b)Methyl 4-carbamoylbicyclo[2.2.2]octane-1-carboxylate (23b)
methyl 4-carbamoylbicyclo[2.2.2]octane-1-carboxylatemethyl 4-carbamoylbicyclo[2.2.2]octane-1-carboxylate
将4-(甲氧羰基)双环[2.2.2]辛烷-1-羧酸23a(10.0g，47.12mmol)溶解于无水二氯甲烷(200mL)，冰浴下加入2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(18.81g,49.47mmol),保持温度反应30min，加入N,N-二异丙基乙胺(24.62mL,141.35mmol),随后缓慢多次加入氯化铵固体(3.78g,70.67mmol)。反应逐步恢复至室温并过夜反应。TLC监测反应结束，反应液直接用0.5N盐酸溶液100mL，分液后有机相依次用水和饱和食盐水各100mL，干燥，浓缩后得目标化合物4-氨基甲酰基双环[2.2.2]辛烷-1-甲酸甲酯23b(白色固体，21g，粗品)。Dissolve 4-(methoxycarbonyl)bicyclo[2.2.2]octane-1-carboxylic acid 23a (10.0g, 47.12mmol) in anhydrous dichloromethane (200mL), add 2-(7-nitrogen under ice bath) Heterobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (18.81g, 49.47mmol), keep the temperature for 30min, add N,N-diisopropylethylamine (24.62mL, 141.35mmol), then slowly added ammonium chloride solid (3.78g, 70.67mmol) several times. The reaction gradually returned to room temperature and reacted overnight. The reaction was monitored by TLC. The reaction solution was directly used with 100 mL of 0.5N hydrochloric acid solution. After separation, the organic phase was separated with 100 mL of water and 100 mL of saturated brine, dried, and concentrated to obtain the target compound 4-carbamoylbicyclo[2.2.2]octane- Methyl 1-formate 23b (white solid, 21 g, crude).
1H NMR(400MHz,DMSO-d6)δ6.94(s,1H),6.73(s,1H),3.57(s,3H),1.72-1.63(m,12H)。1H NMR (400MHz, DMSO-d6) δ 6.94 (s, 1H), 6.73 (s, 1H), 3.57 (s, 3H), 1.72-1.63 (m, 12H).
LC-MS m/z(ESI)＝212.10[M+1]。LC-MS m/z(ESI)=212.10[M+1].
第二步：The second step:
4-氰基双环[2.2.2]辛烷-1-羧酸甲酯(23c)4-cyanobicyclo[2.2.2]octane-1-carboxylic acid methyl ester (23c)
methyl 4-cyanobicyclo[2.2.2]octane-1-carboxylatemethyl 4-cyanobicyclo[2.2.2]octane-1-carboxylate
将4-氨基甲酰基双环[2.2.2]辛烷-1-甲酸甲酯23b(21g,99.40mmol)溶于二氯甲烷(200mL),冰浴加入吡啶(16.02mL,198.81mmol),三氟乙酸酐(21.00ml,149.10mmol),保持温度继续反应1h。TLC监测反应结束，直接将反应液过滤，滤饼用100ml二氯甲烷清洗，合并有机相，随后用1N盐酸溶液，水，饱和食盐水各100mL，干燥，浓缩后经柱层析分离后得目标产物4-氰基双环[2.2.2]辛烷-1-羧酸甲酯23c(白色固体,5.3g,60mg,两步产率58.21％)。Dissolve 4-carbamoyl bicyclo[2.2.2]octane-1-carboxylic acid methyl ester 23b (21g, 99.40mmol) in dichloromethane (200mL), add pyridine (16.02mL, 198.81mmol) in an ice bath, trifluoro Acetic anhydride (21.00ml, 149.10mmol), keep the temperature and continue the reaction for 1h. TLC monitors the end of the reaction, directly filter the reaction solution, wash the filter cake with 100ml of dichloromethane, combine the organic phases, then use 1N hydrochloric acid solution, water, and saturated brine each with 100ml, dry, concentrate and separate by column chromatography to obtain the target The product 4-cyanobicyclo[2.2.2]octane-1-carboxylic acid methyl ester 23c (white solid, 5.3g, 60mg, two-step yield 58.21%).
1H NMR(400MHz,CDCl3-d6)δ3.66(s,3H),1.98-1.94(m,6H),1.86-1.82(m,6H)。1H NMR (400MHz, CDCl3-d6) δ 3.66 (s, 3H), 1.98-1.94 (m, 6H), 1.86-1.82 (m, 6H).
LC-MS m/z(ESI)＝194.10[M+1]。LC-MS m/z(ESI)=194.10[M+1].
第三步：third step:
4-氰基双环[2.2.2]辛烷-1-羧酸(23d)4-cyanobicyclo[2.2.2]octane-1-carboxylic acid (23d)
4-cyanobicyclo[2.2.2]octane-1-carboxylic acid4-cyanobicyclo[2.2.2]octane-1-carboxylic acid
将4-氰基双环[2.2.2]辛烷-1-羧酸甲酯23c(5.3g，27.43mmol)溶解于四氢呋喃50ml，水50mL中，加入氢氧化锂(1.73g,41.14mmol)，室温搅拌1h。TLC监测反应完全，浓 缩除去四氢呋喃，用2N盐酸调pH为5，有白色固体析出，过滤，滤饼用石油醚洗两次，搜集固体得到标题化合物4-氰基双环[2.2.2]辛烷-1-羧酸23d(白色固体，5.0g，粗品)。Dissolve 4-cyanobicyclo[2.2.2]octane-1-carboxylic acid methyl ester 23c (5.3g, 27.43mmol) in 50ml of tetrahydrofuran, 50ml of water, add lithium hydroxide (1.73g, 41.14mmol), at room temperature Stir for 1h. TLC monitored the reaction to complete, concentrated to remove tetrahydrofuran, adjusted pH to 5 with 2N hydrochloric acid, white solid precipitated out, filtered, and the filter cake was washed twice with petroleum ether. The solid was collected to obtain the title compound 4-cyanobicyclo[2.2.2]octane -1-carboxylic acid 23d (white solid, 5.0 g, crude product).
1H NMR(400MHz,DMSO-d6)δ12.23(s,1H),1.89-1.85(m,6H),1.72-1.68(m,6H)。1H NMR (400MHz, DMSO-d6) δ 12.23 (s, 1H), 1.89-1.85 (m, 6H), 1.72-1.68 (m, 6H).
LC-MS m/z(ESI)＝180.10[M+1]。LC-MS m/z(ESI)=180.10[M+1].
第四步：the fourth step:
4-氨基双环[2.2.2]辛烷-1-腈盐酸盐(23e)4-aminobicyclo[2.2.2]octane-1-carbonitrile hydrochloride (23e)
4-aminobicyclo[2.2.2]octane-1-carbonitrile hydrochloride4-aminobicyclo[2.2.2]octane-1-carbonitrile hydrochloride
将4-氰基双环[2.2.2]辛烷-1-羧酸23d(5.0g,27.90mmol)溶于甲苯(60mL)中，冰浴加入叠氮磷酸二苯酯(6.01mL,27.90mmol)和三乙胺(3.88mL,27.90mmol),将反应液室温搅拌1h后升温至90度继续反应3h。TLC监测至反应结束，冷却至室温，缓慢倒入100mL 1N盐酸溶液，出现大量固体，过滤，收集固体，且用乙酸乙酯(150mL)打浆，真空干燥得标题化合物4-氨基双环[2.2.2]辛烷-1-腈盐酸盐23e(白色固体，7.3g，粗品)。Dissolve 4-cyanobicyclo[2.2.2]octane-1-carboxylic acid 23d (5.0g, 27.90mmol) in toluene (60mL), add diphenyl azide phosphate (6.01mL, 27.90mmol) in an ice bath And triethylamine (3.88mL, 27.90mmol), the reaction solution was stirred at room temperature for 1h, then the temperature was raised to 90°C and the reaction was continued for 3h. TLC monitors until the reaction is complete, cool to room temperature, slowly pour 100mL 1N hydrochloric acid solution, a large amount of solids appear, filter, collect the solids, beat with ethyl acetate (150mL), and dry in vacuo to obtain the title compound 4-aminobicyclo[2.2.2 ] Octane-1-nitrile hydrochloride 23e (white solid, 7.3 g, crude product).
1H NMR(401MHz,DMSO-d6)δ8.45(s,2H),2.01–1.97(m,6H),1.81-1.76(m,6H)。1H NMR(401MHz,DMSO-d6)δ8.45(s,2H),2.01–1.97(m,6H),1.81-1.76(m,6H).
LC-MS m/z(ESI)＝151.20[M+1]。LC-MS m/z(ESI)=151.20[M+1].
第五步：the fifth step:
2-氯-4-((4-氰基双环[2.2.2]辛烷-1-基)氨基)嘧啶-5-羧酸乙酯(23f)2-chloro-4-((4-cyanobicyclo[2.2.2]octane-1-yl)amino)pyrimidine-5-carboxylic acid ethyl ester (23f)
ethyl 2-chloro-4-((4-cyanobicyclo[2.2.2]octan-1-yl)amino)pyrimidine-5-carboxylateethyl 2-chloro-4-((4-cyanobicyclo[2.2.2]octan-1-yl)amino)pyrimidine-5-carboxylate
将2,4-二氯嘧啶-5-羧酸乙酯1a(8.74g,39.53mmol),4-氨基双环[2.2.2]辛烷-1-腈盐酸盐23e(7.38g,39.53mmol,60％纯度),碳酸钾(21.85g,158.13mmol)溶于乙腈(200mL)，反应液在室温反应16h。TLC监测反应结束，过滤，并用少量乙腈清洗固体，将滤液合并后浓缩，粗品经硅胶柱色谱分离(石油醚/乙酸乙酯(v/v)＝1:1)后得标题化合物2-氯-4-((4-氰基双环[2.2.2]辛烷-1-基)氨基)嘧啶-5-羧酸乙酯23f(白色固体，4.0g，产率30.23％)。The 2,4-dichloropyrimidine-5-carboxylic acid ethyl ester 1a (8.74g, 39.53mmol), 4-aminobicyclo[2.2.2]octane-1-carbonitrile hydrochloride 23e (7.38g, 39.53mmol, 60% purity), potassium carbonate (21.85g, 158.13mmol) was dissolved in acetonitrile (200mL), and the reaction solution was reacted at room temperature for 16h. The end of the reaction was monitored by TLC, filtered, and the solid was washed with a small amount of acetonitrile. The filtrate was combined and concentrated. The crude product was separated by silica gel column chromatography (petroleum ether/ethyl acetate (v/v)=1:1) to obtain the title compound 2-chloro- 4-((4-Cyanobicyclo[2.2.2]octan-1-yl)amino)pyrimidine-5-carboxylic acid ethyl ester 23f (white solid, 4.0 g, yield 30.23%).
1H NMR(400MHz,DMSO-d6)δ8.63(s,1H),8.29(s,1H),4.30(q,2H),2.10–2.00(m,12H),1.30(t,3H)。1H NMR(400MHz,DMSO-d6)δ8.63(s,1H), 8.29(s,1H), 4.30(q,2H), 2.10–2.00(m,12H), 1.30(t,3H).
LC-MS m/z(ESI)＝335.10[M+1]。LC-MS m/z(ESI)=335.10[M+1].
第六步：The sixth step:
2-氯-4-((4-氰基双环[2.2.2]辛烷-1-基)氨基)嘧啶-5-羧酸(23g)2-chloro-4-((4-cyanobicyclo[2.2.2]octane-1-yl)amino)pyrimidine-5-carboxylic acid (23g)
2-chloro-4-((4-cyanobicyclo[2.2.2]octan-1-yl)amino)pyrimidine-5-carboxylic acid2-chloro-4-((4-cyanobicyclo[2.2.2]octan-1-yl)amino)pyrimidine-5-carboxylic acid
将2-氯-4-((4-氰基双环[2.2.2]辛烷-1-基)氨基)嘧啶-5-羧酸乙酯23f(4g，11.95mmol)溶解于四氢呋喃50mL，水50mL中，加入氢氧化锂(1.01g,23.90mmol)，室温搅拌1h。TLC监测反应完全，浓缩除去四氢呋喃，用2N盐酸调pH为5，有白色固体析出，过滤，滤饼用石油醚洗两次，搜集固体得到标题化合物2-氯-4-((4-氰基双环[2.2.2]辛烷-1-基)氨基)嘧啶-5-羧酸23g(3.6g,白色固体,产率98.23％)，直接进行下一步实验。Dissolve 2-chloro-4-((4-cyanobicyclo[2.2.2]octan-1-yl)amino)pyrimidine-5-carboxylic acid ethyl ester 23f (4g, 11.95mmol) in tetrahydrofuran 50mL, water 50mL Lithium hydroxide (1.01g, 23.90mmol) was added to the mixture and stirred at room temperature for 1h. TLC monitored the reaction to complete, concentrated to remove tetrahydrofuran, adjusted the pH to 5 with 2N hydrochloric acid, a white solid precipitated out, filtered, the filter cake was washed twice with petroleum ether, the solid was collected to obtain the title compound 2-chloro-4-((4-cyano Bicyclo[2.2.2]octane-1-yl)amino)pyrimidine-5-carboxylic acid 23g (3.6g, white solid, yield 98.23%), proceed directly to the next experiment.
1H NMR(600MHz,DMSO-d6)δ13.85(s,1H),8.59(s,1H),8.56(s,1H),2.07–1.98(m,12H)。1H NMR (600MHz, DMSO-d6) δ 13.85 (s, 1H), 8.59 (s, 1H), 8.56 (s, 1H), 2.07-1.98 (m, 12H).
LCMS m/z(ESI)＝307.10[M+l]。LCMS m/z(ESI)=307.10[M+1].
第七步：The seventh step:
4-(2-氯-8-氧代-7,8-二氢-9H-嘌呤-9-基)双环[2.2.2]辛烷-1-腈(23h)4-(2-Chloro-8-oxo-7,8-dihydro-9H-purin-9-yl)bicyclo[2.2.2]octane-1-carbonitrile (23h)
4-(2-chloro-8-oxo-7,8-dihydro-9H-purin-9-yl)bicyclo[2.2.2]octane-1-carbonitrile4-(2-chloro-8-oxo-7,8-dihydro-9H-purin-9-yl)bicyclo[2.2.2]octane-1-carbonitrile
将2-氯-4-((4-氰基双环[2.2.2]辛烷-1-基)氨基)嘧啶-5-羧酸23g(3.8g,12.39mmol)溶解于二甲基乙酰胺(50mL)，加入三乙胺(1.72mL,12.39mmol)、叠氮磷酸二苯酯(2.67mL,12.39mmol),随后逐步升温至120℃,搅拌1.5h。TLC监测反应完毕，将反应液倒入冰水中,过滤搜集固体,水洗3次，真空浓缩干燥得4-(2-氯-8-氧代-7,8-二氢-9H-嘌呤-9-基)双环[2.2.2]辛烷-1-腈23h(3.3g，白色固体,产率87.7％)。Dissolve 23g (3.8g, 12.39mmol) of 2-chloro-4-((4-cyanobicyclo[2.2.2]octan-1-yl)amino)pyrimidine-5-carboxylic acid in dimethylacetamide ( 50mL), triethylamine (1.72mL, 12.39mmol) and diphenyl azide phosphate (2.67mL, 12.39mmol) were added, and then gradually heated to 120°C and stirred for 1.5h. TLC monitors the completion of the reaction, pour the reaction solution into ice water, filter to collect the solid, wash 3 times with water, concentrate and dry in vacuo to obtain 4-(2-chloro-8-oxo-7,8-dihydro-9H-purine-9- Yl)bicyclo[2.2.2]octane-1-carbonitrile 23h (3.3g, white solid, yield 87.7%).
1H NMR(400MHz,DMSO-d6)δ11.61(s,1H),8.09(s,1H),2.48–2.40(m,6H),2.09–2.03(m,6H)。1H NMR(400MHz,DMSO-d6)δ11.61(s,1H), 8.09(s,1H), 2.48–2.40(m,6H), 2.09–2.03(m,6H).
LC-MS m/z(ESI)＝304.20[M+l]。LC-MS m/z(ESI)=304.20[M+1].
第八步：The eighth step:
4-(2-氯-7-甲基-8-氧代7,8-二氢-9H-嘌呤-9-基)双环[2.2.2]辛烷-1-腈(23i)4-(2-Chloro-7-methyl-8-oxo 7,8-dihydro-9H-purin-9-yl)bicyclo[2.2.2]octane-1-carbonitrile (23i)
4-(2-chloro-7-methyl-8-oxo-7,8-dihydro-9H-purin-9-yl)bicyclo[2.2.2]octane-1-4-(2-chloro-7-methyl-8-oxo-7,8-dihydro-9H-purin-9-yl)bicyclo[2.2.2]octane-1-
carbonitrilecarbonitrile
将4-(2-氯-8-氧代-7,8-二氢-9H-嘌呤-9-基)双环[2.2.2]辛烷-1-腈23h(3.3g，11.43mmol)溶解于二甲基甲酰胺(50mL)，在0℃下加入硫酸二甲酯(1.44g，11.43mmol)和碳酸铯(5.59g,17.15mmol)，0度搅拌1h。TLC监测反应结束，将反应液倒入冰水中，有固体析出，过滤、搜集固体得到标题化合物4-(2-氯-7-甲基-8-氧代7,8-二氢-9H-嘌呤-9-基)双环[2.2.2]辛烷-1-腈23i(3.1g，白色固体,产率89.59％)。Dissolve 4-(2-chloro-8-oxo-7,8-dihydro-9H-purin-9-yl)bicyclo[2.2.2]octane-1-nitrile 23h (3.3g, 11.43mmol) in Dimethylformamide (50mL), dimethyl sulfate (1.44g, 11.43mmol) and cesium carbonate (5.59g, 17.15mmol) were added at 0°C, and stirred at 0°C for 1h. TLC monitors the end of the reaction. Pour the reaction solution into ice water. A solid precipitates out. The solid is filtered and collected to obtain the title compound 4-(2-chloro-7-methyl-8-oxo7,8-dihydro-9H-purine -9-yl)bicyclo[2.2.2]octane-1-carbonitrile 23i (3.1 g, white solid, yield 89.59%).
1H NMR(401MHz,DMSO-d6)δ8.33(s,1H),3.29(s,3H),2.48–2.41(m,6H),2.10–2.04(m,6H)。1H NMR(401MHz,DMSO-d6)δ8.33(s,1H), 3.29(s,3H), 2.48–2.41(m,6H), 2.10–2.04(m,6H).
LC-MS m/z(ESI)＝318.20[M+l]。LC-MS m/z(ESI)=318.20[M+1].
第九步：Step 9:
4-(7-甲基-2-((7-甲基-[1,2,4]***[1,5-a]吡啶-6-基)氨基)8-氧代7,8-二氢-9H-嘌呤-9-基)双环[2.2.2]辛烷-1-腈4-(7-methyl-2-((7-methyl-[1,2,4]triazole[1,5-a]pyridin-6-yl)amino)8-oxo7,8-bis Hydrogen-9H-purin-9-yl)bicyclo[2.2.2]octane-1-carbonitrile
4-(7-methyl-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-8-oxo-7,8-dihydro-9H-purin-9-yl)bicyclo[2.2.2]octane-1-carbonitrile4-(7-methyl-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-8-oxo-7,8-dihydro-9H -purin-9-yl)bicyclo[2.2.2]octane-1-carbonitrile
将4-(2-氯-7-甲基-8-氧代7,8-二氢-9H-嘌呤-9-基)双环[2.2.2]辛烷-1-腈23i(150mg,0.47mmol)用1,4-二氧六环(10mL)溶解，常温搅拌下加入7-甲基-[1,2,4]***并[1,5-a]吡啶-6-胺(70mg,0.47mmol)、碳酸铯(307mg,0.94mmol)、甲烷磺酸(2-二环己基膦)-3,6-二甲氧基-2',4',6'-三异丙基-1,1'-联苯)(2'-氨基-1,1'-联苯-2-基)钯(II)(43mg，0.047mmol)，氮气保护并换气，随后升温至110℃回流反应4h。TLC监测至反应结束，浓缩反应液，残留物用硅胶柱色谱分离纯化(二氯甲烷/甲醇(v/v)＝20:1)得标题化合物化合物23(白色固体，60mg，产率29.60％)。The 4-(2-chloro-7-methyl-8-oxo 7,8-dihydro-9H-purin-9-yl)bicyclo[2.2.2]octane-1-carbonitrile 23i (150mg, 0.47mmol ) Dissolve with 1,4-dioxane (10mL), add 7-methyl-[1,2,4]triazolo[1,5-a]pyridine-6-amine (70mg, 0.47 mmol), cesium carbonate (307mg, 0.94mmol), methanesulfonic acid (2-dicyclohexylphosphine)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1 '-Biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (43mg, 0.047mmol), protected by nitrogen and ventilated, then heated to 110°C and refluxed for 4h. The reaction was monitored by TLC until the reaction was over, the reaction solution was concentrated, and the residue was separated and purified by silica gel column chromatography (dichloromethane/methanol (v/v)=20:1) to obtain the title compound 23 (white solid, 60 mg, yield 29.60%) .
1H NMR(401MHz,DMSO-d6)δ9.13(s,1H),8.61(s,1H),8.39(s,1H),8.09(s,1H),7.71(s,1H),3.24(s,3H),2.42-2.46(m,6H),2.39(s,3H),1.98-2.02(m,6H)。1H NMR (401MHz, DMSO-d6) δ 9.13 (s, 1H), 8.61 (s, 1H), 8.39 (s, 1H), 8.09 (s, 1H), 7.71 (s, 1H), 3.24 (s, 3H), 2.42-2.46 (m, 6H), 2.39 (s, 3H), 1.98-2.02 (m, 6H).
LC-MS m/z(ESI)＝430.20[M+l]。LC-MS m/z(ESI)=430.20[M+1].
生物学试验Biological test
1、DNA-PK激酶抑制试验1. DNA-PK kinase inhibition test
通过DNA-PK激酶检测试剂盒(DNA-PK kinase assay kit)(购买自Promega公司，货号：V4107，批号：0000366495)检测化合物对DNA-PK激酶的抑制活性。利用化学发光对结果进行定量，具体实验方案如下：The DNA-PK kinase assay kit (purchased from Promega, product number: V4107, batch number: 0000366495) was used to detect the inhibitory activity of the compound against DNA-PK kinase. Using chemiluminescence to quantify the results, the specific experimental plan is as follows:
i.按照试剂盒说明书构建不同浓度ADP-荧光标准曲线；i. Construct different concentrations of ADP-fluorescence standard curve according to the kit instructions;
ii.于384孔白色板中制备5μL反应体系，每孔中分别加入1μL化合物(分别设定浓度梯度1μM、200nM、40nM、8nM、1.6nM、0.32nM、0.064nM、0.013nM)、20units DNA-PK激酶、0.2μg/μL底物、10μg/μL DNA、50μM ATP、1％DMSO；ii. Prepare a 5μL reaction system in a 384-well white plate, and add 1μL of compound to each well (set concentration gradients of 1μM, 200nM, 40nM, 8nM, 1.6nM, 0.32nM, 0.064nM, 0.013nM), 20units DNA- PK kinase, 0.2μg/μL substrate, 10μg/μL DNA, 50μM ATP, 1% DMSO;
iii.混匀，离心(1000rpm，30s)，37℃孵育60min；iii. Mix well, centrifuge (1000rpm, 30s), and incubate at 37°C for 60min;
iv.加入5μL ADP‐Glo TM Reagent终止反应，混匀，离心(1000rpm，30s)，室温孵育40min； iv. Add 5μL ADP-Glo TM Reagent to terminate the reaction, mix well, centrifuge (1000rpm, 30s), and incubate at room temperature for 40min;
v.加入10μLKinase Detection Reagent，震荡混匀，离心(1000rpm，30s)，室温孵育30min；v. Add 10μL Kinase Detection Reagent, shake and mix, centrifuge (1000rpm, 30s), and incubate at room temperature for 30min;
vi.利用酶标仪(Thermo fisher，Varioskan LUX)测定荧光值。利用GraphPad Pris  m 8进行IC 50的计算，结果如表1所示。 vi. Measure the fluorescence value using a microplate reader (Thermo fisher, Varioskan LUX). Using GraphPad Pris m 8 to calculate IC 50 , the results are shown in Table 1.
表1本发明化合物DNA-PK激酶抑制活性Table 1 DNA-PK kinase inhibitory activity of the compounds of the present invention
化合物编号Compound number IC 50(nM) IC 50 (nM)
11 CC
22 BB
33 BB
44 BB
55 CC
6-16-1 BB
6-26-2 BB
7-17-1 AA
7-27-2 AA
88 AA
99 AA
1111 CC
1212 BB
1313 BB
1414 BB
1515 CC
1616 BB
1717 BB
1818 BB
1919 BB
2020 BB
21twenty one CC
22twenty two BB
23twenty three BB
对照例Control example DD
注：对照例为参考J.Med.Chem(2020),63(7),3461-3471化合物3，对照例按照其制备方法制备得到。Note: The comparative example refers to J. Med. Chem (2020), 63(7), 3461-3471 compound 3, and the comparative example is prepared according to its preparation method.
0<A≤1nM；0<A≤1nM;
1nM<B≤5nM；1nM<B≤5nM;
5nM<C≤50nM；5nM<C≤50nM;
50nM<D≤100nM；50nM<D≤100nM;
100nM<E。100nM<E.
结论：结果表明，与对照例相比，本发明化合物对DNA-PK激酶具有更显著的抑制效果。Conclusion: The results show that, compared with the control example, the compound of the present invention has a more significant inhibitory effect on DNA-PK kinase.
2、增殖抑制实验2. Proliferation inhibition experiment
2.1、实验材料2.1. Experimental materials
A549细胞(购自ATCC)、Doxorubicin hydrochloride(多柔比星，购自上海陶素生化科技有限公司，货号：T1020)、DMEM(10％FBS)培养基、96孔白板、细胞活力检测试剂盒(购自Promega，货号：G9241)。A549 cells (purchased from ATCC), Doxorubicin hydrochloride (doxorubicin, purchased from Shanghai Taosu Biochemical Technology Co., Ltd., catalog number: T1020), DMEM (10% FBS) medium, 96-well white board, cell viability detection kit ( Purchased from Promega, article number: G9241).
2.2、实验步骤2.2. Experimental steps
A549细胞重悬后进行计数，铺96孔板，500个/孔(80μL)；过夜培养。The A549 cells were resuspended and counted, and then spread in a 96-well plate, 500 cells/well (80 μL); cultured overnight.
配置10×药物浓度梯度(1：5)：初始浓度为100μM，用培养基1：5倍比稀释为20μM、4μM、800nM、160nM、32nM、6.4nM、1.3nM(终浓度10μM、2μM、0.4μM、80nM、1 6nM、3.2nM、0.64nM、0.13nM)。Configure 10× drug concentration gradient (1:5): the initial concentration is 100μM, diluted with medium 1:5 ratio to 20μM, 4μM, 800nM, 160nM, 32nM, 6.4nM, 1.3nM (final concentration 10μM, 2μM, 0.4 μM, 80nM, 16nM, 3.2nM, 0.64nM, 0.13nM).
3.每孔中加入10μL待测化合物，每个浓度梯度做2个重复，设置单药组(待测化合物或者Doxorubicin)、联用组、培养基对照组：3. Add 10 μL of the test compound to each well, do 2 replicates for each concentration gradient, set up the single-drug group (test compound or Doxorubicin), combination group, and medium control group:
单药组：加入待测化合物(终浓度10μM、2μM、0.4μM、80nM、16nM、3.2nM、0.64nM、0.13nM)，或者只加入doxorubicin(终浓度10μM、2μM、0.4μM、80nM、16nM、3.2nM、0.64nM、0.13nM)，37℃温箱继续培养120h；Single-drug group: add the test compound (final concentration 10μM, 2μM, 0.4μM, 80nM, 16nM, 3.2nM, 0.64nM, 0.13nM), or only add doxorubicin (final concentration 10μM, 2μM, 0.4μM, 80nM, 16nM, 3.2nM, 0.64nM, 0.13nM), continue to incubate for 120h in a 37°C incubator;
联用组：加入待测化合物(终浓度10μM、2μM、0.4μM、80nM、16nM、3.2nM、0.64nM、0.13nM)，37℃温箱孵育1h后，每孔再加入10nM Doxorubicin(10μL/孔)，37℃温箱继续培养120h；Combination group: add test compound (final concentration 10μM, 2μM, 0.4μM, 80nM, 16nM, 3.2nM, 0.64nM, 0.13nM), incubate at 37℃ for 1h, add 10nM Doxorubicin (10μL/well) ), continue to incubate for 120h in 37℃ incubator;
对照组：加入20μL培养基，37℃温箱继续培养120h。Control group: add 20μL of culture medium and continue to incubate for 120h in 37℃ incubator.
4.取出细胞培养板，加入细胞培养液等体积的检测液(100μL培养基，加入100μL检测液)。4. Take out the cell culture plate and add an equal volume of cell culture medium to the test solution (100 μL medium, add 100 μL test solution).
5.震板机上震动2min，裂解细胞。5. Vibrate on the shaker for 2 minutes to lyse the cells.
6.室温放置10min，使信号稳定。6. Leave at room temperature for 10 minutes to stabilize the signal.
7.酶标仪(Thermo fisher；Varioskan LUX)测定化学发光值。7. Microplate reader (Thermo fisher; Varioskan LUX) measures the chemiluminescence value.
结论：本发明化合物与Doxorubicin联用对A549细胞具有更显著增殖抑制作用，且细胞毒性降低。Conclusion: The combination of the compound of the present invention and Doxorubicin has a more significant inhibitory effect on the proliferation of A549 cells and reduces cytotoxicity.
3、移植瘤抑制实验3. The transplantation tumor inhibition experiment
3.1实验材料：A549细胞(购自ATCC)；Doxorubicin脂质体(Dox)(Lipo Doxorubicin，商品名“里葆多”，购自上海复旦张江生物医药股份有限公司)；6周龄雌性裸鼠(体重18-20g)(北京维通利华实验动物技术有限公司)，每组10只鼠。3.1 Experimental materials: A549 cells (purchased from ATCC); Doxorubicin liposomes (Dox) (Lipo Doxorubicin, trade name "Libaoduo", purchased from Shanghai Fudan Zhangjiang Biomedical Co., Ltd.); 6-week-old female nude mice ( Body weight 18-20g) (Beijing Weitong Lihua Experimental Animal Technology Co., Ltd.), 10 rats in each group.
3.2 Doxorubicin与待筛选化合物联用对A549移植瘤的抑制效果测定：3.2 Determination of the inhibitory effect of Doxorubicin in combination with the compound to be screened on A549 xenograft tumors:
3.2.1收集处于生长对数期的A549细胞，预冷PBS洗2次后备用；3.2.1 Collect the A549 cells in the logarithmic growth phase, wash them twice with pre-cooled PBS and use them for later use;
3.2.2Balb/c裸小鼠实验室环境适应3天，于右肋部皮下接种A549细胞，接种细胞量为5×10 6/只，待肿瘤生长至200mm 3左右时进行药效实验； 3.2.2 Balb/c nude mice were adapted to the laboratory environment for 3 days, and A549 cells were subcutaneously inoculated into the right ribs. The amount of cells inoculated was 5×10 6 per mouse. When the tumor grows to about 200 mm 3 , the efficacy experiment will be carried out;
3.2.3将成功长瘤的小鼠进行随机分组，设置单独Doxorubicin(Dox)组、待测化合物和Dox联用组、对照组(Vehicle)，给药21天；小鼠灌胃给药(i.g.)，每日2次(BID，给药体积5mL/kg；溶剂为5％DMSO+30％2-羟丙基-β-环糊精)。早上灌胃给药1h后，由尾静脉注射Lipo Doxorubicin(2.5mg/kg)；每周1次(QW，给药体积5mL/kg；)；3.2.3 Randomly group the mice that have successfully grown tumors, and set up a single Doxorubicin (Dox) group, a test compound and Dox combined group, and a control group (Vehicle) for 21 days; mice are given intragastric administration (ig ), twice a day (BID, administration volume 5mL/kg; solvent: 5% DMSO+30% 2-hydroxypropyl-β-cyclodextrin). After intragastric administration in the morning for 1 hour, Lipo Doxorubicin (2.5mg/kg) was injected from the tail vein; once a week (QW, administration volume 5mL/kg;);
3.2.4每周称量2次小鼠体重，并同时测定肿瘤体积：肿瘤体积(V)计算公式为：V＝1/2×L 长×L 短 2,并计算抑瘤率，抑瘤率(％)＝(D21肿瘤体积(Vehicle)-D21肿瘤体积(给药组))/D21肿瘤体积(Vehicle)×100； 3.2.4 Weigh the weight of the mice twice a week, and measure the tumor volume at the same time: the tumor volume (V) is calculated as: V = 1/2 × L long × L short 2 , and calculate the tumor inhibition rate and tumor inhibition rate (%)=(D21 tumor volume (Vehicle)-D21 tumor volume (administration group))/D21 tumor volume (Vehicle)×100;
3.2.5给药21天后，分离肿瘤并称重，并计算体重变化率，体重变化率(％)＝(D21体重-D0体重)/D0体重×100。3.2.5 After 21 days of administration, the tumor was isolated and weighed, and the weight change rate was calculated. The weight change rate (%)=(D21 weight-D0 weight)/D0 weight×100.
结论：实验结果表明，本发明化合物与Doxorubicin联用均显著提高Doxorubicin的肿瘤抑制效果，且不会引起明显的体重减轻。Conclusion: The experimental results show that the combination of the compound of the present invention and Doxorubicin can significantly improve the tumor suppressive effect of Doxorubicin, and will not cause significant weight loss.
本发明说明书对具体实施方案进行了详细描述，本领域技术人员应认识到，上述实施方案是示例性的，不能理解为对本发明的限制，对于本领域技术人员来说，在不脱离本发明原理的前提下，通过对本发明进行若干改进和修饰，这些改进和修饰获得技术方案也落在本发明的权利要求书的保护范围内。The specification of the present invention describes the specific embodiments in detail. Those skilled in the art should realize that the above-mentioned embodiments are exemplary and should not be construed as limiting the present invention. For those skilled in the art, the principle of the present invention is not deviated from Under the premise of making several improvements and modifications to the present invention, the technical solutions obtained by these improvements and modifications also fall within the protection scope of the claims of the present invention.

Claims (8)

  1. 通式(I)所示的化合物，或者其立体异构体、溶剂化物、前药、氘代物、代谢产物、药学上可接受的盐或共晶：The compound represented by the general formula (I), or its stereoisomer, solvate, prodrug, deuterium, metabolite, pharmaceutically acceptable salt or co-crystal:
    Figure PCTCN2020141859-appb-100001
    Figure PCTCN2020141859-appb-100001
    其中：among them:
    R 1选自H、-OH、氰基、卤素、-NH 2、C 1-6烷基或者C 1-6烷氧基，所述的C 1-6烷基任选进一步被1-3个选自D或者卤素的取代基所取代； R 1 is selected from H, -OH, cyano, halogen, -NH 2 , C 1-6 alkyl or C 1-6 alkoxy, and the C 1-6 alkyl is optionally further grouped by 1-3 Substituted by a substituent selected from D or halogen;
    R 2选自H或者C 1-6烷基； R 2 is selected from H or C 1-6 alkyl;
    R 3选自C 1-6烷基、C 3-12碳环基、C 3杂环基、C 4-12杂环基、-C 1-6亚烷基-C 3-12碳环基、-C 1-6亚烷基-C 3杂环基或者-C 1-6亚烷基-C 4-12杂环基，所述的C 3杂环基和C 4-12杂环基包含1至3个选自N、O或者S的杂原子，所述的C 1-6烷基、C 3-12碳环基、C 3杂环基和C 4-12杂环基、C 1-6亚烷基任选进一步被1个或者多个选自-OH、羧基、卤素、氰基、＝O、C 1-6烷基、C 1-6杂烷基、C 2-6烯基、C 2-6炔基、-NR a1R a2、-C(＝O)OC 1-6烷基、-C(＝O)NR a1R a2、C 3-12环烷基、C 3杂环烷基、C 4-12杂环烷基、C 6-12芳基或者C 5-12杂芳基的取代基所取代；且所述取代基中的所述的C 1-6烷基、C 1-6杂烷基、C 2-6烯基或者C 2-6炔基任选进一步被1个或者多个选自-OH、羧基、氰基、卤素、-O-R a1、-NR a1R a2、C 3- 12环烷基、C 3杂环烷基、C 4-12杂环烷基、C 6-12芳基或者C 5-12杂芳基的取代基所取代； R 3 is selected from C 1-6 alkyl, C 3-12 carbocyclic group, C 3 heterocyclic group, C 4-12 heterocyclic group, -C 1-6 alkylene-C 3-12 carbocyclic group, -C 1-6 alkylene-C 3 heterocyclic group or -C 1-6 alkylene-C 4-12 heterocyclic group, said C 3 heterocyclic group and C 4-12 heterocyclic group include 1 Up to 3 heteroatoms selected from N, O or S, the C 1-6 alkyl group, C 3-12 carbocyclic group, C 3 heterocyclic group and C 4-12 heterocyclic group, C 1-6 The alkylene group is optionally further selected by one or more selected from -OH, carboxyl, halogen, cyano, =0, C 1-6 alkyl, C 1-6 heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl, -NR a1 R a2 , -C(=O)OC 1-6 alkyl, -C(=O)NR a1 R a2 , C 3-12 cycloalkyl, C 3 heterocycloalkyl , C 4-12 heterocycloalkyl, C 6-12 aryl or C 5-12 heteroaryl substituents; and the C 1-6 alkyl, C 1- 6 heteroalkyl, C 2-6 alkenyl or C 2-6 alkynyl is optionally further selected by one or more selected from -OH, carboxyl, cyano, halogen, -OR a1 , -NR a1 R a2 , C 3-12 cycloalkyl, C 3 heterocycloalkyl, C 4-12 heterocycloalkyl, C 6-12 aryl or C 5-12 heteroaryl group substituents;
    条件是：当R 3为环己基时，所述的环己基至少被一个氰基取代；且R 3不为四氢呋喃基或者氧杂环己基； The condition is: when R 3 is cyclohexyl, the cyclohexyl group is substituted by at least one cyano group; and R 3 is not tetrahydrofuranyl or oxacyclohexyl;
    R a1、R a2各自独立地选自H、C 1-6烷基、-C(＝O)R a3或者-C(＝O)NR a4R a5，其中所述的C 1-6烷基任选进一步被1个或者多个选自OH、卤素、C 1-6烷基、C 1-6烷氧基、C 6-12芳基、C 5-12杂芳基、C 3-12环烷基、C 3杂环烷基、或者C 4-12杂环烷基的取代基所取代； R a1 and R a2 are each independently selected from H, C 1-6 alkyl, -C(=O)R a3 or -C(=O)NR a4 R a5 , wherein the C 1-6 alkyl is any Optionally, one or more selected from OH, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 6-12 aryl, C 5-12 heteroaryl, C 3-12 cycloalkane Group, C 3 heterocycloalkyl, or C 4-12 heterocycloalkyl substituent;
    R a3选自C 1-6烷基、C 1-6烷氧基或者C 6-12芳基； R a3 is selected from C 1-6 alkyl, C 1-6 alkoxy or C 6-12 aryl;
    R a4、R a5各自独立地选自H或者C 1-6烷基；或者R a4与R a5及N原子形成3至8元杂环，所述的3至8元杂环包含1个至4个选自N、O或者S的杂原子； R a4 and R a5 are each independently selected from H or C 1-6 alkyl; or R a4 and R a5 and N atoms form a 3- to 8-membered heterocyclic ring, and the 3- to 8-membered heterocyclic ring includes 1 to 4 One heteroatom selected from N, O or S;
    p选自0、1、2或者3；p is selected from 0, 1, 2 or 3;
    任选地，通式(I)被1个或者多个D原子取代。Optionally, the general formula (I) is substituted with one or more D atoms.
  2. 根据权利要求1所述的化合物，或者其立体异构体、溶剂化物、前药、氘代物、代谢产物、药学上可接受的盐或共晶，其中该化合物选自通式(II)所示的化合物：The compound according to claim 1, or its stereoisomers, solvates, prodrugs, deuterated products, metabolites, pharmaceutically acceptable salts or co-crystals, wherein the compound is selected from general formula (II) compound of:
    Figure PCTCN2020141859-appb-100002
    Figure PCTCN2020141859-appb-100002
    其中：among them:
    R 1选自卤素或者C 1-6烷基，所述的C 1-6烷基任选进一步被1-3个选自D或者卤素的取代基所取代； R 1 is selected from halogen or C 1-6 alkyl, and said C 1-6 alkyl is optionally further substituted with 1-3 substituents selected from D or halogen;
    R 3选自C 1-6烷基、C 3-12碳环基、C 3杂环基、C 4-12杂环基、-C 1-6亚烷基-C 3-12碳环基、-C 1-6亚烷基-C 3杂环基或者-C 1-6亚烷基-C 4-12杂环基，所述的C 3杂环基和C 4-12杂环基包含1至3个选自N、O或者S的杂原子，所述的C 1-6烷基、C 3-12碳环基、C 3杂环基和C 4-12杂环基、C 1-6亚烷基任选进一步被1个或者多个选自-OH、羧基、卤素、氰 基、＝O、C 1-6烷基、C 1-6杂烷基、C 2-6烯基、C 2-6炔基、-NR a1R a2、-C(＝O)OC 1-6烷基、-C(＝O)NR a1R a2、C 3-12环烷基、C 3杂环烷基、C 4-12杂环烷基、C 6-12芳基或者C 5-12杂芳基的取代基所取代；且所述取代基中的所述的C 1-6烷基、C 1-6杂烷基、C 2-6烯基或者C 2-6炔基任选进一步被1个或者多个选自-OH、羧基、氰基、卤素、-O-R a1、-NR a1R a2、C 3- 12环烷基、C 3杂环烷基、C 4-12杂环烷基、C 6-12芳基或者C 5-12杂芳基的取代基所取代； R 3 is selected from C 1-6 alkyl, C 3-12 carbocyclic group, C 3 heterocyclic group, C 4-12 heterocyclic group, -C 1-6 alkylene-C 3-12 carbocyclic group, -C 1-6 alkylene-C 3 heterocyclic group or -C 1-6 alkylene-C 4-12 heterocyclic group, said C 3 heterocyclic group and C 4-12 heterocyclic group include 1 Up to 3 heteroatoms selected from N, O or S, the C 1-6 alkyl group, C 3-12 carbocyclic group, C 3 heterocyclic group and C 4-12 heterocyclic group, C 1-6 The alkylene group is optionally further selected by one or more selected from -OH, carboxyl, halogen, cyano, =0, C 1-6 alkyl, C 1-6 heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl, -NR a1 R a2 , -C(=O)OC 1-6 alkyl, -C(=O)NR a1 R a2 , C 3-12 cycloalkyl, C 3 heterocycloalkyl , C 4-12 heterocycloalkyl, C 6-12 aryl or C 5-12 heteroaryl substituents; and the C 1-6 alkyl, C 1- 6 heteroalkyl, C 2-6 alkenyl or C 2-6 alkynyl is optionally further selected by one or more selected from -OH, carboxyl, cyano, halogen, -OR a1 , -NR a1 R a2 , C 3-12 cycloalkyl, C 3 heterocycloalkyl, C 4-12 heterocycloalkyl, C 6-12 aryl or C 5-12 heteroaryl group substituents;
    条件是：当R 3为环己基时，所述的环己基至少被一个氰基取代；且R 3不为四氢呋喃基或者氧杂环己基； The condition is: when R 3 is cyclohexyl, said cyclohexyl is substituted by at least one cyano group; and R 3 is not tetrahydrofuranyl or oxacyclohexyl;
    R a1、R a2各自独立地选自H、C 1-6烷基、-C(＝O)R a3或者-C(＝O)NR a4R a5，其中所述的C 1-6烷基任选进一步被1个或者多个选自OH、卤素、C 1-6烷基、C 1-6烷氧基、C 6-12芳基、C 5-12杂芳基、C 3-12环烷基、C 3杂环烷基或者C 4-12杂环烷基的取代基所取代； R a1 and R a2 are each independently selected from H, C 1-6 alkyl, -C(=O)R a3 or -C(=O)NR a4 R a5 , wherein the C 1-6 alkyl is any Optionally, one or more selected from OH, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 6-12 aryl, C 5-12 heteroaryl, C 3-12 cycloalkane Substituted by the substituents of C 3 heterocycloalkyl or C 4-12 heterocycloalkyl;
    R a3选自C 1-6烷基、C 1-6烷氧基或者C 6-12芳基； R a3 is selected from C 1-6 alkyl, C 1-6 alkoxy or C 6-12 aryl;
    R a4、R a5各自独立地选自H或者C 1-6烷基；或者R a4与R a5及N原子形成3至8元杂环，所述的3至8元杂环包含1个至4个选自N、O或者S的杂原子； R a4 and R a5 are each independently selected from H or C 1-6 alkyl; or R a4 and R a5 and N atoms form a 3- to 8-membered heterocyclic ring, and the 3- to 8-membered heterocyclic ring includes 1 to 4 One heteroatom selected from N, O or S;
    p选自0、1、2或者3。p is selected from 0, 1, 2 or 3.
  3. 根据权利要求2所述的化合物，或者其立体异构体、溶剂化物、前药、氘代物、代谢产物、药学上可接受的盐或共晶，其中：The compound of claim 2, or its stereoisomers, solvates, prodrugs, deuterated products, metabolites, pharmaceutically acceptable salts or co-crystals thereof, wherein:
    R 1选自卤素或者C 1-4烷基，所述的C 1-6烷基任选进一步被1-3个选自D或者卤素的取代基所取代； R 1 is selected from halogen or C 1-4 alkyl, and said C 1-6 alkyl is optionally further substituted with 1-3 substituents selected from D or halogen;
    R 3选自C 1-4烷基、C 3-8碳环基、C 4-8杂环基、-C 1-2亚烷基-C 3-8碳环基或者-C 1-2亚烷基-C 4-8杂环基，所述的C 4-8杂环基包含1至3个选自N或者O的杂原子，所述的C 1-4烷基、C 3-8碳环基和C 4-8杂环基、C 1-2亚烷基任选进一步被1个或者多个选自-OH、卤素、＝O、氰基或者C 1-4烷基的取代基所取代；且所述取代基中的所述的C 1-4烷基任选进一步被1个或者多个选自-OH、氰基或者卤素的取代基所取代；条件是：当R 3为环己基时，所述的环己基至少被一个氰基取代；且R 3不为四氢呋喃基或者氧杂环己基； R 3 is selected from C 1-4 alkyl, C 3-8 carbocyclic group, C 4-8 heterocyclic group, -C 1-2 alkylene-C 3-8 carbocyclic group or -C 1-2 alkylene Alkyl-C 4-8 heterocyclic group, said C 4-8 heterocyclic group contains 1 to 3 heteroatoms selected from N or O, said C 1-4 alkyl group, C 3-8 carbon The cyclic group, C 4-8 heterocyclic group, and C 1-2 alkylene group are optionally further substituted by one or more substituents selected from -OH, halogen, =0, cyano or C 1-4 alkyl. Substituted; and the C 1-4 alkyl in the substituent is optionally further substituted with one or more substituents selected from -OH, cyano or halogen; provided that: when R 3 is a ring In the case of hexyl, the cyclohexyl group is substituted by at least one cyano group; and R 3 is not tetrahydrofuranyl or oxanyl;
    p选自1。p is selected from 1.
  4. 根据权利要求1-3任一项所述的化合物，或者其立体异构体、溶剂化物、前药、氘代物、代谢产物、药学上可接受的盐或共晶，其中该化合物选自以下结构之一：The compound according to any one of claims 1 to 3, or its stereoisomer, solvate, prodrug, deuterium, metabolite, pharmaceutically acceptable salt or co-crystal, wherein the compound is selected from the following structures one:
    Figure PCTCN2020141859-appb-100003
    Figure PCTCN2020141859-appb-100003
    Figure PCTCN2020141859-appb-100004
    Figure PCTCN2020141859-appb-100005
    或者
    Figure PCTCN2020141859-appb-100006
    Figure PCTCN2020141859-appb-100004
    Figure PCTCN2020141859-appb-100005
    or
    Figure PCTCN2020141859-appb-100006
  5. 制备权利要求1-4任一项所述的化合物的中间体，所述的中间体选自：An intermediate for preparing the compound of any one of claims 1-4, wherein the intermediate is selected from:
    Figure PCTCN2020141859-appb-100007
    Figure PCTCN2020141859-appb-100007
    Figure PCTCN2020141859-appb-100008
    Figure PCTCN2020141859-appb-100009
    或者
    Figure PCTCN2020141859-appb-100010
    Figure PCTCN2020141859-appb-100008
    Figure PCTCN2020141859-appb-100009
    or
    Figure PCTCN2020141859-appb-100010
  6. 药物组合物，所述药物组合物包括：A pharmaceutical composition, the pharmaceutical composition comprising:
    (1)权利要求1至5中任一项所述的化合物或者其立体异构体、溶剂化物、前药、氘代物、代谢产物、药学上可接受的盐或共晶；(1) The compound according to any one of claims 1 to 5 or its stereoisomers, solvates, prodrugs, deuterated products, metabolites, pharmaceutically acceptable salts or co-crystals;
    (2)任选的一种或者多种其他活性成分；以及(2) Optional one or more other active ingredients; and
    (3)药学上可接受的载体和/或赋形剂。(3) A pharmaceutically acceptable carrier and/or excipient.
  7. 权利要求1-4中任一项所述的化合物、或者其立体异构体、溶剂化物、前药、氘代物、代谢产物、药学上可接受的盐或共晶或者权利要求6所述的药物组合物在制备用于治疗癌症的药物中的用途。The compound of any one of claims 1-4, or its stereoisomers, solvates, prodrugs, deuterated products, metabolites, pharmaceutically acceptable salts or co-crystals, or the drug of claim 6 Use of the composition in the preparation of a medicine for treating cancer.
  8. 权利要求1-4中任一项所述的化合物、或者其立体异构体、溶剂化物、前药、氘代物、代谢产物、药学上可接受的盐或共晶或者权利要求6所述的药物组合物在制备DNA-PK抑制剂中的用途。The compound of any one of claims 1-4, or its stereoisomers, solvates, prodrugs, deuterated products, metabolites, pharmaceutically acceptable salts or co-crystals, or the drug of claim 6 Use of the composition in the preparation of a DNA-PK inhibitor.
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