WO2021136461A1 - Dérivé de purine et son utilisation médicale - Google Patents

Dérivé de purine et son utilisation médicale Download PDF

Info

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
Authority
WO
WIPO (PCT)
Prior art keywords
methyl
chloro
amino
dihydro
alkyl
Prior art date
Application number
PCT/CN2020/141859
Other languages
English (en)
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
Original Assignee
成都百裕制药股份有限公司
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 成都百裕制药股份有限公司 filed Critical 成都百裕制药股份有限公司
Publication of WO2021136461A1 publication Critical patent/WO2021136461A1/fr

Links

Classifications

    • 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.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Epidemiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention porte sur un dérivé de triazole et son utilisation médicale. Spécifiquement, la présente invention concerne un dérivé de pyrimidine représenté par la formule générale (I), ou un stéréoisomère de celui-ci, un solvate de celui-ci, un promédicament de celui-ci, un composé deutéré de celui-ci, un métabolite de celui-ci, un sel pharmaceutiquement acceptable ou un eutectique de celui-ci, une composition pharmaceutique le comprenant, et l'utilisation du composé ou de la composition dans le domaine de la préparation d'inhibiteurs d'ADN-PK, les définitions des substituants dans la formule générale (I) étant les mêmes que les définitions dans la description.
PCT/CN2020/141859 2019-12-31 2020-12-30 Dérivé de purine et son utilisation médicale WO2021136461A1 (fr)

Applications Claiming Priority (6)

Application Number Priority Date Filing Date Title
CN201911423498.1 2019-12-31
CN201911423498 2019-12-31
CN202010165176.8 2020-03-11
CN202010165176 2020-03-11
CN202010678867.8 2020-07-15
CN202010678867 2020-07-15

Publications (1)

Publication Number Publication Date
WO2021136461A1 true WO2021136461A1 (fr) 2021-07-08

Family

ID=76686510

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2020/141859 WO2021136461A1 (fr) 2019-12-31 2020-12-30 Dérivé de purine et son utilisation médicale

Country Status (2)

Country Link
CN (1) CN113121573A (fr)
WO (1) WO2021136461A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2022135555A1 (fr) * 2020-12-24 2022-06-30 江苏恒瑞医药股份有限公司 Composé de purinone, son procédé de préparation et son application pharmaceutique

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN116406272A (zh) * 2020-07-20 2023-07-07 首药控股(北京)股份有限公司 Dna-pk选择性抑制剂及其制备方法和用途
CN114249753A (zh) * 2020-09-22 2022-03-29 山东轩竹医药科技有限公司 三唑并吡啶类激酶抑制剂

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110177791A (zh) * 2016-12-20 2019-08-27 阿斯利康(瑞典)有限公司 氨基-三唑并吡啶化合物及其在治疗癌症中的用途
WO2019238929A1 (fr) * 2018-06-15 2019-12-19 Astrazeneca Ab Composés de purinone et leur utilisation dans le traitement du cancer

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
ME03336B (fr) * 2013-03-12 2019-10-20 Vertex Pharma Inhibiteurs d'adn-pk
KR102191256B1 (ko) * 2014-10-30 2020-12-15 강푸 바이오파마슈티칼즈 리미티드 이소인돌린 유도체, 이의 중간체, 제조방법, 약물 조성물 및 응용
WO2019201283A1 (fr) * 2018-04-20 2019-10-24 Xrad Therapeutics, Inc. Inhibiteurs doubles d'atm et d'adn-pk pour une utilisation en thérapie antitumorale
US20230026616A1 (en) * 2019-11-25 2023-01-26 Medshine Discovery Inc. Pyrimidoimidazole compounds used as dna-pk inhibitors
CN114573605A (zh) * 2020-12-01 2022-06-03 武汉光谷亚太医药研究院有限公司 Dna依赖蛋白激酶抑制剂及其应用

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110177791A (zh) * 2016-12-20 2019-08-27 阿斯利康(瑞典)有限公司 氨基-三唑并吡啶化合物及其在治疗癌症中的用途
WO2019238929A1 (fr) * 2018-06-15 2019-12-19 Astrazeneca Ab Composés de purinone et leur utilisation dans le traitement du cancer

Non-Patent Citations (2)

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

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2022135555A1 (fr) * 2020-12-24 2022-06-30 江苏恒瑞医药股份有限公司 Composé de purinone, son procédé de préparation et son application pharmaceutique

Also Published As

Publication number Publication date
CN113121573A (zh) 2021-07-16

Similar Documents

Publication Publication Date Title
EP3753941B1 (fr) Composé cyclique fusionné à une pyrimidine, son procédé de préparation et son application
WO2021136461A1 (fr) Dérivé de purine et son utilisation médicale
WO2021136462A1 (fr) Dérivés furane et leur application en médecine
WO2021209055A1 (fr) Dérivé d'imidazolinone et son utilisation en médecine
CN113121574B (zh) 嘌呤衍生物及其在医药上的用途
JP5579864B2 (ja) Ｎ−９−置換プリン化合物、組成物及び使用の方法
TW200902013A (en) Pyrimidyl cyclopentanes as AKT protein kinase inhibitors
WO2023025116A1 (fr) Dérivé hétérocyclique, son procédé de préparation et son utilisation en médecine
WO2021115457A9 (fr) Composé de pyrazolo[1,5-a]pyridine, son procédé de préparation et son utilisation
WO2020221294A1 (fr) Composé de 3,4-dihydro-pyrido[1,2-a]pyrazine-1,8-dione cyclique en pont et son utilisation pharmaceutique
WO2022247816A1 (fr) Composé hétérocyclique contenant de l'azote, son procédé de préparation et son application dans des médicaments
WO2022134641A1 (fr) Composé hétérocyclique aromatique, composition pharmaceutique et utilisation de celui-ci
WO2021249475A1 (fr) Dérivé de quinazoline condensé, son procédé de préparation et son application en médecine
KR20210129607A (ko) 3-아자바이사이클로알킬 유도체 및 이를 포함하는 약제학적 조성물
CN115477640A (zh) 作为parp7抑制剂的哒嗪酮类化合物
TW202214600A (zh) 嘧啶基衍生物、其製備方法及其用途
WO2020238776A1 (fr) Dérivé bicyclicque condensé substituté, son procédé de préparation et son application en médecine
WO2020192750A1 (fr) Dérivé thiénohétérocyclique, son procédé de préparation et son utilisation médicale
WO2020034987A1 (fr) Promédicament renfermant un dérivé de glucuronide en tant qu'inhibiteur jak, son procédé de préparation et ses applications
WO2022156779A1 (fr) Dérivé de pyrazolo[1,5-a]pyrimidine-7-amine substitué, et compositions et utilisation médicale de celui-ci
JP2021514999A (ja) タンパク質アルギニンメチルトランスフェラーゼの阻害剤としてのエタンジアミン−複素環誘導体
EP4141004A1 (fr) Dérivé amide polycyclique servant d'inhibiteur de cdk9, son procédé de préparation et son utilisation
AU2018417417A1 (en) Triptolide derivative and preparation method therefor and use thereof
CN116783183A (zh) 作为vhl抑制剂用于治疗贫血和癌症的1-(2-(4-环丙基-1h-1,2,3-三唑-1-基)乙酰基)-4-羟基-n-(苄基)吡咯烷-2-甲酰胺衍生物
WO2021088992A1 (fr) Composé spiro tétrahydroisoquinoléine en tant qu'inhibiteur de prmt5

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 20909813

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 20909813

Country of ref document: EP

Kind code of ref document: A1