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WO2020048347A1 - Composé hétérocyclique à cinq chaînons d'aminopyrimido, intermédiaire, procédé de préparation, composition pharmaceutique et utilisation de celui-ci - Google Patents

Composé hétérocyclique à cinq chaînons d'aminopyrimido, intermédiaire, procédé de préparation, composition pharmaceutique et utilisation de celui-ci Download PDF

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Publication number
WO2020048347A1
WO2020048347A1 PCT/CN2019/102678 CN2019102678W WO2020048347A1 WO 2020048347 A1 WO2020048347 A1 WO 2020048347A1 CN 2019102678 W CN2019102678 W CN 2019102678W WO 2020048347 A1 WO2020048347 A1 WO 2020048347A1
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substituted
membered heteroaryl
group
compound
halogen
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Chinese (zh)
Inventor
王玉光
张农
吴添智
吴新亮
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Shanghai Maxinovel Pharmaceuticals Co Ltd
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Shanghai Maxinovel Pharmaceuticals Co Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • 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
    • 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
    • C07D473/36—Sulfur atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • C07D491/048—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being five-membered

Definitions

  • the invention relates to an aminopyrimido five-membered heterocyclic compound, an intermediate thereof, a preparation method, a pharmaceutical composition and an application thereof.
  • Immune regulation is an important means for the body to maintain a stable internal environment and resist harmful external stimuli.
  • Adenosine as an important transmitter and modulator of the body, will increase significantly during metabolic disorders and cell damage, activate adenosine receptors to exert biological effects, and participate in the body's immune regulation.
  • Recent studies have shown that activation of adenosine A2A receptors can play an important role in immunoregulation during many pathological processes such as ischemia, hypoxia, inflammation, trauma, and transplantation. Nuclear macrophages, neutrophils, and other immune cells have higher expression levels (Su, Y., et.al., Cancer, Immunol, Immuno Ther., 2008, 57 (11), 1611-1623.).
  • Adenosine A2A receptor is one of the four adenosine receptors (A1, A2A, A2B, and A3) currently known. It belongs to the G protein coupled receptor family and is mainly coupled to Gs and G ⁇ proteins. It is widely distributed in the body, and is mainly expressed in the striatum in the central nervous system. A2A receptors are also expressed in the tissues of the heart, liver, lung, and kidney (Chu YY, et al., Biol, 1996, 15 (4), 329-337.).
  • adenosine A2A receptor antagonists play an increasingly important role in tumor immunotherapy.
  • the body can rely on a complete immune mechanism to effectively monitor and reject cancerous cells, such as: in terms of cellular immunity, T lymphocytes, antibody-dependent cytotoxic cells (K cells), NK cells and macrophages against tumors The cells are killing.
  • cancerous cells themselves or the functions of the above-mentioned immune cells change, they may escape the body's immune system and form malignant hyperplasia to form tumors.
  • adenosine A2A receptor can promote the body's immune tolerance, and closely participate in the formation of tumor cells' "immunity escape” or "immunosuppression", creating favorable conditions for tumorigenesis and development (Desai A., et al., Mol. Pharmacol., 2005, 67 (5), 1406-1413 .; Lokshin A., et al., Cancer Res, 2006, 66 (15), 7758-7765 .; Hoskin DW, et al., Int. J Oncol., 2008, 32 (3), 527-535 .; Deaglio S., et al., J. Exp. Med., 2007, 204 (6), 1257-1265.).
  • adenosine A2A receptor antagonists can inhibit the activation of adenosine A2A receptors, thereby preventing the body from developing immune tolerance, and ultimately affecting the growth of tumor cells, which has an anti-tumor effect.
  • the technical problem to be solved by the present invention is to fill the current market blank of adenosine A2A receptor antagonist drugs, thereby providing an aminopyrimido five-membered heterocyclic compound, its intermediate, preparation method, pharmaceutical composition and application.
  • the aminopyrimido five-membered heterocyclic compound provided by the invention has obvious antagonistic effect on adenosine A2A receptor, and it can be used as adenosine A2A receptor antagonist, which can effectively alleviate or treat immune tolerance, central nervous system disease and inflammatory Related diseases.
  • the present invention provides a compound represented by Formula I, which is a pharmaceutically acceptable salt, deuterate, tautomer, cis-trans isomer, enantiomer, diastereomer or Prodrugs:
  • Stands for single or double bond Represents a single key
  • W is N or CR 5 ;
  • R 5 is H, deuterium or methyl;
  • W is C
  • the double bond is Z configuration, E configuration, or a mixture of Z configuration and E configuration
  • X is O, CO or NR 3 ;
  • Y is CO, CH 2 or NR 4 ;
  • R 1 is a substituted or unsubstituted C 6 -C 20 aryl group or a substituted or unsubstituted 5-10 membered heteroaryl group;
  • R 1 is a substituted C 6 -C 20 aryl group or a substituted 5-10 membered heteroaryl group, the number of substituents is one or more, and each substituent is independently halogen or C 1 -C 10 alkyl;
  • R 2 is a substituted or unsubstituted C 6 -C 20 aryl group or a substituted or unsubstituted 5-10 membered heteroaryl group;
  • R 2 is a substituted C 6 -C 20 aryl group or a substituted 5-10 membered heteroaryl group
  • the number of substituents is one or more, and each substituent is independently halogen, C 1 -C 10 Alkyl, C 1 -C 10 alkoxy, C 1 -C 10 alkyl mercapto, halogen substituted C 1 -C 10 alkyl, oxo, hydroxyl, amino, Cyano, halogen-substituted C 1 -C 10 alkoxy or halogen-substituted C 1 -C 10 alkylmercapto; wherein R a and R b are each independently hydrogen or C 1 -C 10 alkyl, R c is C 1- C 10 alkyl;
  • R 3 is H, C 1 -C 10 alkyl or C 3 -C 10 cycloalkyl
  • R 4 is H, C 1 -C 10 alkyl or C 3 -C 10 cycloalkyl
  • the number of heteroatoms in the 5- to 10-membered heteroaryl group is 1, 2, 3, or 4, and each heteroatom is independently O, N, or S;
  • I in the compound represented by formula I, Is a double bond; X is O or NR 3 , and Y is CO.
  • X is O or NR 3 , preferably NR 3 ;
  • Y is CO
  • R 3 is H, C 1 -C 10 alkyl or C 3 -C 10 cycloalkyl
  • R 1 is a substituted or unsubstituted 5-10 membered heteroaryl group
  • R 1 is a substituted 5-10 membered heteroaryl group, the number of substituents is one or more, and each substituent is independently halogen or C 1 -C 10 alkyl;
  • R 2 is a substituted or unsubstituted C 6 -C 20 aryl group
  • R 2 is a substituted C 6 -C 20 aryl group
  • the number of substituents is one or more, and each substituent is independently halogen, C 1 -C 10 alkyl, C 1 -C 10 alkoxy Radical, halogen-substituted C 1 -C 10 alkyl or halogen-substituted C 1 -C 10 alkoxy;
  • the number of heteroatoms in the 5-10 membered heteroaryl group is 1, 2, 3 or 4, and each heteroatom is independently O, N or S.
  • the C 1 -C 10 alkyl may be C 1 -C 4 alkyl, such as methyl, ethyl Propyl, isopropyl or n-propyl, such as methyl, ethyl or n-propyl, preferably methyl.
  • the C 3 -C 10 cycloalkyl group may be a C 3 -C 6 cycloalkyl group, such as a cyclo Propyl.
  • the C 1 -C 10 alkyl may be C 1 -C 4 alkyl, such as methyl.
  • the C 3 -C 10 cycloalkyl group may be a C 3 -C 6 cycloalkyl group, such as a cyclo Propyl.
  • R 4 is H or C 1 -C 10 alkyl.
  • the C 6 -C 20 aryl group may be a C 6 -C 10 aryl group, Such as phenyl.
  • the 5-10 membered heteroaryl group when R 1 is a substituted or unsubstituted 5-10 membered heteroaryl group, the 5-10 membered heteroaryl group may be a 5-membered heteroaryl group or a 6-membered Heteroaryl is preferably a 5-membered heteroaryl.
  • the number of heteroatoms in the 5-10 membered heteroaryl group may be one or two.
  • Examples of the 5-membered heteroaryl group are furyl (such as furan-2-yl), thiazolyl (such as thiazol-4-yl), and pyrazolyl (such as pyrazol-3-yl).
  • the 6-membered heteroaryl group is, for example, pyridyl (such as pyridin-2-yl).
  • R 1 when R 1 is a substituted C 6 -C 20 aryl group or a substituted 5-10 membered heteroaryl group, the number of the substituents may be 1, 2, 3 or Four, such as one or two, such as one.
  • the halogen may be fluorine, Chlorine, bromine or iodine, such as chlorine or bromine (for example, chlorine).
  • R 1 is a substituted C 6 -C 20 aryl group or a substituted 5-10 membered heteroaryl group, and the substituent is a C 1 -C 10 alkyl group
  • the C 1 -C 10 alkyl may be a C 1 -C 4 alkyl, such as methyl.
  • the C 6 -C 20 aryl group may be a C 6 -C 10 aryl group, Such as phenyl.
  • the 5-10 membered heteroaryl group when R 2 is a substituted or unsubstituted 5-10 membered heteroaryl group, the 5-10 membered heteroaryl group may be a 5 membered heteroaryl group or a 6 membered member Heteroaryl, such as 6-membered heteroaryl.
  • the number of heteroatoms in the 5-10 membered heteroaryl group may be one or two.
  • the 6-membered heteroaryl group is, for example, pyridyl (such as pyridin-4-yl).
  • R 2 when R 2 is a substituted C 6 -C 20 aryl group or a substituted 5-10 membered heteroaryl group, the number of substituents may be 1, 2, 3 or Four, such as one or two.
  • the halogen may be fluorine, Chlorine, bromine or iodine, such as fluorine or chlorine (such as fluorine).
  • R 2 is a substituted C 6 -C 20 aryl group or a substituted 5-10 membered heteroaryl group, and the substituent is a C 1 -C 10 alkyl group
  • the C 1 -C 10 alkyl may be a C 1 -C 4 alkyl, such as methyl.
  • R 2 is a substituted C 6 -C 20 aryl group or a substituted 5-10 membered heteroaryl group, and the substituent is a C 1 -C 10 alkoxy group
  • the C 1 -C 10 alkoxy group may be a C 1 -C 4 alkoxy group, such as a methoxy group.
  • R 2 is a substituted C 6 -C 20 aryl group or a substituted 5-10 membered heteroaryl group, and the substituent is a C 1 -C 10 alkylthiol group
  • the C 1 -C 10 alkyl mercapto group may be a C 1 -C 4 alkyl mercapto group, such as methyl mercapto.
  • R 2 is a substituted C 6 -C 20 aryl group or a substituted 5-10 membered heteroaryl group
  • the substituent is a halogen substituted C 1 -C 10 alkyl group
  • the "halogen-substituted C 1 -C 10 alkyl" C 1 -C 10 alkyl group may be a C 1 -C 4 alkyl such as methyl.
  • the number of halogens in the "halogen-substituted C 1 -C 10 alkyl" may be 1-5, such as 1, 2 or 3; when the number of halogens is multiple, the halogen Same or different.
  • the halogen in the "halogen-substituted C 1 -C 10 alkyl” may be fluorine, chlorine, bromine or iodine, such as fluorine.
  • the "halogen-substituted C 1 -C 10 alkyl group” may be -CF 3 .
  • R 2 when R 2 is a substituted C 6 -C 20 aryl group or a substituted 5-10 membered heteroaryl group, the substituent is R a and R b may each independently be hydrogen or C 1 -C 3 alkyl, such as for
  • R 2 when R 2 is a substituted C 6 -C 20 aryl group or a substituted 5-10 membered heteroaryl group, the substituent is In this case, R c may be C 1 -C 4 alkyl, such as methyl.
  • R 2 when R 2 is a substituted C 6 -C 20 aryl group or a substituted 5-10 membered heteroaryl group, the substituent is a halogen-substituted C 1 -C 10 alkoxy group.
  • the "halogen-substituted C 1 -C 10 alkoxy" when the "halogen-substituted C 1 -C 10 alkoxy" are C 1 -C 10 alkoxy group may be C 1 -C 4 alkoxy, such as methoxy.
  • the number of halogens in the "halogen-substituted C 1 -C 10 alkoxy group" may be 1-5, such as 1, 2 or 3; when the number of halogens is multiple, the The halogens are the same or different.
  • the halogen in the "halogen-substituted C 1 -C 10 alkoxy group” may be fluorine, chlorine, bromine or iodine, such as fluorine.
  • the "halogen-substituted C 1 -C 10 alkoxy group” may be -OCHF 2 or -OCF 3 .
  • C 1 -C 10 alkylmercapto may be C 1 -C 4 alkylmercapto, for example methylmercapto.
  • the number of halogens in the "halogen-substituted C 1 -C 10 alkylthiol group” may be 1-5, such as 1, 2 or 3; when the number of halogens is multiple, the halogen Same or different.
  • the halogen in the "halogen-substituted C 1 -C 10 alkylthiol group” may be fluorine, chlorine, bromine or iodine, such as fluorine.
  • the substituent when R 2 is a substituted C 6 -C 20 aryl group or a substituted 5-10 membered heteroaryl group, the substituent may be Halogen, C 1 -C 10 alkyl, halogen substituted C 1 -C 10 alkyl, oxo, Cyano, or halogen-substituted C 1 -C 10 alkoxy.
  • R 2 when R 2 is a substituted C 6 -C 20 aryl group or a substituted 5-10 membered heteroaryl group, the substituent is fluorine , Chlorine, methyl, -CF 3 , oxo, Cyano, -OCHF 2 or -OCF 3 .
  • R 1 may be Preferably More preferably
  • R 2 may be Preferably
  • R 2 in the compound represented by formula I, R 2 may be
  • R 2 is preferably Wherein R 13 is H or halogen (for example, fluorine or chlorine, and also fluorine), R 11 , R 12 , R 14 and R 15 are each independently H, halogen (for example, fluorine or chlorine, and also fluorine), halogen-substituted C 1 -C 10 alkyl (for example -CF 3 ) or halogen-substituted C 1 -C 10 alkoxy (for example -OCHF 2 or -OCF 3 ); said halogen, "halogen-substituted C 1 -C 10
  • the definitions of "alkyl” and “halogen-substituted C 1 -C 10 alkoxy" are as described in "Definition of Substitution in R 2 above". More preferably, at least two of R 11 , R 12 , R 14 and R 15 are H.
  • X is NR 3 and Y is CO; Is a double bond
  • R 3 is H, C 1 -C 10 alkyl or C 3 -C 10 cycloalkyl
  • R 2 is The definitions of R 11 , R 12 , R 13 , R 14 and R 15 are as described above.
  • R 11 , R 12 , R 14 and R 15 are each independently H, halogen or halogen-substituted C 1 -C 10 alkyl.
  • R 12 and R 14 are each independently H or halogen.
  • R 11 is H, halogen or halogen-substituted C 1 -C 10 alkyl, and R 15 is hydrogen.
  • R 11 is hydrogen or halogen
  • R 12 , R 13 , R 14 and R 15 are all hydrogen.
  • R 11 is halogen or halogen-substituted C 1 -C 10 alkyl, and R 12 , R 13 , R 14 and R 15 are all hydrogen.
  • X is NR 3 and Y is CO; Is a double bond
  • R 3 is H, C 1 -C 10 alkyl or C 3 -C 10 cycloalkyl
  • R 2 is The definitions of R 11 , R 12 , R 13 , R 14 and R 15 are as described above.
  • R 11 , R 12 , R 14 and R 15 are each independently H, halogen, halogen-substituted C 1 -C 10 alkyl or halogen-substituted C 1 -C 10 alkoxy.
  • R 12 and R 14 are each independently H or halogen.
  • R 11 is H, halogen, halogen-substituted C 1 -C 10 alkyl or halogen-substituted C 1 -C 10 alkoxy
  • R 15 is hydrogen.
  • R 11 is hydrogen or halogen
  • R 12 , R 13 , R 14 and R 15 are all hydrogen.
  • X is NR 3 and Y is CO; Is a double bond
  • R 3 is methyl
  • R 2 is The definitions of R 11 , R 12 , R 13 , R 14 and R 15 are as described above.
  • R 11 , R 12 , R 14 and R 15 are each independently H, halogen, halogen-substituted C 1 -C 10 alkyl or halogen-substituted C 1 -C 10 alkoxy.
  • R 12 and R 14 are each independently H or halogen.
  • R 11 is H, halogen, halogen-substituted C 1 -C 10 alkyl or halogen-substituted C 1 -C 10 alkoxy
  • R 15 is hydrogen.
  • R 11 is hydrogen or halogen
  • R 12 , R 13 , R 14 and R 15 are all hydrogen.
  • X is NR 3 and Y is CO; Is a double bond
  • R 3 is C 3 -C 10 cycloalkyl (such as cyclopropyl);
  • R 2 is The definitions of R 11 , R 12 , R 13 , R 14 and R 15 are as described above.
  • R 11 , R 12 , R 14 and R 15 are each independently H, halogen, halogen-substituted C 1 -C 10 alkyl or halogen-substituted C 1 -C 10 alkoxy.
  • R 12 and R 14 are each independently H or halogen.
  • R 11 is H, halogen, halogen-substituted C 1 -C 10 alkyl or halogen-substituted C 1 -C 10 alkoxy
  • R 15 is hydrogen.
  • R 11 is hydrogen, halogen or halogen-substituted C 1 -C 10 alkoxy
  • R 12 , R 13 , R 14 and R 15 are all hydrogen.
  • the compound represented by formula I is selected from any one of the following structures:
  • the present invention also provides a method for preparing a compound represented by the formula I as described above, which comprises the following steps: in an organic solvent, the compound represented by the formula IA is subjected to an affinity reaction as shown below A nuclear substitution reaction to obtain the compound represented by formula I,
  • X 1 is a halogen (for example, F, Cl, Br, or I, and also Cl) or a C 1 -C 4 alkyl-substituted sulfone group ( (Eg, methylsulfone).
  • the conditions of the nucleophilic substitution reaction may be the conventional conditions for such reactions in the art.
  • the present invention is preferably as follows: the organic solvent can be a conventional organic solvent for such reactions in the art, and an ether solvent is preferred.
  • the ether-based solvent is preferably tetrahydrofuran.
  • the amount of the organic solvent used is not particularly limited as long as it does not affect the progress of the reaction.
  • the amination reagent may be a conventional amination reagent for such reactions in the art, preferably ammonia water or an alcohol solution of ammonia (for example, a methanol solution of ammonia).
  • the molar concentration of the ammonia alcohol solution is preferably 5.0 mol / L to 10.0 mol / L (for example, 7.0 mol / L).
  • the amount of the amination reagent may not be specifically limited, as long as it does not affect the progress of the reaction, and generally, it is a conventional amount of such reactions in the art.
  • the temperature of the nucleophilic substitution may be a temperature conventional for such reactions in the art, for example, 10 ° C-40 ° C.
  • the progress of the nucleophilic substitution reaction can be monitored by conventional detection methods in the art (such as TLC, HPLC, GC, or HNMR, etc.), and generally the end point of the reaction is when the compound represented by Formula I-A is no longer reacted.
  • the nucleophilic substitution reaction may further include a post-processing operation.
  • the post-processing operation may be a conventional post-processing method in the field of organic synthesis.
  • the present invention preferably includes the following steps: the reaction solution after the nucleophilic substitution reaction is completed, after performing solid-liquid separation (preferably concentrated under reduced pressure), and purified by column chromatography (column chromatography conditions can be routinely selected according to TLC conditions) .
  • the invention also provides a compound represented by formula I-A:
  • X, Y, W, R 1 and R 2 are as defined above;
  • X 1 is a halogen (e.g. F, Cl, Br or I, such as Cl) or a C 1 -C 4 alkyl-substituted sulfone group (e.g. Methylsulfone);
  • the compound represented by formula I-A may be selected from any one of the following structures:
  • the method for preparing the compound represented by Formula IA may include the following steps: In an organic solvent, the compound represented by Formula IB and an oxidant are subjected to an oxidation reaction as shown below to obtain the compound represented by Formula IA. Shown compounds, that is;
  • X, Y, W, R 1 and R 2 have the same definitions as above.
  • X 2 is a C 1 -C 4 alkyl-substituted mercapto (such as methyl mercapto), and X 1 is C 1 -C 4 alkyl-substituted.
  • Sulfone such as methylsulfone).
  • the conditions of the oxidation reaction may be conventional conditions for such reactions in the art.
  • the present invention is preferably as follows: the organic solvent may be a conventional organic solvent for such reactions in the art, and a chlorinated hydrocarbon solvent is preferred.
  • the chlorinated hydrocarbon solvent is preferably dichloromethane.
  • the amount of the organic solvent used is not particularly limited as long as it does not affect the progress of the reaction.
  • the oxidant may be a conventional oxidant of this type of reaction in the art, such as m-chloroperoxybenzoic acid.
  • the amount of the oxidizing agent may not be specifically limited, as long as it does not affect the progress of the reaction, and generally, it is a conventional amount of such reactions in the art.
  • the temperature of the nucleophilic substitution may be a temperature conventional for such reactions in the art, for example, 10 ° C-40 ° C.
  • the progress of the nucleophilic substitution reaction can be monitored by conventional detection methods in the art (for example, TLC, HPLC, GC, HNMR, etc.), and generally the end point of the reaction is when the compound represented by Formula I-B is no longer reacted.
  • the method for preparing the compound represented by Formula IB may include the following steps: in an organic solvent, reacting the compound represented by Formula IC with R 2 -CHO in the presence of a base to obtain the following: The compound represented by the formula IB is sufficient;
  • the reaction conditions may be conventional conditions for reactions of this type in the field of organic synthesis.
  • the present invention is preferably as follows: the organic solvent may be a conventional organic solvent for such reactions in the art, preferably an alcoholic solvent (such as ethanol).
  • the amount of the organic solvent used is not particularly limited as long as it does not affect the progress of the reaction.
  • the base may be a base conventional for this type of reaction in the art, such as DBU (1,8-diazabicycloundec-7-ene).
  • the amount of the base is a conventional amount for such reactions in the art.
  • the ratio of the amount of the compound represented by Formula IC to R 2 -CHO may be a conventional ratio of this type of reaction in the art.
  • the reaction temperature may be a temperature conventional for such reactions in the art, for example, 50 ° C to 90 ° C.
  • the progress of the reaction can be monitored by conventional detection methods in the art (such as TLC, HPLC, GC or HNMR, etc.), and generally the end point of the reaction is when the compound represented by Formula IC is no longer reacted.
  • the compound represented by the formula IB prepared by the method for preparing a compound represented by the formula IB as described above is generally a mixture of the Z configuration and the E configuration.
  • the structure of the compound represented by Formula IC and R 2 -CHO are changed, the following situations may occur: the content of the E configuration and the Z configuration in the product is not much different; there may be some dominant configuration, and the product The contents of the E configuration and the Z configuration are quite different.
  • the compounds of the Z configuration and the E configuration as shown in Formula IB can be separated by conventional separation methods in the art, such as silica gel column chromatography or preparative liquid chromatography.
  • the mixture of the compounds represented by formula IB in the Z configuration and the E configuration can also be directly subjected to the next step of the reaction and left for subsequent steps for separation.
  • the content of the E configuration and the Z configuration in the product is relatively large, a product with a less content configuration can be obtained by enlarging the reaction amount.
  • the compound obtained by the above method can also refer to the related methods disclosed in the examples, and further modify the peripheral position to obtain other target compounds of the present invention.
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising the compound represented by Formula I as described above, a pharmaceutically acceptable salt, deuterate, tautomer, cis-trans isomer, enantiomer Isomers, diastereomers or prodrugs, and pharmaceutically acceptable carriers.
  • the compound represented by Formula I its pharmaceutically acceptable salt, deuterate, tautomer, cis-trans isomer, enantiomer
  • the content of diastereomers or prodrugs is a therapeutically effective amount.
  • the present invention also provides a compound represented by formula I, which is a pharmaceutically acceptable salt, deuterate, tautomer, cis-trans isomer, enantiomer, diastereomer Isomers or prodrugs, or the pharmaceutical composition, for use in the preparation of adenosine A2A receptor antagonists.
  • the present invention also provides a method for inhibiting adenosine A2A receptor, which comprises an effective amount of said compound represented by formula I, a pharmaceutically acceptable salt thereof, a deuterate, a tautomer, A cis-trans isomer, an enantiomer, a diastereomer or a prodrug, or the pharmaceutical composition is contacted with an adenosine A2A receptor, and the contact is performed in vivo or in vitro.
  • the present invention also provides a compound represented by formula I, which is a pharmaceutically acceptable salt, deuterate, tautomer, cis-trans isomer, enantiomer, diastereomer Isomers or prodrugs, or the use of said pharmaceutical composition in the manufacture of a medicament for the prevention, alleviation and / or treatment of related diseases caused by adenosine A2A receptors.
  • the present invention also provides a method for preventing, alleviating and / or treating related diseases caused by adenosine A2A receptor, which comprises administering to a patient in need thereof a therapeutically effective amount of said compound represented by formula I , Pharmaceutically acceptable salts, deuterates, tautomers, cis-trans isomers, enantiomers, diastereomers or prodrugs thereof, or said pharmaceutical composition.
  • the related diseases caused by the adenosine A2A receptor include central nervous system diseases, immune tolerance diseases, and inflammatory diseases.
  • the present invention also provides a compound represented by formula I, which is a pharmaceutically acceptable salt, deuterate, tautomer, cis-trans isomer, enantiomer, diastereomer Isomers or prodrugs, or the use of said pharmaceutical composition in the preparation of a medicament for the prevention, alleviation and / or treatment of central nervous system diseases, immune tolerance diseases or inflammatory diseases.
  • the present invention also provides a method for preventing, relieving and / or treating central nervous system disease, immune tolerance disease or inflammatory disease, which comprises administering a therapeutically effective amount of said formula I to a patient in need thereof.
  • the compound shown its pharmaceutically acceptable salt, deuterate, tautomer, cis-trans isomer, enantiomer, diastereomer or prodrug, or said drug combination.
  • the central nervous system diseases include Parkinson's disease, Alzheimer's disease, depression, schizophrenia, epilepsy and Huntington's disease.
  • the immune tolerance diseases include organ transplant rejection and tumor.
  • the tumors include bone marrow fibrosis, hematomas (such as leukemia, lymphoma, etc.) and solid tumors (such as kidney cancer, liver cancer, stomach cancer, lung cancer, breast cancer, prostate cancer, pancreatic cancer, thyroid cancer, ovarian cancer, glia). Blastoma, skin cancer, melanoma, etc.).
  • the inflammatory diseases include acute inflammatory diseases such as pneumonia, hepatitis, nephritis, myocarditis, and sepsis, and chronic inflammatory diseases such as arthritis, asthma, and atherosclerosis.
  • the pharmaceutical composition described in the present invention may be in a form suitable for oral administration or in the form of a sterile injectable aqueous solution, and the oral or injectable composition may be prepared according to any method known in the art for preparing a pharmaceutical composition.
  • the pharmaceutical composition described in the present invention can be used in combination with one or more chemotherapeutic drugs and / or targeted drugs used clinically, which can be made into a single dosage form, especially a lipid, in any suitable ratio according to the conventional methods in the art. Liposomal dosage form to treat various tumor diseases.
  • alkyl refers to branched and straight-chain saturated aliphatic hydrocarbon groups including 1-20 carbon atoms (preferably 1-10 carbon atoms, more preferably 1- 8 carbon atoms), such as methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, 4,4-dimethylpentyl, 2,2,4-trimethylpentyl, undecyl, dodecyl, and various isomers thereof.
  • cycloalkyl refers to the inclusion of saturated or partially unsaturated (containing 1 or 2 double bonds, but none of which has a fully conjugated ⁇ -electron system) 1, 2 or 3 ring cyclic hydrocarbon groups, including monocyclic alkyl, bicycloalkyl, and tricyclic alkyl groups, which contain 3-20 ring-forming carbons, preferably 3-10 carbons, For example: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecane, cyclododecyl, cyclohexenyl and the like.
  • aryl refers to any stable monocyclic or bicyclic carbocyclic ring that can be up to 7 atoms in each ring, at least one of which is an aromatic ring.
  • aryl units include phenyl, naphthyl, tetrahydronaphthyl, 2,3-dihydroindenyl, biphenyl, phenanthryl, anthracenyl, or acenaphthyl. It can be understood that in the case where the aryl substituent is a bicyclic substituent and one of the rings is a non-aromatic ring, the connection is performed through the aromatic ring.
  • heteroaryl (including when used alone and contained in other groups) means a stable monocyclic or bicyclic ring of up to 7 atoms in each ring, at least one of which is an aromatic ring and contains 1, 2, 3 Or 4 heteroatoms selected from O, N and S.
  • heteroaryl when heteroaryl is a 5-membered heteroaryl containing 1 heteroatom, including furyl, thienyl, and pyrrolyl; when heteroaryl is a 5-membered heteroaryl containing 2 heteroatoms, including pyr Oxazolyl, thiazolyl, and oxazolyl.
  • Heteroaryl groups within the scope of this definition include, but are not limited to: acridinyl, carbazolyl, fluorinyl, quinoxalinyl, pyrazolyl, indolyl, benzotriazolyl, furanyl, thienyl , Benzothienyl, benzofuranyl, quinolinyl, isoquinolinyl, oxazolyl, isoxazolyl, indolyl, pyrazinyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, Tetrahydroquinoline.
  • heteroaryl should also be understood to include N-oxide derivatives of any nitrogen-containing heteroaryl.
  • heteroaryl substituent is a bicyclic substituent and one ring is a non-aromatic ring or does not contain a heteroatom, it can be understood that the connection is performed through an aromatic ring or a heteroatom containing a ring, respectively.
  • alkoxy means a cyclic or acyclic alkyl group having the stated number of carbon atoms connected by an oxygen bridge.
  • alkoxy includes the above definitions of alkyl and cycloalkyl.
  • oxo refers to a case where an oxygen atom is directly substituted for a carbon atom or a nitrogen atom, for example, a carbonyl group is formed with a carbon atom, and a nitrogen oxide is formed with a nitrogen atom.
  • halogen means fluorine, chlorine, bromine, iodine, or astatine.
  • hydroxy means -OH.
  • amino means -NH 2.
  • alkylmercapto means -S-alkyl.
  • cyano means -CN.
  • terapéuticaally effective amount refers to an amount of a compound sufficient to effectively treat a disease or disorder described herein when administered to a subject. Although the amount of a compound that constitutes a “therapeutically effective amount” will vary depending on the compound, the disorder and its severity, and the age of the subject to be treated, it can be determined in a conventional manner by one skilled in the art.
  • salt, pharmaceutical composition, composition, excipient, etc. is generally non-toxic, safe, and Suitable for use by a subject, preferably a mammalian subject, and more preferably a human subject.
  • salts refers to a pharmaceutically acceptable organic or inorganic salt of a compound of the invention.
  • Exemplary salts include, but are not limited to: sulfate, citrate, acetate, oxalate, chloride, bromide, iodide, nitrate, hydrogen sulfate, phosphate, acid phosphate, isonicotinic acid Salt, lactate, salicylate, acid citrate, tartrate, oleate, tannin, pantothenate, tartrate, ascorbate, succinate, maleate, dragon Genisinate, fumarate, gluconate, glucuronide, gluconate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonic acid Salts, benzenesulfonates, p-toluenesulfonates and parabens (ie 1-methylene-bis (2-hydroxy-3-naphtho
  • prodrug refers to a derivative of a compound containing a biologically reactive functional group such that under biological conditions (in vitro or in vivo), the biologically reactive functional group can be cleaved from the compound or otherwise react to provide the Mentioned compound.
  • a prodrug is inactive, or at least less active than the compound itself, so that its activity cannot be exerted until the compound is cleaved from a biologically reactive functional group.
  • Bioreactive functional groups can be hydrolyzed or oxidized under biological conditions to provide the compounds.
  • a prodrug may include a biohydrolyzable group.
  • biohydrolyzable groups include, but are not limited to, biohydrolyzable phosphates, biohydrolyzable esters, biohydrolyzable amides, biohydrolyzable carbonates, biohydrolyzable carbamates, and biohydrolyzable Ureide.
  • stereoisomers refers to the cis- (Z) and trans-isomers (E), R- and S-enantiomers and diastereomers. These stereoisomers can be prepared by asymmetric synthesis or chiral separation (for example, separation, crystallization, thin-layer chromatography, column chromatography, gas chromatography, high-performance liquid chromatography). These stereoisomers may also be derived from diastereomers in which a mixture of enantiomers or racemates is reacted with an appropriate chiral compound, and then obtained by crystallization or any other suitable conventional method.
  • the term "deuterate” means that the abundance of deuterium in a certain (or some) hydrogen atom in a molecule is greater than its natural abundance, up to 100%. Deuterates can generally retain the activity equivalent to undeuterated compounds, and can achieve better metabolic stability when deuterated at certain sites, thereby obtaining certain therapeutic advantages (such as increased half-life in the body or reduced dose requirements) ), So deuterates are preferred in some cases.
  • the deuterated product of the present invention can generally be prepared by using a suitable deuterated reagent instead of a non-deuterated reagent according to the preparation method described in the present invention or the method disclosed in the examples.
  • the configuration of the connected double bond is the Z configuration, the E configuration, or a mixture thereof.
  • room temperature means 10-40 ° C.
  • the reagents and raw materials used in the present invention are all commercially available.
  • the compounds of the present invention have obvious antagonistic effects on adenosine A2A receptors, and can be used as adenosine A2A receptor antagonists to effectively alleviate or treat related diseases such as immune tolerance, central nervous system diseases, and inflammatory diseases.
  • the structure of the compound was determined by nuclear magnetic resonance (NMR) or mass spectrometry (MS).
  • the nuclear magnetic resonance spectrum was obtained by Bruker Avance-500 instrument. Deuterated dimethyl sulfoxide, deuterated chloroform and deuterated methanol were used as solvents. Tetramethyl Silane (TMS) is the internal standard. Mass spectra were obtained by a liquid chromatography-mass spectrometer (LC-MS) Agilent 6110, using an ESI ion source.
  • the microwave reaction was performed in an Explorer full-automatic microwave synthesizer produced by CEM Corporation in the United States.
  • the magnetron frequency was 2450 MHz and the continuous microwave output power was 300 W.
  • the instrument used for HPLC preparation was Gilson 281, and the preparative column used was Xbridge, 21.2x250mm C18, 10 ⁇ m.
  • compound 2-d (450 mg, 1.63 mmol) was dissolved in anhydrous tetrahydrofuran (20 mL). To the reaction solution was added dropwise a 1.0 M solution of benzylmagnesium bromide in tetrahydrofuran (1.95 mL, 1.95 mmol) at -78 ° C under the protection of nitrogen. After the dropwise addition was complete, the cooling device was removed, the reaction system was allowed to slowly rise to room temperature, and stirring was continued for 16 hours. A saturated ammonium chloride solution (20 mL) was added, and the mixture was extracted with ethyl acetate (50 mL ⁇ 2).
  • compound 26-d (642 mg, 3.1 mmol) was dissolved in anhydrous tetrahydrofuran (20 mL), and zinc powder (203 mg, 3.1 mmol) and 2,4-difluorobenzyl bromide (300 mg, 1.03) were added to the reaction solution. mmol).
  • the reaction mixture was raised to 55 ° C and stirred for 1 hour.
  • a saturated ammonium chloride solution (20 mL) was added to quench the reaction.
  • the mixture was extracted with ethyl acetate (50 mL ⁇ 2), and the organic phases were combined, washed with water (50 mL) and saturated brine (50 mL), and dried over anhydrous sodium sulfate.
  • Methylamine hydrochloride (680 mg, 10.0 mmol) and sodium acetate (820 mg, 10.0 mmol) were added to methanol (30 mL). After the mixture was stirred at room temperature for 1 hour, the ice-water bath was cooled to 5 ° C, and then compound 38-d (980 mg, 3.35 mmol) and dichloromethane (30 mL) were added. After stirring for 30 minutes, sodium cyanoborohydride (315 mg, 5.0 mmol) was added, and the reaction mixture was warmed to room temperature and stirred for 16 hours. It was concentrated under reduced pressure, and the residue was diluted with water (100 mL), and extracted with dichloromethane (50 mL ⁇ 2).
  • 1,8-Diazabicycloundec-7-ene 60 mg, 0.4 mmol was added to the compound 38-c (261 mg, 1.0 mmol) and o-fluorobenzaldehyde (248 mg, 2.0 mmol) in dioxane (20 mL) solution.
  • the mixture was refluxed under nitrogen for 16 hours, and then cooled to room temperature. It was concentrated under reduced pressure, and the residue was washed with ethyl acetate (20 mL ⁇ 3), and filtered to obtain 38-b (153 mg, yield: 41%) as a brown solid. This product did not require further purification.
  • LC-MS (ESI): m / z 368 [M + H] + .
  • the compound 38-c and o-trifluoromethoxybenzaldehyde were used as raw materials.
  • the synthesis method was the same as that in Example 38.
  • the residue is subjected to high performance liquid chromatography (mobile phase: water (10 mM ammonium bicarbonate), Acetonitrile; gradient: 30% -60% (the initial mobile phase is 30% water-70% acetonitrile, and the mobile phase at the end is 60% water-40% acetonitrile, where% refers to volume percentage), after purification, 47 (8mg , Yield: 4.9%).
  • mobile phase water (10 mM ammonium bicarbonate), Acetonitrile; gradient: 30% -60% (the initial mobile phase is 30% water-70% acetonitrile, and the mobile phase at the end is 60% water-40% acetonitrile, where% refers to volume percentage)
  • Methylamine hydrochloride (1.76 g, 26.1 mmol) and sodium acetate (3.56 g, 26.1 mmol) were added to methanol (30 mL). After the mixture was stirred at room temperature for 1 hour, the ice-water bath was cooled to 0 ° C, and then compound 48-d (2.0 g, 6.5 mmol) and dichloromethane (10 mL) were added. After stirring for 30 minutes, sodium cyanoborohydride (0.61 g, 9.8 mmol) was added, and the reaction mixture was warmed to room temperature and stirred for another 12 hours. It was concentrated under reduced pressure, the residue was diluted with water (100 mL), and extracted with dichloromethane (50 mL ⁇ 2).
  • triphosgene 24 mg, 0.08 mmol was added to a solution of 60-b (98 mg, 0.16 mmol) and triethylamine (50 mg, 0.48 mmol) in dry tetrahydrofuran (5 mL), and the mixture was stirred for 10 minutes and raised to Stirring was continued for 3 hours at room temperature.
  • the reaction solution was concentrated under reduced pressure, and the residue was diluted with water (5 mL), filtered, and the filter cake was dried under vacuum to obtain a light brown solid 60-a (98 mg, yield: 96%). This product did not require further purification.
  • triphosgene 63 mg, 0.21 mmol was added to a solution of 34-b (110 mg, 0.17 mmol) and diisopropylethylamine (0.5 mL, 2.65 mmol) in dry tetrahydrofuran (15 mL) and stirred for 10 minutes After warming to room temperature, stirring was continued for 2 hours.
  • the reaction solution was concentrated under reduced pressure to obtain 61-b (137 mg, yield: 61%) as a yellow oil, which was obtained without further purification.
  • Ethylamine hydrochloride (1.06 g, 13.07 mmol) and sodium acetate (1.18 g, 13.07 mmol) were added to methanol (30 mL). After the mixture was stirred at room temperature for 1 hour, the ice-water bath was cooled to 0 ° C, and then compound 62-d (1.0 g, 3.27 mmol) and dichloromethane (10 mL) were added. After stirring for 30 minutes, sodium cyanoborohydride (0.31 g, 4.9 mmol) was added, and the reaction mixture was warmed to room temperature and stirred for another 12 hours.
  • Acetic acid (1.06 g, 16.6 mmol) was slowly added dropwise to a mixed solvent of cyclopropylamine (950 mg, 16.6 mmol) and compound 62-d (1.7 g, 5.55 mmol) in methanol (10 mL) and dichloromethane (30 mL). The mixture was stirred at room temperature for 2 hours, and sodium cyanoborohydride (520 mg, 8.25 mmol) was added in portions. The reaction mixture was stirred at room temperature for 12 hours. The reaction solution was diluted with water (100 mL), and extracted with dichloromethane (50 mL ⁇ 3). The combined organic phases were washed with water (100 mL) and saturated brine (100 mL).
  • Methylamine hydrochloride (882 mg, 13.0 mmol) and sodium acetate (1.76 g, 13.0 mmol) were added to methanol (50 mL). After the mixture was stirred at room temperature for 1 hour, the ice-water bath was cooled to 0 ° C, and then compound 67-d (1.0 g, 3.26 mmol) and dichloromethane (50 mL) were added. After stirring for 30 minutes, sodium cyanoborohydride (368 mg, 4.89 mmol) was added, and the reaction mixture was warmed to room temperature and stirred for another 12 hours. It was concentrated under reduced pressure, the residue was diluted with water (100 mL), and extracted with dichloromethane (50 mL x 3).
  • Methylamine hydrochloride (938 mg, 13.8 mmol) and sodium acetate (1.13 g, 13.8 mmol) were added to methanol (40 mL). After the mixture was stirred at room temperature for 1 hour, the ice-water bath was cooled to 0 ° C, and then compound 69-d (1.5 g, 4.6 mmol) and dichloromethane (40 mL) were added. After stirring for 30 minutes, sodium cyanoborohydride (434 mg, 6.9 mmol) was added, and the reaction mixture was warmed to room temperature and stirred for 16 hours. It was concentrated under reduced pressure, the residue was diluted with water (100 mL), and extracted with dichloromethane (60 mL ⁇ 2).
  • LC-MS (ESI): m / z 402 [M + H] + .
  • Acetic acid (1.06 g, 16.6 mmol) was slowly added dropwise to a mixed solvent of cyclopropylamine (950 mg, 16.6 mmol) and compound 67-d (1.7 g, 5.55 mmol) in methanol (10 mL) and dichloromethane (30 mL). The mixture was stirred at room temperature for 2 hours, and sodium cyanoborohydride (520 mg, 8.25 mmol) was added in portions. The reaction mixture was stirred at room temperature for 12 hours. The reaction solution was diluted with water (100 mL), and extracted with dichloromethane (50 mL ⁇ 3). The combined organic phases were washed with water (100 mL) and saturated brine (100 mL).
  • LC-MS (ESI): m / z 474 [M + H] + .
  • Ethylamine hydrochloride (972 mg, 12.0 mmol) and sodium acetate (984 mg, 12.0 mmol) were added to methanol (50 mL). After the mixture was stirred at room temperature for 0.5 hours, the ice-water bath was cooled to 0 ° C, and then compound 67-d (1.1 g, 3.0 mmol) and dichloromethane (30 mL) were added. After stirring for 30 minutes, sodium cyanoborohydride (283.5 mg, 4.5 mmol) was added, and the reaction mixture was warmed to room temperature and stirred for another 12 hours. It was concentrated under reduced pressure, the residue was diluted with water (100 mL), and extracted with dichloromethane (50 mL x 3).
  • LC-MS (ESI): m / z 408 [M + H] + .
  • 1,8-Diazabicycloundec-7-ene 152 mg, 1.0 mmol was added to compound 71-c (150 mg, 0.5 mmol) and 2- (trifluoromethyl) benzaldehyde (174 mg, 1.0 mmol) in absolute ethanol (10 mL). The mixture was refluxed for 4 hours under the protection of nitrogen, cooled to room temperature, solids were formed, filtered, and the filter cake was dried under vacuum to obtain 74-b (150 mg, yield: 66%) as a yellow solid. This compound did not require further purification.
  • LC-MS (ESI): m / z 458 [M + H] + .
  • 1,8-Diazabicycloundec-7-ene 152 mg, 1.0 mmol was added to compound 71-c (150 mg, 0.5 mmol) and 2,4-difluorobenzaldehyde (142 mg, 1.0 mmol) Of absolute ethanol (15 mL). The mixture was refluxed for 4 hours under the protection of nitrogen, cooled to room temperature, solids were formed, filtered, and the filter cake was dried under vacuum to obtain 77-b (180 mg, yield: 85%) as a yellow solid. This compound did not require further purification.
  • LC-MS (ESI): m / z 426 [M + H] + .
  • 1,8-Diazabicycloundec-7-ene (152 mg, 1.0 mmol) was added to compound 71-c (150 mg, 0.5 mmol) and 2-trifluoromethyl-4-fluorobenzaldehyde (192 mg , 1.0 mmol) in a solution of absolute ethanol (30 mL). The mixture was refluxed under nitrogen protection for 4 hours, cooled to room temperature, solids were formed, filtered, and the filter cake was dried under vacuum to obtain 78-b (175 mg, yield: 73%) as a yellow solid. This compound did not require further purification.
  • LC-MS (ESI): m / z 476 [M + H] + .
  • 1,8-Diazabicycloundec-7-ene (152 mg, 1.0 mmol) was added to compound 71-c (150 mg, 0.5 mmol) and benzaldehyde (53 mg, 0.5 mmol) in absolute ethanol (10 mL) ) In solution.
  • the mixture was refluxed under nitrogen protection for 4 hours, cooled to room temperature, solids were formed, filtered, and the filter cake was dried under vacuum to obtain 80-b (110 mg, yield: 56%) as a yellow solid. This compound did not require further purification.
  • LC-MS (ESI): m / z 390 [M + H] + .
  • Methylamine hydrochloride (1.1 g, 14.86 mmol) and sodium acetate (1.22 g, 14.86 mmol) were added to methanol (20 mL). After the mixture was stirred at room temperature for 30 minutes, the ice-water bath was cooled to 0 ° C, and then compound 82-d (1.2 g, 3.72 mmol) and dichloromethane (20 mL) were added. After stirring for 30 minutes, sodium cyanoborohydride (360 mg, 5.58 mmol) was added, and the reaction mixture was warmed to room temperature and stirred for another 12 hours. The solution was concentrated under reduced pressure, and the residue was diluted with water (50 mL), and extracted with dichloromethane (50 mL ⁇ 2).
  • 1,8-Diazabicycloundec-7-ene (207 mg, 1.36 mmol) was added to anhydrous compound 82-c (200 mg, 0.68 mmol) and 2-fluorobenzaldehyde (127 mg, 1.03 mmol). In ethanol (5 mL). The mixture was refluxed for 12 hours under the protection of nitrogen, cooled to room temperature, and continued to stir for 3 hours. Solids were formed, filtered, and the filter cake was dried under vacuum to obtain 82-b (173 mg, yield: 64%) as a yellow solid.
  • LC-MS (ESI): m / z 399 [M + H] + .
  • Methylamine hydrochloride (1.76 g, 26.0 mmol) and sodium acetate (3.56 g, 26.0 mmol) were added to methanol (50 mL). After the mixture was stirred at room temperature for 30 minutes, the ice-water bath was cooled to 0 ° C, and then compound 62-d (2.0 g, 6.5 mmol) and dichloromethane (10 mL) were added. After stirring for 1 hour, sodium cyanoborohydride (615 mg, 9.7 mmol) was added, and the reaction mixture was warmed to room temperature and stirred for another 12 hours. It was concentrated under reduced pressure, the residue was diluted with water (100 mL), and extracted with dichloromethane (50 mL ⁇ 2).
  • N-propylamine (1.76 g, 26.0 mmol), acetic acid (1.66 g, 26.0 mmol) were added to methanol (10 mL) and dichloromethane (50 mL). After the mixture was stirred at room temperature for 30 minutes, the ice-water bath was cooled to 0 ° C, and then compound 62-d (2.0 g, 6.5 mmol) and dichloromethane (10 mL) were added. After stirring for 1 hour, sodium cyanoborohydride (614 mg, 9.7 mmol) was added, and the reaction mixture was warmed to room temperature and stirred for another 12 hours.

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Abstract

La présente invention concerne un composé hétérocyclique à cinq chaînons d'aminopyrimido tel que représenté par la formule I, et un intermédiaire, un procédé de préparation, une composition pharmaceutique et une utilisation de celui-ci. Le composé hétérocyclique à cinq chaînons d'aminopyrimido selon la présente invention a un effet antagoniste significatif sur les récepteurs de l'adénosine A2A, et peut être utilisé en tant qu'antagoniste des récepteurs de l'adénosine A2A pour soulager ou traiter de manière efficace la tolérance immunitaire, des maladies du système nerveux central, des maladies inflammatoires et d'autres maladies associées.
PCT/CN2019/102678 2018-09-04 2019-08-27 Composé hétérocyclique à cinq chaînons d'aminopyrimido, intermédiaire, procédé de préparation, composition pharmaceutique et utilisation de celui-ci Ceased WO2020048347A1 (fr)

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