WO2014190949A1 - Inhibiteur cyclique tétracondensé de la kinase du lymphome anaplasique - Google Patents

Inhibiteur cyclique tétracondensé de la kinase du lymphome anaplasique Download PDF

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WO2014190949A1
WO2014190949A1 PCT/CN2014/079072 CN2014079072W WO2014190949A1 WO 2014190949 A1 WO2014190949 A1 WO 2014190949A1 CN 2014079072 W CN2014079072 W CN 2014079072W WO 2014190949 A1 WO2014190949 A1 WO 2014190949A1
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group
alkyl
membered
amino
membered heterocyclic
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PCT/CN2014/079072
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English (en)
Chinese (zh)
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吴永谦
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山东轩竹医药科技有限公司
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Priority to CN201480031459.6A priority Critical patent/CN105579459B/zh
Publication of WO2014190949A1 publication Critical patent/WO2014190949A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems

Definitions

  • the present invention relates to the field of medical technology, and particularly relates to a tetracyclic anaplastic lymphoma kinase inhibitor or a stereoisomer thereof, or a pharmaceutically acceptable salt, ester or solvate thereof, and a method for preparing the same, which comprises the compound Pharmaceutical preparations and pharmaceutical compositions, and the compounds or stereoisomers thereof, or pharmaceutically acceptable salts, esters or solvates thereof, in the manufacture of a medicament for the treatment and/or prevention of ALK-mediated cancer-related diseases application.
  • Background technique
  • Anaplastic lymphoma kinase a member of the receptor acid kinase family, recruits downstream proteins through autophosphorylation to express specific genes and regulate cell metabolism and growth.
  • ALK Anaplastic lymphoma kinase
  • NSCLC non-small cell lung cancer
  • ALK's small molecule inhibitors can affect the growth of tumor cells and play an anti-tumor role.
  • crizotinib developed by Pfizer Inc.
  • the design and screening of second-generation ALK inhibitors with good efficacy in patients with resistance to Crizotinib has significant clinical significance.
  • ALK inhibitors include CH5424802 (Roche), LDK378 (Norartis), and
  • the structure of the compound is modified to find a new compound structure, and efforts are made to improve the rationality of the compound.
  • the nature of the drug such as increasing the exposure or bioavailability of the compound, to find small molecule inhibitors with high activity on ALK mutations, is of great significance for the clinical treatment of diseases caused by ALK mutations. Summary of the invention
  • the present invention aims to develop a small molecule inhibitor against ALK, and has invented a tetracyclic anaplastic lymphoma kinase inhibitor which has a good effect on the treatment and/or prevention of ALK-mediated cancer-related diseases.
  • the specific technical solutions are as follows:
  • a 2 is selected from 1 2 or
  • a 3 is selected from C-R 4 or N, and Ai, A 2 and A 3 are not N at the same time;
  • R 1 , R 2 and R 4 are each independently selected from the group consisting of hydrogen, hydroxy, carboxy, nitro, halogen atom, amino, (C 1-6 alkyl) 2 amino, cyano, C 1-6 alkyl, C 1 -6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl or 3 to 14 membered cycloalkyl;
  • R 3 is selected from the group consisting of hydrogen, cyano, nitro, hydroxy, amino, sulfonyl, alicyclic, CL 6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl or a 14-membered cycloalkyl group, the C 1-6 alkyl group, the C 1-6 alkoxy group, the C 2-6 alkenyl group, the C 2-6 alkynyl group and the 3 to 14 membered cycloalkyl group may be independently Optionally substituted by one or more of the following substituents: hydroxy, carboxy, amino, cyano, halo, nitro or 3 to 14 membered heterocyclyl;
  • M is selected from 0, S or NR 8 and R 8 is selected from hydrogen, C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl or C 2-6 alkynyl, said C 1 -6 alkyl, C 2-6 alkenyl and C 2-6 alkynyl may be independently optionally substituted by C 1-6 alkoxy;
  • R 5 and R 6 are each independently selected from the group consisting of hydrogen, a halogen atom, a C 1-6 alkyl group, a C 1-6 alkoxy group, and a hydroxyl group C 1-6
  • R 5 and R 6 are bonded to each other to form a 3 to 14 membered heterocyclic group or a 3 to 14 membered cycloalkyl group together with the carbon atom to which they are attached;
  • Y is selected from N or CR 9 ;
  • X is selected from 0, S or NR 9 ;
  • R 9 is selected from hydrogen, CL 6 alkyl, C 2 6 alkynyl, or 3 ⁇ 8-membered cycloalkyl group;
  • Q is selected from the following groups:
  • R 1Q is selected from the group consisting of amino, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, (C 1-6 alkyl) 2 amino, CL 6 alkylaminocarbonyl, hydroxy CL 6 Alkyl, hydroxy CL 6 alkylamino, substituted CL 6 alkyl, d. 6 alkylsulfonyl, C alkylsulfonylamino, aminosulfonyl, aminosulfonylamino, alkenyl,
  • R 7 is selected from a 6 to 12 membered bridged ring group, a 6 to 12 membered spirocyclic group, a 3 to 8 membered heterocyclic group or a 6 to 14 membered heterocyclic group which is optionally substituted with a substituent selected from the group consisting of Amino, hydroxy, nitro, alkane, carboxyl, C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, 3 to 8 membered heterocyclic or 3 ⁇ 8-membered cycloalkyl;
  • n is selected from 0, 1, 2, 3, 4, 5 or 6,
  • R 7 may be the same or different
  • n cannot be 0, and R 7 cannot be selected from a 3 to 8 membered heterocyclic group.
  • a 2 is selected from 1 2 or
  • a 3 is selected from C-R 4 or N, and Ai, A 2 and A 3 are not N at the same time;
  • R 1 , R 2 and R 4 are each independently selected from the group consisting of hydrogen, hydroxyl, carboxyl, nitro, halogen atom, amino group, (C 1-6 alkyl) 2 amino, cyano, C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl or 3 to 14 membered cycloalkyl ;
  • R 3 is selected from the group consisting of hydrogen, cyano, hydroxy, amino, halogen atom, C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl or 3 to 14 membered ring
  • the alkyl group, the C 1-6 alkyl group, the C 1-6 alkoxy group, the C 2-6 alkenyl group, the C 2 alkynyl group and the 3 to 14 membered cycloalkyl group may be independently optionally one or more of the following Substituent substitution: a hydroxyl group, a carboxyl group, an amino group, a cyano group, a halogen atom, a nitro group or a 3 to 14 membered heterocyclic group;
  • M is selected from 0, S or NR 8 and R 8 is selected from hydrogen, C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl or C 2-6 alkynyl, said C 1 -6 alkyl, C 2-6 alkenyl and C 2-6 alkynyl may be independently optionally substituted by C 1-6 alkoxy;
  • R 5 and R 6 are each independently selected from the group consisting of hydrogen, a halogen atom, a C 1-6 alkyl group, a C 1-6 alkoxy group, and a hydroxyl group C 1-6
  • R 5 and R 6 are bonded to each other to form a 3 to 14 membered heterocyclic group or a 3 to 14 membered cycloalkyl group together with the carbon atom to which they are attached;
  • Y is selected from N or CR 9 ;
  • X is selected from 0, S or NR 9 ;
  • R 9 is selected from hydrogen, CL 6 alkyl, C 2 6 alkynyl, or 3 ⁇ 8-membered cycloalkyl group;
  • Q is selected from the following groups:
  • R 1Q is selected from the group consisting of amino, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, (C 1-6 alkyl) 2 amino, CL 6 alkylaminocarbonyl, hydroxy CL 6 Alkyl, hydroxy CL 6 alkylamino, substituted CL 6 alkyl, d. 6 alkylsulfonyl, C alkylsulfonylamino, aminosulfonyl, aminosulfonylamino, alkenyl,
  • R 7 is selected from a 6 to 12 membered bridged ring group or a 6 to 12 membered spirocyclic group optionally substituted by a substituent selected from the group consisting of an amino group, a hydroxyl group, a nitro group, a halogen atom, a carboxyl group, and a C 1-6 alkane group. a group, a C 1-6 alkoxy group, a C 2-6 alkenyl group, a C 2-6 alkynyl group, a 3 to 8 membered heterocyclic group or a 3 to 8 membered cycloalkyl group;
  • n 1.
  • a 2 is selected from 1 2 or
  • a 3 is selected from C-R 4 or N, and Ai, A 2 and A 3 are not N at the same time;
  • R 1 , R 2 and R 4 are each independently selected from the group consisting of hydrogen, hydroxy, carboxy, nitro, halogen atom, amino, (C 1-6 alkyl) 2 amino, cyano, C 1-6 alkyl, C 1 -6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl or 3 to 14 membered cycloalkyl;
  • R 3 is selected from the group consisting of hydrogen, cyano, nitro, hydroxy, amino, sulfonyl, alicyclic, CL 6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl or a 14-membered cycloalkyl group, the C 1-6 alkyl group, the C 1-6 alkoxy group, the C 2-6 alkenyl group, the C 2-6 alkynyl group and the 3 to 14 membered cycloalkyl group may be independently Optionally substituted by one or more of the following substituents: hydroxy, carboxy, amino, cyano, halo, nitro or 3 to 14 membered heterocyclyl;
  • M is selected from 0, S or NR 8 and R 8 is selected from hydrogen, C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl or C 2-6 alkynyl, said C 1 -6 alkyl, C 2-6 alkenyl and C 2-6 alkynyl may be independently optionally substituted by C 1-6 alkoxy;
  • R 5 and R 6 are each independently selected from the group consisting of hydrogen, a halogen atom, a C 1-6 alkyl group, a C 1-6 alkoxy group, and a hydroxyl group C 1-6
  • R 5 and R 6 are bonded to each other to form a 3 to 14 membered heterocyclic group or a 3 to 14 membered cycloalkyl group together with the carbon atom to which they are attached;
  • Y is selected from N or CR 9 ;
  • X is selected from 0, S or NR 9 ;
  • R 9 is selected from hydrogen, CL 6 alkyl, C 2 6 alkynyl, or 3 ⁇ 8-membered cycloalkyl group;
  • Q is selected from the following groups:
  • R 1Q is selected from the group consisting of amino, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, (C 1-6 alkyl) 2 amino, CL 6 alkylaminocarbonyl, hydroxy CL 6 Alkyl, hydroxy CL 6 alkylamino, substituted CL 6 alkyl, d. 6 alkylsulfonyl, C alkylsulfonylamino, aminosulfonyl, aminosulfonylamino, alkenyl,
  • R 7 is selected from a 6 to 12 membered bridged ring group optionally substituted with a substituent, a 6 to 12 membered spirocyclic group or a 3 to 8 membered hetero a cyclic group, the substituent is selected from the group consisting of an amino group, a hydroxyl group, a nitro group, a halogen atom, a carboxyl group, a ⁇ 6 alkyl group, an alkoxy group, a C 2-6 alkenyl group, a C 2-6 alkynyl group, and a 3 to 8 membered heterocyclic ring.
  • n is selected from 0, 1, 2, 3, 4, 5 or 6,
  • R 7 may be the same or different.
  • R 1 , R 2 and R 4 are each independently selected from hydrogen, a halogen atom, a C 1-6 alkyl group, a C 1-6 alkoxy group, a C 2-6 alkenyl group, a C 2-6 alkynyl group or a 3 to 8 Metacycloalkyl;
  • R 3 is selected from the group consisting of hydrogen, cyano, nitro, hydroxy, amino, sulfonyl, alicyclic, CL 6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl or ⁇ 8-membered cycloalkyl, the C 1-6 alkyl group, C 1-6 alkoxy group, C 2-6 alkenyl group, C 2-6 alkynyl group and 3 to 8 membered cycloalkyl group may be independently Substituted by one to three substituents: a hydroxyl group, a carboxyl group, an amino group, a cyano group, a halogen atom, a nitro group or a 3 to 8 membered heterocyclic group;
  • M is selected from 0, S or NR 8 and R 8 is selected from hydrogen, C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl or C 2-6 alkynyl, said C 1 -6 alkyl, C 2-6 alkenyl and C 2-6 alkynyl may be independently optionally substituted by C 1-6 alkoxy;
  • R 5 and R 6 are each independently selected from the group consisting of hydrogen, a halogen atom, a C 1-6 alkyl group, a C 1-6 alkoxy group, and a hydroxyl group C 1-6
  • R 5 and R 6 are bonded to each other to form a 5- to 10-membered heterocyclic group or a 3- to 8-membered cycloalkyl group together with the carbon atom to which they are attached;
  • Y is selected from N or CR 9 ;
  • X is selected from 0, S or NR 9 ;
  • R 9 is selected from hydrogen, CL 6 alkyl, C 2 6 alkynyl, or 3 ⁇ 8-membered cycloalkyl group;
  • Q is selected from the following groups: (1) 4 to 7 membered heterocyclic group,
  • R 1Q is selected from the group consisting of amino, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, (C 1-6 alkyl) 2 amino, CL 6 alkylaminocarbonyl, hydroxy CL 6 Alkyl, hydroxy CL 6 alkylamino, substituted CL 4 alkyl, C M alkylsulfonyl, C alkylsulfonylamino, aminosulfonyl, aminosulfonylamino, alkenyl,
  • R 7 is selected from a 6 to 10 membered bridged ring group, a 6 to 12 membered spirocyclic group, a 4 to 7 membered heterocyclic group or a 6 to 12 membered heterocyclic group which is optionally substituted with a substituent selected from the group consisting of Amino group, hydroxyl group, halogen atom, ⁇ 6 alkyl group,
  • n is selected from 0, 1, 2 or 3
  • R 7 may be the same or different
  • n cannot be 0, and R 7 cannot be selected from a 4 to 7 membered heterocyclic group.
  • ⁇ ⁇ , A 2 and A 3 are each independently selected from CH;
  • R 3 is selected from hydrogen or cyano
  • M is selected from Li
  • R 5 and R 6 are each independently selected from hydrogen or C 1-6 alkyl
  • Y is selected from N;
  • X is selected from S.
  • R 1 , R 2 and R 4 are each independently selected from hydrogen, a halogen atom, a C 1-6 alkyl group or a 3 to 8 membered cycloalkyl group; and R 3 is selected from the group consisting of hydrogen, cyano, nitro, hydroxy, amino, sulfonyl Acyl, alkene, CL 6 alkyl or 3 to 8 membered cycloalkyl;
  • M is selected from 0, S or NR 8 , R 8 is selected from hydrogen, C 1-6 alkyl or C 1-6 alkoxy, and the C 1-6 alkyl may be optionally substituted by ⁇ 6 alkoxy ;
  • R 5 and R 6 are each independently selected from hydrogen, a halogen atom, a ⁇ 6 alkyl group, a ⁇ 6 alkoxy group or a hydroxy C 1-6 alkyl group.
  • R 5 and R 6 are bonded to each other to form a 5- to 6-membered heterocyclic group or a 3- to 8-membered cycloalkyl group together with the carbon atom to which they are attached;
  • Y is selected from N or CR 9 ;
  • X is selected from 0, S or NR 9 ;
  • R 9 is selected from hydrogen, CL 6 alkyl, C 2 6 alkynyl, or 3 ⁇ 8-membered cycloalkyl group;
  • Q is selected from the following groups:
  • R 1Q is selected from the group consisting of amino, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, (C 1-6 alkyl) 2 amino, C 1-6 alkylaminocarbonyl, hydroxy C 1-6 alkyl, hydroxy C 1-6 alkylamino, C M alkyl, methylsulfonyl, methylsulfonylamino, aminosulfonyl, aminosulfonylamino, C 2-6 alkenyl, C 2-6 alkynyl;
  • R 7 is selected from a 7 to 10 membered bridged ring group optionally substituted with a substituent, a 7 to 11 membered spirocyclic group, a 5 to 6 membered heterocyclic group or a 6 to 10 membered heterocyclic group, and the substituent is selected from the group consisting of Amino group, hydroxyl group, halogen atom, ⁇ 6 alkyl group,
  • n is selected from 0, 1, 2 or 3
  • R 7 may be the same or different
  • n cannot be 0, and R 7 cannot be selected from a 5- to 6-membered heterocyclic group.
  • R 1 , R 2 and R 4 are each independently selected from hydrogen, methyl or ethyl;
  • R 3 is selected from the group consisting of hydrogen, cyano, hydroxy, amino, fluorine, chlorine, methyl or ethyl;
  • M is selected from NR 8 and R 8 is selected from hydrogen or CL 4 alkyl;
  • R 5 and R 6 are each independently selected from C 1-4 alkyl
  • Y is selected from N or CR 9 ;
  • X is selected from S or NR 9 ;
  • R 9 is selected from the group consisting of hydrogen, methyl, ethyl or n-propyl
  • R 1Q is selected from amino or CL 4 alkyl
  • R 7 is selected from the group consisting of 7 to 9 membered bridged ring groups, 7 to 11 membered spirocyclic groups or 5 to 6 membered heterocyclic groups.
  • n is selected from 0 or 1
  • n cannot be 0, and R 7 cannot be selected from a 5- to 6-membered heterocyclic group.
  • Q is selected from a 4 to 7 membered heterocyclic group, preferably having 1 or 2 nitrogen atoms as a ring atom, more preferably saturated;
  • R 7 is selected from 7 to 8 membered bridged ring groups, preferably containing 1 or 2 ring atoms selected from oxygen and nitrogen, more preferably saturated;
  • ⁇ is selected from 1.
  • Q is selected from optionally substituted with one to two identical or different substituents R 1Q of 7 ⁇ 8 membered bridged ring group, preferably containing 1 or 2 nitrogen atoms as ring atoms, more preferably a saturated,
  • R 1Q is selected from amino or CL 6 alkyl
  • R 7 is selected from a 4 to 7 membered heterocyclic group, preferably contains 1 or 2 ring atoms selected from oxygen and nitrogen, more preferably saturated;
  • n is selected from 0 or 1, and when n is 0, R 7 is absent.
  • n is selected from 0 or 1, and when n is 0, R 7 is absent.
  • Q and R 7 is a bridged ring group, the bridged ring group containing at least one nitrogen atom as a ring member, and the bridge is bridged by two ring atoms (such as carbon atoms) adjacent to the nitrogen atom.
  • Q is selected from, for example, "optionally substituted alkyl CL 4 - ⁇ - one,
  • Q is selected from 7 to 11 membered spirocyclic groups optionally substituted by one to two identical or different R 1Q groups, preferably a spirocyclic group having 1 to 3 hetero atoms, more preferably the spiro group
  • the cyclic group contains 7 to 11 ring atoms, wherein 1 or 2 ring atoms are nitrogen atoms, the remaining ring atoms are carbon atoms, and still more preferably, the spiro group is a saturated group,
  • R 1Q is selected from amino or CL 4 alkyl
  • R 7 does not exist.
  • Q is selected from 6 to 10 membered heterocyclic groups optionally substituted by one to two identical or different R 1Q , and the heterocyclic group is preferably a heterocyclic group having 1 to 3 hetero atoms, more preferably The heterocyclic group contains 6 to 10 ring atoms, wherein 1 to 3 ring atoms are hetero atoms selected from nitrogen and oxygen, and the remaining ring atoms are carbon atoms, still more preferably, the heterocyclic group Is a saturated group,
  • R 1Q is selected from amino or CL 4 alkyl
  • R 7 does not exist.
  • a pharmaceutical composition comprising the compound of any one of the preceding claims 1-17, or a stereoisomer thereof, or a pharmaceutically acceptable salt, ester or solvate thereof, and one or more A pharmaceutically acceptable carrier and/or diluent.
  • a drug related to a disease selected from the group consisting of a brain tumor, a non-small cell lung cancer, a squamous cell carcinoma, a bladder cancer, a stomach cancer, an ovarian cancer, a peritoneal cancer, a pancreatic cancer, a breast cancer, a head and neck cancer , cervical cancer, endometrial cancer, rectal cancer, liver cancer, hepatoblastoma, papillary renal cell tumor, head and neck squamous cell tumor, nephroblastoma, renal cancer, esophageal adenocarcinoma, esophageal squamous cell Cancer, glioma, prostate cancer, thyroid cancer, female genital tract cancer, carcinoma in situ, lymphoma, neuroblastoma,
  • a 2 , A 3 , M, Y, X, R 3 , R 5 , R 6 , R 7 , Q and n are as defined in the technical scheme 1-17, and Q' is as in the technical scheme 1-17
  • Q' is as in the technical scheme 1-17
  • the defined Q or Q, R 7 ' as defined in Technical Schemes 1-17 protected by a protecting group (PG) is protected by R 7 or protected group (PG ) as defined in Technical Schemes 1-17 R 7 as defined in Technical Schemes 1-17.
  • the "prime atom” as used in the present invention means a fluorine atom, a chlorine atom, a bromine atom, an iodine atom or the like.
  • the " ⁇ 6 alkyl group” of the present invention means a linear or branched alkyl group having 1 to 6 carbon atoms, and includes, for example, "C 1-4 alkyl group", “C 1-3 alkyl group” and the like. Such as methyl, ethyl, propyl, butyl, pentyl, hexyl and the like.
  • the alkyl group “the present invention” refers to a specific example in which the number of carbon atoms is 1-4 in the above "C 1-6 alkyl group”.
  • the "C 2-6 alkenyl group” of the present invention means a linear or branched or cyclic alkenyl group having 2 to 6 carbon atoms containing at least one of the bonds, including, for example, "C 2-4 alkenyl group”. ", "C 2-3 alkenyl”, “C 3-6 cycloalkenyl”, etc., such as ethenyl, propenyl, butenyl, pentenyl, hexenyl, butadienyl, pentadienyl And hexadienyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl and cyclohexadienyl and the like.
  • the joy keys can optionally be cis and trans.
  • the " ⁇ 6 alkynyl group” of the present invention means a linear or branched alkynyl group having 2 to 6 carbon atoms containing at least one triple bond, and includes, for example, "C 2-6 alkynyl group”, “C” 2-4 alkynyl", “C 2-3 alkynyl” and the like, such as ethynyl, propynyl, butynyl, pentynyl, hexynyl and the like.
  • the “alkylsulfonylamino group” means a group in which the above “ 6 alkyl group” is bonded to another structure through a thio group, an oxy group, an aminocarbonyl group, a sulfonyl group or a sulfonylamino group, respectively.
  • C M alkylsulfonyl and “C 1-4 alkylsulfonylamino” refer to a group in which the above “ 4 alkyl group” is bonded to another structure through a sulfonyl group and a sulfonylamino group, respectively.
  • hydroxy 6 alkyl group and “halogenated 6 alkyl group” of the present invention respectively mean that a hydroxyl group or a halogen atom replaces one or more hydrogen atoms on the above “d. 6 alkyl group", and passes through an alkyl group and other structures. Connected base Mission.
  • hydroxyl. 14 alkyl and “halo ⁇ 14 alkyl” mean, respectively, a hydroxy group, a halogen atom substituted for one or more hydrogen atoms on the above "C M alkyl group”, and which are bonded to other structures through an alkyl group. a group, wherein "halogen atom” is as described above.
  • hydroxy c 1-6 alkoxy group means a hydroxyl group, an amino group or a carbonyl group to replace the above " ⁇ 6 alkane”
  • One or more hydrogen atoms on the oxy group and a group attached to the other structure through an alkoxy group.
  • hydroxy C 1-6 alkylamino group as used in the present invention means a group in which an atom which can be substituted by any one of the amino groups is substituted by the above-mentioned "hydroxyl 6 alkyl group” and which is bonded to another structure through an amino group.
  • ( ⁇ 6 alkyl) 2 amino and "6 alkylamino” refer to an amino group and any two atoms of a substituent can be substituted with the aforementioned ".6 alkyl group", and by A group in which an amino group is bonded to other structures.
  • the "3- to 14-membered cycloalkyl group" as used in the present invention means that the alkane moiety of 3 to 14 carbon atoms is removed by a hydrogen atom-derived cyclic alkyl group, including a 3- to 8-membered cycloalkyl group (monocyclic ring), 6 -14 membered cyclocycloalkyl (bicyclic or polycyclic).
  • the 3- to 8-membered cycloalkyl group means that the alkane moiety of 3 to 8 carbon atoms is removed by a hydrogen atom-derived cyclic alkyl group, and examples thereof include, but are not limited to, cyclopropyl group, cyclobutylalkyl group, cyclopentyl group. , cyclohexane, cycloheptyl, cyclooctyl, methylcyclopropane, dimethylcyclopropane, methylcyclobutane, dimethylcyclobutane, methylcyclopentanyl , dimethylcyclopentyl, methylcyclohexane, dimethylcyclohexane, and the like.
  • the 6- to 14-membered cyclocycloalkyl group refers to a 6- to 14-membered cyclic group formed by two or more cyclic structures sharing two adjacent carbon atoms, and examples thereof include, but are not limited to: Bicyclo[3.1.0]hexane, bicyclo[4.1.0]heptyl, bicyclo[2.2.0]hexane, bicyclo[3.2.0]heptyl, bicyclo[4.2.0 Octyl, octahydrocyclopentadienyl, octahydro-1/7-fluorenyl, decahydronaphthyl, tetradecafluorophenanyl, re-cyclo[3.1.0]hex-2-enyl, bicyclo [4.1.0]Hept-3-enyl, bicyclo[3.2.0]hept-3-enyl, bicyclo[4.2.0]oct-3-enyl, 1,2,3,3-tetrahydrocyclo Pentadien
  • hetero atom as used in the present invention means ⁇ , 0, C(0), S, SO and/or S0 2 and the like, preferably N, 0, S, more preferably N, 0.
  • the "3- to 14-membered heterocyclic group" of the present invention means a 3- to 14-membered cyclic group containing one to more hetero atoms, including a 3 to 8 membered heterocyclic group (monocyclic) and 6 to 14 members.
  • Heterocyclic group (bicyclic or polycyclic).
  • Heterocyclyl groups can be saturated, partially unsaturated or fully unsaturated.
  • a 3 to 8 membered heterocyclic group which means having 3 to 8 ring atoms (having at least one hetero atom) Monocyclic heterocyclic group.
  • Specific examples include, but are not limited to, 2,5-dihydrothiophenyl, 4,5-dihydropyrazolyl, 3,4-dihydro-2/7-pyranyl, 5,6-dihydro-4/7 -1,3-oxazinyl, aziridine, azetidinyl, s-heterocyclobutane, tetrahydrofuranyl, tetrahydropyrrolyl, imidazolidinyl, pyrazolidinyl, tetrahydrofuranyl, 1,4-dioxanyl group, 1,3-dioxanyl group, 1,3-dithiacyclohexane group, morpholinyl group, piperazinyl group and the like.
  • the 4- to 7-membered heterocyclic group of the present invention and the "5-6-membered heterocyclic group” refer to a specific example in which the number of ring atoms in the above "3 to 8 membered heterocyclic group” is 4 to 7 members and 5 to 6 members.
  • 6-14-membered heterocyclic group means a fused ring containing 6 to 14 ring atoms (having at least one hetero atom) joined by two or more ring structures sharing two adjacent atoms with each other.
  • a structure such as a benzo 3 to 8 to 8 membered heterocyclic group and a 3 to 8 membered heterocyclic group
  • An isocyclic structure replaces a group formed by any substitutable hydrogen atom.
  • the "6- to 12-membered heterocyclic group” and the “6- to 10-membered heterocyclic group” of the present invention mean that the above-mentioned "6- to 14-membered heterocyclic group" has a ring number of 6 to 12, 6 to 10 Specific examples of yuan.
  • the "5- to 10-membered heterocyclic group" as used in the present invention refers to a specific example in which the number of ring atoms in the above “3 to 14-membered heterocyclic group” is 5 to 10 members, and for example, a 5- to 10-membered heterocyclic group includes 5 to 6 members.
  • the "6- to 12-membered bridged ring group" as used in the present invention means that any two rings share two non-adjacent ring atoms and have 6 to 12 ring atoms (including carbon atoms and optional hetero atoms). structure.
  • the bridged ring group can be saturated, partially unsaturated or completely unsaturated.
  • the "6 12-membered spirocyclic group" as used in the present invention means a structure having at least two rings sharing a ring atom and having 6 to 12 ring atoms including a carbon atom and optionally a hetero atom.
  • the spiro group can be saturated, partially unsaturated or completely unsaturated.
  • the present invention provides a compound represented by the formula (I) or a stereoisomer thereof, or a pharmaceutically acceptable salt, ester or solvate thereof:
  • a 2 is selected from CR 2 or N;
  • a 3 is selected from CR 4 or N, and Ai, A 2 and A 3 are not N at the same time;
  • R 1 , R 2 and R 4 are each independently selected from the group consisting of hydrogen, hydroxy, carboxy, nitro, halogen atom, amino, (C 1-6 alkyl) 2 amino, cyano, C 1-6 alkyl, C 1 -6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl or 3 to 14 membered cycloalkyl;
  • R 3 is selected from the group consisting of hydrogen, cyano, nitro, hydroxy, amino, sulfonyl, alicyclic, CL 6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl or a 14-membered cycloalkyl group, the C 1-6 alkyl group, the C 1-6 alkoxy group, the C 2-6 alkenyl group, the C 2-6 alkynyl group and the 3 to 14 membered cycloalkyl group may be independently Optionally substituted by one or more of the following substituents: hydroxy, carboxy, amino, cyano, halo, nitro or 3 to 14 membered heterocyclyl;
  • M is selected from 0, S or NR 8 and R 8 is selected from hydrogen, C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl or C 2-6 alkynyl, said C 1 -6 alkyl, C 2-6 alkenyl and C 2-6 alkynyl may be independently optionally substituted by C 1-6 alkoxy;
  • R 5 and R 6 are each independently selected from the group consisting of hydrogen, a halogen atom, a C 1-6 alkyl group, a C 1-6 alkoxy group, and a hydroxyl group C 1-6
  • R 5 and R 6 are bonded to each other to form a 3 to 14 membered heterocyclic group or a 3 to 14 membered cycloalkyl group together with the carbon atom to which they are attached;
  • Y is selected from N or CR 9 ;
  • X is selected from 0, S or NR 9 ;
  • R 9 is selected from hydrogen, CL 6 alkyl, C 2 6 alkynyl, or 3 ⁇ 8-membered cycloalkyl group;
  • Q is selected from the following groups:
  • R 1Q is selected from the group consisting of amino, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, (C 1-6 alkyl) 2 amino, CL 6 alkylaminocarbonyl, hydroxy CL 6 Alkyl, hydroxy CL 6 alkylamino, substituted CL 6 alkyl, d. 6 alkylsulfonyl, C alkylsulfonylamino, aminosulfonyl, aminosulfonylamino, alkenyl,
  • R 7 is selected from a 6 to 12 membered bridged ring group, a 6 to 12 membered spirocyclic group, a 3 to 8 membered heterocyclic group or a 6 to 14 membered heterocyclic group which is optionally substituted with a substituent selected from the group consisting of Amino, hydroxy, nitro, alkane, carboxyl, C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, 3 to 8 membered heterocyclic or 3 ⁇ 8 yuan naphthenic Base
  • n is selected from 0, 1, 2, 3, 4, 5 or 6,
  • R 7 may be the same or different
  • n cannot be 0, and R 7 cannot be selected from a 3 to 8 membered heterocyclic group.
  • 1 is 1 1 .
  • a 2 is CR 2 .
  • a 3 is CR 4 .
  • R 1 , R 2 and R 4 are each independently selected from the group consisting of hydrogen, halogen atom, ⁇ 6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkyne Base or 3 to 8 membered cycloalkyl.
  • R 1 , R 2 and R 4 are each independently selected from hydrogen, a halogen atom, a C 1-6 alkyl group or a 3 to 8 membered cycloalkyl group.
  • RR 2 and R 4 are each independently selected from hydrogen, methyl or ethyl.
  • R 3 is selected from the group consisting of hydrogen, cyano, nitro, hydroxy, amino, sulfonyl, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl , C 2-6 alkynyl or 3 to 8 membered cycloalkyl, said C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl and 3 ⁇
  • the 8-membered cycloalkyl group may be independently optionally substituted with one to three of the following substituents: a hydroxyl group, a carboxyl group, an amino group, a cyano group, a sulfonic acid atom, a nitro group or a 3 to 8 membered heterocyclic group.
  • R 3 is selected from the group consisting of hydrogen, cyano, nitro, hydroxy, amino, sulfonyl, halogen atom, ⁇ 6 alkyl or 3 to 8 membered cycloalkyl. In a preferred embodiment, R 3 is selected from the group consisting of hydrogen, cyano, hydroxy, amino, fluoro, chloro, methyl or ethyl.
  • M is selected from 0, S or NR 8 and R 8 is selected from the group consisting of hydrogen, C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl or C 2-6 alkyne
  • the C 1-6 alkyl group, the C 2-6 alkenyl group and the C 2-6 alkynyl group may be independently optionally substituted by a 6 alkoxy group.
  • M is selected from 0, S or NR 8 , R 8 is selected from hydrogen, C alkyl or C alkoxy, and said C alkyl group may be optionally substituted by C alkoxy.
  • M is selected from NR 8 and R 8 is selected from hydrogen or C 1-4 alkyl.
  • R 5 and R 6 are each independently selected from hydrogen, a halogen atom, ⁇ 6 alkyl, C 1-6 alkoxy, hydroxy C 1-6 alkyl, C 2-6 alkenyl or The C 2-6 alkynyl group, or R 5 and R 6 are bonded to each other to form a 5- to 10-membered heterocyclic group or a 3- to 8-membered cycloalkyl group together with the carbon atom to which they are attached.
  • R 5 and R 6 are each independently selected from hydrogen, a halogen atom, a ⁇ 6 alkyl group, a ⁇ 6 alkoxy group or a hydroxy group .
  • R 5 and R 6 alkyl group or R 5 and R 6 are bonded to each other, Together with the carbon atom to which they are attached, a 5- to 6-membered heterocyclic group or a 3- to 8-membered cycloalkyl group is formed.
  • R 5 and R 6 independently independently select a Ci_4 3 ⁇ 4* group.
  • the oxime is selected from ruthenium or CR 9 , X is selected from 0, S or NR 9 ; R 9 is selected from hydrogen, C 1-6 alkyl, CM alkynyl or 3 to 8 membered cycloalkyl. In one preferred embodiment, Y is selected from N or CR 9, X is selected from S or NR 9, R 9 is selected from hydrogen, methyl, ethyl or n-propyl.
  • Q is selected from the group consisting of: (1) a 4 to 7 membered heterocyclic group (or a 4 to 7 membered monocyclic heterocyclic group), (2) optionally being one to three identical or different R 1Q substituted 3 to 8 membered cycloalkyl or 6 to 12 membered heterocyclic group, and (3) optionally 7 to 10 membered bridged or substituted by 1 to 3 identical or different R 1Q A spiro ring group;
  • R 1Q is selected from the group consisting of amino, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, (C 1-6 alkyl) 2 amino, ⁇ 6 alkylamino Carbonyl, hydroxy- 6 alkyl, hydroxy- 6 alkylamino, halogenated CL 4 alkyl, CL 4 alkylsulfonyl, CL 4 alkylsulfonylamino, aminosulfonyl, aminosulfonylamino, C 2-6 Alkeny
  • Q is selected from the group consisting of: (1) a 5- to 6-membered heterocyclic group (or a 5- to 6-membered monocyclic heterocyclic group), (2) optionally being one to three identical Or a different R 1Q substituted 3 to 8 membered cycloalkyl or 6 to 10 membered heterocyclic group, and ( 3 ) a 7 to 9 membered bridged ring group optionally substituted by one to three identical or different R 1Q or 7 to 11 membered spiro group, R 1Q is selected from amino, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, (C 1-6 alkyl) 2 amino, C 1 -6 alkylaminocarbonyl group, a hydroxyl CL 6 alkyl, hydroxy ⁇ 6 alkylamino, C M substituting group, methylsulfonyl group, methylsulfonyl group, sulfamoyl group, sulfamoyl
  • Q is selected from the group consisting of (1) 5 to 6 membered heterocyclic groups (or 5 to 6 membered monocyclic heterocyclic groups), (2) optionally being one to two identical or different R a 1Q- substituted 6- to 10-membered heterocyclic group, and (3) a 7- to 9-membered bridged ring group or a 7- to 11-membered spirocyclic group optionally substituted by one or two identical or different R 1Q , and R 1Q is selected from the group consisting of Amino or C M alkyl.
  • Q is selected from a 4 to 7 membered heterocyclic group (or a 4 to 7 membered monocyclic heterocyclic group), preferably having 1 or 2 nitrogen atoms as a ring atom, more preferably ⁇ selected.
  • the ground is saturated.
  • Q is selected from one to two
  • R 1 substituted 7 to 8 membered bridged ring group, preferably having 1 or 2 nitrogen atoms as a ring atom, more preferably saturated, wherein R 1Q is selected from an amino group or a 6 alkyl group .
  • Q is selected from a 7 to 11-membered spiro group optionally substituted by one to two identical or different R 1Q , and the spiro group is preferably a spiro group having 1 to 3 hetero atoms, more preferably The spiro group contains 7 to 11 ring atoms, wherein 1 or 2 ring atoms are nitrogen atoms, the remaining ring atoms are carbon atoms, and still more preferably, The spiro group is a saturated group wherein R 1Q is selected from an amino group or a C M alkyl group.
  • Q is selected from 6 to 10 membered heterocyclyl optionally substituted with one to two identical or different R 1Q groups, preferably having from 1 to 3 heteroatoms And a heterocyclic group, more preferably the heterocyclic group contains 6 to 10 ring atoms, wherein 1 to 3 ring atoms are hetero atoms selected from nitrogen and oxygen, and the remaining ring atoms are carbon atoms, and still more
  • the heterocyclic group is a saturated group, wherein R 1Q is selected from an amino group or an alkyl group.
  • Q is selected from one to two identical or different
  • R 7 is selected from a 6 to 10 membered bridged ring group optionally substituted with a substituent, a 6 to 12 membered spirocyclic group, a 4 to 7 membered heterocyclic group or a 6 to 12 membered heterocyclic group.
  • the substituent is selected from the group consisting of an amino group, a hydroxyl group, a halogen atom, a C 1-6 alkyl group, a C 1-6 alkoxy group, a C 2-6 alkenyl group or a C 2-6 alkynyl group.
  • R 7 is selected from the group consisting of a 7 to 10 membered bridged ring group optionally substituted with a substituent, a 7 to 11 membered spirocyclic group, a 5 to 6 membered heterocyclic group or a 6 to 10 membered heterocyclic group.
  • a ring group the substituent being selected from the group consisting of an amino group, a hydroxyl group, a halogen atom, a C 1-6 alkyl group, a C 1-6 alkoxy group, a C 2-6 alkenyl group or a C 2-6 alkynyl group.
  • R 7 is selected from the group consisting of 7 to 9 membered bridged ring groups, 7 to 11 membered spirocyclic groups or 5 to 6 membered heterocyclic groups. In a preferred embodiment, R 7 is selected from the group consisting of 7 to 8 membered bridged ring groups, preferably containing 1 or 2 selected from the group, more preferably
  • the heterocyclic group preferably contains 1 or 2 ring atoms selected from oxygen and nitrogen, more preferably saturated.
  • n is selected from 0, 1, 2 or 3. In a preferred embodiment, n Selected from 0 or 1. In a preferred embodiment, n is selected from zero. In a preferred embodiment, n is selected from 1.
  • ⁇ 2 and ⁇ 3 are each independently selected from CH; R 3 is selected from hydrogen or cyano; ⁇ is selected from NH; and R 5 and R 6 are each independently selected from hydrogen or C 1-6 Alkyl; Y is selected from N; X is selected from S.
  • At least one of Q and R 7 is a bridged ring group containing at least one nitrogen atom as a ring member, the bridge passing through two ring atoms adjacent to the nitrogen atom (eg, carbon atom) is formed as a bridgehead atom, Q is selected from, for example, "optionally substituted C M alkyl ⁇ N ⁇ H" and N fT -, R 7 is absent or is selected from ⁇ "and a + N ⁇ yo.
  • Q is a bridged ring group containing at least one nitrogen atom as a ring member, and the bridge is formed as a bridgehead atom by two rings (such as carbon atoms) adjacent to the nitrogen atom, for example Q is selected from “optionally ( ⁇ . 4 alkyl substituted) and tenth ⁇ 1-.
  • R 7 is a bridged ring group containing at least one nitrogen atom as two adjacent ring atoms (eg, carbon atoms) as a bridgehead
  • the present invention also includes any one of the embodiments obtained by combining the above embodiments and two or more of the above preferred embodiments.
  • the pharmaceutically acceptable salt of any one of the compounds of the formula (I) of the present invention means a salt prepared from a pharmaceutically acceptable, non-toxic base or acid, including an organic acid salt, a mineral acid salt, an organic alkali salt. , inorganic alkali salt.
  • Organic acid salts include formic acid, acetic acid, benzenesulfonic acid, benzoic acid, p-toluenesulfonic acid, camphorsulfonic acid, citric acid, methanesulfonic acid, ethanesulfonic acid, propanesulfonic acid, fumaric acid, gluconic acid, glutamic acid , salts of isethionate, lactic acid, maleic acid, malic acid, mandelic acid, mucic acid, pamoic acid, pantothenic acid, succinic acid, tartaric acid, and the like.
  • the inorganic acid salt includes a salt of hydrobromic acid, hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid or the like.
  • the organic base salts include primary, secondary and tertiary amines, and the substituted amines include naturally occurring substituted amines, cyclic amines and alkali ion exchange resins selected from the group consisting of betaines, caffeine, choline, N,N,-dibenzylethylene.
  • Natural amino acid salts such as glycine, alanine, valine, leucine, isoleucine, norleucine, tyrosine, cystine, cysteine, methionine, proline, hydroxyguanidine Salts of acid, histidine, ornithine, lysine, arginine, serine, and the like.
  • Inorganic alkali salts include ammonium and 4 liters, sodium, potassium, Salts of calcium, magnesium, zinc, strontium, aluminum, iron, ketone, ferrous, manganese, divalent manganese, and the like.
  • stereoisomer of the compound of formula (I) refers to all stereoisomers, including enantiomers, which are produced when a compound of formula (I) has a chiral center, a bond or the like. Diastereomers, cis-trans isomers, tautomers, geometric isomers, epimers, and mixtures thereof are included within the scope of the invention.
  • Chiral fillers include, but are not limited to:
  • the "ester" of the compound of the formula (I) of the present invention includes an ester which can be formed by esterification reaction with an alcohol when a compound of the formula (I) is present, and an organic acid or an inorganic group when the compound of the formula (I) has a hydroxyl group.
  • the compound represented by the formula (I) or a stereoisomer thereof, or a pharmaceutically acceptable salt or ester thereof may be in the form of a "solvate", and the solvent may be water, methanol, ethanol or the like.
  • the hygroscopicity of the solvate product proceeds gradually.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of the present invention or a stereoisomer thereof, or a pharmaceutically acceptable salt, ester or solvate thereof, together with one or more pharmaceutically acceptable carriers and/or diluents .
  • the present invention further claims any of the compounds of the above formula (I) or a stereoisomer thereof, or a pharmaceutically acceptable salt, ester or solvate thereof, and one or more pharmaceutically acceptable carriers and/or
  • the pharmaceutical composition of the diluent or diluent can be formulated into any of the pharmaceutically acceptable dosage forms. It is administered to a patient in need of such treatment by oral, parenteral, rectal or pulmonary administration.
  • oral administration it can be prepared into conventional solid preparations such as tablets, capsules, pills, granules, etc.; or can be prepared into oral liquid preparations, such as oral solutions, oral suspensions, syrups, etc. .
  • a suitable filler, a binder, a disintegrant, a lubricant or the like may be added.
  • parenteral administration it can be prepared as an injection, including injection, sterile powder for injection and concentrated solution for injection.
  • the injection it can be produced by a conventional method in the prior art pharmaceutical field, and when the injection is formulated, an additional agent may be added, or a suitable additive may be added depending on the nature of the drug.
  • rectal administration it can be made into a suppository or the like.
  • pulmonary administration it can be made into an inhalant or a spray.
  • the invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of the invention or a stereoisomer thereof Or a pharmaceutically acceptable salt, ester or solvate thereof, one or more pharmaceutically acceptable carriers and/or diluents, and one or more anti-tumor agents and immunosuppressive agents.
  • the antitumor agent and immunosuppressive agent are selected from the group consisting of methotrexate, capecitabine, gemcitabine, deoxyfluorouridine, pemetrexed disodium, paclitaxil, imatinib, erlotidine Nipa, lapatinib, gefitinib, vandetanib, Herceptin, bevacizumab, rituximab, trastuzumab, paclitaxel, vinorelbine, docetaxel, multiple Spirulina, hydroxycamptothecin, mitomycin, epirubicin, pirarubicin, bleomycin, letrozole, tamoxifen, fulvestrant, lysine, flutamide , leuprolide, anastrozole, ifosfamide, busulfan, cyclophosphamide, carmustine, nimustine, semustine, nitrogen mustard, melphalan, cocoaine, carboplatin
  • reaction in the presence of a base (e.g., triethylamine) under heating (e.g., about 100-120 ° C) (e.g., at least 30 minutes, such as about 1-2 hours);
  • a base e.g., triethylamine
  • the amide) is reacted at room temperature (eg, 10-30 C) in the presence of indium trichloride (eg, at least 30 minutes, such as about 16 hours), followed by the addition of a reducing agent (eg, sodium cyanoborohydride) (eg, at least 30 Minutes, such as about 2 hours),
  • a reducing agent eg, sodium cyanoborohydride
  • Ai, A 2 , A 3 , M, Y, X, R 3 , R 5 , R 6 , R 7 , Q and n are as defined above, and Q' is a Q or a protected group as defined above ( PG) protected hereinbefore defined Q, R 7 'R is as hereinbefore defined hereinbefore 7 or a protected group (PG) as defined protected R 7.
  • the protecting group (PG) is a commonly used protecting group in the field of organic synthesis, including but not limited to: -Bn (benzyl), -PMB (p-methoxybenzyl), -Tos (p-toluenesulfonyl), -Fmoc (fluorenylmethoxycarbonyl), -Ac (acetyl), -SEM (2-(trimethylsilyl)ethoxymethyl), -Pht (phthaloyl) and -Alloc (allyloxy) Carbonyl).
  • the preparation method of the present invention further comprises the step of deprotecting the protected Q and/or protected R 7 , and optionally alkylating (eg, methylating) the deprotected H atom. step.
  • the reaction equation is as follows:
  • the raw material 1 is dissolved in a solvent (for example, glacial acetic acid), and a 40% hydrobromic acid solution is added thereto. Under ice water bath, a glacial acetic acid solution in which an appropriate amount of bromine is dissolved is added dropwise, and the mixture is stirred until the raw material is consumed, and quenched by adding ice water.
  • the organic solvent is extracted by an organic solvent (for example, ethyl acetate), and the combined organic phase is separated and purified by a suitable method (for example, silica gel column chromatography).
  • the intermediate 1 and the starting material 2 are dissolved in a suitable solvent (e.g., tetrahydrofuran), and the mixture is heated to reflux until the reaction is completed, the solvent is removed, and the intermediate 2 is obtained by an appropriate method.
  • a suitable solvent e.g., tetrahydrofuran
  • Step 3 Preparation of Intermediate 3
  • an organic solvent for example, acetonitrile
  • the t-butyl nitrite is added dropwise in an ice water bath. After completion, the temperature is raised to room temperature, stirred (for example, 2 h), and the solvent is removed. Intermediate 3 was isolated.
  • intermediate 3 the starting material 3 or its hydrochloride (e.g., its hydrochloride) is dissolved in a suitable solvent (e.g., trifluoroacetic acid, acetic acid), heated to completion, cooled, concentrated, and isolated to afford intermediate 4 as appropriate.
  • a suitable solvent e.g., trifluoroacetic acid, acetic acid
  • the intermediate 4 is placed in a suitable solvent, and an appropriate amount of an oxidizing agent (for example, DDQ (2,3-dichloro-5,6-dicyanio-p-benzoquinone) and methyl dichromate) is added, and the reaction is completed at room temperature, and a saturated aqueous solution of sodium hydrogencarbonate is added. It is quenched, extracted with an organic solvent (e.g., dichloromethane), and the organic phase is combined, and Intermediate 5 is isolated by an appropriate method.
  • an oxidizing agent for example, DDQ (2,3-dichloro-5,6-dicyanio-p-benzoquinone) and methyl dichromate
  • the intermediate 5 and the starting material 4 are dissolved in a suitable solvent (e.g., acetonitrile), and a base (e.g., methyl carbonate) is added.
  • a suitable solvent e.g., acetonitrile
  • a base e.g., methyl carbonate
  • the intermediate 6 is dissolved in a suitable solvent (dimethyl sulfoxide and triethylamine), and a suitable oxidizing agent (for example, sulfur trioxide pyridine) is added thereto, and the mixture is stirred at room temperature until the reaction is completed, and the reaction liquid is concentrated, and the intermediate 7 is isolated by an appropriate method. .
  • a suitable solvent dimethyl sulfoxide and triethylamine
  • a suitable oxidizing agent for example, sulfur trioxide pyridine
  • the intermediate 6 is dissolved in a suitable solvent (dichloromethane), and a suitable oxidizing agent (for example, Dess-Martin reagent) is added thereto, and the mixture is stirred at room temperature until the reaction is completed, and the reaction is quenched (for example, with water), and the intermediate 7 is isolated by an appropriate method.
  • a suitable solvent for example, dichloromethane
  • a suitable oxidizing agent for example, Dess-Martin reagent
  • the intermediate 5 and the starting material 4' are dissolved in a solvent (for example, N-methylpyrrolidone), a base (for example, triethylamine) is added, heated (for example, to 120 ° C), and the reaction is stirred (for example, 2 hours), and cooled ( For example, to room temperature, the reaction solution is poured into a solvent (for example, water), stirred (for example, for half an hour), filtered, and dried to give Intermediate 7.
  • a solvent for example, N-methylpyrrolidone
  • a base for example, triethylamine
  • the raw material 1 is dissolved in a solvent (for example, glacial acetic acid), and a 40% hydrobromic acid solution is added thereto. Under ice water bath, a glacial acetic acid solution in which an appropriate amount of bromine is dissolved is added dropwise, and the mixture is stirred until the raw material is consumed, and quenched by adding ice water.
  • the organic solvent is extracted by an organic solvent (for example, ethyl acetate), and the combined organic phase is separated and purified by a suitable method (for example, silica gel column chromatography).
  • the intermediate 1 and the starting material 2 are dissolved in a suitable solvent (e.g., tetrahydrofuran), and the mixture is heated to reflux until the reaction is completed, the solvent is removed, and the intermediate 2 is obtained by an appropriate method.
  • a suitable solvent e.g., tetrahydrofuran
  • the intermediate 2 and the copper bromide are dissolved in an organic solvent (for example, acetonitrile), and the t-butyl nitrite is added dropwise in an ice water bath. After completion, the temperature is raised to room temperature, stirred (for example, 2 h), and the solvent is removed. Intermediate 3 was isolated.
  • organic solvent for example, acetonitrile
  • the intermediate 5 is placed in a suitable solvent, and an appropriate amount of an oxidizing agent (for example, DDQ (2,3-dichloro-5,6-dicyanio-p-benzoquinone) and potassium dichromate) is added, and the reaction is completed at room temperature, and a saturated aqueous solution of sodium hydrogencarbonate is added. It is quenched, extracted with an organic solvent (e.g., dichloromethane), and the organic phase is combined, and Intermediate 6 is isolated by an appropriate method.
  • an oxidizing agent for example, DDQ (2,3-dichloro-5,6-dicyanio-p-benzoquinone) and potassium dichromate
  • AA 2 , A 3 , M, Y, X, R 3 , R 5 , R 6 , Q, R 7 and n are as defined above.
  • the present invention provides the use of a compound of the present invention or a stereoisomer thereof, or a pharmaceutically acceptable salt, ester or solvate thereof, for the manufacture of a medicament for the treatment and/or prevention of an ALK-mediated cancer-related disease.
  • the invention also provides a method of treating and/or preventing an ALK-mediated cancer-related disease, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of the invention or a stereoisomer thereof, or a pharmaceutically acceptable thereof Accepted salts, esters or solvates.
  • the invention also provides a compound of the invention, or a stereoisomer thereof, or a pharmaceutically acceptable salt, ester or solvate thereof, in combination with one or more antitumor agents and immunosuppressive agents, for use in therapy and / or use in drugs that prevent ALK-mediated cancer-related diseases.
  • the invention also provides a method of treating and/or preventing an ALK-mediated cancer-related disease comprising administering to a subject in need thereof a therapeutically effective amount of the combination in combination with one or more anti-tumor agents and an immunosuppressant A compound of the invention or a stereoisomer thereof, or a pharmaceutically acceptable salt, ester or solvate thereof.
  • the antitumor agent and immunosuppressive agent are selected from the group consisting of methotrexate, capecitabine, gemcitabine, deoxyfluorouridine, pemetrexed disodium, paclitaxil, imatinib, erlotidine Nipa, lapatinib, gefitinib, vandetanib, Herceptin, bevacizumab, rituximab, trastuzumab, paclitaxel, vinorelbine, docetaxel, multiple Spirulina, hydroxycamptothecin, mitomycin, epirubicin, pirarubicin, bleomycin, letrozole, tamoxifen, fulvestrant, lysine, flutamide , leuprolide, anastrozole, ifosfamide, busulfan, cyclophosphamide, carmustine, nimustine, Semustine, nitrogen mustard, melphalan, cyclamate, carbo
  • the cancer-related diseases are selected from the group consisting of brain tumors, non-small cell lung cancer, squamous cell carcinoma, bladder cancer, gastric cancer, ovarian cancer, peritoneal cancer, pancreatic cancer, breast cancer, head and neck cancer, cervical cancer, endometrium.
  • Cancer rectal cancer, liver cancer, hepatoblastoma, papillary renal cell tumor, head and neck squamous cell tumor, nephroblastoma, renal cancer, esophageal adenocarcinoma, esophageal squamous cell carcinoma, glioma, prostate Cancer, thyroid cancer, female genital tract cancer, carcinoma in situ, lymphoma, neuroblastoma, neurofibromatosis, bone cancer, skin cancer, colon cancer, testicular cancer, small cell lung cancer, gastrointestinal stromal tumor, Prostate tumors, mast cell tumors, multiple myeloma or melanoma.
  • the cancer-related disease is selected from the group consisting of lymphoma (e.g., anaplastic large cell lymphoma) and lung cancer (e.g., non-small cell lung cancer).
  • lymphoma e.g., anaplastic large cell lymphoma
  • lung cancer e.g., non-small cell lung cancer
  • the cancer-related disease is selected from the group consisting of lung cancer (e.g., non-small cell lung cancer).
  • the compound of the formula (I) of the present invention or a stereoisomer thereof, or a pharmaceutically acceptable salt, ester or solvate thereof, has excellent ALK inhibitory activity;
  • the preparation process of the compound of the invention has a high purity and stable quality, and is easy to carry out large-scale industrial production.
  • Test Specimens Compounds 1-6, 9, 10, 13, 14, 18, 24 and 26 of the present invention, the chemical names and preparation methods thereof, can be found in the preparation examples of the respective compounds.
  • Control drug CH5424802, it can be based on
  • ALK Analytical '1' Lymphoma Kinase
  • a 1 mM stock solution was taken and diluted with DMSO to prepare a solution having a concentration of 200 ⁇ M as a mother liquor.
  • the mother liquor was diluted three times in DMSO to prepare a series of solutions, and then each concentration was diluted 80 times with ALK kinase buffer to prepare 2.5 ⁇ each test solution, the concentrations were: 2500 ⁇ , 833.33 ⁇ , 277.78 ⁇ , 92.59 ⁇ , 30.86 ⁇ , 10.29 ⁇ , 3.43 ⁇ , 1.14 ⁇ , 0.38 ⁇ , 0.13 ⁇ , 0.04 ⁇ .
  • the required 5xALK kinase solution, 5 ⁇ substrate solution, and 5 ⁇ solution were separately prepared in ALK kinase buffer and used.
  • Compound 26 It can be seen from Table 1 that the compound of the present invention has a good inhibitory activity against ALK kinase and is comparable to the inhibitory activity of the reference drug, and can be used for the treatment of a kinase-related disease, particularly an ALK kinase-mediated disorder or condition, which is remarkable. Clinical significance.
  • Experimental Example 2 Pharmacokinetic experiments in rats of the present invention
  • Test article The compounds of the present invention 1 and 7, were prepared by themselves, and their chemical names and preparation methods are shown in the preparation examples of the respective compounds.
  • Control drug 5424802, which can be used as a basis
  • Test animals male SD rats, 3 / route of administration / test article, weight 200-280g
  • For the reference drug weigh 3.29 mg, add 0.1% Tween 80 + 2% HPC (hydroxypropyl cellulose) 6.45 mL, grind thoroughly with a tissue grinder 600 rpm, mix well, that is, as Rat PO administration drug solution.
  • Preparation method of 0.1% Tween 80+2% HPC Weigh 2 g of HPC, slowly add to 80 mL of ultrapure water, stir thoroughly and dissolve thoroughly, add 0.1 mL of Tween 80, vortex and mix, continue to join The ultra-pure water is made up to a final volume of 100 mL, and vortexed and mixed.
  • Preparation method of 28% HP-P-CD Weigh ⁇ - ⁇ -CD 28 g, add 80 mL of sterile water for injection, dissolve in ultrasound, vortex and mix, continue to add sterile water for injection to a final volume of 100 In mL, vortex and mix to clear the clear solution.
  • test solution is administered according to the following method: experiment
  • Plasma must be prepared within 30 minutes of blood collection.
  • the plasma sample was taken by liquid-liquid extraction method: 20 L of plasma was added, and a solution of 600 BEBE (tert-butyl methyl ether) containing internal standard (BEZ-235) (10 ng/mL) was added, and vortex was 1500 rpm. Min, then centrifuge at 12000 rpm for 5 min, take the supernatant 300 ⁇ , blow dry under nitrogen, reconstitute with 300 acetonitrile: water (7:3, V/V), vortex and mix, LC-MS/ MS analysis.
  • 600 BEBE tert-butyl methyl ether
  • BEZ-235 internal standard
  • plasma samples were taken by protein precipitation: 20 plasma, 200 ⁇ L of internal standard (CH5424802) in methanol (50 ng/mL), vortexed at 1500 rpm for 5 min, then centrifuged at 12,000 rpm for 5 min. Take the supernatant 100 ⁇ , add 100 ⁇ M water, vortex and mix, and analyze by LC-MS/MS.
  • internal standard CH5424802
  • methanol 50 ng/mL
  • plasma samples were taken by protein precipitation: 30 plasma was added, 200 ⁇ L of internal standard (CH5424802) in acetonitrile was added, vortexed at 1500 rpm, and then centrifuged at 4000 rpm for 20 min. After centrifugation, take 100 L of the supernatant, add 100 more water, vortex and mix, LC-MS/MS analysis.
  • internal standard CH5424802
  • Test sample dose (mg/kg) AUC last (h*ng/mL) CL (L/h/kg) Control drug 1 1543 0.59 Compound 1 1 1431 0.69 Compound 7 2 7715 0.26 Table 2.2 Rat ⁇ evaluation results ( ⁇ )
  • Test sample dose (mg/kg) AUC last (h*ng/mL) F (%) Control drug 2 1936 59.6 Compound 1 2 2053 72.2 Compound 7 5 9977 51.8
  • AUC last represents the area under the curve of the medicine 0 ⁇ t
  • F% represents absolute bioavailability
  • NBS N-bromosuccinimide
  • 6-Amino-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester 200 mg, 1.01 mmol
  • triethylamine 170 mg, 1.68 mmol
  • dichloromethane 20
  • benzyl chloroformate 175 mg

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Abstract

L'invention concerne des composés tels que représentés par la formule (I) ou les stéréo-isomères correspondants, ou les sels, les esters ou les solvates pharmaceutiquement acceptables correspondants, dans laquelle A1, A2, A3, M, Y, X, R3, R5, R6, R7, Q et n sont tels que définis dans la description, le procédé de préparation de ces composés, des préparations pharmaceutiques et des compositions pharmaceutiques contenant ces composés et l'utilisation des composés ou de leurs stéréo-isomères correspondants, ou des sels, des esters ou des solvates pharmaceutiquement acceptables correspondants dans la préparation de médicaments pour le traitement et/ou la prévention de maladies associées à des cancers médiés par l'ALK.
PCT/CN2014/079072 2013-06-01 2014-06-03 Inhibiteur cyclique tétracondensé de la kinase du lymphome anaplasique WO2014190949A1 (fr)

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102459172A (zh) * 2009-06-10 2012-05-16 中外制药株式会社 四环化合物
CN103052386A (zh) * 2010-08-20 2013-04-17 中外制药株式会社 含有四环化合物的组合物

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102443009B (zh) * 2010-09-30 2014-04-16 山东轩竹医药科技有限公司 并环激酶抑制剂

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102459172A (zh) * 2009-06-10 2012-05-16 中外制药株式会社 四环化合物
CN103052386A (zh) * 2010-08-20 2013-04-17 中外制药株式会社 含有四环化合物的组合物

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