WO2019062328A1 - 苯胺取代的1,2-二氢吡咯并[3,4-c]吡啶/嘧啶-3-酮衍生物及用途 - Google Patents

苯胺取代的1,2-二氢吡咯并[3,4-c]吡啶/嘧啶-3-酮衍生物及用途 Download PDF

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WO2019062328A1
WO2019062328A1 PCT/CN2018/098479 CN2018098479W WO2019062328A1 WO 2019062328 A1 WO2019062328 A1 WO 2019062328A1 CN 2018098479 W CN2018098479 W CN 2018098479W WO 2019062328 A1 WO2019062328 A1 WO 2019062328A1
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alkyl
ring
group
compound
alkoxy
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PCT/CN2018/098479
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English (en)
French (fr)
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郭淑春
周福生
陈祥
赵金柱
黄栋
谢婧
乔长江
何宛
张凯
陈曦
兰炯
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上海海雁医药科技有限公司
扬子江药业集团有限公司
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Priority to CN201880010505.2A priority Critical patent/CN110267954B/zh
Priority to US16/486,110 priority patent/US11174254B2/en
Publication of WO2019062328A1 publication Critical patent/WO2019062328A1/zh

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
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    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • 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
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    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A61P17/06—Antipsoriatics
    • 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
    • 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
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis
    • 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
    • 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
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
    • 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
    • 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
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the invention belongs to the field of medical technology.
  • the present invention particularly relates to an aniline substituted 1,2-dihydropyrrolo[3,4-c]pyridine/pyrimidin-3-one derivative, a process for its preparation and its use as a BTK inhibitor, and A pharmaceutical composition prepared therefrom.
  • BTK kinase is a non-receptor tyrosine kinase in the TEC kinase family and a key regulator of the BCR signaling pathway, which plays an important role in B cell maturation, proliferation and survival.
  • BTK is overexpressed in a variety of B-cell lymphomas and is the only clinically proven and effective drug development target in the TEC kinase family. Inhibition of BTK inhibits proliferation of a range of B cell lymphomas.
  • BCR B cell antigen receptor
  • BTK inhibitors act on chronic lymphocytic leukemia (CLL) cells, induce cytotoxicity, and inhibit the proliferation of CLL cells. It inhibits BCR-activated primary B cell proliferation and inhibits secretion of TNF ⁇ , IL-1 ⁇ and IL-6 in primary monocytes. BTK inhibitors act on collagen-induced arthritis models and significantly reduce clinical arthritis symptoms such as foot swelling and joint inflammation by inhibiting B cell activity.
  • CLL chronic lymphocytic leukemia
  • a first aspect of the invention provides a compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof:
  • X is a bond, NR a1 , S, SO, SO 2 or O; wherein R a1 is hydrogen, hydroxy or C 1-8 alkyl (preferably C 1-6 alkyl, more preferably C 1- 3 alkyl);
  • A is a C 6-10 aryl group (preferably a phenyl group), a 4 to 7 membered saturated or unsaturated monoheterocyclic ring, a 5 to 6 membered monocyclic heteroaryl ring, and an 8 to 10 membered bicyclic heteroaryl ring;
  • Z is N or CR b1 ; wherein R b1 is hydrogen, halogen (preferably fluorine, chlorine, bromine), cyano, C 1-8 alkyl (preferably C 1-6 alkyl, more preferably C 1-3 alkane a halogenated C 1-8 alkyl group (preferably a halogenated C 1-6 alkyl group, more preferably a halogenated C 1-3 alkyl group), a C 1-8 alkoxy group (preferably a C 1-6) Alkoxy, more preferably C 1-3 alkoxy), C 3-8 cycloalkyl (preferably C 3-6 cycloalkyl) or C 3-8 cycloalkoxy (preferably C 3-6) Cycloalkoxy);
  • R b1 is hydrogen, halogen (preferably fluorine, chlorine, bromine), cyano, C 1-8 alkyl (preferably C 1-6 alkyl, more preferably C 1-3 alkane a halogenated C 1-8 alkyl group (preferably a halogenated
  • R 5 and R 6 are each independently hydrogen, halogen (preferably fluorine, chlorine, bromine), C 1-8 alkyl (preferably C 1-6 alkyl, more preferably C 1-3 alkyl), halogenated C 1-8 alkyl (preferably halogenated C 1-6 alkyl, more preferably halogenated C 1-3 alkyl), C 1-8 alkoxy (preferably C 1-6 alkoxy, more Preferred is C 1-3 alkoxy), C 3-8 cycloalkyl (preferably C 3-6 cycloalkyl) or C 3-8 cycloalkoxy (preferably C 3-6 cycloalkoxy) ;
  • halogen preferably fluorine, chlorine, bromine
  • C 1-8 alkyl preferably C 1-6 alkyl, more preferably C 1-3 alkyl
  • halogenated C 1-8 alkyl preferably halogenated C 1-6 alkyl, more preferably halogenated C 1-3 alkyl
  • C 1-8 alkoxy preferably C 1-6 alkoxy, more
  • n 0 or 1
  • R 1 and R 3 are each independently hydrogen, halogen, hydroxy, alkoxy, C 1-8 alkyl (preferably C 1-6 alkyl, more preferably C 1-3 Alkyl); R 2 is bonded to R 4 to form a 4 to 7 membered saturated or unsaturated monoheterocyclic ring;
  • R 2 and R 4 are each independently hydrogen, halogen, hydroxy, alkoxy, C 1-8 alkyl (preferably C 1-6 alkyl, more preferably C 1-3 Alkyl); R 1 is bonded to R 3 to form a 4 to 7 membered saturated or unsaturated monoheterocyclic ring;
  • R 2 is hydrogen, halogen, C 1-8 alkyl (preferably C 1-6 alkyl, more preferably C 1-3 alkyl); R 3 and R 1 , R 4 Linked to form a bridged heterocyclic ring; or R 3 is hydrogen, halogen, C 1-8 alkyl (preferably C 1-6 alkyl, more preferably C 1-3 alkyl); R 2 is attached to R 1 , R 4 Forming a bridged heterocycle;
  • R 2 and R 3 are each independently hydrogen, halogen, hydroxy, alkoxy, C 1-8 alkyl (preferably C 1-6 alkyl, more preferably C 1-3 Alkyl); R a and R 1 and R b are bonded to R 4 to form a spiro heterocycle;
  • R 2 , R 3 and R b are each independently hydrogen, halogen, hydroxy, alkoxy or C 1-8 alkyl (preferably C 1-6 alkyl, more preferably C) 1-3 alkyl); R a is bonded to R 1 and R 4 , respectively, to form a bridged heterocyclic ring;
  • R 1 , R 3 , R a and R b are each independently hydrogen, halogen, hydroxy, alkoxy, C 1-8 alkyl (preferably C 1-6 alkyl, more Preferred is C 1-3 alkyl); R 2 and R 4 are bonded to form a 5- to 7-membered saturated or unsaturated monoheterocyclic ring;
  • alkyl group, cycloalkyl group, alkoxy group, aryl group, saturated or unsaturated monoheterocyclic ring, monocyclic heteroaryl ring, bicyclic heteroaryl ring, spiro heterocyclic ring, bridged heterocyclic ring are unsubstituted or 1, 2 or 3 substituents selected from the group consisting of: hydroxymethyl, hydroxyethyl, hydroxy, carboxy, halogen, -O(CH 2 ) p OC 1-8 alkyl, -O(CH 2 ) p OH, -(CH 2 ) p OC 1-8 alkyl, 4 to 6-membered saturated monoheterocyclic ring, C 1-8 alkyl group (preferably C 1-6 alkyl group, more preferably C 1-3 alkyl group) a C 3-8 cycloalkyl group (preferably a C 3-6 cycloalkyl group), a halogenated C 1-8 alkyl group (preferably a hal
  • the 4 to 7 member or 5 to 7 membered saturated or unsaturated monocyclic ring is selected from the group consisting of azetidine, oxetane, tetrahydrofuran, tetrahydrothiophene, tetrahydropyrrole, Piperidine, oxazolidine, piperazine, dioxolane, dioxane, morpholine, thiomorpholine, thiomorpholine-1,1-dioxide or tetrahydropyran.
  • the 5- to 6-membered monocyclic heteroaryl ring is selected from the group consisting of a thiophene ring, an N-alkylcyclopyrrole ring, a furan ring, a thiazole ring, an imidazole ring, an oxazole ring, a pyrrole ring, and a pyrazole.
  • Ring triazole ring, 1,2,3-triazole ring, 1,2,4-triazole ring, 1,2,5-triazole ring, 1,3,4-triazole ring, tetrazole ring, Isoxazole ring, oxadiazole ring, 1,2,3-oxadiazole ring, 1,2,4-oxadiazole ring, 1,2,5-oxadiazole ring, 1,3,4-oxa Diazole ring, thiadiazole ring, pyridine ring, pyridazine ring, pyrimidine ring, pyrazine ring.
  • the bridged heterocyclic ring is a bicyclic bridged heterocyclic ring containing a 4-, 5- or 6-membered ring.
  • the spiroheterocycle is a bicyclospiroheterocycle containing a 4-, 5- or 6-membered ring.
  • R 2 is bonded to R 4 to form a 4 to 7 membered saturated monoheterocyclic ring containing only a nitrogen hetero atom.
  • R 1 and R 3 are bonded to form a 4 to 7 membered saturated monoheterocyclic ring containing only a nitrogen hetero atom.
  • n is 0, R 3 is connected to R 1, R 4 form a heterocyclic ring containing only nitrogen heteroatom double bridge, or R 2 1, R 4 is connected with R form containing only nitrogen heteroatoms Double bridge heterocycle.
  • R a and R 1 and R b are bonded to R 4 to form a double spiroheterocycle having only a nitrogen-containing hetero atom.
  • R a is bonded to R 1 and R 4 , respectively, to form a double bridge heterocyclic ring containing only a nitrogen hetero atom.
  • R 2 and R 4 are bonded to form a 5- to 7-membered saturated monoheterocyclic ring containing only a nitrogen-containing hetero atom.
  • R 5 and R 6 are hydrogen.
  • Z is N or CR b1 ; wherein R b1 is hydrogen or halogen (preferably fluorine, chlorine, bromine).
  • Z is CR b1 ; wherein R b1 is halogen (preferably fluorine, chlorine, bromine).
  • X is a bond or NH.
  • n11, m21 are each independently 1, 2, 3 or 4; m71 is 1, 2 or 3;
  • M12, m22 are each independently 0, 1, 2, 3 or 4; m72 is 0, 1, 2 or 3;
  • R a1 , R a2 , R a11 are each independently halogen, C 1-8 alkyl (preferably C 1-6 alkyl, more preferably C 1-3 alkyl), halogenated C 1-8 alkyl ( Preferred is a halogenated C 1-6 alkyl group, more preferably a halogenated C 1-3 alkyl group), a hydroxy-substituted C 1-8 alkyl group (preferably a hydroxy-substituted C 1-6 alkyl group, C 1-8) Alkoxy (preferably C 1-6 alkoxy, more preferably C 1-3 alkoxy), C 1-8 alkoxy substituted C 1-8 alkyl (preferably C 1-6 alkoxy) a substituted C 1-6 alkyl group, more preferably a C 1-3 alkoxy substituted C 1-3 alkyl group, a C 3-8 cycloalkyl group (preferably a C 3-6 cycloalkyl group);
  • R 1 , R 2 , R 3 , R 4 , R a , R b are as defined in claim 1.
  • n31, m32, m41, m42, m61, m62 are each independently 0, 1, 2 or 3;
  • M33, m34, m43, m44, m63, m64 are each independently 0, 1, 2 or 3;
  • R a3 , R a4 , R a5 , R a6 , R a9 , and R a10 are each independently halogen, C 1-8 alkyl (preferably C 1-6 alkyl, more preferably C 1-3 alkyl), Halogenated C 1-8 alkyl (preferably halo C 1-6 alkyl, more preferably halo C 1-3 alkyl), hydroxy substituted C 1-8 alkyl (preferably hydroxy substituted C 1 ) -6 alkyl, C 1-8 alkoxy (preferably C 1-6 alkoxy, more preferably C 1-3 alkoxy), C 1-8 alkoxy substituted C 1-8 alkyl (preferably a C 1-6 alkoxy-substituted C 1-6 alkyl group, more preferably a C 1-3 alkoxy-substituted C 1-3 alkyl group), a C 3-8 cycloalkyl group (preferably C 3-6 cycloalkyl);
  • R 2 and R 3 are as defined in claim 1.
  • n51 and m52 are each independently 0, 1, 2 or 3;
  • M53, m54 are each independently 0, 1, 2, 3 or 4;
  • R a7 and R a8 are each independently halogen, C 1-8 alkyl (preferably C 1-6 alkyl, more preferably C 1-3 alkyl), halogenated C 1-8 alkyl (preferably halogen) a C 1-6 alkyl group, more preferably a halogenated C 1-3 alkyl group, a hydroxy substituted C 1-8 alkyl group (preferably a hydroxy substituted C 1-6 alkyl group, a C 1-8 alkoxy group) (preferably C 1-6 alkoxy, more preferably C 1-3 alkoxy), C 1-8 alkoxy substituted C 1-8 alkyl (preferably C 1-6 alkoxy substituted) C 1-6 alkyl, more preferably C 1-3 alkoxy substituted C 1-3 alkyl), C 3-8 cycloalkyl (preferably C 3-6 cycloalkyl);
  • R 2 and R 3 are as defined in claim 1.
  • m11 is 1, 2, 3 or 4;
  • R 3 is hydrogen, halogen or C 1-8 alkyl (preferably C 1-6 alkyl, more preferably C 1-3 alkyl) ;
  • m12 is 0.
  • m21 is 1, 2, 3 or 4;
  • R 2 is hydrogen;
  • R 4 is hydrogen or C 1-8 alkyl (preferably C 1-6 alkyl, more preferably C 1-3 Alkyl);
  • m22 is 0, 1, 2, 3 or 4;
  • R a2 is halogen or C 1-8 alkyl (preferably C 1-6 alkyl, more preferably C 1-3 alkyl).
  • n21 is 1, 2 , 3 or 4; R 2 and R 4 are hydrogen; and m22 is 0.
  • n71 is 1, 2 or 3; R a and R b are hydrogen; and m72 is 0.
  • n31, m32 are each independently 2 or 3; m33, m34 is 0; R 3 is hydrogen, halo or C 1-8 alkyl (preferably C 1-6 alkyl More preferably, it is C 1-3 alkyl).
  • n31 and m32 are each independently 1 or 2; m33 and m34 are 0; and R 3 is hydrogen.
  • n41, m42 are each independently 0, 1, 2 or 3; m43, m44 are 0; R 2 is hydrogen, halogen or C 1-8 alkyl (preferably C 1-6 alkyl) More preferably, it is C 1-3 alkyl).
  • n41 and m42 are 1; m43 and m44 are 0; and R 2 is hydrogen.
  • m61 and m62 are each independently 0, 1, 2 or 3; m63 and m64 are 0; and R 2 and R 3 are each independently hydrogen, halogen or C 1-8 alkyl (preferably C 1-6 alkyl, more preferably C 1-3 alkyl).
  • n61 and m62 are 1; m63 and m64 are 0; and R 2 and R 3 are hydrogen.
  • n51 and m52 are each independently 1 or 2; m53 and m54 are 0; and R 2 and R 3 are hydrogen.
  • X is a bond or NR a1 ; wherein R a1 is hydrogen or C 1-3 alkyl.
  • A is a C 6-10 aryl (preferably phenyl) or a 5 to 6 membered monocyclic heteroaryl ring;
  • A is optionally 1, 2 or 3 substituents selected from the group A1. Substituted, said optionally substituted means that the hydrogen on the ring atoms (including carbon atoms and N atoms) is replaced by a substituent.
  • X is NH;
  • A is a C 6-10 aryl (preferably phenyl) or a 5 to 6 membered monocyclic heteroaryl ring;
  • A is optionally 1, 2 or 3 selected from A1 Substituted by a group of substituents, said optionally substituted means that the hydrogen on the ring atoms (including carbon atoms and N atoms) is replaced by a substituent.
  • X is a bond;
  • A is a 5- to 6-membered monocyclic heteroaryl ring;
  • A is optionally substituted with 1, 2 or 3 substituents selected from the group A1, optionally Ground substitution means that the hydrogen on the ring atoms (including carbon atoms and N atoms) is replaced by a substituent.
  • the 5- to 6-membered monocyclic heteroaryl ring is: a thiophene ring, an N-alkylcyclopyrrole ring, a furan ring, a thiazole ring, an imidazole ring, an oxazole ring, a pyrrole ring, a pyrazole ring.
  • triazole ring 1,2,3-triazole ring, 1,2,4-triazole ring, 1,2,5-triazole ring, 1,3,4-triazole ring, tetrazole ring, different Oxazole ring, oxadiazole ring, 1,2,3-oxadiazole ring, 1,2,4-oxadiazole ring, 1,2,5-oxadiazole ring, 1,3,4-oxo
  • the 5 to 6 membered monocyclic heteroaryl ring is selected from the group consisting of
  • the above 5- to 6-membered monocyclic heteroaryl ring is optionally substituted by 1, 2 or 3 substituents selected from the group A1, which are optionally substituted to mean a ring atom (including a carbon atom and an N atom).
  • the hydrogen is replaced by a substituent.
  • X is NH; A is selected from the group consisting of the B1 group.
  • X is a bond; A is selected from the group consisting of B1 or B2.
  • X is NH;
  • A is a C 6-10 aryl (preferably phenyl) or a 5 to 6 membered monocyclic heteroaryl ring;
  • A is optionally 1, 2 or 3 selected from A1 Substituted by a substituent; said optionally substituted means that the hydrogen on the ring atom (including carbon and N atoms) is replaced by a substituent;
  • R 1 is hydrogen or a C 1-8 alkyl group (preferably a C 1-6 alkyl group, more preferably a C 1-3 alkyl group).
  • X is NH; A is selected from the group consisting of B1;
  • R 1 is hydrogen or a C 1-8 alkyl group (preferably a C 1-6 alkyl group, more preferably a C 1-3 alkyl group).
  • X is a bond;
  • A is a 5- to 6-membered monocyclic heteroaryl ring;
  • A is optionally substituted with 1, 2 or 3 substituents selected from the group A1;
  • Ground substitution means that the hydrogen on the ring atoms (including carbon atoms and N atoms) is replaced by a substituent;
  • R 1 is hydrogen or a C 1-8 alkyl group (preferably a C 1-6 alkyl group, more preferably a C 1-3 alkyl group).
  • X is a bond
  • A is selected from the group consisting of B1 or B2;
  • R 1 is hydrogen or a C 1-8 alkyl group, preferably R 1 is a C 1-8 alkyl group (preferably a C 1-6 alkyl group, more preferably a C 1-3 alkyl group).
  • m11 is 3.
  • formula (D), formula (E), formula (F) or formula (G) is selected from the group consisting of:
  • formula (A) is selected from the group consisting of C1 groups.
  • the C1 group structure is:
  • formula (B) is selected from the group consisting of
  • formula (C) is selected from the group consisting of
  • a second aspect of the invention provides a compound of formula (II), or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof:
  • Y is a bond, NR a1 , S, SO, SO 2 or O; wherein R a1 is hydrogen, hydroxy or C 1-8 alkyl (preferably C 1-6 alkyl, more preferably C 1- 3 alkyl);
  • B is a C 6-10 aryl group (preferably a phenyl group), a 4 to 7 membered saturated or unsaturated monoheterocyclic ring, a 5 to 6 membered monocyclic heteroaryl ring, and an 8 to 10 membered bicyclic heteroaryl ring;
  • Q is N or CR b1 ; wherein R b1 is hydrogen, halogen (preferably fluorine, chlorine, bromine), cyano, C 1-8 alkyl (preferably C 1-6 alkyl, more preferably C 1-3 alkane) a halogenated C 1-8 alkyl group (preferably a halogenated C 1-6 alkyl group, more preferably a halogenated C 1-3 alkyl group), a C 1-8 alkoxy group (preferably a C 1-6) Alkoxy, more preferably C 1-3 alkoxy), C 3-8 cycloalkyl (preferably C 3-6 cycloalkyl) or C 3-8 cycloalkoxy (preferably C 3-6) Cycloalkoxy);
  • R b1 is hydrogen, halogen (preferably fluorine, chlorine, bromine), cyano, C 1-8 alkyl (preferably C 1-6 alkyl, more preferably C 1-3 alkane) a halogenated C 1-8 alkyl group (preferably a hal
  • Z 1, Z 2, Z 3 , Z 4 three is CH, a is N; or Z 1, Z 2, Z 3 , Z 4 are CH;
  • R 5 and R 6 are each independently hydrogen, halogen (preferably fluorine, chlorine, bromine), C 1-8 alkyl (preferably C 1-6 alkyl, more preferably C 1-3 alkyl), halogenated C 1-8 alkyl (preferably halogenated C 1-6 alkyl, more preferably halogenated C 1-3 alkyl), C 1-8 alkoxy (preferably C 1-6 alkoxy, more Preferred is C 1-3 alkoxy), C 3-8 cycloalkyl (preferably C 3-6 cycloalkyl) or C 3-8 cycloalkoxy (preferably C 3-6 cycloalkoxy) ;
  • halogen preferably fluorine, chlorine, bromine
  • C 1-8 alkyl preferably C 1-6 alkyl, more preferably C 1-3 alkyl
  • halogenated C 1-8 alkyl preferably halogenated C 1-6 alkyl, more preferably halogenated C 1-3 alkyl
  • C 1-8 alkoxy preferably C 1-6 alkoxy, more
  • R 7 and R 9 are each independently hydrogen, C 1-8 alkyl (preferably C 1-6 alkyl, more preferably C 1-3 alkyl), halogenated C 1-8 alkyl (preferably halogen) a C 1-6 alkyl group, more preferably a halogenated C 1-3 alkyl group or a C 3-8 cycloalkyl group (preferably a C 3-6 cycloalkyl group);
  • R 8 is hydrogen, halogen, cyano, C 1-8 alkyl (preferably C 1-6 alkyl, more preferably C 1-3 alkyl), C 1-8 alkoxy (preferably C 1- 6 alkoxy, more preferably C 1-3 alkoxy), halogenated C 1-8 alkyl (preferably halogenated C 1-6 alkyl, more preferably halogenated C 1-3 alkyl) or C 3-8 cycloalkyl (preferably C 3-6 cycloalkyl) or NR a0 R b0 ; wherein R a0 , R b0 are each independently hydrogen, acetyl, C 1-8 alkyl (preferably C 1 a -6 alkyl group, more preferably a C 1-3 alkyl group), a C 1-8 alkoxy-substituted C 1-8 alkyl group (preferably a C 1-6 alkoxy-substituted C 1-6 alkyl group, More preferably, C 1-3 alkoxy substituted C 1-3 alkyl);
  • j 0, 1, 2, 3 or 4;
  • alkyl, cycloalkyl, alkoxy, cycloalkoxy, aryl, saturated or unsaturated monoheterocyclic, monocyclic heteroaryl ring, bicyclic heteroaryl ring is unsubstituted or 1, 2 Or 3 substituents selected from the group consisting of halogen, hydroxymethyl, hydroxyethyl, hydroxy, carboxy, -O(CH 2 ) p OC 1-8 alkyl, -O(CH 2 ) p OH, -(CH 2 ) p OC 1-8 alkyl, 4 to 6-membered saturated monoheterocyclic ring, C 1-8 alkyl group (preferably C 1-6 alkyl group, more preferably C 1-3 alkyl group), C 3-8 cycloalkyl (preferably C 3-6 cycloalkyl), halogenated C 1-8 alkyl (preferably halogenated C 1-6 alkyl, more preferably halogenated C 1-3 alkyl) a halogenated
  • Y is a bond or NR a1 ; wherein R a1 is hydrogen, C 1-3 alkyl.
  • B is a phenyl or pyrazole ring.
  • Y is a bond;
  • B is a 5- to 6-membered monocyclic heteroaryl ring; and the 5- to 6-membered monocyclic heteroaryl ring is optionally 1, 2 or 3 selected from A1 Substituted by a group of substituents.
  • Y is a bond; B is selected from the group consisting of B2.
  • Y is a bond; B is a pyrazole ring; and the pyrazole ring is optionally substituted with 1, 2 or 3 substituents selected from the group A1.
  • Y is NR a1 ; wherein R a1 is hydrogen, C 1-3 alkyl; B is phenyl or a 5 to 6 membered monocyclic heteroaryl ring; and said B is optionally 1. Substituting 2 or 3 substituents selected from the group A1, which is optionally substituted means that the hydrogen on the ring atom (including the carbon atom and the N atom) is substituted with a substituent.
  • Y is NR a1 ; wherein R a1 is hydrogen, C 1-3 alkyl; B is phenyl or pyrazole ring; and the phenyl or pyrazole ring is optionally 1, 2 or Three substituents selected from the group A1 were substituted.
  • Y is NR a1 ; wherein R a1 is hydrogen, C 1-3 alkyl; and B is selected from the group consisting of B1.
  • R 7 and R 9 are each independently hydrogen, C 1-3 alkyl, halo C 1-3 alkyl or C 3-6 cycloalkyl.
  • the substituent of the group A1 is: halogen, -O(CH 2 ) p OC 1-8 alkyl, -O(CH 2 ) p OH, -(CH 2 ) p OC 1-8 alkane a 4- to 6-membered saturated monoheterocyclic ring, a C 1-8 alkyl group (preferably a C 1-6 alkyl group, more preferably a C 1-3 alkyl group), a C 3-8 cycloalkyl group (preferably C 3 ) -6 cycloalkyl), halogenated C 1-8 alkyl (preferably halogenated C 1-6 alkyl, more preferably halogenated C 1-3 alkyl), halogenated C 3-8 cycloalkyl ( Preferred is a halogenated C 3-6 cycloalkyl group, a hydroxy-substituted C 1-8 alkyl group (preferably a hydroxy-substituted C 1-6 alkyl group, more
  • the 4- to 6-membered saturated monocyclic ring in the substituent of Group A1 is selected from the group consisting of azetidine, oxetane, tetrahydrofuran, tetrahydrothiophene, tetrahydropyrrole, piperidine, oxazole Alkane, piperazine, dioxolane, dioxane, morpholine, thiomorpholine, thiomorpholine-1,1-dioxide or tetrahydropyran.
  • the substituent of the group A1 is fluorine, chlorine, bromine, hydroxymethyl, hydroxyethyl, hydroxy, carboxy, -O(CH 2 ) p OC 1-3 alkyl, -O(CH 2 p OH, -(CH 2 ) p OC 1-3 alkyl, azetidine, oxetane, tetrahydrofuran, tetrahydrothiophene, tetrahydropyrrole, piperidine, oxazolidine, piperazine, two Oxolane, dioxane, morpholine, thiomorpholine, thiomorpholine-1,1-dioxide, tetrahydropyran, methyl, ethyl, n-propyl, isopropyl, ring Propyl, monochloroethyl, dichloromethyl, 1,2-dichloroethyl, monobromoethyl, mono
  • the B1 group structure is:
  • the B2 group structure is:
  • the compound of formula (I) is selected from the group consisting of the D1 group.
  • the D1 group structure is:
  • the compound of formula (II) is selected from the group consisting of the D2 group.
  • the D2 group structure is:
  • a third aspect of the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising the compound according to the first or second aspect of the invention, or a pharmaceutically acceptable salt, solvate, stereoisomer or pharmaceutically acceptable salt thereof a drug; and a pharmaceutically acceptable carrier or excipient.
  • a fourth aspect of the present invention provides the compound of the first or second aspect of the present invention, or a pharmaceutically acceptable salt, solvate, stereoisomer or prodrug thereof, or the pharmaceutical composition of the third aspect of the present invention Use in the preparation of kinase inhibitor drugs.
  • the medicament is used as a BTK inhibitor.
  • the fifth aspect of the invention provides the compound of the first or second aspect of the invention, or a pharmaceutically acceptable salt, solvate, stereoisomer or prodrug thereof, or the pharmaceutical composition of the third aspect of the invention In the preparation of diseases mediated by B cells.
  • a sixth aspect of the invention provides a method of treating a disease mediated by a B cell comprising administering a therapeutically effective amount of the compound of the first or second aspect of the invention, or a pharmaceutically acceptable salt thereof, to a patient in need thereof A solvate, stereoisomer or prodrug, or a pharmaceutical composition according to the third aspect of the invention.
  • a seventh aspect of the invention provides a method of treating a disease mediated by a B cell comprising administering a therapeutically effective amount of the compound of the first or second aspect of the invention, or a pharmaceutically acceptable salt thereof, to a patient in need thereof , solvates, stereoisomers or prodrugs, as well as another therapeutically active agent.
  • the B cell mediated disease is selected from the group consisting of a neoplastic disease, a proliferative disease, an allergic disease, an autoimmune disease, or an inflammatory disease.
  • the B cell mediated disease is selected from the group consisting of: solid tumor, acute lymphocytic leukemia, chronic lymphocytic leukemia, acute myeloid leukemia, chronic myelogenous leukemia, rheumatoid arthritis, psoriatic joint Inflammation, osteoarthritis, systemic lupus erythematosus, psoriasis, rheumatoid spondylitis and gouty arthritis.
  • the B cell mediated disease is a solid tumor.
  • the solid tumor is at least one selected from the group consisting of lymphoma, soft tissue sarcoma, lymphocytic lymphoma, mantle cell lymphoma, melanoma, and multiple myeloma.
  • the inventors have unexpectedly discovered such aniline-substituted 1,2-dihydropyrrolo[3,4-c]pyridine/pyrimidin-3-one derivatives, especially N-(3), after extensive and intensive research.
  • -aminophenyl)acrylamide substituted 1,2-dihydropyrrolo[3,4-c]pyridine/pyrimidin-3-one derivatives have high inhibition of BTK WT and other cells and cells such as pBTK Y223 and TNF ⁇ active. Therefore, this series of compounds is expected to be developed as a drug for treating tumors. On this basis, the inventors completed the present invention.
  • alkyl refers to both straight and branched saturated aliphatic hydrocarbon groups, and C1-8 alkyl is alkyl having from 1 to 8 carbon atoms, preferably C1-6 alkyl or C. 1-3 alkyl, the definition is similar; non-limiting examples of alkyl include: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl 1,1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methyl Butyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-e
  • cycloalkyl refers to a saturated or partially unsaturated monocyclic cyclic hydrocarbon group
  • C 3-8 cycloalkyl refers to a cyclic hydrocarbon group containing from 3 to 8 carbon atoms, preferably C 3-6 Cycloalkyl, definitionally similar; non-limiting examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl
  • the group, the cycloheptatrienyl group, the cyclooctyl group and the like are preferably a cyclopropyl group, a cyclopentyl group or a cyclohexenyl group.
  • spiroheterocycle refers to a polycyclic hydrocarbon in which one atom (called a spiro atom) is shared between monocyclic rings, wherein one or two ring atoms are selected from nitrogen, oxygen or S(O) n (where n is an integer) From 0 to 2), the remaining atoms are carbon. These may contain one or more double bonds, but none of the rings have a fully conjugated pi-electron system.
  • the spiroheterocycle is classified into a bispiral heterocyclic ring or a polyspirocyclic ring according to the number of rings, preferably a double spiro heterocyclic ring. More preferably, it is 4 yuan/5 yuan, 5 yuan/5 yuan or 5 yuan / 6 yuan double spiro heterocycle.
  • bridge heterocycle refers to a polycyclic group that shares two or more atoms, wherein one or more ring atoms are selected from nitrogen, oxygen, or S(O) n (where n is an integer from 0 to 2) a hetero atom, the remaining ring atoms being carbon. These may contain one or more double bonds, but none of the rings have a fully conjugated pi-electron system. It is preferably a bicyclic or tricyclic bridge heterocycle. E.g:
  • C 1-8 alkoxy refers to -O-(C 1-8 alkyl), wherein alkyl is as defined above.
  • a C 1-6 alkoxy group is preferred, and a C 1-3 alkoxy group is more preferred.
  • Non-limiting examples include methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy, isobutoxy, pentyloxy and the like.
  • C 3-8 cycloalkoxy refers to -O-(C 3-8 cycloalkyl), wherein cycloalkyl is as defined above. Preference is given to C 3-6 cycloalkoxy. Non-limiting examples include cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy, and the like.
  • C 6-10 aryl refers to an all-carbon monocyclic or fused polycyclic ring (ie, a ring that shares a pair of adjacent carbon atoms) having a conjugated ⁇ -electron system, meaning 6 to 10
  • An aryl group of a carbon atom preferably a phenyl group and a naphthyl group, most preferably a phenyl group.
  • a bond refers to the attachment of two groups attached thereto through a covalent bond.
  • halogen refers to fluoro, chloro, bromo or iodo.
  • halo means that one or more (eg 1, 2, 3, 4 or 5) hydrogens in the group are replaced by a halogen.
  • halo C 1-8 alkyl refers to an alkyl group substituted with one or more (eg 1, 2, 3, 4 or 5) halo, wherein alkyl is as defined above. It is selected as a halogenated C 1-6 alkyl group, more preferably a halogenated C 1-3 alkyl group.
  • halogenated C 1-8 alkyl groups include, but are not limited to, monochloromethyl, dichloromethyl, trichloromethyl, monochloroethyl, 1,2-dichloroethyl, trichloroethyl, Monobromoethyl, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoroethyl, difluoroethyl, trifluoroethyl, and the like.
  • halo C 1-8 alkoxy means that the alkoxy group is substituted by one or more (eg 1, 2, 3, 4 or 5) halogens, wherein the alkoxy group is as defined above. It is preferably a halogenated C 1-6 alkoxy group, more preferably a halogenated C 1-3 alkoxy group.
  • halo C 1-8 alkoxy include, but are not limited to, trifluoromethoxy, trifluoroethoxy, monofluoromethoxy, monofluoroethoxy, difluoromethoxy, difluoroethane. Oxyl and the like.
  • halo C 3-8 cycloalkyl refers to a cycloalkyl group substituted with one or more (eg, 1, 2, 3, 4, or 5) halo, wherein cycloalkyl is as defined above. Preferred is a halogenated C 3-6 cycloalkyl group. Examples of halogenated C 3-8 cycloalkyl groups include, but are not limited to, trifluorocyclopropyl, monofluorocyclopropyl, monofluorocyclohexyl, difluorocyclopropyl, difluorocyclohexyl, and the like.
  • deuterated C 1-8 alkyl refers to an alkyl group substituted with one or more (eg 1, 2, 3, 4 or 5) deuterium atoms, wherein alkyl is as defined above. It is preferably a deuterated C 1-6 alkyl group, more preferably a deuterated C 1-3 alkyl group. Examples of deuterated C 1-8 alkyl groups include, but are not limited to, monodeuterated methyl, monodeuterated ethyl, dideuterated methyl, diterpene ethyl, triterpene methyl, triterpenoid B Base.
  • amino refers to NH 2
  • cyano refers to the CN
  • Niro refers to NO 2
  • benzyl refers to -CH 2 - phenyl
  • carboxy refers to -C (O) OH
  • acetyl means a -C (O) CH 3
  • hydroxymethyl group refers to -CH 2 OH
  • hydroxyethyl refers to -CH 2 CH 2 OH
  • hydroxy means - OH
  • thiol refers to SH
  • cyclopropylene structure is:
  • heteroaryl ring and “heteroaryl” are used interchangeably and mean having 5 to 10 ring atoms, preferably 5 or 6 membered monocyclic heteroaryl or 8 to 10 membered bicyclic heteroaryl.
  • the ring array shares 6, 10 or 14 ⁇ electrons; and has a group of 1 to 5 hetero atoms in addition to carbon atoms.
  • Hetero atom means nitrogen, oxygen or sulfur.
  • 4 to 7 membered saturated monoheterocycle means that 1, 2 or 3 carbon atoms in a 4 to 7 membered monocyclic ring are selected from nitrogen, oxygen or S(O) t (where t is an integer 0)
  • the heteroatoms to 2) are substituted, but do not include the ring moiety of -OO-, -OS- or -SS-, and the remaining ring atoms are carbon; preferably 4 to 6 members, more preferably 5 to 6 members.
  • 4- to 7-membered saturated monoheterocycles include, but are not limited to, propylene oxide, azetidine, oxetane, tetrahydrofuran, tetrahydrothiophene, tetrahydropyrrole, piperidine, pyrroline, oxazole Alkane, piperazine, dioxolane, dioxane, morpholine, thiomorpholine, thiomorpholine-1,1-dioxide, tetrahydropyran, and the like.
  • a "5- to 6-membered monocyclic heteroaryl ring” refers to a monoheteroaryl ring containing from 5 to 6 ring atoms, including, for example, but not limited to, a thiophene ring, an N-alkylcyclopyrrole ring, Furan ring, thiazole ring, imidazole ring, oxazole ring, pyrrole ring, pyrazole ring, triazole ring, 1,2,3-triazole ring, 1,2,4-triazole ring, 1,2,5- a triazole ring, a 1,3,4-triazole ring, a tetrazole ring, an isoxazole ring, an oxadiazole ring, a 1,2,3-oxadiazole ring, a 1,2,4-oxadiazole ring, 1,2,5-oxadiazole ring, 1,3,4-oxadiazole ring, ring,
  • 8- to 10-membered bicyclic heteroaryl ring refers to a bi-heteroaryl ring containing from 8 to 10 ring atoms, including, for example, but not limited to, benzofuran, benzothiophene, anthracene, Isoindole, quinoline, isoquinoline, carbazole, benzothiazole, benzimidazole, quinazoline, quinoxaline, porphyrin, pyridazine.
  • substituted refers to one or more hydrogen atoms in the group, preferably 1 to 5 hydrogen atoms are independently substituted with each other by a corresponding number of substituents, more preferably 1 to 3 hydrogen atoms are independent of each other. The ground is replaced by a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and those skilled in the art will be able to determine (by experiment or theory) substitutions that may or may not be possible without undue effort. For example, an amino group or a hydroxyl group having a free hydrogen may be unstable when combined with a carbon atom having an unsaturated (e.g., olefinic) bond.
  • any of the above groups may be substituted or unsubstituted.
  • the substituent is preferably 1 to 5 (more preferably 1 to 3) or less, independently selected from halogen, -O(CH 2 ) p OC 1-8 alkyl, -O ( CH 2 ) p OH, -(CH 2 ) p OC 1-8 alkyl, 4 to 6-membered saturated monoheterocyclic ring, C 1-8 alkyl group (preferably C 1-6 alkyl group, more preferably C 1- 3 alkyl), C 3-8 cycloalkyl (preferably C 3-6 cycloalkyl), halogenated C 1-8 alkyl (preferably halogenated C 1-6 alkyl, more preferably halogen C 1-3 alkyl), halogenated C 3-8 cycloalkyl (preferably halogenated C 3-6 cycloalkyl), hydroxy substituted C 1-8 alkyl (preferably hydroxy substituted C 1-6 alkan
  • the “pharmaceutically acceptable salt” includes pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.
  • “Pharmaceutically acceptable acid addition salt” means a salt formed with an inorganic or organic acid which retains the bioavailability of the free base without any other side effects.
  • “Pharmaceutically acceptable base addition salts” including but not limited to salts of inorganic bases such as sodium, potassium, calcium and magnesium salts, and the like. These include, but are not limited to, salts of organic bases such as ammonium salts, triethylamine salts, lysine salts, arginine salts and the like.
  • solvate refers to a complex of a compound of the invention with a solvent. They either react in a solvent or precipitate out of the solvent or crystallize out. For example, a complex formed with water is referred to as a "hydrate.” Solvates of the compounds of formula (I) are within the scope of the invention.
  • the compounds of formula (I) of the present invention may contain one or more chiral centers and exist in different optically active forms. When the compound contains a chiral center, the compound contains the enantiomer.
  • the invention includes mixtures of the two isomers and isomers, such as racemic mixtures. Enantiomers can be resolved by methods known in the art, such as crystallization and chiral chromatography. When the compound of formula (I) contains more than one chiral center, diastereomers may be present.
  • the present invention includes resolved optically pure specific isomers as well as mixtures of diastereomers. Diastereomers can be resolved by methods known in the art, such as crystallization and preparative chromatography.
  • the invention includes prodrugs of the above compounds.
  • Prodrugs include known amino protecting groups and carboxy protecting groups which are hydrolyzed under physiological conditions or released via an enzymatic reaction to give the parent compound.
  • Specific prodrug preparation methods can be referred to (Saulnier, MG; Frennesson, DB; Deshpande, MS; Hansel, SB and Vysa, DM Bioorg. Med. Chem Lett. 1994, 4, 1985-1990; and Greenwald, RB; Choe, YH; Conover, CD; Shum, K.; Wu, D.; Royzen, MJ Med. Chem. 2000, 43, 475.).
  • a compound of the invention in general, can be administered in a suitable dosage form with one or more pharmaceutically acceptable carriers.
  • dosage forms are suitable for oral, rectal, topical, intraoral, and other parenteral administration (eg, subcutaneous, intramuscular, intravenous, etc.).
  • dosage forms suitable for oral administration include capsules, tablets, granules, and syrups and the like.
  • the compound of the present invention contained in these preparations may be a solid powder or granule; a solution or suspension in an aqueous or non-aqueous liquid; a water-in-oil or oil-in-water emulsion or the like.
  • the above dosage forms can be prepared from the active compound with one or more carriers or excipients via conventional pharmaceutical methods.
  • the above carriers need to be compatible with the active compound or other excipients.
  • commonly used non-toxic carriers include, but are not limited to, mannitol, lactose, starch, magnesium stearate, cellulose, glucose, sucrose, and the like.
  • Carriers for liquid preparations include water, physiological saline, aqueous dextrose, ethylene glycol, polyethylene glycol, and the like.
  • the active compound can form a solution or suspension with the above carriers.
  • compositions of the present invention are formulated, quantified, and administered in a manner consistent with medical practice.
  • the "therapeutically effective amount" of a given compound will be determined by the particular condition being treated, the individual being treated, the cause of the condition, the target of the drug, and the mode of administration.
  • terapéuticaally effective amount refers to a compound of the invention that will elicit a biological or medical response to an individual, such as reducing or inhibiting the activity of an enzyme or protein or ameliorating a condition, alleviating a condition, slowing or delaying the progression of a disease, or preventing a disease, and the like. the amount.
  • pharmaceutically acceptable carrier means a non-toxic, inert, solid, semi-solid substance or liquid filler, diluent, encapsulating or auxiliary formulation or any type of excipient that is compatible with the patient, most Preferably, it is a mammal, more preferably a human, which is suitable for delivering the active agent to a target of interest without terminating the activity of the agent.
  • patient refers to an animal, preferably a mammal, and more preferably a human.
  • mammal refers to warm-blooded vertebrate mammals including, for example, cats, dogs, rabbits, bears, foxes, wolves, monkeys, deer, rats, pigs, and humans.
  • treating refers to alleviating, delaying progression, attenuating, preventing, or maintaining an existing disease or condition (eg, cancer). Treatment also includes curing, preventing, or alleviating one or more symptoms of the disease or condition to some extent.
  • the present invention provides a process for the preparation of a compound of formula (I).
  • the compounds of the present invention can be prepared by a variety of synthetic procedures, and exemplary methods of preparation of such compounds can include, but are not limited to, the schemes described below.
  • the compounds of formula (I) of the present invention can be prepared by the following schemes and exemplary methods described in the Examples and related publications used by those skilled in the art.
  • the steps in the method can be extended or merged as needed during the specific operation.
  • Step 1 Compound 1a is subjected to a nucleophilic substitution reaction with a corresponding amine (primary or secondary amine) under basic conditions.
  • Step 2 Chloride on the pyridine ring and the corresponding amine, Buchwald coupling reaction catalyzed by palladium catalyst under basic conditions.
  • Step 3 The amine is deprotected under acidic conditions.
  • Step 4 The secondary amine on ring A undergoes an amide condensation reaction with an acid chloride under basic conditions.
  • Step 1 The Suzuki coupling reaction is carried out by catalyzing the chlorine on the pyridine ring with the corresponding boronic acid under basic conditions via a palladium catalyst.
  • 1,2-dihydropyrrolo[3,4-c]pyridine/pyrimidin-3-one derivatives especially N-(3-aminophenyl)acrylamide substituted
  • the 1,2-dihydropyrrolo[3,4-c]pyridine/pyrimidin-3-one derivative has high inhibitory activity against BTK WT enzyme and cells such as pBTK Y223, and has a weak inhibitory activity against EGFR WT. It has obvious selective inhibition and can be used as a drug for treating tumors.
  • DMB is 2,4-dimethoxybenzyl
  • THF is tetrahydrofuran
  • EA is ethyl acetate
  • PE is petroleum ether
  • Ac 2 O is acetic anhydride
  • NBS is N-bromosuccinimide.
  • DCM is dichloromethane
  • AIBN is azobisisobutyronitrile
  • Pd(dppf)Cl 2 is 1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride
  • TFA is trifluoroacetic acid
  • TBSCl Is tert-butyldimethylchlorosilane
  • NCS is N-chlorosuccinimide
  • DHP is dihydrotetrahydropyran
  • LiAlH 4 is lithium aluminum hydride
  • PMB is p-methoxybenzyl
  • LiHMDS is two Lithium (trimethylsilyl)amide
  • Pd 2 (dba) 3 is tris(dibenzylideneacetone)dipalladium
  • RuPhos is 2-dicyclohexylphosphorin-2',6'-diisopropoxy-1 , 1 '-biphenyl
  • DMAP is 4-dimethylamin
  • room temperature means about 20-25 °C.
  • Step 2 Compound 5a-1 (2.5 g, 10.5 mmol) was dissolved in 15 ml of methanol, and 2,4-dimethoxybenzylamine (1.84 g, 11.03 mmol) was added, and the mixture was stirred at room temperature for 1 hour, and solid precipitated. The filter cake was washed with petroleum ether and dried to give a white solid 5a-2 (3.14 g, 77.3%).
  • Step 3 To a suspension of compound 5a-2 (3.24 g, 8.37 mmol) in tetrahydrofuran (35 ml) was added dropwise a solution of diethyl ether in diethyl ether (1.6 M, 41.86 mmol). Stirring was continued for two hours, and the reaction mixture was acidified to pH -6 with 1N diluted hydrochloric acid. The mixture was heated to 50 ° C for 5 hours, cooled to room temperature and then extracted with ethyl acetate (2*50ml). The combined organic phases were washed with brine (50 ml), dried over anhydrous sodium sulfate After purification, compound 5a (0.76 g, 23.5%) was obtained.
  • Step 1 To a 250 ml flask was added methyl 2,6-dichloro-4-methylnicotinate (4.24 g, 19.268 mmol), N-bromosuccinimide (4.1 g, 23.036 mmol), azo Isobutyronitrile (160 mg, 0.974 mmol) and 50 ml of carbon tetrachloride were stirred at 85 ° C overnight.
  • reaction mixture was concentrated to remove carbon tetrachloride, and 50 ml of ethyl acetate was added, and the mixture was washed with 50 ml of brine and 50 ml of water, and the organic phase was dried over anhydrous sodium sulfate and evaporated to give 6.4 g of oil 4-(bromomethyl)-2,6 Methyl dichloronicotinate, MS m/z (ESI): 300.1 [M+H] + .
  • Step 2 To a 250 ml flask was added methyl 4-(bromomethyl)-2,6-dichloronicotinate (6.4 g, 21.408 mmol), (2,4-dimethoxyphenyl)methylamine (3.2 g, 19.14 mmol) and 150 ml of acetonitrile. The reaction mixture was stirred at room temperature for 3 h, then EtOAc EtOAcjjjjjj H] + .
  • Compounds 10a-13a are 1-cyclopropyl-1H-pyrazol-4-amine, 1-(2-methoxyethyl)-1H-pyrazole-4-amine, 4-morpholinoaniline and S)-4-(2-methyl-4-(oxetan-3-yl)piperazin-1-yl)aniline was used as a starting material, and was prepared by the method of the compound 9a.
  • Step 1 4,6-Dichloro-7-fluoro-1-hydroxyfuro[3,4-c]pyridine-3(1H)-one (23.12 g, 97.14 mmol) and 2,4-dimethoxybenzyl
  • the amine (17.03 g, 102 mmol) was dissolved in 400 ml of 1,4-dioxane. After stirring at room temperature for half an hour, sodium borohydride (41.19 g, 194.28 mmol) was added and stirring was continued for half an hour and then heated to 50 ° C.
  • Step 2 2-(2,4-Dimethoxybenzyl)-4,6-dichloro-7-fluoro-1,2-dihydropyrrolo[3,4-c]pyridine under ice bath Sodium ketone (5.0 g, 13.48 mmol) was added portionwise over aq. The reaction mixture was slowly warmed to room temperature, and the reaction was continued for 2 hours. The reaction was quenched with water and ethyl acetate (2*100 ml).
  • Step 2 Pd 2 (dba) 3 (52 mg, 0.057 mmol), Xantphos (66 mg, 0.114 mmol) and cesium carbonate (372 mg, 1.14 mmol) were added to compound G-1-1 (260 mg, 0.57 mmol) and 4- (2-methoxyethoxy)aniline (143 mg, 0.86 mmol) in 1,4-dioxane (6 ml), heated to 160 ° C in a microwave reactor under argon atmosphere, stirred for 20 minutes. . After the reaction mixture was cooled to room temperature, the solid was filtered, and the cake was washed with ethyl acetate.
  • Step 4 To a solution of the compound G-1-3 (105 mg, 0.164 mmol) in trifluoroacetic acid (3 ml) was added triethylsilane (38 mg, 0.328 mmol), and reacted at room temperature for two hours. The phase was purified to give compound G-1 (8 mg, 8.7%).
  • Step 1 To a 30 ml microwave reactor was added compound 1a (555 mg, 1.579 mmol), 3-nitroaniline (219 mg, 1.586 mmol), TsOH (296 mg, 1.719 mmol) and 12 ml of 1,4-dioxane. The reaction mixture was stirred at 110 ° C for 30 min, washed with EtOAc EtOAc EtOAc (EtOAc (EtOAc) MS m/z (ESI): 454.4 [M+H] +
  • Step 2 Compound G-2-1 (600 mg, 1.323 mmol), SeO 2 (920 mg, 8.291 mmol) and 20 ml of 1,4-dioxane were added to a 50 ml reaction flask, and the reaction mixture was stirred at 110 ° C overnight. the reaction was filtered, concentrated by combiflash (n-hexane containing 20% -90% ethyl acetate) to give a yellow solid 570mg G-2-2, MS m / z (ESI): 468.2 [m + H] +.
  • Step 3 To a 25 ml flask was added compound G-2-2 (500 mg, 1.07 mmol), (2,4-dimethoxyphenyl)methylamine (200 mg, 1.196 mmol), 20 ml of dichloromethane and 1 ml of tetrahydrofuran. After the reaction mixture was stirred at room temperature for 1.5 h, then NaHH(OAc) 3 (1. combiflash (0-10% methanol in dichloromethane) to yield a yellow oil 65mg G-2-3, MS m / z (ESI): 619.4 [m + H] +.
  • Step 4 To a 50 ml flask was added compound G-2-3 (65 mg, 0.105 mmol), K 2 CO 3 (40 mg, 0.289 mmol) and 10 ml of acetonitrile. The reaction mixture was stirred at 80 ° C for 3 h The oil G-2-4 was directly subjected to the next reaction without purification. MS m/z (ESI): 587.4 [M+H] + .
  • Step 5 To 60 mg of the crude compound G-2-4 was added 5 ml of ethanol, 5 ml of tetrahydrofuran, 5 ml of a saturated ammonium chloride solution and a trace amount of iron powder, and the reaction mixture was stirred at 70 ° C for 3 h. The reaction mixture was washed with water and extracted with EtOAc. EtOAc EtOAc EtOAc EtOAc EtOAc EtOAc. extracted with ethyl acetate, the organic layer was 57mg oil dried and concentrated G-2-5, MS m / z (ESI) : 611.3 [m + H] +.
  • Step 6 To a 10 ml microwave reactor tube was added compound G-2-5 (57 mg, 0.093 mmol) and 2 ml of tetrahydrofuran. The reaction mixture was stirred at 110 ° C for 20 min then concentrated. MS m/z (ESI): 461.4 [M+H] + .
  • Step 1 Pd 2 (dba) 3 (92 mg, 0.01 mmol), Xantphos (100 mg, 0.2 mmol) and cesium carbonate (1 g, 3 mmol) were added to compound 6a (442 mg, 1 mmol) and 4-(2-methoxy)
  • a solution of ethoxy)aniline (170 mg, 1 mmol) in 1,4-dioxane (15 ml) was heated to 160 ° C in a microwave reactor under argon atmosphere and stirred for 20 min. After the reaction mixture was cooled to room temperature, the solid was filtered, and the cake was washed with ethyl acetate.
  • Step 1 Pd 2 (dba) 3 (90 mg, 0.01 mmol), Xantphos (100 mg, 0.2 mmol) and cesium carbonate (1 g, 3 mmol) were added to compound 6a (440 mg, 1 mmol) and 1-(4-(4- Aminophenyl)piperazin-1-yl)propan-2-ol (235 mg, 1 mmol) in 1,4-dioxane (15 ml) was heated to 160 ° C in a microwave reactor under argon atmosphere. The reaction was stirred for 20 minutes. After the reaction mixture was cooled to room temperature, the solid was filtered, and the cake was washed with ethyl acetate.
  • Step 1 To a 30 ml microwave reactor was added compound 8a (883 mg, 2.5 mmol), 4-(2-methoxyethoxy)aniline (418 mg, 2.5 mmol), N,N-diisopropylethylamine ( 647 mg, 5 mmol) and 15 ml of N-methylpyrrolidone, the reaction mixture was stirred at 200 ° C for 1 hour, concentrated to remove N-methylpyrrolidone and subjected to Combi-flash column chromatography [0-80% ethyl acetate in hexanes. The yellow solid G-10-1 (550 mg, 45.5%) was obtained after purification. MS m/z (ESI): 484 [M+H] + .
  • Step 2 Add Pd 2 (dba) 3 (24 mg, 0.026 mmol), Xantphos (30 mg, 0.052 mmol), cesium carbonate (337 mg, 1.034 mmol), compound G-10-1 (250 mg, 0.517) to a 30 ml microwave reactor. Methyl), m-diphenylamine (71 mg, 0.514 mmol) and 1,4-dioxane (10 ml), and the mixture was stirred at 160 ° C for 30 min. The reaction mixture was washed with EtOAc EtOAc (EtOAc)EtOAc. MS m/z (ESI): 586.2 [M+H] + .
  • Step 3 To a 100 ml flask was added compound G-10-2 (270 mg, 0.461 mmol), iron powder (130 mg, 2.321 mmol), ammonium chloride solution (2 ml), THF (4 ml), water (2 ml), ethanol ( 4 ml), the reaction mixture was stirred at 75 ° C for 2 h. The reaction mixture was filtered, and then ethyl acetate (30 ml). MS m/z (ESI): 556.2 [M+H] + .
  • Step 4-5 Compound G-10 was obtained by the same procedure as in Steps 2 and 3 of Example 3 using Compound G-10-3 as a starting material. MS m/z (ESI): 460.2 [M+H] + .
  • Step 1 Methyl 2,4-dichloro-6-methylpyrimidine-5-carboxylate (110 mg, 0.5 mmol) and 4-(2-methoxy-ethoxy)-phenol (84 mg, 0.5 mmol) Dissolved in 3 ml of DMSO, potassium carbonate (138 mg, 1.0 mmol) was added and stirred at room temperature for 16 hours. The reaction was poured into water and extracted with EtOAc EtOAc.
  • Step 4 Compound G-12-3 (300 mg, 0.64 mmol) and 2,4-dimethoxybenzylamine (214 mg, 1.28 mmol) were dissolved in dichloromethane (15 ml). Sodium borohydride (121 mg, 1.92 mmol) was stirred at room temperature for 1 hour and then heated to 60 ° C to continue the reaction for 2 hours.
  • Step 7 To a solution of the compound G-12-6 (94 mg, 0.154 mmol) in trifluoroacetic acid (3 ml), triethylsilane (36 mg, 0.308 mmol) was reacted at room temperature for two hours, and the reaction mixture was concentrated. The phase was purified to give the compound G-12 (5 mg, 7%).
  • the preparation of the compounds G-13 to G-16 was carried out in the same manner as in Example 2 except that the compound 1a in the step 1 was replaced with the intermediates 10a, 11a, 12a and 13a.
  • Test Example 1 Lantha screening kinase reaction assay method
  • the compound was pre-dissolved in 100% DMSO.
  • a 10 mM drug stock solution was dissolved at room temperature and serially diluted with 8 vol% DMSO solution to a final concentration of 10-0.005 [mu]M.
  • In a 384-well plate (Corning 3676), 2.5 ⁇ l of the test substance solution and 2.5 ⁇ l of the kinase diluted with the reaction buffer (Invitrogen PV3363) were added to each well, and 5 ⁇ l of the reaction buffer was added to dilute the Fluososcei-PolyGT (Invitrogen PV3610) substrate.
  • the reaction was initiated with a mixture of ATP (Invitrogen PV3227).
  • the blank was replaced with a reaction buffer instead of the kinase, and the kinase well (Enzyme) was not added with any drug. After shaking at 60 ° C for 60 minutes in the dark. 10 ⁇ l of Detection Solution (mixture of Invitrogen PV3528 and EDTA, dilution with TR-FRET dilution buffer, EDTA working concentration of 5 mM, Lanthascreening Tb PY20 antibody working concentration of 0.2 nM) was added and shaken at room temperature for 30 minutes. The plates were read on a VictorX5 fluorescent plate reader (PerkinElmer), and light absorption at an excitation wavelength of 340 nm and emission wavelengths of 500 nm and 520 nm was measured.
  • Detection Solution mixture of Invitrogen PV3528 and EDTA, dilution with TR-FRET dilution buffer, EDTA working concentration of 5 mM, Lanthascreening Tb PY20 antibody working concentration of 0.2 nM
  • the inhibition rate calculation method (refer to the specification of Invitrogen, PV3363) is as follows:
  • Inhibition rate (ER kinase - ER test compound ) / (ER kinase - ER blank ) ⁇ 100%.
  • the half-inhibitory concentration IC50 was calculated by fitting with XLFIT 5.0 software (IDBS, UK). The results are shown in Table 1:
  • the representative compounds of the present invention have high inhibitory activity against enzymes. It was found that when Y is a hetero atom in the structure of the compound of the present invention, the choice of Y has a significant effect on the final inhibitory activity of the compound. When Y is O, the inhibitory activity of the compound is significantly reduced (such as compounds G-12 and G-2). Or when Y is N and a substituent such as a methyl group, the inhibitory activity of the compound is significantly lowered (e.g., compounds G-17 and G-2).
  • the compound was pre-dissolved in 100% DMSO.
  • the 10 mM drug stock solution was dissolved at room temperature and serially diluted with 5 vol% DMSO solution to a final concentration of 3-0.0014 ⁇ M.
  • Ramos cells were seeded into 96-well plates at a density of 4 ⁇ 10 5 /well, 45 ⁇ l of 1640 medium containing 10% (V/V) FBS per well, and 5 ⁇ l of the diluted analyte solution was added to each well. Incubate at 37 ° C, 5% (V / V) CO 2 for 1 hour.
  • the representative compounds of the present invention have high inhibitory activity against cells.
  • Test Example 3 Activity inhibition test for wild-type EGFR kinase
  • the reagents used in the following z-lyte test methods were purchased from Invitrogen.
  • the inhibitory activity of the test substance against wild-type EGFR kinase was determined by the z-lyte method.
  • the working concentrations of the components in the 10 uL wild-type EGFR kinase reaction system were: 10 ⁇ M ATP, 0.8 ng/ ⁇ L wild-type EGFR kinase (Invitrogen, PV3872), and 2 ⁇ M Tyr04 substrate (Invitrogen, PV3193).
  • the final concentration of DMSO after addition of the test substance was 2%.
  • the 10 mM drug stock solution was diluted at room temperature with a water gradient of 4% DMSO to a final concentration of 10-0.005 [mu]M.
  • 2.5 ⁇ L of the test substance solution and 5 ⁇ L of a mixture of wild-type EGFR kinase and Tyr04 substrate diluted with the reaction buffer were added to each well, and 2.5 ⁇ L of ATP was added to initiate the reaction.
  • the C1 well was replaced with ATP by a reaction buffer, the C2 well was not added with any drug, and the C3 well was added with a phosphorylated substrate as described in the instructions. After 60 minutes of shaking at 25 degrees on a shaker.
  • the inhibition rate calculation method (refer to the specification of Invitrogen, PV3193) is as follows:
  • Phosphorylation rate (1-((ER ⁇ C3 520nm - C3 450nm ) / ((C1 450nm - C3 450nm ) + ER ⁇ (C3 520nm - C1 520nm )))) ⁇ 100%
  • Inhibition rate (IR) (1 - (phosphorylation rate of test compound) / (phosphorylation rate of C2)) ⁇ 100%
  • the half-inhibitory concentration IC 50 was calculated using XLFIT 5.0 software (IDBS, UK).
  • representative compounds of the present invention have lower inhibitory activity against wild-type EGFR kinase.
  • the exemplary compounds of the invention have selective inhibitory activity against BTK WT kinase.

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Abstract

本发明涉及N-(3-氨基苯基)丙烯酰胺取代的1,2-二氢吡咯并[3,4-c]吡啶/嘧啶-3-酮衍生物、其制法与医药上的用途。具体地，本发明公开了式(II)化合物或其药学上可接受的盐、立体异构体、溶剂化物或前药，及其制备方法和应用，式中各基团的定义详见说明书和权利要求书。

Description

苯胺取代的1,2-二氢吡咯并[3,4-c]吡啶/嘧啶-3-酮衍生物及用途 技术领域
本发明属于医药技术领域。具体地，本发明特别涉及一种苯胺取代的1,2-二氢吡咯并[3,4-c]吡啶/嘧啶-3-酮衍生物及其制备方法和作为BTK抑制剂的应用，以及由其制备的药物组合物。
背景技术
BTK激酶是TEC激酶家族中的一种非受体络氨酸激酶，是BCR信号通路的关键调节因子，对于B细胞成熟、增殖、存活具有重要的作用。在多种B细胞淋巴瘤中BTK都有过度表达，是目前TEC激酶家族中唯一经过临床验证的有效的药物开发的靶点。抑制BTK能够抑制一系列B细胞淋巴瘤的增殖。
B细胞抗原受体(BCR)信号通道的活化对诱发和维持B细胞恶性肿瘤及自免疫疾病有重要作用。Bruton's酪氨酸激酶(Btk)在造血细胞BCR信号通道中起着关键作用，是淋巴瘤新疗法研究中非常良好的靶点。BTK抑制剂作用于BCR通路,抑制Btk自磷酸化，Btk's生理底物PLCγ磷酸化和下游激酶ERK的磷酸化。
BTK抑制剂作用于慢性淋巴细胞白血病(CLL)细胞，诱导细胞毒性，抑制CLL细胞增殖能力。抑制BCR激活的原代B细胞增殖，且抑制原代单核细胞中TNFα,IL-1β和IL-6等分泌。BTK抑制剂作用于胶原诱导的关节炎模型，通过抑制B细胞活性，显著降低足肿胀和关节发炎等临床关节炎症状。
目前仅有唯一的BTK抑制剂ibrutinib获批上市，因此有必要开发更多活性更好，更加安全有效的BTK抑制剂。
发明内容
本发明的目的是提供一类结构新颖的可作为Btk抑制剂的化合物。
本发明第一方面提供了一种式(I)所示的化合物，或其药学上可接受的盐、立体异构体、溶剂化物或前药：
Figure PCTCN2018098479-appb-000001
式中，X为一个键、NR a1、S、SO、SO 2或O；其中R a1为氢、羟基或C 1-8烷基(优选为C 1-6烷基，更优选为C 1-3烷基)；
A为C 6-10芳基(优选苯基)、4至7元饱和或不饱和单杂环、5至6元单环杂芳基环、8至10元双环杂芳基环；
Z为N或CR b1；其中R b1为氢、卤素(优选氟、氯、溴)、氰基、C 1-8烷基(优选为C 1-6烷基，更优选为C 1-3烷基)、卤代C 1-8烷基(优选为卤代C 1-6烷基，更优选为卤代C 1-3烷基)、C 1-8烷氧基(优选为C 1-6烷氧基，更优选为C 1-3烷氧基)、C 3-8环烷基(优选为C 3-6环烷基)或C 3-8环烷氧基(优选为C 3-6环烷氧基)；
R 5、R 6各自独立地为氢、卤素(优选氟、氯、溴)、C 1-8烷基(优选为C 1-6烷基，更优选为C 1-3烷基)、卤代C 1-8烷基(优选为卤代C 1-6烷基，更优选为卤代C 1-3烷基)、C 1-8烷氧基(优选为C 1-6烷氧基，更优选为C 1-3烷氧基)、C 3-8环烷基(优选为C 3-6环烷基)或C 3-8环烷氧基(优选为C 3-6环烷氧基)；
n为0或1；其中
(i)n为0时，R 1、R 3各自独立地为氢、卤素、羟基、烷氧基、C 1-8烷基(优选为C 1-6烷基，更优选为C 1-3烷基)；R 2与R 4连接形成4到7元饱和或不饱和单杂环；
(ii)n为0时，R 2、R 4各自独立地为氢、卤素、羟基、烷氧基、C 1-8烷基(优选为C 1-6烷基，更优选为C 1-3烷基)；R 1与R 3连接形成4到7元饱和或不饱和单杂环；
(iii)n为0时，R 2为氢、卤素、C 1-8烷基(优选为C 1-6烷基，更优选为C 1-3烷基)；R 3与R 1、R 4连接形成桥杂环；或R 3为氢、卤素、C 1-8烷基(优选为C 1-6烷基，更优选为C 1-3烷基)；R 2与R 1、R 4连接形成桥杂环；
(iv)n为1时，R 2、R 3各自独立地为氢、卤素、羟基、烷氧基、C 1-8烷基(优选为C 1-6烷基，更优选为C 1-3烷基)；R a与R 1以及R b与R 4连接，共同形成螺杂环；
(v)n为1时，R 2、R 3、R b各自独立地为氢、卤素、羟基、烷氧基、C 1-8烷基(优选为C 1-6烷基，更优选为C 1-3烷基)；R a分别与R 1、R 4连接，共同形成桥杂环；
(vi)n为1时，R 1、R 3、R a、R b各自独立地为氢、卤素、羟基、烷氧基、C 1-8烷基(优选为C 1-6烷基，更优选为C 1-3烷基)；R 2、R 4连接形成5到7元饱和或不饱和单杂环；
所述烷基、环烷基、烷氧基、芳基、饱和或不饱和单杂环、单环杂芳基环、双环杂芳基环、螺杂环、桥杂环为未取代的或被1、2或3个选自下组的取代基所取代：羟甲基、羟乙基、羟基、羧基、卤素、-O(CH 2) pOC 1-8烷基、-O(CH 2) pOH、-(CH 2) pOC 1-8烷基、4至6元饱和单杂环、C 1-8烷基(优选为C 1-6烷基，更优选为C 1-3烷基)、C 3-8环烷基(优选为C 3-6环烷基)、卤代C 1-8烷基(优选为卤代C 1-6烷基，更优选为卤代C 1-3烷基)、卤代C 3-8环烷基(优选为卤代C 3-6环烷基)、羟基取代的C 1-8烷基(优选为羟基取代的C 1-6烷基，更优选为羟基取代的C 1-3烷基)、NR a0R b0、-C(O)OC 1-6烷基、乙酰基、C 1-8烷氧基(优选为C 1-6烷氧基，更优选为C 1-3烷氧基)、C 1-8烷氧基取代的C 1-8烷基(优选为C 1-6烷氧基取代的C 1-6烷基，更优选为C 1-3烷氧基取代的C 1-3烷基)、卤代C 1-8烷氧基(优选为卤代C 1-6烷氧基，更优选为卤代C 1-3烷氧基)、-SO 2C 1-8烷基(优选为-SO 2C 1-6烷基，更优选为-SO 2C 1-3烷基)、C 6-10芳基(优选苯基)、5至6元单环杂芳基或-Y-L；其中Y为(CH 2) q或C(O)；L为4至6元饱和单杂环或5至6元单环杂芳基环；p、q各自独立地为1、2或3；R a0、R b0各自独立地为氢、乙酰基、C 1-8烷基(优选为C 1-6烷基，更优选为C 1-3烷基)、C 1-8烷氧基取代的C 1-8烷基(优选为C 1-6烷氧基取代的C 1-6烷基，更优选为 C 1-3烷氧基取代的C 1-3烷基)。
在另一优选例中，取代基中的4至6元饱和单杂环为未取代的或被1、2或3个选自下组的基团取代：卤素、羟基、C 1-6烷基、O＝、NR a0R b0、羟甲基、羟乙基、羧基、-C(O)OC 1-6烷基、乙酰基、卤代C 1-3烷基、C 1-3烷氧基、C 3-6环烷基、氮杂环丁烷、氧杂环丁烷、四氢呋喃、四氢噻吩、四氢吡咯、哌啶、噁唑烷、哌嗪、二氧戊环、二氧六环、吗啉、硫代吗啉、硫代吗啉-1,1-二氧化物、四氢吡喃、噻吩环、N-烷基吡咯环、呋喃环、噻唑环、咪唑环、噁唑环、吡咯环、吡唑环、三唑环、四唑环、异噁唑环、噁二唑环、噻二唑环、吡啶环、哒嗪环、嘧啶环、吡嗪环；其中R a0、R b0各自独立地为氢或C 1-3烷基。
在另一优选例中，所述4到7元或5到7元饱和或不饱和单杂环选自：氮杂环丁烷、氧杂环丁烷、四氢呋喃、四氢噻吩、四氢吡咯、哌啶、噁唑烷、哌嗪、二氧戊环、二氧六环、吗啉、硫代吗啉、硫代吗啉-1,1-二氧化物或四氢吡喃。
在另一优选例中，所述5至6元单环杂芳基环选自：噻吩环、N-烷环吡咯环、呋喃环、噻唑环、咪唑环、噁唑环、吡咯环、吡唑环、三唑环、1,2,3-三唑环、1,2,4-三唑环、1,2,5-三唑环、1,3,4-三唑环、四唑环、异噁唑环、噁二唑环、1,2,3-噁二唑环、1,2,4-噁二唑环、1,2,5-噁二唑环、1,3,4-恶二唑环、噻二唑环、吡啶环、哒嗪环、嘧啶环、吡嗪环。
在另一优选例中，所述桥杂环为含有4元、5元或6元环的双环桥杂环。
在另一优选例中，所述螺杂环为含有4元、5元或6元环的双环螺杂环。
在另一优选例中，n为0时，R 2与R 4连接形成仅含氮杂原子的4到7元饱和单杂环。
在另一优选例中，n为0时，R 1与R 3连接形成仅含氮杂原子的4到7元饱和单杂环。
在另一优选例中，n为0时，R 3与R 1、R 4连接形成仅含氮杂原子的双桥杂环，或R 2与R 1、R 4连接形成仅含氮杂原子的双桥杂环。
在另一优选例中，n为1时，R a与R 1以及R b与R 4连接，共同形成仅含氮杂原子的双螺杂环。
在另一优选例中，n为1时，R a分别与R 1、R 4连接，共同形成仅含氮杂原子的双桥杂环。
在另一优选例中，n为1时，R 2、R 4连接形成仅含氮杂原子的5到7元饱和单杂环。
在另一优选例中，R 5、R 6为氢。
在另一优选例中，Z为N或CR b1；其中R b1为氢或卤素(优选氟、氯、溴)。
在另一优选例中，Z为CR b1；其中R b1为卤素(优选氟、氯、溴)。
在另一优选例中，X为一个键或NH。
在另一优选例中，
Figure PCTCN2018098479-appb-000002
为式(A)、式(B)或式(C)所示结构：
Figure PCTCN2018098479-appb-000003
Figure PCTCN2018098479-appb-000004
式中，m11、m21各自独立地为1、2、3或4；m71为1、2或3；
m12、m22各自独立地为0、1、2、3或4；m72为0、1、2或3；
R a1、R a2、R a11各自独立地为卤素、C 1-8烷基(优选为C 1-6烷基，更优选为C 1-3烷基)、卤代C 1-8烷基(优选为卤代C 1-6烷基，更优选为卤代C 1-3烷基)、羟基取代的C 1-8烷基(优选为羟基取代的C 1-6烷基、C 1-8烷氧基(优选为C 1-6烷氧基，更优选为C 1-3烷氧基)、C 1-8烷氧基取代的C 1-8烷基(优选为C 1-6烷氧基取代的C 1-6烷基，更优选为C 1-3烷氧基取代的C 1-3烷基)、C 3-8环烷基(优选为C 3-6环烷基)；
R 1、R 2、R 3、R 4、R a、R b如权利要求1所定义。
在另一优选例中，
Figure PCTCN2018098479-appb-000005
为式(D)、式(E)或式(F)所示结构：
Figure PCTCN2018098479-appb-000006
式中，m31、m32、m41、m42、m61、m62各自独立地为0、1、2或3；
m33、m34、m43、m44、m63、m64各自独立地为0、1、2或3；
R a3、R a4、R a5、R a6、R a9、R a10各自独立地为卤素、C 1-8烷基(优选为C 1-6烷基，更优选为C 1-3烷基)、卤代C 1-8烷基(优选为卤代C 1-6烷基，更优选为卤代C 1-3烷基)、羟基取代的C 1-8烷基(优选为羟基取代的C 1-6烷基、C 1-8烷氧基(优选为C 1-6烷氧基，更优选为C 1-3烷氧基)、C 1-8烷氧基取代的C 1-8烷基(优选为C 1-6烷氧基取代的C 1-6烷基，更优选为C 1-3烷氧基取代的C 1-3烷基)、C 3-8环烷基(优选为C 3-6环烷基)；
R 2、R 3如权利要求1所定义。
在另一优选例中，
Figure PCTCN2018098479-appb-000007
为式(G)所示结构：
Figure PCTCN2018098479-appb-000008
式中，m51、m52各自独立地为0、1、2或3；
m53、m54各自独立地为0、1、2、3或4；
R a7、R a8各自独立地为卤素、C 1-8烷基(优选为C 1-6烷基，更优选为C 1-3烷基)、卤代C 1-8烷基(优选为卤代C 1-6烷基，更优选为卤代C 1-3烷基)、羟基取代的C 1-8烷基(优选为羟基取代的C 1-6烷基、C 1-8烷氧基(优选为C 1-6烷氧基，更优选为C 1-3烷氧基)、C 1-8烷氧基取代的C 1-8 烷基(优选为C 1-6烷氧基取代的C 1-6烷基，更优选为C 1-3烷氧基取代的C 1-3烷基)、C 3-8环烷基(优选为C 3-6环烷基)；
R 2、R 3如权利要求1所定义。
在另一优选例中，m11为1、2、3或4；R 3为氢、卤素或C 1-8烷基(优选为C 1-6烷基，更优选为C 1-3烷基)；m12为0。
在另一优选例中，m11为1、2、3或4；R 3为氢；m12为1、2、3或4；R a1为卤素或C 1-8烷基(优选为C 1-6烷基，更优选为C 1-3烷基)。
在另一优选例中，m21为1、2、3或4；R 2为氢；R 4为氢或C 1-8烷基(优选为C 1-6烷基，更优选为C 1-3烷基)；m22为0、1、2、3或4；R a2为卤素或C 1-8烷基(优选为C 1-6烷基，更优选为C 1-3烷基)。
在另一优选例中，m21为1、2、3或4；R 2、R 4为氢；m22为0。
在另一优选例中，m71为1、2或3；R a、R b为氢；m72为0。
在另一优选例中，m31、m32各自独立地为0、1、2或3；m33、m34为0；R 3为氢、卤素或C 1-8烷基(优选为C 1-6烷基，更优选为C 1-3烷基)。
在另一优选例中，m31、m32各自独立地为1或2；m33、m34为0；R 3为氢。
在另一优选例中，m31为1；m32为1或2；m33、m34为0；R 3为氢。
在另一优选例中，m41、m42各自独立地为0、1、2或3；m43、m44为0；R 2为氢、卤素或C 1-8烷基(优选为C 1-6烷基，更优选为C 1-3烷基)。
在另一优选例中，m41、m42为1；m43、m44为0；R 2为氢。
在另一优选例中，m61、m62各自独立地为0、1、2或3；m63、m64为0；R 2、R 3各自独立地为氢、卤素或C 1-8烷基(优选为C 1-6烷基，更优选为C 1-3烷基)。
在另一优选例中，m61、m62为1；m63、m64为0；R 2、R 3为氢。
在另一优选例中，m51、m52各自独立地为1或2；m53、m54为0；R 2、R 3为氢。
在另一优选例中，X为一个键或NR a1；其中R a1为氢或C 1-3烷基。
在另一优选例中，A为C 6-10芳基(优选苯基)或5至6元单环杂芳基环；A任选地被1、2或3个选自A1组的取代基所取代，所述任选地被取代是指环原子(包括碳原子和N原子)上的氢被取代基所取代。
在另一优选例中，X为NH；A为C 6-10芳基(优选苯基)或5至6元单环杂芳基环；A任选地被1、2或3个选自A1组的取代基所取代，所述任选地被取代是指环原子(包括碳原子和N原子)上的氢被取代基所取代。
在另一优选例中，X为一个键；A为5至6元单环杂芳基环；A任选地被1、2或3个选自A1组的取代基所取代，所述任选地被取代是指环原子(包括碳原子和N原子)上的氢被取代基所取代。
在另一优选例中，所述5至6元单环杂芳基环为：噻吩环、N-烷环吡咯环、呋喃环、噻唑环、咪唑环、噁唑环、吡咯环、吡唑环、三唑环、1,2,3-三唑环、1,2,4-三唑环、1,2,5-三唑 环、1,3,4-三唑环、四唑环、异噁唑环、噁二唑环、1,2,3-噁二唑环、1,2,4-噁二唑环、1,2,5-噁二唑环、1,3,4-恶二唑环、噻二唑环、吡啶环、哒嗪环、嘧啶环或吡嗪环。
在另一优选例中，所述5至6元单环杂芳基环选自：
Figure PCTCN2018098479-appb-000009
Figure PCTCN2018098479-appb-000010
上述5至6元单环杂芳基环任选地被1、2或3个选自A1组的取代基所取代，所述任选地被取代是指环原子(包括碳原子和N原子)上的氢被取代基所取代。
在另一优选例中，X为NH；A选自B1组中结构。
在另一优选例中，X为一个键；A选自B1或B2组中结构。
在另一优选例中，X为NH；A为C 6-10芳基(优选苯基)或5至6元单环杂芳基环；A任选地被1、2或3个选自A1组的取代基所取代；所述任选地被取代是指环原子(包括碳原子和N原子)上的氢被取代基所取代；
Figure PCTCN2018098479-appb-000011
为式(A)所示结构；其中式(A)中各基团如权利要求1所定义；
R 1为氢或C 1-8烷基(优选为C 1-6烷基，更优选为C 1-3烷基)。
在另一优选例中，X为NH；A选自B1组中结构；
Figure PCTCN2018098479-appb-000012
为式(A)所示结构；其中式(A)中各基团如权利要求1所定义；
R 1为氢或C 1-8烷基(优选为C 1-6烷基，更优选为C 1-3烷基)。
在另一优选例中，X为一个键；A为5至6元单环杂芳基环；A任选地被1、2或3个选自A1组的取代基所取代；所述任选地被取代是指环原子(包括碳原子和N原子)上的氢被取代基所取代；
Figure PCTCN2018098479-appb-000013
为式(A)所示结构；其中式(A)中各基团如权利要求1所定义；
R 1为氢或C 1-8烷基(优选为C 1-6烷基，更优选为C 1-3烷基)。
在另一优选例中，X为一个键；A选自B1或B2组中结构；
Figure PCTCN2018098479-appb-000014
为式(A)所示结构；其中式(A)中各基团如权利要求1所定义；
R 1为氢或C 1-8烷基，优选地R1为C 1-8烷基(优选为C 1-6烷基，更优选为C 1-3烷基)。
在另一优选例中，m11为3。
在另一优选例中，式(D)、式(E)、式(F)或式(G)选自：
Figure PCTCN2018098479-appb-000015
在另一优选例中，式(A)选自C1组中结构。
在另一优选例中，C1组结构为：
Figure PCTCN2018098479-appb-000016
在另一优选例中，式(B)选自：
Figure PCTCN2018098479-appb-000017
在另一优选例中，式(C)选自：
Figure PCTCN2018098479-appb-000018
本发明第二方面提供了一种式(II)所示的化合物，或其药学上可接受的盐、立体异构体、溶剂化物或前药：
Figure PCTCN2018098479-appb-000019
式中，Y为一个键、NR a1、S、SO、SO 2或O；其中R a1为氢、羟基或C 1-8烷基(优选为C 1-6烷基，更优选为C 1-3烷基)；
B为C 6-10芳基(优选苯基)、4至7元饱和或不饱和单杂环、5至6元单环杂芳基环、8至10元双环杂芳基环；
Q为N或CR b1；其中R b1为氢、卤素(优选氟、氯、溴)、氰基、C 1-8烷基(优选为C 1-6烷基，更优选为C 1-3烷基)、卤代C 1-8烷基(优选为卤代C 1-6烷基，更优选为卤代C 1-3烷基)、C 1-8烷氧基(优选为C 1-6烷氧基，更优选为C 1-3烷氧基)、C 3-8环烷基(优选为C 3-6环烷基)或C 3-8环烷氧基(优选为C 3-6环烷氧基)；
Z 1、Z 2、Z 3、Z 4中的三个为CH，一个为N；或Z 1、Z 2、Z 3、Z 4均为CH；
R 5、R 6各自独立地为氢、卤素(优选氟、氯、溴)、C 1-8烷基(优选为C 1-6烷基，更优选为C 1-3烷基)、卤代C 1-8烷基(优选为卤代C 1-6烷基，更优选为卤代C 1-3烷基)、C 1-8烷氧基(优选为C 1-6烷氧基，更优选为C 1-3烷氧基)、C 3-8环烷基(优选为C 3-6环烷基)或C 3-8环烷氧基(优选为C 3-6环烷氧基)；
R 7、R 9各自独立地为氢、C 1-8烷基(优选为C 1-6烷基，更优选为C 1-3烷基)、卤代C 1-8烷基(优选为卤代C 1-6烷基，更优选为卤代C 1-3烷基)或C 3-8环烷基(优选为C 3-6环烷基)；
R 8为氢、卤素、氰基、C 1-8烷基(优选为C 1-6烷基，更优选为C 1-3烷基)、C 1-8烷氧基(优选为C 1-6烷氧基，更优选为C 1-3烷氧基)、卤代C 1-8烷基(优选为卤代C 1-6烷基，更优选为卤代C 1-3烷基)或C 3-8环烷基(优选为C 3-6环烷基)或NR a0R b0；其中R a0、R b0各自独立地为氢、乙酰基、C 1-8烷基(优选为C 1-6烷基，更优选为C 1-3烷基)、C 1-8烷氧基取代的C 1-8烷基(优选为C 1-6烷氧基取代的C 1-6烷基，更优选为C 1-3烷氧基取代的C 1-3烷基)；
j为0、1、2、3或4；
所述烷基、环烷基、烷氧基、环烷氧基、芳基、饱和或不饱和单杂环、单环杂芳基环、双环杂芳基环为未取代的或被1、2或3个选自下组的取代基所取代：卤素、羟甲基、羟乙基、羟基、羧基、-O(CH 2) pOC 1-8烷基、-O(CH 2) pOH、-(CH 2) pOC 1-8烷基、4至6元饱和单杂环、C 1-8烷基(优选为C 1-6烷基，更优选为C 1-3烷基)、C 3-8环烷基(优选为C 3-6环烷基)、卤代C 1-8烷基(优选为卤代C 1-6烷基，更优选为卤代C 1-3烷基)、卤代C 3-8环烷基(优选为卤代C 3-6环烷基)、羟基取代的C 1-8烷基(优选为羟基取代的C 1-6烷基，更优选为羟基取代的C 1-3烷基)、NR a0R b0、-C(O)OC 1-6烷基、乙酰基、C 1-8烷氧基(优选为C 1-6烷氧基，更优选为C 1-3烷氧基)、C 1-8烷氧基取代的C 1-8烷基(优选为C 1-6烷氧基取代的C 1-6烷基，更优选为C 1-3烷氧基取代的C 1-3烷基)、卤代C 1-8烷氧基(优选为卤代C 1-6烷氧基，更优选为卤代C 1-3烷氧基)、-SO 2C 1-8烷基(优选为-SO 2C 1-6烷基，更优选为-SO 2C 1-3烷基)、C 6-10芳基(优选苯基)、5至6元单环杂芳基或-Y-L；其中Y为(CH 2) q或C(O)；L为4至6元饱和单杂环或5至6元单环杂芳基环；q为1、2或3；R a0、R b0各自独立地为氢、乙酰基、C 1-8烷基(优选为C 1-6烷基，更优选为C 1-3烷基)、C 1-8烷氧基取代的C 1-8烷基(优选为C 1-6烷氧基取代的C 1-6烷基，更优选为C 1-3烷氧基取代的C 1-3烷基)。
在另一优选例中，Y为一个键或NR a1；其中R a1为氢、C 1-3烷基。
在另一优选例中，B为苯基或吡唑环。
在另一优选例中，Y为一个键；B为5至6元单环杂芳基环；所述5至6元单环杂芳基环任选地被1、2或3个选自A1组的取代基所取代。
在另一优选例中，Y为一个键；B选自B2组中结构。
在另一优选例中，Y为一个键；B为吡唑环；所述吡唑环任选地被1、2或3个选自A1组的取代基所取代。
在另一优选例中，Y为NR a1；其中R a1为氢、C 1-3烷基；B为苯基或5至6元单环杂芳基环；所述B任选地被1、2或3个选自A1组的取代基所取代，所述任选地被取代是指环原子(包括碳原子和N原子)上的氢被取代基所取代。
在另一优选例中，Y为NR a1；其中R a1为氢、C 1-3烷基；B为苯基或吡唑环；所述苯基或吡唑环任选地被1、2或3个选自A1组的取代基所取代。
在另一优选例中，Y为NR a1；其中R a1为氢、C 1-3烷基；B选自B1组中结构。
在另一优选例中，R 7、R 9各自独立地为氢、C 1-3烷基、卤代C 1-3烷基或C 3-6环烷基。
在另一优选例中，A1组的取代基为：卤素、-O(CH 2) pOC 1-8烷基、-O(CH 2) pOH、-(CH 2) pOC 1-8烷基、4至6元饱和单杂环、C 1-8烷基(优选为C 1-6烷基，更优选为C 1-3烷基)、C 3-8环烷基(优选为C 3-6环烷基)、卤代C 1-8烷基(优选为卤代C 1-6烷基，更优选为卤代C 1-3烷基)、卤代C 3-8环烷基(优选为卤代C 3-6环烷基)、羟基取代的C 1-8烷基(优选为羟基取代的C 1-6烷基，更优选为羟基取代的C 1-3烷基)、羟甲基、羟乙基、羟基、羧基、NR a0R b0、-C(O)OC 1-6烷基、乙酰基、C 1-8烷氧基(优选为C 1-6烷氧基，更优选为C 1-3烷氧基)、C 1-8烷氧基取代的C 1-8烷基(优选为C 1-6烷氧基取代的C 1-6烷基，更优选为C 1-3烷氧基取代的C 1-3烷基)、卤代C 1-8烷氧基(优选为 卤代C 1-6烷氧基，更优选为卤代C 1-3烷氧基)、-SO 2C 1-8烷基(优选为-SO 2C 1-6烷基，更优选为-SO 2C 1-3烷基)、C 6-10芳基(优选苯基)、5至6元单环杂芳基或-Y-L；其中Y为(CH 2) q或C(O)；L为4至6元饱和单杂环；p、q各自独立地为1、2或3；R a0、R b0各自独立地为氢、乙酰基、C 1-8烷基(优选为C 1-6烷基，更优选为C 1-3烷基)、C 1-8烷氧基取代的C 1-8烷基(优选为C 1-6烷氧基取代的C 1-6烷基，更优选为C 1-3烷氧基取代的C 1-3烷基)。
在另一优选例中，A1组取代基中的4至6元饱和单杂环选自氮杂环丁烷、氧杂环丁烷、四氢呋喃、四氢噻吩、四氢吡咯、哌啶、噁唑烷、哌嗪、二氧戊环、二氧六环、吗啉、硫代吗啉、硫代吗啉-1,1-二氧化物或四氢吡喃。
在另一优选例中，A1组取代基中的4至6元饱和单杂环为未取代的或被1、2或3个选自下组的取代基所取代：卤素、羟基、C 1-3烷基、O＝、NR a0R b0、羟甲基、羟乙基、羟丙基、羧基、-C(O)OC 1-3烷基、乙酰基、卤代C 1-3烷基、C 1-3烷氧基、C 3-6环烷基、氮杂环丁烷、氧杂环丁烷、四氢呋喃、四氢噻吩、四氢吡咯、哌啶、噁唑烷、哌嗪、二氧戊环、二氧六环、吗啉、硫代吗啉、硫代吗啉-1,1-二氧化物、四氢吡喃、噻吩环、N-烷基吡咯环、呋喃环、噻唑环、咪唑环、噁唑环、吡咯环、吡唑环、三唑环、四唑环、异噁唑环、噁二唑环、噻二唑环、吡啶环、哒嗪环、嘧啶环、吡嗪环；其中R a0、R b0各自独立地为氢或C 1-3烷基。
在另一优选例中，A1组的取代基为氟、氯、溴、羟甲基、羟乙基、羟基、羧基、-O(CH 2) pOC 1-3烷基、-O(CH 2) pOH、-(CH 2) pOC 1-3烷基、氮杂环丁烷、氧杂环丁烷、四氢呋喃、四氢噻吩、四氢吡咯、哌啶、噁唑烷、哌嗪、二氧戊环、二氧六环、吗啉、硫代吗啉、硫代吗啉-1,1-二氧化物、四氢吡喃、甲基、乙基、正丙基、异丙基、环丙基、一氯乙基、二氯甲基、1,2-二氯乙基、一溴乙基、一氟甲基、二氟甲基、三氟甲基、一氟乙基、二氟乙基、三氟乙基、一氯环丙基、二氯环丙基、三氯环丙基、一氟环丙基、二氟环丙基、三氟环丙基、NR a0R b0、-C(O)OC 1-3烷基、乙酰基、甲氧基、乙氧基、丙氧基、异丙氧基、三氟甲氧基、三氟乙氧基、一氟甲氧基、一氟乙氧基、二氟甲氧基、二氟乙氧基、苯基、吡啶基或-Y-L；其中Y为(CH 2) q或C(O)；L为氮杂环丁烷、氧杂环丁烷、四氢呋喃、四氢噻吩、四氢吡咯、哌啶、噁唑烷、哌嗪、二氧戊环、二氧六环、吗啉、硫代吗啉、硫代吗啉-1,1-二氧化物、四氢吡喃；p为1、2或3；q为1；R a0、R b0各自独立地为氢、乙酰基、甲基、乙基、正丙基、异丙基、甲氧基取代的C 1-3烷基。
在另一优选例中，B1组结构为：
Figure PCTCN2018098479-appb-000020
Figure PCTCN2018098479-appb-000021
在另一优选例中，B2组结构为：
Figure PCTCN2018098479-appb-000022
在另一优选例中，式(I)化合物选自D1组中结构。
在另一优选例中，D1组结构为：
Figure PCTCN2018098479-appb-000023
Figure PCTCN2018098479-appb-000024
Figure PCTCN2018098479-appb-000025
在另一优选例中，式(II)化合物选自D2组中结构。
在另一优选例中，D2组结构为：
Figure PCTCN2018098479-appb-000026
本发明第三方面提供了一种药物组合物，所述药物组合物包括本发明第一或第二方面所述的化合物、或其药学上可接受的盐、溶剂化物、立体异构体或前药；以及药学可接受的载体或赋形剂。
本发明第四方面提供了本发明第一或第二方面所述的化合物、或其药学上可接受的盐、溶剂化物、立体异构体或前药或本发明第三方面所述药物组合物在制备激酶抑制剂药物中的应用。
在另一优选例中，所述药物用作BTK抑制剂。
本发明第五方面提供了本发明第一或第二方面所述的化合物、或其药学上可接受的盐、溶剂化物、立体异构体或前药或本发明第三方面所述药物组合物在制备由B细胞介导的疾病的应用。
本发明第六方面提供了一种治疗由B细胞介导的疾病的方法，包括给予所需患者治疗有效量的本发明第一或第二方面所述的化合物、或其药学上可接受的盐、溶剂化物、立体异构体或前药，或本发明第三方面所述药物组合物。
本发明第七方面提供了一种治疗由B细胞介导的疾病的方法，包括给予所需患者治疗有效量的本发明第一或第二方面所述的化合物、或其药学上可接受的盐、溶剂化物、立体异构体或前药，以及另一种治疗活性试剂。
在另一优选例中，由B细胞介导的疾病选自：肿瘤疾病、增殖性疾病、变态反应性疾病、自身免疫性疾病或炎症性疾病。
在另一优选例中，由B细胞介导的疾病选自：实体瘤、急性淋巴细胞白血病、慢性淋巴细胞白血病、急性骨髓性白血病、慢性骨髓性白血病、类风湿性关节炎、银屑病关节炎、骨关节炎、系统性红斑狼疮、牛皮癣、类风湿性脊椎炎和痛风性关节炎。
在另一优选例中，由B细胞介导的疾病为实体瘤。
在另一优选例中，所述实体瘤为选自淋巴瘤、软组织肉瘤、淋巴细胞性淋巴瘤、套细胞淋巴瘤、黑色素瘤、多发性骨髓瘤中的至少一种。
应理解，在本发明范围内中，本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合，从而构成新的或优选的技术方案。限于篇幅，在此不再一一累述。
具体实施方式
本发明人经过广泛而深入的研究，意外地发现了这类苯胺取代的1,2-二氢吡咯并[3,4-c]吡啶/嘧啶-3-酮衍生物，特别是N-(3-氨基苯基)丙烯酰胺取代的1,2-二氢吡咯并[3,4-c]吡啶/嘧啶-3-酮衍生物对BTK WT等酶以及pBTK Y223和TNFα等细胞具有较高的抑制活性。因此该系列化合物有望开发成为用于治疗肿瘤的药物。在此基础上，发明人完成了本发明。
术语定义
如本文所用，“烷基”指直链和支链的饱和的脂族烃基，C 1-8烷基为包含1至8个碳原子的烷基，可优选为C 1-6烷基或C 1-3烷基，定义类似；烷基非限制性的例子包括：甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基、1,1-二甲基丙基、1,2-二甲基丙基、2,2-二甲基丙基、1-乙基丙基、2-甲基丁基、3-甲基丁基、正己基、1-乙基-2-甲基丙基、1,1,2-三甲基丙基、1,1-二甲基丁基、1,2-二甲基丁基、2,2-二甲基丁基、1,3-二甲基丁基、2-乙基丁基、2-甲基戊基、3-甲基戊基、4-甲基戊基、2,3-二甲基丁基、正庚基、2-甲基己基、3-甲基己基、4-甲基己基、5-甲基己基、2,3-二甲基戊基、2,4-二甲基戊基、2,2-二甲基戊基、3,3-二甲基戊基、2-乙基戊基、3-乙基戊基、正辛基、2,3-二甲基己基、2,4-二甲基己基、2,5-二甲基己基、2,2-二甲基己基、3,3-二甲基己基、4,4-二甲基己基、2-乙基己基、3-乙基己基、4-乙基己基、2-甲基-2-乙基戊基、2-甲基-3-乙基戊基、正壬基、2-甲基-2-乙基己基、2-甲基-3-乙基己基、2,2-二乙基戊基、正癸基、3,3-二乙基己基、2,2-二乙基己基，及其各种支链异构体等。
如本文所用，“环烷基”指饱和或部分不饱和单环环状烃基，“C 3-8环烷基”是指包含3至8个碳原子的环烃基，可优选为C 3-6环烷基，定义类似；环烷基的非限制性实施例包括环丙基、环丁基、环戊基、环戊烯基、环己基、环己烯基、环己二烯基、环庚基、环庚三烯基、环辛基等，优选环丙基、环戊基、环己烯基。
如本文所用，“螺杂环”指单环之间共用一个原子(称螺原子)的多环烃，其中一个或两个环原子选自氮、氧或S(O) n(其中n是整数0至2)的杂原子，其余环原子为碳。这些可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统。根据环的数目将螺杂环分为双螺杂环或多螺杂环，优选双螺杂环。更优选为4元/5元、5元/5元或5元/6元双螺杂环。例如：
Figure PCTCN2018098479-appb-000027
如本文所用，“桥杂环”指共用两个或两个以上原子的多环基团，其中一个或多个环原子选自氮、氧或S(O) n(其中n是整数0至2)的杂原子，其余环原子为碳。这些可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统。优选为双环或三环桥杂环。例如：
Figure PCTCN2018098479-appb-000028
如本文所用，“C 1-8烷氧基”指-O-(C 1-8烷基)，其中烷基的定义如上所述。优选C 1-6烷氧基，更优选C 1-3烷氧基。非限制性实施例包含甲氧基、乙氧基、丙氧基、异丙氧基、丁氧基、叔丁氧基、异丁氧基、戊氧基等。
如本文所用，“C 3-8环烷氧基”指-O-(C 3-8环烷基)，其中环烷基的定义如上所述。优选C 3-6环烷氧基。非限制性实施例包含环丙氧基、环丁氧基、环戊氧基、环己氧基等。
如本文所用，“C 6-10芳基”指具有共轭的π电子体系的全碳单环或稠合多环(也就是共享毗邻碳原子对的环)基团，指含有6至10个碳原子的芳基；优选苯基和萘基，最优选苯基。
如本文所用，“一个键”指由其连接的两个基团通过一个共价键连接。
如本文所用，“卤素”指氟、氯、溴或碘。
如本文所用，“卤代”指基团中一个或多个(如1、2、3、4或5个)氢被卤素所取代。
例如，“卤代C 1-8烷基”指烷基被一个或多个(如1、2、3、4或5个)卤素取代，其中烷基的定义如上所述。选为卤代C 1-6烷基，更优选为卤代C 1-3烷基。卤代C 1-8烷基的例子包括(但不限于)一氯甲基、二氯甲基、三氯甲基、一氯乙基、1,2-二氯乙基、三氯乙基、一溴乙基、一氟甲基、二氟甲基、三氟甲基、一氟乙基、二氟乙基、三氟乙基等。
又例如，“卤代C 1-8烷氧基”指烷氧基被一个或多个(如1、2、3、4或5个)卤素取代，其中烷氧基的定义如上所述。优选为卤代C 1-6烷氧基，更优选为卤代C 1-3烷氧基。卤代C 1-8烷氧基的例子包括(但不限于)三氟甲氧基、三氟乙氧基、一氟甲氧基、一氟乙氧基、二氟甲氧 基、二氟乙氧基等。
又例如，“卤代C 3-8环烷基”指环烷基被一个或多个(如1、2、3、4或5个)卤素取代，其中环烷基的定义如上所述。优选为卤代C 3-6环烷基。卤代C 3-8环烷基的例子包括(但不限于)三氟环丙基、一氟环丙基、一氟环己基、二氟环丙基、二氟环己基等。
如本文所用，“氘代C 1-8烷基”指烷基被一个或多个(如1、2、3、4或5个)氘原子取代，其中烷基的定义如上所述。优选为氘代C 1-6烷基，更优选为氘代C 1-3烷基。氘代C 1-8烷基的例子包括(但不限于)单氘代甲基、单氘代乙基、二氘代甲基、二氘代乙基、三氘代甲基、三氘代乙基等。
如本文所用，“氨基”指NH 2，“氰基”指CN，“硝基”指NO 2，“苄基”指-CH 2-苯基，“氧代基”指＝O，“羧基”指-C(O)OH，“乙酰基”指-C(O)CH 3，“羟甲基”指-CH 2OH，“羟乙基”指-CH 2CH 2OH，“羟基”指-OH，“硫醇”指SH，“亚环丙基”结构为：
Figure PCTCN2018098479-appb-000029
如本文所用，“杂芳基环”与“杂芳基”可互换使用，是指具有5到10个环原子，优选5或6元单环杂芳基或8至10元双环杂芳基；环阵列中共享6、10或14个π电子；且除碳原子外还具有1到5个杂原子的基团。“杂原子”是指氮、氧或硫。
如本文所用，“4至7元饱和单杂环”是指4至7元单环中的1、2或3个碳原子被选自氮、氧或S(O) t(其中t是整数0至2)的杂原子所取代，但不包括-O-O-、-O-S-或-S-S-的环部分，其余环原子为碳；优选4至6元，更优选5至6元。4至7元饱和单杂环的实例包括(但不限于)环氧丙烷、氮杂环丁烷、氧杂环丁烷、四氢呋喃、四氢噻吩、四氢吡咯、哌啶、吡咯啉、噁唑烷、哌嗪、二氧戊环、二氧六环、吗啉、硫代吗啉、硫代吗啉-1,1-二氧化物、四氢吡喃等。
如本文所用，“5至6元单环杂芳基环”是指含5至6个环原子的单杂芳基环，例如包括(但不限于)：噻吩环、N-烷环吡咯环、呋喃环、噻唑环、咪唑环、噁唑环、吡咯环、吡唑环、三唑环、1,2,3-三唑环、1,2,4-三唑环、1,2,5-三唑环、1,3,4-三唑环、四唑环、异噁唑环、噁二唑环、1,2,3-噁二唑环、1,2,4-噁二唑环、1,2,5-噁二唑环、1,3,4-恶二唑环、噻二唑环、吡啶环、哒嗪环、嘧啶环、吡嗪环等。
如本文所用，“8至10元双环杂芳基环”是指含8至10个环原子的双杂芳基环，例如包括(但不限于)：苯并呋喃、苯并噻吩、吲哚、异吲哚、喹啉、异喹啉、吲唑、苯并噻唑、苯并咪唑、喹唑啉、喹喔啉、噌啉、酞嗪。
如本文所用，“取代的”指基团中的一个或多个氢原子，优选为1～5个氢原子彼此独立地被相应数目的取代基取代，更优选为1～3个氢原子彼此独立地被相应数目的取代基取代。不言而喻，取代基仅处在它们的可能的化学位置，本领域技术人员能够在不付出过多努力的情况下确定(通过实验或理论)可能或不可能的取代。例如，具有游离氢的氨基或羟基与具有不饱和(如烯属)键的碳原子结合时可能是不稳定的。
如本文所用，上述任一基团可以是取代的或未取代的。上述基团为取代时，取代基优选为1至5个(更优选1至3个)以下基团，独立地选自卤素、-O(CH 2) pOC 1-8烷基、-O(CH 2) pOH、-(CH 2) pOC 1-8烷基、4至6元饱和单杂环、C 1-8烷基(优选为C 1-6烷基，更优选为C 1-3烷基)、 C 3-8环烷基(优选为C 3-6环烷基)、卤代C 1-8烷基(优选为卤代C 1-6烷基，更优选为卤代C 1-3烷基)、卤代C 3-8环烷基(优选为卤代C 3-6环烷基)、羟基取代的C 1-8烷基(优选为羟基取代的C 1-6烷基，更优选为羟基取代的C 1-3烷基)、羟甲基、羟乙基、羟基、羧基、NR a0R b0、-C(O)OC 1-6烷基、乙酰基、C 1-8烷氧基(优选为C 1-6烷氧基，更优选为C 1-3烷氧基)、C 1-8烷氧基取代的C 1-8烷基(优选为C 1-6烷氧基取代的C 1-6烷基，更优选为C 1-3烷氧基取代的C 1-3烷基)、卤代C 1-8烷氧基(优选为卤代C 1-6烷氧基，更优选为卤代C 1-3烷氧基)、-SO 2C 1-8烷基(优选为-SO 2C 1-6烷基，更优选为-SO 2C 1-3烷基)、C 6-10芳基(优选苯基)、5至6元单环杂芳基、或-Y-L；其中Y为(CH 2) q或C(O)；L为4至6元饱和单杂环或5至6元单环杂芳基环；p、q各自独立地为1、2或3；R a0、R b0各自独立地为氢、乙酰基、C 1-8烷基(优选为C 1-6烷基，更优选为C 1-3烷基)、C 1-8烷氧基取代的C 1-8烷基(优选为C 1-6烷氧基取代的C 1-6烷基，更优选为C 1-3烷氧基取代的C 1-3烷基)。
本文以上所述的各类取代基团其自身也是可以被本文所描述的基团取代。
本文所述的4至6元饱和单杂环被取代时，取代基的位置可处在它们可能的化学位置，示例性的单杂环的代表性的取代情况如下所示：
Figure PCTCN2018098479-appb-000030
Figure PCTCN2018098479-appb-000031
其中“Sub”表示本文所述的各类取代基；
Figure PCTCN2018098479-appb-000032
表示与其他原子的连接。
当本发明所述的4至6元饱和单杂环为取代基时，其自身也可以为取代或被1、2或3个选自下组的取代基所取代：卤素、羟基、C 1-3烷基、O＝、NR a0R b0、羟甲基、羟乙基、羧基、 -C(O)OC 1-3烷基、乙酰基、卤代C 1-3烷基、C 1-3烷氧基、C 3-6环烷基、氮杂环丁烷、氧杂环丁烷、四氢呋喃、四氢噻吩、四氢吡咯、哌啶、噁唑烷、哌嗪、二氧戊环、二氧六环、吗啉、硫代吗啉、硫代吗啉-1,1-二氧化物、四氢吡喃、噻吩环、N-烷基吡咯环、呋喃环、噻唑环、咪唑环、噁唑环、吡咯环、吡唑环、三唑环、四唑环、异噁唑环、噁二唑环、噻二唑环、吡啶环、哒嗪环、嘧啶环、吡嗪环；其中R a0、R b0各自独立地为氢或C 1-3烷基。
所述“药学上可接受的盐”包括药学可接受的酸加成盐和药学可接受的碱加成盐。
“药学上可接受的酸加成盐”是指能够保留游离碱的生物有效性而无其他副作用的，与无机酸或有机酸所形成的盐。
“药学可接受的碱加成盐”，包括但不限于无机碱的盐如钠盐，钾盐，钙盐和镁盐等。包括但不限于有机碱的盐，比如铵盐，三乙胺盐，赖氨酸盐，精氨酸盐等。
本发明中提及的“溶剂化物”是指本发明的化合物与溶剂形成的配合物。它们或者在溶剂中反应或者从溶剂中沉淀析出或者结晶出来。例如，一个与水形成的配合物称为“水合物”。式(I)化合物的溶剂化物属于本发明范围之内。
本发明式(I)所示的化合物可以含有一个或多个手性中心，并以不同的光学活性形式存在。当化合物含有一个手性中心时，化合物包含对映异构体。本发明包括这两种异构体和异构体的混合物，如外消旋混合物。对映异构体可以通过本专业已知的方法拆分，例如结晶以及手性色谱等方法。当式(I)化合物含有多于一个手性中心时，可以存在非对映异构体。本发明包括拆分过的光学纯的特定异构体以及非对映异构体的混合物。非对映异构体可由本专业已知方法拆分，比如结晶以及制备色谱。
本发明包括上述化合物的前药。前药包括已知的氨基保护基和羧基保护基，在生理条件下被水解或经由酶反应释放得到母体化合物。具体的前药制备方法可参照(Saulnier，M.G.；Frennesson，D.B.；Deshpande，M.S.；Hansel，S.B and Vysa，D.M.Bioorg.Med.Chem Lett.1994，4，1985-1990；和Greenwald，R.B.；Choe，Y.H.；Conover，C.D.；Shum，K.；Wu，D.；Royzen，M.J.Med.Chem.2000，43，475.)。
通常，本发明化合物或其药学可接受的盐、或其溶剂化物、或其立体异构体、或前药可以与一种或多种药用载体形成适合的剂型施用。这些剂型适用于口服、直肠给药、局部给药、口内给药以及其他非胃肠道施用(例如，皮下、肌肉、静脉等)。例如，适合口服给药的剂型包括胶囊、片剂、颗粒剂以及糖浆等。这些制剂中包含的本发明的化合物可以是固体粉末或颗粒；水性或非水性液体中的溶液或是混悬液；油包水或水包油的乳剂等。上述剂型可由活性化合物与一种或多种载体或辅料经由通用的药剂学方法制成。上述的载体需要与活性化合物或其他辅料兼容。对于固体制剂，常用的无毒载体包括但不限于甘露醇、乳糖、淀粉、硬脂酸镁、纤维素、葡萄糖、蔗糖等。用于液体制剂的载体包括水、生理盐水、葡萄糖水溶液、乙二醇和聚乙二醇等。活性化合物可与上述载体形成溶液或是混悬液。
本发明的组合物以符合医学实践规范的方式配制，定量和给药。给予化合物的“治疗有效量”由要治疗的具体病症、治疗的个体、病症的起因、药物的靶点以及给药方式等因素决定。
如本文所用，“治疗有效量”是指将引起个体的生物学或医学响应，例如降低或抑制酶或蛋白质活性或改善症状、缓解病症、减缓或延迟疾病进程或预防疾病等的本发明化合物的量。
如本文所用，“药学可接受的载体”是指无毒、惰性、固态、半固态的物质或液体灌装机、稀释剂、封装材料或辅助制剂或任何类型辅料，其与患者相兼容，最好为哺乳动物，更优选为人，其适合将活性试剂输送到目标靶点而不终止试剂的活性。
如本文所用，“患者”是指一种动物，最好为哺乳动物，更好的为人。术语“哺乳动物”是指温血脊椎类哺乳动物，包括如猫、狗、兔、熊、狐狸、狼、猴子、鹿、鼠、猪和人类。
如本文所用，“治疗”是指减轻、延缓进展、衰减、预防，或维持现有疾病或病症(例如癌症)。治疗还包括将疾病或病症的一个或多个症状治愈、预防其发展或减轻到某种程度。
制备方法
本发明提供了式(I)化合物的制备方法，本发明中的化合物可以通过多种合成操作制备，这些化合物的示例性制备方法可以包括(但不限于)下文所述的流程。
较佳地，本发明式(I)化合物可以通过以下方案及实施例中所述的示例性方法以及本领域技术人员所用的相关公开文献操作完成。
在具体操作过程中，可以根据需要对方法中的步骤进行扩展或合并。
方案1：
Figure PCTCN2018098479-appb-000033
步骤1：化合物1a与相应的胺(伯胺或仲胺)，在碱性条件下发生亲核取代反应。
步骤2：吡啶环上的氯与相应的胺，在碱性条件下，经钯催化剂催化发生Buchwald偶联反应。
步骤3：胺在酸性条件下脱去保护基。
步骤4：环A上的二级胺与酰氯在碱性条件下发生酰胺缩合反应。
方案2：
Figure PCTCN2018098479-appb-000034
步骤1、步骤3、步骤4同方案1的步骤1、步骤3、步骤4。步骤2：吡啶环上的氯与相应的硼酸在碱性条件下经钯催化剂催化发生Suzuki偶联反应。
以上各步骤中的反应均是本领域技术人员已知的常规反应。如无特殊说明，合成路线中所使用的试剂和原料化合物均可市购得到，或本领域技术人员根据所设计的不同化合物结构参考已知方法制备得到。
与现有技术相比，本发明的主要优点在于：
提供了一系列结构新颖的苯胺取代的1,2-二氢吡咯并[3,4-c]吡啶/嘧啶-3-酮衍生物，特别是N-(3-氨基苯基)丙烯酰胺取代的1,2-二氢吡咯并[3,4-c]吡啶/嘧啶-3-酮衍生物对BTK WT酶以及pBTK Y223等细胞具有较高的抑制活性，并且对EGFR WT的抑制活性较弱，具有明显的选择抑制性，可用作治疗肿瘤的药物。
下面结合具体实施例，进一步阐述本发明。应理解，这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法，通常按照常规条件或按照制造厂商所建议的条件。除非另外说明，否则百分比和份数按重量计算。除非另行定义，本文所用的术语与本领域熟练人员所熟悉的意义相同。此外，任何与所记载内容相似或同等的方法及材料皆可应用于本发明中。
如本文所用，DMB为2,4-二甲氧基苄基，THF为四氢呋喃，EA为乙酸乙酯，PE为石油醚，Ac 2O为乙酸酐，NBS为N-溴代琥珀酰亚胺，DCM为二氯甲烷，AIBN为偶氮二异丁腈，Pd(dppf)Cl 2为1,1'-双(二苯基磷)二茂铁]二氯化钯，TFA为三氟乙酸，TBSCl为叔丁基二甲基氯硅烷，NCS为N-氯代丁二酰亚胺，DHP为二氢四氢吡喃，LiAlH 4为氢化铝锂，PMB为对甲氧基苄基，LiHMDS为二(三甲基硅基)氨基锂，Pd 2(dba) 3为三(二亚苄基丙酮)二钯，RuPhos为2-二环己基磷-2',6'-二异丙氧基-1,1'-联苯,DMAP为4-二甲氨基吡啶，THP为四氢四氢吡喃，n-BuLi为正丁基锂，TMsOTf为三氟甲磺酸三甲基硅酯，TEBAC为三乙基苄基氯化铵，HATU为2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯，DMF为二甲基甲酰胺，DMSO为二甲基亚砜，DIEA为N,N-二异丙基乙胺，BINAP为(2R,3S)-2,2'-双二苯膦基-1,1'-联萘。
如本文所用，室温是指约为20-25℃。
中间体1a的制备
Figure PCTCN2018098479-appb-000035
将2,4-二氯-6-甲基嘧啶-5-羧酸甲酯(5.0g，29.9mmol)加入到乙腈(50ml)中，在常温下边搅拌边加入4-(2-甲氧基乙氧基)苯胺(6.5g,29.9mmol)，DIEA(7.7g,59.8mmol)，反应在85℃下回流3个小时，原料反应完全，用乙酸乙酯稀释，有机相用饱和食盐水洗涤，过柱，得到黄色固体1a(6.0g，60％)。ESI-MS m/e 352[M+1] +。
中间体2a的制备
Figure PCTCN2018098479-appb-000036
向100ml烧瓶中加入2,4-二氯-6-甲基嘧啶-5-羧酸甲酯(646mg，2.923mmol)，苯胺(280mg，3.007mmol)，15ml乙腈和DIPEA(570mg，4.410mmol)，反应混合物在40℃下搅拌10h，减压浓缩除去乙腈后加入20ml乙酸乙酯，用20ml水和20ml食盐水洗涤，有机相干燥后浓缩得850mg黄色固体2a，MS m/z(ESI):278.1[M+H] +。
中间体3a的制备
Figure PCTCN2018098479-appb-000037
向100ml烧瓶中加入2,4-二氯-6-甲基嘧啶-5-羧酸甲酯(617mg，2.791mmol)，1-甲基-1H-吡唑-4-胺(373mg，2.792mmol)，15ml乙腈和DIPEA(1.08g，8.357mmol)，反应混合物在40℃下搅拌1h，减压浓缩除去乙腈后加入30ml乙酸乙酯，用60ml水和30ml食盐水洗涤，有机相干燥后浓缩得830mg灰色固体3a，MS m/z(ESI):282.2[M+H] +。
中间体4a的制备
Figure PCTCN2018098479-appb-000038
向充满氮气的100ml烧瓶中加入2,4-二氯-6-甲基嘧啶-5-羧酸甲酯(1g，4.524mmol)，1-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)-1H-吡唑(941mg，4.523mmol)，K 2CO 3(1.25g，9.044mmol)，16ml的1,4-二氧六环，2ml水和Pd(dppf)Cl 2(165mg，9.044mmol)，反应混合物在60℃下搅拌过夜，反应液用水洗涤，用乙酸乙酯萃取，有机相干燥后浓缩，经combiflash(含0-40％乙酸乙酯的正己烷)纯化得960mg黄色油状物，MS m/z(ESI):267.1[M+H] +。
中间体5a的制备
Figure PCTCN2018098479-appb-000039
步骤1：二异丙胺(5.3g,52.36mmol)溶于50ml四氢呋喃中，冷却到零下78℃，滴加正丁基锂(2.5M于己烷中,21ml,52.36mmol)。滴加完毕后，在零下78℃下继续搅拌半小时，继续滴加2,6-二氯-5-氟烟酸的四氢呋喃溶液(20ml)，加完后，再搅拌两小时后，滴加DMF(8.7g,119mmol)，继续反应1小时后用2N的稀盐酸淬灭反应(pH<1)，淬灭时控制温度小于零℃。反应液用乙酸乙酯萃取(2*50ml)，合并有机相，用饱和碳酸氢钠水溶液中和到pH>8，分离出水相，用2N的稀盐酸酸化到pH<1，水相用乙酸乙酯萃取(2*50ml)。合并有机相，依次用水(50ml)和饱和食盐水(50ml)洗，无水硫酸钠干燥，过滤，滤液浓缩后用石油醚和乙酸乙酯的混合溶剂(8:1,135ml)打浆，过滤，减压干燥后得到一白色固体5a-1(3.08g,54.4％)。 1H NMR(400MHz,DMSO-d6)8.81(s,1H),6.82(s,1H).
步骤2：将化合物5a-1(2.5g,10.5mmol)溶解于15ml甲醇中，加入2,4-二甲氧基苄胺(1.84g,11.03mmol)，室温下搅拌反应1小时，有固体析出，过滤，滤饼用石油醚洗涤，干燥，得一白色固体5a-2(3.14g,77.3％)。 1H NMR(400MHz,cdcl 3)δ7.10(d,J＝8.3Hz,1H),6.39(dd,J＝8.3,2.4Hz,1H),6.35(s,1H),6.27(d,J＝2.4Hz,1H),3.88(brs,2H),3.77(s,3H),3.73(s,3H).
步骤3：在零下78℃下，向化合物5a-2(3.24g,8.37mmol)于四氢呋喃(35ml)的悬浮液中滴加甲基锂的乙醚溶液(1.6M，41.86mmol)，滴加完毕后，继续搅拌两小时，反应液用1N的稀盐酸酸化至pH～6，加热到50℃反应5小时，冷却到室温后用乙酸乙酯萃取(2*50ml)。合并有机相，用饱和食盐水(50ml)洗，无水硫酸钠干燥，过滤，滤液减压浓缩后得粗产品，经Combi-flash柱层析[DCM:MeOH＝100:0～95:5]纯化后得化合物5a(0.76g,23.5％)。M +＝385.0[M+1] +； 1H NMR(400MHz,cdcl 3)δ7.26(d,J＝8.8Hz,1H),6.46–6.39(m,2H),5.05(d,J＝14.7Hz,1H),4.51(q,J＝6.7Hz,1H),4.33(d,J＝14.7Hz,1H),3.83(s,3H),3.77(s,3H),1.57(d,J＝6.8Hz,3H).
中间体6a的制备
Figure PCTCN2018098479-appb-000040
步骤1：向2,6-二氯-5-氟烟酸(2g,10mmol)的10ml四氢呋喃溶液中加入20ml的2M的LDA，反应混合物在0℃下搅拌1h后加入10mlDMF，反应液在0℃下搅拌2h后用盐水洗涤，经Na 2CO 3调PH值为4-5后用乙酸乙酯萃取，有机相用饱和碳酸氢钠溶液洗涤，调节水相PH值为6，用乙酸乙酯萃取水相，合并有机相并用无水硫酸钠干燥，浓缩有机相后得2.3g化合物6a-1的粗品，不经纯化直接下一步，M +＝238.0[M+1] +。
步骤2：向化合物6a-1(2.3g,10mmol)的1,4-二氧六环溶液中加入(2,4-二甲氧基苯基)甲胺(3.4g,20mmol)和2ml乙酸，反应混合物在室温下搅拌1h后加入NaBH(OAc) 3(10g,50mmol)，反应液在50℃下搅拌12h，减压除去溶剂，用盐水洗涤，二氯甲烷萃取，无水硫酸 钠干燥，经combiflash纯化后得1.3g化合物6a-2，M +＝371.0[M+1] +。
步骤3：向化合物6a-2(1.1g，3mmol)的10ml甲基吡咯烷酮溶液中加入苯-1,3-二胺(650mg，6mmol)和DIPEA(1.2g，9mmol)后，反应混合物在微波反应器中180℃下搅拌50min，反应液经盐水洗涤，二氯甲烷萃取，无水硫酸钠干燥后经combiflash纯化得1.3g化合物6a，M +＝443.0[M+1] +。
中间体7a的制备
Figure PCTCN2018098479-appb-000041
向100ml烧瓶中加入2,4-二氯-6-甲基嘧啶-5-羧酸甲酯(309mg，1.4mmol)，1-(四氢-2H-吡喃-4-基)-1H-吡唑-4-胺(234mg，1.4mmol)，10ml乙腈和DIPEA(0.54g，4.18mmol)，反应混合物在40℃下搅拌1h，减压浓缩除去乙腈后加入30ml乙酸乙酯，用60ml水和30ml食盐水洗涤，有机相干燥后浓缩得405mg白色固体7a，MS m/z(ESI):352.1[M+H] +。
中间体8a的制备
Figure PCTCN2018098479-appb-000042
步骤1：向250ml烧瓶中加入2,6-二氯-4-甲基烟酸甲酯(4.24g，19.268mmol)，N-溴代琥珀酰亚胺(4.1g，23.036mmol)，偶氮二异丁腈(160mg，0.974mmol)和50ml四氯化碳，反应混合物在85℃下搅拌过夜。浓缩反应液除去四氯化碳，加入50ml乙酸乙酯，分别用50ml盐水和50ml水洗涤，有机相经无水硫酸钠干燥后浓缩得到6.4g油状物4-(溴甲基)-2,6-二氯烟酸甲酯，MS m/z(ESI):300.1[M+H] +。
步骤2：向250ml烧瓶中加入4-(溴甲基)-2,6-二氯烟酸甲酯(6.4g，21.408mmol)，(2,4-二甲氧基苯基)甲胺(3.2g，19.14mmol)和150ml乙腈。反应混合物在室温下搅拌3h，浓缩，经combiflash(含0-10％乙酸乙酯的己烷)纯化得2.1g黄色固体8a，产率30.9％，MS m/z(ESI):353[M+H] +。
中间体9a的制备
Figure PCTCN2018098479-appb-000043
将2,4-二氯-6-甲基嘧啶-5-羧酸甲酯(500mg，2.3mmol)，1-(4-氨基-1H-吡唑-1-基)-2-甲基丙-2-醇(350mg，2.3mmol)和DIPEA(890mg，6.9mmol)的乙腈溶液(10ml)加热到40℃，搅拌2h。向反应液中加水和乙酸乙酯后，萃取，浓缩合并的有机相后经combiflash纯化得400mg化合物9a，MS m/z(ESI):340[M+H] +。
中间体10a-13a的制备
化合物10a-13a分别以1-环丙基-1H-吡唑-4-胺，1-(2-甲氧基乙基)-1H-吡唑-4-胺，4-吗啉代苯胺和(S)-4-(2-甲基-4-(氧杂环丁烷-3-基)哌嗪-1-基)苯胺为原料，参照化合物9a的方法进行制备。
Figure PCTCN2018098479-appb-000044
中间体14a的制备
Figure PCTCN2018098479-appb-000045
步骤1：4,6-二氯-7-氟-1-羟基呋喃[3,4-c]吡啶-3(1H)-酮(23.12g,97.14mmol)和2,4-二甲氧基苄胺(17.03g,102mmol)溶解于400毫升1,4-二氧六环中，在室温下搅拌半小时后 加入醋酸硼氢化钠(41.19g,194.28mmol)，继续搅拌半小时后加热到50℃，在50℃下反应下8小时后冷却到室温，加入400毫升水，搅拌10分钟，有固体析出，过滤，滤饼用水洗，真空干燥得一黄色固体2-(2,4-二甲氧基苄基)-4,6-二氯-7-氟-1,2-二氢吡咯并[3,4-c]吡啶-3-酮(26.23g,72.8％)。M +＝371.0[M+1] +。
步骤2：在冰浴下向2-(2,4-二甲氧基苄基)-4,6-二氯-7-氟-1,2-二氢吡咯并[3,4-c]吡啶-3-酮(5.0g,13.48mmol)于50毫升DMF的悬浮液中分批加入钠氢(1.08g,26.96mmol)，搅拌10分钟后加入碘甲烷(3.83g,26.96mmol)。反应液缓慢升温到室温后继续反应2小时，用水淬灭反应，乙酸乙酯萃取(2*100ml)，合并有机相，依次用水洗(2*100ml)，饱和食盐水洗(100ml)，无水硫酸钠干燥，过滤，滤液浓缩后得粗产品，经Combi-flash柱层析[PE:EA＝100:0～80:20]纯化后得化合物14a(1.3g,17.3％)。M +＝399.1[M+1] +。
实施例1 N-(3-((7-氟-4-((4-(2-甲氧基乙氧基)苯基)氨基)-1-甲基-3-氧代-2,3-二氢-1H-吡咯并[3,4-C]吡啶-6-基)氨基)苯基)丙烯酰胺(G-1)的制备
Figure PCTCN2018098479-appb-000046
步骤1：将化合物5a(500mg,1.35mmol)，间二苯胺(729mg,6.75mmol)，N,N-二异丙基乙胺(871mg,6.75mmol)溶解于5mlNMP中，在微波反应器中加热到180℃反应半小时，浓缩后得粗产品，经Combi-flash柱层析[PE:EA＝100:0～30:70]纯化后得化合物G-1-1(300mg,25％)。M +＝443.2[M+1] +。
步骤2：将Pd 2(dba) 3(52mg,0.057mmol)，Xantphos(66mg,0.114mmol)和碳酸铯(372mg,1.14mmol)加入到化合物G-1-1(260mg,0.57mmol)和4-(2-甲氧基乙氧基)苯胺(143mg,0.86mmol)的1,4-二氧六环(6ml)溶液中，氩气保护下在微波反应器中加热到160℃，搅拌反应20分钟。反应液冷却到室温后，滤去固体，滤饼用乙酸乙酯洗涤，滤液减压浓缩后得到粗产品，经Combi-flash柱层析[PE:EA＝100:0～50:50]纯化后得化合物G-1-2(210mg,52.6％)。M +＝588.2[M+1] +。
步骤3：向化合物G-1-2(210mg,0.36mmol)的二氯甲烷(5ml)溶液中加入丙烯酰氯(40mg,0.43mmol)和N,N-二异丙基乙胺(93mg,0.72mmol)，在室温下搅拌一小时。反应液浓缩后得粗产品，经Combi-flash柱层析[PE:EA＝100:0～50:50]纯化后得化合物G-1-3(120mg,52.4％)。M +＝642.3[M+1] +。
步骤4：向化合物G-1-3(105mg,0.164mmol)的三氟乙酸(3ml)溶液中加入三乙基硅烷(38mg,0.328mmol)，室温下反应两小时，反应液浓缩后用制备液相纯化后得化合物G-1(8mg,8.7％)。M +＝492.1[M+1] +； 1H NMR(400MHz,DMSO)δ10.13(s,1H),9.14(s,1H),8.64(s,1H),8.43(s,1H),7.88(s,1H),7.48(d,J＝9.0Hz,2H),7.37(d,J＝7.6Hz,1H),7.32–7.21(m,2H),6.72(d,J＝9.0Hz,2H),6.45(dd,J＝17.0,10.1Hz,1H),6.24(dd,J＝16.9,2.0Hz,1H),5.74 (dd,J＝10.1,2.0Hz,1H),4.81(q,J＝6.9Hz,1H),4.02–3.95(m,2H),3.66–3.59(m,2H),3.30(s,3H),1.44(d,J＝6.7Hz,3H).
实施例2 N-(3-(4-(4-(2-甲氧基乙氧基)苯基氨基)-5-氧代-6,7-二氢-5H-吡咯并[3,4-d]嘧啶-2-基氨基)苯基)丙烯酰胺(G-2)的制备
Figure PCTCN2018098479-appb-000047
步骤1：向30ml微波反应器中加入化合物1a(555mg，1.578mmol)，3-硝基苯胺(219mg，1.586mmol)，TsOH(296mg，1.719mmol)和12ml的1,4-二氧六环，反应混合物在110℃下搅拌30min，加入40ml乙酸乙酯后用饱和碳酸氢钠溶液(30ml×2)和食盐水(30ml×1)洗涤，干燥有机层后浓缩得到760mg黄色固体G-2-1，MS m/z(ESI):454.4[M+H] +，收率98％。
步骤2：向50ml反应瓶中加入化合物G-2-1(600mg，1.323mmol)，SeO 2(920mg，8.291mmol)和20ml的1,4-二氧六环，反应混合物在110℃下搅拌过夜，反应液过滤，浓缩后经combiflash(含20％-90％乙酸乙酯的正己烷)纯化得570mg黄色固体G-2-2，MS m/z(ESI):468.2[M+H] +。
步骤3：向25ml的烧瓶中加入化合物G-2-2(500mg，1.07mmol)，(2,4-二甲氧基苯基)甲胺(200mg，1.196mmol)，20ml二氯甲烷和1ml四氢呋喃，反应混合物在室温下搅拌1.5h后加入NaBH(OAc) 3(1.15g，5.426mmol)，室温搅拌1h，反应液用饱和碳酸氢钠溶液洗涤，用二氯甲烷萃取，有机相干燥浓缩后经combiflash(含0-10％甲醇的二氯甲烷)纯化后得到65mg黄色油状物G-2-3，MS m/z(ESI):619.4[M+H] +。
步骤4：向50ml烧瓶中加入化合物G-2-3(65mg，0.105mmol)，K 2CO 3(40mg，0.289mmol)和10ml乙腈，反应混合物在80℃下搅拌3h后，过滤浓缩得到60mg黄色油状物G-2-4，不经纯化直接进行下一步反应。MS m/z(ESI):587.4[M+H] +。
步骤5：向60mg化合物G-2-4的粗品加入5ml乙醇，5ml四氢呋喃，5ml饱和氯化铵溶液和微量的铁粉，反应混合物在70℃下搅拌3h。反应液用水洗涤，用乙酸乙酯萃取，有机层浓缩后加入5ml四氢呋喃，在冰浴下加入3滴DIPEA和1滴丙烯酰氯，反应混合物在冰浴下搅拌1h后，用0.5M盐酸洗涤，用乙酸乙酯萃取，有机层干燥浓缩后得到57mg油状物G-2-5，MS m/z(ESI):611.3[M+H] +。
步骤6：向10ml微波反应器试管中加入化合物G-2-5(57mg，0.093mmol)和2ml四氢呋喃。反应混合物在110℃下搅拌20min后浓缩，经制备型HPLC纯化后得1.03mg白色固体G-2。MS m/z(ESI):461.4[M+H] +。 1H NMR(500MHz,DMSO-d 6)δ9.74(s,1H),8.60(s,1H),8.20(s,1H),7.87(s,1H),7.66(d,J＝8.4Hz,2H),7.47(d,J＝8.0Hz,1H),7.34(d,J＝8.3Hz,1H),7.22(t,J＝8.1Hz,1H),6.87(d,J＝8.9Hz,2H),6.47(dd,J＝17.0,10.2Hz,1H),6.25(dd,J＝17.0,2.0Hz,1H),5.75(dd,J＝10.0,2.1Hz,1H),4.25(s,2H),4.09–4.03(m,2H),3.68–3.62(m,2H),3.31(s,3H).
实施例3 N-(3-(7-氟-4-(4-(2-甲氧基乙氧基)苯基氨基)-3-氧代-2,3-二氢-1H-吡咯并[3,4-c]吡啶-6-基氨基)苯基)丙烯酰胺(G-3)的制备
Figure PCTCN2018098479-appb-000048
步骤1：将Pd 2(dba) 3(92mg,0.01mmol)，Xantphos(100mg,0.2mmol)和碳酸铯(1g,3mmol)加入到化合物6a(442mg,1mmol)和4-(2-甲氧基乙氧基)苯胺(170mg,1mmol)的1,4-二氧六环(15ml)溶液中，氩气保护下在微波反应器中加热到160℃，搅拌反应20分钟。反应液冷却到室温后，滤去固体，滤饼用乙酸乙酯洗涤，滤液减压浓缩后得到粗产品，经Combi-flash柱层析[PE:EA＝100:0～50:50]纯化后得化合物G-3-1(420mg)。M +＝574[M+1] +。
步骤2：向化合物G-3-1(420mg,0.7mmol)的二氯甲烷(20ml)溶液中加入丙烯酰氯(65mg,0.7mmol)和N,N-二异丙基乙胺(182mg,1.4mmol)，在室温下搅拌一小时。反应液浓缩后得粗产品，经Combi-flash柱层析[PE:EA＝100:0～50:50]纯化后得化合物G-3-2(300mg)。M +＝628[M+1] +。
步骤3：向化合物G-3-2(270mg,0.45mmol)的三氟乙酸(3ml)溶液中充入氩气，反应混合物在微波条件下110℃反应20min，反应液浓缩后用制备液相纯化后得化合物G-3(13mg,11.2％)。M +＝478[M+1] +。 1H NMR(400MHz,DMSO-d6)δ10.13(s,1H),9.14(s,1H),8.66(s,1H),8.35(s,1H),7.89(s,1H),7.49(d,J＝9.0Hz,2H),7.37(d,J＝7.5Hz,1H),7.31–7.23(m,2H),6.72(d,J＝9.0Hz,2H),6.45(dd,J＝17.0,10.1Hz,1H),6.24(dd,J＝17.0,1.9Hz,1H),5.74(dd,J＝10.1,1.9Hz,1H),4.45(s,2H),4.02–3.95(m,2H),3.64–3.59(m,2H),3.30(s,3H).
实施例4 N-(3-(7-氟-4-(4-(4-(2-羟基丙基)哌嗪-1-基)苯基氨基)-3-氧代-2,3-二氢-1H-吡咯并[3,4c]吡啶-6-基氨基)苯基)丙烯酰胺(G-4)的制备
Figure PCTCN2018098479-appb-000049
步骤1：将Pd 2(dba) 3(90mg,0.01mmol)，Xantphos(100mg,0.2mmol)和碳酸铯(1g,3mmol)加入到化合物6a(440mg,1mmol)和1-(4-(4-氨基苯基)哌嗪-1-基)丙-2-醇(235mg,1mmol)的1,4-二氧六环(15ml)溶液中，氩气保护下在微波反应器中加热到160℃，搅拌反应20分钟。反应液冷却到室温后，滤去固体，滤饼用乙酸乙酯洗涤，滤液减压浓缩后得到粗产品，经Combi-flash柱层析[PE:EA＝100:0～50:50]纯化后得化合物G-4-1(160mg)。M +＝642[M+1] +。
步骤2：向化合物G-4-1(160mg,0.3mmol)的二氯甲烷(15ml)溶液中加入丙烯酰氯(81mg,0.8mmol)和N,N-二异丙基乙胺(200mg,1.5mmol)，在室温下搅拌5小时。反应液浓缩后得粗产品，经Combi-flash柱层析[PE:EA＝100:0～50:50]纯化后得化合物G-4-2(300mg)。M +＝750[M+1] +。
步骤3：向化合物G-4-2(180mg,0.2mmol)的三氟乙酸(5ml)溶液中充入氩气，反应混合物在微波条件下110℃反应20min，反应液浓缩后用制备液相纯化后得化合物G-4-3(130mg)。M +＝600[M+1] +。
步骤4：向化合物G-4-3(130mg，0.2mmol)的THF(10ml)/H 2O(1ml)混合溶液中加入氢氧化锂单水合物(80mg，2mmol)，反应混合物在室温下搅拌5h，反应液经盐水洗涤，乙酸乙酯萃取，combiflash纯化后得20mg化合物G-4，M +＝546.4[M+1] +。 1H NMR(400MHz,DMSO-d6)δ10.16(s,1H),9.13(s,1H),8.63(s,1H),8.34(s,1H),7.86(s,1H),7.45(d,J＝9.0Hz,2H),7.29–7.21(m,2H),6.72(d,J＝9.1Hz,2H),6.45(dd,J＝16.9,10.1Hz,1H),6.24(dd,J＝16.9,2.0Hz,1H),5.77–5.72(m,1H),4.45(s,2H),4.34(d,J＝4.1Hz,1H),3.80(d,J＝5.4Hz,2H),2.97(d,J＝5.1Hz,4H),2.25(ddd,J＝17.9,15.4,5.9Hz,4H),1.06(d,J＝6.2Hz,3H).
实施例5 N-(3-(7-氟-4-(4-(2-甲氧基乙氧基)苯基氨基)-1,1-二甲基-3-氧代-2,3-二氢-1H-吡咯并[3,4-c]吡啶-6-基氨基)苯基)丙烯酰胺(G-5)的制备
Figure PCTCN2018098479-appb-000050
化合物G-5的制备方法同实施例1，不同的是将步骤1中的化合物5a换成中间体14a， M +＝506.3[M+1] +； 1H NMR(400MHz,DMSO-d6)δ10.10(s,1H),9.11(s,1H),8.61(s,1H),8.41(s,1H),7.85(s,1H),7.43(d,J＝9.0Hz,2H),7.32(d,J＝7.7Hz,1H),7.27–7.15(m,2H),6.70(t,J＝8.7Hz,2H),6.42(dd,J＝17.0,10.1Hz,1H),6.21(dd,J＝17.0,2.0Hz,1H),5.71(dd,J＝10.1,2.0Hz,1H),3.97–3.92(m,2H),3.61–3.56(m,2H),3.27(s,3H),1.51(s,6H).
实施例6 N-(3-(5-氧代-4-(苯基氨基)-6,7-二氢-5H-吡咯并[3,4-d]嘧啶-2-基氨基)苯基)丙烯酰胺(G-6)的制备
Figure PCTCN2018098479-appb-000051
化合物G-6的制备方法同实施例2，不同的是将步骤1中的化合物1a换成中间体2a，MS m/z(ESI):387.3[M+H] +。 1H NMR(400MHz,DMSO-d 6)δ10.09(s,1H),9.79(s,1H),8.70(s,1H),8.25(s,1H),7.87(s,1H),7.76(d,J＝7.3Hz,2H),7.44(s,1H),7.37–7.11(m,4H),7.03(t,J＝7.3Hz,1H),6.43(dd,J＝17.0,10.1Hz,1H),6.22(d,J＝15.4Hz,1H),5.72(d,J＝11.9Hz,1H),4.24(s,2H).
实施例7 N-(3-(5-氧代-4-(1-(四氢-2H-吡喃-4-基)-1H-吡唑-4-基氨基)-6,7-二氢-5H-吡咯并[3,4d]嘧啶-2-基氨基)苯基)丙烯酰胺(G-7)的制备
Figure PCTCN2018098479-appb-000052
化合物G-7的制备方法同实施例2，不同的是将步骤1中的化合物1a换成中间体7a，MS m/z(ESI):461.2[M+H] +。 1H NMR(400MHz,DMSO-d 6)δ10.14(s,1H),9.62(s,1H),8.67(s,1H),8.19(s,1H),8.10(s,1H),7.86(s,1H),7.76(s,1H),7.39(s,2H),7.24(t,J＝8.2Hz,1H),6.43(dd,J＝17.1,10.1Hz,1H),6.22(d,J＝17.0Hz,1H),5.72(d,J＝11.8Hz,1H),4.20(s,2H),3.91(d,J＝11.3Hz,2H),3.39(s,3H),1.85(s,4H).
实施例8 N-(3-(4-(1-甲基-1H-吡唑-4-基氨基)-5-氧代-6,7-二氢-5H-吡咯并[3,4-d]嘧啶-2-基氨基)苯基)丙烯酰胺(G-8)的制备
Figure PCTCN2018098479-appb-000053
化合物G-8的制备方法同实施例2，不同的是将步骤1中的化合物1a换成中间体3a，MS m/z(ESI):391.3[M+H] +。 1H NMR(400MHz,DMSO-d 6)δ10.10(s,1H),9.64(s,1H),8.66(s,1H),8.12(d,J＝28.4Hz,2H),7.90(s,1H),7.74(s,1H),7.45(s,1H),7.33(s,1H),7.24(t,J＝8.1Hz,1H),6.44(dd,J＝16.9,10.1Hz,1H),6.29–6.17(m,1H),5.79–5.67(m,1H),4.20(s,2H),3.73(s,3H).
实施例9 N-(3-(4-(1-(2-羟基-2-甲基丙基)-1H-吡唑-4-基氨基)-5-氧代-6,7-二氢-5H-吡咯并[3,4-d]嘧啶-2-基氨基)苯基)丙烯酰胺(G-9)的制备
Figure PCTCN2018098479-appb-000054
化合物G-9的制备方法同实施例2，不同的是将步骤1中的化合物1a换成中间体9a，MS m/z(ESI):449.2[M+H] +。 1H NMR(400MHz,DMSO-d6):δ10.10(s,1H),9.65(s,1H),8.69(s,1H),8.10(s,2H),7.89(s,2H),7.51(d,J＝8.0Hz,1H),7.37(d,J＝8.0Hz,1H),7.26(dd,J 1＝J 2＝8.0Hz,1H),6.47(dd,J 1＝9.6Hz,J 2＝17.2Hz,1H),6.25(dd,J 1＝1.6Hz,J 2＝17.2Hz,1H),5.75(dd,J 1＝1.6Hz,J 2＝9.6Hz,1H),4.64(s,1H),4.23(s,2H),3.92(s,2H),1.04(s,6H).
实施例10 N-(3-(4-(4-(2-甲氧基乙氧基)苯基氨基)-3-氧代-2,3-二氢-1H-吡咯并[3,4-c]吡啶-6-基氨基)苯基)丙烯酰胺(G-10)的制备
Figure PCTCN2018098479-appb-000055
步骤1：向30ml微波反应器中加入化合物8a(883mg,2.5mmol)，4-(2-甲氧基乙氧基)苯胺(418mg,2.5mmol)，N,N-二异丙基乙胺(647mg,5mmol)和15ml的N-甲基吡咯烷酮，反应混合物在200℃下搅拌1小时，浓缩除去N-甲基吡咯烷酮后经Combi-flash柱层析[含 0-80％乙酸乙酯的己烷]纯化后得黄色固体G-10-1(550mg，45.5％)。MS m/z(ESI):484[M+H] +。
步骤2：向30ml微波反应器中加入Pd 2(dba) 3(24mg,0.026mmol)，Xantphos(30mg,0.052mmol)，碳酸铯(337mg,1.034mmol)，化合物G-10-1(250mg,0.517mmol)，间二苯胺(71mg,0.514mmol)和1,4-二氧六环(10ml)，反应混合物在160℃下搅拌30min。反应液用水洗涤，用乙酸乙酯萃取，经Combi-flash柱层析[含0-100％乙酸乙酯的己烷]纯化后得270mg棕色固体G-10-2。MS m/z(ESI):586.2[M+H] +。
步骤3：向100ml烧瓶中加入化合物G-10-2(270mg，0.461mmol)，铁粉(130mg，2.321mmol)，氯化铵溶液(2ml)，THF(4ml)，水(2ml)，乙醇(4ml)，反应混合物在75℃下搅拌2h，过滤反应液后加入30ml乙酸乙酯，用30ml水和30ml盐水洗涤，有机相干燥后浓缩得280mg棕色固体G-10-3。MS m/z(ESI):556.2[M+H] +。
步骤4-5：以化合物G-10-3为原料，参照实施例3中步骤2和3相似的方法得化合物G-10。MS m/z(ESI):460.2[M+H] +。 1H NMR(400MHz,DMSO-d 6)δ10.06(s,1H),9.23(s,1H),8.75(s,1H),8.07(s,1H),7.78(s,1H),7.55(d,J＝8.8Hz,2H),7.37(d,J＝5.9Hz,1H),7.19(d,J＝5.8Hz,2H),6.78(d,J＝8.9Hz,2H),6.42(dd,J＝16.9,10.3Hz,1H),6.22(d,J＝19.7Hz,2H),5.71(d,J＝11.7Hz,1H),4.25(s,2H),4.06–3.92(m,2H),3.67–3.55(m,2H),3.28(s,3H).
实施例11 N-(3-(4-(1-甲基-1H-吡唑-4-基)-5-氧代-6,7-二氢-5H-吡咯并[3,4-d]嘧啶-2-基氨基)苯基)丙烯酰胺(G-11)的制备
Figure PCTCN2018098479-appb-000056
化合物G-11的制备方法同实施例2，不同的是将步骤1中的化合物1a换成中间体4a，MS m/z(ESI):376.1[M+H] +。 1H NMR(400MHz,DMSO-d 6)δ10.16(s,1H),9.96(s,1H),9.15(s,1H),8.65(s,1H),8.36(s,2H),7.59–6.86(m,3H),6.48(s,1H),6.28(s,1H),5.75(s,1H),4.27(s,2H),3.91(s,3H).
实施例12 N-(3-((4-(4-(2-甲氧基乙氧基)苯氧基)-5-氧代-6,7-二氢-5H-吡咯并[3,4-d]嘧啶-2-基)氨基)苯基)丙烯酰胺(G-12)的制备
Figure PCTCN2018098479-appb-000057
步骤1：2,4-二氯-6-甲基嘧啶-5-羧酸甲酯(110mg,0.5mmol)和4-(2-甲氧基-乙氧基)-苯酚(84mg,0.5mmol)溶解于3毫升DMSO中，加入碳酸钾(138mg,1.0mmol)，室温下搅拌16小时。反应物倒入水中，用乙酸乙酯(2*20ml)萃取。合并有机相，依次用水(2*30ml)洗，饱和食盐水(30ml)洗，无水硫酸钠干燥，过滤，滤液浓缩后得粗产品，经Combi-flash柱层析[PE:EA＝100:0～70:30]纯化后得化合物G-12-1(160mg,55.6％)。M +＝353.0[M+1] +。
步骤2：化合物G-12-1(650mg,1.84mmol)和间硝基苯胺(254mg,1.84mmol)溶解于10毫升1,4-二氧六环中，加入对甲苯磺酸(316mg,1.84mmol)，加热到90℃反应16小时。反应液冷却到室温后倒入水中，用乙酸乙酯(3*30ml)萃取，合并有机相，依次用饱和碳酸氢钠水溶液(50ml)洗，饱和食盐水(50ml)洗，无水硫酸钠干燥，过滤，滤液浓缩后得粗产品，经Combi-flash柱层析[PE:EA＝100:0～70:30]纯化后得化合物G-12-2(518mg,62％)。M +＝455.3[M+1] +。
步骤3：向化合物G-12-2(518mg,1.14mmol)的1,4-二氧六环(10ml)溶液中加入二氧化硒(760mg,6.84mmol)加热到回流，反应48小时后，浓缩得粗产品，经Combi-flash柱层析[PE:EA＝100:0～70:30]纯化后得化合物G-12-3(308mg,58％)。M +＝469.2[M+1] +。
步骤4：化合物G-12-3(300mg,0.64mmol)和2,4-二甲氧基苄胺(214mg,1.28mmol)溶解于二氯甲烷(15ml)中，室温下搅拌30分钟后加入氰基硼氢化钠(121mg,1.92mmol)，在室温下搅拌1小时后加热到60℃继续反应2小时。反应液用20毫升二氯甲烷稀释，依次用20毫升水洗，20毫升饱和食盐水洗，无水硫酸钠干燥，过滤，滤液浓缩得粗产品，经Combi-flash柱层析[PE:EA＝100:0～0:100]纯化后得化合物G-12-4(180mg,48％)。M +＝588.2[M+1] +。
步骤5：向化合物G-12-4(90mg,0.15mmol)的乙醇(4ml)和水(2ml)的混合溶液中加入铁粉(42mg,0.75mmol)和氯化铵(81mg,1.5mmol)，加热到60℃反应两小时后过滤除去固体，滤饼用乙酸乙酯洗涤，滤液用饱和食盐水(10ml)洗，无水硫酸钠干燥，过滤，滤液减压浓缩后得化合物G-12-5(76mg,89.4％)。M +＝558.2[M+1] +。
步骤6：向化合物G-12-5(76mg,0.136mmol)的二氯甲烷(5ml)溶液中加入丙烯酰氯 (13mg,0.136mmol)和N,N-二异丙基乙胺(35mg,0.272mmol)，在室温下搅拌两小时。反应液用15毫升二氯甲烷稀释，依次用10毫升水洗，10毫升饱和食盐水洗，无水硫酸钠干燥，过滤，滤液减压浓缩后得化合物G-12-6(94mg,100％)，无需纯化，直接用于下一步反应。M +＝612.2[M+1] +。
步骤7：向化合物G-12-6(94mg,0.154mmol)的三氟乙酸(3ml)溶液中加入三乙基硅烷(36mg,0.308mmol)，室温下反应两小时，反应液浓缩后用制备液相纯化后得化合物G-12(5mg,7％)。M +＝462.2[M+1] +； 1H NMR(400MHz,dmso)δ9.99(s,1H),8.38(s,1H),8.16(s,1H),7.65–7.53(m,1H),7.32–7.06(m,4H),7.02–6.85(m,3H),6.42(dd,J＝16.9,10.3Hz,1H),6.20(dd,J＝17.0,2.1Hz,1H),5.70(dd,J＝10.1,2.0Hz,1H),4.27(s,2H),4.12–4.04(m,2H),3.69–3.61(m,2H),3.30(s,3H).
实施例13-16
化合物G-13至G-16的制备方法同实施例2，不同的是将步骤1中的化合物1a换成中间体10a、11a、12a和13a。
Figure PCTCN2018098479-appb-000058
Figure PCTCN2018098479-appb-000059
生物测试
测试例一 Lantha screening激酶反应实验方法
化合物预先溶解在100％DMSO中。室温溶解10mM的药物储存液，经8vol％DMSO溶液梯度稀释至终浓度10-0.005μM。384孔板(Corning 3676)每孔中加入2.5μl的待测物溶液以及2.5μl经反应缓冲液稀释的激酶(Invitrogen PV3363)，再加入5μl的反应缓冲液稀释Fluososcei-PolyGT(Invitrogen PV3610)底物与ATP(Invitrogen PV3227)的混合物启动反应。其中空白孔(Blank)用反应缓冲液代替激酶，激酶孔(Enzyme)不加入任何药物。在25℃摇床避光反应60分钟后。加入10μl Detection Solution(Invitrogen PV3528与EDTA的混合液，用TR-FRET稀释缓冲液进行稀释，EDTA工作浓度为5mM，Lanthascreening Tb PY20 antibody工作浓度为0.2nM)，于室温摇床反应30分钟。在VictorX5荧光酶标仪(PerkinElmer)上读板，测定激发波长为340nm、发射波长为500nm和520nm的光吸收。
抑制率计算方法(参照Invitrogen，PV3363的说明书)如下：
1.Emission rate(ER):Coumarin Emission(520nm)/Fluorescein Emission(500nm)
2.抑制率(IR):(ER kinase-ER test compound)/(ER kinase-ER blank)×100％。用XLFIT 5.0软件(英国IDBS公司)拟合计算半数抑制浓度IC50。结果如表1所示：
表1 化合物对BTK WT的抑制活性
Figure PCTCN2018098479-appb-000060
从表1可以看出，本发明代表性化合物对酶具有较高的抑制活性。研究发现本发明化合物结构中当Y为杂原子时，Y的选择对化合物最终抑制活性有明显的影响，当Y为O时，化合物的抑制活性明显降低(如化合物G-12和G-2)，或当Y为N，且有取代基(如甲基)时，化合物的抑制活性显著降低(如化合物G-17和G-2)。
测试例二 细胞内βBTK Y223磷酸化检测HTRF实验方法
化合物预先溶解在100％DMSO中。室温溶解10mM的药物储存液，经5vol％DMSO溶液梯度稀释至终浓度3-0.0014μM。将Ramos细胞以4×10 5/孔的密度种到96孔板中，每孔45μl含10％(V/V)FBS的1640培养基，每孔中加入5μl的稀释好的待测物溶液，37℃、5％(V/V)CO 2 培养1小时。加入10μl过钒酸钠稀释液(无血清的1640稀释)，阴性对照孔加入10μl无血清培养基，25℃摇床孵育30分钟。每孔加入20μl裂解液(4x裂解液：封闭母液25:1)，25℃摇床孵育30分钟。振荡器800rpm震荡1分钟，取16μl细胞裂解液加入384孔板(Greiner 784075)中，加入4μl预先混合的抗体溶液(Phospho-BTK d2抗体和Phospho-BTK Cryptate抗体使用检测液稀释20倍)，25℃摇床孵育过夜。在VictorX5荧光酶标仪(PerkinElmer)上读板，测定激发波长为317nm、发射波长为500nm和520nm的光吸收(参照Cisbio，63ADK017PEH的说明书)。用XLFIT 5.0软件(英国IDBS公司)拟合计算半数抑制浓度IC50。结果如表2所示：
表2 化合物对βBTK Y223细胞的抑制活性
Figure PCTCN2018098479-appb-000061
从表2可以看出，本发明代表性化合物对细胞具有较高的抑制活性。
测试例三 对野生型EGFR激酶的活性抑制测试
以下z-lyte测试方法中所用试剂均可购自Invitrogen。
利用z-lyte方法测定待测物对野生型EGFR激酶(Invitrogen，PV3872)的抑制活性。
10uL野生型EGFR激酶反应体系中各组分的工作浓度为：10μM ATP，0.8ng/μL野生型EGFR激酶(Invitrogen，PV3872)，2μM Tyr04底物(Invitrogen，PV3193)。加入待测物后DMSO的终浓度为2％。
室温溶解10mM的药物储存液经4％DMSO的水梯度稀释至终浓度10-0.005μM。每孔中加入2.5μL的待测物溶液以及5μL经反应缓冲液稀释的野生型EGFR激酶与Tyr04底物的混合物，再加入2.5μL的ATP启动反应。其中C1孔用反应缓冲液代替ATP，C2孔不加入任何药物，C3孔按说明书描述加入磷酸化的底物。在25度摇床避光反应60分钟后。加入5μL Development Reagent B(Invitrogen，用TR-FRET稀释缓冲液进行稀释)，于室温摇床反应60分钟。在VictorX5荧光酶标仪(PerkinElmer)上读板，测定激发波长为405nm、发射波长为450nm和520nm的光吸收(例如，C3 520nm表示C3孔在520nm的读值)。
抑制率计算方法(参照Invitrogen，PV3193的说明书)如下：
1、ER＝Coumarin Emission(450nm)/Fluorescein Emission(520nm)
2、磷酸化率＝(1-((ER×C3 520nm-C3 450nm)/((C1 450nm-C3 450nm)+ER×(C3 520nm-C1 520nm))))×100％
3、抑制率(IR)＝(1-(测试化合物的磷酸化率)/(C2的磷酸化率))×100％
用XLFIT 5.0软件(英国IDBS公司)拟合计算半数抑制浓度IC 50。
表3 化合物对EGFR WT的抑制活性
Figure PCTCN2018098479-appb-000062
Figure PCTCN2018098479-appb-000063
从表3可以看出，本发明代表性化合物对野生型EGFR激酶具有较低的抑制活性。因此本发明示例化合物对BTK WT激酶具有选择抑制活性。
在本发明提及的所有文献都在本申请中引用作为参考，就如同每一篇文献被单独引用作为参考那样。此外应理解，在阅读了本发明的上述讲授内容之后，本领域技术人员可以对本发明作各种改动或修改，这些等价形式同样落于本申请所附权利要求书所限定的范围。

Claims (15)

  1. 一种式(II)所示的化合物，或其药学上可接受的盐、立体异构体、溶剂化物或前药：
    Figure PCTCN2018098479-appb-100001
    式中，Y为一个键、NR a1、S、SO、SO 2或O；其中R a1为氢、羟基或C 1-8烷基；
    B为C 6-10芳基、4至7元饱和或不饱和单杂环、5至6元单环杂芳基环、8至10元双环杂芳基环；
    Q为N或CR b1；其中R b1为氢、卤素、氰基、C 1-8烷基、卤代C 1-8烷基、C 1-8烷氧基、C 3-8环烷基或C 3-8环烷氧基；
    Z 1、Z 2、Z 3、Z 4中的三个为CH，一个为N；或Z 1、Z 2、Z 3、Z 4均为CH；
    R 5、R 6各自独立地为氢、卤素、C 1-8烷基、卤代C 1-8烷基、C 1-8烷氧基、C 3-8环烷基或C 3-8环烷氧基；
    R 7、R 9各自独立地为氢、C 1-8烷基、卤代C 1-8烷基或C 3-8环烷基；
    R 8为氢、卤素、氰基、C 1-8烷基、C 1-8烷氧基、卤代C 1-8烷基或C 3-8环烷基或NR a0R b0；其中R a0、R b0各自独立地为氢、乙酰基、C 1-8烷基、C 1-8烷氧基取代的C 1-8烷基；
    j为0、1、2、3或4；
    所述烷基、环烷基、烷氧基、环烷氧基、芳基、饱和或不饱和单杂环、单环杂芳基环、双环杂芳基环为未取代的或被1、2或3个选自下组的取代基所取代：卤素、羟甲基、羟乙基、羟基、羧基、-O(CH 2) pOC 1-8烷基、-O(CH 2) pOH、-(CH 2) pOC 1-8烷基、4至6元饱和单杂环、C 1-8烷基、C 3-8环烷基、卤代C 1-8烷基、卤代C 3-8环烷基、羟基取代的C 1-8烷基、NR a0R b0、-C(O)OC 1-6烷基、乙酰基、C 1-8烷氧基、C 1-8烷氧基取代的C 1-8烷基、卤代C 1-8烷氧基、-SO 2C 1-8烷基、C 6-10芳基()、5至6元单环杂芳基或-Y-L；其中Y为(CH 2) q或C(O)；L为4至6元饱和单杂环或5至6元单环杂芳基环；q为1、2或3；R a0、R b0各自独立地为氢、乙酰基、C 1-8烷基、C 1-8烷氧基取代的C 1-8烷基。
  2. 如权利要求1所述的化合物、或其药学上可接受的盐、立体异构体、溶剂化物或前药，其特征在于，Y为一个键或NR a1；其中R a1为氢、C 1-3烷基。
  3. 如权利要求1所述的化合物、或其药学上可接受的盐、立体异构体、溶剂化物或前药，其特征在于，B为苯基或吡唑环。
  4. 如权利要求1所述的化合物、或其药学上可接受的盐、立体异构体、溶剂化物或前药，其特征在于，Y为一个键；B为5至6元单环杂芳基环；所述5至6元单环杂芳基环任选地 被1、2或3个选自A1组的取代基所取代。
  5. 如权利要求1所述的化合物、或其药学上可接受的盐、立体异构体、溶剂化物或前药，其特征在于，Y为一个键；B选自B2组中结构。
  6. 如权利要求1所述的化合物、或其药学上可接受的盐、立体异构体、溶剂化物或前药，其特征在于，Y为一个键；B为吡唑环；所述吡唑环任选地被1、2或3个选自A1组的取代基所取代。
  7. 如权利要求1所述的化合物、或其药学上可接受的盐、立体异构体、溶剂化物或前药，其特征在于，Y为NR a1；其中R a1为氢、C 1-3烷基；B为苯基或5至6元单环杂芳基环；所述B任选地被1、2或3个选自A1组的取代基所取代。
  8. 如权利要求1所述的化合物、或其药学上可接受的盐、立体异构体、溶剂化物或前药，其特征在于，Y为NR a1；其中R a1为氢、C 1-3烷基；B为苯基或吡唑环；所述苯基或吡唑环任选地被1、2或3个选自A1组的取代基所取代。
  9. 如权利要求1所述的化合物、或其药学上可接受的盐、立体异构体、溶剂化物或前药，其特征在于，Y为NR a1；其中R a1为氢、C 1-3烷基；B选自B1组中结构。
  10. 如权利要求1所述的化合物、或其药学上可接受的盐、立体异构体、溶剂化物或前药，其特征在于，R 7、R 9各自独立地为氢、C 1-3烷基、卤代C 1-3烷基或C 3-6环烷基。
  11. 如权利要求1所述的化合物、或其药学上可接受的盐、立体异构体、溶剂化物或前药，其特征在于，式(II)化合物选自D2组中结构。
  12. 一种药物组合物，包括权利要求1所述的化合物和药学上可接受的载体或赋形剂。
  13. 权利要求1所述化合物或权利要求12所述的药物组合物在制备激酶抑制剂药物中的用途。
  14. 如权利要求13所述的用途，其特征在于，所述药物用于治疗由B细胞介导的疾病。
  15. 如权利要求13所述的用途，其特征在于，所述药物用于治疗肿瘤疾病、增殖性疾病、变态反应性疾病、自身免疫性疾病和炎症性疾病的至少一种。
PCT/CN2018/098479 2017-09-28 2018-08-03 苯胺取代的1,2-二氢吡咯并[3,4-c]吡啶/嘧啶-3-酮衍生物及用途 WO2019062328A1 (zh)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20210395247A1 (en) * 2019-03-18 2021-12-23 Shanghai Haiyan Pharmaceutical Technology Co., Ltd. Btk inhibitors, pharmaceutically acceptable salts, polymorphs and application thereof

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR20190043437A (ko) 2017-10-18 2019-04-26 씨제이헬스케어 주식회사 단백질 키나제 억제제로서의 헤테로고리 화합물
WO2022048551A1 (zh) * 2020-09-01 2022-03-10 上海海雁医药科技有限公司 布鲁顿酪氨酸激酶抑制剂的多晶型物及其制备方法和应用
CN113061137B (zh) * 2021-04-02 2022-08-02 广西医科大学 含氮杂环衍生物或其药学上可接受的盐和用途

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102753548A (zh) * 2009-12-23 2012-10-24 武田药品工业株式会社 作为syk抑制剂的稠合的杂芳族吡咯烷酮
WO2017075394A1 (en) * 2015-10-29 2017-05-04 Effector Therapeutics, Inc. Isoindoline, azaisoindoline, dihydroindenone and dihydroazaindenone inhibitors of mnk1 and mnk2

Family Cites Families (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
TWI398252B (zh) * 2006-05-26 2013-06-11 Novartis Ag 吡咯并嘧啶化合物及其用途
EP2723739B1 (en) * 2011-06-22 2016-08-24 Takeda Pharmaceutical Company Limited Substituted 6-aza-isoindolin-1-one derivatives
SG11201602070TA (en) * 2013-09-30 2016-04-28 Beijing Synercare Pharma Tech Co Ltd Substituted nicotinimide inhibitors of btk and their preparation and use in the treatment of cancer, inflammation and autoimmune disease
SI3060550T1 (sl) 2013-10-21 2019-09-30 Merck Patent Gmbh Heteroarilne spojine kot inhibitorji BTK in uporabe le-teh
EP3110820B1 (en) * 2014-02-28 2022-04-06 Nimbus Lakshmi, Inc. Tyk2 inhibitors and uses thereof
WO2015158310A1 (zh) * 2014-04-18 2015-10-22 山东轩竹医药科技有限公司 一种酪氨酸激酶抑制剂及其用途
CN105777756B (zh) * 2014-07-02 2019-03-01 广东东阳光药业有限公司 杂芳化合物及其在药物中的应用
LT3236943T (lt) * 2014-12-24 2023-04-11 Principia Biopharma Inc. Kompozicija, skirta vaistų pristatymui per klubinę ir tiesiąją žarną
CN107021963A (zh) * 2016-01-29 2017-08-08 北京诺诚健华医药科技有限公司 吡唑稠环类衍生物、其制备方法及其在治疗癌症、炎症和免疫性疾病上的应用

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102753548A (zh) * 2009-12-23 2012-10-24 武田药品工业株式会社 作为syk抑制剂的稠合的杂芳族吡咯烷酮
WO2017075394A1 (en) * 2015-10-29 2017-05-04 Effector Therapeutics, Inc. Isoindoline, azaisoindoline, dihydroindenone and dihydroazaindenone inhibitors of mnk1 and mnk2

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20210395247A1 (en) * 2019-03-18 2021-12-23 Shanghai Haiyan Pharmaceutical Technology Co., Ltd. Btk inhibitors, pharmaceutically acceptable salts, polymorphs and application thereof

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