WO2018228475A1 - Syk抑制剂及其使用方法 - Google Patents

Syk抑制剂及其使用方法 Download PDF

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Publication number
WO2018228475A1
WO2018228475A1 PCT/CN2018/091269 CN2018091269W WO2018228475A1 WO 2018228475 A1 WO2018228475 A1 WO 2018228475A1 CN 2018091269 W CN2018091269 W CN 2018091269W WO 2018228475 A1 WO2018228475 A1 WO 2018228475A1
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group
methyl
mmol
amino
alkyl
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PCT/CN2018/091269
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English (en)
French (fr)
Inventor
刘世岚
梁贵柏
王宏健
张明
陈曙辉
Original Assignee
正大天晴药业集团股份有限公司
南京明德新药研发股份有限公司
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Application filed by 正大天晴药业集团股份有限公司, 南京明德新药研发股份有限公司 filed Critical 正大天晴药业集团股份有限公司
Priority to ES18817720T priority Critical patent/ES2906205T3/es
Priority to EP18817720.8A priority patent/EP3640247B1/en
Priority to AU2018286247A priority patent/AU2018286247B2/en
Priority to JP2019568033A priority patent/JP7299167B2/ja
Priority to CA3065114A priority patent/CA3065114A1/en
Priority to CN201880036803.9A priority patent/CN110678461B/zh
Priority to US16/619,646 priority patent/US11091460B2/en
Publication of WO2018228475A1 publication Critical patent/WO2018228475A1/zh

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • 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
    • C07D487/08—Bridged systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/10—Spiro-condensed systems
    • C07D491/107—Spiro-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring

Definitions

  • the present application belongs to the field of medical technology and relates to a class of Syk inhibitors or pharmaceutically acceptable salts thereof, a process for the preparation thereof and a pharmaceutical composition thereof.
  • Syk spleen tyrosine kinase is an intracellular tyrosine protein kinase belonging to the ZAP70 protein kinase family. Syk plays a key role in the early development of B cells, the development of lymphocytes, and the function of mature B cells. In this process it is involved in a variety of signal transduction pathways and does not need to be activated by phosphorylation of Src kinase. In addition to being commonly expressed in hematopoietic stem cells, Syk is expressed in non-hematopoietic cells such as epithelial cells, hepatocytes, fibroblasts, nerve cells, and breast tissues, and has multiple functions.
  • Syk PTK dysfunction such as allergic reactions, asthma, inflammation and autoimmune diseases
  • Syk is an important mediator of acute or chronic inflammation.
  • Activation of Syk is present in several common B-cell malignancies, such as in follicular lymphoma, diffuse large B-cell lymphoma, mantle cell lymphoma, and B-cell chronic lymphocytic leukemia.
  • Dependent phosphorylation of Syk The researchers found that inhibition of Syk in follicular lymphoma and diffuse large B-cell lymphoma cells can reduce the phosphorylation level of downstream signaling molecules, thereby inhibiting the proliferation and survival of tumor cells.
  • Syk activity can be used to treat a particular type of cancer, including B cell lymphoma and leukemia.
  • W is C(R 7 ) or N
  • R 1 and R 2 are independently selected from the group consisting of H, halogen, amino, hydroxy, cyano, C 1-6 alkyl, C 3-6 cycloalkyl, 3 to 10 membered heterocycloalkyl, 6 to 12 aryl. Or a 5- to 12-membered heteroaryl group, the amino group, a C 1-6 alkyl group, a C 3-6 cycloalkyl group, a 3 to 10 membered heterocycloalkyl group, a 6 to 12 membered aryl group or a 5 to 12 membered heteroaryl group.
  • the base is optionally substituted by R 8 ;
  • R 3 , R 4 , R 7 are independently selected from H, halogen, amino, hydroxy, cyano, C 1-6 alkyl, C 3-6 cycloalkyl or 3- to 6-membered heterocycloalkyl, said amino a C 1-6 alkyl group, a C 3-6 cycloalkyl group or a 3-6 membered heterocycloalkyl group optionally substituted by R 9 ;
  • R 5 is selected from the group consisting of H, C 1-6 alkyl, C 3-6 cycloalkyl, 3-6 -membered heterocycloalkyl, C 1-6 alkyl C(O), C 3-6 cycloalkyl C ( O), 3- to 6-membered heterocycloalkyl C(O), phenyl C(O), 5- to 6-membered heteroaryl C(O), C 1-6 alkyl SO 2 , C 3-6 naphthenic a base SO 2 , a 3- to 6-membered heterocycloalkyl SO 2 , a phenyl SO 2 or a 5- to 6-membered heteroaryl SO 2 , said C 1-6 alkyl group, C 3-6 cycloalkyl group, 3 to 6 Aminoheterocycloalkyl, C 1-6 alkyl C(O), C 3-6 cycloalkyl C(O), 3- to 6-membered heterocycloalkyl C(O), phenyl C(O), 5 ⁇
  • X is selected from a 3 to 12 membered ring in which the H atom is lost at any two positions, and the ring is optionally substituted with R 9 ;
  • L is selected from the group consisting of a bond, NH, O, S, SO, SO 2 , C(O), OC(O), C(O)O, C(O)NH, NHSO 2 , SO 2 NH, NHC(O)NH Or NHSO 2 NH;
  • R 6 is selected from H, halogen, amino, hydroxy, cyano, C 1-6 alkyl, C 3-10 cycloalkyl or 3 to 10 membered heterocycloalkyl, said amino group, C 1-6 alkyl group, C 3-10 cycloalkyl or 3 to 10 membered heterocycloalkyl is optionally substituted by R 10 ;
  • R 8 , R 9 are independently selected from halogen, amino, hydroxy, cyano, C 1-3 alkyl, C 1-3 alkoxy or COOH;
  • R 1 and R 2 are selected from a 6- to 12-membered aryl group or a 5- to 12-membered heteroaryl group, and the 6- to 12-membered aryl group or a 5- to 12-membered heteroaryl group is optionally substituted by R 8 .
  • R 1 , R 2 are independently selected from H, halo or 5 to 12 membered heteroaryl, and said 5 to 12 membered heteroaryl is optionally substituted by R 8 .
  • R 1 , R 2 are independently selected from the group consisting of H, F, Cl, Br, furyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, pyridyl, pyrimidine Or pyrazinyl, pyrazinyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, tetrazolyl or triazinyl, said furyl, thienyl, pyrrolyl, pyrazolyl, imidazole , pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, tetrazolyl or triazinyl is optionally substituted with R 8.
  • R 1 , R 2 are independently selected from H, F, Cl, thiazolyl, pyrazolyl, imidazolyl or pyridyl, said thiazolyl, pyrazolyl, The imidazolyl or pyridyl group is optionally substituted by R 8 .
  • R 8 is selected from amino, methyl, ethyl, propyl or isopropyl.
  • R 8 is selected from methyl or amino group.
  • R 1 is selected from the group consisting of H, F, It may optionally be substituted by R 8 .
  • R 1 is selected from the group consisting of H, F,
  • R 2 is selected from H, F, Cl or
  • R 1 is selected from a 5 to 12 membered heteroaryl; R 2 is selected from H or halo; wherein, R 1 may optionally be substituted with R 8.
  • R 1 is selected from the group consisting of furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, thiazolyl, Isothiazolyl, oxazolyl, isoxazolyl, tetrazolyl or triazinyl;
  • R 2 is selected from H, F, Cl or Br; wherein R 1 may be optionally substituted by R 8 .
  • R 1 is selected from thiazolyl, pyrazolyl, imidazolyl or pyridyl; R 2 is selected from H, F or Cl; wherein R 1 is optionally R 8 replaced.
  • R 1 is selected from R 2 is selected from H, F or Cl; wherein R 1 may be optionally substituted by R 8 .
  • R 1 is selected from R 2 is selected from H, F or Cl.
  • R 1 is selected from H or halo;
  • R 2 is selected from 5-12 membered heteroaryl; wherein, R 2 may be optionally substituted with R 8.
  • R 1 is selected from H, F, Cl or Br
  • R 2 is selected from the group consisting of furyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, pyridyl, pyrimidinyl And pyridazinyl, pyrazinyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, tetrazolyl or triazinyl; wherein R 2 may be optionally substituted by R 8 .
  • R 1 is selected from H or F;
  • R 2 is selected from pyrazolyl; wherein, R 2 may be optionally substituted with R 8.
  • R 3 , R 4 , R 7 are independently selected from H, halo, C 1-6 alkyl or C 3-6 cycloalkyl, said C 1-6 The alkyl or C 3-6 cycloalkyl group is optionally substituted by R 9 .
  • R 3 , R 4 , R 7 are independently selected from H or halogen.
  • R 3 , R 4 , R 7 are independently selected from H, F or Cl.
  • W is N, and R 3 and R 4 are independently selected from H, F, or Cl.
  • R 5 is selected from H, C 1-6 alkyl or C 3-6 cycloalkyl, wherein C 1-6 alkyl or C 3-6 cycloalkyl The choice is replaced by R 9 .
  • R 5 is selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, isobutyl or tert-butyl, said methyl, ethyl, propyl , isopropyl, butyl, isobutyl or tert-butyl is optionally substituted with R 9.
  • R 5 is selected from methyl
  • X is selected from benzene rings which lose H atoms in any two positions, Furan ring, thiophene ring, pyrrole ring, pyrazole ring, imidazole ring, pyridine ring, pyrimidine ring, pyridazine ring, pyrazine ring, thiazole ring, isothiazole ring, oxazole ring, isoxazole ring, tetrazole ring or triazine ring, the X may be optionally substituted with R 9.
  • One embodiment of the compounds (I) of the present application wherein, X is selected from any two positions lost benzene or pyridine ring H atoms of the X-R 9 may be optionally substituted.
  • X is selected from The X may be optionally substituted with R 9 .
  • X is selected from
  • R 9 is selected from halo, C 1-3 alkyl or a C 1-3 alkoxy group.
  • R 9 is selected from F, Cl, methyl, or OCH 3.
  • L is selected from the group consisting of a bond, NH, O, S, SO, SO 2 , NHSO 2 , SO 2 NH or NHSO 2 NH.
  • L is selected from the group consisting of a bond, NH, O, S, SO or SO 2 .
  • L is selected from the group consisting of a bond, NH or SO 2 .
  • R 6 is selected from H, amino, C 1-6 alkyl, C 3-6 cycloalkyl or 3 to 10 membered heterocycloalkyl, said amino group, C The 1-6 alkyl group, the C 3-6 cycloalkyl group or the 3- to 10-membered heterocycloalkyl group may be optionally substituted by R 10 .
  • R 6 is selected from H, amino, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, cyclopropyl, Butyl, cyclopentyl, cyclohexyl, losing a H atom at any position
  • R 6 is selected from the group consisting of H, NH 2 , methyl, isopropyl, cyclobutyl, The NH 2 , methyl, isopropyl, cyclobutyl, It may optionally be substituted by R 10 .
  • R 6 is selected from the group consisting of H, NH 2 , methyl,
  • the compound of formula (I) has formula (II),
  • R 2 is selected from 6 to 12 membered aryl or 5 to 12 membered heteroaryl, and the 6 to 12 membered aryl or 5 to 12 membered heteroaryl is optionally substituted with R 8 ;
  • R 1 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , X and L are as defined in the formula (I).
  • R 2 is selected from pyrazolyl, which may be optionally substituted by R 8 .
  • R 2 is selected from
  • the compound of formula (I) has formula (III),
  • R 1 , R 3 , R 4 , R 6 , R 7 and X are as defined in formula (I).
  • the compound of formula (I) has formula (IV),
  • R 1 is selected from 6 to 12 membered aryl or 5 to 12 membered heteroaryl, and R 1 may be optionally substituted by R 8 ;
  • R 2 , R 3 , R 4 , R 5 , R 6 , R 8 , X and L are as defined in the formula (I).
  • R 1 is selected from a 5 to 12 membered heteroaryl group, the R 1 may be optionally substituted by R 8.
  • R 1 is selected from the group consisting of furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, tetrazolyl or triazinyl, of R 1 may optionally be substituted with R 8.
  • R 1 is selected from thiazolyl, pyrazolyl, imidazolyl or pyridinyl, of R 1 may optionally be substituted with R 8.
  • R 1 is selected from The R 1 may be optionally substituted with R 8 .
  • R 1 is selected from
  • the compound of formula (I) has a compound of formula (V),
  • R 2 , R 3 , R 4 , R 6 , X and L are as defined in the formula (I).
  • the compound of formula (I) is selected from the group consisting of:
  • the present application is directed to a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, of the present application.
  • the pharmaceutical compositions of the present application further comprise one or more pharmaceutically acceptable excipients.
  • compositions of the present application can be prepared by combining a compound of the present application, a pharmaceutically acceptable salt thereof, with a suitable pharmaceutically acceptable adjuvant, for example, as a solid, semi-solid, liquid or gaseous preparation, such as a tablet.
  • a suitable pharmaceutically acceptable adjuvant for example, as a solid, semi-solid, liquid or gaseous preparation, such as a tablet.
  • Typical routes of administration of a compound of the present application, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof include, but are not limited to, oral, rectal, transmucosal, enteral administration, or topical, transdermal, inhalation, parenteral, sublingual , intravaginal, intranasal, intraocular, intraperitoneal, intramuscular, subcutaneous, intravenous.
  • the pharmaceutical composition of the present application can be produced by a method well known in the art, such as a conventional mixing method, a dissolution method, a granulation method, a sugar-coating method, a grinding method, an emulsification method, a freeze-drying method, and the like.
  • the pharmaceutical compositions can be formulated by admixing the active compound with pharmaceutically acceptable excipients known in the art. These excipients enable the compounds of the present application to be formulated into tablets, pills, troches, dragees, capsules, liquids, gels, slurries, suspensions and the like for oral administration to a patient.
  • Solid oral compositions can be prepared by conventional methods of mixing, filling or tabletting. For example, it can be obtained by mixing the active compound with a solid adjuvant, optionally milling the resulting mixture, adding other suitable excipients if necessary, and then processing the mixture into granules to give tablets. Or the core of the sugar coating. Suitable excipients include, but are not limited to, binders, diluents, disintegrants, lubricants, glidants, sweeteners or flavoring agents, and the like.
  • compositions may also be suitable for parenteral administration, such as sterile solutions, suspensions or lyophilized products in a suitable unit dosage form.
  • suitable excipients such as fillers, buffers or surfactants can be used.
  • the compounds of formula (I) described herein, or pharmaceutically acceptable salts thereof, can be administered by any suitable route and method, for example by oral or parenteral (e.g., intravenous) administration.
  • a therapeutically effective amount of a compound of formula (I) is from about 0.0001 to 20 mg/kg body weight per day, such as from 0.001 to 10 mg/kg body weight per day.
  • the dosage frequency of the compound of formula (I) is determined by the needs of the individual patient, for example, once or twice daily, or more times per day. Administration can be intermittent, for example, wherein during a period of several days, the patient receives a daily dose of the compound of formula (I), followed by a period of several days or more, the patient does not receive each of the compounds of formula (I) Daily dose.
  • Another object of the present application is to provide a use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described above, for the manufacture of a medicament for the treatment of a Syk receptor related disorder.
  • Another aspect of the present application provides a method of treating a Syk receptor related disorder, the method comprising administering a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described above.
  • the Syk receptor associated disorder is selected from a cancer or an inflammatory disease.
  • the Syk receptor-associated disorder is selected from the group consisting of a B-cell lymphoma, a Hodgkin's lymphoma, a non-Hodgkin's lymphoma, a hairy cell leukemia, multiple myeloma, chronic myeloid leukemia, acute myeloid leukemia, Chronic lymphocytic leukemia, acute lymphocytic leukemia, rheumatoid arthritis, allergic rhinitis, chronic obstructive pulmonary disease (COPD), adult respiratory distress syndrome (ARDs), allergic-induced inflammatory disease, multiple sclerosis, autoimmune Sexual disease, acute inflammatory response, allergic disorder or polycystic kidney disease.
  • COPD chronic obstructive pulmonary disease
  • ARDs adult respiratory distress syndrome
  • pharmaceutically acceptable is for those compounds, materials, compositions and/or dosage forms that are within the scope of sound medical judgment and are suitable for use in contact with human and animal tissues without Many toxic, irritating, allergic reactions or other problems or complications are commensurate with a reasonable benefit/risk ratio.
  • pharmaceutically acceptable salt refers to a salt of a compound of the present invention prepared from a compound having a particular substituent found herein and a relatively non-toxic acid or base.
  • a base addition salt can be obtained by contacting a suitable base with a neutral form of such a compound.
  • an acid addition salt can be obtained by contacting a suitable acid with a neutral form of such a compound.
  • Certain specific compounds of the present application contain basic and acidic functional groups which can be converted to any base or acid addition salt.
  • Certain compounds of the present application may have asymmetric carbon atoms (optical centers) or double bonds. Racemates, diastereomers, geometric isomers, and individual isomers are included within the scope of this application.
  • included in the structure of the compound Can be
  • included in the structure of the compound Can be or
  • the compounds of the present application may exist in specific geometric or stereoisomeric forms. All such compounds are contemplated by the present application, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereoisomers , (D)-isomer, (L)-isomer, and racemic mixtures thereof and other mixtures, such as enantiomerically or diastereomeric enriched mixtures, all of which belong to the present Within the scope of the application. Additional asymmetric carbon atoms may be present in the substituents such as alkyl groups. All such isomers, as well as mixtures thereof, are included within the scope of this application.
  • optically active (R)- and (S)-isomers as well as the D and L isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If one enantiomer of a compound of the present application is desired, it can be prepared by asymmetric synthesis or by derivatization with a chiral auxiliary wherein the resulting mixture of diastereomers is separated and the auxiliary group cleaved to provide purity. The desired enantiomer.
  • a diastereomeric salt is formed with a suitable optically active acid or base, followed by conventional methods well known in the art.
  • the diastereomers are resolved and the pure enantiomer is recovered.
  • the separation of enantiomers and diastereomers is generally accomplished by the use of chromatography using a chiral stationary phase, optionally in combination with chemical derivatization (eg, formation of an amino group from an amine). Formate).
  • the compounds of the present application may contain unnatural proportions of atomic isotopes on one or more of the atoms that make up the compound.
  • radiolabeled compounds can be used, such as deuterium (2 H), tritium (3 H), iodine -125 (125 I) or C-14 (14 C). All isotopic compositional changes of the compounds of the present application, whether radioactive or not, are included within the scope of the present application.
  • pharmaceutically acceptable excipient refers to those excipients which have no significant irritating effect on the organism and which do not impair the biological activity and properties of the active compound. Suitable excipients are well known to those skilled in the art, such as carbohydrates, waxes, water soluble and/or water swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, and the like.
  • an effective amount or “therapeutically effective amount” refers to a sufficient amount of a drug or agent that achieves the desired effect. The determination of the effective amount will vary from person to person, depending on the age and general condition of the recipient, and also on the particular active substance, and a suitable effective amount in a case can be determined by one skilled in the art based on routine experimentation.
  • active ingredient refers to a chemical entity that is effective in treating a target disorder, disease or condition.
  • an ethyl group “optionally” substituted with halo refers to an ethyl group may be unsubstituted (CH 2 CH 3), monosubstituted (e.g., CH 2 CH 2 F), polysubstituted (e.g. CHFCH 2 F, CH 2 CHF 2, etc.) or completely substituted (CF 2 CF 3 ). It will be understood by those skilled in the art that for any group containing one or more substituents, no substitution or substitution pattern that is sterically impossible to exist and/or which cannot be synthesized is introduced.
  • C mn means having mn carbon atoms in this moiety.
  • C 3-10 cycloalkyl means that the cycloalkyl group has 3 to 10 carbon atoms.
  • C 0-6 alkylene group means that the alkylene group has 0 to 6 carbon atoms, and when the alkylene group has 0 carbon atoms, the group is a bond.
  • C 1-10 means that the group may have 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, 6 carbon atoms, 7 carbon atoms, 8 One carbon atom, nine carbon atoms or ten carbon atoms.
  • substituted means that any one or more hydrogen atoms on a particular atom are replaced by a substituent as long as the valence of the particular atom is normal and the substituted compound is stable.
  • any variable eg, R
  • its definition in each case is independent.
  • the group may optionally be substituted with at most two R, and each case has an independent option.
  • combinations of substituents and/or variants thereof are permissible only if such combinations result in stable compounds.
  • one of the variables When one of the variables is selected from a bond, it indicates that the two groups to which it is attached are directly linked. For example, when L represents a bond in A-L-Z, the structure is actually A-Z.
  • substituent When a substituent is vacant, it means that the substituent is absent. For example, when X is vacant in AX, the structure is actually A. When a bond of a substituent can be cross-linked to two atoms on a ring, the substituent can be bonded to any atom on the ring. When the recited substituents do not indicate which atom is attached to a compound included in the chemical structural formula including but not specifically mentioned, such a substituent may be bonded through any atomic phase thereof. Combinations of substituents and/or variants thereof are permissible only if such combinations result in stable compounds. For example, a structural unit It is indicated that it can be substituted at any position on the cyclohexyl or cyclohexadiene.
  • halo or halogen, by itself or as part of another substituent, denotes a fluorine, chlorine, bromine or iodine atom.
  • haloalkyl is intended to include monohaloalkyl and polyhaloalkyl; for example, the term “halo C 1-3 alkyl” is intended to include, but is not limited to, trifluoromethyl, 2,2,2-trifluoro. Ethyl and 3-bromopropyl and the like. Examples of haloalkyl groups include, but are not limited to, trifluoromethyl, trichloromethyl, pentafluoroethyl, and pentachloroethyl.
  • hydroxy refers to -OH.
  • cyano refers to -CN.
  • amino refers to -NH 2 .
  • alkyl refers to a straight or branched saturated aliphatic hydrocarbon group consisting of a carbon atom and a hydrogen atom, such as methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, ⁇ , ⁇ , etc.
  • the specific alkyl group includes all isomeric forms thereof, for example, the propyl group includes -CH 2 CH 2 CH 3 , -CH(CH 3 ) 2 , for example, butyl includes -CH 2 CH 2 CH 2 CH 3 ,- CH(CH 3 )(CH 2 CH 3 ), -C(CH 3 ) 3 , -CH 2 CH(CH 3 ) 2 .
  • C 1-8 alkyl refers to an alkyl group having from 1 to 8 carbon atoms.
  • C1-6 alkyl refers to an alkyl group having from 1 to 6 carbon atoms.
  • C 1-4 alkyl refers to an alkyl group having from 1 to 4 carbon atoms.
  • C 1-3 alkyl refers to an alkyl group having from 1 to 3 carbon atoms.
  • alkoxy refers to -O-alkyl
  • cycloalkyl refers to a monocyclic saturated aliphatic hydrocarbon group consisting solely of carbon atoms and hydrogen atoms, such as a C 3-10 cycloalkyl group, preferably a C 3-6 cycloalkyl group, such as a cyclopropyl group, Cyclobutyl, cyclopentyl, cyclohexyl and the like.
  • hetero denotes a hetero atom or a hetero atomic group (ie, a radical containing a hetero atom), including atoms other than carbon (C) and hydrogen (H), and radicals containing such heteroatoms, including, for example, oxygen (O).
  • ring means substituted or unsubstituted cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, cycloalkynyl, heterocycloalkynyl, aryl or heteroaryl.
  • the ring includes a single ring, a ring, a spiral ring, a ring or a bridge ring.
  • the number of atoms on the ring is usually defined as the number of elements of the ring.
  • “5 to 7-membered ring” means 5 to 7 atoms arranged in a circle.
  • the ring optionally contains from 1 to 3 heteroatoms.
  • “5- to 7-membered ring” includes, for example, phenyl, pyridine, and piperidinyl.
  • heterocycloalkyl refers to a cyclic group that is fully saturated and can exist as a monocyclic, bicyclic or spiro ring. Unless otherwise indicated, the heterocyclic ring is typically a 3 to 10 membered ring containing from 1 to 3 heteroatoms (preferably 1 or 2 heteroatoms) independently selected from sulfur, oxygen and/or nitrogen.
  • 3-membered heterocycloalkyl groups include, but are not limited to, oxiranyl, cyclohexylethane, cycloalkylethane, non-limiting examples of 4-membered heterocycloalkyl including, but not limited to, azetidinyl, acetophenan
  • Examples of a cyclic group, a thibutyl group, a 5-membered heterocycloalkyl group include, but are not limited to, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, isoxazolidinyl, oxazolidinyl, isothiazolidinyl, thiazolidine
  • Examples of the group, imidazolidinyl group, tetrahydropyrazolyl group, 6-membered heterocycloalkyl group include, but are not limited to, piperidinyl, tetrahydropyranyl, tetrahydrothio
  • aryl refers to an all-carbon monocyclic or fused polycyclic aromatic ring group having a conjugated ⁇ -electron system.
  • an aryl group can have 6-20 carbon atoms, 6-14 carbon atoms or 6-12 carbon atoms.
  • Non-limiting examples of aryl groups include, but are not limited to, phenyl, naphthyl, anthracenyl, 1,2,3,4-tetrahydronaphthalene, and the like.
  • heteroaryl refers to a monocyclic or fused polycyclic ring system containing at least one ring atom selected from N, O, S, preferably containing 1, 2 or 3 ring atoms selected from N, O or S. The remaining ring atoms are C and have at least one aromatic ring.
  • Preferred heteroaryl groups have a single 4 to 8 membered ring, especially a 5 to 8 membered ring, or a plurality of fused rings containing from 6 to 14, especially from 6 to 10 ring atoms.
  • heteroaryl groups include, but are not limited to, pyrrolyl, furyl, thienyl, imidazolyl, oxazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, quinolinyl, isoquinolinyl , tetrazolyl, triazolyl, triazinyl, benzofuranyl, benzothienyl, fluorenyl, isodecyl and the like.
  • the compounds of the present application can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, combinations thereof with other chemical synthesis methods, and those well known to those skilled in the art. Equivalent alternatives, preferred embodiments include, but are not limited to, embodiments of the present application.
  • the temperature is Celsius.
  • the solvent used in the present application is commercially available.
  • TMSCHN 2 stands for trimethylsilylated diazomethane
  • Tf 2 O stands for trifluoromethanesulfonic anhydride
  • DMAP 4-dimethylaminopyridine
  • Pd 2 (dba) 3 stands for three (two) Benzylidene acetone) dipalladium
  • Xantphos represents 4,5-bisdiphenylphosphino-9,9-dimethyloxaxan
  • Pd(dppf)Cl 2 represents [1,1'-bis(diphenylphosphine) Base ferrocene] palladium dichloride
  • NBS stands for N-bromosuccinimide
  • DMF stands for N,N-dimethylformamide
  • DMSO stands for dimethyl sulfoxide
  • DIEA (DIPEA) stands for N, N-diisopropylethylamine
  • Pd(OAc) 2 represents palladium acetate
  • Brettphos represents 2-(dic
  • Step A 6-(1-Benzyl-1H-pyrazol-3-yl)-3-hydroxy-1-methyl-quinoline-2(1H)-one
  • Step B [6-(1-Benzyl-1H-pyrazol-3-yl)-1-methyl-2-oxo-1,2-dihydro-quinolin-3-yl]trifluoromethanesulfonic acid ester
  • Step C 6-(1-Benzyl-1H-pyrazol-3-yl)-1-methyl-3-((4-morpholinephenyl)amino)quinoline-2(1H)-one
  • reaction solution was diluted with 40 mL of water, extracted twice with 40 mL of dichloromethane.
  • Step D 1-Methyl-3-((4-morpholinephenyl)amino)-6-(1H-pyrazol-3-yl)quinoline-2(1H)-one
  • Trifluoromethanesulfonic anhydride (39.14 g, 138.73 mmol) was added dropwise to 6-bromo-3-hydroxy-1-methylquinoline-2(1H)-one (23.50 g, 92.49 mmol) at 0 ° C under N2.
  • Pyridine (21.95 g, 277.47 mmol) and DMAP (1.13 g, 9.25 mmol) in dichloromethane (400 mL). Stir at 25 ° C for 3 hours. The reaction was quenched with 1N hydrochloric acid and the pH was adjusted to 6. The organic phase was washed with saturated sodium chloride (500 mL) Filtration and evaporation gave the title compound.
  • Step D 6-Bromo-1-methyl-3-((5-morpholinepyridin-2-yl)amino)quinolin-2(1H)-one
  • 6-Bromo-1-methyl-2-oxo-1,2-dihydroquinolin-3-yl trifluoromethanesulfonate (28.00 g, 81.95 mmol) was added to tetrahydrofuran (300 mL) under nitrogen.
  • 5-morpholine pyridin-2-amino (16.15 g, 90.15 mmol)
  • Pd 2 (dba) 3 (3.75 g, 4.10 mmol)
  • Xantphos (4.74 g, 8.20 mmol)
  • cesium carbonate 53.40 g, 163.90 mmol
  • Step E 1-Methyl-3-((5-morpholinepyridin-2-yl)amino)-6-(1H-pyrazol-3-yl)quinoline-2(1H)-one
  • Step C 1-Methyl-3((5-(tetrahydro-2H-pyran-4-yl)pyridin-2-yl)amino)-6-(1-((2-(trimethylsilyl)) Ethoxy)methyl)-1H-pyrazol-3-yl)quinoline-2(1H)-one
  • Step D 1-Methyl-6-(1H-pyrazol-3-yl)-((5-)tetrahydro-2H-pyran-4-yl)pyridin-2-yl)amino)quinoline-2 (1H)-ketone
  • Step B 1-(6-Nitropyridin-3-yl)-4-(oxetan-3-yl)piperazine
  • Example 4B A mixture of Example 4B (990 mg, 3.75 mmol) and palladium on carbon (100 mg, 10% purity) in methanol (150 mL) was reacted in hydrogen (15 psi) at 50 ° C for 16 hours. After filtration through celite, the filter cake was washed with EtOAc (EtOAc) MS-ESI (m/z): 235 (M+1).
  • EtOAc EtOAc
  • Step D 6-Chloro-1-methyl-3-[[5-[4-(oxetan-3-yl)piperazin-1-yl]pyridin-2-yl]amino]quinoline-2 (1H)-ketone
  • Example 4C To a solution of Example 4C (100 mg, 426.80 ⁇ mol), (6-chloro-1-methyl-2-oxa-1,2-dihydroquinolin-3-yl)trifluoromethanesulfonate (under nitrogen) 145.83 mg, 426.80 ⁇ mol), a solution of cesium carbonate (278.12 mg, 853.60 ⁇ mol) in tetrahydrofuran (5 mL) was added Xantphos (49.39 mg, 85.36 ⁇ mol), Pd 2 (dba) 3 (39.08 mg, 42.68 ⁇ mol). Stir at 80 ° C for 12 hours. The mixture was cooled to room temperature, EtOAc (EtOAc)EtOAc. Purification by column chromatography gave the title compound.
  • Step E 1-Methyl-3-[[5-(4-(oxetan-3-yl)piperazin-1-yl]pyridin-2-yl]amino]-6-(1H-pyrazole -3-yl)quinoline-2(1H)-one
  • Example 4D (86 mg, 201.92 ⁇ mol), 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyridine Azole (78.36 mg, 403.84 ⁇ mol), cesium carbonate (197.37 mg, 605.76 ⁇ mol) was dissolved in dioxane (8 mL), then Brttphos-Pd (32.26 mg, 40.38 ⁇ mol) was added and stirred at 110 ° C for 15 hours. The mixture was cooled to room temperature, EtOAc (EtOAc)EtOAc. The title compound 4 was obtained by preparative HPLC (trifluoroacetic acid system).
  • Step A tert-Butyl 4-hydroxy-4-(trifluoromethyl)piperidine-1-carboxylate
  • Trimethyl(trifluoromethyl)silane was added dropwise to a solution of tert-butyl 4-carbonylhexahydropyridine-1-carboxylate (1.2 g, 6.02 mmol) in DMF (10 mL). 3.85g, 27.10mmol), after stirring at 25 ° C for 2 hours, was added with water (100 mL), and the aqueous layer was extracted with ethyl acetate (100 mL ⁇ 3). Washed, dried over sodium sulfate, filtered and evaporated to give title crystal.
  • Example 5A (1.6 g, 5.94 mmol) of trifluoroacetic acid (2 mL) and dichloromethane (10 mL) were reacted at 25 ° C for 12 hours under nitrogen. The reaction mixture was evaporated under reduced pressure to give title compound.
  • Example 5B (1.67 g, 5.90 mmol), 5-bromo-2-nitropyridine (1.32 g, 6.49 mmol), potassium carbonate (4.08 g, 29.49 mmol), DMF (50 mL) After stirring at ° C for 10 hours, it was diluted with water (50 mL). The aqueous layer was extracted with ethyl acetate (50 mL ⁇ 3). The combined organic layers were washed with EtOAc EtOAc m.
  • Step D 1-(6-Aminopyridin-3-yl)-4-(trifluoromethyl)piperidin-4-ol
  • Example 5C To a solution of Example 5C (810 mg, 2.78 mmol) in 20 mL of methanol, 10% wet palladium charcoal (81 mg). Then, it was replaced with hydrogen for 3 times, and stirred for 15 hours at 25 ° C under a nitrogen (15 psi) atmosphere.
  • Step E 6-Chloro-3-[[5-[4-hydroxy-4-(trifluoromethyl)piperidin-1-yl]pyridin-2-yl]amino]-1-methyl-quinoline- 2(1H)-ketone
  • Example 5D (275.24 mg, 1.05 mmol), (6-chloro-1-methyl-2-oxy-3-quinolinyl) trifluoromethanesulfonate (300 mg, 877.99 ⁇ mol), Pd2 (dba) 3 (80.40 mg, 87.80 ⁇ mol), cesium carbonate (572.13 mg, 1.76 mmol), Xantphos (76.20 mg, 131.70 ⁇ mol) in tetrahydrofuran (10.00 mL), and the mixture was stirred at 25 ° C for 4 hours. It was diluted with water (20 mL) and the aqueous layer was extracted with dichloromethane. The combined organic layers were washed with EtOAc EtOAc m.
  • Step F 3-((5-(4-Hydroxy-4-(trifluoromethyl)piperidin-1-yl)piperidin-2-yl)amino)-1-methyl-6-(1H-pyridyl Zyrid-3-yl)quinoline-2(1H)-one
  • Example 5E (330 mg, 728.70 ⁇ mol), 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyridyl under nitrogen Azole (212.10 mg, 1.09 mmol), [2-(2-aminoethyl)phenyl]-chloro-palladium; biscyclohexyl-[3,6-dimethoxy-2-(2,4,6-three Isopropylbenzene)phenyl]phosphate (58.21 mg, 72.87 ⁇ mol,), cesium carbonate (712.28 mg, 2.19 mmol) in dimethyl sulfoxide (8 mL) and water (2 mL), the mixture was stirred at 120 ° C 10 hour. It was diluted with water (30 mL) and the aqueous layer was extracted with dichloromethane The combined organic layers were washed with EtOAc EtOAc m.
  • Step A (E)-N-(4-bromo-3-fluorophenyl)-2-(indolyl)acetamide
  • Step E 6-Bromo 7-fluoro-1-methyl-2-oxo-1,2-dihydroquinolin-3-yl-trifluoromethanesulfonate
  • Trifluoromethanesulfonic anhydride (1.87 g, 6.62 mmol) was added dropwise to the 6-bromo-7-fluoro-3-hydroxy-1-methylquinoline-2(1H)-one at 1.2 °C under nitrogen. g, 4.41 mmol), pyridine (697.76 mg, 8.82 mmol) and DMAP (538.85 mg, 4.41 mmol) in dichloromethane (20 mL). Stir at 25 ° C for 16 hours. The reaction was quenched with 1N hydrochloric acid and the pH was adjusted to 6. Extract three times with dichloromethane (50 mL). The combined organic layers were washed with saturated sodium s Filtration and evaporation, the ⁇
  • Step F 6-Bromo-7-fluoro-1-methyl-3-((5-morpholinepyridin-2-yl)amino)quinoline-2(1H)-one
  • Step G 7-Fluoro-1-methyl-3-((5-morpholinepyridin-2-yl)amino)-6-(1H-pyrazol-3-yl)quinoline-2(1H)-one
  • NBS (181.54 mg, 1.02 mmol) was added to 4-chloro-1-methyl porphyrin-2,3-dione (200 mg, 1.02 mmol) in acetonitrile (7 mL) and water (7 mL) . After stirring for 12 hours, the reaction mixture was filtered, and the filtered cake was evaporated.
  • Step C 6-Bromo-5-chloro-1-methyl-2-oxo-1,2-dihydroquinolin-3-yl-trifluoromethanesulfonate
  • Trifluoromethanesulfonic anhydride (1.03 g, 3.65 mmol) was added dropwise to the 6-bromo-5-chloro-3-hydroxy-1-methylquinoline-2(1H)-one (700 mg) at zero temperature under nitrogen. , 2.43 mmol), pyridine (576.64 mg, 7.29 mmol) and DMAP (29.69 mg, 0.243 mmol) in dichloromethane (20 mL). Stir at 25 ° C for 3 hours. The reaction was quenched with 1N hydrochloric acid and the pH was adjusted to 6. Extract three times with dichloromethane (100 mL). The combined organic layers were washed with saturated sodium s Filtration and evaporation, and the ⁇
  • Step D 6-Bromo-5-chloro-1-methyl-3-((5-morpholinepyridin-2-yl)amino)quinolin-2(1H)-one
  • Step E 5-Chloro-1-methyl-3-((5-morpholinepyridin-2-yl)amino)-6-(1H-pyrazol-3-yl)quinoline-2(1H)-one
  • Example 8 can be obtained by referring to the preparation method of Example 6, which is prepared by using 4-bromo-3,5-difluoroaniline.
  • Step B 4-Fluoro-1-methyl porphyrin-2,3-dione
  • NBS 40.04 g, 224.95 mmol
  • 4-fluoro-1-methyl porphyrin-2,3-dione 31.0 g, 173.04 mmol
  • acetonitrile 300 mL
  • water 600 mL
  • Step E 6-Bromo-5-fluoro-1-methyl-2-oxo-1,2-dihydroquinolin-3-yl trifluoromethanesulfonate
  • Trifluoromethanesulfonic anhydride (13.48 g, 47.78 mmol) was added dropwise to the 6-bromo-5-fluoro-3-hydroxy-1-methylquinoline-2(1H)-one at 0 ° under nitrogen (10.0) g, 36.76 mmol), pyridine (8.72 g, 110.27 mmol) and DMAP (449.04 mg, 3.68 mmol) in dichloromethane (200 mL). Stir at 15 degrees for 1 hour. The reaction was quenched with water (300 mL) and EtOAc (EtOAc) The organic phase was washed with saturated sodium chloride (250 mL) Filtration and evaporation gave the title compound.
  • Step F 6-Bromo-5-fluoro-1-methyl-3-((5-(4-(oxetan-3-yl)piperazin-1-yl)pyridin-2-yl)amino) Quinoline-2(1H)-one
  • Step G 5-Fluoro-1-methyl-3-((5-(4-(oxetan-3-yl)piperazin-1-yl)pyridin-2-yl)amino)-6-( 1H-pyrazol-3-yl)quinoline-2(1H)-one
  • Step A 6-Bromo-5-fluoro-3-[[5-[4-hydroxy-4-(trifluoromethyl)piperidin-1-yl]pyridin-2-yl]amino]-1-methyl -quinoline-2(1H)-one
  • Step B 5-Fluoro-3-[[5-[4-hydroxy-4-(trifluoromethyl)piperidin-1-yl]pyridin-2-yl]amino]-1-methyl-6-( 1H-pyrazol-3-yl)quinoline-2(1H)-one
  • Example 10A (220 mg, 426.94 ⁇ mol), 5-(4,4,5,5-tetramethyl 1,3,2-dioxaborolan-2-yl)-1H-pyridine (under nitrogen) 124.27 mg, 640.41 ⁇ mol), Pd(dppf)Cl2 (31.24 mg, 42.69 ⁇ mol), potassium carbonate (177.02 mg, 1.28 mmol) in a mixture of dioxane (8 mL) and water (2 mL) were reacted at 120 ° C for 10 hours. After cooling to room temperature, it was diluted with water (20 mL), EtOAc (EtOAc)EtOAc. Purification by column chromatography gave the title compound 10.
  • Example 11 The preparation method of Example 11 can be obtained by referring to the production method of Example 10.
  • Step A 7-(6-Nitro-3-pyridine)-2-oxazol-7-azaspiro[3.5]decane
  • Step B 5-(2-oxazol-7-azaspiro[3.5]decane-7-yl)pyridin-2-amine
  • Example 12A A mixture of Example 12A (1 g, 4.01 mmol) and Raney nickel (34.35 mg, 401.00 ⁇ mol) in methanol (110 mL) was reacted in hydrogen (15 psi) at 30 ° C for 15 hours. After filtration through celite, the filter cake was washed with EtOAc (EtOAc)
  • Step C 6-Bromo-5-fluoro-1-methyl-3-[[5-(2-oxazole-7-azaspiro[3.5]decane-7-yl)-2-pyridine]amino] Quinoline-2(1H)-one
  • Example 12B To a solution of Example 12B (97.67 mg, 445.40 ⁇ mol), (6-bromo-5-fluoro-1-methyl-2-oxa-3-quinoline) trifluoromethanesulfonate (150.00 mg, 371.17 ⁇ mol), a mixture of cesium carbonate (241.87 mg, 742.34 ⁇ mol) in tetrahydrofuran (5 mL) was added Xantphos (42.95 mg, 74.23 ⁇ mol), Pd 2 (dba) 3 (33.99 mg, 37.12 ⁇ mol). After stirring at 80 ° C for 4 hours, the reaction solution was filtered through a filter paper, and the filter cake was washed three times with a filtrate, and finally, the filter cake was dried to give the title compound.
  • Step D 5-Fluoro-1-methyl-3-[[5-(2-oxazole-7-azaspiro[3.5]decane-7-yl)pyridin-2-yl]amino]-6- (1H-pyrazole-3)quinoline-2(1H)-one
  • Example 12C 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (131.18 mg, 676.04) under nitrogen. ⁇ mol), potassium carbonate (140.15 mg, 1.01 mmol) dissolved in dioxane (4 mL) and water (1 mL), then Pd(dppf)Cl 2 (24.73 mg, 33.80 ⁇ mol), stirred at 110 ° C 12 hours. The mixture was cooled to room temperature, EtOAc (EtOAc)EtOAc.
  • Example 13 The preparation method of Example 13 can be obtained by referring to the production method of Example 12, and preparing with (3R)-3-methylmorpholine.
  • the preparation method of Example 14 can be obtained by referring to the preparation method of Example 12, and preparing with (3S)-3-methylmorpholine.
  • Example 15 can be prepared by referring to the preparation method of Example 12.
  • Example 16 can be prepared by referring to the preparation method of Example 12.
  • Example 17 can be prepared by referring to the preparation method of Example 12.
  • Step A (3R)-1-(6-nitropyridin-3-yl)piperidine-3-carboxylic acid ethyl ester
  • Step B Ethyl (3R)-1-(6-aminopyridin-3-yl)piperidine-3-carboxylate
  • Example 18A A mixture of Example 18A (1 g, 3.58 mmol) and EtOAc (30.67 mg) in MeOH (50 mL) After filtration through celite, the filter cake was washed with EtOAc (EtOAc)
  • Step C (3R)-1-[6-Bromo-5-fluoro-1-methyl-2-oxa-1,2-dihydroquinolin-3-yl)amino]pyridin-3-yl]piperidin Ethyl pyridine-3-carboxylate
  • Example 18B (200 mg, 802.21 ⁇ mol), (6-bromo-5-fluoro-1-methyl-2-oxa-3-quinoline) triflate (356.62 mg, 882.43).
  • Xulphos (69.07 mg, 1.2 mmol) in tetrahydrofuran (15 mL) was added Xantphos (69.63 mg, 120.33 ⁇ mol), Pd 2 (dba) 3 (73.46 mg, 80.22 ⁇ mol), and stirred at 15 ° C for 16 hours. . After the addition of water (50 mL), EtOAc EtOAc.
  • Step D (3R)-1-[6-[[5-fluoro-1-methyl-2-oxa-6-(1H-pyrazol-3-yl)-1,2-dihydroquinoline- 3-yl]amino]pyridin-3-yl]piperidine-3-carboxylic acid
  • Example 1C (350 mg, 695.33 ⁇ mol), 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyridine Azole (148.41 mg, 764.86 ⁇ mol), cesium carbonate (453.10 mg, 1.39 mmol) dissolved in dioxane (8 mL) and water (2 mL), then Pd(dppf)Cl 2 (50.88 mg, 69.53 ⁇ mol) ), stirring at 110 ° C for 12 hours. After cooling to room temperature, the reaction mixture was evaporated to dryness crystals crystals
  • Methyl magnesium chloride 70.10 mL, 3 mol was added dropwise to a solution of methyl 6-aminopyridine-3-carboxylic acid methyl ester (3.2 g, 21.03 mmol) in tetrahydrofuran (300 mL) at 0 ° C under nitrogen. After stirring for 15 hours, water (50 mL) was evaporated, evaporated, evaporated, evaporated. Evaporation provided the title compound.
  • Step B 6-Bromo-5-fluoro-3-[[5-(2-hydroxypropan-2-yl)pyridin-2-yl]amino]-1-methyl-quinolin-2-one
  • Example 20A 400 mg, 2.63 mmol), (6-bromo-5-fluoro-1-methyl-2-oxo-3-quinoline) trifluoromethanesulfonate (1.12 g, 2.76 mmol).
  • a mixture of Pd2(dba)3 240.68 mg, 0.263 mmol
  • Xantphos 228.12 mg, 0.3945 mmol
  • cesium carbonate (1.71 g, 5.26 mmol) in tetrahydrofuran (40 mL) was reacted at 25 ° C for 15 hours. After cooling to room temperature, it was diluted with H.sub.2 (30 mL). EtOAc (EtOAc m. Purification by column chromatography gave the title compound.
  • Step C 5-Fluoro-3-[[5-(2-hydroxypropan-2-yl)pyridin-2-yl]amino]-1-methyl-6-(1H-pyridin-3-yl)quinoline -2(1H)-ketone
  • Example 20B (100 mg, 0.24615 mmol), 3-(4,4,5,5-tetramethyl 1,3,2-dioxaborolan-2-yl)-1 hydrogen-pyrazole under nitrogen. (52.54 mg, 0.27077 mmol), Pd(dppf)Cl2 (18.01 mg, 0.02462 mmol), a mixture of potassium carbonate (102.06 mg, 0.73845 mmol) in dioxane (2 mL) and water (0.5 mL) stirred at 100 °C After 15 hours, the aqueous layer was diluted with H.sub.2 (20 mL). The combined organic layers were washed with EtOAc EtOAc m.
  • Step B 1-(6((diphenylmethylene)amine)pyridin-3-yl)cyclobutanol
  • Example 21A To a solution of Example 21A (1 g, 5.45 mmol), benzophenone imine (1.48 g, 8.18 mmol) and cesium carbonate (3.55 g, 10.90 mmol) in dioxane (25 mL) BINAP (339.36 mg, 545 ⁇ mol) and Pd 2 (dba) 3 (249.53 mg, 272.5 ⁇ mol) were stirred at 100 ° C for 12 hours. After cooling to room temperature, it was diluted with water (50 mL), EtOAc (EtOAc m. Purification by column chromatography gave the title compound.
  • Example 21B Hydroxylamine hydrochloride (347.45 mg, 5 mmol) was added to a solution of Example 21B (820 mg, 2.5 mmol) and potassium acetate (490.7 mg, 5 mmol) in methanol (10 mL), and the mixture was stirred at 17 ° C for 1 hour, then filtered and filtered. Washing with MeOH (5 mL).
  • Step D 6-Bromo-5-fluoro-3-((5-(1-hydroxycyclobutyl)pyridin-2-yl)amine)-1-methylquinolin-2(1H)-one
  • Step E 5-Fluoro-3-[[5-(1-hydroxycyclobutyl)pyridin-2-yl]-1-methyl-6-(1H-pyrazol-3-yl)quinoline-2 ( 1H)-ketone
  • Example 21D (340 mg, 812.89 ⁇ mol), 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyridyl under N2
  • the azole (394.33 mg, 2.03 mmol), potassium carbonate (337.04 mg, 2.44 mmol) was dissolved in dioxane (10 mL) and water (2.5 mL), then Pd(dppf)Cl 2 (59.48 mg, 81.29) ⁇ mol), stirred at 110 ° C for 15 hours; after cooling to room temperature, add 3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1 Hydrogen-pyrazole (394.33 mg, 2.03 mmol) and Pd(dppf)Cl 2 (59.48 mg, 81.29 ⁇ mol) were further stirred at 110 ° C for 15 hours under nitrogen atmosphere.
  • the preparation method of Example 22 can be obtained by referring to the preparation method of Example 21, which is prepared by using the starting material oxetanone.
  • Step A 6-Bromo-5-fluoro-3-[[5-(3-fluorooxetan-3-yl)pyridin-2-yl]amino]-1-methyl-quinoline-2 ( 1H)-ketone
  • Step B 5-Fluoro-3-[[5-(3-fluorooxetan-3-yl)pyridin-2-yl]amino]-1-methyl-6-(1H-pyrazole-3 -yl)quinoline-2(1H)-one
  • Example 23A (130 mg, 307.89 ⁇ mol), 3-(4,4,5,5-tetramethyl 1,3,2-dioxaborolan-2-yl)-1 hydrogen-pyridine under nitrogen. (89.61 mg, 461.84 ⁇ mol), Pd(dppf)Cl2 (22.53 mg, 30.79 ⁇ mol), a mixture of potassium fluoride (53.66 mg, 926.68 ⁇ mol) in dioxane (4 mL) was reacted at 100 ° C for 15 hours. After cooling to rt, EtOAc (EtOAc m. Purification by preparative HPLC gave the title compound 23.
  • Step A 2-(6-chloropyridin-3-yl)-1,1,1-trifluoromethyl-propan-2-ol
  • Step B 2-[6-(Diphenylmethyleneamino)pyridin-3-yl]-1,1,1-trifluoromethyl-propan-2-ol
  • Example 24A (5.5 g, 24.38 mmol), benzophenone imine (6.63 g, 36.57 mmol), Pd2 (dba) 3 (2.23 g, 2.44 mmol), BINAP (2.28 g, 3.66 mmol) And cesium carbonate (15.89 g, 48.76 mmol) in dioxane (100 mL), and the mixture was reacted at 100 ° C for 16 hours. After cooling to room temperature, it was diluted with H.sub.2 (EtOAc (EtOAc) (EtOAc) Purification by column chromatography gave the title compound.
  • Step D 6-Bromo-5-fluoro-1-methyl-3-((5-(1,1,1-trifluoro-2-hydroxypropan-2-yl)pyridin-2-yl)amino)quina Porphyrin-2(1H)-one
  • Step E 5-Fluoro-1-methyl-6-(1H-pyrazol-3-yl)-3-((5-(1,1,1-trifluoro-2-hydroxypropan-2-yl)) Pyridin-2-yl)amino)quinoline-2(1H)-one
  • Step F 5-Fluoro-1-methyl-6-(1H-pyrazol-3-yl)-3-((5-(1,1,1-trifluoro-2-hydroxypropan-2-yl)) Pyridin-2-yl)amino)quinoline-2(1H)-one
  • Step B 5-Bromo-N 1 -methylbenzene-1,2-diamine
  • Step D 7-(1-Benzyl-1H-pyrazol-4-yl)-1-methylquinoxaline-2,3(1H,4H)-dione
  • Step E 7-(1-Benzyl-1H-pyrazol-4-yl)-3-bromo-1-methylquinoxaline-2(1H)-one
  • Step F 7-(1-Benzyl-1H-pyrazol-4-yl)-1-methyl-3-((4-morpholinephenyl)amino)quinoxaline-2(1H)-one
  • Step G 1-Methyl-3-((4-morpholinephenyl)amino)-7-(1H-pyrazol-4-yl)quinoxaline-2(1H)-one
  • Step A 7-(1-Benzyl-1H-pyrazol-3-yl)-1-methylquinoxaline-2,3(1H,4H)-dione
  • Step B 7-(1-Benzyl-1H-pyrazol-3-yl)-3-bromo-1-methylquinoxaline-2(1H)-one
  • Step C 7-(1-Benzyl-1H-pyrazol-3-yl)-1-methyl-3-((4-morpholinephenyl)amino)quinoxaline-2(1H)-one
  • Step D 1-Methyl-3-((4-morpholinephenyl)amino)-7-(1H-pyrazol-3-yl)quinoxaline-2(1H)-one
  • Example 28 can be prepared by referring to the preparation method of Example 27.
  • Step A 1-methyl-3-((4-morpholinephenyl)amino)-7-(4,4,5,5-tetramethyl-1,3,2-dioxahexrolane- 2-yl)quinoxaline-2(1H)-one
  • Step B 1-Methyl-7-(5-methyl-1H-pyrazol-4-yl)-3-((4-morpholinephenyl)amino)quinoxaline-2(1H)-one
  • Examples 30-32 can be prepared by referring to the preparation method of Example 29:
  • Step C 7-(1-Phenyl-1H-pyrazol-4-yl)-1-methyl-3((4-(4-methylpiperazin-1-yl)phenyl)amino)quinidine Porphyrin-2(1H)-one
  • Step D 1-Methyl-3((4-(4-methylpiperazin-1-yl)phenyl)amino)-7-(1H-pyrazol-4-yl)quinoxaline-2 (1H )-ketone
  • Example 34 1-Methyl-3-((4-((4-methylpiperazin-1-yl)sulfonyl)phenyl)amino)-7-(1H-pyrazol-4-yl)quina Porphyrin-2(1H)-one
  • Step B 4-((4-Methylpiperazin-1-yl)sulfonyl)aniline
  • Step C 7-(1-Benzyl-1H-pyrazol-4-yl)-1-methyl-3-((4-((4-methylpiperazin-1-yl)sulfonyl)phenyl) Amino)quinoxaline-2(1H)-one
  • the preparation of the step C of Example 34 can be referred to the preparation method of the step C of Example 33.
  • Step D 1-Methyl-3-((4-((4-methylpiperazin-1-yl)sulfonyl)phenyl)amino)-7-(1H-pyrazol-4-yl)quinoxaquinone Porphyrin-2(1H)-one
  • the preparation of the step D of the example 34 can be referred to the preparation method of the step D of the example 33.
  • Example 35 The preparation of Example 35 can be obtained by referring to the production method of Example 33.
  • Example 36 3-((4-(4-(ethylsulfonyl)piperazin-1-yl)phenyl)amino)-1-methyl-7-(1H-pyrazol-4-yl)quinoxaline Porphyrin-2(1H)-one
  • Example 36 The preparation of Example 36 can be obtained by referring to the production method of Example 33.
  • Example 37 1-Methyl-3-((4-(4-methyl-1,4-diazepan-1-yl)phenyl)amino)-7-(1H-pyrazole-4 -yl)quinoxaline-2(1H)-one
  • Example 37 The preparation of Example 37 can be obtained by referring to the production method of Example 33.
  • Example 38 1-Methyl-3-((4-(piperidin-1-ylsulfonyl)phenyl)amino)-7-(1H-pyrazol-4-yl)quinoxaline-2 (1H )-ketone
  • Example 38 The preparation of Example 38 can be obtained by referring to the production method of Example 34.
  • Example 39 The preparation of Example 39 can be obtained by referring to the production method of Example 33.
  • Example 40 1-Methyl-3-((3-(4-(methylsulfonyl)piperazin-1-yl)phenyl)amino)-7-(1H-pyrazol-4-yl)quinoxaquinone Porphyrin-2(1H)-one
  • Example 40 The preparation of Example 40 can be obtained by referring to the production method of Example 33.
  • Triethylamine (3.07 mL, 22.15 mmol) and methylamine were added to a solution of 5-bromo-1,3-dichloro-2-nitrobenzene (6 g, 22.15 mmol) in DMF (150 mL)
  • the solution (2M, 22.15 mL, 44.3 mmol) was stirred at room temperature for one hour and then heated to 50 ° C for 6 hours. TLC showed the starting material to react completely.
  • water (100 mL) and ethyl acetate (150 mL) were added to the mixture. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and evaporated to give the title compound 5-bromo-3-chloro-N-methyl-2-nitrobenzene.
  • Iron powder (3.16 g, 56.5 mmol) was added portionwise to a solution of 5-bromo-3-chloro-N-methyl-2-nitrobenzene (2.5 g, 22.15 mmol) in ethanol (50 mL) and water (50 mL) And acetic acid (0.56 g, 9.42 mmol), stirred at room temperature for one hour and then heated to 60 ° C for 4 hours. TLC showed the starting material to react completely. The mixture was cooled, filtered, and ethyl acetate (150 mL) was evaporated. The organic phase was washed with brine, dried over anhydrous sodium sulfate, filtered, and evaporated to give the title compound 5-bromo-3-chloro-N1-toluene-1,2-diamine.
  • Step D 7-Bromo-5-chloro-1-methylquinoxaline-2,3(1H,4H)-dione
  • Step F 7-(1-Benzyl-1H-pyrazol-4-yl)-3,5-dichloro-1-methylquinoxaline-2(1H)-one
  • Step G 7-(1-Benzyl-1H-pyrazol-4-yl)-5-chloro-1-methyl-3-((4-morpholinephenyl)amino)quinoxaline-2 (1H )-ketone
  • Step H 5-Chloro-1-methyl-3-((4-morpholinephenyl)amino)-7-(1H-pyrazol-4-yl)quinoxaline-2(1H)-one
  • Example 42A To a solution of Example 42A (20 g, 86.56 mmol), NCS (11.79 g, 88.29 mmol) in DMF (300 mL) at 40 ° C for 18 hours, and diluted with water (500 mL) with ethyl acetate (500 mL ⁇ 2) )extraction. The combined organic layers were washed with EtOAc EtOAc m.
  • Step C 5-Bromo-4-chloro-N1-methylbenzene-1,2- hydrazine
  • Step D 7-Bromo-6-chloro-1-methylquinoxaline-2,3(1H,4H)-dione
  • Step E 7-(1-Benzyl-1H-pyrazol-4-yl)-6-chloro-1-methylquinoxaline-2,3(1H,4H)-dione
  • Example 42D (1 g, 3.45 mmol), 1-benzyl-4-(4,4,5,5-tetramethyl 1,3,2-dioxaborolan-2-yl) under N2.
  • Pyrazole (1.08 g, 3.8 mmol), Pd(dppf)Cl 2 (282.08 mg, 345.41 ⁇ mol), potassium carbonate (954.79 mg, 6.91 mmol) in DMF (15.00 mL) dioxane (15.00 mL) and water ( In 5.00 mL)
  • the mixture was stirred at 100 ° C for 5 hours. Cool to room temperature, dilute with water (100 mL) and filter. The filter cake was purified by column chromatography to give the title compound.
  • Step F 7-(1-Benzyl-1H-pyrazol-4-yl)-3,6-dichloro-1-methylquinoxaline-2(1H)-one
  • Example 42E 900 mg, 2.45 mmol
  • DIEA 265.98 mg, 2.06 mmol
  • toluene 9 mL
  • EtOAc EtOAc
  • Step G 7-(1-Benzyl-1H-pyrazol-4-yl)-6-chloro-1-methyl-3-((4-morpholinephenyl)amino)quinoxaline-2 (1H )-ketone
  • Example 42F To a solution of Example 42F (100 mg, 259.57 ⁇ mol), 4-morpholine aniline (92.53 mg, 519.14 ⁇ mol) in acetonitrile (2 mL), the mixture was reacted at 80 ° C for 18 hours, and the reaction mixture was evaporated under reduced pressure. Purification by column chromatography gave the title compound.
  • Step H 6-Chloro-1-methyl-3-((4-morpholinephenyl)amino)-7-(1H-pyrazol-4-yl)quinoxaline-2(1H)-one
  • Example 42G (80 mg, 151.80 ⁇ mol), t-BuOK (1M, 1.06 mL), DMSO (1.00 mL), and the mixture was stirred at 25 ° C for 4 hours.
  • the reaction solution was diluted with ice water (10 mL), stirred for 10 min, and then adjusted to pH 8 with 1M hydrochloric acid. After extraction with methylene chloride (10 mL, EtOAc), EtOAc (EtOAc)
  • Example 43 The preparation of Example 43 can be obtained by referring to the preparation method of Example 42.
  • Methylamine (21.01 mL, 2.0 mol/L) was added to a solution of 5-bromo-1,3-difluoro-2-nitrobenzene (10.00 g, 42.02 mmol) in DMF (100.00 mL) at 0 °. .
  • the reaction solution was stirred at 0 ° C to room temperature for 16 hours.
  • the reaction solution was poured into water (500.00 mL)
  • the organic phase was washed twice with EtOAc EtOAc EtOAc.
  • Oxalyl chloride monoethyl ester (4.36 g, 31.96 mmol) was added dropwise to 5-bromo-3-fluoro-N1-methylbenzene-1,2 diamine (7.00 g, 31.96 mmol) at 0 ° C under N2.
  • the mixture was reacted with a solution of triethylamine (8.08 g, 79.89 mmol) in 1,2-dichloroethane (70.00 mL) at room temperature for 2 hours, and a white solid was precipitated, and the mixture was heated to 60 ° C and stirred for 3 hours.
  • the reaction mixture was cooled to rt.
  • Step D 7-(1-Benzyl-1H-pyrazol-4-yl)-5-fluoro-1-methylquinoxaline-2,3(1H,4H)-dione
  • reaction solution was cooled to room temperature, and water (100 mL) was added to the mixture, and the mixture was extracted twice with dichloromethane (100 mL). The organic phase was washed twice with saturated brine (100 mL) and dried over anhydrous sodium sulfate. It was beaten with ethyl acetate to give the title compound.
  • Step E 7-(1-Benzyl-1H-pyrazol-4-yl)-3-bromo-5-fluoro-1-methylquinoxaline-2(1H)-one
  • Phosphorus tribromide (368.23 mg, 1.28 mmol) was added dropwise to 7-(1-benzyl-1H-pyrazol-4-yl)-5-fluoro-1-methylquinoxaline at 0 °C.
  • a solution of 2,3(1H,4H)-dione (300.00 mg, 856.29 ⁇ mol) and DIEA (88.53 mg, 685.03 ⁇ mol) in toluene (8 mL) was stirred at 110 ° C for 1.5 hours under nitrogen.
  • the reaction mixture was filtered over EtOAc (EtOAc)EtOAc.
  • the organic phase was washed twice with EtOAcqqqqqqqqqm
  • Step F 7-(1-Benzyl-1H-pyrazol-4-yl)-5-fluoro-1-methyl-3-((4-morpholinephenyl)amino)quinoxaline-2 (1H )-ketone
  • Step G 5-Fluoro-1-methyl-3-((4-morpholinephenyl)amino)-7-(1H-pyrazol-4-yl)quinoxaline-2(1H)-one
  • Step A 5-Bromo-4-fluoro-N1-methyl-benzene-1,2- hydrazine
  • Zinc powder (7.88 g, 120.45 mmol) was added to a solution of 4-bromo-5-fluoro-N2-methyl-benzene-1,2- hydrazine (6 g, 24.09 mmol) in ethanol (120 mL). And the formic acid amine (7.6 g, 120.45 mmol), after stirring at 50 ° C for 2 hours, the reaction solution was filtered, the filter cake was washed with dichloromethane (500 mL), and the filtrate was washed with water (200 mL) Wash with water (500 mL), dry EtOAc EtOAc
  • Step B 7-Bromo-6-fluoro-1-methylquinoxaline-2,3(1H,4H)-dione
  • Example 45B (2.4 g, 8.79 mmol), triethylamine (1.33 g, 13.18 mmol), phosphorus bromide (7.56 g, 26.37 mmol), 1,2-dichloroethane (50 mL) After the mixture was stirred at 90 ° C for 6 hours, the reaction mixture was poured into cold sodium hydrogen sulfate (300 mL) and stirred for 10 min.
  • Step D 7-Bromo-6-fluoro-1-methyl-3-((4-morpholinephenyl)amino)quinoxaline-2(1H)-one
  • Example 45C To a solution of Example 45C (1.95 g, 5.80 mmol), sodium acetate (1.43 g, 17.41 mmol), 4-morpholine aniline (1.24 g, 6.97 mmol) in isopropyl alcohol (30 mL) The reaction was carried out at 100 ° C for 12 hours, the mixture was cooled to room temperature and filtered to give the title compound.
  • Step E 6-Fluoro-1-methyl-3-((4-morpholinephenyl)amino)-7-(1H-pyrazol-4-yl)quinoxaline-2(1H)-one
  • Example 45D (2.3 g, 5.31 mmol), 4-(4,4,5,5-tetramethyl 1,3,2-dioxaborolan-2-yl)-1H-pyridine a mixture of azole (1.55 g, 7.96 mmol), Pd(dppf)Cl 2 (388.43 mg, 530.85 ⁇ mol), potassium carbonate (2.2 mg, 15.93 mmol) in dioxane (40.00 mL) and water (10.00 mL) Stir at 120 ° C for 10 hours. After cooling to room temperature, the aqueous layer was diluted with water (100 mL). The combined organic layers were washed with EtOAcqqqqqqqqqqqqqqqqqqqqqqqqqqqqqq
  • Example 46 can be obtained by referring to the preparation method of Example 44.
  • Step C 7-(1-Phenyl-1H-pyrazol-4-yl)-3-((2-fluoro-4-morpholinephenyl)amino)-1-methylquinoxaline-2 (1H )-ketone
  • Step D 3-((2-Fluoro-4-morpholinephenyl)amino)-1-methyl-7-(1H-pyrazol-4-yl)quinoxaline-2(1H)-one
  • Example 48 The preparation of Example 48 can be obtained by referring to the preparation method of Example 47.
  • Example 49 The preparation of Example 49 can be obtained by referring to the preparation method of Example 47.
  • Example 50 can be obtained by referring to the preparation method of Example 47.
  • Example 51 can be obtained by referring to the preparation method of Example 47.
  • Example 52 can be obtained by referring to the preparation method of Example 47.
  • Example 53 can be obtained by referring to the preparation method of Example 47 using different amines.
  • Example 54 3-[4-(3,8-Diazabicyclo[3.2.1]octane-8-yl)aniline]-1-methyl-7-(1H-pyrazol-4-yl)quina Porphyrin-2(1H)-one
  • Step A tert-Butyl-8-(4-nitrophenyl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate
  • Step B tert-Butyl-8-(4-aminophenyl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate
  • Step C tert-Butyl-8-[4-[[6-(1-benzyl-1H-pyrazol-4-yl)-4-methyl-3-oxo-3,4-dihydroquinoxaline ⁇ -2-yl]amino]phenyl]-3,8-diazabicyclo[3.2.1]octane-3-carboxylate
  • Step D tert-Butyl-8-[4-[[4-methyl-3-oxo-6-(1H-pyrazol-4-yl)-3,4-dihydroquinoxalin-2-yl Amino]phenyl]-3,8-diazabicyclo[3.2.1]octane-3-carboxylate
  • Step E 3-[4-(3,8-Diazabicyclo[3.2.1]octane-8-yl)aniline]-1-methyl-7-(1H-pyrazol-4-yl)quinidine Porphyrin-2(1H)-one
  • Step B Ethyl 1-(4-aminophenyl)piperidine-3-carboxylate
  • Step C 1-(4-((6-(1-phenyl-1H-pyrazol-4-yl)-4-methyl-3-oxo-3,4-dihydroquinoxaline-2- Ethyl)amino)phenyl)piperidine-3-carboxylic acid ethyl ester
  • Step D 1-(4-((4-Hero-3-oxo-6-(1H-pyrazol-4-yl)-3,4-dihydroquinoxalin-2-yl)amino)benzene Piperidine-3-carboxylic acid
  • Example 56 1-Methyl-7-(1H-pyrazol-4-yl)-3-((6-((tetrahydro-2H-pyran-4-yl)amino)pyridin-3-yl) Amino)quinoxaline-2(1H)-one
  • Step B N 2 -(tetrahydro-2H-pyran-4-yl)pyridine-2,5-diamine
  • Step C 7-Bromo-1-methyl-3-((6-((tetrahydro-2H-pyran-4-yl)amino)pyridin-3-yl)amino)quinoxaline-2(1H) -ketone
  • Step D 1-Methyl-7-(1H-pyrazol-4-yl)3-((6-((tetrahydro-2H-pyran-4-yl)amino)pyridin-3-yl)amino) Quinoxaline-2(1H)-one
  • Step A 7-Imidazo[1,2-a]pyrimidin-3-yl-1-methyl-3-((4-morpholinephenyl)amino)quinoxaline-2(1H)-one
  • Step B 7-(2-Amino-1H-imidazol-5-yl)-1-methyl-3-((4-morpholinephenyl)amino)quinoxaline-2(1H)-one
  • Step A 1-methyl-3-((4-morpholinephenyl)amino)-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2- Quinoxaline-2(1H)-one
  • Step B tert-Butyl (5-(4-methyl-2-((4-morpholinephenyl)amino)-3-oxa-3,4-dihydroquinoxalin-6-yl)thiazole- 2-()((2-(trimethylsilyl)ethoxy)methyl)formate
  • Step C 7-(2-Aminothiazol-5-yl)-1-methyl-3-((4-morpholinephenyl)amino)quinoxaline-2(1H)-one
  • Example 59 The preparation of Example 59 can be obtained by referring to the preparation method of Example 58.
  • HTRF homogeneous time-resolved fluorescence
  • SYK tyrosine
  • DTT Dithiothreitol
  • ATP Adenosine triphosphate
  • Magnesium Chloride (MgCl2) (Sigma #63020)
  • Manganese chloride (MnCl2) (Sigma#M1787)
  • Ethylenediaminetetraacetic acid (Invitrogen #15575-020)
  • HEPES Buffer 4-hydroxyethylpiperazine ethanesulfonic acid buffer
  • the compound concentration was diluted to 0.74 mM, and the plate was plated using a fully automated microplate pretreatment system at a concentration of 135 nL per well, with a starting concentration of 10 uM, 11 concentration points, and a 3 fold dilution gradient.
  • test buffer for dilution, dilute the 5 ⁇ HTRF buffer in the kit to 1 ⁇ , and add the specified amount of dithiothreitol and magnesium chloride solution for use.
  • the tyrosinase reaction solution was prepared by using 1 ⁇ HTRF buffer, and the final reaction concentration of tyrosine kinase was 0.0156 ng/ ⁇ L.
  • the tyrosinase solution and the tyrosine kinase-substrate-biotin/adenosine triphosphate mixture were added 5 ul each well and incubated at 23 ° C for 1 hour.
  • Analytical data Analyze the data using XL-Fit and calculate the IC50 value of the compound.
  • lysis buffer trishydroxymethylaminomethane hydrochloride, Invitrogen 15567-1000 ml; sodium chloride, Domestic; sodium deoxycholate, Sigma30970-25G; polyethylene glycol octyl phenyl ether, SigmaT9284-100ml; sodium dodecyl sulfate, SigmaL3771; ethylenediaminetetraacetic acid, Invitrogen 15575-038-100ml; ultrapure water , MilliQ)
  • Phosphatase inhibitor mixture 2 (Sigma, P5726-5ML)
  • Phosphatase inhibitor mixture 3 (Sigma, P0044-5ML)
  • Phosphorylated AKT assay kit Phospho-AKT 1/2/3 (ser473) (TGR Bioscience, EKT002)
  • Multi-purpose microplate reader (Envision Reader)
  • Ramos cells were diluted with a medium to a density of 5 ⁇ 10 6 /mL, and the diluted cells were added to a 96-well cell culture plate (100 ⁇ L/well) with a lance. The cell plates were placed in a 37 ° C, 5% CO 2 incubator overnight.
  • the cells were centrifuged at 1000 rpm for 5 minutes on the next day, the original medium was aspirated by a lance, the serum-free experimental medium was added, and the cell plates were placed in a 37 ° C, 5% CO 2 incubator, and starved overnight. .
  • the compound was diluted with dimethyl sulfoxide to have an initial concentration of 5 mM. Three concentration gradients were made using a compound V-well dilution plate with a three-fold gradient.
  • the cells were centrifuged at 1000 rpm for 1 minute, and the cell plate was placed in a 37 ° C, 5% CO 2 incubator to allow the compound to act for 1 hour.
  • Sheep anti-human immunoglobulin M (F(ab') 2 Goat Anti-Human IgM) (1.2 mg/ml) was diluted to 60 ug/ml with a 1X balanced salt solution preheated at 37 °C.
  • IgM stimulated the cells for 10 minutes, centrifuged at 4000 rpm for 5 minutes, allowed the suspended cells to deposit on the bottom of the 96-well plate, gently drained the liquid in the 96-well plate, and blotted the remaining liquid with a paper towel. Note: Try not to get rid of suspended cells.
  • ADHP 10-acetyl-3,7-dihydroxyphenazine
  • the Envision Reader is a multi-function microplate reader for reading.
  • Test Example 1 The results of Test Example 1 and Test Example 2 are shown in Table 1:

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Abstract

提供Syk抑制剂及其使用方法，具体公开了一种式(I)的喹啉酮或喹唑啉酮衍生物或其药学上可接受的盐，以及制备方法、药物组合物和在制备治疗Syk受体相关病症的药物中的用途。

Description

Syk抑制剂及其使用方法
相关申请的引用
本申请要求于2017年06月14日向中华人民共和国国家知识产权局提交的第201710448438.X号中国发明专利申请的权益，在此将其全部内容以援引的方式整体并入本文中。
技术领域
本申请属于医药技术领域，涉及一类Syk抑制剂或其药学上可接受的盐，其制备方法及其药物组合物。
背景技术
脾酪氨酸激酶(Syk：spleen tyrosine kinase)是一种胞内酪氨酸蛋白激酶，属于ZAP70蛋白激酶家族中的成员。Syk在B细胞早期发育、淋巴细胞个体发育、成熟B细胞发挥功能中起着关键作用。在此过程中它参与了多种信号转导途径，且无需通过Src激酶的磷酸化就能发挥作用。Syk除了在造血干细胞中普遍表达外，在非造血细胞如上皮细胞、肝细胞、成纤维细胞、神经细胞和乳腺组织中均有表达并且具备多种功能。
在人类许多疾病中都存在Syk PTK的功能障碍，如过敏反应、哮喘、炎症及自身免疫性疾病，众多研究显示Syk是急性或慢性炎症中的一个重要介质。在几种常见的B细胞恶性肿瘤中都存在Syk的激活，比如在滤泡淋巴瘤、弥漫性大B细胞淋巴瘤、套细胞淋巴瘤和B细胞慢性淋巴细胞性白血病中都能检测到抗原非依赖性磷酸化的Syk。研究者发现抑制滤泡淋巴瘤、弥漫性大B细胞淋巴瘤细胞中Syk，能够降低下游信号传导分子磷酸化水平，从而抑制肿瘤细胞的增殖和存活。另外，在骨髓增生异常综合征和外周T细胞淋巴瘤中发现了Syk的易位，进一步表明该激酶可以充当原癌基因。因此，可以将Syk活性的抑制用于治疗包括B细胞淋巴瘤和白血病的特定类型的癌症。
发明内容
本申请提供式(I)化合物或其药学上可接受的盐，
Figure PCTCN2018091269-appb-000001
其中，
W为C(R 7)或N；
R 1、R 2独立地选自H、卤素、氨基、羟基、氰基、C 1-6烷基、C 3-6环烷基、3～10元杂环烷基、6～12元芳基或5～12元杂芳基，所述氨基、C 1-6烷基、C 3-6环烷基、3～10元杂环烷基、6～12元芳基或5～12元杂芳基任选地被R 8取代；
R 3、R 4、R 7独立地选自H、卤素、氨基、羟基、氰基、C 1-6烷基、C 3-6环烷基或3～6元杂环烷基，所述氨基、C 1-6烷基、C 3-6环烷基或3～6元杂环烷基任选地被R 9取代；
R 5选自H、C 1-6烷基、C 3-6环烷基、3～6元杂环烷基、C 1-6烷基C(O)、C 3-6环烷基C(O)、3～6元杂环烷基C(O)、苯基C(O)、5～6元杂芳基C(O)、C 1-6烷基SO 2、C 3-6环烷基SO 2、3～6元杂环烷基SO 2、苯基SO 2或5～6元杂芳基SO 2，所述C 1-6烷基、C 3-6环烷基、3～6元杂环烷基、C 1-6烷基C(O)、C 3-6环烷基C(O)、3～6元杂环烷基C(O)、苯基C(O)、5～6元杂芳基C(O)、C 1-6烷基SO 2、C 3-6环烷基SO 2、3～6元杂环烷基SO 2、苯基SO 2或5～6元杂芳基SO 2任选地被R 9取代；
X选自任意两个位置失去H原子的3～12元环，所述环任选地被R 9取代；
L选自键、NH、O、S、SO、SO 2、C(O)、OC(O)、C(O)O、C(O)NH、NHSO 2、SO 2NH、NHC(O)NH 或NHSO 2NH；
R 6选自H、卤素、氨基、羟基、氰基、C 1-6烷基、C 3-10环烷基或3～10元杂环烷基，所述氨基、C 1-6烷基、C 3-10环烷基或3～10元杂环烷基任选地被R 10取代；
R 8、R 9独立地选自卤素、氨基、羟基、氰基、C 1-3烷基、C 1-3烷氧基或COOH；
R 10选自卤素、氨基、羟基、氰基、卤代C 1-3烷基、COOH、＝(O)、C 1-6烷基、C 1-6烷基SO 2、C 3-6环烷基或3～10元杂环烷基；
且R 1和R 2中至少有一个选自6～12元芳基或5～12元杂芳基，所述6～12元芳基或5～12元杂芳基任选地被R 8取代。
本申请式(I)化合物的一个实施方案中，R 1、R 2独立地选自H、卤素或5～12元杂芳基，所述5～12元杂芳基任选地被R 8取代。
本申请式(I)化合物的一个实施方案中，R 1、R 2独立地选自H、F、Cl、Br、呋喃基、噻吩基、吡咯基、吡唑基、咪唑基、吡啶基、嘧啶基、哒嗪基、吡嗪基、噻唑基、异噻唑基、噁唑基、异噁唑基、四唑基或三嗪基，所述呋喃基、噻吩基、吡咯基、吡唑基、咪唑基、吡啶基、嘧啶基、哒嗪基、吡嗪基、噻唑基、异噻唑基、噁唑基、异噁唑基、四唑基或三嗪基任选地被R 8取代。
本申请式(I)化合物的一个实施方案中，R 1、R 2独立地选自H、F、Cl、噻唑基、吡唑基、咪唑基或吡啶基，所述噻唑基、吡唑基、咪唑基或吡啶基任选地被R 8取代。
本申请式(I)化合物的一个实施方案中，R 8选自氨基、甲基、乙基、丙基或异丙基。
本申请式(I)化合物的一个实施方案中，R 8选自氨基或甲基。
本申请式(I)化合物的一个实施方案中，R 1选自H、F、
Figure PCTCN2018091269-appb-000002
Figure PCTCN2018091269-appb-000003
其可任选地被R 8取代。
本申请式(I)化合物的一个实施方案中，R 1选自H、F、
Figure PCTCN2018091269-appb-000004
Figure PCTCN2018091269-appb-000005
本申请式(I)化合物的一个实施方案中，R 2选自H、F、Cl或
Figure PCTCN2018091269-appb-000006
本申请式(I)化合物的一个实施方案中，R 1选自5～12元杂芳基；R 2选自H或卤素；其中，R 1可任选地被R 8取代。
本申请式(I)化合物的一个实施方案中，R 1选自呋喃基、噻吩基、吡咯基、吡唑基、咪唑基、吡啶基、嘧啶基、哒嗪基、吡嗪基、噻唑基、异噻唑基、噁唑基、异噁唑基、四唑基或三嗪基；R 2选自H、F、Cl或Br；其中，R 1可任选地被R 8取代。
本申请式(I)化合物的一个实施方案中，R 1选自噻唑基、吡唑基、咪唑基或吡啶基；R 2选自H、F或Cl；其中，R 1可任选地被R 8取代。
本申请式(I)化合物的一个实施方案中，R 1选自
Figure PCTCN2018091269-appb-000007
Figure PCTCN2018091269-appb-000008
R 2选自H、F或Cl；其中，R 1可任选地被R 8取代。
本申请式(I)化合物的一个实施方案中，R 1选自
Figure PCTCN2018091269-appb-000009
Figure PCTCN2018091269-appb-000010
R 2选自H、F或Cl。
本申请式(I)化合物的一个实施方案中，R 1选自H或卤素；R 2选自5～12元杂芳基；其中，R 2可任选地被R 8取代。
本申请式(I)化合物的一个实施方案中，R 1选自H、F、Cl或Br；R 2选自呋喃基、噻吩基、吡咯基、吡唑基、咪唑基、吡啶基、嘧啶基、哒嗪基、吡嗪基、噻唑基、异噻唑基、噁唑基、异噁唑基、四唑基或三嗪基；其中，R 2可任选地被R 8取代。
本申请式(I)化合物的一个实施方案中，R 1选自H或F；R 2选自吡唑基；其中，R 2可任选地被R 8取代。
本申请式(I)化合物的一个实施方案中，R 1选自H或F；R 2选自
Figure PCTCN2018091269-appb-000011
本申请式(I)化合物的一个实施方案中，R 3、R 4、R 7独立地选自H、卤素、C 1-6烷基或C 3-6环烷基，所述C 1-6烷基或C 3-6环烷基任选地被R 9取代。
本申请式(I)化合物的一个实施方案中，R 3、R 4、R 7独立地选自H或卤素。
本申请式(I)化合物的一个实施方案中，R 3、R 4、R 7独立地选自H、F或Cl。
本申请式(I)化合物的一个实施方案中，W为C(R 7)，R 7为H，R 3、R 4独立地选自H、F、或Cl。
本申请式(I)化合物的一个实施方案中，W为N，R 3、R 4独立地选自H、F、或Cl。
本申请式(I)化合物的一个实施方案中，R 5选自H、C 1-6烷基或C 3-6环烷基，其中C 1-6烷基或C 3-6环烷基任选被R 9取代。
本申请式(I)化合物的一个实施方案中，R 5选自甲基、乙基、丙基、异丙基、丁基、异丁基或叔丁基，所述甲基、乙基、丙基、异丙基、丁基、异丁基或叔丁基任选地被R 9取代。
本申请式(I)化合物的一个实施方案中，R 5选自甲基。
本申请式(I)化合物的一个实施方案中，X选自任意两个位置失去H原子的苯环或5～10元杂芳环，所述X可任选地被R 9取代。
本申请式(I)化合物的一个实施方案中，X选自任意两个位置失去H原子的苯环、
Figure PCTCN2018091269-appb-000012
Figure PCTCN2018091269-appb-000013
呋喃环、噻吩环、吡咯环、吡唑环、咪唑环、吡啶环、嘧啶环、哒嗪环、吡嗪环、噻唑环、异噻唑环、噁唑环、异噁唑环、四唑环或三嗪环，所述X可任选地被R 9取代。
本申请式(I)化合物的一个实施方案中，X选自任意两个位置失去H原子的苯环或吡啶环，所述X可任选地被R 9取代。
本申请式(I)化合物的一个实施方案中，X选自
Figure PCTCN2018091269-appb-000014
所述X可任选地被R 9取代。
本申请式(I)化合物的一个实施方案中，X选自
Figure PCTCN2018091269-appb-000015
Figure PCTCN2018091269-appb-000016
本申请式(I)化合物的一个实施方案中，R 9选自卤素、C 1-3烷基或C 1-3烷氧基。
本申请式(I)化合物的一个实施方案中，R 9选自F、Cl、甲基或OCH 3。
本申请式(I)化合物的一个实施方案中，L选自键、NH、O、S、SO、SO 2、NHSO 2、SO 2NH或NHSO 2NH。
本申请式(I)化合物的一个实施方案中，L选自键、NH、O、S、SO或SO 2。
本申请式(I)化合物的一个实施方案中，L选自键、NH或SO 2。
本申请式(I)化合物的一个实施方案中，R 6选自H、氨基、C 1-6烷基、C 3-6环烷基或3～10元杂环烷基，所述氨基、C 1-6烷基、C 3-6环烷基或3～10元杂环烷基可任选地被R 10取代。
本申请式(I)化合物的一个实施方案中，R 6选自H、氨基、甲基、乙基、丙基、异丙基、丁基、异丁基、叔丁基、环丙基、环丁基、环戊基、环己基、任意位置失去一个H原子的
Figure PCTCN2018091269-appb-000017
Figure PCTCN2018091269-appb-000018
Figure PCTCN2018091269-appb-000019
所述氨基、甲基、乙基、丙基、异丙基、丁基、异丁基、叔丁基、环丙基、环丁基、环戊基、环己基、任意位置失去一个H原子的
Figure PCTCN2018091269-appb-000020
Figure PCTCN2018091269-appb-000021
Figure PCTCN2018091269-appb-000022
Figure PCTCN2018091269-appb-000023
任选地被R 10取代。
本申请式(I)化合物的一个实施方案中，R 6选自H、NH 2、甲基、异丙基、环丁基、
Figure PCTCN2018091269-appb-000024
Figure PCTCN2018091269-appb-000025
所述NH 2、甲基、异丙基、环丁基、
Figure PCTCN2018091269-appb-000026
Figure PCTCN2018091269-appb-000027
可任选地被R 10取代。
本申请式(I)化合物的一个实施方案中，R 6选自H、NH 2、甲基、
Figure PCTCN2018091269-appb-000028
Figure PCTCN2018091269-appb-000029
本申请式(I)化合物的一个实施方案中，R 10选自卤素、羟基、卤代C 1-3烷基、COOH、＝(O)、C 1-6烷基、C 1-6烷基SO 2或3～10元杂环烷基。
本申请式(I)化合物的一个实施方案中，R 10选自F、Cl、Br、OH、一氟甲基、二氟甲基、三氟甲基、一氟乙基、二氟乙基、三氟乙基、四氟乙基、五氟乙基、一氯甲基、二氯甲基、三氯甲基、COOH、＝(O)、甲基、乙基、丙基、异丙基、丁基、异丁基、叔丁基、SO 2CH 3、SO 2CH 2CH 3、SO 2CH 2CH 2CH 3、SO 2CH(CH 3)CH 3、SO 2CH 2CH 2CH 2CH 3、SO 2CH(CH 3)CH 2CH 3、SO 2CH 2CH(CH 3) 2、SO 2C(CH 3) 3、任意位 置失去一个H原子的
Figure PCTCN2018091269-appb-000030
Figure PCTCN2018091269-appb-000031
本申请式(I)化合物的一个实施方案中，R 10选自F、OH、三氟甲基、COOH、＝(O)、甲基、SO 2CH 3、SO 2CH 2CH 3或
Figure PCTCN2018091269-appb-000032
本申请式(I)化合物的一个实施方案中，所述式(I)化合物具有式(Ⅱ)，
Figure PCTCN2018091269-appb-000033
其中，
R 2选自6～12元芳基或5～12元杂芳基，所述6～12元芳基或5～12元杂芳基任选地被R 8取代；
R 1、R 3、R 4、R 5、R 6、R 7、R 8、X和L如式(I)中所定义。
本申请式(Ⅱ)化合物的一个实施方案中，R 2选自吡唑基，其可任选地被R 8取代。
本申请式(Ⅱ)化合物的一个实施方案中，R 2选自
Figure PCTCN2018091269-appb-000034
本申请式(I)化合物的一个实施方案中，所述式(I)化合物具有式(Ⅲ)，
Figure PCTCN2018091269-appb-000035
其中，R 1、R 3、R 4、R 6、R 7和X如式(I)所定义。
本申请式(I)化合物的一个实施方案中，所述式(I)化合物具有式(Ⅳ)，
Figure PCTCN2018091269-appb-000036
其中，
R 1选自6～12元芳基或5～12元杂芳基，所述R 1可任选地被R 8取代；
R 2、R 3、R 4、R 5、R 6、R 8、X和L如式(I)中所定义。
本申请式(Ⅳ)化合物的一个实施方案中，R 1选自5～12元杂芳基，所述R 1可任选地被R 8取代。
本申请式(Ⅳ)化合物的一个实施方案中，R 1选自呋喃基、噻吩基、吡咯基、吡唑基、咪唑基、吡啶基、嘧啶基、哒嗪基、吡嗪基、噻唑基、异噻唑基、噁唑基、异噁唑基、四唑基或三嗪基，所述R 1可任选地被R 8取代。
本申请式(Ⅳ)化合物的一个实施方案中，R 1选自噻唑基、吡唑基、咪唑基或吡啶基，所述R 1可任选地被R 8取代。
本申请式(Ⅳ)化合物的一个实施方案中，R 1选自
Figure PCTCN2018091269-appb-000037
Figure PCTCN2018091269-appb-000038
所述R 1可任选地被R 8取代。
本申请式(Ⅳ)化合物的一个实施方案中，R 1选自
Figure PCTCN2018091269-appb-000039
Figure PCTCN2018091269-appb-000040
本申请式(I)化合物的一个实施方案中，所述式(I)化合物具有式(Ⅴ)化合物，
Figure PCTCN2018091269-appb-000041
其中，R 2、R 3、R 4、R 6、X和L如式(I)中所定义。
本申请式(I)化合物的一个实施方案中，所述式(I)化合物选自以下化合物：
Figure PCTCN2018091269-appb-000042
Figure PCTCN2018091269-appb-000043
Figure PCTCN2018091269-appb-000044
另一方面，本申请涉及药物组合物，其包含本申请的式(I)化合物或其药学上可接受的盐。在一些实施方案中，本申请的药物组合物还包括一种或多种药学上可接受的辅料。
本申请的药物组合物可通过将本申请的化合物、其药学上可接受的盐与适宜的药学上可接受的辅料组合而制备，例如可配制成固态、半固态、液态或气态制剂，如片剂、丸剂、胶囊剂、粉剂、颗粒剂、膏剂、乳剂、悬浮剂、溶液剂、栓剂、注射剂、吸入剂、凝胶剂、微球及气溶胶等。
给予本申请的化合物、其药学上可接受的盐或其药物组合物的典型途径包括但不限于口服、直肠、透黏膜、经肠给药，或者局部、经皮、吸入、肠胃外、舌下、阴道内、鼻内、眼内、腹膜内、肌内、皮下、静脉内给药。
本申请的药物组合物可以采用本领域众所周知的方法制造，如常规的混合法、溶解法、制粒法、制糖衣药丸法、磨细法、乳化法、冷冻干燥法等。
对于口服给药，可以通过将活性化合物与本领域熟知的药学上可接受的辅料混合来配制该药物组合物。这些辅料能使本申请的化合物被配制成片剂、丸剂、锭剂、糖衣剂、胶囊剂、液体、凝胶剂、浆剂、悬浮剂等，用于对患者的口服给药。可以通过常规的混合、填充或压片方法来制备固体口服组合物。例如，可通过下述方法获得：将所述的活性化合物与固体辅料混合，任选地碾磨所得的混合物，如果需要则加入其它合适的辅料，然后将该混合物加工成颗粒，得到了片剂或糖衣剂的核心。适合的辅料包括但不限于：粘合剂、稀释剂、崩解剂、润滑剂、助流剂、甜味剂或矫味剂等。
药物组合物还可适用于肠胃外给药，如合适的单位剂型的无菌溶液剂、混悬剂或冻干产品。能够使用适当的辅料，例如填充剂、缓冲剂或表面活性剂。
本文所述的式(I)化合物或其药学上可接受的盐可以通过任何适用的途径和方法给药，例如通过口服或肠胃外(例如，静脉内)给药。式(I)化合物的治疗有效量为从约0.0001到20mg/Kg体重/天，例如从0.001到10mg/Kg体重/天。
式(I)化合物的剂量频率由患者个体的需求决定，例如，每天1次或2次，或每天更多次。给药可以是间歇性的，例如，其中在若干天的期间内，患者接受式(I)化合物每日剂量，接着在若干天或更多天的期间，患者不接受式(I)化合物的每日剂量。
本申请的另一个目的在于提供式(I)化合物或其药学上可接受的盐或上述药物组合物在制备治疗Syk受体相关病症的药物中的应用。
本申请的另一方面提供了一种治疗Syk受体相关病症的方法，所述方法包括给予治疗有效量的式(I)化合物或其药学上可接受的盐或上述药物组合物。
在一些实施方案中，Syk受体相关病症选自癌症或炎性疾病。在一些实施方案中，Syk受体相关病症选自B细胞淋巴瘤、霍奇金淋巴瘤、非霍奇金淋巴瘤、毛细胞白血病、多发性骨髓瘤、慢性粒细胞白血病、急性粒细胞白血病、慢性淋巴细胞白血病、急性淋巴细胞白血病、类风湿性关节炎、过敏性鼻炎、慢性阻塞性肺病(COPD)、成人呼吸窘迫综合征(ARDs)、过敏诱发的炎性疾病、多发性硬化、自身免疫性疾病、急性炎症反应、变应性紊乱或多囊性肾病。
定义和说明
除非另有说明，本文所用的下列术语和短语旨在具有下列含义。一个特定的术语或短语在没有特别定义的情况下不应该被认为是不确定的或不清楚的，而应该按照本领域普通的含义去理解。当本文中出现商品名时，意在指代其对应的商品或其活性成分。
术语“药学上可接受的”，是针对那些化合物、材料、组合物和/或剂型而言，它们在可靠的医学判断的范围之内，适用于与人类和动物的组织接触使用，而没有过多的毒性、刺激性、过敏性反应或其它问题或并发症，与合理的利益/风险比相称。
术语“药学上可接受的盐”是指本申请化合物的盐，由本申请发现的具有特定取代基的化合物与相对无毒的酸或碱制备。当本申请的化合物中含有相对酸性的功能团时，可以通过合适的碱与这类化合物的中性形式接触的方式获得碱加成盐。当本申请的化合物中含有相对碱性的官能团时，可以通过合适的酸与这类化合物的中性形式接触的方式获得酸加成盐。本申请的某些特定的化合物含有碱性和酸性的官能团，从而可以被转换成任一碱或酸加成盐。
本申请的某些化合物可以具有不对称碳原子(光学中心)或双键。外消旋体、非对映异构体、几何异构体和单个的异构体都包括在本申请的范围之内。例如，化合物结构中包含的
Figure PCTCN2018091269-appb-000045
可以是
Figure PCTCN2018091269-appb-000046
例如化合物结构中包含的
Figure PCTCN2018091269-appb-000047
可以是
Figure PCTCN2018091269-appb-000048
或
Figure PCTCN2018091269-appb-000049
当本文所述化合物含有烯属双键或其它几何不对称中心，除非另有规定，它们包括E、Z几何异构体。同样地，所有的互变异构形式均包括在本申请的范围之内，例如，
Figure PCTCN2018091269-appb-000050
与
Figure PCTCN2018091269-appb-000051
为互变异构形式。
本申请的化合物可以存在特定的几何或立体异构体形式。本申请设想所有的这类化合物，包括顺式和反式异构体、(-)-和(+)-对映体、(R)-和(S)-对映体、非对映异构体、(D)-异构体、(L)-异构体，及 其外消旋混合物和其他混合物，例如对映异构体或非对映体富集的混合物，所有这些混合物都属于本申请的范围之内。烷基等取代基中可存在另外的不对称碳原子。所有这些异构体以及它们的混合物，均包括在本申请的范围之内。
可以通过的手性合成或手性试剂或者其他常规技术制备光学活性的(R)-和(S)-异构体以及D和L异构体。如果想得到本申请某化合物的一种对映体，可以通过不对称合成或者具有手性助剂的衍生作用来制备，其中将所得非对映体混合物分离，并且辅助基团裂开以提供纯的所需对映异构体。或者，当分子中含有碱性官能团(如氨基)或酸性官能团(如羧基)时，与适当的光学活性的酸或碱形成非对映异构体的盐，然后通过本领域所公知的常规方法进行非对映异构体拆分，然后回收得到纯的对映体。此外，对映异构体和非对映异构体的分离通常是通过使用色谱法完成的，所述色谱法采用手性固定相，并任选地与化学衍生法相结合(例如由胺生成氨基甲酸盐)。
本申请的化合物可以在一个或多个构成该化合物的原子上包含非天然比例的原子同位素。例如，可用放射性同位素标记化合物，比如氘( 2H)，氚( 3H)，碘-125( 125I)或C-14( 14C)。本申请的化合物的所有同位素组成的变换，无论放射性与否，都包括在本申请的范围之内。
术语“药学上可接受的辅料”是指对有机体无明显刺激作用，而且不会损害该活性化合物的生物活性及性能的那些辅料。合适的辅料是本领域技术人员熟知的，例如碳水化合物、蜡、水溶性和/或水可膨胀的聚合物、亲水性或疏水性材料、明胶、油、溶剂、水等。
术语“有效量”或“治疗有效量”是指能达到预期效果的药物或药剂的足够用量。有效量的确定因人而异，取决于受体的年龄和一般情况，也取决于具体的活性物质，个案中合适的有效量可以由本领域技术人员根据常规试验确定。
术语“活性成分”、“治疗剂”、“活性物质”或“活性剂”是指一种化学实体，它可以有效地治疗目标紊乱、疾病或病症。
术语“任选”或“任选地”是指随后描述的事件或情况可能发生或可能不发生，该描述包括发生所述事件或情况和不发生所述事件或情况。例如，乙基“任选”被卤素取代，指乙基可以是未被取代的(CH 2CH 3)、单取代的(如CH 2CH 2F)、多取代的(如CHFCH 2F、CH 2CHF 2等)或完全被取代的(CF 2CF 3)。本领域技术人员可理解，对于包含一个或多个取代基的任何基团，不会引入任何在空间上不可能存在和/或不能合成的取代或取代模式。
本文所用的C m-n指该部分中具有m-n个碳原子。例如，“C 3-10环烷基”指该环烷基具有3-10个碳原子。“C 0-6亚烷基”指该亚烷基具有0-6个碳原子，当亚烷基具有0个碳原子时，该基团为键。
本文中的数字范围是指给定范围中的各个整数。例如“C 1-10”是指该基团可具有1个碳原子、2个碳原子、3个碳原子、4个碳原子、5个碳原子、6个碳原子、7个碳原子、8个碳原子、9个碳原子或10个碳原子。
术语“被取代”是指特定原子上的任意一个或多个氢原子被取代基取代，只要特定原子的价态是正常的并且取代后的化合物是稳定的。当取代基为酮基(即＝O)(也称为氧代基)时，意味着两个氢原子被取代，酮取代不会发生在芳香基上。
当任何变量(例如R)在化合物的组成或结构中出现一次以上时，其在每一种情况下的定义都是独立的。因此，例如，如果一个基团被0-2个R所取代，则所述基团可以任选地至多被两个R所取代，并且每种情况下的R都有独立的选项。此外，取代基和/或其变体的组合只有在这样的组合会产生稳定的化合物的情况下才是被允许的。
当其中一个变量选自键时，表示其连接的两个基团直接相连，比如A-L-Z中L代表键时表示该结构实际上是A-Z。
当一个取代基为空缺时，表示该取代基是不存在的，比如A-X中X为空缺时表示该结构实际上是A。当一个取代基的键可以交叉连接到一个环上的两个原子时，这种取代基可以与这个环上的任意原子相键合。当所列举的取代基中没有指明其通过哪一个原子连接到化学结构式中包括但未具体提及的化合物时，这种取代基可以通过其任何原子相键合。取代基和/或其变体的组合只有在这样的组合会产生稳定的化合物的情况下才是被允许的。例如，结构单元
Figure PCTCN2018091269-appb-000052
表示其可在环己基或者环己二烯上的任意一个位置发生取代。
除非另有规定，术语“卤代”或“卤素”本身或作为另一取代基的一部分表示氟、氯、溴或碘原子。此外，术语“卤代烷基”意在包括单卤代烷基和多卤代烷基；例如，术语“卤代C 1-3烷基”意在包括但不仅限 于三氟甲基、2，2，2-三氟乙基和3-溴丙基等等。卤代烷基的实例包括但不仅限于：三氟甲基、三氯甲基、五氟乙基和五氯乙基。
术语“羟基”指-OH。
术语“氰基”指-CN。
术语“氨基”是指-NH 2。
术语“烷基”是指由碳原子和氢原子组成的直链或支链的饱和脂肪烃基团，例如甲基、乙基、丙基、丁基、戊基、己基、庚基、辛基、壬基、癸基等。所述特定烷基包括其所有同分异构体形式，例如丙基包括-CH 2CH 2CH 3、-CH(CH 3) 2，例如丁基包括-CH 2CH 2CH 2CH 3、-CH(CH 3)(CH 2CH 3)、-C(CH 3) 3、-CH 2CH(CH 3) 2。术语“C 1-8烷基”指具有1-8个碳原子的烷基。术语“C 1-6烷基”指具有1-6个碳原子的烷基。术语“C 1-4烷基”指具有1-4个碳原子的烷基。术语“C 1-3烷基”指具有1-3个碳原子的烷基。
术语“烷氧基”指-O-烷基。
术语“环烷基”是指仅由碳原子和氢原子组成的单环的饱和的脂肪烃基团，如C 3-10环烷基，优选为C 3-6环烷基，例如环丙基、环丁基、环戊基、环己基等。
除非另有规定，术语“杂”表示杂原子或杂原子团(即含有杂原子的原子团)，包括碳(C)和氢(H)以外的原子以及含有这些杂原子的原子团，例如包括氧(O)、氮(N)、硫(S)、硅(Si)、锗(Ge)、铝(Al)、硼(B)、-O-、-S-、＝O、＝S、-C(＝O)O-、-C(＝O)-、-C(＝S)-、-S(＝O)、-S(＝O) 2-，以及-C(＝O)N(H)-、-N(H)-、-C(＝NH)-、-S(＝O) 2N(H)-或-S(＝O)N(H)-。
除非另有规定，“环”表示被取代或未被取代的环烷基、杂环烷基、环烯基、杂环烯基、环炔基、杂环炔基、芳基或杂芳基。所述的环包括单环、联环、螺环、并环或桥环。环上原子的数目通常被定义为环的元数，例如，“5～7元环”是指环绕排列5～7个原子。除非另有规定，该环任选地包含1～3个杂原子。因此，“5～7元环”包括例如苯基、吡啶和哌啶基。
术语“杂环烷基”是指完全饱和的并且可以以单环、双环或螺环存在的环状基团。除非另有指示，该杂环通常为含有1至3个独立地选自硫、氧和/或氮的杂原子(优选1或2个杂原子)的3至10元环。3元杂环烷基的实例包括但不限于环氧乙烷基、环硫乙烷基、环氮乙烷基，4元杂环烷基的非限制性实例包括但不限于吖丁啶基、噁丁环基、噻丁环基，5元杂环烷基的实例包括但不限于四氢呋喃基、四氢噻吩基、吡咯烷基、异噁唑烷基、噁唑烷基、异噻唑烷基、噻唑烷基、咪唑烷基、四氢吡唑基，6元杂环烷基的实例包括但不限于哌啶基、四氢吡喃基、四氢噻喃基、吗啉基、哌嗪基、1,4-噻噁烷基、1,4-二氧六环基、硫代吗啉基、1,3-二噻烷基、1,4-二噻烷基，7元杂环烷基的实例包括但不限于氮杂环庚烷基、氧杂环庚烷基、硫杂环庚烷基，8元杂环烷基的实例包括但不限于3,8-二氮杂二环[3.2.1]辛烷基，9元杂环烷基的实例包括但不限于2-氧杂-7-氮杂螺[3,5]壬烷基。
术语“芳基”是指具有共轭的π电子体系的全碳单环或稠合多环的芳香环基团。例如，芳基可以具有6-20个碳原子，6-14个碳原子或6-12个碳原子。芳基的非限制性实例包括但不限于苯基、萘基、蒽基和1,2,3,4-四氢化萘等。
术语“杂芳基”是指单环或稠合多环体系，其中含有至少一个选自N、O、S的环原子，优选含有1、2或3个选自N、O或S的环原子，其余环原子为C，并且具有至少一个芳香环。优选的杂芳基具有单个4至8元环，尤其是5至8元环，或包含6至14个，尤其是6至10个环原子的多个稠合环。杂芳基的非限制性实例包括但不限于吡咯基、呋喃基、噻吩基、咪唑基、噁唑基、吡唑基、吡啶基、嘧啶基、吡嗪基、喹啉基、异喹啉基、四唑基、三唑基、三嗪基、苯并呋喃基、苯并噻吩基、吲哚基、异吲哚基等。
本申请的化合物可以通过本领域技术人员所熟知的多种合成方法来制备，包括下面列举的具体实施方式、其与其他化学合成方法的结合所形成的实施方式以及本领域技术上人员所熟知的等同替换方式，优选的实施方式包括但不限于本申请的实施例。
本申请具体实施方式的化学反应是在合适的溶剂中完成的，所述的溶剂须适合于本申请的化学变化及其所需的试剂和物料。为了获得本申请的化合物，有时需要本领域技术人员在已有实施方式的基础上对合成步骤或者反应流程进行修改或选择。
本领域合成路线规划中的一个重要考量因素是为反应性官能团(如本申请中的氨基)选择合适的保护基，例如，可参考Greene's Protective Groups in Organic Synthesis(4th Ed).Hoboken,New Jersey:John  Wiley&Sons,Inc.本申请引用的所有参考文献整体上并入本申请。
合成路线通式A：
Figure PCTCN2018091269-appb-000053
其中，基团定义如式Ⅲ化合物所述。
合成路线通式B：
Figure PCTCN2018091269-appb-000054
其中，基团定义如式Ⅳ化合物所述。
具体实施方式
下面的具体实施例，其目的是使本领域的技术人员能更清楚地理解和实施本申请。它们不应该被认为是对本申请范围的限制，而只是本申请的示例性说明和典型代表。本领域技术人员应该理解：还有形成本申请化合物的其它合成途径，下面提供的是非限制性的实施例。
除非另有说明，温度是摄氏温度。本申请所使用的溶剂可经市售获得。
本申请采用下述缩略词：TMSCHN 2代表三甲基硅烷化重氮甲烷；Tf 2O代表三氟甲磺酸酐；DMAP代表4-二甲氨基吡啶；Pd 2(dba) 3代表三(二亚苄基丙酮)二钯；Xantphos代表4,5-双二苯基膦-9,9-二甲基氧杂蒽；Pd(dppf)Cl 2代表[1,1'-双(二苯基膦基)二茂铁]二氯化钯；NBS代表N-溴代丁二酰亚胺；DMF代表N,N-二甲基甲酰胺；DMSO代表二甲基亚砜；DIEA(DIPEA)代表N,N-二异丙基乙胺；Pd(OAc) 2代表醋酸钯；Brettphos代表2-(二环己基膦)-3,6-二甲氧基-2'-4'-6'-三-I-丙基-11'-联苯；EDTA代表乙二胺四乙酸；DTT代表二硫苏糖醇；TFA代表三氟乙酸；DCM代表二氯甲烷；BINAP代表2,2'-双-(二苯膦基)-1,1'-联萘；DAST代表二乙胺基三氟化硫；TLC代表薄层色谱法；LCMS代表液质联用；NCS代表N-氯代琥珀酰亚胺；t-Bu代表叔丁基；DME代表二甲醚。
实施例1：1-甲基-3-((4-吗啡啉苯基)氨基)-6-(1H-吡唑-3-基)喹啉-2(1H)-酮
Figure PCTCN2018091269-appb-000055
步骤A：6-(1-苄基-1H-吡唑-3-基)-3-羟基-1-甲基-喹啉-2(1H)-酮
氮气保护下,向6-溴-3-羟基-1-甲基-喹啉-2-酮(0.6g,2.36mmol),1-苄基-3-(4,4,5,5-四甲基-1,3,2-二氧硼烷-2-基)吡唑(805.2mg,2.83mmol)和碳酸钾(652.7mg,4.72mmol)的二氧六环(4.00mL)和水(1.00mL)的溶液中加入Pd(dppf)Cl 2(172.7mg,0.236mmol)。反应液80℃搅拌7小时。反应液40mL水稀释，40mL二氯甲烷萃取两次，有机相食盐水洗涤，无水硫酸钠干燥，过滤，旋干后自动过柱机分离(二氯甲烷/甲醇体系)得到标题化合物。
1H NMR(400MHz,DMSO-d6)δ＝9.51(s,1H),7.97(d,J＝2.0Hz,1H),7.90(d,J＝2.4Hz,1H),7.84(dd,J＝2.0,8.8Hz,1H),7.51-7.45(m,1H),7.39-7.32(m,2H),7.32-7.25(m,3H),7.17(s,1H),6.78(d,J＝2.4Hz,1H),5.39(s,2H),3.71(s,3H)。
步骤B：[6-(1-苄基-1H-吡唑-3-基)-1-甲基-2-氧-1,2-二氢-喹啉-3-基]三氟甲磺酸酯
0℃下，6-(1-苄基-1H-吡唑-3-基)-3-羟基-1-甲基-喹啉-2(1H)-酮(340.00mg，1.03mmol)的二氯甲烷溶液中加入DMAP(125.8mg,1.03mmol),Tf 2O(581.2mg,2.06mmol,0.339mL)，然后加入吡啶(244.4mg,3.09mmol,0.25mL)。反应15℃下搅拌16小时。反应液40mL水稀释，40mL二氯甲烷萃取两次，有机相食盐水洗涤，无水硫酸钠干燥，过滤，旋干后自动过柱机分离(石油醚/四氢呋喃＝50/50)得到标题化合物。
1H NMR(400MHz,DMSO-d6)δ＝8.48(s,1H),8.32(d,J＝2.0Hz,1H),8.16(dd,J＝2.0,8.8Hz,1H),7.95(d,J＝2.3Hz,1H),7.67(d,J＝9.0Hz,1H),7.39-7.25(m,5H),6.82(d,J＝2.3Hz,1H),5.40(s,2H),3.74(s,3H)。
步骤C：6-(1-苄基-1H-吡唑-3-基)-1-甲基-3-((4-吗啡啉苯基)氨基)喹啉-2(1H)-酮
20℃下，往[6-(1-苄基-1H-吡唑-3-基)-1-甲基-2-氧-1,2-二氢-喹啉-3-基]三氟甲磺酸酯(150mg,323.67μmol)和4-吗啡啉苯胺(86.53mg,485.51μmol)的无水二氧六环(3mL)溶液中加入碳酸铯(158.19mg,485.51μmol)，Xantphos(37.46mg,64.73μmol)和Pd 2(dba) 3(29.64mg,32.37μmol)。氮气保护下100℃搅拌7小时。反应液用40mL水稀释，40mL二氯甲烷萃取两次，有机相食盐水洗涤，无水硫酸钠干燥，过滤，旋干后自动过柱机分离(石油醚/四氢呋喃＝100％-60/40)得到标题化合物。
1H NMR(400MHz,DMSO-d6)δ＝7.90(dd,J＝1.8,13.2Hz,1H),7.78-7.73(m,1H),7.46(d,J＝8.8Hz,1H),7.39-7.32(m,2H),7.32-7.24(m,5H),7.21(s,1H),6.97(d,J＝8.8Hz,2H),6.77(d,J＝2.4Hz,1H),5.37(s,2H),3.79-3.72(m,7H),3.10-3.04(m,1H)。
步骤D：1-甲基-3-((4-吗啡啉苯基)氨基)-6-(1H-吡唑-3-基)喹啉-2(1H)-酮
往6-(1-苄基-1H-吡唑-3-基)-1-甲基-3-((4-吗啡啉苯基)氨基)喹啉-2(1H)-酮(30.00mg,61.03μmol)的甲醇加入Pd(OH) 2(30.00mg)，50℃下氢气氛围(45psi)中搅拌16小时。反应液过滤后滤饼使用30mL甲醇洗涤。滤液旋干后通过制备型HPLC分离(三氟乙酸体系)得到标题化合物1。
1H NMR(400MHz,DMSO-d6)δ＝7.93(s,1H),7.78(d,J＝8.0Hz,1H),7.70(d,J＝2.0Hz,1H),7.50(d,J＝8.8Hz,1H),7.34-7.17(m,3H),7.03(s,2H),6.72(d,J＝2.4Hz,1H),3.77(s,7H),3.12(s,4H).
MS-ESI(m/z):402.2(M+H) +.
实施例2：1-甲基-3-((5-吗啡啉吡啶-2-基)氨基)-6-(1H-吡唑-3-基)喹啉-2(1H)-酮
Figure PCTCN2018091269-appb-000056
步骤A：5-溴-1-甲基吲哚啉-2,3-二酮
氮气保护下，向5-溴吲哚啉-2,3-二酮(50.00g,221.21mmol)和碳酸铯(144.15g,442.42mmol)的乙腈(700mL)的溶液中，在0℃下滴加三氟甲磺酸甲酯(39.93g,243.33mmol)，并在0℃下搅拌一小时。将反应液倒入2升水中，用1mol/L的盐酸调节pH值到6.将析出的固体过滤并干燥，得到标题化合物。
1H NMR(400MHz,DMSO-d6)δ＝7.83(dd,J＝2.0,8.3Hz,1H),7.68(d,J＝2.0Hz,1H),7.11(d,J＝8.5Hz,1H),3.11(s,3H)。
步骤B：6-溴-3-羟基-1-甲基喹啉-2(1H)-酮
氮气保护下，向5-溴-1-甲基吲哚啉-2,3-二酮(44.00g,183.30mmol)和三乙胺(37.10g,366.60mmol)的乙醇(1L)的溶液中，在25℃下滴加TMSCHN 2(2mol/L,91.65mL)，并在25℃下搅拌12小时。将反应液浓缩至一半，过滤。滤饼用乙酸乙酯(100mL)洗涤，干燥后得到标题化合物。
1H NMR(400MHz,DMSO-d6)δ＝9.78(br s,1H),7.81(d,J＝2.5Hz,1H),7.54(dd,J＝2.3,8.8Hz,1H),7.42(d,J＝9.0Hz,1H),7.11(s,1H),3.68(s,3H)。
步骤C：6-溴-1-甲基-2-氧-1,2-二氢喹啉-3-基三氟甲磺酸酯
氮气保护下，在0℃时三氟甲磺酸酐(39.14g,138.73mmol)滴加到6-溴-3-羟基-1-甲基喹啉-2(1H)-酮(23.50g,92.49mmol)，吡啶(21.95g，277.47mmol)和DMAP(1.13g，9.25mmol)的二氯甲烷(400mL)中。在25℃下搅拌3小时。1N盐酸淬灭反应，调节pH至6。有机相用饱和氯化钠(500mL)洗涤，无水硫酸钠干燥。过滤并蒸发得到标题化合物。
1H NMR(400MHz,DMSO-d6)δ＝8.38(s,1H),8.15(d,J＝2.3Hz,1H),7.90(dd,J＝2.1,9.2Hz,1H),7.61(d,J＝9.3Hz,1H),3.72(s,3H)。
步骤D：6-溴-1-甲基-3-((5-吗啡啉吡啶-2-基)氨基)喹啉-2(1H)-酮
氮气保护下，向四氢呋喃(300mL)中，加入6-溴-1-甲基-2-氧-1,2-二氢喹啉-3-基三氟甲磺酸酯(28.00g,81.95mmol)，5-吗啡啉吡啶-2-氨基(16.15g,90.15mmol)，Pd 2(dba) 3(3.75g,4.10mmol)，Xantphos(4.74g,8.20mmol)和碳酸铯(53.40g,163.90mmol)。在25℃下搅拌6小时。反应液过滤，滤饼用乙酸乙酯(50mL)和水(200mL)洗涤。固体干燥后得到标题化合物。
1H NMR(400MHz,DMSO-d6)δ＝8.72(d,J＝11.0Hz,2H),7.97(d,J＝2.8Hz,1H),7.66(d,J＝2.5Hz,1H),7.50(d,J＝9.0Hz,1H),7.41(ddd,J＝2.6,9.0,16.9Hz,2H),7.32(d,J＝9.0Hz,1H),3.97-3.67(m,7H),3.13-2.94(m,4H)。
步骤E：1-甲基-3-((5-吗啡啉吡啶-2-基)氨基)-6-(1H-吡唑-3-基)喹啉-2(1H)-酮
氮气保护下，向1,4-二氧六环(200mL)和水(50mL)中，加入6-溴-1-甲基-3-((5-吗啡啉吡啶-2-基)氨基)喹啉-2(1H)-酮(10.00g,24.08mmol)，碳酸钾(8.32g,60.20mmol)，Pd(dppf)Cl 2(7.16g,2.41mmol)和3-(4,4,5,5-四甲基-1,3,2-二氧杂己硼烷-2-基)-1H-吡唑(5.61g,28.90mmol)。在110℃下搅拌12小时。反应液过滤，滤饼用乙酸乙酯(200mL)洗涤。水相分离掉，有机相用无水硫酸钠干燥，浓缩，过滤，干燥后得到标题化合物2。
1H NMR(400MHz,DMSO-d6)δ＝13.60-12.56(m,1H),8.86(s,1H),8.63(br s,1H),8.00(s,2H),8.13-7.93(m,1H),7.92-7.68(m,1H),7.53(br d,J＝8.0Hz,1H),7.43(dd,J＝3.0,9.0Hz,1H),7.32(d,J＝9.0 Hz,1H),6.81(br s,1H),3.85-3.70(m,7H),3.18-2.98(m,4H)。
(ESI)m/z:403(M+1)
实施例3：1-甲基-6-(1H-吡唑-3-基)-((5-)四氢-2H-吡喃-4-基)吡啶-2-基)氨基)喹啉-2(1H)-酮
Figure PCTCN2018091269-appb-000057
步骤A：5-(3,6-二氢-2H-吡喃-4-基)吡啶-2-胺
在氮气保护下，将2-(3,6-二氢-2H-吡喃-4-基)-4,4,5,5-四甲基-1,3-2-二氧杂环己烷环戊硼烷(2.29g,10.91mmol)，碳酸钾(3.77g,27.27mmol)和Pd(dppf)Cl 2(332.56mg,454.50μmol)加入到5-碘吡啶-2-胺(2.00g,9.09mmol)的二氧六环(32mL)和水(8mL)的溶液中，在氮气保护，80℃搅拌3小时。反应液冷却到室温，向反应液中加入水(50mL)，用乙酸乙酯(50mL)萃取两次。有机相用饱和食盐水(50mL)洗两次，用无水硫酸钠干燥，过滤，旋干得到残余物，通过柱层析得到标题化合物。
1H NMR(400MHz,CHLOROFORM-d)δ＝8.12(d,J＝2.3Hz,1H),7.49(dd,J＝2.3,8.5Hz,1H),6.49(d,J＝8.5Hz,1H),6.01-5.94(m,1H),4.58-4.37(m,2H),4.31(q,J＝2.8Hz,2H),3.93(t,J＝5.5Hz,2H),2.51-2.42(m,2H).
步骤B：5-(四氢-2H-吡喃-4-基)吡啶-2-胺
向5-(3,6-二氢-2H-吡喃-4-基)吡啶-2-胺(1.29g,7.32mmol)的乙酸乙酯(5mL)和水溶液中加入10％钯炭(0.12g)，用氢气球置换三次，在室温搅拌16小时。用硅藻土过滤，用乙酸乙酯(50mL)淋洗三次，滤液旋干得到标题化合物。
1H NMR(400MHz,CHLOROFORM-d)δ＝7.94(d,J＝2.0Hz,1H),7.32(dd,J＝2.3,8.5Hz,1H),6.49(d,J＝8.3Hz,1H),4.35(br s,2H),4.10-4.02(m,2H),3.51(dt,J＝3.3,11.2Hz,2H),2.71-2.59(m,1H),1.80-1.71(m,4H).
步骤C：1-甲基-3((5-(四氢-2H-吡喃-4-基)吡啶-2-基)氨基)-6-(1-((2-(三甲基硅烷基)乙氧基)甲基)-1H-吡唑-3-基)喹啉-2(1H)-酮
将5-(四氢-2H-吡喃-4-基)吡啶-2-胺(63.71mg,357.44μmol)，碳酸铯(145.58mg,446.81μmol)，Xantphos(34.47mg,59.57μmol)和Pd 2(dba) 3(27.28mg,29.79μmol)加入到1-甲基-2-氧代-6-(1-((2-(三甲基硅烷基)乙氧基)甲基)-1H-吡唑-3-基)-1,2-二氢喹啉-3-基-三氟甲磺酸酯(150.00mg,297.87μmol)的二氧六环(8mL)的溶液中，在氮气保护，100℃搅拌16小时。反应液冷却到室温，向反应液中加入水(30mL)，用二氯甲烷(30mL)萃取两次。有机相用饱和食盐水(20mL)洗两次，用无水硫酸钠干燥，过滤，旋干得到残余物，通过柱层析得到标题化合物。
MS-ESI(m/z):532(M+H)+
步骤D：1-甲基-6-(1H-吡唑-3-基)-((5-)四氢-2H-吡喃-4-基)吡啶-2-基)氨基)喹啉-2(1H)-酮
在室温下，将1-甲基-3((5-(四氢-2H-吡喃-4-基)吡啶-2-基)氨基)-6-(1-((2-(三甲基硅烷基)乙氧基)甲基)-1H-吡唑-3-基)喹啉-2(1H)-酮(100.00mg,188.07μmol)溶于三氟醋酸(4mL)。在95℃搅拌3小时。反应液冷却到室温，旋干，向反应液中加入水(15mL)，用二氯甲烷(15mL)萃取两次。有机相用饱和食盐水(20mL)洗两次，用无水硫酸钠干燥，过滤，减压浓缩得到的残余物通过 制备型HPLC分离(三氟乙酸)得到标题化合物3。
1H NMR(400MHz,DMSO-d6)δ＝8.99(br s,1H),8.83(br s,1H),8.18(s,1H),8.06(s,1H),7.91(br d,J＝8.5Hz,1H),7.74(d,J＝2.0Hz,1H),7.66(br d,J＝8.8Hz,1H),7.57(d,J＝8.8Hz,1H),7.34(d,J＝8.8Hz,1H),6.81(d,J＝2.3Hz,1H),3.96(br d,J＝10.8Hz,2H),3.79(s,3H),2.81-2.73(m,1H),1.75-1.67(m,4H),-0.01--0.01(m,1H).
MS-ESI(m/z):402(M+H)+.
实施例4：1-甲基-3-[[5-(4-(氧杂环丁-3-基)哌嗪-1-基]吡啶-2-基]氨基]-6-(1H-吡唑-3-基)喹啉-2(1H)-酮
Figure PCTCN2018091269-appb-000058
步骤A：1-(6-硝基吡啶-3-基)哌嗪
氮气保护下，向哌嗪(2.55g，29.56mmol)和5-溴-2-硝基-吡啶(5g，24.63mmol)的乙腈(40mL)溶液中加入碳酸钾(5.11g，36.95mmol)和四丁基碘化胺(636.83mg，1.72mmol)在100℃下搅拌16小时。趁热过滤，滤饼使用热的乙腈洗涤，滤液中会析出固体，再次过滤，滤饼用少量冷的乙腈洗涤，最后将滤饼旋干，得到标题化合物。
MS-ESI(m/z):209(M+1).
1H NMR(400MHz,DMSO-d 6)δ＝8.23(d,J＝3.0Hz,1H),8.13(d,J＝9.3Hz,1H),7.44(dd,J＝3.0,9.3Hz,1H),3.43-3.38(m,4H),2.87-2.76(m,4H)
步骤B：1-(6-硝基吡啶-3-基)-4-(氧杂环丁-3-基)哌嗪
向氯化锌(1M，9.90mL)和氧杂环丁-3-酮(712.92mg，9.90mmol)的甲醇(20mL)溶液中加入实施例4A(1.03g，4.95mmol)，在30℃下搅拌2小时后，再缓慢分批加入氰基硼氢化钠(621.70mg，9.90mmol)，升温至50℃反应14小时。趁热过滤，滤饼分别用滤液和甲醇(50mL)洗涤，然后将滤饼旋干，得到标题化合物。
MS-ESI(m/z):265(M+1).
1H NMR(400MHz,DMSO-d 6)δ＝8.26(br d,J＝3.0Hz,1H),8.20-8.13(m,1H),7.49(dd,J＝3.0,9.3Hz,1H),4.60-4.53(m,2H),4.47(t,J＝6.0Hz,2H),3.54-3.49(m,4H),3.16(d,J＝5.3Hz,1H),2.43-2.38(m,4H)
步骤C：5-[4-(氧杂环丁-3-基)哌嗪-1-基]吡啶-2-胺
实施例4B(990mg，3.75mmol)和钯碳(100mg，10％纯度)的甲醇(150mL)混合物在氢气(15psi),50℃下反应16小时。然后用硅藻土过滤，滤饼用甲醇(100mL)洗涤，滤液旋干，得到标题化合物。MS-ESI(m/z):235(M+1).
1H NMR(400MHz,DMSO-d 6)δ＝7.59(d,J＝3.0Hz,1H),7.24-7.10(m,1H),6.40(d,J＝8.8Hz,1H),5.38(s, 2H),4.58-4.51(m,2H),4.44(t,J＝6.0Hz,2H),3.45-3.42(m,1H),2.97-2.91(m,4H),2.40-2.34(m,4H).
步骤D：6-氯-1-甲基-3-[[5-[4-(氧杂环丁-3-基)哌嗪-1-基]吡啶-2-基]氨基]喹啉-2(1H)-酮
氮气保护下，向实施例4C(100mg，426.80μmol)，(6-氯-1-甲基-2-氧杂-1,2-二氢喹啉-3-基)三氟甲磺酸酯(145.83mg，426.80μmol)，碳酸铯(278.12mg，853.60μmol)的四氢呋喃(5mL)溶液中加入Xantphos(49.39mg，85.36μmol)，Pd 2(dba) 3(39.08mg，42.68μmol)。在80℃下搅拌12小时。冷却至室温，加入水(50mL)淬灭，水层用二氯甲烷(50mL×3)萃取，合并有机层用饱和食盐水(100mL)洗涤，无水硫酸钠干燥，过滤并蒸发，残余物通过柱层析分离纯化得到标题化合物。
MS-ESI(m/z):426.1(M+1).
步骤E：1-甲基-3-[[5-(4-(氧杂环丁-3-基)哌嗪-1-基]吡啶-2-基]氨基]-6-(1H-吡唑-3-基)喹啉-2(1H)-酮
氮气保护下，将实施例4D(86mg，201.92μmol)，3-(4,4,5,5-四甲基-1,3,2-二氧硼戊烷-2-基)-1H-吡唑(78.36mg，403.84μmol)，碳酸铯(197.37mg，605.76μmol)溶于二氧六环(8mL)溶液，再加入Brettphos-Pd(32.26mg，40.38μmol)，在110℃下搅拌15小时。冷却至室温，加入水(50mL)淬灭，水层用乙酸乙酯(50mL×3)萃取，合并有机层用饱和食盐水(100mL)洗涤，无水硫酸钠干燥，过滤并蒸发，残余物通过制备型HPLC(三氟乙酸体系)分离纯化得到标题化合物4。
MS-ESI(m/z):457.5(M+H) +.
1H NMR(400MHz,DMSO-d 6)δ＝8.85(s,1H),8.77(s,1H),8.06(d,J＝3.0Hz,1H),7.98(s,1H),7.87(dd,J＝2.0,8.7Hz,1H),7.73(d,J＝2.1Hz,1H),7.58-7.50(m,2H),7.36(d,J＝9.0Hz,1H),6.79(d,J＝2.2Hz,1H),4.82-4.75(m,4H),4.55-4.43(m,1H),3.88-3.83(m,9H),3.31(br s,2H).
实施例5：3-((5-(4-羟基-4-(三氟甲基)哌啶-1-基)哌啶-2-基)氨基)-1-甲基-6-(1H-吡唑-3-基)喹啉-2(1H)-酮
Figure PCTCN2018091269-appb-000059
步骤A：叔丁基4-羟基-4-(三氟甲基)哌啶-1-甲酸酯
0℃氮气保护下,向叔丁基4-羰基六氢啶-1-羧酸盐(1.2g，6.02mmol)的DMF(10mL)溶液中逐滴加入三甲基(三氟甲基)硅烷(3.85g，27.10mmol)，在25℃下搅拌2小时后，加入水(100mL)淬灭，水层用乙酸乙酯(100mL×3)萃取，将合并的有机层用饱和食盐水(100mL×2)洗，再用硫酸钠干燥，过滤并蒸发，得到标题化合物。
步骤B：4-(三氟甲基)哌啶-4-醇
氮气保护下，实施例5A(1.6g，5.94mmol)的三氟乙酸(2mL)和二氯甲烷(10mL)在25℃反应12小时。反应混合液被减压蒸发得到标题化合物。
步骤C：1-(6-硝基吡啶-3-基)-4-(三氟甲基)哌啶-4-醇
氮气保护下，实施例5B(1.67g，5.90mmol)，5-溴-2-硝基吡啶(1.32g，6.49mmol)，碳酸钾(4.08g，29.49mmol)，的DMF(50mL)混合物在100℃下搅拌10小时后，用水(50mL)稀释。水层用乙酸 乙酯(50mL×3)萃取。合并的有机层用盐水(50mL×2)洗涤后，用硫酸钠干燥，过滤并蒸发，残余物通过柱色谱纯化得到标题化合物。
1H NMR(400MHz,DMSO-d6)δ＝8.29(d,J＝3.0Hz,1H),8.14(d,J＝9.3Hz,1H),7.52(dd,J＝3.0,9.3Hz,1H),6.18(s,1H),4.10-4.03(m,2H),3.29-3.19(m,2H),1.80-1.72(m,4H).
步骤D：1-(6-氨基吡啶-3-基)-4-(三氟甲基)哌啶-4-醇
氮气保护下，向实施例5C(810mg，2.78mmol)的20mL甲醇溶液中，加10％的湿钯炭(81mg)。然后用氢气置换3次，在25℃，氮气(15psi)氛围中搅拌15小时，反应液通过硅藻土过滤并蒸发，残余物通过柱色谱纯化得到标题化合物。
MS-ESI(m/z):262(M+1).
步骤E：6-氯-3-[[5-[4-羟基-4-(三氟甲基)哌啶-1-基]吡啶-2-基]氨基]-1-甲基-喹啉-2(1H)-酮
氮气保护下，实施例5D(275.24mg，1.05mmol)，(6-氯-1-甲基-2-氧基-3-喹啉基)三氟甲磺酸酯(300mg，877.99μmol)，Pd2(dba)3(80.40mg,87.80μmol),碳酸铯(572.13mg,1.76mmol)，Xantphos(76.20mg,131.70μmol)的四氢呋喃(10.00mL)中，混合物25℃搅拌4小时。用水(20mL)稀释，水层用二氯甲烷(20mL×3)萃取。合并的有机层用盐水(20mL×2)洗涤后，用硫酸钠干燥，过滤并蒸发，残余物通过柱色谱纯化得到标题化合物。
MS-ESI(m/z):453(M+1).
1H NMR(400MHz,DMSO-d6)δ＝8.72(s,1H),8.67(s,1H),8.01(d,J＝2.8Hz,1H),7.65(d,J＝2.0Hz,1H),7.50(d,J＝9.0Hz,1H),7.45(dd,J＝2.8,9.0Hz,1H),7.41-7.36(m,1H),7.29(d,J＝9.0Hz,1H),6.01(s,1H),3.75(s,3H),3.53(br d,J＝11.8Hz,2H),2.97-2.87(m,2H),1.84-1.71(m,4H).
步骤F：3-((5-(4-羟基-4-(三氟甲基)哌啶-1-基)哌啶-2-基)氨基)-1-甲基-6-(1H-吡唑-3-基)喹啉-2(1H)-酮
氮气保护下，实施例5E(330mg，728.70μmol)，3-(4,4,5,5-四甲基-1,3,2-二氧杂己硼烷-2-基)-1H-吡唑(212.10mg,1.09mmol)，[2-(2-氨乙基)苯基]-氯-钯；双环己基-[3,6-二甲氧基-2-(2,4,6-三异丙基苯)苯基]磷酸盐(58.21mg,72.87μmol,)，碳酸铯(712.28mg,2.19mmol)的二甲亚砜(8mL)和水(2mL)中，混合物在120℃下搅拌10小时。用水(30mL)稀释，水层用二氯甲烷(30mL×3)萃取。合并的有机层用盐水(30mL×2)洗涤后，用硫酸钠干燥，过滤并蒸发，残余物通过柱色谱纯化得到标题化合物5。
MS-ESI(m/z):485(M+1).
1H NMR(400MHz,DMSO-d6)δ＝13.41-12.81(m,1H),8.85(br s,1H),8.62(br s,1H),8.02(br d,J＝18.3Hz,2H),7.92-7.74(m,1H),7.62-7.41(m,2H),7.30(br d,J＝8.0Hz,1H),6.80(br s,1H),6.00(br s,1H),3.79(br s,3H),3.52(br s,2H),2.93(br t,J＝11.2Hz,2H),1.90-1.69(m,4H)。
实施例6：7-氟-1-甲基-3-((5-吗啡啉吡啶-2-基)氨基)-6-(1H-吡唑-3-基)喹啉-2(1H)-酮
Figure PCTCN2018091269-appb-000060
步骤A：(E)-N-(4-溴-3-氟苯基)-2-(肟基)乙酰胺
向4-溴-3-氟-苯胺(5.00g,26.31mmol)的水溶液(150.00mL)中加入2,2,2-三氯乙烷-1,1-二醇(5.66 g,34.20mmol)，硫酸钠(8.22g,57.88mmol),盐酸羟胺(7.31g,105.24mmol)和盐酸(2.50mL).将反应液升温到100℃搅拌16小时.过滤，滤饼用水(200mL)洗涤.固体干燥后得到标题化合物。
1H NMR(400MHz,DMSO-d6)δ＝12.30(s,1H),10.50(s,1H),7.83(dd,J＝2.4,11.4Hz,1H),7.69-7.61(m,2H),7.46(dd,J＝2.0,8.8Hz,1H)
步骤B：5-溴-6-氟吲哚啉-2,3-二酮
将(E)-N-(4-溴-3-氟苯基)-2-(肟基)乙酰胺(2.00g,7.66mmol)溶解在硫酸(10.00mL)中，反应液升温至80℃搅拌一小时。将反应液倒入水(50mL)中。将析出的固体过滤并且干燥后得到标题化合物。
1H NMR(400MHz,DMSO-d6)δ＝11.30(s,1H),7.99-7.75(m,1H),6.94(d,J＝8.8Hz,1H).
步骤C：5-溴-6-氟-1-甲基吲哚啉-2,3-二酮
氮气保护下在0℃时，向5-溴-6-氟吲哚啉-2,3-二酮(800.00mg,3.28mmol)的乙腈(20.00mL)溶液中加入碳酸铯(2.14g,6.56mmol)和三氟甲磺酸甲酯(645.59mg,3.94mmol)。在0℃下，搅拌2小时.用水(100mL)淬灭,乙酸乙酯(30mL)萃取三次。有机相用饱和食盐水(100mL)洗涤,无水硫酸钠干燥。过滤并蒸发，得到标题化合物。
步骤D：6-溴-7-氟-3-羟基-1-甲基喹啉-2(1H)-酮
氮气保护下，向5-溴-6-氟-1-甲基吲哚啉-2,3-二酮(800mg,3.10mmol)和三乙胺(627.44mg,6.20mmol)的乙醇(30mL)的溶液中，在0℃下滴加TMSCHN2(2mol/L,1.86mL)，并在25℃下搅拌16小时。将反应液浓缩后得到标题化合物。
MS-ESI(m/z):272(M+H)+
步骤E：6-溴7-氟-1-甲基-2-氧-1,2-二氢喹啉-3-基-三氟甲磺酸酯
氮气保护下，在零度时将三氟甲磺酸酐(1.87g,6.62mmol)滴加到6-溴-7-氟-3-羟基-1-甲基喹啉-2(1H)-酮(1.2g,4.41mmol)，吡啶(697.76mg,8.82mmol)和DMAP(538.85mg,4.41mmol)的二氯甲烷(20mL)中。在25℃下搅拌16小时。1N盐酸淬灭反应，调节pH至6。二氯甲烷(50mL)萃取三次。合并有机相，饱和氯化钠(100mL)洗涤，无水硫酸钠干燥。过滤并蒸发，残余物通过硅胶柱色谱法纯化得到标题化合物得到标题化合物。
1H NMR(400MHz,CHLOROFORM-d)δ＝7.85(d,J＝7.0Hz,1H),7.63(s,1H),7.19(d,J＝10.0Hz,1H),3.76(s,3H).
步骤F：6-溴-7-氟-1-甲基-3-((5-吗啡啉吡啶-2-基)氨基)喹啉-2(1H)-酮
氮气保护下，向四氢呋喃(10mL)中，加入6-溴7-氟-1-甲基-2-氧-1,2-二氢喹啉-3-基-三氟甲磺酸酯(300mg,0.742mmol)，5-吗啡啉吡啶-2-氨基(146.35mg,816.57μmol)，Pd2(dba)3(67.98mg,74.23μmol)，Xantphos(85.91mg,148.47μmol)和碳酸铯(483.74mg,1.48mmol)。在25℃下搅拌12小时。反应液过滤，滤饼用乙酸乙酯(20mL)，水(50mL)洗涤。干燥后得到标题化合物。
1H NMR(400MHz,CHLOROFORM-d)δ＝8.72(s,1H),8.03(d,J＝2.8Hz,1H),7.87(s,1H),7.78(d,J＝7.3Hz,1H),7.30(br d,J＝3.0Hz,1H),7.12(d,J＝10.5Hz,1H),6.83(d,J＝9.0Hz,1H),3.97-3.87(m,4H),3.80(s,3H),3.22-3.07(m,4H)。
步骤G：7-氟-1-甲基-3-((5-吗啡啉吡啶-2-基)氨基)-6-(1H-吡唑-3-基)喹啉-2(1H)-酮
氮气保护下，向1,4-二氧六环(4mL)和水(1mL)中，加入6-溴-7-氟-1-甲基-3-((5-吗啡啉吡啶-2-基)氨基)喹啉-2(1H)-酮(50mg,115.4μmol)，碳酸钾(31.9mg,230.8μmol)，Pd(dppf)Cl2(8.44mg,11.54μmol)和3-(4,4,5,5-四甲基-1,3,2-二氧杂己硼烷-2-基)-1H-吡唑(33.59mg,173.1μmol)。在100℃下搅拌8小时。反应液过滤，滤液浓缩，残余物通过制备型HPLC分离得到标题化合物6。
1H NMR(400MHz,DMSO-d6)δ＝8.80(s,1H),8.71(br s,1H),8.11(d,J＝8.0Hz,1H),7.96(d,J＝2.8Hz,1H),7.79(d,J＝1.8Hz,1H),7.54-7.43(m,2H),7.32(d,J＝9.0Hz,1H),6.68(dd,J＝2.3,3.5Hz,1H),3.80-3.71(m,7H),3.13-3.04(m,4H).
(ESI)m/z:421(M+1)
实施例7：5-氯-1-甲基-3-((5-吗啡啉吡啶-2-基)氨基)-6-(1H-吡唑-3-基)喹啉-2(1H)-酮
Figure PCTCN2018091269-appb-000061
步骤A：5-溴-4-氯-1-甲基吲哚啉-2,3-二酮
25℃下，将NBS(181.54mg，1.02mmol)加入到4-氯-1-甲基吲哚啉-2,3-二酮(200mg，1.02mmol)的乙腈(7mL)和水(7mL)中。搅拌12小时，反应液过滤，滤饼干燥后得到标题化合物。
1H NMR(400MHz,DMSO-d6)δ＝8.02(d,J＝8.5Hz,1H),7.10(d,J＝8.5Hz,1H),3.14(s,3H)
步骤B：6-溴-5-氯-3-羟基-1-甲基喹啉-2(1H)-酮
氮气保护下，向5-溴-4-氯-1-甲基吲哚啉-2,3-二酮(500mg,1.82mmol)和三乙胺(368.63mg,3.64mmol)的乙醇(15mL)的溶液中，在25℃下滴加TMSCHN 2(2mol/L,1.09mL)，并在25℃下搅拌12小时。将反应液浓缩后得到标题化合物粗品，直接用于下一步反应。
步骤C：6-溴-5氯-1-甲基-2-氧-1,2-二氢喹啉-3-基-三氟甲磺酸酯
氮气保护下，在零度时将三氟甲磺酸酐(1.03g,3.65mmol)滴加到6-溴-5-氯-3-羟基-1-甲基喹啉-2(1H)-酮(700mg,2.43mmol)，吡啶(576.64mg,7.29mmol)和DMAP(29.69mg,0.243mmol)的二氯甲烷(20mL)中。在25℃下搅拌3小时。1N盐酸淬灭反应，调节pH至6。二氯甲烷(100mL)萃取三次。合并有机相，饱和氯化钠(150mL)洗涤，无水硫酸钠干燥。过滤并蒸发，残余物通过硅胶柱色谱法纯化得到标题化合物。
1H NMR(400MHz,DMSO-d6)δ＝8.46(s,1H),8.09(d,J＝9.3Hz,1H),7.63(d,J＝9.3Hz,1H),3.75(s,3H).
步骤D：6-溴-5氯-1-甲基-3-((5-吗啡啉吡啶-2-基)氨基)喹啉-2(1H)-酮
氮气保护下，向四氢呋喃(10mL)中，加入6-溴-5氯-1-甲基-2-氧-1,2-二氢喹啉-3-基-三氟甲磺酸酯(250mg,0.594mmol)，5-吗啡啉吡啶-2-氨基(127.83mg,713.28μmol)，Pd 2(dba) 3(54.43mg,59.44μmol)，Xantphos(51.59mg,89.16μmol)和碳酸铯(387.33mg,1.19mmol)。在25℃下搅拌3小时。反应液浓缩，用乙酸乙酯(20mL)打浆。过滤，干燥后得到标题化合物。
1H NMR(400MHz,DMSO-d6)δ＝9.27(s,1H),8.93(s,1H),8.01(d,J＝2.5Hz,1H),7.69(d,J＝9.0Hz,1H),7.46(br d,J＝8.8Hz,2H),7.42-7.33(m,1H),3.80-3.72(m,7H),3.10(br s,4H).
步骤E：5-氯-1-甲基-3-((5-吗啡啉吡啶-2-基)氨基)-6-(1H-吡唑-3-基)喹啉-2(1H)-酮
氮气保护下，向1,4-二氧六环(4mL)和水(1mL)中，加入6-溴-5氯-1-甲基-3-((5-吗啡吡啶-2-基)氨基)喹啉-2(1H)-酮(150mg,333.53μmol)，碳酸钾(138.29mg,1.0mmol)，Pd(dppf)Cl2(24.4mg,33.35μmol)和3-(4,4,5,5-四甲基-1,3,2-二氧杂己硼烷-2-基)-1H-吡唑(97.08mg,500.3μmol)。在110℃下搅拌8小时。反应液过滤，滤饼用乙酸乙酯(30mL)洗涤。滤液浓缩，残余物通过高效液相制备分离得到标题化合物7。
1H NMR(400MHz,DMSO-d6)δ＝9.35(s,1H),8.88(s,1H),8.00(d,J＝2.8Hz,1H),7.80(d,J＝2.0Hz,1H),7.74(d,J＝8.8Hz,1H),7.58(d,J＝8.8Hz,1H),7.48(dd,J＝3.0,9.0Hz,1H),7.37(d,J＝9.0Hz,1H),6.77(d,J＝2.3Hz,1H),3.82(s,3H),3.78-3.73(m,4H),3.14-3.08(m,1H),3.39-2.90(m,4H).
(ESI)m/z:437(M+1).
实施例8：5,7-二氟-1-甲基-3-((5-吗啉代吡啶-2-基)氨基)-6-(1H-吡唑-3-基)喹啉-2(1H)-酮
Figure PCTCN2018091269-appb-000062
实施例8的制备方法可参考实施例6的制备方法，用4-溴-3,5-二氟苯胺制备可得。
1H NMR(400MHz,DMSO-d6)δ＝8.98(s,1H),8.80(s,1H),7.99(d,J＝3.0Hz,1H),7.84(br s,1H),7.47-7.39(m,2H),7.37-7.32(m,1H),7.24-6.95(m,1H),6.62(s,1H),3.77(s,3H),3.75(br d,J＝5.5Hz,4H),3.12-3.06(m,4H).
实施例9：5-氟-1-甲基-3-((5-(4-(氧杂环丁-3-基)哌嗪-1-基)吡啶-2-基)氨基)-6-(1H-吡唑-3-基)喹啉-2(1H)-酮
Figure PCTCN2018091269-appb-000063
步骤A：4-氟-1-甲基-1H-吲哚
氮气保护下，向4-氟-1H-吲哚(59.00g,436.59mmol)的四氢呋喃(600mL)的溶液中，在0℃下加入钠氢(19.24g,480.99mmol,60％纯度)，搅拌三十分钟后加入三氟甲磺酸甲酯(93.14g,567.57mmol,62.09mL)。15℃下继续搅拌2小时。反应液用饱和氯化铵(1升)淬灭，乙酸乙酯(500mL)萃取三次。有机相用饱和食盐水(1升)洗涤，无水硫酸钠干燥。过滤浓缩后，残余物通过柱层析得到标题化合物。
1H NMR(400MHz,CHLOROFORM-d)δ＝7.22-7.08(m,2H),7.03(br d,J＝3.0Hz,1H),6.86-6.73(m,1H),6.58(d,J＝2.5Hz,1H),3.81(s,3H)。
步骤B：4-氟-1-甲基吲哚啉-2,3-二酮
氮气保护下，向4-氟-1-甲基-1H-吲哚(55.00g,368.72mmol)的二甲基亚砜(400mL)溶液中，加入NBS(65.63g,368.72mmol)，并在20℃下搅拌1小时。加入另一批NBS(65.63g,368.72mmol)后，将反应液升温到60℃并继续搅拌10小时。将反应液倒入水(6升)中，过滤。滤饼溶解在丙酮(2升)中，不溶物过滤，滤饼用丙酮(500mL)洗涤。滤液浓缩后，残余物通过柱层析得到标题化合物。
1H NMR(400MHz,DMSO-d6)δ＝7.72(dt,J＝5.8,8.2Hz,1H),6.99(d,J＝7.8Hz,1H),6.93(t,J＝8.8Hz,1H),3.15(s,3H).
步骤C：5-溴-4-氟-1-甲基吲哚啉-2,3-二酮
氮气保护下，4-氟-1-甲基吲哚啉-2,3-二酮(31.0g,173.04mmol)的乙腈(300mL)和水(600mL)中加入NBS(40.04g，224.95mmol)。15度下搅拌16小时。反应液过滤，滤饼用水(300mL)洗涤，干燥后得到标题化合物。
1H NMR(400MHz,DMSO-d6)δ＝7.99(dd,J＝7.3,8.3Hz,1H),6.98(d,J＝8.5Hz,1H),3.14(s,3H).
步骤D：6-溴-5-氟-3-羟基-1-甲基喹啉-2(1H)-酮
氮气保护下，向5-溴-4-氟-1-甲基吲哚啉-2,3-二酮(32.00g,124.01mmol)和三乙胺(25.1g,248.02mmol)的乙醇(300mL)的溶液中，在0℃下滴加TMSCHN 2(2mol/L,65.11mL)，并在0-15℃下搅拌1小时。将反应液浓缩，残余物用乙酸乙酯(500mL)打浆。过滤，滤饼干燥后得到标题化合物。
1H NMR(400MHz,DMSO-d6)δ＝10.17(br s,1H),7.65(dd,J＝7.5,9.0Hz,1H),7.30(d,J＝9.0Hz,1H),7.11(s,1H),3.69(s,3H).
步骤E：6-溴-5-氟-1-甲基-2-氧-1,2-二氢喹啉-3-基三氟甲磺酸酯
氮气保护下，在零度时三氟甲磺酸酐(13.48g,47.78mmol)滴加到6-溴-5-氟-3-羟基-1-甲基喹啉-2(1氢)-酮(10.0g,36.76mmol)，吡啶(8.72g,110.27mmol)和DMAP(449.04mg,3.68mmol)的二氯甲烷(200mL)中。在15度下搅拌1小时。反应液用水(300mL)淬灭，1N盐酸调节pH至5。有机相用饱和氯化钠(250mL)洗涤，无水硫酸钠干燥。过滤并蒸发得到标题化合物。
1H NMR(400MHz,CHLOROFORM-d)δ＝7.93(s,1H),7.82-7.75(m,1H),7.11(d,J＝9.0Hz,1H),3.79(s,3H)。
步骤F：6-溴-5-氟-1-甲基-3-((5-(4-(氧杂环丁-3-基)哌嗪-1-基)吡啶-2-基)氨基)喹啉-2(1H)-酮
氮气保护下，向四氢呋喃(200mL)中，加入6-溴-5-氟-1-甲基-2-氧-1,2-二氢喹啉-3-基三氟甲磺酸酯(10.00g,24.74mmol)，5-(4-(氧杂环丁-3-基)哌嗪-1-基)吡啶-2-氨基(6.38g,27.21mmol)，Pd2(dba)3(2.27g,2.47mmol)，Xantphos(2.15g,3.71mmol)和碳酸铯(16.12g,49.48mmol)。在50℃下搅拌16小时。反应液加入水(200mL)中，过滤，滤饼用乙酸乙酯(100mL)打浆。过滤，固体干燥后得到标题化合物。
1H NMR(400MHz,DMSO-d6)δ＝9.07-8.76(m,2H),8.00(br d,J＝2.3Hz,1H),7.68-7.40(m,2H),7.32(br dd,J＝9.0,13.3Hz,2H),4.71-4.39(m,4H),3.75(s,3H),3.52-3.39(m,1H),3.14(br s,4H),2.42(br s,4H)
步骤G：5-氟-1-甲基-3-((5-(4-(氧杂环丁-3-基)哌嗪-1-基)吡啶-2-基)氨基)-6-(1H-吡唑-3-基)喹啉-2(1H)-酮
氮气保护下，向1,4-二氧六环(160mL)和水(40mL)中，加入6-溴-5-氟-1-甲基-3-((5-(4-(氧杂环丁-3-基)哌嗪-1-基)吡啶-2-基)氨基)喹啉-2(1H)-酮(9.00g,18.43mmol)，碳酸钾(6.37g,46.07mmol)，Pd(dppf)Cl2(1.08g,1.47mmol)和3-(4,4,5,5-四甲基-1,3,2-二氧杂己硼烷-2-基)-1H-吡唑(5.36g,27.64mmol)。在110℃下搅拌16小时。反应液冷却后有固体析出，过滤。滤饼用水(200mL)乙酸乙酯(100mL)洗涤。滤饼干燥后得到标题化合物9。
1H NMR(400MHz,DMSO-d6)δ＝13.08(br s,1H),9.04(br s,1H),8.78(br s,1H),8.16-7.70(m,3H),7.57-7.23(m,3H),6.73(br s,1H),4.74-4.37(m,4H),3.79(br s,3H),3.56(br s,2H),3.14(br s,3H),2.42(br s,4H).
实施例10：5-氟-3-[[5-[4-羟基-4-(三氟甲基)哌啶-1-基]吡啶-2-基]氨基]-1-甲基-6-(1H-吡唑-3-基)喹啉-2(1H)-酮
Figure PCTCN2018091269-appb-000064
步骤A：6-溴-5-氟-3-[[5-[4-羟基-4-(三氟甲基)哌啶-1-基]吡啶-2-基]氨基]-1-甲基-喹啉-2(1H)-酮
氮气保护下,向(6-溴-5-氟-1-甲基-2-氧-3-喹啉基)三氟甲磺酸酯(220mg，544.38μmol)，1-(6-氨基-3-氮苯基)-4-(三氟甲基)哌啶-4-醇(213.32mg，544.38μmol)，Pd2(dba)3(49.85mg,54.44μmol),Xantphos(47.25mg,81.66μmol)和碳酸铯(354.74mg,1.09mmol)的四氢呋喃(10mL)，混合物在25℃反应2小时,加入水(20mL)淬灭，水层用二氯甲烷(20mL×2)萃取，将合并的有机层用饱和食盐水(20mL×2)洗，再用硫酸钠干燥，过滤并蒸发，残余物通过柱色谱纯化得到标题化合物。
LCMS(ESI)m/z:515(M+1).
步骤B：5-氟-3-[[5-[4-羟基-4-(三氟甲基)哌啶-1-基]吡啶-2-基]氨基]-1-甲基-6-(1H-吡唑-3-基)喹啉-2(1H)-酮
氮气保护下，实施例10A(220mg，426.94μmol)，5-(4,4,5,5-四甲基1,3,2-二氧杂己硼烷-2-基)-1H-吡啶(124.27mg，640.41μmol)，Pd(dppf)Cl2(31.24mg，42.69μmol)，碳酸钾(177.02mg，1.28mmol)的二氧六环(8mL)和水(2mL)混合物在120℃反应10小时。冷却至室温后，用水(20mL)稀释，水层用二氯甲烷(20mL×3)萃取，合并的有机层用盐水(20mL×3)洗涤后，经硫酸钠干燥，过滤并蒸发，残余物通过柱色谱纯化得到标题化合物10。
LCMS(ESI)m/z:503(M+1) +
1H NMR(400MHz,DMSO-d6)δ＝13.38-13.04(m,1H),9.04(s,1H),8.86-8.72(m,1H),8.06(d,J＝2.8Hz,1H),7.96(br t,J＝8.3Hz,1H),7.87(br s,1H),7.46(dd,J＝2.8,9.0Hz,1H),7.40(br d,J＝9.0Hz,1H),7.32(d,J＝9.0Hz,1H),6.73(br s,1H),6.00(s,1H),3.79(s,3H),3.63-3.50(m,4H),2.93(br t,J＝11.2Hz,2H),1.86-1.77(m,2H).
实施例11：5-氟-1-甲基-3-((5-吗啉代吡啶-2-基)氨基)-6-(1H-吡唑-3-基)喹啉-2(1H)-酮
Figure PCTCN2018091269-appb-000065
实施例11的制备方法可参考实施例10的制备方法得到。
1H NMR(400MHz,DMSO-d6)δ＝9.01(s,1H),8.85(br s,1H),8.01(d,J＝3.0Hz,1H),7.93(t,J＝8.4Hz,1H),7.81(d,J＝2.0Hz,1H),7.47(br d,J＝9.0Hz,1H),7.42(d,J＝8.8Hz,1H),7.35(d,J＝9.0Hz,1H),6.73(dd,J＝2.3,3.5Hz,1H),3.79(s,3H),3.77-3.74(m,4H),3.13-3.06(m,4H).
MS-ESI(m/z):421(M+H)
实施例12：5-氟-1-甲基-3-[[5-(2-噁唑-7-氮杂螺[3.5]壬烷-7-基)吡啶-2-基]氨基]-6-(1H-吡唑-3)喹啉-2(1H)-酮
Figure PCTCN2018091269-appb-000066
步骤A：7-(6-硝基-3-吡啶)-2-噁唑-7-氮杂螺[3.5]壬烷
向2-噁唑-7-氮杂螺[3.5]壬烷草酸盐(1.00g，4.60mmol)和碳酸钾(1.91g，13.80mmol)的二甲亚 砜(15mL)溶液中加入5-溴-2-硝基-吡啶(1.12g，5.52mmol)，使用氮气保护，在100℃下搅拌14小时后，冷却至室温，加入水(50mL)淬灭，水层用二氯甲烷(50mL×3)萃取，将合并的有机层用硫酸钠干燥，过滤并蒸发，残余物通过柱色谱纯化得到标题化合物。
LCMS(ESI)m/z:250(M+1).
1H NMR(400MHz,CHLOROFORM-d)δ＝8.15-8.11(m,2H),7.21(dd,J＝3.1,9.2Hz,1H),4.50(s,4H),3.44-3.38(m,4H),2.06-2.00(m,4H).
步骤B：5-(2-噁唑-7-氮杂螺[3.5]壬烷-7基)吡啶-2-胺
实施例12A(1g，4.01mmol)和雷尼镍(34.35mg，401.00μmol)的甲醇(110mL)混合物在氢气(15psi),30℃下反应15小时。然后用硅藻土过滤，滤饼用甲醇(200mL)洗涤，滤液旋干，得到标题化合物。
LCMS(ESI)m/z:219.9(M+1).
1H NMR(400MHz,DMSO-d6)δ＝7.59(d,J＝2.8Hz,1H),7.14(dd,J＝3.0,8.8Hz,1H),6.37(d,J＝8.8Hz,1H),5.38(s,2H),4.31(s,4H),2.86-2.74(m,4H),1.96-1.80(m,4H).
步骤C：6-溴-5-氟-1-甲基-3-[[5-(2-噁唑-7-氮杂螺[3.5]壬烷-7-基)-2-吡啶]氨基]喹啉-2(1H)-酮
氮气保护下，向实施例12B(97.67mg，445.40μmol)，(6-溴-5-氟-1-甲基-2-氧杂-3-喹啉)三氟甲磺酸酯(150.00mg，371.17μmol)，碳酸铯(241.87mg，742.34μmol)的四氢呋喃(5mL)混合物中加入Xantphos(42.95mg，74.23μmol)，Pd 2(dba) 3(33.99mg，37.12μmol)。在80℃下搅拌4小时后，反应液用滤纸过滤，滤饼用滤液洗涤三次，最后将滤饼干燥得到标题化合物。
LCMS(ESI)m/z:473/475(M/M+2).
1H NMR(400MHz,DMSO-d6)δ＝8.91(s,1H),8.87(s,1H),7.99(d,J＝2.5Hz,1H),7.59(t,J＝8.3Hz,1H),7.43(dd,J＝3.1,9.2Hz,1H),7.35-7.29(m,2H),4.34(s,4H),3.75(s,3H),3.07-3.01(m,4H),1.94-1.86(m,4H).
步骤D：5-氟-1-甲基-3-[[5-(2-噁唑-7-氮杂螺[3.5]壬烷-7-基)吡啶-2-基]氨基]-6-(1H-吡唑-3)喹啉-2(1H)-酮
氮气保护下，将实施例12C，3-(4,4,5,5-四甲基-1,3,2-二氧硼戊烷-2-基)-1H-吡唑(131.18mg，676.04μmol)，碳酸钾(140.15mg，1.01mmol)溶于二氧六环(4mL)和水(1mL)的溶液，再加入Pd(dppf)Cl 2(24.73mg，33.80μmol)，在110℃下搅拌12小时。冷却至室温，加入水(50mL)淬灭，水层用乙酸乙酯(50mL×4)萃取，合并有机层用饱和食盐水(100mL)洗，无水硫酸钠干燥，过滤并蒸发，残余物加入二甲基亚砜(10mL)和三氟乙酸(0.15mL)，然后倒入搅拌中的水(30mL)，过滤，滤饼用乙酸乙酯(20mL)洗涤，最后滤饼用二氯甲烷(20mL)和甲醇(20mL)在50℃重结晶，得到标题化合物12。
MS-ESI(m/z):461(M+H) +
1H NMR(400MHz,DMSO-d6)δ＝9.43(br s,1H),9.08-8.98(m,1H),8.84-8.70(m,1H),8.26-8.11(m,1H),8.05-7.92(m,2H),7.58-7.50(m,1H),7.41(d,J＝8.8Hz,1H),6.84(br s,1H),4.40(s,3H),3.76(s,3H),3.58-3.44(m,5H),2.26(br s,3H),1.96-1.83(m,1H).
实施例13：(R)5-氟-1-甲基-3-((5-(-3-甲基吗啡啉)吡啶-2-基)氨基)-6-(1H-吡唑-3-基)喹啉-2(1H)-酮
Figure PCTCN2018091269-appb-000067
实施例13的制备方法可参考实施例12的制备方法，用(3R)-3-甲基吗啡啉制备可得。
MS-ESI(m/z):435(M+H) +。
1H NMR(400MHz,METHANOL-d4)δ＝8.20(dd,J＝2.6,9.9Hz,1H),7.97(d,J＝2.8Hz,1H),7.88(t,J＝8.4Hz,1H),7.82(d,J＝2.3Hz,1H),7.48(d,J＝9.8Hz,1H),7.42(d,J＝9.0Hz,1H),7.32(s,1H),6.78(t, J＝2.6Hz,1H),4.22(br d,J＝7.5Hz,1H),4.10(dd,J＝3.6,11.4Hz,1H),3.92-3.75(m,1H),3.94-3.75(m,5H),3.75-3.65(m,1H),3.62-3.51(m,1H),1.43(d,J＝6.8Hz,3H).
实施例14：(S)5-氟-1-甲基-3-((5-(-3-甲基吗啡啉)吡啶-2-基)氨基)-6-(1H-吡唑-3-基)喹啉-2(1H)-酮
Figure PCTCN2018091269-appb-000068
实施例14的制备方法可参考实施例12的制备方法，用(3S)-3-甲基吗啡啉制备可得。
1H NMR(400MHz,METHANOL-d4)δ＝8.20(dd,J＝2.6,9.9Hz,1H),7.97(d,J＝2.8Hz,1H),7.88(t,J＝8.4Hz,1H),7.82(d,J＝2.3Hz,1H),7.48(d,J＝9.8Hz,1H),7.42(d,J＝9.0Hz,1H),7.32(s,1H),6.78(t,J＝2.6Hz,1H),4.22(br d,J＝7.5Hz,1H),4.10(dd,J＝3.6,11.4Hz,1H),3.92-3.75(m,1H),3.94-3.75(m,5H),3.75-3.65(m,1H),3.62-3.51(m,1H),1.43(d,J＝6.8Hz,3H).
MS-ESI(m/z):435(M+H) +
实施例15：5-氟-1-甲基-6-(1H-吡唑-3-基)-3-(吡啶-2-胺)-喹啉-2(1H)-酮
Figure PCTCN2018091269-appb-000069
实施例15的制备方法可参考实施例12的制备方法制备得到。
1H NMR(400MHz,DMSO-d6)δ＝13.09(br s,1H),9.18(s,1H),8.98(br s,1H),8.38-8.31(m,1H),8.01(br s,1H),7.87(br s,1H),7.71-7.62(m,1H),7.47-7.37(m,2H),6.95-6.88(m,1H),6.75(br d,J＝2.0Hz,1H),3.80(s,3H).
MS-ESI(m/z):336.0(M+H) +。
实施例16：3-((5-氨基吡啶-2-基)氨基)-5-氟-1-甲基-6-(1H-吡唑-3-基)喹啉-2(1H)-酮
Figure PCTCN2018091269-appb-000070
实施例16的制备方法可参考实施例12的制备方法制备得到。
1H NMR(400MHz,DMSO-d6)δ＝8.98(d,J＝7.5Hz,2H),8.09(s,1H),7.96(t,J＝8.5Hz,1H),7.83(s,1H),7.44(d,J＝9.0Hz,1H),7.42-7.37(m,2H),6.74(br s,1H),3.80(s,3H).
MS-ESI(m/z):350.9(M+H) +。
实施例17：1-(6-((5-氟-1-甲基-2-氧-6-(1H-吡唑-3-基)-1,2-二氢喹啉3-基)胺)吡啶-3-基)-3-哌可啉-3-羧酸
Figure PCTCN2018091269-appb-000071
实施例17的制备方法可参考实施例12的制备方法制备得到。
1H NMR(400MHz,DMSO-d6)δ＝8.99(s,1H),8.86(br s,1H),7.99(br s,1H),7.97-7.92(m,1H),7.83(s,1H),7.43(br d,J＝8.8Hz,2H),7.38-7.31(m,1H),6.74(br s,1H),3.80(s,3H),3.71-3.70(m,1H),3.31(br d,J＝11.8Hz,1H),2.65(br d,J＝16.1Hz,1H),2.05(br d,J＝13.1Hz,1H),1.76-1.63(m,2H),1.33- 1.22(m,1H),1.17(s,3H).
MS-ESI(m/z):477.2(M+H)+。
实施例18：(3R)-1-[6-[[5-氟-1-甲基-2-氧杂-6-(1H-吡唑-3-基)-1,2-二氢喹啉-3-基]氨基]吡啶-3-基]哌啶-3-羧酸
Figure PCTCN2018091269-appb-000072
步骤A：(3R)-1-(6-硝基吡啶-3-基)哌啶-3-甲酸乙酯
向(3R)-哌啶-3-甲酸乙酯(1.00g，6.36mmol)和碳酸钾(2.64g，19.08mmol)的二甲亚砜(10mL)溶液中加入5-溴-2-硝基-吡啶(1.32g，6.49mmol)，在85℃下搅拌14小时后，冷却至室温，加入水(50mL)淬灭，水层用乙酸乙酯(50mL×5)萃取，将合并的有机层用饱和食盐水(100mL×2)洗涤，无水硫酸钠干燥，过滤并蒸发，残余物通过柱色谱纯化得到标题化合物。
LCMS(ESI)m/z:280.1(M+1).
1H NMR(400MHz,CHLOROFORM-d)δ＝8.17-8.13(m,2H),7.24(dd,J＝3.0,9.0Hz,1H),4.18(q,J＝7.3Hz,2H),3.88(dd,J＝3.8,13.3Hz,1H),3.74-3.66(m,1H),3.48(dd,J＝9.0,13.3Hz,1H),3.23(ddd,J＝3.3,9.8,13.1Hz,1H),2.72-2.61(m,1H),2.14-2.05(m,1H),1.94-1.83(m,2H),1.76-1.67(m,1H),1.29-1.25(m,3H)。
步骤B：(3R)-1-(6-氨基吡啶-3-基)哌啶-3-甲酸乙酯
实施例18A(1g，3.58mmol)和雷尼镍(30.67mg)的甲醇(50mL)混合物在氢气(15psi),23℃下反应15小时。然后用硅藻土过滤，滤饼用甲醇(200mL)洗涤，滤液旋干，得到标题化合物。
LCMS(ESI)m/z:250.1(M+1).
1H NMR(400MHz,CHLOROFORM-d)δ＝7.79(br s,1H),7.20(dd,J＝2.4,8.7Hz,1H),6.48(d,J＝8.8Hz,1H),4.19-4.14(m,2H),3.72(s,1H),3.44(br d,J＝9.5Hz,1H),3.22(br d,J＝11.5Hz,1H),2.97-2.87(m,1H),2.76-2.67(m,2H),2.05-1.96(m,1H),1.69-1.58(m,2H),1.28(t,J＝7.2Hz,3H).
步骤C：(3R)-1-[6-溴-5-氟-1-甲基-2-氧杂-1,2-二氢喹啉-3-基)氨基]吡啶-3-基]哌啶-3-甲酸乙酯
氮气保护下，向实施例18B(200mg，802.21μmol)，(6-溴-5-氟-1-甲基-2-氧杂-3-喹啉)三氟甲磺酸酯(356.62mg，882.43μmol)，碳酸铯(392.07mg，1.2mmol)的四氢呋喃(15mL)混合物中加入Xantphos(69.63mg，120.33μmol)，Pd 2(dba) 3(73.46mg，80.22μmol)，在15℃下搅拌16小时。加入水(50mL)淬灭，水层用乙酸乙酯(50mL×3)萃取，将合并的有机层用饱和食盐水(100mL)洗涤，蒸发，残余物通过柱色谱纯化得到标题化合物。
LCMS(ESI)m/z:503/505.0(M/M+2).
1H NMR(400MHz,DMSO-d 6)δ＝8.90(s,1H),8.86(s,1H),7.98(d,J＝2.8Hz,1H),7.57(dd,J＝7.7,8.9Hz,1H),7.45-7.37(m,1H),7.35-7.26(m,2H),4.09(q,J＝7.2Hz,2H),3.74(s,3H),3.61-3.52(m,1H),2.97(dd,J＝9.5,11.8Hz,1H),2.86-2.76(m,1H),2.74-2.61(m,1H),1.95-1.68(m,3H),1.67-1.54(m,2H),1.24-1.14(m,3H)。
步骤D：(3R)-1-[6-[[5-氟-1-甲基-2-氧杂-6-(1H-吡唑-3-基)-1,2-二氢喹啉-3-基]氨基]吡啶-3-基]哌啶-3-羧酸
氮气保护下，将实施例1C(350mg，695.33μmol)，3-(4,4,5,5-四甲基-1,3,2-二氧硼戊烷-2-基)-1H-吡唑(148.41mg，764.86μmol)，碳酸铯(453.10mg，1.39mmol)溶于二氧六环(8mL)和水(2mL)的溶液中，再加入Pd(dppf)Cl 2(50.88mg，69.53μmol)，在110℃下搅拌12小时。冷却至室温，把反应液旋干，残余物通过柱色谱纯化，最后通过手性拆分，得到标题化合物18，ee值98.06％。
1H NMR(400MHz,DMSO-d 6)δ＝9.04(s,1H),8.78(s,1H),8.00(d,J＝2.8Hz,1H),7.92(br t,J＝8.2Hz,1H),7.81(br s,1H),7.45-7.38(m,2H),7.36-7.29(m,1H),6.73(dd,J＝2.1,3.6Hz,1H),3.79(s,3H),3.57(br d,J＝8.8Hz,1H),3.17(d,J＝4.3Hz,1H),2.99-2.87(m,1H),2.79(br t,J＝9.4Hz,1H),2.56(br d,J＝9.5Hz,1H),1.90(br d,J＝8.5Hz,1H),1.79-1.71(m,1H),1.66-1.51(m,2H).
MS-ESI(m/z):463.1(M+H)+。
实施例19：(3S)-1-[6-[[5-氟-1-甲基-2-氧杂-6-(1H-吡唑-3-基)-1,2-二氢喹啉-3-基]胺]吡啶-3-基]哌啶-3-羧酸
Figure PCTCN2018091269-appb-000073
参考实施例18的方法制备，原料为(3S)-哌啶-3-羧酸盐。
1H NMR(400MHz,DMSO-d6)δ＝9.05(s,1H),8.78(s,1H),8.01(d,J＝2.8Hz,1H),7.93(br t,J＝8.4Hz,1H),7.82(br s,1H),7.46-7.38(m,2H),7.32(d,J＝9.0Hz,1H),7.35-7.27(m,1H),6.74(dd,J＝2.1,3.8Hz,1H),4.35(br s,1H),3.80(s,3H),3.77(br d,J＝6.1Hz,1H),3.57(br d,J＝11.2Hz,1H),2.97-2.88(m,1H),2.79(br t,J＝9.4Hz,1H),2.62-2.54(m,1H),1.91(br d,J＝8.9Hz,1H),1.74(br d,J＝3.4Hz,1H),1.67-1.51(m,2H).
MS-ESI(m/z):463.1(M+H)+。
实施例20：5-氟-3-[[5-(2-羟基丙烷-2-基)吡啶-2-基]氨基]-1-甲基-6-(1H-吡啶-3-基)喹啉-2(1H)-酮
Figure PCTCN2018091269-appb-000074
步骤A：2-(6-氨基-3-吡啶)丙-2-醇
0℃氮气保护下,向甲基6-氨基吡啶-3-甲酸甲酯(3.2g，21.03mmol)的四氢呋喃(300mL)溶液中逐滴加入甲基氯化镁(70.10mL，3mol)，在25℃下搅拌15小时后，加入水(50mL)淬灭，水层用乙酸乙酯(50mL×2)萃取，将合并的有机层用饱和食盐水(50mL×2)洗，再用硫酸钠干燥，过滤并蒸发，提供标题化合物。
LCMS(ESI)m/z:153(M+1).
1H NMR(400MHz,DMSO-d6)δ＝7.96(d,J＝2.3Hz,1H),7.45(dd,J＝2.5,8.5Hz,1H),6.39(d,J＝8.5Hz,1H),5.74(br s,2H),4.85(s,1H),1.36(s,6H).
步骤B：6-溴-5-氟-3-[[5-(2-羟基丙烷-2-基)吡啶-2-基]氨基]-1-甲基-喹啉-2-酮
氮气保护下，实施例20A(400mg，2.63mmol)，(6-溴-5-氟-1-甲基-2-氧-3-喹啉)三氟甲磺酸酯(1.12g，2.76mmol)，Pd2(dba)3(240.68mg，0.263mmol)，Xantphos(228.12mg，0.3945mmol)和碳酸铯(1.71g，5.26mmol)的四氢呋喃(40mL)混合物在25℃反应15小时。冷却至室温后，用水(30mL)稀释，水层用乙酸乙酯(30mL×3)萃取，合并的有机层用盐水(30mL×3)洗涤后，经硫酸钠干燥，过滤 并蒸发，残余物通过柱色谱纯化得到标题化合物。
LCMS(ESI)m/z:406(M+1)
1H NMR(400MHz,DMSO-d6)δ＝9.05(s,1H),9.00(s,1H),8.41(d,J＝2.5Hz,1H),7.74(dd,J＝2.4,8.7Hz,1H),7.63(dd,J＝7.5,9.0Hz,1H),7.37-7.31(m,2H),5.08(s,1H),3.76(s,3H),1.45(s,6H).
步骤C：5-氟-3-[[5-(2-羟基丙烷-2-基)吡啶-2-基]氨基]-1-甲基-6-(1H-吡啶-3-基)喹啉-2(1H)-酮
氮气保护下，实施例20B(100mg，0.24615mmol)，3-(4,4,5,5-四甲基1,3,2-二氧硼戊烷-2-基)-1氢-吡唑(52.54mg，0.27077mmol)，Pd(dppf)Cl2(18.01mg，0.02462mmol)，碳酸钾(102.06mg，0.73845mmol)的二氧六环(2mL)和水(0.5mL)混合物在100℃下搅拌15小时后，用水(20mL)稀释水层用二氯甲烷(20mL×3)萃取。合并的有机层用盐水(20mL×2)洗涤后，用硫酸钠干燥，过滤并蒸发，残余物通过制备型HPLC(三氟乙酸体系)纯化得到标题化合物20。
LCMS(ESI)m/z:394(M+1)
1H NMR(400MHz,DMSO-d6)δ＝13.12(br s,1H),9.17(s,1H),8.92(s,1H),8.42(d,J＝1.8Hz,1H),7.96(br t,J＝8.4Hz,1H),7.82(br s,1H),7.74(dd,J＝2.3,8.8Hz,1H),7.43(d,J＝9.0Hz,1H),7.34(d,J＝8.8Hz,1H),6.74(br s,1H),5.08(s,1H),3.80(s,3H),1.46(s,6H).
实施例21：5-氟-3–[[5-(1-羟基环丁基)吡啶-2-基]-1-甲基-6-(1H-吡唑-3-基)喹啉-2(1H)-酮
Figure PCTCN2018091269-appb-000075
步骤A：1-(6-氯-3-吡啶)环丁醇
-10℃氮气保护下，向5-溴-2-氯-吡啶(10g，51.96mmol)的四氢呋喃(100mL)溶液中缓慢滴加异丙基氯化镁氯化锂复合物(1.3M，59.95mL)，在该温度下搅拌1小时，然后环丁酮(4.01g，57.16mmol)在-10-0℃下缓慢滴加，在此温度区间搅拌2小时，最后至0℃下继续搅拌2小时。加入氯化铵的饱和溶液(100mL)淬灭，水层用乙酸乙酯(50mL×4)萃取，将合并的有机层用饱和食盐水(100mL×2)洗涤，无水硫酸钠干燥，过滤并蒸发，残余物通过柱色谱纯化得到标题化合物。
LCMS(ESI)m/z:184.0(M+1).
1H NMR(400MHz,CHLOROFORM-d)δ＝8.51(d,J＝2.5Hz,1H),7.80(dd,J＝2.6,8.4Hz,1H),7.32(d,J＝8.3Hz,1H),2.58-2.49(m,2H),2.48-2.37(m,3H),2.13-2.02(m,1H),1.81-1.69(m,1H).
步骤B：1-(6((二苯亚甲基)胺)吡啶-3-基)环丁醇
氮气保护下，向实施例21A(1g，5.45mmol)，二苯甲酮亚胺(1.48g，8.18mmol)和碳酸铯(3.55g，10.90mmol)的二氧六环(25mL)的溶液中加入BINAP(339.36mg，545μmol)和Pd 2(dba) 3(249.53mg，272.5μmol)，在100℃搅拌12小时。冷却至室温后，用水(50mL)稀释，水层用乙酸乙酯(50mL×4)萃取，合并的有机层用饱和食盐水(100mL)洗涤后，经无水硫酸钠干燥，过滤并蒸发，残余物通过柱色谱分离纯化，得到标题化合物。
LCMS(ESI)m/z:329.2(M+1).
1H NMR(400MHz,CHLOROFORM-d)δ＝8.46(d,J＝2.0Hz,1H),7.80(br d,J＝7.5Hz,2H),7.59(dd, J＝2.5,8.3Hz,1H),7.53-7.47(m,1H),7.45-7.38(m,2H),7.27(s,3H),7.18(br d,J＝6.8Hz,2H),6.58(d,J＝8.3Hz,1H),2.56-2.45(m,2H),2.41-2.30(m,2H),2.04-2.00(m,1H),1.72-1.63(m,1H).
步骤C：1-(6-胺-3-吡啶)环丁醇
向实施例21B(820mg，2.5mmol)和乙酸钾(490.7mg，5mmol)的甲醇(10mL)溶液中加入盐酸羟胺(347.45mg，5mmol)，在17℃下搅拌1小时后，过滤，滤饼用甲醇(5mL)洗涤，将滤液蒸发，残余物通过柱色谱分离纯化，提供标题化合物。
LCMS(ESI)m/z:164.9(M+1).
1H NMR(400MHz,DMSO-d 6)δ＝7.99(d,J＝2.3Hz,1H),7.44(dd,J＝2.5,8.5Hz,1H),6.41(d,J＝8.5Hz,1H),5.74(s,2H),5.28(br s,1H),2.36-2.26(m,2H),2.23-2.13(m,2H),1.87-1.76(m,1H),1.57-1.45(m,1H).
步骤D：6-溴-5-氟-3-((5-(1-羟基环丁基)吡啶-2-基)胺)-1-甲基喹啉-2(1H)-酮
氮气保护下，向实施例21C(250mg，1.52mmol)和碳酸铯(990.49mg，3.04mmol)的四氢呋喃(10mL)的溶液中加入Xantphos(131.93mg，228μmol)和Pd 2(dba) 3(139.19mg，152μmol)，在15℃搅拌12小时后，过滤，滤饼分别用甲醇(20mL)和二氯甲烷(20mL)洗涤，将滤液蒸发，，残余物通过柱色谱分离纯化，提供标题化合物。
LCMS(ESI)m/z:418(M+1).
1H NMR(400MHz,DMSO-d 6)δ＝9.06(d,J＝9.0Hz,2H),8.44(d,J＝2.3Hz,1H),7.75(dd,J＝2.5,8.5Hz,1H),7.63(dd,J＝7.8,8.8Hz,1H),7.40(d,J＝8.5Hz,1H),7.33(d,J＝9.3Hz,1H),5.56(s,1H),3.76(s,3H),2.42(dt,J＝4.3,8.4Hz,2H),2.34-2.22(m,2H),1.94-1.82(m,1H),1.69-1.56(m,1H).
步骤E:5-氟-3–[[5-(1-羟基环丁基)吡啶-2-基]-1-甲基-6-(1H-吡唑-3-基)喹啉-2(1H)-酮
氮气保护下，向实施例21D(340mg，812.89μmol)，3-(4,4,5,5-四甲基-1,3,2-二氧硼戊烷-2-基)-1H-吡唑(394.33mg，2.03mmol)，碳酸钾(337.04mg，2.44mmol)溶于二氧六环(10mL)和水(2.5mL)的溶液中，再加入Pd(dppf)Cl 2(59.48mg，81.29μmol)，在110℃下搅拌15小时；冷却至室温后，再补加3-(4,4,5,5-四甲基-1,3,2-二氧硼戊烷-2-基)-1氢-吡唑(394.33mg，2.03mmol)和Pd(dppf)Cl 2(59.48mg，81.29μmol)，继续在氮气保护下于110℃搅拌15小时。冷却至室温后，将反应液过滤，用乙酸乙酯(100mL)洗涤滤饼，滤液用水(50mL)稀释，水层用乙酸乙酯(50mL×5)萃取，合并的有机层用饱和食盐水(100mL)洗涤，经无水硫酸钠干燥，过滤并蒸发，残余物通过制备型HPLC分离(三氟乙酸体系)，提供标题化合物21。
MS-ESI(m/z):406(M+H) +
1H NMR(400MHz,DMSO-d 6)δ＝9.17(s,1H),9.00(s,1H),8.44(d,J＝1.8Hz,1H),7.97(br t,J＝8.4Hz,1H),7.82(br s,1H),7.76(dd,J＝2.3,8.8Hz,1H),7.41(br dd,J＝8.7,20.0Hz,2H),6.74(br s,1H),3.80(s,3H),2.36-2.20(m,4H),1.94-1.85(m,1H),1.70-1.58(m,1H),1.23(br s,1H),1.30-1.18(m,1H).
实施例22：5-氟-3-[[5-(3-羟基氧杂环丁-3-基)吡啶-2-基]氨基]-1-甲基-6-(1H-吡唑-3-基)喹啉-2(1H)-酮
Figure PCTCN2018091269-appb-000076
实施例22的制备方法可参考实施例21的制备方法，用原料氧杂环丁酮制备可得。
LCMS(ESI)m/z:408(M+1).
1H NMR(400MHz,DMSO-d6)δ＝9.19(s,1H),9.08(s,1H),8.53(d,J＝2.0Hz,1H),7.97(t,J＝8.4Hz,1H),7.87-7.79(m,2H),7.45(dd,J＝3.5,8.8Hz,2H),6.74(br s,1H),4.76(s,4H),3.81(s,3H).
实施例23：5-氟-3-[[5-(3-氟代氧杂环丁-3-基)吡啶-2-基]氨基]-1-甲基-6-(1H-吡唑-3-基)喹啉-2(1H)-酮
Figure PCTCN2018091269-appb-000077
步骤A：6-溴-5-氟-3-[[5-(3-氟代氧杂环丁-3-基)吡啶-2-基]氨基]-1-甲基-喹啉-2(1H)-酮
-10℃氮气保护下,向6-溴-5-氟-3-[[5-(3-羟基氧杂环丁-3-基)-2-氮苯基]氨基]-1-甲基-喹啉-2-酮(150mg，356.95μmol)的二氯甲烷(5mL)中，滴加DAST(103.56mg，642.50μmol),混合物在-50℃反应1小时,加入水(20mL)淬灭，水层用二氯甲烷(20mL×2)萃取，将合并的有机层用饱和食盐水(20mL×2)洗，再用硫酸钠干燥，过滤并蒸发，残余物通过柱色谱纯化得到标题化合物23A。
LCMS(ESI)m/z:422(M+1).
1H NMR(400MHz,CHLOROFORM-d)δ＝9.10(s,1H),8.60(s,1H),8.24(s,1H),7.74(dd,J＝2.3,8.8Hz,1H),7.51(dd,J＝7.3,9.0Hz,1H),7.09-6.90(m,2H),5.22-5.09(m,2H),4.98-4.85(m,2H),3.84(s,3H).
步骤B：5-氟-3-[[5-(3-氟代氧杂环丁-3-基)吡啶-2-基]氨基]-1-甲基-6-(1H-吡唑-3-基)喹啉-2(1H)-酮
氮气保护下，实施例23A(130mg，307.89μmol)，3-(4,4,5,5-四甲基1,3,2-二氧杂己硼烷-2-基)-1氢-吡啶(89.61mg，461.84μmol)，Pd(dppf)Cl2(22.53mg，30.79μmol)，氟化钾(53.66mg，926.68μmol)的二氧六环(4mL)混合物在100℃反应15小时。冷却至室温后，用水(20mL)淬灭，水层用二氯甲烷(20mL×3)萃取，合并的有机层用盐水(20mL×3)洗涤后，经硫酸钠干燥，过滤并蒸发，残余物通过制备型HPLC纯化得到标题化合物23。
LCMS(ESI)m/z:410(M+1)
1H NMR(400MHz,DMSO-d6)δ＝9.30-9.10(m,2H),8.59-8.47(m,1H),7.98(br t,J＝8.4Hz,1H),7.90-7.77(m,2H),7.58-7.40(m,2H),6.74(br s,1H),5.08-4.91(m,2H),4.76(s,2H),3.80(s,3H).
实施例24,25：5-氟-1-甲基-6-(1H-吡唑-3-基)-3-((5-(1,1,1-三氟-2-羟基丙烷-2-基)吡啶-2-基)氨基)喹啉-2(1H)-酮
Figure PCTCN2018091269-appb-000078
步骤A：2-(6-氯吡啶-3-基)-1,1,1-三氟甲基-丙-2-醇
在0℃下，向2-(6-氯-3-氮苯基)-1,1,1-三氟甲基-丙-2-醇(5g，32.14mmol)和碳酸铯(12.57g，38.56mmol)，的DMF(80mL)中滴加三氟甲基三甲基硅烷(20.56g，144.62mmol)，混合物在16℃反应2小时,加入水(100mL)淬灭，水层用乙酸乙酯(100mL×2)萃取，将合并的有机层用饱和食盐水(100mL×2)洗，再用硫酸钠干燥，过滤并蒸发，残余物通过柱色谱纯化得到标题化合物。
1H NMR(400MHz,CHLOROFORM-d)δ＝8.49(d,J＝2.5Hz,1H),7.84(dd,J＝2.4,8.4Hz,1H),7.29(d,J＝8.3Hz,1H),3.58(s,1H),1.74(s,3H).
步骤B：2-[6-(二苯亚甲基氨基)吡啶-3-基]-1,1,1-三氟甲基-丙-2-醇
氮气保护下，实施例24A(5.5g，24.38mmol)，二苯甲酮亚胺(6.63g，36.57mmol)，Pd2(dba)3(2.23g,2.44mmol),BINAP(2.28g,3.66mmol)和碳酸铯(15.89g,48.76mmol)的二氧六环(100mL)，混合物在100℃反应16小时。冷却至室温后，用水(100mL)稀释，水层用乙酸乙酯(100mL×3)萃取，合并的有机层用盐水(100mL×3)洗涤后，经硫酸钠干燥，过滤并蒸发，残余物通过柱色谱纯化得到标题化合物。
步骤C：2-(6-氨基吡啶-3-基)-1,1,1-三氟甲基-丙-2-醇
氮气保护下，24B(8g，21.60mmol)和醋酸钾(4.24g，43.20mmol)，盐酸羟胺(3g，43.20mmol)的甲醇(100mL)，混合物在16℃反应2小时,反应液被过滤，滤饼用甲醇(100mL)洗涤，滤液蒸发，残余物通过柱色谱纯化得到标题化合物。
LCMS(ESI)m/z:207(M+1).
1H NMR(400MHz,CHLOROFORM-d)δ＝8.15(s,1H),7.67(br d,J＝8.5Hz,1H),6.52(d,J＝8.8Hz,1H),5.22(br s,1H),4.13(br d,J＝7.5Hz,2H),1.75(s,3H).
步骤D：6-溴-5-氟-1-甲基-3-((5-(1,1,1-三氟-2-羟基丙烷-2-基)吡啶-2-基)氨基)喹啉-2(1H)-酮
氮气保护下，向四氢呋喃(100mL)中，加入6-溴-5氟-1-甲基-2-氧-1,2-1,2-二氢喹啉-3-基-三氟甲磺酸酯(3.0g,7.42mmol)，2-(6-氨基吡啶-3-基)-1,1,1-三氟丙烷-2-醇(1.53g,7.42mmol)，Pd2(dba)3(679.77mg,742.33μmol)，Xantphos(644.29mg,1.11mmol)和碳酸铯(4.84g,14.85mmol)。在30℃下搅拌16小时。反应液用水(200mL)淬灭，二氯甲烷(100mL)萃取三次。有机相用食盐水(200mL)洗涤，无水硫酸钠干燥。过滤浓缩后，残余物用乙酸乙酯(50mL)打浆。过滤干燥后得到标题化合物。
1H NMR(400MHz,CHLOROFORM-d)δ＝9.12(s,1H),8.60(s,1H),8.21(s,1H),7.83(br d,J＝9.0Hz,1H),7.67-7.44(m,1H),7.06(d,J＝9.0Hz,1H),6.89(d,J＝8.8Hz,1H),3.85(s,3H),2.42(s,1H),1.85(s,3H)。
步骤E：5-氟-1-甲基-6-(1H-吡唑-3-基)-3-((5-(1,1,1-三氟-2-羟基丙烷-2-基)吡啶-2-基)氨基)喹啉-2(1H)-酮
氮气保护下，向1,4-二氧六环(40mL)和水(10mL)中，加入6-溴-5-氟-1-甲基-3-((5-(1,1,1-三氟-2-羟基丙烷-2-基)吡啶-2-基)氨基)喹啉-2(1H)-酮(1.8g,3.91mmol)，碳酸钾(1.62g,11.73mmol)，Pd(dppf)Cl2(286.18mg,391μmol)和3-(4,4,5,5-四甲基-1,3,2-二氧杂己硼烷-2-基)-1H-吡唑(1.14g,5.87mmol)。在100℃下搅拌16小时。反应液用水(200mL)和二氯甲烷(150mL)淬灭。有机相分离后，水相再用二氯甲烷(150mL)萃取。合并有机相，无水硫酸钠干燥。过滤浓缩，残余物用二氯甲烷(60mL)打浆。过滤干燥后得到标题化合物。
1H NMR(400MHz,DMSO-d6)δ＝9.21(s,1H),9.13(s,1H),8.52(d,J＝1.8Hz,1H),7.99(br t,J＝8.5Hz,1H),7.90-7.77(m,2H),7.45(d,J＝9.0Hz,2H),6.75(br s,1H),3.81(s,3H),1.73(s,3H).
步骤F:5-氟-1-甲基-6-(1H-吡唑-3-基)-3-((5-(1,1,1-三氟-2-羟基丙烷-2-基)吡啶-2-基)氨基)喹啉-2(1H)-酮
5-氟-1-甲基-6-(1H-吡唑-3-基)-3-((5-(1,1,1-三氟-2-羟基丙烷-2-基)吡啶-2-基)氨基)喹啉-2(1H)-酮(0.95g,2.12mmol)通过手性拆分(柱子:Chiralpak AD-3 50*4.6mm I.D.,3um流动相:40％乙醇(0.05％二乙醇胺)在二氧化碳里流速:4mL/分钟，柱温:40℃)得到了峰1(0.990分钟,99％ee)为化合物24，峰2(1.601分钟,97％ee)作为化合物25。
化合物24：1H NMR(400MHz,DMSO-d6)δ＝13.56-12.88(m,1H),9.21(s,1H),9.13(br s,1H),8.53(s,1H),8.03(br s,1H),7.94-7.80(m,2H),7.45(br d,J＝8.5Hz,2H),6.75(br s,1H),6.68(s,1H),3.81(s,3H),1.73(s,3H).化合物25：1H NMR(400MHz,DMSO-d6)δ＝13.10(br s,1H),9.20(d,J＝4.3Hz,1H),9.13(br s,1H),8.52(br s,1H),8.10-7.76(m,3H),7.44(br dd,J＝4.5,8.5Hz,2H),6.74(br s,1H),6.67(d,J＝4.3Hz,1H),3.80(d,J＝4.3Hz,3H),1.73(br d,J＝4.0Hz,3H).
(ESI)m/z:448.1(M+1)。
实施例26：1-甲基-3-((4-吗啡啉苯基)氨基)-7-(1H-吡唑-4-基)喹喔啉-2(1H)-酮
Figure PCTCN2018091269-appb-000079
步骤A：5-溴-N-甲基-2-硝基苯胺
氮气保护下，向4-溴-2-氟-1-硝基苯胺(15.0g,68.18mmol)和碳酸钾(11.31g,81.82mmol)的DMF(250mL)的溶液中，在25℃下滴加甲胺的四氢呋喃溶液(2M,68.18mL)，并在25℃下搅拌18小时。将反应液倒入500mL水中，并搅拌10分钟。将析出的固体过滤并干燥，得到标题化合物。
1H NMR(400MHz,CHLOROFORM-d)δ＝8.03(d,J＝9.4Hz,2H),7.01(s,1H),6.77(dd,J＝1.8,9.2Hz,1H),3.02(d,J＝5.1Hz,3H).
步骤B：5-溴-N 1-甲基苯-1,2-二胺
氮气保护下，向5-溴-N-甲基-2-硝基苯胺(9.0g，38.95mmol)的四氢呋喃(300mL)溶液中，加入雷尼镍(1.67g)。该反应液用氢气置换数次后，在50Psi，25℃下反应5小时。反应液过滤，滤液浓缩后得到标题化合物。
1H NMR(400MHz,CHLOROFORM-d)δ＝6.79(dd,J＝2.1,8.2Hz,1H),6.75(d,J＝2.0Hz,1H),6.59(d,J＝8.0Hz,1H),2.87(s,3H).
步骤C：7-溴-1-甲基喹喔啉-2,3(1H,4H)-二酮
氮气保护下，在0℃时向5-溴-N-1-甲基苯-1,2-二胺(7.7g,38.3mmol)和三乙胺(9.69g,95.75mmol)的1,2-二氯乙烷(80mL)中加入草酰氯单乙酯(6.27g，45.96mmol)。在25℃下搅拌2小时。升温至60℃，搅拌3小时。将反应液过滤，滤饼用水(20mL)洗涤2次。滤饼干燥后得到标题化合物。
1H NMR(400MHz,DMSO-d6)δ＝12.07(br.s.,1H),7.51(d,J＝1.2Hz,1H),7.33(dd,J＝1.6,8.2Hz,1H),7.07(d,J＝8.6Hz,1H),3.47(s,3H).
步骤D：7-(1-苄基-1H-吡唑-4-基)-1-甲基喹喔啉-2,3(1H,4H)-二酮
氮气保护下，向DMF(10mL)，二氧六环(10mL)和水(5mL)中，加入7-溴-1-甲基喹喔啉-2,3(1H,4H)-二酮(1.00g,3.92mmol)，1-苄基-4-(4,4,5,5-四甲基-1,3,2-二氧杂己硼烷-2-基)吡唑(1.23g,4.31mmol)，碳酸钾(1.08g,7.84mmol)和Pd(dppf)Cl 2(286.86mg,392.05μmol)。在100℃下搅拌5小时。反应液用水(100mL)淬灭，析出的固体过滤。滤饼通过柱层析得到标题化合物。
1H NMR(400MHz,DMSO-d6)δ＝12.01(s,1H),8.35(s,1H),8.00(s,1H),7.50(s,1H),7.44-7.24(m,6H),7.14(d,J＝8.2Hz,1H),5.35(s,2H),3.57(s,3H).
步骤E：7-(1-苄基-1H-吡唑-4-基)-3-溴-1-甲基喹喔啉-2(1H)-酮
氮气保护下，在0℃时向7-(1-苄基-1H-吡唑-4-基)-1-甲基喹喔啉-2,3(1H,4H)-二酮(500mg,1.5mmol)和三乙胺(152.23mg,1.50mmol)的1,2-二氯乙烷中加入三溴氧磷(1.29g，4.5mmol)。在80℃下搅拌5小时。反应液用饱和碳酸氢钠(100mL)淬灭，二氯甲烷(100mL)萃取2次。有机相用无水硫酸钠干燥，浓缩后的残余物通过柱层析得到标题化合物。
1H NMR(400MHz,DMSO-d6)δ＝8.55(s,1H),8.16(s,1H),7.76-7.66(m,2H),7.62(d,J＝8.2Hz,1H),7.43-7.08(m,5H),5.35(s,2H),3.69(s,3H).
步骤F：7-(1-苄基-1H-吡唑-4-基)-1-甲基-3-((4-吗啡啉苯基)氨基)喹喔啉-2(1H)-酮
氮气保护下，向1,4-二氧六环(10mL)中加入7-(1-苄基-1H-吡唑-4-基)-3-溴-1-甲基喹喔啉-2(1H)-酮(220.0mg,556.61μmol)，4-吗啡啉苯胺(128.97mg，723.59μmol)，碳酸铯(362.71mg,1.50mmol)和[2-(2-胺乙基)苯基]-氯-钯；二叔丁基-[2-(2,4,6-三异丙基苯基)苯基]磷酸盐(38.22mg，55.66μmol)。在70℃下搅拌3小时。反应液用水(40mL)淬灭，二氯甲烷(50mL)萃取2次。有机相用无水硫酸钠干燥，浓缩后的残余物通过高效液相色谱仪制备分离得到标题化合物。
1H NMR(400MHz,DMSO-d6)δ＝9.25(s,1H),8.39(s,1H),8.03(s,1H),7.97(d,J＝8.6Hz,2H),7.56(s,1H),7.51-7.40(m,2H),7.38-7.23(m,4H),6.93(d,J＝9.0Hz,2H),5.34(s,2H),3.72(br.s.,7H),3.06(br.s.,4H).
步骤G：1-甲基-3-((4-吗啡啉苯基)氨基)-7-(1H-吡唑-4-基)喹喔啉-2(1H)-酮
向7-(1-苄基-1氢-吡唑-4-基)-1-甲基-3-((4-吗啡啉苯基)氨基)喹喔啉-2(1氢)-酮(40.0mg,81.21μmol)的DMSO(2mL)溶液中加入叔丁醇钾(63.79mg,568.45μmol)。在25℃下搅拌18小时。反应液直接通过高效液相色谱仪制备分离(三氟乙酸添加剂)得到标题化合物26。
1H NMR(400MHz,DMSO-d6)δ＝9.31(br.s.,1H),8.17(s,2H),7.99(d,J＝8.6Hz,2H),7.60(s,1H),7.56-7.49(m,1H),7.45(d,J＝8.2Hz,1H),6.98(d,J＝8.2Hz,2H),3.73(br.s.,8H),3.09(br.s.,3H).
实施例27：1-甲基-3-((4-吗啡啉苯基)氨基)-7-(1H-吡唑-3-基)喹喔啉-2(1H)-酮
Figure PCTCN2018091269-appb-000080
步骤A：7-(1-苄基-1H-吡唑-3-基)-1-甲基喹喔啉-2,3(1H,4H)-二酮
氮气保护下，向DMF(10mL)，二氧六环(10mL)和水(5mL)中，加入7-溴-1-甲基喹喔啉-2,3(1氢,4氢)-二酮(1.00g,3.92mmol)，1-苄基-3-(4,4,5,5-四甲基-1,3,2-二氧杂己硼烷-2-基)吡唑(1.45g,5.10mmol)，碳酸钾(1.08g,7.84mmol)和Pd(dppf)Cl 2(286.86mg,392.0μmol)。在100℃下搅拌5小时。反应液用水(100mL)淬灭，析出的固体过滤。滤饼通过柱层析得到标题化合物。
1H NMR(400MHz,DMSO-d6)δ＝12.05(br.s.,1H),7.87(br.s.,1H),7.65-7.55(m,2H),7.35-7.11(m,6H),6.81(br.s.,1H),5.36(s,2H),3.54(s,3H).
步骤B：7-(1-苄基-1H-吡唑-3-基)-3-溴-1-甲基喹喔啉-2(1H)-酮
氮气保护下，在0℃时向7-(1-苄基-1H-吡唑-3-基)-1-甲基喹喔啉-2,3(1H,4H)-二酮(700mg,2.11mmol)和三乙胺(213.51mg,2.11mmol)的1,2-二氯乙烷(20mL)中加入三溴氧磷(1.81g，6.33mmol)。在80℃下搅拌5小时。反应液用饱和碳酸氢钠(100mL)淬灭，二氯甲烷(100mL)萃取2次。有机相用无水硫酸钠干燥，浓缩后的残余物通过柱层析得到标题化合物。
1H NMR(400MHz,DMSO-d6)δ＝7.94(d,J＝2.3Hz,1H),7.87-7.79(m,2H),7.78-7.74(m,1H),7.38-7.21(m,5H),7.02(d,J＝2.3Hz,1H),5.40(s,2H),3.70(s,3H).
步骤C：7-(1-苄基-1H-吡唑-3-基)-1-甲基-3-((4-吗啡啉苯基)氨基)喹喔啉-2(1H)-酮
氮气保护下，向1,4-二氧六环(10mL)中加入7-(1-苄基-1H-吡唑-3-基)-3-溴-1-甲基喹喔啉-2(1H)-酮(300.0mg,759.01μmol)4-吗啡啉苯胺(175.86mg，986.71μmol)，碳酸铯(494.60mg,1.52mmol)和[2-(2-胺乙基)苯基]-氯-钯；二叔丁基-[2-(2,4,6-三异丙基苯基)苯基]磷酸盐(52.12mg，75.9μmol)。在70℃下搅拌3小时。反应液用水(40mL)淬灭，二氯甲烷(50mL)萃取2次。有机相用无水硫酸钠干燥，浓缩后的残余物通过柱层析得到标题化合物。
1H NMR(400MHz,DMSO-d6)δ＝9.36(s,1H),8.01(d,J＝9.0Hz,2H),7.93(d,J＝2.3Hz,1H),7.77-7.69(m,2H),7.50(d,J＝8.3Hz,1H),7.40-7.26(m,5H),6.97(d,J＝9.0Hz,2H),6.90(d,J＝2.3Hz,1H),5.42 (s,2H),3.80-3.71(m,7H),3.12-3.06(m,4H).
步骤D：1-甲基-3-((4-吗啡啉苯基)氨基)-7-(1H-吡唑-3-基)喹喔啉-2(1H)-酮
向7-(1-苄基-1H-吡唑-3-基)-1-甲基-3-((4-吗啡啉苯基)氨基)喹喔啉-2(1H)-酮(100.0mg,203.02μmol)的DMSO(5mL)溶液中加入叔丁醇钾(159.47mg,1.42mmol)。在25℃下搅拌18小时。反应液浓缩后，残余物通过高效液相色谱仪制备分离(三氟乙酸添加剂)得到标题化合物27。
1H NMR(400MHz,DMSO-d6)δ＝3.13(br.s.,4H)，3.48-3.64(m,7H)，6.82(br.s.,1H)，7.03(br.s.,2H)，7.50(br.s.,1H)，7.61-7.85(m,3H)，8.00(d,J＝7.83Hz,2H)，9.45(br.s.,1H)。
实施例28：1-甲基-3-((4-吗啡啉苯基)氨基)-7-(吡啶-4-基)喹喔啉-2(1H)-酮
Figure PCTCN2018091269-appb-000081
实施例28的制备可参考实施例27的制备方法制备得到。
1H NMR(400MHz,CHLOROFORM-d)δ＝8.93(d,J＝6.3Hz,1H),8.64(s,1H),8.09(d,J＝6.0Hz,2H),8.00(d,J＝9.0Hz,2H),7.87(d,J＝8.5Hz,1H),7.73(d,J＝9.8Hz,1H),7.60(s,1H),7.25(d,J＝9.0Hz,2H),4.05-4.00(m,4H),3.92(s,3H),3.38-3.32(m,4H).
MS-ESI(m/z):414(M+H)+.
实施例29：1-甲基-7-(5-甲基-1H-吡唑-4-基)-3-((4-吗啡啉苯基)氨基)喹喔啉-2(1H)-酮
Figure PCTCN2018091269-appb-000082
步骤A：1-甲基-3-((4-吗啡啉苯基)氨基)-7-(4,4,5,5-四甲基-1,3,2-二氧杂己硼烷-2-基)喹喔啉-2(1H)-酮
氮气保护下，向7-溴-1-甲基-3-((4-吗啡啉苯基)氨基)喹喔啉-2(1H)-酮(2.00g,4.82mmol)的DMF(30mL)中加入双联频哪醇硼酸酯(1.84g,7.23mmol)，乙酸钠(1.19g,14.46mmol)和Pd(dppf)Cl 2(352.68mg,482μmol)。在100℃下搅拌5小时。反应液用水(100mL)淬灭，乙酸乙酯(30mL)萃取三次。合并有机相，饱和食盐水(100mL)洗涤。过滤，浓缩后残余物通过柱层析得到标题化合物。
1H NMR(400MHz,CHLOROFORM-d)δ＝8.41(s,1H),7.86(d,J＝8.8Hz,2H),7.72(d,J＝8.0Hz,1H),7.67(s,1H),7.65-7.60(m,1H),6.95(d,J＝9.0Hz,2H),3.92-3.85(m,4H),3.83-3.79(m,3H),3.18-3.10(m,4H),1.40-1.33(m,12H).
步骤B：1-甲基-7-(5-甲基-1H-吡唑-4-基)-3-((4-吗啡啉苯基)氨基)喹喔啉-2(1H)-酮
氮气保护下，1-甲基-3-((4-吗啡啉苯基)氨基)-7-(4,4,5,5-四甲基-1,3,2-二氧杂己硼烷-2-基)喹喔啉-2(1H)-酮、5-甲基-1H-吡唑(41.79mg,259.55μmol)，碳酸钾(89.68mg,648.87mmol)和Pd(dppf)Cl 2(15.83mg,21.63μmol)。在80℃下搅拌5小时。反应液过滤，滤液浓缩后残余物通过高效液相制备分离得到标题化合物29。
1H NMR(400MHz,DMSO-d6)δ＝9.43(br.s.,1H),8.17-7.86(m,3H),7.62-7.31(m,3H),7.05(br.s.,2H),3.90-3.63(m,7H),3.15(br.s.,4H)2.44(br.s.,3H)。
MS-ESI(m/z):417(M+H)+
实施例30-32的制备可参考实施例29的制备方法制备得到：
Figure PCTCN2018091269-appb-000083
Figure PCTCN2018091269-appb-000084
实施例33：1-甲基-3((4-(4-甲基哌嗪-1-基)苯基)氨基)-7-(1H-吡唑-4-基)喹喔啉-2(1H)-酮
Figure PCTCN2018091269-appb-000085
步骤A：1-甲基-4-(4-硝基苯基)哌嗪
将碳酸钾(10.77g,77.96mmol)加入到1-氟-4-硝基苯(10.00g,70.87mmol)的二甲亚砜(25mL)的溶液中，在室温搅拌半小时。再向反应液中滴加1-甲基哌嗪(7.17g,71.58mmol)，在室温搅拌16小时。向反应液中加入水(300mL)，有固体析出，过滤，旋干得到标题化合物。
1H NMR(400MHz,DMSO-d6):δ＝8.04(d,J＝9.3Hz,2H),7.02(d,J＝9.3Hz,2H),3.46-3.41(m,4H),2.44-2.39(m,4H),2.21(s,3H).
步骤B：4-(4-甲基哌嗪-1-基)苯胺
向1-甲基-4-(4-硝基苯基)哌嗪(5.00g,22.60mmol)的乙酸乙酯(80mL)溶液中加入10％钯炭(2.00g)，用氢气球置换三次，在室温搅拌16小时。用硅藻土过滤，用二氯甲烷和甲醇(200mL)淋洗五次，旋干得到标题化合物。
1H NMR(400MHz,DMSO-d6):δ＝6.67(d,J＝8.8Hz,2H),6.48(d,J＝8.6Hz,2H),4.54(s,2H),2.93-2.80(m,4H),2.46-2.36(m,4H),2.19(s,3H).
步骤C：7-(1-苯基-1H-吡唑-4-基)-1-甲基-3((4-(4-甲基哌嗪-1-基)苯基)氨基)喹喔啉-2(1H)-酮
将4-(4-甲基哌嗪-1-基)胺(48.39mg,253.00μmol)和DIEA(98.09mg,759.00μmol)加入到7-(1-苯基吡唑-4-基)-3-溴-1-甲基-喹喔啉-2-酮(100.00mg,253.00μmol)的异丙醇(3mL)的溶液中，在氮气保护，115℃搅拌16小时。反应液冷却到室温，有固体析出，过滤，滤饼用乙醇(5mL)淋洗，旋干得到标题化合物。
1H NMR(400MHz,DMSO-d6)δ＝9.26(s,1H),8.41(s,1H),8.06(s,1H),7.97(d,J＝8.8Hz,2H),7.58(s,1H),7.50-7.43(m,2H),7.37-7.28(m,5H),6.94(d,J＝8.8Hz,2H),5.36(s,2H),3.74(s,3H),3.10(br.s.,4H),2.46(br.s.,4H),2.22(s,3H).
步骤D：1-甲基-3((4-(4-甲基哌嗪-1-基)苯基)氨基)-7-(1H-吡唑-4-基)喹喔啉-2(1H)-酮
在室温下，将叔丁醇钾的四氢呋喃溶液(1M,71.02mg,632.88μmol)加入到7-(1-苯基-1H-吡唑-4-基)-1-甲基-3((4-(4-甲基哌嗪-1-基)苯基)氨基)喹喔啉-2(1H)-酮(40.00mg,79.11μmol)的二甲亚砜(3mL)溶液中。在室温下，用氧气球置换三次，再搅拌16小时。向反应液中加入水(15mL)，用乙酸乙酯(15mL)萃取两次。有机相用饱和食盐水(20mL)洗两次，用无水硫酸钠干燥，过滤，减压浓缩得到的残余物通过制备分离(三氟乙酸)得到标题化合物33。
1H NMR(400MHz,DMSO-d6)δ＝9.35(s,1H),8.20(s,2H),8.04(d,J＝9.0Hz,2H),7.62(s,1H),7.56-7.51(m,1H),7.45(d,J＝8.4Hz,1H),7.02(d,J＝8.8Hz,2H),3.81(d,J＝13.2Hz,2H),3.76(s,3H),3.53(d,J＝11.7Hz,2H),3.18(d,J＝10.8Hz,2H),2.97-2.86(m,5H).
MS-ESI(m/z):416(M+H)+.
实施例34：1-甲基-3-((4-((4-甲基哌嗪-1-基)磺酰基)苯基)氨基)-7-(1H-吡唑-4-基)喹喔啉-2(1H)-酮
Figure PCTCN2018091269-appb-000086
步骤A：1-甲基-4-((4-硝基苯)磺酰基)哌嗪
0℃下，向1-甲基哌嗪(4.52g,45.12mmol)的吡啶(40mL)中加入4-硝基苯磺酰氯(10.00g，45.12mmol)的吡啶溶液(20mL)。反应液在0-20℃下搅拌2小时。水(200mL)淬灭，析出的固体过滤。滤饼用二氯甲烷/甲醇(22mL，10/1)重结晶后得到标题化合物。
1H NMR(400MHz,DMSO-d6):δ＝8.44(d,J＝8.8Hz,2H),8.00(d,J＝8.8Hz,2H),2.96(br.s,4H),2.36(t,J＝4.4Hz,4H),2.13(s,3H).
步骤B：4-((4-甲基哌嗪-1-基)磺酰基)苯胺
向1-甲基-4-((4-硝基苯)磺酰基)哌嗪(3.70g,12.97mmol)的甲醇(50.00mL)溶液中加入Pd/C(800mg)。反应液在氢气球(15Psi)、15℃下搅拌2小时。反应液过滤，滤液浓缩后得到标题化合物。
1H NMR(400MHz,DMSO-d6):δ＝7.33(d,J＝8.5Hz,2H),6.64(d,J＝8.5Hz,2H),6.08(s,2H),2.78(br.s.,4H),2.34(br.s.,4H),2.13(s,3H).
步骤C：7-(1-苄基-1H-吡唑-4-基)-1-甲基-3-((4-((4-甲基哌嗪-1-基)磺酰基)苯基)氨基)喹喔啉-2(1H)-酮
实施例34步骤C的制备可参考实施例33步骤C的制备方法。
1H NMR(400MHz,DMSO-d6)δ＝9.95(s,1H),8.51-8.42(m,2H),8.10(s,1H),7.73-7.63(m,3H), 7.59(d,J＝2.6Hz,2H),7.42-7.24(m,5H),5.38(s,2H),3.77(s,3H),2.88(br.s.,4H),2.36(br.s.,4H),2.13(s,3H).
步骤D：1-甲基-3-((4-((4-甲基哌嗪-1-基)磺酰基)苯基)氨基)-7-(1H-吡唑-4-基)喹喔啉-2(1H)-酮
实施例34步骤D的制备可参考实施例33步骤D的制备方法。
1H NMR(400MHz,DMSO-d6)δ＝10.02(s,1H),9.45-9.34(m,1H),8.51(d,J＝8.8Hz,2H),8.24(br.s.,2H),7.76(d,J＝8.4Hz,2H),7.69(s,1H),7.64-7.56(m,2H),3.79(s,5H),3.16(br.s.,6H),2.79(s,3H).
MS-ESI(m/z):480.2(M+H)+.
实施例35：3-((4-(1,1-二氧硫代吗啡啉)苯基)氨基)-1-甲基-7-(1H-吡唑-4-基)喹喔啉-2(1H)-酮
Figure PCTCN2018091269-appb-000087
实施例35的制备可参考实施例33的制备方法得到。
1H NMR(400MHz,DMSO-d6)δ＝12.97(br s,1H),9.33(s,1H),8.32(s,1H),8.04(br d,J＝9.0Hz,3H),7.61(d,J＝1.3Hz,1H),7.56-7.51(m,1H),7.47-7.43(m,1H),7.05(d,J＝9.3Hz,2H),3.75(s,7H),3.14(br s,4H).
LCMS(ESI)m/z:451(M+1).
实施例36：3-((4-(4-(乙磺酰基)哌嗪-1-基)苯基)氨基)-1-甲基-7-(1H-吡唑-4-基)喹喔啉-2(1H)-酮
Figure PCTCN2018091269-appb-000088
实施例36的制备可参考实施例33的制备方法得到。
1H NMR(400MHz,DMSO-d6)δ＝9.35(s,1H),8.20(s,2H),8.01(d,J＝8.8Hz,2H),7.61(s,1H),7.54(d,J＝8.0Hz,1H),7.46(d,J＝8.0Hz,1H),7.01(d,J＝8.0Hz,2H),3.75(s,3H),3.33(br s,4H)，3.19(br s,4H)，3.10～3.22(m,2H),1.22～1.26(m,3H).
LCMS(ESI)m/z:494.1(M+1).
实施例37：1-甲基-3-((4-(4-甲基-1,4-二氮杂庚烷-1-基)苯基)氨基)-7-(1H-吡唑-4-基)喹喔啉-2(1H)-酮
Figure PCTCN2018091269-appb-000089
实施例37的制备可参考实施例33的制备方法得到。
1H NMR(400MHz,DMSO-d6)δ＝9.35(s,1H),8.20(s,2H),8.04(d,J＝9.0Hz,2H),7.62(s,1H),7.56-7.51(m,1H),7.45(d,J＝8.4Hz,1H),7.02(d,J＝8.8Hz,2H),3.80(br,5H),3.52～3.65(m,4H),3.32～3.39(m,2H),2.95(s,3H),2.25-2.29(m,2H).
MS-ESI(m/z):429(M+H) +.
实施例38：1-甲基-3-((4-(哌啶-1-基磺酰基)苯基)氨基)-7-(1H-吡唑-4-基)喹喔啉-2(1H)-酮
Figure PCTCN2018091269-appb-000090
实施例38的制备可参考实施例34的制备方法得到。
1H NMR(400MHz,DMSO-d6)δ＝9.93(s,2H),8.45(d,J＝8.6Hz,2H),8.24(br.s.,1H),7.74-7.53(m,5H),3.78(s,3H),2.87(br.s.,4H),1.54(br.s.,4H),1.35(br.s.,2H)。
实施例39：1-甲基-3-((4-(哌嗪-1-基)苯基)氨基)-7-(1H-吡唑-4-基)喹喔啉-2(1H)-酮
Figure PCTCN2018091269-appb-000091
实施例39的制备可参考实施例33的制备方法得到。
1H NMR(400MHz,DMSO-d6)δ＝9.35(s,1H),8.76(s,2H),8.20(s,2H),8.03(d,J＝8.8Hz,2H),7.62(s,1H),7.54(d,J＝8.4Hz,1H),7.45(d,J＝8.0Hz,1H),7.01(d,J＝8.8Hz,2H),3.75(s,3H),3.28(d,J＝16.0Hz,8H).
LCMS(ESI)m/z:402.1(M+1).
实施例40：1-甲基-3-((3-(4-(甲磺酰基)哌嗪-1-基)苯基)氨基)-7-(1H-吡唑-4-基)喹喔啉-2(1H)-酮
Figure PCTCN2018091269-appb-000092
实施例40的制备可参考实施例33的制备方法得到。
1H NMR(400MHz,DMSO-d6)δ＝12.99(br.s.,1H),9.28(br.s.,1H),8.34(br.s.,1H),8.07(br.s.,1H),7.87(br.s.,1H),7.70(d,J＝7.7Hz,1H),7.64(br.s.,1H),7.54(br.s.,2H),7.21(t,J＝8.0Hz,1H),6.69(d,J＝7.5Hz,1H),3.76(s,3H),3.33(s,8H),2.94(s,3H).
实施例41：5-氯-1-甲基-3-((4-吗啡啉苯基)氨基)-7-(1H-吡唑-4-基)喹喔啉-2(1H)-酮
Figure PCTCN2018091269-appb-000093
步骤A：5-溴-1,3-二氯-2-硝基苯
20℃下，向4-溴-2,6-二氯-苯胺(10g,41.51mmol)的二氯乙烷(250mL)溶液中中分批加入80％间氯过氧苯甲酸(35.82g,166mmol)，室温搅拌一小时后加热至70℃反应8小时。TLC显示原料反应完全。降温，向反应液中缓慢加入饱和硫代硫酸钠水溶液(350mL)淬灭后，加入二氯甲烷280mL萃取。有机相用2M氢氧化钠水溶液(150mL)和饱和食盐水洗涤，无水硫酸钠干燥，过滤，旋干后得到目标化合物5-溴-1,3-二氯-2-硝基苯。
步骤B：5-溴-3-氯-N-甲基-2-硝基苯
0℃下，向5-溴-1,3-二氯-2-硝基苯(6g,22.15mmol)的DMF(150mL)溶液中中分别加入三乙胺(3.07mL,22.15mmol)和甲胺溶液(2M,22.15mL，44.3mmol)，室温搅拌一小时后加热至50℃反应6小时。TLC显示原料反应完全。降温，向反应液中加入水(100mL)和乙酸乙酯萃取(150mL)。有机相用饱和食盐水洗涤，无水硫酸钠干燥，过滤，旋干后得到目标化合物5-溴-3-氯-N-甲基-2-硝基苯。
步骤C：5-溴-3-氯-N1-甲苯-1,2-二胺
向5-溴-3-氯-N-甲基-2-硝基苯(2.5g,22.15mmol)的乙醇(50mL)和水(50mL)的溶液中分批加入铁粉(3.16g,56.5mmol)和乙酸(0.56g,9.42mmol)，室温搅拌一小时后加热至60℃反应4小时。TLC显示原料反应完全。降温，过滤，向滤液中加入乙酸乙酯(150mL)萃取三次。有机相用饱和食盐水洗涤，无水硫酸钠干燥，过滤，旋干后得到目标化合物5-溴-3-氯-N1-甲苯-1,2-二胺。
步骤D：7-溴-5-氯-1-甲基喹喔啉-2,3(1H,4H)-二酮
0℃下，往5-溴-3-氯-N1-甲苯-1,2-二胺(1.2g,5.1mmol)的1,2-二氯乙烷(130.00mL)溶液中加入三乙胺(0.52g,5.1mmol)和乙基-2-氯-2-氧代乙酸酯(1.04g,7.65mmol)。15℃搅拌12小时后TLC显示原料反应完全。反应液浓缩后使用20mL乙酸乙酯洗涤两次得到7-溴-5-氯-1-甲基喹喔啉-2,3(1H,4H)-二酮。
1H NMR(DMSO-d6,400MHz):d＝11.56(br.s.,1H),7.55(dd,J＝12.3,1.8Hz,2H),3.50ppm(s,3H).步骤E：7-(1-苄基-1H-吡唑-4-基)-5-氯-1-甲基喹喔啉-2,3(1H,4H)-二酮
7-溴-5-氯-1-甲基喹喔啉-2,3(1H,4H)-二酮(3.50g,12.09mmol)和1-苄基-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)吡唑(3.78g,13.3mmol)的DMF(20mL)，二氧六环(20.00mL)和水(10.00mL)溶液中加入Pd(dppf)Cl2(0.88mg,1.21mmol)和碳酸钾(5.01g,36.27mmol)。100℃搅拌2小时后TLC显示原料反应完全。反应液浓缩后加入二氯甲烷(100mL)和水(50mL)。水相使用100mL二氯甲烷萃取三次。有机相饱和食盐水洗涤，无水硫酸钠干燥，过滤，旋干后硅胶柱层析得到7-(1-苄基-1H-吡唑-4-基)-5-氯-1-甲基喹喔啉-2,3(1H,4H)-二酮。
1H NMR(CHLOROFORM-d,400MHz):d＝9.12(br.s.,1H),7.82(s,1H),7.67(s,1H),7.34-7.44(m,4H),7.29-7.32(m,2H),7.18(d,J＝1.5Hz,1H),5.37(s,2H),3.71ppm(s,3H).
步骤F：7-(1-苄基-1H-吡唑-4-基)-3,5-二氯-1-甲基喹喔啉-2(1H)-酮
0℃下7-(1-苄基-1H-吡唑-4-基)-5-氯-1-甲基喹喔啉-2,3(1H,4H)-二酮(1.2g,3.27mmol)的甲苯(35.00mL)溶液中加入N,N-二甲基乙二胺(0.43g,3.27mmol)和三氯氧磷(1g,6.54mmol)。100℃下搅拌3小时后，TLC显示原料反应完全。降温至0℃，向反应液中缓慢加入饱和碳酸氢钠水溶液(200mL)淬灭后，加入二氯甲烷120mL萃取。有机相用饱和食盐水洗涤，无水硫酸钠干燥，过滤，旋干后得到目标化合物7-(1-苄基-1H-吡唑-4-基)-3,5-二氯-1-甲基喹喔啉-2(1H)-酮。
1H NMR(CHLOROFORM-d,400MHz):d＝7.90(s,1H),7.74(s,1H),7.55(d,J＝1.3Hz,1H),7.34-7.44(m,3H),7.30(d,J＝6.5Hz,2H),7.23(d,J＝1.3Hz,1H),5.38(s,2H),3.79ppm(s,3H).
步骤G：7-(1-苄基-1H-吡唑-4-基)-5-氯-1-甲基-3-((4-吗啡啉苯基)氨基)喹喔啉-2(1H)-酮
20℃下，7-(1-苄基-1H-吡唑-4-基)-3,5-二氯-1-甲基喹喔啉-2(1H)-酮(700.00mg,1.82mmol)和4-吗啡啉苯胺(647mg,3.63mmol)的乙腈(5.00mL)溶液中搅拌。反应液在100℃下搅拌4小时。反应液浓缩后分别加入1M盐酸(50mL)和二氯甲烷DCM(50mL)萃取三次。有机相用饱和食盐水洗涤，无水硫酸钠干燥，过滤，旋干后得到目标化合物得到7-(1-苄基-1H-吡唑-4-基)-5-氯-1-甲基-3-((4-吗啡啉苯基)氨基)喹喔啉-2(1H)-酮。
MS-ESI(m/z):527.0(M+H).
步骤H：5-氯-1-甲基-3-((4-吗啡啉苯基)氨基)-7-(1H-吡唑-4-基)喹喔啉-2(1H)-酮
20℃下，7-(1-苄基-1H-吡唑-4-基)-5-氯-1-甲基-3-((4-吗啡啉苯基)氨基)喹喔啉-2(1H)-酮(100.00mg,189.75μmol)的DMSO(5.00mL)溶液中加入叔丁醇钾的四氢呋喃溶液(127.75mg,1.14mmol)在氧气氛中搅拌一小时。LCMS显示原料反应完全。反应液浓缩后倒入10mL水中，15mL乙酸乙酯萃取3次。有机相饱和食盐水洗涤，无水硫酸钠干燥，旋干后制备分离(三氟乙酸体系)得到5-氯-1-甲基-3-((4-吗啡啉苯基)氨基)-7-(1H-吡唑-4-基)喹喔啉-2(1H)-酮(化合物41)。
1H NMR(DMSO-d6,400MHz):d＝9.89(br.s.,1H),8.44(d,J＝8.0Hz,2H),8.33(s,2H),7.80(s,1H), 7.63(br.s.,3H),4.02(br.s.,4H),3.76(s,3H),3.48ppm(br.s.,4H).
MS-E SI(m/z):437.1(M+H).
实施例42：6-氯-1-甲基-3-((4-吗啡啉苯基)氨基)-7-(1H-吡唑-4-基)喹喔啉-2(1H)-酮
Figure PCTCN2018091269-appb-000094
步骤A：5-溴-N-甲基2-硝基苯胺
0℃氮气保护下,向5-溴-N-甲基2-硝基苯胺(30g，136.36mmol)，碳酸钾(28.27g，204.54mmol)的DMF(500mL)溶液中滴加甲胺的四氢呋喃溶液(2M，81.82mL)在25℃下搅拌2小时后，反应液倒入冰水(1000mL)中，搅拌10分钟，过滤，滤饼用水(50mL×2)洗涤，提供标题化合物。
1H NMR(400MHz,CHLOROFORM-d)δ＝8.03(d,J＝9.0Hz,2H),7.01(d,J＝1.3Hz,1H),6.77(dd,J＝1.7,9.2Hz,1H),3.02(d,J＝5.1Hz,3H).
步骤B：5-溴-4-氯-N-甲基-2-硝基苯胺
25℃下，向实施例42A(20g，86.56mmol)，NCS(11.79g，88.29mmol)的DMF(300mL)在40℃反应18小时，用水(500mL)稀释水层用乙酸乙酯(500mL×2)萃取。合并的有机层用盐水(1000mL)洗涤后，用硫酸钠干燥，过滤并蒸发，残余物通过柱色谱纯化得到标题化合物。
1H NMR(400MHz,CHLOROFORM-d)δ＝7.94(br.s.,1H),7.26(s,1H),7.15(s,1H),3.02(d,J＝5.1Hz,3H).
步骤C：5-溴-4-氯-N1-甲基苯-1,2-联氨
25℃氮气保护下，实施例42B(4g，15.07mmol)的乙醇(80mL)溶液中加入锌粉(4.93g，75.33mmol)和甲酸胺(4.75g，75.33mmol)，在50℃下搅拌2小时后，反应液被过滤，滤饼用二氯甲烷(100mL)洗涤，滤液被水(50mL)洗，有机层用饱和食盐水(100mL)洗，再用硫酸钠干燥，过滤并蒸发，提供标题化合物。
1H NMR(400MHz,CHLOROFORM-d)δ＝6.78(s,2H),3.40-3.30(m,2H),2.83(s,3H).
步骤D：7-溴-6-氯-1-甲基喹喔啉-2,3(1H,4H)-二酮
0℃下，向实施例42C(3.4g，14.44mmol)，三乙胺(3.65g，36.10mmol)的1,2—二氯乙烷(60mL)中滴加乙基2-氯-2-氧-醋酸盐(2.37g，17.33mmol)，在25℃反应2小时，等有白色固体形成后，在60℃反应3小时，反应液被过滤，滤饼用水(50×2mL)洗涤，滤饼被减压蒸发得到标题化合物。
1H NMR(400MHz,DMSO-d6)δ＝12.08(br.s.,1H),7.66(s,1H),7.26(s,1H),3.46(s,3H).
步骤E：7-(1-苄基-1H-吡唑-4-基)-6氯-1-甲基喹喔啉-2,3(1H,4H)-二酮
氮气保护下，实施例42D(1g，3.45mmol)，1-苄基-4-(4,4,5,5-四甲基1,3,2-二氧杂己硼烷-2-基)吡唑(1.08g，3.8mmol)，Pd(dppf)Cl 2(282.08mg,345.41μmol),碳酸钾(954.79mg,6.91mmol)的DMF(15.00mL)二氧六环(15.00mL)和水(5.00mL)中，混合物100℃搅拌5小时。冷却至室温，用水(100mL)稀释,过滤。滤饼通过柱色谱纯化得到标题化合物。
1H NMR(400MHz,DMSO-d6)δ＝12.06(s,1H),8.36(s,1H),7.95(s,1H),7.43(s,1H),7.38-7.26(m,5H),7.22(s,1H),5.38(s,2H),3.53(s,3H).
步骤F：7-(1-苄基-1H-吡唑-4-基)-3,6-二氯-1-甲基喹喔啉-2(1H)-酮
0℃氮气保护下，实施例42E(900mg，2.45mmol)和DIEA(265.98mg，2.06mmol)的甲苯(9mL)溶液中加入三氯氧磷(589.78g，3.85mmol)，在110℃下搅拌2小时后，反应液缓慢倒入碳酸氢钠水溶液(50mL)中，搅拌10分钟，二氯甲烷(50mL×2)萃取，有机层用饱和食盐水(100mL)洗，再用硫酸钠干燥，过滤并蒸发，通过柱色谱纯化得到标题化合物。
1H NMR(400MHz,DMSO-d6)δ＝8.56(s,1H),8.12(s,1H),7.92(s,1H),7.69(s,1H),7.39-7.33(m,2H),7.33-7.26(m,3H),5.41(s,2H),3.69(s,3H).
步骤G：7-(1-苄基-1H-吡唑-4-基)-6-氯-1-甲基-3-((4-吗啡啉苯基)氨基)喹喔啉-2(1H)-酮
氮气保护下,向实施例42F(100mg，259.57μmol)，4-吗啡啉苯胺(92.53mg，519.14μmol)的乙腈(2mL)，该混合物在80℃反应18小时，反应液被减压蒸发，残渣通过柱色谱纯化得到标题化合物。
1H NMR(400MHz,DMSO-d6)δ＝9.47(s,1H),8.41(s,1H),8.03-7.91(m,3H),7.53(d,J＝11.2Hz,2H),7.41-7.22(m,5H),6.94(d,J＝9.0Hz,2H),5.40(s,2H),3.79-3.66(m,7H),3.11-3.02(m,4H).
步骤H：6-氯-1-甲基-3-((4-吗啡啉苯基)氨基)-7-(1H-吡唑-4-基)喹喔啉-2(1H)-酮
氧气保护下，实施例42G(80mg，151.80μmol)，t-BuOK(1M，1.06mL)，DMSO(1.00mL)，混合物25℃搅拌4小时。反应液倒入冰水(10mL)稀释,搅拌10分钟，用1M盐酸调节pH为8。用二氯甲烷(10mL×2)萃取，有机层用饱和食盐水(20mL)洗，再用硫酸钠干燥，过滤并蒸发，残余物通过制备型HPLC纯化得到标题化合物42。
LCMS(ESI)m/z:437.1(M+1)。
1H NMR(400MHz,DMSO-d6)δ＝9.48(s,1H),8.10(s,2H),7.98(d,J＝8.8Hz,2H),7.51(d,J＝13.5Hz,2H),6.96(d,J＝8.8Hz,2H),3.73(br.s.,4H),3.69(s,3H),3.08(br.s.,4H).
实施例43：8-氯-1-甲基-3-((4-吗啡啉苯基)氨基)-7-(1H-吡唑-4-基)喹喔啉-2(1H)-酮
Figure PCTCN2018091269-appb-000095
实施例43的制备可参考实施例42的制备方法得到。
1H NMR(400MHz,DMSO-d6)δ＝9.53(s,1H),8.06-7.94(m,4H),7.43(s,2H),7.01(d,J＝9.0Hz,2H),3.90(s,3H),3.76(d,J＝4.8Hz,4H),3.15-3.10(m,4H).
LCMS(ESI)m/z:437.1(M+1).
实施例44：5-氟-1-甲基-3-((4-吗啡啉苯基)氨基)-7-(1H-吡唑-4-基)喹啉-2(1H)-酮
Figure PCTCN2018091269-appb-000096
步骤A：5-溴-3-氟-N-甲基-2-硝基苯
在0℃下，将甲胺(21.01mL,2.0mol/L)加入到5-溴-1，3-二氟-2-硝基苯(10.00g,42.02mmol) 的DMF(100.00mL)溶液中。反应液在0℃到室温下搅拌16小时。将反应液倒入水(500.00mL)中，用乙酸乙酯(500.00mL)萃取两次。有机相用饱和食盐水(500mL)洗两次，用无水硫酸钠干燥，减压旋干得到残余物用柱色谱分离得到标题化合物。
1H NMR(400MHz,DMSO-d6)δ＝7.56(d,J＝4.3Hz,1H),6.93-6.85(m,2H),2.86(d,J＝5.0Hz,3H).
步骤B：5-溴-3-氟-N1-甲基苯-1，2-二氨
将铁粉(11.17g,199.98mmol)和醋酸(2.00g,33.33mmol)加入到5-溴-3-氟-N-甲基-2-硝基苯(8.30g,33.33mmol)的乙醇(80mL)和水(80mL)的溶液中，在60℃下搅拌3小时。反应液过滤，将滤液浓缩，用乙酸乙酯(80.00mL)萃取三次。有机相用饱和食盐水(80mL)洗两次，用无水硫酸钠干燥，，有固体析出，过滤，旋干固体得到标题化合物。
1H NMR(400MHz,DMSO-d6)δ＝6.69-6.47(m,1H),6.36-6.18(m,1H),5.27(br.s.,1H),4.54(br.s.,2H),2.78-2.61(m,3H).
步骤C：7-溴-5-氟-1-甲基喹喔啉-2，3(1H,4H)-二酮
在0℃，氮气保护下，将草酰氯单乙酯(4.36g,31.96mmol)滴加到5-溴-3-氟-N1-甲基苯-1，2二氨(7.00g，31.96mmol)和三乙胺(8.08g，79.89mmol)的1,2-二氯乙烷(70.00mL)溶液中，在室温下反应2小时，有白色固体析出，再将其加热到60℃搅拌3小时。将反应液冷却到室温，过滤，滤饼用水(40mL)洗两次，将其滤饼旋干得到的残余物用乙酸乙酯打浆得到标题化合物。
步骤D：7-(1-苄基-1H-吡唑-4-基)-5-氟-1-甲基喹喔啉-2，3(1H,4H)-二酮
在氮气保护，室温下，将1-苄基-4-嚬那醇硼酸酯吡唑(1.04g,3.66mmol)，碳酸钾(1.01g,7.32mmol)和Pd(dppf)Cl2(267.96mg,366.22mmol，1.01mL)加入到7-溴-5-氟-1-甲基喹喔啉-2，3(1H,4H)-二酮(1.00g,3.66mmol)的二氧六环(30mL)和水(6mL)溶液中，在氮气保护下，100℃搅拌4小时。反应液冷却到室温，向反应液中加入水(100mL)，用二氯甲烷(100mL)萃取两次。有机相用饱和食盐水(100mL)洗两次，用无水硫酸钠干燥，过滤，旋干。用乙酸乙酯打浆得到标题化合物。
1H NMR(400MHz,DMSO-d6)δ＝8.30(s,1H),7.95(s,1H),7.38-7.25(m,5H),7.19-7.10(m,2H),5.33(s,2H),3.61-3.52(m,3H).
步骤E：7-(1-苄基-1H-吡唑-4-基)-3-溴-5-氟-1-甲基喹喔啉-2(1H)-酮
在0℃下，将三溴氧磷(368.23mg,1.28mmol)滴加到7-(1-苄基-1H-吡唑-4-基)-5-氟-1-甲基喹喔啉-2，3(1H,4H)-二酮(300.00mg,856.29μmol)和DIEA(88.53mg,685.03μmol)的甲苯(8mL)溶液中，在氮气保护下，110℃搅拌1.5小时。反应液用硅藻土过滤，向滤液中加入水(10mL)，用乙酸乙酯(10mL)萃取三次。有机相用饱和食盐水(15mL)洗两次，用无水硫酸钠干燥，过滤，旋干得到标题化合物。
1H NMR(400MHz,CHLOROFORM-d)δ＝8.62(s,1H),8.23(s,1H),7.62(d,J＝7.3Hz,1H),7.56(s,1H),7.37-7.29(m,5H),5.42-5.33(m,2H),3.70(s,3H)。
步骤F：7-(1-苄基-1H-吡唑-4-基)-5-氟-1-甲基-3-((4-吗啡啉苯基)氨基)喹喔啉-2(1H)-酮
在室温下，将7-(1-苄基-1H-吡唑-4-基)-3-溴-5-氟-1-甲基喹喔啉-2(1H)-酮(100mg,241.99μmol)溶于甲苯(5mL)，再在氮气保护下，向其加入4-吗啡啉苯胺(51.76mg,290.39μmol)，碳酸铯(236.54mg,725.97μmol)，Xphos(23.07mg,48.40μmol)和Pd2(dba)3(22.16mg,24.20μmol)。在氮气保护下，100℃搅拌4小时。反应液冷却到室温，向反应液中加入水(15mL)，用二氯乙烷(15mL)萃取两次。有机相用饱和食盐水(20mL)洗两次，用无水硫酸钠干燥，过滤，减压浓缩得到的残余物通过柱分离得到标题化合物。
1H NMR(400MHz,DMSO-d6)δ＝9.48(d,J＝6.8Hz,1H),8.47(d,J＝6.8Hz,1H),8.12-8.03(m,3H),7.48-7.27(m,6H),6.96(br.s.,2H),5.36(d,J＝6.0Hz,2H),3.73(d,J＝6.5Hz,7H),3.08(br.s.,4H).
步骤G：5-氟-1-甲基-3-((4-吗啡啉苯基)氨基)-7-(1H-吡唑-4-基)喹喔啉-2(1H)-酮
在室温下，将7-(1-苄基-1H-吡唑-4-基)-5-氟-1-甲基-3-((4-吗啡啉苯基)氨基)喹喔啉-2(1H)-酮(30mg,58.76μmol)溶于二甲亚砜(3mL)，再在氮气保护下，向其加入叔丁醇钾(2mol，235.04μL)。再用氧气球置换三次。在氧气保护下，35℃搅拌3小时。反应液慢慢滴加到水(15mL)中，用乙酸乙酯(15mL)萃取两次。有机相用饱和食盐水(20mL)洗两次，用无水硫酸钠干燥，过滤，减压浓缩得到的残 余物通过制备分离(三氟乙酸)得到标题化合物44。
1H NMR(400MHz,DMSO-d6)δ＝9.49(br.s.,1H),8.24(s,2H),8.08(d,J＝8.5Hz,2H),7.55-7.45(m,2H),7.10-6.92(m,2H),3.74(br.s.,7H),3.12(br.s.,4H).
MS-ESI(m/z):421(M+H)+.
实施例45：6-氟-1-甲基-3-((4-吗啡啉苯基)氨基)-7-(1H-吡唑-4-基)喹喔啉-2(1H)-酮
Figure PCTCN2018091269-appb-000097
步骤A：5-溴-4-氟-N1-甲基-苯-1,2-联氨
0℃氮气保护下,向4-溴-5-氟-N2-甲基-苯-1,2-联氨(6g，24.09mmol)的乙醇(120mL)溶液中加入锌粉(7.88g，120.45mmol)和甲酸胺(7.6g，120.45mmol)，在50℃下搅拌2小时后，反应液被过滤，滤饼用二氯甲烷(500mL)洗涤，滤液被水(200mL)洗，有机层用饱和食盐水(500mL)洗，再用硫酸钠干燥，过滤并蒸发，提供标题化合物。
步骤B：7-溴-6-氟-1-甲基喹喔啉-2,3(1H,4H)-二酮
0℃下，向实施例45A(4.65g，21.23mmol)，三乙胺(5.37g，53.08mmol)的1,2—二氯乙烷(120mL)中滴加乙基2-氯-2-氧-醋酸盐(3.48g，25.48mmol)，在25℃反应2小时，等有白色固体形成后，在60℃反应2小时，反应液被过滤，滤饼用水(50×2mL)洗涤，滤饼被减压蒸发得到标题化合物。
LCMS(ESI)m/z:273(M+1).
1H NMR(400MHz,DMSO-d6)δ＝12.14(s,1H),7.65(d,J＝6.3Hz,1H),7.06(d,J＝9.0Hz,1H),3.48(s,3H).
步骤C：3,7-二溴-6-氟-1-甲基-3,4-二氢喹喔啉-2(1H)-酮
氮气保护下，实施例45B(2.4g，8.79mmol)，三乙胺(1.33g，13.18mmol)，三溴氧磷(7.56g，26.37mmol)，的1,2—二氯乙烷(50mL)混合物在90℃下搅拌6小时后，反应液缓慢的倒入冷的碳酸氢钠(300mL)中，搅拌10分钟，混合物被过滤，滤饼减压旋干得到标题化合物。
LCMS(ESI)m/z:337(M+1).
1H NMR(400MHz,DMSO-d6)δ＝8.01(d,J＝6.3Hz,1H),7.89(d,J＝8.8Hz,1H),3.65(s,3H).
步骤D：7-溴-6-氟-1-甲基-3-((4-吗啡啉苯基)氨基)喹喔啉-2(1H)-酮
氮气保护下，向实施例45C(1.95g，5.80mmol)，醋酸钠(1.43g，17.41mmol)，4-吗啡啉苯胺(1.24g，6.97mmol)的异丙醇(30mL)溶液中，混合物在100℃反应12小时，混合物冷却至室温，过滤得到标题化合物。
1H NMR(400MHz,DMSO-d6)δ＝9.56(s,1H),7.96(br d,J＝8.8Hz,2H),7.73(br d,J＝6.0Hz,1H),7.41(br d,J＝9.8Hz,1H),6.94(br d,J＝8.8Hz,2H),3.74(br s,4H),3.67(s,3H),3.08(br s,4H).
步骤E：6-氟-1-甲基-3-((4-吗啡啉苯基)氨基)-7-(1H-吡唑-4-基)喹喔啉-2(1H)-酮
氮气保护下，实施例45D(2.3g，5.31mmol)，4-(4,4,5,5-四甲基1,3,2-二氧杂己硼烷-2-基)-1H-吡唑(1.55g，7.96mmol)，Pd(dppf)Cl 2(388.43mg,530.85μmol),碳酸钾(2.2mg,15.93mmol)的二氧六环 (40.00mL)和水(10.00mL)中，混合物120℃搅拌10小时。冷却至室温，用水(100mL)稀释水层用二氯甲烷(100mL×3)萃取。合并的有机层用盐水(100mL×2)洗涤后，用硫酸钠干燥，过滤并蒸发，残余物通过柱色谱纯化得到标题化合物45。
1H NMR(400MHz,DMSO-d6)δ＝13.12(br s,1H),9.40(s,1H),8.27(br s,1H),8.07(br s,1H),7.97(br d,J＝9.0Hz,2H),7.65(d,J＝7.0Hz,1H),7.31(d,J＝12.0Hz,1H),6.95(br d,J＝8.8Hz,2H),3.75(s,7H),3.10-3.06(m,4H)。LCMS(ESI)m/z:421(M+1).
实施例46：8-氟-1-甲基-3-((4-吗啡啉苯基)氨基)-7-(1H-吡唑-4-基)喹喔啉-2(1H)-酮
Figure PCTCN2018091269-appb-000098
实施例46的制备可参考实施例44的制备方法得到。
1H NMR(400MHz,DMSO-d6)δ＝9.48(br.s.,1H),8.08(br.s.,2H),8.00(d,J＝7.6Hz,2H),7.58(br.s.,1H),7.30(d,J＝8.0Hz,1H),7.01(d,J＝5.8Hz,2H),3.90(d,J＝7.6Hz,7H),3.13(br.s.,4H).
MS-ESI(m/z):421(M+H)+.
实施例47：3-((2-氟-4-吗啡啉苯基)氨基)-1-甲基-7-(1H-吡唑-4-基)喹喔啉-2(1H)-酮
Figure PCTCN2018091269-appb-000099
步骤A：4-(3-氟-4-硝基苯基)吗啡啉
将碳酸钾(9.87g,71.43mmol)和吗啡啉(2.49g,28.57mmol)加入到2,4-二氟-1-硝基-苯(5.00g,31.43mmol)的DMF(50mL)的溶液中，在80℃搅拌2.5小时。再向反应液中滴加1-甲基哌嗪(7.17g,71.58mmol)，在室温搅拌16小时。反应液用乙酸乙酯(200mL)稀释，用饱和食盐水(150mL)洗涤三次，用无水硫酸钠干燥，过滤，旋干得到残余物，通过柱分离得到标题化合物。
1H NMR(400MHz,DMSO-d6)δ＝8.02(t,J＝9.3Hz,1H),6.96(dd,J＝2.5,16.1Hz,1H),6.87(dd,J＝2.5,9.5Hz,1H),3.76-3.68(m,4H),3.48-3.41(m,4H).
步骤B：2-氟-4-吗啡啉苯胺
向4-(3-氟-4-硝基苯基)吗啡啉(1.00g,4.42mmol)的甲醇(20mL)溶液中加入钯炭(517.41mg，486.20μmol)，用氢气球置换三次，在室温搅拌3小时。用硅藻土过滤，旋干得到标题化合物。
1H NMR(400MHz,DMSO-d6)δ＝6.73-6.63(m,2H),6.54(dd,J＝1.9,8.4Hz,1H),4.58(s,2H),3.74-3.65(m,4H),2.97-2.85(m,4H).
步骤C：7-(1-苯基-1H-吡唑-4-基)-3-((2-氟-4-吗啡啉苯基)氨基)-1-甲基喹喔啉-2(1H)-酮
在氮气保护下，将2-氟-4-吗啡啉-苯胺(99.29mg,506.00μmol)，碳酸铯(247.30mg,759.00μmol)，Xantphos(14.64mg,25.30μmol)和Pd(OAc) 2(11.36mg,50.60μmol)加入到7-(1-苯基吡唑-4-基)-3-溴-1-甲基-喹喔啉-2-酮(100.00mg,253.00μmol)的二氧六环(3mL)的溶液中，在氮气保护，110℃搅拌16小时。反应液冷却到室温，用硅藻土过滤，旋干得到残余物。残余物用通过柱分离得到标题化合物。
ES-ESI(m/z):511(M+H) +
步骤D：3-((2-氟-4-吗啡啉苯基)氨基)-1-甲基-7-(1H-吡唑-4-基)喹喔啉-2(1H)-酮
在室温下，将叔丁醇钾(1mol，1.65mL)加入到7-(1-苯基-1H-吡唑-4-基)-3-((2-氟-4-吗啡啉苯基)氨基)-1-甲基喹喔啉-2(1H)-酮(120.00mg,235.04μmol)的二甲亚砜(3mL)溶液中。在35℃下，用氧气球置换三次，再搅拌16小时。向反应液中加入饱和氯化铵水溶液(50mL)，用二氯甲烷比异丙醇(10:1)(50mL)萃取四次。减压浓缩得到的残余物通过制备分离(三氟乙酸)得到标题化合物47。
1H NMR(400MHz,DMSO-d6)δ＝8.75(s,1H),8.21(s,2H),8.11(t,J＝9.0Hz,1H),7.65(s,1H),7.55(d,J＝8.5Hz,1H),7.43(d,J＝8.0Hz,1H),6.95(dd,J＝2.0,14.1Hz,1H),6.84(d,J＝8.5Hz,1H),3.77-3.74(m,7H),3.17-3.13(m,4H).
MS-ESI(m/z):421.1(M+H).
实施例48：3-((3-氟-4-吗啡啉苯基)氨基)-1-甲基-7-(1H-吡唑-4-基)喹喔啉-2(1H)-酮
Figure PCTCN2018091269-appb-000100
实施例48的制备可参考实施47的制备方法得到。
1H NMR(400MHz,DMSO-d6)δ＝9.52(br.s.,1H),8.18(br.s.,2H),8.09(d,J＝15.2Hz,1H),7.86(d,J＝8.2Hz,1H),7.60(br.s.,1H),7.54-7.46(m,2H),7.00(t,J＝9.3Hz,2H),3.72(br.s.,7H),2.94(br.s.,4H).MS-ESI(m/z):421.2(M+H).
实施例49：1-甲基-3-((3-氟-4-吗啡啉苯基)氨基)-7-(1H-吡唑-4-基)喹喔啉-2(1H)-酮
Figure PCTCN2018091269-appb-000101
实施例49的制备可参考实施例47的制备方法得到。
1HNMR(400MHz,DMSO-d6)δ＝9.25(s,1H),8.19(s,2H),7.95(d,J＝8.6Hz,1H),7.88(br.s.,1H),7.60(s,1H),7.56-7.50(m,1H),7.50-7.45(m,1H),7.03(d,J＝8.6Hz,1H),3.74(s,7H),2.82(br.s.,4H),2.28(s,3H).
MS-ESI(m/z):417.1(M+H)+.
实施例50：3-((3-氯-4-吗啡啉苯基)氨基)-1-甲基-7-(1H-吡唑-4-基)喹喔啉-2(1H)-酮
Figure PCTCN2018091269-appb-000102
实施例50的制备可参考实施例47的制备方法得到。
1HNMR(400MHz,DMSO-d6)δ＝9.77-9.42(m,1H),8.54-7.93(m,4H),7.78-7.40(m,3H),7.21(br.s.,1H),3.79(br.s.,7H),2.98(br.s.,4H).
MS-ESI(m/z):437.0(M+H)+.
实施例51：3-((3-甲氧基-4-吗啡啉苯基)氨基)-1-甲基-7-(1H-吡唑-4-基)喹喔啉-2(1H)酮
Figure PCTCN2018091269-appb-000103
实施例51的制备可参考实施例47的制备方法得到.
1H NMR(400MHz,DMSO-d6)δ＝13.03(br.s.,1H),9.36(br.s.,1H),8.46-7.45(m,7H),6.90(br.s.,1H),4.04-3.63(m,10H),2.97(br.s.,4H).
MS-ESI(m/z):433.1(M+H)+.
实施例52：1-甲基-3-((5-吗啡啉吡啶-2-基)氨基)-7-(1H-吡唑-4-基)喹喔啉-2(1H)酮
Figure PCTCN2018091269-appb-000104
实施例52的制备可参考实施例47的制备方法得到。
1H NMR(400MHz,DMSO-d6)δ＝10.93(br.s.,1H),8.27(s,2H),8.16-8.12(m,1H),8.06-8.02(m,2H),7.87(d,J＝8.5Hz,1H),7.72-7.65(m,2H),7.32-7.01(m,1H),3.81-3.76(m,7H),3.19(br.s.,4H).
MS-ESI(m/z):404.1(M+H)+.
实施例53：1-甲基-3-((6-吗啡啉吡啶-3-基)氨基)-7-(1H-吡唑-4-基)喹喔啉-2(1H)酮
Figure PCTCN2018091269-appb-000105
实施例53的制备可参考实施例47的制备方法，使用不同的胺得到。
1H NMR(400MHz,METHANOL-d4)δ＝9.43-9.35(m,1H),8.32(d,J＝9.0Hz,1H),8.10(br.s.,2H),7.59-7.49(m,3H),7.44-7.37(m,1H),3.91-3.85(m,4H),3.79(s,3H),3.63(d,J＝4.5Hz,4H).
MS-ESI(m/z):404.1(M+H)+.
实施例54：3-[4-(3,8-二氮双环[3.2.1]辛烷-8-基)苯胺]-1-甲基-7-(1H-吡唑-4-基)喹喔啉-2(1H)-酮
Figure PCTCN2018091269-appb-000106
步骤A：叔丁基-8-(4-硝基苯)-3,8-二氮双环[3.2.1]辛烷-3-甲酸酯
往叔丁基-3,8-二氮双环[3.2.1]辛烷-3-甲酸酯(399.0mg,1.88mmol)的DMF溶液(4.00mL)中加入碳酸钾(742.19mg,5.37毫摩)和1-氟-4-硝基苯(252.57mg,1.79mmol)。80℃下搅拌36小时。反应冷却后加入20mL水，固体析出后过滤得到标题化合物。
1H NMR(400MHz,CHLOROFORM-d)δ＝8.14(d,J＝9.2Hz,2H),6.71(d,J＝9.2Hz,2H),4.33(d,J＝19.2Hz,2H),3.92-3.62(m,2H),3.30-3.05(m,2H),2.08(br.s.,2H),1.93(dd,J＝7.2,14.2Hz,2H),1.45(s,9H).
步骤B：叔丁基-8-(4-氨基苯基)-3,8-二氮双环[3.2.1]辛烷-3-甲酸酯
叔丁基-8-(4-硝基苯)-3,8-二氮双环[3.2.1]辛烷-3-甲酸酯(400.00mg,1.20mmol)的甲醇(50.00mL)溶液中加入Pd/C(200.00mg,1.20mmol)。氢气氛(15psi)中搅拌一小时。反应后过滤除掉催化剂，母液浓缩得到标题化合物。
1H NMR(400MHz,CHLOROFORM-d)δ＝6.72-6.61(m,4H),4.14-3.96(m,2H),3.72(d,J＝12.0Hz,1H),3.58(d,J＝13.2Hz,1H),3.44-3.15(m,4H),2.07-1.91(m,2H),1.88-1.68(m,2H),1.50-1.38(m,9H).
步骤C：叔丁基-8-[4-[[6-(1-苄基-1H-吡唑-4-基)-4-甲基-3-氧代-3,4-二氢喹喔啉-2-基]氨基]苯基]-3,8-二氮 双环[3.2.1]辛烷-3-甲酸酯
往叔丁基-8-(4-氨基苯基)-3,8-二氮双环[3.2.1]辛烷-3-甲酸酯(340.00mg,1.12mmol)的异丙醇溶液中加入7-(1-苄基吡唑-4-基)-3-溴-1-甲基-喹喔啉-2-酮(486.95mg,1.23mmol)和DIPEA(217.12mg,1.68mmol)，100℃下搅拌12小时。.TLC显示原料反应完全。反应液浓缩后硅胶柱分离(石油醚/乙酸乙酯＝10/1-1/1)得到标题化合物。
1H NMR(400MHz,CHLOROFORM-d)δ＝8.28(s,1H),7.88(s,1H),7.83(d,J＝9.2Hz,2H),7.68(s,1H),7.60(d,J＝8.4Hz,1H),7.42-7.33(m,4H),7.32-7.28(m,3H),6.93-6.80(m,2H),5.38(s,2H),4.24-4.11(m,2H),3.81-3.78(m,3H),3.75(d,J＝12.4Hz,1H),3.61(d,J＝12.4Hz,1H),3.42-3.17(m,2H),1.85(dd,J＝7.2,14.8Hz,2H),1.46(s,9H).
步骤D：叔丁基-8-[4-[[4-甲基-3-氧代-6-(1H-吡唑-4-基)-3,4-二氢喹喔啉-2-基]胺基]苯基]-3,8-二氮双环[3.2.1]辛烷-3-甲酸酯
往叔丁基-8-[4-[[6-(1-苄基-1H-吡唑-4-基)-4-甲基-3-氧代-3,4-二氢喹喔啉-2-基]氨基]苯基]-3,8-二氮双环[3.2.1]辛烷-3-甲酸酯(380.00mg,615.15μmol)的DMSO(10.00mL)溶液中加入叔丁醇钾(345.13mg,3.08mmol)，然后20℃下反应液在O2(15psi)氛中搅拌一小。TLC小时原料反应完全。反应液倒入10mL冰水中，20mL乙酸乙酯萃取三次。有机相使用饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩后得到标题化合物。.
步骤E：3-[4-(3,8-二氮双环[3.2.1]辛烷-8-基)苯胺]-1-甲基-7-(1H-吡唑-4-基)喹喔啉-2(1H)-酮
叔丁基-8-[4-[[4-甲基-3-氧代-6-(1H-吡唑-4-基)-3,4-二氢喹喔啉-2-基]胺基]苯基]-3,8-二氮双环[3.2.1]辛烷-3-甲酸酯(300.00mg,568.59μmol)的4M HCl甲醇溶液(10.00mL)20℃搅拌0.5小时。LCMS显示原料反应完全。反应液浓缩，制备分离(甲酸体系)得到标题化合物54。
1H NMR(400MHz,DMSO-d6)δ＝9.24(s,1H),8.32-8.13(m,3H),7.99(d,J＝8.8Hz,1H),7.61(s,1H),7.55-7.49(m,1H),7.44(d,J＝8.4Hz,1H),6.87(d,J＝8.8Hz,2H),4.24(br.s.,2H),3.75(s,4H),3.05(d,J＝12.4Hz,2H),2.75-2.63(m,2H),1.98(br.s.,3H).
MS-ESI(m/z):428.2(M+H)+.
实施例55：1-(4-((4-甲基-3-氧代-6-(1H-吡唑-4-基)-3,4-二氢喹喔啉-2-基)氨基)苯基)哌啶-3-羧酸
Figure PCTCN2018091269-appb-000107
步骤A：1-(4-硝基苯基)哌啶-3-甲酸乙酯
将三乙胺(7.17g,70.88mmol)和哌啶-3-甲酸乙酯(5.57g,35.44mmol)加入到1-氟-4-硝基苯(5.00g,35.44mmol)的四氢呋喃(100mL)的溶液中，在80℃搅拌16小时。将反应液旋干，用乙酸乙酯(100mL)稀释，用饱和食盐水(100mL)洗两次，用无水硫酸钠干燥，过滤，减压浓缩得到的残余物，通过柱分离得到标题化合物。
1H NMR(400MHz,CHLOROFORM-d)δ＝8.10(d,J＝9.2Hz,2H),6.83(d,J＝9.2Hz,2H),4.23-4.04(m,2H),3.97-3.84(m,1H),3.77-3.63(m,1H),3.35(dd,J＝9.6,13.3Hz,1H),3.20-3.04(m,1H),2.68-2.51(m,1H),2.12-2.03(m,1H),1.88-1.75(m,2H),1.70-1.57(m,1H),1.26(t,J＝7.1Hz,3H).
步骤B：1-(4-氨基苯基)哌啶-3-甲酸乙酯
向1-(4-硝基苯基)哌啶-3-甲酸乙酯(2.00g,7.19mmol)的甲醇(30mL)溶液中加入10％钯炭(0.2g)，用氢气球置换三次，在室温搅拌16小时。用硅藻土过滤，用二氯甲烷和甲醇(15mL)淋洗三次，将 滤液旋干得到标题化合物。
1H NMR(400MHz,CHLOROFORM-d)δ＝6.84(d,J＝8.6Hz,2H),6.70-6.58(m,2H),4.17(q,J＝7.1Hz,2H),3.51(d,J＝10.4Hz,1H),3.44(br.s.,2H),3.29(d,J＝11.7Hz,1H),2.92-2.80(m,1H),2.73-2.56(m,2H),2.05-1.93(m,1H),1.87-1.78(m,1H),1.75-1.57(m,2H),1.28(t,J＝7.2Hz,3H).
步骤C：1-(4-((6-(1-苯基-1H-吡唑-4-基)-4-甲基-3-氧代-3,4-二氢喹喔啉-2-基)氨基)苯基)哌啶-3-甲酸乙酯
将1-(4-胺基苯基)哌啶-3-甲酸乙酯(169.89mg,684.16μmol)和DIEA(221.05mg,1.17mmol)加入到7-(1-苯基吡唑-4-基)-3-氯-1-甲基-喹喔啉-2-酮(200.00mg,570.13μmol)的异丙醇(6mL)的溶液中，在100℃搅拌32小时。反应液冷却到室温，有固体析出，过滤，旋干得到标题化合物。
1H NMR(400MHz,DMSO-d6)δ＝9.27(s,1H),8.42(s,1H),8.06(s,1H),7.97(d,J＝9.0Hz,1H),7.73(d,J＝5.3Hz,1H),7.66(d,J＝7.5Hz,1H),7.58(s,1H),7.53-7.48(m,1H),7.33-7.26(m,4H),6.94(d,J＝8.8Hz,2H),5.38(d,J＝8.8Hz,2H),4.10(q,J＝7.1Hz,2H),3.73(d,J＝5.3Hz,3H),3.58(d,J＝9.5Hz,1H),3.06-2.93(m,2H),2.78(d,J＝9.7Hz,2H),1.89(br.s.,1H),1.72(br.s.,1H),1.60(t,J＝9.3Hz,2H),1.27-1.15(m,3H).
步骤D：1-(4-((4-甲基-3-氧代-6-(1H-吡唑-4-基)-3,4-二氢喹喔啉-2-基)氨基)苯基)哌啶-3-羧酸
在室温下，将叔丁醇钾(159.54mg,1.42mmol)加入到1-(4-((6-(1-苯基-1H-吡唑-4-基)-4-甲基-3-氧代-3,4-二氢喹喔啉-2-基)胺)苯基)哌啶-3-甲酸乙酯(100.00mg,177.73μmol)的二甲亚砜(3mL)溶液中。在室温下，用氧气球置换三次，再在40℃搅拌3小时。向反应液中加入水(15mL)，用乙酸乙酯(15mL)萃取两次。有机相用饱和食盐水(20mL)洗两次，用无水硫酸钠干燥，过滤，减压浓缩得到的残余物通过制备分离(三氟乙酸)得到标题化合物55。
1H NMR(400MHz,DMSO-d6)δ＝9.53(br.s.,1H),8.21(s,2H),8.13(d,J＝5.5Hz,2H),7.64(br.s.,1H),7.59-7.53(m,1H),7.51(br.s.,1H),7.36-7.22(m,2H),3.76(s,3H),3.70-3.57(m,2H),3.48(br.s.,1H),3.30-3.03(m,2H),2.76(br.s.,1H),2.04-1.57(m,3H).
MS-ESI(m/z):445(M+H)+.
实施例56：1-甲基-7-(1H-吡唑-4-基)-3-((6-((四氢-2H-吡喃-4-基)氨基)吡啶-3-基)氨基)喹喔啉-2(1H)-酮
Figure PCTCN2018091269-appb-000108
步骤A：5-硝基-N-(四氢-2H-吡喃-4-基)吡啶-2-胺
将三乙胺(5.11g,50.46mmol)和四氢吡喃-4-胺(2.55g,25.23mmol)加入到2-氯-5-硝基-吡啶(4.00g,25.23mmol)的DME(100mL)的溶液中，在80℃搅拌16小时。将反应液旋干，用乙酸乙酯(100mL)稀释，用饱和食盐水(100mL)洗两次，用无水硫酸钠干燥，过滤，减压浓缩得到的残余物，通过柱分离得到标题化合物。
1H NMR(400MHz,DMSO-d6)δ＝8.91(d,J＝2.4Hz,1H),8.19-8.00(m,2H),6.56(d,J＝9.0Hz,1H),4.13(br.s.,1H),3.87(d,J＝11.2Hz,2H),3.41(t,J＝10.8Hz,2H),1.86(d,J＝12.1Hz,2H),1.57-1.39(m,2H).
步骤B：N 2-(四氢-2H-吡喃-4-基)吡啶-2,5-二胺
向5-硝基-N-(四氢-2H-吡喃-4-基)吡啶-2-胺(800.00mg,3.58mmol)的甲醇(20mL)溶液中加入10％钯炭(0.2g)，用氢气置换三次，在室温搅拌3小时。用硅藻土过滤，将滤液旋干得到标题化合物。
1H NMR(400MHz,CHLOROFORM-d)δ＝7.68(d,J＝2.4Hz,1H),6.94(dd,J＝2.6,8.6Hz,1H),6.31(d,J＝8.8Hz,1H),3.98(d,J＝11.5Hz,3H),3.81-3.68(m,1H),3.52(dt,J＝1.5,11.5Hz,2H),3.21(br.s.,2H),2.02(d,J＝12.6Hz,2H),1.55-1.39(m,2H).
步骤C：7-溴-1-甲基-3-((6-((四氢-2H-吡喃-4-基)氨基)吡啶-3-基)氨基)喹喔啉-2(1H)-酮
将N 2-(四氢-2H-吡喃-4-基)吡啶-2,5-二胺(494.59mg,2.56mmol)和DIEA(992.30mg,7.68mmol)加入到7-溴-3-氯-1-甲基喹喔啉-2(1H)-酮(700.00mg,2.56mmol)的异丙醇(15mL)的溶液中，在100℃搅拌24小时。反应液冷却到室温，有固体析出，过滤，滤饼用乙酸乙酯(5mL)淋洗三次。旋干得到标题化合物。
1H NMR(400MHz,DMSO-d6)δ＝9.39(br.s.,1H),8.63(br.s.,1H),7.98(d,J＝8.3Hz,1H),7.59(br.s.,1H),7.37(br.s.,2H),6.55-6.27(m,2H),3.87(d,J＝9.3Hz,2H),3.65(br.s.,3H),1.88(d,J＝11.8Hz,2H),1.41(d,J＝9.5Hz,2H),1.03(d,J＝5.8Hz,3H).
步骤D：1-甲基-7-(1H-吡唑-4-基)3-((6-((四氢-2H-吡喃-4-基)氨基)吡啶-3-基)氨基)喹喔啉-2(1H)-酮
在氮气保护下，将碳酸钾(192.72mg,1.39mmol)，叔丁基4-(4,4,5,5-四甲基-1,3,2-二氧杂戊硼烷(246.00mg,836.46μmol)和Pd(dppf)Cl2(51.01mg,69.72μmol)加入到7-溴-1-甲基-3-((6-((四氢-2H-吡喃-4-基)氨基)吡啶-3-基)氨基)喹喔啉-2(1H)-酮(300.00mg,697.19μmol)的二氧六环(8mL)和水(2mL)的混合溶液中，在100℃搅拌4小时。反应液冷却到室温，浓缩，向反应液中加入水(20mL)，过滤得到残余物，通过制备分离(三氟乙酸)得到标题化合物56。
1H NMR(400MHz,DMSO-d6)δ＝9.78(s,1H),9.11(br.s.,1H),8.35(d,J＝8.3Hz,1H),8.19(s,2H),7.62-7.53(m,2H),7.45(d,J＝8.3Hz,1H),7.03(d,J＝9.5Hz,1H),3.97-3.81(m,3H),3.71(s,3H),3.41(t,J＝11.2Hz,2H),1.92(d,J＝11.5Hz,2H),1.58-1.39(m,2H).
MS-ESI(m/z):418(M+H)+.
实施例57：7-(2-氨基-1H-咪唑-5-基)-1-甲基-3-((4-吗啡啉苯基)氨基)喹喔啉-2(1H)-酮
Figure PCTCN2018091269-appb-000109
步骤A：7-咪唑[1,2-a]嘧啶-3-基-1-甲基-3-((4-吗啡啉苯基)氨基)喹喔啉-2(1H)-酮
向7-溴-1-甲基-3-((4-吗啡啉苯基)氨基)喹喔啉-2(1H)-酮(100.00mg,240.80μmol)和咪唑[1,2-a]嘧啶(57.80mg,288.96μmol，氢溴酸盐)的二氧六环(2.00mL)中加入三苯基磷(12.63mg,48.16μmol),醋酸钯(5.41mg,24.08μmol)以及碳酸铯(235.37mg,722.40μmol)。反应液在氮气保护下加热搅拌17小时。LCMS显示反应完成。反应液硅藻土过滤二氯甲烷洗涤滤饼。母液旋干，硅胶柱层析(甲醇二氯甲烷＝0～10％)得到标题化合物。
MS-ESI(m/z):456(M+H)+
步骤B：7-(2-氨基-1H-咪唑-5-基)-1-甲基-3-((4-吗啡啉苯基)氨基)喹喔啉-2(1H)-酮
7-咪唑[1,2-a]嘧啶-3-基-1-甲基-3-((4-吗啡啉苯基)氨基)喹喔啉-2(1H)-酮(40.00mg,88.20μmol)和水合肼(1.78g,55.54mmol)的乙醇(3.00mL)溶液闷罐加热(105℃)16小时。LCMS显示原料反应完全。将反应液旋干，制备分离(三氟乙酸体系)得到7-(2-氨基-1H-咪唑-5-基)-1-甲基-3-((4-吗啡啉苯基)氨基)喹喔啉-2(1H)-酮(化合物57)。
1H NMR(400MHz,DMSO-d6)δ＝12.83(br.s.,1H),12.13(br.s.,1H),9.45(s,1H),8.01(d,J＝9.0Hz,2H),7.66(s,1H),7.60(br.s.,2H),7.57-7.51(m,2H),6.97(d,J＝9.0Hz,2H),3.78-3.72(m,7H),3.13-3.06 (m,4H)。
MS-ESI(m/z):418.2(M+H)+.
实施例58：7-(2-氨基噻唑-5-基)-1-甲基-3-((4-吗啡啉苯基)氨基)喹喔啉-2(1H)-酮
Figure PCTCN2018091269-appb-000110
步骤A：1-甲基-3-((4-吗啡啉苯基)氨基)-7-(4,4,5,5-四甲基-1,3,2-二氧硼烷-2-基)喹喔啉-2(1H)-酮
7-溴-1-甲基-3-((4-吗啡啉苯基)氨基)喹喔啉-2(1H)-酮(500.00mg,1.20mmol),4,4,5,5-四甲基-2-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)-1,3,2-二氧杂硼烷(335.20mg,1.32mmol),Pd(dppf)Cl2(70.24mg,96.00μmol)和醋酸钾(353.30mg,3.60mmol)的二氧六环溶液(50.00mL)脱气并用氮气置换，氮气氛中110℃回流1.5小时冷却二氯甲烷(100mL)稀释,饱和食盐水洗涤(50mL三次),无水硫酸钠干燥，浓缩后硅胶柱层析(12g,四氢呋喃/二氯甲烷＝0～5％)得到标题化合物。
MS-ESI(m/z):463(M+H)+.
步骤B：叔丁基(5-(4-甲基-2-((4-吗啡啉苯基)氨基)-3-氧杂-3,4-二氢喹喔啉-6-基)噻唑-2-基)((2-(三甲基硅基)乙氧基)甲基)甲酸酯
往叔丁基N-(5-溴噻唑-2-基)-N-(2-三甲基硅基乙氧基甲基)甲酸酯(102.28mg,249.81μmol)和1-甲基-3-((4-吗啡啉苯基)氨基)-7-(4,4,5,5-四甲基-1,3,2-二氧硼烷-2-基)喹喔啉-2(1H)-酮(100.00mg,166.54μmol)的DMF(2.00mL)溶液中加入Brettphos钯前催化剂(26.61mg,33.31μmol)和碳酸铯(108.52mg,333.08μmol).混合物在氮气氛中90℃加热搅拌5小时。100℃搅拌16小时。LCMS显示原料反应完全。混合物冷却后使用150mL二氯甲烷稀释，饱和食盐水洗涤，无水硫酸钠干燥，过滤，旋干，硅胶柱层析(四氢呋喃/二氯甲烷＝0～30％)得到标题化合物。
MS-ESI(m/z):665.5(M+H)+.
步骤C：7-(2-氨基噻唑-5-基)-1-甲基-3-((4-吗啡啉苯基)氨基)喹喔啉-2(1H)-酮
叔丁基(5-(4-甲基-2-((4-吗啡啉苯基)氨基)-3-氧杂-3,4-二氢喹喔啉-6-基)噻唑-2-基)((2-(三甲基硅基)乙氧基)甲基)甲酸酯(133.33mg,150.40μmol)的二氯甲烷(20.00mL)溶液中加入三氟乙酸(6.12g,53.67mmol)混合物20℃搅拌一小时，35℃搅拌四小时。LCMS显示原料反应完全。二氯甲烷旋干后制备分离(三氟乙酸体系)得到标题化合物58。
1H NMR(400MHz,DMSO-d6)δ＝9.41(s,1H),8.33-8.14(m,1H),8.00(d,J＝9.0Hz,2H),7.74(s,1H),7.47(d,J＝4.0Hz,2H),7.36(d,J＝8.0Hz,1H),6.98(d,J＝9.0Hz,2H),3.78-3.73(m,7H),3.13-3.08(m,4H).
MS-ESI(m/z):435.0(M+H)+.
实施例59：7-(2-氨基噻唑-4-基)-1-甲基-3-((4-吗啡啉苯基)氨基)喹喔啉-2(1H)-酮
Figure PCTCN2018091269-appb-000111
实施例59的制备可参考实施例58的制备方法得到。
1H NMR(400MHz,DMSO-d6)δ＝9.43(br.s.,1H),8.02(d,J＝8.0Hz,2H),7.79(br.s.,1H),7.71(d,J＝8.0Hz,1H),7.50(d,J＝8.0Hz,1H),7.21(br.s.,1H),7.00(d,J＝8.0Hz,2H),3.75(d,J＝13.1Hz,9H),3.12(br.s.,4H).MS-ESI(m/z):435.1(M+H)+.
实验例1：实施例化合物对SYK激酶抑制作用体外测试
1.1实验目的：通过均相时间分辨荧光技术(HTRF)检测底物和酶的相互作用,以化合物的半数细胞抑制浓度(IC50)值为指标，来评价化合物对酪氨酸(SYK)激酶的抑制作用。
1.2实验材料:
酪氨酸激酶(Invitrogen，PV3857)
二硫代苏糖醇(DTT)(Sigma#43815)
三磷酸腺苷(ATP)(Sigma#A7699)
氯化镁(MgCl2)(Sigma#63020)
氯化锰(MnCl2)(Sigma#M1787)
乙二胺四乙酸(EDTA)(Invitrogen#15575-020)
4-羟乙基哌嗪乙磺酸缓冲液(HEPES Buffer)(Invitrogen#15630-080)
Figure PCTCN2018091269-appb-000112
KinEASE TM酪氨酸激酶试剂盒(Cisbio#62TK0PEC,20000 tests)
低容量,384孔,白色聚苯乙烯板(Greiner#784075)
384微孔板(Greiner#781946)
离心机(Eppendorf#5810R)
移液器(Eppendorf)
移液管(Greiner)
移液枪(Eppendorf)
Multidrop自动分液器
POD 810 Plate Assembler全自动微孔板预处理系统
Envision Reader多功能酶标仪
1.3实验步骤和方法：
a)化合物稀释与打板
1)化合物粉末称重，溶解于一定量二甲基亚砜中，初始浓度为10mM。
2)将化合物浓度稀释到0.74mM，使用全自动微孔板预处理系统进行打板，每孔135nL，化合物起始浓度为10uM，11个浓度点，3倍递减梯度稀释。
b)酶与底物反应阶段
1)实验缓冲液稀释准备，将试剂盒内5×HTRF缓冲液稀释至1×，加入指定量的二硫代苏糖醇和氯化镁溶液备用。
2)用1×HTRF缓冲液配制酪氨酸酶反应溶液，使酪氨酸激酶最终反应浓度为0.0156ng/μL。
3)配制酪氨酸激酶-底物-生物素/三磷酸腺苷混合液，使最终底物浓度控制在0.2uM。三磷酸腺苷浓度控制在2uM。
4)使用Multidrop自动分液器加样，酪氨酸酶溶液和酪氨酸激酶-底物-生物素/三磷酸腺苷混合液每孔各加5ul，23℃孵育1小时。
c)检测阶段：
1)向试剂盒检测缓冲液(Detection Buffer)中加入13.33mL乙二胺四乙酸溶液，加入指定量铀(Eu)标记的抗体和链霉亲和素XL-665，配置好检测液。
2)使用Multidrop自动分液器加样，每孔10uL检测液，23℃孵育1小时。使其终止酶和底物混合液的反应。
3)离心后在多功能酶标仪上进行读值。
d)分析数据:用XL-Fit来分析数据，计算化合物的IC50值。
实验例2：实施例化合物对AKT磷酸化抑制作用的体外测试
2.1实验目的：通过酶联免疫吸附测定(ELISA)实验检测细胞内蛋白激酶AKT磷酸化作用,以化合物 的半数细胞抑制浓度(IC50)值为指标，来评价化合物对蛋白激酶AKT磷酸化的抑制作用。
2.2实验材料:
细胞系：Ramos细胞系
细胞培养基(RPMI1640,Invitrogen#22400-105；10％血清Gibco#10099-141；左旋谷酰胺1×，Gibco#25030-081)
实验用培养基(不含血清，RPMI 1640,Invitrogen#22400-105；左旋谷酰胺1×，Gibco#25030)裂解缓冲液(三羟甲基氨基甲烷盐酸盐，Invitrogen15567-1000ml；氯化钠，国产；脱氧胆酸钠，Sigma30970-25G；聚乙二醇辛基苯基醚，SigmaT9284-100ml；十二烷基磺酸钠，SigmaL3771；乙二胺四乙酸，Invitrogen15575-038-100ml；超纯水，MilliQ)
蛋白酶抑制剂(Roche，4693159001-30/BOX)
磷酸酶抑制剂混合物2(Sigma，P5726-5ML)
磷酸酶抑制剂混合物3(Sigma，P0044-5ML)
羊抗人免疫球蛋白M(F(ab’)2 Goat Anti-Human IgM)(JacksonImmuno Research-109-006-129)
磷酸化AKT检测试剂盒(Phospho-AKT 1/2/3(ser473))(TGR Bioscience,EKT002)
10×平衡盐溶液(10×Hank's Balanced Salt Solution)(Gibco#14065-056)
96孔细胞板(Greiner#655090)
化合物V孔稀释板(Axygen#WITP02280)
CO2培养箱(Thermo#371)
离心机(Eppendorf#5810R)
Vi-cell细胞计数仪(Beckman Coulter)
移液器(Eppendorf)
移液管(Greiner)
移液枪(Eppendorf)
多功能酶标仪(Envision Reader)
2.3实验步骤和方法：
a)细胞接种(Ramos细胞)
1)37℃水浴预热培养基。吸取悬浮细胞及其培养液，1000rpm离心
5分钟；
2)吸掉细胞培养基，加入10mL预热过的培养基于离心管中，吹散重悬细胞，吸取1mL细胞重悬液，用Vi-cell计数；
3)用培养基稀释Ramos细胞，使其密度达到5×106/mL，用排枪将稀释好的细胞加入到96孔细胞培养板(100μL/孔)。将细胞板放置于37℃、5％CO2培养箱过夜。
b)细胞饥饿:
1)接种细胞培养过夜后，第二天1000rpm离心5分钟，用排枪吸走原来的培养基，加入无血清的实验用培养基，将细胞板放置于37℃、5％CO2培养箱，饥饿过夜。
c)化合物准备和加药：
1)用二甲基亚砜稀释化合物，使其初始浓度为5mM。使用化合物V孔稀释板三倍梯度稀释，做10个浓度点。
2)另取一块新的化合物V孔稀释板，每孔加入198ul的无血清的实验用培养基，之后每孔中加入2ul上步稀释好的化合物，用排枪将其混匀。此时化合物被稀释100倍，初始浓度为50uM。
3)向细胞培养板中加入配制好的化合物，每孔25uL(细胞培养基为100uL)，化合物被稀释5倍，最终初始反应浓度为10uM，三倍梯度，10个浓度点)。
4)加好药后，1000rpm离心1分钟，将细胞板放置于37℃、5％CO2培养箱，使化合物作用1小时。
d)刺激因子刺激：
1)配制两管1×平衡盐溶液，将10×平衡盐溶液用双蒸水稀释至1×平衡盐溶液，分别置于37℃ 恒温箱和4℃冰箱备用。
2)配制一管裂解混合液，置于4℃冰箱备用。配方如下：1片蛋白酶抑制剂片剂+100ul磷酸酶抑制剂混合2+100ul磷酸酶抑制剂混合3+10ml裂解液。
3)将羊抗人免疫球蛋白M(F(ab’)2 Goat Anti-Human IgM)(1.2mg/ml)用37℃预热的1×平衡盐溶液稀释到60ug/ml。
4)待化合物处理细胞一个小时后，每孔加入25ul稀释过的羊抗人免疫球蛋白M(F(ab’)2 Goat Anti-Human IgM)，此时IgM的作用浓度为10ug/ml。
5)IgM刺激细胞10分钟，4000rpm离心5分钟，使悬浮细胞沉积在96孔板底部，轻轻倒掉96孔板中液体，用擦手纸吸去剩余液体。注意：尽量不要把悬浮细胞弄掉。
6)每孔加入250ul预冷的(4℃)1×平衡盐溶液，4000rpm离心5分钟，终止刺激因子对细胞的刺激。
e)制备细胞裂解液：
1)轻轻倒掉96孔板中液体，用擦手纸吸去剩余液体。每孔加入100ul裂解混合液，4℃摇床摇晃1小时，使细胞裂解。
2)细胞裂解1小时后，4℃，4000rpm离心5分钟，轻轻吸取上清，得到细胞裂解液。
f)酶联免疫吸附测定(Elisa)实验：
1)取出磷酸化AKT检测试剂盒中96孔Elisa板，平衡至室温，每孔加入50ul细胞裂解液。
2)将试剂盒中捕获抗体试剂(Capture Antibody Reagent)和检测抗体试剂(DetectionAntibody Reagent)1：1混匀，然后每孔50ul加入96孔Elisa板。细胞裂解液与抗体混合液室温摇床摇晃1小时。
3)试剂盒中洗涤液(10×)用双蒸水稀释至1×，将Elisa板中液体倒掉，在吸水纸上拍干，每孔加入200ul 1×洗涤液，洗板后拍干，重复4次。
4)将10-乙酰基.3,7.二羟基吩嗪(ADHP)(100×)底物用ADHP稀释液稀释至1×，每孔100ul加入96孔Elisa板中，室温摇床摇晃10分钟。
5)每孔加入10ul终止液，瞬时离心。室温摇床摇晃5分钟。Envision Reader多功能酶标仪进行读值。
g)分析数据:用XL-Fit来分析数据，计算化合物的IC50值。
试验例1和试验例2的结果见表1：
表1
Figure PCTCN2018091269-appb-000113
Figure PCTCN2018091269-appb-000114
Figure PCTCN2018091269-appb-000115
Figure PCTCN2018091269-appb-000116
Figure PCTCN2018091269-appb-000117
Figure PCTCN2018091269-appb-000118
Figure PCTCN2018091269-appb-000119

Claims (36)

  1. 式(I)化合物或其药学上可接受的盐，
    Figure PCTCN2018091269-appb-100001
    其中，
    W为C(R 7)或N；
    R 1、R 2独立地选自H、卤素、氨基、羟基、氰基、C 1-6烷基、C 3-6环烷基、3～10元杂环烷基、6～12元芳基或5～12元杂芳基，所述氨基、C 1-6烷基、C 3-6环烷基、3～10元杂环烷基、6～12元芳基或5～12元杂芳基任选地被R 8取代；
    R 3、R 4、R 7独立地选自H、卤素、氨基、羟基、氰基、C 1-6烷基、C 3-6环烷基或3～6元杂环烷基，所述氨基、C 1-6烷基、C 3-6环烷基或3～6元杂环烷基任选地被R 9取代；
    R 5选自H、C 1-6烷基、C 3-6环烷基、3～6元杂环烷基、C 1-6烷基C(O)、C 3-6环烷基C(O)、3～6元杂环烷基C(O)、苯基C(O)、5～6元杂芳基C(O)、C 1-6烷基SO 2、C 3-6环烷基SO 2、3～6元杂环烷基SO 2、苯基SO 2或5～6元杂芳基SO 2，所述C 1-6烷基、C 3-6环烷基、3～6元杂环烷基、C 1-6烷基C(O)、C 3-6环烷基C(O)、3～6元杂环烷基C(O)、苯基C(O)、5～6元杂芳基C(O)、C 1-6烷基SO 2、C 3-6环烷基SO 2、3～6元杂环烷基SO 2、苯基SO 2或5～6元杂芳基SO 2任选地被R 9取代；
    X选自任意两个位置失去H原子的3～12元环，所述环任选地被R 9取代；
    L选自键、NH、O、S、SO、SO 2、C(O)、OC(O)、C(O)O、C(O)NH、NHSO 2、SO 2NH、NHC(O)NH或NHSO 2NH；
    R 6选自H、卤素、氨基、羟基、氰基、C 1-6烷基、C 3-10环烷基或3～10元杂环烷基，所述氨基、C 1-6烷基、C 3-10环烷基或3～10元杂环烷基任选地被R 10取代；
    R 8、R 9独立地选自卤素、氨基、羟基、氰基、C 1-3烷基、C 1-3烷氧基或COOH；
    R 10选自卤素、氨基、羟基、氰基、卤代C 1-3烷基、COOH、＝(O)、C 1-6烷基、C 1-6烷基SO 2、C 3-6环烷基或3～10元杂环烷基；
    且R 1和R 2中至少有一个选自6～12元芳基或5～12元杂芳基，所述6～12元芳基或5～12元杂芳基任选地被R 8取代。
  2. 权利要求1的化合物，其中R 1、R 2独立地选自H、卤素或5～12元杂芳基，所述5～12元杂芳基任选地被R 8取代。
  3. 权利要求2的化合物，其中R 1、R 2独立地选自H、F、Cl、Br、呋喃基、噻吩基、吡咯基、吡唑基、咪唑基、吡啶基、嘧啶基、哒嗪基、吡嗪基、噻唑基、异噻唑基、噁唑基、异噁唑基、四唑基或三嗪基，所述呋喃基、噻吩基、吡咯基、吡唑基、咪唑基、吡啶基、嘧啶基、哒嗪基、吡嗪基、噻唑基、异噻唑基、噁唑基、异噁唑基、四唑基或三嗪基任选地被R 8取代。
  4. 权利要求3的化合物，其中R 1选自H、F、
    Figure PCTCN2018091269-appb-100002
    Figure PCTCN2018091269-appb-100003
    其可任选地被R 8取代。
  5. 权利要求4的化合物，其中R 1选自H、F、
    Figure PCTCN2018091269-appb-100004
    Figure PCTCN2018091269-appb-100005
  6. 权利要求3的化合物，其中R 2选自H、F、Cl或
    Figure PCTCN2018091269-appb-100006
  7. 权利要求1的化合物，其中R 8选自氨基、甲基、乙基、丙基或异丙基。
  8. 权利要求1的化合物，其中R 1选自5～12元杂芳基；R 2选自H或卤素；其中，R 1可任选地被R 8取代。
  9. 权利要求8的化合物，其中R 1选自呋喃基、噻吩基、吡咯基、吡唑基、咪唑基、吡啶基、嘧啶基、哒嗪基、吡嗪基、噻唑基、异噻唑基、噁唑基、异噁唑基、四唑基或三嗪基；R 2选自H、F、Cl或Br；其中，R 1可任选地被R 8取代。
  10. 权利要求9的化合物，其中R 1选自
    Figure PCTCN2018091269-appb-100007
    Figure PCTCN2018091269-appb-100008
    R 2选自H、F或Cl；其中，R 1可任选地被R 8取代。
  11. 权利要求10的化合物，其中R 1选自
    Figure PCTCN2018091269-appb-100009
    Figure PCTCN2018091269-appb-100010
    R 2选自H、F或Cl。
  12. 权利要求1的化合物，其中R 1选自H或卤素；R 2选自5～12元杂芳基；其中，R 2可任选地被R 8取代。
  13. 权利要求12的化合物，其中R 1选自H、F、Cl或Br；R 2选自呋喃基、噻吩基、吡咯基、吡唑基、咪唑基、吡啶基、嘧啶基、哒嗪基、吡嗪基、噻唑基、异噻唑基、噁唑基、异噁唑基、四唑基或三嗪基；其中，R 2可任选地被R 8取代。
  14. 权利要求13的化合物，其中R 1选自H或F；R 2选自
    Figure PCTCN2018091269-appb-100011
  15. 权利要求1的化合物，其中R 3、R 4、R 7独立地选自H、卤素、C 1-6烷基或C 3-6环烷基，所述C 1-6烷基或C 3-6环烷基任选地被R 9取代。
  16. 权利要求15的化合物，其中R 3、R 4、R 7独立地选自H或卤素。
  17. 权利要求1的化合物，其中R 5选自H、C 1-6烷基或C 3-6环烷基，其中C 1-6烷基或C 3-6环烷基任选被R 9取代。
  18. 权利要求17的化合物，其中R 5选自甲基、乙基、丙基、异丙基、丁基、异丁基或叔丁基，所述甲 基、乙基、丙基、异丙基、丁基、异丁基或叔丁基任选地被R 9取代。
  19. 权利要求1的化合物，其中X选自任意两个位置失去H原子的苯环或5～10元杂芳环，所述X可任选地被R 9取代。
  20. 权利要求19的化合物，其中X选自任意两个位置失去H原子的苯环、
    Figure PCTCN2018091269-appb-100012
    Figure PCTCN2018091269-appb-100013
    呋喃环、噻吩环、吡咯环、吡唑环、咪唑环、吡啶环、嘧啶环、哒嗪环、吡嗪环、噻唑环、异噻唑环、噁唑环、异噁唑环、四唑环或三嗪环，所述X可任选地被R 9取代。
  21. 权利要求20的化合物，其中X选自
    Figure PCTCN2018091269-appb-100014
    所述X可任选地被R 9取代。
  22. 权利要求21的化合物，其中X选自
    Figure PCTCN2018091269-appb-100015
    Figure PCTCN2018091269-appb-100016
  23. 权利要求1的化合物，其中R 9选自卤素、C 1-3烷基或C 1-3烷氧基。
  24. 权利要求23的化合物，其中R 9选自F、Cl、甲基或OCH 3。
  25. 权利要求1的化合物，其中L选自键、NH或SO 2。
  26. 权利要求1的化合物，其中R 6选自H、氨基、C 1-6烷基、C 3-6环烷基或3～10元杂环烷基，所述氨基、C 1-6烷基、C 3-6环烷基或3～10元杂环烷基可任选地被R 10取代。
  27. 权利要求26的化合物，其中R 6选自H、氨基、甲基、乙基、丙基、异丙基、丁基、异丁基、叔丁基、环丙基、环丁基、环戊基、环己基、任意位置失去一个H原子的
    Figure PCTCN2018091269-appb-100017
    Figure PCTCN2018091269-appb-100018
    Figure PCTCN2018091269-appb-100019
    所述氨基、甲基、 乙基、丙基、异丙基、丁基、异丁基、叔丁基、环丙基、环丁基、环戊基、环己基、任意位置失去一个H原子的
    Figure PCTCN2018091269-appb-100020
    Figure PCTCN2018091269-appb-100021
    Figure PCTCN2018091269-appb-100022
    任选地被R 10取代。
  28. 权利要求27的化合物，其中R 6选自H、NH 2、甲基、异丙基、环丁基、
    Figure PCTCN2018091269-appb-100023
    Figure PCTCN2018091269-appb-100024
    所述NH 2、甲基、异丙基、环丁基、
    Figure PCTCN2018091269-appb-100025
    Figure PCTCN2018091269-appb-100026
    可任选地被R 10取代。
  29. 权利要求28的化合物，其中R 6选自H、NH 2、甲基、
    Figure PCTCN2018091269-appb-100027
    Figure PCTCN2018091269-appb-100028
  30. 权利要求1的化合物，其中R 10选自卤素、羟基、卤代C 1-3烷基、COOH、＝(O)、C 1-6烷基、C 1-6烷基SO 2或3～10元杂环烷基。
  31. 权利要求30的化合物，其中R 10选自F、Cl、Br、OH、一氟甲基、二氟甲基、三氟甲基、一氟乙基、二氟乙基、三氟乙基、四氟乙基、五氟乙基、一氯甲基、二氯甲基、三氯甲基、COOH、＝(O)、甲基、乙基、丙基、异丙基、丁基、异丁基、叔丁基、SO 2CH 3、SO 2CH 2CH 3、SO 2CH 2CH 2CH 3、SO 2CH(CH 3)CH 3、SO 2CH 2CH 2CH 2CH 3、SO 2CH(CH 3)CH 2CH 3、SO 2CH 2CH(CH 3) 2、SO 2C(CH 3) 3、任意位置失去一个H原子的
    Figure PCTCN2018091269-appb-100029
    Figure PCTCN2018091269-appb-100030
  32. 权利要求31的化合物，其中R 10选自F、OH、三氟甲基、COOH、＝(O)、甲基、SO 2CH 3、SO 2CH 2CH 3或
    Figure PCTCN2018091269-appb-100031
  33. 权利要求1的化合物，其中式(I)化合物选自以下化合物：
    Figure PCTCN2018091269-appb-100032
    Figure PCTCN2018091269-appb-100033
    Figure PCTCN2018091269-appb-100034
  34. 一种药物组合物，其包含治疗有效量的权利要求1-33任一项所述的化合物和一种或多种药学上可接受的辅料。
  35. 权利要求1-33任一项所述的化合物、或权利要求34所述的药物组合物在制备治疗Syk受体相关病症的药物中的应用。
  36. 一种治疗Syk受体相关病症的方法，包括给予治疗有效量的权利要求1-33任一项所述的化合物、或权利要求34所述的药物组合物。
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