WO2019233459A1 - 人表皮生长因子受体抑制剂及其制备方法和应用 - Google Patents

人表皮生长因子受体抑制剂及其制备方法和应用 Download PDF

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WO2019233459A1
WO2019233459A1 PCT/CN2019/090224 CN2019090224W WO2019233459A1 WO 2019233459 A1 WO2019233459 A1 WO 2019233459A1 CN 2019090224 W CN2019090224 W CN 2019090224W WO 2019233459 A1 WO2019233459 A1 WO 2019233459A1
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mmol
group
alkyl
room temperature
membered
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French (fr)
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吴勇
周文斌
龚彦春
吴小东
刘永强
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江苏威凯尔医药科技有限公司
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • 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
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
    • C07D239/94—Nitrogen atoms
    • 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
    • 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
    • C07D403/06—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 only aliphatic carbon atoms
    • 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
    • C07D403/12—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 chain containing hetero atoms as chain links
    • 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
    • C07D405/02—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 two hetero rings
    • C07D405/06—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 two hetero rings linked by a carbon chain containing only aliphatic carbon atoms

Definitions

  • the present application belongs to the technical field of medicine, and particularly relates to quinoline or quinazoline derivatives and uses thereof for preparing antitumor drugs.
  • Receptor tyrosine kinases are a class of enzymes that span cell membranes. They have extracellular binding regions, transmembrane structural regions, and intracellular parts that bind growth factors. Residues phosphorylate and affect cell proliferation.
  • Human epidermal growth factor receptor human / epidermal growth factor, Her / erbB family, containing 4 members: EGFR (erbB-1 / HER1), erbB-2 (HER2 / neu), erbB-3 (HER3) and erbB -4 (HER4), all belong to type I-receptor tyrosine kinase (TITK).
  • TITK type I-receptor tyrosine kinase
  • the abnormal activation of Her family kinases is the etiology of many tumors.
  • Her2 receptor tyrosine kinase catalytic activity can be activated by receptor overexpression or ligand-mediated dimerization.
  • Her family polymers have two forms of homodimers and heterodimers.
  • homodimerization is the polymerization of HER1 (EGFR) with EGF family ligands (including EGF, transforming growth factor alpha, betacellulin, EGF bound to heparin, epiregulin). Heterodimerization can be accelerated by binding to neuregulin family ligands.
  • EGF family ligands including EGF, transforming growth factor alpha, betacellulin, EGF bound to heparin, epiregulin.
  • Her3 receptor has no enzymatic activity, the heterodimerization of Her2 and Her3, or Her3 and Her4 can also significantly stimulate tyrosine kinase receptor dimerization. In various cell types, overexpression of the receptor can activate the activity of Her2 kinase.
  • Receptor homodimer and heterodimer activation phosphorylates the receptor and other intracellular protein tyrosine sequences, followed by intracellular signaling pathways such as microtubule-associated protein kinase (MAP kinase) and phosphatidylin Alcohol (-3) kinase (PI3 kinase) is also activated, and activation of these signaling pathways promotes cell proliferation and inhibits apoptosis.
  • MAP kinase microtubule-associated protein kinase
  • PI3 kinase phosphatidylin Alcohol
  • EGFR receptor exon 19 deletion and exon 21 mutation are the two most common types of EGFR mutations in non-small cell lung cancer. Lung cancer with these two mutations is highly sensitive to EGFR tyrosine kinase inhibitors (TKIs) Science, 2004, 304, 1497), EGFR-targeted tyrosine kinase inhibitors (such as gefitinib, erlotinib) and other drugs have achieved great success in the clinical treatment of non-small cell lung cancer (N Engl J Med., 2004, 350, 2129; The Lanance Oncology, 2012, 13, 239).
  • TKIs EGFR tyrosine kinase inhibitors
  • the object of the present invention is to provide a quinoline or quinazoline Her / erbB family kinase inhibitor.
  • Another object of the present invention is to provide the use of the Her kinase inhibitor in the manufacture of a medicament for preventing or treating human epidermal growth factor receptor Her / erbB family-related diseases.
  • the technical solution of the present invention is as follows:
  • A is selected from a C 2 -C 6 alkynyl group, a 6-10 membered aryl group, or a 5-10 membered heteroaryl group;
  • X is selected from a C 1 -C 8 alkyl group, a 5-10 membered heteroaryl group, or a 3-8 membered heterocyclic group, and the C 1 -C 8 alkyl group may further be halogen, cyano, hydroxyl, or C 1- C 4 alkoxy is substituted, and the 3-8 membered heterocyclic group may be further substituted with-(CH 2 ) a CN;
  • Y is selected from C 1 -C 8 alkyl, -COR 1 ,-(CH 2 ) a CN,-(CH 2 ) a OR 1 or 3-8 membered heterocyclic group, said 3-8 membered heterocyclic group May be further substituted by C 1 -C 4 alkyl;
  • R 1 is selected from H, OH or C 1 -C 4 alkyl
  • the B is selected from 6-10 membered aryl or 5-10 membered heteroaryl.
  • the 6-10 membered aryl or 5-10 membered heteroaryl may be further selected from one or more members selected from hydroxyl, halogen, C 1 -C 4 alkyl or -O (CH 2 ) a -5-6-membered heteroaryl substituted by a substituent;
  • a is selected from 0, 1 or 2;
  • n is selected from 0, 1 or 2;
  • n is selected from 0, 1 or 2;
  • M is selected from C-CN or N;
  • W is selected from O, S or NH.
  • A is selected from C 2 -C 4 alkynyl, 6-10 membered aryl or 5-6 membered heteroaryl;
  • X is selected from C 1 -C 4 alkyl, 5-6 membered heteroaryl or 4-6 membered heterocyclic group, and the C 1 -C 4 alkyl group may be further substituted by cyano, hydroxyl or C 1 -C 2 Substituted by alkoxy, the 4-6 membered heterocyclic group may be further substituted by-(CH 2 ) a CN;
  • Y is selected from C 1 -C 4 alkyl, -COR 1 ,-(CH 2 ) a CN,-(CH 2 ) a OR 1 or 3-6 membered heterocyclic group, said 3-6 membered heterocyclic group May be further substituted by C 1 -C 2 alkyl;
  • R 1 is selected from H, OH or C 1 -C 4 alkyl
  • B is a 6-10 membered aryl group, and the 6-10 membered aryl group may be further substituted with one or more substituents selected from halogen or -O (CH 2 ) a -5-6 membered heteroaryl group;
  • a is selected from 0, 1 or 2;
  • n is selected from 0, 1 or 2;
  • n is selected from 0, 1 or 2;
  • M is selected from C-CN or N;
  • W is selected from O or NH.
  • A is selected from ethynyl, phenyl or 5-6 membered heteroaryl
  • X is selected from C 1 -C 4 alkyl, 5-6 membered heteroaryl or 4-6 membered heterocyclic group, and the C 1 -C 4 alkyl group may be further substituted by cyano, hydroxyl or C 1 -C 2 Substituted by alkoxy, the 4-6 membered heterocyclic group may be further substituted by-(CH 2 ) a CN;
  • Y is selected from C 1 -C 2 alkyl, -COR 1 ,-(CH 2 ) a CN,-(CH 2 ) a OR 1 or 3-6 membered heterocyclic group, said 3-6 membered heterocyclic group May be further substituted by C 1 -C 2 alkyl;
  • R 1 is selected from OH, methyl or ethyl
  • B is phenyl, said phenyl being substituted by one or more substituents selected from F, Cl or -O (CH 2 ) a pyridine;
  • a is selected from 1 or 2;
  • n 1;
  • n 1;
  • M is selected from C-CN or N;
  • W is selected from O or NH.
  • A is selected from ethynyl, phenyl, imidazolyl, pyrazolyl, pyrrolyl, pyridyl, or pyrimidinyl;
  • X is selected from a C 1 -C 4 alkyl group, a pyrazolyl group, or a 4-6 membered heterocyclic group, and the C 1 -C 4 alkyl group may be further substituted with a cyano group, a hydroxyl group, or a methoxy group.
  • the 4-6 membered heterocyclic group may be further substituted with-(CH 2 ) a CN;
  • Y is selected from C 1 -C 2 alkyl, -COR 1 ,-(CH 2 ) a CN,-(CH 2 ) a OR 1 or 3-6 membered heterocyclic group, said 3-6 membered heterocyclic group May be further substituted by methyl;
  • R 1 is methyl
  • B is phenyl, said phenyl being substituted by one or more substituents selected from F, Cl or -O (CH 2 ) a pyridine;
  • a is selected from 1 or 2;
  • n 1;
  • n 1;
  • M is selected from C-CN or N;
  • W is selected from O or NH.
  • A is selected from ethynyl, imidazolyl or pyrazolyl
  • X is selected from methyl, -CH 2 CN,-(CH 2 ) 2 OH,-(CH 2 ) 2 OCH 3 , pyrazolyl, oxetanyl, azetidinyl, piperidinyl, or tetrahydro Pyranyl, said oxetanyl may be further substituted by -CH 2 CN;
  • Y is selected from methyl, ethyl, -COCH 3 , -CH 2 CN,-(CH 2 ) 2 OCH 3 , oxetanyl, tetrahydropyranyl or piperidinyl.
  • the piperidinyl may be Further substituted by methyl;
  • B is phenyl, said phenyl being substituted by one or more substituents selected from F, Cl or -OCH 2 -pyridine;
  • n 1;
  • n 1;
  • M is selected from C-CN or N;
  • W is O or NH.
  • the compound of the present invention is selected from the following structures:
  • Another aspect of the present invention provides a method for preparing a compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, comprising the following steps:
  • A, X, Y, B, m, n, M, and W are as defined by the compound of formula (I).
  • Another aspect of the present invention provides the use of the aforementioned compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof for preparing a medicament for preventing or treating cancer.
  • Another aspect of the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective dose of the aforementioned compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • Another aspect of the present invention provides the use of the pharmaceutical composition in the preparation of a medicament for preventing or treating cancer.
  • the cancer is selected from the group consisting of ovarian cancer, cervical cancer, colorectal cancer, breast cancer, pancreatic cancer, glioma, glioblastoma, melanoma, prostate cancer, leukemia, lymphoma, and non-Hoar. Chitin lymphoma, gastric cancer, lung cancer, hepatocellular carcinoma, gastrointestinal stromal tumor, thyroid cancer, bile duct cancer, endometrial cancer, kidney cancer, anaplastic large cell lymphoma, acute myeloid leukemia, multiple myeloma , Melanoma or mesothelioma.
  • aryl refers to a full-carbon monocyclic or bicyclic group
  • 6- to 10-membered aryl refers to a full-carbon aryl containing 6 to 10 carbons, such as phenyl and naphthyl.
  • the aryl ring may be fused to a heteroaryl, heterocyclic or cycloalkyl ring, wherein the ring connected to the parent structure is an aryl ring.
  • the aryl group may be substituted or unsubstituted.
  • the substituent is preferably one or more of the following groups, independently selected from halogen, hydroxyl, mercapto, cyano, nitro, azido, C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C 3 -C 8 cycloalkyl, 3-8 membered heterocyclyl, 3-8 membered heterocyclyloxy, 3 -8-membered heterocyclylthio, C 5 -C 10 aryl, C 5 -C 10 aryloxy, C 5 -C 10 arylthio, 5-10 membered heteroaryl, 5-10 membered heteroaryl Aryloxy, 5-10 membered heteroarylthio, -C 0-8 -S (O) rR 2 , -C 0-8 -OR 2 , -OC 0-8 -R 2 , -C 0-
  • heteroaryl refers to a heteroaromatic system containing 1 to 4 heteroatoms including heteroatoms of nitrogen, oxygen, and sulfur, including but not limited to furyl, thienyl, pyridyl, and pyrrole.
  • group pyrazolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, imidazolyl, tetrazolyl, and the like.
  • Heteroaryl may be substituted or unsubstituted.
  • the substituent is preferably one or more of the following groups, independently selected from halogen, hydroxyl, mercapto, cyano, nitro, azido, C 1- C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C 3 -C 8 cycloalkyl, 3-8 membered heterocyclyl, 3-8 membered heterocyclyloxy, 3-8 membered heterocyclylthio, C 5 -C 10 aryl, C 5 -C 10 aryloxy, C 5 -C 10 arylthio, 5-10 membered heteroaryl, 5-10 member Heteroaryloxy, 5-10 membered heteroarylthio, -C 0-8 -S (O) rR 2 , -C 0-8 -OR 2 , -OC 0-8 -R 2 , -C 0 -8 -C (O
  • R 2 and R 3 are selected from H, C 1 -C 8 alkyl, C 3 -C 8 cycloalkyl, optionally further selected from one or more selected from amino, halogen, hydroxyl, C 1 -C 8 alkyl, C 1 -C 8 alkoxy, halogen substituted C 1 -C 8 alkoxy, C 3 -C 8 cycloalkyl, NR 4 R 5 , 4-10 membered heterocyclic group, 6-10 membered aryl group, 5 -10 membered heteroaryl is substituted.
  • R 4 and R 5 are selected from H, C 1 -C 8 alkyl, and C 3 -C 8 cycloalkyl.
  • r is selected from 0, 1, and 2.
  • C 1 -C 8 alkyl refers to a straight-chain alkyl group and a branched alkyl group including 1 to 8 carbon atoms.
  • the alkyl group refers to a saturated aliphatic hydrocarbon group, such as methyl, ethyl, n- Propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2 -Dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-tris Methylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl
  • cycloalkyl refers to a saturated monocyclic hydrocarbon substituent
  • C 3 -C 8 cycloalkyl refers to a monocyclic cycloalkyl including 3 to 8 carbon atoms
  • Restrictive examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and the like.
  • alkenyl refers to an alkyl group as defined above, which is composed of at least two carbon atoms and at least one carbon-carbon double bond
  • C 2 -C 8 alkenyl refers to a straight chain containing 2 to 8 carbons. Or containing branched alkenyl. Examples are vinyl, 1-propenyl, 2-propenyl, 1-, 2- or 3-butenyl, and the like.
  • alkynyl refers to an alkyl group as defined above composed of at least two carbon atoms and at least one carbon-carbon triple bond
  • C 2 -C 8 alkynyl refers to a straight-chain or Contains branched alkynyl. For example, ethynyl, 1-propynyl, 2-propynyl, 1-, 2- or 3-butynyl and the like.
  • heterocyclyl means a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, wherein one or more ring atoms are selected from heteroatoms of nitrogen, oxygen, or S (O) r, but excluding The ring part of -OO-, -OS- or -SS-, and the remaining ring atoms are carbon.
  • S (O) r sulfur-containing ring atoms
  • 4-10 membered heterocyclyl refers to a cyclic group containing 4 to 10 ring atoms.
  • Non-limiting examples of monocyclic heterocyclyls include dihydropyranyl, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, tetrahydropyranyl, piperazinyl, morpholine Group, thiomorpholinyl, homopiperazinyl and the like.
  • Polycyclic heterocyclic groups include spiro, fused and bridged heterocyclic groups.
  • alkoxy means -O- (alkyl), wherein alkyl is as defined above.
  • C 3 -C 8 alkoxy refers to an alkyloxy group containing 1 to 8 carbons. Non-limiting examples include methoxy, ethoxy, propoxy, butoxy, and the like.
  • Halogen means fluorine, chlorine, bromine or iodine.
  • “Pharmaceutical composition” means a mixture containing one or more of the compounds described herein or a physiologically pharmaceutically acceptable salt or prodrug thereof with other chemical components, as well as other components such as physiologically pharmaceutically acceptable carriers and excipients. ⁇ ⁇ Shape agent.
  • the purpose of the pharmaceutical composition is to promote the administration to the organism, which is beneficial to the absorption of the active ingredient and then exerts the biological activity.
  • Figure 23 Proton nuclear magnetic resonance spectrum of the compound of Example 23.
  • Step 1 Synthesis of 5-((1-((benzyloxy) carbonyl) piperidin-4-yl) oxy) -4-bromo-2-nitrobenzoic acid
  • Step 2 Synthesis of (4- (2-bromo-5- (methoxycarbonyl) -4-nitrophenoxy) piperidine-1-carboxylic acid benzyl ester
  • Step 3 Synthesis of 4- (4-amino-2-bromo-5- (methoxycarbonyl) phenoxy) piperidine-1-carboxylic acid benzyl ester
  • Step 4 Synthesis of benzyl 4-((7-bromo-4-oxo-3,4-dihydroquinazolin-6-yl) oxy) piperidine-1-carboxylate
  • Step 5 Synthesis of benzyl 4-((7-bromo-4-chloroquinazolin-6-yl) oxy) piperidine-1-carboxylate
  • Step 6 Synthesis of benzyl 4-((7-bromo-4-((3-chloro-4-fluorophenyl) amine) quinazolin-6-yl) oxy) piperidine-1-carboxylate
  • Step 7 Synthesis of 1-methyl-4- (4,4,5,5-methyl-1,3,2-dioxolane-2-yl) -1H-imidazole
  • Step 8 4-((4-((3-chloro-4-fluorophenyl) amine) -7- (1-methyl-1H-imidazol-4-yl) quinazolin-6-yl) oxy Synthesis of) -piperidine-1-carboxylic acid benzyl ester
  • Step 9 N- (3-chloro-4-fluorophenyl) -7- (1-methyl-1H-imidazol-4-yl) -6- (piperidin-4-yloxy) quinazolin-4 Of amine hydrogen bromide
  • Step 10 1- (4-((4-((3-chloro-4-fluorophenyl) amine) -7- (1-methyl-1H-imidazol-4-yl) quinazolin-6-yl ) Oxy) piperidin-1-yl) propan-2-en-1-one
  • N- (3-chloro-4-fluorophenyl) -7- (1-methyl-1H-pyrazol-4-yl) -6- (piperidin-4-yl) Oxygen) quinazoline-4-amine hydrogen bromide (crude from the previous step, 0.42 mmol), dichloromethane (30 mL), triethylamine (0.215 g, 2.13 mmol), the temperature of the ice bath was lowered to 0-5 ° C, A solution of acryloyl chloride (0.046 g, 0.47 mmol) in dichloromethane (3 mL) was added dropwise, and the reaction was carried out for about half an hour.
  • Step 1 Refer to Example 1 to synthesize 4-((7-bromo-4-((3,4-dichloro-2-fluorophenyl) amine) -quinazolin-6-yl) oxy) piperidine- 1-Benzyl formate.
  • Step 2 4-((4-((3,4-dichloro-2-fluorophenyl) amine) -7- (1-methyl-1H-imidazol-4-yl) quinazolin-6-yl Synthesis of) oxy) piperidine-1-carboxylic acid benzyl ester
  • Step 4 1- (4-((4-((3,4-dichloro-2-fluorophenyl) amine) -7- (1-methyl-1H-imidazol-4-yl) quinazoline- Synthesis of 6-yl) oxy) piperidin-1-yl) propan-2-en-1-one
  • N- (3,4-dichloro-2-fluorophenyl) -7- (1-methyl-1H-imidazol-4-yl) -6- (piperidine-4 -Yloxy) quinazolin-4-amine hydrogen bromide (crude from the previous step, 0.64mmol), dichloromethane (20mL), triethylamine (0.195g, 1.93mmol), the temperature of the ice bath was reduced to 0-5
  • a solution of acryloyl chloride (0.064g, 0.71mmol) in dichloromethane (3mL) was added dropwise, and the reaction was completed for about 10 minutes.
  • Step 1 Synthesis of 4-((7-bromo-4-((3-chloro-4-fluorophenyl) amine) -quinazolin-6-yl) oxy) piperidine-1-carboxylic acid with reference to Example 1 ester.
  • Step 2 4-((4-((3-chloro-4-fluorophenyl) amine) -7- (1-methyl-1H-pyrazol-4-yl) quinazolin-6-yl) oxy Benzyl piperidine-1-carboxylate
  • Step 3 N- (3-chloro-4-fluorophenyl) -7- (1-methyl-1H-pyrazol-4-yl) -6- (piperidin-4-yloxy) quinazoline- 4-amine hydrogen bromide
  • Step 4 1- (4-((4-((3-chloro-4-fluorophenyl) amine) -7- (1-methyl-1H-pyrazol-4-yl) quinazoline-6- Yl) oxy) piperidin-1-yl) prop-2-en-1-one
  • N- (3-chloro-4-fluorophenyl) -7- (1-methyl-1H-pyrazol-4-yl) -6- (piperidin-4-yl) (Oxy) quinazoline-4-amine hydrogen bromide (crude, 0.43 mmol), dichloromethane (30 mL), triethylamine (0.215 g, 2.13 mmol), the temperature of the ice bath was lowered to 0-5, and the solution was added dropwise. A solution of acryloyl chloride (0.046 g, 0.47 mmol) in dichloromethane (3 mL) was reacted for about half an hour.
  • Step 1 Refer to Example 1 to synthesize 4-((7-bromo-4-((3,4-dichloro-2-fluorophenyl) amine) -quinazolin-6-yl) oxy) piperidine- 1-Benzyl formate.
  • Step 2 4-((4-((3,4-dichloro-2-fluorophenyl) amine) -7- (1-methyl-1H-pyrazol-4-yl) quinazoline-6- Of Benzyl) oxy) piperidine-1-carboxylic acid benzyl ester
  • Step 3 N- (3,4-dichloro-2-fluorophenyl) -7- (1-methyl-1H-pyrazol-4-yl) -6- (piperidin-4-yloxy) quine Oxazoline-4-amine hydrogen bromide
  • Step 4 1- (4-((4-((3,4-dichloro-2-fluorophenyl) amine) -7- (1-methyl-1H-pyrazol-4-yl) quinazoline -6-yl) oxy) piperidin-1-yl) propan-2-en-1-one
  • N- (3,4-dichloro-2-fluorophenyl) -7- (1-methyl-1H-pyrazol-4-yl) -6- (piperidine- 4-Alkyloxy) quinazolin-4-amine hydrogen bromide (crude, 0.72 mmol), dichloromethane (20 mL), triethylamine (0.366 g, 3.62 mmol), the temperature of the ice bath was lowered to 0-5 ° C , A solution of acryloyl chloride (0.079 g, 0.87 mmol) in dichloromethane (2 mL) was added dropwise, and the reaction was carried out for about 20 min.
  • Step 1 Synthesis of benzyl 4-((7-bromo-4-chloroquinazolin-6-yl) oxy) piperidine-1-carboxylate with reference to Example 1.
  • Step 4 4-((7-bromo-4-((3-chloro-4- (pyridine-2-methoxy) phenyl) amine) quinazolin-6-yl) oxy) piperidine-1- Synthesis of benzyl carbonate
  • Step 5 4-((4-((3-chloro-4- (pyridine-2-methoxy) phenyl) amine) -7- (1-methyl-1H-pyrazol-4-yl) quine Synthesis of oxazoline-6-yl) oxy) piperidine-1-benzyl carbonate
  • Step 6 N- (3-chloro-4- (pyrazole-2-methoxy) phenyl) -7- (1-methyl-1H-pyrazol-4-yl) -6- (piperidine- 4-yloxy) quinazolin-4-amine hydrogen bromide
  • Step 7 1- (4-((4-((3-chloro-4- (pyridine-2-methoxy) phenyl) amine) -7- (1-methyl-1H-pyrazole-4- Yl) quinazolin-6-yl) oxy) piperidin-1-yl) prop-2-en-1-one
  • Step 1 Synthesis of 4-((7-bromo-4-((3-chloro-4-fluorophenyl) amino) quinazolin-6-yloxy) piperidine-1-carboxylic acid benzyl ester with reference to Example 1 .
  • Step 2 benzyl 4-((4 (3-chloro-4-fluorophenyl) amino) -7- (1- (2-methoxyethyl) -1H-pyrazol-4-yl) quinazole Benzyl-6-oxy) piperidine-1-carboxylate
  • esters (0.50g, 0.85mmol), 1- (2-methoxyethyl) -4- (dioxophosphate reactant-methyl-2-yl) -1H-pyrazole (0.31g, 1.02mmol), potassium carbonate (0.29g, 1.71mmol), DMF ( 8mL), H 2 O (2mL), substituted N 2, was added Pd (dppf) Cl 2 (0.08g , 0.08mmol), substituted N 2 three times, under N 2 The temperature was raised to 70 ° C, the reaction was terminated after overnight, cooled to room temperature, EA was added, washed with water, dried over anhydrous Na 2 SO 4 , filtered and concentrated, and column chromatography (DCM / MeOH system) was obtained to obtain a yellow solid 0.23 g, yield 46%. .
  • Step 3 N- (3-chloro-4-fluorophenyl) -7- (1- (2-methoxyethyl) -1H-pyrazol-4-yl) -6 (piperidine-4-oxo ) Quinazolin-4-amine
  • Step 4 1- (4-((4 (-(3-chloro-4-fluorophenyl) amino) -7- (1- (2-methoxyethyl) -1H-pyrazol-4-yl ] Quinazolin-6-yl] oxy) piperidin-1-yl) prop-2-en-1-one
  • N- (3-chloro-4-fluorophenyl) -7- (1- (2-methoxyethyl) -1H-pyrazol-4-yl) -6 (piperazine) to a single-necked flask.
  • Pyridin-4-oxy) quinazolin-4-amine (0.15 g, 0.30 mmol
  • triethylamine (0.20 g, 1.50 mmol
  • DCM 10 mL
  • acryloyl chloride 0.05 g, 0.42
  • Step 1 Synthesis of 4-((7-bromo-4-((3-chloro-4-fluorophenyl) amino) quinazolin-6-yloxy) piperidine-1-carboxylic acid benzyl ester with reference to Example 1 .
  • Step 2 benzyl 4-((4 (3-chloro-4-fluorophenyl) amino) -7- (1- (2-hydroxyethyl) -1H-pyrazol-4-yl) quinazoline- 6-yloxy) piperidine-1-carboxylic acid benzyl ester
  • Esters (0.50 g, 0.85 mmol), 2 (4- (4-, 4-, 5-, 5-tetramethyl-1,3-dioxorane-2-yl) -1H-pyrazole-1- Alkyl) ethane-1-ol (0.30 g, 1.02 mmol), potassium carbonate (0.29 g, 1.71 mmol), DMF (8 mL), H 2 O (2 mL), N 2 was replaced, and Pd (dppf) Cl 2 ( 0.08mg, 0.08mmol), substituted N 2 three times, heated to 70 deg.] C under N 2, after the termination of the reaction overnight, cooled to room temperature, EA, washed with water, dried over anhydrous Na 2 SO 4, filtered and concentrated, column chromatography ( DCM / MeOH system), 0.37 g of brown oily solid was obtained in a yield of 74%.
  • Step 3 2- (4- (4- (3-chloro-4-fluorophenyl) amino) -6- (piperidin-4-oxy) quinazolin-7-yl-1H-pyrazole-1 -Yl) ethane-1-ol
  • Step 4 1- (4-((4 (-(3-chloro-4-fluorophenyl) amino) -7- (1- (2-hydroxyethyl) -1H-pyrazol-4-yl) quine Oxazolin-6-yl] oxy) piperidin-1-yl) prop-2-en-1-one
  • Step 1 Synthesis of 4-((7-bromo-4-((3-chloro-4-fluorophenyl) amino) quinazolin-6-yloxy) piperidine-1-carboxylic acid benzyl ester with reference to Example 1 .
  • Step 2 7-bromo-N- (3-chloro-4-fluorophenyl) -6 (piperidin-4-oxy) quinazolin-4-amine
  • Step 3 1- (4- (7-bromo-4-((3-chloro-4-fluorophenyl) amino) quinazolin-6-yl) oxy) piperidin-1-yl-propane-2 -En-1-one
  • Step 4 1- (4 (-(4 (-(3-chloro-4-fluorophenyl) amino) -7 (3-methyl-1H-pyrazol-5-yl) oxyquinyl) oxy) Piperidin-1-yl) -2-en-1-one
  • Step 2 Synthesis of 2- (4, (4-, 4-, 5-, 5-tetramethyl-1,3-dioxorane-2-yl) -1H-pyrazol-1-yl) acetonitrile
  • Step 3 2- (4- (6- (1-acryloylpiperidin-4-yl) oxy) -4- (3-chloro-4-fluorophenyl) aminoquinazoline) -7-yl)- Synthesis of 1H-pyrazol-1-yl) acetonitrile formate
  • Step 1 Synthesis of 1- (4- (7-bromo-4-((3-chloro-4-fluorophenyl) amino) quinazolin-6-yl) oxy) piperidine-1- with reference to Example 8 -Prop-2-en-1-one.
  • Step 2 1- (4-((4-((3-chloro-4-fluorophenyl) amino) -7- (1- (oxyethyl-3-yl) -1H-pyrazol-4-yl ) Quinazolin-6-yl) oxy) piperidin-1-yl) -prop-2-en-1-one
  • Step 1 Synthesis of (1-4- (7-bromo-4- (3,4-dichloro-2-fluorophenyl) aminoquinazolin-6-yl) oxy) piperidine-1 with reference to Example 8 -Yl) -2-en-1-one.
  • Step 2 1- (4-((4-((3,4-dichloro-2-fluorophenyl) amino) -7- (1- (oxy-3-yl) -1H-pyrazole-4- Synthesis of yl) quinazolin-6-yl) oxy) piperidin-1-yl) prop-2-en-1-one
  • Step 1 1- (4-((4-((3-chloro-4-fluorophenyl) amino) -7- (1- (tetrahydro-2H-pyran-4-yl) -1H-pyrazole Synthesis of 4--4-yl) quinazolin-6-yl) oxy) piperidin-1-yl) prop-2-en-1-one
  • Step 2 1- (4-((4-((3-chloro-4-fluorophenyl) amino) -7- (1- (1-methylpiperidin-4-yl) -1H-pyrazole- Synthesis of 4-yl) quinazolin-6-yl) oxy) piperidin-1-yl) propan-2-en-1-one
  • Step 1 1- (4-((4-((3-chloro-4-fluorophenyl) amino) -7-((1-methyl-1H-pyrazol-4-yl) ethynyl) quinazole Synthesis of Phenolin-6-yl) oxy) piperidin-1-yl) prop-2-en-1-one
  • Step 1 2- (3- (4- (4,4,5,5-tetramethyl-1,3,2-dioxolane-2-yl) -1H-pyrazol-1-yl Synthesis of oxetan-3-yl) acetonitrile
  • Step 2 2- (3- (4- (6- (1-acryloylpiperidin-4-yl) oxy) -4- (3-chloro-4-fluorophenyl) aminoquinazoline) -7 -Yl) -1H-pyrazol-1-yl) oxetane-3-yl) acetonitrile synthesis
  • Step 1 Synthesis of 4- (4,4,5,5-tetramethyl-1,3,2-dioxolane-2-yl) -1H-pyrazol-1-yl) piperidine
  • the aqueous phase is extracted with DCM, the organic phases are combined, washed twice with water, dried over anhydrous Na 2 SO 4 , filtered and concentrated to obtain 4.8 g of a white gel-like solid.
  • the crude product is directly used in the next step.
  • Step 2 1- (4- (4,4,5,5-tetramethyl-1,3,2-dioxolane-2-yl) -1H-pyrazol-1-yl) piperidine Synthesis of 1-1-yl) ethane-1-one
  • Step 3 1- (4- (7- (1- (1-acetylpiperidin-4-yl) -1H-pyrazol-4-yl) -4- (3-chloro-4-fluorophenyl) amino Synthesis of oxazoline-6-yl) oxy) piperidin-1-yl) -2-en-1-one
  • Step 1 Synthesis of 1- (2-methoxyethyl) -4- (4- (methyl reactant oxophosphate-2-yl) -1H-pyrazol-1-yl) piperidine
  • Step 2 1- (4-((4-((3-chloro-4-fluorophenyl) amino) -7- (1- (1- (2-methoxyethyl) piperidin-4-yl ) -1H-pyrazol-4-yl) quinazolin-6-yl) oxy) piperidin-1-yl) propan-2-en-1-one
  • Step 1 1- (tetrahydro-2H-pyran-4-yl) -4- (4- (4,4,5,5-tetramethyl-1,3,2-dioxorane-2- Synthesis of yl) -1H-pyrazol-1-yl) piperidine
  • Step 2 1- (4-((4-((3-chloro-4-fluorophenyl) amino) -7- (1- (tetrahydro-2H-pyran-4-yl) piperidine-4- (Synthesis) -1H-pyrazol-4-yl) quinazolin-6-yl) oxy) piperidin-1-yl) propan-2-en-1-one
  • Step 2 1- (4-((4-((3-chloro-4-fluorophenyl) amino) -7- (1- (1-ox-3-yl) piperidin-4-yl) -1H -Pyrazol-4-yl) quinazolin-6-yl) oxy) piperidin-1-yl) propan-2-en-1-one
  • Step 1 1-methyl-4- (3- (4- (4,4,5,5, tetramethyl-1-dioxyboronic acid-2-yl) -1H-pyrazol-1-yl) heteroaza Synthesis of cyclobut-1-yl) piperidinepyrazole
  • Step 2 1- (4-((4-((3-chloro-4-fluorophenyl) amino) -7- (1- (1-methylpiperidin-4-yl) azetidin- Synthesis of 3-yl) -1H-pyrazol-4-yl) quinazolin-6-yl) oxy) piperidin-1-yl) propan-2-en-1-one
  • Step 1 Synthesis of tert-butyl 3-((chlorosulfonyl) oxy) azetidine-1-carboxylate
  • Step 2 tert-Butyl 3- (4,4,5,5-tetramethyl-1,3,2-dioxolane-2-yl) -1H-pyrazol-1-yl) aza Synthesis of cyclobutane-1-carboxylate
  • Step 3 Synthesis of 1 (heteroazacyclobut-3-yl) -4- (4,4,5,5tetramethyl-1-dioxoborate-2-yl) -1H-pyrazole
  • Step 4 1- (1- (tetrahydro-2H-pyran-4-yl) azetidin-3-yl) -4- (4,4,5,5-tetramethyl-1,3 Synthesis of 2,2-dioxolane-2-yl) -1H pyrazole
  • Step 5 1- (4-((4-((3-chloro-4-fluorophenyl) amino) -7- (1- (tetrahydro-2H-pyran-4-yl) azetidine -3-yl) -1H-pyrazol-4-yl) quinazolin-6-yl) oxy) piperidin-1-yl) propan-2-en-1-one
  • Step 1 tert-butyl 3- (cyanomethyl) -3- (4- (4,4,5,5-tetramethyl-1,3,2-dioxolane-2-yl) Synthesis of -1H-pyrazol-1-yl) azetidine-1-carboxylate
  • Step 2 2- (3- (4- (4,4,5,5-tetramethyl-1,3,2-dioxolane-2-yl) -1H-pyrazol-1-yl Synthesis of azetidin-3-yl) acetonitrile
  • Step 3 2- (1- (tetrahydro-2H-pyran-4-yl) -3- (4- (4,4,5,5-tetramethyl-1,3,2-dioxane Synthesis of pentyl-2-yl) -1H-pyrazol-1-yl) azetidin-3-yl) acetonitrile
  • Step 4 2- (3- (4- (6- (1-acryloylpiperidin-4-yl) oxy) -4- (3-chloro-4-fluorophenyl) aminoquinazoline) -7 -Yl) -1H-pyrazol-1-yl) -1- (tetrahydro-2H-pyran 4 keto) hetazacyclobut-3-yl) acetonitrile
  • Step 1 Synthesis of 5-((1-((benzyloxy) carbonyl) piperidin-4-yl) oxy) -4-bromo-2-nitrobenzoic acid
  • Step 2 Synthesis of 4- (2-bromo-5- (methoxycarbonyl) -4-nitrophenoxy) -1-benzyloxycarbonylpiperidine
  • Step 3 Synthesis of benzyl 4- (4-amino-2-bromo-5- (methoxycarbonyl) phenoxy) piperidine-1-carboxylic acid ester
  • Step 5 Synthesis of benzyl 4-((7-bromo-3-cyano-4-oxo-3,4-dihydroxyquinolin-6-yl) oxy) piperidine-1-carboxylic acid ester
  • Step 6 Synthesis of benzyl 4-((7-bromo-4-chloro-3-cyanoquinolin-6-yl) oxy) piperidine-1-carboxylic acid ester
  • Step 7 benzyl 4-((7-bromo-4-((3-chloro-4-fluorophenyl) amino) -3-cyanoquinolin-6-yl) oxy) piperidine-1- Synthesis of carboxylic acid esters
  • Step 8 Synthesis of 7-bromo-4-((3-chloro-4-fluorophenyl) amino) -6- (piperidin-4-yloxy) quinoline-3-carbonitrile
  • Step 9 6-((1-acryloylpiperidin-4-yl) oxy) -7-bromo-4-((3-chloro-4-fluorophenyl) amino) quinoline-3-carbonitrile Synthesis
  • Step 10 6-((1-acryloylpiperidin-4-yl) oxy) -4-((3-chloro-4-fluorophenyl) amino) -7- (1-methyl-1H- Synthesis of pyrazol-4-yl) quinoline-3-carbonitrile
  • reaction solution was extracted with EA, washed once with water, and the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (DCM / MeOH system) to obtain 78.20 mg of a yellow solid with a yield of 39%.
  • Step 1 6-((1-acryloylpiperidin-4-yl) oxy) -4-((3-chloro-4-fluorophenyl) amino) -7- (1- (1-methyl Synthesis of piperidin-4-yl) -1H-pyrazol-4-yl) quinoline-3-carbonitrile
  • reaction was terminated after heating to 70 ° C for 2h. After cooling to room temperature, the reaction solution was extracted with EA, washed once with water, and the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (DCM / MeOH system) to obtain 115.5 mg of a yellow solid with a yield of 50%.
  • Step 4 Synthesis of 7- (1-methyl-1H-pyrazol-4-yl) -6-nitroquinazolin-4-ol
  • Step 5 Synthesis of 3-chloro-N- (3,4-dimethoxybenzyl) -4-fluoroaniline
  • Step 6 N- (3-chloro-4-fluorophenyl) -N- (3,4-dimethoxybenzyl) -7- (1-methyl-1H-pyrazol-4-yl)- Synthesis of 6-nitroquinazoline-4-amine
  • Step 7 N 4- (3-chloro-4-fluorophenyl) -N 4- (3,4-dimethoxybenzyl) -7- (1-methyl-1H-pyrazol-4-yl ) Synthesis of quinazoline-4,6-diamine
  • N- (3-chloro-4-fluorophenyl) -N- (3,4-dimethoxybenzyl) -7- (1-methyl-1H-pyrazole- 4-yl) -6-nitroquinazolin-4-amine (1.0 g, 1.82 mmol), Fe (0.51 g, 9.11 mmol), NH 4 Cl (0.98 g, 18.20 mmol), EtOH (20 mL) and H 2 O (8 mL), terminated after 2 hours at 80 ° C, cooled to room temperature, filtered, the filter cake was rinsed with EA, the filtrate was spin-dried, the residue was dissolved in EA, washed with water, saturated NaCl, dried over anhydrous Na 2 SO 4 , filtered and concentrated 0.8 g of yellow solid was obtained with a yield of 85%.
  • Step 8 tert-butyl 4-((4-((3-chloro-4-fluorophenyl) (3,4-dimethoxybenzyl) amino) -7- (1-methyl-1H-pyridine Synthesis of azole-4-yl) quinazolin-6-yl) amino) piperidine-1-carboxylate
  • reaction was terminated at 20 ° C for 1 hour, quenched with water, adjusted to pH 7-8 with saturated NaHCO 3 , extracted with EA, washed with organic phase, and washed with saturated NaCl. , Dried over anhydrous Na 2 SO 4 , concentrated by filtration, and column chromatography (DCM / MeOH system) to obtain 0.7 g of a yellow oily solid with a yield of 76%.
  • Step 9 N 4- (3-chloro-4-fluorophenyl) -7- (1-methyl-1H-pyrazol-4-yl) -N 6- (piperidin-4-yl) quinazoline Synthesis of -4,6-diamine
  • Step 10 1- (4-((4-((3-chloro-4-fluorophenyl) amino) -7- (1-methyl-1H-pyrazol-4-yl) quinazoline-6- Of amino group) amino) piperidin-1-yl) propan-2-en-1-one
  • the ⁇ test 33 p-ATP isotope test was used to test the inhibitory effect of the compound on the kinases HER2 and EGFR (D770_N771insNPG), and the compound's half inhibitory concentration IC 50 was obtained .
  • the exon 20 was used to insert the mutation.
  • the new drug Poziotinb was used as a positive control. Poziotinib was purchased from TargetMol, catalog number T2630, and HKI-272 was purchased from Bellingville, batch number LPB0Q20.
  • the compound was dissolved to a specific concentration with 100% DMSO, and then it was gradient diluted to a different concentration of the test sample (DMSO solution) using an automatic sampling device.
  • the reaction solution was subjected to ion exchange filtration system to remove unreacted ATP and ADP plasma generated by the reaction, and then measured the 33 P isotope radiation in the substrate.
  • the inhibitory effect of different concentrations of compounds on kinase activity was calculated based on the amount of kinase added to the inhibitor system at different concentrations, and the IC 50 was inhibited by graphpad prism fitting.
  • the compound of the present invention has a kinase inhibitory activity equivalent to that of the positive drug, including Her2 and exon 20 insertion mutant EGFR (D770_N771insNPG).
  • A431 cell line was cultured under the conditions of DMEM + 10% FBS.
  • a 96-well cell culture plate was inoculated with 100 ⁇ L of A431 cell suspension in logarithmic growth phase at a density of 8 ⁇ 10 4 / ml. The culture plate was cultured in an incubator for 24 hours to make the cells adhere to (37 ° C, 5% CO 2 ).
  • Each compound has been dissolved in DMSO to prepare a 10 mM stock solution, which is diluted 400 times the target concentration with DMSO and diluted to 2 times the target concentration with serum-free medium to maintain the DMSO concentration in the drug solution at 0.5. %.
  • DMSO fetal sulfate
  • 100 ⁇ L / well of each concentration of drug solution was sequentially added. Three replicates were set for each concentration, and a blank control and a negative control were set. The culture was continued at 37 ° C and 5% CO 2 for 72 hours.
  • the MTT method was used to test the cell activity of the compound on SKBR-3, and the IC 50 value of the half-inhibition concentration of the compound to inhibit cell proliferation activity was obtained.
  • SKBR-3 cell line was cultured under the conditions of DMEM (high sugar) + 10% FBS.
  • DMEM high sugar
  • FBS 10% FBS
  • 100 ⁇ L of a SKBR-3 cell suspension in the logarithmic growth phase was inoculated at a density of 8 ⁇ 10 4 / ml.
  • the culture plate was cultured in an incubator for 24 hours to attach the cells (37 ° C, 5%). CO 2 ).
  • DMEM high glucose medium containing 10% FBS Discard the DMEM high glucose medium containing 10% FBS in the 96-well cell culture plate. Each compound has been dissolved in DMSO to prepare a 10 mM stock solution, which is diluted 400 times the target concentration with DMSO and diluted to 2 times the target concentration with serum-free medium. In a 96-well plate inoculated with cells, 100 ⁇ L / well of each concentration of drug solution was sequentially added. Three replicates were set for each concentration, and a blank control and a negative control were set. The culture was continued at 37 ° C and 5% CO 2 for 72 hours.
  • BT-474 cell line was cultured under the condition of RPMI-1640 + 10% FBS.
  • a 96-well cell culture plate was inoculated with 100 ⁇ L of a suspension of Hcc827 cells in logarithmic growth phase at a density of 8 ⁇ 10 4 / ml.
  • the culture plate was cultured in an incubator for 24 hours to make the cells adhere (37 stickers, 5% CO 2 ).
  • Each compound has been dissolved in DMSO to prepare a 10 mM stock solution, which is diluted 400 times the target concentration with DMSO and diluted to 2 times the target concentration with serum-free medium to maintain the DMSO concentration in the drug solution at 0.5. %.
  • DMSO fetal sulfate
  • 100 ⁇ L / well of each concentration of drug solution was sequentially added. Three replicates were set for each concentration, and a blank control and a negative control were set. The culture was continued for 72 hours in 37 sets and 5% CO 2 .
  • the compounds of the present invention have tumor cell inhibitory activity equivalent to that of positive drugs, including Her2 positive and EGFR positive tumor cells.
  • the total volume of the incubation system was 250 ⁇ L.
  • 2.5 ⁇ L of 100 ⁇ mol / L test compound Mix with 197.5 ⁇ L of the above incubation solution, pre-incubate in a 37 ° C water bath for 5 minutes, and add 50 ⁇ L of the reduced coenzyme II solution (5 mmol / L), which is also pre-incubated for 5 minutes.
  • the compound of the present invention has a very significant advantage of metabolic stability of liver microsomes, and therefore has better drugability and stability in vivo.

Abstract

提供一类具有式(I)结构的喹啉或喹唑啉衍生物、含有式(I)化合物的药物组合物及所述化合物在制备预防或治疗人表皮生长因子受体Her/erbB家族相关疾病药物的用途，特别是用于预防或治疗与蛋白质酪氨酸激酶相关的肿瘤的用途。其中式(I)中的各取代基与说明书中的定义相同。

Description

人表皮生长因子受体抑制剂及其制备方法和应用 技术领域
本申请属于医药技术领域，具体涉及喹啉或喹唑啉衍生物及其用于制备抗肿瘤药物的用途。
本申请要求中国专利CN201810597222.4(申请日2018年6月8日，发明名称人表皮生长因子受体抑制剂及其制备方法和应用)的优先权。
背景技术
受体酪氨酸激酶是横跨细胞膜的一类酶，具有结合生长因子的胞外结合区、跨膜结构区和胞内部分，胞内部分的功能是作为激酶将蛋白质中的特定酪氨酸残基磷酸化并影响细胞的增殖。
人表皮生长因子受体(human epidermal growth factor receptors,Her/erbB)家族，含4个成员即EGFR(erbB-1/HER1)、erbB-2(HER2/neu)、erbB-3(HER3)和erbB-4(HER4)，均属于I型酪氨酸激酶受体(type I-receptor tyrosine kinase，TITK)。Her家族激酶的异常激活是多种肿瘤发生的病因。Her2受体酪氨酸激酶催化活性可通过受体过度表达或配体介导二聚合被激活。Her家族聚合体有同型二聚体和异型二聚体两种形式。同型二聚化的一个例子是HER1(EGFR)与EGF家族配体(包括EGF、转化生长因子α、betacellulin、与肝磷脂结合的EGF、epiregulin)的聚合，四种Her酪氨酸激酶之间的异型二聚合可通过与neuregulin家族配体的结合被加速。虽然Her3的受体没有酶活性，但Her2与Her3，或Her3与Her4的异型二聚也可显著地刺激酪氨酸激酶受体二聚合。在各种类型细胞中，受体过度表达可激活Her2激酶的活性。受体同型二聚体和异型二聚体的激活可将受体和其他细胞内蛋白质酪氨酸序列进行磷酰化，随后细胞内信号途径如微管相关蛋白激酶(MAP激酶)和磷脂酰肌醇(-3)激酶(PI3激酶)也被激活，这些信号途径的激活促使细胞增殖，抑制细胞调亡。临床上约20-30％的乳腺癌病人Her2过表达而过度活化，Her2过表达病人对靶向Her2的单抗药物赫赛汀有较好的应答。同时，小分子蛋白质激酶抑制剂Lapatinib(GW-2016)和Neratinib(HKI-272)都已经通过临床试验批准用于Her2阳性乳腺癌治疗和预防，但这两种药物的疗效比较有限，不能完全满足临床需求(Cancer Res 2009,69(2 Suppl),Abstract nr 3133；Ther Adv Med Oncol.2016,8,339)。
EGFR受体19号外显子缺失和21外显子突变是非小细胞肺癌最长见的两种EGFR突变类型，带有这两种突变的肺癌对EGFR酪氨酸激酶抑制剂(TKIs)高度敏感(Science,2004,304,1497)，以EGFR为靶点的酪氨酸激酶抑制剂(如吉非替尼、厄洛替尼)等药物已在非小细胞肺癌的临床治疗中获得巨大成功(N Engl J Med.,2004,350,2129；The Lancet Oncology,2012,13, 239)。目前该类药物已经研发到第三代，可克服第一代药物耐药的奥希替尼目前已经获批上市。但是，EGFR突变中的20外显子插入突变目前临床上仍然没有药物能用于治疗，这类突变病人对现有上市的EGFR抑制剂类药物都不敏感，基本无药可用(Sci Transl Med.2013,5,216ra177；Mol Cancer Ther.2013,12,220；Lancet Oncol.2012,13,23)。EGFR 20号外显子插入突变新药Poziotinib已经进入临床研究，但该药的代谢稳定性较差。总之，目前急需开发相关治疗药物。
发明内容
本发明的目的是提供一种喹啉或喹唑啉类Her/erbB家族激酶抑制剂。
本发明的另一个目的是提供所述的Her激酶抑制剂在制备预防或治疗人表皮生长因子受体Her/erbB家族相关疾病药物的用途。为实现本发明的目的，本发明的技术方案如下：
本发明所述的如下式(I)所示的化合物、其立体异构体或其药学上可接受盐：
Figure PCTCN2019090224-appb-000001
其中，A选自C 2-C 6炔基、6-10元芳基或5-10元杂芳基；
X选自C 1-C 8烷基、5-10元杂芳基或3-8元杂环基，所述的C 1-C 8烷基可进一步被卤素、氰基、羟基或C 1-C 4烷氧基所取代，所述的3-8元杂环基可进一步被-(CH 2) aCN所取代；
Y选自C 1-C 8烷基、-COR 1、-(CH 2) aCN、-(CH 2) aOR 1或3-8元杂环基，所述的3-8元杂环基可进一步被C 1-C 4烷基所取代；
或者Y不存在；
R 1选自H、OH或C 1-C 4烷基；
B选自6-10元芳基或5-10元杂芳基，所述的6-10元芳基或5-10元杂芳基可进一步被一个或多个选自羟基、卤素、C 1-C 4烷基或-O(CH 2) a-5-6元杂芳基的取代基所取代；
a选自0、1或2；
n选自0、1或2；
m选自0、1或2；
M选自C-CN或N；
W选自O、S或NH。
本发明的一个实施方案中，其特征在于：
A选自C 2-C 4炔基、6-10元芳基或5-6元杂芳基；
X选自C 1-C 4烷基、5-6元杂芳基或4-6元杂环基，所述的C 1-C 4烷基可进一步被氰基、羟基或C 1-C 2烷氧基所取代，所述的4-6元杂环基可进一步被-(CH 2) aCN所取代；
Y选自C 1-C 4烷基、-COR 1、-(CH 2) aCN、-(CH 2) aOR 1或3-6元杂环基，所述的3-6元杂环基可进一步被C 1-C 2烷基所取代；
或者Y不存在；
R 1选自H、OH或C 1-C 4烷基；
B为6-10元芳基,所述的6-10元芳基可进一步被一个或多个选自卤素或-O(CH 2) a-5-6元杂芳基的取代基所取代；
a选自0、1或2；
n选自0、1或2；
m选自0、1或2；
M选自C-CN或N；
W选自O或NH。
本发明的一个实施方案中，其特征在于：
A选自乙炔基、苯基或5-6元杂芳基；
X选自C 1-C 4烷基、5-6元杂芳基或4-6元杂环基，所述的C 1-C 4烷基可进一步被氰基、羟基或C 1-C 2烷氧基所取代，所述的4-6元杂环基可进一步被-(CH 2) aCN所取代；
Y选自C 1-C 2烷基、-COR 1、-(CH 2) aCN、-(CH 2) aOR 1或3-6元杂环基，所述的3-6元杂环基可进一步被C 1-C 2烷基所取代；
或者Y不存在；
R 1选自OH、甲基或乙基；
B为苯基，所述的苯基被一个或多个选自F、Cl或-O(CH 2) a吡啶的取代基所取代；
a选自1或2；
n为1；
m为1；
M选自C-CN或N；
W选自O或NH。
本发明的一个实施方案中，其特征在于：
A选自乙炔基、苯基、咪唑基、吡唑基、吡咯基、吡啶基或嘧啶基；
X选自C 1-C 4烷基、吡唑基或4-6元杂环基，所述的C 1-C 4烷基可进一步被氰基、羟基或甲氧基所取代，所述的4-6元杂环基可进一步被-(CH 2) aCN所取代；
Y选自C 1-C 2烷基、-COR 1、-(CH 2) aCN、-(CH 2) aOR 1或3-6元杂环基，所述的3-6元杂环基可进一步被甲基所取代；
或者Y不存在；
R 1为甲基；
B为苯基，所述的苯基被一个或多个选自F、Cl或-O(CH 2) a吡啶的取代基所取代；
a选自1或2；
n为1；
m为1；
M选自C-CN或N；
W选自O或NH。
本发明的一个实施方案中，其特征在于：
A选自乙炔基、咪唑基或吡唑基；
X选自甲基、-CH 2CN、-(CH 2) 2OH、-(CH 2) 2OCH 3、吡唑基、氧杂环丁基、氮杂环丁基、哌啶基或四氢吡喃基，所述的氧杂环丁基可进一步被-CH 2CN所取代；
Y选自甲基、乙基、-COCH 3、-CH 2CN、-(CH 2) 2OCH 3、氧杂环丁基、四氢吡喃基或哌啶基，所述的哌啶基可进一步被甲基所取代；
或者Y不存在；
B为苯基，所述的苯基被一个或多个选自F、Cl或-OCH 2-吡啶的取代基所取代；
n为1；
m为1；
M选自C-CN或N；
W为O或NH。
本发明优选方案，本发明所述的化合物、其立体异构体或其药学上可接受盐，选自如下结构：
Figure PCTCN2019090224-appb-000002
Figure PCTCN2019090224-appb-000003
Figure PCTCN2019090224-appb-000004
本发明另一方面提供式(I)化合物、其立体异构体或其药学上可接受的盐的制备方法，包括如下步骤：
Figure PCTCN2019090224-appb-000005
其中，A、X、Y、B、m、n、M、W如式(I)化合物所定义。
本发明另一方面提供了前述式(I)化合物、其立体异构体或其药学上可接受盐制备用于预防或治疗癌症的药物中的应用。
本发明另一方面提供一种药物组合物，其包括治疗有效剂量的前述式(I)化合物、其立体异构体或其药学上可接受盐及可药用的载体。
本发明另一方面提供了所述药物组合物在制备预防或治疗癌症的药物中的应用。
作为进一步优选的方案，所述癌症选自卵巢癌、宫颈癌、结肠直肠癌、乳腺癌、胰腺癌、胶质瘤、胶质母细胞瘤,黑色素瘤、前列腺癌、白血病、淋巴瘤、非霍奇金淋巴瘤、胃癌、肺 癌、肝细胞癌、胃肠道间质瘤、甲状腺癌、胆管癌、子宫内膜癌、肾癌、间变性大细胞淋巴瘤、急性髓细胞白血病、多发性骨髓瘤、黑色素瘤或间皮瘤。
除非有相反陈述，下列用在说明书和权利要求书中的术语具有下述含义。
本发明中“芳基”指全碳单环或双环基团，“6-10元芳基”指含有6-10个碳的全碳芳基，例如苯基和萘基。所述芳基环可以稠合于杂芳基、杂环基或环烷基环上，其中与母体结构连接在一起的环为芳基环。
芳基可以是取代的或未取代的，当被取代时，取代基优选为一个或多个以下基团，独立地选自卤素、羟基、巯基、氰基、硝基、叠氮基、C 1-C 8烷基、C 2-C 8烯基、C 2-C 8炔基、C 3-C 8环烷基、3-8元杂环基、3-8元杂环基氧基、3-8元杂环基硫基、C 5-C 10芳基、C 5-C 10芳基氧基、C 5-C 10芳基硫基、5-10元杂芳基、5-10元杂芳基氧基、5-10元杂芳基硫基、-C 0-8-S(O)rR 2、-C 0-8-O-R 2、-O-C 0-8-R 2、-C 0-8-C(O)R 2、-C 0-8-C(O)OR 2、-C 0-8-O-C(O)R 2、-C 0-8-NR 2R 3、-C 0-8-C(O)NR 2R 3、-N(R 2)-C(O)R 3或-N(R 2)-C(O)OR 3的取代基所取代。
本发明中“杂芳基”指包含1至4个杂原子的杂芳族体系，所述杂原子包括氮、氧和硫的杂原子，包括但不限于呋喃基、噻吩基、吡啶基、吡咯基、吡唑基、N-烷基吡咯基、嘧啶基、吡嗪基、咪唑基、四唑基等。
杂芳基可以是取代的或未取代的，当被取代时，取代基优选为一个或多个以下基团，独立地选自卤素、羟基、巯基、氰基、硝基、叠氮基、C 1-C 8烷基、C 2-C 8烯基、C 2-C 8炔基、C 3-C 8环烷基、3-8元杂环基、3-8元杂环基氧基、3-8元杂环基硫基、C 5-C 10芳基、C 5-C 10芳基氧基、C 5-C 10芳基硫基、5-10元杂芳基、5-10元杂芳基氧基、5-10元杂芳基硫基、-C 0-8-S(O)rR 2、-C 0-8-O-R 2、-O-C 0-8-R 2、-C 0-8-C(O)R 2、-C 0-8-C(O)OR 2、-C 0-8-O-C(O)R 2、-C 0-8-NR 2R 3、-C 0-8-C(O)NR 2R 3、-N(R 2)-C(O)R 3或-N(R 2)-C(O)OR 3的取代基所取代。
R 2、R 3选自H、C 1-C 8烷基、C 3-C 8环烷基，任选进一步被一个或多个选自氨基、卤素、羟基、C 1-C 8烷基、C 1-C 8烷氧基、卤取代C 1-C 8烷氧基、C 3-C 8环烷基、NR 4R 5、4-10元杂环基、6-10元芳基、5-10元杂芳基的取代基所取代。
R 4、R 5选自H、C 1-C 8烷基、C 3-C 8环烷基。
r选自0、1、2。
本发明中“C 1-C 8烷基”指包括1至8个碳原子的直链烷基和含支链烷基，烷基指饱和的脂族烃基团，例如甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基、1,1-二甲基丙基、1,2-二甲基丙基、2,2-二甲基丙基、1-乙基丙基、2-甲基丁基、3-甲基丁基、正己基、1-乙基-2-甲基丙基、1,1,2-三甲基丙基、1,1-二甲基丁基、1,2-二甲基丁基、2,2-二甲基丁基、1,3-二甲基丁基、2-乙基丁基、2-甲基戊基、3-甲基戊基、4-甲基戊基、2,3-二甲基丁 基、正庚基、2-甲基己基、3-甲基己基、4-甲基己基、5-甲基己基、2,3-二甲基戊基、2,4-二甲基戊基、2,2-二甲基戊基、3,3-二甲基戊基、2-乙基戊基、3-乙基戊基、正辛基、2,3-二甲基己基、2,4-二甲基己基、2,5-二甲基己基、2,2-二甲基己基、3,3-二甲基己基、4,4-二甲基己基、2-乙基己基、3-乙基己基、4-乙基己基、2-甲基-2-乙基戊基、2-甲基-3-乙基戊基或其各种支链异构体等。
本发明中“环烷基”指饱和单环烃取代基，“C 3-C 8环烷基”指包括3至8个碳原子的单环环烷基，例如：单环环烷基的非限制性实施例包含环丙基、环丁基、环戊基、环己基、环庚基、环辛基等。
本发明中“烯基”指由至少两个碳原子和至少一个碳-碳双键组成的如上述定义的烷基，“C 2-C 8烯基”指含有2-8个碳的直链或含支链烯基。例如乙烯基、1-丙烯基、2-丙烯基、1-，2-或3-丁烯基等。
本发明中“炔基”指至少两个碳原子和至少一个碳-碳三键组成的如上所定义的烷基，“C 2-C 8炔基”指含有2-8个碳的直链或含支链炔基。例如乙炔基、1-丙炔基、2-丙炔基、1-，2-或3-丁炔基等。
本发明中“杂环基”指饱和或部分不饱和单环或多环环状烃取代基，其中一个或多个环原子选自氮、氧或S(O)r的杂原子，但不包括-O-O-、-O-S-或-S-S-的环部分，其余环原子为碳。“4-10元杂环基”指包含4至10个环原子的环基。单环杂环基的非限制性实施例包含二氢吡喃基、氮杂环丁基、氧杂环丁基、吡咯烷基、哌啶基、四氢吡喃基、哌嗪基、吗啉基、硫代吗啉基、高哌嗪基等。多环杂环基包括螺环、稠环和桥环的杂环基。
本发明中“烷氧基”指-O-(烷基)，其中烷基的定义如上所述。“C 3-C 8烷氧基”指含1-8个碳的烷基氧基，非限制性实施例包含甲氧基、乙氧基、丙氧基、丁氧基等。
“卤素”指氟、氯、溴或碘。
“药物组合物”表示含有一种或多种本文所述化合物或其生理学上可药用的盐或前体药物与其他化学组分的混合物，以及其他组分例如生理学可药用的载体和赋形剂。药物组合物的目的是促进对生物体的给药，利于活性成分的吸收进而发挥生物活性。
本发明制备步骤中，所用试剂的缩写分别表示：
DCM                二氯甲烷
THF                四氢呋喃
MTBE               甲基叔丁基醚
EA                 乙酸乙酯
PE                 石油醚
DMF           N，N-二甲基甲酰胺
Pd(dppf)Cl2   [1,1'-双(二苯基膦基)二茂铁]二氯化钯
DBU           1,8-二氮杂二环[5.4.0]十一碳-7-烯
NaBH(oAc) 3    三乙酰氧基硼氢化钠
附图说明
图1实施例1化合物的核磁共振氢谱。
图2实施例2化合物的核磁共振氢谱。
图3实施例3化合物的核磁共振氢谱。
图4实施例4化合物的核磁共振氢谱。
图5实施例5化合物的核磁共振氢谱。
图6实施例6化合物的核磁共振氢谱。
图7实施例7化合物的核磁共振氢谱。
图8实施例8化合物的核磁共振氢谱。
图9实施例9化合物的核磁共振氢谱。
图10实施例10化合物的核磁共振氢谱。
图11实施例11化合物的核磁共振氢谱。
图12实施例12化合物的核磁共振氢谱。
图13实施例13化合物的核磁共振氢谱。
图14实施例14化合物的核磁共振氢谱。
图15实施例15化合物的核磁共振氢谱。
图16实施例16化合物的核磁共振氢谱。
图17实施例17化合物的核磁共振氢谱。
图18实施例18化合物的核磁共振氢谱。
图19实施例19化合物的核磁共振氢谱。
图20实施例20化合物的核磁共振氢谱。
图21实施例21化合物的核磁共振氢谱。
图22实施例22化合物的核磁共振氢谱。
图23实施例23化合物的核磁共振氢谱。
图24实施例24化合物的核磁共振氢谱。
图25实施例25化合物的核磁共振氢谱。
具体实施方式
以下参照具体的实施例来说明本发明。本领域技术人员能够理解，这些实施例仅用于说明本发明，其不以任何方式限制本发明的范围。
下述实施例中的实验方法，如无特殊说明，均为常规方法。下述实施例中所用的药材原料、试剂材料等，如无特殊说明，均为市售购买产品。
实施例1
1-(4-((4-((3-氯-4-氟苯基)胺)-7-(1-甲基-1H-咪唑-4-基)喹唑啉-6-基)氧)哌啶-1-基)丙-2-烯-1-酮
Figure PCTCN2019090224-appb-000006
步骤1:5-((1-((苄氧基)羰基)哌啶-4-基)氧基)-4-溴-2-硝基苯甲酸的合成
Figure PCTCN2019090224-appb-000007
冰浴下，向三口瓶中依次加入4-羟基-1-哌啶甲酸苄酯(17.80g，76.0mmol)、DMF(100ml)，再向体系分批加入60％氢化钠(3.79g，95.0mmol)，0℃下反应0.5h后，分批向上述体系中加入4-溴-5-氟-2-硝基苯甲酸(10.00g，37.9mmol)，0℃下反应1h后，检测反应完全，冰浴下用2N HCl水溶液调节pH至3-4，乙酸乙酯萃取两次，无水硫酸钠干燥，减压蒸干，粗品直接进行下一步。
步骤2:(4-(2-溴-5-(甲氧羰基)-4-硝基苯氧基)哌啶-1-甲酸苄酯的合成
Figure PCTCN2019090224-appb-000008
室温下，向单口瓶中依次加入5-((1-((苄氧基)羰基)哌啶-4-基)氧基)-4-溴-2-硝基苯甲酸(上步粗品，76.0mmol)、二氯亚砜(0.90g，152mmol)、DMF(0.2mL)、DCM(100mL)，加 热回流反应2-3h，反应结束后减压蒸除溶剂，用DCM带两次，每次200mL，冰浴下缓慢加入100mL甲醇，搅拌反应0.5h，减压蒸除溶剂后，柱层析(PE/EA体系)，得到目标产品黄色油状固体15.0g，两步收率80.2％。 1H NMR(400MHz,Chloroform-d)δ8.26(s,1H),7.41-7.30(m,5H),7.04(s,1H),5.15(s,2H),4.77(d,J＝5.6Hz,1H),3.74-3.58(m,4H),1.92(m,4H)。MS(ESI)m/z:493.0,495.0[M+H] +。
步骤3:4-(4-氨基-2-溴-5-(甲氧羰基)苯氧基)哌啶-1-甲酸苄酯的合成
Figure PCTCN2019090224-appb-000009
室温下，向单口瓶中依次加入(4-(2-溴-5-(甲氧羰基)-4-硝基苯氧基)哌啶-1-甲酸苄酯(15.00g，30.4mmol)、乙醇(150mL)、水(50mL)、铁粉(8.50g，152mmol)、氯化铵(8.13g，152mmol)，加热回流反应2-3h，反应结束后加硅藻土过滤，母液减压蒸干，直接用于下一步。
步骤4:4-((7-溴-4-氧-3,4-二氢喹唑啉-6-基)氧基)哌啶-1-甲酸苄酯的合成
Figure PCTCN2019090224-appb-000010
向15mL微波管中依次加入4-(4-氨基-2-溴-5-(甲氧羰基)苯氧基)哌啶-1-甲酸苄酯(2.50g，5.40mmol)、甲酰胺(15mL)，升温至150℃，微波反应半小时，一共五批反应，反应结束后加入100mL乙酸乙酯，水洗(50mL x3)，无水硫酸钠干燥，减压蒸除溶剂后，柱层析(PE/EA体系)，得到目标产品淡黄色固体8.60g，收率69.5％。 1H NMR(400MHz,Chloroform-d)δ10.42(s,1H),8.06(s,1H),7.99(s,1H),7.67(s,1H),7.51-7.31(m,5H),5.18(s,2H),4.84(q,J＝4.7Hz,1H),3.71(s,4H),1.98(s,4H)。MS(ESI)m/z:458.0,460.0[M+H] +。
步骤5:4-((7-溴-4-氯喹唑啉-6-基)氧基)哌啶-1-甲酸苄酯的合成
Figure PCTCN2019090224-appb-000011
室温下，向单口瓶中依次加入4-((7-溴-4-氧-3,4-二氢喹唑啉-6-基)氧基)哌啶-1-甲酸苄酯(2.00g，4.56mmol)、二氯亚砜(20mL)、DMF(0.6mL)，加热回流反应2-3h，反应结束后减压蒸除溶剂，用二氯甲烷带两次后，直接用于下一步。
步骤6:4-((7-溴-4-((3-氯-4-氟苯基)胺)喹唑啉-6-基)氧基)哌啶-1-甲酸苄酯的合成
Figure PCTCN2019090224-appb-000012
室温下，向单口瓶中依次加入4-((7-溴-4-氯喹唑啉-6-基)氧基)哌啶-1-甲酸苄酯(上步粗品，4.56mmol)、异丙醇(30mL)、3-氯-4-氟苯胺(0.76mg，5.24mmol)，加热至60℃反应2-3h，反应结束后降温至室温，过滤，收集固体，固体减压蒸干，得到目标产品黄色固体1.80g，收率70.3％。 1H NMR(400MHz,DMSO-d 6)δ11.46(s,1H),8.83(s,1H),8.55(s,1H),8.18(s,1H),8.08(dd,J＝6.8,2.6Hz,1H),7.79(dd,J＝8.4,3.7Hz,1H),7.56(t,J＝9.0Hz,1H),7.45-7.28(m,5H),5.15(m,1H),5.16(s,2H),3.60(m,4H),2.03(m,2H),1.80(m,2H)。MS(ESI)m/z:585.0,587.0[M+H] +。
步骤7:1-甲基-4-(4,4,5,5-甲基-1,3,2-二氧硼戊环-2-基)-1H-咪唑的合成
Figure PCTCN2019090224-appb-000013
室温下，向三口瓶中依次加入4-碘-1-甲基咪唑(1.00g，4.81mmol)和THF(20mL)，冰浴和氮气保护下，滴加2N异丙基溴化镁(3.6mL，7.21mmol)，反应1.5h后，加入2-甲氧基-4,4,5,5-四甲基-1,3,2-二氧硼戊环(1.14g，7.21mmol)，冰浴下反应0.5h后，将反应体系倒入乙酸乙酯(50mL)和饱和氯化铵水溶液的混合溶液中，搅拌五分钟，分层，水相再用EA(25mL)萃取一次，合并有机相，无水硫酸钠干燥，减压蒸干，直接用于下一步。
步骤8:4-((4-((3-氯-4-氟苯基)胺)-7-(1-甲基-1H-咪唑-4-基)喹唑啉-6-基)氧基)-哌啶-1-甲酸苄酯的合成
Figure PCTCN2019090224-appb-000014
室温下，向单口瓶中依次加入4-((7-溴-4-氯喹唑啉-6-基)氧基)哌啶-1-甲酸苄酯(0.50g，0.85mmol)、1-甲基-1H-吡唑-4-硼酸(0.129g，1.03mmol)、Pd(dppf)Cl 2(0.063g，0.085mmol)、2N K 2CO 3(3.5mL)、DMF(10mL)，加热至70℃反应过夜，反应结束后降温至室温，加入100mL乙酸乙酯，碳酸钠饱和水溶液洗涤(50mL x3)，水相再用EA(50mL)反萃一次，合并有机相，无水硫酸钠干燥，减压蒸干，柱层析(二氯甲烷/甲醇体系)，得到目标产品黄色油状固体0.27g，收率53.9％。MS(ESI)m/z:587.0[M+H] +。
步骤9:N-(3-氯-4-氟苯基)-7-(1-甲基-1H-咪唑-4-基)-6-(哌啶-4-基氧)喹唑啉-4-胺溴化氢盐的合成
Figure PCTCN2019090224-appb-000015
室温下，向单口瓶中依次加入4-((4-((3-氯-4-氟苯基)胺)-7-(1-甲基-1H-咪唑-4-基)喹唑啉-6-基)氧基)哌啶-1-甲酸苄酯(0.25g，0.42mmol)、1,4-二氧六环(20mL)、溴化氢的乙酸溶液(5mL)，加热至30℃反应过夜，反应结束后降温至室温，加入100mL MTBE，搅拌十分钟，过滤，固体用MTBE洗涤，收集固体，减压蒸干，粗品直接用于下一步。
步骤10:1-(4-((4-((3-氯-4-氟苯基)胺)-7-(1-甲基-1H-咪唑-4-基)喹唑啉-6-基)氧)哌啶-1-基)丙-2-烯-1-酮的合成
Figure PCTCN2019090224-appb-000016
室温下，向单口瓶中依次加入N-(3-氯-4-氟苯基)-7-(1-甲基-1H-吡唑-4-基)-6-(哌啶-4-基氧)喹唑啉-4-胺溴化氢盐(上步粗品，0.42mmol)、二氯甲烷(30mL)、三乙胺(0.215g，2.13mmol)，冰浴下降温至0-5℃，滴加丙烯酰氯(0.046g，0.47mmol)的二氯甲烷(3mL)溶液，反应约半小时，反应完全后，加入20mL冰水淬灭反应，搅拌10min，减压蒸除大部分二氯甲烷，加入50mL乙酸乙酯，碳酸钠饱和水溶液洗涤(20mL x2)，无水硫酸钠干燥，减压蒸干，柱层析(二氯甲烷/甲醇体系)，得到101.3mg黄色固体，两步总收率46.9％。 1H NMR(400MHz,Chloroform-d)δ8.66(s,1H),8.66(s,1H),7.80(s 1H),7.80(s 1H),7.56(br,1H),7.51(s,1H),7.32(s,1H),7.13(t,J＝8.7Hz,1H),6.59(dd,J＝16.8,10.5Hz,1H),6.32(d,J＝16.8Hz,1H), 5.73(dd,J＝10.4,1.9Hz,1H),4.83(m,1H),4.09(m,1H),3.82(m,1H),3.75(s,3H),3.45(m,2H),2.08(m,2H),1.89(m,2H)。MS(ESI)m/z:507.0[M+H] +。
实施例2
1-(4-((4-((3,4-二氯-2-氟苯基)胺)-7-(1-甲基-1H-咪唑-4-基)喹唑啉-6-基)氧)哌啶-1-基)丙-2-烯-1-酮
Figure PCTCN2019090224-appb-000017
步骤1:参照实施例1合成4-((7-溴-4-((3,4-二氯-2-氟苯基)胺)-喹唑啉-6-基)氧基)哌啶-1-甲酸苄酯。
步骤2:4-((4-((3,4-二氯-2-氟苯基)胺)-7-(1-甲基-1H-咪唑-4-基)喹唑啉-6-基)氧基)哌啶-1-甲酸苄酯的合成
Figure PCTCN2019090224-appb-000018
室温下，向单口瓶中依次加入4-((7-溴-4-((3,4-二氯-2-氟苯基)胺)-喹唑啉-6-基)氧基)哌啶-1-甲酸苄酯(0.90g，1.45mmol)、1-甲基-1H-咪唑-4-硼酸频哪醇酯(0.362g，1.74mmol)、Pd(dppf)Cl 2(0.106g，0.145mmol)、2N K 2CO 3(4.0mL)、DMF(12mL)，加热至70℃反应过夜，反应结束后降温至室温，加入50mL乙酸乙酯，水溶液洗涤(20mL x2)，水相再用EA(20mL)反萃一次，合并有机相，无水硫酸钠干燥，减压蒸干，柱层析(二氯甲烷/甲醇体系)，得到目标产品黄色油状固体0.44g，收率48.8％。MS(ESI)m/z:621.0[M+H] +。
步骤3:N-(3,4-二氯-2-氟苯基)-7-(1-甲基-1H-咪唑-4-基)-6-(哌啶-4-基氧)喹唑啉-4-胺溴化氢盐的合成
Figure PCTCN2019090224-appb-000019
室温下，向单口瓶中依次加入4-((4-((3,4-二氯-2-氟苯基)胺)-7-(1-甲基-1H-咪唑-4-基)喹唑啉-6-基)氧基)哌啶-1-甲酸苄酯(0.40g，0.64mmol)、1,4-二氧六环(20mL)、溴化氢的乙酸溶液(2mL)，加热至30℃反应过夜，反应结束后降温至室温，加入20mL MTBE，搅拌十分钟，过滤，收集固体，固体减压蒸干，粗品直接用于下一步。
步骤4:1-(4-((4-((3,4-二氯-2-氟苯基)胺)-7-(1-甲基-1H-咪唑-4-基)喹唑啉-6-基)氧)哌啶-1-基)丙-2-烯-1-酮的合成
Figure PCTCN2019090224-appb-000020
室温下，向单口瓶中依次加入N-(3,4-二氯-2-氟苯基)-7-(1-甲基-1H-咪唑-4-基)-6-(哌啶-4-基氧)喹唑啉-4-胺溴化氢盐(上步粗品，0.64mmol)、二氯甲烷(20mL)、三乙胺(0.195g，1.93mmol)，冰浴下降温至0-5℃，滴加丙烯酰氯(0.064g，0.71mmol)的二氯甲烷(3mL)溶液，反应约10min，反应完全后，加入10mL冰水淬灭反应，搅拌10min，减压蒸除大部分二氯甲烷，加入50mL乙酸乙酯，碳酸钠饱和水溶液洗涤(20mL x2)，无水硫酸钠干燥，减压蒸干，柱层析(二氯甲烷/甲醇体系)，再flash柱反相制备(0.1％甲酸水溶液/乙腈)，得到黄色固体0.025g，两步收率7.2％。 1H NMR(400MHz,Chloroform-d)δ8.51(s,1H),8.49(s,1H),8.28(s,1H),8.28(s,1H),7.89(br,1H),7.62(s,1H),7.53(s,1H),7.46(s,1H),6.60(dd,J＝16.8,10.6Hz,1H),6.31(d,J＝16.7Hz,1H),5.73(d,J＝10.6Hz,1H),4.91(m,1H),4.25(m,1H),3.87(m,1H),3.73(s,3H),3.44(m,2H),2.23(m,2H),1.88(m,2H)。MS(ESI)m/z:541.0[M+H] +。
实施例3
1-(4-((4-((3-氯-4-氟苯基)胺)-7-(1-甲基-1H-吡唑-4-基)喹唑啉-6-基)氧)哌啶-1-基)丙-2-烯-1-酮
Figure PCTCN2019090224-appb-000021
步骤1:参照实施例1合成4-((7-溴-4-((3-氯-4-氟苯)胺)-喹唑啉-6-基)氧基)哌啶-1-甲酸苄酯。
步骤2:4-((4-((3-氯-4-氟苯)胺)-7-(1-甲基-1H-吡唑-4-基)喹唑啉-6-基)氧基)哌啶-1-甲酸苄酯
Figure PCTCN2019090224-appb-000022
室温下，向单口瓶中依次加入4-((7-溴-4-((3-氯-4-氟苯)胺)-喹唑啉-6-基)氧基)哌啶-1-甲酸苄酯(0.50g，0.85mmol)、1-甲基-1H-吡唑-4-硼酸(0.129g，1.03mmol)、Pd(dppf)Cl 2(0.063g，0.085mmol)、K 2CO 3(2N，3.5mL)、DMF(10mL)，加热至70℃反应过夜，反应结束后降温至室温，加入100mL乙酸乙酯，水洗(50mL x3)，无水硫酸钠干燥，减压蒸干，柱层析(二氯甲烷/甲醇体系)，得到目标产品黄色油状固体0.25g，收率50.0％。MS(ESI)m/z:587.0[M+H] +。
步骤3:N-(3-氯-4-氟苯基)-7-(1-甲基-1H-吡唑-4-基)-6-(哌啶-4-基氧)喹唑啉-4-胺溴化氢盐
Figure PCTCN2019090224-appb-000023
室温下，向单口瓶中依次加入4-((4-((3-氯-4-氟苯)胺)-7-(1-甲基-1H-吡唑-4-基)喹唑啉-6-基)氧基)哌啶-1-甲酸苄酯(0.25g，0.43mmol)、1,4-二氧六环(30mL)、溴化氢的乙酸溶液(5mL)，加热至30℃反应过夜，反应结束后降温至室温，加入100mL MTBE，搅拌十分钟，过滤，收集固体，固体减压蒸干，粗品直接用于下一步。
步骤4:1-(4-((4-((3-氯-4-氟苯基)胺)-7-(1-甲基-1H-吡唑-4-基)喹唑啉-6-基)氧)哌啶-1-基)丙-2-烯-1-酮
Figure PCTCN2019090224-appb-000024
室温下，向单口瓶中依次加入N-(3-氯-4-氟苯基)-7-(1-甲基-1H-吡唑-4-基)-6-(哌啶-4-基氧)喹唑啉-4-胺溴化氢盐(粗品，0.43mmol)、二氯甲烷(30mL)、三乙胺(0.215g，2.13mmol)，冰浴下降温至0-5降，滴加丙烯酰氯(0.046g，0.47mmol)的二氯甲烷(3mL)溶液，反应约半小时，反应完全后，加入10mL冰水淬灭反应，搅拌5min，减压蒸除大部分二氯甲烷，加入50mL乙酸乙酯，水洗，无水硫酸钠干燥，减压蒸干，柱层析(二氯甲烷/甲醇体系)，得到78.7mg黄色固体，收率36.5％。 1H NMR(400MHz,Chloroform-d)δ8.68(s,1H),8.01(s,1H),8.00(s,1H),7.85(s,1H),7.82(dd,J＝6.6,2.6Hz,1H),7.73(br,1H),7.57(m,1H),7.34(s,1H),7.16(t,J＝8.7Hz,1H),6.59(dd,J＝16.8,10.5Hz,1H),6.30(dd,J＝16.7,1.8Hz,1H),5.72(dd,J＝10.5,1.8Hz,1H),4.78(m,1H),3.99(s,3H),3.84(m,2H),3.56(m,2H),2.06(m,2H),1.93(m,2H)。MS(ESI)m/z:507.0[M+H] +。
实施例4
1-(4-((4-((3,4-二氯-2-氟苯基)胺)-7-(1-甲基-1H-吡唑-4-基)喹唑啉-6-基)氧)哌啶-1-基)丙-2-烯-1-酮
Figure PCTCN2019090224-appb-000025
步骤1:参照实施例1合成4-((7-溴-4-((3,4-二氯-2-氟苯基)胺)-喹唑啉-6-基)氧基)哌啶-1-甲酸苄酯。
步骤2:4-((4-((3,4-二氯-2-氟苯基)胺)-7-(1-甲基-1H-吡唑-4-基)喹唑啉-6-基)氧基)哌啶-1-甲酸苄酯的合成
Figure PCTCN2019090224-appb-000026
室温下，向单口瓶中依次加入4-((7-溴-4-((3,4-二氯-2-氟苯基)胺)-喹唑啉-6-基)氧基)哌啶-1-甲酸苄酯(0.83g，1.34mmol)、1-甲基-1H-咪唑-4-硼酸频哪醇酯(0.202g，1.61mmol)、Pd(dppf)Cl 2(0.098g，0.134mmol)、2N K 2CO 3(4.0mL)、DMF(12mL)，加热至70℃反应过夜，反应结束后降温至室温，加入100mL乙酸乙酯，水溶液洗涤(50mL x2)，水相再用EA(20mL)反萃，合并有机相，无水硫酸钠干燥，减压蒸干，柱层析(二氯甲烷/甲醇体系)，得到目标产品黄色油状固体0.50g，收率60.1％。MS(ESI)m/z:621.0[M+H] +。
步骤3:N-(3,4-二氯-2-氟苯基)-7-(1-甲基-1H-吡唑-4-基)-6-(哌啶-4-基氧)喹唑啉-4-胺溴化氢盐
Figure PCTCN2019090224-appb-000027
室温下，向单口瓶中依次加入4-((4-((3,4-二氯-2-氟苯基)胺)-7-(1-甲基-1H-吡唑-4-基)喹唑啉-6-基)氧基)哌啶-1-甲酸苄酯(0.45g，0.72mmol)、1,4-二氧六环(20mL)、溴化氢的乙酸溶液(2mL)，加热至30热反应约1.5h，反应结束后降温至室温，加入50mL MTBE，搅拌十分钟，过滤，收集固体，固体减压蒸干，粗品直接用于下一步。
步骤4:1-(4-((4-((3,4-二氯-2-氟苯基)胺)-7-(1-甲基-1H-吡唑-4-基)喹唑啉-6-基)氧)哌啶-1-基)丙-2-烯-1-酮
Figure PCTCN2019090224-appb-000028
室温下，向单口瓶中依次加入N-(3,4-二氯-2-氟苯基)-7-(1-甲基-1H-吡唑-4-基)-6-(哌啶-4-基氧)喹唑啉-4-胺溴化氢盐(粗品，0.72mmol)、二氯甲烷(20mL)、三乙胺(0.366g，3.62mmol)，冰浴下降温至0-5℃，滴加丙烯酰氯(0.079g，0.87mmol)的二氯甲烷(2mL)溶 液，反应约20min，反应完全后，加入15mL冰水淬灭反应，搅拌10min，减压蒸除大部分二氯甲烷，加入50mL乙酸乙酯，碳酸钠饱和水溶液洗涤(20mL x2)，无水硫酸钠干燥，减压蒸干，柱层析(二氯甲烷/甲醇体系),得到黄色固体0.112g，两步总收率25.6％。 1H NMR(400MHz,Chloroform-d)δ8.72(d,J＝2.1Hz,1H),8.45(br,1H),8.06(s,1H),8.01(s,1H),7.88(s,1H),7.49(m,1H),7.34(dd,J＝9.1,2.1Hz,1H),7.22(s,1H),6.59(dd,J＝16.8,10.5Hz,1H),6.30(dd,J＝16.7,1.9Hz,1H),5.72(dd,J＝10.5,1.9Hz,1H),4.96–4.75(m,1H),3.99(s,3H),3.91–3.75(m,2H),3.72–3.55(m,2H),2.13(m,2H),1.97(m,2H)。MS(ESI)m/z:541.0[M+H] +。
实施例5
1-(4-((4-((3-氯-4-(吡啶-2-甲氧基)苯基)胺)-7-(1-甲基-1H-吡唑-4-基)喹唑啉-6-基)氧)哌啶-1-基)丙-2-烯-1-酮
Figure PCTCN2019090224-appb-000029
步骤1:参照实施例1合成4-((7-溴-4-氯喹唑啉-6-基)氧基)哌啶-1-甲酸苄酯。
步骤2:2-((2-氯-4-硝基苯氧基)甲基)吡啶的合成
Figure PCTCN2019090224-appb-000030
室温下，向单口瓶中依次加入2-氯甲基吡啶盐酸盐(2.00g，12.2mmol)、碳酸钾(5.06g，36.7mmol)、DMF(20mL)，常温下搅拌十分钟后，加入2-氯-4-硝基苯酚(2.17g，12.2mmol)、KI(0.203g，1.22mmol)，升温至65升反应约3h，监测反应完全后，加入200mL EA和100mL水，分层，除去水相，EA相再用100mL水洗涤一次后，减压蒸干，加入50mL甲醇，搅拌十分钟，过滤，收集固体，固体减压蒸干，得到目标产品类白色固体2.60g，收率80.5％。 1H NMR(400MHz,Chloroform-d)δ8.61(d,J＝4.6Hz,1H),8.33(d,J＝2.7Hz,1H),8.13(dd,J＝9.1,2.7Hz,1H),7.77(td,J＝7.7,1.8Hz,1H),7.59(d,J＝7.9Hz,1H),7.36–7.27(m,1H),7.09(d,J＝9.0Hz,1H),5.38(s,2H)。MS(ESI)m/z:265.0[M+H] +。
步骤3:3-氯-4-(吡啶-2-甲氧基)苯胺的合成
Figure PCTCN2019090224-appb-000031
室温下，向单口瓶中依次加入2-((2-氯-4-硝基苯氧基)甲基)吡啶(2.50g，9.45mmol)、铁粉(2.64g，47.2mmol)、氯化铵(2.52g，47.2mmol)、乙醇(25mL)和水(8mL)，加热至80加反应约4h，反应结束后降温至室温，加硅藻土过滤，收集母液，母液减压蒸干，粗品直接用于下一步。
步骤4:4-((7-溴-4-((3-氯-4-(吡啶-2-甲氧基)苯基)胺)喹唑啉-6-基)氧)哌啶-1-碳酸苄酯的合成
Figure PCTCN2019090224-appb-000032
室温下，向单口瓶中依次加入新制备的4-((7-溴-4-氯喹唑啉-6-基)氧)哌啶-1-碳酸苄酯(3.00g，6.55mmol)、异丙醇(30mL)、3-氯-4-(吡啶-2-甲氧基)苯胺(1.84g，7.85mmol)，加热至60-70m反应约4h，反应完全后，过滤收集固体，固体减压蒸干，得到目标产品2.5g黄色固体，收率56.6％，直接用于下一步。MS(ESI)m/z:674.0[M+H] +。
步骤5:4-((4-((3-氯-4-(吡啶-2-甲氧基)苯基)胺)-7-(1-甲基-1H-吡唑-4-基)喹唑啉-6-基)氧)哌啶-1-碳酸苄酯的合成
Figure PCTCN2019090224-appb-000033
室温下，向单口瓶中依次加入4-((7-溴-4-((3-氯-4-(吡啶-2-甲氧基)苯基)胺)喹唑啉-6-基)氧)哌啶-1-碳酸苄酯(1.50g，2.11mmol)、1-甲基-1H-吡唑-4-硼酸(0.319g，2.53mmol)、Pd(dppf)Cl2(0.154g，0.21mmol)、2N K 2CO 3(3.5mL)和DMF(10mL)，抽真空置换氮气，氮气保护下加热至70至反应搅拌过夜，反应完全后，加入100mL EA，水洗(50mL x3)，水相再用50mL EA反萃一次，合并有机相，有机相减压蒸干，过flash柱(DCM/MeOH体系)，得到目标产品0.57g黄色固体，收率38.0％。 1H NMR(400MHz,Chloroform-d)δ8.65(s,1H),8.59(d,J＝4.9Hz,1H),8.01(s,1H),7.99(s,1H),7.86(s,1H),7.78–7.71(m,2H),7.65(d,J ＝7.8Hz,1H),7.47(dd,J＝8.8,2.6Hz,1H),7.35(d,J＝4.2Hz,6H),7.25–7.22(m,1H),7.20(s,1H),7.00(d,J＝8.8Hz,1H),5.28(s,2H),5.14(s,2H),4.78–4.64(m,1H),3.97(s,3H),3.77(m,2H),3.41(m,2H),2.02(s,2H),1.87(s,2H)。MS(ESI)m/z:676.0[M+H] +。
步骤6:N-(3-氯-4-(吡唑-2-甲氧基)苯基)-7-(1-甲基-1H-吡唑-4-基)-6-(哌啶-4-基氧)喹唑啉-4-胺溴化氢盐
Figure PCTCN2019090224-appb-000034
室温下，向单口瓶中依次加入4-((4-((3-氯-4-(吡啶-2-甲氧基)苯基)胺)-7-(1-甲基-1H-吡唑-4-基)喹唑啉-6-基)氧)哌啶-1-碳酸苄酯(0.54g，0.80mmol)、1,4-二氧六环(20mL)、溴化氢的乙酸溶液(2mL)，加热至30加反应约1.5h，反应结束后降温至室温，加入200mL MTBE，搅拌十分钟，过滤，收集固体，固体减压蒸干，粗品直接用于下一步。
步骤7:1-(4-((4-((3-氯-4-(吡啶-2-甲氧基)苯基)胺)-7-(1-甲基-1H-吡唑-4-基)喹唑啉-6-基)氧)哌啶-1-基)丙-2-烯-1-酮
Figure PCTCN2019090224-appb-000035
室温下，向单口瓶中依次加入N-(3-氯-4-(吡唑-2-甲氧基)苯基)-7-(1-甲基-1H-吡唑-4-基)-6-(哌啶-4-基氧)喹唑啉-4-胺溴化氢盐(粗品，0.80mmol)、二氯甲烷(40mL)、三乙胺(0.403g，4.00mmol)和THF(10mL)，冰浴下降温至0-5降，滴加丙烯酰氯(0.087g，0.96mmol)的二氯甲烷(2mL)溶液，反应约15min，反应完全后，加入20mL冰水淬灭反应，搅拌10min，减压蒸除大部分二氯甲烷，加入50mL乙酸乙酯，碳酸钠饱和水溶液洗涤(20mL x2)，无水硫酸钠干燥，减压蒸干，柱层析(二氯甲烷/甲醇体系)，再过flash反相柱(0.1％甲酸水溶液/乙腈)，最终得到黄色固体0.057g，两步总收率10.7％。 1H NMR(400MHz,DMSO-d 6)δ9.58(br,1H),8.61(d,J＝4.8Hz,1H),8.47(s,1H),8.31(s,1H),8.19(s,1H),8.10(s,1H),7.99(s,1H),7.96(d,J＝2.7Hz,1H),7.89(t,J＝7.9Hz,1H),7.70(dd,J＝9.0,2.6Hz,1H),7.60(d,J＝ 7.8Hz,1H),7.43–7.35(m,1H),7.31(d,J＝9.0Hz,1H),6.87(dd,J＝16.7,10.4Hz,1H),6.14(dd,J＝16.7,2.5Hz,1H),5.70(dd,J＝10.2,2.5Hz,1H),5.31(s,2H),5.00(m,1H),3.92(s,3H),3.53(m,2H),3.42(m,2H),2.14(m,2H),1.82(m,2H)。MS(ESI)m/z:596.0[M+H] +。
实施例6
1-(4-((4(-(3-氯-4-氟苯基)氨基)-7-(1-(2-甲氧基乙基)-1H-吡唑-4-基]喹唑啉-6-基]氧基)哌啶-1-基)丙-2-烯-1-酮
Figure PCTCN2019090224-appb-000036
步骤1:参照实施例1合成4-((7-溴-4-((3-氯-4-氟苯基)氨基)喹唑啉-6-基氧基)哌啶-1-甲酸苄酯。
步骤2:苄基4-((4(3-氯-4-氟苯基)氨基)-7-(1-(2-甲氧基乙基)-1H-吡唑-4-基)喹唑啉-6-氧基)哌啶-1-甲酸苄酯
Figure PCTCN2019090224-appb-000037
室温下，向单口瓶中依次加入4-((7-溴-4-((3-氯-4-氟苯基)氨基)喹唑啉-6-基氧基)哌啶-1-甲酸苄酯(0.50g，0.85mmol)、1-(2-甲氧基乙基)-4-(二氧磷反应物-甲基-2-基)-1H-吡唑(0.31g，1.02mmol)、碳酸钾(0.29g，1.71mmol)、DMF(8mL)、H 2O(2mL)，置换N 2，加入Pd(dppf)Cl 2(0.08g，0.08mmol)，置换N 2三次，N 2保护下升温至70℃，反应过夜后终止，冷却至室温，加EA，水洗，无水Na 2SO 4干燥，过滤浓缩，柱层析(DCM/MeOH体系)，得到黄色固体0.23g，收率46％。
步骤3:N-(3-氯-4-氟苯基)-7-(1-(2-甲氧基乙基)-1H-吡唑-4-基)-6(哌啶-4-氧基)喹唑啉-4-胺
Figure PCTCN2019090224-appb-000038
室温下，向单口瓶中加入苄基4-((4(3-氯-4-氟苯基)氨基)-7-(1-(2-甲氧基乙基)-1H-吡唑-4-基)喹唑啉-6-氧基)哌啶-1-甲酸苄酯(0.23g，0.36mmol)和1,4-二氧六环(8mL)，滴加33％氢溴酸醋酸(2mL)，滴毕后加热至30℃，反应2h后终止，冷却至室温，加MTBE，搅拌30min，过滤，滤饼用MTBE洗涤两次，滤饼减压蒸干，残余物DCM溶解后加入饱和碳酸钾水溶液，搅拌30min，分层，有机相用水洗两次，水相用DCM萃取一次，有机相合并，无水Na 2SO 4干燥，过滤浓缩，得到黄色固体粗品0.15g。
步骤4:1-(4-((4(-(3-氯-4-氟苯基)氨基)-7-(1-(2-甲氧基乙基)-1H-吡唑-4-基]喹唑啉-6-基]氧基)哌啶-1-基)丙-2-烯-1-酮
Figure PCTCN2019090224-appb-000039
室温下，向单口瓶中加入N-(3-氯-4-氟苯基)-7-(1-(2-甲氧基乙基)-1H-吡唑-4-基)-6(哌啶-4-氧基)喹唑啉-4-胺(0.15g，0.30mmol)，三乙胺(0.20g，1.50mmol)和DCM(10mL)，冰浴下滴加丙烯酰氯(0.05g，0.42mmol)的DCM稀释液(2mL)，反应10min后终止，HPLC检测反应完全，加冰水淬灭，分层，有机相水洗两次，水相用DCM反萃一次，有机相合并，无水Na 2SO 4干燥，过滤浓缩，反向柱层析(0.1％甲酸溶液/乙腈体系)，得黄色固体0.06g，两步收率24％。 1H NMR(400MHz,DMSO-d 6)δ9.68(br,1H),8.52(s,1H),8.34(s,1H),8.15(s,1H),8.10(m,1H),8.03(s,1H),7.97(s,1H),7.80(dt,J＝7.8,3.5Hz,1H),7.48(t,J＝9.1Hz,1H),6.86(dd,J＝16.7,10.5Hz,1H),6.12(dd,J＝16.7,2.4Hz,1H),5.69(dd,J＝10.4,2.4Hz,1H),5.02(m,1H),4.34(t,J＝5.2Hz,2H),3.87(m,4H),3.71(m,2H),3.23(s,3H),2.12 (m,2H),1.83(m,2H)。MS(ESI)m/z:550.8[M+H] +。
实施例7
1-(4-((4(-(3-氯-4-氟苯基)氨基)-7-(1-(2-羟基乙基)-1H-吡唑-4-基]喹唑啉-6-基]氧基)哌啶-1-基)丙-2-烯-1-酮
Figure PCTCN2019090224-appb-000040
步骤1:参照实施例1合成4-((7-溴-4-((3-氯-4-氟苯基)氨基)喹唑啉-6-基氧基)哌啶-1-甲酸苄酯。
步骤2:苄基4-((4(3-氯-4-氟苯基)氨基)-7-(1-(2-羟乙基)-1H-吡唑-4-基)喹唑啉-6-基氧基)哌啶-1-甲酸苄酯
Figure PCTCN2019090224-appb-000041
室温下，向单口瓶中依次加入4-((7-溴-4-((3-氯-4-氟苯基)氨基)喹唑啉-6-基氧基)哌啶-1-甲酸苄酯(0.50g，0.85mmol)、2(4-(4-，4-，5-，5-四甲基-1,3-二氧硼烷-2-基)-1H-吡唑-1-基)乙烷-1-醇(0.30g，1.02mmol)、碳酸钾(0.29g，1.71mmol)、DMF(8mL)、H 2O(2mL)，置换N 2，加入Pd(dppf)Cl 2(0.08mg，0.08mmol)，置换N 2三次，N 2保护下升温至70℃，反应过夜后终止，冷却至室温，加EA，水洗，无水Na 2SO 4干燥，过滤浓缩，柱层析(DCM/MeOH体系)，得到棕色油状固体0.37g，收率74％。
步骤3:2-(4-(4-(3-氯-4-氟苯基)氨基)-6-(哌啶-4-氧基)喹唑啉-7-基-1H-吡唑-1-基)乙烷-1-醇
Figure PCTCN2019090224-appb-000042
室温下，向单口瓶中加入苄基4-((4(3-氯-4-氟苯基)氨基)-7-(1-(2-羟乙基)-1H-吡唑-4-基)喹唑啉-6-基氧基)哌啶-1-甲酸苄酯(0.37g，0.60mmol)和1,4-二氧六环(8mL)，滴加33％氢溴酸醋酸(2mL)，加热至30℃，反应2h后终止，冷却至室温，加MTBE，搅拌30min，过滤，滤饼用MTBE洗涤一次，滤饼减压浓缩，残余物用DCM溶解，加入饱和碳酸钾水溶液，搅拌30min，分层，有机相加水洗涤，水相DCM萃取一次，有机相合并，无水Na 2SO 4干燥，过滤浓缩，得到棕色固体粗品0.12g。
步骤4:1-(4-((4(-(3-氯-4-氟苯基)氨基)-7-(1-(2-羟基乙基)-1H-吡唑-4-基]喹唑啉-6-基]氧基)哌啶-1-基)丙-2-烯-1-酮
Figure PCTCN2019090224-appb-000043
室温下，向单口瓶中加入2-(4-(4-(3-氯-4-氟苯基)氨基)-6-(哌啶-4-氧基)喹唑啉-7-基-1H-吡唑-1-基)乙烷-1-醇(0.12g，0.25mmol),三乙胺(0.13g，1.24mmol)和DCM(10mL)，冰浴下滴加丙烯酰氯(0.03g，0.30mmol)的DCM稀释液(2mL)，反应10min后终止，HPLC检测反应完全，反应加冰水淬灭，分层，有机相用水洗两次，水相用DCM萃取一次，有机相合并，无水Na 2SO 4干燥，过滤浓缩，柱层析(DCM/MeOH体系)，反向柱层析(0.1％甲酸溶液/乙腈体系)，得黄色固体0.03g，两步收率9％。 1H NMR(400MHz,DMSO-d 6)δ9.79(br,1H),8.53(s,1H),8.35(s,1H),8.13(m,2H),8.03(s,1H),7.99(s,1H),7.81(dt,J＝7.3,3.5Hz,1H),7.48(t,J＝9.1Hz,1H),6.86(dd,J＝16.7,10.4Hz,1H),6.13(dd,J＝16.7,2.4Hz,1H),5.70(dd,J＝10.4,2.4Hz,1H),5.10-4.90(m,2H),4.22(t,J＝5.6Hz,2H),3.90(m,2H),3.78(d,J＝5.3Hz,2H),3.56(m,2H),2.13(m,2H),1.82(m,2H)。MS(ESI)m/z:536.8[M+H] +。
实施例8
1-(4-((4-((3-氯-4-氟苯基)氨基)-7-(1-(氧乙基-3-基)-1H-吡唑-4-基)喹唑啉-6-基)氧基)哌啶-1-基)-丙-2-烯-1-酮
Figure PCTCN2019090224-appb-000044
步骤1:参照实施例1合成4-((7-溴-4-((3-氯-4-氟苯基)氨基)喹唑啉-6-基氧基)哌啶-1-甲酸苄酯。
步骤2:7-溴-N-(3-氯-4-氟苯基)-6(哌啶-4-氧基)喹唑啉-4-胺
Figure PCTCN2019090224-appb-000045
室温下，向单口瓶中加入苄基4((7-溴-4-((3-氯-4-氟苯基)氨基)喹唑啉-6-基氧基)哌啶-1-甲酸酯(0.30g，0.51mmol)和1,4-二氧六环(10mL)，滴加33％氢溴酸醋酸(2mL)加热至30℃，反应2h后终止，冷却至室温，加MTBE，搅拌30min，过滤，滤饼用MTBE洗涤一次，滤饼减压蒸干，残余物用DCM溶解，加入饱和碳酸钾水溶液，搅拌30min，分层，有机相用水洗两次，水相用DCM萃取一次，有机相合并，无水Na 2SO 4干燥，过滤浓缩，得到黄色固体粗品0.32g，直接用于下一步。
步骤3:1-(4-(7-溴-4-((3-氯-4-氟苯基)氨基)喹唑啉-6-基]氧基)哌啶-1-基-丙-2-烯-1-酮
Figure PCTCN2019090224-appb-000046
室温下，向单口瓶中加入7-溴-N-(3-氯-4-氟苯基)-6(哌啶-4-氧基)喹唑啉-4-胺(0.32g，0.71mmol)，三乙胺(0.36g，3.54mmol)和DCM(10mL)，冰浴下滴加丙烯酰氯(0.08g，0.85mmol)的DCM稀释液(2mL)，反应10min后终止，HPLC检测反应完全，加冰水淬灭，分层，有机相水洗两次，水相用DCM萃取一次，有机相合并，无水Na 2SO 4干燥，过滤浓缩。柱层析(DCM/MeOH体系)，得黄色固体0.15g，两步收率共计50％。
步骤4:1-(4(-(4(-(3-氯-4-氟苯基)氨基)-7(3-甲基-1H-吡唑-5-基)氧喹基)氧基)哌啶-1-基)-2-烯-1-酮
Figure PCTCN2019090224-appb-000047
室温下，向单口瓶中加入1-(4-(7-溴-4-((3-氯-4-氟苯基)氨基)喹唑啉-6-基]氧基)哌啶-1-基-丙-2-烯-1-酮(0.15g，0.30mmol)，(3-甲基-1H-吡唑-5-基)硼酸(0.05g，0.36mmol)和碳酸钾(0.08g，0.60mmol)，加DMF(5mL)和H 2O(1mL)，N 2保护下加入Pd(dppf)Cl 2(0.02g，0.03mmol)，置换N 2三次，升温至70℃，反应过夜后终止，冷却至室温，加EA，水洗两次，水相EA萃取一次，有机相合并，无水Na 2SO 4干燥，过滤浓缩，柱层析(DCM/MeOH体系)，得黄色固体0.04g，收率30％。 1H NMR(400MHz,DMSO-d 6)δ8.47(s,1H),8.22(br,1H),8.07(dd,J＝6.8,2.6Hz,1H),7.96(s,1H),7.76(dt,J＝7.7,3.5Hz,1H),7.43(t,J＝9.1Hz,1H),6.80(dd,J＝16.7,10.5Hz,1H),6.63(s,1H),6.10(dd,J＝16.8,2.2Hz,1H),5.70(dd,J＝10.4,2.2Hz,1H),4.98(s,1H),3.81(m,2H),3.51(m,2H),2.27(s,3H),2.08(m,2H),1.76(m,2H)。MS(ESI)m/z:506.8[M+H] +。
实施例9
2-(4-(6-(1-丙烯酰哌啶-4-基)氧)-4-(3-氯-4-氟苯基)氨基喹唑啉)-7-基)-1H-吡唑-1-基)乙腈甲酸盐
Figure PCTCN2019090224-appb-000048
步骤1：2-(4-溴-1H-吡唑-1-基)乙腈的合成
Figure PCTCN2019090224-appb-000049
室温下，向单口瓶中加入4-溴代-1H-吡唑(1.00g，6.81mmol)，加THF(25mL)，冰浴下加入NaH(0.33g，13.62mmol)，冰浴反应1h后滴加溴乙腈(1.63g，13.62mmol)，0℃反应过夜后终止，加水淬灭，加EA，分层，有机相用水洗两次，水相EA萃取一次，有机相合并，无水Na 2SO 4干燥，过滤浓缩，柱层析(PE/EA体系)，得白色固体1.10g，收率87％。
步骤2：2-(4，(4-，4-，5-，5-四甲基-1,3-二氧硼烷-2-基)-1H-吡唑-1-基)乙腈的合成
Figure PCTCN2019090224-appb-000050
室温下，向单口瓶中加入2-(4-溴-1H-吡唑-1-基)乙腈(1.00g，5.43mmol)，双联频哪醇硼酸酯(2.05g，8.14mmol)，醋酸钾(1.32g，13.57mmol)，加1.4-dioxane(20mL)溶解，N 2保护下加入Pd(dppf)Cl 2(0.39g，0.54mmol)，置换N 2三次，N 2保护下升温至100℃，反应过夜后终止，冷却至室温，加EA，用水洗两次，水相EA萃取一次，有机相合并，无水Na 2SO 4干燥，过滤浓缩，柱层析(PE/EA体系)，得棕黄色油状固体1.20g，收率96％。
步骤3:2-(4-(6-(1-丙烯酰哌啶-4-基)氧)-4-(3-氯-4-氟苯基)氨基喹唑啉)-7-基)-1H-吡唑-1-基)乙腈甲酸盐的合成
Figure PCTCN2019090224-appb-000051
室温下，向单口瓶中加入1-(4-(7-溴-4-((3-氯-4-氟苯基)氨基)喹唑啉-6-基]氧基)哌啶-1-基-丙-2-烯-1-酮(0.15g，0.30mmol)，2-(4，(4-，4-，5-，5-四甲基-1,3-二氧硼烷-2-基)-1H-吡唑-1-基)乙腈(0.11g，0.45mmol)和碳酸钾(0.08g，0.60mmol)，加DMF(5mL)和H 2O(1mL)，N 2保护下加入Pd(dppf)Cl 2(0.02g，0.03mmol)，置换N 2三次，升温至70℃，反应过夜后终止，冷却至室温，加EA，水洗两次，水相EA萃取一次，有机相合并，无水Na 2SO 4干燥，过滤浓缩，柱层析(DCM/MeOH体系)，反向柱层析(0.1％甲酸水溶液/乙腈体系)，得黄色固体0.02g，收率18％。 1H NMR(400MHz,DMSO-d 6)δ8.47(s,1H),8.42(s,1H),8.24(s,1H),8.06(dd,J＝6.9,2.5Hz,1H),8.01(s,1H),7.95(s,1H),7.76(dt,J＝7.7,3.5Hz,1H),7.43(t,J＝9.1Hz,1H),6.81(dd,J＝16.7,10.5Hz,1H),6.11(dd,J＝16.6,2.2Hz,1H),5.70(dd,J＝10.5,2.2Hz,1H),5.52(s,2H),4.98(d,J＝9.5Hz,1H),3.91-3.85(m,2H),3.52-3.46(m,1H),3.39-3.34(m,1H),2.13(m,2H),1.79(m,2H)。MS(ESI)m/z:531.7[M+H] +。
实施例10
1-(4-((4-((3-氯-4-氟苯基)氨基)-7-(1-(氧乙基-3-基)-1H-吡唑-4-基)喹唑啉-6-基)氧基)哌啶-1-基)-丙-2-烯-1-酮
Figure PCTCN2019090224-appb-000052
步骤1:参照实施例8合成1-(4-(7-溴-4-((3-氯-4-氟苯基)氨基)喹唑啉-6-基]氧基)哌啶-1-基-丙-2-烯-1-酮。
步骤2:1-(4-((4-((3-氯-4-氟苯基)氨基)-7-(1-(氧乙基-3-基)-1H-吡唑-4-基)喹唑啉-6-基)氧基)哌啶-1-基)-丙-2-烯-1-酮
Figure PCTCN2019090224-appb-000053
室温下，向单口瓶中加入1-(4-(7-溴-4-((3-氯-4-氟苯基)氨基)喹唑啉-6-基]氧基)哌啶-1-基-丙-2-烯-1-酮(0.15g，0.30mmol)，1-(氧杂环丁烷-3-基)-4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)-1H-吡唑(0.09g，0.36mmol)和碳酸钾(0.08g，0.60mmol)，加DMF(5mL)和H 2O(1mL)，N 2保护下加入Pd(dppf)Cl 2(0.02g，0.03mmol)，置换N 2三次，升温至70℃，反应过夜后终止，冷却至室温，加EA，水洗两次，水相EA萃取一次，有机相合并，无水Na 2SO 4干燥，过滤浓缩，柱层析(DCM/MeOH体系)，得黄色固体0.06g，收率43％。 1H NMR(400MHz,DMSO-d 6)δ8.44(s,1H),8.38(s,1H),8.21(s,1H),8.03(dd,J＝6.8,2.6Hz,1H),7.98(s,1H),7.91(s,1H),7.73(ddd,J＝9.0,4.4,2.7Hz,1H),7.41(t,J＝9.0Hz,1H),6.79(dd,J＝16.7,10.5Hz,1H),6.10(dd,J＝16.8,2.2Hz,1H),5.72-5.62(m,2H),4.96-4.90(m,5H),3.98(m,2H),3.52-3.46(m,1H),3.40-3.34(m,1H),2.12(m,2H),1.77(m,2H)。MS(ESI)m/z:548.8[M+H] +。
实施例11
1-(4-((4-((3,4-二氯-2-氟苯基)氨基)-7-(1-(氧-3-基)-1H-吡唑-4-基)喹唑啉-6-基)氧基)哌啶-1-基)丙-2-烯-1-酮
Figure PCTCN2019090224-appb-000054
步骤1:参照实施例8合成(1-4-(7-溴-4-(3,4-二氯-2-氟苯基)氨基喹唑啉-6-基)氧基)哌啶-1-基)-2-烯-1-酮。
步骤2:1-(4-((4-((3,4-二氯-2-氟苯基)氨基)-7-(1-(氧-3-基)-1H-吡唑-4-基)喹唑啉-6-基)氧基)哌啶-1-基)丙-2-烯-1-酮的合成
Figure PCTCN2019090224-appb-000055
室温下，向单口瓶中加入(1-4-(7-溴-4-(3,4-二氯-2-氟苯基)氨基喹唑啉-6-基)氧基)哌啶-1-基)-2-烯-1-酮(0.1g，0.18mmol)，1-(氧杂环丁烷-3-基)-4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)-1H-吡唑(0.06g，0.22mmol)，碳酸钾(0.06g，0.37mmol)，H 2O(1mL)和DMF(4mL)，N 2保护下加入Pd(dppf)Cl 2(0.02g，0.02mmol)，置换N 2三次，升温至70℃，反应过夜后终止，冷却至室温，加EA，水洗两次，水相EA萃取一次，有机相合并，无水Na 2SO 4干燥，过滤浓缩，柱层析纯化(DCM/MeOH体系)，反向柱层析纯化(0.1％甲酸水溶液/乙腈体系)，得黄色固体0.01g，收率8％。 1H NMR(400MHz,CD 3Cl)δ8.71(s,1H),8.42(s,1H),8.14-8.09(m,3H),7.35(d,J＝9.2Hz,1H),6.64-6.57(m,1H),6.34-6.29(m,1H),5.75-5.73(m,1H),5.53-5.52(m,1H),5.42-5.23(m,1H),5.13(d,J＝7.0Hz,4H),4.89(m,1H),3.89(m,2H),3.62(m,2H),2.16(m,2H),1.99(m,2H)。MS(ESI)m/z:583.1[M+H] +。
实施例12
1-(4-((4-((3-氯-4-氟苯基)氨基)-7-(1-(四氢-2H-吡喃-4-基)-1H-吡唑-4-基)喹唑啉-6-基)氧)哌啶-1-基)丙-2-烯-1-酮
Figure PCTCN2019090224-appb-000056
步骤1:1-(4-((4-((3-氯-4-氟苯基)氨基)-7-(1-(四氢-2H-吡喃-4-基)-1H-吡唑-4-基)喹唑啉-6-基)氧)哌啶-1-基)丙-2-烯-1-酮的合成
Figure PCTCN2019090224-appb-000057
室温下，向单口瓶中加入1-(4-(7-溴-4-((3-氯-4-氟苯基)氨基)喹唑啉-6-基)氧基)哌啶-1-基-丙-2-烯-1-酮(0.15g，0.30mmol)，1-(四氢-2H-吡喃-4-基)-4-(4-，4-，5-，5-四甲基-1,3-二氧硼烷-2-基)-1H吡唑(0.10g，0.36mmol)和碳酸钾(0.08g，0.6mmol)，加DMF(5mL)和H 2O(1mL)，N 2保护下加入Pd(dppf)Cl 2(0.02g，0.03mmol)。置换N 2三次，升温至70℃，反应过夜后终止，冷却至室温，加EA，水洗两次，水相EA萃取一次，有机相合并，无水Na 2SO 4干燥，过滤浓缩，柱层析(DCM/MeOH体系)。得黄色固体0.03g，收率18％。 1H NMR(400MHz,DMSO-d 6)δ8.42(s,1H),8.31(s,1H),8.07(s,1H),8.01(dd,J＝6.9,2.5Hz,1H),7.95(s,1H),7.91(s,1H),7.70(dd,J＝8.3,4.6Hz,1H),7.39(t,J＝9.1Hz,1H),6.78(dd,J＝16.7,10.5Hz,1H),6.09(dd,J＝16.8,2.1Hz,1H),5.70(dd,J＝10.5,2.2Hz,1H),4.96(m,1H),4.51-4.41(m,1H),3.84(m,4H),3.53-3.35(m,4H),2.11(m,2H),1.96(m,4H),1.75(m,2H).。MS(ESI)m/z:576.8[M+H] +。
实施例13
1-(4-((4-((3-氯-4-氟苯基)氨基)-7-(1-(1-甲基哌啶-4-基)-1H-吡唑-4-基)喹唑啉-6-基)氧基)哌啶-1-基)丙-2-烯-1-酮
Figure PCTCN2019090224-appb-000058
步骤1:1-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊环-2-基)-1H-吡唑-1-基)哌啶的合成
Figure PCTCN2019090224-appb-000059
室温下，向单口瓶中加入4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊环-2-基)-1H-吡唑-1-基)哌啶(0.5g，1.80mmol)，甲酸(0.17g，3.60mmol)，甲醛(0.75g，9.02mmol)和H 2O(5mL)，80℃反应过夜后终止，冷却至室温，加饱和NaHCO 3搅拌30min后用EA萃取，有机相用饱和NaCl洗一次，无水Na 2SO 4干燥，过滤浓缩，得0.6g白色固体，粗品直接用于下一步。
步骤2:1-(4-((4-((3-氯-4-氟苯基)氨基)-7-(1-(1-甲基哌啶-4-基)-1H-吡唑-4-基)喹唑啉-6-基)氧基)哌啶-1-基)丙-2-烯-1-酮的合成
Figure PCTCN2019090224-appb-000060
室温下，向单口瓶中加入1-(4-(7-溴-4-((3-氯-4-氟苯基)氨基)喹唑啉-6-基]氧基)哌啶-1-基-丙-2-烯-1-酮(0.20g，0.40mmol)，1-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊环-2-基)-1H-吡唑-1-基)哌啶(0.18g，0.60mmol)和K 2CO 3(0.11g，0.80mmol)，加DMF(8mL)和H 2O(2mL)，N 2保护下加入Pd(dppf)Cl 2(0.03g，0.04mmol)，置换N 2三次，升温至70℃，反应过夜后终止，冷却至室温，加EA，水洗两次，水相EA萃取一次，有机相合并，无水Na 2SO 4干燥，过滤浓缩，柱层析(DCM/MeOH体系)，得黄色固体0.05g，收率19.1％。 1H NMR(400MHz,DMSO-d 6)δ8.50(s,1H),8.36(s,1H),8.12(d,J＝7.9Hz,2H),8.02(s,1H),7.95(s,1H),7.81(dd,J＝8.4,4.1Hz,1H),7.46(t,J＝9.1Hz,1H),6.84(m,1H),6.18-6.06(m,1H),5.69(m,1H),5.00(m,1H),4.20(m,1H),3.89(d,J＝25.2Hz,2H),3.46(m,1H),3.44(m,1H),2.86(d,J＝10.7Hz,2H),2.21(s,3H),2.11(m,2H),2.08(m,2H),2.04-1.94(m,4H),1.80(s,2H)。MS(ESI)m/z:590.2[M+H] +。
实施例14
1-(4-((4-((3-氯-4-氟苯基)氨基)-7-((1-甲基-1H-吡唑-4-基)乙炔基)喹唑啉-6-基)氧基)哌啶-1-基)丙-2-烯-1-酮
Figure PCTCN2019090224-appb-000061
步骤1:1-(4-((4-((3-氯-4-氟苯基)氨基)-7-((1-甲基-1H-吡唑-4-基)乙炔基)喹唑啉-6-基)氧基)哌啶-1-基)丙-2-烯-1-酮的合成
Figure PCTCN2019090224-appb-000062
室温下，向单口瓶中加入1-(4-(7-溴-4-((3-氯-4-氟苯基)氨基)喹唑啉-6-基]氧基)哌啶-1-基-丙-2-烯-1-酮(0.20g，0.40mmol)，4-乙炔基-1-甲基-1H-吡唑(0.09g，0.79mmol)，DIEA(0.13g，0.99mmol)，CuI(0.02g，0.08mmol)和DMF(10mL)，N 2保护下加入Pd(pph 3) 2Cl 2(0.03g，0.04mmol)，置换N 2三次，N 2保护，升温至70℃，反应过夜后终止，冷却至室温，加EA，饱和NaHCO 3洗一次，饱和NaCl洗一次，水相EA萃取一次，合并有机相，无水Na 2SO 4干燥，过滤浓缩，柱层析纯化(DCM/MeOH体系)，得黄色固体0.08g，收率36％。 1H NMR(400MHz,DMSO-d 6)δ8.53(s,1H),8.11(s,2H),8.01(s,1H),7.83(s,1H),7.78(m,1H),7.70(s,1H),7.49-7.47(m,1H),6.89-6.82(m,1H),6.12(dd,J＝16.7,2.3Hz,1H),5.73-5.68(m,1H),4.98(m,1H),3.86(s,3H),3.81(m,1H),3.73(m,2H),3.62(m,1H),1.99(m,2H),1.86(m,2H)。MS(ESI)m/z:531.1[M+H] +。
实施例15
2-(3-(4-(6-(1-丙烯酰哌啶-4-基)氧基)-4-(3-氯-4-氟苯基)氨基喹唑啉)-7-基)-1H-吡唑-1-基)氧杂环丁烷-3-基)乙腈
Figure PCTCN2019090224-appb-000063
步骤1:2-(3-(4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊环-2-基)-1H-吡唑-1-基)氧杂环丁烷-3-基)乙腈的合成
Figure PCTCN2019090224-appb-000064
室温下，向单口瓶中加入4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊环-2-基)-1H吡唑(0.68g，3.47mmol)，(氧杂环丁烷-3-亚基)乙腈(0.30g，3.15mmol)，DBU(0.96g，6.31mmol)和MeCN(10mL)，加热至60℃，反应过夜后终止，冷却至室温，减压浓缩，1N HCl调pH至3-4，用EA萃取，有机相用水洗两次，饱和NaCl洗一次，无水Na 2SO 4干燥，过滤浓缩，柱层析纯化(PE/EA体系)，得到黄色油状固体0.83g粗品，直接进行下一步。
步骤2:2-(3-(4-(6-(1-丙烯酰哌啶-4-基)氧基)-4-(3-氯-4-氟苯基)氨基喹唑啉)-7-基)-1H-吡唑-1-基)氧杂环丁烷-3-基)乙腈的合成
Figure PCTCN2019090224-appb-000065
室温下，向单口瓶中加入1-(4-(7-溴-4-((3-氯-4-氟苯基)氨基)喹唑啉-6-基]氧基)哌啶-1-基-丙-2-烯-1-酮(0.20g，0.40mmol)，2-(3-(4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊环-2-基)-1H-吡唑-1-基)氧杂环丁烷-3-基)乙腈(0.17g，0.60mmol)和K 2CO 3(0.11g，0.80mmol)，加DMF(8mL)和H 2O(2mL)，N 2保护下加入Pd(dppf)Cl 2(0.03g，0.04mmol)，置换N 2三次，N 2保护，升温至70℃，反应过夜后终止，冷却至室温，加EA，水洗两次，水相EA萃取一次，合并有机相，无水Na 2SO 4干燥，过滤浓缩，柱层析纯化(DCM/MeOH 体系)，得黄色固体0.08g，收率34％。 1H NMR(400MHz,DMSO-d 6)δ8.68(s,1H),8.53(s,1H),8.31(s,1H),8.13(d,J＝7.3Hz,2H),7.98(s,1H),7.83-7.79(m,1H),7.49(t,J＝9.1Hz,1H),6.89-6.82(m,1H),6.13(dd,J＝16.7,2.4Hz,1H),5.70(dd,J＝10.4,2.4Hz,1H),5.08(d,J＝7.2Hz,2H),5.01(m,1H),4.83(d,J＝7.2Hz,2H),4.06-3.80(m,2H),3.67(s,2H),3.47-3.41(m,2H),2.14(m,2H),1.84(m,2H)。MS(ESI)m/z:588.1[M+H] +。
实施例16
1-(4-(7-(1-(1-乙酰哌啶-4-基)-1H-吡唑-4-基)-4-(3-氯-4-氟苯基)氨基)唑啉-6-基)氧基)哌啶-1-基)-2-烯-1-酮
Figure PCTCN2019090224-appb-000066
步骤1:4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊环-2-基)-1H-吡唑-1-基)哌啶的合成
Figure PCTCN2019090224-appb-000067
室温下，向单口瓶中加入叔丁基4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊环-2-基)-1H-吡唑-1-基)哌啶-1-羧酸盐(5g，13.2mmol)和HCl/EtOH(50mL)，室温反应2h后终止，减压浓缩，用DCM带三次，加入DCM和饱和K 2CO 3水溶液室温搅拌30min，静置分层，水相用DCM萃取，有机相合并，水洗两次，无水Na 2SO 4干燥，过滤浓缩，得4.8g白色胶状固体，粗品直接用于下一步。
步骤2:1-(4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊环-2-基)-1H-吡唑-1-基)哌啶-1-基)乙烷-1-酮的合成
Figure PCTCN2019090224-appb-000068
室温下，向单口瓶中加入4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊环-2-基)-1H-吡唑-1-基)哌啶(1g，3.61mmol)，TEA(1.8g，18.03mmol)和DCM(20mL)，冰浴下滴加乙酰氯(0.43g，5.41mmol)的DCM稀释液(3mL)，冰浴下反应2h后终止，加冰水淬灭，分层，有机相用水洗两次，水相用DCM反萃一次，有机相合并，无水Na 2SO 4干燥，过滤浓缩，得0.7g黄色油状固体，粗品直接用于下一步。
步骤3:1-(4-(7-(1-(1-乙酰哌啶-4-基)-1H-吡唑-4-基)-4-(3-氯-4-氟苯基)氨基)唑啉-6-基)氧基)哌啶-1-基)-2-烯-1-酮的合成
Figure PCTCN2019090224-appb-000069
室温下，向单口瓶中加入1-(4-(7-溴-4-((3-氯-4-氟苯基)氨基)喹唑啉-6-基]氧基)哌啶-1-基-丙-2-烯-1-酮(0.20g，0.40mmol)，1-(4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊环-2-基)-1H-吡唑-1-基)哌啶-1-基)乙烷-1-酮(0.19g，0.60mmol)和K 2CO 3(0.11g，0.80mmol)，加DMF(8mL)和H 2O(2mL)，N 2保护下加入Pd(dppf)Cl 2(0.03g，0.04mmol)，置换N 2三次，升温至70℃，反应过夜后终止，冷却至室温，加EA，水洗两次，水相用EA萃取一次，有机相合并，无水Na 2SO 4干燥，过滤浓缩，柱层析纯化(DCM/MeOH体系)，得黄色固体0.05g，收率19％。 1H NMR(400MHz,DMSO-d 6)δ8.50(s,1H),8.39(s,1H),8.11(s,2H),8.02(s,1H),7.94(s,1H),7.82-7.78(m,1H),7.46(t,J＝9.1Hz,1H),6.88-6.81(m,1H),6.18-6.07(m,1H),5.74-5.65(m,1H),4.99(s,1H),4.50(q,J＝13.5,12.8Hz,2H),3.93(d,J＝13.5Hz,2H),3.86(s,1H),3.54(s,1H),3.41(s,1H),3.21(t,J＝12.9Hz,1H),2.73(t,J＝12.6Hz,1H),2.12(s,2H),2.07(s,1H),2.05(s,3H),2.00(s,1H),1.92(d,J＝11.7Hz,1H),1.84-1.78(m,2H),1.76(dd,J＝10.7,4.6Hz,1H)。MS(ESI)m/z:618.2[M+H] +。
实施例17
1-(4-((4-((3-氯-4-氟苯基)氨基)-7-(1-(1-(2-甲氧基乙基)哌啶-4-基)-1H-吡唑-4-基)喹唑啉-6-基)氧基)哌啶-1-基)丙-2-烯-1-酮
Figure PCTCN2019090224-appb-000070
步骤1:1-(2-甲氧基乙基)-4-(4-(甲基反应物氧磷杂环-2-基)-1H-吡唑-1-基)哌啶的合成
Figure PCTCN2019090224-appb-000071
室温下，向单口瓶中加入4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊环-2-基)-1H-吡唑-1-基)哌啶(0.6g，2.16mmol)，1-溴-2-甲氧基乙烷(0.45g，3.25mmol)，CS 2CO 3(1.41g，4.32mmol)和DMF(10mL)，80℃反应过夜后终止，冷却至室温，用EA萃取，有机相用饱和NaCl洗一次，无水Na 2SO 4干燥，过滤浓缩，得0.55g黄色液体，粗品直接用于下一步。
步骤2:1-(4-((4-((3-氯-4-氟苯基)氨基)-7-(1-(1-(2-甲氧基乙基)哌啶-4-基)-1H-吡唑-4-基)喹唑啉-6-基)氧基)哌啶-1-基)丙-2-烯-1-酮的合成
Figure PCTCN2019090224-appb-000072
室温下，向单口瓶中加入1-(4-(7-溴-4-((3-氯-4-氟苯基)氨基)喹唑啉-6-基]氧基)哌啶-1-基-丙-2-烯-1-酮(0.20g，0.40mmol)，1-(2-甲氧基乙基)-4-(4-(甲基反应物氧磷杂环-2-基)-1H-吡唑-1-基)哌啶(0.20g，0.60mmol)和K 2CO 3(0.11g，0.80mmol)，加 DMF(8mL)和H 2O(2mL)，N 2保护下加入Pd(dppf)Cl 2(0.03g，0.04mmol)，置换N 2三次，升温至70℃，反应过夜后终止，冷却至室温，加EA，水洗两次，水相EA萃取一次，有机相合并，无水Na 2SO 4干燥，过滤浓缩，柱层析(DCM/MeOH体系)，得黄色固体0.06g，收率20.6％。 1H NMR(400MHz,DMSO-d 6)δ8.49(s,1H),8.35(s,1H),8.10(d,J＝7.5Hz,2H),8.01(s,1H),7.94(s,1H),7.83-7.76(m,1H),7.45(t,J＝9.1Hz,1H),6.84(dd,J＝16.7,10.5Hz,1H),6.12(dd,J＝16.7,2.3Hz,1H),5.70(dd,J＝10.4,2.3Hz,1H),4.99(m,1H),4.24-4.16(m,1H),4.00-3.75(m,2H),3.46-3.43(m,3H),3.40(m,1H),3.23(s,3H),2.97(m,2H),2.52(m,2H),2.20-2.08(m,4H),2.03-1.94(m,4H),1.80(m,2H)。MS(ESI)m/z:634.2[M+H] +。
实施例18
1-(4-((4-((3-氯-4-氟苯基)氨基)-7-(1-(四氢-2H-吡喃-4-基)哌啶-4-基)-1H-吡唑-4-基)喹唑啉-6-基)氧基)哌啶-1-基)丙-2-烯-1-酮
Figure PCTCN2019090224-appb-000073
步骤1:1-(四氢-2H-吡喃-4-基)-4-(4-(4，4，5，5-四甲基-1，3，2-二氧硼烷-2-基)-1H-吡唑-1-基)哌啶的合成
Figure PCTCN2019090224-appb-000074
室温下，向单口瓶中加入4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊环-2-基)-1H-吡唑-1-基)哌啶(0.6g，2.16mmol)，四氢-4H-吡喃-4-酮(0.33g，3.25mmol)，AcOH(0.26g，4.32mmol)和DCM(10mL)，30℃反应2h后，分批加入NaBH(oAc) 3(2.30g，10.8mmol)，反应1h后终止，加水淬灭，用DCM萃取，有机相用水洗一次，用饱和NaCl洗一次，无水Na 2SO 4干燥，过滤浓缩，得0.32g黄色固体，粗品直接用于下一步。
步骤2:1-(4-((4-((3-氯-4-氟苯基)氨基)-7-(1-(四氢-2H-吡喃-4-基)哌啶-4-基)-1H-吡唑-4-基)喹唑啉-6-基)氧基)哌啶-1-基)丙-2-烯-1-酮的合成
Figure PCTCN2019090224-appb-000075
室温下，向单口瓶中加入1-(4-(7-溴-4-((3-氯-4-氟苯基)氨基)喹唑啉-6-基]氧基)哌啶-1-基-丙-2-烯-1-酮(0.15g，0.30mmol)，1-(四氢-2H-吡喃-4-基)-4-(4-(4，4，5，5-四甲基-1，3，2-二氧硼烷-2-基)-1H-吡唑-1-基)哌啶(0.32g，0.90mmol)和K 2CO 3(0.09g，0.60mmol)，加DMF(6mL)和H 2O(1.5mL)，N 2保护下加入Pd(dppf)Cl 2(0.02g，0.03mmol)，置换N 2三次，升温至80℃，反应过夜后终止，冷却至室温，加EA，水洗两次，水相EA萃取一次，有机相合并，无水Na 2SO 4干燥，过滤浓缩，柱层析(DCM/MeOH体系)，得淡黄色固体0.02g，收率6.8％。 1H NMR(400MHz,DMSO-d 6)δ8.52(s,1H),8.39(s,1H),8.13(s,2H),8.05(s,1H),7.96(s,1H),7.81(s,1H),7.49(t,J＝9.1Hz,1H),6.87(dd,J＝16.7,10.5Hz,1H),6.14(dd,J＝16.6,2.4Hz,1H),5.71(dd,J＝10.5,2.4Hz,1H),5.01(s,1H),4.23(d,J＝11.6Hz,1H),3.96(s,1H),3.93-3.88(m,2H),3.85(s,1H),3.58-3.51(m,1H),3.46(d,J＝6.5Hz,1H),3.29(m,2H),3.26(s,1H),3.01(d,J＝11.1Hz,2H),2.32(d,J＝12.1Hz,2H),2.14(s,2H),2.09-2.03(m,2H),2.01-1.92(m,2H),1.83(s,2H),1.75-1.66(m,2H),1.50-1.44(m,2H)。MS(ESI)m/z:660.2[M+H] +。
实施例19
1-(4-((4-((3-氯-4-氟苯基)氨基)-7-(1-(1-氧-3-基)哌啶-4-基)-1H-吡唑-4-基)喹唑啉-6-基)氧基)哌啶-1-基)丙-2-烯-1-酮
Figure PCTCN2019090224-appb-000076
步骤1:1-(氧-3-基)-4-(4-(4,4,5,5-四甲基-1-二氧硼酸-2-基)-1H-吡唑-1-基)哌啶的合成
Figure PCTCN2019090224-appb-000077
室温下，向单口瓶中加入4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊环-2-基)-1H-吡唑-1-基)哌啶(0.5g，1.80mmol)，氧杂环丁烷-3-酮(0.16g，2.10mmol)，AcOH(0.22g，3.60mmol)和DCM(10mL)，30℃反应2h后，分批加入NaBH(oAc) 3(1.9g，9.00mmol)，反应1h后终止，加水淬灭，用DCM萃取，有机相用水洗一次，用饱和NaCl洗一次，无水Na 2SO 4干燥，过滤浓缩，得0.30g黄色固体，粗品直接用于下一步。
步骤2:1-(4-((4-((3-氯-4-氟苯基)氨基)-7-(1-(1-氧-3-基)哌啶-4-基)-1H-吡唑-4-基)喹唑啉-6-基)氧基)哌啶-1-基)丙-2-烯-1-酮的合成
Figure PCTCN2019090224-appb-000078
室温下，向单口瓶中加入1-(4-(7-溴-4-((3-氯-4-氟苯基)氨基)喹唑啉-6-基]氧基)哌啶-1-基-丙-2-烯-1-酮(0.20g，0.40mmol)，1-(氧-3-基)-4-(4-(4,4,5,5-四甲基-1-二氧硼酸-2-基)-1H-吡唑-1-基)哌啶(0.20g，0.60mmol)和K 2CO 3(0.11g，0.80mmol)，加 DMF(8mL)和H 2O(2mL)，N 2保护下加入Pd(dppf)Cl 2(0.03g，0.04mmol)，置换N 2三次，升温至70℃，反应过夜后终止，冷却至室温，加EA，水洗两次，水相EA萃取一次，有机相合并，无水Na 2SO 4干燥，过滤浓缩，柱层析(DCM/MeOH体系)，得淡黄色固体0.05g，收率18.9％。 1H NMR(400MHz,DMSO-d 6)δ 1H NMR(400MHz,DMSO-d 6)δ8.52(s,1H),8.40(s,1H),8.12(d,J＝8.8Hz,2H),8.04(s,1H),7.95(s,1H),7.84-7.77(m,1H),7.48(t,J＝9.1Hz,1H),6.87(dd,J＝16.7,10.4Hz,1H),6.13(dd,J＝16.7,2.4Hz,1H),5.70(dd,J＝10.5,2.4Hz,1H),5.00(m,1H),4.55(t,J＝6.5Hz,2H),4.45(t,J＝6.1Hz,2H),4.30-4.21(m,1H),3.91(d,J＝15.3Hz,2H),3.53(m,1H),3.44(m,2H),2.81(d,J＝8.3Hz,2H),2.14(m,2H),2.01(m,6H),1.83(m,2H)。MS(ESI)m/z:632.2[M+H] +。
实施例20
1-(4-((4-((3-氯-4-氟苯基)氨基)-7-(1-(1-甲基哌啶-4-基)氮杂环丁烷-3-基)-1H-吡唑-4-基)喹唑啉-6-基)氧基)哌啶-1-基)丙-2-烯-1-酮
Figure PCTCN2019090224-appb-000079
步骤1:1-甲基-4-(3-(4-(4,4,5,5四甲基-1-二氧硼酸-2-基)-1H-吡唑-1-基)杂氮环丁-1-基)哌啶吡唑的合成
Figure PCTCN2019090224-appb-000080
室温下，向单口瓶中加入1(杂氮环丁-3-基)-4-(4,4,5,5四甲基-1-二氧硼酸-2-基)-1H-吡唑(1.0g，4.0mmol)，K 2CO 3(0.56g，4.0mmol)和DCM(10mL)，室温反应1h后加入乙酸(1.22g，20.0mmol)，四氢-4H-吡喃-4-酮(0.68g，6.02mmol)，30℃反应2h后冷却至室温，分批加入NaBH(oAc) 3(4.20g，20.1mmol)，室温反应1h后终止，加水淬灭，浓缩，用DCM/MeOH溶解，过滤，滤饼用DCM/MeOH洗涤，得0.33g黄色固体，粗 品直接用于下一步。
步骤2:1-(4-((4-((3-氯-4-氟苯基)氨基)-7-(1-(1-甲基哌啶-4-基)氮杂环丁烷-3-基)-1H-吡唑-4-基)喹唑啉-6-基)氧基)哌啶-1-基)丙-2-烯-1-酮的合成
Figure PCTCN2019090224-appb-000081
室温下，向单口瓶中加入1-(4-(7-溴-4-((3-氯-4-氟苯基)氨基)喹唑啉-6-基]氧基)哌啶-1-基-丙-2-烯-1-酮(0.20g，0.40mmol)，1-甲基-4-(3-(4-(4,4,5,5四甲基-1-二氧硼酸-2-基)-1H-吡唑-1-基)杂氮环丁-1-基)哌啶吡唑(0.21g，0.60mmol)和K 2CO 3(0.11g，0.80mmol)，加DMF(8mL)和H 2O(2mL)，N 2保护下加入Pd(dppf)Cl 2(0.03g，0.04mmol)，置换N 2三次，升温至70℃，反应过夜后终止，冷却至室温，加EA，水洗两次，水相EA萃取一次，有机相合并，无水Na 2SO 4干燥，过滤浓缩，柱层析(DCM/MeOH体系)，得黄绿色固体0.08g，收率32.4％。 1H NMR(400MHz,DMSO-d 6)δ8.50(d,J＝9.3Hz,2H),8.22(s,1H),8.16(dd,J＝6.9,2.5Hz,1H),8.07(d,J＝9.4Hz,2H),7.85(dt,J＝7.9,3.4Hz,1H),7.46(t,J＝9.1Hz,1H),6.85(dd,J＝16.7,10.4Hz,1H),6.12(dd,J＝16.7,2.3Hz,1H),5.73-5.64(m,1H),5.22-5.05(m,2H),4.01-3.98(m,3H),3.67(m,2H),3.58-3.44(m,3H),3.31(m,2H),2.99(m,2H),2.72(s,3H),2.68(m,1H),2.18-2.09(m,2H),1.94(d,J＝12.8Hz,2H),1.80(dd,J＝11.6,6.7Hz,2H),1.61(m,2H)。MS(ESI)m/z:645.3[M+H] +。
实施例21
1-(4-((4-((3-氯-4-氟苯基)氨基)-7-(1-(四氢-2H-吡喃-4-基)氮杂环丁烷-3-基)-1H-吡唑-4-基)喹唑啉-6-基)氧基)哌啶-1-基)丙-2-烯-1-酮
Figure PCTCN2019090224-appb-000082
步骤1:叔丁基3-((氯磺酰)氧基)氮杂环丁烷-1-羧酸盐的合成
Figure PCTCN2019090224-appb-000083
室温下，向单口瓶中加入叔丁基3-羟基氮杂环丁烷-1-羧酸盐(5.0g，28.9mmol)，TEA(8.75g，86.6mmol)和THF(50mL)，N 2保护下加入MsCl(4.0g，34.6mmol)，室温反应2h后终止，加饱和NaHCO 3淬灭反应，用EA萃取，有机相用饱和NaCl洗一次，无水Na 2SO 4干燥，过滤浓缩，粗品直接用于下一步。
步骤2:叔丁基3-(4,4,5,5-四甲基-1,3,2-二氧杂环戊环-2-基)-1H-吡唑-1-基)氮杂环丁烷-1-羧酸盐的合成
Figure PCTCN2019090224-appb-000084
室温下，向单口瓶中加入4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊环-2-基)-1H吡唑(5.6g，28.9mmol)和DMF(60mL)，冰浴下加入NaH(2.4g，57.7mmol)，冰浴反应1h后加入叔丁基3-((氯磺酰)氧基)氮杂环丁烷-1-羧酸盐(粗品，28.9mmol)的DMF溶液(50mL)，95℃反应16h后终止，冷却至室温，加水淬灭，用EA萃取，有机相饱和NaCl洗一次，无水Na 2SO 4干燥，过滤浓缩，柱层析(PE/EA体系)，得3.2g白色固体。
步骤3:1(杂氮环丁-3-基)-4-(4,4,5,5四甲基-1-二氧硼酸-2-基)-1H-吡唑的合成
Figure PCTCN2019090224-appb-000085
室温下，向单口瓶中加入叔丁基3-(4,4,5,5-四甲基-1,3,2-二氧杂环戊环-2-基)-1H-吡唑-1-基)氮杂环丁烷-1-羧酸盐(3.2g，9.16mmol)和HCl/EA(32mL)，室温反应2h后终止， 浓缩溶剂，用DCM带三次，粗品直接用于下一步。
步骤4:1-(1-(四氢-2H-吡喃-4-基)氮杂环丁烷-3-基)-4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊环-2-基)-1H吡唑的合成
Figure PCTCN2019090224-appb-000086
室温下，向单口瓶中加入1(杂氮环丁-3-基)-4-(4,4,5,5四甲基-1-二氧硼酸-2-基)-1H-吡唑(0.50g，2.0mmol)，K 2CO 3(0.28g，2.0mmol)和DCM(5mL)，室温反应1h后加入乙酸(0.61g，10.0mmol)，四氢-4H-吡喃-4-酮(0.31g，3.01mmol)，30℃反应16h后冷却至室温，分批加入NaBH(oAc) 3(2.10g，10.0mmol)，室温反应1h后终止，加水淬灭，分层，有机相用水洗两次，水相用DCM反萃一次，有机相合并，无水Na 2SO 4干燥，过滤浓缩，得0.35g黄色油状固体，粗品直接用于下一步。
步骤5:1-(4-((4-((3-氯-4-氟苯基)氨基)-7-(1-(四氢-2H-吡喃-4-基)氮杂环丁烷-3-基)-1H-吡唑-4-基)喹唑啉-6-基)氧基)哌啶-1-基)丙-2-烯-1-酮的合成
Figure PCTCN2019090224-appb-000087
室温下，向单口瓶中加入1-(4-(7-溴-4-((3-氯-4-氟苯基)氨基)喹唑啉-6-基]氧基)哌啶-1-基-丙-2-烯-1-酮(0.20g，0.40mmol)，1-(1-(四氢-2H-吡喃-4-基)氮杂环丁烷-3-基)-4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊环-2-基)-1H吡唑(0.20g，0.60mmol)和K 2CO 3(0.11g，0.80mmol)，加DMF(8mL)和H 2O(2mL)，N 2保护下加入Pd(dppf)Cl 2(0.03g，0.04mmol)，置换N 2三次，升温至70℃，反应过夜后终止，冷却至室温，加EA，水洗两次，水相EA萃取一次，有机相合并，无水Na 2SO 4干燥，过滤浓缩，柱层析(DCM/MeOH体系)，得黄色固体0.03g，收率12.0％。 1H NMR(400MHz,DMSO-d 6)δ8.50(s,2H),8.17(s,1H),8.11(dd,J＝6.9,2.7Hz,1H),8.04(s,1H),7.96(s,1H),7.80(dt,J＝9.5,3.4Hz,1H),7.46(t,J＝9.1Hz,1H),6.83(dd,J＝16.7,10.5Hz,1H),6.12(dd,J＝16.7,2.3Hz,1H),5.70(dd,J＝10.4,2.3Hz,1H),5.05(dd,J＝15.6,8.7Hz,2H),3.92-3.78(m,4H),3.70(t,J＝7.3Hz,2H),3.57(m,1H),3.41(t,J＝7.1Hz,2H),3.30(t,J＝11.0Hz,2H),2.37(m,1H),2.12(m,2H),1.81(m,2H), 1.66-1.59(m,2H),1.25-1.07(m,3H)。MS(ESI)m/z:632.2[M+H] +。
实施例22
2-(3-(4-(6-(1-丙烯酰哌啶-4-基)氧基)-4-(3-氯-4-氟苯基)氨基喹唑啉)-7-基)-1H-吡唑-1-基)-1-(四氢-2H-吡喃4酮基)杂氮环丁-3-基)乙腈
Figure PCTCN2019090224-appb-000088
步骤1:叔丁基3-(氰基甲基)-3-(4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊环-2-基)-1H-吡唑-1-基)氮杂环丁烷-1-羧酸盐的合成
Figure PCTCN2019090224-appb-000089
室温下，向单口瓶中加入4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊环-2-基)-1H-吡唑(1.8g，9.28mmol)，叔丁基3-氰基亚甲基氮杂环丁烷-1-羧酸盐(2.2g，11.13mmol)，DBU(2.8g，18.55mmol)和乙腈(20mL)，60℃反应16h后终止，冷却至室温，浓缩溶剂，用1N HCl调pH至3-4，用EA萃取，有机相用饱和NaCl洗一次，无水Na 2SO 4干燥，过滤浓缩，柱层析(PE/EA体系)，得2.30g白色固体。
步骤2:2-(3-(4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊环-2-基)-1H-吡唑-1-基)氮杂环丁烷-3-基)乙腈的合成
Figure PCTCN2019090224-appb-000090
室温下，向单口瓶中加入叔丁基3-(氰基甲基)-3-(4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊环-2-基)-1H-吡唑-1-基)氮杂环丁烷-1-羧酸盐(2.30g，5.92mmol)和HCl/EA(23mL)，室温反应2h后终止，浓缩溶剂，用DCM带三次，加入DCM和饱和K 2CO 3室温搅拌30min，静止分层，水相用DCM萃取，有机相合并，水洗两次，无水Na 2SO 4干燥，过滤浓缩，得2.3g黄色固体，粗品直接用于下一步。
步骤3:2-(1-(四氢-2H-吡喃-4-基)-3-(4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊环-2-基)-1H-吡唑-1-基)氮杂环丁烷-3-基)乙腈的合成
Figure PCTCN2019090224-appb-000091
室温下，向单口瓶中加入2-(3-(4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊环-2-基)-1H-吡唑-1-基)氮杂环丁烷-3-基)乙腈(0.50g，1.73mmol)，四氢-4H-吡喃-4-酮(0.21g，2.08mmol)，乙酸(0.21g，3.47mmol)和DCM(15mL)，30℃反应2h后分批加入NaBH(oAc) 3(1.84g，8.68mmol)，室温反应1h后终止，加水淬灭，分层，有机相用水洗两次，水相用DCM反萃一次，有机相合并，无水Na 2SO 4干燥，过滤浓缩，柱层析(PE/EA体系)，得0.37g黄色油状固体。
步骤4:2-(3-(4-(6-(1-丙烯酰哌啶-4-基)氧基)-4-(3-氯-4-氟苯基)氨基喹唑啉)-7-基)-1H-吡唑-1-基)-1-(四氢-2H-吡喃4酮基)杂氮环丁-3-基)乙腈的合成
Figure PCTCN2019090224-appb-000092
室温下，向单口瓶中加入1-(4-(7-溴-4-((3-氯-4-氟苯基)氨基)喹唑啉-6-基]氧基)哌啶-1-基-丙-2-烯-1-酮(0.20g，0.40mmol)，2-(1-(四氢-2H-吡喃-4-基)-3-(4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊环-2-基)-1H-吡唑-1-基)氮杂环丁烷-3-基)乙腈(0.22g，0.60mmol)和K 2CO 3(0.11g，0.80mmol)，加DMF(8mL)和H 2O(2mL)，N 2保护下加入Pd(dppf)Cl 2(0.03g，0.04mmol)，置换N 2三次，升温至70℃，反应过夜后终止，冷却至室温，加EA，水洗两次，水相EA萃取一次，有机相合并，无水Na 2SO 4干燥，过滤浓缩，柱层析(DCM/MeOH体系)，得黄色固体0.06g，收率23.5％。 1H NMR(400MHz,DMSO-d 6)δ8.63(s,1H),8.52(s,1H),8.25(s,1H),8.12(d,J＝7.5Hz,2H),7.98(s,1H),7.83-7.77(m,1H),7.46(t,J＝9.1Hz,1H),6.82(dd,J＝16.7,10.5Hz,1H),6.11(dd,J＝16.7,2.4Hz,1H),5.69(dd,J＝10.5,2.3Hz,1H),5.02(dt,J＝8.3,5.0Hz,1H),3.88-3.77(m,4H),3.63(d,J＝8.0Hz,2H),3.54(d,J＝8.2Hz,4H),3.50(m,2H),3.27(t,J＝10.9Hz,2H),2.40(dt,J＝10.0,5.7Hz,1H),2.12(m,2H),1.83(m, 2H),1.63(d,J＝12.7Hz,2H),1.19(d,J＝10.3Hz,1H),1.13(d,J＝7.8Hz,1H)。MS(ESI)m/z:671.2[M+H] +。
实施例23
6-((1-丙烯酰哌啶-4-基)氧基)-4-((3-氯-4-氟苯基)胺基)-7-(1-甲基-1H-吡唑-4-基)喹啉-3-甲腈
Figure PCTCN2019090224-appb-000093
步骤1:5-((1-((苄氧基)羰基)哌啶-4-基)氧)-4-溴-2-硝基苯甲酸的合成
Figure PCTCN2019090224-appb-000094
室温下，向250mL单口瓶中加入4-羟基-1-苄氧基羰基哌啶(8.91g，37.88mmol)和DMF(50mL)，并于冰浴下分批加入60％的NaH(1.89g，47.35mmol)，搅拌30min后，分批加入4-溴-5-氟-2-硝基苯甲酸(2.00g，18.94mmol)，冰浴下搅拌2.5h终止。冰浴下，用1N的HCl调节pH～3-4，回升室温，反应液采用EA萃取，水洗一次，有机相经无水硫酸钠干燥，过滤，浓缩得黄色油状物16.11g，收率100％计，直接进行下一步。
步骤2:4-(2-溴-5-(甲氧羰基)-4-硝基苯氧基)-1-苄氧羰基哌啶的合成
Figure PCTCN2019090224-appb-000095
室温下，依次向250mL单口瓶中加入5-((1-((苄氧基)羰基)哌啶-4-基)氧)-4-溴-2-硝基苯甲酸(粗品，18.94mmol)、DCM(50mL)和DMF(0.1mL)，并于冰浴下滴加入SOCl 2(4.51g，37.88mmol)，升温50℃下，反应3.0h终止。冷却至室温，减压浓缩，除去DCM和SOCl 2。于冰浴下滴加MeOH(50mL),加毕后反应2.5h终止。减压浓缩除去溶剂，柱层析纯化(PE/EA体系)得黄色油状物8.69g，收率83％。
步骤3:苄基4-(4-胺基-2-溴-5-(甲氧羰基)苯氧基)哌啶-1-羧酸酯的合成
Figure PCTCN2019090224-appb-000096
室温下，依次向250mL单口瓶中加入4-(2-溴-5-(甲氧羰基)-4-硝基苯氧基)-1-苄氧羰基哌啶(8.69g，17.62mmol)，NH 4Cl(4.71g，88.08mmol)，乙醇(90mL)和水(30mL)，搅拌全溶后，分批加入铁粉(4.92g，88.08mmol)，氮气保护，升温至80℃反应2h终止。冷却至室温，通过硅藻土过滤，滤液减压蒸干，残留物采用EA溶解，水洗涤两次，有机相经无水硫酸钠干燥，过滤，浓缩得红色油状物7.15g，收率88％。
步骤4:苄基(E)-4-(2-溴-4-(((二甲胺基)亚甲基)胺基)-5-(甲氧羰基)苯氧基)哌啶-1-羧酸酯的合成
Figure PCTCN2019090224-appb-000097
室温下，依次向250mL单口瓶中加入苄基4-(4-胺基-2-溴-5-(甲氧羰基)苯氧基)哌啶-1-羧酸酯(7.15g，15.43mmol)和DMF-DMA(72mL)。溶解后氮气保护，升温至125℃反应22h终止。冷却至室温，反应液用油泵拉干，得黑色油状物8.71g，收率100％计，直接进行下一步。MS(ESI)m/z:519.1[M+H] +。
步骤5:苄基4-((7-溴-3-氰基-4-氧-3,4-二羟基喹啉-6-基)氧)哌啶-1-羧酸酯的合成
Figure PCTCN2019090224-appb-000098
室温下，向250mL的四口瓶中加入MeCN(0.98g，23.96mmol)和THF(40mL)，氮气保护降温至-70℃，滴加n-BuLi(10mL)，加毕，在-70℃下搅拌1.5h后，滴加苄基(E)-4-(2-溴-4-(((二甲胺基)亚甲基)胺基)-5-(甲氧羰基)苯氧基)哌啶-1-羧酸酯(6.21g，11.98mmol)的THF(25mL)溶液，加毕在-70℃下搅拌4.5h终止。用AcOH的THF溶液淬灭，恢复至室温，反应液采用EA萃取，饱和食盐水洗涤一次，有机相经无水硫酸钠干燥，过滤，浓缩，柱层析纯化(DCM/MeOH体系)得黄色固体5.20g，收率90％。MS(ESI)m/z:483.0[M+H] +。
步骤6:苄基4-((7-溴-4-氯-3-氰基喹啉-6-基)氧基)哌啶-1-羧酸酯的合成
Figure PCTCN2019090224-appb-000099
室温下，向250mL的单口瓶中加入苄基4-((7-溴-3-氰基-4-氧-3,4-二羟基喹啉-6-基)氧)哌啶-1-羧酸酯(5.20g，10.78mmol)，SOCl 2(52mL)和DMF(1mL)。溶解后，氮气保护，升温至80℃反应2h终止。冷却至室温，浓缩得红色油状物粗品，收率100％计，直接进行下一步。
步骤7:苄基4-((7-溴-4-((3-氯-4-氟苯基)胺基)-3-氰基喹啉-6-基)氧基)哌啶-1-羧酸酯的合成
Figure PCTCN2019090224-appb-000100
室温下，向250mL单口瓶中加入苄基4-((7-溴-4-氯-3-氰基喹啉-6-基)氧基)哌啶-1-羧酸酯(粗品，10.78mmol)，IPA(75mL)和4-氟-3-氯苯胺(1.88g，12.94mmol)。氮气保护，升温至60℃反应15h终止。冷却至室温，过滤，IPA洗涤滤饼两次，收集滤饼，减压蒸至恒重得淡黄色固体4.64g，收率71％。
步骤8:7-溴-4-((3-氯-4-氟苯基)胺基)-6-(哌啶-4-基氧)喹啉-3-甲腈的合成
Figure PCTCN2019090224-appb-000101
室温下，向250mL的单口瓶中加入苄基4-((7-溴-4-((3-氯-4-氟苯基)胺基)-3-氰基喹啉-6-基)氧基)哌啶-1-羧酸酯(4.64g，7.61mmol)和1,4-二氧六环(5mL)，分散后加入33％的HBr/AcOH溶液(46mL)溶解。氮气保护，升温至30℃反应2h终止。冷却至室温，反应液中加入MTBE，搅拌半小时后过滤，并用MTBE洗涤滤饼，收集滤饼。向滤饼中加入1N的Na 2CO 3水溶液搅拌溶解，用DCM萃取两次，收集有机相，经无水硫酸钠干燥，过滤，浓缩得黄色固体2.87g，收率79％。
步骤9:6-((1-丙烯酰基哌啶-4-基)氧基)-7-溴-4-((3-氯-4-氟苯基)胺基)喹啉-3-甲腈的合成
Figure PCTCN2019090224-appb-000102
室温下，向250mL的单口瓶中加入7-溴-4-((3-氯-4-氟苯基)胺基)-6-(哌啶-4-基氧)喹啉-3-甲腈(2.62g，5.51mmol),DCM(50mL)和TEA(2.78g，27.53mmol)，溶解后降温0℃，滴加丙烯酰氯(0.60g，6.61mmol)。滴毕后再0℃反应2h终止。冰水猝灭反应，恢复室温，分液，并用DCM萃取水相两次，合并有机相，经无水硫酸钠干燥，过滤，浓缩，柱层析纯化(DCM/EA体系)得黄色固体1.22g，收率42％。MS(ESI)m/z:530.0[M+H] +。
步骤10:6-((1-丙烯酰哌啶-4-基)氧基)-4-((3-氯-4-氟苯基)胺基)-7-(1-甲基-1H-吡唑-4-基)喹啉-3-甲腈的合成
Figure PCTCN2019090224-appb-000103
室温下，依次向25mL的单口瓶中加入6-((1-丙烯酰基哌啶-4-基)氧基)-7-溴-4-((3-氯-4-氟苯基)胺基)喹啉-3-甲腈(0.20g，0.38mmol)，(1-甲基-1H-吡唑-4-基)硼酸(57.10mg，0.45mmol)，Pd(dppf)Cl 2(27.60mg，0.04mmol)，K 2CO 3(0.11g，0.76mmol)和H 2O(2.50ml),并用DMF(10mL)溶解。氮气保护，升温至70℃反应15h终止。冷却至室温，反应液采用EA萃取，水洗一次，有机相经无水硫酸钠干燥，过滤，浓缩，柱层析纯化(DCM/MeOH体系)得黄色固体78.20mg，收率39％。 1H NMR(400MHz,DMSO-d 6)δ9.60(s,1H),8.49(s,1H),8.31(s,1H),8.13(d,J＝18.1Hz,2H),7.82(d,J＝4.9Hz,1H),7.60(d,J＝6.4Hz,1H),7.49(t,J＝9.1Hz,1H),7.35(d,J＝8.5Hz,1H),6.85(dd,J＝16.6,10.6Hz,1H),6.12(d,J＝16.7Hz,1H),5.69(d,J＝10.6Hz,1H),4.92(d,J＝10.4Hz,1H),4.00(s,1H),3.92(s,3H),3.90–3.81(m,1H),3.54–3.36(m,2H),2.06(m,2H),1.77(m,2H).MS(ESI)m/z:531.1[M+H] +.
实施例24
7-((1-丙烯酰基哌啶-4-基)氧基)-4-((3-氯-4-氟苯基)胺基)-7-(1-(1-甲基哌啶-4-基)-1H-吡唑-4-基)喹啉-3-甲腈
Figure PCTCN2019090224-appb-000104
步骤1:6-((1-丙烯酰基哌啶-4-基)氧基)-4-((3-氯-4-氟苯基)胺基)-7-(1-(1-甲基哌啶-4-基)-1H-吡唑-4-基)喹啉-3-甲腈的合成
Figure PCTCN2019090224-appb-000105
室温下，依次向25mL的单口瓶中加入6-((1-丙烯酰基哌啶-4-基)氧基)-7-溴-4-((3-氯-4-氟苯基)胺基)喹啉-3-甲腈(0.20g，0.38mmol)，1-甲基-4-(4-(4,4,5,5-四甲基-1,3,2-硼酸乙二酯-2-基)-1H-吡唑-1-基)哌啶(0.22mg，0.76mmol)，Pd(dppf)Cl 2(27.60mg，0.04mmol)，K 2CO 3(0.11g，0.76mmol)和H 2O(2.50ml),并用DMF(10mL)溶解。氮气保护，升温至70℃反应2h终止。冷却至室温，反应液采用EA萃取，水洗一次，有机相经无水硫酸钠干燥，过滤，浓缩，柱层析纯化(DCM/MeOH体系)得黄色固体115.5mg，收率50％。 1H NMR(400MHz,DMSO-d 6)δ9.62(s,1H),8.48(s,1H),8.39(s,1H),8.16(d,J＝18.8Hz,2H),7.83(s,1H),7.63–7.58(m,1H),7.48(t,J＝9.0Hz,1H),7.38–7.32(m,1H),6.85(dd,J＝16.7,10.4Hz,1H),6.12(dd,J＝16.7,2.4Hz,1H),5.69(dd,J＝10.4,2.4Hz,1H),4.94(tt,J＝7.6,3.7Hz,1H),4.21(t,J＝7.6Hz,1H),3.91m,2H),3.49(m,2H),2.89–2.82(m,2H),2.21(s,3H),2.12–1.97(m,8H),1.79(m,2H).MS(ESI)m/z:613.8[M+H] +.
实施例25
1-(4-((4-((3-氯-4-氟苯基)氨基)-7-(1-甲基-1H-吡唑-4-基)喹唑啉-6-基)氨基)哌啶-1-基)丙-2-烯-1-酮
Figure PCTCN2019090224-appb-000106
步骤1:2-氨基-4-溴苯甲酸甲酯的合成
Figure PCTCN2019090224-appb-000107
室温下，向单口瓶中加入2-氨基-4-溴苯甲酸(12.0g，55.5mmol)和MeOH(200mL)， 0℃下滴加浓硫酸(12mL)，80℃反应48h后终止，将反应冷却至室温，浓缩，将残余液体倒入缓慢倒入冰水中，用饱和NaHCO 3调pH至8，用EA萃取，有机相水洗，饱和NaCl洗，无水Na 2SO 4干燥，过滤浓缩，柱层析(PE/EA体系)，得白色固体11g，收率87％。
步骤2:7-溴喹唑啉-4-醇的合成
Figure PCTCN2019090224-appb-000108
室温下，向30mL微波管中加入2-氨基-4-溴苯甲酸甲酯(2.5g，10.86mmol)和甲酰胺(18mL)，200℃微波反应1h后终止，共两批，冷却至室温，加EA溶解，水洗两次，无水Na 2SO 4干燥，过滤浓缩，粗品直接用于下一步。
步骤3:7-溴-6-硝基喹唑啉-4-醇的合成
Figure PCTCN2019090224-appb-000109
室温下，向单口瓶中加入7-溴喹唑啉-4-醇(粗品，21.73mmol)和浓硫酸(80mL)，0℃下缓慢加入KNO 3(3.3g，32.60mmol)，100℃反应1h后终止，冷却至室温，将反应液缓慢倒入冰水中，用饱和NaHCO 3调pH至7-8，用EA萃取，水洗，饱和NaCl洗，无水Na 2SO 4干燥，过滤浓缩，柱层析(DCM/MeOH体系)，得红色固体3.4g，收率58％。
步骤4:7-(1-甲基-1H-吡唑-4-基)-6-硝基喹唑啉-4-醇的合成
Figure PCTCN2019090224-appb-000110
室温下，向单口瓶中加入7-溴-6-硝基喹唑啉-4-醇(1.5g，5.55mmol)，(1-甲基-1H-吡唑-4-基)硼酸(0.84g，6.66mmol)，K 2CO 3(1.54g，11.11mmol)，DMF(30mL)和H 2O(5mL)，置换N 2，N 2保护下加入Pd(dppf)Cl 2(0.41g，0.56mmol)，85℃反应5h后终止，冷却至室温，加入EA，水洗，饱和NaCl洗，无水Na 2SO 4干燥，过滤浓缩，得红色固体1g。
步骤5:3-氯-N-(3,4-二甲氧基苄基)-4-氟苯胺的合成
Figure PCTCN2019090224-appb-000111
室温下，向单口瓶中加入3-氯-4-氟苯胺(6.0g，41.22mmol)，3,4-二甲氧基苯甲醛(6.85g，41.22mmol)，AcOH(5.0g，82.44mmol)和DCM(60mL)，20℃反应2h后，冰浴 下加入NaBH(OAc) 3(22.0g，103.05mmol)，20℃反应1h后终止，加水淬灭，用DCM萃取，有机相水洗，饱和NaCl洗，无水Na 2SO 4干燥，过滤浓缩，柱层析(PE/EA体系)，得白色固体12g，收率98％。
步骤6:N-(3-氯-4-氟苯基)-N-(3,4-二甲氧基苄基)-7-(1-甲基-1H-吡唑-4-基)-6-硝基喹唑啉-4-胺的合成
Figure PCTCN2019090224-appb-000112
室温下，向单口瓶中加入7-(1-甲基-1H-吡唑-4-基)-6-硝基喹唑啉-4-醇(0.9g，3.32mmol)，SOCl 2(10mL)和DMF(0.5mL)，80℃反应3h后终止，冷却至室温，浓缩，残渣用DCM带三次，加入MeCN(10mL)和3-氯-N-(3,4-二甲氧基苄基)-4-氟苯胺(1.18g，3.98mmol)，85℃反应16h后终止，浓缩溶剂，加水，用饱和NaHCO 3调pH至7-8，EA萃取，有机相饱和NaCl洗，无水Na 2SO 4干燥，过滤浓缩，柱层析(DCM/MeOH体系)，得黑色固体1g，收率56％。
步骤7:N 4-(3-氯-4-氟苯基)-N 4-(3,4-二甲氧基苄基)-7-(1-甲基-1H-吡唑-4-基)喹唑啉-4,6-二胺的合成
Figure PCTCN2019090224-appb-000113
室温下，向单口瓶中加入N-(3-氯-4-氟苯基)-N-(3,4-二甲氧基苄基)-7-(1-甲基-1H-吡唑-4-基)-6-硝基喹唑啉-4-胺(1.0g，1.82mmol)，Fe(0.51g，9.11mmol)，NH 4Cl(0.98g，18.20mmol)，EtOH(20mL)和H 2O(8mL)，80℃反应2h后终止，冷却至室温，过滤，滤饼用EA冲洗，滤液旋干，残渣加EA溶解，水洗，饱和NaCl洗，无水Na 2SO 4干燥，过滤浓缩，得0.8g黄色固体，收率85％。
步骤8:叔丁基4-((4-((3-氯-4-氟苯基)(3,4-二甲氧基苄基)氨基)-7-(1-甲基-1H-吡唑-4-基)喹唑啉-6-基)氨基)哌啶-1-羧酸盐的合成
Figure PCTCN2019090224-appb-000114
室温下，向单口瓶中加入N-(3-氯-4-氟苯基)-N-(3,4-二甲氧基苄基)-7-(1-甲基-1H-吡唑-4-基)喹唑啉-4,6-二胺(0.8g，1.54mmol)，4-氧代哌啶-1-甲酸叔丁酯(0.37g，1.85mmol)和AcOH(12mL)，20℃反应2h后加入NaBH(oAc) 3(1.63g，7.71mmol)，20℃反应1h后终止，加水淬灭，用饱和NaHCO 3调pH至7-8，用EA萃取，有机相水洗，饱和NaCl洗，无水Na 2SO 4干燥，过滤浓缩，柱层析(DCM/MeOH体系)，得黄色油状固体0.7g，收率76％。
步骤9:N 4-(3-氯-4-氟苯基)-7-(1-甲基-1H-吡唑-4-基)-N 6-(哌啶-4-基)喹唑啉-4,6-二胺的合成
Figure PCTCN2019090224-appb-000115
室温下，向单口瓶中加入叔丁基4-((4-((3-氯-4-氟苯基)(3,4-二甲氧基苄基)氨基)-7-(1-甲基-1H-吡唑-4-基)喹唑啉-6-基)氨基)哌啶-1-羧酸盐(0.7g，0.99mmol)，和TFA(15mL)，70℃反应2h后终止，将反应冷却至室温，浓缩溶剂，用DCM带三次，残渣用DCM溶解，加入K 2CO 3，搅拌0.5h，水洗，水相用DCM萃取一次，有机相合并，饱和NaCl洗，无水Na 2SO 4干燥，过滤浓缩，得黄色固体0.4g，收率94％。
步骤10:1-(4-((4-((3-氯-4-氟苯基)氨基)-7-(1-甲基-1H-吡唑-4-基)喹唑啉-6-基)氨基)哌啶-1-基)丙-2-烯-1-酮的合成
Figure PCTCN2019090224-appb-000116
室温下，向单口瓶中加入N 4-(3-氯-4-氟苯基)-7-(1-甲基-1H-吡唑-4-基)-N 6-(哌啶-4-基)喹唑啉-4,6-二胺(0.4g，0.89mmol)，TEA(0.45g，4.42mmol)和DCM(10mL)，冰浴下滴加丙烯酰氯(0.12g，1.33mmol)的DCM稀释液(4mL)，0℃反应0.5h后终止， 加冰水淬灭，搅拌0.5h，用DCM萃取，有机相水洗，饱和NaCl洗，无水Na 2SO 4干燥，过滤浓缩，柱层析(DCM/MeOH体系)，得黄色固体0.12g，收率29％。 1H NMR(400MHz,DMSO-d 6)δ8.37(s,1H),8.13(d,J＝5.4Hz,2H),7.82(d,J＝10.9Hz,2H),7.56(s,1H),7.44(t,J＝9.0Hz,1H),7.38(s,1H),6.82(dd,J＝16.6,10.4Hz,1H),6.09(dd,J＝16.6,2.5Hz,1H),5.70-5.64(m,1H),4.34(d,J＝13.1Hz,1H),4.04(d,J＝13.9Hz,1H),3.91(s,3H),3.89-3.83(m,1H),3.29(t,J＝12.7Hz,1H),2.97(t,J＝12.5Hz,1H),2.06(d,J＝8.8Hz,2H),1.45(t,J＝11.3Hz,2H)。MS(ESI)m/z:505.8[M+H] +。
实施例26
化合物对激酶抑制活性测试
本试验采用γ试 33p-ATP同位素测试法测试化合物对激酶HER2，EGFR(D770_N771insNPG)的抑制作用，并得出化合物对该酶抑制活性的半数抑制浓度IC 50，采用EGFR 20号外显子插入突变新药Poziotinb作为阳性对照，Poziotinib购于TargetMol，产品目录号T2630，HKI-272购于百灵威，批号LPB0Q20。
1.基础反应缓冲液
20mM Hepes(pH 7.5),10mM MgCl 2,1mM EGTA,0.02％Brij35,0.02mg/ml BSA,0.1mM Na3VO4,2mM DTT,1％DMSO。
2.化合物配制
化合物采用100％DMSO溶解至特定的浓度，之后采用自动加样装置梯度稀释成不同浓度的待测样品(DMSO溶解液)。
3.反应步骤
3.1使用基础反应缓冲液稀释反应底物；
3.2将激酶加入底物溶液中，轻柔混匀；
3.3采用自动加样系统将100％DMSO稀释的不同浓度化合物加入激酶溶液中，室温下孵育20min；
3.4室温下加入 33P-ATP(10μM,10μCi/μl)启动激酶反应，反应2h。
4.检测
反应液经离子交换过滤系统除去未反应的ATP及反应产生的ADP等离子后检测底物中 33P同位素放射量。
5.数据处理
依据放射量计算加入不同浓度抑制剂体系中的激酶活性从而得到不同浓度化合物对激酶 活性的抑制作用，采用graphpad prism拟合得化合物抑制IC 50。
本发明化合物的生物化学活性通过以上的试验进行测定，测得的IC 50值参见表1：
表1激酶抑制活性测试结果
Figure PCTCN2019090224-appb-000117
注：表格中“-”代表未测试
结论：本发明化合物具有与阳性药相当的激酶抑制活性，包括Her2和20外显子插入突变体EGFR(D770_N771insNPG)。
实施例27
A431细胞增殖抑制试验
本实验采用MTT的方法测试化合物对A431的细胞活性作用，并得出化合物抑制细胞增殖活性的半数抑制浓度IC 50
1.A431细胞株在DMEM+10％FBS的条件下进行培养。在96孔细胞培养板中接种100μL的处于对数生长期的A431细胞悬液，密度为8X 10  4/ml，将培养板于培养箱中培养24h令细胞贴壁(37℃，5％CO 2)。
2.各化合物已事先溶解在DMSO中配制成10mM的储存液，采用DMSO梯度稀释为目标浓度的400倍，采用无血清培养基稀释到目的浓度的2倍，维持药液中DMSO浓度均为0.5％。在接种细胞的96孔板中依次加入不同浓度药液，100μL/孔。每个浓度设3个复孔，并设空白对照及阴性对照，继续在37℃、5％CO 2中继续培养72h。
3.终止培养，每孔加入20μL MTT溶液(5mg/ml)，继续在37℃、5％CO 2中继续培养4h后弃除培养基，加入DMSO 150μL/孔，室温震荡10min，在570nM、620nM双波长测OD值(OD 570-OD 620)，并经Graphpad Prism 6.0数据处理计算IC 50值。
实施例28
SKBR-3细胞增殖抑制试验
本实验采用MTT的方法测试化合物对SKBR-3的细胞活性作用，并得出化合物抑制细胞增殖活性的半数抑制浓度IC 50值。
1.SKBR-3细胞株在DMEM(高糖)+10％FBS的条件下进行培养。在96孔细胞培养板中接种100μL的处于对数生长期的SKBR-3细胞悬液，密度为8X 10 4/ml，将培养板于培养箱中培养24h令细胞贴壁(37℃，5％CO 2)。
2.弃除96孔细胞培养板中含10％FBS的DMEM高糖培养基。各化合物已事先溶解在DMSO中配制成10mM的储存液，采用DMSO梯度稀释为目标浓度的400倍，采用无血清培养基将其稀释到目的浓度的2倍。在接种细胞的96孔板中依次加入不同浓度药液，100μL/孔。每个浓度设3个复孔，并设空白对照及阴性对照，继续在37℃、5％CO 2中继续培养72h。
3.终止培养，每孔加入20μL MTT溶液(5mg/ml)，继续在37℃、5％CO 2中继续培养4h后弃除培养基，加入DMSO 150μL/孔，室温震荡10min，在570nM、620nM双波长测OD值(OD 570-OD 620)，并经Graphpad Prism6.0数据处理计算IC 50值。
实施例29
BT-474细胞增殖抑制试验
本实验采用MTT的方法测试化合物对BT-474的细胞活性作用，并得出化合物抑制细胞增殖活性的半数抑制浓度IC 50
1.BT-474细胞株在RPMI-1640+10％FBS的条件下进行培养。在96孔细胞培养板中接种100μL的处于对数生长期的Hcc827细胞悬液，密度为8X 10 4/ml，将培养板于培养箱中培养24h令细胞贴壁(37贴，5％CO 2)。
2.各化合物已事先溶解在DMSO中配制成10mM的储存液，采用DMSO梯度稀释为目标浓度的400倍，采用无血清培养基稀释到目的浓度的2倍，维持药液中DMSO浓度均为0.5％。在接种细胞的96孔板中依次加入不同浓度药液，100μL/孔。每个浓度设3个复孔，并设空白对照及阴性对照，继续在37设、5％CO 2中继续培养72h。
3.终止培养，每孔加入20μL MTT溶液(5mg/ml)，继续在37在、5％CO 2中继续培养4h后弃除培养基，加入DMSO 150μL/孔，室温震荡10min，在570nM、620nM双波长测OD值(OD 570-OD 620)，并经Graphpad Prism 6.0数据处理计算IC 50值。
本发明化合物的生物化学活性通过以上的试验进行测定，测得的IC 50值参见表2：
表2细胞增殖抑制实验结果
Figure PCTCN2019090224-appb-000118
Figure PCTCN2019090224-appb-000119
结论：本发明化合物具有与阳性药相当的肿瘤细胞抑制活性，包括Her2阳性和EGFR阳性肿瘤细胞。
实施例30
肝微粒体测试
孵育体系总体积为250μL，用50mmol/L PBS缓冲液(pH＝7.4)配制其中含有蛋白浓度为0.5mg/mL的人源肝微粒体孵育液，孵育开始前将100μmol/L待测化合物2.5μL与上述孵育液197.5μL混合，在37℃水浴中预孵育5min后加入同样经预孵育5min的还原性辅酶Ⅱ溶液(5mmol/L)50μL启动反应，(反应体系中种属肝微粒体蛋白含量为0.5g/L、待测化合物终浓度为1μmol/L)，在37℃水浴中振荡孵育，并分别于0，5，15，30，60min取出，立即加入内标为Terfenadine(正离子内标，25ng/mL)和Tolbutamide(负离子内标，50ng/mL)的正负内标混合甲醇溶液600μL以终止反应。将终止后的孵育液振荡2min、离心(4℃、16000r/min)10min后取上清液进行LC-MS/MS检测，定量分析母药的剩余量。(DMSO＝0.1％)
将孵育0min化合物的浓度作为100％，其他孵育时间点的浓度转换为百分剩余量，将各时间点的百分剩余量的自然对数对孵育时间作线性回归，求算得斜率k，根据公式，T 1/2＝-0.693/k计算得到体外半衰期。肝微粒体中的清除率(CLint(μL/min/mg protein)＝Ln(2)*1000/T 1/2(min)/Protein Conc(mg/ml))，实施例测试数据详见表3：
表3肝微粒体测试结果
Figure PCTCN2019090224-appb-000120
结论：本发明化合物与阳性药相比具有非常显著的肝微粒体代谢稳定性优势，因此具有更好的成药性和体内稳定性。

Claims (11)

  1. 一种具有式(I)化合物、其立体异构体或其药学上可接受的盐：
    Figure PCTCN2019090224-appb-100001
    其中，A选自C 2-C 6炔基、6-10元芳基或5-10元杂芳基；
    X选自C 1-C 8烷基、5-10元杂芳基或3-8元杂环基，所述的C 1-C 8烷基可进一步被卤素、氰基、羟基或C 1-C 4烷氧基所取代，所述的3-8元杂环基可进一步被-(CH 2) aCN所取代；
    Y选自C 1-C 8烷基、-COR 1、-(CH 2) aCN、-(CH 2) aOR 1或3-8元杂环基，所述的3-8元杂环基可进一步被C 1-C 4烷基所取代；
    或者Y不存在；
    R 1选自H、OH或C 1-C 4烷基；
    B选自6-10元芳基或5-10元杂芳基，所述的6-10元芳基或5-10元杂芳基可进一步被一个或多个选自羟基、卤素、C 1-C 4烷基或-O(CH 2) a-5-6元杂芳基的取代基所取代；
    a选自0、1或2；
    n选自0、1或2；
    m选自0、1或2；
    M选自C-CN或N；
    W选自O、S或NH。
  2. 根据权利要求1所述的化合物，其特征在于：
    A选自C 2-C 4炔基、6-10元芳基或5-6元杂芳基；
    X选自C 1-C 4烷基、5-6元杂芳基或4-6元杂环基，所述的C 1-C 4烷基可进一步被氰基、羟基或C 1-C 2烷氧基所取代，所述的4-6元杂环基可进一步被-(CH 2) aCN所取代；
    Y选自C 1-C 4烷基、-COR 1、-(CH 2) aCN、-(CH 2) aOR 1或3-6元杂环基，所述的3-6元杂环基可进一步被C 1-C 2烷基所取代；
    或者Y不存在；
    R 1选自H、OH或C 1-C 4烷基；
    B为6-10元芳基，所述的6-10元芳基可进一步被一个或多个选自卤素或-O(CH 2) a-5-6元杂芳基的取代基所取代；
    a选自0、1或2；
    n选自0、1或2；
    m选自0、1或2；
    M选自C-CN或N；
    W选自O或NH。
  3. 根据权利要求1或2所述的化合物，其特征在于：
    A选自乙炔基、苯基或5-6元杂芳基；
    X选自C 1-C 4烷基、5-6元杂芳基或4-6元杂环基，所述的C 1-C 4烷基可进一步被氰基、羟基或C 1-C 2烷氧基所取代，所述的4-6元杂环基可进一步被-(CH 2) aCN所取代；
    Y选自C 1-C 2烷基、-COR 1、-(CH 2) aCN、-(CH 2) aOR 1或3-6元杂环基，所述的3-6元杂环基可进一步被C 1-C 2烷基所取代；
    或者Y不存在；
    R 1选自OH、甲基或乙基；
    B为苯基，所述的苯基被一个或多个选自F、Cl或-O(CH 2) a吡啶的取代基所取代；
    a选自1或2；
    n为1；
    m为1；
    M选自C-CN或N；
    W选自O或NH。
  4. 如权利要求3所述的化合物，其特征在于：
    A选自乙炔基、苯基、咪唑基、吡唑基、吡咯基、吡啶基或嘧啶基；
    X选自C 1-C 4烷基、吡唑基或4-6元杂环基，所述的C 1-C 4烷基可进一步被氰基、羟基或甲氧基所取代，所述的4-6元杂环基可进一步被-(CH 2) aCN所取代；
    Y选自C 1-C 2烷基、-COR 1、-(CH 2) aCN、-(CH 2) aOR 1或3-6元杂环基，所述的3-6元杂环基可进一步被甲基所取代；
    或者Y不存在；
    R 1为甲基；
    B为苯基，所述的苯基被一个或多个选自F、Cl或-O(CH 2) a吡啶的取代基所取代；
    a选自1或2；
    n为1；
    m为1；
    M选自C-CN或N；
    W选自O或NH。
  5. 如权利要求4所述的化合物，其特征在于：
    A选自乙炔基、咪唑基或吡唑基；
    X选自甲基、-CH 2CN、-(CH 2) 2OH、-(CH 2) 2OCH 3、吡唑基、氧杂环丁基、氮杂环丁基、哌啶基或四氢吡喃基，所述的氧杂环丁基可进一步被-CH 2CN所取代；
    Y选自甲基、乙基、-COCH 3、-CH 2CN、-(CH 2) 2OCH 3、氧杂环丁基、四氢吡喃基或哌啶基，所述的哌啶基可进一步被甲基所取代；
    或者Y不存在；
    B为苯基，所述的苯基被一个或多个选自F、Cl或-OCH 2-吡啶的取代基所取代；
    n为1；
    m为1；
    M选自C-CN或N；
    W为O或NH。
  6. 化合物、其立体异构体或其药学上可接受盐，其特征在于，选自如下结构的化合物：
    Figure PCTCN2019090224-appb-100002
    Figure PCTCN2019090224-appb-100003
    Figure PCTCN2019090224-appb-100004
  7. 一种药物组合物，其包含如权利要求1～6任一项所述的化合物、其立体异构体或其药学上可接受盐和可药用的载体。
  8. 根据权利要求7所述的药物组合物，其特征在于，所述药物组合物是胶囊剂、散剂、片剂、颗粒剂、丸剂、注射剂、糖浆剂、口服液、吸入剂、软膏剂、栓剂或贴剂。
  9. 根据权利要求1-6中任一项所述的化合物、其立体异构体或其药学上可接受盐，或权利要求7所述的药物组合物在制备用于预防或治疗单独或部分地由人表皮生长因子受体Her/erbB家族激酶活性介导的疾病的治疗药物中的应用。
  10. 根据权利要求1-6中任一项所述的化合物、其立体异构体或其药学上可接受盐，或权利要求7所述的药物组合物在制备用于预防或治疗癌症的药物中的应用。
  11. 根据权利要求10所述的应用，其特征在于，所述癌症选自卵巢癌、宫颈癌、结肠直肠癌、乳腺癌、胰腺癌、胶质瘤、胶质母细胞瘤、黑色素瘤、前列腺癌、白血病、淋巴瘤、非霍奇金淋巴瘤、胃癌、肺癌、肝细胞癌、胃癌、胃肠道间质瘤、甲状腺癌、胆管癌、子宫内膜癌、肾癌、间变性大细胞淋巴瘤、急性髓细胞白血病、多发性骨髓瘤、黑色素瘤或间皮瘤。
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