WO2014086284A1 - Deuterated 3-cyano quinoline compound, pharmaceutical composition, preparation method and use thereof - Google Patents

Deuterated 3-cyano quinoline compound, pharmaceutical composition, preparation method and use thereof Download PDF

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WO2014086284A1
WO2014086284A1 PCT/CN2013/088479 CN2013088479W WO2014086284A1 WO 2014086284 A1 WO2014086284 A1 WO 2014086284A1 CN 2013088479 W CN2013088479 W CN 2013088479W WO 2014086284 A1 WO2014086284 A1 WO 2014086284A1
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group
methoxy
compound
phenylamino
cancer
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PCT/CN2013/088479
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French (fr)
Chinese (zh)
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万惠新
沈竞康
李春丽
韩雅男
刘海燕
周兆丽
李萍
李玉峰
陈岗
徐佳
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上海医药集团股份有限公司
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Publication of WO2014086284A1 publication Critical patent/WO2014086284A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C07D215/54—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • 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
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—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
    • C07D405/04—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 directly linked by a ring-member-to-ring-member bond
    • 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
    • C07D405/12—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 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
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
    • C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
    • C07D407/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
    • C07D407/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings

Definitions

  • the present invention relates to the field of chemical medicine, and in particular to a class of deuterated 3-cyanoquinoline compounds or pharmaceutically acceptable salts, solvates, prodrugs, stereoisomers, tautomers thereof, Polymorphs or metabolites and the like, and pharmaceutical compositions containing such compounds, and the use of these compounds or compositions in the manufacture of a medicament for the treatment or prevention of tumors, particularly protein kinase inhibitors.
  • Background technique
  • 3-cyanoquinolines have been widely used as a class of protein kinase inhibitors, such as SKI606, EKB569, HKI272, etc., which have similar protein kinase activities that are capable of inhibiting one or more closely related to tumor development. And/or inhibit the growth activity of tumor cells.
  • SKI606, Bosutinib a potent protein kinase inhibitor developed by Wyeth Pharmaceuticals, Inc., is currently used to treat Philadelphia chromosome-positive chronic myeloid leukemia, which was administered by the US FDA in September 2012. Approved for listing.
  • the drug still has some unavoidable shortcomings, such as poor metabolism and short half-life in the study.
  • the present invention has deuterated 3-cyanoquinoline compounds of the formula I, and has been found to have excellent in vitro and in vivo pharmacological and pharmacokinetic properties.
  • the present invention contemplates compounds having the structural features of Formula I which are effective in inhibiting more than one protein kinase activity and/or inhibiting the growth of tumor cells and exhibiting excellent Pharmacokinetic properties and/or pharmacodynamic properties in animals.
  • the present invention provides a novel deuterated 3-cyanoquinoline derivative which is capable of inhibiting one or more protein kinase activities closely related to the development of a tumor and/or inhibiting the growth of tumor cells.
  • R 1 is a C1 to C6 alkoxy group, and one or more H groups on the C1 to C6 alkoxy group are optionally substituted by deuterium; preferably a C1 to C4 alkoxy group, the C1 to C4 alkoxy group One or more H's are optionally substituted by deuterium; more preferably a methoxy group, one or more H groups on the methoxy group are optionally substituted by deuterium;
  • Ar is a 6- to 10-membered aryl group which is unsubstituted or substituted by a substituent, or a 6- to 10-membered heteroaryl group which is unsubstituted or substituted with a substituent, and the 6- to 10-membered heteroaryl group has 1 to 2 a hetero atom selected from the group consisting of N, S and 0, wherein the substituent is a halogen, a C1 to C6 alkoxy group, a C1 to C6 alkyl group or a C3 to C6 cycloalkyl group, wherein the C1 to C6 alkoxy group, C1 One or more H groups on the ⁇ C6 alkyl group or the C3 ⁇ C6 cycloalkyl group are optionally substituted by deuterium; preferably, Ar is a phenyl group which is unsubstituted or substituted by a substituent, or is unsubstituted or substituted by a substituent a substituted 6-membered heteroary
  • H groups on the C1 ⁇ C4 alkoxy group, C1 ⁇ C4 alkyl group or C3 ⁇ C6 cycloalkyl group are optionally substituted by deuterium;
  • Ar is unsubstituted or substituted by a substituent a substituted phenyl group, or a pyridyl group which is unsubstituted or substituted by a substituent, wherein the substituent is chloro, methoxy or cyclopropyl, wherein one or more of the methoxy group and the cyclopropyl group H is not required to be shackled
  • Ar is a phenyl group which is unsubstituted or substituted with a substituent which is a chlorine, a methoxy group or a cyclopropyl group, wherein the methoxy group, one or more of the cyclopropyl groups H is not necessarily replaced by ⁇ ;
  • L1 - C ⁇ CL 2 - wherein L1 and L 2 are each independently -(CH 2 ) n - or a direct bond, and n is an integer from 1 to 3; preferably L " c ⁇ c - L 2 - wherein Li And L 2 are each independently -(CH 2 ) n - or a direct bond, and n is an integer of 1 to 3; more preferably, Li- C ⁇ c is a methylene group or -(CH 2 ) 2 -, L 2 is a direct bond and is directly linked to the quinoline ring, or CR 6 L 3 - ⁇ C— R 6 - L 3 - iii ) R 5 , or wherein R 4 and R 5 are each independently H, F or a halogen atom, preferably H or a halogen atom; R 6 is 5 ⁇ a 6-membered arylene or heteroarylene group, preferably a phenylene group, a furylene group
  • CH CH -i ⁇ G ⁇ G _ ⁇ or a direct bond, preferably a direct bond and directly attached to the quinoline ring;
  • R 2 and R 3 are each independently H or a C1 to C6 alkyl group, and one or more H groups on the C1 to C6 alkyl group are optionally substituted by deuterium; preferably, R 2 and R 3 are each independently H or a C1 to C4 alkyl group, wherein one or more H groups on the C1 to C4 alkyl group are optionally substituted with deuterium; more preferably, R 2 and R 3 are each independently H, methyl or ethyl, the methyl group Or one or more H groups on the ethyl group are optionally substituted by deuterium; or R 2 , R 3 and the N atom to which they are attached form a 4 to 7 membered nitrogen-containing heterocyclic group, said nitrogen-containing heterocyclic group
  • a hetero atom comprising one selected from the group consisting of N, S and 0 is optionally substituted with a substituent which is a C1 to C6 alkyl group, a mono(C1 to C6 alkyl
  • One or more H groups are optionally substituted by deuterium; preferably, R 2 , R 3 and the N atom to which they are attached form azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, Thiomorpholinyl, piperazinyl or homopiperazinyl, and
  • the group is optionally substituted by a substituent which is a C1 to C4 alkyl group, a mono(C1 to C4 alkyl group) amino group, a di(C1 to C4 alkyl group:) amino group, (C1 to C4).
  • R 2 , R 3 and the N atom to which they are attached form a piperazinyl, pyrrolidinyl, morpholinyl or piperidinyl group, and the above groups are optionally substituted by a substituent, said substitution
  • the group is methyl, methylamino, dimethylamino, tert-butoxy or cyclopropyl, wherein one or more of the methyl, methylamino, dimethylamino, tert-butoxy or cyclopropyl groups H is not necessarily replaced by ⁇ ;
  • the compound represented by the formula (I) contains at least one deuterium atom.
  • compositions comprising a therapeutically effective amount of a compound selected from Formula I or a pharmaceutically acceptable salt, solvate, prodrug thereof, stereoisomeric One or more of a conformation, tautomer, polymorph or metabolite, and at least one pharmaceutically acceptable excipient.
  • the pharmaceutical compositions described herein include, but are not limited to, oral dosage forms, parenteral dosage forms, topical dosage forms, and rectal administration dosage forms, preferably oral dosage forms.
  • the oral dosage form of the pharmaceutical composition includes tablets, capsules, pills, powders, sustained release preparations, solutions and suspensions, and the like, and parenteral dosage forms include sterile solutions, suspensions or emulsions, Topical dosage forms include ointments, oils, lotions, gels, suspensions, solutions, lotions or creams, and rectal administration forms include suppositories and drops.
  • the pharmaceutical composition is in a unit dosage form suitable for single administration of precise dosages.
  • the amount of the compound of formula I is in the range of from about 0.001 mg/kg body weight/day to about 1000 mg/kg body weight/day.
  • the amount of the compound of formula I ranges from about 0.5 mg/kg body weight/day to about 50 mg/kg body weight/day. In some embodiments, the amount of the compound of Formula I is from about 0.001 g/day to about 7 g/day. In other embodiments, the amount of the compound of formula I is from about 0.002 g/day to about 6 g/day. In other embodiments, the amount of the compound of formula I is about 0.005 g/ Day ⁇ about 5 g / day. In other embodiments, the amount of the compound of formula I is from about 0.01 g/day to about 5 g/day. In other embodiments, the amount of the compound of formula I is from about 0.02 g/day to about 5 g/day.
  • the amount of the compound of formula I is from about 0.05 g/day to about 2.5 g/day. In other embodiments, the amount of the compound of formula I is from about 0.1 g/day to about 1 g/day. In other embodiments, a dose level below the lower limit of the above range may already be sufficient. In other embodiments, dose levels above the upper limit of the above range may be required. In some embodiments, the compound of formula I is administered in a single dose, once a day. In other embodiments, the compound of formula I is administered in multiple doses, more than once a day. In some embodiments, the compound of formula I is administered twice daily. In other embodiments, the compound of formula I is administered three times a day.
  • the compound of formula I is administered four times a day. In other embodiments, the compound of formula I is administered more than four times a day. In some embodiments, the pharmaceutical composition is administered to a mammal. In other embodiments, the mammal is a human. In other embodiments, the pharmaceutical composition further comprises a pharmaceutical carrier, excipient, and/or adjuvant. In other embodiments, the pharmaceutical composition further comprises at least one therapeutic agent.
  • a compound of Formula I or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, tautomer, polymorph thereof or Use of a metabolite, or a pharmaceutical composition comprising the above active substance, in the preparation of one or more protein kinase inhibitors selected from the group consisting of EGFR, VEGFR, HER-2, HER-3, HER-4, Bcr -Abl, c-Src, JAK3, PDGFR, c-Kit, LCK, LYNA, FGR, EphB, ECK, FY, MAP4K, SIK, MST1, YES, ARG, BTK, HCK, BLK, ALK, PKC, NEK, MARK , FLT3, RET, FGFR, PDK and Syk.
  • protein kinase inhibitors selected from the group consisting of EGFR, VEGFR, HER-2, HER-3, HER-4, Bcr -Abl, c-Sr
  • the tumor is selected from the group consisting of leukemia, gastrointestinal stromal tumor, histiocytic lymphoma, non-small cell lung cancer, small cell lung cancer, pancreatic cancer, lung squamous cell carcinoma, lung adenocarcinoma, breast cancer, prostate cancer, liver cancer, Any of skin cancer, epithelial cell carcinoma, cervical cancer, ovarian cancer, intestinal cancer, nasopharyngeal cancer, brain cancer, bone cancer, esophageal cancer, melanoma, renal cancer, oral cancer, and the like.
  • the present invention provides a method for modulating a protein activating enzyme activity, which comprises the protein kinase and the above compound or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph thereof
  • a protein activating enzyme activity which comprises the protein kinase and the above compound or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph thereof
  • the substance, solvate, prodrug or metabolite, or pharmaceutical composition comprising the above active substance is contacted.
  • This method can be used in vivo as well as in vitro.
  • the protein kinase is selected from EGFR, VEGFR, HER-2, HER-3, HER-4, Bcr-Abl, c-Src, JAK3, PDGFR, c-Kit, LCK, LY A, FGR, EphB, ECK, FY, MAP4K, SIK, MST1 At least one of YES, ARG, BTK, HCK, BLK, ALK, PKC, NEK, MARK, FLT3, RET, FGFR, PDK, Syk.
  • the invention relates to a compound of the invention and a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, tautomer, polymorph or metabolite thereof, or A pharmaceutical composition comprising the above active substance for use in a method of treating or preventing a tumor.
  • the method comprises the step of contacting the active substance with a mammal in need of treatment.
  • the tumor includes, but is not limited to, leukemia, gastrointestinal stromal tumor, histiocytic lymphoma, non-small cell lung cancer, small cell lung cancer, pancreatic cancer, lung squamous cell carcinoma, lung adenocarcinoma, breast cancer, prostate cancer, Any of liver cancer, skin cancer, epithelial cell carcinoma, cervical cancer, ovarian cancer, intestinal cancer, nasopharyngeal cancer, brain cancer, bone cancer, esophageal cancer, melanoma, renal cancer, oral cancer, and the like.
  • leukemia gastrointestinal stromal tumor
  • histiocytic lymphoma non-small cell lung cancer
  • small cell lung cancer pancreatic cancer
  • lung squamous cell carcinoma lung adenocarcinoma
  • breast cancer prostate cancer
  • the manufacturer's instructions for use of the kit can be utilized, or the reaction can be carried out and purified according to methods well known in the art or as described in the present invention.
  • the above techniques and methods can generally be carried out according to conventional methods well known in the art, as described in the various summaries and more specific references cited and discussed in this specification.
  • a group and its substituents can be selected by those skilled in the art to provide stable structural moieties and compounds.
  • substituent When a substituent is described by a conventional chemical formula written from left to right, the substituent also includes the chemically equivalent substituent obtained when the structural formula is written from right to left.
  • CH 2 0 is equivalent to OC3 ⁇ 4.
  • optionally substituted alkyl means “unsubstituted alkyl” (alkyl substituted without a substituent) or “substituted alkyl” (alkyl substituted with a substituent) .
  • Cl ⁇ Cn used herein includes C1 ⁇ C2, C1 ⁇ C3, ... Cl ⁇ Cn (n is an integer).
  • the "C1 ⁇ C4" group means that the moiety has from 1 to 4 carbon atoms, i.e., the group contains one carbon atom, two carbon atoms, three carbon atoms or four carbon atoms.
  • “C1 ⁇ C4 alkyl” refers to an alkyl group having from 1 to 4 carbon atoms, that is, the alkyl group is selected from the group consisting of methyl, ethyl, propyl, isopropyl, n-butyl, iso Butyl, sec-butyl and tert-butyl.
  • hydroxy as used herein, alone or in combination, refers to -OH.
  • halogen as used herein, alone or in combination, means fluoro, chloro, bromo or iodo, preferably fluoro or chloro.
  • cyano as used herein, alone or in combination, refers to -CN.
  • amino means -NH 2.
  • aryl or aryl as used herein, alone or in combination, means an optionally substituted cyclic conjugated aromatic hydrocarbon group having from 6 to about 20 or from 6 to 14 or from 6 to 10 ring-forming carbon atoms. Includes single, double, triple or more rings.
  • monocyclic aryl groups include from 6 to about 12, from 6 to about 10 or from 6 to about 8 monocyclic aryl groups of a ring-forming carbon atom, such as phenyl. The remainder of the compound molecule can be attached to the carbon atom on the aryl ring by a single bond.
  • the substituent may be substituted at any available point of attachment, preferably one or more of the following groups: alkyl, alkenyl, alkynyl, alkoxy, alkane Base, alkylamino, 3 ⁇ 4, thiol, hydroxy, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, cycloalkylthio, heterocycloalkylthio, carbonyl, Carboxylic acid or carboxylic acid ester.
  • a 6 to 10 membered monocyclic or bicyclic aryl group is preferred.
  • heteroaryl or aromatic heterocyclic as used herein, alone or in combination, means an optionally substituted conjugated aromatic ring system consisting of a carbon atom and a hetero atom, which comprises from about 5 to about 20 or 5 to about 14 or 5 to about 10 or 6 to about 10 skeletons into ring atoms (or 5 to 20 membered rings, 5 to 14 membered rings, 5 to 10 membered rings, 6 to 10 membered rings), One or more (eg, 1 to 6, 1 to 4, 1 to 3, 1 to 2) ring-forming atoms are heteroatoms independently selected from the group consisting of oxygen, nitrogen, sulfur, phosphorus, Heteroatoms in silicon, selenium and tin, but are not limited thereto.
  • Heteroaryl groups include monocyclic and polycyclic (eg, 2, 3 or 4 fused rings) systems. Any ring-forming nitrogen atom in the heteroaromatic ring can be oxidized to form a nitrogen oxide component. In embodiments in which two or more heteroatoms are present in the ring, the two or more heteroatoms may be identical to each other, or some or all of the two or more heteroatoms may be different from each other. The remainder of the compound molecule can be attached to the carbon or hetero atom on the heteroaryl ring by a single bond.
  • an imidazole may be passed through any of its carbon atoms (imidazol-2-yl, imidazol-4-yl or imidazol-5-yl:) or its nitrogen atom (imidazol-1-yl or imidazol-3-yl) :) Connected to the parent molecule.
  • a heteroaryl group can be substituted by any or all of its carbon atoms and/or any or all of the heteroatoms.
  • monocyclic heteroaryl groups include from 5 to about 12, from 5 to about 10, from 5 to about 7, or 6 monocyclic heteroaryl groups which are backbone-ringed.
  • the substituent may be substituted at any available point of attachment, preferably one or more of the following groups: alkyl, alkenyl, alkynyl, alkoxy, alkane Thio group, alkylamino group, 3 ⁇ 4 element, thiol, hydroxy group, cyano group, cycloalkyl group, heterocyclic group, aryl group, heteroaryl group, cycloalkoxy group, cycloalkylthio group, heterocycloalkylthio group, carbonyl group , a carboxylic acid or a carboxylic acid ester.
  • a heteroaryl group of a monocyclic or bicyclic ring system of 6 to 10 members and containing 1 to 2 hetero atoms selected from N, S and 0 is preferred.
  • heterocyclyl refers to an optionally substituted non-aromatic cyclic group consisting of a carbon atom and a hetero atom, including saturated or partially unsaturated monocyclic, bicyclic or polycyclic systems. Examples include heterocycloalkyl and heterocycloalkenyl groups.
  • One or more of the ring-forming atoms e.g., 1 to 4, 1 to 3, 1 to 2) are heteroatoms such as oxygen, nitrogen or sulfur atoms, and the nitrogen or sulfur atom may be optionally oxidized.
  • the remainder of the compound molecule can be attached to the heteroatom or carbon atom on the heterocyclyl ring via a single bond.
  • the substituent may be substituted at any available point of attachment, preferably one or more of the following groups: alkyl, alkenyl, alkynyl, alkoxy, alkane Thio group, alkylamino group, 3 ⁇ 4 element, thiol, hydroxy group, cyano group, cycloalkyl group, heterocyclic group, aryl group, heteroaryl group, cycloalkoxy group, cycloalkylthio group, heterocycloalkylthio group, carbonyl group , a carboxylic acid or a carboxylic acid ester.
  • a saturated, monocyclic heterocyclic group of 4 to 7 members and containing at least one nitrogen atom is preferred.
  • cycloalkyl refers to an optionally substituted stable non-aromatic hydrocarbon group consisting solely of carbon atoms and hydrogen atoms, including saturated or partially unsaturated monocyclic, bicyclic or polycyclic systems. The remainder of the compound molecule can be attached to the carbon atom on the cycloalkyl ring by a single bond.
  • the substituent may be substituted at any available point of attachment, preferably one or more of the following groups: alkyl, alkenyl, alkynyl, alkoxy, alkane Thio group, alkylamino group, halogen, thiol, hydroxy group, cyano group, cycloalkyl group, heterocyclic group, aryl group, heteroaryl group, cycloalkoxy group, cycloalkylthio group, heterocycloalkylthio group, carbonyl group, Carboxylic acid or carboxylic acid ester.
  • a cycloalkyl group of a 3 to 6 membered monocyclic system is preferred.
  • mammals include, but are not limited to, any member of the mammalian class: humans, non-human primates (eg, chimpanzees and other mites and monkeys); livestock, such as cattle, horses, sheep, goats, pigs; domestic animals For example, rabbits, dogs and cats; laboratory animals, including rodents such as rats, mice and guinea pigs.
  • non-human mammals include, but are not limited to, birds and fish.
  • the mammal is a human.
  • treatment includes alleviating, alleviating or ameliorating the symptoms of a disease or condition, preventing other symptoms, ameliorating or preventing a potential metabolic cause of the symptoms, inhibiting the disease or condition, such as preventing the progression of the disease or condition, Relieve a disease or condition, make a disease or condition good Turning, alleviating the symptoms caused by a disease or condition, or stopping the symptoms of a disease or condition.
  • the term includes the purpose of prevention.
  • the term also includes obtaining a therapeutic effect and/or a preventive effect.
  • the therapeutic effect refers to curing or ameliorating the underlying disease to be treated.
  • the healing or amelioration of one or more physiological symptoms associated with a underlying disease is also a therapeutic effect, for example, although the patient may still be affected by the underlying disease, an improvement in the patient's condition is observed.
  • the composition can be administered to a patient at risk of developing a particular disease, or the composition can be administered to a patient who develops one or more physiological symptoms of the disease, even if a diagnosis of the disease has not been made.
  • an "effective amount” for treatment refers to at least one agent or compound that, after administration, is sufficient to alleviate one or more symptoms of the disease or condition being treated to some extent. The amount. The result can be the reduction and/or alleviation of signs, symptoms or causes, or any other desired changes in the biological system.
  • an "effective amount” for treatment is an amount of a composition comprising a compound disclosed herein that is required to provide a significant conditional relief effect in the clinic.
  • An effective amount suitable for any individual case can be determined using techniques such as dose escalation assays.
  • administering refers to a method of delivering a compound or composition to a desired site for biological action. These methods include, but are not limited to, oral routes, duodenal routes, parenteral injections (including intravenous, subcutaneous, intraperitoneal, intramuscular, intraarterial injection or infusion:), topical and rectal administration.
  • parenteral injections including intravenous, subcutaneous, intraperitoneal, intramuscular, intraarterial injection or infusion:
  • topical and rectal administration topical and rectal administration.
  • the techniques of administration of the compounds and methods described herein are well known to those skilled in the art, for example, in Goodman and Gilman, The Pharmacological Basis of Therapeutics, current ed.; Pergamon; and Remington's, Pharmaceutical Sciences (current edition), Mack Publishing Co., Those discussed in Easton, Pa.
  • the compounds and compositions discussed herein are administered orally.
  • pharmaceutically acceptable refers to a substance (eg, carrier, excipient, and/or adjuvant) that does not affect the biological activity or properties of the compound of the invention, and is relatively non-toxic, ie, the substance can be administered to The individual does not cause an adverse biological reaction or interacts in an undesirable manner with any of the components contained in the composition.
  • composition refers to a biologically active compound, optionally in admixture with at least one pharmaceutically acceptable chemical component, including but not limited to carriers, excipients and/or Or additives, such as stabilizers, diluents, dispersants, suspending agents, thickeners, and the like.
  • carrier refers to a relatively non-toxic chemical compound or agent that facilitates the introduction of a compound into a cell or tissue.
  • pharmaceutically acceptable salt refers to a salt which retains the biological effectiveness of the free acid and free base of the specified compound and which has no adverse effects biologically or otherwise.
  • the compounds of the invention also include pharmaceutically acceptable salts.
  • a pharmaceutically acceptable salt refers to a form in which a base group in a parent compound is converted into a salt.
  • Pharmaceutically acceptable salts include, but are not limited to, base or inorganic or organic acid salts of amine (amino) groups.
  • the pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound, i.e., the basic group in the parent compound is reacted with from 1 to 4 equivalents of acid in a solvent system.
  • Pharmaceutically acceptable acid addition salts can be prepared from inorganic and organic acids.
  • the inorganic acid derived from the derivatized acid includes hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like.
  • Organic acids derived from derivatized acid include acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, and cinnamon. Acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like.
  • solvate refers to a combination of a compound of the invention and a solvent molecule formed by solvation.
  • a solvate refers to a hydrate, that is, a solvent molecule is a water molecule.
  • stereoisomer refers to a compound composed of the same atoms, bonded by the same bond, but having a different three-dimensional structure.
  • the compounds of formula I according to the invention encompass various possible optical isomers, cis and trans isomers and mixtures thereof.
  • tautomer refers to an isomer formed by the transfer of a proton from one atom of a molecule to another atom of the same molecule.
  • the compounds of formula I described herein encompass a wide variety of possible tautomers and mixtures thereof.
  • polymorph or "polymorph” as used herein, refers to a compound of the invention that exists in a different lattice form.
  • prodrug or prodrug refers to any pharmaceutically acceptable salt, ester, ester salt or other derivative of a compound of the invention which is capable of providing the product directly or indirectly after administration to a recipient.
  • Particularly preferred derivatives or prodrugs are those compounds which, when administered to a patient, increase the bioavailability of the compounds of the invention (for example, may render the orally administered compound more readily absorbed into the blood:) or promote the parent compound to the biological organ Or those compounds that are delivered at a site of action (eg, brain or lymphatic system:).
  • Prodrugs of the substance include, but are not limited to, esters, carbonates, thiocarbonates, N-acyl derivatives, N-acyloxyalkyl derivatives, quaternized derivatives of tertiary amines, N-Manny N-Mannich bases, Schiff base:, amino acid conjugates, phosphates, metal salts and sulfonates.
  • Various prodrug forms are well known in the art. See, for example, Prodrugs, Bundgaard, A. Ed., Elseview, 1985 and Method in Enzymology, Widder, K. et al., Ed.; Academic, 1985, vol. 42, p. 309-396; Bundgaard, H.
  • Prodrugs as described herein include, but are not limited to, the materials of the following groups and combinations of these: amine-derived prodrugs; hydroxy prodrugs include, but are not limited to, acyloxyalkyl esters, alkoxycarbonyl oxyalkyl esters, alkanes A base ester, an aryl ester, and an ester containing a disulfide bond.
  • pharmaceutical combination refers to pharmaceutical treatments obtained by mixing or combining more than one active ingredient, including fixed and unfixed combinations of the active ingredients.
  • fixed combination refers to the simultaneous administration of at least one compound described herein and at least one synergistic agent to a patient in the form of a single entity or a single dosage form.
  • unfixed combination refers to the simultaneous administration, combination or sequential administration of at least one compound described herein and at least one synergistic formulation to a patient in the form of separate entities, wherein such administration is in a patient An effective level of two or more compounds is provided in the body. These are also applied to cocktail therapy, such as the administration of three or more active ingredients.
  • administered in combination are intended to mean the administration of a selected therapeutic agent to the same patient, and are intended to encompass the same or different routes of administration or the same or different.
  • the compounds described herein are administered in combination with other agents. These terms encompass the administration of two or more agents to an animal to allow the simultaneous presence of the agent and/or its metabolite within the animal. These terms include the simultaneous administration of different compositions, the administration of different compositions at different times and/or the application of a composition containing different active ingredients.
  • a compound of the invention and other agents are administered in a combination.
  • metabolite or metabolite refers to a derivative of the compound formed upon metabolism of the compound.
  • the term "metabolism” as used herein refers to all processes by which an organism converts a particular substance (including but not limited to hydrolysis and enzymatic reactions:). Thus, the enzyme can cause specific structural changes in the compound.
  • Cytochrome P450 catalyzes a variety of redox reactions
  • uridine diphosphate glucuronyl transferase catalyzes the transfer of activated glucuronic acid molecules to aromatic alcohols, fatty alcohols, carboxylic acids, amines, and free sulfhydryl groups. Further information on metabolism can be found in The Pharmacological Basis of Therapeutics, 9th Edition, McGraw-Hill (1996).
  • the compound of the formula (I) of the present invention can be synthesized by a method well known in the chemical art, in particular, according to the method of the present invention.
  • the starting materials can be obtained from commercial sources or prepared using methods well known to those skilled in the art.
  • the compound of the formula (I) of the present invention can be produced by the following method:
  • the starting material (1) can be synthesized by a method described in the literature (J. Med. Chem., 2006, 49, 7868-7876), and then subjected to a transition metal-catalyzed coupling reaction such as a Suzuki reaction, a Sonogashira reaction, or a Stille reaction (Coupling).
  • the compound (2) is obtained, wherein Lm is ⁇ 6 - ⁇ - (R 6 , L 3 are as defined above); the compound (2) may optionally be in methanol, ethanol, dichloromethane, tetrahydrofuran or ethyl acetate.
  • the reducing agent may be sodium borohydride or sodium borohydride or sodium cyanoborohydride, respectively.
  • the formula (I) does not contain ruthenium
  • the formula (I) is an intermediate product, and the target compound can be produced by the reductive amination reaction into the ruthenium atom of the formula (I);
  • the formula (p) can be used as a target compound or as an intermediate product to introduce a ruthenium atom into R2 by a reductive amination reaction to form another target compound.
  • the starting material (1) is subjected to a Suzuki reaction, or a Sonogashira reaction, or a transition metal-catalyzed coupling reaction such as a Stille reaction to obtain a compound (3), wherein n is 1 or 2, and Lm is c ⁇ C— or R 6 — (L 2 , L 3 and R 6 are as defined above), which may be directly introduced by using a deuterated starting material or reagent in the coupling reaction; a hydroxyl group in the compound (3)
  • the functional group is converted into a compound (4) containing a mesylate, a halogen or the like leaving group (LG, Leaving group) by a conventional functional group conversion reaction; a compound (4) and a different amine (R 2 -NH-R 3 ) , R 2 and R 3 are as defined above.
  • Substitution reaction occurs under basic conditions to obtain the formula (11).
  • the formula (II) does not contain ruthenium
  • the formula ( ⁇ ) is an intermediate product
  • the target compound can be formed by introducing a ruthenium atom into the R 2 in the formula (II) by a reductive amination reaction;
  • the formula ( ⁇ ) can be used as a target compound or as an intermediate product to introduce a ruthenium atom into R2 by a reductive amination reaction to form another target compound.
  • the starting material (5) can be synthesized by a method described in the literature (WO2004075898 Al, US2007208164 Al, Tetrahedron Letters, 50(14), 1600-1602; 2009), and then subjected to a substitution reaction with the reagent Y LG to obtain a compound (6) wherein Y is a halogen. , a sulfonate, etc.
  • the reducing agent may be sodium borohydride or sodium borohydride or sodium cyanoborohydride, etc.
  • the aldehyde or ketone may be a fatty aldehyde or ketone such as formaldehyde, acetaldehyde or acetone, or may be deuterated. a fatty aldehyde or a ketone containing a halogen atom such as formaldehyde or deuterated acetaldehyde.
  • the reducing agent (with or without a ruthenium atom) and the fatty aldehyde or ketone (with or without) may be substituted according to the number of hydrogen atoms on the same carbon. Contains helium atoms) for selection and combination.
  • the structure of the compound is determined by nuclear magnetic resonance (H-NMR) and/or liquid chromatography-mass spectrometry (LC-MS).
  • the ifi-NMR shift ( ⁇ ) is given in parts per million (ppm).
  • the ifi-NMR was measured using a Bruker Avance-400 MHz or Varian-300 MHz NMR instrument, and the solvent was deuterated methanol (CD 3 OD ), deuterated chloroform (CDC1 3 ), hexamethylene dimethyl sulfoxide (DMSO-d6). ), the internal standard is tetramethylsilane (TMS);
  • LC-MS is determined by Agilent's 6110 SQ LC/MS (SB, C18 50mmX 4.6mm column).
  • the eluent system used for column chromatography includes: A: Dichloromethane and A Alcohol system, B: Ethyl acetate and petroleum ether system, the volume ratio of the solvent is adjusted according to the polarity of the compound, and may be adjusted by adding a small amount of ammonia or glacial acetic acid.
  • the starting materials to which the present invention relates may be synthesized by literature methods or by methods known in the art, or may be purchased from suppliers of reagents such as Acros Organics, J&K Chemicals, TCI, Sigma-Aldrich, Adamas, and the like. Unless otherwise specified in the present invention, the reaction is carried out under the protection of nitrogen or argon.
  • 2,4-Dichloro-5-methoxyaniline (1.9 g, 10 mmol), pyridine hydrochloride (1.2 g, 10 mmol) and 4-chloro-7-(3-chloro-propoxy) 6-Methoxy-quinoline-3-carbonitrile (3.1 g, 10 mmol) was placed in a sealed tube, anhydrous 2-ethoxyethanol (30 mL) was added, and the mixture was heated at 140 °C. hour.
  • reaction mixture is cooled to room temperature, diluted with water (500 mL), dichloromethane (250 mL ⁇ 2), and the organic phase is combined, washed with water, brine, dried over anhydrous sodium sulfate Purification by silica gel column chromatography to give 7-(3-chloro-propoxy:)-4-(2,4-dichloro-5-methoxy-phenylamino: )-6-methoxy-quinoline 3-methyl cyanide (grey solid, 3.0 g), yield 67%.
  • Second 7 7-[3-(3-Amino-pyrrolidin-1-yl)-propoxy]-4-(2,4-dichloro-5-methoxy-phenylamino) -6 -A Oxy-quinoline- 3 cyano
  • Second 7 7- (4-chloro-butoxy)-4-(2,4-dichloro-5-methoxy-phenylamino)-6-methoxy-quinoline-3-cyanide
  • the third group 4- ⁇ 3-[4-(4-chloro-2-cyclopropyl-5-methoxy-phenylamino)-3-cyano-6-methoxy-quinoline
  • 6-Chloro-3-methoxyaniline ( 1.57 g, 10 mmol) was dissolved in ethyl acetate (15 mL), and 1,3-dibromo-5 was added portionwise to the above solution under ice-cooling.
  • 5-Dimethylhydantoin (3.1 g, 11 mmol).
  • the reaction mixture was reacted in an ice bath for 1 hour.
  • the reaction mixture was quenched with saturated aqueous potassium carbonate.
  • the organic phase was separated and washed with water and brine. After drying over anhydrous sodium sulfate, filtered and evaporated tolululululululululululululu
  • Ifi-NMR (400MHz, DMS0-d6): ⁇ 9.99(1H, s), 8.55(1H, s), 8.23(1H, s), 8.03(1H, s), 7.78(1H, s), 7.41(1H , s), 4.07 (3H, s).
  • Ifi-NMR (400MHz, DMSO-d6): ⁇ 9.86 (1H, s), 9.71 (1H, s), 8.76 (1H, s), 8.48 (1H, s), 8.29 (2H, s), 8.00 (1H) , s), 7.77 (1H, s), 7.39 (1H, s), 4.09 (3H, s).
  • Example 2 4-(4-Chloro-2-cyclopropyl-5-methoxy-phenylamino: )-7-[3-(4-didecylmethyl-piperazin-1-propoxylate) -6-methoxy-quinoline-3-cyanate
  • Example 3 4-(4-Chloro-2-cyclopropyl-5-methoxy-phenylamino: )-7-[3-(4-tridemethyl-piperazin-1-propoxylate) -6-methoxy-quinoline-3-cyanate
  • the target compound 4-(2,4-dichloro-5-methoxy-phenylamino:)-7-[3-() was synthesized in a similar manner to Example 1 except that Intermediate 1 was used instead of Intermediate 8. 4--deuterated methyl-piperazin-1-yl)-propoxy]-6-methoxy-quinoline-3-carbonitrile (yellow solid, 34.5 mg).
  • the target compound 4-(2,4-dichloro-5-methoxy-phenylamino: )-7-[3-() was synthesized in a similar manner to Example 3 except that Intermediate 1 was used instead of Intermediate 8. 4-tridemethyl-piperazin-1-yl:)-propoxy]-6-methoxy-quinoline-3-carbonitrile (yellow solid, 22.5 mg).
  • the target compound 4-(2,4-dichloro-5-methoxy-phenylamino:)-7-[3-() was synthesized in a similar manner to Example 2 except that Intermediate 1 was used instead of Intermediate 8. 4-Deuteromethyl-piperazin-1-yl)-propoxy]-6-methoxy-quinoline-3-carbonitrile (yellow solid, 18 mg).
  • Example 7 4-(2,4-Dichloro-5-methoxy-phenylamino)-7- ⁇ 3-[4-(l-deutero-cyclopropyl)-piperazin-1-yl] -propoxy ⁇ -6-methoxy-quinoline-3-cyanide
  • Example 8 7- ⁇ 3-[3-(Bis-monodecylmethyl-amino)-pyrrolidin-1-yl]-propoxy H-(2,4-dichloro-5-phenylamino -6-methoxy-quinoline- 3 -cyanocyanate
  • the target compound 7- ⁇ 3-[3-(bis-monodecylmethyl-amino)-pyrrolidin-1-yl] was synthesized by a method similar to Example 1 except that Intermediate 2 was used instead of Intermediate 8.
  • Intermediate 2 was used instead of Intermediate 8.
  • Example 9 7- ⁇ 3-[3-(Bis-tris-methyl-amino)-pyrrolidin-1-yl]-propoxy H-(2,4-dichloro-5-methoxy -phenylamino)-6-methoxy-quinoline- 3 -cyanocyanate I3/: O 6/-iil£iiAV
  • the target compound 4-(2,4-dichloro-5-methoxy-phenylamino:)-7-[3-() was synthesized in a similar manner to Example 2 except that Intermediate 6 was used instead of Intermediate 8.
  • Example 12 4-(2,4-Dichloro-5-methoxy-phenylamino)-7- ⁇ 5-[(4-methyl-piperazin-1-yl)-indolyl-quinoline Porphyrin-3-cyanide
  • the target compound 4-(2,4-dichloro-5-methoxy-phenylamino) was synthesized in a similar manner to Example 1 except that Intermediate 3 and N-methylpiperazine were used instead of formaldehyde and Intermediate 8. :) -7- ⁇ 5-[(4-Methyl-piperazin-1-yl:)--deuteromethyl]-furan-3-yl 6-methoxy-quinoline-3-carbonitrile Yellow solid, 21 mg).
  • the target aqueous compound 4-(2,4-dichloro-5-methoxy-phenylamino) was synthesized by the similar method of Example 1 by replacing the aqueous formaldehyde solution and the intermediate 8 with Intermediate 3 and dimethylamine hydrochloride, respectively.
  • - 7 -[ 5 -( dimethylamino-monodecylmethyl)-furan-3-yl]-6-methoxy-quinoline-3-cyanoic acid (yellow solid, 11 mg) o
  • Example 14 4-(2-Chloro-4-cyclopropyl-5-methoxy-phenylamino)-7-[3-(4--deuteromethyl-piperazin-1-propoxy) ]-6-methoxy-quinoline-3-cyanide
  • Example 17 4-(2,4-Dichloro-5-methoxy-phenylamino)-7-[5-(morpholin-4-yl-monodecylmethyl)-furan cyanide
  • the target compound 4-(2,4-dichloro-5-methoxy-phenylamino:)-7- was synthesized by the similar method of Example 1 using Intermediate 3 and morpholine in place of the aqueous formaldehyde solution and Intermediate 8. [5-(morpholin-4-yl-monodecylmethyl)-furan-3-yl]-6-methoxy-quinoline-3-carbonitrile (yellow solid, 12 mg).
  • the target compound 4-(2,4-dichloro-5-methoxy-phenylamino:)-7- was synthesized by the similar method of Example 1 using Intermediate 5 and morpholine in place of the aqueous formaldehyde solution and Intermediate 8. [4-(morpholine-4-yl-monodeuteromethyl:)-furan-2-yl]-6-methoxy-quinoline-3-carbonitrile (yellow solid, 15 mg).
  • the target compound 4-(2,4-dichloro-5-methoxy-phenylamino:)-7-[4-() was synthesized in a similar manner to Example 2 except that Intermediate 4 was used instead of Intermediate 8.
  • the target compound 4-(2,4-dichloro-5-methoxy-phenylamino: )-7-[4-() was synthesized in a similar manner to Example 3 except that Intermediate 4 was used instead of Intermediate 8.
  • the target compound 4-(2,4-dichloro-5-methoxy-phenylamino)-7-[5-(4) was synthesized in a similar manner to Example 1 except that Intermediate 10 was used instead of Intermediate 8.
  • Intermediate 10 was used instead of Intermediate 8.
  • Example 24 4-(2,4-Dichloro-5-methoxy-phenylamino)-7-[5-(4-dioxomethyl-piperazin-1-ylmethyl)-furan- 3-yl-6-methoxy-quinoline-3-cyanide ⁇ ] ⁇ - ⁇ - ⁇ - ⁇ - ⁇ -B, ⁇ -[ - - ⁇ - 3 ⁇ 43 ⁇ 4 ⁇ -9-(3 ⁇ 43 ⁇ 43 ⁇ 4-3 ⁇ 43 ⁇ 4 ⁇ - ⁇ - ⁇ 9 ⁇
  • the intermediate compound 3 and N-tert-butoxycarbonylpiperazine were used to replace the aqueous formaldehyde solution and the intermediate 8, and the target compound 4-( ⁇ 4-[3-cyano-4-(2,4) was synthesized by a similar method as in Example 1.
  • -Dichloro-5-methoxy-phenylamino)-6-methoxy-quinolin-7-yl]-furan-2-yl-deuterated-methyl)-piperazine-1-carboxylic acid tert-butyl ester (yellow solid, 450 mg).
  • Example 28 4-(2,4-Dichloro-5-methoxy-phenylamino)-7- ⁇ 5-[(4--deuteromethyl-piperazin-1-yl)-mono-quin Porphyrin-3-cyanide
  • Example 29 4-(2,4-Dichloro-5-methoxy-phenylamino)-7- ⁇ 5-[(4-dioxomethyl-piperazin-1-yl)-mono-furan -3-yl ⁇ -6-methoxy-quinoline-3-cyanide
  • the intermediate compound 8 was replaced with Example 27, and the title compound 4-(2,4-dichloro-5-methoxy-phenylamino:)-7- ⁇ 5-[(4- Di-deuterated methyl-piperazin-1-yl)-monodecylmethyl]-furan-3-yl 6-methoxy-quinoline-3-carbonitrile (yellow solid, 13 mg).
  • Example 30 4-(2,4-Dichloro-5-methoxy-phenylamino)-7- ⁇ 5-[(4-tridemethyl-piperazin-1-yl)-anthracene Methyl]-furan-3-yl ⁇ -6-methoxy-quinoline-3-cyanate
  • the target compound 4-(2,4-dichloro-5-methoxy-phenylamino:)-7- ⁇ 4 was synthesized by a similar method as in Example 1. -[(4-Methyl-piperazin-1-yl)-indolylmethyl]-furan-2-yl 6-methoxy-quinoline-3-carbonitrile (yellow solid, 28 mg).
  • Example 34 4-(2,4-Dichloro-5-tridecylmethoxy-phenylamino)-7-[5-(piperazin-1-yl-monodecylmethyl-furan-3- -6-methoxy-quinoline-3-carbonitrile hydrochloride
  • the target compound 4-(2,4-dichloro-5-tridecylmethoxy) was synthesized by a similar method as in Example 1.
  • Example 36 4-(2,4-Dichloro-5-tridecylmethoxy-phenylamino)-7- ⁇ 5-[(4-didecylmethyl-piperazin-1-yl) Methyl]-furan-3-yl ⁇ -6-methoxy-quinoline-3-cyanate
  • Example 34 Using the heavy aqueous solution of Example 34 and 25% of deuterated formaldehyde as the starting material and sodium borohydride as the reducing agent, the target compound 4-(2,4-dichloro-5-triindole) was synthesized by a similar method as in Example 2.
  • Example 39 is a compound known in the art which can be synthesized by a literature method as a positive reference compound for comparison with the activity of the deuterated compound of the present invention.
  • a literature method for comparison with the activity of the deuterated compound of the present invention.
  • J. Med. Chem. 2006, 49, 7868-7876 i.e., the synthesis method of compound 10 in Scheme 1 on page 7869.
  • the kinase inhibitory activity assay described in this test example is used to determine the in vitro inhibitory activity of the compound of the present invention against kinases such as c-Src and Bcr-Ab EGFR, and the test compound has inhibitory activity against kinase enzyme activity using a semi-inhibitory concentration. IC 5 . The value is expressed. Homogeneous time-resolved fluorescence
  • HTRF concentration gradient test compounds are incubated with a specific concentration of enzyme solution for 5 minutes at room temperature; then an appropriate amount of enzyme reaction is added. ATP, start the enzyme reaction process; 30 minutes later, add appropriate amount of reaction stop solution and detection solution to the enzyme reaction system; after 1 hour of incubation, determine the specific compound on Molecular device's Flexstation III multi-function microplate reader. The enzyme activity at the concentration, and the inhibitory activity of the compounds at different concentrations on the enzyme activity were calculated. Then, according to the four-parameter equation, the inhibitory activities of the enzyme activities under different concentrations of the compounds were fitted, and the IC 5Q value was calculated.
  • kinases c-Src and Bcr-Abl used in this test were purchased from Cama Biotech Co., Ltd., and the test kit HTRF KinEASE-TK (purchased from Cisbio Bioassays) was used in the HTRF assay.
  • ATP was purchased from Sigma Aldrich. the company.
  • the inhibitory activity of the compounds of the invention on kinases is represented by the IC 5Q value, wherein IC 5Q ⁇ 5 nM is represented by the symbol ++++; 5 nM ⁇ IC 5 . ⁇ 50 nM is represented by the symbol +++; IC 5 . >50 nM is represented by the symbol ++.
  • Table 1 The results of the kinase inhibitory activity of some of the examples are shown in Table 1 below:
  • Example Compound 39 the compound of the present invention is still capable of inhibiting the kinases such as Bcr-Abl and c-Src after deuteration modification of Bosutinib or the positive control compound (Example Compound 39).
  • Example compound IC 5 12 a value of 1.8 nM, compound of Example IC 5Q 39 value of 1.2 nM
  • Example compound IC 5 12 may be used to treat such diseases caused by abnormal kinase activity.
  • Test Example 2 Cell Inhibition Test
  • the cell proliferation inhibitory activity test described in the test example is for measuring the proliferation inhibitory activity of the compound of the present invention against a cell line highly expressed such as EGFR, Bcr-Abl, etc., and the inhibitory activity of the test compound on cell proliferation is determined by a half inhibitory concentration. : IC 5Q to indicate.
  • the experimental protocol for this type of experiment is as follows: Select different cells, such as K-562 cells, A431 cells, A549, DU145, H1650, H1975, etc. (The cells are purchased from the Cell Culture Bank of the Chinese Academy of Sciences and the Shanghai Institute of Life Sciences, Chinese Academy of Sciences) Cell Resource Center), cells were seeded on white opaque 384-well culture plates at appropriate cell concentrations (eg.
  • the compound of the present invention has an activity of inhibiting proliferation of K562 cells, and the cell proliferation inhibitory activity results of some of the examples are shown below (inhibition activity is represented by IC 5Q value, wherein IC 5Q ⁇ 100 nM is represented by the symbol ++++; 100 nM ⁇ IC 5G ⁇ 500nM is represented by the symbol +++; IC 5G >500nM is represented by the symbol ++).
  • Example Compound 39 As can be seen from Table 2, after deuteration modification of Bosutinib or a positive control compound (Example Compound 39), the compounds of the present invention still have a high inhibitory activity against K562 cell proliferation growth (as in Example 12 of Example).
  • the IC 5Q value was 17.0 nM
  • the compound of Example 39 had an IC 5 () value of 23.9 nM), which can be used as a treatment for diseases caused by such abnormal cell proliferation.
  • the pharmacokinetic tests of the compounds of the examples of the invention include in vitro microsomal and metabolic enzyme assays and in vivo metabolic kinetic testing of rats or mice as test animals.
  • Metabolic stability test Metabolic stability incubation with 150 ⁇ of liver microsomes (final concentration 0.5 mg/ml) containing NADPH (final concentration 1 mM), 1 ⁇ test compound and positive control Midazolam or negative control atenolol was stopped at 0 min, 5 min, 10 min and 30 min with tinidazole-containing acetonitrile, vortexed for 10 min, centrifuged at 15000 rmp for 10 min, and taken on 50 ⁇ M. Inject into the 96-well plate. The metabolic stability of the compound was calculated by measuring the relative reduction in the original drug.
  • Direct inhibition test Direct inhibition of incubation with 100 ⁇ human liver microsomes (final concentration 0.2 mg/ml) containing NADPH (final concentration 1 mM), 10 ⁇ compound, positive Inhibitor cocktail (ketoconazole 10 ⁇ , quinidine 10 ⁇ , sulfaphenazole 100 ⁇ , ⁇ -naphthoflavone 10 ⁇ , tranylcypromine 1000 ⁇ ), negative control (0.1% DMSO BPS) and mixed probe
  • the needle substrate (midazolam 10 ⁇ , testosterone 100 ⁇ , dextromethorphan 10 ⁇ , diclofenac 20 ⁇ , phenacetin 100 ⁇ , mefenazine 100 ⁇ ) was stopped after incubation for 20 min. The relative activity of the enzyme was calculated by measuring the relative amount of production of the metabolite.
  • Test Results The compound of Example 12 and the positive reference compound 39 showed significant differences in the metabolic properties due to the substitution effect of hydrogen and hydrazine.
  • the compound of Example 39 has a strong inhibitory effect on the metabolic enzyme 2D6 (direct to the metabolic enzyme) The inhibition rate was 86%), while Example 12 had no significant inhibitory effect on the metabolic enzyme 2D6 (the direct inhibition rate to metabolic enzymes was 40%).
  • the drug concentration in plasma at different times after intragastric administration and intravenous administration of the compound of the present invention was determined by LC/MS/MS method, and the pharmacokinetic behavior of the compound of the present invention in rats or mice was studied. , to evaluate its pharmacokinetic characteristics.
  • test animals were healthy adult male SD rats or BALB/c mice, provided by Shanghai Xipuerkekai Experimental Animal Co., Ltd.; administration mode and sample collection: respectively given to SD rats or BALB/c mice Intravenous (3 mg/kg, 1 mg/mL suspension of test compound) and intragastric administration (10 mg/kg, 1 mg/mL suspension of test compound) Liquid), taking 0.4 mL of blood from the fundus venous plexus of rats or mice before administration and 2, 5, 15, 30, 60, 90, 120, 240, 360, 480, 1440 min after administration; Sample 50 L, respectively, add 200 ⁇ containing the internal standard acetonitrile solution to precipitate protein, vortex for 10 min, 6000 rpm / separation of the heart for 10 min; take 200 supernatant 6,000 rpm for another 10 min; then take 75 supernatant, Gradient initial mobile phase dilution, 6000 rpm / separation of the core for 10 min; Finally, the supernatant 70 was injected
  • the positive control compound (Example Compound 39) has a half-life of about 32 min, which is much lower than the half-life of the compounds of the examples of the present invention.
  • Test Examples 1 to 3 show that the compounds of the examples of the present invention have a large improvement in in vitro activity and in vivo pharmacokinetic properties. Positive compounds constituting the prior art
  • Bosutinib (SKI606, available from Adamas Technology) or non-deuterated positive control compound (Example Compound 39), in terms of plasma concentration, half-life, clearance, microsomal stability, bioavailability, or enzyme inhibition It has obvious superiority.
  • Test case four in vivo efficacy test
  • BALB/c nude mice (Shanghai Xipuer-Beikai Experimental Animals Co., Ltd.) were used, weighing 18-20 g, female.
  • BD Matrigel, K562 cells (Shanghai Cell Bank).
  • Dosing cycle It is administered once a day by intragastric administration for 8 consecutive days.
  • Cell culture and passage Cells were harvested, centrifuged and redispersed in RPMI-1640 medium and passaged 1:4.
  • Cell seeding The cells in the logarithmic growth phase were collected, medium and Matrigel 1 :1, and the cell concentration was adjusted to 5.0 ⁇ 10 7 /ml, placed in an ice box, and inoculated into the lower side of the mouse armpit with 0.2 ml/mouse.
  • Parameter measurement The tumor volume and body weight were measured. When measuring the tumor volume, the long diameter and the broad diameter of the tumor were measured with vernier calipers, and then the volume and relative volume of the tumor were calculated.
  • the compounds of the present invention have strong growth inhibition effects on human leukemia K562 xenografts at doses of 5 mg/kg, 10 mg/kg, and 20 mg/kg.
  • Example Compounds 12 and 37 have a T/C ratio of less than 35% at Day 10; at doses of 10 mg/kg and 20 mg/kg, Examples Compounds 12 and 37 are at Day 10 T
  • the /C ratio was less than 20% until the tumor completely disappeared, and the survival time of the test animals was significantly prolonged.
  • the compounds of this example caused significant abnormalities in body weight and other clinical symptoms of the test group.

Abstract

Disclosed in the invention are a deuterated 3-cyano quinoline compound or pharmaceutically acceptable salts, solvates, prodrugs, stereoisomers, tautomers, polymorphic substances, metabolites etc., and a pharmaceutical composition containing such compounds, and the use of these compounds or compositions in the preparation of drugs for treating or preventing tumours, especially drugs such as protein kinase inhibitors. Compared with the prior art, the compounds of the present invention have the clear advantages of properties such as plasma drug concentration, half-life, clearance, microsomal stability, bioavailability or enzyme inhibition and the like, and thus can more effectively inhibit the activities of more than one protein kinase and/or inhibit the growth of tumuor cells.

Description

一类氘代 3-氰基喹啉类化合物、 其药用组合物、 制备方法 及其用途  Deuterated 3-cyanoquinoline compound, pharmaceutical composition thereof, preparation method and use thereof
技术领域 本发明属于化学医药领域， 具体涉及一类氘代 3-氰基喹啉类化合物或其 药学上可接受的盐、 溶剂化物、 前体药物、 立体异构体、 互变异构体、 多晶 型物或代谢产物等和含有这类化合物的药物组合物， 以及这些化合物或组合 物在制备治疗或预防肿瘤的药物特别是蛋白激酶抑制剂类药物中的用途。 背景技术  FIELD OF THE INVENTION The present invention relates to the field of chemical medicine, and in particular to a class of deuterated 3-cyanoquinoline compounds or pharmaceutically acceptable salts, solvates, prodrugs, stereoisomers, tautomers thereof, Polymorphs or metabolites and the like, and pharmaceutical compositions containing such compounds, and the use of these compounds or compositions in the manufacture of a medicament for the treatment or prevention of tumors, particularly protein kinase inhibitors. Background technique
3-氰基喹啉类化合物作为一类蛋白激酶抑制剂已经被广泛使用， 如 SKI606, EKB569、 HKI272等， 它们具有类似的能够抑制一种或者多种与肿 瘤的发生发展密切相关的蛋白激酶活性和 /或抑制肿瘤细胞的生长活性。 SKI606, 即博舒替尼（Bosutinib) , 由美国惠氏制药公司研制的一种强效蛋白 激酶抑制剂， 目前被用于治疗费城染色体阳性的慢性粒细胞白血病， 已经于 2012年 9月被美国 FDA批准上市。 然而， 该药物仍然有一些不可避免的缺 点， 如在研究中发现代谢性质不佳、 血浆半衰期短等特点， 因此仍有必要寻 找和发现具有更高体内外药效、 更好的药代动力学性质的药物。 经过不懈努 力， 本发明设计了具有通式 I所示的氘代 3-氰基喹啉类化合物， 并且发现该 类化合物具有优异的体内外药效和药代动力学性质。 发明内容 为了克服现有技术的缺点，本发明设计了具有通式 I结构特征的化合物， 该类化合物可有效抑制一种以上的蛋白激酶活性和 /或抑制肿瘤细胞的生长， 并且可表现出优异的药代动力学性质和 /或动物体内药效性质。 3-cyanoquinolines have been widely used as a class of protein kinase inhibitors, such as SKI606, EKB569, HKI272, etc., which have similar protein kinase activities that are capable of inhibiting one or more closely related to tumor development. And/or inhibit the growth activity of tumor cells. SKI606, Bosutinib, a potent protein kinase inhibitor developed by Wyeth Pharmaceuticals, Inc., is currently used to treat Philadelphia chromosome-positive chronic myeloid leukemia, which was administered by the US FDA in September 2012. Approved for listing. However, the drug still has some unavoidable shortcomings, such as poor metabolism and short half-life in the study. Therefore, it is still necessary to find and find higher pharmacokinetics and better pharmacokinetics. The nature of the drug. Through unremitting efforts, the present invention has deuterated 3-cyanoquinoline compounds of the formula I, and has been found to have excellent in vitro and in vivo pharmacological and pharmacokinetic properties. SUMMARY OF THE INVENTION To overcome the shortcomings of the prior art, the present invention contemplates compounds having the structural features of Formula I which are effective in inhibiting more than one protein kinase activity and/or inhibiting the growth of tumor cells and exhibiting excellent Pharmacokinetic properties and/or pharmacodynamic properties in animals.
本发明提供了一种新型的氘代 3-氰基喹啉类衍生物， 其能够抑制一种或 多种与肿瘤的发生发展密切相关的蛋白激酶活性和 /或抑制肿瘤细胞的生长。  The present invention provides a novel deuterated 3-cyanoquinoline derivative which is capable of inhibiting one or more protein kinase activities closely related to the development of a tumor and/or inhibiting the growth of tumor cells.
根据本发明的一个方面， 本发明提供了式（I)化合物或其药学上可接受 的盐、 溶剂化物、 前体药物、 立体异构体、 互变异构体、 多晶型物或代谢产 物：
Figure imgf000003_0001
According to one aspect of the invention there is provided a compound of formula (I), or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, tautomer, polymorph or metabolite thereof :
Figure imgf000003_0001
(I)  (I)
其中，  among them,
R1为 C1~C6烷氧基， 所述 C1~C6烷氧基上的一个或多个 H非必须地被 氘取代； 优选为 C1~C4烷氧基， 所述 C1~C4烷氧基上的一个或多个 H非必 须地被氘取代； 更优选为甲氧基， 所述甲氧基上的一个或多个 H非必须地被 氘取代； R 1 is a C1 to C6 alkoxy group, and one or more H groups on the C1 to C6 alkoxy group are optionally substituted by deuterium; preferably a C1 to C4 alkoxy group, the C1 to C4 alkoxy group One or more H's are optionally substituted by deuterium; more preferably a methoxy group, one or more H groups on the methoxy group are optionally substituted by deuterium;
Ar为未取代或由取代基所取代的 6~10元芳基、 或未取代或由取代基所 取代的 6~10元杂芳基， 所述 6~10元杂芳基含有 1~2个选自 N、 S和 0中的 杂原子， 所述取代基为卤素、 C1~C6烷氧基、 C1~C6烷基或 C3~C6环烷基， 其中所述 C1~C6烷氧基、 C1~C6烷基或 C3~C6环烷基上的一个或多个 H非 必须地被氘取代； 优选地， Ar为未取代或由取代基所取代的苯基、 或未取代 或由取代基所取代的 6元杂芳基， 所述 6元杂芳基含有 1~2个 N原子， 所述 取代基为卤素、 C1~C4烷氧基、 C1~C4烷基或 C3~C6环烷基，其中所述 C1~C4 烷氧基、 C1~C4烷基或 C3~C6环烷基上的一个或多个 H非必须地被氘取代； 进一歩优选地， Ar为未取代或由取代基所取代的苯基， 或者未取代的或由取 代基所取代的吡啶基， 所述取代基为氯、 甲氧基或环丙基， 其中所述甲氧基、 环丙基上的一个或多个 H非必须地被氘取代； 更优选地， Ar为未取代或由 取代基所取代的苯基， 所述取代基为氯、 甲氧基或环丙基， 其中所述甲氧基、 环丙基上的一个或多个 H非必须地被氘取代；  Ar is a 6- to 10-membered aryl group which is unsubstituted or substituted by a substituent, or a 6- to 10-membered heteroaryl group which is unsubstituted or substituted with a substituent, and the 6- to 10-membered heteroaryl group has 1 to 2 a hetero atom selected from the group consisting of N, S and 0, wherein the substituent is a halogen, a C1 to C6 alkoxy group, a C1 to C6 alkyl group or a C3 to C6 cycloalkyl group, wherein the C1 to C6 alkoxy group, C1 One or more H groups on the ~C6 alkyl group or the C3~C6 cycloalkyl group are optionally substituted by deuterium; preferably, Ar is a phenyl group which is unsubstituted or substituted by a substituent, or is unsubstituted or substituted by a substituent a substituted 6-membered heteroaryl group having 1 to 2 N atoms, the substituent being a halogen, a C1 to C4 alkoxy group, a C1 to C4 alkyl group or a C3 to C6 cycloalkyl group. Wherein one or more H groups on the C1~C4 alkoxy group, C1~C4 alkyl group or C3~C6 cycloalkyl group are optionally substituted by deuterium; further preferably, Ar is unsubstituted or substituted by a substituent a substituted phenyl group, or a pyridyl group which is unsubstituted or substituted by a substituent, wherein the substituent is chloro, methoxy or cyclopropyl, wherein one or more of the methoxy group and the cyclopropyl group H is not required to be shackled More preferably, Ar is a phenyl group which is unsubstituted or substituted with a substituent which is a chlorine, a methoxy group or a cyclopropyl group, wherein the methoxy group, one or more of the cyclopropyl groups H is not necessarily replaced by 氘;
L为  L is
i) -(CH2)mO-, 其中 m为 2~5的整数； 优选 m为 3或 4， 且其 0原子直 接与式 （I) 中所示的喹啉环相连， i) -(CH 2 ) m O-, wherein m is an integer from 2 to 5; preferably m is 3 or 4, and its 0 atom is directly bonded to the quinoline ring shown in formula (I),
ϋ)
Figure imgf000003_0002
或卜 L1- C≡C L2- 其中 Ll、 L2各自独立地为 -(CH2)n- 或直接键， n为 1~3的整数； 优选为 L「c≡c—L 2- 其中 Li、 L2各自独立地 为 -(CH2)n-或直接键， n为 1~3的整数； 更优选为卜 Li-C≡c 其中 为亚 甲基或 -(CH2)2-， L2为直接键且直接与喹啉环相连， 或 C-R6 L3-^ C— R6- L3- iii ) R5 ， 或 ， 其中 R4、 R5各自独立地为 H、 F或氘原 子， 优选为 H或氘原子； R6为 5~6元亚芳基或亚杂芳基， 优选为亚苯基、 亚 呋喃基或亚吡啶基， 进一歩优选为亚呋喃基， 更优选为 2,4-亚呋喃基； L3为ϋ)
Figure imgf000003_0002
Or L1 - C ≡CL 2 - wherein L1 and L 2 are each independently -(CH 2 ) n - or a direct bond, and n is an integer from 1 to 3; preferably L " c ≡ c - L 2 - wherein Li And L 2 are each independently -(CH 2 ) n - or a direct bond, and n is an integer of 1 to 3; more preferably, Li- C ≡ c is a methylene group or -(CH 2 ) 2 -, L 2 is a direct bond and is directly linked to the quinoline ring, or CR 6 L 3 -^ C— R 6 - L 3 - iii ) R 5 , or wherein R 4 and R 5 are each independently H, F or a halogen atom, preferably H or a halogen atom; R 6 is 5~ a 6-membered arylene or heteroarylene group, preferably a phenylene group, a furylene group or a pyridylene group, further preferably a furanyl group, more preferably a 2,4-furanyl group; L 3 is
CH=CH-i ^G≡G_ ^或直接键， 优选为直接键且直接与喹啉环相连； CH=CH -i ^ G ≡ G _ ^ or a direct bond, preferably a direct bond and directly attached to the quinoline ring;
R2、 R3各自独立地为 H或 C1~C6烷基， 所述 C1~C6烷基上的一个或多 个 H非必须地被氘取代； 优选 R2、 R3各自独立地为 H或 C1~C4烷基， 所述 C1~C4烷基上的一个或多个 H非必须地被氘取代； 更优选 R2、 R3各自独立 地为 H、甲基或乙基，所述甲基或乙基上的一个或多个 H非必须地被氘取代； 或者， R2、 R3和与它们相连的 N原子共同形成 4~7元含氮杂环基， 所述 含氮杂环基非必须地进一歩包含一个选自 N、 S和 0中的杂原子且非必须地 被取代基所取代， 所述的取代基为 C1~C6烷基、 单 (C1~C6烷基:)氨基、 二 (C1~C6烷基)氨基、 （C1~C6烷氧基)酰基或 C3~C6环烷基， 其中所述 C1~C6 烷基、 C1-C6烷氧基或 C3~C6环烷基上的一个或多个 H非必须地被氘取代； 优选地， R2、 R3和与它们相连的 N原子共同形成氮杂环丁烷基、 吡咯烷基、 哌啶基、 吗啉基、 硫代吗啉基、 哌嗪基或高哌嗪基， 且上述基团非必须地被 取代基所取代，所述的取代基为 C1~C4烷基、单 (C1~C4烷基:)氨基、二 (C1~C4 烷基:)氨基、 （C1~C4烷氧基)酰基或 C3~C6环烷基， 其中所述 C1~C4烷基、 C1~C4烷氧基或 C3~C6环烷基上的一个或多个 H非必须地被氘取代； 更优 选地， R2、 R3和与它们相连的 N原子共同形成哌嗪基、 吡咯烷基、 吗啉基或 哌啶基， 且上述基团非必须地被取代基所取代， 所述的取代基为甲基、 甲氨 基、 二甲氨基、 叔丁氧基酰基或环丙基， 其中所述甲基、 甲氨基、 二甲氨基、 叔丁氧基酰基或环丙基上的一个或多个 H非必须地被氘取代； R 2 and R 3 are each independently H or a C1 to C6 alkyl group, and one or more H groups on the C1 to C6 alkyl group are optionally substituted by deuterium; preferably, R 2 and R 3 are each independently H or a C1 to C4 alkyl group, wherein one or more H groups on the C1 to C4 alkyl group are optionally substituted with deuterium; more preferably, R 2 and R 3 are each independently H, methyl or ethyl, the methyl group Or one or more H groups on the ethyl group are optionally substituted by deuterium; or R 2 , R 3 and the N atom to which they are attached form a 4 to 7 membered nitrogen-containing heterocyclic group, said nitrogen-containing heterocyclic group Optionally, a hetero atom comprising one selected from the group consisting of N, S and 0 is optionally substituted with a substituent which is a C1 to C6 alkyl group, a mono(C1 to C6 alkyl:) amino group. a (C1~C6 alkyl)amino group, a (C1~C6 alkoxy) acyl group or a C3~C6 cycloalkyl group, wherein the C1~C6 alkyl group, the C1-C6 alkoxy group or the C3~C6 cycloalkyl group One or more H groups are optionally substituted by deuterium; preferably, R 2 , R 3 and the N atom to which they are attached form azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, Thiomorpholinyl, piperazinyl or homopiperazinyl, and The group is optionally substituted by a substituent which is a C1 to C4 alkyl group, a mono(C1 to C4 alkyl group) amino group, a di(C1 to C4 alkyl group:) amino group, (C1 to C4). An alkoxy) acyl group or a C3 to C6 cycloalkyl group, wherein one or more H groups on said C1 to C4 alkyl group, C1 to C4 alkoxy group or C3 to C6 cycloalkyl group are optionally substituted by deuterium; Preferably, R 2 , R 3 and the N atom to which they are attached form a piperazinyl, pyrrolidinyl, morpholinyl or piperidinyl group, and the above groups are optionally substituted by a substituent, said substitution The group is methyl, methylamino, dimethylamino, tert-butoxy or cyclopropyl, wherein one or more of the methyl, methylamino, dimethylamino, tert-butoxy or cyclopropyl groups H is not necessarily replaced by 氘;
并且， 式 （I) 所示的化合物至少含有一个氘原子。  Further, the compound represented by the formula (I) contains at least one deuterium atom.
在本发明的一个优选实施方式中， 提供了一种式（I)所示的化合物或其 药学上可接受的盐、 溶剂化物、 前体药物、 立体异构体、 互变异构体、 多晶 型物或代谢产物， 其特征在于， 所述的式（I)所示的化合物为如下任一化合 物： D 化合物 2In a preferred embodiment of the present invention, there is provided a compound of the formula (I) or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, tautomer thereof, or more a crystalline form or a metabolite characterized in that the compound represented by the formula (I) is any one of the following compounds: D compound 2
H 化合物 1 H compound 1
Figure imgf000005_0001
Figure imgf000005_0001
D 1 化合物 4  D 1 compound 4
D 化合物 3
Figure imgf000005_0002
 D compound 3
Figure imgf000005_0002
化合物 5 化合物 6 、■ f、、y、- D 化合物 7  Compound 5 Compound 6 , ■ f, y, - D Compound 7
[¾C一 N CD3 [3⁄4C一N CD 3
化合物 9  Compound 9
HD2C\ 、、 I J J HD 2 C\ , IJJ
、、、 、、 , , , , ,
Figure imgf000005_0003
Figure imgf000005_0003
化合物 11 12 化合物 13 Compound 11 12 Compound 13
Figure imgf000006_0001
Figure imgf000006_0001
化合物 24
Figure imgf000007_0001
Compound 24
Figure imgf000007_0001
化合物 26 Compound 26
〇 。 Oh.
化合物 27  Compound 27
Η Η 化合物 28
Figure imgf000007_0002
化合物 30 Η Η compound 28
Figure imgf000007_0002
Compound 30
CIYYCI CI YY CI
合物 化合物 31 化 32
Figure imgf000008_0001
在本发明的另一个实施方式中， 提供了一种药物组合物， 其包含治疗有 效量的选自式 I所示的化合物或其药学上可接受的盐、溶剂化物、前体药物、 立体异构体、 互变异构体、 多晶型物或代谢产物中的一种或多种， 以及至少 一种药学上可接受的辅料。 本文所述药物组合物包括但不限于口服剂型、 胃 肠外给药剂型、 外用剂型和直肠给药剂型， 优选口服剂型。 在一些实施方式 中， 所述药物组合物的口服剂型包括片剂、 胶囊、 丸剂、 粉剂、 缓释制剂、 溶液和悬浮液等， 胃肠外给药剂型包括无菌溶液、 悬浮液或乳液， 外用剂型 包括软膏、 油剂、 乳液、 凝胶、 悬浮液、 溶液、 洗剂或乳膏， 直肠给药剂型 包括栓剂、 滴剂。 在一些实施方式中， 所述药物组合物为适合单次施予精确 剂量的单位剂型。在其它实施方式中， 式 I化合物的量在约 0.001 mg/kg体重 /天〜约 1000 mg/kg体重 /天的范围内。在其它实施方式中， 式 I化合物的量的 范围为约 0.5 mg/kg体重 /天〜约 50 mg/kg体重 /天。 在一些实施方式中， 式 I 化合物的量为约 0.001 g/天〜约 7 g/天。 在其它实施方式中， 式 I化合物的量 为约 0.002 g/天〜约 6 g/天。在其它实施方式中， 式 I化合物的量为约 0.005 g/ 天〜约 5 g/天。 在其它实施方式中， 式 I化合物的量为约 0.01 g/天〜约 5 g/天。 在其它实施方式中， 式 I化合物的量为约 0.02 g/天〜约 5 g/天。 在其它实施方 式中， 式 I化合物的量为约 0.05 g/天〜约 2.5 g/天。 在其它实施方式中， 式 I 化合物的量为约 0.1 g/天〜约 1 g/天。 在其它实施方式中， 低于上述范围下限 的剂量水平可能已经是足够的。 在其它实施方式中， 可能需要高于上述范围 上限的剂量水平。 在一些实施方式中， 以单剂量施用式 I化合物， 每天一次。 在其它实施方式中， 以多剂量施用式 I化合物， 每天不只一次。 在一些实施 方式中， 每天施用两次式 I化合物。 在其它实施方式中， 每天施用三次式 I 化合物。在其它实施方式中， 每天施用四次式 I化合物。在其它实施方式中， 每天施用四次以上的式 I化合物。 在一些实施方式中， 所述药物组合物施用 于哺乳动物。 在其它实施方式中， 所述哺乳动物是人。 在其它实施方式中， 所述药物组合物还包含药物载体、 赋形剂和 /或助剂。 在其它实施方式中， 所 述药物组合物还包含至少一种治疗剂。 Compound 31
Figure imgf000008_0001
In another embodiment of the present invention, there is provided a pharmaceutical composition comprising a therapeutically effective amount of a compound selected from Formula I or a pharmaceutically acceptable salt, solvate, prodrug thereof, stereoisomeric One or more of a conformation, tautomer, polymorph or metabolite, and at least one pharmaceutically acceptable excipient. The pharmaceutical compositions described herein include, but are not limited to, oral dosage forms, parenteral dosage forms, topical dosage forms, and rectal administration dosage forms, preferably oral dosage forms. In some embodiments, the oral dosage form of the pharmaceutical composition includes tablets, capsules, pills, powders, sustained release preparations, solutions and suspensions, and the like, and parenteral dosage forms include sterile solutions, suspensions or emulsions, Topical dosage forms include ointments, oils, lotions, gels, suspensions, solutions, lotions or creams, and rectal administration forms include suppositories and drops. In some embodiments, the pharmaceutical composition is in a unit dosage form suitable for single administration of precise dosages. In other embodiments, the amount of the compound of formula I is in the range of from about 0.001 mg/kg body weight/day to about 1000 mg/kg body weight/day. In other embodiments, the amount of the compound of formula I ranges from about 0.5 mg/kg body weight/day to about 50 mg/kg body weight/day. In some embodiments, the amount of the compound of Formula I is from about 0.001 g/day to about 7 g/day. In other embodiments, the amount of the compound of formula I is from about 0.002 g/day to about 6 g/day. In other embodiments, the amount of the compound of formula I is about 0.005 g/ Day ~ about 5 g / day. In other embodiments, the amount of the compound of formula I is from about 0.01 g/day to about 5 g/day. In other embodiments, the amount of the compound of formula I is from about 0.02 g/day to about 5 g/day. In other embodiments, the amount of the compound of formula I is from about 0.05 g/day to about 2.5 g/day. In other embodiments, the amount of the compound of formula I is from about 0.1 g/day to about 1 g/day. In other embodiments, a dose level below the lower limit of the above range may already be sufficient. In other embodiments, dose levels above the upper limit of the above range may be required. In some embodiments, the compound of formula I is administered in a single dose, once a day. In other embodiments, the compound of formula I is administered in multiple doses, more than once a day. In some embodiments, the compound of formula I is administered twice daily. In other embodiments, the compound of formula I is administered three times a day. In other embodiments, the compound of formula I is administered four times a day. In other embodiments, the compound of formula I is administered more than four times a day. In some embodiments, the pharmaceutical composition is administered to a mammal. In other embodiments, the mammal is a human. In other embodiments, the pharmaceutical composition further comprises a pharmaceutical carrier, excipient, and/or adjuvant. In other embodiments, the pharmaceutical composition further comprises at least one therapeutic agent.
在本发明的另一个实施方式中， 提供了式 I所示的化合物或其药学上可 接受的盐、 溶剂化物、 前体药物、 立体异构体、 互变异构体、 多晶型物或代 谢产物， 或包含上述活性物质的药物组合物在制备一种或多种蛋白激酶抑制 剂中的用途， 所述蛋白激酶选自 EGFR， VEGFR, HER-2 , HER-3 , HER-4, Bcr-Abl, c-Src, JAK3 , PDGFR, c-Kit, LCK, LYNA, FGR， EphB, ECK, FY , MAP4K, SIK, MST1， YES, ARG， BTK, HCK, BLK, ALK, PKC, NEK, MARK, FLT3， RET, FGFR， PDK和 Syk。  In another embodiment of the present invention, there is provided a compound of Formula I or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, tautomer, polymorph thereof or Use of a metabolite, or a pharmaceutical composition comprising the above active substance, in the preparation of one or more protein kinase inhibitors selected from the group consisting of EGFR, VEGFR, HER-2, HER-3, HER-4, Bcr -Abl, c-Src, JAK3, PDGFR, c-Kit, LCK, LYNA, FGR, EphB, ECK, FY, MAP4K, SIK, MST1, YES, ARG, BTK, HCK, BLK, ALK, PKC, NEK, MARK , FLT3, RET, FGFR, PDK and Syk.
在本发明的再一个实施方式中， 提供了式 I所示的化合物或其药学上可 接受的盐、 溶剂化物、 前体药物、 立体异构体、 互变异构体、 多晶型物或代 谢产物， 或包含上述活性物质的药物组合物在制备治疗或预防肿瘤的药物中 的用途。 优选地， 所述肿瘤选自白血病、 胃肠间质瘤、 组织细胞性淋巴瘤、 非小细胞肺癌、 小细胞肺癌、 胰腺癌、 肺鳞癌、 肺腺癌、 乳腺癌、 前列腺癌、 肝癌、 皮肤癌、 上皮细胞癌、 宫颈癌、 卵巢癌、 肠癌、 鼻咽癌、 脑癌、 骨癌、 食道癌、 黑色素瘤、 肾癌、 口腔癌等中的任一种。  In still another embodiment of the present invention, there is provided a compound of Formula I or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, tautomer, polymorph thereof or Use of a metabolite, or a pharmaceutical composition comprising the above active substance, for the manufacture of a medicament for treating or preventing a tumor. Preferably, the tumor is selected from the group consisting of leukemia, gastrointestinal stromal tumor, histiocytic lymphoma, non-small cell lung cancer, small cell lung cancer, pancreatic cancer, lung squamous cell carcinoma, lung adenocarcinoma, breast cancer, prostate cancer, liver cancer, Any of skin cancer, epithelial cell carcinoma, cervical cancer, ovarian cancer, intestinal cancer, nasopharyngeal cancer, brain cancer, bone cancer, esophageal cancer, melanoma, renal cancer, oral cancer, and the like.
再一方面， 本发明提供一种调节蛋白激活酶活性的方法， 其中包括将所 述蛋白激酶与上述化合物或其药学上可接受的盐、立体异构体、互变异构体、 多晶型物、 溶剂化物、 前药或代谢产物， 或包含上述活性物质的药物组合物 接触。 该方法可以用于体内， 也可用于体外。 优选地， 所述蛋白激酶选自 EGFR, VEGFR, HER-2, HER-3 , HER-4, Bcr-Abl, c-Src, JAK3 , PDGFR, c-Kit, LCK, LY A, FGR， EphB , ECK, FY , MAP4K, SIK, MST1 , YES, ARG， BTK, HCK, BLK, ALK, PKC, NEK, MARK, FLT3， RET, FGFR， PDK, Syk中至少之一。 In still another aspect, the present invention provides a method for modulating a protein activating enzyme activity, which comprises the protein kinase and the above compound or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph thereof The substance, solvate, prodrug or metabolite, or pharmaceutical composition comprising the above active substance is contacted. This method can be used in vivo as well as in vitro. Preferably, the protein kinase is selected from EGFR, VEGFR, HER-2, HER-3, HER-4, Bcr-Abl, c-Src, JAK3, PDGFR, c-Kit, LCK, LY A, FGR, EphB, ECK, FY, MAP4K, SIK, MST1 At least one of YES, ARG, BTK, HCK, BLK, ALK, PKC, NEK, MARK, FLT3, RET, FGFR, PDK, Syk.
另一方面， 本发明涉及将本发明所述的化合物及其药学上可接受的盐、 溶剂化物、 前体药物、 立体异构体、 互变异构体、 多晶型物或代谢产物， 或 包含上述活性物质的药物组合物用于治疗或预防肿瘤的方法。 在一个实施方 式中， 所述方法包括将所述活性物质与需要治疗的哺乳动物接触的歩骤。 优 选地， 所述肿瘤包括但不仅限于白血病、 胃肠间质瘤、 组织细胞性淋巴瘤、 非小细胞肺癌、 小细胞肺癌、 胰腺癌、 肺鳞癌、 肺腺癌、 乳腺癌、 前列腺癌、 肝癌、 皮肤癌、 上皮细胞癌、 宫颈癌、 卵巢癌、 肠癌、 鼻咽癌、 脑癌、 骨癌、 食道癌、 黑色素瘤、 肾癌、 口腔癌等中的任一种。 具体实施方式 本发明的权利要求书特别陈述了本发明的特征。 在下文的发明详述中陈 述了利用本发明原理的示例性实施方式。 通过参考以下发明内容可更好地理 解本发明的特征和优点。  In another aspect, the invention relates to a compound of the invention and a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, tautomer, polymorph or metabolite thereof, or A pharmaceutical composition comprising the above active substance for use in a method of treating or preventing a tumor. In one embodiment, the method comprises the step of contacting the active substance with a mammal in need of treatment. Preferably, the tumor includes, but is not limited to, leukemia, gastrointestinal stromal tumor, histiocytic lymphoma, non-small cell lung cancer, small cell lung cancer, pancreatic cancer, lung squamous cell carcinoma, lung adenocarcinoma, breast cancer, prostate cancer, Any of liver cancer, skin cancer, epithelial cell carcinoma, cervical cancer, ovarian cancer, intestinal cancer, nasopharyngeal cancer, brain cancer, bone cancer, esophageal cancer, melanoma, renal cancer, oral cancer, and the like. DETAILED DESCRIPTION OF THE INVENTION The features of the present invention are particularly set forth in the claims of the present invention. Exemplary embodiments utilizing the principles of the present invention are set forth in the Detailed Description of the Invention. The features and advantages of the present invention are better understood by referring to the following description.
尽管本文描述了本发明的优选实施方式， 但是这些实施方式仅作为示例 提供。 应理解本文所述的本发明实施方式的变体也可用于实施本发明。 本领 域普通技术人员应理解， 可出现多种变体、 变化和替换而不脱离本发明的范 围。 应理解本发明各个方面的保护范围由权利要求书决定， 并且这些权利要 求范围内的方法和结构以及其等价的方法和结构均在本权利要求书涵盖的范 围之内。  Although preferred embodiments of the invention have been described herein, these embodiments are provided by way of example only. It will be appreciated that variations of the embodiments of the invention described herein may also be used in the practice of the invention. It will be appreciated by those skilled in the art that various modifications, changes and substitutions may be made without departing from the scope of the invention. It is to be understood that the scope of the invention is defined by the scope of the claims and the scope of the claims
本文所用的章节标题仅用于组织文章的目的， 而不应被解释为对所述主 题的限制。 本申请中引用的所有文献或文献部分包括但不限于专利、 专利申 请、 文章、 书籍、 操作手册和论文， 均通过引用方式整体并入本文。  The section headings used herein are for the purpose of organizing articles only and should not be construed as limiting the subject matter. All documents or parts of the literature cited in this application, including but not limited to patents, patent applications, articles, books, operating manuals and papers, are hereby incorporated by reference in their entirety.
某些化学术语  Certain chemical terms
除非另有定义， 否则本文所有科技术语具有的涵义与权利要求主题所属 领域技术人员通常理解的涵义相同。 除非另有说明， 本文全文引用的所有专 利、 专利申请、 公开材料通过引用方式整体并入本文。 应理解， 上述简述和下文的详述为示例性且仅用于解释， 而不对本发明 主题作任何限制。 在本申请中， 除非另有具体说明， 否则使用单数时也包括 复数。 还应注意， 除非另有说明， 否则所用"或"、 "或者 "表示 "和 /或"。 此外， 所用术语"包括"以及其它形式， 例如"包含"、 "含"和"含有"并非限制性。 Unless otherwise defined, all technical and scientific terms used herein have the same meaning meaning meaning All patents, patent applications, and publications cited herein are hereby incorporated by reference in their entirety herein in their entirety herein The above description and the following detailed description are to be considered as illustrative and not restrictive. In the present application, the use of the singular includes the plural unless otherwise specified. It should also be noted that "or", "or" is used to mean "and/or" unless otherwise indicated. In addition, the terms "comprising" and "comprises" and "comprising" and "comprising" and "comprising" are not limiting.
可在参考文献（包括 Carey and Sundberg "ADVANCED ORGANIC CHEMISTRY 4th ED. "Vols. A (2000) and B (2001), Plenum Press, New York)中 找到对标准化学术语的定义。 除非另有说明， 否则采用本领域技术范围内的 常规方法， 如质谱、 NMR、 IR和 UV/Vis光谱法和药理学方法。 除非提出具 体定义， 否则本文在分析化学、 有机合成化学以及药物和药物化学的有关描 述中采用的术语是本领域已知的。 可在化学合成、 化学分析、 药物制备、 制 剂和递送， 以及对患者的治疗中使用标准技术。 例如， 可利用厂商对试剂盒 的使用说明， 或者按照本领域公知的方式或本发明的说明来实施反应和进行 纯化。 通常可根据本说明书中引用和讨论的多个概要性和较具体的文献中的 描述， 按照本领域熟知的常规方法实施上述技术和方法。 在本说明书中， 可 由本领域技术人员选择基团及其取代基以提供稳定的结构部分和化合物。 The definition of standard chemical terms can be found in references (including Carey and Sundberg "ADVANCED ORGANIC CHEMISTRY 4 th ED. "Vols. A (2000) and B (2001), Plenum Press, New York). Conventional methods within the skill of the art, such as mass spectrometry, NMR, IR and UV/Vis spectroscopy and pharmacological methods, are employed unless otherwise indicated. Unless specifically defined, the terms used herein in relation to analytical chemistry, organic synthetic chemistry, and pharmaceutical and pharmaceutical chemistry are known in the art. Standard techniques can be used in chemical synthesis, chemical analysis, pharmaceutical preparation, formulation and delivery, and in the treatment of patients. For example, the manufacturer's instructions for use of the kit can be utilized, or the reaction can be carried out and purified according to methods well known in the art or as described in the present invention. The above techniques and methods can generally be carried out according to conventional methods well known in the art, as described in the various summaries and more specific references cited and discussed in this specification. In the present specification, a group and its substituents can be selected by those skilled in the art to provide stable structural moieties and compounds.
当通过从左向右书写的常规化学式描述取代基时， 该取代基也同样包括 从右向左书写结构式时所得到的在化学上等同的取代基。 举例而言， CH20 等同于 OC¾。 When a substituent is described by a conventional chemical formula written from left to right, the substituent also includes the chemically equivalent substituent obtained when the structural formula is written from right to left. For example, CH 2 0 is equivalent to OC3⁄4.
术语"任选 /任意"或"任选地 /任意地"是指随后描述的事件或情况可能发 生或可能不发生，该描述包括发生所述事件或情况和不发生所述事件或情况。 例如， 根据下文的定义， "任选取代的烷基"是指"未取代的烷基" (未被取代基 取代的烷基)或"取代的烷基" (被取代基取代的烷基)。  The term "optional / arbitrary" or "optionally / arbitrarily" means that the subsequently described event or circumstance may or may not occur, the description including the occurrence of the event or circumstance and the occurrence of the event or circumstance. For example, according to the definition below, "optionally substituted alkyl" means "unsubstituted alkyl" (alkyl substituted without a substituent) or "substituted alkyl" (alkyl substituted with a substituent) .
本文所用 Cl~Cn包括 C1~C2、 C1~C3、 ...... Cl~Cn (n为整数）。举例而 言， 所述" C1~C4"基团是指该部分中具有 1~4个碳原子， 即基团包含 1个碳 原子， 2个碳原子、 3个碳原子或 4个碳原子。 因此， 举例而言" C1~C4烷基" 是指具有 1~4个碳原子的烷基， 即所述烷基选自甲基、 乙基、 丙基、异丙基、 正丁基、 异丁基、 仲丁基和叔丁基。 本文中的数字范围， 例如" 1~10"是指给 定范围中的各个整数， 例如" 1~10个碳原子"是指该基团可具有 1个碳原子、 2个碳原子、 3个碳原子、 4个碳原子、 5个碳原子、 6个碳原子、 7个碳原子、 8个碳原子、 9个碳原子或 10个碳原子。  Cl~Cn used herein includes C1~C2, C1~C3, ... Cl~Cn (n is an integer). By way of example, the "C1~C4" group means that the moiety has from 1 to 4 carbon atoms, i.e., the group contains one carbon atom, two carbon atoms, three carbon atoms or four carbon atoms. Thus, for example, "C1~C4 alkyl" refers to an alkyl group having from 1 to 4 carbon atoms, that is, the alkyl group is selected from the group consisting of methyl, ethyl, propyl, isopropyl, n-butyl, iso Butyl, sec-butyl and tert-butyl. The numerical range in the text, for example "1~10" refers to each integer in a given range, for example "1~10 carbon atoms" means that the group may have 1 carbon atom, 2 carbon atoms, 3 Carbon atom, 4 carbon atoms, 5 carbon atoms, 6 carbon atoms, 7 carbon atoms, 8 carbon atoms, 9 carbon atoms or 10 carbon atoms.
本文单独或组合使用的术语 "羟基 "指 -OH。 本文单独或组合使用的术语"卤素"指氟、 氯、 溴或碘， 优选氟或氯。 本文单独或组合使用的术语 "氰基 "指 -CN。 The term "hydroxy" as used herein, alone or in combination, refers to -OH. The term "halogen" as used herein, alone or in combination, means fluoro, chloro, bromo or iodo, preferably fluoro or chloro. The term "cyano" as used herein, alone or in combination, refers to -CN.
本文单独或组合使用的术语 "氨基 "指 -NH2。 Alone or in combination herein, the term "amino" means -NH 2.
本文单独或组合使用的术语 "芳香基或芳基"是指任选取代的环状共轭芳 香烃基， 其具有 6〜约 20个或 6~14个或 6~10个成环碳原子， 可包括单环、 双环、三环或更多环。单环芳基的非限定性实例包括 6至约 12个、 6至约 10 个或 6至约 8个成环碳原子的单环芳基， 例如苯基。 化合物分子的其余部分 可通过单键与芳基环上的碳原子相连接。 当芳基被取代时， 取代基可以在任 何可使用的连接点上进行取代， 所述取代基优选为一个或多个以下基团： 烷 基、 烯基、 炔基、 烷氧基、 烷硫基、 烷基氨基、 ¾素、 硫醇、 羟基、 氰基、 环烷基、 杂环基、 芳基、 杂芳基、 环烷氧基、 环烷硫基、 杂环烷硫基、 羰基、 羧酸或羧酸酯。 就本发明的目的而言， 优选 6~10元单环或双环体系的芳基。  The term "aryl or aryl" as used herein, alone or in combination, means an optionally substituted cyclic conjugated aromatic hydrocarbon group having from 6 to about 20 or from 6 to 14 or from 6 to 10 ring-forming carbon atoms. Includes single, double, triple or more rings. Non-limiting examples of monocyclic aryl groups include from 6 to about 12, from 6 to about 10 or from 6 to about 8 monocyclic aryl groups of a ring-forming carbon atom, such as phenyl. The remainder of the compound molecule can be attached to the carbon atom on the aryl ring by a single bond. When an aryl group is substituted, the substituent may be substituted at any available point of attachment, preferably one or more of the following groups: alkyl, alkenyl, alkynyl, alkoxy, alkane Base, alkylamino, 3⁄4, thiol, hydroxy, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, cycloalkylthio, heterocycloalkylthio, carbonyl, Carboxylic acid or carboxylic acid ester. For the purposes of the present invention, a 6 to 10 membered monocyclic or bicyclic aryl group is preferred.
本文单独或组合使用的术语 "杂芳基或芳香杂环基"是指任选取代的由碳 原子和杂原子共同组成的共轭芳香性环系基团， 其包含约 5至约 20个或 5 至约 14个或 5至约 10个或 6至约 10个骨架成环原子 （或称为 5~20元环、 5~14元环、 5~10元环、 6~10元环）， 其中一个或多个 （如 1~6个、 1~4个、 1~3 个、 1~2个） 成环原子为杂原子， 所述杂原子独立地选自氧、 氮、 硫、 磷、 硅、 硒和锡中的杂原子， 但不限于此。 杂芳基包括单环和多环 （例如有 2、 3或 4个稠合环） 的体系。 任何在杂芳环里的成环氮原子可以被氧化而形 成氮氧成分。 在环中出现两个或更多杂原子的实施方式中， 所述两个或更多 杂原子可彼此相同， 或者所述两个或更多杂原子中的一些或全部彼此不同。 化合物分子的其余部分可通过单键与杂芳基环上的碳原子或杂原子相连接。 因此，举例而言，咪唑可通过其任意的碳原子 (咪唑 -2-基、咪唑 -4-基或咪唑 -5- 基:)或其氮原子 (咪唑 -1-基或咪唑 -3-基:)与母体分子相连。类似地， 可通过其任 意或全部碳原子和 /或任意或全部杂原子进一歩取代杂芳基基团。单环杂芳基 的非限定性实例包括 5至约 12个、 5至约 10个、 5至约 7个或 6个骨架成环 原子的单环杂芳基。 当杂芳基被取代时， 取代基可以在任何可使用的连接点 上进行取代， 所述取代基优选为一个或多个以下基团： 烷基、 烯基、 炔基、 烷氧基、 烷硫基、 烷基氨基、 ¾素、 硫醇、 羟基、 氰基、 环烷基、 杂环基、 芳基、 杂芳基、 环烷氧基、 环烷硫基、 杂环烷硫基、 羰基、 羧酸或羧酸酯。 就本发明的目的而言， 优选 6~10元且含有 1~2个选自 N、 S和 0的杂原子 的单环或双环体系的杂芳基。 The term "heteroaryl or aromatic heterocyclic" as used herein, alone or in combination, means an optionally substituted conjugated aromatic ring system consisting of a carbon atom and a hetero atom, which comprises from about 5 to about 20 or 5 to about 14 or 5 to about 10 or 6 to about 10 skeletons into ring atoms (or 5 to 20 membered rings, 5 to 14 membered rings, 5 to 10 membered rings, 6 to 10 membered rings), One or more (eg, 1 to 6, 1 to 4, 1 to 3, 1 to 2) ring-forming atoms are heteroatoms independently selected from the group consisting of oxygen, nitrogen, sulfur, phosphorus, Heteroatoms in silicon, selenium and tin, but are not limited thereto. Heteroaryl groups include monocyclic and polycyclic (eg, 2, 3 or 4 fused rings) systems. Any ring-forming nitrogen atom in the heteroaromatic ring can be oxidized to form a nitrogen oxide component. In embodiments in which two or more heteroatoms are present in the ring, the two or more heteroatoms may be identical to each other, or some or all of the two or more heteroatoms may be different from each other. The remainder of the compound molecule can be attached to the carbon or hetero atom on the heteroaryl ring by a single bond. Thus, for example, an imidazole may be passed through any of its carbon atoms (imidazol-2-yl, imidazol-4-yl or imidazol-5-yl:) or its nitrogen atom (imidazol-1-yl or imidazol-3-yl) :) Connected to the parent molecule. Similarly, a heteroaryl group can be substituted by any or all of its carbon atoms and/or any or all of the heteroatoms. Non-limiting examples of monocyclic heteroaryl groups include from 5 to about 12, from 5 to about 10, from 5 to about 7, or 6 monocyclic heteroaryl groups which are backbone-ringed. When a heteroaryl group is substituted, the substituent may be substituted at any available point of attachment, preferably one or more of the following groups: alkyl, alkenyl, alkynyl, alkoxy, alkane Thio group, alkylamino group, 3⁄4 element, thiol, hydroxy group, cyano group, cycloalkyl group, heterocyclic group, aryl group, heteroaryl group, cycloalkoxy group, cycloalkylthio group, heterocycloalkylthio group, carbonyl group , a carboxylic acid or a carboxylic acid ester. For the purpose of the present invention, a heteroaryl group of a monocyclic or bicyclic ring system of 6 to 10 members and containing 1 to 2 hetero atoms selected from N, S and 0 is preferred.
本文单独或组合使用的术语 "杂环基"是指任选取代的由碳原子和杂原子 共同组成的非芳香性环状基团， 包括饱和或部分不饱和的单环、 双环或多环 体系， 例如包括杂环烷基和杂环烯基。 其中一个或者多个 （如 1~4个、 1~3 个、 1~2个） 成环原子是杂原子， 如氧、 氮或硫原子， 并且氮或硫原子可任 选被氧化。 化合物分子的其余部分可通过单键与杂环基环上的杂原子或碳原 子相连接。 当杂环基被取代时， 取代基可以在任何可使用的连接点上进行取 代， 所述取代基优选为一个或多个以下基团： 烷基、 烯基、 炔基、 烷氧基、 烷硫基、 烷基氨基、 ¾素、 硫醇、 羟基、 氰基、 环烷基、 杂环基、 芳基、 杂 芳基、 环烷氧基、 环烷硫基、 杂环烷硫基、 羰基、 羧酸或羧酸酯。 就本发明 的目的而言，优选 4~7元且至少含有 1个氮原子的饱和、单环体系的杂环基。  The term "heterocyclyl" as used herein, alone or in combination, refers to an optionally substituted non-aromatic cyclic group consisting of a carbon atom and a hetero atom, including saturated or partially unsaturated monocyclic, bicyclic or polycyclic systems. Examples include heterocycloalkyl and heterocycloalkenyl groups. One or more of the ring-forming atoms (e.g., 1 to 4, 1 to 3, 1 to 2) are heteroatoms such as oxygen, nitrogen or sulfur atoms, and the nitrogen or sulfur atom may be optionally oxidized. The remainder of the compound molecule can be attached to the heteroatom or carbon atom on the heterocyclyl ring via a single bond. When a heterocyclic group is substituted, the substituent may be substituted at any available point of attachment, preferably one or more of the following groups: alkyl, alkenyl, alkynyl, alkoxy, alkane Thio group, alkylamino group, 3⁄4 element, thiol, hydroxy group, cyano group, cycloalkyl group, heterocyclic group, aryl group, heteroaryl group, cycloalkoxy group, cycloalkylthio group, heterocycloalkylthio group, carbonyl group , a carboxylic acid or a carboxylic acid ester. For the purpose of the present invention, a saturated, monocyclic heterocyclic group of 4 to 7 members and containing at least one nitrogen atom is preferred.
本文单独或组合使用的术语 "环烷基"是指任选取代的仅由碳原子和氢原 子组成的稳定的非芳香族烃基， 包括饱和或部分不饱和的单环、 双环或多环 体系。 化合物分子的其余部分可通过单键与环烷基环上的碳原子相连接。 当 环烷基被取代时， 取代基可以在任何可使用的连接点上进行取代， 所述取代 基优选为一个或多个以下基团： 烷基、 烯基、 炔基、 烷氧基、 烷硫基、 烷基 氨基、 卤素、 硫醇、 羟基、 氰基、 环烷基、 杂环基、 芳基、 杂芳基、 环烷氧 基、 环烷硫基、 杂环烷硫基、 羰基、 羧酸或羧酸酯。 就本发明的目的而言， 优选 3~6元单环体系的环烷基。  The term "cycloalkyl" as used herein, alone or in combination, refers to an optionally substituted stable non-aromatic hydrocarbon group consisting solely of carbon atoms and hydrogen atoms, including saturated or partially unsaturated monocyclic, bicyclic or polycyclic systems. The remainder of the compound molecule can be attached to the carbon atom on the cycloalkyl ring by a single bond. When a cycloalkyl group is substituted, the substituent may be substituted at any available point of attachment, preferably one or more of the following groups: alkyl, alkenyl, alkynyl, alkoxy, alkane Thio group, alkylamino group, halogen, thiol, hydroxy group, cyano group, cycloalkyl group, heterocyclic group, aryl group, heteroaryl group, cycloalkoxy group, cycloalkylthio group, heterocycloalkylthio group, carbonyl group, Carboxylic acid or carboxylic acid ester. For the purposes of the present invention, a cycloalkyl group of a 3 to 6 membered monocyclic system is preferred.
某些药学术语  Certain pharmacy terms
某些药学术语本文所用的有关术语"受试者"、 "患者 "或"个体"是指患有 疾病、 病症或病况等的个体， 包括哺乳动物和非哺乳动物。 哺乳动物的实例 包括但不限于哺乳动物纲的任何成员： 人， 非人的灵长类动物 (例如黑猩猩和 其它猿类和猴)； 家畜， 例如牛、 马、 绵羊、 山羊、 猪； 家养动物， 例如兔、 狗和猫； 实验室动物， 包括啮齿类动物， 例如大鼠、 小鼠和豚鼠等。 非人哺 乳动物的实例包括但不限于鸟类和鱼类等。 在本文提供的一个有关方法和组 合物的实施方式中， 所述哺乳动物为人。  Certain pharmacy terms as used herein with respect to the terms "subject," "patient," or "individual" refers to an individual having a disease, disorder, condition, or the like, including mammals and non-mammals. Examples of mammals include, but are not limited to, any member of the mammalian class: humans, non-human primates (eg, chimpanzees and other mites and monkeys); livestock, such as cattle, horses, sheep, goats, pigs; domestic animals For example, rabbits, dogs and cats; laboratory animals, including rodents such as rats, mice and guinea pigs. Examples of non-human mammals include, but are not limited to, birds and fish. In one embodiment of the methods and compositions provided herein, the mammal is a human.
本文所用的术语"治疗"和其它类似的同义词包括缓解、 减轻或改善疾病 或病症症状， 预防其它症状， 改善或预防导致症状的潜在代谢原因， 抑制疾 病或病症， 例如阻止疾病或病症的发展， 缓解疾病或病症， 使疾病或病症好 转， 缓解由疾病或病症导致的症状， 或者中止疾病或病症的症状， 此外， 该 术语包含预防的目的。 该术语还包括获得治疗效果和 /或预防效果。所述治疗 效果是指治愈或改善所治疗的潜在疾病。 此外， 对与潜在疾病相关的一种或 多种生理症状的治愈或改善也是治疗效果， 例如尽管患者可能仍然受到潜在 疾病的影响， 但观察到患者情况改善。 就预防效果而言， 可向具有患特定疾 病风险的患者施用所述组合物， 或者即便尚未做出疾病诊断， 但向出现该疾 病的一个或多个生理症状的患者施用所述组合物。 The term "treatment" and other similar synonyms as used herein includes alleviating, alleviating or ameliorating the symptoms of a disease or condition, preventing other symptoms, ameliorating or preventing a potential metabolic cause of the symptoms, inhibiting the disease or condition, such as preventing the progression of the disease or condition, Relieve a disease or condition, make a disease or condition good Turning, alleviating the symptoms caused by a disease or condition, or stopping the symptoms of a disease or condition. In addition, the term includes the purpose of prevention. The term also includes obtaining a therapeutic effect and/or a preventive effect. The therapeutic effect refers to curing or ameliorating the underlying disease to be treated. In addition, the healing or amelioration of one or more physiological symptoms associated with a underlying disease is also a therapeutic effect, for example, although the patient may still be affected by the underlying disease, an improvement in the patient's condition is observed. In terms of prophylactic effect, the composition can be administered to a patient at risk of developing a particular disease, or the composition can be administered to a patient who develops one or more physiological symptoms of the disease, even if a diagnosis of the disease has not been made.
本文所使用术语"有效量"、 "治疗有效量 "或"药学有效量"是指服用后足 以在某种程度上缓解所治疗的疾病或病症的一个或多个症状的至少一种药剂 或化合物的量。 其结果可以为迹象、 症状或病因的消减和 /或缓解， 或生物系 统的任何其它所需变化。 例如， 用于治疗的"有效量 "是在临床上提供显著的 病症缓解效果所需的包含本文公开化合物的组合物的量。 可使用诸如剂量递 增试验的技术测定适合于任意个体病例中的有效量。  The term "effective amount," "therapeutically effective amount," or "pharmaceutically effective amount," as used herein, refers to at least one agent or compound that, after administration, is sufficient to alleviate one or more symptoms of the disease or condition being treated to some extent. The amount. The result can be the reduction and/or alleviation of signs, symptoms or causes, or any other desired changes in the biological system. For example, an "effective amount" for treatment is an amount of a composition comprising a compound disclosed herein that is required to provide a significant conditional relief effect in the clinic. An effective amount suitable for any individual case can be determined using techniques such as dose escalation assays.
本文所用术语 "服用"、 "施用"、 "给药 "等是指能够将化合物或组合物递 送到进行生物作用的所需位点的方法。 这些方法包括但不限于口服途径、 经 十二指肠途径、 胃肠外注射 (包括静脉内、 皮下、 腹膜内、 肌内、 动脉内注射 或输注：)、外用和经直肠给药。本领域技术人员熟知可用于本文所述化合物和 方法的施用技术， 例如在 Goodman and Gilman, The Pharmacological Basis of Therapeutics, current ed.; Pergamon; and Remington's, Pharmaceutical Sciences (current edition), Mack Publishing Co., Easton, Pa 中讨论的那些。 在优选的实 施方式中， 本文讨论的化合物和组合物通过口服施用。  The terms "administering," "administering," "administering," and the like, as used herein, refer to a method of delivering a compound or composition to a desired site for biological action. These methods include, but are not limited to, oral routes, duodenal routes, parenteral injections (including intravenous, subcutaneous, intraperitoneal, intramuscular, intraarterial injection or infusion:), topical and rectal administration. The techniques of administration of the compounds and methods described herein are well known to those skilled in the art, for example, in Goodman and Gilman, The Pharmacological Basis of Therapeutics, current ed.; Pergamon; and Remington's, Pharmaceutical Sciences (current edition), Mack Publishing Co., Those discussed in Easton, Pa. In a preferred embodiment, the compounds and compositions discussed herein are administered orally.
本文针对制剂、 组合物或成分所用术语"可接受的"是指对接受治疗的受 试者的一般健康情况没有长期的有害影响。  The term "acceptable" as used herein with respect to a formulation, composition or ingredient means that there is no long-term detrimental effect on the general health of the subject being treated.
本文所用术语 "药学上可接受的"是指不影响本发明化合物的生物活性或 性质的物质 (如载体、 赋形剂和 /或助剂：)， 并且相对无毒， 即该物质可施用于 个体而不造成不良的生物反应或以不良方式与组合物中包含的任意组分相互 作用。  The term "pharmaceutically acceptable" as used herein, refers to a substance (eg, carrier, excipient, and/or adjuvant) that does not affect the biological activity or properties of the compound of the invention, and is relatively non-toxic, ie, the substance can be administered to The individual does not cause an adverse biological reaction or interacts in an undesirable manner with any of the components contained in the composition.
本文所用术语 "药物组合物 "是指任选地混合有至少一种药学上可接受的 化学成分的生物活性化合物， 所述药学上可接受的化学成分包括但不限于载 体、 赋形剂和 /或助剂， 如稳定剂、 稀释剂、 分散剂、 悬浮剂、 增稠剂等。 本文所用术语 "载体 "是指相对无毒的化学化合物或试剂， 其有助于将化 合物引入到细胞或组织中。 The term "pharmaceutical composition" as used herein, refers to a biologically active compound, optionally in admixture with at least one pharmaceutically acceptable chemical component, including but not limited to carriers, excipients and/or Or additives, such as stabilizers, diluents, dispersants, suspending agents, thickeners, and the like. The term "carrier," as used herein, refers to a relatively non-toxic chemical compound or agent that facilitates the introduction of a compound into a cell or tissue.
本文所用术语 "药学上可接受的盐 "是指保留了指定化合物的游离酸和游 离碱的生物效力， 并且在生物学或其它方面上没有不良作用的盐。 本发明化 合物还包括药学上可以接受的盐。 药学上可接受的盐是指把母体化合物中的 碱基基团转换成盐的形式。 药学上可接受的盐包括， 但不仅限于， 碱基基团 例如胺 （氨） 基的无机或有机酸盐类。 本发明药学上可接受的盐可以由母体 化合物合成， 即母体化合物中的碱性基团与 1-4当量的酸在一个溶剂系统中 反应。 合适的盐歹 Li举在 Remingtong's Pharmaceutical Scicences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418禾口 Journal of Pharmaceutical Science, 66, 2(1977)中。 药学上可接受的酸加成盐可以由无机和有机酸制备。 由衍生酸加成盐的无机酸包括盐酸、 氢溴酸、 硫酸、 硝酸、 磷酸等。 由衍生 酸加成盐的有机酸包括乙酸、 丙酸、 乙醇酸、 丙酮酸、 草酸、 苹果酸、 丙二 酸、 琥珀酸、 马来酸、 富马酸、 酒石酸、 柠檬酸、 苯甲酸、 肉桂酸、 扁桃酸、 甲磺酸、 乙磺酸、 对甲苯磺酸、 水杨酸等。 The term "pharmaceutically acceptable salt" as used herein, refers to a salt which retains the biological effectiveness of the free acid and free base of the specified compound and which has no adverse effects biologically or otherwise. The compounds of the invention also include pharmaceutically acceptable salts. A pharmaceutically acceptable salt refers to a form in which a base group in a parent compound is converted into a salt. Pharmaceutically acceptable salts include, but are not limited to, base or inorganic or organic acid salts of amine (amino) groups. The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound, i.e., the basic group in the parent compound is reacted with from 1 to 4 equivalents of acid in a solvent system. Suitable salts of Li held in bad Remingtong's Pharmaceutical Scicences, 17 th ed ., Mack Publishing Company, Easton, Pa., 1985, p. 1418 Hekou Journal of Pharmaceutical Science, 66, 2 (1977) in. Pharmaceutically acceptable acid addition salts can be prepared from inorganic and organic acids. The inorganic acid derived from the derivatized acid includes hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Organic acids derived from derivatized acid include acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, and cinnamon. Acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like.
本文所用术语 "溶剂化物"是指通过溶剂化作用形成的本发明化合物与溶 剂分子的组合。 在某些情况下， 溶剂化物指水合物， 即溶剂分子为水分子。  The term "solvate" as used herein refers to a combination of a compound of the invention and a solvent molecule formed by solvation. In some cases, a solvate refers to a hydrate, that is, a solvent molecule is a water molecule.
本文所用术语 "立体异构体 "是指由相同原子组成， 通过相同的键键合， 但具有不同三维结构的化合物。 本发明所述的式 I化合物涵盖各种可能的旋 光异构体、 顺反异构体及其混合物。  The term "stereoisomer" as used herein, refers to a compound composed of the same atoms, bonded by the same bond, but having a different three-dimensional structure. The compounds of formula I according to the invention encompass various possible optical isomers, cis and trans isomers and mixtures thereof.
本文所用术语 "互变异构体 "是指质子从分子的一个原子转移至相同分子 的另一个原子而形成的异构体。 本发明所述的式 I化合物涵盖各种可能的互 变异构体及其混合物。  The term "tautomer" as used herein refers to an isomer formed by the transfer of a proton from one atom of a molecule to another atom of the same molecule. The compounds of formula I described herein encompass a wide variety of possible tautomers and mixtures thereof.
本文所用术语 "多晶型物"或"多晶形"是指以不同的晶格形式存在的本发 明化合物。  The term "polymorph" or "polymorph" as used herein, refers to a compound of the invention that exists in a different lattice form.
本文所使用术语"前体药物或前药"是指本发明化合物的任何药学上可接 受的盐、 酯、 酯的盐或其它衍生物， 其在向受体施用后能够直接或间接地提 供本发明的化合物或其具有药学活性的代谢物或残基。 特别优选的衍生物或 前药是在施用于患者时可以提高本发明化合物生物利用度的那些化合物 (例 如， 可以使口服的化合物更易于被吸收到血液中：)， 或者促进母体化合物向生 物器官或作用位点 (例如脑部或淋巴系统:)递送的那些化合物。 本文所述化合 物的前体药物包括但不限于酯、 碳酸盐、 硫代碳酸盐、 N-酰基衍生物、 N-酰 氧基烷基衍生物、 叔胺的季铵化衍生物、 N-曼尼奇碱 (N-Mannich bases), 锡 夫氏碱 (Schiff base：)、 氨基酸结合物、 磷酸酯、 金属盐和磺酸酯。 各种前药形 式是本领域熟知的。参见，例如 of Prodrugs, Bundgaard, A. Ed., Elseview, 1985 and Method in Enzymology, Widder, K. et al., Ed.; Academic, 1985, vol. 42, p. 309-396; Bundgaard, H. "Design and Application of Prodrugs" m A Textbook of Drug Design and Development, Krosgaard-Larsen and H. Bundgaard, Ed., 1991, 第五章，113-191 页；以及 Bundgaard, H. , Advanced Drug Delivery Review, 1992, 8, 1-38， 以上文献通过引用并入本文。 本文所述前体药物包括但不限于以下 组中的物质和这些物质的组合： 胺衍生的前药； 羟基前药包括但不限于酰氧 基烷基酯、 烷氧羰基氧烷基酯、 烷基酯、 芳基酯和含有二硫化键的酯。 The term "prodrug or prodrug" as used herein, refers to any pharmaceutically acceptable salt, ester, ester salt or other derivative of a compound of the invention which is capable of providing the product directly or indirectly after administration to a recipient. A compound of the invention or a pharmaceutically active metabolite or residue thereof. Particularly preferred derivatives or prodrugs are those compounds which, when administered to a patient, increase the bioavailability of the compounds of the invention (for example, may render the orally administered compound more readily absorbed into the blood:) or promote the parent compound to the biological organ Or those compounds that are delivered at a site of action (eg, brain or lymphatic system:). Compounding described herein Prodrugs of the substance include, but are not limited to, esters, carbonates, thiocarbonates, N-acyl derivatives, N-acyloxyalkyl derivatives, quaternized derivatives of tertiary amines, N-Manny N-Mannich bases, Schiff base:, amino acid conjugates, phosphates, metal salts and sulfonates. Various prodrug forms are well known in the art. See, for example, Prodrugs, Bundgaard, A. Ed., Elseview, 1985 and Method in Enzymology, Widder, K. et al., Ed.; Academic, 1985, vol. 42, p. 309-396; Bundgaard, H. "Design and Application of Prodrugs" m A Textbook of Drug Design and Development, Krosgaard-Larsen and H. Bundgaard, Ed., 1991, Chapter 5, pages 113-191; and Bundgaard, H., Advanced Drug Delivery Review, 1992 8, 8, 1-38, the above references are incorporated herein by reference. Prodrugs as described herein include, but are not limited to, the materials of the following groups and combinations of these: amine-derived prodrugs; hydroxy prodrugs include, but are not limited to, acyloxyalkyl esters, alkoxycarbonyl oxyalkyl esters, alkanes A base ester, an aryl ester, and an ester containing a disulfide bond.
本文所使用术语"药物组合"、 "施用其它治疗"、 "施用其它治疗剂"等是 指通过混合或组合不止一种活性成分而获得的药物治疗， 其包括活性成分的 固定和不固定组合。 术语"固定组合"是指以单个实体或单个剂型的形式向患 者同时施用至少一种本文所述的化合物和至少一种协同药剂。术语"不固定组 合"是指以单独实体的形式向患者同时施用、合用或以可变的间隔时间顺次施 用至少一种本文所述的化合物和至少一种协同制剂， 其中此类施用在患者体 内提供有效水平的两种或多种化合物。 这些也应用到鸡尾酒疗法中， 例如施 用三种或更多种活性成分。  The terms "pharmaceutical combination", "administering other treatments", "administering other therapeutic agents" and the like, as used herein, refer to pharmaceutical treatments obtained by mixing or combining more than one active ingredient, including fixed and unfixed combinations of the active ingredients. The term "fixed combination" refers to the simultaneous administration of at least one compound described herein and at least one synergistic agent to a patient in the form of a single entity or a single dosage form. The term "unfixed combination" refers to the simultaneous administration, combination or sequential administration of at least one compound described herein and at least one synergistic formulation to a patient in the form of separate entities, wherein such administration is in a patient An effective level of two or more compounds is provided in the body. These are also applied to cocktail therapy, such as the administration of three or more active ingredients.
本文所用术语"联合施用"、 "与 ......组合施用"和其同义词等是指向同一 患者施用所选的治疗剂， 并旨在涵盖通过相同或不同的给药途径或相同或不 同的给药次数来施用药剂的治疗策略。 在一些实施方式中， 将本文所述的化 合物与其它药剂联合施用。 这些术语涵盖向动物施用两种或更多药剂以使动 物体内同时存在所述药剂和 /或其代谢物。这些术语包括同时施用不同的组合 物， 不同时间施用不同的组合物和 /或施用含有不同活性成分的一种组合物。 因此， 在一些实施方式中， 将本发明的化合物和其它药剂混合在一种组合物 中施用。  The terms "administered in combination," "administered in combination with," and the like, and the like, are intended to mean the administration of a selected therapeutic agent to the same patient, and are intended to encompass the same or different routes of administration or the same or different. The number of doses to administer the therapeutic strategy of the agent. In some embodiments, the compounds described herein are administered in combination with other agents. These terms encompass the administration of two or more agents to an animal to allow the simultaneous presence of the agent and/or its metabolite within the animal. These terms include the simultaneous administration of different compositions, the administration of different compositions at different times and/or the application of a composition containing different active ingredients. Thus, in some embodiments, a compound of the invention and other agents are administered in a combination.
本文所用术语 "代谢物或代谢产物 "是指在化合物代谢时形成的该化合物 的衍生物。  The term "metabolite or metabolite" as used herein refers to a derivative of the compound formed upon metabolism of the compound.
本文所用术语 "代谢 "是指生物体转化特定物质的所有过程 (包括但不限 于水解反应和酶催化反应：)。因此，酶可使化合物产生特异的结构变化。例如， 细胞色素 P450催化多种氧化还原反应， 而尿苷二磷酸葡萄糖醛酸基转移酶 催化活化的葡萄糖醛酸分子向芳香醇、 脂肪醇、 羧酸、 胺和游离巯基基团的 转移。 关于代谢的更多信息可参见 The Pharmacological Basis of Therapeutics, 9th Edition, McGraw-Hill (1996)。 The term "metabolism" as used herein refers to all processes by which an organism converts a particular substance (including but not limited to hydrolysis and enzymatic reactions:). Thus, the enzyme can cause specific structural changes in the compound. E.g, Cytochrome P450 catalyzes a variety of redox reactions, while uridine diphosphate glucuronyl transferase catalyzes the transfer of activated glucuronic acid molecules to aromatic alcohols, fatty alcohols, carboxylic acids, amines, and free sulfhydryl groups. Further information on metabolism can be found in The Pharmacological Basis of Therapeutics, 9th Edition, McGraw-Hill (1996).
本发明实施例化合物及其中间体的合成方法  Method for synthesizing compound of the embodiment of the invention and intermediate thereof
本发明通式（I)所示的化合物可以通过包括化学领域众所周知的方法来 合成， 尤其根据本发明所述的方法来合成。 原料可以从商业来源获得， 或者 使用本领域技术人员熟知的方法制备。  The compound of the formula (I) of the present invention can be synthesized by a method well known in the chemical art, in particular, according to the method of the present invention. The starting materials can be obtained from commercial sources or prepared using methods well known to those skilled in the art.
例如， 本发明通式 （I) 所示的化合物可以通过如下方法制备：  For example, the compound of the formula (I) of the present invention can be produced by the following method:
方法一：  method one:
Figure imgf000017_0001
Figure imgf000017_0001
原料 ( 1 ) 可以参照文献 (J. Med. Chem., 2006,49,7868-7876) 的方法合 成得到， 然后经过 Suzuki反应， 或者 Sonogashira反应， 或者 Stille反应等过 渡金属催化的偶联反应 （Coupling reaction) 获得化合物 （2)， 其中 Lm为 →6-^- (R6、 L3如前所定义）； 化合物 （2 ) 可任选在甲醇、 乙醇、 二氯甲 烷、 四氢呋喃或乙酸乙酯等不同溶剂中与不同的胺 （R2-NH-R3， R2及 R3如 前所定义） 进行还原氨化反应生成式 （1)。 根据在还原氨化反应过程中是否 需要向化合物分子引入氘原子， 还原剂可以分别为硼氢化钠或者硼氘化钠或 者氰基硼氢化钠等。 当式 （I) 中不含有氘 、子时， 式 （I) 为中间产物， 可 通过还原氨化反应进一歩向式 （I) 中的 引入氘原子而生成目标化合物； 当式 （I) 中含有氘原子时， 式 （p 既可作为目标化合物， 也可作为中间产 物通过还原氨化反应进一歩向 R2引入氘原子而生成其他目标化合物。 The starting material (1) can be synthesized by a method described in the literature (J. Med. Chem., 2006, 49, 7868-7876), and then subjected to a transition metal-catalyzed coupling reaction such as a Suzuki reaction, a Sonogashira reaction, or a Stille reaction (Coupling). The compound (2) is obtained, wherein Lm is → 6 -^- (R 6 , L 3 are as defined above); the compound (2) may optionally be in methanol, ethanol, dichloromethane, tetrahydrofuran or ethyl acetate. Different amines in different solvents (R 2 -NH-R 3 , R 2 and R 3 As defined previously) Reductive amination is carried out to form formula (1). According to whether it is necessary to introduce a ruthenium atom into the compound molecule during the reductive amination reaction, the reducing agent may be sodium borohydride or sodium borohydride or sodium cyanoborohydride, respectively. When the formula (I) does not contain ruthenium, the formula (I) is an intermediate product, and the target compound can be produced by the reductive amination reaction into the ruthenium atom of the formula (I); when the formula (I) When a ruthenium atom is contained, the formula (p can be used as a target compound or as an intermediate product to introduce a ruthenium atom into R2 by a reductive amination reaction to form another target compound.
或者， 原料 （1 ) 经过 Suzuki反应， 或者 Sonogashira反应， 或者 Stille 反应等过渡金属催化的偶联反应获得化合物 （3 )， 其中 n为 1或 2， Lm为
Figure imgf000018_0001
c≡C— 或卜 R6- (L2, L3和 R6如前所定义）， 氘原子可 通过在偶联反应中使用氘代原料或试剂而直接引入； 化合物（3 )中的羟基官 能团经过传统的官能团转化反应，转化成含甲磺酸酯、卤素等离去基团（LG， Leaving group) 的化合物 （4); 化合物 （4) 与不同的胺 （R2-NH-R3， R2及 R3如前所定义） 在碱性条件下发生取代反应， 获得式 （11)。 当式 （II) 中不 含有氘 、子时， 式 （Π) 为中间产物， 可通过还原氨化反应进一歩向式 （II) 中的 R2引入氘原子而生成目标化合物； 当式（Π) 中含有氘原子时， 式（Π) 既可作为目标化合物， 也可作为中间产物通过还原氨化反应进一歩向 R2引 入氘原子而生成其他目标化合物。 Alternatively, the starting material (1) is subjected to a Suzuki reaction, or a Sonogashira reaction, or a transition metal-catalyzed coupling reaction such as a Stille reaction to obtain a compound (3), wherein n is 1 or 2, and Lm is
Figure imgf000018_0001
c≡C— or R 6 — (L 2 , L 3 and R 6 are as defined above), which may be directly introduced by using a deuterated starting material or reagent in the coupling reaction; a hydroxyl group in the compound (3) The functional group is converted into a compound (4) containing a mesylate, a halogen or the like leaving group (LG, Leaving group) by a conventional functional group conversion reaction; a compound (4) and a different amine (R 2 -NH-R 3 ) , R 2 and R 3 are as defined above. Substitution reaction occurs under basic conditions to obtain the formula (11). When the formula (II) does not contain ruthenium, the formula (Π) is an intermediate product, and the target compound can be formed by introducing a ruthenium atom into the R 2 in the formula (II) by a reductive amination reaction; When a ruthenium atom is contained, the formula (Π) can be used as a target compound or as an intermediate product to introduce a ruthenium atom into R2 by a reductive amination reaction to form another target compound.
Figure imgf000018_0002
Figure imgf000018_0002
原料（5 )可以参照文献（WO2004075898Al,US2007208164Al, Tetrahedron Letters, 50(14), 1600-1602; 2009) 的方法合成得到， 然后经过与试剂 Y LG发 生取代反应得到化合物 （6)， 其中 Y为卤素、 磺酸酯等离去基团， m如前所 定义； 化合物 （6) 与不同的芳香胺 （ArN¾， 其中 Ar如前所定义） 发生取 代反应得到化合物 （7) ; 化合物 （7 ) 在碱性条件下与不同的胺 （R2-NH-R3， R2及 R3如前所定义） 可任选在 N， N-二甲基甲酰胺、 乙腈、 二氯甲烷、 N- 甲基吡咯烷酮、 四氢呋喃或乙酸乙酯等不同溶剂中取代反应得到中间产物式The starting material (5) can be synthesized by a method described in the literature (WO2004075898 Al, US2007208164 Al, Tetrahedron Letters, 50(14), 1600-1602; 2009), and then subjected to a substitution reaction with the reagent Y LG to obtain a compound (6) wherein Y is a halogen. , a sulfonate, etc. leaving group, m as defined above; compound (6) is substituted with a different aromatic amine (ArN3⁄4, wherein Ar is as defined above) to give compound (7); compound (7) in base Under different conditions, different amines (R 2 -NH-R 3 , R 2 and R 3 as defined above) may optionally be used in N, N-dimethylformamide, acetonitrile, dichloromethane, N- Substitution reaction in different solvents such as methylpyrrolidone, tetrahydrofuran or ethyl acetate to give an intermediate product
(111)。 (111).
还可以使原料（5 )与二羟基化合物发生 Mitsunobu反应获得（8)， 其中 m如前所定义； 化合物（8 )与不同的芳香胺（ArN¾， 其中 Ar如前所定义） 发生取代反应得到化合物（9); 化合物（9)的羟基进行简单官能团转化可获 得含有卤素、 甲磺酸酯等离去基团 （LG) 的化合物 （10) ; 化合物 （10) 在 碱性条件下与不同的胺 （R2-NH-R3， R2及 R3如前所定义） 在任选 N， N-二 甲基甲酰胺、 乙腈、 二氯甲烷、 N-甲基吡咯烷酮、 四氢呋喃或乙酸乙酯等不 同溶剂中反应得到中间产物式 （111)。 It is also possible to carry out the Mitsunobu reaction of the starting material (5) with the dihydroxy compound to obtain (8), wherein m is as defined above; the compound (8) is substituted with a different aromatic amine (ArN3⁄4, wherein Ar is as defined above) to give a compound (9); a simple functional group conversion of a hydroxyl group of the compound (9) to obtain a compound (10) containing a leaving group (LG) such as a halogen or a mesylate; the compound (10) and a different amine under basic conditions (R 2 -NH-R 3 , R 2 and R 3 are as defined above), optionally N,N-dimethylformamide, acetonitrile, dichloromethane, N-methylpyrrolidone, tetrahydrofuran or ethyl acetate Reaction in a different solvent gives the intermediate product of formula (111).
当用上述两种合成方法得到的、 作为中间产物的式 （1)、 (II) 或 （III) 中的 R2、 R3里至少有一个为 H， 或者 R2、 R3和与它们相连的 N原子共同围 成含氮杂环基且该氮杂环基中含有其他伯胺基团或仲胺基团时， 本身（当 R2、 R3里至少有一个为 H) 或者其上含有的伯胺基团或仲胺基团 （当 R2、 R3和与它们相连的 N原子共同围成含氮杂环基时）可以进一歩发生还原氨化 (与醛或酮反应） 或者取代反应进行衍生化引入取代基团。 当发生还原氨化 反应时， 还原剂可以分别为硼氢化钠或者硼氘化钠或者氰基硼氢化钠等， 醛 或者酮可以为甲醛、 乙醛、 丙酮等脂肪醛或酮， 或者是氘代甲醛、 氘代乙醛 等含氘原子的脂肪醛或酮等， 可根据同一碳上氢原子被氘代的数目对上述还 原剂 （含有或不含有氘原子） 及脂肪醛或酮 （含有或不含有氘原子） 进行选 择与组合使用。 When at least one of R 2 and R 3 in the formula (1), (II) or (III) obtained by the above two synthesis methods as an intermediate product is H, or R 2 , R 3 and are attached thereto When the N atoms together form a nitrogen-containing heterocyclic group and the other nitrogen-containing heterocyclic group contains a primary or secondary amine group, itself (when at least one of R 2 and R 3 is H) or contains a primary or secondary amine group (when R 2 , R 3 and the N atom to which they are attached together form a nitrogen-containing heterocyclic group) can undergo reductive amination (reaction with an aldehyde or a ketone) or a substitution The reaction is derivatized to introduce a substituent group. When the reductive amination reaction occurs, the reducing agent may be sodium borohydride or sodium borohydride or sodium cyanoborohydride, etc. The aldehyde or ketone may be a fatty aldehyde or ketone such as formaldehyde, acetaldehyde or acetone, or may be deuterated. a fatty aldehyde or a ketone containing a halogen atom such as formaldehyde or deuterated acetaldehyde. The reducing agent (with or without a ruthenium atom) and the fatty aldehyde or ketone (with or without) may be substituted according to the number of hydrogen atoms on the same carbon. Contains helium atoms) for selection and combination.
本发明化合物及中间体的合成实施例  Synthesis Examples of Compounds and Intermediates of the Invention
化合物的结构是通过核磁共振 ^H-NMR) 和 /或液相色谱 -质谱联用仪 (LC-MS)来确定的。 ifi-NMR位移（δ) 以百万分之一（ppm)的单位给出。 ifi-NMR的测定是用 Bruker Avance-400MHz或 Varian-300MHz核磁仪，测定 溶剂为氘代甲醇 （CD3OD )、 氘代氯仿 （CDC13 )、 六氘代二甲基亚砜 (DMSO-d6)， 内标为四甲基硅烷 （TMS); LC-MS测定是用 Agilent公司的 6110 SQ液质联用仪 （SB, C18 50mmX4.6mm色谱柱）。 The structure of the compound is determined by nuclear magnetic resonance (H-NMR) and/or liquid chromatography-mass spectrometry (LC-MS). The ifi-NMR shift (δ) is given in parts per million (ppm). The ifi-NMR was measured using a Bruker Avance-400 MHz or Varian-300 MHz NMR instrument, and the solvent was deuterated methanol (CD 3 OD ), deuterated chloroform (CDC1 3 ), hexamethylene dimethyl sulfoxide (DMSO-d6). ), the internal standard is tetramethylsilane (TMS); LC-MS is determined by Agilent's 6110 SQ LC/MS (SB, C18 50mmX 4.6mm column).
硅胶柱层析分离纯化采用 Biotage 公司的快速分离仪器 (Isolera One , SNAP Catridge KP-Sil, lOg-lOOg), 薄层层析制备板纯化采用青岛海洋化工的 GF254 (0.4mm-0.5mm)。 柱层析采用的洗脱剂体系包括： A: 二氯甲烷和甲 醇体系， B: 乙酸乙酯和石油醚体系， 溶剂的体积比根据化合物的极性不同 而调节， 也可以加入少量的氨水或者冰醋酸等试剂进行调节。 Separation and purification by silica gel column chromatography using Biotage's rapid separation instrument (Isolera One, SNAP Catridge KP-Sil, lOg-lOOg), and thin layer chromatography preparative plate purification was performed using GF254 (0.4mm-0.5mm) of Qingdao Ocean Chemical. The eluent system used for column chromatography includes: A: Dichloromethane and A Alcohol system, B: Ethyl acetate and petroleum ether system, the volume ratio of the solvent is adjusted according to the polarity of the compound, and may be adjusted by adding a small amount of ammonia or glacial acetic acid.
本发明所涉及的起始原料可以采用文献方法或按照本领域已知的方法来 合成，或者可以从 Acros Organics, J&K Chemicals, TCI, Sigma-Aldrich, Adamas 等试剂品牌供应商处购买。 本发明中如无特殊说明， 反应均指在氮气或氩 保护下进行。  The starting materials to which the present invention relates may be synthesized by literature methods or by methods known in the art, or may be purchased from suppliers of reagents such as Acros Organics, J&K Chemicals, TCI, Sigma-Aldrich, Adamas, and the like. Unless otherwise specified in the present invention, the reaction is carried out under the protection of nitrogen or argon.
中间体实施例  Intermediate example
中间体 1 : 4-(2,4-二氯 -5-甲氧基-苯氨基) -6-甲氧基 -7-(3-哌嗪 -1-基-丙 基) -喹啉 -3-甲氰  Intermediate 1: 4-(2,4-Dichloro-5-methoxy-phenylamino)-6-methoxy-7-(3-piperazin-1-yl-propyl)-quinoline-3 -Cyanine
Figure imgf000020_0001
Figure imgf000020_0001
第一歩： 4-氯 -7-(3-氯-丙氧基 )-6-甲氧基 -喹啉 -3-甲氰  First 歩: 4-chloro-7-(3-chloro-propoxy)-6-methoxy-quinoline-3-cyanocyanate
冰浴下将无水碳酸钾 (10.6 g, 6 eq)加入 4-氯 -7-羟基 -6-甲氧基喹啉 -3-甲氰 (3 g, 12.7 mmol)的 DMF溶液 (30 mL),搅拌半小时后，将 1-氯 -3-碘丙烷（13 g， 63.9 mmol)加入上述混悬液后室温下搅拌过夜。反应液用水稀释（500 mL)， 二氯甲烷萃取 （250 mLX2) ，合并有机相， 分别用水， 饱和食盐水洗涤， 无 水硫酸钠干燥， 过滤， 减压浓缩， 硅胶柱色谱法纯化得到 4-氯 -7-(3-氯 -丙氧 基) -6-甲氧基 -喹啉 -3-甲氰 （黄色固体， 3.1 g) ，收率 77%。  Anhydrous potassium carbonate (10.6 g, 6 eq) was added to a solution of 4-chloro-7-hydroxy-6-methoxyquinoline-3-carbonitrile (3 g, 12.7 mmol) in DMF (30 mL) After stirring for half an hour, 1-chloro-3-iodopropane (13 g, 63.9 mmol) was added to the above suspension and stirred at room temperature overnight. The reaction mixture is diluted with water (500 mL), EtOAc (EtOAc (EtOAc) Chloro-7-(3-chloro-propoxy)-6-methoxy-quinoline-3-carbonitrile (yellow solid, 3.1 g), yield 77%.
lH NMR (300 MHz, DMSO-d6): δ 8.99 (s, 1Η), 7.59 (s, 1H), 7.46 (s, 1H), 4.36 (t, J= 6.00 Hz, 2H), 4.02 (s, 3H), 3.83 (t, J= 6.00 Hz, 2H)， 2.28 (m, 2H)。 lH NMR (300 MHz, DMSO-d 6 ): δ 8.99 (s, 1 Η), 7.59 (s, 1H), 7.46 (s, 1H), 4.36 (t, J = 6.00 Hz, 2H), 4.02 (s, 3H), 3.83 (t, J= 6.00 Hz, 2H), 2.28 (m, 2H).
MS m/z (ESI): 311.0 [M+H]。  MS m/z (ESI): 311.0 [M+H].
第二歩： 7-(3-氯-丙氧基 )-4-(2,4-二氯 -5-甲氧基-苯氨基 )-6-甲氧基 -喹啉 -3- 甲氰  Second: 7-(3-Chloro-propoxy)-4-(2,4-dichloro-5-methoxy-phenylamino)-6-methoxy-quinoline-3-carbonitrile
将 2， 4-二氯 -5-甲氧基苯胺（ 1.9 g,10 mmol) ,吡啶盐酸盐（ 1.2 g, 10 mmol) 和 4-氯 -7-(3-氯-丙氧基) -6-甲氧基 -喹啉 -3-甲氰（3.1 g, 10 mmol)置于封管中， 加入无水 2-乙氧基乙醇（30 mL)， 将混合液在 140 °C下加热 2小时。 反应完 毕，将反应液冷却到室温后，用水稀释（ 500 mL)，二氯甲烷萃取（250 mLX2 ) , 合并有机相， 分别用水， 饱和食盐水洗涤， 无水硫酸钠干燥， 过滤， 减压浓 缩， 硅胶柱色谱法纯化得到 7-(3-氯-丙氧基: )-4-(2,4-二氯 -5-甲氧基-苯氨基: )-6- 甲氧基 -喹啉 -3-甲氰 （灰色固体， 3.0 g) ，收率 67%。 2,4-Dichloro-5-methoxyaniline (1.9 g, 10 mmol), pyridine hydrochloride (1.2 g, 10 mmol) and 4-chloro-7-(3-chloro-propoxy) 6-Methoxy-quinoline-3-carbonitrile (3.1 g, 10 mmol) was placed in a sealed tube, anhydrous 2-ethoxyethanol (30 mL) was added, and the mixture was heated at 140 °C. hour. After the reaction is completed, the reaction mixture is cooled to room temperature, diluted with water (500 mL), dichloromethane (250 mL×2), and the organic phase is combined, washed with water, brine, dried over anhydrous sodium sulfate Purification by silica gel column chromatography to give 7-(3-chloro-propoxy:)-4-(2,4-dichloro-5-methoxy-phenylamino: )-6-methoxy-quinoline 3-methyl cyanide (grey solid, 3.0 g), yield 67%.
lH NMR (300 MHz, DMSO-d6): δ 9.64 (s, 1Η), 8.41 (s, 1H), 7.84 (s, 1H), 7.73 (s, 1H), 7.33 (m, 2H), 4.29 (t, J= 5.4 Hz, 2H), 3.90 (m, 8H)， 2.26 (m, 2H)。 lH NMR (300 MHz, DMSO-d 6 ): δ 9.64 (s, 1 Η), 8.41 (s, 1H), 7.84 (s, 1H), 7.73 (s, 1H), 7.33 (m, 2H), 4.29 ( t, J = 5.4 Hz, 2H), 3.90 (m, 8H), 2.26 (m, 2H).
MS m/z (ESI): 466.0[M+H]。  MS m/z (ESI): 466.0 [M+H].
第三歩： 4-{3-[3-氰基 -4-(2,4-二氯 -5-甲氧基-苯氨基) -6-甲氧基 -喹啉 -7-基 氧基] -丙基 哌嗪 -1-甲酸叔丁酯  Third 歩: 4-{3-[3-Cyano-4-(2,4-dichloro-5-methoxy-phenylamino)-6-methoxy-quinolin-7-yloxy] -propyl piperazine-1-carboxylic acid tert-butyl ester
将 7-(3-氯-丙氧基 )-4-(2,4-二氯 -5-甲氧基-苯氨基: )-6-甲氧基 -喹啉 -3-甲氰 (460 mg, l mmol) 和 1-叔丁氧羰基哌嗪 （558 mg, 3 mmol) 溶于无水 Ν,Ν- 二甲基甲酰胺 （10 mL) 中， 加入碘化钾 （10 mg)， 加热到 100°C过夜。 反 应完毕， 将反应液冷却到室温后， 用水稀释 （250 mL)， 二氯甲烷萃取 （100 mL X 2 ) ,合并有机相， 分别用水， 饱和食盐水洗涤， 无水硫酸钠干燥， 过滤， 减压浓缩， 硅胶柱色谱法纯化得到 4-{3-[3-氰基 -4-(2,4-二氯 -5-甲氧基 -苯氨 基) -6-甲氧基 -喹啉 -7-基氧基] -丙基 } -哌嗪 -1-甲酸叔丁酯（黄色固体， 380 mg) o lH NMR (300 MHz, CDC13): 58.64 (s, 1H), 7.49 (s, 1H), 7.42 (s, 1H), 6.95 (s7-(3-Chloro-propoxy)-4-(2,4-dichloro-5-methoxy-phenylamino: )-6-methoxy-quinoline-3-carbonitrile (460 mg , l mmol) and 1-tert-butoxycarbonylpiperazine (558 mg, 3 mmol) dissolved in anhydrous hydrazine, hydrazine-dimethylformamide (10 mL), added potassium iodide (10 mg), heated to 100 ° C overnight. After the reaction is completed, the reaction solution is cooled to room temperature, diluted with water (250 mL), extracted with dichloromethane (100 mL X 2 ), and the organic phase is combined, washed with water, brine, dried over anhydrous sodium sulfate, filtered, Concentration by pressure, purification by silica gel column chromatography to give 4-{3-[3-cyano-4-(2,4-dichloro-5-methoxy-phenylamino)-6-methoxy-quinoline-7 -Phenyloxy]-propyl}-piperazine-l-carboxylic acid tert-butyl ester (yellow solid, 380 mg) o lH NMR (300 MHz, CDC1 3 ): 58.64 (s, 1H), 7.49 (s, 1H) , 7.42 (s, 1H), 6.95 (s
1H), 6.88 (s, 1H), 6.51 ( s, 1H) , 4.25 (t, J= 5.4 Hz, 2H), 3.76 (s, 3H)， 3.48(s, 3H), 2.68-2.94(m, 10H), 2.16 (t, J= 5.4Hz, 2H), 1.46(s, 9H)。 1H), 6.88 (s, 1H), 6.51 ( s, 1H) , 4.25 (t, J = 5.4 Hz, 2H), 3.76 (s, 3H), 3.48(s, 3H), 2.68-2.94(m, 10H ), 2.16 (t, J = 5.4 Hz, 2H), 1.46 (s, 9H).
MS m/z (ESI): 617·0[Μ+Η]。  MS m/z (ESI): 617·0 [Μ+Η].
第四歩： 4-(2,4-二氯 -5-甲氧基-苯氨基) -6-甲氧基 -7-(3-哌嗪 -1-基-丙氧基) - 喹啉 -3-甲氰  Fourth 歩: 4-(2,4-Dichloro-5-methoxy-phenylamino)-6-methoxy-7-(3-piperazin-1-yl-propoxy)-quinoline- 3-cyanocyanate
将 4-{3-[3-氰基 -4-(2,4-二氯 -5-甲氧基-苯氨基: )-6-甲氧基 -喹啉 -7-基氧基] - 丙基 哌嗪 -1-甲酸叔丁酯 （300 mg, 0.49 mmol) 溶于二氯甲烷 （10 mL) 中， 冰浴冷却下向上述溶液滴加 4N氯化氢的二氧六环溶液 （3 mL)， 室温搅拌 2 小时， 析出白色固体。 减压过滤， 滤饼用无水乙醚洗涤， 干燥得到 4-(2,4-二 氯 -5-甲氧基-苯氨基 )-6-甲氧基 -7-(3-哌嗪 -1-基-丙氧基) -喹啉 -3-甲氰 （白色固 体， 230 mg)， 直接用于下一歩反应。 4-{3-[3-Cyano-4-(2,4-dichloro-5-methoxy-phenylamino: )-6-methoxy-quinolin-7-yloxy]-propane Tert-butyl-piperazine-1-carboxylate (300 mg, 0.49 mmol) was dissolved in dichloromethane (10 mL), and 4N hydrogen chloride in dioxane (3 mL) was added dropwise to the above solution under ice-cooling. After stirring at room temperature for 2 hours, a white solid precipitated. Filtration under reduced pressure, the filter cake was washed with anhydrous diethyl ether and dried to give 4-(2,4-dichloro- 5 -methoxy-phenylamino) -6 -methoxy- 7- (3-piperazin-1- Base-propoxy)-quinoline-3-carbonitrile (white solid, 230 mg) was used directly in the next reaction.
中间体 2 : 7-[3-(3-氨基-吡咯烷 -1-基) -丙氧基] -4-(2,4-二氯 -5-甲氧基 -苯氨 基 )-6-甲氧基 -喹啉 -3-甲氰 Intermediate 2 : 7-[3-(3-Amino-pyrrolidin-1-yl)-propoxy]-4-(2,4-dichloro-5-methoxy-phenylamino) -6 -A Oxy-quinoline- 3 cyano
Figure imgf000022_0001
第一歩： （1-{3-[3-氰基 -4-(2,4-二氯 -5-甲氧基-苯氨基) -6-甲氧基 -喹啉 -7- 基氧基] -丙基 }-吡咯烷 -3-基：) -氨基甲酸叔丁酯
Figure imgf000022_0001
First 歩: (1-{3-[3-Cyano-4-(2,4-dichloro-5-methoxy-phenylamino)-6-methoxy-quinolin-7-yloxy ]-propyl}-pyrrolidin-3-yl:)-tert-butyl carbamate
采用中间体 1 类似的合成方法， 将吡咯烷 -3-基-氨基甲酸叔丁酯替换 1-Boc-哌嗪，得到中间体，（1-{3-[3-氰基 -4-(2,4-二氯 -5-甲氧基-苯氨基) -6-甲氧 基 -喹啉 -7-基氧基] -丙基 吡咯烷 -3-基：) -氨基甲酸叔丁酯（黄色固体， 850 mg) o lH NMR (400 MHz, DMSO-d6): 58.55 ( s, lH ) ,8.16(s, 1H), 7.34(s, 1H),7.19(S, 1H),6.56(S, lH),4.23(t, J=4.8Hz, 2H), 3.88(m, 1H), 3.76(s, 3H),3.65(s, 3H), 3.56-3.62(m, 4H), 3.29-3.54(m, 3H), 2.43(m, 3H), 2.10-2.17(m, 2H), 1.38(3, 9H)。  Substituting the pyrrolidin-3-yl-carbamic acid tert-butyl ester for 1-Boc-piperazine using an analogous analogy to Intermediate 1 to give the intermediate, (1-{3-[3-cyano-4-(2) ,4-dichloro-5-methoxy-phenylamino)-6-methoxy-quinolin-7-yloxy]-propylpyrrolidin-3-yl:)-tert-butyl carbamate (yellow Solid, 850 mg) o lH NMR (400 MHz, DMSO-d6): 58.55 (s, lH), 8.16 (s, 1H), 7.34 (s, 1H), 7.19 (S, 1H), 6.56 (S, lH ), 4.23 (t, J = 4.8 Hz, 2H), 3.88 (m, 1H), 3.76 (s, 3H), 3.65 (s, 3H), 3.56-3.62 (m, 4H), 3.29-3.54 (m, 3H), 2.43 (m, 3H), 2.10-2.17 (m, 2H), 1.38 (3, 9H).
MS m/z (ESI): 517·0[Μ+Η]。  MS m/z (ESI): 517·0 [Μ+Η].
第二歩： 7-[3-(3-氨基-吡咯烷 -1-基) -丙氧基] -4-(2,4-二氯 -5-甲氧基 -苯氨 基 )-6-甲氧基 -喹啉 -3-甲氰 Second 7: 7-[3-(3-Amino-pyrrolidin-1-yl)-propoxy]-4-(2,4-dichloro-5-methoxy-phenylamino) -6 -A Oxy-quinoline- 3 cyano
采用中间体 1类似的方法合成得到中间体 2， 7-[3-(3-氨基-吡咯烷 -1-基:) - 丙氧基 ]-4-(2,4-二氯 -5-甲氧基 -苯氨基:) -6-甲氧基 -喹啉 -3-甲氰（黄色固体， 620 mg)， 直接用于下一歩反应。  Intermediate 2, 7-[3-(3-amino-pyrrolidin-1-yl:)-propoxy]-4-(2,4-dichloro-5-methyl) was synthesized by a similar method to Intermediate 1. Oxy-phenylamino:)-6-methoxy-quinoline-3-carbonitrile (yellow solid, 620 mg), used directly in the next reaction.
中间体 3 : 4-(2,4-二氯 -5-甲氧基-苯氨基) -7-(5-甲醛基 -呋喃 -3-基) -6-甲氧 基 -  Intermediate 3 : 4-(2,4-Dichloro-5-methoxy-phenylamino)-7-(5-carbamoyl-furan-3-yl)-6-methoxy-
Figure imgf000022_0002
Figure imgf000022_0002
第一歩： 4-(2,4-二氯 -5-甲氧基-苯氨基: )-7-羟基 -6-甲氧基 -喹啉 -3-甲氰 以 3-氰基 -4-氯 -6-甲氧基 -7-羟基喹啉和 2,4-二氯 -5-甲氧基苯胺为原料， 采用中间体 1第二歩类似的方法合成得到中间体， 4-(2,4-二氯 -5-甲氧基 -苯氨 基) -7-羟基 -6-甲氧基 -喹啉 -3-甲氰 （黄色固体， 3.5g)。 H NMR (400 MHz, DMSO-d6): δ 10.44 (s, IH), 9.54 (s, IH), 8.35 (s, IH), 7.81 (s, IH), 7.74 (s, IH), 7.31 (s, IH), 7.20 (s, IH), 3.94 (s, 3H), 3.85 (s, 3H)。 First 歩: 4-(2,4-Dichloro-5-methoxy-phenylamino: )-7-hydroxy-6-methoxy-quinoline-3-carbonitrile as 3-cyano-4- Chloro-6-methoxy-7-hydroxyquinoline and 2,4-dichloro-5-methoxyaniline are used as starting materials, and intermediates are synthesized by the similar method of the second intermediate of intermediate 1, 4-(2, 4-Dichloro-5-methoxy-phenylamino)-7-hydroxy-6-methoxy-quinoline-3-carbonitrile (yellow solid, 3.5 g). H NMR (400 MHz, DMSO-d 6 ): δ 10.44 (s, IH), 9.54 (s, IH), 8.35 (s, IH), 7.81 (s, IH), 7.74 (s, IH), 7.31 ( s, IH), 7.20 (s, IH), 3.94 (s, 3H), 3.85 (s, 3H).
MS m/z (ESI): 390·0[Μ+Η]。  MS m/z (ESI): 390·0 [Μ+Η].
第二歩：3-氰基 -4-(2,4-二氯 -5-甲氧基-苯氨基) -6-甲氧基 -喹啉 -7-三氟甲磺 酸酯  Second: 3-cyano-4-(2,4-dichloro-5-methoxy-phenylamino)-6-methoxy-quinoline-7-trifluoromethanesulfonate
将 4-(2,4-二氯 -5-甲氧基-苯氨基： )-7-羟基 -6-甲氧基 -喹啉 -3-甲氰（3.5g, 9.0 mmol) 悬浮于二氯甲烷 （20 mL) 和吡啶 （8 mL) 的混合溶液中， 冰浴冷却 下向上述悬浮液中缓慢滴加三氟甲磺酸酐 （3.8 g, 13.5 mmol)。 滴加完毕， 室 温搅拌两小时后， 继续补加三氟甲磺酸酐（1.2 g)， 室温搅拌过夜。 加入蒸馏 水淬灭反应， 二氯甲烷萃取， 有机相分别用饱和碳酸氢钠溶液， 水， 饱和氯 化铵溶液洗涤， 无水硫酸钠干燥， 过滤， 减压浓缩。 剩余物用硅胶柱层析分 离纯化得到中间体 3-氰基 -4-(2,4-二氯 -5-甲氧基-苯氨基: )-6-甲氧基 -喹啉 -7-三 氟甲磺酸酯 （黄色固体， 3.7g)。  Suspension of 4-(2,4-dichloro-5-methoxy-phenylamino: )-7-hydroxy-6-methoxy-quinoline-3-carbonitrile (3.5 g, 9.0 mmol) in dichloro To a mixed solution of methane (20 mL) and pyridine (8 mL), trifluoromethanesulfonic anhydride (3.8 g, 13.5 mmol) was slowly added dropwise to the above suspension under ice-cooling. After the dropwise addition was completed, the mixture was stirred at room temperature for two hours, and trifluoromethanesulfonic anhydride (1.2 g) was further added thereto, and the mixture was stirred at room temperature overnight. The reaction was quenched with EtOAc (EtOAc)EtOAc. The residue was purified by silica gel column chromatography to afford Intermediate 3-cyano-4-(2,4-dichloro-5-methoxy-phenylamino:)-6-methoxy-quinoline-7- Fluoromethanesulfonate (yellow solid, 3.7 g).
H NMR (400 MHz, CD3OD): δ 8.80 (s, IH), 8.22 (s, IH), 7.96 (s, IH), 7.65 (s, IH), 7.35 (s, IH), 4.15 (s, 3H), 3.92 (s, 3H)。 H NMR (400 MHz, CD 3 OD): δ 8.80 (s, IH), 8.22 (s, IH), 7.96 (s, IH), 7.65 (s, IH), 7.35 (s, IH), 4.15 (s , 3H), 3.92 (s, 3H).
MS m/z (ESI): 522·2[Μ+Η]。  MS m/z (ESI): 522·2 [Μ+Η].
第三歩： 4-(2,4-二氯 -5-甲氧基-苯氨基) -7-(5-甲醛基 -呋喃 -3-基) -6-甲氧基- 喹啉 -3-甲氰  Third: 4-(2,4-Dichloro-5-methoxy-phenylamino)-7-(5-carbamoyl-furan-3-yl)-6-methoxy-quinoline-3- Cyanide
将 3-氰基 -4-(2,4-二氯 -5-甲氧基-苯氨基) -6-甲氧基 -喹啉 -7-三氟甲磺酸酯 (2.5 g,4.8 mmol) , 2-醛基呋喃 -4-硼酸 ( 0.633 g, 5.7 mmol) ,碳酸钠（1.27 g, 12 mmol)和四三苯基膦钯（278 mg, 0.24 mmol)悬浮于无水二氧六环（15 mL) 中， 氮气鼓泡 5分钟后， 混合物加热至 lOOoC搅拌过夜。 反应完毕， 冷却至 室温， 二氯甲烷萃取， 有机相用水， 饱和食盐水洗涤， 无水硫酸钠干燥， 过 滤减压浓缩， 剩余物用硅胶柱层析分离纯化得到中间体 3 4-(2,4-二氯 -5-甲氧 基-苯氨基) -7-(5-甲醛基 -呋喃 -3-基) -6-甲氧基 -喹啉 -3-甲氰（1.2 g,黄色固体 ）。  3-cyano-4-(2,4-dichloro-5-methoxy-phenylamino)-6-methoxy-quinoline-7-trifluoromethanesulfonate (2.5 g, 4.8 mmol) , 2-aldehyde furan-4-boronic acid (0.633 g, 5.7 mmol), sodium carbonate (1.27 g, 12 mmol) and tetrakistriphenylphosphine palladium (278 mg, 0.24 mmol) suspended in anhydrous dioxane ( In 15 mL), after bubbling nitrogen for 5 minutes, the mixture was heated to 100 ° C and stirred overnight. After the reaction is completed, the mixture is cooled to room temperature, and the organic layer is washed with EtOAc EtOAc. 4-Dichloro-5-methoxy-phenylamino)-7-(5-carbamoyl-furan-3-yl)-6-methoxy-quinoline-3-carbonitrile (1.2 g, yellow solid) .
^ NMR (400 MHz, CD3OD): δ 9.69 (s, IH), 8.56 (s, IH), 8.44 (s, IH), 8.16 (s, IH), 8.03 (s, IH), 7.86 (s, IH), 7.58 (s, IH), 7.25 (s, IH), 4.13 (s, 3H), 3.91 (s, 3H)。 ^ NMR (400 MHz, CD 3 OD): δ 9.69 (s, IH), 8.56 (s, IH), 8.44 (s, IH), 8.16 (s, IH), 8.03 (s, IH), 7.86 (s , IH), 7.58 (s, IH), 7.25 (s, IH), 4.13 (s, 3H), 3.91 (s, 3H).
MS m/z (ESI):468.1 [M+H]。  MS m/z (ESI): 468.1 [M+H].
中间体 4: 4-(2,4-二氯 -5-甲氧基-苯氨基) -6-甲氧基 -7-(4-哌嗪 -1-基 -丁氧 基) -喹啉 -3-甲氰
Figure imgf000024_0001
Intermediate 4: 4-(2,4-Dichloro-5-methoxy-phenylamino)-6-methoxy-7-(4-piperazin-1-yl-butoxy)-quinoline- 3-cyanocyanate
Figure imgf000024_0001
第一歩： 4-氯 -7-(4-氯-丁氧基 )-6-甲氧基 -喹啉 -3-甲氰  First choice: 4-chloro-7-(4-chloro-butoxy)-6-methoxy-quinoline-3-cyanide
以 1-氯 -4-碘丁烷替换中间体 1第一歩合成中的 1-氯 -3-碘丙烷，采用相同 的方法合成得到中间体， 4-氯 -7-(4-氯-丁氧基 )-6-甲氧基 -喹啉 -3-甲氰（类白色 粉末， 1.2 g)。  The 1-chloro-3-iodopropane in the first hydrazine synthesis of the intermediate 1 was replaced with 1-chloro-4-iodobutane, and the intermediate was synthesized by the same method, 4-chloro-7-(4-chloro-butyl) Oxy)-6-methoxy-quinoline-3-carbonitrile (white powder, 1.2 g).
lR NMR (400 MHz, CDC13): δ 8.77 (s, 1H), 7.41 (m, 2H), 4.25 (m, 2H), 4.06 (s, 3H), 3.66 (m, 2H),2.08 (m, 4H)。 lR NMR (400 MHz, CDC1 3 ): δ 8.77 (s, 1H), 7.41 (m, 2H), 4.25 (m, 2H), 4.06 (s, 3H), 3.66 (m, 2H), 2.08 (m, 4H).
MS m/z (ESI): 325· 1 [Μ+Η]。  MS m/z (ESI): 325·1 [Μ+Η].
第二歩： 7-(4-氯-丁氧基 )-4-(2,4-二氯 -5-甲氧基 -苯基氨基 )-6-甲氧基 -喹啉 -3-甲氰 Second 7 : 7- (4-chloro-butoxy)-4-(2,4-dichloro-5-methoxy-phenylamino)-6-methoxy-quinoline-3-cyanide
以 4-氯 -7-(4-氯-丁氧基 )-6-甲氧基 -喹啉 -3-甲氰替换中间体 1第二歩合成 中的原料 7-(3-氯-丙氧基 )-4-(2,4-二氯 -5-甲氧基-苯氨基 )-6-甲氧基 -喹啉 -3-甲 氰， 采用相同的方法合成得到中间体， 7-(4-氯-丁氧基 )-4-(2,4-二氯 -5-甲氧基- 苯基氨基：) -6-甲氧基 -喹啉 -3-甲氰 （黄色固体， 1 g)。  Substituting 4-chloro-7-(4-chloro-butoxy)-6-methoxy-quinoline-3-cyanate for the starting material 7-(3-chloro-propoxy) in the second hydrazine synthesis of intermediate 1. 4-(2,4-Dichloro-5-methoxy-phenylamino)-6-methoxy-quinoline-3-cyanide, synthesized in the same manner, 7-(4 -Chloro-butoxy)-4-(2,4-dichloro-5-methoxy-phenylamino:)-6-methoxy-quinoline-3-carbonitrile (yellow solid, 1 g) .
lH NMR (400 MHz, OMSO-d6): δ 9.62 (s, 1H), 8.41 (s, 1H), 7.83 (s, 1H), lH NMR (400 MHz, OMSO-d6): δ 9.62 (s, 1H), 8.41 (s, 1H), 7.83 (s, 1H),
7.75 (s, 1H), 7.34 (m, 2H), 4.21 (m, 2H), 3.94 (s, 3H), 3.85 (s, 3H), 3.76 (m, 2H), 1.93 (m, 4H)。 7.75 (s, 1H), 7.34 (m, 2H), 4.21 (m, 2H), 3.94 (s, 3H), 3.85 (s, 3H), 3.76 (m, 2H), 1.93 (m, 4H).
MS m/z (ESI): 480· 1 [Μ+Η]。  MS m/z (ESI): 480·1 [Μ+Η].
第三歩： 4-(2,4-二氯 -5-甲氧基-苯氨基) -6-甲氧基 -7-(4-哌嗪 -1-基-丁氧基) - 喹啉 -3-甲氰  The third group: 4-(2,4-dichloro-5-methoxy-phenylamino)-6-methoxy-7-(4-piperazin-1-yl-butoxy)-quinoline- 3-cyanocyanate
以 7-(4-氯-丁氧基) -4-(2,4-二氯 -5-甲氧基 -苯基氨基) -6-甲氧基 -喹啉 -3-甲 氰替换中间体 1第三歩合成中的原料 7-(3-氯-丙氧基： )-4-(2,4-二氯 -5-甲氧基- 苯氨基 )-6-甲氧基 -喹啉 -3-甲氰合成得到中间体 4， 4-(2,4-二氯 -5-甲氧基 -苯氨 基) -6-甲氧基 -7-(4-哌嗪 -1-基-丁氧基) -喹啉 -3-甲氰 （黄色固体， 760 mg)。 Replacing intermediate with 7- (4-chloro-butoxy)-4-(2,4-dichloro-5-methoxy-phenylamino)-6-methoxy-quinoline-3-carbonitrile 1 7-(3-chloro-propoxy:)-4-(2,4-dichloro-5-methoxy-phenylamino)-6-methoxy-quinoline- Synthesis of 3-methicone to give intermediate 4, 4-(2,4-dichloro-5-methoxy-phenylamino)-6-methoxy-7-(4-piperazin-1-yl-butoxy -Quinoline-3-carbonitrile (yellow solid, 760 mg).
lR NMR (400 MHz, CD3OD): δ 8.91 - 8.82 (m, 1H), 8.08 - 7.97 (m, 1H),lR NMR (400 MHz, CD 3 OD): δ 8.91 - 8.82 (m, 1H), 8.08 - 7.97 (m, 1H),
7.66 (s, 1H), 7.50 - 7.34 (m, 2H), 4.22 - 3.83 (m, 8H), 3.73 - 3.42 (m, 10H), 2.20 - 2.03 (m, 4H)。 7.66 (s, 1H), 7.50 - 7.34 (m, 2H), 4.22 - 3.83 (m, 8H), 3.73 - 3.42 (m, 10H), 2.20 - 2.03 (m, 4H).
MS m/z (ESI): 531 ·2[Μ+Η]。 中间体 5: 4-(2,4-二氯 -5-甲氧基-苯氨基) -7-(4-甲醛基 -呋喃 -2-基) -6-甲氧 基 -喹啉 -3-甲氰 MS m/z (ESI): 531 ·2 [Μ+Η]. Intermediate 5: 4-(2,4-Dichloro-5-methoxy-phenylamino)-7-(4-carbaldehyde-furan-2-yl)-6-methoxy-quinoline-3- Cyanide
Figure imgf000025_0001
以 3-醛基呋喃 -5-硼酸替换中间体 3合成中的原料 2-醛基呋喃 -4-硼酸，采 用中间体 3类似的方法合成得到中间体 5， 4-(2,4-二氯 -5-甲氧基 -苯氨基:) -7-(4- 甲醛基 -呋喃 -2-基) -6-甲氧基 -喹啉 -3-甲氰 （黄色固体， 260 mg)。
Figure imgf000025_0001
The 2-aldehyde aldehyde furan-4-boronic acid in the synthesis of the intermediate 3 was replaced by 3-aldehyde-furan-5-boronic acid, and the intermediate 5, 4-(2,4-dichloro) was synthesized by a similar method to Intermediate 3. -5-Methoxy-phenylamino:)-7-(4-Mercapto-furan-2-yl)-6-methoxy-quinoline-3-carbonitrile (yellow solid, 260 mg).
H NMR (400 MHz, DMSO-d6): δ 10.00 (s, 1Η), 9.91 (ά, J = 1.8 Hz, 1H), 8.83 (s, 1H), 8.49 (d, J = 0.6 Hz, 1H), 8.28 (s, 1H), 8.09 - 7.98 (m, 1H), 7.84 - 7.72 (m, 1H), 7.44 (s, 2H), 4.13 (s, 3H), 3.88 (s, 3H)。  H NMR (400 MHz, DMSO-d6): δ 10.00 (s, 1 Η), 9.91 (ά, J = 1.8 Hz, 1H), 8.83 (s, 1H), 8.49 (d, J = 0.6 Hz, 1H), 8.28 (s, 1H), 8.09 - 7.98 (m, 1H), 7.84 - 7.72 (m, 1H), 7.44 (s, 2H), 4.13 (s, 3H), 3.88 (s, 3H).
MS m/z (ESI):468.1 [M+H]。  MS m/z (ESI): 468.1 [M+H].
中间体 6: 4-(2,4-二氯 -5-甲氧基-苯氨基) -6-甲氧基 -7-(3-哌嗪 -1-基-丙 -1- 炔基) -喹啉 -3-甲氰  Intermediate 6: 4-(2,4-Dichloro-5-methoxy-phenylamino)-6-methoxy-7-(3-piperazin-1-yl-prop-1-ynyl) Quinoline-3-cyanide
Figure imgf000025_0002
Figure imgf000025_0002
第一歩： 4-(2,4-二氯 -5-甲氧基-苯氨基) -7-(3-羟基 -丙基 -1-炔基) -6-甲氧基- 喹啉 -3-甲氰  First 歩: 4-(2,4-Dichloro-5-methoxy-phenylamino)-7-(3-hydroxy-propyl-1-ynyl)-6-methoxy-quinoline-3 -Cyanine
将 3-氰基 -4-(2,4-二氯 -5-甲氧基-苯氨基) -6-甲氧基 -喹啉 -7-三氟甲磺酸酯 ( 520 mg, 1 mmol) , 叔丁基二甲基-丙 -2-炔氧基 -硅烷 （340 mg, 2 mmol)， 二 三苯基膦二氯化钯（70 mg, 0.1 mmol) , N，N-二异丙基乙胺（322 mg, 2.5 mmol) 混合于无水 Ν,Ν-二甲基甲酰胺（8 mL) 中， 氮气鼓泡 5分钟后， 混合液加热 至 80°C反应过夜。反应完毕， 混合物用二氯甲烷萃取， 有机相分别用饱和碳 酸氢钠溶液， 水， 饱和食盐水洗涤， 无水硫酸钠干燥， 过滤减压浓缩。 剩余 物直接溶于二氯甲烷中， 然后加入 2M 的四丁基氟化铵的四氢呋喃溶液 （1 mL) ，反应完毕直接浓缩进行硅胶柱层析分离， 得到中间体 4-(2,4-二氯 -5-甲 氧基-苯氨基 )-7-(3-羟基 -丙基 -1-炔基) -6-甲氧基 -喹啉 -3-甲氰 （黄色固体， 220 mg)。 3-cyano-4-(2,4-dichloro-5-methoxy-phenylamino)-6-methoxy-quinoline-7-trifluoromethanesulfonate (520 mg, 1 mmol) , tert-Butyldimethyl-prop-2-ynyloxy-silane (340 mg, 2 mmol), ditriphenylphosphine palladium dichloride (70 mg, 0.1 mmol), N,N-diisopropyl Ethylamine (322 mg, 2.5 mmol) was combined in anhydrous hydrazine, hexane-dimethylformamide (8 mL), and the mixture was stirred for 5 minutes, and the mixture was heated to 80 ° C overnight. After the completion of the reaction, the mixture was extracted with methylene chloride. The residue was dissolved directly in dichloromethane, then 2M tetrabutylammonium fluoride in tetrahydrofuran (1) (mL), the reaction is directly concentrated and subjected to silica gel column chromatography to obtain the intermediate 4-(2,4-dichloro-5-methoxy-phenylamino)-7-(3-hydroxy-propyl-1-yne Base) -6-methoxy-quinoline-3-carbonitrile (yellow solid, 220 mg).
lR NMR (400 MHz, CD3OD): δ 8.64 - 8.35 (m, 1H), 7.96 (d, J = 1.6 Hz, 1H), 7.76 (d, J= 0.7 Hz, 1H), 7.57 (s, 1H), 7.24 (s, 1H), 4.64 (s, 1H), 4.48 (s, 2H),lR NMR (400 MHz, CD 3 OD): δ 8.64 - 8.35 (m, 1H), 7.96 (d, J = 1.6 Hz, 1H), 7.76 (d, J = 0.7 Hz, 1H), 7.57 (s, 1H) ), 7.24 (s, 1H), 4.64 (s, 1H), 4.48 (s, 2H),
4.02 (s, 3H), 3.89 (s, 3H)。 4.02 (s, 3H), 3.89 (s, 3H).
MS m/z (ESI):428.2[M+H]。  MS m/z (ESI): 428.2 [M+H].
第二歩： 甲烷磺酸 3-[3-氰基 -4-(2,4-二氯 -5-甲氧基-苯氨基: )-6-甲氧基-喹 啉 -7-基] -丙 -2-炔基酯  Second 歩: 3-[3-Cyano-4-(2,4-dichloro-5-methoxy-phenylamino: )-6-methoxy-quinolin-7-yl] methanesulfonate Prop-2-ynyl ester
将 4-(2,4-二氯 -5-甲氧基-苯氨基) -7-(3-羟基 -丙基 -1-炔基) -6-甲氧基 -喹啉 4-(2,4-Dichloro-5-methoxy-phenylamino)-7-(3-hydroxy-propyl-1-ynyl)-6-methoxy-quinoline
-3-甲氰（220 mg, 0.52 mmol)和 N， N-二异丙基乙胺（129 mg, l .O mmol)溶 于无水二氯甲烷（10 mL)中， 冰浴冷却下向上述溶液中滴加甲烷磺酰氯（37 mg, 0.32 mmol) , 滴加完毕室温反应 3小时。 加入水和二氯甲烷淬灭反应， 分出有机相， 有机相分别用饱和碳酸氢钠溶液， 水， 饱和食盐水洗涤， 无水 硫酸钠干燥， 过滤减压浓缩， 剩余物用硅胶柱层析分离纯化得到甲烷磺酸Benzonitrile (220 mg, 0.52 mmol) and N,N-diisopropylethylamine (129 mg, 1.0 mmol) were dissolved in anhydrous dichloromethane (10 mL). Methanesulfonyl chloride (37 mg, 0.32 mmol) was added dropwise to the above solution, and the mixture was reacted at room temperature for 3 hours. The reaction was quenched by the addition of water and methylene chloride. The organic layer was separated and evaporated, evaporated, evaporated, evaporated Separation and purification to obtain methanesulfonic acid
3-[3-氰基 -4-(2,4-二氯 -5-甲氧基-苯氨基) -6-甲氧基 -喹啉 -7-基] -丙 -2-炔基酯（黄 色固体， 89 mg)。 3-[3-Cyano-4-(2,4-dichloro-5-methoxy-phenylamino)-6-methoxy-quinolin-7-yl]-prop-2-ynyl ester ( Yellow solid, 89 mg).
lH NMR (400 MHz, CD3OD): 8.36 (s, 1H), 7.93 (s, 1H), 7.73 (s, 1H), 7.51 (s, 1H), 7.17 (s, 1H), 5.16 (s, 2H), 3.97 (s, 3H), 3.83 (s, 3H), 3.21 (s, 3H)。 lH NMR (400 MHz, CD 3 OD): 8.36 (s, 1H), 7.93 (s, 1H), 7.73 (s, 1H), 7.51 (s, 1H), 7.17 (s, 1H), 5.16 (s, 2H), 3.97 (s, 3H), 3.83 (s, 3H), 3.21 (s, 3H).
MS m/z (ESI): 506.2 [M+H]。  MS m/z (ESI): 506.2 [M+H].
第三歩： 4-{3-[3-氰基 -4-(2,4-二氯 -5-甲氧基-苯氨基) -6-甲氧基 -喹啉 -7- 基] -丙 -2-炔基 哌嗪 -1-甲酸叔丁酯  Third 歩: 4-{3-[3-Cyano-4-(2,4-dichloro-5-methoxy-phenylamino)-6-methoxy-quinolin-7-yl]-prop 2-ynylpiperazine-1-carboxylic acid tert-butyl ester
以甲烷磺酸 3-[3-氰基 -4-(2,4-二氯 -5-甲氧基-苯氨基) -6-甲氧基 -喹啉 -7- 基] -丙 -2-炔基酯和 N-叔丁氧羰基哌嗪为原料， 采用中间体 1第三歩类似的方 法合成得到中间体， 4-{3-[3-氰基 -4-(2,4-二氯 -5-甲氧基-苯氨基) -6-甲氧基-喹 啉 -7-基] -丙 -2-炔基 哌嗪 -1-甲酸叔丁酯 （黄色固体， 65mg)。  3-[3-Cyano-4-(2,4-dichloro-5-methoxy-phenylamino)-6-methoxy-quinolin-7-yl]-propan-2-sulfonate The alkynyl ester and N-tert-butoxycarbonylpiperazine are used as starting materials, and the intermediate is synthesized by a similar method to the third intermediate of intermediate 1, 4-{3-[3-cyano-4-(2,4-dichloro) -5-Methoxy-phenylamino)-6-methoxy-quinolin-7-yl]-prop-2-ynylpiperazine-1-carboxylic acid tert-butyl ester (yellow solid, 65 mg).
lR NMR (400 MHz, OMS0-d6): 58.51(s, lH), 8.28(s, 1H), 8.22(s, 1H), 7.49(s, 1H), 7.16(s, 1H), 4.26(s, 2H), 4.06(s, 3H), 3.90(s, 3H), 3.32-3.46(m, 8H), 1.42(s, 9H)。  lR NMR (400 MHz, OMS0-d6): 58.51 (s, lH), 8.28 (s, 1H), 8.22 (s, 1H), 7.49 (s, 1H), 7.16 (s, 1H), 4.26 (s, 2H), 4.06 (s, 3H), 3.90 (s, 3H), 3.32-3.46 (m, 8H), 1.42 (s, 9H).
MS m/z (ESI):596.2[M+H]。 第四歩： 4-(2,4-二氯 -5-甲氧基-苯氨基) -6-甲氧基 -7-(3-哌嗪 -1-基-丙 -1-炔 基) -喹啉 -3-甲氰 MS m/z (ESI): 596.2 [M+H]. Fourth 歩: 4-(2,4-Dichloro-5-methoxy-phenylamino)-6-methoxy-7-(3-piperazin-1-yl-prop-1-ynyl) Quinoline-3-cyanide
以 4-{3-[3-氰基 -4-(2,4-二氯 -5-甲氧基-苯氨基) -6-甲氧基 -喹啉 -7-基] -丙 -2- 炔基 } -哌嗪 -1-甲酸叔丁酯为原料， 采用中间体 1第四歩类似的方法合成得到 中间体， 4-(2,4-二氯 -5-甲氧基-苯氨基) -6-甲氧基 -7-(3-哌嗪 -1-基-丙 -1-炔基) - 喹啉 -3-甲氰 （黄色固体， 35 mg) ，未经纯化直接用于下一歩反应。  4-{3-[3-Cyano-4-(2,4-dichloro-5-methoxy-phenylamino)-6-methoxy-quinolin-7-yl]-propan-2- Starting from alkynyl}-piperazine-1-carboxylic acid tert-butyl ester, an intermediate, 4-(2,4-dichloro-5-methoxy-phenylamino), is synthesized by a similar method to Intermediate 1 -6-Methoxy-7-(3-piperazin-1-yl-prop-1-ynyl)-quinoline-3-carbonitrile (yellow solid, 35 mg). reaction.
中间体 7: 4-(2,4-二氯 -5-甲氧基-苯氨基) -6-甲氧基 -7-(4-哌嗪 -1-基-丁 -1- 炔基 -喹啉 -3-甲氰  Intermediate 7: 4-(2,4-Dichloro-5-methoxy-phenylamino)-6-methoxy-7-(4-piperazin-1-yl-but-1-ynyl-quinoline Porphyrin-3-cyanide
Figure imgf000027_0001
Figure imgf000027_0001
第一歩： 4-(2,4-二氯 -5-甲氧基-苯氨基) -7-(4-羟基-丁 -1-炔基) -6-甲氧基- 喹啉 -3-甲氰  First 歩: 4-(2,4-Dichloro-5-methoxy-phenylamino)-7-(4-hydroxy-but-1-ynyl)-6-methoxy-quinoline-3- Cyanide
以 3-氰基 -4-(2,4-二氯 -5-甲氧基-苯氨基) -6-甲氧基 -喹啉 -7-三氟甲磺酸酯 和 4-羟基 -1-丁炔为原料， 采用中间体 6第一歩类似的方法合成得到中间体， 4-(2,4-二氯 -5-甲氧基 -苯氨基:) -7-(4-羟基-丁 -1-炔基: )-6-甲氧基 -喹啉 -3-甲氰（黄 色固体， 850 mg)。  3-cyano-4-(2,4-dichloro-5-methoxy-phenylamino)-6-methoxy-quinoline-7-trifluoromethanesulfonate and 4-hydroxy-1- Butane is used as a raw material, and an intermediate is synthesized by a similar method to the first step of Intermediate 6, 4-(2,4-dichloro-5-methoxy-phenylamino:)-7-(4-hydroxy-butyl- 1-Alkynyl: )-6-methoxy-quinoline-3-carbonitrile (yellow solid, 850 mg).
^ NMR (400 MHz, CD3OD): δ 8.39 (s, 1H), 7.98 (s, 1H), 7.71 (s, 1H), 7.57 (s, 1H), 7.22 (s, 1H), 4.01 (s, 3H), 3.90 (s, 3H), 3.78 (t, J= 6.7 Hz, 2H), 2.73 (t, J = 6.7 Hz, 2H)。 ^ NMR (400 MHz, CD 3 OD): δ 8.39 (s, 1H), 7.98 (s, 1H), 7.71 (s, 1H), 7.57 (s, 1H), 7.22 (s, 1H), 4.01 (s , 3H), 3.90 (s, 3H), 3.78 (t, J = 6.7 Hz, 2H), 2.73 (t, J = 6.7 Hz, 2H).
MS m/z (ESI):442.1 [M+H]。  MS m/z (ESI): 4421. [M+H].
第二歩： 甲烷磺酸 4-[3-氰基 -4-(2,4-二氯 -5-甲氧基 -苯氨基:) -6-甲氧基-喹 啉 -7-基] -丁 -3-炔基酯  Second 歩: 4-[3-Cyano-4-(2,4-dichloro-5-methoxy-phenylamino:)-6-methoxy-quinolin-7-yl] methanesulfonate But-3-ynyl ester
以 4-(2,4-二氯 -5-甲氧基-苯氨基) -7-(4-羟基-丁 -1-炔基) -6-甲氧基 -喹啉 -3- 甲氰和甲烷磺酰氯为原料， 采用中间体 6第二歩类似的方法合成得到中间体 甲烷磺酸 4-[3-氰基 -4-(2,4-二氯 -5-甲氧基-苯氨基) -6-甲氧基 -喹啉 -7-基] -丁 -3- 炔基酯 （黄色固体， 580 mg)。 NMR (400 MHz, CD3OD): δ 8.10 (s, 1H), 8.00 (s, 1H), 7.50 (s, 1H), 7.02 (s, 1H), 6.60 (s, 1H), 4.44 (t, J = 6.7 Hz, 2H), 3.82 (s, 3H), 3.73 (s, 3H), 3.09 (s, 3H), 2.95 (s, 2H)。 4-(2,4-Dichloro-5-methoxy-phenylamino)-7-(4-hydroxy-but-1-ynyl)-6-methoxy-quinoline-3-carbonitrile Methanesulfonyl chloride was used as the starting material, and the intermediate methanesulfonic acid 4-[3-cyano-4-(2,4-dichloro-5-methoxy-phenylamino) was synthesized by the similar method of Intermediate 6 second. -6-Methoxy-quinolin-7-yl]-but-3-ynyl ester (yellow solid, 580 mg). NMR (400 MHz, CD 3 OD): δ 8.10 (s, 1H), 8.00 (s, 1H), 7.50 (s, 1H), 7.02 (s, 1H), 6.60 (s, 1H), 4.44 (t, J = 6.7 Hz, 2H), 3.82 (s, 3H), 3.73 (s, 3H), 3.09 (s, 3H), 2.95 (s, 2H).
MS m/z (ESI):520.4[M+H]。  MS m/z (ESI): 520.4 [M+H].
第三歩： 4-(2,4-二氯 -5-甲氧基-苯氨基) -6-甲氧基 -7-(4-哌嗪 -1-基-丁 -1-炔 基) -喹啉 -3-甲氰  Third choice: 4-(2,4-dichloro-5-methoxy-phenylamino)-6-methoxy-7-(4-piperazin-1-yl-but-1-ynyl) Quinoline-3-cyanide
以甲烷磺酸 4-[3-氰基 -4-(2,4-二氯 -5-甲氧基-苯氨基) -6-甲氧基 -喹啉 -7- 基] -丁 -3-炔基酯为原料， 采用中间体 6第三、 第四歩类似的方法合成得到中 间体 7， 4-(2,4-二氯 -5-甲氧基-苯氨基) -6-甲氧基 -7-(4-哌嗪 -1-基-丁 -1-炔基) -喹 啉 -3-甲氰 （黄色固体， 260 mg) ，未经纯化直接用于下一歩反应。  4-[3-Cyano-4-(2,4-dichloro-5-methoxy-phenylamino)-6-methoxy-quinolin-7-yl]-but-3-yl methanesulfonate The alkynyl ester is used as a raw material, and the intermediate 7, 4-(2,4-dichloro-5-methoxy-phenylamino)-6-methoxy is synthesized by a similar method to the intermediate 3, the third and the fourth. -7-(4-Piperazin-1-yl-but-1-ynyl)-quinoline-3-carbonitrile (yellow solid, 260 mg) was used for the next reaction without purification.
H NMR (400 MHz, CD3OD): δ 8.91 (s, 1H), 8.12 (d, J= 9.5 Hz, 2H), 7.66 (s 1H), 7.42 (s, 1H), 4.11 (s, 3H), 3.93 (s, 3H), 3.83 - 3.72 (m, 4H), 3.72 - 3.65 (m, 4H), 3.61 (t, J= 6.9 Hz, 2H), 3.22 (t, J= 7.0 Hz, 2H)。 H NMR (400 MHz, CD 3 OD): δ 8.91 (s, 1H), 8.12 (d, J = 9.5 Hz, 2H), 7.66 (s 1H), 7.42 (s, 1H), 4.11 (s, 3H) , 3.93 (s, 3H), 3.83 - 3.72 (m, 4H), 3.72 - 3.65 (m, 4H), 3.61 (t, J = 6.9 Hz, 2H), 3.22 (t, J = 7.0 Hz, 2H).
MS m/z (ESI) : 511 · 1 [M+H]。  MS m/z (ESI): 511 · 1 [M+H].
中间体 8: 4-(4-氯 -2-环丙基 -5-甲氧基-苯氨基) -6-甲氧基 -7-(3-哌嗪 -1-基- 丙氧基 -喹啉 -3-甲氰  Intermediate 8: 4-(4-Chloro-2-cyclopropyl-5-methoxy-phenylamino)-6-methoxy-7-(3-piperazin-1-yl-propoxy-quin Porphyrin-3-cyanide
Figure imgf000028_0001
Figure imgf000028_0001
第一歩： 4-氯 -2-环丙基 -5-甲氧基 -苯胺  First choice: 4-chloro-2-cyclopropyl-5-methoxy-aniline
将 4-氯 -3-甲氧基苯胺 （1.57 g, 10 mmol)溶于二氯甲烷 （15 mL)， 冰浴冷 却下向上述溶液中分批加入 N-溴代丁二酰亚胺 （1.95 g, 11 mmol), 加完后升 温至室温反应 10分钟。 反应完毕， 加入 5%的亚硫酸钠水溶液淬灭反应， 分 出有机相， 分别用水， 饱和食盐水洗涤， 无水硫酸钠干燥， 过滤减压浓缩。 剩余物用少量正庚烷稀释，析出固体， 过滤收集固体得到 2-溴 -4-氯 -5-甲氧基 苯胺 （灰白色固体， 1.8 g)。  4-Chloro-3-methoxyaniline (1.57 g, 10 mmol) was dissolved in dichloromethane (15 mL), and N-bromosuccinimide (1.95) was added portionwise to the above solution under ice-cooling. g, 11 mmol), after the addition was completed, the temperature was raised to room temperature for 10 minutes. After the completion of the reaction, the reaction mixture was evaporated. The residue was diluted with a small amount of n-heptane to give a solid, which was collected to give 2-bromo-4-chloro-5-methoxyaniline (yellow white solid, 1.8 g).
将 2-溴 -4-氯 -5-甲氧基苯胺 （ 1.6 g, 8.1 mmol) , 环丙基硼酸 （838 mg, 9.7 mmol) , 醋酸钯 （91 mg, 0.4 mmol) , 环己基膦 （224 mg, 0.8 mmol) 和磷酸 钾（4.3 g, 20.2 mmol)悬浮于无水甲苯（15 mL) 中， 氮气鼓泡 5分钟， 加热 至 lOOoC反应过夜。 反应完毕， 加入水 （20 mL) 和乙酸乙酯 （50 mL)， 分 出有机相， 分别用水和饱和食盐水洗涤， 无水硫酸钠干燥， 过滤减压浓缩， 剩余物用硅胶柱层析分离纯化得到中间体 4-氯 -2-环丙基 -5-甲氧基 -苯胺 （浅 褐色固体， 1.2 g)。 2-Bromo-4-chloro-5-methoxyaniline (1.6 g, 8.1 mmol), cyclopropylboronic acid (838 mg, 9.7 mmol), palladium acetate (91 mg, 0.4 mmol), cyclohexylphosphine (224 Mg, 0.8 mmol) and potassium phosphate (4.3 g, 20.2 mmol) were suspended in anhydrous toluene (15 mL), nitrogen was bubbled for 5 minutes, heated React overnight at lOOoC. After completion of the reaction, water (20 mL) and ethyl acetate (50 mL) were added, and the organic phase was separated, washed with water and brine, dried over anhydrous sodium sulfate. Purification afforded the intermediate 4-chloro-2-cyclopropyl-5-methoxy-phenylamine (light brown solid, 1.2 g).
lH NMR (400 MHz, OMSO-d6): 56.83 (s, 1H), 6.42 (s, 1H), 3.76 (s, 3H), lH NMR (400 MHz, OMSO-d6): 56.83 (s, 1H), 6.42 (s, 1H), 3.76 (s, 3H),
1.63 - 1.54 (m, 1H), 0.87 - 0.82 (m, 2H), 0.48 - 0.43 (m, 2H)。 1.63 - 1.54 (m, 1H), 0.87 - 0.82 (m, 2H), 0.48 - 0.43 (m, 2H).
MS m/z (ESI): 198.1 [M+H]。  MS m/z (ESI): 198.1 [M+H].
第二歩： 4-(4-氯 -2-环丙基 -5-甲氧基-苯氨基) -7-(3-氯-丙氧基) -6-甲氧基- 喹啉 -3-甲氰  Second: 4-(4-Chloro-2-cyclopropyl-5-methoxy-phenylamino)-7-(3-chloro-propoxy)-6-methoxy-quinoline-3- Cyanide
以 4-氯 -2-环丙基 -5-甲氧基-苯胺替换 2,4-二氯 -5-甲氧基苯胺， 采用中间 体 1 第二歩类似的方法合成得到中间体， 4-(4-氯 -2-环丙基 -5-甲氧基 -苯氨 基) -7-(3-氯-丙氧基) -6-甲氧基 -喹啉 -3-甲氰 （黄色固体， 685 mg)。  Substituting 4-chloro-2-cyclopropyl-5-methoxy-aniline for 2,4-dichloro-5-methoxyaniline, using Intermediate 1 to prepare an intermediate, 4- (4-chloro-2-cyclopropyl-5-methoxy-phenylamino)-7-(3-chloro-propoxy)-6-methoxy-quinoline-3-carbonitrile (yellow solid, 685 mg).
ifi-NMR (400MHz, CD3OD): δ8.35(1Η, s), 7.73(1H, s), 7.30(1H, s), 7.03(2H， s), 4.32(2H, t, J=6.0Hz), 4.00(3H, s), 3.86(3H, s), 3.83(2H, t, J=6.4Hz), 2.31-2.37(2H, m), 1.79-1.83(1H， m), 0.75-0.79(2H， m), 0.65-0.69(2H， m)。 Ifi-NMR (400MHz, CD 3 OD): δ 8.35 (1Η, s), 7.73(1H, s), 7.30(1H, s), 7.03(2H, s), 4.32(2H, t, J=6.0 Hz), 4.00(3H, s), 3.86(3H, s), 3.83(2H, t, J=6.4Hz), 2.31-2.37(2H, m), 1.79-1.83(1H, m), 0.75-0.79 (2H, m), 0.65-0.69 (2H, m).
MS m/z (ESI):471.8[M+H]。  MS m/z (ESI): 471.8 [M+H].
第三歩： 4-{3-[4-(4-氯 -2-环丙基 -5-甲氧基-苯氨基) -3-氰基 -6-甲氧基 -喹啉 The third group: 4-{3-[4-(4-chloro-2-cyclopropyl-5-methoxy-phenylamino)-3-cyano-6-methoxy-quinoline
-7-基氧基] -丙基 哌嗪 -1-甲酸叔丁酯 -7-yloxy]-propyl piperazine-1-carboxylic acid tert-butyl ester
以 4-(4-氯 -2-环丙基 -5-甲氧基-苯氨基) -7-(3-氯-丙氧基) -6-甲氧基 -喹啉 -3- 甲氰为原料， 采用中间体 1 第三歩类似的方法合成得到中间体， 4-{3-[4-(4- 氯 -2-环丙基 -5-甲氧基-苯氨基 )-3-氰基 -6-甲氧基 -喹啉 -7-基氧基] -丙基 哌嗪4-(4-Chloro-2-cyclopropyl-5-methoxy-phenylamino)-7-(3-chloro-propoxy)-6-methoxy-quinoline-3-carbonitrile The starting material was synthesized in the same manner as the intermediate 1 by the third method, 4-{3-[4-(4-chloro-2-cyclopropyl- 5 -methoxy-phenylamino) -3 -cyano - 6 -methoxy-quinoline- 7 -yloxy]-propylpiperazine
-1-甲酸叔丁酯 （黄色固体， 698 mg) o Tert-butyl 1-carboxylic acid (yellow solid, 698 mg) o
^-NMR (400MHz, CD3OD): δ8.33(1Η, s), 7.70(1H, s), 7.27(1H, s), 7.03(2H， d, J=2.8Hz), 4.24(2H, t, J=6.0Hz), 3.98(3H, s), 3.86(3H, s), 3.43-3.49 (4H, m), 2.61-2.65(2H, m), 2.46-2.49(2H, m), 2.07-2.14(2H , m), 1.77-1.83(1H , m), 0.74-0.79(2H， m), 0.69-0.72(2H， m)。 ^-NMR (400 MHz, CD 3 OD): δ 8.33 (1 Η, s), 7.70 (1H, s), 7.27 (1H, s), 7.03 (2H, d, J = 2.8 Hz), 4.24 (2H, t, J=6.0Hz), 3.98(3H, s), 3.86(3H, s), 3.43-3.49 (4H, m), 2.61-2.65(2H, m), 2.46-2.49(2H, m), 2.07 - 2.14 (2H, m), 1.77-1.83 (1H, m), 0.74-0.79 (2H, m), 0.69-0.72 (2H, m).
MS m/z (ESI):621.8[M+H]。  MS m/z (ESI): 621.8 [M+H].
第四歩： 4-(4-氯 -2-环丙基 -5-甲氧基-苯氨基 )-6-甲氧基 -7-(3-哌嗪- μ基-丙 氧基) -喹啉 -3-甲氰 Fourth: 4-(4-Chloro-2-cyclopropyl-5-methoxy-phenylamino)-6-methoxy- 7- (3-piperazine-μyl-propoxy)-quin Porphyrin-3-cyanide
以 4-{3-[4-(4-氯 -2-环丙基 -5-甲氧基-苯氨基) -3-氰基 -6-甲氧基 -喹啉 -7-基 氧基] -丙基 哌嗪 -1-甲酸叔丁酯为原料， 采用中间体 1第四歩类似的方法合 成得到中间体 8， 4-(4-氯 -2-环丙基 -5-甲氧基-苯氨基 )-6-甲氧基 -7-(3-哌嗪 -1- 基-丙氧基) -喹啉 -3-甲氰 （黄色固体， 520 mg)。 4-{3-[4-(4-Chloro-2-cyclopropyl-5-methoxy-phenylamino)-3-cyano-6-methoxy-quinolin-7-yloxy] -propyl piperazine-1-carboxylic acid tert-butyl ester as raw material, using a similar method of intermediate 1 Intermediate 8, 4-(4-chloro-2-cyclopropyl-5-methoxy-phenylamino)-6-methoxy-7-(3-piperazin-1-yl-propoxy ) - Quinoline-3-methicone (yellow solid, 520 mg).
^-NMR (400MHz, CD3OD): δ8.34(1Η, s), 7.71(1H, s), 7.28(1H, s), 7.03(2H， s), 4.24(2H, t, J=6.0Hz), 3.98(3H, s), 3.86(3H, s), 2.94-2.96(3H, m), 2.53-2.65(7H, m), 2.08-2.15(2H, m), 1.78-1.82(1H , m), 0.74-0.78(2H , m), 0·65-0·69(2Η , m)。 ^-NMR (400MHz, CD 3 OD): δ 8.34(1Η, s), 7.71(1H, s), 7.28(1H, s), 7.03(2H, s), 4.24(2H, t, J=6.0 Hz), 3.98(3H, s), 3.86(3H, s), 2.94-2.96(3H, m), 2.53-2.65(7H, m), 2.08-2.15(2H, m), 1.78-1.82(1H , m), 0.74-0.78 (2H, m), 0·65-0·69 (2Η, m).
MS m/z (ESI):261.4[M+2H]。  MS m/z (ESI): 261.4 [M+2].
中间体 9: 4-(2-氯 -4-环丙基 -5-甲氧基-苯氨基) -6-甲氧基 -7-(3-哌嗪 -1-基- 丙氧 -喹啉 -3-甲氰  Intermediate 9: 4-(2-Chloro-4-cyclopropyl-5-methoxy-phenylamino)-6-methoxy-7-(3-piperazin-1-yl-propoxy-quinoline -3-methionine
Figure imgf000030_0001
Figure imgf000030_0001
第一歩： 2-氯 -4-环丙基 -5-甲氧基苯胺  First choice: 2-chloro-4-cyclopropyl-5-methoxyaniline
将 6-氯 -3-甲氧基苯胺 ( 1.57 g, lO mmol)溶于乙酸乙酯 ( 15 mL) 中， 冰 浴冷却下， 向上述溶液中分批加入 1,3-二溴 -5,5-二甲基海因 (3.1 g, 11 mmol), 加完后反应液在冰浴下反应 1小时， 反应液用饱和碳酸钾溶液淬灭， 分出有 机相， 分别用水， 饱和食盐水洗涤， 无水硫酸钠干燥， 过滤减压浓缩， 得到 4-溴 -2-氯 -5-甲氧基苯胺 （褐色固体， 1.96 g)。  6-Chloro-3-methoxyaniline ( 1.57 g, 10 mmol) was dissolved in ethyl acetate (15 mL), and 1,3-dibromo-5 was added portionwise to the above solution under ice-cooling. 5-Dimethylhydantoin (3.1 g, 11 mmol). After the addition, the reaction mixture was reacted in an ice bath for 1 hour. The reaction mixture was quenched with saturated aqueous potassium carbonate. The organic phase was separated and washed with water and brine. After drying over anhydrous sodium sulfate, filtered and evaporated tolulululululululululululu
以 4-溴 -2-氯 -5-甲氧基苯胺替换 2-溴 -4-氯 -5-甲氧基苯胺， 采用中间体 8 第一歩类似的合成方法得到中间体， 2-氯 -4-环丙基 -5-甲氧基苯胺（灰白色固 体， 1.5 g)。  Substituting 4-bromo-2-chloro-5-methoxyaniline for 2-bromo-4-chloro-5-methoxyaniline, using intermediate 8 as the first synthetic method to obtain the intermediate, 2-chloro- 4-Cyclopropyl-5-methoxyaniline (off-white solid, 1.5 g).
lH NMR (400 MHz, OMSO-d6): 56.65 (s, 1H), 6.44 (s, 1H), 3.77 (s, 3H), 1.92 (ddt, J = 13.8, 8.8, 5.4 Hz, 1H), 0.78 (ddd, J = 8.5, 6.1, 4.2 Hz, 2H), 0.49 - 0.44 (m, 2H)。  lH NMR (400 MHz, OMSO-d6): 56.65 (s, 1H), 6.44 (s, 1H), 3.77 (s, 3H), 1.92 (ddt, J = 13.8, 8.8, 5.4 Hz, 1H), 0.78 ( Ddd, J = 8.5, 6.1, 4.2 Hz, 2H), 0.49 - 0.44 (m, 2H).
MS m/z (ESI): 198.2[M+H]。  MS m/z (ESI): 198.2 [M+H].
第二歩： 4-(2-氯 -4-环丙基 -5-甲氧基-苯氨基) -7-(3-氯-丙氧基) -6-甲氧基- 喹啉 -3-甲氰 以 2-氯 -4-环丙基 -5-甲氧基苯胺和 3-氰基 -4-氯 -6-甲氧基 -7-羟基喹啉为原 料， 采用中间体 1 第二歩类似的方法合成得到中间体， 4-(2-氯 -4-环丙基 -5- 甲氧基-苯氨基) -7-(3-氯-丙氧基: )-6-甲氧基 -喹啉 -3-甲氰 （黄色固体， 1.26 g)。 Second 歩: 4-(2-chloro-4-cyclopropyl-5-methoxy-phenylamino)-7-(3-chloro-propoxy)-6-methoxy-quinoline-3- Cyanide Using 2-chloro-4-cyclopropyl-5-methoxyaniline and 3-cyano-4-chloro-6-methoxy-7-hydroxyquinoline as starting materials, using intermediate 1 Method for the synthesis of intermediate, 4-(2-chloro-4-cyclopropyl-5-methoxy-phenylamino)-7-(3-chloro-propoxy:)-6-methoxy-quinoline 3-methyl cyanide (yellow solid, 1.26 g).
^ NMR (400 MHz, CD3OD): δ 8.36 (s, 1H), 7.72 (s, 1H), 7.32 (s, 1H), 7.03 (s, 1H), 6.97 (s, 1H), 4.34 (t, J= 5.9 Hz, 2H), 4.01 (s, 3H), 3.88 (s, 3H), 3.85 (t, J^ NMR (400 MHz, CD 3 OD): δ 8.36 (s, 1H), 7.72 (s, 1H), 7.32 (s, 1H), 7.03 (s, 1H), 6.97 (s, 1H), 4.34 (t , J= 5.9 Hz, 2H), 4.01 (s, 3H), 3.88 (s, 3H), 3.85 (t, J
= 6.4 Hz, 2H), 2.36 (dd, J = 9.2, 3.1 Hz, 2H), 2.24 - 2.16 (m, 1H), 0.99 (dd, J = 8.5, 2.1 Hz, 2H), 0.75 - 0.68 (m, 2H)。 = 6.4 Hz, 2H), 2.36 (dd, J = 9.2, 3.1 Hz, 2H), 2.24 - 2.16 (m, 1H), 0.99 (dd, J = 8.5, 2.1 Hz, 2H), 0.75 - 0.68 (m, 2H).
MS m/z (ESI):473.1 [M+H]。  MS m/z (ESI): 473.1 [M+H].
第三歩： 4-(2-氯 -4-环丙基 -5-甲氧基-苯氨基) -6-甲氧基 -7-(3-哌嗪 -1-基-丙 氧基:) -喹啉 -3-甲氰  Third order: 4-(2-chloro-4-cyclopropyl-5-methoxy-phenylamino)-6-methoxy-7-(3-piperazin-1-yl-propoxy:) -quinoline-3-cyanocyanate
以 4-(2-氯 -4-环丙基 -5-甲氧基-苯氨基) -7-(3-氯-丙氧基) -6-甲氧基 -喹啉 -3- 甲氰和 N-叔丁氧羰基哌嗪为原料， 采用中间体 8第三、第四歩类似的方法合 成得到中间体 9， 4-(2-氯 -4-环丙基 -5-甲氧基-苯氨基) -6-甲氧基 -7-(3-哌嗪 -1- 基-丙氧基) -喹啉 -3-甲氰 （黄色固体， 890 mg)。  4-(2-Chloro-4-cyclopropyl-5-methoxy-phenylamino)-7-(3-chloro-propoxy)-6-methoxy-quinoline-3-carbonitrile N-tert-butoxycarbonylpiperazine is used as a raw material, and Intermediate 9, 4-(2-chloro-4-cyclopropyl-5-methoxy-benzene) is synthesized by a similar method to Intermediate 8 and the third. Amino)-6-methoxy-7-(3-piperazin-1-yl-propoxy)-quinoline-3-carbonitrile (yellow solid, 890 mg).
^ NMR (400 MHz, CD3OD): δ 8.85 (s, 1H), 8.02 (s, 1H), 7.40 (s, 1H), 7.19^ NMR (400 MHz, CD 3 OD): δ 8.85 (s, 1H), 8.02 (s, 1H), 7.40 (s, 1H), 7.19
(s, 1H), 7.04 (s, 1H), 4.50 (t, J = 5.5 Hz, 2H), 4.09 (s, 3H), 3.92 (s, 3H), 3.81 - 3.70 (m, 4H), 3.62 (t, J = 7.2 Hz, 2H), 3.51 - 3.45 (m, 1H), 2.86 (s, 1H), 2.58 - 2.48 (m, 2H), 2.39 (d, J= 8.2 Hz, 1H), 2.29 - 2.21 (m, 1H), 2.07 (dd, J= 8.2, 7.3 Hz, 1H), 1.03 (dd, J= 8.5, 1.9 Hz, 2H), 0.75 (dd, J= 5.3, 1.6 Hz, 2H)。 (s, 1H), 7.04 (s, 1H), 4.50 (t, J = 5.5 Hz, 2H), 4.09 (s, 3H), 3.92 (s, 3H), 3.81 - 3.70 (m, 4H), 3.62 ( t, J = 7.2 Hz, 2H), 3.51 - 3.45 (m, 1H), 2.86 (s, 1H), 2.58 - 2.48 (m, 2H), 2.39 (d, J = 8.2 Hz, 1H), 2.29 - 2.21 (m, 1H), 2.07 (dd, J= 8.2, 7.3 Hz, 1H), 1.03 (dd, J= 8.5, 1.9 Hz, 2H), 0.75 (dd, J= 5.3, 1.6 Hz, 2H).
MS m/z (ESI):523.2[M+H]。  MS m/z (ESI): 523.2 [M+H].
中间体 10: 4-(2,4-二氯 -5-甲氧基-苯氨基) -6-甲氧基 -7-(5-哌嗪 -1-基甲基- 呋喃 - -基:) -喹啉 -3-甲氰  Intermediate 10: 4-(2,4-Dichloro-5-methoxy-phenylamino)-6-methoxy-7-(5-piperazin-1-ylmethyl-furan-yl:) -quinoline-3-cyanocyanate
Figure imgf000031_0001
Figure imgf000031_0001
第一歩： 4-{4-[3-氰基 -4-(2,4-二氯 -5-甲氧基-苯氨基) -6-甲氧基 -喹啉 -7- 基] -呋喃 -2-基甲基 哌嗪 -1-甲酸叔丁酯  First 歩: 4-{4-[3-Cyano-4-(2,4-dichloro-5-methoxy-phenylamino)-6-methoxy-quinolin-7-yl]-furan Tert-butyl 2-methylmethylpiperazine-1-carboxylate
将 4-(2,4-二氯 -5-甲氧基-苯氨基) -7-(5-甲醛基 -呋喃 -3-基) -6-甲氧基 -喹啉 -3-甲氰 （中间体 3 ) ( 500 mg, 1.07 mmol)、 N-Boc-哌嗪 （400 mg, 2.2 mmol) 溶于甲醇 （10 mL) 中， 加入冰醋酸 （O. l mL) , 室温搅拌 2小时后， 在冰浴 冷却下分批加入硼氢化钠固体（12 mg, 3.2 mmol)。加完， 反应液室温搅拌过 夜。 向上述反应液中加入饱和氯化铵溶液及二氯甲烷， 分出有机相， 分别用 水和饱和食盐水洗涤， 无水硫酸钠干燥， 过滤减压浓缩。 剩余物用硅胶逐层 新分离纯化得到中间体 4-{4-[3-氰基 -4-(2,4-二氯 -5-甲氧基 -苯氨基:) -6-甲氧基- 喹啉 -7-基] -呋喃 -2-基甲基 哌嗪 -1-甲酸叔丁酯 （黄色固体， 495 mg)。 4-(2,4-Dichloro-5-methoxy-phenylamino)-7-(5-carbamoyl-furan-3-yl)-6-methoxy-quinoline-3-carbonitrile Intermediate 3) (500 mg, 1.07 mmol), N-Boc-piperazine (400 mg, 2.2 mmol) Dissolved in MeOH (10 mL), EtOAc (EtOAc)EtOAc. After the addition was completed, the reaction solution was stirred at room temperature overnight. To the above reaction mixture, a saturated aqueous solution of ammonium chloride and methylene chloride were added, and the organic phase was separated, washed with water and brine, dried over anhydrous sodium sulfate The residue was purified by silica gel layer chromatography to give the intermediate 4-{4-[3-cyano-4-(2,4-dichloro-5-methoxy-phenylamino:)-6-methoxy- tert-Butyl quinoline-7-yl]-furan-2-ylmethylpiperazine-1-carboxylate (yellow solid, 495 mg).
^ NMR (400 MHz, CD3OD): δ 8.41 (s, 1H), 8.23 (s, 1H), 8.06 (s, 1H), 7.80 (s, 1H), 7.57 (s, 1H), 7.22 (s, 1H), 6.95 (s, 1H), 4.11 (s, 3H), 3.90 (s, 3H), 3.67 (s, 2H), 3.47 - 3.45 (m, 4H), 2.51 (dd, J= 6.4, 3.0 Hz, 4H), 1.45 (s, 9H)。 ^ NMR (400 MHz, CD 3 OD): δ 8.41 (s, 1H), 8.23 (s, 1H), 8.06 (s, 1H), 7.80 (s, 1H), 7.57 (s, 1H), 7.22 (s , 1H), 6.95 (s, 1H), 4.11 (s, 3H), 3.90 (s, 3H), 3.67 (s, 2H), 3.47 - 3.45 (m, 4H), 2.51 (dd, J= 6.4, 3.0 Hz, 4H), 1.45 (s, 9H).
第二歩： 4-(2,4-二氯 -5-甲氧基-苯氨基) -6-甲氧基 -7-(5-哌嗪 -1-基甲基-呋 喃 -3-基:) -喹啉 -3-甲氰  Second: 4-(2,4-Dichloro-5-methoxy-phenylamino)-6-methoxy-7-(5-piperazin-1-ylmethyl-furan-3-yl: - quinoline-3-cyanide
将 4-{4-[3-氰基 -4-(2,4-二氯 -5-甲氧基-苯氨基: )-6-甲氧基 -喹啉 -7-基] -呋喃 4-{4-[3-Cyano-4-(2,4-dichloro-5-methoxy-phenylamino: )-6-methoxy-quinoline-7-yl]-furan
-2-基甲基 哌嗪 -1-甲酸叔丁酯 （495 mg, 0.78 mmol)溶于二氯甲烷 （10 mL) 中， 向上述溶液中加入 4N氯化氢的二氧六环溶液 （4 mL)， 室温搅拌过夜， 析出黄色固体。 减压过滤， 滤饼用无水乙醚洗涤， 干燥得到中间体 4-(2,4-二 氯 -5-甲氧基-苯氨基 )-6-甲氧基 -7-(5-哌嗪- μ基甲基 -呋喃 -3-基) -喹啉 -3-甲氰tert-Butyl -2-methylmethylpiperazine-1-carboxylate (495 mg, 0.78 mmol) was dissolved in dichloromethane (10 mL), and 4N hydrogen chloride in dioxane (4 mL) was added to the above solution. Stir at room temperature overnight to precipitate a yellow solid. Filtration under reduced pressure, the filter cake was washed with anhydrous diethyl ether and dried to give intermediate 4-(2,4-dichloro- 5 -methoxy-phenylamino) -6 -methoxy- 7- ( 5 -piperazine- Μ-methyl-furan- 3 -yl)-quinoline- 3 -cyanocyanate
(黄色固体， 360 mg)。 (yellow solid, 360 mg).
^ NMR (400 MHz, CD3OD): δ 8.95 (s, 1H), 8.54 (s, 1H), 8.20 (s, 1H), 8.15 (s, 1H), 7.70 (s, 1H), 7.47 (s, 1H), 7.44 (s, 1H), 4.55 (s, 2H), 4.21 (s, 3H), 3.95 (s, 3H), 3.62 - 3.51 (m, 8H)。 ^ NMR (400 MHz, CD 3 OD): δ 8.95 (s, 1H), 8.54 (s, 1H), 8.20 (s, 1H), 8.15 (s, 1H), 7.70 (s, 1H), 7.47 (s , 1H), 7.44 (s, 1H), 4.55 (s, 2H), 4.21 (s, 3H), 3.95 (s, 3H), 3.62 - 3.51 (m, 8H).
中间体 11 : 4-(2,4-二氯 -5-三氘代甲氧基-苯氨基) -7-(5-甲酰基 -呋喃 -3- 基) -6- -喹啉 -3-甲氰  Intermediate 11: 4-(2,4-Dichloro-5-tridecylmethoxy-phenylamino)-7-(5-formyl-furan-3-yl)-6--quinoline-3- Cyanide
Figure imgf000032_0001
Figure imgf000032_0001
第一歩： 1,5-二氯 -2-硝基 -4-三氘代甲氧基苯  The first choice: 1,5-dichloro-2-nitro-4-tridemethoxybenzene
将 2,4-二氯 -5-硝基苯酚 (2.6 g, 1 mmol)及无水碳酸钾粉末 (3.5 g, 2 mmol) 混合于 Ν,Ν-二甲基甲酰胺中 (40 mL), 搅拌半小时后向其中加入氘代碘甲烷 (0.94 mL, 15.1 mmol), 然后室温反应过夜。 TLC检测反应结束后， 加水炸灭 反应， 析出固体， 减压过滤， 滤饼分别用蒸馏水和少量无水乙醇洗涤， 真空 干燥， 得 1,5-二氯 -2-硝基 -4-三氘代甲氧基苯 (白色固体， 2.8 g)。 Mix 2,4-dichloro-5-nitrophenol (2.6 g, 1 mmol) and anhydrous potassium carbonate powder (3.5 g, 2 mmol) in hydrazine, hydrazine-dimethylformamide (40 mL). After stirring for half an hour, deuterated methyl iodide (0.94 mL, 15.1 mmol) was added and then allowed to react at room temperature overnight. After TLC detects the reaction, add water to destroy The reaction was carried out, and the solid was separated, and filtered under reduced pressure. The filter cake was washed with distilled water and a small amount of anhydrous ethanol, and dried in vacuo to give 1,5-dichloro-2-nitro-4-tridecyl methoxybenzene (white solid, 2.8 g).
H-NMR (400MHz, CDC13): δ7.57(1Η， s), 7.49(1H, s)。  H-NMR (400 MHz, CDC13): δ 7.57 (1 Η, s), 7.49 (1H, s).
MS m/z (ESI): 226·85[Μ+Η]。  MS m/z (ESI): 226.85 [Μ+Η].
第二歩： 2,4-二氯 -5-三氘代甲氧基 -苯胺  Second choice: 2,4-dichloro-5-tridecylmethoxy-aniline
将 1,5-二氯 -2-硝基 -4- (三氘代甲氧基)苯 (2.8 g, 12.52 mmol)溶于乙醇 /水 ( 50 mL/50 mL)的混合溶剂中， 向其中加入氯化铵固体 (335 mg, 6.26 mmol), 将反应混合物加热至 75GC， 向其中加入还原铁粉 （6.9 g, 125.2 mmol), 维持 在 75°C反应 2 h。 TLC检测显示反应结束后， 反应液冷却至室温， 过滤， 滤 液蒸干， 残余物溶于饱和 NaHC03溶液， 用二氯甲烷萃取， 有机相用无水硫 酸钠干燥， 过滤， 减压浓缩， 干燥得 2,4-二氯 -5-三氘代甲氧基 -苯胺 (白色固 体， 2.3 g)。 Dissolve 1,5-dichloro-2-nitro-4-(tridemethoxy)benzene (2.8 g, 12.52 mmol) in a mixed solvent of ethanol/water (50 mL/50 mL) to Ammonium chloride solid (335 mg, 6.26 mmol) was added, and the reaction mixture was heated to 75 G C, and reduced iron powder (6.9 g, 125.2 mmol) was added thereto, and the reaction was maintained at 75 ° C for 2 h. TLC analysis showed After the reaction, the reaction solution was cooled to room temperature, filtered, the filtrate was evaporated to dryness, the residue was dissolved in saturated NaHC0 3 solution, extracted with dichloromethane, the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and dried 2,4-Dichloro-5-trideuteromethoxy-phenylamine (white solid, 2.3 g).
ifi-NMR (400MHz, DMSO-d6): δ 7.21(1H， s), 6.54(1H, s), 5.48(2H, s)。 MS m/z (ESI): 198·9[Μ+Η]。  Ifi-NMR (400 MHz, DMSO-d6): δ 7.21. (1H, s), 6.54 (1H, s), 5.48 (2H, s). MS m/z (ESI): 198·9 [Μ+Η].
第三歩：三氟甲磺酸 -3-氰基 -4-(2,4-二氯 -5-三氘代甲氧基-苯氨基) -6-甲氧 基 -喹啉 -7-基酯  Third 歩: 3-cyano-4-(2,4-dichloro-5-tridecylmethoxy-phenylamino)-6-methoxy-quinolin-7-yl trifluoromethanesulfonate Ester
将 (4-氯 -3-氰基 -6-甲氧基 -7-喹啉基:)三氟甲磺酸酯 （参照文献 US2007208164A1 方法合成） (2 g, 5.47 mmol)及吡啶盐酸盐 (630 mg, 5.47 mmol)溶于 2-甲氧基乙醇 (10 mL), 向其中加入 2,4-二氯 -5- (三氘代甲氧基)苯 胺 （1.168 g, 6.02 mmol)。 然后将此混合物加热至 140°C反应 2 h。 TLC检测 反应结束后， 冷却至室温， 向其中加入水炸灭反应， 依次加入三乙胺及饱和 碳酸氢钠水溶液， 混合物用乙酸乙酯萃取， 有机相依次用水， 饱和食盐水洗 涤， 无水硫酸钠干燥， 蒸干溶剂， 残余物用硅胶柱层析纯化得三氟甲磺酸 -3- 氰基 -4-(2,4-二氯 -5-三氘代甲氧基-苯氨基: )-6-甲氧基 -喹啉 -7-基酯 （黄色固体， 2.16 g)。  (4-Chloro-3-cyano-6-methoxy-7-quinolyl:)trifluoromethanesulfonate (synthesized by the method US2007208164A1) (2 g, 5.47 mmol) and pyridine hydrochloride ( 630 mg, 5.47 mmol) was dissolved in 2-methoxyethanol (10 mL), and 2,4-dichloro-5-(tris-methoxy)anilide (1.168 g, 6.02 mmol) was added. The mixture was then heated to 140 ° C for 2 h. After the end of the TLC reaction, the reaction mixture was cooled to room temperature, and water was added to the mixture. The mixture was stirred and evaporated, and the mixture was evaporated. The sodium was dried, the solvent was evaporated to dryness, and the residue was purified to silica gel column chromatography -6-Methoxy-quinolin-7-yl ester (yellow solid, 2.16 g).
ifi-NMR (400MHz, DMS0-d6): δ 9.99(1H, s), 8.55(1H, s), 8.23(1H, s), 8.03(1H， s), 7.78(1H, s), 7.41(1H, s), 4.07(3H, s)。  Ifi-NMR (400MHz, DMS0-d6): δ 9.99(1H, s), 8.55(1H, s), 8.23(1H, s), 8.03(1H, s), 7.78(1H, s), 7.41(1H , s), 4.07 (3H, s).
MS m/z (ESI): 528·60[Μ+Η]。  MS m/z (ESI): 528·60 [Μ+Η].
第四歩： 4-(2,4-二氯 -5-三氘代甲氧基-苯氨基) -7-(5-甲酰基 -呋喃 -3-基) -6- 甲氧基 -喹啉 -3-甲氰 将 [3-氰基 -4-[2,4-二氯 -5- (三氘代甲氧基:)苯氨基 ]-6-甲氧基 -7-喹啉基]三 氟甲磺酸酯 (1.5 g, 3 mmol), (5-甲酰基 -3-呋喃基)硼酸 （839 mg, 6 mmol)及无 水碳酸钾粉末 （1.24 g, 9 mmol) 混合溶于 Ν,Ν-二甲基甲酰胺 (20 mL)中， 混 合物用氩气鼓泡 15分钟后向其中再加入催化剂 Pd(dppf)Cl2-C¾Cl2 (245 mg, 10 mol%), 加热至 100°C反应 18h。 TLC检测反应结束后， 冷却至室温， 向 反应液中加入饱和 NaHC03溶液， 乙酸乙酯萃取， 有机相依次用水和饱和食 盐水洗涤， 无水硫酸钠干燥， 过滤减压浓缩， 残余物用硅胶柱层析纯化得 4-(2,4-二氯 -5-三氘代甲氧基-苯氨基) -7-(5-甲酰基 -呋喃 -3-基:) -6-甲氧基 -喹啉 —3-甲氰 （黄色固体， 947 mg) o Fourth 歩: 4-(2,4-Dichloro-5-tridecylmethoxy-phenylamino)-7-(5-formyl-furan-3-yl)-6-methoxy-quinoline -3-methionine [3-Cyano-4-[2,4-dichloro-5-(tridemethoxymethoxy)phenylamino]-6-methoxy-7-quinolinyl]trifluoromethanesulfonate (1.5 g, 3 mmol), (5-formyl-3-furanyl)boronic acid (839 mg, 6 mmol) and anhydrous potassium carbonate powder (1.24 g, 9 mmol) dissolved in hydrazine, hydrazine-dimethyl In the formamide (20 mL), the mixture was bubbled with argon for 15 minutes, and then a catalyst Pd(dppf)Cl 2 -C3⁄4Cl 2 (245 mg, 10 mol%) was further added thereto, and the mixture was heated to 100 ° C for 18 hours. After completion of the reaction by TLC, cooled to room temperature, saturated NaHC0 3 solution was added to the reaction liquid, extracted with ethyl acetate, the organic phase was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure, the residue was purified by silica gel Purification by column chromatography to give 4-(2,4-dichloro-5-tridecylmethoxy-phenylamino)-7-(5-formyl-furan-3-yl:)-6-methoxy- Quinoline-3-carbonitrile (yellow solid, 947 mg) o
ifi-NMR (400MHz, DMSO-d6): δ 9.86(1H, s), 9.71(1H, s), 8.76(1H, s), 8.48(1H， s), 8.29(2H, s), 8.00(1H, s), 7.77(1H, s), 7.39(1H, s), 4.09(3H, s)。  Ifi-NMR (400MHz, DMSO-d6): δ 9.86 (1H, s), 9.71 (1H, s), 8.76 (1H, s), 8.48 (1H, s), 8.29 (2H, s), 8.00 (1H) , s), 7.77 (1H, s), 7.39 (1H, s), 4.09 (3H, s).
MS m/z (ESI): 474·70[Μ+Η]。  MS m/z (ESI): 474·70 [Μ+Η].
化合物实施例  Compound example
实施例 4-(4-氯 -2-环丙基 -5-甲氧基-苯氨基： )-7-[3-(4-—氘代甲基 -哌嗪 -1- -丙氧基 1-6-甲氧基 -喹啉 -3-甲氰  Example 4-(4-Chloro-2-cyclopropyl-5-methoxy-phenylamino: )-7-[3-(4--deuteromethyl-piperazin-1-propoxyl 1 -6-methoxy-quinoline-3-cyanate
Figure imgf000034_0001
Figure imgf000034_0001
将 4-(4-氯 -2-环丙基 -5-甲氧基-苯氨基： )-6-甲氧基 -7-(3-哌嗪 -1-基丙氧 基:) -3-腈基喹啉 (中间体 8)(69 mg, 0.13 mmol)溶于甲醇 （2 mL)中，依次向其中 加入 37% 的甲醛水溶液 (63 mg, 0.78 mmol) 及冰醋酸 (0.1 mL), 反应液室温 搅拌 2小时后向其中加入硼氘化钠 (16 mg, 0.39 mmol), 反应液继续在室温搅 拌 2小时。 反应结束后， 加入饱和氯化铵溶液淬灭反应， 二氯甲烷萃取， 有 机相用饱和食盐水洗涤， 干燥减压浓缩。 残余物硅胶柱层析分离纯化得目标 化合物 4-(4-氯 -2-环丙基 -5-甲氧基-苯氨基) -7-[3-(4-—氘代甲基 -哌嗪 -1-基) -丙 氧基] -6-甲氧基 -喹啉 -3-甲氰 （黄色固体， 36.5 mg)。  4-(4-Chloro-2-cyclopropyl-5-methoxy-phenylamino: )-6-methoxy-7-(3-piperazin-1-ylpropoxy:)-3- The nitrile quinoline (Intermediate 8) (69 mg, 0.13 mmol) was dissolved in methanol (2 mL), and then 37% aqueous formaldehyde (63 mg, 0.78 mmol) and glacial acetic acid (0.1 mL) were added to the reaction. After stirring at room temperature for 2 hours, sodium borohydride (16 mg, 0.39 mmol) was added and the mixture was stirred at room temperature for 2 hr. After completion of the reaction, the reaction was quenched with EtOAc (EtOAc)EtOAc. The residue was purified by silica gel column chromatography toield 4-(4-chloro-2-cyclopropyl-5-methoxy-phenylamino)-7-[3-(4--deuteromethyl-piperazine). -1-yl)-propoxy]-6-methoxy-quinoline-3-carbonitrile (yellow solid, 36.5 mg).
ifi-NMR (400MHz, CD3OD): δ8.34(1Η, d, J=3.6Hz), 7.72(1H, s), 7.28(1H, d, J=3.6Hz), 7.04(2H , s), 4.26(2H, t, J=6.0Hz), 3.99(3H, s), 3.86(3H, s), 2.70-2.89(10H, m), 2.52(2H, d, J=5.2Hz), 2.10-2.16(2H , m), 1.78-1.82(1H , m), 0.69-0.77(2H， m), 0.65-0.68(2H， m)。 Ifi-NMR (400MHz, CD 3 OD): δ 8.34 (1Η, d, J=3.6Hz), 7.72(1H, s), 7.28(1H, d, J=3.6Hz), 7.04(2H , s) , 4.26(2H, t, J=6.0Hz), 3.99(3H, s), 3.86(3H, s), 2.70-2.89(10H, m), 2.52(2H, d, J=5.2Hz), 2.10-2.16(2H , m), 1.78-1.82(1H , m), 0.69-0.77(2H, m), 0.65- 0.68 (2H, m).
MS m/z (ESI): 536·70[Μ+Η]。  MS m/z (ESI): 536.70 [Μ+Η].
实施例 2: 4-(4-氯 -2-环丙基 -5-甲氧基-苯氨基： )-7-[3-(4-二氘代甲基 -哌嗪 -1- -丙氧基 ]-6-甲氧基 -喹啉 -3-甲氰  Example 2: 4-(4-Chloro-2-cyclopropyl-5-methoxy-phenylamino: )-7-[3-(4-didecylmethyl-piperazin-1-propoxylate) -6-methoxy-quinoline-3-cyanate
Figure imgf000035_0001
Figure imgf000035_0001
将 4-(4-氯 -2-环丙基 -5-甲氧基-苯氨基： )-6-甲氧基 -7-(3-哌嗪 -1-基丙氧 基:) -3-腈基喹啉 (中间体 8 69 mg, 0.13 mmol)溶于甲醇 (2 mL)中， 向其中加入 浓度为 20%的二氘代甲醛溶液 (125 mg， 0.78 mmol)及冰醋酸 (0.05 mL)， 反应 液室温搅拌 2小时后向其中加入硼氢化钠固体 (15 mg, 0.39 mmol), 加完反应 液室温搅拌过夜。 反应结束后， 加入饱和氯化铵溶液淬灭反应， 二氯甲烷萃 取， 有机相用饱和食盐水洗涤， 干燥， 过滤减压浓缩， 残余物硅胶柱层析分 离纯化得到目标化合物 4-(4-氯 -2-环丙基 -5-甲氧基 -苯氨基：) -7-[3-(4-二氘代甲 基 -哌嗪 -1-基:) -丙氧基] -6-甲氧基 -喹啉 -3-甲氰 （黄色固体， 51.3 mg)。  4-(4-Chloro-2-cyclopropyl-5-methoxy-phenylamino: )-6-methoxy-7-(3-piperazin-1-ylpropoxy:)-3- The nitrile quinoline (intermediate 8 69 mg, 0.13 mmol) was dissolved in methanol (2 mL), and a 20% dioxane solution (125 mg, 0.78 mmol) and glacial acetic acid (0.05 mL) were added. After the reaction mixture was stirred at room temperature for 2 hours, sodium borohydride solid (15 mg, 0.39 mmol) was added, and the mixture was stirred at room temperature overnight. After the reaction is completed, the reaction is quenched with saturated aqueous ammonium chloride, and the mixture is evaporated. The organic phase is washed with brine, dried, filtered and evaporated Chloro-2-cyclopropyl-5-methoxy-phenylamino:)-7-[3-(4-dioxomethyl-piperazin-1-yl:)-propoxy]-6-A Oxy-quinoline-3-carbonitrile (yellow solid, 51.3 mg).
^-NMR (400MHz, CD3OD): δ8.34(1Η, s), 7.72(1H, s), 7.28(1H, s), 7.04(2H， s), 4.26(2H, t, J=6.0Hz), 3.99(3H, s), 3.86(3H, s), 2.74-2.99(10H, m), 2.57(1H, s), 2.12-2.17(2H , m), 1.78-1.82(1H , m), 0.75-0.79(2H , m), 0·65-0·74(2Η , m)。 ^-NMR (400MHz, CD 3 OD): δ 8.34(1Η, s), 7.72(1H, s), 7.28(1H, s), 7.04(2H, s), 4.26(2H, t, J=6.0 Hz), 3.99(3H, s), 3.86(3H, s), 2.74-2.99(10H, m), 2.57(1H, s), 2.12-2.17(2H , m), 1.78-1.82(1H , m) , 0.75-0.79 (2H , m), 0·65-0·74 (2Η, m).
MS m/z (ESI): 269·40[Μ+2Η]。  MS m/z (ESI): 269·40 [Μ+2Η].
实施例 3 : 4-(4-氯 -2-环丙基 -5-甲氧基-苯氨基： )-7-[3-(4-三氘代甲基 -哌嗪 -1- -丙氧基 ]-6-甲氧基 -喹啉 -3-甲氰  Example 3: 4-(4-Chloro-2-cyclopropyl-5-methoxy-phenylamino: )-7-[3-(4-tridemethyl-piperazin-1-propoxylate) -6-methoxy-quinoline-3-cyanate
Figure imgf000035_0002
将 4-(4-氯 -2-环丙基 -5-甲氧基-苯氨基： )-6-甲氧基 -7-(3-哌嗪 -1-基丙氧 基:) -3-腈基喹啉 (中间体 8 69 mg, 0.13 mmol)溶于甲醇 (2 mL)中， 依次向其中 加入浓度为 20%的二氘代甲醛溶液 (125 mg, 0.78 mmol)及冰醋酸 (0.05 mL) , 反应液在室温搅拌 2小时后向其中加入硼氘化钠固体 (16 mg, 0.39 mmol), 加 完反应液室温搅拌过夜。 反应结束后， 加入饱和氯化铵溶液淬灭反应， 二氯 甲烷萃取， 有机相分别用饱和碳酸氢钠溶液， 水和饱和食盐水洗涤， 干燥， 过滤减压浓缩。残余物硅胶柱层析分离纯化得到目标化合物 4-(4-氯 -2-环丙基 -5-甲氧基-苯氨基) -7-[3-(4-三氘代甲基 -哌嗪 -1-基)-丙氧基 ]-6-甲氧基 -喹啉 -3- 甲氰 （黄色固体， 36.5 mg)。
Figure imgf000035_0002
4-(4-Chloro-2-cyclopropyl-5-methoxy-phenylamino: )-6-methoxy-7-(3-piperazin-1-ylpropoxy:)-3- The nitrile quinoline (intermediate 8 69 mg, 0.13 mmol) was dissolved in methanol (2 mL), and a 20% dioxane-formaldehyde solution (125 mg, 0.78 mmol) and glacial acetic acid (0.05 mL) After the reaction mixture was stirred at room temperature for 2 hours, sodium borohydride solid (16 mg, 0.39 mmol) was added thereto, and the reaction mixture was stirred at room temperature overnight. After the reaction was completed, the mixture was evaporated to dryness crystals crystals crystals The residue was purified by silica gel column chromatography toield 4-(4-chloro-2-cyclopropyl-5-methoxy-phenylamino)-7-[3-(4-tridecylmethyl-piperazine). 1-yl)-propoxy]-6-methoxy-quinoline-3-carbonitrile (yellow solid, 36.5 mg).
ifi-NMR (400MHz, CD3OD): δ=8.33(1Η, s), 7.71(1H, s), 7.27(1H, s), 7.03(2H ， d, J=2.8Hz), 4.24(2H, t, J=6.0Hz), 3.98(3H, s), 3.86(3H, s), 2.57-2.77(10H, m), 2.08-2.15(2H, m), 1.77-1.82(1H ， m), 0.74-0.79(2H ， m), 0·65-0·69(2Η , m)。 Ifi-NMR (400MHz, CD 3 OD): δ=8.33(1Η, s), 7.71(1H, s), 7.27(1H, s), 7.03(2H , d, J=2.8Hz), 4.24(2H, t, J=6.0Hz), 3.98(3H, s), 3.86(3H, s), 2.57-2.77(10H, m), 2.08-2.15(2H, m), 1.77-1.82(1H , m), 0.74 -0.79 (2H , m), 0·65-0·69 (2Η, m).
MS m/z (ESI): 269·95[Μ+2Η]。  MS m/z (ESI): 269.95 [Μ+2Η].
实施例 4: 4-(2,4-二氯 -5-甲氧基-苯氨基) -7-[3-(4-—氘代甲基 -哌嗪 -1-基) - 丙 -6-甲氧基 -喹啉 -3-甲氰  Example 4: 4-(2,4-Dichloro-5-methoxy-phenylamino)-7-[3-(4--deuteromethyl-piperazin-1-yl)-propan-6- Methoxy-quinoline-3-cyanate
Figure imgf000036_0001
Figure imgf000036_0001
除了使用中间体 1代替中间体 8以外， 采用与实施例 1类似的方法合成 得到目标化合物 4-(2,4-二氯 -5-甲氧基 -苯氨基:) -7-[3-(4-—氘代甲基 -哌嗪 -1- 基) -丙氧基] -6-甲氧基 -喹啉 -3-甲氰 （黄色固体， 34.5 mg)。  The target compound 4-(2,4-dichloro-5-methoxy-phenylamino:)-7-[3-() was synthesized in a similar manner to Example 1 except that Intermediate 1 was used instead of Intermediate 8. 4--deuterated methyl-piperazin-1-yl)-propoxy]-6-methoxy-quinoline-3-carbonitrile (yellow solid, 34.5 mg).
lR NMR (400 MHz, CDC13): 58.69 ( s, lH ) ,7.48(s, 1H), 7.41(s, 1H),6.94(S, 1H),6.86(S, lH),6.49(s, lH),4.25(t, J=6.8Hz, 2H),3.78(s, 3H),3.67(s, 3H),2.62-2.71(m, 10H),2.45(s, 2H),2.12(t, J=6.8Hz, 2H)。  lR NMR (400 MHz, CDC13): 58.69 (s, lH), 7.48 (s, 1H), 7.41 (s, 1H), 6.94 (S, 1H), 6.86 (S, lH), 6.49 (s, lH) , 4.25 (t, J = 6.8 Hz, 2H), 3.78 (s, 3H), 3.67 (s, 3H), 2.62-2.71 (m, 10H), 2.45 (s, 2H), 2.12 (t, J = 6.8 Hz, 2H).
MS m/z (ESI):531.4[M+H]。  MS m/z (ESI): 531.4 [M+H].
实施例 5 : 4-(2,4-二氯 -5-甲氧基-苯氨基) -7-[3-(4-三氘代甲基 -哌嗪 -1-基) - 丙氧基 ]-6-甲氧基 -喹啉 -3-甲氰
Figure imgf000037_0001
Example 5: 4-(2,4-Dichloro-5-methoxy-phenylamino)-7-[3-(4-tridemethyl-piperazin-1-yl)-propoxy] -6-methoxy-quinoline-3-cyanate
Figure imgf000037_0001
除了使用中间体 1代替中间体 8以外， 采用与实施例 3类似的方法合成 得到目标化合物 4-(2,4-二氯 -5-甲氧基-苯氨基: )-7-[3-(4-三氘代甲基 -哌嗪 -1- 基:) -丙氧基] -6-甲氧基 -喹啉 -3-甲氰 （黄色固体， 22.5 mg)。  The target compound 4-(2,4-dichloro-5-methoxy-phenylamino: )-7-[3-() was synthesized in a similar manner to Example 3 except that Intermediate 1 was used instead of Intermediate 8. 4-tridemethyl-piperazin-1-yl:)-propoxy]-6-methoxy-quinoline-3-carbonitrile (yellow solid, 22.5 mg).
lR NMR (400 MHz, CDC13): 58.68(s, lH),7.49(s, 1H), 7.41(s, lH),6.95(s, 1H), 6.87(s, lH),6.51(s, lH),4.25(t, J=6.4Hz, 2H),3.79(s, 3H), 3.68(s, 3H),2.68-2.96(m, 10H),2.133-2.154(m,2H)。  lR NMR (400 MHz, CDC13): 58.68 (s, lH), 7.49 (s, 1H), 7.41 (s, lH), 6.95 (s, 1H), 6.87 (s, lH), 6.51 (s, lH) , 4.25 (t, J = 6.4 Hz, 2H), 3.79 (s, 3H), 3.68 (s, 3H), 2.68-2.96 (m, 10H), 2.133-2.154 (m, 2H).
MS m/z (ESI): 533·2[Μ+Η]。  MS m/z (ESI): 533·2 [Μ+Η].
实施例 6: 4-(2,4-二氯 -5-甲氧基-苯氨基) -7-[3-(4-二氘代甲基 -哌嗪 -1-基) - 丙氧 ]-6-甲氧基 -喹啉 -3-甲氰  Example 6: 4-(2,4-Dichloro-5-methoxy-phenylamino)-7-[3-(4-dioxomethyl-piperazin-1-yl)-propoxy]- 6-methoxy-quinoline-3-cyanate
除了使用中间体 1代替中间体 8以外， 采用与实施例 2类似的方法合成 得到目标化合物 4-(2,4-二氯 -5-甲氧基 -苯氨基:) -7-[3-(4-二氘代甲基 -哌嗪 -1- 基) -丙氧基] -6-甲氧基 -喹啉 -3-甲氰 (黄色固体， 18 mg)。  The target compound 4-(2,4-dichloro-5-methoxy-phenylamino:)-7-[3-() was synthesized in a similar manner to Example 2 except that Intermediate 1 was used instead of Intermediate 8. 4-Deuteromethyl-piperazin-1-yl)-propoxy]-6-methoxy-quinoline-3-carbonitrile (yellow solid, 18 mg).
^ NMR (400 MHz, OMSO-d6): 58.68(s, lH),7.49(s, lH),7.41(s, lH),6.94(s lH),6.86(s, lH),6.63(s, 1H), 4.30(t, J = 6.4 Hz, 2H),3.85(s, 3H),3.74(s, 3H),3.30-3.34(m, 2H),2.79-2.99(m, 6H),2.73-2.78(m, 3H),2.17-2.24(m,2H)。  ^ NMR (400 MHz, OMSO-d6): 58.68 (s, lH), 7.49 (s, lH), 7.41 (s, lH), 6.94 (s lH), 6.86 (s, lH), 6.63 (s, 1H) ), 4.30 (t, J = 6.4 Hz, 2H), 3.85 (s, 3H), 3.74 (s, 3H), 3.30-3.34 (m, 2H), 2.79-2.99 (m, 6H), 2.73-2.78 ( m, 3H), 2.17-2.24 (m, 2H).
MS m/z (ESI): 532·4[Μ+Η]。  MS m/z (ESI): 532·4 [Μ+Η].
实施例 7: 4-(2,4-二氯 -5-甲氧基-苯氨基) -7-{3-[4-(l-氘代-环丙基) -哌嗪 -1- 基] -丙氧基}-6-甲氧基 -喹啉 -3-甲氰  Example 7: 4-(2,4-Dichloro-5-methoxy-phenylamino)-7-{3-[4-(l-deutero-cyclopropyl)-piperazin-1-yl] -propoxy}-6-methoxy-quinoline-3-cyanide
Figure imgf000037_0003
将 4-(2,4-二氯 -5-甲氧基-苯氨基) -6-甲氧基 -7-(3-哌嗪 -1-基丙氧基)喹啉 -3- 甲氰（中间体 1 100 mg, 0.1936 mmol)溶于甲醇 (5 mL)中， 向上述溶液中依次 加入 (1-乙氧基环丙氧基) -三甲基 -硅烷 (1.936 mmol), 冰醋酸 (1.936 mmol), 加 完， 反应液在 60 °C加热搅拌 1小时后， 冰浴冷却下， 向上述反应液中缓慢分 批加入四氘代硼氢化钠固体 (1.936 mmol), 加完， 反应液室温搅拌过夜。 向反 应液中加入饱和氯化铵溶液淬灭反应， 二氯甲烷萃取， 有机相分别用水， 饱 和食盐水洗涤， 无水硫酸钠干燥， 过滤减压浓缩。 剩余物用硅胶柱层析分离 纯化得到目标化合物 4-(2,4-二氯 -5-甲氧基-苯氨基： )-7-{3-[4-(1-氘代 -环丙基) - 哌嗪 -1-基] -丙氧基 6-甲氧基 -喹啉 -3-甲氰 （白色固体， 26 mg)。
Figure imgf000037_0003
4-(2,4-Dichloro-5-methoxy-phenylamino)-6-methoxy-7-(3-piperazin-1-ylpropoxy)quinoline-3-carbonitrile Intermediate 1 100 mg, 0.1936 mmol) was dissolved in methanol (5 mL). (1-ethoxycyclopropoxy)-trimethyl-silane (1.936 mmol), glacial acetic acid (1.936). After the addition, the reaction mixture was heated and stirred at 60 ° C for 1 hour. After cooling in an ice bath, sodium tetrahydroborohydride solid (1.936 mmol) was slowly added portionwise to the above reaction mixture, and the reaction mixture was allowed to stand at room temperature. Stir overnight. The reaction mixture was quenched with aq. EtOAc EtOAc. The residue was purified by silica gel column chromatography to give the title compound 4-(2,4-dichloro-5-methoxy-phenylamino:)-7-{3-[4-(1-indole-cyclopropyl) ) - piperazin-1-yl]-propoxy 6-methoxy-quinoline-3-carbonitrile (white solid, 26 mg).
lR NMR (400 MHz, CDC13): 58.63(s,lH),7.41(s, lH),7.34(s, lH),6.86(s, lH),6.74(s, lH),6.42(s, lH),4.19-4.22(m,2H),3.71(s,3H),3.61(s, 3H),2.54-2.99(m, 10H),2.22(m, 2H),0.79-0.86(m, 2H),0.68-0.71(m, 2H)。  lR NMR (400 MHz, CDC13): 58.63 (s, lH), 7.41 (s, lH), 7.34 (s, lH), 6.86 (s, lH), 6.74 (s, lH), 6.42 (s, lH) , 4.19-4.22 (m, 2H), 3.71 (s, 3H), 3.61 (s, 3H), 2.54-2.99 (m, 10H), 2.22 (m, 2H), 0.79-0.86 (m, 2H), 0.68 -0.71 (m, 2H).
MS m/z (ESI):556.2[M+H]。  MS m/z (ESI): 556.2 [M+H].
实施例 8: 7-{3-[3- (双-一氘代甲基-氨基) -吡咯烷 -1-基] -丙氧基 H-(2,4-二 氯—5— -苯氨基 )-6—甲氧基 -喹啉 -3-甲氰 Example 8: 7-{3-[3-(Bis-monodecylmethyl-amino)-pyrrolidin-1-yl]-propoxy H-(2,4-dichloro-5-phenylamino -6-methoxy-quinoline- 3 -cyanocyanate
Figure imgf000038_0001
Figure imgf000038_0001
除了使用中间体 2代替中间体 8以外， 采用与实施例 1类似的方法合成 得到目标化合物 7-{3-[3- (双-一氘代甲基-氨基) -吡咯烷 -1-基] -丙氧基 }-4-(2,4- 二氯 -5-甲氧基 -苯氨基:) -6-甲氧基 -喹啉 -3-甲氰 （黄色固体， 18 mg)。  The target compound 7-{3-[3-(bis-monodecylmethyl-amino)-pyrrolidin-1-yl] was synthesized by a method similar to Example 1 except that Intermediate 2 was used instead of Intermediate 8. -propoxy}-4-(2,4-dichloro-5-methoxy-phenylamino:)-6-methoxy-quinoline-3-carbonitrile (yellow solid, 18 mg).
lR NMR (400 MHz, CDC13): 58.64(s, lH),7.48(s, 1H), 7.39(s, lH),6.99(m, 2H), 6.54(s, lH),4.25(m, 2H),3.81(s, 3H), 3.69(s, 3H), 3.33(m, 2H),2.77-2.91(m, 7H),2.48(m, 4H),2.16(m, 3H),2.00(m, 1H)。  lR NMR (400 MHz, CDC13): 58.64 (s, lH), 7.48 (s, 1H), 7.39 (s, lH), 6.99 (m, 2H), 6.54 (s, lH), 4.25 (m, 2H) , 3.81(s, 3H), 3.69(s, 3H), 3.33(m, 2H), 2.77-2.91(m, 7H), 2.48(m, 4H), 2.16(m, 3H), 2.00(m, 1H) ).
MS m/z (ESI):274.4[M+2H]。  MS m/z (ESI): 274.4 [M+2].
实施例 9: 7-{3-[3- (双-三氘代甲基-氨基) -吡咯烷 -1-基]-丙氧基 H-(2,4-二 氯—5—甲氧基-苯氨基 )-6—甲氧基 -喹啉 -3-甲氰 i3/: O 6/-iil£iiAV Example 9: 7-{3-[3-(Bis-tris-methyl-amino)-pyrrolidin-1-yl]-propoxy H-(2,4-dichloro-5-methoxy -phenylamino)-6-methoxy-quinoline- 3 -cyanocyanate I3/: O 6/-iil£iiAV
Figure imgf000039_0001
Figure imgf000039_0001
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Figure imgf000040_0001
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Figure imgf000040_0001
除了使用中间体 6代替中间体 8以外， 采用与实施例 2类似的方法合成 得到目标化合物 4-(2,4-二氯 -5-甲氧基 -苯氨基:) -7-[3-(4-二氘代甲基 -哌嗪 -1- 基) -丙小炔基] -6-甲氧基 -喹啉 -3-甲氰 （黄色固体， 12 mg)。  The target compound 4-(2,4-dichloro-5-methoxy-phenylamino:)-7-[3-() was synthesized in a similar manner to Example 2 except that Intermediate 6 was used instead of Intermediate 8. 4-Di-deuterated methyl-piperazin-1-yl)-propandinyl]-6-methoxy-quinoline-3-carbonitrile (yellow solid, 12 mg).
lH NMR (400 MHz, CDC13): 58.56(s, lH),8.17(s, lH),7.53(s, 1H), 7.47(s, lH),6.92(s, lH),3.96(s, 3H),3.81(s, 3H),3.72(s, 2H),3.47(m, 2H),3.16-3.19(m, 2H),3.02-3.04(m, 4H),2.78(s, 1H)。  lH NMR (400 MHz, CDC13): 58.56 (s, lH), 8.17 (s, lH), 7.53 (s, 1H), 7.47 (s, lH), 6.92 (s, lH), 3.96 (s, 3H) , 3.81 (s, 3H), 3.72 (s, 2H), 3.47 (m, 2H), 3.16-3.19 (m, 2H), 3.02-3.04 (m, 4H), 2.78 (s, 1H).
MS m/z ESI):512.4[M+H]。  MS m/z ESI): 512.4 [M+H].
实施例 12: 4-(2,4-二氯 -5-甲氧基-苯氨基) -7-{5-[(4-甲基 -哌嗪 -1-基) -一氘 代甲 -喹啉 -3-甲氰  Example 12: 4-(2,4-Dichloro-5-methoxy-phenylamino)-7-{5-[(4-methyl-piperazin-1-yl)-indolyl-quinoline Porphyrin-3-cyanide
Figure imgf000040_0002
Figure imgf000040_0002
分别采用中间体 3和 N-甲基哌嗪代替甲醛和中间体 8以外，采用与实施 例 1类似的方法合成得到目标化合物 4-(2,4-二氯 -5-甲氧基 -苯氨基:) -7-{5-[(4- 甲基 -哌嗪 -1-基:) -一氘代甲基] -呋喃 -3-基 6-甲氧基 -喹啉 -3-甲氰 （黄色固体， 21 mg)。  The target compound 4-(2,4-dichloro-5-methoxy-phenylamino) was synthesized in a similar manner to Example 1 except that Intermediate 3 and N-methylpiperazine were used instead of formaldehyde and Intermediate 8. :) -7-{5-[(4-Methyl-piperazin-1-yl:)--deuteromethyl]-furan-3-yl 6-methoxy-quinoline-3-carbonitrile Yellow solid, 21 mg).
lH NMR (300 MHz, OMSO-d6): 58.72(s, lH),8.17(s, 1H), 8.08(s, lH),7.51(m, 2H),6.99(s, lH),6.85(s, lH),6.76(s, lH),6.54(s, lH),3.84(s, 3H),3.69(s, 3H),3.63(s, lH),2.68-2.94(m, 8H),2.38(s, 3H)。  lH NMR (300 MHz, OMSO-d6): 58.72 (s, lH), 8.17 (s, 1H), 8.08 (s, lH), 7.51 (m, 2H), 6.99 (s, lH), 6.85 (s, lH), 6.76 (s, lH), 6.54 (s, lH), 3.84 (s, 3H), 3.69 (s, 3H), 3.63 (s, lH), 2.68-2.94 (m, 8H), 2.38 (s) , 3H).
MS m/z (ESI):277.9[M+2H]。  MS m/z (ESI): 277.9 [M+2].
实施例 13 : 4-(2,4-二氯 -5-甲氧基-苯氨基) -7-[5- (二甲胺基-一氘代甲基) - 呋喃 -甲氰  Example 13: 4-(2,4-Dichloro-5-methoxy-phenylamino)-7-[5-(dimethylamino-monodecylmethyl)-furan-cyanate
Figure imgf000040_0003
分别采用中间体 3和二甲胺盐酸盐替换甲醛水溶液和中间体 8， 采用实 施例 1 类似的方法合成得到目标化合物 4-(2,4-二氯 -5-甲氧基 -苯氨 基 )-7-[5- (二甲胺基-一氘代甲基) -呋喃—3—基 ]-6—甲氧基 -喹啉—3—甲氰 （黄色固 体， 11 mg) o
Figure imgf000040_0003
The target aqueous compound 4-(2,4-dichloro-5-methoxy-phenylamino) was synthesized by the similar method of Example 1 by replacing the aqueous formaldehyde solution and the intermediate 8 with Intermediate 3 and dimethylamine hydrochloride, respectively. - 7 -[ 5 -( dimethylamino-monodecylmethyl)-furan-3-yl]-6-methoxy-quinoline-3-cyanoic acid (yellow solid, 11 mg) o
^ NMR (300 MHz, OMSO-d6): 58.38(s, lH),8.14(s, lH),7.99(s, lH),7.50(s lH),7.20-7.26(m, 2H),6.83(s, lH),4.15(s, lH),3.94(s, 3H),3.77(s, 3H),3.00-3.07(m, 3H),2.72(s, 3H)。  ^ NMR (300 MHz, OMSO-d6): 58.38 (s, lH), 8.14 (s, lH), 7.99 (s, lH), 7.50 (s lH), 7.20-7.26 (m, 2H), 6.83 (s) , lH), 4.15 (s, lH), 3.94 (s, 3H), 3.77 (s, 3H), 3.00-3.07 (m, 3H), 2.72 (s, 3H).
MS m/z (ESI):249.4[M+2H]。  MS m/z (ESI): 249.4 [M+2].
实施例 14: 4-(2-氯 -4-环丙基 -5-甲氧基-苯氨基) -7-[3-(4-—氘代甲基 -哌嗪 -1- -丙氧基 ]-6-甲氧基 -喹啉 -3-甲氰  Example 14: 4-(2-Chloro-4-cyclopropyl-5-methoxy-phenylamino)-7-[3-(4--deuteromethyl-piperazin-1-propoxy) ]-6-methoxy-quinoline-3-cyanide
Figure imgf000041_0001
Figure imgf000041_0001
除了使用中间体 9代替中间体 8以外， 采用与实施例 1类似的方法合成 得到目标化合物 4-(2-氯 -4-环丙基 -5-甲氧基 -苯氨基:) -7-[3-(4-—氘代甲基 -哌嗪 -1-基) -丙氧基] -6-甲氧基 -喹啉 -3-甲氰 （黄色固体， 54 mg)。  The target compound 4-(2-chloro-4-cyclopropyl-5-methoxy-phenylamino:)-7-[ 3-(4-Deuteromethyl-piperazin-1-yl)-propoxy]-6-methoxy-quinoline-3-carbonitrile (yellow solid, 54 mg).
lR NMR (400 MHz, CD3OD): δ 8.37 (s, 1H), 7.74 - 7.70 (m, 1H), 7.34 - 7.30 (m, 1H), 7.03 (s, 1H), 6.99 - 6.94 (m, 1H), 4.33 - 4.26 (m, 2H), 4.01 (s, 3H), 3.88 (s, 3H), 3.16 - 3.00 (m, 4H), 2.90 - 2.78 (m, 2H), 2.72 - 2.67 (m, 2H), 2.26 - 2.11 (m, 4H), 2.08 - 2.01 (m, 1H), 1.02 - 0.96 (m, 2H), 0.75-0.69 (m, 2H)。 lR NMR (400 MHz, CD 3 OD): δ 8.37 (s, 1H), 7.74 - 7.70 (m, 1H), 7.34 - 7.30 (m, 1H), 7.03 (s, 1H), 6.99 - 6.94 (m, 1H), 4.33 - 4.26 (m, 2H), 4.01 (s, 3H), 3.88 (s, 3H), 3.16 - 3.00 (m, 4H), 2.90 - 2.78 (m, 2H), 2.72 - 2.67 (m, 2H), 2.26 - 2.11 (m, 4H), 2.08 - 2.01 (m, 1H), 1.02 - 0.96 (m, 2H), 0.75-0.69 (m, 2H).
MS m/z (ESI):537.1 [M+H]。  MS m/z (ESI): 537.1 [M+H].
实施例 15 : 4-(2-氯 -4-环丙基 -5-甲氧基-苯氨基) -7-[3-(4-二氘代甲基 -哌嗪 -1- -丙氧基 ]-6-甲氧基 -喹啉 -3-甲氰  Example 15: 4-(2-Chloro-4-cyclopropyl-5-methoxy-phenylamino)-7-[3-(4-dioxomethyl-piperazin-1-propoxy) ]-6-methoxy-quinoline-3-cyanide
Figure imgf000041_0002
除了使用中间体 9代替中间体 8以外， 采用与实施例 2类似的方法合成 得到目标化合物 4-(2-氯 -4-环丙基 -5-甲氧基 -苯氨基:) -7-[3-(4-二氘代甲基 -哌嗪 -1-基) -丙氧基] -6-甲氧基 -喹啉 -3-甲氰 （黄色固体， 34 mg)。
Figure imgf000041_0002
The target compound 4-(2-chloro-4-cyclopropyl-5-methoxy-phenylamino:)-7-[ 3-(4-Di-deuteromethyl-piperazin-1-yl)-propoxy]-6-methoxy-quinoline-3-carbonitrile (yellow solid, 34 mg).
lR NMR (400 MHz, CD3OD): δ 8.37 (s, 1H), 7.72 (d, J = 1.9 Hz, 1H), 7.32 (s, 1H), 7.03 (s, 1H), 6.96 (s, 1H), 4.33 - 4.26 (m, 2H), 4.01 (s, 3H), 3.88 (s, 3H), 3.20 - 3.01 (m, 4H), 2.89 - 2.77 (m, 4H), 2.73 - 2.67 (m, 1H), 2.24 - 2.12 (m, 4H), 2.08 - 2.03 (m, 1H), 1.01 - 0.96 (m, 2H), 0.74 - 0.68 (m, 2H)。 lR NMR (400 MHz, CD 3 OD): δ 8.37 (s, 1H), 7.72 (d, J = 1.9 Hz, 1H), 7.32 (s, 1H), 7.03 (s, 1H), 6.96 (s, 1H) ), 4.33 - 4.26 (m, 2H), 4.01 (s, 3H), 3.88 (s, 3H), 3.20 - 3.01 (m, 4H), 2.89 - 2.77 (m, 4H), 2.73 - 2.67 (m, 1H) ), 2.24 - 2.12 (m, 4H), 2.08 - 2.03 (m, 1H), 1.01 - 0.96 (m, 2H), 0.74 - 0.68 (m, 2H).
MS m/z (ESI):538.2[M+H]。  MS m/z (ESI): 538.2 [M+H].
实施例 16: 4-(2-氯 -4-环丙基 -5-甲氧基-苯氨基) -7-[3-(4-三氘代甲基 -哌嗪 -1- -丙氧基 ]-6-甲氧基 -喹啉 -3-甲氰  Example 16: 4-(2-Chloro-4-cyclopropyl-5-methoxy-phenylamino)-7-[3-(4-tridemethyl-piperazin-1-propoxy) ]-6-methoxy-quinoline-3-cyanide
Figure imgf000042_0001
Figure imgf000042_0001
除了使用中间体 9代替中间体 8以外， 采用与实施例 3类似的方法合成 得到目标化合物 4-(2-氯 -4-环丙基 -5-甲氧基-苯氨基： )-7-[3-(4-三氘代甲基 -哌嗪 -1-基) -丙氧基] -6-甲氧基 -喹啉 -3-甲氰 （黄色固体， 26 mg)。  The target compound 4-(2-chloro-4-cyclopropyl-5-methoxy-phenylamino: )-7-[ 3-(4-Tridecylmethyl-piperazin-1-yl)-propoxy]-6-methoxy-quinoline-3-carbonitrile (yellow solid, 26 mg).
^ NMR (400 MHz, CD3OD): δ 8.37 (s, 1H), 7.72 (s, 1H), 7.32 (s, 1H), 7.03 (s, 1H), 6.96 (s, 1H), 4.30 (t, J = 6.2 Hz, 2H), 4.01 (s, 3H), 3.89 (s, 3H), 3.30 - 3.03 (m, 4H), 2.91 - 2.76 (m, 2H), 2.26 - 2.13 (m, 4H), 2.09 - 2.02 (m, 1H), 1.02 - 0.96 (m, 2H), 0.75 - 0.70 (m, 2H)。 ^ NMR (400 MHz, CD 3 OD): δ 8.37 (s, 1H), 7.72 (s, 1H), 7.32 (s, 1H), 7.03 (s, 1H), 6.96 (s, 1H), 4.30 (t , J = 6.2 Hz, 2H), 4.01 (s, 3H), 3.89 (s, 3H), 3.30 - 3.03 (m, 4H), 2.91 - 2.76 (m, 2H), 2.26 - 2.13 (m, 4H), 2.09 - 2.02 (m, 1H), 1.02 - 0.96 (m, 2H), 0.75 - 0.70 (m, 2H).
MS m/z (ESI):539.2[M+H]。  MS m/z (ESI): 539.2 [M+H].
实施例 17: 4-(2,4-二氯 -5-甲氧基-苯氨基) -7-[5- (吗啉 -4-基-一氘代甲基) - 呋喃 氰
Figure imgf000042_0002
分别采用中间体 3和吗啡啉代替甲醛水溶液和中间体 8， 用实施例 1类 似的方法合成得到目标化合物 4-(2,4-二氯 -5-甲氧基 -苯氨基:) -7-[5- (吗啉 -4-基- 一氘代甲基) -呋喃 -3-基] -6-甲氧基 -喹啉 -3-甲氰 （黄色固体， 12 mg)。 Example 17: 4-(2,4-Dichloro-5-methoxy-phenylamino)-7-[5-(morpholin-4-yl-monodecylmethyl)-furan cyanide
Figure imgf000042_0002
The target compound 4-(2,4-dichloro-5-methoxy-phenylamino:)-7- was synthesized by the similar method of Example 1 using Intermediate 3 and morpholine in place of the aqueous formaldehyde solution and Intermediate 8. [5-(morpholin-4-yl-monodecylmethyl)-furan-3-yl]-6-methoxy-quinoline-3-carbonitrile (yellow solid, 12 mg).
^ NMR (400 MHz, CD3OD):5 8.42 (s, 1H), 8.24 (s, 1H), 8.07 (s, 1H), 7.81 (s, 1H), 7.57 (s, 1H), 7.22 (s, 1H), 6.97 (s, 1H), 4.11 (s, 3H), 3.90 (s, 3H), 3.74 - 3.70 (m, 4H), 3.64 (s, 1H), 2.60 - 2.55 (m, 4H)。 ^ NMR (400 MHz, CD 3 OD): 5 8.42 (s, 1H), 8.24 (s, 1H), 8.07 (s, 1H), 7.81 (s, 1H), 7.57 (s, 1H), 7.22 (s , 1H), 6.97 (s, 1H), 4.11 (s, 3H), 3.90 (s, 3H), 3.74 - 3.70 (m, 4H), 3.64 (s, 1H), 2.60 - 2.55 (m, 4H).
MS m/z (ESI):540.4[M+H]。  MS m/z (ESI): 540.4 [M+H].
实施例 18: 4-(2,4-二氯 -5-甲氧基-苯氨基) -7-{5-[(4-二甲基氨基 -哌啶 -1- 基)-一氘代甲基 -呋喃 -3-基}-6-甲氧基 -喹啉 -3-甲氰  Example 18: 4-(2,4-Dichloro-5-methoxy-phenylamino)-7-{5-[(4-dimethylamino-piperidin-1-yl)-indolyl Radyl-furan-3-yl}-6-methoxy-quinoline-3-cyanate
Figure imgf000043_0001
Figure imgf000043_0001
分别采用中间体 3和 4-N， N-二甲基氨基哌啶代替甲醛和中间体 8， 用 实施例 1 类似的方法合成得到目标化合物 4-(2,4-二氯 -5-甲氧基 -苯氨 基 )-7-{5-[(4-二甲基氨基 -哌啶 -1-基) -一氘代甲基] -呋喃 -3-基 6-甲氧基 -喹啉 —3-甲氰 （黄色固体， 9 mg) o Intermediate 3 and 4-N,N-dimethylaminopiperidine were used instead of formaldehyde and intermediate 8, respectively, and the target compound 4-(2,4-dichloro-5-methoxy) was synthesized by a similar method as in Example 1. -Benzylamino)- 7 - {5 -[(4-dimethylamino-piperidin-1-yl)-monodeuteromethyl]-furan-3-yl 6-methoxy-quinoline-3 - methionine (yellow solid, 9 mg) o
^ NMR (400 MHz, CD3OD): δ 8.43 (s, 1H), 8.24 (s, 1H), 8.07 (s, 1H), 7.82 (s, 1H), 7.58 (s, 1H), 7.23 (s, 1H), 6.97 (s, 1H), 4.12 (s, 3H), 3.90 (s, 3H), 3.70 (s, 1H), 2.82 (s, 6H), 2.32 - 2.16 (m, 4H), 2.13 - 2.00 (m, 5H)。 ^ NMR (400 MHz, CD 3 OD): δ 8.43 (s, 1H), 8.24 (s, 1H), 8.07 (s, 1H), 7.82 (s, 1H), 7.58 (s, 1H), 7.23 (s , 1H), 6.97 (s, 1H), 4.12 (s, 3H), 3.90 (s, 3H), 3.70 (s, 1H), 2.82 (s, 6H), 2.32 - 2.16 (m, 4H), 2.13 - 2.00 (m, 5H).
MS m/z (ESI):581.2[M+H]。  MS m/z (ESI): 581.2 [M+H].
实施例 19 : 4-(2,4-二氯 -5-甲氧基-苯氨基) -7-[4- (吗啡啉 -4-基-一氘代甲 基) - 3-甲氰
Figure imgf000043_0002
Example 19: 4-(2,4-Dichloro-5-methoxy-phenylamino)-7-[4-(morpholine-4-yl-monodecylmethyl)-3-cyanoic acid
Figure imgf000043_0002
分别采用中间体 5和吗啡啉代替甲醛水溶液和中间体 8， 用实施例 1类 似的方法合成得到 目标化合物 4-(2,4-二氯 -5-甲氧基 -苯氨基：) -7-[4- (吗啡啉 -4-基-一氘代甲基：) -呋喃 -2-基] -6-甲氧基 -喹啉 -3-甲氰 （黄色固体， 15 mg)。  The target compound 4-(2,4-dichloro-5-methoxy-phenylamino:)-7- was synthesized by the similar method of Example 1 using Intermediate 5 and morpholine in place of the aqueous formaldehyde solution and Intermediate 8. [4-(morpholine-4-yl-monodeuteromethyl:)-furan-2-yl]-6-methoxy-quinoline-3-carbonitrile (yellow solid, 15 mg).
^ NMR (400 MHz, CD3OD): δ 8.41 (s, 1H), 8.31 (s, 1H), 7.83 (s, 1H), 7.70 (s, 1H), 7.57 (s, 1H), 7.32 (s, 1H), 7.22 (s, 1H), 4.14 (s, 3H), 3.90 (s, 3H), 3.77 - 3.73 (m, 4H), 3.57 (s, 1H), 2.67 - 2.61 (m, 4H)。 MS m/z (ESI):540.4[M+H]。 ^ NMR (400 MHz, CD 3 OD): δ 8.41 (s, 1H), 8.31 (s, 1H), 7.83 (s, 1H), 7.70 (s, 1H), 7.57 (s, 1H), 7.32 (s , 1H), 7.22 (s, 1H), 4.14 (s, 3H), 3.90 (s, 3H), 3.77 - 3.73 (m, 4H), 3.57 (s, 1H), 2.67 - 2.61 (m, 4H). MS m/z (ESI): 540.4 [M+H].
实施例 20: 4-(2,4-二氯 -5-甲氧基-苯氨基) -7-[4-(4-—氘代甲基 -哌嗪 -1-基) - 丁氧基 ]-6-甲氧基 -喹啉 -3-甲氰  Example 20: 4-(2,4-Dichloro-5-methoxy-phenylamino)-7-[4-(4--deuteromethyl-piperazin-1-yl)-butoxy] -6-methoxy-quinoline-3-cyanate
Figure imgf000044_0001
Figure imgf000044_0001
除了使用中间体 4代替中间体 8以外， 采用与实施例 1类似的方法合成 得到目标化合物 4-(2,4-二氯 -5-甲氧基 -苯氨基:) -7-[4-(4-—氘代甲基 -哌嗪 -1- 基) -丁氧基] -6-甲氧基 -喹啉 -3-甲氰 （黄色固体， 20 mg)。  In the same manner as in Example 1, except that Intermediate 4 was used instead of Intermediate 8, the title compound 4-(2,4-dichloro-5-methoxy-phenylamino:)-7-[4-( 4--deuterated methyl-piperazin-1-yl)-butoxy]-6-methoxy-quinoline-3-carbonitrile (yellow solid, 20 mg).
^ NMR (400 MHz, CD3OD): δ 8.41 (s, 1H), 7.73 (s, 1H), 7.58 (s, 1H), 7.34 (s, 1H), 7.20 (s, 1H), 4.26 (t, J = 6.1 Hz, 2H), 4.02 (s, 3H), 3.91 (s, 3H), 3.18 - 2.89 (m, 6H), 2.79 (s, 4H), 2.66 (s, 2H), 2.03 - 1.96 (m, 2H), 1.87 (d, J = 6.9 Hz, 2H)。 ^ NMR (400 MHz, CD 3 OD): δ 8.41 (s, 1H), 7.73 (s, 1H), 7.58 (s, 1H), 7.34 (s, 1H), 7.20 (s, 1H), 4.26 (t , J = 6.1 Hz, 2H), 4.02 (s, 3H), 3.91 (s, 3H), 3.18 - 2.89 (m, 6H), 2.79 (s, 4H), 2.66 (s, 2H), 2.03 - 1.96 ( m, 2H), 1.87 (d, J = 6.9 Hz, 2H).
MS m/z (ESI):545.5[M+H]。  MS m/z (ESI): 545.5 [M+H].
实施例 21 : 4-(2,4-二氯 -5-甲氧基-苯氨基) -7-[4-(4-二氘代甲基 -哌嗪 -1-基) - 丁氧基-6-甲氧基 -喹啉 -3-甲氰  Example 21: 4-(2,4-Dichloro-5-methoxy-phenylamino)-7-[4-(4-dioxomethyl-piperazin-1-yl)-butoxy- 6-methoxy-quinoline-3-cyanate
Figure imgf000044_0002
Figure imgf000044_0002
除了使用中间体 4代替中间体 8以外， 采用与实施例 2类似的方法合成 得到目标化合物 4-(2,4-二氯 -5-甲氧基 -苯氨基:) -7-[4-(4-二氘代甲基 -哌嗪 -1- 基:) -丁氧基] -6-甲氧基 -喹啉 -3-甲氰 （黄色固体， 32 mg)。  The target compound 4-(2,4-dichloro-5-methoxy-phenylamino:)-7-[4-() was synthesized in a similar manner to Example 2 except that Intermediate 4 was used instead of Intermediate 8. 4-Deuteromethyl-piperazin-1-yl:)-butoxy]-6-methoxy-quinoline-3-carbonitrile (yellow solid, 32 mg).
^ NMR (400 MHz, CD3OD): δ 8.41 (s, 1H), 7.72 (s, 1H), 7.58 (s, 1H), 7.33 (s, 1H), 7.21 (s, 1H), 4.26 (t, J = 6.2 Hz, 2H), 4.02 (s, 3H), 3.91 (s, 3H), 3.19 - 2.89 (m, 6H), 2.89 - 2.69 (m, 4H), 2.64 (s, 1H), 2.02 - 1.95 (m, 2H), 1.91-1.82 (m: 2H)。 ^ NMR (400 MHz, CD 3 OD): δ 8.41 (s, 1H), 7.72 (s, 1H), 7.58 (s, 1H), 7.33 (s, 1H), 7.21 (s, 1H), 4.26 (t , J = 6.2 Hz, 2H), 4.02 (s, 3H), 3.91 (s, 3H), 3.19 - 2.89 (m, 6H), 2.89 - 2.69 (m, 4H), 2.64 (s, 1H), 2.02 - 1.95 (m, 2H), 1.91-1.82 (m: 2H).
MS m/z (ESI) : 546.2 [M+H]。 实施例 22: 4-(2,4-二氯 -5-甲氧基-苯氨基) -7-[4-(4-三氘代甲基 -哌嗪 -1-基) - 基] -6-甲氧基 -喹啉 -3-甲氰 MS m/z (ESI): 546.2 [M+H]. Example 22: 4-(2,4-Dichloro-5-methoxy-phenylamino)-7-[4-(4-tridemethyl-piperazin-1-yl)-yl]-6 -methoxy-quinoline-3-cyanate
Figure imgf000045_0001
除了使用中间体 4代替中间体 8以外， 采用与实施例 3类似的方法合成 得到目标化合物 4-(2,4-二氯 -5-甲氧基-苯氨基: )-7-[4-(4-三氘代甲基 -哌嗪 -1- 基:) -丁氧基] -6-甲氧基 -喹啉 -3-甲氰 （黄色固体， 32 mg)。
Figure imgf000045_0001
The target compound 4-(2,4-dichloro-5-methoxy-phenylamino: )-7-[4-() was synthesized in a similar manner to Example 3 except that Intermediate 4 was used instead of Intermediate 8. 4-tridemethyl-piperazin-1-yl:)-butoxy]-6-methoxy-quinoline-3-carbonitrile (yellow solid, 32 mg).
^ NMR (400 MHz, CD3OD):5 8.39 (s, IH), 7.70 (s, IH), 7.56 (s, IH), 7.31 (s, IH), 7.18 (s, IH), 4.24 (t, J = 6.2 Hz, 2H), 4.00 (s, 3H), 3.89 (s, 3H), 3.16 - 2.90 (m, 6H), 2.87 - 2.69 (m, 4H), 1.97 (m, 2H), 1.88 - 1.79 (m, 2H)。 ^ NMR (400 MHz, CD 3 OD): 5 8.39 (s, IH), 7.70 (s, IH), 7.56 (s, IH), 7.31 (s, IH), 7.18 (s, IH), 4.24 (t , J = 6.2 Hz, 2H), 4.00 (s, 3H), 3.89 (s, 3H), 3.16 - 2.90 (m, 6H), 2.87 - 2.69 (m, 4H), 1.97 (m, 2H), 1.88 - 1.79 (m, 2H).
MS m/z (ESI):547.4[M+H]。  MS m/z (ESI): 547.4 [M+H].
实施例 23 : 4-(2,4-二氯 -5-甲氧基-苯氨基) -7-[5-(4-—氘代甲基 -哌嗪 -1-基 甲基) -呋喃 -3-基 1-6-甲氧基 -喹啉 -3-甲氰  Example 23: 4-(2,4-Dichloro-5-methoxy-phenylamino)-7-[5-(4--deuteromethyl-piperazin-1-ylmethyl)-furan- 3-yl-6-methoxy-quinoline-3-cyanide
Figure imgf000045_0002
除了使用中间体 10代替中间体 8以外，采用与实施例 1类似的方法合成 得到目标化合物 4-(2,4-二氯 -5-甲氧基-苯氨基) -7-[5-(4-—氘代甲基 -哌嗪 -1-基 甲基) -呋喃 -3-基] -6-甲氧基 -喹啉 -3-甲氰 （黄色固体， 18 mg)。
Figure imgf000045_0002
The target compound 4-(2,4-dichloro-5-methoxy-phenylamino)-7-[5-(4) was synthesized in a similar manner to Example 1 except that Intermediate 10 was used instead of Intermediate 8. - Deuterated methyl-piperazin-1-ylmethyl)-furan-3-yl]-6-methoxy-quinoline-3-carbonitrile (yellow solid, 18 mg).
^ NMR (400 MHz, CD3OD): δ 8.43 (s, IH), 8.24 (s, IH), 8.07 (s, IH), 7.82 (s, IH), 7.58 (s, IH), 7.23 (s, IH), 7.00 (s, IH), 4.11 (s, 3H), 3.90 (s, 3H), 3.78 (s, 2H), 3.27 - 3.09 (m, 4H), 3.02 - 2.69 (m, 6H)。 ^ NMR (400 MHz, CD 3 OD): δ 8.43 (s, IH), 8.24 (s, IH), 8.07 (s, IH), 7.82 (s, IH), 7.58 (s, IH), 7.23 (s , IH), 7.00 (s, IH), 4.11 (s, 3H), 3.90 (s, 3H), 3.78 (s, 2H), 3.27 - 3.09 (m, 4H), 3.02 - 2.69 (m, 6H).
MS m/z (ESI):553.4[M+H]。  MS m/z (ESI): 553.4 [M+H].
实施例 24: 4-(2,4-二氯 -5-甲氧基-苯氨基) -7-[5-(4-二氘代甲基 -哌嗪 -1-基 甲基) -呋喃 -3-基 1-6-甲氧基 -喹啉 -3-甲氰 ^丄] 邈 -ΐ-翁 ΐΗ - 一 -{ -乙, ¥ΰ-[ - -糊^- ¾¾ώ-9-(¾¾¾-¾¾ώ-^莺二 -·9Ζ Example 24: 4-(2,4-Dichloro-5-methoxy-phenylamino)-7-[5-(4-dioxomethyl-piperazin-1-ylmethyl)-furan- 3-yl-6-methoxy-quinoline-3-cyanide ^丄] 邈-ΐ-翁ΐΗ-一-{-B, ¥ΰ-[ - -糊^- 3⁄43⁄4ώ-9-(3⁄43⁄43⁄4-3⁄43⁄4ώ-^莺二-·9Ζ
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¾-ΐ-翁 |ίϋ- 三 ]- -( ¾- —S-蔦二 ^ 目「ιί 3⁄4-ΐ-翁 |ίϋ- 三]- -( 3⁄4- —S-茑二^目“ιί
Figure imgf000046_0001
Figure imgf000046_0001
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°[H+ ]1 '1 SS:(IS3) z/ui S  °[H+ ]1 '1 SS:(IS3) z/ui S
°(HS 'm) 99 - 86 '(H17 'ui) ore - 8 '(ίΚ 's) Sf£ '(He 's) 06 '(He 's) \VP '(HI 'S) 66·9 '(Ηΐ 's) £Z'L '(HI 's) S^L '(HI 's) Z^L '(HI 's) 0·8 '(Ηΐ 's) Z^ '(HI 's) £V^ 9 -(QO£QD 'z腦 OOP) ¾ NHT °(HS 'm) 99 - 86 '(H17 'ui) ore - 8 '(ίΚ 's) Sf£ '(He 's) 06 '(He 's) \VP '(HI 'S) 66·9 '(Ηΐ 's) £Z'L '(HI 's) S^L '(HI 's) Z^L '(HI 's) 0·8 '(Ηΐ 's) Z^ '(HI 's ) £V^ 9 -(QO £ QD 'z brain OOP) 3⁄4 NH T
¾-ΐ-翁 |ίϋ- 二 ]- -( ¾- —S-蔦二 ^ 目「ιί 3⁄4-ΐ-翁 |ίϋ- 二 ]- -( 3⁄4- —S-茑二^目“ιί
Figure imgf000046_0002
980/ 0Z OAV
Figure imgf000046_0002
980/ 0Z OAV
Figure imgf000047_0001
Figure imgf000047_0001
采用中间体 3及 N-叔丁氧羰基哌嗪替换甲醛水溶液和中间体 8， 采用实 施例 1 类似的方法合成得到目标化合物 4-({4-[3-氰基 -4-(2,4-二氯 -5-甲氧基- 苯氨基 )-6-甲氧基 -喹啉 -7-基] -呋喃 -2-基 一氘代-甲基) -哌嗪 -1-甲酸叔丁酯 (黄色固体， 450 mg)。  The intermediate compound 3 and N-tert-butoxycarbonylpiperazine were used to replace the aqueous formaldehyde solution and the intermediate 8, and the target compound 4-({4-[3-cyano-4-(2,4) was synthesized by a similar method as in Example 1. -Dichloro-5-methoxy-phenylamino)-6-methoxy-quinolin-7-yl]-furan-2-yl-deuterated-methyl)-piperazine-1-carboxylic acid tert-butyl ester (yellow solid, 450 mg).
lR NMR (400 MHz, DMSO-i 6): 58.42(s, lH),8.22(d, J=6.0Hz, lH),8.07(s, lH),7.80(s, lH),7.57(s, lH),7.23(s, lH),6.95(d, J=7.2Hz, lH),4.11(s, 3H),3.92(s, 3H),3.66(s, lH),3.46-3.47(m, 4H),2.51-2.53(m, 4H), 1.45(s, 9H)。  lR NMR (400 MHz, DMSO-i 6): 58.42 (s, lH), 8.22 (d, J = 6.0 Hz, lH), 8.07 (s, lH), 7.80 (s, lH), 7.57 (s, lH) ), 7.23 (s, lH), 6.95 (d, J = 7.2 Hz, lH), 4.11 (s, 3H), 3.92 (s, 3H), 3.66 (s, lH), 3.46-3.47 (m, 4H) , 2.51-2.53 (m, 4H), 1.45 (s, 9H).
MS m/z (ESI):539.7[M+H-Boc] o  MS m/z (ESI): 539.7 [M+H-Boc] o
实施例 27 : 4-(2,4-二氯 -5-甲氧基-苯氨基) -7-[5- (哌嗪 -1-基-一氘代甲基) - 呋 -3-基] -6-甲氧基 -喹啉 -3-甲氰  Example 27: 4-(2,4-Dichloro-5-methoxy-phenylamino)-7-[5-(piperazin-1-yl-monodeuteromethyl)-fur-3-yl] -6-methoxy-quinoline-3-cyanate
Figure imgf000047_0002
Figure imgf000047_0002
将 4-({4-[3-氰基 -4-(2,4-二氯 -5-甲氧基-苯氨基) -6-甲氧基 -喹啉 -7-基] -呋 喃 -2-基 一氘代-甲基) -哌嗪 -1-甲酸叔丁酯（实施例 31的产物）（450 mg, 0.71 mmol) 溶于二氯甲烷 （10 mL) 中， 冰浴冷却下向上述溶液滴加 4N氯化氢 的二氧六环溶液 （5 mL) , 室温搅拌 2小时， 析出白色固体。 减压过滤， 滤 饼用无水乙醚洗涤， 干燥得到 4-(2,4-二氯 -5-甲氧基 -苯氨基:) -7-[5- (—氘代-哌 嗪 -1-基-甲基) -呋喃 -3-基] -6-甲氧基 -喹啉 -3-甲氰 （黄色固体， 320 mg) , 直接 用于下一歩反应。 Ή NMR (400 MHz, CD30D): 58.93(s, lH),8.49(s, lH),8.17(s, lH),8.13(s, lH),7.69(s, lH),7.43(s, lH),7.32(s, lH),4.29(s, lH),4.28(s, 3H),3.94(s, 3H),3.46-3.48(m, 4H),2.03-2.05(m, 4H)。 4-({4-[3-Cyano-4-(2,4-dichloro-5-methoxy-phenylamino)-6-methoxy-quinolin-7-yl]-furan-2 -yl-deuterated-methyl)-piperazine-l-carboxylic acid tert-butyl ester (product of Example 31) (450 mg, 0.71 mmol) dissolved in dichloromethane (10 mL) A solution of 4N hydrogen chloride in dioxane (5 mL) was added dropwise and the mixture was stirred at room temperature for 2 hr. Filtration under reduced pressure, the filter cake was washed with anhydrous diethyl ether and dried to give 4-(2,4-dichloro-5-methoxy-phenylamino:)-7-[5-(-deutero-piperazin-1- Base-methyl)-furan-3-yl]-6-methoxy-quinoline-3-carbonitrile (yellow solid, 320 mg) was used directly in the next reaction. NMR NMR (400 MHz, CD30D): 58.93 (s, lH), 8.49 (s, lH), 8.17 (s, lH), 8.13 (s, lH), 7.69 (s, lH), 7.43 (s, lH) , 7.32 (s, lH), 4.29 (s, lH), 4.28 (s, 3H), 3.94 (s, 3H), 3.46-3.48 (m, 4H), 2.03-2.05 (m, 4H).
MS m/z (ESI):269.9[M+2H]。  MS m/z (ESI): 269.9 [M+2].
实施例 28 : 4-(2,4-二氯 -5-甲氧基-苯氨基) -7- {5-[(4-—氘代甲基 -哌嗪 - 1- 基)-一 -喹啉 -3-甲氰  Example 28: 4-(2,4-Dichloro-5-methoxy-phenylamino)-7- {5-[(4--deuteromethyl-piperazin-1-yl)-mono-quin Porphyrin-3-cyanide
Figure imgf000048_0001
Figure imgf000048_0001
采用实施例 27替换中间体 8，采用实施例 1类似的方法合成得到目标化 合物 4-(2,4-二氯 -5-甲氧基 -苯氨基:) -7- {5-[(4-—氘代甲基 -哌嗪 -1-基) -一氘代甲 基] -呋喃 -3-基 6-甲氧基 -喹啉 -3-甲氰 （黄色固体， 17 mg)。  The title compound 4-(2,4-dichloro-5-methoxy-phenylamino:)-7- {5-[(4-) was synthesized by the same procedure as in Example 1 using the same procedure as in Example 1. - deuterated methyl-piperazin-1-yl)-monodecylmethyl]-furan-3-yl 6-methoxy-quinoline-3-carbonitrile (yellow solid, 17 mg).
^ NMR (400 MHz, OMSO-d6): 58.42(s, lH),8.24(s, lH),8.07(s, lH),7.82(s lH),7.58(s, lH),7.22(s, lH),6.98(s, lH),4.11 (s, 3H),3.91 (s, 3H),3.72(s, lH),2.82-2.85(m, 8H),2.51 (s, 2H)。  ^ NMR (400 MHz, OMSO-d6): 58.42 (s, lH), 8.24 (s, lH), 8.07 (s, lH), 7.82 (s lH), 7.58 (s, lH), 7.22 (s, lH) ), 6.98 (s, lH), 4.11 (s, 3H), 3.91 (s, 3H), 3.72 (s, lH), 2.82-2.85 (m, 8H), 2.51 (s, 2H).
MS m/z (ESI):277.4[M+2H]。  MS m/z (ESI): 277.4 [M+2].
实施例 29 : 4-(2,4-二氯 -5-甲氧基-苯氨基) -7- {5-[(4-二氘代甲基 -哌嗪 - 1- 基)-一 -呋喃 -3-基}-6-甲氧基 -喹啉 -3-甲氰  Example 29: 4-(2,4-Dichloro-5-methoxy-phenylamino)-7-{5-[(4-dioxomethyl-piperazin-1-yl)-mono-furan -3-yl}-6-methoxy-quinoline-3-cyanide
Figure imgf000048_0002
Figure imgf000048_0002
采用实施例 27替换中间体 8，采用实施例 2类似的方法合成得到目标化 合物 4-(2,4-二氯 -5-甲氧基 -苯氨基:) -7- {5-[(4-二氘代甲基 -哌嗪 -1-基) -一氘代甲 基] -呋喃 -3-基 6-甲氧基 -喹啉 -3-甲氰 （黄色固体， 13 mg)。 NMR (400 MHz, OMSO-d6): 58.43(s, lH),8.25(s, lH),8.07(s, lH),7.82(s lH),7.58(s, lH),7.23(s, lH),6.99(s, lH),4.11 (3,3H),3.90(s, 3H),3.75(s, lH),3.04-3.05(m, 4H),2.76-2.79(m, 4H),2.65(s, 1H)。 The intermediate compound 8 was replaced with Example 27, and the title compound 4-(2,4-dichloro-5-methoxy-phenylamino:)-7- {5-[(4- Di-deuterated methyl-piperazin-1-yl)-monodecylmethyl]-furan-3-yl 6-methoxy-quinoline-3-carbonitrile (yellow solid, 13 mg). NMR (400 MHz, OMSO-d6): 58.43 (s, lH), 8.25 (s, lH), 8.07 (s, lH), 7.82 (s lH), 7.58 (s, lH), 7.23 (s, lH) , 6.99 (s, lH), 4.11 (3,3H), 3.90 (s, 3H), 3.75 (s, lH), 3.04-3.05 (m, 4H), 2.76-2.79 (m, 4H), 2.65 (s , 1H).
MS m/z (ESI): 278.5。  MS m/z (ESI): 278.5.
实施例 30 : 4-(2,4-二氯 -5-甲氧基-苯氨基) -7- {5-[(4-三氘代甲基 -哌嗪 - 1- 基)-一氘代甲基] -呋喃 -3-基}-6-甲氧基 -喹啉 -3-甲氰  Example 30: 4-(2,4-Dichloro-5-methoxy-phenylamino)-7- {5-[(4-tridemethyl-piperazin-1-yl)-anthracene Methyl]-furan-3-yl}-6-methoxy-quinoline-3-cyanate
Figure imgf000049_0001
采用实施例 27替换中间体 8，采用实施例 3类似的方法合成得到目标化 合物 4-(2,4-二氯 -5-甲氧基-苯氨基: )-7- {5-[(4-三氘代甲基 -哌嗪 -1-基) -一氘代甲 基] -呋喃 -3-基 6-甲氧基 -喹啉 -3-甲氰 （黄色固体， 31 mg)。
Figure imgf000049_0001
The title compound 4-(2,4-dichloro-5-methoxy-phenylamino: )-7- {5-[(4-) was synthesized by the same procedure as in Example 3, using the same procedure as in Example 3. Triterpene methyl-piperazin-1-yl)-monodeuteromethyl]-furan-3-yl 6-methoxy-quinoline-3-carbonitrile (yellow solid, 31 mg).
^ NMR (300 MHz, OMSO-d6): 58.44(s, lH),8.25(s, lH),8.07(s, lH),7.82(s lH),7.58(s, lH),7.22(s, lH),6.99(s, lH),4.11 (s, 3H),3.90(s, 3H),3.77(s, lH),3.06-3.09(m, 4H),2.77-2.82(m, 4H)。  ^ NMR (300 MHz, OMSO-d6): 58.44 (s, lH), 8.25 (s, lH), 8.07 (s, lH), 7.82 (s lH), 7.58 (s, lH), 7.22 (s, lH) ), 6.99 (s, lH), 4.11 (s, 3H), 3.90 (s, 3H), 3.77 (s, lH), 3.06-3.09 (m, 4H), 2.77-2.82 (m, 4H).
MS m/z (ESI):279.4[M+2H]。  MS m/z (ESI): 279.4 [M+2].
实施例 31 : 4-(2,4-二氯 -5-甲氧基-苯氨基) -7- {4-[(4-甲基 -哌嗪 -1-基) -一氘 代甲基] -呋喃 -2-基}-6-甲氧基 -喹啉 -3-甲氰  Example 31: 4-(2,4-Dichloro-5-methoxy-phenylamino)-7- {4-[(4-methyl-piperazin-1-yl)-monodecylmethyl] -furan-2-yl}-6-methoxy-quinoline-3-cyanate
Figure imgf000049_0002
采用中间体 5和 N-甲基哌嗪为原料，采用实施例 1类似的方法合成得到 目标化合物 4-(2,4-二氯 -5-甲氧基 -苯氨基：) -7- {4-[(4-甲基 -哌嗪 -1-基) -一氘代甲 基] -呋喃 -2-基 6-甲氧基 -喹啉 -3-甲氰 （黄色固体， 28 mg)。 i3/: O 6/-iil£iiAV -()()() g ()9ΐ Sΐ ΐ∞ΐ 1寸∞οΗ 001 LLΗΗΗαHpv ¾VNH<7sss-..
Figure imgf000049_0002
Using the intermediate 5 and N-methylpiperazine as starting materials, the target compound 4-(2,4-dichloro-5-methoxy-phenylamino:)-7- {4 was synthesized by a similar method as in Example 1. -[(4-Methyl-piperazin-1-yl)-indolylmethyl]-furan-2-yl 6-methoxy-quinoline-3-carbonitrile (yellow solid, 28 mg). I3/: O 6/-iil£iiAV -()()() g ()9ΐ Sΐ ΐ∞ΐ 1 inch ∞οΗ 001 LLΗΗΗαHpv 3⁄4VNH<7sss-..
p)()()()()()()寸£e ΐ6£e u寸ΐ Hΐ 6ΓΐΐHHΗLΗΗ L LΗssssss·.-- p)()()()()()() inch £e ΐ6£e u inchΐ Hΐ 6ΓΐΐHHΗLΗΗ L LΗssssss·.--
()TS N ()TS N
ϋ番¾¾i卜(e【 ΐ ΐ -- -- - -- -  ϋ番3⁄43⁄4i卜(e[ ΐ ΐ -- -- - -- -
Figure imgf000050_0001
Figure imgf000050_0001
()()()()()()ΐζ££ΐΐ寸ΐ∞69ΐζΓΐΐΐ∞ ¾ ¾ ¾ ¾ ¾ς ΗSSSsss···· .· ()()(£09τΤ Ηςsss 。 ... MS nVz (ESI): 279.40[M+2H]。 ()()()()()()ΐζ££ΐΐ inchΐ∞69ΐζΓΐΐΐ∞ 3⁄4 3⁄4 3⁄4 3⁄4 3⁄4ς ΗSSSsss···· .· ()()(£09τΤ Ηςsss.... MS nVz (ESI): 279.40 [M+2H].
实施例 34: 4-(2,4-二氯 -5-三氘代甲氧基-苯氨基) -7-[5- (哌嗪 -1 -基-一氘代 甲基 -呋喃 -3-基] -6-甲氧基 -喹啉 -3-甲氰盐酸盐  Example 34: 4-(2,4-Dichloro-5-tridecylmethoxy-phenylamino)-7-[5-(piperazin-1-yl-monodecylmethyl-furan-3- -6-methoxy-quinoline-3-carbonitrile hydrochloride
Figure imgf000051_0001
Figure imgf000051_0001
将中间体 11 (500 mg, 1.06 mmol)溶于甲醇 (25 mL) , 向其中加入 N-叔丁 氧羰基哌嗪 (595 mg, 3.19 mmol)及三异丙氧基钛 (0.96 mL, 3.19 mmol) ,此混合 物室温搅拌过夜， 再向上述反应液中加入固体硼氘化钠 (267 mg, 6.38 mmol) , 室温搅拌 2h。 反应结束后， 蒸干溶剂， 残余物溶于饱和碳酸氢钠水溶液， 二 氯甲烷萃取， 有机相依次用水和饱和食盐水洗涤， 无水硫酸钠干燥， 过滤减 压浓缩， 残余物用硅胶柱层析分离纯化得化合物 4-({4-[3-氰基 -4-(2,4-二氯 -5- 三氘代甲氧基-苯氨基) -6-甲氧基 -喹啉 -7-基] -呋喃 -2-基} -一氘代-甲基) -哌嗪 -1-甲酸叔丁酯 （637 mg， 黄色固体）。  Intermediate 11 (500 mg, 1.06 mmol) was dissolved in methanol (25 mL). N-t-butoxycarbonylpiperazine (595 mg, 3.19 mmol) and triisopropoxytitanium (0.96 mL, 3.19 mmol) After the mixture was stirred at room temperature overnight, solid sodium boron hydride (267 mg, 6.38 mmol) was added to the mixture and stirred at room temperature for 2 h. After completion of the reaction, the solvent was evaporated to dryness crystals crystals crystals crystals The compound 4-({4-[3-cyano-4-(2,4-dichloro-5-tridecylmethoxy-phenylamino)-6-methoxy-quinoline-7 was isolated and purified. -yl]-furan-2-yl}--deuterated-methyl)-piperazine-l-carboxylic acid tert-butyl ester (637 mg, yellow solid).
[H-NMR (400MHz, CDC13): δ 8.71 (1 Η, s), 8.17(1Η, s), 8. 10(1Η, s), 7.51 (1 Η , s), 7·04(1Η, s), 6.83(1Η, s), 6.57(1 Η, s), 3.85(3Η, s), 3.68(1Η, s), 3.52(4Η， s), 2.56(4Η， s), 1.45(9Η , s)。 [ H-NMR (400MHz, CDC1 3 ): δ 8.71 (1 Η, s), 8.17 (1Η, s), 8. 10(1Η, s), 7.51 (1 Η , s), 7·04 (1Η, s), 6.83(1Η, s), 6.57(1 Η, s), 3.85(3Η, s), 3.68(1Η, s), 3.52(4Η, s), 2.56(4Η, s), 1.45(9Η , s).
MS m/z (ESI): 543.80 [M-Boc+H]。  MS m/z (ESI): 543.80 [M-Boc+H].
将上述化合物 4-({4-[3-氰基 -4-(2,4-二氯 -5-三氘代甲氧基-苯氨基) -6-甲氧 基 -喹啉 -7-基] -呋喃 -2-基} -一氘代-甲基) -哌嗪 -1 -甲酸叔丁酯溶于二氯甲烷后， 加入氯化氢的二氧六环溶液搅拌 2小时脱除保护基后得到 4-(2,4-二氯 -5-三氘 代甲氧基-苯氨基) -7-[5- (哌嗪 -1 -基-一氘代甲基) -呋喃 -3-基] -6-甲氧基 -喹啉 -3- 甲氰盐酸盐 （白色固体， 572 mg)。  The above compound 4-({4-[3-cyano-4-(2,4-dichloro-5-tridecylmethoxy-phenylamino)-6-methoxy-quinolin-7-yl) ] -furan-2-yl}-monodeutero-methyl)-piperazine-1 -carboxylic acid tert-butyl ester was dissolved in dichloromethane, and then a solution of hydrogen chloride in dioxane was added and stirred for 2 hours to obtain a protective group. 4-(2,4-Dichloro-5-tridecylmethoxy-phenylamino)-7-[5-(piperazine-1-yl-monodecylmethyl)-furan-3-yl]- 6-Methoxy-quinoline-3-carbonitrile hydrochloride (white solid, 572 mg).
!H-NMR (400MHz, CD3OD): δ 8.95(1H, s), 8.54(1H, s), 8.20(1H, s), 8.16(1H , s), 7.80(1H, s), 7.46(2H, d, J=8.4Hz), 4.22(3H, s), 3.66(1H, s), 3.54-3.58(8H , m)。 ! H-NMR (400MHz, CD 3 OD): δ 8.95 (1H, s), 8.54 (1H, s), 8.20 (1H, s), 8.16 (1H, s), 7.80 (1H, s), 7.46 ( 2H, d, J = 8.4 Hz), 4.22 (3H, s), 3.66 (1H, s), 3.54-3.58 (8H, m).
MS m/z (ESI): 272.40 [M+2H]。 实施例 35: 4-(2,4-二氯 -5-三氘代甲氧基-苯氨基) -7-{5-[(4-—氘代甲基-哌 嗪 -1- -一氘代甲基] -呋喃 -3-基}-6-甲氧基 -喹啉 -3-甲氰 MS m/z (ESI): 272.40 [M+2H]. Example 35: 4-(2,4-Dichloro-5-tridecylmethoxy-phenylamino)-7-{5-[(4--deuteromethyl-piperazin-1-yl) Methyl]-furan-3-yl}-6-methoxy-quinoline-3-cyanate
Figure imgf000052_0001
Figure imgf000052_0001
使用实施例 34和 37%的甲醛水溶液为原料， 硼氘化钠为还原剂， 采用 实施例 1类似的方法合成得到目标化合物 4-(2,4-二氯 -5-三氘代甲氧基 -苯氨 基 )-7-{5-[(4-—氘代甲基 -哌嗪 -1-基) -一氘代甲基] -呋喃 -3-基 6-甲氧基 -喹啉 —3-甲氰 （黄色固体， 18 mg) o Using the example 34 and 37% aqueous formaldehyde solution as the starting material and sodium borohydride as the reducing agent, the target compound 4-(2,4-dichloro-5-tridecylmethoxy) was synthesized by a similar method as in Example 1. - phenylamino) - 7 - {5 - [(4-- deuterated methyl - piperazin-1-yl) - a deuterated methyl] - furan-3-yl 6-methoxy - quinoline - 3 - carbamide (yellow solid, 18 mg) o
ifi-NMR (400MHz, CD3OD): δ 8.42(1H, s), 8.24(1H, s), 8.06(1H, s), 7.81(1H ， s), 7.58(1H, s), 7.23(1H, s), 6.99(1H, s), 4.11(3H, s), 3.74(1H, s), 3.02(4H， s), 2.78(4H， s), 2.65(2H， d. J=3.6Hz)。 Ifi-NMR (400MHz, CD 3 OD): δ 8.42 (1H, s), 8.24 (1H, s), 8.06 (1H, s), 7.81 (1H, s), 7.58 (1H, s), 7.23 (1H) , s), 6.99(1H, s), 4.11(3H, s), 3.74(1H, s), 3.02(4H, s), 2.78(4H, s), 2.65(2H, d. J=3.6Hz) .
MS m/z (ESI): 279·90[Μ+2Η]。  MS m/z (ESI): 279.90 [Μ+2Η].
实施例 36: 4-(2,4-二氯 -5-三氘代甲氧基-苯氨基) -7-{5-[(4-二氘代甲基-哌 嗪 -1- -一氘代甲基] -呋喃 -3-基}-6-甲氧基 -喹啉 -3-甲氰  Example 36: 4-(2,4-Dichloro-5-tridecylmethoxy-phenylamino)-7-{5-[(4-didecylmethyl-piperazin-1-yl) Methyl]-furan-3-yl}-6-methoxy-quinoline-3-cyanate
Figure imgf000052_0002
Figure imgf000052_0002
使用实施例 34和 25%的氘代甲醛的重水溶液为原料， 硼氢化钠为还原 剂， 采用实施例 2类似的方法合成得到目标化合物 4-(2,4-二氯 -5-三氘代甲氧 基-苯氨基: )-7-{5-[(4-二氘代甲基 -哌嗪 -1-基) -一氘代甲基] -呋喃 -3-基 6-甲氧 基 -喹啉 -3-甲氰 （黄色固体， 56mg)。 ζς Using the heavy aqueous solution of Example 34 and 25% of deuterated formaldehyde as the starting material and sodium borohydride as the reducing agent, the target compound 4-(2,4-dichloro-5-triindole) was synthesized by a similar method as in Example 2. Methoxy-phenylamino: )-7-{5-[(4-dioxomethyl-piperazin-1-yl)-monodecylmethyl]-furan-3-yl 6-methoxy- Quinoline-3-methicone (yellow solid, 56 mg). Ζς
'膨缀 ¥
Figure imgf000053_0001
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6 80/nOZN:)Ai:)d ^81980/1-101 OAV 化反应得到中间体 4-{5-[3-氰基 -4-(2,4-二氯 -5-甲氧基 -苯氨基:) -6-甲氧基 -喹啉 -7-基] -呋喃 -3-基甲基 哌嗪 -1-甲酸叔丁酯 （黄色固体， 420 mg)， 将上述中间 体用 4N氯化氢的二氧六环溶液脱除保护基后， 得到中间体 4-(2,4-二氯 -5-甲 氧基-苯氨基 )-6-甲氧基 -7-(4-哌嗪 -1-基甲基 -呋喃 -2-基) -喹啉 -3-甲氰盐酸盐 (黄 色固体， 235 mg)， 以该中间体 (60 mg)和甲醛水溶液 （浓度为 37%) 为原料， 硼氘化钠为还原剂， 采用实施例 1类似的方法合成得到目标化合物 4-(2,4-二 氯 -5-甲氧基-苯氨基) -7-[4-(4-—氘代甲基 -哌嗪 -1-基甲基) -呋喃 -2-基] -6-甲氧 基 -喹啉 -3-甲氰 （黄色固体， 21 mg)。 6 80/nOZN:) Ai:)d ^81980/1-101 OAV The reaction gave the intermediate 4-{5-[3-cyano-4-(2,4-dichloro-5-methoxy-phenylamino:)-6-methoxy-quinolin-7-yl] - furan-3-ylmethylpiperazine-1-carboxylic acid tert-butyl ester (yellow solid, 420 mg). After removing the above-mentioned intermediate from 4N hydrogen chloride in dioxane solution, the intermediate 4-( 2,4-Dichloro-5-methoxy-phenylamino)-6-methoxy-7-(4-piperazin-1-ylmethyl-furan-2-yl)-quinoline-3-methyl Cyanide hydrochloride (yellow solid, 235 mg), using the intermediate (60 mg) and aqueous formaldehyde (concentration: 37%) as the starting material, and sodium borohydride as the reducing agent, the target was synthesized in a similar manner to that in Example 1. Compound 4-(2,4-Dichloro-5-methoxy-phenylamino)-7-[4-(4--deuteromethyl-piperazin-1-ylmethyl)-furan-2-yl -6-Methoxy-quinoline-3-carbonitrile (yellow solid, 21 mg).
lR NMR (400 MHz, CD3OD): δ 8.42 (s, 1H), 8.32 (s, 1H), 7.85 (s, 1H), 7.72 (s, 1H), 7.59 (s, 1H), 7.29 (s, 1H), 7.25 (s, 1H), 4.15 (s, 3H), 3.93 (s, 3H), 3.65 (s, 2H), 3.18 (s, 4H), 2.97 - 2.58 (m, 6H)。 lR NMR (400 MHz, CD 3 OD): δ 8.42 (s, 1H), 8.32 (s, 1H), 7.85 (s, 1H), 7.72 (s, 1H), 7.59 (s, 1H), 7.29 (s , 1H), 7.25 (s, 1H), 4.15 (s, 3H), 3.93 (s, 3H), 3.65 (s, 2H), 3.18 (s, 4H), 2.97 - 2.58 (m, 6H).
MS m/z (ESI): 549· 1 [Μ+Η]。  MS m/z (ESI): 549·1 [Μ+Η].
实施例 39: 4-(2,4-二氯 -5-甲氧基-苯氨基) -6-甲氧基 -7-[5-(4-甲基 -哌嗪 -1- 基甲  Example 39: 4-(2,4-Dichloro-5-methoxy-phenylamino)-6-methoxy-7-[5-(4-methyl-piperazine-1-yl-methyl)
Figure imgf000054_0001
Figure imgf000054_0001
实施例 39为现有技术中已知的化合物，可采用文献方法合成得到，作为 与本发明所涉及的氘代化合物进行活性对比的阳性参照化合物。 其具体合成 方法参见 J. Med. Chem. 2006, 49, 7868-7876 (即第 7869页 Scheme 1中化合 物 10的合成方法）。 测试例  Example 39 is a compound known in the art which can be synthesized by a literature method as a positive reference compound for comparison with the activity of the deuterated compound of the present invention. For the specific synthesis method, see J. Med. Chem. 2006, 49, 7868-7876 (i.e., the synthesis method of compound 10 in Scheme 1 on page 7869). Test case
测试例一 激酶抑制测试  Test Example 1 Kinase inhibition test
本测试例所描述的激酶抑制活性测定试验， 是用来测定本发明化合物对 c-Src、 Bcr-Ab EGFR等激酶的体外抑制活性的， 受试化合物对激酶酶活力 的抑制活性用半抑制浓度 IC5。值来表示。 该类试验采用均相时间分辨荧光The kinase inhibitory activity assay described in this test example is used to determine the in vitro inhibitory activity of the compound of the present invention against kinases such as c-Src and Bcr-Ab EGFR, and the test compound has inhibitory activity against kinase enzyme activity using a semi-inhibitory concentration. IC 5 . The value is expressed. Homogeneous time-resolved fluorescence
( HTRF) 技术进行测定， 方法如下： 将一系列浓度梯度的受试化合物， 在 室温条件下与特定浓度的酶溶液共同孵育 5分钟； 之后加入适量的酶反应底 物： ATP， 启动酶反应过程； 30分钟后， 向酶反应体系中加入适量的反应终 止液和检测液； 孵育 1小时后， 在 Molecular device公司的 Flexstation III多 功能酶标仪上， 测定特定化合物浓度下的酶活力， 并计算不同浓度的化合物 对酶活力的抑制活性； 之后根据四参数方程， 对不同浓度化合物下酶活力的 抑制活性进行拟合， 计算出 IC5Q值。 本测试例所采用的激酶 c-Src、 Bcr-Abl 购自 Cama生物科技有限公司，在 HTRF测定中所使用的是检测试剂盒 HTRF KinEASE-TK (购自 Cisbio Bioassays公司）， ATP购自 Sigma Aldrich公司。 (HTRF) technique is performed as follows: A series of concentration gradient test compounds are incubated with a specific concentration of enzyme solution for 5 minutes at room temperature; then an appropriate amount of enzyme reaction is added. ATP, start the enzyme reaction process; 30 minutes later, add appropriate amount of reaction stop solution and detection solution to the enzyme reaction system; after 1 hour of incubation, determine the specific compound on Molecular device's Flexstation III multi-function microplate reader The enzyme activity at the concentration, and the inhibitory activity of the compounds at different concentrations on the enzyme activity were calculated. Then, according to the four-parameter equation, the inhibitory activities of the enzyme activities under different concentrations of the compounds were fitted, and the IC 5Q value was calculated. The kinases c-Src and Bcr-Abl used in this test were purchased from Cama Biotech Co., Ltd., and the test kit HTRF KinEASE-TK (purchased from Cisbio Bioassays) was used in the HTRF assay. ATP was purchased from Sigma Aldrich. the company.
本发明化合物对激酶的抑制活性用 IC5Q值表示， 其中 IC5Q<5 nM用符号 ++++表示； 5 nM<IC5。<50 nM用符号 +++表示； IC5。>50 nM用符号 ++表示。 部分实施例的激酶抑制活性结果如下表 1所示： The inhibitory activity of the compounds of the invention on kinases is represented by the IC 5Q value, wherein IC 5Q <5 nM is represented by the symbol ++++; 5 nM < IC 5 . <50 nM is represented by the symbol +++; IC 5 . >50 nM is represented by the symbol ++. The results of the kinase inhibitory activity of some of the examples are shown in Table 1 below:
表 1  Table 1
Figure imgf000055_0001
根据表 1 可以看出， 在对 Bosutinib或阳性对照化合物 （实施例化合物 39)进行氘代修饰后， 本发明的实施例化合物仍然能够对 Bcr-Abl以及 c-Src 等激酶具有较高的抑制活性 （如实施例化合物 12的 IC5。值为 1.8 nM, 实施 例化合物 39的 IC5Q值为 1.2 nM) , 可以用作对于此类激酶活性异常引起的疾 病的治疗。
Figure imgf000055_0001
It can be seen from Table 1 that the compound of the present invention is still capable of inhibiting the kinases such as Bcr-Abl and c-Src after deuteration modification of Bosutinib or the positive control compound (Example Compound 39). (e.g., Example compound IC 5 12 a value of 1.8 nM, compound of Example IC 5Q 39 value of 1.2 nM), may be used to treat such diseases caused by abnormal kinase activity.
测试例二 细胞抑制测试 本测试例所描述的细胞增殖抑制活性实验， 是用来测定本发明化合物对 于如 EGFR, Bcr-Abl等高表达的细胞株的增殖抑制活性， 受试化合物对细胞 增殖的抑制活性用半数抑制浓度： IC5Q来表示。 该类试验的试验方案如下： 选择不同细胞， 如 K-562细胞、 A431细胞、 A549、 DU145、 H1650、 H1975 等（细胞购于中国科学院典型培养物保藏委员会细胞库 /中国科学院上海生命 科学研究院细胞资源中心）， 以适宜的细胞浓度 （eg. 25000个细胞 /ml培养 基） 将细胞接种于白色不透明的 384孔培养板上； 之后将细胞放置于 37°C， 5%C02的环境中进行培养； 24小时后， 向培养的细胞培养基中加入一系列浓 度梯度的药物，一般选择 10个浓度；之后将细胞放回原培养环境中继续培养 48小时， 之后按照 CellTiter-Glo Luminescent Cell Viability Assay的方法， 测 定受试化合物对不同细胞增殖的影响， 并计算不同浓度的化合物对细胞增殖 的抑制活性。 （CellTiter-Glo Luminescent Cell Viability Assay检测试剂购自 Promega) ; 之后对不同浓度的化合物下细胞增殖抑制活性进行四参数拟合， 计算出 IC5()数据。 Test Example 2 Cell Inhibition Test The cell proliferation inhibitory activity test described in the test example is for measuring the proliferation inhibitory activity of the compound of the present invention against a cell line highly expressed such as EGFR, Bcr-Abl, etc., and the inhibitory activity of the test compound on cell proliferation is determined by a half inhibitory concentration. : IC 5Q to indicate. The experimental protocol for this type of experiment is as follows: Select different cells, such as K-562 cells, A431 cells, A549, DU145, H1650, H1975, etc. (The cells are purchased from the Cell Culture Bank of the Chinese Academy of Sciences and the Shanghai Institute of Life Sciences, Chinese Academy of Sciences) Cell Resource Center), cells were seeded on white opaque 384-well culture plates at appropriate cell concentrations (eg. 25,000 cells/ml medium); cells were then placed in a 37 ° C, 5% CO 2 environment. After 24 hours, a series of concentration gradients of the drug were added to the cultured cell culture medium, generally 10 concentrations were selected; then the cells were returned to the original culture environment for further 48 hours, followed by CellTiter-Glo Luminescent Cell Viability. Assay's method measures the effect of test compounds on the proliferation of different cells and calculates the inhibitory activity of compounds at different concentrations on cell proliferation. (CellTiter-Glo Luminescent Cell Viability Assay was purchased from Promega); four-parameter fit was then performed on cell proliferation inhibitory activity at various concentrations of compounds, and IC 5 () data was calculated.
本发明化合物具有对 K562细胞增殖抑制的活性， 部分实施例的细胞增 殖抑制活性结果如下所示 (抑制活性用 IC5Q值表示， 其中 IC5Q<100nM用符号 ++++表示； 100nM<IC5G<500nM用符号 +++表示； IC5G>500nM用符号 ++表示）。 The compound of the present invention has an activity of inhibiting proliferation of K562 cells, and the cell proliferation inhibitory activity results of some of the examples are shown below (inhibition activity is represented by IC 5Q value, wherein IC 5Q <100 nM is represented by the symbol ++++; 100 nM < IC 5G <500nM is represented by the symbol +++; IC 5G >500nM is represented by the symbol ++).
表 2  Table 2
Figure imgf000056_0001
根据表 2可以看出， 在对 Bosutinib或阳性对照化合物 （实施例化合物 39) 进行氘代修饰后， 本发明实施例化合物对 K562细胞增殖生长仍然具有 较高的抑制活性（如实施例化合物 12的 IC5Q值为 17.0 nM，实施例化合物 39 的 IC5()值为 23.9 nM)， 可以用作由此类细胞增殖异常引起的疾病的治疗。
Figure imgf000056_0001
As can be seen from Table 2, after deuteration modification of Bosutinib or a positive control compound (Example Compound 39), the compounds of the present invention still have a high inhibitory activity against K562 cell proliferation growth (as in Example 12 of Example). The IC 5Q value was 17.0 nM, and the compound of Example 39 had an IC 5 () value of 23.9 nM), which can be used as a treatment for diseases caused by such abnormal cell proliferation.
测试例三 药代动力 价  Test Example 3 Pharmacokinetic Price
本发明实施例化合物的药代动力学测试包括体外微粒体和代谢酶测试以 及以大鼠或小鼠为受试动物的体内代谢动力学测试。  The pharmacokinetic tests of the compounds of the examples of the invention include in vitro microsomal and metabolic enzyme assays and in vivo metabolic kinetic testing of rats or mice as test animals.
1. 体外肝微粒体试验  In vitro liver microsome test
( 1 ) 代谢稳定性试验： 用体系为 150 μΐ 的肝微粒体 （终浓度 0.5 mg/ml) 进 行代谢稳定性温孵， 体系含 NADPH (终浓度 1 mM)、 1 μΜ受试化合物和阳 性对照咪达唑仑或阴性对照阿替洛尔，分别在 0 min、 5 min, 10 min和 30 min 用含替硝唑的乙腈终止反应，涡旋 10 min, 15000 rmp 离心 10 min，取 50 μΐ上 清于 96 孔板中进样。 通过测定原药的相对减少量计算化合物代谢稳定性。  (1) Metabolic stability test: Metabolic stability incubation with 150 μΐ of liver microsomes (final concentration 0.5 mg/ml) containing NADPH (final concentration 1 mM), 1 μΜ test compound and positive control Midazolam or negative control atenolol was stopped at 0 min, 5 min, 10 min and 30 min with tinidazole-containing acetonitrile, vortexed for 10 min, centrifuged at 15000 rmp for 10 min, and taken on 50 μM. Inject into the 96-well plate. The metabolic stability of the compound was calculated by measuring the relative reduction in the original drug.
(2) 直接抑制试验 （DI试验）： 用体系为 100 μΐ 的人肝微粒体 （终浓度 0.2 mg/ml)进行直接抑制温孵， 体系含 NADPH (终浓度 1 mM)、 10 μΜ 化合物、 阳性抑制剂 cocktail (酮康唑 10 μΜ， 奎尼丁 10 μΜ， 磺胺苯吡唑 100 μΜ， α- 萘黄酮 10 μΜ， 反苯环丙胺 1000 μΜ)、 阴性对照 （0.1%DMSO的 BPS) 和混 合探针底物 （咪达唑仑 10 μΜ、 睾酮 100 μΜ、 右美沙芬 10 μΜ、 双氯芬酸 20 μΜ、 非那西丁 100 μΜ， 美芬妥英 100 μΜ)， 温孵 20 min后终止反应。 通过 测定代谢物的相对生成量计算酶相对活性。  (2) Direct inhibition test (DI test): Direct inhibition of incubation with 100 μΐ human liver microsomes (final concentration 0.2 mg/ml) containing NADPH (final concentration 1 mM), 10 μΜ compound, positive Inhibitor cocktail (ketoconazole 10 μΜ, quinidine 10 μΜ, sulfaphenazole 100 μΜ, α-naphthoflavone 10 μΜ, tranylcypromine 1000 μΜ), negative control (0.1% DMSO BPS) and mixed probe The needle substrate (midazolam 10 μΜ, testosterone 100 μΜ, dextromethorphan 10 μΜ, diclofenac 20 μΜ, phenacetin 100 μΜ, mefenazine 100 μΜ) was stopped after incubation for 20 min. The relative activity of the enzyme was calculated by measuring the relative amount of production of the metabolite.
试验结果： 实施例化合物 12与阳性参照化合物 39在代谢性质上由于氢和 氘的取代效应产生了明显的差异， 如实施例化合物 39对代谢酶 2D6有较强的 抑制作用 （对代谢酶的直接抑制率为 86%)， 而实施例 12对代谢酶 2D6无明显 抑制作用 （对代谢酶的直接抑制率为 40%)。  Test Results: The compound of Example 12 and the positive reference compound 39 showed significant differences in the metabolic properties due to the substitution effect of hydrogen and hydrazine. For example, the compound of Example 39 has a strong inhibitory effect on the metabolic enzyme 2D6 (direct to the metabolic enzyme) The inhibition rate was 86%), while Example 12 had no significant inhibitory effect on the metabolic enzyme 2D6 (the direct inhibition rate to metabolic enzymes was 40%).
2. 大鼠或小鼠体内试验  2. Rat or mouse in vivo test
应用 LC/MS/MS法测定了大鼠或小鼠分别灌胃和静注给予实施例化合物 后不同时刻血浆中的药物浓度， 研究本发明化合物在大鼠或小鼠体内的药代 动力学行为， 评价其药动学特征。 实验方案： 试验动物为健康成年雄性 SD 大鼠或 BALB/c小鼠， 由上海西普尔必凯实验动物有限公司提供； 给药方式 及样品采集：分别给于 SD大鼠或 BALB/c小鼠静脉注射（3 mg/kg, 1 mg/mL 受试化合物的混悬液） 和灌胃给药 （10 mg/kg， 1 mg/mL受试化合物的混悬 液）， 分别于给药前和给药后 2、 5、 15、 30、 60、 90、 120、 240、 360、 480、 1440 min于大鼠或小鼠眼底静脉丛取血 0.4 mL; 取血浆样品 50 L， 分别加 入 200 μΙ^含内标的乙腈溶液沉淀蛋白，涡旋 10 min，6000 转 /分离心 10 min; 取 200 上清 6000转 /分再次离心 10 min; 再取 75 上清液， 加梯度初 始流动相稀释， 6000转 /分离心 10 min; 最终取上清液 70 于 96 孔板中进 样， 进样量 5 L， 进行 LC-MS-MS分析。 The drug concentration in plasma at different times after intragastric administration and intravenous administration of the compound of the present invention was determined by LC/MS/MS method, and the pharmacokinetic behavior of the compound of the present invention in rats or mice was studied. , to evaluate its pharmacokinetic characteristics. Experimental protocol: The test animals were healthy adult male SD rats or BALB/c mice, provided by Shanghai Xipuerkekai Experimental Animal Co., Ltd.; administration mode and sample collection: respectively given to SD rats or BALB/c mice Intravenous (3 mg/kg, 1 mg/mL suspension of test compound) and intragastric administration (10 mg/kg, 1 mg/mL suspension of test compound) Liquid), taking 0.4 mL of blood from the fundus venous plexus of rats or mice before administration and 2, 5, 15, 30, 60, 90, 120, 240, 360, 480, 1440 min after administration; Sample 50 L, respectively, add 200 μΙ^ containing the internal standard acetonitrile solution to precipitate protein, vortex for 10 min, 6000 rpm / separation of the heart for 10 min; take 200 supernatant 6,000 rpm for another 10 min; then take 75 supernatant, Gradient initial mobile phase dilution, 6000 rpm / separation of the core for 10 min; Finally, the supernatant 70 was injected into a 96-well plate, and the injection volume was 5 L, and LC-MS-MS analysis was performed.
本发明部分实施例化合物在相同剂量和给药方式下大鼠和小鼠体内的药 代动力学性质参数如下表 3和表 4所示：  The pharmacokinetic properties of some of the compounds of the present invention in rats and mice at the same dosage and mode of administration are shown in Tables 3 and 4 below:
表 3 化合物在大鼠体内药代动力学参数  Table 3 Pharmacokinetic parameters of compounds in rats
Figure imgf000058_0001
Figure imgf000058_0001
表 4 化合物在小鼠体内药代动力学参数  Table 4 Pharmacokinetic parameters of compounds in mice
Figure imgf000058_0002
Figure imgf000058_0002
根据文献（J. M . Chem. 2006, 49， 7868-7876)报道，阳性对照化合物（实 施例化合物 39 )的半衰期约为 32 min, 远低于本发明的实施例化合物的半衰 期。  According to the literature (J. M. Chem. 2006, 49, 7868-7876), the positive control compound (Example Compound 39) has a half-life of about 32 min, which is much lower than the half-life of the compounds of the examples of the present invention.
测试例一〜三的试验结果表明， 本发明的实施例化合物在体外活性以及 体内药代动力学性质方面有较大的改善。 与构成现有技术的阳性化合物 The test results of Test Examples 1 to 3 show that the compounds of the examples of the present invention have a large improvement in in vitro activity and in vivo pharmacokinetic properties. Positive compounds constituting the prior art
Bosutinib ( SKI606, 由 Adamas Technology购得） 或非氘代的阳性对照化合 物（实施例化合物 39 )相比， 在血药浓度、 半衰期、清除率、微粒体稳定性、 生物利用度或者酶抑制等性质上具有明显的优异性。 测试例四 体内药效测试 Bosutinib (SKI606, available from Adamas Technology) or non-deuterated positive control compound (Example Compound 39), in terms of plasma concentration, half-life, clearance, microsomal stability, bioavailability, or enzyme inhibition It has obvious superiority. Test case four in vivo efficacy test
采用 BALB/c裸小鼠 （上海西普尔-必凯实验动物公司）， 体重 18-20g， 雌性。 BD基质胶， K562细胞 （上海细胞库）。 给药周期： 每天灌胃给药一 次， 连续给药 8天。 细胞培养及传代： 收集细胞， 离心后用 RPMI-1640培养 基重新分散， 按 1 :4传代。 细胞接种： 收集对数生长期细胞， 培养基与基质 胶 1 :1， 调节细胞浓度为 5.0x l07/ml， 放入冰盒内， 以 0.2 ml/只接种于小鼠腋 窝下侧。 参数测量： 测量肿瘤体积和体重， 测量肿瘤体积时用游标卡尺分别 测量肿瘤的长径和宽径， 然后计算肿瘤的体积和相对体积。 BALB/c nude mice (Shanghai Xipuer-Beikai Experimental Animals Co., Ltd.) were used, weighing 18-20 g, female. BD Matrigel, K562 cells (Shanghai Cell Bank). Dosing cycle: It is administered once a day by intragastric administration for 8 consecutive days. Cell culture and passage: Cells were harvested, centrifuged and redispersed in RPMI-1640 medium and passaged 1:4. Cell seeding: The cells in the logarithmic growth phase were collected, medium and Matrigel 1 :1, and the cell concentration was adjusted to 5.0×10 7 /ml, placed in an ice box, and inoculated into the lower side of the mouse armpit with 0.2 ml/mouse. Parameter measurement: The tumor volume and body weight were measured. When measuring the tumor volume, the long diameter and the broad diameter of the tumor were measured with vernier calipers, and then the volume and relative volume of the tumor were calculated.
本次试验中， 本发明实施例化合物在 5 mg/kg、 10 mg/kg、 20 mg/kg剂量 下，对人白血病 K562裸鼠移植瘤均具有较强的生长抑制作用。例如， 5 mg/kg 剂量下， 实施例化合物 12和 37在 Day 10的 T/C比小于 35%; 10 mg/kg和 20 mg/kg剂量下， 实施例化合物 12和 37在 Day 10 的 T/C比均小于 20%， 直至肿瘤完全消褪， 并且试验动物的生存期明显延长。 在试验过程中， 未观 察到本实施例化合物会引起试验组动物体重及其他临床症状明显异常。  In this test, the compounds of the present invention have strong growth inhibition effects on human leukemia K562 xenografts at doses of 5 mg/kg, 10 mg/kg, and 20 mg/kg. For example, at a dose of 5 mg/kg, Example Compounds 12 and 37 have a T/C ratio of less than 35% at Day 10; at doses of 10 mg/kg and 20 mg/kg, Examples Compounds 12 and 37 are at Day 10 T The /C ratio was less than 20% until the tumor completely disappeared, and the survival time of the test animals was significantly prolonged. During the test, it was not observed that the compounds of this example caused significant abnormalities in body weight and other clinical symptoms of the test group.

Claims

权 利 要 求 Rights request
1、 一种式 （I) 所示的化合物或其药学上可接受的盐、 溶剂化物、 前体 药物 立体异构体、 互变异构体、 多晶型物或代谢产物： 1. A compound represented by formula (I) or its pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, tautomer, polymorph or metabolite:
Figure imgf000060_0001
Figure imgf000060_0001
R1为 C1~C6烷氧基， 所述 C1~C6烷氧基上的一个或多个 H非必须地被 氘取代； R 1 is a C1~C6 alkoxy group, and one or more H's on the C1~C6 alkoxy group are optionally substituted with deuterium;
Ar为未取代或由取代基所取代的 6~10元芳基、 或未取代或由取代基所 取代的 6~10元杂芳基， 所述 6~10元杂芳基含有 1~2个选自 N、 S和 0中的 杂原子， 所述取代基为卤素、 C1~C6烷氧基、 C1~C6烷基或 C3~C6环烷基， 其中所述 C1~C6烷氧基、 C1~C6烷基或 C3~C6环烷基上的一个或多个 H非 必须地被氘取代； i) -(CH2)mO-， 其中 m为 2~5的整数； Ar is a 6- to 10-membered aryl group that is unsubstituted or substituted with a substituent, or a 6- to 10-membered heteroaryl group that is unsubstituted or substituted with a substituent, and the 6- to 10-membered heteroaryl group contains 1 to 2 Heteroatom selected from N, S and 0, the substituent is halogen, C1~C6 alkoxy, C1~C6 alkyl or C3~C6 cycloalkyl, wherein the C1~C6 alkoxy, C1 One or more H on the ~C6 alkyl or C3~C6 cycloalkyl group are optionally substituted with deuterium; i) -(CH 2 ) m O-, where m is an integer from 2 to 5;
ii)
Figure imgf000060_0002
或卜 L1- C≡C—L2- 其中 Ll、 L2各自独立地为 -(CH 或直接键， n为 1~3的整数； 或 ii)
Figure imgf000060_0002
Or L1 - C≡C—L 2 - where Ll and L 2 are each independently -(CH or direct bond, n is an integer from 1 to 3; or
R' iii) R5 ， 其中 R4、 R5各自独立地为 H、 F或氘原子， R6为 5~6 元亚芳基或亚杂芳基， L3为 ^CH=CH—^、 ^_G≡C_ ^或直接键； R' iii) R 5 , wherein R 4 and R 5 are each independently H, F or deuterium atom, R 6 is a 5~6-membered arylene group or heteroarylene group, L 3 is ^CH=CH—^, ^_G≡C_ ^or direct key;
R2、 R3各自独立地为 H或 C1~C6烷基， 所述 C1~C6烷基上的一个或多 个 H非必须地被氘取代； R 2 and R 3 are each independently H or C1~C6 alkyl, and one or more H on the C1~C6 alkyl is optionally substituted with deuterium;
或者， R2、 R3和与它们相连的 N原子共同形成 4~7元含氮杂环基， 所述 含氮杂环基非必须地进一歩包含一个选自 N、 S和 0中的杂原子且非必须地 被取代基所取代， 所述的取代基为 C1~C6烷基、 单 (C1~C6烷基:)氨基、 二 (C1-C6 烷基:)氨基、 （C1~C6烷氧基:)酰基或 C3~C6 环烷基， 其中所述各个 C1~C6烷基、 C1~C6烷氧基或 C3~C6环烷基上的一个或多个 H非必须地被 氘取代； Alternatively, R 2 , R 3 and the N atom connected to them together form a 4 to 7-membered nitrogen-containing heterocyclic group, and the nitrogen-containing heterocyclic group optionally further contains a heterocyclic group selected from N, S and 0. Atoms and optionally substituted by substituents, the substituents are C1~C6 alkyl, mono(C1~C6 alkyl:)amino, di(C1~C6 alkyl:)amino, (C1~C6 alkyl:) Oxygen:)acyl or C3~C6 cycloalkyl, wherein each of the One or more H on C1~C6 alkyl, C1~C6 alkoxy or C3~C6 cycloalkyl are optionally substituted with deuterium;
并且， 式 （I) 所示的化合物至少含有一个氘原子。 Moreover, the compound represented by formula (I) contains at least one deuterium atom.
2、根据权利要求 1所述的化合物或其药学上可接受的盐、溶剂化物、前 体药物、立体异构体、互变异构体、多晶型物或代谢产物，其中， R1为 C1~C4 烷氧基； Ar为未取代或由取代基所取代的苯基， 或未取代或由取代基所取代 的 6元杂芳基，所述 6元杂芳基含有 1~2个氮原子，所述取代基为卤素、 C1~C4 烷氧基、 C1~C4烷基或 C3~C6环烷基， 其中所述 C1~C4烷氧基、 C1~C4烷 基或 C3~C6环烷基上的一个或多个 H非必须地被氘取代。 2. The compound of claim 1 or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, tautomer, polymorph or metabolite thereof, wherein R 1 is C1~C4 alkoxy; Ar is a phenyl group that is unsubstituted or substituted by a substituent, or a 6-membered heteroaryl group that is unsubstituted or substituted by a substituent, and the 6-membered heteroaryl group contains 1 to 2 nitrogens Atom, the substituent is halogen, C1~C4 alkoxy, C1~C4 alkyl or C3~C6 cycloalkyl, wherein the C1~C4 alkoxy, C1~C4 alkyl or C3~C6 cycloalkyl One or more H's on the radical are optionally substituted with deuterium.
3、根据权利要求 2所述的化合物或其药学上可接受的盐、溶剂化物、前 体药物、 立体异构体、 互变异构体、 多晶型物或代谢产物， 其中， R1为甲氧 基； Ar为未取代或由取代基所取代的苯基， 或未取代或由取代基所取代的吡 啶基， 所述取代基为氯、 甲氧基或环丙基， 其中所述甲氧基、 环丙基上的一 个或多个 H非必须地被氘取代。 3. The compound according to claim 2 or its pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, tautomer, polymorph or metabolite, wherein R 1 is Methoxy; Ar is a phenyl group that is unsubstituted or substituted by a substituent, or a pyridyl group that is unsubstituted or substituted by a substituent, and the substituent is chlorine, methoxy or cyclopropyl, wherein the methyl group One or more H on the oxygen group and cyclopropyl group are optionally substituted with deuterium.
4、根据权利要求 1所述的化合物或其药学上可接受的盐、溶剂化物、前 体药物、 立体异构体、 互变异构体、 多晶型物或代谢产物， 其中， L为 4. The compound according to claim 1 or its pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, tautomer, polymorph or metabolite, wherein L is
i) -(CH2)mO-, 其中 m为 3或 4， 且 0原子直接与喹啉环相连； ii)
Figure imgf000061_0001
其中 Ll、 L2各自独立地为 -(CH2)n-或直接键， n为 1~3 的整数； 或 iii) R5 ， 其中 R4、 R5各自独立地为 H、 F或氘原子， R6为 5~6 元亚苯基、 亚呋喃基或亚吡啶基， L3为_CH=CH—^、 G≡C_ ^或直接键， 且 i) -(CH 2 ) m O-, where m is 3 or 4, and the 0 atom is directly connected to the quinoline ring; ii)
Figure imgf000061_0001
Where Ll and L 2 are each independently -(CH 2 ) n - or a direct bond, n is an integer from 1 to 3; or iii) R 5 , where R 4 and R 5 are each independently H, F or deuterium atoms , R 6 is a 5~6-membered phenylene group, furylene group or pyridylene group, L 3 is _CH=CH—^, G≡C_ ^ or a direct bond, and
L3直接与喹啉环相连。 L 3 is directly connected to the quinoline ring.
5、根据权利要求 4所述的化合物或其药学上可接受的盐、溶剂化物、前 体药物、 立体异构体、 互变异构体、 多晶型物或代谢产物， 其中， 当 L 为 Ll-C≡C_L2 时， Ll为亚甲基或 -(CH2)2-， L2为直接键且直接与喹啉环相连。 5. The compound according to claim 4 or its pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, tautomer, polymorph or metabolite, wherein, when L is When L l - C ≡ C _ L2 , Ll is methylene or -(CH 2 ) 2 -, L 2 is a direct bond and is directly connected to the quinoline ring.
6、根据权利要求 4所述的化合物或其药学上可接受的盐、溶剂化物、前 体药物、 立体异构体、 互变异构体、 多晶型物或代谢产物， 其中， 当 L 为
Figure imgf000061_0002
R4、 R5各自独立地为 H或氘原子， R6为亚呋喃基， L3为直 接键。 6. The compound according to claim 4 or its pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, tautomer, polymorph or metabolite, wherein, when L is
Figure imgf000061_0002
R 4 and R 5 are each independently H or a deuterium atom, R 6 is a furylene group, and L 3 is a direct bond.
7、根据权利要求 6所述的化合物或其药学上可接受的盐、溶剂化物、前 体药物、 立体异构体、 互变异构体、 多晶型物或代谢产物， 其中， R6为 2,4- 亚呋喃基。 7. The compound according to claim 6 or its pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, tautomer, polymorph or metabolite, wherein R 6 is 2,4-furylidene.
8、根据权利要求 1所述的化合物或其药学上可接受的盐、溶剂化物、前 体药物、 立体异构体、 互变异构体、 多晶型物或代谢产物， 其中， R2、 R3各 自独立地为 H或 C1~C4烷基， 所述烷基上的一个或多个 H非必须地被氘取 代； 8. The compound according to claim 1 or its pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, tautomer, polymorph or metabolite, wherein, R 2 , R 3 is each independently H or C1~C4 alkyl, and one or more H on the alkyl group is optionally substituted with deuterium;
或者， R2、 R3和与它们相连的 N原子共同形成氮杂环丁烷基、吡咯烷基、 哌啶基、 吗啉基、 硫代吗啉基、 哌嗪基或高哌嗪基， 且上述基团非必须地被 取代基所取代，所述的取代基为 C1~C4烷基、单 (C1~C4烷基:)氨基、二 (C1~C4 烷基:)氨基、 （C1~C4烷氧基)酰基或 C3~C6环烷基， 其中所述 C1~C4烷基、 C1~C4烷氧基或 C3~C6环烷基上的一个或多个 H非必须地被氘取代。 Alternatively, R 2 , R 3 and the N atom connected to them together form an azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl or homopiperazinyl group, And the above-mentioned groups are optionally substituted by substituents, and the substituents are C1~C4 alkyl, mono(C1~C4 alkyl:)amino, di(C1~C4 alkyl:)amino, (C1~ C4 alkoxy)acyl or C3~C6 cycloalkyl, wherein one or more H on the C1~C4 alkyl, C1~C4 alkoxy or C3~C6 cycloalkyl is optionally replaced by deuterium.
9、根据权利要求 8所述的化合物或其药学上可接受的盐、溶剂化物、前 体药物、 立体异构体、 互变异构体、 多晶型物或代谢产物， 其中， R2、 R3各 自独立地为 H、 甲基或乙基， 所述甲基或乙基上的一个或多个 H非必须地被 氘取代； 9. The compound according to claim 8 or its pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, tautomer, polymorph or metabolite, wherein, R 2 , R 3 is each independently H, methyl or ethyl, and one or more H on the methyl or ethyl group is optionally substituted with deuterium;
或者， R2、 R3和与它们相连的 N原子共同形成哌嗪基、 吡咯烷基、 吗啉 基或哌啶基， 且上述基团非必须地被取代基所取代， 所述的取代基为甲基、 甲氨基、 二甲氨基、 叔丁氧基酰基或环丙基， 其中所述甲基、 叔丁氧基酰基 或环丙基上的一个或多个 H非必须地被氘取代。 Alternatively, R 2 , R 3 and the N atom connected to them together form a piperazinyl group, a pyrrolidinyl group, a morpholinyl group or a piperidinyl group, and the above groups are optionally substituted by substituents, and the substituents are It is methyl, methylamino, dimethylamino, tert-butoxyacyl or cyclopropyl, wherein one or more H on the methyl, tert-butoxyacyl or cyclopropyl group are optionally substituted with deuterium.
10、 根据权利要求 8所述的化合物或其药学上可接受的盐、 溶剂化物、 前体药物、 立体异构体、 互变异构体、 多晶型物或代谢产物， 其中， R2、 R3 各自独立地为 H、 甲基或乙基， 所述甲基或乙基上的一个或多个 H非必须地 被氘取代； 10. The compound according to claim 8 or its pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, tautomer, polymorph or metabolite, wherein, R 2 , R 3 is each independently H, methyl or ethyl, and one or more H on the methyl or ethyl group is optionally substituted with deuterium;
或者， R2、 R3和与它们相连的 N原子共同形成哌嗪基、 吡咯烷基、 吗啉 基或哌啶基， 且上述基团非必须地被取代基所取代， 所述的取代基为甲基、 甲氨基、 二甲氨基、 叔丁氧基酰基或环丙基， 其中所述甲基、 甲氨基、 二甲 氨基、 叔丁氧基酰基或环丙基上的一个或多个 H非必须地被氘取代。 Alternatively, R 2 , R 3 and the N atom connected to them together form a piperazinyl group, a pyrrolidinyl group, a morpholinyl group or a piperidinyl group, and the above groups are optionally substituted by substituents, and the substituents are is methyl, methylamino, dimethylamino, tert-butoxyacyl or cyclopropyl, wherein one or more H on the methyl, methylamino, dimethylamino, tert-butoxyacyl or cyclopropyl group Optionally replaced by deuterium.
11、 根据权利要求 1所述的化合物或其药学上可接受的盐、 溶剂化物、 前体药物、 立体异构体、 互变异构体、 多晶型物或代谢产物： 其中， 所述的 式 （I) 所示的化合物为如下任一化合物： D 化合物 2 11. The compound according to claim 1 or its pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, tautomer, polymorph or metabolite: wherein, the The compound represented by formula (I) is any of the following compounds: D compound 2
H 化合物 1 H compound 1
Figure imgf000063_0001
化合物 6 化合物 5
Figure imgf000063_0002
Figure imgf000063_0001
Compound 6 Compound 5
Figure imgf000063_0002
11 12
Figure imgf000064_0001
 11 12
Figure imgf000064_0001
化合物 15 Compound 15
化合物 16 Compound 16
〜〜 N 化合物 17 化合物 18
Figure imgf000064_0002
~~ N compound 17 compound 18
Figure imgf000064_0002
化合物 20 Compound 20
αχγα 化合物 21 αχγ α compound 21
化合物 23
Figure imgf000064_0003
Compound 23
Figure imgf000064_0003
化合物 24
Figure imgf000065_0001
Figure imgf000066_0001
 Compound 24
Figure imgf000065_0001
Figure imgf000066_0001
化合物 37 化合物 38 Compound 37 Compound 38
12、一种药物组合物，其包含治疗有效量的选自根据权利要求 1~11中任 一项所述的化合物或其药学上可接受的盐、 溶剂化物、 前体药物、 立体异构 体、 互变异构体、 多晶型物或代谢产物中的一种或多种， 以及至少一种药学 上可接受的辅料。 12. A pharmaceutical composition comprising a therapeutically effective amount selected from the compound according to any one of claims 1 to 11 or a pharmaceutically acceptable salt, solvate, prodrug, or stereoisomer thereof. , one or more of tautomers, polymorphs or metabolites, and at least one pharmaceutically acceptable excipient.
13、 根据权利要求 1~11中任一项所述的化合物或其药学上可接受的盐、 溶剂化物、 前体药物、 立体异构体、 互变异构体、 多晶型物或代谢产物， 或 权利要求 12 中所述的药物组合物在制备一种或多种蛋白激酶抑制剂中的用 途， 所述蛋白激酶选自 EGFR、 VEGFR、 HER-2、 HER-3、 HER-4、 Bcr-Ab c-Src、 JAK3、 PDGFR、 c-Kit、 LCK：、 LY A、 FGR、 EphB、 ECK：、 FY 、 MAP4K、 SIK：、 MST1、 YES、 ARG、 BTK：、 HCK：、 BLK：、 ALK：、 PKC、 NEK, MARK, FLT3、 RET、 FGFR、 PDK和 Syk。 13. The compound according to any one of claims 1 to 11 or its pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, tautomer, polymorph or metabolite , or the use of the pharmaceutical composition described in claim 12 in the preparation of one or more protein kinase inhibitors, the protein kinase being selected from EGFR, VEGFR, HER-2, HER-3, HER-4, Bcr -Ab c-Src, JAK3, PDGFR, c-Kit, LCK:, LY A, FGR, EphB, ECK:, FY, MAP4K, SIK:, MST1, YES, ARG, BTK:, HCK:, BLK:, ALK :, PKC, NEK, MARK, FLT3, RET, FGFR, PDK and Syk.
14、 根据权利要求 1~11中任一项所述的化合物或其药学上可接受的盐、 溶剂化物、 前体药物、 立体异构体、 互变异构体、 多晶型物或代谢产物， 或 权利要求 12中所述的药物组合物在制备治疗或预防肿瘤的药物中的用途。 14. The compound according to any one of claims 1 to 11 or its pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, tautomer, polymorph or metabolite , or the use of the pharmaceutical composition described in claim 12 in the preparation of drugs for treating or preventing tumors.
15、 根据权利要求 14所述的用途， 所述肿瘤选自白血病、 胃肠间质瘤、 组织细胞性淋巴瘤、 非小细胞肺癌、 小细胞肺癌、 胰腺癌、 肺鳞癌、 肺腺癌、 乳腺癌、 前列腺癌、 肝癌、 皮肤癌、 上皮细胞癌、 宫颈癌、 卵巢癌、 肠癌、 鼻咽癌、 脑癌、 骨癌、 食道癌、 黑色素瘤、 肾癌和口腔癌中的任一种。 15. The use according to claim 14, the tumor is selected from leukemia, gastrointestinal stromal tumor, histiocytic lymphoma, non-small cell lung cancer, small cell lung cancer, pancreatic cancer, lung squamous cell carcinoma, lung adenocarcinoma, Any of breast cancer, prostate cancer, liver cancer, skin cancer, epithelial cell cancer, cervical cancer, ovarian cancer, intestinal cancer, nasopharyngeal cancer, brain cancer, bone cancer, esophageal cancer, melanoma, kidney cancer and oral cancer .
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