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WO2014086284A1 - Composé de 3-cyanoquinoléine deutéré, composition pharmaceutique le comprenant, leur procédé de préparation et leur utilisation - Google Patents

Composé de 3-cyanoquinoléine deutéré, composition pharmaceutique le comprenant, leur procédé de préparation et leur utilisation Download PDF

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Publication number
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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English (en)
Chinese (zh)
Inventor
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/fr

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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.

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Abstract

L'invention porte sur un composé de 3-cyanoquinoléine deutéré ou des sels pharmaceutiquement acceptables, solvates, promédicaments, stéréoisomères, tautomères, substances polymorphes, métabolites, etc. de celui-ci, sur une composition pharmaceutique contenant de tels composés et sur l'utilisation de ces composés ou compositions dans la préparation de médicaments pour le traitement ou la prévention de tumeurs, en particulier de médicaments tels que des inhibiteurs de protéines kinases. Par comparaison avec l'état antérieur de la technique, les composés de la présente invention ont les nets avantages de propriétés telles que la concentration plasmatique des médicaments, leur demi-vie, leur clairance, leur stabilité microsomiale, leur biodisponibilité ou leur inhibition d'enzymes et similaire et permettent ainsi d'inhiber plus efficacement les activités de plus d'une protéine kinase et/ou d'inhiber efficacement la croissance de cellules tumorales.
PCT/CN2013/088479 2012-12-04 2013-12-04 Composé de 3-cyanoquinoléine deutéré, composition pharmaceutique le comprenant, leur procédé de préparation et leur utilisation WO2014086284A1 (fr)

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