WO2015058661A1 - Inhibiteur de bcr-abl kinase et application correspondante - Google Patents

Inhibiteur de bcr-abl kinase et application correspondante Download PDF

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WO2015058661A1
WO2015058661A1 PCT/CN2014/088911 CN2014088911W WO2015058661A1 WO 2015058661 A1 WO2015058661 A1 WO 2015058661A1 CN 2014088911 W CN2014088911 W CN 2014088911W WO 2015058661 A1 WO2015058661 A1 WO 2015058661A1
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alkyl
group
hydrogen
halogen
compound
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PCT/CN2014/088911
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English (en)
Chinese (zh)
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王勇
赵立文
刘阳
张景忠
王德忠
高毅平
陈宏雁
张仓
张迪
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南京圣和药业股份有限公司
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Publication of WO2015058661A1 publication Critical patent/WO2015058661A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4995—Pyrazines or piperazines forming part of bridged ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Definitions

  • the present invention belongs to the field of chemical medicine, and in particular relates to a compound having BCR-ABL kinase inhibitory activity or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof, and a pharmaceutical composition containing the same The use of these compounds or compositions in the preparation of pharmaceuticals.
  • Protein tyrosine kinases are a class of kinases that catalyze the transfer of gamma-phosphate on ATP to protein tyrosine residues, which are initiated by catalyzing the phosphorylation of phenolic hydroxyl groups on various protein tyrosine residues.
  • a proteinase system that functions as a functional protein.
  • Protein tyrosine kinases (PTKs) play an important role in the signal transduction pathways in cells, regulating a series of physiological and biochemical processes such as cell growth, differentiation and death. Abnormal expression of protein tyrosine kinase can lead to disturbances in cell proliferation regulation, which in turn leads to tumorigenesis.
  • Tyrosine kinase inhibitors act as competitive inhibitors of adenosine triphosphate (ATP) binding to tyrosine kinases, competitively bind to tyrosine kinases, block tyrosine kinase activity, and inhibit cell proliferation.
  • ATP adenosine triphosphate
  • tyrosines already exist. Acid protein kinase inhibitors have been successfully developed.
  • CML chronic myeloid leukemia
  • the long arm of chromosome 22 translocates to chromosome 9, forming a Philadelphia chromosome, and leads to the fusion of BCR gene and ABL gene to form a BCR-ABL fusion gene, expressing BCR-ABL protein tyrosine kinase.
  • BCR-ABL is not expressed in normal cells and has become an ideal drug target for the treatment of CML.
  • BCR-ABL tyrosine kinase inhibitors have become the first-line treatment for most chronic myeloid leukemias.
  • Imatinib is the first protein-targeted therapeutic protein tyrosine kinase inhibitor that inhibits BCR-ABL tyrosine kinase at the cellular level, selectively inhibits BCR-ABL-positive cell lines and Philadelphia Proliferation of fresh leukemia cells in chromosome-positive (Ph+) chronic myeloid leukemia (CML) and acute lymphoblastic leukemia (ALL) patients induces apoptosis.
  • Ph+ chromosome-positive
  • CML chronic myeloid leukemia
  • ALL acute lymphoblastic leukemia
  • the development and clinical use of imatinib has opened a new era of tumor molecular targeting, but long-term use of imatinib will produce drug resistance, leading to relapse. With the widespread clinical application of imatinib, the problem of drug resistance has become increasingly prominent.
  • imatinib resistance has ignited a wave of research and development of a new generation of tyrosine kinase inhibitors, in order to develop better CML, Ph+ for the treatment of leukemia, such as drug resistance or non-resistance. ALL's new drug.
  • Another object of the invention is to provide a process for the preparation of a compound of formula I of the invention, or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof.
  • a further object of the present invention is to provide a composition comprising a compound of Formula I of the present invention, or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof, and a pharmaceutically acceptable carrier, and a composition comprising the same A composition of a compound of formula I or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof and another protein tyrosine kinase inhibitor.
  • a further object of the present invention is to provide a compound of the formula I according to the invention, or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof, for treating and/or preventing a tumor, and the method of the invention Use of a compound of formula I or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof for the manufacture of a medicament for the treatment and/or prevention of a tumor.
  • the present invention provides a compound of formula I or a pharmaceutically acceptable salt, isomer, solvent thereof Compound, crystal or prodrug,
  • X is selected from N and C(R 5 ), wherein R 5 is selected from the group consisting of hydrogen, halogen, C 1-6 alkyl, halo C 1-6 alkyl;
  • Y is selected from N and C(R 6 ), wherein R 6 is selected from the group consisting of hydrogen, halogen, C 1-6 alkyl, halo C 1-6 alkyl;
  • R 1 is selected from the group consisting of hydrogen, alkyl, alkoxy, haloalkyl, haloalkoxy, -OH, -NH 2 , halogen, and CN;
  • R 2 is selected from the group consisting of hydrogen, alkyl, alkoxy, haloalkyl, haloalkoxy, -OH, -NH 2 , halogen, and CN;
  • W is selected from C 1-6 alkylene, -C(O)-, forms a 4-8 membered cycloalkyl group with R 4 or is absent;
  • R 3 is selected from substituted or unsubstituted five-, six-, seven- and eight-membered nitrogen-containing heterocyclic groups
  • R 4 is selected from hydrogen, alkyl, haloalkyl, or together with W to form a 4-8 membered cycloalkyl;
  • the compounds of the invention are compounds of formula I, and pharmaceutically acceptable salts, isomers, solvates, crystals or prodrugs thereof, wherein:
  • X is selected from N and C(R 5 ), wherein R 5 is selected from the group consisting of hydrogen, fluorine, chlorine, bromine, C 1-4 alkyl, halo C 1-4 alkyl;
  • Y is selected from N and C(R 6 ), wherein R 6 is selected from the group consisting of hydrogen, fluorine, chlorine, bromine, C 1-4 alkyl, halo C 1-4 alkyl;
  • R 1 is selected from the group consisting of hydrogen, C 1-4 alkyl, C 1-4 alkoxy, halo C 1-4 alkyl, halo C 1-4 alkoxy, -OH, -NH 2 , fluorine, chlorine , bromine and CN;
  • R 2 is selected from the group consisting of hydrogen, C 1-4 alkyl, C 1-4 alkoxy, halo C 1-4 alkyl, halo C 1-4 alkoxy, -OH, -NH 2 , fluorine, chlorine , bromine and CN;
  • W is selected from C 1-4 alkylene, -C(O)-, forms a 4-8 membered cycloalkyl group with R 4 or is absent;
  • R3 is selected from substituted or unsubstituted azacyclohexanes having 1, 2 or 3 nitrogen atoms selected from alkyl, hydroxy, hydroxyalkyl, alkoxy, amino, monoalkylamino, Dialkylamino, amido, An alkylamido group, an aryl amido group, a heteroaryl amido group, a halogen, a halogen-substituted alkyl group, a halogen-substituted alkoxy group, preferably the substituent is selected from a C1-6 alkyl group, a hydroxyl group, a hydroxy group C1- 6 alkyl, C1-6 alkoxy, amino, mono C1-6 alkylamino, bis C1-6 alkylamino, acylamino, C1-6 alkylamido, aryl amide, heteroaryl amide A halogen, a halogen-substituted C1-6 alkyl group, or a halogen-substitute
  • R 4 is selected from hydrogen, C 1-6 alkyl, halo C 1-6 alkyl or, together with W, a cyclopentyl group, a cyclobutane group, a cyclohexane group or a cycloheptyl group.
  • the compounds of the invention are compounds of formula I, and pharmaceutically acceptable salts, isomers, solvates, crystals or prodrugs thereof, wherein:
  • X is selected from N and C(R 5 ), wherein R 5 is selected from the group consisting of hydrogen, fluorine, chlorine, bromine, C 1-4 alkyl, halo C 1-4 alkyl;
  • Y is selected from N and C(R 6 ), wherein R 6 is selected from the group consisting of hydrogen, fluorine, chlorine, bromine, C 1-4 alkyl, halo C 1-4 alkyl;
  • R 1 is selected from the group consisting of hydrogen, C 1-4 alkyl, C 1-4 alkoxy, halo C 1-4 alkyl, halo C 1-4 alkoxy, -OH, -NH 2 , fluorine, chlorine , bromine and CN;
  • R 2 is selected from the group consisting of hydrogen, C 1-4 alkyl, C 1-4 alkoxy, halo C 1-4 alkyl, halo C 1-4 alkoxy, -OH, -NH 2 , fluorine, chlorine , bromine and CN;
  • W is selected from C 1-4 alkylene, -C(O)-, forms a 4-8 membered cycloalkyl group with R 4 or is absent;
  • R 3 is selected from pyridazinyl, pyridyl, azabicycloalkyl, imidazolyl, pyrazolyl, pyrrolyl, triazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, acridinyl, triazinyl, Or substituted pyridazinyl, pyridyl, azabicycloalkyl, imidazolyl, pyrazolyl, pyrrolyl, triazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, acridinyl, triazinyl, wherein The substitution is selected from the group consisting of alkyl, hydroxy, hydroxyalkyl, alkoxy, amino, monoalkylamino, bisalkylamino, acylamino, alkylamido, aryl amide, heteroaryl amide, halogen a halogen-
  • C 1-6 alkylamino bis C 1-6 alkylamino, acylamino, C 1-6 alkylamido, aryl amide, heteroaryl amide, halogen, halogen substituted C 1-6 alkane a halogen-substituted C 1-6 alkoxy group.
  • R 4 is selected from hydrogen, C 1-6 alkyl, halo C 1-6 alkyl or, together with W, a cyclopentyl group, a cyclobutane group, a cyclohexane group or a cycloheptyl group.
  • the compounds of the invention include a compound of formula I, and pharmaceutically acceptable salts, isomers, solvates, crystals or prodrugs thereof, wherein:
  • X is selected from N and C(R 5 ), wherein R 5 is selected from the group consisting of hydrogen, fluorine, chlorine, bromine, C 1-3 alkyl, halo C 1-3 alkyl;
  • Y is selected from N and C(R 6 ), wherein R 6 is selected from the group consisting of hydrogen, fluorine, chlorine, bromine, C 1-3 alkyl, halo C 1-3 alkyl;
  • R 1 is selected from the group consisting of hydrogen, C 1-3 alkyl, C 1-3 alkoxy, halo C 1-3 alkyl, halo C 1-3 alkoxy, -OH, -NH 2 , fluorine, chlorine , bromine and CN;
  • R 2 is selected from the group consisting of hydrogen, C 1-3 alkyl, C 1-3 alkoxy, halo C 1-3 alkyl, halo C 1-3 alkoxy, -OH, -NH 2 , fluorine, chlorine , bromine and CN;
  • W is selected from C 1-3 alkylene (eg, -CH 2 -, -CH 2 -CH 2 -), -C(O)-, and forms a cyclopentyl group with R 4 or is absent;
  • R 3 is selected from pyridazinyl, acridin-4-yl, diazabicyclooctylalkyl such as 3,8-diazabicyclo[3.2.1]octyl, said pyridazinyl, acridine- 4-Based, diazabicyclooctylalkyl may be substituted by one or more C 1-6 alkyl, C 1-6 alkoxy groups, for example by one or more methyl, ethyl, propyl, isopropyl Substituted by a base, a methoxy group, an ethoxy group or a propoxy group;
  • R 4 is selected from hydrogen, C 1-4 alkyl, halo C 1-4 alkyl, or together with W constitutes a cyclopentyl group.
  • R 6 is selected from the group consisting of hydrogen, halogen, C 1-6 alkyl, halo C 1-6 alkane
  • R 6 is selected from the group consisting of hydrogen, fluorine, chlorine, bromine, C 1-4 alkyl, halo C 1-4 alkyl, more preferably R 6 is selected from the group consisting of hydrogen, fluorine, chlorine, bromine, C 1- 3- alkyl, halo C 1-3 alkyl.
  • R 5 is selected from the group consisting of hydrogen, halogen, C 1-6 alkyl, halo C 1-6 alkane a group, preferably R 5 is selected from the group consisting of hydrogen, fluorine, chlorine, bromine, C 1-4 alkyl, halogenated C 1-4 alkyl, more preferably R 5 is selected from the group consisting of hydrogen, fluorine, chlorine, bromine, C 1- 3- alkyl, halo C 1-3 alkyl.
  • R 5 and R 6 are each independently selected from hydrogen, halogen, C 1-6
  • the invention provides a compound of formula Ia, or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof,
  • X is selected from N and C(R 5 ), wherein R 5 is selected from the group consisting of hydrogen, halogen, C 1-6 alkyl, halo C 1-6 alkyl;
  • Y is selected from N and C(R 6 ), wherein R 6 is selected from the group consisting of hydrogen, halogen, C 1-6 alkyl, halo C 1-6 alkyl;
  • R 1 is selected from the group consisting of hydrogen, alkyl, alkoxy, haloalkyl, haloalkoxy, -OH, -NH 2 , halogen, and CN;
  • R 2 is selected from the group consisting of hydrogen, alkyl, alkoxy, haloalkyl, haloalkoxy, -OH, -NH 2 , halogen, and CN;
  • W is selected from C 1-6 alkylene, -C(O)- or absent;
  • R 3 is selected from substituted or unsubstituted five-, six-, seven- and eight-membered nitrogen-containing heterocyclic groups, preferably R 3 is a substituted or unsubstituted azacyclohexane having 1, 2 or 3 nitrogen atoms Alkane, further preferably R 3 is pyridazinyl, pyridyl, azabicycloalkyl, imidazolyl, pyrazolyl, pyrrolyl, triazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, acridinyl, Triazinyl, or substituted pyridazinyl, pyridyl, azabicycloalkyl, imidazolyl, pyrazolyl, pyrrolyl, triazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, acridinyl, tri a pyridyl group
  • R 4 is selected from the group consisting of hydrogen, C 1-6 alkyl, halo C 1-6 alkyl;
  • the present invention provides a compound of Formula Ib, or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof,
  • X is selected from N and C(R 5 ), wherein R 5 is selected from the group consisting of hydrogen, halogen, C 1-6 alkyl, halo C 1-6 alkyl;
  • Y is selected from N and C(R 6 ), wherein R 6 is selected from the group consisting of hydrogen, halogen, C 1-6 alkyl, halo C 1-6 alkyl;
  • R 1 is selected from the group consisting of hydrogen, alkyl, alkoxy, haloalkyl, haloalkoxy, -OH, -NH 2 , halogen, and CN;
  • R 2 is selected from the group consisting of hydrogen, alkyl, alkoxy, haloalkyl, haloalkoxy, -OH, -NH 2 , halogen, and CN;
  • W is selected from C 1-6 alkylene, -C(O)- or absent;
  • R 3 is selected from substituted or unsubstituted five-, six-, seven- and eight-membered nitrogen-containing heterocyclic groups, preferably R 3 is a substituted or unsubstituted azacyclohexane having 1, 2 or 3 nitrogen atoms Alkane, further preferably R 3 is pyridazinyl, pyridyl, azabicycloalkyl, imidazolyl, pyrazolyl, pyrrolyl, triazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, acridinyl, Triazinyl, or substituted pyridazinyl, pyridyl, azabicycloalkyl, imidazolyl, pyrazolyl, pyrrolyl, triazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, acridinyl, tri a pyridyl group
  • R 4 is selected from the group consisting of hydrogen, C 1-6 alkyl, halo C 1-6 alkyl.
  • the invention provides a compound of formula Ic, or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof,
  • X is selected from N and C(R 5 ), wherein R 5 is selected from the group consisting of hydrogen, halogen, C 1-6 alkyl, halo C 1-6 alkyl;
  • Y is selected from N and C(R 6 ), wherein R 6 is selected from the group consisting of hydrogen, halogen, C 1-6 alkyl, halo C 1-6 alkyl;
  • R 1 is selected from the group consisting of hydrogen, alkyl, alkoxy, haloalkyl, haloalkoxy, -OH, -NH 2 , halogen, and CN;
  • R 2 is selected from the group consisting of hydrogen, alkyl, alkoxy, haloalkyl, haloalkoxy, -OH, -NH 2 , halogen, and CN;
  • R 3 is selected from substituted or unsubstituted five-, six-, seven- and eight-membered nitrogen-containing heterocyclic groups, preferably R 3 is a substituted or unsubstituted azacyclohexane having 1, 2 or 3 nitrogen atoms Alkane, further preferably R 3 is pyridazinyl, pyridyl, azabicycloalkyl, imidazolyl, pyrazolyl, pyrrolyl, triazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, acridinyl, Triazinyl, or substituted pyridazinyl, pyridyl, azabicycloalkyl, imidazolyl, pyrazolyl, pyrrolyl, triazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, acridinyl, tri a pyridyl group
  • the invention provides a compound of formula Id, or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof,
  • X is selected from N and C(R 5 ), wherein R 5 is selected from the group consisting of hydrogen, halogen, C 1-6 alkyl, halo C 1-6 alkyl;
  • Y is selected from N and C(R 6 ), wherein R 6 is selected from the group consisting of hydrogen, halogen, C 1-6 alkyl, halo C 1-6 alkyl;
  • R 1 is selected from the group consisting of hydrogen, alkyl, alkoxy, haloalkyl, haloalkoxy, -OH, -NH 2 , halogen, and CN;
  • R 2 is selected from the group consisting of hydrogen, alkyl, alkoxy, haloalkyl, haloalkoxy, -OH, -NH 2 , halogen, and CN;
  • R 3 is selected from substituted or unsubstituted five-, six-, seven- and eight-membered nitrogen-containing heterocyclic groups, preferably R 3 is a substituted or unsubstituted azacyclohexane having 1, 2 or 3 nitrogen atoms Alkane, further preferably R 3 is pyridazinyl, pyridyl, azabicycloalkyl, imidazolyl, pyrazolyl, pyrrolyl, triazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, acridinyl, Triazinyl, or substituted pyridazinyl, pyridyl, azabicycloalkyl, imidazolyl, pyrazolyl, pyrrolyl, triazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, acridinyl, tri a pyridyl group
  • R 1 is selected from the group consisting of hydrogen, alkyl, alkoxy, haloalkyl, halogen and CN, especially R 1 is selected from the group consisting of hydrogen, C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkyl, halogen, and CN.
  • R 2 is selected from the group consisting of hydrogen, alkyl, haloalkyl, halogen, and CN, particularly R 2 is selected from hydrogen. , C 1-6 alkyl, halo C 1-6 alkyl, halogen and CN.
  • R 3 is selected from the group consisting of 4-methylpyridazin-1-yl, acridin-4-yl, 1 -methyl acridin-4-yl, 3,8-diazabicyclo[3.2.1]octane-8-yl, 1-methyl-3,8-diazabicyclo[3.2.1]octane -8-based.
  • R 4 is selected from methyl and trifluoromethyl.
  • in Formulas I, Ia, Ib, Ic, Id, W and R 4 together form a cyclopentyl group.
  • R 5 is selected from hydrogen, halogen.
  • R 6 is selected from hydrogen, halogen.
  • R 1 is selected from the group consisting of hydrogen, methyl, trifluoromethyl, methoxy, ethoxy, C. Oxy or isopropoxy.
  • R 2 is selected from hydrogen, methyl, ethyl, propyl and isopropyl.
  • R 5 is selected from hydrogen, fluoro.
  • R 6 is selected from hydrogen, fluoro.
  • the present invention provides the following specific compounds:
  • the invention provides a process for the preparation of a compound of the formula of the invention.
  • the method for preparing a compound of formula I comprises the steps of:
  • R 1 , R 2 , R 3 , R 4 , W, X, Y have the meanings in the formula I, and M is selected from the group consisting of chlorine, bromine and iodine.
  • the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of the invention, or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof.
  • the invention provides a compound of the invention, or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof, and a compound comprising the same, or a pharmaceutically acceptable salt, isomer thereof
  • the invention provides a pharmaceutical composition comprising a compound, isomer, solvate, crystal or prodrug of the invention, further comprising one or more selected from the group consisting of a tyrosine protease Inhibitor, EGFR inhibitor, VEGFR inhibitor, BCR-ABL inhibitor, c-kit inhibitor, c-Met inhibitor, Raf inhibitor, MEK inhibitor, histone deacetylase inhibitor, VEGF antibody, EGF antibody , HIV protein kinase inhibitor, HMG-CoA reductase inhibitor, and the like.
  • a tyrosine protease Inhibitor EGFR inhibitor, VEGFR inhibitor, BCR-ABL inhibitor, c-kit inhibitor, c-Met inhibitor, Raf inhibitor, MEK inhibitor, histone deacetylase inhibitor, VEGF antibody, EGF antibody , HIV protein kinase inhibitor, HMG-CoA reductase inhibitor, and the like.
  • the compound, isomer, solvate, crystal or prodrug of the present invention may be mixed with a pharmaceutically acceptable carrier, diluent or excipient to prepare a pharmaceutical preparation suitable for oral or parenteral administration.
  • Methods of administration include, but are not limited to, intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, and oral routes.
  • the formulation may be administered by any route, for example by infusion or bolus injection, by a route of absorption through the epithelium or skin mucosa (e.g., oral mucosa or rectum, etc.). Administration can be systemic or topical.
  • orally administered preparations include solid or liquid dosage forms, specifically, tablets, pills, granules, powders, capsules, syrups, emulsions, suspensions and the like.
  • the formulations may be prepared by methods known in the art and comprise carriers, diluents or excipients conventionally employed in the field of pharmaceutical formulations.
  • the present invention provides a method, a method for treating and/or preventing a tumor of a compound, an isomer, a solvate, a crystal or a prodrug of the present invention or a pharmaceutical composition of the present invention, and in the preparation of a medicament for preventing and/or treating cancer
  • a compound, isomer, solvate, crystal or prodrug of the invention or a compound, isomer, solvate, crystal or prodrug of the invention to a tumor-prone population or tumor patient
  • the pharmaceutical composition is effective to reduce the incidence of tumors and prolong the life of tumor patients.
  • the invention provides methods for treating and/or preventing a tumor comprising administering to a subject in need thereof a therapeutically and/or prophylactically effective amount of a compound, isomer, solvate, crystal of the invention Or a prodrug or a pharmaceutical composition of the invention.
  • the compounds, isomers, solvates, crystals or prodrugs of the invention or pharmaceutical compositions of the invention may be administered to a mammal in need thereof to inhibit tumor growth, progression and/or metastasis, including solid tumors
  • tumor growth, progression and/or metastasis including solid tumors
  • solid tumors for example, breast cancer, colon cancer, gastric cancer, pancreatic cancer, central nervous system tumors, and head and neck cancers, as well as various forms of leukemia, including leukemia and other cancers that are resistant to other treatments such as imatinib or other kinase inhibitors,
  • the kinase is inhibited by a compound or composition of the invention.
  • alkyl group of the present invention means a linear, branched or cyclic saturated hydrocarbon group, preferably a C 1-6 alkyl group.
  • a suitable C 1-6 alkyl group includes, but is not limited to, a methyl group, a Base, n-propyl, isopropyl, cyclopropyl, n-butyl, isobutyl, tert-butyl, cyclobutyl, n-pentyl, isopentyl, cyclopentyl, cyclohexyl, n-hexyl.
  • the alkyl group is further preferably a C 1-3 alkyl group, and a suitable C 1-3 alkyl group is a methyl group, an ethyl group, a propyl group, an isopropyl group, or a cyclopropyl group.
  • an alkyl group in the present invention includes a substituted or unsubstituted alkyl group, which may be optionally substituted with one or more groups selected from the group consisting of an alkyl group, an alkoxy group, an aryloxy group, Alkylamino, arylamino, halogen, hydroxy, amino, nitro, cyano, alkyl acyl, aminoacyl, alkylaminoacyl, sulfonyl, sulfinyl, decyl, aryl or heteroaryl.
  • alkoxy group of the present invention means an alkyl-O- group, preferably a C 1-6 alkyl-O- group, further preferably a C 1-3 alkyl-O- group, a suitable C 1-3 alkyl group - O- is methoxy, ethoxy, propoxy or isopropoxy.
  • halogen of the present invention means fluorine, chlorine, bromine or iodine, preferably fluorine or chlorine.
  • haloalkyl group of the present invention means an alkyl group substituted with at least one halogen, preferably a halogenated C 1-6 alkyl group, further preferably a halogenated C 1-3 alkyl group, a suitable halogenated C 1-3 alkane.
  • Base is chloromethyl, fluoromethyl, dichloromethyl, difluoromethyl, trichloromethyl, trifluoromethyl, chloroethyl, fluoroethyl, dichloroethyl, difluoroethyl, trichloro Ethyl, trifluoroethyl.
  • haloalkoxy group of the present invention means an alkoxy group substituted with at least one halogen, preferably a C 1-6 alkoxy group substituted with at least one halogen, and further preferably a halogenated C 1-3 alkoxy group, suitably Halogenated C 1-3 alkoxy is chloromethoxy, fluoromethoxy, dichloromethoxy, difluoromethoxy, trichloromethoxy, trifluoromethoxy; dichloroethoxy , difluoroethoxy, trichloroethoxy, trifluoroethoxy.
  • the "five-membered, six-membered, seven-membered, eight-membered nitrogen-containing heterocyclic group" of the present invention means that the substituted or unsubstituted has at least one ring, and the total number of ring atoms is five, six, seven, eight and A saturated, partially saturated, and fully unsaturated heterocyclic group containing at least one nitrogen atom.
  • the "five-membered, six-membered, seven-membered, eight-membered nitrogen-containing heterocyclic group” is pyridazinyl, pyridyl, azabicycloalkyl, imidazolyl, pyrazolyl, pyrrolyl, triazolyl , pyridazinyl, pyrimidinyl, pyrazinyl, acridinyl, triazinyl, or substituted pyridazinyl, pyridyl, azabicycloalkyl, imidazolyl, pyrazolyl, pyrrolyl, triazolyl, Pyridazinyl, pyrimidinyl, pyrazinyl, acridinyl, triazinyl, wherein said substituent is selected from the group consisting of alkyl, hydroxy, hydroxyalkyl, alkoxy, amino, monoalkylamino, bisalkylamino An
  • the "4-8 membered cycloalkyl group" of the present invention means a monocyclic or bicyclic saturated hydrocarbon group having 4 to 8 carbon atoms.
  • Suitable cycloalkyl groups include cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl and the like.
  • Other suitable cycloalkyl groups include spiropentyl, bicyclo[2.1.0]pentyl and bicyclo[3.1.0]hexyl, and the like.
  • Solvent refers to a solvent known or readily determinable by those skilled in the art. In the case of water, the solvate is generally referred to as a hydrate such as a monohydrate, a dihydrate, a trihydrate or the like.
  • Crystal as used in the present invention refers to various solid forms formed by the compounds of the present invention, including crystalline forms and amorphous forms.
  • “Isomers” of the invention include the compounds cis conformation, conformational isomer and enantiomer.
  • a conformational isomer refers to a cis-trans isomer of the cis or trans configuration.
  • a conformational isomer refers to a stereoisomer resulting from the rotation of a single bond.
  • the "prodrug” of the present invention refers to a compound which is converted into a compound of the present invention by reaction with an enzyme, gastric acid or the like under physiological conditions of a living body, that is, a compound which is converted into a compound of the invention by oxidation, reduction, hydrolysis or the like of an enzyme. And/or a compound which converts to the compound of the invention by a hydrolysis reaction such as gastric acid or the like.
  • the "pharmaceutically acceptable salt” of the present invention means a pharmaceutically acceptable salt of the compound of the present invention and an acid, which includes, but is not limited to, phosphoric acid, sulfuric acid, hydrochloric acid, hydrobromic acid, citric acid, and Malay. Acid, malonic acid, mandelic acid, succinic acid, fumaric acid, acetic acid, lactic acid, nitric acid, and the like.
  • a "pharmaceutical composition” is meant to comprise any one of the compounds described herein, including isomers, prodrugs, solvates, pharmaceutically acceptable salts or chemically protected forms thereof, and one or more A mixture of pharmaceutically acceptable carriers.
  • the "pharmaceutically acceptable carrier” of the present invention means a carrier which does not cause significant irritation to an organism and does not interfere with the biological activity and properties of the administered compound, and includes a solvent, a diluent or other excipient, a dispersing agent, and a surface active agent. Agents, isotonic agents, thickeners or emulsifiers, preservatives, solid binders, lubricants, and the like. Unless any conventional carrier medium is incompatible with the compounds of the invention.
  • pharmaceutically acceptable carriers include, but are not limited to, sugars such as lactose, glucose, and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives, such as sodium carboxymethylcellulose, And cellulose and cellulose acetate; malt, gelatin and the like.
  • Excipient refers to an inert substance that is added to a pharmaceutical composition to further facilitate administration of the compound.
  • Excipients may include calcium carbonate, calcium phosphate, various sugars, and various types of starch, cellulose. Derivatives, gelatin, vegetable oil, polyethylene glycol.
  • the "application in the preparation of a medicament for treating and/or preventing a tumor” of the present invention means that the growth, development and/or metastasis of the tumor can be inhibited, and the therapeutically effective dose is mainly administered to a human or animal in need thereof.
  • the compounds of the invention inhibit, slow or reverse the growth, progression or spread of a tumor in a subject.
  • the compounds of the present invention refer to all compounds of the general formula of the present invention, including the compounds of the formula I, formula Ia, formula Ib, formula Ic or formula Id and specific compounds.
  • the product of the step 2 (1.59 g, 3.3 mmol), potassium carbonate (1.82 g, 13.2 mmol), and 20 ml of methanol were mixed in a reactor, and the mixture was stirred at room temperature for 3 hours under an inert gas atmosphere.
  • the reaction completed the methanol was removed by rotary evaporation, ethyl acetate and the organic layer was extracted with water, combined, washed with saturated NaCl solution, dried over anhydrous added Na 2 SO 4. The organic solution was then concentrated on a rotary evaporator.
  • Methyl 3-amino-6-bromopyrazine-2-carboxylate (4.62 g, 20 mmol), aqueous hydrobromic acid (48%, 24 ml), acetic acid (3.2 ml) was added to the mixture and cooled to -5 °C.
  • Methyl 3,6-dibromopyrazine-2-carboxylate (5.0 g, 17 mmol), tetrahydrofuran (100 ml) was added to the reactor and cooled to -78 °C.
  • Diisobutylaluminum hydride (34 ml, 34 mmol) was slowly added dropwise, and the mixture was reacted at -78 ° C for 2 h. The reaction was completed, and quenched by the addition of glacial acetic acid at -78 ° C.
  • Step 2 was added to the reactor to give 1-((3-tert-butoxycarbonyl-3,8-diazabicyclo[3.2.1]octane-8-yl)methyl)-2-trifluoromethyl 4-Nitrobenzene (8 g, 19.2 mmol), amine chloride (10 g, 190 mmol), iron powder (2 g), ethanol (50 mL), refluxed for 2 h. After completion of the reaction, filtration, solvent was distilled off under reduced pressure, water was added and extracted with ethyl acetate, washed with saturated aqueous NaCl, dried over anhydrous Na 2 SO 4, filtered, rotary evaporation, purified by column chromatography to give the title compound.
  • Step 4 was added to the reactor to give 3-ethynyl-4-methyl-N-(4-((3-tert-butoxycarbonyl-3,8-diazabicyclo[3.2.1]octane-8) -Methyl)-3-(trifluoromethyl)phenyl)benzamide (5 g, 9.4 mmol), 40% aqueous formaldehyde (10 mL), EtOAc (50 mL). After completion of the reaction, water was added and extracted with ethyl acetate, washed with saturated aqueous NaCl, dried over anhydrous Na 2 SO 4, filtered, rotary evaporation, purified by column chromatography to give the title compound.
  • Step 6 3-((1H-pyrrolo[2,3-b]pyrazin-5-yl)ethynyl)-4-methyl-N-(4-((3-methyl-3,8-di) Azabicyclo[3.2.1]octane-8-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide
  • Imatinib was prepared according to the method described in Chinese Patent No. CN1043531C and identified by hydrogen spectroscopy and mass spectrometry.
  • Ponatinib was purchased from Shanghai Xinkuo Chemical Technology Co., Ltd., and Ponatinib hydrochloride was prepared according to the method of Example 3 of the present invention and passed through hydrogen spectrum. And mass spectrometry identification.
  • the compounds of the above representative examples 2, 4, 5, 8, 9, 10 and imatinib and Ponatinib were used. Each compound was dissolved in DMSO to 10 mM, diluted to 50 ⁇ M with complete medium, and then diluted to 10 ⁇ M with complete medium containing 0.1% DMSO, and then diluted 10-fold in total for 10 concentrations.
  • K562 leukemia cells purchased from ATCC, USA
  • Imatinib-tolerant K562 leukemia cells purchased from ATCC, USA
  • DMSO Dimethyl sulfoxide
  • Luminescent cell viability assay kit CellTiter- Luminescent Cell Viability Assay Kit, purchased from Promega, USA;
  • IMEM medium (IMEM medium), purchased from Gibco, USA;
  • Penicillin/streptomycin (Pen/Strep), purchased from Gibco, USA;
  • Fetal bovine serun purchased from Gibco, USA;
  • 0.25% containing EDTA trypsin (0.25% Trypsin-EDTA), purchased from Gibco, USA;
  • 10cm cell culture dish (10cm cell culture dish), purchased from Corning, USA;
  • 50mL centrifuge tube 50mL centrifuge tube, purchased from Corning, USA;
  • Phosphate Buffered Saline was prepared weekly.
  • the compound of the present invention has a strong inhibitory activity against leukemia cells with an IC 50 value at the nM level.
  • the compounds of the invention are comparable to Ponatinib and far superior to imatinib.
  • the compounds of the invention exhibited better inhibitory activity than Ponatinib.
  • This experiment tested the inhibition of ABL (T315I) kinase activity by the compounds prepared in the examples of the present invention, using imatinib as a control.
  • Imatinib was prepared by the method described in Chinese Patent No. CN1043531C and identified by hydrogen spectroscopy and mass spectrometry.
  • ABL (T315I) tyrosine kinase activity was tested using a commercially available human ABL T315I mutant enzyme (Human ABL1 (T315I), active, Cat. #14-522, Millipore Corporation, USA). Kinase activity assays were performed according to the manufacturer's instructions.
  • the Peptide substrate was Abltide (EAIYAAPFAKKK) and was purchased from Millipore Corporation of the United States.
  • Ion exchange chromatography paper (P81) was purchased from Whatman Company of the United Kingdom.
  • [ ⁇ -33P] ATP was purchased from Perkin Elmer.
  • the compound of the present invention and imatinib were serially diluted 3 times from 1 ⁇ M, respectively, for a total of 10 concentrations (50.8 pM, 152.0 pM, 457.0 pM, 1.37 nM, 4.12 nM, 12.3 nM, 37.0 nM, 111.0 nM, 333.0 nM and 1.0 ⁇ M).
  • 5.0 ⁇ M Abltide was added to each well and then human T315I mutant enzyme was added.
  • [ ⁇ - 33 P]ATP was added at room temperature to a final concentration of 1.0 ⁇ M, and the reaction was carried out for 120 minutes. A 20 ⁇ l aliquot was transferred to a P81 ion exchange chromatography paper. The chromatography paper was then washed thoroughly 3 times with a 0.75% phosphoric acid solution and once with acetone. Finally, a gamma- 33P radioactivity assay was performed. The experimental results are shown in Table 2.
  • the compound of the present invention not only has a very good effect on leukemia cells without mutation, but also can significantly inhibit the T315I mutant enzyme, and thus is a broad-spectrum BCR-ABL inhibitor.
  • TKI tyrosine kinase inhibitor
  • CML chronic myeloid leukemia
  • blast blast
  • accelerated Philadelphia chromosome-positive
  • Ph+ Philadelphia chromosome-positive
  • the compounds of the invention prepared using the above representative examples 3 and 6 were used.
  • the oral drug formulation is dissolved in physiological saline to prepare a suspension of 3 mg/ml;
  • mice Male Sprague-Dawley rats, 3 in each group, weighing 150-250 g, were provided by Shanghai Xipuer-Beikai Experimental Animal Co., Ltd. The rats in the test group were given an environmental adaptation period of 2 to 4 days before the experiment, and were fasted for 8-12 hours before administration, and given water for 2 hours after administration, and fed after 4 hours.
  • Acetonitrile (chromatographically pure): produced by Spectrum;
  • step 2) Take 3 rats in step 1), intragastric administration (I.G.) to give Example 3 compound 15mg / kg;
  • the intravenous vein (Intravenous administration, I.V.) was given the compound of Example 3 3mg / kg;
  • the intravenous vein (Intravenous administration, I.V.) was given the compound of Example 6 5mg / kg;
  • the fundus venous plexus was continuously taken from the EP tube with heparin. After centrifugation at 8000 rpm/min for 5 min, the upper layer of plasma was taken. Cryopreservation at 20 ° C, to be analyzed by LC-MS/MS.
  • the oral pharmaceutical formulation was: physiological saline dissolved.
  • mice Male mice, 24, weighing 18 ⁇ 2 g, were purchased from Qinglong Mountain Animal Breeding Farm in Jiangning District, Nanjing. The test mice were given an environmental adaptation period of 2 to 4 days before the experiment, and were fasted for 8-12 hours before administration, and given water for 2 hours after administration, and fed after 4 hours.
  • Ultrapure water Milli-Q ultra pure water purifier (Millipore Inc) instrument homemade;
  • Milli-Q Ultra Water Purifier (Millipore Inc); LT501 Electronic Balance.
  • mice were randomly divided into 3 groups: blank control group, Ponatinib hydrochloride drug group, and Example 6 drug group, 6 rats in each group;
  • mice are administered by intragastric administration, the administration method is: day 0-2, the administration dose is 10 mg/kg; on the 3-5th day, the administration dose is 20 mg/kg; on the sixth to the ninth day, the administration dose is 40mg/kg;
  • * indicates p ⁇ 0.05 compared to the blank control group.
  • the above subacute toxicity test results showed that the Ponatinib group had a significant effect on the body weight of the mice compared with the blank control group, and the P value was ⁇ 0.05, while the compound of the present invention had no effect on the body weight of the mice and showed extremely low toxicity.
  • the medicament of the present invention is significantly superior to Ponatinib in terms of toxic side effects.

Abstract

La présente invention concerne le domaine des médicaments chimiques, en particulier des composés tels que représentés par la formule I présentant une activité inhibitrice de la BCR-ABL kinase, ou un sel, un isomère, un solvate, un cristal pharmaceutiquement acceptables ou un promédicament correspondants et une composition pharmaceutique contenant les composés et l'application des composés ou compositions dans la préparation de médicaments. Les composés de la présente invention présentent un effet d'inhibition puissant sur la BCR-ABL kinase et peuvent être utilisés pour traiter des maladies telles que des tumeurs.
PCT/CN2014/088911 2013-10-23 2014-10-20 Inhibiteur de bcr-abl kinase et application correspondante WO2015058661A1 (fr)

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