WO2019062637A1 - 喹啉衍生物及其作为酪氨酸激酶抑制剂的应用 - Google Patents

喹啉衍生物及其作为酪氨酸激酶抑制剂的应用 Download PDF

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WO2019062637A1
WO2019062637A1 PCT/CN2018/106674 CN2018106674W WO2019062637A1 WO 2019062637 A1 WO2019062637 A1 WO 2019062637A1 CN 2018106674 W CN2018106674 W CN 2018106674W WO 2019062637 A1 WO2019062637 A1 WO 2019062637A1
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group
compound
acid
stands
reaction
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PCT/CN2018/106674
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English (en)
French (fr)
Inventor
张杨
陈正霞
戴美碧
李文举
黎健
陈曙辉
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南京明德新药研发股份有限公司
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Priority to JP2020517877A priority Critical patent/JP7177829B2/ja
Priority to ES18862179T priority patent/ES2932805T3/es
Priority to US16/651,521 priority patent/US11161817B2/en
Priority to EP18862179.1A priority patent/EP3689351B1/en
Priority to PL18862179.1T priority patent/PL3689351T3/pl
Publication of WO2019062637A1 publication Critical patent/WO2019062637A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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

Definitions

  • This invention relates to a class of quinoline derivatives and their use in the manufacture of a medicament for the treatment of diseases associated with tyrosine kinase inhibitors. Specifically, it relates to a compound of the formula (II) and a pharmaceutically acceptable salt thereof.
  • PTK Protein tyrosine kinase
  • HGF hepatocyte growth factor
  • PDGF platelet-derived growth factor
  • FGF and VEGF vascular endothelial growth factor
  • Akinase which includes LCK, ABL, and the like.
  • the c-Met protein also known as hepatocyte growth factor (HGF) receptor
  • HGF hepatocyte growth factor
  • the HGF/c-Met signaling pathway has been shown to demonstrate a variety of cellular responses, including mitogenic activity, value-adding activity, morphogenic activity, and angiogenic activity.
  • Inhibitors of the HGF/c-Met pathway have significant potential for the treatment of cancer.
  • ABL is a proto-oncogene-encoded tyrosine kinase that activates ABL to promote cell proliferation, differentiation, and EMT. In hematomas, it is mainly activated by fusion of genes such as BCR-ABL. In solid tumors, activation is mainly through gene amplification, overexpression, and upstream receptor tyrosine kinases such as PDGFR, EGFR, and the like.
  • TNIK is a serine/threonine kinase that binds to ⁇ -catenin/TCF in the wnt signaling pathway, activates the target gene downstream of the wnt signal, and promotes tumor growth.
  • MINK is a member of the STE20 protein kinase family and has high expression in the central nervous system, which activates JNK and the p38 signaling pathway.
  • FGFR Fibroblast growth factor receptor
  • FGF fibroblast growth factor
  • the FGFRs family includes the following types: FGFR1b, FGFR1c, FGFR2b, FGFR2c, FGFR3b, FGFR3c, FGFR4. .
  • Different subtypes of FGFR are different from FGF. FGFs bind to FGFRs and lead to autophosphorylation of multiple tyrosine residues in the cell.
  • FGFR4 is highly expressed in liver cancer, colon cancer, gastric cancer, esophageal cancer and testicular cancer
  • FGF19 which specifically binds to FGFR4 is highly expressed in human colon cancer, liver cancer and lung cancer cells, and the signal abnormalities of FGFR4 and FGF19 binding specifically are various.
  • VEGF Vascular endothelial growth factor
  • PDGF platelet-derived growth factor
  • PDGFR In the treatment of tumor cells with several targets such as ABL, C-Met, TNIK, FGFR1-4, VEGFR (FLT1, KDR, FLT4), PDGFR can synergistically complement each other in terms of molecular mechanism of action.
  • targets such as ABL, C-Met, TNIK, FGFR1-4, VEGFR (FLT1, KDR, FLT4)
  • PDGFR can synergistically complement each other in terms of molecular mechanism of action.
  • the escape of tumor cells reduces drug resistance and improves the therapeutic effect, so drugs that act on these targets at the same time are highly anticipated.
  • the currently marketed drug multi-kinase inhibits levalinib, which can simultaneously have ABL, TNIK, FGFR, VEGFR, PDGFR activity, is excellent in clinical treatment effect, and has high patient response rate.
  • the present invention provides a compound of the formula (II) or a pharmaceutically acceptable salt thereof,
  • R 1 is selected from C 1-6 alkoxy optionally substituted by 1, 2 or 3 R;
  • Ring B is selected from C 3-6 cycloalkyl
  • R is selected from the group consisting of F, Cl, Br, I, OH, and NH 2 .
  • R 1 is selected from the group consisting of Other variables are as defined by the present invention.
  • Ring B is selected from the group consisting of cyclopropyl, and other variables are as defined herein.
  • the present invention provides a compound of the formula (I) or a pharmaceutically acceptable salt thereof,
  • R 1 is selected from C 1-6 alkoxy optionally substituted by 1, 2 or 3 R;
  • R 3 is selected from the group consisting of H, F, Cl, Br, I, OH, and NH 2 ;
  • Ring B is selected from C 3-6 cycloalkyl
  • n is selected from 2 and 3;
  • R is selected from the group consisting of F, Cl, Br, I, OH, and NH 2 .
  • R 1 is selected from the group consisting of Other variables are as defined by the present invention.
  • R 3 is selected from the group consisting of F and Cl, and other variables are as defined in the present invention.
  • Ring B is selected from the group consisting of cyclopropyl, and other variables are as defined herein.
  • n is selected from 2, and other variables are as defined in the present invention.
  • the above compound or a pharmaceutically acceptable salt thereof selected from the group consisting of
  • R 1 , R 2 , and R 3 are as defined in the present invention.
  • the present invention also provides the following compounds selected from the group consisting of
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of the above compound or a pharmaceutically acceptable salt thereof as an active ingredient together with a pharmaceutically acceptable carrier.
  • the present invention also provides the use of the above compound or a pharmaceutically acceptable salt thereof or a composition as described above for the preparation of a medicament for treating a tyrosine kinase inhibitor-related disorder.
  • the use of the above, wherein the tyrosine kinase inhibitor-associated disorder refers to a neoplastic disease and an immune disorder.
  • pharmaceutically acceptable salt refers to a salt of a compound of the invention prepared from a compound having a particular substituent found in the present invention and a relatively non-toxic acid or base.
  • a base addition salt can be obtained by contacting a neutral amount of such a compound with a sufficient amount of a base in a neat solution or a suitable inert solvent.
  • Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amine or magnesium salts or similar salts.
  • an acid addition salt can be obtained by contacting a neutral form of such a compound with a sufficient amount of an acid in a neat solution or a suitable inert solvent.
  • pharmaceutically acceptable acid addition salts include inorganic acid salts including, for example, hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, hydrogencarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, Hydrogen sulfate, hydroiodic acid, phosphorous acid, etc.; and an organic acid salt, such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, Similar acids such as fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, and me
  • the pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound containing an acid group or a base by conventional chemical methods.
  • such salts are prepared by reacting these compounds in water or an organic solvent or a mixture of the two via a free acid or base form with a stoichiometric amount of a suitable base or acid.
  • Certain compounds of the invention may exist in unsolvated or solvated forms, including hydrated forms.
  • the solvated forms are equivalent to the unsolvated forms and are included within the scope of the invention.
  • the compounds of the invention may exist in specific geometric or stereoisomeric forms.
  • the present invention contemplates all such compounds, including the cis and trans isomers, the (-)- and (+)-p-enantiomers, the (R)- and (S)-enantiomers, and the diastereomeric a conformation, a (D)-isomer, a (L)-isomer, and a racemic mixture thereof, and other mixtures, such as enantiomerically or diastereomeric enriched mixtures, all of which belong to It is within the scope of the invention.
  • Additional asymmetric carbon atoms may be present in the substituents such as alkyl groups. All such isomers, as well as mixtures thereof, are included within the scope of the invention.
  • enantiomer or “optical isomer” refer to stereoisomers that are mirror images of one another.
  • cis-trans isomer or “geometric isomer” is caused by the inability to freely rotate a single bond due to a double bond or a ring-forming carbon atom.
  • diastereomer refers to a stereoisomer in which the molecule has two or more chiral centers and the molecules are in a non-mirrored relationship.
  • wedge-shaped dashed keys Represents the absolute configuration of a solid center with straight solid keys
  • straight dashed keys Indicates the relative configuration of the stereocenter, using wavy lines Indicates a wedge solid key Or wedge-shaped dotted key Or with wavy lines Represents a straight solid key And straight dashed keys
  • tautomer or “tautomeric form” mean that the different functional isomers are in dynamic equilibrium at room temperature and can be rapidly converted into each other. If tautomers are possible (as in solution), the chemical equilibrium of the tautomers can be achieved.
  • proton tautomers also known as prototropic tautomers
  • prototropic tautomers include interconversions by proton transfer, such as keto-enol isomerization and imine-enes. Amine isomerization.
  • the valence tautomer includes the mutual transformation of some of the bonding electrons.
  • keto-enol tautomerization is the interconversion between two tautomers of pentane-2,4-dione and 4-hydroxypent-3-en-2-one.
  • the terms "enriched in one isomer”, “isomer enriched”, “enriched in one enantiomer” or “enantiomeric enriched” refer to one of the isomers or pairs
  • the content of the oligo is less than 100%, and the content of the isomer or enantiomer is 60% or more, or 70% or more, or 80% or more, or 90% or more, or 95% or more, or 96% or more, or 97% or more, 98% or more, 99% or more, 99.5% or more, 99.6% or more, 99.7% or more, 99.8% or more, or greater than or equal to 99.9%.
  • the term “isomer excess” or “enantiomeric excess” refers to the difference between the two isomers or the relative percentages of the two enantiomers. For example, if one of the isomers or enantiomers is present in an amount of 90% and the other isomer or enantiomer is present in an amount of 10%, the isomer or enantiomeric excess (ee value) is 80%. .
  • optically active (R)- and (S)-isomers as well as the D and L isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If an enantiomer of a compound of the invention is desired, it can be prepared by asymmetric synthesis or by derivatization with a chiral auxiliary wherein the resulting mixture of diastereomers is separated and the auxiliary group cleaved to provide pure The desired enantiomer.
  • a diastereomeric salt is formed with a suitable optically active acid or base, and then by conventional methods well known in the art.
  • the diastereomers are resolved and the pure enantiomer is recovered.
  • the separation of enantiomers and diastereomers is generally accomplished by the use of chromatography using a chiral stationary phase, optionally in combination with chemical derivatization (eg, formation of an amino group from an amine). Formate).
  • the compounds of the present invention may contain unnatural proportions of atomic isotopes on one or more of the atoms that make up the compound.
  • radiolabeled compounds can be used, such as tritium (3 H), iodine -125 (125 I) or C-14 (14 C).
  • hydrogen can be replaced by heavy hydrogen to form a deuterated drug.
  • the bond composed of barium and carbon is stronger than the bond composed of common hydrogen and carbon.
  • deuterated drugs have reduced side effects and increased drug stability. Enhance the efficacy and prolong the biological half-life of the drug. Alterations of all isotopic compositions of the compounds of the invention, whether radioactive or not, are included within the scope of the invention.
  • an "effective amount” or “therapeutically effective amount” with respect to a pharmaceutical or pharmacologically active agent refers to a sufficient amount of a drug or agent that is non-toxic but that achieves the desired effect.
  • an "effective amount” of an active substance in a composition refers to the amount required to achieve the desired effect when used in combination with another active substance in the composition. The determination of the effective amount will vary from person to person, depending on the age and general condition of the recipient, and also on the particular active substance, and a suitable effective amount in a case can be determined by one skilled in the art based on routine experimentation.
  • active ingredient refers to a chemical entity that is effective in treating a target disorder, disease or condition.
  • substituted means that any one or more hydrogen atoms on a particular atom are replaced by a substituent, and may include variants of heavy hydrogen and hydrogen, as long as the valence of the particular atom is normal and the substituted compound is stable. of.
  • Oxygen substitution does not occur on the aromatic group.
  • optionally substituted means that it may or may not be substituted, and unless otherwise specified, the kind and number of substituents may be arbitrary on the basis of chemically achievable.
  • any variable eg, R
  • its definition in each case is independent.
  • the group may optionally be substituted with at most two R, and each case has an independent option.
  • combinations of substituents and/or variants thereof are permissible only if such combinations result in stable compounds.
  • linking group When the number of one linking group is 0, such as -(CRR) 0 -, it indicates that the linking group is a single bond.
  • one of the variables When one of the variables is selected from a single bond, it means that the two groups to which it is attached are directly linked. For example, when L represents a single bond in A-L-Z, the structure is actually A-Z.
  • a substituent When a substituent is vacant, it means that the substituent is absent.
  • X when X is vacant in AX, the structure is actually A.
  • the listed linking group does not indicate its direction of attachment, its connection direction is arbitrary, for example, The medium linking group L is -MW-, and at this time, -MW- can be connected in the same direction as the reading order from left to right to form ring A and ring B. It is also possible to connect the ring A and the ring B in a direction opposite to the reading order from left to right. Combinations of the linking groups, substituents and/or variants thereof are permissible only if such combinations result in stable compounds.
  • hetero denotes a hetero atom or a hetero atomic group (ie, a radical containing a hetero atom), including atoms other than carbon (C) and hydrogen (H), and radicals containing such heteroatoms, including, for example, oxygen (O).
  • ring means substituted or unsubstituted cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, cycloalkynyl, heterocycloalkynyl, aryl or heteroaryl. So-called rings include single rings, interlocking rings, spiral rings, parallel rings or bridge rings. The number of atoms on the ring is usually defined as the number of elements of the ring. For example, "5 to 7-membered ring” means 5 to 7 atoms arranged in a circle. Unless otherwise specified, the ring optionally contains from 1 to 3 heteroatoms.
  • 5- to 7-membered ring includes, for example, phenyl, pyridine, and piperidinyl; on the other hand, the term “5- to 7-membered heterocycloalkyl ring” includes pyridyl and piperidinyl, but does not include phenyl.
  • ring also includes ring systems containing at least one ring, each of which "ring” independently conforms to the above definition.
  • hydrocarbyl or its subordinate concept (such as alkyl, alkenyl, alkynyl, aryl, etc.), by itself or as part of another substituent, is meant to be straight-chain, branched or cyclic.
  • the hydrocarbon atom group or a combination thereof may be fully saturated (such as an alkyl group), a unit or a polyunsaturated (such as an alkenyl group, an alkynyl group, an aryl group), may be monosubstituted or polysubstituted, and may be monovalent (such as Methyl), divalent (such as methylene) or polyvalent (such as methine), may include divalent or polyvalent radicals with a specified number of carbon atoms (eg, C 1 -C 12 represents 1 to 12 carbons) , C 1-12 is selected from C 1 , C 2 , C 3 , C 4 , C 5 , C 6 , C 7 , C 8 , C 9 , C 10 , C 11 and C 12 ; C 3-12 is selected from C 3 , C 4 , C 5 , C 6 , C 7 , C 8 , C 9 , C 10 , C 11 and C 12 .).
  • C 1-12 is selected from C 1
  • Hydrocarbyl includes, but is not limited to, aliphatic hydrocarbyl groups including chain and cyclic, including but not limited to alkyl, alkenyl, alkynyl groups including, but not limited to, 6-12 members.
  • An aromatic hydrocarbon group such as benzene, naphthalene or the like.
  • hydrocarbyl means a straight or branched chain radical or a combination thereof, which may be fully saturated, unitary or polyunsaturated, and may include divalent and multivalent radicals.
  • saturated hydrocarbon radicals include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, isobutyl, cyclohexyl, (cyclohexyl).
  • a homolog or isomer of a methyl group, a cyclopropylmethyl group, and an atomic group such as n-pentyl, n-hexyl, n-heptyl, n-octyl.
  • the unsaturated hydrocarbon group has one or more double or triple bonds, and examples thereof include, but are not limited to, a vinyl group, a 2-propenyl group, a butenyl group, a crotyl group, a 2-isopentenyl group, and a 2-(butadienyl group). , 2,4-pentadienyl, 3-(1,4-pentadienyl), ethynyl, 1- and 3-propynyl, 3-butynyl, and higher homologs and isomers body.
  • heterohydrocarbyl or its subordinate concept (such as heteroalkyl, heteroalkenyl, heteroalkynyl, heteroaryl, etc.), by itself or in combination with another term, means a stable straight chain, branched chain. Or a cyclic hydrocarbon radical or a combination thereof having a number of carbon atoms and at least one heteroatom.
  • heteroalkyl by itself or in conjunction with another term refers to a stable straight chain, branched hydrocarbon radical or combination thereof, having a number of carbon atoms and at least one heteroatom.
  • the heteroatoms are selected from the group consisting of B, O, N, and S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen heteroatoms are optionally quaternized.
  • the hetero atom or heteroatom group may be located at any internal position of the heterohydrocarbyl group, including where the hydrocarbyl group is attached to the rest of the molecule, but the terms "alkoxy”, “alkylamino” and “alkylthio” (or thioalkoxy). By customary expression, those alkyl groups which are attached to the remainder of the molecule through an oxygen atom, an amino group or a sulfur atom, respectively.
  • Up to two heteroatoms may be consecutive, for example, -CH 2 -NH-OCH 3.
  • cycloalkyl refers to any heterocyclic alkynyl group, etc., by itself or in combination with other terms, denotes a cyclized “hydrocarbyl group” or “heterohydrocarbyl group”, respectively.
  • a hetero atom may occupy a position at which the hetero ring is attached to the rest of the molecule.
  • cycloalkyl groups include, but are not limited to, cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl, and the like.
  • heterocyclic groups include 1-(1,2,5,6-tetrahydropyridyl), 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-morpholinyl, 3-morpholinyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrothiophen-2-yl, tetrahydrothiophen-3-yl, 1-piperazinyl and 2-piperazinyl.
  • alkyl is used to denote a straight or branched saturated hydrocarbon group, which may be monosubstituted (eg, -CH 2 F) or polysubstituted (eg, -CF 3 ), and may be monovalent (eg, Methyl), divalent (such as methylene) or polyvalent (such as methine).
  • alkyl group include methyl (Me), ethyl (Et), propyl (e.g., n-propyl and isopropyl), butyl (e.g., n-butyl, isobutyl, s-butyl). , t-butyl), pentyl (eg, n-pentyl, isopentyl, neopentyl) and the like.
  • a cycloalkyl group includes any stable cyclic or polycyclic hydrocarbon group, any carbon atom which is saturated, may be monosubstituted or polysubstituted, and may be monovalent, divalent or multivalent.
  • Examples of such cycloalkyl groups include, but are not limited to, cyclopropyl, norbornyl, [2.2.2]bicyclooctane, [4.4.0]bicyclononane, and the like.
  • halo or “halogen”, by itself or as part of another substituent, denotes a fluorine, chlorine, bromine or iodine atom.
  • haloalkyl is intended to include both monohaloalkyl and polyhaloalkyl.
  • halo(C 1 -C 4 )alkyl is intended to include, but is not limited to, trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the like. Wait.
  • examples of haloalkyl include, but are not limited to, trifluoromethyl, trichloromethyl, pentafluoroethyl, and pentachloroethyl.
  • alkoxy represents attached through an oxygen bridge
  • C 1-6 alkoxy groups include C 1, C 2, C 3 , C 4, C 5 , and C 6 alkoxy groups.
  • alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentyloxy and S- Pentyloxy.
  • leaving group refers to a functional group or atom which may be substituted by another functional group or atom by a substitution reaction (for example, an affinity substitution reaction).
  • substituent groups include triflate; chlorine, bromine, iodine; sulfonate groups such as mesylate, tosylate, p-bromobenzenesulfonate, p-toluenesulfonic acid Esters and the like; acyloxy groups such as acetoxy, trifluoroacetoxy and the like.
  • protecting group includes, but is not limited to, "amino protecting group", “hydroxy protecting group” or “thiol protecting group”.
  • amino protecting group refers to a protecting group suitable for preventing side reactions at the amino nitrogen position.
  • Representative amino protecting groups include, but are not limited to, formyl; acyl, such as alkanoyl (e.g., acetyl, trichloroacetyl or trifluoroacetyl); alkoxycarbonyl, e.g., tert-butoxycarbonyl (Boc) Arylmethoxycarbonyl, such as benzyloxycarbonyl (Cbz) and 9-fluorenylmethoxycarbonyl (Fmoc); arylmethyl, such as benzyl (Bn), trityl (Tr), 1, 1-di -(4'-methoxyphenyl)methyl; silyl groups such as trimethylsilyl (TMS) and tert-
  • hydroxy protecting group refers to a protecting group suitable for use in preventing hydroxy side reactions.
  • Representative hydroxy protecting groups include, but are not limited to, alkyl groups such as methyl, ethyl and t-butyl groups; acyl groups such as alkanoyl groups (e.g., acetyl); arylmethyl groups such as benzyl (Bn), Oxybenzyl (PMB), 9-fluorenylmethyl (Fm) and diphenylmethyl (diphenylmethyl, DPM); silyl groups such as trimethylsilyl (TMS) and tert-butyl Dimethylsilyl (TBS) and the like.
  • alkyl groups such as methyl, ethyl and t-butyl groups
  • acyl groups such as alkanoyl groups (e.g., acetyl)
  • arylmethyl groups such as benzyl (Bn), Oxybenzyl (PMB), 9-fluoreny
  • the compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments set forth below, combinations thereof with other chemical synthetic methods, and those well known to those skilled in the art. Equivalent alternatives, preferred embodiments include, but are not limited to, embodiments of the invention.
  • the solvent used in the present invention is commercially available.
  • the present invention employs the following abbreviations: aq for water; HATU for O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate ; EDC stands for N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride; m-CPBA stands for 3-chloroperoxybenzoic acid; eq stands for equivalent, equivalent; CDI stands for Carbonyldiimidazole; DCM stands for dichloromethane; PE stands for petroleum ether; DIAD stands for diisopropyl azodicarboxylate; DMF stands for N,N-dimethylformamide; DMSO stands for dimethyl sulfoxide; EtOAc stands for acetic acid Esters; EtOH for ethanol; MeOH for methanol; CBz for benzyl
  • the compound of the present invention Compared with the control compound 1, the compound of the present invention not only has the same multi-target, but also has a 5- to 10-fold increase in the activity of targets such as ABL, TNIK, FGFR1, FGFR3, and FGFR4, and introduces a new c- Met activity with an IC 50 value of 100 nM.
  • the activity of the ABL of the present invention was nearly 70 times higher than that of the compound 2, and the TNIK was increased by 8 times, which was very remarkable and unexpected; the compound of the present invention was compared with the control compound 3, 4, 5, 6, 7 and fluorine. And the chlorine is located on the same side of the benzene ring than at other positions, and has a significant increase in FGFR1 and FGFR4, ABL kinase inhibitory activity.
  • the compound of the present invention is capable of having superior therapeutic activity in cancers in which BCR-ABL and the like are fused; the increase in activity of these important targets makes Compound 1B have superior tumor therapeutic effects, especially for FGFR, c- The improvement of Met activity will have better therapeutic effects in patients with gastric cancer and lung cancer with high expression of FGFR and c-Met.
  • the compounds of the present invention have low clearance rate, high oral bioavailability, and excellent drug-acceptability in mouse and rat species.
  • Example 1A (6.05 g) was added to a three-necked flask containing NMP (60 mL), pyridine (1.32 g), phenyl chloroformate (5.20 g) was added to the reaction system at room temperature (25-30 ° C) After stirring for 1 hour, the intermediate reaction was completed, and cyclopropylamine (2.84 g) was also added to the reaction system. The reaction solution was stirred at room temperature (25 to 30 ° C) for 0.5 hour, the reaction was completed, 20 mL of ethanol was added to the reaction system, and the mixture was stirred.
  • ⁇ RTI ID 0.0># ⁇ /RTI> ⁇ RTIgt; ⁇ /RTI> ⁇ RTIgt; ⁇ /RTI> ⁇ RTIgt; ⁇ / RTI> ⁇ / RTI> ⁇ / RTI> ⁇ / RTI> ⁇ / RTI> ⁇ / RTI> ⁇ / RTI> ⁇ RTIgt;
  • This compound is obtained by adding 1 equivalent of hydrochloric acid or sulfuric acid or methanesulfonic acid to a solution of acetone or ethanol to obtain the corresponding salt.
  • Example 1B (1.5 g, 3.37 mmol) was added to EtOH (45 mL), and the reaction temperature was raised to 60 ° C. At this temperature, CH 3 SO 3 H (324.07 mg, 3.37 mmol, 240.05 ⁇ L) was added dropwise to the reaction. In the liquid, after the dropwise addition is completed, the reaction solution is dissolved, and the reaction liquid is naturally cooled to 15 to 20 ° C under stirring, and stirred at this temperature for 2 hours. A large amount of brown solid was precipitated, filtered, and the filter cake was rinsed with anhydrous ethanol (5 mL), and the obtained cake was evaporated to dryness at 50 ° C under reduced pressure to give Example 1.
  • Comparative Example 4A was prepared by the preparation method of Comparative Example 3A to obtain a product.
  • Comparative Example 6A was prepared by the preparation method of Comparative Example 5A.
  • Comparative Example 6A 50 mg, 152.76 ⁇ mol was added to dichloromethane (5 mL), and triphosgene (36.27 mg, 122.21 ⁇ mol) and DIEA (59.23 mg, 458.28 ⁇ mol, 79.82 ⁇ L) were added to the reaction solution with stirring. After stirring at 15 to 20 ° C for 15 minutes, cyclopropylamine (17.44 mg, 305.52 ⁇ mol, 21.17 ⁇ L) was added to the reaction mixture, and the reaction mixture was stirred at room temperature for 30 minutes. LCMS showed that the reaction was completed and the reaction mixture was concentrated under reduced pressure to give crude product. The crude product was purified by high performance liquid chromatography (TLA conditions) to give the title compound 6. Control compound 6 can be obtained by washing it in dichloromethane then 1N sodium bicarbonate to give the free base.
  • TLA high performance liquid chromatography
  • Comparative Example 7A was prepared by the preparation method of Comparative Example 3A.
  • Protein kinase (see Table 1) at a concentration X corresponding to the enzyme, Y concentration of the peptide substrate, ATP concentration, 8 mM MOPS (pH 7.0), 10 mM MgCl 2 were added .
  • the detection plate was P30 filtermat, and the reaction was carried out for T minutes at room temperature, and the reaction system was 10 ⁇ l.
  • the reaction was stopped by adding 0.5% phosphoric acid to the kinase reaction solution, and the plate was read by Envision instrument.
  • Example 1B significantly increased the activity of multiple kinases compared to Control Compound 1, wherein C-Met activity was increased 5-fold, TNIK activity was increased by 6.5-fold, ABL activity was increased 5-fold, and FGFR was significantly increased.
  • the activity of each subtype increased 8 times in FGFR1, 2 times in FGFR2, 5 times in FGFR3, and 12 times in FGFR4.
  • the increase in activity of these important targets makes Compound 1B have superior tumor therapeutic effects, especially for FGFR, c-Met activity, and will be highly expressed in patients with FGFR, c-Met, lung cancer, etc. There is a better therapeutic effect.
  • Example 1B greatly improved the activity of ABL by nearly 70 times and the TNIK by 8 times, which was very unexpected and capable of having superior therapeutic activity in cancers in which BCR-ABL and the like were fused.
  • Example 1B showed a significant increase in FBLR1 and FGFR4, ABL kinase inhibitory activity compared to the control compounds 3, 4, 5, 6, and 7, where the fluorine and chlorine were located on the same side of the benzene ring as at other positions.
  • mice Balb/c nude mice, EDTA-K2
  • Test Example 1 0.5 mg/ml 5% DMSO/95% (10% HP- ⁇ -CD) The clear solution of Test Example 1 was injected into male Balb/c nude mice via the tail vein (fasting overnight, 7- At 9 weeks of age, the dose was 1 mg/kg. A 0.5 mg/ml test compound suspended in 0.5% Methocel/0.2% Tween 80 was orally administered to male Balb/c nude mice (overnight fast, 7-9 weeks old) at a dose of 5 mg/kg.
  • Both groups of animals were collected from the jugular vein or tail vein at a dose of 0.25, 0.5, 1.0, 2.0, 4.0, 8.0, and 24 h after administration, and about 30 ⁇ L was placed in an anticoagulant tube to which EDTA-K2 was added, and plasma was centrifuged. Determination of plasma concentration, using WinNonlin TM Version 6.3 (Pharsight, Mountain View, CA) software pharmacokinetics, trapezoidal method to calculate the number of linearly related noncompartmental pharmacokinetic parameters using LC-MS / MS method.
  • the plasma clearance (CL) was 11 mL/min/kg and the apparent apparent volume of distribution (Vdss) was 1.48 L/kg.
  • the elimination half-life (T 1/2 ) and the area under the plasma concentration curve (AUC 0-last ) from 0 to the last quantifiable time point were 2.68 h and 3213 nM ⁇ h, respectively.
  • mice Male Balb/c nude mice were given a single dose of 5 mg/kg of Example 1 with a bioavailability of 144%, AUC 0-last of 24899 nM ⁇ h, peak concentration (C max ) of 9825 nM, peak time. Appeared 0.5 h after administration.
  • Both groups of animals were collected from the jugular vein or tail vein at a dose of 0.25, 0.5, 1.0, 2.0, 4.0, 8.0, and 24 h after administration, and about 30 ⁇ L was placed in an anticoagulant tube to which EDTA-K2 was added, and plasma was centrifuged. Determination of plasma concentration, using WinNonlin TM Version 6.3 (Pharsight, Mountain View, CA) software pharmacokinetics, trapezoidal method to calculate the number of linearly related noncompartmental pharmacokinetic parameters using LC-MS / MS method.
  • the plasma clearance rate (CL) was 1.6 mL/min/kg, and the apparent apparent volume of distribution (Vdss) was 0.259 L/kg.
  • the half-life (T 1/2 ) and the area under the plasma concentration curve (AUC 0-last ) from 0 to the last quantifiable time point were 2.64 h and 23441 nM ⁇ h, respectively.
  • Example 1 of the present invention has a low clearance rate, a high oral bioavailability, and an excellent drug-producibility in mouse and rat species.
  • the introduction of F atoms on the benzene ring of the quinoline core structure significantly reduced the drug metabolism rate in rats and significantly increased the oral absorption exposure of the drug.

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Abstract

式(II)所示的喹啉衍生物化合物及其药学上可接受的盐以及它们在制备治疗与酪氨酸激酶抑制剂相关疾病的药物中的应用。

Description

喹啉衍生物及其作为酪氨酸激酶抑制剂的应用
相关申请的引用
本申请主张如下优先权：
CN201710900497.6，申请日2017-09-28；
CN201810732319.1，申请日2018-07-05；
技术领域
本发明涉及一类喹啉衍生物，及其在制备治疗与酪氨酸激酶抑制剂相关疾病的药物中的应用。具体涉及式(Ⅱ)所示化合物及其药学上可接受的盐。
背景技术
蛋白酪氨酸激酶(PTK)是一种酶，它与作为底物的ATP一起，将肽和蛋白质中的酪氨酸残基磷酸化。这些酶在细胞信号传导的调控中是关键因素，如细胞增值、分化等。PTK特别还包括受体酪氨酸激酶，它包括肝细胞生长因子(HGF)，血小板衍生生长因子(PDGF)和在血管形成中起作用的激酶(FGF和VEGF)；此外还包括非受体酪氨酸激酶，这包括LCK，ABL等。
c-Met蛋白(也称为肝细胞生长因子(HGF)受体)是具有酪氨酸激酶活性的跨膜190kDa异源二聚体，其有c-Met癌基因编码。已经显示，HGF/c-Met信号途径证明各种细胞反应，包括促有丝分裂活性、增值活性、形态发生活性和血管生成活性。HGF/c-Met途径的抑制剂具有显著的治疗癌症的潜力。
ABL是一个原癌基因编码的酪氨酸激酶，激活的ABL能促进细胞增殖、分化以及EMT等。在血液瘤中主要通过BCR-ABL等基因融合的方式被激活。在实体瘤中主要通过基因扩增，过表达以及上游受体酪氨酸激酶如PDGFR，EGFR等激活。TNIK是一个丝氨酸/苏氨酸激酶，能与wnt信号通路中的β-catenin/TCF结合，激活wnt信号下游靶基因，促进肿瘤生长。MINK是STE20蛋白激酶家族的成员，在中枢神经系统中有较高的表达，能够激活JNK以及p38信号通路。
FGFR是一类具有传导生物信号、调节细胞生长、参与组织修复等功能的生物活性物质，近年来，已有多个FGFR家族成员被发现在肿瘤发生、发展过程中起重要作用。成纤维细胞生长因子受体(FGFR)是一类可与成纤维细胞生长因子(FGF)特异性结合的受体蛋白，FGFRs家族包括以下类型：FGFR1b、FGFR1c、FGFR2b、FGFR2c、FGFR3b、FGFR3c、FGFR4。不同亚型的FGFR与之结合的FGF不一样，FGFs与FGFRs结合后导致胞内多个酪氨酸残基的自身磷酸化，磷酸化的FGFRs激活下游的信号通路包括MEK/MAPK、PLCy/PKC、PI3K/AKT、STATS等。其中FGFR4在肝癌、结肠癌、胃癌、食道癌、睾丸癌中高表达，而与FGFR4特异性结合的FGF19在人结肠癌、肝癌和肺癌细胞高表达，FGFR4与FGF19特异性结合的信号异常是多种肿瘤发生及转移的重要因素。
血管内皮细胞生长因子(VEGF)和血小板衍生生长因子(PDGF)对肿瘤新生血管的生成发挥重要的作用，它们与其受体VEGFR，PDGFR结合，将信号传递到胞内区，进而发生磷酸化二聚体，激活这一信号通路，并将能量向下游传递，从而导致肿瘤细胞生长、转移、增殖等不受控制。
如上几个靶点如ABL，C-Met，TNIK，FGFR1-4，VEGFR(FLT1,KDR,FLT4)，PDGFR对肿瘤细胞的治疗中，从分子作用机制上来看，靶点间能够协同互补，减少肿瘤细胞的逃逸，减少药物耐药性，提高治疗效果，因此同时作用于这些靶点的药物是非常期待。
目前上市药物多激酶抑制乐伐替尼，能够能同时具有ABL,TNIK,FGFR,VEGFR,PDGFR活性，在临床治疗效果中非常优异，患者应答率高。
Figure PCTCN2018106674-appb-000001
发明内容
本发明提供了式(Ⅱ)所示化合物或其药学上可接受的盐，
Figure PCTCN2018106674-appb-000002
其中，
R 1选自任选被1、2或3个R取代的C 1-6烷氧基；
R 2选自-C(＝O)NH 2和-C(＝O)NH-C 1-3烷基；
环B选自C 3-6环烷基；
R选自F、Cl、Br、I、OH和NH 2。
本发明的一些方案中，上述R 1选自
Figure PCTCN2018106674-appb-000003
其他变量如本发明所定义。
本发明的一些方案中，上述R 2选自-C(＝O)NH 2，其他变量如本发明所定义。
本发明的一些方案中，上述环B选自环丙基，其他变量如本发明所定义。
本发明提供了式(Ⅰ)所示化合物或其药学上可接受的盐，
Figure PCTCN2018106674-appb-000004
其中，
R 1选自任选被1、2或3个R取代的C 1-6烷氧基；
R 2选自-C(＝O)NH 2和-C(＝O)NH-C 1-3烷基；
R 3选自H、F、Cl、Br、I、OH和NH 2；
环B选自C 3-6环烷基；
n选自2和3；
R选自F、Cl、Br、I、OH和NH 2。
本发明的一些方案中，上述R 1选自
Figure PCTCN2018106674-appb-000005
其他变量如本发明所定义。
本发明的一些方案中，上述R 2选自-C(＝O)NH 2，其他变量如本发明所定义。
本发明的一些方案中，上述R 3选自F、Cl，其他变量如本发明所定义。
本发明的一些方案中，上述环B选自环丙基，其他变量如本发明所定义。
本发明的一些方案中，上述n选自2，其他变量如本发明所定义。
本发明还有一些方案由上述变量任意组合而来。
本发明的一些方案中，上述化合物或其药学上可接受的盐，其选自
Figure PCTCN2018106674-appb-000006
其中，R 1、R 2、R 3如本发明所定义。
本发明还提供了下列化合物，其选自
Figure PCTCN2018106674-appb-000007
本发明还提供了一种药物组合物，包括治疗有效量的上述的化合物或其药学上可接受的盐作为活性成分以及药学上可接受的载体。
本发明还提供了上述的化合物或其药学上可接受的盐或者上述组合物在制备治疗酪氨酸激酶抑制剂相关病症的药物上的应用。
本发明的一些方案中，上述的应用，其中所述酪氨酸激酶抑制剂相关病症是指肿瘤疾病和免疫失调。
定义和说明
除非另有说明，本文所用的下列术语和短语旨在具有下列含义。一个特定的术语或短语在没有特别定义的情况下不应该被认为是不确定的或不清楚的，而应该按照普通的含义去理解。当本文中出现商品名时，意在指代其对应的商品或其活性成分。这里所采用的术语“药学上可接受的”，是针对那些化合物、材料、组合物和/或剂型而言，它们在可靠的医学判断的范围之内，适用于与人类和动物的组织接触使用，而没有过多的毒性、刺激性、过敏性反应或其它问题或并发症，与合理的利益/风险比相称。
术语“药学上可接受的盐”是指本发明化合物的盐，由本发明发现的具有特定取代基的化合物与相对无毒的酸或碱制备。当本发明的化合物中含有相对酸性的功能团时，可以通过在纯的溶液或合适的惰性溶剂中用足够量的碱与这类化合物的中性形式接触的方式获得碱加成盐。药学上可接受的碱加成盐包括钠、钾、钙、铵、有机胺或镁盐或类似的盐。当本发明的化合物中含有相对碱性的官能团时，可以通过在纯的溶液或合适的惰性溶剂中用足够量的酸与这类化合物的中性形式接触的方式获得酸加成盐。药学上可接受的酸加成盐的实例包括无机酸盐，所述无机酸包括例如盐酸、氢溴酸、硝酸、碳酸，碳酸氢根，磷酸、磷酸一氢根、磷酸二氢根、硫酸、硫酸氢根、氢碘酸、亚磷酸等；以及有机酸盐，所述有机酸包括如乙酸、丙酸、异丁酸、马来酸、丙二酸、苯甲酸、琥珀酸、辛二酸、反丁烯二酸、乳酸、扁桃酸、邻苯二甲酸、苯磺酸、对甲苯磺酸、柠檬酸、酒石酸和甲磺酸等类似的酸；还包括氨基酸(如精氨酸等)的盐，以及如葡糖醛酸等有机酸的盐。本发明的某些特定的化合物含有碱性和酸性的官能团，从而可以被转换成任一碱或酸加成盐。
本发明的药学上可接受的盐可由含有酸根或碱基的母体化合物通过常规化学方法合成。一般情况下，这样的盐的制备方法是：在水或有机溶剂或两者的混合物中，经由游离酸或碱形式的这些化合物与化学计量的适当的碱或酸反应来制备。
本发明的某些化合物可以以非溶剂化形式或者溶剂化形式存在，包括水合物形式。一般而言，溶剂化形式与非溶剂化的形式相当，都包含在本发明的范围之内。
本发明的化合物可以存在特定的几何或立体异构体形式。本发明设想所有的这类化合物，包括顺式和反式异构体、(-)-和(+)-对对映体、(R)-和(S)-对映体、非对映异构体、(D)-异构体、(L)-异构体，及其外消旋混合物和其他混合物，例如对映异构体或非对映体富集的混合物，所有这些混合物都属于本发明的范围之内。烷基等取代基中可存在另外的不对称碳原子。所有这些异构体以及它们的混合物，均包括在本发 明的范围之内。
除非另有说明，术语“对映异构体”或者“旋光异构体”是指互为镜像关系的立体异构体。
除非另有说明，术语“顺反异构体”或者“几何异构体”系由因双键或者成环碳原子单键不能自由旋转而引起。
除非另有说明，术语“非对映异构体”是指分子具有两个或多个手性中心，并且分子间为非镜像的关系的立体异构体。
除非另有说明，“(D)”或者“(+)”表示右旋，“(L)”或者“(-)”表示左旋，“(DL)”或者“(±)”表示外消旋。
除非另有说明，用楔形实线键
Figure PCTCN2018106674-appb-000008
和楔形虚线键
Figure PCTCN2018106674-appb-000009
表示一个立体中心的绝对构型，用直形实线键
Figure PCTCN2018106674-appb-000010
和直形虚线键
Figure PCTCN2018106674-appb-000011
表示立体中心的相对构型，用波浪线
Figure PCTCN2018106674-appb-000012
表示楔形实线键
Figure PCTCN2018106674-appb-000013
或楔形虚线键
Figure PCTCN2018106674-appb-000014
或用波浪线
Figure PCTCN2018106674-appb-000015
表示直形实线键
Figure PCTCN2018106674-appb-000016
和直形虚线键
Figure PCTCN2018106674-appb-000017
本发明的化合物可以存在特定的。除非另有说明，术语“互变异构体”或“互变异构体形式”是指在室温下，不同官能团异构体处于动态平衡，并能很快的相互转化。若互变异构体是可能的(如在溶液中)，则可以达到互变异构体的化学平衡。例如，质子互变异构体(proton tautomer)(也称质子转移互变异构体(prototropic tautomer))包括通过质子迁移来进行的互相转化，如酮-烯醇异构化和亚胺-烯胺异构化。价键异构体(valence tautomer)包括一些成键电子的重组来进行的相互转化。其中酮-烯醇互变异构化的具体实例是戊烷-2,4-二酮与4-羟基戊-3-烯-2-酮两个互变异构体之间的互变。
除非另有说明，术语“富含一种异构体”、“异构体富集”、“富含一种对映体”或者“对映体富集”指其中一种异构体或对映体的含量小于100％，并且，该异构体或对映体的含量大于等于60％，或者大于等于70％，或者大于等于80％，或者大于等于90％，或者大于等于95％，或者大于等于96％，或者大于等于97％，或者大于等于98％，或者大于等于99％，或者大于等于99.5％，或者大于等于99.6％，或者大于等于99.7％，或者大于等于99.8％，或者大于等于99.9％。
除非另有说明，术语“异构体过量”或“对映体过量”指两种异构体或两种对映体相对百分数之间的差值。例如，其中一种异构体或对映体的含量为90％，另一种异构体或对映体的含量为10％，则异构体或对映体过量(ee值)为80％。
可以通过的手性合成或手性试剂或者其他常规技术制备光学活性的(R)-和(S)-异构体以及D和L异构体。如果想得到本发明某化合物的一种对映体，可以通过不对称合成或者具有手性助剂的衍生作用来制备，其中将所得非对映体混合物分离，并且辅助基团裂开以提供纯的所需对映异构体。或者，当分子中含有碱性官能团(如氨基)或酸性官能团(如羧基)时，与适当的光学活性的酸或碱形成非对映异构体的盐，然后通过本领域所公知的常规方法进行非对映异构体拆分，然后回收得到纯的对映体。此外，对映异构体和非对映异构体的分离通常是通过使用色谱法完成的，所述色谱法采用手性固定相，并任选地与化学衍生法 相结合(例如由胺生成氨基甲酸盐)。本发明的化合物可以在一个或多个构成该化合物的原子上包含非天然比例的原子同位素。例如，可用放射性同位素标记化合物，比如氚( 3H)，碘-125( 125I)或C-14( 14C)。又例如，可用重氢取代氢形成氘代药物，氘与碳构成的键比普通氢与碳构成的键更坚固，相比于未氘化药物，氘代药物有降低毒副作用、增加药物稳定性、增强疗效、延长药物生物半衰期等优势。本发明的化合物的所有同位素组成的变换，无论放射性与否，都包括在本发明的范围之内。
针对药物或药理学活性剂而言，术语“有效量”或“治疗有效量”是指无毒的但能达到预期效果的药物或药剂的足够用量。对于本发明中的口服剂型，组合物中一种活性物质的“有效量”是指与该组合物中另一种活性物质联用时为了达到预期效果所需要的用量。有效量的确定因人而异，取决于受体的年龄和一般情况，也取决于具体的活性物质，个案中合适的有效量可以由本领域技术人员根据常规试验确定。
术语“活性成分”、“治疗剂”，“活性物质”或“活性剂”是指一种化学实体，它可以有效地治疗目标紊乱、疾病或病症。
“任选”或“任选地”指的是随后描述的事件或状况可能但不是必需出现的，并且该描述包括其中所述事件或状况发生的情况以及所述事件或状况不发生的情况。
术语“被取代的”是指特定原子上的任意一个或多个氢原子被取代基取代，可以包括重氢和氢的变体，只要特定原子的价态是正常的并且取代后的化合物是稳定的。当取代基为氧(即＝O)时，意味着两个氢原子被取代。氧取代不会发生在芳香基上。术语“任选被取代的”是指可以被取代，也可以不被取代，除非另有规定，取代基的种类和数目在化学上可以实现的基础上可以是任意的。
当任何变量(例如R)在化合物的组成或结构中出现一次以上时，其在每一种情况下的定义都是独立的。因此，例如，如果一个基团被0-2个R所取代，则所述基团可以任选地至多被两个R所取代，并且每种情况下的R都有独立的选项。此外，取代基和/或其变体的组合只有在这样的组合会产生稳定的化合物的情况下才是被允许的。
当一个连接基团的数量为0时，比如-(CRR) 0-，表示该连接基团为单键。
当其中一个变量选自单键时，表示其连接的两个基团直接相连，比如A-L-Z中L代表单键时表示该结构实际上是A-Z。
当一个取代基为空缺时，表示该取代基是不存在的，比如A-X中X为空缺时表示该结构实际上是A。当所列举的连接基团没有指明其连接方向，其连接方向是任意的，例如，
Figure PCTCN2018106674-appb-000018
中连接基团L为-M-W-，此时-M-W-既可以按与从左往右的读取顺序相同的方向连接环A和环B构成
Figure PCTCN2018106674-appb-000019
也可以按照与从左往右的读取顺序相反的方向连接环A和环B构成
Figure PCTCN2018106674-appb-000020
所述连接基团、取代基和/或其变体的组合只有在这样的组合会产生稳定的化合物的情况下才是被允许的。
除非另有规定，术语“杂”表示杂原子或杂原子团(即含有杂原子的原子团)，包括碳(C)和氢(H)以外的原子以及含有这些杂原子的原子团，例如包括氧(O)、氮(N)、硫(S)、硅(Si)、锗(Ge)、铝(Al)、硼(B)、-O-、-S-、＝O、＝S、-C(＝O)O-、-C(＝O)-、-C(＝S)-、-S(＝O)、-S(＝O) 2-，以及任选被取代的-C(＝O)N(H)-、-N(H)-、-C(＝NH)-、-S(＝O) 2N(H)-或-S(＝O)N(H)-。
除非另有规定，“环”表示被取代或未被取代的环烷基、杂环烷基、环烯基、杂环烯基、环炔基、杂环炔基、芳基或杂芳基。所谓的环包括单环、联环、螺环、并环或桥环。环上原子的数目通常被定义为环的元数，例如，“5～7元环”是指环绕排列5～7个原子。除非另有规定，该环任选地包含1～3个杂原子。因此，“5～7元环”包括例如苯基、吡啶和哌啶基；另一方面，术语“5～7元杂环烷基环”包括吡啶基和哌啶基，但不包括苯基。术语“环”还包括含有至少一个环的环系，其中的每一个“环”均独立地符合上述定义。
除非另有规定，术语“烃基”或者其下位概念(比如烷基、烯基、炔基、芳基等等)本身或者作为另一取代基的一部分表示直链的、支链的或环状的烃原子团或其组合，可以是完全饱和的(如烷基)、单元或多元不饱和的(如烯基、炔基、芳基)，可以是单取代或多取代的，可以是一价(如甲基)、二价(如亚甲基)或者多价(如次甲基)，可以包括二价或多价原子团，具有指定数量的碳原子(如C 1-C 12表示1至12个碳，C 1-12选自C 1、C 2、C 3、C 4、C 5、C 6、C 7、C 8、C 9、C 10、C 11和C 12；C 3-12选自C 3、C 4、C 5、C 6、C 7、C 8、C 9、C 10、C 11和C 12。)。“烃基”包括但不限于脂肪烃基和芳香烃基，所述脂肪烃基包括链状和环状，具体包括但不限于烷基、烯基、炔基，所述芳香烃基包括但不限于6-12元的芳香烃基，例如苯、萘等。在一些实施例中，术语“烃基”表示直链的或支链的原子团或它们的组合，可以是完全饱和的、单元或多元不饱和的，可以包括二价和多价原子团。饱和烃原子团的实例包括但不限于甲基、乙基、正丙基、异丙基、正丁基、叔丁基、异丁基、仲丁基、异丁基、环己基、(环己基)甲基、环丙基甲基，以及正戊基、正己基、正庚基、正辛基等原子团的同系物或异构体。不饱和烃基具有一个或多个双键或三键，其实例包括但不限于乙烯基、2-丙烯基、丁烯基、巴豆基、2-异戊烯基、2-(丁二烯基)、2，4-戊二烯基、3-(1，4-戊二烯基)、乙炔基、1-和3-丙炔基，3-丁炔基，以及更高级的同系物和异构体。
除非另有规定，术语“杂烃基”或者其下位概念(比如杂烷基、杂烯基、杂炔基、杂芳基等等)本身或者与另一术语联合表示稳定的直链的、支链的或环状的烃原子团或其组合，有一定数目的碳原子和至少一个杂原子组成。在一些实施例中，术语“杂烷基”本身或者与另一术语联合表示稳定的直链的、支链的烃原子团或其组合物，有一定数目的碳原子和至少一个杂原子组成。在一个典型实施例中，杂原子选自B、O、N和S，其中氮和硫原子任选地被氧化，氮杂原子任选地被季铵化。杂原子或杂原子团可以位于杂烃基的任何内部位置，包括该烃基附着于分子其余部分的位置，但术语“烷氧基”、“烷氨基”和“烷硫基”(或硫代 烷氧基)属于惯用表达，是指分别通过一个氧原子、氨基或硫原子连接到分子的其余部分的那些烷基基团。实例包括但不限于-CH 2-CH 2-O-CH 3、-CH 2-CH 2-NH-CH 3、-CH 2-CH 2-N(CH 3)-CH 3、-CH 2-S-CH 2-CH 3、-CH 2-CH 2、-S(O)-CH 3、-CH 2-CH 2-S(O) 2-CH 3、-CH＝CH-O-CH 3、-CH 2-CH＝N-OCH 3和–CH＝CH-N(CH 3)-CH 3。至多两个杂原子可以是连续的，例如-CH 2-NH-OCH 3。
除非另有规定，术语“环烃基”、“杂环烃基”或者其下位概念(比如芳基、杂芳基、环烷基、杂环烷基、环烯基、杂环烯基、环炔基、杂环炔基等等)本身或与其他术语联合分别表示环化的“烃基”、“杂烃基”。此外，就杂烃基或杂环烃基(比如杂烷基、杂环烷基)而言，杂原子可以占据该杂环附着于分子其余部分的位置。环烃基的实例包括但不限于环戊基、环己基、1-环己烯基、3-环己烯基、环庚基等。杂环基的非限制性实例包括1-(1,2,5,6-四氢吡啶基)、1-哌啶基、2-哌啶基，3-哌啶基、4-吗啉基、3-吗啉基、四氢呋喃-2-基、四氢呋喃吲哚-3-基、四氢噻吩-2-基、四氢噻吩-3-基，1-哌嗪基和2-哌嗪基。
除非另有规定，术语“烷基”用于表示直链或支链的饱和烃基,可以是单取代(如-CH 2F)或多取代的(如-CF 3)，可以是一价(如甲基)、二价(如亚甲基)或者多价(如次甲基)。烷基的例子包括甲基(Me)，乙基(Et)，丙基(如，n-丙基和异丙基)，丁基(如，n-丁基，异丁基，s-丁基，t-丁基)，戊基(如，n-戊基，异戊基，新戊基)等。
除非另有规定，环烷基包括任何稳定的环状或多环烃基，任何碳原子都是饱和的，可以是单取代或多取代的，可以是一价、二价或者多价。这些环烷基的实例包括，但不限于，环丙基、降冰片烷基、[2.2.2]二环辛烷、[4.4.0]二环癸烷等。
除非另有规定，术语“卤代素”或“卤素”本身或作为另一取代基的一部分表示氟、氯、溴或碘原子。此外，术语“卤代烷基”意在包括单卤代烷基和多卤代烷基。例如，术语“卤代(C 1-C 4)烷基”意在包括但不仅限于三氟甲基、2，2，2-三氟乙基、4-氯丁基和3-溴丙基等等。除非另有规定，卤代烷基的实例包括但不仅限于：三氟甲基、三氯甲基、五氟乙基，和五氯乙基。
“烷氧基”代表通过氧桥连接的具有特定数目碳原子的上述烷基，除非另有规定，C 1-6烷氧基包括C 1、C 2、C 3、C 4、C 5和C 6的烷氧基。烷氧基的例子包括但不限于：甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、仲丁氧基、叔丁氧基、正戊氧基和S-戊氧基。
术语“离去基团”是指可以被另一种官能团或原子通过取代反应(例如亲和取代反应)所取代的官能团或原子。例如，代表性的离去基团包括三氟甲磺酸酯；氯、溴、碘；磺酸酯基，如甲磺酸酯、甲苯磺酸酯、对溴苯磺酸酯、对甲苯磺酸酯等；酰氧基，如乙酰氧基、三氟乙酰氧基等等。
术语“保护基”包括但不限于“氨基保护基”、“羟基保护基”或“巯基保护基”。术语“氨基保护基”是指适合用于阻止氨基氮位上副反应的保护基团。代表性的氨基保护基包括但不限于：甲酰基；酰基，例如链烷酰基(如乙酰基、三氯乙酰基或三氟乙酰基)；烷氧基羰基，如叔丁氧基羰基(Boc)；芳基甲氧羰基，如苄氧羰基(Cbz)和9-芴甲氧羰基(Fmoc)；芳基甲基，如苄基(Bn)、三苯甲基(Tr)、1,1-二-(4'-甲氧基苯基)甲 基；甲硅烷基，如三甲基甲硅烷基(TMS)和叔丁基二甲基甲硅烷基(TBS)等等。术语“羟基保护基”是指适合用于阻止羟基副反应的保护基。代表性羟基保护基包括但不限于：烷基，如甲基、乙基和叔丁基；酰基，例如链烷酰基(如乙酰基)；芳基甲基，如苄基(Bn)，对甲氧基苄基(PMB)、9-芴基甲基(Fm)和二苯基甲基(二苯甲基，DPM)；甲硅烷基，如三甲基甲硅烷基(TMS)和叔丁基二甲基甲硅烷基(TBS)等等。
本发明的化合物可以通过本领域技术人员所熟知的多种合成方法来制备，包括下面列举的具体实施方式、其与其他化学合成方法的结合所形成的实施方式以及本领域技术上人员所熟知的等同替换方式，优选的实施方式包括但不限于本发明的实施例。
本发明所使用的溶剂可经市售获得。本发明采用下述缩略词：aq代表水；HATU代表O-(7-氮杂苯并三唑-1-基)-N，N，N'，N'-四甲基脲六氟磷酸盐；EDC代表N-(3-二甲基氨基丙基)-N'-乙基碳二亚胺盐酸盐；m-CPBA代表3-氯过氧苯甲酸；eq代表当量、等量；CDI代表羰基二咪唑；DCM代表二氯甲烷；PE代表石油醚；DIAD代表偶氮二羧酸二异丙酯；DMF代表N，N-二甲基甲酰胺；DMSO代表二甲亚砜；EtOAc代表乙酸乙酯；EtOH代表乙醇；MeOH代表甲醇；CBz代表苄氧羰基，是一种胺保护基团；BOC代表叔丁氧羰基是一种胺保护基团；HOAc代表乙酸；NaCNBH 3代表氰基硼氢化钠；r.t.代表室温；O/N代表过夜；THF代表四氢呋喃；Boc 2O代表二-叔丁基二碳酸酯；TFA代表三氟乙酸；DIPEA代表二异丙基乙基胺；SOCl 2代表氯化亚砜；CS 2代表二硫化碳；TsOH代表对甲苯磺酸；NFSI代表N-氟-N-(苯磺酰基)苯磺酰胺；NCS代表1-氯吡咯烷-2,5-二酮；n-Bu 4NF代表氟化四丁基铵；iPrOH代表2-丙醇；mp代表熔点；LDA代表二异丙基胺基锂；EDCI代表1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐；dppf代表1,1'-双(二苯基膦)二茂铁；HATU代表2-(7-氧化苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯；Ti(i-PrO)4代表四异丙醇钛；NBS代表N-溴代琥珀酰亚胺；dast代表二乙胺基三氟化硫；LiHMDS六甲基二硅基胺基锂；AIBN代表偶氮二异丁腈；POCl 3代表三氯氧磷；PEG400代表聚乙二醇400；NMP代表N-甲基吡咯烷酮；MOPS代表3-吗啉丙磺酸。
化合物经手工或者
Figure PCTCN2018106674-appb-000021
软件命名，市售化合物采用供应商目录名称。
技术效果
本发明化合物相比对照化合物1，不仅具有相同的多作用靶点，而且在ABL,TNIK,FGFR1,FGFR3,FGFR4等靶点的活性具有有5到10倍的提高，同时引入了新的c-Met活性，IC 50值100nM。
本发明化合物相比对照化合物2，ABL的活性提高近70倍，TNIK提高了8倍，这是非常显著且意想不到的；本发明化合物相比对照化合物3,4,5,6,7，氟和氯位于苯环的同侧比在其它位置，对FGFR1和FGFR4，ABL激酶抑制活性具有显著的提高。
本发明化合物能够在BCR-ABL等基因融合的癌症中具有更优的治疗活性；对这几个重要靶点活性的提高，使得化合物1B有更优异的肿瘤治疗效果，特别是对FGFR，c-Met活性的提高，将会在FGFR，c-Met高表达的胃癌，肺癌等患者中有更优的治疗效果。
本发明化合物在小鼠和大鼠种属中，具有较低的清除率，较高的口服生物利用度，具有优异的可成药性。
具体实施方式
下面通过实施例对本发明进行详细描述，但并不意味着对本发明任何不利限制。本文已经详细地描述了本发明，其中也公开了其具体实施例方式，对本领域的技术人员而言，在不脱离本发明精神和范围的情况下针对本发明具体实施方式进行各种变化和改进将是显而易见的。
流程A
Figure PCTCN2018106674-appb-000022
实施例1A
Figure PCTCN2018106674-appb-000023
在20-30℃，将4-氯-7-甲氧基喹啉-6-甲酰胺(550.0g)加入到反应釜中。在20-30℃，将DMSO(16.5L)加入到反应釜中。在20-30℃，将2-氟-3氯-4-氨基苯酚加入到反应釜中。在20-35℃，在搅拌下10-15分钟内将叔丁醇钠(229g)缓慢加入到反应釜中。反应釜经过1.5小时加热到96℃(内温)。反应在96-100℃搅拌6.5小时，4-氨基-3-氯-2氟苯酚无剩余。反应冷却至20-30℃。搅拌下，向反应液中缓慢加入23.1L水，过程中有深褐色固体析出，保持内温低于40℃。在30-40℃搅拌0.5小时。冷却至20-30℃， 过滤。在20-30℃,将滤饼和3.5L水加入反应釜。在20-30℃,搅拌0.5小时。过滤。在20-30℃,将滤饼和4.0L水加入反应釜。在20-30℃，搅拌0.5小时。过滤，滤饼在真空干燥器中40℃干燥18小时(五氧化二磷做干燥剂，油泵抽真空)。将固体研碎，得758g灰白色固体并将其在40℃继续干燥18小时(五氧化二磷做干燥剂，油泵抽真空)，得到实施例1A。
LCMS(ESI)m/z:362.0[M+1] +
1H NMR(400MHz,DMSO-d6)δppm 8.68(br s,2H),7.82-7.96(m,1H),7.67-7.82(m,1H),7.46-7.59(m,1H),7.12-7.26(m,1H),6.67-6.80(m,1H),6.43-6.58(m,1H),5.84(s,2H),4.04(s,3H).
实施例1B
Figure PCTCN2018106674-appb-000024
实施例1A(6.05g)加入到盛有NMP(60mL)的三口瓶中,吡啶(1.32g)，氯甲酸苯酯(5.20g)加入到反应体系中，反应体系在室温下(25～30℃)搅拌1小时，生成中间体反应完全，环丙胺(2.84g)也加入到反应体系中，反应液在室温下(25～30℃)搅拌0.5小时，反应完成，反应体系中加入20mL乙醇，搅拌下向反应体系中加入自来水(500mL)，有固体析出，过滤，滤饼减压旋干，得到粗品(土黄色固体，5.26g)；粗品通过层析柱(DCM：MeOH＝20/1～10/1)纯化，得到产物(土黄色固体，3.12g)，产物中加入4mL无水乙醇常温搅拌18h，过滤，滤饼用1mL乙醇洗涤，减压干燥，得到实施例1B。此化合物通过在丙酮或乙醇溶液中加入1个当量的盐酸或硫酸或甲磺酸得到对应的盐。
LCMS(ESI)m/z:445.0[M+1] +
1H NMR(400MHz,DMSO-d6)ppm 8.66-8.71(m,2H),8.12-8.20(m,2H),7.72-7.93(m,2H),7.45(t,J＝9.16Hz,1H),7.28(d,J＝2.76Hz,1H),6.58(d,J＝5.02Hz,1H),4.05(s,3H),2.56-2.64(m,1H),0.38-0.77(m,4H)
实施例1
Figure PCTCN2018106674-appb-000025
实施例1B(1.5g,3.37mmol)加入到EtOH(45mL)中，反应温度升至60℃，在该温度下，将CH 3SO 3H(324.07mg,3.37mmol,240.05μL)滴加到反应液中，滴加完毕，反应液溶清，搅拌下反应液自然降温至15～20℃，在该温度下搅拌2h。有大量棕色固体析出,过滤，滤饼用无水乙醇(5mL)淋洗，得到的滤饼50℃减压旋干,不纯化,得到实施例1。
LCMS(ESI)m/z:445.0[M+1] +
1H NMR(400MHz,DMSO-d6)δppm 9.02(d,J＝6.53Hz,1H)8.72(s,1H)8.18-8.27(m,2H)7.87-8.03(m,2H)7.65(s,1H)7.53(t,J＝9.03Hz,1H)7.32(br s,1H)7.11(d,J＝6.27Hz,1H)4.08(s,3H)2.55-2.62(m,1H)2.35(s,3H)0.34-0.75(m,4H)
流程B
Figure PCTCN2018106674-appb-000026
对照例3A
Figure PCTCN2018106674-appb-000027
将4-氯-7-甲氧基喹啉-6-甲酰胺(200mg,845.12μmol)，4氨基-2，5-二氟苯酚(184.13mg,1.01mmol)和叔丁醇钾(113.80mg,1.01mmol)一起加到装有氮甲基吡咯烷酮(5mL)的微波管中，然后通过微波合成仪氮气保护下加热到140℃并且搅拌反应1小时。将反应液加到30毫升水中，析出固体，过滤得到对照例3A。得到产物未进行纯化，直接用于下一步。
LCMS(ESI)m/z:346.1[M+H] +
对照例3
Figure PCTCN2018106674-appb-000028
将三光气(34.38mg,115.84μmol)加到装有对照例3A(200mg,579.21μmol)和三乙胺(175.83mg,1.74mmol,241.86μL)的二氯甲烷(5mL)中，氮气保护以及15-20℃下搅拌15分钟。然后把环丙胺(66.14mg,1.16mmol,80.27uL)加到搅拌中的反应液中，最后反应液在氮气保护以及15-20℃下搅拌反应45分钟。将反应液直接旋干，得到粗品。粗品经过高效液相色谱分离纯化(TFA体系)得到对照化合物3。对照化合物3可以通过将其在二氯甲烷中，然后通过1N碳酸氢钠洗涤，得到游离碱。
LCMS(ESI)m/z:429.2[M+H] +
1H NMR(400MHz,CD 3OD)δ9.03(s,1H),8.90(d,J＝6.8Hz,1H),8.29～8.34(m,1H),7.60(s,1H),7.44～7.68(m,1H),7.03(d,J＝6.0Hz,2H),4.21(s,3H),2.63～2.68(m,1H),0.79～0.80(m,2H),0.55(s,2H)
流程C
Figure PCTCN2018106674-appb-000029
对照例4A
Figure PCTCN2018106674-appb-000030
对照例4A采用对照例3A的制备方法，得到产品。
LCMS(ESI)m/z:346.1[M+H] +
1H NMR(400MHz,CD 3OD)δ8.66～8.73(m,2H),7.80(s,1H),7.76(s,1H),7.49～7.57(m,1H),7.02(t,J＝8.0Hz,1H),6.68(t,J＝8.0Hz,1H),6.49～6.54(m,1H),5.63(s,2H),4.03(s,3H)
对照例4
Figure PCTCN2018106674-appb-000031
将三光气(34.38mg,115.84μmol)加到装有实施例1A(200mg,579.21μmol)和三乙胺(175.83mg, 1.74mmol,241.86μL)的二氯甲烷(5mL)中，氮气保护以及15-20℃下搅拌15分钟，然后把环丙胺(66.14mg,1.16mmol,80.27μL)加到搅拌中的反应液中，最后反应液在氮气保护以及15-20℃下搅拌反应45分钟。将反应液直接旋干，得到粗品。粗品送高效液相色谱分离纯化(HCl条件)得到产物。最终得到对照化合物4。对照化合物4可以通过将其在二氯甲烷中，然后通过1N碳酸氢钠洗涤，得到游离碱。LCMS(ESI)m/z:429.2[M+H] +
1H NMR(400MHz,CD 3OD)δ9.05(s,1H),8.97(d,J＝6.8Hz,1H),8.07(s,1H),7.65(s,1H),7.30～7.34(m,1H),7.16(d,J＝6.8Hz,2H),4.24(s,3H),2.63～2.68(m,1H),0.78～0.82(m,2H),0.57(s,2H)
流程D
Figure PCTCN2018106674-appb-000032
对照例5A
Figure PCTCN2018106674-appb-000033
向4-氯-7-甲氧基喹啉-6-甲酰胺(200mg,845.12umol)和4-氨基-5-氯-2氟-苯酚(341.35mg,2.11mmol)的氮甲基吡咯烷酮(2mL)反应液中加入Cs2CO3(550.71mg,1.69mmol)，微波条件下，加热到140℃反应2hr。LCMS(es8146-386-p1a)检测部分原料未反应完成，反应液慢慢滴加到冰水(10mL)，大量固体析出，过滤，滤饼真空旋干，得到对照例5A。LCMS(ESI)m/z:384.1[M+23] +
对照例5
Figure PCTCN2018106674-appb-000034
对照例5A(50mg,138.22μmol)加入到二氯甲烷(5mL)中，搅拌下将三光气(32.81mg,110.57μmol)和二异丙基乙氨DIEA(53.59mg,414.65μmol,72.22μL)加入到反应液中，反应15～20℃搅拌15分钟,将环丙胺(15.78mg,276.43umol,19.15μL)加入到反应液中，反应液继续室温搅拌30分钟，LCMS显示原料反应完全，反应液直接减压浓缩，得粗品粗品,通过高效液相色谱分离纯化(TFA条件)纯化得 到对照化合物5。对照化合物5可以通过将其在二氯甲烷中，然后通过1N碳酸氢钠洗涤，得到游离碱。LCMS(ESI)m/z:467.1[M+23] +
1H NMR(400MHz,METHANOL-d4)δppm 9.03(s,1H)8.89(d,J＝6.52Hz,1H)8.39(d,J＝13.30Hz,1H)7.68(d,J＝8.03Hz,1H)7.60(s,1H)7.01(d,J＝7.03Hz,1H)4.21(s,3H)2.61-2.72(m,1H)0.50-0.86(m,4H)
流程E
Figure PCTCN2018106674-appb-000035
对照例6A
Figure PCTCN2018106674-appb-000036
对照例6A采用对照例5A的制备方法，得到产品。
LCMS(ESI)m/z:328.2[M+1] +
对照例6
Figure PCTCN2018106674-appb-000037
对照例6A(50mg,152.76μmol)加入到二氯甲烷(5mL)中，搅拌下将三光气(36.27mg,122.21μmol)和DIEA(59.23mg,458.28μmol,79.82μL)加入到反应液中，反应15～20℃搅拌15分钟，将环丙胺(17.44mg,305.52μmol,21.17μL)加入到反应液中，反应液继续室温搅拌30分钟，LCMS显示原料反应完全，反应液直接减压浓缩，得粗品，粗品通过高效液相色谱分离纯化(TFA条件)纯化得到对照化合物6。对照化合物6可以通过将其在二氯甲烷中，然后通过1N碳酸氢钠洗涤，得到游离碱。
LCMS(ESI)m/z:411.0[M+1] +
1H NMR(400MHz,CD 3OD)δppm 9.12(s,1H)8.38(d,J＝7.03Hz,1H)7.54(t,J＝8.66Hz,1H)7.41(s,1H)7.25-7.33(m,1H)7.19(br d,J＝8.78Hz,1H)6.61(br d,J＝5.27Hz,1H)4.18(s,3H)0.55-0.90(m,4H)
流程E
Figure PCTCN2018106674-appb-000038
对照例7A
Figure PCTCN2018106674-appb-000039
对照例7A采用对照例3A的制备方法，得到产品。
LCMS(ESI)m/z:362.1[M+H] +
对照例7
Figure PCTCN2018106674-appb-000040
将三光气(34.38mg,115.84μmol)加到装有对照例7A(50mg,138.22μmol)和三乙胺(41.96mg,414.65μmol,57.71μL)的二氯甲烷(2mL)中，氮气保护以及15-20℃下搅拌10分钟，然后把环丙胺(15.78mg,276.43μmol,19.15μL)加到搅拌中的反应液中，最后反应液在氮气保护以及15-20℃下搅拌反应50分钟。将反应液直接旋干得到粗品，通过高效液相色谱分离纯化(TFA条件)最终得到对照化合物7，LCMS和核磁检测。对照例7可以通过将其在二氯甲烷中，然后通过1N碳酸氢钠洗涤，得到游离碱。
LCMS(ESI)m/z:445.2[M+H] +
1H NMR(400MHz,CD 3OD)δ8.94(s,1H),8.72(d,J＝5.2Hz,1H),7.56(s,1H),7.34(m,1H),7.20～7.24(m,1H),6.90(d,J＝5.2Hz,1H),4.15(s,3H),2.62～2.68(m,1H),0.80～0.81(m,2H),0.61(s,2H)
生物测试数据：
实验例1：本发明化合物的体外酶活性测试
实验目的
通过Z′-LYTE TM Detection Kinase Assay检测酶活性,以化合物的IC 50值为指标，来评价化合物1B和乐伐替尼(Lenvatinib)，对照化合物2对ABL,c-Met,TNIK,FGFR1-4,Flt1,Flt4,KDR,MINK,LCK,cKIT,PDGFRα,PDGFRβ,cKit(V560G)十七种激酶的抑制作用。
实验方法
c-Met，FGFR1,FGFR4三个激酶的测试所用化合物进行4倍浓度稀释，浓度为10μM到0.038nM；其余激酶测试所用化合物分别进行3倍浓度梯度稀释，终浓度为10μM到1nM 9个浓度，每个浓度两个复孔；DMSO在检测反应中的含量为2％。
通用酶的反应过程：
加入对应酶的浓度X的蛋白激酶(见表1),肽底物的Y浓度,ATP浓度,8mM MOPS(pH 7.0),10mM MgCl 2。检测板为P30filtermat，室温反应T分钟，反应体系为10μl。
表1激酶测试的条件
激酶 酶的浓度(X)(nM) Tyr peptide(Y) ATP(uM)浓度 反应时间(T)(分钟)
Abl(h) 7.65 50μM 10 40
c-Met 8 20μM 10 120
TNIK(h) 8.65 250μM 10 40
FGFR1(h) 1.75 0.2mg/mL 5 120
FGFR2(h) 2.99 0.1mg/mL 10 40
FGFR3(h) 13.03 0.1mg/mL 10 40
FGFR4(h) 2.5 0.2mg/mL 100 120
Flt1(h) 157.27 250μM 10 40
Flt4(h) 64.91 500μM 10 40
KDR(h) 55.23 0.33mg/mL 10 40
MINK(h) 35.40 0.33mg/mL 10 40
Lck(h) 366.10 250uM 10 40
cKit(h) 383.75 0.1mg/mL 10 40
PDGFRα(h) 270.87 0.1mg/mL 10 40
PDGFRβ(h) 310.83 0.1mg/mL 10 40
cKit(V560G)(h) 83.44 250μM 10 40
Aurora-A(h) 3.08 200μM 10 40
反应检测：
激酶反应液中添加0.5％浓度的磷酸终止反应，Envision仪器读板。
数据分析
将数据转化为磷酸化率和抑制率，参数曲线拟合(GraphPad Software)得到化合物IC 50数据。
实验结果见表2：
表2实施例1B和对照化合物主要激酶活性IC 50测试结果
Figure PCTCN2018106674-appb-000041
NA:未测试。
表3实施例1B和对照化合物针对FGFR1，FGFR4和VEGFR2激酶活性IC 50(nM)测试结果
FGFR1(h) FGFR4(h) c-Met ABL(h)
实施例1B 9 92 45.6 注1 7
对照化合物3 160 509 >10,000 817
对照化合物4 31 108 79.8 292
对照化合物5 89 137 32 207
对照化合物6 1744 4557 282 2210
对照化合物7 54 1115 >10,000 NA
注1：第二次测试
NA：未测试。
实验结论：
表2中实施例1B相比对照化合物1，显著提高了多个激酶的活性，其中，C-Met的活性提高了5倍，TNIK活性提高了6.5倍，ABL活性提高了5倍,显著增加FGFR各个亚型的活性，FGFR1提高8倍，FGFR2提高2倍，FGFR3提高5倍的，FGFR4提高了12倍。对这几个重要靶点活性的提高，使得化合物1B有更优异的肿瘤治疗效果，特别是对FGFR，c-Met活性的提高，将会在FGFR，c-Met高表达的胃癌，肺癌等患者中有更优的治疗效果。
实施例1B相比对照化合物2，大大提高ABL的活性近70倍，TNIK提高了8倍，是非常意想不到的，能够在BCR-ABL等基因融合的癌症中具有更优的治疗活性。
表3中显示，实施例1B相比对照化合物3、4、5、6、7，氟和氯位于苯环的同侧比在其它位置，对FGFR1和FGFR4，ABL激酶抑制活性具有显著的提高。
实验例2：化合物药代动力学评价
实验目的：通过小鼠静脉和口服给药，评价实施例1的动物口服吸收情况
实验材料：Balb/c nude小鼠，EDTA-K2
实验操作：
实验过程：将0.5mg/ml 5％DMSO/95％(10％HP-β-CD)试验实施例1的澄清溶液经尾静脉注射到雄性Balb/c nude小鼠体内(过夜禁食，7-9周龄)，给药剂量为1mg/kg。将0.5mg/ml悬浮在0.5％Methocel/0.2％Tween 80的试验化合物灌胃给予到雄性Balb/c nude小鼠(过夜禁食，7-9周龄)，给药剂量为5mg/kg。两组动物均于给药后0.25、0.5、1.0、2.0、4.0、8.0和24h从颈静脉或尾静脉采血约30μL置于添加了EDTA-K2的抗凝管中，离心分离血浆。采用LC-MS/MS法测定血药浓度，使用WinNonlin TM Version 6.3(Pharsight,Mountain View,CA)药动学软件，以非房室模型线性对数梯形法计算相关药代动力学参数。
实验结果：
雄性Balb/c nude小鼠单次静脉注射给药1.0mg/kg实施例1后，其血浆清除率(CL)为11mL/min/kg，稳态表观分布容积(Vdss)为1.48L/kg，消除半衰期(T 1/2)和0点到最后一个可定量时间点血浆浓度曲 线下面积(AUC 0-last)的值分别为2.68h和3213nM·h。
雄性Balb/c nude小鼠单次灌胃给予5mg/kg实施例1后，其生物利用度为144％,AUC 0-last为24899nM·h，达峰浓度(C max)为9825nM，达峰时间出现在给药后0.5h。
实验例3：化合物药代动力学评价
实验目的：通过大鼠静脉和口服给药，评价实施例1的动物口服吸收情况
实验材料：雄性，SD大鼠，EDTA-K2
实验操作：
实验过程：将0.5mg/ml 5％DMSO/95％(10％HP-β-CD)试验实施例1或对照化合物1的澄清溶液经尾静脉注射到雄性SD大鼠体内(过夜禁食，7-11周龄)，给药剂量为1mg/kg。将0.5mg/ml悬浮在0.5％Methocel/0.2％Tween 80的试验化合物灌胃给予到雄性，SD大鼠(过夜禁食，7-11周龄)，给药剂量为5mg/kg。两组动物均于给药后0.25、0.5、1.0、2.0、4.0、8.0和24h从颈静脉或尾静脉采血约30μL置于添加了EDTA-K2的抗凝管中，离心分离血浆。采用LC-MS/MS法测定血药浓度，使用WinNonlin TM Version 6.3(Pharsight,Mountain View,CA)药动学软件，以非房室模型线性对数梯形法计算相关药代动力学参数。
实验结果：
实施例1：
雄性SD大鼠单次静脉注射给药1.0mg/kg实施例1后，其血浆清除率(CL)为1.6mL/min/kg，稳态表观分布容积(Vdss)为0.259L/kg，消除半衰期(T 1/2)和0点到最后一个可定量时间点血浆浓度曲线下面积(AUC 0-last)的值分别为2.64h和23441nM·h。
雄性SD大鼠单次灌胃给予5mg/kg实施例1后，其生物利用度为60.8％,AUC 0-last为71053nM·h，达峰浓度(Cmax)为19600nM，达峰时间出现在给药后0.375h。
对照化合物1：
雄性SD大鼠单次静脉注射给药1.0mg/kg对照化合物1后，其血浆清除率(CL)为2.6mL/min/kg，稳态表观分布容积(Vdss)为0.407L/kg，消除半衰期(T 1/2)和0点到最后一个可定量时间点血浆浓度曲线下面积(AUC 0-last)的值分别为2.53h和15149nM·h。
雄性SD大鼠单次灌胃给予5mg/kg对照化合物1后，其生物利用度为58.7％,时间血浆浓度曲线下面积(AUC 0-last)为44476nM·h，达峰浓度(Cmax)为10095nM，达峰时间出现在给药后1.25h。
实施例1与对照化合物1相比，大鼠药代动力学数据显示，血浆清除率降低了约：(2.6-1.6)/2.6*100％＝38％。静脉给药，药物时间血浆浓度曲线下面积(AUC 0-last)显著增加：(23441-15149)/15149*100％＝55％；口服吸收，药物时间血浆浓度曲线下面积(AUC 0-last)显著增加：(71053-44476)/44476*100％＝27％。
结论：本发明实施例1在小鼠和大鼠种属中，具有较低的清除率，高的口服生物利用度，具有优异的可成 药性。相比对照化合物1(上市药物乐伐替尼)，在喹啉母核结构的苯环上引入F原子，显著降低大鼠体内药物代谢速率，显著提高药物的口服吸收暴露量。

Claims (7)

  1. 式(Ⅱ)所示化合物或其药学上可接受的盐，
    Figure PCTCN2018106674-appb-100001
    其中，
    R 1选自任选被1、2或3个R取代的C 1-6烷氧基；
    R 2选自-C(＝O)NH 2和-C(＝O)NH-C 1-3烷基；
    环B选自C 3-6环烷基；
    R选自F、Cl、Br、I、OH和NH 2。
  2. 根据权利要求1所述化合物或其药学上可接受的盐，其中，R 1选自
    Figure PCTCN2018106674-appb-100002
  3. 根据权利要求1所述化合物或其药学上可接受的盐，其中，R 2选自-C(＝O)NH 2。
  4. 根据权利要求1所述化合物或其药学上可接受的盐，其中，环B选自环丙基。
  5. 根据权利要求1～3任意一项所述化合物或其药学上可接受的盐，其选自
    Figure PCTCN2018106674-appb-100003
    其中，R 1、R 2如权利要求1～3任意一项所定义。
  6. 下式所示化合物或其药学上可接受的盐，其选自
    Figure PCTCN2018106674-appb-100004
  7. 根据权利要求1～6任意一项所述的化合物或其药学上可接受的盐在制备治疗酪氨酸激酶抑制剂相关病症的药物上的应用。
PCT/CN2018/106674 2017-09-28 2018-09-20 喹啉衍生物及其作为酪氨酸激酶抑制剂的应用 WO2019062637A1 (zh)

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PL3689351T3 (pl) 2023-03-20
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