WO2016050016A1 - Composé hétérocyclique substitué utile en tant qu'inhibiteur de kinase, son procédé de préparation et les utilisations de celui-ci - Google Patents

Composé hétérocyclique substitué utile en tant qu'inhibiteur de kinase, son procédé de préparation et les utilisations de celui-ci Download PDF

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WO2016050016A1
WO2016050016A1 PCT/CN2015/070904 CN2015070904W WO2016050016A1 WO 2016050016 A1 WO2016050016 A1 WO 2016050016A1 CN 2015070904 W CN2015070904 W CN 2015070904W WO 2016050016 A1 WO2016050016 A1 WO 2016050016A1
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group
compound
cancer
formula
alkyl
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Chinese (zh)
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王学海
许勇
李莉娥
黄璐
乐洋
田华
盛锡军
张绪文
肖强
冯权武
夏庆丰
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湖北生物医药产业技术研究院有限公司
人福医药集团股份公司
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Publication of WO2016050016A1 publication Critical patent/WO2016050016A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A61K31/502—Pyridazines; Hydrogenated pyridazines ortho- or peri-condensed with carbocyclic ring systems, e.g. cinnoline, phthalazine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • 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
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/541—Non-condensed thiazines containing further heterocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
    • C07D237/26—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings condensed with carbocyclic rings or ring systems
    • C07D237/28—Cinnolines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to the field of medicine, and in particular, the present invention relates to a substituted heterocyclic compound as a kinase inhibitor, a preparation method and use thereof, and more particularly, to a compound, a method for preparing a compound, a pharmaceutical composition, and a compound for preparing a medicament Use in.
  • EGF epidermal growth factor
  • the EGF receptor is a transmembrane tyrosine kinase receptor belonging to a family of four related receptors. Most human epithelial cancers are characterized by the growth of growth factors and receptors of this family, thus EGF.
  • EGFR is a target for cancer treatment.
  • ErbB2 also known as neu or HER2, epidermal growth factor receptor-2.
  • the ErbB2 gene is often found to be amplified in breast or ovarian cancer as well as glioblastoma. Transfection studies in cell models and animal models have demonstrated that overexpression of ErbB2 results in increased tumorigenicity, tumor invasion, increased likelihood of metastasis, and altered sensitivity to hormonal therapeutics and chemotherapeutic agents.
  • HER2 is a well-researched target in the field of breast cancer.
  • tyrosine kinase inhibitor inhibits the intracellular tyrosine kinase region of HER1, HER2 and HER4, and HER2-related HER receptors can directly act.
  • the HER2 receptors thus affect each other's activity and subsequent malignant growth of the tumor.
  • the present invention is directed to solving at least some of the above technical problems or at least providing a useful commercial choice. To this end, it is an object of the present invention to provide a substituted heterocyclic compound for use as a kinase inhibitor.
  • Another object of the invention is to provide a process for the preparation of a compound of formula I, or a pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof.
  • a further object of the present invention is to provide a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of the present invention, the pharmaceutical composition further comprising one or more pharmaceutically acceptable excipients and a therapeutically effective amount of at least one of the present invention a compound, or a pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof.
  • a further object of the invention is to provide the use of a compound of the invention, or a pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof, for the manufacture of a medicament.
  • the medicament as a tyrosine kinase inhibitor, can be used for the preparation of an anticancer drug for the treatment of a HER2-positive cancer patient.
  • the invention provides a compound which is useful as a kinase inhibitor Substituted heterocyclic compounds.
  • the compound is a compound of formula I or a pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof,
  • R 1 and R 2 are each independently hydrogen, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 acyl, C 3 -C 7 Cycloalkyl, C 1 -C 8 alkoxy, C 1 -C 8 alkoxyalkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, nitrile, nitro, OR 5 , SR 5 , NHR 5 , NR 5 R 6 , N(O)R 5 R 6 , (CR 5 R 6 ) m NR 7 R 8 , COR 5 , COOR 5 , CONR 5 R 6 , C(O)NR 5 SO 2 R 6 , NR 5 SO 2 R 6 , C(O)NR 5 OR 6 , SO 2 NR 5 R 6 , (CR 5 R 6 ) m -aryl, (CR 5 R 6 ) m -
  • up to 4 ring-forming carbon atoms in the carbocyclic group are substituted by a hetero atom independently selected from oxygen, sulfur or nitrogen, provided that at least one of the carbocyclic groups
  • the ring atom is a carbon atom, and when the carbocyclic group contains not less than two epoxy atoms, the epoxy atoms are not adjacent to each other.
  • the carbocyclic group is unsubstituted or one, two or three are each independently halogen, hydroxy, hydroxyalkyl, nitrile, lower C 1 -C 8 alkyl, C 1 - C 8 alkoxy, alkoxycarbonyl, alkylcarbonyl, alkylcarbonylamino, aminoalkyl, carboxyalkyl, trifluoromethyl, amino, (CH 2 ) m C(O)R 5 R 6 , or The group of O(CH 2 ) m C(O)OR 5 is substituted, and m is an integer of 0-6.
  • R 5 and R 6 are each independently hydrogen, C 1 -C 6 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, arylalkyl, naphthenic Or a heterocycloalkyl, aryl, heteroaryl, or heteroarylalkyl group, wherein the aryl, heteroaryl, or heteroarylalkyl group is unsubstituted or is substituted by one, two or three Alternately substituted with a halogen, hydroxy, hydroxyalkyl, nitro or acyl group, or, when R 5 and R 6 are attached to the same nitrogen atom, R 5 and R 6 together with the nitrogen atom to which they are attached form a 3 -8 membered heterocyclic ring A, provided that at least one of the ring-forming atoms in the 3-8 membered heterocyclic ring A is a carbon atom.
  • At most four ring-forming atoms in the 3-8 membered heterocyclic ring A are independently oxygen, sulfur, S(O), S(O) 2 or nitrogen, when the 3-8 member
  • the heterocyclic ring A contains not less than two epoxy atoms, the epoxy atoms are not adjacent to each other.
  • the 3-8 membered heterocyclic ring A is unsubstituted or one, two or three are each independently halogen, hydroxy, hydroxyalkyl, nitrile, nitro, aryl, heteroaryl NR 7 SO 2 R 8 , C(O)NR 7 R 8 , NR 7 C(O)R 8 , C(O)OR 7 , C(O)NR7SO 2 R 8 , (CH 2 ) m S(O R 7 , (CH 2 ) m -heteroaryl, O(CH 2 ) m -heteroaryl, (CH 2 ) m C(O)NR 7 R 8 , O(CH 2 ) m C(O)OR a group substituted with 7 or (CH 2 )SO 2 NR 7 R 8 ;
  • R 7 and R 8 are each independently hydrogen, C 1 -C 6 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, arylalkyl, naphthenic Or a heterocycloalkyl group, an aryl group, a heteroaryl group, or a heteroarylalkyl group; or, when R 7 and R 8 are bonded to the same nitrogen atom, R 7 and R 8 together with the nitrogen atom to which they are attached form a 3-8 membered heterocyclic ring B, provided that at least one of the ring-forming atoms in the 3-8 membered heterocyclic ring B is a carbon atom.
  • At most four ring-forming atoms in the 3-8 membered heterocyclic ring B are independently oxygen, sulfur, S(O), S(O) 2 or nitrogen, wherein when 3- When the 8-membered heterocyclic ring B contains not less than two epoxy atoms, the epoxy atoms are not adjacent to each other.
  • the 3-8 membered heterocyclic ring B is unsubstituted or one, two or three are each independently halogen, hydroxy, hydroxyalkyl, nitrile, lower C 1 -C 8 alkyl, Substitution with a C 1 -C 8 alkoxy group, an alkoxycarbonyl group, an alkylcarbonyl group, an alkylcarbonylamino group, an aminoalkyl group, a carboxyalkyl group, a trifluoromethyl group or an amino group.
  • R 3 is C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, or C 3 -C 7 cycloalkyl.
  • R 4 is one of the following:
  • R 9 is hydrogen, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, carboxy, C 1 -C 6 carbonyl alkoxy, C 2 -C 7 carbonylalkyl, phenyl, R 11 -(C(R 10 ) 2 ) s -, R 11 -(C(R 10 ) 2 ) p -M-(C(R 10 ) 2 ) r -, R 12 R 13 -CH-M-(C (R 10 ) 2 ) r -, Het-(C(R 10 ) 2 ) r -, or Het-W-(C(R 10 ) 2 ) r -;
  • R 10 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C 3 - C 7 cycloalkyl, C 2 -C 8 carbonylalkyl, C 2 -C 8 carboxyalkyl, phenyl, phenyl optionally substituted by one or more halogens, C 1 -C 8 alkoxy, three Fluoromethyl, amino, C 1 -C 6 alkylamino, C 2 -C 6 dialkylamino, nitro, nitrile, halomethyl, C 2 -C 7 alkoxymethyl, C 2 - C 7 carbonyl alkoxy, hydroxy, carboxy, phenoxy, benzoyl, benzyl, phenylamino, benzylamino, C 2 -C 7 alkanoyloxymethyl, or C 1
  • R 10 is a C2-C8 alkenyl group, or a C2-C8 alkynyl group, these alkenyl or alkynyl moieties are attached to the nitrogen or oxygen atom through a saturated carbon atom;
  • R 11 is -NR 10 R 10 , -OR 10 , -NHR 10 , -C(R 10 ) 3 , -CHR 10 R 10 , or -CH 2 R 10 ;
  • R 12 and R 13 are each independently -(C(R 10 ) 2 ) r NR 10 R 10 , or -(C(R 10 ) 2 ) r OR 10 ;
  • M is >NR 10 , -O-, >N-(C(R 10 ) 2 ) p -NR 10 R 10 , or >N-(C(R 10 ) 2 ) p -OR 10 ;
  • W is >NR 10 , -O-, or a bond
  • p is an integer from 1 to 4.
  • r is an integer from 1 to 4.
  • s is an integer from 1 to 6;
  • Het is a heterocyclic ring
  • Het heterocycle is piperidine, dihydropyridine, pyrrole, tetrahydropyrrole, imidazole, oxazole, piperazine, furan, tetrahydrofuran, tetrahydropyran, pyran, morpholine, thiomorpholine, Thiazole, or thiophene.
  • the Het heterocycle is mono- or disubstituted by R 10 on a carbon or nitrogen atom or substituted by -CH 2 OR 10 - on a carbon atom.
  • the Het heterocyclic ring is mono- or disubstituted at a carbon atom from a hydroxyl group, a phenyl group, N(R 10 ) 2 , or OR 10 , and a monovalent group at a carbon atom - (C( R 10 ) 2 ) s OR 10 , or -(C(R 10 ) 2 ) s NR 10 R 10 monosubstituted or disubstituted, or via a divalent group -O-, or -O(C) on a saturated carbon atom (R 10 ) 2 ) s O-monosubstituted or disubstituted.
  • alkyl as used herein, includes both straight and branched alkyl moieties which may contain up to 12 carbon atoms.
  • the alkyl moiety preferably contains from 1 to 6 carbon atoms, more preferably from 1 to 4 carbon atoms.
  • alkoxy is defined as a C 1 -C 6 alkyl group -O-, where alkyl is as defined above.
  • halogen as used in the present invention is fluorine, chlorine, bromine or iodine, preferably halogen is selected from the group consisting of fluorine and chlorine.
  • alkenyl refers to an aliphatic hydrocarbon group containing one double bond and includes straight-chain and branched alkenyl moieties containing from 2 to 6 carbon atoms.
  • the alkenyl moiety can exist in the E or Z configuration and the compounds of the invention include both configurations.
  • alkynyl as used in the present invention includes straight-chain and branched-chain moieties having from 2 to 6 carbon atoms having at least one triple bond.
  • cycloalkyl refers to an aliphatic hydrocarbon group having 3 to 12 carbon atoms and includes, but is not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, Or adamantyl.
  • aryl as used herein is defined as an aromatic moiety and may be substituted or unsubstituted.
  • the aryl group preferably has 6 to 12 carbon atoms and may be selected from, but not limited to, the following groups: phenyl, ⁇ -naphthyl, ⁇ -naphthyl, biphenyl, anthracenyl, tetrahydronaphthyl, indane Base, or biphenylene.
  • the aryl group may be mono-, di-, tri- or tetra-substituted, optionally, by way of example, but not limited to, a group consisting of an alkyl group, an acyl group, an alkoxycarbonyl group, an alkoxy group, Alkoxyalkyl, alkoxyalkoxy, cyano, halogen, hydroxy, nitro, trifluoromethyl, trifluoromethoxy, trifluoropropyl, amino, alkylamino, dialkylamino, Dialkylaminoalkyl, hydroxyalkyl, alkoxyalkyl, alkylthio, -SO 3 H, -SO 2 NH 2 , -SO 2 NH-alkyl, -SO 2 N-(alkyl) 2 -CO 2 H, -CO 2 NH 2 , -CO 2 NH-alkyl, -CO 2 N-(alkyl) 2 .
  • heteroaryl as used in the present invention is defined as an aromatic heterocyclic ring system (monocyclic or bicyclic) wherein the heteroaryl moiety is a heterocyclic moiety containing from 1 to 4 selected from the group consisting of S, N and O.
  • a five- or six-membered ring of an atom including but not limited to: (1) furan, thiophene, anthracene, azaindole, oxazole, thiazole, isoxazole, isothiazole, imidazole, N-methyl Imidazole, pyridine, pyrimidine, pyrazine, pyrrole, N-methylpyrrole, pyrazole, N-methylpyrazole, 1,2,4-triazole, 1-methyl-1,2,4-triazole, 1H-tetrazole, 1-methyltetrazole, benzimidazole, benzofuran, quinazoline, quinoline, isoquinoline, pyrrolidinyl; (2) bicyclic aromatic heterocycle, wherein phenyl, pyridine, Pyrimidine or pyridazine ring: (i) fused to a six-membered aromatic (unsaturated) heterocyclic ring having one nitrogen atom; (
  • alkylthio as used in the present invention is defined as C 1 -C 6 alkyl-S-.
  • alkoxyalkyl denotes an alkyl group as defined above which is further substituted with an alkoxy group as defined above, and a preferred alkoxy moiety is an alkoxymethyl group (e.g., alkoxy group) -CH 2 -).
  • hydroxy as used herein is defined as the -OH moiety.
  • hydroxyalkyl as used herein is defined as a HO-alkyl- moiety wherein the alkyl moiety consists of from 1 to 6 carbon atoms.
  • benzoyl as used herein is defined as a Ph-OC(O)- moiety.
  • alkylamino as used herein, and “dialkylamino” refers to a moiety having one or two alkyl groups, wherein the alkyl chain has from 1 to 6 carbons and the groups may be the same or different .
  • alkylaminoalkyl and "dialkylaminoalkyl” as used herein, refers to an alkane having one or two nitrogen atoms bonded to an alkyl group having from 1 to 6 carbon atoms at the point of attachment. Monoalkylamino and dialkylamino moieties of the same or different.
  • the dialkylaminoalkyl moiety preferably consists of 3 to 10 carbon atoms and the alkylaminoalkyl moiety preferably consists of 2 to 9 carbon atoms.
  • alkoxycarbonyl as used herein is defined as -COOR, wherein R is an alkyl group having from 1 to 6 carbon atoms.
  • Carboxyalkyl as used herein is defined as a HOOCR- moiety wherein R is an alkyl group having from 1 to 6 carbon atoms.
  • aminoalkyl is defined as an H 2 N-, wherein the alkyl from 1 to 5 carbon atoms.
  • alkanoylamino as used herein is defined as the -NH-COOR moiety wherein R is an alkyl group having from 1 to 6 carbon atoms.
  • substituted as used herein, is used herein to refer to an atomic group, functional group or moiety that replaces a hydrogen group on a molecule. Unless otherwise specifically stated, it is assumed that any substituent may be optionally substituted with one or more groups selected from the group consisting of alkyl, halo, haloalkyl, hydroxyalkyl, nitro, amino, hydroxy, Cyano, alkylamino, dialkylamino, alkoxy, haloalkoxy, alkoxyalkyl, alkoxyalkoxy, oxo, alkylthio, decyl, haloalkylthio, aryl, aryl Oxyl, arylthio, heteroaryl, heteroaryloxy, heteroarylthio, acyl, -CO 2 -alkyl, -SO 3 H, -SO 2 NH 2 , -SO 2 NH-alkyl, - SO 2 N-(alkyl) 2
  • substituted refers to the situation in which a hydrogen group on a molecule has been replaced by another atomic group, a functional group, or a moiety, and these groups are generally referred to as “substituents.”
  • yield refers to the amount of a compound produced by a reaction or method, also referred to as "amount”. Generally, this refers to the amount of compound recovered after any purification step employed (eg, after recrystallization, or after chromatographic separation). This amount is usually expressed as a percentage of the amount of product recovered relative to the starting material, and is usually in moles. For example, if 1.0 mole of starting material starting material is reacted and the product recovered after purification is 0.85 mole, the yield of the product is 85.0%. This concept will be readily understood by those skilled in the art of the present invention.
  • pharmaceutically acceptable salt is a conventional non-toxic salt formed by reacting a compound of the formula I with an inorganic or organic acid.
  • the conventional non-toxic salt can be obtained by reacting a compound of the formula I with an inorganic or organic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, aminosulfonic acid, phosphoric acid, and the like.
  • the organic acid comprises citric acid, tartaric acid, lactic acid, pyruvic acid, acetic acid, benzenesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, naphthalenesulfonic acid, ethanesulfonic acid, naphthalene disulfonic acid, maleic acid, malic acid , malonic acid, fumaric acid, succinic acid, propionic acid, oxalic acid, trifluoroacetic acid, stearic acid, pamoic acid, hydroxymaleic acid, phenylacetic acid, benzoic acid, salicylic acid, glutamic acid, ascorbic acid, Aminobenzenesulfonic acid, 2-acetoxybenzoic acid, isethionate, etc.; or a compound of formula I with propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid,
  • preferred pharmaceutically acceptable salts of the invention are the hydrochloride, besylate, p-toluenesulfonate or maleate.
  • prodrug means that once the compound is administered to a subject, the compound is chemically converted by metabolic or chemical processes to provide a compound of formula I and/or its salt and/or Or solvate.
  • Any compound that can be converted in vivo to provide a biologically active substance i.e., a compound of formula I
  • a prodrug within the scope and spirit of the invention.
  • a compound containing a carboxyl group can form a physiologically hydrolyzable ester which is prepared by hydrolysis in vivo to give the compound of formula I itself.
  • the prodrug is preferably administered orally because hydrolysis occurs in many cases primarily under the influence of digestive enzymes. Parenteral administration can be used when the ester itself is active or hydrolysis occurs in the blood.
  • R 1 is hydrogen, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 acyl, or nitrile;
  • R 2 is hydrogen, halogen, C 1 -C 6 alkyl, OR 5 , NHR 5 , NR 5 R 6 , COR 5 , COOR 5 , or CONR 5 R 6 ;
  • R 5 and R 6 are each independently hydrogen, C 1 -C 6 alkyl or aryl, wherein the aryl group is unsubstituted or one, two or three are each independently a halogen, C 1 -C 6 acyl group Substitute
  • R 3 is C 1 -C 6 alkyl, preferably R 3 is methyl, ethyl, n-propyl, isopropyl or t-butyl;
  • R 4 is one of the following:
  • R 9 is hydrogen, halogen, C 1 -C 6 alkyl, R 11 -(C(R 10 ) 2 ) s -, or Het-(C(R 10 ) 2 ) r -;
  • R 10 is hydrogen or a C 1 -C 6 alkyl group
  • R 11 is -NR 10 R 10 , -OR 10 , -NHR 10 , -C(R 10 ) 3 , -CHR 10 R 10 , or -CH 2 R 10 ;
  • s is an integer from 1 to 4.
  • the Het heterocycle is piperidine, dihydropyridine, pyrrole, tetrahydropyrrole, imidazole, piperazine, tetrahydropyran, tetrahydropyridyl Methane, morpholine, thiomorpholine, or thiophene.
  • hydrates, solvates e.g., methanolates, DMSOs
  • Methods of solvation are well known in the art.
  • the compound of formula I according to the invention is at least one selected from the group consisting of:
  • the inventors have found that the compounds of the invention are useful as kinase inhibitors in modulating tyrosine kinase signaling.
  • This invention The compound is a potent inhibitor of both EGFR and ErbB2 (HER2), and the compound of the present invention has an inhibitory effect on EGFR and ErbB2 superior to the existing drug neratinib, and the compound of the present invention can be effectively treated or Prevention of cancer or neoplastic disease mediated by at least one of EGFR and ErbB2.
  • the compounds of the present invention also exhibit improved solubility and properties that are less likely to flow out of the cells, thereby increasing bioavailability.
  • the invention provides a process for the preparation of the compounds described above.
  • the method comprises contacting a compound of formula a with a compound of formula b to obtain a compound of formula I.
  • R 1 , R 2 , R 3 and R 4 are as defined above.
  • the inventors have found that the method of the present invention enables rapid and efficient preparation of a compound of formula I, or a pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof, with a short synthetic route, environmental friendliness, yield of the desired product, and High purity, easy to obtain raw materials, simple operation and post-treatment, suitable for industrial production.
  • the contacting the compound of the formula a with the compound of the formula b further comprises: mixing the compound of the formula b and the N-methylpyrrolidone at -10 ° C to 10 ° C The solution is mixed with the compound of the formula a, and the resulting mixture is reacted at room temperature for 8 to 16 hours.
  • the method for preparing the compound described above comprises: adding a compound of the formula a to a reaction flask at -10 ° C to 10 ° C, and dropwise adding a compound of the formula b to the reaction solution A solution consisting of N-methylpyrrolidone (NMP) is added over 15 to 60 minutes and reacted at room temperature for 8 to 16 hours. After the TLC detection reaction was completed, an appropriate amount of water was added, and the obtained mixed solution was adjusted to a pH of 10.0 to 11.0 with a 2.5 mol/liter sodium hydroxide aqueous solution to precipitate a large amount of solid, and the obtained solid was sequentially subjected to suction filtration, washing, and drying. An off-white solid which is purified by recrystallization from a solvent to give a white solid product which is the compound previously described (ie, a compound of the invention).
  • NMP N-methylpyrrolidone
  • the compound of the invention may be a compound of formula I or a pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof.
  • the invention provides a pharmaceutical composition comprising a compound as described above, in accordance with an embodiment of the invention.
  • the pharmaceutical composition may further comprise a pharmaceutically acceptable excipient.
  • the pharmaceutical composition may further comprise conventional additives such as odorants, flavoring agents and the like.
  • the pharmaceutical composition provided by the present invention preferably contains the compound described above in an amount of from 1% to 95% by weight, based on the total mass of the pharmaceutical composition, as an active ingredient, and more preferably, the foregoing
  • the compound is present as an active ingredient in an amount of 20% to 40% by weight based on the total weight of the pharmaceutical composition, and the remainder is at least one of a pharmaceutically acceptable carrier, an excipient, and a conventional additive.
  • the pharmaceutical composition provided by the present invention may be in various forms including, but not limited to, tablets, capsules, injections, powders for injection, powders, syrups, solutions, suspensions, aerosols, and the like. And can exist Suitably in a suitable solid or liquid carrier or diluent and in a sterile device for injection or drip.
  • compositions of the present invention can be prepared according to conventional methods of preparation in the pharmaceutical arts.
  • the compounds and pharmaceutical compositions of the present invention can be administered to mammals clinically, including humans and animals, and can be administered by the route of the mouth, nose, skin, lungs or the gastrointestinal tract. Regardless of the method of administration, the optimal dosage for the individual should be based on the specific treatment regimen. Usually starting with a small dose, gradually increase the dose until the most suitable dose is found. The most preferred route of administration is oral.
  • the invention provides the use of a compound of the formula guanidine or a pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof for the preparation of a medicament.
  • the medicament is used as a kinase inhibitor.
  • the inventors have found that the compounds of the invention are useful as kinase inhibitors in modulating tyrosine kinase signaling.
  • the compounds described herein are potent inhibitors of both EGFR and ErbB2 (HER2), and the compounds of the invention have a superior inhibitory effect on EGFR and ErbB2 over the existing drug neratinib.
  • the use of the compounds of the invention is effective in treating or preventing cancer or neoplastic disease mediated by at least one of EGFR and ErbB2.
  • the compounds of the present invention are effective as kinase inhibitors for treating or preventing cancer or neoplastic diseases mediated by at least one of EGFR and ErbB2 selected from leukemia, colon cancer, renal cell carcinoma , gastrointestinal stromal cancer, solid tumor, multiple myeloma, breast cancer, brain cancer, glioblastoma, pancreatic cancer, non-small cell lung cancer, non-Hodgkin's lymphoma, hepatocellular carcinoma, thyroid cancer, At least one of bladder cancer, colorectal cancer, and prostate cancer.
  • the compound of the formula I prepared by the present invention is applied to human lung adenocarcinoma cells (A-549), human colorectal cancer cells (Colo205), human breast cancer cells (MCF-7), human leukemia cells ( HL-60), both have good inhibitory effects (IC 50 ⁇ 100 ⁇ g/ml), among which human breast cancer cells (MCF-7) have the strongest inhibitory effect, and the results show that the present invention can be used for preparation of non-small treatments.
  • Antitumor drugs for cell lung cancer, colorectal cancer, breast cancer, or leukemia are especially useful for preparing drugs for treating breast cancer.
  • the compound of the present invention inhibits the action of human breast cancer cells better than natetinib, and the compounds of the embodiments of the present invention show a comparative advantage. Natini has better in vitro activity and efficacy. In certain embodiments of the invention, most preferably the tumor is breast cancer.
  • the compound of formula I, or a pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof, for use as a kinase inhibitor according to the invention, as an EGFR and/or ErbB2 inhibitor, has good clinical application and medical use .
  • a method of preparing a compound of the formula ⁇ , or a pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof comprises contacting a compound of the formula a with a compound of the formula b, In order to obtain a compound of formula I.
  • R 1 , R 2 , R 3 and R 4 are as defined above.
  • the method of preparing the compound of formula I-68 to the compound of formula I-72 is the same as the method of preparing the compound of formula I-29 of example 3.
  • Base reaction buffer 20 mM 4-hydroxyethylpiperazineethanesulfonic acid (Hepes, pH 7.5), 10 mM MgCl 2 , 1 mM ethylene glycol bis(2-aminoethyl ether) tetraacetic acid (EGTA), 0.02% twelve Alkyl polyglycol ether (Brij35), 0.02 mg/ml bovine serum albumin (BSA), 0.1 mM Na 3 VO 4 , 2 mM dithiothreitol (DTT), 1% dimethyl sulfoxide (DMSO) .
  • the kinase reaction was incubated for 120 min at room temperature;
  • the reaction was spotted onto P81 ion exchange paper (Whatman #3698-915);
  • the compound of the formula I-1 prepared according to the present invention is a compound of the formula I-72.
  • the compound of formula I-2 produced by the present invention has a activity of ⁇ 2 ⁇ M (IC 50 ) for both EGFR and ErbB2 assays, and the compound of formula I-2.
  • the compounds of formula I-72 inhibited both EGFR and ErbB2 more strongly than neratinib, and the compounds of formula I of the present invention have higher EGFR and ErbB2 kinase inhibitory activities than neratinib.
  • the compounds prepared according to the invention were tested in human tumor cell line growth assays.
  • the inventors found that the compound obtained in Preparation Example 1 according to formula I-1 inhibit the growth of several solid tumor cell lines at 10 IC 50 dose pattern 3-fold serial dilutions starting from 10 ⁇ M, the solid tumor cells
  • A431 (reported to express EGFR); NCI-H1975 (reported to express EGFR mutant L858R/T790M); NCI-H 1650 (reported to express EGFR mutant E746-A750); BT-474 (overreported) ErbB2); and SKBR3 and A549 (both EGFR and ErbB2 are reported to be overexpressed).
  • IC 50 as follows:
  • Exemplary cell line Compound of formula I-1 (IC50) A431 ⁇ 1mM NCI-H1975 ⁇ 10mM NCI-H1650 ⁇ 10mM BT-474 ⁇ 1mM SKBR3 ⁇ 1mM A549 ⁇ 1mM
  • the compound of the formula I-2 prepared by the present invention has a compound represented by the formula I-72 against solid tumor cell lines such as A431, NCI-H1975, NCI-H1650, BT-474, A549 and SKBR3 are active (IC 50)-1 I the compound of formula according to.
  • Cell lines human lung adenocarcinoma cells (A-549), human colorectal cancer cells (Colo205), human breast cancer cells (MCF-7), human leukemia cells (HL-60).
  • Reagents MTT, Amresco; DMEM, DMEM/F12 medium, Gibco; calf serum, Lanzhou Minhai; trypsin, Amresco.
  • Instrument Ultra-clean workbench, Suzhou Purification Equipment Factory; CO2 incubator, Thermo, model: HERA Cell150; Inverted microscope, Carl Zeiss, model: Axiovert 200; enzyme-linked immunosorbent assay, TECAN, model: Sunrise; centrifuge, Kerdro, model: Heraeus.
  • Cell culture cells were seeded in DMEM or DMEM/F12 complete medium containing 10% calf serum, 100 IU/ml penicillin G sodium salt and 100 ug/ml streptomycin sulfate, and placed at 37 ° C, 100% relative humidity, containing 5 In the incubator of %CO2, it was used after 3 passages.
  • MTT colorimetric assay cells in logarithmic growth phase were digested with 0.25% trypsin (the suspension cells did not need to be digested), suspended in a medium containing 10% calf serum, and gently blown with a glass dropper. Single cell suspension, microscopically counted living cells using a blood cell counting plate. 90 ⁇ l of the cell suspension was inoculated into each well of a 96-well culture plate (cell concentration: 3 to 6 ⁇ 10 4 /mL), and after incubating for 24 hours, 10 ⁇ l of the drug solution was added to each well.
  • each concentration was set to a negative control (equal concentration of DMSO) and a blank background (no cells added), and each group was provided with 6 duplicate wells.
  • the cells were further cultured for 48 hours, and then 10 ⁇ l of 5 mg/mL MTT solution was added to each well. After further incubation for 4 hours, the supernatant was carefully aspirated. 100 ⁇ l of DMSO was added to each well, and the micro-vibrator was shaken for 5 min to completely dissolve the crystal. The OD value was measured by a single-wavelength colorimetric measurement at 492 nm, and the test results are shown in Table 1.
  • Inhibition rate (%) [1 - (experiment group OD mean - blank group OD mean) / (control group OD mean - blank group OD mean)] x 100%. 50 value of the test compound is calculated IC Bliss method.
  • the compound of the formula I-1 prepared by the present invention is a compound represented by the formula I-72 against human lung adenocarcinoma cells (A-549), human colorectal cancer cells (Colo205), human breast cancer cells. (MCF-7) and human leukemia cells (HL-60) all had good inhibitory effects (IC 50 ⁇ 100 ⁇ g/ml), and the inhibition effect on human breast cancer cells (MCF-7) was the strongest.
  • the present invention can be used for the preparation of a medicament for treating anti-tumor/anti-cancer, and is particularly suitable for the preparation of a medicament for treating breast cancer.
  • the compounds of the present invention inhibit human breast cancer cells more strongly than neratinib relative to the existing anticancer drug for treating breast cancer, neratinib.
  • Example 12 Capsules for oral administration
  • the ingredients in the above table are mixed, and the active ingredient (the compound of the present invention) is dispensed in a capsule and prepared into 1000 in total.
  • the powder is filled into capsules, and the active ingredient of each capsule is 400 mg.
  • Example 13 Tablets for oral administration
  • ingredient % weight / weight Active ingredient 20.0% lactose 75.5% Croscone sodium 3.0% Polyvinylpyrrolidone 1.0% Magnesium stearate 0.5%
  • the ingredients in the above table are mixed and granulated using a solvent such as ethanol.
  • the preparation was then dried, prepared into a total of 1000 g of powder, and formed into tablets using a suitable tableting machine, and the active ingredient (the compound of the present invention) per tablet was 200 mg.
  • Example 14 Capsules for oral administration
  • ingredient % weight / weight Active ingredient 30.0% lactose 45.0% Microcrystalline cellulose 24.5% Magnesium stearate 0.5%
  • the ingredients in the above table were mixed, and the active ingredient (the compound of the present invention) was dispensed in a capsule, and a total of 1000 g of powder was prepared and filled into capsules each having an active ingredient of 300 mg.
  • the active ingredient (the compound of the invention) is dissolved in a portion of the water for injection. A sufficient amount of sodium chloride is then added with stirring to make the solution isotonic. The solution was made up to the weight with the remaining water for injection, filtered through a 0.45 micron membrane filter, and packaged under sterile conditions to give an injection.

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Abstract

La présente invention concerne un composé hétérocyclique substitué utile en tant qu'inhibiteur de kinase, un procédé de préparation correspondant et les utilisations de celui-ci. Le composé est un composé représenté par la formule I ou un sel, un hydrate ou un solvate pharmaceutiquement acceptable du composé représenté par la formule I dans laquelle, R1, R2, R3 et R4 sont tels que définis dans la description.
PCT/CN2015/070904 2014-09-29 2015-01-16 Composé hétérocyclique substitué utile en tant qu'inhibiteur de kinase, son procédé de préparation et les utilisations de celui-ci WO2016050016A1 (fr)

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CN103965120A (zh) * 2013-01-25 2014-08-06 上海医药集团股份有限公司 喹啉及喹唑啉衍生物、制备方法、中间体、组合物及应用
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