WO2012136080A1 - Benzomorpholine derivatives, preparation method and use thereof - Google Patents

Benzomorpholine derivatives, preparation method and use thereof Download PDF

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Publication number
WO2012136080A1
WO2012136080A1 PCT/CN2012/000462 CN2012000462W WO2012136080A1 WO 2012136080 A1 WO2012136080 A1 WO 2012136080A1 CN 2012000462 W CN2012000462 W CN 2012000462W WO 2012136080 A1 WO2012136080 A1 WO 2012136080A1
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group
compound
formula
substituted
unsubstituted
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PCT/CN2012/000462
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French (fr)
Chinese (zh)
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WO2012136080A8 (en
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匡荣仁
郭建辉
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上海艾力斯医药科技有限公司
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Priority to CN201280012517.1A priority Critical patent/CN103534252B/en
Publication of WO2012136080A1 publication Critical patent/WO2012136080A1/en
Publication of WO2012136080A8 publication Critical patent/WO2012136080A8/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
    • C07D495/14—Ortho-condensed systems
    • 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
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems

Definitions

  • the present invention relates to a benzomorpholine derivative and a process for the preparation thereof, a pharmaceutical composition containing the same, and their use as a phosphatidylinositol 3-kinase (PI3K) inhibitor for the preparation of a medicament and for the prevention and/or treatment of diseases application.
  • PI3K phosphatidylinositol 3-kinase
  • Phosphotidylinositol is one of a variety of phospholipids found in cell membranes and plays an important role in intracellular signal transduction. Phosphatidylinositol 3-kinase
  • PI3Ks Phosphoinositide 3-kinases
  • PI(3,4)P2 and PI(3,4,5)P3 play an important role as a second messenger in a range of cellular processes (such as cell growth, differentiation, migration, proliferation, survival) ( Carlos Garcia-Echeverria et ⁇ , Purinergic Signalling, 2009, 5 : 1 17-125 ).
  • Type I is a heterodimer consisting of a pi 10 catalytic subunit and a p85 regulatory subunit.
  • the family is further divided into types la (pi 10 ⁇ , ⁇ ⁇ ⁇ , ⁇ ⁇ ) and type lb ( ⁇ ⁇ ⁇ ) enzymes based on regulatory partners and regulatory mechanisms.
  • Type la is activated by a tyrosine kinase system and type lb is activated by a G protein coupled receptor.
  • Type II includes the PI3KC20U C2p and C2y subtypes, which are characterized by a C2 domain at the C-terminus, and PI and PI(4)P are known to be substrates for class II PI3K.
  • Class III PI3K substrates are only PI.
  • the most widely studied of the PDK subtypes is type Ia.
  • Type la is composed of the catalytic subunit of HOkDa and the regulatory subunit of 85/55 kDa. The regulatory subunit contains the SH2 domain and can be expressed by a growth factor receptor or oncogene with tyrosine kinase activity.
  • PI3K activity of the pi 10 catalytic subunit phosphorylation of its lipid substrate.
  • the la-like PI3K enzyme has a metaplastic effect directly or indirectly in various human cancers (Vivanco and Sawyers et al., Nature Reviews Cancer, 2002, 2: 489-501).
  • Other subtypes of PI3K are associated with the development of cardiovascular and immunosuppressive diseases ( Emilio Hirsch et al, Cardiovascular Research, 2009, 82: 262-271; Anne FOUGERAT et al, Clinical Science, 2009, 1 16: 791-804).
  • PI3K inhibitors have attracted much attention as anticancer agents and have become a research hotspot in the field of cancer.
  • Wortmannin Alexandre et al., Biochem. J, 1993, 296: 297-301
  • LY294002 CJ Vlahos et al., J Biol Chem, 1994, 269: 5241-5248
  • the first generation of broad-spectrum PI3K inhibitors They are less selective for PI3K subtypes and are more toxic.
  • PI3K-targeted compounds have entered clinical research, some of which are PI3K selective inhibitors, such as GDC-0941 (Class I PI3K inhibitor, Institute of Cancer Research UK), XL-147 (Class) I PI3K inhibitor, Exelixis Inc ) , and PX-866 (PI3K ⁇ , ⁇ and ⁇ isoforms inhibitor, Oncothyreon); and some are PI3K/mTOR dual inhibitors, such as ⁇ 235 and BGT226 (Novartis AG) entering clinical phase II, Entering Phase I of SF-1 126 (Semafore Pharmaceuticals Inc) and XL-765 (Exelixis Inc) (Jeffrey A. Engelman et al., NATURE REVIEWS CANCER, 2009, 9: 550-562; Zhao et al., NATURE REVIEWS Drug Discovery, 2009, 6: 627-644 ).
  • PI3K selective inhibitors such as GDC-0941 (Class I PI3K
  • the international patent application WO 2008/144463 Al discloses quinoline derivatives having the structure shown in the following formula (a), which are indicated to have inhibitory activity against PI3K, for the treatment of autoimmune diseases, inflammatory diseases, cardiovascular diseases, Neurodegenerative diseases, allergies, asthma, pancreas Inflammation, multiple organ failure, kidney disease, platelet aggregation, cancer, sperm motility, transplant rejection, graft rejection, and lung injury.
  • WO 2008/157191 A2 discloses a class of quinazoline compounds having a structure inhibiting PI3K activity, such as the following formula (b), for autoimmune diseases, platelet aggregation, cancer, sperm motility, transplantation. Rejection, graft rejection, and lung injury.
  • the international patent application WO 2009/055418 A1 discloses a structure which inhibits the activity of PI3K enzyme, such as a sulfapyridine derivative represented by the following formula (c), for the treatment of autoimmune diseases, inflammatory diseases, cardiovascular diseases, neurodegenerative diseases. Disease, allergy, asthma, pancreatitis, multiple organ failure, kidney disease, platelet aggregation, cancer, sperm motility, transplant rejection, graft rejection, and lung injury.
  • PI3K enzyme such as a sulfapyridine derivative represented by the following formula (c)
  • the international patent application WO 2009/039140 A1 describes a pyridopyrimidine derivative having the structure as a PI3K inhibitor as shown in the following formula (d), which can be used for the treatment of autoimmune diseases, inflammatory diseases, cardiovascular diseases, and neurodegenerative diseases.
  • the present invention provides a benzomorpholine compound of the following formula (I), or a pharmaceutically acceptable salt thereof,
  • R 1 is selected from the group consisting of hydrogen, halogen, acyl, amino, hydroxy, decyl, cyano, nitro, carboxy, Cr alkoxy, and substituted or unsubstituted Cr alkyl;
  • R 2 is selected from the group consisting of amino, substituted or unsubstituted ( ⁇ ( 6 alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted C 3 ⁇ a C 7 cycloalkyl group and a substituted or unsubstituted 3-7 membered heterocycloalkyl group;
  • R 3 is selected from aryl, heteroaryl or fused heteroaryl having 0 to 5, for example, 0, 1, 2, 3, 4 or 5 substituents selected from Group A groups or R 3 is - CO-R 4 , wherein R 4 is an aryl, heteroaryl or fused heteroaryl group having 0 to 5, for example, 0, 1, 2, 3, 4 or 5 substituents selected from Group A groups ; as well as
  • Group A groups are selected from the group consisting of: aryl, hydroxy, decyl, cyano, nitro, carboxy, Ci alkoxy, ( ⁇ ( 6 alkylalkyl, substituted or unsubstituted d Cs alkyl, substituted or not) Substituted C 3 -C 7 cycloalkyl, substituted or unsubstituted 3-7-membered heterocycloalkyl, -NRR', -S0 2 R, -CONRR', -NHS0 2 R and -NHCOR, wherein R and R' are each independently hydrogen, substituted or unsubstituted ( ⁇ ( 6 alkyl, substituted or unsubstituted aryl, substituted or unsubstituted Heteroaryl, substituted or unsubstituted C 3 ⁇ (: 7 cycloalkyl, or substituted or unsubstituted 3 to 7 membered heterocycloalkyl.
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising the above-mentioned compound of the formula (I) of the present invention or a pharmaceutically acceptable salt thereof, as an excipient or a diluent.
  • the present invention also provides the use of a compound of the formula (I) or a pharmaceutically acceptable salt thereof for the preparation of a medicament for inhibiting PI3K enzyme activity.
  • the present invention also provides the use of a compound of the formula (I) or a pharmaceutically acceptable salt thereof for the preparation of a medicament for treating a tumor.
  • the present invention also provides a method of treating a disease which can be alleviated or treated by inhibiting PI3K activity, comprising administering to a subject in need of such treatment a compound of the formula (I) of the present invention or a pharmaceutically acceptable compound thereof The steps of the salt.
  • the present invention also provides a process for the preparation of a compound of the formula (I), which comprises the steps of: when R 3 is an aryl group, a heteroaryl group or a fused aryl group,
  • R 1 R 2 , R 3 and R 4 are as defined above; la is halogenated R 3 , preferably chloro R 3 ; and X represents [ 3 ⁇ 4] , preferably bromine.
  • the "transition metal catalyst” is a conventional transition metal catalyst commonly used in the coupling reaction in the art, including, but not limited to, for example, bis(triphenylphosphine).
  • halogen means fluorine, chlorine, bromine or iodine.
  • alkyl means an alkyl group having 1 to 6 carbon atoms, and includes, for example, a C ⁇ alkyl group; and the like includes, but is not limited to, for example, methyl, ethyl, propyl, isopropyl, butyl Base, isobutyl, sec-butyl or tert-butyl, pentyl, hexyl, etc.; preferably decyl, ethyl, propyl, isopropyl and butyl.
  • CH ⁇ alkoxy refers to a "C -0- alkyl” group, wherein “C ⁇ Cs alkyl” is as defined above, including, for example, d ⁇ C 4 alkoxy; include, but are Not limited to, for example, methoxy, ethoxy, propoxy! ⁇ , isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, hexyloxy, etc.; preferably methoxy, ethoxy, propoxy, isopropyl Oxyl and butoxy.
  • C 3 -C 7 cycloalkyl means a cycloalkyl group having 3 to 7 carbon atoms, and includes, for example, a C 4 -C 7 cycloalkyl group, a C 5 -C 6 cycloalkyl group, and the like. And include, but are not limited to, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl; preferably cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
  • the term "3 to 7-membered heterocycloalkyl” means 1 to 4 selected from N, S and
  • the 3- to 7-membered cycloalkyl group of the hetero atom of O includes, for example, a 4-6-membered heterocycloalkyl group, a 5- to 6-membered heterocycloalkyl group, and the like, and preferably, for example, an oxiranyl group, a tetrahydrofuranyl group, a tetrahydrothiophenyl group, Tetrahydropyranyl, piperidinyl, pyrrolidinyl, morpholinyl and the like.
  • aryl refers to a carbon number of 6 ⁇ 14 aromatic hydrocarbon ring group or a fused aromatic hydrocarbon ring group, including, for example, C 6 ⁇ 1G aryl group and the like; preferably phenyl, naphthyl A phenyl group, a fluorenyl group and a phenanthryl group are more preferred.
  • heteroaryl means a 5- to 6-membered monocyclic heteroaryl group having 1 to 4 hetero atoms selected from N, S and 0, which may be partially saturated.
  • preferred heteroaryl is pyrimidinyl, furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl , thiadiazolyl, pyridyl, pyridazinyl, pyrazinyl; as partially saturated heteroaryl, including but not limited to, for example, 1,4-dihydropyridine; and more preferred are pyrimidinyl and pyridyl.
  • fused heteroaryl means 1 to 4 of a tricyclic fused heteroaryl selected from N, S and 0, which may be partially saturated.
  • the bicyclic fused heteroaryl group a benzopyrimidinyl group, a thienopyrimidinyl group, a furopyrimidinyl group, a benzothienyl group, a benzothiadiazolyl group, a benzothiazolyl group, a benzimidazolyl group, a fluorene group are preferable.
  • a benzothienopyrimidinyl group As the tricyclic fused heteroaryl group, a benzothienopyrimidinyl group, a pyrazinothienophenyl group, a pyrazinothienopyrimidinyl group, a pyrazinofuranopyrimidinyl group, a benzofuranpyrimidinyl group, and a pyridyl group are preferable.
  • RR 2 and A and R and R of the formula (I) are as defined in the definition of "substituted or unsubstituted ( ⁇ 6 alkyl", “substituted or unsubstituted aryl”," a substituted or unsubstituted heteroaryl ",” substituted or unsubstituted C 3 ⁇ (: 7 cycloalkyl "and” substituted or unsubstituted 3- to 7-membered heterocyclic group "in the term” substituted "are Refers to halogen, cyano, ammonia Substituted with a hydroxy, nitro or carboxy substituent; for example, the "substituted or unsubstituted ( ⁇ ( 6 alkyl” refers to a cyclin, cyano, amino, hydroxy, nitro or carboxy substituent a substituted or unsubstituted d ⁇ C 6 alkyl group "in one preferred compounds of the formula (I) according to the present embodiment
  • R 1 is selected from the group consisting of hydrogen, C ⁇ alkyl and C ⁇ alkoxy, more preferably decyloxy and ethoxy.
  • R 2 is selected from C! C ⁇ alkyl or halogen substituted C 6 ⁇ 1Q aryl, 5 to 6 membered heteroaryl or 5 to 6 A heterocyclic group, particularly a halogen such as a fluorine or chlorine substituted phenyl group, more preferably a 2,4-difluorophenyl group and a 2,4-dichlorophenyl group.
  • a halogen such as a fluorine or chlorine substituted phenyl group, more preferably a 2,4-difluorophenyl group and a 2,4-dichlorophenyl group.
  • R 3 is a C 6 -14 aryl group having from 0 to 4 substituents selected from the group A group, preferably phenyl, naphthyl, Mercapto or phenanthryl, more preferably phenyl; Group A substituent selected from:
  • R 3 is a heterocyclic group having 0 to 4 groups selected from the group A, and contains 1 to 4 kinds of impurities selected from N, S and 0. a 5- to 6-membered monocyclic heteroaryl group of an atom, wherein a pyrimidinyl group, a pyridyl group, a pyridazinyl group, and a pyrazinyl group are preferred, and a pyrimidinyl group and a pyridyl group are more preferred;
  • the group A group is selected from the group consisting of: a fluorene group, a hydroxyl group, Anthracenyl, cyano, nitro, carboxy, ( 6 : alkoxy, C ⁇ alkylindenyl, substituted or unsubstituted ( ⁇ ( 6 alkyl, -NRR', -NHCOR and -S0 2 R, wherein R and R' are each independently
  • R 3 is a heterocyclic group having 0 to 4 groups selected from the group A, and contains 1 to 4 kinds of impurities selected from N, S and 0.
  • Atomic 5 ⁇ 6 Preferred among them are a benzopyrimidinyl group, a thienopyrimidinyl group, a furanopyrimidinyl group, a benzothienyl group, a benzothiadiazolyl group, a benzothiazolyl group, a benzimidazolyl group, a fluorenyl group, an isoindole group.
  • the base is selected from the group consisting of: a phenol, a hydroxy group, a decyl group, a cyano group, a nitro group, a carboxy group, a aryl group, a (meth) group, a substituted or unsubstituted d-C 6 alkyl group, -NRR', NHCOR and -S0 2 R, wherein R and R' are each independently hydrogen, or a substituted or unsubstituted d-C 6 alkyl group or a C 3 -C 6 cycloalkyl group.
  • R 3 is -CO-R 4 , wherein R 4 is an aryl or a heterocyclic group having 0 to 4 substituents selected from the group A group.
  • Aryl is an aryl or a heterocyclic group having 0 to 4 substituents selected from the group A group.
  • R 4 is phenyl, naphthyl, anthracenyl, phenanthryl, pyrimidinyl, pyridyl, pyridazinyl or pyrazinyl, more preferably R 4 is phenyl and pyridyl;
  • Group A substituents are selected from:
  • R 1 is selected group the group consisting of: hydrogen, hydroxy, (: Canton ⁇ alkyl and alkoxy; and / or
  • R 2 is selected from the group consisting of d-C 6 alkyl or halogen-substituted C 6 -14 aryl, 5- to 6-membered heteroaryl or 5- to 6-membered heterocyclic;
  • R 3 is C substituted with 0-4 substituents selected from Group A group having 6 to 14 aryl group, containing ⁇ 4 heteroatoms selected from N, 5 ⁇ 6 membered S heteroatom and monocyclic heteroaryl 0 a bicyclic or tricyclic fused heteroaryl group having 5 to 6 membered monocyclic heteroaryl groups containing 1 to 4 hetero atoms selected from N, S and 0 fused to each other or fused to a benzene ring.
  • R 3 is -CO-R 4, wherein R 4 is with C 0 ⁇ 4 substituents selected from the group consisting of a 6 to 14 or an aryl group containing 1 to 4 heteroatoms selected from N, S and a 5- to 6-membered heteroaryl group of a hetero atom of 0; the substituent of the group A is selected from the group consisting of a halogen, an amino group, and a hydroxyl group.
  • R and R' are each independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl or substituted or unsubstituted C 3 -C 6 heterocycloalkyl.
  • R 3 is a C 6 ⁇ 14 aryl group having 0-3 substituents selected from group A, preferably phenyl, naphthyl, anthracenyl And a phenanthryl group; or a 5- to 6-membered monocyclic heteroaryl group having 1 to 3 hetero atoms selected from N, S, O, having 0 to 3 substituents selected from the group A, particularly containing 1 ⁇ 3 to 6-membered monocyclic heteroaryl groups of N atoms, preferably 6-membered monocyclic heteroaryl groups having 1 to 2 N atoms, preferably pyrimidinyl, pyridyl, pyridazinyl, pyrazinyl; or a 5- to 6-membered monocyclic heteroaryl group having 1 to 3 hetero atoms selected from N, S and 0, which are fused to a benzene ring, having 0 to 3 substituents selected from Group A
  • R 3 is a phenyl group having 0 to 2 substituents selected from the group consisting of halogen, d- 4 alkyl or d ⁇ 4 alkoxy.
  • R 3 is taken with 0 to 2 One selected from the group consisting of a steroid, an amino group, a hydroxy group, a decyl group, a cyano group, a nitro group, a carboxy group, ( ⁇ (: 4 alkoxy, alkanoyl, d ⁇ C 4 alkyl, -NRR', -NHCOR and -S0 2 R Substituted pyrimidinyl, pyridyl, pyridazinyl or pyrazinyl.
  • R 3 is taken from 0 to 3 selected from the group consisting of 13 ⁇ 4, amino, hydroxy, decyl, cyano, nitro, carboxy, d-C 4 alkane.
  • a benzopyrimidinyl group a thienopyrimidinyl group, a furanopyrimidinyl group, a quinolinyl group, an isoquinoline of a substituent of an oxy group, a C 4 alkyl group, a C alkyl group, a -NRR', -NHCOR and -S0 2 R a quinazolinyl group, a benzothienopyrimidinyl group, a pyrazinothienophenyl group, a pyrazinothienopyrimidinyl group or a pyrazinofuranopyrimidinyl group, wherein R and R' are each independently hydrogen, Ci ⁇ C 4 alkyl or C 3 ⁇ C 6 naphthenic.
  • R 3 is -CO-R 4 , wherein R 4 is 0 to 2 selected from halogen, d-C 4 alkoxy or ⁇ ⁇ (phenyl, pyridyl or pyrimidinyl of a 4- alkyl substituent.
  • R 4 is 0 to 2 selected from halogen, d-C 4 alkoxy or ⁇ ⁇ (phenyl, pyridyl or pyrimidinyl of a 4- alkyl substituent.
  • the compound of the present invention sometimes has geometric isomers and tautomers depending on the kind of the substituent, and the present invention includes the isolated isomers or a mixture thereof; the compound of the present invention sometimes has a chiral carbon atom, and thus is based on Optical isomers of chiral carbon atoms, and the present invention includes all possible optical isomers and mixtures thereof.
  • the invention also includes pharmaceutically acceptable salts of the compounds of formula (I).
  • pharmaceutically acceptable salt refers to an acid addition or base addition salt of a compound of formula (I) of the present invention which is relatively non-toxic.
  • the acid addition salt is a salt of a compound of formula (I) with a suitable inorganic or organic acid which may be prepared during the final isolation and purification of the compound or by the purification of the compound in its free base form. A suitable organic or inorganic acid is reacted and the formed salt is isolated to prepare.
  • Representative acid addition salts include, but are not limited to, for example, hydrobromide, hydrochloride, sulfate, sulfite, acetate, oxalate, valerate, oleate, palmitate, hard Fatty acid, laurate, borate, benzoate, lactate, phosphate, phthalate, citrate, maleate, fumarate, succinate, tartrate , Benzoate, sulfonate, p-toluenesulfonate, gluconate, lactobionate, lauryl sulfonate, and the like.
  • the base addition salt is a salt of a compound of formula (I) with a suitable inorganic or organic base, including, for example, a salt formed with an alkali metal, an alkaline earth metal, a quaternary ammonium cation, such as a sodium salt, a lithium salt, a potassium salt, a calcium salt, a magnesium salt, a tetradecyl quaternary ammonium salt, a tetraethyl quaternary ammonium salt, etc.; an amine salt, including a salt formed with ammonia (NH 3 ), a primary amine, a secondary amine or a tertiary amine, such as: a guanamine salt, Diammonium salt, trimethylamine salt, triethylamine salt, ethylamine salt, and the like.
  • a salt formed with an alkali metal, an alkaline earth metal a quaternary ammonium cation, such as a sodium salt,
  • the compound of the formula (I) of the present invention and a pharmaceutically acceptable salt thereof can be administered to a mammal such as a human, and can be administered orally, rectally, parenterally (intravenously, intramuscularly or subcutaneously), or topically (for example, In the form of powder, ointment or drops, etc.).
  • the compound of the formula (I) of the present invention and a pharmaceutically acceptable salt thereof can be formulated into a solid dosage form for oral administration, including, but not limited to, for example, a capsule, a tablet, a pill, a powder, a powder, and the like. .
  • the compound of the invention is mixed with at least one conventional inert excipient (or carrier), such as with sodium citrate or dicalcium phosphate, or with the following ingredients: (a) Fillers or compatibilizers, for example, starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders, for example, hydroxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone , sucrose and gum arabic, etc.; (c) humectants, for example, glycerol, etc.; (d) disintegrants, for example, agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain complex silicates and sodium carbonate (e) a slow solvent such as paraffin or the like; (f) an absorption accelerator such as a quaternary ammonium compound; (g) a wetting agent such as cetyl alcohol and
  • the solid dosage forms such as tablets, dragees, capsules, pills and granules can be prepared with coatings and shells such as enteric coatings and other materials known in the art. They may contain opacifying agents and the release of the active compound in such compositions may be released in a portion of the digestive tract in a delayed manner.
  • Embedding materials that can be employed include, for example, polymeric materials and waxy materials.
  • the compound of the present invention or a pharmaceutically acceptable salt thereof may also be combined with the above excipients as necessary One or more of them form a microcapsule form.
  • the compound of the formula (I) of the present invention and a pharmaceutically acceptable salt thereof can be formulated into a liquid dosage form for oral administration, including, but not limited to, for example, pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs. Wait.
  • the liquid dosage form may further comprise an inert diluent conventionally employed in the art, such as water or other solvents, solubilizers and/or emulsifiers.
  • ethanol for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butanediol, dimethylformamide or oil, especially cottonseed oil, peanut oil, corn germ oil, olive oil, alfalfa Sesame oil or sesame oil or a mixture of these substances.
  • adjuvants such as wetting agents, emulsifying and suspending agents, sweetening agents, flavoring agents and/or perfumes may be included in these dosage forms.
  • the suspension may contain a suspending agent, for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol, sorbitan ester, micro Crystal cellulose, aluminum methoxide, agar or a mixture of these substances.
  • a suspending agent for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol, sorbitan ester, micro Crystal cellulose, aluminum methoxide, agar or a mixture of these substances.
  • the compound of the formula (I) of the present invention and a pharmaceutically acceptable salt thereof may be formulated into a dosage form for parenteral injection, including, but not limited to, for example, a physiologically acceptable sterile aqueous or nonaqueous solution, dispersion, suspension.
  • a physiologically acceptable sterile aqueous or nonaqueous solution, dispersion, suspension A liquid or emulsion, and a sterile powder for reconstitution into a sterile injectable solution or dispersion.
  • Suitable aqueous and nonaqueous vehicles, diluents, solvents or vehicles include water, ethanol, polyols and suitable mixtures thereof and the like.
  • the compound of the formula (I) of the present invention and a pharmaceutically acceptable salt thereof can be formulated into a dosage form for topical administration, including an ointment, a powder, a propellant, an inhalant and the like.
  • the compound of the formula (I) of the present invention or a pharmaceutically acceptable salt thereof can be mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants which may be required if necessary.
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising 0.05 to 1000 mg, for example, 1 mg, 5 mg, 10 mg, 50 mg, 100 mg, 150 mg, 200 mg, 250 mg > 300 mg, 500 mg, 800 mg or 1000 mg, of the above compound of the formula (I) or A pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, excipient or diluent.
  • the pharmaceutical composition of the present invention can be obtained by combining the general formula (I) of the present invention by a conventional method.
  • the preparation or a pharmaceutically acceptable salt thereof is prepared by mixing with a pharmaceutically acceptable carrier, excipient or diluent.
  • the present invention also provides a method for treating a disease which can be alleviated or treated by inhibiting PI3K activity, such as a tumor, including a formula (I) of 0.05-50 mg/kg body weight/day for a patient in need of treatment.
  • the disease is a tumor.
  • the compound of the formula (I) of the present invention or a pharmaceutically acceptable salt thereof can be administered alone or in combination with other pharmaceutically acceptable therapeutic agents, particularly in combination with other antitumor drugs.
  • the therapeutic agent includes, but is not limited to, for example, an antitumor drug acting on the chemical structure of DNA such as cisplatin, an antitumor drug affecting nucleic acid synthesis such as methotrexate (MTX), 5-fluorouracil (5FU), etc., affecting nucleic acid transcription
  • Antitumor drugs such as doxorubicin, epirubicin, aclarithromycin, phosfomycin, etc., antitumor drugs acting on tubulin synthesis such as paclitaxel, vinorelbine, etc., aromatase inhibitors such as ammonia Mitt, lantron, letrozole, ruined, etc., cell signaling pathway inhibitors such as epidermal growth factor receptor inhibitor imatinib (Imatinib), gefitin
  • the ingredients used in combination may be administered simultaneously or sequentially, in the form of a single preparation or in the form of separate preparations.
  • the combination includes not only combinations of the compounds of the invention and one other active agent, but also combinations of the compounds of the invention and two or more other active agents.
  • the compound of the present invention has a cancer cell proliferation inhibiting action and can be used for the preparation of a medicament for treating cancer.
  • the pharmacological effect of the compound of the present invention for inhibiting the proliferation of cancer cells can be determined by a conventional method.
  • a preferred evaluation method is Sulforhodamine B (SRB) protein staining: SRB is a protein-binding dye and can be used with biological macromolecules. The combination of basic amino acids and its optical density (OD) reading at 510 nm has a good linear relationship with the amount of protein, so it can be used as a quantification of the number of cells by measuring the light absorption value of the drug after it acts on cancer cells. Changes in the rate of inhibition of cancer cell proliferation by drugs.
  • Inhibition rate (%) (OD control - OD inhibitor - OD blank control) / (OD
  • OD control refers to the OD value of the wells of cells that have no drug to function normally.
  • OD inhibitor refers to the OD value of a well of a cell to which a positive or a compound to be screened is added.
  • OD blank control refers to the OD value of parallel control wells that were not seeded.
  • the half inhibitor concentration (IC 5 D) value was calculated by the software GraphPad Prism 5.
  • the invention is further illustrated below in conjunction with specific embodiments. It is to be understood that the examples are not intended to limit the scope of the invention.
  • the experimental methods in the following examples which do not specify the specific conditions are usually in accordance with conventional conditions or according to the conditions recommended by the manufacturer. Parts and percentages are parts by weight and percentage by weight unless otherwise stated. detailed description
  • the compound Ie-3 (0.71 mmol) prepared in Example 3 was refluxed with 4-chloro-pyrimidine hydrochloride (Ia-5, 0.71 mmol) and triethylamine (0.71 mmol) in an appropriate amount of isopropanol.
  • the compound If-5 (0.15 mmol) was obtained in an hour.
  • the compound If-5 (0.15 mmol), 1,2-dibromoethane (0.18 mmol) and potassium hydrogencarbonate (0.18 mmol) were sequentially added to DMF (5 mL), and then reacted at 60 ° C overnight. 10 mL of water was added to the reaction mixture, and the mixture was extracted three times with dichloromethane. The organic phase was combined, washed three times with saturated brine and dried over anhydrous sodium sulfate.
  • the title compound (1)-5 (0.06 mmol, yield 40%).
  • Microcrystalline cellulose 68 g According to a conventional method, the above materials are mixed and hooked, and then filled into ordinary gelatin capsules to obtain 1000 capsules.
  • Test Example 1 Inhibition of proliferation of human prostate cancer cells (PC-3) by the compound of the present invention
  • PC-3 Human prostate cancer cells in logarithmic growth phase were seeded at a density of about 5500 cells/well in a 96-well culture plate, 180 ⁇ / hole. Three holes are provided for each concentration. The corresponding concentration of the vehicle control and the cell-free zeroing hole were set.
  • TCA cold trichloroacetic acid
  • the test results showed that the compound of the present invention has a good proliferation inhibitory effect on human prostate cancer cells (PC-3).
  • Test Example 2 Inhibition of proliferation of human breast cancer cells (MDA-MB-231) by the compounds of the present invention
  • Test Example 3 Compound of the present invention inhibits proliferation of human non-small cell lung cancer cells ( ⁇ 549)
  • the IC 5 () value of the example compound for ⁇ 549 cells was obtained by calculation with reference to Test Example 1 Experimental Method: The test results show that the compound of the present invention has a good proliferation inhibition effect on human non-small cell lung cancer cells (A549).
  • Test Example 4 Inhibition of proliferation of human ovarian cancer cells (SK-OV-3) by the compound of the present invention The measurement was carried out by referring to Test Method Example 1, and the IC 5 o of the Example compound for SK-OV-3 cells was obtained by calculation. value:
  • test results show that the compound of the present invention has a good proliferation inhibition effect on human ovarian cancer cells (SK-OV-3).
  • Test Example 5 Compound of the present invention against mutant non-small cell lung cancer cells H1975
  • test results show that the compound of the present invention has a good proliferation inhibition effect on non-small cell lung cancer cells H1975 (L858R/T790M-EGFR).
  • the applicant has made a complete and detailed description of the invention. It will be apparent to those skilled in the art that the present invention may be modified, modified or modified without departing from the spirit and scope of the invention. The scope defined by the book.

Abstract

Disclosed are benzomorpholine derivatives as represented by the following formula (I) and pharmaceutical compositions comprising the derivatives as well as methods of preparation thereof, R1, R2 and R3 are as defined in the specification. The benzomorpholine derivatives of formula (I) are an inhibitor of phosphatidylinositol 3-kinases (PI3K), and have a good inhibitory effect on PI3K and on cancer cell proliferation, thereby serving as a therapeutic agent for the treatment of tumors.

Description

苯并吗啉衍生物及其制备方法和应用 技术领域  Benzomorpholine derivative, preparation method and application thereof
本发明涉及苯并吗啉衍生物及其制备方法、 .含所述衍生物的药物 组合物以及它们作为磷脂酰肌醇 3-激酶 (PI3K)抑制剂在制备药物和预 防和 /治疗疾病方面的应用。 背景技术  The present invention relates to a benzomorpholine derivative and a process for the preparation thereof, a pharmaceutical composition containing the same, and their use as a phosphatidylinositol 3-kinase (PI3K) inhibitor for the preparation of a medicament and for the prevention and/or treatment of diseases application. Background technique
磷脂酰月几醇（ phosphotidylinositol, PI )是在细胞膜中发现的多种磷 脂中的一种， 在细胞内信号转导中起重要作用。 磷脂酰肌醇 3-激酶 Phosphotidylinositol (PI) is one of a variety of phospholipids found in cell membranes and plays an important role in intracellular signal transduction. Phosphatidylinositol 3-kinase
( Phosphoinositide 3-kinases, PI3Ks )是使磷脂酰肌醇的肌醇环的 3位 磷酸化的酶。 PI3K 催化磷脂酰肌醇形成 3,4-二磷酸磷脂酰肌醇( Phosphoinositide 3-kinases, PI3Ks) is an enzyme that phosphorylates the 3-position of the inositol ring of phosphatidylinositol. PI3K catalyzes the formation of phosphatidylinositol 3,4-diphosphate phosphatidylinositol
( phosphatidylinositol 3,4 bisphosphate, PI(3，4)P2 ) 和 3，4,5-三石舞酸石舞月旨 酰肌醇 ( phosphatidylinositol 3 ,4,5 trisphosphate, PI(3,4,5)P3 ) ， 引起蛋 白激酶 C的活化和细胞内钙动员（ M. J. Berridge et a Nature, 1984, 312: 315-320; Y. Nishizuka, Science, 1984, 225 : 1365-1370 ) 。 PI(3,4)P2和 PI(3，4，5)P3作为第二信使在一系列细胞进程 (如细胞生长、 分化、 迁移、 增生、 存活） 中发挥重要的作用 （ Carlos Garcia-Echeverria et αί , Purinergic Signalling, 2009, 5 : 1 17-125 ) 。 ( phosphatidylinositol 3,4 bisphosphate, PI(3,4)P2 ) and 3,4,5-three-stone gemstone dance phosphatidylinositol 3 (4,5 trisphosphate, PI(3,4,5)P3 ), causing activation of protein kinase C and intracellular calcium mobilization (MJ Berridge et a Nature, 1984, 312: 315-320; Y. Nishizuka, Science, 1984, 225: 1365-1370). PI(3,4)P2 and PI(3,4,5)P3 play an important role as a second messenger in a range of cellular processes (such as cell growth, differentiation, migration, proliferation, survival) ( Carlos Garcia-Echeverria et Ίί , Purinergic Signalling, 2009, 5 : 1 17-125 ).
PI3K根据生理底物特异性可分为 I、 II和 III型。 类型 I是由 pi 10 催化亚单元和 p85 调节亚单元组成的杂二聚体。 该家族以调节伙伴和 调节机理为基础进一步被分成类型 la (pi 10α, ρΐ ΐ θβ, ρΐ ΐθδ)和类型 lb (ρΐ ΐ θγ) 酶。 类型 la被酪氨酸激酶体系活化， 类型 lb被 G蛋白偶联的 受体活化。 类型 II包括 PI3KC20U C2p和 C2y亚型， 其特征为在 C末 端含有 C2结构域， 已知 PI和 PI(4)P为 II类 PI3K的底物。 III类 PI3K 底物只有 PI。 PDK亚型中研究进行得最广泛的是类型 Ia。 类型 la是由 HOkDa的催化亚单位和 85/55kDa的调节亚单位构成的。调节亚单位含 有 SH2结构域， 可由与具有酪氨酸激酶活性的生长因子受体或癌基因 产物磷酸化的酪氨酸残基结合，诱导 p i 10催化性亚单位 (使其脂类底物 磷酸化）的 PI3K活性。 已有证据表明， la类 PI3K酶直接或间接地在各 种人类癌症中有致月中瘤性 ( Vivanco and Sawyers et αί , Nature Reviews Cancer, 2002, 2: 489-501 ) 。 PI3K其它亚型与心血管和免疫抑制疾病的 发生相关 ( Emilio Hirsch et al , Cardiovascular Research, 2009, 82: 262-271； Anne FOUGERAT et al , Clinical Science, 2009， 1 16: 791-804 ) 。 PI3K can be classified into types I, II and III according to physiological substrate specificity. Type I is a heterodimer consisting of a pi 10 catalytic subunit and a p85 regulatory subunit. The family is further divided into types la (pi 10α, ρΐ θ θβ, ρΐ ΐθδ) and type lb (ρΐ ΐ θγ) enzymes based on regulatory partners and regulatory mechanisms. Type la is activated by a tyrosine kinase system and type lb is activated by a G protein coupled receptor. Type II includes the PI3KC20U C2p and C2y subtypes, which are characterized by a C2 domain at the C-terminus, and PI and PI(4)P are known to be substrates for class II PI3K. Class III PI3K substrates are only PI. The most widely studied of the PDK subtypes is type Ia. Type la is composed of the catalytic subunit of HOkDa and the regulatory subunit of 85/55 kDa. The regulatory subunit contains the SH2 domain and can be expressed by a growth factor receptor or oncogene with tyrosine kinase activity. The product phosphorylated tyrosine residue binds to induce PI3K activity of the pi 10 catalytic subunit (phosphorylation of its lipid substrate). There is evidence that the la-like PI3K enzyme has a metaplastic effect directly or indirectly in various human cancers (Vivanco and Sawyers et al., Nature Reviews Cancer, 2002, 2: 489-501). Other subtypes of PI3K are associated with the development of cardiovascular and immunosuppressive diseases ( Emilio Hirsch et al, Cardiovascular Research, 2009, 82: 262-271; Anne FOUGERAT et al, Clinical Science, 2009, 1 16: 791-804).
因此， PI3K抑制剂可用作抗癌剂而倍受关注， 并成为肿瘤领域一 大研究热点。 Wortmannin ( Alexandre et al. , Biochem. J, 1993, 296: 297-301 )和下式表示的 LY294002( C. J. Vlahos et al. , J Biol Chem, 1994, 269: 5241 -5248 )是两个已知的第一代广谱 PI3K抑制剂。 它们对 PI3K 各亚型选择性小， 且毒性大。 随后众多以 PI3K为靶点的化合物纷纷进 入临床研究， 其中一部分为 PI3K选择性抑制剂， 如进入临床 I 期的 GDC-0941 ( Class I PI3K inhibitor, Institute of Cancer Research UK ) , XL- 147 ( Class I PI3K inhibitor, Exelixis Inc ) ,和 PX-866 (PI3K α、 δ and γ isoforms inhibitor, Oncothyreon); 还有部分为 PI3K/mTOR双重抑制 剂， 如进入临床 II期的 ΒΕΖ235和 BGT226 (Novartis AG), 进入临床 I 期的 SF- 1 126 ( Semafore Pharmaceuticals Inc )和 XL-765 ( Exelixis Inc ) ( Jeffrey A. Engelman et al. , NATURE REVIEWS CANCER, 2009, 9: 550-562 ; Zhao et al. , NATURE REVIEWS Drug Discovery, 2009, 6: 627-644 ) 。 Therefore, PI3K inhibitors have attracted much attention as anticancer agents and have become a research hotspot in the field of cancer. Wortmannin (Alexandre et al., Biochem. J, 1993, 296: 297-301) and LY294002 (CJ Vlahos et al., J Biol Chem, 1994, 269: 5241-5248) represented by the following formula are two known The first generation of broad-spectrum PI3K inhibitors. They are less selective for PI3K subtypes and are more toxic. Subsequently, many PI3K-targeted compounds have entered clinical research, some of which are PI3K selective inhibitors, such as GDC-0941 (Class I PI3K inhibitor, Institute of Cancer Research UK), XL-147 (Class) I PI3K inhibitor, Exelixis Inc ) , and PX-866 (PI3K α, δ and γ isoforms inhibitor, Oncothyreon); and some are PI3K/mTOR dual inhibitors, such as ΒΕΖ235 and BGT226 (Novartis AG) entering clinical phase II, Entering Phase I of SF-1 126 (Semafore Pharmaceuticals Inc) and XL-765 (Exelixis Inc) (Jeffrey A. Engelman et al., NATURE REVIEWS CANCER, 2009, 9: 550-562; Zhao et al., NATURE REVIEWS Drug Discovery, 2009, 6: 627-644 ).
Figure imgf000004_0001
Figure imgf000004_0001
国际专利申请 WO 2008/144463 Al公开了结构如下述通式 (a)所示 的喹啉衍生物， 指出它们具有抑制 PI3K酶活性， 用于治疗自身免疫性 疾病、 炎性疾病、 心血管疾病、 神经退行性疾病、 过敏、 哮喘、 胰腺 炎、 多器官功能衰竭、 肾脏疾病、 血小板聚集、 癌症、 ***活力、 移 植排斥反应、 移植物排斥反应和肺损伤。 The international patent application WO 2008/144463 Al discloses quinoline derivatives having the structure shown in the following formula (a), which are indicated to have inhibitory activity against PI3K, for the treatment of autoimmune diseases, inflammatory diseases, cardiovascular diseases, Neurodegenerative diseases, allergies, asthma, pancreas Inflammation, multiple organ failure, kidney disease, platelet aggregation, cancer, sperm motility, transplant rejection, graft rejection, and lung injury.
Figure imgf000005_0001
Figure imgf000005_0001
国际专利申请 WO 2008/157191 A2公开了一类具有抑制 PI3K酶 活性的结构如下述通式 (b)所示的喹唑啉化合物，用于自身免疫性疾病、 血小板聚集、 癌症、 ***活力、 移植排斥反应、 移植物排斥反应和肺 损伤。  International Patent Application No. WO 2008/157191 A2 discloses a class of quinazoline compounds having a structure inhibiting PI3K activity, such as the following formula (b), for autoimmune diseases, platelet aggregation, cancer, sperm motility, transplantation. Rejection, graft rejection, and lung injury.
Figure imgf000005_0002
Figure imgf000005_0002
国际专利申请 WO 2009/055418 A1公开了抑制 PI3K酶活性的结 构如下述通式 (c)所示的磺胺吡啶衍生物， 用于治疗自身免疫性疾病、 炎性疾病、 心血管疾病、 神经退行性疾病、 过敏、 哮喘、 胰腺炎、 多 器官衰竭、 肾脏疾病、 血小板聚集、 癌症、 ***活力、 移植排斥反应、 移植物排斥反应和肺损伤。  The international patent application WO 2009/055418 A1 discloses a structure which inhibits the activity of PI3K enzyme, such as a sulfapyridine derivative represented by the following formula (c), for the treatment of autoimmune diseases, inflammatory diseases, cardiovascular diseases, neurodegenerative diseases. Disease, allergy, asthma, pancreatitis, multiple organ failure, kidney disease, platelet aggregation, cancer, sperm motility, transplant rejection, graft rejection, and lung injury.
Figure imgf000005_0003
Figure imgf000005_0003
国际专利申请 WO 2009/039140 A1描述了作为 PI3K抑制剂的结 构如下述通式 (d)所示的吡啶并嘧啶衍生物， 可用于治疗自身免疫性疾 病、 炎性疾病、 心血管疾病、 神经退行性疾病、 过敏、 哮喘、 胰腺炎、 多器官衰竭、 腎脏疾病、 血小板聚集、 癌症、 ***活力、 移植排斥反 应、 移植物排斥反应和肺损伤。
Figure imgf000006_0001
The international patent application WO 2009/039140 A1 describes a pyridopyrimidine derivative having the structure as a PI3K inhibitor as shown in the following formula (d), which can be used for the treatment of autoimmune diseases, inflammatory diseases, cardiovascular diseases, and neurodegenerative diseases. Sexual diseases, allergies, asthma, pancreatitis, multiple organ failure, kidney disease, platelet aggregation, cancer, sperm motility, transplant rejection, graft rejection, and lung injury.
Figure imgf000006_0001
(d)  (d)
因此， PI3K通路为肿瘤治疗提供了很大机遇。 对 PI3K靶点进行 小分子抑制剂研究， 将为人类抗肿瘤治疗带来新的希望。 发明内容  Therefore, the PI3K pathway provides a great opportunity for cancer therapy. The study of small molecule inhibitors on PI3K targets will bring new hopes for human anti-tumor therapy. Summary of the invention
因此， 本发明提供了下式 (I)苯并吗啉化合物， 或其药学上可接受 的盐，  Accordingly, the present invention provides a benzomorpholine compound of the following formula (I), or a pharmaceutically acceptable salt thereof,
Figure imgf000006_0002
Figure imgf000006_0002
R1选自下列一组基团： 氢、 鹵素、 酰基、 氨基、 羟基、 巯基、 氰 基、 硝基、 羧基、 Cr^ 烷氧基以及取代或未取代的 Cr^ 烷基； R 1 is selected from the group consisting of hydrogen, halogen, acyl, amino, hydroxy, decyl, cyano, nitro, carboxy, Cr alkoxy, and substituted or unsubstituted Cr alkyl;
R2选自下列一组基团： 氨基、 取代或未取代的（^~( 6烷基、 取代 或未取代的芳基、 取代或未取代的杂芳基、 取代或未取代的 C3〜C7环 烷基以及取代或未取代的 3~7元杂环烷基； R 2 is selected from the group consisting of amino, substituted or unsubstituted (^~( 6 alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted C 3 〜 a C 7 cycloalkyl group and a substituted or unsubstituted 3-7 membered heterocycloalkyl group;
R3选自带有 0~5个例如 0、 1、 2、 3、 4或 5个选自 A组基团的取 代基的芳基、 杂芳基或稠合杂芳基或者 R3为 -CO-R4, 其中 R4为带有 0〜5个例如 0、 1、 2、 3、 4或 5个选自 A组基团的取代基的芳基、 杂 芳基或稠合杂芳基； 以及 R 3 is selected from aryl, heteroaryl or fused heteroaryl having 0 to 5, for example, 0, 1, 2, 3, 4 or 5 substituents selected from Group A groups or R 3 is - CO-R 4 , wherein R 4 is an aryl, heteroaryl or fused heteroaryl group having 0 to 5, for example, 0, 1, 2, 3, 4 or 5 substituents selected from Group A groups ; as well as
A组基团选自下列一组： 素、 羟基、 巯基、 氰基、 硝基、 羧基、 Ci 烷氧基、 （^~( 6烷巯基、 取代或未取代的 d Cs烷基、 取代或未 取代的 C3~C7环烷基、取代或未取代的 3~7元杂环烷基、 -NRR'、 -S02R、 -CONRR'、 -NHS02R以及 -NHCOR, 其中的 R和 R'分别独立地为氢、 取代或未取代的 （^〜( 6烷基、 取代或未取代的芳基、 取代或未取代的 杂芳基、 取代或未取代的 C3〜(： 7环烷基、 或者取代或未取代的 3〜7元 杂环烷基。 Group A groups are selected from the group consisting of: aryl, hydroxy, decyl, cyano, nitro, carboxy, Ci alkoxy, (^~( 6 alkylalkyl, substituted or unsubstituted d Cs alkyl, substituted or not) Substituted C 3 -C 7 cycloalkyl, substituted or unsubstituted 3-7-membered heterocycloalkyl, -NRR', -S0 2 R, -CONRR', -NHS0 2 R and -NHCOR, wherein R and R' are each independently hydrogen, substituted or unsubstituted (^~( 6 alkyl, substituted or unsubstituted aryl, substituted or unsubstituted Heteroaryl, substituted or unsubstituted C 3 ～(: 7 cycloalkyl, or substituted or unsubstituted 3 to 7 membered heterocycloalkyl.
本发明还提供药物组合物， 它含有上述本发明通式 (I)化合物或其 药学上可接受的盐， 以 赋形剂或稀释剂。  The present invention also provides a pharmaceutical composition comprising the above-mentioned compound of the formula (I) of the present invention or a pharmaceutically acceptable salt thereof, as an excipient or a diluent.
本发明还提供通式 (I)化合物或其药学上可接受的盐在制备抑制 PI3K酶活性的药物方面的应用。  The present invention also provides the use of a compound of the formula (I) or a pharmaceutically acceptable salt thereof for the preparation of a medicament for inhibiting PI3K enzyme activity.
本发明还提供通式 (I)化合物或其药学上可接受的盐在制备用于治 疗肿瘤的药物方面的应用。  The present invention also provides the use of a compound of the formula (I) or a pharmaceutically acceptable salt thereof for the preparation of a medicament for treating a tumor.
本发明还提供一种疾病的治疗方法，所述疾病可通过抑制 PI3K活 性而得以减轻或治疗， 包括给需要此治疗的个体施用所述本发明通式 (I) 化合物或其药学上可接受的盐的步骤。  The present invention also provides a method of treating a disease which can be alleviated or treated by inhibiting PI3K activity, comprising administering to a subject in need of such treatment a compound of the formula (I) of the present invention or a pharmaceutically acceptable compound thereof The steps of the salt.
本发明还提供通式 (I)化合物的制备方法， 所述方法包括下列步骤： 当 R3为芳基、 杂芳基或稠合芳基时， The present invention also provides a process for the preparation of a compound of the formula (I), which comprises the steps of: when R 3 is an aryl group, a heteroaryl group or a fused aryl group,
方法一： method one:
Figure imgf000007_0001
Figure imgf000007_0001
以 2-氨基 -4-溴苯酚为起始原料，与式 la化合物发生亲核取代反应， 得到式 lb化合物， 式 lb化合物与 1，2-二溴乙烷发生闭环反应， 得到式 Ic化合物， 在常规过渡金属催化剂存在的奈件下， 式 Ic化合物与联硼 酸频那醇酯发生偶联反应，生成式 Id化合物，式 Id化合物与 A45-X-2-R1 吡啶 -3-基] -R2-磺酰胺在常规过渡金属催化剂催化下发生偶联反应， 得 到通式 (I)化合物； 或者 Starting from 2-amino-4-bromophenol as a starting material, a nucleophilic substitution reaction with a compound of the formula la gives a compound of the formula lb, and a compound of the formula lb is subjected to ring closure reaction with 1,2-dibromoethane to obtain a compound of the formula Ic. In the presence of a conventional transition metal catalyst, a compound of formula Ic is coupled with a boronic acid pinacol ester to form a compound of formula Id, a compound of formula Id and A45-X-2-R 1 pyridin-3-yl]- The coupling reaction of R 2 -sulfonamide under the catalysis of a conventional transition metal catalyst gives To a compound of formula (I); or
方法二： Method Two:
Figure imgf000008_0001
Figure imgf000008_0001
(I)  (I)
以 2-氨基 -4-溴苯酚为起始原料， 在常规过渡金属催化剂存在下与 联硼酸频那醇酯发生偶联反应，得到 3-氨基 -4-羟基苯基硼酸频那醇酯， 然后使其在常规过渡金属催化剂存在的条件下与 A45-X-2-R1吡啶 -3- 基] -R2-磺酰胺发生偶联反应， 得到化合物 le, 化合物 le与 la化合物发 生亲核取代反应， 得到式 If化合物， 式 If化合物与 1，2-二溴乙烷发生 闭环反应， 得到通式 (I)化合物； Using 2-amino-4-bromophenol as a starting material, coupling reaction with pinacol borate in the presence of a conventional transition metal catalyst to obtain 3-amino-4-hydroxyphenylboronic acid pinacol ester, and then The coupling reaction with A45-X-2-R 1 pyridin-3-yl]-R 2 -sulfonamide is carried out in the presence of a conventional transition metal catalyst to obtain a compound le, and the compound le and the la compound are nucleophilic substituted. The reaction is carried out to obtain a compound of the formula If, the compound of the formula If is subjected to ring closure reaction with 1,2-dibromoethane to obtain a compound of the formula (I);
当 R3为 -CO-R4时， When R 3 is -CO-R 4 ,
Figure imgf000008_0002
Figure imgf000008_0002
以 6-溴 -3,4-二氢 苯并 [b][l，4]嚅嗪为起始原料， 在常规过渡金 属催化剂存在下与联硼酸频那醇酯发生偶联反应， 得到化合物 Ig， 在 常规过渡金属催化剂存在的条件下， 化合物 Ig与 N-C5-X-2-R1吡啶 -3- 基] -R2-磺酰胺发生偶联反应， 得到化合物 Ih， 化合物 Ih 与酰卤 ( X-CO-R4 )发生酰化反应， 得到式 Ii化合物， 式 Ii化合物在碱性条 件下反应， 得到通式 (I)化合物； Starting from 6-bromo-3,4-dihydrobenzo[b][l,4]oxazine, coupling reaction with pinacol borate in the presence of a conventional transition metal catalyst gives compound Ig , in the presence of a conventional transition metal catalyst, compound Ig with N-C5-X-2- R 1 -3 Coupling reaction of -R 2 -sulfonamide to obtain compound Ih, compound Ih is acylated with acid halide (X-CO-R 4 ) to obtain a compound of formula Ii, and the compound of formula Ii is reacted under basic conditions. Obtaining a compound of the formula (I);
上述反应流程中， R1 R2、 R3和 R4如前文所定义； la为卤代的 R3， 优 选是氯代的 R3; 以及 X代表 [¾素， 优选溴。 In the above reaction scheme, R 1 R 2 , R 3 and R 4 are as defined above; la is halogenated R 3 , preferably chloro R 3 ; and X represents [ 3⁄4] , preferably bromine.
在所述本发明通式 (I)化合物的制备方法中， 所述 "过渡金属催化 剂" 为本领域偶联反应常用的常规过渡金属催化剂， 包括， 但不限于， 例如双 (三苯基磷)二氯化钯、 四 (三苯基磷)钯、 1,1'-二 (二苯基膦)二茂铁 二氯化巴、 醋酸巴等； 所述 "碱性" 条件可以通过向反应体系中加入 常用的无机或有机碱来形成， 所述常用的无机或有机碱包括， 但不限 于， 例如氢氧化钠、 氢氧化钾、 碳酸钾、 碳酸钠、 醋酸钾、 吡啶、 三 乙胺等。 在本发明中， 术语"卤素"是指氟、 氯、 溴或碘。  In the preparation method of the compound of the general formula (I) of the present invention, the "transition metal catalyst" is a conventional transition metal catalyst commonly used in the coupling reaction in the art, including, but not limited to, for example, bis(triphenylphosphine). Palladium dichloride, tetrakis(triphenylphosphine)palladium, 1,1'-bis(diphenylphosphino)ferrocene dichloride, barium acetate, etc.; the "alkaline" condition can be passed to the reaction system It is formed by adding a usual inorganic or organic base including, but not limited to, sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, potassium acetate, pyridine, triethylamine and the like. In the present invention, the term "halogen" means fluorine, chlorine, bromine or iodine.
在本发明中 , 术语" 烷基"是指含有 1至 6个碳原子的烷基， 包括例如 C ^ 烷基等； 包括但不限于例如甲基、 乙基、 丙基、 异丙 基、 丁基、 异丁基、 仲丁基或叔丁基、 戊基、 己基等； 优选曱基、 乙 基、 丙基、 异丙基和丁基。  In the present invention, the term "alkyl" means an alkyl group having 1 to 6 carbon atoms, and includes, for example, a C^ alkyl group; and the like includes, but is not limited to, for example, methyl, ethyl, propyl, isopropyl, butyl Base, isobutyl, sec-butyl or tert-butyl, pentyl, hexyl, etc.; preferably decyl, ethyl, propyl, isopropyl and butyl.
在本发明中， 术语" CH^烷氧基 "是指 "C 烷基 -0-"基团， 其中 "C^Cs烷基"如上定义， 包括例如 d~C4烷氧基等； 包括但不限于例如 甲氧基、 乙氧基、 丙氧！^、 异丙氧基、 丁氧基、 异丁氧基、 仲丁氧基、 叔丁氧基、 戊氧基、 己氧基等； 优选甲氧基、 乙氧基、 丙氧基、 异丙 氧基和丁氧基。 In the present invention, the term "CH ^ alkoxy" refers to a "C -0- alkyl" group, wherein "C ^ Cs alkyl" is as defined above, including, for example, d ~ C 4 alkoxy; include, but are Not limited to, for example, methoxy, ethoxy, propoxy! ^, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, hexyloxy, etc.; preferably methoxy, ethoxy, propoxy, isopropyl Oxyl and butoxy.
在本发明中， 术语" C3~C7环烷基 "是指含有 3~7 个碳原子的环烷 基， 包括例如 C4~C7环烷基、 C5~C6环烷基等， 包括但不限于例如环丙 基、 环丁基、 环戊基、 环己基、 环庚基和环辛基； 优选环丙基、 环丁 基、 环戊基和环己基。 In the present invention, the term "C 3 -C 7 cycloalkyl" means a cycloalkyl group having 3 to 7 carbon atoms, and includes, for example, a C 4 -C 7 cycloalkyl group, a C 5 -C 6 cycloalkyl group, and the like. And include, but are not limited to, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl; preferably cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
在本发明中， 术语" 3〜7元杂环烷基"是指含有 1~4个选自 N、 S和 O的杂原子的 3~7元环烷基， 包括例如 4~6元杂环烷基、 5~6元杂环烷 基等， 优选例如环氧乙烷基， 四氢呋喃基， 四氢噻吩基， 四氢吡喃基， 哌啶基， 吡咯烷基， 吗啉基等。 In the present invention, the term "3 to 7-membered heterocycloalkyl" means 1 to 4 selected from N, S and The 3- to 7-membered cycloalkyl group of the hetero atom of O includes, for example, a 4-6-membered heterocycloalkyl group, a 5- to 6-membered heterocycloalkyl group, and the like, and preferably, for example, an oxiranyl group, a tetrahydrofuranyl group, a tetrahydrothiophenyl group, Tetrahydropyranyl, piperidinyl, pyrrolidinyl, morpholinyl and the like.
在本发明中， 术语"芳基"是指碳原子数为 6〜14个的芳香族烃环基 或芳香族稠合烃环基， 包括例如 C6~1G芳基等； 优选苯基、 萘基、 蒽基 和菲基， 更优选苯基。 In the present invention, the term "aryl" refers to a carbon number of 6~14 aromatic hydrocarbon ring group or a fused aromatic hydrocarbon ring group, including, for example, C 6 ~ 1G aryl group and the like; preferably phenyl, naphthyl A phenyl group, a fluorenyl group and a phenanthryl group are more preferred.
在本发明中， 术语"杂芳基 "是指含有 1~4个选自 N、 S和 0的杂 原子的 5〜6元单环杂芳基， 它可以是部分饱和的。 这里， 优选的杂芳 基是嘧啶基、 呋喃基、 噻吩基、 吡咯基、 咪唑基、 吡唑基、 噻唑基、 异噻唑基、 嚅唑基、 异喝唑基、 ***基、 四唑基、 噻二唑基、 吡啶基、 哒嗪基、 吡嗪基； 作为部分饱和的杂芳基， 包括但不限于例如 1，4-二氢 吡啶等； 其中更优选的是嘧啶基和吡啶基。  In the present invention, the term "heteroaryl" means a 5- to 6-membered monocyclic heteroaryl group having 1 to 4 hetero atoms selected from N, S and 0, which may be partially saturated. Here, preferred heteroaryl is pyrimidinyl, furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl , thiadiazolyl, pyridyl, pyridazinyl, pyrazinyl; as partially saturated heteroaryl, including but not limited to, for example, 1,4-dihydropyridine; and more preferred are pyrimidinyl and pyridyl.
在本发明中， 术语"稠合杂芳基"是指含有 1〜4个选自 N、 S和 0 三环式稠合杂芳基， 它可以是部分饱和的。 这里， 作为双环式稠合杂 芳基， 优选苯并嘧啶基、 噻吩并嘧啶基、 呋喃并嘧啶基、 苯并噻吩基、 苯并噻二唑基、 苯并噻唑基、 苯并咪唑基、 吲哚基、 异吲哚基、 吲唑 基、 喹啉基、 异喹啉基、 喹唑啉基； 特别优选苯并嘧啶基、 噻吩并嘧 啶基。 作为部分饱和的双环式稠合杂芳基， 包括但不限于例如 1,2,3,4- 四氢喹啉基等。 作为三环式稠合杂芳基， 优选苯并噻吩并嘧啶基、 吡 嗪并噻吩并苯基、 吡嗪并噻吩并嘧啶基、 吡嗪并呋喃并嘧啶基、 苯并 呋喃并嘧啶基、 吡嗪并呋喃并苯基、 苯并噻吩并吡啶基、 吡嗪并噻吩 并吡啶基、 苯并呋喃并吡啶基、 吡嗪并呋喃并吡啶基， 特别优选吡嗪 并噻吩并嘧啶基。  In the present invention, the term "fused heteroaryl" means 1 to 4 of a tricyclic fused heteroaryl selected from N, S and 0, which may be partially saturated. Here, as the bicyclic fused heteroaryl group, a benzopyrimidinyl group, a thienopyrimidinyl group, a furopyrimidinyl group, a benzothienyl group, a benzothiadiazolyl group, a benzothiazolyl group, a benzimidazolyl group, a fluorene group are preferable. Mercapto, isodecyl, oxazolyl, quinolyl, isoquinolyl, quinazolinyl; benzopyrimidinyl, thienopyrimidinyl is particularly preferred. As the partially saturated bicyclic fused heteroaryl group, including but not limited to, for example, 1,2,3,4-tetrahydroquinolinyl and the like. As the tricyclic fused heteroaryl group, a benzothienopyrimidinyl group, a pyrazinothienophenyl group, a pyrazinothienopyrimidinyl group, a pyrazinofuranopyrimidinyl group, a benzofuranpyrimidinyl group, and a pyridyl group are preferable. Pyrazinofuranophenyl, benzothienopyridinyl, pyrazinothienopyridinyl, benzofuropyridinyl, pyrazinofuranopyridyl, and particularly preferably pyrazinothienopyrimidinyl.
在本发明中， 通式 (I)的 R R2和 A 以及 R和 R， 定义中所述 "取 代或未取代的 （^~< 6烷基" 、 "取代或未取代的芳基" 、 "取代或未 取代的杂芳基" 、 "取代或未取代的 C3〜(： 7环烷基" 以及 "取代或未 取代的 3~7元杂环烷基" 中的术语 "取代的" 均指被卤素、 氰基、 氨 基、 羟基、 硝基或羧基取代基取代的； 例如， 所述 "取代或未取代的 (^~( 6烷基" 是指 "被 素、 氰基、 氨基、 羟基、 硝基或羧基取代基取 代的或未取代的 d~C6烷基" 。 在本发明通式 (I)化合物的一个优选的实施方案中， R1选自下列一 组基团： 氢、 1¾素、 羟基、 烷基和 C广 C6烷氧基。 In the present invention, RR 2 and A and R and R of the formula (I) are as defined in the definition of "substituted or unsubstituted (^~< 6 alkyl", "substituted or unsubstituted aryl"," a substituted or unsubstituted heteroaryl "," substituted or unsubstituted C 3 ~ (: 7 cycloalkyl "and" substituted or unsubstituted 3- to 7-membered heterocyclic group "in the term" substituted "are Refers to halogen, cyano, ammonia Substituted with a hydroxy, nitro or carboxy substituent; for example, the "substituted or unsubstituted (^~( 6 alkyl" refers to a cyclin, cyano, amino, hydroxy, nitro or carboxy substituent a substituted or unsubstituted d ~ C 6 alkyl group "in one preferred compounds of the formula (I) according to the present embodiment of the invention, R 1 is a group selected from the group consisting of: hydrogen, 1¾, hydroxy, alkyl And C-C 6 alkoxy groups.
在本发明通式 (I)化合物的一个优选的实施方案中， R1选自氢、 C^ 烷基和 C^ 烷氧基， 更优选曱氧基和乙氧基。 In a preferred embodiment of the compound of the formula (I) according to the invention, R 1 is selected from the group consisting of hydrogen, C^alkyl and C^alkoxy, more preferably decyloxy and ethoxy.
在本发明通式 (I)化合物的一个优选的实施方案中， R2选自 C! C^ 烷基或者卤素取代的 C6~1Q芳基、 5~6元杂芳基或 5~6元杂环基， 特别 是卤素例如氟或氯取代的苯基，更优选 2,4-二氟代苯基和 2,4-二氯代苯 基。 In a preferred embodiment of the compound of the formula (I) according to the invention, R 2 is selected from C! C^ alkyl or halogen substituted C 6 ~ 1Q aryl, 5 to 6 membered heteroaryl or 5 to 6 A heterocyclic group, particularly a halogen such as a fluorine or chlorine substituted phenyl group, more preferably a 2,4-difluorophenyl group and a 2,4-dichlorophenyl group.
在本发明通式 (I)化合物的一个优选的实施方案中， R3为带有 0~4 个选自 A组基团的取代基的 C6~14芳基，优选苯基、萘基、蒽基或菲基， 更优选苯基； A组取代基选自： |¾素、 氨基、 羟基、 巯基、 氰基、 硝 基、 羧基、 （^~( 6烷氧基、 d~C6烷巯基以及取代或未取代的（：广( 6烷 基。 In a preferred embodiment of the compound of the formula (I) according to the invention, R 3 is a C 6 -14 aryl group having from 0 to 4 substituents selected from the group A group, preferably phenyl, naphthyl, Mercapto or phenanthryl, more preferably phenyl; Group A substituent selected from: |3⁄4, amino, hydroxy, decyl, cyano, nitro, carboxy, (^~( 6 alkoxy, d~C 6 alkane) Mercapto and substituted or unsubstituted (: broad ( 6 alkyl).
在本发明通式 (I)化合物的一个优选的实施方案中， R3为带有 0~4 个选自 A组基团的取代基的含有 1〜4个选自 N、S和 0的杂原子的 5~6 元单环杂芳基， 其中优选嘧啶基、 吡啶基、 哒嗪基和吡嗪基， 更优选 的是嘧啶基和吡啶基； A组基团选自： 1¾素、 羟基、 巯基、 氰基、 硝 基、 羧基、 （：广( 6烷氧基、 C ^烷巯基、 取代或未取代的（^~( 6烷基、 -NRR'、 -NHCOR和 -S02R, 其中的 R和 R'分别独立地为氢、 取代或未 取代的 CrC6烷基、 取代或未取代的 C3-C7环烷基， 取代或未取代的 C3-C7杂环烷基。 In a preferred embodiment of the compound of the formula (I) of the present invention, R 3 is a heterocyclic group having 0 to 4 groups selected from the group A, and contains 1 to 4 kinds of impurities selected from N, S and 0. a 5- to 6-membered monocyclic heteroaryl group of an atom, wherein a pyrimidinyl group, a pyridyl group, a pyridazinyl group, and a pyrazinyl group are preferred, and a pyrimidinyl group and a pyridyl group are more preferred; the group A group is selected from the group consisting of: a fluorene group, a hydroxyl group, Anthracenyl, cyano, nitro, carboxy, ( 6 : alkoxy, C^alkylindenyl, substituted or unsubstituted (^~( 6 alkyl, -NRR', -NHCOR and -S0 2 R, wherein R and R' are each independently hydrogen, substituted or unsubstituted C r C 6 alkyl, substituted or unsubstituted C 3 -C 7 cycloalkyl, substituted or unsubstituted C 3 -C 7 heterocycloalkane base.
在本发明通式 (I)化合物的一个优选的实施方案中， R3为带有 0~4 个选自 A组基团的取代基的含有 1~4个选自 N、S和 0的杂原子的 5~6 基， 其中优选的是苯并嘧啶基、 噻吩并嘧啶基、 呋喃并嘧啶基、 苯并 噻吩基、 苯并噻二唑基、 苯并噻唑基、 苯并咪唑基、 吲哚基、 异吲哚 基、 吲唑基、 喹啉基、 异喹啉基、 喹唑啉基、 苯并噻 p分并嘧啶基、 吡 嗪并噻吩并苯基、 吡嗪并噻吩并嘧啶基、 吡嗪并呋喃并嘧啶基、 苯并 呋喃并嘧啶基、 吡秦并呋喃并苯基、 苯并噻 ρ分并吡啶基、 吡。秦并 ρ塞吩 并吡啶基、 苯并呋喃并吡啶基和吡嗪并呋喃并吡啶基， 其中更优选的 是苯并嘧啶基、 噻吩并嘧啶基和吡嗪并噻吩并嘧啶基； Α 组取代基选 自 ： 素、 羟基、 巯基、 氰基、 硝基、 羧基、 （ 广^烷氧基、 （^〜(^烷 巯基、 取代或未取代的 d~C6烷基、 -NRR'、 -NHCOR和 -S02R, 其中 R和 R'分别独立地为氢、或者取代或未取代的 d~C6烷基或 C3~C6环烷 基。 In a preferred embodiment of the compound of the formula (I) of the present invention, R 3 is a heterocyclic group having 0 to 4 groups selected from the group A, and contains 1 to 4 kinds of impurities selected from N, S and 0. Atomic 5~6 Preferred among them are a benzopyrimidinyl group, a thienopyrimidinyl group, a furanopyrimidinyl group, a benzothienyl group, a benzothiadiazolyl group, a benzothiazolyl group, a benzimidazolyl group, a fluorenyl group, an isoindole group. , carbazolyl, quinolyl, isoquinolinyl, quinazolinyl, benzothiazep- p -pyrimidinyl, pyrazino-thienophenyl, pyrazinothienopyrimidinyl, pyrazinofuran pyrimidinyl, benzofuranyl and pyrimidyl, pyrazolyl and Qin furo phenyl, benzothiazol ρ min and pyridyl, pyrazolyl. And p- pyridinopyridyl, benzofuropyridinyl and pyrazinofuranopyridyl, of which benzopyrimidinyl, thienopyrimidinyl and pyrazinothienopyrimidinyl are more preferred; The base is selected from the group consisting of: a phenol, a hydroxy group, a decyl group, a cyano group, a nitro group, a carboxy group, a aryl group, a (meth) group, a substituted or unsubstituted d-C 6 alkyl group, -NRR', NHCOR and -S0 2 R, wherein R and R' are each independently hydrogen, or a substituted or unsubstituted d-C 6 alkyl group or a C 3 -C 6 cycloalkyl group.
在本发明通式 (I)化合物的一个优选的实施方案中， R3为 -CO-R4， 其中 R4为带有 0〜4个选自 A组基团的取代基的芳基或杂芳基。 优选 R4为苯基、 萘基、 蒽基、 菲基、 嘧啶基、 吡啶基、 哒嗪基或吡嗪基， 更优选 R4为苯基和吡啶基； A组取代基选自： |¾素、 氨基、 羟基、 巯 基、 氰基、 硝基、 羧基、 （^~( 6烷氧基、 d-C6烷巯基以及取代或未取 代的 d~C6烷基。 In a preferred embodiment of the compound of the formula (I) according to the invention, R 3 is -CO-R 4 , wherein R 4 is an aryl or a heterocyclic group having 0 to 4 substituents selected from the group A group. Aryl. Preferably, R 4 is phenyl, naphthyl, anthracenyl, phenanthryl, pyrimidinyl, pyridyl, pyridazinyl or pyrazinyl, more preferably R 4 is phenyl and pyridyl; Group A substituents are selected from: |3⁄4 , amino, hydroxy, decyl, cyano, nitro, carboxy, (^~( 6 alkoxy, dC 6 alkyl) and substituted or unsubstituted d~C 6 alkyl.
在本发明通式 (I)化合物的另一优选实施方案中：  In another preferred embodiment of the compound of formula (I) according to the invention:
R1选自下列一组基团： 氢、 素、 羟基、 （：广^烷基和 烷 氧基； 和 /或 R 1 is selected group the group consisting of: hydrogen, hydroxy, (: Canton ^ alkyl and alkoxy; and / or
R2选自 d~C6烷基或者卤素取代的 C6~14芳基、 5〜6元杂芳基或 5~6 元杂环基； 和 /或 R 2 is selected from the group consisting of d-C 6 alkyl or halogen-substituted C 6 -14 aryl, 5- to 6-membered heteroaryl or 5- to 6-membered heterocyclic;
R3为带有 0~4个选自 A组基团的取代基的 C6~14芳基、 含有 1〜4 个选自 N、S和 0的杂原子的 5〜6元单环杂芳基或者含有 1~4个选自 N、 S和 0的杂原子的 5〜6元单环杂芳基相互稠合或与苯环稠合而成的双 环式或三环式稠合杂芳基， 或者 R3为 -CO-R4, 其中的 R4为带有 0〜4 个选自 A组基团的取代基的 C6~14芳基或含有 1~4个选自 N、 S和 0的 杂原子的 5~6元杂芳基； 所述的 A组取代基选自卤素、 氨基、 羟基、 巯基、 氰基、 硝基、 羧基、 < 广( 6烷氧基、 （^〜( 6烷巯基、 取代或未取 代的（^~( 6烷基、 -NRR'、 -NHCOR和 -S02R， 其中的 R和 R'分别独立 地为氢、 取代或未取代的 烷基、 取代或未取代的 C3-C6环烷基或 者取代或未取代的 C3-C6杂环烷基。 R 3 is C substituted with 0-4 substituents selected from Group A group having 6 to 14 aryl group, containing ~ 4 heteroatoms selected from N, 5~6 membered S heteroatom and monocyclic heteroaryl 0 a bicyclic or tricyclic fused heteroaryl group having 5 to 6 membered monocyclic heteroaryl groups containing 1 to 4 hetero atoms selected from N, S and 0 fused to each other or fused to a benzene ring. or R 3 is -CO-R 4, wherein R 4 is with C 0~4 substituents selected from the group consisting of a 6 to 14 or an aryl group containing 1 to 4 heteroatoms selected from N, S and a 5- to 6-membered heteroaryl group of a hetero atom of 0; the substituent of the group A is selected from the group consisting of a halogen, an amino group, and a hydroxyl group. Anthracenyl, cyano, nitro, carboxy, < ubi ( 6 alkoxy, (^~( 6 alkyl fluorenyl), substituted or unsubstituted (^~( 6 alkyl, -NRR', -NHCOR and -S0 2 R Wherein R and R' are each independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl or substituted or unsubstituted C 3 -C 6 heterocycloalkyl.
在本发明通式 (I)化合物的一个优选的实施方案中， R3为带有 0-3 个选自 A组的取代基的 C6~14芳基， 优选苯基、 萘基、 蒽基和菲基； 或 者为带有 0~3个选自 A组的取代基的含有 1〜3个选自 N、 S、 O的杂原 子 5~6元单环杂芳基、特别是含有 1~3个 N原子的 5〜6元单环杂芳基、 优选含有 1~2个 N原子的 6元单环杂芳基， 优选嘧啶基、 吡啶基、 哒 嗪基、 吡嗪基； 或者为带有 0〜3个选自 A组的取代基的含有 1~3个选 自 N、 S和 0的杂原子的 5~6元单环杂芳基相互稠合或与苯环稠合而 成的双环式或三环式稠合杂芳基， 其中所述双环式稠合杂芳基优选苯 并嘧啶基、 噻吩并嘧啶基、 呋喃并嘧啶基、 苯并噻 p分基、 苯并噻二唑 基、 苯并噻唑基、 苯并咪唑基、 吲哚基、 异吲哚基、 吲唑基、 喹啉基、 异喹啉基和喹唑啉基， 其中所述三环式稠合杂芳基优选苯并噻吩并嘧 啶基、 吡嗪并噻吩并苯基、 吡嗪并噻吩并嘧啶基、 吡嗪并呋喃并嘧啶 基、 苯并呋喃并嘧啶基、 吡嗪并呋喃并苯基、 苯并噻吩并吡啶基、 吡 嗪并噻吩并吡啶基、 苯并呋喃并吡啶基和吡嗪并呋喃并吡啶基； 或者 R3为 -CO-R4， 其中的 R4为带有 0〜3个选自 A组基团的取代基的 C6~10 芳基， 优选苯基和萘基； 或者为带有 0~3个选自 A组基团的取代基的 含有 1~3个 N原子的 5~6元单环杂芳基， 优选嘧啶基、 吡啶基、 哒嗪 基和吡嗪基； 其中所述的 A组取代基选自 素、 氨基、 羟基、 巯基、 氰基、 硝基、 羧基、 d~C4烷氧基、 （ 广^烷巯基、 d 烷基、 -NRR'、 -NHCOR和 -S02R,其中的 R和 R'分别独立地为氢、 d~C4烷基、 C3~C6 环烷基或 3~6元杂环烷基。 In a preferred embodiment of the compound of the formula (I) according to the invention, R 3 is a C 6 ~ 14 aryl group having 0-3 substituents selected from group A, preferably phenyl, naphthyl, anthracenyl And a phenanthryl group; or a 5- to 6-membered monocyclic heteroaryl group having 1 to 3 hetero atoms selected from N, S, O, having 0 to 3 substituents selected from the group A, particularly containing 1~ 3 to 6-membered monocyclic heteroaryl groups of N atoms, preferably 6-membered monocyclic heteroaryl groups having 1 to 2 N atoms, preferably pyrimidinyl, pyridyl, pyridazinyl, pyrazinyl; or a 5- to 6-membered monocyclic heteroaryl group having 1 to 3 hetero atoms selected from N, S and 0, which are fused to a benzene ring, having 0 to 3 substituents selected from Group A a bicyclic or tricyclic fused heteroaryl group, wherein the bicyclic fused heteroaryl group is preferably a benzopyrimidinyl group, a thienopyrimidinyl group, a furopyrimidinyl group, a benzothiazyl p group, a benzothiadiazole a benzothiazolyl, benzimidazolyl, fluorenyl, isodecyl, oxazolyl, quinolyl, isoquinolyl and quinazolinyl, wherein the tricyclic fused heteroaryl Preferred is benzothienopyrimidinyl, pyrazinothiazide And phenyl, pyrazinothienopyrimidinyl, pyrazinofuranopyrimidinyl, benzofuranpyrimidinyl, pyrazinofuranophenyl, benzothienopyridyl, pyrazinothienopyridinyl, Benzofuropyridinyl and pyrazinofuranopyridyl; or R 3 is -CO-R 4 , wherein R 4 is C 6 to 10 having 0 to 3 substituents selected from Group A groups An aryl group, preferably a phenyl group and a naphthyl group; or a 5- to 6-membered monocyclic heteroaryl group having 1 to 3 N atoms, having 0 to 3 substituents selected from the group A group, preferably a pyrimidinyl group, Pyridyl, pyridazinyl and pyrazinyl; wherein the group A substituent is selected from the group consisting of a steroid, an amino group, a hydroxyl group, a thiol group, a cyano group, a nitro group, a carboxyl group, a d-C 4 alkoxy group, , d alkyl, -NRR', -NHCOR and -S0 2 R, wherein R and R' are each independently hydrogen, d-C 4 alkyl, C 3 -C 6 cycloalkyl or 3-6-membered Cycloalkyl.
在本发明通式 (I)化合物的一个优选的实施方案中， R3为带有 0〜2 个选自卣素、 d〜4烷基或 d〜4烷氧基的取代基的苯基。 In a preferred embodiment of the compound of the formula (I) according to the invention, R 3 is a phenyl group having 0 to 2 substituents selected from the group consisting of halogen, d- 4 alkyl or d~ 4 alkoxy.
在本发明通式 (I)化合物的一个优选的实施方案中， R3为带有 0~2 个选自 素、 氨基、 羟基、 巯基、 氰基、 硝基、 羧基、 （^〜(：4烷氧基、 烷巯基、 d~C4烷基、 -NRR'、 -NHCOR和 -S02R的取代基的嘧啶 基、 吡啶基、 哒嗪基或吡嗪基。 In a preferred embodiment of the compound of the formula (I) according to the invention, R 3 is taken with 0 to 2 One selected from the group consisting of a steroid, an amino group, a hydroxy group, a decyl group, a cyano group, a nitro group, a carboxy group, (^~(: 4 alkoxy, alkanoyl, d~C 4 alkyl, -NRR', -NHCOR and -S0 2 R Substituted pyrimidinyl, pyridyl, pyridazinyl or pyrazinyl.
在本发明通式 (I)化合物的一个优选的实施方案中， R3为带有 0~3 个选自 1¾素、 氨基、 羟基、 巯基、 氰基、 硝基、 羧基、 d~C4烷氧基、 ~C4烷巯基、 C 烷基、 -NRR'、 -NHCOR和 -S02R的取代基的苯并 嘧啶基、 噻吩并嘧啶基、 呋喃并嘧啶基、 喹啉基、 异喹啉基、 喹唑啉 基、 苯并噻吩并嘧啶基、 吡嗪并噻吩并苯基、 吡嗪并噻吩并嘧啶基或 吡嗪并呋喃并嘧啶基，其中 R和 R'分別独立地为氢、 Ci~C4烷基或 C3~C6 环烷。 In a preferred embodiment of the compound of the formula (I) according to the invention, R 3 is taken from 0 to 3 selected from the group consisting of 13⁄4, amino, hydroxy, decyl, cyano, nitro, carboxy, d-C 4 alkane. a benzopyrimidinyl group, a thienopyrimidinyl group, a furanopyrimidinyl group, a quinolinyl group, an isoquinoline of a substituent of an oxy group, a C 4 alkyl group, a C alkyl group, a -NRR', -NHCOR and -S0 2 R a quinazolinyl group, a benzothienopyrimidinyl group, a pyrazinothienophenyl group, a pyrazinothienopyrimidinyl group or a pyrazinofuranopyrimidinyl group, wherein R and R' are each independently hydrogen, Ci ~C 4 alkyl or C 3 ~C 6 naphthenic.
在本发明通式 (I)化合物的一个优选的实施方案中， R3为 -CO-R4 , 其中的 R4为带有 0〜2个选自卤素、 d~C4烷氧基或 <^~( 4烷基的取代 基的苯基、 吡啶基或嘧啶基。 学上可接受的盐： In a preferred embodiment of the compound of the formula (I) according to the invention, R 3 is -CO-R 4 , wherein R 4 is 0 to 2 selected from halogen, d-C 4 alkoxy or < ^~(phenyl, pyridyl or pyrimidinyl of a 4- alkyl substituent. Acceptable salts:
2，4-二氟 -iV- {2-曱氧基 -5-[4- (吡嗪并 [3 ',2':4,5]噻吩并 [3，2-d]嘧啶 -4- 基) -3,4-二氢 -2 /-1 ,4-苯并 [b][l ,4] 嗪 -6-基]吡啶 -3-基}苯磺酰胺；  2,4-difluoro-iV- {2-decyloxy-5-[4-(pyrazino[3 ',2':4,5]thieno[3,2-d]pyrimidin-4-yl -3,4-dihydro-2 /-1 ,4-benzo[b][l ,4]oxazin-6-yl]pyridin-3-yl}benzenesulfonamide;
2,4-二氟 - {2-甲氧基 -5-[4-(噻吩并 [3，2-d]嘧啶 -4-基 )-3,4-二氢 -2 -1，4-苯并 [b][l ,4]嘌嗪 -6-基]吡啶 -3-基}苯磺酰胺；  2,4-Difluoro-{2-methoxy-5-[4-(thieno[3,2-d]pyrimidin-4-yl)-3,4-dihydro-2-1,4-benzene And [b][l,4]oxazin-6-yl]pyridin-3-yl}benzenesulfonamide;
2，4-二氟 {2-甲氧基 -5-[4-(6-硝基喹唑啉 -4-基) -3，4-二氢 -Zf - 1 ,4- 苯并 [b][l ,4]嚅嗪 -6-基]吡啶 -3-基}苯磺酰胺；  2,4-difluoro{2-methoxy-5-[4-(6-nitroquinazolin-4-yl)-3,4-dihydro-Zf-1,4-benzo[b] [l , 4 ] pyridazin-6-yl]pyridin-3-yl}benzenesulfonamide;
2,4-二氟 - - {2-甲氧基 -5-[4-(6-乙酰胺基喹唑啉 -4-基） -3，4-二氢 -2f ,4-苯并 [b][l，4]嚅嗪 -6-基]吡啶 -3-基}苯磺酰胺；  2,4-Difluoro-{2-methoxy-5-[4-(6-acetamidoquinazolin-4-yl)-3,4-dihydro-2f,4-benzo[b ] [l,4]pyridazine-6-yl]pyridin-3-yl}benzenesulfonamide;
2,4-二氟 -N- {2-甲氧基 -5-[4-(嘧啶 -4-基 )-3,4-二氢 -2H-\ ,4-苯并 [b][l ,4]p恶嗪 -6-基]吡啶 -3-基}苯磺酰胺；  2,4-Difluoro-N-{2-methoxy-5-[4-(pyrimidin-4-yl)-3,4-dihydro-2H-\,4-benzo[b][l, 4] poxazin-6-yl]pyridin-3-yl}benzenesulfonamide;
2,4-二氟 - ^- {2-曱氧基 -5-[4-(2-氨基嘧啶 -4-基) -3,4-二氢 -2f -l，4-苯 并 [b][l ,4]^嗪 -6-基]吡啶 -3-基}苯磺酰胺；  2,4-Difluoro-^- {2-decyloxy-5-[4-(2-aminopyrimidin-4-yl)-3,4-dihydro-2f-1,4-benzo[b] [l , 4 ] oxazino-6-yl]pyridin-3-yl}benzenesulfonamide;
2,4-二氟 -7V- {2-甲氧基 -5-[4_(6- (甲磺酰基）噻吩并 [3,2-d]嘧啶 -4- 基) -3，4-二氢 -2^-l，4-苯并 [b][l ,4]p恶嗪 -6-基]吡啶 -3-基}苯磺酰胺； 2,4-Difluoro-7V- {2-methoxy-5-[ 4 _(6-(methylsulfonyl)thieno[3,2-d]pyrimidine-4- -3,4-dihydro-2^-l,4-benzo[b][l,4]poxazin-6-yl]pyridin-3-yl}benzenesulfonamide;
2,4-二氟 - V- {2-甲氧基 -5-[4-(2-环丙曱酰胺基嘧啶 -4-基) -3,4-二氢 -2 -1 ,4-苯并 [b][l ,4 恶咯 -6-基]吡啶 -3-基}苯磺酰胺；  2,4-Difluoro-V-{2-methoxy-5-[4-(2-cyclopropionamidopyrimidin-4-yl)-3,4-dihydro-2 -1 ,4-benzene And [b][l,4oxo-6-yl]pyridin-3-yl}benzenesulfonamide;
2,4-二氟 -N- {2-曱氧基 -5-[4-(2-乙酰胺基嘧啶 -4-基 )-3,4-二氢 -2f ，4-苯并 [b][l，4]嚅嗪 -6-基]吡啶 -3-基}苯磺酰胺；  2,4-Difluoro-N- {2-decyloxy-5-[4-(2-acetamidopyrimidin-4-yl)-3,4-dihydro-2f,4-benzo[b] [l,4]oxazin-6-yl]pyridin-3-yl}benzenesulfonamide;
2,4-二氟 -N- {2-曱氧基 -5-[4-(烟酰基 )-3,4-二氢 -21/- 1 ,4-苯并 [b][l，4]哺嗪 -6-基]吡啶 -3-基}苯磺酰胺；  2,4-Difluoro-N- {2-decyloxy-5-[4-(nicotinoyl)-3,4-dihydro-21/- 1 ,4-benzo[b][l,4] Carbazin-6-yl]pyridin-3-yl}benzenesulfonamide;
2，4-二氟 -N-{2-曱氧基 -5-[4-(6-异丙氧基烟酰基) -3,4-二氢 - F/-1，4- 苯并 [b][l，4] ^嗪 -6-基]吡啶 -3-基}苯磺酰胺；  2,4-Difluoro-N-{2-decyloxy-5-[4-(6-isopropoxynicotinoyl)-3,4-dihydro-F/-1,4-benzo[b ][l,4]oxazin-6-yl]pyridin-3-yl}benzenesulfonamide;
2,4-二氟善 1-甲氧基 -5-[4-(2-异丙氧基异烟酰基）-3，4-二氢 2,4-difluoro-n-methoxy-5-[4-(2-isopropoxyisoisonicoyl)-3,4-dihydro
-2 -1，4-苯并 [b][l，4]嚅嗪 -6-基]吡啶 -3-基}苯磺酰胺； -2 -1,4-benzo[b][l,4]oxazin-6-yl]pyridin-3-yl}benzenesulfonamide;
2,4-二氟 - - {2-曱氧基 -5-[4-(2-氨基 -6-曱基嘧啶 -4-基) -3,4-二氢 - ί -1，4-苯并 [1?][1 ,4 恶。秦 -6-基]吡啶 -3-基}苯磺酰胺； 和  2,4-Difluoro-{2-decyloxy-5-[4-(2-amino-6-mercaptopyrimidin-4-yl)-3,4-dihydro- ί-1,4-benzene And [1?][1,4 evil. Qin-6-yl]pyridin-3-yl}benzenesulfonamide;
2,4-二氟 -Ν- {2-甲氧基 -5-[4-(吡啶 -4-基 )-3,4-二氢 -2Η- 1，4-苯并 [b][l ,4]哺嗪 -6-基]吡啶 -3-基}苯磺酰胺。  2,4-Difluoro-indole-{2-methoxy-5-[4-(pyridin-4-yl)-3,4-dihydro-2Η-1,4-benzo[b][l, 4] oxazin-6-yl]pyridin-3-yl}benzenesulfonamide.
本发明化合物根据取代基的种类， 有时存在几何异构体和互变异 构体， 本发明包括经分离的这些异构体或它们的混合物； 本发明化合 物有时存在手性碳原子， 因此存在基于手性碳原子的光学异构体， 本 发明包括所有可能的光学异构体及其混合物。  The compound of the present invention sometimes has geometric isomers and tautomers depending on the kind of the substituent, and the present invention includes the isolated isomers or a mixture thereof; the compound of the present invention sometimes has a chiral carbon atom, and thus is based on Optical isomers of chiral carbon atoms, and the present invention includes all possible optical isomers and mixtures thereof.
本发明还包括通式 (I)化合物在药学上可接受的盐。术语"药学上可 接受的盐"是指相对无毒的本发明通式 (I)化合物的酸加成盐或碱加成 盐。 所述酸加成盐为式 (I)化合物与合适的无机酸或者有机酸形成的盐， 这些盐可在化合物最后的分离和提纯过程中制备， 或者是使纯化的化 合物以其游离碱形式与适宜的有机酸或无机酸进行反应， 再将形成的 盐分离来制备。 代表性酸加成盐包括， 但不限于， 例如氢溴酸盐、 盐 酸盐、 硫酸盐、 亚硫酸盐、 乙酸盐、 草酸盐、 戊酸盐、 油酸盐、 棕榈 酸盐、 硬脂酸盐、 月桂酸盐、 硼酸盐、 苯甲酸盐、 乳酸盐、 磷酸盐、 曱苯曱酸盐、 柠檬酸盐、 马来酸盐、 富马酸盐、 琥珀酸盐、 酒石酸盐、 苯曱酸盐、 曱磺酸盐、 对曱苯磺酸盐、 葡萄糖酸盐、 乳糖酸盐和月桂 基磺酸盐等。 The invention also includes pharmaceutically acceptable salts of the compounds of formula (I). The term "pharmaceutically acceptable salt" refers to an acid addition or base addition salt of a compound of formula (I) of the present invention which is relatively non-toxic. The acid addition salt is a salt of a compound of formula (I) with a suitable inorganic or organic acid which may be prepared during the final isolation and purification of the compound or by the purification of the compound in its free base form. A suitable organic or inorganic acid is reacted and the formed salt is isolated to prepare. Representative acid addition salts include, but are not limited to, for example, hydrobromide, hydrochloride, sulfate, sulfite, acetate, oxalate, valerate, oleate, palmitate, hard Fatty acid, laurate, borate, benzoate, lactate, phosphate, phthalate, citrate, maleate, fumarate, succinate, tartrate , Benzoate, sulfonate, p-toluenesulfonate, gluconate, lactobionate, lauryl sulfonate, and the like.
所述碱加成盐为式（I)化合物与合适的无机碱或者有机碱形成的 盐， 包括例如与碱金属、 碱土金属、 季铵阳离子形成的盐, 如钠盐、 锂盐、 钾盐、 钙盐、 镁盐、 四曱基季铵盐、 四乙基季铵盐等； 胺盐， 包括与氨 (NH3)、 伯胺、 仲胺或叔胺形成的盐， 如： 曱胺盐、 二曱胺盐、 三甲胺盐、 三乙胺盐、 乙胺盐等。 The base addition salt is a salt of a compound of formula (I) with a suitable inorganic or organic base, including, for example, a salt formed with an alkali metal, an alkaline earth metal, a quaternary ammonium cation, such as a sodium salt, a lithium salt, a potassium salt, a calcium salt, a magnesium salt, a tetradecyl quaternary ammonium salt, a tetraethyl quaternary ammonium salt, etc.; an amine salt, including a salt formed with ammonia (NH 3 ), a primary amine, a secondary amine or a tertiary amine, such as: a guanamine salt, Diammonium salt, trimethylamine salt, triethylamine salt, ethylamine salt, and the like.
本发明通式 (I)化合物及其药学上可接受的盐可给药于哺乳动物例 如人， 可以采用口服、 直肠、 肠胃外 （静脉内、 肌肉内或皮下）给药、 局部给药 （例如以粉剂、 软膏剂或滴剂等剂型） 等方式。  The compound of the formula (I) of the present invention and a pharmaceutically acceptable salt thereof can be administered to a mammal such as a human, and can be administered orally, rectally, parenterally (intravenously, intramuscularly or subcutaneously), or topically (for example, In the form of powder, ointment or drops, etc.).
本发明通式 (I)化合物及其药学上可接受的盐可以配制为用于口服 给药的固体剂型， 包括， 但不限于， 例如胶嚢剂、 片剂、 丸剂、 散剂 和颗杜剂等。 在这些固体剂型中， 本发明化合物或其药学上可接受的 盐与至少一种常规惰性赋形剂（或载体)混合，如与柠檬酸钠或磷酸二钙 混合， 或与下述成分混合： （a) 填料或增容剂， 例如， 淀粉、 乳糖、 蔗 糖、 葡萄糖、 甘露醇和硅酸等； （b)粘合剂， 例如， 羟曱基纤维素、 藻 酸盐、 明胶、 聚乙烯基吡咯烷酮、 蔗糖和***胶等； （c)保湿剂， 例 如， 甘油等； （d)崩解剂， 例如， 琼脂、 碳酸钙、 马铃薯淀粉或木薯淀 粉、 藻酸、 某些复合硅酸盐和碳酸钠等； （e)緩溶剂， 例如石蜡等； （f) 吸收加速剂， 例如， 季铵化合物等； （g)润湿剂， 例如鲸蜡醇和单硬脂 酸甘油酯等； （h)吸附剂， 例如， 高岭土等； 和 /或 (i)润滑剂， 例如， 滑 石、 硬脂酸钙、 硬脂酸镁、 固体聚乙二醇、 十二烷基硫酸钠， 或其混 合物等。 在胶嚢剂、 片剂和丸剂中， 也可包含緩沖剂。  The compound of the formula (I) of the present invention and a pharmaceutically acceptable salt thereof can be formulated into a solid dosage form for oral administration, including, but not limited to, for example, a capsule, a tablet, a pill, a powder, a powder, and the like. . In these solid dosage forms, the compound of the invention, or a pharmaceutically acceptable salt thereof, is mixed with at least one conventional inert excipient (or carrier), such as with sodium citrate or dicalcium phosphate, or with the following ingredients: (a) Fillers or compatibilizers, for example, starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders, for example, hydroxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone , sucrose and gum arabic, etc.; (c) humectants, for example, glycerol, etc.; (d) disintegrants, for example, agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain complex silicates and sodium carbonate (e) a slow solvent such as paraffin or the like; (f) an absorption accelerator such as a quaternary ammonium compound; (g) a wetting agent such as cetyl alcohol and glyceryl monostearate; (h) an adsorbent For example, kaolin, etc.; and/or (i) a lubricant, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, or a mixture thereof. Buffering agents may also be included in capsules, tablets and pills.
所述固体剂型如片剂、 糖丸、 胶嚢剂、 丸剂和颗粒剂可采用包衣 和壳材， 如肠衣和其它本领域公知的材料来制备。 它们可包含不透明 剂， 并且， 这种组合物中活性化合物的释放可以延迟的方式在消化道 内的某一部分中释放。 可采用的包埋材料包括例如聚合物质和蜡类物 质。 必要时， 本发明化合物或其药学上可接受的盐也可与上述赋形剂 中的一种或多种形成微胶嚢形式。 The solid dosage forms such as tablets, dragees, capsules, pills and granules can be prepared with coatings and shells such as enteric coatings and other materials known in the art. They may contain opacifying agents and the release of the active compound in such compositions may be released in a portion of the digestive tract in a delayed manner. Embedding materials that can be employed include, for example, polymeric materials and waxy materials. The compound of the present invention or a pharmaceutically acceptable salt thereof may also be combined with the above excipients as necessary One or more of them form a microcapsule form.
本发明通式 (I)化合物及其药学上可接受的盐可以配制为用于口服 给药的液体剂型， 包括， 但不限于， 例如药学上可接受的乳液、 溶液、 悬浮液、 糖浆和酊剂等。 除了作为活性化合物的本发明通式 (I)化合物 或其药学上可接受的盐外， 液体剂型还可包含本领域中常规采用的惰 性稀释剂， 如水或其它溶剂， 增溶剂和 /或乳化剂， 例如， 乙醇、 异丙 醇、碳酸乙酯、 乙酸乙酯、 丙二醇、 1，3 -丁二醇、二甲基曱酰胺或者油， 特别是棉籽油、 花生油、 玉米胚油、 橄榄油、 蓖麻油或芝麻油或这些 物质的混合物等。  The compound of the formula (I) of the present invention and a pharmaceutically acceptable salt thereof can be formulated into a liquid dosage form for oral administration, including, but not limited to, for example, pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs. Wait. In addition to the compound of the formula (I) of the present invention as an active compound or a pharmaceutically acceptable salt thereof, the liquid dosage form may further comprise an inert diluent conventionally employed in the art, such as water or other solvents, solubilizers and/or emulsifiers. , for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butanediol, dimethylformamide or oil, especially cottonseed oil, peanut oil, corn germ oil, olive oil, alfalfa Sesame oil or sesame oil or a mixture of these substances.
除了这些惰性稀释剂外， 这些剂型中也可包含助剂， 如润湿剂、 乳化剂和悬浮剂、 甜味剂、 矫味剂和 /或香料等。  Besides these inert diluents, adjuvants such as wetting agents, emulsifying and suspending agents, sweetening agents, flavoring agents and/or perfumes may be included in these dosage forms.
除了本发明通式 (I)化合物或其药学上可接受的盐外， 悬浮液可包 含悬浮剂， 例如， 乙氧基化异十八烷醇、 聚氧乙烯山梨醇、 脱水山梨 醇酯、 微晶纤维素、 甲醇铝、 琼脂或这些物质的混合物等。  In addition to the compound of the formula (I) of the present invention or a pharmaceutically acceptable salt thereof, the suspension may contain a suspending agent, for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol, sorbitan ester, micro Crystal cellulose, aluminum methoxide, agar or a mixture of these substances.
本发明通式 (I)化合物及其药学上可接受的盐可以配制为用于肠胃 外注射的剂型， 包括， 但不限于， 例如生理上可接受的无菌含水或无 水溶液、 分散液、 悬浮液或乳液， 和用于重新溶解成无菌的可注射溶 液或分散液的无菌粉末等。 适宜的含水和非水载体、 稀释剂.、 溶剂或 赋形剂包括水、 乙醇、 多元醇及其适宜的混合物等。  The compound of the formula (I) of the present invention and a pharmaceutically acceptable salt thereof may be formulated into a dosage form for parenteral injection, including, but not limited to, for example, a physiologically acceptable sterile aqueous or nonaqueous solution, dispersion, suspension. A liquid or emulsion, and a sterile powder for reconstitution into a sterile injectable solution or dispersion. Suitable aqueous and nonaqueous vehicles, diluents, solvents or vehicles include water, ethanol, polyols and suitable mixtures thereof and the like.
本发明通式 (I)化合物及其药学上可接受的盐可以配制为用于局部 给药的剂型， 包括软膏剂、 散剂、 喷射剂和吸入剂等。 本发明通式 (I) 化合物或其药学上可接受的盐可以在无菌条件下与生理上可接受的载 体及任何防腐剂、 緩冲剂， 或必要时可能需要的推进剂等一起混合。  The compound of the formula (I) of the present invention and a pharmaceutically acceptable salt thereof can be formulated into a dosage form for topical administration, including an ointment, a powder, a propellant, an inhalant and the like. The compound of the formula (I) of the present invention or a pharmaceutically acceptable salt thereof can be mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants which may be required if necessary.
本发明还提供了药物组合物，它含有 0.05-1000 mg例如 lmg、5mg、 10mg、 50mg、 100mg、 150mg、 200mg、 250mg> 300mg、 500mg、 800mg 或 lOOOmg等含量的上述通式 (I)化合物或其药学上可接受的盐，以及药 学上可接受的载体、 赋形剂或稀释剂。  The present invention also provides a pharmaceutical composition comprising 0.05 to 1000 mg, for example, 1 mg, 5 mg, 10 mg, 50 mg, 100 mg, 150 mg, 200 mg, 250 mg > 300 mg, 500 mg, 800 mg or 1000 mg, of the above compound of the formula (I) or A pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, excipient or diluent.
本发明药物组合物可以采用常规方法， 通过将本发明通式 (I)化合 物或其药学上可接受的盐与药学上可接受的载体、 赋形剂或稀释剂混 合来制备。 The pharmaceutical composition of the present invention can be obtained by combining the general formula (I) of the present invention by a conventional method. The preparation or a pharmaceutically acceptable salt thereof is prepared by mixing with a pharmaceutically acceptable carrier, excipient or diluent.
本发明还提供了一种治疗疾病的方法， 所述疾病可通过抑制 PI3K 活性而得以减轻或治疗， 如肿瘤， 包括给需要治疗的病人使用 0.05-50 mg/kg体重 /天的式 (I)化合物或其药学上可接受的盐的步骤。 在优选的 实施方案中， 所述的疾病是肿瘤。  The present invention also provides a method for treating a disease which can be alleviated or treated by inhibiting PI3K activity, such as a tumor, including a formula (I) of 0.05-50 mg/kg body weight/day for a patient in need of treatment. A step of a compound or a pharmaceutically acceptable salt thereof. In a preferred embodiment, the disease is a tumor.
本发明通式 (I)化合物或其药学上可接受的盐可以单独给药， 或者 与其他药学上可接受的治疗剂联合给药， 特别是与其他抗肿瘤药物组 合使用。 所述治疗剂包括但不限于例如： 作用于 DNA化学结构的抗肿 瘤药如顺铂， 影响核酸合成的抗肿瘤药物如曱氨蝶呤 (MTX)、 5-氟尿嘧 啶 (5FU)等， 影响核酸转录的抗肿瘤药物如阿霉素、 表阿霉素、 阿克拉 霉素、 光辉霉素等， 作用于微管蛋白合成的抗肿瘤药物如紫杉醇、 长 春瑞滨等， 芳香化酶抑制剂如氨鲁米特、 兰特隆、 来曲唑、 瑞宁德等， 细胞信号通路抑制剂如表皮生长因子受体抑制剂伊马替尼 (Imatinib)、 吉非替尼 (Gefitinib)、 埃罗替尼 (Erlotinib)等。 所述组合使用的各成分可 同时或顺序地给予， 以单一制剂形式或以分开的制剂的形式给予。 所 述组合不仅包括本发明化合物和一种其它活性剂的组合， 而且也包括 本发明化合物和两种或更多种其它活性剂的组合。  The compound of the formula (I) of the present invention or a pharmaceutically acceptable salt thereof can be administered alone or in combination with other pharmaceutically acceptable therapeutic agents, particularly in combination with other antitumor drugs. The therapeutic agent includes, but is not limited to, for example, an antitumor drug acting on the chemical structure of DNA such as cisplatin, an antitumor drug affecting nucleic acid synthesis such as methotrexate (MTX), 5-fluorouracil (5FU), etc., affecting nucleic acid transcription Antitumor drugs such as doxorubicin, epirubicin, aclarithromycin, phosfomycin, etc., antitumor drugs acting on tubulin synthesis such as paclitaxel, vinorelbine, etc., aromatase inhibitors such as ammonia Mitt, lantron, letrozole, ruined, etc., cell signaling pathway inhibitors such as epidermal growth factor receptor inhibitor imatinib (Imatinib), gefitinib (Gefitinib), erlotinib (Erlotinib) )Wait. The ingredients used in combination may be administered simultaneously or sequentially, in the form of a single preparation or in the form of separate preparations. The combination includes not only combinations of the compounds of the invention and one other active agent, but also combinations of the compounds of the invention and two or more other active agents.
实验证明， 本发明化合物具有癌细胞增殖抑制作用， 可用于制备 治疗癌症的药物。  Experiments have shown that the compound of the present invention has a cancer cell proliferation inhibiting action and can be used for the preparation of a medicament for treating cancer.
本发明化合物抑制癌细胞增殖的药效可用常规方法测定， 一种优 选的评价方法为磺酰罗丹明 B(Sulforhodamine B， SRB)蛋白染色法： SRB 是一种蛋白结合染料， 可与生物大分子中的碱性氨基酸结合， 其 在 510 nm的光密度 (OD)读数与蛋白量呈良好的线性关系， 故可用作细 胞数的定量， 通过测定药物作用于癌细胞后所产生的光吸收值的变化 来计算药物对癌细胞增殖的抑制率。  The pharmacological effect of the compound of the present invention for inhibiting the proliferation of cancer cells can be determined by a conventional method. A preferred evaluation method is Sulforhodamine B (SRB) protein staining: SRB is a protein-binding dye and can be used with biological macromolecules. The combination of basic amino acids and its optical density (OD) reading at 510 nm has a good linear relationship with the amount of protein, so it can be used as a quantification of the number of cells by measuring the light absorption value of the drug after it acts on cancer cells. Changes in the rate of inhibition of cancer cell proliferation by drugs.
抑制率 (％)=(OD对照 -OD抑制剂- OD空白对照 )/(OD  Inhibition rate (%) = (OD control - OD inhibitor - OD blank control) / (OD
对照 -OD空白对照） χ 100%  Control - OD blank control) χ 100%
OD对照： 指没有药物作用正常生长的细胞的孔的 OD值。 OD抑制剂： 指加入阳性或者待筛选化合物作用的细胞的孔的 OD值。 OD空白对照： 指没有接种细胞的平行对照孔的 OD值。 OD control: refers to the OD value of the wells of cells that have no drug to function normally. OD inhibitor: refers to the OD value of a well of a cell to which a positive or a compound to be screened is added. OD blank control: Refers to the OD value of parallel control wells that were not seeded.
半数抑制剂浓度 (IC5D)值通过软件 GraphPad Prism 5计算得到。 下面结合具体实施例， 进一步阐述本发明。 应理解， 这些实施例 仅用于举例说明本发明而不用于限制本发明的范围。 下列实施例中未 注明具体条件的实验方法， 通常按照常规条件， 或按照制造厂商所建 议的条件。 除非另外说明， 否则份数和百分比为重量份和重量百分比。 具体实施方式 The half inhibitor concentration (IC 5 D) value was calculated by the software GraphPad Prism 5. The invention is further illustrated below in conjunction with specific embodiments. It is to be understood that the examples are not intended to limit the scope of the invention. The experimental methods in the following examples which do not specify the specific conditions are usually in accordance with conventional conditions or according to the conditions recommended by the manufacturer. Parts and percentages are parts by weight and percentage by weight unless otherwise stated. detailed description
I. 本发明化合物制备实施例  I. Preparation Examples of Compounds of the Invention
实施例 1 : 2,4-二氟 -Λ 2-甲氧基 -5-Γ4- (吡嗪并「3 '，2':4,51噻吩并「3,2-dl 嘧啶 -4-基) -3,4-二氢 -2 -1,4-苯并「bl ,4 恶嗪 -6-基 1吡啶 -3-基} 苯磺酰胺的合成  Example 1: 2,4-Difluoro-indole 2-methoxy-5-indole 4- (pyrazino "3 ', 2': 4, 51 thieno" 3,2-dl pyrimidin-4-yl) Synthesis of -3,4-dihydro-2-1,4-benzo-"bl,4oxazin-6-yl-pyridin-3-yl}benzenesulfonamide
Figure imgf000019_0001
Figure imgf000019_0001
将 3-氨基噻吩 [2，3-b]吡嗪 -2-曱酸曱酯（ 20 mmol )在适量曱酰胺中 回流过夜， 得到中间体 A ( 15 mmol ) 。 将此中间体 A ( 15 mmol )在 15mL三氯氧磷中回流 3小时,得到化合物 Ia-1 ( 10 mmol)。 使 2-氨基 -4-溴苯酚（5 mmol) 与化合物 Ia-1 (5 mmol)在适量异丙醇中回流 2 小时， 得到化合物 Ib-1 ( 4.4 mmol ) 。 将 Ib-1 ( 4.4 mmol ) 、 1,2-二溴 乙烷（ 8.8 mmol)和碳酸钾（ 9.0 mmol )在 DMF中于 60°C搅拌 5小时， 得到化合物 Ic-1 (3.1 mmol) 。 将化合物 Ic-1 (3.1 mmol) 、 联硼酸频 那醇酯（ 3.4 mmol )、 [Ι,Γ-双 (二苯基膦基)二茂铁]二氯化钯（ 0.3 mmol ) 和醋酸钾（ 6.2 mmol )加入到 20 mL 1,4-二氧六环中， 回流过夜， 得到 Id-1 (3.1 mmol) 。 将化合物 Id-1 ( 1.5 mmol) 、 Λ45-溴 -2-曱氧基吡啶 -3-基] -2，4-二氟苯磺酰胺（ 1.6 mmol )、双 (三苯基膦)二氯化钯（ 0.2 mmol ) 和 2M碳酸钾水溶液（0.3mL)依次加入到 15 mL 1，4-二氧六环中， 于 100。C反应过夜。 将所得混合物减压浓缩， 加入 10mL水， 用二氯曱烷 反复萃取 3次， 合并有机相， 用饱和食盐水洗 3次并以无水硫酸钠干 燥后经硅胶柱层析分离 （甲醇 /二氯曱烷： 0〜50%) , 得到黄色固体状 标题化合物 (1)-1 (0.79 mmol, 收率为 52%) 。 3-Aminothiophene [2,3-b]pyrazine-2-furic acid decyl ester (20 mmol) was refluxed in an appropriate amount of phthalamide overnight to afford Intermediate A (15 mmol). This intermediate A ( 15 mmol ) at 15 mL of phosphorus oxychloride was refluxed for 3 hours to give Compound Ia-1 (10 mmol). 2-Amino-4-bromophenol (5 mmol) and compound Ia-1 (5 mmol) were refluxed in an appropriate amount of isopropyl alcohol for 2 hr to afford compound Ib-1 ( 4.4 mmol). Ib-1 (4.4 mmol), 1,2-dibromoethane (8.8 mmol) and potassium carbonate (9.0 mmol) were stirred in DMF at 60 ° C for 5 hours to give Compound Ic-1 (3.1 mmol). Compound Ic-1 (3.1 mmol), pinacol borate (3.4 mmol), [Ι, Γ-bis(diphenylphosphino)ferrocene]palladium dichloride (0.3 mmol) and potassium acetate ( 6.2 mmol) was added to 20 mL of 1,4-dioxane and refluxed overnight to afford Id-1 (3.1 mmol). Compound Id-1 (1.5 mmol), Λ45-bromo-2-indolylpyridin-3-yl]-2,4-difluorobenzenesulfonamide (1.6 mmol), bis(triphenylphosphine) dichloride Palladium (0.2 mmol) and 2M aqueous potassium carbonate (0.3 mL) were added sequentially to 15 mL of 1,4-dioxane at 100. C reacted overnight. The obtained mixture was concentrated under reduced pressure, and then added to 10 mL of water, and the mixture was extracted three times with dichloromethane. The organic phase was combined, washed three times with saturated brine and dried over anhydrous sodium sulfate. The title compound (1)-1 (0.79 mmol, yield 52%).
ESI(+) m/z: 620。 实施例 2: 2,4-二氟 -A 2-曱氧基 -5-「4- (噻吩并「3,2-dl嘧啶 -4-基) -3,4-二 氢 -2 -1,4-苯并「b1「l,41 嗪 -6-基 1吡啶 -3-基}苯磺酰胺的合成  ESI(+) m/z: 620. Example 2: 2,4-Difluoro-A 2-decyloxy-5-"4-(thieno"3,2-dl-pyrimidin-4-yl)-3,4-dihydro-2 -1, Synthesis of 4-Benzo"b1"l,41-azine-6-yl-1pyridin-3-yl}benzenesulfonamide
Figure imgf000020_0001
Figure imgf000020_0001
ld-2 (0-2  Ld-2 (0-2
将 2-氨基 -4-溴苯酚（5 mmol) 与化合物 4-氯噻吩并 [3,2-d]嘧啶 (Ia-2, 5 mmol)在适量异丙醇中回流 小时， 得到化合物 Ib-2 (3.8 mmol )。 将 Ib-2 ( 3.8 mmol )、 1，2-二溴乙烷 ( 7.6 mmol )和碳酸钾 ( 8.1 mmol )在 DMF中于 60°C搅拌 5小时， 得到化合物 Ic-2 ( 2.8 mmol ) 。 将化合物 Ic-2 ( 2.8 mmol )、 联硼酸频那醇酯 ( 3.1 mmol ) 、 [1，Γ-双 (二 苯基膦基)二茂铁]二氯化钯（ 0.27 mmol )和醋酸钾（ 5.6 mmol )加入到 20 mL 1,4-二氧六环中， 回流过夜， 得到 Id-2 ( 2.7 mmol ) 。 将化合物 Id-2 ( 1.5 mmol ) 、 -[5-溴 -2-曱氧基吡啶 -3-基] -2,4-二氟苯磺酰胺 ( 1.6 mmol )、双 (三苯基膦)二氯化钯（ 0.2 mmol )以及 2M碳酸钾水溶液（ 0.3 mL )依次加入到 15 mL 1,4-二氧六环中， 于 100°C反应过夜。 将所得混 合物减压浓缩， 加入 10 mL水， 用二氯曱烷反复萃取 3次， 合并有机 相，用饱和食盐水洗 3次并用无水硫酸钠干燥后经硅胶柱层析分离（甲 醇 /二氯曱烷： 0〜50 % ) , 得到白色固体状标题化合物 (1)-2 ( 0.71 mmol, 收率为 47 % ) 。 2-Amino-4-bromophenol (5 mmol) and the compound 4-chlorothieno[3,2-d]pyrimidine (Ia-2, 5 mmol) were refluxed in an appropriate amount of isopropanol to give Compound Ib-2. (3.8 Mmmol). Ib-2 (3.8 mmol), 1,2-dibromoethane (7.6 mmol) and potassium carbonate (8.1 mmol) were stirred in DMF at 60 ° C for 5 hours to give compound Ic-2 ( 2.8 mmol). Compound Ic-2 (2.8 mmol), pinacol borate (3.1 mmol), [1, bis-bis(diphenylphosphino)ferrocene]palladium dichloride (0.27 mmol) and potassium acetate ( 5.6 mmol) was added to 20 mL of 1,4-dioxane and refluxed overnight to afford Id-2 (2.7 mmol). Compound Id-2 (1.5 mmol), -[5-bromo-2-indolylpyridin-3-yl]-2,4-difluorobenzenesulfonamide (1.6 mmol), bis(triphenylphosphine) Palladium chloride (0.2 mmol) and 2M aqueous potassium carbonate solution (0.3 mL) were sequentially added to 15 mL of 1,4-dioxane, and reacted at 100 ° C overnight. The obtained mixture was concentrated under reduced pressure, and then added to 10 mL of water, and the mixture was extracted with EtOAc (3 mL), and the organic phase was combined, washed three times with saturated brine and dried over anhydrous sodium sulfate. The title compound (1)-2 (0.71 mmol, yield 47%).
ESI (+) m/z: 568。 实施例 3 : 2,4-二氟 -A 2-甲氧基 -5-「4-(6-硝基喹唑啉 -4-基) -3,4-二氢  ESI (+) m/z: 568. Example 3: 2,4-Difluoro-A 2-methoxy-5-"4-(6-nitroquinazolin-4-yl)-3,4-dihydrogen
-2^-1，4-苯并「blf l，4 恶嗪 -6-基 "1吡啶 -3-基}苯磺酰胺的合成  Synthesis of -2^-1,4-benzo-"blf l,4 oxazin-6-yl"1pyridin-3-yl}benzenesulfonamide
Figure imgf000021_0001
Figure imgf000021_0001
lf-3 (1)-3  Lf-3 (1)-3
将 2-氨基 -4-溴苯酚（30 mmol ) 、 联硼酸频那醇酯 （36 mmol ) 、 [Ι,Γ-双 (二苯基膦基)二茂铁]二氯化钯（ 3.0 mmol )和醋酸钾（ 90 mmol ) 加入到 120 mL 1，4-二氧六环中， 回流过夜， 得到 3-氨基 -4-羟基苯基硼 酸频哪醇酯 （28.8 mmol ) 。 将 3-氨基 -4-羟基苯基硼酸频哪醇酯 （28.8 mmol ) 、 N-[5-溴 -2-曱氧基吡啶 -3-基] -2，4-二氟苯磺酰胺（ 24 mmol ) 、 双 (三苯基膦)二氯化钯 ( 2.1 mmol ) 、 醋酸钾（ 72 mmol )和 3 mL水依 次加入到 120 mL 1,4-二氧六环中， 于 90°C反应过夜， 得到化合物 Ie-3 ( 15 mmol )。 将化合物 Ie-3 ( 0.71 mmol )与 4-氯 -6-硝基喹唑啉 ( 0.71 mmol )在适量异丙醇中回流 3小时， 得到化合物 If-3 ( 0.69 mmol ) 。 将化合物 If-3 ( 0.69 mmol )、 1,2-二溴乙烷（ 0.71 mmol )和碳酸钾（ 0.71 mmol )依次加入到 DMF ( 10 mL )中， 于 60°C反应 4小时。加入 20 mL 水， 用二氯曱烷反复萃取 3次， 合并有机相， 用饱和食盐水洗 3次并用 无水 酸钠干燥后， 经硅胶柱层析分离 （曱醇 /二氯曱烷： 0~50 % ) , 得到黄色固体状标题化合物 (1)-3 ( 0.29 mmol, 收率为 42 % ) 。 2-Amino-4-bromophenol (30 mmol), pinacol borate (36 mmol), [Ι, Γ-bis(diphenylphosphino)ferrocene] palladium dichloride (3.0 mmol) Potassium acetate (90 mmol) was added to 120 mL of 1,4-dioxane and refluxed overnight to give 3-amino-4-hydroxyphenylboronic acid pinacol ester (28.8 mmol). 3-Amino-4-hydroxyphenylboronic acid pinacol ester (28.8 mmol), N-[5-bromo-2-indolylpyridin-3-yl]-2,4-difluorobenzenesulfonamide (24 Mm), Bis(triphenylphosphine)palladium dichloride (2.1 mmol), potassium acetate (72 mmol) and 3 mL of water were sequentially added to 120 mL of 1,4-dioxane, and reacted at 90 ° C overnight to obtain a compound. Ie-3 (15 mmol). Compound Ie-3 (0.71 mmol) and 4-chloro-6-nitroquinazoline (0.71 mmol) were refluxed in an appropriate amount of isopropanol for 3 hours to give compound If-3 (0.69 mmol). Compound If-3 (0.69 mmol), 1,2-dibromoethane (0.71 mmol) and potassium carbonate (0.71 mmol) were sequentially added to DMF (10 mL), and reacted at 60 ° C for 4 hours. After adding 20 mL of water and extracting 3 times with dichloromethane, the organic phase was combined, washed with saturated brine for 3 times and dried over anhydrous sodium sulfate, and then separated by silica gel column chromatography (methanol/dichloromethane: 0~) The title compound (1)-3 (0.29 mmol, yield: 42%)
H^NMRCCDC^): δ 9.05 (s, 1H), δ 8.95 (s, IH), δ 8.60 (d, IH), δ H^NMRCCDC^): δ 9.05 (s, 1H), δ 8.95 (s, IH), δ 8.60 (d, IH), δ
8.18 (d， IH), δ 7.78 (s， 1H)， δ 7.62 (m， 1H)， δ 7.58 (s， 1H)， δ 7.22-7.12 (m, 3H), δ 6.95-6.84 (m， 3H), δ 4.60 (m, 2H), δ 4.38 (m, 2H), δ 3.88 (s， 3H)。 8.18 (d, IH), δ 7.78 (s, 1H), δ 7.62 (m, 1H), δ 7.58 (s, 1H), δ 7.22-7.12 (m, 3H), δ 6.95-6.84 (m, 3H) , δ 4.60 (m, 2H), δ 4.38 (m, 2H), δ 3.88 (s, 3H).
ESI(+)m/z: 608。 实施例 4: 2，4-二氟 U2-曱氧基 -5-「4-(6-乙酰胺基喹唑啉 -4-基) -3,4-二  ESI (+) m/z: 608. Example 4: 2,4-Difluoro U2-decyloxy-5-"4-(6-acetamidoquinazolin-4-yl)-3,4-di
-2^-1,4-苯并 Π)1Π ,4 恶嗪 -6-基 1吡啶 -3-基}苯磺酰胺的合成  Synthesis of -2^-1,4-benzopyrene)1Π,4 Oxazine-6-yl 1pyridine-3-yl}benzenesulfonamide
Figure imgf000022_0001
Figure imgf000022_0001
将化合物 （1)-3 ( 0.2 mmol )和还原铁粉 ( 1 mmol )加入到醋酸（ 8 mL )中回流 2小时 ,得到中间体 B (0.11 mmol)。将中间体 B (0.11 mmol), 醋酸酐（0.13 mmol )和醋酸钠（0.13 mmol )加入到 15 mL二氯甲烷中， 室温下搅拌过夜。 向反应液中加入 10 mL水， 用二氯曱烷反复萃取 3 次， 合并有机相， 用饱和食盐水洗 3 次并用无水硫酸钠干燥后， 经硅 胶柱层析分离（甲醇 /二氯甲烷： 0~50%) ,得到固体状标题化合物 (1)-4 (0.041 mmol, 收率为 37%) 。 Compound (1)-3 (0.2 mmol) and reduced iron powder (1 mmol) were added to acetic acid (8 mL) and refluxed for 2 hr to afford Intermediate B (0.11 mmol). Intermediate B (0.11 mmol), acetic anhydride (0.13 mmol) and sodium acetate (0.13 mmol) were added to 15 mL dichloromethane and stirred at room temperature overnight. 10 mL of water was added to the reaction solution, and the mixture was extracted three times with dichloromethane. The organic phase was combined, washed three times with saturated brine and dried over anhydrous sodium sulfate. The title compound (1)-4 (0.041 mmol, yield: 37%)
ESI(+)m/z: 619。  ESI(+)m/z: 619.
ESI(-)m/z: 617。 实施例 5: 2,4-二氟 -N-{2-甲氧基 -5-「4- (嘧啶 -4-基) -3,4-二氢 -2i -l,4-苯并  ESI (-) m/z: 617. Example 5: 2,4-Difluoro-N-{2-methoxy-5-"4-(pyrimidin-4-yl)-3,4-dihydro-2i-l,4-benzo
-6-基 1吡啶 -3-基}苯磺酰胺的合成  Synthesis of -6-yl 1 pyridin-3-yl}benzenesulfonamide
Figure imgf000023_0001
将实施例 3中制备得到的化合物 Ie-3 ( 0.71 mmol)与 4-氯-嘧啶盐 酸盐（Ia-5，0.71 mmol) 、 三乙胺（0.71 mmol)一起在适量异丙醇中回 流 36小时，得到化合物 If-5( 0.15 mmol )。把化合物 If-5( 0.15 mmol )、 1,2-二溴乙烷（0.18 mmol)和碳酸氢钾（0.18 mmol)依次加入到 DMF ( 5 mL) 中， 于 60°C反应过夜。 向反应液中加入 10 mL水， 用二氯甲 烷反复萃取 3次， 合并有机相， 用饱和食盐水洗 3次并用无水硫酸钠 干燥后， 经硅胶柱层析分离 （甲醇 /二氯曱烷： 0~50%) , 得到黄色固 体状标题化合物（1)-5 (0.06 mmol, 收率为 40%) 。
Figure imgf000023_0001
The compound Ie-3 (0.71 mmol) prepared in Example 3 was refluxed with 4-chloro-pyrimidine hydrochloride (Ia-5, 0.71 mmol) and triethylamine (0.71 mmol) in an appropriate amount of isopropanol. The compound If-5 (0.15 mmol) was obtained in an hour. The compound If-5 (0.15 mmol), 1,2-dibromoethane (0.18 mmol) and potassium hydrogencarbonate (0.18 mmol) were sequentially added to DMF (5 mL), and then reacted at 60 ° C overnight. 10 mL of water was added to the reaction mixture, and the mixture was extracted three times with dichloromethane. The organic phase was combined, washed three times with saturated brine and dried over anhydrous sodium sulfate. The title compound (1)-5 (0.06 mmol, yield 40%).
ESI(+)m/z: 512。 实施例 6: 2,4-二氟 -A 2-甲氧基 -5-「4-(2-氨基嘧啶 -4-基) -3,4-二氢  ESI (+) m/z: 512. Example 6: 2,4-Difluoro-A 2-methoxy-5-"4-(2-Aminopyrimidin-4-yl)-3,4-dihydrogen
-2 -1,4-苯并 R)l「l,41哺嗪 -6-基 1吡啶 -3-基）苯磺酰胺的合成 Synthesis of 2-(4-benzo-R)l "l,41-oxazol-6-yl-pyridin-3-yl)benzenesulfonamide
Figure imgf000024_0001
Figure imgf000024_0001
Figure imgf000024_0002
将实施例 3 中制备得到的化合物 Ie-3 (0.71 mmol) 和 2-氨基 -4- 氧 -嘧啶（Ia-6, 0.71 mmol)在适量异丙醇中回流过夜， 得到化合物 If-6 ( 0.48 mmol )。把化合物 If-6 ( 0.48 mmol )、 1,2-二溴乙烷 ( 0.56 mmol ) 以及碳酸钾（ 0.5 mmol )依次加入到 DMF ( 8 mL ) 中， 于 60°C反应过 夜。向反应液中加入 15mL水， 用二氯曱烷反复萃取 3次，合并有机相， 用饱和食盐水洗 3 次并用无水硫酸钠干燥后， 经硅胶柱层析分离 （甲 醇 /二氯曱烷: 0〜50 % ) , 得到白色固体状标题化合物 (1)-6 ( 0.06 mmol, 收率为 40%) 。
Figure imgf000024_0002
The compound Ie-3 (0.71 mmol) obtained in Example 3 and 2-amino-4-oxo-pyrimidine (Ia-6, 0.71 mmol) were refluxed in an appropriate amount of isopropanol overnight to give compound If-6 (0.48). Mmmol). The compound If-6 (0.48 mmol), 1,2-dibromoethane (0.56 mmol) and potassium carbonate (0.5 mmol) were sequentially added to DMF (8 mL), and reacted at 60 ° C overnight. 15 mL of water was added to the reaction mixture, and the mixture was extracted three times with dichloromethane. The organic phase was combined, washed with brine and dried over anhydrous sodium sulfate. The title compound (1)-6 (0.06 mmol, yield 40%) was obtained as white solid.
ESI(+)m/z: 527。 实施例 7: 2,4-二氟 -Λ 2-曱氧基 -5-「4-(6- (曱磺酰基)噻吩并 n,2-dl嘧啶  ESI (+) m/z: 527. Example 7: 2,4-Difluoro-indole 2-decyloxy-5-"4-(6-(sulfonyl)thiophene n,2-dl pyrimidine
Figure imgf000024_0003
将实施例 3中制备得到的化合物 Ie-3 ( 0.71 mmol)和 4-氯 -6-甲磺 酰噻吩并 [3,2-d]嘧啶（Ia-7， 0.71 mmol )在适量异丙醇中回流过夜， 得 到化合物 If-7 ( 0.57 mmol )。 把化合物 If-7 ( 0.57 mmol ) 、 1,2-二溴乙 烷 （0.68 mmol) 以及碳酸氢钾 ( 0.6 mmol )依次加入到丙酮 （20mL) 中， 回流过夜， 之后浓缩混合物以除去丙酮， 向其中加入 5 mL水， 用 二氯曱烷反复萃取 3次， 合并有机相， 用饱和食盐水洗 3次并用无水 硫酸钠干燥后， 经硅胶柱层析（曱醇 /二氯曱烷： 0~50%) ， 得到黄色 固体状标题化合物 (1)-7 (0.26 mmol, 收率为 45%) 。
Figure imgf000024_0003
The compound Ie-3 (0.71 mmol) prepared in Example 3 and 4-chloro-6-methanesulfonylthieno[3,2-d]pyrimidine (Ia-7, 0.71 mmol) were dissolved in an appropriate amount of isopropanol. After refluxing overnight, the compound If-7 (0.57 mmol) was obtained. The compound If-7 (0.57 mmol), 1,2-dibromoethane (0.68 mmol) and potassium hydrogencarbonate (0.6 mmol) were sequentially added to acetone (20 mL) and refluxed overnight, then the mixture was concentrated to remove acetone. 5 mL of water was added thereto, and the mixture was extracted three times with dichloromethane, and the organic phase was combined, washed three times with saturated brine and dried over anhydrous sodium sulfate, and then purified by silica gel column chromatography (methanol/dichloromethane: 0~) The title compound (1)-7 (0.26 mmol, yield 45%).
ESI(+)m/z: 646。 实施例 8: 2,4-二氟 -A 2-曱氧基 -5-「4-(2-环丙甲酰胺基嘧啶 -4-基) -3,4- 二氢 -2 /-1,4-苯并「bl「l,41 ^嗪 -6-基 1吡啶 -3-基}苯磺酰胺的合  ESI (+) m/z: 646. Example 8: 2,4-Difluoro-A 2-decyloxy-5-"4-(2-cyclopropylamidopyrimidin-4-yl)-3,4-dihydro-2 /-1, 4-Benzo"bl"l,41^azine-6-yl-1pyridin-3-yl}benzenesulfonamide
Figure imgf000025_0001
Figure imgf000025_0001
将异胞嘧啶（ 18 mmol)溶于 50mL吡啶中， 于 0°C加入环丙曱酰 氯 ( 19.8 mmol ) ， 搅拌 2小时后得到中间体 Ia-8 ( 15 mmol ) 。 将中间 体 Ia-8 ( 0.71 mmol )与实施例 3中制备得到的化合物 Ie-3 ( 0.71 mmol ) 在适量异丙醇中回流 48小时， 得到化合物 If-8 (0.11 mmol) 。 把化合 物 If-8( 0.11 mmol )、1, 2-二溴乙烷（ 0.12 mmol )以及碳酸钾 ( 0.12 mmol ) 依次加入到 DMF ( 10mL) 中， 于 60°C反应过夜。 向反应液中加入 15 mL水， 用二氯甲烷反复萃取 3次， 合并有机相， 用饱和食盐水洗 3次 并用无水硫酸钠干燥后，经硅胶柱层析分离（曱醇 /二氯甲烷： 0-50 % ) , 得到白色固体状标题化合物 (1)-8 ( 0.025 mmol ) , 收率为 23 %。 Dissolve isocytosine (18 mmol) in 50 mL pyridine and add cyclopropanoyl at 0 °C Chlorine ( 19.8 mmol), after stirring for 2 h, gave Intermediate Ia-8 (15 mmol). The intermediate Ia-8 (0.71 mmol) and the compound Ie-3 (0.71 mmol) obtained in Example 3 were refluxed in an appropriate amount of isopropanol for 48 hours to obtain Compound If-8 (0.11 mmol). The compound If-8 (0.11 mmol), 1,2-dibromoethane (0.12 mmol) and potassium carbonate (0.12 mmol) were sequentially added to DMF (10 mL), and the mixture was reacted at 60 ° C overnight. 15 mL of water was added to the reaction solution, and the mixture was extracted three times with dichloromethane. The organic phase was combined, washed three times with brine and dried over anhydrous sodium sulfate. The title compound (1)-8 (0.025 mmol) was obtained as a white solid.
ESI(+)m/z: 595。  ESI (+) m/z: 595.
ESI(-)m/z: 593 实施例 9: 2,4-二氟 -Λ 2-曱氧基 -5-μ-(2-乙酰胺基嘧啶 -4-基) -3,4-二氢  ESI(-)m/z: 593 Example 9: 2,4-Difluoro-indole 2-decyloxy-5-μ-(2-acetamidopyrimidin-4-yl)-3,4-dihydrogen
-2 -1,4-苯并 [bin,41 嗪 -6-基 1吡啶 -3-基}苯磺酰胺的合成  Synthesis of 2-2-1,4-benzo[bin,41 azine-6-yl 1pyridine-3-yl}benzenesulfonamide
Figure imgf000026_0001
Figure imgf000026_0001
(1)-9  (1)-9
将 2-氨基 -4-氯 -嘧啶（4 mmol)加入到 6 mL醋酸 中， 回流 45 分钟得到 Ia-9 ( 2.5 mmol) 。 将中间体 Ia-9 ( 0.71 mmol) 与实施例 3 中制备得到的化合物 Ie-3 (0.71 mmol)在适量异丙醇中回流 48小时， 得到化合物 If-9 (0.31 mmol) 。 将化合物 If-9 (0.31mmol) 、 1，2-二溴 乙垸（ 0.34mmol )以及碳酸钟 ( 0.34 mmol )依次加入到 DMF ( 15 mL) 中， 于 60°C反应过夜。 向反应液中加入 15 mL水， 用二氯曱烷反复萃 取 3次， 合并有机相， 用饱和食盐水洗 3次并用无水硫酸钠干燥后， 经硅胶柱层析分离 （曱醇 /二氯曱垸： 0~50%) , 得到白色固体状标题 化合物 (1)-9 (0.18 mmol, 收率为 53 %) 。 2-Amino-4-chloro-pyrimidine (4 mmol) was added to 6 mL of acetic acid and refluxed for 45 min to give Ia-9 (2.5 mmol). Intermediate Ia-9 (0.71 mmol) and Compound Ie-3 (0.71 mmol) obtained in Example 3 were refluxed in an appropriate amount of isopropanol for 48 hours to give Compound If-9 (0.31 mmol). The compound If-9 (0.31 mmol), 1,2-dibromoacetamidine (0.34 mmol), and a carbonic acid clock (0.34 mmol) were sequentially added to DMF (15 mL), and the mixture was reacted at 60 ° C overnight. 15 mL of water was added to the reaction solution, and the mixture was repeatedly extracted with dichloromethane. The organic phase was combined and washed with EtOAc (3 mL). 1)-9 (0.18 mmol, yield 53%).
ESI(+)m/z: 569。  ESI (+) m/z: 569.
ESI(-)m/z: 567。 实施例 10: 2,4-二氟 -Λ 2-曱氧基 -5-[4- (烟酰基) -3,4-二氢 -2 -1，4-苯并  ESI(-)m/z: 567. Example 10: 2,4-Difluoro-indole 2-decyloxy-5-[4-(nicotinoyl)-3,4-dihydro-2-1-1,4-benzo
-6-基 1吡啶 -3-基 }苯磺酰胺的合成  Synthesis of -6-yl 1 pyridin-3-yl }benzenesulfonamide
Figure imgf000027_0001
Figure imgf000027_0001
M -10 (1)-10  M -10 (1)-10
将 6-溴 -3,4-二氢 -2/ -苯并 [b][l,4 恶嗪（ 18.0mmol) 、 联硼酸频那 醇酯 ( 21.6 mmol) 、 [1，Γ-双 (二苯基膦基)二茂铁]二氯化钯 ( 1.5 mmol) 以及醋酸钟 ( 54 mmol )依次加入到 1,4-二氧六环 （ 100 mL ) 中， 回流 过夜， 得到化合物 Ig ( 17.5 mmol)。 把化合物 Ig ( 17.5 mmol) 、 N-[5- 溴 _2-曱氧基吡啶 -3-基] -2,4-二氟苯磺酰胺（ 17.5 mmol) 、 2M碳酸钾水 溶液（ 26 mL )以及双 (三苯基膦)二氯化钯（ 1.7 mmol )依次加入到 1，4- 二氧六环（ 250 mL)中，于 100°C反应过夜，得到化合物 Ih( 10 mmol )。 将化合物 Ih ( 0.3 mmol ) 、 N, -二异丙基乙胺（ DIPEA， 0.9 mmol )和 烟酰氯盐酸盐 （0.6 mmol)依次加入到二氯甲烷（ 15 mL) 中， 室温搅 拌 30分钟 ,得到 Ii-10化合物 ( 0.25mmol )。将化合物 Ii-10 ( 0.25 mmol ) 溶于 3 mL二氯甲烷和 3 mL甲醇混合溶剂中，加入 4.0N氢氧化钠水溶 液（0.4mL) ， 室温搅拌 30分钟， 得到标题化合物 (I)-10 (0.19mmol, 收率为 76%) 。 H^NMRCCDC^): δ 8.78 (s, 2H), δ 7.93-6.94 (m, 11H), δ 4.47 (s, 2H) 64.10(s, 2H), 83.89 (s, 3H)0 6-Bromo-3,4-dihydro-2/-benzo[b][l,4 oxazine (18.0 mmol), boronic acid pinacol ester (21.6 mmol), [1, Γ-double (two Phenylphosphino)ferrocene]palladium dichloride (1.5 mmol) and acetic acid clock (54 mmol) were sequentially added to 1,4-dioxane (100 mL) and refluxed overnight to give compound Ig (17.5 mmol). ). Compound Ig (17.5 mmol), N-[5-bromo-2-methoxypyridin-3-yl]-2,4-difluorobenzenesulfonamide (17.5 mmol), 2M aqueous potassium carbonate (26 mL) Bis(triphenylphosphine)palladium dichloride (1.7 mmol) was added to 1,4-dioxane (250 mL), and the reaction was carried out at 100 ° C overnight to give compound Ih (10 mmol). Compound Ih (0.3 mmol), N,-diisopropylethylamine (DIPEA, 0.9 mmol) and nicotinic acid chloride (0.6 mmol) were added to dichloromethane (15 mL), and stirred at room temperature for 30 min. The Ii-10 compound (0.25 mmol) was obtained. The compound Ii-10 (0.25 mmol) was dissolved in a mixture of 3 mL of dichloromethane and 3 mL of methanol. 0.19 mmol, yield 76%). H^NMRCCDC^): δ 8.78 (s, 2H), δ 7.93-6.94 (m, 11H), δ 4.47 (s, 2H) 64.10(s, 2H), 83.89 (s, 3H) 0
ESI(+)m/z: 539。  ESI (+) m/z: 539.
ESI(+)m/z: 537。 实施例 11: 2,4-二氟 -Λ 2-曱氧基 -5-「4-(6-异丙氧基烟酰基) -3,4-二氢  ESI(+)m/z: 537. Example 11: 2,4-Difluoro-indole 2-decyloxy-5-"4-(6-isopropoxynicotinoyl)-3,4-dihydrogen
-2/-1,4-苯并「bl「l,41^嗪 -6-基 1吡啶 -3-基}苯磺酰胺的合成  Synthesis of -2/-1,4-benzo-"bl"l,41-azine-6-yl-1pyridin-3-yl}benzenesulfonamide
Figure imgf000028_0001
将实施例 10中制备的化合物 Ih ( 0.3 mmol )、 N, N-二异丙基乙胺 ( DIPEA, 0.9 mmol )以及 6-异丙氧基烟酰氯（ 0.6 mmol )依次加入到 二氯曱烷（ 15 mL )中，室温搅拌 30分钟，得到 Ii-11化合物（ 0.23 mmol )。 将化合物 Ii-11 ( 0.23 mmol )溶于 3 mL二氯曱烷和 3 mL甲醇混合溶剂 中， 加入 4.0N氢氧化钠水溶液（0.4mL) , 室温搅拌 30分钟， 得到标 题化合物（1)-11 (0.20 mmol, 收率为 87%) 。
Figure imgf000028_0001
The compound Ih (0.3 mmol), N,N-diisopropylethylamine (DIPEA, 0.9 mmol) and 6-isopropoxy nicotinyl chloride (0.6 mmol) prepared in Example 10 were sequentially added to dichloromethane. (15 mL), stirring at room temperature for 30 minutes gave an Ii-11 compound (0.23 mmol). The compound Ii-11 (0.23 mmol) was dissolved in a mixture of 3 mL of dichloromethane and 3 mL of methanol. (0.20 mmol, yield 87%).
ESI(+)m/z: 597。  ESI(+)m/z: 597.
ESI(+)m/z: 595。 实施例 12: 2，4-二氟 -Λ 2-曱氧基 -5-[4-(2-异丙氧基异烟酰基) -3,4-二氢  ESI (+) m/z: 595. Example 12: 2,4-Difluoro-indole 2-decyloxy-5-[4-(2-isopropoxyisonicotinoyl)-3,4-dihydrogen
-2 -1,4-苯并「bl「l,41 嗪 -6-基 1吡啶 -3-基}苯磺酰胺的合成 Synthesis of -2 -1,4-benzo-"bl"l,41-azine-6-yl-pyridin-3-yl}benzenesulfonamide
Figure imgf000029_0001
Figure imgf000029_0001
将化合物 Ih ( 0.3 mmol ) , N, TV-二异丙基乙胺（ DIPEA, 0.9 mmol ) 和 2-异丙氧基异烟酰氯（ 0.6 mmol )依次加入到二氯曱烷（ 15 mL )中， 室温搅拌 30分钟，得到化合物 Ii-12( 0.24 mmol )。将化合物 Ii-12( 0.24 mmol )溶于 3 mL二氯曱烷和 3 mL曱醇混合溶剂中， 加入 4.0N氢氧 化钠水溶液（0.4 mL ) , 室温搅拌 30分钟，得到标题化合物 (1)-12 ( 0.22 mmol, 收率为 92% ) 。  Compound Ih (0.3 mmol), N, TV-diisopropylethylamine (DIPEA, 0.9 mmol) and 2-isopropoxyisonicotinoyl chloride (0.6 mmol) were sequentially added to dichloromethane (15 mL) The mixture was stirred at room temperature for 30 minutes to give Compound Ii-12 (0.24 mmol). The compound Ii-12 (0.24 mmol) was dissolved in a mixture of 3 mL of dichloromethane and 3 mL of methanol. 12 (0.22 mmol, yield 92%).
ESI(+)m/z: 597。  ESI(+)m/z: 597.
ESI(+)m/z: 595。 实施例 13: 2,4-二氟 -Λ 2-曱氧基 -5-Γ4-(2-氨基 -6-甲基嘧啶 -4-基) -3,4- 二氢 -2^-1,4-苯并「bl「l,4 恶嗪 -6-基 1吡啶 -3-基 苯磺酰胺的合  ESI (+) m/z: 595. Example 13: 2,4-Difluoro-indole 2-decyloxy-5-indole 4-(2-amino-6-methylpyrimidin-4-yl)-3,4-dihydro-2^-1, 4-benzo-"bl"l,4oxazin-6-yl-1pyridin-3-ylbenzenesulfonamide
Figure imgf000029_0002
Figure imgf000029_0002
(，)-13 将 2-氨基 -4-氯 -6-曱基嘧啶（0.52 mmol)和实施例 3中制备得到 的化合物 Ie-3 ( 0.52 mmol )在适量异丙醇中回流 48小时， 得到化合物 If-13 ( 0.21 mmol )。 将化合物 If-13 ( 0.21 mmol )、 1, 2-二溴乙烷 ( 0.22 mmol) 以及碳酸钟 ( 0.25 mmol)依次加入到 DMF ( 10 mL) 中， 于 60°C反应过夜。 向反应液中加入 15 mL水， 用二氯甲烷反复萃取 3次， 合并有机相， 用饱和食盐水洗 3 次并用无水硫酸钠千燥后， 经硅胶柱 层析分离（甲醇 /二氯甲烷： 0~50%)，得到白色固体状标题化合物 (1)-13 ( 0.046 mmol, 收率为 21.9%) 。 (,)-13 2-Amino-4-chloro-6-mercaptopyrimidine (0.52 mmol) and the compound Ie-3 (0.52 mmol) obtained in Example 3 were refluxed in an appropriate amount of isopropanol for 48 hours to obtain compound If-13 ( 0.21 mmol). The compound If-13 (0.21 mmol), 1,2-dibromoethane (0.22 mmol) and a carbonic acid clock (0.25 mmol) were sequentially added to DMF (10 mL) and reacted at 60 ° C overnight. 15 mL of water was added to the reaction mixture, and the mixture was extracted three times with dichloromethane. The organic phase was combined, washed three times with saturated brine and dried over anhydrous sodium sulfate. The title compound (1)-13 (0.046 mmol, yield: 21.9%) was obtained as white solid.
ESI(+)m/z: 541。  ESI(+)m/z: 541.
ESI(-)m/z: 539。 实施例 14: 2，4-二氟-^-{2-曱氧基-5-「4-(吡啶-4-基)-3,4-二氢-2^-1,4-苯 并 Π3πΐ，4 恶嗪 -6-基 1吡啶 -3-基}苯磺酰胺的合成  ESI(-)m/z: 539. Example 14: 2,4-Difluoro-^-{2-decyloxy-5-"4-(pyridin-4-yl)-3,4-dihydro-2^-1,4-benzoxanthene 3πΐ Synthesis of 4 oxazin-6-yl 1pyridin-3-yl}benzenesulfonamide
Figure imgf000030_0001
将 4-氯吡啶盐酸盐（0.32 mmol)和实施例 3中制备得到的化合物
Figure imgf000030_0001
4-chloropyridine hydrochloride (0.32 mmol) and the compound prepared in Example 3
Ie-3 (0.32 mmol)在异丙醇中回流 24小时， 得到化合物 If-14 (0.13 mmol) 。 将化合物 If-14 (0.13 mmol) 、 1， 2-二溴乙烷 （0.15 mmol) 以及碳酸钟 ( 0.20 mmol )依次加入到 DMF ( lOmL) 中， 于 60°C反应 过夜。 向反应液中加入 15 mL水， 用二氯曱烷反复萃取 3次，合并有机 相， 用饱和食盐水洗 3 次并用无水硫酸钠干燥后， 经硅胶柱层析分离 (曱醇 /二氯甲烷： 0~50%) ， 得到白色固体 (I)-14 ( 0.036mmol， 收率 为 27.2 % ) 。 Ie-3 (0.32 mmol) was refluxed in isopropanol for 24 hours to give compound If-14 (0.13 mmol). To the mixture, DMF (10. 15 mL of water was added to the reaction mixture, and the mixture was extracted three times with dichloromethane. The organic phase was combined, washed with brine and dried over anhydrous sodium sulfate. : 0~50%) , gave white solid (I)-14 (0.036mmol, yield It is 27.2%).
ESI(+)m/z: 511。  ESI (+) m/z: 511.
II. 本发明化合物的制剂制备实施例  II. Preparation Preparation Example of Compound of the Present Invention
实施例 15: 胶嚢剂的制备 Example 15: Preparation of an anthraquinone
配方： Recipe:
实施例 2化合物 20 g  Example 2 Compound 20 g
淀粉 140 g  Starch 140 g
微晶纤维素 68 g 按常规方法， 将上述物质混合均勾后， 装入普通明胶胶嚢， 得到 1000颗胶嚢。  Microcrystalline cellulose 68 g According to a conventional method, the above materials are mixed and hooked, and then filled into ordinary gelatin capsules to obtain 1000 capsules.
按类似方法， 分别制得含其它实施例化合物的胶嚢剂。 III. 本发明化合物活性测试实施例  In a similar manner, a capsule containing the other example compounds was separately prepared. III. Example of activity test of the compound of the present invention
测试实施例 1 : 本发明化合物对人***癌细胞 (PC-3)增殖抑制作用 将处于对数生长期的人***癌细胞以约 5500 个 /孔的密度接种 于 96孔培养板， 180 μΐ/孔。 每个浓度设三复孔。 并设相应浓度的溶媒 对照及无细胞调零孔。 贴壁生长 24hr再加实施例化合物或阳性对照药 (LY294002) 20 μΐ/孔， 细胞在 10% Hyclone胎牛血清、 37°C及 5% C02 条件下培养 72小时。 加入 50 %的冷三氯乙酸 (TCA) 50 L, 4°C放置 1 小时， 固定细胞。 倾去液体， 用蒸馏水轻緩洗涤 5 次， 空气中自然干 燥。 加入由 1 %冰醋酸配制的 SRB 4 mg/mL溶液 100 μΙ 孔， 室温中染 色 15分钟。 弃上清液， 用 1%醋酸洗涤 5次， 空气中干燥。 每孔加入 150 μL的 10 mM的 Tris溶液 （ pH=10.5 ) ， 溶解结合的 SRB。 酶标仪 510 nm波长下测定 OD值，通过计算获得实施例化合物对于 PC-3细胞 的 IC5G值： 化合物 Test Example 1: Inhibition of proliferation of human prostate cancer cells (PC-3) by the compound of the present invention Human prostate cancer cells in logarithmic growth phase were seeded at a density of about 5500 cells/well in a 96-well culture plate, 180 μΐ/ hole. Three holes are provided for each concentration. The corresponding concentration of the vehicle control and the cell-free zeroing hole were set. Adherently grown for 24 hr plus the example compound or positive control drug (LY294002) 20 μΐ/well, and the cells were cultured for 72 hours under conditions of 10% Hyclone fetal calf serum, 37 ° C and 5% CO 2 . 50% cold trichloroacetic acid (TCA) 50 L was added and allowed to stand at 4 ° C for 1 hour to fix the cells. The liquid was decanted, washed gently with distilled water 5 times, and naturally dried in the air. A 100 μΙ well of SRB 4 mg/mL solution prepared from 1% glacial acetic acid was added and stained for 15 minutes at room temperature. The supernatant was discarded, washed 5 times with 1% acetic acid, and dried in air. 150 μL of 10 mM Tris solution (pH = 10.5) was added to each well to dissolve the bound SRB. The OD value was measured at a wavelength of 510 nm by a microplate reader, and the IC 5 G value of the compound of the example for PC-3 cells was obtained by calculation: Compound
LY294002 5.47  LY294002 5.47
实施例化合物 3 13.40  Example compound 3 13.40
实施例化合物 5 0.17  Example compound 5 0.17
实施例化合物 6 0.20  Example compound 6 0.20
实施例化合物 7 4.61  Example Compound 7 4.61
实施例化合物 10 2.26  Example Compound 10 2.26
实施例化合物 1 1 16.63  Example Compound 1 1 16.63
实施例化合物 12 2.55  Example Compound 12 2.55
测试结果表明：本发明化合物对人***癌细胞 (PC-3)有良好的增 殖抑制作用。 The test results showed that the compound of the present invention has a good proliferation inhibitory effect on human prostate cancer cells (PC-3).
1 。  1 .
测试实施例 2: 本发明化合物对人乳腺癌细胞 (MDA-MB-231)增殖抑制 作用 Test Example 2: Inhibition of proliferation of human breast cancer cells (MDA-MB-231) by the compounds of the present invention
参照测试实施例 1 实验方法进行测定， 通过计算获得实施例化合 物对于 MDA-MB-231细胞的 IC5o值： The IC 5 o values of the example compounds for MDA-MB-231 cells were determined by calculation with reference to Test Example 1 Experimental Method:
Figure imgf000032_0001
测试结果表明：本发明化合物对人乳腺癌细胞 (MDA-MB-231)有良 好的增殖抑制作用。 测试实施例 3: 本发明化合物对人非小细胞肺癌细胞 (Α549)增殖抑制作
Figure imgf000032_0001
The test results show that the compound of the present invention has a good proliferation inhibition effect on human breast cancer cells (MDA-MB-231). Test Example 3: Compound of the present invention inhibits proliferation of human non-small cell lung cancer cells (Α549)
歷  Calendar
参照测试实施例 1 实验方法进行测定， 通过计算获得实施例化合 物对于 Α549细胞的 IC5()值：
Figure imgf000033_0001
测试结果表明： 本发明化合物对人非小细胞肺癌细胞 (A549)有良 好的增殖抑制作用。 测试实施例 4: 本发明化合物对人卵巢癌细胞 (SK-OV-3)增殖抑制作用 参照测试实施例 1 实验方法进行测定， 通过计算获得实施例化合 物对于 SK-OV-3细胞的 IC5o值： The IC 5 () value of the example compound for Α549 cells was obtained by calculation with reference to Test Example 1 Experimental Method:
Figure imgf000033_0001
The test results show that the compound of the present invention has a good proliferation inhibition effect on human non-small cell lung cancer cells (A549). Test Example 4: Inhibition of proliferation of human ovarian cancer cells (SK-OV-3) by the compound of the present invention The measurement was carried out by referring to Test Method Example 1, and the IC 5 o of the Example compound for SK-OV-3 cells was obtained by calculation. value:
Figure imgf000033_0002
测试结果表明：本发明化合物对人卵巢癌细胞 (SK-OV-3)有良好的 增殖抑制作用。
Figure imgf000033_0002
The test results show that the compound of the present invention has a good proliferation inhibition effect on human ovarian cancer cells (SK-OV-3).
测试实施例 5 : 本发明化合物对突变的非小细胞肺癌细胞 H1975 Test Example 5: Compound of the present invention against mutant non-small cell lung cancer cells H1975
(L858R/T790M-EGFR)增殖抑制作用  (L858R/T790M-EGFR) proliferation inhibition
参照测试实施例 1 实验方法进行测定， 通过计算获得实施例化合 物对于 H1975细胞的 IC50值: Refer to Test Example 1 Experimental method for measurement, and obtain the example compound by calculation. IC 50 values for H1975 cells:
Figure imgf000034_0001
测试结果表明： 本发明化合物对非小细胞肺癌细胞 H1975 (L858R/T790M-EGFR)有良好的增殖抑制作用。 申请人已对本发明作了完整详细的说明。 显然， 在阅读了本发明的 上述内容之后， 本领域技术人员可以在不违背本发明精神的原则下对本 发明作出各种修饰、改动或修改，这些等价形式同样落于本申请所附权 利要求书所限定的范围。
Figure imgf000034_0001
The test results show that the compound of the present invention has a good proliferation inhibition effect on non-small cell lung cancer cells H1975 (L858R/T790M-EGFR). The applicant has made a complete and detailed description of the invention. It will be apparent to those skilled in the art that the present invention may be modified, modified or modified without departing from the spirit and scope of the invention. The scope defined by the book.

Claims

权 利 要 求 Rights request
1. 通式 (I)表示的苯并吗啉化合物或其药学上可接受的盐 , A benzomorpholine compound represented by the formula (I) or a pharmaceutically acceptable salt thereof,
Figure imgf000035_0001
Figure imgf000035_0001
(I) (I)
其中： among them:
R1选自下列一组基团： 氢、 素、 酰基、 氨基、 羟基、 巯基、 氰 基、 硝基、 羧基、 C^Ce烷氧基以及取代或未取代的（^~( 6烷基； R 1 is selected from the group consisting of hydrogen, ketone, acyl, amino, hydroxy, decyl, cyano, nitro, carboxy, C^Ce alkoxy, and substituted or unsubstituted (^~( 6 alkyl;
R2选自下列一组基团： 氨基、 取代或未取代的 烷基、 取代 或未取代的芳基、 取代或未取代的杂芳基、 取代或未取代的 C3〜(： 7环 烷基以及取代或未取代的 3~7元杂环烷基； R 2 is selected from the group consisting of amino, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted C 3 ～(: 7 naphthenic a substituted or unsubstituted 3-7 membered heterocycloalkyl group;
R3选自带有 0~5个选自 A组基团的取代基的芳基、 杂芳基或稠合 杂芳基或者 R3为 -CO-R4, 其中 R4为带有 0~5个选自 A组基团的取代 基的芳基、 杂芳基或稠合杂芳基； 以及 R 3 is selected from an aryl group, a heteroaryl group or a fused heteroaryl group having 0 to 5 substituents selected from the group A group or R 3 is -CO-R 4 , wherein R 4 is a group having 0~ 5 aryl, heteroaryl or fused heteroaryl groups selected from the group consisting of Group A groups;
A组基团选自下列一组： 1¾素、 羟基、 巯基、 氰基、 硝基、 羧基、 C广 C6烷氧基、 （^〜0：6烷巯基、 取代或未取代的（^〜( 6烷基、 取代或未 取代的 C3~C7环烷基、取代或未取代的 3~7元杂环烷基、 -NRR'、 -S02R、 -CONRR，、 -NHS02R以及 -NHCOR, 其中的 R和 R'分别独立地为氢、 取代或未取代的 C 烷基、 取代或未取代的芳基、 取代或未取代的 杂芳基、 取代或未取代的 C3〜C7环烷基、 或者取代或未取代的 3~7元 杂环烷基。 Group A groups are selected from the group consisting of: 13⁄4, hydroxy, decyl, cyano, nitro, carboxy, C-C 6 alkoxy, (^~0: 6 alkyl fluorenyl, substituted or unsubstituted (^~ ( 6- alkyl, substituted or unsubstituted C 3 -C 7 cycloalkyl, substituted or unsubstituted 3-7-membered heterocycloalkyl, -NRR', -S0 2 R, -CONRR, -NHS0 2 R alkyl and C -NHCOR, wherein R and R 'are each independently hydrogen, a substituted or unsubstituted, a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, a substituted or unsubstituted C 3 ~ C 7 cycloalkyl, or substituted or unsubstituted 3-7-membered heterocycloalkyl.
2. 如权利要求 1所述的通式 (I)化合物或其药学上可接受的盐， 其 中：  2. A compound of formula (I), or a pharmaceutically acceptable salt thereof, according to claim 1, wherein:
R1选自下列一组基团： 氢、 卤素、 羟基、 烷基和 〜0 6烷 氧基； 和 /或 R 1 is selected group the group consisting of: hydrogen, halo, hydroxy, alkoxy, alkyl, and ~ 0 6; and / or
R2选自 d~C6烷基或者卤素取代的 C6~14芳基、 5~6元杂芳基或 5〜6 元杂环基； 和 /或 R 2 is selected from d to C 6 alkyl or halogen substituted C 6 ~ 14 aryl, 5 to 6 -membered heteroaryl or 5 to 6 a heterocyclic group; and/or
R3为带有 0~4个选自 A组基团的取代基的 C6~14芳基、 含有 1~4 个选自 N、S和 0的杂原子的 5〜6元单环杂芳基或者含有 1〜4个选自 N、 S和 0的杂原子的 5~6元单环杂芳基相互稠合或与苯环稠合而成的双 环式或三环式稠合杂芳基， 或者 R3为 -CO-R4， 其中的 R4为带有 0〜4 个选自 A组基团的取代基的 C6~14芳基或含有 1~4个选自 N、 S和 0的 杂原子的 5~6元杂芳基； 所述的 A组取代基选自卤素、 氨基、 羟基、 巯基、 氰基、 硝基、 羧基、 烷氧基、 （^~ 6烷巯基、 取代或未取 代的 C广 C6烷基、 -NRR'、 -NHCOR和 -S02R， 其中的 R和 R'分别独立 地为氢、 取代或未取代的 C C6烷基、 取代或未取代的 CrC6环烷基或 者取代或未取代的 C3-C6杂环烷基。 R 3 is C substituted with 0-4 substituents selected from Group A group having 6 to 14 aryl group, containing 1 to 4 heteroatoms selected from N, 5~6 membered S heteroatom and monocyclic heteroaryl 0 a bicyclic or tricyclic fused heteroaryl group formed by condensing a 5- to 6-membered monocyclic heteroaryl group having 1 to 4 hetero atoms selected from N, S and 0 or fused to a benzene ring. or R 3 is -CO-R 4, wherein R 4 is with C 0~4 substituents selected from the group consisting of a 6 to 14 or an aryl group containing 1 to 4 heteroatoms selected from N, S and a 5- to 6-membered heteroaryl group of a hetero atom of 0; the substituent of the group A is selected from the group consisting of halogen, amino, hydroxy, decyl, cyano, nitro, carboxy, alkoxy, (^~ 6 alkyl fluorenyl, substituted) Or unsubstituted C-C 6 alkyl, -NRR', -NHCOR and -S0 2 R, wherein R and R' are each independently hydrogen, substituted or unsubstituted C 6 alkyl, substituted or unsubstituted C r C 6 cycloalkyl or substituted or unsubstituted C 3 -C 6 heterocycloalkyl.
3. 如权利要求 2所述的通式 (I)化合物或其药学上可接受的盐， 其 中 R1为 C^ 烷基或 d~C4烷氧基。 Formula (I) compound or a pharmaceutically acceptable salt thereof according to claim 2, wherein R 1 is C ^ alkyl or d ~ C 4 alkoxy.
4. 如权利要求 2所述的通式 (I)化合物或其药学上可接受的盐， 其 中 R2为 素取代的苯基。 2 according to the general formula as claimed in claim (I) compound or a pharmaceutically acceptable salt thereof, wherein R 2 is phenyl substituted prime.
5. 如权利要求 2所述的通式 (I)化合物或其药学上可接受的盐， 其 中 R3为带有 0~3个选自 A组的取代基的 C6~14芳基， 优选苯基、 萘基、 蒽基和菲基； 或者为带有 0〜3个选自 A组的取代基的含有 1~3个选自 N、 S、 0的杂原子 5~6元单环杂芳基、特别是含有 1~3个 N原子的 5~6 元单环杂芳基、 优选含有 1~2个 N原子的 6元单环杂芳基， 优选嘧啶 基、 吡啶基、 哒嗪基、 吡嗪基； 或者为带有 0~3个选自 A组的取代基 的含有 1~3个选自 N、 S和 0的杂原子的 5~6元单环杂芳基相互稠合 或与苯环稠合而成的双环式或三环式稠合杂芳基， 其中所述 环式稠 合杂芳基优选苯并嘧啶基、 噻吩并嘧啶基、 呋喃并嘧啶基、 苯并噻吩 基、 苯并噻二唑基、 苯并噻唑基、 苯并咪唑基、 吲哚基、 异吲哚基、 吲唑基、 喹啉基、 异喹啉基和喹唑啉基， 其中所述三环式稠合杂芳基 优选苯并噻吩并嘧啶基、 吡 "秦并噻吩并苯基、 吡嗪并噻吩并嘧啶基、 吡嗪并呋喃并嘧啶基、 苯并呋喃并嘧啶基、 吡嗪并呋喃并苯基、 苯并 噻吩并吡啶基、 吡嗪并噻吩并吡啶基、 苯并呋喃并吡啶基和吡嗪并呋 喃并吡啶基； 或者 R3为 -CO-R4, 其中的 R4为带有 0〜3个选自 A组基 团的取代基的 。芳基， 优选苯基和萘基； 或者为带有 0~3个选自 A 组基团的取代基的含有 1~3个 N原子的 5〜6元单环杂芳基， 优选嘧啶 基、 吡啶基、 哒嗪基和吡嗪基； 其中所述的 A组取代基选自 [¾素、 氨 基、 羟基、 巯基、 氰基、 硝基、 羧基、 C! 烷氧基、 （^〜( 4烷巯基、 C Ct烷基、 -NRR'、 -NHCOR和 -S02R, 其中的 R和 R'分别独立地为 氢、 C广 C4烷基、 C3〜C6环烷基或 3~6元杂环烷基。 5. The claim 2 of the formula (I) compound or a pharmaceutically acceptable salt thereof, wherein R 3 is C substituted with 0 to 3 substituents selected from the group A having 6 to 14 aryl group, preferably a phenyl group, a naphthyl group, an anthracenyl group and a phenanthryl group; or a 5- to 6-membered monocyclic heterocyclic ring having 1 to 3 hetero atoms selected from N, S, and 0, having 0 to 3 substituents selected from the group A; An aryl group, particularly a 5- to 6-membered monocyclic heteroaryl group having 1 to 3 N atoms, preferably a 6-membered monocyclic heteroaryl group having 1 to 2 N atoms, preferably a pyrimidinyl group, a pyridyl group or a pyridazinyl group. Or a pyridyl group; or a 5- to 6-membered monocyclic heteroaryl group having 1 to 3 hetero atoms selected from N, S and 0, having 0 to 3 substituents selected from Group A, or fused to each other or a bicyclic or tricyclic fused heteroaryl group fused to a benzene ring, wherein the cyclic fused heteroaryl group is preferably a benzopyrimidinyl group, a thienopyrimidinyl group, a furanopyrimidinyl group, a benzothienyl group a benzothiadiazolyl, a benzothiazolyl, benzimidazolyl, anthracenyl, isodecyl, oxazolyl, quinolyl, isoquinolyl and quinazolinyl, wherein the tricyclic ring Fused fused heteroaryl is preferably benzothienopyrimidinyl, pyridyl "Qinthylthienophenyl, pyrazinothienopyrimidinyl, pyrazinofuranopyrimidinyl, benzofuranpyrimidinyl, pyrazinofuranophenyl, benzo Thienopyridyl, pyrazino and thienopyridyl, benzofuropyridinyl and pyrazinofuranopyridyl; or R 3 is -CO-R 4 , wherein R 4 is 0 to 3 Substituents from Group A groups. An aryl group, preferably a phenyl group and a naphthyl group; or a 5- to 6-membered monocyclic heteroaryl group having 1 to 3 N atoms, having 0 to 3 substituents selected from the group A group, preferably a pyrimidinyl group, Pyridyl, pyridazinyl and pyrazinyl; wherein the group A substituent is selected from the group consisting of [3⁄4, amino, hydroxy, decyl, cyano, nitro, carboxy, C! alkoxy, (^~( 4 Alkanoyl, C Ct alkyl, -NRR', -NHCOR and -S0 2 R, wherein R and R' are each independently hydrogen, C-C 4 alkyl, C 3 -C 6 cycloalkyl or 3~ 6-membered heterocycloalkyl.
6. 如权利要求 5所述的通式 (I)化合物或其药学上可接受的盐， 其 中 R3为带有 0~2个选自 素、 (^~4烷基或 d~4烷氧基的取代基的苯基。 The compound of the formula (I) or a pharmaceutically acceptable salt thereof, according to claim 5, wherein R 3 is a group having 0 to 2 selected from a group consisting of a substance, a (^~ 4 alkyl group or a d- 4 alkoxy group) a phenyl group of a substituent.
7. 如权利要求 5所述的通式 (I)化合物或其药学上可接受的盐， 其 中 R3为带有 0~2个选自 ι¾素、 氨基、 羟基、 巯基、 氰基、 硝基、 羧基、 CH:4烷氧基、 d 烷巯基、 C广 C4烷基、 -NRR'、 -NHCOR和 -S02R 的取代基的嘧啶基、 吡啶基、 哒嗪基或吡嗪基。 The compound of the formula (I) or a pharmaceutically acceptable salt thereof, according to claim 5, wherein R 3 is a group having 0 to 2 selected from the group consisting of ι3⁄4, amino, hydroxy, decyl, cyano, nitro a pyrimidinyl group, a pyridyl group, a pyridazinyl group or a pyrazinyl group having a substituent of a carboxyl group, a CH: 4 alkoxy group, a d-alkyl group, a C-C 4 alkyl group, -NRR', -NHCOR and -S0 2 R.
8. 如权利要求 5所述的通式 (I)化合物或其药学上可接受的盐， 其 中 R3为带有 0~3个选自 1¾素、 氨基、 羟基、 巯基、 氰基、 硝基、 羧基、 C广 C4烷氧基、 烷巯棊、 C广 烷基、 -NRR'、 -NHCOR和 -S02R 的取代基的苯并嘧啶基、 噻吩并嘧啶基、 呋喃并嘧啶基、 喹啉基、 异 喹啉基、 喹唑啉基、 苯并噻吩并嘧啶基、 吡嗪并噻吩并苯基、 吡嗪并 噻，，分并嘧啶基或吡嗪并呋喃并嘧啶基， 其中 R和 R'分别独立地为氢、 C广 C4烷基或 C3〜C6环烷。 The compound of the formula (I) or a pharmaceutically acceptable salt thereof, according to claim 5, wherein R 3 is a group having 0 to 3 selected from the group consisting of a tetra-, an amino group, a hydroxyl group, a decyl group, a cyano group and a nitro group. a benzopyrimidinyl group, a thienopyrimidinyl group, a furanopyrimidinyl group of a substituent of a carboxyl group, a C-C 4 alkoxy group, an alkane oxime, a C-polyalkyl group, -NRR', -NHCOR and -S0 2 R, Quinolinyl, isoquinolyl, quinazolinyl, benzothienopyrimidinyl, pyrazinothienophenyl, pyrazinothio, pyridopyrimidyl or pyrazinofuranopyrimidinyl, wherein R And R' are each independently hydrogen, C-C 4 alkyl or C 3 -C 6 naphthenic.
9. 如权利要求 5所述的通式 (I)化合物或其药学上可接受的盐， 其 中 R3为 -CO-R4, 其中的 R4为带有 0~2个选自卤素、 C C4烷氧基或 C^ 烷基的取代基的苯基、 吡啶基或嘧啶基。 The compound of the formula (I) or a pharmaceutically acceptable salt thereof, according to claim 5, wherein R 3 is -CO-R 4 , wherein R 4 is 0 to 2 selected from halogen, CC a phenyl, pyridyl or pyrimidinyl group of a 4 -alkoxy or C^ alkyl substituent.
10. 如权利要求 1 所述的通式 (I)化合物， 选自下列化合物或其药 学上可接受的盐：  10. A compound of formula (I) according to claim 1 selected from the group consisting of the following compounds or a pharmaceutically acceptable salt thereof:
2，4-二氟 -N- {2-曱氧基 -5-[4- (吡嗪并 [3'，2':4,5]噻吩并 [3,2-d]嘧啶 -4- 基) -3,4-二氢 -2//-1 ,4-苯并 [b][l,4]哺嗪 -6-基]吡啶 -3-基}苯磺酰胺； 2,4-二氟善 {2-甲氧基 -5-[4- (噻吩并 [3,2-d]嘧啶 -4-基 )-3,4-二氢 -2 -1,4-苯并 [b][l，4]恶嗪 -6-基]吡啶 -3-基}苯磺酰胺； . 2,4-Difluoro-N- {2-decyloxy-5-[4-(pyrazino[3',2':4,5]thieno[3,2-d]pyrimidin-4-yl -3,4-dihydro-2//-1,4-benzo[b][l,4]oxazin-6-yl]pyridin-3-yl}benzenesulfonamide; 2,4-difluoro-{2-methoxy-5-[4-(thieno[3,2-d]pyrimidin-4-yl)-3,4-dihydro-2-1,4-benzene And [b][l,4]oxazin-6-yl]pyridin-3-yl}benzenesulfonamide;
2,4-二氟 - {2-甲氧基 -5-[4-(6-硝基喹唑啉 -4-基) -3,4-二氢 - ^-l，4- 苯并[b][l,4]哺嗪-6-基]吡啶-3-基}苯磺酰胺；  2,4-Difluoro-{2-methoxy-5-[4-(6-nitroquinazolin-4-yl)-3,4-dihydro-^-l,4-benzo[b [l,4] oxazin-6-yl]pyridin-3-yl}benzenesulfonamide;
2,4-二氟 - -{2-甲氧基 -5-[4-(6-乙酰胺基喹唑啉 -4-基） -3,4-二氢 -2 -1，4-苯并 [b][l，4]嚅嗪 -6-基]吡啶 -3-基}苯磺酰胺；  2,4-Difluoro-{2-methoxy-5-[4-(6-acetamidoquinazolin-4-yl)-3,4-dihydro-2-1,4-benzo [b][l,4]oxazin-6-yl]pyridin-3-yl}benzenesulfonamide;
2,4-二氟 -N- {2-曱氧基 -5-[4-(嘧啶 -4-基 )-3,4-二氢 -2H- 1，4-苯并 [b][l,4 恶嗪 -6-基]吡啶 -3-基}苯磺酰胺；  2,4-Difluoro-N- {2-decyloxy-5-[4-(pyrimidin-4-yl)-3,4-dihydro-2H-1,4-benzo[b][l, 4 Oxazine-6-yl]pyridin-3-yl}benzenesulfonamide;
2，4-二氟 -V-{2-甲氧基 -5-[4-(2-氨基嘧啶 -4-基) -3,4-二氢 -2/ -1,4-苯 并 [b][l，4] 嗪 -6-基]吡啶 -3-基}苯磺酰胺；  2,4-Difluoro-V-{2-methoxy-5-[4-(2-aminopyrimidin-4-yl)-3,4-dihydro-2/-1,4-benzo[b ][l,4]azin-6-yl]pyridin-3-yl}benzenesulfonamide;
2,4-二氟 - -{2-曱氧基 -5-[4-(6-(甲磺酰基）噻吩并 [3 ,2-d]嘧啶 -4- 基) -3,4-二氢 -2 -1，4-苯并 [b][l,4]哺嗪 -6-基]吡啶 -3-基}苯磺酰胺；  2,4-Difluoro-{2-decyloxy-5-[4-(6-(methylsulfonyl)thieno[3,2-d]pyrimidin-4-yl)-3,4-dihydro -2-1,4-benzo[b][l,4]oxazin-6-yl]pyridin-3-yl}benzenesulfonamide;
2,4-二氟 -N-{2-甲氧基 -5-[4-(2-环丙曱酰胺基嘧啶 -4-基) -3,4-二氢 -2? -1，4-苯并 [b][l,4]嚅嗪 -6-基]吡啶 -3-基}苯磺酰胺；  2,4-Difluoro-N-{2-methoxy-5-[4-(2-cyclopropionamidopyrimidin-4-yl)-3,4-dihydro-2?-1,4- Benzo[b][l,4]oxazin-6-yl]pyridin-3-yl}benzenesulfonamide;
2,4-二氟善 {2-甲氧基 -5-[4-(2-乙酰胺基嘧啶 -4-基）-3 ,4-二氢 -2 -1,4-苯并 [b][l，4]嚅嗪 -6-基]吡啶 -3-基}苯磺酰胺；  2,4-difluoro-{2-methoxy-5-[4-(2-acetamidopyrimidin-4-yl)-3,4-dihydro-2-1,4-benzo[b] [l,4]oxazin-6-yl]pyridin-3-yl}benzenesulfonamide;
2，4-二氟 -TV- {2-曱氧基 -5-[4- (烟酰基） -3,4-二氢 - ?/- 1，4-苯并 [b][l,4]嚅嗪 -6-基]吡啶 -3-基}苯磺酰胺；  2,4-Difluoro-TV- {2-decyloxy-5-[4-(nicotinoyl)-3,4-dihydro-?/- 1,4-benzo[b][l,4] Pyridazin-6-yl]pyridin-3-yl}benzenesulfonamide;
2，4-二氟 - -{2-甲氧基 -5-[4-(6-异丙氧基烟酰基) -3,4-二氢 -2 ,4- 苯并 [b][l，4]嚅嗪 -6-基]吡啶 -3-基}苯磺酰胺；  2,4-difluoro-{2-methoxy-5-[4-(6-isopropoxynicotinoyl)-3,4-dihydro-2,4-benzo[b][l, 4] pyridazin-6-yl]pyridin-3-yl}benzenesulfonamide;
2,4-二氟 -N- {2-曱氧基 -5-[4-(2-异丙氧基异烟酰基）-3,4-二氢 -2 /-1,4_苯并 [b][l,4 恶嗪 -6-基]吡啶 -3-基}苯磺酰胺； 2,4-Difluoro-N- {2-decyloxy-5-[4-(2-isopropoxy-isonicotinyl)-3,4-dihydro- 2 /-1, 4 _benzo[ b] [l, 4 oxazin-6-yl] pyridin-3-yl} benzenesulfonamide;
2,4-二氟 - {2-甲氧基 -5-[4-(2-氨基 -6-曱基嘧啶 -4-基) -3,4-二氢 -2/7-1,4-苯并 [b][l，4]嚅嗪 -6-基]吡啶 -3-基}苯磺酰胺； 以及  2,4-Difluoro-{2-methoxy-5-[4-(2-amino-6-mercaptopyrimidin-4-yl)-3,4-dihydro-2/7-1,4- Benzo[b][l,4]oxazin-6-yl]pyridin-3-yl}benzenesulfonamide;
2,4-二氟 -N- {2-曱氧基 -5-[4-(吡啶 -4-基 )-3,4-二氢 -2H- 1 ,4-苯并 [b][ 1，4]-恶嗪 -6-基]吡啶 -3-基}苯磺酰胺。  2,4-Difluoro-N- {2-decyloxy-5-[4-(pyridin-4-yl)-3,4-dihydro-2H- 1 ,4-benzo[b][ 1, 4]-oxazin-6-yl]pyridin-3-yl}benzenesulfonamide.
11. 药物组合物， 它包含权利要求 1-10之任一项所述的通式 (I)化 合物或其药学上可接受的盐和药学上可接受的载体。 A pharmaceutical composition comprising the compound of the formula (I) according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
12. 权利要求 1-10之任一项的式 (I)化合物或其药学上可接受的盐 在制备用于***的药物方面的应用。 12. Use of a compound of formula (I) according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of a tumor.
13. 疾病的治疗方法， 所述疾病可通过抑制 PI3K活性而得以减轻 或治疗， 优选肿瘤， 包括给需要对此治疗的个体施用权利要求 1-10之 任一项的式 (I)化合物或其药学上可接受的盐的步骤。  13. A method of treating a disease, which can be alleviated or treated by inhibiting PI3K activity, preferably a tumor, comprising administering to a subject in need of such treatment a compound of formula (I) according to any one of claims 1 to 10 or A step of a pharmaceutically acceptable salt.
14.制备权利要求 1所述的式 (I)化合物的方法， 它包括下列步骤： 当 R3为芳基、 杂芳基或稠合芳基时， 14. A process for the preparation of a compound of formula (I) according to claim 1 which comprises the steps of: when R 3 is aryl, heteroaryl or fused aryl,
方法一： method one:
Figure imgf000039_0001
Figure imgf000039_0001
以 2-氨基 -4-溴苯酚为起始原料，与式 la化合物发生亲核取代反应， 得到式 lb化合物， 式 lb化合物与 1,2-二溴乙烷发生闭环反应， 得到式 Ic化合物， 在常规过渡金属催化剂存在的条件下， 式 Ic化合物与联硼 酸频那醇酯发生偶联反应，生成式 Id化合物，式 Id化合物与 A 5-X-2-R1 吡啶 -3-基] -R2-磺酰胺在常规过渡金属催化剂催化下发生偶联反应， 得 到通式 (I)化合物； 或者 Starting from 2-amino-4-bromophenol as a starting material, a nucleophilic substitution reaction with a compound of the formula la gives a compound of the formula lb, and a compound of the formula lb is subjected to ring closure reaction with 1,2-dibromoethane to obtain a compound of the formula Ic. The compound of formula Ic is coupled with the boronic acid pinacol ester in the presence of a conventional transition metal catalyst to form a compound of formula Id, a compound of formula Id and A 5-X-2-R 1 pyridin-3-yl] - The R 2 -sulfonamide is subjected to a coupling reaction under the catalysis of a conventional transition metal catalyst to obtain a compound of the formula (I);
方法 Method
Figure imgf000039_0002
Figure imgf000039_0002
(I) 以 2-氨基 -4-溴苯酴为起始原料， 在常规过渡金属催化剂存在下与 联硼酸 3-氨基 -4-羟基苯基硼酸频那醇酯， 然后使其在常规过渡金属催化剂存在的条件下与 A 5-X-2-R1吡啶 -3- 基] -R2-磺酰胺发生偶联反应， 得到化合物 Ie， 化合物 Ie与 la化合物发 生亲核取代反应， 得到式 If化合物， 式 If化合物与 1,2-二溴乙烷发生 闭环反应， 得到通式 (I)化合物； (I) Starting from 2-amino-4-bromophenylhydrazine in the presence of a conventional transition metal catalyst with triammonium 3-amino-4-hydroxyphenylboronic acid, and then allowing it to be present in a conventional transition metal catalyst. Under the condition, a coupling reaction with A 5-X-2-R 1 pyridin-3-yl]-R 2 -sulfonamide is carried out to obtain a compound Ie, and a compound of the compound Ie and the la compound is subjected to a nucleophilic substitution reaction to obtain a compound of the formula If If the compound is ring-closed with 1,2-dibromoethane to obtain a compound of the formula (I);
当 R3为 -CO-R4时， When R 3 is -CO-R 4 ,
Figure imgf000040_0001
Figure imgf000040_0001
以 6-溴 -3,4-二氢 苯并 [b][l，4 恶嗪为起始原料， 在常规过渡金 属催化剂存在下与联硼酸频那醇酯发生偶联反应， 得到化合物 Ig， 在 常规过渡金属催化剂存在的条件下， 化合物 Ig与 A45-X-2-R1吡啶 -3- 基] -R2-磺酰胺发生偶联反应，得到化合物 Ih,化合物 Ih与酰氯 X-CO-R4 发生酰化反应， 得到式 li化合物， 式 li化合物在碱性条件下反应， 得 到通式 (I)化合物； The compound Ig is obtained by coupling with 6-bromo-3,4-dihydrobenzo[b][l,4 oxazine as a starting material in the presence of a conventional transition metal catalyst with a boranoic acid pinacol ester. The compound Ig is coupled with A45-X-2-R 1 pyridin-3-yl]-R 2 -sulfonamide in the presence of a conventional transition metal catalyst to give compound Ih, compound Ih and acid chloride X-CO- R 4 is acylated to give a compound of formula li, and the compound of formula li is reacted under basic conditions to give a compound of formula (I);
上述反应流程中， R1 R2、 R3和 R4的定义与权利要求 1 中的相同； la 为卤代的 R3; 以及 X代表卤素。 In the above reaction scheme, R 1 R 2 , R 3 and R 4 have the same definitions as in claim 1; la is a halogenated R 3 ; and X represents a halogen.
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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2015506344A (en) * 2011-12-22 2015-03-02 ノバルティス アーゲー Dihydro-benzo-oxazine and dihydro-pyrido-oxazine derivatives

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106146534B (en) * 2016-06-29 2017-12-08 福州大学 A kind of three ring Benzomorpholine derivatives and preparation method thereof
CN108239075B (en) * 2016-12-26 2021-07-02 中国医学科学院药物研究所 Quinazoline compound, preparation method, application and pharmaceutical composition thereof

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004056820A1 (en) * 2002-12-20 2004-07-08 Warner-Lambert Company Llc Benzoxazines and derivatives thereof as inhibitors of pi3ks
WO2009055418A1 (en) * 2007-10-22 2009-04-30 Smithkline Beecham Corporation Pyridosulfonamide derivatives as pi3 kinase inhibitors
WO2009155121A2 (en) * 2008-05-30 2009-12-23 Amgen Inc. Inhibitors of pi3 kinase

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE69811867T2 (en) * 1997-03-03 2003-11-20 Boehringer Ingelheim Pharma SMALL MOLECULES APPLICABLE IN TREATING INFLAMMATORY DISEASES
US6087350A (en) * 1997-08-29 2000-07-11 University Of Pittsburgh Of The Commonwealth System Of Higher Education Use of pretreatment chemicals to enhance efficacy of cytotoxic agents
WO2001081346A2 (en) * 2000-04-25 2001-11-01 Icos Corporation Inhibitors of human phosphatidyl-inositol 3-kinase delta
WO2001083456A1 (en) * 2000-04-27 2001-11-08 Yamanouchi Pharmaceutical Co., Ltd. Condensed heteroaryl derivatives
GB0524786D0 (en) * 2005-12-05 2006-01-11 Glaxo Group Ltd Compounds

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004056820A1 (en) * 2002-12-20 2004-07-08 Warner-Lambert Company Llc Benzoxazines and derivatives thereof as inhibitors of pi3ks
WO2009055418A1 (en) * 2007-10-22 2009-04-30 Smithkline Beecham Corporation Pyridosulfonamide derivatives as pi3 kinase inhibitors
WO2009155121A2 (en) * 2008-05-30 2009-12-23 Amgen Inc. Inhibitors of pi3 kinase

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2015506344A (en) * 2011-12-22 2015-03-02 ノバルティス アーゲー Dihydro-benzo-oxazine and dihydro-pyrido-oxazine derivatives
US9539260B2 (en) 2011-12-22 2017-01-10 Novartis Ag Dihydro-benzo-oxazine and dihydro-pyrido-oxazine derivatives
US9763952B2 (en) 2011-12-22 2017-09-19 Novartis Ag Dihydro-benzo-oxazine and dihydro-pyrido-oxazine derivatives

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