WO2015081783A1 - Dérivé de pyrrolo[2,1-f][1,2,4]triazine, son procédé de préparation et utilisation - Google Patents

Dérivé de pyrrolo[2,1-f][1,2,4]triazine, son procédé de préparation et utilisation Download PDF

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WO2015081783A1
WO2015081783A1 PCT/CN2014/091238 CN2014091238W WO2015081783A1 WO 2015081783 A1 WO2015081783 A1 WO 2015081783A1 CN 2014091238 W CN2014091238 W CN 2014091238W WO 2015081783 A1 WO2015081783 A1 WO 2015081783A1
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amino
methylpyrrolo
amide
triazin
compound
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PCT/CN2014/091238
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English (en)
Chinese (zh)
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陈庆财
戴建国
陈祥峰
孙敏
孙焕亮
王飞栋
陈磊
孔陵生
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江苏奥赛康药业股份有限公司
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Priority claimed from CN201310655586.0A external-priority patent/CN104693203A/zh
Priority claimed from CN201310656253.XA external-priority patent/CN104693204A/zh
Application filed by 江苏奥赛康药业股份有限公司 filed Critical 江苏奥赛康药业股份有限公司
Publication of WO2015081783A1 publication Critical patent/WO2015081783A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
    • 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
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the present invention relates to a pyrrolo[2,1-f][1,2,4]triazine derivative, a process for the preparation thereof, and a pharmaceutical composition containing the same, and as a therapeutic agent (particularly protein kinase inhibition Use of the agent, the invention also relates to intermediates of such compounds.
  • Protein Kinases are the largest family of proteins known to date. All kinases have very conserved catalytic cores and diverse regulatory patterns, and the primary structures of these catalytic cores have high homology, but each Classes have their specificity. The role of protein kinases is to transfer the gamma-phosphate groups of ATP to specific amino acid residues on their substrates. Based on the specificity of these amino acid residues, protein kinases can be classified into four classes, the main two of which are Protein Tyrosine Kinase (PTK) and protein serine/threonine kinase (STK).
  • PTK Protein Tyrosine Kinase
  • STK protein serine/threonine kinase
  • the kinase domains of these two classes of enzymes are approximately 250 to 300 amino acid residues in size, and the amino acid residue sequences of the catalytic domains are approximately similar. More importantly, these sequences appear as a set of highly conserved, even fully conserved amino acid motifs embedded in regions of poor conservation of amino acid residue sequences.
  • the tyrosine kinase family is widely involved in cell signaling in a transmembrane receptor or cytoplasmic form, and can be broadly classified into three categories according to its location in the cell: 1) Receptor Tyrosine Kinases (RTKs) ), a single transmembrane protein; 2) cytoplasmic tyrosine kinases, such as the Src family, the Tec family, the ZAP70 family, the JAK family, etc.; 3) nuclear tyrosine kinases such as Abl and Wee; They can be divided into two categories: oncogene products and growth factor receptors.
  • the protein kinase in the human genome consists of 30 tyrosine kinase families and contains about 90 different protein tyrosine kinases, 58 of which are receptor tyrosine kinases.
  • Tyrosine kinases play an important role in the carcinogenic transformation of cells: gene amplification and overexpression of PTK (eg, overexpression of EGFR and HER-2 in many cancers) leads to increased tyrosine kinase activity, which in turn changes downstream Cell signaling; gene rearrangement (similar to chromosomal translocation) also produces fusion proteins with sustained kinase activity, such as the P210 BCR-ABL fusion protein found in chronic myeloid leukemia; in addition, PTK kinase region or extracellular domain function Sexual variation or deletion will continue to activate kinase activity, for example due to the absence of amino acids 6-273 in the extracellular region, the EGFRvIII mutant is in a continuous activation state and is common in solid tumors.
  • PTK eg, overexpression of EGFR and HER-2 in many cancers
  • gene rearrangement similar to chromosomal translocation
  • fusion proteins with sustained kinase activity such as the P210 BCR
  • tyrosine kinases both receptor and non-receptor
  • EGFR HER-1 overexpression and ovarian cancer
  • head and neck cancer esophageal cancer
  • breast cancer breast cancer
  • stomach cancer esophageal cancer
  • breast cancer breast cancer
  • stomach cancer etc.
  • HER-2 overexpression and breast cancer, ovarian cancer, prostate cancer, lung The poor treatment effect of cancer and bone cancer patients.
  • tyrosine kinase inhibitors play an important role in cancer treatment, the problem of primary and acquired drug resistance has become a bottleneck restricting the further improvement of its efficacy. Therefore, in-depth study of its drug resistance mechanism, seeking to overcome drug resistance The treatment has become an urgent task in the field of cancer research.
  • the clinical treatment strategies for tyrosine kinase inhibitors are mainly involved in some aspects: (1) The study found that irreversible tyrosine kinase inhibitors can be used against gefitinib and erlotidine in patients with cancer with EGFR mutations. Nie's resistance.
  • irreversible tyrosine kinase inhibitors bind permanently to the tyrosine kinase domain of EGFR; (2) "bypass activation pathway" is resistant to EGFR tyrosine kinase inhibitors Drugs play an important role, tumor cell signaling is interlaced, single-target drugs can not block all signal transduction of tumor cells, so the development of multi-target targeted therapeutic drugs has become a new research trend; (3) some biology Molecular markers are associated with the efficacy of EGFR tyrosine kinase inhibitors.
  • the object of the present invention is to provide a novel pyrrolo[2,1-f][1,2,4]triazine derivative, the tautomers, stereoisomers thereof and pharmaceutically acceptable thereof salt. It is also an object of the present invention to provide a process for the preparation of the above compounds, and the use thereof as a receptor tyrosine kinase inhibitor for the preparation of a medicament for the treatment of a proliferative disease such as cancer.
  • novel pyrrolo[2,1-f][1,2,4]triazine derivatives are compounds of formula I:
  • R 1 is phenyl or heteroaryl, which is optionally substituted by one or more groups selected from the group consisting of halogen, alkyl, alkenyl, alkynyl, alkoxy, nitro, hydroxy, cycloalkane Or heteroalicyclic, cyano, decyl, acyl, thioacyl, amino, haloalkyl, haloalkoxy, ester, aryl and heteroaryl;
  • R 2 is halogen, -NR 3 R 4 , -OR 5 or -SR 6 ;
  • R 3 and R 4 are independently hydrogen, alkyl, cycloalkyl, aryl or heteroaryl, or R 3 and R 4 are taken together with the N atom to form an N-containing heteroaryl or heteroalicyclic group;
  • R 5 and R 6 are independently hydrogen, alkyl, cycloalkyl, aryl or heteroaryl.
  • R 1 is phenyl and pyridyl, optionally substituted with one or more groups selected from a group consisting of: halogen or alkynyl group
  • R 1 is 3-fluorophenyl, 3-fluoro-4-chlorophenyl, 3-ethynylphenyl or pyridyl.
  • R 2 is -NR 3 R 4 ,
  • R 3 and R 4 are independently hydrogen, alkyl, cycloalkyl, aryl or heteroaryl, or R 3 and R 4 are taken together with the N atom to form an N-containing heteroaryl or heteroalicyclic group;
  • R 2 is -NR 3 R 4 ,
  • R 3 and R 4 are independently alkyl, or R 3 and R 4 are taken together with the N atom to form an N-containing heteroaryl or heteroalicyclic group;
  • R 2 is -NR 3 R 4 ,
  • R 3 and R 4 are independently alkyl, or R 3 and R 4 are taken together with the N atom to form an N-containing heteroaryl, unsubstituted or alkyl substituted heteroalicyclic group;
  • R 2 is -NR 3 R 4 ,
  • R 3 and R 4 are independently alkyl, or R 3 and R 4 are taken together with the N atom to form an optionally substituted group: piperazino, morpholino, piperidino, pyrrolidino. Or imidazolyl.
  • Preferred compounds of formula I of the invention include, but are not limited to:
  • the "pharmaceutically acceptable salt” means those salts which retain the biological effectiveness and properties of the parent compound. Such salts include, but are not limited to:
  • Inorganic acids include, but are not limited to, hydrochloric acid, hydrobromic acid, nitric acid, phosphoric acid, metaphosphoric acid, sulfuric acid, sulfurous acid, perchloric acid, etc.
  • organic acids include, but are not limited to, acetic acid, propionic acid, acrylic acid, oxalic acid, (D) or (L) Malic acid, fumaric acid, maleic acid, hydroxybenzoic acid, ⁇ -hydroxybutyric acid, methoxybenzoic acid, phthalic acid, methanesulfonic acid, ethanesulfonic acid, naphthalene-1-sulfonic acid, naphthalene- 2-sulfonic acid, p-toluenesulfonic acid, salicylic acid, tartaric acid, citric acid, lactic acid, mandelic acid, succ
  • an organic base such as ethanolamine, diethanolamine, or the like. Ethanolamine, tromethamine, N-methylglucamine, and the like.
  • Another aspect of the invention provides a process for the preparation of a compound of formula I or a pharmaceutically acceptable salt thereof.
  • the present invention first provides a compound of formula II as a key intermediate for the preparation of compounds of formula I:
  • the compound of the formula Ia can be directly prepared from the compound of the formula II, and the compound of the formula Ia can be further prepared to obtain the compound of the formula I, thereby completing the preparation of the compound of the formula I.
  • Z is a halogen and Y is as defined in the above compound of formula I.
  • the compound of the formula Ia is subjected to a nucleophilic substitution reaction with a substituted amine to further obtain a compound of the formula I,
  • Z is a halogen
  • Y and R 2 are as defined in the compound of formula I above, R 2 is not halogen
  • the resulting compound of formula I is converted, if desired, to its salt, especially to a pharmaceutically acceptable salt.
  • compositions characterized in that the pharmaceutical composition comprises the above compound of the formula I or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable diluent or carrier.
  • the compounds of the invention may be administered in the form of a prodrug.
  • a prodrug is a compound of the above formula I which has a pharmacological action after transformation in vivo.
  • Prodrugs can be used to modify the physicochemical or pharmacokinetic properties of the compounds of the invention.
  • Prodrugs can be formed when the compounds of the present invention contain suitable groups or substituent groups to which a modifying nature group can be attached.
  • Another aspect of the present invention provides a use of a compound of the formula I or a pharmaceutically acceptable salt thereof, and a pharmaceutical composition comprising the compound or a salt thereof for the preparation of a medicament for treating a protein kinase-related disease.
  • the protein kinase is selected from the group consisting of an EGFR receptor tyrosine kinase and a HER-2 receptor tyrosine kinase.
  • Alkyl means a saturated aliphatic hydrocarbon group of 1 to 20 carbon atoms, including both straight-chain and branched-chain groups (the range of numbers referred to in this application, such as “1-20", refers to the group, In the case of an alkyl group, it may contain 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 20 carbon atoms).
  • An alkyl group having 1 to 4 carbon atoms is referred to as a lower alkyl group. When the lower alkyl group has no substituent, it is referred to as an unsubstituted lower alkyl group.
  • the alkyl group is an alkyl group having 1 to 10 carbon atoms, such as methyl, ethyl, propyl, 2-propyl, n-butyl, isobutyl, t-butyl, pentyl and the like.
  • the alkyl group is a lower alkyl group having 1 to 4 carbon atoms, such as a methyl group, an ethyl group, a propyl group, a 2-propyl group, a n-butyl group, an isobutyl group or a t-butyl group.
  • the alkyl group can be substituted or unsubstituted.
  • the substituent is preferably one or more, more preferably 1 to 3, preferably 1 or 2 substituents, which are independently preferably selected from the group consisting of halogen, hydroxy, lower alkoxy A aryl group, an aryl group, an aryloxy group, a heteroaryl ring group, a heteroalicyclic group, and an ester group.
  • Cycloalkyl means a monocyclic or fused ring that is all carbon (the "fused” ring means that each ring in the system shares an adjacent pair of carbon atoms with other rings in the system), containing 4 -9 carbon atoms, preferably 5, 6 or 7 carbon atoms, more preferably 5 or 6 carbon atoms, wherein one or more of the rings does not have a fully linked pi-electron system, optionally comprising one or more double bonds and / or three-button form of unsaturated state.
  • the cycloalkyl group can be substituted and unsubstituted.
  • unsubstituted cycloalkyl groups are, without limitation, cyclopropane, cyclobutane, cyclopentane, cyclohexane, adamantane, cyclohexadiene, cycloheptane and cycloheptatriene.
  • the substituent is preferably one or more groups each selected from the group consisting of alkyl, aryl, heteroaryl, heteroalicyclic, hydroxy, alkoxy, aryloxy, fluorenyl, Alkyl, cyano, halogen, carbonyl, thiocarbonyl, C-amido, N-amido, nitro and amino.
  • Aryl means an all-carbon monocyclic or fused polycyclic group of 6 to 18 carbon atoms, preferably 6 to 12 carbon atoms, more preferably 6 to 10 carbon atoms, having a fully conjugated pi-electron system.
  • the aryl group can be substituted or unsubstituted.
  • Non-limiting examples of unsubstituted aryl groups are phenyl, naphthyl, anthryl and phenanthryl.
  • the substituents are preferably selected as one or more, more preferably one, two or three, still more preferably one or two, independently selected from halo, alkyl, alkenyl, alkynyl, Alkoxy, nitro, hydroxy, cycloalkyl or heteroalicyclic, cyano, decyl, acyl, thioacyl, amino, nitro, haloalkyl, haloalkoxy, ester, aryl or heteroaryl And other groups.
  • the aryl group is optionally substituted by one or two substituents independently selected from halo, lower alkyl, trihaloalkyl, alkenyl, alkynyl, cyano, ester or nitro.
  • Heteroaryl means a monocyclic or fused ring radical of 5 to 18 ring atoms, preferably containing from 5 to 12 ring atoms, more preferably from 6 to 10 ring atoms, containing one, two, three Or four ring heteroatoms selected from N, O or S, the remaining ring atoms being C, and additionally having a fully conjugated pi-electron system.
  • Non-limiting examples of unsubstituted heteroaryl groups are pyrrole, furan, thiophene, imidazole, oxazole, thiazole, pyrazole, pyrimidine, quinoline, isoquinoline, indole, tetrazole, triazine, oxazole, pyridine, iso Oxazole, isothiazole, furazan, pyridazine, thiadiazole, hydrazine, isoindole, benzofuran, benzothiophene, benzimidazole, benzothiazole, benzofurazan, Quinazoline, naphthyridine, pyrazolopyrimidine.
  • the heteroaryl ring can be substituted or unsubstituted.
  • the substituents are preferably one or more, more preferably one, two or three, and even more preferably one or two, independently selected from the group consisting of halogen, alkyl, alkene. , alkynyl, alkoxy, nitro, hydroxy, cycloalkyl or heteroalicyclic, cyano, decyl, acyl, thioacyl, amino, nitro, haloalkyl, haloalkoxy, ester, aromatic a group such as a base or a heteroaryl group.
  • Preferred heteroaryl groups are optionally substituted by one or two substituents independently selected from halo, lower alkyl, trihaloalkyl, alkenyl, alkynyl, cyano, ester or nitro.
  • Heteroalicyclic means a monocyclic or fused ring radical having from 5 to 18, preferably from 6 to 12, more preferably from 6 to 9 ring atoms in the ring, wherein one or two ring atoms are selected from N a hetero atom of O or S(O)m (where m is an integer from 0 to 2), and the remaining ring atoms are C. These rings may have one or more double bonds, but these rings do not have a fully conjugated pi-electron system.
  • Non-limiting examples of unsubstituted heteroalicyclic groups are pyrrolidinyl, piperidino, morpholinyl, piperazino, thiomorpholinyl, homopiperazino and the like.
  • the heteroalicyclic group can be substituted or unsubstituted.
  • the substituents are preferably one or more, more preferably one, two or three, and still more preferably one or two, independently selected from the group consisting of lower alkyl, trihalo Alkyl, halogen, hydroxy, lower alkoxy, fluorenyl, (lower alkyl)thio, cyano, carbonyl, thiocarbonyl, O-carbamoyl, N-carbamoyl, O-thiocarbamoyl , N-thiocarbamoyl, C-amido, N-acylamino, nitro, N-sulfonylamino, S-sulfonylamino.
  • Preferred heteroaryl groups are optionally substituted by one or two substituents independently selected from halo, lower alkyl, trihaloalkyl, cyano, ester or nitro.
  • Hydroxyl means an -OH group.
  • alkenyl means a straight or branched chain group having 2 to 6 carbon atoms and 1 to 3 double bonds.
  • Alkynyl means a straight or branched chain group having 2 to 6 carbon atoms and 1 to 3 triple bonds.
  • Alkoxy means -O-(alkyl) and -O-(cycloalkyl), wherein alkyl and cycloalkyl are as defined above. Representative examples include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy, and the like.
  • Aryloxy means -O-aryl and -O-heteroaryl, wherein aryl and heteroaryl are as defined above. Representative examples include, but are not limited to, phenoxy, pyridyloxy, furanoxy, thienyloxy, pyrimidinyloxy, pyrazinyloxy, and the like, and derivatives thereof.
  • Indexl means a -SH group.
  • Acyl means a -C(O)-R' group wherein R' is selected from the group consisting of hydrogen, unsubstituted alkyl, trihalomethyl, unsubstituted cycloalkyl, optionally one. Or a plurality, preferably 1, 2 or 3 aryl groups selected from the group consisting of an unsubstituted alkyl group, a trihalomethyl group, an unsubstituted alkoxy group and a halogen, the above alkyl group, a cycloalkyl group, an alkoxy group and The aryl group is as defined above.
  • Thioacyl means -C(S)-R', wherein R' is as defined above.
  • Ester group means a -C(O)O-R' group wherein R' is as defined above, but R' cannot be hydrogen.
  • Halogen means fluoro, chloro, bromo or iodo, preferably fluoro, chloro or bromo.
  • Cyano means a -CN group.
  • Amino means a -NH 2 group.
  • Niro means a -NO 2 group.
  • Haloalkyl means that the alkyl group is substituted by one or more of the same or different halo atoms, preferably the lower alkyl group as defined above is substituted by one or more of the same or different halo atoms, wherein the alkyl group is as defined above, for example -CH 2 Cl, -CF 3 , -CH 2 CF 3 , -CH 2 CCl 3 and the like.
  • Haloalkoxy means an alkoxy group substituted with one or more identical or different halogen atoms, wherein the alkoxy group is as defined above, e.g. -OCH 2 Cl, -OCF 3, -OCH2CF 3, -OCH 2 CCl 3 and the like.
  • heteroaryl optionally substituted with one or two substituents means that the heteroaryl group may be unsubstituted or substituted with one or two substituents.
  • “Pharmaceutical composition” means a mixture comprising one or more of the compounds described herein, or a physiologically/pharmaceutically acceptable salt or prodrug thereof, and other chemical components, as well as other components such as physiological/pharmaceutically acceptable Carrier and excipients.
  • the purpose of the pharmaceutical composition is to promote the administration of the organism and to exert biological activity by absorption of the active ingredient.
  • Step 1 1a (20.0 g, 0.09 mol), phosphorus oxychloride (41.4 g, 0.27 mol), 4-dimethylaminopyridine (DMAP) (32.0 g, 0.27 mol) and 150 ml of toluene were placed in a 250 ml reaction flask. Heated to 110 ° C under nitrogen for 6 h. After the end of the reaction was monitored by TLC (the same), the reaction mixture was cooled to room temperature, and the solvent was evaporated under reduced pressure. The mixture was stirred and evaporated to dryness. ) 19.1 g, yield 88.8%.
  • DMAP 4-dimethylaminopyridine
  • Step 2 Compound 1b (19.0 g, 79.5 mmol), 3-chloro-4-[(3-fluorobenzyl)oxyaniline (19.9 g, 79.5 mmol) and 300 ml of isopropanol were placed in a 500 ml reaction flask. After reacting at 80 ° C for 2 h, the reaction solution was cooled to room temperature, filtered, and the filter cake was washed with isopropyl alcohol and dried in vacuo to give 33.2 g (yel. ESI-MS m/z: 455 [M+H] + .
  • Step 3 Compound 1c (33.0 g, 0.07 mol), sodium hydroxide (9.60 g, 0.22 mol), 150 ml of methanol and 150 ml of water were placed in a 500 ml reaction flask, reacted at 60 ° C for 2 h, and the reaction solution was cooled to room temperature with acetic acid. After adjusting to a pH of about 7, a large amount of solid was precipitated, filtered, and the filter cake was washed with water and dried in vacuo to give a pale yellow solid (Compound 1d) 28.4 g, yield 95.3%. ESI-MS m/z: 427 [M+H] + .
  • Step 4 Compound 1d (28.0 g, 65.7 mmol), diphenylphosphoryl DPPA (24.8 g, 78.9 mmol), triethylamine (7.96 g, 78.9 mmol), 300 ml of toluene were placed in a 500 ml reaction flask, nitrogen The mixture was heated to 85 ° C under the protection for 4 h, then tert-butanol (11.1 g, 0.15 mol) was added and the mixture was stirred at 85 ° C overnight. The reaction solution was cooled to room temperature, and then purified and purified, mjjjjjjj ESI-MS m/z: 498 [M+H] + .
  • Step 5 Compound 1e (7.50 g, 15.1 mmol), 14 ml of trifluoroacetic acid and 150 ml of dichloromethane were placed in a 250 ml reaction flask and allowed to react at room temperature for 4 h. The reaction mixture was concentrated to give crystals crystals crystals crystals crystals crystals crystals ESI-MS m/z: 398[M+H] + .
  • Step 6 Compound 1f (4.00 g, 9.00 mmol), 4-bromocrotonic acid (1.47 g, 9.00 mmol), HATU (5.13 g, 13.5 mmol), triethylamine (1.36 g, 13.5 mmol), DMF 50 ml
  • 4-bromocrotonic acid (1.47 g, 9.00 mmol
  • HATU 5.13 g, 13.5 mmol
  • triethylamine (1.36 g, 13.5 mmol
  • DMF 50 ml In a 250 ml reaction flask, react at room temperature for 1 h. The reaction mixture was poured into 200 ml of water, and extracted with methylene chloride (100 m ⁇ 3).
  • Step 1 Intermediate 1b (19.0 g, 79.5 mmol), 3-chloro-4-(pyridin-2-ylmethoxy)phenylamine (18.7 g, 79.5 mmol) and 300 mL of isopropanol were placed in a 500 ml reaction flask. After reacting at 80 ° C for 2 h, the reaction solution was cooled to room temperature, filtered, washed with EtOAc EtOAc (EtOAc) ESI-MS m/z: 438 [M+H] + .
  • EtOAc EtOAc EtOAc
  • Step 2 Compound 1h (31.0 g, 0.07 mol), sodium hydroxide (9.60 g, 0.21 mol), 150 ml of methanol and 150 ml of water were placed in a 500 ml reaction flask, reacted at 60 ° C for 2 h, and the reaction solution was cooled to room temperature with acetic acid. Adjusted to a pH of about 7, a large amount of solids precipitated. Filtration, washing with solid water and drying in vacuo to give a pale yellow solid (Compound 1 i) 29.3 g. ESI-MS m/z: 410 [M+H] + .
  • Step 3 Compound 1i (29.0 g, 66.2 mmol), diphenylphosphoryl DPPA (27.3 g, 99.3 mmol), triethylamine (10.1 g, 99.3 mmol), 300 ml of toluene were placed in a 500 ml reaction flask, nitrogen The reaction was carried out at 85 ° C for 4 h under protection. Then tert-butanol (14.7 g, 0.20 mol) was added at 85 ° C overnight. The reaction mixture was cooled to room temperature, and then purified and purified, mjjjjjjj ESI-MS m/z: 481 [M+H] + .
  • Step 4 Compound 1j (8.50 g, 16.1 mmol), 14 ml of trifluoroacetic acid and 150 ml of dichloromethane were placed in a 250 ml reaction flask and allowed to react at room temperature for 4 h. The reaction was quenched by TLC. EtOAc was evaporated. ESI-MS m/z: 381 [M+H] + .
  • Step 5 Compound 1k (4.50 g, 10.6 mmol), 4-bromocrotonic acid (1.72 g, 10.6 mmol), HATU (6.04 g, 15.9 mmol), triethylamine (1.61 g, 15.9 mmol), DMF 50 ml
  • EtOAc EtOAc
  • EtOAc EtOAc
  • ESI-MS m/z 527 [M+H] + .
  • Step 1 Compound 1a (20.0 g, 0.09 mol), phosphorus oxychloride (41.4 g, 0.27 mol), 4-dimethylaminopyridine (DMAP) (32.0 g, 0.27 mol) and 150 ml of toluene were placed in a 250 ml reaction flask. The reaction was carried out at 110 ° C for 6 h under a nitrogen atmosphere. The reaction liquid was cooled to room temperature, and the solvent was evaporated under reduced pressure. Water (200 ml) was added and stirred, and a large amount of solid was precipitated. Filtration, the filter cake was washed with ice water and dried in vacuo to give a pale yellow solid (Compound 1b) 19.1 g.
  • DMAP 4-dimethylaminopyridine
  • Step 2 Compound 1b (19.0 g, 79.5 mmol), 3-chloro-4-fluoroaniline (11.6 g, 79.5 mmol) and 300 ml of isopropanol were placed in a 500 ml reaction flask, reacted at 80 ° C for 2 h, and the reaction solution was cooled to After filtration at room temperature, the solid was washed with isopropyl alcohol and dried under vacuum overnight to yield 28.5 g (yield of compound 1c').
  • Step 4 Compound 1d' (24.0 g, 75.0 mmol), diphenylphosphoryl DPPA (24.8 g, 0.09 mol), triethylamine (9.09 g, 0.09 mol), 300 ml of toluene were placed in a 500 ml reaction flask. Heat to 85 ° C under nitrogen for 4 h. Then tert-butanol (11.1 g, 0.15 mol) was added at 85 ° C overnight. The reaction mixture was cooled to room temperature, and then purified and purified tolulululululululululululululululululululululululu ESI-MS m/z: 392[M+H] + .
  • Step 5 Compound 1e' (7.00 g, 17.9 mmol), 14 ml of trifluoroacetic acid and 150 ml of dichloromethane were placed in a 250 ml reaction flask and allowed to react at room temperature for 4 h. The reaction mixture was concentrated to give crystals crystals crystals crystals crystals crystals crystals ESI-MS m/z: 292 [M+H] + .
  • Step 6 Compound 1f' (3.50 g, 12.0 mmol), 4-bromocrotonic acid (1.96 g, 12.0 mmol), 2-(7-azobenzotriazole)-N,N,N',N 'Tetramethylurea hexafluorophosphate HATU (5.47 g, 14.4 mmol), triethylamine (2.42 g, 24.0 mmol) and DMF 50 ml were placed in a 250 ml reaction flask and allowed to react at room temperature for 1 h.
  • Step 1 Compound 1b (19.0 g, 79.5 mmol), 3-ethynylaniline (9.22 g, 79.5 mmol) and 300 ml of isopropanol were placed in a 500 ml reaction flask and reacted at 80 ° C for 2 h. After completion of the reaction, the reaction mixture was cooled to room temperature and filtered, and the solid was washed with isopropyl alcohol and dried under vacuum overnight to give a yellow solid (compound 1h') 23.8 g, yield 93.7%.
  • Step 2 Compound 1h' (23.0 g, 71.8 mmol), sodium hydroxide (8.62 g, 0.22 mol), 150 ml of methanol and 150 ml of water were placed in a 500 ml reaction flask, reacted at 60 ° C for 2 h, and the reaction solution was cooled to room temperature. The acetic acid was adjusted to a pH of about 7, and a large amount of solid was precipitated. Filtration, washing with solid water and drying in vacuo to give a pale yellow solid (Comp. ESI-MS m/z: 293 [M+H] + .
  • Step 4 Compound 1j' (6.50 g, 17.9 mmol), 14 ml of trifluoroacetic acid and 150 ml of dichloromethane were placed in a 250 ml reaction flask and allowed to react at room temperature for 4 h. The reaction mixture was concentrated to give crystals crystals crystals crystals crystals crystals crystals ESI-MS m/z: 264 [M+H] + .
  • Step 5 Compound 1k' (3.00 g, 11.5 mmol), 4-bromocrotonic acid (1.87 g, 11.5 mmol), HATU (6.56 g, 17.3 mmol), triethylamine (1.77 g, 17.3 mmol) DMF 50 ml
  • a 250 ml reaction flask react at room temperature for 1 h.
  • the reaction mixture was poured into 200 ml of water, and extracted with methylene chloride (100 ml ⁇ 3).
  • the organic phase was combined and dried over anhydrous sodium sulfate.
  • the yellow solid (Compound 1L') was obtained in a yield of 48.2%.
  • the activity of the EGFR inhibitor at the cellular level was determined. ELSA using methods, IC 50 values of inhibitors of EGFR intracellular levels of EGF-induced EGFR phosphorylation inhibition.
  • the EGFR protein was captured in the cell lysate by coating the antibody with EGFR on a solid support.
  • the phosphorylated EGFR protein in the cells is then detected with an antibody against phosphotyrosine: since the phosphorylated EGFR protein is recognized by an antibody against phosphotyrosine, the HRP secondary antibody, TMB is used to display the post reading. Different levels of phosphorylation have different readings; the greater the degree of phosphorylation, the higher the reading.
  • Human oral epidermoid carcinoma KB cell line (Chinese Academy of Sciences Type Culture Collection Cell Bank); DMEM medium (Gibco, C12430); FBS (Gibco, 12657-029); trypsin-EDTA (Gibco, 25200) double antibody ( Biyuntian Biotechnology Research Institute, C0222); 100mm cell culture dish (Corning, 430167); 96-well cell culture plate (Costar, 3599); 96-well V-bottom plate (Costar, 3896); 96-well ELISA plate (Costar, 2592) ;Recombinant Human EGF (Peprotech, AF-100-15); Lysis (Sheng Xing, SN338); Anti-human EGF R/ErbB1 Antibody (R&D, AF231); Anti-phosphotyrosine clone 4G10 (Millipore, 05-231) ; Goat Anti-Mouse IgG HRP Conjugate (Novagen, 71045-3);
  • Anti-human EGF R/ErbB1 Antibody was diluted to 0.2 ⁇ g/mL, 100 ⁇ L per well, added to an ELISA plate, and coated at 4 ° C overnight.
  • the inhibition rate is calculated using the following formula:
  • the cellular level of EGFR kinase activity of the compounds of the present invention was determined by the above test, and the measured IC 50 values are shown in the following table.
  • the measurement was carried out by conventional use of a tetrazolium bromide (MTT) method.
  • MTT tetrazolium bromide
  • the succinate dehydrogenase in the living cell mitochondria reduces the exogenous tetrazolium bromide to insoluble blue-violet crystals (Formazan) and deposits in the cells, whereas dead cells do not.
  • Dimethyl sulfoxide (DMSO) can dissolve purple crystals in cells, and its light absorption value is detected by an enzyme-linked immunosorbent detector at a wavelength of 570 nm, which can indirectly reflect the number of living cells.
  • DMSO dimethyl sulfoxide
  • adopt The MTT assay measures the ability of a target compound to inhibit cell proliferation while using similar assays for any cancer cell using methods well known in the art.
  • Human gastric cancer NCI-N87 cell line (Chinese Academy of Sciences Type Culture Collection Cell Bank); 100mm cell culture dish (Corning, 430167); 96-well cell culture plate (Costar, 3599); 96-well V bottom plate (Costar, 3896); Disposable pipette (Costar, Cat. No.
  • RMPI-1640 medium Gibco, C22400
  • FBS Gibco, 12657
  • Trypsin-EDTA Gibco, 25200
  • Double antibody Double antibody
  • MTT SIGMA, M2128
  • centrifuge Eppendorf, centrifuge 5810R
  • carbon dioxide incubator Thermo, FORMA SERIES II
  • ultra clean bench Thermo, 1300SERIES A2
  • constant temperature oscillator Eppendorf, Thermomixer comfort
  • microplate reader TECAN, Infinite M200pro
  • NCI-N87 cells with a degree of fusion greater than 80% were collected by centrifugation, centrifuged at 15,000 cells/well, and plated in a 96-well cell culture plate at 100 ⁇ L per well, placed in a 37 ° C, 5% CO 2 incubator overnight. .
  • the pernatrine was aspirated, 180 ⁇ L of fresh medium was added to each well, and 20 ⁇ L of a medium containing the test compound (concentration from 10 ⁇ M to 1 nM) was added, and 20 ⁇ L of the medium was added to the blank group, and three parallel holes were set for each concentration.
  • the data fit was processed by Prism software (GraphPad Software, Inc) using the lg (IC50) formula.
  • the calculated IC 50 value is cellular toxic effects of a particular compound.
  • the N87 cell proliferation-inhibiting activity of the compound of the present invention was measured by the above test, and the measured IC 50 values are shown in the following table.

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Abstract

Cette invention concerne un composé représenté par la formule (I), et un tautomère, stéréoisomère et sel de celui-ci, leur procédé de préparation et utilisation, ledit composé pouvant servir d'inhibiteur de tyrosine kinase pour prévenir ou traiter les maladies prolifératives telles que le cancer.
PCT/CN2014/091238 2013-12-06 2014-11-17 Dérivé de pyrrolo[2,1-f][1,2,4]triazine, son procédé de préparation et utilisation WO2015081783A1 (fr)

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CN201310655586.0A CN104693203A (zh) 2013-12-06 2013-12-06 一种吡咯并[2,1-f][1,2,4]三嗪类衍生物及其制备方法和用途
CN201310656253.XA CN104693204A (zh) 2013-12-06 2013-12-06 吡咯并[2,1-f][1,2,4]三嗪类衍生物及其制备方法和用途
CN201310656253.X 2013-12-06
CN201310655586.0 2013-12-06

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CN1351498A (zh) * 1999-05-21 2002-05-29 布里斯托尔-迈尔斯斯奎布公司 激酶的吡咯并三嗪抑制剂
CN1622946A (zh) * 2000-11-17 2005-06-01 布里斯托尔-迈尔斯斯奎布公司 治疗与p38激酶有关的症状的方法以及用作激酶抑制剂的吡咯并三嗪化合物
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CN1665817A (zh) * 2002-07-19 2005-09-07 百时美施贵宝公司 制备某些吡咯并三嗪化合物的方法
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CN102918045A (zh) * 2010-03-31 2013-02-06 百时美施贵宝公司 作为蛋白激酶抑制剂的取代的吡咯并三嗪

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