WO2015081783A1 - Pyrrolo[2,1-f][1,2,4]triazine derivative, and preparation method and use thereof - Google Patents

Pyrrolo[2,1-f][1,2,4]triazine derivative, and preparation method and use thereof Download PDF

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Publication number
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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French (fr)
Chinese (zh)
Inventor
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 CN201310656253.XA external-priority patent/CN104693204A/en
Priority claimed from CN201310655586.0A external-priority patent/CN104693203A/en
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/en

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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.

Abstract

A compound as represented by formula (I), and tautomer, stereoisomer and salt thereof, and preparation method and use thereof; the compound can serve as a tyrosine kinase inhibitor for preventing or treating proliferative diseases such as cancer.

Description

吡咯并[2,1-f][1,2,4]三嗪类衍生物及其制备方法和用途Pyrrolo[2,1-f][1,2,4]triazine derivatives, preparation method and use thereof 技术领域Technical field
本发明涉及一种吡咯并[2,1-f][1,2,4]三嗪类衍生物、其制备方法及含有该衍生物的药物组合物以及其作为治疗剂(特别是蛋白激酶抑制剂)的用途，本发明还涉及该类化合物的中间体。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.
背景技术Background technique
蛋白激酶(Protein Kinases)是目前已知的最大蛋白家族，所有激酶都有非常保守的催化核心和多样的调控模式，并且这些催化核心的一级结构都有很高的同源性，但每一类都有其特异性。蛋白激酶的作用是将ATP的γ-磷酸基转移至它们底物上特定的氨基酸残基。依据这些氨基酸残基的特异性，蛋白激酶可以分为4类，其中主要的两类是蛋白酪氨酸激酶(Protein Tyrosine Kinase,PTK)和蛋白丝氨酸/苏氨酸激酶(STK)。这两类酶的激酶结构域大小约为250～300个氨基酸残基，催化域的氨基酸残基序列大致相近。更重要的是，这些序列表现为一组高度保守的，甚至是完全保守的氨基酸模体，这些模体却嵌埋在氨基酸残基序列保守性很差的区域之内。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). 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.
酪氨酸激酶家族以跨膜受体或胞质形式广泛地参与细胞信号传导，按其在细胞内的存在位置可大致分为三类：1)受体酪氨酸激酶(Receptor Tyrosine Kinases，RTKs)，为单次跨膜蛋白；2)胞质酪氨酸激酶，如Src家族、Tec家族、ZAP70家族、JAK家族等；3)核内酪氨酸激酶如Abl和Wee；如按基因的类型则可以分为两类：癌基因产物和生长因子受体。人类基因组中的蛋白激酶由30种酪氨酸激酶家族构成，包含约90种不同的蛋白酪氨酸激酶，其中58种为受体酪氨酸激酶。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.
酪氨酸激酶在细胞致癌性转化中具有重要作用：基因扩增和PTK的过度表达(例如在许多癌症中都发现EGFR和HER-2的过表达)导致酪氨酸激酶活性增强，进而改变下游细胞信号；基因重排(类似于染色体易位)也会产生具有持续激酶活性的融合蛋白，例如在慢性髓细胞白血病中发现的P210BCR-ABL融合蛋白；此外，PTK激酶区域或胞外区域功能性变异或缺失将持续激活激酶活性，例如由于缺少胞外区域中的6-273位氨基酸，EGFRvIII突变型处于持续激活状态，且常见于实体瘤。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.
许多酪氨酸激酶(包括受体型和非受体型)都与肿瘤有密切联系。临床研究显示酪氨酸激酶的过度表达或失调对肿瘤病人的预后以及病症的预测具有重要参考价值，如EGFR(HER-1)过度表达与卵巢癌、头颈癌、食道癌、乳腺癌、胃癌等多种癌症的预后不良有关。HER-2过度表达与乳腺癌、卵巢癌、前列腺癌、肺 癌和骨癌患者的差治疗效果有关。Many tyrosine kinases, both receptor and non-receptor, are closely associated with tumors. Clinical studies have shown that overexpression or dysregulation of tyrosine kinase has important reference value for the prognosis of tumor patients and the prediction of the disease, such as EGFR (HER-1) overexpression and ovarian cancer, head and neck cancer, esophageal cancer, breast cancer, stomach cancer, etc. A poor prognosis for many cancers. HER-2 overexpression and breast cancer, ovarian cancer, prostate cancer, lung The poor treatment effect of cancer and bone cancer patients.
酪氨酸激酶抑制剂虽然在癌症治疗中发挥了重要作用，但其原发与获得性耐药问题已经成为限制其疗效进一步提高的瓶颈，因此对其耐药机制的深入研究，寻找克服耐药的治疗方法，已经成为肿瘤研究领域的迫切任务。目前针对酪氨酸激酶抑制剂耐药问题，临床治疗策略主要涉及一些方面：(1)研究发现不可逆的酪氨酸激酶抑制剂可用于对抗有EGFR突变癌症患者的吉非替尼和厄洛替尼的耐药性。与可逆性酪氨酸激酶抑制剂不同的是，不可逆酪氨酸激酶抑制剂与EGFR的酪氨酸激酶区永久性结合；(2)“旁路激活途径”在EGFR酪氨酸激酶抑制剂耐药中发挥重要作用，肿瘤细胞信号传导相互交错，单靶点药物不能阻断肿瘤细胞所有信号转导，因此开发多靶点的靶向治疗药物成为新的研究趋势；(3)某些生物学分子标记物与EGFR酪氨酸激酶抑制剂疗效相关。为使EGFR酪氨酸激酶抑制剂的临床应用更为合理有效，需确定有效的预测靶标及最佳的检测方法，选择适合的患者接受酪氨酸激酶抑制剂治疗，进一步提高癌症的疗效和生存，最大限度地避免无效的治疗。Although 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. At present, 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. Unlike reversible tyrosine kinase inhibitors, 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. In order to make the clinical application of EGFR tyrosine kinase inhibitors more reasonable and effective, it is necessary to determine effective predictive targets and the best detection methods, and select suitable patients to receive tyrosine kinase inhibitor treatment to further improve the efficacy and survival of cancer. To minimize ineffective treatment.
发明内容Summary of the invention
本发明的目的在于提供一种新型的吡咯并[2,1-f][1,2,4]三嗪类衍生物，其互变异构体、立体异构体及其药学上可接受的盐。本发明的目的还包括提供上述化合物的制备方法，及其作为受体酪氨酸激酶抑制剂制备治疗增生性疾病如癌症的药物中的应用。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.
所述的新型的吡咯并[2,1-f][1,2,4]三嗪类衍生物为式I所示化合物：The novel pyrrolo[2,1-f][1,2,4]triazine derivatives are compounds of formula I:
Figure PCTCN2014091238-appb-000001
Figure PCTCN2014091238-appb-000001
其中，Y为-R1或
Figure PCTCN2014091238-appb-000002
Where Y is -R 1 or
Figure PCTCN2014091238-appb-000002
R1为苯基或杂芳基，其可选地被一个或多个选自下列的基团所取代：卤素、烷基、烯基、炔基、烷氧基、硝基、羟基、环烷基或杂脂环基、氰基、巯基、酰基、硫代酰基、氨基、卤代烷基、卤代烷氧基、酯基、芳基和杂芳基；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;
R2为卤素、-NR3R4、-OR5或-SR6；R 2 is halogen, -NR 3 R 4 , -OR 5 or -SR 6 ;
R3和R4独立地为氢、烷基、环烷基、芳基或杂芳基，或者R3和R4与N原子合起来形成一个含N的杂芳基或杂脂环基；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;
R5和R6独立地为氢、烷基、环烷基、芳基或杂芳基。 R 5 and R 6 are independently hydrogen, alkyl, cycloalkyl, aryl or heteroaryl.
在一种实施方式中，上述化合物或其药学上可接受的盐，其中R1为苯基和吡啶基，其可选地被一个或多个选自下列的基团所取代：卤素或炔基；优选地，R1为3-氟苯基、3-氟-4-氯苯基、3-乙炔基苯基或吡啶基。In one embodiment, the above-described compound or a pharmaceutically acceptable salt thereof, wherein R 1 is phenyl and pyridyl, optionally substituted with one or more groups selected from a group consisting of: halogen or alkynyl group Preferably, R 1 is 3-fluorophenyl, 3-fluoro-4-chlorophenyl, 3-ethynylphenyl or pyridyl.
在一种实施方式中，上述化合物或其药学上可接受的盐，其中，In one embodiment, the above compound or a pharmaceutically acceptable salt thereof, wherein
优选地，R2为-NR3R4，Preferably, R 2 is -NR 3 R 4 ,
R3和R4独立地为氢、烷基、环烷基、芳基或杂芳基，或者R3和R4与N原子合起来形成一个含N的杂芳基或杂脂环基；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;
再优选地，R2为-NR3R4，Still preferably, R 2 is -NR 3 R 4 ,
R3和R4独立地为烷基，或者R3和R4与N原子合起来形成一个含N的杂芳基或杂脂环基；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;
再优选地，R2为-NR3R4，Still preferably, R 2 is -NR 3 R 4 ,
R3和R4独立地为烷基，或者R3和R4与N原子合起来形成一个含N的杂芳基、未取代的或烷基取代杂脂环基；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;
更优选地，R2为-NR3R4，More preferably, R 2 is -NR 3 R 4 ,
R3和R4独立地为烷基，或者R3和R4与N原子合起来形成任选取代的如下基团：哌嗪子基、吗啉子基、哌啶子基、吡咯烷子基或咪唑基。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.
本发明优选的通式I化合物包括但不限于：Preferred compounds of formula I of the invention include, but are not limited to:
(E)-N-{4-{{3-氯-4-[(3-氟苯基)甲氧基]苯基}氨基}-5-甲基吡咯并[2,1-f][1,2,4]三嗪-6基}-4-吗啉丁烯-2-酰胺(化合物1)；(E)-N-{4-{{3-chloro-4-[(3-fluorophenyl)methoxy]phenyl}amino}-5-methylpyrrolo[2,1-f][1 , 2,4]triazin-6-yl}-4-morpholinate-2-amide (Compound 1);
(E)-N-{4-{{3-氯-4-[(3-氟苯基)甲氧基]苯基}氨基}-5-甲基吡咯并[2,1-f][1,2,4]三嗪-6基}-4-(哌啶-1-基)丁烯-2-酰胺(化合物2)；(E)-N-{4-{{3-chloro-4-[(3-fluorophenyl)methoxy]phenyl}amino}-5-methylpyrrolo[2,1-f][1 , 2,4]triazin-6-yl}-4-(piperidin-1-yl)buten-2-amide (Compound 2);
(E)-N-{4-{{3-氯-4-[(3-氟苯基)甲氧基]苯基}氨基}-5-甲基吡咯并[2,1-f][1,2,4]三嗪-6基}-4-(4-甲基哌啶-1-基)丁烯-2-酰胺(化合物3)；(E)-N-{4-{{3-chloro-4-[(3-fluorophenyl)methoxy]phenyl}amino}-5-methylpyrrolo[2,1-f][1 , 2,4]triazin-6-yl}-4-(4-methylpiperidin-1-yl)buten-2-amide (Compound 3);
(E)-N-{4-{{3-氯-4-[(3-氟苯基)甲氧基]苯基}氨基}-5-甲基吡咯并[2,1-f][1,2,4]三嗪-6基}-4-(2-甲基哌啶-1-基)丁烯-2-酰胺(化合物4)；(E)-N-{4-{{3-chloro-4-[(3-fluorophenyl)methoxy]phenyl}amino}-5-methylpyrrolo[2,1-f][1 , 2,4]triazin-6-yl}-4-(2-methylpiperidin-1-yl)buten-2-amide (Compound 4);
(E)-N-{4-{{3-氯-4-[(3-氟苯基)甲氧基]苯基}氨基}-5-甲基吡咯并[2,1-f][1,2,4]三嗪-6基}-4-(1H-咪唑-1-基)丁烯-2-酰胺(化合物5)；(E)-N-{4-{{3-chloro-4-[(3-fluorophenyl)methoxy]phenyl}amino}-5-methylpyrrolo[2,1-f][1 , 2,4]triazin-6-yl}-4-(1H-imidazol-1-yl)buten-2-amide (Compound 5);
(E)-N-{4-{{3-氯-4-[(3-氟苯基)甲氧基]苯基}氨基}-5-甲基吡咯并[2,1-f][1,2,4]三嗪-6基}-4-(二甲胺基)丁烯-2-酰胺(化合物6)；(E)-N-{4-{{3-chloro-4-[(3-fluorophenyl)methoxy]phenyl}amino}-5-methylpyrrolo[2,1-f][1 , 2,4]triazin-6-yl}-4-(dimethylamino)buten-2-amide (compound 6);
(E)-N-{4-{{3-氯-4-[(3-氟苯基)甲氧基]苯基}氨基}-5-甲基吡咯并[2,1-f][1,2,4]三嗪-6基}-4-(二乙胺基)丁烯-2-酰胺(化合物7)；(E)-N-{4-{{3-chloro-4-[(3-fluorophenyl)methoxy]phenyl}amino}-5-methylpyrrolo[2,1-f][1 , 2,4]triazin-6-yl}-4-(diethylamino)buten-2-amide (compound 7);
(E)-N-{4-{{3-氯-4-[(3-氟苯基)甲氧基]苯基}氨基}-5-甲基吡咯并[2,1-f][1,2,4]三嗪-6基}-4-(吡咯烷-1-基)丁烯-2-酰胺(化合物8)；(E)-N-{4-{{3-chloro-4-[(3-fluorophenyl)methoxy]phenyl}amino}-5-methylpyrrolo[2,1-f][1 , 2,4]triazin-6-yl}-4-(pyrrolidin-1-yl)buten-2-amide (Compound 8);
(E)-N-{4-{{3-氯-4-[(3-氟苯基)甲氧基]苯基}氨基}-5-甲基吡咯并[2,1-f][1,2,4]三嗪-6基}-4-(4-甲基哌嗪-1-基)丁烯-2-酰胺(化合物9)； (E)-N-{4-{{3-chloro-4-[(3-fluorophenyl)methoxy]phenyl}amino}-5-methylpyrrolo[2,1-f][1 , 2,4]triazin-6-yl}-4-(4-methylpiperazin-1-yl)buten-2-amide (Compound 9);
(E)-N-{4-{{3-氯-4-[(吡啶-2-基)甲氧基]苯基}氨基}-5-甲基吡咯并[2,1-f][1,2,4]三嗪-6基}-4-(4-甲基哌啶-1-基)丁烯-2-酰胺(化合物10)；(E)-N-{4-{{3-chloro-4-[(pyridin-2-yl)methoxy]phenyl}amino}-5-methylpyrrolo[2,1-f][1 , 2,4]triazin-6-yl}-4-(4-methylpiperidin-1-yl)buten-2-amide (Compound 10);
(E)-N-{4-{{3-氯-4-[(吡啶-2-基)甲氧基]苯基}氨基}-5-甲基吡咯并[2,1-f][1,2,4]三嗪-6基}-4-(哌啶-1-基)丁烯-2-酰胺(化合物11)；(E)-N-{4-{{3-chloro-4-[(pyridin-2-yl)methoxy]phenyl}amino}-5-methylpyrrolo[2,1-f][1 , 2,4]triazin-6-yl}-4-(piperidin-1-yl)buten-2-amide (Compound 11);
(E)-N-{4-{{3-氯-4-[(吡啶-2-基)甲氧基]苯基}氨基}-5-甲基吡咯并[2,1-f][1,2,4]三嗪-6基}-4-(吡咯烷-1-基)丁烯-2-酰胺(化合物12)；(E)-N-{4-{{3-chloro-4-[(pyridin-2-yl)methoxy]phenyl}amino}-5-methylpyrrolo[2,1-f][1 , 2,4]triazin-6-yl}-4-(pyrrolidin-1-yl)buten-2-amide (Compound 12);
(E)-N-{4-{{3-氯-4-[(吡啶-2-基)甲氧基]苯基}氨基}-5-甲基吡咯并[2,1-f][1,2,4]三嗪-6基}-4-(1H-咪唑-1-基)丁烯-2-酰胺(化合物13)；(E)-N-{4-{{3-chloro-4-[(pyridin-2-yl)methoxy]phenyl}amino}-5-methylpyrrolo[2,1-f][1 , 2,4]triazin-6-yl}-4-(1H-imidazol-1-yl)buten-2-amide (compound 13);
(E)-N-{4-{{3-氯-4-[(吡啶-2-基)甲氧基]苯基}氨基}-5-甲基吡咯并[2,1-f][1,2,4]三嗪-6基}-4-(4-甲基哌嗪-1-基)丁烯-2-酰胺(化合物14)；(E)-N-{4-{{3-chloro-4-[(pyridin-2-yl)methoxy]phenyl}amino}-5-methylpyrrolo[2,1-f][1 , 2,4]triazin-6-yl}-4-(4-methylpiperazin-1-yl)buten-2-amide (Compound 14);
(E)-N-{4-{{3-氯-4-[(吡啶-2-基)甲氧基]苯基}氨基}-5-甲基吡咯并[2,1-f][1,2,4]三嗪-6基}-4-吗啉丁烯-2-酰胺(化合物15)；(E)-N-{4-{{3-chloro-4-[(pyridin-2-yl)methoxy]phenyl}amino}-5-methylpyrrolo[2,1-f][1 , 2,4]triazin-6-yl}-4-morpholinate-2-amide (compound 15);
(E)-N-{4-{{3-氯-4-[(吡啶-2-基)甲氧基]苯基}氨基}-5-甲基吡咯并[2,1-f][1,2,4]三嗪-6基}-4-(二乙胺基)丁烯-2-酰胺(化合物16)；(E)-N-{4-{{3-chloro-4-[(pyridin-2-yl)methoxy]phenyl}amino}-5-methylpyrrolo[2,1-f][1 , 2,4]triazin-6-yl}-4-(diethylamino)buten-2-amide (Compound 16);
(E)-N-{4-{{3-氯-4-[(吡啶-2-基)甲氧基]苯基}氨基}-5-甲基吡咯并[2,1-f][1,2,4]三嗪-6基}-4-(二甲胺基)丁烯-2-酰胺(化合物17)；(E)-N-{4-{{3-chloro-4-[(pyridin-2-yl)methoxy]phenyl}amino}-5-methylpyrrolo[2,1-f][1 , 2,4]triazin-6-yl}-4-(dimethylamino)buten-2-amide (compound 17);
(E)-N-{4-[(3-氯-4-氟苯基)氨基]-5-甲基吡咯并[2,1-f][1,2,4]三嗪-6-基}-4-(哌啶-1-基)丁烯-2-酰胺(化合物18)；(E)-N-{4-[(3-chloro-4-fluorophenyl)amino]-5-methylpyrrolo[2,1-f][1,2,4]triazin-6-yl }-4-(piperidin-1-yl)buten-2-amide (compound 18);
(E)-N-{4-[(3-氯-4-氟苯基)氨基]-5-甲基吡咯并[2,1-f][1,2,4]三嗪-6-基}-4-(4-甲基哌啶-1-基)丁烯-2-酰胺(化合物19)；(E)-N-{4-[(3-chloro-4-fluorophenyl)amino]-5-methylpyrrolo[2,1-f][1,2,4]triazin-6-yl }-4-(4-Methylpiperidin-1-yl)buten-2-amide (Compound 19);
(E)-N-{4-[(3-氯-4-氟苯基)氨基]-5-甲基吡咯并[2,1-f][1,2,4]三嗪-6-基}-4-(2-甲基哌啶-1-基)丁烯-2-酰胺(化合物20)；(E)-N-{4-[(3-chloro-4-fluorophenyl)amino]-5-methylpyrrolo[2,1-f][1,2,4]triazin-6-yl }-4-(2-methylpiperidin-1-yl)buten-2-amide (compound 20);
(E)-N-{4-[(3-氯-4-氟苯基)氨基]-5-甲基吡咯并[2,1-f][1,2,4]三嗪-6-基}-4-(二乙胺基)丁烯-2-酰胺(化合物21)；(E)-N-{4-[(3-chloro-4-fluorophenyl)amino]-5-methylpyrrolo[2,1-f][1,2,4]triazin-6-yl }-4-(diethylamino)buten-2-amide (Compound 21);
(E)-N-{4-[(3-氯-4-氟苯基)氨基]-5-甲基吡咯并[2,1-f][1,2,4]三嗪-6-基}-4-(吗啉-1-基)丁烯-2-酰胺(化合物22)；(E)-N-{4-[(3-chloro-4-fluorophenyl)amino]-5-methylpyrrolo[2,1-f][1,2,4]triazin-6-yl }-4-(morpholin-1-yl)buten-2-amide (compound 22);
(E)-N-{4-[(3-氯-4-氟苯基)氨基]-5-甲基吡咯并[2,1-f][1,2,4]三嗪-6-基}-4-(吡咯烷-1-基)丁烯-2-酰胺(化合物23)；(E)-N-{4-[(3-chloro-4-fluorophenyl)amino]-5-methylpyrrolo[2,1-f][1,2,4]triazin-6-yl }-4-(pyrrolidin-1-yl)buten-2-amide (compound 23);
(E)-N-{4-[(3-氯-4-氟苯基)氨基]-5-甲基吡咯并[2,1-f][1,2,4]三嗪-6-基}-4-(1H-咪唑-1-基)丁烯-2-酰胺(化合物24)；(E)-N-{4-[(3-chloro-4-fluorophenyl)amino]-5-methylpyrrolo[2,1-f][1,2,4]triazin-6-yl }-4-(1H-imidazol-1-yl)buten-2-amide (compound 24);
(E)-N-{4-[(3-氯-4-氟苯基)氨基]-5-甲基吡咯并[2,1-f][1,2,4]三嗪-6-基}-4-(二甲胺基)丁烯-2-酰胺(化合物25)；(E)-N-{4-[(3-chloro-4-fluorophenyl)amino]-5-methylpyrrolo[2,1-f][1,2,4]triazin-6-yl }-4-(dimethylamino)butene-2-amide (compound 25);
(E)-N-{4-[(3-氯-4-氟苯基)氨基]-5-甲基吡咯并[2,1-f][1,2,4]三嗪-6-基}-4-(N-甲基哌嗪-1-基)丁烯-2-酰胺(化合物26)；(E)-N-{4-[(3-chloro-4-fluorophenyl)amino]-5-methylpyrrolo[2,1-f][1,2,4]triazin-6-yl }-4-(N-methylpiperazin-1-yl)buten-2-amide (Compound 26);
(E)-N-{4-[(3-乙炔基苯基)氨基]-5-甲基吡咯并[2,1-f][1,2,4]三嗪-6-基}-4-(4- 甲基哌啶-1-基)丁烯-2-酰胺(化合物27)；(E)-N-{4-[(3-ethynylphenyl)amino]-5-methylpyrrolo[2,1-f][1,2,4]triazin-6-yl}-4 -(4- Methylpiperidin-1-yl)buten-2-amide (Compound 27);
(E)-N-{4-[(3-乙炔基苯基)氨基]-5-甲基吡咯并[2,1-f][1,2,4]三嗪-6-基}-4-(N-甲基哌嗪-1-基)丁烯-2-酰胺(化合物28)；(E)-N-{4-[(3-ethynylphenyl)amino]-5-methylpyrrolo[2,1-f][1,2,4]triazin-6-yl}-4 -(N-methylpiperazin-1-yl)buten-2-amide (Compound 28);
(E)-N-{4-[(3-乙炔基苯基)氨基]-5-甲基吡咯并[2,1-f][1,2,4]三嗪-6-基}-4-(二甲胺基)丁烯-2-酰胺(化合物29)；(E)-N-{4-[(3-ethynylphenyl)amino]-5-methylpyrrolo[2,1-f][1,2,4]triazin-6-yl}-4 -(dimethylamino)butene-2-amide (compound 29);
(E)-N-{4-[(3-乙炔基苯基)氨基]-5-甲基吡咯并[2,1-f][1,2,4]三嗪-6-基}-4-(1H-咪唑-1-基)丁烯-2-酰胺(化合物30)；(E)-N-{4-[(3-ethynylphenyl)amino]-5-methylpyrrolo[2,1-f][1,2,4]triazin-6-yl}-4 -(1H-imidazol-1-yl)buten-2-amide (compound 30);
(E)-N-{4-[(3-乙炔基苯基)氨基]-5-甲基吡咯并[2,1-f][1,2,4]三嗪-6-基}-4-(2-甲基哌啶-1-基)丁烯-2-酰胺(化合物31)；(E)-N-{4-[(3-ethynylphenyl)amino]-5-methylpyrrolo[2,1-f][1,2,4]triazin-6-yl}-4 -(2-methylpiperidin-1-yl)buten-2-amide (Compound 31);
(E)-N-{4-[(3-乙炔基苯基)氨基]-5-甲基吡咯并[2,1-f][1,2,4]三嗪-6-基}-4-(二乙胺基)丁烯-2-酰胺(化合物32)；(E)-N-{4-[(3-ethynylphenyl)amino]-5-methylpyrrolo[2,1-f][1,2,4]triazin-6-yl}-4 -(diethylamino)buten-2-amide (compound 32);
(E)-N-{4-[(3-乙炔基苯基)氨基]-5-甲基吡咯并[2,1-f][1,2,4]三嗪-6-基}-4-(吗啉-1-基)丁烯-2-酰胺(化合物33)；(E)-N-{4-[(3-ethynylphenyl)amino]-5-methylpyrrolo[2,1-f][1,2,4]triazin-6-yl}-4 -(morpholin-1-yl)buten-2-amide (compound 33);
(E)-N-{4-[(3-乙炔基苯基)氨基]-5-甲基吡咯并[2,1-f][1,2,4]三嗪-6-基}-4-(吡咯烷-1-基)丁烯-2-酰胺(化合物34)；(E)-N-{4-[(3-ethynylphenyl)amino]-5-methylpyrrolo[2,1-f][1,2,4]triazin-6-yl}-4 -(pyrrolidin-1-yl)buten-2-amide (compound 34);
(E)-N-{4-[(3-乙炔基苯基)氨基]-5-甲基吡咯并[2,1-f][1,2,4]三嗪-6-基}-4-(哌啶-1-基)丁烯-2-酰胺(化合物35)；(E)-N-{4-[(3-ethynylphenyl)amino]-5-methylpyrrolo[2,1-f][1,2,4]triazin-6-yl}-4 -(piperidin-1-yl)buten-2-amide (compound 35);
及其互变异构体、立体异构体和其盐。And tautomers, stereoisomers and salts thereof.
本发明中，所述“药学上可接受的盐”表示保留母体化合物的生物有效性和性质的那些盐。这类盐包括但不限于：In the present invention, 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:
(1)与酸成盐，通过母体化合物的游离碱与无机酸或有机酸的反应而得。无机酸包括但不限于盐酸、氢溴酸、硝酸、磷酸、偏磷酸、硫酸、亚硫酸和高氯酸等；有机酸包括但不限于乙酸、丙酸、丙烯酸、草酸、(D)或(L)苹果酸、富马酸、马来酸、羟基苯甲酸、γ-羟基丁酸、甲氧基苯甲酸、邻苯二甲酸、甲磺酸、乙磺酸、萘-1-磺酸、萘-2-磺酸、对甲苯磺酸、水杨酸、酒石酸、柠檬酸、乳酸、扁桃酸、琥珀酸和丙二酸等，优选盐酸或对甲苯磺酸。(1) A salt formed with an acid obtained by a reaction of a free base of a parent compound with an inorganic acid or an organic acid. 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, γ-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, succinic acid, malonic acid, etc., preferably hydrochloric acid or p-toluenesulfonic acid.
(2)存在于母体化合物中的酸性质子被金属离子代替或者与有机碱配位化合所生成的盐，金属离子例如碱金属离子、碱土金属离子或铝离子，有机碱例如乙醇胺、二乙醇胺、三乙醇胺、氨丁三醇、N-甲基葡糖胺等。(2) a salt formed by replacing an acidic proton in a parent compound with a metal ion or by complexing with an organic base, such as an alkali metal ion, an alkaline earth metal ion or an aluminum ion, an organic base such as ethanolamine, diethanolamine, or the like. Ethanolamine, tromethamine, N-methylglucamine, and the like.
本发明的另一方面是提供一种制备通式I化合物或其药学上可接受的盐的方法。Another aspect of the invention provides a process for the preparation of a compound of formula I or a pharmaceutically acceptable salt thereof.
本发明首先提供了一种式II化合物作为制备通式I化合物的关键中间体： The present invention first provides a compound of formula II as a key intermediate for the preparation of compounds of formula I:
Figure PCTCN2014091238-appb-000003
Figure PCTCN2014091238-appb-000003
其中Y的定义如前述式I化合物中所述。Wherein Y is as defined in the compounds of formula I above.
式II化合物可以直接制备式Ia化合物，Ia化合物可以进一步制备得到其他式I化合物，从而完成通式I化合物的制备。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.
所述式II化合物与卤代巴豆酰氯进行酰化，得到式Ia化合物，Acylation of the compound of formula II with a halocrotonyl chloride to provide a compound of formula Ia,
Figure PCTCN2014091238-appb-000004
Figure PCTCN2014091238-appb-000004
其中，Z为卤素，Y的定义如前述式I化合物中所述。Wherein Z is a halogen and Y is as defined in the above compound of formula I.
所述式Ia化合物与取代胺进行亲核取代反应，进一步得到通式I化合物，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,
Figure PCTCN2014091238-appb-000005
Figure PCTCN2014091238-appb-000005
其中Z为卤素，Y和R2的定义如前述式I化合物中所述，R2不为卤素，并且Wherein Z is a halogen, and Y and R 2 are as defined in the compound of formula I above, R 2 is not halogen, and
如有需要，再裂解去除上述反应中所用的任何保护基；及/或If necessary, re-cracking to remove any protecting groups used in the above reaction; and / or
如有需要，将制得的通式I化合物解析成为其立体异构体；及/或If desired, the resulting compound of formula I is resolved into its stereoisomer; and/or
如有需要，将制得的通式I化合物转化成为其盐，特别是转化成药学上可接受的盐。The resulting compound of formula I is converted, if desired, to its salt, especially to a pharmaceutically acceptable salt.
本发明的另一个方面在于提供一种药物组合物，其特征在于所述药物组合物包含上述的通式I化合物或其药学上可接受的盐以及药学上可接受的稀释剂或载体。Another aspect of the present invention provides a pharmaceutical composition 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.
本发明的化合物可以以前药的形式给药。前药是指经过生物体内转化后成为具有药理作用的上述通式I化合物。可使用前药可以改变本发明化合物的物理化学性质或药物动力学方面性质。当本发明的化合物含有可连接改变性质基团的适当基团或取代基团时，可形成前药。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.
本发明的另一方面是提供通式I化合物或其药学上可接受的盐以及含有所述化合物或其盐的药物组合物在制备治疗与蛋白激酶有关的疾病的药物中的用途。所述蛋白激酶选自EGFR受体酪氨酸激酶和HER-2受体酪氨酸激酶。 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.
除非有相反陈述，在说明书和权利要求书中使用的术语具有下述含义。Terms used in the specification and claims have the following meanings unless stated to the contrary.
“烷基”表示1-20个碳原子的饱和的脂烃基，包括直链和支链基团(本申请书中提到的数字范围，例如“1-20”，是指该基团，此时为烷基，可以含1个碳原子、2个碳原子、3个碳原子等，直至包括20个碳原子)。含1-4个碳原子的烷基称为低级烷基。当低级烷基没有取代基时，称其为未取代的低级烷基。更优选的是，烷基是有1-10个碳原子的烷基，例如甲基、乙基、丙基、2-丙基、正丁基、异丁基、叔丁基、戊基等。昀好是，烷基为有1-4个碳原子的低级烷基，例如甲基、乙基、丙基、2-丙基、正丁基、异丁基或叔丁基等。烷基可以是取代的或未取代的。当是取代烷基时，该取代基优选是一或多个，更优选1-3个，昀优选1或2个取代基，它们独立地优选自以下的基团：卤素、羟基、低级烷氧基、芳基、芳氧基、杂芳环基、杂脂环基和酯基。"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. More preferably, 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. Preferably, 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. When it is a substituted alkyl group, 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.
“环烷基”表示全部为碳的单环或稠合的环(“稠合”环意味着系统中的每个环与系统中的其他环共享毗邻的一对碳原子)基团，含有4-9个碳原子，优选5、6或7个碳原子，更优选5或6个碳原子，其中一个或多个环不具有完全连接的π电子系统，任选包含一个或多个双键和/或三键形式的不饱和状态。环烷基的可为取代的和未取代的。未取代环烷基实例(不局限于)为环丙烷、环丁烷、环戊烷、环己烷、金刚烷、环己二烯、环庚烷和环庚三烯。当被取代时，取代基优选为一个或多个各自选自以下的基团，包括：烷基、芳基、杂芳基、杂脂环基、羟基、烷氧基、芳氧基、巯基、烷巯基、氰基、卤素、羰基、硫代羰基、C-酰氨基、N酰氨基、硝基和氨基。"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. Examples of unsubstituted cycloalkyl groups are, without limitation, cyclopropane, cyclobutane, cyclopentane, cyclohexane, adamantane, cyclohexadiene, cycloheptane and cycloheptatriene. When substituted, 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.
“芳基”表示6至18个碳原子、优选6-12个碳原子、更优选6-10个碳原子的全碳单环或稠合多环基团，具有完全共轭的π电子系统。芳基可以是取代的或未取代的。未取代的芳基的非限制性实例有苯基、萘基、蒽基和菲基。当被取代时，取代基优先选为一个或多个，更优选为一个、两个或三个，进而更优选为一个或两个，独立地选自卤素、烷基、烯基、炔基、烷氧基、硝基、羟基、环烷基或杂脂环基、氰基、巯基、酰基、硫代酰基、氨基、硝基、卤代烷基、卤代烷氧基、酯基、芳基或杂芳基等基团。优选的，芳基任选地被一个或两个取代基取代，取代基独立地选自卤素、低级烷基、三卤烷基、烯基、炔基、氰基、酯基或硝基。"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. When substituted, 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. Preferably, the aryl group is optionally substituted by one or two substituents independently selected from halo, lower alkyl, trihaloalkyl, alkenyl, alkynyl, cyano, ester or nitro.
“杂芳基”表示5-18个环原子的单环或稠合环基团，优选含有5-12个环原子，更优选含有6-10个环原子，其含有一个、两个、三个或四个选自N、O或S的环杂原子，其余环原子是C，另外具有完全共轭的π电子系统。未取代的杂芳基非限制性实例有吡咯、呋喃、噻吩、咪唑、噁唑、噻唑、吡唑、嘧啶、喹啉、异喹啉、嘌呤、四唑、三嗪、咔唑、吡啶、异噁唑、异噻唑、呋咱、哒嗪、噻二唑、吲哚、异吲哚、苯并呋喃、苯并噻吩、苯并咪唑、苯并噻唑、苯并呋咱、 喹唑啉、萘啶、吡唑并嘧啶。杂芳环可以是取代的或未取代的。当被取代时，取代基优选为一个或多个，更为优选为一个、两个或三个，进而更为优选一个或两个，独立地选自以下基团，包括卤素、烷基、烯基、炔基、烷氧基、硝基、羟基、环烷基或杂脂环基、氰基、巯基、酰基、硫代酰基、氨基、硝基、卤代烷基、卤代烷氧基、酯基、芳基或杂芳基等基团。优选的杂芳基任选地被一个或两个取代基取代，取代基独立地选自卤素、低级烷基、三卤烷基、烯基、炔基、氰基、酯基或硝基。"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. When substituted, 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.
“杂脂环基”表示单环或稠合环基团，在环中具有5-18个、优选6-12个，更优选6-9个环原子，其中一个或两个环原子选自N、O或S(O)m(其中m是0至2的整数)的杂原子，其余环原子是C。这些环可以具有一条或多条双键，但这些环不具有完全共轭的π电子系统。未取代的杂脂环基的非限制性实例有吡咯烷基、哌啶子基、吗啉子基、哌嗪子基、硫代吗啉子基、高哌嗪子基等。杂脂环基可以是取代的或未取代的。当被取代时，取代基优选为一个或多个、更优选为一个、两个或三个，进而更优选为一个或两个，独立地选自以下基团，包括：低级烷基、三卤烷基、卤素、羟基、低级烷氧基、巯基、(低级烷基)硫基、氰基、羰基、硫代羰基、O-氨基甲酰基、N-氨基甲酰基、O-硫代氨基甲酰基、N-硫代氨基甲酰基、C-酰氨基、N-酰氨基、硝基、N-磺酰氨基、S-磺酰氨基。优选的杂芳基任选地被一个或两个取代基取代，取代基独立地选自卤素、低级烷基、三卤烷基、氰基、酯基或硝基。"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. When substituted, 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.
“羟基”表示-OH基团。“烯基”表示具有2～6个碳原子和1～3根双键的直链或支链基团。“炔基”表示具有2～6个碳原子和1～3根三键的直链或支链基团。"Hydroxy" 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.
“烷氧基”表示-O-(烷基)和-O-(环烷基)，其中烷基和环烷基定义如上。代表性实例包括但不限于甲氧基、乙氧基、丙氧基、丁氧基、环丙氧基、环丁氧基、环戊氧基、环己氧基等。"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.
“芳氧基”表示-O-芳基和-O-杂芳基，其中芳基和杂芳基定义如上。代表性实例包括但不限于苯氧基、吡啶氧基、呋喃氧基、噻吩氧基、嘧啶氧基、吡嗪氧基等及其衍生物。"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.
“巯基”表示-SH基团。"Indenyl" means a -SH group.
“酰基”表示-C(O)-R’基团，其中R’是选自以下基团：氢，未取代的烷基、三卤甲基、未取代的环烷基、任选地被一或多个、优选被1、2或3个选自未取代的烷基、三卤甲基、未取代的烷氧基和卤素取代的芳基，上述烷基、环烷基、烷氧基和芳基定义如上。"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.
“硫代酰基”表示-C(S)-R’，其中R’定义同上。"Thioacyl" means -C(S)-R', wherein R' is as defined above.
“酯基”表示-C(O)O-R’基团，其中R’定义同上，但是R’不能是氢。"Ester group" means a -C(O)O-R' group wherein R' is as defined above, but R' cannot be hydrogen.
“卤素”表示氟、氯、溴或碘，优选氟、氯或溴。 "Halogen" means fluoro, chloro, bromo or iodo, preferably fluoro, chloro or bromo.
“氰基”表示-CN基团。"Cyano" means a -CN group.
“氨基”表示-NH2基团。"Amino" means a -NH 2 group.
“硝基”表示-NO2基团。"Nitro" means a -NO 2 group.
“卤代烷基”表示烷基被一个或多个相同或不同的卤原子取代，优选如上所定义的低级烷基被一个或多个相同或不同的卤原子取代，其中烷基定义如上，例如-CH2Cl、-CF3、-CH2CF3、-CH2CCl3等。"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.
“卤代烷氧基”表示烷氧基被一个或多个相同或不同的卤原子取代，其中烷氧基定义如上，例如-OCH2Cl、-OCF3、-OCH2CF3、-OCH2CCl3等。"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.
“可选”或“可选地”意味着随后所描述的事件或环境可以但不必发生，该说明包括该事件或环境发生和不发生的场合。例如，“杂芳基任选地可被一个或两个取代基取代”意味着杂芳基可以不被取代，或者可以被一个或两个取代基取代。"Optional" or "optionally" means that the subsequently described event or environment may, but need not, occur, including where the event or environment occurs and does not occur. For example, "heteroaryl optionally substituted with one or two substituents" means that the heteroaryl group may be unsubstituted or substituted with one or two substituents.
“药物组合物”表示含有一种或多种本文所述化合物或其生理学上/药学上可接受的盐或前体药物与其他化学组分的混合物，以及其他组分例如生理学/药学上可接受的载体和赋形剂。药物组合物的目的是促进生物体的给药，利用活性成分的吸收进而发挥生物活性。"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.
具体实施方式detailed description
以下结合实施例用于进一步描述本发明，但这些实施例并非限制本发明的范围。The invention is further described in the following examples, but these examples are not intended to limit the scope of the invention.
本发明通式I部分化合物的编号及结构式：The numbering and structural formula of the compound of the formula I of the present invention:
Figure PCTCN2014091238-appb-000006
Figure PCTCN2014091238-appb-000006
Figure PCTCN2014091238-appb-000007
Figure PCTCN2014091238-appb-000007
制备例1(E)-4-溴-N-{4-{{3-氯-4-[(3-氟苯基)甲氧基]苯基}氨基}-5-甲基吡咯并[2,1-f][1,2,4]三嗪-6-基}-丁烯-2-酰胺 Preparation 1 (E)-4-bromo-N-{4-{{3-chloro-4-[(3-fluorophenyl)methoxy]phenyl}amino}-5-methylpyrrolo[2 , 1-f][1,2,4]triazin-6-yl}-butene-2-amide
Figure PCTCN2014091238-appb-000008
Figure PCTCN2014091238-appb-000008
步骤1：将1a(20.0g，0.09mol)，三氯氧磷(41.4g，0.27mol)，4-二甲氨基吡啶(DMAP)(32.0g，0.27mol)和150ml甲苯置入250ml反应瓶中，氮气保护下加热至110℃反应6h。TLC监测反应结束后(下同)，反应液冷却至室温，减压除去溶剂，加入200ml冰水搅拌，析出大量固体，过滤，滤饼冰水洗涤，真空干燥过夜，得淡黄色固体(化合物1b)19.1g，收率88.8％。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%.
步骤2：将化合物1b(19.0g，79.5mmol)，3-氯-4-[(3-氟苄基)氧代]苯胺(19.9g，79.5mmol)和300ml异丙醇置入500ml反应瓶中，80℃反应2h，反应液冷却至室温，过滤，滤饼异丙醇洗涤，真空干燥，得黄色固体(化合物1c)33.2g，收率91.9％。ESI-MS m/z：455[M+H]+。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] + .
步骤3：将化合物1c(33.0g，0.07mol)，氢氧化钠(9.60g，0.22mol)，150ml甲醇和150ml水置入500ml反应瓶中，60℃反应2h，反应液冷却至室温，用乙酸调至pH约为7，析出大量固体，过滤，滤饼用水洗涤，真空干燥，得淡黄色固体(化合物1d)28.4g，收率95.3％。ESI-MS m/z：427[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] + .
步骤4：将化合物1d(28.0g，65.7mmol)，叠氮磷酸二苯酯DPPA(24.8g，78.9mmol)，三乙胺(7.96g，78.9mmol)，300ml甲苯置入500ml反应瓶中，氮气保护下加热至85℃反应4h，然后加入叔丁醇(11.1g，0.15mol)，85℃过夜。反应液冷却至室温，浓缩后柱层析纯化[洗脱剂：乙酸乙酯：石油醚＝1:4]，得黄色固体(化合物1e)7.77g，收率23.8％。ESI-MS m/z：498[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, mjjjjjjjj ESI-MS m/z: 498 [M+H] + .
步骤5：将化合物1e(7.50g，15.1mmol)，三氟乙酸14ml，二氯甲烷150ml置入250ml反应瓶中，室温反应4h。反应液浓缩除去溶剂，所得油状物经柱层析提纯[洗脱剂：乙酸乙酯：石油醚＝1:1]，得黄色固体(化合物1f)4.17g，收率65.1％。 ESI-MS m/z：398[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 ESI-MS m/z: 398[M+H] + .
步骤6：将化合物1f(4.00g，9.00mmol)，4-溴巴豆酸(1.47g，9.00mmol)，HATU(5.13g，13.5mmol)，三乙胺(1.36g，13.5mmol)，DMF50ml置入250ml反应瓶中，室温反应1h。反应液加入200ml水，用二氯甲烷100m×3萃取，合并有机相，无水硫酸钠干燥，浓缩后油状物经柱层析提纯[洗脱剂：乙酸乙酯：石油醚＝3:1]，得黄色固体(化合物1g)2.22g，收率48.6％。ESI-MS m/z：544[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 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). The organic phase was combined and dried over anhydrous sodium sulfate, and the oil was purified by column chromatography (eluent: ethyl acetate: petroleum ether = 3:1) A yellow solid (Compound 1 g) of 2.22 g was obtained in a yield of 48.6%. ESI-MS m/z: 544 [M+H] + .
实施例1(E)-N-{4-{{3-氯-4-[(3-氟苯基)甲氧基]苯基}氨基}-5-甲基吡咯并[2,1-f][1,2,4]三嗪-6基}-4-吗啉丁烯-2-酰胺(化合物1)Example 1 (E)-N-{4-{{3-chloro-4-[(3-fluorophenyl)methoxy]phenyl}amino}-5-methylpyrrolo[2,1-f ][1,2,4]triazin-6-yl}-4-morpholinate-2-amide (Compound 1)
将化合物1g(150mg)溶解于DMF(5ml)中，加入吗啉(29mg)和碳酸钾(83mg)，室温反应4h，反应液过滤，减压除去溶剂，粗品用柱层析(二氯甲烷/甲醇＝20：1)纯化，得到白色固体(化合物1)60mg，收率44.1％。ESI-MS m/z：551[M+H]+；1H-NMR(DMSO-d6,500MHz)δ(ppm)：9.66(s,1H,CONH),8.43(s,1H,NH),8.10(s,1H,Ar-H),7.86(s,1H,Ar-H),7.84(d,J＝2.5Hz,1H,Ar-H),7.58(dd,J＝2.5,8.9Hz,1H,Ar-H),7.44-7.49(m,1H,Ar-H),7.29-7.33(m,2H,Ar-H),7.23(d,J＝9.0Hz,1H,Ar-H),7.15-7.19(m,1H,Ar-H),6.74(td,J＝5.9,15.4Hz,1H,CH＝CH),6.48(d,J＝15.4Hz,1H,CH＝CH),5.25(s,2H,CH2),3.61(s,4H,2×CH2),3.13(d,2H,J＝5.4Hz,CH2),2.55(s,3H,CH3),2.41(s,4H,2×CH2).Compound 1g (150mg) was dissolved in DMF (5ml), morpholine (29mg) and potassium carbonate (83mg) were added, and the reaction mixture was stirred at room temperature for 4h. Purification with methanol = 20:1) gave a white solid (Compound 1) 60 mg, yield 44.1%. ESI-MS m/z: 551 [M+H] + ; 1 H-NMR (DMSO-d6, 500 MHz) δ (ppm): 9.66 (s, 1H, CONH), 8.43 (s, 1H, NH), 8.10 (s, 1H, Ar-H), 7.86 (s, 1H, Ar-H), 7.84 (d, J = 2.5 Hz, 1H, Ar-H), 7.58 (dd, J = 2.5, 8.9 Hz, 1H, Ar-H), 7.44-7.49 (m, 1H, Ar-H), 7.29-7.33 (m, 2H, Ar-H), 7.23 (d, J = 9.0 Hz, 1H, Ar-H), 7.15-7.19 (m,1H,Ar-H), 6.74 (td, J=5.9, 15.4 Hz, 1H, CH=CH), 6.48 (d, J = 15.4 Hz, 1H, CH=CH), 5.25 (s, 2H, CH 2 ), 3.61 (s, 4H, 2 × CH 2 ), 3.13 (d, 2H, J = 5.4 Hz, CH 2 ), 2.55 (s, 3H, CH 3 ), 2.41 (s, 4H, 2 × CH 2 ).
实施例2(E)-N-{4-{{3-氯-4-[(3-氟苯基)甲氧基]苯基}氨基}-5-甲基吡咯并[2,1-f][1,2,4]三嗪-6基}-4-(哌啶-1-基)丁烯-2-酰胺(化合物2)Example 2(E)-N-{4-{{3-chloro-4-[(3-fluorophenyl)methoxy]phenyl}amino}-5-methylpyrrolo[2,1-f ][1,2,4]triazin-6-yl}-4-(piperidin-1-yl)buten-2-amide (Compound 2)
方法同实施例1，投入化合物1g(150mg)、哌啶(28mg)和碳酸钾(83mg)，得白色固体(化合物2)46mg，收率56.6％。ESI-MS m/z：549[M+H]+；1H-NMR(DMSO-d6,500MHz)δ(ppm)：9.70(s,1H,CONH),8.48(s,1H,NH),8.12(s,1H,Ar-H),7.87(s,1H,Ar-H),7.84(d,J＝2.0Hz,1H,Ar-H),7.58(dd,J＝2.0,9.0Hz,1H,Ar-H),7.45-7.50(m,1H,Ar-H),7.30-7.34(m,2H,Ar-H),7.24(d,J＝9.0Hz,1H,Ar-H),7.19-7.21(m,1H,Ar-H),6.74(td,J＝6.0,15.5Hz,1H,CH＝CH),6.47(d,J＝15.5Hz,1H,CH＝CH),5.26(s,2H,CH2),3.09(d,2H,J＝6.0Hz,CH2),2.56(s,3H,CH3),2.36(s,4H,2×CH2),1.53(s,4H,2×CH2),1.40(s,2H,CH2).In the same manner as in Example 1, 1 g of a compound (150 mg), piperidine (28 mg), and potassium carbonate (83 mg) were added to give a white solid (Comp. ESI-MS m/z: 549 [M+H] + ; 1 H-NMR (DMSO-d6, 500 MHz) δ (ppm): 9.70 (s, 1H, CONH), 8.48 (s, 1H, NH), 8.12 (s, 1H, Ar-H), 7.87 (s, 1H, Ar-H), 7.84 (d, J = 2.0 Hz, 1H, Ar-H), 7.58 (dd, J = 2.0, 9.0 Hz, 1H, Ar-H), 7.45-7.50 (m, 1H, Ar-H), 7.30-7.34 (m, 2H, Ar-H), 7.24 (d, J = 9.0 Hz, 1H, Ar-H), 7.19-7.21 (m,1H,Ar-H), 6.74 (td, J=6.0, 15.5 Hz, 1H, CH=CH), 6.47 (d, J = 15.5 Hz, 1H, CH=CH), 5.26 (s, 2H, CH 2 ), 3.09 (d, 2H, J = 6.0 Hz, CH 2 ), 2.56 (s, 3H, CH 3 ), 2.36 (s, 4H, 2 × CH 2 ), 1.53 (s, 4H, 2 × CH 2 ), 1.40(s, 2H, CH 2 ).
实施例3(E)-N-{4-{{3-氯-4-[(3-氟苯基)甲氧基]苯基}氨基}-5-甲基吡咯并[2,1-f][1,2,4]三嗪-6基}-4-(4-甲基哌啶-1-基)丁烯-2-酰胺(化合物3)Example 3(E)-N-{4-{{3-chloro-4-[(3-fluorophenyl)methoxy]phenyl}amino}-5-methylpyrrolo[2,1-f ][1,2,4]triazin-6-yl}-4-(4-methylpiperidin-1-yl)buten-2-amide (Compound 3)
方法同实施例2，投入化合物1g(100mg)、4-甲基哌啶(32mg)和碳酸钾(83mg)，得白色固体(化合物3)50mg，收率33.0％。ESI-MS m/z：563[M+H]+；1H-NMR(DMSO-d6,500MHz)δ(ppm)：9.75(br s,1H,CONH),8.48(s,1H,NH),8.12(s,1H,Ar-H),7.87(s,1H,Ar-H),7.84(d,J＝2.0Hz,1H,Ar-H),7.58(dd,J＝2.0,9.0Hz,1H,Ar-H),7.45-7.50(m,1H,Ar-H),7.30-7.34(m,2H,Ar-H),7.24(d,J＝9.0Hz,1H,Ar-H),7.19-7.21(m,1H,Ar-H),6.74(td,J＝6.0,15.5Hz,1H,CH＝CH),6.52(d,J＝15.5Hz,1H, CH＝CH),5.27(s,2H,CH2),3.12(d,2H,J＝6.0Hz,CH2),2.86(s,2H,CH2),2.56(s,3H,CH3),1.92(s,2H,CH2),1.65(s,2H,CH2),1.40(s,1H,CH),1.24(s,2H,CH2),0.92(s,J＝6.5Hz,3H,CH3).In the same manner as in Example 2, 1 g of a compound (100 mg), 4-methylpiperidine (32 mg) and potassium carbonate (83 mg) were added to give a white solid (comp. 3) 50 mg (yield: 33.0%). ESI-MS m/z: 563 [M+H] + ; 1 H-NMR (DMSO-d6, 500 MHz) δ (ppm): 9.75 (br s, 1H, CONH), 8.48 (s, 1H, NH), 8.12 (s, 1H, Ar-H), 7.87 (s, 1H, Ar-H), 7.84 (d, J = 2.0 Hz, 1H, Ar-H), 7.58 (dd, J = 2.0, 9.0 Hz, 1H) , Ar-H), 7.45-7.50 (m, 1H, Ar-H), 7.30-7.34 (m, 2H, Ar-H), 7.24 (d, J = 9.0 Hz, 1H, Ar-H), 7.19- 7.21 (m, 1H, Ar-H), 6.74 (td, J = 6.0, 15.5 Hz, 1H, CH = CH), 6.52 (d, J = 15.5 Hz, 1H, CH = CH), 5.27 (s, 2H) , CH 2 ), 3.12 (d, 2H, J = 6.0 Hz, CH 2 ), 2.86 (s, 2H, CH 2 ), 2.56 (s, 3H, CH 3 ), 1.92 (s, 2H, CH 2 ), 1.65 (s, 2H, CH 2 ), 1.40 (s, 1H, CH), 1.24 (s, 2H, CH 2 ), 0.92 (s, J = 6.5 Hz, 3H, CH 3 ).
实施例4(E)-N-{4-{{3-氯-4-[(3-氟苯基)甲氧基]苯基}氨基}-5-甲基吡咯并[2,1-f][1,2,4]三嗪-6基}-4-(2-甲基哌啶-1-基)丁烯-2-酰胺(化合物4)Example 4(E)-N-{4-{{3-chloro-4-[(3-fluorophenyl)methoxy]phenyl}amino}-5-methylpyrrolo[2,1-f ][1,2,4]triazin-6-yl}-4-(2-methylpiperidin-1-yl)buten-2-amide (Compound 4)
方法同实施例2，投入化合物1g(150mg)、2-甲基哌啶(44mg)和碳酸钾(83mg)，得白色固体(化合物4)40mg，收率26.4％。ESI-MS m/z：563[M+H]+；1H-NMR(DMSO-d6,500MHz)δ(ppm)：9.67(br s,1H,CONH),8.44(s,1H,NH),8.10(s,1H,Ar-H),7.86(s,1H,Ar-H),7.84(d,J＝2.6Hz,1H,Ar-H),7.57(dd,J＝2.6,9.0Hz,1H,Ar-H),7.44-7.49(m,1H,Ar-H),7.29-7.33(m,2H,Ar-H),7.24(d,J＝9.0Hz,1H,Ar-H),7.15-7.19(m,1H,Ar-H),6.75(td,J＝6.0,15.5Hz,1H,CH＝CH),6.49(d,J＝15.5Hz,1H,CH＝CH),5.27(s,2H,CH2),3.12(d,2H,J＝6.0Hz,CH2),2.84(s,2H,CH2),2.55(s,3H,CH3),1.99(s,2H,CH2),1.63(s,2H,CH2),1.40(s,1H,CH),1.19(s,2H,CH2),0.91(s,J＝6.4Hz,3H,CH3).In the same manner as in Example 2, 1 g of a compound (150 mg), 2-methylpiperidine (44 mg) and potassium carbonate (83 mg) were added to give a white solid (comp. 4) 40 mg (yield: 26.4%). ESI-MS m/z: 563 [M+H] + ; 1 H-NMR (DMSO-d6, 500 MHz) δ (ppm): 9.67 (br s, 1H, CONH), 8.44 (s, 1H, NH), 8.10 (s, 1H, Ar-H), 7.86 (s, 1H, Ar-H), 7.84 (d, J = 2.6 Hz, 1H, Ar-H), 7.57 (dd, J = 2.6, 9.0 Hz, 1H , Ar-H), 7.44-7.49 (m, 1H, Ar-H), 7.29-7.33 (m, 2H, Ar-H), 7.24 (d, J = 9.0 Hz, 1H, Ar-H), 7.15- 7.19 (m, 1H, Ar-H), 6.75 (td, J = 6.0, 15.5 Hz, 1H, CH = CH), 6.49 (d, J = 15.5 Hz, 1H, CH = CH), 5.27 (s, 2H) , CH 2 ), 3.12 (d, 2H, J = 6.0 Hz, CH 2 ), 2.84 (s, 2H, CH 2 ), 2.55 (s, 3H, CH 3 ), 1.99 (s, 2H, CH 2 ), 1.63 (s, 2H, CH 2 ), 1.40 (s, 1H, CH), 1.19 (s, 2H, CH 2 ), 0.91 (s, J = 6.4 Hz, 3H, CH 3 ).
实施例5(E)-N-{4-{{3-氯-4-[(3-氟苯基)甲氧基]苯基}氨基}-5-甲基吡咯并[2,1-f][1,2,4]三嗪-6基}-4-(1H-咪唑-1-基)丁烯-2-酰胺(化合物5)Example 5(E)-N-{4-{{3-chloro-4-[(3-fluorophenyl)methoxy]phenyl}amino}-5-methylpyrrolo[2,1-f ][1,2,4]triazin-6-yl}-4-(1H-imidazol-1-yl)buten-2-amide (Compound 5)
方法同实施例2，投入化合物1g(100mg)、咪唑(15mg)和碳酸钾(41mg)，得白色固体(化合物5)30mg，收率30.4％。ESI-MS m/z：532[M+H]+；1H-NMR(DMSO-d6,300MHz)δ(ppm)：9.75(br s,1H,CONH),8.44(s,1H,NH),8.09(s,1H,Ar-H),7.86(s,1H,Ar-H),7.83(d,J＝2.2Hz,1H,Ar-H),7.70(s,1H,Ar-H),7.55(dd,J＝2.2,9.0Hz,1H,Ar-H),7.43-7.50(m,1H,Ar-H),7.28-7.33(m,2H,Ar-H),7.24(d,J＝9.0Hz,1H,Ar-H),7.15-7.25(m,3H,Ar-H),6.99(s,1H,Ar-H),6.80(td,J＝4.5,15.4Hz,1H,CH＝CH),6.11(d,J＝15.5Hz,1H,CH＝CH),5.25(s,2H,CH2),4.88(d,2H,J＝3.8Hz,CH2),2.50(s,3H,CH3).In the same manner as in Example 2, 1 g of a compound (100 mg), imidazole (15 mg) and potassium carbonate (41 mg) were added to give a white solid (compound 5) 30 mg (yield: 30.4%). ESI-MS m/z: 532 [M+H] + ; 1 H-NMR (DMSO-d6, 300 MHz) δ (ppm): 9.75 (br s, 1H, CONH), 8.44 (s, 1H, NH), 8.09 (s, 1H, Ar-H), 7.86 (s, 1H, Ar-H), 7.83 (d, J = 2.2 Hz, 1H, Ar-H), 7.70 (s, 1H, Ar-H), 7.55 (dd, J = 2.2, 9.0 Hz, 1H, Ar-H), 7.43-7.50 (m, 1H, Ar-H), 7.28-7.33 (m, 2H, Ar-H), 7.24 (d, J = 9.0 Hz, 1H, Ar-H), 7.15-7.25 (m, 3H, Ar-H), 6.99 (s, 1H, Ar-H), 6.80 (td, J=4.5, 15.4 Hz, 1H, CH=CH) , 6.11 (d, J = 15.5 Hz, 1H, CH = CH), 5.25 (s, 2H, CH 2 ), 4.88 (d, 2H, J = 3.8 Hz, CH 2 ), 2.50 (s, 3H, CH 3 ) ).
实施例6(E)-N-{4-{{3-氯-4-[(3-氟苯基)甲氧基]苯基}氨基}-5-甲基吡咯并[2,1-f][1,2,4]三嗪-6基}-4-(二甲胺基)丁烯-2-酰胺(化合物6)Example 6(E)-N-{4-{{3-chloro-4-[(3-fluorophenyl)methoxy]phenyl}amino}-5-methylpyrrolo[2,1-f ][1,2,4]triazin-6-yl}-4-(dimethylamino)buten-2-amide (Compound 6)
方法同实施例2，投入化合物1g(150mg)、二甲胺盐酸盐(29mg)和碳酸钾78mg，得白色固体(化合物6)40mg，收率36.1％。ESI-MS m/z：509[M+H]+；1H-NMR(DMSO-d6,500MHz)δ(ppm)：9.70(br s,1H,CONH),8.44(s,1H,NH),8.11(s,1H,Ar-H),7.86(s,1H,Ar-H),7.84(d,J＝2.6Hz,1H,Ar-H),7.57(dd,J＝2.5,8.9Hz,1H,Ar-H),7.44-7.49(m,1H,Ar-H),7.29-7.33(m,2H,Ar-H),7.24(d,J＝9.0Hz,1H,Ar-H),7.17(dt,J＝2.2,8.9Hz,1H,Ar-H),6.74(td,J＝6.1,15.4Hz,1H,CH＝CH),6.50(d,J＝15.5Hz,1H,CH＝CH),5.25(s,2H,CH2),3.16(d,2H,J＝5.2Hz,CH2),2.55(s,3H,CH3),2.27(s,6H,2×CH3).In the same manner as in Example 2, 1 g of a compound (150 mg), dimethylamine hydrochloride (29 mg), and 78 mg of potassium carbonate were added to give a white solid (compound 6) 40 mg (yield: 36.1%). ESI-MS m/z: 509 [M+H] + ; 1 H-NMR (DMSO-d6, 500 MHz) δ (ppm): 9.70 (br s, 1H, CONH), 8.44 (s, 1H, NH), 8.11 (s, 1H, Ar-H), 7.86 (s, 1H, Ar-H), 7.84 (d, J = 2.6 Hz, 1H, Ar-H), 7.57 (dd, J = 2.5, 8.9 Hz, 1H , Ar-H), 7.44-7.49 (m, 1H, Ar-H), 7.29-7.33 (m, 2H, Ar-H), 7.24 (d, J = 9.0 Hz, 1H, Ar-H), 7.17 ( Dt, J=2.2, 8.9 Hz, 1H, Ar-H), 6.74 (td, J=6.1, 15.4 Hz, 1H, CH=CH), 6.50 (d, J = 15.5 Hz, 1H, CH=CH), 5.25 (s, 2H, CH 2 ), 3.16 (d, 2H, J = 5.2 Hz, CH 2 ), 2.55 (s, 3H, CH 3 ), 2.27 (s, 6H, 2 × CH 3 ).
实施例7(E)-N-{4-{{3-氯-4-[(3-氟苯基)甲氧基]苯基}氨基}-5-甲基吡咯并 [2,1-f][1,2,4]三嗪-6基}-4-(二乙胺基)丁烯-2-酰胺(化合物7)Example 7(E)-N-{4-{{3-chloro-4-[(3-fluorophenyl)methoxy]phenyl}amino}-5-methylpyrrole [2,1-f][1,2,4]triazin-6-yl}-4-(diethylamino)buten-2-amide (Compound 7)
方法同实施例2，投入化合物1g(100mg)、二乙胺(17mg)和碳酸钾(42mg)，得白色固体(化合物7)36mg，收率32.4％。ESI-MS m/z：537[M+H]+；1H-NMR(DMSO-d6,300MHz)δ(ppm)：9.67(br s,1H,CONH),8.45(s,1H,NH),8.11(s,1H,Ar-H),7.86(s,1H,Ar-H),7.83(s,1H,Ar-H),7.57(d,J＝14.7Hz,1H,Ar-H),7.43-7.51(m,1H,Ar-H),7.29-7.33(m,2H,Ar-H),7.24(d,J＝9.0Hz,1H,Ar-H),7.18(t,J＝8.0Hz,1H,Ar-H),6.77(td,J＝5.6,15.7Hz,1H,CH＝CH),6.49(d,J＝14.9z,1H,CH＝CH),5.26(s,2H,CH2),3.22(s,2H,CH2),2.55(s,3H,CH3),2.50(s,4H,2×CH2),1.00(s,6H,2×CH3).In the same manner as in Example 2, 1 g of a compound (100 mg), diethylamine (17 mg) and potassium carbonate (42 mg) were added to give a white solid (compound 7) 36 mg (yield: 32.4%). ESI-MS m/z: 537 [M+H] + ; 1 H-NMR (DMSO-d6, 300 MHz) δ (ppm): 9.67 (br s, 1H, CONH), 8.45 (s, 1H, NH), 8.11 (s, 1H, Ar-H), 7.86 (s, 1H, Ar-H), 7.83 (s, 1H, Ar-H), 7.57 (d, J = 14.7 Hz, 1H, Ar-H), 7.43 -7.51 (m, 1H, Ar-H), 7.29-7.33 (m, 2H, Ar-H), 7.24 (d, J = 9.0 Hz, 1H, Ar-H), 7.18 (t, J = 8.0 Hz, 1H,Ar-H), 6.77 (td, J=5.6, 15.7 Hz, 1H, CH=CH), 6.49 (d, J = 14.9z, 1H, CH=CH), 5.26 (s, 2H, CH 2 ) , 3.22 (s, 2H, CH 2 ), 2.55 (s, 3H, CH 3 ), 2.50 (s, 4H, 2 × CH 2 ), 1.00 (s, 6H, 2 × CH 3 ).
实施例8(E)-N-{4-{{3-氯-4-[(3-氟苯基)甲氧基]苯基}氨基}-5-甲基吡咯并[2,1-f][1,2,4]三嗪-6基}-4-(吡咯烷-1-基)丁烯-2-酰胺(化合物8)Example 8(E)-N-{4-{{3-chloro-4-[(3-fluorophenyl)methoxy]phenyl}amino}-5-methylpyrrolo[2,1-f ][1,2,4]triazin-6-yl}-4-(pyrrolidin-1-yl)buten-2-amide (Compound 8)
方法同实施例2，投入化合物1g(100mg)、吡咯烷(15mg)和碳酸钾(41mg)，得白色固体(化合物8)40mg，收率40.6％。ESI-MS m/z：535[M+H]+；1H-NMR(DMSO-d6,500MHz)δ(ppm)：9.76(br s,1H,CONH),8.44(s,1H,NH),8.11(s,1H,Ar-H),7.86(s,1H,Ar-H),7.83(s,J＝2.5Hz,1H,Ar-H),7.57(dd,J＝2.6,8.9Hz,1H,Ar-H),7.44-7.49(m,1H,Ar-H),7.29-7.33(m,2H,Ar-H),7.24(d,J＝9.0Hz,1H,Ar-H),7.17(t,J＝8.8Hz,1H,Ar-H),6.78(td,J＝6.1,15.4Hz,1H,CH＝CH),6.55(d,J＝15.7z,1H,CH＝CH),5.26(s,2H,CH2),3.52(s,2H,CH2),2.77(s,4H,2×CH2),2.56(s,3H,CH3),1.81(s,4H,2×CH2).In the same manner as in Example 2, 1 g of a compound (100 mg), pyrrolidine (15 mg) and potassium carbonate (41 mg) were added to give a white solid (compound 8) 40 mg (yield 40.6%). ESI-MS m/z: 535 [M+H] + ; 1 H-NMR (DMSO-d6, 500 MHz) δ (ppm): 9.76 (br s, 1H, CONH), 8.44 (s, 1H, NH), 8.11 (s, 1H, Ar-H), 7.86 (s, 1H, Ar-H), 7.83 (s, J = 2.5 Hz, 1H, Ar-H), 7.57 (dd, J = 2.6, 8.9 Hz, 1H , Ar-H), 7.44-7.49 (m, 1H, Ar-H), 7.29-7.33 (m, 2H, Ar-H), 7.24 (d, J = 9.0 Hz, 1H, Ar-H), 7.17 ( t, J = 8.8 Hz, 1H, Ar-H), 6.78 (td, J = 6.1, 15.4 Hz, 1H, CH = CH), 6.55 (d, J = 15.7z, 1H, CH = CH), 5.26 ( s, 2H, CH 2 ), 3.52 (s, 2H, CH 2 ), 2.77 (s, 4H, 2 × CH 2 ), 2.56 (s, 3H, CH 3 ), 1.81 (s, 4H, 2 × CH 2 ) ).
实施例9(E)-N-{4-{{3-氯-4-[(3-氟苯基)甲氧基]苯基}氨基}-5-甲基吡咯并[2,1-f][1,2,4]三嗪-6基}-4-(4-甲基哌嗪-1-基)丁烯-2-酰胺(化合物9)Example 9(E)-N-{4-{{3-chloro-4-[(3-fluorophenyl)methoxy]phenyl}amino}-5-methylpyrrolo[2,1-f ][1,2,4]triazin-6-yl}-4-(4-methylpiperazin-1-yl)buten-2-amide (Compound 9)
方法同实施例2，投入化合物1g(100mg)、N-甲基哌嗪(20mg)和碳酸钾(41mg)，得白色固体(化合物9)30mg，收率26.2％。ESI-MS m/z：564[M+H]+；1H-NMR(DMSO-d6,500MHz)δ(ppm)：9.66(br s,1H,CONH),8.44(s,1H,NH),8.10(s,1H,Ar-H),7.86(s,1H,Ar-H),7.83(s,J＝2.6Hz,1H,Ar-H),7.57(dd,J＝2.5,8.9Hz,1H,Ar-H),7.44-7.49(m,1H,Ar-H),7.29-7.33(m,2H,Ar-H),7.24(d,J＝9.0Hz,1H,Ar-H),7.17(t,J＝10.9Hz,1H,Ar-H),6.73(td,J＝6.0,15.4Hz,1H,CH＝CH),6.47(d,J＝15.4z,1H,CH＝CH),5.25(s,2H,CH2),3.14(d,J＝5.3Hz,2H,CH2),2.55(s,3H,CH3),2.50(s,8H,4×CH2),2.27(s,3H,CH3).In the same manner as in Example 2, 1 g of a compound (100 mg), N-methylpiperazine (20 mg) and potassium carbonate (41 mg) were added to give a white solid (compound 9) 30 mg (yield: 26.2%). ESI-MS m/z: 564 [M+H] + ; 1 H-NMR (DMSO-d6, 500 MHz) δ (ppm): 9.66 (br s, 1H, CONH), 8.44 (s, 1H, NH), 8.10 (s, 1H, Ar-H), 7.86 (s, 1H, Ar-H), 7.83 (s, J = 2.6 Hz, 1H, Ar-H), 7.57 (dd, J = 2.5, 8.9 Hz, 1H , Ar-H), 7.44-7.49 (m, 1H, Ar-H), 7.29-7.33 (m, 2H, Ar-H), 7.24 (d, J = 9.0 Hz, 1H, Ar-H), 7.17 ( t, J = 10.9 Hz, 1H, Ar-H), 6.73 (td, J = 6.0, 15.4 Hz, 1H, CH = CH), 6.47 (d, J = 15.4z, 1H, CH = CH), 5.25 ( s, 2H, CH 2 ), 3.14 (d, J = 5.3 Hz, 2H, CH 2 ), 2.55 (s, 3H, CH 3 ), 2.50 (s, 8H, 4 × CH 2 ), 2.27 (s, 3H) , CH 3 ).
制备例2(E)-4-溴-N-{4-{{3-氯-4-[(吡啶-2-基)甲氧基]苯基}氨基}-5-甲基吡咯并[2,1-f][1,2,4]三嗪-6基}丁烯-2-酰胺 Preparation 2(E)-4-bromo-N-{4-{{3-chloro-4-[(pyridin-2-yl)methoxy]phenyl}amino}-5-methylpyrrolo[2 ,1-f][1,2,4]triazin-6-yl}buten-2-amide
Figure PCTCN2014091238-appb-000009
Figure PCTCN2014091238-appb-000009
步骤1；将中间体1b(19.0g，79.5mmol)，3-氯-4-(吡啶-2-基甲氧基)苯胺(18.7g，79.5mmol)和300ml异丙醇置入500ml反应瓶中，80℃反应2h，反应液冷却至室温，过滤，固体异丙醇洗涤，真空干燥过夜，得黄色固体(化合物1h)31.8g，收率91.9％。ESI-MS m/z：438[M+H]+。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] + .
步骤2：将化合物1h(31.0g，0.07mol)，氢氧化钠(9.60g，0.21mol)，150ml甲醇和150ml水置入500ml反应瓶中，60℃反应2h，反应液冷却至室温，用乙酸调至pH约为7，析出大量固体。过滤，固体水洗涤，真空干燥过夜，得淡黄色固体(化合物1i)29.3g，收率95.5％。ESI-MS m/z：410[M+H]+。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] + .
步骤3：将化合物1i(29.0g，66.2mmol)，叠氮磷酸二苯酯DPPA(27.3g，99.3mmol)，三乙胺(10.1g，99.3mmol)，300ml甲苯置入500ml反应瓶中，氮气保护下85℃反应4h。然后加入叔丁醇(14.7g，0.20mol)，85℃过夜。反应液冷却至室温，浓缩后柱层析纯化[洗脱剂：乙酸乙酯：石油醚＝1:4]，得黄色固体(化合物1j)8.68g，收率24.9％。ESI-MS m/z：481[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, mjjjjjjjj ESI-MS m/z: 481 [M+H] + .
步骤4：将化合物1j(8.50g，16.1mmol)，三氟乙酸14ml，二氯甲烷150ml置入250ml反应瓶中，室温反应4h。TLC监测反应结束，浓缩除去溶剂得油状物，柱层析纯化[洗脱剂：乙酸乙酯：石油醚＝1:1]，得黄色固体(化合物1k)4.80g，收率70.1％。ESI-MS m/z：381[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] + .
步骤5：将化合物1k(4.50g，10.6mmol)，4-溴巴豆酸(1.72g，10.6mmol)，HATU(6.04g，15.9mmol)，三乙胺(1.61g，15.9mmol)，DMF 50ml置入250ml反应瓶中，室温反应1h。TLC监测反应结束，加入200ml水，用二氯甲烷100ml×3萃取，合并有机相，无水硫酸钠干燥，浓缩后油状物，柱层析纯化[洗脱剂：乙酸乙酯：石油醚＝3:1]，得黄色固体(化合物1L)2.62g，收率43.2％。ESI-MS m/z：527[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 Into a 250 ml reaction flask, react at room temperature for 1 h. The reaction was completed by TLC. EtOAc (EtOAc: EtOAc = EtOAc) :1], a yellow solid (Compound 1L) was obtained 2.62 g, yield 43.2%. ESI-MS m/z: 527 [M+H] + .
实施例10(E)-N-{4-{{3-氯-4-[(吡啶-2-基)甲氧基]苯基}氨基}-5-甲基吡咯并[2,1-f][1,2,4]三嗪-6基}-4-(4-甲基哌啶-1-基)丁烯-2-酰胺(化合物10) Example 10(E)-N-{4-{{3-chloro-4-[(pyridin-2-yl)methoxy]phenyl}amino}-5-methylpyrrolo[2,1-f ][1,2,4]triazin-6-yl}-4-(4-methylpiperidin-1-yl)buten-2-amide (Compound 10)
方法同实施例2，投入化合物1L(200mg)和4-甲基吡啶(60mg)，得白色固体(化合物10)40mg，收率19.4％。ESI-MS m/z：546[M+H]+；1H-NMR(DMSO-d6,500MHz)δ(ppm)：9.68(br s,1H,CONH),8.61(d,J＝4.5Hz,1H,Ar-H),8.47(s,1H,NH),8.12(s,1H,Ar-H),7.85-7.91(m,3H,Ar-H),7.57-7.59(m,2H,Ar-H),7.37-7.39(m,1H,Ar-H),7.25(d,J＝9.0Hz,1H,Ar-H),6.75(td,J＝5.5,15.5Hz,1H,CH＝CH),6.47(d,J＝15.5z,1H,CH＝CH),5.30(s,2H,CH2),3.10(d,J＝4.5Hz,2H,CH2),2.82(d,J＝11.0Hz,2H,CH2),2.56(s,3H,CH3),1.94(t,J＝10.5Hz,2H,CH2),1.60(d,J＝12.0Hz,2H,CH2),1.34(s,1H,CH),1.15-1.22(m,2H,CH2),0.91(d,J＝6.5Hz,3H,CH3).In the same manner as in Example 2, the compound 1 L (200 mg) and 4-methylpyridine (60 mg) were added to give 40 mg (yield: Compound 10) (yield: 19.4%). ESI-MS m/z: 546 [M+H] + ; 1 H-NMR (DMSO-d6, 500 MHz) δ (ppm): 9.68 (br s, 1H, CONH), 8.61 (d, J = 4.5 Hz, 1H, Ar-H), 8.47 (s, 1H, NH), 8.12 (s, 1H, Ar-H), 7.85-7.91 (m, 3H, Ar-H), 7.57-7.59 (m, 2H, Ar- H), 7.37-7.39 (m, 1H, Ar-H), 7.25 (d, J = 9.0 Hz, 1H, Ar-H), 6.75 (td, J = 5.5, 15.5 Hz, 1H, CH = CH), 6.47 (d, J = 15.5z, 1H, CH = CH), 5.30 (s, 2H, CH 2 ), 3.10 (d, J = 4.5 Hz, 2H, CH 2 ), 2.82 (d, J = 11.0 Hz, 2H, CH 2 ), 2.56 (s, 3H, CH 3 ), 1.94 (t, J = 10.5 Hz, 2H, CH 2 ), 1.60 (d, J = 12.0 Hz, 2H, CH 2 ), 1.34 (s, 1H, CH), 1.15 - 1.22 (m, 2H, CH 2 ), 0.91 (d, J = 6.5 Hz, 3H, CH 3 ).
实施例11(E)-N-{4-{{3-氯-4-[(吡啶-2-基)甲氧基]苯基}氨基}-5-甲基吡咯并[2,1-f][1,2,4]三嗪-6基}-4-(哌啶-1-基)丁烯-2-酰胺(化合物11)Example 11(E)-N-{4-{{3-chloro-4-[(pyridin-2-yl)methoxy]phenyl}amino}-5-methylpyrrolo[2,1-f ][1,2,4]triazin-6-yl}-4-(piperidin-1-yl)buten-2-amide (Compound 11)
方法同实施例2，投入化合物1L(200mg)和哌啶(60mg)，得白色固体(化合物11)40mg，收率19.6％。ESI-MS m/z：532[M+H]+；1H-NMR(DMSO-d6,300MHz)δ(ppm)：9.66(brs,1H,CONH),8.60(d,J＝4.4Hz,1H,Ar-H),8.46(s,1H,NH),8.11(s,1H,Ar-H),7.84-7.91(m,3H,Ar-H),7.53-7.59(m,2H,Ar-H),7.35-7.39(m,1H,Ar-H),7.24(d,J＝9.0Hz,1H,Ar-H),6.74(td,J＝5.7,15.4Hz,1H,CH＝CH),6.45(d,J＝15.1z,1H,CH＝CH),5.29(s,2H,CH2),3.09(d,J＝5.6Hz,2H,CH2),2.55(s,3H,CH3),2.36(s,4H,2×CH2),1.53(s,4H,2×CH2),1.41(s,2H,CH2).In the same manner as in Example 2, the compound 1 L (200 mg) and piperidine (60 mg) were added to give a white solid (Compound 11) 40 mg (yield: 19.6%). ESI-MS m/z: 532 [M+H] + ; 1 H-NMR (DMSO-d6, 300 MHz) δ (ppm): 9.66 (brs, 1H, CONH), 8.60 (d, J = 4.4 Hz, 1H) , Ar-H), 8.46 (s, 1H, NH), 8.11 (s, 1H, Ar-H), 7.84-7.91 (m, 3H, Ar-H), 7.53-7.59 (m, 2H, Ar-H ), 7.35-7.39 (m, 1H, Ar-H), 7.24 (d, J = 9.0 Hz, 1H, Ar-H), 6.74 (td, J = 5.7, 15.4 Hz, 1H, CH = CH), 6.45 (d, J = 15.1z, 1H, CH = CH), 5.29 (s, 2H, CH2), 3.09 (d, J = 5.6 Hz, 2H, CH2), 2.55 (s, 3H, CH3), 2.36 (s , 4H, 2 × CH2), 1.53 (s, 4H, 2 × CH2), 1.41 (s, 2H, CH2).
实施例12(E)-N-{4-{{3-氯-4-[(吡啶-2-基)甲氧基]苯基}氨基}-5-甲基吡咯并[2,1-f][1,2,4]三嗪-6基}-4-(吡咯烷-1-基)丁烯-2-酰胺(化合物12)Example 12(E)-N-{4-{{3-chloro-4-[(pyridin-2-yl)methoxy]phenyl}amino}-5-methylpyrrolo[2,1-f ][1,2,4]triazin-6-yl}-4-(pyrrolidin-1-yl)buten-2-amide (Compound 12)
方法同实施例2，投入化合物1L(150mg)和吡咯烷(56mg)，得白色固体(化合物12)50mg，收率36.8％。ESI-MS m/z：518[M+H]+；1H-NMR(DMSO-d6,300MHz)δ(ppm)：9.67(br s,1H,CONH),8.60(d,J＝4.5Hz,1H,Ar-H),8.45(s,1H,NH),8.12(s,1H,Ar-H),7.84-7.91(m,3H,Ar-H),7.55-7.59(m,2H,Ar-H),7.35-7.39(m,1H,Ar-H),7.24(d,J＝9.0Hz,1H,Ar-H),6.79(td,J＝5.6,15.2Hz,1H,CH＝CH),6.49(d,J＝15.7z,1H,CH＝CH),5.29(s,2H,CH2),3.25(d,J＝5.2Hz,2H,CH2),2.55(s,3H,CH3),2.50(s,4H,2×CH2),1.72(s,4H,2×CH2).In the same manner as in Example 2, the compound 1 L (150 mg) and pyrrolidine (56 mg) were added to give a white solid (compound 12) 50 mg (yield: 36.8%). ESI-MS m/z: 518 [M+H] + ; 1 H-NMR (DMSO-d6, 300 MHz) δ (ppm): 9.67 (br s, 1H, CONH), 8.60 (d, J = 4.5 Hz, 1H, Ar-H), 8.45 (s, 1H, NH), 8.12 (s, 1H, Ar-H), 7.84-7.91 (m, 3H, Ar-H), 7.55-7.59 (m, 2H, Ar- H), 7.35-7.39 (m, 1H, Ar-H), 7.24 (d, J = 9.0 Hz, 1H, Ar-H), 6.79 (td, J = 5.6, 15.2 Hz, 1H, CH=CH), 6.49 (d, J = 15.7z, 1H, CH=CH), 5.29 (s, 2H, CH 2 ), 3.25 (d, J = 5.2 Hz, 2H, CH 2 ), 2.55 (s, 3H, CH 3 ) , 2.50 (s, 4H, 2 × CH 2 ), 1.72 (s, 4H, 2 × CH 2 ).
实施例13(E)-N-{4-{{3-氯-4-[(吡啶-2-基)甲氧基]苯基}氨基}-5-甲基吡咯并[2,1-f][1,2,4]三嗪-6基}-4-(1H-咪唑-1-基)丁烯-2-酰胺(化合物13)Example 13(E)-N-{4-{{3-chloro-4-[(pyridin-2-yl)methoxy]phenyl}amino}-5-methylpyrrolo[2,1-f ][1,2,4]triazin-6-yl}-4-(1H-imidazol-1-yl)buten-2-amide (Compound 13)
方法同实施例2，投入化合物1L(150mg)和咪唑(53mg)，得白色固体(化合物13)30mg，收率21.3％。ESI-MS m/z：515[M+H]+；1H-NMR(DMSO-d6,300MHz)δ(ppm)：9.76(br s,1H,CONH),8.59(d,J＝4.4Hz,1H,Ar-H),8.45(s,1H,NH),8.09(s,1H,Ar-H),7.83-7.91(m,3H,Ar-H),7.73(s,1H,Ar-H),7.54-7.58(m,2H,Ar-H),7.35-7.39(m,1H,Ar-H),7.21-7.25(m,2H,Ar-H),7.00(s,1H,Ar-H),6.94(td,J＝4.7,15.4Hz,1H,CH＝CH),6.12(d,J＝15.4z,1H,CH＝CH),5.29(s,2H,CH2),4.89(d, J＝4.2Hz,2H,CH2),2.50(s,3H,CH3).In the same manner as in Example 2, the compound 1 L (150 mg) and imidazole (53 mg) were added to give a white solid (comp. 13) 30 mg (yield: 21.3%). ESI-MS m/z: 515 [M+H] + ; 1 H-NMR (DMSO-d6, 300 MHz) δ (ppm): 9.76 (br s, 1H, CONH), 8.59 (d, J = 4.4 Hz, 1H, Ar-H), 8.45 (s, 1H, NH), 8.09 (s, 1H, Ar-H), 7.83-7.91 (m, 3H, Ar-H), 7.73 (s, 1H, Ar-H) , 7.54 - 7.58 (m, 2H, Ar-H), 7.35-7.39 (m, 1H, Ar-H), 7.21 - 7.25 (m, 2H, Ar-H), 7.00 (s, 1H, Ar-H) , 6.94 (td, J = 4.7, 15.4 Hz, 1H, CH = CH), 6.12 (d, J = 15.4z, 1H, CH = CH), 5.29 (s, 2H, CH 2 ), 4.89 (d, J =4.2 Hz, 2H, CH 2 ), 2.50 (s, 3H, CH 3 ).
实施例14(E)-N-{4-{{3-氯-4-[(吡啶-2-基)甲氧基]苯基}氨基}-5-甲基吡咯并[2,1-f][1,2,4]三嗪-6基}-4-(4-甲基哌嗪-1-基)丁烯-2-酰胺(化合物14)Example 14(E)-N-{4-{{3-chloro-4-[(pyridin-2-yl)methoxy]phenyl}amino}-5-methylpyrrolo[2,1-f ][1,2,4]triazin-6-yl}-4-(4-methylpiperazin-1-yl)buten-2-amide (Compound 14)
方法同实施例2，投入化合物1L(150mg)和N-甲基哌嗪60mg，得白色固体(化合物14)40mg，收率24.2％。ESI-MS m/z：547[M+H]+；1H-NMR(DMSO-d6,500MHz)δ(ppm)：9.66(br s,1H,CONH),8.59(d,J＝4.2Hz,1H,Ar-H),8.44(s,1H,NH),8.10(s,1H,Ar-H),7.84-7.89(m,3H,Ar-H),7.56-7.58(m,2H,Ar-H),7.35-7.38(m,1H,Ar-H),7.24(d,J＝9.1Hz,1H,Ar-H),6.73(td,J＝6.0,15.4Hz,1H,CH＝CH),6.46(d,J＝15.4z,1H,CH＝CH),5.29(s,2H,CH2),3.12(d,J＝5.1Hz,2H,CH2),2.55(s,3H,CH3),2.36-2.41(m,8H,4×CH2),2.17(s,3H,CH3).In the same manner as in Example 2, 1 L of a compound (150 mg) and 60 mg of N-methylpiperazine were added to give a white solid (Compound 14) 40 mg (yield: 24.2%). ESI-MS m/z: 547 [M+H] + ; 1 H-NMR (DMSO-d6, 500 MHz) δ (ppm): 9.66 (br s, 1H, CONH), 8.59 (d, J = 4.2 Hz, 1H, Ar-H), 8.44 (s, 1H, NH), 8.10 (s, 1H, Ar-H), 7.84-7.89 (m, 3H, Ar-H), 7.56-7.58 (m, 2H, Ar- H), 7.35-7.38 (m, 1H, Ar-H), 7.24 (d, J = 9.1 Hz, 1H, Ar-H), 6.73 (td, J = 6.0, 15.4 Hz, 1H, CH=CH), 6.46 (d, J = 15.4z, 1H, CH=CH), 5.29 (s, 2H, CH 2 ), 3.12 (d, J = 5.1 Hz, 2H, CH 2 ), 2.55 (s, 3H, CH 3 ) , 2.36-2.41 (m, 8H, 4 × CH 2 ), 2.17 (s, 3H, CH 3 ).
实施例15(E)-N-{4-{{3-氯-4-[(吡啶-2-基)甲氧基]苯基}氨基}-5-甲基吡咯并[2,1-f][1,2,4]三嗪-6基}-4-吗啉丁烯-2-酰胺(化合物15)Example 15(E)-N-{4-{{3-chloro-4-[(pyridin-2-yl)methoxy]phenyl}amino}-5-methylpyrrolo[2,1-f ][1,2,4]triazin-6-yl}-4-morpholinate-2-amide (compound 15)
方法同实施例2，投入化合物1L(150mg)和吗啉60mg，得白色固体(化合物15)34mg，收率22.6％。ESI-MS m/z：534[M+H]+；1H-NMR(DMSO-d6,500MHz)δ(ppm)：9.66(br s,1H,CONH),8.59(d,J＝4.2Hz,1H,Ar-H),8.44(s,1H,NH),8.10(s,1H,Ar-H),7.84-7.89(m,3H,Ar-H),7.56-7.58(m,2H,Ar-H),7.35-7.38(m,1H,Ar-H),7.24(d,J＝9.1Hz,1H,Ar-H),6.74(td,J＝5.9,15.4Hz,1H,CH＝CH),6.48(d,J＝15.4z,1H,CH＝CH),5.29(s,2H,CH2),3.61(t,J＝4.5Hz,4H,2×CH2),3.13(d,J＝5.9Hz,2H,CH2),2.55(s,3H,CH3),2.40(s,4H,2×CH2).In the same manner as in Example 2, the compound 1 L (150 mg) and morpholine 60 mg were added to give a white solid (Compound 15) (yield: 22.6%). ESI-MS m/z: 534 [M+H] + ; 1 H-NMR (DMSO-d6, 500 MHz) δ (ppm): 9.66 (br s, 1H, CONH), 8.59 (d, J = 4.2 Hz, 1H, Ar-H), 8.44 (s, 1H, NH), 8.10 (s, 1H, Ar-H), 7.84-7.89 (m, 3H, Ar-H), 7.56-7.58 (m, 2H, Ar- H), 7.35-7.38 (m, 1H, Ar-H), 7.24 (d, J = 9.1 Hz, 1H, Ar-H), 6.74 (td, J = 5.9, 15.4 Hz, 1H, CH = CH), 6.48 (d, J = 15.4z, 1H, CH = CH), 5.29 (s, 2H, CH 2 ), 3.61 (t, J = 4.5 Hz, 4H, 2 × CH 2 ), 3.13 (d, J = 5.9 Hz, 2H, CH 2 ), 2.55 (s, 3H, CH 3 ), 2.40 (s, 4H, 2 × CH 2 ).
实施例16(E)-N-{4-{{3-氯-4-[(吡啶-2-基)甲氧基]苯基}氨基}-5-甲基吡咯并[2,1-f][1,2,4]三嗪-6基}-4-(二乙胺基)丁烯-2-酰胺(化合物16)Example 16(E)-N-{4-{{3-chloro-4-[(pyridin-2-yl)methoxy]phenyl}amino}-5-methylpyrrolo[2,1-f ][1,2,4]triazin-6-yl}-4-(diethylamino)buten-2-amide (Compound 16)
方法同实施例2，投入化合物1L(150mg)和二乙胺(58mg)，得白色固体(化合物16)30mg，收率21.8％。ESI-MS m/z：520[M+H]+；1H-NMR(DMSO-d6,500MHz)δ(ppm)：9.65(br s,1H,CONH),8.59(d,J＝4.2Hz,1H,Ar-H),8.44(s,1H,NH),8.11(s,1H,Ar-H),7.84-7.89(m,3H,Ar-H),7.56-7.58(m,2H,Ar-H),7.35-7.38(m,1H,Ar-H),7.24(d,J＝9.1Hz,1H,Ar-H),6.78(td,J＝5.9,15.4Hz,1H,CH＝CH),6.49(d,J＝15.4z,1H,CH＝CH),5.29(s,2H,CH2),3.17(d,J＝4.8Hz,2H,CH2),2.55(s,3H,CH3),2.50(s,4H,2×CH2),1.00(t,J＝7.1Hz,6H,2×CH3).In the same manner as in Example 2, the compound 1 L (150 mg) and diethylamine (yield: 58 mg) were obtained to give white solid (comp. 16) 30 mg (yield: 21.8%). ESI-MS m/z: 520 [M+H] + ; 1 H-NMR (DMSO-d6, 500 MHz) δ (ppm): 9.65 (br s, 1H, CONH), 8.59 (d, J = 4.2 Hz, 1H, Ar-H), 8.44 (s, 1H, NH), 8.11 (s, 1H, Ar-H), 7.84-7.89 (m, 3H, Ar-H), 7.56-7.58 (m, 2H, Ar- H), 7.35-7.38 (m, 1H, Ar-H), 7.24 (d, J = 9.1 Hz, 1H, Ar-H), 6.78 (td, J = 5.9, 15.4 Hz, 1H, CH = CH), 6.49 (d, J = 15.4z, 1H, CH=CH), 5.29 (s, 2H, CH 2 ), 3.17 (d, J = 4.8 Hz, 2H, CH 2 ), 2.55 (s, 3H, CH 3 ) , 2.50 (s, 4H, 2 × CH 2 ), 1.00 (t, J = 7.1 Hz, 6H, 2 × CH 3 ).
实施例17(E)-N-{4-{{3-氯-4-[(吡啶-2-基)甲氧基]苯基}氨基}-5-甲基吡咯并[2,1-f][1,2,4]三嗪-6基}-4-(二甲胺基)丁烯-2-酰胺(化合物17)Example 17(E)-N-{4-{{3-chloro-4-[(pyridin-2-yl)methoxy]phenyl}amino}-5-methylpyrrolo[2,1-f ][1,2,4]triazin-6-yl}-4-(dimethylamino)buten-2-amide (Compound 17)
方法同实施例2，投入化合物1L(150mg)和二甲胺盐酸盐(60mg)和碳酸钾(108mg)，得白色固体(化合物17)32mg，收率21.4％。ESI-MS m/z：492[M+H]+；1H-NMR(DMSO-d6,500MHz)δ(ppm)：9.66(br s,1H,CONH),8.59(d,J＝4.2Hz,1H,Ar-H),8.44(s,1H,NH),8.11(s,1H,Ar-H),7.84-7.89(m,3H,Ar-H),7.56-7.58(m,2H,Ar-H),7.35-7.38(m,1H,Ar-H),7.24(d,J＝9.1Hz,1H,Ar-H),6.74(td,J＝5.9,15.4Hz, 1H,CH＝CH),6.48(d,J＝15.4z,1H,CH＝CH),5.29(s,2H,CH2),3.07(d,J＝4.5Hz,2H,CH2),2.55(s,3H,CH3),2.19(s,6H,2×CH3),1.00(t,J＝7.1Hz,6H,2×CH3).In the same manner as in Example 2, the compound 1 L (150 mg) and dimethylamine hydrochloride (60 mg) and potassium carbonate (108 mg) were obtained to give a white solid (Comp. ESI-MS m/z: 492 [M+H] + ; 1 H-NMR (DMSO-d6, 500 MHz) δ (ppm): 9.66 (br s, 1H, CONH), 8.59 (d, J = 4.2 Hz, 1H, Ar-H), 8.44 (s, 1H, NH), 8.11 (s, 1H, Ar-H), 7.84-7.89 (m, 3H, Ar-H), 7.56-7.58 (m, 2H, Ar- H), 7.35-7.38 (m, 1H, Ar-H), 7.24 (d, J = 9.1 Hz, 1H, Ar-H), 6.74 (td, J = 5.9, 15.4 Hz, 1H, CH = CH), 6.48 (d, J = 15.4z, 1H, CH=CH), 5.29 (s, 2H, CH 2 ), 3.07 (d, J = 4.5 Hz, 2H, CH 2 ), 2.55 (s, 3H, CH 3 ) , 2.19 (s, 6H, 2 × CH 3 ), 1.00 (t, J = 7.1 Hz, 6H, 2 × CH 3 ).
制备例34-[(3-氯-4-氟苯基)氨基]-6-{[4-溴-1-氧-2-丁烯-1-基]氨基}-吡咯并[2,1-f][1,2,4]三嗪Preparation 34-[(3-Chloro-4-fluorophenyl)amino]-6-{[4-bromo-1-oxo-2-buten-1-yl]amino}-pyrrolo[2,1- f][1,2,4]triazine
Figure PCTCN2014091238-appb-000010
Figure PCTCN2014091238-appb-000010
步骤1：将化合物1a(20.0g，0.09mol)，三氯氧磷(41.4g，0.27mol)，4-二甲氨基吡啶(DMAP)(32.0g，0.27mol)和150ml甲苯置入250ml反应瓶中，氮气保护下110℃反应6h。反应液冷却至室温，减压蒸除溶剂，加入200ml冰水，搅拌，析出大量固体。过滤，滤饼用冰水洗涤，真空干燥过夜，得淡黄色固体(化合物1b)19.1g，收率88.8％。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.
步骤2：将化合物1b(19.0g，79.5mmol)，3-氯-4-氟苯胺(11.6g，79.5mmol)和300ml异丙醇置入500ml反应瓶中，80℃反应2h，反应液冷却至室温，过滤，固体用异丙醇洗涤，真空干燥过夜，得黄色固体(化合物1c’)28.5g，收率92.8％。ESI-MS m/z：349[M+H]+。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'). ESI-MS m/z: 349[M+H] + .
步骤3：将化合物1c’(28.0g，0.08mol)，氢氧化钠(9.60g，0.24mol)，150ml甲醇和150ml水置入500ml反应瓶中，60℃反应2h，反应液冷却至室温，用乙酸调至pH约为7，大量固体析出。过滤，固体用水洗涤，真空干燥过夜，得淡黄色固体(化合物1d’)24.6g，收率96.1％。ESI-MS m/z：321[M+H]+。Step 3: Compound 1c' (28.0 g, 0.08 mol), sodium hydroxide (9.60 g, 0.24 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 precipitated. Filtration, the solid was washed with water and dried <RTI ID=0.0> ESI-MS m/z: 321 [M+H] + .
步骤4：将化合物1d’(24.0g，75.0mmol)，叠氮磷酸二苯酯DPPA(24.8g，0.09mol)，三乙胺(9.09g，0.09mol)，300ml甲苯置入500ml反应瓶中，氮气保护下加热至85℃反应4h。然后加入叔丁醇(11.1g，0.15mol)，85℃过夜。反应液冷却至室温，浓缩后柱层析纯化[洗脱剂：乙酸乙酯：石油醚＝1:4]，得黄色固体(化 合物1e’)7.35g，收率25.1％。ESI-MS m/z：392[M+H]+。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 tolulululululululululululululululululu ESI-MS m/z: 392[M+H] + .
步骤5：将化合物1e’(7.00g，17.9mmol)，三氟乙酸14ml，二氯甲烷150ml置入250ml反应瓶中，室温反应4h。反应液浓缩除去溶剂得油状物，柱层析提纯[洗脱剂：乙酸乙酯：石油醚＝1:1]，得黄色固体(化合物1f’)3.53g，收率67.8％。ESI-MSm/z：292[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 ESI-MS m/z: 292 [M+H] + .
步骤6：将化合物1f’(3.50g，12.0mmol)，4-溴巴豆酸(1.96g，12.0mmol)，2-(7-偶氮苯并三氮唑)-N,N,N',N'四甲基脲六氟磷酸酯HATU(5.47g，14.4mmol)，三乙胺(2.42g，24.0mmol)和DMF50ml置入250ml反应瓶中，室温反应1h。反应液加入200ml水，用二氯甲烷100ml×3萃取，合并有机相，无水硫酸钠干燥，浓缩得油状物，柱层析提纯[洗脱剂：乙酸乙酯：石油醚＝3:1]，得黄色固体(化合物1g’)2.45g，收率46.7％。ESI-MS m/z：438[M+H]+。1H-NMR(DMSO-d6,500MHz)δ(ppm)：9.74(br s,1H,CONH),8.58(s,1H,NH),8.04(s,1H,Ar-H),7.98(dd,J＝2.5,6.5Hz,1H,Ar-H),7.91(s,1H,Ar-H),7.67-7.70(m,1H,Ar-H),7.42(t,J＝9.0Hz,1H,Ar-H),6.59(td,J＝6.0,9.0Hz,1H,CH＝CH),6.51(d,J＝13.5Hz,1H,CH＝CH),3.40(s,2H,CH2),2.54(s,3H,CH3).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. The reaction mixture was poured into water (200 ml), and the mixture was evaporated to mjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj A yellow solid (compound 1 g') of 2.45 g was obtained in a yield of 46.7%. ESI-MS m/z: 438 [M+H] + . 1 H-NMR (DMSO-d6, 500 MHz) δ (ppm): 9.74 (br s, 1H, CONH), 8.58 (s, 1H, NH), 8.04 (s, 1H, Ar-H), 7.98 (dd, J = 2.5, 6.5 Hz, 1H, Ar-H), 7.91 (s, 1H, Ar-H), 7.67-7.70 (m, 1H, Ar-H), 7.42 (t, J = 9.0 Hz, 1H, Ar -H), 6.59 (td, J = 6.0, 9.0 Hz, 1H, CH = CH), 6.51 (d, J = 13.5 Hz, 1H, CH = CH), 3.40 (s, 2H, CH 2 ), 2.54 ( s, 3H, CH 3 ).
实施例18(E)-N-{4-[(3-氯-4-氟苯基)氨基]-5-甲基吡咯并[2,1-f][1,2,4]三嗪-6-基}-4-(哌啶-1-基)丁烯-2-酰胺(化合物18)Example 18(E)-N-{4-[(3-Chloro-4-fluorophenyl)amino]-5-methylpyrrolo[2,1-f][1,2,4]triazine- 6-yl}-4-(piperidin-1-yl)buten-2-amide (compound 18)
将化合物1g’(200mg)溶解于丙酮(5ml)中，加入哌啶(39mg)和碳酸钾(95mg)。室温反应2h，TLC检测反应基本完全。反应液过滤，减压蒸除溶剂，残余物用柱层析(二氯甲烷/甲醇＝10:1)纯化，得到白色固体(化合物18)82mg，收率40.6％。ESI-MS m/z：443[M+H]+，1H-NMR(DMSO-d6,300MHz)δ(ppm)：9.69(s,1H,CONH),8.59(s,1H,NH),8.14(s,1H,Ar-H),7.97-7.99(m,1H,Ar-H),7.91(s,1H,Ar-H),7.68-7.70(m,1H,Ar-H),7.42(t,J＝9.1Hz,1H,Ar-H),6.75(td,J＝5.8,9.6Hz,1H,CH＝CH),6.47(d,J＝15.5Hz,1H,CH＝CH),3.11(s,2H,CH2),2.56(s,3H,CH3),2.39(s,4H,2×CH2),1.54(s,4H,2×CH2),1.40(s.2H,CH2).Compound 1g' (200 mg) was dissolved in acetone (5 ml), and piperidine (39 mg) and potassium carbonate (95 mg) were added. The reaction was carried out for 2 h at room temperature, and the reaction was almost complete by TLC. The reaction mixture was filtered, and the solvent was evaporated, evaporated, mjjjjjj ESI-MS m/z: 443 [M+H] + , 1 H-NMR (DMSO-d6, 300 MHz) δ (ppm): 9.69 (s, 1H, CONH), 8.59 (s, 1H, NH), 8.14 (s, 1H, Ar-H), 7.97-7.99 (m, 1H, Ar-H), 7.91 (s, 1H, Ar-H), 7.68-7.70 (m, 1H, Ar-H), 7.42 (t , J = 9.1 Hz, 1H, Ar-H), 6.75 (td, J = 5.8, 9.6 Hz, 1H, CH = CH), 6.47 (d, J = 15.5 Hz, 1H, CH = CH), 3.11 (s , 2H, CH2), 2.56 (s, 3H, CH3), 2.39 (s, 4H, 2 × CH2), 1.54 (s, 4H, 2 × CH2), 1.40 (s. 2H, CH2).
实施例19(E)-N-{4-[(3-氯-4-氟苯基)氨基]-5-甲基吡咯并[2,1-f][1,2,4]三嗪-6-基}-4-(4-甲基哌啶-1-基)丁烯-2-酰胺(化合物19)Example 19(E)-N-{4-[(3-Chloro-4-fluorophenyl)amino]-5-methylpyrrolo[2,1-f][1,2,4]triazine- 6-yl}-4-(4-methylpiperidin-1-yl)buten-2-amide (Compound 19)
方法同实施例18，投入化合物1g’(100mg)、4-甲基哌啶(25mg)和碳酸钾48mg，得白色固体(化合物19)40mg，收率38.4％。ESI-MS m/z：457[M+H]+；1H-NMR(DMSO-d6,500MHz)δ(ppm)：9.74(br s,1H,CONH),8.62(s,1H,NH),8.16(s,1H,Ar-H),7.99(dd,J＝2.5,6.5Hz,1H,Ar-H),7.71(s,1H,Ar-H),7.68-7.71(m,1H,Ar-H),7.44(t,J＝9.0Hz,1H,Ar-H),6.76(td,J＝6.0,9.0Hz,1H,CH＝CH),6.50(d,J＝13.5Hz,1H,CH＝CH),3.13(s,2H,CH2),2.84(s,2H,CH2),2.57(s,3H,CH3),1.95(s,2H,CH2),1.62(s,2H,CH2),1.37(s,1H,CH),1.21(s,2H,CH2),0.91(d,J＝6.0Hz,3H,CH3).In the same manner as in Example 18, the compound 1 g' (100 mg), 4-methylpiperidine (25 mg), and potassium carbonate (48 mg) were added to give 40 mg (yield of compound 19) (yield: 38.4%). ESI-MS m / z: 457 [M + H] +; 1 H-NMR (DMSO-d6,500MHz) δ (ppm): 9.74 (br s, 1H, CONH), 8.62 (s, 1H, NH), 8.16 (s, 1H, Ar-H), 7.99 (dd, J = 2.5, 6.5 Hz, 1H, Ar-H), 7.71 (s, 1H, Ar-H), 7.68-7.71 (m, 1H, Ar- H), 7.44 (t, J = 9.0 Hz, 1H, Ar-H), 6.76 (td, J = 6.0, 9.0 Hz, 1H, CH = CH), 6.50 (d, J = 13.5 Hz, 1H, CH = CH), 3.13 (s, 2H, CH 2 ), 2.84 (s, 2H, CH 2 ), 2.57 (s, 3H, CH 3 ), 1.95 (s, 2H, CH 2 ), 1.62 (s, 2H, CH) 2 ), 1.37 (s, 1H, CH), 1.21 (s, 2H, CH 2 ), 0.91 (d, J = 6.0 Hz, 3H, CH 3 ).
实施例20(E)-N-{4-[(3-氯-4-氟苯基)氨基]-5-甲基吡咯并[2,1-f][1,2,4]三嗪-6- 基}-4-(2-甲基哌啶-1-基)丁烯-2-酰胺(化合物20)Example 20(E)-N-{4-[(3-Chloro-4-fluorophenyl)amino]-5-methylpyrrolo[2,1-f][1,2,4]triazine- 6- }-4-(2-methylpiperidin-1-yl)butene-2-amide (compound 20)
方法同实施例18，投入化合物1g’(100mg)、2-甲基哌啶(25mg)和碳酸钾48mg，得白色固体(化合物20)30mg，收率28.8％。ESI-MS m/z：457[M+H]+；1H-NMR(DMSO-d6,300MHz)δ(ppm)：9.69(br s,1H,CONH),8.59(s,1H,NH),8.15(s,1H,Ar-H),7.98(dd,J＝2.3,6.7Hz,1H,Ar-H),7.91(s,1H,Ar-H),7.67-7.70(m,1H,Ar-H),7.42(t,J＝9.1Hz,1H,Ar-H),6.74(td,J＝5.8,15.4Hz,1H,CH＝CH),6.46(d,J＝15.3Hz,1H,CH＝CH),3.10(d,J＝5.4Hz,2H,CH2),2.81(d,J＝11.0Hz,2H,CH2),2.56(s,3H,CH3),1.93(t,J＝10.8Hz,2H,CH2),1.59(d,J＝15.3Hz,2H,CH2),1.33(s,1H,CH),1.15-1.22(m,2H,CH2),0.90(d,J＝6.3Hz,3H,CH3).In the same manner as in Example 18, the compound 1 g' (100 mg), 2-methylpiperidine (25 mg), and potassium carbonate (48 mg) were added to give a white solid (comp. 20) 30 mg (yield 28.8%). ESI-MS m/z: 457 [M+H] + ; 1 H-NMR (DMSO-d6, 300 MHz) δ (ppm): 9.69 (br s, 1H, CONH), 8.59 (s, 1H, NH), 8.15 (s, 1H, Ar-H), 7.98 (dd, J = 2.3, 6.7 Hz, 1H, Ar-H), 7.91 (s, 1H, Ar-H), 7.67-7.70 (m, 1H, Ar- H), 7.42 (t, J = 9.1 Hz, 1H, Ar-H), 6.74 (td, J = 5.8, 15.4 Hz, 1H, CH = CH), 6.46 (d, J = 15.3 Hz, 1H, CH = CH), 3.10 (d, J = 5.4 Hz, 2H, CH 2 ), 2.81 (d, J = 11.0 Hz, 2H, CH 2 ), 2.56 (s, 3H, CH 3 ), 1.93 (t, J = 10.8) Hz, 2H, CH 2 ), 1.59 (d, J = 15.3 Hz, 2H, CH 2 ), 1.33 (s, 1H, CH), 1.15.12.22 (m, 2H, CH2), 0.90 (d, J = 6.3) Hz, 3H, CH 3 ).
实施例21(E)-N-{4-[(3-氯-4-氟苯基)氨基]-5-甲基吡咯并[2,1-f][1,2,4]三嗪-6-基}-4-(二乙胺基)丁烯-2-酰胺(化合物21)Example 21(E)-N-{4-[(3-Chloro-4-fluorophenyl)amino]-5-methylpyrrolo[2,1-f][1,2,4]triazine- 6-yl}-4-(diethylamino)buten-2-amide (Compound 21)
方法同实施例18，投入化合物1g’(100mg)、二乙胺(17mg)和碳酸钾48mg，得白色固体(化合物21)30mg，收率30.3％。ESI-MS m/z：431[M+H]+；1H-NMR(DMSO-d6,500MHz)δ(ppm)：9.76(br s,1H,CONH),8.62(s,1H,NH),8.16(s,1H,Ar-H),7.99(dd,J＝2.5,7.0Hz,1H,Ar-H),7.92(s,1H,Ar-H),7.69-7.71(m,1H,Ar-H),7.44(t,J＝9.0Hz,1H,Ar-H),6.79(td,J＝6.0,15.5Hz,1H,CH＝CH),6.56(d,J＝15.5Hz,1H,CH＝CH),2.58(s,5H,CH2,CH3),2.51(s,4H,2×CH2),1.05(s,6H,2×CH3).In the same manner as in Example 18, the compound 1 g' (100 mg), diethylamine (17 mg), and potassium carbonate (48 mg) were added to give white solid (Comp. 21) 30 mg (yield 30.3%). ESI-MS m/z: 431 [M+H] + ; 1 H-NMR (DMSO-d6, 500 MHz) δ (ppm): 9.76 (br s, 1H, CONH), 8.62 (s, 1H, NH), 8.16 (s, 1H, Ar-H), 7.99 (dd, J = 2.5, 7.0 Hz, 1H, Ar-H), 7.92 (s, 1H, Ar-H), 7.69-7.71 (m, 1H, Ar- H), 7.44 (t, J = 9.0 Hz, 1H, Ar-H), 6.79 (td, J = 6.0, 15.5 Hz, 1H, CH = CH), 6.56 (d, J = 15.5 Hz, 1H, CH = CH), 2.58 (s, 5H, CH2, CH 3 ), 2.51 (s, 4H, 2 × CH 2 ), 1.05 (s, 6H, 2 × CH 3 ).
实施例22(E)-N-{4-[(3-氯-4-氟苯基)氨基]-5-甲基吡咯并[2,1-f][1,2,4]三嗪-6-基}-4-(吗啉-1-基)丁烯-2-酰胺(化合物22)Example 22(E)-N-{4-[(3-Chloro-4-fluorophenyl)amino]-5-methylpyrrolo[2,1-f][1,2,4]triazine- 6-yl}-4-(morpholin-1-yl)buten-2-amide (Compound 22)
方法同实施例18，投入化合物1g(200mg)、吗啉(42mg)和碳酸钾127mg，得白色固体(化合物22)87mg，收率43.3％。ESI-MS m/z：445[M+H]+；1H-NMR(DMSO-d6,500MHz)δ(ppm)：9.74(br s,1H,CONH),8.63(s,1H,NH),8.16(s,1H,Ar-H),7.97(dd,J＝2.5,9.5Hz,1H,Ar-H),7.92(s,1H,Ar-H),7.68-7.70(m,1H,Ar-H),7.44(t,J＝9.5Hz,1H,Ar-H),6.74(td,J＝5.5,15.0Hz,1H,CH＝CH),6.50(d,J＝15.0Hz,1H,CH＝CH),3.62(s,4H,2×CH2),3.14(d,J＝4.5Hz,2H,CH2),2.64(s,3H,CH3),2.41(s,4H,2×CH2).In the same manner as in Example 18, 1 g (200 mg), morpholine (42 mg), and 127 mg of potassium carbonate were added to afford white crystals ( Compound 22) (yield: 43.3%). ESI-MS m / z: 445 [M + H] +; 1 H-NMR (DMSO-d6,500MHz) δ (ppm): 9.74 (br s, 1H, CONH), 8.63 (s, 1H, NH), 8.16 (s, 1H, Ar-H), 7.97 (dd, J = 2.5, 9.5 Hz, 1H, Ar-H), 7.92 (s, 1H, Ar-H), 7.68-7.70 (m, 1H, Ar- H), 7.44 (t, J = 9.5 Hz, 1H, Ar-H), 6.74 (td, J = 5.5, 15.0 Hz, 1H, CH = CH), 6.50 (d, J = 15.0 Hz, 1H, CH = CH), 3.62 (s, 4H, 2 × CH 2 ), 3.14 (d, J = 4.5 Hz, 2H, CH 2 ), 2.64 (s, 3H, CH 3 ), 2.41 (s, 4H, 2 × CH 2 ) ).
实施例23(E)-N-{4-[(3-氯-4-氟苯基)氨基]-5-甲基吡咯并[2,1-f][1,2,4]三嗪-6-基}-4-(吡咯烷-1-基)丁烯-2-酰胺(化合物23)Example 23(E)-N-{4-[(3-Chloro-4-fluorophenyl)amino]-5-methylpyrrolo[2,1-f][1,2,4]triazine- 6-yl}-4-(pyrrolidin-1-yl)buten-2-amide (compound 23)
方法同实施例18，投入化合物1g’(150mg)、吡咯烷(25mg)和碳酸钾94mg，得白色固体(化合物23)64mg，收率42.8％。ESI-MS m/z：429[M+H]+；1H-NMR(DMSO-d6,500MHz)δ(ppm)：9.67(br s,1H,CONH),8.58(s,1H,NH),8.15(s,1H,Ar-H),7.98(dd,J＝2.3,6.8Hz,1H,Ar-H),7.90(s,1H,Ar-H),7.68-7.70(m,1H,Ar-H),7.42(t,J＝9.1Hz,1H,Ar-H),6.79(td,J＝5.6,15.4Hz,1H,CH＝CH),6.49(d,J＝15.6Hz,1H,CH＝CH),3.25(d,J＝5.5Hz,2H,CH2),2.56(s,3H,CH3),2.50(s,4H,2×CH2),1.72(s,4H,2×CH2). In the same manner as in Example 18, the compound 1 g' (150 mg), pyrrolidine (25 mg), and potassium carbonate (94 mg) were added to give a white solid (compound 23) (yield: 42. ESI-MS m/z: 429 [M+H] + ; 1 H-NMR (DMSO-d6, 500 MHz) δ (ppm): 9.67 (br s, 1H, CONH), 8.58 (s, 1H, NH), 8.15 (s, 1H, Ar-H), 7.98 (dd, J = 2.3, 6.8 Hz, 1H, Ar-H), 7.90 (s, 1H, Ar-H), 7.68-7.70 (m, 1H, Ar- H), 7.42 (t, J = 9.1 Hz, 1H, Ar-H), 6.79 (td, J = 5.6, 15.4 Hz, 1H, CH = CH), 6.49 (d, J = 15.6 Hz, 1H, CH = CH), 3.25 (d, J = 5.5 Hz, 2H, CH 2 ), 2.56 (s, 3H, CH 3 ), 2.50 (s, 4H, 2 × CH 2 ), 1.72 (s, 4H, 2 × CH 2 ) ).
实施例24(E)-N-{4-[(3-氯-4-氟苯基)氨基]-5-甲基吡咯并[2,1-f][1,2,4]三嗪-6-基}-4-(1H-咪唑-1-基)丁烯-2-酰胺(化合物24)Example 24(E)-N-{4-[(3-Chloro-4-fluorophenyl)amino]-5-methylpyrrolo[2,1-f][1,2,4]triazine- 6-yl}-4-(1H-imidazol-1-yl)buten-2-amide (compound 24)
方法同实施例18，投入化合物1g’(150mg)、咪唑(23mg)和碳酸钾94mg，得白色固体(化合物24)60mg，收率40.4％。ESI-MS m/z：426[M+H]+；1H-NMR(DMSO-d6,500MHz)δ(ppm)：9.77(br s,1H,CONH),8.59(s,1H,NH),8.13(s,1H,Ar-H),7.95(dd,J＝2.3,6.8Hz,1H,Ar-H),7.90(s,1H,Ar-H),7.67-7.69(m,2H,Ar-H),7.42(t,J＝9.1Hz,1H,Ar-H),7.20(s,1H,Ar-H),6.98(s,1H,Ar-H),6.93(td,J＝4.810.9Hz,1H,CH＝CH),6.12(d,J＝15.4Hz,1H,CH＝CH),4.89(d,J＝3.8Hz,2H,CH2),2.53(s,3H,CH3).In the same manner as in Example 18, the compound 1 g' (150 mg), imidazole (23 mg), and potassium carbonate (94 mg) were added to give white solid (compound 24) 60 mg (yield: 40.4%). ESI-MS m/z: 426 [M+H] + ; 1 H-NMR (DMSO-d6, 500 MHz) δ (ppm): 9.77 (br s, 1H, CONH), 8.59 (s, 1H, NH), 8.13 (s, 1H, Ar-H), 7.95 (dd, J = 2.3, 6.8 Hz, 1H, Ar-H), 7.90 (s, 1H, Ar-H), 7.67-7.69 (m, 2H, Ar- H), 7.42 (t, J = 9.1 Hz, 1H, Ar-H), 7.20 (s, 1H, Ar-H), 6.98 (s, 1H, Ar-H), 6.93 (td, J = 4.810.9 Hz) , 1H, CH=CH), 6.12 (d, J = 15.4 Hz, 1H, CH = CH), 4.89 (d, J = 3.8 Hz, 2H, CH 2 ), 2.53 (s, 3H, CH 3 ).
实施例25(E)-N-{4-[(3-氯-4-氟苯基)氨基]-5-甲基吡咯并[2,1-f][1,2,4]三嗪-6-基}-4-(二甲胺基)丁烯-2-酰胺(化合物25)Example 25(E)-N-{4-[(3-Chloro-4-fluorophenyl)amino]-5-methylpyrrolo[2,1-f][1,2,4]triazine- 6-yl}-4-(dimethylamino)butene-2-amide (compound 25)
方法同实施例18，投入化合物1g’(200mg)、二甲胺盐酸盐(45mg)和碳酸钾190mg，得白色固体(化合物25)100mg，收率54.2％。ESI-MS m/z：403[M+H]+；1H-NMR(DMSO-d6,500MHz)δ(ppm)：9.74(br s,1H,CONH),8.61(s,1H,NH),8.15(s,1H,Ar-H),7.99(dd,J＝2.2,6.6Hz,1H,Ar-H),7.91(s,1H,Ar-H),7.68-7.70(m,1H,Ar-H),7.42(t,J＝9.1Hz,1H,Ar-H),6.75(td,J＝5.9,15.4Hz,1H,CH＝CH),6.51(d,J＝15.5Hz,1H,CH＝CH),3.14(s,2H,CH2),2.57(s,3H,CH3),2.24(s,6H,2×CH3).In the same manner as in Example 18, the compound 1 g' (200 mg), dimethylamine hydrochloride (45 mg), and 190 mg of potassium carbonate were added to give a white solid (Comp. ESI-MS m/z: 403 [M+H] + ; 1 H-NMR (DMSO-d6, 500 MHz) δ (ppm): 9.74 (br s, 1H, CONH), 8.61 (s, 1H, NH), 8.15 (s, 1H, Ar-H), 7.99 (dd, J = 2.2, 6.6 Hz, 1H, Ar-H), 7.91 (s, 1H, Ar-H), 7.68-7.70 (m, 1H, Ar- H), 7.42 (t, J = 9.1 Hz, 1H, Ar-H), 6.75 (td, J = 5.9, 15.4 Hz, 1H, CH = CH), 6.51 (d, J = 15.5 Hz, 1H, CH = CH), 3.14 (s, 2H, CH 2 ), 2.57 (s, 3H, CH 3 ), 2.24 (s, 6H, 2 × CH 3 ).
实施例26(E)-N-{4-[(3-氯-4-氟苯基)氨基]-5-甲基吡咯并[2,1-f][1,2,4]三嗪-6-基}-4-(N-甲基哌嗪-1-基)丁烯-2-酰胺(化合物26)Example 26(E)-N-{4-[(3-Chloro-4-fluorophenyl)amino]-5-methylpyrrolo[2,1-f][1,2,4]triazine- 6-yl}-4-(N-methylpiperazin-1-yl)buten-2-amide (Compound 26)
方法同实施例18，投入化合物1g’(150mg)、N-甲基哌嗪(34mg)和碳酸钾94mg，得白色固体(化合物26)45mg，收率29.0％。ESI-MS m/z：458[M+H]+；1H-NMR(DMSO-d6,500MHz)δ(ppm)：9.66(br s,1H,CONH),8.61(s,1H,NH),8.09(s,1H,Ar-H),7.93(s,2H,Ar-H),7.85(s,1H,Ar-H),7.39(t,J＝9.1Hz,1H,Ar-H),6.72(td,J＝6.0,15.4Hz,1H,CH＝CH),6.46(d,J＝15.5Hz,1H,CH＝CH),3.01(s,2H,CH2),2.36-2.41(m,8H,2×CH2),2.16(s,3H,CH3).In the same manner as in Example 18, the compound 1 g' (150 mg), N-methylpiperazine (34 mg), and potassium carbonate (yield: 94 mg) was obtained. ESI-MS m/z: 458 [M+H] + ; 1 H-NMR (DMSO-d6, 500 MHz) δ (ppm): 9.66 (br s, 1H, CONH), 8.61 (s, 1H, NH), 8.09 (s, 1H, Ar-H), 7.93 (s, 2H, Ar-H), 7.85 (s, 1H, Ar-H), 7.39 (t, J = 9.1 Hz, 1H, Ar-H), 6.72 (td, J=6.0, 15.4 Hz, 1H, CH=CH), 6.46 (d, J = 15.5 Hz, 1H, CH=CH), 3.01 (s, 2H, CH 2 ), 2.36-2.41 (m, 8H) , 2 × CH 2 ), 2.16 (s, 3H, CH 3 ).
制备例44-[(3-乙炔基苯基)氨基]-6-{[4-溴-1-氧-2-丁烯-1-基]氨基}-吡咯并[2,1-f][1,2,4]三嗪Preparation 44-[(3-Ethynylphenyl)amino]-6-{[4-bromo-1-oxo-2-buten-1-yl]amino}-pyrrolo[2,1-f][ 1,2,4]triazine
Figure PCTCN2014091238-appb-000011
Figure PCTCN2014091238-appb-000011
步骤1：将化合物1b(19.0g,79.5mmol)，3-乙炔苯胺(9.22g，79.5mmol)和300ml异丙醇置入500ml反应瓶中，80℃反应2h。反应结束后，反应液冷却至室温，过滤，固体用异丙醇洗涤，真空干燥过夜,得黄色固体(化合物1h’)23.8g，收率93.7％。ESI-MS m/z：321[M+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%. ESI-MS m/z: 321 [M+H] + .
步骤2：将化合物1h’(23.0g，71.8mmol)，氢氧化钠(8.62g，0.22mol)，150ml甲醇和150ml水置入500ml反应瓶中，60℃反应2h，反应液冷却至室温，用乙酸调至pH约为7，析出大量固体。过滤，固体水洗涤，真空干燥过夜，得淡黄色固体(化合物1i’)20.3g，收率97.0％。ESI-MS m/z：293[M+H]+。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] + .
步骤3：将化合物1i’(20.0g，68.5mmol)，叠氮磷酸二苯酯DPPA(22.0g，0.08mol)，三乙胺(8.08g，0.08mol)，300ml甲苯置入500ml反应瓶中，氮气保护下85℃反应4h。然后加入叔丁醇(10.2g，0.14mol)，85℃过夜。反应液冷却至室温，浓缩后柱层析纯化[洗脱剂：乙酸乙酯：石油醚＝1:4]，得黄色固体(化合物1j’)6.74g，收率27.1％。ESI-MS m/z：364[M+H]+。Step 3: Compound 1i' (20.0 g, 68.5 mmol), diphenylphosphoryl DPPA (22.0 g, 0.08 mol), triethylamine (8.08 g, 0.08 mol), 300 ml of toluene were placed in a 500 ml reaction flask. The reaction was carried out at 85 ° C for 4 h under a nitrogen atmosphere. Then tert-butanol (10.2 g, 0.14 mol) was added at 85 ° C overnight. The reaction solution was cooled to room temperature, and then purified and purified by column chromatography (eluent: ethyl acetate: petroleum ether = 1:4) to yield 6.74 g (yel. ESI-MS m/z: 364[M+H] + .
步骤4：将化合物1j’(6.50g，17.9mmol)，三氟乙酸14ml，二氯甲烷150ml置入250ml反应瓶中，室温反应4h。反应液浓缩除去溶剂得油状物，柱层析提纯[洗脱剂：乙酸乙酯：石油醚＝1:1]，得黄色固体(化合物1k’)3.07g，收率65.4％。ESI-MSm/z：264[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 ESI-MS m/z: 264 [M+H] + .
步骤5：将化合物1k’(3.00g，11.5mmol)，4-溴巴豆酸(1.87g，11.5mmol)，HATU(6.56g，17.3mmol)，三乙胺(1.77g，17.3mmol)DMF 50ml置入250ml反应瓶中，室温反应1h。反应液加入200ml水，用二氯甲烷100ml×3萃取，合并有机相，无水硫酸钠干燥，浓缩后油状物，柱层析提纯[洗脱剂：乙酸乙酯：石油醚＝3:1]，得黄色固体(化合物1L’)1.92g，收率48.2％。ESI-MS m/z：410[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 Into 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%. ESI-MS m/z: 410 [M+H] + .
实施例27(E)-N-{4-[(3-乙炔基苯基)氨基]-5-甲基吡咯并[2,1-f][1,2,4]三嗪-6-基}-4-(4-甲基哌啶-1-基)丁烯-2-酰胺(化合物27)Example 27(E)-N-{4-[(3-ethynylphenyl)amino]-5-methylpyrrolo[2,1-f][1,2,4]triazin-6-yl }-4-(4-Methylpiperidin-1-yl)buten-2-amide (Compound 27)
方法同实施例18，投入化合物1L’(150mg)、4-甲基哌啶47mg和碳酸钾89mg，得白色固体(化合物27)30mg，收率19.2％。ESI-MS m/z：429[M+H]+；1H-NMR(DMSO-d6,300MHz)δ(ppm)：9.77(br s,1H,CONH),8.55(s,1H,NH),8.15(s,1H,Ar-H),7.92(s,1H,Ar-H),7.87(s,1H,Ar-H),7.76(d,J＝8.2Hz,1H,Ar-H),7.38(t,J＝7.8Hz,1H,Ar-H),7.23(d,J＝7.7Hz,1H,Ar-H),6.76(td,J＝5.9,15.5Hz,1H,CH＝CH),6.51(d,J＝14.9Hz,1H,CH＝CH),4.21(s,1H,ethynyl-H),2.89(s,2H,CH2),2.57(s,3H,CH3),1.99(s,2H,CH2),1.64(s,2H,CH2),1.40(s,1H,CH),1.23(s,2H,CH2),0.91(d,J＝6.3Hz,3H,CH3).In the same manner as in Example 18, the compound 1L' (150 mg), 4-methylpiperidine (47 mg), and potassium carbonate (yield: ESI-MS m/z: 429 [M+H]+; 1 H-NMR (DMSO-d6, 300 MHz) δ (ppm): 9.77 (br s, 1H, CONH), 8.55 (s, 1H, NH), 8.15 (s, 1H, Ar-H), 7.92 (s, 1H, Ar-H), 7.87 (s, 1H, Ar-H), 7.76 (d, J = 8.2 Hz, 1H, Ar-H), 7.38 (t, J = 7.8 Hz, 1H, Ar-H), 7.23 (d, J = 7.7 Hz, 1H, Ar-H), 6.76 (td, J = 5.9, 15.5 Hz, 1H, CH = CH), 6.51 (d, J = 14.9 Hz, 1H, CH = CH), 4.21 (s, 1H, ethynyl-H), 2.89 (s, 2H, CH 2 ), 2.57 (s, 3H, CH 3 ), 1.99 (s, 2H, CH 2 ), 1.64 (s, 2H, CH 2 ), 1.40 (s, 1H, CH), 1.23 (s, 2H, CH 2 ), 0.91 (d, J = 6.3 Hz, 3H, CH 3 ).
实施例28(E)-N-{4-[(3-乙炔基苯基)氨基]-5-甲基吡咯并[2,1-f][1,2,4]三嗪-6-基}-4-(N-甲基哌嗪-1-基)丁烯-2-酰胺(化合物28)Example 28(E)-N-{4-[(3-ethynylphenyl)amino]-5-methylpyrrolo[2,1-f][1,2,4]triazin-6-yl }-4-(N-Methylpiperazin-1-yl)buten-2-amide (Compound 28)
方法同实施例18，投入化合物1L’(150mg)、N-甲基哌啶47mg和碳酸钾89mg， 得白色固体(化合物28)40mg，收率25.4％。ESI-MS m/z：430[M+H]+；1H-NMR(DMSO-d6,500MHz)δ(ppm)：9.70(br s,1H,CONH),8.53(s,1H,NH),8.14(s,1H,Ar-H),7.92(s,1H,Ar-H),7.87(s,1H,Ar-H),7.76(d,J＝8.2Hz,1H,Ar-H),7.38(t,J＝7.9Hz,1H,Ar-H),7.22(d,J＝7.6Hz,1H,Ar-H),6.73(td,J＝6.0,15.4Hz,1H,CH＝CH),6.48(d,J＝15.4Hz,1H,CH＝CH),4.18(s,1H,ethynyl-H),3.16(d,J＝5.5Hz,2H,CH2),2.57(s,3H,CH3),2.50(s,8H,4×CH2),2.32(s,3H,CH3).In the same manner as in Example 18, the compound 1L' (150 mg), N-methylpiperidine (47 mg), and potassium carbonate (yield: 89 mg) was obtained as a white solid (comp. 28) (yield: 25.4%). ESI-MS m/z: 430 [M+H] + ; 1 H-NMR (DMSO-d6, 500 MHz) δ (ppm): 9.70 (br s, 1H, CONH), 8.53 (s, 1H, NH), 8.14 (s, 1H, Ar-H), 7.92 (s, 1H, Ar-H), 7.87 (s, 1H, Ar-H), 7.76 (d, J = 8.2 Hz, 1H, Ar-H), 7.38 (t, J = 7.9 Hz, 1H, Ar-H), 7.22 (d, J = 7.6 Hz, 1H, Ar-H), 6.73 (td, J = 6.0, 15.4 Hz, 1H, CH = CH), 6.48 (d, J = 15.4 Hz, 1H, CH = CH), 4.18 (s, 1H, ethynyl-H), 3.16 (d, J = 5.5 Hz, 2H, CH 2 ), 2.57 (s, 3H, CH 3 ) , 2.50 (s, 8H, 4 × CH 2 ), 2.32 (s, 3H, CH 3 ).
实施例29(E)-N-{4-[(3-乙炔基苯基)氨基]-5-甲基吡咯并[2,1-f][1,2,4]三嗪-6-基}-4-(二甲胺基)丁烯-2-酰胺(化合物29)Example 29(E)-N-{4-[(3-ethynylphenyl)amino]-5-methylpyrrolo[2,1-f][1,2,4]triazin-6-yl }-4-(dimethylamino)butene-2-amide (compound 29)
方法同实施例18，投入化合物1L’(150mg)、二甲胺盐酸盐39mg和碳酸钾148mg，得白色固体(化合物29)50mg，收率37.6％。ESI-MS m/z：375[M+H]+；1H-NMR(DMSO-d6,500MHz)δ(ppm)：9.69(br s,1H,CONH),8.52(s,1H,NH),8.15(s,1H,Ar-H),7.92(s,1H,Ar-H),7.88(s,1H,Ar-H),7.76(d,J＝8.2Hz,1H,Ar-H),7.38(t,J＝7.9Hz,1H,Ar-H),7.22(d,J＝7.6Hz,1H,Ar-H),6.74(td,J＝5.9,15.4Hz,1H,CH＝CH),6.48(d,J＝15.4Hz,1H,CH＝CH),4.18(s,1H,ethynyl-H),3.07(d,J＝4.9Hz,2H,CH2),2.57(s,3H,CH3),2.20(s,6H,2×CH3).In the same manner as in Example 18, the compound 1L' (150 mg), dimethylamine hydrochloride (yield: 39 mg) and 148 mg of potassium carbonate were added to give 50 mg (yield: Compound 29) (yield: 37.6%). ESI-MS m / z: 375 [M + H] +; 1 H-NMR (DMSO-d6,500MHz) δ (ppm): 9.69 (br s, 1H, CONH), 8.52 (s, 1H, NH), 8.15 (s, 1H, Ar-H), 7.92 (s, 1H, Ar-H), 7.88 (s, 1H, Ar-H), 7.76 (d, J = 8.2 Hz, 1H, Ar-H), 7.38 (t, J = 7.9 Hz, 1H, Ar-H), 7.22 (d, J = 7.6 Hz, 1H, Ar-H), 6.74 (td, J = 5.9, 15.4 Hz, 1H, CH = CH), 6.48 (d, J = 15.4 Hz, 1H, CH = CH), 4.18 (s, 1H, ethynyl-H), 3.07 (d, J = 4.9 Hz, 2H, CH 2 ), 2.57 (s, 3H, CH 3 ) , 2.20 (s, 6H, 2 × CH 3 ).
实施例30(E)-N-{4-[(3-乙炔基苯基)氨基]-5-甲基吡咯并[2,1-f][1,2,4]三嗪-6-基}-4-(1H-咪唑-1-基)丁烯-2-酰胺(化合物30)Example 30(E)-N-{4-[(3-ethynylphenyl)amino]-5-methylpyrrolo[2,1-f][1,2,4]triazin-6-yl }-4-(1H-imidazol-1-yl)buten-2-amide (compound 30)
方法同实施例18，投入化合物1L’(150mg)、咪唑30mg和碳酸钾89mg，得白色固体(化合物30)40mg，收率23.2％。ESI-MS m/z：398[M+H]+；1H-NMR(DMSO-d6,500MHz)δ(ppm)：9.76(br s,1H,CONH),8.51(s,1H,NH),8.12(s,1H,Ar-H),7.91(s,1H,Ar-H),7.86(s,1H,Ar-H),7.75(d,J＝8.2Hz,1H,Ar-H),7.69(s,1H,Ar-H),7.37(t,J＝7.9Hz,1H,Ar-H),7.22(d,J＝7.7Hz,1H,Ar-H),7.20(s,1H,Ar-H),6.98(s,1H,Ar-H),6.93(td,J＝4.7,15.4Hz,1H,CH＝CH),6.12(d,J＝15.4Hz,1H,CH＝CH),4.88(d,J＝3.1Hz,2H,CH2),4.18(s,1H,ethynyl-H),2.53(s,3H,CH3).In the same manner as in Example 18, the compound 1L' (150 mg), imidazole 30 mg, and potassium carbonate (89 mg) were added to give a white solid (Compound 30) 40 mg, yield 23.2%. ESI-MS m/z: 398 [M+H] + ; 1H-NMR (DMSO-d6, 500 MHz) δ (ppm): 9.76 (br s, 1H, CONH), 8.51 (s, 1H, NH), 8.12 (s, 1H, Ar-H), 7.91 (s, 1H, Ar-H), 7.86 (s, 1H, Ar-H), 7.75 (d, J = 8.2 Hz, 1H, Ar-H), 7.69 ( s, 1H, Ar-H), 7.37 (t, J = 7.9 Hz, 1H, Ar-H), 7.22 (d, J = 7.7 Hz, 1H, Ar-H), 7.20 (s, 1H, Ar-H) ), 6.98 (s, 1H, Ar-H), 6.93 (td, J = 4.7, 15.4 Hz, 1H, CH = CH), 6.12 (d, J = 15.4 Hz, 1H, CH = CH), 4.88 (d) , J = 3.1 Hz, 2H, CH 2 ), 4.18 (s, 1H, ethynyl-H), 2.53 (s, 3H, CH 3 ).
实施例31(E)-N-{4-[(3-乙炔基苯基)氨基]-5-甲基吡咯并[2,1-f][1,2,4]三嗪-6-基}-4-(2-甲基哌啶-1-基)丁烯-2-酰胺(化合物31)Example 31(E)-N-{4-[(3-ethynylphenyl)amino]-5-methylpyrrolo[2,1-f][1,2,4]triazin-6-yl }-4-(2-Methylpiperidin-1-yl)buten-2-amide (Compound 31)
方法同实施例18，投入化合物1L’(150mg)、2-甲基哌啶47mg和碳酸钾89mg，得白色固体(化合物31)30mg，收率19.2％。ESI-MS m/z：429[M+H]+；1H-NMR(DMSO-d6,500MHz)δ(ppm)：9.96(br s,1H,CONH),8.55(s,1H,NH),8.14(s,1H,Ar-H),7.93(s,1H,Ar-H),7.87(s,1H,Ar-H),7.76(d,J＝8.2Hz,1H,Ar-H),7.38(t,J＝7.9Hz,1H,Ar-H),7.22(d,J＝7.6Hz,1H,Ar-H),6.84(td,J＝5.9,15.4Hz,1H,CH＝CH),6.69(d,J＝15.4Hz,1H,CH＝CH),4.18(s,1H,ethynyl-H),3.30(s,2H,CH2),2.59(s,3H,CH3),2.50(s,2H,CH2),1.91(s,2H,CH2),1.68(s,2H,CH2),1.45(s,1H,CH2),1.29(s,5H,CH2,CH3).In the same manner as in Example 18, the compound 1L' (150 mg), 2-methylpiperidine (47 mg), and potassium carbonate (yield: 89 mg) was obtained. ESI-MS m/z: 429 [M+H]+; 1 H-NMR (DMSO-d6, 500 MHz) δ (ppm): 9.96 (br s, 1H, CONH), 8.55 (s, 1H, NH), 8.14 (s, 1H, Ar-H), 7.93 (s, 1H, Ar-H), 7.87 (s, 1H, Ar-H), 7.76 (d, J = 8.2 Hz, 1H, Ar-H), 7.38 (t, J = 7.9 Hz, 1H, Ar-H), 7.22 (d, J = 7.6 Hz, 1H, Ar-H), 6.84 (td, J = 5.9, 15.4 Hz, 1H, CH = CH), 6.69 (d, J = 15.4 Hz, 1H, CH = CH), 4.18 (s, 1H, ethynyl-H), 3.30 (s, 2H, CH 2 ), 2.59 (s, 3H, CH 3 ), 2.50 (s, 2H, CH 2 ), 1.91 (s, 2H, CH 2 ), 1.68 (s, 2H, CH 2 ), 1.45 (s, 1H, CH 2 ), 1.29 (s, 5H, CH 2 , CH 3 ).
实施例32(E)-N-{4-[(3-乙炔基苯基)氨基]-5-甲基吡咯并[2,1-f][1,2,4]三嗪-6- 基}-4-(二乙胺基)丁烯-2-酰胺(化合物32)Example 32(E)-N-{4-[(3-ethynylphenyl)amino]-5-methylpyrrolo[2,1-f][1,2,4]triazine-6- }-4-(diethylamino)buten-2-amide (compound 32)
方法同实施例18，投入化合物1L’(150mg)、二乙胺24mg和碳酸钾89mg，得白色固体(化合物32)40mg，收率27.4％。ESI-MS m/z：403[M+H]+；1H-NMR(DMSO-d6,500MHz)δ(ppm)：9.99(br s,1H,CONH),8.55(s,1H,NH),8.15(s,1H,Ar-H),7.93(s,1H,Ar-H),7.88(s,1H,Ar-H),7.76(d,J＝8.2Hz,1H,Ar-H),7.38(t,J＝7.9Hz,1H,Ar-H),7.22(d,J＝7.6Hz,1H,Ar-H),6.80(td,J＝5.9,15.4Hz,1H,CH＝CH),6.72(d,J＝15.4Hz,1H,CH＝CH),4.18(s,1H,ethynyl-H),3.96(s,2H,CH2),3.14(s,4H,2×CH2),2.59(s,3H,CH3),1.25(s,6H,2×CH3).In the same manner as in Example 18, the compound 1L' (150 mg), diethylamine (24 mg), and potassium carbonate (yield: ESI-MS m/z: 403 [M+H]+; 1H-NMR (DMSO-d6, 500 MHz) δ (ppm): 9.99 (br s, 1H, CONH), 8.55 (s, 1H, NH), 8.15 (s, 1H, Ar-H), 7.93 (s, 1H, Ar-H), 7.88 (s, 1H, Ar-H), 7.76 (d, J = 8.2 Hz, 1H, Ar-H), 7.38 ( t, J = 7.9 Hz, 1H, Ar-H), 7.22 (d, J = 7.6 Hz, 1H, Ar-H), 6.80 (td, J = 5.9, 15.4 Hz, 1H, CH = CH), 6.72 ( d, J = 15.4 Hz, 1H, CH = CH), 4.18 (s, 1H, ethynyl-H), 3.96 (s, 2H, CH 2 ), 3.14 (s, 4H, 2 × CH 2 ), 2.59 (s , 3H, CH 3 ), 1.25 (s, 6H, 2 × CH 3 ).
实施例33(E)-N-{4-[(3-乙炔基苯基)氨基]-5-甲基吡咯并[2,1-f][1,2,4]三嗪-6-基}-4-(吗啉-1-基)丁烯-2-酰胺(化合物33)Example 33(E)-N-{4-[(3-ethynylphenyl)amino]-5-methylpyrrolo[2,1-f][1,2,4]triazin-6-yl }-4-(morpholin-1-yl)buten-2-amide (compound 33)
方法同实施例18，投入化合物1L’(150mg)、吗啉41mg和碳酸钾89mg，得白色固体(化合物33)50mg，收率33.4％。ESI-MS m/z：417[M+H]+；1H-NMR(DMSO-d6,500MHz)δ(ppm)：9.69(s,1H,Ar-H),8.52(s,1H,Ar-H),8.14(s,1H,Ar-H),7.92(s,1H,Ar-H),7.88(s,1H,Ar-H),7.76(d,J＝8.2Hz,1H,Ar-H),7.38(t,J＝7.9Hz,1H,Ar-H),7.22(d,J＝7.6Hz,1H,Ar-H),6.74(td,J＝6.0,15.4Hz,1H,CH＝CH),6.49(d,J＝15.5Hz,1H,CH＝CH),4.18(s,1H,ethynyl-H),3.48(s,2H,CH2),2.74(s,4H,2×CH2),2.58(s,3H,CH3),1.80(s,4H,2×CH2).In the same manner as in Example 18, the compound 1L' (150 mg), morpholine 41 mg, and potassium carbonate (89 mg) were added to give 50 mg (yield: Compound 33) (yield: 33.4%). ESI-MS m/z: 417 [M+H] + ; 1 H-NMR (DMSO-d6, 500 MHz) δ (ppm): 9.69 (s, 1H, Ar-H), 8.52 (s, 1H, Ar- H), 8.14 (s, 1H, Ar-H), 7.92 (s, 1H, Ar-H), 7.88 (s, 1H, Ar-H), 7.76 (d, J = 8.2 Hz, 1H, Ar-H ), 7.38 (t, J = 7.9 Hz, 1H, Ar-H), 7.22 (d, J = 7.6 Hz, 1H, Ar-H), 6.74 (td, J = 6.0, 15.4 Hz, 1H, CH=CH) ), 6.49 (d, J = 15.5 Hz, 1H, CH = CH), 4.18 (s, 1H, ethynyl-H), 3.48 (s, 2H, CH 2 ), 2.74 (s, 4H, 2 × CH 2 ) , 2.58 (s, 3H, CH 3 ), 1.80 (s, 4H, 2 × CH 2 ).
实施例34(E)-N-{4-[(3-乙炔基苯基)氨基]-5-甲基吡咯并[2,1-f][1,2,4]三嗪-6-基}-4-(吡咯烷-1-基)丁烯-2-酰胺(化合物34)Example 34(E)-N-{4-[(3-ethynylphenyl)amino]-5-methylpyrrolo[2,1-f][1,2,4]triazin-6-yl }-4-(pyrrolidin-1-yl)buten-2-amide (compound 34)
方法同实施例18，投入化合物1L’(150mg)、吡咯烷34mg和碳酸钾89mg，得白色固体(化合物34)30mg，收率21.2％。ESI-MS m/z：401[M+H]+；1H-NMR(DMSO-d6,500MHz)δ(ppm)：9.79(s,1H,Ar-H),8.54(s,1H,Ar-H),8.15(s,1H,Ar-H),7.92(s,1H,Ar-H),7.88(s,1H,Ar-H),7.76(d,J＝8.2Hz,1H,Ar-H),7.38(t,J＝7.9Hz,1H,Ar-H),7.22(d,J＝7.6Hz,1H,Ar-H),6.80(td,J＝6.0,15.4Hz,1H,CH＝CH),6.56(d,J＝15.1Hz,1H,CH＝CH),4.18(s,1H,ethynyl-H),3.49(s,2H,CH2),2.74(s,4H,2×CH2),2.58(s,3H,CH3),1.80(s,4H,2×CH2).In the same manner as in Example 18, the compound 1L' (150 mg), pyrrolidine 34 mg, and potassium carbonate (89 mg) were added to give white solid (comp. 34) 30 mg (yield: 21.2%). ESI-MS m/z: 401 [M+H] + ; 1 H-NMR (DMSO-d6, 500 MHz) δ (ppm): 9.79 (s, 1H, Ar-H), 8.54 (s, 1H, Ar- H), 8.15 (s, 1H, Ar-H), 7.92 (s, 1H, Ar-H), 7.88 (s, 1H, Ar-H), 7.76 (d, J = 8.2 Hz, 1H, Ar-H) ), 7.38 (t, J = 7.9 Hz, 1H, Ar-H), 7.22 (d, J = 7.6 Hz, 1H, Ar-H), 6.80 (td, J = 6.0, 15.4 Hz, 1H, CH=CH) ), 6.56 (d, J = 15.1 Hz, 1H, CH = CH), 4.18 (s, 1H, ethynyl-H), 3.49 (s, 2H, CH2), 2.74 (s, 4H, 2 x CH2), 2.58 (s, 3H, CH3), 1.80 (s, 4H, 2 × CH2).
实施例35(E)-N-{4-[(3-乙炔基苯基)氨基]-5-甲基吡咯并[2,1-f][1,2,4]三嗪-6-基}-4-(哌啶-1-基)丁烯-2-酰胺(化合物35)Example 35(E)-N-{4-[(3-ethynylphenyl)amino]-5-methylpyrrolo[2,1-f][1,2,4]triazin-6-yl }-4-(piperidin-1-yl)buten-2-amide (compound 35)
方法同实施例18，投入化合物1L’(150mg)、哌啶41mg和碳酸钾89mg，得白色固体(化合物35)30mg，收率19.4％。ESI-MS m/z：415[M+H]+；1H-NMR(DMSO-d6,500MHz)δ(ppm)：9.69(s,1H,Ar-H),8.52(s,1H,Ar-H),8.14(s,1H,Ar-H),7.92(s,1H,Ar-H),7.87(s,1H,Ar-H),7.76(d,J＝8.2Hz,1H,Ar-H),7.38(t,J＝7.9Hz,1H,Ar-H),7.22(d,J＝7.7Hz,1H,Ar-H),6.75(td,J＝6.0,15.4Hz,1H,CH＝CH),6.48(d,J＝15.1Hz,1H,CH＝CH),4.18(s,1H,ethynyl-H),3.11(s,2H,CH2),2.57(s,3H,CH3),2.36(s,4H,2×CH2),1.55(s,4H,2×CH2),1.41(s,2H,CH2). In the same manner as in Example 18, Compound 1L' (150 mg), &lt;RTI ID=0.0&gt;&gt; ESI-MS m/z: 415 [M+H] + ; 1 H-NMR (DMSO-d6, 500 MHz) δ (ppm): 9.69 (s, 1H, Ar-H), 8.52 (s, 1H, Ar- H), 8.14 (s, 1H, Ar-H), 7.92 (s, 1H, Ar-H), 7.87 (s, 1H, Ar-H), 7.76 (d, J = 8.2 Hz, 1H, Ar-H ), 7.38 (t, J = 7.9 Hz, 1H, Ar-H), 7.22 (d, J = 7.7 Hz, 1H, Ar-H), 6.75 (td, J = 6.0, 15.4 Hz, 1H, CH = CH) ), 6.48 (d, J = 15.1 Hz, 1H, CH = CH), 4.18 (s, 1H, ethynyl-H), 3.11 (s, 2H, CH 2 ), 2.57 (s, 3H, CH 3 ), 2.36 (s, 4H, 2 × CH 2 ), 1.55 (s, 4H, 2 × CH 2 ), 1.41 (s, 2H, CH 2 ).
生物学实施例Biological example
1.细胞水平EGFR激酶活性测定1. Determination of EGFR kinase activity at the cellular level
测定EGFR抑制剂在细胞水平的活性。利用ELSA法，检测EGFR抑制剂对EGF诱导的细胞水平EGFR磷酸化抑制的IC50值。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.
用EGFR的抗体包被在固相载体上，来抓取细胞裂解液中的EGFR蛋白。然后用抗磷酸化酪氨酸的抗体检测细胞中磷酸化的EGFR蛋白：由于磷酸化的EGFR蛋白能被抗磷酸化酪氨酸的抗体识别，用HRP二抗、TMB显示后读数。不同的磷酸化程度有不同的读数值；磷酸化程度越大，读数值越高。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.
1.1 实验材料与仪器1.1 Experimental materials and instruments
人口腔表皮样癌KB细胞株(中国科学院典型培养物保藏委员会细胞库)；DMEM培养基(Gibco,C12430)；FBS(Gibco,12657-029)；胰酶-EDTA(Gibco，25200)双抗(碧云天生物技术研究所，C0222)；100mm细胞培养皿(Corning,430167)；96孔细胞培养板(Costar，3599)；96孔V底板(Costar，3896)；96孔酶标板(Costar，2592)；Recombinant Human EGF(Peprotech,AF-100-15)；裂解液(生兴生物,SN338)；Anti-human EGF R/ErbB1Antibody(R&D,AF231)；Anti-phosphotyrosine clone 4G10(Millipore,05-231)；Goat Anti-Mouse IgG HRP Conjugate(Novagen,71045-3)；TMB(Pierce,34028)；离心机(Eppendorf，_centrifuge5810R)；二氧化碳培养箱(Thermo，FORMA SERIES II)；超净工作台(Thermo，1300SERIES A2)；恒温振荡仪(Eppendorf，Thermomixer comfort)；酶标仪(TECAN，Infinite M200pro)。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); TMB (Pierce, 34428); 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).
1.2 实验方法1.2 Experimental methods
1.2.1化合物配置将化合物用DMSO配制成1mM的母液，-20℃保存备用。1.2.1 Compound Configuration The compound was formulated into a 1 mM mother liquor in DMSO and stored at -20 ° C until use.
1.2.2试验步骤1.2.2 Test procedure
(1)将Anti-human EGF R/ErbB1Antibody稀释到0.2μg/mL，每孔100μL，加入到酶标板中，4℃包被过夜。(1) Anti-human EGF R/ErbB1 Antibody was diluted to 0.2 μg/mL, 100 μL per well, added to an ELISA plate, and coated at 4 ° C overnight.
(2)取包被过夜的酶标板，吸去上清，PBST(PBS/0.05％Tween20，pH7.4)洗涤3遍，每孔加入200μL封闭液(5％BSA/PBS)，37℃封闭2h，PBST洗涤三遍，4℃保存备用。(2) Take the overnight-labeled plate, aspirate the supernatant, wash 3 times with PBST (PBS/0.05% Tween20, pH 7.4), add 200 μL blocking solution (5% BSA/PBS) to each well, and block at 37 °C. 2h, PBST was washed three times and stored at 4 ° C for later use.
(3)将80-90％融合度的KB细胞接种到96孔细胞培养板中，贴壁后更换无血清培基饥饿过夜。(3) Inoculate 80-90% confluent KB cells into 96-well cell culture plates, and after adherence, replace the serum-free medium with starvation overnight.
(4)吸去96孔板中上清，每孔加入90μL新鲜无血清培基，再加入10μL无血清培基稀释后的化合物(浓度从0-10μM)，37℃孵育1.5h。(4) Aspirate the supernatant from a 96-well plate, add 90 μL of fresh serum-free medium to each well, and add 10 μL of the serum-free compound (concentration from 0-10 μM) and incubate at 37 ° C for 1.5 h.
(5)每孔加入5μL稀释后的EGF(10μg/mL)，快速混匀，37℃刺激8min。(5) Add 5 μL of diluted EGF (10 μg/mL) to each well, mix rapidly, and stimulate at 37 ° C for 8 min.
(6)快速吸去96孔板中上清，每孔加入100μL裂解液，4℃裂解1h。(6) The supernatant in the 96-well plate was quickly aspirated, 100 μL of the lysate was added to each well, and lysed at 4 ° C for 1 h.
(7)取90μL细胞裂解液加入到酶标板中，37℃孵育1.5h。 (7) 90 μL of cell lysate was added to the ELISA plate and incubated at 37 ° C for 1.5 h.
(8)取出酶标板，吸去上清，PBST洗涤3遍，每孔加入100μLAnti-phosphor-tyrosine(1:2000稀释)，37℃孵育1h。(8) The plate was taken out, the supernatant was aspirated, washed 3 times with PBST, 100 μL of Anti-phosphor-tyrosine (1:2000 dilution) was added to each well, and incubated at 37 ° C for 1 h.
(9)取出酶标板，吸去上清，PBST洗涤3遍，每孔加入100μLGoat Anti-Mouse IgG HRP Conjugate(1:4000稀释)，37℃孵育1h。(9) The plate was taken out, the supernatant was aspirated, washed 3 times with PBST, and 100 μL of Goat Anti-Mouse IgG HRP Conjugate (1:4000 dilution) was added to each well, and incubated at 37 ° C for 1 h.
(10)取出酶标板，吸去上清，PBST洗涤6遍，每孔加入100μL TMB，室温避光反应至适当颜色后，每孔加入50μL 2M的硫酸终止反应(10) Remove the microtiter plate, aspirate the supernatant, wash 6 times with PBST, add 100 μL of TMB to each well, and react to the appropriate color at room temperature, then add 50 μL of 2M sulfuric acid per well to stop the reaction.
(11)在OD450下检测吸光度值。(11) The absorbance value was measured at OD 450 .
1.3数据处理以化合物浓度为横坐标，相对吸收值为纵坐标绘图，数据拟合用lg(IC50)公式经Prism软件(GraphPad Software,Inc)处理，求出IC50。1.3 Data processing The compound concentration was plotted on the abscissa and the relative absorbance was plotted on the ordinate. The data fit was processed by Prism software (GraphPad Software, Inc) using the lg (IC 50 ) formula to determine the IC 50 .
抑制率采用以下公式计算：The inhibition rate is calculated using the following formula:
Figure PCTCN2014091238-appb-000012
Figure PCTCN2014091238-appb-000012
本发明化合物的活性Activity of the compounds of the invention
本发明化合物的细胞水平EGFR激酶活性通过以上的试验进行测定，测得的IC50值见下表。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.
Figure PCTCN2014091238-appb-000013
Figure PCTCN2014091238-appb-000013
2.抑制细胞增殖测试下面的体外测试是用来测定本发明化合物对于人类肿瘤细胞NCI-N87(HER-2高表达)细胞株抑制增殖活性。2. Inhibition of cell proliferation assay The following in vitro assay was used to determine the inhibitory activity of the compounds of the invention against human tumor cell NCI-N87 (HER-2 high expression) cell lines.
测定按常规采用溴化四氮唑蓝(MTT)法。活细胞线粒体中的琥珀酸脱氢酶能使外源性溴化四氮唑蓝还原为难溶的蓝紫色结晶物(Formazan)并沉积在细胞中，而死细胞无此功能。二甲基亚砜(DMSO)能溶解细胞中的紫色结晶物，用酶联免疫检测仪在570nm波长处检测其光吸收值，可间接反映活细胞数量。因而，采用 MTT法可测定目标化合物抑制细胞的增殖能力，同时利用本领域熟知的方法，可以对任意癌细胞使用相似的测定方法。The measurement was carried out by conventional use of a tetrazolium bromide (MTT) method. 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. Thus, 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.
2.1 实验材料与仪器2.1 Experimental materials and instruments
人胃癌NCI-N87细胞株(中国科学院典型培养物保藏委员会细胞库)；100mm细胞培养皿(Corning，430167)；96孔细胞培养板(Costar，3599)；96孔V底板(Costar，3896)；一次性移液管(Costar，货号：4488)；RMPI-1640培养基(Gibco，C22400)；FBS(Gibco,12657)；胰酶-EDTA(Gibco，25200)；双抗(碧云天生物技术研究所，C0222)；MTT(SIGMA，M2128)；离心机(Eppendorf，centrifuge 5810R)；二氧化碳培养箱(Thermo，FORMA SERIES II)；超净工作台(Thermo，1300SERIES A2)；恒温振荡仪(Eppendorf，Thermomixer comfort)；酶标仪(TECAN，Infinite M200pro)。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. 4488); RMPI-1640 medium (Gibco, C22400); FBS (Gibco, 12657); Trypsin-EDTA (Gibco, 25200); Double antibody (Biyuntian Biotechnology Research Institute) , C0222); 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).
2.2 试验方法2.2 Test methods
取融合度大于80％的NCI-N87细胞，胰酶消化后离心计数，按15000个/孔接种于96孔细胞培养板中，每孔100μL，置于37℃，5％CO2培养箱中过夜。次日，吸去培基，每孔加入180μL新鲜培基，再加入20μL含待测化合物(浓度从10μM至1nM)的培基，空白组加入20μL培基，每个浓度设3个平行孔。置于37℃，5％CO2培养箱中继续培养72h后，每孔加入20μL含5mg/mL MTT的PBS。在培养箱中继续培养4h后吸去培基，每孔加入100μL DMSO。室温下避光振荡10min。用多功能读数仪，在参考波长690nm，吸收波长550nm条件下测定吸光度值(OD值)。相对吸收值为550nm减去690nm。以化合物浓度为横坐标，相对吸收值为纵坐标绘图，数据拟合用lg(IC50)公式经Prism软件(GraphPad Software,Inc)处理。图形曲线拟合公式如下：相对OD值＝最低OD值+(最高OD值-最低OD值)/(1+10^(浓度-LogIC50))。其中，最低OD值是阳性化物100％抑制时的吸光度值，最高OD值是空白对照组的吸光度值。计算出的IC50值是指特定化合物的细胞毒性作用。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 μL per well, placed in a 37 ° C, 5% CO 2 incubator overnight. . On the next day, the pernatrine was aspirated, 180 μL of fresh medium was added to each well, and 20 μL of a medium containing the test compound (concentration from 10 μM to 1 nM) was added, and 20 μL of the medium was added to the blank group, and three parallel holes were set for each concentration. After continuing to incubate for 72 h at 37 ° C in a 5% CO 2 incubator, 20 μL of PBS containing 5 mg/mL MTT was added to each well. The culture was continued for 4 hours in the incubator, and the perfusate was aspirated, and 100 μL of DMSO was added to each well. Shake for 10 min at room temperature in the dark. The absorbance value (OD value) was measured with a multi-function reader at a reference wavelength of 690 nm and an absorption wavelength of 550 nm. The relative absorption value was 550 nm minus 690 nm. The compound concentration was plotted on the abscissa and the relative absorbance was plotted on the ordinate. The data fit was processed by Prism software (GraphPad Software, Inc) using the lg (IC50) formula. The graph curve fitting formula is as follows: relative OD value = lowest OD value + (highest OD value - lowest OD value) / (1 + 10 ^ (concentration - LogIC 50 )). Among them, the lowest OD value is the absorbance value when the positive compound is 100% inhibited, and the highest OD value is the absorbance value of the blank control group. The calculated IC 50 value is cellular toxic effects of a particular compound.
本发明化合物的活性Activity of the compounds of the invention
本发明化合物的抑制N87细胞增殖活性通过以上的试验进行测定，测得的IC50值见下表。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.
Figure PCTCN2014091238-appb-000014
Figure PCTCN2014091238-appb-000014
Figure PCTCN2014091238-appb-000015
Figure PCTCN2014091238-appb-000015
结论：本发明实施例中制备的具有式I结构的化合物1-35在细胞水平EGFR激酶活性测定中显示出显著的抑制活性，此外对HER-2高表达的人胃癌细胞NCI-N87也显示出显著的抑制增殖活性。 Conclusion: Compounds 1-35 having the structure of formula I prepared in the examples of the present invention showed significant inhibitory activity in the measurement of EGFR kinase activity at the cellular level, and also showed that human gastric cancer cell NCI-N87 with high expression of HER-2 also showed Significant inhibition of proliferative activity.

Claims (10)

  1. 式I所示的化合物或其药学上可接受的盐：a compound of formula I or a pharmaceutically acceptable salt thereof:
    Figure PCTCN2014091238-appb-100001
    Figure PCTCN2014091238-appb-100001
    其中，Y为-R1或
    Figure PCTCN2014091238-appb-100002
    Where Y is -R 1 or
    Figure PCTCN2014091238-appb-100002
    R1为苯基或杂芳基，其可选地被一个或多个选自下列的基团所取代：卤素、烷基、烯基、炔基、烷氧基、硝基、羟基、环烷基或杂脂环基、氰基、巯基、酰基、硫代酰基、氨基、卤代烷基、卤代烷氧基、酯基、芳基和杂芳基；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;
    R2为卤素、-NR3R4、-OR5或-SR6；R 2 is halogen, -NR 3 R 4 , -OR 5 or -SR 6 ;
    R3和R4独立地为氢、烷基、环烷基、芳基或杂芳基，或者R3和R4与N原子合起来形成一个含N的杂芳基或杂脂环基；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;
    R5和R6独立地为氢、烷基、环烷基、芳基或杂芳基。R 5 and R 6 are independently hydrogen, alkyl, cycloalkyl, aryl or heteroaryl.
  2. 根据权利要求1所述的化合物或其药学上可接受的盐，其中R1为苯基或吡啶基，其可选地被一个或多个选自下列的基团所取代：卤素、炔基；优选地，R1为3-氟苯基、3-氟-4-氯-苯基、3-乙炔基苯基或吡啶基。The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 1 is phenyl or pyridyl, which is optionally substituted by one or more groups selected from the group consisting of halogen, alkynyl; Preferably, R 1 is 3-fluorophenyl, 3-fluoro-4-chloro-phenyl, 3-ethynylphenyl or pyridyl.
  3. 根据权利要求1所述的化合物或其药学上可接受的盐，其中R2为-NR3R4，R3和R4独立地为氢、烷基、环烷基、芳基或杂芳基，或者R3和R4与N原子合起来形成一个含N的杂芳基或杂脂环基；The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 2 is -NR 3 R 4 , and R 3 and R 4 are independently hydrogen, alkyl, cycloalkyl, aryl or heteroaryl Or R 3 and R 4 together with the N atom form an N-containing heteroaryl or heteroalicyclic group;
    优选地：Preferably:
    R2为-NR3R4，R 2 is -NR 3 R 4 ,
    R3和R4独立地为烷基，或者R3和R4与N原子合起来形成一个含N的杂芳基或杂脂环基；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;
    再优选地：More preferably:
    R2为-NR3R4，R 2 is -NR 3 R 4 ,
    R3和R4独立地为烷基，或者R3和R4与N原子合起来形成一个含N的杂芳基、未取代的或烷基取代的杂脂环基；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;
    更优选地：More preferably:
    R2为-NR3R4，R 2 is -NR 3 R 4 ,
    R3和R4独立地为烷基，或者R3和R4与N原子合起来形成任选的取代的如下基团：哌嗪子基、吗啉子基、哌啶子基、吡咯烷子基或咪唑基。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, pyrrolidine Base or imidazolyl.
  4. 根据权利要求1所述的化合物或其药学上可接受的盐，选自： A compound according to claim 1 or a pharmaceutically acceptable salt thereof, selected from the group consisting of:
    (E)-N-{4-{{3-氯-4-[(3-氟苯基)甲氧基]苯基}氨基}-5-甲基吡咯并[2,1-f][1,2,4]三嗪-6基}-4-吗啉丁烯-2-酰胺；(E)-N-{4-{{3-chloro-4-[(3-fluorophenyl)methoxy]phenyl}amino}-5-methylpyrrolo[2,1-f][1 , 2,4]triazin-6-yl}-4-morpholinate-2-amide;
    (E)-N-{4-{{3-氯-4-[(3-氟苯基)甲氧基]苯基}氨基}-5-甲基吡咯并[2,1-f][1,2,4]三嗪-6基}-4-(哌啶-1-基)丁烯-2-酰胺；(E)-N-{4-{{3-chloro-4-[(3-fluorophenyl)methoxy]phenyl}amino}-5-methylpyrrolo[2,1-f][1 , 2,4]triazin-6-yl}-4-(piperidin-1-yl)buten-2-amide;
    (E)-N-{4-{{3-氯-4-[(3-氟苯基)甲氧基]苯基}氨基}-5-甲基吡咯并[2,1-f][1,2,4]三嗪-6基}-4-(4-甲基哌啶-1-基)丁烯-2-酰胺；(E)-N-{4-{{3-chloro-4-[(3-fluorophenyl)methoxy]phenyl}amino}-5-methylpyrrolo[2,1-f][1 , 2,4]triazin-6-yl}-4-(4-methylpiperidin-1-yl)buten-2-amide;
    (E)-N-{4-{{3-氯-4-[(3-氟苯基)甲氧基]苯基}氨基}-5-甲基吡咯并[2,1-f][1,2,4]三嗪-6基}-4-(2-甲基哌啶-1-基)丁烯-2-酰胺；(E)-N-{4-{{3-chloro-4-[(3-fluorophenyl)methoxy]phenyl}amino}-5-methylpyrrolo[2,1-f][1 , 2,4]triazin-6-yl}-4-(2-methylpiperidin-1-yl)buten-2-amide;
    (E)-N-{4-{{3-氯-4-[(3-氟苯基)甲氧基]苯基}氨基}-5-甲基吡咯并[2,1-f][1,2,4]三嗪-6基}-4-(1H-咪唑-1-基)丁烯-2-酰胺；(E)-N-{4-{{3-chloro-4-[(3-fluorophenyl)methoxy]phenyl}amino}-5-methylpyrrolo[2,1-f][1 , 2,4]triazin-6-yl}-4-(1H-imidazol-1-yl)buten-2-amide;
    (E)-N-{4-{{3-氯-4-[(3-氟苯基)甲氧基]苯基}氨基}-5-甲基吡咯并[2,1-f][1,2,4]三嗪-6基}-4-(二甲胺基)丁烯-2-酰胺；(E)-N-{4-{{3-chloro-4-[(3-fluorophenyl)methoxy]phenyl}amino}-5-methylpyrrolo[2,1-f][1 , 2,4]triazin-6-yl}-4-(dimethylamino)buten-2-amide;
    (E)-N-{4-{{3-氯-4-[(3-氟苯基)甲氧基]苯基}氨基}-5-甲基吡咯并[2,1-f][1,2,4]三嗪-6基}-4-(二乙胺基)丁烯-2-酰胺；(E)-N-{4-{{3-chloro-4-[(3-fluorophenyl)methoxy]phenyl}amino}-5-methylpyrrolo[2,1-f][1 , 2,4]triazin-6-yl}-4-(diethylamino)buten-2-amide;
    (E)-N-{4-{{3-氯-4-[(3-氟苯基)甲氧基]苯基}氨基}-5-甲基吡咯并[2,1-f][1,2,4]三嗪-6基}-4-(吡咯烷-1-基)丁烯-2-酰胺；(E)-N-{4-{{3-chloro-4-[(3-fluorophenyl)methoxy]phenyl}amino}-5-methylpyrrolo[2,1-f][1 , 2,4]triazin-6-yl}-4-(pyrrolidin-1-yl)buten-2-amide;
    (E)-N-{4-{{3-氯-4-[(3-氟苯基)甲氧基]苯基}氨基}-5-甲基吡咯并[2,1-f][1,2,4]三嗪-6基}-4-(4-甲基哌嗪-1-基)丁烯-2-酰胺；(E)-N-{4-{{3-chloro-4-[(3-fluorophenyl)methoxy]phenyl}amino}-5-methylpyrrolo[2,1-f][1 , 2,4]triazin-6-yl}-4-(4-methylpiperazin-1-yl)buten-2-amide;
    (E)-N-{4-{{3-氯-4-[(吡啶-2-基)甲氧基]苯基}氨基}-5-甲基吡咯并[2,1-f][1,2,4]三嗪-6基}-4-(4-甲基哌啶-1-基)丁烯-2-酰胺；(E)-N-{4-{{3-chloro-4-[(pyridin-2-yl)methoxy]phenyl}amino}-5-methylpyrrolo[2,1-f][1 , 2,4]triazin-6-yl}-4-(4-methylpiperidin-1-yl)buten-2-amide;
    (E)-N-{4-{{3-氯-4-[(吡啶-2-基)甲氧基]苯基}氨基}-5-甲基吡咯并[2,1-f][1,2,4]三嗪-6基}-4-(哌啶-1-基)丁烯-2-酰胺；(E)-N-{4-{{3-chloro-4-[(pyridin-2-yl)methoxy]phenyl}amino}-5-methylpyrrolo[2,1-f][1 , 2,4]triazin-6-yl}-4-(piperidin-1-yl)buten-2-amide;
    (E)-N-{4-{{3-氯-4-[(吡啶-2-基)甲氧基]苯基}氨基}-5-甲基吡咯并[2,1-f][1,2,4]三嗪-6基}-4-(吡咯烷-1-基)丁烯-2-酰胺；(E)-N-{4-{{3-chloro-4-[(pyridin-2-yl)methoxy]phenyl}amino}-5-methylpyrrolo[2,1-f][1 , 2,4]triazin-6-yl}-4-(pyrrolidin-1-yl)buten-2-amide;
    (E)-N-{4-{{3-氯-4-[(吡啶-2-基)甲氧基]苯基}氨基}-5-甲基吡咯并[2,1-f][1,2,4]三嗪-6基}-4-(1H-咪唑-1-基)丁烯-2-酰胺；(E)-N-{4-{{3-chloro-4-[(pyridin-2-yl)methoxy]phenyl}amino}-5-methylpyrrolo[2,1-f][1 , 2,4]triazin-6-yl}-4-(1H-imidazol-1-yl)buten-2-amide;
    (E)-N-{4-{{3-氯-4-[(吡啶-2-基)甲氧基]苯基}氨基}-5-甲基吡咯并[2,1-f][1,2,4]三嗪-6基}-4-(4-甲基哌嗪-1-基)丁烯-2-酰胺；(E)-N-{4-{{3-chloro-4-[(pyridin-2-yl)methoxy]phenyl}amino}-5-methylpyrrolo[2,1-f][1 , 2,4]triazin-6-yl}-4-(4-methylpiperazin-1-yl)buten-2-amide;
    (E)-N-{4-{{3-氯-4-[(吡啶-2-基)甲氧基]苯基}氨基}-5-甲基吡咯并[2,1-f][1,2,4]三嗪-6基}-4-吗啉丁烯-2-酰胺；(E)-N-{4-{{3-chloro-4-[(pyridin-2-yl)methoxy]phenyl}amino}-5-methylpyrrolo[2,1-f][1 , 2,4]triazin-6-yl}-4-morpholinate-2-amide;
    (E)-N-{4-{{3-氯-4-[(吡啶-2-基)甲氧基]苯基}氨基}-5-甲基吡咯并[2,1-f][1,2,4]三嗪-6基}-4-(二乙胺基)丁烯-2-酰胺；(E)-N-{4-{{3-chloro-4-[(pyridin-2-yl)methoxy]phenyl}amino}-5-methylpyrrolo[2,1-f][1 , 2,4]triazin-6-yl}-4-(diethylamino)buten-2-amide;
    (E)-N-{4-{{3-氯-4-[(吡啶-2-基)甲氧基]苯基}氨基}-5-甲基吡咯并[2,1-f][1,2,4]三嗪-6基}-4-(二甲胺基)丁烯-2-酰胺；(E)-N-{4-{{3-chloro-4-[(pyridin-2-yl)methoxy]phenyl}amino}-5-methylpyrrolo[2,1-f][1 , 2,4]triazin-6-yl}-4-(dimethylamino)buten-2-amide;
    (E)-N-{4-[(3-氯-4-氟苯基)氨基]-5-甲基吡咯并[2,1-f][1,2,4]三嗪-6-基}-4-(哌 啶-1-基)丁烯-2-酰胺；(E)-N-{4-[(3-chloro-4-fluorophenyl)amino]-5-methylpyrrolo[2,1-f][1,2,4]triazin-6-yl }-4-(piper Pyridin-1-yl)buten-2-amide;
    (E)-N-{4-[(3-氯-4-氟苯基)氨基]-5-甲基吡咯并[2,1-f][1,2,4]三嗪-6-基}-4-(4-甲基哌啶-1-基)丁烯-2-酰胺；(E)-N-{4-[(3-chloro-4-fluorophenyl)amino]-5-methylpyrrolo[2,1-f][1,2,4]triazin-6-yl }-4-(4-Methylpiperidin-1-yl)butene-2-amide;
    (E)-N-{4-[(3-氯-4-氟苯基)氨基]-5-甲基吡咯并[2,1-f][1,2,4]三嗪-6-基}-4-(2-甲基哌啶-1-基)丁烯-2-酰胺；(E)-N-{4-[(3-chloro-4-fluorophenyl)amino]-5-methylpyrrolo[2,1-f][1,2,4]triazin-6-yl }-4-(2-methylpiperidin-1-yl)butene-2-amide;
    (E)-N-{4-[(3-氯-4-氟苯基)氨基]-5-甲基吡咯并[2,1-f][1,2,4]三嗪-6-基}-4-(二乙胺基)丁烯-2-酰胺；(E)-N-{4-[(3-chloro-4-fluorophenyl)amino]-5-methylpyrrolo[2,1-f][1,2,4]triazin-6-yl }-4-(diethylamino)butene-2-amide;
    (E)-N-{4-[(3-氯-4-氟苯基)氨基]-5-甲基吡咯并[2,1-f][1,2,4]三嗪-6-基}-4-(吗啉-1-基)丁烯-2-酰胺；(E)-N-{4-[(3-chloro-4-fluorophenyl)amino]-5-methylpyrrolo[2,1-f][1,2,4]triazin-6-yl }-4-(morpholin-1-yl)buten-2-amide;
    (E)-N-{4-[(3-氯-4-氟苯基)氨基]-5-甲基吡咯并[2,1-f][1,2,4]三嗪-6-基}-4-(吡咯烷-1-基)丁烯-2-酰胺；(E)-N-{4-[(3-chloro-4-fluorophenyl)amino]-5-methylpyrrolo[2,1-f][1,2,4]triazin-6-yl }-4-(pyrrolidin-1-yl)butene-2-amide;
    (E)-N-{4-[(3-氯-4-氟苯基)氨基]-5-甲基吡咯并[2,1-f][1,2,4]三嗪-6-基}-4-(1H-咪唑-1-基)丁烯-2-酰胺；(E)-N-{4-[(3-chloro-4-fluorophenyl)amino]-5-methylpyrrolo[2,1-f][1,2,4]triazin-6-yl }-4-(1H-imidazol-1-yl)buten-2-amide;
    (E)-N-{4-[(3-氯-4-氟苯基)氨基]-5-甲基吡咯并[2,1-f][1,2,4]三嗪-6-基}-4-(二甲胺基)丁烯-2-酰胺；(E)-N-{4-[(3-chloro-4-fluorophenyl)amino]-5-methylpyrrolo[2,1-f][1,2,4]triazin-6-yl }-4-(dimethylamino)butene-2-amide;
    (E)-N-{4-[(3-氯-4-氟苯基)氨基]-5-甲基吡咯并[2,1-f][1,2,4]三嗪-6-基}-4-(N-甲基哌嗪-1-基)丁烯-2-酰胺；(E)-N-{4-[(3-chloro-4-fluorophenyl)amino]-5-methylpyrrolo[2,1-f][1,2,4]triazin-6-yl }-4-(N-methylpiperazin-1-yl)butene-2-amide;
    (E)-N-{4-[(3-乙炔基苯基)氨基]-5-甲基吡咯并[2,1-f][1,2,4]三嗪-6-基}-4-(4-甲基哌啶-1-基)丁烯-2-酰胺；(E)-N-{4-[(3-ethynylphenyl)amino]-5-methylpyrrolo[2,1-f][1,2,4]triazin-6-yl}-4 -(4-methylpiperidin-1-yl)buten-2-amide;
    (E)-N-{4-[(3-乙炔基苯基)氨基]-5-甲基吡咯并[2,1-f][1,2,4]三嗪-6-基}-4-(N-甲基哌嗪-1-基)丁烯-2-酰胺；(E)-N-{4-[(3-ethynylphenyl)amino]-5-methylpyrrolo[2,1-f][1,2,4]triazin-6-yl}-4 -(N-methylpiperazin-1-yl)buten-2-amide;
    (E)-N-{4-[(3-乙炔基苯基)氨基]-5-甲基吡咯并[2,1-f][1,2,4]三嗪-6-基}-4-(二甲胺基)丁烯-2-酰胺；(E)-N-{4-[(3-ethynylphenyl)amino]-5-methylpyrrolo[2,1-f][1,2,4]triazin-6-yl}-4 -(dimethylamino)butene-2-amide;
    (E)-N-{4-[(3-乙炔基苯基)氨基]-5-甲基吡咯并[2,1-f][1,2,4]三嗪-6-基}-4-(1H-咪唑-1-基)丁烯-2-酰胺；(E)-N-{4-[(3-ethynylphenyl)amino]-5-methylpyrrolo[2,1-f][1,2,4]triazin-6-yl}-4 -(1H-imidazol-1-yl)buten-2-amide;
    (E)-N-{4-[(3-乙炔基苯基)氨基]-5-甲基吡咯并[2,1-f][1,2,4]三嗪-6-基}-4-(2-甲基哌啶-1-基)丁烯-2-酰胺；(E)-N-{4-[(3-ethynylphenyl)amino]-5-methylpyrrolo[2,1-f][1,2,4]triazin-6-yl}-4 -(2-methylpiperidin-1-yl)butene-2-amide;
    (E)-N-{4-[(3-乙炔基苯基)氨基]-5-甲基吡咯并[2,1-f][1,2,4]三嗪-6-基}-4-(二乙胺基)丁烯-2-酰胺；(E)-N-{4-[(3-ethynylphenyl)amino]-5-methylpyrrolo[2,1-f][1,2,4]triazin-6-yl}-4 -(diethylamino)butene-2-amide;
    (E)-N-{4-[(3-乙炔基苯基)氨基]-5-甲基吡咯并[2,1-f][1,2,4]三嗪-6-基}-4-(吗啉-1-基)丁烯-2-酰胺；(E)-N-{4-[(3-ethynylphenyl)amino]-5-methylpyrrolo[2,1-f][1,2,4]triazin-6-yl}-4 -(morpholin-1-yl)buten-2-amide;
    (E)-N-{4-[(3-乙炔基苯基)氨基]-5-甲基吡咯并[2,1-f][1,2,4]三嗪-6-基}-4-(吡咯烷-1-基)丁烯-2-酰胺；(E)-N-{4-[(3-ethynylphenyl)amino]-5-methylpyrrolo[2,1-f][1,2,4]triazin-6-yl}-4 -(pyrrolidin-1-yl)buten-2-amide;
    (E)-N-{4-[(3-乙炔基苯基)氨基]-5-甲基吡咯并[2,1-f][1,2,4]三嗪-6-基}-4-(哌啶-1-基)丁烯-2-酰胺； (E)-N-{4-[(3-ethynylphenyl)amino]-5-methylpyrrolo[2,1-f][1,2,4]triazin-6-yl}-4 -(piperidin-1-yl)butene-2-amide;
    及其互变异构体、立体异构体和盐。And tautomers, stereoisomers and salts thereof.
  5. 根据权利要求1-4中任一项所述的化合物或其药学上可接受的盐，其中所述盐为所述化合物与无机或有机酸或碱所成的药学上可接受的盐。The compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein the salt is a pharmaceutically acceptable salt of the compound with an inorganic or organic acid or base.
  6. 一种制备式Ia化合物的方法，包括步骤：A method of preparing a compound of formula Ia, comprising the steps of:
    式II化合物与卤代巴豆酰氯进行酰化，得到式Ia化合物，Acylation of a compound of formula II with a halocrotonyl chloride to provide a compound of formula Ia,
    Figure PCTCN2014091238-appb-100003
    Figure PCTCN2014091238-appb-100003
    其中，Z为卤素，Y的定义如权利要求1所述，并且Wherein Z is a halogen, and Y is as defined in claim 1, and
    如有需要，再裂解去除上述反应中所用的任何保护基，及/或If necessary, re-cracking to remove any protecting groups used in the above reaction, and / or
    如有需要，将制得的通式Ia化合物解析成为其立体异构体，及/或If desired, the resulting compound of formula Ia is resolved into its stereoisomers, and/or
    如有需要，将制得的通式Ia化合物转化成为其盐，特别是转化成药学上可接受的盐。The resulting compound of formula Ia is converted, if desired, to its salt, especially to a pharmaceutically acceptable salt.
  7. 一种制备式I化合物的方法，包括步骤：A method of preparing a compound of formula I, comprising the steps of:
    式Ia化合物与取代胺进行亲核取代反应，得到式I化合物，A nucleophilic substitution reaction of a compound of formula Ia with a substituted amine to provide a compound of formula I,
    Figure PCTCN2014091238-appb-100004
    Figure PCTCN2014091238-appb-100004
    其中，Z为卤素，Y和R2的定义如权利要求1所述，R2不为卤素，并且Wherein Z is a halogen, and Y and R 2 are as defined in claim 1, R 2 is not halogen, and
    如有需要，再裂解去除上述反应中所用的任何保护基，及/或If necessary, re-cracking to remove any protecting groups used in the above reaction, and / or
    如有需要，将制得的通式I化合物解析成为其立体异构体，及/或If desired, the resulting compound of formula I is resolved into its stereoisomers, and/or
    如有需要，将制得的通式I化合物转化成为其盐，特别是转化成药学上可接受的盐。The resulting compound of formula I is converted, if desired, to its salt, especially to a pharmaceutically acceptable salt.
  8. 一种药物组合物，包括权利要求1-5任一项所述的化合物或其药学上可接受的盐，以及药学上可接受的稀释剂或载体。A pharmaceutical composition comprising a compound of any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable diluent or carrier.
  9. 权利要求1-5任一项所述的化合物或其药学上可接受的盐在制备预防或治疗与蛋白激酶有关的疾病的药物中的用途。Use of a compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for preventing or treating a protein kinase-associated disease.
  10. 根据权利要求9所述的用途，其中所述蛋白激酶选自EGFR受体酪氨酸激酶或HER-2受体酪氨酸激酶。 The use according to claim 9, wherein the protein kinase is selected from the group consisting of an EGFR receptor tyrosine kinase or a HER-2 receptor tyrosine kinase.
PCT/CN2014/091238 2013-12-06 2014-11-17 Pyrrolo[2,1-f][1,2,4]triazine derivative, and preparation method and use thereof WO2015081783A1 (en)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
CN201310656253.XA CN104693204A (en) 2013-12-06 2013-12-06 Pyrrolo[2,1-f][1,2,4]triazine derivatives, preparing methods thereof and uses of the derivatives
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CN201310655586.0 2013-12-06
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Citations (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1351498A (en) * 1999-05-21 2002-05-29 布里斯托尔-迈尔斯斯奎布公司 Pyrrolotriazines inhibitors of kinases
CN1615306A (en) * 2001-11-14 2005-05-11 布里斯托尔-迈尔斯斯奎布公司 C-5 modified indazolylpyrrolotriazines
CN1622946A (en) * 2000-11-17 2005-06-01 布里斯托尔-迈尔斯斯奎布公司 Methods of treating p38 kinase-associated conditions and pyrrolotriazine compounds useful as kinase inhibitors
CN1665817A (en) * 2002-07-19 2005-09-07 百时美施贵宝公司 Process for preparing certain pyrrolotriazine compounds
CN101084218A (en) * 2004-07-20 2007-12-05 Osi制药公司 Imidazotriazines as protein kinase inhibitors
CN101511835A (en) * 2006-07-07 2009-08-19 布里斯托尔-迈尔斯斯奎布公司 Pyrrolotriazine kinase inhibitors
CN101723948A (en) * 2002-12-13 2010-06-09 布里斯托尔-迈尔斯斯奎布公司 C-6 modified indazolylpyrrolotriazines
CN102015713A (en) * 2008-05-09 2011-04-13 雅培制药有限公司 Inhibitors of protein kinases
CN102015719A (en) * 2008-03-06 2011-04-13 百时美施贵宝公司 Pyrrolotriazine kinase inhibitors
CN102918045A (en) * 2010-03-31 2013-02-06 百时美施贵宝公司 Substituted pyrrolotriazines as protein kinase inhibitors

Patent Citations (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1351498A (en) * 1999-05-21 2002-05-29 布里斯托尔-迈尔斯斯奎布公司 Pyrrolotriazines inhibitors of kinases
CN1622946A (en) * 2000-11-17 2005-06-01 布里斯托尔-迈尔斯斯奎布公司 Methods of treating p38 kinase-associated conditions and pyrrolotriazine compounds useful as kinase inhibitors
CN1615306A (en) * 2001-11-14 2005-05-11 布里斯托尔-迈尔斯斯奎布公司 C-5 modified indazolylpyrrolotriazines
CN1665817A (en) * 2002-07-19 2005-09-07 百时美施贵宝公司 Process for preparing certain pyrrolotriazine compounds
CN101723948A (en) * 2002-12-13 2010-06-09 布里斯托尔-迈尔斯斯奎布公司 C-6 modified indazolylpyrrolotriazines
CN101084218A (en) * 2004-07-20 2007-12-05 Osi制药公司 Imidazotriazines as protein kinase inhibitors
CN101511835A (en) * 2006-07-07 2009-08-19 布里斯托尔-迈尔斯斯奎布公司 Pyrrolotriazine kinase inhibitors
CN102015719A (en) * 2008-03-06 2011-04-13 百时美施贵宝公司 Pyrrolotriazine kinase inhibitors
CN102015713A (en) * 2008-05-09 2011-04-13 雅培制药有限公司 Inhibitors of protein kinases
CN102918045A (en) * 2010-03-31 2013-02-06 百时美施贵宝公司 Substituted pyrrolotriazines as protein kinase inhibitors

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