CN111018860B - Pyrrolotriazines and application thereof - Google Patents

Pyrrolotriazines and application thereof Download PDF

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CN111018860B
CN111018860B CN201811212157.5A CN201811212157A CN111018860B CN 111018860 B CN111018860 B CN 111018860B CN 201811212157 A CN201811212157 A CN 201811212157A CN 111018860 B CN111018860 B CN 111018860B
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amino
methyl
triazin
pyrrolo
benzamide
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CN111018860A (en
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陆涛
陈亚东
朱雍
李红玫
耿爱新
崔昊
钮家琪
戴炜辰
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China Pharmaceutical University
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    • 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
    • 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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia

Abstract

The invention belongs to the field of medicinal chemistry, and particularly relates to a lactam histone deacetylase inhibitor, a preparation method thereof, a pharmaceutical composition containing the histone deacetylase inhibitor, and application of the inhibitor in medicines for preventing and/or treating diseases related to the loss of control of histone deacetylase activity.

Description

Pyrrolotriazines and application thereof
Technical Field
The invention belongs to the field of medicinal chemistry, and particularly relates to a histone deacetylase inhibitor with a pyrrolo [2, 1-f ] [1, 2, 4] triazine structure, a preparation method, a pharmaceutical composition containing the histone deacetylase inhibitor, and application of the inhibitor in medicines for preventing and/or treating diseases related to the loss of histone deacetylase activity.
Background
The ordered transcription regulation of genes is a prerequisite for maintaining normal functions of body cells, and if the gene transcription regulation function is disordered, the cells can become cancerous. Acetylation and deacetylation of core histones are closely related to gene regulation, while responsible for histone acetylation and deacetylation are a pair of functionally antagonistic proteases-Histone Acetyltransferases (HATs) and Histone Deacetylases (HDACs). HDACs are a group of enzymes that regulate a series of biological effects including chromatin reorganization, transcriptional activation or inhibition, cell cycle, cell differentiation and apoptosis at the cellular chromatin level by inducing histone deacetylation, and are particularly involved in the regulation of gene transcriptional expression after cell activation. Histone deacetylase inhibitors induce apoptosis, differentiation and inhibition of proliferation by inhibiting the activity of HDACs, and are considered as anticancer drug targets with promising prospects for development. The current research on HDACs inhibitors involves numerous tumor areas, such as the blood system, melanoma, breast, ovarian, prostate, lung and colon cancers. It is thought that inhibition of HDACs subtypes 1-5 and 7, 9, etc. may contribute to tumor therapy, and inhibition of HDACs 6, 8 may be associated with toxicity of these compounds.
The HDACs targets are anti-tumor targets with application prospects, the existing HDACs inhibitors still cannot completely meet clinical requirements, and novel-structure selective HDACs inhibitors are to be found for preventing and/or treating diseases related to the out-of-control of histone deacetylase activity, particularly tumor diseases.
Disclosure of Invention
The object of the present invention is to provide a novel and potent class of HDACs inhibitors and pharmaceutically acceptable salts thereof.
The technical scheme of the invention is as follows:
a compound of the general formula (I) or a pharmaceutically acceptable salt thereof:
Figure BSA0000172130500000011
wherein R is1Is hydroxy, or is optionally substituted by one or more R5Substituted 2-aminophenyl radicals, R5Selected from hydrogen, (C)1-C6) Alkyl, cyano, halogen, halo (C)1-C6) Alkyl, hydroxy, mercapto, amino, (C)1-C6) Alkoxy group, (C)1-C6) Alkylthio group, (C)1-C6) Amino, phenyl, 5 or 6 membered heteroaryl;
R2is-L-R3Wherein L is a bond, O, S, NR4；R3Is aryl, heteroaryl, saturated or partially saturated heterocyclyl, each aryl, heteroaryl, saturated or partially saturated heterocyclyl being optionally substituted with one or more R6Substituted, R6Selected from hydrogen, (C)1-C6) Alkyl, cyano, halogen, halo (C)1-C6) Alkyl, hydroxy, mercapto, amino, (C)1-C6) Alkoxy group, (C) 1-C6) Alkylthio, (C)1-C6) Alkylamino, tert-butoxycarbonyl;
wherein R is4Selected from hydrogen, (C)1-C6) An alkyl group;
x is NH, NR7、O、S(O)n，R7Is selected from (C)1-C6) The value range of n is 0-2;
q is aryl or heteroaryl, wherein aryl or heteroaryl are each independently optionally substituted with one or more R8Substituted, R8Selected from hydrogen, (C)1-C6) Alkyl, cyano, halogen, halo (C)1-C6) Alkyl, hydroxy, mercapto, (C)1-C6) An alkoxy group;
wherein the aryl group is a 6-10 membered aryl group; the heteroaryl is a five or six membered heteroaryl, wherein 1 to 4 ring atoms are heteroatoms selected from oxygen, nitrogen, sulphur and the remaining ring atoms are carbon; said heterocyclyl contains 5 to 10 ring atoms, of which 1 to 4 are heteroatoms selected from oxygen, nitrogen, sulphur and the remaining ring atoms are carbon.
The preferred scheme of the invention is as follows:
R1is hydroxy or is selected from the group consisting of5Substituted 2-aminophenyl radicals, R5Selected from hydrogen, (C)1-C6) Alkyl, cyano, halogen, phenyl, thienyl;
R2is-L-R3Wherein L is a bond, O, S, NR4；R3Is aryl, heteroaryl, saturated or partially saturated heterocyclyl, each aryl, heteroaryl, saturated or partially saturated heterocyclyl being optionally substituted by one or morePlural R6Substituted, R6Selected from hydrogen, (C)1-C6) Alkyl, cyano, halogen, trifluoromethyl, hydroxy, mercapto, amino, methoxy, methylamino, tert-butoxycarbonyl;
Wherein R is4Selected from H, (C)1-C6) An alkyl group;
x is NH, NR7、O、S(O)n，R7The compound is selected from methyl, ethyl and propyl, and the value range of n is 0-2;
q is phenyl, pyridyl;
wherein said aryl is phenyl; heterocyclyl is piperidinyl, morpholinyl, piperazinyl; the heteroaryl is pyrrolyl, pyrazolyl, imidazolyl, furyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyrimidinyl, pyrazinyl or pyridazinyl.
Another preferred embodiment of the present invention is:
R1is hydroxy or is selected from the group consisting of5Substituted 2-aminophenyl radicals, R5Selected from hydrogen, halogen;
R2is-L-R3Wherein L is a bond, -NH; r3Is an aromatic, heterocyclic or substituted aromatic, substituted heterocyclic ring of: phenyl, pyrrolyl, furyl, thienyl, pyrazolyl, imidazolyl, pyridyl, pyrazinyl, pyrimidinyl, morpholinyl, piperazinyl, piperidinyl, 1, 4-oxazin-4-yl, the substituents being selected from methyl, ethyl, tert-butyl, 1-2 halogens, trifluoromethyl, methoxy, tert-butoxycarbonyl;
x is NH, O, S (O) n, and the value range of n is 0-2;
q is phenyl, pyridyl;
according to the invention, pharmaceutically acceptable salts include the acid addition salts of the compounds of formula I with the following acids: hydrochloric, hydrobromic, sulphuric, phosphoric, methanesulphonic, benzenesulphonic, p-toluenesulphonic, naphthalenesulphonic, citric, tartaric, lactic, pyruvic, acetic, maleic or succinic, fumaric, salicylic, phenylacetic, mandelic acid. Also included are acid salts of inorganic bases such as: contains alkali metal cation, alkaline earth metal cation, and ammonium cation salt.
The compounds of formula I are preferably compounds of the following structure:
n- (2-aminophenyl) -4- [ [ [4- [ (5-methyl-1H-pyrazol-3-yl) amino ] pyrrolo [2, 1-f ] [1, 2, 4] triazin-2-yl ] thio ] methyl ] benzamide (I-1)
N- (2-amino-4-fluorophenyl) -4- [ [ [4- [ (5-methyl-1H-pyrazol-3-yl) amino ] pyrrolo [2, 1-f ] [1, 2, 4] triazin-2-yl ] thio ] methyl ] benzamide (I-2)
N- (2-aminophenyl) -4- [ [ [4- [ (1H-pyrazol-3-yl) amino ] pyrrolo [2, 1-f ] [1, 2, 4] triazin-2-yl ] thio ] methyl ] benzamide (I-3)
N- (2-amino-4-fluorophenyl) -4- [ [ [4- [ (1H-pyrazol-3-yl) amino ] pyrrolo [2, 1-f ] [1, 2, 4] triazin-2-yl ] thio ] methyl ] benzamide (I-4)
N- (2-aminophenyl) -4- [ [ [4- [ (5-tert-butyl-1H-pyrazol-3-yl) amino ] pyrrolo [2, 1-f ] [1, 2, 4] triazin-2-yl ] thio ] methyl ] benzamide (I-5)
N- (2-amino-4-fluorophenyl) -4- [ [ [4- [ (5-tert-butyl-1H-pyrazol-3-yl) amino ] pyrrolo [2, 1-f ] [1, 2, 4] triazin-2-yl ] thio ] methyl ] benzamide (I-6)
N- (2-aminophenyl) -4- [ [ [ 4-morpholinylpyrrolo [2, 1-f ] [1, 2, 4] triazin-2-yl ] thio ] methyl ] benzamide (I-7)
N- (2-amino-4-fluorophenyl) -4- [ [ [ 4-morpholinylpyrrolo [2, 1-f ] [1, 2, 4] triazin-2-yl ] thio ] methyl ] benzamide (I-8)
N- (2-aminophenyl) -4- [ [ [4- [ (4-fluorobenzyl) amino ] pyrrolo [2, 1-f ] [1, 2, 4] triazin-2-yl ] thio ] methyl ] benzamide (I-9)
N- (2-amino-4-fluorophenyl) -4- [ [ [4- [ (4-fluorobenzyl) amino ] pyrrolo [2, 1-f ] [1, 2, 4] triazin-2-yl ] thio ] methyl ] benzamide (I-10)
N- (2-aminophenyl) -4- [ [ [4- [ (4-trifluoromethylbenzyl) amino ] pyrrolo [2, 1-f ] [1, 2, 4] triazin-2-yl ] thio ] methyl ] benzamide (I-11)
N- (2-amino-4-fluorophenyl) -4- [ [ [4- [ (4-trifluoromethylbenzyl) amino ] pyrrolo [2, 1-f ] [1, 2, 4] triazin-2-yl ] thio ] methyl ] benzamide (I-12)
N- (2-aminophenyl) -4- [ [ [4- [ (4-methoxybenzyl) amino ] pyrrolo [2, 1-f ] [1, 2, 4] triazin-2-yl ] thio ] methyl ] benzamide (I-13)
N- (2-amino-4-fluorophenyl) -4- [ [ [4- [ (4-methoxybenzyl) amino ] pyrrolo [2, 1-f ] [1, 2, 4] triazin-2-yl ] thio ] methyl ] benzamide (I-14)
N- (2-aminophenyl) -4- [ [ [4- [ (3, 4-dimethoxybenzyl) amino ] pyrrolo [2, 1-f ] [1, 2, 4] triazin-2-yl ] thio ] methyl ] benzamide (I-15)
N- (2-amino-4-fluorophenyl) -4- [ [ [4- [ (3, 4-dimethoxybenzyl) amino ] pyrrolo [2, 1-f ] [1, 2, 4] triazin-2-yl ] thio ] methyl ] benzamide (I-16)
N- (2-aminophenyl) -4- [ [ [4- [ (2, 4-dimethoxybenzyl) amino ] pyrrolo [2, 1-f ] [1, 2, 4] triazin-2-yl ] thio ] methyl ] benzamide (I-17)
N- (2-amino-4-fluorophenyl) -4- [ [ [4- [ (2, 4-dimethoxybenzyl) amino ] pyrrolo [2, 1-f ] [1, 2, 4] triazin-2-yl ] thio ] methyl ] benzamide (I-18)
N- (2-aminophenyl) -4- [ [ [4- [ (3-methylpyridin-2-yl) amino ] pyrrolo [2, 1-f ] [1, 2, 4] triazin-2-yl ] thio ] methyl ] benzamide (I-19)
N- (2-amino-4-fluorophenyl) -4- [ [ [4- [ (3-methylpyridin-2-yl) amino ] pyrrolo [2, 1-f ] [1, 2, 4] triazin-2-yl ] thio ] methyl ] benzamide (I-20)
N- (2-aminophenyl) -4- [ [ [4- [ (N-Boc-piperidin-4-yl) amino ] pyrrolo [2, 1-f ] [1, 2, 4] triazin-2-yl ] thio ] methyl ] benzamide (I-21)
N- (2-amino-4-fluorophenyl) -4- [ [ [4- [ (N-Boc piperidin-4-yl) amino ] pyrrolo [2, 1-f ] [1, 2, 4] triazin-2-yl ] thio ] methyl ] benzamide (I-22)
N- (2-aminophenyl) -4- [ [ [4- [ (piperidin-4-yl) amino ] pyrrolo [2, 1-f ] [1, 2, 4] triazin-2-yl ] thio ] methyl ] benzamide (I-23)
N- (2-amino-4-fluorophenyl) -4- [ [ [4- [ (piperidin-4-yl) amino ] pyrrolo [2, 1-f ] [1, 2, 4] triazin-2-yl ] thio ] methyl ] benzamide (I-24)
N-hydroxy-4- [ [ [4- [ (5-methyl-1H-pyrazol-3-yl) amino ] pyrrolo [2, 1-f ] [1, 2, 4] triazin-2-yl ] thio ] methyl ] benzamide (I-25)
N- (2-amino-4-chlorophenyl) -4- [ [ [4- [ (5-methyl-1H-pyrazol-3-yl) amino ] pyrrolo [2, 1-f ] [1, 2, 4] triazin-2-yl ] thio ] methyl ] benzamide (I-26)
N- (2-amino-4-methylphenyl) -4- [ [ [4- [ (5-methyl-1H-pyrazol-3-yl) amino ] pyrrolo [2, 1-f ] [1, 2, 4] triazin-2-yl ] thio ] methyl ] benzamide (I-27)
N- (2-amino-5-cyanophenyl) -4- [ [ [4- [ (5-methyl-1H-pyrazol-3-yl) amino ] pyrrolo [2, 1-f ] [1, 2, 4] triazin-2-yl ] thio ] methyl ] benzamide (I-28)
N- (2-amino-5-phenylphenyl) -4- [ [ [4- [ (5-methyl-1H-pyrazol-3-yl) amino ] pyrrolo [2, 1-f ] [1, 2, 4] triazin-2-yl ] thio ] methyl ] benzamide (I-29)
N- (2-amino-5- (2-thienyl) phenyl) -4- [ [ [4- [ (5-methyl-1H-pyrazol-3-yl) amino ] pyrrolo [2, 1-f ] [1, 2, 4] triazin-2-yl ] thio ] methyl ] benzamide (I-30)
N- (2-aminophenyl) -4- [ [ [4- [ (5-methyl-1H-pyrazol-3-yl) amino ] pyrrolo [2, 1-f ] [1, 2, 4] triazin-2-yl ] oxy ] methyl ] benzamide (I-31)
N- (2-aminophenyl) -4- [ [ [4- [ (5-methyl-1H-pyrazol-3-yl) amino ] pyrrolo [2, 1-f ] [1, 2, 4] triazin-2-yl ] amino ] methyl ] benzamide (I-32)
N- (2-aminophenyl) -4- [ [ [4- [ (5-methyl-1H-pyrazol-3-yl) amino ] pyrrolo [2, 1-f ] [1, 2, 4] triazin-2-yl ] sulfoxy ] methyl ] benzamide (I-33)
N- (2-aminophenyl) -4- [ [ [4- [ (5-methyl-1H-pyrazol-3-yl) amino ] pyrrolo [2, 1-f ] [1, 2, 4] triazin-2-yl ] sulfonyl ] methyl ] benzamide (I-34)
N- (2-aminophenyl) -4- [ [ ethyl [4- [ (5-methyl-1H-pyrazol-3-yl) amino ] pyrrolo [2, 1-f ] [1, 2, 4] triazin-2-yl ] amino ] methyl ] benzamide (I-35)
N- (2-aminophenyl) -4- [ [ [4- [ (4-methoxyphenyl) amino ] pyrrolo [2, 1-f ] [1, 2, 4] triazin-2-yl ] amino ] methyl ] benzamide (I-36)
N- (2-aminophenyl) -4- [ [ [4H- (1, 4-oxazin-4-yl) pyrrolo [2, 1-f ] [1, 2, 4] triazin-2-yl ] amino ] methyl ] benzamide (I-37)
N- (2-aminophenyl) -4- [ [ [ 4-piperidinylpyrrolo [2, 1-f ] [1, 2, 4] triazin-2-yl ] amino ] methyl ] benzamide (I-38)
N- (2-aminophenyl) -5- [ [ [4- (2-furan) aminopyrrolo [2, 1-f ] [1, 2, 4] triazin-2-yl ] amino ] methyl ] pyridinecarboxamide (I-39)
N- (2-aminophenyl) -4- [ [ [4- (3-pyridyl) pyrrolo [2, 1-f ] [1, 2, 4] triazin-2-yl ] amino ] methyl ] benzamide (I-40)
N- (2-aminophenyl) -4- [ [ [4- (4-methoxyphenyl) pyrrolo [2, 1-f ] [1, 2, 4] triazin-2-yl ] amino ] methyl ] benzamide (I-41)
The compounds of the invention are prepared as follows:
the method comprises the following steps:
Figure BSA0000172130500000051
Figure BSA0000172130500000061
the second method comprises the following steps:
Figure BSA0000172130500000062
the third method comprises the following steps:
Figure BSA0000172130500000063
the method four comprises the following steps:
Figure BSA0000172130500000064
the compound of the invention can be prepared by the preparation method or similar preparation methods, and corresponding raw materials are selected according to different substituents and different positions of the substituents.
Pharmacological test results show that the compound shown in the general formula I and the pharmaceutically acceptable salt thereof have excellent inhibitory activity on HDAC1, so that the compound shown in the general formula I and the pharmaceutically acceptable salt thereof can be used for treating clinical symptoms related to the targets. The disease associated with HDAC1 may be, but is not limited to: lung cancer, melanoma, liver cancer, kidney cancer, leukemia, non-small cell lung cancer, prostate cancer, thyroid cancer, skin cancer, pancreatic cancer, rectal cancer, colon cancer, ovarian cancer, testicular cancer, breast cancer, bladder cancer, gall bladder cancer, myelodysplastic syndrome, lymphoma, esophageal cancer, thyroid follicular cancer, gastrointestinal cancer, tumors of the central or peripheral nervous system (e.g., astrocytomas, neuroblastomas, gliomas, or schwannomas), mesothelioma, type II or non-insulin dependent diabetes mellitus, autoimmune diseases.
The following are some of the pharmacological tests and results:
(1) HDAC1 inhibition activity determination of target compound and result
The synthesized compound is tested for inhibiting activity on HDAC1 by Fluorescence Resonance Energy Transfer (FRET) method, and compared with a positive control drug, the compound with better activity is screened out. HDAC1 was obtained by purification or direct purchase of kits.
The specific method comprises the following steps: the enzyme was added to the reaction wells and the reaction buffer was added to the control wells. Samples dissolved in DMSO were added to the reaction wells and incubated using a non-contact nanoliter sonication system. Adding corresponding fluorescent substrate into each reaction hole, and rotating and shaking. And (3) performing sealed incubation for 1-2h at 30 ℃. The reaction was stopped by the addition of a color developer containing TMP26, which produced fluorescence. Fluorescence intensity (excitation: 490nM, emission: 520nM) was measured using an EnVision MultiMark microplate detector (Perkin Elmer). Reading the endpoint value after the color development is stable. Calculations of percentage (relative to DMSO control) and half inhibition were performed using GraphPad Prism 4 software.
Results of partial Compounds on HDAC1 inhibitory Activity
Figure BSA0000172130500000071
Figure BSA0000172130500000081
(2) In vitro anti-tumor Activity assay for Compounds of interest
The CTG method is adopted in the experiment to determine the inhibition effect of the compound on leukemia cell strains HL60 and K562, colon cancer cell strain HCT116, lymphoma cell strain HuT78 and other tumor cell strains.
The experimental method comprises the following steps: cells in exponential growth phase were collected for viable cell count. The cell suspension concentration was adjusted with the corresponding medium for each cell. Add 90. mu.L of cell suspension to each well in 96-well cell culture plates. Each test compound was dissolved in DMSO to give a 10mM or 5mM stock solution. Then diluted to 10-fold solution with medium, 2 wells each. 10 mu L of corresponding 10-fold solution is added into each cell, the final concentration of the prepared drug is 5 mu M or 20 mu M, and the final concentration of DMSO is 0.1-0.5% respectively (see compound preparation method and sample adding design: experimental orifice plate sample adding design). Standing at 37 deg.C and 5% CO2Culturing in an incubator for 72 h. After 72h of drug treatment, 50. mu.L (1/2 culture volume) of CTG solution which is pre-melted and equilibrated to room temperature is added to each well, mixed evenly for 2min by a microplate shaker, placed for 10min at room temperature, and then the fluorescence signal value is measured by an Envision2104 plate reader. The cell inhibition rate is expressed by the formula: (1-V)sample/Vvehicle controlX 100%) calculated. Wherein VsampleAverage value of drug treatment group, Vvehicle controlMean values for the solvent control group.
Inhibition ratio of compound to four tumor cell lines at 5. mu.M%
Figure BSA0000172130500000082
Figure BSA0000172130500000091
Detailed Description
Example 1
N- (2-aminophenyl) -4- [ [ [4- [ (5-methyl-1H-pyrazol-3-yl) amino ] pyrrolo [2, 1-f ] [1, 2, 4] triazin-2-yl ] thio ] methyl ] benzamide (I-1)
Figure BSA0000172130500000092
Step a: preparation of 1-amino-1H-pyrrole-2-carboxylic acid methyl ester (1)
Preparation of an ether monochloramine solution: slowly adding ammonium chloride (8.00g, 0.150mol) into ether (100mL) at the temperature of-25 ℃, adding ammonia water (15mL), slowly dropwise adding a sodium hypochlorite solution (100mL) within 15min at the temperature of-10 ℃, continuously stirring for 15min after the addition is finished, stopping the reaction, standing for 3min, quickly separating an organic layer, and drying for 1h by using anhydrous magnesium sulfate at the temperature of-25 ℃, thus obtaining the ether solution of monochloramine.
Dissolving 1H-pyrrole-2-methyl formate (1.00g, 7.99mmol) in anhydrous tetrahydrofuran (15mL), reacting for 15min under the protection of nitrogen, adding anhydrous tetrahydrofuran suspension (45mL) dissolved with sodium hydrogen (1.20g, 50.00mmol), reacting for 45min at room temperature, then dropwise adding the ether solution of the newly prepared monochloramine under the protection of nitrogen and ice bath conditions. TLC after 2h showed the reaction was complete. Anhydrous ethanol (1mL) was added to quench excess sodium hydrogen, filtered, the solvent was evaporated under reduced pressure, and separated by silica gel column chromatography (petroleum ether: ethyl acetate: 40: 1) to give 0.91g of pale yellow solid, yield: 81.25 percent. The operation was repeated several times to obtain 11.32g of a pale yellow solid. mp: 40-42 ℃;1H-NMR(300MHz，DMSO-d6)δ(ppm)：7.03-7.01(m，1H)，6.71(dd，J＝4.2Hz，2.0Hz，1H)，6.26(s，2H)，5.98(dd，J＝4.2Hz，2.6Hz，1H)，3.74(s，3H).
step b: preparation of 1- (3-benzoylthioureido) -1H-pyrrole-2-carboxylic acid methyl ester (2)
Compound 1(9.90g, 70.64mmol) prepared above was dissolved in tetrahydrofuran (300mL)Benzoyl isothiocyanate (13.83g, 84.77mmol) was added dropwise and reacted at room temperature for 10h, TLC showed the reaction was complete. The reaction solution was concentrated and separated by silica gel column chromatography (petroleum ether) to obtain 16.12g of a white solid, yield: 75.23 percent. mp: 159-161 ℃ C; ESI-MS m/z: 326.0[ M + Na ]]+；1H-NMR(300MHz，DMSO-d6)δ(ppm)：12.90(s，1H)，11.93(s，1H)，7.99(d，J＝7.4Hz，2H)，7.71-7.66(m，1H)，7.56(t，J＝7.4Hz，2H)，7.20-7.18(m，1H)，6.89(dd，J＝4.2Hz，1.8Hz，1H)，6.20(dd，J＝4.1Hz，3Hz，1H)，3.69(s，3H).
Step c: preparation of 2-mercapto-4-hydroxypyrrolo [2, 1-f ] [1, 2, 4] triazine (3)
Compound 2(15.20g, 50.11mmol) prepared above was dissolved in methanol (400mL), sodium methoxide (22.70g, 420.21mmol) was added in portions, and after reaction for 3h at room temperature, TLC showed the reaction to be complete. The pH was adjusted to neutral, concentrated and separated by silica gel column chromatography (dichloromethane: methanol 10: 1) to give 6.52g of a white solid, yield: 77.83 percent. mp: more than 280 ℃; ESI-MS m/z: 166.0[ M-H]+；1H-NMR(300MHz，DMSO-d6)δ(ppm)：9.93(br.s，1H)，7.10-7.09(m，1H)，6.53(dd，J＝4.2Hz，1.7Hz，1H)，6.21(dd，J＝4.2Hz，2.5Hz，1H).
Step d: preparation of ethyl 4- [ [ (4-hydroxypyrrolo [2, 1-f ] [1, 2, 4] triazin-2-yl) thio ] methyl ] benzoate (4)
Compound 3(6.00g, 35.89mmol) prepared above, methanol (400mL), ethyl p-chloromethylbenzoate (7.13g, 35.89mmol) were placed in a 250mL eggplant-shaped bottle, and reacted for 3 hours in ice bath, followed by TLC to show completion of the reaction. The reaction mixture was poured into water (70mL), extracted with ethyl acetate (60mL × 5), the organic phases were combined, washed with saturated brine (70mL), dried over anhydrous sodium sulfate, allowed to stand, filtered, and evaporated under reduced pressure to remove the solvent, and separated by silica gel column chromatography (petroleum ether: ethyl acetate: 5: 1) to obtain 8.58g of a white solid, yield: 72.58 percent. mp: 198-200 ℃; ESI-MS m/z: 352.1[ M + Na ] ]+；1H-NMR(300MHz，DMSO-d6)δ(ppm)：12.08(s，1H，-OH)，7.91(d，J＝8.2Hz，2H)，7.62(d，J＝8.2Hz，2H)，7.57-7.56(m，1H)，6.84(dd，J＝4.2Hz，1.4Hz，1H)，6.49(dd，J＝4.2Hz，2.7Hz，1H)，4.45(s，2H)，4.30(q，J＝7.1Hz，2H)，1.31(t，J＝7.1Hz，3H).
Step e: preparation of ethyl 4- [ [ (4-chloropyrrolo [2, 1-f ] [1, 2, 4] triazin-2-yl) thio ] methyl ] benzoate (5)
Compound 4(8.10g, 24.59mmol) prepared above was dissolved in phosphorus oxychloride (15mL) under ice-bath conditions, N-diethylaniline (11.01g, 73.78mmol) was added under nitrogen, and the reaction was terminated by TLC after heating to reflux for 10 h. Most of phosphorus oxychloride was evaporated under reduced pressure, the reaction mixture was poured into ice water (400mL) and extracted with ethyl acetate (60mL × 3), the organic layers were combined, washed with saturated brine (60mL), dried over anhydrous sodium sulfate, allowed to stand, filtered, the solvent was evaporated under reduced pressure, and the mixture was separated by silica gel column chromatography (petroleum ether: ethyl acetate: 60: 1) to give 7.10g of a white solid, yield: 83.01 percent. mp: 106 ℃ to 108 ℃; ESI-MS m/z: 370.0[ M + Na ]]+；1H-NMR(300MHz DMSO-d6)δ(ppm)：8.19-8.20(m，1H)，7.91(d，J＝8.2Hz)，7.65(d，J＝8.2Hz，2H)，7.06(dd，J＝4.6Hz，1.3Hz，1H)，7.00(dd，J＝4.6Hz，2.5Hz，1H)，4.47(s，2H)，4.30(q，J＝7.1Hz，2H)，1.30(t，J＝7.1Hz，3H).
Step f: preparation of ethyl 4- [ [ [4- [ (5-methyl-1H-pyrazol-3-yl) amino ] pyrrolo [2, 1-f ] [1, 2, 4] triazin-2-yl ] thio ] methyl ] benzoate (6a)
5(400mg, 1.15mmol) prepared above was dissolved in N, N-dimethylformamide (20mL), potassium iodide (1.91g, 11.50mmol) was added, and the mixture was stirred at 70 ℃ for 5 minutes. N, N-diisopropylethylamine (743mg, 5.75mmol) and 5-methyl-3-aminopyrazole (223mg, 2.30mmol) were added and reacted at 80 ℃ for 36h with TLC detection complete. To the reaction mixture was added water (80mL), and extracted with ethyl acetate (30mL × 3), the organic layers were combined, washed with saturated brine (50mL), dried over anhydrous sodium sulfate, allowed to stand, filtered, and the solvent was distilled off under reduced pressure, and separated by silica gel column chromatography (petroleum ether: ethyl acetate 3: 1) to obtain 321mg of a white solid, yield: 68.33 percent. mp: 200 ℃ and 202 ℃; ESI-MS m/z: 431.1[ M + Na ] ]+；1H-NMR(300MHz，DMSO-d6)δ(ppm)：12.25(br.s，1H)，10.62(s，1H)，7.89(d，J＝8.2Hz，2H)，7.66(s，1H)，7.60(d，J＝8.2Hz，2H)，7.21(s，1H)，6.59(dd，J＝4.2Hz，2.6Hz，1H)，6.44(s，1H)，4.42(s，2H)，4.29(q，J＝7.1Hz，2H)，2.22(s，3H)，1.30(t，J＝7.1Hz，3H).
Step g: preparation of 4- [ [ [4- [ (5-methyl-1H-pyrazol-3-yl) amino ] pyrrolo [2, 1-f ] [1, 2, 4] triazin-2-yl ] thio ] methyl ] benzoic acid (7a)
To a 25mL eggplant-shaped bottle, the compound 6a (300mg, 0.73mmol) obtained by the above preparation and sodium hydroxide (59mg, 1.46mmol) were added, water (10mL) and ethanol (20mL) were added, and the reaction was carried out at 60 ℃ for 12 hours and was checked by TLC to be complete. And (3) evaporating the solvent under reduced pressure, adding water (5mL), adjusting the pH to 6-7 with a glacial acetic acid solution in an ice bath, freezing and standing for 2h in a refrigerator, performing suction filtration, and performing vacuum drying on a filter cake to obtain a white solid 262mg and yield: 92.86 percent. mp: more than 270 ℃; ESI-MS m/z: 379.1[ M-H]-；1H-NMR(300MHz，DMSO-d6)δ(ppm)：12.61(br.s，2H)，10.65(s，1H)，7.87(d，J＝8.2Hz，2H)，7.66-7.65(m，1H)，7.56(d，J＝8.2Hz，2H)，7.21(s，1H)，6.60(dd，J＝4.3Hz，2.6Hz，1H)，6.44(s，1H)，4.41(s，2H)，2.22(s，3H).
Step h: preparation of N- (2-aminophenyl) -4- [ [ [4- [ (5-methyl-1H-pyrazol-3-yl) amino ] pyrrolo [2, 1-f ] [1, 2, 4] triazin-2-yl ] thio ] methyl ] benzamide (I-1)
A25 mL eggplant type bottle was charged with 7a (100mg, 0.26mmol) and TBTU (93mg, 0.29mmol) prepared as described above, N-dimethylformamide (10mL) was added, N-diisopropylethylamine (136mg, 1.05mmol) was further added, and the mixture was stirred at room temperature for 1 hour, further o-phenylenediamine (31mg, 0.29mmol) was added, and after stirring at room temperature for 4 hours, the reaction was completed by TLC. To the reaction mixture was added water (80mL), and extracted with ethyl acetate (30mL × 3), the organic layers were combined, washed with saturated brine (50mL), dried over anhydrous sodium sulfate, allowed to stand, filtered, and the solvent was distilled off under reduced pressure, and separated by silica gel column chromatography (petroleum ether: ethyl acetate 1: 1) to obtain 28mg of a white solid, yield: 22.64 percent. mp: 145-147 ℃; ESI-MS m/z: 493.1[ M + Na ] ]+；1H-NMR(300MHz，DMSO-d6)δ(ppm)：12.26(br.s，1H)，10.63(s，1H)，9.65(s，1H)，7.91(d，J＝8.1Hz，2H)，7.68-7.67(m，1H)，7.58(d，J＝8.1Hz，2H)，7.22(s，1H)，7.17-7.14(m，1H)，7.02-6.95(m，1H)，6.80-6.78(m，1H)，6.94-6.59(m，2H)，6.48(s，1H)，5.17(br.s，2H)，4.43(s，2H)，2.24(s，3H).
Example 2
N- (2-amino-4-fluorophenyl) -4- [ [ [4- [ (5-methyl-1H-pyrazol-3-yl) amino ] pyrrolo [2, 1-f ] [1, 2, 4] triazin-2-yl ] thio ] methyl ] benzamide (I-2)
Figure BSA0000172130500000121
Step a: preparation of N- (2-amino-4-fluorophenyl) -4- [ [ [4- [ (5-methyl-1H-pyrazol-3-yl) amino ] pyrrolo [2, 1-f ] [1, 2, 4] triazin-2-yl ] thio ] methyl ] benzamide (I-2)
To a 25mL eggplant-type flask were added 7a (150mg, 0.39mmol) and TBTU (140mg, 0.43mmol) prepared as described above, N-dimethylformamide (10mL) and N, N-diisopropylethylamine (204mg, 1.58mmol) were added, and the mixture was stirred at room temperature for 1 hour, then p-fluorophenyldiamine (55mg, 0.43mmol) was added, and after stirring at room temperature for 4 hours, the reaction was completed by TLC. To the reaction mixture was added water (80mL), extracted with ethyl acetate (30mL × 3), the organic layers were combined, washed with saturated brine (50mL), dried over anhydrous sodium sulfate, left to stand, filtered, the solvent was distilled off under reduced pressure, and separated by silica gel column chromatography (petroleum ether: ethyl acetate 1: 1) to give 25mg of a white solid, yield: 12.98 percent. mp: 147 ℃ and 149 ℃; ESI-MS m/z: 511.2[ M + Na ]]+；1H-NMR(300MHz，DMSO-d6)δ(ppm)：12.25(br.s，1H)，10.64(s，1H)，9.54(s，1H)，7.90(d，J＝8.2Hz，2H)，7.68-7.67(m，1H)，7.57(d，J＝8.2Hz，2H)，7.22(s，1H)，7.11-7.06(m，1H)，6.60(dd，J＝4.2Hz，2.6Hz，1H)，6.54-6.49(m，2H)，6.37-6.31(m，1H)，5.23(s，2H)，4.42(s，2H)，2.24(s，3H).
Example 3
N- (2-aminophenyl) -4- [ [ [4- [ (1H-pyrazol-3-yl) amino ] pyrrolo [2, 1-f ] [1, 2, 4] triazin-2-yl ] thio ] methyl ] benzamide (I-3)
Figure BSA0000172130500000131
A, step a: preparation of ethyl 4- [ [ [4- [ (1H-pyrazol-3-yl) amino ] pyrrolo [2, 1-f ] [1, 2, 4] triazin-2-yl ] thio ] methyl ] benzoate (6b)
5(500mg, 1.44mmol) prepared above was dissolved in N, N-dimethylformamide (20mL), potassium iodide (2.39g, 14.38mmol) was added, and the mixture was stirred at 70 ℃ for 5 minutes. N, N-diisopropylethylamine (929mg, 7.19mmol) and 3-aminopyrazole (239mg, 2.88mmol) were added and reacted at 80 ℃ for 36h, and TLC showed complete reaction. To the reaction mixture was added water (80mL), and extracted with ethyl acetate (30mL × 3), the organic layers were combined, washed with saturated brine (50mL), dried over anhydrous sodium sulfate, allowed to stand, filtered, and the solvent was distilled off under reduced pressure, and separated by silica gel column chromatography (petroleum ether: ethyl acetate 3: 1) to obtain 314mg of a white solid, yield: 55.38 percent. mp: 185-187 deg.C; ESI-MS m/z: 393.1[ M-H]-；1H-NMR(300MHz，DMSO-d6)δ(ppm)：12.58(br.s，1H)，10.74(s，1H)，7.88(d，J＝8.1Hz，2H)，7.71(s，1H)，7.67(s，1H)，7.59(d，J＝8.1Hz，2H)，7.23(s，1H)，6.71(s，1H)，6.62-6.60(m，1H)，4.42(s，2H)，4.29(q，J＝7.1Hz，2H)，1.30(t，J＝7.1Hz，3H).
Step b: preparation of 4- [ [ [4- [ (1H-pyrazol-3-yl) amino ] pyrrolo [2, 1-f ] [1, 2, 4] triazin-2-yl ] thio ] methyl ] benzoic acid (7b)
To a 25mL eggplant-shaped bottle, the compound 6b (300mg, 0.76mmol) obtained by the above preparation and sodium hydroxide (61mg, 1.52mmol) were added, water (10mL) and ethanol (20mL) were added, and the reaction was carried out at 60 ℃ for 12 hours and was checked by TLC to be complete. And (3) evaporating the solvent under reduced pressure, adding water (5mL), adjusting the pH to 6-7 with a glacial acetic acid solution under ice bath, freezing and standing for 2h in a refrigerator, performing suction filtration, and performing vacuum drying on a filter cake to obtain a white solid 233mg, wherein the yield is as follows: 83.54 percent. mp: more than 270 ℃; ESI-MS m/z: 389.1[ M + Na ] ]+；1H-NMR(300MHz，DMSO-d6)δ(ppm)：12.73(br.s，2H)，10.80(s，1H)，7.86(d，J＝8.0Hz，2H)，7.69-7.66(m，2H)，7.53(d，J＝8.0Hz，2H)，7.23(s，1H)，6.70(s，1H)，6.62-6.60(m，1H)，4.41(s，2H).
Step c: preparation of N- (2-aminophenyl) -4- [ [ [4- [ (1H-pyrazol-3-yl) amino ] pyrrolo [2, 1-f ] [1, 2, 4] triazin-2-yl ] thio ] methyl ] benzamide (I-3)
A25 mL eggplant type bottle was charged with 7b (100mg, 0.27mmol) and TBTU (97mg, 0.30mmol) prepared as described above, N-dimethylformamide (10mL) was added, N-diisopropylethylamine (141mg, 1.09mmol) was further added, and the mixture was stirred at room temperature for 1 hour, further o-phenylenediamine (32mg, 0.30mmol) was added, and after stirring at room temperature for 4 hours, the reaction was completed by TLC. To the reaction mixture was added water (80mL), and extracted with ethyl acetate (30mL × 3), the organic layers were combined, washed with saturated brine (50mL), dried over anhydrous sodium sulfate, allowed to stand, filtered, and the solvent was distilled off under reduced pressure, and separated by silica gel column chromatography (petroleum ether: ethyl acetate 1: 1) to obtain a white solid 69mg, yield: 55.38 percent. mp: 194 ℃ and 196 ℃; ESI-MS m/z: 479.1[ M + Na ]]+；1H-NMR(300MHz，DMSO-d6)δ(ppm)：12.58(s，1H)，10.75(s，1H)，9.61(s，1H)，7.90(d，J＝8.1Hz，2H)，7.72(d，1H)，7.69-7.68(m，1H)，7.57(d，J＝8.1Hz，2H)，7.24(s，1H)，7.15-7.13(m，1H)，6.99-6.93(m，1H)，6.78-6.75(m，2H)，6.63-6.56(m，2H)，4.92(s，2H)，4.43(s，2H).
Example 4
N- (2-amino-4-fluorophenyl) -4- [ [ [4- [ (1H-pyrazol-3-yl) amino ] pyrrolo [2, 1-f ] [1, 2, 4] triazin-2-yl ] thio ] methyl ] benzamide (I-4)
Figure BSA0000172130500000141
Step a: preparation of N- (2-amino-4-fluorophenyl) -4- [ [ [4- [ (1H-pyrazol-3-yl) amino ] pyrrolo [2, 1-f ] [1, 2, 4] triazin-2-yl ] thio ] methyl ] benzamide (I-4)
A25 mL eggplant type bottle was charged with 7b (100mg, 0.27mmol) obtained in the above preparation and TBTU (97mg, 0.30mmol), N-dimethylformamide (10mL) was added, N-diisopropylethylamine (141mg, 1.09mmol) was further added, and stirring was carried out at ordinary temperature for 1 hour, and p-fluorophenyldiamine (38mg, 1.09mmol) was further added0.30mmol) and stirring at normal temperature for 4h, and detecting the reaction by TLC. To the reaction mixture was added water (80mL), and extracted with ethyl acetate (30mL × 3), the organic layers were combined, washed with saturated brine (50mL), dried over anhydrous sodium sulfate, allowed to stand, filtered, and the solvent was distilled off under reduced pressure, and separated by silica gel column chromatography (petroleum ether: ethyl acetate 1: 1) to obtain 82mg of a white solid, yield: 63.32 percent. mp: 166-168 ℃; ESI-MS m/z: 473.1[ M-H]-；1H-NMR(300MHz，DMSO-d6)δ(ppm)：12.58(s，1H)，10.74(s，1H)，9.53(s，1H)，7.90(d，J＝8.1Hz，2H)，7.72-7.68(m，2H)，7.56(d，J＝8.1Hz，2H)，7.27-7.23(m，1H)，7.11-7.06(m，1H)，6.74(s，1H)，6.61(dd，J＝4.2Hz，2.5Hz，1H)，6.54-6.50(m，1H)，6.37-6.30(m，1H)，5.22(s，2H)，4.43(s，2H).
Example 5
N- (2-aminophenyl) -4- [ [ [4- [ (5-tert-butyl-1H-pyrazol-3-yl) amino ] pyrrolo [2, 1-f ] [1, 2, 4] triazin-2-yl ] thio ] methyl ] benzamide (I-5)
Figure BSA0000172130500000151
Step a: preparation of ethyl 4- [ [ [4- [ (5-tert-butyl-1H-pyrazol-3-yl) amino ] pyrrolo [2, 1-f ] [1, 2, 4] triazin-2-yl ] thio ] methyl ] benzoate (6c)
5(500mg, 1.44mmol) prepared above was dissolved in N, N-dimethylformamide (20mL), potassium iodide (2.39g, 14.38mmol) was added, and the mixture was stirred at 70 ℃ for 5 minutes. N, N-diisopropylethylamine (929mg, 7.19mmol) and 5-tert-butyl-3-aminopyrazole (400mg, 2.88mmol) were added and reacted at 80 ℃ for 3h with TLC detection of completion. To the reaction mixture was added water (80mL), extracted with ethyl acetate (30mL × 3), the organic layers were combined, washed with saturated brine (50mL), dried over anhydrous sodium sulfate, allowed to stand, filtered, and the solvent was distilled off under reduced pressure, and separated by silica gel column chromatography (petroleum ether: ethyl acetate 5: 1) to give 579mg of a yellow solid, yield: 89.39 percent. mp: 130 ℃ to 132 ℃; ESI-MS m/z: 473.1[ M + Na ] ]+；1H-NMR(300MHz，CDCl3-d6)δ(ppm)：8.88(s，1H)，7.97(d，J＝8.2Hz，2H)，7.54-7.51(m，3H)，6.73(s，1H)，6.64-6.63(m，1H)，6.56(dd，J＝4.3Hz，2.6Hz，1H)，4.45(s，2H)，4.36(q，J＝7.1Hz，2H)，1.37(t，J＝7.1Hz，3H)，1.32(s，9H).
Step b: preparation of 4- [ [ [4- [ (5-tert-butyl-1H-pyrazol-3-yl) amino ] pyrrolo [2, 1-f ] [1, 2, 4] triazin-2-yl ] thio ] methyl ] benzoic acid (7c)
To a 25mL eggplant-shaped bottle were added compound 6c (500mg, 1.11mmol) obtained by the above preparation and sodium hydroxide (89mg, 2.22mmol), and water (20mL) and ethanol (40mL) were added, followed by reaction at 60 ℃ for 12 hours and completion of the reaction by TLC. The solvent was evaporated under reduced pressure, water (20mL) was added, the pH was adjusted to 6-7 with glacial acetic acid solution in ice bath, frozen and left to stand in refrigerator for 2h, filtered, the filter cake was vacuum dried to obtain 369mg of white solid, yield: 78.70 percent. mp: 269-271 deg.C; ESI-MS m/z: 423.2[ M + H]+；1H-NMR(300MHz，DMSO-d6)δ(ppm)：12.51(br.s，2H)，10.71(s，1H)，7.86(d，J＝8.2Hz，2H)，7.66-7.65(m，1H)，7.54(d，J＝8.2Hz，2H)，7.24(s，1H)，6.61(dd，J＝4.3Hz，2.6Hz，1H)，6.54(s，1H)，4.45(s，2H)，1.23(s，9H).
Step c: preparation of N- (2-aminophenyl) -4- [ [ [4- [ (5-tert-butyl-1H-pyrazol-3-yl) amino ] pyrrolo [2, 1-f ] [1, 2, 4] triazin-2-yl ] thio ] methyl ] benzamide (I-5)
A25 mL eggplant type bottle was charged with 7c (150mg, 0.36mmol) and TBTU (126mg, 0.39mmol) obtained in the above preparation, N-dimethylformamide (10mL) was added, N-diisopropylethylamine (183mg, 1.42mmol) was further added, and the mixture was stirred at room temperature for 1 hour, further o-phenylenediamine (42mg, 0.39mmol) was added, and after stirring at room temperature for 8 hours, the reaction was completed by TLC. To the reaction mixture was added water (80mL), and extracted with ethyl acetate (30mL × 3), the organic layers were combined, washed with saturated brine (50mL), dried over anhydrous sodium sulfate, allowed to stand, filtered, and the solvent was distilled off under reduced pressure, and separated by silica gel column chromatography (petroleum ether: ethyl acetate 1: 1) to obtain 134mg of a white solid, yield: 73.63 percent. mp: 160-162 ℃; ESI-MS m/z: 535.2[ M + Na ]+；1H-NMR(300MHz，DMSO-d6)δ(ppm)：12.30(br.s，1H)，10.68(s，1H)，9.60(s，1H)，7.90(d，J＝7.8Hz，2H)，7.66(m，1H)，7.56(d，J＝7.8Hz，2H)，7.23(s，1H)，7.15-7.13(m，1H)，6.98-6.93(m，1H)，6.77-6.75(m，1H)，6.60-6.56(m，3H)，4.88(s，2H)，4.47(s，2H)，1.26(s，9H).
Example 6
N- (2-amino-4-fluorophenyl) -4- [ [ [4- [ (5-tert-butyl-1H-pyrazol-3-yl) amino ] pyrrolo [2, 1-f ] [1, 2, 4] triazin-2-yl ] thio ] methyl ] benzamide (I-6)
Figure BSA0000172130500000161
Step a: preparation of N- (2-amino-4-fluorophenyl) -4- [ [ [4- [ (5-tert-butyl-1H-pyrazol-3-yl) amino ] pyrrolo [2, 1-f ] [1, 2, 4] triazin-2-yl ] thio ] methyl ] benzamide (I-6)
A25 mL eggplant type bottle was charged with 7c (150mg, 0.36mmol) and TBTU (126mg, 0.39mmol) obtained in the above preparation, N-dimethylformamide (10mL) was added, N-diisopropylethylamine (183mg, 1.42mmol) was further added, and the mixture was stirred at room temperature for 1 hour, p-fluorophenyldiamine (49mg, 0.39mmol) was further added, and after stirring at room temperature for 8 hours, the reaction was completed by TLC detection. To the reaction mixture was added water (80mL), extracted with ethyl acetate (30mL × 3), the organic layers were combined, washed with saturated brine (50mL), dried over anhydrous sodium sulfate, allowed to stand, filtered, and the solvent was evaporated under reduced pressure, and separated by silica gel column chromatography (petroleum ether: ethyl acetate 1: 1) to give 144mg of a pale yellow solid, yield: 76.60 percent. mp: 152 ℃ and 154 ℃; ESI-MS m/z: 553.2[ M + Na ]]+；1H-NMR(300MHz，DMSO-d6)δ(ppm)：12.30(s，1H)，10.68(s，1H)，9.53(s，1H)，7.89(d，J＝7.7Hz，2H)，7.66(s，1H)，7.55(d，J＝7.7Hz，2H)，7.24(s，1H)，7.11-7.06(m，1H)，6.60-6.50(m，3H)，6.36-6.31(m，1H)，5.21(s，2H)，4.46(s，2H)，1.26(s，9H).
Example 7
N- (2-aminophenyl) -4- [ [ [ 4-morpholinylpyrrolo [2, 1-f ] [1, 2, 4] triazin-2-yl ] thio ] methyl ] benzamide (I-7)
Figure BSA0000172130500000171
Step a: preparation of ethyl 4- [ [ [ 4-morpholinylpyrrolo [2, 1-f ] [1, 2, 4] triazin-2-yl ] thio ] methyl ] benzoate (6d)
5(500mg, 1.44mmol) prepared above was dissolved in N, N-dimethylformamide (20mL), potassium iodide (2.39g, 14.38mmol) was added, and the mixture was stirred at 70 ℃ for 5 minutes. N, N-diisopropylethylamine (929mg, 7.19mmol) and morpholine (250mg, 2.88mmol) were added and reacted at 80 ℃ for 3h with TLC check for completion. Water (80mL) was added to the reaction mixture, and ethyl acetate was extracted (30mL × 3), and the organic layers were combined, washed with saturated brine (50mL), dried over anhydrous sodium sulfate, left to stand, filtered, and the solvent was distilled off under reduced pressure, and separated by silica gel column chromatography (petroleum ether: ethyl acetate 5: 1) to obtain 563mg of a white solid, yield: 98.28 percent. mp: 95-97 ℃; ESI-MS m/z: 421.1[ M + Na ]]+；1H-NMR(300MHz，DMSO-d6)δ(ppm)：7.89(d，J＝8.1Hz，2H)，7.69(s，1H)，7.59(d，J＝7.9Hz，2H)，6.96-6.95(m，1H)，6.63(s，1H)，4.38(s，2H)，4.29(q，J＝7.1Hz，2H)，3.94-3.92(m，4H)，3.71-3.69(m，4H)，1.30(t，J＝7.1Hz，3H).
Step b: preparation of 4- [ [ [ 4-morpholinylpyrrolo [2, 1-f ] [1, 2, 4] triazin-2-yl ] thio ] methyl ] benzoic acid (7d)
To a 100mL eggplant-shaped bottle, compound 6d (500mg, 1.25mmol) obtained by the above preparation and sodium hydroxide (100mg, 2.50mmol) were added, and water (20mL) and ethanol (40mL) were added, followed by refluxing for 10 hours and completion of the reaction by TLC. And (3) evaporating the solvent under reduced pressure, adding water (30mL), adjusting the pH to 6-7 with a glacial acetic acid solution under ice bath, freezing and standing for 2h in a refrigerator, performing suction filtration, and performing vacuum drying on a filter cake to obtain a white solid 350mg, wherein the yield is as follows: 75.30 percent. mp: 156 ℃ and 158 ℃; ESI-MS m/z: 371.1[ M + H ]+；1H-NMR(300MHz，DMSO-d6)δ(ppm)：7.86(d，J＝8.0Hz，2H)，7.69(s，1H)，7.52(d，J＝8.0Hz，2H)，6.96-6.94(m，1H)，6.62(dd，J＝4.2Hz，2.7Hz，1H)，4.37(s，2H)，3.93-3.91(m，4H)，3.72-3.70(m，4H).
Step c: preparation of N- (2-aminophenyl) -4- [ [ [ 4-morpholinylpyrrolo [2, 1-f ] [1, 2, 4] triazin-2-yl ] thio ] methyl ] benzamide (I-7)
To a 25mL eggplant type bottle were added 7d (150mg, 0.41mmol) and TBTU (143mg, 0.45mmol) obtained in the above preparation, N-dimethylformamide (10mL) was added, N-diisopropylethylamine (209mg, 1.62mmol) was further added, and the mixture was stirred at room temperature for 1 hour, then o-phenylenediamine (44mg, 0.41mmol) was added, and further stirred at room temperature for 8 hours, after which the reaction was detected by TLC to be complete. To the reaction mixture was added water (80mL), and extracted with ethyl acetate (30mL × 3), the organic layers were combined, washed with saturated brine (50mL), dried over anhydrous sodium sulfate, allowed to stand, filtered, and the solvent was distilled off under reduced pressure, and separated by silica gel column chromatography (petroleum ether: ethyl acetate 1: 1) to obtain 61mg of a white solid, yield: 32.62 percent. mp: 180 ℃ and 182 ℃; ESI-MS m/z: 483.2[ M + Na ]]+；1H-NMR(300MHz，DMSO-d6)δ(ppm)：9.61(s，1H)，7.91(d，J＝8.1Hz，2H)，7.71-7.70(m，1H)，7.57(d，J＝8.2Hz，2H)，7.14(d，J＝7.4Hz，1H)，6.98-6.94(m，2H)，6.78-6.75(m，1H)，6.64-6.56(m，2H)，4.89(s，2H)，4.39(s，2H)，3.94-3.93(m，4H)，3.74-3.72(m，4H).
Example 8
N- (2-amino-4-fluorophenyl) -4- [ [ [ 4-morpholinylpyrrolo [2, 1-f ] [1, 2, 4] triazin-2-yl ] thio ] methyl ] benzamide (I-8)
Figure BSA0000172130500000181
Step a: preparation of N- (2-amino-4-fluorophenyl) -4- [ [ [ 4-morpholinylpyrrolo [2, 1-f ] [1, 2, 4] triazin-2-yl ] thio ] methyl ] benzamide (I-8)
A25 mL eggplant type bottle was charged with 7d (150mg, 0.41mmol) and TBTU (143mg, 0.45mmol) prepared as described above, N-dimethylformamide (10mL) was added, N-diisopropylethylamine (209mg, 1.62mmol) was further added, and the mixture was stirred at room temperature for 1 hour, p-fluorophenyldiamine (51mg, 0.41mmol) was further added, and after stirring at room temperature for 8 hours, the reaction was completed by TLC. Water (80mL) was added to the reaction mixture, ethyl acetate extraction (30 mL. times.3) was performed, the organic layers were combined, washed with saturated brine (50mL), dried over anhydrous sodium sulfate, allowed to stand, filtered, the solvent was evaporated under reduced pressure, Separation by column chromatography on silica gel (petroleum ether: ethyl acetate 1: 1) gave 68mg of a white solid, yield: 35.05 percent. mp: 198-200 ℃; ESI-MS m/z: 501.1[ M + Na ]]+；1H-NMR(300MHz，DMSO-d6)δ(ppm)：9.54(s，1H)，7.90(d，J＝8.1Hz，2H)，7.71-7.70(m，1H)，7.56(d，J＝8.1Hz，2H)，7.11-7.06(m，1H)，6.96(dd，J＝4.6Hz，1.2Hz，1H)，6.63(dd，J＝4.6Hz，2.7Hz，1H)，6.55-6.50(m，1H)，6.35-6.34(m，1H)，5.22(s，2H)，4.38(s，2H)，3.96-3.93(m，4H)，3.73-3.70(m，4H).
Example 9
N- (2-aminophenyl) -4- [ [ [4- [ (4-fluorobenzyl) amino ] pyrrolo [2, 1-f ] [1, 2, 4] triazin-2-yl ] thio ] methyl ] benzamide (I-9)
Figure BSA0000172130500000191
Step a: preparation of ethyl 4- [ [ [4- [ (4-fluorobenzyl) amino ] pyrrolo [2, 1-f ] [1, 2, 4] triazin-2-yl ] thio ] methyl ] benzoate (6e)
5(500mg, 1.44mmol) prepared above was dissolved in N, N-dimethylformamide (20mL), potassium iodide (2.39g, 14.38mmol) was added, and the mixture was stirred at 70 ℃ for 5 minutes. N, N-diisopropylethylamine (929mg, 7.19mmol) and p-fluorobenzylamine (360mg, 2.88mmol) were added and reacted at 80 ℃ for 4h, and the reaction was complete by TLC. Water (80mL) was added to the reaction mixture, and ethyl acetate was extracted (30mL × 3), and the organic layers were combined, washed with saturated brine (50mL), dried over anhydrous sodium sulfate, left to stand, filtered, and the solvent was evaporated under reduced pressure, and separated by silica gel column chromatography (petroleum ether: ethyl acetate: 5: 1) to obtain 594mg of a white solid, yield: 94.66 percent. mp: 94-96 ℃; ESI-MS m/z: 459.2[ M + Na ]]+；1H-NMR(300MHz，DMSO-d6)δ(ppm)：8.91(s，1H)，7.82(d，J＝8.2Hz，2H)，7.57(s，1H)，7.48(d，J＝8.2Hz，2H)，7.36-7.31(m，2H)，7.16-7.10(m，2H)，6.90(dd，J＝4.2Hz，1.2Hz，1H)，6.55(dd，J＝4.3Hz，2.6Hz，1H)，4.69(d，J＝5.7Hz，2H)，4.36(s，2H)，4.27(q，J＝7.1Hz，2H)，1.31(t，J＝7.1Hz，3H).
Step b: preparation of 4- [ [ [4- [ (4-fluorobenzyl) amino ] pyrrolo [2, 1-f ] [1, 2, 4] triazin-2-yl ] thio ] methyl ] benzoic acid (7e)
To a 100mL eggplant-shaped flask were added the compound 6e (500mg, 1.15mmol) prepared above and sodium hydroxide (92mg, 2.30mmol), added water (20mL) and ethanol (40mL), refluxed for 10h, and checked by TLC for completion. And (3) evaporating the solvent under reduced pressure, adding water (30mL), adjusting the pH to 6-7 with a glacial acetic acid solution under ice bath, freezing and standing for 2h in a refrigerator, performing suction filtration, and performing vacuum drying on a filter cake to obtain a white solid 368mg, wherein the yield is as follows: 78.66 percent. mp: 180 ℃ and 182 ℃; ESI-MS m/z: 409.1[ M + H]+；1H-NMR(300MHz，DMSO-d6)δ(ppm)：12.90(br.s，1H，COOH)，8.95(t，J＝5.7Hz，1H，NH-CH2-)，7.82(d，J＝8.2Hz，2H，ph-H)，7.59-7.57(m，1H，pyrrole-H)，7.45(d，J＝8.2Hz，2H，ph-H)，7.37-7.33(m，2H，ph-H)，7.17-7.12(m，2H，ph-H)，6.90(dd，J＝4.3Hz，1.3Hz，1H，pyrrole-H)，6.55(dd，J＝4.3Hz，2.6Hz，1H，pyrrole-H)，4.69(d，J＝5.8Hz，2H，NH-CH2-)，4.35(s，2H，-SCH2-).
Step c: preparation of N- (2-aminophenyl) -4- [ [ [4- [ (4-fluorobenzyl) amino ] pyrrolo [2, 1-f ] [1, 2, 4] triazin-2-yl ] thio ] methyl ] benzamide (I-9)
To a 25mL eggplant-type bottle were added 7e (150mg, 0.37mmol) prepared above and TBTU (130mg, 0.40mmol), N-dimethylformamide (10mL) was added, N-diisopropylethylamine (190mg, 1.47mmol) was further added, stirring was carried out at normal temperature for 1 hour, o-phenylenediamine (40mg, 0.37mmol) was further added, stirring was carried out at normal temperature for 8 hours, and then completion of the reaction was detected by TLC. To the reaction mixture was added water (80mL), extracted with ethyl acetate (30mL × 3), the organic layers were combined, washed with saturated brine (50mL), dried over anhydrous sodium sulfate, allowed to stand, filtered, and the solvent was evaporated under reduced pressure, and separated by silica gel column chromatography (petroleum ether: ethyl acetate 1: 1) to give 94mg of a yellow solid, yield: 51.34 percent. mp: 133 ℃ and 135 ℃; ESI-MS m/z: 521.1[ M + Na ] ]+；1H-NMR(300MHz，DMSO-d6)δ(ppm)：9.60(s，1H)，8.93(t，J＝5.5Hz，1H)，7.87(d，J＝8.0Hz，2H)，7.59-7.58(m，1H)，7.49(d，J＝8.0Hz，2H)，7.39-7.35(m，2H)，7.19-7.13(m，3H)，6.98-6.94(m，1H)，6.91-6.90(m，1H)，6.78-6.75(m，1H)，6.61-6.54(m，2H)，4.89(s，2H)，4.70(d，J＝5.5Hz，2H)，4.36(s，2H).
Example 10
N- (2-amino-4-fluorophenyl) -4- [ [ [4- [ (4-fluorobenzyl) amino ] pyrrolo [2, 1-f ] [1, 2, 4] triazin-2-yl ] thio ] methyl ] benzamide (I-10)
Figure BSA0000172130500000201
A, step a: preparation of N- (2-amino-4-fluorophenyl) -4- [ [ [4- [ (4-fluorobenzyl) amino ] pyrrolo [2, 1-f ] [1, 2, 4] triazin-2-yl ] thio ] methyl ] benzamide (I-10)
A25 mL eggplant type bottle was charged with 7e (200mg, 0.49mmol) and TBTU (173mg, 0.54mmol) prepared as described above, N-dimethylformamide (10mL) was added, N-diisopropylethylamine (253mg, 1.96mmol) was further added, and the mixture was stirred at room temperature for 1 hour, p-fluorophenyldiamine (62mg, 0.49mmol) was further added, and after stirring at room temperature for 8 hours, the reaction was completed by TLC. Water (80mL) was added to the reaction mixture, and ethyl acetate was extracted (30mL × 3), and the organic layers were combined, washed with saturated brine (50mL), dried over anhydrous sodium sulfate, left to stand, filtered, and the solvent was distilled off under reduced pressure, and separated by silica gel column chromatography (petroleum ether: ethyl acetate 1: 1) to obtain 145mg of an off-white solid, yield: 57.31 percent. mp: 205 ℃ and 207 ℃; ESI-MS m/z: 539.1[ M + Na ]]+；1H-NMR(300MHz，DMSO-d6)δ(ppm)：9.53(s，1H)，8.93(t，J＝5.9Hz，1H)，7.86(d，J＝8.1Hz，2H)，7.59-7.58(m，1H)，7.48(d，J＝8.1Hz，2H)，7.39-7.34(m，2H)，7.19-7.06(m，3H)，6.90(dd，J＝4.3Hz，1.4Hz，1H)，6.57-6.50(m，2H)，6.35-6.34(m，1H)，5.23(s，2H)，4.70(d，J＝5.7Hz，2H)，4.36(s，2H).
Example 11
N- (2-aminophenyl) -4- [ [ [4- [ (4-trifluoromethylbenzyl) amino ] pyrrolo [2, 1-f ] [1, 2, 4] triazin-2-yl ] thio ] methyl ] benzamide (I-11)
Figure BSA0000172130500000211
Step a: preparation of ethyl 4- [ [ [4- [ (4-trifluoromethylbenzyl) amino ] pyrrolo [2, 1-f ] [1, 2, 4] triazin-2-yl ] thio ] methyl ] benzoate (6f)
5(500mg, 1.44mmol) prepared above was dissolved in N, N-dimethylformamide (20mL), potassium iodide (2.39g, 14.38mmol) was added, and the mixture was stirred at 70 ℃ for 5 minutes. N, N-diisopropylethylamine (929mg, 7.19mmol) and p-trifluoromethylbenzylamine (504mg, 2.88mmol) were added, and the reaction was completed by TLC at 80 ℃ for 3 hours. Water (80mL) was added to the reaction mixture, and ethyl acetate was extracted (30mL × 3), and the organic layers were combined, washed with saturated brine (50mL), dried over anhydrous sodium sulfate, left to stand, filtered, and the solvent was distilled off under reduced pressure, and separated by silica gel column chromatography (petroleum ether: ethyl acetate 5: 1) to obtain 658mg of a white solid, yield: 94.08 percent. mp: 91-93 ℃; ESI-MS m/z: 509.2[ M + Na]+；1H-NMR(300MHz，CDCl3-d6)δ(ppm)：7.34(d，J＝8.2Hz，2H)，7.59(d，J＝8.1Hz，2H)，7.48-7.42(m，5H)，6.57-6.51(m，2H)，4.86(d，J＝5.6Hz，2H)，4.39-4.32(m，4H)，1.37(t，J＝7.1Hz，3H).
Step b: preparation of 4- [ [ [4- [ (4-trifluoromethylbenzyl) amino ] pyrrolo [2, 1-f ] [1, 2, 4] triazin-2-yl ] thio ] methyl ] benzoic acid (7f)
To a 100mL eggplant-shaped bottle, the compound 6f (600mg, 1.23mmol) obtained by the above preparation and sodium hydroxide (98mg, 2.46mmol) were added, and water (20mL) and ethanol (40mL) were added, followed by refluxing for 10 hours and completion of the reaction by TLC. And (3) evaporating the solvent under reduced pressure, adding water (30mL), adjusting the pH to 6-7 with a glacial acetic acid solution under ice bath, freezing and standing for 2h in a refrigerator, performing suction filtration, and performing vacuum drying on a filter cake to obtain a white solid 459mg, wherein the yield is as follows: 81.18 percent. mp: 200 ℃ and 202 ℃; ESI-MS m/z: 481.1[ M + Na ] ]+；1H-NMR(300MHz，DMSO-d6)δ(ppm)：13.00(br.s，1H)，9.07(t，J＝5.9Hz，1H)，7.78(d，J＝8.2Hz，2H)，7.69(d，J＝8.2Hz，2H)，7.60-7.59(m，1H)，7.53(d，J＝8.0Hz，2H)，7.38(d，J＝8.2Hz，2H)，6.92(dd，J＝4.3Hz，1.4Hz，1H)，6.57(dd，J＝4.3Hz，2.6Hz，1H)，4.80(d，J＝5.6Hz，2H)，4.31(s，2H).
Step c: preparation of N- (2-aminophenyl) -4- [ [ [4- [ (4-trifluoromethylbenzyl) amino ] pyrrolo [2, 1-f ] [1, 2, 4] triazin-2-yl ] thio ] methyl ] benzamide (I-11)
To a 25mL eggplant type bottle were added 7f (150mg, 0.33mmol) and TBTU (116mg, 0.36mmol) obtained in the above preparation, N-dimethylformamide (10mL) was added, N-diisopropylethylamine (169mg, 1.31mmol) was further added, and the mixture was stirred at ordinary temperature for 1 hour, further o-phenylenediamine (35mg, 0.33mmol) was added, and after stirring at ordinary temperature for 4 hours, the reaction was completed by TLC. To the reaction mixture was added water (80mL), and extracted with ethyl acetate (30mL × 3), the organic layers were combined, washed with saturated brine (50mL), dried over anhydrous sodium sulfate, allowed to stand, filtered, and the solvent was distilled off under reduced pressure, and separated by silica gel column chromatography (petroleum ether: ethyl acetate 1: 1) to obtain 115mg of a white solid, yield: 64.25 percent. mp: 172-174 ℃; ESI-MS m/z: 571.1[ M + Na ]]+；1H-NMR(300MHz，DMSO-d6)δ(ppm)：9.59(s，1H)，9.03(t，J＝5.8Hz，1H)，7.85(d，J＝8.1Hz，2H)，7.71(d，J＝7.2Hz，2H)，7.61(dd，J＝2.3Hz，1.6Hz，1H)，7.55(d，J＝8.0Hz，2H)，7.45(d，J＝8.2Hz，2H)，7.14(d，J＝7.2Hz，1H)，6.99-6.91(m，2H)，6.78-6.75(m，1H)，6.59-6.56(m，2H)，4.89(s，2H)，4.81(d，J＝5.6Hz，2H)，4.33(s，2H).
Example 12
N- (2-amino-4-fluorophenyl) -4- [ [ [4- [ (4-trifluoromethylbenzyl) amino ] pyrrolo [2, 1-f ] [1, 2, 4] triazin-2-yl ] thio ] methyl ] benzamide (I-12)
Figure BSA0000172130500000221
Step a: preparation of N- (2-amino-4-fluorophenyl) -4- [ [ [4- [ (4-trifluoromethylbenzyl) amino ] pyrrolo [2, 1-f ] [1, 2, 4] triazin-2-yl ] thio ] methyl ] benzamide (I-12)
To a 25mL eggplant type bottle were added 7f (150mg, 0.33mmol) prepared above and TBTU (116mg, 0.36mmol), N-dimethylformamide (10mL) and N, N-diiso-formamidePropylethylamine (169mg, 1.31mmol) was stirred at room temperature for 1 hour, p-fluorophenylenediamine (41mg, 0.33mmol) was added thereto, and stirring was continued at room temperature for 8 hours, after which the reaction was detected by TLC to be complete. To the reaction mixture was added water (80mL), and extracted with ethyl acetate (30mL × 3), the organic layers were combined, washed with saturated brine (50mL), dried over anhydrous sodium sulfate, allowed to stand, filtered, and the solvent was distilled off under reduced pressure, and separated by silica gel column chromatography (petroleum ether: ethyl acetate 1: 1) to obtain 123mg of a white solid, yield: 66.49 percent. mp: 129-131 ℃; ESI-MS m/z: 589.1[ M + Na ]]+；1H-NMR(300MHz，DMSO-d6)δ(ppm)：9.52(s，1H)，9.02(s，1H)，7.84(d，J＝6.9Hz，2H)，7.70(d，J＝7.2Hz，2H)，7.60-7.53(m，3H)，7.44(d，J＝7.1Hz，2H)，7.09-7.07(m，1H)，6.92(s，1H)，6.57-6.50(m，2H)，6.35-6.33(m，1H)，5.21(s，2H)，4.81(s，2H)，4.32(s，2H)。
Example 13
N- (2-aminophenyl) -4- [ [ [4- [ (4-methoxybenzyl) amino ] pyrrolo [2, 1-f ] [1, 2, 4] triazin-2-yl ] thio ] methyl ] benzamide (I-13)
Figure BSA0000172130500000231
Step a: preparation of ethyl 4- [ [ [4- [ (4-methoxybenzyl) amino ] pyrrolo [2, 1-f ] [1, 2, 4] triazin-2-yl ] thio ] methyl ] benzoate (6g)
5(500mg, 1.44mmol) prepared above was dissolved in N, N-dimethylformamide (20mL), potassium iodide (2.39g, 14.38mmol) was added, and the mixture was stirred at 70 ℃ for 5 minutes. N, N-diisopropylethylamine (929mg, 7.19mmol) and p-methoxybenzylamine (394mg, 2.88mmol) were added and reacted at 80 ℃ for 3h with TLC detection of completion. To the reaction mixture was added water (80mL), extracted with ethyl acetate (30mL × 3), the organic layers were combined, washed with saturated brine (50mL), dried over anhydrous sodium sulfate, allowed to stand, filtered, and the solvent was distilled off under reduced pressure, and separated by silica gel column chromatography (petroleum ether: ethyl acetate 5: 1) to obtain 582mg of a yellow solid, yield: 90.26 percent. mp: 74-76 ℃; ESI-MS m/z: 471.1[ M + Na ]+；1H-NMR(300MHz，DMSO-d6)δ(ppm)：8.88(t，J＝5.8Hz，1H)，7.82(d，J＝8.3Hz，2H)，7.56-7.55(m，1H)，7.48(d，J＝8.3Hz，2H)，7.23(d，J＝8.6Hz，2H)，6.89-6.86(m，3H)，6.53(dd，J＝4.3Hz，2.6Hz，1H)，4.63(d，J＝5.8Hz，2H)，4.37(s，2H)，4.28(q，J＝7.1Hz，2H)，3.71(s，3H)，1.30(t，J＝7.1Hz，3H)。
Step b: preparation of 4- [ [ [4- [ (4-methoxybenzyl) amino ] pyrrolo [2, 1-f ] [1, 2, 4] triazin-2-yl ] thio ] methyl ] benzoic acid (7g)
A100 mL eggplant type bottle was charged with 6g (500mg, 1.11mmol) of the compound obtained by the above preparation and sodium hydroxide (89mg, 2.22mmol), and water (20mL) and ethanol (40mL) were added, followed by refluxing for 10 hours and TLC to complete the reaction. And (3) evaporating the solvent under reduced pressure, adding water (30mL), adjusting the pH to 6-7 with a glacial acetic acid solution under ice bath, freezing and standing for 2h in a refrigerator, performing suction filtration, and performing vacuum drying on a filter cake to obtain a white solid 383mg, wherein the yield is as follows: 81.71 percent. mp: 185-187 deg.C; ESI-MS m/z: 421.1[ M + H]+；1H-NMR(300MHz，DMSO-d6)δ(ppm)：13.00(br.s，1H)，8.89(t，J＝5.7Hz，1H)，7.81(d，J＝8.2Hz，2H)，7.57-7.55(m，1H)，7.44(d，J＝8.1Hz，2H)，7.24(d，J＝8.6Hz，2H)，6.90-6.86(m，3H)，6.53(dd，J＝4.3Hz，2.6Hz，1H)，4.63(d，J＝5.7Hz，2H)，4.36(s，2H)，3.71(s，3H).
Step c: preparation of N- (2-aminophenyl) -4- [ [ [4- [ (4-methoxybenzyl) amino ] pyrrolo [2, 1-f ] [1, 2, 4] triazin-2-yl ] thio ] methyl ] benzamide (I-13)
To a 25mL eggplant type bottle were added 7g (150mg, 0.36mmol) of the above-prepared TBTU (126mg, 0.39mmol), N-dimethylformamide (10mL), N-diisopropylethylamine (185mg, 1.43mmol), and the mixture was stirred at room temperature for 1 hour, then o-phenylenediamine (39mg, 0.36mmol) was added, and the mixture was further stirred at room temperature for 8 hours, whereupon completion of the reaction was detected by TLC. To the reaction mixture was added water (80mL), and extracted with ethyl acetate (30mL × 3), the organic layers were combined, washed with saturated brine (50mL), dried over anhydrous sodium sulfate, allowed to stand, filtered, and the solvent was distilled off under reduced pressure, and separated by silica gel column chromatography (petroleum ether: ethyl acetate 1: 1) to obtain 79mg of a white solid, yield: 43.41 percent. mp: 184-186 ℃; ESI-MS m/z: 533.2[ M + Na ]+；1H-NMR(300MHz，DMSO-d6)6(ppm)：9.60(s，1H)，8.87(t，J＝5.8Hz，1H)，7.87(d，J＝8.1Hz，2H)，7.57(dd，J＝2.4Hz，1.6Hz，1H)，7.49(d，J＝8.3Hz，2H)，7.26(d，J＝8.6Hz，2H)，7.15(d，J＝7.1Hz，1H)，6.99-6.93(m，1H)，6.90-6.87(m，3H)，6.78-6.75(m，1H)，6.61-6.53(m，2H)，4.89(s，2H)，4.64(d，J＝5.7Hz，2H)，4.38(s，2H)，3.71(s，3H).
Example 14
N- (2-amino-4-fluorophenyl) -4- [ [ [4- [ (4-methoxybenzyl) amino ] pyrrolo [2, 1-f ] [1, 2, 4] triazin-2-yl ] thio ] methyl ] benzamide (I-14)
Figure BSA0000172130500000241
A, step a: preparation of N- (2-amino-4-fluorophenyl) -4- [ [ [4- [ (4-methoxybenzyl) amino ] pyrrolo [2, 1-f ] [1, 2, 4] triazin-2-yl ] thio ] methyl ] benzamide (I-14)
To a 25mL eggplant type bottle were added 7g (150mg, 0.36mmol) of the above-prepared TBTU (126mg, 0.39mmol), N-dimethylformamide (10mL), N-diisopropylethylamine (185mg, 1.43mmol), and the mixture was stirred at room temperature for 1 hour, then p-fluorophenyldiamine (45mg, 0.36mmol) was added, and the mixture was further stirred at room temperature for 8 hours, after which the reaction was detected by TLC to be complete. To the reaction mixture was added water (80mL), and extracted with ethyl acetate (30mL × 3), the organic layers were combined, washed with saturated brine (50mL), dried over anhydrous sodium sulfate, allowed to stand, filtered, and the solvent was distilled off under reduced pressure, and separated by silica gel column chromatography (petroleum ether: ethyl acetate 1: 1) to obtain 90mg of a yellow solid, yield: 47.62 percent. mp: 116 ℃ and 118 ℃; ESI-MS m/z: 551.2[ M + Na ]]+；1H-NMR(300MHz，DMSO-d6)δ(ppm)：9.53(s，1H)，8.86(t，J＝5.7Hz，1H)，7.86(d，J＝8.1Hz，2H)，7.58-7.56(m，1H)，7.49(d，J＝8.1Hz，2H)，7.26(d，J＝8.6Hz，2H)，7.11-7.06(m，1H)，6.90-6.87(m，3H)，6.55-6.50(m，2H)，6.38-6.34(m，1H)，5.22(s，2H)，4.64(d，J＝5.7Hz，2H)，4.37(s，2H)，3.71(s，3H).
Example 15
N- (2-aminophenyl) -4- [ [ [4- [ (3, 4-dimethoxybenzyl) amino ] pyrrolo [2, 1-f ] [1, 2, 4] triazin-2-yl ] thio ] methyl ] benzamide (I-15)
Figure BSA0000172130500000251
Step a: preparation of ethyl 4- [ [ [4- [ (3, 4-dimethoxybenzyl) amino ] pyrrolo [2, 1-f ] [1, 2, 4] triazin-2-yl ] thio ] methyl ] benzoate (6h)
5(500mg, 1.44mmol) prepared above was dissolved in N, N-dimethylformamide (20mL), potassium iodide (2.39g, 14.38mmol) was added, and the mixture was stirred at 70 ℃ for 5 minutes. N, N-diisopropylethylamine (929mg, 7.19mmol) and 3, 4-dimethoxybenzylamine (481mg, 2.88mmol) were added and reacted at 80 ℃ for 3h, and the reaction was detected by TLC to be complete. Water (80mL) was added to the reaction mixture, and ethyl acetate was extracted (30mL × 3), and the organic layers were combined, washed with saturated brine (50mL), dried over anhydrous sodium sulfate, left to stand, filtered, and the solvent was distilled off under reduced pressure, and separated by silica gel column chromatography (petroleum ether: ethyl acetate 5: 1) to obtain 637mg of a white solid, yield: 92.59 percent. mp: 149-151 ℃ C; ESI-MS m/z: 501.1[ M + Na ]]+；1H-NMR(300MHz，DMSO-d6)δ(ppm)：8.86(t，J＝5.7Hz，1H)，7.83(d，J＝8.2Hz，2H)，7.56-7.55(m，1H)，7.48(d，J＝8.2Hz，2H)，6.99-6.87(m，3H)，6.83-6.80(m，1H)，6.53(dd，J＝4.3Hz，2.6Hz，1H)，4.62(d，J＝5.6Hz，2H)，4.37(s，2H)，4.28(q，J＝7.1Hz，2H)，3.70(d，J＝2.4Hz，6H)，1.30(t，J＝7.1Hz，3H).
Step b: preparation of 4- [ [ [4- [ (3, 4-dimethoxybenzyl) amino ] pyrrolo [2, 1-f ] [1, 2, 4] triazin-2-yl ] thio ] methyl ] benzoic acid (7h)
A100 mL eggplant-shaped bottle was charged with the compound prepared above for 6h (600mg, 1.25mmol) and sodium hydroxide (100mg, 2.50mmol), water (20mL) and ethanol (40mL) were added, the reaction was refluxed for 10h, and the reaction was checked by TLC to completion. Evaporating under reduced pressure to remove solvent, adding water (30mL), adjusting pH to 6-7 with glacial acetic acid solution in ice bath, freezing and standing in refrigerator for 2 hr, vacuum filtering, vacuum drying filter cake to obtain white solid 453mg, Yield: 81.71 percent. mp: 111-113 ℃; ESI-MS m/z: 473.1[ M + Na ]]+；1H-NMR(300MHz，DMSO-d6)δ(ppm)：9.02(t，J＝5.6Hz，1H)，7.81(d，J＝7.9Hz，2H)，7.55(s，1H)，7.29(d，J＝8.0Hz，2H)，7.02(s，1H)，6.93-6.92(m，1H)，6.90-6.83(m，2H)，6.52(dd，J＝4.0Hz，2.6Hz，1H)，4.62(d，J＝5.5Hz，2H)，4.32(s，2H)，3.70(s，6H).
Step c: preparation of N- (2-aminophenyl) -4- [ [ [4- [ (3, 4-dimethoxybenzyl) amino ] pyrrolo [2, 1-f ] [1, 2, 4] triazin-2-yl ] thio ] methyl ] benzamide (I-15)
To a 25mL eggplant type bottle were added 7h (150mg, 0.33mmol) and TBTU (118mg, 0.37mmol) prepared above, N-dimethylformamide (10mL) was added, N-diisopropylethylamine (172mg, 1.33mmol) was added, and the mixture was stirred at room temperature for 1h, then o-phenylenediamine (36mg, 0.33mmol) was added, and further stirred at room temperature for 4h, after which the reaction was detected by TLC to be complete. To the reaction mixture was added water (80mL), extracted with ethyl acetate (30mL × 3), the organic layers were combined, washed with saturated brine (50mL), dried over anhydrous sodium sulfate, allowed to stand, filtered, and the solvent was distilled off under reduced pressure, and separated by silica gel column chromatography (petroleum ether: ethyl acetate 1: 1) to obtain 115mg of a yellow solid, yield: 63.89 percent. mp: 98-100 ℃; ESI-MS m/z: 563.2[ M + Na ]]+；1H-NMR(300MHz，DMSO-d6)δ(ppm)：9.62(s，1H)，8.86(t，J＝5.5Hz，1H)，7.86(d，J＝8.1Hz，2H)，7.58-7.56(m，1H)，7.50(d，J＝8.1Hz，2H)，7.15(d，J＝7.7Hz，1H)，7.02-6.78(m，6H)，6.61(m，1H)，6.54(dd，J＝4.3Hz，2.6Hz，1H)，5.10(br.s，2H)，4.63(d，J＝5.5Hz，2H)，4.38(s，2H)，3.71(d，J＝2.6Hz，6H).
Example 16
N- (2-amino-4-fluorophenyl) -4- [ [ [4- [ (3, 4-dimethoxybenzyl) amino ] pyrrolo [2, 1-f ] [1, 2, 4] triazin-2-yl ] thio ] methyl ] benzamide (I-16)
Figure BSA0000172130500000271
Step a: preparation of N- (2-amino-4-fluorophenyl) -4- [ [ [4- [ (3, 4-dimethoxybenzyl) amino ] pyrrolo [2, 1-f ] [1, 2, 4] triazin-2-yl ] thio ] methyl ] benzamide (I-16)
To a 25mL eggplant type bottle were added 7h (200mg, 0.44mmol) and TBTU (157mg, 0.49mmol) prepared above, N-dimethylformamide (10mL) was added, N-diisopropylethylamine (230mg, 1.78mmol) was added, and the mixture was stirred at room temperature for 1h, then p-fluorophenyldiamine (56mg, 0.44mmol) was added, and after stirring at room temperature for 4h, the reaction was completed by TLC. To the reaction mixture was added water (80mL), and extracted with ethyl acetate (30mL × 3), the organic layers were combined, washed with saturated brine (50mL), dried over anhydrous sodium sulfate, allowed to stand, filtered, and the solvent was distilled off under reduced pressure, and separated by silica gel column chromatography (petroleum ether: ethyl acetate 1: 1) to obtain 85mg of a yellow solid, yield: 34.27 percent. mp: 118 ℃ and 120 ℃; ESI-MS m/z: 581.2[ M + Na ]]+；1H-NMR(300MHz，DMSO-d6)δ(ppm)：9.52(s，1H)，8.85(t，J＝5.6Hz，1H)，7.86(d，J＝8.1Hz，2H)，7.58-7.56(m，1H)，7.49(d，J＝8.1Hz，2H)，7.10(m，1H)，7.02-7.01(m，1H)，6.91-6.83(m，3H)，6.54-6.50(m，2H)，6.38-6.32(m，1H)，5.22(s，2H)，4.63(d，J＝5.6Hz，2H)，4.38(s，2H)，3.71(d，J＝2.2Hz，6H).
Example 17
Preparation of N- (2-aminophenyl) -4- [ [ [4- [ (2, 4-dimethoxybenzyl) amino ] pyrrolo [2, 1-f ] [1, 2, 4] triazin-2-yl ] thio ] methyl ] benzamide (I-17)
Figure BSA0000172130500000272
Step a: preparation of ethyl 4- [ [ [4- [ (2, 4-dimethoxybenzyl) amino ] pyrrolo [2, 1-f ] [1, 2, 4] triazin-2-yl ] thio ] methyl ] benzoate (6i)
5(300mg, 0.86mmol) prepared above was dissolved in N, N-dimethylformamide (15mL), potassium iodide (1.43g, 8.63mmol) was added, and the mixture was stirred at 70 ℃ for 5 minutes. N, N-diisopropylethylamine (557mg, 4.31mmol) and 2, 4-dimethoxybenzylamine (288mg, 1.73mmol) were added and reacted at 80 ℃ for 3h with TLC detection complete. Adding water into the reaction solution (80mL), extracted with ethyl acetate (30mL × 3), the organic layers were combined, washed with saturated brine (50mL), dried over anhydrous sodium sulfate, left to stand, filtered, the solvent was evaporated under reduced pressure, and separated by silica gel column chromatography (petroleum ether: ethyl acetate 5: 1) to obtain 341mg of a white solid, yield: 82.61 percent. mp: 84-86 ℃; ESI-MS m/z: 501.1[ M + Na ]]+；1H-NMR(300MHz，DMSO-d6)δ(ppm)：8.71(t，J＝5.5Hz，1H)，7.80(d，J＝8.2Hz，2H)，7.55-7.54(m，1H)，7.45(d，J＝8.2Hz，2H)，7.07(d，J＝8.3Hz，1H)，6.94(dd，J＝4.3Hz，1.4Hz，1H)，6.56-6.53(m，2H)，6.49-6.45(m，1H)，4.59(d，J＝5.6Hz，2H)，4.34(s，2H)，4.28(q，J＝7.1Hz，2H)，3.79(s，3H)，3.73(s，3H)，1.30(t，J＝7.1Hz，3H).
Step b: preparation of 4- [ [ [4- [ (2, 4-dimethoxybenzyl) amino ] pyrrolo [2, 1-f ] [1, 2, 4] triazin-2-yl ] thio ] methyl ] benzoic acid (7i)
To a 100mL eggplant-shaped bottle were added the compound 6i (335mg, 0.70mmol) obtained by the above preparation and sodium hydroxide (56mg, 1.40mmol), and water (15mL) and ethanol (30mL) were added, followed by refluxing for 10 hours and completion of the reaction by TLC. And (3) evaporating the solvent under reduced pressure, adding water (30mL), adjusting the pH to 6-7 with a glacial acetic acid solution in an ice bath, freezing and standing for 2h in a refrigerator, performing suction filtration, and performing vacuum drying on a filter cake to obtain a white solid 260mg and yield: 82.45 percent. mp: 93-95 ℃; ESI-MS m/z: 451.1[ M + H]+；1H-NMR(300MHz，DMSO-d6)δ(ppm)：12.91(br.s，1H)，8.72(t，J＝5.6Hz，1H)，7.80(d，J＝8.2Hz，2H)，7.56-7.55(m，1H)，7.43(d，J＝8.2Hz，2H)，7.08(d，J＝8.3Hz，1H)，6.94(dd，J＝4.3Hz，1.4Hz，1H)，6.57-6.52(m，2H)，6.49-6.45(m，1H)，4.59(d，J＝5.6Hz，2H)，4.34(s，2H)，3.79(s，3H)，3.73(s，3H).
Step c: preparation of N- (2-aminophenyl) -4- [ [ [4- [ (2, 4-dimethoxybenzyl) amino ] pyrrolo [2, 1-f ] [1, 2, 4] triazin-2-yl ] thio ] methyl ] benzamide (I-17)
To a 25mL eggplant type bottle were added 9i (120mg, 0.27mmol) prepared above and TBTU (94mg, 0.29mmol), N-dimethylformamide (10mL) was added, N-diisopropylethylamine (137mg, 1.06mmol) and stirred at normal temperature for 1h, then o-phenylenediamine (29mg, 0.27mmol) is added, and the mixture is stirred at normal temperature for 5h, then the TLC detection reaction is complete. To the reaction mixture was added water (80mL), and extracted with ethyl acetate (30mL × 3), the organic layers were combined, washed with saturated brine (50mL), dried over anhydrous sodium sulfate, allowed to stand, filtered, and the solvent was distilled off under reduced pressure, and separated by silica gel column chromatography (petroleum ether: ethyl acetate 1: 1) to obtain 71mg of a white solid, yield: 49.31 percent. mp: 177-179 ℃ C; ESI-MS m/z: 539.2[ M-H]-；1H-NMR(300MHz，DMSO-d6)δ(ppm)：9.60(s，1H)，8.71(t，J＝5.5Hz，1H)，7.85(d，J＝8.1Hz，2H)，7.57-7.55(m，1H)，7.47(d，J＝8.2Hz，2H)，7.15-7.09(m，2H)，6.99-6.94(m，2H)，6.76(m，1H)，6.61-6.52(m，3H)，6.48(dd，J＝8.3Hz，2.3Hz，1H)，4.89(s，2H)，4.60(d，J＝5.5Hz，2H)，4.36(s，2H)，3.80(s，3H)，3.73(s，3H).
Example 18
N- (2-amino-4-fluorophenyl) -4- [ [ [4- [ (2, 4-dimethoxybenzyl) amino ] pyrrolo [2, 1-f ] [1, 2, 4] triazin-2-yl ] thio ] methyl ] benzamide (I-18)
Figure BSA0000172130500000291
Step a: preparation of N- (2-amino-4-fluorophenyl) -4- [ [ [4- [ (2, 4-dimethoxybenzyl) amino ] pyrrolo [2, 1-f ] [1, 2, 4] triazin-2-yl ] thio ] methyl ] benzamide (I-18)
A25 mL eggplant type bottle was charged with 9i (120mg, 0.27mmol) and TBTU (94mg, 0.29mmol) prepared as described above, N-dimethylformamide (10mL) was added, N-diisopropylethylamine (137mg, 1.06mmol) was further added, and the mixture was stirred at room temperature for 1 hour, p-fluorophenyldiamine (34mg, 0.27mmol) was further added, and after stirring at room temperature for 5 hours, the reaction was completed by TLC. To the reaction mixture was added water (80mL), and extracted with ethyl acetate (30mL × 3), the organic layers were combined, washed with saturated brine (50mL), dried over anhydrous sodium sulfate, allowed to stand, filtered, and the solvent was distilled off under reduced pressure, and separated by silica gel column chromatography (petroleum ether: ethyl acetate 1: 1) to obtain 65mg of a white solid, yield: 43.62 percent. mp: 182 ℃ and 184 ℃; ESI-MS m- z：581.2[M+Na]+；1H-NMR(300MHz，DMSO-d6)δ(ppm)：9.52(s，1H)，8.69(t，J＝5.4Hz，1H)，7.85(d，J＝8.0Hz，2H)，7.57-7.55(m，1H)，7.47(d，J＝8.1Hz，2H)，7.11(d，J＝8.4Hz，2H)，6.94-6.93(m，1H)，6.57-6.47(m，4H)，6.38-6.34(m，1H)，5.22(s，2H)，4.60(d，J＝5.4Hz，2H)，4.35(s，2H)，3.80(s，3H)，3.73(s，3H).
Example 19
N- (2-aminophenyl) -4- [ [ [4- [ (3-methylpyridin-2-yl) amino ] pyrrolo [2, 1-f ] [1, 2, 4] triazin-2-yl ] thio ] methyl ] benzamide (I-19)
Figure BSA0000172130500000301
A, step a: preparation of ethyl 4- [ [ [4- [ (3-methylpyridin-2-yl) amino ] pyrrolo [2, 1-f ] [1, 2, 4] triazin-2-yl ] thio ] methyl ] benzoate (6j)
5(500mg, 1.44mmol) prepared above was dissolved in N, N-dimethylformamide (20mL), potassium iodide (2.39g, 14.38mmol) was added, and the mixture was stirred at 70 ℃ for 5 minutes. N, N-diisopropylethylamine (929mg, 7.19mmol) and 2-amino-3-methylpyridine (311mg, 2.88mmol) were added and reacted at 80 ℃ for 12h with TLC detection complete. To the reaction mixture was added water (80mL), and extracted with ethyl acetate (30mL × 3), the organic layers were combined, washed with saturated brine (50mL), dried over anhydrous sodium sulfate, allowed to stand, filtered, and the solvent was distilled off under reduced pressure, and separated by silica gel column chromatography (petroleum ether: ethyl acetate 5: 1) to obtain 491mg of a white solid, yield: 81.42 percent. mp: 87-89 deg.C; ESI-MS m/z: 442.2[ M + Na ]]+；1H-NMR(300MHz，DMSO-d6)δ(ppm)：10.44(s，1H)，8.39-8.37(m，1H)，7.83-7.78(m，3H)，7.69(s，1H)，7.38-7.32(m，3H)，6.95-6.94(m，1H)，6.65-6.63(m，1H)，4.28(q，2H，J＝7.1Hz，2H)，4.22(s，2H)，1.29(t，J＝7.1Hz，3H)，2.18(s，3H).
Step b: preparation of 4- [ [ [4- [ (3-methylpyridin-2-yl) amino ] pyrrolo [2, 1-f ] [1, 2, 4] triazin-2-yl ] thio ] methyl ] benzoic acid (7j)
To a 100mL eggplant type bottle, compound 6j (491mg, 1.17mmol) obtained by the above preparation and sodium hydroxide (94mg, 2.34mmol) were added, and water (20mL) and ethanol (40mL) were added, followed by refluxing for 10 hours and completion of the reaction by TLC. The solvent was evaporated under reduced pressure, water (30mL) was added, the pH was adjusted to 6-7 with glacial acetic acid solution in ice bath, frozen and left to stand in refrigerator for 2h, filtered, and the filter cake was vacuum dried to obtain 420mg of white solid with a yield of 91.67%. mp: 240 ℃ and 242 ℃; ESI-MS m/z: 390.1[ M-H ]-；1H-NMR(300MHz，DMSO-d6)δ(ppm)：12.91(br.s，1H)，10.51(s，1H)，8.38-8.37(m，1H)，7.80-7.73(m，3H)，7.69(s，1H)，7.34-7.30(m，1H)，7.16(d，J＝8.0Hz，2H)，6.96-6.95(m，1H)，6.64-6.62(m，1H)，4.17(s，2H)，2.19(s，3H).
Step c: preparation of N- (2-aminophenyl) -4- [ [ [4- [ (3-methylpyridin-2-yl) amino ] pyrrolo [2, 1-f ] [1, 2, 4] triazin-2-yl ] thio ] methyl ] benzamide (I-19)
A25 mL eggplant-shaped bottle was charged with 7j (200mg, 0.51mmol) and TBTU (180mg, 0.56mmol) obtained in the above preparation, N-dimethylformamide (10mL) was added, N-diisopropylethylamine (264mg, 2.04mmol) was further added, and after stirring at room temperature for 1 hour, o-phenylenediamine (55mg, 0.51mmol) was further added, and further stirring at room temperature for 8 hours, the reaction was detected by TLC to be complete. To the reaction mixture was added water (80mL), and extracted with ethyl acetate (30mL × 3), the organic layers were combined, washed with saturated brine (50mL), dried over anhydrous sodium sulfate, allowed to stand, filtered, and the solvent was distilled off under reduced pressure, and separated by silica gel column chromatography (petroleum ether: ethyl acetate 1: 1) to obtain 146mg of a white solid, yield: 59.35 percent. mp: 165-167 ℃; ESI-MS m/z: 504.2[ M + Na]+；1H-NMR(300MHz，DMSO-d6)δ(ppm)：10.46(s，1H)，9.60(s，1H)，8.40-8.37(m，1H)，7.85-7.80(m，3H)，7.71(s，1H)，7.36-7.34(m，3H)，7.14-7.12(m，1H)，6.98-6.94(m，2H)，6.77-6.75(m，1H)，6.66-6.63(m，1H)，6.58(m，1H)，4.89(s，2H)，4.23(s，2H)，2.21(s，3H).
Example 20
N- (2-amino-4-fluorophenyl) -4- [ [ [4- [ (3-methylpyridin-2-yl) amino ] pyrrolo [2, 1-f ] [1, 2, 4] triazin-2-yl ] thio ] methyl ] benzamide (I-20)
Figure BSA0000172130500000311
Step a: preparation of N- (2-amino-4-fluorophenyl) -4- [ [ [4- [ (3-methylpyridin-2-yl) amino ] pyrrolo [2, 1-f ] [1, 2, 4] triazin-2-yl ] thio ] methyl ] benzamide (I-20)
To a 25mL eggplant-shaped flask were added 7j (200mg, 0.51mmol) obtained by the above preparation and TBTU (180mg, 0.56mmol), N-dimethylformamide (10mL) and N, N-diisopropylethylamine (264mg, 2.04mmol) were added, and the mixture was stirred at normal temperature for 1 hour, then p-fluorophenyldiamine (64mg, 0.51mmol) was added, and after stirring at normal temperature for 8 hours, the reaction was completed by TLC. To the reaction mixture was added water (80mL), and extracted with ethyl acetate (30mL × 3), the organic layers were combined, washed with saturated brine (50mL), dried over anhydrous sodium sulfate, allowed to stand, filtered, and the solvent was distilled off under reduced pressure, and separated by silica gel column chromatography (petroleum ether: ethyl acetate 1: 1) to obtain 74mg of a white solid, yield: 29.02 percent. mp: 212-214 ℃; ESI-MS m/z: 522.2[ M + Na ]]+；1H-NMR(300MHz，DMSO-d6)δ(ppm)：10.46(s，1H)，9.53(s，1H)，8.40-8.39(m，1H)，7.85-7.80(m，3H)，7.70(s，1H)，7.35-7.33(m，3H)，7.10-7.05(m，1H)，6.96-6.95(m，1H)，6.65-6.63(m，1H)，6.54-6.49(dd，J＝11.3Hz，2.7Hz，1H)，6.37-6.30(td，J＝8.6Hz，2.7Hz，1H)，5.22(s，2H)，4.22(s，2H)，2.21(s，3H).
Example 21
N- (2-aminophenyl) -4- [ [ [4- [ (N-Boc-piperidin-4-yl) amino ] pyrrolo [2, 1-f ] [1, 2, 4] triazin-2-yl ] thio ] methyl ] benzamide (I-21)
Figure BSA0000172130500000321
Step a: preparation of ethyl 4- [ [ [4- [ (N-Boc piperidin-4-yl) amino ] pyrrolo [2, 1-f ] [1, 2, 4] triazin-2-yl ] thio ] methyl ] benzoate (6k)
5(2g, 5.75mmol) prepared above was dissolved in N, N-dimethylformamide (50mL), and iodine was addedPotassium chloride (9.55g, 57.50mmol) was stirred at 70 ℃ for 5 minutes. N, N-diisopropylethylamine (3.72g, 28.75mmol) and 1-Boc-4-aminopiperidine (2.30g, 11.50mmol) were added, and the mixture was reacted at 80 ℃ for 10 hours, followed by completion of the reaction by TLC. Water (200mL) was added to the reaction mixture, and ethyl acetate was extracted (80mL × 3), and the organic layers were combined, washed with saturated brine (100mL), dried over anhydrous sodium sulfate, left to stand, filtered, and the solvent was evaporated under reduced pressure, and separated by silica gel column chromatography (petroleum ether: ethyl acetate: 5: 1) to obtain a yellow-green solid 1.83g, yield: 62.20 percent. mp: 220 ℃ and 222 ℃; ESI-MS m/z: 510.2[ M-H ]-；1H-NMR(300MHz，DMSO-d6)δ(ppm)：8.11(d，J＝7.9Hz，1H)，7.89(d，J＝8.2Hz，2H)，7.59(d，J＝8.2Hz，2H)，7.55(s，1H)，6.86(dd，J＝4.3Hz，1.3Hz，1H)，6.52(dd，J＝4.2Hz，2.6Hz，1H)，4.39(s，2H)，4.27(q，J＝7.1Hz，2H)，4.24-4.16(m，1H)，3.94(d，J＝12.0Hz，2H)，2.83(s，2H)，1.80(d，J＝12.0Hz，2H)，1.41(s，9H)，1.38(s，2H)，1.30(t，3H).
Step b: preparation of 4- [ [ [4- [ (N-Boc piperidin-4-yl) amino ] pyrrolo [2, 1-f ] [1, 2, 4] triazin-2-yl ] thio ] methyl ] benzoic acid (7k)
To a 100mL eggplant-shaped bottle, compound 6k (300mg, 0.59mmol) obtained by the above preparation and sodium hydroxide (47mg, 1.17mmol) were added, and water (20mL) and ethanol (40mL) were added, followed by refluxing for 10 hours and completion of the reaction by TLC. And (3) evaporating the solvent under reduced pressure, adding water (30mL), adjusting the pH to 6-7 with a glacial acetic acid solution under ice bath, freezing and standing for 2h in a refrigerator, performing suction filtration, and performing vacuum drying on a filter cake to obtain a white solid 204mg, wherein the yield is as follows: 71.94 percent. This was repeated several times to obtain about 1.10g of a white solid. mp: 218 ℃ and 220 ℃; ESI-MS m/z: 482.2[ M-H ]]-；1H-NMR(300MHz，DMSO-d6)δ(ppm)：12.88(br.s，1H)，8.11(d，J＝7.8Hz，1H)，7.87(d，J＝8.2Hz，2H)，7.58-7.55(m，3H)，6.86(dd，J＝4.2Hz，1.3Hz，1H)，6.52(dd，J＝4.2Hz，2.6Hz，1H)，4.39(s，2H)，4.23-4.20(m，1H)，3.94(d，J＝10.7Hz，2H)，2.83(s，2H)，1.81(d，J＝10.8Hz，2H)，1.41(s，11H).
Step c: preparation of N- (2-aminophenyl) -4- [ [ [4- [ (N-Boc-piperidin-4-yl) amino ] pyrrolo [2, 1-f ] [1, 2, 4] triazin-2-yl ] thio ] methyl ] benzamide (I-21)
To a 25mL eggplant-type bottle were added 7k (500mg, 1.03mmol) and TBTU (124mg, 1.14mmol) prepared as described above, N-dimethylformamide (30mL) was added, N-diisopropylethylamine (534mg, 4.14mmol) was added, stirring was carried out at normal temperature for 1 hour, o-phenylenediamine (124mg, 1.14mmol) was added, stirring was carried out at normal temperature for 8 hours, and then the reaction completion was detected by TLC. Water (160mL) was added to the reaction mixture, and ethyl acetate was extracted (60mL × 3), and the organic layers were combined, washed with saturated brine (100mL), dried over anhydrous sodium sulfate, left to stand, filtered, and the solvent was evaporated under reduced pressure, and separated by silica gel column chromatography (petroleum ether: ethyl acetate 1: 1) to obtain 414mg of a white solid, yield: 69.79 percent. mp: 116 ℃ and 118 ℃; ESI-MS m/z: 596.2[ M + Na ]+；1H-NMR(300MHz，DMSO-d6)δ(ppm)：9.63(s，1H)，8.11(d，J＝8.0Hz，1H)，7.91(d，J＝8.0Hz，2H)，7.59-7.56(m，3H)，7.14(d，J＝7.5Hz，1H)，6.99-6.94(m，1H)，6.87-6.86(m，1H)，6.78(d，J＝7.5Hz，1H)，6.62-6.57(m，1H)，6.63(dd，J＝4.1Hz，2.6Hz，1H)，5.00(s，2H)，4.39(s，2H)，4.30-4.20(m，1H)，3.99-3.95(m，2H)，2.89(s，2H)，1.86-1.83(m，2H)，1.41(m，11H).
Example 22
N- (2-amino-4-fluorophenyl) -4- [ [ [4- [ (N-Boc piperidin-4-yl) amino ] pyrrolo [2, 1-f ] [1, 2, 4] triazin-2-yl ] thio ] methyl ] benzamide (I-22)
Figure BSA0000172130500000331
Step a: preparation of N- (2-amino-4-fluorophenyl) -4- [ [ [4- [ (N-Boc piperidin-4-yl) amino ] pyrrolo [2, 1-f ] [1, 2, 4] triazin-2-yl ] thio ] methyl ] benzamide (I-22)
To a 25mL eggplant type bottle were added 7k (500mg, 1.03mmol) and TBTU (124mg, 1.14mmol) obtained in the above preparation, N-dimethylformamide (30mL) and N, N-diisopropylethylamine (534mg, 4.14mmol) were added, and the mixture was stirred at room temperature for 1 hour, then p-fluorophenyldiamine (144mg, 1.14mmol) was added, and after stirring at room temperature for 8 hours, the reaction was completed by TLC.To the reaction mixture was added water (160mL), extracted with ethyl acetate (60mL × 3), the organic layers were combined, washed with saturated brine (100mL), dried over anhydrous sodium sulfate, left to stand, filtered, and the solvent was distilled off under reduced pressure, and separated by silica gel column chromatography (petroleum ether: ethyl acetate: 1) to give 386mg of a white solid, yield: 63.09%. mp: 159-161 ℃ C; ESI-MS m/z: 614.2[ M + Na ]]+；1H-NMR(300MHz，DMSO-d6)δ(ppm)：9.54(s，1H)，8.11(d，J＝8.0Hz，1H)，7.91(d，J＝8.1Hz，2H)，7.58-7.56(m，3H)，7.11-7.06(m，1H)，6.87-6.86(m，1H)，6.55-6.50(m，2H)，6.38-6.32(m，1H)，5.21(br.s，2H)，4.39(s，2H)，4.27-4.25(m，1H)，3.97(m，2H)，2.89(s，2H)，1.86-1.83(m，2H)，1.41(s，11H).
Example 23
N- (2-aminophenyl) -4- [ [ [4- [ (piperidin-4-yl) amino ] pyrrolo [2, 1-f ] [1, 2, 4] triazin-2-yl ] thio ] methyl ] benzamide (I-23)
Figure BSA0000172130500000341
Step a: preparation of N- (2-aminophenyl) -4- [ [ [4- [ (piperidin-4-yl) amino ] pyrrolo [2, 1-f ] [1, 2, 4] triazin-2-yl ] thio ] methyl ] benzamide (I-23)
A25 mL eggplant-shaped bottle was charged with I-21(250mg, 0.44mmol) prepared above, dissolved in dichloromethane (2mL), added with trifluoroacetic acid (1mL), stirred at room temperature for 3h, and then checked for completion by TLC. The solvent was distilled off under reduced pressure, and the residue was separated by silica gel column chromatography (dichloromethane: methanol 10: 1) to obtain 168mg of a yellow solid, yield: 81.41 percent. mp: 88 to 90 ℃; ESI-MS m/z: 474.2[ M + H]+；1H-NMR(300MHz，DMSO-d6)δ(ppm)：9.64(s，1H)，8.27(d，J＝7.8Hz，1H)，7.91(d，J＝8.0Hz，2H)，7.58-7.55(m，3H)，7.15(d，J＝7.6Hz，1H)，6.98-6.95(m，1H)，6.91(m，1H)，6.79(d，J＝8.0Hz，1H)，6.56(m，1H)，6.55-6.54(m，1H)，5.00(s，2H)，4.40(s，2H)，4.34-4.32(m，1H)，3.43-3.33(m，2H)，3.17-3.05(m，2H)，2.06-1.99(m，2H)，1.73-1.66(m，2H).
Example 24
N- (2-amino-4-fluorophenyl) -4- [ [ [4- [ (piperidin-4-yl) amino ] pyrrolo [2, 1-f ] [1, 2, 4] triazin-2-yl ] thio ] methyl ] benzamide (I-24)
Figure BSA0000172130500000342
Step a: preparation of N- (2-amino-4-fluorophenyl) -4- [ [ [4- [ (piperidin-4-yl) amino ] pyrrolo [2, 1-f ] [1, 2, 4] triazin-2-yl ] thio ] methyl ] benzamide (I-24)
A25 mL eggplant-shaped bottle was charged with I-22(250mg, 0.42mmol) prepared above, dissolved in dichloromethane (2mL), added with trifluoroacetic acid (1mL), stirred at room temperature for 3 hours, and then checked for completion by TLC. The solvent was distilled off under reduced pressure, and the residue was separated by silica gel column chromatography (dichloromethane: methanol 10: 1) to obtain 78mg of a white solid, yield: 37.55 percent. mp: 225 ℃ and 227 ℃; ESI-MS m/z: 492.2[ M + H ]+；1H-NMR(300MHz，DMSO-d6)δ(ppm)：9.55(s，1H)，8.29(d，J＝7.4Hz，1H)，7.91(d，J＝8.0Hz，2H)，7.58-7.55(m，3H)，7.11-7.06(m，1H)，6.93(dd，J＝4.3Hz，1.2Hz，1H)，6.55-6.50(m，2H)，6.37-6.34(m，1H)，5.22(s，2H)，4.40(s，2H)，4.33-4.31(m，1H)，3.35-3.33(m，2H)，3.09-3.01(m，2H)，2.04-2.01(m，2H)，1.79-1.67(m，2H).
Example 25
N-hydroxy-4- [ [ [4- [ (5-methyl-1H-pyrazol-3-yl) amino ] pyrrolo [2, 1-f ] [1, 2, 4] triazin-2-yl ] thio ] methyl ] benzamide (I-25)
Figure BSA0000172130500000351
A, step a: preparation of N-hydroxy-4- [ [ [4- [ (5-methyl-1H-pyrazol-3-yl) amino ] pyrrolo [2, 1-f ] [1, 2, 4] triazin-2-yl ] thio ] methyl ] benzamide (I-25)
Add 7a (100mg, 0.26mmol) prepared above and anhydrous THF (10mL) to a 25mL eggplant type flask, cool to-5 deg.C, add ethyl chloroformate (35mg, 0.32mmol) and trisEthylamine (0.045mL, 0.32mmol) was stirred at room temperature for 30min, and the precipitated solid was filtered off. The mother liquor was further charged with freshly prepared hydroxylamine methanol solution (10mg/mL) (3 mL). After stirring the reaction mixture at room temperature for 1 hour, the solvent was distilled off under reduced pressure, and the residue was separated by silica gel column chromatography (dichloromethane: methanol 40: 1) to obtain 45mg of a white solid, yield: 43.7 percent. mp: 175-176 ℃; ESI-MS m/z: 396.3[ M + H]+；1H-NMR(300MHz，DMSO-d6)δ(ppm)：12.26(br.s，1H)，11.12(s，1H)，10.63(s，1H)，10.57(s，1H)，7.91(d，J＝8.1Hz，2H)，7.68-7.67(m，1H)，7.58(d，J＝8.1Hz，2H)，7.22(s，1H)，6.94-6.77(m，1H)，6.48(s，1H)，4.43(s，2H)，2.24(s，3H).
Example 26
N- (2-amino-4-chlorophenyl) -4- [ [ [4- [ (5-methyl-1H-pyrazol-3-yl) amino ] pyrrolo [2, 1-f ] [1, 2, 4] triazin-2-yl ] thio ] methyl ] benzamide (I-26)
Figure BSA0000172130500000352
Step a: preparation of N- (2-amino-4-chlorophenyl) -4- [ [ [4- [ (5-methyl-1H-pyrazol-3-yl) amino ] pyrrolo [2, 1-f ] [1, 2, 4] triazin-2-yl ] thio ] methyl ] benzamide (I-26)
A25 mL eggplant type bottle was charged with 7a (150mg, 0.39mmol) and TBTU (140mg, 0.43mmol) prepared as described above, N-dimethylformamide (10mL) was added, N-diisopropylethylamine (204mg, 1.58mmol) was further added, and the mixture was stirred at room temperature for 1 hour, then p-chlorophthalimide (62mg, 0.43mmol) was added, and after stirring at room temperature for 4 hours, the reaction was completed by TLC. To the reaction mixture was added water (80mL), and extracted with ethyl acetate (30mL × 3), the organic layers were combined, washed with saturated brine (50mL), dried over anhydrous sodium sulfate, allowed to stand, filtered, and the solvent was distilled off under reduced pressure, and separated by silica gel column chromatography (petroleum ether: ethyl acetate 1: 1) to obtain 45mg of a white solid, yield: 22.60 percent. mp: 161-163 ℃; ESI-MS m/z: 506.2[ M + H]+；1H-NMR(300MHz，DMSO-d6)δ(ppm)：12.24(br.s，1H)，10.64(s，1H)，9.54(s，1H)，7.90(d，J＝8.2Hz，2H)，7.65-7.62(m，1H)，7.57(d，J＝8.2Hz，2H)，7.20(s，1H)，7.10-7.06(m，1H)，6.61(dd，J＝4.2Hz，2.6Hz，1H)，6.54-6.49(m，2H)，6.37-6.31(m，1H)，5.23(s，2H)，4.42(s，2H)，2.24(s，3H).
Example 27
N- (2-amino-4-methylphenyl) -4- [ [ [4- [ (5-methyl-1H-pyrazol-3-yl) amino ] pyrrolo [2, 1-f ] [1, 2, 4] triazin-2-yl ] thio ] methyl ] benzamide (I-27)
Figure BSA0000172130500000361
Step a: preparation of N- (2-amino-4-methylphenyl) -4- [ [ [4- [ (5-methyl-1H-pyrazol-3-yl) amino ] pyrrolo [2, 1-f ] [1, 2, 4] triazin-2-yl ] thio ] methyl ] benzamide (I-27)
A25 mL eggplant type bottle was charged with 7a (150mg, 0.39mmol) and TBTU (140mg, 0.43mmol) obtained in the above preparation, N-dimethylformamide (10mL) was added, N-diisopropylethylamine (204mg, 1.58mmol) was further added, and the mixture was stirred at room temperature for 1 hour, p-methylphthalenediamine (53mg, 0.43mmol) was further added, and after stirring at room temperature for 4 hours, the reaction was completed by TLC detection. To the reaction mixture was added water (80mL), and extracted with ethyl acetate (30mL × 3), the organic layers were combined, washed with saturated brine (50mL), dried over anhydrous sodium sulfate, allowed to stand, filtered, and the solvent was distilled off under reduced pressure, and separated by silica gel column chromatography (petroleum ether: ethyl acetate 1: 1) to obtain 76mg of a white solid, yield: 39.78 percent. mp: 145-147 ℃; ESI-MS m/z: 485.2[ M + H ]+；1H-NMR(300MHz，DMSO-d6)δ(ppm)：12.20(br.s，1H)，10.62(s，1H)，9.53(s，1H)，7.87(d，J＝8.2Hz，2H)，7.63-7.60(m，1H)，7.50(d，J＝8.2Hz，2H)，7.20(s，1H)，7.10-7.07(m，1H)，6.57(dd，J＝4.2Hz，2.6Hz，1H)，6.52-6.46(m，2H)，6.30-6.27(m，1H)，5.01(s，2H)，4.41(s，2H)，2.24(s，3H)，2.22(s，3H).
Example 28
N- (2-amino-5-cyanophenyl) -4- [ [ [4- [ (5-methyl-1H-pyrazol-3-yl) amino ] pyrrolo [2, 1-f ] [1, 2, 4] triazin-2-yl ] thio ] methyl ] benzamide (I-28)
Figure BSA0000172130500000371
Step a: preparation of N- (2-amino-5-cyanophenyl) -4- [ [ [4- [ (5-methyl-1H-pyrazol-3-yl) amino ] pyrrolo [2, 1-f ] [1, 2, 4] triazin-2-yl ] thio ] methyl ] benzamide (I-28)
A25 mL eggplant type bottle was charged with 7a (150mg, 0.39mmol) and TBTU (140mg, 0.43mmol) obtained in the above preparation, N-dimethylformamide (10mL) was added, N-diisopropylethylamine (204mg, 1.58mmol) was further added, and the mixture was stirred at room temperature for 1 hour, p-methylphthalenediamine (58mg, 0.43mmol) was further added, and after stirring at room temperature for 4 hours, the reaction was completed by TLC detection. To the reaction mixture was added water (80mL), and extracted with ethyl acetate (30mL × 3), the organic layers were combined, washed with saturated brine (50mL), dried over anhydrous sodium sulfate, allowed to stand, filtered, and the solvent was distilled off under reduced pressure, and separated by silica gel column chromatography (petroleum ether: ethyl acetate 1: 1) to obtain 31mg of a white solid, yield: 15.86 percent. mp: 177-179 ℃ C; ESI-MS m/z: 496.2[ M + H]+；1H-NMR(300MHz，DMSO-d6)δ(ppm)：12.25(br.s，1H)，10.66(s，1H)，9.54(s，1H)，7.87(d，J＝8.2Hz，2H)，7.79-7.75(m，2H)，7.55(d，J＝8.2Hz，2H)，7.32-7.25(m，2H)，7.20(s，1H)，7.10-7.07(m，1H)，6.57(dd，J＝4.2Hz，2.6Hz，1H)，5.04(s，2H)，4.42(s，2H)，2.26(s，3H).
Example 29
N- (2-amino-5-phenylphenyl) -4- [ [ [4- [ (5-methyl-1H-pyrazol-3-yl) amino ] pyrrolo [2, 1-f ] [1, 2, 4] triazin-2-yl ] thio ] methyl ] benzamide (I-29)
Figure BSA0000172130500000381
Step a: preparation of N- (2-amino-5-phenylphenyl) -4- [ [ [4- [ (5-methyl-1H-pyrazol-3-yl) amino ] pyrrolo [2, 1-f ] [1, 2, 4] triazin-2-yl ] thio ] methyl ] benzamide (I-29)
To a 25mL eggplant type bottle were added 7a (150mg, 0.39mmol) prepared above, TBTU (14)0mg, 0.43mmol), N-dimethylformamide (10mL), N-diisopropylethylamine (204mg, 1.58mmol), stirring at room temperature for 1h, p-phenylphenylenediamine (80mg, 0.43mmol), stirring at room temperature for 4h, and detecting by TLC to completion of the reaction. To the reaction mixture was added water (80mL), and extracted with ethyl acetate (30mL × 3), the organic layers were combined, washed with saturated brine (50mL), dried over anhydrous sodium sulfate, allowed to stand, filtered, and the solvent was distilled off under reduced pressure, and separated by silica gel column chromatography (petroleum ether: ethyl acetate 1: 1) to obtain 56mg of a white solid, yield: 25.98 percent. mp: 182 ℃ and 184 ℃; ESI-MS m/z: 547.2[ M + H]+；1H-NMR(300MHz，DMSO-d6)δ(ppm)：12.25(br.s，1H)，10.65(s，1H)，9.55(s，1H)，7.86(d，J＝8.2Hz，2H)，7.79-7.74(m，2H)，7.62-7.50(m，7H)，7.31-7.25(m，2H)，7.21(s，1H)，7.10-7.05(m，1H)，6.56(dd，J＝4.2Hz，2.6Hz，1H)，5.04(s，2H)，4.42(s，2H)，2.26(s，3H).
Example 30
N- (2-amino-5- (2-thienyl) phenyl) -4- [ [ [4- [ (5-methyl-1H-pyrazol-3-yl) amino ] pyrrolo [2, 1-f ] [1, 2, 4] triazin-2-yl ] thio ] methyl ] benzamide (I-30)
Figure BSA0000172130500000382
Step a: preparation of N- (2-amino-5- (2-thienyl) phenyl) -4- [ [ [4- [ (5-methyl-1H-pyrazol-3-yl) amino ] pyrrolo [2, 1-f ] [1, 2, 4] triazin-2-yl ] thio ] methyl ] benzamide (I-30)
A25 mL eggplant type bottle was charged with 7a (150mg, 0.39mmol) and TBTU (140mg, 0.43mmol) prepared as described above, N-dimethylformamide (10mL) was added, N-diisopropylethylamine (204mg, 1.58mmol) was further added, and the mixture was stirred at ordinary temperature for 1 hour, and then 2-amino-4- (2-thienyl) aniline (83mg, 0.43mmol) was further added, and after stirring at ordinary temperature for 4 hours, the reaction was completed by TLC. To the reaction mixture was added water (80mL), extracted with ethyl acetate (30mL × 3), the organic layers were combined, washed with saturated brine (50mL), dried over anhydrous sodium sulfate, allowed to stand, filtered, the solvent was evaporated under reduced pressure, and separated by silica gel column chromatography (petroleum ether: ethyl acetate ═ 3)1: 1) to give 63mg of a white solid, yield: 28.91 percent. mp: 189-191 deg.C; ESI-MS m/z: 553.2[ M + H]+；1H-NMR(300MHz，DMSO-d6)δ(ppm)：12.25(br.s，1H)，10.65(s，1H)，9.55(s，1H)，7.86(d，J＝8.2Hz，2H)，7.79-7.70(m，3H)，7.55-7.51(m，2H)，7.35-7.27(m，3H)，7.21(s，1H)，7.16-7.06(m，2H)，6.56(dd，J＝4.2Hz，2.6Hz，1H)，5.04(s，2H)，4.43(s，2H)，2.26(s，3H).
Example 31
N- (2-aminophenyl) -4- [ [ [4- [ (5-methyl-1H-pyrazol-3-yl) amino ] pyrrolo [2, 1-f ] [1, 2, 4] triazin-2-yl ] oxy ] methyl ] benzamide (I-31)
Figure BSA0000172130500000391
Step a: preparation of 2-thiomethyl-4-hydroxypyrrolo [2, 1-f ] [1, 2, 4] triazine (8)
Compound 4(2.38g, 14.25mmol) prepared above was dissolved in methanol (20mL), sodium methoxide (769.06m g, 14.5mmol) and methyl iodide (886.23mml, 14.25mmol) were added in that order and heated to 45 ℃ for 4h, and TLC indicated the completion of the reaction. Washing with water, adjusting pH to neutrality, precipitating solid, filtering, washing with methanol to obtain white solid 1.9g, yield: 79.83 percent. ESI-MS m/z: 180.0[ M-H ]+；1H NMR(300MHz，DMSO-d6)δ(ppm)：12.03(s，1H)，7.53(dd，J＝2.7，1.7Hz，1H)，6.84(dd，J＝4.3，1.7Hz，1H)，6.48(dd，J＝4.3，2.6Hz，1H)，2.53(s，3H).
Step b: preparation of 4-chloro-2-thiomethylpyrrolo [2, 1-f ] [1, 2, 4] triazine (9)
Compound 8(1.9g, 10.49mmol) prepared above was dissolved in phosphorus oxychloride (20mL), heated at reflux for 3h and TLC indicated the reaction was complete. Distilling off most of phosphorus oxychloride under reduced pressure, cooling to room temperature under vacuum, pouring the reaction mixture into ice water (100mL), extracting with ethyl acetate (60 mL. times.3), combining organic layers, washing with saturated saline (60mL), drying with anhydrous sodium sulfate, standing, filtering, distilling off the solvent under reduced pressure, and separating by silica gel column chromatography (petroleum ether: ethyl acetate)Ethyl acetate 5: 1) to give 1.58g of white solid, yield: 83.01 percent. ESI-MS m/z: 199[ M-H ]]+；1H NMR(300MHz，DMSO-d6)δ(ppm)：8.13(s，1H)，7.10-6.94(m，2H)，2.56(d，J＝1.9Hz，3H).
Step c: preparation of 2-thiomethyl-4- [ (5-methyl-1H-pyrazol-3-methyl) amino ] pyrrolo [2, 1-f ] [1, 2, 4] triazine (10)
Compound 9(1.58g, 7.9mmol) prepared above was dissolved in N, N-dimethylformamide (20mL), potassium iodide (1.31g, 79mmol) was added, and the mixture was stirred at 70 ℃ for 5 minutes. N, N-diisopropylethylamine (5.11g, 39.5mmol) and 5-methyl-3-aminopyrazole (845mg, 8.69mmol) were added and reacted at 120 ℃ for 6h with TLC check to completion. To the reaction mixture was added water (80mL), extracted with ethyl acetate (30mL × 3), the organic layers were combined, washed with saturated brine (50mL), dried over anhydrous sodium sulfate, allowed to stand, filtered, and the solvent was distilled off under reduced pressure, and separated by silica gel column chromatography (dichloromethane: methanol ═ 10: 1) to give 758mg of a white solid, yield: 48 percent. ESI-MS m/z: 259[ M-H ]+；1H NMR(300MHz，DMSO-d6)δ(ppm)：12.20(s，1H)，10.56(s，1H)，7.62(dd，J＝2.6，1.6Hz，1H)，7.20(s，1H)，6.65(s，1H)，6.48(s，1H)，2.48(s，3H)，2.33-2.23(s，3H).
Step d: preparation of 2-sulfonemethyl-4- [ (5-methyl-1H-pyrazol-3-methyl) amino ] pyrrolo [2, 1-f ] [1, 2, 4] triazine (11)
Compound 10(758mg, 2.92mmol) prepared above was dissolved in analytically pure dichloromethane (15mL), m-chloroperoxybenzoic acid (1g, 5.84mmol) was added and reacted at normal temperature for 3 hours, then extracted and washed with water and saturated ammonium chloride solution (50mL), dried over anhydrous sodium sulfate and left to stand, filtered, the solvent was evaporated under reduced pressure, and separated by silica gel column chromatography (dichloromethane: methanol ═ 10: 1) to give 646mg of white solid, yield: 85.21 percent. ESI-MS m/z: 291[ M-H ]]+；1H NMR(300MHz，DMSO-d6)δ(ppm)：12.20(s，1H)，10.56(s，1H)，7.27(dd，J＝2.6，1.6Hz，1H)，7.20(s，1H)，6.67(s，1H)，6.11(s，1H)，3.00(s，3H)，2.29(s，3H).
Step e: preparation of methyl 4- (((4- ((5-methyl-1H-pyrazol-3-yl) amino) pyrrolo [2, 1-f ] [1, 2, 4] triazin-2-yl) oxy) methyl) benzoate (12a)
Compound 11(600mg, 2.05mmol) prepared above, methyl 4-hydroxymethylbenzoate (512mg, 3.08mmol), NaH (164mg, 4.11mmol), and dried NMP (10mL) were placed in a sealed tube, reacted at 200 ℃ for 8 hours, a saturated ammonium chloride solution (50mL) was added, extracted with ethyl acetate (30mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate and left to stand, filtered, the solvent was distilled off under reduced pressure, and separated by silica gel column chromatography (dichloromethane: methanol ═ 10: 1) to obtain 320mg of a white solid, yield: 41.20 percent. ESI-MS m/z: 379.2[ M + H ]+.
Step f: preparation of 4- (((4- ((5-methyl-1H-pyrazol-3-yl) amino) pyrrolo [2, 1-f ] [1, 2, 4] triazin-2-yl) oxy) methyl) benzoic acid (13a)
Compound 12a (300mg, 0.79mmol) prepared above and sodium hydroxide (64mg, 1.59mmol) were added to a 25mL eggplant-shaped flask, water (10mL) and ethanol (20mL) were added, and the reaction was carried out at 60 ℃ for 12 hours and checked by TLC to be complete. And (3) evaporating the solvent under reduced pressure, adding water (5mL), adjusting the pH to 6-7 with a glacial acetic acid solution under ice bath, freezing and standing for 2h in a refrigerator, performing suction filtration, and performing vacuum drying on a filter cake to obtain a white solid 250mg, wherein the yield is as follows: 86.54 percent. ESI-MS m/z: 365.2[ M + H ].
Step g: preparation of N- (2-aminophenyl) -4- [ [ [4- [ (5-methyl-1H-pyrazol-3-yl) amino ] pyrrolo [2, 1-f ] [1, 2, 4] triazin-2-yl ] oxy ] methyl ] benzamide (I-31)
To a 25mL eggplant type bottle were added 13a (95mg, 0.26mmol) obtained in the above preparation and TBTU (93mg, 0.29mmol), N-dimethylformamide (10mL) was added, N-diisopropylethylamine (136mg, 1.05mmol) was further added, and the mixture was stirred at room temperature for 1 hour, further o-phenylenediamine (31mg, 0.29mmol) was added, and after stirring at room temperature for 4 hours, the reaction was completed by TLC. To the reaction mixture was added water (80mL), and extracted with ethyl acetate (30mL × 3), the organic layers were combined, washed with saturated brine (50mL), dried over anhydrous sodium sulfate, allowed to stand, filtered, and the solvent was distilled off under reduced pressure, and separated by silica gel column chromatography (petroleum ether: ethyl acetate 1: 1) to obtain 52mg of a white solid, yield: 44.00 percent. mp: 151 ℃ and 153 ℃; ESI-MS m/z: 455.2[ M + H ]+；1H-NMR(300MHz，DMSO-d6)δ(ppm)：12.26(br.s，1H)，10.63(s，1H)，9.65(s，1H)，7.91(d，J＝8.1Hz，2H)，7.68-7.67(m，1H)，7.58(d，J＝8.1Hz，2H)，7.22(s，1H)，7.17-7.14(m，1H)，7.02-6.95(m，1H)，6.80-6.78(m，1H)，6.94-6.59(m，2H)，6.48(s，1H)，5.24(s，2H)，5.10(br.s，2H)，2.24(s，3H).
Example 32
N- (2-aminophenyl) -4- [ [ [4- [ (5-methyl-1H-pyrazol-3-yl) amino ] pyrrolo [2, 1-f ] [1, 2, 4] triazin-2-yl ] amino ] methyl ] benzamide (I-32)
Figure BSA0000172130500000411
Step a: preparation of methyl 4- (((4- ((5-methyl-1H-pyrazol-3-yl) amino) pyrrolo [2, 1-f ] [1, 2, 4] triazin-2-yl) amino) methyl) benzoate (12b)
Compound 11(600mg, 2.05mmol) prepared above, methyl 4-aminomethylbenzoate (510mg, 3.08mmol), NaH (164mg, 4.11mmol), and dried NMP (10mL) were placed in a sealed tube, reacted at 200 ℃ for 8 hours, a saturated ammonium chloride solution (50mL) was added, extracted with ethyl acetate (30mL × 3), the organic fractions were combined, dried over anhydrous sodium sulfate and left to stand, filtered, the solvent was distilled off under reduced pressure, and separated by silica gel column chromatography (dichloromethane: methanol ═ 10: 1) to obtain 303mg of a white solid, yield: 39.11 percent. ESI-MS m/z: 378.2[ M + H]+.
Step b: preparation of 4- (((4- ((5-methyl-1H-pyrazol-3-yl) amino) pyrrolo [2, 1-f ] [1, 2, 4] triazin-2-yl) amino) methyl) benzoic acid (13b)
Compound 12b (300mg, 0.79mmol) prepared above and sodium hydroxide (64mg, 1.59mmol) were added to a 25mL eggplant-shaped flask, water (10mL) and ethanol (20mL) were added, and the reaction was carried out at 60 ℃ for 12 hours and checked by TLC to be complete. And (3) evaporating the solvent under reduced pressure, adding water (5mL), adjusting the pH to 6-7 with a glacial acetic acid solution under ice bath, freezing and standing for 2h in a refrigerator, performing suction filtration, and performing vacuum drying on a filter cake to obtain a white solid 259mg, wherein the yield is as follows: 89.67 percent. ESI-MS m/z: 364.2[ M + H ]+.
Step g: preparation of N- (2-aminophenyl) -4- [ [ [4- [ (5-methyl-1H-pyrazol-3-yl) amino ] pyrrolo [2, 1-f ] [1, 2, 4] triazin-2-yl ] oxy ] methyl ] benzamide (I-32)
To a 25mL eggplant type bottle were added 13b (95mg, 0.26mmol) obtained in the above preparation and TBTU (93mg, 0.29mmol), N-dimethylformamide (10mL) was added, N-diisopropylethylamine (136mg, 1.05mmol) was further added, and the mixture was stirred at room temperature for 1 hour, further o-phenylenediamine (31mg, 0.29mmol) was added, and after stirring at room temperature for 4 hours, the reaction was completed by TLC. To the reaction mixture was added water (80mL), and extracted with ethyl acetate (30mL × 3), the organic layers were combined, washed with saturated brine (50mL), dried over anhydrous sodium sulfate, allowed to stand, filtered, and the solvent was distilled off under reduced pressure, and separated by silica gel column chromatography (petroleum ether: ethyl acetate 1: 1) to obtain a white solid (48 mg, yield: 40.71 percent. mp: 166-169 ℃ of reaction; ESI-MS m/z: 454.2[ M + H]+；1H-NMR(300MHz，DMSO-d6)δ(ppm)：12.26(br.s，1H)，10.63(s，1H)，9.65(s，1H)，7.91(d，J＝8.1Hz，2H)，7.68-7.67(m，1H)，7.58(d，J＝8.1Hz，2H)，7.22(s，1H)，7.17-7.14(m，1H)，7.02-6.95(m，1H)，6.80-6.78(m，1H)，6.94-6.59(m，3H)，6.48(s，1H)，5.12(br.s，2H)，4.65(s，2H)，2.24(s，3H).
Example 33
N- (2-aminophenyl) -4- [ [ [4- [ (5-methyl-1H-pyrazol-3-yl) amino ] pyrrolo [2, 1-f ] [1, 2, 4] triazin-2-yl ] sulfinyl ] methyl ] benzamide (I-33)
Figure BSA0000172130500000421
Step a: preparation of 4- (((4- ((5-methyl-1H-pyrazol-3-yl) amino) pyrrolo [2, 1-f ] [1, 2, 4] triazin-2-yl) sulfinyl) methyl) benzoic acid (14a)
Compound 7a (1.00g, 2.63mmol) prepared above was dissolved in analytically pure dichloromethane (30mL), m-chloroperoxybenzoic acid (0.635g, 3.68mmol) was added to react at room temperature for 3 hours, then extracted and washed with water and a saturated ammonium chloride solution (50mL), dried over anhydrous sodium sulfate and left to stand, filtered, the solvent was distilled off under reduced pressure, and separated by silica gel column chromatography (dichloromethane: methanol ═ 10: 1) to obtain 438mg of a white solid, yield: 42.03 percent. ESI-MSm/z：396.2[M+H]+.
Step b: preparation of N- (2-aminophenyl) -4- [ [ [4- [ (5-methyl-1H-pyrazol-3-yl) amino ] pyrrolo [2, 1-f ] [1, 2, 4] triazin-2-yl ] sulfinyl ] methyl ] benzamide (I-33)
To a 25mL eggplant type bottle were added 14a (103mg, 0.26mmol) obtained in the above preparation and TBTU (93mg, 0.29mmol), N-dimethylformamide (10mL) was added, N-diisopropylethylamine (136mg, 1.05mmol) was further added, and the mixture was stirred at room temperature for 1 hour, further o-phenylenediamine (31mg, 0.29mmol) was added, and after stirring at room temperature for 4 hours, the reaction was completed by TLC. To the reaction mixture was added water (80mL), and extracted with ethyl acetate (30mL × 3), the organic layers were combined, washed with saturated brine (50mL), dried over anhydrous sodium sulfate, allowed to stand, filtered, and the solvent was distilled off under reduced pressure, and separated by silica gel column chromatography (petroleum ether: ethyl acetate 1: 1) to obtain 52mg of a white solid, yield: 41.11 percent. mp: 188-190 ℃; ESI-MS m/z: 487.2[ M + H ]+；1H-NMR(300MHz，DMSO-d6)δ(ppm)：12.26(br.s，1H)，10.63(s，1H)，9.65(s，1H)，7.91(d，J＝8.1Hz，2H)，7.68-7.67(m，1H)，7.58(d，J＝8.1Hz，2H)，7.22(s，1H)，7.17-7.14(m，1H)，7.02-6.95(m，1H)，6.80-6.78(m，1H)，6.94-6.59(m，2H)，6.48(s，1H)，5.12(br.s，2H)，4.07(s，2H)，2.24(s，3H).
Example 34
N- (2-aminophenyl) -4- [ [ [4- [ (5-methyl-1H-pyrazol-3-yl) amino ] pyrrolo [2, 1-f ] [1, 2, 4] triazin-2-yl ] sulfonyl ] methyl ] benzamide (I-34)
Figure BSA0000172130500000431
A, step a: preparation of 4- (((4- ((5-methyl-1H-pyrazol-3-yl) amino) pyrrolo [2, 1-f ] [1, 2, 4] triazin-2-yl) sulfonyl) methyl) benzoic acid (14b)
Compound 7a (1.00g, 2.63mmol) prepared above was dissolved in analytically pure dichloromethane (30mL), m-chloroperoxybenzoic acid (1.36g, 7.89mmol) was added and reacted at room temperature for 3 hours, followed by extraction washing with water and saturated ammonium chloride solution (50mL) and addition of anhydrous sodium sulfateDried, allowed to stand, filtered, the solvent was evaporated under reduced pressure, and separated by silica gel column chromatography (dichloromethane: methanol 10: 1) to obtain 898mg of a white solid, yield: 82.83 percent. ESI-MS m/z: 413.2[ M + H]+.
Step b: preparation of N- (2-aminophenyl) -4- [ [ [4- [ (5-methyl-1H-pyrazol-3-yl) amino ] pyrrolo [2, 1-f ] [1, 2, 4] triazin-2-yl ] sulfonyl ] methyl ] benzamide (I-34)
To a 25mL eggplant type bottle were added 14b (107mg, 0.26mmol) and TBTU (93mg, 0.29mmol) obtained in the above preparation, N-dimethylformamide (10mL) was added, N-diisopropylethylamine (136mg, 1.05mmol) was further added, and the mixture was stirred at room temperature for 1 hour, then o-phenylenediamine (31mg, 0.29mmol) was added, and further stirred at room temperature for 4 hours, whereupon completion of the reaction was detected by TLC. To the reaction mixture was added water (80mL), and extracted with ethyl acetate (30mL × 3), the organic layers were combined, washed with saturated brine (50mL), dried over anhydrous sodium sulfate, allowed to stand, filtered, and the solvent was distilled off under reduced pressure, and separated by silica gel column chromatography (petroleum ether: ethyl acetate 1: 1) to obtain 76mg of a white solid, yield: 58.16 percent. mp: 195-198 deg.c; ESI-MS m/z: 503.2[ M + H ]+；1H-NMR(300MHz，DMSO-d6)δ(ppm)：12.26(br.s，1H)，10.63(s，1H)，9.65(s，1H)，7.91(d，J＝8.1Hz，2H)，7.68-7.67(m，1H)，7.58(d，J＝8.1Hz，2H)，7.22(s，1H)，7.17-7.14(m，1H)，7.02-6.95(m，1H)，6.80-6.78(m，1H)，6.94-6.59(m，2H)，6.48(s，1H)，5.31(s，2H)，5.12(br.s，2H)，2.24(s，3H).
Example 35
N- (2-aminophenyl) -4- [ [ ethyl [4- [ (5-methyl-1H-pyrazol-3-yl) amino ] pyrrolo [2, 1-f ] [1, 2, 4] triazin-2-yl ] amino ] methyl ] benzamide (I-35)
Figure BSA0000172130500000441
A, step a: preparation of methyl 4- ((ethyl (4- ((5-methyl-1H-pyrazol-3-yl) amino) pyrrolo [2, 1-f ] [1, 2, 4] triazin-2-yl) amino) methyl) benzoate (12c)
The compound 11(600mg, 2.05mmol) prepared above, N-Methyl ethyl-4-aminomethylbenzoate (595mg, 3.08mmol), NaH (164mg, 4.11mmol), and dried NMP (10mL) were placed in a sealed tube, reacted at 200 ℃ for 8 hours, a saturated ammonium chloride solution (50mL) was added, and then extracted with ethyl acetate (30mL × 3), the organic fractions were combined, dried over anhydrous sodium sulfate and left to stand, filtered, the solvent was distilled off under reduced pressure, and separated by silica gel column chromatography (dichloromethane: methanol ═ 10: 1) to obtain 387mg of a white solid, yield: 46.50 percent. ESI-MS m/z: 406.2[ M + H]+.
Step b: preparation of 4- ((ethyl (4- ((5-methyl-1H-pyrazol-3-yl) amino) pyrrolo [2, 1-f ] [1, 2, 4] triazin-2-yl) amino) methyl) benzoic acid (13c)
Compound 12c (300mg, 0.74mmol) prepared above and sodium hydroxide (59mg, 1.48mmol) were added to a 25mL eggplant-shaped flask, water (10mL) and ethanol (20mL) were added, and the reaction was carried out at 60 ℃ for 12 hours and checked by TLC to be complete. And (3) evaporating the solvent under reduced pressure, adding water (5mL), adjusting the pH to 6-7 with a glacial acetic acid solution under ice bath, freezing and standing for 2h in a refrigerator, performing suction filtration, and performing vacuum drying on a filter cake to obtain a white solid 252mg, wherein the yield is as follows: 87.01 percent. ESI-MS m/z: 392.2[ M + H ]+.
Step c: preparation of N- (2-aminophenyl) -4- [ [ ethyl [4- [ (5-methyl-1H-pyrazol-3-yl) amino ] pyrrolo [2, 1-f ] [1, 2, 4] triazin-2-yl ] amino ] methyl ] benzamide (I-35)
To a 25mL eggplant type bottle were added 13c (102mg, 0.26mmol) and TBTU (93mg, 0.29mmol) obtained in the above preparation, N-dimethylformamide (10mL) and N, N-diisopropylethylamine (136mg, 1.05mmol) were added, and the mixture was stirred at room temperature for 1 hour, then o-phenylenediamine (31mg, 0.29mmol) was added, and further stirred at room temperature for 4 hours, after which the reaction was detected by TLC to be complete. To the reaction mixture was added water (80mL), and extracted with ethyl acetate (30mL × 3), the organic layers were combined, washed with saturated brine (50mL), dried over anhydrous sodium sulfate, allowed to stand, filtered, and the solvent was distilled off under reduced pressure, and separated by silica gel column chromatography (petroleum ether: ethyl acetate 1: 1) to obtain 62mg of a white solid, yield: 49.52 percent. mp: 159 ℃ to 162 ℃; ESI-MS m/z: 482.2[ M + H ]]+；1H-NMR(300MHz，DMSO-d6)δ(ppm)：12.26(br.s，1H)，10.63(s，1H)，9.65(s，1H)，7.91(d，J＝8.1Hz，2H)，7.68-7.67(m，1H)，7.58(d，J＝8.1Hz，2H)，7.22(s，1H)，7.17-7.14(m，1H)，7.02-6.95(m，1H)，6.80-6.78(m，1H)，6.94-6.59(m，2H)，6.48(s，1H)，5.12(br.s，2H)，4.97(s，2H)，3.32(m，2H)2.24(s，3H)，1.39(m，3H).
Example 36
N- (2-aminophenyl) -4- [ [ [4- [ (4-methoxyphenyl) amino ] pyrrolo [2, 1-f ] [1, 2, 4] triazin-2-yl ] amino ] methyl ] benzamide (I-36)
Figure BSA0000172130500000451
Step a: preparation of ethyl 4- [ [ [4- [ (4-methoxyphenyl) amino ] pyrrolo [2, 1-f ] [1, 2, 4] triazin-2-yl ] thio ] methyl ] benzoate (61)
5(500mg, 1.44mmol) prepared above was dissolved in N, N-dimethylformamide (20mL), potassium iodide (2.39g, 14.38mmol) was added, and the mixture was stirred at 70 ℃ for 5 minutes. N, N-diisopropylethylamine (929mg, 7.19mmol) and p-anisidine (354mg, 2.88mmol) were added and reacted at 80 ℃ for 4h with TLC detection of completion. To the reaction mixture was added water (80mL), and extracted with ethyl acetate (30mL × 3), the organic layers were combined, washed with saturated brine (50mL), dried over anhydrous sodium sulfate, allowed to stand, filtered, and the solvent was distilled off under reduced pressure, and separated by silica gel column chromatography (petroleum ether: ethyl acetate: 5: 1) to obtain 560mg of a white solid, yield: 89.46 percent. ESI-MS m/z: 435.2[ M + H]+；
Step b: preparation of 4- [ [ [4- [ (4-methoxyphenyl) amino ] pyrrolo [2, 1-f ] [1, 2, 4] triazin-2-yl ] thio ] methyl ] benzoic acid (71)
To a 100mL eggplant-shaped bottle were added compound 61(500mg, 1.15mmol) obtained by the above preparation and sodium hydroxide (92mg, 2.30mmol), and water (20mL) and ethanol (40mL) were added, followed by refluxing for 10 hours and completion of the reaction by TLC. And (3) evaporating the solvent under reduced pressure, adding water (30mL), adjusting the pH to 6-7 with a glacial acetic acid solution under ice bath, freezing and standing for 2h in a refrigerator, performing suction filtration, and performing vacuum drying on a filter cake to obtain a white solid 351mg, wherein the yield is as follows: 86.45 percent. ESI-MS m/z: 407.1[ M + H ]+.
Step c: preparation of N- (2-aminophenyl) -4- [ [ [4- [ (4-methoxyphenyl) amino ] pyrrolo [2, 1-f ] [1, 2, 4] triazin-2-yl ] thio ] methyl ] benzamide (I-36)
To a 25mL eggplant type bottle, 71(150mg, 0.37mmol) and TBTU (130mg, 0.40mmol) prepared above were added, N-dimethylformamide (10mL) was added, N-diisopropylethylamine (190mg, 1.47mmol) was added, and the mixture was stirred at room temperature for 1 hour, further o-phenylenediamine (40mg, 0.37mmol) was added, and stirring was continued at room temperature for 8 hours, after which completion of the reaction was detected by TLC. To the reaction mixture was added water (80mL), extracted with ethyl acetate (30mL × 3), the organic layers were combined, washed with saturated brine (50mL), dried over anhydrous sodium sulfate, allowed to stand, filtered, and the solvent was evaporated under reduced pressure, and separated by silica gel column chromatography (petroleum ether: ethyl acetate 1: 1) to give 94mg of a yellow solid, yield: 51.34 percent. mp: 173-175 ℃; ESI-MS m/z: 497.2[ M + H]+；1H-NMR(300MHz，DMSO-d6)δ(ppm)：9.60(s，1H)，8.93(t，J＝5.5Hz，1H)，7.87(d，J＝8.0Hz，2H)，7.59-7.58(m，1H)，7.49(d，J＝8.0Hz，2H)，7.39-7.35(m，2H)，7.19-7.13(m，3H)，6.98-6.94(m，1H)，6.91-6.90(m，1H)，6.78-6.75(m，1H)，6.61-6.54(m，2H，ph-H)，4.89(s，2H)，4.70(d，J＝5.5Hz，2H)，4.36(s，2H)，3.83(s，3H).
Example 37
N- (2-aminophenyl) -4- [ [ [4H- (1, 4-oxazin-4-yl) pyrrolo [2, 1-f ] [1, 2, 4] triazin-2-yl ] amino ] methyl ] benzamide (I-37)
Figure BSA0000172130500000461
Step a: preparation of ethyl 4- [ [ [4H- (1, 4-oxazin-4-yl) pyrrolo [2, 1-f ] [1, 2, 4] triazin-2-yl ] thio ] methyl ] benzoate (6m)
5(2g, 5.75mmol) prepared above was dissolved in N, N-dimethylformamide (50mL), and potassium iodide (9.55g, 57.50mmol) was added and stirred at 70 ℃ for 5 minutes. N, N-diisopropylethylamine (3.72g, 28.75mmol) and 4H-1, 4-oxazine (0.96g, 11.50mmol) were added and reacted at 80 ℃ for 10H, with TLC detection complete. Water (200mL) was added to the reaction mixture, extraction was performed with ethyl acetate (80 mL. times.3), the organic layers were combined, After washing with saturated brine (100mL), the mixture was dried over anhydrous sodium sulfate, allowed to stand, filtered, and the solvent was evaporated under reduced pressure, and separated by silica gel column chromatography (petroleum ether: ethyl acetate 5: 1) to obtain 1.56g of a yellowish green solid, yield: 68.72 percent. ESI-MS m/z: 395.2[ M + H ]]+.
Step b: preparation of 4- [ [ [4H- (1, 4-oxazin-4-yl) amino ] pyrrolo [2, 1-f ] [1, 2, 4] triazin-2-yl ] thio ] methyl ] benzoic acid (7m)
To a 100mL eggplant type bottle were added compound 6m (300mg, 0.76mmol) obtained by the above preparation and sodium hydroxide (47mg, 1.17mmol), water (20mL) and ethanol (40mL) were added, the reaction was refluxed for 10 hours, and the reaction was checked by TLC to be complete. And (3) evaporating the solvent under reduced pressure, adding water (30mL), adjusting the pH to 6-7 with a glacial acetic acid solution under ice bath, freezing and standing for 2h in a refrigerator, performing suction filtration, and performing vacuum drying on a filter cake to obtain a white solid 182mg, wherein the yield is as follows: 65.67 percent. Repeating the operation for several times to obtain about 1.10g of white solid; ESI-MS m/z: 367.2[ M + H]+.
Step c: preparation of N- (2-aminophenyl) -4- [ [ [4H- (1, 4-oxazin-4-yl) pyrrolo [2, 1-f ] [1, 2, 4] triazin-2-yl ] amino ] methyl ] benzamide (I-37)
To a 25mL eggplant type bottle were added 7m (377mg, 1.03mmol) and TBTU (124mg, 1.14mmol) prepared above, N-dimethylformamide (30mL) was added, N-diisopropylethylamine (534mg, 4.14mmol) was added, and the mixture was stirred at room temperature for 1 hour, then o-phenylenediamine (124mg, 1.14mmol) was added, and further stirred at room temperature for 8 hours, after which the reaction was detected by TLC to be complete. Water (160mL) was added to the reaction mixture, and ethyl acetate was extracted (60mL × 3), and the organic layers were combined, washed with saturated brine (100mL), dried over anhydrous sodium sulfate, left to stand, filtered, and the solvent was distilled off under reduced pressure, and separated by silica gel column chromatography (petroleum ether: ethyl acetate 1: 1) to obtain 271mg of a white solid, yield: 59.33 percent. mp: 136 ℃ and 139 ℃; ESI-MS m/z: 457.2[ M + H ]+；1H-NMR(300MHz，DMSO-d6)δ(ppm)：9.63(s，1H)，8.11(d，J＝8.0Hz，1H)，7.91(d，J＝8.0Hz，2H，)，7.59-7.56(m，3H)，7.14(d，J＝7.5Hz，1H)，6.99-6.94(m，1H)，6.87-6.86(m，1H)，6.78(d，J＝7.5Hz，1H)，6.62-6.57(m，1H)，6.63(dd，J＝4.1Hz，2.6Hz，1H)，5.50-5.45(m，4H)，5.00(s，2H)，4.39(s，2H).
Example 38
N- (2-aminophenyl) -4- [ [ [ 4-piperidinylpyrrolo [2, 1-f ] [1, 2, 4] triazin-2-yl ] amino ] methyl ] benzamide (I-38)
Figure BSA0000172130500000471
Step a: preparation of ethyl 4- [ [ [ 4-piperidinylpyrrolo [2, 1-f ] [1, 2, 4] triazin-2-yl ] thio ] methyl ] benzoate (6n)
5(500mg, 1.44mmol) prepared above was dissolved in N, N-dimethylformamide (20mL), potassium iodide (2.39g, 14.38mmol) was added, and the mixture was stirred at 70 ℃ for 5 minutes. N, N-diisopropylethylamine (929mg, 7.19mmol) and piperidine (245mg, 2.88mmol) were added and reacted at 80 ℃ for 3h with TLC detection of completion. To the reaction mixture was added water (80mL), and extracted with ethyl acetate (30mL × 3), the organic layers were combined, washed with saturated brine (50mL), dried over anhydrous sodium sulfate, allowed to stand, filtered, and the solvent was distilled off under reduced pressure, and separated by silica gel column chromatography (petroleum ether: ethyl acetate 5: 1) to obtain 552mg of a white solid, yield: 96.68 percent. ESI-MS m/z: 397.2[ M + H]+.
Step b: preparation of 4- [ [ [ 4-piperidinyl-pyrrolo [2, 1-f ] [1, 2, 4] triazin-2-yl ] thio ] methyl ] benzoic acid (7n)
To a 100mL eggplant-shaped bottle, compound 6n (500mg, 1.26mmol) obtained by the above preparation and sodium hydroxide (101mg, 2.52mmol) were added, and water (20mL) and ethanol (40mL) were added, followed by refluxing for 10 hours and completion of the reaction by TLC. And (3) evaporating the solvent under reduced pressure, adding water (30mL), adjusting the pH to 6-7 with a glacial acetic acid solution under ice bath, freezing and standing for 2h in a refrigerator, performing suction filtration, and performing vacuum drying on a filter cake to obtain a white solid 338mg, wherein the yield is as follows: 72.75 percent; ESI-MS m/z: 369.2[ M + H ]+.
Step c: preparation of N- (2-aminophenyl) -4- [ [ [ 4-piperidinylpyrrolo [2, 1-f ] [1, 2, 4] triazin-2-yl ] thio ] methyl ] benzamide (I-38)
To a 25mL eggplant type bottle were added 7N (151mg, 0.41mmol) prepared above and TBTU (143mg, 0.45mmol), N-dimethylformamide (10mL) was added, N was further added,n-diisopropylethylamine (209mg, 1.62mmol) was stirred at room temperature for 1 hour, o-phenylenediamine (44mg, 0.41mmol) was added, and the mixture was further stirred at room temperature for 8 hours, after which the reaction was detected by TLC to be complete. To the reaction mixture was added water (80mL), and extracted with ethyl acetate (30mL × 3), the organic layers were combined, washed with saturated brine (50mL), dried over anhydrous sodium sulfate, allowed to stand, filtered, and the solvent was distilled off under reduced pressure, and separated by silica gel column chromatography (petroleum ether: ethyl acetate 1: 1) to obtain 65mg of a white solid, yield: 34.57 percent. mp: 176 ℃ and 178 ℃; ESI-MS m/z: 459.2[ M + H]+；1H-NMR(300MHz，DMSO-d6)δ(ppm)：9.61(s，1H)，7.91(d，J＝8.1Hz，2H)，7.71-7.70(m，1H)，7.57(d，J＝8.2Hz，2H)，7.14(d，J＝7.4Hz，1H)，6.98-6.94(m，2H)，6.78-6.75(m，1H)，6.64-6.56(m，2H)，4.89(s，2H)，4.39(s，2H)，3.98-3.96(m，4H)，1.72-1.69(m，5H).
Example 39
N- (2-aminophenyl) -5- [ [ [4- (2-furan) aminopyrrolo [2, 1-f ] [1, 2, 4] triazin-2-yl ] amino ] methyl ] pyridinecarboxamide (I-39)
Figure BSA0000172130500000481
Step a: preparation of ethyl 5- [ [ [4- (2-furan) aminopyrrolo [2, 1-f ] [1, 2, 4] triazin-2-yl ] thio ] methyl ] picolinate (6o)
5(500mg, 1.44mmol) prepared above was dissolved in N, N-dimethylformamide (20mL), potassium iodide (2.39g, 14.38mmol) was added, and the mixture was stirred at 70 ℃ for 5 minutes. N, N-diisopropylethylamine (929mg, 7.19mmol) and 2-aminofuran (239mg, 2.88mmol) were added and reacted at 80 ℃ for 3h with TLC detection of completion. Water (80mL) was added to the reaction mixture, and ethyl acetate was extracted (30mL × 3), and the organic layers were combined, washed with saturated brine (50mL), dried over anhydrous sodium sulfate, left to stand, filtered, and the solvent was evaporated under reduced pressure, and separated by silica gel column chromatography (petroleum ether: ethyl acetate: 5: 1) to obtain 533mg of a white solid, yield: 94.00 percent. ESI-MS m/z: 396.2[ M + H ]+.
Step b: preparation of 4- [ [ [4- (2-furan) aminopyrrolo [2, 1-f ] [1, 2, 4] triazin-2-yl ] thio ] methyl ] benzoic acid (7o)
To a 100mL eggplant-shaped flask were added the compound 6o (500mg, 1.27mmol) prepared above and sodium hydroxide (101mg, 2.54mmol), water (20mL) and ethanol (40mL) were added, the reaction was refluxed for 10h, and the reaction was checked by TLC to completion. And (3) evaporating the solvent under reduced pressure, adding water (30mL), adjusting the pH to 6-7 with a glacial acetic acid solution under ice bath, freezing and standing for 2h in a refrigerator, performing suction filtration, and performing vacuum drying on a filter cake to obtain 320mg of a white solid, wherein the yield is as follows: 68.90 percent; ESI-MS m/z: 368.2[ M + H]+.
Step c: preparation of N- (2-aminophenyl) -4- [ [ [4- (2-furan) aminopyrrolo [2, 1-f ] [1, 2, 4] triazin-2-yl ] thio ] methyl ] benzamide (I-39)
To a 25mL eggplant type bottle were added 7o (150mg, 0.41mmol) prepared above and TBTU (143mg, 0.45mmol), N-dimethylformamide (10mL) was added, N-diisopropylethylamine (209mg, 1.62mmol) was further added, and the mixture was stirred at room temperature for 1 hour, further o-phenylenediamine (44mg, 0.41mmol) was added, and after stirring at room temperature for 8 hours, the reaction was completed by TLC. To the reaction mixture was added water (80mL), and extracted with ethyl acetate (30mL × 3), the organic layers were combined, washed with saturated brine (50mL), dried over anhydrous sodium sulfate, allowed to stand, filtered, and the solvent was distilled off under reduced pressure, and separated by silica gel column chromatography (petroleum ether: ethyl acetate 1: 1) to obtain 59mg of a white solid, yield: 31.52 percent. mp: 185-188 ℃; ESI-MS m/z: 458.2[ M + H ]+；1H-NMR(300MHz，DMSO-d6)δ(ppm)：10.78(s，1H)，8.66(m，1H)，8.50(s，1H)，8.08-8.05(m，2H)，7.92-7.88(m，2H)，7.71-7.70(m，1H)，7.67-7.63(m，1H)，7.44-7.41(m，1H)，7.10-7.05(m，2H)，6.88-6.85(m，1H)，6.68-6.56(m，2H)，4.89(s，2H)，4.39(s，2H).
Example 40
N- (2-aminophenyl) -4- [ [ [4- (3-pyridyl) pyrrolo [2, 1-f ] [1, 2, 4] triazin-2-yl ] amino ] methyl ] benzamide (I-40)
Figure BSA0000172130500000491
A, step a: preparation of ethyl 4- [ [ [4- (3-pyridinyl) pyrrolo [2, 1-f ] [1, 2, 4] triazin-2-yl ] thio ] methyl ] benzoate (6p)
5(660mg, 1.91mmol), 3- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridine (590mg, 2.86mmol), [1, 1' -bis (diphenylphosphino) ferrocene, prepared as described above]Palladium dichloride (156mg, 0.21mmol), 2M aqueous potassium phosphate (2.86mL) was added to THF (8.2mL) and the reaction refluxed for 6 h. The reaction mixture was extracted with water and ethyl acetate (30mL × 3), the organic layers were combined, washed with saturated brine (50mL), dried over anhydrous sodium sulfate, allowed to stand, filtered, the solvent was evaporated under reduced pressure, and separated by silica gel column chromatography (petroleum ether: ethyl acetate 5: 1) to obtain 255mg of a white solid, yield: 34.19 percent. ESI-MS m/z: 391.2[ M + H]+.
Step b: preparation of 4- [ [ [4- (3-pyridinyl) pyrrolo [2, 1-f ] [1, 2, 4] triazin-2-yl ] thio ] methyl ] benzoic acid (7p)
To a 100mL eggplant-shaped bottle were added the compound 6p (500mg, 1.28mmol) prepared above and accumulated and sodium hydroxide (102mg, 2.56mmol), water (20mL) and ethanol (40mL) were added, the reaction was refluxed for 10h, and the reaction was checked by TLC to be complete. And (3) evaporating the solvent under reduced pressure, adding water (30mL), adjusting the pH to 6-7 with a glacial acetic acid solution under ice bath, freezing and standing for 2h in a refrigerator, performing suction filtration, and performing vacuum drying on a filter cake to obtain a white solid 336mg, wherein the yield is as follows: 72.40 percent. ESI-MS m/z: 363.2[ M + H ]+.
Step c: preparation of N- (2-aminophenyl) -4- [ [ [4- (3-pyridyl) aminopyrrolo [2, 1-f ] [1, 2, 4] triazin-2-yl ] thio ] methyl ] benzamide (I-40)
A25 mL eggplant type bottle was charged with 7p (150mg, 0.41mmol) and TBTU (143mg, 0.45mmol) prepared as described above, N-dimethylformamide (10mL) was added, N-diisopropylethylamine (209mg, 1.62mmol) was further added, and the mixture was stirred at room temperature for 1 hour, further o-phenylenediamine (44mg, 0.41mmol) was added, and stirring was continued at room temperature for 8 hours, after which completion of the reaction was detected by TLC. To the reaction mixture was added water (80mL), and extracted with ethyl acetate (30mL × 3), the organic layers were combined, washed with saturated brine (50mL), dried over anhydrous sodium sulfate, allowed to stand, filtered, and the solvent was distilled off under reduced pressure, and separated by silica gel column chromatography (petroleum ether: ethyl acetate 1: 1) to obtain 66mg of a white solid, yield: 35.57 percent. mp: 180-183℃；ESI-MS m/z：453.2[M+H]+；1H-NMR(300MHz，DMSO-d6)δ(ppm)：9.62(s，1H)，9.23(s，1H)，8.72-8.69(m，1H)，8.30-8.27(m，1H)，7.92-7.88(m，1H)，7.71-7.70(m，1H)，7.57-7.55(m，3H)，7.14(d，J＝7.4Hz，1H)，6.99-6.94(m，2H)，6.78-6.75(m，1H)，6.68-6.56(m，2H)，4.89(s，2H)，4.39(s，2H).
EXAMPLE 41
N- (2-aminophenyl) -4- [ [ [4- (4-methoxyphenyl) pyrrolo [2, 1-f ] [1, 2, 4] triazin-2-yl ] amino ] methyl ] benzamide (I-41)
Figure BSA0000172130500000501
Step a: preparation of ethyl 4- [ [ [4- (4-methoxyphenyl) pyrrolo [2, 1-f ] [1, 2, 4] triazin-2-yl ] thio ] methyl ] benzoate (6q)
The 5(660mg, 1.91mmol), 2- (4-methoxyphenyl) -4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborane (670mg, 2.86mmol) and [1, 1' -bis (diphenylphosphino) ferrocene prepared above were added ]Palladium dichloride (156mg, 0.21mmol), 2M aqueous potassium phosphate (2.86mL) was added to THF (8.2mL) and the reaction refluxed for 6 h. The reaction mixture was extracted with water and ethyl acetate (30mL × 3), the organic layers were combined, washed with saturated brine (50mL), dried over anhydrous sodium sulfate, allowed to stand, filtered, the solvent was evaporated under reduced pressure, and separated by silica gel column chromatography (petroleum ether: ethyl acetate 5: 1) to give 289mg of a white solid, yield: 36.07 percent. ESI-MS m/z: 420.2[ M + H]+.
Step b: preparation of 4- [ [ [4- (4-methoxyphenyl) pyrrolo [2, 1-f ] [1, 2, 4] triazin-2-yl ] thio ] methyl ] benzoic acid (7q)
To a 100mL eggplant-shaped bottle, the compound 6q (500mg, 1.19mmol) and sodium hydroxide (95mg, 2.38mmol) prepared and accumulated as described above were added, water (20mL) and ethanol (40mL) were added, the reaction was refluxed for 10 hours, and the reaction was checked by TLC to be complete. Evaporating under reduced pressure to remove solvent, adding water (30mL), adjusting pH to 6-7 with glacial acetic acid solution in ice bath, freezing and standing in refrigerator for 2 hr, vacuum filtering, and vacuum drying filter cake to obtain white solid 330mgRate: 70.73 percent. ESI-MS m/z: 392.2[ M + H]+.
Step c: preparation of N- (2-aminophenyl) -4- [ [ [4- (4-methoxyphenyl) aminopyrrolo [2, 1-f ] [1, 2, 4] triazin-2-yl ] thio ] methyl ] benzamide (I-41)
A25 mL eggplant type bottle was charged with 7p (160mg, 0.41mmol) and TBTU (143mg, 0.45mmol) prepared as described above, N-dimethylformamide (10mL) was added, N-diisopropylethylamine (209mg, 1.62mmol) was further added, and the mixture was stirred at room temperature for 1 hour, further o-phenylenediamine (44mg, 0.41mmol) was added, and stirring was continued at room temperature for 8 hours, after which the reaction was detected by TLC to be complete. To the reaction mixture was added water (80mL), and extracted with ethyl acetate (30mL × 3), the organic layers were combined, washed with saturated brine (50mL), dried over anhydrous sodium sulfate, allowed to stand, filtered, and the solvent was distilled off under reduced pressure, and separated by silica gel column chromatography (petroleum ether: ethyl acetate 1: 1) to obtain 74mg of a white solid, yield: 37.48 percent. mp: 169 ℃ and 172 ℃; ESI-MS m/z: 482.2[ M + H ]]+；1H-NMR(300MHz，DMSO-d6)δ(ppm)：9.62(s，1H)，7.82(d，J＝8.3Hz，2H)，7.70-7.66(m，1H)，7.56-7.55(m，1H)，7.53(d，J＝8.3Hz，2H)，7.48-7.43(m，3H)，7.15(d，J＝7.1Hz，1H)，7.05-7.00(m，3H)，6.89-6.86(m，3H)，6.53(m，1H)，4.37(s，2H)，3.71(s，3H)。

Claims (8)

1. A compound of the general formula (I) or a pharmaceutically acceptable salt thereof:
Figure 881706DEST_PATH_IMAGE001
wherein R is1Is hydroxy, or is optionally substituted by one or more R5Substituted 2-aminophenyl radicals, R5Selected from hydrogen, C1 -C 6Alkyl, cyano, halogen, phenyl, 5-membered heteroaryl;
R 2is-L-R3Wherein L is a bond, NR4 ；R 3Is aryl, heteroaryl, saturated or partially saturated heterocyclyl, each aryl, heteroaryl, saturated or partially saturated heterocyclyl being optionally substituted by one or moreR is6Substituted, R6Selected from hydrogen, C1-C 6Alkyl, halogen, halogeno C 1 -C 6Alkyl radical, C1 -C 6Alkoxy, tert-butoxycarbonyl;
wherein R is4Selected from hydrogen, C1 -C 6An alkyl group;
x is NH, NR7 、O、S(O)n，R 7Is selected from C1 -C 6The value range of n is 0-2;
q is phenyl, pyridyl;
wherein the aryl group is a 6-10 membered aryl group; the heteroaryl is a five or six membered heteroaryl, wherein 1 to 4 ring atoms are heteroatoms selected from oxygen, nitrogen, sulphur and the remaining ring atoms are carbon; said heterocyclyl contains 5 to 10 ring atoms, of which 1 to 4 are heteroatoms selected from oxygen, nitrogen, sulphur and the remaining ring atoms are carbon.
2. The compound of claim 1, characterized in that:
R 1is hydroxy or is selected from the group consisting of5Substituted 2-aminophenyl radicals, R5Selected from hydrogen, C1 -C 6Alkyl, cyano, halogen, phenyl, thienyl;
R 2is-L-R3Wherein L is a bond, NR4 ；R 3Is aryl, heteroaryl, saturated or partially saturated heterocyclyl, each aryl, heteroaryl, saturated or partially saturated heterocyclyl being optionally substituted with one or more R6Substituted, R6Selected from hydrogen, C1-C 6Alkyl, halogen, trifluoromethyl, methoxy, tert-butoxycarbonyl;
wherein R is4Selected from H, C1 -C 6An alkyl group;
x is NH, NR7 、O、S(O)n，R 7Is selected from ethyl, and the value range of n is 0-2;
q is phenyl, pyridyl;
wherein said aryl is phenyl; heterocyclyl is piperidinyl, morpholinyl; the heteroaryl is pyrazolyl, furyl or pyridyl.
3. The compound of claim 1, characterized in that:
R 1is hydroxy or is selected from the group consisting of5Substituted 2-aminophenyl radicals, R5Selected from hydrogen, halogen;
R 2is-L-R3Wherein L is a bond, NH; r3Is an aromatic, heterocyclic or substituted aromatic, substituted heterocyclic ring of: phenyl, furyl, pyrazolyl, pyridyl, morpholinyl, piperidyl and 1, 4-oxazin-4-yl, wherein the substituent is selected from methyl, tert-butyl, 1-2 halogens, trifluoromethyl, methoxy and tert-butoxycarbonyl;
x is NH, O, S (O) n, and the value range of n is 0-2;
q is phenyl or pyridyl.
4. The compound of claim 1, characterized by being the following:
n- (2-aminophenyl) -4- [ [ [4- [ (5-methyl-1H-pyrazol-3-yl) amino ] pyrrolo [2, 1-f ] [1, 2, 4] triazin-2-yl ] thio ] methyl ] benzamide (I-1)
N- (2-amino-4-fluorophenyl) -4- [ [ [4- [ (5-methyl-1H-pyrazol-3-yl) amino ] pyrrolo [2, 1-f ] [1, 2, 4] triazin-2-yl ] thio ] methyl ] benzamide (I-2)
N- (2-aminophenyl) -4- [ [ [4- [ (1H-pyrazol-3-yl) amino ] pyrrolo [2, 1-f ] [1, 2, 4] triazin-2-yl ] thio ] methyl ] benzamide (I-3)
N- (2-amino-4-fluorophenyl) -4- [ [ [4- [ (1H-pyrazol-3-yl) amino ] pyrrolo [2, 1-f ] [1, 2, 4] triazin-2-yl ] thio ] methyl ] benzamide (I-4)
N- (2-aminophenyl) -4- [ [ [4- [ (5-tert-butyl-1H-pyrazol-3-yl) amino ] pyrrolo [2, 1-f ] [1, 2, 4] triazin-2-yl ] thio ] methyl ] benzamide (I-5)
N- (2-amino-4-fluorophenyl) -4- [ [ [4- [ (5-tert-butyl-1H-pyrazol-3-yl) amino ] pyrrolo [2, 1-f ] [1, 2, 4] triazin-2-yl ] thio ] methyl ] benzamide (I-6)
N- (2-aminophenyl) -4- [ [ [ 4-morpholinylpyrrolo [2, 1-f ] [1, 2, 4] triazin-2-yl ] thio ] methyl ] benzamide (I-7)
N- (2-amino-4-fluorophenyl) -4- [ [ [ 4-morpholinylpyrrolo [2, 1-f ] [1, 2, 4] triazin-2-yl ] thio ] methyl ] benzamide (I-8)
N- (2-aminophenyl) -4- [ [ [4- [ (4-fluorobenzyl) amino ] pyrrolo [2, 1-f ] [1, 2, 4] triazin-2-yl ] thio ] methyl ] benzamide (I-9)
N- (2-amino-4-fluorophenyl) -4- [ [ [4- [ (4-fluorobenzyl) amino ] pyrrolo [2, 1-f ] [1, 2, 4] triazin-2-yl ] thio ] methyl ] benzamide (I-10)
N- (2-aminophenyl) -4- [ [ [4- [ (4-trifluoromethylbenzyl) amino ] pyrrolo [2, 1-f ] [1, 2, 4] triazin-2-yl ] thio ] methyl ] benzamide (I-11)
N- (2-amino-4-fluorophenyl) -4- [ [ [4- [ (4-trifluoromethylbenzyl) amino ] pyrrolo [2, 1-f ] [1, 2, 4] triazin-2-yl ] thio ] methyl ] benzamide (I-12)
N- (2-aminophenyl) -4- [ [ [4- [ (4-methoxybenzyl) amino ] pyrrolo [2, 1-f ] [1, 2, 4] triazin-2-yl ] thio ] methyl ] benzamide (I-13)
N- (2-amino-4-fluorophenyl) -4- [ [ [4- [ (4-methoxybenzyl) amino ] pyrrolo [2, 1-f ] [1, 2, 4] triazin-2-yl ] thio ] methyl ] benzamide (I-14)
N- (2-aminophenyl) -4- [ [ [4- [ (3, 4-dimethoxybenzyl) amino ] pyrrolo [2, 1-f ] [1, 2, 4] triazin-2-yl ] thio ] methyl ] benzamide (I-15)
N- (2-amino-4-fluorophenyl) -4- [ [ [4- [ (3, 4-dimethoxybenzyl) amino ] pyrrolo [2, 1-f ] [1, 2, 4] triazin-2-yl ] thio ] methyl ] benzamide (I-16)
N- (2-aminophenyl) -4- [ [ [4- [ (2, 4-dimethoxybenzyl) amino ] pyrrolo [2, 1-f ] [1, 2, 4] triazin-2-yl ] thio ] methyl ] benzamide (I-17)
N- (2-amino-4-fluorophenyl) -4- [ [ [4- [ (2, 4-dimethoxybenzyl) amino ] pyrrolo [2, 1-f ] [1, 2, 4] triazin-2-yl ] thio ] methyl ] benzamide (I-18)
N- (2-aminophenyl) -4- [ [ [4- [ (3-methylpyridin-2-yl) amino ] pyrrolo [2, 1-f ] [1, 2, 4] triazin-2-yl ] thio ] methyl ] benzamide (I-19)
N- (2-amino-4-fluorophenyl) -4- [ [ [4- [ (3-methylpyridin-2-yl) amino ] pyrrolo [2, 1-f ] [1, 2, 4] triazin-2-yl ] thio ] methyl ] benzamide (I-20)
N- (2-aminophenyl) -4- [ [ [4- [ (N-Boc-piperidin-4-yl) amino ] pyrrolo [2, 1-f ] [1, 2, 4] triazin-2-yl ] thio ] methyl ] benzamide (I-21)
N- (2-amino-4-fluorophenyl) -4- [ [ [4- [ (N-Boc piperidin-4-yl) amino ] pyrrolo [2, 1-f ] [1, 2, 4] triazin-2-yl ] thio ] methyl ] benzamide (I-22)
N- (2-aminophenyl) -4- [ [ [4- [ (piperidin-4-yl) amino ] pyrrolo [2, 1-f ] [1, 2, 4] triazin-2-yl ] thio ] methyl ] benzamide (I-23)
N- (2-amino-4-fluorophenyl) -4- [ [ [4- [ (piperidin-4-yl) amino ] pyrrolo [2, 1-f ] [1, 2, 4] triazin-2-yl ] thio ] methyl ] benzamide (I-24)
N-hydroxy-4- [ [ [4- [ (5-methyl-1H-pyrazol-3-yl) amino ] pyrrolo [2, 1-f ] [1, 2, 4] triazin-2-yl ] thio ] methyl ] benzamide (I-25)
N- (2-amino-4-chlorophenyl) -4- [ [ [4- [ (5-methyl-1H-pyrazol-3-yl) amino ] pyrrolo [2, 1-f ] [1, 2, 4] triazin-2-yl ] thio ] methyl ] benzamide (I-26)
N- (2-amino-4-methylphenyl) -4- [ [ [4- [ (5-methyl-1H-pyrazol-3-yl) amino ] pyrrolo [2, 1-f ] [1, 2, 4] triazin-2-yl ] thio ] methyl ] benzamide (I-27)
N- (2-amino-5-cyanophenyl) -4- [ [ [4- [ (5-methyl-1H-pyrazol-3-yl) amino ] pyrrolo [2, 1-f ] [1, 2, 4] triazin-2-yl ] thio ] methyl ] benzamide (I-28)
N- (2-amino-5-phenylphenyl) -4- [ [ [4- [ (5-methyl-1H-pyrazol-3-yl) amino ] pyrrolo [2, 1-f ] [1, 2, 4] triazin-2-yl ] thio ] methyl ] benzamide (I-29)
N- (2-amino-5- (2-thienyl) phenyl) -4- [ [ [4- [ (5-methyl-1H-pyrazol-3-yl) amino ] pyrrolo [2, 1-f ] [1, 2, 4] triazin-2-yl ] thio ] methyl ] benzamide (I-30)
N- (2-aminophenyl) -4- [ [ [4- [ (5-methyl-1H-pyrazol-3-yl) amino ] pyrrolo [2, 1-f ] [1, 2, 4] triazin-2-yl ] oxy ] methyl ] benzamide (I-31)
N- (2-aminophenyl) -4- [ [ [4- [ (5-methyl-1H-pyrazol-3-yl) amino ] pyrrolo [2, 1-f ] [1, 2, 4] triazin-2-yl ] amino ] methyl ] benzamide (I-32)
N- (2-aminophenyl) -4- [ [ [4- [ (5-methyl-1H-pyrazol-3-yl) amino ] pyrrolo [2, 1-f ] [1, 2, 4] triazin-2-yl ] sulfoxy ] methyl ] benzamide (I-33)
N- (2-aminophenyl) -4- [ [ [4- [ (5-methyl-1H-pyrazol-3-yl) amino ] pyrrolo [2, 1-f ] [1, 2, 4] triazin-2-yl ] sulfonyl ] methyl ] benzamide (I-34)
N- (2-aminophenyl) -4- [ [ ethyl [4- [ (5-methyl-1H-pyrazol-3-yl) amino ] pyrrolo [2, 1-f ] [1, 2, 4] triazin-2-yl ] amino ] methyl ] benzamide (I-35)
N- (2-aminophenyl) -4- [ [ [4- [ (4-methoxyphenyl) amino ] pyrrolo [2, 1-f ] [1, 2, 4] triazin-2-yl ] amino ] methyl ] benzamide (I-36)
N- (2-aminophenyl) -4- [ [ [4H- (1, 4-oxazin-4-yl) pyrrolo [2, 1-f ] [1, 2, 4] triazin-2-yl ] amino ] methyl ] benzamide (I-37)
N- (2-aminophenyl) -4- [ [ [ 4-piperidinylpyrrolo [2, 1-f ] [1, 2, 4] triazin-2-yl ] amino ] methyl ] benzamide (I-38)
N- (2-aminophenyl) -5- [ [ [4- (2-furan) aminopyrrolo [2, 1-f ] [1, 2, 4] triazin-2-yl ] amino ] methyl ] pyridinecarboxamide (I-39)
N- (2-aminophenyl) -4- [ [ [4- (3-pyridyl) pyrrolo [2, 1-f ] [1, 2, 4] triazin-2-yl ] amino ] methyl ] benzamide (I-40)
N- (2-aminophenyl) -4- [ [ [4- (4-methoxyphenyl) pyrrolo [2, 1-f ] [1, 2, 4] triazin-2-yl ] amino ] methyl ] benzamide (I-41).
5. The compound of any one of claims 1-4, or a pharmaceutically acceptable salt thereof, wherein the pharmaceutically acceptable salt is an acid addition salt of the compound of formula (I) with: hydrochloric, hydrobromic, sulphuric, phosphoric, methanesulphonic, benzenesulphonic, p-toluenesulphonic, naphthalenesulphonic, citric, tartaric, lactic, pyruvic, acetic, maleic or succinic, fumaric, salicylic, phenylacetic, mandelic acid.
6. A pharmaceutical composition comprising a compound according to any one of claims 1 to 4 and a pharmaceutically acceptable carrier.
7. Use of a compound according to any one of claims 1 to 4 in the manufacture of a medicament for the prevention or treatment of clinical conditions associated with HDACs.
8. The use of claim 7 wherein the disease associated with HDACs is lung cancer, melanoma, liver cancer, kidney cancer, leukemia, prostate cancer, thyroid cancer, skin cancer, pancreatic cancer, rectal cancer, colon cancer, ovarian cancer, testicular cancer, breast cancer, bladder cancer, gall bladder cancer, myelodysplastic syndrome, lymphoma, esophageal cancer, astrocytoma, neuroblastoma, glioma, schwannoma, mesothelioma, non-insulin dependent diabetes mellitus, an autoimmune disease.
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