WO2020073749A1 - Pyrrolotriazine compound and uses thereof - Google Patents

Abstract

The present invention belongs to the field of medical chemistry, and particularly relates to a lactam-based histone deacetylase inhibitor, a preparation method thereof, a pharmaceutical composition thereof, and uses of a drug thereof in preventing and/or treating diseases related to inactivation of histone deacetylase.

Description

Pyrrolotriazine compounds and their applications Technical field

The invention belongs to the field of medicinal chemistry, and specifically relates to a class of histone deacetylase inhibitors with pyrrolo [2,1-f] [1,2,4] triazine structure, preparation method, Pharmaceutical combinations of acetylase inhibitors, and the use of such inhibitors in drugs for the prevention and / or treatment of diseases associated with uncontrolled histone deacetylase activity.

Background technique

Ordered transcriptional regulation of genes is a prerequisite for normal cell function. If the transcriptional regulation of genes is dysfunctional, cells may become cancerous. The acetylation and deacetylation of core histones are closely related to gene regulation, and the histone acetylation and deacetylation are a pair of antagonistic proteases-histone acetyltransferases (HATs) and histone deacetylation Enzymes (HDACs). HDACs are a group of enzymes that regulate a series of biological effects including chromatin reorganization, transcription activation or inhibition, cell cycle, cell differentiation and apoptosis by inducing histone deacetylation at the cellular chromatin level, especially with The regulation of gene transcription and expression after cell activation. Histone deacetylase inhibitors are considered as promising anticancer drug targets by inhibiting the activity of HDACs, inducing apoptosis, differentiation and inhibiting proliferation. The current research on HDACs inhibitors involves many tumor fields, such as blood system, melanoma, breast cancer, ovarian cancer, prostate cancer, lung cancer and colon cancer. Studies have suggested that the inhibition of HDACs subtypes 1-5 and 7, 9 and other helpful for the treatment of tumors, the inhibition of HDAC6, 8 may be related to the toxicity of such compounds.

HDACs targets are a class of anti-tumor targets with application prospects. The existing HDACs inhibitors still cannot fully meet the clinical needs. It is to be found that novel and selective HDACs inhibitors are used to prevent and / or treat histones Diseases related to uncontrolled acetylase activity, especially tumor diseases.

Summary of the invention

The object of the present invention is to provide a new class of effective HDACs inhibitors and their pharmaceutically acceptable salts.

The technical solution of the present invention is as follows:

The compound of general formula (I) or a pharmaceutically acceptable salt thereof:

Where R ¹ is hydroxy, or 2-aminophenyl optionally substituted with one or more R ⁵ , R ^{5 is} selected from hydrogen, (C ₁ -C ₆ ) alkyl, cyano, halogen, halo (C ₁ -C ₆ ) alkyl, hydroxy, mercapto, amino, (C ₁ -C ₆ ) alkoxy, (C ₁ -C ₆ ) alkylthio, (C ₁ -C ₆ ) amino, phenyl, 5 or 6 Elementary heteroaryl

R ² is -LR ³ , where L is a bond, O, S, NR ⁴ ; R ³ is aryl, heteroaryl, saturated or partially saturated heterocyclic group, each aryl, heteroaryl, saturated or partially saturated heterocyclic groups optionally substituted with one or more substituents R ^6, R ⁶ is selected from hydrogen, (C ₁ -C ₆₎ alkyl, cyano, halo, halo (C ₁ -C ₆₎ alkyl, hydroxy , Mercapto, amino, (C ₁ -C ₆ ) alkoxy, (C ₁ -C ₆ ) alkylthio, (C ₁ -C ₆ ) alkylamino, tert-butoxycarbonyl;

Wherein R ^{4 is} selected from hydrogen and (C ₁ -C ₆ ) alkyl;

X is NH, NR ⁷ , O, S (O) n, R ^{7 is} selected from (C ₁ -C ₆ ) alkyl, and the value of n ranges from 0 to 2;

Q is aryl or heteroaryl, wherein aryl or heteroaryl are each independently optionally substituted with one or more substituents R ^8, R ⁸ is selected from hydrogen, (C ₁ -C ₆₎ alkyl, cyano, halo , Halo (C ₁ -C ₆ ) alkyl, hydroxyl, mercapto, (C ₁ -C ₆ ) alkoxy;

Wherein, the aryl group is a 6-10 membered aryl group; the heteroaryl group is a five-membered or six-membered heteroaryl group, wherein 1-4 ring atoms are heteroatoms selected from oxygen, nitrogen, sulfur, and the rest The ring atom is carbon; the heterocyclic group contains 5-10 ring atoms, of which 1-4 ring atoms are heteroatoms selected from oxygen, nitrogen and sulfur, and the remaining ring atoms are carbon.

The preferred solution of the present invention lies in:

R ¹ is hydroxy, or selected from 2-aminophenyl substituted by one or more R ⁵ , R ^{5 is} selected from hydrogen, (C ₁ -C ₆ ) alkyl, cyano, halogen, phenyl, thienyl;

R ² is -LR ³ , where L is a bond, O, S, NR ⁴ ; R ³ is aryl, heteroaryl, saturated or partially saturated heterocyclic group, each aryl, heteroaryl, saturated or partially saturated heterocyclic groups optionally substituted with one or more substituents R ^6, R ⁶ is selected from hydrogen, (C ₁ -C ₆₎ alkyl, cyano, halo, trifluoromethyl, hydroxy, mercapto, amino, methoxy Group, methylamino, tert-butoxycarbonyl;

Wherein R ^{4 is} selected from H, (C ₁ -C ₆ ) alkyl;

X is NH, NR ⁷ , O, S (O) n, R ^{7 is} selected from methyl, ethyl, and propyl, and the value of n ranges from 0 to 2;

Q is phenyl, pyridyl;

Wherein, the aryl group is phenyl; the heterocyclic group is piperidinyl, morpholinyl, piperazinyl; the aryl hetero group is pyrrolyl, pyrazolyl, imidazolyl, furyl, thienyl, oxo Oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyrimidinyl, pyrazinyl or pyridazinyl.

Another preferred solution of the present invention lies in:

R ¹ is hydroxy, or selected from 2-aminophenyl substituted by one or more R ⁵ , R ^{5 is} selected from hydrogen, halogen;

R ² is -LR ³ , where L is a bond, -NH; R ³ is the following aromatic ring, heterocyclic ring or substituted aromatic ring, substituted heterocyclic ring: phenyl, pyrrolyl, furyl, thienyl, pyrazole Group, imidazolyl, pyridyl, pyrazinyl, pyrimidinyl, morpholinyl, piperazinyl, piperidinyl, 1,4-oxazin-4-yl, substituents selected from methyl, ethyl, tert-butyl Group, 1 to 2 halogens, trifluoromethyl, methoxy, tert-butoxycarbonyl;

X is NH, O, S (O) n, the value range of n is 0 ～ 2;

Q is phenyl, pyridyl;

According to the present invention, pharmaceutically acceptable salts include acid addition salts of compounds of general formula I with the following acids: hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid Acid, citric acid, tartaric acid, lactic acid, pyruvic acid, acetic acid, maleic acid or succinic acid, fumaric acid, salicylic acid, phenylacetic acid, mandelic acid. In addition, it also includes acid salts of inorganic bases, such as salts containing alkaline metal cations, alkaline earth metal cations, and ammonium cations.

The compound of general formula I preferably has the following structural compounds:

N- (2-aminophenyl) -4-[[[4-[(5-methyl-1H-pyrazol-3-yl) amino] pyrrolo [2,1-f] [1,2,4 ] Triazin-2-yl] sulfur] 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] triazine-2 -Yl] sulfur] 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] benzyl Amide (I-7)

N- (2-amino-4-fluorophenyl) -4-[[[4-morpholinylpyrrolo [2,1-f] [1,2,4] triazin-2-yl] thio] methyl Group] benzamide (I-8)

N- (2-aminophenyl) -4-[[[4-[(4-fluorobenzyl) amino] pyrrolo [2,1-f] [1,2,4] triazin-2-yl] Sulfur] methyl] benzamide (I-9)

N- (2-amino-4-fluorophenyl) -4-[[[4-[(4-fluorobenzyl) amino] pyrrolo [2,1-f] [1,2,4] triazine- 2-yl] thio] methyl] benzamide (I-10)

N- (2-aminophenyl) -4-[[[4-[(4-trifluoromethylbenzyl) amino] pyrrolo [2,1-f] [1,2,4] triazine-2 -Yl] sulfur] 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] triazine-2- Yl] thio] methyl] benzamide (I-13)

N- (2-amino-4-fluorophenyl) -4-[[[4-[(4-methoxybenzyl) amino] pyrrolo [2,1-f] [1,2,4] tri Oxazin-2-yl] thio] methyl] benzamide (I-14)

N- (2-aminophenyl) -4-[[[4-[(3,4-dimethoxybenzyl) amino] pyrrolo [2,1-f] [1,2,4] triazine -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] triazine -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] triazine- 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] sulfur] methyl] benzamide (I-20)

N- (2-aminophenyl) -4-[[[4-[(N-Bocpiperidin-4-yl) amino] pyrrolo [2,1-f] [1,2,4] triazine- 2-yl] thio] methyl] benzamide (I-21)

N- (2-amino-4-fluorophenyl) -4-[[[4-[(N-Bocpiperidin-4-yl) amino] pyrrolo [2,1-f] [1,2,4 ] Triazin-2-yl] sulfur] 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] triazine -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] triazine-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] sulfoxide] 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] sulfone] 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] triazine-2- Group] amino] methyl] benzamide (I-36)

N- (2-aminophenyl) -4-[[[4H- (1,4-oxazin-4-yl) pyrrolo [2,1-f] [1,2,4] triazine-2- Group] amino] methyl] benzamide (I-37)

N- (2-aminophenyl) -4-[[[4-piperidylpyrrolo [2,1-f] [1,2,4] triazin-2-yl] amino] methyl] benzyl Amide (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 preparation method of the compound of the present invention is as follows:

method one:

Method Two:

Method three:

Method 4:

The compounds of the present invention can be prepared by the above-mentioned or similar preparation methods, and the corresponding raw materials can be selected according to the different substituents and the positions of the substituents.

The pharmacological test results show that the compound of formula I and its pharmaceutically acceptable salts have excellent inhibitory activity on HDAC1, therefore, the compound of formula I and its pharmaceutically acceptable salts can be used to treat those related to the above targets Clinical illness. The diseases related to HDAC1 may be, but 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, gallbladder cancer, myelodysplastic syndrome, lymphoma, esophageal cancer, thyroid follicular cancer, gastrointestinal cancer, tumors of the central or peripheral nervous system (e.g. astrocytoma, neuroma Cell tumors, gliomas or schwannomas), mesothelioma, type II or non-insulin-dependent diabetes, autoimmune diseases.

The following are some pharmacological tests and results:

(1) Determination and results of target compound's inhibitory activity against HDAC1

The synthesized compound was tested for its inhibitory activity against HDAC1 by fluorescence resonance energy transfer (FRET) method, and compared with the positive control drug, the compound with better activity was selected. HDAC1 is obtained by purification or direct purchase of kits.

Specific method: Add enzyme to the reaction well, and add reaction buffer to the control well. Add the sample dissolved in DMSO to the reaction well and incubate using a non-contact nanoscale sonic pipetting system. Add the corresponding fluorescent substrate to each reaction well and vortex. Incubate at 30 ℃ for 1-2h. Add a color reagent containing TMP26 to stop the reaction and produce fluorescence. The fluorescence intensity (excitation light: 490 nM, emission light: 520 nM) was detected using an EnVision multi-label microplate detector (Perkin Elmer). After the color development is stable, read the endpoint value. GraphPad Prism 4 software was used to calculate the percentage (relative to the DMSO control group) and half the inhibition rate.

Inhibitory activity of some compounds on HDAC1

Examples	HDAC1IC 50 (μm)	Examples	HDAC1IC 50 (μm)
Cidabenamide	0.163	I-21	0.372
I-1	0.152	I-22	3.12

I-2	0.615	I-23	0.0841
I-4	0.659	I-24	2.37
I-5	0.238	I-25	0.0932
I-6	1.54	I-26	4.15
I-7	0.204	I-27	> 10
I-8	2.31	I-28	9.21
I-9	0.159	I-29	3.30
I-10	1.22	I-30	1.17
I-11	0.267	I-31	0.0531
I-12	0.977	I-32	0.0728
I-13	0.812	I-33	0.398
I-14	5.04	I-34	0.122
I-15	0.696	I-35	0.212
I-16	5.16	I-37	0.0773
I-17	0.773	I-38	0.0612
I-18	2.13	I-39	2.46
I-19	0.104	I-40	2.98
I-20	1.33	I-41	5.73

(2) In vitro anti-tumor activity of target compounds

In this experiment, the CTG method was used to determine the inhibitory effects of compounds on tumor cell lines such as leukemia cell lines HL60 and K562, colon cancer cell line HCT116, and lymphoma cell line HuT78.

Experimental method: Collect cells in the exponential growth phase to count the viable cells. Adjust the cell suspension concentration with the corresponding medium for each cell. Add 90 μL of cell suspension to each 96-well cell culture plate. Each test compound was dissolved in DMSO as a 10 mM or 5 mM stock solution. Then dilute the solution to a 10-fold solution with the medium, each with 2 replicate wells. Add 10 μL of the corresponding 10-fold solution to each well of each cell, and the final concentration of the prepared drug is 5 μM or 20 μM, and the final concentration of DMSO is 0.1% to 0.5%, respectively (see compound preparation method and sample addition design: experimental well plate sample addition design) . Placed in 37 ℃, 5% CO ₂ incubator for 72h. After 72 hours of drug treatment, add 50 μL (1/2 culture volume) of CTG solution pre-melted to room temperature and equilibrate to room temperature. Mix with a microplate shaker for 2 minutes. After leaving at room temperature for 10 minutes, measure the fluorescence signal with the Envision 2104 plate reader . The cell inhibition rate is calculated by the formula: (1-V _sample / V _{vehicle control} × 100%). Where V _sample is the average value of the drug treatment group, and V _{vehicle control} is the average value of the solvent control group.

The inhibition rate of the compound on four tumor cell lines at a concentration of 5 μM%

Examples	HCT116	HL60	K562	HuT78	HuT78 (IC 50 )
I-1	97.9	99.9	99.5	99.8	0.093
I-2	96.5	99.8	99.4	99.8	0.108
I-3	97.9	99.6	99.3	99.8	0.088
I-4	94.3	99.9	99.0	99.9	0.062
I-5	97.0	99.9	99.4	99.8	0.072

I-6	91.1	99.9	94.7	98.8	0.088
I-7	98.7	99.8	99.4	99.7	0.205
I-8	96.2	99.9	99.1	99.7	0.115
I-9	94.9	99.6	98.0	99.8	0.163
I-11	84.0	99.9	90.2	99.4	0.322
I-13	96.3	99.8	99.3	99.6	0.517
I-15	96.1	99.3	98.2	99.6	0.221
I-17	92.3	99.9	96.5	99.7	0.123
I-23	89.9	99.6	96.5	99.1	0.093
I-25	99.0	96.2	97.8	99.0	0.101
I-30	99.3	87.1	91.3	99.5	0.119
I-31	99.3	98.7	98.8	99.7	0.082
I-32	99.5	90.1	95.2	99.4	0.203
I-33	99.4	96.9	99.0	99.6	0.187
I-34	99.4	94.4	99.1	99.5	0.154
I-35	99.4	97.7	99.2	99.7	0.253
I-37	99.5	97.5	98.8	99.6	0.421
I-38	99.5	93.2	98.7	99.3	0.398
MS-275	95.7	95.8	95.6	97.2	ND
Cidabenamide	88.5	95.9	95.6	96.8	0.687

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] sulfur] methyl] benzamide (I-1)

Step a: Preparation of methyl 1-amino-1H-pyrrole-2-carboxylate (1)

Preparation of monochloramine ether solution: at -25 ° C, slowly add ammonium chloride (8.00g, 0.150mol) to ether (100mL), add ammonia water (15mL), at -10 ° C, within 15min Sodium hypochlorite solution (100mL) was slowly added dropwise. After addition, stirring was continued for 15min to stop the reaction. After standing for 3min, the organic layer was quickly separated and dried with anhydrous magnesium sulfate at -25 ℃ for 1h. This is the ether of monochloramine Solution.

Dissolve 1H-pyrrole-2-carboxylic acid methyl ester (1.00g, 7.99mmol) in anhydrous tetrahydrofuran (15mL), react under nitrogen protection for 15min, add anhydrous tetrahydrofuran dissolved in sodium hydrogen (1.20g, 50.00mmol) The suspension (45 mL) was reacted at room temperature for 45 min, protected by nitrogen, and under ice bath, the above newly prepared monochloramine in ether was added dropwise. TLC showed that the reaction was over after 2h. Add anhydrous ethanol (1mL) to quench the excess sodium hydrogen, filter, distill off the solvent under reduced pressure, and separate by silica gel column chromatography (petroleum ether: ethyl acetate = 40: 1) to give a light yellow solid 0.91g, yield: 81.25%. Repeat the operation several times to obtain 11.32g of light yellow solid. mp: 40-42 ° C; ¹ H-NMR (300 MHz, DMSO-d ₆ ) δ (ppm): 7.03-7.01 (m, 1H), 6.71 (dd, J = 4.2 Hz, 2.0 Hz, 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)

The compound 1 (9.90 g, 70.64 mmol) prepared above was dissolved in tetrahydrofuran (300 mL), and benzoyl isothiocyanate (13.83 g, 84.77 mmol) was added dropwise. The reaction was carried out at room temperature for 10 h. TLC showed that the reaction was completed. The reaction solution was concentrated and separated by silica gel column chromatography (petroleum ether) to obtain 16.12 g of white solid with a yield of 75.23%. mp: 159-161 ° C; ESI-MS m / z: 326.0 [M + Na] ⁺ ; ¹ H-NMR (300 MHz, DMSO-d ₆ ) 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 (15.20 g, 50.11 mmol) prepared above was dissolved in methanol (400 mL), and sodium methoxide (22.70 g, 420.21 mmol) was added in portions. After reaction at room temperature for 3 h, TLC showed that the reaction was completed. The pH was adjusted to neutral, and after concentration, it was separated by silica gel column chromatography (dichloromethane: methanol = 10: 1) to obtain 6.52 g of white solid with a yield of 77.83%. mp:> 280 ° C; ESI-MS m / z: 166.0 [MH] ⁺ ; ¹ H-NMR (300MHz, DMSO-d ₆ ) 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)

In a 250 mL eggplant-shaped bottle, add the prepared compound 3 (6.00 g, 35.89 mmol), methanol (400 mL), and ethyl p-chloromethylbenzoate (7.13 g, 35.89 mmol). After an ice bath reaction for 3 h, TLC showed The reaction is over. The reaction solution was poured into water (70 mL), extracted with ethyl acetate (60 mL × 5), the organic phases were combined, washed with saturated brine (70 mL), dried over anhydrous sodium sulfate, left to stand, filtered, and the solvent was distilled off under reduced pressure , Separated by silica gel column chromatography (petroleum ether: ethyl acetate = 5: 1) to obtain 8.58 g of white solid, yield: 72.58%. mp: 198-200 ° C; ESI-MS m / z: 352.1 [M + Na] ⁺ ; ¹ H-NMR (300 MHz, DMSO-d ₆ ) 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)

Under ice bath conditions, the compound 4 (8.10 g, 24.59 mmol) prepared above was dissolved in phosphorous oxychloride (15 mL), N, N-diethylaniline (11.01 g, 73.78 mmol) was added, protected by nitrogen, and heated After refluxing for 10h, TLC showed that the reaction was over. Most of the phosphorus oxychloride was distilled off under reduced pressure. After cooling to room temperature in vacuo, the reaction was poured into ice water (400 mL), extracted with ethyl acetate (60 mL × 3), the organic layers were combined, and washed with saturated brine (60 mL) After adding anhydrous sodium sulfate to dry, let stand, filter, evaporate the solvent under reduced pressure, and separate by silica gel column chromatography (petroleum ether: ethyl acetate = 60: 1), to obtain a white solid 7.10g, yield: 83.01%. mp: 106-108 ° C; ESI-MS m / z: 370.0 [M + Na] ⁺ ; ¹ H-NMR (300 MHz DMSO-d ₆ ) δ (ppm): 8.19-8.20 (m, 1H), 7.91 (d , J = 8.2 Hz), 7.65 (d, J = 8.2 Hz, 2H), 7.06 (dd, J = 4.6 Hz, 1.3 Hz, 1H), 7.00 (dd, J = 4.6 Hz, 2.5 Hz, 1H), 4.47 (s, 2H), 4.30 (q, J = 7.1 Hz, 2H), 1.30 (t, J = 7.1 Hz, 3H).

Step f: 4-[[[4-[(5-methyl-1H-pyrazol-3-yl) amino] pyrrolo [2,1-f] [1,2,4] triazin-2-yl ] Thio] methyl] ethyl benzoate (6a) Preparation

5 (400 mg, 1.15 mmol) prepared above was dissolved in N, N-dimethylformamide (20 mL), potassium iodide (1.91 g, 11.50 mmol) was added, and stirred at 70 ° C. for 5 minutes. Then, N, N-diisopropylethylamine (743mg, 5.75mmol) and 5-methyl-3-aminopyrazole (223mg, 2.30mmol) were added, and the reaction was performed at 80 ° C for 36h. The reaction was detected by TLC. Water (80 mL) was added to the reaction solution, extracted with ethyl acetate (30 mL × 3), the organic layers were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, left to stand, filtered, and the solvent was distilled off under reduced pressure, silica gel column Chromatographic separation (petroleum ether: ethyl acetate = 3: 1) gave 321 mg of white solid, yield: 68.33%. mp: 200-202 ° C; ESI-MS m / z: 431.1 [M + Na] ⁺ ; ¹ H-NMR (300 MHz, DMSO-d ₆ ) 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: 4-[[[4-[(5-methyl-1H-pyrazol-3-yl) amino] pyrrolo [2,1-f] [1,2,4] triazin-2-yl ] Thio] methyl] benzoic acid (7a)

Add the compound 6a (300mg, 0.73mmol) and sodium hydroxide (59mg, 1.46mmol) prepared above to 25mL eggplant-shaped bottle, add water (10mL) and ethanol (20mL), react at 60 ℃ for 12h, and complete the reaction by TLC . The solvent was distilled off under reduced pressure, water (5 mL) was added, the pH was adjusted to 6-7 with glacial acetic acid solution under ice bath, frozen in a refrigerator for 2 h, suction filtered, and the filter cake was vacuum dried to obtain 262 mg of white solid, yield: 92.86% . mp:> 270 ℃; ESI-MS m / z: 379.1 [MH] ^- ; ¹ H-NMR (300 MHz, DMSO-d ₆ ) 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: N- (2-aminophenyl) -4-[[[4-[(5-methyl-1H-pyrazol-3-yl) amino] pyrrolo [2,1-f] [1, Preparation of 2,4] triazin-2-yl] thio] methyl] benzamide (I-1)

To a 25mL eggplant-shaped bottle, add 7a (100mg, 0.26mmol) and TBTU (93mg, 0.29mmol) prepared above, add N, N-dimethylformamide (10mL), and then add N, N-diisopropyl Ethylamine (136mg, 1.05mmol), stirred at room temperature for 1h, and then added o-phenylenediamine (31mg, 0.29mmol), continued stirring at room temperature for 4h, TLC detected the reaction was complete. Water (80 mL) was added to the reaction solution, extracted with ethyl acetate (30 mL × 3), the organic layers were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, left to stand, filtered, and the solvent was distilled off under reduced pressure, silica gel column Chromatographic separation (petroleum ether: ethyl acetate = 1: 1) gave 28 mg of white solid, yield: 22.64%. mp: 145-147 ° C; ESI-MS m / z: 493.1 [M + Na] ⁺ ; ¹ H-NMR (300 MHz, DMSO-d ₆ ) δ (ppm): 12.26 (br.s, 1H), 10.63 ( s, 1H), 9.65 (s, 1H), 7.91 (d, J = 8.1 Hz, 2H), 7.68-7.67 (m, 1H), 7.58 (d, J = 8.1 Hz, 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)

Step a: 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-shaped bottle, add 7a (150mg, 0.39mmol) and TBTU (140mg, 0.43mmol) prepared above, add N, N-dimethylformamide (10mL), and then add N, N-diisopropyl Ethylamine (204mg, 1.58mmol), stirred at room temperature for 1h, and then added p-fluoro-o-phenylenediamine (55mg, 0.43mmol), continued stirring at room temperature for 4h, TLC detection reaction was complete. Water (80 mL) was added to the reaction solution, extracted with ethyl acetate (30 mL × 3), the organic layers were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, left to stand, filtered, and the solvent was distilled off under reduced pressure, silica gel column Chromatographic separation (petroleum ether: ethyl acetate = 1: 1) gave a white solid 25 mg, yield: 12.98%. mp: 147-149 ° C; ESI-MS m / z: 511.2 [M + Na] ⁺ ; ¹ H-NMR (300 MHz, DMSO-d ₆ ) 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] triazine-2 -Yl] sulfur] methyl] benzamide (I-3)

Step a: 4-[[[4-[(1H-pyrazol-3-yl) amino] pyrrolo [2,1-f] [1,2,4] triazin-2-yl] thio] methyl ] Preparation of ethyl benzoate (6b)

5 (500 mg, 1.44 mmol) prepared above was dissolved in N, N-dimethylformamide (20 mL), potassium iodide (2.39 g, 14.38 mmol) was added, and stirred at 70 ° C. for 5 minutes. Then, N, N-diisopropylethylamine (929 mg, 7.19 mmol) and 3-aminopyrazole (239 mg, 2.88 mmol) were added, and the reaction was performed at 80 ° C for 36 h. The reaction was detected by TLC. Water (80 mL) was added to the reaction solution, extracted with ethyl acetate (30 mL × 3), the organic layers were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, left to stand, filtered, and the solvent was distilled off under reduced pressure, silica gel column Chromatographic separation (petroleum ether: ethyl acetate = 3: 1) gave 314 mg of white solid, yield: 55.38%. mp: 185-187 ° C; ESI-MS m / z: 393.1 [MH] ^- ; ¹ H-NMR (300 MHz, DMSO-d ₆ ) δ (ppm): 12.58 (br.s, 1H), 10.74 (s, 1H), 7.88 (d, J = 8.1 Hz, 2H), 7.71 (s, 1H), 7.67 (s, 1H), 7.59 (d, J = 8.1 Hz, 2H), 7.23 (s, 1H), 6.71 ( s, 1H), 6.62-6.60 (m, 1H), 4.42 (s, 2H), 4.29 (q, J = 7.1 Hz, 2H), 1.30 (t, J = 7.1 Hz, 3H).

Step b: 4-[[[4-[(1H-pyrazol-3-yl) amino] pyrrolo [2,1-f] [1,2,4] triazin-2-yl] thio] methyl ] Preparation of benzoic acid (7b)

Into a 25mL eggplant-shaped bottle, add the above-prepared compound 6b (300mg, 0.76mmol) and sodium hydroxide (61mg, 1.52mmol), add water (10mL) and ethanol (20mL), react at 60 ℃ for 12h, the reaction is complete by TLC detection . The solvent was distilled off under reduced pressure, water (5 mL) was added, the pH was adjusted to 6-7 with glacial acetic acid solution under ice bath, frozen in a refrigerator for 2 h, suction filtered, and the filter cake was vacuum dried to obtain 233 mg of white solid, yield: 83.54% . mp:> 270 ° C; ESI-MS m / z: 389.1 [M + Na] ⁺ ; ¹ H-NMR (300 MHz, DMSO-d ₆ ) 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: N- (2-aminophenyl) -4-[[[4-[(1H-pyrazol-3-yl) amino] pyrrolo [2,1-f] [1,2,4] Preparation of aziridin-2-yl] thio] methyl] benzamide (I-3)

To a 25mL eggplant-shaped bottle, add 7b (100mg, 0.27mmol) and TBTU (97mg, 0.30mmol) prepared above, add N, N-dimethylformamide (10mL), and then add N, N-diisopropyl Ethylamine (141mg, 1.09mmol), stirred at room temperature for 1h, then added o-phenylenediamine (32mg, 0.30mmol), continued stirring at room temperature for 4h, TLC detected the reaction was complete. Water (80 mL) was added to the reaction solution, extracted with ethyl acetate (30 mL × 3), the organic layers were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, left to stand, filtered, and the solvent was distilled off under reduced pressure, silica gel column Chromatographic separation (petroleum ether: ethyl acetate = 1: 1) gave a white solid 69 mg, yield: 55.38%. mp: 194-196 ° C; ESI-MS m / z: 479.1 [M + Na] ⁺ ; ¹ H-NMR (300 MHz, DMSO-d ₆ ) δ (ppm): 12.58 (s, 1H), 10.75 (s, 1H), 9.61 (s, 1H), 7.90 (d, J = 8.1 Hz, 2H), 7.72 (d, 1H), 7.69-7.68 (m, 1H), 7.57 (d, J = 8.1 Hz, 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)

Step a: N- (2-Amino-4-fluorophenyl) -4-[[[4-[(1H-pyrazol-3-yl) amino] pyrrolo [2,1-f] [1,2 , 4] Triazine-2-yl] thio] methyl] benzamide (I-4)

To a 25mL eggplant-shaped bottle, add 7b (100mg, 0.27mmol) and TBTU (97mg, 0.30mmol) prepared above, add N, N-dimethylformamide (10mL), and then add N, N-diisopropyl Ethylamine (141mg, 1.09mmol), stirred at room temperature for 1h, then added p-fluoro-o-phenylenediamine (38mg, 0.30mmol), continued stirring at room temperature for 4h, TLC detected the reaction was complete. Water (80 mL) was added to the reaction solution, extracted with ethyl acetate (30 mL × 3), the organic layers were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, left to stand, filtered, and the solvent was distilled off under reduced pressure, silica gel column Chromatographic separation (petroleum ether: ethyl acetate = 1: 1) gave 82 mg of white solid, yield: 63.32%. mp: 166-168 ° C; ESI-MS m / z: 473.1 [MH] ^- ; ¹ H-NMR (300 MHz, DMSO-d ₆ ) δ (ppm): 12.58 (s, 1H), 10.74 (s, 1H) , 9.53 (s, 1H), 7.90 (d, J = 8.1 Hz, 2H), 7.72-7.68 (m, 2H), 7.56 (d, J = 8.1 Hz, 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)

Step a: 4-[[[4-[(5-tert-butyl-1H-pyrazol-3-yl) amino] pyrrolo [2,1-f] [1,2,4] triazine-2- Of ethyl] thio] methyl] benzoate (6c)

5 (500 mg, 1.44 mmol) prepared above was dissolved in N, N-dimethylformamide (20 mL), potassium iodide (2.39 g, 14.38 mmol) was added, and stirred at 70 ° C. for 5 minutes. Then, N, N-diisopropylethylamine (929 mg, 7.19 mmol) and 5-tert-butyl-3-aminopyrazole (400 mg, 2.88 mmol) were added, and the reaction was performed at 80 ° C for 3 h. The reaction was detected by TLC. Water (80 mL) was added to the reaction solution, extracted with ethyl acetate (30 mL × 3), the organic layers were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, left to stand, filtered, and the solvent was distilled off under reduced pressure, silica gel column Chromatographic separation (petroleum ether: ethyl acetate = 5: 1) gave 579 mg of yellow solid, yield: 89.39%. mp: 130-132 ° C; ESI-MS m / z: 473.1 [M + Na] ⁺ ; ¹ H-NMR (300 MHz, CDCl ₃ -d ₆ ) δ (ppm): 8.88 (s, 1H), 7.97 (d , J = 8.2 Hz, 2H), 7.54-7.51 (m, 3H), 6.73 (s, 1H), 6.64-6.63 (m, 1H), 6.56 (dd, J = 4.3 Hz, 2.6 Hz, 1H), 4.45 (s, 2H), 4.36 (q, J = 7.1 Hz, 2H), 1.37 (t, J = 7.1 Hz, 3H), 1.32 (s, 9H).

Step b: 4-[[[4-[(5-tert-butyl-1H-pyrazol-3-yl) amino] pyrrolo [2,1-f] [1,2,4] triazine-2- Of thio] thio] methyl] benzoic acid (7c)

Into a 25mL eggplant-shaped bottle, add the above-prepared compound 6c (500mg, 1.11mmol) and sodium hydroxide (89mg, 2.22mmol), add water (20mL) and ethanol (40mL), react at 60 ℃ for 12h, and complete the reaction by TLC. . The solvent was distilled off under reduced pressure, water (20 mL) was added, the pH was adjusted to 6-7 with glacial acetic acid solution under ice bath, frozen in a refrigerator for 2 h, suction filtered, and the filter cake was vacuum dried to obtain 369 mg of white solid, yield: 78.70% . mp: 269-271 ° C; ESI-MS m / z: 423.2 [M + H] ⁺ ; ¹ H-NMR (300 MHz, DMSO-d ₆ ) 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: N- (2-aminophenyl) -4-[[[4-[(5-tert-butyl-1H-pyrazol-3-yl) amino] pyrrolo [2,1-f] [1 Of 2,2,4] triazin-2-yl] thio] methyl] benzamide (I-5)

To a 25mL eggplant-shaped bottle, add 7c (150mg, 0.36mmol) and TBTU (126mg, 0.39mmol) prepared above, add N, N-dimethylformamide (10mL), and then add N, N-diisopropyl Ethylamine (183mg, 1.42mmol), stirred at room temperature for 1h, then added o-phenylenediamine (42mg, 0.39mmol), continued stirring at room temperature for 8h, TLC detected the reaction was complete. Water (80 mL) was added to the reaction solution, extracted with ethyl acetate (30 mL × 3), the organic layers were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, left to stand, filtered, and the solvent was distilled off under reduced pressure, silica gel column Chromatographic separation (petroleum ether: ethyl acetate = 1: 1) gave 134 mg of white solid, yield: 73.63%. mp: 160-162 ° C; ESI-MS m / z: 535.2 [M + Na] ⁺ ; ¹ H-NMR (300 MHz, DMSO-d ₆ ) 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)

Step a: 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)

To a 25mL eggplant-shaped bottle, add 7c (150mg, 0.36mmol) and TBTU (126mg, 0.39mmol) prepared above, add N, N-dimethylformamide (10mL), and then add N, N-diisopropyl Ethylamine (183mg, 1.42mmol), stirred at room temperature for 1h, then added p-fluoro-o-phenylenediamine (49mg, 0.39mmol), continued stirring at room temperature for 8h, TLC detected the reaction was complete. Water (80 mL) was added to the reaction solution, extracted with ethyl acetate (30 mL × 3), the organic layers were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, left to stand, filtered, and the solvent was distilled off under reduced pressure, silica gel column Chromatographic separation (petroleum ether: ethyl acetate = 1: 1) gave 144 mg of light yellow solid, yield: 76.60%. mp: 152-154 ° C; ESI-MS m / z: 553.2 [M + Na] ⁺ ; ¹ H-NMR (300 MHz, DMSO-d ₆ ) 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] benzyl Amide (I-7)

Step a: Preparation of ethyl 4-[[[4-morpholinylpyrrolo [2,1-f] [1,2,4] triazin-2-yl] thio] methyl] benzoate (6d)

5 (500 mg, 1.44 mmol) prepared above was dissolved in N, N-dimethylformamide (20 mL), potassium iodide (2.39 g, 14.38 mmol) was added, and stirred at 70 ° C. for 5 minutes. Then, N, N-diisopropylethylamine (929 mg, 7.19 mmol) and morpholine (250 mg, 2.88 mmol) were added, and the reaction was performed at 80 ° C. for 3 h. The reaction was completed by TLC. Water (80 mL) was added to the reaction solution, extracted with ethyl acetate (30 mL × 3), the organic layers were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, left to stand, filtered, and the solvent was distilled off under reduced pressure, silica gel column Chromatographic separation (petroleum ether: ethyl acetate = 5: 1) gave 563 mg of white solid, yield: 98.28%. mp: 95-97 ° C; ESI-MS m / z: 421.1 [M + Na] ⁺ ; ¹ H-NMR (300 MHz, DMSO-d ₆ ) δ (ppm): 7.89 (d, J = 8.1 Hz, 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 = 7.1 Hz, 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)

Into a 100mL eggplant-shaped bottle was added the compound 6d (500mg, 1.25mmol) and sodium hydroxide (100mg, 2.50mmol) prepared above, added water (20mL) and ethanol (40mL), the reaction was refluxed for 10h, TLC detection reaction was complete. The solvent was distilled off under reduced pressure, water (30 mL) was added, the pH was adjusted to 6-7 with glacial acetic acid solution in an ice bath, frozen in a refrigerator for 2 h, suction filtered, and the filter cake was dried in vacuum to obtain a white solid 350 mg, yield: 75.30% . mp: 156-158 ° C; ESI-MS m / z: 371.1 [M + H] ⁺ ; ¹ H-NMR (300 MHz, DMSO-d ₆ ) δ (ppm): 7.86 (d, J = 8.0 Hz, 2H) , 7.69 (s, 1H), 7.52 (d, J = 8.0 Hz, 2H), 6.96-6.94 (m, 1H), 6.62 (dd, J = 4.2 Hz, 2.7 Hz, 1H), 4.37 (s, 2H) , 3.93-3.91 (m, 4H), 3.72-3.70 (m, 4H).

Step c: N- (2-aminophenyl) -4-[[[4-morpholinylpyrrolo [2,1-f] [1,2,4] triazin-2-yl] thio] methyl ] Preparation of benzamide (I-7)

Into a 25mL eggplant-shaped bottle, add 7d (150mg, 0.41mmol) and TBTU (143mg, 0.45mmol) prepared above, add N, N-dimethylformamide (10mL), and then add N, N-diisopropyl Ethylamine (209mg, 1.62mmol), stirred at room temperature for 1h, then added o-phenylenediamine (44mg, 0.41mmol), continued stirring at room temperature for 8h, TLC detected the reaction was complete. Water (80 mL) was added to the reaction solution, extracted with ethyl acetate (30 mL × 3), the organic layers were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, left to stand, filtered, and the solvent was distilled off under reduced pressure, silica gel column Chromatographic separation (petroleum ether: ethyl acetate = 1: 1) gave 61 mg of white solid, yield: 32.62%. mp: 180-182 ° C; ESI-MS m / z: 483.2 [M + Na] ⁺ ; ¹ H-NMR (300 MHz, DMSO-d ₆ ) δ (ppm): 9.61 (s, 1H), 7.91 (d, J = 8.1 Hz, 2H), 7.71-7.70 (m, 1H), 7.57 (d, J = 8.2 Hz, 2H), 7.14 (d, J = 7.4 Hz, 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 Group] benzamide (I-8)

Step a: N- (2-amino-4-fluorophenyl) -4-[[[4-morpholinylpyrrolo [2,1-f] [1,2,4] triazin-2-yl] Preparation of sulfur] methyl] benzamide (I-8)

Into a 25mL eggplant-shaped bottle, add 7d (150mg, 0.41mmol) and TBTU (143mg, 0.45mmol) prepared above, add N, N-dimethylformamide (10mL), and then add N, N-diisopropyl Ethylamine (209mg, 1.62mmol), stirred at room temperature for 1h, then added p-fluoro-o-phenylenediamine (51mg, 0.41mmol), continued stirring at room temperature for 8h, TLC detected the reaction was complete. Water (80 mL) was added to the reaction solution, extracted with ethyl acetate (30 mL × 3), the organic layers were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, left to stand, filtered, and the solvent was distilled off under reduced pressure, silica gel column Chromatographic separation (petroleum ether: ethyl acetate = 1: 1) gave 68 mg of white solid, yield: 35.05%. mp: 198-200 ° C; ESI-MS m / z: 501.1 [M + Na] ⁺ ; ¹ H-NMR (300 MHz, DMSO-d ₆ ) δ (ppm): 9.54 (s, 1H), 7.90 (d, J = 8.1 Hz, 2H), 7.71-7.70 (m, 1H), 7.56 (d, J = 8.1 Hz, 2H), 7.11-7.06 (m, 1H), 6.96 (dd, J = 4.6 Hz, 1.2 Hz, 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] Sulfur] methyl] benzamide (I-9)

Step a: 4-[[[4-[(4-fluorobenzyl) amino] pyrrolo [2,1-f] [1,2,4] triazin-2-yl] thio] methyl] benzoic acid Preparation of ethyl ester (6e)

5 (500 mg, 1.44 mmol) prepared above was dissolved in N, N-dimethylformamide (20 mL), potassium iodide (2.39 g, 14.38 mmol) was added, and stirred at 70 ° C. for 5 minutes. Then, N, N-diisopropylethylamine (929 mg, 7.19 mmol) and p-fluorobenzylamine (360 mg, 2.88 mmol) were added, and the reaction was performed at 80 ° C. for 4 h. The reaction was completed by TLC. Water (80 mL) was added to the reaction solution, extracted with ethyl acetate (30 mL × 3), the organic layers were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, left to stand, filtered, and the solvent was distilled off under reduced pressure, silica gel column Chromatographic separation (petroleum ether: ethyl acetate = 5: 1) gave 594 mg of white solid, yield: 94.66%. mp: 94-96 ° C; ESI-MS m / z: 459.2 [M + Na] ⁺ ; ¹ H-NMR (300 MHz, DMSO-d ₆ ) 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 = 4.2 Hz, 1.2 Hz, 1H), 6.55 (dd, J = 4.3 Hz, 2.6 Hz, 1H), 4.69 (d, J = 5.7 Hz, 2H), 4.36 (s, 2H), 4.27 (q, J = 7.1Hz, 2H), 1.31 (t, J = 7.1Hz, 3H).

Step b: 4-[[[4-[(4-fluorobenzyl) amino] pyrrolo [2,1-f] [1,2,4] triazin-2-yl] thio] methyl] benzoic acid (7e) Preparation

To a 100 mL eggplant-shaped bottle, the compound 6e (500 mg, 1.15 mmol) and sodium hydroxide (92 mg, 2.30 mmol) obtained above were added, water (20 mL) and ethanol (40 mL) were added, and the reaction was refluxed for 10 h. The reaction was completed by TLC. The solvent was distilled off under reduced pressure, water (30 mL) was added, the pH was adjusted to 6-7 with glacial acetic acid solution in an ice bath, frozen in a refrigerator for 2 h, filtered with suction, and the filter cake was vacuum dried to obtain 368 mg of white solid, yield: 78.66% . mp: 180-182 ° C; ESI-MS m / z: 409.1 [M + H] ⁺ ; ¹ H-NMR (300 MHz, DMSO-d ₆ ) δ (ppm): 12.90 (br.s, 1H, COOH), 8.95 (t, J = 5.7 Hz, 1H, NH-CH _2- ), 7.82 (d, J = 8.2 Hz, 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-CH _2- ), 4.35 (s, 2H , -SCH _2- ).

Step c: N- (2-aminophenyl) -4-[[[4-[(4-fluorobenzyl) amino] pyrrolo [2,1-f] [1,2,4] triazine-2 -Yl] thio] methyl] benzamide (I-9)

Into a 25mL eggplant-shaped bottle, add 7e (150mg, 0.37mmol) and TBTU (130mg, 0.40mmol) prepared above, add N, N-dimethylformamide (10mL), and then add N, N-diisopropyl Ethylamine (190mg, 1.47mmol), stirred at room temperature for 1h, and then added o-phenylenediamine (40mg, 0.37mmol), continued stirring at room temperature for 8h, TLC detection reaction was complete. Water (80 mL) was added to the reaction solution, extracted with ethyl acetate (30 mL × 3), the organic layers were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, left to stand, filtered, and the solvent was distilled off under reduced pressure, silica gel column Chromatographic separation (petroleum ether: ethyl acetate = 1: 1) gave a yellow solid 94 mg, yield: 51.34%. mp: 133-135 ° C; ESI-MS m / z: 521.1 [M + Na] ⁺ ; ¹ H-NMR (300 MHz, DMSO-d ₆ ) δ (ppm): 9.60 (s, 1H), 8.93 (t, J = 5.5 Hz, 1H), 7.87 (d, J = 8.0 Hz, 2H), 7.59-7.58 (m, 1H), 7.49 (d, J = 8.0 Hz, 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 = 5.5 Hz, 2H), 4.36 (s, 2H).

Example 10

N- (2-amino-4-fluorophenyl) -4-[[[4-[(4-fluorobenzyl) amino] pyrrolo [2,1-f] [1,2,4] triazine- 2-yl] thio] methyl] benzamide (I-10)

Step a: N- (2-Amino-4-fluorophenyl) -4-[[[4-[(4-fluorobenzyl) amino] pyrrolo [2,1-f] [1,2,4] Preparation of triazin-2-yl] thio] methyl] benzamide (I-10)

To a 25mL eggplant-shaped bottle, add 7e (200mg, 0.49mmol) and TBTU (173mg, 0.54mmol) prepared above, add N, N-dimethylformamide (10mL), and then add N, N-diisopropyl Ethylamine (253mg, 1.96mmol), stirred at room temperature for 1h, then added p-fluoro-o-phenylenediamine (62mg, 0.49mmol), continued stirring at room temperature for 8h, TLC detected the reaction was complete. Water (80 mL) was added to the reaction solution, extracted with ethyl acetate (30 mL × 3), the organic layers were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, left to stand, filtered, and the solvent was distilled off under reduced pressure, silica gel column Chromatographic separation (petroleum ether: ethyl acetate = 1: 1) gave 145 mg of off-white solid, yield: 57.31%. mp: 205-207 ° C; ESI-MS m / z: 539.1 [M + Na] ⁺ ; ¹ H-NMR (300 MHz, DMSO-d ₆ ) 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 = 5.7 Hz, 2H), 4.36 (s, 2H).

Example 11

N- (2-aminophenyl) -4-[[[4-[(4-trifluoromethylbenzyl) amino] pyrrolo [2,1-f] [1,2,4] triazine-2 -Yl] sulfur] methyl] benzamide (I-11)

Step a: 4-[[[4-[(4-trifluoromethylbenzyl) amino] pyrrolo [2,1-f] [1,2,4] triazin-2-yl] thio] methyl ] Preparation of ethyl benzoate (6f)

5 (500 mg, 1.44 mmol) prepared above was dissolved in N, N-dimethylformamide (20 mL), potassium iodide (2.39 g, 14.38 mmol) was added, and stirred at 70 ° C. for 5 minutes. Then, N, N-diisopropylethylamine (929 mg, 7.19 mmol) and p-trifluoromethylbenzylamine (504 mg, 2.88 mmol) were added, and the reaction was performed at 80 ° C. for 3 h. The reaction was completed by TLC. Water (80 mL) was added to the reaction solution, extracted with ethyl acetate (30 mL × 3), the organic layers were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, left to stand, filtered, and the solvent was distilled off under reduced pressure, silica gel column Chromatographic separation (petroleum ether: ethyl acetate = 5: 1) gave 658 mg of white solid, yield: 94.08%. mp: 91-93 ° C; ESI-MS m / z: 509.2 [M + Na] ⁺ ; ¹ H-NMR (300 MHz, CDCl ₃ -d ₆ ) δ (ppm): 7.34 (d, J = 8.2 Hz, 2H ), 7.59 (d, J = 8.1 Hz, 2H), 7.48-7.42 (m, 5H), 6.57-6.51 (m, 2H), 4.86 (d, J = 5.6 Hz, 2H), 4.39-4.32 (m, 4H), 1.37 (t, J = 7.1Hz, 3H).

Step b: 4-[[[4-[(4-trifluoromethylbenzyl) amino] pyrrolo [2,1-f] [1,2,4] triazin-2-yl] thio] methyl ] Preparation of benzoic acid (7f)

Into a 100mL eggplant-shaped bottle was added the above-prepared compound 6f (600mg, 1.23mmol) and sodium hydroxide (98mg, 2.46mmol), added water (20mL) and ethanol (40mL), the reaction was refluxed for 10h, TLC detection reaction was complete. The solvent was distilled off under reduced pressure, water (30 mL) was added, and the pH was adjusted to 6-7 with glacial acetic acid solution in an ice bath, frozen and allowed to stand in the refrigerator for 2 h, suction filtered, and the filter cake was vacuum dried to obtain a white solid 459 mg, yield: 81.18% . mp: 200-202 ° C; ESI-MS m / z: 481.1 [M + Na] ⁺ ; ¹ H-NMR (300 MHz, DMSO-d ₆ ) 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 = 8.0 Hz, 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 = 5.6 Hz, 2H), 4.31 (s, 2H).

Step c: N- (2-aminophenyl) -4-[[[4-[(4-trifluoromethylbenzyl) amino] pyrrolo [2,1-f] [1,2,4] tri Preparation of aziridin-2-yl] thio] methyl] benzamide (I-11)

Into a 25mL eggplant-shaped bottle, add 7f (150mg, 0.33mmol) and TBTU (116mg, 0.36mmol) prepared above, add N, N-dimethylformamide (10mL), and then add N, N-diisopropyl Ethylamine (169mg, 1.31mmol), stirred at room temperature for 1h, then added o-phenylenediamine (35mg, 0.33mmol), and continued stirring at room temperature for 4h, TLC detected the reaction was complete. Water (80 mL) was added to the reaction solution, extracted with ethyl acetate (30 mL × 3), the organic layers were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, left to stand, filtered, and the solvent was distilled off under reduced pressure, silica gel column Chromatographic separation (petroleum ether: ethyl acetate = 1: 1) gave 115 mg of white solid, yield: 64.25%. mp: 172-174 ° C; ESI-MS m / z: 571.1 [M + Na] ⁺ ; ¹ H-NMR (300 MHz, DMSO-d ₆ ) δ (ppm): 9.59 (s, 1H), 9.03 (t, J = 5.8 Hz, 1H), 7.85 (d, J = 8.1 Hz, 2H), 7.71 (d, J = 7.2 Hz, 2H), 7.61 (dd, J = 2.3 Hz, 1.6 Hz, 1H), 7.55 (d , J = 8.0 Hz, 2H), 7.45 (d, J = 8.2 Hz, 2H), 7.14 (d, J = 7.2 Hz, 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 = 5.6 Hz, 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)

Step a: N- (2-amino-4-fluorophenyl) -4-[[[4-[(4-trifluoromethylbenzyl) amino] pyrrolo [2,1-f] [1,2 , 4] Triazine-2-yl] thio] methyl] benzamide (I-12) Preparation

Into a 25mL eggplant-shaped bottle, add 7f (150mg, 0.33mmol) and TBTU (116mg, 0.36mmol) prepared above, add N, N-dimethylformamide (10mL), and then add N, N-diisopropyl Ethylamine (169mg, 1.31mmol), stirred at room temperature for 1h, then added p-fluoro-o-phenylenediamine (41mg, 0.33mmol), continued stirring at room temperature for 8h, the reaction was complete by TLC. Water (80 mL) was added to the reaction solution, extracted with ethyl acetate (30 mL × 3), the organic layers were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, left to stand, filtered, and the solvent was distilled off under reduced pressure, silica gel column Chromatographic separation (petroleum ether: ethyl acetate = 1: 1) gave 123 mg of white solid, yield: 66.49%. mp: 129-131 ° C; ESI-MS m / z: 589.1 [M + Na] ⁺ ; ¹ H-NMR (300 MHz, DMSO-d ₆ ) 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] triazine-2- Yl] thio] methyl] benzamide (I-13)

Step a: 4-[[[4-[(4-methoxybenzyl) amino] pyrrolo [2,1-f] [1,2,4] triazin-2-yl] thio] methyl] Preparation of ethyl benzoate (6g)

5 (500 mg, 1.44 mmol) prepared above was dissolved in N, N-dimethylformamide (20 mL), potassium iodide (2.39 g, 14.38 mmol) was added, and stirred at 70 ° C. for 5 minutes. Then, N, N-diisopropylethylamine (929 mg, 7.19 mmol) and p-methoxybenzylamine (394 mg, 2.88 mmol) were added, and the reaction was performed at 80 ° C. for 3 h. The reaction was detected by TLC. Water (80 mL) was added to the reaction solution, extracted with ethyl acetate (30 mL × 3), the organic layers were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, left to stand, filtered, and the solvent was distilled off under reduced pressure, silica gel column Chromatographic separation (petroleum ether: ethyl acetate = 5: 1) gave 582 mg of yellow solid, yield: 90.26%. mp: 74-76 ° C; ESI-MS m / z: 471.1 [M + Na] ⁺ ; ¹ H-NMR (300 MHz, DMSO-d ₆ ) δ (ppm): 8.88 (t, J = 5.8 Hz, 1H) , 7.82 (d, J = 8.3 Hz, 2H), 7.56-7.55 (m, 1H), 7.48 (d, J = 8.3 Hz, 2H), 7.23 (d, J = 8.6 Hz, 2H), 6.89-6.86 ( m, 3H), 6.53 (dd, J = 4.3 Hz, 2.6 Hz, 1H), 4.63 (d, J = 5.8 Hz, 2H), 4.37 (s, 2H), 4.28 (q, J = 7.1 Hz, 2H) , 3.71 (s, 3H), 1.30 (t, J = 7.1 Hz, 3H).

Step b: 4-[[[4-[(4-methoxybenzyl) amino] pyrrolo [2,1-f] [1,2,4] triazin-2-yl] thio] methyl] Preparation of benzoic acid (7g)

To a 100 mL eggplant-shaped bottle, 6 g (500 mg, 1.11 mmol) and sodium hydroxide (89 mg, 2.22 mmol) of the compound prepared above were added, water (20 mL) and ethanol (40 mL) were added, the reaction was refluxed for 10 h, and the reaction was detected by TLC. The solvent was distilled off under reduced pressure, water (30 mL) was added, the pH was adjusted to 6-7 with glacial acetic acid solution under ice bath, frozen in a refrigerator for 2 h, suction filtered, and the filter cake was vacuum dried to obtain 383 mg of white solid, yield: 81.71% . mp: 185-187 ° C; ESI-MS m / z: 421.1 [M + H] ⁺ ; ¹ H-NMR (300 MHz, DMSO-d ₆ ) δ (ppm): 13.00 (br.s, 1H), 8.89 ( t, J = 5.7 Hz, 1H), 7.81 (d, J = 8.2 Hz, 2H), 7.57-7.55 (m, 1H), 7.44 (d, J = 8.1 Hz, 2H), 7.24 (d, J = 8.6 Hz, 2H), 6.90-6.86 (m, 3H), 6.53 (dd, J = 4.3 Hz, 2.6 Hz, 1H), 4.63 (d, J = 5.7 Hz, 2H), 4.36 (s, 2H), 3.71 ( s, 3H).

Step c: N- (2-aminophenyl) -4-[[[4-[(4-methoxybenzyl) amino] pyrrolo [2,1-f] [1,2,4] triazine Preparation of -2-yl] thio] methyl] benzamide (I-13)

To a 25mL eggplant-shaped bottle, add 7g (150mg, 0.36mmol) and TBTU (126mg, 0.39mmol) prepared above, add N, N-dimethylformamide (10mL), and then add N, N-diisopropyl Ethylamine (185mg, 1.43mmol), stirred at room temperature for 1h, then added o-phenylenediamine (39mg, 0.36mmol), continued stirring at room temperature for 8h, TLC detected the reaction was complete. Water (80 mL) was added to the reaction solution, extracted with ethyl acetate (30 mL × 3), the organic layers were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, left to stand, filtered, and the solvent was distilled off under reduced pressure, silica gel column Chromatographic separation (petroleum ether: ethyl acetate = 1: 1) gave 79 mg of white solid, yield: 43.41%. mp: 184-186 ° C; ESI-MS m / z: 533.2 [M + Na] ⁺ ; ¹ H-NMR (300 MHz, DMSO-d ₆ ) δ (ppm): 9.60 (s, 1H), 8.87 (t, J = 5.8 Hz, 1H), 7.87 (d, J = 8.1 Hz, 2H), 7.57 (dd, J = 2.4 Hz, 1.6 Hz, 1H), 7.49 (d, J = 8.3 Hz, 2H), 7.26 (d , J = 8.6 Hz, 2H), 7.15 (d, J = 7.1 Hz, 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 = 5.7 Hz, 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] tri Oxazin-2-yl] thio] methyl] benzamide (I-14)

Step a: N- (2-amino-4-fluorophenyl) -4-[[[4-[(4-methoxybenzyl) amino] pyrrolo [2,1-f] [1,2, 4] Preparation of triazin-2-yl] thio] methyl] benzamide (I-14)

To a 25mL eggplant-shaped bottle, add 7g (150mg, 0.36mmol) and TBTU (126mg, 0.39mmol) prepared above, add N, N-dimethylformamide (10mL), and then add N, N-diisopropyl Ethylamine (185mg, 1.43mmol), stirred at room temperature for 1h, then added p-fluoro-o-phenylenediamine (45mg, 0.36mmol), continued stirring at room temperature for 8h, TLC detected the reaction was complete. Water (80 mL) was added to the reaction solution, extracted with ethyl acetate (30 mL × 3), the organic layers were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, left to stand, filtered, and the solvent was distilled off under reduced pressure, silica gel column Chromatographic separation (petroleum ether: ethyl acetate = 1: 1) gave 90 mg of yellow solid, yield: 47.62%. mp: 116-118 ° C; ESI-MS m / z: 551.2 [M + Na] ⁺ ; ¹ H-NMR (300 MHz, DMSO-d ₆ ) δ (ppm): 9.53 (s, 1H), 8.86 (t, J = 5.7 Hz, 1H), 7.86 (d, J = 8.1 Hz, 2H), 7.58-7.56 (m, 1H), 7.49 (d, J = 8.1 Hz, 2H), 7.26 (d, J = 8.6 Hz, 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 = 5.7 Hz, 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] triazine -2-yl] thio] methyl] benzamide (I-15)

Step a: 4-[[[4-[(3,4-dimethoxybenzyl) amino] pyrrolo [2,1-f] [1,2,4] triazin-2-yl] sulfur] Preparation of ethyl methyl] benzoate (6h)

5 (500 mg, 1.44 mmol) prepared above was dissolved in N, N-dimethylformamide (20 mL), potassium iodide (2.39 g, 14.38 mmol) was added, and stirred at 70 ° C. for 5 minutes. Then, N, N-diisopropylethylamine (929 mg, 7.19 mmol) and 3,4-dimethoxybenzylamine (481 mg, 2.88 mmol) were added, and the reaction was performed at 80 ° C for 3 h. The reaction was detected by TLC. Water (80 mL) was added to the reaction solution, extracted with ethyl acetate (30 mL × 3), the organic layers were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, left to stand, filtered, and the solvent was distilled off under reduced pressure, silica gel column Chromatographic separation (petroleum ether: ethyl acetate = 5: 1) gave 637 mg of white solid, yield: 92.59%. mp: 149-151 ° C; ESI-MS m / z: 501.1 [M + Na] ⁺ ; ¹ H-NMR (300 MHz, DMSO-d ₆ ) δ (ppm): 8.86 (t, J = 5.7 Hz, 1H) , 7.83 (d, J = 8.2 Hz, 2H), 7.56-7.55 (m, 1H), 7.48 (d, J = 8.2 Hz, 2H), 6.99-6.87 (m, 3H), 6.83-6.80 (m, 1H) ), 6.53 (dd, J = 4.3 Hz, 2.6 Hz, 1H), 4.62 (d, J = 5.6 Hz, 2H), 4.37 (s, 2H), 4.28 (q, J = 7.1 Hz, 2H), 3.70 ( d, J = 2.4 Hz, 6H), 1.30 (t, J = 7.1 Hz, 3H).

Step b: 4-[[[4-[(3,4-dimethoxybenzyl) amino] pyrrolo [2,1-f] [1,2,4] triazin-2-yl] sulfur] Preparation of methyl] benzoic acid (7h)

Into a 100mL eggplant-shaped bottle was added the compound prepared above for 6h (600mg, 1.25mmol) and sodium hydroxide (100mg, 2.50mmol), added water (20mL) and ethanol (40mL), the reaction was refluxed for 10h, TLC detection reaction was complete. The solvent was distilled off under reduced pressure, water (30 mL) was added, the pH was adjusted to 6-7 with glacial acetic acid solution under ice bath, frozen in a refrigerator for 2 h, suction filtered, and the filter cake was vacuum dried to obtain 453 mg of white solid, yield: 81.71% . mp: 111-113 ° C; ESI-MS m / z: 473.1 [M + Na] ⁺ ; ¹ H-NMR (300 MHz, DMSO-d ₆ ) δ (ppm): 9.02 (t, J = 5.6 Hz, 1H) , 7.81 (d, J = 7.9 Hz, 2H), 7.55 (s, 1H), 7.29 (d, J = 8.0 Hz, 2H), 7.02 (s, 1H), 6.93-6.92 (m, 1H), 6.90- 6.83 (m, 2H), 6.52 (dd, J = 4.0 Hz, 2.6 Hz, 1H), 4.62 (d, J = 5.5 Hz, 2H), 4.32 (s, 2H), 3.70 (s, 6H).

Step c: N- (2-aminophenyl) -4-[[[4-[(3,4-dimethoxybenzyl) amino] pyrrolo [2,1-f] [1,2,4 ] Triazine-2-yl] thio] methyl] benzamide (I-15)

To a 25mL eggplant-shaped bottle, add the 7h (150mg, 0.33mmol) and TBTU (118mg, 0.37mmol) obtained above, add N, N-dimethylformamide (10mL), and then add N, N-diisopropyl Ethylamine (172mg, 1.33mmol), stirred at room temperature for 1h, then added o-phenylenediamine (36mg, 0.33mmol), continued stirring at room temperature for 4h, TLC detected the reaction was complete. Water (80 mL) was added to the reaction solution, extracted with ethyl acetate (30 mL × 3), the organic layers were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, left to stand, filtered, the solvent was distilled off under reduced pressure, silica gel column Chromatographic separation (petroleum ether: ethyl acetate = 1: 1) gave 115 mg of yellow solid, yield: 63.89%. mp: 98-100 ° C; ESI-MS m / z: 563.2 [M + Na] ⁺ ; ¹ H-NMR (300 MHz, DMSO-d ₆ ) δ (ppm): 9.62 (s, 1H), 8.86 (t, J = 5.5 Hz, 1H), 7.86 (d, J = 8.1 Hz, 2H), 7.58-7.56 (m, 1H), 7.50 (d, J = 8.1 Hz, 2H), 7.15 (d, J = 7.7 Hz, 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 = 5.5 Hz, 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)

Step a: N- (2-Amino-4-fluorophenyl) -4-[[[4-[(3,4-dimethoxybenzyl) amino] pyrrolo [2,1-f] [1 Of 2,2,4] triazin-2-yl] thio] methyl] benzamide (I-16)

To a 25mL eggplant-shaped bottle, add the 7h (200mg, 0.44mmol) and TBTU (157mg, 0.49mmol) obtained above, add N, N-dimethylformamide (10mL), and then add N, N-diisopropyl Ethylamine (230mg, 1.78mmol), stirred at room temperature for 1h, then added p-fluoro-o-phenylenediamine (56mg, 0.44mmol), continued stirring at room temperature for 4h, TLC detected the reaction was complete. Water (80 mL) was added to the reaction solution, extracted with ethyl acetate (30 mL × 3), the organic layers were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, left to stand, filtered, and the solvent was distilled off under reduced pressure, silica gel column Chromatographic separation (petroleum ether: ethyl acetate = 1: 1) gave 85 mg of yellow solid, yield: 34.27%. mp: 118-120 ° C; ESI-MS m / z: 581.2 [M + Na] ⁺ ; ¹ H-NMR (300 MHz, DMSO-d ₆ ) δ (ppm): 9.52 (s, 1H), 8.85 (t, J = 5.6 Hz, 1H), 7.86 (d, J = 8.1 Hz, 2H), 7.58-7.56 (m, 1H), 7.49 (d, J = 8.1 Hz, 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

N- (2-aminophenyl) -4-[[[4-[(2,4-dimethoxybenzyl) amino] pyrrolo [2,1-f] [1,2,4] triazine Preparation of -2-yl] thio] methyl] benzamide (I-17)

Step a: 4-[[[4-[(2,4-dimethoxybenzyl) amino] pyrrolo [2,1-f] [1,2,4] triazin-2-yl] sulfur] Preparation of ethyl methyl] benzoate (6i)

5 (300 mg, 0.86 mmol) prepared above was dissolved in N, N-dimethylformamide (15 mL), potassium iodide (1.43 g, 8.63 mmol) was added, and stirred at 70 ° C. for 5 minutes. Then, N, N-diisopropylethylamine (557mg, 4.31mmol) and 2,4-dimethoxybenzylamine (288mg, 1.73mmol) were added, and the reaction was performed at 80 ° C for 3h. The reaction was detected by TLC. Water (80 mL) was added to the reaction solution, extracted with ethyl acetate (30 mL × 3), the organic layers were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, left to stand, filtered, and the solvent was distilled off under reduced pressure, silica gel column Chromatographic separation (petroleum ether: ethyl acetate = 5: 1) gave 341 mg of white solid, yield: 82.61%. mp: 84-86 ° C; ESI-MS m / z: 501.1 [M + Na] ⁺ ; ¹ H-NMR (300 MHz, DMSO-d ₆ ) δ (ppm): 8.71 (t, J = 5.5 Hz, 1H) , 7.80 (d, J = 8.2 Hz, 2H), 7.55-7.54 (m, 1H), 7.45 (d, J = 8.2 Hz, 2H), 7.07 (d, J = 8.3 Hz, 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 = 7.1 Hz, 2H), 3.79 (s, 3H), 3.73 (s, 3H), 1.30 (t, J = 7.1 Hz, 3H).

Step b: 4-[[[4-[(2,4-dimethoxybenzyl) amino] pyrrolo [2,1-f] [1,2,4] triazin-2-yl] sulfur] Preparation of methyl] benzoic acid (7i)

To a 100 mL eggplant-shaped bottle was added the compound 6i (335 mg, 0.70 mmol) and sodium hydroxide (56 mg, 1.40 mmol) prepared above, and water (15 mL) and ethanol (30 mL) were added. The reaction was refluxed for 10 h, and the reaction was detected by TLC. The solvent was distilled off under reduced pressure, water (30 mL) was added, the pH was adjusted to 6-7 with glacial acetic acid solution under ice bath, frozen in a refrigerator for 2 h, suction filtered, and the filter cake was vacuum dried to obtain a white solid 260 mg, yield: 82.45% . mp: 93-95 ° C; ESI-MS m / z: 451.1 [M + H] ⁺ ; ¹ H-NMR (300 MHz, DMSO-d ₆ ) δ (ppm): 12.91 (br.s, 1H), 8.72 ( t, J = 5.6 Hz, 1H), 7.80 (d, J = 8.2 Hz, 2H), 7.56-7.55 (m, 1H), 7.43 (d, J = 8.2 Hz, 2H), 7.08 (d, J = 8.3 Hz, 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: N- (2-aminophenyl) -4-[[[4-[(2,4-dimethoxybenzyl) amino] pyrrolo [2,1-f] [1,2,4 ] Triazine-2-yl] thio] methyl] benzamide (I-17)

Add 25i (120mg, 0.27mmol) and TBTU (94mg, 0.29mmol) prepared above to 25mL eggplant type bottle, add N, N-dimethylformamide (10mL), and then add N, N-diisopropyl Ethylamine (137mg, 1.06mmol), stirred at room temperature for 1h, then added o-phenylenediamine (29mg, 0.27mmol), and continued stirring at room temperature for 5h, TLC detected the reaction was complete. Water (80 mL) was added to the reaction solution, extracted with ethyl acetate (30 mL × 3), the organic layers were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, left to stand, filtered, and the solvent was distilled off under reduced pressure, silica gel column Chromatographic separation (petroleum ether: ethyl acetate = 1: 1) gave 71 mg of white solid, yield: 49.31%. mp: 177-179 ° C; ESI-MS m / z: 539.2 [MH] ^- ; ¹ H-NMR (300 MHz, DMSO-d ₆ ) 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 = 5.5 Hz, 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)

Step a: N- (2-amino-4-fluorophenyl) -4-[[[4-[(2,4-dimethoxybenzyl) amino] pyrrolo [2,1-f] [1 Of 2,2,4] triazin-2-yl] thio] methyl] benzamide (I-18)

Add 25i (120mg, 0.27mmol) and TBTU (94mg, 0.29mmol) prepared above to 25mL eggplant type bottle, add N, N-dimethylformamide (10mL), and then add N, N-diisopropyl Ethylamine (137mg, 1.06mmol), stirred at room temperature for 1h, then added p-fluoro-o-phenylenediamine (34mg, 0.27mmol), and continued stirring at room temperature for 5h, TLC detected the reaction was complete. Water (80 mL) was added to the reaction solution, extracted with ethyl acetate (30 mL × 3), the organic layers were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, left to stand, filtered, and the solvent was distilled off under reduced pressure, silica gel column Chromatographic separation (petroleum ether: ethyl acetate = 1: 1) gave a white solid 65 mg, yield: 43.62%. mp: 182-184 ° C; ESI-MS m / z: 581.2 [M + Na] ⁺ ; ¹ H-NMR (300 MHz, DMSO-d ₆ ) δ (ppm): 9.52 (s, 1H), 8.69 (t, J = 5.4 Hz, 1H), 7.85 (d, J = 8.0 Hz, 2H), 7.57-7.55 (m, 1H), 7.47 (d, J = 8.1 Hz, 2H), 7.11 (d, J = 8.4 Hz, 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] triazine- 2-yl] thio] methyl] benzamide (I-19)

Step a: 4-[[[4-[(3-methylpyridin-2-yl) amino] pyrrolo [2,1-f] [1,2,4] triazin-2-yl] thio] methyl Of ethyl] benzoate (6j)

5 (500 mg, 1.44 mmol) prepared above was dissolved in N, N-dimethylformamide (20 mL), potassium iodide (2.39 g, 14.38 mmol) was added, and stirred at 70 ° C. for 5 minutes. Then, N, N-diisopropylethylamine (929 mg, 7.19 mmol) and 2-amino-3-methylpyridine (311 mg, 2.88 mmol) were added, and the reaction was performed at 80 ° C for 12 h. The reaction was detected by TLC. Water (80 mL) was added to the reaction solution, extracted with ethyl acetate (30 mL × 3), the organic layers were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, left to stand, filtered, and the solvent was distilled off under reduced pressure, silica gel column Chromatographic separation (petroleum ether: ethyl acetate = 5: 1) gave 491 mg of white solid with a yield of 81.42%. mp: 87-89 ° C; ESI-MS m / z: 442.2 [M + Na] ⁺ ; ¹ H-NMR (300 MHz, DMSO-d ₆ ) 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 = 7.1 Hz, 2H), 4.22 (s, 2H), 1.29 (t, J = 7.1 Hz, 3H), 2.18 (s, 3H).

Step b: 4-[[[4-[(3-methylpyridin-2-yl) amino] pyrrolo [2,1-f] [1,2,4] triazin-2-yl] thio] methyl Of benzoic acid (7j)

To a 100 mL eggplant-shaped bottle was added the compound 6j (491 mg, 1.17 mmol) and sodium hydroxide (94 mg, 2.34 mmol) prepared above, and water (20 mL) and ethanol (40 mL) were added. The reaction was refluxed for 10 h, and the reaction was completed by TLC. The solvent was distilled off under reduced pressure, water (30 mL) was added, the pH was adjusted to 6-7 with glacial acetic acid solution in an ice bath, frozen and allowed to stand in the refrigerator for 2 h, suction filtered, and the filter cake was dried in vacuum to obtain 420 mg of white solid with a yield of 91.67%. mp: 240-242 ° C; ESI-MS m / z: 390.1 [MH] ^- ; ¹ H-NMR (300 MHz, DMSO-d ₆ ) 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: N- (2-aminophenyl) -4-[[[4-[(3-methylpyridin-2-yl) amino] pyrrolo [2,1-f] [1,2,4] Preparation of triazin-2-yl] thio] methyl] benzamide (I-19)

Add 7j (200mg, 0.51mmol) and TBTU (180mg, 0.56mmol) prepared above to 25mL eggplant type bottle, add N, N-dimethylformamide (10mL), and then add N, N-diisopropyl Ethylamine (264mg, 2.04mmol), stirred at room temperature for 1h, then added o-phenylenediamine (55mg, 0.51mmol), continued stirring at room temperature for 8h, TLC detected the reaction was complete. Water (80 mL) was added to the reaction solution, extracted with ethyl acetate (30 mL × 3), the organic layers were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, left to stand, filtered, and the solvent was distilled off under reduced pressure, silica gel column Chromatographic separation (petroleum ether: ethyl acetate = 1: 1) gave 146 mg of white solid, yield: 59.35%. mp: 165-167 ° C; ESI-MS m / z: 504.2 [M + Na] ⁺ ; ¹ H-NMR (300 MHz, DMSO-d ₆ ) 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] sulfur] methyl] benzamide (I-20)

Step a: N- (2-amino-4-fluorophenyl) -4-[[[4-[(3-methylpyridin-2-yl) amino] pyrrolo [2,1-f] [1, Preparation of 2,4] triazin-2-yl] thio] methyl] benzamide (I-20)

Add 7j (200mg, 0.51mmol) and TBTU (180mg, 0.56mmol) prepared above to 25mL eggplant type bottle, add N, N-dimethylformamide (10mL), and then add N, N-diisopropyl Ethylamine (264mg, 2.04mmol), stirred at room temperature for 1h, then added p-fluoro-o-phenylenediamine (64mg, 0.51mmol), continued stirring at room temperature for 8h, TLC detected the reaction was complete. Water (80 mL) was added to the reaction solution, extracted with ethyl acetate (30 mL × 3), the organic layers were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, left to stand, filtered, and the solvent was distilled off under reduced pressure, silica gel column Chromatographic separation (petroleum ether: ethyl acetate = 1: 1) gave 74 mg of white solid, yield: 29.02%. mp: 212-214 ° C; ESI-MS m / z: 522.2 [M + Na] ⁺ ; ¹ H-NMR (300 MHz, DMSO-d ₆ ) 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-Bocpiperidin-4-yl) amino] pyrrolo [2,1-f] [1,2,4] triazine- 2-yl] thio] methyl] benzamide (I-21)

Step a: 4-[[[4-[(N-Bocpiperidin-4-yl) amino] pyrrolo [2,1-f] [1,2,4] triazin-2-yl] thio] methyl Of ethyl] benzoate (6k)

5 (2g, 5.75mmol) prepared above was dissolved in N, N-dimethylformamide (50mL), potassium iodide (9.55g, 57.50mmol) was added, and stirred at 70 ° C for 5 minutes. Then, N, N-diisopropylethylamine (3.72g, 28.75mmol) and 1-Boc-4-aminopiperidine (2.30g, 11.50mmol) were added, and the reaction was performed at 80 ° C for 10h. The reaction was detected by TLC. The reaction solution was added with water (200 mL), extracted with ethyl acetate (80 mL × 3), the organic layers were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, left to stand, filtered, the solvent was distilled off under reduced pressure, silica gel column Chromatographic separation (petroleum ether: ethyl acetate = 5: 1) gave 1.83 g of yellow-green solid with a yield of 62.20%. mp: 220-222 ° C; ESI-MS m / z: 510.2 [MH] ^- ; ¹ H-NMR (300 MHz, DMSO-d ₆ ) δ (ppm): 8.11 (d, J = 7.9 Hz, 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 = 12.0 Hz, 2H), 1.41 (s, 9H), 1.38 (s, 2H), 1.30 (t, 3H).

Step b: 4-[[[4-[(N-Bocpiperidin-4-yl) amino] pyrrolo [2,1-f] [1,2,4] triazin-2-yl] thio] methyl Of benzoic acid (7k)

Into a 100mL eggplant-shaped bottle was added the above prepared compound 6k (300mg, 0.59mmol) and sodium hydroxide (47mg, 1.17mmol), added water (20mL) and ethanol (40mL), the reaction was refluxed for 10h, TLC detection reaction was complete. The solvent was distilled off under reduced pressure, water (30 mL) was added, the pH was adjusted to 6-7 with glacial acetic acid solution in an ice bath, frozen in a refrigerator for 2 h, suction filtered, and the filter cake was vacuum dried to obtain a white solid 204 mg, yield: 71.94% . Repeat the operation several times to obtain about 1.10g of white solid. mp: 218-220 ° C; ESI-MS m / z: 482.2 [MH] ^- ; ¹ H-NMR (300 MHz, DMSO-d ₆ ) 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: N- (2-aminophenyl) -4-[[[4-[(N-Bocpiperidin-4-yl) amino] pyrrolo [2,1-f] [1,2,4] Preparation of triazin-2-yl] thio] methyl] benzamide (I-21)

Into a 25mL eggplant-shaped bottle, add 7k (500mg, 1.03mmol) and TBTU (124mg, 1.14mmol) prepared above, add N, N-dimethylformamide (30mL), and then add N, N-diisopropyl Ethylamine (534mg, 4.14mmol), stirred at room temperature for 1h, then added o-phenylenediamine (124mg, 1.14mmol), continued stirring at room temperature for 8h, TLC detected the reaction was complete. Water (160 mL) was added to the reaction solution, and ethyl acetate was extracted (60 mL × 3). The organic layers were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, allowed to stand, filtered, and the solvent was distilled off under reduced pressure. Chromatographic separation (petroleum ether: ethyl acetate = 1: 1) gave 414 mg of white solid, yield: 69.79%. mp: 116-118 ° C; ESI-MS m / z: 596.2 [M + Na] ⁺ ; ¹ H-NMR (300 MHz, DMSO-d ₆ ) 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-Bocpiperidin-4-yl) amino] pyrrolo [2,1-f] [1,2,4 ] Triazin-2-yl] sulfur] methyl] benzamide (I-22)

Step a: N- (2-amino-4-fluorophenyl) -4-[[[4-[(N-Bocpiperidin-4-yl) amino] pyrrolo [2,1-f] [1, Preparation of 2,4] triazin-2-yl] thio] methyl] benzamide (I-22)

Into a 25mL eggplant-shaped bottle, add 7k (500mg, 1.03mmol) and TBTU (124mg, 1.14mmol) prepared above, add N, N-dimethylformamide (30mL), and then add N, N-diisopropyl Ethylamine (534mg, 4.14mmol), stirred at room temperature for 1h, then added p-fluoro-o-phenylenediamine (144mg, 1.14mmol), continued stirring at room temperature for 8h, TLC detected the reaction was complete. Water (160 mL) was added to the reaction solution, and ethyl acetate was extracted (60 mL × 3). The organic layers were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, allowed to stand, filtered, and the solvent was distilled off under reduced pressure. Chromatographic separation (petroleum ether: ethyl acetate = 1: 1) gave 386 mg of white solid, yield: 63.09%. mp: 159-161 ° C; ESI-MS m / z: 614.2 [M + Na] ⁺ ; ¹ H-NMR (300 MHz, DMSO-d ₆ ) 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)

Step a: N- (2-aminophenyl) -4-[[[4-[(piperidin-4-yl) amino] pyrrolo [2,1-f] [1,2,4] triazine- Preparation of 2-yl] thio] methyl] benzamide (I-23)

To a 25mL eggplant-shaped bottle was added I-21 (250mg, 0.44mmol) prepared above, dissolved in dichloromethane (2mL), and then added trifluoroacetic acid (1mL), stirred at room temperature for 3h, TLC detection reaction was complete. The solvent was distilled off under reduced pressure and separated by silica gel column chromatography (dichloromethane: methanol = 10: 1) to obtain 168 mg of a yellow solid with a yield of 81.41%. mp: 88-90 ° C; ESI-MS m / z: 474.2 [M + H] ⁺ ; ¹ H-NMR (300 MHz, DMSO-d ₆ ) 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] triazine -2-yl] thio] methyl] benzamide (I-24)

Step a: N- (2-Amino-4-fluorophenyl) -4-[[[4-[(piperidin-4-yl) amino] pyrrolo [2,1-f] [1,2,4 ] Triazine-2-yl] thio] methyl] benzamide (I-24)

To a 25mL eggplant-shaped bottle was added I-22 (250mg, 0.42mmol) prepared above, dissolved in dichloromethane (2mL), and then added trifluoroacetic acid (1mL), stirred at room temperature for 3h, TLC detection reaction was complete. The solvent was distilled off under reduced pressure and separated by silica gel column chromatography (dichloromethane: methanol = 10: 1) to obtain 78 mg of a white solid with a yield of 37.55%. mp: 225-227 ° C; ESI-MS m / z: 492.2 [M + H] ⁺ ; ¹ H-NMR (300 MHz, DMSO-d ₆ ) δ (ppm): 9.55 (s, 1H), 8.29 (d, J = 7.4 Hz, 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] triazine-2- Yl] thio] methyl] benzamide (I-25)

Step a: N-hydroxy-4-[[[4-[(5-methyl-1H-pyrazol-3-yl) amino] pyrrolo [2,1-f] [1,2,4] triazine Preparation of -2-yl] thio] methyl] benzamide (I-25)

To a 25 mL eggplant-shaped bottle, add 7a (100 mg, 0.26 mmol) and anhydrous THF (10 mL) prepared above. After cooling to -5 ° C, add ethyl chloroformate (35 mg, 0.32 mmol) and triethylamine (0.045 mL , 0.32mmol), after stirring at room temperature for 30min, the precipitated solid was filtered off. The freshly prepared hydroxylamine methanol solution (10 mg / mL) (3 mL) was continuously added to the mother liquor. After stirring the reaction at room temperature for 1 h, the solvent was distilled off under reduced pressure and separated by silica gel column chromatography (dichloromethane: methanol = 40: 1) to obtain 45 mg of a white solid with a yield of 43.7%. mp: 175-176 ° C; ESI-MS m / z: 396.3 [M + H] ⁺ ; ¹ H-NMR (300 MHz, DMSO-d ₆ ) δ (ppm): 12.26 (br.s, 1H), 11.12 ( s, 1H), 10.63 (s, 1H), 10.57 (s, 1H), 7.91 (d, J = 8.1 Hz, 2H), 7.68-7.67 (m, 1H), 7.58 (d, J = 8.1 Hz, 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)

Step a: 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)

To a 25mL eggplant-shaped bottle, add 7a (150mg, 0.39mmol) and TBTU (140mg, 0.43mmol) prepared above, add N, N-dimethylformamide (10mL), and then add N, N-diisopropyl Ethylamine (204mg, 1.58mmol), stirred at room temperature for 1h, then added p-chloro-o-phenylenediamine (62mg, 0.43mmol), and continued stirring at room temperature for 4h, TLC detected the reaction was complete. Water (80 mL) was added to the reaction solution, extracted with ethyl acetate (30 mL × 3), the organic layers were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, left to stand, filtered, and the solvent was distilled off under reduced pressure, silica gel column Chromatographic separation (petroleum ether: ethyl acetate = 1: 1) gave 45 mg of white solid, yield: 22.60%. mp: 161-163 ° C; ESI-MS m / z: 506.2 [M + H] ⁺ ; ¹ H-NMR (300 MHz, DMSO-d ₆ ) 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)

Step a: N- (2-amino-4-methylphenyl) -4-[[[4-[(5-methyl-1H-pyrazol-3-yl) amino] pyrrolo [2,1- f] Preparation of [1,2,4] triazin-2-yl] thio] methyl] benzamide (I-27)

To a 25mL eggplant-shaped bottle, add 7a (150mg, 0.39mmol) and TBTU (140mg, 0.43mmol) prepared above, add N, N-dimethylformamide (10mL), and then add N, N-diisopropyl Ethylamine (204mg, 1.58mmol), stirred at room temperature for 1h, then added p-methyl o-phenylenediamine (53mg, 0.43mmol), and continued stirring at room temperature for 4h, TLC detected the reaction was complete. Water (80 mL) was added to the reaction solution, extracted with ethyl acetate (30 mL × 3), the organic layers were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, left to stand, filtered, and the solvent was distilled off under reduced pressure, silica gel column Chromatographic separation (petroleum ether: ethyl acetate = 1: 1) gave a white solid 76 mg, yield: 39.78%. mp: 145-147 ° C; ESI-MS m / z: 485.2 [M + H] ⁺ ; ¹ H-NMR (300 MHz, DMSO-d ₆ ) 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)

Step a: N- (2-Amino-5-cyanophenyl) -4-[[[4-[(5-methyl-1H-pyrazol-3-yl) amino] pyrrolo [2,1- f] Preparation of [1,2,4] triazin-2-yl] thio] methyl] benzamide (I-28)

To a 25mL eggplant-shaped bottle, add 7a (150mg, 0.39mmol) and TBTU (140mg, 0.43mmol) prepared above, add N, N-dimethylformamide (10mL), and then add N, N-diisopropyl Ethylamine (204mg, 1.58mmol), stirred at room temperature for 1h, then added p-methyl o-phenylenediamine (58mg, 0.43mmol), continued stirring at room temperature for 4h, TLC detected the reaction was complete. Water (80 mL) was added to the reaction solution, extracted with ethyl acetate (30 mL × 3), the organic layers were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, left to stand, filtered, the solvent was distilled off under reduced pressure, silica gel Column chromatography (petroleum ether: ethyl acetate = 1: 1) to obtain a white solid 31mg, yield: 15.86%. mp: 177-179 ° C; ESI-MS m / z: 496.2 [M + H] ⁺ ; ¹ H-NMR (300 MHz, DMSO-d ₆ ) 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)

Step a: N- (2-Amino-5-phenylphenyl) -4-[[[4-[(5-methyl-1H-pyrazol-3-yl) amino] pyrrolo [2,1- f] Preparation of [1,2,4] triazin-2-yl] thio] methyl] benzamide (I-29)

To a 25mL eggplant-shaped bottle, add 7a (150mg, 0.39mmol) and TBTU (140mg, 0.43mmol) prepared above, add N, N-dimethylformamide (10mL), and then add N, N-diisopropyl Ethylamine (204mg, 1.58mmol), stirred at room temperature for 1h, then added p-phenyl o-phenylenediamine (80mg, 0.43mmol), continued stirring at room temperature for 4h, TLC detection reaction was complete. Water (80 mL) was added to the reaction solution, extracted with ethyl acetate (30 mL × 3), the organic layers were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, left to stand, filtered, and the solvent was distilled off under reduced pressure, silica gel column Chromatographic separation (petroleum ether: ethyl acetate = 1: 1) gave 56 mg of white solid, yield: 25.98%. mp: 182-184 ° C; ESI-MS m / z: 547.2 [M + H] ⁺ ; ¹ H-NMR (300 MHz, DMSO-d ₆ ) 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)

Step a: N- (2-Amino-5- (2-thienyl) phenyl) -4-[[[4-[(5-methyl-1H-pyrazol-3-yl) amino] pyrrolo [ Preparation of 2,1-f] [1,2,4] triazin-2-yl] thio] methyl] benzamide (I-30)

To a 25mL eggplant-shaped bottle, add 7a (150mg, 0.39mmol) and TBTU (140mg, 0.43mmol) prepared above, add N, N-dimethylformamide (10mL), and then add N, N-diisopropyl Ethylamine (204mg, 1.58mmol), stirred at room temperature for 1h, then added 2-amino 4- (2-thienyl) aniline (83mg, 0.43mmol), and continued to stir at room temperature for 4h, TLC detection reaction was complete. Water (80 mL) was added to the reaction solution, extracted with ethyl acetate (30 mL × 3), the organic layers were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, left to stand, filtered, and the solvent was distilled off under reduced pressure, silica gel column Chromatographic separation (petroleum ether: ethyl acetate = 1: 1) gave 63 mg of white solid, yield: 28.91%. mp: 189-191 ° C; ESI-MS m / z: 553.2 [M + H] ⁺ ; ¹ H-NMR (300 MHz, DMSO-d ₆ ) 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)

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 (769.06mg, 14.5mmol) was added in sequence, and methyl iodide (886.23mml, 14.25mmol) was heated to 45 ° C for 4h, TLC showed that the reaction was over. Wash with water, adjust pH to neutral, precipitate solid, filter with suction, and wash with methanol to obtain 1.9g of white solid, yield: 79.83%. ESI-MS m / z: 180.0 [MH] ⁺ ; 1H NMR (300 MHz, DMSO-d6) δ (ppm): 12.03 (s, 1H), 7.53 (dd, J = 2.7, 1.7 Hz, 1H), 6.84 ( dd, J = 4.3, 1.7 Hz, 1H), 6.48 (dd, J = 4.3, 2.6 Hz, 1H), 2.53 (s, 3H).

Step b: Preparation of 4-chloro-2-thiomethylpyrrolo [2,1-f] [1,2,4] triazine (9)

The above-prepared compound 8 (1.9 g, 10.49 mmol) was dissolved in phosphorus oxychloride (20 mL) and heated to reflux for 3 h. TLC showed that the reaction was completed. Most of the phosphorus oxychloride was distilled off under reduced pressure. After cooling to room temperature in vacuo, the reaction was poured into ice water (100 mL), extracted with ethyl acetate (60 mL × 3), the organic layers were combined, and washed with saturated brine (60 mL) After adding anhydrous sodium sulfate to dry, let stand, filter, evaporate the solvent under reduced pressure, and separate by silica gel column chromatography (petroleum ether: ethyl acetate = 5: 1) to obtain a white solid 1.58g, yield: 83.01%. ESI-MS m / z: 199 [MH] ⁺ ; 1H NMR (300 MHz, DMSO-d6) δ (ppm): 8.13 (s, 1H), 7.10–6.94 (m, 2H), 2.56 (d, J = 1.9 Hz, 3H).

Step c: 2-thiomethyl-4-[(5-methyl-1H-pyrazole-3-methyl) amino] pyrrolo [2,1-f] [1,2,4] triazine (10 ) Preparation

Compound 9 (1.58 g, 7.9 mmol) prepared above was dissolved in N, N-dimethylformamide (20 mL), potassium iodide (1.31 g, 79 mmol) was added, and stirred at 70 ° C. for 5 minutes. N, N-diisopropylethylamine (5.11g, 39.5mmol) and 5-methyl-3-aminopyrazole (845mg, 8.69mmol) were added and reacted at 120 ° C for 6h. The reaction was detected by TLC. Water (80 mL) was added to the reaction solution, extracted with ethyl acetate (30 mL × 3), the organic layers were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, left to stand, filtered, and the solvent was distilled off under reduced pressure, silica gel column Chromatographic separation (dichloromethane: methanol = 10: 1) to obtain 758 mg of white solid, yield: 48%. ESI-MS m / z: 259 [MH] ⁺ ; 1H NMR (300 MHz, DMSO-d6) δ (ppm): 12.20 (s, 1H), 10.56 (s, 1H), 7.62 (dd, J = 2.6, 1.6 Hz, 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: 2-sulfonemethyl-4-[(5-methyl-1H-pyrazole-3-methyl) amino] pyrrolo [2,1-f] [1,2,4] triazine (11 ) Preparation

The compound 10 (758 mg, 2.92 mmol) prepared above was dissolved in analytically pure dichloromethane (15 mL). After adding m-chloroperoxybenzoic acid (1 g, 5.84 mmol) at room temperature for 3 h, water and saturated ammonium chloride solution (50 mL) ) After extraction and washing, add anhydrous sodium sulfate to dry and stand, filter, distill off the solvent under reduced pressure, and separate by silica gel column chromatography (dichloromethane: methanol = 10: 1) to obtain 646 mg of white solid, yield: 85.21%. ESI-MS m / z: 291 [MH] ⁺ ; 1H NMR (300 MHz, DMSO-d6) δ (ppm): 12.20 (s, 1H), 10.56 (s, 1H), 7.27 (dd, J = 2.6, 1.6 Hz, 1H), 7.20 (s, 1H), 6.67 (s, 1H), 6.11 (s, 1H), 3.00 (s, 3H), 2.29 (s, 3H).

Step e: 4-(((4-((5-methyl-1H-pyrazol-3-yl) amino) pyrrolo [2,1-f] [1,2,4] triazin-2-yl ) Preparation of oxy) methyl) benzoic acid methyl ester (12a)

Compound 11 (600 mg, 2.05 mmol), methyl 4-hydroxymethylbenzoate (512 mg, 3.08 mmol), NaH (164 mg, 4.11 mmol), and dried NMP (10 mL) were placed in a sealed tube. The reaction was carried out at 200 ° C for 8h. After adding saturated ammonium chloride solution (50mL), it was extracted with ethyl acetate (30mL × 3). The organic items were combined, dried and dried with anhydrous sodium sulfate, filtered, and the solvent was distilled off under reduced pressure. Chromatographic separation (dichloromethane: methanol = 10: 1) to obtain 320 mg of white solid, yield: 41.20%. ESI-MS m / z: 379.2 [M + H] ⁺ .

Step f: 4-(((4-((5-methyl-1H-pyrazol-3-yl) amino) pyrrolo [2,1-f] [1,2,4] triazin-2-yl ) Preparation of oxy) methyl) benzoic acid (13a)

Into a 25mL eggplant-shaped bottle, add the above-prepared compound 12a (300mg, 0.79mmol) and sodium hydroxide (64mg, 1.59mmol), add water (10mL) and ethanol (20mL), react at 60 ℃ for 12h, TLC detection reaction complete . The solvent was distilled off under reduced pressure, water (5 mL) was added, the pH was adjusted to 6-7 with glacial acetic acid solution under ice bath, frozen in a refrigerator for 2 h, suction filtered, and the filter cake was vacuum dried to obtain a white solid 250 mg, yield: 86.54% . ESI-MS / m: z.365.2 [M + H].

Step g: N- (2-aminophenyl) -4-[[[4-[(5-methyl-1H-pyrazol-3-yl) amino] pyrrolo [2,1-f] [1, Preparation of 2,4] triazin-2-yl] oxy] methyl] benzamide (I-31)

To a 25mL eggplant-shaped bottle, add 13a (95mg, 0.26mmol) and TBTU (93mg, 0.29mmol) prepared above, add N, N-dimethylformamide (10mL), and then add N, N-diisopropyl Ethylamine (136mg, 1.05mmol), stirred at room temperature for 1h, and then added o-phenylenediamine (31mg, 0.29mmol), continued stirring at room temperature for 4h, TLC detected the reaction was complete. Water (80 mL) was added to the reaction solution, extracted with ethyl acetate (30 mL × 3), the organic layers were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, left to stand, filtered, and the solvent was distilled off under reduced pressure, silica gel column Chromatographic separation (petroleum ether: ethyl acetate = 1: 1) gave 52 mg of white solid, yield: 44.00%. mp: 151-153 ° C; ESI-MS m / z: 455.2 [M + H] ⁺ ; ¹ H-NMR (300 MHz, DMSO-d ₆ ) δ (ppm): 12.26 (br.s, 1H), 10.63 ( s, 1H), 9.65 (s, 1H), 7.91 (d, J = 8.1 Hz, 2H), 7.68-7.67 (m, 1H), 7.58 (d, J = 8.1 Hz, 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)

Step a: 4-(((4-((5-methyl-1H-pyrazol-3-yl) amino) pyrrolo [2,1-f] [1,2,4] triazin-2-yl ) Preparation of amino) methyl) benzoic acid methyl ester (12b)

Compound 11 (600 mg, 2.05 mmol), methyl 4-aminomethylbenzoate (510 mg, 3.08 mmol), NaH (164 mg, 4.11 mmol), and dried NMP (10 mL) were placed in a sealed tube. The reaction was carried out at 200 ° C for 8h. After adding saturated ammonium chloride solution (50mL), it was extracted with ethyl acetate (30mL × 3). The organic items were combined, dried and dried with anhydrous sodium sulfate, filtered, and the solvent was distilled off under reduced pressure. Chromatographic separation (dichloromethane: methanol = 10: 1) to obtain 303 mg of white solid, yield: 39.11%. ESI-MS m / z: 378.2 [M + H] ⁺ .

Step b: 4-(((4-((5-methyl-1H-pyrazol-3-yl) amino) pyrrolo [2,1-f] [1,2,4] triazin-2-yl ) Preparation of amino) methyl) benzoic acid (13b)

Into a 25mL eggplant-shaped bottle, add the above-prepared compound 12b (300mg, 0.79mmol) and sodium hydroxide (64mg, 1.59mmol), add water (10mL) and ethanol (20mL), react at 60 ℃ for 12h, and the reaction is complete by TLC. . The solvent was distilled off under reduced pressure, water (5 mL) was added, the pH was adjusted to 6-7 with glacial acetic acid solution under ice bath, frozen in a refrigerator for 2 h, suction filtered, and the filter cake was vacuum dried to obtain a white solid 259 mg, yield: 89.67% . ESI-MS m / z: 364.2 [M + H] ⁺ .

Step g: N- (2-aminophenyl) -4-[[[4-[(5-methyl-1H-pyrazol-3-yl) amino] pyrrolo [2,1-f] [1, Preparation of 2,4] triazin-2-yl] oxy] methyl] benzamide (I-32)

To a 25mL eggplant-shaped bottle, add 13b (95mg, 0.26mmol) and TBTU (93mg, 0.29mmol) prepared above, add N, N-dimethylformamide (10mL), and then add N, N-diisopropyl Ethylamine (136mg, 1.05mmol), stirred at room temperature for 1h, and then added o-phenylenediamine (31mg, 0.29mmol), continued stirring at room temperature for 4h, TLC detected the reaction was complete. Water (80 mL) was added to the reaction solution, extracted with ethyl acetate (30 mL × 3), the organic layers were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, left to stand, filtered, and the solvent was distilled off under reduced pressure, silica gel column Chromatographic separation (petroleum ether: ethyl acetate = 1: 1) gave 48 mg of white solid, yield: 40.71%. mp: 166-169 ° C; ESI-MS m / z: 454.2 [M + H] ⁺ ; ¹ H-NMR (300 MHz, DMSO-d ₆ ) δ (ppm): 12.26 (br.s, 1H), 10.63 ( s, 1H), 9.65 (s, 1H), 7.91 (d, J = 8.1 Hz, 2H), 7.68-7.67 (m, 1H), 7.58 (d, J = 8.1 Hz, 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)

Step a: 4-(((4-((5-methyl-1H-pyrazol-3-yl) amino) pyrrolo [2,1-f] [1,2,4] triazin-2-yl ) Preparation of sulfinyl) methyl) benzoic acid (14a)

The 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 3h, then water and saturated ammonium chloride solution (50mL) After extraction and washing, add anhydrous sodium sulfate to dry and stand, filter, evaporate the solvent under reduced pressure, and separate by silica gel column chromatography (dichloromethane: methanol = 10: 1) to obtain 438mg of white solid, yield: 42.03% . ESI-MS m / z: 396.2 [M + H] ⁺ .

Step b: N- (2-aminophenyl) -4-[[[4-[(5-methyl-1H-pyrazol-3-yl) amino] pyrrolo [2,1-f] [1, Preparation of 2,4] triazin-2-yl] sulfinyl] methyl] benzamide (I-33)

To a 25mL eggplant-shaped bottle, add 14a (103mg, 0.26mmol) and TBTU (93mg, 0.29mmol) prepared above, add N, N-dimethylformamide (10mL), and then add N, N-diisopropyl Ethylamine (136mg, 1.05mmol), stirred at room temperature for 1h, and then added o-phenylenediamine (31mg, 0.29mmol), continued stirring at room temperature for 4h, TLC detected the reaction was complete. Water (80 mL) was added to the reaction solution, extracted with ethyl acetate (30 mL × 3), the organic layers were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, left to stand, filtered, and the solvent was distilled off under reduced pressure, silica gel column Chromatographic separation (petroleum ether: ethyl acetate = 1: 1) gave 52 mg of white solid, yield: 41.11%. mp: 188-190 ° C; ESI-MS m / z: 487.2 [M + H] ⁺ ; ¹ H-NMR (300 MHz, DMSO-d ₆ ) δ (ppm): 12.26 (br.s, 1H), 10.63 ( s, 1H), 9.65 (s, 1H), 7.91 (d, J = 8.1 Hz, 2H), 7.68-7.67 (m, 1H), 7.58 (d, J = 8.1 Hz, 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)

Step a: 4-(((4-((5-methyl-1H-pyrazol-3-yl) amino) pyrrolo [2,1-f] [1,2,4] triazin-2-yl ) Preparation of sulfonyl) methyl) benzoic acid (14b)

The compound 7a (1.00g, 2.63mmol) prepared above was dissolved in analytically pure dichloromethane (30mL), m-chloroperoxybenzoic acid (1.36g, 7.89mmol) was added to react at room temperature for 3h, then water and saturated ammonium chloride solution (50mL) After extraction and washing, add anhydrous sodium sulfate to dry and stand, filter, evaporate the solvent under reduced pressure, and separate by silica gel column chromatography (dichloromethane: methanol = 10: 1) to obtain 898mg of white solid, yield: 82.83% . ESI-MS m / z: 413.2 [M + H] ⁺ .

Step b: N- (2-aminophenyl) -4-[[[4-[(5-methyl-1H-pyrazol-3-yl) amino] pyrrolo [2,1-f] [1, Preparation of 2,4] triazin-2-yl] sulfonyl] methyl] benzamide (I-34)

To a 25mL eggplant-shaped bottle, add 14b (107mg, 0.26mmol) and TBTU (93mg, 0.29mmol) prepared above, add N, N-dimethylformamide (10mL), and then add N, N-diisopropyl Ethylamine (136mg, 1.05mmol), stirred at room temperature for 1h, and then added o-phenylenediamine (31mg, 0.29mmol), continued stirring at room temperature for 4h, TLC detected the reaction was complete. Water (80 mL) was added to the reaction solution, extracted with ethyl acetate (30 mL × 3), the organic layers were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, left to stand, filtered, and the solvent was distilled off under reduced pressure, silica gel column Chromatographic separation (petroleum ether: ethyl acetate = 1: 1) gave a white solid 76 mg, yield: 58.16%. mp: 195-198 ° C; ESI-MS m / z: 503.2 [M + H] ⁺ ; ¹ H-NMR (300 MHz, DMSO-d ₆ ) δ (ppm): 12.26 (br.s, 1H), 10.63 ( s, 1H), 9.65 (s, 1H), 7.91 (d, J = 8.1 Hz, 2H), 7.68-7.67 (m, 1H), 7.58 (d, J = 8.1 Hz, 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)

Step a: 4-((ethyl (4-((5-methyl-1H-pyrazol-3-yl) amino) pyrrolo [2,1-f] [1,2,4] triazine-2 -Yl) amino) methyl) benzoic acid methyl ester (12c)

The above-prepared compound 11 (600 mg, 2.05 mmol), methyl N-ethyl-4-aminomethylbenzoate (595 mg, 3.08 mmol), NaH (164 mg, 4.11 mmol), and dried NMP (10 mL) were placed In a sealed tube, react at 200 ° C for 8h, add saturated ammonium chloride solution (50mL), extract with ethyl acetate (30mL × 3), combine the organic items, dry and rest with anhydrous sodium sulfate, filter, and evaporate under reduced pressure The solvent was removed, and the silica gel column chromatography was separated (dichloromethane: methanol = 10: 1) to obtain 387 mg of white solid, yield: 46.50%. ESI-MS m / z: 406.2 [M + H] ⁺ .

Step b: 4-((ethyl (4-((5-methyl-1H-pyrazol-3-yl) amino) pyrrolo [2,1-f] [1,2,4] triazine-2 -Yl) amino) methyl) benzoic acid (13c)

Into a 25mL eggplant-shaped bottle, add the above-prepared compound 12c (300mg, 0.74mmol) and sodium hydroxide (59mg, 1.48mmol), add water (10mL) and ethanol (20mL), react at 60 ℃ for 12h, and the reaction is complete by TLC. . The solvent was distilled off under reduced pressure, water (5 mL) was added, the pH was adjusted to 6-7 with glacial acetic acid solution in an ice bath, frozen in a refrigerator for 2 h, filtered with suction, and the filter cake was vacuum dried to obtain a white solid 252 mg, yield: 87.01% . ESI-MS m / z: 392.2 [M + H] ⁺ .

Step c: N- (2-aminophenyl) -4-[[ethyl [4-[(5-methyl-1H-pyrazol-3-yl) amino] pyrrolo [2,1-f] [ Preparation of 1,2,4] triazin-2-yl] amino] methyl] benzamide (I-35)

To a 25mL eggplant-shaped bottle, add 13c (102mg, 0.26mmol) and TBTU (93mg, 0.29mmol) prepared above, add N, N-dimethylformamide (10mL), and then add N, N-diisopropyl Ethylamine (136mg, 1.05mmol), stirred at room temperature for 1h, and then added o-phenylenediamine (31mg, 0.29mmol), continued stirring at room temperature for 4h, TLC detected the reaction was complete. Water (80 mL) was added to the reaction solution, extracted with ethyl acetate (30 mL × 3), the organic layers were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, left to stand, filtered, and the solvent was distilled off under reduced pressure, silica gel column Chromatographic separation (petroleum ether: ethyl acetate = 1: 1) gave 62 mg of white solid, yield: 49.52%. mp: 159-162 ° C; ESI-MS m / z: 482.2 [M + H] ⁺ ; ¹ H-NMR (300 MHz, DMSO-d ₆ ) δ (ppm): 12.26 (br.s, 1H), 10.63 ( s, 1H), 9.65 (s, 1H), 7.91 (d, J = 8.1 Hz, 2H), 7.68-7.67 (m, 1H), 7.58 (d, J = 8.1 Hz, 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] triazine-2- Group] amino] methyl] benzamide (I-36)

Step a: 4-[[[4-[(4-methoxyphenyl) amino] pyrrolo [2,1-f] [1,2,4] triazin-2-yl] thio] methyl] Preparation of ethyl benzoate (6l)

5 (500 mg, 1.44 mmol) prepared above was dissolved in N, N-dimethylformamide (20 mL), potassium iodide (2.39 g, 14.38 mmol) was added, and stirred at 70 ° C. for 5 minutes. Then, N, N-diisopropylethylamine (929 mg, 7.19 mmol) and p-methoxyaniline (354 mg, 2.88 mmol) were added, and the reaction was performed at 80 ° C. for 4 h. The reaction was detected by TLC. Water (80 mL) was added to the reaction solution, and ethyl acetate was extracted (30 mL × 3). The organic layers were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, left to stand, filtered, and the solvent was distilled off under reduced pressure. Chromatographic separation (petroleum ether: ethyl acetate = 5: 1) gave 560 mg of white solid, yield: 89.46%. ESI-MS m / z: 435.2 [M + H] ⁺ ;

Step b: 4-[[[4-[(4-methoxyphenyl) amino] pyrrolo [2,1-f] [1,2,4] triazin-2-yl] thio] methyl] Preparation of benzoic acid (7l)

Into a 100 mL eggplant-shaped bottle was added the compound 6l (500 mg, 1.15 mmol) and sodium hydroxide (92 mg, 2.30 mmol) prepared above, and water (20 mL) and ethanol (40 mL) were added. The reaction was refluxed for 10 h, and the reaction was detected by TLC. The solvent was distilled off under reduced pressure, water (30 mL) was added, the pH was adjusted to 6-7 with glacial acetic acid solution under ice bath, frozen in a refrigerator for 2 h, suction filtered, and the filter cake was vacuum dried to obtain 351 mg of white solid, yield: 86.45% . ESI-MS m / z: 407.1 [M + H] ⁺ .

Step c: N- (2-aminophenyl) -4-[[[4-[(4-methoxyphenyl) amino] pyrrolo [2,1-f] [1,2,4] triazine Preparation of -2-yl] thio] methyl] benzamide (I-36)

To a 25mL eggplant-shaped bottle, add 7l (150mg, 0.37mmol) and TBTU (130mg, 0.40mmol) prepared above, add N, N-dimethylformamide (10mL), and then add N, N-diisopropyl Ethylamine (190mg, 1.47mmol), stirred at room temperature for 1h, and then added o-phenylenediamine (40mg, 0.37mmol), continued stirring at room temperature for 8h, TLC detection reaction was complete. Water (80 mL) was added to the reaction solution, extracted with ethyl acetate (30 mL × 3), the organic layers were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, left to stand, filtered, and the solvent was distilled off under reduced pressure, silica gel column Chromatographic separation (petroleum ether: ethyl acetate = 1: 1) gave a yellow solid 94 mg, yield: 51.34%. mp: 173-175 ° C; ESI-MS m / z: 497.2 [M + H] ⁺ ; ¹ H-NMR (300 MHz, DMSO-d ₆ ) δ (ppm): 9.60 (s, 1H), 8.93 (t, J = 5.5 Hz, 1H), 7.87 (d, J = 8.0 Hz, 2H), 7.59-7.58 (m, 1H), 7.49 (d, J = 8.0 Hz, 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 = 5.5 Hz, 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] triazine-2- Group] amino] methyl] benzamide (I-37)

Step a: 4-[[[4H- (1,4-oxazin-4-yl) pyrrolo [2,1-f] [1,2,4] triazin-2-yl] thio] methyl] Preparation of ethyl benzoate (6m)

5 (2g, 5.75mmol) prepared above was dissolved in N, N-dimethylformamide (50mL), potassium iodide (9.55g, 57.50mmol) was added, and stirred at 70 ° C for 5 minutes. Then, N, N-diisopropylethylamine (3.72g, 28.75mmol) and 4H-1,4-oxazine (0.96g, 11.50mmol) were added, and the reaction was performed at 80 ℃ for 10h. The reaction was detected by TLC. The reaction solution was added with water (200 mL), extracted with ethyl acetate (80 mL × 3), the organic layers were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, left to stand, filtered, the solvent was distilled off under reduced pressure, silica gel column Chromatographic separation (petroleum ether: ethyl acetate = 5: 1) gave yellow-green solid 1.56g, yield: 68.72%. ESI-MS m / z: 395.2 [M + H] ⁺ .

Step b: 4-[[[4H- (1,4-oxazin-4-yl) amino] pyrrolo [2,1-f] [1,2,4] triazin-2-yl] thio] methyl Of benzoic acid (7m)

A 100 mL eggplant-shaped bottle was added with the compound 6m (300 mg, 0.76 mmol) and sodium hydroxide (47 mg, 1.17 mmol) prepared above, and water (20 mL) and ethanol (40 mL) were added. The reaction was refluxed for 10 h. The reaction was completed by TLC. The solvent was distilled off under reduced pressure, water (30 mL) was added, the pH was adjusted to 6-7 with glacial acetic acid solution in an ice bath, frozen in a refrigerator for 2 h, filtered with suction, and the filter cake was vacuum dried to obtain 182 mg of white solid, yield: 65.67% . Repeat the operation several times to get about 1.10g of white solid; ESI-MS m / z: 367.2 [M + H] ⁺ .

Step c: N- (2-aminophenyl) -4-[[[4H- (1,4-oxazin-4-yl) pyrrolo [2,1-f] [1,2,4] triazine Preparation of -2-yl] amino] methyl] benzamide (I-37)

To a 25mL eggplant-shaped bottle, add 7m (377mg, 1.03mmol) and TBTU (124mg, 1.14mmol) prepared above, add N, N-dimethylformamide (30mL), and then add N, N-diisopropyl Ethylamine (534mg, 4.14mmol), stirred at room temperature for 1h, then added o-phenylenediamine (124mg, 1.14mmol), continued stirring at room temperature for 8h, TLC detected the reaction was complete. Water (160 mL) was added to the reaction solution, and ethyl acetate was extracted (60 mL × 3). The organic layers were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, allowed to stand, filtered, and the solvent was distilled off under reduced pressure. Chromatographic separation (petroleum ether: ethyl acetate = 1: 1) gave a white solid 271 mg, yield: 59.33%. mp: 136-139 ° C; ESI-MS m / z: 457.2 [M + H] ⁺ ; ¹ H-NMR (300 MHz, DMSO-d ₆ ) 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-piperidylpyrrolo [2,1-f] [1,2,4] triazin-2-yl] amino] methyl] benzyl Amide (I-38)

Step a: Preparation of ethyl 4-[[[4-piperidinylpyrrolo [2,1-f] [1,2,4] triazin-2-yl] thio] methyl] benzoate (6n)

5 (500 mg, 1.44 mmol) prepared above was dissolved in N, N-dimethylformamide (20 mL), potassium iodide (2.39 g, 14.38 mmol) was added, and stirred at 70 ° C. for 5 minutes. Then, N, N-diisopropylethylamine (929 mg, 7.19 mmol) and piperidine (245 mg, 2.88 mmol) were added, and the reaction was performed at 80 ° C. for 3 h. The reaction was detected by TLC. Water (80 mL) was added to the reaction solution, extracted with ethyl acetate (30 mL × 3), the organic layers were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, left to stand, filtered, and the solvent was distilled off under reduced pressure, silica gel column Chromatographic separation (petroleum ether: ethyl acetate = 5: 1) gave 552 mg of white solid, yield: 96.68%. ESI-MS m / z: 397.2 [M + H] ⁺ .

Step b: Preparation of 4-[[[4-piperidylpyrrolo [2,1-f] [1,2,4] triazin-2-yl] thio] methyl] benzoic acid (7n)

Into a 100mL eggplant-shaped bottle was added the compound 6n (500mg, 1.26mmol) and sodium hydroxide (101mg, 2.52mmol) prepared above, added water (20mL) and ethanol (40mL), the reaction was refluxed for 10h, TLC detection reaction was complete. The solvent was distilled off under reduced pressure, water (30 mL) was added, the pH was adjusted to 6-7 with glacial acetic acid solution in an ice bath, frozen in a refrigerator for 2 h, filtered with suction, and the filter cake was vacuum dried to obtain 338 mg of white solid, yield: 72.75% ; ESI-MS m / z: 369.2 [M + H] ⁺ .

Step c: N- (2-aminophenyl) -4-[[[4-piperidinylpyrrolo [2,1-f] [1,2,4] triazin-2-yl] thio] methyl ] Preparation of benzamide (I-38)

To a 25mL eggplant-shaped bottle, add 7n (151mg, 0.41mmol) and TBTU (143mg, 0.45mmol) prepared above, add N, N-dimethylformamide (10mL), and then add N, N-diisopropyl Ethylamine (209mg, 1.62mmol), stirred at room temperature for 1h, then added o-phenylenediamine (44mg, 0.41mmol), continued stirring at room temperature for 8h, TLC detected the reaction was complete. Water (80 mL) was added to the reaction solution, extracted with ethyl acetate (30 mL × 3), the organic layers were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, left to stand, filtered, and the solvent was distilled off under reduced pressure, silica gel column Chromatographic separation (petroleum ether: ethyl acetate = 1: 1) gave a white solid 65 mg, yield: 34.57%. mp: 176-178 ° C; ESI-MS m / z: 459.2 [M + H] ⁺ ; ¹ H-NMR (300 MHz, DMSO-d ₆ ) δ (ppm): 9.61 (s, 1H), 7.91 (d, J = 8.1 Hz, 2H), 7.71-7.70 (m, 1H), 7.57 (d, J = 8.2 Hz, 2H), 7.14 (d, J = 7.4 Hz, 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)

Step a: ethyl 5-[[[4- (2-furan) aminopyrrolo [2,1-f] [1,2,4] triazin-2-yl] thio] methyl] picolinate (6o ) Preparation

5 (500 mg, 1.44 mmol) prepared above was dissolved in N, N-dimethylformamide (20 mL), potassium iodide (2.39 g, 14.38 mmol) was added, and stirred at 70 ° C. for 5 minutes. Then, N, N-diisopropylethylamine (929 mg, 7.19 mmol) and 2-aminofuran (239 mg, 2.88 mmol) were added, and the reaction was performed at 80 ° C. for 3 h. The reaction was detected by TLC. Water (80 mL) was added to the reaction solution, extracted with ethyl acetate (30 mL × 3), the organic layers were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, left to stand, filtered, and the solvent was distilled off under reduced pressure, silica gel column Chromatographic separation (petroleum ether: ethyl acetate = 5: 1) gave 533 mg of white solid, yield: 94.00%. ESI-MS m / z: 396.2 [M + H] ⁺ .

Step b: 4-[[[4- (2-furan) aminopyrrolo [2,1-f] [1,2,4] triazin-2-yl] thio] methyl] benzoic acid (7o) preparation

Into a 100mL eggplant-shaped bottle was added the above prepared compound 6o (500mg, 1.27mmol) and sodium hydroxide (101mg, 2.54mmol), added water (20mL) and ethanol (40mL), the reaction was refluxed for 10h, TLC detection reaction was complete. The solvent was distilled off under reduced pressure, water (30 mL) was added, the pH was adjusted to 6-7 with glacial acetic acid solution under ice bath, frozen in a refrigerator for 2 h, suction filtered, and the filter cake was vacuum dried to obtain a white solid 320 mg, yield: 68.90% ; ESI-MS m / z: 368.2 [M + H] ⁺ .

Step c: N- (2-aminophenyl) -4-[[[4- (2-furan) aminopyrrolo [2,1-f] [1,2,4] triazin-2-yl] sulfur ] Methyl] benzamide (I-39) Preparation

To a 25mL eggplant-shaped bottle, add 7o (150mg, 0.41mmol) and TBTU (143mg, 0.45mmol) prepared above, add N, N-dimethylformamide (10mL), and then add N, N-diisopropyl Ethylamine (209mg, 1.62mmol), stirred at room temperature for 1h, then added o-phenylenediamine (44mg, 0.41mmol), continued stirring at room temperature for 8h, TLC detected the reaction was complete. Water (80 mL) was added to the reaction solution, extracted with ethyl acetate (30 mL × 3), the organic layers were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, left to stand, filtered, and the solvent was distilled off under reduced pressure, silica gel column Chromatographic separation (petroleum ether: ethyl acetate = 1: 1) gave 59 mg of white solid, yield: 31.52%. mp: 185-188 ° C; ESI-MS m / z: 458.2 [M + H] ⁺ ; ¹ H-NMR (300 MHz, DMSO-d ₆ ) 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)

Step a: 4-[[[4- (3-pyridyl) pyrrolo [2,1-f] [1,2,4] triazin-2-yl] thio] methyl] benzoic acid ethyl ester (6p ) Preparation

5 (660mg, 1.91mmol), 3- (4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl) pyridine (590mg, 2.86) mmol), [1,1'-bis (diphenylphosphino) ferrocene] palladium dichloride (156mg, 0.21mmol), 2M potassium phosphate aqueous solution (2.86mL) was added to THF (8.2mL), Reflux for 6h. The reaction solution was added with water, extracted with ethyl acetate (30mL × 3), the organic layers were combined, washed with saturated brine (50mL) and 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 = 5: 1), to obtain 255 mg of white solid, yield: 34.19%. ESI-MS m / z: 391.2 [M + H] ⁺ .

Step b: 4-[[[4- (3-pyridyl) pyrrolo [2,1-f] [1,2,4] triazin-2-yl] thio] methyl] benzoic acid (7p) preparation

To a 100mL eggplant-shaped bottle, add the above-prepared and accumulated compound 6p (500mg, 1.28mmol) and sodium hydroxide (102mg, 2.56mmol), add water (20mL) and ethanol (40mL), reflux for 10h, and complete the reaction by TLC. . The solvent was distilled off under reduced pressure, water (30 mL) was added, the pH was adjusted to 6-7 with glacial acetic acid solution in an ice bath, frozen in a refrigerator for 2 h, suction filtered, and the filter cake was vacuum dried to obtain 336 mg of white solid, yield: 72.40% . ESI-MS m / z: 363.2 [M + H] ⁺ . Step c: N- (2-aminophenyl) -4-[[[4- (3-pyridyl) aminopyrrolo [2,1-f ] [1,2,4] Triazin-2-yl] thio] methyl] benzamide (I-40)

To a 25mL eggplant-shaped bottle, add 7p (150mg, 0.41mmol) and TBTU (143mg, 0.45mmol) prepared above, add N, N-dimethylformamide (10mL), and then add N, N-diisopropyl Ethylamine (209mg, 1.62mmol), stirred at room temperature for 1h, then added o-phenylenediamine (44mg, 0.41mmol), continued stirring at room temperature for 8h, TLC detected the reaction was complete. Water (80 mL) was added to the reaction solution, extracted with ethyl acetate (30 mL × 3), the organic layers were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, left to stand, filtered, and the solvent was distilled off under reduced pressure, silica gel column Chromatographic separation (petroleum ether: ethyl acetate = 1: 1) gave 66 mg of white solid, yield: 35.57%. mp: 180-183 ° C; ESI-MS m / z: 453.2 [M + H] ⁺ ; ¹ H-NMR (300 MHz, DMSO-d ₆ ) 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)

Step a: 4-[[[4- (4-methoxyphenyl) pyrrolo [2,1-f] [1,2,4] triazin-2-yl] thio] methyl] benzoic acid ethyl Preparation of ester (6q)

The 5 (660 mg, 1.91 mmol), 2- (4-methoxyphenyl) -4,4,5,5-tetramethyl-1,3,2-dioxaborolane (670 mg, 2.86mmol), [1,1'-bis (diphenylphosphino) ferrocene] palladium dichloride (156mg, 0.21mmol), 2M potassium phosphate aqueous solution (2.86mL) was added to THF (8.2mL) , Reflux for 6h. The reaction solution was added with water and extracted with ethyl acetate (30 mL × 3). The organic layers were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and left to stand, filtered, and the solvent was distilled off under reduced pressure. (Petroleum ether: ethyl acetate = 5: 1), to obtain 289 mg of white solid, yield: 36.07%. ESI-MS m / z: 420.2 [M + H] ⁺ .

Step b: 4-[[[4- (4-methoxyphenyl) pyrrolo [2,1-f] [1,2,4] triazin-2-yl] thio] methyl] benzoic acid ( 7q) Preparation

Into a 100mL eggplant-shaped bottle, add the above-prepared and accumulated compound 6q (500mg, 1.19mmol) and sodium hydroxide (95mg, 2.38mmol), add water (20mL) and ethanol (40mL), reflux for 10h, and complete the reaction by TLC. . The solvent was distilled off under reduced pressure, water (30 mL) was added, the pH was adjusted to 6-7 with glacial acetic acid solution in an ice bath, frozen in a refrigerator for 2 h, suction filtered, and the filter cake was vacuum dried to obtain a white solid 330 mg, yield: 70.73% . ESI-MS m / z: 392.2 [M + H] ⁺ .

Step c: N- (2-aminophenyl) -4-[[[4- (4-methoxyphenyl) aminopyrrolo [2,1-f] [1,2,4] triazine-2 -Yl] thio] methyl] benzamide (I-41)

To a 25mL eggplant-shaped bottle, add 7p (160mg, 0.41mmol) and TBTU (143mg, 0.45mmol) prepared above, add N, N-dimethylformamide (10mL), and then add N, N-diisopropyl Ethylamine (209mg, 1.62mmol), stirred at room temperature for 1h, then added o-phenylenediamine (44mg, 0.41mmol), continued stirring at room temperature for 8h, TLC detected the reaction was complete. Water (80 mL) was added to the reaction solution, extracted with ethyl acetate (30 mL × 3), the organic layers were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, left to stand, filtered, and the solvent was distilled off under reduced pressure, silica gel column Chromatographic separation (petroleum ether: ethyl acetate = 1: 1) gave 74 mg of white solid, yield: 37.48%. mp: 169-172 ° C; ESI-MS m / z: 482.2 [M + H] ⁺ ; ¹ H-NMR (300 MHz, DMSO-d ₆ ) 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 (9)

1. The compound of general formula (I) or a pharmaceutically acceptable salt thereof:

   

   Where R ¹ is hydroxy, or 2-aminophenyl optionally substituted with one or more R ⁵ , R ^{5 is} selected from hydrogen, (C ₁ -C ₆ ) alkyl, cyano, halogen, halo (C ₁ -C ₆ ) alkyl, hydroxy, mercapto, amino, (C ₁ -C ₆ ) alkoxy, (C ₁ -C ₆ ) alkylthio, (C ₁ -C ₆ ) amino, phenyl, 5 or 6 Elementary heteroaryl

   R ² is -LR ³ , where L is a bond, O, S, NR ⁴ ; R ³ is aryl, heteroaryl, saturated or partially saturated heterocyclic group, each aryl, heteroaryl, saturated or partially saturated heterocyclic groups optionally substituted with one or more substituents R ^6, R ⁶ is selected from hydrogen, (C ₁ -C ₆₎ alkyl, cyano, halo, halo (C ₁ -C ₆₎ alkyl, hydroxy , Mercapto, amino, (C ₁ -C ₆ ) alkoxy, (C ₁ -C ₆ ) alkylthio, (C ₁ -C ₆ ) alkylamino, tert-butoxycarbonyl;

   Wherein R ^{4 is} selected from hydrogen and (C ₁ -C ₆ ) alkyl;

   X is NH, NR ⁷ , O, S (O) n, R ^{7 is} selected from (C ₁ -C ₆ ) alkyl, and the value of n ranges from 0 to 2;

   Q is aryl or heteroaryl, wherein aryl or heteroaryl are each independently optionally substituted with one or more substituents R ^8, R ⁸ is selected from hydrogen, (C ₁ -C ₆₎ alkyl, cyano, halo , Halo (C ₁ -C ₆ ) alkyl, hydroxyl, mercapto, (C ₁ -C ₆ ) alkoxy;

   Wherein, the aryl group is a 6-10 membered aryl group; the heteroaryl group is a five-membered or six-membered heteroaryl group, wherein 1-4 ring atoms are heteroatoms selected from oxygen, nitrogen, sulfur, and the rest The ring atom is carbon; the heterocyclic group contains 5-10 ring atoms, of which 1-4 ring atoms are heteroatoms selected from oxygen, nitrogen and sulfur, and the remaining ring atoms are carbon.
2. The compound of claim 1, characterized in that:

   R ¹ is hydroxy, or selected from 2-aminophenyl substituted by one or more R ⁵ , R ^{5 is} selected from hydrogen, (C ₁ -C ₆ ) alkyl, cyano, halogen, phenyl, thienyl;

   R ² is -LR ³ , where L is a bond, O, S, NR ⁴ ; R ³ is aryl, heteroaryl, saturated or partially saturated heterocyclic group, each aryl, heteroaryl, saturated or partially saturated heterocyclic groups optionally substituted with one or more substituents R ^6, R ⁶ is selected from hydrogen, (C ₁ -C ₆₎ alkyl, cyano, halo, trifluoromethyl, hydroxy, mercapto, amino, methoxy Group, methylamino, tert-butoxycarbonyl;

   Wherein R ^{4 is} selected from H, (C ₁ -C ₆ ) alkyl;

   X is NH, NR ⁷ , O, S (O) n, R ^{7 is} selected from methyl, ethyl, and propyl, and the value of n ranges from 0 to 2;

   Q is phenyl, pyridyl;

   Wherein, the aryl group is phenyl; the heterocyclic group is piperidinyl, morpholinyl, piperazinyl; the aryl hetero group is pyrrolyl, pyrazolyl, imidazolyl, furyl, thienyl, oxo Oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyrimidinyl, pyrazinyl or pyridazinyl.
3. The compound of claim 1, characterized in that:

   R ¹ is hydroxy, or selected from 2-aminophenyl substituted by one or more R ⁵ , R ^{5 is} selected from hydrogen, halogen;

   R ² is -LR ³ , where L is a bond, -NH; R ³ is the following aromatic ring, heterocyclic ring or substituted aromatic ring, substituted heterocyclic ring: phenyl, pyrrolyl, furyl, thienyl, pyrazole Group, imidazolyl, pyridyl, pyrazinyl, pyrimidinyl, morpholinyl, piperazinyl, piperidinyl, 1,4-oxazin-4-yl, substituents selected from methyl, ethyl, tert-butyl Group, 1 to 2 halogens, trifluoromethyl, methoxy, tert-butoxycarbonyl;

   X is NH, O, S (O) n, the value range of n is 0 ～ 2;

   Q is phenyl, pyridyl;
4. The compound of claim 1, characterized by the following compounds:

   N- (2-aminophenyl) -4-[[[4-[(5-methyl-1H-pyrazol-3-yl) amino] pyrrolo [2,1-f] [1,2,4 ] Triazin-2-yl] sulfur] 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] triazine-2 -Yl] sulfur] 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] benzyl Amide (I-7)

   N- (2-amino-4-fluorophenyl) -4-[[[4-morpholinylpyrrolo [2,1-f] [1,2,4] triazin-2-yl] thio] methyl Group] benzamide (I-8)

   N- (2-aminophenyl) -4-[[[4-[(4-fluorobenzyl) amino] pyrrolo [2,1-f] [1,2,4] triazin-2-yl] Sulfur] methyl] benzamide (I-9)

   N- (2-amino-4-fluorophenyl) -4-[[[4-[(4-fluorobenzyl) amino] pyrrolo [2,1-f] [1,2,4] triazine- 2-yl] thio] methyl] benzamide (I-10)

   N- (2-aminophenyl) -4-[[[4-[(4-trifluoromethylbenzyl) amino] pyrrolo [2,1-f] [1,2,4] triazine-2 -Yl] sulfur] 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] triazine-2- Yl] thio] methyl] benzamide (I-13)

   N- (2-amino-4-fluorophenyl) -4-[[[4-[(4-methoxybenzyl) amino] pyrrolo [2,1-f] [1,2,4] tri Oxazin-2-yl] thio] methyl] benzamide (I-14)

   N- (2-aminophenyl) -4-[[[4-[(3,4-dimethoxybenzyl) amino] pyrrolo [2,1-f] [1,2,4] triazine -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] triazine -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] triazine- 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] sulfur] methyl] benzamide (I-20)

   N- (2-aminophenyl) -4-[[[4-[(N-Bocpiperidin-4-yl) amino] pyrrolo [2,1-f] [1,2,4] triazine- 2-yl] thio] methyl] benzamide (I-21)

   N- (2-amino-4-fluorophenyl) -4-[[[4-[(N-Bocpiperidin-4-yl) amino] pyrrolo [2,1-f] [1,2,4 ] Triazin-2-yl] sulfur] 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] triazine -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] triazine-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] sulfoxide] 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] sulfone] 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] triazine-2- Group] amino] methyl] benzamide (I-36)

   N- (2-aminophenyl) -4-[[[4H- (1,4-oxazin-4-yl) pyrrolo [2,1-f] [1,2,4] triazine-2- Group] amino] methyl] benzamide (I-37)

   N- (2-aminophenyl) -4-[[[4-piperidylpyrrolo [2,1-f] [1,2,4] triazin-2-yl] amino] methyl] benzyl Amide (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 according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof, wherein the pharmaceutically acceptable salt is an acid addition salt of a compound of general formula (I) and the following acids: hydrochloric acid, hydrobromic acid, sulfuric acid , Phosphoric acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid, citric acid, tartaric acid, lactic acid, pyruvic acid, acetic acid, maleic acid or succinic acid, fumaric acid, salicylic acid, phenylacetic acid , Mandelic acid; or the pharmaceutically acceptable salt is an acid salt of an inorganic base.
6. The compound according to claim 5 or a pharmaceutically acceptable salt thereof, wherein the acid salt of an inorganic base is a basic metal cation salt, an alkaline earth metal cation salt or an ammonium cation salt.
7. A pharmaceutical composition containing the compound according to any one of claims 1 to 4 and a pharmaceutically acceptable carrier.
8. Use of the compound according to any one of claims 1 to 4 in the preparation of a medicament for the prevention or treatment of clinical disorders related to HDACs.
9. The use according to claim 8, wherein the diseases related to HDACs are 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, gallbladder cancer, myelodysplastic syndrome, lymphoma, esophageal cancer, gastrointestinal cancer, astrocytoma, neuroblastoma, glioma, schwannomas, mesothelioma, non-insulin Dependent diabetes, autoimmune diseases.