Methods for preparing KRAS G12C inhibitors imidazotriazine and pyrrolopyrimidine derivatives

Abstract

The present application discloses a method for preparing G12C inhibitors, imidazotriazine and pyrrolopyrimidine derivatives or stereoisomers thereof or pharmaceutically acceptable salts thereof, wherein the imidazotriazine and pyrrolopyrimidine derivatives or stereoisomers thereof or pharmaceutically acceptable salts thereof are used as G12C inhibitors for treating cancer.

Description

Technical Field

[0001] The present application discloses a method for preparing G12C inhibitors, imidazotriazine and pyrrolopyrimidine derivatives or stereoisomers thereof or pharmaceutically acceptable salts thereof, wherein the imidazotriazine and pyrrolopyrimidine derivatives or stereoisomers thereof or pharmaceutically acceptable salts thereof are used as G12C inhibitors for treating cancer. Background Art

[0002] RAS is one of the most well-known oncogenes. In humans, three RAS genes (HRAS, KRAS, and NRAS) encode four highly homologous RAS proteins (HRAS, KRAS-4A, KRAS-4B, and NRAS). RAS proteins are small GTPases that function as binary molecular switches and are involved in extracellular growth and differentiation signaling.

[0003] RAS normally cycles between a GDP-bound "off" state and a GTP-bound "on" state. This cycle is regulated by several factors. Guanine nucleotide exchange factors (GEFs), including SOS1 and SOS2, promote the exchange and formation of GTP-bound RAS. At the same time, GTPase activating proteins (GAPs), such as NF-1, promote GTP hydrolysis, thereby returning RAS to an inactive state bound to GDP (Kessler et al., PNAS, 2019, 116(32): 15823-15829). Once bound to GTP, RAS begins conformational changes in two specific regions, Switch 1 and Switch 2, allowing the binding and activation of downstream effector proteins to initiate a cascade of intracellular signaling pathways. These effectors include the RAF-MEK-ERK and PI3K-AKT-mTOR pathways, both of which play important roles in regulating cell proliferation, differentiation, and survival (Cox et al., Nature Reviews Drug Discovery, 2014, 13:828-851).

[0004] RAS mutations have been identified in approximately 30% of human tumors. These mutations often occur as single-base missense mutations in codons 12, 13, or 61, resulting in stabilization of the activated GTP-bound RAS form and constitutive activation of RAS downstream signaling pathways. KRAS is the most commonly mutated RAS in cancer, accounting for 85% of all RAS-driven cancers, followed by NRAS (12%) and HRAS (3%). KRAS mutations have been detected in approximately 95% of pancreatic ductal adenocarcinomas, 50% of colorectal adenocarcinomas, and 30% of lung adenocarcinomas. Most KRAS mutations occur at residue 12, and the mutation type varies in different cancers. In colon and pancreatic cancer, the predominant KRAS mutation is G12D (glycine to lysine), whereas in non-small cell lung cancer (NSCLC), almost half of KRAS mutations are G12C (glycine to cysteine) (Cox et al., Nature Reviews Drug Discovery, 2014, 13:828-851).

[0005] Based on the key role of RAS in cell proliferation and its high mutation rate in human cancer, RAS has long been regarded as a therapeutic target for many cancers. However, despite decades of research efforts, no anti-RAS small molecules have been clinically approved. The main reason is the lack of druggable pockets on the surface of RAS (Papke et al., Science, 2017, 355: 1158–1163). Recently, more and more studies have shown that RAS may be treated with small molecules. Several inhibitors directly targeting KRAS G12C are under study (Patricelli et al., Cancer Discovery, 2016, 6 (3); 316–29) (Fell et al., ACS Med. Chem. Lett. 2018, 9, 12, 1230-1234).

[0006] Small molecule selective inhibitors of KRAS are being developed to prevent or treat diseases, for example, WO2015 / 054572A1 provides compounds having activity as inhibitors of G12C mutant RAS proteins. WO2016 / 164675A1 and WO2017 / 015562A1 disclose substituted quinazoline compounds as KRAS G12C inhibitors. WO2014 / 152588A1, WO2016 / 049524A1, WO2016 / 168540A1, WO2017 / 058728A1, WO2017 / 058792A1, WO2017 / 058805A1, WO2017 / 058915A1, WO2017 / 087 528A1, WO2018 / 064510A1, WO2018 / 068017A1, WO2018 / 119183A2, WO2018 / 206539A1, WO2018 / 218069A1, WO2019 / 051291A1, WO2019 / 055540A1, WO201 9 / 137985A1, WO2019 / 141250A1, WO2019 / 150305A1, WO2019 / 155399A1, WO2019 / 213516A1, WO2019 / 213526A1, WO2019 / 215203A1, WO20192 / 17307A1, WO2019 / 217691A1, WO2019 / 232419A1, WO2020 / 028706A1, WO2020 / 027084A1, WO2020 / 027083A1, WO2020 / 035031A1, and WO2020 / 047192A1 further report compounds with KRAS G12C inhibitory activity.

[0007] Therefore, there is still a great need for new inhibitors that selectively target mutant KRAS with high efficacy and safety and methods for their preparation. Continued efforts to develop KRAS G12C inhibitors will suggest new treatment modalities for KRAS G12C-driven cancers. Summary of the invention

[0008] The present invention relates to the following aspects:

[0009] Item 1. A method for preparing a compound of formula (I),

[0010] The steps include:

[0011]

[0012] L1 and L2 are independently selected from a single bond, -CO-, -CO-NH-, -NH-CO-, -O-, -NR a -、-NR a (CH2) m -、-(CH2) m -、-O-(CH2) m -、-O-CH(R a )-、-CH(R a )-、-CH(R a )(CH2) m -、-(CH2) m -O-;

[0013] R 1 is selected from cycloalkyl, heterocyclic, aryl, or heteroaryl, wherein the cycloalkyl, heterocyclic, aryl, or heteroaryl is optionally composed of at least one R 6 Substituent substitution (e.g. –(R 6 ) q1 , when q1 is greater than 1, each R 6 are the same or different substituents);

[0014] R 2 Selected from -NR b R c , cycloalkyl, heterocyclic, aryl, heteroaryl, the -NR b R c , cycloalkyl, heterocyclyl, aryl, heteroaryl, optionally with at least one R 6 Substituent substitution (e.g. –(R 6 ) q2 , when q2 is greater than 1, each R 6 are the same or different substituents);

[0015] R 6 Selected from -C 1-8 Alkyl, halogen, hydroxy, oxo, -C 1-8 Alkoxy, -NR b R c , cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein -C 1-8 Alkyl, -C 1-8 The alkoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with at least one halogen, hydroxy, amino, CN, cycloalkyl, heterocyclyl, aryl, or heteroaryl;

[0016] Or when R 6 When connected to two adjacent atoms in the ring, the two R 6Together with the carbon atom to which it is attached, it forms a 5-8 membered ring, wherein the 5-8 membered ring contains 0, 1 or 2 heteroatoms selected from N, O or S which is optionally oxidized; R 3 Selected from hydrogen, halogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, the -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally substituted by halogen, hydroxyl, -C 1-8 alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl;

[0017] R 4 Selected from

[0018] R 5 Selected from hydrogen, halogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, oxo, -NR b R c 、-(CH2) m -C(O)-NR d R e , cycloalkyl, heterocyclyl, aryl, heteroaryl or -(CH2) m -CN;

[0019] Each R a , R b and R c are independently selected from hydrogen, deuterium, cyano, halogen, hydroxyl, -C 1-8 Alkoxy, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -NR d R e or -CO-NR d R e , the -C 1-8 Alkoxy, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally substituted by R f Replace, or

[0020] (R a and R b )、(R a and R c )、(Rb and R c ) and the atoms to which they are attached form a 4-6 membered ring, wherein the 4-6 membered ring is optionally substituted by at least one R g replace;

[0021] Each R f Selected from halogen, hydroxy, oxo, -C 1-8 Alkoxy, -NR d R e 、-CO-NR d R e 、-NR d -CO-R e , cycloalkyl, heterocyclyl, aryl or heteroaryl, the -C 1-8 The alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl groups are optionally substituted with halogen, hydroxyl or -C 1-4 Alkyl substitution;

[0022] R d , R e and R g Each independently selected from hydrogen, deuterium, halogen, oxo, or -C 1-8 Alkyl, the -C 1-8 The alkyl group is optionally substituted with at least one halogen, oxo, -CF3 or -COCH3;

[0023] PR 1 is selected from ether protecting groups, ester protecting groups, carbamate protecting groups, preferably neopentyl, tert-butyl, benzyl, acetyl, propionyl, pivaloyl, Boc, Cbz, more preferably tert-butyl;

[0024] PR 2 Selected from Boc or Cbz;

[0025] p is independently selected from 0, 1, 2, 3 or 4;

[0026] q1 and q2 are independently selected from 0, 1, 2, 3, 4, 5, 6, 7 or 8;

[0027] Each m and n is independently selected from 0, 1, 2, 3, 4, 5 or 6.

[0028] Item 2. The preparation method according to Item 1, characterized in that:

[0029] The reagent used in step 1 is selected from NBS and Br2.

[0030] Item 3. The preparation method according to Item 1, characterized in that:

[0031] The reagents used in step 2 and step 7 are independently selected from phosphorus oxychloride, phosphorus trichloride, phosphorus pentachloride, Lucas reagent, a mixture of concentrated hydrochloric acid and anhydrous zinc chloride, Vilesmier-Haack reagent, thionyl chloride, sulfonyl chloride, chlorine, preferably POCl3, PCl5, SOCl2, more preferably POCl3.

[0032] Item 4. The preparation method according to Item 1, characterized in that:

[0033] The reagent used in step 3 is selected from alkali metal salts of alcohols, preferably sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, potassium tert-butoxide, lithium tert-butoxide, sodium benzyl alcohol, potassium benzyl alcohol, lithium benzyl alcohol, more preferably lithium tert-butoxide.

[0034] Item 5. The preparation method according to Item 1, characterized in that:

[0035] The reagent used in step 4 is selected from alkali metal hydrides, alkali metal salts, alkyl lithium compounds, and lithium amide compounds, preferably sodium hydride, potassium hydride, lithium hydride, sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, potassium tert-butoxide, n-butyl lithium, sec-butyl lithium, tert-butyl lithium, lithium diisopropylamide, and lithium hexamethyldisilazide, and more preferably sodium hydride.

[0036] Item 6. The preparation method according to Item 1, characterized in that:

[0037] The reagent used in step 5 is selected from alkali metal salts of alcohols, alkyl lithium compounds, and lithium amide compounds, preferably sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, potassium tert-butoxide, n-butyl lithium, sec-butyl lithium, tert-butyl lithium, lithium diisopropylamide, and lithium hexamethyldisilazide, and more preferably n-butyl lithium.

[0038] Item 7. The preparation method according to Item 1, characterized in that:

[0039] The deprotection conditions in step 6 and step 9 are independently selected from catalytic hydrogenation or acidic deprotection, preferably a combination of trifluoroacetic acid and triethylsilane, a combination of BBr3, Pd / C and hydrogen, a combination of trifluoroacetic acid, hydrochloric acid, Pd / C and cyclohexadiene, and more preferably a combination of trifluoroacetic acid and triethylsilane, a combination of BBr3, Pd / C and hydrogen.

[0040] Item 8. The preparation method according to Item 1, characterized in that:

[0041] The reagent used in step 8 is selected from nitrogen-containing organic bases, preferably triethylamine, diethylamine, diisopropylethylamine, pyridine, methylimidazole, piperidine, morpholine, indoline, quinoline, isoquinoline, dimethylaminopyridine, more preferably triethylamine, diethylamine, diisopropylethylamine, dimethylaminopyridine, and further more preferably diisopropylethylamine.

[0042] Item 9. The preparation method according to Item 1, characterized in that:

[0043] The reagent used in step 9 is selected from an inorganic base, a nitrogen-containing organic base, and an alkali metal hydride, preferably sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, triethylamine, diethylamine, diisopropylethylamine, pyridine, methylimidazole, piperidine, morpholine, indoline, quinoline, isoquinoline, and dimethylaminopyridine, and more preferably sodium bicarbonate.

[0044] Item 10. The preparation method according to Item 1, characterized in that:

[0045] L1 is selected from a single bond, -CO-, -(CH2) m -、-CH(R a )-、-CH(R a )(CH2) m -、-(CH2) m -O-, further preferably selected from -(CH2) m -、-CH(R a )-; and / or

[0046] L2 is selected from a single bond, -O-, -O-(CH2) m -、-O-CH(R a )-、-O-CH(R a )-(CH2) m -; and / or

[0047] R 1 Selected from and / or

[0048] R 2 Selected from -NR b R c , and / or

[0049] R 3 Selected from hydrogen, halogen or -C 1-8 Alkyl; and / or

[0050] R 3 ' is selected from hydrogen, -C 1-8 Alkyl, -C 2-8 Alkenyl or -C 2-8 Alkynyl; and / or

[0051] R 4 Selected from and / or

[0052] R 5 Selected from hydrogen, -CH3, -C2H5, -C3H7, -C4H9, -C5H 11 、-(CH2) m -C(O)-NR d R e 、-(CH2) m -CN.

[0053] Item 11. The preparation method according to Item 1, characterized in that:

[0054] R 1 Selected from

[0055] and / or

[0056] R 2 Selected from (For example ), (For example ),

[0057] Item 12. The preparation method according to Item 1, characterized in that:

[0058] The compound of formula (I) or (II) is

[0059]

[0060] Example

[0061] The following examples are intended to be illustrative only and should not be construed as limiting in any way. Unless otherwise stated, the experimental methods in the following examples are conventional methods. Unless otherwise stated, reagents and materials are commercially available. All solvents and chemicals used are of analytical grade or chemical purity. Solvents are redistilled before use. Anhydrous solvents are prepared according to standard methods or reference methods. Silica gel (100-200 mesh) for column chromatography and silica gel (GF254) for thin layer chromatography (TLC) are commercially available from Qingdao Ocean Chemical Co., Ltd. or Yantai Chemical Co., Ltd. in China; unless otherwise stated, all silica gel is eluted with petroleum ether (60-90°C) / ethyl acetate (v / v) and developed with a solution of iodine or phosphomolybdic acid in ethanol. Unless otherwise stated, all extraction solvents are dried over anhydrous Na2SO4. Recorded on a Bruck-400 nuclear magnetic resonance spectrometer with TMS (tetramethylsilane) as an internal standard 1H NMR spectra. LC / MS data were recorded using an Agilent 1100 high performance liquid chromatograph-ion trap mass spectrometer (LC-MSD trap) equipped with a diode array detector (DAD) detecting at 214 nm and 254 nm and an ion trap (ESI source). All compound names except reagents are generate.

[0062] In the following examples, the following abbreviations are used:

[0063] Ac Acetyl

[0064] AcOH Acetic acid

[0065] Aq Water-based

[0066] Brine saturated sodium chloride aqueous solution

[0067] Bn Benzyl

[0068] Boc tert-Butyloxycarbonyl

[0069] Cbz benzyloxycarbonyl

[0070] DMF N,N-Dimethylformamide

[0071] Dppf 1,1"-Bis(diphenylphosphino)ferrocene

[0072] DBU 1,8-diazabicyclo[5.4.0]undec-7-ene

[0073] DCE 1,2-Dichloroethane

[0074] DCM Dichloromethane

[0075] DIEA or DIPEA N,N-diisopropylethylamine

[0076] DMAP 4-N,N-dimethylaminopyridine

[0077] DMF N,N-Dimethylformamide

[0078] DMSO Dimethyl sulfoxide

[0079] EA or EtOAc Ethyl acetate

[0080] eq equivalent

[0081] g

[0082] h or hr hour

[0083] HCl

[0084] HPLC High Performance Liquid Chromatography

[0085] IPA 2-Propanol

[0086] i-PrOH Isopropyl alcohol

[0087] mg milligram

[0088] mL milliliters

[0089] Mmol millimole

[0090] MeCN Acetonitrile

[0091] MeOH Methanol

[0092] Min Minutes

[0093] ms or MS mass spectrometry

[0094] NMR Nuclear Magnetic Resonance

[0095] Pd / C Palladium Carbon

[0096] PE Petroleum Ether

[0097] PMB 4-methoxybenzyl

[0098] PPA Polyphosphoric Acid

[0099] Rt., RT. or rt. Room temperature

[0100] Ru-Phos / Ru-PHOS 2-Dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl

[0101] SEM 2-Trimethylsilylethoxymethoxy

[0102] TBSCl tert-Butyldimethylsilyl chloride

[0103] TEA Triethanolamine

[0104] TFA Trifluoroacetic acid

[0105] THF Tetrahydrofuran

[0106] THP Tetrahydropyran

[0107] TLC Thin layer chromatography

[0108] Synthesis Example 3: Compound A3: 2-((S)-1-acryloyl-4-(7-(3-methoxynaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)imidazo[2,1-f][1,2,4]triazine-4-yl)piperazin-2-yl)acetonitrile

[0109] Step A: 7-Bromoimidazo[2,1-f][1,2,4]triazine-2,4(1H,3H)-dione

[0110]

[0111] To a solution of imidazo[2,1-f][1,2,4]triazine-2,4(1H,3H)-dione (30 g, 0.20 mol) in H2O (1.2 L) was added NBS (24.6 g, 0.14 mol) in several portions at below 25°C. The mixture was stirred at room temperature for 1 h. The mixture was filtered. The filtrate was concentrated to remove the solvent. The resulting residue and the previous filter cake were mixed and slurried in MeOH (20 V) and then MeOH:H2O (1:1, 20 V) to give the product (30.4 g, 94%). MS: M / e 231 (M+1) + .

[0112] Step B: 7-Bromo-2,4-dichloroimidazo[2,1-f][1,2,4]triazine

[0113]

[0114] A 350 ml sealed tube was charged with 7-bromoimidazo[2,1-f][1,2,4]triazine-2,4(1H,3H)-dione (10 g, 43 mmol), triethylamine hydrochloride (12 g, 88 mmol) and POCl3 (100 ml). The mixture was stirred at 120°C overnight. The mixture was concentrated to remove POCl3. The residue was diluted with EA (200 ml) and saturated NaHCO3 (aqueous solution) was added dropwise at below 20°C until the pH was above 7. The solution was separated. The organic layer was washed with H2O, dried over Na2SO4, filtered and concentrated. The resulting residue was purified by column chromatography using 0-20% EA in PE to give the product (8.5 g, 73%). MS: M / e 267 (M+1) + .

[0115] Step C: (S)-4-(7-bromo-2-chloroimidazo[2,1-f][1,2,4]triazin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylic acid benzyl ester

[0116]

[0117] (S)-2-(Cyanomethyl)piperazine-1-carboxylic acid benzyl ester hydrochloride (974mg, 3.29mmol) was added to a solution of 7-bromo-2,4-dichloroimidazo[2,1-f][1,2,4]triazine (1g, 3.76mmol), DIEA (1.2g, 9.3mmol) in THF (10ml). The reaction was then stirred at room temperature for 2h. The reaction mixture was diluted in water and extracted with DCM. The combined organic extracts were washed with saturated aqueous NaCl solution, dried over Na2SO4 and concentrated. The crude product was purified by silica gel column chromatography (EA:PE=1:2) to give the target compound (1.4g, 86.8%). 1 H NMR (400MHz, CDCl3) δ7.55(s,1H),7.44–7.32(m,5H),6.03(s,1H),5.24–5.14(m ,2H),4.75(s,2H),4.27(s,1H),3.67–3.16(m,3H),2.83–2.58(m,2H)ppm,MS:M / e 490(M+1) + .

[0118] Step D: (S)-benzyl 4-(7-bromo-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)imidazo[2,1-f][1,2,4]triazin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate

[0119]

[0120] To a solution of NaH (74 mg, 1.84 mmol, 60%) in THF (5 mL) at 0°C was added (S)-(1-methylpyrrolidin-2-yl)methanol (169 mg, 1.47 mmol). After 30 min, a solution of the product of step A (600 mg, 1.23 mmol) in THF (5 mL) was added. The reaction was then stirred at 60°C overnight. The mixture was cooled to room temperature, diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by combi flash to give the target compound (180 mg, 26%). MS: M / e 569 (M+1) + .

[0121] Step E: (S)-benzyl 2-(cyanomethyl)-4-(7-(3-methoxynaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)imidazo[2,1-f][1,2,4]triazin-4-yl)piperazine-1-carboxylate

[0122]

[0123] A flask was charged with Pd(dppf)Cl2 (12.4 mg, 0.017 mmol), the product of step B (100 mg, 0.17 mmol), (3-methoxynaphthalen-1-yl)boronic acid (38 mg, 0.19 mmol), Na2CO3 (22 mg, 0.2 mmol), dioxane (3 ml) and H2O (0.3 ml). The resulting mixture was stirred at 90°C for 4 h and then cooled to room temperature. The reaction was quenched with water, extracted with EtOAc, washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by combi flash to give the title compound (90 mg, 79%). MS: M / e 647 (M+1) + .

[0124] Step F: 2-((S)-4-(7-(3-methoxynaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)imidazo[2,1-f][1,2,4]triazin-4-yl)piperazin-2-yl)acetonitrile

[0125]

[0126] BBr3 (1M in DCM, 0.61 ml) was added dropwise to a mixture of the product of step C (160 mg, 0.25 mmol) in DCM (2 mL) at -10°C. The reaction was stirred at -10°C for 1 hour. The mixture was filtered and the filter cake was dried in an oven. The filter cake (20 mg, crude) was used directly in the next step without further purification. MS: M / e 513 (M+1) + .

[0127] Step G: 2-((S)-1-acryloyl-4-(7-(3-methoxynaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)imidazo[2,1-f][1,2,4]triazin-4-yl)piperazin-2-yl)acetonitrile

[0128]

[0129] To a mixture of the product of step D (20 mg, crude) in CH3CN (1 mL) was added saturated NaHCO3 (0.5 mL) at 0°C, followed by a solution of acryloyl chloride (4 mg) in CH3CN (0.3 mL). The resulting mixture was stirred at room temperature for 30 min. The reactant was diluted with water, extracted with EA, washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by preparative TLC to give the target compound (1.7 mg, 10% over two steps). 1H NMR (400MHz, DMSO-d6) δ7.93(d,J=8.2Hz,1H),7.83(s,1H),7.61–7.48(m,3H),7.34(s,2H),6.93–6.85(m,1H),6.23(d,J=16.6Hz ,1H),5.82(d,J=10.4Hz,1H),5.03(m,2H),4.17(s,2H),3.88(s,3H),3.67–3.44(m,5H),3.17–2.76(m,6H),2.07–1.38(m,6H)ppm. MS:M / e 567(M+1) + .

[0130] Example 4: Compound A4: 2-((S)-1-acryloyl-4-(2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(naphthalen-1-ylmethyl)imidazo[2,1-f][1,2,4]triazin-4-yl)piperazin-2-yl)acetonitrile

[0131] Step A: 7-Bromo-4-(tert-butoxy)-2-chloroimidazo[2,1-f][1,2,4]triazine

[0132]

[0133] To a solution of 7-bromo-2,4-dichloroimidazo[2,1-f][1,2,4]triazine (0.53 g, 2 mmol) in THF (6 mL) was added t-BuOLi (176 mg, 2.2 mmol) in portions. The mixture was then stirred at room temperature for 0.4 h. The residue was purified by combi flash to give the target compound (400 mg, 66%). 1 H NMR (400MHz, CDCl3) δ7.67 (s, 1H), 1.78 (s, 9H) ppm.

[0134] Step B: (S)-7-Bromo-4-(tert-butoxy)-2-((1-methylpyrrolidin-2-yl)methoxy)imidazo[2,1-f][1,2,4]triazine

[0135]

[0136] To a solution of NaH (448 mg, 11.2 mmol, 60%) in THF (10 mL) at 0°C was added (S)-(1-methylpyrrolidin-2-yl)methanol (0.7 g, 6.15 mmol). After 30 min, a solution of the product of step A (1.6 g, 5.6 mmol) in THF (5 mL) was added. The reaction was then stirred at 60°C for 1 h. The mixture was cooled to room temperature, diluted with water (30 mL) and extracted with EtOAc (60 mL x 2). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by combi flash to give the title compound (0.7 g, 33%). MS: M / e 384 (M+1) + .

[0137] Step C: (4-(tert-Butyloxy)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)imidazo[2,1-f][1,2,4]triazin-7-yl)(naphthalen-1-yl)methanol

[0138]

[0139] To a solution of the product of step B (250 mg, 0.7 mmol) in THF (10 mL) was added n-butyl lithium (0.6 mL, 0.96 mmol, 1.6 M in hexane), maintaining the temperature between -75 and -65 ° C. After 30 min, a mixture of 1-naphthaldehyde (120 mg, 0.77 mmol) in THF (2 mL) was added dropwise. The resulting mixture was stirred at -70 ° C for 1 h, then warmed to room temperature for 1 h. The reaction was quenched with saturated NH4Cl solution, extracted with EtOAc (60 mL x 2), washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by combi flash to give the target compound (230 mg, 71%). MS: M / e 462 (M+1) + .

[0140] Step D: (S)-2-((1-methylpyrrolidin-2-yl)methoxy)-7-(naphthalen-1-ylmethyl)imidazo[2,1-f][1,2,4]triazin-4-ol

[0141]

[0142] To a mixture of the product of step C (230 mg, 0.5 mmol) in DCM (4 mL) was added TFA (2 mL) and Et3SiH (2 mL). The reaction was heated at 25 °C overnight. The mixture was concentrated to dryness and the residue was used directly in the next step without further purification. MS: M / e 390 (M+1) + .

[0143] Step E: (S)-benzyl 2-(cyanomethyl)-4-(2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(naphthalen-1-ylmethyl)imidazo[2,1-f][1,2,4]triazin-4-yl)piperazine-1-carboxylate

[0144]

[0145] To the residue of step D (200 mg, crude) in toluene (10 mL), POCl3 (465 mg, 3 mmol) and DIEA (258 mg, 2 mmol) were added. The resulting mixture was stirred at 100 ° C overnight. The mixture was concentrated to dryness and treated with THF (15 mL). DIEA (258 mg, 2 mmol) and (S)-2-(cyanomethyl)piperazine-1-carboxylic acid benzyl ester (130 mg, 0.5 mmol) were then added and the reaction was stirred at room temperature for 3 hours. The reaction was quenched with saturated water and extracted with EtOAc (80 mL). The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by combi flash to give the target compound (100 mg, 32% over two steps). MS: M / e 631 (M+1) + .

[0146] Step F: 2-((S)-4-(2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(naphthalen-1-ylmethyl)imidazo[2,1-f][1,2,4]triazin-4-yl)piperazin-2-yl)acetonitrile

[0147]

[0148] To a mixture of the product of step E (50 mg, 0.079 mmol) in EtOH / THF (2.5 mL / 2.5 mL) was added Pd / C (30 mg, 10% Pd). The reaction was stirred at room temperature under H2 (balloon) for 8 h. The mixture was filtered and the solid was washed with THF (5 mL). The filtrate was concentrated to dryness (50 mg) and the residue was used directly in the next step without further purification. MS: M / e 497 (M+1) + .

[0149] Step G: 2-((S)-1-acryloyl-4-(2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(naphthalen-1-ylmethyl)imidazo[2,1-f][1,2,4]triazin-4-yl)piperazin-2-yl)acetonitrile

[0150]

[0151] To a mixture of the product of step F (50 mg, crude) in CH3CN (3 mL) was added saturated NaHCO3 (0.5 mL) at 0°C, followed by a solution of acryloyl chloride (6 mg, 0.1 mmol) in CH3CN (0.3 mL). The resulting mixture was stirred at room temperature for 30 min. The reaction was diluted with water and extracted with EA (60 mL). The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by preparative TLC to give the target compound (4 mg, 10% over two steps). 1 HNMR (400MHz, DMSO-d6) δ8.21(d,J=7.6Hz,1H),7.95(d,J=8.0Hz,1H),7.83(d,J=8.0Hz,1 H),7.62–7.49(m,2H),7.48–7.38(m,2H),7.34(s,1H),7.00–6.75(m,1H),6.19(d,J=16.4H z,1H),5.78(d,J=10.8Hz,1H),5.19–4.75(m,2H),4.64(s,2H),4.57–4.08(m,3H),3.57–3. 02(m,5H),2.89–2.67(m,2H),2.53-2.47(m,5H),2.16–1.90(m,1H),1.86–1.57(m,3H)ppm. MS:M / e551(M+1) + .

[0152] Example 5: Compound A5: 2-((S)-1-acryloyl-4-(7-((3-hydroxynaphthalen-1-yl)methyl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)imidazo[2,1-f][1,2,4]triazin-4-yl)piperazin-2-yl)acetonitrile

[0153] Step A: 4-Formylnaphth-2-yl pivalate

[0154]

[0155] To a solution of 3-hydroxy-1-naphthaldehyde (0.86 g, 5 mmol) in THF (10 mL) was added pyridine (790 mg, 10 mmol), followed by the dropwise addition of pivaloyl chloride (720 mg, 6 mmol). The mixture was then stirred at room temperature for 16 h. The reaction was quenched with water, extracted with EtOAc (60 mL x 2), washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by combiflash to give the target compound (620 mg, 48%). MS: M / e 257 (M+1) + .

[0156] Step B: 4-((4-(tert-Butoxy)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)imidazo[2,1-f][1,2,4]triazin-7-yl)(hydroxy)methyl)naphthalen-2-yl pivalate

[0157]

[0158] To a solution of (S)-7-bromo-4-(tert-butoxy)-2-((1-methylpyrrolidin-2-yl)methoxy)imidazo[2,1-f][1,2,4]triazine (383 mg, 1 mmol) in THF (6 mL) was added n-butyllithium (1 mL, 1.6 mmol) dropwise, maintaining the temperature between -75 and -65 °C. After 30 min, a mixture of the product of step A (307 mg, 1.2 mmol) in THF (1 mL) was added dropwise. The resulting mixture was stirred at -70 °C for 1 h and then warmed to room temperature for 3 h. The reaction was quenched with saturated NH4Cl solution, extracted with EtOAc (60 mL x 2), washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by combi flash to give the title compound (340 mg, 60%). MS: M / e 562 (M+1) + .

[0159] Step C: (S)-4-((4-hydroxy-2-((1-methylpyrrolidin-2-yl)methoxy)imidazo[2,1-f][1,2,4]triazin-7-yl)methyl)naphthalen-2-yl pivalate

[0160]

[0161] To a mixture of the product of step B (340 mg, 0.6 mmol) in DCM (8 mL) was added TFA (2 mL) and Et3SiH (4 mL). The reaction was heated at 40 °C overnight. The mixture was concentrated to dryness and the residue was used directly in the next step without further purification. MS: M / e 490 (M+1) + .

[0162] Step D: (S)-benzyl 2-(cyanomethyl)-4-(2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-7-((3-(pivaloyloxy)naphthalen-1-yl)methyl)imidazo[2,1-f][1,2,4]triazin-4-yl)piperazine-1-carboxylate

[0163]

[0164] To the residue of step C (crude) in toluene (10 mL) was added POCl3 (567 mg, 3.6 mmol) and DIEA (314 mg, 2.44 mmol). The resulting mixture was stirred at 100 ° C overnight. The mixture was concentrated to dryness and treated with THF (10 mL). DIEA (619 mg, 4.8 mmol) and (S)-2-(cyanomethyl)piperazine-1-carboxylic acid benzyl ester (155 mg, 0.6 mmol) were then added and the reaction was stirred at room temperature for 16 hours. The reaction was quenched with saturated water, extracted with EtOAc (60 mL), washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by combi flash to give the target compound (130 mg, 29% over two steps). MS: M / e 731 (M+1) + .

[0165] Step E: 4-((4-((S)-3-(cyanomethyl)piperazin-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)imidazo[2,1-f][1,2,4]triazin-7-yl)methyl)naphthalen-2-yl pivalate

[0166]

[0167] To a mixture of the product of step D (130 mg, 0.178 mmol) in EtOH / THF (6 mL / 6 mL) was added Pd / C (100 mg, 10% Pd). The reaction was stirred at room temperature under H2 (balloon) for 16 h. The mixture was filtered and the solid was washed with DCM / MeOH (5 mL / 5 mL). The filtrate was concentrated to dryness (100 mg) and the residue was used directly in the next step without further purification. MS: M / e 597 (M+1) + .

[0168] Step F: 4-((4-((S)-4-acryloyl-3-(cyanomethyl)piperazin-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)imidazo[2,1-f][1,2,4]triazin-7-yl)methyl)naphthalen-2-yl pivalate

[0169]

[0170] To a mixture of 4-((4-((S)-3-(cyanomethyl)piperazin-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)imidazo[2,1-f][1,2,4]triazin-7-yl)methyl)naphthalen-2-yl pivalate (40 mg, crude) in CH3CN (2 mL) was added saturated NaHCO3 (1 mL) at 0°C, followed by a solution of acryloyl chloride (6.6 mg, 0.1 mmol) in CH3CN (0.5 mL). The resulting mixture was stirred at room temperature for 1 hour. The reaction was diluted with water and extracted with EA. The organic layer was washed with brine, dried over MgSO4, filtered and concentrated. The residue was purified by preparative TLC to give the target compound 50 mg. MS: M / e 651 (M+1) + .

[0171] Step G: 2-((S)-1-acryloyl-4-(7-((3-hydroxynaphthalen-1-yl)methyl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)imidazo[2,1-f][1,2,4]triazin-4-yl)piperazin-2-yl)acetonitrile

[0172]

[0173] To a mixture of the product of step F (50 mg) in THF (2 mL) was added NaOH (2 M, 1 ml). The reaction was stirred at room temperature for 2 hours. The pH of the mixture was adjusted to 5% by volume with citric acid. The residue was extracted with EA. The combined organic layers were washed with brine, dried over Na2SO4 and concentrated. The residue was purified by preparative TLC to give the target compound (8 mg, 18%). 1H NMR(400MHz,DMSO-d6)δ8.08(d,J=8.2Hz,1H),7.70(d,J=8.1Hz,1H),7.54- 7.40(m,2H),7.32(s,1H),7.05(s,1H),6.96–6.83(m,2H),6.20(d,J=16.5H z,1H),5.81(d,J=10.2Hz,1H),4.89-5.06(m,2H),4.58(s,5H),4.16(s,1H) ,3.33-3.50(m,4H),2.70-3.07(m,8H),2.10(s,1H),1.51-1.74(m,3H)ppm. MS:M / e 567(M+1) + .

[0174] Example 6: Compound A6: 2-((S)-1-acryloyl-4-(7-((8-chloronaphthalen-1-yl)methyl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)imidazo[2,1-f][1,2,4]triazin-4-yl)piperazin-2-yl)acetonitrile

[0175] Step A: (4-(tert-Butyloxy)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)imidazo[2,1-f][1,2,4]triazin-7-yl)(8-chloronaphthalen-1-yl)methanol

[0176]

[0177] To a solution of (S)-7-bromo-4-(tert-butoxy)-2-((1-methylpyrrolidin-2-yl)methoxy)imidazo[2,1-f][1,2,4]triazine (383 mg, 1 mmol) in THF (10 mL) was added n-butyllithium (1 mL, 1.6 mmol) dropwise, maintaining the temperature between -75 and -65 °C. After 30 min, a mixture of 8-chloro-1-naphthaldehyde (200 mg, 1.1 mmol) in THF (2 mL) was added dropwise. The resulting mixture was stirred at -70 °C for 1 h and then warmed to room temperature for 16 h. The reaction was quenched with saturated aqueous NH4Cl and extracted with EtOAc (50 mL x 2). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by combi flash to give the title compound (400 mg, 80%). MS: M / e 496 (M+1) + .

[0178] Step B: (S)-7-((8-chloronaphthalen-1-yl)methyl)-2-((1-methylpyrrolidin-2-yl)methoxy)imidazo[2,1-f][1,2,4]triazin-4-ol

[0179]

[0180] To a mixture of the product of step A (400 mg, 0.8 mmol) in DCM (4 mL) was added TFA (4 mL) and Et3SiH (4 mL). The reaction was stirred at 25 °C overnight. The mixture was concentrated to dryness and the residue was used directly in the next step without further purification. MS: M / e 424 (M+1) + .

[0181] Step C: (S)-4-(7-((8-chloronaphthalen-1-yl)methyl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)imidazo[2,1-f][1,2,4]triazin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylic acid benzyl ester

[0182]

[0183] To the above residue of step B (crude) in toluene (8 mL) was added POCl3 (1 g, 6.5 mmol) and DIEA (428 mg, 3.23 mmol). The resulting mixture was stirred at 100 °C overnight. The mixture was concentrated to dryness and treated with THF (15 mL). DIEA (825 mg, 6.4 mmol) and (S)-2-(cyanomethyl)piperazine-1-carboxylic acid benzyl ester (209 mg, 0.8 mmol) were then added and the reaction was stirred at room temperature for 3 hours. The reaction was quenched with water and extracted with EtOAc (80 mL). The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by combi flash to give the title compound (40 mg, 6% over two steps). MS: M / e 665 (M+1) + .

[0184] Step D: 2-((S)-4-(7-((8-chloronaphthalen-1-yl)methyl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)imidazo[2,1-f][1,2,4]triazin-4-yl)piperazin-2-yl)acetonitrile

[0185]

[0186] To a mixture of the product of step C (30 mg, 0.05 mmol) in DCM (5 mL) was added 1N BBr3 (0.1 mL, 0.1 mmol) in DCM at -70°C. The reaction was slowly warmed to room temperature for 2 hours. Another portion of 1N BBr3 (0.1 mL, 0.1 mmol) in DCM was added and stirred overnight. The reaction was diluted with water and extracted with DCM (60 mL). The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated to give the target compound (20 mg, crude), which was used directly in the next step without further purification. MS: M / e 531 (M+1) + .

[0187] Step E: 2-((S)-1-acryloyl-4-(7-((8-chloronaphthalen-1-yl)methyl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)imidazo[2,1-f][1,2,4]triazin-4-yl)piperazin-2-yl)acetonitrile

[0188]

[0189] To a mixture of the product of step D (20 mg, crude) in CH3CN (4 mL) was added saturated NaHCO3 (0.3 mL) at 0°C, followed by a solution of acryloyl chloride (6 mg, 0.1 mmol) in CH3CN (0.3 mL). The resulting mixture was stirred at room temperature for 30 min. The reaction was diluted with water and extracted with EA (60 mL). The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by preparative TLC to give the target compound (0.4 mg, 1.3% over two steps). 1 HNMR (400MHz, CD3OD) δ7.94–7.86(m,2H),7.60–7.35(m,4H),6.90–6.75(m,2H),6.24–6.22(m,1H),5.90–5.76(m,1H),5.69(dd,J=3.6Hz,8.8Hz 1H),5.25–4.95(m,4H),4.65–4.55(m,1H),4.40–4.26(m,2H),4.25–4.10(m,1H),3.70–3.55(m,1H),3.14– 3.04(m,2H),2.95–2.70(m,3H),2.48(s,3H),2.42–2.30(m,1H),2.13–1.98(m,1H),1.86–1.65(m,3H)ppm. MS:M / e586(M+1) + .

[0190] Example 7: Compound A07: 2-((S)-1-acryloyl-4-(7-((8-methylnaphthalen-1-yl)methyl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)imidazo[2,1-f][1,2,4]triazin-4-yl)piperazin-2-yl)acetonitrile

[0191] Step A: (4-(tert-Butyloxy)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)imidazo[2,1-f][1,2,4]triazin-7-yl)(8-methylnaphthalen-1-yl)methanol

[0192]

[0193] To a solution of (S)-7-bromo-4-(tert-butoxy)-2-((1-methylpyrrolidin-2-yl)methoxy)imidazo[2,1-f][1,2,4]triazine (550 mg, 1.43 mmol) in THF (10 mL) was added n-butyllithium (1.43 mL, 1.6 mmol) dropwise, maintaining the temperature between -75 and -65 °C. After 30 min, a mixture of 8-methyl-1-naphthaldehyde (294 mg, 1.72 mmol) in THF (2 mL) was added dropwise. The resulting mixture was stirred at -70 °C for 1 h and then warmed to room temperature for 16 h. The reaction was quenched with saturated aqueous NH4Cl and extracted with EtOAc (50 mL x 2). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by combi flash to give the title compound (340 mg, 50%). MS:M / e 476(M+1) + .

[0194] Step B: (S)-7-((8-methylnaphthalen-1-yl)methyl)-2-((1-methylpyrrolidin-2-yl)methoxy)imidazo[2,1-f][1,2,4]triazin-4-ol

[0195]

[0196] To a mixture of the product of step A (340 mg, 0.715 mmol) in DCM (4 mL) was added TFA (4 mL) and Et3SiH (4 mL). The reaction was heated at 25 °C for 3 hours. The mixture was concentrated to dryness and the residue was used directly in the next step without further purification. MS: M / e 404 (M+1) + .

[0197] Step C: (S)-benzyl 2-(cyanomethyl)-4-(7-((8-methylnaphthalen-1-yl)methyl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)imidazo[2,1-f][1,2,4]triazin-4-yl)piperazine-1-carboxylate

[0198]

[0199] To the residue of step B (crude) in toluene (8 mL), POCl3 (868 mg, 5.6 mmol) and DIEA (360 mg, 2.8 mmol) were added. The resulting mixture was stirred at 100 °C overnight. The mixture was concentrated to dryness and treated with THF (15 mL). DIEA (720 mg, 5.6 mmol) and (S)-2-(cyanomethyl)piperazine-1-carboxylic acid benzyl ester (217 mg, 0.84 mmol) were then added and the reaction was stirred at room temperature for 2 hours. The reaction was quenched with water and extracted with EtOAc (60 mL x 2). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by combi flash to give the target compound (120 mg, 26% over two steps). MS: M / e 645 (M+1) + .

[0200] Step D: 2-((S)-4-(7-((8-methylnaphthalen-1-yl)methyl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)imidazo[2,1-f][1,2,4]triazin-4-yl)piperazin-2-yl)acetonitrile

[0201]

[0202] To a mixture of the product of step C (120 mg, 0.186 mmol) in EtOH / THF (5 mL / 5 mL) was added Pd / C (80 mg, 10% Pd). The reaction was stirred at room temperature under H2 (balloon) for 16 h. The suspension was filtered and the solid was washed with MeOH (5 mL). The filtrate was concentrated to dryness (90 mg) and the residue was used directly in the next step without further purification. MS: M / e511 (M+1) + .

[0203] Step E: 2-((S)-1-acryloyl-4-(7-((8-methylnaphthalen-1-yl)methyl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)imidazo[2,1-f][1,2,4]triazin-4-yl)piperazin-2-yl)acetonitrile

[0204]

[0205] To the mixture of the product of step D (90 mg, crude) in CH3CN (4 mL) was added saturated NaHCO3 (0.5 mL) at 0 ° C, followed by a solution of acryloyl chloride (16 mg, 0.17 mmol) in CH3CN (0.3 mL). The resulting mixture was stirred at room temperature for 1 hour. The reaction was diluted with water and extracted with EA (60 mL x 2). The combined organic phases were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by preparative TLC to obtain the target compound (25 mg, 24% over two steps). 1 HNMR(400MHz,DMSO-d6)δ7.90–7.76(m,2H),7.44–7.31(m,2H),7.32–7.23(m,2H),6.95–6.75(m,2H),6.19(d,J=17.6Hz 1H),5.78(dd,J=10.8Hz 1H),5.15–4.83(m,2H),4.78(s,2H),4.55–3.94(m,3H),3.90–3.40(m,2H),3.15–2.85(m,5H) ,2.76–2.71(m,4H),2.31(s,3H),2.24–2.10(m,1H),1.96–1.83(m,1H),1.80–1.50(m,3H)ppm. MS:M / e 565(M+1) + .

[0206] Example 8: Compound A8: 2-((S)-1-acryloyl-4-(2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(naphthalen-2-ylmethyl)imidazo[2,1-f][1,2,4]triazin-4-yl)piperazin-2-yl)acetonitrile

[0207] Step A: (4-(tert-Butyloxy)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)imidazo[2,1-f][1,2,4]triazin-7-yl)(naphthalen-2-yl)methanol

[0208]

[0209] To a solution of (S)-7-bromo-4-(tert-butoxy)-2-((1-methylpyrrolidin-2-yl)methoxy)imidazo[2,1-f][1,2,4]triazine (383 mg, 1 mmol) in THF (10 mL) was added n-butyllithium (1 mL, 1.6 mmol) dropwise, maintaining the temperature between -75 and -65 °C. After 30 min, a mixture of 2-naphthaldehyde (170 mg, 1.1 mmol) in THF (2 mL) was added dropwise. The resulting mixture was stirred at -70 °C for 1 h and then warmed to room temperature for 1 h. The reaction was quenched with saturated aqueous NH4Cl and extracted with EtOAc (60 mL x 2). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by combi flash to give the title compound (150 mg, 32%). MS: M / e 462 (M+1) + .

[0210] Step B: (S)-2-((1-methylpyrrolidin-2-yl)methoxy)-7-(naphthalen-2-ylmethyl)imidazo[2,1-f][1,2,4]triazin-4-ol

[0211]

[0212] To a mixture of the product of step A (150 mg, 0.32 mmol) in DCM (2 mL) was added TFA (2 mL) and Et3SiH (2 mL). The reaction was stirred at 25 °C for 5 hours. The mixture was concentrated to dryness and the residue was used directly in the next step without further purification. MS: M / e 390 (M+1) + .

[0213] Step C: (S)-benzyl 2-(cyanomethyl)-4-(2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(naphthalen-2-ylmethyl)imidazo[2,1-f][1,2,4]triazin-4-yl)piperazine-1-carboxylate

[0214]

[0215] To the residue (200 mg, crude) of step B above in POCl3 (4 mL), triethylamine hydrochloride (137 mg, 1 mmol) was added. The resulting mixture was stirred overnight at 120 ° C in a sealed tube. The mixture was concentrated to dryness and treated with THF (6 mL). DIEA (340 mg, 2.64 mmol) and (S)-2-(cyanomethyl)piperazine-1-carboxylic acid benzyl ester (85 mg, 0.33 mmol) were then added, and the reaction was stirred at room temperature for 3 hours. The reaction was quenched with water and extracted with EtOAc (60 mL x 2). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by combi flash to give the target compound (60 mg, 29% over two steps). MS: M / e 631 (M+1) + .

[0216] Step D: 2-((S)-4-(2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(naphthalen-2-ylmethyl)imidazo[2,1-f][1,2,4]triazin-4-yl)piperazin-2-yl)acetonitrile

[0217]

[0218] To a mixture of the product of step C (60 mg, 0.095 mmol) in EtOH / THF (3 mL / 3 mL) was added Pd / C (50 mg, 10% Pd). The reaction was stirred at room temperature under H2 (balloon) overnight. The mixture was filtered and the solid was washed with DCM / MeOH (20 mL / 1 mL). The filtrate was concentrated to dryness (40 mg) and the residue was used directly in the next step without further purification. MS: M / e 497 (M+1) + .

[0219] Step E: 2-((S)-1-acryloyl-4-(2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(naphthalen-2-ylmethyl)imidazo[2,1-f][1,2,4]triazin-4-yl)piperazin-2-yl)acetonitrile

[0220]

[0221] To a mixture of the product of step D (40 mg, crude) in CH3CN (5 mL) was added saturated NaHCO3 (0.5 mL) at 0°C, followed by a solution of acryloyl chloride (9 mg, 0.1 mmol) in CH3CN (0.3 mL). The resulting mixture was stirred at room temperature for 30 min. The reaction was diluted with water and extracted with EA (60 mL). The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by preparative TLC to give the target compound (8 mg, 15% over two steps). 1 HNMR(400MHz,DMSO-d6)δ7.92–7.70(m,4H),7.54–7.33(m,4H),6.90–6.79(m, 1H),6.17(d,J=16.4Hz,1H),5.76(d,J=9.6Hz,1H),5.15–4.75(m,2H),4.65–4 .39(m,1H),4.33(s,2H),4.26–3.77(m,3H),3.54–3.36(m,2H),3.19–2.67(m, 6H),2.28(s,3H),2.16-2.04(m,1H),1.95-1.76(m,1H),1.74-1.50(m,2H)ppm. MS:M / e 551(M+1) + .

[0222] Example 9: Compound A09: 2-((S)-1-acryloyl-4-(7-((2,3-dihydrobenzofuran-4-yl)methyl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)imidazo[2,1-f][1,2,4]triazin-4-yl)piperazin-2-yl)acetonitrile

[0223] Step A: 7-Bromo-4-(tert-butoxy)-2-chloroimidazo[2,1-f][1,2,4]triazine

[0224]

[0225] To a solution of 7-bromo-2,4-dichloroimidazo[2,1-f][1,2,4]triazine (2 g, 7.5 mmol) in THF (20 mL) cooled at 0 ° C was added tert-butyl lithium (660 mg, 8.3 mmol) in portions. After addition, the reaction mixture was stirred at room temperature for 30 minutes. The solution was quenched with ice water and extracted with EA. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated. The crude product was purified by Combi Flash (PE:EA=9:1) to give the product (1.4 g, 64%). MS: M / e 305 (M+1)+

[0226] Step B: (S)-7-Bromo-4-(tert-butoxy)-2-((1-methylpyrrolidin-2-yl)methoxy)imidazo[2,1-f][1,2,4]triazine

[0227]

[0228] NaH (276 mg, 6.9 mmol) was added to a solution of (S)-(1-methylpyrrolidin-2-yl)methanol (637 mg, 5.5 mmol) in THF (20 mL). After stirring at room temperature for 30 minutes, 7-bromo-4-(tert-butoxy)-2-chloroimidazo[2,1-f][1,2,4]triazine (1.4 g, 4.6 mmol) in THF (5 mL) was added dropwise. The resulting mixture was transferred to a 60 ° C oil bath and stirred at 60 ° C for 30 minutes. The solution was quenched with NH4Cl solution (5 mL) and extracted with EA (15 mL). The organic layer was dried, concentrated and purified by Combi Flash (DCM: NH3 (7M in methanol) = 20: 1) to give the product (0.9 g, 51%). 1 H NMR (400MHz, DMSO-d6) δ7.73 (s, 1H), 4.29-4.33 (m, 1H), 4.19-4.15 (m, 1H), 2.95 (d, J = 8.0Hz, 1H), 2.6 6-2.63(m,1H),2.38(s,3H),2.19-2.14(m,1H),1.95-1.91(m,1H),1.69(s,9H),1.68-1.62(m,3H)ppm. MS:M / e 384(M+1)+

[0229] Step C: (4-(tert-Butyloxy)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)imidazo[2,1-f][1,2,4]triazin-7-yl)(2,3-dihydrobenzofuran-4-yl)methanol

[0230]

[0231] To a solution of (S)-7-bromo-4-(tert-butoxy)-2-((1-methylpyrrolidin-2-yl)methoxy)imidazo[2,1-f][1,2,4]triazine (300 mg, 0.78 mmol) in THF (5 mL) cooled at -78 ° C was added n-butyllithium (1.6 M in n-hexane, 0.7 mL, 1.12 mmol). After stirring for 30 minutes, 2,3-dihydrobenzofuran-4-carboxaldehyde (139 mg, 0.9 mmol) in THF (3 mL) was added dropwise. The resulting mixture was gradually stirred to room temperature overnight. The solution was quenched with NH4Cl solution (5 mL) and extracted with EA (15 mL). The organic layer was dried, concentrated and purified by Combi Flash (DCM: NH3 (7 M in methanol) = 100: 3) to give the product (290 mg, 82%). MS:M / e 454(M+1)+

[0232] Step D: (S)-7-((2,3-dihydrobenzofuran-4-yl)methyl)-2-((1-methylpyrrolidin-2-yl)methoxy)imidazo[2,1-f][1,2,4]triazin-4-ol

[0233]

[0234] Et3SiH (2 mL) and TFA (2 mL) were added to a solution of (4-(tert-butoxy)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)imidazo[2,1-f][1,2,4]triazin-7-yl)(2,3-dihydrobenzofuran-4-yl)methanol (290 mg, 0.6 mmol) in DCM (2 mL). The solution was stirred at room temperature for 6 hours and then heated at 40°C overnight. The solvent was evaporated under an oil pump and then co-distilled with toluene. The crude product was used directly in the next step (240 mg, crude). MS: M / e 382 (M+1) +

[0235] Step E: (S)-4-chloro-7-((2,3-dihydrobenzofuran-4-yl)methyl)-2-((1-methylpyrrolidin-2-yl)methoxy)imidazo[2,1-f][1,2,4]triazine

[0236]

[0237] A sealed tube containing (S)-7-((2,3-dihydrobenzofuran-4-yl)methyl)-2-((1-methylpyrrolidin-2-yl)methoxy)imidazo[2,1-f][1,2,4]triazin-4-ol (190 mg, 0.5 mmol), Et3N.HCl (138 mg, 1 mmol) and POCl3 (8 mL) was heated at 120°C overnight. After cooling, the solvent was evaporated under an oil pump and co-distilled with toluene to give the crude product, which was used directly in the next step (200 mg, crude). MS: M / e 400 (M+1) +。

[0238] Step F: (S)-benzyl 2-(cyanomethyl)-4-(7-((2,3-dihydrobenzofuran-4-yl)methyl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)imidazo[2,1-f][1,2,4]triazin-4-yl)piperazine-1-carboxylate

[0239]

[0240] (S)-2-(Cyanomethyl)piperazine-1-carboxylic acid benzyl ester (208 mg, 0.8 mmol) was added to a solution of (S)-4-chloro-7-((2,3-dihydrobenzofuran-4-yl)methyl)-2-((1-methylpyrrolidin-2-yl)methoxy)imidazo[2,1-f][1,2,4]triazine (200 mg, 0.52 mmol) in THF (20 mL), followed by DIEA (520 mg, 4 mmol). The reaction mixture was stirred at room temperature for 1 hour. Water (10 mL) was added to the solution and extracted with EA (15 mL). The organic layer was dried over Na2SO4, concentrated and purified by Combi Flash (DCM:NH3 (7M in MeOH) = 100:7) to give the product (150 mg, 48%). MS: M / e 623 (M+1) + .

[0241] Step G: 2-((S)-4-(7-((2,3-dihydrobenzofuran-4-yl)methyl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)imidazo[2,1-f][1,2,4]triazin-4-yl)piperazin-2-yl)acetonitrile

[0242]

[0243] A solution of (S)-benzyl 2-(cyanomethyl)-4-(7-((2,3-dihydrobenzofuran-4-yl)methyl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)imidazo[2,1-f][1,2,4]triazin-4-yl)piperazine-1-carboxylate (75 mg, 0.12 mmol) and Pd / C (wet, 10%, 50 mg) in THF / EtOH (2 mL / 2 mL) was stirred at room temperature overnight under a balloon of H2. The catalyst was filtered and the filtrate was concentrated to give the crude product which was used directly (55 mg, crude). MS: M / e 489 (M+1) +

[0244] Step H: 2-((S)-1-acryloyl-4-(7-((2,3-dihydrobenzofuran-4-yl)methyl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)imidazo[2,1-f][1,2,4]triazin-4-yl)piperazin-2-yl)acetonitrile

[0245]

[0246] NaHCO3 solution (saturated, 0.5 mL) was added to a solution of 2-((S)-4-(7-((2,3-dihydrobenzofuran-4-yl)methyl)2-(((S)-1-methylpyrrolidin-2-yl)methoxy)imidazo[2,1-f][1,2,4]triazine-4-yl)piperazin-2-yl)acetonitrile (30 mg, crude) in CH3CN (5 mL) followed by acryloyl chloride (7 mg, 0.07 mmol). The reaction mixture was stirred at room temperature for 1 hour. The solution was evaporated, water (4 mL) was added, and extracted with EA (8 mL). The organic layer was dried, concentrated and purified by preparative TLC (DCM:NH3 (7 M in MeOH) = 10:1) to give the product (6 mg, 18%). 1H NMR (400MHz, CD3OD) δ7.31(s,1H),7.00(t,J=8.0Hz,1H),6.82(br.s,1H),6.67(d,J=8.0Hz,1H),6.5 9(d,J=8.0Hz,1H),6.28(d,J=16.0Hz,1H),5.83(d,J=8.0Hz,1H),5.12(br.s,1H),4.59(s,2H),4.51( t,J=8.0Hz,2H),4.40(br.s,2H),4.35-4.29(m,2H),4.15(s,2H),3.63-3.48(m,2H),3.24(s,1H),3. 14(d,J=8.0Hz,2H),3.02(s,1H),2.88(s,2H),2.61(s,3H),2.19-2.00(m,2H),1.87-1.60(m,3H)ppm. MS:M / e 543(M+1) + .

[0247] Example 10: Compound A10: 2-((S)-1-acryloyl-4-(7-((4-methoxynaphthalen-1-yl)methyl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)imidazo[2,1-f][1,2,4]triazin-4-yl)piperazin-2-yl)acetonitrile

[0248] Step A: (4-(tert-Butyloxy)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)imidazo[2,1-f][1,2,4]triazin-7-yl)(4-methoxynaphthalen-1-yl)methanol

[0249]

[0250] To a solution of (S)-7-bromo-4-(tert-butoxy)-2-((1-methylpyrrolidin-2-yl)methoxy)imidazo[2,1-f][1,2,4]triazine (383 mg, 1 mmol) in THF (5 mL) was added n-butyllithium (0.94 mL, 1.5 mmol) dropwise, maintaining the temperature between -75 and -65 °C. After 30 min, a mixture of 4-methoxy-1-naphthaldehyde (223.2 mg, 1.2 mmol) in THF (5 mL) was added dropwise. The resulting mixture was stirred at -70 °C for 1 h and then warmed to room temperature for 1 h. The reaction was quenched with saturated NH4Cl solution and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by combiflash to give the title compound (320 mg, 65%). MS: M / e 492 (M+1) + .

[0251] Step B: (S)-7-((4-methoxynaphthalen-1-yl)methyl)-2-((1-methylpyrrolidin-2-yl)methoxy)imidazo[2,1-f][1,2,4]triazin-4-ol

[0252]

[0253] To a mixture of the product of step A (250 mg) in DCE (2 mL) was added TFA (2 mL) and Et3SiH (2 mL). The reaction was stirred at 25 °C overnight. The mixture was concentrated to dryness. The residue was used directly in the next step without further purification. MS: M / e 420 (M+1) + .

[0254] Step C: (S)-benzyl 2-(cyanomethyl)-4-(7-((4-methoxynaphthalen-1-yl)methyl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)imidazo[2,1-f][1,2,4]triazin-4-yl)piperazine-1-carboxylate

[0255]

[0256] To the residue of step B above (200 mg, crude) in POCl3 (3 mL), triethylamine hydrochloride (204 mg, 1.5 mmol) was added. The resulting mixture was stirred at 120 ° C overnight. The mixture was concentrated to dryness and treated with THF (5 mL). DIEA (177 mg, 1.5 mmol) and (S)-2-(cyanomethyl)piperazine-1-carboxylic acid benzyl ester (130 mg, 0.5 mmol) were then added and the reaction was stirred at room temperature for 2 hours. The reaction was quenched with water and extracted with EtOAc (80 mL). The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by combi flash to give the target compound (75 mg, 24% over two steps). MS: M / e 661 (M+1) + .

[0257] Step D: 2-((S)-4-(7-((4-methoxynaphthalen-1-yl)methyl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)imidazo[2,1-f][1,2,4]triazin-4-yl)piperazin-2-yl)acetonitrile

[0258]

[0259] To a mixture of the product of step C (60 mg) in EtOH / THF (2 mL / 2 mL) was added Pd / C (10 mg, 10% Pd). The reaction was stirred at room temperature under H2 (balloon) for 8 h. The mixture was filtered and the solid was washed with THF (5 mL). The filtrate was concentrated to dryness (40 mg) and the residue was used directly in the next step without further purification. MS: M / e 527 (M+1) + .

[0260] Step E: 2-((S)-1-acryloyl-4-(7-((4-methoxynaphthalen-1-yl)methyl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)imidazo[2,1-f][1,2,4]triazin-4-yl)piperazin-2-yl)acetonitrile

[0261]

[0262] To a mixture of the product of step D (40 mg, crude) in CH3CN (2 mL) was added saturated NaHCO3 (0.5 mL) at 0°C, followed by a solution of acryloyl chloride (8 mg, 0.1 mmol) in CH3CN (0.3 mL). The resulting mixture was stirred at room temperature for 30 min. The reaction was diluted with water and extracted with EA (60 mL). The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by preparative TLC to give the target compound (2.17 mg, 10% over two steps). 1H NMR(400MHz, DMSO-d6)δ8.19(d,J=7.5Hz,1H),8.10(d,J=9.0Hz,1H),7.58–7.45(m,2 H),7.34(d,J=7.6Hz,1H),7.25(s,1H),6.89(d,J=7.8Hz,2H),6.18(d,J=16.4Hz,1H), 5.77(d,J=10.3Hz,1H),4.85(s,2H),4.52(s,2H),4.24(s,1H),4.10(s,1H),3.94(s,3 H),3.30(s,3H),2.94(s,5H),2.31(s,4H),2.17(s,1H),1.91(s,1H),1.67(s,3H)ppm. MS:M / e 581(M+1) + .

[0263] Example 11: Compound A11: 2-((S)-1-acryloyl-4-(7-(2-chloro-6-fluorobenzyl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)imidazo[2,1-f][1,2,4]triazin-4-yl)piperazin-2-yl)acetonitrile

[0264] Step A: (4-(tert-Butyloxy)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)imidazo[2,1-f][1,2,4]triazin-7-yl)(2-chloro-6-fluorophenyl)methanol

[0265]

[0266] To a solution of (S)-7-bromo-4-(tert-butoxy)-2-((1-methylpyrrolidin-2-yl)methoxy)imidazo[2,1-f][1,2,4]triazine (300 mg, 0.78 mmol) in THF (8 mL) was added n-butyllithium (1.6 M, 0.69 mL, 1.1 mmol) dropwise, maintaining the temperature between -75 and -65 °C. After 1 h, a suspension of 2-chloro-6-fluorobenzaldehyde (148 mg, 0.93 mmol) in THF (2 mL) was added dropwise. The resulting mixture was stirred at -70 °C for 2 h and then warmed to room temperature overnight. The reaction was quenched with saturated aqueous NH4Cl and extracted with EtOAc (20 mL x 3). The combined organic phases were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by preparative TLC to give the target compound (150 mg, 41.5%). MS:M / e 464(M+1) + .

[0267] Step B: (S)-7-(2-chloro-6-fluorobenzyl)-2-((1-methylpyrrolidin-2-yl)methoxy)imidazo[2,1-f][1,2,4]triazin-4-ol

[0268]

[0269] To a solution of the product of step A (150 mg, 0.323 mmol) in DCM (5 mL) was added TFA (5 mL) and Et3SiH (5 mL). The reaction mixture was stirred at 40 ° C overnight. The mixture was concentrated in vacuo. To the residue was added NaHCO3 solution (1 M, 10 mL) and extracted with ethyl acetate. The combined organic extracts were dried over sodium sulfate, filtered and evaporated. The residue was purified by preparative TLC to give the title product (180 mg, 100%). MS: m / e 392 (M+1) + .

[0270] Step C: (S)-4-chloro-7-(2-chloro-6-fluorobenzyl)-2-((1-methylpyrrolidin-2-yl)methoxy)imidazo[2,1-f][1,2,4]triazine

[0271]

[0272] To a solution of (S)-7-(2-chloro-6-fluorobenzyl)-2-((1-methylpyrrolidin-2-yl)methoxy)imidazo[2,1-f][1,2,4]triazine-4-ol (180 mg, 0.46 mmol) in POCl3 (10 mL) was added triethylamine hydrochloride (137 mg, 1 mmol). The mixture was sealed and stirred at 110°C overnight. The mixture was cooled to room temperature and concentrated in vacuo. The residue was used directly in the next step. MS: m / e 410 (M+1) + .

[0273] Step D: 2-((S)-4-(7-(2-chloro-6-fluorobenzyl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)imidazo[2,1-f][1,2,4]triazin-4-yl)piperazin-2-yl)acetonitrile

[0274]

[0275] To the product of step C in acetonitrile (10 mL) was slowly added a solution of (S)-2-(piperazin-2-yl)acetonitrile (125 mg, 1 mmol) and DIEA (258 mg, 2 mmol) in acetonitrile (2 ml). The mixture was stirred at room temperature for 2 h. The mixture was used directly in the next step. MS: m / e 499 (M+1) + .

[0276] Step E: 2-((S)-1-acryloyl-4-(7-(2-chloro-6-fluorobenzyl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)imidazo[2,1-f][1,2,4]triazin-4-yl)piperazin-2-yl)acetonitrile

[0277]

[0278] NaHCO3 solution (1M, 10 mL) was added to the mixture from step D. Acryloyl chloride (90 mg, 0.1 mol) was slowly added to the mixture. The reaction was stirred at room temperature for 2 h. The resulting mixture was extracted with ethyl acetate. The combined organic extracts were dried over sodium sulfate, filtered and evaporated. The title product (1.1 mg, 0.4%, over three steps) was purified by preparative TLC. 1H NMR (400 MHz, DMSO-d6) δ 7.33 (br.s, 2H), 7.16 (br.s, 2H), 6.85 (s, 1H), 6.28 (d, J = 16.4 Hz, 1H), 5.83 (d, J = 9.6 Hz, 1H), 4.75 (s, 1H), 4.53 (d, J = 7.3 Hz, 1H), 4.37 (s, 2H), 4.1 5(s,1H),3.88(s,1H),3.71(s,1H),3.58–3.49(m,1H),3.13(s,1H),3.06(s,3H),2.8 9(s,1H),2.83–2.74(m,3H),2.41(s,1H),2.19(s,1H),2.03(s,2H),1.29(s,3H)ppm. MS:M / e 553(M+1) + .

[0279] Example 12: Compound A12: 2-((S)-1-acryloyl-4-(7-(2-chlorobenzyl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)imidazo[2,1-f][1,2,4]triazin-4-yl)piperazin-2-yl)acetonitrile

[0280] Step A: (4-(tert-Butyloxy)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)imidazo[2,1-f][1,2,4]triazin-7-yl)(2-chlorophenyl)methanol

[0281]

[0282] To a solution of (S)-7-bromo-4-(tert-butoxy)-2-((1-methylpyrrolidin-2-yl)methoxy)imidazo[2,1-f][1,2,4]triazine (383 mg, 1 mmol) in THF (8 mL) was added n-butyllithium solution (1.6 M, 0.94 mL, 1.5 mmol) dropwise, maintaining the temperature between -75 and -65 °C. After 1 h, a suspension of 2-chlorobenzaldehyde (168 mg, 1.2 mmol) in THF (2 mL) was added dropwise. The resulting mixture was stirred at -70 °C for 2 h and then warmed to room temperature overnight. The reaction was quenched with saturated aqueous NH4Cl and extracted with EtOAc (20 mL x 3). The combined organic phases were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by preparative TLC to give the target compound (420 mg, 94.3%). MS:M / e 446(M+1) + .

[0283] Step B: (S)-7-(2-chlorobenzyl)-2-((1-methylpyrrolidin-2-yl)methoxy)imidazo[2,1-f][1,2,4]triazin-4-ol

[0284]

[0285] To a solution of (4-(tert-butoxy)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)imidazo[2,1-f][1,2,4]triazine-7-yl)(2-chlorophenyl)methanol (420 mg, 0.94 mmol) in DCM (10 mL) was added TFA (5 mL) and Et3SiH (5 mL). The reaction mixture was stirred at 40°C overnight. The mixture was concentrated in vacuo. To the residue was added NaHCO3 solution (1 M, 10 mL) and extracted with ethyl acetate. The combined organic extracts were dried over sodium sulfate, filtered and evaporated. The residue was purified by preparative TLC to give the title product (200 mg, 56.8%). MS: m / e374 (M+1) + .

[0286] Step C: (S)-4-chloro-7-(2-chlorobenzyl)-2-((1-methylpyrrolidin-2-yl)methoxy)imidazo[2,1-f][1,2,4]triazine

[0287]

[0288] To a solution of (S)-7-(2-chlorobenzyl)-2-((1-methylpyrrolidin-2-yl)methoxy)imidazo[2,1-f][1,2,4]triazine-4-ol (130 mg, 0.35 mmol) in POCl3 (5 mL) was added triethylamine hydrochloride (137 mg, 1 mmol). The mixture was sealed and stirred at 110°C overnight. The mixture was cooled to room temperature and concentrated in vacuo. The residue was used directly in the next step. MS: m / e 392 (M+1) + .

[0289] Step D: 2-((S)-4-(7-(2-chlorobenzyl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)imidazo[2,1-f][1,2,4]triazin-4-yl)piperazin-2-yl)acetonitrile

[0290]

[0291] To the product of step C in acetonitrile (10 mL) was slowly added a solution of (S)-2-(piperazin-2-yl)acetonitrile (125 mg, 1 mmol) and DIEA (258 mg, 2 mmol) in acetonitrile (2 ml). The mixture was stirred at room temperature for 2 h. The mixture was used directly in the next step. MS: m / e 481 (M+1) + .

[0292] Step E: 2-((S)-1-acryloyl-4-(7-(2-chlorobenzyl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)imidazo[2,1-f][1,2,4]triazin-4-yl)piperazin-2-yl)acetonitrile

[0293]

[0294] To the mixture of the product of step D was added NaHCO3 solution (1M, 10 mL). Acryloyl chloride (90 mg, 0.1 mol) was slowly added to the mixture. The reaction was stirred at room temperature for 2 h. The resulting mixture was extracted with ethyl acetate. The combined organic extracts were dried over sodium sulfate, filtered and evaporated. The residue was purified by preparative TLC to give the title product (3.2 mg, 1.7% over three steps). 1H NMR (400 MHz, DMSO-d6) δ 7.42 (d, J = 7.2 Hz, 1H), 7.32 (s, 1H), 7.25 (d, J = 4.3 Hz, 3H), 6.82 (s, 1H), 6.29 (d, J = 16.5 Hz, 1H), 5.83 (d, J = 10.4 Hz, 1H), 4.72 (s, 1H), 4.50 (dd, J = 12.2, 7. 3Hz,1H),4.34(s,2H),4.18(s,1H),3.84(s,1H),3.69(s,1H),3.26–3.15(m,3H),3.03(s ,3H),2.90(s,1H),2.79(s,2H),2.36(s,1H),2.19(s,1H),2.05(s,2H),1.29(s,3H)ppm. MS:M / e 536(M+1) + .

[0295] Example 13: Compound A13: 2-((S)-1-acryloyl-4-(7-((2,3-dihydrobenzofuran-7-yl)methyl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)imidazo[2,1-f][1,2,4]triazin-4-yl)piperazin-2-yl)acetonitrile

[0296] Step A: (4-(tert-Butyloxy)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)imidazo[2,1-f][1,2,4]triazin-7-yl)(2,3-dihydrobenzofuran-7-yl)methanol

[0297]

[0298] To a solution of (S)-7-bromo-4-(tert-butoxy)-2-((1-methylpyrrolidin-2-yl)methoxy)imidazo[2,1-f][1,2,4]triazine (300 mg, 0.78 mmol) in THF (8 mL) cooled at -78°C was added n-butyllithium (1.6 M in n-hexane, 0.7 mL, 1.2 mmol) dropwise. After stirring for 30 minutes, 2,3-dihydrobenzofuran-7-carbaldehyde (139 mg, 0.9 mmol) in THF (1 mL) was added dropwise. The resulting mixture was gradually stirred to room temperature overnight. The solution was quenched with NH4Cl solution (5 mL) and extracted with EA (15 mL). The organic layer was dried, concentrated and purified by CombiFlash (DCM:NH3.MeOH=4%) to give the product (280 mg, 79%). MS: M / e 454 (M+1) + .

[0299] Step B: (S)-7-((2,3-dihydrobenzofuran-7-yl)methyl)-2-((1-methylpyrrolidin-2-yl)methoxy)imidazo[2,1-f][1,2,4]triazin-4-ol

[0300]

[0301] Et3SiH (2 mL) and TFA (2 mL) were added to a solution of (4-(tert-butoxy)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)imidazo[2,1-f][1,2,4]triazin-7-yl)(2,3-dihydrobenzofuran-7-yl)methanol (280 mg, 0.6 mmol) in DCM (2 mL). The solution was heated at 40°C overnight. The solvent was evaporated under an oil pump and then co-distilled with toluene. The crude product was used directly in the next step (235 mg, crude). MS: M / e 382 (M+1) + .

[0302] Step C: (S)-4-chloro-7-((2,3-dihydrobenzofuran-7-yl)methyl)-2-((1-methylpyrrolidin-2-yl)methoxy)imidazo[2,1-f][1,2,4]triazine

[0303]

[0304] A sealed tube containing (S)-7-((2,3-dihydrobenzofuran-7-yl)methyl)-2-((1-methylpyrrolidin-2-yl)methoxy)imidazo[2,1-f][1,2,4]triazin-4-ol (235 mg, 0.6 mmol), Et3N.HCl (106 mg, 1.2 mmol) and POCl3 (5 mL) was heated at 120°C overnight. After cooling, the solvent was evaporated under an oil pump and co-distilled with toluene to give the crude product, which was used directly in the next step (240 mg, crude). MS: M / e 400 (M+1) + .

[0305] Step D: (S)-benzyl 2-(cyanomethyl)-4-(7-((2,3-dihydrobenzofuran-7-yl)methyl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)imidazo[2,1-f][1,2,4]triazin-4-yl)piperazine-1-carboxylate

[0306]

[0307] (S)-2-(Cyanomethyl)piperazine-1-carboxylic acid benzyl ester (259 mg, 1.0 mmol) was added to a solution of (S)-4-chloro-7-((2,3-dihydrobenzofuran-7-yl)methyl)-2-((1-methylpyrrolidin-2-yl)methoxy)imidazo[2,1-f][1,2,4]triazine (190 mg, 0.5 mmol) in THF (10 mL), followed by DIEA (516 mg, 4 mmol). The reaction mixture was stirred at room temperature for 1 hour. The solution was quenched with water (5 mL) and extracted with EA (10 mL). The organic layer was dried over Na2SO4, concentrated and purified by CombiFlash (DCM:NH3 (7M in MeOH) = 10:1) to give the product (100 mg, 34%). MS: M / e623 (M+1) + .

[0308] Step E: 2-((S)-4-(7-((2,3-dihydrobenzofuran-7-yl)methyl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)imidazo[2,1-f][1,2,4]triazin-4-yl)piperazin-2-yl)acetonitrile

[0309]

[0310] A suspension of (S)-benzyl 2-(cyanomethyl)-4-(7-((2,3-dihydrobenzofuran-7-yl)methyl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)imidazo[2,1-f][1,2,4]triazin-4-yl)piperazine-1-carboxylate (100 mg, 0.16 mmol) and Pd / C (wet, 10%, 100 mg) in THF / EtOH (4 mL / 4 mL) was stirred at room temperature overnight under a balloon of H2. The catalyst was filtered and the filtrate was concentrated to give the crude product which was used directly (60 mg, 76%). MS: M / e 489 (M+1) +

[0311] Step F: 2-((S)-1-acryloyl-4-(7-((2,3-dihydrobenzofuran-7-yl)methyl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)imidazo[2,1-f][1,2,4]triazin-4-yl)piperazin-2-yl)acetonitrile

[0312]

[0313] NaHCO3 solution (saturated, 0.5 mL) was added to a solution of 2-((S)-4-(7-((2,3-dihydrobenzofuran-7-yl)methyl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)imidazo[2,1-f][1,2,4]triazine-4-yl)piperazin-2-yl)acetonitrile (60 mg, 0.12 mmol) in CH3CN (5 mL), acryloyl chloride (17 mg, 0.18 mmol) was added. The reaction mixture was stirred at room temperature for 1 hour. The solution was evaporated, water (4 mL) was added, and extracted with EA (10 mL). The organic layer was dried, concentrated and purified by preparative TLC (DCM:NH3 (7 M in MeOH) = 9:1) to give the product (6 mg, 9%). 1H NMR (400MHz, CD3OD) δ7.25(s,1H),7.08(t,J=8.0Hz,1H),6.93(d,J=8.0Hz,1H),6.81( br.s,1H),6.73(t,J=8.0Hz,1H),6.28(d,J=16.0Hz,1H),5.83(d,J=12.0Hz,1H),5.12( br.s,1H),4.59-4.51(m,3H),4.37(s,2H),4.10(s,3H),3.6-3.47(m,2H),3.22-3.18(m ,4H),2.87(s,3H),2.56(s,3H),2.50(s,1H),2.12-2.10(m,1H),1.87-1.78(m,4H)ppm. MS:M / e 543(M+1) +

[0314] Example 14: Compound A14: 2-((S)-1-acryloyl-4-(2-(((S)-4,4-difluoro-1-methylpyrrolidin-2-yl)methoxy)-7-(naphthalen-1-ylmethyl)imidazo[2,1-f][1,2,4]triazin-4-yl)piperazin-2-yl)acetonitrile

[0315] Step A: (S)-7-Bromo-4-(tert-butoxy)-2-((4,4-difluoro-1-methylpyrrolidin-2-yl)methoxy)imidazo[2,1-f][1,2,4]triazine

[0316]

[0317] To a solution of (S)-(4,4-difluoro-1-methylpyrrolidin-2-yl)methanol (500 mg, 3.3 mmol) in THF (5 mL) was added NaH (264 mg, 60%, 6.6 mmol) at 0°C, and the mixture was stirred for 5 min. A solution of 7-bromo-4-(tert-butoxy)-2-chloroimidazo[2,1-f][1,2,4]triazine (1.0 g, 3.3 mmol) in THF (5 mL) was then added, and the resulting mixture was stirred at 60°C for 1 hour. The mixture was cooled and then poured into H2O (20 mL). The mixture was extracted with EA (20 mL x 3). The combined organic phases were washed with brine (20 mL x 3), dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography to give the title compound (825 mg, yield: 60%). MS: M / e 420 (M+1) + .

[0318] Step B: (4-(tert-Butyloxy)-2-(((S)-4,4-difluoro-1-methylpyrrolidin-2-yl)methoxy)imidazo[2,1-f][1,2,4]triazin-7-yl)(naphthalen-1-yl)methanol

[0319]

[0320] To a solution of (S)-7-bromo-4-(tert-butoxy)-2-((4,4-difluoro-1-methylpyrrolidin-2-yl)methoxy)imidazo[2,1-f][1,2,4]triazine (825 mg, 1.97 mmol) in THF (5 mL) was added n-butyllithium (1.6 M, 2.5 mL, 4.0 mmol) at -78 ° C in a N2 atmosphere. The mixture was stirred at -78 ° C for 30 min. Then a solution of 1-naphthaldehyde (624 mg, 4.0 mmol) in THF (4 mL) was added to the system at -78 ° C. The reaction was stirred for 30 min, then warmed to room temperature and stirred for 30 min. The reaction mixture was quenched with saturated NH4Cl (20 mL) at room temperature and extracted with EA (20 mL x 2). The combined organic phases were washed with brine (20 mL x 3), dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography to give the title compound (590 mg, yield: 61%). MS: M / e 498 (M+1) + .

[0321] Step C: (S)-2-((4,4-difluoro-1-methylpyrrolidin-2-yl)methoxy)-7-(naphthalen-1-ylmethyl)imidazo[2,1-f][1,2,4]triazin-4-ol

[0322]

[0323] To (4-(tert-butoxy)-2-(((S)-4,4-difluoro-1-methylpyrrolidin-2-yl)methoxy)imidazo[2,1-f][1,2,4]triazin-7-yl)(naphthalen-1-yl)methanol (590 mg, 1.19 mmol) in TFA (5 mL) was added Et3SiH (5 mL) and the mixture was stirred at 40°C for 16 hours. The reaction mixture was concentrated under reduced pressure. The residue was treated with HCl (5 mL, 4 M) and extracted with DCM (5 mL x 3). The aqueous layer was basified to pH ~10 with NaOH (4 M) and extracted with DCM / IPA (5:1, 10 mL x 5). The combined organic phases were washed with brine (20 mL x 3), dried over Na2SO4, concentrated and purified by column chromatography to give the title compound (350 mg, yield: 69%). MS: M / e 426 (M+1) + .

[0324] Step D: (S)-4-chloro-2-((4,4-difluoro-1-methylpyrrolidin-2-yl)methoxy)-7-(naphthalen-1-ylmethyl)imidazo[2,1-f][1,2,4]triazine

[0325]

[0326] A mixture of (S)-2-((4,4-difluoro-1-methylpyrrolidin-2-yl)methoxy)-7-(naphthalen-1-ylmethyl)imidazo[2,1-f][1,2,4]triazin-4-ol (120 mg, 0.28 mmol) and Et3NHCl (500 mg, 3.6 mmol) in POCl3 (5 mL) was stirred at 100°C for 16 hours. The mixture was concentrated and diluted with 5 mL of THF and the resulting mixture was used directly in the next step. MS: M / e 444 (M+1) + .

[0327] Step E: 2-((S)-4-(2-(((S)-4,4-difluoro-1-methylpyrrolidin-2-yl)methoxy)-7-(naphthalen-1-ylmethyl)imidazo[2,1-f][1,2,4]triazin-4-yl)piperazin-2-yl)acetonitrile

[0328]

[0329] To a solution of (S)-4-chloro-2-((4,4-difluoro-1-methylpyrrolidin-2-yl)methoxy)-7-(naphthalen-1-ylmethyl)imidazo[2,1-f][1,2,4]triazine in THF (5 mL) was added DIEA (500 mg, 3.87 mmol) at room temperature, followed by a solution of (S)-2-(piperazin-2-yl)acetonitrile (71 mg, 0.568 mmol) in DCM (1.5 mL). The resulting mixture was stirred at room temperature for 2 hours. The mixture was concentrated and diluted with DCM (20 mL). The mixture was washed with brine (10 mL x 2), dried over Na2SO4, concentrated, and purified by preparative HPLC to give the title compound (55 mg, yield: 30% over two steps). MS: M / e533 (M+1) + .

[0330] Step F: 2-((S)-1-acryloyl-4-(2-(((S)-4,4-difluoro-1-methylpyrrolidin-2-yl)methoxy)-7-(naphthalen-1-ylmethyl)imidazo[2,1-f][1,2,4]triazin-4-yl)piperazin-2-yl)acetonitrile

[0331]

[0332] To a mixture of 2-((S)-4-(2-(((S)-4,4-difluoro-1-methylpyrrolidin-2-yl)methoxy)-7-(naphthalen-1-ylmethyl)imidazo[2,1-f][1,2,4]triazine-4-yl)piperazine-2-yl)acetonitrile (55 mg, 0.085 mmol) and NaHCO3 / H2O (200 mg, 1 mL) in MeCN (1 mL) was added dropwise a solution of acryloyl chloride (25 mg, 0.27 mmol) in MeCN (1 mL). The resulting mixture was stirred at room temperature for 2 hours. The mixture was diluted with 10 mL of EA and washed with brine (5 mL x 3). The combined organic phases were dried over Na2SO4, concentrated and purified by preparative TLC (PE / EA=1:2) to give the title compound (18 mg, yield: 27%). 1 H NMR (400MHz, DMSO-d6) δ8.19(d,J=7.2Hz,1H),7.92(d,J=8.8Hz,1H),7.81(d,J=7.2Hz,1H),7.5 8–7.46(m,2H),7.46–7.34(m,2H),7.28(s,1H),6.80(dd,J=16.4,10.4Hz,1H),6.15(d,J=16.4Hz ,1H),5.74(d,J=10.4Hz,1H),5.46–4.77(m,2H),4.63(s,2H),4.40–4.03(m,3H),3.84–3.46(m,1 H),3.47–3.17(m,3H),3.04–2.55(m,5H),2.46–2.37(m,1H),2.32(s,3H),2.25-2.05(m,1H)ppm. MS:M / e 587(M+1) + .

[0333] Example 15: Compound A15: 2-((S)-4-(7-((1H-indazol-4-yl)methyl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)imidazo[2,1-f][1,2,4]triazine-4-yl)-1-acryloylpiperazin-2-yl)acetonitrile

[0334] Step A: tert-Butyl 4-((4-(tert-Butoxy)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)imidazo[2,1-f][1,2,4]triazin-7-yl)(hydroxy)methyl)-1H-indazole-1-carboxylate

[0335]

[0336] To a solution of (S)-7-bromo-4-(tert-butoxy)-2-((1-methylpyrrolidin-2-yl)methoxy)imidazo[2,1-f][1,2,4]triazine (300 mg, 0.78 mmol) in THF (8 mL) cooled at -78 ° C was added n-butyllithium (1.6 M in n-hexane, 0.7 mL, 1.2 mmol). After stirring for 30 minutes, tert-butyl 4-formyl-1H-indazole-1-carboxylate (231 mg, 0.9 mmol) in THF (2 mL) was added dropwise. The resulting mixture was gradually stirred to room temperature overnight. The solution was quenched with NH4Cl solution (5 mL) and extracted with EA (15 mL). The organic layer was dried, concentrated and purified by CombiFlash (DCM: NH3 (7 M in MeOH) = 10: 1) to give the product (230 mg, 53%). MS:M / e 552(M+1) + .

[0337] Step B: (S)-7-((1H-indazol-4-yl)methyl)-2-((1-methylpyrrolidin-2-yl)methoxy)imidazo[2,1-f][1,2,4]triazin-4-ol

[0338]

[0339] Et3SiH (2 mL) and TFA (2 mL) were added to a solution of tert-butyl 4-((4-(tert-butoxy)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)imidazo[2,1-f][1,2,4]triazin-7-yl)(hydroxy)methyl)-1H-indazole-1-carboxylate (230 mg, 0.4 mmol) in DCM (2 mL). The solution was heated at 80°C overnight. The solvent was evaporated under an oil pump and then azeotroped with toluene. The crude product was used directly in the next step (160 mg, crude). MS: M / e 380 (M+1) + .

[0340] Step C: (S)-7-((1H-indazol-4-yl)methyl)-4-chloro-2-((1-methylpyrrolidin-2-yl)methoxy)imidazo[2,1-f][1,2,4]triazine

[0341]

[0342] A sealed tube containing (S)-7-((1H-indazol-4-yl)methyl)-2-((1-methylpyrrolidin-2-yl)methoxy)imidazo[2,1-f][1,2,4]triazin-4-ol (160 mg, 0.4 mmol), Et3N.HCl (222 mg, 1.6 mmol) and POCl3 (8 mL) was heated at 120°C overnight. After cooling, the solvent was evaporated under an oil pump and co-distilled with toluene to give the crude product, which was used directly in the next step (160 mg, crude). MS: M / e398 ​​(M+1) + .

[0343] Step D: (S)-benzyl 4-(7-((1H-indazol-4-yl)methyl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)imidazo[2,1-f][1,2,4]triazin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate

[0344]

[0345] (S)-2-(Cyanomethyl)piperazine-1-carboxylic acid benzyl ester (207 mg, 0.8 mmol) was added to a solution of (S)-7-((1H-indazol-4-yl)methyl)-4-chloro-2-((1-methylpyrrolidin-2-yl)methoxy)imidazo[2,1-f][1,2,4]triazine (160 mg, 0.4 mmol) in THF (10 mL), followed by DIEA (413 mg, 3.2 mmol). The reaction mixture was stirred at room temperature for 1 hour. Water (5 mL) was added to the solution and extracted with EA (10 mL). The organic layer was dried over Na2SO4, concentrated and purified by CombiFlash (DCM:NH3 (7M in MeOH) = 20:3) to give the product (80 mg, 32%). MS: M / e621 (M+1) + .

[0346] Step E: tert-Butyl 4-((4-((S)-4-((benzyloxy)carbonyl)-3-(cyanomethyl)piperazin-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)imidazo[2,1-f][1,2,4]triazin-7-yl)methyl)-1H-indazole-1-carboxylate

[0347]

[0348] (Boc)2O (34 mg, 0.16 mmol) was added to a solution of (S)-benzyl 4-(7-((1H-indazol-4-yl)methyl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)imidazo[2,1-f][1,2,4]triazin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate (80 mg, 0.13 mmol), DMAP (2 mg) and triethylamine (20 mg, 0.2 mmol) in DCM (5 mL). The reaction mixture was stirred at room temperature for 2 hours, then concentrated and purified by CombiFlash (DCM:MeOH=8%) to give the product (35 mg, 38%) MS: M / e 721 (M+1) + .

[0349] Step F: tert-Butyl 4-((4-((S)-3-(cyanomethyl)piperazin-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)imidazo[2,1-f][1,2,4]triazin-7-yl)methyl)-1H-indazole-1-carboxylate

[0350]

[0351] A solution of tert-butyl 4-((4-((S)-4-((benzyloxy)carbonyl)-3-(cyanomethyl)piperazin-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)imidazo[2,1-f][1,2,4]triazin-7-yl)methyl)-1H-indazole-1-carboxylate (35 mg, 0.05 mmol) and Pd / C (wet, 10%, 23 mg) in THF / EtOH (3 mL / 3 mL) was stirred under a H2 balloon at room temperature overnight. The catalyst was filtered off and the filtrate was concentrated to give the crude product which was used directly (20 mg, 71%). MS: M / e 587 (M+1) + .

[0352] Step G: tert-Butyl 4-((4-((S)-4-acryloyl-3-(cyanomethyl)piperazin-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)imidazo[2,1-f][1,2,4]triazin-7-yl)methyl)-1H-indazole-1-carboxylate

[0353]

[0354] NaHCO solution (saturated, 0.3 mL) was added to a solution of tert-butyl 4-((4-((S)-3-(cyanomethyl)piperazin-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)imidazo[2,1-f][1,2,4]triazin-7-yl)methyl)-1H-indazole-1-carboxylate (20 mg, 0.03 mmol) in CHCN (3 mL) followed by acryloyl chloride (5 mg, 0.06 mmol). The reaction mixture was stirred at room temperature for 1 hour. The solution was evaporated, water (2 mL) was added and extracted with EA (5 mL). The organic layer was dried, concentrated and used directly in the next step (20 mg, crude). MS: M / e 641 (M+1) + .

[0355] Step H: 2-((S)-4-(7-((1H-indazol-4-yl)methyl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)imidazo[2,1-f][1,2,4]triazin-4-yl)-1-acryloylpiperazin-2-yl)acetonitrile

[0356]

[0357] TFA (0.2 mL) was added to a solution of tert-butyl 4-((4-((S)-4-acryloyl-3-(cyanomethyl)piperazin-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)imidazo[2,1-f][1,2,4]triazine-7-yl)methyl)-1H-indazole-1-carboxylate (20 mg, 0.03 mmol) in DCM (3 mL). After stirring at room temperature for 1 hour, water was added to the solution, extracted with DCM and washed with NaHCO3 solution. The organic layer was dried, concentrated and purified by preparative TLC (DCM: NH3 (7M in MeOH) = 10: 1) to give the product (6 mg, 38%). 1H NMR (400MHz, CD3OD) δ8.12(s,1H),7.45(s,1H),7.42(d,J=8.0Hz,1H),7.30(t,J=8. 0Hz,1H),6.97(d,J=8.0Hz,1H),6.81(br.s,1H),6.28(d,J=16.0Hz,1H),5.83(d,J=8 .0Hz,1H),5.09(s,1H),4.62(s,1H),4.57(s,3H),4.42-4.37(m,1H),4.15(s,1H),3. 78-3.48(m,5H),3.20(s,2H),2.97(s,3H),2.91-2.85(m,2H),2.28-1.94(m,4H)ppm. MS:M / e541(M+1) + .

[0358] Example 18: Compound A18: 2-((S)-1-acryloyl-4-(2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(2-(trifluoromethyl)benzyl)imidazo[2,1-f][1,2,4]triazin-4-yl)piperazin-2-yl)acetonitrile

[0359] Step A: (4-(tert-Butyloxy)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)imidazo[2,1-f][1,2,4]triazin-7-yl)(2-(trifluoromethyl)phenyl)methanol

[0360]

[0361] To a solution of (S)-7-bromo-4-(tert-butoxy)-2-((1-methylpyrrolidin-2-yl)methoxy)imidazo[2,1-f][1,2,4]triazine (200 mg, 0.5 mmol) in THF (8 mL) was added n-butyllithium solution (1.6 M, 0.77 mL, 1 mmol) dropwise, maintaining the temperature between -75 and -65 °C. After 1 h, a suspension of 2-(trifluoromethyl)benzaldehyde (174 mg, 1 mmol) in THF (2 mL) was added dropwise. The resulting mixture was stirred at -70 °C for 2 h and then warmed to room temperature overnight. The reaction was quenched with saturated aqueous NH4Cl and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by preparative TLC to give the target compound (210 mg, 87.8%). MS:M / e 480(M+1) + .

[0362] Step B: (S)-2-((1-methylpyrrolidin-2-yl)methoxy)-7-(2-(trifluoromethyl)benzyl)imidazo[2,1-f][1,2,4]triazin-4-ol

[0363]

[0364] To a solution of (4-(tert-butoxy)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)imidazo[2,1-f][1,2,4]triazine-7-yl)(2-(trifluoromethyl)phenyl)methanol (310 mg, 0.67 mmol) in DCM (10 mL) was added TFA (5 mL) and Et3SiH (5 mL). The reaction mixture was stirred at 40°C overnight. The mixture was concentrated in vacuo. To the residue was added NaHCO3 solution (1 M, 10 mL) and extracted with ethyl acetate. The combined organic extracts were dried over sodium sulfate, filtered and evaporated. Purification by preparative TLC gave the title product (200 mg, 65.7%). MS: m / e 408 (M+1) + .

[0365] Step C: (S)-4-chloro-2-((1-methylpyrrolidin-2-yl)methoxy)-7-(2-(trifluoromethyl)benzyl)imidazo[2,1-f][1,2,4]triazine

[0366]

[0367] To a solution of (S)-2-((1-methylpyrrolidin-2-yl)methoxy)-7-(2-(trifluoromethyl)benzyl)imidazo[2,1-f][1,2,4]triazine-4-ol (200 mg, 0.49 mmol) in POCl3 (5 mL) was added triethylamine hydrochloride (137 mg, 1 mmol). The mixture was sealed and stirred at 110°C overnight. The mixture was cooled to room temperature and concentrated in vacuo. The residue was used directly in the next step. MS: m / e 426 (M+1) + .

[0368] Step D: 2-((S)-4-(2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(2-(trifluoromethyl)benzyl)imidazo[2,1-f][1,2,4]triazin-4-yl)piperazin-2-yl)acetonitrile

[0369]

[0370] To the product of step C in acetonitrile (10 mL) was slowly added a solution of (S)-2-(piperazin-2-yl)acetonitrile (125 mg, 1 mmol) and DIEA (258 mg, 2 mmol) in acetonitrile (2 ml). The mixture was stirred at room temperature for 2 h. The mixture was used directly in the next step. MS: m / e 515 (M+1) + .

[0371] Step E: 2-((S)-1-acryloyl-4-(2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(2-(trifluoromethyl)benzyl)imidazo[2,1-f][1,2,4]triazin-4-yl)piperazin-2-yl)acetonitrile

[0372]

[0373] To the mixture of the product of step D was added NaHCO3 solution (1M, 10 mL). Acryloyl chloride (90 mg, 0.1 mol) was slowly added to the mixture. The reaction was stirred at room temperature for 2 h. The resulting mixture was extracted with ethyl acetate. The combined organic extracts were dried over sodium sulfate, filtered and evaporated. The title product (1.2 mg, 0.43%, over three steps) was purified by preparative TLC. 1H NMR (400 MHz, CD3OD) δ 7.74 (d, J = 7.7 Hz, 1H), 7.52 (t, J = 7.2 Hz, 1H), 7.44 (t, J = 7.3 Hz, 1H), 7.28 (d, J = 7.3 Hz, 1H), 7.24 (s, 1H), 6.82 (s, 1H), 6.29 (d, J = 16.7 Hz, 1H), 5.84 (d, J = 10.1 Hz, 1H), 5.34 (s, 1H) ,5.10(s,1H),4.69(s,1H),4.51–4.44(m,1H),4.42(s,2H),3.82(s,1H),3.70-3.61(m,4H),3.21(s ,1H),3.02(s,3H),2.91(s,1H),2.34(s,1H),2.25–2.13(m,2H),2.05–1.93(m,3H),1.60(s,1H)ppm. MS:M / e 569(M+1) + .

[0374] Example 19: Compound A19: 2-((S)-1-acryloyl-4-(7-((4-hydroxynaphthalen-1-yl)methyl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)imidazo[2,1-f][1,2,4]triazin-4-yl)piperazin-2-yl)acetonitrile

[0375] Step A: 2-((S)-4-(7-((4-hydroxynaphthalen-1-yl)methyl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)imidazo[2,1-f][1,2,4]triazin-4-yl)piperazin-2-yl)acetonitrile

[0376]

[0377] (S)-Benzyl 2-(cyanomethyl)-4-(7-((4-methoxynaphthalen-1-yl)methyl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)imidazo[2,1-f][1,2,4]triazin-4-yl)piperazine-1-carboxylate (50 mg, 0.075 mmol) was dissolved in DCM (3 ml) and BBr3 (1 M in DCM, 2.3 ml, 2.27 mmol) was added. The mixture was stirred at room temperature for 2 hours. The reaction was concentrated to dryness (40 mg) and the residue was used directly in the next step without further purification. MS: M / e 513 (M+1) + .

[0378] Step B: 2-((S)-1-acryloyl-4-(7-((4-hydroxynaphthalen-1-yl)methyl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)imidazo[2,1-f][1,2,4]triazin-4-yl)piperazin-2-yl)acetonitrile

[0379]

[0380] To a mixture of the product of step A (100 mg, crude) in CH3CN (2 mL) was added saturated NaHCO3 (1 mL) at 0°C, followed by a solution of acryloyl chloride (20 mg, 0.22 mmol) in CH3CN (0.5 mL). The resulting mixture was stirred at room temperature for 30 min. The reaction was diluted with water and extracted with EA (60 mL). The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by preparative TLC to give the target compound (1.9 mg, 10% over two steps). 1H NMR (400MHz, DMSO-d6) δ10.08(s,1H),9.71(s,1H),8.18(d,J=8.0Hz,1H),8.04(d,J=8.0Hz,1 H),7.51–5.40(m,2H),7.29(s,1H),7.20(d,J=7.4Hz,1H),6.83–6.51(m,2H),6.20(d,J=16.6 Hz,1H),5.79(d,J=10.1Hz,1H),5.07–4.98(m,2H),4.68–4.54(m,1H),4.50(s,3H),4.10(s,1 H),3.79(s,2H),3.10–3.01(m,4H),2.92(d,J=3.2Hz,6H),2.20(s,1H),2.05–1.89(m,3H)ppm. MS:M / e 567(M+1) + .

[0381] Example 20: Compound A20: 2-((S)-1-acryloyl-4-(7-(2-fluoro-6-hydroxybenzyl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)imidazo[2,1-f][1,2,4]triazin-4-yl)piperazin-2-yl)acetonitrile

[0382] Step A: (2-(Benzyloxy)-6-fluorophenyl)(4-(tert-butoxy)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)imidazo[2,1-f][1,2,4]triazin-7-yl)methanol

[0383]

[0384] To a solution of (S)-7-bromo-4-(tert-butoxy)-2-((1-methylpyrrolidin-2-yl)methoxy)imidazo[2,1-f][1,2,4]triazine (383 mg, 1 mmol) in THF (10 mL) was added n-butyllithium (1 mL, 1.6 mmol) dropwise, maintaining the temperature between -75 and -65 °C. After 30 min, a mixture of 2-(benzyloxy)-6-fluorobenzaldehyde (276 mg, 1.2 mmol) in THF (2 mL) was added dropwise. The resulting mixture was stirred at -70 °C for 1 h and then warmed to room temperature for 16 h. The reaction was quenched with saturated aqueous NH4Cl and extracted with EtOAc (50 mL x 2). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by combi flash to give the target compound (320 mg, 63%). MS:M / e 536(M+1) + .

[0385] Step B: (S)-7-(2-(Benzyloxy)-6-fluorobenzyl)-2-((1-methylpyrrolidin-2-yl)methoxy)imidazo[2,1-f][1,2,4]triazin-4-ol

[0386]

[0387] To a mixture of the product of step A (320 mg) in DCE (3 mL) was added TFA (3 mL) and Et3SiH (3 mL). The reaction was stirred at 25 °C overnight. The mixture was concentrated to dryness and the residue was used directly in the next step without further purification. MS: M / e 464 (M+1) + .

[0388] Step C: (S)-7-(2-(Benzyloxy)-6-fluorobenzyl)-4-chloro-2-((1-methylpyrrolidin-2-yl)methoxy)imidazo[2,1-f][1,2,4]triazine

[0389]

[0390] The product of step B (120 mg, 0.26 mmol) was dissolved in POCl3 (2 ml), and triethylamine hydrochloride (106 mg, 0.78 mmol) was added. The reaction was heated at 100°C overnight. The mixture was concentrated to dryness and the residue was used directly in the next step without further purification (100 mg, crude). MS: M / e 482 (M+1) + .

[0391] Step D: (S)-benzyl 4-(7-(2-(benzyloxy)-6-fluorobenzyl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)imidazo[2,1-f][1,2,4]triazin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate

[0392]

[0393] The product of step C (100 mg, 0.21 mmol) was dissolved in THF (3 ml), then DIEA (81 mg, 0.63 mmol) and (S)-2-(cyanomethyl)piperazine-1-carboxylic acid benzyl ester (59 mg, 0.23 mmol) were added and the reaction was stirred at room temperature for 3 hours. The reaction was quenched with saturated water and extracted with EtOAc (80 mL). The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by combi flash to give the target compound (40 mg, 10% over two steps). MS: M / e 705 (M+1) + .

[0394] Step E: 2-((S)-4-(7-(2-fluoro-6-hydroxybenzyl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)imidazo[2,1-f][1,2,4]triazin-4-yl)piperazin-2-yl)acetonitrile

[0395]

[0396] The product of step D (40 mg) was dissolved in a mixture of EtOH (2 mL) and THF (2 ml), followed by the addition of Pd / C (10 mg, 10%). The reaction mixture was hydrogenated under a balloon, stirred overnight, and filtered through a pad of celite. The filtrate was evaporated to give the title compound (40 mg, crude), which was used directly in the next step without further purification. MS: M / e 481 (M+1) + .

[0397] Step F: 2-((S)-1-acryloyl-4-(7-(2-fluoro-6-hydroxybenzyl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)imidazo[2,1-f][1,2,4]triazin-4-yl)piperazin-2-yl)acetonitrile

[0398]

[0399] To a mixture of the product of step E (50 mg, crude) in CH3CN (1 mL) was added saturated NaHCO3 (1 mL) at 0°C, followed by a solution of acryloyl chloride (10 mg, 0.1 mmol) in CH3CN (0.3 mL). The resulting mixture was stirred at room temperature for 30 min. The reaction was diluted with water and extracted with EA (60 mL). The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by preparative TLC to give the target compound (0.5 mg, 3% over two steps). 1H NMR(400MHz,cd3od)δ7.20–7.04(m,2H),6.80(s,1H),6.69–6.53(m,2H),6.28(d,J =17.3Hz,1H),5.83(d,J=10.3Hz,1H),5.09(s,1H),4.80(s,2H),4.54–4.49(m,1H) ,4.17(s,3H),3.96–3.87(m,1H),3.84–3.74(m,1H),3.53-3.48(m,2H),3.29–3.17 (m,2H),3.08(s,3H),2.88–2.65(m,3H),2.47-2.40(m,1H),2.21-2.08(m,3H)ppm. MS:M / e 535(M+1) + .

[0400] Example 21: Compound A21: 2-((S)-1-acryloyl-4-(7-((2-hydroxynaphthalen-1-yl)methyl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)imidazo[2,1-f][1,2,4]triazin-4-yl)piperazin-2-yl)acetonitrile

[0401] Step A: (4-(tert-Butyloxy)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)imidazo[2,1-f][1,2,4]triazin-7-yl)(2-methoxynaphthalen-1-yl)methanol

[0402]

[0403] To a solution of (S)-7-bromo-4-(tert-butoxy)-2-((1-methylpyrrolidin-2-yl)methoxy)imidazo[2,1-f][1,2,4]triazine (383 mg, 1 mmol) in THF (10 mL) was added n-butyllithium (1 mL, 1.6 mmol) dropwise, maintaining the temperature between -75 and -65 °C. After 30 min, a mixture of 2-methoxy-1-naphthaldehyde (223 mg, 1.2 mmol) in THF (2 mL) was added dropwise. The resulting mixture was stirred at -70 °C for 1 h and then warmed to room temperature for 16 h. The reaction was quenched with saturated aqueous NH4Cl and extracted with EtOAc (50 mL x 2). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by combi flash to give the title compound (340 mg, 69%). MS: M / e 492 (M+1) + .

[0404] Step B: (S)-7-((2-methoxynaphthalen-1-yl)methyl)-2-((1-methylpyrrolidin-2-yl)methoxy)imidazo[2,1-f][1,2,4]triazin-4-ol

[0405]

[0406] To a mixture of the product of step A (340 mg, 0.8 mmol) in DCE (3 mL) was added TFA (3 mL) and Et3SiH (3 mL). The reaction was heated at 25 °C overnight. The mixture was concentrated to dryness and the residue was used directly in the next step without further purification. MS: M / e 420 (M+1) + .

[0407] Step C: (S)-benzyl 2-(cyanomethyl)-4-(7-((2-methoxynaphthalen-1-yl)methyl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)imidazo[2,1-f][1,2,4]triazin-4-yl)piperazine-1-carboxylate

[0408]

[0409] To the residue of step B (300 mg, crude) in POCl3 (4 mL), triethylamine hydrochloride (292 mg, 2.15 mmol) was added. The resulting mixture was stirred at 100 ° C overnight. The mixture was concentrated to dryness and treated with THF (15 mL). DIEA (387 mg, 2.04 mmol) and (S)-2-(cyanomethyl)piperazine-1-carboxylic acid benzyl ester (194 mg, 0.75 mmol) were then added and the reaction was stirred at room temperature for 2 hours. The reaction was quenched with water and extracted with EtOAc (80 mL). The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by combi flash to give the target compound (130 mg, 27% over two steps). MS: M / e 661 (M+1) + .

[0410] Step D: 2-((S)-4-(7-((2-hydroxynaphthalen-1-yl)methyl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)imidazo[2,1-f][1,2,4]triazin-4-yl)piperazin-2-yl)acetonitrile

[0411]

[0412] To a mixture of the product of step C (30 mg, 0.05 mmol) in DCM (3 mL) was added 1N BBr3 (0.5 mL, 0.5 mmol) in DCM at room temperature. The reaction was stirred at room temperature for 2 hours. The reaction was filtered and the filter cake was washed with MTBE to give the title compound (20 mg, crude), which was used directly in the next step without further purification. MS: M / e 513 (M+1) + .

[0413] Step E: 2-((S)-1-acryloyl-4-(7-((2-hydroxynaphthalen-1-yl)methyl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)imidazo[2,1-f][1,2,4]triazin-4-yl)piperazin-2-yl)acetonitrile

[0414]

[0415] To a mixture of the product of step D (20 mg, crude) in CH3CN (1 mL) was added saturated NaHCO3 (0.5 mL) at 0°C, followed by a solution of acryloyl chloride (6 mg, 0.1 mmol) in CH3CN (0.3 mL). The resulting mixture was stirred at room temperature for 30 min. The reaction was diluted with water and extracted with EA. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by preparative TLC to give the target compound (2.25 mg, 10% over two steps). 1H NMR (400MHz, DMSO-d6) δ10.01(s,1H),7.95(d,J=7.8Hz,1H),7.87(d,J=7.8Hz,1H),7.80(d,J =8.7Hz,1H),7.47(t,J=7.3Hz,1H),7.34(d,J=6.9Hz,3H),6.71-6.91(m,2H),6.24(d,J=16.5H z,1H),5.84(d,J=9.7Hz,1H),5.19–4.85(m,2H),4.80-4.71(m,2H),4.55(s,2H),4.18(s,1H), 3.92(s,1H),3.67(s,1H),3.21(s,2H),3.11–2.84(m,6H),2.38(s,2H),2.07–1.83(m,3H)ppm. MS:M / e 567(M+1) + .

[0416] Biochemical function assay

[0417] KRAS (aa 1-169) G12C, C51S, C80L, C118S with His tag were expressed, purified and loaded with GDP in-house. All protein and substrate solutions were prepared in assay buffer containing 25mM HEPES pH7.5, 10mM MgCl2 and 0.01% Triton X-100. Purified GDP-loaded KRAS (aa 1-169) G12C, C51S, C80L, C118S proteins were pre-incubated with serially diluted compounds at 24°C for 3 hours. Purified SOS1 (aa 564-1049) protein, GTP S (Sigma) and GST-cRaf RBD (aa 1-149) were then added to each well and incubated for another 3 hours at 24°C. This addition initiates the nucleotide exchange reaction and the conversion of inactive GDP-loaded KRASG12C to active GTP S KRASG12C bound to GST-cRaf RBD. After incubation, Mab anti-6HIS-Tb cryptate (Cisbio) and Mab anti-GST-XL665 (Cisbio) were added and further incubated at 24°C for 3 hours. The binding interaction between active GTP S KRASG12C and GST-cRaf RBD brings Tb and XL665 into close proximity, thereby increasing the FRET signal (Ex337nm, Em665nm / 620nm). The percentage inhibition of the nucleotide exchange reaction in the presence of increasing compound concentrations was calculated based on the fluorescence ratio at 665nm to 620nm detected on a BMG PHERAstar FSX instrument. The IC50 value for each compound was calculated by fitting the data to a four-parameter logistic model by Dotmatics.

[0418] Table 1: Compound A series

[0419] Compound No. IC50(nmol) Compound No. IC50(nmol) A4 46.7 A5 29 A6 100 A7 47.8 A8 7700 A9 1060 A10 187 A11 215 A12 217 A13 101 A14 506 A15 1180 A18 235 A19 9.6 A20 19.1 A21 20.8

Claims

1. A method for preparing a compound of formula (I), The steps include: L1 is selected from (CH2) m -; L2 is selected from -O-(CH2) m -; R 1 Selected from R 2 Selected from R 3 Selected from hydrogen; R 4 Selected from R 5 Selected from -(CH2) m -CN; PR 1 Selected from tert-butyl; PR 2 Selected from Cbz; p is 1; m is selected from 1.

2. The preparation method according to claim 1, characterized in that: The reagent used in step 1 is selected from NBS and Br2.

3. The preparation method according to claim 1, characterized in that: The reagents used in step 2 and step 7 are independently selected from POCl3, PCl5, and SOCl2.

4. The preparation method according to claim 1, characterized in that: The reagent used in step 3 is selected from sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, potassium tert-butoxide, lithium tert-butoxide, sodium benzyl alcoholate, potassium benzyl alcoholate, and lithium benzyl alcoholate.

5. The preparation method according to claim 1, characterized in that: The reagent used in step 4 is selected from sodium hydride, potassium hydride, lithium hydride, sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, potassium tert-butoxide, n-butyl lithium, sec-butyl lithium, tert-butyl lithium, lithium diisopropylamide, and lithium hexamethyldisilazide.

6. The preparation method according to claim 1, characterized in that: The reagent used in step 5 is selected from sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, potassium tert-butoxide, n-butyl lithium, sec-butyl lithium, tert-butyl lithium, lithium diisopropylamide, and lithium hexamethyldisilazide.

7. The preparation method according to claim 1, characterized in that: The deprotection conditions in step 6 and step 9 are independently selected from the combination of trifluoroacetic acid and triethylsilane, the combination of BBr3, Pd / C and hydrogen, and the combination of trifluoroacetic acid, hydrochloric acid, Pd / C and cyclohexadiene.

8. The preparation method according to claim 1, characterized in that: The reagent used in step 8 is selected from triethylamine, diethylamine, diisopropylethylamine, pyridine, methylimidazole, piperidine, morpholine, indoline, quinoline, isoquinoline, and dimethylaminopyridine.

9. The preparation method according to claim 1, characterized in that: The reagent used in step 8 is selected from triethylamine, diethylamine, diisopropylethylamine, and dimethylaminopyridine.

10. The preparation method according to claim 1, characterized in that: The reagent used in step 9 is selected from sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, triethylamine, diethylamine, diisopropylethylamine, pyridine, methylimidazole, piperidine, morpholine, indoline, quinoline, isoquinoline, and dimethylaminopyridine.

11. The preparation method according to claim 1, characterized in that: The compound of formula (I) is

Images