CN117229205A - Preparation method and pharmaceutical application of phenyl acrylamide RHbDD1 inhibitor - Google Patents
Preparation method and pharmaceutical application of phenyl acrylamide RHbDD1 inhibitor Download PDFInfo
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- CN117229205A CN117229205A CN202311187577.3A CN202311187577A CN117229205A CN 117229205 A CN117229205 A CN 117229205A CN 202311187577 A CN202311187577 A CN 202311187577A CN 117229205 A CN117229205 A CN 117229205A
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- China
- Prior art keywords
- mmol
- pharmaceutically acceptable
- acryloyl
- ethyl acetate
- ylmethoxy
- Prior art date
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- 238000002360 preparation method Methods 0.000 title claims abstract description 45
- IMOLAGKJZFODRK-UHFFFAOYSA-N 2-phenylprop-2-enamide Chemical compound NC(=O)C(=C)C1=CC=CC=C1 IMOLAGKJZFODRK-UHFFFAOYSA-N 0.000 title abstract description 5
- 239000003112 inhibitor Substances 0.000 title description 5
- 150000001875 compounds Chemical class 0.000 claims abstract description 71
- 101000709000 Homo sapiens Rhomboid-related protein 4 Proteins 0.000 claims abstract description 18
- 150000003839 salts Chemical class 0.000 claims abstract description 17
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- 239000003814 drug Substances 0.000 claims abstract description 10
- 201000010099 disease Diseases 0.000 claims abstract description 5
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 5
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 5
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 84
- -1 methoxy, 2-methoxyethoxy Chemical group 0.000 claims description 82
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 claims description 56
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 42
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 39
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 35
- VVWRJUBEIPHGQF-UHFFFAOYSA-N propan-2-yl n-propan-2-yloxycarbonyliminocarbamate Chemical compound CC(C)OC(=O)N=NC(=O)OC(C)C VVWRJUBEIPHGQF-UHFFFAOYSA-N 0.000 claims description 28
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 19
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 claims description 18
- OXRRHYRRQWIHIV-UHFFFAOYSA-N 2,3-dihydro-1h-pyridin-6-one Chemical compound O=C1NCCC=C1 OXRRHYRRQWIHIV-UHFFFAOYSA-N 0.000 claims description 12
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 12
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 9
- 239000001257 hydrogen Substances 0.000 claims description 8
- 229910052739 hydrogen Inorganic materials 0.000 claims description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 6
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- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 claims description 3
- FMKOJHQHASLBPH-UHFFFAOYSA-N isopropyl iodide Chemical compound CC(C)I FMKOJHQHASLBPH-UHFFFAOYSA-N 0.000 claims description 3
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- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 claims description 2
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims description 2
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- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 34
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Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to the field of medicaments, in particular to a compound containing a phenylacrylamide structure or pharmaceutically acceptable salt thereof, a preparation method thereof, a pharmaceutical composition containing the compound and application of the compound in preparing medicaments for treating diseases related to functions of serine proteolytic enzymes (Rhomboid domain containing 1, RHbDD 1) in a membrane.
Description
Technical Field
The invention relates to the field of medicaments, in particular to a compound containing a phenylacrylamide structure or pharmaceutically acceptable salt thereof, a preparation method thereof, a pharmaceutical composition containing the compound and application of the compound in preparing medicaments for treating diseases related to functions of serine proteolytic enzymes (Rhomboid domain containing 1, RHbDD 1) in a membrane.
Background
RHBDD1 is an intramembrane serine proteolytic enzyme, is one of members of the Rhomboid family, is widely distributed in the biological world, and has important regulatory functions. RHBDD1 can cleave tumor suppressor activation pathway protein 6 (tumour suppressor activated pathway, TSAP 6), apoptosis-preconditioning protein BIK, and transforming growth factor α (transforming growth factor alpha, TGF-a).
RHBDD1 has high protein expression levels in a variety of tumor cells such as pancreatic adenocarcinoma, breast cancer, small cell lung cancer, renal cell carcinoma, and colorectal cancer. Colorectal cancer is a high-frequency malignant tumor worldwide, and the occurrence and development of colorectal cancer are closely related to related oncogenes, oncogenes and growth factor pathways. Clinical relevance studies showed that RHBDD1 expression was significantly correlated with survival, tumor differentiation, TNM stage and N stage in colorectal cancer patients. The RHBDD1 endogenous mutation can inhibit the growth of tumor cells after being inactivated. Mechanism studies indicate that RHBDD1 interacts with tgfα and is able to induce tgfα cleavage and secretion in an ADAM independent manner. Secretion of tgfα further stimulates the EGFR/Raf/MEK/ERK signaling pathway, thereby participating in the development and progression of colorectal cancer. There is currently no relevant report on RHDDD 1 inhibitors, and there is a great need to discover novel RHDDD 1 inhibitors.
Disclosure of Invention
The invention provides a compound containing a phenyl acrylamide structure or pharmaceutically acceptable salt thereof, a preparation method thereof, a pharmaceutical composition containing the compound and application of the compound in preparing medicines for treating diseases related to RHbDD1 functions.
In order to solve the technical problems of the invention, the invention provides the following technical scheme:
a first aspect of the present invention provides a compound represented by the general formula (I):
wherein R is 1 Selected from the following structures:
R 2 selected from hydrogen, substituted or unsubstituted C 1-4 Straight-chain or branched oxaalkyl, C 3-6 Cyclic methoxy, C 4-8 Oxacycloalkoxy or
R 3 Selected from hydrogen, methoxy, 2-methoxyethoxy or oxetan-4-ylmethoxy;
R 4 selected from hydrogen or methoxy.
Further, a compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 2 Selected from the group consisting of hydrogen, methoxy, ethoxy, N-propoxy, isopropoxy, cyclopropylmethoxy, cyclobutylmethoxy, cyclohexylmethoxy, 2-methoxyethoxy, 3-methoxyethoxy, oxetan-3-ylmethoxy, oxolan-3-ylmethoxy, oxetan-4-ylethoxy, N, N-diethylaminoethoxy, pyrrolidin-1-ylethoxy, piperidin-1-ylethoxy, 1-Boc-piperidin-4-methoxy, 2-morpholinylethoxy, 3-morpholinylethoxy, 2- (4-methylpiperazin-1-ylethoxy, 2- (pyridinamido) ethoxy, 2- (2-oxopyrrolidin-1-ylethoxy, pyridin-4-ylmethoxy, pyridin-3-ylethoxy, pyridazin-4-ylmethoxy, thiophen-3-ylmethyleneOxy, 3-fluoro-pyridin-4-ylmethoxy, 2-fluoro-pyridin-4-ylmethoxy.
As a preferred embodiment, the pharmaceutically acceptable salt is selected from organic or inorganic acid salts, including hydrochloride, hydrobromide, sulfate, phosphate, acetate, citrate, malate, fumarate, tartrate or mesylate salts.
As a preferred embodiment of the present invention, the compound of formula (I) has the structure:
another aspect of the present invention provides a method for synthesizing a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, which comprises the following steps:
route (1):
reagents and conditions: (a) Oxalyl chloride, N-dimethylformamide, dichloromethane, 0 ℃; (b) R is R 1 H, sodium hydrogen, tetrahydrofuran, 0deg.C.
Route (2):
reagents and conditions: (a) 2-iodopropane, potassium hydroxide, acetonitrile: water=1:1, 90 ℃; (b) Oxalyl chloride, N-dimethylformamide, dichloromethane, 0 ℃;5, 6-dihydro-2 (1H) -pyridone, sodium hydrogen, tetrahydrofuran, 0 ℃; (c) anhydrous aluminum trichloride, methylene chloride, 0 ℃; (d) R is R 2 OH, diisopropyl azodicarboxylate, triphenylphosphine, tetrahydrofuran, 0 ℃ to room temperature;
wherein R is 1 、R 2 、R 3 、R 4 The definition is the same as described above.
Another aspect of the present invention provides a pharmaceutical composition, which includes a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
Another aspect of the technical scheme of the invention is to provide application of a compound shown as a general formula (I) or pharmaceutically acceptable salt thereof in preparing medicines for treating diseases related to RHBDD1 function.
Another aspect of the technical scheme of the invention is to provide application of a compound shown as a general formula (I) or pharmaceutically acceptable salt thereof in preparing a medicament for treating tumors.
Beneficial technical effects
Examples 1-31 in the technical scheme of the invention all have obvious inhibition activity on RHBDD1 and obvious proliferation inhibition on tumor cells.
Detailed Description
Example 1
(E) -1- (3, 4, 5-trimethoxyphenyl) propenoyl) quinolin-2 (1H) one
(1) Preparation of (E) -3- (3, 4, 5-trimethoxyphenyl) acryloyl chloride
(E) -3,4, 5-trimethoxycinnamic acid (0.100 g,0.42 mmol) was dissolved in ultra-dry dichloromethane, ice-cooled to 0deg.C under argon, oxalyl chloride (274.4 mg,2.1 mmol) and N, N-dimethylformamide (0.29 mg, 0.04 mmol) were slowly added and the mixture was allowed to react at room temperature for 3h. After the raw materials are reacted completely, the solvent is removed by reduced pressure distillation to obtain the crude product of (E) -3- (3, 4, 5-trimethoxyphenyl) acryloyl chloride, which is directly used for the next reaction without further purification.
(2) Preparation of the title compound
Quinolin-2 (1H) one (0.092 g,0.63 mmol) was dissolved in ultra-dry tetrahydrofuran, ice-cooled to 0deg.C, and a 60% sodium hydride mineral oil mixture (0.027 g,0.69 mmol) was added in two portions and reacted under ice-cooled conditions for 40min. The crude (E) -3- (3, 4, 5-trimethoxyphenyl) acryloyl chloride (0.107 g,0.42 mmol) obtained in the previous step was dissolved in 1ml of ultra-dry tetrahydrofuran, added dropwise to the system, and then allowed to react at room temperature for 1h. After the reaction is completed, adding water for quenching, extracting with ethyl acetate, washing an ethyl acetate layer twice with 10ml of saturated sodium chloride aqueous solution, then decompressing and distilling to remove the solvent, separating petroleum ether from an ethyl acetate system by column chromatography to obtain a white solid with the yield of 56mg and the melting point of 76-78 ℃.
1 H NMR(400MHz,Chloroform-d)δ8.28(d,J＝8.5Hz,1H),8.04(d,J＝8.5Hz,1H),7.90(d,J＝16.1Hz,2H),7.75(s,1H),7.58(t,J＝7.6Hz,1H),7.33(d,J＝8.8Hz,1H),6.82(m,2H),6.60(d,J＝15.9Hz,1H),3.92(s,9H)；HRMS calcd.For C21H19NO5(M+H) + 366.13139,found 366.25935.
Example 2
(E) -1- (3- (2, 3-dihydrobenzo [ b ] [1,4] dioxan-6-yl) acryloyl) -5, 6-dihydropyridin-2 (1H) one
(1) Preparation of (E) -3- (2, 3-dihydrobenzo [ b ] [1,4] dioxan-6-yl) acryloyl chloride
(E) -3- (2, 3-Dihydrobenzo [ b ] [1,4] dioxan-6-yl) acrylic acid (0.100 g,0.48 mmol) was dissolved in ultra-dry dichloromethane, ice-cooled to 0℃under argon, oxalyl chloride (304.5 mg,2.4 mmol) and N, N-dimethylformamide (0.29 mg, 0.04 mmol) were slowly added and the mixture was allowed to react at room temperature for 3h. After the raw materials are reacted completely, the solvent is removed by reduced pressure distillation to obtain (E) -3- (2, 3-dihydrobenzo [ b ] [1,4] dioxan-6-yl) acryloyl chloride crude product which is directly used for the next reaction without further purification.
(2) Preparation of the title compound
5, 6-dihydro-2 (1H) -pyridone (69.8 mg,0.72 mmol) was dissolved in ultra-dry tetrahydrofuran, ice-cooled to 0deg.C under argon, and a 60% sodium hydride mineral oil mixture (0.031 g,0.79 mmol) was added in two portions and reacted for 40min under ice-bath conditions. The crude product of (E) -3- (2, 3-dihydrobenzo [ b ] [1,4] dioxan-6-yl) acryloyl chloride obtained in the last step is dissolved in 1ml of ultra-dry tetrahydrofuran, added into the system dropwise, and then moved to room temperature for reaction for 1h. After the reaction is completed, water is added for quenching, ethyl acetate is used for extraction, an ethyl acetate layer is washed twice by 10ml of saturated sodium chloride aqueous solution, then the solvent is removed by reduced pressure distillation, and the petroleum ether and ethyl acetate system are subjected to column chromatography separation to obtain 45mg of white solid, the yield is 32.8 percent, and the melting point is 72-73 ℃.
1 H NMR(700MHz,Chloroform-d)δ7.65(d,J＝15.6Hz,1H),7.37(d,J＝15.5Hz,1H),7.13–7.06(m,2H),6.93(dt,J＝9.2,4.2Hz,1H),6.85(d,J＝8.2Hz,1H),6.04(dt,J＝9.7,1.9Hz,1H),4.30–4.25(m,4H),4.03(t,J＝6.5Hz,2H),2.47(dq,J＝6.2,4.3,3.1Hz,2H).HRMS calcd.For C16H15NO4(M+H) + 286.10193,found286.10953.
Example 3
(E) -1- (3- (3-methoxy-4- (2- (tetrahydro-2H-pyran-4-yl) ethoxy) phenyl) acryloyl) -5, 6-dihydropyridin-2 (1H) one
(1) Preparation of (E) -3- (3-methoxy-4- (2- (tetrahydro-2H-pyran-4-yl) ethoxy) phenyl) acryloyl chloride
(E) -3- (3-methoxy-4- (2- (tetrahydro-2H-pyran-4-yl) ethoxy) phenyl) acrylic acid (0.100 g,0.32 mmol) was dissolved in ultra-dry dichloromethane, ice-cooled to 0deg.C under argon, oxalyl chloride (205.8 mg,1.6 mmol) and N, N-dimethylformamide (0.21 mg, 0.003mmol) were slowly added and then allowed to react for 3H at room temperature. After the raw materials are reacted completely, the solvent is removed by reduced pressure distillation to obtain (E) -3- (3-methoxy-4- (2- (tetrahydro-2H-pyran-4-yl) ethoxy) phenyl) acryloyl chloride crude product which is directly used for the next reaction without further purification.
(2) Preparation of the title compound
5, 6-dihydro-2 (1H) -pyridone (46.6 mg,0.48 mmol) was dissolved in ultra-dry tetrahydrofuran, ice-cooled to 0deg.C, and a 60% sodium hydride mineral oil mixture (0.014 g,0.35 mmol) was added in two portions and reacted for 40min under ice-bath conditions. The crude product of (E) -3- (3-methoxy-4- (2- (tetrahydro-2H-pyran-4-yl) ethoxy) phenyl) acryloyl chloride obtained in the previous step is dissolved in 1ml of ultra-dry tetrahydrofuran, added into the system dropwise, and then moved to room temperature for reaction for 1H. After the reaction is completed, water is added for quenching, ethyl acetate is used for extraction, an ethyl acetate layer is washed twice by 5ml of saturated sodium chloride aqueous solution, then the solvent is removed by reduced pressure distillation, and the petroleum ether and ethyl acetate system are subjected to column chromatography separation to obtain 40mg of white solid, the yield is 32.4 percent, and the melting point is 70-71 ℃.
1 H NMR(400MHz,Chloroform-d)δ7.70(m,1H),7.40(d,J＝15.9Hz,1H),7.11(s,2H),6.93(s,1H),6.85(s,1H),6.04(s,1H),4.00(m,9H),3.40(s,2H),2.47(s,2H),1.81(s,3H),1.67(s,2H),1.35(s,2H).HRMS calcd.For C22H27NO5(M+H) + 386.19622,found 386.19562.
Example 4
(E) -1- (3- (3-methoxy-4- (2-methoxyethoxy) phenyl) acryloyl) -5, 6-dihydropyridin-2 (1H) one
(1) Preparation of (E) -3- (3-methoxy-4- (2-methoxyethoxy) phenyl) acryloyl chloride
(E) -3- (3-methoxy-4- (2-methoxyethoxy) phenyl) acrylic acid (0.100 g,0.39 mmol) was dissolved in ultra-dry dichloromethane, ice-cooled to 0deg.C under argon, oxalyl chloride (251.7 mg,1.98 mmol) and N, N-dimethylformamide (0.24 mg, 0.04 mmol) were slowly added and then allowed to react for 3h at room temperature. After the raw materials are reacted completely, the solvent is removed by reduced pressure distillation to obtain the crude product of (E) -3- (3-methoxy-4- (2-methoxyethoxy) phenyl) acryloyl chloride, which is directly used for the next reaction without further purification.
(2) Preparation of the title compound
5, 6-dihydro-2 (1H) -pyridone (46.6 mg,0.48 mmol) was dissolved in ultra-dry tetrahydrofuran, ice-cooled to 0deg.C, and a 60% sodium hydride mineral oil mixture (0.014 g,0.35 mmol) was added in two portions and reacted for 40min under ice-bath conditions. The crude product of (E) -3- (3-methoxy-4- (2-methoxyethoxy) phenyl) acryloyl chloride obtained in the last step is dissolved in 1ml of ultra-dry tetrahydrofuran, added into the system dropwise, and then moved to room temperature for reaction for 1h. After the reaction was completed, water was added to quench, extraction was performed with ethyl acetate, the ethyl acetate layer was washed twice with 5ml of saturated aqueous sodium chloride solution, the solvent was removed by distillation under reduced pressure, and column chromatography was performed on the petroleum ether and ethyl acetate system to obtain 43mg of a white solid, yield 34.5%, melting point 72-73 ℃.
1 H NMR(400MHz,Chloroform-d)δ7.71(d,J＝15.5Hz,1H),7.41(d,J＝15.5Hz,1H),7.16–7.08(m,2H),6.94-6.87(m,2H),6.04(d,J＝9.7Hz,1H),4.20(s,2H),4.03(d,J＝6.8Hz,2H),3.89(s,3H),3.80(d,J＝5.2Hz,2H),3.45(d,J＝3.8Hz,3H),2.47(s,2H).HRMS calcd.For C18H21NO5(M+H) + 332.14865,found332.14925.
Example 5
1- (3-ethoxyphenyl) acryloyl-5, 6-dihydropyridin-2 (1H) one
(1) Preparation of (E) -3- (3-isopropoxyphenyl) acrylic acid
3-hydroxy cinnamic acid (2.0 g,12.19 mmol) was dissolved in 20ml acetonitrile: to a solution of water=1:1, 2-iodopropane (2.48 g,14.62 mmol) and potassium hydroxide (1.37 g,24.38 mmol) were added in this order and reacted at 90℃for 5h under argon. After the completion of the reaction, the pH was adjusted to 2-3 with 1M aqueous hydrochloric acid, extraction was performed with ethyl acetate, and the organic layer was washed twice with 25ml of saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. Concentrating, separating by column chromatography, eluting with ethyl acetate, and drying to obtain white solid 1.78g with yield of 70.8% and melting point of 112-114 ℃.
1 H NMR(400MHz,Chloroform-d)δ7.75(d,J＝15.9Hz,1H),7.34–7.26(m,1H),7.12(d,J＝7.7Hz,1H),7.06(s,1H),6.97–6.90(m,1H),6.43(d,J＝16.0Hz,1H),4.58(m,1H),1.36(m,6H).MS(ESI)m/z207.14(M+H) + .
(2) Preparation of (E) -3- (3-isopropoxyphenyl) acryloyl chloride
(E) -3- (3-isopropoxyphenyl) acrylic acid (2.8 g,13.58 mmol) was dissolved in ultra-dry dichloromethane, ice-bath was performed to 0℃under argon protection, oxalyl chloride (8.62 g,67.93 mmol) and N, N-dimethylformamide (9.9 mg,0.136 mmol) were slowly added, and then the mixture was allowed to react for 3 hours at room temperature. After the raw materials are reacted completely, the solvent is removed by reduced pressure distillation to obtain the crude product of (E) -3- (3-isopropoxyphenyl) acryloyl chloride, which is directly used for the next reaction without further purification. (3) Preparation of (E) -1- (3-isopropoxyphenyl) acryloyl-5, 6-dihydropyridin-2 (1H) one
5, 6-dihydro-2 (1H) -pyridone (1.18 g,12.22 mmol) was dissolved in ultra-dry tetrahydrofuran, ice-cooled to 0deg.C, and a 60% sodium hydride mineral oil mixture (356 mg,14.94 mmol) was added in two portions and reacted for 40min under ice-bath conditions. A solution of (E) -3- (3-isopropoxyphenyl) acryloyl chloride (2.8 g,13.58 mmol) in ultra-dry tetrahydrofuran was added dropwise to the system, followed by reaction at room temperature for 1h. After the reaction was completed, water was added to quench, extraction was performed with ethyl acetate, the ethyl acetate layer was washed twice with 10ml of saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, then the solvent was distilled off under reduced pressure, and column chromatography was performed on the petroleum ether and ethyl acetate system to obtain 1.2g of yellow oily substance, with a yield of 55.6%.
1 H NMR(400MHz,Chloroform-d)δ7.71(d,J＝15.5Hz,1H),7.49(d,J＝15.6,1H),7.31-7.23(m,1H),7.16(d,J＝7.6Hz,1H),7.10(d,J＝2.4Hz,1H),6.93(m,2H),6.05(m,1H),4.58(m,1H),4.05(t,J＝6.4Hz,2H),2.51-2.45(m,2H),1.35(m,6H).MS(ESI)m/z286.22(M+H) + .
(4) Preparation of 1- (3-hydroxyphenyl) acryloyl-5, 6-dihydropyridin-2 (1H) one
(E) -1- (3-isopropoxyphenyl) acryloyl-5, 6-dihydropyridin-2 (1H) one (750 mg,3.34 mmol) was dissolved in 20ml of ultra-dry dichloromethane and anhydrous aluminum trichloride (1.33 g,10.0 mmol) was added at 0deg.C and reacted for 2H. After the completion of the reaction, the pH was adjusted to 3-4 with 1M aqueous hydrochloric acid, extracted with methylene chloride, and the organic layer was washed twice with 10ml of saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. Concentrating, separating by column chromatography, eluting with ethyl acetate, and drying to obtain light yellow solid 800g with yield of 98.8% and melting point of 123-124 ℃.
1 H NMR(400MHz,Chloroform-d)δ7.67(dd,J＝15.6,1.8Hz,1H),7.44(dd,J＝15.7,1.8Hz,1H),7.24-7.16(m,1H),7.12-7.06(m,2H),6.94(m,1H),6.90-6.84(m,1H),6.04(dd,J＝9.7,1.9Hz,1H),4.03(td,J＝6.5,1.7Hz,2H),2.47(m,2H).MS(ESI)m/z244.07(M+H) + .
(5) Preparation of the title compound
Ethanol (17.06 mg,0.37 mmol), triphenylphosphine (97.05 mg,0.37 mmol) was added sequentially to a solution of 1- (3-hydroxyphenyl) acryloyl-5, 6-dihydropyridin-2 (1H) one (60.0 mg,0.25 mmol) in ultra-dry tetrahydrofuran, ice-cooled to 0deg.C, diisopropyl azodicarboxylate (74.8 mg,0.37 mmol) was added dropwise and the mixture was allowed to react at room temperature for 5H. After the completion of the reaction, water was added to quench, extraction was performed with ethyl acetate, and the organic layer was washed twice with 5ml of saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. Concentrating, separating by column chromatography, eluting with ethyl acetate, and drying to obtain white oily substance 20mg with a yield of 30.8%.
1 H NMR(400MHz,Chloroform-d)δ7.75–7.67(m,1H),7.53–7.45(m,1H),7.27(m,1H),7.16(d,J＝7.7Hz,1H),7.10(t,J＝2.1Hz,1H),6.97–6.87(m,2H),6.04(m,1H),4.12-4.01(m,4H),2.48-2.45(m,2H),1.42(t,J＝1.7Hz,3H).HRMS calcd.For C16H17NO3(M+H) + 272.12775,found 272.12812.
Example 6
(E) -1- (3- (3-propoxyphenyl) acryloyl) -5, 6-dihydropyridin-2 (1H) one
(1) Preparation of the title compound
1-propanol (18.2 mg,0.31 mmol), triphenylphosphine (81.3 mg,0.31 mmol) was added successively to a solution of 1- (3-hydroxyphenyl) acryloyl-5, 6-dihydropyridin-2 (1H) one (50.0 mg,0.21 mmol) in ultra-dry tetrahydrofuran, ice-cooled to 0℃and diisopropyl azodicarboxylate (62.7 mg,0.31 mmol) was added dropwise thereto and the mixture was allowed to react at room temperature for 5 hours. After the completion of the reaction, water was added to quench, extraction was performed with ethyl acetate, and the organic layer was washed twice with 5ml of saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. Concentrating, separating by column chromatography, eluting with ethyl acetate, and drying to obtain transparent oily substance 23mg with a yield of 26.0%.
1 H NMR(400MHz,Chloroform-d)δ7.71(dd,J＝15.5,2.8Hz,1H),7.48(dd,J＝15.6,2.8Hz,1H),7.27(m,1H),7.15(d,J＝7.7Hz,1H),7.10(s,1H),6.97–6.87(m,2H),6.08–6.01(m,1H),4.04(t,J＝6.4Hz,2H),3.94(t,J＝6.5Hz,2H),2.47(m,2H),1.81(m,2H),1.04(m,3H).HRMS calcd.For C17H19NO3(M+H) + 286.14377,found 286.14346.
Example 7
(E) -1- (3-isopropoxyphenyl) acryloyl-5, 6-dihydropyridin-2 (1H) one
(1) Preparation of the title compound
Isopropanol (18.2 mg,0.31 mmol), triphenylphosphine (81.3 mg,0.31 mmol) were added sequentially to a solution of 1- (3-hydroxyphenyl) acryloyl-5, 6-dihydropyridin-2 (1H) one (50.0 mg,0.21 mmol) in ultra-dry tetrahydrofuran, ice-cooled to 0deg.C, diisopropyl azodicarboxylate (62.7 mg,0.31 mmol) was added dropwise and the mixture was allowed to react at room temperature for 5H. After the completion of the reaction, water was added to quench, extraction was performed with ethyl acetate, and the organic layer was washed twice with 5ml of saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. Concentrating, separating by column chromatography, eluting with ethyl acetate, and drying to obtain yellow oily substance 25mg, with yield 28.3.0%.
1 H NMR(400MHz,Chloroform-d)δ7.71(d,J＝15.5Hz,1H),7.49(d,J＝15.6,1H),7.31–7.23(m,1H),7.16(d,J＝7.6Hz,1H),7.10(d,J＝2.4Hz,1H),6.93(m,2H),6.05(m,1H),4.58(m,1H),4.05(t,J＝6.4Hz,2H),2.51–2.45(m,2H),1.35(m,6H).HRMS calcd.For C17H19NO3(M+H) + 286.14377,found 286.14365.
Example 8
(E) -1- (3- (3- (cyclopropylmethoxy) phenyl) acryloyl) -5, 6-dihydropyridin-2 (1H) one
(1) Preparation of the title compound
Hydroxymethyl cyclopropane (22.7 mg,0.31 mmol), triphenylphosphine (81.3 mg,0.31 mmol) was added sequentially to a solution of 1- (3-hydroxyphenyl) acryloyl-5, 6-dihydropyridin-2 (1H) one (50.0 mg,0.21 mmol) in ultra-dry tetrahydrofuran, ice-cooled to 0deg.C, diisopropyl azodicarboxylate (62.7 mg,0.31 mmol) was added dropwise and the mixture was allowed to react at room temperature for 5H. After the completion of the reaction, water was added to quench, extraction was performed with ethyl acetate, and the organic layer was washed twice with 5ml of saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. Concentrating, separating by column chromatography, eluting with ethyl acetate, and drying to obtain transparent oily substance 27mg, with a yield of 29.3.0%.
1 H NMR(400MHz,Chloroform-d)δ7.71(dd,J＝15.6,3.4Hz,1H),7.49(dd,J＝15.6,3.4Hz,1H),7.27(p,J＝4.3Hz,1H),7.19–7.14(m,1H),7.11(s,1H),6.94(m,2H),6.08–6.01(m,1H),4.06-4.02(m,2H),3.83(m,2H),2.50-2.45(m,2H),1.28(s,1H),0.65(q,J＝3.8Hz,2H),0.37(d,J＝4.7Hz,2H).HRMS calcd.For C18H19NO3(M+H) + 298.14377,found 298.14345.
Example 9
(E) -1- (3- (3- (cyclobutylmethoxy) phenyl) acryloyl) -5, 6-dihydropyridin-2 (1H) one
(1) Preparation of the title compound
Cyclobutylmethanol (31.9 mg,0.37 mmol), triphenylphosphine (97.1 mg,0.37 mmol) was added sequentially to a solution of 1- (3-hydroxyphenyl) acryloyl-5, 6-dihydropyridin-2 (1H) one (60.0 mg,0.25 mmol) in ultra-dry tetrahydrofuran, ice-cooled to 0deg.C, diisopropyl azodicarboxylate (72.9 mg,0.37 mmol) was added dropwise and the mixture was allowed to react at room temperature for 5H. After the completion of the reaction, water was added to quench, extraction was performed with ethyl acetate, and the organic layer was washed twice with 5ml of saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. Concentrating, separating by column chromatography, eluting with ethyl acetate, and drying to obtain transparent oily substance 25mg with yield of 32.1% and melting point of 80-81 ℃.
1 H NMR(700MHz,Chloroform-d)δ7.71(dd,J＝15.6,1.9Hz,1H),7.49(dd,J＝15.6,1.9Hz,1H),7.29–7.25(m,1H),7.11(d,J＝2.5Hz,1H),6.96–6.89(m,2H),6.07–6.03(m,1H),4.04(td,J＝6.5,2.0Hz,2H),3.94(dd,J＝6.5,1.9Hz,2H),2.77(m,1H),2.48(m,2H),2.18–2.11(m,2H),1.99–1.85(m,4H).HRMS calcd.For C19H21NO3(M+H) + 312.15942,found 312.15887.
Example 10
(E) -1- (3- (3- (2-methoxyethoxy) phenyl) acryloyl) -5, 6-dihydropyridin-2 (1H) one
(1) Preparation of the title compound
Ethylene glycol methyl ether (28.17 mg,0.37 mmol), triphenylphosphine (97.1 mg,0.37 mmol) was added sequentially to a solution of 1- (3-hydroxyphenyl) acryloyl-5, 6-dihydropyridin-2 (1H) one (60.0 mg,0.25 mmol) in ultra-dry tetrahydrofuran, ice-cooled to 0deg.C, diisopropyl azodicarboxylate (72.9 mg,0.37 mmol) was added dropwise and the mixture was allowed to react at room temperature for 5H. After the completion of the reaction, water was added to quench, extraction was performed with ethyl acetate, and the organic layer was washed twice with 5ml of saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. Concentrating, separating by column chromatography, eluting with ethyl acetate, and drying to obtain transparent oily substance 24mg with a yield of 31.9%.
1 H NMR(400MHz,Chloroform-d)δ7.70(dd,J＝15.8,2.4Hz,1H),7.48(dd,J＝15.5,2.4Hz,1H),7.30–7.23(m,1H),7.18(d,J＝7.7Hz,1H),7.13(s,1H),6.94(d,J＝8.5Hz,2H),6.04(d,J＝9.7Hz,1H),4.14(p,J＝2.6Hz,2H),4.04(td,J＝6.6,2.3Hz,2H),3.76(dt,J＝6.1,2.7Hz,2H),3.46(d,J＝2.4Hz,3H),2.47(d,J＝7.7Hz,2H).HRMS calcd.For C17H19NO4(M+H) + 302.13868,found 302.13831.
Example 11
(E) -1- (3- (3- (3-methoxypropoxy) phenyl) acryloyl) -5, 6-dihydropyridin-2 (1H) one
(1) Preparation of the title compound
3-methoxy-1-propanol (25.23 mg,0.28 mmol), triphenylphosphine (73.4 mg,0.28 mmol) was added sequentially to a solution of 1- (3-hydroxyphenyl) acryloyl-5, 6-dihydropyridin-2 (1H) one (46.0 mg,0.19 mmol) in ultra-dry tetrahydrofuran, ice-cooled to 0deg.C, diisopropyl azodicarboxylate (56.6 mg,0.28 mmol) was added dropwise, and the mixture was allowed to react at room temperature for 5H. After the completion of the reaction, water was added to quench, extraction was performed with ethyl acetate, and the organic layer was washed twice with 5ml of saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. Concentrating, separating by column chromatography, eluting with ethyl acetate, and drying to obtain transparent oily substance 25mg with yield of 41.7%.
1 H NMR(400MHz,Chloroform-d)δ7.71(d,J＝15.6Hz,1H),7.48(d,J＝15.6Hz,1H),7.31–7.23(m,1H),7.16(d,J＝7.6Hz,1H),7.11(s,1H),6.92(m,2H),6.08–6.01(m,1H),4.06(m,4H),3.56(t,J＝6.1Hz,2H),3.36(s,3H),2.48(q,J＝5.8Hz,2H),2.05(p,J＝6.3Hz,2H).HRMS calcd.For C18H21NO4(M+H) + 316.15433,found 316.15393.
Example 12
(E) -1- (3- (3- (oxetan-3-ylmethoxy) phenyl) acryloyl) -5, 6-dihydropyridin-2 (1H) one
(1) Preparation of the title compound
Cyclobutylmethanol (33.0 mg,0.37 mmol), triphenylphosphine (98.1 mg,0.37 mmol) was added sequentially to a solution of 1- (3-hydroxyphenyl) acryloyl-5, 6-dihydropyridin-2 (1H) one (60.0 mg,0.25 mmol) in ultra-dry tetrahydrofuran, ice-cooled to 0deg.C, diisopropyl azodicarboxylate (72.9 mg,0.37 mmol) was added dropwise and the mixture was allowed to react at room temperature for 5H. After the completion of the reaction, water was added to quench, extraction was performed with ethyl acetate, and the organic layer was washed twice with 5ml of saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. Concentrating, separating by column chromatography, eluting with ethyl acetate, and drying to obtain 47mg of transparent oily substance with a yield of 60.1%.
1 H NMR(400MHz,Chloroform-d)δ7.70(d,J＝15.6Hz,1H),7.49(dd,J＝15.7,1.8Hz,1H),7.31–7.25(m,1H),7.18(d,J＝7.7Hz,1H),7.12(s,1H),6.94(m,2H),6.04(m,1H),4.88(m,2H),4.58(m,2H),4.22(d,J＝6.7Hz,2H),4.04(t,J＝6.5Hz,2H),3.43(m,1H),2.54–2.41(m,2H).HRMS calcd.For C18H19NO4(M+H) + 314.13868,found 314.13812.
Example 13
(E) -1- (3- (3- ((tetrahydrofuran-3-yl) methoxy) phenyl) acryloyl) -5, 6-dihydropyridin-2 (1H) one
(1) Preparation of the title compound
3-Tetrahydrofuranmethanol (38.3 mg,0.37 mmol), triphenylphosphine (97.1 mg,0.37 mmol) was added sequentially to a solution of 1- (3-hydroxyphenyl) acryloyl-5, 6-dihydropyridin-2 (1H) one (60.0 mg,0.25 mmol) in ultra-dry tetrahydrofuran, ice-cooled to 0deg.C, diisopropyl azodicarboxylate (72.9 mg,0.37 mmol) was added dropwise and the mixture was allowed to react at room temperature for 5H. After the completion of the reaction, water was added to quench, extraction was performed with ethyl acetate, and the organic layer was washed twice with 5ml of saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. Concentrating, separating by column chromatography, eluting with ethyl acetate, and drying to obtain transparent oily substance 17mg with 20.7% yield.
1 H NMR(400MHz,Chloroform-d)δ7.70(dd,J＝15.6,2.1Hz,1H),7.48(dd,J＝15.6,2.1Hz,1H),7.32–7.24(m,1H),7.18-7.14(m,1H),7.10-7.01(m,1H),6.96-6.86(m,2H),6.06-6.01(m,1H),4.04(td,J＝6.5,2.0Hz,2H),3.99–3.85(m,4H),3.79(m,1H),3.70(m,1H),2.74(m,1H),2.50–2.45(m,2H),2.12(m,1H),1.75(m,1H).HRMS calcd.For C19H21NO4(M+H) + 328.15433,found 328.1539.
Example 14
(E) -1- (3- (3- ((tetrahydropyran-4-yl) methoxy) phenyl) acryloyl) -5, 6-dihydropyridin-2 (1H) one
(1) Preparation of the title compound
Ethylene glycol methyl ether (32.98 mg,0.28 mmol), triphenylphosphine (73.4 mg,0.28 mmol) was added sequentially to a solution of 1- (3-hydroxyphenyl) acryloyl-5, 6-dihydropyridin-2 (1H) one (46.0 mg,0.19 mmol) in ultra-dry tetrahydrofuran, ice-cooled to 0℃and diisopropyl azodicarboxylate (56.6 mg,0.28 mmol) was added dropwise thereto and the mixture was allowed to react at room temperature for 5 hours. After the completion of the reaction, water was added to quench, extraction was performed with ethyl acetate, and the organic layer was washed twice with 5ml of saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. Concentrating, separating by column chromatography, eluting with ethyl acetate, and drying to obtain white oily substance 24mg with a yield of 37.9%.
1 H NMR(400MHz,Chloroform-d)δ7.71(d,J＝15.7Hz,1H),7.49(d,J＝15.6Hz,1H),7.27(d,J＝6.6Hz,1H),7.16(d,J＝7.6Hz,1H),7.09(s,1H),6.99-6.87(m,2H),6.05(d,J＝9.7Hz,1H),4.03(m,4H),3.83(d,J＝6.5Hz,2H),3.45(t,J＝11.4Hz,2H),2.48(d,J＝6.1Hz,2H),2.06(s,2H),1.77(m,2H),1.51–1.43(m,1H).HRMS calcd.For C20H23NO4(M+H) + 342.16998,found 342.16983.
Example 15
(E) -1- (3- (3- (2- (tetrahydro-2H-pyran-4-yl) ethoxy) phenyl) acryloyl) -5, 6-dihydropyridin-2 (1H) one
(1) Preparation of the title compound
2-tetrahydropyran-4-ethanol (48.8 mg,0.37 mmol), triphenylphosphine (97.1 mg,0.37 mmol) was added sequentially to a solution of 1- (3-hydroxyphenyl) acryloyl-5, 6-dihydropyridin-2 (1H) one (60.0 mg,0.25 mmol) in ultra-dry tetrahydrofuran, ice-cooled to 0deg.C, diisopropyl azodicarboxylate (72.9 mg,0.37 mmol) was added dropwise and the mixture was allowed to react at room temperature for 5H. After the completion of the reaction, water was added to quench, extraction was performed with ethyl acetate, and the organic layer was washed twice with 5ml of saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. Concentrating, separating by column chromatography, eluting with ethyl acetate, and drying to obtain white solid 23mg with yield of 25.9% and melting point of 90-91 ℃.
1 H NMR(400MHz,Chloroform-d)δ7.72(dd,J＝15.6,4.3Hz,1H),7.50(dd,J＝15.7,4.3Hz,1H),7.30–7.24(m,1H),7.14(d,J＝25.1Hz,2H),6.94(dt,J＝15.1,4.4Hz,2H),6.08–6.02(m,1H),4.11–3.90(m,6H),3.42(m,2H),2.51–2.47(m,2H),1.77–1.60(m,3H),1.53(m,2H),1.33(m,2H).HRMS calcd.For C21H25NO4(M+H) + 356.18563,found 356.18573.
Example 16
(E) -1- (3- (3- (cyclohexylmethoxy) phenyl) acryloyl) -5, 6-dihydropyridin-2 (1H) one
(1) Preparation of the title compound
Cyclohexanemethanol (42.25 mg,0.37 mmol), triphenylphosphine (97.1 mg,0.37 mmol) were added sequentially to a solution of 1- (3-hydroxyphenyl) acryloyl-5, 6-dihydropyridin-2 (1H) one (60.0 mg,0.25 mmol) in ultra-dry tetrahydrofuran, ice-cooled to 0deg.C, diisopropyl azodicarboxylate (72.9 mg,0.37 mmol) was added dropwise and the mixture was allowed to react at room temperature for 5H. After the completion of the reaction, water was added to quench, extraction was performed with ethyl acetate, and the organic layer was washed twice with 5ml of saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. Concentrating, separating by column chromatography, eluting with ethyl acetate, and drying to obtain white solid 18mg, with yield of 21.2% and melting point of 80-81 ℃.
1 H NMR(400MHz,Chloroform-d)δ7.72(d,J＝15.7Hz,1H),7.53–7.45(m,1H),7.28–7.23(m,1H),7.15(d,J＝7.8Hz,1H),7.10(s,1H),6.91(m,2H),6.05(d,J＝9.8Hz,1H),4.04(dt,J＝6.4,3.6Hz,2H),3.80–3.75(m,2H),2.48(s,2H),1.91-1.82(m,2H),1.81-1.66(m,3H),1.38-1.18(m,4H),1.17-1.03(m,2H).HRMS calcd.For C21H25NO3(M+H) + 340.19072,found 340.19019.
Example 17
(E) -1- (3- (3- (2- (diethylamino) ethoxy) phenyl) acryloyl) -5, 6-dihydropyridin-2 (1H) one
(1) Preparation of the title compound
Diethylaminoethanol (57.2 mg,0.49 mmol), triphenylphosphine (147.1 mg,0.56 mmol) were added sequentially to a solution of 1- (3-hydroxyphenyl) acryloyl-5, 6-dihydropyridin-2 (1H) one (80.0 mg,0.33 mmol) in ultra-dry tetrahydrofuran, ice-cooled to 0℃and diisopropyl azodicarboxylate (99.8 mg,0.49 mmol) was added dropwise and the mixture was allowed to react at room temperature for 5H. After the completion of the reaction, water was added to quench, extraction was performed with ethyl acetate, and the organic layer was washed twice with 5ml of saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. Concentrating, separating by column chromatography, eluting with ethyl acetate, and drying to obtain light yellow oily substance 45mg with 39.8% yield.
1 H NMR(500MHz,Chloroform-d)δ7.72–7.65(m,1H),7.49–7.42(m,1H),7.28–7.22(m,1H),7.17–7.12(m,1H),7.11–7.06(m,1H),6.96–6.87(m,2H),6.02(dt,J＝9.7,1.8Hz,1H),4.11–3.99(m,4H),2.86(t,J＝6.2Hz,2H),2.62(t,J＝7.1Hz,4H),2.46(m,2H),1.06(t,J＝7.1Hz,6H).HRMS calcd.For C20H26N2O3(M+H) + 343.20162,found 343.20117.
Example 18
(E) -1- (3- (3- (2- (pyrrolidin-1-yl) ethoxy) phenyl) acryloyl) -5, 6-dihydropyridin-2 (1H) one
(1) Preparation of the title compound
N- (2-hydroxyethyl) -pyrrolidine (56.4 mg,0.49 mmol), triphenylphosphine (147.1 mg,0.56 mmol) was added sequentially to a solution of 1- (3-hydroxyphenyl) acryloyl-5, 6-dihydropyridin-2 (1H) one (80.0 mg,0.33 mmol) in ultra-dry tetrahydrofuran, ice-cooled to 0deg.C, diisopropyl azodicarboxylate (99.8 mg,0.49 mmol) was added dropwise and the mixture was allowed to react at room temperature for 5H. After the completion of the reaction, water was added to quench, extraction was performed with ethyl acetate, and the organic layer was washed twice with 5ml of saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. Concentrating, separating by column chromatography, eluting with ethyl acetate, and drying to obtain light yellow oily substance 33mg with 29.4% yield.
1 H NMR(500MHz,Chloroform-d)δ7.68(d,J＝15.6Hz,1H),7.46(d,J＝15.6Hz,1H),7.29–7.22(m,1H),7.17–7.05(m,2H),6.95–6.88(m,2H),6.02(dt,J＝9.7,1.8Hz,1H),4.11(t,J＝5.9Hz,2H),4.02(t,J＝6.5Hz,2H),2.89(t,J＝5.9Hz,2H),2.65–2.59(m,4H),2.46(m,2H),1.83–1.77(m,4H).HRMS calcd.For C20H24N2O3(M+H) + 341.18597,found 341.18564.
Example 19
(E) -1- (3- (3- (2- (piperidin-1-yl) ethoxy) phenyl) acryloyl) -5, 6-dihydropyridin-2 (1H) one
(1) Preparation of the title compound
N-hydroxyethyl piperidine (53.2 mg,0.41 mmol), triphenylphosphine (93.6 mg,0.35 mmol) was added sequentially to a solution of 1- (3-hydroxyphenyl) acryloyl-5, 6-dihydropyridin-2 (1H) one (50.0 mg,0.21 mmol) in ultra-dry tetrahydrofuran, ice-cooled to 0deg.C, diisopropyl azodicarboxylate (63.7 mg,0.31 mmol) was added dropwise and the reaction was allowed to proceed to room temperature for 5H. After the completion of the reaction, water was added to quench, extraction was performed with ethyl acetate, and the organic layer was washed twice with 5ml of saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. Concentrating, separating by column chromatography, eluting with ethyl acetate, and drying to obtain light yellow oily substance 24mg with yield of 32.9%.
1 H NMR(500MHz,Chloroform-d)δ7.68(d,J＝15.6Hz,1H),7.46(d,J＝15.6Hz,1H),7.29–7.22(m,1H),7.18–7.13(m,1H),7.09(dd,J＝2.6,1.6Hz,1H),6.96–6.87(m,2H),6.03(dt,J＝9.7,1.9Hz,1H),4.13(t,J＝6.0Hz,2H),4.02(t,J＝6.5Hz,2H),2.79(t,J＝6.0Hz,2H),2.55–2.51(m,4H),2.46(m,2H),1.62(m,4H),1.45(m,2H).HRMS calcd.For C21H26N2O3(M+H) + 355.20162,found 355.20123.
Example 20
(3- (3-oxo-3- (6-oxo-3, 6-dihydropyridin-1 (2H) -yl) propen-1-yl) phenoxy) methylpiperidine-1-carboxylic acid tert-butyl ester
(1) Preparation of the title compound
N-Boc-4-piperidinemethanol (491.5 mg,2.28 mmol), triphenylphosphine (677.7 mg,2.58 mmol) was added sequentially to a solution of 1- (3-hydroxyphenyl) acryloyl-5, 6-dihydropyridin-2 (1H) one (370 mg,1.52 mmol) in ultra-dry tetrahydrofuran, ice-cooled to 0deg.C, diisopropyl azodicarboxylate (461.1 mg,2.28 mmol) was added dropwise, and the mixture was allowed to react at room temperature for 5H. After the completion of the reaction, water was added to quench, extraction was performed with ethyl acetate, and the organic layer was washed twice with 5ml of saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. Concentrating, separating by column chromatography, eluting with ethyl acetate, and drying to obtain transparent oily substance 280mg with yield of 41.8%.
1 H NMR(700MHz,Chloroform-d)δ7.71(d,J＝15.6Hz,1H),7.48(d,J＝15.7Hz,1H),7.27(d,J＝8.9Hz,1H),7.16(d,J＝7.5Hz,1H),7.09(t,J＝2.0Hz,1H),6.95(m,1H),6.89(m,1H),6.05(d,1.8Hz,1H),4.16(m,2H),4.04(t,J＝6.4Hz,2H),3.82(d,J＝6.3Hz,2H),2.75(m,2H),2.48(m,2H),1.96(m,1H),1.85–1.81(m,2H),1.47(d,J＝1.4Hz,9H),1.28–1.26(m,2H).HRMS calcd.For C25H32N2O5(M+H) + 441.2319,found 441.2395.
Example 21
(E) -1- (3- (3- (2-morpholinoethoxy) phenyl) acryloyl) -5, 6-dihydropyridin-2 (1H) one
(1) Preparation of the title compound
2-morpholinoethanol (41.3 mg,0.31 mmol), triphenylphosphine (82.6 mg,0.31 mmol) was added sequentially to a solution of 1- (3-hydroxyphenyl) acryloyl-5, 6-dihydropyridin-2 (1H) one (50.0 mg,0.21 mmol) in ultra-dry tetrahydrofuran, ice-cooled to 0℃and diisopropyl azodicarboxylate (63.7 mg,0.31 mmol) was added dropwise thereto and the mixture was allowed to react at room temperature for 5 hours. After the completion of the reaction, water was added to quench, extraction was performed with ethyl acetate, and the organic layer was washed twice with 5ml of saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. Concentrating, separating by column chromatography, eluting with ethyl acetate, and drying to obtain 33mg of transparent oily substance with 44.1% yield.
1 H NMR(500MHz,Chloroform-d)δ7.68(d,J＝15.6Hz,1H),7.47(d,J＝15.6Hz,1H),7.30–7.23(m,1H),7.15(dp,J＝7.5,0.7Hz,1H),7.10(dd,J＝2.5,1.6Hz,1H),6.96–6.87(m,2H),6.03(dt,J＝9.7,1.8Hz,1H),4.12(t,J＝5.7Hz,2H),4.02(t,J＝6.5Hz,2H),3.78–3.70(m,4H),2.80(t,J＝5.6Hz,2H),2.58(t,J＝4.7Hz,4H),2.46(tdd,J＝6.3,4.2,1.9Hz,2H).HRMS calcd.For C20H24N2O4(M+H) + 357.18088,found 357.1803.
Example 22
(E) -1- (3- (3- (morpholinylpropoxy) phenyl) acryloyl) -5, 6-dihydropyridin-2 (1H) one
(1) Preparation of the title compound
3- (4-morpholino) -1-propanol (24.5 mg,0.15 mmol) and potassium carbonate (52.0 mg,0.42 mmol) were successively added to a solution of 1- (3-hydroxyphenyl) acryloyl-5, 6-dihydropyridin-2 (1H) one (30.0 mg,0.13 mmol) in acetonitrile and reacted at 60℃for 5H. After the completion of the reaction, water was added to quench, extraction was performed with ethyl acetate, and the organic layer was washed twice with 5ml of saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. Concentrating, separating by column chromatography, eluting with ethyl acetate, and drying to obtain transparent oily substance 12mg with a yield of 27.0%.
1 H NMR(500MHz,Chloroform-d)δ7.69(d,J＝15.6Hz,1H),7.47(d,J＝15.6Hz,1H),7.29–7.23(m,1H),7.17–7.12(m,1H),7.09(dd,J＝2.5,1.6Hz,1H),6.97–6.86(m,2H),6.03(dt,J＝9.7,1.8Hz,1H),4.03(td,J＝6.3,2.1Hz,4H),3.73(s,4H),2.57–2.43(m,8H),1.98(d,J＝6.1Hz,2H).HRMS calcd.For C21H26N2O4(M+H) + 371.19653,found 371.19604.
Example 23
(E) -1- (3- (3- (2- (4-methylpiperazin-1-yl) ethoxy) phenyl) propenoyl) -5, 6-dihydropyridin-2 (1H) one
(1) Preparation of the title compound
1-hydroxyethyl-4-methylpiperazine (70.66 mg,0.49 mmol), triphenylphosphine (147.1 mg,0.56 mmol) were added sequentially to a solution of 1- (3-hydroxyphenyl) acryloyl-5, 6-dihydropyridin-2 (1H) one (80.0 mg,0.33 mmol) in ultra-dry tetrahydrofuran, ice-cooled to 0deg.C, diisopropyl azodicarboxylate (99.8 mg,0.49 mmol) was added dropwise, and the mixture was allowed to react at room temperature for 5H. After the completion of the reaction, water was added to quench, extraction was performed with ethyl acetate, and the organic layer was washed twice with 5ml of saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. Concentrating, separating by column chromatography, eluting with ethyl acetate, and drying to obtain transparent oily substance 43mg with 35.3% yield.
1 H NMR(500MHz,Chloroform-d)δ7.68(d,J＝15.5Hz,1H),7.46(d,J＝15.6Hz,1H),7.29–7.21(m,1H),7.19–7.10(m,1H),7.11–7.07(m,1H),6.96–6.89(m,2H),6.03(m,1.9Hz,1H),4.11(td,J＝5.8,1.7Hz,2H),4.02(t,J＝6.5Hz,2H),2.81(t,J＝5.8Hz,2H),2.62(s,4H),2.46(m,4H).HRMS calcd.For C21H27N3O3(M+H) + 370.21252,found 370.21219.
Example 24
(E) -N- (2- (3- (3-oxo-3- (6-oxo-3, 6-dihydropyridin-1 (2H) -yl) prop-1-en-1-yl) phenoxy) ethyl) pyridine carboxamide
(1) Preparation of the title compound
N- (2-hydroxyethyl) pyridine carboxamide (52.2 mg,0.31 mmol), triphenylphosphine (82.6 mg,0.31 mmol) was added sequentially to a solution of 1- (3-hydroxyphenyl) acryloyl-5, 6-dihydropyridin-2 (1H) one (50.0 mg,0.21 mmol) in ultra-dry tetrahydrofuran, ice-cooled to 0deg.C, diisopropyl azodicarboxylate (63.7 mg,0.31 mmol) was added dropwise and the mixture was allowed to react at room temperature for 5H. After the completion of the reaction, water was added to quench, extraction was performed with ethyl acetate, and the organic layer was washed twice with 5ml of saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. Concentrating, separating by column chromatography, eluting with ethyl acetate, and drying to obtain transparent oily substance 24mg with 29.2% yield.
1 H NMR(400MHz,Chloroform-d)δ8.58(d,J＝4.8Hz,1H),8.22(d,J＝7.8Hz,1H),7.86(td,J＝7.8,1.7Hz,1H),7.70(d,J＝15.6Hz,1H),7.52–7.40(m,2H),7.33–7.24(m,1H),7.18(d,J＝7.7Hz,1H),7.14(s,1H),6.94(m,2H),6.08–6.01(m,1H),4.19(t,J＝5.2Hz,2H),4.04(t,J＝6.5Hz,2H),3.91(q,J＝5.5Hz,2H),2.51–2.45(m,2H).HRMS calcd.For C22H21N3O4(M+H) + 392.16048,found392.15988.
Example 25
(E) -1- (3- (3- (2- (2-oxopyrrolidin-1-yl) ethoxy) phenyl) acryloyl) -5, 6-dihydropyridin-2 (1H) one
(1) Preparation of the title compound
N- (2-hydroxyethyl) -2-pyrrolidone (63.3 mg,0.49 mmol), triphenylphosphine (147.2 mg,0.56 mmol) was added sequentially to a solution of 1- (3-hydroxyphenyl) acryloyl-5, 6-dihydropyridin-2 (1H) one (80.0 mg,0.33 mmol) in ultra-dry tetrahydrofuran, ice-bath to 0deg.C, diisopropyl azodicarboxylate (99.8 mg,0.49 mmol) was added dropwise and the mixture was allowed to react at room temperature for 5H. After the completion of the reaction, water was added to quench, extraction was performed with ethyl acetate, and the organic layer was washed twice with 5ml of saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. Concentrating, separating by column chromatography, eluting with ethyl acetate, and drying to obtain transparent oily substance 44mg with a yield of 37.6%.
1 H NMR(400MHz,Chloroform-d)δ7.70(d,J＝15.8Hz,1H),7.48(d,J＝15.7Hz,1H),7.30(d,J＝8.4Hz,1H),7.18(d,J＝7.7Hz,1H),7.09(s,1H),6.96–6.86(m,2H),6.05(d,J＝9.7Hz,1H),4.14(t,J＝5.2Hz,2H),4.04(t,J＝6.4Hz,2H),3.70(d,J＝5.3Hz,2H),3.60(t,J＝7.1Hz,2H),2.49(s,2H),2.41(t,J＝8.1Hz,2H),2.06–2.02(m,2H).HRMS calcd.For C20H22N2O4(M+H) + 355.16523,found355.16476.
Example 26
(E) -1- (3- (3- (4-ylmethoxypyridine) phenyl) acryloyl) -5, 6-dihydropyridin-2 (1H) one
(1) Preparation of the title compound
4-hydroxymethylpyridine (53.47 mg,0.33 mmol), triphenylphosphine (147.2 mg,0.56 mmol) were added sequentially to a solution of 1- (3-hydroxyphenyl) acryloyl-5, 6-dihydropyridin-2 (1H) one (80.0 mg,0.33 mmol) in ultra-dry tetrahydrofuran, ice-cooled to 0deg.C, diisopropyl azodicarboxylate (99.8 mg,0.49 mmol) was added dropwise and the mixture was allowed to react at room temperature for 5H. After the completion of the reaction, water was added to quench, extraction was performed with ethyl acetate, and the organic layer was washed twice with 5ml of saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. Concentrating, separating by column chromatography, eluting with ethyl acetate, and drying to obtain white solid 32mg with yield of 29.0% and melting point of 122-123 ℃.
1 H NMR(400MHz,Chloroform-d)δ8.66(s,2H),7.70(d,J＝15.7Hz,1H),7.49(m,3H),7.32(t,J＝8.0Hz,1H),7.23(d,J＝7.7Hz,1H),7.17(s,1H),6.96(t,J＝6.9Hz,2H),6.06(m,1H),5.17(s,2H),4.05(t,J＝6.4Hz,2H),2.49(s,2H).HRMS calcd.For C20H18N2O3(M+H) + 335.13902,found 335.13889.
Example 27
(E) -1- (3- (3- (2- (pyridin-3-yl) ethoxy) phenyl) acryloyl) -5, 6-dihydropyridin-2 (1H) one
(1) Preparation of the title compound
2- (3-pyridyl) ethanol (30.4 mg,0.25 mmol), triphenylphosphine (71.3 mg,0.27 mmol) was added sequentially to a solution of 1- (3-hydroxyphenyl) acryloyl-5, 6-dihydropyridin-2 (1H) one (40.0 mg,0.16 mmol) in ultra-dry tetrahydrofuran, ice-cooled to 0deg.C, diisopropyl azodicarboxylate (50.5 mg,0.25 mmol) was added dropwise and the mixture was allowed to react at room temperature for 5H. After the completion of the reaction, water was added to quench, extraction was performed with ethyl acetate, and the organic layer was washed twice with 5ml of saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. Concentrating, separating by column chromatography, eluting with ethyl acetate, and drying to obtain transparent oily substance 24mg with a yield of 43.1%.
1 H NMR(400MHz,Chloroform-d)δ8.58(s,1H),8.51(s,1H),7.74-7.64(m,3H),7.49-7.45(d,J＝14.8Hz,1H),7.31(d,J＝8.1Hz,1H),7.17(d,J＝7.7Hz,1H),7.09(s,1H),6.98-6.87(m,2H),6.07-6.02(s,1H),4.22(t,J＝6.4Hz,2H),4.04(t,J＝6.3Hz,2H),3.13(d,J＝6.6Hz,2H),2.48(s,2H).HRMS calcd.For C21H20N2O3(M+H) + 349.15467,found 349.15408.
Example 28
(E) -1- (3- (3- (pyridazin-4-ylmethoxy) phenyl) acryloyl) -5, 6-dihydropyridin-2 (1H) one
(1) Preparation of the title compound
4-Pyridazinemethanol (27.5 mg,0.25 mmol), triphenylphosphine (71.3 mg,0.27 mmol) was added successively to a solution of 1- (3-hydroxyphenyl) acryloyl-5, 6-dihydropyridin-2 (1H) one (40.0 mg,0.16 mmol) in ultra-dry tetrahydrofuran, ice-cooled to 0℃and diisopropyl azodicarboxylate (50.5 mg,0.25 mmol) was added dropwise thereto and the mixture was allowed to react at room temperature for 5 hours. After the completion of the reaction, water was added to quench, extraction was performed with ethyl acetate, and the organic layer was washed twice with 5ml of saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. Concentrating, separating by column chromatography, eluting with ethyl acetate, and drying to obtain white solid 23mg with yield of 42.9% and melting point of 160-161 ℃.
1 H NMR(400MHz,Chloroform-d)δ9.30(s,1H),9.23(s,1H),7.74–7.60(m,2H),7.49(d,J＝15.9Hz,1H),7.31(d,J＝7.6Hz,2H),7.17(s,1H),6.96(s,2H),6.04(d,J＝9.9Hz,1H),5.16(s,2H),4.04(m,2H),2.48(m,2H).HRMS calcd.For C19H17N3O3(M+H) + 336.13192,found 336.13952.
Example 29
(E) -1- (3- (3- (thiophen-3-ylmethoxy) phenyl) acryloyl) -5, 6-dihydropyridin-2 (1H) one
(1) Preparation of the title compound
3-thiophenecanol (24.6 mg,0.25 mmol), triphenylphosphine (71.3 mg,0.27 mmol) was successively added to a solution of 1- (3-hydroxyphenyl) acryloyl-5, 6-dihydropyridin-2 (1H) one (40.0 mg,0.16 mmol) in ultra-dry tetrahydrofuran, and diisopropyl azodicarboxylate (50.5 mg,0.25 mmol) was added dropwise to the solution in ice bath to 0℃and allowed to react at room temperature for 5 hours. After the completion of the reaction, water was added to quench, extraction was performed with ethyl acetate, and the organic layer was washed twice with 5ml of saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. Concentrating, separating by column chromatography, eluting with ethyl acetate, and drying to obtain transparent oily substance 17mg with a yield of 21.0%.
1 H NMR(400MHz,Chloroform-d)δ7.71(d,J＝15.6Hz,1H),7.49(d,J＝15.7Hz,1H),7.34(s,2H),7.30(d,J＝8.0Hz,1H),7.19(d,J＝7.5Hz,3H),7.01–6.91(m,2H),6.05(d,J＝9.7Hz,1H),5.10(s,2H),4.04(t,J＝6.5Hz,2H),2.48(d,J＝5.7Hz,2H).HRMS calcd.For C19H17NO3S(M+H) + 340.10019,found 340.09946.
Example 30
(E) -1- (3- (3- (3-fluoropyridin-4-yl) methoxy) phenyl) acryloyl) -5, 6-dihydropyridin-2 (1H) one
(1) Preparation of the title compound
(3-Fluoropyridin-4-yl) methanol (31.8 mg,0.25 mmol), triphenylphosphine (71.3 mg,0.27 mmol) was added sequentially to a solution of 1- (3-hydroxyphenyl) acryloyl-5, 6-dihydropyridin-2 (1H) one (40.0 mg,0.16 mmol) in ultra-dry tetrahydrofuran, ice-cooled to 0℃and diisopropyl azodicarboxylate (50.5 mg,0.25 mmol) was added dropwise and the mixture was allowed to react at room temperature for 5H. After the completion of the reaction, water was added to quench, extraction was performed with ethyl acetate, and the organic layer was washed twice with 5ml of saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. Concentrating, separating by column chromatography, eluting with ethyl acetate, and drying to obtain white solid 23mg with yield of 40.8% and melting point of 92-93 ℃.
1 H NMR(400MHz,Chloroform-d)δ8.51–8.44(m,2H),7.70(d,J＝15.7Hz,1H),7.55(s,1H),7.49(dd,J＝15.6,2.5Hz,1H),7.36–7.20(m,2H),7.19(s,1H),6.96(t,J＝9.4Hz,2H),6.05(d,J＝9.8Hz,1H),5.21(s,2H),4.05(t,J＝6.5Hz,2H),2.49(d,J＝6.0Hz,2H).HRMS calcd.For C20H17FN2O3(M+H) + 353.12963,found353.12903.
Example 31
(E) -1- (3- (3- ((2-fluoropyridin-4-yl) methoxy) phenyl) acryloyl) -5, 6-dihydropyridin-2 (1H) one
(1) Preparation of the title compound
2-fluoro-4-pyridinemethanol (31.8 mg,0.25 mmol), triphenylphosphine (71.3 mg,0.27 mmol) was added sequentially to a solution of 1- (3-hydroxyphenyl) acryloyl-5, 6-dihydropyridin-2 (1H) one (40.0 mg,0.16 mmol) in ultra-dry tetrahydrofuran, ice-cooled to 0deg.C, diisopropyl azodicarboxylate (50.5 mg,0.25 mmol) was added dropwise, and the mixture was allowed to react at room temperature for 5H. After the completion of the reaction, water was added to quench, extraction was performed with ethyl acetate, and the organic layer was washed twice with 5ml of saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. Concentrating, separating by column chromatography, eluting with ethyl acetate, and drying to obtain white solid 25mg with yield 44.3% and melting point 150-151 ℃.
1 H NMR(400MHz,Chloroform-d)δ8.26(s,1H),7.73(d,J＝15.5,1H),7.52(d,J＝15.6,1H),7.38–7.25(m,3H),7.19(s,1H),7.08(s,1H),6.99(d,J＝8.7Hz,2H),6.08(d,J＝9.8Hz,1H),5.17(s,2H),4.08(m,2H),2.51(m,2H).HRMS calcd.For C20H17FN2O3(M+H) + 353.12963,found 353.12878.
Pharmacological experiments
Experimental example 1, verification of the inhibitory Effect of Compounds on the Enmembranous serine protease RHBDD1 enzymatic Activity
The purpose of the experiment is as follows: the compounds of the present invention were evaluated for their inhibitory effect on the in vitro serine protease RHBDD1 enzyme activity.
The experimental method comprises the following steps: a small molecule inhibition screening model (mimicking the process of in vivo RHBDD1 hydrolysis of the substrate) was used that targets RHBDD 1. In vitro, liponame simulating cell membrane was used as hydrolysis reaction carrier, transmembrane substrate Keren (with fluorescent group FTIC) was used as substrate, keren fluorescent group was fluorescence quenched in liponame. When RHbDD1 plays a role in hydrolysis to cut the substrate, the fluorescent group is released, and the measured fluorescence value is increased; when the RHDDD 1 enzyme activity is inhibited by the addition of the compound, cleavage of the fluorogenic substrate Keren is inhibited and the fluorescence value is lowered. Within a certain range, the fluorescence value is proportional to the RHBDD1 enzyme activity. Therefore, the inhibition of RHBDD1 enzyme activity by the compound can be judged according to the change of the fluorescence value.
The reaction was carried out in 384 well plates according to the following 50. Mu.L system, incubated at 37℃for 4 hours in the absence of light, and fluorescence values (relative fluorescence units, RFU) at 485/528nm were measured using a Synergy H1 full-function microplate detector. The formula for calculating the inhibition rate: inhibition (%) = [1- (RFU) Experimental group -RFU System of )/(RFU Negative control -RFU System of )]X 100%. IC was calculated using the cvxpt32 software by GraphPad Prism mapping 50 。
Table 1 Small molecule inhibitor screening model system of RHBDD1 target spot
Experimental results: as shown in Table 2, the compounds of the invention have a strong inhibition effect on the activity of the serine protease RHBDD1 enzyme in the membrane. Multiple compound ICs 50 The value is smaller than 1 mu M, which shows that the compound has stronger RHBDD1 enzyme activity inhibition effect.
TABLE 2 inhibition of RHBDD1 enzymatic Activity by Compounds of the invention
Experimental example 2, the inhibition of HCT116 and RKO cell proliferation by the compounds was validated.
The purpose of the experiment is as follows: the test detects the inhibition of HCT and RKO cell proliferation by compounds through a cytotoxicity test CCK-8 method
The experimental method comprises the following steps: cells in logarithmic growth phase were grown at 5X10 3 Cell/well seeding into 96 well plates200ul PBS was added to the edge wells to prevent medium evaporation. After 12h of cell plating, 100ul of medium containing gradient concentration of compound was added, DMSO as a blank, and 3 duplicate wells were set for each concentration of compound. After 48h, the medium was discarded, 100ul of medium containing 10% CCK-8 solution was added to each well, incubated in a cell incubator for 1.5h in the absence of light, and the absorbance OD at 450/630nm was measured by a microplate reader. According to the inhibition ratio (%) = [1- (OD) Administration of drugs -OD Empty space )/(OD Control -OD Empty space )]Inhibition was calculated by x 100%, graphPad Prism was plotted and IC50 was calculated using cvxpt32 software.
Experimental results: as shown in Table 3, the compounds of the present invention have high inhibitory effect on HCT116 and RKO cell proliferation and are concentration-dependent. As shown in Table 3, ICs of a plurality of compounds 50 The value is between 1 and 10. Mu.M.
TABLE 3 proliferation inhibitory Activity of the inventive Compounds against HCT116 and RKO cells
Claims (8)
1. A compound represented by the general formula (I):
wherein R is 1 Selected from the following structures:
R 2 selected from hydrogen, substituted or unsubstituted C 1-4 Straight-chain or branched oxaalkyl, C 3-6 Ring armorOxy, C 4-8 Oxacycloalkoxy or
R 3 Selected from hydrogen, methoxy, 2-methoxyethoxy or oxetan-4-ylmethoxy;
R 4 selected from hydrogen or methoxy.
2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R 2 Selected from the group consisting of hydrogen, methoxy, ethoxy, N-propoxy, isopropoxy, cyclopropylmethoxy, cyclobutylmethoxy, cyclohexylmethoxy, 2-methoxyethoxy, 3-methoxyethoxy, oxetan-3-ylmethoxy, oxolan-3-ylmethoxy, oxetan-4-ylethoxy, N, N-diethylaminoethoxy, pyrrolidin-1-ylethoxy, piperidin-1-ylethoxy, 1-Boc-piperidin-4-methoxy, 2-morpholinylethoxy, 3-morpholinylethoxy, 2- (4-methylpiperazin-1-yl) ethoxy, 2- (pyridinamido) ethoxy, 2- (2-oxopyrrolidin-1-yl) ethoxy, pyridin-4-ylmethoxy, pyridin-3-ylethoxy, pyridazin-4-ylmethoxy, thiophen-3-ylmethoxy, 3-fluoro-pyridin-4-ylmethoxy, 2-fluoro-pyridin-4-ylmethoxy.
3. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, characterized in that the pharmaceutically acceptable salt is selected from organic or inorganic acid salts, including hydrochloride, hydrobromide, sulfate, phosphate, acetate, citrate, malate, fumarate, tartrate or mesylate salts.
4. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound has the structure:
5. a process for the preparation of a compound according to claim 1 or a pharmaceutically acceptable salt thereof, characterized by the steps of:
route (1):
reagents and conditions: (a) Oxalyl chloride, N-dimethylformamide, dichloromethane, 0 ℃; (b) R is R 1 H, sodium hydrogen, tetrahydrofuran, 0deg.C.
Route (2):
reagents and conditions: (a) 2-iodopropane, potassium hydroxide, acetonitrile: water=1:1, 90 ℃; (b) Oxalyl chloride, N-dimethylformamide, dichloromethane, 0 ℃;5, 6-dihydro-2 (1H) -pyridone, sodium hydrogen, tetrahydrofuran, 0 ℃; (c) anhydrous aluminum trichloride, methylene chloride, 0 ℃; (d) R is R 2 OH, diisopropyl azodicarboxylate, triphenylphosphine, tetrahydrofuran, 0 ℃ to room temperature.
Wherein R is 1 、R 2 、R 3 、R 4 Is as defined in any one of claims 1 to 4.
6. A pharmaceutical composition comprising a compound of any one of claims 1-4, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
7. Use of a compound of any one of claims 1-4, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a disease associated with RHBDD1 function.
8. Use of a compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a tumor.
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