CN103360407B - A kind of Thienopyrimidine analog derivative, its preparation method and in application pharmaceutically - Google Patents
A kind of Thienopyrimidine analog derivative, its preparation method and in application pharmaceutically Download PDFInfo
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- CN103360407B CN103360407B CN201210102818.5A CN201210102818A CN103360407B CN 103360407 B CN103360407 B CN 103360407B CN 201210102818 A CN201210102818 A CN 201210102818A CN 103360407 B CN103360407 B CN 103360407B
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- general formula
- alkyl
- phenyl
- substituted
- thienopyrimidine
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- 238000002360 preparation method Methods 0.000 title claims abstract description 44
- RBNBDIMXFJYDLQ-UHFFFAOYSA-N thieno[3,2-d]pyrimidine Chemical class C1=NC=C2SC=CC2=N1 RBNBDIMXFJYDLQ-UHFFFAOYSA-N 0.000 title claims abstract description 35
- 150000001875 compounds Chemical class 0.000 claims abstract description 51
- 229910052799 carbon Inorganic materials 0.000 claims abstract description 10
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 10
- 229940121358 tyrosine kinase inhibitor Drugs 0.000 claims abstract description 10
- 239000005483 tyrosine kinase inhibitor Substances 0.000 claims abstract description 10
- 150000004917 tyrosine kinase inhibitor derivatives Chemical class 0.000 claims abstract description 8
- 125000004433 nitrogen atom Chemical group N* 0.000 claims abstract description 7
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 6
- 102000052116 epidermal growth factor receptor activity proteins Human genes 0.000 claims abstract 3
- 108700015053 epidermal growth factor receptor activity proteins Proteins 0.000 claims abstract 3
- YOHYSYJDKVYCJI-UHFFFAOYSA-N n-[3-[[6-[3-(trifluoromethyl)anilino]pyrimidin-4-yl]amino]phenyl]cyclopropanecarboxamide Chemical compound FC(F)(F)C1=CC=CC(NC=2N=CN=C(NC=3C=C(NC(=O)C4CC4)C=CC=3)C=2)=C1 YOHYSYJDKVYCJI-UHFFFAOYSA-N 0.000 claims abstract 3
- 238000006243 chemical reaction Methods 0.000 claims description 104
- -1 inorganic acid salt Chemical class 0.000 claims description 49
- 102000001301 EGF receptor Human genes 0.000 claims description 33
- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 claims description 33
- 229910052757 nitrogen Inorganic materials 0.000 claims description 31
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- 102100033177 Vascular endothelial growth factor receptor 2 Human genes 0.000 claims description 18
- NXQGGXCHGDYOHB-UHFFFAOYSA-L cyclopenta-1,4-dien-1-yl(diphenyl)phosphane;dichloropalladium;iron(2+) Chemical compound [Fe+2].Cl[Pd]Cl.[CH-]1C=CC(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1.[CH-]1C=CC(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1 NXQGGXCHGDYOHB-UHFFFAOYSA-L 0.000 claims description 16
- 239000003814 drug Substances 0.000 claims description 15
- 229910052739 hydrogen Inorganic materials 0.000 claims description 14
- 239000001257 hydrogen Substances 0.000 claims description 13
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- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 8
- 125000002252 acyl group Chemical class 0.000 claims description 8
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- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 5
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Abstract
The invention discloses a kind of Thienopyrimidine analog derivative, its preparation method and in application pharmaceutically。Described derivant is the compound with formula I or formula II or general formula III:In above-mentioned formula: Ar is phenyl, the phenyl of halogen substiuted, C1-6The phenyl of alkyl replacement, xenyl, the xenyl of halogen substiuted, naphthyl, pyridine radicals, thienyl, the thienyl of halogen substiuted, C1-3The thienyl of alkyl replacement, furyl, the furyl of halogen substiuted, C1-3Alkyl replace furyl in any one；A, D, E respectively carbon atom or nitrogen-atoms, but be carbon atom during A, D, E difference；R is R1——NH——、
Description
Technical Field
The invention relates to a thienopyrimidine derivative, a preparation method and application thereof, in particular to a thienopyrimidine derivative with epidermal growth factor receptor EGFR and/or vascular growth factor receptor VEGFR inhibitory activity, a preparation method and application thereof in medicine, and belongs to the technical field of pharmaceutical chemistry.
Background
Tumors are one of the most serious diseases threatening human health, and the treatment mainly comprises radiotherapy, chemotherapy and surgical treatment. With the development of cell biology and tumor pharmacology in recent years, the chemical drug therapy of tumors has changed greatly. The traditional chemotherapy drugs are gradually abandoned because cell division is nonspecifically blocked, so that normal cell death is caused while tumor cells are killed, and meanwhile, by taking key node proteins in abnormally activated signal channels in the tumor cells as targets, the discovery of high-efficiency, low-toxicity and strong-specificity micromolecule inhibitors becomes an important direction for the research and development of current antitumor drugs. Receptor Tyrosine Kinases (RTKs) which are abnormally expressed and activated in tumors play a key role in various links such as tumor occurrence and development, invasion and metastasis, chemotherapy resistance and the like, and become hot spots for research on antitumor drugs.
The Epidermal Growth Factor Receptor (EGFR), also known as HER1 or cerbB1, is the HER family member of the tyrosine kinases most widely expressed in human cancers. The EGFR structure includes three regions: extracellular, transmembrane and intracellular regions; the amino terminal of the extracellular region consists of 622 amino acids, and has 2 cysteine-rich segments forming a ligand binding region; the transmembrane region is a single alpha helix; the intracellular region includes the kinase domain and a carboxy-terminal tail with a number of tyrosine phosphorylation sites. Tyrosine Kinases (RTKs) transport the gamma phosphate of ATP to tyrosine residues, and upon binding to a ligand, EGFR undergoes homodimerization or heterodimerization to form a tight junction in the TK region. Phosphorylation at the carboxy-terminal tail RTK mediated tyrosine phosphorylation site creates binding sites for enzymes and linker proteins (Y992, Y1068, Y1086, Y1148 and Y11730) that can initiate intracellular signaling reactions. These signals form diverse cellular responses including proliferation, differentiation, adhesion and angiogenesis, metastasis and inhibition of apoptosis.
Research shows that EGFR is expressed in non-small cell lung cancer, prostatic cancer, breast cancer, colorectal cancer, head and neck cancer, gastric cancer, ovarian cancer and pancreatic cancer, and EGFR activation triggers complex signaling reaction. In different types of solid tumors, EGFR is proliferated and overexpressed, leading to uncontrolled downstream signaling leading to the formation of various tumors. Mutations in the ATP-binding site of EGFR affect the RTK activity of the receptor, interfering with the formation of tumorigenic signals, while EGFR is also closely associated with tumor progression and poor prognosis.
Due to the unique role of EGFR and VEGFR in tumorigenesis, monoclonal antibodies and small molecule inhibitors thereof have become hot spots for the development of targeting antitumor drugs. Currently, there are several EGFR or VEGFR targeted inhibitors on the market, and nearly 20 drug candidates are in clinical stages of development. Among them, gefitinib and erlotinib represent the early marketed small molecule inhibitors targeting EGFR. Gefitinib (Gefitinib, also referred to as ZD1839 or Iressa) is used as a triple-line monotherapy for advanced non-small cell lung cancer (NSCLC). Erlotinib (also called OSI774 or Tarceva) is used as a second-line or third-line therapeutic agent for advanced NSCLC where standard treatment is ineffective.
However, with the clinical use of these drugs, not all patients with high expression of EGFR have been found to be effective against these drugs, and some tumors that initially responded to Gefitinib (Gefitinib) develop disease after several months of treatment. These results indicate that the currently used EGFR inhibitor antitumor drugs have natural or secondary drug resistance phenomena, and therefore, the development of novel drugs having low drug resistance or capable of relieving early inhibitor drug resistance has become a new development direction of tyrosine kinase inhibitors.
Disclosure of Invention
In view of the above problems in the prior art, the present invention aims to provide thienopyrimidine derivatives having inhibitory activity against epidermal growth factor receptor EGFR and/or vascular growth factor receptor VEGFR, a preparation method thereof, and a pharmaceutical use thereof.
The thienopyrimidine derivative provided by the invention is a compound with a general formula I or a general formula II or a general formula III:
in the above general formula:
ar is phenyl, halogen substituted phenyl, C1-6Alkyl-substituted phenyl, biphenyl, halogen-substituted biphenyl, naphthyl, pyridyl, thienyl, halogen-substituted thienyl, C1-3Alkyl-substituted thienyl, furyl, halogen-substituted furyl, C1-3Alkyl substituted furanAny one of furyl;
A. d, E is carbon atom or nitrogen atom respectively, but A, D, E is not carbon atom at the same time;
r is R1——NH——、 Wherein: r1Is hydrogen, C1～C6Alkyl radical, C3～C6Cycloalkyl radical, C1～C6Alkyl-substituted acyl, C3～C6Cycloalkyl-substituted acyl, C1～C6Alkyl-substituted ester group or C3～C6Cycloalkyl-substituted ester groups; r2Is hydrogen, C1～C6Alkyl radical, C3～C6Cycloalkyl, hydroxy-substituted C1～C6Alkyl radical, C1～C6Alkyl-substituted acyl, C1～C6Acyl substituted by alkyl hydroxy, C3～C6Cycloalkyl-substituted acyl, C1～C6Alkyl-substituted ester group, C3～C6Cycloalkyl-substituted ester, sulfonyl or C1～C6An alkyl-substituted sulfonyl group; r3、R4、R5Are respectively hydrogen and C1～C6Alkyl radical, C3～C6Cycloalkyl or hydroxy substituted C1～C6An alkyl group.
As a preferable mode, the thienopyrimidine derivative is a compound having a general formula I or a general formula II or a general formula III, wherein: ar is phenyl; A. d, E is carbon atom or nitrogen atom respectively, but A, D, E is not carbon atom at the same time; r is R1——NH——、 Wherein: r1Is hydrogen or C1～C6An alkyl-substituted ester group; r2Is hydrogen, C1～C6Alkyl, hydroxy substituted C1～C6Alkyl radical, C1～C6Alkyl-substituted acyl, C1～C6Acyl substituted by alkyl hydroxy, C3～C6Cycloalkyl-substituted acyl or C1～C6An alkyl-substituted sulfonyl group; r3、R4、R5Are each hydrogen or C1～C6An alkyl group.
In a further preferred embodiment, the thienopyrimidine derivative is a compound having the following chemical formula:
the invention relates to a preparation method of thienopyrimidine derivatives represented by a general formula I, which comprises the following steps of (I), (ii), (iii), (iv) and (v):
ar, A, D, E and R in the schemes are as defined above.
The invention relates to a preparation method of thienopyrimidine derivatives represented by a general formula II, which comprises the following steps (v), (v) and (v):
ar, A, D, E and R in the schemes are as defined above.
The preparation method of the thienopyrimidine derivative represented by the general formula III comprises the following steps:
ar, A, D, E and R in the schemes are as defined above.
As a preferred scheme, the step three, the step five and the step sixteenth are Suzuki coupling reactions carried out under the action of a Pd-catalyst.
As a further preferred embodiment, the Pd-catalyst is dichlorobis (triphenylphosphine) palladium, tetrakis (triphenylphosphine) palladium or [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium.
Another preparation method of the thienopyrimidine derivative represented by the general formula II is to perform amide reduction reaction on the thienopyrimidine derivative represented by the general formula I.
Preferably, the reducing agent for the amide reduction is LiAlH4Red aluminum (Red-Al) or borane complexes.
As researches show that the thienopyrimidine derivatives have inhibitory activity on Epidermal Growth Factor Receptor (EGFR) and/or vascular growth factor receptor (VEGFR), the thienopyrimidine derivatives or any one or a mixture of several of tautomers, racemates, enantiomers, diastereomers, pharmaceutically acceptable salts and pharmaceutically acceptable solvates of the thienopyrimidine derivatives can be used for preparing tyrosine kinase inhibitors, and especially can be used for preparing EGFR and/or VEGFR inhibitors.
Meanwhile, the inhibitor can be applied to preparing medicaments for preventing or treating diseases related to epidermal growth factor receptor EGFR and/or vascular growth factor receptor VEGFR; in particular to the application of the compound in preparing the medicine for preventing or treating abnormal cell proliferation, morphological change, hyperkinesia, angiogenesis and tumor metastasis diseases related to epidermal growth factor receptor EGFR and/or vascular growth factor receptor VEGFR.
In addition, the inhibitor can be applied to the preparation of medicines for treating or preventing tumor growth and metastasis related to epidermal growth factor receptor EGFR and/or vascular growth factor receptor VEGFR.
Furthermore, the active ingredient of the inhibitor described in the patent is preferably any one or a mixture of several of compounds shown in table 1 or tautomers, racemates, enantiomers, diastereomers, pharmaceutically acceptable salts and pharmaceutically acceptable solvates of the compounds shown in table 1:
TABLE 1
The pharmaceutically acceptable salts include, but are not limited to: inorganic acid salts such as hydrochloride, hydrobromide, nitrate, sulfate, phosphate and the like; organic acid salts such as formate, acetate, propionate, benzoate, maleate, fumarate, succinate, tartrate, citrate, and the like; alkyl sulfonates such as methylsulfonate, ethylsulfonate, and the like; aryl sulfonates such as benzenesulfonate, p-toluenesulfonate, and the like.
The pharmaceutically acceptable solvates include, but are not limited to, solvates of the compounds with water, ethanol, isopropanol, diethyl ether, acetone, and the like.
Compared with the prior art, the thienopyrimidine derivatives provided by the invention have novel structures, obvious EGFR inhibitory activity and obvious inhibitory activity to VEGFR of partial compounds, are expected to be developed into tyrosine kinase EGFR or/and VEGFR inhibitors, are used for preparing medicines for preventing or treating related diseases such as abnormal cell proliferation, morphological change and hyperkinesia related to epidermal growth factor receptor EGFR and/or vascular growth factor receptor VEGFR and related diseases related to angiogenesis or tumor metastasis, are especially expected to be used for preparing medicines for preventing or treating tumor growth and metastasis related to epidermal growth factor receptor EGFR and/or vascular growth factor receptor VEGFR, provide new development directions and ways for developing novel tyrosine kinase inhibitor medicines with low drug resistance or capable of relieving early inhibitor drug resistance, has wide application prospect and medicinal value.
Detailed Description
The invention is further illustrated by the following specific examples. The following examples are to be construed as merely illustrative and not limitative of the remainder of the disclosure.
The structures of the compounds prepared in the following examples are by nuclear magnetic resonance (1HNMR) and Mass Spectrometry (MS).
1HNMR shift () is given in units of parts per million (ppm).1HNMR was measured using a Bruker AVANCE-400 NMR spectrometer using deuterated dimethyl sulfoxide (DMSO-d)6) Deuterated chloroform (CDCl)3) The internal standard is Tetramethylsilane (TMS) and the chemical shifts are given in units of 10-6.
MS was determined using a FINNIGANLCQad (ESI) mass spectrometer (manufacturer: Therm, model: Finnigan LCQadvadiatageMAX).
IC50The values were determined with a NovoStar microplate reader (BMG, Germany).
The thin silica gel layer is prepared from HSGF254 or GF254 silica gel plate.
The silica gel column chromatography uses 200-300 mesh silica gel of the Tibet Huanghai silica gel as a carrier.
HPLC tests were carried out using an Agilent 1200DAD high pressure liquid chromatograph (SunfireC 18150X 4.6mm column) and a Waters2695-2996 high pressure liquid chromatograph (GiminiC 18150X 4.6mm column).
The microwave reaction was carried out using a CEMDiscover-S908860 type microwave reactor.
In the following examples, the reaction was carried out in a nitrogen atmosphere unless otherwise specified.
The argon atmosphere means that the reaction flask is connected with an argon balloon having a volume of about 1L.
The hydrogen atmosphere refers to a reaction flask connected with a hydrogen balloon with a volume of about 1L.
In the following examples, the solution in the reaction is an aqueous solution, unless otherwise specified.
Example 1: preparation of Compound I-1
The first step is as follows:
5-bromo-2-pyridinecarboxylic acid (2.02g, 10mmol) and N-methylpiperazine (1g, 10mmol) were dissolved in dichloromethane (50ml) at room temperature, then 1-hydroxybenzotriazole (2.03g, 15mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (2.88g, 15mmol) and N, N-diisopropylethylamine (3.88g, 30mmol) were added in this order, stirred at room temperature for 24 hours, water (200ml) was added to the reaction solution, dichloromethane (100ml) was extracted, washing with saturated sodium chloride (100ml 3) was then performed, the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography to give (5-bromo-pyridin-2-yl) - (4-methyl-piperazin-1-yl) -methanone (1.7g, orange red oil), yield: 60 percent; directly used for the next reaction.
The second step is that:
(5-bromo-pyridin-2-yl) - (4-methyl-piperazin-1-yl) -methanone (400mg, 1.41mmol) and pinacol diboron ester (393mg, 1.55mmol) were dissolved in dioxane (10ml) at room temperature, then [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride (57mg, 0.07mmol), potassium acetate (414mg, 4.23mmol) were added, replaced with nitrogen, heated to 120 ℃ for reaction for 24 hours, the reaction solution was concentrated under reduced pressure, the residue was dissolved in methanol, filtered, and the filtrate was concentrated under reduced pressure to give the corresponding pyridine substituted boronic acid (300mg, brown solid) in yield: 64 percent; directly used for the next reaction.
The third step:
corresponding pyridine-substituted boronic acid (300mg, 1.2mmol) and 2- (6-bromo-thieno [3, 2-d ] pyrimidin-4-ylamine) -2-phenyll-ethanol (220mg, 0.63mmol) were dissolved in N, N-dimethylformamide (8ml) at room temperature, tetrakis (triphenylphosphine) palladium (73mg, 0.063mmol) and a sodium carbonate solution (1N, 2.0ml) were then added, the reaction was reacted at 85 ℃ for 2 hours, 200ml of water was added to the reaction solution after cooling, ethyl acetate (100ml 3) was used for extraction, and then a saturated sodium chloride solution (100ml 3) was used for washing, and the resulting organic phase was dried over anhydrous magnesium sulfate, filtered, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography to give (S) - {5- [4- (2-hydroxy-1-phenyl-ethylamine) -thiophene [3, 2-d ] pyrimidin-6-yl ] -pyridin-2-yl } - (4-methyl-piperazin-1-yl) -methanone (260mg, brown solid) in 87.5% yield.
MSm/z(ESI)：475.6[M+1]；
1HNMR(400Hz，DMSO-d6)：9.10(s，1H)，8.39(m，3H)，8.04(s，1H)，7.75(d，1H)，7.46(m，2H)，7.30(m，2H)，7.24(m，1H)，5.48(m，1H)，5.03(m，1H)，3.80(m.2H)，3.69(m，4H)，2.47(m，4H)，2.19(s，3H)。
Example 2: preparation of Compound I-2
The first step is as follows:
5-bromo-2-pyridinecarboxylic acid (303mg, 1.5mmol) and N-ethylpiperazine (172mg, 1.5mmol) were dissolved in dichloromethane (15ml) at room temperature, then 1-hydroxybenzotriazole (244mg, 1.8mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (346mg, 1.8mmol) and N, N-diisopropylethylamine (582mg, 4.5mmol) were added in this order, stirred at room temperature for 24 hours, water (100ml) was added to the reaction solution, dichloromethane (50ml) was extracted, washed with saturated sodium chloride (100 ml. times.2), the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography to give (5-bromo-pyridin-2-yl) - (4-ethyl-piperazin-1-yl) -methanone (400mg, yellow oil), yield: 89 percent; directly used for the next reaction.
The second step is that:
(5-bromo-pyridin-2-yl) - (4-ethyl-piperazin-1-yl) -methanone (400mg, 1.34mmol) and pinacol diboron ester (381mg, 1.5mmol) were dissolved in dioxane at room temperature, then [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride (33mg, 0.04mmol), potassium acetate (395mg, 4.02mmol) were added, nitrogen was replaced, heating was carried out to 120 ℃ for 24 hours, the reaction solution was concentrated under reduced pressure, the residue was dissolved in methanol, filtered, and the filtrate was concentrated under reduced pressure to give the corresponding pyridine substituted boronic acid (313mg, brown solid), yield: 67%; directly used for the next reaction.
The third step:
corresponding pyridine-substituted boronic acid (313mg, 1.19mmol) and 2- (6-bromo-thieno [3, 2-d ] pyrimidin-4-ylamine) -2-phenyll-ethanol (378mg, 1.08mmol) were dissolved in N, N-dimethylformamide (10ml) at room temperature, tetrakis (triphenylphosphine) palladium (124.8mg, 0.108mmol) and a sodium carbonate solution (1N, 3.0ml) were added, the mixture was replaced with nitrogen, reacted at 85 ℃ for 2 hours, cooled, 200ml of water was added to the reaction solution, extracted with ethyl acetate (100 ml. about.3), washed with a saturated sodium chloride solution (100 ml. about.3), and the resulting organic phase was dried over anhydrous magnesium sulfate, filtered under reduced pressure, and the resulting residue was purified by silica gel column chromatography to give (S) - {5- [4- (2-hydroxy-1-phenyl-ethylamine) -thieno [3 ], 2-d ] pyrimidin-6-yl ] -pyridin-2-yl } - (4-ethyl-piperazin-1-yl) -methanone (454mg, brown solid) in 86% yield.
MSm/z(ESI)：489.6[M+1]；
1HNMR(400Hz，DMSO-d6)：9.10(s，1H)，8.39(m，3H)，8.04(s，1H)，7.76(d，1H)，7.46(m，2H)，7.30(m，2H)，7.24(m，1H)，5.47(m，1H)，5.02(m，1H)，3.81(m.2H)，3.65(m，4H)，2.43(m，4H)，2.35(m，2H)，1.01(t，3H)。
Example 3: preparation of Compound I-3
The first step is as follows:
5-bromo-2-pyridinecarboxylic acid (2.02g, 10mmol) and N-ethylpiperazine (1.30g, 10mmol) were dissolved in dichloromethane (50ml) at room temperature, then 1-hydroxybenzotriazole (2.03g, 15mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (2.88g, 15mmol) and N, N-diisopropylethylamine (3.88g, 30mmol) were added in this order, stirred at room temperature for 24 hours, water (200ml) was added to the reaction solution, dichloromethane (100ml) was extracted, washing with saturated sodium chloride (100 ml. times.2) was then performed, the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography to give (5-bromo-pyridin-2-yl) - (4-hydroxyethyl-piperazin-1-yl) -methanone (2.2g, white solid), yield: 88 percent.
1HNMR(400Hz，CDCl3)：8.64(s，1H)，7.94(m，1H)，7.59(m，1H)，3.83(m，2H)，3.66(m，4H)，2.63(m，6H)。
The second step is that:
(5-bromo-pyridin-2-yl) - (4-hydroxyethyl-piperazin-1-yl) -methanone (628mg, 2.0mmol) and pinacol diboron (1014mg, 4mmol) were dissolved in dioxane at room temperature, then [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium (81.6mg, 0.1mmol), potassium acetate (588mg, 6mmol), displaced with nitrogen, heated to 120 ℃ for 24 hours, the reaction solution was concentrated under reduced pressure, the residue was dissolved in methanol, filtered, and the filtrate was concentrated under reduced pressure to give the corresponding pyridine substituted boronic acid (350mg, brown solid) in yield: 62 percent; directly used for the next reaction.
The third step:
the corresponding pyridine-substituted boronic acid (216.6mg, 0.77mmol) and 2- (6-bromo-thieno [3, 2-d ] pyrimidin-4-ylamine) -2-phenyl l-ethanol (105mg, 0.3mmol) were dissolved in N, N-dimethylformamide (6ml) at room temperature, tetrakis (triphenylphosphine) palladium (35mg, 0.03mmol) and a sodium carbonate solution (95mg, 0.9mmol) were added, the mixture was replaced with nitrogen, reacted at 85 ℃ for 2 hours, cooled, 100ml of water was added to the reaction solution, extracted with ethyl acetate (50ml 3), washed with a saturated sodium chloride solution (100ml 2), the resulting organic phase was dried over anhydrous magnesium sulfate, filtered under reduced pressure, and the resulting residue was purified by silica gel column chromatography to give (S) -4- (2-hydroxy-ethyl) -piperazin-1-yl ] - {5- [4- (2-hydroxy- 1-phenyl-ethylamine) -thiophen [3, 2-d ] pyrimidin-6-yl ] -pyridin-2-yl } -methanone (50mg, yellow solid) in 33% yield.
MSm/z(ESI)：538.98[M+1]；
1HNMR(400Hz，DMSO-d6)：9.07(s，1H)，8.47-8.25(m，3H)，8.01(s，1H)，7.72(d，1H)，7.42(d，2H)，7.29(t，2H)，7.19(t，1H)，5.43(d，1H)，5.07(s，1H)，4.58(s，1H)，3.86-3.60(m，4H)，3.52(d，4H)，3.02(m，3H)，2.54(s，6H)。
Example 4: preparation of Compound I-4
The first step is as follows:
5-bromo-2-pyridinecarboxylic acid (2.02g, 10mmol) and 1-methanesulfonylpiperazine (2.46g, 15mmol) were dissolved in dichloromethane (50ml) at room temperature, then 1-hydroxybenzotriazole (2.7g, 20mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (3.83g, 20mmol) and N, N-diisopropylethylamine (6.46g, 50mmol) were added in this order, stirred at room temperature for 24 hours, water (200ml) and dichloromethane (100 ml. times.3) were added to the reaction solution, followed by extraction with saturated sodium chloride (100 ml. times.2), the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography to give (5-bromo-pyridin-2-yl) - (4-methanesulfonyl-piperazin-1-yl) -methanone (3.05g, white solid), yield: 87.6 percent.
MSm/z(ESI)：349[M+1]；
1HNMR(400Hz，DMSO-d6)：8.74(s，1H)，8.22(d，1H)，7.60(d，1H)，3.75(m，2H)，3.54(m，2H)，3.22(m，2H)，3.12(m，2H)，2.91(s，3H)。
The second step is that:
(5-bromo-pyridin-2-yl) - (4-methanesulfonyl-piperazin-1-yl) -methanone (696mg, 2mmol) and pinacol diboron (1016mg, 4mmol) were dissolved in dioxane at room temperature, then [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium (163.2mg, 0.2mmol), potassium acetate (588mg, 6mmol), displaced with nitrogen, heated to 120 ℃ for 24 hours, the reaction solution was concentrated under reduced pressure, the residue was dissolved in ethyl acetate, filtered, and the filtrate was concentrated under reduced pressure to give the corresponding pyridine substituted boronic acid (237mg, brown solid); directly used for the next reaction.
The third step:
corresponding pyridine-substituted boronic acid (237mg, 0.75mmol) and 2- (6-bromo-thieno [3, 2-d ] pyrimidin-4-ylamine) -2-phenyl l-ethanol (105mg, 0.3mmol) were dissolved in N, N-dimethylformamide (6ml) at room temperature, tetrakis (triphenylphosphine) palladium (35mg, 0.03mmol) and sodium carbonate (95mg, 0.9mmol) were added, nitrogen substitution was performed, reaction was performed at 85 ℃ for 2 hours, 100ml of water was added to the reaction solution after cooling, extraction was performed with ethyl acetate (50ml _ 3), washing was performed with a saturated sodium chloride solution (100ml _ 2), the obtained organic phase was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography to obtain (S) - {5- [4- (2-hydroxy-1-phenyl-ethylamine) -thiophene [3 ], 2-d ] pyrimidin-6-yl ] - - (4-methanesulfonyl-piperazin-1-yl) -methanone (40mg, yellow solid) in 26% yield.
MSm/z(ESI)：504.6[M+1]；
1HNMR(400Hz，DMSO-d6)：9.07(d，1H)，8.44(m，3H)，8.06(s，1H)，7.79(d，1H)，7.44(d，2H)，7.31(d，2H)，7.24(d，1H)，5.46(s，1H)，5.04(s，1H)，3.79(s，1H)，3.62(s，2H)，3.25(s，2H)，3.16(s，2H)，2.93(s，3H)。
Example 5: preparation of Compound I-5
The first step is as follows:
5-bromo-2-pyridinecarboxylic acid (2.5g, 12.4mmol) and morpholine (11g, 12.4mmol) were dissolved in dichloromethane (50ml) at room temperature, then 1-hydroxybenzotriazole (2.5g, 18.6mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (3.6g, 18.6mmol) and N, N-diisopropylethylamine (4.8g, 37.2mmol) were added in this order, stirred at room temperature for 24 hours, water (200ml) was added to the reaction solution, dichloromethane (100 ml. times.3) was extracted, washed with saturated sodium chloride (100 ml. times.2), the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography to give (5-bromo-pyridin-2-yl) -morpholin-4-yl-methanone (2.13g, white solid), yield: and 64 percent.
MSm/z(ESI)：272[M+1]；
1HNMR(400Hz，DMSO-d6)：8.74(s，1H)，8.22(m，1H)，7.59(m，1H)，3.55(m，4H)，3.43(m，4H)。
The second step is that:
dissolving (5-bromo-pyridin-2-yl) -morpholin-4-yl-methanone (271mg, 1mmol) and pinacol diboron ester (330mg, 1.3mmol) in dioxane at room temperature, adding [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium (40.8mg, 0.04mmol), potassium acetate (294mg, 3mmol), displacing with nitrogen, heating to 120 ℃ for reaction for 24 hours, concentrating the reaction solution under reduced pressure, dissolving the residue in ethyl acetate, filtering, and concentrating the filtrate under reduced pressure to obtain the corresponding pyridine substituted boric acid (218mg, brown solid); directly used for the next reaction.
The third step:
the corresponding pyridine-substituted boronic acid (218mg, 0.92mmol) and 2- (6-bromo-thieno [3, 2-d ] pyrimidin-4-ylamine) -2-phenyll-ethanol (200mg, 0.57mmol) were dissolved in N, N-dimethylformamide (10ml) at room temperature, tetrakis (triphenylphosphine) palladium (33mg, 0.108mmol) and a sodium carbonate solution (1N, 3.0ml) were added, nitrogen gas was substituted, the reaction was allowed to react at 85 ℃ for 2 hours, 200ml of water was added to the reaction solution after cooling, extraction was performed with ethyl acetate (100 ml. about.3), washing was performed with a saturated sodium chloride solution (100 ml. about.3), the resulting organic phase was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography to give (S) - {5- [4- (2-hydroxy-1-phenyl-ethylamine) -thiophene [3 ], 2-d ] pyrimidin-6-yl ] -pyridin-2-yl } -morpholin-4-yl-methanone (80mg, brown solid) in 26% yield.
MSm/z(ESI)：461.89[M+1]；
1HNMR(400Hz，DMSO-d6)：9.10(s，1H)，8.41(m，3H)，8.04(s，1H)，7.77(d，1H)，7.45(m，2H)，7.32(m，2H)，7.22(m，1H)，5.47(m，1H)，5.04(m，1H)，3.81(m.2H)，3.69(m，4H)，3.59(m，4H)。
Example 6: preparation of Compound I-6
The first step is as follows:
5-bromo-2-pyridinecarboxylic acid (2.0g, 9.9mmol) and 2, 6-dimethylmorpholine (1.14g, 9.9mmol) were dissolved in dichloromethane (50ml) at room temperature, then 1-hydroxybenzotriazole (2.0g, 14.9mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (2.85g, 14.9mmol) and N, N-diisopropylethylamine (3.8g, 29.7mmol) were added in this order, stirring was carried out at room temperature for 24 hours, water (200ml) was added to the reaction solution, dichloromethane (100ml 3) was extracted, followed by washing with saturated sodium chloride (100ml 2), the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography to give (5-bromo-pyridin-2-yl) - (2, 6-dimethylmorpholin-4-yl) -methanone (2.18 g), white solid), yield: 75 percent.
1HNMR(400Hz，DMSO-d6)：8.75(s，1H)，8.21(d，1H)，7.59(d，1H)，4.35(d，1H)，3.55(m，4H)，2.78(t，1H)，1.16(d，3H)，0.99(d，3H)。
The second step is that:
dissolving (5-bromo-pyridin-2-yl) - (2, 6-dimethylmorpholin-4-yl) -methanone (299.2mg, 1mmol) and pinacol diboron (330mg, 1.3mmol) in dioxane at room temperature, adding [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride (40.8mg, 0.04mmol), potassium acetate (294mg, 3mmol), displacing with nitrogen, heating to 120 ℃ for reaction for 24 hours, concentrating the reaction solution under reduced pressure, dissolving the residue in ethyl acetate, filtering, and concentrating the filtrate under reduced pressure to obtain corresponding pyridine substituted boric acid (320mg, brown solid); directly used for the next reaction.
The third step:
dissolving corresponding pyridine-substituted boronic acid (320mg, 1.2mmol) and 2- (6-bromo-thieno [3, 2-d ] pyrimidin-4-ylamine) -2-phenyll-ethanol (250mg, 0.71mmol) in N, N-dimethylformamide (10ml) at room temperature, adding tetrakis (triphenylphosphine) palladium (41mg, 0.036mmol) and sodium carbonate (225mg, 2.13mmol), displacing with nitrogen, reacting at 85 ℃ for 2 hours, cooling, adding 200ml water to the reaction solution, extracting with ethyl acetate (100ml 3), washing with saturated sodium chloride solution (100ml 3), drying and filtering the obtained organic phase with anhydrous magnesium sulfate, concentrating under reduced pressure, and purifying the obtained residue with silica gel column chromatography to obtain (S) - (2, 6-dimethyl-morpholin-4-yl) - {5- [4- (2-hydroxy-1-phenyl- Ethylamine) -thiophene [3, 2-d ] pyrimidin-6-yl ] -pyridin-2-yl } -methanone (85mg, brown solid) in 24% yield.
MSm/z(ESI)：489.98[M+1]；
1HNMR(400Hz，DMSO-d6)：9.09(s，1H)，8.42(m，3H)，8.02(s，1H)，7.73(d，1H)，7.42(d，2H)，7.30(t，2H)，7.21(d，1H)，5.45(d，1H)，4.98(s，1H)，4.39(d，1H)，3.72(d，3H)，3.55(s，2H)，2.90-2.75(m，1H)，1.20-1.09(m，3H)，1.00(d，3H)。
Example 7: preparation of Compound I-7
The first step is as follows:
5-bromo-2-pyridinecarboxylic acid (1.0g, 4.95mmol) and tetrahydropyrrole (0.35g, 4.95mmol) were dissolved in dichloromethane (30ml) at room temperature, and then 1-hydroxybenzotriazole (0.8g, 5.94mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (1.14g, 5.94mmol) and N, N-diisopropylethylamine (1.92g, 14.85mmol) were added in this order, stirred at room temperature for 24 hours, water (100ml) was added to the reaction solution, dichloromethane (50ml 3) was extracted, followed by washing with saturated sodium chloride (100ml 2), the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography to give (5-bromo-pyridin-2-yl) -pyrrolidinyl-piperazin-1-yl) -methanone (800mg, white solid), yield: 61.5 percent.
1HNMR(400Hz，DMSO-d6)：8.76(s，1H)，8.22(d，1H)，7.70(d，1H)，3.50-3.63(d，4H)，1.87(s，4H).
The second step is that:
(5-bromo-pyridin-2-yl) -pyrrolidinyl-piperazin-1-yl) -methanone (300mg, 118mmol) and pinacol diboron ester (388mg, 1.53mmol) were dissolved in dioxane at room temperature, then [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium (43mg, 0.059mmol), potassium acetate (347mg, 3.54mmol) were added, nitrogen was replaced, the reaction was heated to 120 ℃ for 24 hours, the reaction solution was concentrated under reduced pressure, the residue was dissolved in ethyl acetate, filtered, and the filtrate was concentrated under reduced pressure to give the corresponding pyridine substituted boronic acid (340mg, brown solid); directly used for the next reaction.
The third step:
corresponding pyridine-substituted boronic acid (340mg, 1.54mmol) and 2- (6-bromo-thieno [3, 2-d ] pyrimidin-4-ylamine) -2-phenyl l-ethanol (200mg, 0.57mmol) were dissolved in N, N-dimethylformamide (10ml) at room temperature, tetrakis (triphenylphosphine) palladium (40mg, 0.034mmol), sodium carbonate (181mg, 1.71mmol) were added, nitrogen substitution was performed, reaction was performed at 85 ℃ for 2 hours, 100ml of water was added to the reaction solution after cooling, extraction was performed with ethyl acetate (100 ml. sup.3), washing was performed with a saturated sodium chloride solution (100 ml. sup.2), the obtained organic phase was dried over anhydrous magnesium sulfate, filtered, concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography to obtain (S) - {5- [4- (2-hydroxy-1-phenyl-ethylamine) -thiophene [3 ], 2-d ] pyrimidin-6-yl ] -pyridin-2-yl } -pyrrolidin-1-yl-methanone (56mg, off-white solid) in 22% yield.
MSm/z(ESI)：445.96；
1HNMR(400Hz，DMSO-d6)：9.05(s，1H)，8.38(m，3H)，8.05(s，1H)，7.88(d，1H)，7.45(d，2H)，7.32(m，2H)，7.25(m，1H)，5.47(m，1H)，4.99(m，1H)，3.79(m，2H)，3.75(m，2H)，3.54(m，2H)，1.88(m，4H)。
Example 8: preparation of Compound II-1
The first step is as follows:
at room temperature, 5-bromo-2-pyridinecarboxylic acid (1.65g, 8.19mmol) was dissolved in methanol solution (30ml), concentrated sulfuric acid (2.5ml) was added dropwise, heating was carried out, reflux condensation was carried out, reaction was carried out for 12 hours, the reaction solution was slowly added dropwise to saturated sodium bicarbonate solution (200ml), extraction was carried out with ethyl acetate (100ml × 3), washing was carried out with saturated sodium chloride solution (100ml × 2), the organic phase was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to obtain methyl 5-bromo-2-pyridinecarboxylate (white solid, 1.39g), yield: 79 percent.
The second step is that:
dissolving 5-bromo-2-pyridinecarboxylic acid methyl ester (648mg, 3mmol) in methanol solution (10ml), slowly adding sodium borohydride (340mg, 9mmol) in ice bath, removing ice bath after adding, heating to room temperature, and stirring for reaction for 12 hours; then 1N HCl was added to adjust the pH to 1, then saturated sodium bicarbonate solution was added thereto to adjust the pH to 8, followed by extraction with ethyl acetate, and the organic phase was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give 5-bromo-2-pyridinemethanol (535mg, white solid) in yield: 94.8 percent.
The third step:
5-bromo-2-pyridinemethanol (500mg, 2.66mmol) was dissolved in thionyl chloride (5ml) at room temperature, stirred at room temperature, reacted for 12 hours, and concentrated under reduced pressure to give 5-bromo-2-chloromethylpyridine (635mg, white solid) in yield: 98 percent.
The fourth step:
after 5-bromo-2-chloromethylpyridine (2.43g, 10mmol) and N-Boc piperazine (2.8g, 15mmol) were dissolved in N, N-dimethylformamide (20ml), potassium carbonate (4.84g, 35mmol) was added, the reaction was stirred at room temperature for 12 hours, after cooling, 200ml of water was added to the reaction solution, extraction was performed with ethyl acetate (100ml × 3), followed by washing with a saturated sodium chloride solution (100ml × 2), and the resulting organic phase was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to give tert-butyl 4- (5-bromo-pyridine-2-methyl) -piperazine-1-carboxylate (3g, off-white solid) in yield: 84 percent.
The fifth step:
tert-butyl 4- (5-bromo-pyridine-2-methyl) -piperazine-1-carboxylate (3g, 8.42mmol) and pinacol diboron (2.56g, 10.1mmol) were dissolved in N, N-dimethylformamide (15ml) at room temperature, then [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium (0.308g, 0.42mmol) and potassium acetate (1g, 10.1mmol) were added, nitrogen was substituted, reaction was carried out at 85 ℃ for 12 hours, the reaction solution was concentrated under reduced pressure, the residue was dissolved in ethyl acetate, filtered, and the filtrate was concentrated under reduced pressure to give the corresponding pyridine-substituted boronic acid (1.97g, brown solid) in yield: 73 percent; directly used for the next reaction.
And a sixth step:
corresponding pyridine-substituted boronic acid (1.97g, 6.13mmol) and 2- (6-bromo-thieno [3, 2-d ] pyrimidin-4-ylamine) -2-phenyl l-ethanol (1.95g, 5.57mmol) were dissolved in N, N-dimethylformamide (15ml) at room temperature, then tetrakis (triphenylphosphine) palladium (0.644g, 0.56mmol), sodium carbonate (1.77g, 16.7mmol) were added, nitrogen substitution was performed, reaction was performed at 85 ℃ for 2 hours, after cooling, 100ml of water was added to the reaction solution, extraction was performed with ethyl acetate (100ml 3), then washing was performed with a saturated sodium chloride solution (100ml 2), the resulting organic phase was dried over anhydrous magnesium sulfate, filtered, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography to give (S) -4- {5- [4- (2-hydroxy-1-phenyl-ethylamine) -thiophene [3, 2-d ] pyrimidin-6-yl ] -pyridine-2-methyl } -piperazine-1-carboxylic acid tert-butyl ester (2.3g, red solid) yield 76%.
MSm/z(ESI)：547.6。
The seventh step:
slowly adding hydrochloric acid solution of ethyl acetate (1.1N, 70ml) into dichloromethane solution of (S) -4- {5- [4- (2-hydroxy-1-phenyl-ethylamine) -thiophene [3, 2-d ] pyrimidin-6-yl ] -pyridine-2-methyl } -piperazine-1-carboxylic acid tert-butyl ester under ice bath, removing ice bath, stirring at room temperature, reacting for 4 hours, concentrating under reduced pressure, adding saturated sodium carbonate solution (100ml), extracting with ethyl acetate (100ml x 3), washing with saturated sodium chloride solution (100ml x 2), drying and filtering the obtained organic phase with anhydrous magnesium sulfate, concentrating under reduced pressure to obtain product 2-phenyl-2- [6- (6-piperazin-1-methyl-pyridin-3-yl) -thiophene [3 ], 2-d ] pyrimidin-4-amino ] -ethanol (1.69g, brown solid), yield: 89.9 percent.
Example 9: preparation of Compound II-2
The first step is as follows:
n-methylpiperazine (301mg, 3mmol) and 5-bromo-2-pyrimidinecarboxylic acid (507mg, 2.5mmol) were dissolved in dichloromethane (10ml) at room temperature, then 1-hydroxybenzotriazole (405mg, 3mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (575mg, 3mmol), triethylamine (0.8ml) were added in this order, stirred at room temperature, reacted for 12 hours, water (100ml) was added thereto, extracted with dichloromethane (100ml x 2), washed with a saturated sodium chloride solution (100ml x 2), the resulting organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography to give (5-bromo-pyrimidin-2-yl) - (4-methyl-piperazin-1-yl) -methanone (320mg, yellow solid), yield: 45 percent.
MSm/z(ESI)：285.96；
1HNMR(400Hz，DMSO-d6)：9.11(s，2H)，3.64(m，2H)，3.17(m，2H)，2.51(m，2H)，2.37(m，2H)，2.25(s，3H)。
The second step is that:
(5-bromo-pyrimidin-2-yl) - (4-methyl-piperazin-1-yl) -methanone (300mg, 1.05mmol) and pinacol diboron (321mg, 1.26mmol) were dissolved in N, N-dimethylformamide (10ml) at room temperature, then [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium (38mg, 0.053mmol) and potassium acetate (308mg, 3.15mmol) were added, nitrogen was substituted, reaction was carried out at 85 ℃ for 12 hours, the reaction solution was concentrated under reduced pressure, the residue was dissolved in ethyl acetate, filtered, and the filtrate was concentrated under reduced pressure to give the corresponding pyrimidine-substituted boronic acid (200mg, brown solid) in yield: 76%; directly used for the next reaction.
The third step:
corresponding pyridine-substituted boronic acid (200mg, 0.80mmol) and 2- (6-bromo-thieno [3, 2-d ] pyrimidin-4-ylamine) -2-phenyl l-ethanol (223mg, 0.67mmol) were dissolved in N, N-dimethylformamide (10ml) at room temperature, tetrakis (triphenylphosphine) palladium (39mg, 0.034mmol) and sodium carbonate (213mg, 2.01mmol) were added, nitrogen substitution was performed, reaction was performed at 85 ℃ for 4 hours, 100ml of water was added to the reaction solution after cooling, extraction was performed with ethyl acetate (100ml 3), washing was performed with saturated sodium chloride solution (100ml 2), the obtained organic phase was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography to obtain (S) - (4-methyl-piperazin-1-yl) - {5- [4- (2-hydroxy-1-phenyl-ethylamine) - (S) - (4-methyl-piperazin-1-yl) - {5- [4- (2-hydroxy-1-phenyl-ethylamine) ) -thieno [3, 2-d ] pyrimidin-6-yl ] -pyrimidin-2-yl } -methanone (120mg, white solid), yield: 37 percent.
MSm/z(ESI)：475.98；
1HNMR(400Hz，DMSO-d6)：9.10(s，2H)，8.30(m，1H)，7.95(s，1H)，7.63(s，1H)，7.45(m，2H)，7.33(m，2H)，7.24(m，1H)，5.45(m，1H)，5.00(m，1H)，3.79(m，2H)，3.64(m，2H)，3.18(m，2H)，2.51(m，2H)，2.38(m，2H)，2.26(s，3H)。
Example 10: preparation of Compound II-3
The first step is as follows:
n-ethylpiperazine (274mg, 2.4mmol) and 5-bromo-2-pyrimidinecarboxylic acid (406mg, 2mmol) were dissolved in dichloromethane (10ml) at room temperature, then 1-hydroxybenzotriazole (324mg, 2.4mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (460mg, 2.4mmol), triethylamine (0.8ml) were added in this order, stirred at room temperature, reacted for 12 hours, water (100ml) was added thereto, extracted with dichloromethane (100ml x 2), washed with a saturated sodium chloride solution (100ml x 2), the resulting organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography to give (5-bromo-pyrimidin-2-yl) - (4-ethyl-piperazin-1-yl) -methanone (287mg, white solid), yield: 48 percent.
MSm/z(ESI)：300.06；
1HNMR(400Hz，DMSO-d6)：9.11(s，2H)，3.64(m，2H)，3.18(m，2H)，2.28-2.24(m，6H)，1.00(m，3H)。
The second step is that:
(5-bromo-pyrimidin-2-yl) - (4-ethyl-piperazin-1-yl) -methanone (280mg, 0.94mmol) and pinacol diboron (285mg, 1.12mmol) were dissolved in N, N-dimethylformamide (10ml) at room temperature, then [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride (34mg, 0.047mmol) and potassium acetate (276mg, 2.82mmol) were added, nitrogen was substituted, reaction was carried out at 85 ℃ for 12 hours, the reaction solution was concentrated under reduced pressure, the residue was dissolved in ethyl acetate, filtered, and the filtrate was concentrated under reduced pressure to give the corresponding pyrimidine-substituted boronic acid (194mg, brown solid) in yield: 78 percent; directly used for the next reaction.
The third step:
corresponding pyridine-substituted boronic acid (194mg, 0.73mmol) and 2- (6-bromo-thieno [3, 2-d ] pyrimidin-4-ylamine) -2-phenyll-ethanol (214mg, 0.61mmol) were dissolved in N, N-dimethylformamide (10ml) at room temperature, tetrakis (triphenylphosphine) palladium (35mg, 0.031mmol) and sodium carbonate (194mg, 1.83mmol) were added, nitrogen substitution was performed, reaction was performed at 85 ℃ for 4 hours, 100ml of water was added to the reaction solution after cooling, extraction was performed with ethyl acetate (100ml 3), washing was performed with saturated sodium chloride solution (100ml 2), the obtained organic phase was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography to obtain (S) - (4-ethyl-piperazin-1-yl) - {5- [4- (2-hydroxy-1-phenyl-ethylamine) ) -thieno [3, 2-d ] pyrimidin-6-yl ] -pyrimidin-2-yl } -methanone (87mg, white solid), yield: 29 percent.
MSm/z(ESI)：490.23；
1HNMR(400Hz，DMSO-d6)：9.11(s，2H)，8.29(m，1H)，7.94(s，1H)，7.63(s，1H)，7.45(m，2H)，7.33(m，2H)，7.24(m，1H)，5.46(m，1H)，5.01(m，1H)，3.79(m，2H)，3.64(m，2H)，3.18(m，2H)，2.28-2.24(m，6H)，1.01(m，3H)。
Example 11: preparation of Compound II-4
The first step is as follows:
2-phenyl-2- [6- (6-piperazin-1-methyl-pyridin-3-yl) -thieno [3, 2-d ] pyrimidin-4-amino ] -ethanol (334mg, 0.6mmol) and bromoethanol (113mg, 0.9mmol) were dissolved in N, N-dimethylformamide (15ml) at room temperature, potassium carbonate (497mg, 3.6mmol) was added, stirring was carried out overnight at room temperature, water (100ml) was added thereto, extraction was carried out with ethyl acetate (100 ml. times.3), washing was carried out with a saturated sodium chloride solution (100 ml. times.2), the resulting organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography to give 2- (6- {6- [4- (2-hydroxy-ethyl) -piperazin-1-methyl ] -pyridin-3-yl } -thiophene) [3, 2-d ] pyrimidin-4-amino) -2-phenyl-ethanol (25mg, white powder), yield: 8 percent.
MSm/z(ESI)：490.92；
1HNMR(400Hz，DMSO-d6)：9.03(d，1H)，8.43(s，1H)，8.37(m，1H)，8.28(m，1H)，7.96(s，1H)，7.63(d，1H)，7.49(d，2H)，7.35(m，2H)，7.28(m，1H)，5.49(m，1H)，5.07(m，1H)，3.84(m，2H)，3.75(s，2H)，3.46(m，6H)，2.55(m，6H)。
Example 12: preparation of Compound II-5
The first step is as follows:
wherein 5-bromo-2-chloromethylpyridine was prepared as described in example 8.
5-bromo-2-chloromethylpyridine (243mg, 2mmol) and N-isobutyrylpiperazine (289mg, 3mmol) were dissolved in N, N-dimethylformamide (10ml), potassium carbonate (691mg, 10mmol) was then added, the reaction was stirred at room temperature for 12 hours, after cooling, 100ml of water was added to the reaction solution, extraction was performed with ethyl acetate (50ml _ 3), washing was performed with a saturated sodium chloride solution (100ml _ 2), and the resulting organic phase was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to give 1- [4- (5-bromo-pyridin-2-methyl) -piperazin-1-yl ] -2-methyl-propan-1-one (282mg, oil) in yield: 86 percent.
The second step is that:
1- [4- (5-bromo-pyridin-2-methyl) -piperazin-1-yl ] -2-methyl-propan-1-one (280mg, 0.86mmol) and pinacolate diboron (262mg, 1.03mmol) were dissolved in N, N-dimethylformamide (10ml) at room temperature, then [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium (32mg, 0.43mmol) and potassium acetate (102mg, 1.03mmol) were added, nitrogen was replaced, reaction was carried out at 85 ℃ for 12 hours, the reaction solution was concentrated under reduced pressure, the residue was dissolved in ethyl acetate, filtration was carried out, the filtrate was concentrated under reduced pressure to give the corresponding pyridine-substituted boronic acid (204mg, brown solid) in yield: 82%; directly used for the next reaction.
The third step:
corresponding pyridine-substituted boronic acid (204mg, 0.7mmol) and 2- (6-bromo-thieno [3, 2-d ] pyrimidin-4-ylamine) -2-phenyll-ethanol (223mg, 0.64mmol) were dissolved in N, N-dimethylformamide (10ml) at room temperature, tetrakis (triphenylphosphine) palladium (74mg, 0.064mmol), sodium carbonate (203mg, 1.92mmol) were added, nitrogen substitution was performed, reaction was performed at 85 ℃ for 2 hours, 100ml of water was added to the reaction solution after cooling, extraction was performed with ethyl acetate (100 ml. sup.3), washing was performed with a saturated sodium chloride solution (100 ml. sup.2), the obtained organic phase was dried over anhydrous magnesium sulfate, filtered under reduced pressure, and the obtained residue was purified by silica gel column chromatography to obtain (S) -1- (4- {5- [4- (2-hydroxy-1-phenyl-ethylamine) -thiophene [3 ], 2-d ] pyrimidin-6-yl ] -pyridin-2-methyl } -piperazin-1-yl) -2-methyl-propan-1-one (192mg, light yellow solid), yield: 58 percent.
MSm/z(ESI)：517.6；
1HNMR(400Hz，DMSO-d6)：9.01(s，1H)，8.39(s，1H)，8.29(m，2H)，7.94(s，1H)，7.63(d，1H)，7.45(d，2H)，7.33(m，2H)，7.24(m，1H)，5.46(m，1H)，5.01(m，1H)，3.79(m，2H)，3.72(s，2H)，3.51(m，4H)，2.86(m，1H)，2.41(m，4H)，0.99(d，6H)。
Example 13: preparation of Compound II-6
The first step is as follows:
2-phenyl-2- [6- (6-piperazin-1-methyl-pyridin-3-yl) -thieno [3, 2-d ] pyrimidin-4-amino ] -ethanol (166mg, 0.3mmol) and glycolic acid (35mg, 0.45mmol) were dissolved in N, N-dimethylformamide (8ml) at room temperature, O-benzotriazole-N, N, N ', N' -tetramethyluronium tetrafluoroborate (145mg, 0.45mmol) and N, N-diisopropylethylamine (388mg, 3mmol) were added, the reaction was stirred at room temperature for 30 minutes, water (100ml) was added, extraction was performed with ethyl acetate (100 ml. multidot.2), washing was performed with a saturated sodium chloride solution (100 ml. multidot.2), the resulting organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, the resulting residue was purified by silica gel column chromatography to give 2-hydroxy-1- (4- {5- [4- (2-hydroxy-1-phenyl-ethylamino) -thiophen [3, 2-d ] pyrimidin-6-yl ] -pyridin-2-methyl } -piperazin-1-yl) -ethanone (80mg, off-white solid) yield: 53 percent.
MSm/z(ESI)：504.9；
1HNMR(400Hz，DMSO-d6)：9.00(d，1H)，8.39(s，1H)，8.26(m，2H)，7.93(s，1H)，7.62(d，1H)，7.44(d，2H)，7.27(m，2H)，7.21(m，1H)，5.46(m，1H)，4.98(m，1H)，3.80(m，2H)，3.70(s，2H)，3.46(m，4H)，3.33(s，2H)，2.47(m，4H)。
Example 14: preparation of Compound II-7
The first step is as follows:
2-phenyl-2- [6- (6-piperazin-1-methyl-pyridin-3-yl) -thieno [3, 2-d ] pyrimidin-4-amino ] -ethanol (166.8mg, 0.3mmol) and 2-hydroxyisobutyric acid (46.8mg, 0.45mmol) were dissolved in N, N-dimethylformamide (8ml) at room temperature, then O-benzotriazol-N, N, N ', N' -tetramethyluronium tetrafluoroborate (144.5mg, 0.45mmol) and N, N-diisopropylethylamine (388.5mg, 3mmol) were added, the reaction was stirred at room temperature for 30 minutes, water (100ml) was added thereto, extraction was performed with ethyl acetate (100 ml. about.2), washing was performed with a saturated sodium chloride solution (100 ml. about.2), and the resulting organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography to give 2-hydroxy-1- (4- {5- [4- (2-hydroxy-1-phenyl-ethylamine) -thieno [3, 2-d ] pyrimidin-6-yl ] -pyridin-2-methyl } -piperazin-1-yl) -2-methyl-propan-1-one (70mg, off-white solid), yield: 43.8 percent.
MSm/z(ESI)：533.0；
1HNMR(400Hz，DMSO-d6)：9.01(d，1H)，8.39(s，1H)，8.27(m，2H)，7.94(s，1H)，7.63(d，1H)，7.45(d，2H)，7.29(m，2H)，7.22(m，1H)，5.45(m，1H)，5.03(m，1H)，3.80(m，4H)，3.71(m，4H)，2.45(m，4H)，1.32(s，6H)。
Example 15: preparation of Compound II-8
The first step is as follows:
wherein 5-bromo-2-chloromethylpyridine was prepared as described in example 8.
After 5-bromo-2-chloromethylpyridine (500mg, 2.06mmol) and 1-methanesulfonylpiperazine (440mg, 2.68mmol) were dissolved in N, N-dimethylformamide (10ml), potassium carbonate (996mg, 7.21mmol) was added, the reaction was stirred at room temperature for 12 hours, after cooling, 100ml of water was added to the reaction solution, extraction was performed with ethyl acetate (100ml × 3), and then washing was performed with a saturated sodium chloride solution (100ml × 2), and the resulting organic phase was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give 1- (5-bromo-pyridine-2-methyl) -4-methanesulfonyl-piperazine (520mg, off-white solid) in yield: 75.6 percent.
The second step is that:
1- (5-bromo-pyridin-2-methyl) -4-methanesulfonyl-piperazine (334mg, 1mmol) and pinacol diboron (330mg, 1.3mmol) were dissolved in N, N-dimethylformamide (10ml) at room temperature, followed by addition of [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium (40mg, 0.05mmol) and potassium acetate (294mg, 3mmol), nitrogen substitution, reaction at 85 ℃ for 12 hours, reaction solution was concentrated under reduced pressure, residue was dissolved in ethyl acetate, filtered, filtrate was concentrated under reduced pressure to give the corresponding pyridine-substituted boronic acid (230mg, brown solid) in yield: 76 percent.
The third step:
dissolving corresponding pyridine-substituted boric acid (230mg, 0.77mmol) and 2- (6-bromo-thieno [3, 2-d ] pyrimidin-4-ylamine) -2-phenyl l-ethanol (170mg, 0.48mmol) in N, N-dimethylformamide (10ml) at room temperature, adding tetrakis (triphenylphosphine) palladium (28mg, 0.024mmol), sodium carbonate (153mg, 1.44mmol), displacing with nitrogen, reacting at 85 ℃ for 2 hours, cooling, adding 100ml water to the reaction solution, extracting with ethyl acetate (50ml 3), washing with saturated sodium chloride solution (100ml 2), drying the obtained organic phase with anhydrous magnesium sulfate, filtering, concentrating under reduced pressure, and purifying the obtained residue with silica gel column chromatography to obtain (S) -2- {6- [6- (4-methanesulfonyl-piperazin-1-methyl) -pyridin-3-yl ] - Thiophene [3, 2-d ] pyrimidin-4-amino } -2-phenyl-ethanol (50mg, yellow solid) in 20% yield.
MSm/z(ESI)：524.98；
1HNMR(400Hz，DMSO-d6)：9.04(d，1H)，8.40(s，1H)，8.27(m，2H)，7.95(s，1H)，7.56(d，1H)，7.43(d，2H)，7.30(m，2H)，7.22(m，1H)，5.46(m，1H)，5.24(s，2H)，4.96(m，1H)，3.77(m，2H)，3.56(m，4H)，3.16(m，4H)，2.91(s，3H)。
Example 16: preparation of Compound II-9
The first step is as follows:
wherein 5-bromo-2-chloromethylpyridine was prepared as described in example 8.
5-bromo-2-chloromethylpyridine (486mg, 2mmol) and thiomorpholine 1, 1-dioxide (406mg, 3mmol) were dissolved in N, N-dimethylformamide (10ml), and then potassium carbonate (986mg, 7mmol) was added, the reaction was stirred at room temperature for 12 hours, after cooling, 100ml of water was added to the reaction solution, extraction was performed with ethyl acetate (100ml × 3), followed by washing with a saturated sodium chloride solution (100ml × 2), and the resulting organic phase was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to give 1- (5-bromo-pyridine-2-methyl) - (1, 1-dioxo-thiomorpholine) -piperazine (499mg, off-white solid) yield: 81.8 percent.
The second step is that:
1- (5-bromo-pyridin-2-methyl) - (1, 1-dioxo-thiomorpholine) -piperazine (152mg, 0.5mmol) and pinacol diboron (153mg, 0.6mmol) were dissolved in N, N-dimethylformamide (10ml) at room temperature, then [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium (21mg, 0.025mmol) and potassium acetate (59mg, 0.6mmol) were added, nitrogen was substituted, reaction was carried out at 85 ℃ for 12 hours, the reaction solution was concentrated under reduced pressure, the residue was dissolved in ethyl acetate, filtered, and the filtrate was concentrated under reduced pressure to give the corresponding pyridine-substituted boronic acid (118mg, brown solid) in yield: 87 percent.
The third step:
corresponding pyridine-substituted boronic acid (118mg, 0.44mmol) and 2- (6-bromo-thiophene [3, 2-d ] pyrimidin-4-ylamine) -2-phenyl l-ethanol (140mg, 0.40mmol) were dissolved in N, N-dimethylformamide (10ml) at room temperature, tetrakis (triphenylphosphine) palladium (47mg, 0.04mmol) and sodium carbonate (85mg, 0.8mmol) were added, nitrogen substitution was performed, reaction was performed at 85 ℃ for 2 hours, 100ml of water was added to the reaction solution after cooling, extraction was performed with ethyl acetate (50ml 3), washing was performed with a saturated sodium chloride solution (100ml 2), the obtained organic phase was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography to obtain (S) -2- {6- [6- (1, 1-dioxo-thiomorpholin-4-methyl) -pyridin-3-yl ] -thieno [3, 2-d ] pyrimidin-4-amino } -2-phenyl-ethanol (60mg, yellow solid) in 30% yield.
MSm/z(ESI)：496.63；
1HNMR(400Hz，DMSO-d6)：9.00(d，1H)，8.39(s，1H)，8.23(m，2H)，7.92(s，1H)，7.66(d，1H)，7.43(d，2H)，7.31(m，2H)，7.23(m，1H)，5.45(m，1H)，4.94(m，1H)，3.86(s，2H)，3.76(m，2H)，3.14(m，4H)，2.99(m，4H)。
Example 17: preparation of Compound III-1
{5- [4- (2-hydroxy-1-phenyl l-ethylamine) -thieno [3, 2-d ] pyrimidin-6-yl ] -pyridin-2-yl } -carbamic acid tert-butyl ester was dissolved in dichloromethane (2ml) at room temperature, then trifluoroacetic acid (257.4mg, 2.58mmol) was added, reaction was carried out at room temperature for 2 hours, a saturated sodium carbonate solution (100ml) was added thereto, extraction was carried out with dichloromethane (50ml × 2), washing was carried out with a saturated sodium chloride solution (100ml × 3), the resulting organic phase was dried over anhydrous magnesium sulfate, filtered under reduced pressure, and the resulting residue was purified by silica gel column chromatography to give 2- [6- (6-amino-pyridin-3-yl) -thieno [3, 2-d ] pyrimidin-4-ylamine ] -2-phenyl-ethanol (30mg, white solid), yield: 76 percent.
MSm/z(ESI)：363.92[M+1]；
1HNMR(400Hz，DMSO-d6)：8.47(m，3H)，7.92(d，1H)，7.64(s，1H)，7.53(d，2H)，7.46(m，3H)，6.81(m，3H)，5.48(m，1H)，5.10(m，1H)，3.86(m，2H)。
Example 18: preparation of Compound III-2
The first step is as follows:
2-amino-5-bromopyridine (5g, 29mmol) and di-tert-butyl dicarbonate (6.9g, 32mmol) were dissolved in tetrahydrofuran (28ml) at room temperature, heated to 70 ℃, condensed under reflux, reacted for 24 hours, concentrated under reduced pressure to give a crude product, which was washed with diethyl ether: petroleum ether (1: 1), concentrated under reduced pressure to give 2-Boc amino-5-bromopyridine (5g, white solid) in yield: and 63 percent.
1HNMR(400Hz，DMSO-d6)：9.99(s，1H)，8.36(s，1H)，7.80(d，1H)，7.77(d，1H)，1.47(d，9H)。
The second step is that:
after 2-Boc amino-5-bromopyridine (150mg, 0.55mmol) and pinacol diborate (181mg, 0.71mmol) were dissolved in N, N-dimethylformamide (5ml) at room temperature, potassium acetate (161mg, 1.65mmol) and [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride (23mg, 0.028mmol) were added, and the reaction mixture was reacted at 100 ℃ for 15 minutes by microwave, 200ml of water was added to the reaction mixture, extracted with ethyl acetate (100ml x 3), washed with saturated sodium chloride solution (100ml x 3), and the resulting organic phase was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography to give pyridine 2-Boc amino-5-pinacol diborate (17mg, white solid) in yield: 20 percent.
1HNMR(400Hz，DMSO-d6)：9.99(s，1H)，8.47(s，1H)，7.93(m，2H)，1.48(s，9H)，1.28(m，12H)。
The third step:
2-Boc amino-5-boronic acid pinacol ester pyridine (96.7mg, 0.3mmol) and 2- (6-bromo-thieno [3, 2-d ] pyrimidin-4-ylamine) -2-phenyl l-ethanol (70mg, 0.2mmol) were dissolved in N, N-dimethylformamide (3ml) at room temperature, then tetrakis (triphenylphosphine) palladium (23mg, 0.02mmol) and a sodium carbonate solution (1N, 0.6ml) were added, reacted at 85 ℃ for 2 hours, 200ml of water was added to the reaction solution after cooling, extracted with ethyl acetate (100ml 3), washed with a saturated sodium chloride solution (100ml 3), the resulting organic phase was dried over anhydrous magnesium sulfate, filtered, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography to give {5- [4- (2-hydroxy-1-phenyl l-ethylamine) -thiophene [3 ], 2-d ] pyrimidin-6-yl ] -pyridin-2-yl } -carbamic acid tert-butyl ester (60mg, off-white solid) in 67% yield.
MSm/z(ESI)：463.76[M+1]；
1HNMR(400Hz，DMSO-d6)：10.1(s，1H)，8.77(s，1H)，8.39(s，1H)，8.23(m，2H)，7.99(d，1H)，7.83(s，1H)，7.47(d，2H)，7.35(t，2H)，7.26(t，1H)，5.50(m，1H)，4.99(m，1H)，3.76(m，2H)，1.52(s，9H)。
Example 19: preparation of Compound III-3
The first step is as follows:
2- [6- (6-fluoro-pyridin-3-yl) -thieno [3, 2-d ] pyrimidin-4-ylamine ] -2-phenyl-ethanol (146mg, 0.4mmol) and N-Boc piperazine (223mg, 1.2mmol) were dissolved in N, N-dimethylformamide (5ml) at room temperature, stirred at room temperature for 20 hours, 100ml of water was added to the reaction solution, extracted with ethyl acetate (100 ml. about.2), washed with a saturated sodium chloride solution (100 ml. about.2), the resulting organic phase was dried over anhydrous magnesium sulfate, filtered, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography to give 4- {5- [4- (2-hydroxy-1-phenyll-ethylamine) -thieno [3, 2-d ] pyrimidin-6-yl ] -pyridin-2-yl } -piperazine- Tert-butyl 1-carboxylate (200mg, light yellow solid), yield: 94 percent; it was used directly as the next reaction.
The second step is that:
dissolving tert-butyl 4- {5- [4- (2-hydroxy-1-phenyl l-ethylamine) -thieno [3, 2-d ] pyrimidin-6-yl ] -pyridin-2-yl } -piperazine-1-carboxylate (200mg, 0.38mmol) in dichloromethane (10ml), adding trifluoroacetic acid (0.6ml, 0.008mmol), stirring at room temperature until the TLC monitoring of the completion of the reaction of the starting materials, adding 200ml of ethyl acetate, slowly adding saturated sodium bicarbonate dropwise with stirring, extracting, washing the organic phase with saturated sodium chloride solution (100 ml. times.2), drying and filtering the resulting organic phase with anhydrous magnesium sulfate, concentrating under reduced pressure, and purifying the resulting residue with silica gel column chromatography to obtain 2-phenyl-2- [6- (6-piperazin-1-yl-pyridin-3-yl) -thieno [ 3-yl ] -2-phenyl-2- [6- (6-piperazin-1-yl-pyridin-3-yl ] -thiophene [ 3-yl ] -piperazine-1-carboxylic acid 2-d ] pyrimidin-4-ylamine ] -ethanol (13mg, yellow solid), yield: 8 percent.
MSm/z(ESI)：433.15[M+1]；
1HNMR(400Hz，DMSO-d6)：8.61(d，1H)，8.34(s，1H)，8.09(d，1H)，8.03(dd，1H)，7.68(s，1H)，7.45(d，2H)，7.24(m，3H)，7.01(d，1H)，5.45(m，1H)，4.99(m，1H)，3.80(m，2H)，3.55(m，9H)。
Example 20: preparation of Compound III-4
2- [6- (6-fluoro-pyridin-3-yl) -thiophen [3, 2-d ] pyrimidin-4-ylamine ] -2-phenyl-ethanol (96mg, 0.26mmol) and N-methylpiperazine (79mg, 0.79mmol) were dissolved in N, N-dimethylformamide (3ml) at room temperature, stirred at room temperature for 20 hours, 100ml of water was added to the reaction solution, extracted with ethyl acetate (100 ml. times.2), washed with a saturated sodium chloride solution (100 ml. times.2), the resulting organic phase was dried over anhydrous magnesium sulfate, filtered under reduced pressure, concentrated, and the resulting residue was purified by silica gel column chromatography to give 2- {6- [6- (4-methyl-piperazin-1-yl) -pyridin-3-yl ] -thiophene [3 ], 2-d ] pyrimidin-4-ylamine } -2-phenyl-ethanol (23mg, yellow-green solid), yield: 20 percent.
MSm/z(ESI)：447.07[M+1]；
1HNMR(400Hz，DMSO-d6)：8.60(d，1H)，8.35(s，1H)，8.08(d，1H)，8.01(dd，1H)，7.66(s，1H)，7.46(d，2H)，7.29(m，3H)，6.96(d，1H)，5.44(m，1H)，4.97(m，1H)，3.78(m，2H)，3.62(m，4H)，2.41(m，4H)，2.23(s，3H)。
Example 21: preparation of Compound III-5
The first step is as follows:
2-Fluoropyridine-5-boronic acid (282mg, 2.0mmol) and 2- (6-bromo-thiophene [3, 2-d ] pyrimidin-4-ylamine) -2-phenyl l-ethanol (800.8mg, 2.2mmol) were dissolved in N, N-dimethylformamide (20ml) at room temperature, followed by the addition of tetrakistriphenylphosphine palladium (231mg, 0.2mmol), potassium carbonate (828mg, 6mmol) in that order, under nitrogen, heating to 85 ℃ and reacting for 12 hours. To the reaction solution was added 200ml of water, extracted with ethyl acetate (100ml × 3), washed with saturated sodium chloride solution (100ml × 2), and the resulting organic phase was dried over anhydrous magnesium sulfate, filtered, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography to give 2- [6- (6-fluoro-pyridin-3-yl) -thieno [3, 2-d ] pyrimidin-4-ylamine ] -2-phenyl-ethanol (580mg, off-white solid) in yield: 79 percent.
MSm/z(ESI)：367.13[M+1]。
The second step is that:
2- [6- (6-fluoro-pyridin-3-yl) -thiophen [3, 2-d ] pyrimidin-4-ylamine ] -2-phenyl-ethanol (146mg, 0.4mmol) and N-ethylpiperazine (88mg, 0.6mmol) were dissolved in N, N-dimethylformamide (3ml) at room temperature, stirred at room temperature for 20 hours, 100ml of water was added to the reaction solution, extracted with ethyl acetate (100 ml. times.2), washed with a saturated sodium chloride solution (100 ml. times.2), the resulting organic phase was dried over anhydrous magnesium sulfate, filtered under reduced pressure, concentrated, and the resulting residue was purified by silica gel column chromatography to give 2- {6- [6- (4-ethyl-piperazin-1-yl) -pyridin-3-yl ] -thiophene [3 ], 2-d ] pyrimidin-4-ylamine } -2-phenyl-ethanol (100mg, light yellow solid), yield: 54 percent.
MSm/z(ESI)：461.64[M+1]；
1HNMR(400Hz，DMSO-d6)：8.60(s，1H)，8.34(s，1H)，8.09(d，1H)，8.01(d，1H)，7.66(s，1H)，7.40(d，2H)，7.24(m，3H)，6.98(d，1H)，5.44(m，1H)，4.98(m，1H)，3.79(m，2H)，3.64(m，4H)，2.47(m，6H)，1.07(t，3H)。
Example 22: preparation of Compound III-6
2- [6- (6-fluoro-pyridin-3-yl) -thiophen [3, 2-d ] pyrimidin-4-ylamine ] -2-phenyl-ethanol (96mg, 0.26mmol) and N-hydroxyethylpiperazine (102mg, 0.79mmol) were dissolved in N, N-dimethylformamide (3ml) at room temperature, stirred at room temperature for 20 hours, 100ml of water was added to the reaction solution, extracted with ethyl acetate (100 ml. times.2), washed with a saturated sodium chloride solution (100 ml. times.2), the resulting organic phase was dried over anhydrous magnesium sulfate, filtered, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography to give 2- {6- [6- (4- - (2-hydroxy-ethyl) -piperazin-1-yl) -pyridin-3-yl ] -thiophen [3 ], 2-d ] pyrimidin-4-ylamine } -2-phenyl-ethanol (38mg, yellow-green solid), yield: 31 percent.
MSm/z(ESI)：477.06[M+1]；
1HNMR(400Hz，DMSO-d6)：8.59(d，1H)，8.35(s，1H)，8.06(d，1H)，7.99(dd，1H)，7.66(s，1H)，7.46(d，2H)，7.29(m，3H)，6.97(d，1H)，5.44(m，1H)，4.97(m，1H)，4.46(m，1H)，3.76(m，2H)，3.58(m，8H)，2.39(m，4H)。
Example 23: preparation of Compound III-7
2- [6- (6-fluoro-pyridin-3-yl) -thiophen [3, 2-d ] pyrimidin-4-ylamine ] -2-phenyl-ethanol (110mg, 0.3mmol) and N-cyclopropylcarbonylpiperazine (138mg, 0.9mmol) were dissolved in N, N-dimethylformamide (5ml) at room temperature, stirred at room temperature for 20 hours, 200ml of water was added to the reaction solution, extracted with ethyl acetate (100 ml. times.3), washed with a saturated sodium chloride solution (100 ml. times.3), the resulting organic phase was dried over anhydrous magnesium sulfate, filtered, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography to give cyclopropyl- (4- {5- [4- (2-hydroxy-1-phenyl-ethylamine) -thiophen [3 ], 2-d ] pyrimidin-6-yl ] -pyridin-2-yl } -piperazin-1-yl) -methanone (15mg, light yellow solid), yield: 10 percent.
MSm/z(ESI)：501.19[M+1]；
1HNMR(400Hz，DMSO-d6)：8.63(d，1H)，8.35(s，1H)，8.09(d，1H)，8.02(dd，1H)，7.68(s，1H)，7.45(d，2H)，7.32(m，3H)，7.01(d，1H)，5.45(m，1H)，4.97(m，1H)，3.79(m，2H)，3.69(m，8H)，2.01(m，1H)，0.77(m，4H)。
Example 24: preparation of Compound III-8
2- [6- (6-fluoro-pyridin-3-yl) -thiophen [3, 2-d ] pyrimidin-4-ylamine ] -2-phenyl-ethanol (100mg, 0.27mmol) and 1-methanesulfonylpiperazine (44.8mg, 0.27mmol) were dissolved in N-methylpyrrolidone (3ml) at room temperature, potassium carbonate (138mg, 0.410mmol) was then added, stirring was carried out at room temperature for 20 hours, 200ml of water was added to the reaction solution, extraction was carried out with ethyl acetate (100 ml. about.3), washing was carried out with a saturated sodium chloride solution (100 ml. about.3), the obtained organic phase was dried over anhydrous magnesium sulfate, filtered under reduced pressure, and the obtained residue was purified by silica gel column chromatography to give 2- {6- [6- (4-methanesulfonyl-piperazin-1-yl) -pyridin-3-yl ] -thiophen [3, 2-d ] pyrimidin-4-ylamine } -2-phenyl-ethanol (35mg, yellow-green solid), yield: 25 percent.
MSm/z(ESI)：510.76[M+1]；
1HNMR(400Hz，DMSO-d6)：8.60(d，1H)，8.40(s，1H)，8.10(d，1H)，8.07(dd，1H)，7.75(s，1H)，7.48(d，2H)，7.30(m，3H)，7.11(d，1H)，5.48(m，1H)，5.08(m，1H)，3.89(m，6H)，3.21(m，4H)，2.97(s，3H)。
Example 25: preparation of Compound III-9
2- [6- (6-fluoro-pyridin-3-yl) -thieno [3, 2-d ] pyrimidin-4-ylamine ] -2-phenyl-ethanol (150mg, 0.4mmol) and morpholine (52mg, 0.6mmol) were dissolved in N, N-dimethylformamide (5ml) at room temperature, stirred at room temperature for 20 hours, 200ml of water was added to the reaction solution, extracted with ethyl acetate (100 ml. times.3), washed with a saturated sodium chloride solution (100 ml. times.3), the resulting organic phase was dried over anhydrous magnesium sulfate, filtered under reduced pressure, and the resulting residue was purified by silica gel column chromatography to give 2- [6- (6-morpholin-4-yl-pyridin-3-yl) -thieno [3, 2-d ] pyrimidin-4-ylamine ] -2-phenyl-ethanol (70mg, yellow-green solid), yield: 40 percent.
MSm/z(ESI)：434.16[M+1]；
1HNMR(400Hz，DMSO-d6)：8.63(s，1H)，8.36(s，1H)，8.09(d，1H)，8.01(d，1H)，7.68(s，1H)，7.45(d，2H)，7.34(m，3H)，6.98(d，1H)，5.46(m，1H)，4.98(m，1H)，3.72(m.2H)，3.65(m，4H)，3.57(m，4H)。
Example 26: preparation of Compound III-10
2- [6- (6-fluoro-pyridin-3-yl) -thieno [3, 2-d ] pyrimidin-4-ylamine ] -2-phenyl-ethanol (110mg, 0.3mmol) and 2-methyl-octahydro-pyrrolo [3, 4-c ] pyrrole (113mg, 0.9mmol) were dissolved in N, N-dimethylformamide (5ml) at room temperature, stirred at room temperature for 20 hours, 200ml of water was added to the reaction solution, extracted with ethyl acetate (100ml of x 3), washed with a saturated sodium chloride solution (100ml of x 3), and the resulting organic phase was dried over anhydrous magnesium sulfate, filtered under reduced pressure, and the resulting residue was purified by silica gel column chromatography to give 2- {6- [6- (5-methyl-hexahydro-pyrrolo [3 ], 4-c ] pyrrol-2-yl) -pyridin-3-yl ] -thiophen [3, 2-d ] pyrimidin-4-ylamine } -2-phenyl-ethanol (34mg, yellow-green solid), yield: 24 percent.
MSm/z(ESI)：473.15[M+1]；
1HNMR(400Hz，DMSO-d6)：8.60(d，1H)，8.35(s，1H)，8.08(d，1H)，8.01(dd，1H)，7.66(s，1H)，7.46(d，2H)，7.29(m，3H)，6.96(d，1H)，5.44(m，1H)，4.97(m，1H)，3.78(m.2H)，3.52(m，8H)，2.91(m，2H)，2.83(s，3H)。
Example 27: preparation of Compound III-11
2- [6- (6-fluoro-pyridin-3-yl) -thiophen [3, 2-d ] pyrimidin-4-ylamine ] -2-phenyl-ethanol (109.8mg, 0.3mmol) and thiomorpholine 1, 1-dioxide (60.8mg, 0.45mmol) were dissolved in N, N-dimethylformamide (3ml) at room temperature, stirred at room temperature for 20 hours, 200ml of water was added to the reaction solution, extracted with ethyl acetate (100 ml. times.3), washed with saturated sodium chloride solution (100 ml. times.3), the resulting organic phase was dried over anhydrous magnesium sulfate, filtered under reduced pressure, and the resulting residue was purified by silica gel column chromatography to give 2- {6- [6- (1, 1-bisoxo-thiomorpholine-4-yl) -pyridin-3-yl ] -thiophen [3 ], 2-d ] pyrimidin-4-ylamine } -2-phenyl-ethanol (30mg, yellow-green solid), yield: 21 percent.
MSm/z(ESI)：482.03[M+1]；
1HNMR(400Hz，DMSO-d6)：8.61(d，1H)，8.28(s，1H)，8.25(d，1H)，8.04(dd，1H)，7.68(s，1H)，7.39(d，2H)，7.27(m，2H)，7.16(m，2H)，5.37(m，1H)，5.14(m，1H)，3.78(m，2H)，3.21(m，4H)，2.95(m，4H)。
Biological evaluation
1. Preliminary evaluation of enzyme activity inhibition of receptor tyrosine kinases EGFR and VEGFR molecular level
(1) An enzyme reaction substrate Poly (Glu, Tyr) 4: 1 is diluted into 20 mu g/ml by PBS (10mM sodium phosphate buffer solution, 150mmol/LNaCl, pH 7.2-7.4) without potassium ions and coated on an enzyme label plate at 125 mu l/hole, the enzyme label plate is placed at 37 ℃ for reaction for 12-16 hours, liquid in the hole is discarded, the plate is washed, and the plate is washed by T-PBS (containing 0.1% Tween-20 and without potassium ions) at 200 mu l/hole for three times, and each time is 5 minutes; and drying the ELISA plate in an oven at 37 ℃ for 1-2 hours.
(2) Reaction buffer (50mmol/LHEPESpH7.4, 50 mmol/LMgCl) was added to each well2，0.5mmol/LMnCl2，0.2mmol/LNa3VO41mmol/LDTT) at a final concentration of 5. mu. mol/L. Mu.l of compound solution (1% DMSO dissolved to a final concentration of 10. mu. mol/L) was added to each well, and 50. mu.l of c-Met tyrosine kinase protein diluted with reaction buffer was added; reacting for 1 hour in a shaker (100rpm) at 37 ℃; two wells without ATP control wells and corresponding DMSO solvent control wells (negative control wells) were set for each experiment; the wells were discarded and the plate washed three times with T-PBS.
(3) Adding 99100 μ l/well of PY antibody (antibody diluted with T-PBS containing BSA5mg/ml, concentration 0.4 μ g/ml), and performing shake reaction at 37 deg.C for 0.5 hr; the wells were discarded and the plate washed three times with T-PBS.
(4) Adding 100 μ l/well of goat anti-mouse secondary antibody labeled with horseradish peroxidase (the antibody is diluted with T-PBS containing BSA5mg/ml, the concentration is 0.5 μ g/ml), performing shaking table reaction at 37 ℃ for 0.5 h, discarding the liquid in the well, and washing the plate with T-PBS three times.
(5) Adding 2mg/ml OPD developing solution 100 μ l/well (containing 0.03% H)2O2Diluting with 0.1M citric acid-sodium citrate buffer solution (pH is 5.4), and reacting for 1-10 minutes at 25 ℃ in a dark place; (ultrasonic wave is needed when dissolving OPD, and the color developing solution needs to be prepared at present).
(6) 2mol/LH is added2SO4The reaction was stopped at 50. mu.l/well and read using a variable wavelength microplate reader VERSAmax at a wavelength of 490 nm.
(7) The inhibition ratio of the sample was obtained by the following formula:
2. inhibition of receptor tyrosine kinase EGFR enzyme activity IC50Evaluation experiment
The compound (compound 10) with EGFR or VEGFR enzyme activity inhibition effect obtained by the screening-5The inhibition rate of M to receptor tyrosine kinase EGFR or VEGFR is more than 50 percent) to prepare gradient concentration for IC50(median inhibitory concentration) evaluation.
By testing, the measured activities of a number of compounds according to the invention are shown in table 1. In these tables, "a" represents an inhibitory activity of less than 50 nanomolar (nM) according to the test; "b" represents an inhibitory activity of > 50 but < 250 nanomolar (nM); "c" represents an inhibitory activity of 250 or more but < 500 nanomolar (nM) and "d" represents an inhibitory activity of 500 nanomolar (nM) or more; "e" indicates no activity.
3. IC against tumor cell proliferation in vitro50Measurement of
Detection of cytotoxicity inhibition IC of candidate compound on human skin squamous cell carcinoma cell line A431 by CCK-8 detection kit50The value is obtained.
(1) Materials and methods
Cell lines: a431 human skin squamous cell carcinoma cell line (Shanghai cell bank of Chinese academy of sciences)
Reagents and consumables:
CellCountingKit-8(Cat#CK04-13，Dojindo)
96-well culture plate (Cat #3599, Corning Costar)
Fetal bovine serum (Cat #10099-141, GIBCO)
Culture medium (Invitrogen)
Desk type enzyme labeling instrument SpectraMaxM5MicroplateReader (molecular devices)
(2) Experimental procedure
Reagent preparation
Preparation of culture Medium
Cell line: a431
Culture medium: DMEM + 10% FBS
Preparation of the compound: the compounds were diluted with DMSO to a final concentration of 10 mM.
Cell culture
a) Collecting cells in logarithmic growth phase, counting, resuspending the cells with complete medium,
b) the cell concentration was adjusted to the appropriate concentration and seeded in 96-well plates, 100. mu.l of cell suspension per well.
c) Cells were incubated at 37 ℃ and 100% relative humidity, 5% CO2Incubate in incubator for 24 hours.
IC50Experiment of
a) Cells in the logarithmic growth phase were collected, counted, resuspended in complete medium, adjusted to the appropriate concentration (as determined by the cell density optimization assay) and seeded into 96-well plates with 100. mu.l of cell suspension per well. Cells were incubated at 37 ℃ and 100% relative humidity, 5% CO2Incubate in incubator for 24 hours.
b) The test compound was diluted to 500. mu.M with the medium and then diluted 8 times in gradient. Cells were added at 25. mu.l/well. The final concentration of action of 23 candidate compounds was from 100. mu.M to 0. mu.M, and was diluted in 5-fold gradient, for 10 concentration points.
c) Cells were incubated at 37 ℃ and 100% relative humidity, 5% CO2Incubate in incubator for 72 hours.
d) The medium was aspirated off, complete medium containing 10% CCK-8 was added and incubated in an incubator at 37 ℃ for 2-4 hours.
e) After gentle shaking, the absorbance at 450nm was measured on a SpectraMaxM5MicroplateReader, and the inhibition was calculated using the absorbance at 650nm as a reference.
Data processing
The inhibition rate of the drug on the growth of tumor cells was calculated according to the following formula: the inhibition rate of tumor cell growth [ (% A)c-As)/(Ac-Ab)]×100％
As: OA of the sample (cell + CCK-8+ test Compound)
Ac: OA of negative control (cell + CCK-8+ DMSO)
Ab: OA of positive control (Medium + CCK-8+ DMSO)
IC50 curves were fitted and IC calculated using software Graphpadprism550Value of
This experiment tested the anti-proliferative effect of candidate compounds on human skin squamous cell carcinoma cell line a 431. The final concentration of the compound was diluted in 5-fold gradient from 100. mu.M to 0. mu.M for 10 points.
The results of the experiment are shown in table 2.
TABLE 2
As can be seen from table 2: the thienopyrimidine derivative has better tyrosine kinase EGFR inhibitory activity, and particularly has better activity than that of gefitinib serving as a medicine on the market at 10 nanomolar levels of compounds II-2, II-5, II-6, III-3, III-4, III-5, III-6, III-7 and III-10; at the cellular level, the compounds II-1, II-2, II-3, II-5, II-6, III-3, III-5, III-6 and III-10 also show obvious inhibition of A431 cell activity; can be expected to be developed into a tyrosine kinase inhibitor, and has wide application prospect and medicinal value.
Claims (18)
1. A thienopyrimidine derivative having the general formula I:
in the general formula (I): ar is phenyl; a is a nitrogen atom, D, E is a carbon atom, R isWherein R is2Is C1～C6Alkyl, hydroxy substituted C1～C6Alkyl or C1～C6Alkyl-substituted sulfonyl, R3、R4Are each hydrogen or C1～C6An alkyl group; or,
is of the general formula II:
in the general formula (I): ar is phenyl; a is a nitrogen atom, D is a carbon atom or a nitrogen atom, E is a carbon atom, R isWherein R is2Is hydrogen, C1～C6Alkyl, hydroxy substituted C1～C6Alkyl radical, C1～C6Alkyl-substituted acyl, C1～C6Acyl or C substituted by alkylhydroxy1～C6An alkyl-substituted sulfonyl group; or,
is of the general formula III:
in the general formula (I): ar is phenyl; a is nitrogen atom, D, E is carbon atom, R is R1-NH-、 Wherein: r1Is hydrogen or C1～C6An alkyl-substituted ester group; r2Is hydrogen, C1～C6Alkyl, hydroxy substituted C1～C6Alkyl radical, C3～C6Cycloalkyl-substituted acyl or C1～C6An alkyl-substituted sulfonyl group; r3、R4Are all hydrogen; r5Is C1～C6An alkyl group.
2. The thienopyrimidine derivative according to claim 1 is a compound having the following chemical structural formula:
3. a process for the preparation of thienopyrimidine derivatives of general formula I as claimed in claim 1, characterized by comprising the steps (c) or (c) and (c) or (c) to (c) in the following scheme:
the definitions of Ar, A, D, E and R in the schemes are as described in claim 1.
4. The process for producing a thienopyrimidine derivative represented by the general formula I according to claim 3, characterized in that: and the step III is a Suzuki coupling reaction carried out under the action of a Pd-catalyst.
5. A process for producing a thienopyrimidine derivative represented by the general formula II according to claim 1, characterized by comprising the steps (v) or (II) and (v) or (iv), (iv) and (v) in the following scheme:
the definitions of Ar, A, D, E and R in the schemes are as described in claim 1.
6. The process for producing a thienopyrimidine derivative represented by the general formula II according to claim 5, wherein: the step five is Suzuki coupling reaction carried out under the action of Pd-catalyst.
7. A process for the preparation of thienopyrimidine derivatives of general formula iii as claimed in claim 1, characterized by comprising the steps of or both of the following schemes:
the definitions of Ar, A, D, E and R in the schemes are as described in claim 1.
8. The process for producing a thienopyrimidine derivative represented by the general formula III according to claim 7, wherein: the step of sixthly, the Suzuki coupling reaction is carried out under the action of a Pd-catalyst.
9. The process for producing a thienopyrimidine derivative according to claim 4, 6 or 8, characterized in that: the Pd-catalyst is dichlorobis (triphenylphosphine) palladium, tetrakis (triphenylphosphine) palladium or [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride.
10. A process for producing a thienopyrimidine derivative represented by the general formula II as claimed in claim 1, characterized in that: the thienopyrimidine derivative represented by the general formula I is subjected to an amide reduction reaction.
11. The process for producing a thienopyrimidine derivative represented by the general formula II according to claim 10, wherein: carrying out the amide reductionThe reducing agent of the primary reaction is LiAlH4Red aluminum or borane complexes.
12. A tyrosine kinase inhibitor characterized by: comprising the thienopyrimidine derivative or a pharmaceutically acceptable salt thereof according to claim 1.
13. A tyrosine kinase inhibitor according to claim 12, characterized by: the inhibitor refers to an EGFR and/or VEGFR inhibitor.
14. Use of an EGFR and/or VEGFR inhibitor according to claim 13 for the preparation of a medicament for the prevention or treatment of a disease associated with the epidermal growth factor receptor EGFR and/or the vascular growth factor receptor VEGFR.
15. The use of claim 14, wherein: the medicine is related to epidermal growth factor receptor EGFR and/or vascular growth factor receptor VEGFR, and can be used for treating abnormal cell proliferation, morphological change, hyperkinesia, angiogenesis, tumor growth and/or metastasis.
16. A tyrosine kinase inhibitor according to claim 13, characterized in that: the active ingredient in the inhibitor is selected from the following specific compounds or pharmaceutically acceptable salts thereof:
17. a tyrosine kinase inhibitor according to claim 12 or 16, characterized in that: the pharmaceutically acceptable salt of the thienopyrimidine derivative is inorganic acid salt or organic acid salt.
18. A tyrosine kinase inhibitor according to claim 17, wherein: the pharmaceutically acceptable salt of the thienopyrimidine derivative refers to any one or more of hydrochloride, hydrobromide, nitrate, sulfate, phosphate, formate, acetate, propionate, benzoate, maleate, fumarate, succinate, tartrate, citrate, methylsulfonate, ethylsulfonate, benzenesulfonate and p-toluenesulfonate.
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| WO2016041201A1 (en) * | 2014-09-19 | 2016-03-24 | 上海创诺医药集团有限公司 | Thienopyrimidine derivatives and preparation method therefor and medical application thereof |
| CN111170998B (en) | 2014-11-05 | 2023-04-11 | 益方生物科技(上海)股份有限公司 | Pyrimidine or pyridine compound, preparation method and medical application thereof |
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