CN106565673B - 5-fluoropyrimidine heterocyclic compound with Wnt signal channel inhibition activity and application thereof - Google Patents

5-fluoropyrimidine heterocyclic compound with Wnt signal channel inhibition activity and application thereof Download PDF

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CN106565673B
CN106565673B CN201610850360.XA CN201610850360A CN106565673B CN 106565673 B CN106565673 B CN 106565673B CN 201610850360 A CN201610850360 A CN 201610850360A CN 106565673 B CN106565673 B CN 106565673B
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cancer
sodium sulfate
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ethyl acetate
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CN106565673A (en
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张小虎
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SUZHOU YUNXUAN PHARMACEUTICAL Co Ltd
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Priority to PCT/US2016/055851 priority patent/WO2017062688A1/en
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Abstract

the invention provides a 5-fluoropyrimidine heterocyclic compound with Wnt signal channel inhibition activity. The heterocyclic compound and pharmaceutically acceptable salts, isotopes, isomers and crystal structures thereof have a structure shown in a general formula I: the invention also provides application of the 5-fluoropyrimidine heterocyclic compound with Wnt signal channel inhibition activity. The 5-fluoropyrimidine heterocyclic compound having an inhibitory activity on a Wnt signaling pathway of the present invention is useful as an effective antagonist for a Wnt signaling pathway and can be used for treating or preventing disorders caused by malfunction of a Wnt signaling pathway.

Description

5-fluoropyrimidine heterocyclic compound with Wnt signal channel inhibition activity and application thereof
Technical Field
the invention relates to a 5-fluoropyrimidine heterocyclic compound with Wnt signal channel inhibition activity and application thereof, belonging to the technical field of medicines.
Background
The earliest findings of Wnt signaling pathways came from studies of oncogenic viruses and drosophila developmental mechanisms. The Wnt gene was discovered in 1982 and was originally identified as a site for preferential integration of mouse mammary tumor virus, which is an oncogene that transmits proliferation and differentiation information between cells, and was then designated the Int gene (mouse Int-1 and Int-3). It was then found to belong to the same source gene (orthologousgene) as the wingless gene (wingless) of Drosophila, and thus the combination of both was named Wnt gene. To date, 19 members of the Wnt gene family have been discovered and cloned, and the signal transduction pathway mediated by the Wnt gene has been termed Wnt signaling pathway. The Wnt pathway is a very conserved signaling pathway. Members of the lower organism drosophila are highly homologous, ranging from higher mammals to lower organisms. The Wnt signaling pathway is involved in the regulation of a variety of biological processes, including embryonic growth and morphological development, tissue stabilization, balance of energy metabolism, and maintenance of stem cells (Logan et al, annu. rev. cell. dev. biol.,2004,20,781 810). In recent years, stem cell studies have found that the Wnt signaling pathway plays an important role in the regulation of the maintenance of epidermal stem cells, intestinal stem cells, hematopoietic stem cells, neural stem cells, embryonic stem cells, and tumor stem cells (Reya et al, Nature,2005,434, 843-850).
the canonical Wnt signaling pathway is formed by that the extracellular ligand Wnts protein simultaneously combines with the 7 Cell transmembrane Frizzled receptor and the helper receptor LRP5/6 to open the Wnt/beta-catenin signaling pathway, and activates the intracytoplasmic Dsh protein, and the activated Dsh protein can inhibit the activity of the key component GSK-3 beta in the degradation complex formed by APC protein, GSK-3 beta, Axin, beta-catenin, etc., so that the beta-catenin is not phosphorylated by GSK-3 beta, thereby avoiding the ubiquitin proteasome from recognizing and degrading the protein, and further accumulating in cytoplasm gradually (Bortros et al, Mech.Dev.,1999,83, 27-37; Perrimon, Cell,1994,76, 781-784). When the beta-catenin accumulates in cytoplasm to a certain concentration, the beta-catenin begins to transfer to nucleus and is combined with transcription factors TCF/LEFs in the nucleus to cause the exposure of a promoter of a downstream target gene of the beta-catenin to be activated and expressed, such as c-myc, cyclin-D1, survivin, gatrin, VEGF, ASEF and the like to cause abnormal cell proliferation. In normal somatic cells, most of the intracytoplasmic beta-catenin is combined with cell membrane adhesion protein E-cadherin and alpha-catenin to form a complex which participates in the regulation of cytoskeleton, maintains the adhesion of homotypic cells and prevents cell transfer, a small part of free beta-catenin is phosphorylated in cytoplasm by a degradation complex and then recognized and degraded by ubiquitin proteasomes, and the low-level state of the intracellular beta-catenin is kept, so that the Wnt signal pathway is in a closed state.
it is found that when Wnt gene itself or any other member factor of the pathway is changed to make it abnormally activated, it may cause tumor. For example, regulators of the Wnt pathway, including mutations in the APC, β -catenin, Axin, TCF, etc., are widely present in colon cancer patients, resulting in the overexpression of growth-related genes (Klaus et al, nat. rev. cancer,2008,8, 387-398). Lozzo et al found that Wnt-5amRNA was overexpressed in all of breast, lung, prostate, and melanoma cancers, and that expression was particularly pronounced in breast Cancer, as determined by studies on more than 100 normal and tumor tissues and 10 human tumor cell lines (Lozzo et al, Cancer Research,1995,55, 3495).
The abnormal activation of the Wnt pathway plays an important role in the processes of cell canceration, tumorigenesis and tumor invasiveness, and the blocking of the abnormal Wnt signal pathway can inhibit the proliferation of tumor cells and induce the apoptosis of the tumor cells. Therefore, the Wnt signal pathway has better anti-tumor targeting effect.
studies have shown that aberrant Wnt signaling caused by LRP5 overexpression in the Wnt signaling pathway is associated with some cancers (Hoang et al, int. J. cancer,2004,109, 106-. Such as prostate cancer, colorectal cancer, ovarian cancer, esophageal cancer, and gastric cancer.
Activation of the Wnt signaling pathway by β -catenin increases the cycling and expansion of neural progenitor cells, and deletion results in deletion of the progenitor cell compartment (Chenn et al, Science,2002,297, 365-. Aberrant activation of Wnt signaling is tumorigenic in the nervous system (Dahmen et al, Cancer Res.,2001,61, 7039-.
the Wnt signaling pathway can promote the renewal and maintenance of totipotent hematopoietic stem cells, and aberrant Wnt signaling is responsible for various diseases caused by totipotent hematopoietic stem cells and other blood-related cancers (Reya et al, Nature,2005,434, 843-.
Dysregulation of Wnt signaling also leads to the development of diabetic retinopathy by inducing retinal inflammation, vascular leakage, and neovascularization.
in recent years, tumor immunotherapy has become a hot point of research. The main strategy of tumor immunotherapy is to block the activation of immunosuppressive receptors on T cells using immune checkpoint inhibitors, such as CTLA-4, PD-1 and monoclonal antibodies to PD-L1. This strategy is particularly effective in patients with a variety of tumors (e.g., melanoma and lung cancer), particularly T cell-infiltrated tumors, whereas in tumor tissues that are not T cell-infiltrated, it is often immune against tumors. Studies have shown (Stefani Spranger et al, Nature,2015,523,231-235), that 49% of melanoma patients without T-cell infiltration present high levels of active β -catenin, whereas T-cell infiltration only occurs in 4% of patients with T-cell infiltration. The activated Wnt/β -catenin signalling pathway blocks the recruitment of CD103+ dendritic cells (DC cells, the sentinel of T cell immunity) in tumors, and thus the blocking of T cell activation does not infiltrate the tumor. Therefore, inhibition of the Wnt signaling pathway would help to enhance the anti-tumor effect of immune checkpoint inhibitors. The combined application of the Wnt signal pathway inhibitor and the immune checkpoint inhibitor has an additive effect, which is better than the single application of the Wnt signal pathway inhibitor and the immune checkpoint inhibitor.
as can be seen, in order to improve the disorders caused by the above-mentioned Wnt signaling pathway disorders, it is necessary to provide potent Wnt signaling pathway modulators.
Disclosure of Invention
in view of the above-mentioned drawbacks of the prior art, the present invention provides a 5-fluoropyrimidine heterocycle compound having Wnt signaling pathway inhibitory activity and its use, wherein the 5-fluoropyrimidine heterocycle compound having Wnt signaling pathway inhibitory activity can effectively antagonize Wnt signaling pathway, and can be used for treating or preventing disorders caused by Wnt signaling pathway malfunction
The purpose of the invention is realized by the following technical scheme:
A5-fluoropyrimidine heterocyclic compound having Wnt signal pathway inhibitory activity, and pharmaceutically acceptable salts, isotopes, isomers and crystal structures thereof, has a structure represented by general formula I:
wherein a is a 6-membered aromatic ring, a 10-membered aromatic ring, or a 5-10-membered heteroaromatic ring containing 1-4 heteroatoms including one or more of N, O and S, substituted or unsubstituted with 1-3R 4 groups;
B is a hydrogen atom, cyano, halogen, hydroxyl, C1-8 alkyl, C3-8 cycloalkyl, C2-8 alkenyl, C2-8 alkynyl, C1-8 sulfone, C1-8 amido, C1-8 ureido, C1-8 oxoureido, C1-8 sulfonamide, C1-8 alkoxy, C2-8 ester, a benzene ring substituted or unsubstituted with 1-3R 5 groups, a 5-6 membered heteroaromatic ring containing 1-3 heteroatoms substituted or unsubstituted with 1-3R 5 groups, or a 5-7 membered saturated heterocyclic ring containing 1-2 heteroatoms substituted or unsubstituted with 1-3R 5 groups, the heteroatoms of the heteroaromatic ring and heterocyclic ring including one or more of N, O and S;
u is a 6-12 membered aromatic ring, a 5-12 membered heteroaromatic ring, a 5-7 membered heterocycloacene ring or a 5-7 membered heterocycloaromatic 5-6 membered heteroaromatic ring which is substituted or unsubstituted with 1-3R 6 groups, said heterocycle, heteroaromatic ring containing 1-4 heteroatoms independently selected from N, O and S;
r1, R2 and R3 are respectively and independently selected from a hydrogen atom, a C1-6 alkyl group which is substituted or not substituted by a substituent group, wherein the substituent group comprises 1-3 of halogen, hydroxyl, cyano, C1-3 alkyl, C3-5 cycloalkyl and C1-3 alkoxy;
r4, R5 and R6 are respectively and independently selected from halogen, cyano, hydroxyl, C1-8 alkyl, C3-8 cycloalkyl, C1-8 alkoxy, C2-8 alkenyl, C2-8 alkynyl, C1-8 sulfonyl, C1-8 amido, C1-8 ureido, C1-8 oxoureido, C1-8 sulfonamide, C1-8 ester, C2-8 heterocycloalkyl containing 1-3 heteroatoms, wherein the heteroatoms comprise one or more of N, O and S;
or, R4, R5, R6 are each independently selected from C1-8 alkyl, C3-8 cycloalkyl, C1-8 alkoxy, C2-8 alkenyl, C2-8 alkynyl, C1-8 sulfone, C1-8 amide, C1-8 ureido, C1-8 oxoureido, C1-8 sulfonamide, C1-8 ester, C2-8 heterocycloalkyl containing 1-3 heteroatoms including one or more of N, O and S, substituted with 1-3 of hydrogen, halogen, hydroxy, cyano, C1-3 alkyl, C1-3 alkoxy, and C3-8 cycloalkyl;
r7 is selected from hydrogen atom, deuterium atom, tritium atom, halogen, hydroxy, cyano, C1-8 alkyl, C3-8 cycloalkyl, or C1-8 alkoxy.
in the above 5-fluoropyrimidine heterocyclic compound having an inhibitory activity on the Wnt signaling pathway, the 6-membered aromatic ring, the 10-membered aromatic ring, or the 5-10-membered heteroaromatic ring containing 1 to 4 heteroatoms, which may be substituted or unsubstituted with 1 to 3R 4 groups, means a 6-membered aromatic ring which may be substituted or unsubstituted with 1 to 3R 4 groups, a 10-membered aromatic ring which may be substituted or unsubstituted with 1 to 3R 4 groups, or a 5-10-membered heteroaromatic ring containing 1 to 4 heteroatoms, which may be substituted or unsubstituted with 1 to 3R 4 groups;
the 6-12-membered aromatic ring, 5-12-membered heteroaromatic ring, 5-7-membered heterocycloacene or 5-7-membered heterocycloaromatic ring, which is substituted or unsubstituted with 1 to 3 groups of R6, means a 6-12-membered aromatic ring, which is substituted or unsubstituted with 1 to 3 groups of R6, a 5-12-membered heteroaromatic ring, which is substituted or unsubstituted with 1 to 3 groups of R6, a 5-7-membered heterocycloacene ring, which is substituted or unsubstituted with 1 to 3 groups of R6, or a 5-7-membered heterocycloaromatic ring, which is substituted or unsubstituted with 1 to 3 groups of R6, and a 5-6-membered heteroaromatic ring;
C1-8 alkyl substituted by 1-3 groups selected from hydrogen, halogen, hydroxyl, cyano, C1-3 alkyl, C1-3 alkoxy and C3-8 cycloalkyl, C3-8 cycloalkyl, C1-8 alkoxy, C2-8 alkenyl, C2-8 alkynyl, C1-8 sulfone, C1-8 amido, C1-8 ureido, C1-8 oxoureido, C1-8 sulfonamide, C1-8 ester, C2-8 heterocycloalkyl containing 1-3 hetero atoms, which means C1-8 alkyl, C3-8 cycloalkyl, C1-8 alkoxy, C2-8 alkenyl, C2-8 alkynyl, C1-8 sulfone, C1-8 amido, C1-8 ureido, C1-8 oxoureido, C1-8 sulfonamide, C1-8 ester group and C2-8 heterocycloalkyl group containing 1-3 heteroatoms are substituted with 1-3 groups selected from hydrogen, halogen, hydroxy, cyano, C1-3 alkyl, C1-3 alkoxy and C3-8 cycloalkyl.
in the above 5-fluoropyrimidine heterocyclic compound having an inhibitory activity on a Wnt signaling pathway, preferably, U is any one of the following groups substituted or unsubstituted with 1 to 3R 6 groups:
in the above 5-fluoropyrimidine heterocyclic compound having an inhibitory activity on a Wnt signaling pathway, preferably, a is any one of the following groups substituted or unsubstituted with 1 to 3R 4 groups:
in the above 5-fluoropyrimidine heterocyclic compound having an inhibitory activity on a Wnt signaling pathway, preferably, B is any one of the following groups:
in the above 5-fluoropyrimidine heterocyclic compound having an inhibitory activity on a Wnt signaling pathway, preferably, the heterocyclic compound includes:
the invention also provides a combined application composition of the 5-fluoropyrimidine heterocyclic compound with the Wnt signal channel inhibition activity, which comprises a composition obtained by combining the 5-fluoropyrimidine heterocyclic compound with the Wnt signal channel inhibition activity and pharmaceutically acceptable salts, isotopes, isomers or crystal forms thereof with one or more of antitumor drugs, antibacterial drugs, antiviral drugs, antiparasitic drugs, central nervous system drugs, anti-hyperosteogeny drugs and diabetes drugs.
the invention also provides the application of the 5-fluoropyrimidine heterocyclic compound with the Wnt signal pathway inhibition activity and pharmaceutically acceptable salts, isotopes, isomers or crystal forms thereof in preparing medicines for antagonizing the Wnt signal pathway;
In the above applications, preferably, the Wnt signaling pathway antagonizing drug is used for the treatment of cancer including breast cancer, lung cancer, bladder cancer, pancreatic cancer, liver cancer, head and neck squamous carcinoma, thyroid cancer, sarcoma, osteosarcoma, desmoid tumor, melanoma, prostate cancer, colorectal cancer, ovarian cancer, cervical cancer, esophageal cancer, gastric cancer, myeloma, lymphoma, mantle cell lymphoma, cutaneous T-cell lymphoma, chronic and non-progressive anemia, idiopathic or essential thrombocytosis, idiopathic myelofibrosis, pulmonary fibrosis, renal fibrosis, hepatic fibrosis, liver cirrhosis, diabetic retinopathy, macroglobulinemia, leukemia, acute leukemia, chronic leukemia, lymphatic leukemia, myeloid leukemia, myelodysplastic syndrome, myeloproliferative disorders, brain tumors, astrocytomas, medulloblastoma, Schwannoma, primary neuroectoblastoma, pituitary tumor, and one or more of parasitic disease, schistosomiasis, and malaria.
the invention also provides application of the combined application composition of the 5-fluoropyrimidine heterocyclic compound with the Wnt signaling pathway inhibitory activity in preparing a medicament for antagonizing the Wnt signaling pathway.
in the above applications, preferably, the Wnt signaling pathway antagonizing drug is used for the treatment of cancer including breast cancer, lung cancer, bladder cancer, pancreatic cancer, liver cancer, head and neck squamous carcinoma, thyroid cancer, sarcoma, osteosarcoma, desmoid tumor, melanoma, prostate cancer, colorectal cancer, ovarian cancer, cervical cancer, esophageal cancer, gastric cancer, myeloma, lymphoma, mantle cell lymphoma, cutaneous T-cell lymphoma, chronic and non-progressive anemia, idiopathic or essential thrombocytosis, idiopathic myelofibrosis, pulmonary fibrosis, renal fibrosis, hepatic fibrosis, liver cirrhosis, diabetic retinopathy, macroglobulinemia, leukemia, acute leukemia, chronic leukemia, lymphatic leukemia, myeloid leukemia, myelodysplastic syndrome, myeloproliferative disorders, brain tumors, astrocytomas, medulloblastoma, Schwannoma, primary neuroectoblastoma, pituitary tumor, and one or more of parasitic disease, schistosomiasis, and malaria.
according to a specific embodiment, preferred isotopes of the invention include, but are not limited to, 2H, 3H, 11C, 13C, 14C, 15N, 17O, 18O, 18F, 32P, 35S, 36Cl, and the like. Various isomers, including but not limited to stereoisomers, cis-trans isomers, tautomers, and the like.
the invention has the outstanding effects that:
The 5-fluoropyrimidine heterocyclic compound having an inhibitory activity on a Wnt signaling pathway of the present invention is useful as an effective antagonist for a Wnt signaling pathway and can be used for treating or preventing disorders caused by malfunction of a Wnt signaling pathway.
Drawings
FIG. 1 is a graph showing the results of the test of heterocyclic compound A12 in example 2;
FIG. 2 is a graph showing the results of the test of the heterocyclic compound A36 in example 2.
Detailed Description
the technical solutions of the present invention will be described in detail below in order to clearly understand the technical features, objects, and advantages of the present invention, but the present invention is not limited to the practical scope of the present invention. The experimental methods described in the following examples are all conventional methods unless otherwise specified; the reagents and materials are commercially available, unless otherwise specified.
In the following examples, the solvents and drugs used are either analytically or chemically pure; the solvent is redistilled before use; the anhydrous solvent is treated according to standard or literature methods. Column chromatography silica gel (100-200 mesh) and thin layer chromatography silica gel (GF254) are products of Qingdao oceanic plant and tobacco station chemical plant; petroleum ether (60-90 ℃)/ethyl acetate (v/v) were used as eluents unless otherwise specified; the color developing agent is an ethanol solution of iodine or phosphomolybdic acid; all extraction solvents are not described as being dried over anhydrous Na2SO 4.1 HNMR was recorded using a varian-400 NMR spectrometer with TMS as an internal standard. LC-MS was recorded using an Agilent model 1100 high performance liquid chromatography-ion trap Mass spectrometer (LC-MSDTrap), Diode Array Detector (DAD), detection wavelengths 214nm and 254nm, ion trap Mass Spectrometry (ESI source). HPLC column is AgelaDurashellC18 (4.6X 50mm, 3.5 μm); mobile phase 0.1% aqueous NH4HCO3 solution: acetonitrile (from 5: 95 to 95: 5 in 5 minutes); the flow rate was 1.8 mL/min.
example 1
this example provides 5-fluoropyrimidine heterocycles A1-A96 having Wnt signaling pathway inhibitory activity and methods of synthesis thereof.
(1) a heterocyclic compound a1 synthesized by the method comprising:
1) synthesis of intermediate A1-2:
To a 250mL round bottom flask was added Compound A1-1(6.9g, 40mmol), bis pinacolato borate (11.2g, 44mmol), KOAc (7.8g, 80mmol), Pd (dppf)2Cl2(1.63g, 2.0mmol) and tetrahydrofuran (100mL), replaced with nitrogen, stirred at reflux overnight, cooled to room temperature, filtered with celite, and the filtrate was spin-dried to give crude product as a black oil (15.6g, content: 27%) which was used directly in the next step.
2) synthesis of intermediate A1-3:
Crude intermediate A1-2(8g, 27%, 9.86mmol) was dissolved in dioxane/water (100mL/20mL), p-bromobenzylamine (1.65g, 8.88mmol), potassium carbonate (2.72g, 19.73mmol), Pd (dba)2(567mg, 0.99mmol) and SPhos (810mg, 1.97mmol) were added, and the mixture was reacted overnight at 80 ℃ under nitrogen. Cooling to normal temperature, suction-filtering with celite, adding 100mL of water to the filtrate, extracting with ethyl acetate (150mL × 3), combining the organic phases, washing with saturated brine (300mL × 2), drying the organic phase with anhydrous sodium sulfate, filtering off sodium sulfate, spin-drying ethyl acetate, and purifying the residue by column chromatography (dichloromethane: methanol ═ 50:1-30:1 with ammonia water) to obtain a brown solid (1.27g, 72%).
3) synthesis of intermediate A1-4:
Intermediate a1-3(100mg, 0.51mmol), 4, 6-dichloro-5-fluoropyrimidine (101mg, 0.61mmol) were dissolved in tetrahydrofuran (10mL), diisopropylethylamine (260mg, 2.02mmol) was added, stirring was carried out overnight at 50 ℃, cooling was carried out to normal temperature, the solvent was dried by spinning, and the residue was purified by column chromatography (dichloromethane: methanol ═ 100:1) to give an off-white solid (140mg, 84%). 1HNMR (400MHz, CDCl3) δ 8.54(d, J ═ 5.2Hz, 1H), 8.23(s, 1H), 7.62(d, J ═ 8.4Hz, 2H), 7.45(d, J ═ 8.4Hz, 2H), 7.36(s, 1H), 7.30(d, J ═ 5.2Hz, 1H), 5.60(s, 1H),4.79(d, J ═ 6.0Hz,2H), 2.62(s, 3H).
4) Synthesis of product a 1:
Intermediate a1-4(66mg, 0.20mmol), 2-naphthalene boronic acid (52mg, 0.30mmol) were dissolved in dioxane/water (5mL/1mL), potassium carbonate (116mg, 0.84mmol), tetrakistriphenylphosphine palladium (12mg, 0.010mmol) were added, nitrogen replaced, stirred overnight at 100 ℃, cooled to room temperature, filtered through celite, the filtrate was diluted with ethyl acetate (15mL), dried over anhydrous sodium sulfate, filtered through sodium sulfate, the solvent was spun off, and the residue was purified by column chromatography (dichloromethane: methanol ═ 200:1-50:1) to give a white solid (45mg, 54%). After NMR analysis (data shown in Table 1), the obtained solid was Compound A1
(2) a heterocyclic compound a2 synthesized by the method comprising:
1) synthesis of intermediate A2-2:
compound A2-1(100mg, 0.48mmol) was dissolved in tetrahydrofuran (10mL), bis pinacolato borate (146mg, 0.58mmol), KOAc (141mg, 1.44mmol), Pd (dppf)2Cl2(39mg, 0.048mmol) was added, nitrogen replaced, refluxed overnight, cooled to room temperature, filtered through celite, and the filtrate was spin dried to give a crude black oil (250mg) which was used directly in the next step.
2) synthesis of product a 2:
A1-4(66mg, 0.20mmol), A2-2(150mg, crude) were dissolved in dioxane/water (5mL/1mL), potassium carbonate (110mg, 0.80mmol), tetrakistriphenylphosphine palladium (23mg, 0.02mmol) were added, nitrogen was replaced, stirring was carried out overnight at 100 ℃, cooling was carried out to room temperature, suction filtration was carried out with celite, the filtrate was diluted with ethyl acetate (15mL), dried over anhydrous sodium sulfate, filtered off sodium sulfate, the solvent was spin-dried, and the residue was purified by column chromatography (dichloromethane: methanol 100:1-50:1) to give a white solid (64mg, 79%). After NMR analysis (data shown in Table 1), the obtained solid was Compound A2
(3) a heterocyclic compound a3 synthesized by the method comprising:
1) synthesis of intermediate A3-2:
Compound A3-1(105mg, 0.51mmol) was dissolved in dioxane (10mL), bis-pinacolato borate (191mg, 0.75mmol), KOAc (147mg, 1.50mmol), Pd (dppf)2Cl2(20mg, 0.024mmol) was added, nitrogen replaced, stirred overnight at 90 deg.C, cooled to room temperature, filtered with celite, and the filtrate was spin-dried to give a crude black oil (360mg) which was used directly in the next step.
2) Synthesis of product a 3:
a1-4(50mg,0.15mmol), A3-2(360mg, crude) were dissolved in dioxane/water (5mL/1mL), potassium carbonate (84mg, 0.61mmol), tetrakistriphenylphosphine palladium (17mg, 0.015mmol) were added, nitrogen was replaced, stirring was carried out overnight at 100 ℃, cooling was carried out to room temperature, suction filtration was carried out with celite, the filtrate was diluted with ethyl acetate (15mL), dried over anhydrous sodium sulfate, filtered off sodium sulfate, the solvent was spin-dried, and the residue was purified by column chromatography (dichloromethane: methanol 100:1-50:1) to give a brown solid (40mg, 63%). After NMR analysis (data shown in Table 1), the obtained solid was Compound A3
(4) a heterocyclic compound a4 synthesized by the method comprising:
1) Synthesis of intermediate A4-2:
Compound a4-1(210mg, 1.01mmol) was dissolved in tetrahydrofuran (10mL), bis pinacolato borate (760mg, 2.99mmol), KOAc (150mg, 1.53mmol), pd (dppf)2Cl2(80mg, 0.10mmol) was added, nitrogen was replaced, reflux was allowed to stand overnight, cooled to room temperature, suction filtered through celite, the filtrate was spin-dried, and the residue was purified by column chromatography (petroleum ether: ethyl acetate ═ 10:1) to give a colorless oil (240mg, 93%).
2) Synthesis of product a 4:
intermediate a1-4(50mg,0.15mmol), intermediate a4-2(57mg, 0.22mmol) were dissolved in dioxane/water (5mL/1mL), potassium carbonate (83mg, 0.60mmol), tetrakistriphenylphosphine palladium (17mg, 0.015mmol) were added, nitrogen replaced, stirred at 100 ℃ overnight, cooled to room temperature, filtered through celite, the filtrate was diluted with ethyl acetate (15mL), dried over anhydrous sodium sulfate, sodium sulfate filtered off, the solvent was spun off, and the residue was purified by column chromatography (dichloromethane: methanol: 100:1-50:1) to give a white solid (53mg, 83%). After NMR analysis (data shown in Table 1), the obtained solid was Compound A4
(5) A heterocyclic compound a5 synthesized by the method comprising:
1) Synthesis of intermediate A5-2:
A5-1(22mg, 0.099mmol) was dissolved in dioxane (2mL), bis pinacolato borate (30mg, 0.12mmol), KOAc (29mg, 0.30mmol), Pd (dppf)2Cl2(8mg, 0.01mmol) was added, nitrogen was replaced, stirring was carried out at 90 ℃ for 4 hours, cooling to room temperature, suction filtration was carried out with celite, and the filtrate was spin-dried to give a crude black oil (60mg) which was used directly in the next step.
2) synthesis of product a 5:
A1-4(20mg, 0.061mmol), A5-2(60mg, crude) were dissolved in dioxane/water (2mL/0.4mL), potassium carbonate (34mg, 0.24mmol), tetrakistriphenylphosphine palladium (7mg, 0.006mmol) were added, nitrogen was replaced, stirring was carried out overnight at 100 ℃, cooling was carried out to room temperature, suction filtration was carried out with celite, the filtrate was diluted with ethyl acetate (10mL), dried over anhydrous sodium sulfate, sodium sulfate was filtered off, the solvent was spun dry, and the residue was purified by column chromatography (dichloromethane: methanol: 100:1-50:1) to give an off-white solid (15mg, 58%). After NMR analysis (data shown in Table 1), the obtained solid was Compound A5
(6) A heterocyclic compound a6 synthesized by the method comprising:
1) synthesis of intermediate A6-2:
A6-1(210mg, 1.01mmol) was dissolved in tetrahydrofuran (10mL), bis pinacolato borate (305mg, 1.20mmol), KOAc (294mg, 3.00mmol), pd (dppf)2Cl2(80mg, 0.10mmol) was added, nitrogen was replaced, reflux was allowed to stand overnight, cooled to room temperature, suction filtered through celite, the filtrate was spin-dried, and the residue was purified by column chromatography (petroleum ether: ethyl acetate ═ 4:1) to give a yellow gummy solid (270mg, 106%).
2) synthesis of product a 6:
a1-4(50mg,0.15mmol), A6-2(114mg, 0.45mmol) were dissolved in dioxane/water (5mL/1mL), potassium carbonate (83mg, 0.60mmol), tetrakistriphenylphosphine palladium (17mg, 0.015mmol) were added, nitrogen was replaced, stirring was carried out overnight at 100 ℃, cooling was carried out to room temperature, suction filtration was carried out with celite, the filtrate was diluted with ethyl acetate (15mL), dried over anhydrous sodium sulfate, sodium sulfate was filtered off, the solvent was spun dry, and the residue was purified by column chromatography (dichloromethane: methanol: 100:1-50:1) to give a white solid (48mg, 75%). After NMR analysis (data shown in Table 1), the obtained solid was Compound A6
(7) A heterocyclic compound a7 synthesized by the method comprising:
1) Synthesis of intermediate A7-2:
a7-1(150mg, 0.72mmol) was dissolved in dioxane (10mL), bis pinacolato borate (220mg, 0.87mmol), KOAc (212mg, 2.16mmol), Pd (dppf)2Cl2(59mg, 0.072mmol) was added, nitrogen replaced, stirred at 90 ℃ overnight, cooled to room temperature, filtered through suction with celite, and the filtrate was spin-dried to give a crude black oil (409mg) which was used directly in the next step.
2) Synthesis of product a 7:
A1-4(66mg, 0.20mmol), A7-2(409mg, crude) were dissolved in dioxane/water (5mL/1mL), potassium carbonate (110mg, 0.80mmol), tetrakistriphenylphosphine palladium (23mg, 0.02mmol) were added, nitrogen was replaced, stirring was carried out overnight at 100 ℃, cooling was carried out to room temperature, suction filtration was carried out with celite, the filtrate was diluted with ethyl acetate (15mL), dried over anhydrous sodium sulfate, filtered off sodium sulfate, the solvent was spin-dried, and the residue was purified by column chromatography (dichloromethane: methanol 100:1-50:1) to give an off-white solid (50mg, 59%). After NMR analysis (data shown in Table 1), the obtained solid was Compound A7
(8) a heterocyclic compound A8 synthesized by the method comprising:
1) synthesis of intermediate A8-2:
a8-1(63mg, 0.30mmol) was dissolved in dioxane (6mL), bis pinacolato borate (91mg, 0.36mmol), KOAc (59mg, 0.60mmol), Pd (dppf)2Cl2(25mg, 0.03mmol) was added, nitrogen was replaced, stirring was carried out at 90 ℃ for 2 hours, cooling to room temperature, suction filtration with celite, and the filtrate was spin-dried to give a crude black oil (160mg) which was used directly in the next step.
2) Synthesis of product A8:
A1-4(66mg, 0.20mmol), A8-2(160mg, crude) were dissolved in dioxane/water (5mL/1mL), potassium carbonate (110mg, 080mmol), tetrakistriphenylphosphine palladium (23mg, 0.02mmol) were added, nitrogen was replaced, stirring was carried out overnight at 100 ℃, cooling was carried out to room temperature, suction filtration was carried out with celite, the filtrate was diluted with ethyl acetate (15mL), dried over anhydrous sodium sulfate, sodium sulfate was filtered off, the solvent was spin-dried, and the residue was purified by column chromatography (dichloromethane: methanol: 100:1-50:1) to give an off-white solid (60mg, 71%). After NMR analysis (data shown in Table 1), the obtained solid was Compound A8
(9) a heterocyclic compound a9 synthesized by the method comprising:
1) Synthesis of intermediate A9-2:
a9-1(63mg, 0.30mmol) was dissolved in dioxane (5mL), bis pinacolato borate (91mg, 0.36mmol), KOAc (59mg, 0.60mmol), Pd (dppf)2Cl2(25mg, 0.03mmol) was added, nitrogen was replaced, stirring was carried out at 90 ℃ for 4 hours, cooling to room temperature, suction filtration with celite, and the filtrate was spin-dried to give a crude black oil (183mg) which was used directly in the next step.
2) Synthesis of product a 9:
a1-4(50mg,0.15mmol), A9-2(183mg, crude) were dissolved in dioxane/water (5mL/1mL), potassium carbonate (84mg, 0.61mmol), tetrakistriphenylphosphine palladium (17mg, 0.015mmol) were added, nitrogen was replaced, stirring was carried out overnight at 100 ℃, cooling was carried out to room temperature, suction filtration was carried out with celite, the filtrate was diluted with ethyl acetate (15mL), dried over anhydrous sodium sulfate, filtered off sodium sulfate, the solvent was spin-dried, and the residue was purified by column chromatography (dichloromethane: methanol 100:1-50:1) to give an off-white solid (35mg, 55%). After NMR analysis (data shown in Table 1), the obtained solid was Compound A9
(10) a heterocyclic compound a10 synthesized by the method comprising:
1) synthesis of intermediate A10-2:
A10-1(250mg, 0.84mmol) was dissolved in dioxane (5mL), bis pinacolato borate (257mg, 1.01mmol), KOAc (247mg, 2.53mmol), Pd (dppf)2Cl2(68mg, 0.084mmol) was added, nitrogen replaced, stirred overnight at 100 deg.C, cooled to room temperature, filtered through suction with celite, and the filtrate was spin-dried to give a crude black oil (556mg) which was used directly in the next step.
2) Synthesis of product a 10:
a1-4(50mg,0.15mmol), A10-2(200mg, crude) were dissolved in dioxane/water (5mL/1mL), potassium carbonate (84mg, 0.61mmol), tetrakistriphenylphosphine palladium (17mg, 0.015mmol) were added, nitrogen was replaced, stirring was carried out overnight at 100 ℃, cooling was carried out to room temperature, suction filtration was carried out with celite, the filtrate was diluted with ethyl acetate (15mL), dried over anhydrous sodium sulfate, filtered off sodium sulfate, the solvent was spin-dried, and the residue was purified by column chromatography (dichloromethane: methanol ═ 50:1-20:1) to give an off-white solid (31mg, 50%). After NMR analysis (data shown in Table 1), the obtained solid was Compound A10
(11) A heterocyclic compound a11 synthesized by the method comprising:
1) synthesis of intermediate A11-2:
A11-1(60mg, 0.31mmol) was dissolved in dioxane (5mL), bis pinacolato borate (91mg, 0.36mmol), KOAc (88mg, 0.90mmol), Pd (dppf)2Cl2(25mg, 0.031mmol) was added, nitrogen replaced, stirred at 90 ℃ for 4 hours, cooled to room temperature, suction filtered through celite, and the filtrate was spin-dried to give a crude black oil (190mg) which was used directly in the next step.
2) Synthesis of product a 11:
A1-4(50mg,0.15mmol), A11-2(190mg, crude) were dissolved in dioxane/water (5mL/1mL), potassium carbonate (84mg, 0.61mmol), tetrakistriphenylphosphine palladium (17mg, 0.015mmol) were added, nitrogen was replaced, stirring was carried out overnight at 100 ℃, cooling was carried out to room temperature, suction filtration was carried out with celite, the filtrate was diluted with ethyl acetate (15mL), dried over anhydrous sodium sulfate, filtered off sodium sulfate, the solvent was spin-dried, and the residue was purified by column chromatography (dichloromethane: methanol ═ 50:1-30:1) to give an off-white solid (22mg, 35%). After NMR analysis (data shown in Table 1), the obtained solid was Compound A11
(12) A heterocyclic compound a12 synthesized by the method comprising:
1) Synthesis of intermediate A12-2:
A12-1(43mg, 0.20mmol) was dissolved in dioxane (4mL), bis pinacolato borate (61mg, 0.24mmol), KOAc (59mg, 0.60mmol), Pd (dppf)2Cl2(16mg, 0.02mmol) was added, nitrogen was replaced, stirring was carried out at 90 ℃ for 4 hours, cooling to room temperature, suction filtration with celite, and the filtrate was spin-dried to give a crude black oil (126mg) which was used directly in the next step.
2) synthesis of product a 12:
A1-4(50mg,0.15mmol), A12-2(126mg, crude) were dissolved in dioxane/water (5mL/1mL), potassium carbonate (84mg, 0.61mmol), tetrakistriphenylphosphine palladium (17mg, 0.015mmol) were added, nitrogen was replaced, stirring was carried out overnight at 100 ℃, cooling was carried out to room temperature, suction filtration was carried out with celite, the filtrate was diluted with ethyl acetate (15mL), dried over anhydrous sodium sulfate, filtered off sodium sulfate, the solvent was spin-dried, and the residue was purified by column chromatography (dichloromethane: methanol 100:1-50:1) to give an off-white solid (28mg, 43%). After NMR analysis (data shown in Table 1), the obtained solid was Compound A12
(13) a heterocyclic compound a13 synthesized by the method comprising:
1) Synthesis of intermediate A13-2:
A13-1(300mg, 1.52mmol) was dissolved in DMSO (10mL), bis pinacolato borate (570mg, 2.24mmol), KOAc (440mg, 4.49mmol), Pd (dppf)2Cl2(60mg, 0.073mmol) was added, nitrogen substitution was performed, stirring was performed at 90 ℃ for 24 hours, cooling was performed to normal temperature, suction filtration was performed with celite, the filtrate was diluted with ethyl acetate (20mL), washed with saturated brine (20 mL. times.3), dried over anhydrous sodium sulfate, sodium sulfate was filtered off, the solvent was spin-dried, and the residue was purified by column chromatography (dichloromethane to dichloromethane: methanol 100:1) to give a brown oil (300mg, 81%).
2) synthesis of product a 13:
A1-4(66mg, 0.20mmol), A13-2(146mg, 0.60mmol) were dissolved in dioxane/water (5mL/1mL), potassium carbonate (110mg, 0.80mmol), tetrakistriphenylphosphine palladium (23mg, 0.02mmol) were added, nitrogen replaced, stirred overnight at 100 deg.C, cooled to room temperature, filtered through celite, the filtrate was diluted with ethyl acetate (15mL), dried over anhydrous sodium sulfate, filtered off sodium sulfate, the solvent was spun dry, and the residue was purified by column chromatography (dichloromethane: methanol: 100:1-25:1) to give a white solid (40mg, 49%). After NMR analysis (data shown in Table 1), the obtained solid was Compound A13
(14) a heterocyclic compound a14 synthesized by the method comprising:
1) synthesis of intermediates A14-2 and A14-3:
A14-1(590mg, 2.99mmol) was dissolved in tetrahydrofuran (10mL), NaH (180mg 80%, 6.00mmol) was added while stirring in an ice bath, CH3I (468mg, 3.30mmol) was added after stirring for 30 minutes, stirring was continued for 3 hours, the temperature was raised to room temperature, water (20mL) was added, ethyl acetate (20 mL. times.3) was extracted, the organic phase was washed with saturated brine (50 mL. times.3), dried over anhydrous sodium sulfate, the solvent was dried by spin-drying, and the residue was purified by column chromatography (petroleum ether: ethyl acetate ═ 10: 1-3:1), yielding A14-2(230mg, 36%) and A14-3(330mg, 52%).
a14-2: off-white solid. 1HNMR (400MHz, DMSO) δ 8.33(s, 1H), 7.96-7.95(m, 1H), 7.57(d, J ═ 9.2Hz, 1H), 7.31-7.28(m, 1H),4.16(s,3H).
A14-3: a white solid. 1HNMR (400MHz, DMSO) δ 8.03(s, 1H), 7.99(d, J ═ 1.6Hz, 1H), 7.64(d, J ═ 8.8Hz, 1H), 7.51-7.49(m, 1H), 4.04(s, 3H).
2) synthesis of intermediate A14-4:
A14-2(190mg, 0.90mmol) was dissolved in DMSO (10mL), bis pinacolato borate (274mg, 1.08mmol), KOAc (265mg, 2.70mmol), Pd (dppf)2Cl2(37mg, 0.045mmol) was added, nitrogen replaced, stirred at 90 ℃ overnight, cooled to room temperature, filtered through celite, the filtrate was diluted with ethyl acetate (20mL), washed with saturated brine (20 mL. times.3), dried over anhydrous sodium sulfate, filtered off sodium sulfate, and the solvent was spin-dried to give a black oil (410mg) which was used directly in the next step.
3) Synthesis of product a 14:
a1-4(66mg, 0.20mmol), A14-4(400mg, crude) were dissolved in dioxane/water (5mL/1mL), potassium carbonate (110mg, 0.80mmol), tetrakistriphenylphosphine palladium (23mg, 0.02mmol) were added, nitrogen was replaced, stirring was carried out overnight at 100 ℃, cooling was carried out to room temperature, suction filtration was carried out with celite, the filtrate was diluted with ethyl acetate (15mL), dried over anhydrous sodium sulfate, filtered off sodium sulfate, the solvent was spin-dried, and the residue was purified by column chromatography (dichloromethane: methanol 100:1-50:1) to give an off-white solid (50mg, 59%). After NMR analysis (data shown in Table 1), the obtained solid was Compound A14
(15) a heterocyclic compound a15 synthesized by the method comprising:
1) Synthesis of intermediate A15-1:
a14-3(63mg, 0.30mmol) was dissolved in DMSO (6mL), bis pinacolato borate (91mg, 0.36mmol), KOAc (88mg, 0.90mmol), Pd (dppf)2Cl2(25mg, 0.03mmol) was added, nitrogen replaced, stirred at 90 ℃ overnight, cooled to room temperature, filtered through celite, the filtrate was diluted with ethyl acetate (15mL), washed with saturated brine (15 mL. times.3), dried over anhydrous sodium sulfate, filtered off sodium sulfate, and the solvent was spin-dried to give a black oil (120mg) which was used directly in the next step.
2) Synthesis of product a 15:
a1-4(50mg,0.15mmol), A15-1(120mg, crude) were dissolved in dioxane/water (5mL/1mL), potassium carbonate (84mg, 0.61mmol), tetrakistriphenylphosphine palladium (17mg, 0.015mmol) were added, nitrogen was replaced, stirring was carried out overnight at 100 ℃, cooling was carried out to room temperature, suction filtration was carried out with celite, the filtrate was diluted with ethyl acetate (15mL), dried over anhydrous sodium sulfate, filtered off sodium sulfate, the solvent was spin-dried, and the residue was purified by column chromatography (dichloromethane: methanol 100:1-50:1) to give a white solid (53mg, 82%). After NMR analysis (data shown in Table 1), the obtained solid was Compound A15
(16) A heterocyclic compound a16 synthesized by the method comprising:
1) Synthesis of intermediate A16-2:
A16-1(73mg, 0.32mmol) was dissolved in dioxane (4mL), bis pinacolato borate (98mg, 0.39mmol), KOAc (95mg, 0.97mmol), Pd (dppf)2Cl2(26mg, 0.032mmol) was added, nitrogen replaced, stirred at 90 ℃ for 4 hours, cooled to room temperature, suction filtered through celite, and the filtrate was spin-dried to give a crude black oil (213mg) which was used directly in the next step.
2) Synthesis of product a 16:
A1-4(50mg,0.15mmol), A16-2(213mg, crude) were dissolved in dioxane/water (5mL/1mL), potassium carbonate (84mg, 0.61mmol), tetrakistriphenylphosphine palladium (17mg, 0.015mmol) were added, nitrogen replaced, stirred overnight at 100 deg.C, cooled to room temperature, filtered through celite, the filtrate was diluted with ethyl acetate (15mL), dried over anhydrous sodium sulfate, filtered off sodium sulfate, the solvent was spun off, and the residue was purified by column chromatography (dichloromethane: methanol 100:1) to give a brown oil (48mg, 74%). After NMR analysis (data shown in Table 1), the obtained solid was Compound A16
(17) A heterocyclic compound a17 synthesized by the method comprising:
a1-4(50mg, 0.152mmol), phenylboronic acid (28mg, 0.23mmol) were dissolved in dioxane/water (5mL/1mL), potassium carbonate (84mg, 0.61mmol), tetrakistriphenylphosphine palladium (17mg, 0.015mmol) were added, nitrogen was replaced, stirring was carried out overnight at 100 ℃, cooling was carried out to room temperature, suction filtration was carried out with celite, the filtrate was diluted with ethyl acetate (15mL), dried over anhydrous sodium sulfate, filtered off sodium sulfate, the solvent was spin-dried, and the residue was purified by column chromatography (dichloromethane: methanol: 150:1-100:1) to give a white solid (30mg, 54%). After NMR analysis (data shown in Table 1), the obtained solid was Compound A17
(18) A heterocyclic compound a18 synthesized by the method comprising:
a1-4(50mg,0.15mmol), o-chlorobenzoic acid (28mg, 0.18mmol) were dissolved in dioxane/water (5mL/1mL), potassium phosphate (64mg, 0.30mmol), pd (dppf)2Cl2(12mg, 0.015mmol), dppf (8mg, 0.015mmol) were added, nitrogen substitution was performed, stirring was performed at 100 ℃ overnight, cooling was performed to normal temperature, suction filtration was performed with celite, the filtrate was diluted with ethyl acetate (15mL), dried over anhydrous sodium sulfate, sodium sulfate was filtered off, the solvent was spin-dried, and the residue was purified by column chromatography (dichloromethane: methanol ═ 100:1) to give an off-white solid (15mg, 24%). After NMR analysis (data shown in Table 1), the obtained solid was Compound A18
(19) A heterocyclic compound a19 synthesized by the method comprising:
a1-4(50mg,0.15mmol), m-chlorobenzoic acid (28mg, 0.18mmol) were dissolved in dioxane/water (5mL/1mL), potassium phosphate (64mg, 0.304mmol), pd (dppf)2Cl2(12mg, 0.015mmol), dppf (8mg, 0.015mmol) were added, nitrogen replaced, stirred overnight at 100 ℃, cooled to room temperature, filtered off sodium sulfate, the solvent was filtered off, the residue was purified by column chromatography (dichloromethane: methanol ═ 100:1) to give a white solid, and recrystallized from n-hexane/ethyl acetate to give a white solid (15mg, 24%). After NMR analysis (data shown in Table 1), the obtained solid was Compound A19
(20) A heterocyclic compound a20 synthesized by the method comprising:
a1-4(50mg,0.15mmol), p-chlorobenzoic acid (28mg, 0.18mmol) was dissolved in dioxane/water (5mL/1mL), potassium phosphate (64mg, 0.30mmol), pd (dppf)2Cl2(12mg, 0.015mmol), dppf (8mg, 0.015mmol) was added, nitrogen replaced, stirred overnight at 100 ℃, cooled to room temperature, filtered off with celite, the filtrate was diluted with ethyl acetate (15mL), dried over anhydrous sodium sulfate, sodium sulfate filtered off, the solvent was spin-dried, and the residue was purified by column chromatography (dichloromethane: methanol ═ 100:1) to give a white solid (40mg, 71%). After NMR analysis (data shown in Table 1), the obtained solid was Compound A20
(21) a heterocyclic compound a21 synthesized by the method comprising:
A1-4(50mg,0.15mmol), 3, 4-dichlorophenylboronic acid (28mg, 0.18mmol) were dissolved in dioxane/water (5mL/1mL), potassium phosphate (64mg, 0.30mmol), pd (dppf)2Cl2(12mg, 0.015mmol), dppf (8mg, 0.015mmol) were added, nitrogen replaced, stirred at 100 ℃ overnight, cooled to room temperature, filtered with celite, the filtrate was diluted with ethyl acetate (15mL), dried over anhydrous sodium sulfate, filtered off sodium sulfate, the solvent was dried, and the residue was purified by column chromatography (dichloromethane: methanol ═ 100:1) to give an off-white solid (14mg, 23%). After NMR analysis (data shown in Table 1), the obtained solid was Compound A21
(22) a heterocyclic compound a22 synthesized by the method comprising:
A1-4(44mg, 0.13mmol) was dissolved in N-methylpyrrolidone (2mL) in a sealed tube, 1, 2, 3, 4-tetrahydroisoquinoline (178mg, 1.34mmol) and diisopropylethylamine (86mg, 0.67mmol) were added, stirring was carried out at 120 ℃ overnight, cooling was carried out to normal temperature, water (10mL) was added, ethyl acetate (10 mL. times.3) was extracted, the organic phase was washed with saturated brine (20 mL. times.6), dried over anhydrous sodium sulfate, sodium sulfate was filtered off, the solvent was spin-dried, and the residue was purified by column chromatography (dichloromethane: methanol ═ 100:1) to give a brown oil (45mg, 79%). After NMR analysis (data shown in Table 1), the obtained solid was Compound A22
(23) a heterocyclic compound a23 synthesized by the method comprising:
1) Synthesis of intermediate A23-2:
A23-1(300mg, 2.16mmol) was dissolved in dichloromethane (6mL) and cooled to 0 ℃ under nitrogen. Triethylamine (254mg, 2.37mmol) was added, followed by trifluoroacetic anhydride (499mg, 2.37mmol), and the mixture was stirred at room temperature for 0.5 h. Ice water was added thereto, extraction was carried out three times with ethyl acetate, the combined organic phases were washed three times with a saturated sodium chloride solution, dried by adding anhydrous sodium sulfate, and the organic solvent was removed by evaporation to give a colorless oily compound (500mg, 98%).
2) Synthesis of intermediate A23-3:
A23-2(500mg, 2.13mmol) and paraformaldehyde (109mg, 3.40mmol) were dissolved in glacial acetic acid (2.9mL), concentrated sulfuric acid (1.88mL) was slowly added dropwise while cooling on ice, and then stirred at room temperature for 8 hours. 10mL of ice water was poured into the reaction mixture, extracted three times with ethyl acetate, the combined organic phases were washed with a saturated aqueous solution of sodium bicarbonate until no bubbles were generated, then washed once with a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, evaporated to remove the solvent, and purified by column chromatography (petroleum ether: ethyl acetate 1:0-200:1) to give a colorless oily compound (260mg, 49%).
3) Synthesis of intermediate A23-4:
a23-3(200mg, 0.81mmol), saturated aqueous sodium carbonate (0.8mL) and methanol (0.8mL) were added to the flask, stirred at 60 ℃ for 1h, methanol was spun off, water was added at 15mL, extracted three times with ethyl acetate, the organic phases were combined, washed once with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, and spun to give the compound as a colorless oil (58mg, 47%).
4) synthesis of product a 23:
A1-4(56mg, 0.17mmol), A23-4(130mg, 0.86mmol), diisopropylethylamine (119mg, 0.86mmol) and N-methylpyrrolidinone (1.5mL) were added to the reaction flask. Reaction at 120 deg.c for 8 hr, cooling to room temperature, adding water, extracting with ethyl acetate three times, combining the organic phases, washing with saturated aqueous sodium chloride solution, drying over anhydrous sodium sulfate, evaporating to remove the solvent, and purifying by column chromatography (petroleum ether: ethyl acetate 5:1-3:1) to obtain an oily compound (50mg, 60%). After NMR analysis (data shown in Table 1), the obtained solid was Compound A23
(24) a heterocyclic compound a24 synthesized by the method comprising:
1) synthesis of intermediate A24-2:
a24-1(300mg, 2.16mmol) was dissolved in dichloromethane (6mL) and cooled to 0 ℃ under nitrogen. Triethylamine (254mg, 2.37mmol) was added, followed by trifluoroacetic anhydride (499mg, 2.37mmol), and the mixture was stirred at room temperature for 0.5 h. Ice water was added thereto, extraction was carried out three times with ethyl acetate, the combined organic phases were washed three times with a saturated sodium chloride solution, dried by adding anhydrous sodium sulfate, and the organic solvent was removed by evaporation to give a colorless oily compound (500mg, 98%).
2) synthesis of intermediate A24-3:
a24-2(500mg, 2.13mmol) and paraformaldehyde (109mg, 3.40mmol) were dissolved in glacial acetic acid (2.9mL), concentrated sulfuric acid (1.88mL) was slowly added dropwise while cooling on ice, and then stirred at room temperature for 8 hours. 10mL of ice water was poured into the reaction mixture, extracted three times with ethyl acetate, the combined organic phases were washed with a saturated aqueous solution of sodium bicarbonate until no bubbles were generated, then washed once with a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, evaporated to remove the solvent, and purified by column chromatography (petroleum ether: ethyl acetate 1:0-200:1) to give a colorless oily compound (260mg, 49%).
3) Synthesis of intermediate A24-4:
A24-3(260mg, 0.89mmol), saturated aqueous sodium carbonate (0.8mL) and methanol (0.8mL) were added to the flask, stirred at 60 ℃ for 1h, methanol was spun off, water was added at 15mL, extracted three times with ethyl acetate, the organic phases were combined, washed once with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, and spun to give the compound as a colorless oil (130mg, 69%).
4) synthesis of product a 24:
A1-4(50mg,0.15mmol), A23-4(116mg, 0.76mmol), diisopropylethylamine (100mg, 0.77mmol) and N-methylpyrrolidinone (1.5mL) were added to the reaction flask. Reaction at 120 deg.c for 8 hr, cooling to room temperature, adding water, extracting with ethyl acetate three times, combining the organic phases, washing with saturated aqueous sodium chloride solution, drying over anhydrous sodium sulfate, evaporating to remove the solvent, and purifying by column chromatography (petroleum ether: ethyl acetate 5:1-3:1) to obtain an oily compound (40mg, 59%). After NMR analysis (data shown in Table 1), the obtained solid was Compound A24
(25) A heterocyclic compound a25 synthesized by the method comprising:
1) synthesis of intermediate A25-2:
a25-1(1.0g, 5.0mmol) was dissolved in dichloromethane (20mL) and cooled to 0 ℃ under nitrogen. Triethylamine (556mg, 5.5mmol) was added, followed by trifluoroacetic anhydride (1.16g, 5.5mmol), and the mixture was stirred at room temperature for 0.5 h. Ice water was added and extraction was carried out three times with ethyl acetate, the combined organic phases were washed three times with a saturated sodium chloride solution, dried by adding anhydrous sodium sulfate, and the organic solvent was removed by spinning to give a colorless oily compound (1.5g, quantitative).
2) Synthesis of intermediate A25-3:
A25-2(1.5g, 5.0mmol) and paraformaldehyde (291mg, 9.1mmol) were dissolved in glacial acetic acid (5.9mL), and concentrated sulfuric acid (3.76mL) was slowly added dropwise while cooling on ice, followed by stirring at room temperature for 8 hours. 20mL of ice water was poured into the reaction mixture, extracted three times with ethyl acetate, the combined organic phases were washed with a saturated aqueous solution of sodium bicarbonate until no bubbles were generated, washed once with a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, evaporated to remove the solvent, and purified by column chromatography (petroleum ether: ethyl acetate 1:0-200:1) to give a colorless oily compound (1.26g, 82%).
3) Synthesis of intermediate A25-4:
A25-3(590mg, 1.92mmol), saturated aqueous sodium carbonate (2.4mL) and methanol (2.4mL) were added to the flask, stirred at 60 ℃ for 1h, methanol was spun off, water was added at 15mL, extracted three times with ethyl acetate, the organic phases were combined, washed once with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, and spun dry to give the compound as a colorless oil (200mg, 49%).
4) synthesis of product a 25:
a1-4(60mg, 0.18mmol), A25-4(194mg, 0.92mmol), diisopropylethylamine (119mg, 0.92mmol) and N-methylpyrrolidinone (1.5mL) were added to the reaction flask. Reaction at 120 deg.c for 8 hr, cooling to room temperature, adding water, extracting with ethyl acetate three times, combining the organic phases, washing with saturated aqueous sodium chloride solution, drying over anhydrous sodium sulfate, evaporating to remove the solvent, and purifying by column chromatography (petroleum ether: ethyl acetate 5:1-3:1) to obtain an oily compound (40mg, 44%). After NMR analysis (data shown in Table 1), the obtained solid was Compound A25
(26) a heterocyclic compound a26 synthesized by the method comprising:
1) synthesis of intermediate A26-2:
a28-1(5.25g, 27.8mmol) and propargylamine (3.05g, 55.5mmol) were dissolved in absolute ethanol (50mL) followed by addition of sodium chloroaurate (252mg, 0.70mmol) and reflux overnight. Cooled to room temperature, concentrated under reduced pressure, added with water (30mL), extracted with dichloromethane (30mL × 3), combined organic phases dried over anhydrous sodium sulfate, concentrated under reduced pressure, and subjected to column chromatography (ethyl acetate: petroleum ether ═ 1:1) to give a yellow oil (3.08g, 50%). 1HNMR (400MHz, CDCl3) δ 8.39(d, J ═ 4.4Hz,1H), 7.41-7.32(m, 4H), 7.30(d, J ═ 6.4Hz, 2H), 7.06-7.03(m, 1H), 3.71(s, 2H), 3.62(s, 2H), 3.06(t, J ═ 5.8Hz,2H), 2.86(t, J ═ 6.0Hz, 2H).
2) synthesis of intermediate A26-3:
intermediate A26-2(2.8g, 12.5mmol) was dissolved in acetic acid (10mL), 10% Pd/C (560mg) was added, and the mixture was heated to 60 ℃ under hydrogen for 2 hours. Cooled to room temperature, filtered and the filtrate was spin-dried to give a brown oil (3.4g, crude, content: 56%). 1HNMR (400MHz, CDCl3) δ 8.48(d, J ═ 4.4Hz,1H), 7.43(d, J ═ 8.0Hz, 1H), 7.20-7.16(m, 1H), 4.23(s, 2H), 3.42(t, J ═ 6.2Hz, 2H), 3.17(t, J ═ 6.2Hz, 2H).
3) synthesis of product a 26:
intermediate a1-4(50mg,0.15mmol) was dissolved in N-methylpyrrolidone (2mL) in a sealed tube, a26-3(102mg, 0.76mmol) and diisopropylethylamine (98mg, 0.76mmol) were added, stirring was carried out overnight at 120 ℃, cooling was carried out to normal temperature, water (10mL) was added, ethyl acetate (10mL × 3) was extracted, the organic phase was washed with saturated brine (20mL × 6), dried over anhydrous sodium sulfate, sodium sulfate was filtered off, the solvent was dried by spin-drying, and the residue was purified by column chromatography (dichloromethane: methanol ═ 50:1) to give a white solid (23mg, 35%). After NMR analysis (data shown in Table 1), the obtained solid was Compound A26
(27) A heterocyclic compound a27 synthesized by the method comprising:
Compound a1(30mg, 0.07mmol) was dissolved in tetrahydrofuran (3mL), NaH (6mg 80%, 0.20mmol) was added with stirring in an ice bath, CH3I (20mg, 0.14mmol) was added after stirring for an additional 30 minutes, the reaction was continued for 6 hours, the solvent was dried, and the residue was purified by column chromatography (dichloromethane: methanol 100:1) to give a light yellow oil (30mg, 97%). After NMR analysis (data shown in Table 1), the obtained solid was Compound A27
(28) A heterocyclic compound a28 synthesized by the method comprising:
1) Synthesis of intermediate A28-2:
Crude intermediate a1-2(1.57g, 27%, 2.75mmol) was dissolved in dioxane/water (20mL/4mL), compound a28-1(500mg, 2.50mmol), potassium carbonate (690mg, 5.00mmol), pd (dba)2(144mg, 0.25mmol) and SPhos (206mg, 0.50mmol) were added, the mixture was reacted overnight at 80 ℃, cooled to room temperature, filtered through suction with celite, the filtrate was extracted with 50mL of water, ethyl acetate (60mL × 3), the combined organic phases were washed with saturated brine (150mL × 2), the organic phases were dried over anhydrous sodium sulfate, sodium sulfate was filtered off, ethyl acetate was spin-dried, and the residue was purified by column chromatography (dichloromethane: methanol ═ 50:1-30:1 with aqueous ammonia) to give a brown solid (340mg, 64%).
2) synthesis of intermediate A28-3:
intermediate a28-2(100mg, 0.47mmol) was dissolved in tetrahydrofuran (5mL), 4, 6-dichloro-5-fluoropyrimidine (79mg, 0.47mmol), diisopropylethylamine (180mg, 1.40mmol) was added, stirring was carried out overnight at 50 ℃, cooling was carried out to room temperature, the solvent was dried, and the residue was purified by column chromatography (dichloromethane: methanol: 100:1) to give a colorless oil (110mg, 68%). 1HNMR (400MHz, CDCl3) δ 8.54(d, J ═ 4.8Hz, 1H), 8.16(s, 1H), 7.62(d, J ═ 8.0Hz,2H), 7.48(d, J ═ 8.0Hz,2H), 7.37(s, 1H), 7.32(d, J ═ 4.8Hz, 1H), 5.39(s, 2H), 2.64(s, 3H), 1.66(d, 3H), 3.6 (d, 3H).
3) synthesis of product a 25:
Intermediate a28-3(50mg, 0.15mmol), 2-naphthoic acid (38mg, 0.22mmol) were dissolved in dioxane/water (5mL/1mL), potassium carbonate (80mg, 0.60mmol), tetrakistriphenylphosphine palladium (17mg, 0.015mmol) were added, nitrogen replaced, stirred overnight at 100 ℃, cooled to room temperature, filtered through celite, the filtrate was diluted with ethyl acetate (15mL), dried over anhydrous sodium sulfate, filtered off sodium sulfate, the solvent was spun off, and the residue was purified by column chromatography (dichloromethane: methanol ═ 100:1) to give a white solid (27mg, 43%). After NMR analysis (data shown in Table 1), the obtained solid was Compound A28
(29) a heterocyclic compound a29 synthesized by the method comprising:
1) Synthesis of intermediate A29-2:
compound a29-1(1.42g, 7.43mmol) was dissolved in acetonitrile (30mL), tert-butyl carbamate (1.22g, 10.4mmol), triethylsilane (2.61g, 22.3mmol), trifluoroacetic acid (2.54g, 22.3mmol) were added, stirred at room temperature for 24 hours, saturated aqueous sodium carbonate solution was slowly added with stirring until no bubbles were generated, ethyl acetate (100mL × 3) was extracted, the organic phase was washed with saturated brine (150mL × 2), dried over anhydrous sodium sulfate, sodium sulfate was filtered off, the solvent was spin-dried, and the residue was purified by column chromatography (petroleum ether: ethyl acetate ═ 40:1-20:1) to give a colorless oil (1.19g, 55%). 1HNMR (400MHz, CDCl3) × 6.87(s, 1H), 6.69(s, 1H), 4.90(s, 1H), 4.37(s, 2H), 1.46(s, 9H).
2) Synthesis of intermediate A29-3:
intermediate A29-2(1.16g, 3.97mmol) was dissolved in dichloromethane/trifluoroacetic acid (10mL/10mL), stirred at room temperature for 3 hours, saturated aqueous sodium carbonate was slowly added until no air bubbles were formed, dichloromethane (30 mL. times.3) was extracted, dried over anhydrous sodium sulfate, sodium sulfate was filtered off, and the solvent was dried by spinning to give a yellow oil (660mg, 87%).
3) Synthesis of intermediate A29-4:
intermediate a29-3(580mg, 3.02mmol) was dissolved in dioxane/water (20mL/4mL), crude intermediate a1-2(1.17g, 27%, 3.32mmol), potassium carbonate (1.67g, 12.1mmol), tetrakis triphenylphosphine palladium (175mg, 0.15mmol) were added, replaced with nitrogen, stirred overnight at 100 ℃, cooled to room temperature, water (30mL) was added, dichloromethane (30mL × 6) was extracted, the organic phase was dried over anhydrous sodium sulfate, sodium sulfate was filtered off, the solvent was dried, and the residue was purified by column chromatography (dichloromethane: methanol ═ 50:1) to give a black oil (360mg, 58%).
4) Synthesis of intermediate A29-5:
Intermediate a29-4(180mg, 0.88mmol) was dissolved in tetrahydrofuran (10mL), 4, 6-dichloro-5-fluoropyrimidine (147mg, 0.88mmol), diisopropylethylamine (341mg, 2.64mmol) were added, stirring was carried out overnight at 50 ℃, the solvent was cooled to normal temperature, the solvent was dried by spinning, and the residue was purified by column chromatography (dichloromethane: methanol ═ 100:1) to give a pale yellow solid (190mg, 64%). 1HNMR (400MHz, CDCl3) δ 8.46(d, J ═ 5.2Hz, 1H), 8.27(s,1H), 7.34(d, J ═ 3.6Hz,1H), 7.29(s, 1H), 7.24(d, J ═ 5.2Hz, 1H), 7.06(d, J ═ 3.2Hz, 1H), 5.62(s, 1H), 4.92(d, J ═ 6.0Hz,2H), 2.58(s, 3H).
5) synthesis of product a 29:
A29-5(50mg, 0.15mmol), 2-naphthoic acid (39mg, 0.23mmol) were dissolved in dioxane/water (5mL/1mL), potassium carbonate (82mg, 0.59mmol), tetrakistriphenylphosphine palladium (17mg, 0.015mmol) were added, nitrogen replaced, stirred overnight at 100 deg.C, cooled to room temperature, filtered through celite, the filtrate was diluted with ethyl acetate (15mL), dried over anhydrous sodium sulfate, filtered off sodium sulfate, the solvent was spin-dried, and the residue was purified by column chromatography (dichloromethane: methanol: 100:1) to give a white solid (50mg, 78%). After NMR analysis (data shown in Table 1), the obtained solid was Compound A29
(30) A heterocyclic compound a30 synthesized by the method comprising:
1) synthesis of intermediate A30-2:
compound A30-1(500mg, 3.50mmol) was dissolved in dioxane/water (20mL/4mL), crude intermediate A1-2(1.51g, 27%, 3.85mmol), potassium carbonate (1.93g, 14.0mmol), tetrakistriphenylphosphine palladium (202mg, 0.175mmol) were added, replaced with nitrogen, stirred overnight at 100 deg.C, cooled to room temperature, water (30mL) was added, dichloromethane (50 mL. times.6) was extracted, the organic phase was dried over anhydrous sodium sulfate, sodium sulfate was filtered off, the solvent was dried to give a brown oil (620mg, 89%).
2) Synthesis of intermediate A30-3:
a30-2(200mg, 1.01mmol) was dissolved in tetrahydrofuran (10mL), 4, 6-dichloro-5-fluoropyrimidine (168mg, 1.01mmol), diisopropylethylamine (389mg, 3.02mmol) were added, stirring was carried out overnight at 50 ℃, the solvent was cooled to normal temperature, and the residue was purified by column chromatography (dichloromethane: methanol ═ 50:1) to give an off-white solid (230mg, 69%). 1HNMR (400MHz, CDCl3) δ 8.74(s, 1H), 8.59(d, J ═ 5.2Hz, 1H), 8.23(s, 1H), 7.84-7.75 (m, 3H), 7.65(d, J ═ 5.2Hz, 1H), 5.76(s, 1H), 4.82(d, J ═ 6.0Hz,2H), 2.65(s, 3H).
3) synthesis of product a 30:
Intermediate a30-3(50mg, 0.15mmol), 2-naphthoic acid (39mg, 0.23mmol) were dissolved in dioxane/water (5mL/1mL), potassium carbonate (84mg, 0.61mmol), tetrakistriphenylphosphine palladium (17mg, 0.015mmol) were added, nitrogen replaced, stirred overnight at 100 ℃, cooled to room temperature, filtered through celite, the filtrate was diluted with ethyl acetate (15mL), dried over anhydrous sodium sulfate, filtered off sodium sulfate, the solvent was spun off, and the residue was purified by column chromatography (dichloromethane: methanol ═ 50:1) to give a white solid (52mg, 81%). After NMR analysis (data shown in Table 1), the obtained solid was Compound A30
(31) a heterocyclic compound a31 synthesized by the method comprising:
Intermediate a30-3(50mg, 0.15mmol), intermediate a4-2(58mg, 0.23mmol) were dissolved in dioxane/water (5mL/1mL), potassium carbonate (84mg, 0.61mmol), tetrakistriphenylphosphine palladium (18mg,0.015mmol) were added, nitrogen was replaced, stirring was performed at 100 ℃ overnight, cooling was performed to normal temperature, suction filtration was performed with celite, the filtrate was diluted with ethyl acetate (15mL), dried over anhydrous sodium sulfate, sodium sulfate was filtered off, the solvent was spun off, and the residue was purified by column chromatography (dichloromethane: methanol: 50:1-30:1) to give a white solid (44mg, 69%). After NMR analysis (data shown in Table 1), the obtained solid was Compound A31
(32) a heterocyclic compound a32 synthesized by the method comprising:
Intermediate a30-3(50mg, 0.15mmol) was dissolved in N-methylpyrrolidone (2mL) in a sealed tube, a26-3(102mg, 0.76mmol) and diisopropylethylamine (98mg, 0.76mmol) were added, stirring was carried out overnight at 120 ℃, cooling was carried out to normal temperature, water (10mL) was added, ethyl acetate (10mL × 3) was extracted, the organic phase was washed with saturated brine (20mL × 6), dried over anhydrous sodium sulfate, sodium sulfate was filtered off, the solvent was dried by spin-drying, and the residue was purified by column chromatography (dichloromethane: methanol ═ 50:1-30:1) to give a brown solid (25mg, 39%). After NMR analysis (data shown in Table 1), the obtained solid was Compound A32
(33) A heterocyclic compound a33 synthesized by the method comprising:
1) Synthesis of intermediate A33-2:
POCl3(18.3mL, 200mmol) was added to a 100mL two-necked flask, and stirred at 100 ℃, compound a33-1(10.43g, 70%, 90mmol) was dissolved in DMF (15.4mL, 200mmol) and slowly added dropwise to the above solution, and after dropping, 110 ℃ was stirred for 24 hours, cooled to room temperature, diluted with dichloromethane (100mL), poured slowly into ice water, extracted with dichloromethane (100mL × 3), the organic phase was washed with saturated brine (200mL × 3), dried over anhydrous sodium sulfate, filtered off sodium sulfate, the solvent was dried by spinning, and the residue was purified by column chromatography (petroleum ether: ethyl acetate ═ 10:1) to give a white solid (2.9g, 21%). 1HNMR (400MHz, CDCl3) delta 10.08(s, 1H),8.70(s,1H), 8.03(s, 1H), 2.48(s, 3H).
2) synthesis of intermediate A33-3:
Compound a33-2(1.00g, 6.41mmol) was dissolved in acetonitrile (50mL), tert-butyl carbamate (1.50g, 12.8mmol), Et3SiH (7.40g, 63.8mmol), trifluoroacetic acid (2.20g, 19.3mmol) was added, stirred at room temperature for 24 hours, saturated aqueous sodium carbonate solution was slowly added with stirring until no bubbles were generated, ethyl acetate (100mL × 3) was extracted, the organic phase was washed with saturated saline (150mL × 2), dried over anhydrous sodium sulfate, sodium sulfate was filtered off, the solvent was spin-dried, and the residue was purified by column chromatography (petroleum ether: ethyl acetate ═ 5:1) to give a colorless oil (1.60g, 97%).
3) synthesis of intermediate A33-4:
Intermediate A33-3(1.60g, 6.23mmol) was dissolved in dichloromethane/trifluoroacetic acid (10mL/10mL), stirred at room temperature for 3 hours, saturated aqueous sodium carbonate was slowly added until no air bubbles were formed, dichloromethane (30 mL. times.6) was extracted, dried over anhydrous sodium sulfate, sodium sulfate was filtered off, and the solvent was dried by spinning to give a yellow oil (810mg, 83%).
4) synthesis of intermediate A33-5:
intermediate A33-4(780mg, 4.97mmol) was dissolved in dioxane/water (20mL/4mL), crude intermediate A1-2(1.92g, 27%, 5.46mmol), potassium carbonate (2.74g, 19.8mmol), tetrakistriphenylphosphine palladium (287mg, 0.248mmol) was added, replaced with nitrogen, stirred overnight at 100 deg.C, cooled to room temperature, water (30mL) was added, dichloromethane (50 mL. times.6) was extracted, the organic phase was dried over anhydrous sodium sulfate, sodium sulfate was filtered off, the solvent was spin dried to give a brown oil (1.07g, 100%).
5) Synthesis of intermediate A33-6:
intermediate a33-5(200mg, 0.94mmol) was dissolved in tetrahydrofuran (10mL), 4, 6-dichloro-5-fluoropyrimidine (160mg, 0.96mmol), diisopropylethylamine (360mg, 2.79mmol) were added, stirring was carried out overnight at 50 ℃, the solvent was cooled to normal temperature, and the residue was purified by column chromatography (dichloromethane: methanol ═ 50:1) to give a white solid (220mg, 68%). 1HNMR (400MHz, CDCl3) δ 8.57(d, J ═ 5.2Hz, 1H), 8.55(s, 1H), 8.23(s, 1H), 7.62(s, 1H), 7.32(s, 1H), 7.24(d, J ═ 4.8Hz, 1H), 5.86(s, 1H), 4.78(d, J ═ 6.0Hz, 3H), 2.63(s, 3H), 2.37(s, 3H).
6) synthesis of product a 33:
intermediate a33-6(50mg,0.15mmol), 2-naphthoic acid (37mg, 0.22mmol) were dissolved in dioxane/water (5mL/1mL), potassium carbonate (80mg, 0.58mmol), tetrakistriphenylphosphine palladium (17mg, 0.015mmol) were added, nitrogen replaced, stirred overnight at 100 ℃, cooled to room temperature, filtered through celite, the filtrate was diluted with ethyl acetate (15mL), dried over anhydrous sodium sulfate, filtered off sodium sulfate, the solvent was spun off, and the residue was purified by column chromatography (dichloromethane: methanol ═ 50:1) to give a white solid (40mg, 63%). After NMR analysis (data shown in Table 1), the obtained solid was Compound A33
(34) A heterocyclic compound a34 synthesized by the method comprising:
intermediate a33-6(50mg,0.15mmol), intermediate a4-2(56mg, 0.22mmol) were dissolved in dioxane/water (5mL/1mL), potassium carbonate (80mg, 0.58mmol), tetrakistriphenylphosphine palladium (17mg, 0.015mmol) were added, nitrogen was replaced, stirring was performed at 100 ℃ overnight, cooling was performed to normal temperature, suction filtration was performed with celite, the filtrate was diluted with ethyl acetate (15mL), dried over anhydrous sodium sulfate, sodium sulfate was filtered off, the solvent was spun off, and the residue was purified by column chromatography (dichloromethane: methanol: 50:1-30:1) to give an off-white solid (30mg, 48%). After NMR analysis (data shown in Table 1), the obtained solid was Compound A34
(35) A heterocyclic compound a35 synthesized by the method comprising:
1) synthesis of intermediate A35-2:
compound a35-1(5g, 34.3mmol) was dissolved in acetonitrile (100mL), NBS (18.3g, 103mmol) and benzoyl peroxide (829mg, 3.43mmol) were added, refluxed overnight, cooled to room temperature, water (200mL), ethyl acetate (200mL × 3) were added for extraction, the organic phase was washed with saturated brine (300mL × 3), dried over anhydrous sodium sulfate, sodium sulfate was filtered off, the solvent was dried by spin-drying, and the residue was purified by column chromatography (petroleum ether: ethyl acetate ═ 100:1) to give a yellow oil (7.45g, 97%). 1HNMR (400MHz, CDCl3) δ 8.23(d, J ═ 1.2Hz, 1H),7.56-7.53(m,1H), 4.45(s, 2H).
2) Synthesis of intermediate A35-3:
Intermediate a35-2(7.45g, 33.1mmol) was dissolved in DMF (50mL), NaN3(8.61g, 132mmol) was added under ice bath, stirred at 50 ℃ overnight, cooled to room temperature, water (100mL) was added, ethyl acetate (100mL × 3) was extracted, the organic phase was washed with saturated brine (200mL × 3), dried over anhydrous sodium sulfate, sodium sulfate was filtered off, the solvent was dried by spin-drying, and the residue was purified by column chromatography (petroleum ether: ethyl acetate ═ 50:1) to give a colorless oil (5.6g, 90%). 1HNMR (400MHz, CDCl3) δ 8.19(s, 1H), 7.50(d, J ═ 8.0Hz, 1H), 4.45(s, 2H).
3) synthesis of intermediate A35-4:
intermediate a35-3(5.6g, 29.9mmol) was dissolved in tetrahydrofuran (50mL), PPh3(8.6g, 32.9mmol) was added portionwise with stirring in an ice bath, heated to reflux, water (10mL) was slowly added dropwise, stirred under reflux for 8 hours, cooled to room temperature, diluted with ethyl acetate (100mL), extracted with 0.2M hydrochloric acid (100mL × 2), the aqueous phase was washed once with ethyl acetate (100mL), the PH of the aqueous phase was then adjusted to 9 with 2M aqueous NaOH, ethyl acetate (200mL × 3) was extracted, the resulting organic phase was dried over anhydrous sodium sulfate, sodium sulfate was filtered off, the solvent was dried, and the residue was purified by column chromatography (dichloromethane: methanol ═ 50:1) to give a brown oil (2.57g, 53%). 1HNMR (400MHz, DMSO) δ 8.23(s, 1H), 7.89(d, J ═ 9.6Hz, 1H), 3.75(s, 2H).
4) synthesis of intermediate A35-5:
Intermediate a35-4(2.36g, 14.6mmol) was dissolved in dioxane/water (50mL/10mL), crude intermediate a1-2(6.31g, 27%, 16.1mmol), potassium carbonate (8.09g, 58.6mmol), tetrakistriphenylphosphine palladium (847mg, 0.73mmol) were added, replaced with nitrogen, stirred overnight at 100 ℃, cooled to room temperature, water (100mL) was added, dichloromethane (100mL × 6) was extracted, the organic phase was dried over anhydrous sodium sulfate, sodium sulfate was filtered off, the solvent was dried, and the residue was purified by column chromatography (dichloromethane: methanol ═ 50:1-20:1 with ammonia) to give a brown solid (2.5g, 79%). 1HNMR (400MHz, CDCl3) δ 8.61(d, J ═ 4.8Hz, 1H), 8.50(s, 1H), 7.77(s, 1H), 7.69(d, J ═ 4.0Hz, 1H), 7.58(d, J ═ 12.0Hz, 1H), 4.01(s, 2H), 2.65(s, 3H).
5) synthesis of intermediate A35-6:
Intermediate a35-5(200mg, 0.92mmol) was dissolved in tetrahydrofuran (10mL), 4, 6-dichloro-5-fluoropyrimidine (154mg, 0.92mmol), diisopropylethylamine (357mg, 2.77mmol) were added, stirring was carried out overnight at 50 ℃, the solvent was cooled to room temperature, the solvent was dried by spinning, and the residue was purified by column chromatography (dichloromethane: methanol ═ 50:1) to give an off-white solid (200mg, 62%). 1HNMR (400MHz, CDCl3) δ 8.61(d, J ═ 4.8Hz, 1H), 8.56(s, 1H), 8.24(s, 1H), 7.76(s, 1H), 7.69(s, 1H), 7.55(d, J ═ 11.6Hz, 1H), 5.78(s, 1H), 4.84(d, J ═ 6.0Hz,2H), 2.65(s, 3H).
6) synthesis of product a 35:
Intermediate a35-6(50mg,0.15mmol), 2-naphthalene boronic acid (37mg, 0.22mmol) were dissolved in dioxane/water (5mL/1mL), potassium carbonate (79mg, 0.57mmol), tetrakistriphenylphosphine palladium (17mg, 0.015mmol) were added, nitrogen replaced, stirred overnight at 100 ℃, cooled to room temperature, filtered through celite, the filtrate was diluted with ethyl acetate (15mL), dried over anhydrous sodium sulfate, filtered through sodium sulfate, the solvent was spun dry, and the residue was purified by column chromatography (dichloromethane: methanol 100:1-50:1) to give a white solid (68mg, 100%). After NMR analysis (data shown in Table 1), the obtained solid was Compound A35
(36) a heterocyclic compound a36 synthesized by the method comprising:
intermediate a35-6(50mg,0.15mmol), intermediate a4-2(55mg, 0.22mmol) were dissolved in dioxane/water (5mL/1mL), potassium carbonate (80mg, 0.58mmol), tetrakistriphenylphosphine palladium (17mg, 0.015mmol) were added, nitrogen was replaced, stirring was performed at 100 ℃ overnight, cooling was performed to normal temperature, suction filtration was performed with celite, the filtrate was diluted with ethyl acetate (15mL), dried over anhydrous sodium sulfate, sodium sulfate was filtered off, the solvent was spun off, and the residue was purified by column chromatography (dichloromethane: methanol ═ 50:1-30:1) to give an off-white solid (28mg, 44%). After NMR analysis (data shown in Table 1), the obtained solid was Compound A36
(37) A heterocyclic compound a37 synthesized by the method comprising:
1) Synthesis of intermediate A37-2:
a37-1(800mg, 4.28mmol) was dissolved in dioxane/water (20mL/4mL), crude intermediate A1-2(1.84g, 27%, 4.71mmol), potassium carbonate (1.77g, 12.8mmol), tetrakis triphenylphosphine palladium (247mg, 0.21mmol) were added, nitrogen was substituted, stirring overnight at 100 deg.C, cooling to room temperature, suction filtration with celite was performed, water (30mL) was added to the filtrate, dichloromethane (50 mL. times.6) was extracted, the organic phase was dried over anhydrous sodium sulfate, sodium sulfate was filtered off, the solvent was dried, and the residue was purified by column chromatography (dichloromethane: methanol ═ 50:1-20:1) to give a brown solid (300mg, 35%).
2) Synthesis of intermediate A37-3:
Intermediate a37-2(150mg, 0.75mmol) was dissolved in tetrahydrofuran (5mL), 4, 6-dichloro-5-fluoropyrimidine (126mg, 0.75mmol), diisopropylethylamine (292mg, 2.26mmol) were added, stirring was carried out overnight at 50 ℃, the solvent was cooled to room temperature, the solvent was dried by spinning, and the residue was purified by column chromatography (dichloromethane: methanol ═ 50:1) to give an off-white solid (136mg, 55%). 1HNMR (400MHz, CDCl3) δ 8.85(s, 1H), 8.61(d, J ═ 5.2Hz, 1H),8.22(s,1H), 7.93(d, J ═ 8.0Hz, 1H), 7.44(d, J ═ 8.0Hz, 1H), 7.37(s, 1H), 7.31(d, J ═ 5.2Hz, 1H), 6.65(s, 1H), 4.87(d, J ═ 4.8Hz, 2H), 2.65(s, 3H).
3) Synthesis of product a 37:
a37-3(50mg, 0.15mmol), compound 12(39mg, 0.23mmol) was dissolved in dioxane/water (5mL/1mL), potassium carbonate (84mg, 0.61mmol), tetrakistriphenylphosphine palladium (17mg, 0.015mmol) were added, nitrogen was replaced, stirring was performed overnight at 100 ℃, cooling was performed to room temperature, suction filtration was performed with celite, the filtrate was diluted with ethyl acetate (15mL), dried over anhydrous sodium sulfate, sodium sulfate was filtered off, the solvent was spin-dried, and the residue was purified by column chromatography (dichloromethane: methanol ═ 50:1) to give a white solid (47mg, 74%). After NMR analysis (data shown in Table 1), the obtained solid was Compound A37
(38) A heterocyclic compound a38 synthesized by the method comprising:
1) Synthesis of intermediate A38-2:
4-Pyridineboronic acid (397mg, 3.23mmol) was dissolved in dioxane/water (20mL/4mL), p-bromobenzylamine (500mg, 2.69mmol), potassium carbonate (742mg, 5.38mmol), Pd (dba)2(155mg, 0.27mmol) and SPhos (220mg, 0.54mmol) were added, the reaction was carried out overnight under nitrogen, the temperature was cooled to room temperature, suction filtration was carried out on celite, 50mL of water was added to the filtrate, ethyl acetate (60 mL. times.3) was extracted, the combined organic phases were washed with saturated brine (150 mL. times.2), the organic phases were dried over anhydrous sodium sulfate, sodium sulfate was filtered off, ethyl acetate was spin-dried, and the residue was purified by column chromatography (dichloromethane: methanol: 50:1-30:1 with aqueous ammonia) to give a brown solid (240mg, 48%).
2) synthesis of intermediate A38-3:
intermediate a38-2(100mg, 0.54mmol) was dissolved in tetrahydrofuran (5mL), 4, 6-dichloro-5-fluoropyrimidine (90mg, 0.54mmol), diisopropylethylamine (210mg, 1.63mmol) were added, stirring was carried out overnight at 50 ℃, the solvent was cooled to normal temperature, the solvent was dried by spinning, and the residue was purified by column chromatography (dichloromethane: methanol ═ 100:1) to give a yellow solid (80mg, 47%). 1HNMR (400MHz, CDCl3) δ 8.69(brs, 2H), 8.23(s, 1H), 7.64(d, J ═ 6.8Hz, 2H), 7.58-7.39 (m, 4H), 5.60(s, 1H), 4.80(d, J ═ 5.2Hz, 2H).
3) Synthesis of product a 38:
intermediate a38-3(63mg, 0.20mmol), 2-naphthalene boronic acid (52mg, 0.30mmol) were dissolved in dioxane/water (5mL/1mL), potassium carbonate (110mg, 0.80mmol), tetrakistriphenylphosphine palladium (23mg, 0.02mmol) were added, nitrogen replaced, stirred overnight at 100 ℃, cooled to room temperature, filtered through celite, the filtrate was diluted with ethyl acetate (15mL), dried over anhydrous sodium sulfate, filtered off sodium sulfate, the solvent was spun dry, and the residue was purified by column chromatography (dichloromethane: methanol: 100:1) to give a white solid (46mg, 57%). After NMR analysis (data shown in Table 1), the obtained solid was Compound A38
(39) A heterocyclic compound a39 synthesized by the method comprising:
1) Synthesis of intermediate A39-2:
p-bromobenzylamine (800mg, 4.30mmol) was dissolved in dioxane/water, A39-1(1.52g, 12.1mmol) was added, potassium phosphate (1.82g, 8.58mmol), Pd (dppf)2Cl2(176mg, 0.22mmol), dppf (119mg, 0.22mmol) was added, nitrogen substitution was performed, stirring was performed overnight at 100 ℃, cooling was performed to normal temperature, suction filtration was performed with diatomaceous earth, water (30mL) was added to the filtrate, dichloromethane (50 mL. times.6) was extracted, the organic phase was dried with anhydrous sodium sulfate, sodium sulfate was filtered off, the solvent was dried, and the residue was purified by column chromatography (dichloromethane: methanol: 50:1-20:1 with ammonia water) to give a brown oil (410mg, 51%).
2) synthesis of intermediate A38-3:
Intermediate a39-2(200mg, 1.07mmol) was dissolved in tetrahydrofuran (5mL), 4, 6-dichloro-5-fluoropyrimidine (179mg, 1.07mmol), diisopropylethylamine (414mg, 3.21mmol) were added, stirring was carried out overnight at 50 ℃, the solvent was cooled to room temperature, and the residue was purified by column chromatography (dichloromethane: methanol ═ 150:1) to give a colorless oil (240mg, 71%). 1HNMR (400MHz, CDCl3) δ 8.23(s, 1H), 7.51(s, 1H), 7.45-7.40(m, 4H), 6.30(s, 1H), 5.55(s, 1H),4.79(d, J ═ 6.0Hz,2H), 3.89(s, 3H).
3) Synthesis of product a 38:
Intermediate a39-3(50mg, 0.16mmol), 2-naphthoic acid (41mg, 0.24mmol) were dissolved in dioxane/water (5mL/1mL), potassium carbonate (87mg, 0.63mmol), tetrakistriphenylphosphine palladium (18mg, 0.016mmol) were added, nitrogen replaced, stirred overnight at 100 ℃, cooled to room temperature, filtered through celite, the filtrate was diluted with ethyl acetate (15mL), dried over anhydrous sodium sulfate, filtered off sodium sulfate, the solvent was spun off, and the residue was purified by column chromatography (dichloromethane: methanol ═ 150:1) to give a white solid (37mg, 58%). After NMR analysis (data shown in Table 1), the obtained solid was Compound A39
(40) a heterocyclic compound a40 synthesized by the method comprising:
1) Synthesis of intermediate A40-2:
LiAlH4(450mg, 11.8mmol) was charged into a 50mL two-necked flask, the flask was purged with nitrogen, tetrahydrofuran (10mL) was added by syringe, A40-1(500mg, 2.96mmol) was dissolved in tetrahydrofuran (10mL), and the solution was added slowly by syringe and stirred under reflux for 2 hours. After cooling to room temperature, saturated aqueous sodium sulfate solution was slowly added dropwise in an ice bath until no more bubbles were generated, stirred for 1 hour, filtered under suction, the filtrate was dried over anhydrous sodium sulfate, sodium sulfate was filtered off, and the solvent was dried by spin-drying to give a brown oil (570mg, 100%).
2) synthesis of intermediate A40-3:
Intermediate a40-2(200mg, 1.16mmol) was dissolved in tetrahydrofuran (5mL), 4, 6-dichloro-5-fluoropyrimidine (193mg, 1.16mmol), diisopropylethylamine (447mg, 3.46mmol) were added, stirring was carried out overnight at 50 ℃, the solvent was cooled to room temperature, the solvent was dried by spinning, and the residue was purified by column chromatography (dichloromethane: methanol ═ 50:1) to give an off-white solid (150mg, 43%). 1HNMR (400MHz, CDCl3) δ 8.22(s,1H), 7.84(s, 1H), 7.47(d, J ═ 8.4Hz, 2H), 7.39(d, J ═ 8.4Hz, 2H), 7.27(s, 1H), 7.21(s, 1H), 5.69(s, 1H),4.79(d, J ═ 5.6Hz, 2H).
3) Synthesis of product a 40:
intermediate a40-3(50mg, 0.16mmol), 2-naphthoic acid (42mg, 0.24mmol) were dissolved in dioxane/water (5mL/1mL), potassium carbonate (91mg, 0.66mmol), tetrakistriphenylphosphine palladium (19mg, 0.016mmol) were added, nitrogen substitution was performed, stirring was performed overnight at 100 ℃, cooling was performed to normal temperature, suction filtration was performed with celite, the filtrate was diluted with ethyl acetate (15mL), dried over anhydrous sodium sulfate, sodium sulfate was filtered off, the solvent was spin-dried, and the residue was purified by column chromatography (dichloromethane: methanol ═ 100:1-50:1) to obtain a white solid (36mg, 55%). After NMR analysis (data shown in Table 1), the obtained solid was Compound A40
(41) a heterocyclic compound a41 synthesized by the method comprising:
1) Synthesis of intermediate A41-2:
a41-1(200mg, 1.26mmol) was dissolved in tetrahydrofuran (5mL), 4, 6-dichloro-5-fluoropyrimidine (211mg, 1.26mmol), diisopropylethylamine (490mg, 3.80mmol) were added, stirring was carried out overnight at 50 ℃, the solvent was cooled to normal temperature, and the residue was purified by column chromatography (dichloromethane: methanol ═ 150:1) to give a yellow solid (120mg, 33%). 1HNMR (400MHz, CDCl3) δ 9.24(s, 1H), 8.54(d, J ═ 5.6Hz, 1H), 8.23(s, 1H), 7.98(d, J ═ 8.4Hz,1H), 7.76(s, 1H), 7.63(d, J ═ 5.6Hz, 1H), 7.58(d, J ═ 8.0Hz, 1H), 5.70(s, 1H), 4.95(d, J ═ 6.0Hz, 2H).
2) Synthesis of product a 41:
Intermediate a41-2(50mg, 0.17mmol), a4-2(66mg, 0.26mmol) were dissolved in dioxane/water (5mL/1mL), potassium carbonate (96mg, 0.69mmol), tetrakistriphenylphosphine palladium (20mg, 0.017mmol) were added, nitrogen was replaced, stirring was performed at 100 ℃ overnight, cooling was performed to normal temperature, suction filtration was performed with celite, the filtrate was diluted with ethyl acetate (15mL), dried over anhydrous sodium sulfate, sodium sulfate was filtered off, the solvent was spun dry, and the residue was purified by column chromatography (dichloromethane: methanol: 100:1-50:1) to give a white solid (43mg, 65%). After NMR analysis (data shown in Table 1), the obtained solid was Compound A41
(42) a heterocyclic compound a42 synthesized by the method comprising:
1) Synthesis of intermediate A42-2:
a42-1(1.0g, 5.92mmol) was dissolved in dichloromethane (30mL), triethylamine (896mg, 8.88mmol), trifluoromethanesulfonic anhydride (2.5g, 8.88mmol) were added in this order, stirring was carried out at normal temperature overnight, water was added thereto and quenched, ethyl acetate was extracted three times, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, the solvent was evaporated off, and the residue was purified by column chromatography (petroleum ether: ethyl acetate: 30:1) to give a white solid (1.65g, 93%).
2) Synthesis of intermediate A42-3:
a42-2(1.35g, 4.49mmol), potassium phosphate (1.27g, 5.99mmol), Pd (dba)2(114mg, 0.20mmol), XPhos (143mg, 0.30mmol), vacuum pumping, nitrogen replacement, nitromethane (4mL), dioxane (25mL), heating to 80 ℃ and stirring for 18 hours, cooling to room temperature, acetic acid (8mL), zinc powder (2.93g, 45mmol) addition, reaction at 35 ℃ for 3 hours, filtering to remove unreacted zinc powder, water (30mL) addition, ethyl acetate extraction twice, aqueous phase pH 10 adjusted with 1M NaOH, ethyl acetate extraction three times, organic phase column chromatography with saturated sodium chloride, anhydrous sodium sulfate drying, solvent evaporation, and residue purification (petroleum ether: ethyl acetate: 3:1-0:1) to obtain pale yellow solid (280mg, 34%).
3) synthesis of intermediate A42-4:
a42-3(182mg, 1.0mmol) was dissolved in tetrahydrofuran (1mL), 4, 6-dichloro-5-fluoropyrimidine (167mg, 1.0mmol), diisopropylethylamine (260mg, 2.0mmol) were added, stirring was carried out overnight at 50 ℃, cooling was carried out to normal temperature, the solvent was dried by spinning, and the residue was purified by column chromatography (petroleum ether: ethyl acetate ═ 5:1-3:1) to give a pale yellow solid (120mg, 38%).
4) Synthesis of product a 42:
Intermediate a42-4(53mg, 0.17mmol), a4-2(66mg, 0.26mmol) were dissolved in dioxane/water (5mL/1mL), potassium carbonate (96mg, 0.69mmol), tetrakistriphenylphosphine palladium (20mg, 0.017mmol) were added, nitrogen was replaced, stirring was performed at 100 ℃ overnight, cooling was performed to normal temperature, suction filtration was performed with celite, the filtrate was diluted with ethyl acetate (15mL), dried over anhydrous sodium sulfate, sodium sulfate was filtered off, the solvent was spun dry, and the residue was purified by column chromatography (dichloromethane: methanol: 100:1-50:1) to give a pale yellow solid (35mg, 66%). After NMR analysis (data shown in Table 1), the obtained solid was Compound A42
(43) A heterocyclic compound a43 synthesized by the method comprising:
a42(17mg, 0.04mmol), potassium carbonate (2.8mg, 0.02mmol) were dissolved in DMSO (1mL), 30% H2O2(6mg, 0.05mmol) was added, stirred at room temperature for 3 hours, poured into water, filtered with suction, washed with water, washed with n-hexane, and dried under vacuum to give a pale yellow solid (14mg, 83%). After NMR analysis (data shown in Table 1), the obtained solid was Compound A43
(44) A heterocyclic compound a44 synthesized by the method comprising:
Dissolving A42-4(40mg,0.13mmol), A26-3(51mg,0.39mmol) and DIPEA (83mg,0.64mmol) in NMP (1.5mL), heating to 130 ℃ for reaction for 12h, cooling to room temperature, adding water, extracting with ethyl acetate for three times, combining organic phases, washing with saturated sodium chloride aqueous solution once, drying with anhydrous sodium sulfate, evaporating the solvent under reduced pressure, purifying by column chromatography (petroleum ether: ethyl acetate: 5:1-3:1) to obtain brown solid (20mg, 38%) which is analyzed by nuclear magnetic spectrum (spectrum data is shown in Table 1), and obtaining the solid which is the compound A44
(45) a heterocyclic compound a45 synthesized by the method comprising:
A35-6(50mg,0.15mmol), A26-3(97mg,0.72mmol), DIPEA (93mg,0.72mmol) were dissolved in NMP (1.5mL), heated to 130 ℃ for reaction for 8h, cooled to room temperature, added with water, extracted three times with ethyl acetate, the organic phases were combined, washed once with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and purified by column chromatography (petroleum ether: ethyl acetate: 5:1-3:1) to give a brown solid (25mg, 39%). After NMR analysis (data shown in Table 1), the obtained solid was Compound A45
(46) A heterocyclic compound a46 synthesized by the method comprising:
a33-6(50mg,0.15mmol) was dissolved in NMP (2mL) in a sealed tube, A26-3(97mg,0.73mmol) and DIPEA (94mg,0.73mmol) were added, stirring was carried out overnight at 120 ℃, cooling was carried out to room temperature, water (10mL) was added, ethyl acetate (10 mL. times.3) was extracted, the organic phase was washed with saturated brine (20 mL. times.6), dried over anhydrous sodium sulfate, sodium sulfate was filtered off, the solvent was distilled off under reduced pressure, and purification was carried out by column chromatography (dichloromethane: methanol: 50:1-30:1) to give a brown oil (50mg, 78%). After NMR analysis (data shown in Table 1), the obtained solid was Compound A46
(47) a heterocyclic compound a47 synthesized by the method comprising:
1) synthesis of intermediate A47-2:
a flask of 100mL was charged with A47-1(10g, 50mmol), sulfur (3.22g, 100mmol), cyanamide (4.36g,100mmol) and pyridine (40mL), and heated to 130 ℃ for 90 minutes. Cooled to room temperature and the solid was filtered off, washed with ethyl acetate and dried to give a dark brown solid (9.7g, 76%). 1H NMR (400MHz, DMSO). delta.6.86 (s,2H),4.29(s,2H),3.56(m,2H),2.43(s,2H),1.41(s,9H).
2) Synthesis of intermediate A47-3:
a47-2(9.7g, 38mmol), isoamyl nitrite (11g, 95mmol) were dissolved in tetrahydrofuran 150mL, reacted at 80 ℃ for 2h, cooled to room temperature, added with water, extracted three times with ethyl acetate, the organic phases were combined, washed once with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and purified by column chromatography (petroleum ether: ethyl acetate ═ 10:1-5:1) to give a yellow solid (3.3g, 36%). 1H NMR (400MHz in CDCl 3). delta.8.67 (s,1H),4.67(s,2H),3.76(s,2H),2.93(s,2H),1.49(s,9H).
3) synthesis of intermediate A47-4:
A47-4(800mg, 3.3mmol) was dissolved in a solution of hydrogen chloride in ethyl acetate (3M,5mL) and stirred at room temperature for 2 h. The solvent was distilled off under reduced pressure to give a yellow solid (580mg, 100%). 1H NMR (400MHz, DMSO) δ 9.76(s,2H),9.08(s,1H),4.41(s,2H),3.43(s,2H),3.04(t, J ═ 5.8Hz,2H).
3) synthesis of product a 47:
A1-4(50mg,0.15mmol), A47-4(107mg,0.77mmol), DIPEA (198mg,1.53mmol) were dissolved in NMP (2mL) and heated to 120 ℃ for 8 h. Cooling to room temperature, adding water, extracting with ethyl acetate three times, combining the organic phases, washing once with saturated aqueous sodium chloride solution, drying over anhydrous sodium sulfate, evaporating the solvent under reduced pressure, and purifying by column chromatography (petroleum ether: ethyl acetate: 5:1-3:1) to obtain a brown solid compound (30mg, 45%). After NMR analysis (data shown in Table 1), the obtained solid was Compound A47
(48) a heterocyclic compound a48 synthesized by the method comprising:
1) Synthesis of intermediate A48-2:
A48-1(180mg,0.91mmol), bis pinacolato borate (348mg,1.37mmol),1,1' -bis (diphenylphosphino) ferrocene dichloropalladium (II) (37mg,0.045mmol), potassium acetate (180mg,1.83mmol) were dissolved in tetrahydrofuran (10 mL). Reacting at 80 deg.C for 8h under nitrogen protection, cooling to room temperature, filtering with diatomaceous earth, and evaporating under reduced pressure to remove solvent to obtain black solid (300mg, content: 74%).
2) Synthesis of product a 48:
a1-4(50mg,0.15mmol), A48-2(54mg,0.23mmol), tetrakistriphenylphosphine palladium (18mg,0.015mmol), potassium carbonate (74mg,0.53mmol) were dissolved in dioxane (5mL) and water (1 mL). And reacting for 8 hours at 100 ℃ under the protection of nitrogen. Cooling to room temperature, celite filtration, addition of water, extraction three times with ethyl acetate, combination of the organic phases, washing once with saturated aqueous sodium chloride solution, anhydrous sodium sulfate, evaporation of the solvent under reduced pressure, and purification by column chromatography (petroleum ether: ethyl acetate ═ 2:1-1:1) gave a white solid (24mg, 39%). After NMR analysis (data shown in Table 1), the obtained solid was Compound A48
(49) a heterocyclic compound a64 synthesized by the method comprising:
1) synthesis of intermediate A64-2:
intermediate a1-4(133mg,0.404mmol) was dissolved in dichloromethane (5mL), m-chloroperoxybenzoic acid (174mg,1.01mmol) was added slowly with stirring at room temperature overnight, dichloromethane (15mL) was added for dilution, a saturated sodium bicarbonate solution was added, stirring was carried out for 30 minutes, the organic phase was separated and dried over anhydrous sodium sulfate, sodium sulfate was filtered off, the solvent was spun off, and column chromatography was carried out on the residue (dichloromethane: methanol: 100:1 to 50:1) to obtain a white solid (130mg, 96%). 1H NMR (400MHz, CDCl3) δ 8.25(d, J ═ 6.8Hz,1H),8.22(s,1H),7.54(d, J ═ 8.0Hz,2H),7.43(d, J ═ 8.0Hz,3H), 7.35-7.29 (m,1H),5.91(s,1H),4.79(d, J ═ 6.0H), 2H, 57H), 5.57 (s,3H).
2) Synthesis of product a 64:
Intermediate A4-2(67mg,0.194mmol) was dissolved in dioxane/water (5mL/1mL), and intermediate 2(74mg,0.291mmol), potassium carbonate (107mg,0.777mmol), and tetrakistriphenylphosphine palladium (22mg,0.019mmol) were added, and the reaction was refluxed overnight with replacement with nitrogen. Cooling to room temperature, suction filtration over celite, dilution of the filtrate with ethyl acetate (15mL), drying over anhydrous sodium sulfate, filtration of sodium sulfate, spin drying of the solvent, and column chromatography of the residue (dichloromethane: methanol ═ 50:1 to 30:1) gave a white solid (65mg, 77%). After NMR analysis (data shown in Table 1), the obtained solid was Compound A64
(50) A heterocyclic compound a69 synthesized by the method comprising:
a33-6(100mg,0.29mmol), 3-ethynylpyridine (92mg, 0.87mmol), dichlorodiphenylpalladium (9mg,0.012mmol), triphenylphosphine (6.1m g,0.023mmol), cuprous iodide (0.55mg,0,023mmol) was added to 2mL of diisopropylammonia and 2mL of N-methylpyrrolidone. Reacting for 24 hours at 100 ℃ under the protection of nitrogen. Cooled to room temperature and filtered through celite. The filtrate was diluted with water and extracted with ethyl acetate (10 mL. times.3). The organic phases were combined, washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether: ethyl acetate ═ 2:1-1:1) to give a white solid (17mg, 14%). After NMR analysis (data shown in Table 1), the obtained solid was Compound A69
(51) A heterocyclic compound a85 synthesized by the method comprising:
1) Synthesis of intermediate A85-2:
a85-1(45.6g,200mmol), formamidine acetate (20.8g,200mmol) and sodium ethoxide (13.6g,200mmol) were dissolved in this order in 200mL anhydrous ethanol. After refluxing for 12h, the solvent was spin-dried. 2N HCl (100mL) was added. The aqueous phase was extracted with ethyl acetate. The organic phases were combined and dried, and the solvent was removed by evaporation to give a brown solid (22g) which was used directly in the next reaction.
2) synthesis of intermediate A85-3:
a85-2(21.0g,112.9mmol) and 0.5mL DMF were dissolved in 200mL dichloromethane, and oxalyl chloride (43.0g,338.7mmol) was added dropwise thereto under ice bath. After dropping, the reaction was refluxed overnight. After cooling to room temperature, the solvent was spin dried. The solute was dissolved in ethyl acetate, and the organic phase was washed successively with saturated sodium bicarbonate and saturated brine. After drying and spinning the organic phase, the solute was purified by column chromatography (petroleum ether: ethyl acetate: 10:1 as mobile phase) to give a colorless oil (17.8g, 77%). 1HNMR (400MHz, CDCl3) δ 8.90(s,1H),4.52(q, J ═ 7.1Hz,2H),1.44(t, J ═ 7.2Hz,3H).
3) Synthesis of intermediate A85-4:
a85-3(6.14g,30.0mmol) was dissolved in 50mL of methanol, and triethylamine (3.03g,30.0mmol) was added dropwise thereto at room temperature. After the reaction was carried out overnight at room temperature, the solvent was spin-dried. The solute was purified by column chromatography (mobile phase petroleum ether: ethyl acetate: 10:1) to give a white solid (4.14g, 74%) 1H NMR (400MHz, CDCl3) δ 8.59(s,1H),4.11(s,3H),4.01(s,3H).
4) synthesis of intermediate A85-5:
Tert-butyl 3-methyl-2-pyridinecarboxylate (2.69g,14.0mmol) was dissolved in 50mL of anhydrous tetrahydrofuran, and LDA (2M,28mL,56.0mmol) was added dropwise thereto at-40 ℃. Reacting at-40 deg.C for 30min, and cooling to-60 deg.C. A85-4(2.60g,14.0mmol) was added rapidly. After 1h of continued reaction, it was quenched by the addition of 10mL of saturated NH4 Cl. Extraction with ethyl acetate, organic phase synthesis and drying, solvent spin-drying, and purification of the solute by column chromatography (mobile phase petroleum ether: ethyl acetate 3:1) gave a yellow solid (1.36g, 28%) 1H NMR (400MHz, CDCl3) δ 8.61(s,1H),8.48(d, J ═ 4.4Hz,1H),8.08(s,1H),7.60(d, J ═ 7.6Hz,1H),7.41-7.37(m,1H),4.86(s,2H),4.13(s,3H),1.40(s,9H).
5) Synthesis of intermediate A85-6:
A85-5(1.36g,3.93mmol) and ammonium acetate (3.03g,39.3mmol) were dissolved in 20mL of acetic acid. After an overnight reaction at 108 ℃ the solvent was spin dried. The solute was dissolved in ethyl acetate and washed with saturated NaHCO 3. The organic phase was dried and spun to give a yellow solid (880mg) which was used directly in the next reaction.
6) synthesis of intermediate A85-7:
a85-6(440mg,1.62mmol) and triethylamine (327mg,3.24mmol) were dissolved in 10mL (POCl3: toluene 3: 1). After 1h of reaction at 100 ℃, the solvent was spin-dried. After the solute was diluted with ethyl acetate, the organic phase was washed with saturated NaHCO 3. The organic phase is dried and spin-dried. The solute was purified by column chromatography (mobile phase petroleum ether: ethyl acetate 2: 1) to give a white solid (440mg, 100%).
7) Synthesis of intermediate A85-8:
A85-7(440mg,1.62mmol), formic acid (253mg,5.50mmol), triethylamine (924mg,9.15mmol) and Pd (PPh3)4(200mg,0.173mmol) were dissolved in 10mL DMSO. Reacting for 1h at 100 ℃ under the protection of nitrogen, and filtering. The filtrate was diluted with ethyl acetate. The organic phase was washed three times with saturated brine. The organic phase was dried and spun dry and the solute refined by column chromatography (mobile phase petroleum ether: ethyl acetate 3:1) to give a white solid (400mg, 96%). 1H NMR (400MHz, CDCl3) δ 9.70(s,1H),9.12(d, J ═ 3.6Hz,1H),8.70(s,1H),8.52(s,1H),8.30(d, J ═ 8.4Hz,1H),7.56-7.53(m,1H),4.16(s,3H).
8) synthesis of intermediate A85-9:
a85-8(400mg,1.56mmol) was dissolved in 10mL hydrobromic acid (37%) solution. After 1h of reaction at 100 ℃, the solvent was spin-dried. The solute was added to 10mL of isopropanol and the precipitated solid was filtered and rinsed with diethyl ether to give a yellow solid (400mg) which was used directly in the next reaction.
9) synthesis of product a 85:
a85-9(25mg,0.1mmol), A35-5(22mg,0.1mmol) and DIPEA (26mg,0.2mmol) were dissolved in 1mL DMF. To this was added PyBOP (78mg,0.15mmol) in portions, and the mixture was stirred at room temperature for 12 hours. Diluted with ethyl acetate and the organic phase washed three times with saturated brine. The organic phase was dried and spun dry and the solute was purified by column chromatography (mobile phase dichloromethane: methanol: 100: 4) to give a white solid (30mg, 68%). After NMR analysis (data shown in Table 1), the obtained solid was Compound A85
(52) A heterocyclic compound a92 synthesized by the method comprising:
1) Synthesis of intermediate A92-2:
a92-1(100mg,0.8mmol), 4, 6-dichloro-5-fluoropyrimidine (134mg,0.8mmol), and N, N-diisopropylethylamine (310mg,2.4mmol) were dissolved in 3mL of tetrahydrofuran and reacted at 50 ℃ for 12 hours. Concentrated under reduced pressure and purified by column chromatography (petroleum ether: ethyl acetate 1: 1-0:1) to give a grey solid (180mg, 88%). 1H NMR (400MHz in CDCl 3). delta.8.27 (s,1H),7.61(s,1H),5.10(s,2H),4.60(m,2H),4.29(m,2H).
2) synthesis of product a 92:
a92-2(80mg,0.32mmol) and A92-3(123mg,0.47mmol) were dissolved in N-methylpyrrolidone (2mL), diisopropylethylamine (408mg,3.16mmol) was added, and the mixture was heated to 135 ℃ for reaction for 24 hours. After cooling to room temperature, 5mL of water was added and extracted with ethyl acetate (10 mL. times.3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered off sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether: ethyl acetate: 2:1-1:1) to give a yellow solid (50mg, 36%). After NMR analysis (data shown in Table 1), the obtained solid was Compound A92
Using the above synthesis procedure, compounds A1-A96 were synthesized from similar starting materials, the structures and spectral data of which are shown in Table 1.
TABLE 1 analytical Structure and spectral data for heterocyclic Compounds A1-A96
example 2
in this example, the inhibitory activity of the 5-fluoropyrimidine heterocyclic compound a1-a96 having Wnt signaling pathway inhibitory activity prepared in example 1 on the Wnt signaling pathway was measured.
LWnt3A cells (CRL-2647, ATCC) were cultured in DMEM medium (Gibico) containing 10% fetal bovine serum (Hyclone). HEK293STF stable clonal cells (HEK 293 cells transfected with "Super-TopFlash" TCF fluorescent reporter plasmid) were cultured in complete medium (DMEM medium containing 4 mML-glutamine, 1.5g/L sodium bicarbonate, 4.5g/L glucose, 6. mu.g/mL blasticidin and 10% fetal bovine serum). LWnt3A cells and HEK293STF stable clones were harvested separately when cultured to 90% confluence and mixed at a ratio of 1: 1. 100 μ L/well of the mixed cell culture solution was added to a 96-well plate to give a final cell concentration of 12000 cells/well, followed by further culture for 24 hours. The test compound was diluted stepwise with DMSO and then diluted to a desired concentration with DMEM medium. mu.L of the compound solution was added to the aforementioned 96-well plate containing the cell culture solution, followed by incubation at 37 ℃ for 48 hours. Finally, 50. mu.L of luciferase solution (Brigh-Glo, Promega) was added to each well and shaken at room temperature for 5 minutes. The luminescence signal was measured with a microplate reader (PHERAStarFS, BMG), and the IC50 value (titer) of the compound was calculated from the inhibition of the luminescence signal by the compound at different concentrations. The results are shown in Table 2 (results of experiments for determining the inhibitory activity of heterocyclic compound A1-A96 on the Wnt signaling pathway). The lower the IC50 value, the higher the activity of the heterocyclic compound.
TABLE 2 results of experiments for determining the inhibitory potency of heterocyclic compounds A1-A96 on Wnt signaling pathway
as can be seen from table 2 above, the heterocyclic compound of the present invention can be used as an effective antagonist of a Wnt signaling pathway, can effectively block the Wnt signaling pathway, and can be used for treating or preventing disorders caused by the malfunction of the Wnt signaling pathway.

Claims (11)

1. A5-fluoropyrimidine heterocyclic compound having an inhibitory activity on a Wnt signal pathway, and pharmaceutically acceptable salts thereof, has a structure represented by general formula I:
wherein A is any one of the following groups substituted or unsubstituted with 1 to 3R 4 groups:
B is any one of the following groups:
u is any one of the following groups substituted or unsubstituted with 1 to 3R 6 groups:
R1, R2 and R3 are respectively and independently selected from a hydrogen atom and C1-6 alkyl which is not substituted by a substituent group;
R4, R5 and R6 are respectively and independently selected from halogen, cyano, C1-8 alkyl and C1-8 alkoxy;
or, R4, R5, R6 are each independently selected from C1-8 alkyl substituted with halogen;
R7 is a hydrogen atom.
2. The heterocyclic 5-fluoropyrimidine compound having an inhibitory activity on a Wnt signaling pathway according to claim 1, characterized in that the heterocyclic compound comprises:
3. the combination composition of 5-fluoropyrimidine heterocycle compound having Wnt signaling pathway inhibitory activity according to claim 1 or 2, comprising a combination of one or more of an antitumor agent, an antibacterial agent, an antiviral agent, an antiparasitic agent, a central nervous system agent, an anti-hyperosteogeny agent, and a diabetic agent with the 5-fluoropyrimidine heterocycle compound having Wnt signaling pathway inhibitory activity and a pharmaceutically acceptable salt thereof.
4. the use of a 5-fluoropyrimidine heterocycle compound having Wnt signaling pathway inhibiting activity and pharmaceutically acceptable salts thereof according to claim 1 or 2 for the preparation of a medicament that antagonizes the Wnt signaling pathway.
5. use according to claim 4, characterized in that: the medicament for antagonizing the Wnt signaling pathway is a medicament for treating one or a combination of several of breast cancer, lung cancer, bladder cancer, pancreatic cancer, liver cancer, head and neck squamous epithelial cancer, thyroid cancer, sarcoma, desmoid tumor, melanoma, prostate cancer, colorectal cancer, ovarian cancer, cervical cancer, esophageal cancer, gastric cancer, myeloma, lymphoma, chronic and non-progressive anemia, idiopathic or essential thrombocythemia, idiopathic myelofibrosis, pulmonary fibrosis, renal fibrosis, hepatic fibrosis, cirrhosis, diabetic retinopathy, macroglobulinemia, leukemia, myelodysplastic syndrome, myeloproliferative disorders, brain tumors, astrocytomas, medulloblastoma, Schwannoma, primary neuroectoblastoma, pituitary tumor, and parasitic diseases.
6. Use according to claim 4, characterized in that: the medicament for antagonizing the Wnt signal pathway is a medicament for treating one or a combination of a plurality of symptoms of osteosarcoma, mantle cell lymphoma, cutaneous T cell lymphoma, acute leukemia, chronic leukemia, lymphatic leukemia and myeloid leukemia.
7. Use according to claim 4, characterized in that: the medicament for antagonizing the Wnt signal path is a medicament for treating one or a combination of several symptoms including schistosomiasis and malaria.
8. The use of the combination composition of 5-fluoropyrimidine heterocycles having Wnt signaling pathway inhibiting activity according to claim 3 in the preparation of a medicament for antagonizing the Wnt signaling pathway.
9. Use according to claim 8, characterized in that: the medicament for antagonizing the Wnt signaling pathway is a medicament for treating one or a combination of several of breast cancer, lung cancer, bladder cancer, pancreatic cancer, liver cancer, head and neck squamous epithelial cancer, thyroid cancer, sarcoma, desmoid tumor, melanoma, prostate cancer, colorectal cancer, ovarian cancer, cervical cancer, esophageal cancer, gastric cancer, myeloma, lymphoma, chronic and non-progressive anemia, idiopathic or essential thrombocythemia, idiopathic myelofibrosis, pulmonary fibrosis, renal fibrosis, hepatic fibrosis, cirrhosis, diabetic retinopathy, macroglobulinemia, leukemia, myelodysplastic syndrome, myeloproliferative disorders, brain tumors, astrocytomas, medulloblastoma, Schwannoma, primary neuroectoblastoma, pituitary tumor, and parasitic diseases.
10. Use according to claim 8, characterized in that: the medicament for antagonizing the Wnt signal pathway is a medicament for treating one or a combination of a plurality of symptoms of osteosarcoma, mantle cell lymphoma, cutaneous T cell lymphoma, acute leukemia, chronic leukemia, lymphatic leukemia and myeloid leukemia.
11. use according to claim 8, characterized in that: the medicament for antagonizing the Wnt signal path is a medicament for treating one or a combination of several symptoms including schistosomiasis and malaria.
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