CN111057065B - Preparation method and application of thienopyrimidine compound - Google Patents
Preparation method and application of thienopyrimidine compound Download PDFInfo
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- CN111057065B CN111057065B CN201911345321.4A CN201911345321A CN111057065B CN 111057065 B CN111057065 B CN 111057065B CN 201911345321 A CN201911345321 A CN 201911345321A CN 111057065 B CN111057065 B CN 111057065B
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- China
- Prior art keywords
- pyrimidine
- carbohydrazide
- morpholinothieno
- indazol
- pharmaceutically acceptable
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- -1 thienopyrimidine compound Chemical class 0.000 title claims description 31
- 238000002360 preparation method Methods 0.000 title abstract description 36
- 150000001875 compounds Chemical class 0.000 claims abstract description 31
- 150000003839 salts Chemical class 0.000 claims abstract description 18
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 15
- 239000003814 drug Substances 0.000 claims abstract description 12
- 201000010099 disease Diseases 0.000 claims abstract description 7
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 7
- NWTQBXDLKZTWAH-UHFFFAOYSA-N pyrimidine-4-carbohydrazide Chemical compound NNC(=O)C1=CC=NC=N1 NWTQBXDLKZTWAH-UHFFFAOYSA-N 0.000 claims description 21
- WARCRYXKINZHGQ-UHFFFAOYSA-N benzohydrazide Chemical compound NNC(=O)C1=CC=CC=C1 WARCRYXKINZHGQ-UHFFFAOYSA-N 0.000 claims description 11
- 201000011510 cancer Diseases 0.000 claims description 9
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 6
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 claims description 5
- 239000008194 pharmaceutical composition Substances 0.000 claims description 5
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Substances C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 5
- 125000004943 pyrimidin-6-yl group Chemical group N1=CN=CC=C1* 0.000 claims description 5
- 229910052736 halogen Inorganic materials 0.000 claims description 4
- 150000002367 halogens Chemical class 0.000 claims description 4
- 125000002757 morpholinyl group Chemical group 0.000 claims description 4
- 238000006467 substitution reaction Methods 0.000 claims description 4
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims description 3
- CGTYKLRAFSYATG-UHFFFAOYSA-N N1N=CC2=C(C=CC=C12)C=1N=C(C2=C(N=1)C=C(S2)C(=O)NNC(C1=CN=CC=C1)=O)N1CCOCC1 Chemical compound N1N=CC2=C(C=CC=C12)C=1N=C(C2=C(N=1)C=C(S2)C(=O)NNC(C1=CN=CC=C1)=O)N1CCOCC1 CGTYKLRAFSYATG-UHFFFAOYSA-N 0.000 claims description 3
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- BAQLNPIEFOYKNB-UHFFFAOYSA-N pyridine-2-carbohydrazide Chemical compound NNC(=O)C1=CC=CC=N1 BAQLNPIEFOYKNB-UHFFFAOYSA-N 0.000 claims description 3
- 125000004076 pyridyl group Chemical group 0.000 claims description 3
- UAFXCZVAAKZFRG-UHFFFAOYSA-N 2-(2-aminopyrimidin-5-yl)-N'-benzoyl-4-morpholin-4-ylthieno[3,2-d]pyrimidine-6-carbohydrazide Chemical compound NC1=NC=C(C=N1)C=1N=C(C2=C(N=1)C=C(S2)C(=O)NNC(C1=CC=CC=C1)=O)N1CCOCC1 UAFXCZVAAKZFRG-UHFFFAOYSA-N 0.000 claims description 2
- YLGHPZOEPCCLHM-UHFFFAOYSA-N C(C)(=O)C1=CC=C(C(=O)NNC(=O)C2=CC=3N=C(N=C(C=3S2)N2CCOCC2)C2=C3C=NNC3=CC=C2)C=C1 Chemical compound C(C)(=O)C1=CC=C(C(=O)NNC(=O)C2=CC=3N=C(N=C(C=3S2)N2CCOCC2)C2=C3C=NNC3=CC=C2)C=C1 YLGHPZOEPCCLHM-UHFFFAOYSA-N 0.000 claims description 2
- MAGZGWWRFWIRQL-UHFFFAOYSA-N C(C1=CC=CC=C1)(=O)NNC(=O)C1=CC=2N=C(N=C(C=2S1)N1CCOCC1)C1=C2C=NNC2=CC=C1 Chemical compound C(C1=CC=CC=C1)(=O)NNC(=O)C1=CC=2N=C(N=C(C=2S1)N1CCOCC1)C1=C2C=NNC2=CC=C1 MAGZGWWRFWIRQL-UHFFFAOYSA-N 0.000 claims description 2
- OUKOPRJSYYBYOD-UHFFFAOYSA-N C(C1=CC=CC=C1)(=O)NNC(=O)C1=CC=2N=C(N=C(C=2S1)N1CCOCC1)N1CCOCC1 Chemical compound C(C1=CC=CC=C1)(=O)NNC(=O)C1=CC=2N=C(N=C(C=2S1)N1CCOCC1)N1CCOCC1 OUKOPRJSYYBYOD-UHFFFAOYSA-N 0.000 claims description 2
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- HVWNCDKEFDPNTH-UHFFFAOYSA-N N1N=CC2=C(C=CC=C12)C=1N=C(C2=C(N=1)C=C(S2)C(=O)NNC(C1=C(C=CC=C1)OC)=O)N1CCOCC1 Chemical compound N1N=CC2=C(C=CC=C12)C=1N=C(C2=C(N=1)C=C(S2)C(=O)NNC(C1=C(C=CC=C1)OC)=O)N1CCOCC1 HVWNCDKEFDPNTH-UHFFFAOYSA-N 0.000 claims description 2
- LNEMDGSZXJXDPS-UHFFFAOYSA-N N1N=CC2=C(C=CC=C12)C=1N=C(C2=C(N=1)C=C(S2)C(=O)NNC(C1=CC=C(C=C1)OC)=O)N1CCOCC1 Chemical compound N1N=CC2=C(C=CC=C12)C=1N=C(C2=C(N=1)C=C(S2)C(=O)NNC(C1=CC=C(C=C1)OC)=O)N1CCOCC1 LNEMDGSZXJXDPS-UHFFFAOYSA-N 0.000 claims description 2
- 125000003453 indazolyl group Chemical group N1N=C(C2=C1C=CC=C2)* 0.000 claims description 2
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- 230000002159 abnormal effect Effects 0.000 abstract description 4
- RBNBDIMXFJYDLQ-UHFFFAOYSA-N thieno[3,2-d]pyrimidine Chemical class C1=NC=C2SC=CC2=N1 RBNBDIMXFJYDLQ-UHFFFAOYSA-N 0.000 abstract description 4
- 230000014509 gene expression Effects 0.000 abstract description 3
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- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 7
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- TWEQNZZOOFKOER-UHFFFAOYSA-N methyl 3-aminothiophene-2-carboxylate Chemical compound COC(=O)C=1SC=CC=1N TWEQNZZOOFKOER-UHFFFAOYSA-N 0.000 description 1
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- 125000000962 organic group Chemical group 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 230000002018 overexpression Effects 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 1
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
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- 235000011056 potassium acetate Nutrition 0.000 description 1
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical class [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
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- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- KFUSANSHCADHNJ-UHFFFAOYSA-N pyridine-3-carbohydrazide Chemical compound NNC(=O)C1=CC=CN=C1 KFUSANSHCADHNJ-UHFFFAOYSA-N 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 230000007115 recruitment Effects 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- CDAISMWEOUEBRE-UHFFFAOYSA-N scyllo-inosotol Natural products OC1C(O)C(O)C(O)C(O)C1O CDAISMWEOUEBRE-UHFFFAOYSA-N 0.000 description 1
- 229910001961 silver nitrate Inorganic materials 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
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- 125000001424 substituent group Chemical group 0.000 description 1
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- 230000008685 targeting Effects 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 150000003536 tetrazoles Chemical class 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 125000002769 thiazolinyl group Chemical group 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- GKTQKQTXHNUFSP-UHFFFAOYSA-N thieno[3,4-c]pyrrole-4,6-dione Chemical compound S1C=C2C(=O)NC(=O)C2=C1 GKTQKQTXHNUFSP-UHFFFAOYSA-N 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
- C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D495/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
Abstract
The invention relates to thienopyrimidine derivatives shown in a general formula I, pharmaceutically acceptable salts or prodrugs and a preparation method thereof, and belongs to the technical field of pharmaceutical chemistry. In the general formula I, a substituent L, R2Have the meanings given in the description. The invention also relates to a compound with a general formula I, which has a strong effect of inhibiting PI3K, and also relates to application of the compound and pharmaceutically acceptable salts, solvates or prodrugs thereof in preparing medicaments for treating and/or preventing diseases caused by abnormal high expression of PI3K, in particular to application in preparing medicaments for treating and/or preventing cancers.
Description
Technical Field
The present invention relates to novel thienopyrimidine compounds and pharmaceutically acceptable salts or prodrugs thereof, processes for their preparation and pharmaceutical compositions containing them. The invention also relates to application of the compounds and pharmaceutically acceptable salts, solvates or prodrugs thereof in medicaments for treating and/or preventing diseases caused by abnormally high expression of PI3K, in particular to application in preparing medicaments for treating and/or preventing cancers.
Background
Cancer, also known as malignant tumor, is a disease caused by abnormal differentiation and proliferation of cells. Cancer is a frequently encountered disease that seriously threatens human health, and the incidence and mortality of cancer increase year by year with the global population proliferation, environmental pollution, and irregular and unhealthy lifestyles of people. Research has shown that cancer has become a leading cause of death among residents of china, and also places a heavy burden of disease on a large number of households. According to the latest data published by the national cancer center in 2018, it is shown that: in 2014, 380.4 ten thousands of new cancer confirmed cases and 229.6 thousands of cancer death cases are newly added in China.
The PI3K-Akt-mTOR signal pathway (PI 3K pathway) composed of Phosphoinositide-3-kinase (PI 3K) and Protein kinase B (Akt/PKB) and rapamycin target Protein (Mammalian target of rapamycin, mTOR) at the downstream of the PI 3-Akt-mTOR signal pathway plays an important role in the biological process of tumor cells, and is closely related to the cell cycle, angiogenesis, tumorigenesis and invasion. Over-expression of this signaling pathway can lead to abnormal cellular proliferation, transcription, translation, and metabolic processes, leading to tumorigenesis. Therefore, small molecule inhibitors targeting key molecules in the PI3K/Akt signaling pathway have become hot spots for research on current antitumor drugs.
Phosphatidylinositol-3 kinase is a kind of specific Receptor Tyrosine Kinases (RTKs), PI3K is a heterodimer composed of regulatory subunit p85 and catalytic subunit p110, and is classified into type I, type II and type III according to the difference of substrate and catalytic subunit p110 structure, and type I can be further classified into type IAClass I and IBClass, known as the PI3Ks family, includes several phosphatidylinositol kinases and DNA-dependent protein kinases such as ATM, ATR and DNA-PK etc., which phosphorylate the third hydroxyl group of phosphatidylinositol, producing the inositol substance phosphatidylinositol-3-phosphate (PIP3) with a second messenger role. The second messenger, PIP3, can bind PI3K to downstream effector (especially AKt) pairs, leading to membrane recruitment and phosphorylation. The research shows that: the PI3K family is associated with numerous processes such as cell proliferation, anti-apoptosis, cell migration, bubble transport, and cancerous transformation of cells, and these biological effects are mediated primarily by the "anchor" molecule 3-phosphoinositide (PIP, PIP2, PIP3) catalyzed by PI 3K. It has been found that the PI3K pathway is universally disregulated in a wide range of human tumor spectra, and that dysfunction or deletion of certain genetic mutations in this pathway leads to transformation of normal cells, promotes tumor cell proliferation and survival, and mediates invasion and migration of tumor cells, and is therefore smallThe better action target of the molecular inhibitor provides an opportunity for treating cancer.
The PI3K-Akt signaling pathway is widely involved in cell life activities including survival, proliferation, apoptosis, invasion, etc., and is overactivated in almost all human tumors. After the PI3K-Akt signal channel is activated, the apoptosis can be inhibited, the tolerance of cells to hypoxia and nutrition deficiency is enhanced, the survival and the proliferation of the cells are promoted, the cells participate in the formation of blood vessels, the growth of tumors is assisted, the metastasis of the tumors is promoted, and the occurrence and the development of the tumors are influenced by other carcinogenic factors. Therefore, in recent years, a plurality of small molecule inhibitors acting on the PI3K-Alt signal pathway have entered the clinical stage.
The inventor designs and synthesizes a series of thienopyrimidine derivatives on the basis of a reference document, and shows that the compound has good antitumor activity and obvious inhibitory activity on PI3K through pharmacological activity screening, and simultaneously has obvious inhibitory action on various human tumor cells.
Disclosure of Invention
The invention relates to compounds of general formula (I) and pharmaceutically acceptable salts, solvates or prodrugs thereof,
wherein,
Ar is C6-C10Aryl or 5-10 membered heteroaryl, wherein the heteroaryl contains 1-3 heteroatoms selected from N, O or S, and Ar is optionally 1-3R, the same or different1Substitution;
R1is 1-3 same or different groups selected from hydrogen, hydroxyl, halogen, nitro, amino, cyano, azido, mercapto, (C)1-C6) Alkyl, (C)1-C6) Alkoxy, optionally hydroxy, amino or halo (C)1-C6) Alkyl or (C)1-C6) Alkoxy group, (C)1-C6) Alkanemercapto, allyl, mono-or di (C)1-C6Alkyl) substituted amino, (C)1-C6) Alkylamido, free, salified, esterified and amidated carboxyl, (C)1-C6) Alkylsulfinyl (C)1-C6) Alkylsulfonyl group, (C)1-C6) Alkanoyl, carbamoyl, mono-or di (C)1-C6Alkyl) substituted carbamoyl group.
R2Is C1-C6Alkyl radical, C3-C6Cycloalkyl, phenyl or 4-6 membered heterocyclyl or heteroaryl or fused bicyclic C1-C20Heteroaryl, said heteroaryl and heterocyclyl containing 1-3 heteroatoms, optionally selected from O, N and S;
the present invention also preferably relates to compounds of formula I as defined below, and pharmaceutically acceptable salts, solvates or prodrugs thereof, wherein,
ar is phenyl, naphthyl, quinolyl, 5-6 membered heteroaryl, wherein the heteroaryl contains 1-3 heteroatoms selected from N, O or S, and Ar optionally 1-3R, the same or different1Substitution;
R1is 1-3 same or different groups selected from hydrogen, hydroxyl, halogen, nitro, amino, cyano, (C)1-C6) Alkyl, (C)1-C6) Alkoxy, optionally hydroxy, amino or halo (C)1-C6) Alkyl or (C)1-C6) Alkoxy group, (C)1-C6) Alkanemercapto, allyl, mono-or di (C)1-C6Alkyl) substituted amino, (C)1-C6) Alkylamido, free, salified, esterified and amidated carboxyl;
the invention also preferably relates to compounds of the general formula I as defined below and to pharmaceutically acceptable salts, solvates or prodrugs thereof,
wherein,
R2Is morpholinyl, phenyl or 4-6 membered heterocyclyl or heteroaryl or fused bicyclic C1-C20Heteroaryl, said heteroaryl and heterocyclyl containing 1-3 heteroatoms, optionally selected from O, N and S;
the invention also preferably relates to compounds of the general formula I as defined below and to pharmaceutically acceptable salts, solvates or prodrugs thereof,
wherein,
ar is phenyl, pyridyl, furyl, thienyl, pyrrolyl, and Ar optionally 1-3 of the same or different R1And (4) substitution.
R1Is 1-3 same or different groups selected from hydrogen, hydroxyl, halogen, nitro, amino, cyano, (C)1-C6) Alkyl, (C)1-C6) An alkoxy group;
R2is morpholinyl, indazolyl or 2-aminopyrimidinyl.
The compounds of formula I of the present invention and pharmaceutically acceptable salts, solvates or prodrugs thereof are preferably the following compounds, but these compounds are not meant to limit the present invention in any way,
(E) -N' - (((2, 4-dimorpholinthieno [3,2-d ] pyrimidin-6-yl) methylene) benzoyl hydrazine
2, 4-dimorpholino-N' -benzoylthieno [3,2-d ] pyrimidine-6-carbohydrazide
(E) -N' - ((((2, 4-dimorpholinthieno [3,2-d ] pyrimidin-6-yl) methylene) pyridohydrazide
2, 4-dimorpholino-N' - (4-fluorobenzoyl) thieno [3,2-d ] pyrimidine-6-carbohydrazide
2, 4-dimorpholino-N' -pyridylthieno [3,2-d ] pyrimidine-6-carbohydrazide
2, 4-dimorpholino-N' - (4-methylbenzoyl) thieno [3,2-d ] pyrimidine-6-carbohydrazide
2- (2-aminopyrimidin-5-yl) -N' -benzoyl-4-morpholinyl thieno [3,2-d ] pyrimidine-6-carbohydrazide
2- (1H-indazol-4-yl) -N' -benzoyl-4-morpholinothieno [3,2-d ] pyrimidine-6-carbohydrazide
2- (1H-indazol-4-yl) -N' -nicotinoyl-4-morpholinothieno [3,2-d ] pyrimidine-6-carbohydrazide
2- (1H-indazol-4-yl) -N' - (2-fluorobenzoyl) -4-morpholinothieno [3,2-d ] pyrimidine-6-
Carbohydrazide
2- (1H-indazol-4-yl) -N' - (4-methoxybenzoyl) -4-morpholinothieno [3,2-d ] pyrimidine-6-carbohydrazide
2- (1H-indazol-4-yl) -N' - (4-acetylbenzoyl) -4-morpholinothieno [3,2-d ] pyrimidine-6-carbohydrazide
2- (1H-indazol-4-yl) -N' -pyridinoformyl-4-morpholinothieno [3,2-d ] pyrimidine-6-carbohydrazide
2- (1H-indazol-4-yl) -N' - (3-fluorobenzoyl) -4-morpholinothieno [3,2-d ] pyrimidine-6-carbohydrazide
2- (1H-indazol-4-yl) -N' - (2-methoxybenzoyl) -4-morpholinothieno [3,2-d ] pyrimidine-6-carbohydrazide
Furthermore, the thiophene derivatives of formula I of the present invention may be reacted with an acid to form pharmaceutically acceptable salts thereof according to conventional methods in the art. The acid may include inorganic or organic acids, and salts with the following acids are particularly preferred: hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid, naphthalenedisulfonic acid, acetic acid, propionic acid, lactic acid, trifluoroacetic acid, maleic acid, citric acid, fumaric acid, tartaric acid, benzenesulfonic acid, benzoic acid, p-toluenesulfonic acid, and the like.
In addition, the present invention also includes prodrugs of the compounds of the present invention. Prodrugs, according to the present invention, are derivatives of compounds of formula i which may themselves have poor or even no activity, but which, upon administration, are converted under physiological conditions (e.g., by metabolism, solvolysis or otherwise) to the corresponding biologically active form.
The term "halo" as used herein, unless otherwise indicated, refers to fluoro, chloro, bromo or iodo; "alkyl" refers to straight or branched chain alkyl; "aryl" refers to an organic group obtained by removing one hydrogen atom from an aromatic hydrocarbon, such as phenyl, naphthyl; 5-to 10-membered heteroaryl includes those containing one or more heteroatoms selected from N, O and S, wherein the ring system of each heteroaryl group may be monocyclic or polycyclic, the ring system is aromatic, and contains a total of 5 to 10 atoms, and examples thereof include imidazolyl, pyridyl, pyrimidinyl, pyrazolyl, (1,2,3) -and (1,2,4) -triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, oxazolyl, pyrazolyl, pyrrolyl, thiazolyl, benzothienyl, benzofuryl, benzimidazolyl, benzothiazolyl, indolyl, quinolyl and the like; 5-10 membered heterocyclic groups include those containing one or more heteroatoms selected from N, O and S, wherein the ring system of each heteroaryl group may be monocyclic or polycyclic but is non-aromatic, the ring system containing a total of 5 to 10 atoms and may optionally include 1 or 2 carbon-carbon double or triple bonds, and there may be mentioned, for example, pyrrolidinyl, morpholinyl, piperazinyl, piperidinyl, thiazolinyl and the like.
The invention also relates to a compound with a general formula I, which has a strong effect of inhibiting PI3K, and also relates to application of the compound and pharmaceutically acceptable salts, hydrates, solvates or prodrugs thereof in preparing medicaments for treating and/or preventing diseases caused by abnormal high expression of PI3K, in particular to application in preparing medicaments for treating and/or preventing cancers.
The derivatives of formula I according to the invention can be prepared according to the methods described in scheme one, scheme two, scheme three, scheme four, all starting materials being prepared by the methods described in these schemes, by methods well known to the person skilled in the art of organic chemistry or being commercially available. Wherein the substituents T1-T4 are as defined for compounds of formula I. All of the final compounds of the present invention are prepared by the methods described in these schemes or by methods analogous thereto, which are well known to those of ordinary skill in the art of organic chemistry. All the variable factors applied in these routes are as defined below or in the claims.
Route one:
and a second route:
and a third route:
and a fourth route:
the specific implementation mode is as follows:
in the following examples, methods of preparing some of the compounds are depicted. It is to be understood that the following methods, as well as other methods known to those of ordinary skill in the art, can be applied to the preparation of all of the compounds described herein. The examples are intended to illustrate, but not to limit, the scope of the invention.
Example preparation of 12, 4-dimorpholino-N' -benzoylthieno [3,2-d ] pyrimidine-6-carbohydrazide
1.1 preparation of thieno [3,2-d ] pyrimidine-2, 4(1H,3H) -dione (b)
47.0g (0.64mol) of urea was put into a 250mL round bottom flask at room temperature, heated to 140 ℃ to melt the urea, and 20.0g (0.13mol) of methyl 3-aminothiophene-2-carboxylate (a) was added in two portions with stirring, and then heated to 190 ℃ to react for 2.5 hours. The reaction solution was cooled to 120 ℃ and added to 200mL of 20% aqueous sodium hydroxide while hot, and the mixture was stirred until most of the solid was dissolved, filtered off, and insoluble matter was removed, and the pH of the filtrate was adjusted to 3 with 2M hydrochloric acid, filtered off, and dried to give 18.5g of a pale yellow solid with a yield of 86.4%.
Preparation of 22, 4-dichlorothieno [3,2-d ] pyrimidine (c)
16.0g (0.095mol) of intermediate b are slowly added to 44mL (0.48mol) of phosphorus oxychloride at room temperature, and the temperature is raised to reflux for 8 h. Most of the solvent is evaporated under reduced pressure, the residue is slowly poured into ice water, stirred vigorously to precipitate a large amount of white solid, filtered by suction, the filter cake is washed to be neutral by water (100mL), and dried to obtain light yellow solid 15.8g with the yield of 81.4%.
Preparation of 32-chloro-4-morpholinothieno [3,2-d ] pyrimidine (d)
15.0g (0.078mol) of intermediate c are dissolved in 150mL of methanol at room temperature, and 16.8mL (0.17mol) of morpholine are slowly added dropwise with stirring at room temperature. After dropping, the reaction was carried out at room temperature for 2 hours. Suction filtration was carried out, and the filter cake was thoroughly washed with ethanol (100mL) and water (20mL) in this order. After drying, the crude product was recrystallized from 1, 4-dioxane (100mL) to give 15.6g of pale yellow crystals, yield 79.0%.
Preparation of 42-chloro-4-morpholinothieno [3,2-d ] pyrimidine-6-carbaldehyde (e)
Under the protection of nitrogen, 15.0g (0.059mol) of the intermediate d is dissolved in 150mL of tetrahydrofuran, the reaction solution is cooled to below-10 ℃, 14.8mL (2M,0.03mol) of a tetrahydrofuran solution of isopropyl magnesium chloride is slowly dripped into the reaction solution, reaction is carried out for 1.5h at the temperature of-10 ℃, 44.3mL (1.6M,0.071mol) of N-hexane solution of N-butyllithium is slowly dripped into the reaction solution, reaction is carried out for 1h at the temperature of-10 ℃, 11.4mL (0.148mol) of N, N-dimethylformamide is slowly dripped into the reaction solution, and reaction is carried out for 4h at the temperature of-10 ℃. The reaction solution was slowly poured into 750mL (0.25M) of hydrochloric acid, stirred at room temperature for 1h, then heated to 50 ℃ and stirred for 4h, cooled to room temperature, filtered, the filter cake was washed thoroughly with water (300mL), dried to give 11.4g of a yellow solid with a yield of 68.2%.
Preparation of 52-chloro-4-morpholinothieno [3,2-d ] pyrimidine-6-carboxylic acid (f)
In an ice bath, a 2N NaOH aqueous solution was slowly dropped into a silver nitrate aqueous solution, and after stirring for 10min, a 2.0g (0,007mol) THF solution of intermediate e was dropped into the above mixed solution. After dropping, the reaction was carried out at room temperature for 5 hours. Suction-filtering the reaction solution with diatomite, concentrating the filtrate under reduced pressure, adjusting pH to 1 with 0.25M hydrochloric acid, precipitating pale yellow solid, and suction-filtering to obtain yellow solid 1,5g with yield of 80.1%.
1.6 preparation of Ethyl benzoate (i)
2.0g (0.016mol) of the reaction solution is dissolved in 20mL of absolute ethanol, 1mL of concentrated sulfuric acid is added, and the reaction solution is refluxed at 80 ℃. The solvent was concentrated under reduced pressure, water was added, dichloromethane (200 mL. times.3) was extracted, the organic phases were combined, the organic phase was washed with saturated potassium carbonate (100 mL. times.2), washed with saturated brine, dried over anhydrous sodium sulfate, and evaporated to dryness to give 2.0g of a transparent oil, with a yield of 90.2%.
1.7 preparation of benzoyl hydrazine (j)
1.5g (0.010mol) of intermediate i was dissolved in 15mL of anhydrous ethanol, and 2.4mL of hydrazine hydrate was added thereto, followed by reflux reaction at 80 ℃. The organic solvent was concentrated under reduced pressure to give 1.6g of a white solid in 87.4% yield.
Preparation of 1.8N' -benzoyl-2-chloro-4-morpholinothieno [3,2-d ] pyrimidine-6-carbohydrazide (k)
2.0g (0.006mol) of intermediate f, 1.0g (0.007mol) of intermediate j, and 2.6g (0.014mol) of EDCI were added to dry 20mL of DMF, and reacted at room temperature. Pouring the reaction liquid into water, precipitating yellow solid, and performing suction filtration to obtain 1.2g of yellow solid, wherein the yield is 60.5%.
Preparation of 92, 4-dimorpholino-N' -benzoylthieno [3,2-d ] pyrimidine-6-carbohydrazide (T1)
0.2g (0.0004mol) of intermediate k was dissolved in 2mL of n-butanol, and 0.16g (0.0014mol) of trifluoroacetic acid and 0.08g (0.0009mol) of morpholine were added thereto, and the mixture was heated to 125 ℃ for reaction. Filtering while hot, filtering to remove insoluble substances, cooling filtrate sufficiently, precipitating yellow brown crystal, filtering to obtain solid 0.16g, purifying product by column chromatography to obtain pure product 0.1g, and obtaining yield 30.2%.
1H NMR(600MHz,DMSO-d6)δ10.89(s,1H),10.66(s,1H),7.93(d,J=1.2Hz,1H),7.92(d,J=1.5Hz,1H),7.88(s,1H),7.64–7.60(m,1H),7.56–7.52(m,2H),3.87–3.83(m,4H),3.76–3.73(m,4H),3.67(s,8H)
EXAMPLE 22 preparation of 4, 4-dimorpholino-N' - (4-methoxybenzoyl) thieno [3,2-d ] pyrimidine-6-carbohydrazide
2, 4-dimorpholino-N' - (4-methoxybenzoyl) thieno [3,2-d ] was prepared from intermediate 4-methoxybenzoyl hydrazine as the starting material according to the synthesis method of 1.9 in example 1]Pyrimidine-6-carbohydrazide, yield 50.2%. MS (ESI) M/z (%) < 497.3[ M-H >]-
1H NMR(400MHz,DMSO-d6)δ10.89(s,1H),10.69(s,1H),8.00(dd,J=8.7,5.5Hz,2H),7.87(s,1H),7.38(t,J=8.8Hz,2H),3.87–3.84(m,4H),3.76–3.73(m,4H),3.67(s,8H).
Example preparation of 32, 4-dimorpholino-N' -pyridineformylthieno [3,2-d ] pyrimidine-6-carbohydrazide
2, 4-dimorpholino-N' -pyridine formyl thiophene [3,2-d ] is prepared by taking intermediate pyridine formyl hydrazine as raw material and adopting the synthetic method of 1.9 in example 1]Pyrimidine-6-carbohydrazide, yield 42.5%. MS (ESI) M/z (%): 468.2[ M-H]-
EXAMPLE 42 preparation of 4, 4-dimorpholino-N' - (4-methylbenzoyl) thieno [3,2-d ] pyrimidine-6-carbohydrazide
2, 4-dimorpholino-N' - (4-methylbenzoyl) thieno [3, 2-d) was prepared from intermediate 4-methylbenzoyl hydrazine by the synthetic method of 1.9 in example 1]Pyrimidine-6-carbohydrazide, yield 42.5%. MS (ESI) M/z (%): 481.6[ M-H]-
1H NMR(600MHz,DMSO-d6)δ10.84(s,1H),10.57(s,1H),7.87(s,1H),7.83(d,J=8.1Hz,2H),7.34(d,J=7.9Hz,2H),3.87–3.82(m,4H),3.76–3.73(m,4H),3.67(s,8H),2.39(s,3H).
Example 5 preparation of (E) -N' - ((((2, 4-Dimorpholinothieno [3,2-d ] pyrimidin-6-yl) methylene) benzoyl hydrazine
5.1 preparation of (E) -N' - ((((2-chloro-4-morpholinothieno [3,2-d ] pyrimidin-6-yl) methylene) benzoyl hydrazine (l)
2.0g (0.070mol) of intermediate e is dissolved in 10mL ethanol, the temperature is raised to 80 ℃, 1d glacial acetic acid is added, after stirring for 30min, 1.0g (0.0073mol) of intermediate j is added, and the reaction is carried out for 4h at 80 ℃. The filtrate was then filtered to give 2.0g of a yellow solid in 80.8% yield.
Preparation of (E) -N' - ((((2, 4-dimorpholinthieno [3,2-d ] pyrimidin-6-yl) methylene) benzoyl hydrazine (T2)
0.2g (0.0004mol) of intermediate l was dissolved in 2mL of n-butanol, and 0.16g (0.0014mol) of trifluoroacetic acid and 0.08g (0.0009mol) of morpholine were added thereto, and the mixture was heated to 125 ℃ for reaction. Filtering to remove insoluble substances, cooling filtrate, separating out brown crystals, vacuum filtering to obtain solid 0.16g, and purifying by column chromatography to obtain the final product0.1g of pure product and 30.2% of yield. MS (ESI) M/z (%): 451.3[ M-H]-
Example 6(E) -N' - ((((2, 4-Dimorpholinothieno [3,2-d ] pyrimidin-6-yl) methylene) pyridohydrazide
2, 4-dimorpholino-N' -pyridine formyl thiophene [3,2-d ] is prepared by taking intermediate pyridine formyl hydrazine as raw material and adopting the synthesis method of 5.2 in the embodiment 5]Pyrimidine-6-carbohydrazide, yield 42.5%. MS (ESI) M/z (%): 452.2[ M-H)]-
1H NMR(400MHz,DMSO-d6)δ12.49(s,1H),8.93(s,1H),8.73(d,J=4.6Hz,1H),8.13(d,J=7.8Hz,1H),8.07(td,J=7.7,1.7Hz,1H),7.69(dd,J=7.5,4.7,1.2Hz,1H),7.46(s,1H),3.89–3.83(m,4H),3.78–3.74(m,4H),3.66(s,8H).
Example 72 preparation of- (1H-indazol-4-yl) -N' -benzoyl-4-morpholinothieno [3,2-d ] pyrimidine-6-carbohydrazide
Preparation of 14-bromo-1- (tetrahydro-2H-pyran-2-yl) -1H-indazole (n)
10g (0.050mol) of 4-bromo-1H-indazole (m) and 8.54g (0.10mol) of 3, 4-dihydropyran were dissolved in 100mL of ethyl acetate, and 0.88g (0.005mol) of p-toluenesulfonic acid was added thereto and reacted at room temperature for 10 hours. The reaction solution was poured into 200mL of water, extracted with ethyl acetate (400mL × 3), the organic layers were combined, washed twice with a saturated aqueous sodium bicarbonate solution (200mL × 2), dried over anhydrous sodium sulfate, and the organic layer was concentrated under reduced pressure to give a red oily substance, which was purified by column chromatography to give 8.2g of a white solid with a yield of 70.3%.
Preparation of 21- (tetrahydro-2H-pyran-2-yl) -4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-indazole (o)
14.0g (0.050mol) of intermediate n, 19.0g (0.075mol) of bis (pinacolato) diboron and 15.0g (0.15mol) of potassium acetate were introduced into 140mL of dioxane, and 1.7g (0.002mol) of Pd (PPh) were added under nitrogen atmosphere3)2Cl2And heating to 80 ℃ for reaction for 12 h. Suction filtering the reaction solution pad with diatomite, washing the filter cake with hot dioxane, concentrating the filtrate, separating out black solid at 0 deg.c, and pulping the solid with 60mL petroleum ether to obtain brown solid 10.0g in 60.5% yield.
Preparation of 34-morpholino-2- (1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-4-yl) thieno [3,2-d ] pyrimidine-6-carboxylic acid (p)
5.0g (0.017mol) of intermediate f are dissolved in 50mL of dioxane, 10.8g (0.033mol) of intermediate o and 3.6g (0.034mol) of 2N aqueous sodium carbonate solution are added, 0.6g (0.0008mol) of bis (triphenylphosphine) palladium dichloride is added under nitrogen protection, and the temperature is raised to 90 ℃ for reaction for 12 hours. The reaction mixture was cooled to room temperature, filtered through celite, the filtrate was concentrated and taken up with water, extracted with dichloromethane (200 mL. times.3) and discarded, the aqueous layer was adjusted to pH 3 with 2M aqueous hydrochloric acid to precipitate a milky solid, which was filtered to give 4.5g of white solid with a yield of 75.5%.
Preparation of 4N' -benzoyl-4-morpholino-2- (1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-4-yl) thieno [3,2-d ] pyrimidine-6-carbohydrazide (q)
0.2g (0.004mol) of intermediate p, 0.06g (0.0004mol) of intermediate j, 0.11g (0.0003mol) of HATU, and 0.06g (0.0005mol) of triethylamine were added to 2mL of dichloromethane, and the mixture was reacted at room temperature for 15 hours. The reaction solution was filtered by suction to obtain 0.15g of a white solid with a yield of 73.2%.
Preparation of 52- (1H-indazol-4-yl) -N' -benzoyl-4-morpholinothieno [3,2-d ] pyrimidine-6-carbohydrazide (T3)
0.15g (0.004mol) of intermediate q is dissolved in 10mL of methanol, and 0.2g (0.024mol) of methanesulfonic acid is slowly added dropwise and reacted at room temperature for 24 hours. The reaction solution was concentrated and water was added, and the pH was adjusted to 8 with ammonia water to precipitate a solid. Filtering, purifying by column chromatography to obtain white solid 0.05g, yield 20.8%.
1H NMR(400MHz,DMSO-d6)δ13.25(s,1H),11.08(s,1H),10.73(s,1H),8.87(s,1H),8.35(s,1H),8.25(d,J=7.2Hz,1H),7.95(d,J=7.2Hz,2H),7.71(d,J=8.3Hz,1H),7.63(t,J=7.3Hz,1H),7.55(t,J=7.5Hz,2H),7.53–7.48(m,1H),4.15–4.02(m,4H),3.92–3.80(m,4H).
Example 82 preparation of (1H-indazol-4-yl) -N' -nicotinoyl-4-morpholinothieno [3,2-d ] pyrimidine-6-carbohydrazide
2- (1H-indazol-4-yl) -N' -nicotinoyl-4-morpholinothieno [3, 2-d) was prepared according to the synthesis method of 7.5 in example 7 using intermediate nicotinoyl hydrazine as a raw material]Pyrimidine-6-carbohydrazide, yield 42.5%. MS (ESI) M/z (%): 499.3[ M-H)]-
1H NMR(600MHz,DMSO-d6)δ13.26(s,1H),11.18(s,1H),10.98(s,1H),9.11(s,1H),8.87(s,1H),8.83–8.80(m,1H),8.36(s,1H),8.30(d,J=7.8Hz,1H),8.25(d,J=7.2Hz,1H),7.71(d,J=8.1Hz,1H),7.63–7.59(m,1H),7.50(t,J=7.7Hz,1H),4.08(s,4H),3.86(s,4H).
Example preparation of 92- (1H-indazol-4-yl) -N' - (2-fluorobenzoyl) -4-morpholinothieno [3,2-d ] pyrimidine-6-carbohydrazide
2- (1H-indazol-4-yl) -N' - (2-fluorobenzoyl) -4-morpholinothieno [3, 2-d) was prepared according to the synthesis method of 7.5 in example 7 using intermediate 2-fluorobenzoyl hydrazine as a raw material]Pyrimidine-6-carbohydrazide, yield 32.5%. MS (ESI) M/z (%): 516.4[ M-H]-
1H NMR(600MHz,DMSO-d6)δ13.25(s,1H),11.16(s,1H),10.59(s,1H),8.87(s,1H),8.31(s,1H),8.25(d,J=7.2Hz,1H),7.74–7.69(m,2H),7.63(q,J=6.7,5.9Hz,1H),7.50(t,J=7.7Hz,1H),7.38(q,J=7.9,7.2Hz,2H),4.10–4.06(m,4H),3.88–3.85(m,4H).
Example 102 preparation of- (1H-indazol-4-yl) -N' - (4-methoxybenzoyl) -4-morpholinothieno [3,2-d ] pyrimidine-6-carbohydrazide
2- (1H-indazol-4-yl) -N' - (4-methoxybenzoyl) -4-morpholinothieno [3, 2-d) was prepared according to the synthesis method of 7.5 in example 7, using intermediate 4-methoxybenzoyl hydrazine as a raw material]Pyrimidine-6-carbohydrazide, yield 32.5%. MS (ESI) M/z (%): 528.3[ M-H]-
1H NMR(600MHz,DMSO-d6)δ13.26(s,1H),11.01(s,1H),10.58(s,1H),8.34(s,1H),8.25(d,J=7.2Hz,1H),8.07(s,1H),7.94(d,J=8.7Hz,2H),7.70(d,J=8.2Hz,1H),7.52–7.48(m,1H),7.08(d,J=8.8Hz,2H),4.12–4.05(m,4H),3.86(m,4H),3.85(s,3H).
Example preparation of 112- (1H-indazol-4-yl) -N' - (4-acetylbenzoyl) -4-morpholinothieno [3,2-d ] pyrimidine-6-carbohydrazide
2- (1H-indazol-4-yl) -N' - (3-methoxybenzoyl) was prepared from intermediate 4-acetylbenzoyl hydrazine as a starting material by the synthetic method of 7.5 in example 7Yl) -4-morpholinothieno [3,2-d]Pyrimidine-6-carbohydrazide, yield 42.5%. MS (ESI) M/z (%) 540.2[ M-H]-
1H NMR(600MHz,DMSO-d6)δ13.26(s,1H),11.13(s,1H),10.97(s,1H),8.87(s,1H),8.34(s,1H),8.25(d,J=7.2Hz,1H),8.11(d,J=8.4Hz,2H),8.07(d,J=8.3Hz,2H),7.71(d,J=8.3Hz,1H),7.53–7.47(m,1H),4.13–4.04(m,4H),3.91–3.81(m,4H),2.66(s,3H).
Example 122 preparation of (1H-indazol-4-yl) -N' -picolinoyl-4-morpholinothieno [3,2-d ] pyrimidine-6-carbohydrazide
2- (1H-indazol-4-yl) -N' - (3-methoxybenzoyl) -4-morpholinothieno [3, 2-d) was prepared according to the synthesis method of 7.5 in example 7 using an intermediate pyridine formhydrazide as a raw material]Pyrimidine-6-carbohydrazide, yield 35.5%. MS (ESI) M/z (%): 499.4[ M-H)]-
Example 132- (1H-indazol-4-yl) -N' - (3-fluorobenzoyl) -4-morpholinothieno [3,2-d ] pyrimidine-6-carbohydrazide
Using intermediate 3-fluorobenzoyl hydrazine as a raw material, preparing 2- (1H-indazol-4-yl) -N' - (3-fluorobenzoyl) -4-morpholinothieno [3, 2-d) according to the synthesis method of 7.5 in example 7]Pyrimidine-6-carbohydrazide, yield 40.6%. MS (ESI) M/z (%): 516.2[ M-H]-
1H NMR(400MHz,DMSO-d6)δ13.26(s,1H),11.15(s,1H),10.87(s,1H),8.88(s,1H),8.35(s,1H),8.26(d,J=7.2Hz,1H),7.82(d,J=7.7Hz,1H),7.73(dd,J=13.6,9.1Hz,2H),7.63(q,J=7.9Hz,1H),7.50(t,J=7.8Hz,2H),4.08(m,4H),3.86(m,4H).
Example 142 preparation of- (1H-indazol-4-yl) -N' - (2-methoxybenzoyl) -4-morpholinothieno [3,2-d ] pyrimidine-6-carbohydrazide
2- (1H-indazol-4-yl) -N' - (2-methoxybenzoyl) -4-morpholinothieno [3, 2-d) was prepared according to the synthesis method of 7.5 in example 7, using intermediate 2-methoxybenzoyl hydrazine as a raw material]Pyrimidine-6-carbohydrazide, yield 39.8%. MS (ESI) M/z (%): 528.4[ M-H)]-
1H NMR(600MHz,DMSO-d6)δ13.25(s,1H),11.16(s,1H),10.26(s,1H),8.86(s,1H),8.32(s,1H),8.25(d,J=7.2Hz,1H),7.78(d,J=6.5Hz,1H),7.70(d,J=8.2Hz,1H),7.57–7.54(m,1H),7.52–7.48(m,1H),7.21(d,J=8.3Hz,1H),7.10(t,J=7.4Hz,1H),4.09–4.06(m,4H),3.93(s,3H),3.88–3.84(m,4H).
Example preparation of 152- (2-aminopyrimidin-5-yl) -N' -benzoyl-4-morpholinylthieno [3,2-d ] pyrimidine-6-carbohydrazide
15.12- (2-Aminopyrimidin-5-yl) -4-morpholinylthieno [3,2-d ] pyrimidine-6-carboxylic acid (r) preparation
1.0g (0.003mol) of intermediate f are dissolved in 10mL of dioxane, and 2.7g (0.008mol) of 5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyrimidin-2-amine, 2.2g (0.007mol) of 2N aqueous cesium carbonate solution, 0.1g (0.0001mol) of PdCl2(dppf)2And heating to 90 ℃ for reaction under the protection of nitrogen. The reaction solution was cooled to room temperature, filtered through celite, the filtrate was evaporated to dryness, water was added, extraction was performed with dichloromethane (100mL × 3), the PH of the aqueous layer was adjusted to 1 with 2M hydrochloric acid, extraction was performed with ethyl acetate (100mL × 3), drying was performed with anhydrous sodium sulfate, the solvent was concentrated under reduced pressure, and beating was performed with ether to obtain 0.8g of a yellow solid, with a yield of 60.5%.
15.22 preparation of- (2-aminopyrimidin-5-yl) -N' -benzoyl-4-morpholinylthieno [3,2-d ] pyrimidine-6-carbohydrazide (T4)
0.2g (0.0004mol) of intermediate r, 0.07g (0.0005mol) of intermediate j, and 0.17g (0.0008mol) of EDCI were added to dry 2ml of DMF and reacted at room temperature for 12 hours. Adding water into the reaction solution, precipitating yellow solid, filtering to obtain yellow solid, and purifying by column chromatography to obtain white solid 0.05g with yield of 30.1%.
1H NMR(400MHz,DMSO-d6)δ11.03(s,1H),10.71(s,1H),9.14(s,2H),8.18(s,1H),7.94(d,J=7.2Hz,2H),7.63(t,J=7.4Hz,1H),7.55(t,J=7.4Hz,2H),7.15(s,2H),4.05–3.98(m,4H),3.83–3.78(m,4H).
Table structure of the Compounds of one example and1h NMR, MS m/z data are given in the following Table
In vitro antitumor cell Activity
The thienopyrimidine derivatives of the above formula I according to the invention are screened for inhibiting the activity of human colon gastric cancer cell HCT-116, prostate cancer cell PC-3 and lung cancer cell A549 in vitro.
(1) After cells were thawed and passaged for 2-3 stabilities, they were digested from the bottom of the flask with trypsin solution (0.25%). After pouring the cell digest into the centrifuge tube, the culture medium is added to stop the digestion. Centrifuging the centrifuge tube at 800r/min for 10min, discarding supernatant, adding 5mL culture solution, blowing and beating the mixed cells, sucking 10 μ L cell suspension, adding into cell counting plate, counting, and adjusting cell concentration to 104Per well. 100. mu.L of the cell suspension was added to the 96-well plate except that the A1 well was a blank well and no cells were added. The 96-well plate was placed in an incubator for 24 h.
(2) The test sample was dissolved in 50. mu.L of dimethyl sulfoxide, and then an appropriate amount of culture solution was added to dissolve the sample to 2mg/mL of the liquid, and then the sample was diluted to 20,4,0.8,0.16, 0.032. mu.g/mL in a 24-well plate.
3 wells were added for each concentration, two columns of cells surrounding each, which were greatly affected by the environment, and only used as blank wells. The 96-well plate was placed in an incubator for 72 h.
(3) The drug-containing culture solution in the 96-well plate is discarded, the cells are washed twice by using Phosphate Buffer Solution (PBS), 100 mu L of MTT (tetrazole) (0.5mg/mL) is added into each well and put into an incubator for 4h, the MTT solution is discarded, and 100 mu L of dimethyl sulfoxide is added. And oscillating on a magnetic oscillator to fully dissolve the viable cells and the MTT reaction product formazan, and putting the formazan into an enzyme labeling instrument to measure the result. Determination of drug IC by Bliss method50The value is obtained.
The results of the proliferation inhibition activity of the compound on human colon gastric cancer cell HCT-116, prostate cancer cell PC-3 and lung cancer cell A549 are shown in Table II, and GDC-0941 is used as a positive control.
Watch two
PI3K alpha enzyme Activity assay
Since PI3K can phosphorylate PIP2 and convert it to PIP3, the inhibitory activity of PI3K is typically determined using a competitive fluorescence polarization kinase activity screening method. Specifically, PI3K was reacted at 50mM HEPES (pH 7.5),3mM MgCl21mM EGTA,100mM NaCl, 0.03% CHAPS and 25. mu.M ATP, PIP2 as substrate, and the final reaction volume was 10. mu.L. In the determination of the compounds of the examples, 2.5. mu.L of the corresponding PI3K enzyme and 50. mu.M of substrate were added to 10. mu.L of the reaction solution, as well as the compounds of the examples at a concentration between 0.16. mu.M and 10. mu.M. After 1 hour incubation at room temperature, the reaction was quenched with a chelator. Then the protein combined with phosphoinositide is added into the reaction system, and the phosphoinositide developing agent marked by the fluorophore is added after uniform mixing. The samples were placed in a 384 well blackboard and allowed to equilibrate for one hour. Finally, the polarization value is obtained by red fluorescence with a proper filter, and the obtained data is used for calculating the inhibition rate.
Inhibition data of example compounds and positive control (GDC-0941) on PI3K (see table three).
Table three:
from the above test results, it is clear that the compound of formula I to be protected by the present invention has good in vitro anti-tumor activity, which is equivalent to or superior to that of the control drug GDC-0941.
While the invention has been described with reference to specific embodiments, modifications and equivalent arrangements will be apparent to those skilled in the art and are intended to be included within the scope of the invention.
Claims (6)
1. A compound of formula (I) or a pharmaceutically acceptable salt thereof,
wherein,
Ar is phenyl, pyridyl and Ar is optionally substituted with 1-3R, which may be the same or different1Substitution;
R1is halogen, C1-C6Alkyl radical, C1-C6Alkoxy or C1-C6An alkylamide group;
R2is morpholinyl, indazolyl or 2-aminopyrimidinyl.
2. The following compound or a pharmaceutically acceptable salt thereof:
(E)-N'- (((2, 4-dimorpholinothiopheno [3, 2-)d]Pyrimidin-6-yl) methylene) benzoyl hydrazine;
2, 4-dimorpholino-N'-benzoylthieno [3,2-d]Pyrimidine-6-carbohydrazide;
(E)- N'- (((2, 4-dimorpholinothiopheno [3, 2-)d]Pyrimidin-6-yl) methylene) pyridohydrazide;
2, 4-dimorpholino-N'- (4-methoxybenzoyl) thieno [3,2-d]Pyrimidine-6-carbohydrazide;
2, 4-dimorpholino-N'-pyridine formyl thieno [3,2-d]Pyrimidine-6-carbohydrazide;
2, 4-dimorpholino-N'- (4-methylbenzoyl) thiopheneAnd [3,2-d]Pyrimidine-6-carbohydrazide;
2- (2-aminopyrimidin-5-yl) -N' -benzoyl-4-morpholinylthieno [3,2-d]Pyrimidine-6-carbohydrazide;
2-(1H-indazol-4-yl) -N'-benzoyl-4-morpholinothieno [3,2-d]Pyrimidine-6-carbohydrazide;
2-(1H-indazol-4-yl) -N'-nicotinoyl-4-morpholinothieno [3,2-d]Pyrimidine-6-carbohydrazide;
2-(1H-indazol-4-yl) -N'- (2-fluorobenzoyl) -4-morpholinothieno [3,2-d]Pyrimidine-6-carbohydrazide;
2-(1H-indazol-4-yl) -N' - (4-methoxybenzoyl) -4-morpholinothieno [3,2-d]Pyrimidine-6-carbohydrazide;
2-(1H-indazol-4-yl) -N'- (4-acetylbenzoyl) -4-morpholinothieno [3,2-d]Pyrimidine-6-carbohydrazide;
2-(1H-indazol-4-yl) -N'-pyridylyl-4-morpholinothieno [3,2-d]Pyrimidine-6-carbohydrazide;
2-(1H-indazol-4-yl) -N'- (3-fluorobenzoyl) -4-morpholinothieno [3,2-d]Pyrimidine-6-carbohydrazide;
2-(1H-indazol-4-yl) -N'- (2-methoxybenzoyl) -4-morpholinothieno [3,2-d]Pyrimidine-6-carbohydrazide.
3. A pharmaceutical composition comprising a compound of claim 1 or 2 or a pharmaceutically acceptable salt thereof as an active ingredient and a pharmaceutically acceptable excipient.
4. Use of a compound according to claim 1 or 2 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to claim 3 in the manufacture of a medicament for the treatment and/or prevention of a proliferative disease.
5. Use of a compound according to claim 1 or 2 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to claim 3 for the manufacture of a medicament for the treatment and/or prevention of cancer.
6. Use of a compound according to claim 1 or 2 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to claim 3 for the manufacture of a medicament for the treatment and/or prophylaxis of ovarian, prostate, gastric, colon, lung cancer.
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