CN116425743B - A benzoheterocyclic compound as a PI3Kα kinase inhibitor and its preparation method and application - Google Patents
A benzoheterocyclic compound as a PI3Kα kinase inhibitor and its preparation method and application Download PDFInfo
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Abstract
The invention relates to the technical field of pharmaceutical chemicals, in particular to a benzoheterocycle compound serving as a PI3K alpha kinase inhibitor, and a preparation method and application thereof. The invention obtains a brand new benzoxazole PI3K alpha selective inhibitor compound. The compounds of the invention can effectively inhibit PI3K alpha kinase, and a plurality of compounds have PI3K alpha inhibition activity superior to that of a positive control TAK-117. The compound has novel structure, smaller molecular weight, compliance with drug-like rules and remarkable anti-tumor activity, and can be potentially used for treating related tumors. The compound has positive and foreseeable clinical application value of anti-proliferative diseases, especially anti-tumor, and has good development prospect. The compound has the characteristics of low cost, good curative effect and low toxicity. The intermediate product of the compound in the synthesis process has high yield, reduces the resource waste, and is further beneficial to reducing the cost.
Description
Technical Field
The invention relates to the technical field of pharmaceutical chemicals, in particular to a benzoheterocycle compound serving as a PI3K alpha kinase inhibitor, and a preparation method and application thereof.
Background
According to world health organization statistics, the number of cancer patients diagnosed in 2020 reaches 1930 ten thousand, and the number of cancer patients dying increases to 1000 ten thousand. Studies have shown that malignant tumors are closely related to a kinase system, and excessive activation of various kinases can cause abnormal downstream signal transduction, so that important influences on the occurrence, development, metastasis and prognosis of tumors are generated. The PI3K pathway is one of the most frequent pathways activated in human cancers, which affects approximately 50% of malignant tumors, and the PI3K signal pathway also affects the proliferation, survival, transcription, translation, metabolism and other processes of malignant tumor cells, so that the organic small molecule kinase inhibitors for kinases such as PI3K in the pathway have become hot spots for research and development of molecular targeted antitumor drugs.
Phosphatidylinositol 3-kinases (PI 3 Ks) are a family of serine/threonine lipid kinases, key signaling elements of the PI3K/AKT/mTOR signaling pathway, playing an important role in regulating cell growth, proliferation, movement and survival. The main mechanism of the PI3K pathway is that PI3K is activated mainly by two different ways after stimulation of cell membrane surface receptors by signals, one is through the combination of p110 and Ras, and the other is through interaction with RTKs or GPCRs, changing the dimer spatial conformation to form an active form. Activated PI3K is capable of specifically phosphorylating PIP2 to produce PIP3.PIP3 acts as a second messenger binding to the PH domain of downstream AKT, translocating AKT in the cytosol to the cell membrane, phosphorylating the Thr308 and Ser473 sites of AKT catalyzed by PDK1 on the cell membrane, resulting in activation of AKT. Activated AKT breaks away from cell membrane and enters cytoplasm or nucleus, activates or inhibits downstream various proteins such as mTOR, bad, GSK-3, FOXO, caspase, PARP and the like, and regulates various physiological links such as growth, differentiation, apoptosis, angiogenesis and the like of cells. PI3ks can be classified into I, II and III classes based on differences in their activation mechanisms, structural features, and substrate selection. Class I PI3K kinases include the pi3kα, pi3kβ, pi3kγ and pi3kδ subtypes. All four subtypes are related to the occurrence and development of tumors, and especially PI3K alpha is closely related to the tumors. PI3K alpha is a dimer containing the catalytic subunit p110α and the regulatory subunit p85/55/50, encoded by the PIK3CA gene. According to the action targets, the PI3K inhibitor can be roughly divided into 3 types, namely a PI3K-mTOR dual-targeting inhibitor, a general PI3K inhibitor and a PI3K selective inhibitor, wherein the PI3K selective inhibitor has high importance of PIK3CA genes in solid tumors and high mutation rate, so that the PI3K alpha inhibitor becomes a research hot spot.
PI3K inhibitors have been studied for 20 years, more than 30 candidate drugs have been entered into clinical trials, half of which have entered phase II clinical trials, and given the close relationship of PI3K inhibitors to malignancy and kinase system, inhibitors have become potential anticancer drugs, and the following 6 PI3K inhibitors have been approved by the united states Food and Drug Administration (FDA) for marketing:
Currently, among the four class I PI3K subtypes (α, β, δ, and γ), PI3kα causes the occurrence and development of various malignant tumors by PIK3CA gene amplification or mutation. It is counted that 29% of breast cancers and approximately 40% of hr+/HER 2-breast cancers carry abnormal PI3K alpha signals. Non-target related side effects, such as myelosuppression and the like, are generated due to lack of subtype selectivity of the general PI3K inhibitor, and the PI3K/mTOR double-target inhibitor is not marketed until now due to the large side effects. Therefore, the development of subtype selective PI3K alpha inhibitors is an important direction of current research, and the search for subtype selective PI3K alpha inhibitors with higher kinase inhibition and cell antiproliferative activity is the focus of current research.
Disclosure of Invention
In order to solve the technical problems in the prior art, the invention provides a benzoheterocycle compound serving as a PI3K alpha kinase inhibitor, and a preparation method and application thereof, and the benzoheterocycle compound is realized by the following technical scheme:
a benzoheterocycle compound as PI3K alpha kinase inhibitor, which contains a structure represented by the following general formula (I):
Further, in the general formula (I), a is one of the following structures:
further, R1 is one of the following structures:
(1) R1 is R2NH-, wherein R2 is 1-6 straight or branched alkyl groups;
(2) R1 is R2NH-, wherein R2 is a ternary to eight-membered nitrogen-containing heterocyclic compound, a nitrogen-containing spiro compound or a bridged ring compound;
(3) R1 is R2NHCO-, wherein R2 is 1-6 straight or branched alkyl groups;
(4) R1 is R2NHCO-, wherein R2 is a ternary to eight-membered nitrogen-containing heterocyclic compound, a nitrogen-containing spiro compound or a bridged ring compound.
Further, the R1 is one of the following structures:
Further, the carbon-linked hydrogen in the general formula (I) may be replaced with deuterium, an isotope of hydrogen. For example, alkyl groups may be replaced with deuterated alkyl groups, alkoxy groups may be replaced with deuterated epoxy groups, benzene rings with deuterated benzene rings, and aromatic rings with deuterated aromatic rings.
Further, the benzoheterocycle compound comprises one of the following structures:
(1) (R) -N- (1-amino-1-oxopropan-2-yl) -6- (2-aminobenzo [ d ] oxazol-5-yl) imidazo [1,2-a ] pyridine-3-carboxamide;
(2) Methyl 2- (6- (2-aminobenzo [ d ] oxazol-5-yl) imidazo [1,2-a ] pyridine-3-carboxamide) butyrate;
(3) N- (1-amino-1-oxobutan-2-yl) -6- (2-aminobenzo [ d ] oxazol-5-yl) imidazo [1,2-a ] pyridine-3-carboxamide;
(4) 2- (6- (2-aminobenzo [ d ] oxazol-5-yl) imidazo [1,2-a ] pyridine-3-carboxamide) -2-methylpropionate;
(5) N- (1-amino-2-methyl-1-oxopropan-2-yl) -6- (2-aminobenzo [ d ] oxazol-5-yl) imidazo [1,2-a ] pyridine-3-carboxamide;
(6) (6- (2-aminobenzo [ d ] oxazol-5-yl) imidazo [1,2-a ] pyridine-3-carbonyl) -L-alanine methyl ester;
(7) (6- (2-aminobenzo [ d ] oxazol-5-yl) imidazo [1,2-a ] pyridine-3-carbonyl) -L-alanine;
(8) (S) -N- (1-amino-1-oxopropan-2-yl) -6- (2-aminobenzo [ d ] oxazol-5-yl) imidazo [1,2-a ] pyridine-3-carboxamide;
(9) (6- (2-aminobenzo [ d ] oxazol-5-yl) imidazo [1,2-a ] pyridin-3-yl) ((4 ar,7 as) -hexahydro-6H- [1,4] dioxin [2,3-c ] pyrrol-6-yl) methanone;
(10) (6- (2-aminobenzo [ d ] oxazol-5-yl) imidazo [1,2-a ] pyridin-3-yl) ((4 aR) -hexahydro-6H- [1,4] dioxin [2,3-c ] pyrrol-6-yl) methanone;
(11) N- (2-amino-2-oxo-1-phenethyl) -6- (2-aminobenzo [ d ] oxazol-5-yl) imidazo [1,2-a ] pyridine-3-carboxamide;
(12) (S) -N- (2-amino-2-oxo-1-phenethyl) -6- (2-aminobenzo [ d ] oxazol-5-yl) imidazo [1,2-a ] pyridine-3-carboxamide;
(13) (R) -N- (2-amino-2-oxo-1-phenethyl) -6- (2-aminobenzo [ d ] oxazol-5-yl) imidazo [1,2-a ] pyridine-3-carboxamide;
(14) (S) -N- (1-amino-3- (4-fluorophenyl) -1-oxopropan-2-yl) -6- (2-aminobenzo [ d ] oxazol-5-yl) imidazo [1,2-a ] pyridine-3-carboxamide;
(15) (S, E) -N- (2-amino-1- (4-hydroxyphenyl) -2-oxoethyl) -1- (2- (2-aminobenzo [ d ] oxazol-5-yl) prop-1-en-1-yl) -1H-imidazole-5-carboxamide;
(16) N- (1-amino-1-oxo-3-phenylpropan-2-yl) -6- (2-aminobenzo [ d ] oxazol-5-yl) imidazo [1,2-a ] pyridine-3-carboxamide;
(17) (S) -N- (1-amino-3- (4-hydroxyphenyl) -1-oxopropan-2-yl) -6- (2-aminobenzo [ d ] oxazol-5-yl) imidazo [1,2-a ] pyridine-3-carboxamide;
(18) (6- (2-aminobenzo [ d ] oxazol-6-yl) imidazo [1,2-a ] pyridin-3-yl) (2- (hydroxymethyl) morpholino) methanone;
(19) (6- (2-aminobenzo [ d ] oxazol-5-yl) imidazo [1,2-a ] pyridin-3-yl) (4- (dimethylamino) piperidin-1-yl) methanone;
(20) (6- (2-aminobenzo [ d ] oxazol-5-yl) imidazo [1,2-a ] pyridin-3-yl) (piperazin-1-yl) methanone;
(21) 1- (6- (2-aminobenzo [ d ] oxazol-5-yl) imidazo [1,2-a ] pyridine-3-carbonyl) pyrrolidine-2-carboxamide;
(22) (6- (2-aminobenzo [ d ] oxazol-5-yl) imidazo [1,2-a ] pyridin-3-yl) (3-methoxypyrrolidin-1-yl) methanone;
(23) (6- (2-aminobenzo [ d ] oxazol-5-yl) imidazo [1,2-a ] pyridin-3-yl) (3- (dimethylamino) pyrrolidin-1-yl) methanone;
(24) 5- (2- ((4 aR) -hexahydro-6H- [1,4] dioxin [2,3-c ] pyrrol-6-yl) quinoxalin-6-yl) benzo [ d ] oxazol-2-amine;
(25) 5- (2- ((4 ar,7 as) -hexahydro-6H- [1,4] dioxin [2,3-c ] pyrrol-6-yl) quinoxalin-6-yl) benzo [ d ] oxazol-2-amine;
(26) 5- (3- ((4 ar,7 as) -hexahydro-6H- [1,4] dioxy [2,3-c ] pyrrol-6-yl) quinoxalin-6-yl) benzo [ d ] oxazol-2-amine;
(27) 5- (4- ((4 ar,7 as) -hexahydro-6H- [1,4] dioxy [2,3-c ] pyrrol-6-yl) quinazolin-6-yl) benzo [ d ] oxazol-2-amine;
(28) (S) -2- ((6- (2-aminobenzo [ d ] oxazol-5-yl) quinazolin-4-yl) amino) propanamide;
(29) (S) -2- ((7- (2-aminobenzo [ d ] oxazol-5-yl) quinoxalin-2-yl) amino) propanamide;
(30) 2- ((6- (2-aminobenzo [ d ] oxazol-5-yl) quinazolin-4-yl) amino) acetamide;
(31) 2- ((7- (2-aminobenzo [ d ] oxazol-5-yl) quinoxalin-2-yl) amino) acetamide;
(32) 2- ((6- (2-aminobenzo [ d ] oxazol-5-yl) quinoxalin-2-yl) amino) acetamide.
According to the preparation method of the benzo heterocyclic compound, 2-amino-4-bromophenol (A) is used as a raw material, the raw material (A) and cyanogen bromide are subjected to cyclization reaction to obtain an intermediate (B), the intermediate (B) and the bis-pinacolato diboron are subjected to Suzuki coupling reaction to obtain an intermediate (C), and boron esters of the intermediate (C) are connected with different bromine-containing substituent fragments through the Suzuki coupling reaction to obtain the target compound (D) with the structure shown in the general formula (I).
Further, the specific reaction formula is as follows:
further, in the specific reaction formula D, the substituents R1 and A are defined as the substituents R1 and A in the general formula (I).
A PI3K alpha kinase inhibitor having selectivity comprising a benzoheterocycle compound of claim 1 or a stereoisomer, hydrate or pharmaceutically acceptable salt thereof.
Pharmaceutically acceptable salts refer to salts that convert the basic groups in the parent compound to the salt form. Pharmaceutically acceptable salts include, but are not limited to, inorganic or organic acid salts of basic groups such as amine (ammonia) groups. Pharmaceutically acceptable salts of the invention can be synthesized from the parent compound by reacting the basic group of the parent compound with 1 to 4 equivalents of an acid in a solvent system. Examples of the basic group of the compound of the present invention may be salified with acids, and examples of such salified acids include, but are not limited to, salts with inorganic acids, particularly hydrohalic acids (e.g., hydrochloric acid, hydrobromic acid, hydroiodic acid), nitric acid, sulfuric acid, phosphoric acid, carbonic acid, etc., salts with lower alkylsulfonic acids such as methanesulfonic acid, trifluoromethanesulfonic acid, salts with arylsulfonic acids such as benzenesulfonic acid or p-toluenesulfonic acid, salts with organic acids such as acetic acid, fumaric acid, tartaric acid, oxalic acid, citric acid, maleic acid, malic acid or succinic acid, and salts with amino acids such as aspartic acid or glutamic acid.
PI3K alpha kinase inhibitors of the invention also include forms of solvates or hydrates, generally, forms of solvates or hydrates that are equivalent to unsolvated or unhydrated forms and are encompassed within the scope of the present invention. Certain compounds of the present invention may exist in polycrystalline or amorphous forms. In general, all physical forms have equivalent uses and are intended to be encompassed within the scope of the present invention.
In addition, unless otherwise indicated, the structural formulae of the substituted benzoxazole compounds in the selective PI3K alpha kinase inhibitors described herein include all isomeric forms (e.g., enantiomers, diastereomers, and geometric isomers (or conformational isomers)), such as the R, S configuration with an asymmetric center, the (Z), (E) isomers of double bonds, and the conformational isomers of (Z), (E). Thus, individual stereochemical isomers of the compounds of the invention, or enantiomers, diastereomers, or mixtures of geometric isomers (or conformational isomers) thereof, are all within the scope of the invention. All tautomeric forms of pyrimidine compounds in the selective PI3K alpha kinase inhibitors of the invention are included within the scope of the invention.
In addition, the structural formula of the compounds described herein include enriched isotopes of one or more different atoms.
A pharmaceutical composition comprising a benzoheterocycle compound as described above or a stereoisomer, hydrate or pharmaceutically acceptable salt thereof.
The benzoheterocycle compounds, the PI3K alpha kinase inhibitor with selectivity and the pharmaceutical composition are applied to the preparation of medicaments for preventing and/or treating and/or assisting in treating proliferative diseases, metabolic diseases, nervous system diseases and diseases related to malignant tumors caused by excessive activation of PI3K alpha kinase.
Further, the metabolic disease is diabetes.
Further, the proliferative disease includes colorectal cancer, gastric cancer, breast cancer, lung cancer, liver cancer, prostate cancer, pancreatic cancer, thyroid cancer, bladder cancer, renal cancer, brain tumor, neck cancer, cancer of the CNS, glioblastoma, myeloproliferative disease, leukemia or lymphoma.
Furthermore, the application in preparing the medicine for preventing and/or treating and/or assisting in treating proliferative diseases, metabolic diseases, nervous system diseases and related diseases of malignant tumors caused by excessive activation of PI3K alpha kinase, in particular the application in preparing the medicine for inhibiting the growth of cancer cells in vitro.
The inventor is in the team and is devoted to the research of PI3K-Akt-mTOR signal channel inhibitors for a long time, a series of innovative achievements (Journal of Medicinal Chemistry,2016,59,7268-7274;European Journal of Medicinal Chemistry,2020,204,112637;European Journal of Medicinal Chemistry,2022,229,114055.). are obtained, on the basis of earlier work, a benzoxazole PI3K alpha selective inhibitor is disclosed, and compared with benzoxazole clinical candidate medicine TAK-117, the preferred compound has higher kinase inhibition and cell antiproliferative activity and better subtype selectivity.
The terms used herein have the following meanings:
the term "alkyl" is a monovalent hydrocarbon radical comprising 1 to 20 carbon atoms saturated straight or branched, wherein the alkyl radical may be independently optionally substituted with one or more substituents described herein. It may be that the alkyl group contains 1 to 10 carbon atoms, the alkyl group contains 1 to 8 carbon atoms, the alkyl group contains 1 to 6 carbon atoms, and the alkyl group contains 1 to 4 carbon atoms. The alkyl groups further include, but are not limited to, methyl (Me, -CH 3), ethyl (Et, -CH 2CH3), n-propyl (n-Pr, -CH 2CH2CH3), isopropyl (i-Pr, -CH (CH 3)2), n-butyl (n-Bu, -CH 2CH2CH2CH3), isobutyl (i-Bu, -CH 2CH(CH3)2), sec-butyl (s-Bu, -CH (CH 3)CH2CH3), tert-butyl (t-Bu, -C (CH 3)3), and the like the term "alkyl" and its prefix "alk" are used herein to include straight and branched saturated carbon chains.
The term "alkoxy" refers to the moiety of an alkyl group as defined above for "alkyl" which is attached to the main carbon chain of the "alkyl" group via an oxygen atom.
The term "haloalkyl" or "haloalkoxy" is intended to mean that the "alkyl" or "alkoxy" groups may be substituted with one or more halogen atoms which may be the same or different. Wherein alkyl and alkoxy groups have the meaning as previously described herein, such examples include, but are not limited to, trifluoromethyl, trifluoromethoxy, and the like.
The term "hydroxyalkyl" or "hydroxyalkoxy" is intended to mean that the "alkyl" or "alkoxy" may be substituted with one or more hydroxy groups. Wherein "alkyl" and "alkoxy" groups have the meaning as previously described herein, such examples include, but are not limited to, hydroxymethyl, 1-hydroxyethyl, hydroxypropyl, 1, 2-dihydroxypropyl, hydroxymethyl, 1-hydroxyethoxy, and the like.
The term "halogen", "halogen atom" or "halogen atom" includes fluorine, chlorine, bromine, iodine.
The term "heterocyclyl" may be a carbon or heteroatom group. "heterocyclyl" also includes groups formed by the merging of a heterocyclic group with a saturated or partially unsaturated ring or heterocycle. Heterocycles include, but are not limited to, pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidinyl, thiazanyl, azetidinyl, oxetanyl, thietanyl, piperidinyl, homopiperidinyl, epoxypropyl, azepanyl, oxepinyl, thiepanyl, N-morpholinyl, 2-morpholinyl, 3-morpholinyl, thiomorpholinyl, N-piperazinyl, 2-piperazinyl, 3-piperazinyl, homopiperazinyl, 4-methoxy-piperidin-1-yl, 1,2,3, 6-tetrahydropyridin-1-yl, oxazepinyl, diazanyl, thiazepinyl, pyrrolin-1-yl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1, 3-dioxanyl, pyrazolinyl, dithianyl, pyrazolidinyl, imidazolyl, 1, 3-pyrrolinyl, 1, 2-quinolinyl, 2-dioxidinyl, 1, 2-isoquinolinyl, 1-naphthyridinyl, 1-2-naphthyridinyl, and N-isoquinolinyl. And the heterocyclic group may be substituted or unsubstituted, wherein the substituent may be, but is not limited to, oxo (=o), hydroxy, amino, halogen, cyano, heteroaryl, alkoxy, alkylamino, alkyl, alkenyl, alkynyl, heterocyclic, mercapto, nitro, aryloxy, hydroxy-substituted alkoxy, hydroxy-substituted alkyl-C (=o), carboxyalkoxy, and the like.
The terms "fused bicyclic", "fused ring", "fused bicyclic group" or "fused ring group" refer to a saturated or unsaturated fused ring system, and refer to a non-aromatic bicyclic ring system. Such systems may contain independent or conjugated unsaturation, but the core structure does not contain aromatic or heteroaromatic rings (but the aromatic may be a substituent thereon). Each ring in the fused bicyclic ring is either carbocyclic or heteroalicyclic, examples of which include, but are not limited to, 2, 3a,4,7 a-hexahydro-1H-indenyl, 7-azabicyclo [2.2.1] heptyl, fused bicyclo [3.3.0] octyl, fused bicyclo [3.1.0] hexyl, 1,2,3, 4a,5,8 a-octahydronaphthyl, all of which are included in the fused bicyclic ring system. And the fused bicyclic group may be substituted or unsubstituted, wherein the substituents may be, but are not limited to, halogen, hydroxy, amino, cyano, aryl, heteroaryl, alkoxy, alkyl, alkenyl, alkynyl, heterocyclyl, mercapto, nitro, aryloxy, and the like.
The term "fused heterobicyclic group" means a saturated or unsaturated fused ring system, and refers to a non-aromatic bicyclic ring system. Such systems may contain independent or conjugated unsaturation, but the core structure does not contain aromatic or heteroaromatic rings (but the aromatic may be a substituent thereon). And at least one ring system comprises one or more heteroatoms, wherein each ring system comprises a 3-7 membered ring, i.e., comprising 1-6 carbon atoms and 1-3 heteroatoms selected from N, O, P, S, where S or P is optionally substituted with one or more oxygen atoms to give a group like SO, SO 2、PO、PO2, examples of which include, but are not limited to, hexahydro-2H- [1,4] dioxa [2,3-c ] pyrrolyl, and the like. And the fused heterobicyclic group may be substituted or unsubstituted, wherein the substituents may be, but are not limited to, halogen, hydroxy, amino, cyano, aryl, heteroaryl, alkoxy, alkyl, alkenyl, alkynyl, heterocyclyl, mercapto, nitro, aryloxy, and the like.
Compared with the prior art, the invention has the technical effects that:
(1) The invention obtains a brand new benzoxazole PI3K alpha selective inhibitor compound.
(2) The compounds of the invention can effectively inhibit PI3K alpha kinase, and a plurality of compounds have PI3K alpha inhibition activity superior to that of a positive control TAK-117.
(3) The compound has novel structure, smaller molecular weight, compliance with drug-like rules and remarkable anti-tumor activity, and can be potentially used for treating related tumors.
(4) The compound has positive and foreseeable clinical application value of anti-proliferative diseases, especially anti-tumor, and has good development prospect.
(5) The compound has the characteristics of low cost, good curative effect and low toxicity. The intermediate product of the compound in the synthesis process has high yield, reduces the resource waste, and is further beneficial to reducing the cost.
Detailed Description
The technical scheme of the present invention is further defined below in conjunction with the specific embodiments, but the scope of the claimed invention is not limited to the description.
All temperatures are set in degrees celsius in the examples described below unless otherwise indicated. Reagents were purchased from commercial suppliers such as ALFA AESAR CHEMICAL Company, carboline technologies, inc., aba Ding Shiji, beijing coupling technologies, inc., and used without further purification unless otherwise indicated. The general reagent is purchased from Shanzhou chemical plant, guangzhou chemical plant, tianjin chemical agent Limited company, qingdao ocean chemical plant, etc.
The chromatographic column in the examples described below uses a silica gel column, silica gel (200-300 mesh) purchased from Qingdao ocean chemical plant. Nuclear magnetic resonance spectroscopy was performed using CDC13 or DMSO-d 6 as a solvent (in ppm) and TMS (0 ppm) or chloroform (7.26 ppm) as reference standards. When multiple peaks occur, the abbreviations s (singlet ), d (doublet, doublet), t (triplet ), m (multiplet, multiplet), br (broadened, broad), dd (doublet of doublets, quartet), dt (doublet of triplets, double triplet) will be used. Coupling constants are expressed in hertz (Hz).
The low resolution Mass Spectrometry (MS) data in the examples described below were determined by a spectrometer of Agilent6120 series LC-MS equipped with a G1311B quaternary pump and a G1316BTCC (column temperature maintained at 30 ℃) for analysis, a G1329B autosampler and a G1315CDAD detector for analysis, and an ESI source for LC-MS spectrometer.
The injection volume was determined by the sample concentration in the examples described below, the flow rate was 0.5mL/min, and the peak of HPLC was read by recording the UV-Vis wavelengths at 210nm and 254 nm. The mobile phase was isopropanol/n-hexane (40:60).
For convenience of description, some of the raw materials will be described in terms of short descriptions, and the short descriptions are fully contrasted with short descriptions of DCM being CH 2Cl2, namely dichloromethane, CDC13 being deuterated chloroform, PE being petroleum ether, etOAc and EA being ethyl acetate, meOH and CH 3 OH being methanol, pd (PPh 3)4 being tetra-triphenylphosphine palladium, DIPEA being N, N-diisopropylethylamine, DMSO-d 6 being hexadeuterated dimethyl sulfoxide, DME being ethylene glycol dimethyl ether, and Na 2SO4 being sodium sulfate.
Example 1 (R) -N- (1-amino-1-oxopropan-2-yl) -6- (2-aminobenzo [ d ] oxazol-5-yl) imidazo [1,2-a ] pyridine-3-carboxamide, the structural formula is as follows:
the synthesis method comprises the following steps:
Step 1 Synthesis of 5-bromobenzo [ d ] oxazol-2-amine
5-Bromobenzo [ d ] oxazol-2-amine of formula:
The raw material 2-amino-4-bromophenol (16.04 mmol) is weighed into a 250mL eggplant-shaped bottle, meOH is added for dissolution, cyanogen bromide (19.25 mmol) is added under stirring, stirring reaction is carried out at room temperature, TLC monitors that the reaction is finished, the reaction liquid is concentrated in vacuum under reduced pressure, naHCO 3 aqueous solution is added for quenching, water and EA (3X 100 mL) are used for extraction, anhydrous Na 2SO4 is dried, deep yellow solid is obtained by vacuum concentration under reduced pressure, and the product is obtained by washing with EA for multiple times. Yellow solid, yield 88.13%. HRMS (ESI) calcd.for C 7H6BrN2 O [ M+H ] +:212.9585, found:212.9588;
step 2 Synthesis of 5- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzo [ d ] oxazol-2-amine
5- (4, 5-Tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzo [ d ] oxazol-2-amine of the formula:
5-bromobenzo [ d ] oxazol-2-amine (10.37 mmol), dipyryl diboron (12.45 mmol), potassium acetate (31.14 mmol), pd (dppf) Cl2 (1.03 mmol) were added sequentially to a 100mL eggplant-shaped bottle, the reaction was replaced with nitrogen by dissolving with 1, 4-dioxane, the reaction was refluxed overnight at 100℃and monitored by TLC, nitrogen was removed, water and EA (3X 50 mL) were added to the reaction mixture for extraction, anhydrous Na 2SO4 was dried, concentrated under vacuum under reduced pressure to give a yellow solid, and the product was obtained by multiple washes with EA. Yellow solid, yield 78.63%. HRMS (ESI) calcd.for C 13H18BN2O3 [ M+H ] +:261.1332, found:261.1456;
Step 3 Synthesis of 6-bromoimidazo [1,2-a ] pyridine-3-carboxylic acid ethyl ester
6-Bromoimidazo [1,2-a ] pyridine-3-carboxylic acid ethyl ester of formula:
The starting materials, 2-amino-5-bromopyridine (6.66 mmol) and ethyl 2-chloro-3-oxopropionate (6.66 mmol), were weighed into a 100mL eggplant-shaped bottle, acetonitrile was added to dissolve, the reaction was replaced with nitrogen, and was moved to 80 ℃ for reflux overnight, TLC monitored the completion of the starting material reaction, nitrogen was removed, water and EA (3X 50 mL) were added to the reaction mixture for extraction, anhydrous Na 2SO4 was dried, concentrated under reduced pressure in vacuo to give a yellow oil, and silica gel column chromatography (PE: EA=10:1) was purified to give a white solid, yield ：89.14％.HRMS(ESI)calcd.for C10H10BrN2O2[M+H]+:268.9847,found:268.9854.
Step 4 Synthesis of 6-bromoimidazo [1,2-a ] pyridine-3-carboxylic acid
6-Bromoimidazo [1,2-a ] pyridine-3-carboxylic acid of formula:
6-bromoimidazo [1,2-a ] pyridine-3-ethyl formate (4.47 mmol) and lithium hydroxide hydrate (13.43 mmol) are sequentially added into a 100mL eggplant-shaped bottle, the mixture is dissolved by MeOH/THF/H 2 O (4:1:1), the mixture is stirred and reacted for 1H at room temperature, TLC monitors that the raw materials react, the mixture is concentrated in vacuum under reduced pressure, 1NHCl is added to adjust the PH to 1-2, a large amount of solids are separated out, and the mixture is filtered under reduced pressure, and a filter cake is taken to obtain the product. White solid, yield ：88.65％.HRMS(ESI)calcd.for C8H4BrN2O2[M+H]-:238.9534,found:238.9532.
Step 5 Synthesis of (R) -N- (1-amino-1-oxopropan-2-yl-6-bromoimidazo [1,2-a ] pyridine-3-carboxamide
(R) -N- (1-amino-1-oxopropan-2-yl-6-bromoimidazo [1,2-a ] pyridine-3-carboxamide has the structural formula:
6-Bromoimidazo [1,2-a ] pyridine-3-carboxylic acid (2.08 mmol), D-alaninamide (3.12 mmol), TCFH (2.5 mmol) and NMI (7.28 mmol) were sequentially added to a 100mL eggplant-shaped bottle, dissolved with acetonitrile, the reaction was replaced with nitrogen, stirred at room temperature overnight, TLC monitored the completion of the reaction of the starting materials, concentrated under reduced pressure in vacuo, the reaction mixture was extracted with water and EA (3X 50 mL), dried over anhydrous Na 2SO4, concentrated under reduced pressure in vacuo to give a white floccule, filtered under reduced pressure, and washed with DCM multiple times to give the product. White solid, yield ：88.08％.HRMS(ESI)calcd.for C11H12BrN4O2[M+H]+:311.0065,found:311.0078.
Step 6 Synthesis of (R) -N- (1-amino-1-oxopropan-2-yl) -6- (2-aminobenzo [ d ] oxazol-5-yl) imidazo [1,2-a ] pyridine-3-carboxamide
(R) -N- (1-amino-1-oxopropan-2-yl) -6- (2-aminobenzo [ d ] oxazol-5-yl) imidazo [1,2-a ] pyridine-3-carboxamide of formula:
(R) -N- (1-amino-1-oxopropan-2-yl-6-bromoimidazo [1,2-a ] pyridine-3-carboxamide (0.48 mmol), 5- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzo [ d ] oxazol-2-amine (0.48 mmol), sodium carbonate (1.45 mmol), and palladium tetraphenylphosphine (0.048 mmol) were sequentially added to a 100mL eggplant-shaped bottle, the reaction was replaced with nitrogen gas by dissolving with 1, 4-dioxane, the reaction was refluxed overnight at 100 ℃, TLC was monitored for the completion of the reaction, nitrogen gas was removed, water and EA (3X 50 mL) were added to the reaction mixture, dried over anhydrous Na 2SO4, and concentrated under reduced pressure to give a yellow oil, which was purified by silica gel column chromatography (DCM: 10:1) to give a white solid in 69.14%. HRMS (ESI) calcd. 18H17N6O3 [ M+H ] + ] 4.128365. 128..
EXAMPLE 2 methyl 2- (6- (2-aminobenzo [ d ] oxazol-5-yl) imidazo [1,2-a ] pyridine-3-carboxamide) butyrate having the following structural formula:
The synthesis method comprises the steps of replacing the heterocyclic fragment in the step 6 in the example 1 with methyl 2-aminobutyrate, and obtaining a white solid product in the step 6 in the same manner as the example 1, wherein the yield is 49.84%. HRMS (ESI) calcd.for C 20H20N5O4 [ M+H ] +:394.1437, found:394.1456.
Example 3:N- (1-amino-1-oxobutan-2-yl) -6- (2-aminobenzo [ d ] oxazol-5-yl) imidazo [1,2-a ] pyridine-3-carboxamide has the following structural formula:
The synthesis method comprises the steps of changing the substituted heterocyclic fragment in the step 6 in the example 1 into 2-aminobutanamide, and obtaining a white solid as a product in the step 6, wherein the yield is 38.84 percent. HRMS (ESI) calcd.for C 19H19N6O3 [ M+H ] +:379.1440, found:379.1444.
EXAMPLE 4 methyl 2- (6- (2-aminobenzo [ d ] oxazol-5-yl) imidazo [1,2-a ] pyridine-3-carboxamide) -2-methylpropionate, the structural formula is as follows:
The synthesis method comprises the steps of replacing the heterocyclic fragment in the step 6 in the example 1 with 2-amino-2-methyl propionate, and obtaining a white solid as a product in the step 6, wherein the yield is 45.84% in other steps and operations in the example 1. HRMS (ESI) calcd.for C 20H20N5O4 [ M+H ] +:394.1437, found:394.1456.
EXAMPLE 5N- (1-amino-2-methyl-1-oxopropan-2-yl) -6- (2-aminobenzo [ d ] oxazol-5-yl) imidazo [1,2-a ] pyridine-3-carboxamide, the structural formula is as follows:
The synthesis method comprises the steps of replacing the heterocyclic fragment in the step 6 in the example 1 with 2-amino-2-methylpropanamide, and obtaining a white solid as a product in the step 6, wherein the yield is 48.84 percent. HRMS (ESI) calcd.for C 19H19N6O3 [ M+H ] +:379.1440, found:379.1444.
Example 6 (6- (2-aminobenzo [ d ] oxazol-5-yl) imidazo [1,2-a ] pyridine-3-carbonyl) -L-alanine methyl ester, having the structural formula:
The synthesis method comprises the steps of replacing the heterocyclic fragment in the step 6 in the example 1 with L-alanine methyl ester, and obtaining a white solid as a product in the step 6, wherein the yield is 48.84 percent. HRMS (ESI) calcd.for C 19H18N5O4 [ M+H ] +:379.1281, found:379.1444.
Example 7 (6- (2-aminobenzo [ d ] oxazol-5-yl) imidazo [1,2-a ] pyridine-3-carbonyl) -L-alanine, the structural formula is as follows:
The synthesis method comprises the steps of replacing the heterocyclic fragment in the step 6 in the example 1 with L-alanine, and obtaining a white solid product in the step 6, wherein the yield is 48.84% by other steps and operations in the example 1. HRMS (ESI) calcd.for C 18H16N5O4 [ M+H ] -:364.1124, found:364.1444.
Example 8 (S) -N- (1-amino-1-oxopropan-2-yl) -6- (2-aminobenzo [ d ] oxazol-5-yl) imidazo [1,2-a ] pyridine-3-carboxamide, the structural formula is as follows:
the synthesis method comprises the steps of replacing the heterocyclic fragment in the step 6 in the example 1 with L-alanyl amide, and obtaining a white solid product in the step 6, wherein the yield is 45.84 percent. HRMS (ESI) calcd.for C 18H17N6O3 [ M+H ] +:365.1284, found:365.1288.
Example 9 (6- (2-aminobenzo [ d ] oxazol-5-yl) imidazo [1,2-a ] pyridin-3-yl) ((4 aR,7 aS) -hexahydro-6H- [1,4] dioxin [2,3-c ] pyrrol-6-yl) methanone having the structural formula:
The synthesis method comprises the steps of replacing the heterocyclic fragment in the step 6 in the example 1 with (4 aR,7 aS) -hexahydro-5H- [1,4] dioxin [2,3-c ] pyrrole, and obtaining a white solid in the step 6 with the yield of 45.84% by other steps and operation as in the example 1. HRMS (ESI) calcd.for C 21H20N5O4 [ M+H ] +:406.1437, found 406.1445.
Example 10 (6- (2-aminobenzo [ d ] oxazol-5-yl) imidazo [1,2-a ] pyridin-3-yl) ((4 aR,7 aR) -hexahydro-6H- [1,4] dioxin [2,3-c ] pyrrol-6-yl) methanone having the structural formula:
the synthesis method comprises the steps of replacing the heterocyclic fragment in the step 6 in the example 1 with (4 aR,7 aR) -hexahydro-5H- [1,4] dioxin [2,3-c ] pyrrole, and obtaining a white solid in the step 6 with the yield of 45.84% by other steps and operation as in the example 1. HRMS (ESI) calcd.for C 21H20N5O4 [ M+H ] +:406.1437, found 406.1445.
EXAMPLE 11N- (2-amino-2-oxo-1-phenethyl) -6- (2-aminobenzo [ d ] oxazol-5-yl) imidazo [1,2-a ] pyridine-3-carboxamide, the structural formula is as follows:
The synthesis method comprises the steps of replacing the heterocyclic fragment in the step 6 in the example 1 with 2-amino-2-phenylacetamide, and obtaining a white solid in the step 6 in the yield of 55.84 percent by other steps and operation as in the example 1. HRMS (ESI) calcd.for C 23H19N6O3 [ M+H ] +:427.1440, found:427.1445.
Example 12 (S) N- (2-amino-2-oxo-1-phenethyl) -6- (2-aminobenzo [ d ] oxazol-5-yl) imidazo [1,2-a ] pyridine-3-carboxamide, the structural formula is as follows:
the synthesis method comprises the steps of replacing the substituted heterocyclic fragment in the step 6 in the example 1 with (S) 2-amino-2-phenylacetamide, and obtaining a white solid in the step 6 in the yield of 55.84 percent by other steps and operation as in the example 1. HRMS (ESI) calcd.for C 23H19N6O3 [ M+H ] +:427.1440, found:427.1445.
Example 13 (R) N- (2-amino-2-oxo-1-phenethyl) -6- (2-aminobenzo [ d ] oxazol-5-yl) imidazo [1,2-a ] pyridine-3-carboxamide, the structural formula is as follows:
The synthesis method comprises the steps of replacing the heterocyclic fragment in the step 6 in the example 1 with (R) 2-amino-2-phenylacetamide, and obtaining a white solid in the step 6 in the yield of 55.84 percent by other steps and operation as in the example 1. HRMS (ESI) calcd.for C 23H19N6O3 [ M+H ] +:427.1440, found:427.1445.
Example 14 (S) -N- (1-amino-3- (4-fluorophenyl) -1-oxopropan-2-yl) -6- (2-aminobenzo [ d ] oxazol-5-yl) imidazo [1,2-a ] pyridine-3-carboxamide having the following structural formula:
The synthesis method comprises the steps of replacing the heterocyclic fragment in the step 6 in the example 1 with (S) -2-amino-3- (4-fluorophenyl) propionamide, and obtaining the product in the step 6 as a white solid with the yield of 34.67 percent by other steps and operation as in the example 1. HRMS (ESI) calcd.for C 24H20FN6O3 [ M+H ] +:459.1503, found:459.1445.
Example 15 (S, E) -N- (2-amino-1- (4-hydroxyphenyl) -2-oxoethyl) -1- (2- (2-aminobenzo [ d ] oxazol-5-yl) prop-1-en-1-yl) -1H-imidazole-5-carboxamide has the following structural formula:
The synthesis method comprises the steps of replacing the heterocyclic fragment in the step 6 in the example 1 with (S) 2-amino-3- (4-hydroxyphenyl) acetamide, and obtaining a white solid as a product in the step 6, wherein the yield is 52.84 percent. HRMS (ESI) calcd.for C 23H19N6O4 [ M+H ] +:443.1390, found:443.1445.
EXAMPLE 16N- (1-amino-1-oxo-3-phenylpropan-2-yl) -6- (2-aminobenzo [ d ] oxazol-5-yl) imidazo [1,2-a ] pyridine-3-carboxamide, the structural formula is as follows:
The synthesis method comprises the steps of replacing the heterocyclic fragment in the step 6 in the example 1 with 2-amino-3-phenethyl-propionamide, and obtaining a white solid as a product in the step 6, wherein the yield is 23.76 percent. HRMS (ESI) calcd.for C 24H21N6O3 [ M+H ] +:441.1597, found:441.1445.
Example 17 (S) -N- (1-amino-3- (4-hydroxyphenyl) -1-oxopropan-2-yl) -6- (2-aminobenzo [ d ] oxazol-5-yl) imidazo [1,2-a ] pyridine-3-carboxamide, the structural formula is as follows:
The synthesis method comprises the steps of replacing the heterocyclic fragment in the step 6 in the example 1 with L-tyramine amide, and obtaining a white solid as a product in the step 6, wherein the yield is 53.84 percent. HRMS (ESI) calcd.for C 24H21N6O4 [ M+H ] +:457.1546, found:457.1445.
Example 18 (6- (2-aminobenzo [ d ] oxazol-6-yl) imidazo [1,2-a ] pyridin-3-yl) (2- (hydroxymethyl) morpholino) methanone of the formula:
The synthesis method comprises the steps of replacing the heterocyclic fragment in the step 6 in the example 1 with hydroxymethyl morpholine, and obtaining a white solid product in the step 6, wherein the yield is 41.12 percent. HRMS (ESI) calcd.for C 20H20N5O4 [ M+H ] +:394.1437, found:394.1445.
Example 19 (6- (2-aminobenzo [ d ] oxazol-5-yl) imidazo [1,2-a ] pyridin-3-yl) (4- (dimethylamino) piperidin-1-yl) methanone, the structural formula is as follows:
The synthesis method comprises the steps of replacing the heterocyclic fragment in the step 6 in the example 1 with 4- (dimethylamino) piperidine, and carrying out other steps and operations in the same manner as in the example 1, wherein the product obtained in the step 6 is white solid, and the yield is 55.84%. HRMS (ESI) calcd.for C 22H25N6O2 [ M+H ] +:405.1961, found:405.1945.
Example 20 (6- (2-aminobenzo [ d ] oxazol-5-yl) imidazo [1,2-a ] pyridin-3-yl) (piperazin-1-yl) methanone of the formula:
The synthesis method comprises the steps of replacing the heterocyclic fragment in the step 6 in the example 1 with piperazine, and obtaining the product in the step 6 as white solid with the yield of 55.84 percent by other steps and operation as in the example 1. HRMS (ESI) calcd.for C 19H19N6O2 [ M+H ] +:363.1491, found:363.1445.
EXAMPLE 21 1- (6- (2-aminobenzo [ d ] oxazol-5-yl) imidazo [1,2-a ] pyridine-3-carbonyl) pyrrolidine-2-carboxamide, the structural formula is as follows:
The synthesis method comprises the steps of replacing the heterocyclic fragment in the step 6 in the example 1 with prolyl, and obtaining the white solid product in the step 6 with the yield of 55.84 percent by other steps and operation as in the example 1. HRMS (ESI) calcd.for C 20H19N6O3 [ M+H ] +:391.1440, found:391.1445.
Example 22 (6- (2-aminobenzo [ d ] oxazol-5-yl) imidazo [1,2-a ] pyridin-3-yl) (3-methoxypyrrolidin-1-yl) methanone of the formula:
The synthesis method comprises the steps of replacing the heterocyclic fragment in the step 6 in the example 1 with 3-methoxy pyrrolidine, and obtaining a white solid as a product in the step 6, wherein the yield is 55.84 percent. HRMS (ESI) calcd.for C 20H20N5O3 [ M+H ] +:378.1488, found:378.1445.
Example 23 (6- (2-aminobenzo [ d ] oxazol-5-yl) imidazo [1,2-a ] pyridin-3-yl) (3- (dimethylamino) pyrrolidin-1-yl) methanone having the structural formula:
The synthesis method comprises the steps of replacing the substituted heterocyclic fragment in the step 6 in the example 1 with 3- (dimethylamino) pyrrolidine, and carrying out other steps and operations in the same way as in the example 1, wherein the product obtained in the step 6 is white solid, and the yield is 55.84%. HRMS (ESI) calcd.for C 21H23N6O2 [ M+H ] +:391.1804, found:391.1845.
EXAMPLE 24 5- (2- ((4 aR,7 aR) -hexahydro-6H- [1,4] dioxin [2,3-c ] pyrrol-6-yl) quinoxalin-6-yl) benzo [ d ] oxazol-2-amine having the following structural formula:
the synthesis method comprises the following steps:
step 1 Synthesis of 6-bromoquinoxalin-2-ol
6-Bromoquinoxalin-2-ol of the formula:
Quinoxalin-2-ol (13.7 mmol), concentrated sulfuric acid (14 mL), ag 2SO4 (6.8 mmol) and Br 2 (13.6 mmol) were added sequentially to a 100mL eggplant-shaped bottle and stirred at room temperature for 15h, TLC monitored the reaction of the starting materials, the mixture was filtered to remove AgBr, the solid was washed with sulfuric acid, the combined filtrates were poured onto ice, the white solid was collected by filtration, washed with water, ethanol and diethyl ether, and then dried to give the product. White solid, yield 80.13%. HRMS (ESI) calcd.for C 8H6BrN2 O [ M+H ] +:224.9585, found:224.9556;
step 2 Synthesis of 6-bromo-2-chloroquinoxaline
The structural formula of the 6-bromo-2-chloroquinoxaline is as follows:
To a well stirred suspension of 6-bromo-quinoxalin-2-ol (5.28 mmol) in phosphorus oxychloride (4.5 mL) was added DMF (3 mL). The temperature was slowly raised to 80 ℃ and HCl was evolved vigorously, and the temperature was slowly raised to 120 ℃ for 1.5 hours. The dark residue was poured onto ice containing NaHCO 3 and kept at a temperature below 15 ℃ to neutralize, the solid was filtered, washed with water and the solid was dissolved in dichloromethane. It was dried over anhydrous Na 2SO4 and filtered through celite. The solvent was removed in vacuo to give 6-bromo-2-chloro-quinoxaline. White solid, yield 58.71%. HRMS (ESI) calcd.for C 8H5BrClN2 [ M+H ] +:242.9246, found:242.9556;
step 3 Synthesis of (4 aR,7 aR) -6- (6-bromoquinoxalin-2-yl) hexahydro-5H- [1,4] dioxin [2,3-c ] pyrrole
(4 AR) -6- (6-bromoquinoxalin-2-yl) hexahydro-5H- [1,4] dioxin [2,3-c ] pyrrole of the formula:
6-bromo-2-chloro-quinoxaline (3.3 mmol), (4 aR,7 aR) -hexahydro-5H- [1,4] dioxin [2,3-C ] pyrrole (9.9 mmol) was added sequentially to a 100mL eggplant-shaped bottle, dissolved in DMSO, replaced with nitrogen protection, stirred for 15H at 80 ℃, TLC monitored the completion of the reaction of the starting material, nitrogen removed, extracted with water and EA (3X 100 mL), dried over anhydrous Na 2SO4, concentrated under vacuum under reduced pressure to give a dark yellow solid, and silica gel column chromatography (PE: EA=2:1) was used to give the product. White solid, yield ：60.13％.HRMS(ESI)calcd.for C14H15BrN3O2[M+H]+:336.0269,found:336.0278;
Step 4 Synthesis of 5- (2- ((4 aR,7 aR) -hexahydro-6H- [1,4] dioxin [2,3-c ] pyrrol-6-yl) quinoxalin-6-yl) benzo [ d ] oxazol-2-amine
5- (2- ((4 Ar,7 ar) -hexahydro-6H- [1,4] dioxin [2,3-c ] pyrrol-6-yl) quinoxalin-6-yl) benzo [ d ] oxazol-2-amine of the formula:
In a 100mL eggplant flask were successively added (4 aR) -6- (6-bromoquinoxalin-2-yl) hexahydro-5H- [1,4] dioxin [2,3-C ] pyrrole (8.3 mmol), 5- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzo [ d ] oxazol-2-amine (8.3 mmol), sodium carbonate (24.9 mmol), tetrakis triphenylphosphine palladium (0.83 mmol), dissolved with 1, 4-dioxane, the reaction was replaced with nitrogen, the reaction was refluxed overnight at 100 ℃, TLC was monitored for the completion of the starting material reaction, nitrogen was removed, water and EA (3X 50 mL) were added to the reaction mixture, dried over anhydrous Na 2SO4, concentrated under vacuum under reduced pressure to give a yellow oil, which was purified by silica gel column chromatography (DCM: 10:1) to give a white solid in 41.09% yield. HRMS (ESI) calcd.for C 21H20N5O3 [ M+H ] +:390.1488, found:390.1489;
EXAMPLE 25 5- (2- ((4 aR,7 aS) -hexahydro-6H- [1,4] dioxin [2,3-c ] pyrrol-6-yl) quinoxalin-6-yl) benzo [ d ] oxazol-2-amine having the following structural formula:
The synthesis method comprises the steps of replacing the heterocyclic fragment in the step 3 in the example 24 with (4 aR,7 aS) -hexahydro-5H- [1,4] dioxin [2,3-c ] pyrrole, carrying out other steps and operating in the example 24, and obtaining a yellow solid as a product in the step 4, wherein the yield is 32.26%. HRMS (ESI) calcd.for C 21H20N5O3 [ M+H ] +:390.1488, found:390.1489;
EXAMPLE 26 5- (3- ((4 aR,7 aS) -hexahydro-6H- [1,4] dioxin [2,3-c ] pyrrol-6-yl) quinoxalin-6-yl) benzo [ d ] oxazol-2-amine having the following structural formula:
the synthesis method comprises the following steps:
step 1 Synthesis of 7-bromoquinoxalin-2-ol
7-Bromoquinoxalin-2-ol of the formula:
The raw material 4-bromobenzene-1, 2-diamine (10.7 mmol) is weighed into a 250mL eggplant-shaped bottle, acetonitrile is added for dissolution, glyoxylic acid-2-ethyl ester (10.7 mmol) is added under stirring, reflux reaction is carried out overnight at 80 ℃, TLC monitors the reaction completion of the raw material, water and EA (3X 50 mL) are added into the reaction mixture for extraction, anhydrous Na 2SO4 is dried, vacuum concentration is carried out under reduced pressure to obtain yellow solid, and the yellow solid is washed with EA for multiple times to obtain the product. White solid, yield 88.63%. HRMS (ESI) calcd.for C 8H6BrN2 O [ M+H ] +:224.9585, found:224.9556;
Step 2 Synthesis of 7-bromo-2-chloroquinoxaline
7-Bromo-2-chloroquinoxaline of the formula:
7-bromoquinoxaline-2-ol (5.3 mmol) was weighed into a 100mL eggplant-shaped bottle, dissolved with acetonitrile, phosphorus oxychloride (6.9 mmol), DIPEA (10.6 mmol) and NMM (4.24 mmol) were added at 0℃and reacted for 10min under ice bath, after which the reaction was moved to 80℃overnight, TLC monitored the reaction of the starting materials was completed, water and EA (3X 50 mL) were added to the reaction mixture for extraction, anhydrous Na 2SO4 was dried, concentrated under vacuum under reduced pressure to give a yellow oil, and the product was obtained by silica gel column chromatography. White solid, yield 81.13%. HRMS (ESI) calcd.for C 8H5BrClN2 [ M+H ] +:242.9246, found:242.9556;
Step 3 Synthesis of 6- (4 aR,7 aS) - (7-bromoquinoxalin-2-yl) hexahydro-5H- [1,4] dioxin [2,3-c ] pyrrole
6- (4 AR,7 aS) - (7-bromoquinoxalin-2-yl) hexahydro-5H- [1,4] dioxin [2,3-c ] pyrrole has the structural formula:
6-bromo-2-chloro-quinoxaline (3.3 mmol), (4 aR,7 aS) -hexahydro-5H- [1,4] dioxin [2,3-C ] pyrrole (9.9 mmol) and TEA (19.8 mmol) are sequentially added into a 100mL eggplant-shaped bottle, the mixture is dissolved by DMF and reacted overnight at 100 ℃, the TLC monitors the reaction completion of the raw materials, water and EA (3X 50 mL) are added into the reaction mixture for extraction, anhydrous Na 2SO4 is dried, vacuum concentration is carried out under reduced pressure to obtain yellow oily matters, and silica gel column chromatography can obtain the product. Yellow solid, yield ：71.36％.HRMS(ESI)calcd.for C14H15BrN3O2[M+H]+:336.0269,found:336.0278;
Step 4 Synthesis of 5- (3- ((4 aR,7 aS) -hexahydro-6H- [1,4] dioxin [2,3-c ] pyrrol-6-yl) quinoxalin-6-yl) benzo [ d ] oxazol-2-amine
5- (3- ((4 AR,7 aS) -hexahydro-6H- [1,4] dioxin [2,3-c ] pyrrol-6-yl) quinoxalin-6-yl) benzo [ d ] oxazol-2-amine of the formula:
6- (4 aR,7 aS) - (7-Bromoquinoxalin-2-yl) hexahydro-5H- [1,4] dioxin [2,3-C ] pyrrole (8.3 mmol), 5- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzo [ d ] oxazol-2-amine (8.3 mmol), sodium carbonate (24.9 mmol) and tetraphenylphosphine palladium (0.83 mmol) were added sequentially to a 100mL eggplant-shaped bottle, the reaction was replaced with 1, 4-dioxane, nitrogen was replaced, the reaction was refluxed overnight at 100℃and TLC was monitored for the completion of the starting material reaction, nitrogen was removed, water and EA (3X 50 mL) were added to the reaction mixture, dried over anhydrous Na 2SO4, and concentrated under vacuum under reduced pressure to give a yellow oil, which was purified by silica gel column chromatography (DCM: =10:1) to give a yellow solid in 37.29% yield. HRMS (ESI) calcd.for C 21H20N5O3 [ M+H ] +:390.1488, found:390.1489;
EXAMPLE 27 5- (4- ((4 aR,7 aS) -hexahydro-6H- [1,4] dioxy [2,3-c ] pyrrol-6-yl) quinazolin-6-yl) benzo [ d ] oxazol-2-amine having the structural formula:
the synthesis method comprises the following steps:
Step 1 Synthesis of 6-bromoquinazolin-4-ol
Structural formula of 6-bromoquinazolin-4-ol:
The raw material 2-amino-5-bromobenzoic acid (10.0 mmol) is weighed and put into a 250mL eggplant-shaped bottle, acetic acid is added for dissolution, formamidine hydrochloride (10.0 mmol) is added under the condition of stirring, stirring is carried out at 120 ℃, TLC monitoring reaction is finished, naHCO 3 aqueous solution is added for quenching, water and EA (3X 100 mL) are used for extraction, anhydrous Na 2SO4 is dried, vacuum concentration is carried out under reduced pressure to obtain a dark yellow solid, and the dark yellow solid is washed with EA for multiple times to obtain the product. Yellow solid, yield 68.13%. HRMS (ESI) calcd.for C 7H6BrN2 O [ M+H ] +:224.9585, found:224.9588;
step 2 Synthesis of 6-bromo-4-chloroquinazoline
The structural formula of the 6-bromo-4-chloroquinazoline is as follows:
6-bromoquinazolin-4-ol (5.3 mmol) was weighed into a 100mL eggplant-shaped bottle, dissolved in acetonitrile, phosphorus oxychloride (6.9 mmol) was added at 0 ℃, DIPEA (10.6 mmol) and NMM (4.24 mmol) were reacted for 10min under ice bath, then the reaction was carried out at 80 ℃ overnight, TLC monitoring the reaction of the raw materials was completed, water and EA (3X 50 mL) were added to the reaction mixture for extraction, anhydrous Na 2SO4 was dried, and vacuum concentration was carried out under reduced pressure to obtain a yellow oil, and silica gel column chromatography was carried out to obtain the product. White solid, yield 75.68%. HRMS (ESI) calcd.for C 8H5BrClN2 [ M+H ] +:242.9246, found:242.9556;
Step 3 Synthesis of (4 aR,7 aS) -6- (6-bromoquinazolin-4-yl) hexahydro-5H- [1,4] dioxin [2,3-c ] pyrrole
(4 Ar,7 as) -6- (6-bromoquinazolin-4-yl) hexahydro-5H- [1,4] dioxin [2,3-c ] pyrrole of the formula:
6-bromo-4-chloro-quinazoline (3.3 mmol), (4 aR,7 aS) -hexahydro-5H- [1,4] dioxin [2,3-C ] pyrrole (9.9 mmol) and TEA (19.8 mmol) were sequentially added into a 100mL eggplant-shaped bottle, dissolved in DMF and reacted overnight at 100 ℃, TLC monitored the reaction completion of the raw materials, water and EA (3X 50 mL) were added to the reaction mixture for extraction, anhydrous Na 2SO4 was dried, and concentrated under vacuum under reduced pressure to give a yellow oil, which was then chromatographed on silica gel to give the product. White solid, yield ：80.62％.HRMS(ESI)calcd.for C14H15BrN3O2[M+H]+:336.0269,found:336.0278;
Step 4 Synthesis of 5- (4- ((4 aR,7 aS) -hexahydro-6H- [1,4] dioxy [2,3-c ] pyrrol-6-yl) quinazolin-6-yl) benzo [ d ] oxazol-2-amine
5- (4- ((4 Ar,7 as) -hexahydro-6H- [1,4] dioxy [2,3-c ] pyrrol-6-yl) quinazolin-6-yl) benzo [ d ] oxazol-2-amine of the structural formula:
In a 100mL eggplant flask, (4 aR,7 aS) -6- (6-bromoquinazolin-4-yl) hexahydro-5H- [1,4] dioxin [2,3-C ] pyrrole (8.3 mmol), 5- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzo [ d ] oxazol-2-amine (8.3 mmol), sodium carbonate (24.9 mmol) and tetrakis triphenylphosphine palladium (0.83 mmol) were added sequentially, the reaction was replaced with 1, 4-dioxane, nitrogen was replaced, reflux reacted overnight at 100℃and TLC was monitored for the completion of the starting material reaction, nitrogen was removed, water and EA (3X 50 mL) were added to the reaction mixture, dried over anhydrous Na 2SO4, concentrated under vacuum under reduced pressure to give a yellow oil, which was purified by silica gel column chromatography (DCM: =10:1) to give a yellow solid with a yield of 41.04%. HRMS (ESI) calcd.for C 21H20N5O3 [ M+H ] +:390.1488, found:390.1489;
example 28 (S) -2- ((6- (2-aminobenzo [ d ] oxazol-5-yl) quinazolin-4-yl) amino) propanamide having the structural formula:
The synthesis method comprises the steps of replacing the heterocyclic fragment in the step 3 in the example 27 with L-alanyl amide, and obtaining an intermediate in the step 4 as a yellow solid with the yield of 46.47 percent by the other steps and the operation as in the example 27. HRMS (ESI) calcd.for C 18H17N6O2 [ M+H ] +:349.1350, found:349.1378;
example 29 (S) -2- ((7- (2-aminobenzo [ d ] oxazol-5-yl) quinoxalin-2-yl) amino) propanamide of the formula:
The synthesis method comprises the steps of replacing the heterocyclic fragment in the step 3 in the example 26 with L-alanyl amide, and obtaining a yellow solid as a product in the step 4, wherein the yield is 45.47 percent. HRMS (ESI) calcd.for C 18H17N6O2 [ M+H ] +:349.1350, found 349.1398;
EXAMPLE 30- ((6- (2-aminobenzo [ d ] oxazol-5-yl) quinazolin-4-yl) amino) acetamide of the formula:
The synthesis method comprises the steps of replacing heterocyclic fragment in step 3 in the example 27 with glycinamide, and obtaining an intermediate in the step 4 as yellow solid with the yield of 45.47% in other steps and operation as in the example 27. HRMS (ESI) calcd.for C 17H15N6O2 [ M+H ] +:335.1178, found:335.1178;
EXAMPLE 31- ((7- (2-aminobenzo [ d ] oxazol-5-yl) quinoxalin-2-yl) amino) acetamide of the formula:
The synthesis method comprises the steps of replacing the heterocyclic fragment in the step 3 in the example 26 with glycinamide, and obtaining a yellow solid as a product in the step 4, wherein the yield is 42.40 percent. HRMS (ESI) calcd.for C 17H15N6O2 [ M+H ] +:335.1178, found:335.1178;
EXAMPLE 32- ((6- (2-aminobenzo [ d ] oxazol-5-yl) quinoxalin-2-yl) amino) acetamide of the formula:
the synthesis method comprises the steps of replacing heterocyclic fragment in step 3 in the example 24 with glycinamide, and obtaining an intermediate in the step 4 as yellow solid with the yield of 45.90% in other steps and operation as in the example 24. HRMS (ESI) calcd.for C 17H15N6O2 [ M+H ] +:335.1178, found:335.1178.
The beneficial effects and applications of the compound represented by the general formula (I) of the present invention are illustrated by the following experiments.
In vitro PI3K alpha kinase inhibition assay:
The compounds of the invention inhibit PI3K alpha kinase activity, thereby inhibiting transduction of cellular signaling pathways, thereby affecting cell cycle and cell proliferation. The inhibition of PI3K alpha kinase by such compounds was evaluated by the following Lance Ultra fluorescence assay method.
The detection principle is that the Lance Ultra fluorescent test is a homogeneous non-radioactive detection method, and the activity of the purified kinase is quantitatively determined by detecting the ATP content in a kinase reaction system. The ATP content was determined by the light intensity generated after oxidation of firefly luciferin (beetle luciferin) catalyzed by Mg 2+, ATP and oxygen. A certain amount of ATP is added into the reaction system, the Kinase reaction needs to consume ATP, and the rest ATP can react with firefly luciferase in a Kinase Glo reagent to emit light, so that the rest ATP can be quantitatively detected, and the activity of the reaction Kinase can be indirectly measured.
The detection method comprises preparing 1 Xkinase buffer containing 50mM HEPES,PH 7.5,1mM EGTA,0.01%Tween-20, dissolving compound with 100% DMSO, performing gradient dilution, transferring 10nL diluted compound into detection plate, and preparing Control group without compound and blank group without kinase. 1 Xkinase buffer was added to PI3K alpha to prepare kinase solution, and 5. Mu.L was added to the assay plate and vortexed. In addition, 1X kinase reaction buffer containing 4E-BP1 (Thr 37/46, PE) polypeptide and ATP substrate was prepared, 5. Mu.L was added to the well plate for starting reaction, after 1 hour of reaction at room temperature, 10. Mu.L of PBS buffer containing EDTA and Eu-anti-P-4E-BP1 (Thr 37/46, PE) antibody was added to the well plate, incubated at room temperature for 60 minutes, the well plate was read and the inhibition of PI3K alpha kinase by the compound was calculated by statistical data. Substituting the inhibition rate and the corresponding concentration into
The GRAPHPAD PRISM software performs curve fitting to calculate the IC 50 values.
Cell activity assay:
The compound was evaluated for proliferation inhibitory activity on cells by Cell Counting Kit (CCK-8) method, and half inhibitory concentration IC 50 values were determined by single-concentration activity primary screening and multiple concentration.
Cytotoxicity (CCK-8 method) detection principle: the CCK-8 reagent contains WST-8, which is reduced into yellow formazan product (Formazan) with high water solubility by dehydrogenase in cell mitochondria under the action of electron carrier 1-methoxy-5-methylphenazine dimethyl sulfate (1-MethoxyPMS). The amount of formazan produced is proportional to the number of living cells.
The experimental method comprises the following steps:
(1) Cell inoculation the cells were prepared as single cell suspensions with 10% fetal bovine serum in culture, and 90. Mu.L of 5X 10 4/mL adherent cells and 9X 10 4/mL suspension cells were inoculated per well in 96-well plates and pre-cultured at 5% CO 2, 37℃for 24h.
(2) Adding sample solution to be tested, namely adding 10 mu L of sample solution into each hole, setting 1 concentration and 3 compound holes for each sample by an active primary screen, measuring 8 concentrations (containing 0 concentration) by IC50, setting 3 compound holes for each concentration, and culturing for 48 hours in an incubator. Experiments set up Blank (Blank), control and Drug.
(3) Color development, adherent cells aspirate old medium and drug solution (suspension cells were added directly to 10. Mu. LCCK-8 stock solution), 100. Mu. LCCK-8 solution diluted ten times per well was added, and culture was continued at 37℃with 5% CO 2 for 1-4h (operation protected from light, real-time observation).
(4) And (3) detecting, namely measuring absorbance at 450nm by using an enzyme-labeled instrument and recording the original data result.
(5) Raw data normalization was performed using Excel software, and cell proliferation inhibition was calculated by the OD value per well (formula = (ODControl-ODDrug)/(ODControl-ODBlank) ×100%) and was counted. IC 50 was calculated by GraphPadPrism8 (version 8.0.2, graphpadsoftwareinc) and experimental results were expressed as ± SD.
(6) Positive control doxorubicin hydrochloride Doxorubicin (Dox).
As can be seen from the activity data in table 1 below, the compounds of the present invention are effective in inhibiting PI3K alpha kinase, i.e., most of the compounds of PI3K alpha kinase have inhibitory activity (IC 50) at nanomolar level (1-999 nM), and several compounds of the present invention have PI3K alpha inhibitory activity superior to positive control TAK-117, as compared to phase II clinical drug candidate TAK-117, such as example 1, example 2, example 4, example 5, example 8, example 11, example 13, example 14, example 18, example 20, example 21, example 26 and example 27, especially example 9, example 26, example 27, with IC50 values as high as 7.0nM, 2.5nM and 5.5nM, respectively. To further verify the selectivity of compounds for pi3kα, compounds example 9, example 26 and example 27, which were excellent in kinase activity, were selected for PI3K subtype kinase inhibitory activity assays, and the results are shown in table 2, and example 9, example 26 and example 27 each had better selectivity for pi3kα than TAK-117, wherein pi3kα selectivity of example 9 was about 100-fold higher than other subtypes, especially excellent for pi3kβ, pi3kα selectivity of example 26 was about 200-fold higher than other subtypes, and PI3kα selectivity was found for all three subtypes, and example 27 had general selectivity, and activities of four subtypes were comparable. Further selection of compounds excellent in kinase activity example 9 and example 26 for testing cell activity, the antiproliferative activity results are shown in Table 3, which clearly show that compound 26 shows high anticancer activity superior to TAK-117 for all the multiple cancer cells, whereas compound 9 shows only anticancer activity comparable to TAK-117. It is noted that the compounds having high inhibitory activity against PI3K alpha kinase also show high anticancer activity against multiple strains of cancer cells, especially among these cells, MKN-45, HCT116, heLa, K-562, 5637, GBC-SD, MCF-7, hepG2, CAL-62, a-375 and 293, all of which have excellent activity results against TAK-117, especially HepG2 human liver cancer cells, with antiproliferative activity up to 80.32%, about 5-fold better than that of the positive drug TAK-117. The results show that the compound has positive and foreseeable clinical application value of antiproliferative diseases, especially antitumor diseases, and has good development prospect.
TABLE 1 in vitro inhibitory Activity of the target Compounds PI3K alpha kinase
Table 2 Activity of selected Compounds against class I PI3Ks
TABLE 3 antiproliferative activity of target compounds on various cancer cells
Finally, it should be noted that the above embodiments are merely representative examples of the present invention. Obviously, the technical solution of the invention is not limited to the above-described embodiments, but many variations are possible. All modifications directly derived or suggested to one skilled in the art from the present disclosure should be considered as being within the scope of the present invention.
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