CN113004303A - Pyrimido-oxazine tricyclic derivative, preparation method and application thereof in medicine - Google Patents

Pyrimido-oxazine tricyclic derivative, preparation method and application thereof in medicine Download PDF

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Publication number
CN113004303A
CN113004303A CN202011501602.7A CN202011501602A CN113004303A CN 113004303 A CN113004303 A CN 113004303A CN 202011501602 A CN202011501602 A CN 202011501602A CN 113004303 A CN113004303 A CN 113004303A
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group
compound
pharmaceutically acceptable
tautomer
mixture
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李心
陈阳
贺峰
陶伟康
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Jiangsu Hengrui Medicine Co Ltd
Shanghai Hengrui Pharmaceutical Co Ltd
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Jiangsu Hengrui Medicine Co Ltd
Shanghai Hengrui Pharmaceutical Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
    • C07D498/14—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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Abstract

The disclosure relates to pyrimido oxazine tricyclic derivatives, a preparation method thereof and application thereof in medicines. Specifically, the disclosure relates to a pyrimido oxazine tricyclic derivative shown in a general formula (I), a preparation method thereof, a pharmaceutical composition containing the derivative, and application of the derivative as a therapeutic agent, especially application of the derivative as an ATR kinase inhibitor and application of the derivative in preparation of drugs for treating or preventing hyperproliferative diseases.

Description

Pyrimido-oxazine tricyclic derivative, preparation method and application thereof in medicine
Technical Field
The disclosure belongs to the field of medicine, and relates to a pyrimido-oxazine tricyclic derivative shown in a general formula (I), a preparation method thereof, a pharmaceutical composition containing the derivative, and application of the derivative as a therapeutic agent, in particular application of the derivative as an ATR kinase inhibitor and application of the derivative in preparation of drugs for treating and preventing hyperproliferative diseases.
Background
DNA damage occurs millions of times a day, both in normal and tumor cells. This makes DNA damage repair a crucial role in maintaining genomic stability and cell survival. Tumor cells are subject to greater replicative stress, carry more endogenous DNA damage, and often suffer from the loss of one or more DNA damage repair pathways compared to normal cells. This makes the survival of tumor cells more dependent on the successful repair of DNA damage.
Homologous recombination repair is the main repair mode of DNA double-strand break, and takes the homologous sequence of undamaged sister chromatids as a template for repair to copy the DNA sequence at the damaged part, thereby precisely repairing the DNA. This repair occurs primarily in the G2 and S phases of the cell. ATR is a key enzyme in the homologous recombination repair pathway and belongs to the PIKK family. When ATR/ATRIP complex binds to damaged DNA covered by Replication Protein A (RPA), ATR is activated and regulates various cell cycle checkpoints by phosphorylating downstream proteins Chk1 and SMARCAL, etc., causing cell cycle arrest; ensuring the stability of damaged DNA; the dNTP concentration is increased, and the DNA damage is promoted to be repaired. Repair of DNA damage occurring during the S phase of the cell cycle is mainly accomplished by the ATR pathway, suggesting that ATR is important to ensure cell proliferation. Analysis of clinical tumor samples shows that elevated ATR expression levels are observed in a variety of tumor tissues, such as gastric cancer, liver cancer, colorectal cancer, ovarian cancer, pancreatic cancer, and the like. And in ovarian, pancreatic cancer patients, high levels of ATR tend to be associated with lower survival rates. It follows that ATR is an important target for tumor therapy.
Patent applications for ATR inhibitors that have been disclosed include WO2010071837, WO2011154737, WO2016020320, WO2016130581, WO2017121684, WO2017118734, WO2018049400, WO2019050889, and WO2014140644, among others.
Disclosure of Invention
The purpose of the present disclosure is to provide a compound represented by the general formula (I), or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof:
Figure BDA0002843765200000021
wherein:
R1is heteroaryl or heterocyclyl; wherein said heteroaryl and heterocyclyl are optionally substituted with one or more substituents selected from the group consisting of hydrogen, halogen, alkyl, alkenyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, cyano, -NR8R9and-SO2R10Is substituted with one or more substituents of (1);
R2selected from-SO (NH) R5Or cyano;
R3and R4Are the same or different and are each independently selected from the group consisting of a hydrogen atom, an alkyl group, a haloalkyl group, and a hydroxyalkyl group;
or R3And R4Together with the carbon atom to which they are attached form a cycloalkyl or heterocyclyl group;
R5selected from the group consisting of alkyl, haloalkyl, and hydroxyalkyl;
R8and R9Are the same or different and are each independently selected from the group consisting of a hydrogen atom, an alkyl group, a haloalkyl group, a cycloalkyl group, and a heterocyclic group;
R10selected from the group consisting of alkyl, cycloalkyl, heterocyclyl and aryl.
In some preferred embodiments of the present disclosure, the compound of formula (I), or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereofForm or a pharmaceutically acceptable salt thereof, wherein R3And R4Are the same or different and are each independently selected from the group consisting of alkyl, haloalkyl, and hydroxyalkyl; or R3And R4Together with the carbon atom to which they are attached form a cycloalkyl or heterocyclyl group.
In some preferred embodiments of the present disclosure, the compound represented by the general formula (I), or a tautomer, a meso form, a racemate, an enantiomer, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, is a compound represented by the general formula (II) or the general formula (III), or a tautomer, a meso form, a racemate, an enantiomer, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof:
Figure BDA0002843765200000022
wherein:
R1、R3and R4As defined in formula (I).
In some preferred embodiments of the present disclosure, the compound represented by the general formula (I), or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, is a compound represented by the general formula (II'), or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof:
Figure BDA0002843765200000031
wherein:
R1、R3-R5as defined in formula (I).
In some embodiments of the present disclosure, the compound of formula (I) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereofSalt of formula (I), wherein R1Is composed of
Figure BDA0002843765200000032
R6And R7The same or different and each is independently selected from the group consisting of hydrogen atom, halogen, alkyl, alkenyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, cyano, -NR8R9and-SO2R10(ii) a n is 0,1, 2,3 or 4; s is 0,1, 2 or 3; r8、R9And R10As defined in formula (I).
In some embodiments of the disclosure, the compound of formula (I) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R is1Is composed of
Figure BDA0002843765200000033
R6The same or different and each is independently selected from the group consisting of hydrogen atom, halogen, alkyl, alkenyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, cyano, -NR8R9and-SO2R10(ii) a n is 0,1, 2,3 or 4; r8、R9And R10As defined in formula (I).
In some preferred embodiments of the present disclosure, the compound represented by formula (I), or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, is a compound represented by formula (IIaa) or formula (IIIaa), or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof:
Figure BDA0002843765200000041
wherein:
R6selected from hydrogen atom, halogen, alkyl, alkenyl, alkoxyHaloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, cyano, -NR8R9and-SO2R10；
R3、R4、R8～R10And n is as defined in formula (I).
In some embodiments of the disclosure, the compound of formula (I) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R is3And R4Identical or different, each being a hydrogen atom or an alkyl group, preferably an alkyl group, more preferably a methyl group; or R3And R4Together with the carbon atom to which they are attached form a 3 to 6 membered cycloalkyl group, preferably cyclopropyl.
In some embodiments of the disclosure, the compound of formula (I) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R is5Selected from alkyl groups, preferably methyl or ethyl groups.
Typical compounds of the present disclosure include, but are not limited to:
Figure BDA0002843765200000042
Figure BDA0002843765200000051
Figure BDA0002843765200000061
Figure BDA0002843765200000071
or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof.
Another aspect of the present disclosure relates to compounds of formula (IA) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof,
Figure BDA0002843765200000072
wherein:
x is halogen; preferably Cl;
R2selected from-SO (NH) R5Or cyano;
R3and R4Are the same or different and are each independently selected from the group consisting of a hydrogen atom, an alkyl group, a haloalkyl group, and a hydroxyalkyl group;
or R3And R4Together with the carbon atom to which they are attached form a cycloalkyl or heterocyclyl group;
R5selected from the group consisting of alkyl, haloalkyl, and hydroxyalkyl.
Another aspect of the present disclosure relates to compounds of formula (IA) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R is3And R4Are the same or different and are each independently selected from the group consisting of alkyl, haloalkyl, and hydroxyalkyl; or R3And R4Together with the carbon atom to which they are attached form a cycloalkyl or heterocyclyl group.
Another aspect of the present disclosure relates to a compound of formula (IIA) or formula (IIIA) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof,
Figure BDA0002843765200000081
wherein:
x is halogen; preferably Cl;
R3and R4As defined in formula (I).
Another aspect of the present disclosure relates to a compound of formula (II' A) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof,
Figure BDA0002843765200000082
wherein:
x is halogen; preferably Cl;
R3-R5as defined in formula (II').
Typical intermediate compounds of the present disclosure include, but are not limited to:
Figure BDA0002843765200000083
Figure BDA0002843765200000091
another aspect of the present disclosure relates to a process for preparing a compound of formula (I), or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, comprising:
Figure BDA0002843765200000092
compounds of the general formula (IA) and R1-M is subjected to a coupling reaction to obtain a compound of general formula (I),
wherein:
x is halogen; preferably Cl;
m is
Figure BDA0002843765200000101
R1～R4As defined in formula (I).
Another aspect of the present disclosure relates to a method of preparing a compound of formula (II), or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, comprising:
Figure BDA0002843765200000102
a compound of the formula (IIA) and R1-M is subjected to a coupling reaction to obtain a compound of formula (II),
wherein:
x is halogen; preferably Cl;
m is
Figure BDA0002843765200000103
R1、R3And R4As defined in formula (II).
Another aspect of the present disclosure relates to a method of preparing a compound of formula (II'), or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, comprising:
Figure BDA0002843765200000104
compounds of the formula (II' A) and R1-M is subjected to a coupling reaction to give a compound of formula (II'),
wherein:
x is halogen; preferably Cl;
m is
Figure BDA0002843765200000105
R1、R3-R5As defined in formula (II').
Another aspect of the present disclosure relates to a method of preparing a compound of formula (III), or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, comprising:
Figure BDA0002843765200000111
a compound of the formula (IIIA) and R1-M is subjected to a coupling reaction to obtain a compound of formula (III),
wherein:
x is halogen; preferably Cl;
m is
Figure BDA0002843765200000112
R1、R3And R4As defined in formula (III).
Another aspect of the present disclosure relates to a method of preparing a compound of formula (IIaa), or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, comprising:
Figure BDA0002843765200000113
carrying out coupling reaction on the compound of the general formula (IIA) and the compound of the general formula (IIB) to obtain a compound of the general formula (IIaa),
wherein:
x is halogen; preferably Cl;
m is
Figure BDA0002843765200000114
R3、R4、R6And n is as defined in formula (IIaa).
Another aspect of the present disclosure relates to a method of preparing a compound of formula (IIIaa), or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, comprising:
Figure BDA0002843765200000121
the compound of the general formula (IIIA) and the compound of the general formula (IIB) are subjected to coupling reaction to obtain the compound of the general formula (IIIaa),
wherein:
x is halogen; preferably Cl;
m is
Figure BDA0002843765200000122
R3、R4、R6And n is as defined in formula (IIIaa).
Another aspect of the present disclosure relates to a pharmaceutical composition comprising a compound of formula (I) of the present disclosure, or a tautomer, mesomer, racemate, enantiomer, or diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents, or excipients.
The disclosure further relates to the use of a compound of formula (I) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, in the manufacture of a medicament for inhibiting ATR kinase.
The present disclosure further relates to the use of a compound of formula (I) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for the manufacture of a medicament for the treatment or prevention of a hyperproliferative disease.
The disclosure further relates to the use of a compound of formula (I) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for the preparation of a medicament for the treatment or prevention of a tumor.
The disclosure further relates to the use of a compound of formula (I) or a tautomer, mesomer, racemate, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for the preparation of a medicament for the treatment of a tumor.
The present disclosure also relates to a method of inhibiting ATR kinase comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.
The present disclosure also relates to a method for treating or preventing hyperproliferative diseases, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I) or a tautomer, mesomer, racemate, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.
The present disclosure also relates to a method for treating or preventing a tumor, which comprises administering to a patient in need thereof a therapeutically effective amount of a compound represented by the general formula (I) or a tautomer, mesomer, racemate, enantiomer, or diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.
The present disclosure further relates to a compound of general formula (I) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for use as a medicament.
The present disclosure also relates to compounds of formula (I) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for use as an ATR kinase inhibitor.
The present disclosure also relates to a compound represented by the general formula (I) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for use in the treatment or prevention of a hyperproliferative disease.
The present disclosure further relates to compounds of general formula (I) or a tautomer, mesomer, racemate, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for use in the treatment of a tumor.
The tumor described in the present disclosure is selected from melanoma, brain tumor, esophageal cancer, gastric cancer, liver cancer, pancreatic cancer, colorectal cancer, lung cancer, kidney cancer, breast cancer, cervical cancer, ovarian cancer, prostate cancer, skin cancer, neuroblastoma, glioma, sarcoma, bone cancer, uterine cancer, endometrial cancer, head and neck tumor, multiple myeloma, B-cell lymphoma, polycythemia vera, leukemia, thyroid tumor, bladder cancer, and gallbladder cancer.
The active compound may be formulated so as to be suitable for administration by any suitable route, preferably in unit dose form, or in such a way that the patient may self-administer it in a single dose. The unit dose of a compound or composition of the present disclosure may be expressed in the form of a tablet, capsule, cachet, bottled liquid, powder, granule, lozenge, suppository, reconstituted powder, or liquid.
The dosage of the compound or composition used in the treatment methods of the present disclosure will generally vary with the severity of the disease, the weight of the patient, and the relative efficacy of the compound. However, as a general guide, a suitable unit dose may be 0.1 to 1000 mg.
The pharmaceutical compositions of the present disclosure may contain, in addition to the active compound, one or more excipients selected from the following: fillers (diluents), binders, wetting agents, disintegrants, excipients, and the like. Depending on the method of administration, the compositions may contain from 0.1 to 99% by weight of active compound.
The pharmaceutical compositions containing the active ingredient may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. Oral compositions may be prepared according to any method known in the art for preparing pharmaceutical compositions, and such compositions may contain one or more ingredients selected from the group consisting of: sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide a pleasant to the eye and palatable pharmaceutical preparation. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients may be inert excipients, granulating agents, disintegrating agents, binding agents and lubricating agents. These tablets may be uncoated or they may be coated by known techniques which mask the taste of the drug or delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.
Oral formulations may also be provided in soft gelatin capsules wherein the active ingredient is mixed with an inert solid diluent or wherein the active ingredient is mixed with a water soluble carrier or an oil vehicle.
Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending, dispersing or wetting agents. Aqueous suspensions may also contain one or more preservatives, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents.
Oil suspensions may be formulated by suspending the active ingredient in a vegetable oil, or in a mineral oil. The oil suspension may contain a thickener. Sweetening agents such as those set forth above, and flavoring agents may be added to provide a palatable preparation. These compositions can be preserved by the addition of antioxidants.
Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent or one or more preservatives. Suitable dispersing or wetting agents and suspending agents are illustrative of the examples given above. Other excipients, for example sweetening, flavoring and coloring agents, may also be present. These compositions are preserved by the addition of an antioxidant such as ascorbic acid.
The pharmaceutical compositions of the present disclosure may also be in the form of oil-in-water emulsions. The oily phase may be a vegetable oil, or a mineral oil or a mixture thereof. Suitable emulsifiers may be naturally occurring phospholipids, and the emulsions may also contain sweetening, flavoring, preservative and antioxidant agents. Such formulations may also contain a demulcent, a preservative, a colorant and an antioxidant.
The pharmaceutical compositions of the present disclosure may be in the form of a sterile injectable aqueous solution. Among the acceptable vehicles or solvents that may be employed are water, ringer's solution and isotonic sodium chloride solution. The sterile injectable preparation may be a sterile injectable oil-in-water microemulsion in which the active ingredient is dissolved in an oil phase, and the injection or microemulsion may be injected into the bloodstream of a patient by local mass injection. Alternatively, it may be desirable to administer the solution and microemulsion in a manner that maintains a constant circulating concentration of the disclosed compounds. To maintain such a constant concentration, a continuous intravenous delivery device may be used. An example of such a device is an intravenous pump model Deltec CADD-PLUS. TM.5400.
The pharmaceutical compositions of the present disclosure may be in the form of sterile injectable aqueous or oleaginous suspensions for intramuscular and subcutaneous administration. The suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a parenterally-acceptable, non-toxic diluent or solvent. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. Any blend fixed oil may be used for this purpose. In addition, fatty acids can also be prepared into injections.
The compounds of the present disclosure may be administered in the form of suppositories for rectal administration. These pharmaceutical compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid in the rectum and therefore will melt in the rectum to release the drug.
As is well known to those skilled in the art, the dosage of a drug administered depends on a variety of factors, including, but not limited to: the activity of the particular compound employed, the age of the patient, the weight of the patient, the health condition of the patient, the behavior of the patient, the diet of the patient, the time of administration, the mode of administration, the rate of excretion, the combination of drugs, and the like; in addition, the optimal treatment regimen, such as the mode of treatment, the daily amount of compound (I) of the formula or the type of pharmaceutically acceptable salt, can be verified according to conventional treatment protocols.
The present disclosure provides a novel structure of ATR inhibitor having high ATR selectivity and good solubility characteristics.
Detailed description of the invention
Unless stated to the contrary, terms used in the specification and claims have the following meanings.
The term "alkyl" refers to a saturated aliphatic hydrocarbon group which is a straight or branched chain group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 12 (e.g., 1,2, 3,4, 5, 6, 7, 8, 9,10, 11, and 12) carbon atoms, more preferably an alkyl group containing 1 to 6 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1-dimethylpropyl, 1, 2-dimethylpropyl, 2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1, 2-trimethylpropyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2, 3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2, 3-dimethylpentyl, 2, 4-dimethylpentyl, 2-dimethylpentyl, 3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2, 3-dimethylhexyl, 2, 4-dimethylhexyl, 2, 5-dimethylhexyl, 2-dimethylhexyl, 3-dimethylhexyl, 4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2-dimethylpentyl, 2-dimethylhexyl, 3-dimethylpentyl, 2-ethylhexyl, 3-dimethylhexyl, 2, 2-diethylpentyl, n-decyl, 3-diethylhexyl, 2-diethylhexyl, and various branched isomers thereof. More preferred are lower alkyl groups having 1 to 6 carbon atoms, non-limiting examples of which include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1-dimethylpropyl, 1, 2-dimethylpropyl, 2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1, 2-trimethylpropyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2, 3-dimethylbutyl and the like. The alkyl group may be substituted or unsubstituted, and when substituted, the substituents may be substituted at any available point of attachment, preferably independently with one or more substituents optionally selected from H atoms, D atoms, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl.
The term "alkylene" refers to a saturated straight or branched chain aliphatic hydrocarbon group having 2 residues derived from the parent alkane by removal of two hydrogen atoms from the same carbon atom or two different carbon atoms, and is a straight or branched chain group containing 1 to 20 carbon atoms, preferably 1 to 12 (e.g., 1,2, 3,4, 5, 6, 7, 8, 9,10, 11, and 12) carbon atoms, more preferably an alkylene group containing 1 to 6 carbon atoms. Non-limiting examples of alkylene groups include, but are not limited to, methylene (-CH)2-), 1-ethylidene (-CH (CH)3) -), 1, 2-ethylene (-CH)2CH2) -, 1-propylene (-CH (CH)2CH3) -), 1, 2-propylene (-CH)2CH(CH3) -), 1, 3-propylene (-CH)2CH2CH2-) 1, 4-butylene (-CH2CH2CH2CH2-) and the like. The alkylene groups may be substituted or unsubstituted, and when substituted, substituents may be substituted at any available point of attachment, said substituents preferably being independently optionally selected from alkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, cycloalkyloxy, heterocyclyloxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocycleOne or more substituents of alkoxy, cycloalkylthio, heterocycloalkylthio and oxo.
The term "alkenyl" refers to an alkyl compound containing a carbon-carbon double bond in the molecule, wherein alkyl is as defined above. The alkenyl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more substituents independently selected from one or more of hydrogen atom, alkyl group, alkoxy group, halogen, haloalkyl group, haloalkoxy group, cycloalkyloxy group, heterocyclyloxy group, hydroxyl group, hydroxyalkyl group, cyano group, amino group, nitro group, cycloalkyl group, heterocyclyl group, aryl group and heteroaryl group.
The term "alkynyl" refers to an alkyl compound containing a carbon-carbon triple bond in the molecule, wherein alkyl is as defined above. The alkynyl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more substituents independently selected from one or more of hydrogen atom, alkyl group, alkoxy group, halogen, haloalkyl group, haloalkoxy group, cycloalkyloxy group, heterocyclyloxy group, hydroxyl group, hydroxyalkyl group, cyano group, amino group, nitro group, cycloalkyl group, heterocyclyl group, aryl group and heteroaryl group.
The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, the cycloalkyl ring containing from 3 to 20 carbon atoms, preferably from 3 to 12 carbon atoms, more preferably from 3 to 8 (e.g., 3,4, 5, 6, 7, and 8) carbon atoms, more preferably from 3 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, and the like; polycyclic cycloalkyl groups include spiro, fused and bridged cycloalkyl groups.
The term "spirocycloalkyl" refers to a 5 to 20 membered polycyclic group sharing one carbon atom (referred to as a spiro atom) between monocyclic rings, which may contain one or more double bonds. Preferably 6 to 14, more preferably 7 to 10 (e.g.7, 8, 9 or 10). Spirocycloalkyl groups are classified into a single spirocycloalkyl group, a double spirocycloalkyl group or a multi spirocycloalkyl group, preferably a single spirocycloalkyl group and a double spirocycloalkyl group, according to the number of spiro atoms shared between rings. More preferably 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered or 5-membered/6-membered. Non-limiting examples of spirocycloalkyl groups include:
Figure BDA0002843765200000161
the term "fused cyclic alkyl" refers to a 5 to 20 membered all carbon polycyclic group in which each ring in the system shares an adjacent pair of carbon atoms with other rings in the system, wherein one or more of the rings may contain one or more double bonds. Preferably 6 to 14, more preferably 7 to 10. (e.g., 7-, 8-, 9-or 10-membered) may be classified into bicyclic, tricyclic, tetracyclic or polycyclic fused-ring alkyls, preferably bicyclic or tricyclic, more preferably 3-membered/4-membered, 3-membered/5-membered, 3-membered/6-membered, 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/4-membered, 5-membered/5-membered, 5-membered/6-membered, 6-membered/3-membered, 6-membered/4-membered, 6-membered/5-membered and 6-membered/6-membered bicycloalkyl groups, depending on the number of constituent rings. Non-limiting examples of fused ring alkyl groups include:
Figure BDA0002843765200000171
the term "bridged cycloalkyl" refers to a 5 to 20 membered all carbon polycyclic group in which any two rings share two carbon atoms not directly attached, which may contain one or more double bonds. Preferably 6 to 14, more preferably 7 to 10 (e.g.7, 8, 9 or 10). They may be classified into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl groups according to the number of constituent rings, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of bridged cycloalkyl groups include:
Figure BDA0002843765200000172
the cycloalkyl ring includes a cycloalkyl ring (including monocyclic, spiro, fused and bridged rings) fused to an aryl, heteroaryl or heterocycloalkyl ring as described above, wherein the rings attached to the parent structure are cycloalkyl, non-limiting examples of which include indanyl, tetrahydronaphthyl, benzocycloheptanyl, and the like; indanyl and tetrahydronaphthyl are preferred.
Cycloalkyl groups may be substituted or unsubstituted, and when substituted, substituents may be substituted at any available point of attachment, preferably independently with one or more substituents optionally selected from hydrogen, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl.
The term "alkoxy" refers to-O- (alkyl) and-O- (unsubstituted cycloalkyl), wherein alkyl and cycloalkyl are as defined above. Non-limiting examples of alkoxy groups include: methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy. Alkoxy groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from H atoms, D atoms, halogens, alkyl groups, alkoxy groups, haloalkyl groups, haloalkoxy groups, cycloalkyloxy groups, heterocyclyloxy groups, hydroxy groups, hydroxyalkyl groups, cyano groups, amino groups, nitro groups, cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups.
The term "heterocyclyl" refers to a saturated or partially unsaturated mono-or polycyclic cyclic hydrocarbon substituent containing from 3 to 20 ring atoms wherein one or more of the ring atoms is selected from nitrogen, oxygen, or S (O)m(wherein m is an integer from 0 to 2) but excludes the ring moiety of-O-O-, -O-S-, or-S-S-, the remaining ring atoms being carbon. Preferably 3 to 12 (e.g., 3,4, 5, 6, 7, 8, 9,10, 11 and 12) ring atoms, of which 1 to 4 (e.g., 1,2, 3 and 4) are heteroatoms; more preferably from 3 to 8 (e.g., 3,4, 5, 6, 7 and 8) ring atoms, of which 1-3 (e.g., 1,2 and 3) are heteroatoms; more preferably 3 to 6 ring atoms, of which 1-3 are heteroatoms; most preferably 5 or 6 ring atoms, of which 1 to 3 are heteroatoms. Non-limiting examples of monocyclic heterocyclyl groups include pyrrolidinyl, tetrahydropyranyl, 1, 2.3.6-tetrahydropyridinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, and the like. Polycyclic heterocyclic radicalsHeterocyclic groups including spiro rings, fused rings, and bridged rings.
The term "spiroheterocyclyl" refers to a 5-to 20-membered polycyclic heterocyclic group in which one atom (referred to as the spiro atom) is shared between monocyclic rings, and in which one or more ring atoms is selected from nitrogen, oxygen, or S (O)m(wherein m is an integer of 0 to 2) and the remaining ring atoms are carbon. It may contain one or more double bonds. Preferably 6 to 14, more preferably 7 to 10 (e.g.7, 8, 9 or 10). The spiro heterocyclic group is classified into a mono-spiro heterocyclic group, a di-spiro heterocyclic group or a multi-spiro heterocyclic group, preferably a mono-spiro heterocyclic group and a di-spiro heterocyclic group, according to the number of spiro atoms shared between rings. More preferred are 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered or 5-membered/6-membered mono spiroheterocyclic groups. Non-limiting examples of spiro heterocyclic groups include:
Figure BDA0002843765200000181
the term "fused heterocyclyl" refers to 5 to 20 membered polycyclic heterocyclic groups in which each ring in the system shares an adjacent pair of atoms with the other rings in the system, one or more of the rings may contain one or more double bonds in which one or more of the ring atoms is selected from nitrogen, oxygen or S (O)m(wherein m is an integer of 0 to 2) and the remaining ring atoms are carbon. Preferably 6 to 14, more preferably 7 to 10 (e.g.7, 8, 9 or 10). They may be classified into bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic groups according to the number of constituting rings, preferably bicyclic or tricyclic, more preferably 3-membered/4-membered, 3-membered/5-membered, 3-membered/6-membered, 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/4-membered, 5-membered/5-membered, 5-membered/6-membered, 6-membered/3-membered, 6-membered/4-membered, 6-membered/5-membered and 6-membered/6-membered bicyclic fused heterocyclic groups. Non-limiting examples of fused heterocyclic groups include:
Figure BDA0002843765200000182
Figure BDA0002843765200000191
the term "bridged heterocyclyl" refers to a 5 to 14 membered polycyclic heterocyclic group in which any two rings share two atoms which are not directly attached, which may contain one or more double bonds in which one or more ring atoms is selected from nitrogen, oxygen or S (O)m(wherein m is an integer of 0 to 2) and the remaining ring atoms are carbon. Preferably 6 to 14, more preferably 7 to 10 (e.g.7, 8, 9 or 10). They may be classified into bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclic groups according to the number of constituent rings, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of bridged heterocyclic groups include:
Figure BDA0002843765200000192
the heterocyclyl ring includes a heterocyclyl (including monocyclic, spiroheterocyclic, fused heterocyclic and bridged heterocyclic) fused to an aryl, heteroaryl or cycloalkyl ring as described above, wherein the ring to which the parent structure is attached is a heterocyclyl, non-limiting examples of which include:
Figure BDA0002843765200000193
the heterocyclyl group may be substituted or unsubstituted and when substituted, the substituents may be substituted at any available point of attachment, preferably the substituents are independently optionally one or more substituents selected from hydrogen, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl.
The term "aryl" refers to a 6 to 14 membered all carbon monocyclic or fused polycyclic (fused polycyclic is a ring sharing adjacent pairs of carbon atoms) group having a conjugated pi-electron system, preferably 6 to 10 membered, such as phenyl and naphthyl. Such aryl rings include those wherein the aryl ring as described above is fused to a heteroaryl, heterocyclyl or cycloalkyl ring, wherein the ring attached to the parent structure is an aryl ring, non-limiting examples of which include:
Figure BDA0002843765200000194
Figure BDA0002843765200000201
aryl groups may be substituted or unsubstituted, and when substituted, the substituents may be substituted at any available point of attachment, preferably independently with one or more substituents optionally selected from hydrogen, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl.
The term "heteroaryl" refers to a heteroaromatic system comprising 1 to 4 (e.g., 1,2, 3, and 4) heteroatoms, 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur, and nitrogen. Heteroaryl is preferably 5 to 10 membered (e.g. 5, 6, 7, 8, 9 or 10 membered), more preferably 5 or 6 membered, e.g. furyl, thienyl, pyridyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl and the like. The heteroaryl ring includes a heteroaryl fused to an aryl, heterocyclyl or cycloalkyl ring as described above, wherein the ring joined together with the parent structure is a heteroaryl ring, non-limiting examples of which include:
Figure BDA0002843765200000202
heteroaryl groups may be substituted or unsubstituted, and when substituted, substituents may be substituted at any available point of attachment, preferably independently with one or more substituents optionally selected from hydrogen, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl.
The above-mentioned cycloalkyl, heterocyclyl, aryl and heteroaryl groups have 1 residue derived from the parent ring atom by removal of one hydrogen atom, or2 residues derived from the parent ring atom by removal of two hydrogen atoms from the same or two different ring atoms, i.e., "divalent cycloalkyl", "divalent heterocyclyl", "arylene", "heteroarylene".
The term "amino protecting group" is intended to protect an amino group with a group that can be easily removed in order to keep the amino group unchanged when the rest of the molecule is subjected to a reaction. Non-limiting examples include tetrahydropyranyl, t-butyloxycarbonyl, acetyl, benzyl, allyl, and p-methoxybenzyl, and the like. These groups may be optionally substituted with 1 to 3 substituents selected from halogen, alkoxy or nitro.
The term "cycloalkyloxy" refers to cycloalkyl-O-wherein cycloalkyl is as defined above.
The term "heterocyclyloxy" refers to heterocyclyl-O-, wherein heterocyclyl is as defined above.
The term "alkylthio" refers to an alkyl-S-group wherein alkyl is as defined above. The term "haloalkyl" refers to an alkyl group substituted with one or more halogens, wherein alkyl is as defined above.
The term "haloalkoxy" refers to an alkoxy group substituted with one or more halogens, wherein the alkoxy group is as defined above.
The term "deuterated alkyl" refers to an alkyl group substituted with one or more deuterium atoms, wherein alkyl is as defined above.
The term "hydroxy" refers to an-OH group.
The term "mercapto" refers to-SH.
The term "hydroxyalkyl" refers to an alkyl group substituted with one or more hydroxyl groups, wherein alkyl is as defined above.
The term "halogen" refers to fluorine, chlorine, bromine or iodine.
The term "amino" refers to the group-NH2。
The term "cyano" refers to — CN.
The term "nitro" means-NO2。
The term "carbonyl" refers to C ═ O.
The term "oxo" refers to "═ O".
The term "carboxy" refers to-C (O) OH.
The term "carboxylate" refers to-C (O) O (alkyl), -C (O) O (cycloalkyl), (alkyl) C (O) O-or (cycloalkyl) C (O) O-, wherein alkyl and cycloalkyl are as defined above.
The compounds of the present disclosure include isotopic derivatives thereof. The term "isotopic derivative" refers to a compound that differs in structure only in the presence of one or more isotopically enriched atoms. For example, having the structure of the present disclosure, replacing hydrogen with "deuterium" or "tritium", or18F-fluorine labeling: (18Isotope of F) instead of fluorine, or with11C-，13C-, or14C-enriched carbon (C11C-，13C-, or14C-carbon labeling;11C-，13c-, or14C-isotopes) instead of carbon atoms are within the scope of the present disclosure. Such compounds are useful as analytical tools or probes in, for example, biological assays, or as tracers for in vivo diagnostic imaging of disease, or as tracers for pharmacodynamic, pharmacokinetic or receptor studies.
The present disclosure also includes various deuterated forms of the compounds of formula (I) meaning that each available hydrogen atom attached to a carbon atom can be independently replaced by a deuterium atom. The person skilled in the art is able to synthesize the deuterated forms of the compounds of the formula (I) with reference to the relevant literature. Commercially available deuterated starting materials can be used in preparing the deuterated forms of the compounds of formula (I), or they can be synthesized using conventional techniques using deuterated reagents including, but not limited to, deuterated boranes, trideuteroborane tetrahydrofuran solutions, deuterated lithium aluminum hydrides, deuterated iodoethanes, deuterated iodomethanes, and the like. Deuterations can generally retain activity comparable to non-deuterated compounds and can achieve better metabolic stability when deuterated at certain specific sites, thereby achieving certain therapeutic advantages.
"optional" or "optionally" means that the subsequently described event or circumstance may, but need not, occur, and that the description includes instances where the event or circumstance occurs or does not. For example, "a heterocyclic group optionally substituted with an alkyl" means that an alkyl may, but need not, be present, and the description includes the case where the heterocyclic group is substituted with an alkyl and the heterocyclic group is not substituted with an alkyl.
"substituted" means that one or more, preferably 1 to 5, more preferably 1 to 3, hydrogen atoms in the group are independently substituted with a corresponding number of substituents. Those skilled in the art are able to ascertain (by experiment or theory) without undue effort, substitutions that are possible or impossible. For example, amino or hydroxyl groups having free hydrogen may be unstable in combination with carbon atoms having unsaturated (e.g., olefinic) bonds.
"pharmaceutical composition" means a mixture containing one or more compounds described herein or a physiologically/pharmaceutically acceptable salt or prodrug thereof in admixture with other chemical components, as well as other components such as physiologically/pharmaceutically acceptable carriers and excipients. The purpose of the pharmaceutical composition is to facilitate administration to an organism, facilitate absorption of the active ingredient and exert biological activity.
"pharmaceutically acceptable salts" refers to salts of the disclosed compounds which are safe and effective for use in the body of a mammal and which possess the requisite biological activity. Salts may be prepared separately during the final isolation and purification of the compound, or by reacting the appropriate group with an appropriate base or acid. Bases commonly used to form pharmaceutically acceptable salts include inorganic bases such as sodium hydroxide and potassium hydroxide, and organic bases such as ammonia. Acids commonly used to form pharmaceutically acceptable salts include inorganic acids as well as organic acids.
The term "therapeutically effective amount" with respect to a drug or pharmacologically active agent refers to a sufficient amount of the drug or agent that is non-toxic but achieves the desired effect. The determination of an effective amount varies from person to person, depending on the age and general condition of the recipient and also on the particular active substance, and an appropriate effective amount in an individual case can be determined by a person skilled in the art according to routine tests.
The term "solvate" as used herein refers to a physical association of a compound of the present disclosure with one or more, preferably 1-3, solvent molecules, whether organic or inorganic. The physical bonding includes hydrogen bonding. In some cases, for example, when one or more, preferably 1-3, solvent molecules are incorporated into the crystal lattice of a crystalline solid, the solvate will be isolated. Exemplary solvates include, but are not limited to, hydrates, ethanolates, methanolates, and isopropanolates. Solvation methods are well known in the art.
By "prodrug" is meant a compound that can be converted in vivo under physiological conditions, for example, by hydrolysis in blood, to yield the active parent compound.
The term "pharmaceutically acceptable" as used herein refers to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of patients without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio, and effective for the intended use.
As used herein, the singular forms "a", "an" and "the" include plural references and vice versa unless the context clearly dictates otherwise.
When the term "about" is applied to a parameter such as pH, concentration, temperature, etc., it is meant that the parameter may vary by ± 10%, and sometimes more preferably within ± 5%. As will be appreciated by those skilled in the art, when the parameters are not critical, the numbers are generally given for illustrative purposes only and are not limiting.
Synthesis of the Compounds of the disclosure
In order to achieve the purpose of the present disclosure, the present disclosure adopts the following technical solutions:
scheme one
The preparation method of the compound shown in the general formula (I) or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer or a mixture thereof or a pharmaceutically acceptable salt thereof comprises the following steps:
Figure BDA0002843765200000231
compounds of the general formula (IA) and R1-M, in the presence of a catalyst, under alkaline conditions, to give a compound of general formula (I),
wherein:
x is halogen; preferably Cl;
m is
Figure BDA0002843765200000232
R1～R4As defined in formula (I).
Scheme two
The preparation method of the compound shown in the general formula (II) or the tautomer, the mesomer, the racemate, the enantiomer, the diastereomer or the mixture form or the pharmaceutically acceptable salt form comprises the following steps:
Figure BDA0002843765200000233
a compound of the formula (IIA) and R1-M, in the presence of a catalyst, under alkaline conditions, to give a compound of general formula (II),
wherein:
x is halogen; preferably Cl;
m is
Figure BDA0002843765200000241
R1、R3And R4As defined in formula (II).
Scheme three
The preparation method of the compound shown in the general formula (III) or the tautomer, the mesomer, the racemate, the enantiomer, the diastereomer or the mixture form or the pharmaceutically acceptable salt form comprises the following steps:
Figure BDA0002843765200000242
a compound of the formula (IIIA) and R1-M, in the presence of a catalyst, under alkaline conditions, to give a compound of general formula (III),
wherein:
x is halogen; preferably Cl;
m is
Figure BDA0002843765200000243
R1、R3And R4As defined in formula (III).
Scheme four
The preparation method of the compound shown in the general formula (IIaa) or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer or a mixture thereof or a pharmaceutically acceptable salt thereof comprises the following steps:
Figure BDA0002843765200000244
carrying out coupling reaction on the compound of the general formula (IIA) and the compound of the general formula (IIB) in the presence of a catalyst under an alkaline condition to obtain a compound of the general formula (IIaa),
wherein:
x is halogen; preferably Cl;
m is
Figure BDA0002843765200000251
R3、R4、R6And n is as defined in formula (IIaa).
Scheme five
The preparation method of the compound shown in the general formula (IIIaa) or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer or a mixture thereof or a pharmaceutically acceptable salt thereof comprises the following steps:
Figure BDA0002843765200000252
the compound of the general formula (IIIA) and the compound of the general formula (IIB) are subjected to coupling reaction under the alkaline condition in the presence of a catalyst to obtain the compound of the general formula (IIIaa),
wherein:
x is halogen; preferably Cl;
m is
Figure BDA0002843765200000253
R3、R4、R6And n is as defined in formula (IIIaa).
Scheme six
The preparation method of the compound shown in the general formula (II') or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer or a mixture thereof or a pharmaceutically acceptable salt thereof comprises the following steps:
Figure BDA0002843765200000261
compounds of the formula (II' A) and R1-M, in the presence of a catalyst, under basic conditions, to give a compound of formula (II'),
wherein:
x is halogen; preferably Cl;
m is
Figure BDA0002843765200000262
R1、R3-R5As defined in formula (II').
The reagents that provide basic conditions in the above synthesis schemes include organic bases including, but not limited to, triethylamine, N-diisopropylethylamine, N-butyllithium, lithium diisopropylamide, lithium bistrimethylsilyl amide, potassium acetate, sodium t-butoxide, potassium t-butoxide, and sodium N-butoxide, and inorganic bases including, but not limited to, sodium hydride, potassium phosphate, sodium carbonate, potassium acetate, cesium carbonate, sodium hydroxide, and lithium hydroxide.
The catalysts described in the above synthetic schemes include, but are not limited to, palladium on carbon, tetrakis-triphenylphosphine palladium, palladium dichloride, palladium acetate, bis (dibenzylideneacetone) palladium, chloro (2-dicyclohexylphosphino-2 ',4',6' -triisopropyl-1, 1' -biphenyl) [2- (2' -amino-1, 1' -biphenyl) ] palladium, [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride, 1' -bis (dibenzylphosphine) dichloropentairon palladium or tris (dibenzylideneacetone) dipalladium, preferably [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride.
The above reaction is preferably carried out in a solvent including, but not limited to: ethylene glycol dimethyl ether, acetic acid, methanol, ethanol, N-butanol, toluene, tetrahydrofuran, dichloromethane, petroleum ether, ethyl acetate, N-hexane, dimethyl sulfoxide, 1, 4-dioxane, water, N-dimethylformamide and mixtures thereof.
Detailed Description
The present disclosure is further described below with reference to examples, but these examples do not limit the scope of the present disclosure.
Examples
The structure of the compounds is determined by Nuclear Magnetic Resonance (NMR) or/and Mass Spectrometry (MS). NMR shift (. delta.) of 10-6The units in (ppm) are given. NMR was measured using a Bruker AVANCE-400 NMR spectrometer using deuterated dimethyl sulfoxide (DMSO-d)6) Deuterated chloroform (CDCl)3) Deuterated methanol (CD)3OD), internal standard Tetramethylsilane (TMS).
MS was determined using an Agilent 1200/1290DAD-6110/6120Quadrupole MS LC MS (manufacturer: Agilent, MS model: 6110/6120Quadrupole MS).
waters ACQuity UPLC-QD/SQD (manufacturer: waters, MS model: waters ACQuity Qda Detector/waters SQ Detector) THERMO Ultimate 3000-Q active (manufacturer: THERMO, MS model: THERMO Q active)
High Performance Liquid Chromatography (HPLC) analysis was performed using Agilent HPLC 1200DAD, Agilent HPLC 1200VWD and Waters HPLC e2695-2489 HPLC.
Chiral HPLC assay using Agilent 1260DAD HPLC.
High performance liquid phase preparation Waters 2545-2767, Waters 2767-SQ Detector 2, Shimadzu LC-20AP and Gilson GX-281 preparative chromatographs were used.
Chiral preparation was performed using Shimadzu LC-20AP preparative chromatograph.
The CombiFlash rapid preparation instrument uses CombiFlash Rf200(TELEDYNE ISCO).
The thin layer chromatography silica gel plate adopts HSGF254 of tobacco yellow sea or GF254 of Qingdao, the specification of the silica gel plate used by Thin Layer Chromatography (TLC) is 0.15 mm-0.2 mm, and the specification of the thin layer chromatography separation and purification product is 0.4 mm-0.5 mm.
Silica gel column chromatography generally uses 200-300 mesh silica gel of the Tibet Huanghai silica gel as a carrier.
Average inhibition rate of kinase and IC50The values were determined with a NovoStar microplate reader (BMG, Germany).
Known starting materials of the present disclosure may be synthesized using or according to methods known in the art, or may be purchased from companies such as ABCR GmbH & co.kg, Acros Organics, Aldrich Chemical Company, nephelo Chemical science and technology (Accela ChemBio Inc), dare chemicals, and the like.
In the examples, the reaction can be carried out in an argon atmosphere or a nitrogen atmosphere, unless otherwise specified.
An argon atmosphere or nitrogen atmosphere means that the reaction flask is connected to a balloon of argon or nitrogen with a volume of about 1L.
The hydrogen atmosphere refers to a reaction flask connected with a hydrogen balloon with a volume of about 1L.
The pressure hydrogenation reaction used a hydrogenation apparatus of Parr 3916EKX type and a hydrogen generator of Qinglan QL-500 type or a hydrogenation apparatus of HC2-SS type.
The hydrogenation reaction was usually evacuated and charged with hydrogen and repeated 3 times.
The microwave reaction was carried out using a CEM Discover-S908860 type microwave reactor.
In the examples, the solution means an aqueous solution unless otherwise specified.
In the examples, the reaction temperature is, unless otherwise specified, from 20 ℃ to 30 ℃ at room temperature.
The monitoring of the progress of the reaction in the examples employed Thin Layer Chromatography (TLC), a developing solvent used for the reaction, a system of eluents for column chromatography used for purifying compounds and a developing solvent system for thin layer chromatography including: a: dichloromethane/methanol system, B: n-hexane/ethyl acetate system, C: petroleum ether/ethyl acetate system, the volume ratio of solvent is regulated according to different polarity of compound, and small amount of basic or acidic reagents such as triethylamine and acetic acid can be added for regulation.
Example 1
(6aS,10R) -10-methyl-4- (1- ((R) -S-methylaminothiolsulfonyl) cyclopropyl) -2- (1H-pyrrolo [2,3-b ] pyridin-4-yl) -6a,7,9, 10-tetrahydro-6H- [1,4] oxazino [4,3-d ] pyrimido [5,4-b ] [1,4] oxazine 1-A
(6aS,10R) -10-methyl-4- (1- ((S) -S-methylaminothiolsulfonyl) cyclopropyl) -2- (1H-pyrrolo [2,3-B ] pyridin-4-yl) -6a,7,9, 10-tetrahydro-6H- [1,4] oxazino [4,3-d ] pyrimido [5,4-B ] [1,4] oxazine 1-B
Figure BDA0002843765200000281
First step of
((6aS,10R) -2-chloro-10-methyl-6 a,7,9, 10-tetrahydro-6H- [1,4] oxazino [4,3-d ] pyrimido [5,4-b ] [1,4] oxazin-4-yl) methyl methanesulfonate 1b
((6aS,10R) -2-chloro-10-methyl-6 a,7,9, 10-tetrahydro-6H- [1,4] oxazino [4,3-d ] pyrimido [5,4-b ] [1,4] oxazin-4-yl) methanol 1a (516mg, 1.72mmol, prepared by the method disclosed in intermediate (R) -Me-8, page 58 of the specification of patent application WO 2017202748), triethylamine (1.23g, 12.1mmol) was dissolved in 20mL of dichloromethane, methanesulfonyl chloride (835mg, 7.3mmol) was added dropwise at 0 ℃ and the reaction was stirred for 3 hours after completion of the addition. Dilution with 30mL of dichloromethane, washing sequentially with water (15 mL. times.3), saturated sodium chloride solution (15 mL. times.2), drying over anhydrous sodium sulfate, filtration, and concentration of the filtrate under reduced pressure gave the crude title product 1b (2.05g), yield: 96.5 percent, and the product is directly used for the next reaction without purification.
MS m/z(ESI):350.2[M+1]
Second step of
(6aS,10R) -2-chloro-10-methyl-4- ((methylthio) methyl) -6a,7,9, 10-tetrahydro-6H- [1,4] oxazino [4,3-d ] pyrimido [5,4-b ] [1,4] oxazine 1c
The crude compound 1b (1.33g, 3.8mmol), sodium thiomethoxide (533mg, 7.6mmol) was dissolved in 20mL dioxane and the reaction was stirred for 2 hours. The reaction solution was concentrated under reduced pressure and purified by silica gel column chromatography with eluent system C to give the title compound 1C (1.12g), yield: 97.6 percent.
MS m/z(ESI):302.2[M+1]
The third step
(6aS,10R) -2-chloro-10-methyl-4- ((methylsulfinyl) methyl) -6a,7,9, 10-tetrahydro-6H- [1,4] oxazino [4,3-d ] pyrimido [5,4-b ] [1,4] oxazine 1d
Compound 1C (1.12g, 3.71mmol) was dissolved in 12mL of water, methanol and ethyl acetate (v/v/v ═ 1/1/2), sodium periodate (1.03g, 4.82mmol) was added and stirred for 3 hours, the reaction solution was filtered, concentrated under reduced pressure, and purified by silica gel column chromatography with eluent system C to give the title compound 1d (1.05g), yield: 89 percent. MS M/z (ESI) 318.2[ M +1]
The fourth step
N- [ { [ (6aS,10R) -2-chloro-10-methyl-6 a,7,9, 10-tetrahydro-6H- [1,4] oxazino [4,3-d ] pyrimido [5,4-b ] [1,4] oxazin-4-yl ] methyl } (methyl) oxyanion-6-ylidene ] -2,2, 2-trifluoroacetamide 1e
Compound 1d (1.05g, 3.32mmol) was dissolved in 15mL of dichloromethane, and trifluoroacetamide (750mg, 6.65mmol), iodobenzene diacetic acid (1.60g, 5.0mmol), rhodium diacetate dimer (147mg, 0.33mmol) and magnesium oxide (536mg, 13.3mmol) were added in that order and stirred at room temperature for 15 hours. Filtration and concentration of the filtrate under reduced pressure followed by purification by silica gel column chromatography with eluent system C gave the title compound 1e (1.0g), yield: 70.1 percent. MS M/z (ESI):429.1[ M +1]
The fifth step
(6aS,10R) -2-chloro-10-methyl-4- (1- (methylaminothiolsulfonyl) cyclopropyl) -6a,7,9, 10-tetrahydro-6H- [1,4] oxazino [4,3-d ] pyrimido [5,4-b ] [1,4] oxazine 1f
Compound 1e (900mg, 2.10mmol) was dissolved in 10mL of DMF, and anhydrous potassium carbonate (870mg, 6.30mmol) was added dropwise to 1, 2-dibromoethane (1.97g, 10.5mmol), and after the addition, the reaction was stirred at 80 ℃ for 0.5 hour, the reaction was cooled to room temperature, 5mL of anhydrous methanol was added, and the reaction was continued at 80 ℃ for 0.5 hour with stirring. Cooling to room temperature, reaction filtration, concentration of filtrate under reduced pressure and purification by silica gel column chromatography with eluent system a gave the title compound 1f (680mg), yield: 90.2 percent.
MS m/z(ESI):359.1[M+1]
The sixth step
(6aS,10R) -10-methyl-4- (1- ((R) -S-methylaminothiolsulfonyl) cyclopropyl) -2- (1H-pyrrolo [2,3-b ] pyridin-4-yl) -6a,7,9, 10-tetrahydro-6H- [1,4] oxazino [4,3-d ] pyrimido [5,4-b ] [1,4] oxazine 1-A
(6aS,10R) -10-methyl-4- (1- ((S) -S-methylaminothiolsulfonyl) cyclopropyl) -2- (1H-pyrrolo [2,3-B ] pyridin-4-yl) -6a,7,9, 10-tetrahydro-6H- [1,4] oxazino [4,3-d ] pyrimido [5,4-B ] [1,4] oxazine 1-B
Compound 1f (300mg, 0.83mmol) was dissolved in 6mL of a mixed solvent of dioxane and water (v/v ═ 5:1), 4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrrolo [2,3-b ] pyridine (510mg, 2.01mmol, obtained from shanghai) and [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium (122mg, 0.16mmol), anhydrous sodium carbonate (266mg, 2.50mmol) were added, and the reaction was stirred at 105 ℃ for 5 hours. The resulting residue was purified by silica gel column chromatography with eluent system a to give a crude compound (190mg), and the resulting crude product was purified by high performance liquid chromatography (Waters-2767, elution system: ammonium bicarbonate, water, acetonitrile) to give compound 1(85mg), which was further subjected to chiral preparation (separation conditions: chiral preparation column CHIRALCEL OD,2.5cm i.d. × 25cm L, 10 μm mobile phase: MeOH 100%, flow rate: 23.0mL/min), and the corresponding fractions were collected and concentrated under reduced pressure to give the title compound (35mg ).
Single configuration compound (shorter retention time):
MS m/z(ESI):441.2[M+1]
chiral HPLC analysis: retention time 3.140 minutes, chiral purity: 99.62% (column: CHIRALCEL OD-H (ODH0CD-TC012),0.46cm I.D.. times.15 cm L, mobile phase: MeOH: 100%, flow rate: 1.0 mL/min).
1H NMR(400MHz,CD3OD):δ8.25(d,1H),8.00(d,1H),7.47(d,1H),7.37(d,1H),4.43-4.41(m,1H),3.98-3.95(m,3H),3.93-3.90(m,2H),3.81-3.77(m,1H),3.25(t,1H),3.10(s,3H),1.82-1.79(m,2H),1.50-1.46(m,2H),1.39(d,3H)。
Single configuration compound (longer retention time):
MS m/z(ESI):441.2[M+1]
chiral HPLC analysis: retention time 3.935 minutes, chiral purity: 99.97% (column: CHIRALCEL OD-H (ODH0CD-TC012),0.46cm I.D.. times.15 cm L, mobile phase: MeOH 100%, flow rate: 1.0 mL/min).
1H NMR(400MHz,CD3OD):δ8.25(d,1H),8.00(d,1H),7.47(d,1H),7.38(d,1H),4.59-4.56(m,1H),4.46(d,2H),4.02-3.99(m,1H),3.94-3.91(m,2H),3.83(d,1H),3.24(d,1H),3.10(s,3H),1.82-1.79(m,2H),1.51-1.47(m,2H),1.39(d,3H)。
Example 2
2-methyl-2- ((6aS,10R) -10-methyl) -2- (1H-pyrrolo [2,3-b ] pyridin-4-yl) -6a,7,9, 10-tetrahydro-6H- [1,4] oxazino [4,3-d ] pyrimido [5,4-b ] [1,4] oxazin-4-yl) propionitrile 2
Figure BDA0002843765200000311
First step of
2- (6aS,10R) -2-chloro-10-methyl-6 a,7,9, 10-tetrahydro-6H- [1,4] oxazino [4,3-d ] pyrimido [5,4-b ] [1,4] oxazin-4-yl) acetonitrile 2a
Compound 1b (500g, 1.43mmol), trimethylsilyl cyanide (425mg, 4.28mmol, obtained after Shanghai) were dissolved in 12mL of acetonitrile, and tetrabutylammonium fluoride (643mg, 2.85mmol) was added and the reaction was stirred at 50 ℃ for 2 hours. The reaction was cooled to room temperature, and then 30mL of a saturated solution of sodium hydrogencarbonate was added, the reaction was extracted with ethyl acetate, and the combined organic phases were concentrated under reduced pressure and purified by silica gel column chromatography with eluent system C to give the title compound 2a (200mg), yield: 49.8 percent.
MS m/z(ESI):281.2[M+1]
Second step of
2- ((6aS,10R) -2-chloro-10-methyl-6 a,7,9, 10-tetrahydro-6H- [1,4] oxazino [4,3-d ] pyrimido [5,4-b ] [1,4] oxazin-4-yl) -2-methylpropanenitrile 2b
Compound 2a (200mg, 0.71mmol) was dissolved in 5mL DMF, methyl iodide (300mg, 2.13mmol) was added at 0 ℃, sodium tert-butoxide (205mg, 2.13mmol) was added, after addition, the reaction was stirred at room temperature for 2 hours, 5mL water was added, the reaction solution was extracted with ethyl acetate, the combined organic phases were concentrated under reduced pressure to give crude title compound 2b (180mg), yield: 81.8 percent, and directly carrying out the next reaction on the product without purification.
MS m/z(ESI):309.2[M+1]
The third step
2-methyl-2- ((6aS,10R) -10-methyl) -2- (1H-pyrrolo [2,3-b ] pyridin-4-yl) -6a,7,9, 10-tetrahydro-6H- [1,4] oxazino [4,3-d ] pyrimido [5,4-b ] [1,4] oxazin-4-yl) propionitrile 2
The crude compound 2b (220mg, 0.71mmol) was dissolved in 6mL of a mixed solvent of dioxane and water (v/v ═ 5:1), and 4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrrolo [2,3-b ] pyridine (385mg, 1.56mmol), [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium (120mg, 0.15mmol), anhydrous sodium carbonate (226mg, 2.13mmol) and stirred at 105 ℃ for 3 hours. Cooled to room temperature, filtered, the filtrate concentrated under reduced pressure, and the resulting residue purified by high performance liquid chromatography (Waters-2767, eluent: ammonium bicarbonate, water, acetonitrile) to give the title compound 2(50mg, 17.9%)
MS m/z(ESI):391.1[M+1]
1H NMR(400MHz,CD3OD):δ8.25(d,1H),8.06(d,1H),7.46(s,2H),4.59(s,3H),4.48-4.45(m,1H),4.01-3.99(m,2H),3.95-3.92(m,2H),1.86(d,6H),1.39(d,3H)。
Example 3
1- ((6aS,10R) -10-methyl-2- (1H-pyrrolo [2,3-b ] pyridin-4-yl) -6a,7,9, 10-tetrahydro-6H- [1,4] oxazino [4,3-d ] pyrimido [5,4-b ] [1,4] oxazin-4-yl) cyclopropanecarbonitrile 3
Figure BDA0002843765200000321
Figure BDA0002843765200000331
First step of
1- ((6aS,10R) -2-chloro-10-methyl-6 a,7,9, 10-tetrahydro-6H- [1,4] oxazino [4,3-d ] pyrimido [5,4-b ] [1,4] oxazin-4-yl) cyclopropanecarbonitrile 3a
Compound 2a (50mg, 0.18mmol) was dissolved in 5mL of DMF, 1, 2-dibromoethane (170mg, 0.89mmol) was added at 0 ℃ and sodium hydride (60%, 35mg, 0.89mmol) was added, and after the addition, the reaction was stirred at room temperature for 2 hours. 5mL of water was added, the reaction was extracted with ethyl acetate, and the combined organic phases were concentrated under reduced pressure to give the crude title compound 3a (40mg), yield: 73.1 percent, and the product is directly used for the next reaction without purification.
MS m/z(ESI):307.2[M+1]
Second step of
1- ((6aS,10R) -10-methyl-2- (1H-pyrrolo [2,3-b ] pyridin-4-yl) -6a,7,9, 10-tetrahydro-6H- [1,4] oxazino [4,3-d ] pyrimido [5,4-b ] [1,4] oxazin-4-yl) cyclopropanecarbonitrile 3
The crude compound 3a (100mg, 0.33mmol) was dissolved in 6mL of a mixed solvent of dioxane and water (v/v ═ 5:1), 4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrrolo [2,3-b ] pyridine (160mg, 0.65mmol, obtained from shanghai) was added, and [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium (48mg, 0.065mmol), anhydrous sodium carbonate (104mg, 0.98mmol) was added, and the reaction was stirred at 105 ℃ for 3 hours. Cooled to room temperature, filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by high performance liquid chromatography (Waters-2767, eluent: ammonium bicarbonate, water, acetonitrile) to give the title compound 3(35mg, 27.6%).
MS m/z(ESI):389.1[M+1]
1H NMR(400MHz,CD3OD):δ8.23(d,1H),7.97(d,1H),7.46(d,1H),7.30(d,1H),4.84-4.82(m,1H),4.48-4.44(m,1H),4.01-3.98(m,2H),3.93-3.90(m,2H),3.82-3.80(m,1H),3.26-3.23(m,1H),1.96-1.93(m,1H),1.89-1.87(m,1H),1.71(d,2H),1.38(d,3H)。
Example 4
2- ((6aS,10R) -2- (2, 6-dihydropyrrolo [3,4-c ] pyrazol-5 (4H) -yl) -10-methyl-6 a,7,9, 10-tetrahydro-6H- [1,4] oxazino [4,3-d ] pyrimido [5,4-b ] [1,4] oxazin-4-yl) -2-methylpropanenitrile 4
Figure BDA0002843765200000341
The compound tert-butyl 2, 6-dihydro-4H-pyrrolo [3,4-c ] pyrazole-5-carboxylate (35mg, 0.16mmol, obtained from Shanghai Biao) was dissolved in 2mL of dichloromethane, 0.7mL of trifluoroacetic acid was added thereto, the mixture was stirred for 2 hours, the mixture was concentrated under reduced pressure to dryness, the residue was dissolved in 3mL of dioxane, the compound 2b (20mg, 0.064mmol) and N, N-diisopropylethylamine (83mg, 0.64mmol) were added thereto, and the mixture was reacted at 120 ℃ for 1 hour by microwave. Cooled to room temperature, concentrated under reduced pressure, and the resulting residue purified by high performance liquid chromatography (Waters-2767, eluent: water (10mM ammonium bicarbonate)/acetonitrile, gradient: water (10mM ammonium bicarbonate) 30% -55%) to give the title compound 4(6mg), yield: 24.3 percent.
MS m/z(ESI):382.1[M+1]。
1H NMR(400MHz,CD3OD):δ7.45(s,1H),4.73(d,1H),4.59-4.46(m,4H),4.28-4.26(m,1H),3.95-3.92(m,2H),3.87-3.852(m,1H),3.73-3.70(m,2H),3.20-3.17(m,1H),1.72(d,6H),1.33(d,3H)。
Example 5
(R) -Ethyl (Aminoylidene) ((R) -1- ((6aS,10R) -10-methyl-2- (1H-pyrrolo [2, 3-b)]Pyridin-4-yl) -6a,7,9, 10-tetrahydro-6H- [1,4]Oxazino [4,3-d]Pyrimido [5,4-b ] s][1,4]Oxazin-4-yl) ethyl) -lambda6-Thioalkanone 5-A
(S) -Ethyl (Aminoylidene) ((S) -1- ((6aS,10R) -10-methyl-2- (1H-pyrrolo [2, 3-b)]Pyridin-4-yl) -6a,7,9, 10-tetrahydro-6H- [1,4]Oxazino [4,3-d]Pyrimido [5,4-b ] s][1,4]Oxazines-4-yl) ethyl) -lambda6-Thioalkanone 5-B
Figure BDA0002843765200000351
First step of
(1- ((6aS,10R) -2-chloro-10-methyl-6 a,7,9, 10-tetrahydro-6H- [1, 4)]Oxazino [4,3-d]Pyrimido [5,4-b ] s][1,4]Oxazin-4-yl) ethyl) (aminoylidene) -lambda6-Thioalkanone 5a
Compound 1e (500mg, 1.67mmol) was dissolved in 10mL of tetrahydrofuran, the reaction was cooled to-78 deg.C, lithium bistrimethylsilylamide (3.5mL, 1M tetrahydrofuran solution) was added thereto, stirred for 0.5 hour, iodomethane (560mg, 3.94mmol) was added thereto, stirred for 0.5 hour, and then warmed to room temperature for 1 hour. 10mL of water was added, extracted with ethyl acetate, concentrated under reduced pressure, and purified by silica gel column chromatography with eluent system A to give the title compound 5a (100mg), yield: 23.7 percent.
MS m/z(ESI):361.3[M+1]。
Second step of
(R) -Ethyl (Aminoylidene) ((R) -1- ((6aS,10R) -10-methyl-2- (1H-pyrrolo [2, 3-b)]Pyridin-4-yl) -6a,7,9, 10-tetrahydro-6H- [1,4]Oxazino [4,3-d]Pyrimido [5,4-b ] s][1,4]Oxazin-4-yl) ethyl) -lambda6-Thioalkanone 5-A
(S) -Ethyl (Aminoylidene) ((S) -1- ((6aS,10R) -10-methyl-2- (1H-pyrrolo [2, 3-b)]Pyridin-4-yl) -6a,7,9, 10-tetrahydro-6H- [1,4]Oxazino [4,3-d]Pyrimido [5,4-b ] s][1,4]Oxazin-4-yl) ethyl) -lambda6-Thioalkanone 5-B
Compound 5a (230mg, 0.64mmol) was dissolved in 12mL of a mixed solvent of dioxane and water (v/v ═ 5:1), 4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrrolo [2,3-b ] pyridine (310mg, 1.27mmol, obtained from shanghai) and [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium (69mg, 0.09mmol), anhydrous sodium carbonate (168mg, 1.58mmol) were added, and the reaction was stirred at 105 ℃ for 5 hours. Cooling to room temperature, filtration, concentration of the filtrate under reduced pressure, purification of the resulting residue by silica gel column chromatography with eluent system a to give crude compound (85mg), purification of the resulting crude by high performance liquid chromatography (Waters-2767, elution system: water (10mM ammonium bicarbonate)/acetonitrile, gradient: water (10mM ammonium bicarbonate) 30% -55%) to give compound 5(40mg), chiral preparation (separation conditions: chiral preparation column CHIRALCEL OD,2.5cm i.d. × 25cm L, 10 μm mobile phase: MeOH ═ 100%, flow rate: 23.0mL/min), collection of the corresponding fractions, concentration under reduced pressure to give the title compound (10mg ).
Single configuration compound (shorter retention time):
MS m/z(ESI):443.2[M+1]。
chiral HPLC analysis: retention time 4.534 minutes, chiral purity: 99.62% (column: CHIRALCEL OD-H (ODH0CD-TC012),0.46cm I.D.. times.15 cm L, mobile phase: MeOH: 100%, flow rate: 1.0 mL/min).
1H NMR(400MHz,CD3OD)δ8.26(dd,1H),8.06-7.89(m,1H),7.48(d,1H),7.38(t,1H),4.43(dt,1H),4.10-3.99(m,2H),3.99-3.83(m,2H),3.79(dd,1H),3.42-3.32(m,2H),3.31-3.11(m,3H),1.95-1.78(m,3H),1.52-1.26(m,6H)。
Single configuration compound (longer retention time):
MS m/z(ESI):443.3[M+1]。
chiral HPLC analysis: retention time 4.816 min, chiral purity: 99.97% (column: CHIRALCEL OD-H (ODH0CD-TC012),0.46cm I.D.. times.15 cm L, mobile phase: MeOH 100%, flow rate: 1.0 mL/min).
1H NMR(400MHz,CD3OD)δ8.26(dd,1H),8.02(dd,1H),7.48(d,1H),7.39(dd,1H),4.42(dd,1H),4.05-3.87(m,4H),3.81(dd,1H),3.42-3.11(m,5H),1.86(d,3H),1.39-1.34(m,6H)。
Test example:
biological evaluation
Test example 1. compounds of the present disclosure were tested for their inhibitory effect on ATR enzyme.
The following method was used to determine the inhibitory effect of the compounds of the present disclosure on ATR enzyme. The experimental method is briefly described as follows:
first, experimental material and instrument
ATR enzyme (Eurofins Pharma Discovery Services, 14-953-M)
GST tag P53 protein (Eurofins Pharma Discovery Services, 14-952-M)
3.384 orifice plate (Thermo Scientific, 267462)
U-shaped bottom 96-well plate (Corning, 3795)
5. Europium cryptate-labeled anti-phosphorylated P53 protein antibody (cisbio, 61P08KAE)
6. anti-GST antibody to d2 (cisbio, 61 GSTTDLF)
ATP solution (Promega, V916B)
8.EDTA(Thermo Scientific，AM9260G)
9.HEPES(Gibco，15630-080)
10. Enzyme mark instrument (BMG, PHERASta)
Second, the experimental procedure
ATR enzyme 1nM, P53 protein 50nM, 7.435. mu.M ATP and different concentrations (first concentration 1uM, 3 fold gradient dilution 11 concentrations) of small molecule compounds were mixed and incubated at room temperature for 2 hours, then stop buffer (12.5mM HEPES, 250mM EDTA) was added and mixed well, followed by 0.42 ng/well of europium cryptate-labeled anti-phosphorylated P53 protein antibody and 25 ng/well of d2 anti-GST antibody. After overnight incubation at room temperature, fluorescence signals at 620nm and 665nm were detected using PHERAStar. Data were processed using GraphPad software.
Third, experimental data
The inhibitory activity of the disclosed compounds against ATR enzyme can be measured by the above test, and the IC measured50The values are shown in Table 1.
TABLE 1 IC inhibition of ATR enzyme by the compounds of this disclosure50The value is obtained.
Figure BDA0002843765200000371
And (4) conclusion: the disclosed compound has good inhibitory activity to ATR enzyme.
Test example 2, selectivity test of the disclosed compounds for ATR enzyme.
The inhibitory effects of the compounds of the present disclosure on ATM enzyme, DNA-PK enzyme, mTOR enzyme, and PI3K enzyme, respectively, were determined by the following methods to demonstrate the selectivity of the compounds of the present disclosure for ATR enzyme. The experimental method is briefly described as follows:
(I) inhibitory effect of compounds of the disclosure on ATM enzymes.
First, experimental material and instrument
ATM enzyme (Eurofins Pharma Discovery Services, 14-933-M)
GST tag P53 protein (Eurofins Pharma Discovery Services, 14-952-M)
13.384 orifice plate (Thermo Scientific, 267462)
U type bottom 96 well plate (Corning, 3795)
15. Europium cryptate-labeled anti-phosphorylated P53 protein antibody (cisbio, 61P08KAE)
16. anti-GST antibody to d2 (cisbio, 61 GSTTDLF)
ATP solution (Promega, V916B)
18.EDTA(Thermo Scientific，AM9260G)
19.HEPES(Gibco，15630-080)
20. Enzyme mark instrument (BMG, PHERASta)
Second, the experimental procedure
ATM enzyme 1nM, P53 protein 30nM, 11. mu.M ATP and different concentrations (first concentration 10uM, 3 fold gradient dilution 11 concentrations) of small molecule compounds were mixed and incubated at room temperature for 2 hours, then stop buffer (12.5mM HEPES, 250mM EDTA) was added and mixed, 0.42 ng/well of europium cryptate labeled anti-phosphorylated P53 protein antibody and 25 ng/well of d2 linked anti-GST antibody were added. After overnight incubation at room temperature, fluorescence signals at 620nm and 665nm were detected using PHERAStar. Data were processed using GraphPad software. Inhibition of ATM enzymes by the presently disclosed compounds IC50The values are shown in Table 2.
(II) inhibitory effects of the disclosed compounds on DNA-PK enzymes.
First, experimental material and instrument
DNA-PK enzyme (Eurofins Pharma Discovery Services, 14-950-M)
GST tag P53 protein (Eurofins Pharma Discovery Services, 14-952-M)
3.384 orifice plate (Thermo Scientific, 267462)
U-shaped bottom 96-well plate (Corning, 3795)
5. Europium cryptate-labeled anti-phosphorylated P53 protein antibody (cisbio, 61P08KAE)
6. anti-GST antibody to d2 (cisbio, 61 GSTTDLF)
ATP solution (Promega, V916B)
8.EDTA(Thermo Scientific，AM9260G)
9.HEPES(Gibco，15630-080)
10. Enzyme mark instrument (BMG, PHERASta)
Second, the experimental procedure
DNA-PK enzyme 0.02nM, P53 protein 50nM, 7.3. mu.M ATP and different concentrations (first 10uM, 11 concentrations in a 3-fold gradient) of small molecule compounds were mixed and incubated at room temperature for 1 hour, then stop buffer (12.5mM HEPES, 250mM EDTA) was added and mixed well, and 0.42 ng/well of europium cryptate anti-phosphorylated P53 protein antibody and 25 ng/well of d2 linked anti-GST antibody were added. After overnight incubation at room temperature, fluorescence signals at 620nm and 665nm were detected using PHERAStar. Data were processed using GraphPad software. Inhibition of DNA-PK enzymes by Compounds of the disclosure IC50The values are shown in Table 2.
(III) inhibitory effect of the disclosed compounds on PI3K enzyme.
First, experimental material and instrument
PIK3CA/PIK3R1(p110 alpha/p85 alpha) kinase (Invitrogen, PV4788)
PIP2 PS Lipid substrate (Invitrogen, PV5100)
23.DTT(Sigma，43815-1G)
Tris-HCl (1M, pH7.5) (101205 one 100, Beijing Tianenzze Biotechnology Co., Ltd.)
ATP solution (Promega, V916B)
26. Magnesium chloride hexahydrate (Sigma, M2393)
27. Sodium chloride (national drug group chemical agents Co., Ltd., 10019318)
28.CHAPS(Sigma，C3023-5G)
29.HEPES(Gibco，15630-080)
30.ADP-GloTMKinase Assay(Promega，V9102)
31.384 orifice plate (Thermo Scientific, 267462)
U type bottom 96 well plate (Corning, 3795)
33. Enzyme mark instrument (BMG, PHERAStar)
Second, the experimental procedure
PI3K enzyme with final concentration of 0.625nM, mixing with small molecule compounds with different concentrations (initial concentration of 10 μ M, 3 times gradient dilution of 10 concentrations), incubating at room temperature for 30min, adding PIP2: PS Lipid substrate (final concentration of 50 μ M) and 1 × ATP (final concentration of 50 μ M), mixing at 37 deg.C, incubating for 30min, adding detection reagent ADP-Glo (Promega, V9102), mixing, incubating at room temperature for 40 min, adding ADP-GloTMDetection reagent from Kinase Assay (Promega, V9102) was incubated for 40 minutes at room temperature. Fluorescence signals were detected with PHERAstar and data were processed using GraphPad software. Inhibition IC of PI3K enzyme by the disclosed compounds50The values are shown in Table 2.
And (IV) the inhibitory effect of the disclosed compounds on mTOR enzyme.
First, experimental material and instrument
1.MTOR Recombinant Human Protein(Invitrogen，PV4753)
ATP solution (Promega, V916B)
3.EDTA(Thermo Scientific，AM9260G)
4.HEPES(Gibco，15630-080)
U type bottom 96-well plate (Corning, 3795)
6.DTT(Sigma，43815-1G)
Tris-HCl (1M, pH7.5) (101205 one 100, Beijing Tianenzze Biotechnology Co., Ltd.)
8. Magnesium chloride hexahydrate (Sigma, M2393)
9.ULIGHT-4E-BP1(THR37/46)(PerkinElmer，TRF0128-D)
10.EU-ANTI-P-4E-BP1(THR37/46)(PerkinElmer，TRF0216-D)
11. 21O-LANCE DETECTION BUFFER(PerkinElmer，CR97-100)
12.384 pore plate (Corning, 4513)
EnVision multimode test platform (Perkinelmer, EnVision)
Second, the experimental procedure
mTOThe final concentration of the enzyme R is 3nM, small molecule compounds with different concentrations (10 muM at the first concentration and 10 concentrations diluted by 3-fold gradient) are added and mixed, ATP and ULight-4E-BP1 Peptide (the final concentrations are respectively 10 muM ATP and 50nM substrate) are added and mixed for 2 hours at room temperature, then EDTA stop solution with the final concentration of 8mM is added and mixed for 5 minutes at room temperature, Eu-anti-phosphorus-4E-BP 1(Thr37/46) Antibody (the final concentration is 2nM) is added and incubated for 1 hour at room temperature. HTRF was detected using an EnVision multimode detection platform with an excitation wavelength of 320nm and an emission wavelength of 665 nm. Data were processed using GraphPad software. The compound disclosed by the invention inhibits the mTOR enzyme by IC50The values are shown in Table 2.
TABLE 2 IC of inhibition of ATM enzyme, DNA-PK enzyme, PI3K enzyme and mTOR enzyme by the presently disclosed compounds50The value is obtained.
Figure BDA0002843765200000401
And (4) conclusion: the disclosed compound has weak inhibitory activity on ATM enzyme, DNA-PK enzyme, PI3K enzyme and mTOR enzyme, and the disclosed compound has selectivity on ATR enzyme as can be seen by comparing test examples 1 and 2.
Test example 3 cell proliferation test
The following method was performed by measuring intracellular ATP content based on IC50The effect of the disclosed compounds on inhibition of LoVo cell proliferation was evaluated. The experimental method is briefly described as follows:
first, experimental material and instrument
LoVo, human colon cancer tumor cell (Nanjing Kebai, CBP60032)
15. Fetal bovine serum (GIBCO,10091-
F-12K Medium (Gibco, 21127030)
CellTite-Glo reagent (Promega, G7573)
18.96 well cell culture plate (corning, 3903)
19. Pancreatin (invitrogen, 25200-
20. Enzyme mark instrument (BMG, PHERASta)
21. Cell counter (Shanghai Rui Yu biological science and technology Co., Ltd., IC1000)
Second, the experimental procedure
The LoVo cells are cultured in a F-12K culture medium containing 10% FBS, and are subjected to 2-3 times of subculture in a week at a subculture ratio of 1:3 or 1: 5. And during passage, digesting the cells with pancreatin, transferring the cells into a centrifuge tube, centrifuging the cells at 1200rpm for 3 minutes, removing the residual liquid of the supernatant culture medium, and adding a fresh culture medium to resuspend the cells. 90 μ L of cell suspension was added to a 96-well cell culture plate at a density of 3.88X 104Cells/ml, only 100. mu.L of complete medium was added to the periphery of the 96-well plate. The plates were incubated in an incubator for 24 hours (37 ℃, 5% CO)2)。
The test samples were diluted to 2mM in DMSO and sequentially diluted to 10 concentrations by 3 fold, and blank and control wells were set. mu.L of the test compound solution prepared to a gradient concentration was added to 95. mu.L of fresh medium. Then, 10. mu.L of the above-mentioned drug-containing medium solution was added to the plate. The plates were incubated in an incubator for 3 days (37 ℃, 5% CO)2). 50 μ L of CellTiter-Glo reagent was added to each well of a 96-well cell culture plate, and left at room temperature in the dark for 5-10min, and the chemiluminescent signal values were read in the PHERAStar and the data were processed using GraphPad software.
Third, experimental data
The inhibitory activity of the disclosed compounds on the proliferation of LoVo cells can be determined by the above assay, and the IC measured50The values are shown in Table 3.
TABLE 3 IC of compounds of the present disclosure for inhibition of LoVo cell proliferation50。
Figure BDA0002843765200000411
And (4) conclusion: the compounds disclosed herein have good inhibitory activity against LoVo cell proliferation.
Test example 4 solubility testing of Compounds of the present disclosure
1. Experimental Material
Reagent: dimethyl sulfoxide (analytically pure), ethanol (analytically pure), acetonitrile (chromatographically pure), NaH2PO4·2H2O (analytically pure) and Na2HPO4212H2O (analytically pure), ammonium acetate (analytically pure), sodium taurocholate, lecithin, sodium hydroxide, sodium chloride (analytically pure)
The instrument comprises the following steps: liquid chromatograph
2. Experimental procedure
2.1 solution preparation
Test of (I) Compounds in FassiF solution
A10 mM stock solution was prepared by weighing an appropriate amount of the test compound in DMSO as a solvent. mu.L of stock solution (10mM in DMSO) and 990. mu.L of organic solvent mixture (usually DMSO: acetonitrile: ethanol: 1:1:1) were precisely measured in a 2mL sample bottle and mixed to obtain a clear 100. mu.M sample solution as a reference solution.
Dissolving 1mg of sample to be detected into 900 mu L of FaSSIF solution, strongly mixing, and preparing two solutions in parallel; after shaking in a 37 ℃ water bath for 24 hours, the mixture was centrifuged at 4000rpm for 30min, and the supernatant was transferred to liquid chromatography as a sample solution.
Testing of (di) Compounds in PBS solution at pH7.4
preparation of a pH7.4 PBS solution: 0.57g of NaH2PO 4.2H2O, 5.55g of Na2HPO 4.12H2O and 6.48g of NaCl were weighed, ultrapure water was added, the pH was adjusted to 7.4. + -. 0.05 with 1M NaOH or 1M HCl, and water was added to the volume of 1L. Storing in a refrigerator at 4 deg.C (shelf life of 6 months)
Preparation of compound PBS 7.4 solution: weighing a proper amount of a test compound, and adding DMSO or DMSO: acetonitrile: ethanol 1:1:1 was dissolved to prepare a 10mM stock solution of the test compound. Precisely measuring 10 mu L of stock solution of the compound to be detected and 990 mu L of PBS solution with pH7.4 in a 2mL sample bottle, and uniformly mixing, wherein the final DMSO concentration of the solution is 1% (v/v). The solution was prepared in two portions in parallel, shaken on a flat bed at room temperature for 24 hours, centrifuged at 5000rpm for 20min, and the supernatant was transferred to a liquid chromatograph for analysis.
Preparation of a reference solution: a sample stock solution (concentration 10mM, dissolved in DMSO) of 10 μ L to be measured and 990 μ L of an organic mixed solvent (usually DMSO: acetonitrile: ethanol ═ 1:1:1) were precisely measured and mixed in a 2mL sample bottle to obtain a clear 100 μ M sample solution. Filtering with 0.45 μm organic phase microporous membrane, and analyzing the filtrate with liquid chromatograph.
3. Data processing
Solubility (μ M) — peak area of sample/peak area of reference — (μ M) — (dilution factor of sample solution);
the average of the two measurements was taken as the final solubility, and the specific values are shown in Table 4.
Table 4 solubility of compounds of the present disclosure
Figure BDA0002843765200000431
And (4) conclusion: the compounds of the present disclosure have good solubility.
Pharmacokinetic evaluation
Test example 5 pharmacokinetic testing of Compounds with short Retention time in inventive examples 1-A and 1-B
1. Abstract
The drug concentrations in plasma at different times after gastric gavage of BALB/C nude mice to which the compounds of examples 1-A and 1-B having short retention time were administered were determined by LC/MS/MS method using BALB/C nude mice as test animals. The pharmacokinetic behavior of the compounds of the invention in BALB/C nude mice was studied and their pharmacokinetic profile was evaluated.
2. Test protocol
2.1 test drugs
Compounds of examples 1-A and 1-B with short retention times
2.2 test animals
BALB/C nude mice 9, female, were purchased from Witongliwa laboratory animals, Inc.
2.3 pharmaceutical formulation
An appropriate amount of sample was weighed, and 15% PEG400+ 85% (1% HPMC) aqueous solution was added sequentially in order.
2.4 administration
BALB/C nude mice 9, female; after fasting overnight, the administration was effected by gavage in a volume of 0.2ml/10 g.
3. Operation of
9 Balb/C nude mice, female; gavage was performed after one night fasting. 0.1ml of blood is collected at 0.25,0.5,1.0,2.0,4.0,6.0,8.0,11.0 and 24.0h after administration, the blood is placed in an EDTA-K2 anticoagulation test tube, centrifuged at 10000rpm for 1min (4 ℃), the plasma is separated within 1h, and the blood is stored at-20 ℃ for testing. The blood collection to centrifugation process is operated under ice bath condition.
The concentration of the drug as received in plasma and dosing solutions was determined by liquid chromatography-tandem mass spectrometry (LC/MS/MS).
4. Results of pharmacokinetic parameters of BALB/C nude mice
The pharmacokinetic parameters for the compounds with short retention times in inventive examples 1-A and 1-B are as follows:
pharmacokinetic parameters of the Compounds of Table 5
Figure BDA0002843765200000432
Figure BDA0002843765200000441
And (4) conclusion: the compound of the invention has good drug absorption and obvious drug absorption effect.

Claims (16)

1.A compound of formula (I), or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof:
Figure FDA0002843765190000011
wherein:
R1is heteroaryl or heterocyclyl; wherein said heteroaryl and heterocyclyl are optionally substituted with one or more substituents selected from the group consisting of hydrogen, halogen, alkyl, alkenyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, cyano, -NR8R9and-SO2R10Is substituted with one or more substituents of (1);
R2is selected from-SO (N)H)R5Or cyano;
R3and R4Are the same or different and are each independently selected from the group consisting of a hydrogen atom, an alkyl group, a haloalkyl group, and a hydroxyalkyl group;
or R3And R4Together with the carbon atom to which they are attached form a cycloalkyl or heterocyclyl group;
R5selected from the group consisting of alkyl, haloalkyl, and hydroxyalkyl;
R8and R9Are the same or different and are each independently selected from the group consisting of a hydrogen atom, an alkyl group, a haloalkyl group, a cycloalkyl group, and a heterocyclic group;
R10selected from the group consisting of alkyl, cycloalkyl, heterocyclyl and aryl.
2. The compound of formula (I) according to claim 1, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R is3And R4Are the same or different and are each independently selected from the group consisting of alkyl, haloalkyl, and hydroxyalkyl;
or R3And R4Together with the carbon atom to which they are attached form a cycloalkyl or heterocyclyl group.
3. The compound of the general formula (I), or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, according to claim 1 or2, which is a compound of the general formula (II) or (III), or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof:
Figure FDA0002843765190000012
wherein:
R1、R3and R4As defined in claim 1 or 2.
4. A compound of formula (I) according to claims 1 to 3, wherein R is R, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof1Is composed of
Figure FDA0002843765190000021
R6And R7The same or different and each is independently selected from the group consisting of hydrogen atom, halogen, alkyl, alkenyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, cyano, -NR8R9and-SO2R10(ii) a n is 0,1, 2,3 or 4; s is 0,1, 2 or 3; r8、R9And R10As defined in claim 1 or 2.
5. The compound of the general formula (I), or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, according to claims 1 to 4, which is a compound of the general formula (IIaa) or (IIIaa), or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof:
Figure FDA0002843765190000022
wherein:
R6selected from the group consisting of hydrogen, halogen, alkyl, alkenyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, cyano, -NR8R9and-SO2R10；
R3、R4、R8～R10And n is as defined in claim 1 or 2.
6. The general formula according to any one of claims 1 to 5(I) A compound of formula (I), or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R is3And R4Identical or different, each is an alkyl group; or R3And R4Together with the carbon atom to which they are attached form a 3 to 6 membered cycloalkyl group.
7. The compound of general formula (I), or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 6, selected from any one of the following compounds:
Figure FDA0002843765190000031
8. a compound of formula (IA), or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof,
Figure FDA0002843765190000041
wherein:
x is halogen;
R2selected from-SO (NH) R5Or cyano;
R3and R4Are the same or different and are each independently selected from the group consisting of a hydrogen atom, an alkyl group, a haloalkyl group, and a hydroxyalkyl group;
or R3And R4Together with the carbon atom to which they are attached form a cycloalkyl or heterocyclyl group;
R5selected from the group consisting of alkyl, haloalkyl, and hydroxyalkyl.
9. The compound of the general formula (IA) according to claim 8, or a tautomer thereofA isomer, diastereoisomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R3And R4Are the same or different and are each independently selected from the group consisting of alkyl, haloalkyl, and hydroxyalkyl;
or R3And R4Together with the carbon atom to which they are attached form a cycloalkyl or heterocyclyl group.
10. The compound of general formula (IA) according to claim 8 or 9, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, selected from any one of the following compounds:
Figure FDA0002843765190000042
11.a process for the preparation of a compound of formula (I), or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, according to claim 1 or2, comprising:
Figure FDA0002843765190000051
compounds of the general formula (IA) and R1-M is subjected to a coupling reaction to obtain a compound of general formula (I),
wherein:
x is halogen; preferably Cl;
m is
Figure FDA0002843765190000052
R1～R4As defined in claim 1 or 2.
12. A pharmaceutical composition comprising a compound of general formula (I) according to any one of claims 1 to 7, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents, or excipients.
13. Use of a compound of general formula (I) according to any one of claims 1 to 7, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 12, for the preparation of a medicament for inhibiting ATR kinase.
14. Use of a compound of general formula (I) according to any one of claims 1 to 7, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 12, for the preparation of a medicament for the treatment or prevention of a hyperproliferative disease.
15. Use of a compound of general formula (I) according to any one of claims 1 to 7, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 12, for the preparation of a medicament for the treatment or prevention of a tumor.
16. The use according to claim 15, wherein the tumor is selected from the group consisting of melanoma, brain tumor, esophageal cancer, gastric cancer, liver cancer, pancreatic cancer, colorectal cancer, lung cancer, kidney cancer, breast cancer, cervical cancer, ovarian cancer, prostate cancer, skin cancer, neuroblastoma, glioma, sarcoma, bone cancer, uterine cancer, endometrial cancer, head and neck tumors, multiple myeloma, B-cell lymphoma, polycythemia vera, leukemia, thyroid tumor, bladder cancer, and gallbladder cancer.
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