CN113135942B - Condensed pyrimidine derivative, preparation method and medical application thereof - Google Patents

Abstract

The present disclosure relates to fused pyrimidine derivatives, methods for their preparation, and their use in medicine. Specifically, the disclosure relates to a fused pyrimidine derivative shown in a general formula (I), a preparation method thereof, a pharmaceutical composition containing the derivative, and an application of the derivative as a therapeutic agent, in particular an application of the derivative as an ATR kinase inhibitor and an application of the derivative in preparation of a medicament for treating or preventing a hyperproliferative disease.

Description

Condensed pyrimidine derivative, preparation method and medical application thereof

Technical Field

The disclosure belongs to the field of medicine, and relates to a condensed pyrimidine 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 chromatid as the template for repair to replicate the DNA sequence at the damaged part and precisely repair 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 with Replication Protein A (RPA), ATR is activated and regulates various check points of cell cycle 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:

wherein:

R ¹ is heteroaryl or heterocyclyl; wherein said heteroaryl and heterocyclyl are optionally selected from halogen, alkyl, alkenyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, cyano, -NR ² R ³ and-SO ₂ R ⁴ Is substituted with one or more substituents of (a);

-L-is a single bond or is selected from-C (O) -, -S (O) ₂ -, -S (O) -, -C (S) -and-CH ₂ -；

Y is selected from the group consisting of alkyl, alkoxy, hydroxy, hydroxyalkyl, cyano, amino, -NR ⁵ R ⁶ 、-OR ⁷ Cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein said alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally selected from halogen, alkoxy, haloalkoxy, hydroxy, hydroxyalkyl, cyano, -NR ⁵ R ⁶ 、OR ⁷ Cycloalkyl, heterocyclyl, aryl and heteroaryl;

R ^’ the same or different and each is independently selected from the group consisting of hydrogen atom, halogen, alkyl, alkenyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, cyano, -NR ² R ³ and-SO ₂ R ⁴ ；

R ² And R ³ Are 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;

R ⁴ selected from the group consisting of hydrogen atoms, alkyl groups, cycloalkyl groups, heterocyclic groups, and aryl groups;

R ⁵ 、R ⁶ and R ⁷ The same or different and each is independently selected from the group consisting of hydrogen atoms, alkyl groups and cycloalkyl groups, wherein said alkyl and cycloalkyl groups are optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl, alkenyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, cyano, amino, cycloalkyl, heterocyclyl, aryl and heteroaryl;

p is 1 or 2;

q is 0, 1,2, 3, 4,5 or 6.

In some embodiments of the present disclosureIn one embodiment, the compound of formula (I) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R is ¹ Is composed of

R ⁸ The same or different and each is independently selected from the group consisting of hydrogen atom, halogen, alkyl, alkenyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, cyano, -NR ² R ³ and-SO ₂ R ⁴ (ii) a n is 0, 1,2, 3 or 4; r ² 、R ³ And R ⁴ As defined in formula (I);

preferably, R ¹ Is composed of

R ⁸ Are the same or different and are each independently selected from the group consisting of hydrogen, halogen, C _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _1-6 Haloalkyl, C _1-6 Haloalkoxy, hydroxy, C _1-6 Hydroxyalkyl and cyano, n is 1 or 2;

more preferably, R ¹ Is composed of

R ⁸ Selected from hydrogen atoms, halogens, C _1-6 Alkyl and C _1-6 Haloalkyl, n is 1. In some preferred embodiments of the present disclosure, the compound of formula (I), or a tautomer, mesomer, racemate, enantiomer, or diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, is a compound of formula (II), or a tautomer, mesomer, racemate, enantiomer, or diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof:

wherein:

R ⁸ the same or different, each independently selected from hydrogen atom, halogen, alkyl, alkenyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, cyano, -NR ² R ³ and-SO ₂ R ⁴ ；

n is 0, 1,2, 3 or 4;

l and Y are as defined in formula (I).

In some embodiments of the disclosure, the compounds of formula (I) and (II) or tautomers, mesomers, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, wherein-L-is-C (O) -or-S (O) ₂ -; preferably-C (O) -.

In some embodiments of the disclosure, the compounds of formula (I) and (II) or tautomers, mesomers, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, wherein Y is selected from the group consisting of alkyl, alkoxy, and-NR ⁵ R ⁶ Wherein said alkyl is optionally substituted with one or more substituents selected from the group consisting of hydroxy, cyano and alkoxy; r ⁵ And R ⁶ As defined in general formulae (I) and (II);

preferably, Y is selected from C _1-6 Alkyl radical, C _1-6 Alkoxy and-NHR ⁶ Wherein said C _1-6 Alkyl is optionally selected from hydroxy, cyano and C _1-6 Substituted with one or more substituents of alkoxy; r ⁶ Is C _1-6 Alkyl or 3-6 membered cycloalkyl, said C _1-6 The alkyl group is optionally substituted with a 3-6 membered cycloalkyl group.

In some embodiments of the present disclosure, the compound of formula (I) or a tautomer, mesomer, racemate, enantiomer, or diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R' is the same or different and is independently selected from the group consisting of hydrogen, halogen, and C _1-6 An alkyl group; preferably a hydrogen atom.

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 thereof, wherein q is 0 or 1, preferably 0.

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 thereof, wherein p is 1.

In some embodiments of the disclosure, the compound of formula (II) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R is ⁸ Are the same or different and are each independently selected from the group consisting of hydrogen, halogen, C _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _1-6 Haloalkyl, C _1-6 Haloalkoxy, hydroxy, C _1-6 Hydroxyalkyl and cyano; preferably selected from hydrogen atoms, halogens, C _1-6 Alkyl and C _1-6 A haloalkyl group; more preferably a hydrogen atom.

In some embodiments of the present disclosure, the compound of formula (II) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein n is 1 or2, preferably 1.

In some embodiments of the present disclosure, the compounds of formula (I) and (II) or a pharmaceutically acceptable salt thereof, or a tautomer, mesomer, racemate, enantiomer, or diastereomer thereof, or mixture thereof, wherein R is ⁵ And R ⁶ The same or different, each independently selected from a hydrogen atom, an alkyl group or a cycloalkyl group, wherein the alkyl group may be substituted with the cycloalkyl group.

In some embodiments of the disclosure, the compounds of formula (I) and (II) or a tautomer, mesomer, racemate, enantiomer, or diastereomer thereof, or mixture thereof, are pharmaceutically acceptable salts, wherein R is ⁵ And R ⁶ Are the same or different and are each independently an alkyl groupOr cycloalkyl, wherein alkyl may be substituted by cycloalkyl.

In some embodiments of the disclosure, the compounds of formula (I) and (II) or a tautomer, mesomer, racemate, enantiomer, or diastereomer thereof, or mixture thereof, are pharmaceutically acceptable salts, wherein R is ⁵ Is a hydrogen atom.

In some embodiments of the disclosure, the compounds of formula (I) and (II) or a tautomer, mesomer, racemate, enantiomer, or diastereomer thereof, or mixture thereof, are pharmaceutically acceptable salts, wherein R is ⁶ Is C _1-6 Alkyl or 3-6 membered cycloalkyl, said C _1-6 The alkyl group is optionally substituted with a 3-6 membered cycloalkyl group.

In some embodiments of the disclosure, the compound of formula (II) or a tautomer, mesomer, racemate, enantiomer, or diastereomer thereof, or mixture thereof, wherein-L-is-C (O) -or-S (O) ₂ -; y is selected from C _1-6 Alkyl radical, C _1-6 Alkoxy and NHR ⁶ Said C is _1-6 Alkyl is optionally substituted with cyano or hydroxy; r ⁸ Selected from hydrogen atoms, halogens, C _1-6 Alkyl and C _1-6 A haloalkyl group; n is 1; r ⁶ Is C _1-6 Alkyl or 3-6 membered cycloalkyl, said C _1-6 The alkyl group is optionally substituted with a 3-6 membered cycloalkyl group.

Typical compounds of the present disclosure include, but are not limited to:

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,

wherein:

x is halogen;

l is a single bond or is selected from-C (O) -, -S (O) ₂ -, -S (O) -, -C (S) -and-CH ₂ -；

Y is selected from the group consisting of alkyl, alkoxy, hydroxy, hydroxyalkyl, cyano, amino, -NR ⁵ R ⁶ 、-OR ⁷ Cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein said alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally selected from halogen, alkoxy, haloalkoxy, hydroxy, hydroxyalkyl, cyano, -NR ⁵ R ⁶ 、OR ⁷ Cycloalkyl, heterocyclyl, aryl and heteroaryl;

R ^’ the same or different and each is independently selected from the group consisting of hydrogen atom, halogen, alkyl, alkenyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, cyano, -NR ² R ³ and-SO ₂ R ⁴ ；

R ² And R ³ Are 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;

R ⁴ selected from the group consisting of hydrogen atoms, alkyl groups, cycloalkyl groups, heterocyclic groups, and aryl groups; r is ⁵ 、R ⁶ And R ⁷ The same or different and each is independently selected from the group consisting of hydrogen atoms, alkyl groups and cycloalkyl groups, wherein said alkyl and cycloalkyl groups are optionally selected from the group consisting of halogen, alkyl, alkenyl, alkoxy, haloalkyl, haloalkoxy, hydroxySubstituted with one or more substituents selected from the group consisting of alkyl, hydroxyalkyl, cyano, amino, cycloalkyl, heterocyclyl, aryl and heteroaryl;

p is 1 or 2;

q is 0, 1,2, 3, 4,5 or 6.

Another aspect of the present disclosure relates to a compound of formula (IIA) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof,

wherein:

x is halogen;

l is a single bond or is selected from-C (O) -, -S (O) ₂ -, -S (O) -, -C (S) -and-CH ₂ -；

Y is selected from the group consisting of alkyl, alkoxy, hydroxy, hydroxyalkyl, cyano, amino, -NR ⁵ R ⁶ 、-OR ⁷ Cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein said alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally selected from halogen, alkoxy, haloalkoxy, hydroxy, hydroxyalkyl, cyano, -NR ⁵ R ⁶ 、OR ⁷ Cycloalkyl, heterocyclyl, aryl and heteroaryl;

R ⁵ 、R ⁶ and R ⁷ The same or different, and each is independently selected from the group consisting of hydrogen atoms, alkyl groups, and cycloalkyl groups, wherein the alkyl and cycloalkyl groups are optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl, alkenyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, cyano, amino, cycloalkyl, heterocyclyl, aryl, and heteroaryl.

Typical intermediate compounds of the present disclosure include, but are not limited to:

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:

compounds of the general formula (IA) and R ¹ -M is subjected to a coupling reaction to obtain a compound of general formula (I),

wherein:

x is halogen; preferably Cl;

m is

R ¹ 、L、Y、R ^’ P and q are as 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:

the compound of the general formula (IIA) and the compound of the general formula (IIB) are subjected to coupling reaction to obtain a compound of a general formula (II),

wherein:

x is halogen; preferably Cl;

m is

R ⁸ Y, L and n are as defined in formula (II).

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 tautomers, mesomers, racemates, enantiomers, diastereomers or mixtures thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the same, for use in the treatment of tumors.

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 1000mg.

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.

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 the oil phase, the injection or microemulsion being injectable in the bloodstream of the patient by local bolus 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 of the 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 suitable dispersing or wetting agents and suspending agents. 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 mode of treatment, daily amount of compound or 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, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-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-methylhexyl, 3-methylhexyl, 4-methylhexyl 2,3-dimethylpentyl group, 2,4-dimethylpentyl group, 2,2-dimethylpentyl group, 3,3-dimethylpentyl group, 2-ethylpentyl group, 3-ethylpentyl group, n-octyl group, 2,3-dimethylhexyl group, 2,4-dimethylhexyl group, 2,5-dimethylhexyl group, 2,2-dimethylhexyl group, 3,3-dimethylhexyl group, 4,4-dimethylhexyl group, 2-ethylhexyl group, 3-ethylhexyl group, 4-ethylhexyl group, 2-methyl-2-ethylpentyl group, 2-methyl-3-ethylpentyl group, n-nonyl group, 2-methyl-2-ethylhexyl group, 2-methyl-3-ethylhexyl group, 2,2-diethylpentyl group, n-decyl group, 3,3-diethylhexyl group, 2,2-diethylhexyl group, and various branched chain isomers thereof, and the like. More preferred are lower alkyl groups containing 1 to 6 carbon atoms, non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-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 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, which is a straight or branched chain group containing from 1 to 20 carbon atoms, preferably containingAlkylene groups having 1 to 12 (e.g., 1,2, 3, 4,5, 6,7, 8, 9, 10, 11, and 12) carbon atoms, more preferably 1 to 6 carbon atoms. Non-limiting examples of alkylene groups include, but are not limited to, methylene (-CH) ₂ -), 1,1-ethylene (-CH (CH) ₃ ) -), 1,2-ethylene (-CH) ₂ CH ₂ ) -, 1,1-propylene (-CH (CH) ₂ CH ₃ ) -), 1,2-propylene (-CH) ₂ CH(CH ₃ ) -), 1,3-propylene (-CH) ₂ CH ₂ CH ₂ -), 1,4-butylidene (-CH) ₂ CH ₂ CH ₂ CH ₂ -) and the like. The alkylene 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 alkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, cycloalkyloxy, heterocyclyloxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocyclyloxy, cycloalkylthio, heterocyclylthio 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 groups substituted with one or more substituents independently selected from the group consisting of hydrogen atom, alkyl group, alkoxy group, halogen, haloalkyl group, haloalkoxy group, cycloalkyloxy group, heterocyclyloxy group, hydroxy 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:

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). Bicyclic, tricyclic, tetracyclic, or polycyclic fused ring alkyls may be classified according to the number of constituent 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 bicycloalkyl groups. Non-limiting examples of fused ring alkyl groups include:

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 as bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl groups, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic, according to the number of constituent rings. Non-limiting examples of bridged cycloalkyl groups include:

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), wherein alkyl is as defined above. Non-limiting examples of alkoxy groups include: methoxy, ethoxy, propoxy and butoxy. Alkoxy groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from D atoms, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

Term(s) for"Heterocyclyl" means a saturated or partially unsaturated monocyclic 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, sulfur, S (O) or S (O) ₂ <xnotran> , -O-O-, -O-S- -S-S- , . </xnotran> 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 3 to 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 groups include spiro, fused and bridged heterocyclic groups.

The term "spiroheterocyclyl" refers to 5 to 20 membered polycyclic heterocyclic group having one atom (referred to as a spiro atom) in common between monocyclic rings, wherein one or more of the ring atoms is selected from nitrogen, oxygen, sulfur, S (O) or S (O) ₂ 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 heterocyclyl groups include:

the term "fused heterocyclyl" refers to a 5 to 20 membered polycyclic heterocyclic group in which each ring in the system shares an adjacent pair of atoms with the other rings in the system, and 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, sulfur, S (O) or S (O) ₂ With the remaining ring atoms beingCarbon. 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, and are 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:

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, sulfur, S (O) or S (O) ₂ 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:

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:

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 is fused to a heteroaryl, heterocyclyl or cycloalkyl ring as described above, wherein the ring to which the parent structure is attached is an aryl ring, non-limiting examples of which include:

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 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 containing 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:

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 amino protecting group is preferably tetrahydropyranyl.

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-NH ₂ 。

The term "cyano" refers to — CN.

The term "nitro" means-NO ₂ 。

The term "carbonyl" refers to C = O.

The term "oxo" means "= 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, 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 except that "deuterium" or "tritium" is substituted for hydrogen, or ¹⁸ F-fluorine labeling: ( ¹⁸ Isotope of F) instead of fluorine, or with ¹¹ C-， ¹³ C-, or ¹⁴ C-enrichment carbon (C) of (C) ¹¹ C-， ¹³ C-, or ¹⁴ C-carbon labeling; ¹¹ C-， ¹³ c-, or ¹⁴ C-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.

Various deuterated forms of the compounds of the general formula of the present disclosure. Each available hydrogen atom attached to a carbon atom may be independently replaced by a deuterium atom. The person skilled in the art is able to synthesize compounds of the general formula in deuterated form with reference to the relevant literature. Commercially available deuterated starting materials can be used in preparing the deuterated forms of the compounds of formula or they can be synthesized using conventional techniques using deuterated reagents including, but not limited to, deuterated boranes, trideuteroborane in tetrahydrofuran, 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 hydrogen atoms, preferably 1 to 5, more preferably 1 to 3, of the hydrogen atoms in the group are independently substituted with a corresponding number of substituents. Those skilled in the art will be 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 compounds, 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 "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 following technical solutions are adopted in the present disclosure:

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:

a compound of the general formula (IA) and R ¹ -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

R ¹ 、L、Y、R ^’ P and q are as 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:

the compound of the general formula (IIA) and the compound of the general formula (IIB) are subjected to coupling reaction in the presence of a catalyst under an alkaline condition to obtain a compound of a general formula (II),

wherein:

x is halogen; preferably Cl;

m is

R ⁸ Y, L and n are as 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, chlorine (2-dicyclohexylphosphino-2 ',4',6 '-triisopropyl-1,1' -biphenyl) [2- (2 '-amino-1,1' -biphenyl) ] palladium, [1,1 '-bis (diphenylphosphino) ferrocene ] palladium dichloride, [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride dichloromethane, 1,1 '-bis (dibenzylphosphine) ferrocene palladium dichloride, 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 ^-6 The 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) ₃ OD), internal standard Tetramethylsilane (TMS).

MS was measured 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 analytical determination Agilent 1260DAD HPLC was used.

High Performance liquid preparation preparative chromatographs were prepared using Waters 2545-2767, waters 2767-SQ Detector 2, shimadzu LC-20AP and Gilson GX-281.

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 a cigarette platform yellow sea HSGF254 or Qingdao GF254 silica gel plate, the specification of the silica gel plate used by the 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 Litsea crassirhizomes as a carrier.

Average inhibition rate of kinase and IC ₅₀ The values were determined with a NovoStar microplate reader (BMG, germany).

Known starting materials of the present disclosure can be synthesized using or according to methods known in the art, or can be purchased from companies such as ABCR GmbH & Co. KG, acros Organics, aldrich Chemical Company, shaoyuan ChemBiotech (Accela ChemBio Inc), darril 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 uses 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 is usually carried out by vacuum pumping, hydrogen filling and repeated operation for 3 times.

The microwave reaction was carried out using a CEM Discover-S908860 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: in the petroleum ether/ethyl acetate system, the volume ratio of the solvent is adjusted according to different polarities of the compounds, and a small amount of basic or acidic reagents such as triethylamine, acetic acid and the like can be added for adjustment.

Example 1

(R) -N-Ethyl-2- (3-methylmorpholinyl) -4- (1H-pyrrolo [2,3-b ] pyridin-4-yl) -5H-pyrrolo [2,3-d ] pyrimidine

-7 (6H) -carboxamide 1

First step of

6,7-dihydro-5H-pyrrolo [2,3-d ] pyrimidine-2,4-diol trifluoroacetate 1b

The compound 2,4-dihydroxypyrrolo [2,3-d ] pyrimidine 1a (3g, 19.9mmol, obtained after completion of shanghai) was dissolved in trifluoroacetic acid, cooled in ice water, triethylchlorosilane (9g, 59.7mmol) was slowly added dropwise, and after completion of the addition, stirring was carried out for 14 hours, the reaction solution was concentrated under reduced pressure, and the residue was washed with n-hexane, filtered, and the filter cake was dried to obtain the title compound 1b (3 g), yield: 61 percent.

MS m/z(ESI):154.2[M+1]

Second step of

2,4-dichloro-6,7-dihydro-5H-pyrrolo [2,3-d ] pyrimidine 1c

Compound 1b (2.3g, 8.6 mmol) was dissolved in 16mL of phosphorus oxychloride, N-diisopropylethylamine (3.89g, 30.1 mmol) was added dropwise, and after completion of the addition, stirring was carried out at 90 ℃ for 14 hours. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and the resulting residue was added dropwise to ice water, extracted with ethyl acetate (50 mL × 3), the organic phase was collected, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was sampled with silica gel and purified by silica gel column chromatography with eluent system a to give the title compound 1c (900 mg), yield: and 55 percent.

MS m/z(ESI):190.0[M+1]

The third step

(R) -4- (4-chloro-6,7-dihydro-5H-pyrrolo [2,3-d ] pyrimidin-2-yl) -3-methylmorpholine 1e

Compound 1c (900mg, 4.7mmol) was dissolved in 10mL of N, N-dimethylacetamide, N-diisopropylethylamine (1.2g, 9.8mmol) and compound (R) -3-methylmorpholine 1d (955mg, 9.4mmol, obtained after shanghai) were added, and the mixture was heated to 120 ℃ with microwave and stirred for 4 hours, and the reaction mixture was cooled to room temperature, concentrated under reduced pressure, and purified by silica gel column chromatography with eluent system a to give the title compound 1e (330 mg), yield: 22 percent.

MS m/z(ESI):255.1[M+1]

The fourth step

(R) -4-chloro-N-ethyl-2- (3-methylmorpholinyl) -5H-pyrrolo [2,3-d ] pyrimidine-7 (6H) -carboxamide 1g

Compound 1e (330mg, 1.3mmol) and compound ethyl isocyanate 1f (184mg, 2.6mmol, adamas) were dissolved in 5mL of n, n-dimethylformamide, triethylamine (262mg, 2.6 mmol) was added, the mixture was stirred at 80 ℃ for 14 hours with a tube sealed, the reaction was cooled to room temperature, concentrated under reduced pressure, and purified by silica gel column chromatography using eluent system a to give the title compound 1g (400 mg), yield: 94 percent.

MS m/z(ESI):326.1[M+1]

The fifth step

(R) -N-Ethyl-2- (3-methylmorpholinyl) -4- (1H-pyrrolo [2,3-b ] pyridin-4-yl) -5H-pyrrolo [2,3-d ] pyrimidine-7 (6H) -carboxamide 1

Compound 1g (400mg, 1.3 mmol) was dissolved in 10mL of 1, 4-dioxane, 2mL of water under argon atmosphere, 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrrolo [2,3-b ] pyridine 1H (369mg, 1.5mmol, obtained from shanghai, 1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride (180 mg,0.13 mmol), sodium carbonate (275mg, 2.6 mmol), heated to 80 ℃ and stirred for 2 hours, the reaction solution was cooled to room temperature, cooled, filtered through celite, the filtrate was concentrated under reduced pressure, and the resulting crude product was purified by high performance liquid chromatography (Waters-2767, elution system: ammonium bicarbonate, water, acetonitrile) to give the title 1 (210 mg), yield: 42 percent.

MS m/z(ESI):408.1[M+1]

¹ H NMR(400MHz,CDCl ₃ ):δ9.50(s,1H),8.77(t,1H),8.39(d,1H),7.42(s,1H), 6.86(s,1H),4.59(s,1H),4.28(d,1H),4.11(t,2H),4.02(dd,1H),3.78(m 2H),3.61 (m,1H),3.49-3.31(m,3H),3.17-3.03(m,2H),1.39(d,3H),1.26(t,3H).

Example 2

(R) -N-cyclopropyl-2- (3-methylmorpholinyl) -4- (1H-pyrrolo [2,3-b ] pyridin-4-yl) -5H-pyrrolo [2,3-d ] pyrimidine-7 (6H) -carboxamide 2

First step of

(R) -4-chloro-N-cyclopropyl-2- (3-methylmorpholinyl) -5H-pyrrolo [2,3-d ] pyrimidine-7 (6H) -carboxamide 2b

Compound 1e (35mg, 0.137mmol) was dissolved in 5mL of dichloromethane, and N, N-diethylethylamine (42mg, 0.415mmol) and triphosgene (120mg, 0.404mmol) were added thereto at room temperature, followed by stirring for 1 hour. The reaction mixture was concentrated under reduced pressure, and methylene chloride (5 mL) was added to dissolve the reaction mixture, and cyclopropylamine 2a (39mg, 0.683mmol, obtained after finishing Shanghai) was added thereto and stirred for 1 hour. The reaction mixture was concentrated under reduced pressure to give the title compound 2b (46 mg), which was directly subjected to the next reaction without purification.

MS m/z(ESI):338.0[M+1]。

Second step of

(R) -N-cyclopropyl-2- (3-methylmorpholinyl) -4- (1H-pyrrolo [2,3-b ] pyridin-4-yl) -5H-pyrrolo [2,3-d ] pyrimidine-7 (6H) -carboxamide 2

Compound 2b (46mg, 0.136mmol) was dissolved in 2mL of 1, 4-dioxane, 0.5mL of water under argon atmosphere, 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrrolo [2,3-b ] pyridine 1H (46mg, 0.188mmol, obtained from shanghai peei), [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium (15 mg,0.02 mmol), sodium carbonate (28mg, 0.26mmol), heated to 80 ℃ and stirred for 2 hours, the reaction was cooled to room temperature, cooled, filtered through celite, the filtrate was concentrated under reduced pressure, the resulting crude product was purified by high performance liquid chromatography (Waters-2767, elution system: ammonium bicarbonate, water, acetonitrile) to give the title 2 (15 mg) product in yield: 26 percent.

MS m/z(ESI):420.1[M+1]

¹ H NMR(400MHz,CD ₃ OD):δ8.28(d,1H),7.48(d,1H),7.32(d,1H),6.81(d,1H), 4.55(s,1H),4.24(d,1H),4.11-3.94(m,3H),3.86-3.79(m,1H),3.78-3.71(m,1H), 3.60(dt,1H),3.38(dd,1H),3.19-3.07(m,2H),2.79(tt,1H),1.36(d,3H),0.84(dd, 2H),0.63-0.52(m,2H).

Example 3

(R) -N- (cyclopropylmethyl) -2- (3-methylmorpholinyl) -4- (1H-pyrrolo [2,3-b ] pyridin-4-yl) -5H-pyrrolo [2,3-d ] pyrimidine-7 (6H) -carboxamide 3

First step of

(R) -4-chloro-N- (cyclopropylmethyl) -2- (3-methylmorpholinyl) -5H-pyrrolo [2,3-d ] pyrimidine-7 (6H) -carboxamide 3b

Compound 1e (45mg, 0.176mmol) was dissolved in 5mL of dichloromethane, N-diethylethylamine (53mg, 0.52mmol) and triphosgene (157mg, 0.53mmol) were added at room temperature, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and methylene chloride (5 mL) was added to dissolve the mixture, and cyclopropylmethylamine 3a (62mg, 0.871mmol, obtained after finishing Shanghai) was added thereto and stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure to give the title compound 3b (106 mg), which was directly subjected to the next reaction without purification.

MS m/z(ESI):352.0[M+1]。

Second step of

(R) -N- (cyclopropylmethyl) -2- (3-methylmorpholinyl) -4- (1H-pyrrolo [2,3-b ] pyridin-4-yl) -5H-pyrrolo [2,3-d ] pyrimidine-7 (6H) -carboxamide 3

Compound 3b (106mg, 0.301mmol) was dissolved in 3mL of 1, 4-dioxane, 1mL of water under argon, 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrrolo [2,3-b ] pyridine 1H (88mg, 0.36mmol, obtained from shanghai pee), [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride (33mg, 0.045 mmol), sodium carbonate (95mg, 0.896mmol), heated to 80 ℃ and stirred for 2 hours, the reaction was cooled to room temperature, cooled, filtered through celite, the filtrate was concentrated under reduced pressure, and the resulting crude product was purified by high performance liquid chromatography (Waters-2767, elution system: ammonium bicarbonate, water, acetonitrile) to give the title 3 (50 mg) in yield: 38 percent.

MS m/z(ESI):434.2[M+1]

¹ H NMR(400MHz,CD ₃ OD):δ8.28(d,1H),7.48(d,1H),7.32(d,1H),6.82(d,1H), 4.30(d,1H),4.09-3.95(m,3H),3.84-3.69(m,2H),3.60(dt,1H),3.42-3.33(m,2H), 3.28-3.18(m,2H),3.17-3.08(m,2H),1.36(d,3H),1.14-1.05(m,1H),0.57(d,2H), 0.30(d,2H).

Example 4

(R) -N-methyl-2- (3-methylmorpholinyl) -4- (1H-pyrrolo [2,3-b ] pyridin-4-yl) -5H-pyrrolo [2,3-d ] pyrimidine-7 (6H) -carboxamide 4

First step of

(R) -4-chloro-N-methyl-2- (3-methylmorpholinyl) -5H-pyrrolo [2,3-d ] pyrimidine-7 (6H) -carboxamide 4a

Compound 1e (20mg, 0.08mmol) was dissolved in 5mL of methylene chloride, and N, N-diisopropylethylamine (158.91mg, 1.57mmol) and triphosgene (104.85mg, 0.35mmol) were added at room temperature, followed by stirring at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and methylene chloride (5 mL) was added to dissolve the mixture, and a methylamine tetrahydrofuran solution (5 mL, alfa) was added thereto and stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system A to give the title compound 4a (10 mg, yield: 40.8%).

MS m/z(ESI):312.0[M+1]。

Second step of

(R) -N-methyl-2- (3-methylmorpholinyl) -4- (1H-pyrrolo [2,3-b ] pyridin-4-yl) -5H-pyrrolo [2,3-d ] pyrimidine-7 (6H) -carboxamide 4

Compound 4a (10mg, 0.032mmol) was dissolved in 3mL of 1, 4-dioxane, 1mL of water under argon atmosphere, 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrrolo [2,3-b ] pyridine 1H (11.74mg, 0.048mmol), [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride dichloromethane (2.35 mg, 0.0032 mmol), sodium carbonate (10.2mg, 0.096mmol), microwave-heated to 100 ℃ and stirred for 1 hour, the reaction was cooled to room temperature, concentrated under reduced pressure, cooled, filtered through celite, the filtrate was concentrated, and the resulting crude product was purified by high performance liquid chromatography (Waters-2767, elution system: ammonium bicarbonate, water, acetonitrile) to give the title product 4 (5 mg), yield: 39.7 percent.

MS m/z(ESI):394.0[M+1]

¹ H NMR(400MHz,CDCl ₃ ):δ8.67(s,1H),8.37(t,1H),7.53(s,1H),7.32(s,1H), 7.00(s,1H),6.89(s,1H),4.61(s,1H),4.27-4.05(m,5H),3.85-3.61(m,4H),3.49-3.25 (m,1H),3.10(s,3H),1.40(d,3H)

Example 5

(R) -3- (2- (3-methylmorpholinyl) -4- (1H-pyrrolo [2,3-b ] pyridin-4-yl) -5H-pyrrolo [2,3-d ] pyrimidin-7 (6H) -yl) -3-oxopropanenitrile 5

First step of

2-Cyanoacetyl chloride 5b

2-Cyanoacetic acid 5a (500mg, 5.88mmol) was dissolved in 20mL of dichloromethane, and 0.1mL of N, N-dimethylformamide and oxalyl chloride (1.6g, 12.6 mmol) were added, and the reaction was stirred for 0.5 hour. The reaction was concentrated under reduced pressure to give the title compound 5b (600 mg), which was directly subjected to the next reaction without purification.

Second step of

(R) -3- (4-chloro-2- (3-methylmorpholinyl) -5H-pyrrolo [2,3-d ] pyrimidin-7 (6H) -yl) -3-oxopropanenitrile 5c

Compound 1e (70mg, 0.27mmol), 5b (600mg, 5.8mmol) was dissolved in 10mL of acetonitrile, pyridine (1mL, 12.4 mmol), 4-dimethylaminopyridine (10mg, 0.081mmol) was added at room temperature, and the mixture was heated to 100 ℃ with a sealed tube and reacted for 14 hours. The reaction solution was cooled to room temperature, concentrated under reduced pressure, added with water (20 mL), extracted with ethyl acetate (20 mL. Times.2), the combined organic phases were concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system A to give the title compound 5c (80 mg, yield: 90.4%).

MS m/z(ESI):322.2[M+1]。

The third step

(R) -3- (2- (3-methylmorpholinyl) -4- (1H-pyrrolo [2,3-b ] pyridin-4-yl) -5H-pyrrolo [2,3-d ] pyrimidin-7 (6H) -yl) -3-oxopropanenitrile 5

Dissolving compound 5c (80mg, 0.25mmol) in 5mL of 1, 4-dioxane, 1mL of water under argon atmosphere, adding 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrrolo [2,3-b ] pyridine 1H (78mg, 0.32mmol), [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium (27mg, 0.037mmol), sodium carbonate (79mg, 0.74mmol), microwave heating to 80 ℃ for 1 hour, cooling the reaction solution to room temperature, concentrating under reduced pressure, cooling, filtering through diatomaceous earth, concentrating the filtrate, purifying the resulting crude product with high performance liquid chromatography (Waters-2767, elution system: ammonium bicarbonate, water, acetonitrile) to obtain compound 5 (25 mg), yield: 24.9 percent.

MS m/z(ESI):404.2[M+1]

¹ H NMR(400MHz,CDCl ₃ ):δ9.07(s,1H),8.42(d,1H),7.44(s,1H),7.26(s,1H), 6.84(d,1H),4.70(s,1H),4.41-4.28(m,3H),4.14(t,2H),4.09-4.00(m,1H),3.87 -3.72(m,2H),3.66-3.56(m,1H),3.46-3.35(m,1H),3.24-3.11(m,2H),1.40(d, 3H)

Example 6

(R) -2-hydroxy-1- (2- (3-methylmorpholinyl) -4- (1H-pyrrolo [2,3-b ] pyridin-4-yl) -5H-pyrrolo [2,3-d ] pyrimidin-7 (6H) -yl) ethanone 6

First step of

(R) -2- (4-chloro-2- (3-methylmorpholinyl) -5H-pyrrolo [2,3-d ] pyrimidin-7 (6H) -yl) -2-oxoethyl acetate 6b

Compound 1e (60mg, 0.23mmol), 2-chloro-2-oxoethyl acetate 6a (160mg, 1.17 mmol, obtained after Shanghai Biao) were dissolved in 5mL of acetonitrile, pyridine (117mg, 1.48mmol), 4-dimethylaminopyridine (6 mg, 0.048mmol) were added thereto at room temperature, and the mixture was heated to 80 ℃ with a sealed tube and reacted for 14 hours. The reaction solution was cooled to room temperature, concentrated under reduced pressure, added with water (20 mL), extracted with ethyl acetate (20 mL. Times.2), the combined organic phases were concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system A to give the title compound 6b (80 mg, yield: 95.7%). MS m/z (ESI) 355.1[ 2 ] M +1].

Second step of

(R) -2- (2- (3-methylmorpholinyl) -4- (1H-pyrrolo [2,3-b ] pyridin-4-yl) -5H-pyrrolo [2,3-d ] pyrimidin-7 (6H) -yl) -2-oxoethyl acetate 6c

Compound 6b (80mg, 0.22mmol) was dissolved in 5mL of 1, 4-dioxane, 1mL of water under argon, 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrrolo [2,3-b ] pyridine 1H (66mg, 0.27mmol), [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium (24mg, 0.032mmol), sodium carbonate (47mg, 0.44mmol) were added sequentially, microwave heated to 80 ℃ and stirred for 1 hour, the reaction solution was cooled to room temperature, concentrated under reduced pressure, cooled, the filtrate was concentrated by filtration through celite, and purified by silica gel column chromatography with eluent system a to give the title compound 6c (98 mg), yield: 99.5 percent.

MS m/z(ESI):437.2[M+1]

The third step

(R) -2-hydroxy-1- (2- (3-methylmorpholinyl) -4- (1H-pyrrolo [2,3-b ] pyridin-4-yl) -5H-pyrrolo [2,3-d ] pyrimidin-7 (6H) -yl) ethanone 6

Compound 6c (40mg, 0.091mmol) was dissolved in 5mL of methanol and 1mL of water, and sodium hydrogencarbonate (28mg, 0.33mmol) was added at room temperature, followed by stirring for 5 hours. The reaction solution was adjusted to pH =7 with 1N HCl, concentrated under reduced pressure, and the resulting crude product was purified by high performance liquid chromatography (Waters-2767, elution: ammonium bicarbonate, water, acetonitrile) to give the title product 6 (6 mg, yield: 16.6%).

MS m/z(ESI):395.1[M+1]

¹ H NMR(400MHz,CDCl ₃ ):δ9.49(s,1H),8.39(d,1H),7.43(d,1H),7.25-7.11(m, 1H),6.85(d,1H),4.88(d,2H),4.69(s,1H),4.35(d,1H),4.15(t,2H),4.02(dd,1 H),3.83-3.70(m,2H),3.59(dt,1H),3.37(dt,1H),3.25-3.16(m,2H),1.30-1.22 (m,3H)

Example 7

(R) -2- (3-Methylmorpholinyl) -4- (1H-pyrrolo [2,3-b ] pyridin-4-yl) -5H-pyrrolo [2,3-d ] pyrimidine-7 (6H) -carboxylic acid methyl ester 7

First step of

(R) -4-chloro-2- (3-methylmorpholinyl) -5H-pyrrolo [2,3-d ] pyrimidine-7 (6H) -carboxylic acid methyl ester 7b

Compound 1e (70mg, 0.27mmol) was dissolved in 5mL of N, N-dimethylformamide, and sodium hydride (30mg, 0.75mmol, 60%) was added thereto at room temperature, followed by stirring for 0.5 hour, methyl chloroformate 7a (54 mg, 0.57 mmol) was added thereto at room temperature, followed by stirring for 14 hours. The reaction solution was quenched with 30mL of water, extracted with ethyl acetate (20 mL. Times.2), the combined organic phases were concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system A to give the title compound 7b (75 mg, yield: 87.2%).

MS m/z(ESI):313.0[M+1]。

Second step of

(R) -2- (3-Methylmorpholinyl) -4- (1H-pyrrolo [2,3-b ] pyridin-4-yl) -5H-pyrrolo [2,3-d ] pyrimidine-7 (6H) -carboxylic acid methyl ester 7

Compound 7b (75mg, 0.24mmol) was dissolved in 5mL of 1, 4-dioxane, 1mL of water under argon atmosphere, 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrrolo [2,3-b ] pyridine 1H (276mg, 0.36mmol), [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium (22.6mg, 0.027 mmol), sodium carbonate (54.7mg, 0.51mmol), microwave heated to 80 ℃ and stirred for 1 hour, the reaction was cooled to room temperature, concentrated under reduced pressure, cooled, filtered through celite, the filtrate was concentrated, and the resulting crude product was purified by high performance liquid chromatography (Waters-2767, elution system: ammonium bicarbonate, water, acetonitrile) to give the title product 7 (70 mg), yield: 57.8 percent.

MS m/z(ESI):395.1[M+1]

¹ H NMR(400MHz,CDCl ₃ ):δ13.74(s,1H),8.28(d,1H),7.63(m,1H),7.52(d, 1H),7.00(m,1H),4.81(m,1H),4.44(d,1H),4.10-3.99(m,3H),3.92(s,3H), 3.81-3.73(m,2H),3.61-3.55(m,1H),3.42-3.35(m,1H),3.19-3.04(m,2H),1.37(d,3H).

Example 8

(R) -3-methyl-4- (7- (methylsulfonyl) -4- (1H-pyrrolo [2,3-b ] pyridin-4-yl) -6,7-dihydro-5H-pyrrolo [2,3-d ] pyrimidin-2-yl) morpholine 8

First step of

(R) -4- (4-chloro-7- (methylsulfonyl) -6,7-dihydro-5H-pyrrolo [2,3-d ] pyrimidin-2-yl) -3-methylmorpholine 8b

Compound 1e (10mg, 0.04mmol), methanesulfonyl chloride 8a (500mg, 0.39mmol) was dissolved in 5mL of acetonitrile, pyridine (200mg, 2.52mmol), 4-dimethylaminopyridine (10mg, 0.081mmol) were added at room temperature, and the mixture was heated to 80 ℃ with a sealed tube and reacted for 14 hours. The reaction solution was cooled to room temperature, concentrated under reduced pressure, added with water (20 mL), extracted with ethyl acetate (20 mL. Times.2), the combined organic phases were concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system A to give the title compound 8b (10 mg, yield: 76.5%).

MS m/z(ESI):333.0[M+1]。

Second step of

(R) -3-methyl-4- (7- (methylsulfonyl) -4- (1H-pyrrolo [2,3-b ] pyridin-4-yl) -6,7-dihydro-5H-pyrrolo [2,3-d ] pyrimidin-2-yl) morpholine 8

Compound 8b (10mg, 0.03mmol) was dissolved in 5mL of 1, 4-dioxane and 1mL of water under an argon atmosphere, and 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrrolo [2,3-b ] pyridine 1H (14.7mg, 0.06mmol), [1,1' -bis (diphenylphosphine) ferrocene ] dichloropalladium (6.7mg, 0.0045 mmol), sodium carbonate (10mg, 0.06mmol), microwave-heated to 80 ℃ and stirred for 1 hour, the reaction solution was cooled to room temperature, concentrated under reduced pressure and cooled, and the resulting crude product was purified by high performance liquid chromatography (Waters-2767, elution system: ammonium bicarbonate, water, acetonitrile) to give the title product 8 (3.3 mg, yield: 26.7%).

MS m/z(ESI):415.2[M+1]

¹ H NMR(400MHz,CD ₃ OD):δ8.27(d,1H),7.47(d,1H),7.30(d,1H),6.81(d,1H), 4.76-4.72(m,1H),4.60(s,1H),4.40(d,1H),4.05(t,2H),4.03(d,1H),3.77-3.72(m, 2H),3.56-3.53(m,1H),3.36-3.33(m,3H),3.17(t,2H),1.33(d,3H)

Example 9

(R) -N-methyl-2- (3-methylmorpholinyl) -4- (1H-pyrrolo [2,3-b ] pyridin-4-yl) -5H-pyrrolo [2,3-d ] pyrimidine-7 (6H) -sulfonamide 9

First step of

(R) -4-chloro-N-methyl-2- (3-methylmorpholinyl) -5H-pyrrolo [2,3-d ] pyrimidine-7 (6H) -sulfonamide 9b

Compound 1e (30mg, 0.12mmol), methylaminosulfonyl chloride 9a (30.5mg, 0.24mmol, obtained from Shanghai) were dissolved in 5mL acetonitrile, pyridine (29mg, 0.36mmol), 4-dimethylaminopyridine (14.5mg, 0.12mmol) were added at room temperature, and the mixture was heated to 80 ℃ with a sealed tube and reacted for 14 hours. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, added with water (20 mL), extracted with ethyl acetate (20 mL. Times.2), the combined organic phases were concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system A to give the title compound 9b (30 mg, yield: 59.3%). MS m/z (ESI) 348.0[ m +1].

Second step of

(R) -N-methyl-2- (3-methylmorpholinyl) -4- (1H-pyrrolo [2,3-b ] pyridin-4-yl) -5H-pyrrolo [2,3-d ] pyrimidine-7 (6H) -sulfonamide 9

Compound 9b (30mg, 0.086 mmol) was dissolved in 5mL of 1, 4-dioxane, 1mL of water under argon, 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrrolo [2,3-b ] pyridine 1H (31.6mg, 0.13mmol), [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride (6.4mg, 0.009 mmol), sodium carbonate (18.3mg, 0.17mmol), heated to 70 ℃ and stirred for 2 hours, the reaction was cooled to room temperature, concentrated under reduced pressure, cooled, and the resulting crude product was purified by high performance liquid chromatography (Waters-2767, eluent: ammonium bicarbonate, water, acetonitrile) to give the title product 9 (5 mg, yield: 13.5%).

MS m/z(ESI):430.1[M+1]

¹ H NMR(400MHz,CDCl ₃ ):δ9.50(s,1H),8.40(s,1H),7.44(d,1H),6.88(s,1H), 5.57(d,1H),4.66(s,1H),4.32(d,1H),4.11(t,2H),4.01(d,1H),3.88-3.71(m,2H), 3.59(dd,1H),3.46-3.31(m,1H),3.21(t,2H),2.81(d,3H),1.37(d,3H).

Test example:

biological evaluation

Test example 1 inhibitory Effect of the Compounds of the present disclosure 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:

1. experimental materials and instruments

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)

4.U model bottom 96-well plate (Corning, 3795)

5. Europium cryptate-labeled anti-phosphorylated P53 protein antibody (cisbio, 61P08 KAE)

6. anti-GST antibody linked to d2 (cisbio, 61 GSTDLF)

ATP solution (Promega, V916B)

8.EDTA(Thermo Scientific，AM9260G)

9.HEPES(Gibco，15630-080)

10. Enzyme mark instrument (BMG, PHERASta)

2. Experimental procedure

ATR enzyme 1nM, P53 protein 50nM, 7.435. Mu.M ATP and different concentrations (first concentration 1. Mu.M, 3-fold gradient dilution 11 concentrations, dilution solvent 25mM HEPES pH8.0,0.01% Brij-35,1% glycerol) of small molecule compounds were mixed and incubated at room temperature for 2 hours, then stop buffer (12.5 mM HEPES, 250mM EDTA) was added and mixed, and 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.

3. Experimental data

The inhibitory activity of the disclosed compounds against ATR enzyme can be measured by the above test, and the IC measured ₅₀ The values are shown in Table 1.

TABLE 1 IC inhibition of ATR enzyme by the compounds of this disclosure ₅₀ Value of

Example numbering	IC 50 /nM	Max Inhibition(％)
			1	15	99
2	18	100
			3	9	100
4	60	97
			5	155	94
6	66	93

And (4) conclusion: the disclosed compound has good inhibitory activity to ATR enzyme.

Test example 2 selectivity test for ATR enzyme with Compound of the present disclosure

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.

1. Experimental materials and instruments

ATM enzyme (Eurofins Pharma Discovery Services, 14-933-M)

GST tag P53 protein (Eurofins Pharma Discovery Services, 14-952-M)

3.384 orifice plate (Thermo Scientific, 267462)

4.U model bottom 96-well plate (Corning, 3795)

5. Europium cryptate-labeled anti-phosphorylated P53 protein antibody (cisbio, 61P08 KAE)

6. anti-GST antibody linked to d2 (cisbio, 61 GSTDLF)

ATP solution (Promega, V916B)

8.EDTA(Thermo Scientific，AM9260G)

9.HEPES(Gibco，15630-080)

10. Enzyme mark instrument (BMG, PHERASta)

2. Experimental procedure

ATM enzyme 1nM, P53 protein 30nM, 11. Mu.M ATP and different concentrations (first concentration 10. Mu.M, 3-fold gradient dilution 11 concentrations, solvent 25mM HEPES pH8.0,0.01% Brij-35,1% glycerol) of small molecule compounds were mixed and incubated at room temperature for 2 hours, then stop buffer (12.5 mM 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 linked d2 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 IC ₅₀ The values are shown in Table 2.

(II) inhibitory effect of the disclosed compounds on PI3K enzyme.

1. Experimental materials and instruments

PIK3CA/PIK3R1 (p 110 alpha/p85 alpha) kinase (Invitrogen, PV 4788)

pIP2

3.DTT(Sigma，43815-1G)

Tris-HCl (1M, pH 7.5) (Beijing Tian Enze Biotechnology Co., ltd., 101205-100)

ATP solution (Promega, V916B)

6. Magnesium chloride hexahydrate (Sigma, M2393)

7. Sodium chloride (national drug group chemical agents, inc., 10019318)

8.CHAPS(Sigma，C3023-5G)

9.HEPES(Gibco，15630-080)

10.ADP-Glo ^TM Kinase kit (Promega, V9102)

11.384 orifice plate (Thermo Scientific, 267462)

type-U bottom 96-well plate (Corning, 3795)

13. Enzyme mark instrument (BMG, PHERAStar)

2. Experimental procedure

The final concentration of the PI3K enzyme was 0.625nM, and the concentrations were varied (initial concentration 10. Mu.M, 3-fold gradient dilution 10 concentrations, solvent 10mM Tris-HCl pH7.5, 50mM NaCl,3mM MgCl ₂ 0.05% CHAPS, 100. Mu.M) ofMixing the molecular compounds, incubating at room temperature for 30 min, adding PIP2: PS lipid substrate (final concentration 50 μ M) and 1 × ATP (final concentration 50 μ M), mixing at 37 deg.C, incubating for 30 min, adding detection reagent ADP-Glo (Promega, V9102), mixing, incubating at room temperature for 40 min, adding ADP-Glo ^TM The detection reagent of the kinase assay kit (Promega, V9102) was incubated at room temperature for 40 minutes. Fluorescence signals were detected with PHERAstar and data were processed using GraphPad software. Inhibition IC of PI3K enzyme by the disclosed compounds ₅₀ The values are shown in Table 2.

TABLE 2 IC of inhibition of ATM enzyme and PI3K enzyme by the compounds of this disclosure ₅₀ Value of

And (4) conclusion: the compounds disclosed in the disclosure have weak inhibitory activity against ATM enzyme and PI3K enzyme, and it can be seen from comparative test examples 1 and 2 that the compounds disclosed in the disclosure have selectivity for ATR enzyme.

Test example 3 cell proliferation test

The following method was performed by measuring intracellular ATP content based on IC ₅₀ The effect of the disclosed compounds on inhibition of LoVo cell proliferation was evaluated. The experimental method is briefly described as follows:

1. experimental materials and instruments

LoVo, human colon cancer tumor cell (Nanjing Kebai, CBP 60032)

2. Fetal bovine serum (GIBCO, 10091-148)

3.F-12K medium (Gibco, 21127030)

CellTite-Glo reagent (Promega, G7573)

5.96 well cell culture plate (corning, 3903)

6. Pancreatin (invitrogen, 25200-072)

7. Enzyme mark instrument (BMG, PHERASta)

8. Cell counter (Shanghai Rui Yu biological science and technology Co., ltd., IC 1000)

2. Experimental procedure

The LoVo cells were cultured in F-12K medium containing 10% FBS, passaged 2 to 3 times a weekThe ratio 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 10 ⁴ cells/mL, 96-well plate periphery only 100. Mu.L of complete medium was added. 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 3-fold to 10 concentrations, 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. Incubate the plates in the 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.

3. 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 measured ₅₀ The values are shown in Table 3.

TABLE 3 IC of compounds of the present disclosure for inhibition of LoVo cell proliferation ₅₀

Example numbering	IC 50 /nM	Max Inhibition(％)
			1	1111	89
2	580	93
			3	971	92

And (4) conclusion: the compounds disclosed herein have good inhibitory activity against LoVo cell proliferation.

Claims (12)

1.A compound of formula (I), or a tautomer thereof, or a pharmaceutically acceptable salt thereof:

wherein:

R ¹ is composed of

R ⁸ Selected from hydrogen atoms, halogens, C _1-6 Alkyl and C _1-6 A haloalkyl group; n is 1;

-L-is-C (O) -or-S (O) ₂ -；

Y is selected from C _1-6 Alkyl radical, C _1-6 Alkoxy and-NHR ⁶ Wherein said C _1-6 Alkyl is optionally selected from hydroxy, cyano and C _1-6 Substituted with one or more substituents of alkoxy;

r' is selected from hydrogen atom, halogen and C _1-6 An alkyl group;

R ⁶ is C _1-6 Alkyl or 3 to 6 membered cycloalkyl wherein said C is _1-6 Alkyl is optionally substituted with one or more 3 to 6 membered cycloalkyl;

p is 1; and is provided with

q is 0 or 1.

2. The compound of formula (I), or a tautomer thereof, or a pharmaceutically acceptable salt thereof, according to claim 1, which is a compound of formula (II), or a tautomer thereof, or a pharmaceutically acceptable salt thereof:

wherein:

R ⁸ n, L and Y are as defined in claim 1.

3. The compound of the general formula (I), or a tautomer thereof, or a pharmaceutically acceptable salt thereof, according to claim 1 or2, selected from any one of the following compounds:

4. a compound represented by the general formula (IA), or a tautomer thereof, or a pharmaceutically acceptable salt thereof,

wherein:

x is halogen;

-L-is-C (O) -or-S (O) ₂ -；

Y is selected from C _1-6 Alkyl radical, C _1-6 Alkoxy and-NHR ⁶ Wherein said C _1-6 Alkyl is optionally selected from hydroxy, cyano and C _1-6 Substituted with one or more substituents of alkoxy;

r' is selected from hydrogen atom, halogen and C _1-6 An alkyl group;

R ⁶ is C _1-6 Alkyl or 3 to 6 membered cycloalkyl wherein said C is _1-6 Alkyl is optionally substituted with 3 to 6 membered cycloalkyl;

p is 1; and is

q is 0 or 1.

5.A compound selected from any one of the following structures:

6. a process for preparing a compound of formula (I), or a tautomer thereof, or a pharmaceutically acceptable salt thereof, according to claim 1, comprising:

compounds of the general formula (IA) and R ¹ -M is subjected to a coupling reaction to obtain a compound of general formula (I),

wherein:

x is halogen;

m is

R ¹ L, Y, R', p and q are as defined in claim 1.

7. The method of claim 6, wherein X is Cl.

8. A pharmaceutical composition comprising a compound of general formula (I), or a tautomer thereof, or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 3, and one or more pharmaceutically acceptable carriers, diluents, or excipients.

9. Use of a compound of general formula (I), or a tautomer thereof, or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 3, or a pharmaceutical composition according to claim 8, for the preparation of a medicament for inhibiting ATR kinase.

10. Use of a compound of general formula (I), or a tautomer thereof, or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 3, or a pharmaceutical composition according to claim 8, for the preparation of a medicament for the treatment or prevention of a hyperproliferative disease.

11. Use of a compound of general formula (I), or a tautomer thereof, or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 3, or a pharmaceutical composition according to claim 8, for the preparation of a medicament for the treatment or prevention of tumors.

12. The use according to claim 11, 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, endometrial cancer, head and neck tumor, multiple myeloma, B-cell lymphoma, polycythemia vera, leukemia, thyroid tumor, bladder cancer, and gallbladder cancer.