Patent Description:
DNA damage response (DDR) ensures the genome integrity of living cells by diverse signaling pathways. Intracellular proteins directly recognize abnormal DNA structures and activate related kinases of DDR pathway in response to extensive DNA damage and increased replication stress within cancer cells. The DDR pathway enables cells to survive in the face of genomic instability and replication stress, or mediate irreparable damage, cellular senescence or programmed death. Defects in DDR genes promote driver gene variation, tumor heterogeneity, and evasion of apoptosis through multiple ways, so as to promote tumor growth.

ATR (ataxia telangiectasia and RAD-<NUM>-related protein kinase) belongs to the PIKKs (phosphatidylinositol-<NUM>-kinase-related kinase) family and is involved in DNA damage repair to maintain gene stability. ATR protein kinase produces a synergistic response to DNA damage, replication stress and cell cycle disturbance. ATR and ATM belong to the PIKK family of serine/threonine protein kinases, and they are common components of cell cycle and DNA damage repair. Others include Chkl, BRCA1, and p53. ATR is mainly responsible for the repair of DNA replication stress (replication fork stalling) and single-strand breakages. ATR is activated by DNA single-strand structures when DNA double-strand breaks appear to be excised or replication forks are stalled. DNA polymerase stays in the DNA replication process, and the replication helicase continues to unwind at the front end of the DNA replication fork, resulting in the production of long single-strand DNA (ssDNA), which is then bound by the single-strand DNA and RPA (replication protein A). When replication stress or DNA damage occurs, the complex of ATR/ATR-acting proteins recruited by RPA bind to the injury site, and the RPA-single-strand DNA complex activates the RAD17/rfc2-<NUM> complex to bind to the injury site. The DNA-ssDNA junction activates the Rad9-HUS1-RAD1 (<NUM>-<NUM>-<NUM>) heterotrimer, and <NUM>-<NUM>-<NUM> in turn recruits TopBP1 to activate ATR. Once ATR is activated, ATR promotes DNA repair, stabilization and restart of stalled replication forks and transient cell cycle arrest through downstream targets. These functions are achieved by ATR by mediating the downstream target Chk1. ATR functions as a DNA damage cell cycle checkpoint in S phase. It can mediate the degradation of CDC25A through Chk1, thereby delaying the process of DNA replication and providing time for the repair of replication forks. ATR is also a master regulator of the G2/M cell cycle checkpoint, preventing premature entry of cells into mitosis until DNA replication is completed or DNA damage occurs. This ATR-dependent G2/M cell cycle arrest is mainly mediated by two mechanisms: <NUM>. degradation of CDC25A. Cdc25C is phosphorylated by Chk1 to bind to the <NUM>-<NUM>-protein. The binding of Cdc25C to the <NUM>-<NUM>-<NUM> protein promotes its output from the nucleus and cytoplasmic isolation, thereby inhibiting its ability to dephosphorylate and activate nuclear Cdc2, which in turn prevents it from entering mitosis.

ATM gene often mutates in tumor cells, which indicates that the loss of ATM activity is beneficial to the survival of cancer cells. ATM kinase inactivation makes cells more dependent on ATR-mediated signaling pathways, and combined inactivation of ATR and ATM can induce synthetic lethality in cancer cells. Therefore, inhibiting ATR can be an effective method in future cancer treatments.

<CIT> discloses a compound of the following formula as inhibitor of ATR:
<CHM>.

<CIT> discloses a compound of the following formula as inhibitor of ATR kinase:
<CHM>.

The present disclosure provides a compound represented by formula (II) or a pharmaceutically acceptable salt thereof,
<CHM>
wherein,.

The present disclosure provides a compound represented by formula (I) or a pharmaceutically acceptable salt thereof,
<CHM>.

In some embodiments of the present disclosure, the R<NUM> is H or CH<NUM>, wherein the CH<NUM> is optionally substituted with <NUM>, <NUM> or <NUM> Ra, and other variables are as defined in the present disclosure.

In some embodiments of the present disclosure, the R<NUM> is CH<NUM>, and other variables are as defined in the present disclosure.

In some embodiments of the present disclosure, the R<NUM> is H or CH<NUM>, and other variables are as defined in the present disclosure.

In some embodiments of the present disclosure, the R<NUM> is H or CH<NUM>, wherein the CH<NUM> is optionally substituted with <NUM>, <NUM> or <NUM> Rb, and other variables are as defined in the present disclosure.

In some embodiments of the present disclosure, the R<NUM> is each independently H or CH<NUM>, and other variables are as defined in the present disclosure.

In some embodiments of the present disclosure, the R<NUM> is each independently H, CH<NUM>, -O-CH<NUM> or -S(O)<NUM>-CH<NUM>, and other variables are as defined in the present disclosure.

In some embodiments of the present disclosure, the ring A is
<CHM>
<CHM>
<CHM>
and other variables are as defined in the present disclosure.

In some embodiments of the present disclosure, the compound has the structure of formula (I-<NUM>) or (I-<NUM>)
<CHM>
wherein, R<NUM> and R<NUM> are as defined in the present disclosure.

Other embodiments of the present disclosure are derived from any combination of above variables.

In some embodiments, the present disclosure provides a compound represented by the following formula or a pharmaceutically acceptable salt thereof,
<CHM>
<CHM>
<CHM>
<CHM>.

The compounds of the present disclosure have strong inhibitory activity against ATR enzyme; at the same time, they have a good inhibitory effect on LoVo tumor cells lacking the ATM signaling pathway; at the same time, the compounds of the present disclosure have good PK parameters such as exposure and bioavailability, and are suitable for medication; in addition, the compounds of the present disclosure can significantly inhibit the growth of human gastric cancer SNU-<NUM> xenograft tumor, and are relatively tolerated to mice.

Unless otherwise specified, the following terms and phrases when used herein have the following meanings. A specific term or phrase should not be considered indefinite or unclear in the absence of a particular definition, but should be understood in the ordinary sense. When a trade name appears herein, it is intended to refer to its corresponding commodity or active ingredient thereof.

The term "pharmaceutically acceptable" is used herein in terms of those compounds, materials, compositions, and/or dosage forms, which are suitable for use in contact with human and animal tissues within the scope of reliable medical judgment, with no excessive toxicity, irritation, an allergic reaction or other problems or complications, commensurate with a reasonable benefit/risk ratio.

The term "pharmaceutically acceptable salt" refers to a salt of the compound of the present disclosure that is prepared by reacting the compound having a specific substituent of the present disclosure with a relatively non-toxic acid or base. When the compound of the present disclosure contains a relatively acidic functional group, a base addition salt can be obtained by bringing the compound into contact with a sufficient amount of base in a pure solution or a suitable inert solvent. The pharmaceutically acceptable base addition salt includes a salt of sodium, potassium, calcium, ammonium, organic amine or magnesium, or similar salts. When the compound of the present disclosure contains a relatively basic functional group, an acid addition salt can be obtained by bringing the compound into contact with a sufficient amount of acid in a pure solution or a suitable inert solvent. Examples of the pharmaceutically acceptable acid addition salt include an inorganic acid salt, wherein the inorganic acid includes, for example, hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, hydrogen sulfate, hydroiodic acid, phosphorous acid, and the like; and an organic acid salt, wherein the organic acid includes, for example, acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, and methanesulfonic acid, and the like; and salts of amino acid (such as arginine and the like), and a salt of an organic acid such as glucuronic acid and the like. Certain specific compounds of the present disclosure contain both basic and acidic functional groups, thus can be converted to any base or acid addition salt.

The pharmaceutically acceptable salt of the present disclosure can be prepared from the parent compound that contains an acidic or basic moiety by conventional chemical method. Generally, such salt can be prepared by reacting the free acid or base form of the compound with a stoichiometric amount of an appropriate base or acid in water or an organic solvent or a mixture thereof.

The compounds of the present disclosure may exist in specific geometric or stereoisomeric forms. The present disclosure contemplates all such compounds, including cis and trans isomers, (-)-and (+)-enantiomers, (R)-and (S)-enantiomers, diastereomers isomers, (D)-isomers, (L)-isomers, and racemic and other mixtures thereof, such as enantiomers or diastereomeric enriched mixtures, all of which are within the scope of the present disclosure. Additional asymmetric carbon atoms may be present in substituents such as alkyl. All these isomers and their mixtures are included within the scope of the present disclosure.

Unless otherwise specified, the term "enantiomer" or "optical isomer" refers to stereoisomers that are mirror images of each other.

Unless otherwise specified, the term "cis-trans isomer" or "geometric isomer" is caused by the inability to rotate freely of double bonds or single bonds of ring-forming carbon atoms. Unless otherwise specified, the term "diastereomer" refers to a stereoisomer in which a molecule has two or more chiral centers and the relationship between the molecules is not mirror images.

Unless otherwise specified, "(+)" refers to dextrorotation, "(-)" refers to levorotation, and or "(±)" refers to racemic.

Unless otherwise specified, the absolute configuration of a stereogenic center is represented by a wedged solid bond (<IMG>) and a wedged dashed bond (<IMG>), and the relative configuration of a stereogenic center is represented by a straight solid bond (<IMG>) and a straight dashed bond (<IMG>), a wave line (<IMG>) is used to represent a wedged solid bond (<IMG>) or a wedged dashed bond (<IMG>), or the wave line (<IMG>) is used to represent a straight solid bond (<IMG>) and a straight dashed bond (<IMG>).

Unless otherwise specified, when double bond structure, such as carbon-carbon double bond, carbon-nitrogen double bond, and nitrogen-nitrogen double bond, exists in the compound, and each of the atoms on the double bond is connected to two different substituents (including the condition where a double bond contains a nitrogen atom, the lone pair of electrons attached on the nitrogen atom is regarded as a substituent connected), if the atom on the double bond in the compound is connected to its substituent by a wave line (<IMG>), this refers to the (Z) isomer, (E) isomer or a mixture of two isomers of the compound. For example, the following formula (A) means that the compound exists as a single isomer of formula (A-<NUM>) or formula (A-<NUM>) or as a mixture of two isomers of formula (A-<NUM>) and formula (A-<NUM>); the following formula (B) means that the compound exists in the form of a single isomer of formula (B-<NUM>) or formula (B-<NUM>) or in the form of a mixture of two isomers of formula (B-<NUM>) and formula (B-<NUM>). The following formula (C) means that the compound exists as a single isomer of formula (C-<NUM>) or formula (C-<NUM>) or as two a mixture of two isomers of formula (C-<NUM>) and formula (C-<NUM>). <CHM>
<CHM>.

Unless otherwise specified, the term "tautomer" or "tautomeric form" means that at room temperature, the isomers of different functional groups are in dynamic equilibrium and can be transformed into each other quickly. If tautomers possibly exist (such as in solution), the chemical equilibrium of tautomers can be reached. For example, proton tautomer (also called prototropic tautomer) includes interconversion through proton migration, such as keto-enol isomerization and imine-enamine isomerization. Valence tautomer includes some recombination of bonding electrons for mutual transformation. A specific example of keto-enol tautomerization is the tautomerism between two tautomers of pentan-<NUM>,<NUM>-dione and <NUM>-hydroxypent-<NUM>-en-<NUM>-one.

Unless otherwise specified, the terms "enriched in one isomer", "enriched in isomers", "enriched in one enantiomer" or "enriched in enantiomers" refer to the content of one of the isomers or enantiomers is less than <NUM>%, and the content of the isomer or enantiomer is greater than or equal to <NUM>%, or greater than or equal to <NUM>%, or greater than or equal to <NUM>%, or greater than or equal to <NUM>%, or greater than or equal to <NUM>%, or greater than or equal to <NUM>%, or greater than or equal to <NUM>%, or greater than or equal to <NUM>%, or greater than or equal to <NUM>%, or greater than or equal to <NUM>%, or greater than or equal to <NUM>%, or greater than or equal to <NUM>%, or greater than or equal to <NUM>%, or greater than or equal to <NUM>%.

Unless otherwise specified, the term "isomer excess" or "enantiomeric excess" refers to the difference between the relative percentages of two isomers or two enantiomers. For example, if the content of one isomer or enantiomer is <NUM>%, and the content of the other isomer or enantiomer is <NUM>%, the isomer or enantiomer excess (ee value) is <NUM>%.

Optically active (R)- and (S)-isomer, or D and L isomer can be prepared using chiral synthesis or chiral reagents or other conventional techniques. If one kind of enantiomer of certain compound of the present disclosure is to be obtained, the pure desired enantiomer can be obtained by asymmetric synthesis or derivative action of chiral auxiliary followed by separating the resulting diastereomeric mixture and cleaving the auxiliary group. Alternatively, when the molecule contains a basic functional group (such as amino) or an acidic functional group (such as carboxyl), the compound reacts with an appropriate optically active acid or base to form a salt of the diastereomeric isomer which is then subjected to diastereomeric resolution through the conventional method in the art to obtain the pure enantiomer. In addition, the enantiomer and the diastereoisomer are generally isolated through chromatography which uses a chiral stationary phase and optionally combines with a chemical derivative method (such as carbamate generated from amine).

The compound of the present disclosure may contain an unnatural proportion of atomic isotope at one or more than one atom(s) that constitute the compound. For example, the compound can be radiolabeled with a radioactive isotope, such as tritium (<NUM>H), iodine-<NUM> (<NUM>I) or C-<NUM> (<NUM>C). For another example, deuterated drugs can be formed by replacing hydrogen with heavy hydrogen, the bond formed by deuterium and carbon is stronger than that of ordinary hydrogen and carbon, compared with non-deuterated drugs, deuterated drugs have the advantages of reduced toxic and side effects, increased drug stability, enhanced efficacy, extended biological half-life of drugs, etc. All isotopic variations of the compound of the present disclosure, whether radioactive or not, are encompassed within the scope of the present disclosure. The term "optional" or "optionally" means that the subsequent event or condition may occur but not requisite, that the term includes the instance in which the event or condition occurs and the instance in which the event or condition does not occur.

The term "substituted" means one or more than one hydrogen atom(s) on a specific atom are substituted with the substituent,which may include deuterium and hydrogen variables, as long as the valence of the specific atom is normal and the substituted compound is stable. When the substituent is an oxygen (i.e., =O), it means two hydrogen atoms are substituted. Positions on an aromatic ring cannot be substituted with a ketone. The term "optionally substituted" means an atom can be substituted with a substituent or not, unless otherwise specified, the type and number of the substituent may be arbitrary as long as being chemically achievable.

When any variable (such as R) occurs in the constitution or structure of the compound more than once, the definition of the variable at each occurrence is independent. Thus, for example, if a group is substituted with <NUM>-<NUM> R, the group can be optionally substituted with up to two R, wherein the definition of R at each occurrence is independent. Moreover, a combination of the substituent and/or the variant thereof is allowed only when the combination results in a stable compound.

When the number of a linking group is <NUM>, such as -(CRR)<NUM>-, it means that the linking group is a single bond.

When one of the variables is selected from a single bond, it means that the two groups linked by the single bond are connected directly. For example, when L in A-L-Z represents a single bond, the structure of A-L-Z is actually A-Z.

When a substituent is vacant, it means that the substituent does not exist, for example, when X is vacant in A-X, the structure of A-X is actually A. When the enumerative substituent does not indicate by which atom it is linked to the group to be substituted, such substituent can be bonded by any atom thereof. For example, when pyridyl acts as a substituent, it can be linked to the group to be substituted with any carbon atom on the pyridine ring.

When the enumerative linking group does not indicate the direction for linking, the direction for linking is arbitrary, for example, the linking group L contained in
<CHM>
is - M-W-, then -M-W- can link ring A and ring B to form
<CHM>
in the direction same as left-to-right reading order, and form
<CHM>
in the direction contrary to left-to-right reading order. A combination of the linking groups, substituents and/or variables thereof is allowed only when such combination can result in a stable compound.

Unless otherwise specified, when a group has one or more linkable sites, any one or more sites of the group can be linked to other groups through chemical bonds. When the linking site of the chemical bond is not positioned, and there is H atom at the linkable site, then the number of H atom at the site will decrease correspondingly with the number of chemical bond linking thereto so as to meet the corresponding valence. The chemical bond between the site and other groups can be represented by a straight solid bond (<IMG>), a straight dashed bond (<IMG>) or a wavy line (<IMG>). For example, the straight solid bond in -OCH<NUM> means that it is linked to other groups through the oxygen atom in the group; the straight dashed bonds in
<CHM>
means that it is linked to other groups through the two ends of nitrogen atom in the group; the wave lines in
<CHM>
means that the phenyl group is linked to other groups through carbon atoms at position <NUM> and position <NUM>;
<CHM>
means that it can be linked to other groups through any linkable sites on the piperidinyl by one chemical bond, including at least four types of linkage, including
<CHM>
Even though the H atom is drawn on the -N-,
<CHM>
still includes the linkage of
<CHM>
merely when one chemical bond was connected, the H of this site will be reduced by one to the corresponding monovalent piperidinyl.

Unless otherwise specified, the term "C<NUM>-<NUM> alkyl" refers to a linear or branched saturated hydrocarbon group containing <NUM> to <NUM> carbon atoms. The C<NUM>-<NUM> alkyl includes C<NUM>-<NUM> and C<NUM>-<NUM> alkyl, etc; it can be monovalent (such as methyl), divalent (such as methylene) or multivalent (such as methine). Examples of C<NUM>-<NUM> alkyl include but are not limited to methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), etc..

Unless otherwise specified, Cn-n+m or Cn-Cn+m includes any specific case of n to n+m carbons, for example, C<NUM>-<NUM> includes C<NUM>, C<NUM>, C<NUM>, C<NUM>, C<NUM>, C<NUM>, C<NUM>, C<NUM>, C<NUM>, C<NUM>, C<NUM>, and C<NUM>, and any range from n to n+m is also included, for example C<NUM>-<NUM> includes C<NUM>-<NUM>, C<NUM>-<NUM>, C<NUM>-<NUM>, C<NUM>-<NUM>, C<NUM>-<NUM>, C<NUM>-<NUM>, C<NUM>-<NUM>, C<NUM>-<NUM>, and C<NUM>-<NUM>, etc.; similarly, n membered to n+m membered means that the number of atoms on the ring is from n to n+m, for example, <NUM>-<NUM> membered ring includes <NUM> membered ring, <NUM> membered ring, <NUM> membered ring, <NUM> membered ring, <NUM> membered ring, <NUM> membered ring, <NUM> membered ring, <NUM> membered ring, <NUM> membered ring, and <NUM> membered ring, and any range from n to n+m is also included, for example, <NUM>-<NUM> membered ring includes <NUM>-<NUM> membered ring, <NUM>-<NUM> membered ring, <NUM>-<NUM> membered ring, <NUM>-<NUM> membered ring, <NUM>-<NUM> membered ring, <NUM>-<NUM> membered ring, and <NUM>-<NUM> membered ring, etc..

The term "leaving group" refers to a functional group or atom which can be replaced by another functional group or atom through a substitution reaction (such as affinity substitution reaction). For example, representative leaving groups include triflate; chlorine, bromine, and iodine; sulfonate group, such as mesylate, tosylate, p-bromobenzenesulfonate, p-toluenesulfonates, etc.; acyloxy, such as acetoxy, trifluoroacetoxy, etc..

The term "protecting group" includes, but is not limited to "amino protecting group", "hydroxyl protecting group" or "thio protecting group". The term "amino protecting group" refers to a protecting group suitable for blocking the side reaction on the nitrogen of an amino. Representative amino protecting groups include, but are not limited to: formyl; acyl, such as alkanoyl (e.g., acetyl, trichloroacetyl or trifluoroacetyl); alkoxycarbonyl, such as tert-butoxycarbonyl (Boc); arylmethoxycarbonyl such as benzyloxycarbonyl (Cbz) and <NUM>-fluorenylmethoxycarbonyl (Fmoc); arylmethyl, such as benzyl (Bn), trityl (Tr), <NUM>,<NUM>-bis-(<NUM>'-methoxyphenyl)methyl; silyl, such as trimethylsilyl (TMS) and tert-butyldimethylsilyl (TBS), etc. The term "hydroxyl protecting group" refers to a protecting group suitable for blocking the side reaction on hydroxyl. Representative hydroxyl protecting groups include, but are not limited to: alkyl, such as methyl, ethyl, and tert-butyl; acyl, such as alkanoyl (e.g., acetyl); arylmethyl, such as benzyl (Bn), p-methoxybenzyl (PMB), <NUM>-fluorenylmethyl (Fm), and diphenylmethyl (benzhydryl, DPM); silyl, such as trimethylsilyl (TMS) and tert-butyl dimethyl silyl (TBS), etc..

The compounds of the present disclosure can be prepared by a variety of synthetic methods known to those skilled in the art, including the specific embodiments listed below, the embodiments formed by their combination with other chemical synthesis methods, and equivalent alternatives known to those skilled in the art, preferred implementations include but are not limited to the embodiments of the present disclosure.

The structure of the compounds of the present disclosure can be confirmed by conventional methods known to those skilled in the art, and if the disclosure involves an absolute configuration of a compound, then the absolute configuration can be confirmed by means of conventional techniques in the art. For example, in the case of single crystal X-ray diffraction (SXRD), diffraction intensity data of a cultured single crystal are collected by a Bruker D8 venture diffractometer, using CuKα radiation as a light source and φ/ω scanning as a scanning mode. After collecting relevant data, the absolute configuration can be confirmed by further analyzing the structure of the crystal form with a direct method (Shelxs97).

The solvent used in the present disclosure is commercially available. The following abbreviations are used in the present disclosure: aq stands for water; eq stands for equivalent or equivalence.

The compounds of the present disclosure are named according to the conventional naming principles in the art or by ChemDraw® software, and the commercially available compounds use the supplier catalog names.

The present disclosure will be specifically described below by way of embodiments, but it does not mean that there is any adverse restriction on the present disclosure. The present disclosure is described in detail herein, wherein specific embodiments thereof have also been disclosed.

Sodium hydride (<NUM>, <NUM> mmol, <NUM>%) was added to a solution of compound I-<NUM> (<NUM>, <NUM> mmol) in tetrahydrofuran (<NUM>), and the mixture was reacted at room temperature of <NUM> for <NUM> hour. Triisopropylsilane (<NUM>, <NUM> mmol) was added thereto, and the mixture was reacted at room temperature of <NUM> for <NUM> hours. After the reaction was completed, <NUM> of saturated aqueous ammonium chloride solution was added to the reaction solution to quench the reaction. <NUM> of water was added thereto, and the mixture was extracted with ethyl acetate (<NUM>*<NUM>). The organic phase was washed once with saturated brine, dried over anhydrous sodium sulfate, filtered to obtain filtrate, and dried under reduced pressure. The crude product was separated by column chromatography (ethyl acetate/petroleum ether: <NUM>-<NUM>%) to obtain compound I-<NUM>.

Compound I-<NUM> (<NUM>, <NUM>µmol) was placed in a three-necked flask, and anhydrous tetrahydrofuran (<NUM>) was added thereto, and the system was replaced with nitrogen. The reaction solution was cooled to -<NUM>, and lithium diisopropylamide (<NUM>, <NUM>µL, <NUM> eq) was added thereto, and the mixture was stirred for <NUM> minutes. Trimethyl borate (<NUM>, <NUM>µmol, <NUM>µL, <NUM> eq) was added thereto, and the mixture was heated to room temperature of <NUM> and stirred for <NUM> hour. After the reaction was completed, <NUM> of saturated aqueous ammonium chloride solution was added to the reaction solution and the mixture was stirred for <NUM> minutes. The mixture was extracted with ethyl acetate (<NUM> *<NUM>), and the organic phase was washed once with saturated brine, dried over anhydrous sodium sulfate, filtered to obtain filtrate, and dried under reduced pressure. Intermediate I was obtained.

(R)-<NUM>-Methylmorpholine (<NUM>, <NUM> mmol, <NUM> eq) and potassium carbonate (<NUM>, <NUM> mmol, <NUM>µL, <NUM> eq) were added to a solution of compound <NUM>-A (<NUM>, <NUM> mmol, <NUM> eq) in N,N-dimethylformamide (<NUM>) at room temperature, and then the mixture was stirred at <NUM> under nitrogen atmosphere for <NUM> hours. The reaction system was diluted with water (<NUM>), washed with ethyl acetate (<NUM>×<NUM>), washed with saturated brine (<NUM>), and dried over anhydrous sodium sulfate. After filtering off the desiccant, the solvent was removed under reduced pressure to obtain a crude product. The crude product was purified by column chromatography (petroleum ether/ethyl acetate: <NUM>%-<NUM>%) to obtain compound <NUM>-B.

Palladium acetate (<NUM>, <NUM>µmol, <NUM> eq) and tricyclohexylphosphine (<NUM>, <NUM>µmol, <NUM>µL, <NUM> eq) were added to a solution of compound <NUM>-B (<NUM>, <NUM> mmol, <NUM> eq), <NUM>,<NUM>-dimethyl-<NUM>H-<NUM>,<NUM>,<NUM>-triazole (<NUM>, <NUM> mmol, <NUM> eq) and potassium carbonate (<NUM>, <NUM> mmol, <NUM> eq) in N,N-dimethylacetamide (<NUM>), bubbled with nitrogen, and the reaction was stirred at <NUM> for <NUM> hour under microwave irradiation. After the reaction solution was cooled, the reaction solution was filtered and concentrated under reduced pressure to obtain a crude product, and the crude product was purified by column chromatography (petroleum ether/ethyl acetate: <NUM>%-<NUM>%) to obtain compound <NUM>-C.

Compound <NUM>-C (<NUM>, <NUM>µmol) was placed in a microwave reactor, then ethylene glycol dimethyl ether (<NUM>) was added thereto, and intermediate I (<NUM>, <NUM>µmol), aqueous sodium carbonate solution (<NUM>, <NUM>) and [<NUM>,<NUM>-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (<NUM>, <NUM>µmol) were added thereto. The mixture was bubbled with nitrogen for <NUM> minutes, heated to <NUM> and stirred for <NUM> hours under microwave irradiation. After the reaction was completed, <NUM> of water was added to the reaction solution, and the reaction solution was extracted with <NUM> (<NUM>*<NUM>) of ethyl acetate. The organic phase was washed once with saturated brine, dried over anhydrous sodium sulfate, filtered to obtain filtrate, and dried under reduced pressure. The crude product was separated by column chromatography (tetrahydrofuran/petroleum ether: <NUM>-<NUM>%) to obtain compound <NUM>.

<NUM>H NMR (<NUM>, CDCl<NUM>) δ ppm <NUM> (br d, J=<NUM>, <NUM>) <NUM> (s, <NUM>) <NUM> - <NUM> (m, <NUM>) <NUM> (br t, J=<NUM>, <NUM>) <NUM> (br s, <NUM>) <NUM> - <NUM> (m, <NUM>) <NUM> (br d, J=<NUM>, <NUM>) <NUM> (br s, <NUM>) <NUM> (br s, <NUM>) <NUM> (br s, <NUM>) <NUM> (br s, <NUM>) <NUM> (br s, <NUM>) <NUM> (br s, <NUM>).

Sodium carbonate (<NUM>, <NUM> mmol) was added to a solution of compound <NUM>-A (<NUM>, <NUM> mmol), (R)-<NUM>-methylmorpholine (<NUM>, <NUM> mmol) in <NUM>-methyl-<NUM>-pyrrolidone (<NUM>). After the reaction was stirred at <NUM> for <NUM> hours under microwave irradiation and then heated to <NUM> and stirred for <NUM>*<NUM> hours (reaction in <NUM> batches), the reaction solution was diluted with water (<NUM>). The aqueous phase was extracted with ethyl acetate (<NUM> × <NUM>), and the organic phases were combined. The organic phases were washed with water (<NUM> × <NUM>) and saturated brine (<NUM>) respectively, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. The crude product was purified by column chromatography (petroleum ether/ethyl acetate: <NUM>%-<NUM>%) to obtain compound <NUM>-B.

N,N-Dimethylacetamide dimethyl acetal (<NUM>, <NUM> mmol) was added to a solution of compound <NUM>-B (<NUM>, <NUM> mmol) in N,N-dimethylformamide (<NUM>). The reaction solution was stirred at <NUM> for <NUM> hour, and then concentrated under reduced pressure to obtain a crude product of compound <NUM>-C.

Glacial acetic acid (<NUM>) was added to compound <NUM>-C (<NUM>, <NUM> mmol) and acethydrazide (<NUM>, <NUM> mmol), and the reaction was heated to <NUM> and stirred for <NUM> hours. The pH of the reaction solution was adjusted to <NUM>-<NUM> with saturated sodium carbonate, and the reaction solution was extracted with ethyl acetate (<NUM> × <NUM>). The organic phase was concentrated under reduced pressure to obtain a crude product, and the crude product was purified by column chromatography (petroleum ether/ethyl acetate: <NUM>%-<NUM>%) to obtain compound <NUM>-D.

Compound <NUM>-D (<NUM>, <NUM>µmol) was placed in a microwave reactor, then ethylene glycol dimethyl ether (<NUM>) was added thereto, and intermediate I (<NUM>, <NUM>µmol), aqueous sodium carbonate solution (<NUM>, <NUM>) and [<NUM>,<NUM>-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (<NUM>, <NUM>µmol) were added thereto. The mixture was bubbled with nitrogen for <NUM> minutes, heated to <NUM> and stirred for <NUM> hours under microwave irradiation. After the reaction was completed, the reaction solution was washed once with saturated sodium bicarbonate, and the organic phase was extracted with <NUM> (<NUM>*<NUM>) of ethyl acetate, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered to obtain filtrate, and dried under reduced pressure. The crude product was separated by column chromatography (methanol/dichloromethane: <NUM>-<NUM>%) to obtain compound <NUM>, and then further purified by preparative chromatographic column (Phenomenex Gemini-NX <NUM>*<NUM>*<NUM>; mobile phase: [water (<NUM> NH<NUM>HCO<NUM>)-ACN]; ACN%: <NUM>%-<NUM>%, <NUM> minutes) to obtain compound <NUM>. MS m/z: <NUM>[M+H]+.

<NUM>H NMR (<NUM>, CDCl<NUM>) δ ppm <NUM> (d, J=<NUM>, <NUM>) <NUM> (s, <NUM>) <NUM> (td, J=<NUM>, <NUM>, <NUM>) <NUM> (td, J=<NUM>, <NUM>, <NUM>) <NUM> - <NUM> (m, <NUM>) <NUM> - <NUM> (m, <NUM>) <NUM> (br d, J=<NUM>, <NUM>) <NUM> (s, <NUM>) <NUM> - <NUM> (m, <NUM>) <NUM> (t, J=<NUM>, <NUM>) <NUM> (s, <NUM>) <NUM> (br s, <NUM>).

Compound <NUM>-A (<NUM>, <NUM> mmol) was placed in a microwave reactor, and <NUM>,<NUM>-dioxane (<NUM>) and water (<NUM>) were added thereto. Compound <NUM>-B (<NUM>, <NUM> mmol), sodium carbonate (<NUM>, <NUM> mmol) and [<NUM>,<NUM>-bis(diphenylphosphino)ferrocene]dichloropalladium (<NUM>, <NUM>µmol) were added thereto, bubbled with nitrogen for <NUM> minutes, heated to <NUM> and stirred for <NUM> hours under microwave irradiation. After the reaction was completed, <NUM> of water was added to the reaction solution, and the reaction solution was extracted with <NUM> (<NUM>*<NUM>) of ethyl acetate. The organic phase was washed once with saturated brine, dried over anhydrous sodium sulfate, filtered to obtain filtrate, and dried under reduced pressure. The crude product was separated by column chromatography (ethyl acetate/petroleum ether: <NUM>-<NUM>%) to obtain compound <NUM>-C. MS m/z: <NUM>/<NUM> [M+H]+.

Compound <NUM>-C (<NUM>, <NUM> mmol) was placed in a microwave reactor, and (R)-<NUM>-methylmorpholine (<NUM>) was added thereto. The mixture was heated to <NUM> and stirred for <NUM> hour under microwave irradiation. After the reaction was completed, the reaction solution was dried under reduced pressure. The crude product was separated by column chromatography (ethyl acetate/petroleum ether: <NUM>-<NUM>%) to obtain compound <NUM>-D. MS m/z: <NUM> [M+H]+.

Compound <NUM>-D (<NUM>, <NUM> mmol) was dissolved in <NUM>,<NUM>-dioxane (<NUM>), and then intermediate I (<NUM>, <NUM> mmol), aqueous sodium carbonate solution (<NUM>, <NUM>) and [<NUM>,<NUM>-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (<NUM>, <NUM>µmol) were added thereto. The mixture was heated to <NUM> and reacted for <NUM> hours, and then the temperature was lowered to room temperature of <NUM>. Tetraethylammonium fluoride hydrate (<NUM>, <NUM> mmol) was added thereto and stirred for <NUM> hours. TLC monitored that the reaction was completed. After the reaction was completed, <NUM> of water was added to the reaction solution. The reaction solution was filtered through diatomite, and the filtrate was extracted with <NUM> (<NUM>*<NUM>) of ethyl acetate. The organic phase was washed once with saturated brine, dried over anhydrous sodium sulfate, filtered to obtain filtrate, and dried under reduced pressure. The crude product was separated by column chromatography (tetrahydrofuran/petroleum ether: <NUM>-<NUM>%), and then further purified by preparative chromatographic column (Phenomenex Gemini-NX <NUM>*<NUM>*<NUM>; mobile phase: [water (<NUM> NH<NUM>HCO<NUM>)-ACN]; ACN%: <NUM>%-<NUM>%, <NUM> minutes) to obtain compound <NUM>. MS m/z: <NUM>[M+H]+.

<NUM>H NMR (<NUM>, CDCl<NUM>) δ <NUM> (br d, J=<NUM>, <NUM>), <NUM> (br s, <NUM>), <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (d, J=<NUM>, <NUM>), <NUM> (t, J=<NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (br s, <NUM>), <NUM> (br d, J=<NUM>, <NUM>), <NUM> (br d, J=<NUM>, <NUM>), <NUM> (d, J=<NUM>, <NUM>), <NUM> (d, J=<NUM>, <NUM>), <NUM> (dt, J=<NUM>, <NUM>, <NUM>), <NUM> (dt, J=<NUM>, <NUM>, <NUM>), <NUM> (d, J=<NUM>, <NUM>).

Compound <NUM>-A (<NUM>, <NUM> mmol) was placed in a microwave reactor, and <NUM>,<NUM>-dioxane (<NUM>) and water (<NUM>) were added thereto. Compound <NUM>-B (<NUM>, <NUM> mmol), sodium carbonate (<NUM>, <NUM> mmol) and [<NUM>,<NUM>-bis(diphenylphosphino)ferrocene]dichloropalladium (<NUM>, <NUM>µmol) were added thereto, purged with nitrogen for <NUM> minutes, heated to <NUM> and stirred for <NUM> hours under microwave irradiation. After the reaction was completed, <NUM> of water was added to the reaction solution, and the reaction solution was extracted with <NUM> (<NUM>*<NUM>) of ethyl acetate. The organic phase was washed once with saturated brine, dried over anhydrous sodium sulfate, filtered to obtain filtrate, and dried under reduced pressure. The crude product was separated by column chromatography (ethyl acetate/petroleum ether: <NUM>-<NUM>%) to obtain compound <NUM>-B. MS m/z: <NUM>[M+H]+.

Compound <NUM>-B (<NUM>, <NUM> mmol) was placed in a microwave reactor, and (R)-<NUM>-methylmorpholine (<NUM>, <NUM> mmol) was added thereto. The mixture was heated to <NUM> and stirred for <NUM> hour under microwave irradiation. After the reaction was completed, the reaction solution was dried under reduced pressure. The crude product was separated by column chromatography (ethyl acetate/petroleum ether: <NUM>-<NUM>%) to obtain compound <NUM>-C. MS m/z: <NUM> [M+H]+.

Compound <NUM>-C (<NUM>, <NUM> mmol) was dissolved in <NUM>,<NUM>-dioxane (<NUM>), and then intermediate I (<NUM>, <NUM> mmol), aqueous sodium carbonate solution (<NUM>, <NUM>) and [<NUM>,<NUM>-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (<NUM>, <NUM>µmol) were added thereto. After the mixture was heated to <NUM> and reacted for <NUM> hours, the protecting group was not completely removed, and the temperature was lowered to room temperature of about <NUM>, and tetraethylammonium fluoride hydrate (<NUM>, <NUM> mmol) was added thereto and stirred for <NUM> hours. TLC monitored that the reaction was completed. After the reaction was completed, the reaction solution was filtered through diatomite, and the filtrate was directly dried under reduced pressure. The crude product was separated by column chromatography (tetrahydrofuran/petroleum ether: <NUM>-<NUM>%) to obtain compound <NUM>. MS m/z: <NUM> [M+H]+.

<NUM>H NMR (<NUM>, CDCl<NUM>) δ <NUM> (br s, <NUM>), <NUM> (d, J=<NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> (d, J=<NUM>, <NUM>), <NUM> (t, J=<NUM>, <NUM>), <NUM> (d, J=<NUM>, <NUM>), <NUM> (d, J=<NUM>, <NUM>), <NUM> (br s, <NUM>), <NUM> (s, <NUM>), <NUM> (br d, J=<NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> (dt, J=<NUM>, <NUM>, <NUM>), <NUM> (dt, J=<NUM>, <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> (d, J=<NUM>, <NUM>).

Compound <NUM>-B (<NUM>, <NUM>µmol) was placed in a microwave reactor, and <NUM>,<NUM>-dioxane (<NUM>) and water (<NUM>) were added thereto. Compound <NUM>-A (<NUM>, <NUM>µmol), sodium carbonate (<NUM>, <NUM> mmol) and [<NUM>,<NUM>-bis(diphenylphosphino)ferrocene]dichloropalladium (<NUM>, <NUM>µmol) were added thereto, bubbled with nitrogen for <NUM> minutes, heated to <NUM> and stirred for <NUM> hour under microwave irradiation. After the reaction was completed, the reaction solution was dried under reduced pressure, and then the sample was mixed with silica gel and purified. The crude product was separated by column chromatography (ethyl acetate/petroleum ether: <NUM>-<NUM>%) to obtain compound <NUM>-B. MS m/z: <NUM> [M+H]+.

Compound <NUM>-B (<NUM>, <NUM>µmol) was dissolved in <NUM>,<NUM>-dioxane (<NUM>), and then intermediate I (<NUM>, <NUM>µmol), aqueous sodium carbonate solution (<NUM>, <NUM>µL) and [<NUM>,<NUM>-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (<NUM>, <NUM>µmol) were added thereto. The mixture was heated to <NUM> and reacted for <NUM> hours. After the reaction was completed, the reaction solution was filtered through diatomite, and the filtrate was directly dried under reduced pressure. The crude product was separated by column chromatography (ethyl acetate/dichloromethane: <NUM>-<NUM>%) to obtain compound <NUM>. MS m/z: <NUM>[M+H]+.

<NUM>H NMR (<NUM>, CDCl<NUM>) δ <NUM> (br s, <NUM>), <NUM> (s, <NUM>), <NUM> (t, J=<NUM>, <NUM>), <NUM> (br s, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (br d, J=<NUM>, <NUM>), <NUM> (t, J=<NUM>, <NUM>), <NUM> (br d, J=<NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (dt, J=<NUM>, <NUM>, <NUM>), <NUM> (d, J=<NUM>, <NUM>).

Palladium acetate (<NUM>, <NUM>µmol, <NUM> eq) and tricyclohexylphosphine (<NUM>, <NUM>µmol, <NUM> eq) were added to a solution of compound <NUM>-B (<NUM>, <NUM> mmol, <NUM> eq), <NUM>-methyl-<NUM>,<NUM>,<NUM>-triazole (<NUM>, <NUM> mmol, <NUM> eq) and potassium acetate (<NUM>, <NUM> mmol) in N,N-dimethylformamide (<NUM>), bubbled with nitrogen, and the reaction was stirred at <NUM> for <NUM> hour under microwave irradiation. After the reaction solution was cooled, the reaction system was diluted with water (<NUM>), washed with ethyl acetate (<NUM>×<NUM>), washed with saturated brine (<NUM>), and dried over anhydrous sodium sulfate. After filtering off the desiccant, the solvent was removed under reduced pressure to obtain a crude product. The crude product was purified by column chromatography (petroleum ether/ethyl acetate: <NUM>%-<NUM>%) to obtain compound <NUM>-A.

Compound <NUM>-A (<NUM>, <NUM> mmol) was placed in a microwave reactor, and <NUM>,<NUM>-dioxane (<NUM>) and water (<NUM>) were added thereto. Intermediate I (<NUM>, <NUM> mmol), sodium carbonate (<NUM>, <NUM> mmol) and [<NUM>,<NUM>-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (<NUM>, <NUM>µmol) were added thereto, and the system was replaced with nitrogen for <NUM> times, and the mixture was stirred at <NUM> for <NUM> hours. After the reaction solution was cooled, the reaction system was diluted with water (<NUM>), washed with ethyl acetate (<NUM>×<NUM>), washed with saturated brine (<NUM>), and dried over anhydrous sodium sulfate. After filtering off the desiccant, the solvent was removed under reduced pressure to obtain a crude product. The crude product was separated by column chromatography (tetrahydrofuran/petroleum ether: <NUM>-<NUM>%) to obtain compound <NUM>.

<NUM>H NMR (<NUM>, CDCl<NUM>) δ <NUM> (br s, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (t, J=<NUM>, <NUM>), <NUM> (dd, J=<NUM>, <NUM>, <NUM>), <NUM> (t, J=<NUM>, <NUM>), <NUM> (d, J=<NUM>, <NUM>), <NUM> (br d, J=<NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (dt, J=<NUM>, <NUM>, <NUM>), <NUM> (dt, J=<NUM>, <NUM>, <NUM>), <NUM> (d, J=<NUM>, <NUM>).

Compound <NUM>-B (<NUM>, <NUM>µmol) was placed in a microwave reactor, and <NUM>,<NUM>-dioxane (<NUM>) and water (<NUM>) were added thereto. Compound <NUM>-A (<NUM>, <NUM>µmol), sodium carbonate (<NUM>, <NUM> mmol) and [<NUM>,<NUM>-bis(diphenylphosphino)ferrocene]dichloropalladium (<NUM>, <NUM>µmol) were added thereto, purged with nitrogen for <NUM> minutes, heated to <NUM> and stirred for <NUM> hours under microwave irradiation. After the reaction was completed, the reaction solution was dried under reduced pressure, and then the sample was mixed with silica gel and purified. The crude product was separated by column chromatography (ethyl acetate/petroleum ether: <NUM>-<NUM>%) to obtain compound <NUM>-B. MS m/z: <NUM> [M+H]+.

Compound <NUM>-B (<NUM>, <NUM>µmol) was dissolved in <NUM>,<NUM>-dioxane (<NUM>), and then intermediate I (<NUM>, <NUM> mmol), aqueous sodium carbonate solution (<NUM>, <NUM>) and [<NUM>,<NUM>-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (<NUM>, <NUM>µmol) were added thereto. The system was replaced with nitrogen for <NUM> times, and the mixture was heated to <NUM> and reacted for <NUM> hours. After the reaction was completed, the reaction solution was cooled to room temperature, then <NUM> of water was added to the reaction solution, and the reaction solution was extracted with <NUM> (<NUM>*<NUM>) of ethyl acetate. The organic phase was washed once with saturated brine, dried over anhydrous sodium sulfate, filtered to obtain filtrate, and dried under reduced pressure. The crude product was separated by column chromatography (ethyl acetate/dichloromethane: <NUM>-<NUM>%) to obtain compound <NUM>. MS m/z: <NUM>[M+H]+.

<NUM>H NMR (<NUM>, CDCl<NUM>) δ <NUM> - <NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> (br d, J=<NUM>, <NUM>), <NUM> (br s, <NUM>), <NUM> (br s, <NUM>), <NUM> (br d, J=<NUM>, <NUM>), <NUM> (br s, <NUM>), <NUM> (s, <NUM>), <NUM> (br d, J=<NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> (br d, J=<NUM>, <NUM>).

Compound <NUM>-B (<NUM>, <NUM>µmol) was placed in a microwave reactor, and <NUM>,<NUM>-dioxane (<NUM>) and water (<NUM>) were added thereto. Compound <NUM>-A (<NUM>, <NUM>µmol), sodium carbonate (<NUM>, <NUM> mmol) and [<NUM>,<NUM>-bis(diphenylphosphino)ferrocene]dichloropalladium (<NUM>, <NUM>µmol) were added thereto, bubbled with nitrogen for <NUM> minutes, heated to <NUM> and stirred for <NUM> hours under microwave irradiation. After the reaction was completed, the reaction solution was dried under reduced pressure, and then the sample was mixed with silica gel and purified. The crude product was separated by column chromatography (ethyl acetate/petroleum ether: <NUM>-<NUM>%) to obtain compound <NUM>-B. MS m/z: <NUM> [M+H]+.

Compound <NUM>-B (<NUM>, <NUM>µmol) was dissolved in <NUM>,<NUM>-dioxane (<NUM>), and then intermediate I (<NUM>, <NUM> mmol), aqueous sodium carbonate solution (<NUM>, <NUM>) and [<NUM>,<NUM>-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (<NUM>, <NUM>µmol) were added thereto. The system was replaced with nitrogen for <NUM> times, and the mixture was heated to <NUM> and reacted for <NUM> hours. After the reaction was completed, <NUM> of water was added to the reaction solution, and the reaction solution was extracted with <NUM> (<NUM>*<NUM>) of ethyl acetate. The organic phase was washed once with saturated brine, dried over anhydrous sodium sulfate, filtered to obtain filtrate, and dried under reduced pressure. The crude product was separated by column chromatography (ethyl acetate/dichloromethane: <NUM>-<NUM>%) to obtain compound <NUM>. MS m/z: <NUM>[M+H]+.

<NUM>H NMR (<NUM>, CDCl<NUM>) δ <NUM> (br s, <NUM>), <NUM> (br d, J=<NUM>, <NUM>), <NUM> (br s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (br s, <NUM>), <NUM> (br s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (br s, <NUM>), <NUM> (br s, <NUM>), <NUM> (br s, <NUM>), <NUM> (s, <NUM>), <NUM> (br d, J=<NUM>, <NUM>).

[<NUM>,<NUM>-Bis(diphenylphosphino)ferrocene]dichloropalladium (<NUM>, <NUM>µmol, <NUM> eq) was added to a solution of compound <NUM>-B (<NUM>, <NUM>µmol, <NUM> eq), <NUM>,<NUM>-dimethylpyrazole-<NUM>-boronic acid, pinacol ester (<NUM>, <NUM>µmol, <NUM> eq), sodium carbonate (<NUM> , <NUM> mmol, <NUM>µL, <NUM> eq) in <NUM>,<NUM>-dioxane (<NUM>), bubbled with nitrogen, and the reaction was stirred at <NUM> for <NUM> hour under microwave irradiation. After the reaction solution was cooled, the reaction system was diluted with water (<NUM>), washed with ethyl acetate (<NUM>×<NUM>), washed with saturated brine (<NUM>), and dried over anhydrous sodium sulfate. After filtering off the desiccant, the solvent was removed under reduced pressure to obtain a crude product. The crude product was purified by column chromatography (petroleum ether/ethyl acetate: <NUM>%-<NUM>%) to obtain compound <NUM>-A.

Compound <NUM>-A (<NUM>, <NUM>µmol) was placed in a microwave reactor, and <NUM>,<NUM>-dioxane (<NUM>) and water (<NUM>) were added thereto. Intermediate I (<NUM>, <NUM> mmol), sodium carbonate (<NUM>, <NUM> mmol) and [<NUM>,<NUM>-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (<NUM>, <NUM>µmol) were added thereto. The mixture was bubbled with nitrogen for <NUM> minutes, heated to <NUM> and stirred for <NUM> hour under microwave irradiation. After the reaction solution was cooled, the reaction system was diluted with water (<NUM>), washed with ethyl acetate (<NUM>×<NUM>), washed with saturated brine (<NUM>), and dried over anhydrous sodium sulfate. After filtering off the desiccant, the solvent was removed under reduced pressure to obtain a crude product. The crude product was separated by column chromatography (tetrahydrofuran/petroleum ether: <NUM>-<NUM>%) to obtain compound <NUM>.

<NUM>H NMR (<NUM>, DMSO-d<NUM>) δ <NUM> (br s, <NUM>), <NUM> (br s, <NUM>), <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (d, J=<NUM>, <NUM>), <NUM> (br s, <NUM>), <NUM> (s, <NUM>), <NUM> (br s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (br d, J=<NUM>, <NUM>), <NUM> (br d, J=<NUM>, <NUM>).

Compound <NUM>-A (<NUM>, <NUM> mmol) was placed in a microwave reactor, and <NUM>,<NUM>-dioxane (<NUM>) and water (<NUM>) were added thereto. Compound <NUM>-B (<NUM>, <NUM> mmol), sodium carbonate (<NUM>, <NUM> mmol) and [<NUM>,<NUM>-bis(diphenylphosphino)ferrocene]dichloropalladium (<NUM>, <NUM>µmol) were added thereto, purged with nitrogen for <NUM> minutes, heated to <NUM> and stirred for <NUM> hours under microwave irradiation. After the reaction was completed, <NUM> of water was added to the reaction solution, and the reaction solution was extracted with <NUM> (<NUM>*<NUM>) of ethyl acetate. The organic phase was washed once with saturated brine, dried over anhydrous sodium sulfate, filtered to obtain filtrate, and dried under reduced pressure. The crude product was separated by column chromatography (ethyl acetate/petroleum ether: <NUM>-<NUM>%) to obtain compound <NUM>-B. MS m/z: <NUM> [M+H]+.

Compound <NUM>-B (<NUM>, <NUM> mmol) was placed in a microwave reactor, and (R)-<NUM>-methylmorpholine (<NUM>, <NUM> mmol) was added thereto. The mixture was heated to <NUM> and stirred for <NUM> hours under microwave irradiation. After the reaction was completed, the reaction solution was dried under reduced pressure, and most of (R)-<NUM>-methylmorpholine was removed under reduced pressure. The crude product was separated by column chromatography (ethyl acetate/petroleum ether: <NUM>-<NUM>%) to obtain compound <NUM>-C. MS m/z: <NUM> [M+H]+.

Compound <NUM>-C (<NUM>, <NUM>µmol) was dissolved in <NUM>,<NUM>-dioxane (<NUM>), and then intermediate I (<NUM>, <NUM> mmol), aqueous sodium carbonate solution (<NUM>, <NUM>) and [<NUM>,<NUM>-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (<NUM>, <NUM>µmol) were added thereto. The system was replaced with nitrogen for three times, and the mixture was heated to <NUM> and reacted for <NUM> hours, and then the temperature was lowered to room temperature of about <NUM>. Tetraethylammonium fluoride hydrate (<NUM>, <NUM>µmol) was added thereto and stirred for <NUM> hours. After the reaction was completed, <NUM> of water was added to the reaction solution. The mixture was extracted with <NUM> (<NUM>*<NUM>) of ethyl acetate, and the organic phase was washed once with saturated brine, dried over anhydrous sodium sulfate, filtered to obtain filtrate, and dried under reduced pressure. The crude product was separated by column chromatography (ethyl acetate/dichloromethane: <NUM>-<NUM>%) to obtain compound <NUM>. MS m/z: <NUM>[M+H]+.

<NUM>H NMR (<NUM>, CDCl<NUM>) δ <NUM> (br s, <NUM>), <NUM> (br s, <NUM>), <NUM> (s, <NUM>), <NUM> (br s, <NUM>), <NUM> (d, J=<NUM>, <NUM>), <NUM> (br s, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (br d, J=<NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> (d, J=<NUM>, <NUM>).

Compound <NUM>-B (<NUM>, <NUM> mmol) was placed in a microwave reactor, and <NUM>,<NUM>-dioxane (<NUM>) and water (<NUM>) were added thereto. Compound <NUM>-A (<NUM>, <NUM> mmol), sodium carbonate (<NUM>, <NUM> mmol) and [<NUM>,<NUM>-bis(diphenylphosphino)ferrocene]dichloropalladium (<NUM>, <NUM>µmol) were added thereto, purged with nitrogen for <NUM> minutes, heated to <NUM> and stirred for <NUM> hours under microwave irradiation. After the reaction was completed, the reaction solution was added with <NUM> of water, extracted with <NUM> (<NUM>*<NUM>) of ethyl acetate, and the organic phase was washed once with saturated brine, dried over anhydrous sodium sulfate, filtered to obtain filtrate, and dried under reduced pressure. The crude product was separated by column chromatography (ethyl acetate/petroleum ether: <NUM>-<NUM>%) to obtain compound <NUM>-B. MS m/z: <NUM> [M+H]+.

Compound <NUM>-B (<NUM>, <NUM> mmol) was placed in a microwave reactor, and <NUM>,<NUM>-dioxane (<NUM>) and water (<NUM>) were added thereto. Intermediate I (<NUM>, <NUM> mmol), sodium carbonate (<NUM>, <NUM> mmol) and [<NUM>,<NUM>-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (<NUM>, <NUM>µmol) were added thereto. The mixture was bubbled with nitrogen for <NUM> minutes, heated to <NUM> and reacted for <NUM> hour. After the reaction was completed, the reaction solution was filtered through diatomite to obtain filtrate, and then dried under reduced pressure to obtain the crude product of compound <NUM>-C. MS m/z: <NUM>[M+H]+.

Compound <NUM>-C (<NUM>, <NUM> mmol) was dissolved in <NUM>,<NUM>-dioxane (<NUM>), and tetraethylammonium fluoride hydrate (<NUM>, <NUM> mmol) was added thereto, heated to <NUM> and stirred for <NUM> hours. After the reaction was completed, the reaction solution was added with <NUM> of water, extracted with <NUM> (<NUM>*<NUM>) of ethyl acetate, and the organic phase was washed once with saturated brine, dried over anhydrous sodium sulfate, filtered to obtain filtrate, and dried under reduced pressure. The crude product was separated by column chromatography (ethyl acetate/dichloromethane: <NUM>-<NUM>%) to obtain compound <NUM>. MS m/z: <NUM> [M+H]+.

<NUM>H NMR (<NUM>, DMSO-d<NUM>) δ <NUM> (br s, <NUM>), <NUM> (br s, <NUM>), <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (t, J=<NUM>, <NUM>), <NUM> (br s, <NUM>), <NUM> (s, <NUM>), <NUM> (d, J=<NUM>, <NUM>), <NUM> (br s, <NUM>), <NUM> (br d, J=<NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (dt, J=<NUM>, <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (d, J=<NUM>, <NUM>).

Compound <NUM>-B (<NUM> mmol) was placed in a microwave reactor, and <NUM>,<NUM>-dioxane (<NUM>) and water (<NUM>) were added thereto. Intermediate I (<NUM>, <NUM> mmol), sodium carbonate (<NUM>, <NUM> mmol) and [<NUM>,<NUM>-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (<NUM>, <NUM>µmol) were added thereto. The mixture was purged with nitrogen for <NUM> minutes, heated to <NUM> and reacted for <NUM> hour. After the reaction was completed, the reaction solution was filtered through diatomite to obtain filtrate, and then dried under reduced pressure to obtain the crude product of compound <NUM>-C. MS m/z: <NUM>[M+H]+.

<NUM>H NMR (<NUM>, DMSO-d<NUM>) δ <NUM> (br s, <NUM>), <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (br s, <NUM>), <NUM> (br s, <NUM>), <NUM> (s, <NUM>), <NUM> (br s, <NUM>), <NUM> (br d, J=<NUM>, <NUM>), <NUM> (br d, J=<NUM>, <NUM>), <NUM> (br d, J=<NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (br t, J=<NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (br d, J=<NUM>, <NUM>).

Compound <NUM>-A (<NUM>, <NUM>µmol) was placed in a microwave reactor, and <NUM>,<NUM>-dioxane (<NUM>) and water (<NUM>) were added thereto. Intermediate I (<NUM>, <NUM> mmol), sodium carbonate (<NUM>, <NUM> mmol) and [<NUM>,<NUM>-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (<NUM>, <NUM>µmol) were added thereto. The mixture was bubbled with nitrogen for <NUM> minutes, heated to <NUM> and stirred for <NUM> hour under microwave irradiation. After the reaction solution was cooled, tetraethylammonium fluoride hydrate (<NUM>, <NUM>µmol) was added to the reaction solution, and the mixture was stirred at <NUM> for <NUM> hours. The reaction system was diluted with water (<NUM>), washed with ethyl acetate (<NUM>×<NUM>), washed with saturated brine (<NUM>), and dried over anhydrous sodium sulfate. After filtering off the desiccant, the solvent was removed under reduced pressure to obtain a crude product. The crude product was separated by column chromatography (tetrahydrofuran/petroleum ether: <NUM>-<NUM>%) to obtain compound <NUM>.

<NUM>H NMR (<NUM>, DMSO-d<NUM>) δ <NUM> (br s, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (br s, <NUM>), <NUM> (d, J=<NUM>, <NUM>), <NUM> (br s, <NUM>), <NUM> (s, <NUM>), <NUM> (br d, J=<NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (dt, J=<NUM>, <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> (d, J=<NUM>, <NUM>).

[<NUM>,<NUM>-Bis(diphenylphosphino)ferrocene]dichloropalladium (<NUM>, <NUM>µmol, <NUM> eq) was added to a solution of compound <NUM>-B (<NUM>, <NUM>µmol, <NUM> eq), <NUM>,<NUM>-dimethylpyrazole-<NUM>-boronic acid, pinacol ester (<NUM>, <NUM>µmol, <NUM> eq), sodium carbonate (<NUM>, <NUM> mmol, <NUM>µL, <NUM> eq) in <NUM>,<NUM>-dioxane (<NUM>), bubbled with nitrogen, and the reaction was stirred at <NUM> for <NUM> hour under microwave irradiation. After the reaction solution was cooled, the reaction system was diluted with water (<NUM>), washed with ethyl acetate (<NUM>×<NUM>), washed with saturated brine (<NUM>), and dried over anhydrous sodium sulfate. After filtering off the desiccant, the solvent was removed under reduced pressure to obtain a crude product. The crude product was purified by column chromatography (petroleum ether/ethyl acetate: <NUM>%-<NUM>%) to obtain compound <NUM>-A.

Compound <NUM>-B (<NUM>, <NUM>µmol) was placed in a microwave reactor, and <NUM>,<NUM>-dioxane (<NUM>) and water (<NUM>) were added thereto. Intermediate I (<NUM>, <NUM> mmol), sodium carbonate (<NUM>, <NUM> mmol) and [<NUM>,<NUM>-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (<NUM>, <NUM>µmol) were added thereto. The mixture was bubbled with nitrogen for <NUM> minutes, heated to <NUM> and stirred for <NUM> hour under microwave irradiation. After the reaction solution was cooled, tetraethylammonium fluoride hydrate (<NUM>, <NUM> mmol) was added to the reaction solution, and the mixture was stirred at <NUM> for <NUM> hours. The reaction system was diluted with water (<NUM>), washed with ethyl acetate (<NUM>×<NUM>), washed with saturated brine (<NUM>), and dried over anhydrous sodium sulfate. After filtering off the desiccant, the solvent was removed under reduced pressure to obtain a crude product. The crude product was separated by column chromatography (tetrahydrofuran/petroleum ether: <NUM>-<NUM>%) to obtain compound <NUM>.

<NUM>H NMR (<NUM>, DMSO-d<NUM>) δ <NUM> (br s, <NUM>), <NUM> (s, <NUM>), <NUM> (t, J=<NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> (d, J=<NUM>, <NUM>), <NUM> (br s, <NUM>), <NUM> (s, <NUM>), <NUM> (br d, J=<NUM>, <NUM>), <NUM> (br d, J=<NUM>, <NUM>), <NUM> (br dd, J=<NUM>, <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (dt, J=<NUM>, <NUM>, <NUM>), <NUM> (dt, J=<NUM>, <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> (d, J=<NUM>, <NUM>).

[<NUM>,<NUM>-Bis(diphenylphosphino)ferrocene]dichloropalladium (<NUM>, <NUM>µmol, <NUM> eq) was added to a solution of compound <NUM>-B (<NUM>, <NUM>µmol, <NUM> eq), intermediate I (<NUM>, <NUM>µmol, <NUM> eq), sodium carbonate (<NUM> , <NUM> mmol, <NUM>µL, <NUM> eq) in <NUM>,<NUM>-dioxane (<NUM>), bubbled with nitrogen, and the reaction was stirred at <NUM> for <NUM> hour under microwave irradiation. After the reaction solution was cooled, the reaction system was diluted with water (<NUM>), washed with ethyl acetate (<NUM>×<NUM>), washed with saturated brine (<NUM>), and dried over anhydrous sodium sulfate. After filtering off the desiccant, the solvent was removed under reduced pressure to obtain a crude product. The crude product was purified by column chromatography (petroleum ether/ethyl acetate: <NUM>%-<NUM>%) to obtain compound <NUM>-A.

Compound <NUM>-A (<NUM>, <NUM>µmol) was placed in a microwave reactor, and <NUM>,<NUM>-dioxane (<NUM>) and water (<NUM>) were added thereto. Intermediate I (<NUM>, <NUM>µmol), sodium carbonate (<NUM>, <NUM> mmol) and [<NUM>,<NUM>-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (<NUM>, <NUM>µmol) were added thereto. The mixture was bubbled with nitrogen for <NUM> minutes, heated to <NUM> and stirred for <NUM> hour under microwave irradiation. After the reaction solution was cooled, tetraethylammonium fluoride hydrate (<NUM>, <NUM>µmol) was added to the reaction solution, and the mixture was stirred at <NUM> for <NUM> hours. The reaction system was diluted with water (<NUM>), washed with ethyl acetate (<NUM>×<NUM>), washed with saturated brine (<NUM>), and dried over anhydrous sodium sulfate. After filtering off the desiccant, the solvent was removed under reduced pressure to obtain a crude product. The crude product was separated by column chromatography (ethyl acetate/dichloromethane: <NUM>-<NUM>%) to obtain compound <NUM>.

<NUM>H NMR (<NUM>, DMSO-d<NUM>) δ <NUM> (br s, <NUM>), <NUM> (s, <NUM>), <NUM> (t, J=<NUM>, <NUM>), <NUM> (d, J=<NUM>, <NUM>), <NUM> (d, J=<NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> (br s, <NUM>), <NUM> (d, J=<NUM>, <NUM>), <NUM> (br d, J=<NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (dt, J=<NUM>, <NUM>, <NUM>), <NUM> (dt, J=<NUM>, <NUM>, <NUM>), <NUM> (d, J=<NUM>, <NUM>).

[<NUM>,<NUM>-Bis(diphenylphosphino)ferrocene]dichloropalladium (<NUM>, <NUM>µmol, <NUM> eq) was added to a solution of compound <NUM>-B (<NUM>, <NUM> mmol, <NUM> eq), <NUM>,<NUM>-dimethylisoxazole-<NUM>-boronic acid, pinacol ester (<NUM>, <NUM> mmol, <NUM> eq), sodium carbonate (<NUM>, <NUM> mmol, <NUM>, <NUM> eq) in <NUM>,<NUM>-dioxane (<NUM>). The system was replaced with nitrogen for <NUM> times, and the reaction was stirred at <NUM> for <NUM> hours. After the reaction solution was cooled, the reaction system was diluted with water (<NUM>), washed with ethyl acetate (<NUM>×<NUM>), washed with saturated brine (<NUM>), and dried over anhydrous sodium sulfate. After filtering off the desiccant, the solvent was removed under reduced pressure to obtain a crude product. The crude product was purified by column chromatography (petroleum ether/ethyl acetate: <NUM>%-<NUM>%) to obtain compound <NUM>-A.

Compound <NUM>-A (<NUM>, <NUM> mmol) was placed in a microwave reactor, and <NUM>,<NUM>-dioxane (<NUM>) and water (<NUM>) were added thereto. Intermediate I (<NUM>, <NUM> mmol), sodium carbonate (<NUM>, <NUM> mmol) and [<NUM>,<NUM>-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (<NUM>, <NUM>µmol) were added thereto, the system was replaced with nitrogen for <NUM> times, and the mixture was stirred at <NUM> for <NUM> hours. After the reaction solution was cooled, tetraethylammonium fluoride hydrate (<NUM>, <NUM> mmol) was added to the reaction solution, and the mixture was stirred at <NUM> for <NUM> hours. The reaction system was diluted with water (<NUM>), washed with ethyl acetate (<NUM>×<NUM>), washed with saturated brine (<NUM>), and dried over anhydrous sodium sulfate. After filtering off the desiccant, the solvent was removed under reduced pressure to obtain a crude product. The crude product was separated by column chromatography (ethyl acetate/petroleum ether: <NUM>-<NUM>%) to obtain compound <NUM>.

<NUM>H NMR (<NUM>, CHLOROFORM-d) δ <NUM> (br s, <NUM>), <NUM> (s, <NUM>), <NUM> (t, J=<NUM>, <NUM>), <NUM> (d, J=<NUM>, <NUM>), <NUM> (br s, <NUM>), <NUM> (s, <NUM>), <NUM> (br d, J=<NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (dt, J=<NUM>, <NUM>, <NUM>), <NUM> (dt, J=<NUM>, <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (d, J=<NUM>, <NUM>).

The inhibitory activity of the test compounds against human ATR kinase was evaluated by measuring IC<NUM> value.

ATR/ATRIP (h) was incubated in detection buffer containing <NUM> GST-cMyc-p53 and Mg/ATP (<NUM>). The reaction was initiated by adding Mg/ATP mixture. After incubation at room temperature for <NUM> minutes, the reaction was terminated by adding a termination solution containing EDTA. Finally, a detection buffer containing d<NUM>-labeled anti-GST monoclonal antibody and europium-labeled anti-phospho-Ser15 antibody against phosphorylated p53 were added. Plates were then read in time-resolved fluorescence mode for homogeneous time resolution.

The fluorescence (HTRF) signal was determined according to the formula HTRF = <NUM> × (Em665 nm/Em620 nm).

The experimental results show that the compounds of the present disclosure have strong inhibitory activity against ATR enzyme.

In this experiment, the inhibitory effect of the compounds on cell proliferation was studied by detecting the effect of the compounds on the in vitro cell activity in the tumor cell line LoVo.

The following steps were carried out according to the instructions of PromegaCellTiter-Glo luminescent cell viability assay kit (Promega-G7573).

The Inhibition rate (IR) of the test compound was calculated using the following formula: IR (%) = (<NUM> - (RLU compound - RLU blank control)/(RLU solvent control - RLU blank control))*<NUM>%. The inhibition rates of different concentrations of the compounds were calculated in Excel, and then the inhibition curves were made by GraphPad Prism software and the related parameters were calculated, including the minimum inhibition rate, the maximum inhibition rate and IC<NUM>.

Experimental results are shown in Table <NUM>:.

The experimental results show that the compounds of the present disclosure have a good inhibitory effect on LoVo tumor cells lacking the ATM signaling pathway.

Test sample: On the basis of the above experiments, compound <NUM> was selected for further experiments.

Experimental methods: The purpose of this study was to determine the pharmacokinetic parameters of compound <NUM> and to calculate its oral bioavailability in female Balb/c Nude mice. This project used <NUM> female Balb/c Nude mice. Two mice were administered intravenously at a dose of <NUM>/kg, and plasma samples were collected at <NUM> hours (before administration) and <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM> hours after administration. The other two mice were administered orally by gavage at a dose of <NUM>/kg or <NUM>/kg, and plasma samples were collected at <NUM> hours (before administration) and <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM> hours after administration. The collected samples were then analyzed by LC/MS/MS and data were collected. The collected analysis data were used to calculate the relevant pharmacokinetic parameters by Phoenix WinNonlin <NUM>. <NUM> software.

Experimental conclusion: The compound of the present disclosure has good in vivo pharmacokinetic properties such as exposure and bioavailability.

The main objective of this study was to study the antitumor efficacy of the test sample on the xenograft tumor model of human gastric cancer cell SNU-<NUM>.

Tumor diameters were measured with vernier calipers three times a week. The tumor volume was calculated by the formula: V = <NUM> × a × b<NUM>, wherein a and b referred to the long and short diameter of the tumor, respectively. The calculation formula of relative tumor volume (RTV) was: RTV (%) = (Vt / V1) × <NUM>; the calculation formula of animal body weight change (BWC) was: BWC (%) = (BWt - BW1) / BW1 × <NUM>, wherein V1 and BW1 referred to the tumor volume and body weight of a certain animal on the day of group administration, and Vt and BWt referred to the tumor volume and body weight of a certain animal at a certain measurement. The antitumor efficacy of the compounds was evaluated by TGI (%) or relative tumor proliferation rate T/C (%). Relative tumor proliferation rate T/C (%) =TRTV / CRTV × <NUM> (TRTV: mean RTV of the treatment group; CRTV: mean RTV of the negative control group). The relative tumor volume (RTV) was calculated according to the results of tumor measurement, and the calculation formula was RTV =Vt / V1, wherein V1 was the tumor volume measured at the time of group administration (that is, D1), Vt was the tumor volume at a certain measurement, and the data of TRTV and CRTV were taken on the same day.

TGI (%) reflected the tumor growth inhibition rate. TGI (%)=[(<NUM>-(average tumor volume at the end of administration of a certain treatment group - average tumor volume at the beginning of administration of this treatment group))/(average tumor volume at the end of treatment in the solvent control group - average tumor volume at the beginning of treatment in the solvent control group)] × <NUM>.

After the experiment, the tumor weight would be detected, and the percentage of Tweight/Cweight would be calculated. Tweight and Cweight referred to the tumor weight of the administration group and the solvent control group, respectively.

In this experiment, the xenograft tumor model of human gastric cancer cell SNU601 was used to evaluate the in vivo efficacy of the test compounds. During the whole administration period, no animals were discontinued due to body weight loss of more than <NUM>%, and the efficacy test was terminated on the 21st day after administration.

On the 21st day after administration, the tumor volume of the solvent group reached <NUM> ± <NUM><NUM>. Compared with the solvent control group, compound <NUM> showed a certain antitumor effect at the doses of <NUM>/kg, <NUM>/kg and <NUM>/kg. Their corresponding tumor volumes were <NUM>±<NUM><NUM>, <NUM>±<NUM><NUM> and <NUM>±<NUM><NUM>, respectively, and their tumor inhibition rates TGI were <NUM>% (p <<NUM>), <NUM>% (P < <NUM>) and <NUM>% (p <<NUM>).

Claim 1:
A compound represented by formula (II) or a pharmaceutically acceptable salt thereof,
<CHM>
wherein,
ring A is
<CHM>
<CHM>
R<NUM> is each independently H or C<NUM>-<NUM> alkyl, wherein the C<NUM>-<NUM> alkyl is optionally substituted with <NUM>, <NUM> or <NUM> Ra;
R<NUM> is each independently H or C<NUM>-<NUM> alkyl, wherein the C<NUM>-<NUM> alkyl is optionally substituted with <NUM>, <NUM> or <NUM> Rb;
R<NUM> is H or C<NUM>-<NUM> alkyl;
R<NUM> is each independently H, C<NUM>-<NUM> alkyl, -O-C<NUM>-<NUM> alkyl or -S(O)<NUM>-C<NUM>-<NUM> alkyl, wherein the C<NUM>-<NUM> alkyl, -O-C<NUM>-<NUM> alkyl and -S(O)<NUM>-C<NUM>-<NUM> alkyl are each independently optionally substituted with <NUM>, <NUM> or <NUM> Rc;
Ra, Rb and Rc are each independently F, Cl, Br or I.