Substituted condensed heterocyclic compound, its production method and application

Abstract

The present invention provides a substituted fused heterocyclic compound and its preparation method and application. The present invention provides a compound having the structure represented by the following formula I or a pharma- ceutically acceptable salt thereof. The compound or a pharma- ceutically acceptable salt thereof is used as an ATR inhibitor and has high activity. [Formula 1] TIFF2025503506000084.tif63161(Y 1 , Y 2 , Y 3 , Y 4 , R 1 , R 2 are defined as such in the specification).

Description

[Technical field]

[0001] The present invention relates to a substituted fused heterocyclic compound, and a production method and application thereof. [Background technology]

[0002] Every cell cycle, human cells need to accurately and efficiently replicate their entire genome. This means copying over 6 billion DNA fragments (bases), which is a very challenging and complex project, as it places high demands on accuracy and efficiency. In this process, there are inevitably many obstacles that prevent or affect the normal replication of DNA. Therefore, normal human cells have a powerful response mechanism to ensure that the entire genome is accurately replicated once every cell cycle (Non-Patent Document 1).

[0003] Human cells have many regulatory molecules to maintain genome stability and integrity, among which the important one is ataxia telangiectasia gene and Rad3-related (ATR) protein kinase. When intracellular DNA damage or replication stress is generated, ATR is recruited to the appropriate location and activated. Activated ATR plays important regulatory roles in many aspects, such as cell cycle retardation, inhibition of replication origins, promotion of deoxynucleotide synthesis, and initiation of replication forks.

[0004] Unlike normal cells, cancer cells have defective DNA damage response and / or increased replication stress, making their genome unstable, which is also an important characteristic of cancer. Because cancer cells have these characteristics that are different from normal cells, they are more likely to accumulate conditions such as gene mutations, rearrangements, and changes in copy number during cancer cell division, and may further promote the cloning evolution of cancer cells. At the same time, these characteristics are also defective, which causes vulnerabilities specific to cancer cells. It is predicted that making the most of these vulnerabilities can enhance the effectiveness of anti-cancer treatment and improve the prognosis of cancer patients (Non-Patent Document 2).

[0005] As one of the vulnerabilities, cancer cells are more dependent on ATR than normal cells. Given that replication stress caused by oncogenes is a factor in the instability of cancer genomes, cancer cell survival becomes highly dependent on a skilled and complete replication stress response, making them more susceptible to ATR inhibitors. Early studies on cell lines and mouse models provide preclinical support for this concept. Furthermore, there is evidence that mice with reduced ATR levels are highly resistant to cancer development. These results highlight the potential of targeting ATR in cancer therapy. Thus, the development of ATR inhibitors with high activity and good drug formability is expected to provide mankind with a novel weapon to resist cancer. (Non-Patent Document 3).

[0006] In the prior art, Patent Documents 1 to 3 and the like, compounds having ATR kinase inhibitory activity are reported, and several ATR kinase inhibitors as described below have entered the clinical trial stage.

[0007] [ka]

[0008] [ka] [Prior art documents] [Patent documents]

[0009] [Patent Document 1] International Publication No. 2014 / 089379 [Patent Document 2] International Publication No. 2011 / 1154737 [Patent Document 3] International Publication No. 2016 / 020320 [Non-patent literature]

[0010] [Non-Patent Document 1] Saldivar JC et al, 2017, Nat.Rev.Mol.CellBiol.18, 622-636 [Non-Patent Document 2] Pilie.PGetal, 2019, Nat.Rev.Clin.Oncol.16, 81-104 [Non-Patent Document 3] Lecona, E.etal, 2018, Nat.Rev.Cancer18, 586―595 [Non-Patent Document 4] ACS Med.Chem.Lett.2015,6,42-46 Summary of the Invention

[0011] An object of the present invention is to provide a novel compound as an ATR inhibitor.

[0012] Another object of the present invention is to provide a method for preparing the compound.

[0013] Another object of the present invention is to provide applications of said compounds.

[0014] Another object of the present invention is to provide a pharmaceutical composition containing said compound and its application.

[0015] Another object of the present invention is to provide intermediates for preparing said compounds.

[0016] Another object of the present invention is to provide a method for producing the intermediate.

[0017] Further, the present invention provides a compound having a structure represented by formula I below, or a pharma- ceutically acceptable salt thereof.

[0018] [ka] R1 is a 5- or 6-membered fused heteroaromatic ring group or a 6- or 6-membered fused heteroaromatic ring group containing n heteroatoms, or a 5- or 6-membered aromatic ring group containing m heteroatoms, where n is selected from an integer of 1 to 4, m is selected from an integer of 0 to 3, and the heteroatom is one or two selected from O, N and S. In the 5- or 6-membered fused heteroaromatic ring group or the 6- or 6-membered fused heteroaromatic ring group containing n heteroatoms, the heteroaromatic ring group is optionally substituted with one or more substituents selected from halogen, -OH, -OMe, -NH2, -NHMe, -NMe2, -CN, -CONH2 and -Me. In the 5- or 6-membered aromatic ring group containing m heteroatoms, the aromatic ring group is optionally substituted with one or more substituents selected from a 4- to 6-membered heterocycloalkyl group, a halogen, -OH, -OMe, -NH2, -NHMe, -NMe2, -CN, -CONH2, and -Me. When the aromatic ring group is substituted with a 4- to 6-membered heterocycloalkyl group, they may be connected to each other by a single bond or may form a condensed ring.

[0019] R 2 -OH, C 1-6 Alkoxy group, -NR 3 R 4 , -CN,C 1-6 Alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 3-6 It is a cycloalkyl group or a 4- to 6-membered heterocycloalkyl group, and the heteroatom is one selected from O and N. 1-6 Alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 3-6 The cycloalkyl group or the 4- to 6-membered heterocycloalkyl group may optionally be substituted with halogen, -OH, C 1-6 Alkoxy group, -NR 5 R 6 , -CN.

[0020] R 3 , R 4 are each independently hydrogen or C 1-6 It is an alkyl group.

[0021] R 5 , R 6 are each independently hydrogen or C 1-6 an alkyl group, or -NR 5 R 6 represents an azetidine group, a pyrrolidine group, a piperidyl group, a morpholinyl group, or a 4-methylpiperazinyl group. According to some specific embodiments of the present invention, in the compound having the structure represented by formula I of the present invention, or a pharma- ceutically acceptable salt thereof, Y 3 and Y 4 are CH. Y 1 , Y 2 are each independently CH or N, and Y 1 and Y 2 At least one of is N. Thus, these preferred specific embodiments of the present invention provide compounds having the structure represented by formula I-1 below.

[0022] [ka] According to some specific embodiments of the present invention, in the compound having the structure represented by formula I of the present invention, or a pharma- ceutically acceptable salt thereof, Y 1 and Y 2 are N respectively.

[0023] According to some specific embodiments of the present invention, in the compound having the structure represented by formula I of the present invention, or a pharma- ceutically acceptable salt thereof, Y 1 and Y 2 are N and Y 3 and Y 4 and each is CH. Thus, these preferred embodiments of the present invention provide compounds having the structure represented by formula I-2 below.

[0024] [ka] According to some specific embodiments of the present invention, in the compound having the structure represented by formula I of the present invention, or a pharma- ceutically acceptable salt thereof, R 1 is a 5- or 6-membered fused heteroaromatic ring group containing n heteroatoms, n being an integer of 1 to 4, and the heteroatoms being one or two selected from O, N and S. The heteroaromatic ring group is optionally substituted with one or more substituents selected from halogen, -OH, -OMe, -NH2, -NHMe, -NMe2, -CN, -CONH2 and -Me.

[0025] According to some specific embodiments of the present invention, in the compound having the structure represented by formula I of the present invention, or a pharma- ceutically acceptable salt thereof, R 1 is selected from the following group:

[0026] [ka] According to some specific embodiments of the present invention, in the compound having the structure represented by Formula I of the present invention, or a pharma- ceutically acceptable salt thereof, the compound is selected from the following:

[0027] [ka] The present invention also provides an intermediate compound, including, but not limited to, any one of the intermediates in the scheme for preparing the compound or a pharma- ceutically acceptable salt thereof. Preferably, the intermediate has the same basic structural unit (substantially the same basic core moiety or basic ring) as the compound of formula I or a pharma- ceutically acceptable salt thereof, or the basic structural unit of the intermediate is included in the chemical structure of the compound of formula I or a pharma- ceutically acceptable salt thereof.

[0028] According to some specific embodiments of the present invention, the intermediate compound has a structure represented by Formula II:

[0029] [ka] R 3 is halogen or

[0030] [ka] wherein the halogen is preferably chlorine.

[0031] The present invention further relates to a method for preparing an intermediate compound represented by the following formula II by reacting R 1 The present invention provides a method for preparing a compound having a structure represented by formula I, or a pharma- ceutically acceptable salt thereof, comprising: reacting a compound having a structure represented by formula I, with -M to prepare a compound having a structure represented by formula I.

[0032] [ka] R 3 When is halogen, M is

[0033] [ka] It is.

[0034] R 3 but

[0035] [ka] When M is a halogen, preferably bromine. Y 1 , Y 2 , Y 3 , Y 4 , R 1 and R 2 are each independently as defined above.

[0036] According to a specific embodiment of the present invention, the process for preparing a compound of the present invention having the structure represented by formula I, or a pharma- ceutically acceptable salt thereof, comprises the step of preparing the intermediate compound.

[0037] According to some specific embodiments of the present invention, there is provided a method for producing a compound having a structure represented by formula I of the present invention or a pharma- ceutically acceptable salt thereof, comprising preparing and obtaining a compound of formula I or a pharma- ceutically acceptable salt thereof according to any of the schemes of Preparation Example 1 to Preparation Example 27, but not limited thereto. Here, each substituent in the compound obtained by preparation is not limited to those in the specific compounds of Preparation Example 1 to Preparation Example 27, and the definition of each substituent may refer to the definition range of each substituent in the compound having a structure represented by formula I.

[0038] The present invention further provides a pharmaceutical composition comprising a compound having the structure represented by formula I of the present invention or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable carrier.

[0039] The present invention further provides the application of the compound or its pharma- ceutically acceptable salt or the pharmaceutical composition as an ATR kinase inhibitor. When the compound or its pharma- ceutically acceptable salt or the pharmaceutical composition of the present invention is specifically applied as an ATR inhibitor, it may be for non-therapeutic purposes (e.g., in vitro experimental research purposes, etc.) or for therapeutic purposes. That is, the present invention provides the application of the compound or its pharma- ceutically acceptable salt or the pharmaceutical composition in the preparation of a drug for inhibiting ATR kinase.

[0040] The present invention further provides the application of said compound or its pharma- ceutically acceptable salt or said pharmaceutical composition in the preparation of a drug for treating a hyperproliferative disease, which comprises the step of administering said compound or its pharma- ceutically acceptable salt or said pharmaceutical composition to a subject in need thereof when treating a hyperproliferative disease with said compound or its pharma- ceutically acceptable salt of the present invention as a pharmaceutical active ingredient.

[0041] In the above applications provided by the present invention, the hyperproliferative disease includes, for example, 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, or gallbladder cancer.

[0042] Definitions and Explanations Unless otherwise specified, the following terms and phrases used herein have the following meanings: A particular term or phrase should not be considered uncertain or unclear, but should be understood in its general sense, unless specifically defined. When a trade name appears in this specification, it is intended to refer to the corresponding product or its active ingredients.

[0043] The term "pharmacologically acceptable" means that those compounds, materials, compositions and / or dosage forms are suitable for use in contact with the tissues of human beings and animals, within the scope of sound medical judgment, without significant toxicity, irritation, allergic response or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0044] The term "pharmaceutically acceptable salt" refers to a salt of a compound of the present invention prepared from a relatively non-toxic acid or base with a compound having a specific substituent according to the present invention. When the compounds of the present invention contain a relatively acidic functional group, an alkali addition salt can be obtained by contacting a pure solution or a suitable inert solvent with a sufficient amount of an alkali in the neutral form of these compounds. Pharmaceutically acceptable alkali addition salts include sodium, potassium, calcium, ammonium, organic ammonia or magnesium salts or similar salts. When the compounds of the present invention contain a relatively alkaline functional group, an acid addition salt can be obtained by contacting a pure solution or a suitable inert solvent with a sufficient amount of an acid in the neutral form of these compounds. Examples of pharma- ceutically acceptable acid addition salts include, for example, salts of inorganic acids including hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate, phosphoric acid, hydrogen phosphate, dihydrogen phosphate, sulfuric acid, hydrogen sulfate, iodic acid, phosphorous acid, and the like; salts of acetic acid, propionic acid, isobutanoic 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, methanesulfonic acid, and the like; and salts of organic acids such as amino acids (e.g., arginine, etc.). Certain compounds of the present invention contain alkaline and acidic functional groups, which may be converted into any alkali or acid addition salt.

[0045] The pharma- ceutically acceptable salts of the present invention can be synthesized from parent compounds containing an acid or base group by conventional chemical methods. In general, the method for preparing such salts involves reacting these compounds in the form of a free acid or base with a suitable base or acid that is chemically proportioned in water or an organic solvent or a mixture of both.

[0046] Unless otherwise indicated, the absolute configuration of one stereocenter is indicated by a solid wedge bond.

[0047] [ka] and wedge-shaped broken line bond

[0048] [ka] and the relative configuration of stereocenters is represented by straight solid bonds.

[0049] [ka] and straight dashed bonds

[0050] [ka] and wavy line bond

[0051] [ka] Solid wedge joint

[0052] [ka] or wedge-shaped broken line bond

[0053] [ka] or a wavy line bond

[0054] [ka] Straight solid bond with

[0055] [ka] and straight dashed bonds

[0056] [ka] Represents.

[0057] "Optional" or "optionally" means that the case or circumstance described below may occur but need not occur, and the description includes cases where the case or circumstance occurs and cases where it does not occur.

[0058] "Substituted" means that any one or more hydrogen atoms at a particular atom are replaced with a substituent, which may include deuterium and hydrogen variants, so long as the valence state of the particular atom is normal and the substituted compound is stable. When the substituent is oxygen (i.e., =O), it means that two hydrogen atoms are replaced. Oxygen substitution cannot occur in aromatic groups. The term "optionally substituted" means that it may or may not be substituted, and unless otherwise specified, the type and number of substituents are optional as long as they are chemically feasible.

[0059] When any variable (e.g., R) occurs more than one time in any composition or structure of a compound, its definition is independent at each occurrence. Thus, for example, if a group is substituted with 0-2 R, the group may optionally be substituted with up to 2 R, with R having an independent option at each occurrence. Further, combinations of substituents and / or variables thereof are permissible only if they result in stable compounds.

[0060] When one of these variables is selected from a bond, it means that the two groups joined by that bond are directly linked, eg, when L in ALZ represents a bond, the structure is actually AZ.

[0061] If one of the variables is selected from the gap, it indicates that it is not present, for example, in C-R3, if R3 is selected from the gap, it means that the structure is actually C.

[0062] Substituents may be bonded to any atom of the substituent unless it is specified which atom the substituent is connected to; for example, a phenyl group may be bonded to the group it replaces through any of the carbon atoms in the benzene ring as a substituent.

[0063] Unless otherwise specified, the term "alkyl group" refers to a straight or branched chain saturated hydrocarbon group, which may be mono-substituted (e.g., -CH2F) or poly-substituted (e.g., -CF3), and may be monovalent (e.g., methyl), divalent (e.g., methylene) or polyvalent (e.g., methine). Alkyl groups include methyl (Me), ethyl (Et), propyl (n-propyl and isopropyl), butyl (n-butyl, isobutyl, s-butyl, t-butyl), pentyl (e.g., n-pentyl, isopentyl, neopentyl), and the like.

[0064] Unless otherwise specified, a "cycloalkyl group" includes any stable cyclic or polycyclic hydrocarbon group, which is saturated at any of the carbon atoms, which may be mono- or polysubstituted, and which may be mono-, di- or polyvalent. Examples of these cycloalkyl groups include cyclopropyl, norbornyl, [2.2.2]dicyclooctane, [4.4.0]dicyclodecane, and the like.

[0065] Unless otherwise specified, the term "alkenyl group" refers to a straight or branched chain hydrocarbon group containing at least one carbon-carbon double bond, and includes the terms "C 2-6 The term "alkenyl group" refers to the above-mentioned hydrocarbon group having 2, 3, 4, 5 or 6 carbon atoms, and "C 2-4 The term "alkenyl group" refers to a hydrocarbon group as described above having 2, 3 or 4 carbon atoms, and it is also understood that when an alkenyl group contains one or more carbon-carbon double bonds, the double bonds may be separate or conjugated with each other. 2-6Examples of the "alkenyl group" include, but are not limited to, a vinyl group, an allyl group, a butenyl group, a pentenyl group, a hexenyl group, a butadienyl group, a pentadienyl group, a hexadienyl group, and the like.

[0066] The term "alkynyl group" refers to a straight or branched chain hydrocarbon group having at least one carbon-carbon triple bond, and includes the terms "C 2-6 The term "alkynyl group" refers to the above-mentioned hydrocarbon group having 2, 3, 4, 5 or 6 carbon atoms, and "C 2-4 The term "alkynyl group" refers to the above-mentioned hydrocarbon groups having 2, 3 or 4 carbon atoms, and exemplary "C 2-6 Examples of the "alkynyl group" include, but are not limited to, an ethynyl group, a propynyl group, a butynyl group, a pentynyl group, a hexynyl group, a methylpropynyl group, and a 4-methyl-1-butynyl group.

[0067] Unless otherwise stated, the term "halogen" by itself or as part of another substituent means a fluorine (F), chlorine (Cl), bromine (Br), or iodine (I) atom.

[0068] Unless otherwise specified, the term "alkoxy group" means an alkyl group attached to the remainder of the molecule through an oxygen atom. Here, the alkyl group is defined as described in the present invention. 1-5 Alkoxy groups include C1, C2, C3, C4 and C5 alkoxy groups, unless otherwise specified. Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, s-butoxy, t-butoxy, n-pentyloxy and s-pentyloxy groups. The alkoxy group may be optionally substituted with one or more of the substituents described in the present invention.

[0069] Unless otherwise specified, "amine group" means -NH2, -NH(alkyl) or -N(alkyl)(alkyl group).

[0070] Unless otherwise specified, the term "aromatic ring" refers to a multiply unsaturated aromatic alkane monocyclic ring, which may be mono- or polysubstituted.

[0071] Unless otherwise specified, the term "4- to 6-membered heterocycloalkyl group" refers to a group having 3, 4, or 5 carbon atoms and one or more O, NR a and a heteroatom group selected from the group consisting of: a is a hydrogen atom or C 1-6 The "4- to 6-membered heterocycloalkyl group" may be linked to the remainder of the molecule at any of the carbon atoms or, if present, at a nitrogen atom.

[0072] Unless otherwise specified, the term "heteroaromatic ring" means an aromatic ring containing 1 to 4 heteroatoms selected from one or more of N, O and S.

[0073] Unless otherwise specified, the term "fused aromatic ring" means a fused aromatic ring having two or more aromatic rings.

[0074] Unless otherwise specified, the term "5-membered-6-membered fused heteroaromatic ring" refers to a 5-membered-6-membered fused heteroaromatic ring, in which at least one of the two fused rings contains one or more heteroatoms (including, but not limited to, O, S or N) and the entire group has aromatic properties, and is not limited to the benzene-5-membered heteroaryl group fused compound and the 6-membered heteroaromatic ring-5-membered heteroaromatic ring fused compound described in the examples.

[0075] Unless otherwise specified, the term "6-membered-6-membered heteroaromatic ring" refers to a 6-membered-6-membered fused heteroaromatic ring, in which at least one of the two fused rings contains one or more heteroatoms (including, but not limited to, O, S or N) and the entire group has aromatic properties, including, but not limited to, benzene-6-membered heteroaryl group fused products and 6-membered heteroaromatic ring-6-membered heteroaromatic ring fused products described in the examples.

[0076] Unless otherwise specified, the term "pharmaceutically acceptable salt" or "a pharmaceutically acceptable salt thereof" refers to a salt obtained by reacting said free acid with a non-toxic inorganic or organic alkali, and said free base with a non-toxic inorganic or organic acid, such that the compounds of the present invention retain the biological effectiveness and properties of the free acid or free base.

[0077] Unless otherwise specified, the term "drug composition" refers to a mixture of one or more compounds according to the present invention or pharma- ceutically acceptable salts with other chemical components, and "other chemical components" refers to pharma- ceutically acceptable carriers, excipients, and / or other therapeutic agents. A "carrier" is a material that is not significantly irritating to the living body and does not eliminate the biological activity or properties of the compound of interest. An "excipient" is an inert substance added to a drug composition to facilitate administration of the compound. Non-limiting examples include calcium carbonate, calcium phosphate, sugars, starches, cellulose derivatives (including microcrystalline cellulose), gelatin, vegetable oils, polyethylene glycols, diluents, granulating agents, lubricants, binders, and disintegrants.

[0078] The compound of the present invention has good ATR kinase inhibitory activity and tumor cell proliferation inhibitory activity, and has potential application value in the treatment of diseases related to cell proliferation. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0079] Hereinafter, the embodiments of the present invention will be described in detail with reference to the following examples. However, it is obvious to those skilled in the art that the following examples are used only to explain the present invention and do not limit the scope of the present invention. If no specific conditions are specified in the examples, they are carried out according to normal conditions or conditions recommended by the manufacturer. If the manufacturer of the reagent or equipment used is not specified, it is available commercially.

[0080] The structure of the compound is determined by nuclear magnetic resonance or mass spectrometry. Nuclear magnetic resonance is determined by BRUKER The measurements were performed using a 400M nuclear magnetometer, the measurement solvent was deuterated dimethyl sulfoxide (DMSO-d6) or deuterated chloroform (CDCl3), the internal standard was tetramethylsilane (TMS), and the chemical shift (δ) was 10 -6 Mass spectrometry was performed using Water ACQUITY Arc / ACQUITY Measurements are performed using a QDa or Thermo U3000-ISQ EC liquid chromatography mass spectrometer.

[0081] Thermo Scientific for high performance liquid chromatography analysis Use a U3000 high pressure liquid chromatograph. For high pressure liquid preparation, use a Hanban DAC-50 or Shimadzu LC-20AP preparative chromatograph.

[0082] Reaction monitoring is performed using a thin-layer chromatography or liquid chromatography mass spectrometer. The eluent systems used in thin-layer chromatography include a system of dichloromethane and methanol, and a system of petroleum ether and ethyl acetate. The volume ratio of the solvents is adjusted according to the polarity of the compounds, or by adding a small amount of triethylamine. ACQUITY Arc / ACQUITY QDa or Thermo A U3000-ISQEC liquid chromatography mass spectrometry system is used.

[0083] In column chromatography, 200-300 mesh silica gel is used as a carrier. The eluent system is a system of dichloromethane and methanol, or a system of petroleum ether and ethyl acetate, and the volume ratio of the solvent is adjusted according to the polarity of the compound, or by adding a small amount of triethylamine.

[0084] In the following examples, unless otherwise specified, the reaction temperature is room temperature (20° C. to 30° C.), and the solvent is dried and purified by a standard method.

[0085] In the conventional synthesis and in the embodiments of the present invention, the following abbreviations have the following meanings:

[0086] [Table 1] Example 1: (R)-3-Methyl-4-(1'-(methylsulfonyl)-1H,1'H-[4,6'-dipyrrolo[2,3-b]pyridin]-4'-yl)morpholine (Compound 1)

[0087] [ka] 4-Bromo-1H-pyrrolo[2,3-b]pyridine (10.0 g, 50.8 mmol) was dissolved in tetrahydrofuran (200 mL), cooled to 0°C, metachloroperbenzoic acid (17.5 g, 101.5 mmol) was added, and the mixture was stirred at room temperature for 4 hours to precipitate a solid. The solid was collected by filtration, dissolved, and purified by silica gel column chromatography to obtain the title compound (7.8 g, 72% yield).

[0088] LC-MS (ESI) m / z 213.0, 215.0 [M+H] + . STEP 2: 4-Bromo-6-chloro-1H-pyrrolo[2,3-b]pyridine 4-Bromo-1H-pyrrolo[2,3-b]pyridine-7-oxide (5.0 g, 23.5 mmol) was dissolved in N,N-dimethylformamide (250 The mixture was dissolved in methanesulfonyl chloride (13.5 mL) and heated to 50°C. g, 118.0 mmol) was added, and the mixture was further heated to 75° C. and reacted with stirring for 1 hour. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and purified by HPLC to obtain the title compound (2.2 g, yield 41%).

[0089] LC-MS (ESI) m / z 230.9, 232.9 [M+H] + . STEP 3: 4-Bromo-6-chloro-1-(2-(trimethylsilyl)ethoxymethyl)-1H-pyrrolo[2,3-b]pyridine 4-Bromo-6-chloro-1H-pyrrolo[2,3-b]pyridine (1.1 g, 4.8 mmol) was dissolved in tetrahydrofuran (35 The mixture was dissolved in 2.5 mL of 2-(trimethylsilyl)ethoxymethylchloroisocyanate (2.5 mL), and 60% sodium hydride (400 mg, 10.0 mmol) was slowly added at room temperature. The mixture was stirred for 5 minutes and then reacted. g, 15.0 mmol) was added and the reaction was continued with stirring at room temperature to ensure complete conversion of the raw materials. A small amount of water was added to quench the reaction, and dichloromethane (100 mL) was added, followed by washing with water. The layers were separated and the organic phase was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography to obtain the title compound (1.5 g, yield 87%).

[0090] LC-MS (ESI) m / z 361.0, 363.0 [M+H] + . Step 4: (R)-4-(6-chloro-1-(2-(trimethylsilyl)ethoxymethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-3-methylmorpholine 4-Bromo-6-chloro-1-(2-(trimethylsilyl)ethoxymethyl)-1H-pyrrolo[2,3-b]pyridine (1.0 g, 2.8 mmol) and (R)-3-methylmorpholine (280 mg, 2.8 mmol) were dissolved in 1,4-dioxane (20 mL). The atmosphere was replaced with nitrogen gas, and Pd(XantPhos)Cl2 (210 mL) was added under the protection of nitrogen. After adding 100 mg (0.28 mmol) and sodium t-butoxide (270 mg, 2.8 mmol), the mixture was heated to 80° C. and reacted with stirring under nitrogen protection for 6 hours. The reaction mixture was cooled to room temperature and added dichloromethane (100 The mixture was washed with water. The layers were separated, and the organic phase was dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography to obtain the title compound (437 mg, yield 41%).

[0091] LC-MS (ESI) m / z 382.2 [M+H] + . Step 5: (R)-4-(6-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)-3-methylmorpholine (R)-4-(6-chloro-1-(2-(trimethylsilyl)ethoxymethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-3-methylmorpholine (110 mg, 0.29 mmol) and trifluoroacetic acid (1 mL) were added to a reaction bottle. The mixture was stirred at room temperature to completely convert the raw materials. The reaction solution was concentrated under reduced pressure, and tetrahydrofuran (5 mL) and 1M aqueous sodium hydroxide solution (2 mL) were added. The resulting mixture was stirred at room temperature for 30 minutes, and then ethyl acetate (50 mL) was added, followed by washing with water. The organic phase was separated and dried over anhydrous sodium sulfate. Filtration and concentration of the filtrate under reduced pressure gave the crude product of the title compound. This was carried to the next step without purification.

[0092] LC-MS (ESI) m / z 252.1 [M+H] + . SDP 6: (R)-4-(6-chloro-1-(methylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-3-methylmorpholine The entire crude (R)-4-(6-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)-3-methylmorpholine product obtained in the previous step was dissolved in tetrahydrofuran (6 The mixture was dissolved in 1 mL of 60% sodium hydride (48 mg, 1.2 mmol) at room temperature and reacted with stirring for 5 minutes. The reaction was continued with stirring at room temperature for 3 hours. A small amount of water was added to quench the reaction, and ethyl acetate (40 mL) was added and washed with water. The organic phase was separated and dried over anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography to obtain the title compound (76 mg, yield 80%).

[0093] LC-MS (ESI) m / z 330.1 [M+H] + . Sdep 7: (R)-3-Methyl-4-(1'-(methylsulfonyl)-1H,1'H-[4,6'-dipyrrolo[2,3-b]pyridin]-4'-yl)morpholine In a reaction bottle, add (R)-4-(6-chloro-1-(methylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-3-methylmorpholine (50 mg, 0.15 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (73.5 mg, 0.3 mmol), Pd(dppf)Cl2 (22 mg, 0.03 mmol) and sodium carbonate (47.5 mg, 0.45 The mixture was heated to 100° C. under nitrogen protection and stirred for 3 hours. The reaction mixture was cooled to room temperature and dichloromethane (20 mmol) was added. The mixture was washed with water. The layers were separated, and the organic phase was dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure and purified by HPLC to obtain compound 1 (51 mg, yield 82%).

[0094] LC-MS (ESI) m / z 412.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 11.77 (s, 1H), 8.32 (d, J = 5.0 Hz, 1H), 7.67 (d, J = 5.1 Hz, 1H), 7.61 (d, J = 4.1 Hz, 1H), 7.57 (dd, J = 3.5, 2.5 Hz, 1H), 7.31 (s, 1H), 7.27 (dd, J = 3.4, 1.9 Hz, 1H), 6.98 (d, J = 4.2 Hz, 1H), 4.42-4.34 (m, 1H), 4.03-3.95 (m, 1H), 3.84 (dd, J = 11.3, 2.7 Hz, 1H), 3.79 (s, 3H), 3.73 (d, J = 11.3 Hz, 1H), 3.69-3.59 (m, 2H), 3.51 (td, J = 12.3, 3.5 Hz, 1H), 1.18 (d, J = 6.7 Hz, 3H). 13 C NMR (100 MHz, DMSO-d6) δ 153.11, 152.00, 150.79, 149.64, 143.44, 139.42, 127.84, 123.59, 118.25, 114.68, 111.58, 105.64, 104.16, 101.94, 71.45, 67.08, 51.42, 43.70, 42.51, 13.89. 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine was converted to other aromatic pinacol borate esters or aromatic boric acids by a coupling reaction similar to step 7 in Example 1, and compounds 2 to 11 were prepared from the intermediate (R)-4-(6-chloro-1-(methylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-3-methylmorpholine. The aromatic pinacol borate esters were either commercially available or prepared by the Miyaura boration reaction from aryl halides and biboric pinacol esters. The aromatic boric acids were either commercially available or prepared by the reaction of aryl halides with butyllithium and boric acid esters.

[0095] Example 2: (R)-4-(6-(1H-indol-4-yl)-1-(methylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-3-methylmorpholine (Compound 2)

[0096] [ka] LC-MS (ESI) m / z 411.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 11.26 (s, 1H), 7.57 (dd, J = 7.4, 0.9 Hz, 1H), 7.55 (d, J = 4.1 Hz, 1H), 7.48 (d, J = 8.1 Hz, 1H), 7.44 (t, J = 2.8 Hz, 1H), 7.24-7.18 (m, 2H), 7.16 (s, 1H), 6.94 (d, J = 4.2 Hz, 1H), 4.36-4.28 (m, 1H), 4.02-3.94 (m, 1H), 3.87-3.78 (m, 4H), 3.72 (d, J = 11.4 Hz, 1H), 3.65 (td, J = 11.2, 3.3 Hz, 1H), 3.55 (d, J = 12.1 Hz, 1H), 3.48 (td, J = 11.8, 3.4 Hz, 1H), 1.17 (d, J = 6.6 Hz, 3H). Example 3: (R)-3-Methyl-4-(1-(methylsulfonyl)-6-(1H-pyrrolo[2,3-c]pyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)morpholine (compound 3)

[0097]

change

[0098]

change

[0099]

change

[0100] [ka] LC-MS (ESI) m / z 426.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 11.47 (s, 1H), 8.24 (d, J = 4.8 Hz, 1H), 7.58 (d, J = 4.2 Hz, 1H), 7.30-7.23 (m, 1H), 7.08 (d, J = 4.8 Hz, 1H), 6.98 (d, J = 4.2 Hz, 1H), 6.82 (s, 1H), 4.37-4.29 (m, 1H), 3.97-3.89 (m, 1H), 3.80 (dd, J = 11.3, 2.8 Hz, 1H), 3.74-3.67 (m, 4H), 3.61 (td, J = 11.3, 3.0 Hz, 1H), 3.55-3.41 (m, 2H), 1.94 (s, 3H), 1.16 (d, J = 6.6 Hz, 3H). Example 7: (R)-4-(6-(6-fluoro-1H-indol-4-yl)-1-(methylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-3-methylmorpholine (compound 7)

[0101] [ka] LC-MS (ESI) m / z 429.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 11.32 (s, 1H), 7.57 (d, J = 4.1 Hz, 1H), 7.47 (dd, J = 11.2, 2.3 Hz, 1H), 7.45-7.43 (m, 1H), 7.26 (dd, J = 9.5, 2.2 Hz, 1H), 7.23-7.20 (m, 1H), 7.18 (s, 1H), 6.95 (d, J = 4.2 Hz, 1H), 4.40-4.32 (m, 1H), 4.02-3.94 (m, 1H), 3.83 (dd, J = 11.4, 2.7 Hz, 1H), 3.79 (s, 3H), 3.72 (d, J = 11.2 Hz, 1H), 3.69-3.57 (m, 2H), 3.49 (td, J = 12.4, 3.5 Hz, 1H), 1.18 (d, J = 6.7 Hz, 3H). Example 8: (R)-4-(6-(7-fluoro-1H-indol-4-yl)-1-(methylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-3-methylmorpholine (compound 8)

[0102] [ka] LC-MS (ESI) m / z 429.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 11.75 (s, 1H), 7.59-7.53 (m, 2H), 7.51 (t, J = 2.7 Hz, 1H), 7.33-7.29 (m, 1H), 7.13 (s, 1H), 7.04 (dd, J = 11.0, 8.2 Hz, 1H), 6.93 (d, J = 4.2 Hz, 1H), 4.37-4.29 (m, 1H), 4.02-3.94 (m, 1H), 3.83 (dd, J = 11.3, 2.9 Hz, 1H), 3.79 (s, 3H), 3.72 (d, J = 10.6 Hz, 1H), 3.65 (td, J = 11.3, 2.9 Hz, 1H), 3.56 (d, J = 11.6 Hz, 1H), 3.48 (td, J = 12.2, 3.5 Hz, 1H), 1.17 (d, J = 6.6 Hz, 3H). Example 9: (R)-3-Methyl-4-(1-(methylsulfonyl)-6-(1H-pyrazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)morpholine (Compound 9)

[0103] [ka] LC-MS (ESI) m / z 362.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 12.98 (s, 1H), 7.82 (s, 1H), 7.51 (d, J = 4.1 Hz, 1H), 7.31 (s, 1H), 6.90 (d, J = 4.2 Hz, 1H), 6.83 (s, 1H), 4.34-4.22 (m, 1H), 3.98 (d, J = 10.8 Hz, 1H), 3.93-3.77 (m, 4H), 3.71 (d, J = 11.2 Hz, 1H), 3.67-3.57 (m, 1H), 3.50-3.39 (m, 2H), 1.14 (d, J = 6.5 Hz, 3H). Example 10: (R)-3-Methyl-4-(1-(methylsulfonyl)-6-(1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)morpholine (Compound 10)

[0104] [ka] LC-MS (ESI) m / z 362.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 13.03 (s, 1H), 8.35 (s, 1H), 8.08 (s, 1H), 7.44 (d, J = 4.1 Hz, 1H), 6.98 (s, 1H), 6.84 (d, J = 4.1 Hz, 1H), 4.35-4.27 (m, 1H), 3.96 (d, J = 13.1 Hz, 1H), 3.85-3.77 (m, 4H), 3.71 (d, J = 11.3 Hz, 1H), 3.62 (td, J = 11.5, 3.3 Hz, 1H), 3.51 (d, J = 12.1 Hz, 1H), 3.45 (dd, J = 11.4, 3.4Hz, 1H), 1.13 (d, J = 6.6 Hz, 3H). Example 11: (R)-4-(6-(1H-benzo[d]imidazol-2-yl)-1-(methylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-3-methylmorpholine (compound 11)

[0105] [ka] LC-MS (ESI) m / z 412.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 12.68 (s, 1H), 7.73-7.68 (m, 2H), 7.66-7.61 (m, 2H), 7.30-7.19 (m, 2H), 6.99 (d, J = 4.2 Hz, 1H), 4.39-4.31 (m, 1H), 4.06-3.96 (m, 4H), 3.84 (dd, J = 11.5, 2.5 Hz, 1H), 3.74 (d, J = 11.2 Hz, 1H), 3.65 (td, J = 11.0, 3.8 Hz, 1H), 3.59-3.50 (m, 2H), 1.18 (d, J = 6.6 Hz, 3H). Example 12: (R)-3-Methyl-4-(1-(methylsulfonyl)-6-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-morpholine (compound 12)

[0106] [ka] A reaction bottle was charged with (R)-4-(6-chloro-1-(methylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-3-methylmorpholine (200 mg, 0.61 mmol), biboric acid pinacol ester (230 mg, 0.91 mmol), Pd(dppf)Cl2 (88 mg, 0.12 mmol) and potassium acetate (101 mg, 1.03 mmol) was added, and 1,4-dioxane (4 mL) was further added. The atmosphere was replaced with nitrogen gas, and the mixture was heated to 110° C. under nitrogen protection and reacted with stirring for 1.5 hours. The reaction solution was cooled to room temperature, and ethyl acetate (20 The mixture was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure to give the crude title compound (300 mL). This was carried forward to the next step without purification.

[0107] Sdep 2: (R)-3-Methyl-4-(1-(methylsulfonyl)-6-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-morpholine A reaction bottle was charged with (R)-3-methyl-4-(1-(methylsulfonyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)morpholine (200 mg crude, 0.40 mmol), 4-bromo-7H-pyrrolo[2,3-d]pyrimidine (48 mg, 0.24 mmol), Pd(dppf)Cl2 (51 mg, 0.07 mmol) and sodium carbonate (153 mg, 1.44 1,4-dioxane (5 mL) and water (1 The atmosphere was replaced with nitrogen gas, and the mixture was heated to 85° C. under nitrogen protection and reacted with stirring for 1 hour. The reaction solution was cooled to room temperature, and dichloromethane (25 mL) was added. The mixture was washed with water. The layers were separated, and the organic phase was dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure and purified by HPLC to obtain compound 12 (40 mg, yield 40%).

[0108] LC-MS (ESI) m / z 413.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 12.19 (s, 1H), 8.85 (s, 1H), 8.01 (s, 1H), 7.72-7.63 (m, 3H), 7.02 (d, J = 4.2 Hz, 1H), 4.40-4.32 (m, 1H), 4.02 (d, J = 11.0 Hz, 1H), 3.85 (dd, J = 11.5, 2.8 Hz, 1H), 3.79-3.70 (m, 4H), 3.65 (td, J = 10.7, 4.0 Hz, 1H), 3.59-3.50 (m, 2H), 1.18 (d, J = 6.6 Hz, 3H). Example 13: (R)-4-(6-(3H-imidazo[4,5-b]pyridin-7-yl)-1-(methylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-3-methylmorpholine (compound 13)

[0109] [ka] LC-MS (ESI) m / z 413.1 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ 12.00 (s, 1H), 8.66 (d, J = 5.1 Hz, 1H), 8.41 (s, 1H), 7.65 (d, J = 5.2 Hz, 1H), 7.51 (d, J = 4.1 Hz, 1H), 7.29 (s, 1H), 6.74 (d, J = 4.1 Hz, 1H), 4.31-4.23 (m, 1H), 4.15-4.08 (m, 1H), 3.97 (dd, J = 11.4, 3.0 Hz, 1H), 3.85 (d, J = 11.0 Hz, 1H), 3.80 (td, J = 11.4, 2.9 Hz, 1H), 3.68 (td, J = 11.7, 3.5 Hz, 1H), 3.53 (d, J = 12.1 Hz, 1H), 3.40 (s, 3H), 1.34 (d, J = 6.7 Hz, 3H). Example 14: (R)-4-(1'-(isopropylsulfonyl)-1H,1'H-[4,6'-dipyrrolo[2,3-b]pyridin]-4'-yl)-3-methylmorpholine (compound 14)

[0110] [ka] LC-MS (ESI) m / z 440.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 11.74 (s, 1H), 8.31 (d, J = 5.0 Hz, 1H), 7.68 (d, J = 5.1 Hz, 1H), 7.61-7.56 (m, 2H), 7.36 (dd, J = 3.5, 2.0 Hz, 1H), 7.33 (s, 1H), 7.00 (d, J = 4.2 Hz, 1H), 4.45-4.35 (m, 2H), 3.99 (dd, J = 11.7, 2.5 Hz, 1H), 3.83 (dd, J = 11.4, 2.8 Hz, 1H), 3.73 (d, J = 11.3 Hz, 1H), 3.69-3.60 (m, 2H), 3.51 (td, J = 12.7, 3.4 Hz, 1H), 1.29 (d, J = 6.9 Hz, 3H), 1.23 (d, J = 6.8 Hz, 3H), 1.19 (d, J = 6.6 Hz, 3H). Example 15: (R)-4-(1'-(シクロプロピルスルホニル)-1H,1'H-[4,6 '-ジピロロ[2,3-b]ピリジン]-4'-イル)-3-メチルモルホリン (Compound 15)

[0111]

change

[0112] [ka] LC-MS (ESI) m / z 441.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 11.74 (s, 1H), 8.31 (d, J = 5.0 Hz, 1H), 7.61 (d, J = 5.1 Hz, 1H), 7.59-7.55 (m, 2H), 7.28 (dd, J = 3.4, 1.9 Hz, 1H), 7.25 (s, 1H), 6.91 (d, J = 4.2 Hz, 1H), 4.39-4.31 (m, 1H), 4.02-3.95 (m, 1H), 3.84 (dd, J = 11.4, 2.7 Hz, 1H), 3.72 (d, J = 11.2 Hz, 1H), 3.69-3.56 (m, 2H), 3.50 (td, J = 12.0, 3.4 Hz, 1H), 2.89 (s, 6H), 1.18 (d, J = 6.6 Hz, 3H). Example 17: (R)-3-Methyl-4-(7-(methylsulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)morpholine (compound 17)

[0113] [ka] 2,4-Dichloro-7H-pyrrolo[2,3-d]pyrimidine (1.00 g, 5.3 mmol) and (R)-3-methylmorpholine (2.70 g, 26.7 mmol) in 1,4-dioxane (25 The reaction mixture was dissolved in 100 mL of dichloromethane. Triethylamine (3.80 g, 37.6 mmol) was gradually added, and the mixture was heated to 90° C. and reacted with stirring for 8 hours. The reaction mixture was cooled to room temperature and dissolved in 100 mL of dichloromethane. The mixture was washed with water. The layers were separated, and the organic phase was dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography to obtain the title compound (1.02 g, yield 76%).

[0114] LC-MS (ESI) m / z 253.1 [M+H] + . STEP 2: (R)-4-(2-chloro-7-(methylsulfonyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylmorpholine (R)-4-(2-chloro-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylmorpholine (152 mg, 0.6 mmol) was dissolved in tetrahydrofuran (7.5 The mixture was dissolved in 1 mL of 60% sodium hydride (48 mg, 1.2 mmol) at room temperature and reacted with stirring for 5 minutes. The reaction was continued with stirring at room temperature to ensure complete conversion of the raw materials. A small amount of water was added to quench the reaction, and dichloromethane (100 mL) was added, followed by washing with water. The organic phase was separated and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography to give the title compound (149 mg, yield 75%).

[0115] LC-MS (ESI) m / z 331.1 [M+H] + . SDP 3: (R)-3-Methyl-4-(7-(methylsulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)morpholine (R)-4-(2-chloro-7-(methylsulfonyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylmorpholine (180 mg, 0.54 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (264 mg, 1.08 mmol), Pd(dppf)Cl2 (80 mg, 0.11 mmol) and potassium carbonate (299 mg, 2.16 mmol) were added to a reaction bottle, and 1,4-dioxane (17.5 mL) and water (3.5 mL) were further added. The atmosphere was replaced with nitrogen gas, and the mixture was heated to 90° C. under nitrogen protection and reacted with stirring for 1 hour. The reaction solution was cooled to room temperature, dichloromethane (100 mL) was added, and the mixture was washed with water. The layers were separated and the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by HPLC to give compound 17 (130 mg, 58% yield).

[0116] LC-MS (ESI) m / z 413.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 11.79 (s, 1H), 8.35 (d, J = 5.0 Hz, 1H), 8.04 (d, J = 5.0 Hz, 1H), 7.63-7.57 (m, 2H), 7.48 (dd, J = 3.2, 1.9 Hz, 1H), 7.02 (d, J = 4.1 Hz, 1H), 4.92-4.80 (m, 1H), 4.62-4.50 (m, 1H), 4.04 (dd, J = 11.1, 3.0 Hz, 1H), 3.85-3.71 (m, 5H), 3.60 (td, J = 12.2, 3.2 Hz, 1H), 3.55-3.45 (m, 1H), 1.36 (d, J = 6.8Hz, 3H). 13 C NMR (100 MHz, DMSO-d6) δ 158.60, 157.15, 153.14, 151.17, 143.19, 137.50, 128.22, 123.07, 118.76, 115.52, 105.90, 104.00, 102.74, 71.17, 67.13, 48.81, 48.79, 42.64, 15.25. A coupling reaction similar to step 3 in Example 17 was employed to convert 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine into other aromatic boronic acid pinacol esters or aromatic boronic acids, and the intermediate (R)-4-(2-chloro-7-(methylsulfonyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylmorpholine was used to synthesize compounds 18 to 20 and 27.

[0117] Example 18: (R)-4-(2-(1H-indol-4-yl)-7-(methylsulfonyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylmorpholine (compound 18)

[0118] [ka] LC-MS (ESI) m / z 412.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 11.26 (s, 1H), 8.15 (d, J = 7.5 Hz, 1H), 7.62-7.42 (m, 4H), 7.21 (t, J = 7.7 Hz, 1H), 6.97 (d, J = 4.1 Hz, 1H), 4.92-4.77 (m, 1H), 4.61-4.46 (m, 1H), 4.09-3.99 (m, 1H), 3.85-3.70 (m, 5H), 3.65-3.55 (m, 1H), 3.53-3.42 (m, 1H), 1.35 (d, J = 6.7 Hz, 3H). Example 19: (R)-3-Methyl-4-(7-(methylsulfonyl)-2-(1H-pyrrolo[2,3-c]pyridin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)morpholine (compound 19)

[0119] [ka] LC-MS (ESI) m / z 413.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 11.79 (s, 1H), 9.17 (s, 1H), 8.83 (s, 1H), 7.74 (t, J = 2.6 Hz, 1H), 7.56-7.51 (m, 2H), 6.99 (d, J = 4.1 Hz, 1H), 4.91-4.80 (m, 1H), 4.61-4.48 (m, 1H), 4.04 (dd, J = 10.8, 2.9 Hz, 1H), 3.85-3.71 (m, 5H), 3.60 (td, J = 11.8, 2.8 Hz, 1H), 3.55-3.45 (m, 1H), 1.36 (d, J = 6.7 Hz, 3H). Example 20: (R)-4-(2-(6-fluoro-1H-indol-4-yl)-7-(methylsulfonyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylmorpholine (compound 20)

[0120] [ka] LC-MS (ESI) m / z 430.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 11.33 (s, 1H), 7.92 (dd, J = 11.5, 2.5 Hz, 1H), 7.59 (br s, 1H), 7.55 (d, J = 4.0 Hz, 1H), 7.48 (t, J = 2.8 Hz, 1H), 7.32 (dd, J = 9.2, 2.5 Hz, 1H), 6.99 (d, J = 4.2 Hz, 1H), 4.90-4.76 (m, 1H), 4.59-4.46 (m, 1H), 4.08-4.00 (m, 1H), 3.85-3.71 (m, 5H), 3.64-3.55 (m, 1H), 3.53-3.43 (m, 1H), 1.35 (d, J = 6.8 Hz, 3H). Example 21: (R)-2-((4-(3-methylmorpholinyl)-2-(1H-pyrrolo[2,3-b]pyridin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)sulfonyl)ethanol (compound 21)

[0121] [ka] (R)-4-(2-chloro-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylmorpholine (200 mg, 0.79 mmol) was dissolved in tetrahydrofuran (5 The mixture was dissolved in 10 mL of 2-methoxyethylsulfonyl chloride (251 The reaction was allowed to continue stirring at room temperature to ensure complete conversion of the starting material. A small amount of water was added to quench the reaction, followed by the addition of more ethyl acetate (50 mg, 1.58 mmol). After adding 1 mL of 1,0 ... mg, yield 92%).

[0122] LC-MS (ESI) m / z 375.1 [M+H] + . SDP 2: (R)-2-((2-chloro-4-(3-methylmorpholinyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)sulfonyl)ethanol (R)-4-(2-chloro-7-((2-methoxyethyl)sulfonyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylmorpholine (270 mg, 0.72 mmol) was dissolved in dichloromethane (20 The mixture was dissolved in 1 mL of ethyl acetate, cooled to 0° C., and boron tribromide (1.21 g, 4.83 mmol) was added. The mixture was then stirred at room temperature for 1 hour. Water (20 mL) was added to quench the reaction, and the dichloromethane was removed by concentration under reduced pressure. The organic phase was dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography to give the title compound (223 mg, yield 86%).

[0123] LC-MS (ESI) m / z 361.1 [M+H] + . SDP 3: (R)-2-((4-(3-methylmorpholinyl)-2-(1H-pyrrolo[2,3-b]pyridin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)sulfonyl)ethanol Add (R)-2-((2-chloro-4-(3-methylmorpholinyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)sulfonyl)ethanol (100 mg, 0.28 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (135 mg, 0.55 mmol), Pd(dppf)Cl2 (40 mg, 0.055 mmol) and potassium acetate (27 mg, 0.28 The mixture was heated to 85° C. under nitrogen protection and stirred for 4 hours. The reaction mixture was cooled to room temperature and ethyl acetate (50 The mixture was washed with water (20 mL) and the layers were separated, and the organic phase was dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure and purified by HPLC to give compound 21 (49 mg, yield 40%).

[0124] LC-MS (ESI) m / z 443.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 11.77 (s, 1H), 8.34 (d, J = 5.0 Hz, 1H), 8.04 (d, J = 5.0 Hz, 1H), 7.60 (t, J = 3.0 Hz, 1H), 7.54 (d, J = 4.1 Hz, 2H), 7.51 (dd, J = 3.4, 2.0 Hz, 1H), 6.99 (d, J = 4.1 Hz, 1H), 4.94-4.80 (m, 2H), 4.62-4.48 (m, 1H), 4.13 (t, J = 5.9 Hz, 2H), 4.04 (dd, J = 11.3, 3.5 Hz, 1H), 3.81 (d, J = 11.5 Hz, 1H), 3.78-3.68 (m, 3H), 3.60 (td, J = 11.6, 2.7 Hz, 1H), 3.55-3.45 (m, 1H), 1.36 (d, J = 6.7 Hz, 3H). Example 22: (R)-3-Methyl-4-(9-(methylsulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-4-yl)-9H-purin-6-yl)morpholine (compound 22)

[0125] [ka] 2,6-Dichloro-9H-purine (1.0 g, 5.3 mmol) was dissolved in N,N-dimethylformamide (15 The mixture was dissolved in (R)-3-methylmorpholine (2.1 g, 21 mmol) and triethylamine (5.4 mL). g, 53 mmol) was gradually added, and the mixture was further heated to 120° C. and reacted with stirring for 1 hour. The reaction mixture was cooled and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title compound (1.2 g, yield 89%).

[0126] LC-MS (ESI) m / z 254.1 [M+H] + . Sdep 2: (R)-4-(2-chloro-9-(methylsulfonyl)-9H-purin-6-yl)-3-methylmorpholine (R)-4-(2-chloro-9H-purin-6-yl)-3-methylmorpholine (800 mg, 3.15 mmol) was dissolved in tetrahydrofuran (15 The mixture was dissolved in 1 mL of 60% sodium hydride (505 mg, 12.6 mmol) at room temperature and reacted with stirring for 5 minutes. g, 12.6 mmol) was added dropwise. The reaction was continued with stirring at room temperature for 3 hours, a small amount of water was added to quench the reaction, and ethyl acetate (50 mL) was added and washed with water. The layers were separated, and the organic phase was dried over anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography to obtain the title compound (785 mg, yield 75%).

[0127] LC-MS (ESI) m / z 332.1 [M+H] + . Sdep 3: (R)-3-Methyl-4-(9-(methylsulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-4-yl)-9H-purin-6-yl)morpholine A reaction bottle was charged with (R)-4-(2-chloro-9-(methylsulfonyl)-9H-purin-6-yl)-3-methylmorpholine (100 mg, 0.30 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (183 mg, 0.75 mmol), Pd(dppf)Cl2 (44 mg, 0.060 mmol) and potassium acetate (118 mg, 1.20 The mixture was heated to 85° C. under nitrogen protection and stirred for 1 hour. The reaction mixture was cooled to room temperature and ethyl acetate (20 The mixture was washed with water. The layers were separated, and the organic phase was dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure and purified by HPLC to obtain compound 22 (31 mg, yield 25%).

[0128] LC-MS (ESI) m / z 414.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 11.83 (s, 1H), 8.55 (s, 1H), 8.36 (d, J = 5.0 Hz, 1H), 8.04 (d, J = 5.0 Hz, 1H), 7.63 (t, J = 3.0 Hz, 1H), 7.39 (dd, J = 3.4, 2.0 Hz, 1H), 5.56-5.38 (br, 1H), 5.18-5.06 (br, 1H), 4.05 (d, J = 8.6 Hz, 1H), 3.88 (s, 3H), 3.84 (d, J = 11.2 Hz, 1H), 3.75 (dd, J = 11.5, 3.0 Hz, 1H), 3.65-3.47 (m, 2H), 1.40 (d, J = 6.8 Hz, 3H). Example 23: (R)-3-Methyl-4-(1-(methylsulfonyl)-6-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)morpholine (compound 23)

[0129] [ka] 4,6-Dichloro-1H-pyrazolo[3,4-d]pyrimidine (0.40 g, 2.1 mmol) was dissolved in 1,4-dioxane (2 mL) and (R)-3-methylmorpholine (0.86 g, 8.5 mmol) and triethylamine (2.14 g, 21.1 mmol) was gradually added, and the mixture was further heated to 120° C. and reacted with stirring for 2 hours. The reaction mixture was cooled and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title compound (0.50 g, yield 93%).

[0130] LC-MS (ESI) m / z 254.1 [M+H] + . STEP 2: (R)-4-(6-chloro-1-(methylsulfonyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-3-methylmorpholine (R)-4-(6-chloro-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-3-methylmorpholine (650 mg, 2.56 mmol) was dissolved in tetrahydrofuran (4 The mixture was dissolved in 10 mL of 60% sodium hydride (205 mg, 5.13 mmol) at room temperature and reacted with stirring for 5 minutes. mg, 5.12 mmol) was added dropwise. The mixture was then stirred at room temperature for 1 hour. A small amount of water was added to quench the reaction, and ethyl acetate (30 mL) was added, followed by washing with water. The layers were separated, and the organic phase was dried over anhydrous sodium sulfate. The mixture was filtered, the filtrate was concentrated under reduced pressure, and the title compound was obtained (765 mg, yield 90%).

[0131] LC-MS (ESI) m / z 332.1 [M+H] + . SDP 3: (R)-3-Methyl-4-(1-(methylsulfonyl)-6-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)morpholine A reaction bottle was charged with (R)-4-(6-chloro-1-(methylsulfonyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-3-methylmorpholine (100 mg, 0.30 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (147 mg, 0.60 mmol), Pd(dppf)Cl2 (44 mg, 0.060 mmol) and potassium fluoride (70 mg, 1.20 The mixture was heated to 90° C. under nitrogen protection and reacted with stirring for 1 hour. The reaction solution was cooled to room temperature and ethyl acetate (20 The mixture was washed with water. The layers were separated, and the organic phase was dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure and purified by HPLC to obtain compound 23 (19 mg, yield 15%).

[0132] LC-MS (ESI) m / z 414.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 11.84 (s, 1H), 8.70 (s, 1H), 8.37 (d, J = 5.0 Hz, 1H), 8.10 (d, J = 5.0 Hz, 1H), 7.66-7.62 (m, 1H), 7.55-7.51 (m, 1H), 4.72-7.42 (br, 2H), 4.07 (d, J = 8.4 Hz, 1H), 3.84 (d, J = 12.0 Hz, 1H), 3.77 (d, J = 12.0 Hz, 1H), 3.70 (s, 3H), 3.67-3.48 (m, 2H), 1.40 (d, J = 6.7 Hz, 3H). Example 24: (R)-3-Methyl-4-(3-(methylsulfonyl)-5-(1H-pyrrolo[2,3-b]pyridin-4-yl)-3H-imidazo[4,5-b]pyridin-7-yl)morpholine (compound 24)

[0133] [ka] 5,7-Dichloro-3H-imidazo[4,5-b]pyridine (500 mg, 2.66 mmol) was dissolved in N,N-diisopropylethylamine ( The reaction mixture was dissolved in ethyl acetate (50 mL, 51.7 mmol), (R)-3-methylmorpholine (3 mL, 26.4 mmol) was added at room temperature, and the mixture was heated to 145° C. and reacted with stirring for 8 days. The reaction mixture was cooled to room temperature and reacted with ethyl acetate (50 mL, 51.7 mmol). The mixture was washed with water. The layers were separated, and the organic phase was dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography to obtain the title compound (605 mg, yield 90%).

[0134] LC-MS (ESI) m / z 253.1 [M+H] + . SDP 2: (R)-4-(5-chloro-3-(methylsulfonyl)-3H-imidazo[4,5-b]pyridin-7-yl)-3-methylmorpholine (R)-4-(5-chloro-3H-imidazo[4,5-b]pyridin-7-yl)-3-methylmorpholine (350 mg, 1.39 mmol) was dissolved in tetrahydrofuran (20 mL), and 60% sodium hydride (180 mg, 4.50 mmol) was added slowly at room temperature, and the mixture was stirred for 5 minutes. Methanesulfonyl chloride (518 mg, 4.52 mmol) was added dropwise. The mixture was stirred at room temperature to ensure complete conversion of the raw material. A small amount of water was added to quench the reaction, and dichloromethane (100 mL) was added, followed by washing with water. The organic phase was separated and dried over anhydrous sodium sulfate. The mixture was filtered, the filtrate was concentrated under reduced pressure, and the product was purified by silica gel column chromatography to obtain the title compound (357 mg, 78% yield).

[0135] LC-MS (ESI) m / z 331.1 [M+H] + . Sdep 3: (R)-3-Methyl-4-(3-(methylsulfonyl)-5-(1H-pyrrolo[2,3-b]pyridin-4-yl)-3H-imidazo[4,5-b]pyridin-7-yl)morpholine In a reaction bottle, add (R)-4-(5-chloro-3-(methylsulfonyl)-3H-imidazo[4,5-b]pyridin-7-yl)-3-methylmorpholine (20 mg, 0.06 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (30 mg, 0.12 mmol), Pd(dppf)Cl2 (9 mg, 0.012 mmol) and potassium fluoride (20 mg, 0.344 1,4-dioxane (2 mL) and water (0.1 mmol) were added. The atmosphere was replaced with nitrogen gas, and the mixture was heated to 85° C. under nitrogen protection and reacted with stirring for 2 hours. The reaction solution was cooled to room temperature, and dichloromethane (50 The mixture was washed with water. The layers were separated, and the organic phase was dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure and purified by HPLC to obtain compound 24 (11 mg, yield 44%).

[0136] LC-MS (ESI) m / z 413.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 11.79 (s, 1H), 8.51 (s, 1H), 8.32 (d, J = 5.0 Hz, 1H), 7.66 (d, J = 5.0 Hz, 1H), 7.58 (dd, J = 3.4, 2.5 Hz, 1H), 7.30 (s, 1H), 7.17 (dd, J = 3.4, 1.9 Hz, 1H), 5.25-5.14 (m, 1H), 4.48-4.33 (m, 1H), 4.02 (dd, J = 11.5, 3.5 Hz, 1H), 3.87 (s, 3H), 3.79 (d, J = 2.2 Hz, 2H), 3.64 (td, J = 11.7, 2.7 Hz, 1H), 3.45 (td, J = 12.7, 3.6 Hz, 1H), 1.26 (d, J = 6.7 Hz, 3H). Example 25: (R)-3-Methyl-4-(1-(methylsulfonyl)-6-(1H-pyrrolo[2,3-c]pyridin-4-yl)-1H-imidazo[4,5-c]pyridin-4-yl)morpholine (compound 25)

[0137] [ka] SDP 1: (R)-4-(6-chloro-1-(methylsulfonyl)-1H-imidazo[4,5-c]pyridin-4-yl)-3-methylmorpholine (R)-4-(6-chloro-1H-imidazo[4,5-c]pyridin-4-yl)-3-methylmorpholine (150 mg, 0.59 mmol) was dissolved in tetrahydrofuran (10 The mixture was dissolved in 1 mL of 60% sodium hydride (48 mg, 1.20 mmol) at room temperature and reacted with stirring for 5 minutes. The reaction was quenched with a small amount of water and further ethyl acetate (200 mg, 1.19 mmol) was added dropwise and the reaction was allowed to continue stirring at room temperature until the starting material was completely converted. After adding 150 mL of ethyl acetate, the mixture was washed with water. The layers were separated, and the organic phase was dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography to obtain the title compound (150 mg, yield 76%).

[0138] LC-MS (ESI) m / z 331.1 [M+H] + . Sdep 2: (R)-3-Methyl-4-(1-(methylsulfonyl)-6-(1H-pyrrolo[2,3-c]pyridin-4-yl)-1H-imidazo[4,5-c]pyridin-4-yl)morpholine A reaction bottle was charged with (R)-4-(6-chloro-1-(methylsulfonyl)-1H-imidazo[4,5-c]pyridin-4-yl)-3-methylmorpholine (50 mg, 0.15 mmol), (1H-pyrrolo[2,3-c]pyridin-4-yl)boronic acid (49 mg, 0.30 mmol), Pd(dppf)Cl2 (11 mg, 0.015 mmol) and sodium carbonate (32 mg, 0.30 The mixture was heated to 80° C. under nitrogen protection and stirred for 2 hours. The reaction mixture was cooled to room temperature and ethyl acetate (50 The mixture was washed with water. The layers were separated, and the organic phase was dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure and purified by HPLC to obtain compound 25 (20 mg, yield 32%).

[0139] LC-MS (ESI) m / z 413.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 11.79 (s, 1H), 8.78 (s, 1H), 8.66 (s, 1H), 8.49 (s, 1H), 7.73 (t, J = 2.7 Hz, 1H), 7.64 (s, 1H), 6.94-6.89 (m, 1H), 5.48-5.38 (m, 1H), 4.89 (d, J = 13.4 Hz, 1H), 4.01 (dd, J = 11.1, 2.7 Hz, 1H), 3.83-3.72 (m, 5H), 3.60 (td, J = 11.7, 2.6 Hz, 1H), 3.47-3.38 (m, 1H), 1.31 (d, J = 6.7 Hz, 3H). Example 26: (R)-3-Methyl-4-(1-(methylsulfonyl)-6-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrrolo[3,2-c]pyridin-4-yl)morpholine (compound 26)

[0140] [ka] 4,6-Dichloro-1H-pyrrolo[3,2-c]pyridine (500 mg, 2.67 mmol) was dissolved in N,N-diisopropylethylamine ( The reaction mixture was dissolved in ethyl acetate (50 mL, 51.7 mmol), (R)-3-methylmorpholine (3 mL, 26.4 mmol) was added at room temperature, and the mixture was heated to 145° C. and reacted with stirring for 8 days. The reaction mixture was cooled to room temperature and reacted with ethyl acetate (50 mL, 51.7 mmol). The mixture was washed with water. The layers were separated, and the organic phase was dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography to obtain the title compound (603 mg, yield 90%).

[0141] LC-MS (ESI) m / z 252.1 [M+H] + . SDP 2: (R)-4-(6-chloro-1-(methylsulfonyl)-1H-pyrrolo[3,2-c]pyridin-4-yl)-3-methylmorpholine (R)-4-(6-chloro-1H-pyrrolo[3,2-c]pyridin-4-yl)-3-methylmorpholine (550 mg, 2.19 mmol) was dissolved in tetrahydrofuran (20 The mixture was dissolved in 10 mL of 60% sodium hydride (367 mg, 9.18 mmol) at room temperature and reacted with stirring for 5 minutes. The reaction was continued with stirring at room temperature to ensure complete conversion of the raw materials. A small amount of water was added to quench the reaction, and dichloromethane (100 mL) was added, followed by washing with water. The organic phase was separated and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography to give the title compound (591 mg, yield 82%).

[0142] LC-MS (ESI) m / z 330.1 [M+H] + . SDP 3: (R)-3-Methyl-4-(1-(methylsulfonyl)-6-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrrolo[3,2-c]pyridin-4-yl)morpholine In a reaction bottle, add (R)-4-(6-chloro-1-(methylsulfonyl)-1H-pyrrolo[3,2-c]pyridin-4-yl)-3-methylmorpholine (20 mg, 0.06 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (30 mg, 0.12 mmol), Pd(dppf)Cl2 (9 mg, 0.012 mmol) and sodium carbonate (20 mg, 0.19 1,4-dioxane (1 mL) and water (0.2 mmol) were added. The atmosphere was replaced with nitrogen gas, and the mixture was heated to 100° C. under nitrogen protection and reacted with stirring for 2 hours. The reaction solution was cooled to room temperature, and dichloromethane (20 The mixture was washed with water. The layers were separated, and the organic phase was dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure and purified by HPLC to obtain compound 26 (10 mg, yield 40%).

[0143] LC-MS (ESI) m / z 412.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 11.79 (s, 1H), 8.31 (d, J = 5.0 Hz, 1H), 7.93 (s, 1H), 7.64-7.61 (m, 2H), 7.59 (t, J = 3.0 Hz, 1H), 7.08 (d, J = 3.8 Hz, 1H), 6.90 (dd, J = 3.5, 1.9 Hz, 1H), 4.66-4.58 (m, 1H), 4.08 (d, J = 12.8 Hz, 1H), 4.02-3.96 (m, 1H), 3.80 (dd, J = 11.4, 2.9 Hz, 1H), 3.73 (d, J = 10.8 Hz, 1H), 3.63 (td, J = 11.3, 2.6 Hz, 1H), 3.58 (s, 3H), 3.49 (td, J = 12.5, 3.4 Hz, 1H), 1.26 (d, J = 6.7 Hz, 3H). Example 27: (R)-4-(2-(1H-benzo[d]imidazol-2-yl)-7-(methylsulfonyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylmorpholine (compound 27)

[0144] [ka] LC-MS (ESI) m / z 413.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 9.19 (s, 1H), 8.65 (d, J = 8.0 Hz, 1H), 7.78 (d, J = 7.9 Hz, 1H), 7.52 (d, J = 4.1 Hz, 1H), 7.45-7.39 (m, 1H), 7.38-7.32 (m, 1H), 7.03 (d, J = 4.1 Hz, 1H), 4.91-4.75 (br, 1H), 4.65-4.49 (br, 1H), 4.02 (dd, J = 11.2, 3.0 Hz, 1H), 3.80 (d, J = 11.5 Hz, 1H), 3.77-3.70 (m, 4H), 3.59 (td, J = 11.6, 2.5 Hz, 1H), 3.54-3.45 (m, 1H), 1.37 (d, J = 6.8 Hz, 3H). Example 28: (R)-N-methyl-1-(4-(3-methylmorpholinyl)-7-(methylsulfonyl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)-1H-benzo[d]imidazol-2-amine (Compound 28)

[0145] [ka] LC-MS (ESI) m / z 442.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 8.56 (q, J = 4.5 Hz, 1H), 8.24 (d, J = 7.9 Hz, 1H), 7.51 (d, J = 4.1 Hz, 1H), 7.28 (d, J = 7.7 Hz, 1H), 7.14-7.08 (m, 1H), 7.05 (d, J = 4.1 Hz, 1H), 7.04-6.98 (m, 1H), 4.78-4.68 (m, 1H), 4.41-4.31 (m, 1H), 4.10-4.01 (m, 1H), 3.86-3.72 (m, 2H), 3.65 (s, 3H), 3.63-3.51 (m, 2H), 3.08 (d, J = 4.8 Hz, 3H), 1.39 (d, J = 6.8 Hz, 3H). Example 29: (R)-3-Methyl-4-(2-(6-methyl-1H-indol-4-yl)-7-(methylsulfonyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)morpholine (Compound 29)

[0146] [ka] (R)-4-(2-chloro-7-(methylsulfonyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylmorpholine (200 mg, 0.60 mmol), biboric acid pinacol ester (384 mg, 1.51 mmol), Pd(dppf)Cl2 (88 mg, 0.12 mmol) and potassium acetate (245 mg, 2.50 mmol) were added to a reaction bottle, and 1,4-dioxane (2 mL) was further added. The atmosphere was replaced with nitrogen gas, and the mixture was heated to 100° C. under nitrogen protection and reacted with stirring for 2 hours. The reaction solution was cooled to room temperature, ethyl acetate (80 mL) was added, and the resulting mixture was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure to obtain the crude product of the title compound (252 mg). This was carried to the next step without purification.

[0147] Sdep 2: (R)-3-methyl-4-(2-(6-methyl-1H-indol-4-yl)-7-(methylsulfonyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)morpholine Into a reaction bottle, (R)-3-methyl-4-(7-(methylsulfonyl)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)morpholine (126 mg crude, 0.30 mmol), 4-bromo-6-methyl-1H-indole (25 mg, 0.12 mmol), Pd(dppf)Cl2 (17.3 mg, 0.024 mmol) and sodium carbonate (50 mg, 0.47 mmol) were added, followed by 1,4-dioxane (5 mL) and water (1 mL). The atmosphere was replaced with nitrogen gas, and the mixture was heated to 85° C. under nitrogen protection and stirred for 2 hours. The reaction solution was cooled to room temperature, dichloromethane (40 mL) was added, and the mixture was washed with water. The layers were separated, and the organic phase was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure and purified by HPLC to give compound 29 (26 mg, 51% yield).

[0148] LC-MS (ESI) m / z 426.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 11.08 (s, 1H), 7.96 (d, J = 1.5 Hz, 1H), 7.51 (d, J = 4.1 Hz, 1H), 7.50-7.47 (m, 1H), 7.36 (t, J = 2.7 Hz, 1H), 7.32 (d, J = 1.5 Hz, 1H), 6.96 (d, J = 4.1 Hz, 1H), 4.88-4.78 (m, 1H), 4.60-4.50 (m, 1H), 4.05 (dd, J = 11.2, 3.5 Hz, 1H), 3.86-3.71 (m, 5H), 3.60 (td, J = 11.7, 2.9 Hz, 1H), 3.52-3.41 (m, 1H), 2.48 (s, 3H), 1.35 (d, J = 6.8 Hz, 3H). Example 30: (R)-4-(4-(3-methylmorpholinyl)-7-(methylsulfonyl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)-1H-indole-6-carbonitrile (Compound 30)

[0149] [ka] LC-MS (ESI) m / z 437.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 11.87 (s, 1H), 8.36 (d, J = 1.5 Hz, 1H), 8.02 (t, J = 1.2 Hz, 1H), 7.80 (t, J = 2.8 Hz, 1H), 7.75-7.71 (m, 1H), 7.57 (d, J = 4.1 Hz, 1H), 7.01 (d, J = 4.2 Hz, 1H), 4.90-4.78 (m, 1H), 4.62-4.48 (m, 1H), 4.11-4.01 (m, 1H), 3.86-3.70 (m, 5H), 3.60 (td, J = 11.5, 11.1, 2.5 Hz, 1H), 3.54-3.44 (m, 1H), 1.36 (d, J = 6.7 Hz, 3H). Example 31: (R)-4-(2-(6-chloro-1H-indol-4-yl)-7-(methylsulfonyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylmorpholine (compound 31)

[0150] [ka] LC-MS (ESI) m / z 446.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 11.41 (s, 1H), 8.08 (d, J = 2.0 Hz, 1H), 7.59 (t, J = 2.5 Hz, 1H), 7.57 (d, J = 1.6 Hz, 1H), 7.55 (d, J = 4.1 Hz, 1H), 7.52 (t, J = 2.8 Hz, 1H), 6.99 (d, J = 4.1 Hz, 1H), 4.88-4.76 (m, 1H), 4.58-4.46 (m, 1H), 4.05 (dd, J = 11.0, 2.8 Hz, 1H), 3.86-3.70 (m, 5H), 3.60 (td, J = 11.8, 2.4 Hz, 1H), 3.54-3.43 (m, 1H), 1.36 (d, J = 6.8 Hz, 3H). Example 32: (R)-4-(2-(6-methoxy-1H-indol-4-yl)-7-(methylsulfonyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylmorpholine (compound 32)

[0151] [ka] Reaction as shown above (analogous to step 2 in example 29) gave compound 32 (30 mg, 25% yield).

[0152] LC-MS (ESI) m / z 442.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 11.04 (s, 1H), 7.78 (d, J = 2.4 Hz, 1H), 7.52 (d, J = 4.1 Hz, 1H), 7.49-7.45 (m, 1H), 7.31 (t, J = 2.7 Hz, 1H), 7.06 (dd, J = 2.3, 0.9 Hz, 1H), 6.97 (d, J = 4.2 Hz, 1H), 4.89-4.77 (m, 1H), 4.57-4.45 (m, 1H), 4.04 (dd, J = 11.0, 3.0 Hz, 1H), 3.83 (s, 3H), 3.81-3.71 (m, 5H), 3.60 (td, J = 11.6, 2.8 Hz, 1H), 3.53-3.43 (m, 1H), 1.35 (d, J = 6.7 Hz, 3H). Example 33: (R)-4-(7-(ethylsulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylmorpholine (compound 33)

[0153] [ka] Reaction as shown above (analogous to steps 2 and 3 in Example 17) gave compound 33 (195 mg, 92% and 79% yields for the two steps, respectively).

[0154] LC-MS (ESI) m / z 427.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 11.78 (s, 1H), 8.34 (d, J = 5.0 Hz, 1H), 8.04 (d, J = 5.0 Hz, 1H), 7.63-7.57 (m, 2H), 7.50 (dd, J = 3.4, 2.0 Hz, 1H), 7.03 (d, J = 4.1 Hz, 1H), 4.92-4.80 (m, 1H), 4.62-4.50 (m, 1H), 4.09-3.95 (m, 3H), 3.85-3.71 (m, 2H), 3.61 (td, J = 11.6, 2.7 Hz, 1H), 3.55-3.45 (m, 1H), 1.37 (d, J = 6.8 Hz, 3H), 1.12 (t, J = 7.3 Hz, 3H). Example 34: (R)-N,N-Dimethyl-4-(3-methylmorpholinyl)-2-(1H-pyrrolo[2,3-b]pyridin-4-yl)-7H-pyrrolo[2,3-d]pyrimidine-7-sulfonamide (Compound 34)

[0155] [ka] Reaction as shown above (analogous to steps 2 and 3 in Example 17) gave compound 34 (40 mg, 13% and 32% yields for the two steps, respectively).

[0156] LC-MS (ESI) m / z 442.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 11.74 (s, 1H), 8.33 (d, J = 5.0 Hz, 1H), 7.99 (d, J = 5.0 Hz, 1H), 7.62-7.56 (m, 2H), 7.53 (dd, J = 3.4, 2.0 Hz, 1H), 6.96 (d, J = 4.1 Hz, 1H), 4.90-4.80 (m, 1H), 4.60-4.50 (m, 1H), 4.08-4.00 (m, 1H), 3.84-3.71 (m, 2H), 3.65-3.56 (m, 1H), 3.55-3.45 (m, 1H), 2.92 (s, 6H), 1.37 (d, J = 6.7 Hz, 3H). Comparative Example As comparative compounds, compounds 1' to 7' having the structures shown in Table 1 were synthesized.

[0157] [Table 2] TIFF0007670265000061.tif186169 Compound 1' is a known compound and is described in the literature (ACS Med. Chem. Lett. 2015, 6, 42-46) according to the scheme described therein.

[0158] Compound 2' was prepared according to the following scheme:

[0159] [ka] Compound 3' was prepared according to the following scheme:

[0160] [ka] Compound 4' was prepared according to the following scheme:

[0161] [ka] Compound 5' was prepared according to the following scheme:

[0162] [ka] Compound 6' was prepared according to the following scheme:

[0163] [ka] Compound 7' is a known compound and was prepared by referring to the scheme described in the literature (ACS Med. Chem. Lett. 2015, 6, 42-46). Compound 7' is a mixture of two diastereomers (ratio is about 1:1), and the following two diastereomers are obtained by HPLC chiral resolution, and their nuclear magnetic properties are as follows.

[0164] [ka] Diastereomer 1: 1 H NMR (400 MHz, Chloroform-d) δ 8.84 (s, 1H), 8.80 (br s, 1H), 8.72 (s, 1H), 8.04 (s, 1H), 7.50 (d, J = 3.1 Hz, 1H), 7.23 (s, 1H), 7.09 (d, J = 3.1 Hz, 1H), 5.62- 5.55 (m, 1H), 5.51 (q, J = 7.1 Hz, 1H), 5.05 (d, J = 13.4 Hz, 1H), 4.07 (dd, J = 11.2, 3.4 Hz, 1H), 3.91 (dd, J = 11.4, 3.1 Hz, 1H), 3.84 (d, J = 11.3 Hz, 1H), 3.74 (td, J = 11.7, 2.8 Hz, 1H), 3.59 (td, J = 12.9, 3.5 Hz, 1H), 2.72 (s, 3H), 2.11 (d, J = 7.1 Hz, 3H), 1.44 (d, J = 6.8 Hz, 3H). ジアステレオマー2: 1 H NMR (400 MHz, Chloroform-d) δ 8.97 (br s, 1H), 8.84 (s, 1H), 8.72 (s, 1H), 8.05 (s, 1H), 7.50 (d, J = 3.2 Hz, 1H), 7.23 (s, 1H), 7.09 (d, J = 3.1 Hz, 1H), 5.64- 5.56 (m, 1H), 5.52 (q, J = 7.0 Hz, 1H), 5.02 (d, J = 13.5 Hz, 1H), 4.07 (dd, J = 11.2, 3.5 Hz, 1H), 3.91 (dd, J = 11.4, 3.1 Hz, 1H), 3.84 (d, J = 11.3 Hz, 1H), 3.75 (td, J = 11.8, 2.8 Hz, 1H), 3.58 (td, J = 12.9, 3.6 Hz, 1H), 2.69 (s, 3H), 2.11 (d, J = 7.1 Hz, 3H), 1.44 (d, J = 6.8 Hz, 3H). Biological Test Examples In the general biological assays and the example assays below, the following abbreviations have the following meanings:

[0165] [Table 3] Test Example 1: In vitro ATR kinase inhibition experiment Experimental method: Caliper The EZ Reader uses a microfluidic chip-based mobility detection technique to measure the ATP concentration. m If so, the mobility shift analysis The ATR kinase inhibitory activity of the compounds was measured in vitro using a 3D Shift Assay.

[0166] Materials and equipment: ATR kinase (Eurofins, Cat. No. 14-953); 5-FAM-AK-17 (GL Biochem, Cat. No. 524315); 1x kinase buffer (50 mM HEPES pH 7.5, 0.0015% Brij-35, 1 M MnCl2); termination buffer (100 mM HEPES pH 7.5, 0.015% Brij-35, 0.2% Coating Reagent #3, 50 mM Caliper EZ Reader (Caliper Life Sciences).

[0167] Experimental procedure: (1) Test compounds were dissolved in DMSO and serially diluted 4-fold to prepare 10 concentrations in total. (2) 0.06 μL of compounds with different concentrations were transferred to a 384-well plate using an Echo pipette system. (3) A 2x kinase solution was prepared with ATR kinase and 1x kinase buffer, with ATR kinase at a concentration of 10 nM. A 2x substrate solution was prepared with 5-FAM-AK-17, ATP, and 1x kinase buffer, with 5-FAM-AK-17 at a concentration of 6 μM and ATP at a concentration of 4 μM. (4) 10 μL of the 2x kinase solution was dropped onto the 384-well plate and incubated at room temperature for 10 minutes. An additional 10 μL of the 2x substrate solution was added and incubated at 28°C for 4 hours. (5) 30 μL of termination buffer was added to terminate the reaction, and the 384-well plate was then placed in a Caliper It was placed in the EZ Reader and the conversion data was read.

[0168] Data processing: (1) The inhibition rate was calculated from the conversion rate. "max" is the conversion rate of the DMSO blank control group (no compound added), "min" is the conversion rate of the kinase-free control group (no ATR kinase added), and "conversion" is the conversion rate of the compound test group. Inhibition rate = (max - conversion) / (max - min) × 100%. (2) Excel Using the add-in XLFit (version number 5.4.0.8), curve fitting was performed to obtain the IC 50 The value was calculated.

[0169] Experimental results: The inhibitory effects of the compounds of the examples on ATR kinase are shown in Table 2.

[0170] [Table 4] The above results demonstrate that the compounds of the Examples exhibit good inhibitory activity against ATR kinase.

[0171] Table 3 shows the inhibitory effects of the comparative compounds 1' to 6' on ATR kinase.

[0172] [Table 5] Test Example 2: Cell proliferation inhibition experiment Experimental method: The inhibitory effect of the compounds on the in vitro proliferation of human colon cancer cells LoVo was measured using the CellTiter-Glo cell activity detection kit.

[0173] Materials: LoVo cells (ATCC, Cat. No. CCL-29); F-12K medium (Invitrogen, Cat. No. 21127-022); fetal bovine serum (Biological Industries, catalog number 04-002-1A); GlutaMAX (Gibco, catalog number 35050-061); 0.25% pancreatic enzymes-EDTA (Invitrogen, catalog number 25200-072); CellTiter-Glo kit (Promega, catalog number G7558).

[0174] Experimental procedure: (1) A complete medium was prepared with F-12K medium, fetal bovine serum, and GlutaMAX, and used to culture LoVo cells. (2) LoVo cells in good growth state were taken, digested with pancreatic enzymes, transferred to a centrifuge tube, centrifuged, the supernatant was discarded, and fresh medium resuspended cells were added, counted with a Vi-CELL XR cell counter, and the density of the cell suspension was adjusted to 25000-30000 cells / mL. The cell suspension was added to a 96-well cell culture plate at 100μL / well, along with a blank control group without adding cells, and the culture plate was incubated overnight in a carbon dioxide culture tank. (3) A DMSO solution of the test compound was dropped into the above 96-well cell culture plate with a HPD300 ultra-micro sample injector, and 0.5μL was added to each well, and 10 concentrations were prepared for each compound (3-fold dilution), along with a DMSO control group without adding the compound, and the culture plate was subsequently incubated in a carbon dioxide culture tank for 96 hours. (4) The culture plate was removed, allowed to balance to room temperature, and 100 μL of CellTiter-Glo reagent was added per well, shaken in the dark for 10 minutes, and incubated for 10 minutes. (5) The culture plate was placed on the EnSpire reading plate, and the luminescence value RLU was recorded.

[0175] Data processing: (1) The inhibition rate was calculated from the luminescence value. RLU DMSO " is the luminescence value of the DMSO control group to which no compound was added, and "RLU blank " is the luminescence value of the blank control group without adding cells, and "RLU compound " is the luminescence value of the compound test group, and the inhibition rate = [ 1 - (RLU compound - RLU blank ) / (RLU DMSO - RLU blank )] × 100%; (2) Use Excel add-in XLFit to fit the curve and calculate the IC 50 The value was calculated. Experimental results: The inhibitory effects of the example compounds on the in vitro proliferation of LoVo cells are shown in Table 4.

[0176] [Table 6] The above results demonstrate that the compounds of the Examples of the present invention exhibit good inhibitory effects on the proliferation of LoVo cells. The inhibitory activity of compound 1 of the present invention against ATR kinase and against the proliferation of LoVo cells is shown in Table 5 below in comparison with compounds 4' and 5' of the comparative examples.

[0177] [Table 7] The above describes in detail the embodiments for carrying out the present invention, and the present disclosure is not limited to the above embodiments. Various changes, modifications, substitutions, additions, deletions, and combinations are possible within the scope of the claims. These naturally fall within the technical scope of the present disclosure.

Claims

1. A compound having the structure represented by Formula I: or a pharma- ceutically acceptable salt thereof. 【Chemistry 1】 (In the formula, Y １ , Y ２ , Y ３ , Y ４ are each independently CH or N; and Y １ and Y ２ At least one of Y is N; ３ and Y ４ At least one of is CH. R 1 is 【Chemistry 2】 is selected from the group R ２ is -OH, C １-６ Alkoxy group, -NR ３ R ４ , -C.N., C. １-６ Alkyl group, C ２-６ Alkenyl group, C ２-６ Alkynyl group, C ３-６ It is a cycloalkyl group or a 4- to 6-membered heterocycloalkyl group, and the heteroatom is one selected from O and N. １-６ Alkyl group, C ２-６ Alkenyl group, C ２-６ Alkynyl group, C ３-６ The cycloalkyl group or the 4- to 6-membered heterocycloalkyl group may optionally be selected from the group consisting of halogen, —OH, C １-６ Alkoxy group, -NR ５ R ６ , -CN R ３ , R ４ are each independently hydrogen or C １-６ It is an alkyl group. R ５ , R ６ are each independently hydrogen or C １-６ an alkyl group, or -NR ５ R ６ represents an azetidine group, a pyrrolidine group, a piperidyl group, a morpholinyl group, or a 4-methylpiperazinyl group together with

2. Y ３ and Y ４ are CH, and Y １ , Y ２ are each independently CH or N, and Y １ and Y ２ or a pharma- ceutically acceptable salt thereof, according to claim 1, wherein at least one of is N.

3. Y １ and Y ２ or a pharma- ceutically acceptable salt thereof.

2. The compound of claim 1, wherein each is N.

4. R ２ is -OH, C １-３ Alkoxy group, -NR ３ R ４ , -C.N., C. １-４ Alkyl group, C ２-４ Alkenyl group, C ２-４ Alkynyl group, C ３-４ is a cycloalkyl group or a 4- to 6-membered heterocycloalkyl group, the heteroatom being one selected from O and N; １-４ Alkyl group, C ２-４ Alkenyl group, C ２-４ Alkynyl group, C ３-４ The cycloalkyl group or the 4- to 6-membered heterocycloalkyl group may optionally be selected from the group consisting of halogen, —OH, C １-３ Alkoxy group, -NR ５ R ６ , -CN; R ３ , R ４ are each independently hydrogen or C １-３ is an alkyl group, R ５ , R ６ are each independently hydrogen or C １-３ an alkyl group, or -NR ５ R ６ 2. The compound according to claim 1, wherein: and represent an azetidine group, a pyrrolidine group, a piperidyl group, a morpholinyl group or a 4-methylpiperazinyl group, or a pharma- ceutically acceptable salt thereof.

5. R ２ is a hydroxy group, a methoxy group, an ethoxy group, an amino group, a methylamine group, a dimethylamine group, a cyano group, a methyl group, an ethyl group, a propyl group, an isopropyl group, a vinyl group, a propenyl group, an allyl group, an ethynyl group, a propynyl group, a propargyl group, a cyclopropyl group, a methylol group, a methoxymethyl group, a 2-hydroxyethyl group, a 2-methoxyethyl group, a 2-dimethylamineethyl group, an N-morpholinyl group, or a 4-methylpiperazinyl group, or a pharma- ceutically acceptable salt thereof.

6. The compound is 【Chemistry 3】 【change】 【change】 2. The compound of claim 1, selected from:

7. An intermediate compound having the structure represented by Formula II: 【Chemistry 4】 (In formula II, Y １ , Y ２ , Y ３ , Y ４ and R ２ are each independently as defined in claim 1. R ３ is halogen or 【Chemistry 5】 (It is)

8. As shown in the following scheme, the intermediate compound of formula II is reacted with R １ 7. A method for preparing a compound of claim 1 or a pharma- ceutically acceptable salt thereof, comprising coupling reaction with -M to prepare a compound having a structure represented by formula I. 【Chemistry 6】 (R ３ When is halogen, M is 【Chemistry 7】 or R ３ but 【Chemistry 8】 when M is halogen; Y １ , Y ２ , Y ３ , Y ４ , R １ and R ２ are each independently defined as in any one of claims 1 to 6.

9. R 3 is 【Chemistry 9】 9. The method of claim 8, wherein when

10. The process according to claim 8, comprising the step of preparing an intermediate compound.

11. 10. A pharmaceutical composition comprising the compound of claim 1 or a pharma- ceutically acceptable salt thereof and a pharma- ceutically acceptable carrier.

12. A drug for inhibiting ATR kinase, comprising the compound according to any one of claims 1 to 6 or a pharma- ceutically acceptable salt thereof and a pharma- ceutically acceptable carrier.

13. A medicament for treating a hyperproliferative disease, comprising a compound according to any one of claims 1 to 6 or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable carrier.

14. 14. The method of claim 13, wherein the hyperproliferative disease comprises cancer, including 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 or gallbladder cancer.

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