CN114591324A - Pyrazinone derivatives, preparation and application thereof - Google Patents

Abstract

The invention relates to a class of pyrazinone derivatives, preparation and application thereof, and particularly provides a compound with a structure shown in a general formula (I), wherein the compound has excellent ATR inhibition effect and action, can be used for treating and/or preventing related diseases mediated by ATR,

Description

Pyrazinone derivatives, preparation and application thereof

the technical field is as follows:

the invention relates to the field of medicines, in particular to a compound serving as an ATR inhibitor and application thereof in preparation of a medicine serving as the ATR inhibitor.

Technical background:

ataxia Telangiectasia Mutated gene Rad3 Related protein (Ataxia Telangiectasia Mutated and Rad3 Related Kinase, ATR) is a member of phosphatidylinositol 3-Kinase associated Kinase (PIKK) family Related to DNA damage signaling and repair, and consists of 2644 amino acids, and has an ATR interacting protein (atrp) binding domain at the N-terminus, which is an important domain for ATR activation, and a Kinase domain at the C-terminus, which is phosphorylated by a downstream protein, and has a function of phosphorylating serine or threonine of a target protein such as cell cycle checkpoint Kinase 1 (Chk 1). ATR plays an important role in DNA repair, is responsible for initiating cellular response and repair of genomic instability, is rapidly activated upon sensing DNA damage and replication fork pressure, and directly phosphorylates downstream effector proteins to initiate regulation of genomic stability (Nat Rev Mol Cell biol.2008 Aug; 9(8): 616-27).

DNA damage or replication stress induces single-stranded DNA (ssDNA) to recruit replication-associated Protein A (RPA) to form an RPA-ssDNA complex, which can recruit regulatory factors required for ATR activation, including ATRIP complex, RAD9-RAD1-HUS1(9-1-1) complex, RPA complex, Topoisomerase II beta Binding Protein 1 (TopBP 1), and the like. ATR is recruited to RPA-ssDNA to form ATR-ATRIP compound by combining with ligand ATRIP, and ATR is autophosphorylated at the same time; subsequent recruitment of complexes such as TopBP1 at the dsDNA-ssDNA junction under the control of RPA-ssDNA, the activation of ATRIP by binding to ATR autophosphorylation sites of TopBP1 recruited to the dsDNA-ssDNA junction; once ATR is activated, it phosphorylates Chk1 and other effector proteins, and activated Chk1 continues to phosphorylate its downstream effectors (e.g., CDC25A), eventually promoting cell cycle arrest, stabilizing replication forks, and promoting DNA damage repair (J Hematol Oncol.2019 Apr 24; 12(1): 43).

Genomic instability is one of the basic characteristics of tumor cells. Many tumor cells present abnormal damage to DNA, rendering them more dependent on undamaged DNA repair pathways, and ATR is therefore considered a potential therapeutic target for tumors. A large number of functional and preclinical experimental data indicate that ATR kinase inhibitors can kill tumor cells with high efficiency. In addition, chemotherapy and radiotherapy can further exacerbate the genomic instability of tumor cells, and inhibition of ATR activity can synergistically enhance the anti-tumor effect. Therefore, ATR kinase inhibitors have important application prospects in tumor therapy (JNeurosci.2017Jan 25; 37(4): 893-905).

ATR, a key protein for DNA damage repair, plays an important role in cell survival. Inhibition of ATR can induce apoptosis of ATR pathway-dependent malignant tumor cells with less influence on normal cell growth and proliferation, so ATR can be used as an ideal target for low-toxicity and highly effective targeted antitumor drugs.

VX-970, AZD6738, BAY1895344 and VX-803 have been introduced into clinical trials and there are several patents published on ATR pathway, such as: WO2019/014618, WO2019/050889, WO2019/154365, CN111205310A, CN11046761A, WO2015/084384, WO2017/180723, WO2016/061097 and the like, but corresponding medicaments are not yet on the market. Based on the promise exhibited by ATR inhibitors in cancer and the like, there remains a need to develop new compounds.

The invention content is as follows:

the present inventors have made intensive studies in order to solve the above problems, and as a result of extensive efforts, the present inventors have designed compounds having a structure represented by general formula (I), and have found that compounds having such a structure exhibit excellent ATR inhibitory effect and action, and can achieve the desired object, thereby completing the present invention.

Specifically, the first aspect of the present invention relates to a pyrazinone derivative of a compound represented by the following formula (I) or a pharmaceutically acceptable salt, solvate, isotopic label, metabolite or prodrug thereof.

Wherein:

R¹selected from phenyl, heteroaryl, said phenyl or heteroaryl being unsubstituted or each independently substituted by one or more groups selected from R^4aDeuterium, halogen, hydroxy, amino, cyano, carboxy, halogeno C_1-6Alkyl, hydroxy substituted C_1-6Alkyl, -OR^4a、-NR^4aR^4b、-N(CN)R^4a、-N(OR^4a)R^4b、-S(O)_0-2R^4b、-C(O)OR^4a、-C(O)NR^4aR^4b、-NR^4aC(O)R^4b、-NR^4aC(O)NR^4aR^4b、-NR^4aS(O)₂R^4band-OC (O) R^4aThe substituent(s) is substituted at any substitutable position;

R^4aand R^4bEach independently selected from hydrogen and C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-8Cycloalkyl, 3-8 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, C_3-8Cycloalkyl radical C_1-6Alkyl, 3-8 membered heterocycloalkyl C_1-6Alkyl, phenyl C_1-6Alkyl, 5-6 membered heteroaryl C_1-6An alkyl group; said C is_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-8Cycloalkyl, 3-8 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, C_3-8Cycloalkyl radical C_1-6Alkyl, 3-8 membered heterocycloalkyl C_1-6Alkyl, phenyl C_1-6Alkyl, 5-6 membered heteroaryl C_1-6Alkyl is unsubstituted or each independently is substituted with one or more substituents selected from deuterium, oxo, halogen,Hydroxy, amino, cyano, halogeno C_1-6Alkyl, halo C_1-6Alkoxy radical, C_1-6Alkoxy radical, C_1-6Alkylamino, 3-8 membered cycloalkyl, 3-8 membered heterocycloalkyl, -NHC (O) -C_2-6Alkenyl, -NHC (O) -C_1-6Alkyl, -NHC (O) -NH-C_1-6Alkyl, -NHC (O) -O-C_1-6Alkyl and-NHS (O)₂-C_1-6The substituent of the alkyl group is substituted at any substitutable position;

R²is selected from C_1-6Alkyl radical, C_1-6Alkoxy, 3-8 membered cycloalkyl, 4-10 membered heterocycloalkyl, 4-8 membered heterocycloalkenyl, phenyl, heteroaryl, -C (O) R⁵、-C(O)OR⁵、-(CO)NR⁵R⁶、-(SO₂)R⁵、-(SO₂)NR⁵R⁶、-NR⁵R⁶(ii) a Wherein said C_1-6Alkyl radical, C_1-6Alkoxy, 3-to 8-membered cycloalkyl, 4-to 10-membered heterocycloalkyl, 4-to 8-membered heterocycloalkenyl, phenyl, heteroaryl are unsubstituted or each independently substituted with one or more substituents selected from deuterium, oxo, halogen, cyano, hydroxy, -NR⁵R⁶Optionally substituted by hydroxy or C_1-6Alkoxy or phenyl or-NR⁵R⁶Substituted C_1-6Alkyl radical, C_1-6Alkoxy radical, C_1-6Haloalkyl, 3-8 membered cycloalkyl, 4-10 membered heterocycloalkyl, phenyl, heteroaryl, -C (O) R⁵、-C(O)OR⁵、-(CO)NR⁵R⁶、-(SO₂)R⁵、-(SO)R⁵、-SR⁵、-(SO₂)NR⁵R⁶、-NR⁵(SO₂)R⁶、-((SO)＝NR⁵)R⁶、-N＝(SO)R⁵R⁶、-(PO)(OR⁵)₂、-(PO)(OR⁵)R⁶And- (PO) (R)⁵)₂The substituent(s) is substituted at any substitutable position;

R³selected from hydrogen, deuterium, halogen, cyano, C_1-6Alkyl radical, C_3-8A cycloalkyl group;

R⁴is selected from C_1-6Alkyl radical, C_3-8A cycloalkyl group;

R⁵and R⁶Each independently selected from hydrogen and C_1-6Alkyl, 3-8 membered cycloalkyl, 4-10 membered heterocycloalkyl, 3-15 membered bridged cyclic group, 3-15 membered bridged heterocyclic group, phenyl, heteroaryl;

or R⁵And R⁶And the atoms to which they are attached together form a nitrogen-containing 4-8 membered heterocyclic ring, said nitrogen-containing 4-8 membered heterocyclic ring being unsubstituted or substituted with one or more groups selected from deuterium, halogen, cyano, hydroxy, optionally substituted with hydroxy or C_1-6Alkoxy-substituted C_1-6Alkyl radical, C_1-6Haloalkyl, C_1-6Alkoxy, 3-to 8-membered cycloalkyl, 4-to 10-membered heterocycloalkyl and- (SO)₂)R⁷Said nitrogen-containing 4-8 membered heterocyclic ring optionally containing an additional heteroatom selected from O, N and S; r⁷Is selected from C_1-6Alkyl radical, C_1-6Alkoxy, -NH (C)_1-6Alkyl), -N (C)_1-6Alkyl radical)₂3-8 membered cycloalkyl, phenyl.

In some embodiments, R¹Selected from the group consisting of pyridyl, pyrimidinyl, pyridazinyl, indolyl, 5-azaindolyl, pyrrolo [2,3-d ]]Pyrimidinyl, indazolyl, benzo [ d ]]Imidazolyl, imidazo [4,5-b ]]Pyridyl, pyrrole [2,3-d ]]Pyridazinyl, pyrrole [2,3-c ]]Pyridazinyl, 6-azaindolyl, 7-azaindolyl; the pyridyl, pyrimidyl, pyridazinyl, indolyl, 5-azaindolyl, pyrrolo [2,3-d ] group]Pyrimidinyl, indazolyl, benzo [ d ]]Imidazolyl, imidazo [4,5-b ]]Pyridyl, pyrrole [2,3-d ]]Pyridazinyl, pyrrole [2,3-c ]]Pyridazinyl, 6-azaindolyl, 7-azaindolyl being unsubstituted or each independently substituted by one or more groups selected from deuterium, C_1-6Alkyl, halo C_1-6Alkyl, hydroxy substituted C_1-6Alkyl, -C (O) OR^4a、-C(O)NR^4aR^4b3-6 membered cycloalkyl, halogen, hydroxy, amino, cyano, carboxy, -OR^4aand-NR^4aR^4bThe substituent(s) of (b) is substituted at any substitutable position.

In some embodiments, R¹Selected from indolyl, 5-azaindolyl, indazolyl, benzo [ d ]]Imidazolyl, 6-azaindolyl, 7-azaIndolyl, said indolyl, 5-azaindolyl, indazolyl, benzo [ d]Imidazolyl, 6-azaindolyl, 7-azaindolyl are unsubstituted or each independently substituted by one or more groups selected from C_1-6Alkyl, halogen, hydroxy, amino, cyano, carboxy, -OR^4aand-NR^4aR^4bThe substituent(s) of (b) is substituted at any substitutable position.

In some embodiments, R¹Selected from indolyl, 5-azaindolyl, indazolyl, benzo [ d]Imidazolyl, 6-azaindolyl, 7-azaindolyl, said indolyl, 5-azaindolyl, indazolyl, benzo [ d ]]Imidazolyl, 6-azaindolyl, 7-azaindolyl are unsubstituted or each independently substituted by one or more groups selected from halogen and-NR^4aR^4bThe substituent(s) of (a) is substituted at any substitutable position.

In some embodiments, R¹Selected from indolyl, benzo [ d ]]Imidazolyl, 6-azaindolyl, 7-azaindolyl, said indolyl, benzo [ d]Imidazolyl, 6-azaindolyl, 7-azaindolyl are unsubstituted or each independently substituted by one group from the group consisting of F, -NR^4aR^4bThe substituent(s) of (a) is substituted at any substitutable position.

In some embodiments, R²Is selected from C_1-6Alkyl, 3-8 membered cycloalkyl, 4-10 membered heterocycloalkyl, phenyl, heteroaryl, -NR⁵R⁶(ii) a Wherein said C_1-6The alkyl, 3-8 membered cycloalkyl, 4-10 membered heterocycloalkyl, phenyl, heteroaryl are unsubstituted or each independently substituted by one or more groups selected from oxo, halo, cyano, hydroxy, C_1-6Alkyl radical, C_1-6Haloalkyl, 3-to 8-membered cycloalkyl, 4-to 10-membered heterocycloalkyl, -C (O) R⁵、-C(O)OR⁵、-(CO)NR⁵R⁶、-(SO₂)R⁵、-(SO)R⁵、-(SO₂)NR⁵R⁶、-(PO)(OR⁵)₂、-(PO)(OR⁵)R⁶And- (PO) (R)⁵)₂The substituent(s) of (a) is substituted at any substitutable position.

In some embodiments, R²Is selected from C_1-6Alkyl, 3-6 membered cycloalkyl, 5-6 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, -NR⁵R⁶(ii) a Wherein said C_1-6Alkyl, 3-6 membered cycloalkyl, 5-6 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl are unsubstituted or each independently substituted with one or more groups selected from oxo, halo, cyano, hydroxy, C_1-6Alkyl radical, C_1-6Haloalkyl, 3-6-membered cycloalkyl, 5-6 membered heterocycloalkyl, -C (O) R⁵、-(CO)NR⁵R⁶、-(SO₂)R⁵And- (SO)₂)NR⁵R⁶The substituent(s) of (a) is substituted at any substitutable position.

In some embodiments, R²Is selected from C_1-6Alkyl, 3-to 6-membered cycloalkyl, phenyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, and the like,

Pyrazolyl, imidazolyl, pyrimidinyl, pyrazinyl, pyridazinyl, -NR⁵R⁶(ii) a Wherein said C_1-6Alkyl, 3-to 6-membered cycloalkyl, phenyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, and the like,

Pyrazolyl, imidazolyl, pyrimidinyl, pyrazinyl, pyridazinyl being unsubstituted or each independently substituted by one or more groups selected from C_1-6Alkyl, 3-6 membered cycloalkyl, C_1-6Haloalkyl, oxo, halogen, cyano, hydroxy, tetrahydropyrrolyl, piperidinyl, -C (O) R⁵、-(CO)NR⁵R⁶、-(SO₂)R⁵And- (SO)₂)NR⁵R⁶The substituent(s) of (a) is substituted at any substitutable position.

In some embodiments, R²Is selected from C_1-6Alkyl, 3-to 6-membered cycloalkyl, phenyl, tetrahydropyranyl, piperidinyl,

Pyrazolyl, tetrahydropyrroleA base; wherein said C_1-6Alkyl, 3-to 6-membered cycloalkyl, phenyl, tetrahydropyranyl, piperidinyl,

Pyrazolyl, tetrahydropyrrolyl is unsubstituted or each independently is substituted by one or more groups selected from C_1-6Alkyl, cyclopropyl, C_1-6Haloalkyl, oxo, halogen, cyano, hydroxy, piperidinyl, -C (O) R⁵、-(CO)NR⁵R⁶、-(SO₂)R⁵And- (SO)₂)NR⁵R⁶The substituent(s) of (a) is substituted at any substitutable position.

In some embodiments, R²Selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclopentyl, phenyl, tetrahydropyranyl, piperidinyl, and mixtures thereof,

Pyrazolyl, tetrahydropyrrolyl, wherein said methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclopentyl, phenyl, tetrahydropyranyl, piperidinyl, piperazinyl, piperidinyl, and piperazinyl,

Pyrazolyl, tetrahydropyrrolyl being unsubstituted or substituted independently of one another by one, two or three radicals from the group consisting of methyl, cyclopropyl, difluoromethyl, oxo, fluoro, hydroxy, cyano, piperidinyl, - (SO)₂)R⁵、-(SO₂)NR⁵R⁶、-(CO)NR⁵R⁶and-C (O) R⁵The substituent(s) of (a) is substituted at any substitutable position.

In some embodiments, R^4aAnd R^4bEach independently selected from hydrogen and C_1-6Alkyl, 3-6 membered cycloalkyl.

In some embodiments, R^4aAnd R^4bEach independently selected from hydrogen and C_1-6An alkyl group.

In some embodiments, R^4aAnd R^4bEach independently selected from hydrogen, methyl.

In some embodiments, R³Selected from hydrogen, C_1-6An alkyl group.

In some embodiments, R³Selected from hydrogen, methyl, ethyl, propyl or butyl.

In some embodiments, R³Is hydrogen.

In some embodiments, R⁴Is selected from C_1-6An alkyl group.

In some embodiments, R⁴Selected from hydrogen, methyl, ethyl, propyl or butyl.

In some embodiments, R⁴Is a methyl group.

In some embodiments, R⁵And R⁶Each independently selected from hydrogen and C_1-6Alkyl, 3-8 membered cycloalkyl, 3-15 membered bridged cyclic group, 3-15 membered bridged heterocyclic group, phenyl, heteroaryl;

or R⁵And R⁶And the atoms to which they are attached form a nitrogen-containing 4-8 membered heterocyclic ring, said nitrogen-containing 4-8 membered heterocyclic ring being unsubstituted or substituted with one or more groups selected from deuterium, halogen, hydroxy, C_1-6Alkoxy, 3-to 8-membered cycloalkyl, 4-to 10-membered heterocycloalkyl and- (SO)₂)R⁷Said nitrogen-containing 4-8 membered heterocyclic ring optionally containing an additional heteroatom selected from O, N and S.

In some embodiments, R⁵And R⁶Each independently selected from hydrogen, C_1-6Alkyl, 3-6 membered cycloalkyl, regular tetrahedral alkyl, adamantyl, trigonal alkyl, cubic alkyl, higher cubic alkyl, basketball alkyl, pentagonal alkyl, dipentagonal alkyl, di-n-butyl, tri-butyl, tetra-butyl, tri-n-butyl, tri-butyl, tetra-n-butyl, tetra-n-butyl, tri-n-butyl, tri-n-butyl, tri-n-butyl, tri-n-butyl, n-butyl, n-,

In some embodiments, R⁵And R⁶Each independently selected from hydrogen and C_1-6Alkyl, 3-6 membered cycloalkyl,

In some embodiments, R⁵And R⁶Each independently selected from hydrogen and C_1-6Alkyl, 3-6 membered cycloalkyl.

In some embodiments, R⁵And R⁶Each independently selected from hydrogen and C_1-6Alkyl, cyclopropyl.

In some embodiments, R⁵And R⁶Each independently selected from hydrogen, methyl, ethyl, cyclopropyl.

In some embodiments, R⁵And R⁶And the atoms to which they are attached form a nitrogen-containing 5-6 membered heterocyclic ring, said nitrogen-containing 5-6 membered heterocyclic ring being unsubstituted or substituted with one or more groups selected from C_1-6The substituents of the alkyl group are substituted at any substitutable position.

In some embodiments, R⁵And R⁶And the atoms to which they are attached together form a tetrahydropyrrole, a tetrahydroimidazole, a tetrahydropyrazole, a piperidine, or a piperazine.

In some embodiments, R⁵And R⁶And the atoms to which they are attached together form a tetrahydropyrrole.

In some embodiments, R⁷Is selected from C_1-6Alkyl, 3-8 membered cycloalkyl, phenyl.

In some embodiments, R¹Selected from:

in some embodiments, R¹Is selected from

In some embodiments, R²Selected from:

in some embodiments, R²Is selected from

In some embodiments, R²Is selected from

In some embodiments, R₃Is H, R₄Is methyl, then formula (I) has the following structure of formula (I'):

wherein R is¹And R²As defined above.

In some embodiments, the compound is selected from:

in a second aspect of the invention, there is provided a composition or pharmaceutical formulation comprising a compound as hereinbefore described, or a pharmaceutically acceptable salt, solvate, isotopic label, metabolite or prodrug thereof, and optionally a pharmaceutically acceptable carrier and/or adjuvant and/or diluent.

Methods of preparing various pharmaceutical compositions or formulations containing certain amounts of active ingredient are known or will be apparent to those skilled in the art in view of this disclosure. The process for preparing the PHARMACEUTICAL composition or formulation comprises incorporating suitable PHARMACEUTICAL excipients, carriers, diluents and the like, as described in REMINGTON' S PHARMACEUTICAL SCIENCES, Martin, e.w., ed., Mack Publishing Company,19th ed. (1995).

Preferably, the pharmaceutically acceptable adjuvant is preferably a pharmaceutically acceptable carrier, diluent, excipient, or combination thereof.

In a third aspect of the present invention, there is provided a use of the aforementioned compound or a pharmaceutically acceptable salt, solvate, isotopic label, metabolite or prodrug thereof, or a composition or formulation of the aforementioned in the manufacture of a medicament for the treatment and/or prevention of an ATR-mediated associated disease.

In another aspect, there is provided a compound of the foregoing or a pharmaceutically acceptable salt, solvate, isotopic label, metabolite or prodrug thereof, or a composition or formulation of the foregoing for use in the treatment and/or prevention of an ATR mediated disease.

In yet another aspect, there is provided a method of treating and/or preventing an ATR-mediated disease, comprising administering to a subject an effective amount of the aforementioned compound or a pharmaceutically acceptable salt, solvate, isotopic label, metabolite or prodrug thereof, or a composition or formulation of the aforementioned.

In the present invention, the "ATR-mediated associated disease" is a related disease caused by a disorder in ATR level, preferably a value-added disease, more preferably a malignant tumor.

In the present invention, "treatment" generally means obtaining a desired pharmacological and/or physiological effect. The effect may be prophylactic, in terms of preventing the disease or its symptoms, in whole or in part; and/or may be therapeutic in terms of partially or completely stabilizing or curing the disease and/or side effects due to the disease. As used herein, "treatment" encompasses any treatment of a disease in a patient, including: (a) preventing a disease or condition that occurs in a patient susceptible to the disease or condition but has not yet been diagnosed as having the disease; (b) inhibiting the symptoms of the disease, i.e., arresting its development; or (c) alleviating the symptoms of the disease, i.e., causing regression of the disease or symptoms.

In the present invention, "subject" refers to a vertebrate. In certain embodiments, the vertebrate is a mammal. Mammals include, but are not limited to, livestock (such as cattle), pets (such as cats, dogs, and horses), primates, mice, and rats. In certain embodiments, the mammal refers to a human.

In the present invention, an "effective amount" refers to an amount effective in achieving the desired therapeutic or prophylactic effect at the necessary dosage and time. The "therapeutically effective amount" of a substance/molecule of the invention may vary depending on factors such as the disease state, age, sex and weight of the individual and the ability of the substance/molecule to elicit a desired response in the individual. A therapeutically effective amount also encompasses an amount of the substance/molecule that outweighs any toxic or detrimental consequences. A "prophylactically effective amount" refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired prophylactic effect. Typically, but not necessarily, since a prophylactic dose is administered to a subject prior to the onset of disease or at an early stage of disease, the prophylactically effective amount will be lower than the therapeutically effective amount. In the case of cancer, a therapeutically effective amount of the drug may reduce the number of cancer cells; reducing the tumor volume; inhibit (i.e., slow to some extent, preferably stop) cancer cell infiltration into peripheral organs; inhibit (i.e., slow to some extent, preferably stop) tumor metastasis; inhibit tumor growth to some extent; and/or to some extent alleviate one or more symptoms associated with cancer.

The terms define:

it is to be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting. In addition, although any methods, devices and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, the preferred methods, devices and materials are now described.

In accordance with the convention in the art,

the bond used in the structural formulae herein to describe the point of attachment of the moiety or substituent to the parent or main structure.

A dash "-" that does not appear between two letters or symbols is used to indicate a point of attachment for a substituent. For example, -CONH₂Attached through a carbon atom.

As used herein, unless otherwise expressly specified, the recitations "… are each independently selected from" as used throughout this document may mean that the particular options expressed between the same or different symbols do not affect each other in different groups, or that the particular options expressed between the same or different symbols do not affect each other in the same group.

The substituents of the compounds of the present invention are disclosed in terms of group type or range. It is specifically intended that the invention includes each and every independent subcombination of the various members of these groups and ranges. For example, the term "C_1-6Alkyl "means in particular independently disclosed methyl, ethyl, C₃Alkyl radical, C₄Alkyl radical, C₅Alkyl and C₆An alkyl group.

The term "alkyl" as used herein is meant to include both branched and straight chain saturated aliphatic hydrocarbon groups having the indicated number of carbon atoms. For example, "C_1-6Alkyl "means C₁、C₂、C₃、C₄、C₅And C₆. In addition, for example "C_1-6Alkyl "refers to an alkyl group having 1 to 6 carbon atoms. An alkyl group may be unsubstituted or substituted such that one or more of its hydrogens is replaced with another chemical group. Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl (e.g., n-propyl and isopropyl), butyl (e.g., n-butyl, isobutyl, tert-butyl), pentyl (e.g., n-pentyl, isopentyl, neopentyl), and the like.

"alkenyl" means a hydrocarbon chain comprising a straight or branched configuration and having one or more carbon-carbon double bonds that may be present at any stable point along the chain. For example, "C_2-6Alkenyl "means including C₂、C₃、C₄、C₅And C₆. Examples of alkenyl groups include, but are not limited to, ethenyl, 1-propenyl, 2-butenyl, 3-butenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 2-methyl-2-propenyl, 4-methyl-3-pentenyl, and the like.

"alkynyl" refers to a hydrocarbon group including straight or branched chain configurations and having one or more carbon-carbon triple bonds that may be present at any stable point along the chain. E.g. "C_2-6Alkenyl "means including C₂、C₃、C₄、C₅And C₆Alkynyl. Examples of alkynyl groups include, but are not limited to, ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like.

It will be understood by those skilled in the art that when used herein, "CO" is used₂When used in the specification, this means that the group

The term "alkoxy" refers to an oxygen atom substituted with an alkyl or substituted alkyl group as defined herein. For example, the term "alkoxy" includes the group-O-C_1-6Alkyl, e.g. methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, pentyloxy, 2-pentyloxy, isopentyloxyNeopentyloxy, hexyloxy, 2-hexyloxy, 3-hexyloxy and the like. "lower alkoxy" refers to alkoxy having 1 to 4 carbons. Similarly, the term "alkylamino" refers to an amino group substituted with an alkyl or substituted alkyl group as defined herein. For example, the term "alkylamino" includes the group-NH-C_1-6An alkyl group.

The term "halo C_1-6Alkyl and the term "C_1-6Haloalkyl "may be used interchangeably, as such, the term" halo C_1-6Alkoxy "and the term" C_1-6Haloalkoxy "may be used alternatively. It means that one or more hydrogen atoms in the alkyl and alkoxy groups are replaced by halogen atoms, in particular fluorine or chlorine atoms. In some embodiments, fluoro is preferred, e.g., "C_1-6Haloalkyl "may be-CF₃、-CHF₂、-CH₂F、-CH₂CH₂F、-CH₂CHF₂、-CH₂CF₃，“C_1-6Haloalkoxy "may be-OCF₃、-OCHF₂、-OCH₂F、-OCH₂CH₂F、-OCH₂CHF₂or-OCH₂CF₃。

The term "hydroxy-substituted C_1-6Alkyl "means said C_1-6One or more hydrogen atoms in the alkyl group are substituted with a hydroxyl group, and in some embodiments, is preferably "hydroxyl-substituted C₁-C₄Alkyl radicals, e.g. -C (OH)₃、-CH(OH)₂、-CH₂(OH)、-CH₂CH₂(OH)、-CH₂CH(OH)₂or-CH₂C(OH)₃。

The term "oxo" refers to

For example,

by oxo-substitution (by oxo) then

The term "substituted" as used herein refers to the selective replacement of any one or more hydrogens on the designated atom or group with the designated group, provided that the designated atom's normal valence is not exceeded.

The term "XXX is substituted at any substitutable position with one or more substituents selected from YYY" means that XXX may be substituted at any substitutable position with one or more substituents selected from yy. When XXX is substituted by a plurality of substituents selected from YYY at any substitutable position, the plurality of substituents may be the same or different. Wherein the plurality is 2 or more, preferably 2,3 or 4, more preferably 2 or 3. E.g. C_1-6Alkyl is substituted in any substitutable position by one or more substituents selected from cyano and hydroxy, which signifies, C_1-6The alkyl group may be substituted by one or more cyano groups at any substitutable position, by one or more hydroxyl groups at any substitutable position, and by one or more cyano groups and hydroxyl groups (for example, one cyano group and one hydroxyl group, or two cyano groups and two hydroxyl groups, etc.) at any substitutable position.

The term "cycloalkyl" refers to a cyclized alkyl group, including monocyclic, bicyclic, or polycyclic ring systems, which do not contain double bonds or the like unsaturation, e.g., C_3-8Cycloalkyl radical, C_3-7Cycloalkyl or C_3-6A cycloalkyl group. C_3-7Cycloalkyl is meant to include C₃、C₄、C₅、C₆And C₇A cycloalkyl group. "3-7 membered cycloalkyl" and "C_3-7Cycloalkyl "may be used interchangeably. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.

As used herein, "carbocycle" or "carbocyclic residue" refers to any stable 3-membered, 4-membered, 5-membered, 6-membered, or 7-membered monocyclic or bicyclic or 7-membered, 8-membered, 9-membered, 10-membered, 11-membered, 12-membered bicyclic or tricyclic, any of which can be saturated, partially saturated, unsaturated, or aromatic. Examples of such carbocycles include, but are not limited to, cyclopropyl, cyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptenyl, cycloheptyl, adamantyl, cyclooctyl, phenyl, naphthyl, and the like. As indicated above, bridged rings are also included within the definition of carbocyclic rings, such as [2,2,2] bicyclooctane. Preferred carbocycles, unless otherwise indicated, are cyclopropyl, cyclobutyl, cyclopentyl and phenyl. When one or more carbon atoms connect two non-adjacent carbon atoms, a bridged ring results. Preferred bridges are one or two carbon atoms. It should be noted that bridges always convert a single ring into a bicyclic ring. When the rings are bridged, the substituents described for the rings may also be present on the bridge.

The terms "heterocycle", "heterocyclic" or "heterocyclyl" are used interchangeably and refer to substituted and unsubstituted 3-to 7-membered monocyclic groups, 7-to 11-membered bicyclic groups, and 10-to 15-membered tricyclic groups, which may contain one or more double bonds, but do not constitute aromatic rings; wherein at least one ring has at least one heteroatom (O, S or N), the heteroatom-containing ring preferably also has 1, 2 or 3 heteroatoms selected from O, S and N. Each heteroatom-containing ring in the group may contain 1 or 2 oxygen or sulfur atoms and/or 1 to 4 nitrogen atoms, provided that the total number of heteroatoms in each ring is 4 or less, and further provided that the ring contains at least one carbon atom. The nitrogen and sulfur atoms may optionally be oxidized and the nitrogen atoms may optionally be quaternized. Fused rings completing bicyclic and tricyclic groups may contain only carbon atoms and may be saturated or partially saturated, not constituting aromatic rings. The heterocyclic group may be attached at any available nitrogen or carbon atom.

Exemplary monocyclic heterocyclyl groups include azetidinyl, oxetanyl, pyrrolidinyl, imidazolinyl, oxazolidinyl, isoxazolinyl, thiazolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, 2-oxopazepinyl, 1-pyridonyl, 4-piperidonyl, tetrahydropyranyl, morpholinyl, 1, 3-dioxolanyl, and the like. Exemplary bicyclic heterocyclic groups expose quinuclidinyl groups.

The term "heterocycloalkyl group" means that the above-mentioned heterocyclic group does not contain a double bond and is a saturated heterocyclic group. For example, the 5-6 membered heterocycloalkyl group may be, tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyrrolyl, piperidinyl, and the like. The term "heterocycloalkenyl" means that the heterocyclic group contains a double bond and includes a heterocyclic group as a part thereof, for example, an imidazolinyl group, an isoxazolinyl group, and the like.

The term "bridged cyclic group" refers to a 3-15 membered polycyclic hydrocarbon that shares two or more carbon atoms between monocyclic rings, does not contain heteroatoms in the ring atoms, and may contain one or more double bonds, but none of the rings have a conjugated pi-electron system. And is classified into bicyclic hydrocarbons, tricyclic hydrocarbons, tetracyclic hydrocarbons, etc. according to the number of constituting rings. Specific examples thereof include regular tetrahedral alkyl, adamantyl, trigonal alkyl, cubic alkyl, cuboidal alkyl, basketball alkyl, pentagonal alkyl, and dipentagonal alkyl, with adamantyl such as

The term "bridged heterocyclyl" refers to a 3-15 membered polycyclic hydrocarbon in which more than two carbon atoms are shared between monocyclic rings, the ring atoms containing at least one heteroatom which may contain one or more double bonds, but none of the rings have a conjugated pi-electron system. According to the number of constituting rings, they are classified into di-heterocyclic hydrocarbons, tri-heterocyclic hydrocarbons, tetra-heterocyclic hydrocarbons, etc. Preferred heteroatoms include N, O and S, more preferably N. Specific examples are as

Preference is given to

The term "heteroaryl" refers to substituted and unsubstituted aromatic 5-or 6-membered monocyclic groups, 9-or 10-membered bicyclic groups, and 11-to 14-membered tricyclic groups having at least one heteroatom (O, N or S) in at least one ring, preferably 1, 2, or 3 heteroatoms selected from O, N or S. Each heteroatom-containing ring of the heteroaryl group can contain 1 or 2 oxygen or sulfur atoms and/or 1 to 4 nitrogen atoms, provided that the total number of heteroatoms in each ring is 4 or less and each ring has at least one carbon atom. Fused rings completing bicyclic and tricyclic groups may contain only carbon atoms and may be saturated, partially saturated, or unsaturated. The nitrogen and sulfur atoms may optionally be oxidized and the nitrogen atoms may optionally be quaternized. Heteroaryl groups that are bicyclic or tricyclic must include at least one fully aromatic ring, but the other fused ring or rings may be aromatic or non-aromatic. Heteroaryl groups may be attached at any available nitrogen or carbon atom of any ring. When valency permits, if the other ring is cycloalkyl or heterocyclic, it is additionally optionally substituted by ═ O (oxo).

Exemplary monocyclic heteroaryl rings include, but are not limited to: pyrrolyl, pyrazolyl, pyrazolinyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, isothiazolyl, furyl, thienyl, oxadiazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, triazolyl and the like.

Exemplary bicyclic heteroaryls include, but are not limited to: indolyl, 5-azaindolyl, pyrrolo [2,3-d ] pyrimidinyl, 5, 6-diazaindolyl, 6-azaindolyl, 7-azaindolyl, pyrazolo [3,4-b ] pyridinyl, pyrrolo [2,3-c ] pyridazinyl, thieno [2,3-d ] imidazolyl, 7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridinyl, pyrazolo [3,4-c ] pyridinyl, benzothiazolyl, benzimidazolyl, benzodioxolyl, benzoxazolyl, benzothienyl, quinolinyl, tetrahydroisoquinolinyl, isoquinolinyl, benzofuranyl, indolizinyl, benzopyranyl, chromonyl, coumarinyl, pyridazinyl, thieno [2,3-d ] imidazolyl, 7-azaindolyl, 7-dihydro-1H-pyrrolo [2,3-c ] pyridinyl, 7-oxo-6, 1H-pyrrolo [2,3-c ] pyridinyl, pyrazolo [3,4-c ] pyridinyl, benzothiazolyl, benzimidazolyl, benzodioxolyl, benzoxazolyl, benzothienyl, and coumarinyl, Benzopyranyl, quinoxalinyl, indazolyl, pyrrolopyrimidyl, furopyridinyl, isoindolyl, tetrahydroquinolinyl, and the like.

Solid (-), wavy, lines may be used herein

Solid wedge shape

Or virtual wedge shape

Carbon-carbon bonds of the compounds of the invention are depicted. The solid line is used to depict a representation of the bond to an asymmetric carbon atom, including all possible stereoisomers (e.g., particular enantiomers, diastereomers, racemic mixtures, etc.) at that carbon atom. A wavy line is used to depict a representation of the bond to an asymmetric carbon atom, including a mixture (e.g., a racemic mixture) of all possible stereoisomers at that carbon atom. The stereoisomers shown exist using solid or dashed wedges to depict bonds to asymmetric carbon atoms. Unless otherwise indicated, the compounds of the present invention may exist as stereoisomers (including cis, trans, atropisomers and mixtures thereof). The compounds of the invention may exhibit more than one type of isomerism and consist of mixtures thereof (e.g. racemic mixtures, pairs of diastereoisomers, pairs of atropisomers).

Herein, when a complex group in which two or more groups are linked is present, the linking site is according to the general principles of chemistry, i.e., the point of attachment is the last noun group in the name of the complex group. For example, the occurrence of "C_3-8Cycloalkyl radical C_1-6Alkyl, 3-8 membered heterocycloalkyl C_1-6Alkyl, phenyl C_1-6Alkyl, 5-6 membered heteroaryl C_1-6When an alkyl group "is present, the point of attachment to the main structural group or other groups is" C_1-6Alkyl groups "; other similar groups, unless otherwise specified, are understood with reference to the subcategories.

The invention also encompasses all possible crystalline forms or polymorphs of a compound of the invention, which may be single polymorphs or mixtures of more than one polymorph in any ratio.

Throughout the specification, groups and substituents thereof may be selected by one of skill in the art to provide stabilizing moieties and compounds useful as pharmaceutically acceptable compounds and/or intermediate compounds useful in the preparation of pharmaceutically acceptable compounds.

In some embodiments, the method is performed by:

wherein: r¹、R²、R³And R⁴PG represents H or an amino protecting group (e.g., Boc (tert-butyloxycarbonyl), Cbz (benzyloxycarbonyl)), as defined above; LG independently represents a leaving group (e.g. OMs (methanesulphonyloxy), Cl, Br or I); hal represents halogen (e.g., Cl or Br); in step 2, manipulation of a deaminating protecting group PG (e.g. Boc, Cbz) may be involved.

In other embodiments, the method is performed by:

wherein: r is¹、R³、R⁴、R⁵And Hal is as defined above.

In other embodiments, the method is carried out by:

wherein: r¹、R³、R⁴、R⁵、R⁶And LG is as defined above; wherein R is⁵And R⁶May form together with the atoms to which they are attached a 4-8 membered saturated, partially saturated or unsaturated carbocyclic ring or a 4-8 membered heterocyclic ring, said 4-8 membered saturated, partially saturated or unsaturated carbocyclic ring or 4-8 membered heterocyclic ring being optionally substituted by one or more groups selected from deuterium, halogen, cyano, hydroxy, optionally substituted by hydroxy or C_1-6Alkoxy-substituted C_1-6Alkyl radical, C_1-6Haloalkyl, C_1-6Alkoxy, 3-to 8-membered cycloalkyl, 4-to 10-membered heterocycloalkyl and- (SO)₂)R⁷Said 4-8 membered heterocyclic ring optionally containing an additional heteroatom selected from O, N and S.

Advantageous effects

The pyrazinone compound of the formula (I) of the present invention exhibits a good ATR inhibitory effect, and is useful as a drug related to the treatment and/or prevention of diseases associated with this effect.

The specific embodiment is as follows:

the structure of the compounds is determined by Nuclear Magnetic Resonance (NMR) or Mass Spectrometry (MS). NMR was measured using Bruker ASCEND-400 NMR spectrometer using deuterated dimethyl sulfoxide (DMSO-d)₆) Deuterated chloroform (CDCl)₃) Deuterated methanol (CD)₃OD), internal standard of Tetramethylsilane (TMS), chemical shift of 10^-6(ppm) is given as a unit.

Reaction monitoring and determination of MS using a thermodisser ESQ (ESI) mass spectrometer.

HPLC was performed using a Saimerfiu 3000 DAD high pressure liquid chromatograph (GL Sciences ODS-HL HP 3 μm 3.0 × 100mm column).

The thin-layer chromatography silica gel plate is a Qingdao ocean GF254 silica gel plate, the specification of the silica gel plate used by thin-layer chromatography (TLC) is 0.15-0.2 mm, and the specification of the thin-layer chromatography separation and purification product is 0.9-1.0 mm. Column chromatography generally uses Qingdao ocean silica gel of 200-300 meshes as a carrier, and a system used by a developing agent is as follows: dichloromethane and methanol systems; b: petroleum ether and ethyl acetate, the volume ratio of the solvent is adjusted according to the polarity of the compound. For the purification of the medium-pressure preparative liquid phase, a Biotage Isolera One type preparative liquid phase was used.

The reaction raw materials in the following examples are commercially available unless otherwise specified.

Unless otherwise specified, the abbreviations used in the examples have the following meanings:

the present invention is described in detail below by way of examples, but is not meant to be limited to any of the disadvantages of the present invention. Having described the invention in detail and having disclosed specific embodiments thereof, it will be apparent to one skilled in the art that various changes and modifications can be made therein without departing from the spirit and scope thereof.

Example 1

(R) -1- (1-methyl-1H-pyrazol-5-yl) -3- (3-methylmorpholine) -5- (1H-pyrrolo [2,3-b ] pyridin-4-yl) pyrazin-2 (1H) -one

Step 1: 1-methyl-5-aminopyrazole (1-a,5g,51.5mmol) was dissolved in dichloromethane (50mL), and triethylamine (14.3mL,103.0mmol) and di-tert-butyl dicarbonate (14.6g,66.9mmol) were added, respectively, at room temperature. Stirring at room temperature overnight, monitoring by TLC that a small amount of 1-methyl-5-aminopyrazole remains, heating to 50 deg.C, stirring for 2 hours, and monitoring by TLC that the reaction is complete. After cooling to room temperature, the mixture was diluted with dichloromethane, washed with 10% acetic acid solution, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography (dichloromethane: methanol ═ 50:1) to give (tert-butyl carbamate-5-yl) -1-methylpyrazole (1-b,4.2g, yield 50%). MS Calcd: 197; MS Found 198([ M + H ]]⁺).

And 2, step: (carbamic acid tert-butyl ester-5-yl) -1-methylpyrazole (1-b,4.2g,21.3mmol) was dissolved in tetrahydrofuran (70mL), the reaction solution was cooled in an ice-water bath, and then sodium hydride (3.07g,25.5mmol), N, were slowly added₂Stirring for 0.5 hour under protection. Bromoacetonitrile (3.07g,25.5mmol) was then added, the ice-water bath removed, stirred at room temperature for 0.5 hour, warmed to 60 ℃ and kept stirring for 5 hours. TLC to monitor the reaction, add saturated ammonium chloride to quench, extract with ethyl acetate, wash with saturated saline, dry with anhydrous sodium sulfate. After concentration under reduced pressure, column chromatography purification (petroleum ether: ethyl acetate 1:1) was performed to give (tert-butyl carbamate-cyanomethyl-5-yl) -1-methylpyrazole (1-c,3.3g, yield 66%). MS Calcd: 236; 237([ M + H)]⁺).

And step 3: (tert-butyl carbamate-cyanomethyl-5-yl) -1-methylpyrazole (1-c,3.3g,14.0mmol) was dissolved in dichloromethane (30mL), trifluoroacetic acid (10mL) was added under ice-water bath, and ice water was addedStir 15 minutes under bath. The ice water bath was then removed and stirred at room temperature for 3 hours and TLC monitored for completion of the reaction. After concentration under reduced pressure, the mixture was diluted with methylene chloride, washed with a saturated sodium carbonate solution and a saturated brine in this order, and dried over anhydrous sodium sulfate to give 2- (1-methylpyrazol-5-yl) -aminoacetonitrile (1-d,1.7g, yield 90%). MS Calcd: 136; MS Found 137([ M + H ]]⁺).

And 4, step 4: 2- (1-methylpyrazol-5-yl) -aminoacetonitrile (1-d,475mg,3.5mmol) was dissolved in dichloromethane (20mL) and oxalyl chloride (1.5mL,17.5mmol) and N, N-dimethylformamide (180mg,1.05mmol) were added successively under an ice-water bath. The ice-water bath was removed and stirred at room temperature for 0.5 hour, then warmed to 50 ℃ and stirred for 16 hours. TLC to monitor the reaction completion, the reaction solution was cooled to room temperature, diluted with dichloromethane, washed with saturated sodium carbonate solution, saturated brine and dried over anhydrous sodium sulfate. After concentration under reduced pressure, column chromatography purification (petroleum ether: ethyl acetate ═ 2:1) was performed to give 3, 5-dichloro-1- (1-methyl-1H-pyrazol-5-yl) -pyrazin-2 (1H) -one (1-e, 250mg, yield 30%). 244/246 for MS Calcd; 245/247([ M + H ]) for MS Found]⁺).

And 5: 3, 5-dichloro-1- (1-methyl-1H-pyrazol-5-yl) -pyrazin-2 (1H) -one (1-e,225mg,0.9mmol) was dissolved in N-methylpyrrolidone (6mL), and (R) -3-methylmorpholine (139mg,1.35mmol), diisopropylethylamine (305. mu.L, 1.8mmol) was added at room temperature. Then, the temperature was raised to 80 ℃ and the mixture was stirred for 4 hours. The reaction was monitored by TLC and cooled to room temperature, diluted with ethyl acetate, washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. After concentration under reduced pressure, column chromatography purification (petroleum ether: ethyl acetate ═ 2:1) was performed to give (R) -5-chloro-1- (1-methyl-1H-pyrazol-5-yl) -3- (3-methylmorpholine) -pyrazin-2 (1H) -one (1-f,210mg, yield 75%). 309/311 for MS Calcd; MS Found 310/312([ M + H ]]⁺).

And 6: (R) -5-chloro-1- (1-methyl-1H-pyrazol-5-yl) -3- (3-methylmorpholine) -pyrazin-2 (1H) -one (1-f,70mg,0.23mmol), 7-azaindole-4-boronic acid pinacol ester (73mg,0.3mmol), tetratriphenylphosphine palladium (27mg,0.02mmol), anhydrous potassium carbonate (96mg,0.69mmol) was added to a mixed solvent of dioxane (2mL) and water (0.4mL), and N was added at room temperature₂The replacement was performed 3 times. Then the temperature was raised to 100 ℃ and the stirring was maintained for 7 hours, followed by TLC monitoringAfter completion of the reaction, the reaction solution was cooled to room temperature, concentrated under reduced pressure, and then subjected to reverse phase column (0.05% aqueous trifluoroacetic acid: acetonitrile 3:2) to obtain the title compound: (R) -1- (1-methyl-1H-pyrazol-5-yl) -3- (3-methylmorpholine) -5- (1H-pyrrolo [2, 3-b)]Pyridin-4-yl) pyrazin-2 (1H) -one (1, 60mg, 67% yield). MS Calcd: 391; MS Found:392([ M + H ]]⁺).¹H NMR(400MHz,DMSO)δ11.73(s,1H),8.22(d,J＝5.2Hz,1H),7.65(s,1H),7.57(d,J＝2.0Hz,1H),7.52–7.49(m,1H),7.47(d,J＝5.2Hz,1H),6.87(dd,J＝3.2,2.0Hz,1H),6.54(d,J＝2.0Hz,1H),5.00(d,J＝6.4Hz,1H),4.44(d,J＝13.6Hz,1H),4.02–3.90(m,1H),3.79–3.66(m,5H),3.59(td,J＝11.6,2.4Hz,2H),1.33(d,J＝6.4Hz,3H).

Example 2

(R) -5- (1H-indol-4-yl) -1- (1-methyl-1H-pyrazol-5-yl) -3- (3-methylmorpholine) pyrazin-2 (1H) -one

Step 1: (R) -5-chloro-1- (1-methyl-1H-pyrazol-5-yl) -3- (3-methylmorpholine) -pyrazin-2 (1H) -one (1-f,60mg,0.19mmol), pinacol 4-indoleborate (62mg,0.25mmol), tetratriphenylphosphine palladium (22mg,0.02mmol), and anhydrous potassium carbonate (79mg,0.58mmol) were added to a mixed solvent of dioxane (2mL) and water (0.4mL), and N was added at room temperature₂The replacement was performed 3 times. Then, the reaction mixture was heated to 100 ℃ and kept stirred for 7 hours, TLC monitored for completion of the reaction, cooled to room temperature, concentrated under reduced pressure, and purified by column chromatography (petroleum ether: ethyl acetate ═ 1:1) to obtain the title compound: (R) -5- (1H-indol-4-yl) -1- (1-methyl-1H-pyrazol-5-yl) -3- (3-methylmorpholine) pyrazin-2 (1H) -one (2,30mg, yield 47%). MS Calcd: 390; MS Found:391([ M + H ]]⁺).¹H NMR(400MHz,DMSO)δ11.23(s,1H),7.56(d,J＝2.4Hz,1H),7.41-7.37(m,3H),7.34(s,1H),7.13(t,J＝7.6Hz,1H),6.79(s,1H),6.54(d,J＝2.0Hz,1H),5.00(d,J＝6.0Hz,1H),4.42(d,J＝14.0Hz,1H),3.92(dd,J＝11.2,2.4Hz,1H),3.78–3.65(m,5H),3.58(td,J＝12.0,2.8Hz,1H),3.39(dd,J＝13.6,3.6Hz,1H),1.32(d,J＝6.8Hz,3H).

Example 3

(R) -1- [ 1-methyl-1H-pyrazol-5-yl) -5- (2-methylamino) -1H-benzo [ d ] imidazol-1-yl ] -3- (3-methylmorpholine) pyrazin-2 (1H) -one

Step 1: mixing (R) -5-chloro-1- (1-methyl-1H-pyrazol-5-yl) -3- (3-methylmorpholine) -pyrazin-2 (1H) -one (1-f,60mg,0.19mmol), N-methyl-1H-benzo [ d ]]Imidazol-2-amine (44mg,0.3mmol), tris (dibenzylideneacetone) dipalladium (27mg,0.02mmol), X-phos (28mg, 0.04mmol), cesium carbonate (255mg,0.6mmol) were added to toluene (2 mL). N at room temperature₂The displacement is carried out for 2 times, and then the reaction is carried out for 3 hours by microwave heating to 130 ℃. TLC monitored a small amount of starting material remaining and stopped the reaction. The reaction was cooled to room temperature, concentrated under reduced pressure and purified by reverse phase column (0.05% aqueous trifluoroacetic acid: acetonitrile 5:1) to give the title compound: (R) -1- [ 1-methyl-1H-pyrazol-5-yl) -5- (2-methylamino) -1H-benzo [ d]Imidazol-1-yl]-3- (3-methylmorpholine) pyrazin-2 (1H) -one (3, 8mg, yield 10%). MS Calcd: 420; found:421([ M + H ]]⁺).¹H NMR(400MHz,DMSO)δ7.56(d,J＝2.0Hz,1H),7.52(s,1H),7.45(d,J＝7.2Hz,1H),7.38(d,J＝7.2Hz,1H),7.32–7.20(m,2H),6.43(d,J＝2.0Hz,1H),4.80(s,1H),4.46(s,1H),3.87(d,J＝9.2Hz,1H),3.70(s,3H),3.66-3.65(m,2H),3.53-3.47(m,2H),3.03(d,J＝4.8Hz,3H),1.28(d,J＝6.8Hz,3H).

Example 4

(R) -3- (3-methylmorpholine) -1 ((methylsulfonyl) methylene) 5- (1H-pyrrolo [2,3-b ] pyridin-4-yl) pyrazin-2 (1H) -one

Step 1: 3, 5-Dibromopyrazin-2 (1H) -one (4-a,2.5g,9.5mmol) was dissolved in N, N-dimethylformamide (30mL), cesium carbonate (4.17g,12.3mmol) was added under ice-water bath, and then N₂Chloromethyl methyl sulfide (1mL) was slowly added dropwise under protection, and after the addition was completed, the mixture was stirred for 15 minutes, and then the ice-water bath was removed and stirred at room temperature overnight. TLC monitoringWhen the reaction is complete, adding saturated ammonium chloride solution to quench the reaction, and extracting with ethyl acetate. The organic phase was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. After concentration under reduced pressure, the mixture was purified by column chromatography (petroleum ether: ethyl acetate: 4:1) to give 3, 5-dibromo-1- ((methylthio) methyl) pyrazin-2 (1H) -one (4-b,1.2g, yield 40%).

Step 2:3, 5-dibromo-1- ((methylthio) methyl) pyrazin-2 (1H) -one (4-b,350mg,1mmol) was dissolved in dichloromethane (10mL), and m-chloroperoxybenzoic acid (466mg,2.5mmol) was added under an ice-water bath, followed by stirring for 15 minutes under an ice-water bath. The ice water bath was removed, stirred at room temperature for 2 hours and the reaction was monitored by TLC for completion. The mixture was diluted with dichloromethane and washed with saturated aqueous sodium carbonate and saturated brine in this order. Concentration under reduced pressure gave 3, 5-dibromo-1- ((methanesulfonyl) methylene) pyrazin-2 (1H) -one (4-c,250mg, crude, yield 70%).

And step 3: 3, 5-dibromo-1- ((methylsulfonyl) methylene) pyrazin-2 (1H) -one (4-c,250mg, 0.7mmol) and (R) -3-methylmorpholine (79mg,0.77mmol), diisopropylethylamine (141. mu.L, 0.84mmol) were added to N-methylpyrrolidinone (5mL) at room temperature. The temperature was raised to 60 ℃ and stirring was maintained for 3 hours. TLC to monitor the reaction completion, add ethyl acetate to dilute, wash with water and saturated brine in order, and dry over anhydrous sodium sulfate. After concentration under reduced pressure, column chromatography (petroleum ether: ethyl acetate 1:1) was performed to give (R) -5-bromo-3- ((3-methylmorpholine) -1- (methylsulfonyl) methylene) pyrazin-2 (1H) -one (4-d,160mg, yield 63%). 365/367 for MS Calcd; found 366/368([ M + H ]]⁺).

And 4, step 4: (R) -5-bromo-3- ((3-methylmorpholine) -1- (methylsulfonyl) methylene) pyrazin-2 (1H) -one (4-d,40mg,0.11mmol), 7-azaindole-4-boronic acid pinacol ester (32mg,0.13mmol), tetratriphenylphosphine palladium (13mg,0.01mmol), anhydrous potassium carbonate (46mg,0.33mmol) were added to a mixed solvent of dioxane (2mL) and water (0.4mL), and N was added at room temperature₂The replacement was performed 3 times. Then, the temperature was raised to 105 ℃ and the reaction was kept under stirring for 7 hours, the reaction was monitored by TLC for completion, the reaction solution was cooled to room temperature, concentrated under reduced pressure and purified by plate chromatography (dichloromethane: methanol ═ 10:1) to obtain the title compound: (R) -3- (3-methylmorpholine) -1 ((methylsulfonyl) methylene) 5- (1H-pyrrolo [2, 3-b)]Pyridin-4-yl) pyrazine-2 (1H)-ketone (4,10mg, yield 25%). MS Calcd: 403; found 404([ M + H ]]⁺).¹H NMR(400MHz,DMSO)δ11.77(s,1H),8.25(d,J＝4.8Hz,1H),7.89(s,1H),7.56(s,1H),7.47(d,J＝4.8Hz,1H),6.92(s,1H),5.61(q,J＝14.0Hz,2H),4.99(s,1H),4.42(d,J＝12.4Hz,1H),3.99–3.86(m,1H),3.70-3.66(m,2H),3.57(t,J＝9.6Hz,1H),3.43–3.38(m,1H),3.14(s,3H),1.30(d,J＝6.8Hz,3H).

Example 5

(R) -5- (1H-indol-4-yl) -3- (3-methylmorpholine) -1- ((methylsulfonyl) methylene) pyrazin-2 (1H) -one

Step 1: (R) -5-bromo-3- ((3-methylmorpholine) -1- (methylsulfonyl) methylene) pyrazin-2 (1H) -one (4-d,40mg,0.11mmol), 4-indolboronic acid pinacol ester (80mg,0.33mmol), tetratriphenylphosphine palladium (13mg,0.01mmol), anhydrous potassium carbonate (46mg,0.33mmol) were added to a mixed solvent of dioxane (2mL) and water (0.4mL), and N was added at room temperature₂The replacement was performed 3 times. Then, the reaction solution was warmed to 105 ℃ and kept stirred for 12 hours, and the reaction solution was cooled to room temperature by TLC, concentrated under reduced pressure, and purified by plate chromatography (petroleum ether: ethyl acetate ═ 2:3) to obtain the objective compound (R) -5- (1H-indol-4-yl) -3- (3-methylmorpholine) -1- ((methylsulfonyl) methylene) pyrazin-2 (1H) -one (5, 20mg, yield 50%). MS Calcd: 402; found:403([ M + H ]]⁺).¹H NMR(400MHz,DMSO)δ11.25(s,1H),7.64(s,1H),7.49–7.33(m,3H),7.15(t,J＝7.6Hz,1H),6.87(s,1H),5.59(q,J＝14.0Hz,2H),4.99(s,1H),4.38(d,J＝12.6Hz,1H),3.91(d,J＝10.4Hz,1H),3.74-3.66(m,2H),3.57(t,J＝9.6Hz,1H),3.43–3.38(m,1H),3.13(s,3H),1.28(d,J＝6.8Hz,3H).

Example 6

(R) -3- (3-methylmorpholine) -1- ((methylsulfonyl) methylene) -5- (1H-pyrrolo [2,3-c ] pyridin-4-yl) pyrazin-2 (1H) -one

Step 1: (R) -5-bromo-3- ((3-methylmorpholine) -1- (methylsulfonyl) methylene) pyrazin-2 (1H) -one (4-d,40mg,0.11mmol), 6-azaindole-4-boronic acid pinacol ester (35mg,0.22mmol), tetratriphenylphosphine palladium (13mg,0.01mmol), anhydrous potassium carbonate (46mg,0.33mmol) were added to a mixed solvent of dioxane (2mL) and water (0.4mL), and N was added at room temperature₂The replacement was performed 3 times. Then, the reaction mixture was warmed to 105 ℃ and kept stirred for 14 hours, TLC monitored the completion of the reaction, the reaction mixture was cooled to room temperature, concentrated under reduced pressure, and purified by a reverse phase column (0.05% aqueous trifluoroacetic acid solution: acetonitrile 3:2) to obtain the objective compound (R) -3- (3-methylmorpholine) -1- ((methylsulfonyl) methylene) -5- (1H-pyrrolo [2,3-c ] p]Pyridin-4-yl) pyrazin-2 (1H) -one (6, 10mg, yield 25%). MS Calcd: 403; found 404([ M + H ]]⁺).¹H NMR(400MHz,DMSO)δ13.13(s,1H),9.14(s,1H),8.59(s,1H),8.41(s,1H),7.95(s,1H),7.34(s,1H),5.61(q,J＝12.4Hz,2H),5.01(s,1H),4.46(d,J＝9.2Hz,1H),3.93(d,J＝9.6Hz,1H),3.71(s,2H),3.63–3.53(m,2H),3.16(s,3H),1.31(d,J＝6.4Hz,3H).

Example 7

3- ((R) -3-methylmorpholine) -1- ((methylsulfonyl) ethyl) -5- (1H-pyrrolo [2,3-b ] pyridin-4-yl) pyrazin-2 (1H) -one

Step 1: (R) -5-bromo-3- ((3-methylmorpholine) -1- (methylsulfonyl) methylene) pyrazin-2 (1H) -one (4-d,140mg,0.38mmol) was dissolved in anhydrous tetrahydrofuran (5mL), and sodium hydride (46mg,1.14mmol) was added under an ice-water bath and stirring was maintained for 20 minutes. Methyl iodide (95. mu.L, 1.44mmol) was then added, the ice-water bath removed and the mixture stirred at room temperature for 2 hours. TLC monitoring material has little residue, stop reaction, add saturated ammonium chloride aqueous solution to quench reaction, extract with ethyl acetate, wash with saturated saline solution, dry with anhydrous sodium sulfate. After concentration under reduced pressure, the mixture was purified by column chromatography (petroleum ether: ethyl acetate ═ 2:1) to give 5-bromo-3- ((R) -3-methylmorpholine) -1- ((1-methanesulfonyl) ethyl) pyrazin-2 (1H) -one (7-a,120mg, yield 85%). 379/381 for MS Calcd; found 380/382([ M + H ]]⁺).

Step 2: 5-bromo-3- ((R) -3-methylmorpholine) -1- ((1-methanesulfonyl) ethyl) pyrazin-2 (1H) -one (7-a,40mg,0.10mmol), 7-azaindole-4-boronic acid pinacol ester (52mg,0.20mmol), tetratriphenylphosphine palladium (13mg,0.01mmol), anhydrous potassium carbonate (46mg,0.33mmol) were added to a mixed solvent of dioxane (2mL) and water (0.4mL), and N was added at room temperature₂The replacement was performed 3 times. Then, the temperature was raised to 105 ℃ and the reaction was kept under stirring for 7 hours, TLC monitored for completion of the reaction, the reaction solution was cooled to room temperature, concentrated under reduced pressure and purified by a reverse phase column (0.05% aqueous trifluoroacetic acid: acetonitrile: 3:2) to obtain the title compound: 3- ((R) -3-methylmorpholine) -1- ((methylsulfonyl) ethyl) -5- (1H-pyrrolo [2, 3-b)]Pyridin-4-yl) pyrazin-2 (1H) -one (7, 20mg, 47% yield). MS Calcd: 417; found 418([ M + H ]]⁺).¹H NMR(400MHz,DMSO)δ12.11(s,1H),8.33(s,1H),7.73(s,1H),7.63-7.61(m,2H),6.90(s,1H),6.33(s,1H),4.98(s,1H),4.47–4.30(m,1H),3.93(d,J＝11.6Hz,1H),3.71(s,2H),3.60-3.54(m,1H),3.42-3.33(m,1H),3.12(s,3H),1.81(d,J＝4.8Hz,3H),1.32(s,3H).

Example 8

5- (1H-indol-4-yl) -3- ((R) -3-methylmorpholine) -1- (1- (methylsulfonyl) ethyl) pyrazin-2 (1H) -one

Step 1: 5-bromo-3- ((R) -3-methylmorpholine) -1- ((1-methanesulfonyl) ethyl) pyrazin-2 (1H) -one (7-a,40mg,0.10mmol), pinacol 4-indoleborate (52mg,0.20mmol), tetratriphenylphosphine palladium (13mg,0.01mmol), anhydrous potassium carbonate (46mg,0.33mmol) were added to a mixed solvent of dioxane (2mL) and water (0.4mL), and N was added at room temperature₂The replacement was performed 3 times. Then, the temperature was raised to 105 ℃ and the reaction was kept under stirring for 7 hours, TLC monitored for completion of the reaction, the reaction solution was cooled to room temperature, concentrated under reduced pressure and purified by column chromatography (petroleum ether: ethyl acetate ═ 1:1) to give the title compound: 5- (1H-indol-4-yl) -3- ((R) -3-methylmorpholine) -1- (1- (methylsulfonyl) ethyl) pyrazin-2 (1H) -one (8, 15mg, yield 37%). MS Calcd: 416; found:417([ M + H)]⁺).¹H NMR(400MHz,DMSO)δ11.27(s,1H),7.47–7.36(m,4H),7.15(t,J＝7.6Hz,1H),6.77(s,1H),6.34(d,J＝4.8Hz,1H),5.01-4.96(m,1H),4.45-4.35(m,,1H),3.94-3.90(m,1H),3.76–3.65(m,2H),3.62–3.52(m,1H),3.41–3.35(m,1H),3.10(d,J＝1.2Hz,3H),1.78(dd,J＝7.2,3.6Hz,3H),1.32–1.26(t,J＝5.6Hz,3H).

Example 9

1- (1- (ethylsulfonyl) ethyl) -3- ((R) -3-methylmorpholine) -5- (1H-pyrrolo [2,3-b ] pyridin-4-yl) pyrazin-2 (1H) -one

Step 1: (R) -5-bromo-3- ((3-methylmorpholine) -1- (methylsulfonyl) methylene) pyrazin-2 (1H) -one (4-d,60mg,0.17mmol) was dissolved in anhydrous tetrahydrofuran (2mL), and sodium hydride (39mg,1.0mmol) was added under an ice-water bath and stirring was maintained for 20 minutes. Methyl iodide (40. mu.L, 0.68mmol) was then added, the ice-water bath removed and the mixture stirred at room temperature for 2 hours. TLC monitoring material has little residue, stop reaction, add saturated ammonium chloride aqueous solution to quench reaction, extract with ethyl acetate, wash with saturated saline solution, dry with anhydrous sodium sulfate. After concentration under reduced pressure, the mixture was purified by column chromatography (petroleum ether: ethyl acetate ═ 2:1) to give 5-bromo-1- (1- (ethanesulfonyl) ethyl) -3- ((R) -methylmorpholine) pyrazin-2 (1H) -one (9-a,30mg, yield 49%). 393/395 for MS Calcd; found 394/396([ M + H ]]⁺).

Step 2: 5-bromo-1- (1- (ethylsulfonyl) ethyl) -3- ((R) -methylmorpholine) pyrazin-2 (1H) -one (9-a,30mg,0.08mmol), 7-azaindole-4-boronic acid pinacol ester (28mg,0.12mmol), tetratriphenylphosphine palladium (10mg,0.008mmol), anhydrous potassium carbonate (33mg,0.24mmol) were added to a mixed solvent of dioxane (1mL) and water (0.2mL), and N was added at room temperature₂The replacement was performed 3 times. Then, the temperature was raised to 105 ℃ and the reaction was kept under stirring for 7 hours, TLC monitored for completion of the reaction, the reaction solution was cooled to room temperature, concentrated under reduced pressure and purified by a reverse phase column (0.05% aqueous trifluoroacetic acid: acetonitrile: 3:2) to obtain the title compound: 1- (1- (ethylsulfonyl) ethyl) -3- ((R) -3-methylmorpholine) -5- (1H-pyrrolo [2, 3-b)]Pyridin-4-yl) pyrazin-2 (1H) -one (9,7mg, yield 21%). MS Calcd: 431; found 432([ M + H ]]⁺).¹H NMR(400MHz,DMSO)δ11.79(s,1H),8.26(d,J＝4.8Hz,1H),7.66(s,1H),7.58–7.52(m,1H),7.47(d,J＝4.8Hz,1H),6.80-6.78(m,1H),6.34(d,J＝6.8Hz,1H),4.98(dd,J＝22.4,6.8Hz,1H),4.54–4.33(m,1H),3.93(d,J＝11.2Hz,1H),3.79–3.64(m,2H),3.65–3.51(m,1H),3.46–3.38(m,1H),3.27–3.13(m,2H),1.80(dd,J＝7.2,3.6Hz,3H),1.36–1.20(m,6H).

Example 10

(R) -1- (1-methyl-1H-pyrazol-3-yl) -3- (3-methylmorpholino) -5- (1H-pyrrolo [2,3-b ] pyridin-4-yl) pyrazin-2 (1H) -

Ketones

Step 1: 1-methyl-1H-pyrazol-3-amine (10-a,1g, 10.3mmol) and 40mL of THF (tetrahydrofuran) are added to a 100mL single-neck flask, bromoacetonitrile (1.34g, 11.3mmol) and DIPEA (2.56g, 20.6mmol) are sequentially added, and stirring is carried out at 80 ℃ for 12 hours. After TLC detection reaction is completed, 20mL of water is added to dilute the mother liquor, ethyl acetate is used for extraction for three times, organic phases are combined and washed by saturated salt water, anhydrous sodium sulfate is used for drying, and column chromatography is carried out to obtain 2- ((1-methyl-1H-pyrazol-3-yl) amino) acetonitrile (10-b, 1.1mg, 8.01mmol, 78% yield). MS Calcd: 136; MS Found 137([ M + H ]]⁺)。

Step 2: adding 2- ((1-methyl-1H-pyrazol-3-yl) amino) acetonitrile (10-b, 600mg, 4.4mmol) into a 50mL reaction bottle, adding 30mL of LPCM as a solvent, sequentially adding oxalyl chloride (13.2mmol, 1.6g) and DMF (0.44mmol, 32mg), stirring at 60 ℃ for 12 hours, detecting the reaction by TLC (thin layer chromatography), adding a saturated sodium bicarbonate solution into the reaction liquid after the reaction is cooled, quenching, adjusting the pH to 7, extracting with ethyl acetate and water, retaining an organic phase, washing with a saturated sodium chloride solution, and drying with anhydrous sodium sulfate. The solvent was removed by rotation to give 3, 5-dichloro-1- (1-methyl-1H-pyrazol-3-yl) pyrazin-2 (1H) -one (10-c, 480mg, 1.9mmol, 44% yield). MS Calcd: 244; MS Found 245([ M + H ]]⁺).

And step 3: 3, 5-dichloro-1- (1-methyl-1H-pyrazol-3-yl) pyrazin-2 (1H) -one (10-c, 400mg, 1.63mmol), (R) -3-methylmorpholine (198mg, 1.63mmol) was added to a 50mL bottle in that order96mmol), DIPEA (315mg, 2.44mmol) were added to 30ml NMP as solvent and stirred at 60 ℃ for 3 h. TLC detection reaction is complete, ethyl acetate and water are used for extraction, an organic phase is retained, and after drying and concentration, the organic phase is purified by silica gel column chromatography to obtain (R) -5-chloro-1- (1-methyl-1H-pyrazol-3-yl) -3- (3-methylmorpholino) pyrazine-2 (1H) -ketone (10-d, 430mg, 1.38mmol and 85 percent yield). MS Calcd: 309; MS Found 310([ M + H ]]⁺).

And 4, step 4: taking (R) -5-chloro-1- (1-methyl-1H-pyrazol-3-yl) -3- (3-methylmorpholino) pyrazin-2 (1H) -one (10-d, 60mg,0.2 mmol), 4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrrolo [2, 3-b)]Pyridine (94mg, 0.38mmol), potassium carbonate (78mg, 0.57mmol), and Pd (PPh)₃)₄(21mg, 0.02mmol) was added to a 50mL flask and dioxane/water (8: 1) (3mL) was added, nitrogen was replaced three times, the mixture was heated to 110 ℃ and stirred for 8H, filtered, the filtrate was concentrated and purified by HPLC using plates to give (R) -1- (1-methyl-1H-pyrazol-3-yl) -3- (3-methylmorpholino) -5- (1H-pyrrolo [2,3-b ]]Pyridin-4-yl) pyrazin-2 (1H) -one (10, 20mg,0.05mmol, 27% yield). MS Calcd: 391; MS Found:392([ M + H ]]⁺)。¹H NMR(400MHz,DMSO-d₆)δ11.79(s,1H),8.25(d,J＝5.2Hz,1H),8.18(s,1H),7.85(d,J＝2.4Hz,1H),7.56(t,J＝3.2Hz,1H),7.49(d,J＝5.2Hz,1H),6.81(d,J＝2.4Hz,1H),6.79(dd,J＝3.6,2.0Hz,1H),5.03(d,J＝7.6Hz,1H),4.40(d,J＝13.6Hz,1H),3.97-3.89(m,4H),3.77–3.67(m,2H),3.62-3.56(m,1H),3.44–3.35(m,1H),1.31(d,J＝6.8Hz,3H).

Example 11

(R) -5- (1H-indol-4-yl) -1- (1-methyl-1H-pyrazol-3-yl) -3- (3-methylmorpholino) pyrazin-2 (1H) -one

Step 1: taking (R) -5-chloro-1- (1-methyl-1H-pyrazol-3-yl) -3- (3-methylmorpholino) pyrazin-2 (1H) -one (10-d, 50mg, 0.2mmol), 4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -1H-indole (78mg, 0.32mmol), potassium carbonate (66mg, 0.48mmol), and Pd (PPh)₃)₄(18mg, 0.016mmol) was added to a 50mL flask and added to dioxane/water (8: 1) (3mL), nitrogen was replaced three times, the mixture was warmed to 110 ℃ and stirred for 8H, filtered, concentrated, and the filtrate was purified by HPLC prep to give (R) -5- (1H-indol-4-yl) -1- (1-methyl-1H-pyrazol-3-yl) -3- (3-methylmorpholino) pyrazin-2 (1H) -one (11, 17mg, 0.043mmol, 27% yield). MS Calcd: 390; MS Found:391([ M + H ]]⁺)。¹H NMR(400MHz,DMSO-d₆)δ11.27(s,1H),7.96(s,1H),7.84(d,J＝2.4Hz,1H),7.47–7.32(m,3H),7.15(t,J＝7.6Hz,1H),6.83(d,J＝2.4Hz,1H),6.75(d,J＝2.4Hz,1H),5.03(d,J＝7.6Hz,1H),4.36(d,J＝13.6Hz,1H),3.94-3.90(m,4H),3.77–3.66(m,2H),3.59(td,J＝11.6,2.8Hz,1H),3.44–3.35(m,1H),1.29(d,J＝6.8Hz,3H).

Example 12

(R) -1- (1-methyl-1H-pyrazol-3-yl) -5- (2- (methylamino) -1H-benzo [ d ] imidazol-1-yl) -3- (3-methylmorpholino) pyrazin-2 (1H) -one

Step 1: taking (R) -5-chloro-1- (1-methyl-1H-pyrazol-3-yl) -3- (3-methylmorpholino) pyrazine-2 (1H) -ketone (10-d, 40mg, 0.12mmol), N-methyl-1H-benzo [ d ] benzene]Imidazol-2-amine (28mg, 0.19mmol), cesium carbonate (117mg, 0.36mmol), Pd₂(dba)₃(22mg, 0.024mmol), X-phos (0.048mmol,22mg) was added to a 10mL microwave tube, dioxane (3mL) was added, nitrogen gas was substituted three times, the mixture was stirred at 140 ℃ under microwave conditions for 2 hours, the reaction solution was suction-filtered, the organic phase was retained, the organic phase was concentrated and purified by reverse column chromatography to give (R) -1- (1-methyl-1H-pyrazol-3-yl) -5- (2- (methylamino) -1H-benzo [ d ] n]Imidazol-1-yl) -3- (3-methylmorpholino) pyrazin-2 (1H) -one (12, 5mg, 0.01mmol, 10% yield). MS Calcd: 420; MS Found 421([ M + H ]]⁺)。

Example 13

(R) -1- (1, 3-dimethyl-1H-pyrazol-5-yl) -3- (3-methylmorpholinyl) -5- (1H-pyrrolo [2,3-b ] pyridin-4-yl) pyrazin-2 (1H) -one

Step 1: 5-amino-1, 3-dimethylpyrazole (13-a, 2g, 0.018mol), bromoacetonitrile (2.37g, 0.019mol) were weighed, DIPEA (4.65g, 0.036mol) was added to a 100mL single-neck flask, and about 40mL of anhydrous THF was added as a solvent, and the reaction was stirred at 85 ℃ for 10 hours with TLC detection of only a small amount of starting material remaining. 200-mesh 300-mesh silica gel is added into the reaction liquid for sample mixing, the mixture is decompressed and concentrated to be dry at 40 ℃, and the mixture is separated and purified by column chromatography, and mobile phase DCM, MEOH is 30:1, so as to obtain 2- ((1, 3-dimethyl-1H-pyrazol-5-yl) amino) acetonitrile (13-b, 0.407g, 2.713mmol, 18.43 percent yield). MS Calcd: 150; MS Found 151([ M + H ]]⁺)。

Step 2: weighing 2- ((1, 3-dimethyl-1H-pyrazol-5-yl) amino) acetonitrile (13-b, 230mg, 1.52mmol) into a 50ml single-neck bottle, adding 8ml of dichloromethane for dissolution, dropwise adding oxalyl chloride (959.60mg, 7.616mmol) in an ice water bath, adding 2 drops of DMF after dropwise addition is finished, stirring at room temperature for five minutes, and moving to 60 ℃ for reaction for 6 hours. After the reaction is completed, water and saturated sodium bicarbonate solution are added, then ethyl acetate is used for extraction, the organic phase is dehydrated by anhydrous sodium sulfate and then is separated and purified by column chromatography, and petroleum ether, ethyl acetate is 3:1, so that 3, 5-dichloro-1- (1, 3-dimethyl-1H-pyrazol-5-yl) pyrazine-2 (1H) -ketone (13-c, 143mg, 0.554mmol, 36.47% Yeild) is obtained. MS Calcd: 258; MS Found 259([ M + H ]]⁺)。

And step 3: 3, 5-dichloro-1- (2, 5-dimethyl-2H-pyrazol-3-yl) -1H-pyrazin-2-one (13-c, 134mg, 0.554mmol) was weighed into a 50ml single-neck flask, about 5ml of NMP was added, R-3-methylmorpholine (67.17mg, 0.665mmol) was added, and finally ethyl acetate (107.25mg, 0.831mmol) was added, and reacted at 65 ℃ for three hours. After the reaction is finished, water and ethyl acetate are added for extraction, an organic phase is extracted and washed by water, anhydrous sodium sulfate is used for dewatering, and the mixture is separated and purified by column chromatography, petroleum ether and ethyl acetate are 1:1, so that 5-chloro-1- (2, 5-dimethyl-2H-pyrazol-3-yl) -3- (3-methyl-morpholin-4-yl) -1H-pyrazine-2-ketone (13-d, 70mg, 0.216mmol, 39.10% Yeild) is obtained. MS Calcd: 323; MS Found 324([ M + H ]]⁺)。

And 4, step 4: weighing 5-chloro-1- (2, 5-di)methyl-2H-pyrazol-3-yl) -3- (3-methyl-morpholin-4-yl) -1H-pyrazin-2-one (13-d, 35mg, 0.108mmol), palladium tetratriphenylphosphine (12.52mg, 0.011mmol), potassium carbonate (44.86mg, 0.325mmol), 7-azaindole-4-boronic acid ester (39.66mg, 0.163mmol) in a 25ml round-bottomed flask, about 2ml of 1.4-dioxane and about 0.4ml of tap water were added, then replaced with nitrogen three times, and left to react at 105 ℃ for 8 hours. After the reaction is finished, the target compound is separated and purified by column chromatography, and DCM: MEOH 20:1 is obtained, so that the title compound: (R) -1- (1, 3-dimethyl-1H-pyrazol-5-yl) -3- (3-methylmorpholinyl) -5- (1H-pyrrole [2, 3-b)]Pyridin-4-yl) pyrazin-2 (1H) -one (13, 15mg, 0.037mmol, 34.88% Yeild). MS Calcd: 405; MS Found 406([ M + H ]]⁺)。¹HNMR(400MHz,DMSO-d₆)δ11.73(s,1H),8.21(d,J＝5.2Hz,1H),7.64(s,1H),7.54–7.43(m,2H),6.86(dd,J＝3.6,2.0Hz,1H),6.32(s,1H),4.99(d,J＝7.6Hz,1H),4.43(d,J＝13.6Hz,1H),3.96-3.92(m,2H),3.78–3.67(m,2H),3.60(s,3H),3.43-3.39(m,1H),2.20(s,3H),1.32(d,J＝6.8Hz,3H).

Example 14

(R) -1- (1, 3-dimethyl-1H-pyrazol-5-yl) -5- (1H-indol-4-yl) -3- (3-methylmorpholinyl) pyrazin-2 (1H) -one

Step 1: 5-chloro-1- (2, 5-dimethyl-2H-pyrazol-3-yl) -3- (3-methyl-morpholin-4-yl) -1H-pyrazin-2-one (13-d, 35mg, 0.108mmol), tetratriphenylphosphine palladium (12.52mg, 0.011mmol), potassium carbonate (44.86mg, 0.325mmol), 4-indoleboronic acid pinacol ester (39.60mg, 0.163mmol) were weighed into a 25ml round-bottomed flask, 2ml or so of 1.4-dioxane and 0.4ml or so of tap water were added, then replaced with nitrogen three times, and placed at 105 ℃ for reaction for 8 hours. After the reaction, the target compound was separated and purified by column chromatography, and petroleum ether ethyl acetate 2:1 to give (R) -1- (1, 3-dimethyl-1H-pyrazol-5-yl) -5- (1H-indol-4-yl) -3- (3-methylmorpholinyl) pyrazin-2 (1H) -one (14, 17mg, 0.042mmol, 39.53% Yeild). MS Calcd 404; MS Found 405([ M + H ]]⁺)。¹H NMR(400MHz,DMSO-d₆)δ11.23(s,1H),7.42–7.36(m,3H),7.33(s,1H),7.12(t,J＝7.6Hz,1H),6.77(t,J＝2.4Hz,1H),6.32(s,1H),4.99(d,J＝8.6Hz,1H),4.41(d,J＝13.6Hz,1H),3.92(dd,J＝11.6,3.2Hz,1H),3.76–3.65(m,2H),3.60(s,3H),3.56(dd,J＝11.6,3.2Hz,1H),3.41–3.36(m,1H),2.19(s,3H),1.31(d,J＝6.8Hz,3H).

Example 15

((R) -5- (1H-indol-4-yl) -1- (1-methyl-1H-pyrazol-4-yl) -3- (3-methylmorpholino) pyrazin-2 (1H) -one

Step 1: 1-methyl-1H-pyrazol-4-amine (15-a, 1.0g, 10.3mmol), N-diisopropylethylamine (2.66g,20.6mmol) and bromoacetonitrile (1.36g,11.34mmol) were sequentially added to a tetrahydrofuran (15mL) solvent, and the reaction solution was stirred for 5 hours while being heated to 80 ℃. TLC (thin layer chromatography) for monitoring the completion of the reaction, cooling the reaction solution to room temperature, concentrating under reduced pressure, adding water (30mL) into the reaction solution, extracting with ethyl acetate (50mL), washing with saturated saline, drying with anhydrous sodium sulfate, and concentrating under reduced pressure to obtain 2- ((1 methyl-1H-pyrazol-4-yl) amino) acetonitrile (15-b,460mg,3.38mmol, 32% yield), wherein the product is directly used in the next step without purification. MS Calcd: 136.07; 137.15([ M + H ]) for MS Found]⁺).

And 2, step: 2- ((1-methyl-1H-pyrazol-4-yl) amino) acetonitrile (15-b,460mg,3.38mmol) and oxalyl chloride (468mg,3.72mmol) were sequentially added to a dichloromethane solvent (20mL), then one drop of DMF was added, vacuum nitrogen was applied to replace the solution for 3 times, and the solution was left to react at 45 ℃ for 10 hours. The reaction was monitored by TLC for completion, the reaction was concentrated and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate ═ 3:1) to give the product 3, 5-dichloro-1- (1-methyl-1H-pyrazol-4-yl) pyrazin-2 (1H) -one (15-c, 70mg,0.28mmol, 8% yield). 243.99 for MS Calcd; 244.17([ M + H ]) for MS Found]⁺).

And step 3: 3, 5-dichloro-1- (1-methyl-1H-pyrazol-4-yl) pyrazin-2 (1H) -one (15-c, 70mg,0.28mmol), (R) -3-methylmorpholine (32mg,0.32mmol) and N, N-diisopropylethylamine (75mg,0.58mmol) were sequentially added to an acetonitrile solution (2ml), and vacuum was applied to replace with nitrogen gasAfter stirring 3 times at 85 ℃ for 5 hours, the reaction was monitored by TLC for completion, the reaction was cooled to room temperature, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate: 3:1) to give the product (R) -5-chloro-1- (1-methyl-1H-pyrazol-4-yl) -3- (3-methylmorpholino) pyrazin-2 (1H) -one (15-d, 60mg,0.19mmol, 67% yield). 309.10 for MS Calcd; 310.12([ M + H ]) for MS Found]⁺).

And 4, step 4: (R) -5-chloro-1- (1-methyl-1H-pyrazol-4-yl) -3- (3-methylmorpholino) pyrazin-2 (1H) -one (15-d, 30mg,0.1mmol), 4-indolboronic acid pinacol ester (48mg,0.2mmol), potassium carbonate (41mg,0.3mmol), and tetrakis (triphenylphosphine) palladium (12mg,0.01mmol) were sequentially added to 2mL of a dioxane/water (6:1) mixed solvent, vacuum was applied, nitrogen was replaced 3 times, and the mixture was stirred at 110 ℃ for 8 hours. The reaction was monitored by TLC for completion, the reaction was concentrated completely and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate ═ 1:1) to give the title compound: (R) -5- (1H-indol-4-yl) -1- (1-methyl-1H-pyrazol-4-yl) -3- (3-methylmorpholino) pyrazin-2 (1H) -one (15, 30mg,0.07mmol, 77% yield). 390.18 for MS Calcd; 391.19([ M + H ]) for MS Found]⁺).¹H NMR(400MHz,DMSO-d₆)δ11.22(s,1H),8.42(s,1H),8.00(s,1H),7.56–7.53(m,2H),7.41–7.38(m,2H),7.13(t,J＝7.6Hz,1H),6.84–6.78(m,1H),5.05(d,J＝7.6Hz,1H),4.35(d,J＝12.6Hz,1H),3.90(s,3H),3.74–3.55(m,4H),3.39-3.35(m,1H),1.28(d,J＝6.8Hz,3H).

Example 16

(R) -1- (1-methyl-1H-pyrazol-4-yl) -3- (3-methylmorpholino) -5- (1H-pyrrolo [2,3-b ] pyridin-4-yl) pyrazin-2 (1H) -one

Step 1: (R) -5-chloro-1- (1-methyl-1H-pyrazol-4-yl) -3- (3-methylmorpholino) pyrazin-2 (1H) -one (15-d, 30mg,0.1mmol), 7-azaindole-4-boronic acid ester (49mg,0.2mmol), potassium carbonate (41mg,0.3mmol), and tetrakis (triphenylphosphine) palladium (12mg,0.01mmol) were sequentially added to 2mL of a dioxane/water (6:1) mixed solvent, vacuum was applied, nitrogen was replaced 3 times, and the mixture was stirred at 110 ℃ for 8 hours.The reaction was monitored by TLC for completion, the reaction was concentrated completely and the residue was purified by silica gel column chromatography (ethyl acetate) to afford the title compound: (R) -1- (1-methyl-1H-pyrazol-4-yl) -3- (3-methylmorpholino) -5- (1H-pyrrolo [2, 3-b)]Pyridin-4-yl) pyrazin-2 (1H) -one (16, 10mg,0.02mmol, 25% yield). 391.18 for MS Calcd; 392.15([ M + H ]) for MS Found]⁺).¹H NMR(400MHz,DMSO-d₆)δ12.52(s,1H),9.22(s,1H),9.03(d,J＝5.2Hz,1H),8.82(s,1H),8.66(s,1H),8.32-8.29(m,2H),7.70(dd,J＝3.2,2.0Hz,1H),5.85(d,J＝7.6Hz,1H),5.18(d,J＝13.6Hz,1H),4.77–4.71(m,4H),4.56–4.46(m,2H),4.42-4.35(m,1H),4.24–4.16(m,1H),2.09(d,J＝6.8Hz,3H).

Example 17

(R) -5- (1H-indol-4-yl) -3- (3-methylmorpholino) -1- (tetrahydro-2H-pyran-4-yl) pyrazin-2 (1H) -one

Step 1: 4-Aminotetrahydropyran hydrochloride (17-a, 1.41g, 10.3mmol), N-diisopropylethylamine (2.66g,20.6mmol) and bromoacetonitrile (1.36g,11.34mmol) were sequentially added to a tetrahydrofuran (15mL) solvent, and the reaction solution was heated to 80 ℃ and stirred for 5 hours. TLC to monitor the completion of the reaction, the reaction solution was cooled to room temperature, concentrated under reduced pressure, added with water (30mL), extracted with ethyl acetate (50mL), washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the product 2- ((tetrahydro-2H-pyran-4-yl) amino) acetonitrile (17-b,220mg,1.57mmol, 15% yield), which was used in the next step without purification. 140.09 for MS Calcd; 141.12([ M + H ]) for MS Found]⁺).

And 2, step: 2- ((tetrahydro-2H-pyran-4-yl) amino) acetonitrile (17-b,220mg,1.57mmol), oxalyl chloride (242mg,1.72mmol) were sequentially added to a dichloromethane solvent (10mL), then a drop of DMF was added, vacuum was applied and nitrogen was replaced 3 times, and the mixture was left to react at 45 ℃ for 10H. The reaction was monitored by TLC for completion, the reaction was concentrated and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate ═ 3:1) to give 3, 5-dichloro-1- (tetrahydro-2H-pyran-4-yl) pyrazin-2 (1H) -one (17-c, 60mg, 0).24mmol,15％yield)。MS Calcd:249.09；MS Found:250.12([M+H]⁺).

And step 3: 3, 5-dichloro-1- (tetrahydro-2H-pyran-4-yl) pyrazin-2 (1H) -one (17-c, 60mg,0.24mmol), (R) -3-methylmorpholine (27mg,0.27mmol) and N, N-diisopropylethylamine (62mg,0.48mmol) were added in this order to an acetonitrile solution (2ml), vacuum-pumped under nitrogen substitution 3 times, stirred at 85 ℃ for 5 hours, TLC monitored for completion of the reaction, the reaction solution was cooled to room temperature, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate ═ 3:1) to give a compound: (R) -5-chloro-3- (3-methylmorpholino) -1- (tetrahydro-2H-pyran-4-yl) pyrazin-2 (1H) -one (17-d, 70mg,0.22mmol, 93% yield). 313.12 for MS Calcd; 314.17([ M + H ]) for MS Found]⁺).

And 4, step 4: (R) -5-chloro-3- (3-methylmorpholino) -1- (tetrahydro-2H-pyran-4-yl) pyrazin-2 (1H) -one (17-d, 70mg,0.22mmol), pinacol 4-indoleborate (107mg,0.44mmol), potassium carbonate (91mg,0.66mmol), and tetrakis (triphenylphosphine) palladium (25mg,0.022mmol) were sequentially added to 2mL of a dioxane/water (6:1) mixed solvent, vacuum was applied, nitrogen was replaced 3 times, and the mixture was stirred at 110 ℃ for 8H. The reaction was monitored by TLC for completion, the reaction was concentrated completely and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate ═ 1:1) to give the product (R) -5- (1H-indol-4-yl) -3- (3-methylmorpholino) -1- (tetrahydro-2H-pyran-4-yl) pyrazin-2 (1H) -one (17, 20mg,0.05mmol, 23% yield). 394.20 for MS Calcd; 395.18([ M + H ]) for MS Found]⁺).

Example 18

(R) -1- (1, 4-dimethyl-1H-pyrazol-3-yl) -3- (3-methylmorpholino) -5- (1H-pyrrolo [2,3-b ] pyridin-4-yl) pyrazin-2 (1H) -one

Step 1:1, 4-dimethyl-1H-pyrazol-3-amine (18-a,750mg, 6.7mmol) is added into a 100mL single-neck bottle, 10mL DCM is used as a solvent, Boc anhydride (2.9g, 13.5mmol) and triethylamine (2.0g, 20mmol) are sequentially added, a small amount of DMAP is added for catalytic reaction, and the mixture is stirred at 60 ℃ for 12 hours. After the TLC detection reaction is completed, directly concentratingThe reaction solution was condensed and purified by forward column chromatography to obtain 1, 4-dimethyl-1H-pyrazole-3-di-Boc amine (18-b,1g, 3.2mmol, 50% yield). 311.38 for MS Calcd; 312.38([ M + H ]) for MS Found]⁺)。

Step 2: adding 1, 4-dimethyl-1H-pyrazole-3-di-Boc amine (18-b,900mg, 2.8mmol) into a 50mL reaction bottle, adding 20mL methanol as a solvent, adding 10mL of 1N sodium hydroxide solution, stirring at 50 ℃ for 3H, after TLC detection reaction is completed, adding dilute hydrochloric acid into a reaction solution to adjust the pH to 7 after the reaction is cooled, extracting with ethyl acetate and water, retaining an organic phase, washing with a saturated sodium chloride solution, and drying with anhydrous sodium sulfate. The solvent was removed by rotation to give (1, 4-dimethyl-1H-pyrazol-3-yl) carbamic acid tert-butyl ester (18-c,540mg, 2.52mmol, 90% yield). 211.27 for MS Calcd; 212.27([ M + H ]) for MS Found]⁺)。

And step 3: adding (1, 4-dimethyl-1H-pyrazol-3-yl) carbamic acid tert-butyl ester (18-c,650mg, 3.06mmol) into a 50mL bottle, adding 20mL of DMF as a solvent, adding NaH (613mg, 15mmol) at room temperature, stirring for 1H, adding bromoacetonitrile (714mg, 6mmol) into a reaction system, reacting for 2H at room temperature, detecting complete reaction by TLC, extracting with ethyl acetate and water, retaining an organic phase, drying, concentrating, and purifying by forward column chromatography to obtain (cyanomethyl) (1, 4-dimethyl-1H-pyrazol-3-yl) carbamic acid tert-butyl ester (18-d,580mg, 2.01mmol, 67% yield). 250.30 for MS Calcd; 251.30([ M + H ]) for MS Found]⁺). And 4, step 4: taking tert-butyl (cyanomethyl) (1, 4-dimethyl-1H-pyrazol-3-yl) carbamate (18-d,580mg, 2.01mmol) and adding into a 50mL bottle, adding 5mL DCM and 3mL TFA as solvents, reacting at room temperature for 3H, adjusting the pH to be neutral by using a sodium bicarbonate solution after the reaction is finished, and purifying by using forward column chromatography to obtain 2- ((1, 4-dimethyl-1H-pyrazol-3-yl) amino) acetonitrile (18-e,300mg, 1.98mmol, 90% yield). 150.19 for MS Calcd; MS Found 151.19([ M + H ]]⁺)。

Step 5, taking 2- ((1, 4-dimethyl-1H-pyrazol-3-yl) amino) acetonitrile (18-e,300mg, 1.98mmol) in a 100mL bottle, adding DCM (DCM) as a solvent, adding oxalyl chloride (2.4g, 19.8mmol), adding 0.3mL of DMF for catalytic reaction, reacting at 60 ℃ for 12H, neutralizing the reaction solution with saturated sodium bicarbonate solution after the reaction is finished, and using acetic acid to neutralize the reaction solutionEthyl ester extraction and water washing three times, concentrating the organic phase and then obtaining 3, 5-dichloro-1- (1, 4-dimethyl-1H-pyrazol-3-yl) pyrazine-2 (1H) -ketone (18-f,80mg, 0.37mmol, 15% yield) by column chromatography. 259.09 for MS Calcd; 260.09([ M + H ]) for MS Found]⁺)。

Step 6: taking 3, 5-dichloro-1- (1, 4-dimethyl-1H-pyrazol-3-yl) pyrazine-2 (1H) -ketone (18-f,80mg, 0.37mmol) in a 50mL bottle, adding NMP as solvent, adding (R) -3-methylmorpholine (34mg, 0.34mmol) and DIPEA (77mg,0.6mmol), reacting at 60 deg.C for 3h, after the reaction is completed, extracted with ethyl acetate and washed three times with water, the organic phase was concentrated and purified by column chromatography to give (R) -5-chloro-1- (1, 4-dimethyl-1H-pyrazol-3-yl) -3- (3-methylmorpholino) pyrazin-2 (1H) -one (18-g,55mg,0.2mmol, 56% yield). 323.78 for MS Calcd; 324.78([ M + H ]) for MS Found]⁺)。

And 7: taking (R) -5-chloro-1- (1, 4-dimethyl-1H-pyrazol-3-yl) -3- (3-methylmorpholino) pyrazin-2 (1H) -one (18-g,23mg,0.07 mmol) and adding 4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrrolo [2,3-b ] to a 25mL bottle]Pyridine (26mg, 0.1mmol), potassium carbonate (30mg, 0.21mmol), and Pd (pph)₃)₄(16.7mg, 0.014mmol) and 3ml dioxane/water (5: 1) as solvent, nitrogen is added for three times, the temperature is raised to 110 ℃, stirring is carried out for 8H, and after the reaction is finished, (R) -1- (1, 4-dimethyl-1H-pyrazol-3-yl) -3- (3-methylmorpholino) -5- (1H-pyrrolo [2, 3-b) is obtained by reverse column chromatography]Pyridin-4-yl) pyrazin-2 (1H) -one (18,8mg, 0.02mmol, 28% yield). 405.42 for MS Calcd; 406.42([ M + H ]) for MS Found]⁺)。

Example 19

(R) -1- (3, 5-dimethyl-1- (piperidin-4-yl) -1H-pyrazol-4-yl) -3- (3-methylmorpholino) -5- (1H-pyrrolo [2,3-b ] pyridin-4-yl) pyrazin-2 (1H) -one

Step 1: adding 4-hydroxypiperidine (19-a,5g, 49mmol) into a 100mL single-neck flask, adding 40mL EDCM as solvent, adding triethylamine (7.4g, 73mmol) under ice bath, stirring for 5min, addingBenzyl chloroformate (9.2g, 54.4mmol) was added and allowed to warm to room temperature and stir for 3 h. After TLC detection reaction is completed, ethyl acetate and water are used for extracting reaction liquid, organic phase is concentrated and dried, and then 4-hydroxypiperidine-1-carboxylic acid benzyl ester (19-b,6g, 25.4mmol, 54% yield) is obtained by column chromatography purification. 235.28 for MS Calcd; 236.28([ M + H ]) for MS Found]⁺)。

And 2, step: benzyl 4-hydroxypiperidine-1-carboxylate (19-b,2g, 8.5mmol) was charged into a 100mL reaction flask, triethylamine (1.1g, 11.05mmol) was added under ice-bath, and after stirring for 5min, MsCl (1.06g, 9.3mmol) was added, and the reaction was stirred at 0 ℃ for 3 h. After the TLC detection reaction was complete, the reaction solution was extracted with ethyl acetate and water, the organic phase was washed three times with water, twice with saturated sodium chloride solution and concentrated to give benzyl 4- ((methanesulfonyl) oxy) piperidine-1-carboxylate (19-c,2.6g, 8.2mmol, 92% yield). 313.37 for MS Calcd; 314.38([ M + H ]) for MS Found]⁺)。

And step 3: in a 50mL bottle was added benzyl 4- ((methanesulfonyl) oxy) piperidine-1-carboxylate (19-c,2.6g, 8.3mmol), 3, 5-dimethyl-4-nitro-1H-pyrazole (800mg, 5.67mmol), cesium carbonate (5.5g, 17mmol) in sequence, 30mL of DMMF as solvent, and stirred at 100 ℃ for 6H. TLC detects the reaction completely, uses ethyl acetate and water to extract, reserves organic phase, dries and concentrates, and then uses column chromatography to purify to obtain 4- (3, 5-dimethyl-4-nitro-1H-pyrazol-1-yl) piperidine-1-benzyl formate (19-d,2g, 5.5mmol, 90% yield). 358.40 for MS Calcd; 359.40([ M + H ]) for MS Found]⁺)。

And 4, step 4: taking 4- (3, 5-dimethyl-4-nitro-1H-pyrazol-1-yl) piperidine-1-benzyl formate (19-d,2g, 5.5mmol) in a 100mL bottle, adding Fe (1.5g, 27mmol) and NH₄Cl (2.97g, 55mmol), using ethanol and water as solvent (5:1, 40mL), the reaction was carried out at 90 ℃ for 3H, after completion of the reaction, the reaction solution was diluted with ethyl acetate, then filtered to remove solid impurities, the liquid phase was extracted with ethyl acetate and washed with water three times, and the organic phase was concentrated to give benzyl 4- (4-amino-3, 5-dimethyl-1H-pyrazol-1-yl) piperidine-1-carboxylate (19-e,1.5g, 4.5mmol, 83% yield). 328.42 for MS Calcd; 329.42([ M + H ]) for MS Found]⁺). And 5: taking 4- (4-amino-3, 5-dimethyl-1H-pyrazol-1-yl) piperidine-1-benzyl formate (19-e,1.4g and 4.2mmol) in a 100mL bottle,bromoacetonitrile (558mg, 4.6mmol), DIPEA (1g, 8.4mmol) were added, the reaction was carried out at 90 ℃ for 4H using 30mL acetonitrile as solvent, after completion of the reaction, extraction with ethyl acetate and washing with water three times, the organic phase was concentrated and column chromatography was carried out to give benzyl 4- (4- ((cyanomethyl) amino) -3, 5-dimethyl-1H-pyrazol-1-yl) piperidine-1-carboxylate (19-f,1.5g, 4.01mmol, 95% yield). 367.45 for MS Calcd; 368.45([ M + H ]) for MS Found]⁺)。

Step 6: putting 4- (4- ((cyanomethyl) amino) -3, 5-dimethyl-1H-pyrazol-1-yl) piperidine-1-benzyl formate (19-f,1.5g and 4.01mmol) into a 100mL bottle, adding DCM (DCM) as a solvent, adding oxalyl chloride (5.6g and 46mmol), adding 0.5mL of DMF (diethyl formamide) for catalytic reaction, reacting at 60 ℃ for 12H, neutralizing the reaction solution with saturated sodium bicarbonate solution after the reaction is finished, extracting with ethyl acetate and washing with water for three times, concentrating an organic phase, and performing column chromatography to obtain 4- (4- (3, 5-dichloro-2-oxa-pyrazine-1 (2H) -yl) -3, 5-dimethyl-1H-pyrazol-1-yl) piperidine-1-benzyl formate (19-g,400mg, 0.84mmol, 20% yield). 475.12 for MS Calcd; 476.12([ M + H ]) for MS Found]⁺)。

And 7: taking benzyl 4- (4- (3, 5-dichloro-2-oxopyrazin-1 (2H) -yl) -3, 5-dimethyl-1H-pyrazol-1-yl) piperidine-1-carboxylate (19-g,400mg, 0.84mmol) in a 100mL bottle, adding NMP as a solvent, adding (R) -3-methylmorpholine (127mg, 1.26mmol) and DIPEA (216mg,1.68mmol), reacting at 60 ℃ for 3H, after the reaction is completed, extracting with ethyl acetate and washing with water for three times, concentrating an organic phase, and performing column chromatography to obtain (R) -4- (4- (5-chloro-3- (3-methylmorpholino) -2-oxopyrazin-1 (2H) -yl) -3, benzyl 5-dimethyl-1H-pyrazol-1-yl) piperidine-1-carboxylate (19-H,180mg, 0.33mmol, 39% yield). 541.05 for MS Calcd; 542.05([ M + H ]) for MS Found]⁺)。

And 8: (R) -benzyl 4- (4- (5-chloro-3- (3-methylmorpholino) -2-oxopyrazin-1 (2H) -yl) -3, 5-dimethyl-1H-pyrazol-1-yl) piperidine-1-carboxylate (19-H,60mg,0.11mmol) was taken in a 25mL bottle and 4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrrolo [2,3-b ] borane was added]Pyridine (40mg, 0.16mmol), potassium carbonate (45mg,0.33mmol), and Pd (pph)₃)₄(12.7mg, 0.011mmol), and 3ml dioxane/water (5: 1) as solvent, and nitrogen was substituted three timesHeating to 110 ℃, stirring for 8H, and obtaining (R) -4- (3, 5-dimethyl-4- (3- (3-methylmorpholino) -2-oxo-5- (1H-pyrrolo [2,3-b ] by reverse column chromatography after the reaction is finished]Pyridin-4-yl) pyrazin-1 (2H) -yl) -1H-pyrazol-1-yl) piperidine-1-carboxylic acid benzyl ester (19-i,20mg, 0.032mmol, 29% yield). 622.73 for MS Calcd; 623.73([ M + H ]) for MS Found]⁺)。

And step 9: taking (R) -4- (3, 5-dimethyl-4- (3- (3-methylmorpholino) -2-oxo-5- (1H-pyrrolo [2, 3-b)]Pyridine-4-yl) pyrazine-1 (2H) -1H-pyrazole-1-yl piperidine-1-benzyl formate (19-i,20mg, 0.032mol) is placed in a 25mL bottle, 1mL acetic acid and 1mL hydrobromic acid aqueous solution are added as solvents, the reaction is carried out at 50 ℃ for 2H, and after the reaction is finished, (R) -1- (3, 5-dimethyl-1- (piperidine-4-yl) -1H-pyrazole-4-yl) -3- (3-methylmorpholino) -5- (1H-pyrrolo [2,3-b ] is obtained by reverse column chromatography]Pyridin-4-yl) pyrazin-2 (1H) -one (19,15mg,0.03 mmol, 95% yield). 488.60 for MS Calcd; 489.60([ M + H ]) for MS Found]⁺)。¹H NMR(400MHz,DMSO-d₆)δ12.01(s,1H),8.26(d,J＝5.2Hz,1H),7.73(s,1H),7.60–7.50(m,2H),6.98–6.91(m,1H),5.03(s,1H),3.99–3.90(m,1H),3.77–3.66(m,2H),3.64-3.56(m,1H),3.49–3.34(m,1H),3.16-3.06(m,6H),2.29–2.14(m,6H),2.10–1.96(m,5H),1.30(dd,J＝6.8Hz,3H).

Example 20

N-methyl-2- (3- ((R) -3-methylmorpholino) -2-oxo-5- (1H-pyrrolo [2,3-b ] pyridin-4-yl) pyrazin-1 (2H) -ylpropanamide

Step 1: in a 100mL single-neck flask was added 3, 5-dibromopyrazine-2 (1H) -one (4-a,1g, 3.9mmol), 10mL of DMF was added as a solvent, and then ethyl 2-bromopropionate (1g, 5.9mmol), cesium carbonate (2.5g, 7.8mmol) and stirred at 60 ℃ for 3H. After TLC detection reaction is completed, the reaction solution is extracted by ethyl acetate, and the organic phase is concentrated and purified by forward column chromatography to obtain ethyl 2- (3, 5-dibromo-2-oxopyrazin-1 (2H) -yl) propionate (20-a, 741mg, 2.23mmol, 57% yield). 354.00 for MS Calcd; 355.00([ M + H ]) for MS Found]⁺)。

Step 2: adding ethyl 2- (3, 5-dibromo-2-oxopyrazin-1 (2H) -yl) propionate (20-a, 600mg, 1.69mmol) into a 50mL reaction bottle, adding 20mL acetonitrile serving as a solvent, adding R-3-methylmorpholine (256mg, 2.54mmol) and DIPEA (654mg, 5.07mmol), reacting at 85 ℃ for 4H, detecting by TLC (thin layer chromatography), directly concentrating the reaction solution, and purifying by column chromatography to obtain ethyl 2- (5-bromo-3- ((R) -3-methylmorpholino) -2-oxopyrazin-1 (2H) -yl) propionate (20-b, 680mg, 1.58mmol, 94% yield). 374.24 for MS Calcd; 375.24([ M + H ]) for MS Found]⁺)。

And step 3: a50 mL bottle was charged with ethyl 2- (5-bromo-3- ((R) -3-methylmorpholino) -2-oxopyrazin-1 (2H) -yl) propionate (20-b, 680mg, 1.8mmol), 20mL methanol and 10mL water as solvents, NaOH (216mg, 5.4mmol) was added at room temperature and stirred for 2H, TLC checked for completion, the pH was adjusted to neutral with HCl, the organic phase was extracted with ethyl acetate and water, dried and concentrated to give 2- (5-bromo-3- ((R) -3-methylmorpholino) -2-oxopyrazin-1 (2H) -yl) propionic acid (20-c, 580mg, 1.7mmol, 90% yield). 346.18 for MS Calcd; 347.18([ M + H ]) for MS Found]⁺)。

And 4, step 4: 2- (5-bromo-3- ((R) -3-methylmorpholino) -2-oxopyrazin-1 (2H) -yl) propionic acid (20-c, 150mg, 0.42mmol) was dissolved in DCM and added to a 50mL vial, HOBT (69mg, 0.51mmol) and EDCI (96mg, 0.51mmol), TEA (127mg, 1.26mmol), methylamine hydrochloride (56mg, 0.84mmol) were added, the reaction was allowed to proceed at room temperature for 3H, and after completion of the reaction, the reaction mixture was concentrated and purified by forward column chromatography to give 2- (5-bromo-3- ((R) -3-methylmorpholino) -2-oxopyrazin-1 (2H) -yl) -N-methylpropanamide (20-d, 53mg, 0.147mmol, 35% yield. 359.22 for MS Calcd; 359.22([ M + H ]) for MS Found]⁺)。

Step 5 taking 2- (5-bromo-3- ((R) -3-methylmorpholino) -2-oxopyrazin-1 (2H) -yl) -N-methylpropanamide (20-d, 53mg, 0.147mmol) in a 25mL bottle, add 4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrrolo [2,3-b ] boron]Pyridine (54mg, 0.22mmol), cesium carbonate (143mg, 0.44mmol), and Pd (dppf) Cl₂(10mg, 0.014mmol), and 3ml dioxane/water (5: 1) as solvent, replacing with nitrogen gas for three times, heating to 110 deg.C, stirring for 8 hrAfter the reaction is finished, N-methyl-2- (3- ((R) -3-methylmorpholino) -2-oxo-5- (1H-pyrrolo [2, 3-b) is obtained by reverse column chromatography]Pyridin-4-yl) pyrazin-1 (2H) -ylpropanamide (20, 23mg, 0.058mmol, 40% yield). 396.45 for MS Calcd; 397.45([ M + H ]) for MS Found]⁺).¹H NMR(400MHz,DMSO-d₆)δ11.74(s,1H),8.27-8.21(m,2H),7.79(s,0.5H),7.76(s,0.5H),7.53(d,J＝3.2Hz,1H),7.46(d,J＝5.2,0.5H),7.45(d,J＝5.2Hz,0.5H),6.83-6.81(m,1H),5.41-5.34(m,1H),5.02-4.94(m,1H),4.43-4.31(m,1H),3.94-3.89(m,1H),3.76–3.65(m,2H),3.59-3.53(m,1H),3.39-3.29(m,1H),2.62(t,J＝4.4Hz,3H),1.58-1.54(m,3H),1.29-1.23(m,3H).

Example 21

(R) -3- (3-methylmorpholinyl) -1- (1-methylpiperidin-4-yl) -5- (1H-pyrrolo [2,3-b ] pyridin-4-yl) pyrazin-2 (1H) -one

Step 1: 1-Boc-4-aminopiperidine (21-a,1.5g, 7.489mmol) and bromoacetonitrile (898.37mg, 7.489mmol) were weighed into a 100ml single-neck flask, acetonitrile (40ml) was added, DIPEA (1.161g, 8.987mmol) was added thereto with stirring at room temperature, and the reaction was carried out at room temperature for 4 hours. The reaction was monitored by TLC for completion, and the reaction mixture was stirred with 100-200 mesh silica gel and purified by column chromatography (petroleum ether: ethyl acetate: 1) to give tert-butyl 4- ((cyanomethyl) amino) piperidine-1-carboxylate (21-b, 1.33g, 5.561mmol, 74.71% yeild).

Step 2: weighing tert-butyl 4- ((cyanomethyl) amino) piperidine-1-carboxylate (21-b, 1.1g, 4.602mmol) into a 50ml single-neck bottle, adding dichloromethane (25ml), slowly dropwise adding oxalyl chloride (1.740g, 13.807mmol) under an ice bath, adding 3 drops of DMF after dropwise adding, then removing the ice bath, and moving to 50 ℃ for reaction for 8 hours after the reaction system is returned to room temperature. TLC monitored the reaction was complete, the reaction was transferred to an ice bath, water and saturated sodium bicarbonate solution were slowly added dropwise, finally extracted with ethyl acetate, the organic phase was concentrated to dryness under reduced pressure, and purified by plate chromatography (petroleum ether: ethyl acetate 1:1) to give intermediate tert-butyl 4- (3, 5-dichloro-2-oxopyrazin-1 (2H) -yl) piperidine-1-carboxylate (21-c, 180mg, 0.518mmol, 11.25% yield).

And step 3: tert-butyl 4- (3, 5-dichloro-2-oxopyrazin-1 (2H) -yl) piperidine-1-carboxylate (21-c, 180mg, 0.518mmol), (R) -3-methylmorpholine (62.68mg, 0.620mmol) was weighed into a 50ml single-neck flask, acetonitrile (3ml) was added, DIPEA (100.08mg, 0.775mmol) was added with stirring at room temperature, and the flask was transferred to 85 ℃ and reacted for 3 hours. The reaction was monitored by TLC, and the reaction mixture was concentrated to dryness under reduced pressure and purified by plate chromatography (petroleum ether: ethyl acetate: 1) to give the target intermediate (R) -tert-butyl 4- (5-chloro-3- (3-methylmorpholinyl) -2-oxopyrazin-1 (2H) -yl) piperidine-1-carboxylate (21-d, 198mg,0.480mmol, 95.95% yeild). 412.19 for MS Calcd; 413.21([ M + H ]) for MS Found]⁺)。

And 4, step 4: tert-butyl (R) -4- (5-chloro-3- (3-methylmorpholinyl) -2-oxopyrazin-1 (2H) -yl) piperidine-1-carboxylate (21-d, 198mg,0.480mmol) was weighed into a 25ml single-neck flask, dichloromethane (2ml) and trifluoroacetic acid (0.5ml) were added, and the mixture was stirred at room temperature for 2 hours. TLC monitored the reaction was complete and the reaction was concentrated to dryness under reduced pressure to give intermediate (R) -5-chloro-3- (3-methylmorpholinyl) -1- (piperidin-4-yl) pyrazin-2 (1H) -one (21-e, 149mg, 0.477mmol, 90% yeild). 312.14 for MS Calcd; 313.12([ M + H ]) for MS Found]⁺)。

And 5: (R) -5-chloro-3- (3-methylmorpholinyl) -1- (piperidin-4-yl) pyrazin-2 (1H) -one (21-e, 75mg, 0.240mmol) was weighed into a 25ml single-necked flask, THF (2ml) was added, then an aqueous formaldehyde solution (35% -40%, 100.96mg, 1.346mmol) was added, after stirring for three minutes, sodium triacetoxyborohydride (101mg, 0.48mmol) was added, and reaction was carried out at room temperature for 1 hour. TLC was used to monitor the completion of the reaction, and the reaction mixture was concentrated under reduced pressure to dryness to give intermediate (R) -5-chloro-3- (3-methylmorpholinyl) -1- (1-methylpiperidin-4-yl) pyrazin-2 (1H) -one (21-f, 100mg, 0.236mmol, 73.98% yield). 426.15 for MS Calcd; 313.12([ M + H ]) for MS Found]⁺)。

Step 6: (R) -5-chloro-3- (3-methylmorpholinyl) -1- (1-methylpiperidin-4-yl) pyrazin-2 (1H) -one (21-f, 50mg, 0.152mmol), 7-azaindole-4-boronic acid ester (55.96mg, 0.229mmol), Pd (pph) were weighed out₃)₄(17.32mg, 0.015mmol), potassium carbonate (73.85mg, 0.535mmol) in a 25ml single-necked bottle,1, 4-dioxane (2mL) and water (0.5mL) were added, the mixture was purged with nitrogen three times, and the reaction was carried out at 110 ℃ for 8 hours. TLC monitored the reaction was complete, cooled to room temperature, concentrated to dryness under reduced pressure, and purified by plate chromatography (dichloromethane: methanol 15:1) to afford the title compound: (R) -3- (3-methylmorpholinyl) -1- (1-methylpiperidin-4-yl) -5- (1H-pyrrolo [2, 3-b)]Pyridin-4-yl) pyrazin-2 (1H) -one (21, 14mg, 0.034mmol, 22.58% yeild). 408.23 for MS Calcd; 313.12([ M + H ]) for MS Found]⁺)。¹H NMR(400MHz,DMSO-d₆)δ11.71(s,1H),8.21(d,J＝5.2Hz,1H),7.71(s,1H),7.53–7.46(m,2H),6.82(dd,J＝3.6,2.0Hz,1H),5.02(brs,1H),4.65(brs,1H),4.35(d,J＝13.6Hz,1H),3.92(d,J＝9.6Hz,1H),3.74–3.64(m,2H),3.56(td,J＝11.6,2.8Hz,1H),2.92(d,J＝8.4Hz,2H),2.68–2.66(m,1H),2.34–2.32(m,1H),2.22(s,3H),2.08–1.79(m,5H),1.26(d,J＝6.8Hz,3H).

Example 22

(R) -1- (1- (cyclopropylformyl) piperidin-4-yl) -3- (3-methylmorpholinyl) -5- (1H-pyrrolo [2,3-b ] pyridin-4-yl) pyrazin

-2(1H) -one

Step 1: (R) -5-chloro-3- (3-methylmorpholinyl) -1- (piperidin-4-yl) pyrazin-2 (1H) -one (21-f, 75mg, 0.240mmol) was weighed into a 25ml single-necked flask, DCM (2ml) was added, triethylamine (97.14mg, 0.96mmol) was then added, and after stirring for three minutes, cyclopropanecarbonyl chloride (50.17mg, 0.48mmol) was added and the reaction was carried out at room temperature for 1 hour. TLC monitored the reaction was complete, quenched with water, extracted with ethyl acetate, concentrated to dryness under reduced pressure, and purified by plate chromatography (DCM: MEOH ═ 20:1) to give intermediate (R) -5-chloro-1- (1- (cyclopropylformyl) piperidin-4-yl) -3- (3-methylmorpholinyl) pyrazin-2 (1H) -one (22-a, 52mg, 0.136mmol, 44.44% yield). 380.16 for MS Calcd; MS Found 381.20([ M + H ] +).

Step 2: weighing (R) -5-chloro-1- (1- (cyclopropylformyl) piperidin-4-yl) -3- (3-methylmorpholinyl) pyrazin-2 (1H) -one (22-a, 25mg, 0.065mmol), 7-azaindole-4-boronic acid ester(23.79mg，0.097mmol)，Pd(pph₃)₄(6.93mg, 0.006mmol), potassium carbonate (27.16mg, 0.196mmol) to a 25mL single-necked flask, 1, 4-dioxane (2mL) and water (0.5mL) were added, and the mixture was reacted with nitrogen three times at 110 ℃ for 8 hours. TLC monitored the reaction completion, cooling the reaction to room temperature, concentrating the reaction to dryness under reduced pressure, and purification by reverse phase column chromatography (0.05% TFA/water: acetonitrile, 35% acetonitrile peak) to afford the title compound: (R) -1- (1- (cyclopropanecarbonyl) piperidin-4-yl) -3- (3-methylmorpholinyl) -5- (1H-pyrrolo [2, 3-b)]Pyridin-4-yl) pyrazin-2 (1H) -one (22, 9mg, 0.019mmol, 23.33% yeild). 462.24 for MS Calcd; 463.26([ M + H ]) for MS Found]⁺)。

Example 23

(R) -1- (3-cyclopropyl-1-methyl-1H-pyrazol-5-yl) -5- (1H-indol-4-yl) -3- (3-methylmorpholino) pyrazin-2 (1H) -one

Step 1: 3-cyclopropyl-1-methyl-pyrazol-5-amine (23-a,1.0g,7.29mmol), N-diisopropylethylamine (1.88g,14.58mmol) and bromoacetonitrile (0.96g,8.01mmol) were sequentially added to a tetrahydrofuran (15mL) solvent, and the reaction solution was stirred at 80 ℃ for 5 hours. TLC (thin layer chromatography) for monitoring the completion of the reaction, cooling the reaction solution to room temperature, concentrating under reduced pressure, adding water (30mL) into the reaction solution, extracting with ethyl acetate (50mL), washing with saturated saline, drying with anhydrous sodium sulfate, and concentrating under reduced pressure to obtain 2- ((3-cyclopropyl-1-methyl-1H-pyrazol-5-yl) amino) acetonitrile (23-b,140mg,2.32mmol, 10% yield), wherein the product is directly used in the next step without purification.

Step 2: 2- ((3-cyclopropyl-1-methyl-1H-pyrazol-5-yl) amino) acetonitrile (23-b,140mg,2.32mmol) and oxalyl chloride (112mg,0.88mmol) were sequentially added to a dichloromethane solvent (10mL), then one drop of DMF was added, vacuum was applied to replace nitrogen gas for 3 times, and the mixture was left to react at 45 ℃ for 10 hours. The reaction was monitored by TLC for completion, the reaction was concentrated and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate ═ 3:1) to give 3, 5-dichloro-1- (3-cyclopropyl-1-methyl-1H-pyrazol-5-yl) pyrazin-2 (1H) -one (23-c, 70mg,0.24mmol, 10% yield)。MS Calcd:284.02；MS Found:285.04([M+H]⁺).

And step 3: adding 3, 5-dichloro-1- (3-cyclopropyl-1-methyl-1H-pyrazol-5-yl) pyrazine-2 (1H) -ketone (23-c, 70mg,0.24mmol), (R) -3-methylmorpholine (30mg,0.3mmol) and N, N-diisopropylethylamine (65mg,0.5mmol) into acetonitrile solution (2ml) in sequence, vacuumizing and replacing with nitrogen for 3 times, stirring at 85 ℃ for 5 hours, monitoring by TLC for reaction completion, cooling the reaction solution to room temperature, concentrating under reduced pressure, and purifying the residue by silica gel column chromatography (petroleum ether: ethyl acetate ═ 3:1) to obtain (R) -5-chloro-1- (3-cyclopropyl-1-methyl-1H-pyrazol-5-yl) -3- (3-methylmorpholino) pyrazine-2 (1H-5-yl) -pyrazine-2 ) -ketone (23-d, 20mg,0.057mmol, 22% yield). 349.13 for MS Calcd; 350.14([ M + H ]) for MS Found]⁺).

And 4, step 4: (R) -5-chloro-1- (3-cyclopropyl-1-methyl-1H-pyrazol-5-yl) -3- (3-methylmorpholino) pyrazin-2 (1H) -one (23-d, 20mg,0.057mmol), 4-indoleboronic acid pinacol ester (30mg,0.12mmol), potassium carbonate (25mg,0.18mmol) and tetrakis (triphenylphosphine) palladium (7mg,0.006mmol) were sequentially added to 2mL of a dioxane/water (6:1) mixed solvent, evacuated, replaced with nitrogen 3 times, and stirred at 110 ℃ for 8H. The reaction was monitored by TLC for completion, the reaction was completely concentrated, and the residue was purified by silica gel column chromatography (PE: EA ═ 1:1) to give the title compound: (R) -1- (3-cyclopropyl-1-methyl-1H-pyrazol-5-yl) -5- (1H-indol-4-yl) -3- (3-methylmorpholino) pyrazin-2 (1H) -one (23, 8mg,0.0018mmol, 31% yield). 430.21 for MS Calcd; 431.25([ M + H ]) for MS Found]⁺).¹H NMR(400MHz,DMSO-d6)δ11.25(s,1H),7.41–7.36(m,3H),7.32(s,1H),7.12(t,J＝7.6Hz,1H),6.78(s,1H),6.26(s,1H),5.04–4.93(m,1H),4.39(d,J＝12.8Hz,1H),3.97–3.86(m,1H),3.73–3.66(m,2H),3.59-3.56(m,5H),1.92–1.80(m,1H),1.30(d,J＝6.8Hz,3H),0.90–0.85(m,2H),0.70–0.65(m,2H).

Example 24

(R) -1- (1-methyl-1H-pyrazol-4-yl) -3- (3-methylmorpholino) -5- (1H-pyrrolo [2,3-c ] pyridin-4-yl) pyrazin-2 (1H) -one

Step 1: mixing (R) -5-chloro-1- (1-methyl-1H-pyrazol-4-yl) -3- (3-methylmorpholino) pyrazin-2 (1H) -one (15-d, 44mg,0.14mmol), (1H-pyrrolo [2, 3-c)]Pyridin-4-yl) boronic acid (45mg,0.28mmol), potassium carbonate (51mg,0.42mmol) and tetrakis (triphenylphosphine) palladium (16mg,0.014mmol) were sequentially added to a dioxane/water (6:1) mixed solvent 2mL, vacuum-pumped, replaced with nitrogen 3 times, and stirred at 110 ℃ for 8 h. TLC monitored the reaction was complete, the reaction was concentrated completely and the residue was purified by silica gel column chromatography (DCM: MeOH ═ 10:1) to afford the title compound: (R) -1- (1-methyl-1H-pyrazol-4-yl) -3- (3-methylmorpholino) -5- (1H-pyrrolo [2, 3-c)]Pyridin-4-yl) pyrazin-2 (1H) -one (24, 30mg,0.07mmol, 77% yield). 391.18 for MS Calcd; 392.18([ M + H ]) for MS Found]⁺).¹H NMR(400MHz,DMSO-d₆)δ11.80(s,1H),8.71(s,1H),8.51(s,1H),8.44(s,1H),8.03(s,1H),7.72(s,1H),7.66(s,1H),6.88(s,1H),5.09–5.00(m,1H),4.37(dd,J＝12.6,5.6Hz,1H),3.90(s,3H),3.70(d,J＝9.6Hz,2H),3.62–3.52(m,3H),1.28(d,J＝6.8Hz,3H).

Example 25

(R) -1- (1-methyl-1H-pyrazol-5-yl) -3- (3-methylmorpholino) -5- (1H-pyrrolo [2,3-c ] pyridin-4-yl) pyrazin-2 (1H) -one

Step 1: mixing (R) -5-chloro-1- (1-methyl-1H-pyrazol-5-yl) -3- (3-methylmorpholino) pyrazin-2 (1H) -one (1-f, 90mg,0.29mmol), (1H-pyrrolo [2, 3-c)]Pyridin-4-yl) boronic acid (94mg,0.58mmol), potassium carbonate (116mg,0.84mmol) and tetrakis (triphenylphosphine) palladium (33mg,0.029mmol) were sequentially added to 3mL of a dioxane/water (6:1) mixed solvent, vacuum-pumped, replaced with nitrogen 3 times, and stirred at 110 ℃ for 8 hours. TLC monitored the reaction was complete, the reaction was concentrated completely and the residue was purified by silica gel column chromatography (MeOH: DCM ═ 1:10) to afford the title compound: (R) -1- (1-methyl-1H-pyrazol-5-yl) -3- (3-methylmorpholino) -5- (1H-pyrrolo [2, 3-c)]Pyridin-4-yl) pyrazin-2 (1H) -one (25, 15mg,0.038mmol, 13% yield). 391.18 for MS Calcd; 392.24([ M + H ]) for MS Found]⁺).¹H NMR(400MHz,DMSO-d₆)δ11.76(s,1H),8.70(s,1H),8.50(s,1H),7.65(s,1H),7.56(d,J＝1.6Hz,1H),7.47(s,1H),6.86(s,1H),6.54(d,J＝1.6Hz,1H),5.04–4.93(m,1H),4.48–4.38(m,1H),3.93(dd,J＝11.6,2.8Hz,1H),3.72-3.69(m,5H),3.62–3.53(m,2H),1.32(d,J＝6.8Hz,3H).

Example 26

((R) -5- (6-fluoro-1H-indol-4-yl) -1- (1-methyl-1H-pyrazol-5-yl) -3- (3-methylmorpholino) pyrazin-2 (1H) -one

Step 1: (R) -5-chloro-1- (1-methyl-1H-pyrazol-5-yl) -3- (3-methylmorpholino) pyrazin-2 (1H) -one (1-f, 35mg,0.11mmol), 6-fluoro-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-indole (58mg,0.22mmol), potassium carbonate (45mg,0.33mmol), and tetrakis (triphenylphosphine) palladium (13mg,0.011mmol) were sequentially added to 2mL of dioxane/water (6:1) mixed solvent, and vacuum was applied thereto, nitrogen was substituted 3 times, and the mixture was stirred at 110 ℃ for 8 hours. TLC monitored the reaction was complete, the reaction was concentrated completely and the residue was purified by silica gel column chromatography (MeOH: DCM ═ 1:10) to afford the title compound: (R) -5- (6-fluoro-1H-indol-4-yl) -1- (1-methyl-1H-pyrazol-5-yl) -3- (3-methylmorpholino) pyrazin-2 (1H) -one (26, 25mg,0.06mmol, 55% yield). 408.44 for MS Calcd; 409.21([ M + H ]) for MS Found]⁺).¹H NMR(400MHz,Chloroform-d)δ8.32(s,1H),7.59(s,1H),7.29(d,J＝2.8Hz,1H),7.16(s,1H),7.09(d,J＝10.4Hz,1H),6.77(s,1H),6.37(s,1H),5.22–5.10(m,1H),4.69–4.57(m,1H),4.03–3.95(m,1H),3.88-3.72(m,7H),3.58–3.45(m,1H),1.44(d,J＝6.8Hz,3H).

Example 27

(R) -3- (3-methylmorpholino) -1- (4-methyltetrahydro-2H-pyran-4-yl) -5- (1H-pyrrolo [2,3-b ] pyridin-4-yl) pyrazin-2 (1H) -one

Step 1: 4-Methyltetrahydro-2H-pyran-4-amine hydrochloride (27-a,0.2g,1.31mmol), N-diisopropylethylamine (0.42g,3.93mmol) and bromoacetonitrile (0.32g,2.62mmol) were successively added to an acetonitrile (5mL) solvent, and stirred at room temperature overnight. The reaction was monitored by TLC for completion, concentrated under reduced pressure and the residue was purified by silica gel column chromatography (DCM: MeOH ═ 10:1) to give the product 2- (4-methyltetrahydro-2H-pyran-4-yl) amino) acetonitrile (27-b,180mg,1.17mmol, 89% yield).

Step 2: 2- (4-Methyltetrahydro-2H-pyran-4-yl) amino) acetonitrile (27-b,180mg,1.17mmol), oxalyl chloride (741mg,5.84mmol) were sequentially added to a dichloromethane solvent (10mL), and then a drop of DMF was added, replaced with nitrogen gas under vacuum 3 times, and left to react at 45 ℃ for 10 hours. The reaction was monitored by TLC for completion, the reaction was concentrated and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate 1:1) to give the product 3, 5-dichloro-1- (4-methyltetrahydro-2H-pyran-4-yl) pyrazin-2 (1H) -one (27-c, 100mg,0.38mmol, 32% yield).

And step 3: adding 3, 5-dichloro-1- (4-methyltetrahydro-2H-pyran-4-yl) pyrazine-2 (1H) -one (27-c, 100mg,0.38mmol), (R) -3-methylmorpholine (46mg,0.46mmol) and N, N-diisopropylethylamine (98mg,0.76mmol) to an acetonitrile solution (4ml) in this order, evacuating the mixture for 3 times with nitrogen, stirring at 85 ℃ for 5 hours, monitoring the completion of the reaction by TLC, cooling the reaction mixture to room temperature, concentrating under reduced pressure, purifying the residue by silica gel column chromatography (petroleum ether: ethyl acetate ═ 1:1) to obtain the product (R) -5-chloro-3- (3-methylmorpholino) -1- (4-methyltetrahydro-2H-pyran-4-yl) pyrazine-2 (1H) -one (27-d, 60mg,0.18mmol, 48% yield). 327.13 for MS Calcd; 328.15([ M + H ]) for MS Found]⁺).

And 4, step 4: (R) -5-chloro-3- (3-methylmorpholino) -1- (4-methyltetrahydro-2H-pyran-4-yl) pyrazin-2 (1H) -one (27-d, 60mg,0.18mmol), 7-azaindole-4-boronic acid ester (54mg,0.12mmol), potassium carbonate (75mg,0.54mmol), and tetrakis (triphenylphosphine) palladium (21mg,0.018mmol) were sequentially added to 2mL of dioxane/water (6:1) mixed solvent, vacuum was applied, nitrogen was replaced 3 times, and stirring was carried out at 110 ℃ for 8H. The reaction was monitored by TLC for completion, the reaction was completely concentrated and the residue was purified by silica gel column chromatography (PE: EA ═ 1:1) to give the product (R) -3- (3-methylmorpholino) -1- (4-methyltetrahydro-2H-pyran-4-yl) -5- (1H-pyrrolo: -pyrrole)[2,3-b]Pyridin-4-yl) pyrazin-2 (1H) -one (27, 20mg,0.049mmol, 27% yield). 409.21 for MS Calcd; 410.27([ M + H ]) for MS Found]⁺).¹H NMR(400MHz,DMSO-d₆)δ11.73(s,1H),8.21(d,J＝5.2Hz,1H),7.69(s,1H),7.53–7.49(m,1H),7.45(d,J＝5.2Hz,1H),6.79(dd,J＝3.2,1.6Hz,1H),4.87(d,J＝7.6Hz,1H),4.15(d,J＝12.6Hz,1H),3.95–3.88(m,1H),3.78–3.63(m,6H),3.63–3.50(m,2H),3.33-3.29(m,1H),2.40–2.24(m,3H),1.69(s,3H),1.24(d,J＝6.8Hz,3H).

Example 28

(R) -3- (3-methylmorpholino) -1- (2- (methylsulfonyl) ethyl) -5- (1H-pyrrolo [2,3-b ] pyridin-4-yl) pyrazin-2 (1H) -one

Step 1: 2- (methylsulfonyl) ethylamine hydrochloride (28-a,1.0g,6.29mmol), N-diisopropylethylamine (2.44g,18.87mmol) and bromoacetonitrile (0.83g,6.92mmol) were added sequentially to acetonitrile (15mL) solvent and stirred at room temperature for 5 hours. The reaction was monitored by TLC for completion, the reaction was cooled to room temperature, concentrated under reduced pressure, water (30mL) was added to the reaction, extracted with ethyl acetate (50mL), washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (DCM: MeOH ═ 20:1) to give 2- ((2- (methylsulfonyl) ethyl) amino) acetonitrile (28-b,400mg,2.47mmol, 39% yield).

Step 2: 2- ((2- (methylsulfonyl) ethyl) amino) acetonitrile (28-b,400mg,2.47mmol), oxalyl chloride (1.56mg,12.35mmol) were added sequentially to dichloromethane solvent (10mL), then a drop of DMF was added, replaced with nitrogen under vacuum 3 times, and left to react at 45 ℃ for 10 h. The reaction was monitored by TLC for completion, the reaction was concentrated and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate 1: 3) to give 3, 5-dichloro-1- (2- (methylsulfonyl) ethyl) pyrazin-2 (1H) -one (28-c, 230mg,0.85mmol, 34% yield).

And step 3: 3, 5-dichloro-1- (2- (methylsulfonyl) ethyl) pyrazin-2 (1H) -one (28-c, 230mg,0.85mmol), (R) -3-methylmorpholine (103mg,1.02mmol) and N, N-diisopropylethylamine(220mg,1.7mmol) was added to acetonitrile solution (5ml) in this order, vacuum nitrogen was applied for 3 times, the mixture was stirred at 85 ℃ for 5 hours, TLC monitored completion of the reaction, the reaction mixture was cooled to room temperature, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate ═ 1: 3) to give the product (R) -5-chloro-3- (3-methylmorpholino) -1- (2- (methylsulfonyl) ethyl) pyrazin-2 (1H) -one (28-d, 70mg,0.21mmol, 24% yield). 335.07 for MS Calcd; 336.05([ M + H ]) for MS Found]⁺).

And 4, step 4: (R) -5-chloro-3- (3-methylmorpholino) -1- (2- (methylsulfonyl) ethyl) pyrazin-2 (1H) -one (28-d, 70mg,0.21mmol), 7-azaindole-4-boronic acid ester (61mg,0.25mmol), potassium carbonate (87mg,0.63mmol) and tetrakis (triphenylphosphine) palladium (25mg,0.021mmol) were sequentially added to 2mL of a dioxane/water (6:1) mixed solvent, vacuum was applied, nitrogen was replaced 3 times, and the mixture was stirred at 110 ℃ for 8H. The reaction was monitored by TLC and was completely concentrated, and the residue was purified by silica gel column chromatography (DCM: MeOH: 20:1) to give the product (R) -3- (3-methylmorpholino) -1- (2- (methylsulfonyl) ethyl) -5- (1H-pyrrolo [2,3-b ] pyrrole]Pyridin-4-yl) pyrazin-2 (1H) -one (28, 10mg,0.0024mmol, 11% yield). 417.15 for MS Calcd; MS Found 418.21([ M + H ]]⁺).¹H NMR(400MHz,DMSO-d₆)δ11.72(s,1H),8.22(d,J＝5.2Hz,1H),7.91(s,1H),7.54–7.50(m,1H),7.45(d,J＝5.2Hz,1H),6.97(dd,J＝3.2,1.6Hz,1H),5.07–4.99(m,1H),4.42-4.34(m,3H),3.95–3.90(m,1H),3.72–3.63(m,4H),3.59-3.53(m,2H),3.10(s,3H),1.26(d,J＝6.8Hz,3H).

Example 29

3- ((R) -3-Methylmorpholinyl) -1- (1- (methylsulfonyl) propyl) -5- (1H-pyrrolo [2,3-b ] pyridin-4-yl) pyrazin-2 (1H) -one

Step 1: (R) -5-bromo-3- (3-methylmorpholinyl) -1- ((methylsulfonyl) methyl) pyrazin-2 (1H) -one (4-d, 150mg, 0.410mmol) was weighed into a 25ml single-neck flask, DMF (5ml) was added, nitrogen was substituted three times, sodium hydride (49.31mg, 1.232mmol) was added under ice bath, stirring was carried out for 15 minutes, and thenIodomethane (76.90mg, 0.493mmol) was slowly added, followed by reaction at room temperature for 2 hours. TLC is used for monitoring the reaction completion, the reaction liquid is quenched by saturated ammonium chloride, extracted by ethyl acetate, an organic phase is dehydrated by anhydrous sodium sulfate, and is separated and purified by column chromatography with a sample stirring column (PE: EA is 2:1), and 5-bromo-3- ((R) -3-methylmorpholinyl) -1- (1- (methylsulfonyl) propyl) pyrazin-2 (1H) -one (29-a, 75mg, 0.190mmol, 34.88% yield) is obtained. 393.04 for MS Calcd; 394.13([ M + H ]) for MS Found]⁺)。

Step 2: 5-bromo-3- ((R) -3-methylmorpholinyl) -1- (1- (methylsulfonyl) propyl) pyrazin-2 (1H) -one (29-a, 40mg, 0.101mmol), 7-azaindole-4-boronic acid ester (32.59mg, 0.152mmol), tetrakis (triphenylphosphine) palladium (11.55mg, 0.01mmol), potassium carbonate (41.81mg, 0.303mmol) were weighed into a 25ml single-neck flask, 1, 4-dioxane (2ml) and water (0.5ml) were added, replaced with nitrogen three times, and reacted at 110 ℃ for 3 hours. TLC monitored the reaction was complete, the reaction was concentrated to dryness under reduced pressure, purified by plate chromatography (DCM: MeOH ═ 20:1) and purified by reverse phase column chromatography using 0.1% FA/water: MeCN, title compound: 3- ((R) -3-Methylmorpholinyl) -1- (1- (methylsulfonyl) propyl) -5- (1H-pyrrolo [2, 3-b)]Pyridin-4-yl) pyrazin-2 (1H) -one (29, 25mg, 0.058mmol, 58.13% yeild). 431.16 for MS Calcd; 432.23([ M + H ]) for MS Found]⁺)。¹H NMR(400MHz,DMSO-d₆)δ11.79(s,1H),8.26(d,J＝5.2Hz,1H),7.62(s,1H),7.55(t,J＝3.2Hz,1H),7.49(dd,J＝5.2,1.6Hz,1H),6.77(s,1H),6.22(d,J＝11.6Hz,1H),5.03-4.98(m,1H),4.44-4.40(m,1H),3.93(dd,J＝11.6,3.2Hz,1H),3.79–3.67(m,2H),3.63-3.55(m,1H),3.41–3.35(m,1H),3.13(s,3H),2.39–2.35(m,1H),2.20–2.15(m,1H),1.32-1.29(m,3H),0.88-0.83(m,3H).

Example 30

1- (1- (ethylsulfonyl) ethyl) -5- (1H-indol-4-yl) -3- ((R) -3-methylmorpholinyl) pyrazin-2 (1H) -one

Step 1: weighing 5-bromo-1- (1- (ethylsulfonyl) ethyl) -3- ((R) -3-methylmorpholinyl) pyrazin-2 (1H) -one (9-a, 50mg, 0.127mmol), 7-azaindoleIndole-4-boronic acid ester (46.40mg, 0.190mmol), tetrakis (triphenylphosphine) palladium (15.01mg, 0.013mmol), potassium carbonate (52.58mg, 0.381mmol) were charged into a 25ml single-necked flask, 1, 4-dioxane (2ml) and water (0.5ml) were added, nitrogen was substituted three times, and reaction was carried out at 110 ℃ for 3 hours. TLC monitored the reaction was complete, the reaction was concentrated to dryness under reduced pressure and purified by plate chromatography (DCM: MeOH ═ 25:1) to afford the title compound: 1- (1- (ethylsulfonyl) ethyl) -5- (1H-indol-4-yl) -3- ((R) -3-methylmorpholinyl) pyrazin-2 (1H) -one (30, 25mg, 0.058mmol, 42.59% yeild). 430.17 for MS Calcd; 431.22([ M + H ]) for MS Found]⁺)。¹H NMR(400MHz,DMSO-d₆)δ11.27(s,1H),7.48–7.33(m,4H),7.15(t,J＝7.6Hz,1H),6.79-6.76(m,1H),6.34(d,J＝7.6Hz,1H),5.00-4.94(m,1H),4.45-4.33(m,1H),3.91(d,J＝11.2Hz,1H),3.78–3.64(m,2H),3.61–3.50(m,1H),3.41–3.35(m,1H),3.25-3.14(m,2H),1.79-1.76(m,3H),1.31-1.23(m,6H).

Example 31

1- (3-hydroxy-1- (methylsulfonyl) propyl) -3- ((R) -3-methylmorpholinyl) -5- (1H-pyrrolo [2,3-b ] pyridin-4-yl) pyrazin-2 (1H) -one

Step 1: (R) -5-bromo-3- (3-methylmorpholinyl) -1- ((methylsulfonyl) methyl) pyrazin-2 (1H) -one (4-d, 250mg, 0.684mmol) was weighed into a 25ml single-neck flask, DMF (5ml) was added, nitrogen was substituted three times, sodium hydride (82.2mg, 2.055mmol) was added under ice bath and stirred for 15 minutes, then ((2-iodoethoxy) methyl) benzene (31-a, 214.54mg, 0.822mmol) was slowly added, followed by reaction at room temperature for 2 hours. The reaction was monitored by TLC and quenched with saturated ammonium chloride, extracted with ethyl acetate, the organic phase was purified by anhydrous sodium sulfate, and purified by column chromatography (petroleum ether: ethyl acetate: 3:1) to give 1- (3- (benzyloxy) -1- (methylsulfonyl) propyl) -5-bromo-3- ((R) -3-methylmorpholinyl) pyrazin-2 (1H) -one (31-b, 102mg, 0.204mmol, 24.87% yeild). 499.08 for MS Calcd; MS Found 500.23([ M + H ]]⁺)。

Step 2: 1- (3- (benzyloxy) -1- (methylsulfonyl) propyl) -5-bromo-3- ((R) -3-Methylmorpholinyl) pyrazin-2 (1H) -one (31-b, 50mg, 0.101mmol), 7-azaindole-4-boronic acid ester (36.67mg, 0.152mmol), tetrakistriphenylphosphine-palladium (11.55mg, 0.01mmol), potassium carbonate (41.81mg, 0.303mmol) were added to a 25ml single-neck flask, 1, 4-dioxane (2ml) and water (0.5ml) were added, nitrogen was replaced three times, and reaction was carried out at 110 ℃ for 3 hours. TLC (thin layer chromatography) to monitor the reaction, the reaction solution was concentrated to dryness under reduced pressure, and purified by plate chromatography (petroleum ether: ethyl acetate: 1:2) to give 1- (3- (benzyloxy) -1- (methylsulfonyl) propyl) -3- ((R) -3-methylmorpholinyl) -5- (1H-pyrrolo [2, 3-b)]Pyridin-4-yl) pyrazin-2 (1H) -one (31-c, 42mg, 0.078mmol, 79.24% yield). 537.20 for MS Calcd; 538.23([ M + H ]) for MS Found]⁺)。

And step 3: intermediate 1- (3- (benzyloxy) -1- (methylsulfonyl) propyl) -3- ((R) -3-methylmorpholinyl) -5- (1H-pyrrolo [2, 3-b) was weighed]Pyridin-4-yl) pyrazin-2 (1H) -one (31-c, 30mg, 0.055mmol) was charged to a 25ml single-necked flask, ammonium formate (280mg, 4.4mmol) and palladium on carbon (30mg) were added, ethanol (5ml) was added, and the reaction was carried out at 85 ℃ for 8 hours. TLC to monitor the reaction, suction filtration of the reaction solution, concentration of the filtrate under reduced pressure to dryness, purification by reverse phase column chromatography (0.1% FA/water: MeCN) to give the title compound: 1- (3-hydroxy-1- (methylsulfonyl) propyl) -3- ((R) -3-methylmorpholinyl) -5- (1H-pyrrolo [2, 3-b)]Pyridin-4-yl) pyrazin-2 (1H) -one (31, 6mg, 0.013mmol, 25% yed). 447.16 for MS Calcd; 448.17([ M + H ]) for MS Found]⁺)。¹H NMR(400MHz,DMSO-d₆)δ11.77(s,1H),8.26(d,J＝5.2Hz,1H),7.63(d,J＝2.8Hz,1H),7.54(t,J＝3.2Hz,1H),7.48(dd,J＝5.2,1.6Hz,1H),6.78(s,1H),6.43–6.28(m,1H),5.00(brs,1H),4.79(brs,1H),4.44(d,J＝11.2Hz,1H),3.98–3.86(m,1H),3.79–3.66(m,2H),3.62-3.54(m,2H),3.41–3.35(m,2H),3.16–2.97(m,3H),1.48–1.21(m,5H).

Example 32

3- ((R) -3-methylmorpholino) -1- ((R) -1- (methylsulfonyl) pyrrolidin-3-yl) -5- (1H-pyrrolo [2,3-b ] pyridin-4-yl) pyrazine 2(1H) -one

Step 1: (R) -3-tert-Butoxycarbonylaminopyrrolidine (32-a,800mg,4.3mmol), methanesulfonyl chloride (587mg,5.15mmol) and N, N-diisopropylethylamine (1.67g,12.9mmol) were successively added to a dichloromethane (20mL) solution, and stirred at room temperature overnight. The reaction was monitored by TLC for completion, the reaction was concentrated completely, and the purified product (R) -1-methylsulfonyl-3- (Boc-amino) pyrrolidine (32-b,400mg,1.52mmol, 35% yield) was isolated from the residue by silica gel column chromatography (MeOH: DCM ═ 1: 10).

Step 2: (R) -1-methylsulfonyl-3- (Boc-amino) pyrrolidine (32-b,250mg,0.95mmol) was dissolved in dichloromethane (5mL), trifluoroacetic acid (1.08g,9.5mmol) was added, and the mixture was stirred at room temperature for 2 hours. The reaction was monitored by TLC for completion and the reaction was concentrated completely to give the product (R) -1- (methylsulfonyl) pyrrolidin-3-amine (32-c,155mg,0.95mmol, 99% yield) which was used in the next step without purification.

And step 3: (R) -1- (methylsulfonyl) pyrrolidin-3-amine (32-c,155mg,0.95mmol), N-diisopropylethylamine (368mg,2.85mmol) and bromoacetonitrile (170mg,1.43mmol) were added successively to an acetonitrile (5mL) solvent and stirred at room temperature for 5 hours. The reaction was monitored by TLC for completion, the reaction mixture was cooled to room temperature, concentrated under reduced pressure, water (10mL) was added to the reaction mixture, extracted with ethyl acetate (10mL), washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (DCM: MeOH ═ 20:1) to give the product (R) -2- ((1- (methylsulfonyl) pyrrolidin-3-yl) amino) acetonitrile (32-d,100mg,0.5mmol, 52% yield).

And 4, step 4: (R) -2- ((1- (methylsulfonyl) pyrrolidin-3-yl) amino) acetonitrile (32-d,100mg,0.5mmol), oxalyl chloride (317mg,2.5mmol) were added to dichloromethane solvent (5mL) in sequence, then one drop of DMF was added, vacuum was applied and nitrogen was replaced 3 times, and the mixture was left to react at 45 ℃ for 10 hours. The reaction was monitored by TLC for completion, the reaction was concentrated and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate 1: 3) to give the product (R) -3, 5-dichloro-1- (1- (methylsulfonyl) pyrrolidinyl-3-yl) pyrazin-2 (1H) -one (32-e, 40mg,0.13mmol, 25% yield).

And 5: (R) -3, 5-dichloro-1- (1- (methylsulfonyl) pyrrolidin-3-yl) pyrazin-2 (1H) -one (32-e, 40mg,0.13mmol), (R) -3-methylmorpholine (15mg,0.15mmol) and N, N-diisopropylethyl etherAmine (34mg,0.26mmol) was added to acetonitrile solution (3ml) in this order, the mixture was purged with nitrogen under vacuum for 3 times, stirred at 85 ℃ for 5 hours, TLC monitored for completion of the reaction, the reaction solution was cooled to room temperature, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate ═ 1: 3) to give the product 5-chloro-3- ((R) -3-methylmorpholino) -1- ((R) -1- (methylsulfonyl) pyrrolidin-3-yl) pyrazin-2 (1H) -one (32-f, 40mg,0.1mmol, 82% yield). 376.86 for MS Calcd; MS Found 377.23([ M + H ]]⁺).

Step 6: 5-chloro-3- ((R) -3-methylmorpholino) -1- ((R) -1- (methylsulfonyl) pyrrolidin-3-yl) pyrazin-2 (1H) -one (32-f, 40mg,0.1mmol), 7-azaindole-4-boronic acid ester (32mg,0.13mmol), potassium carbonate (16mg,0.33mmol) and tetrakis (triphenylphosphine) palladium (12mg,0.011mmol) were sequentially added to 2mL of a dioxane/water (6:1) mixed solvent, vacuum was applied, nitrogen was replaced 3 times, and stirring was carried out at 110 ℃ for 8H. The reaction was monitored by TLC for completion, the reaction was concentrated completely and the residue was purified by silica gel column chromatography (DCM: MeOH ═ 20:1) to give the product 3- ((R) -3-methylmorpholino) -1- ((R) -1- (methylsulfonyl) pyrrolidin-3-yl) -5- (1H-pyrrolo [2, 3-b)]Pyridin-4-yl) pyrazine 2(1H) -one (32, 18mg,0.04mmol, 36% yield). 458.17 for MS Calcd; MS Found 459.24([ M + H ]]⁺).¹H NMR(400MHz,DMSO-d₆)δ11.74(s,1H),8.23(d,J＝5.2Hz,1H),7.77(s,1H),7.52–7.49(m,1H),7.47(d,J＝5.2Hz,1H),6.84(dd,J＝3.6,2.0Hz,1H),5.36–5.30(m,1H),5.03(d,J＝6.8Hz,1H),4.36(d,J＝12.0Hz,1H),3.93(dd,J＝11.6,3.2Hz,1H),3.76–3.71(m,1H),3.71–3.67(m,2H),3.60–3.50(m,3H),3.48–3.42(m,1H),3.39(d,J＝3.6Hz,1H),3.02(s,3H),2.45–2.39(m,1H),2.33–2.26(m,1H),1.27(d,J＝6.8Hz,3H).

Example 33: evaluation of enzymatic Activity in vitro

By measuring IC₅₀Values to evaluate the inhibitory activity of the compounds on human ATR kinase.

Main reagents and consumables:

the experimental scheme is as follows: recombinant human ATRIP was incubated at a final concentration of 0.25 ng/. mu.l in assay buffer containing a final concentration of 20nM GST-cMyc-p53 and 4. mu.M ATP, and the reaction was initiated by addition of ATP. After incubation at room temperature for 30 minutes, the reaction was stopped by addition of EDTA. Finally, an antibody (Anti-phosphor-p 53(ser15) -K) containing a d 2-labeled monoclonal antibody against GST (Anti-GST-d2) and a europium-labeled antibody against phosphorylated p53(ser15) was added, incubated overnight in a thermostated incubator (25 ℃), and the fluorescence signals of the reaction systems at 665nm and 615nm were read by Envision in a time-resolved fluorescence mode to determine the fluorescence (HTRF) signal by homogeneous time-resolved fluorescence and according to the formula HTRF (Em665nm/Em615 nm).

The data analysis software GraphPad Prism 8 was used, using the equation "log (inhibition) vs. normalized response- -variable slope" (equation Y100/(1 +10 ^) ((LogIC)₅₀-X) HillSlope) to obtain IC of the compound₅₀The value is obtained. Wherein, the 'LogIC' is₅₀"refers to the logarithm of the half inhibitory concentration; "Y" represents the percent inhibition of cellular activity; "X" represents the molar concentration of the compound; "HillSlope" refers to the absolute value of the maximum slope of the curve.

The experimental results are as follows: as shown in table 1:

TABLE 1 half inhibitory concentration IC of compounds of the invention on ATR₅₀

Compound (I)	ATR average IC50(μM)	Compound (I)	ATR average IC50(μM)
				2	0.01531	7	0.0815
8	0.0252	9	0.03704
				25	0.05414	26	0.058
27	0.08973

And (4) conclusion: the compound of the invention has good inhibitory activity on ATR kinase.

Claims (10)

1. A compound represented by formula (I) or a pharmaceutically acceptable salt, solvate, isotopic label, metabolite or prodrug thereof:

wherein:

R¹selected from phenyl, heteroaryl, said phenyl or heteroaryl being unsubstituted or each independently substituted by one or more groups selected from R^4aDeuterium, halogen, hydroxy, amino, cyano, carboxy, haloC_1-6Alkyl, hydroxy substituted C_1-6Alkyl, -OR^4a、-NR^4aR^4b、-N(CN)R^4a、-N(OR^4a)R^4b、-S(O)_0-2R^4b、-C(O)OR^4a、-C(O)NR^4aR^4b、-NR^4aC(O)R^4b、-NR^4aC(O)NR^4aR^4b、-NR^4aS(O)₂R^4band-OC (O) R^4aThe substituent(s) is substituted at any substitutable position;

R^4aand R^4bEach independently selected from hydrogen and C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-8Cycloalkyl, 3-8 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, C_3-8Cycloalkyl radical C_1-6Alkyl, 3-8 membered heterocycloalkyl C_1-6Alkyl, phenyl C_1-6Alkyl, 5-6 membered heteroaryl C_1-6An alkyl group; said C is_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-8Cycloalkyl, 3-8 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, C_3-8Cycloalkyl radical C_1-6Alkyl, 3-8 membered heterocycloalkyl C_1-6Alkyl, phenyl C_1-6Alkyl, 5-6 membered heteroaryl C_1-6Alkyl is unsubstituted or each independently substituted by one or more groups selected from deuterium, oxo, halogen, hydroxy, amino, cyano, halo C_1-6Alkyl, halo C_1-6Alkoxy radical, C_1-6Alkoxy radical, C_1-6Alkylamino, 3-8 membered cycloalkyl, 3-8 membered heterocycloalkyl, -NHC (O) -C_2-6Alkenyl, -NHC (O) -C_1-6Alkyl, -NHC (O) -NH-C_1-6Alkyl, -NHC (O) -O-C_1-6Alkyl and-NHS (O)₂-C_1-6The substituent of the alkyl group is substituted at any substitutable position;

R²is selected from C_1-6Alkyl radical, C_1-6Alkoxy, 3-8 membered cycloalkyl, 4-10 membered heterocycloalkyl, 4-8 membered heterocycloalkenyl, phenyl, heteroaryl, -C (O) R⁵、-C(O)OR⁵、-(CO)NR⁵R⁶、-(SO₂)R⁵、-(SO₂)NR⁵R⁶、-NR⁵R⁶(ii) a Wherein said C_1-6Alkyl radical, C_1-6Alkoxy, 3-8 membered cycloalkyl, 4-10 membered heterocycloalkyl, 4-8 membered heterocycloalkenyl, phenyl, heteroarylThe radicals being unsubstituted or each independently being substituted by one or more radicals selected from deuterium, oxo, halogen, cyano, hydroxy, -NR⁵R⁶Optionally with hydroxy or C_1-6Alkoxy or phenyl or-NR⁵R⁶Substituted C_1-6Alkyl radical, C_1-6Alkoxy radical, C_1-6Haloalkyl, 3-to 8-membered cycloalkyl, 4-to 10-membered heterocycloalkyl, phenyl, heteroaryl, -C (O) R⁵、-C(O)OR⁵、-(CO)NR⁵R⁶、-(SO₂)R⁵、-(SO)R⁵、-SR⁵、-(SO₂)NR⁵R⁶、-NR⁵(SO₂)R⁶、-((SO)＝NR⁵)R⁶、-N＝(SO)R⁵R⁶、-(PO)(OR⁵)₂、-(PO)(OR⁵)R⁶And- (PO) (R)⁵)₂The substituent(s) is substituted at any substitutable position;

R³selected from hydrogen, deuterium, halogen, cyano, C_1-6Alkyl radical, C_3-8A cycloalkyl group;

preferably, R³Selected from hydrogen, C_1-6An alkyl group;

further preferably, R³Selected from hydrogen, methyl, ethyl, propyl or butyl;

most preferably, R³Is hydrogen;

R⁴is selected from C_1-6Alkyl radical, C_3-8A cycloalkyl group;

preferably, R⁴Is selected from C_1-6An alkyl group;

further preferably, R⁴Selected from hydrogen, methyl, ethyl, propyl or butyl;

most preferably, R⁴Is methyl;

R⁵and R⁶Each independently selected from hydrogen and C_1-6Alkyl, 3-8 membered cycloalkyl, 4-10 membered heterocycloalkyl, 3-15 membered bridged cyclic group, 3-15 membered bridged heterocyclic group, phenyl, heteroaryl;

or R⁵And R⁶And the atoms to which they are attached together form a nitrogen-containing 4-8 membered heterocyclic ring, which nitrogen-containing 4-8 membered heterocyclic ring is unsubstituted or substituted with one or moreEach selected from deuterium, halogen, cyano, hydroxy, optionally substituted by hydroxy or C_1-6Alkoxy-substituted C_1-6Alkyl radical, C_1-6Haloalkyl, C_1-6Alkoxy, 3-to 8-membered cycloalkyl, 4-to 10-membered heterocycloalkyl and- (SO)₂)R⁷Said nitrogen-containing 4-8 membered heterocyclic ring optionally containing an additional heteroatom selected from O, N and S;

R⁷is selected from C_1-6Alkyl radical, C_1-6Alkoxy, -NH (C)_1-6Alkyl), -N (C)_1-6Alkyl radical)₂3-8 membered cycloalkyl, phenyl.

2. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, isotopic label, metabolite or prodrug thereof, wherein:

R¹selected from the group consisting of pyridyl, pyrimidinyl, pyridazinyl, indolyl, 5-azaindolyl, pyrrolo [2,3-d ]]Pyrimidinyl, indazolyl, benzo [ d ]]Imidazolyl, imidazo [4,5-b ]]Pyridyl, pyrrole [2,3-d ]]Pyridazinyl, pyrrole [2,3-c ]]Pyridazinyl, 6-azaindolyl, 7-azaindolyl; the pyridyl, pyrimidyl, pyridazinyl, indolyl, 5-azaindolyl, pyrrolo [2,3-d ] group]Pyrimidinyl, indazolyl, benzo [ d ]]Imidazolyl, imidazo [4,5-b]Pyridyl, pyrrole [2,3-d ]]Pyridazinyl, pyrrole [2,3-c ]]Pyridazinyl, 6-azaindolyl, 7-azaindolyl being unsubstituted or each independently substituted by one or more radicals selected from deuterium, C_1-6Alkyl, halo C_1-6Alkyl, hydroxy substituted C_1-6Alkyl, -C (O) OR^4a、-C(O)NR^4aR^4b3-6 membered cycloalkyl, halogen, hydroxy, amino, cyano, carboxy, -OR^4aand-NR^4aR^4bThe substituent(s) is substituted at any substitutable position;

preferably, R¹Selected from indolyl, 5-azaindolyl, indazolyl, benzo [ d]Imidazolyl, 6-azaindolyl, 7-azaindolyl, said indolyl, 5-azaindolyl, indazolyl, benzo [ d ]]Imidazolyl, 6-azaindolyl, 7-azaindolyl are unsubstituted or each independentlyOne or more selected from C_1-6Alkyl, halogen, hydroxy, amino, cyano, carboxy, -OR^4aand-NR^4aR^4bThe substituent(s) is substituted at any substitutable position;

more preferably, R¹Selected from indolyl, 5-azaindolyl, indazolyl, benzo [ d ]]Imidazolyl, 6-azaindolyl, 7-azaindolyl, said indolyl, 5-azaindolyl, indazolyl, benzo [ d ]]Imidazolyl, 6-azaindolyl, 7-azaindolyl are unsubstituted or each independently substituted by one or more radicals selected from halogen and-NR^4aR^4bThe substituent of (b) is substituted at any substitutable position;

most preferably, R¹Selected from indolyl, benzo [ d ]]Imidazolyl, 6-azaindolyl, 7-azaindolyl, said indolyl, benzo [ d]Imidazolyl, 6-azaindolyl, 7-azaindolyl are unsubstituted or each independently substituted by one group from the group consisting of F, -NR^4aR^4bThe substituent(s) is substituted at any substitutable position;

preferably, R^4aAnd R^4bEach independently selected from hydrogen, C_1-6Alkyl, 3-6 membered cycloalkyl;

further preferably, R^4aAnd R^4bEach independently selected from hydrogen and C_1-6An alkyl group;

more preferably, R^4aAnd R^4bEach independently selected from hydrogen, methyl.

3. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, isotopic label, metabolite or prodrug thereof, wherein:

R²is selected from C_1-6Alkyl, 3-8 membered cycloalkyl, 4-10 membered heterocycloalkyl, phenyl, heteroaryl, -NR⁵R⁶(ii) a Wherein said C_1-6The alkyl, 3-8 membered cycloalkyl, 4-10 membered heterocycloalkyl, phenyl, heteroaryl are unsubstituted or each independently substituted by one or more groups selected from oxo, halo, cyano, hydroxy, C_1-6Alkyl radical, C_1-6Haloalkyl, 3-8 membered cycloalkyl, 4-10 membered heterocycloalkylC(O)R⁵、-C(O)OR⁵、-(CO)NR⁵R⁶、-(SO₂)R⁵、-(SO)R⁵、-(SO₂)NR⁵R⁶、-(PO)(OR⁵)₂、-(PO)(OR⁵)R⁶And- (PO) (R)⁵)₂The substituent(s) is substituted at any substitutable position;

preferably, R²Is selected from C_1-6Alkyl, 3-6 membered cycloalkyl, 5-6 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, -NR⁵R⁶(ii) a Wherein said C_1-6Alkyl, 3-6 membered cycloalkyl, 5-6 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl are unsubstituted or each independently substituted with one or more substituents selected from oxo, halo, cyano, hydroxy, C_1-6Alkyl radical, C_1-6Haloalkyl, 3-6-membered cycloalkyl, 5-6 membered heterocycloalkyl, -C (O) R⁵、-(CO)NR⁵R⁶、-(SO₂)R⁵And- (SO)₂)NR⁵R⁶The substituent of (b) is substituted at any substitutable position;

more preferably, R²Is selected from C_1-6Alkyl, 3-to 6-membered cycloalkyl, phenyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, and the like,

Pyrazolyl, imidazolyl, pyrimidinyl, pyrazinyl, pyridazinyl, -NR⁵R⁶(ii) a Wherein said C_1-6Alkyl, 3-to 6-membered cycloalkyl, phenyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, and the like,

Pyrazolyl, imidazolyl, pyrimidinyl, pyrazinyl, pyridazinyl being unsubstituted or each independently substituted by one or more groups selected from C_1-6Alkyl, 3-6 membered cycloalkyl, C_1-6Haloalkyl, oxo, halogen, cyano, hydroxy, tetrahydropyrrolyl, piperidinyl, -C (O) R⁵、-(CO)NR⁵R⁶、-(SO₂)R⁵And- (SO)₂)NR⁵R⁶The substituent of (b) is substituted at any substitutable position;

further preferably, R₂Is selected from C_1-6Alkyl, 3-to 6-membered cycloalkyl, phenyl, tetrahydropyranyl, piperidinyl,

Pyrazolyl, tetrahydropyrrole; wherein said C_1-6Alkyl, 3-to 6-membered cycloalkyl, phenyl, tetrahydropyranyl, piperidinyl,

Pyrazolyl, tetrahydropyrrolyl or pyrazolyl, pyrrolyl is unsubstituted or each independently substituted by one or more groups selected from C_1-6Alkyl, cyclopropyl, C_1-6Haloalkyl, oxo, halogen, cyano, hydroxy, piperidinyl, -C (O) R⁵、-(CO)NR⁵R⁶、-(SO₂)R⁵And- (SO)₂)NR⁵R⁶The substituent of (b) is substituted at any substitutable position;

most preferably, R²Selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclopentyl, phenyl, tetrahydropyranyl, piperidinyl, and mixtures thereof,

Pyrazolyl, tetrahydropyrrolyl, wherein said methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclopentyl, phenyl, tetrahydropyranyl, piperidinyl, piperazinyl, piperidinyl, and piperazinyl,

Pyrazolyl, tetrahydropyrrolyl being unsubstituted or substituted independently of one another by one, two or three radicals from the group consisting of methyl, cyclopropyl, difluoromethyl, oxo, fluoro, hydroxy, cyano, piperidinyl, - (SO)₂)R⁵、-(SO₂)NR⁵R⁶、-(CO)NR⁵R⁶and-C (O) R⁵The substituent(s) is substituted at any substitutable position; preferably, R⁵And R⁶Each independently selected from hydrogen and C_1-6Alkyl, 3-8 membered cycloalkyl, 3-15 membered bridged cyclic group, 3-15 membered bridged heterocyclic group, phenyl, heteroaryl;

or R⁵And R⁶And the atoms to which they are attached form a nitrogen-containing 4-8 membered heterocyclic ring, said nitrogen-containing 4-8 membered heterocyclic ring being unsubstituted or substituted with one or more groups selected from deuterium, halogen, hydroxy, C_1-6Alkoxy, 3-to 8-membered cycloalkyl, 4-to 10-membered heterocycloalkyl and- (SO)₂)R⁷Said nitrogen-containing 4-8 membered heterocyclic ring optionally containing an additional heteroatom selected from O, N and S;

preferably, R⁵And R⁶Each independently selected from hydrogen, C_1-6Alkyl, 3-6 membered cycloalkyl, regular tetrahedral alkyl, adamantyl, trigonal alkyl, cubic alkyl, higher cubic alkyl, basketball alkyl, pentagonal alkyl, dipentagonal alkyl, di-n-butyl, tri-butyl, tetra-butyl, tri-n-butyl, tri-butyl, tetra-n-butyl, tetra-n-butyl, tri-n-butyl, tri-n-butyl, tri-n-butyl, tri-n-butyl, n-butyl, n-,

More preferably, R⁵And R⁶Each independently selected from hydrogen and C_1-6Alkyl, 3-6 membered cycloalkyl,

Further preferably, R⁵And R⁶Each independently selected from hydrogen and C_1-6Alkyl, 3-6 membered cycloalkyl;

even further preferably, R⁵And R⁶Each independently selected from hydrogen and C_1-6Alkyl, cyclopropyl;

most preferably, R⁵And R⁶Each independently selected from hydrogen, methyl, ethyl, cyclopropyl;

or preferably, R⁵And R⁶And the atoms to which they are attached form a nitrogen-containing 5-6 membered heterocyclic ring, said nitrogen-containing 5-6 membered heterocyclic ringThe heterocyclic ring being unsubstituted or substituted by one or more radicals selected from C_1-6The substituent of the alkyl group is substituted at any substitutable position;

or more preferably, R⁵And R⁶And the atoms to which they are attached together form a tetrahydropyrrole, a tetrahydroimidazole, a tetrahydropyrazole, a piperidine, or a piperazine;

or most preferably, R⁵And R⁶And the atoms to which they are attached together form a tetrahydropyrrole;

preferably, R⁷Is selected from C_1-6Alkyl, 3-8 membered cycloalkyl, phenyl.

4. The compound of any one of claims 1-3, or a pharmaceutically acceptable salt, solvate, isotopic label, metabolite or prodrug thereof, wherein R is¹Selected from:

preferably, R¹Is selected from

5. The compound of any one of claims 1-4, or a pharmaceutically acceptable salt, solvate, isotopic label, metabolite or prodrug thereof, wherein R is²Selected from:

preferably, R²Is selected from

Preferably, R²Is selected from

6. The compound of any one of claims 1-5, or a pharmaceutically acceptable salt, solvate, isotopic label, metabolite or prodrug thereof, wherein formula (I) has the following structure of formula (I'):

wherein R is¹And R²As defined in formula (I).

7. The compound according to any one of claims 1-6, or a pharmaceutically acceptable salt, solvate, isotopic label, metabolite or prodrug thereof, selected from the group consisting of:

8. a composition or formulation comprising a compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt, solvate, isotopic label, metabolite or prodrug thereof, and optionally a pharmaceutically acceptable carrier and/or adjuvant and/or diluent.

9. Use of a compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt, solvate, isotopic label, metabolite or prodrug thereof, or a composition or formulation according to claim 8, in the manufacture of a medicament for the treatment and/or prevention of an associated disease mediated by ATR, and/or for the treatment and/or prevention of an ATR mediated disease;

preferably, the ATR-mediated associated disease is a value-added disease;

more preferably, the ATR-mediated associated disease is a malignant tumor.

10. A method of treating and/or preventing an ATR-mediated disease, comprising administering to a subject an effective amount of a compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt, solvate, isotopic label, metabolite or prodrug thereof, or a composition or formulation according to claim 8;

preferably, the ATR-mediated associated disease is a value-added disease;

more preferably, the ATR-mediated associated disease is a malignant tumor.