WO2023020604A1

WO2023020604A1 - Five-membered nitrogen-containing heterocyclic and heteroaryl derivative and use thereof

Info

Publication number: WO2023020604A1
Application number: PCT/CN2022/113490
Authority: WO
Inventors: 李上; 侯少华
Original assignee: 南京大美生物制药有限公司
Priority date: 2021-08-20
Filing date: 2022-08-19
Publication date: 2023-02-23
Also published as: CN117751127A

Abstract

A five-membered nitrogen-containing heterocyclic and heteroaryl derivative as shown in general formula (I), a preparation method therefor, a pharmaceutical composition containing the derivative, and a use thereof as a therapeutic agent, and in particular a use thereof as an ATR kinase inhibitor and a use in preparation of a drug for preventing an ATR kinase-mediated disease.

Description

A five-membered nitrogen-containing heterocyclic heteroaryl derivative and its use

technical field

The invention belongs to the field of medicinal chemistry, and specifically relates to a five-membered nitrogen-containing heterocyclic and heteroaryl derivative and its application.

Background technique

ATR (ataxia telangiectasia mutated and RAD-3-related protein kinase) belongs to the PIKKs (phosphatidylinositol-3-kinase-related kinase) family and is involved in DNA damage repair to maintain gene stability. ATR kinase works with ATM ("ataxia telangiectasia mutated") kinase and many other proteins to regulate the cellular response to DNA damage, commonly referred to as the DNA damage response ("DDR"). DDR stimulates DNA repair, promotes survival and stalls cell cycle progression by activating cell cycle checkpoints that provide time for repair. Without DDR, cells are more sensitive to DNA damage and prone to die from DNA damage induced by endogenous cellular processes such as DNA repair or by exogenous DNA damaging agents commonly used in cancer therapy.

Healthy cells can depend on different host proteins for DNA repair, including the DDR kinase ATR. In some cases, these proteins can compensate each other by functionally activating redundant DNA repair processes. In contrast, many cancer cells harbor defects in some of their DNA repair processes such as ATM signaling and thus display a greater dependence on their remaining intact DNA repair proteins including ATR. In addition, many cancer cells express activated oncogenes or lack key tumor suppressor genes, and this situation can predispose these cancer cells to periods of dysregulated DNA replication, thereby leading to DNA damage.

ATR is activated by DNA single-strand structures when DNA double-strand breaks occur excision or replication fork stalls. The DNA polymerase stays in the DNA replication process, and the replicative helicase continues to unwind at the front of the DNA replication fork, resulting in the generation of long single-stranded DNA (ssDNA), which is then bound by ssDNA and RPA (replication protein A). Complexes of ATR/ATR-acting proteins recruited by RPA during replication stress or DNA damage to damage sites, RPA-ssDNA complexes activate RAD17/rfc2-5 complexes to bind to damage sites, DNA-ssDNA junctions Activates the Rad9-HUS1-RAD1 (9-1-1) heterotrimer, which in turn recruits TopBP1 to activate ATR. Once activated, ATR promotes DNA repair, stabilization and restart of stalled replication forks and transient cell cycle arrest through downstream targets. These functions are realized by ATR through mediating the downstream target Chk1. ATR functions as a DNA damage cell cycle checkpoint during S phase. It can mediate the degradation of CDC25A through Chk1, thereby delaying the process of DNA replication and providing time for the repair of replication forks. ATR is also a master regulator of the G2/M cell cycle checkpoint, preventing cells from entering mitosis prematurely until DNA replication is complete or DNA damage occurs. This ATR-dependent G2/M cell cycle arrest is mainly mediated by two mechanisms: 1. Degradation of CDC25A. 2. Phosphorylation of Cdc25C by Chk1 to bind to 14-3-protein. Binding of Cdc25C to 14-3-3 proteins promotes its export from the nucleus and sequestration into the cytoplasm, thereby inhibiting its ability to dephosphorylate and activate nuclear Cdc2, which in turn prevents entry into mitosis.

Since ATR is essential for the self-replication of cells, it is activated in S phase to regulate origins of replication and repair damaged replication forks. Replication fork damage can increase the sensitivity of cancer cells to platinum and hydroxyurea anticancer drugs and reduce the drug resistance of cancer cells. Therefore, inhibition of ATR may be an effective approach in future cancer therapy.

The currently disclosed ATR inhibitor compounds include M6620, AZD-6738 and the like. In April 2021, Merck KGaA announced the pivotal clinical progress of berzosertib (M6620). Berzosertib is an investigational potent and selective ataxia telangiectasia and Rad3-related protein (ATR) inhibitor.

Contents of the invention

The compound of the present invention has a core structure different from the above structure, and the obtained compound can produce a good inhibitory effect on ATR. The compounds of the present invention and pharmaceutically acceptable compositions thereof are useful in the treatment of a variety of cancers.

Unless otherwise indicated, structures depicted herein are also intended to include all isomeric (e.g., enantiomers, diastereoisomers, and geometric (or configuration) isomers) forms of the described structures; e.g. R and S configurations, Z and E double bond isomers, and Z and E configuration isomers for each asymmetric center. Thus, single stereochemical isomers as well as enantiomeric, diastereoisomer and geometric (or configurational) isomer mixtures of the compounds of the present invention are within the scope of the present invention. Unless otherwise stated, all tautomeric forms of the compounds of the invention are within the scope of the invention. Additionally, unless otherwise indicated, structures depicted herein are also intended to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having structures of the invention that include substitution of deuterium or tritium for hydrogen, or substitution of carbon for ¹³ C or ¹⁴ C enriched carbon are within the scope of the invention. Said compounds are suitable, for example, as analytical tools, probes in biological assays or therapeutic agents according to the invention.

A pharmaceutically acceptable excipient or vehicle refers to a non-toxic carrier, excipient or vehicle that does not destroy the pharmacological activity of the compound with which it is formulated. Pharmaceutically acceptable carriers, excipients or vehicles that may be used in the compositions of the present invention include, but are not limited to, ion exchangers; aluminum oxide; aluminum stearate; lecithin; serum proteins such as human serum albumin ; buffer substances such as phosphate; glycine; sorbic acid; potassium sorbate; partial glyceride mixtures of saturated vegetable fatty acids; water; salts or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate , sodium chloride, zinc salts; colloidal silicon dioxide; magnesium trisilicate; polyvinylpyrrolidone; cellulose-based substances; polyethylene glycol; sodium carboxymethylcellulose; polyacrylates; waxes; polyethylene-polyethylene Oxypropylene - block polymer; polyethylene glycol and lanolin.

In specific embodiments, a combination of two or more therapeutic agents may be administered with a compound of the invention. In specific embodiments, a combination of three or more therapeutic agents may be administered with the compounds of the invention.

In specific embodiments, compounds of the invention, or pharmaceutically acceptable compositions thereof, are administered in combination with antisense agents, monoclonal or polyclonal antibodies, or siRNA therapeutics.

Those additional agents may be administered separately from the compound or composition of the invention as part of a multiple dosing regimen. Alternatively, those agents may be part of a single dosage form, mixed together with the compounds of this invention in a single composition. If administered as part of a multiple dosing regimen, the two active agents may be given simultaneously, sequentially or within a period of time from each other (usually within 5 hours of each other).

The terms "combination", "combination" and related terms as used herein refer to the simultaneous or sequential administration of the therapeutic agents according to the invention. For example, a compound of the invention may be administered simultaneously or sequentially with another therapeutic agent in separate unit dosage forms or together in a single unit dosage form. Accordingly, the present invention provides single unit dosage forms comprising a compound of the invention, an additional therapeutic agent and a pharmaceutically acceptable carrier, excipient or vehicle.

The amount of both a compound of the invention and the other therapeutic agent (in those compositions containing the other therapeutic agent as described above) which can be combined with a carrier material to produce a single dosage form will vary depending upon the host treated and the particular mode of administration . Preferably, the compositions of the invention should be formulated such that a dosage of between 0.01 mg and 100 mg per kilogram body weight per day can be administered.

In those compositions that include other therapeutic agents, the other therapeutic agents and the compounds of this invention may act synergistically. Accordingly, the amount of other therapeutic agent in these compositions will be lower than that required in monotherapy using only that therapeutic agent. In these compositions, the additional therapeutic agent may be administered at a dose of between 0.01 μg and 100 μg per kilogram body weight per day.

The amount of other therapeutic agent present in the compositions of the invention will be no greater than the amount normally administered in a composition comprising that therapeutic agent as the only active agent. Preferably, the amount of other therapeutic agent in the compositions disclosed herein will range from about 50% to 100% of the amount normally present in a composition comprising that agent as the only therapeutically active agent.

In order to realize the present invention, the present invention adopts following technical scheme.

a compound of formula (I) or a pharmaceutically acceptable salt thereof,

in:

X ₁ is NR ₅ , O or CR ₆ , wherein R ₅ and R ₆ are independently hydrogen, alkyl, cycloalkyl, alkoxy, hydroxyalkyl, halogen or hydroxyl, wherein the alkyl, cycloalkyl , alkoxy and hydroxyalkyl are each independently selected from halogen, hydroxyl, carboxyl, amino, nitro, cyano, C1-C6 amido, C1-C6 acyloxy, C1-C6 alkoxy, aryloxy Base, alkylthio, C1-C6 alkyl, C1-C6 acyl, C6-C10 aryl, C3-C8 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, heterocyclyl, heteroaryl , methylenedioxy, ureido, mercapto, azido, carbonyl, alkylsulfonyl, sulfamoyl, dialkylsulfamoyl and alkylsulfinyl are substituted by one or more substituents;

_X2 is C or N;

_X3 is CH or N;

_X4 is CH or N;

_X5 is CH or N;

_R1 is

_Each R is independently hydrogen, alkyl, cycloalkyl, alkoxy, cyano or halogen; wherein said alkyl, cycloalkyl and alkoxy are each independently selected from halogen, hydroxy, carboxyl, amino , Nitro, cyano, C1-C6 amido, C1-C6 acyloxy, C1-C6 alkoxy, aryloxy, alkylthio, C1-C6 alkyl, C1-C6 acyl, C6-C10 aromatic C3-C8 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, heterocyclyl, heteroaryl, methylenedioxy, ureido, mercapto, azido, carbonyl, alkanesulfonyl One or more substituents in acyl, sulfamoyl, dialkylsulfamoyl and alkylsulfinyl;

_R2 is selected from:

R ₈ , R ₉ and R ₁₀ are independently hydrogen, alkyl, cycloalkyl, alkoxy, cyano, halogen or NR ₁₁ R ₁₂ , wherein R ₁₁ and R ₁₂ are independently hydrogen, alkyl, cycloalkane group, alkoxy group, cyano group or halogen; wherein said alkyl group, cycloalkyl group and alkoxy group are each independently selected from halogen, hydroxyl group, carboxyl group, amino group, nitro group, cyano group, C1-C6 amido, C1-C6 acyloxy, C1-C6 alkoxy, aryloxy, alkylthio, C1-C6 alkyl, C1-C6 acyl, C6-C10 aryl, C3-C8 cycloalkyl, C2-C6 chain Alkenyl, C2-C6 alkynyl, heterocyclyl, heteroaryl, methylenedioxy, ureido, mercapto, azido, carbonyl, alkylsulfonyl, sulfamoyl, dialkylsulfamoyl and One or more substituents in the alkylsulfinyl group are substituted;

R ₃ is alkyl, aryl, heterocyclyl, cycloalkyl, heteroaryl, carbonyl, -S(=O)R ₁₃ , -alkyl-S(=O)R ₁₃ , -cycloalkyl-S (=O)R ₁₃ , -S(=O) ₂ R ₁₃ , -alkyl-S(=O) ₂ R ₁₃ , -cycloalkyl-S(=O) ₂ R ₁₃ , -S(=O) (=NH)R ₁₃ , -alkyl-S(=O)(=NH)R ₁₃ or -cycloalkyl-S(=O)(=NH)R ₁₃ , wherein the alkyl, aryl, hetero Cyclic group, cycloalkyl group and heteroaryl group are each independently selected from halogen, hydroxyl, carboxyl, amino, nitro, cyano, C1-C6 amido, C1-C6 acyloxy, C1-C6 alkoxy, Aryloxy, alkylthio, C1-C6 alkyl, C1-C6 acyl, C6-C10 aryl, C3-C8 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, heterocyclyl, hetero One or more substituents in aryl, methylenedioxy, ureido, mercapto, azido, carbonyl, alkylsulfonyl, sulfamoyl, dialkylsulfamoyl and alkylsulfinyl replace;

R ₁₃ is alkyl, cycloalkyl, heteroaryl, aryl or heterocyclyl;

_R is hydrogen, alkyl, cycloalkyl, alkoxy, cyano or halogen; wherein said alkyl, cycloalkyl and alkoxy are each independently selected from halogen, hydroxyl, carboxyl, amino, nitro , cyano, C1-C6 amido, C1-C6 acyloxy, C1-C6 alkoxy, aryloxy, alkylthio, C1-C6 alkyl, C1-C6 acyl, C6-C10 aryl, C3 -C8 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, heterocyclyl, heteroaryl, methylenedioxy, ureido, mercapto, azido, carbonyl, alkanesulfonyl, ammonia One or more substituents in sulfonyl, dialkylsulfamoyl and alkylsulfinyl;

Or, R ₄ and X ₂ together form a carbonyl group, or, R ₄ and R ₃ form a 5-7 membered ring together with the group they are connected to;

n, m, p represent 0, 1, 2 or 3;

In some specific embodiments, said R ₁ is

In certain embodiments, R ₇ is methyl or ethyl. In certain embodiments, p is 0 or 1.

In some specific embodiments, said R ₁ is selected from the following groups:

In some specific embodiments, said R _is selected from the following groups:

In certain embodiments, said R ₃ is alkyl or cycloalkyl. In some specific embodiments, the alkyl and cycloalkyl are optionally substituted with 1-3 substituents selected from cycloalkyl, halogen, cyano or pyridyl.

In some specific embodiments, the R ₃ is a group such as methyl, cyclopropyl, cyclopentyl, isopropyl, cyclopropylmethylene.

In some specific embodiments, the R ₃ is an N-containing six-membered or five-membered unsaturated heterocyclic ring. In certain embodiments, the unsaturated heterocycle is optionally substituted with an alkyl group.

In some specific embodiments, said _R is selected from:

In certain embodiments, said R ₃ is a benzene ring. In some specific embodiments, the ortho, meta or para positions of the benzene ring are optionally independently selected from halogen, hydroxyl, carboxyl, amino, nitro, cyano, C1-C6 amido, C1- C6 acyloxy, C1-C6 alkoxy, aryloxy, alkylthio, C1-C6 alkyl, C1-C6 acyl, C6-C10 aryl, C3-C8 cycloalkyl, C2-C6 alkenyl , C2-C6 alkynyl, heterocyclyl, heteroaryl, methylenedioxy, isopropylcyano, ureido, mercapto, azido, carbonyl, alkanesulfonyl, sulfamoyl, dialkyl One or more substituents in sulfamoyl and alkylsulfinyl groups.

In certain embodiments, said R ₃ is -S(=O)R ₁₃ , -S(=O) ₂ R ₁₃ or S(=O)(=NH)R ₁₃ . In certain specific embodiments, said _R is optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted benzene ring, optionally substituted containing N six-membered saturated heterocycle or optionally substituted N-containing six-member unsaturated heterocycle, the benzene ring or heterocycle may be substituted by alkyl, halogen, or alkoxy.

In some specific embodiments, said R ₃ is -alkyl-S(=O)R ₁₃ , -cycloalkyl-S(=O)R ₁₃ , -alkyl-S(=O) ₂ R ₁₃ , -cycloalkyl-S(=O) ₂ R ₁₃ , -alkyl-S(=O)(=NH)R ₁₃ or -cycloalkyl-S(=O)(=NH)R ₁₃ . In certain embodiments, the alkyl group is methylene, ethylene, propylene, butylene or -CH( _CH3 )-. In certain embodiments, the cycloalkyl is cyclopropyl, cyclobutyl or cyclopentyl. In certain embodiments, said R ₁₃ is optionally substituted alkyl (eg, methyl, ethyl or propyl).

In some specific embodiments, said X ₁ is C, X ₂ is C, and X ₃ is N.

In some specific embodiments, said X ₁ is N, X ₂ is C, and X ₃ is N.

In some specific embodiments, the R ₄ and R ₃ together form a six-membered N,O-containing heterocyclic ring.

In certain embodiments, said m and n are each independently zero.

In certain embodiments, said R ₄ and X ₂ together form a carbonyl group.

In certain embodiments, said R ₅ is H.

In some specific embodiments, said R ₆ is H, C _1-6 alkyl, alkoxy or halogen.

In certain embodiments, said R ₈ is H or halogen.

In certain embodiments, the halogen is a chlorine atom.

In certain embodiments, said R ₉ is H or halogen.

In certain embodiments, the halogen is a chlorine atom.

In certain embodiments, said R ₁₀ is H.

In some specific embodiments, the R ₁₁ and R ₁₂ are H, C _1-6 alkyl, halogen or alkyl substituted by 1-3 halogen atoms.

In certain embodiments, said R ₁₃ is cyclopropyl, isopropyl, methyl, ethyl or cyclopropylmethylene.

In some specific embodiments, said R ₁₃ is selected from the following groups:

In certain specific embodiments, the structure of the compound of formula (I) is as follows:

In certain embodiments, the compound is selected from:

In certain embodiments, the pharmaceutical composition contains a therapeutically effective amount of a compound described above and at least one pharmaceutically acceptable excipient.

In certain embodiments, the compound is used in the manufacture of a medicament for treating or preventing a disease mediated by ATR kinase; preferably, the disease is cancer.

In certain embodiments, wherein the cancer is liver cancer, melanoma, Hodgkin's disease, non-Hodgkin's lymphoma, acute lymphoblastic leukemia, chronic lymphocytic leukemia, multiple myeloma, neuroblastoma, breast cancer , ovarian cancer, lung cancer, Wilms tumor, cervical cancer, testicular cancer, soft tissue sarcoma, primary macroglobulinemia, bladder cancer, chronic myeloid leukemia, primary brain cancer, malignant melanoma, small Cell lung cancer, gastric cancer, colon cancer, malignant pancreatic insulinoma, malignant carcinoid cancer, choriocarcinoma, head and neck cancer, osteogenic sarcoma, pancreatic cancer, acute myeloid leukemia, hairy cell leukemia, rhabdomyosarcoma, Kaposi's sarcoma , genitourinary system tumor disease, thyroid cancer, esophageal cancer, malignant hypercalcemia, cervical hyperplasia, renal cell carcinoma, endometrial cancer, polycythemia vera, essential thrombocythemia, adrenal cortical carcinoma, skin cancer and prostate cancer.

Detailed term

Unless stated to the contrary, the terms used in the specification and claims have the following meanings.

The term "alkyl" refers to a saturated aliphatic hydrocarbon group which is a straight or branched chain group containing 1 to 20 carbon atoms, preferably containing 1 to 12 (e.g. 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12) carbon atoms, more preferably an alkyl group having 1 to 6 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1 , 2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2- Methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3 -Dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2 -Methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethyl Pentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2 , 5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethyl ylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethyl 2,2-diethylhexyl, 2,2-diethylpentyl, n-decyl, 3,3-diethylhexyl, 2,2-diethylhexyl, and various branched isomers thereof. More preferred are lower alkyl groups containing 1 to 6 carbon atoms, non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl Base, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethyl Dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl group, 2,3-dimethylbutyl group, etc. Alkyl groups may be substituted or unsubstituted, and when substituted, the substituents may be substituted at any available point of attachment, preferably independently and optionally selected from H atoms, D atoms, halogens, alkane One or more substituents in radical, alkoxy, haloalkyl, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl.

The term "alkylene" refers to a saturated straight or branched chain aliphatic hydrocarbon group having two residues derived from the same carbon atom or two different carbon atoms of a parent alkane by removing two hydrogen atoms, which are Straight or branched chain groups containing 1 to 20 carbon atoms, preferably 1 to 12 (eg 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12) carbons atoms, more preferably an alkylene group containing 1 to 6 carbon atoms. Non-limiting examples of alkylene include, but are not limited to, methylene (-CH ₂ -), 1,1-ethylene (-CH(CH ₃ )-), 1,2-ethylene (-CH ₂ CH ₂ )-, 1,1-propylene (-CH(CH ₂ CH ₃ )-), 1,2-propylene (-CH ₂ CH(CH ₃ )-), 1,3-propylene (-CH ₂ CH ₂ CH ₂ -), 1,4-butylene (-CH ₂ CH ₂ CH ₂ CH ₂ -), etc. Alkylene may be substituted or unsubstituted, and when substituted, substituents may be substituted at any available point of attachment, preferably independently optionally selected from alkyl, alkenyl, alkynyl , Alkoxy, Alkylthio, Alkylamino, Halogen, Thiol, Hydroxy, Nitro, Cyano, Cycloalkyl, Heterocyclyl, Aryl, Heteroaryl, Cycloalkoxy, Heterocycloalkoxy One or more substituents in radical, cycloalkylthio, heterocycloalkylthio and oxo.

The term "alkenyl" refers to an alkyl compound containing at least one carbon-carbon double bond in the molecule, wherein alkyl is as defined above. Alkenyl groups may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from a hydrogen atom, an alkyl group, an alkoxy group, a halogen, a haloalkyl group, a hydroxyl group, One or more substituents in hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

The term "alkynyl" refers to an alkyl compound containing at least one carbon-carbon triple bond in the molecule, wherein alkyl is as defined above. Alkynyl groups may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from hydrogen atom, alkyl, alkoxy, halogen, haloalkyl, hydroxyl, One or more substituents in hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, the cycloalkyl ring containing 3 to 20 carbon atoms, preferably containing 3 to 12 carbon atoms, more preferably containing 3 to 8 (eg 3, 4, 5, 6, 7 or 8) carbon atoms, more preferably comprising 3 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatriene Base, cyclooctyl, etc.; polycyclic cycloalkyl includes spiro ring, fused ring and bridged ring cycloalkyl.

The cycloalkyl ring includes a cycloalkyl group as described above (including monocyclic, spiro, fused and bridged rings) fused to an aryl, heteroaryl or heterocycloalkyl ring wherein the parent structure is bonded to The rings taken together are cycloalkyl, non-limiting examples include indanyl, tetrahydronaphthyl, phenylcyclopentyl, and benzocycloheptyl, etc.; preferably phenylcyclopentyl and tetrahydronaphthyl .

Cycloalkyl groups may be substituted or unsubstituted, and when substituted, the substituents may be substituted at any available point of attachment, preferably independently and optionally selected from hydrogen atoms, halogen, alkyl, One or more substituents in alkoxy, haloalkyl, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl.

The term "alkoxy" refers to -O-(alkyl) and -O-(unsubstituted cycloalkyl), wherein alkyl is as defined above. Non-limiting examples of alkoxy include: methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy. Alkoxy may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from H atom, D atom, halogen, alkyl, alkoxy , Haloalkyl, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl are substituted by one or more substituents. The term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent comprising 3 to 20 ring atoms, wherein one or more ring atoms are selected from nitrogen, oxygen, S, S( O) and S(O) ₂ heteroatoms, but excluding ring portions of -OO-, -OS- or -SS-, the remaining ring atoms being carbon. Preferably comprising 3 to 12 ring atoms, of which 1 to 4 (eg 1, 2, 3 and 4) are heteroatoms; more preferably comprising 3 to 8 (eg 3, 4, 5, 6, 7 or 8) ring atoms, of which 1-3 (eg 1, 2 or 3) are heteroatoms; more preferably contain 3 to 6 ring atoms, of which 1-3 are heteroatoms; most preferably contain 5 or 6 ring atoms, of which 1 -3 are heteroatoms. Non-limiting examples of monocyclic heterocyclyl groups include pyrrolidinyl, tetrahydropyranyl, 1,2,3,6-tetrahydropyridyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholine base, homopiperazinyl, etc. Polycyclic heterocyclyls include spiro, fused and bridged heterocyclyls.

Heterocyclyl rings include heterocyclyl groups as described above (including monocyclic, spiro heterocyclic, fused heterocyclic and bridged heterocyclic rings) fused to aryl, heteroaryl or cycloalkyl rings wherein the parent structure is bonded to The rings taken together are heterocyclyl, non-limiting examples of which include:

The heterocyclyl group may be substituted or unsubstituted, and when substituted, the substituents may be substituted at any available attachment points, preferably independently and optionally selected from hydrogen atoms, halogens, alkyls, One or more substituents in alkoxy, haloalkyl, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl.

The term "aryl" refers to a 6 to 14 membered all-carbon monocyclic or fused polycyclic (a fused polycyclic is a ring sharing adjacent pairs of carbon atoms) group having a conjugated π-electron system, preferably 6 to 10 membered , such as phenyl and naphthyl. The aryl ring includes an aryl ring as described above fused to a heteroaryl, heterocyclyl or cycloalkyl ring, wherein the ring bonded to the parent structure is an aryl ring.

Aryl groups may be substituted or unsubstituted, and when substituted, substituents may be substituted at any available point of attachment, preferably independently and optionally selected from hydrogen atoms, halogen, alkyl, alkane One or more substituents in oxy, haloalkyl, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl.

The term "heteroaryl" refers to a heteroaromatic system comprising 1 to 4 (eg 1, 2, 3 and 4) heteroatoms, 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur and nitrogen. Heteroaryl is preferably 5 to 10 membered (e.g. 5, 6, 7, 8, 9 and 10), more preferably 5 or 6 membered, e.g. furyl, thienyl, pyridyl, pyrrolyl, N-alkyl Pyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, etc. The heteroaryl ring includes a heteroaryl as described above fused to an aryl, heterocyclyl or cycloalkyl ring, wherein the ring attached to the parent structure is a heteroaryl ring.

Heteroaryl groups may be substituted or unsubstituted, and when substituted, the substituents may be substituted at any available point of attachment, preferably independently and optionally selected from hydrogen atoms, halogens, alkyls, One or more substituents in alkoxy, haloalkyl, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl.

The above-mentioned cycloalkyl, heterocyclyl, aryl and heteroaryl groups have 1 residue derived from the removal of a hydrogen atom from the parent ring atom, or 2 residues derived from the same or two different ring atoms of the parent A residue derived from a hydrogen atom, namely "divalent cycloalkyl", "divalent heterocyclyl", "arylene", "heteroarylene".

The term "amino-protecting group" is used to protect the amino group with a group that can be easily removed in order to keep the amino group unchanged when other parts of the molecule react. Non-limiting examples include tetrahydropyranyl, tert-butoxycarbonyl, acetyl, benzyl, allyl, p-methoxybenzyl, and the like. These groups may be optionally substituted with 1 to 3 substituents selected from halogen, alkoxy or nitro. The amino protecting group is preferably tetrahydropyranyl.

The term "cycloalkyloxy" refers to cycloalkyl-O-, wherein cycloalkyl is as defined above.

The term "haloalkyl" refers to an alkyl group substituted with one or more halogens, wherein alkyl is as defined above.

The term "hydroxyl" refers to a -OH group.

The term "hydroxyalkyl" refers to an alkyl group substituted by a hydroxy group, wherein alkyl is as defined above.

The term "halogen" refers to fluorine, chlorine, bromine or iodine.

The term "amino" refers to _-NH2 .

The term "cyano" refers to -CN.

The term "nitro" refers to _-NO2 .

The term "carbonyl" refers to C=O.

The term "carboxy" refers to -C(O)OH.

The term "carboxylate" refers to -C(O)O(alkyl) or -C(O)O(cycloalkyl), wherein alkyl and cycloalkyl are as defined above.

Compounds of the present disclosure may exist as tautomers. For the purposes of this disclosure, a reference to a compound of formula (I) refers to the compound itself, or any tautomer itself, or a mixture of two or more tautomers mentioned. For example, when referring to pyrazolyl, it should be understood as including any one of the following two structures or a mixture of two tautomers,

"Optional" or "optionally" means that the subsequently described event or circumstance can but need not occur, and that the description includes instances where the event or circumstance occurs or does not occur. For example, a "heterocyclic group optionally substituted with an alkyl group" means that an alkyl group may but need not be present, and the description includes cases where the heterocycle group is substituted with an alkyl group and cases where the heterocycle group is not substituted with an alkyl group .

"Substituted" means that one or more hydrogen atoms in a group, preferably up to 5, more preferably 1 to 3 hydrogen atoms are independently substituted by the corresponding number of substituents. It goes without saying that substituents are only in their possible chemical positions and that a person skilled in the art can determine (by experiment or theory) possible or impossible substitutions without undue effort. For example, an amino or hydroxyl group with free hydrogen may be unstable when bonded to a carbon atom with an unsaturated (eg, ethylenic) bond.

"Pharmaceutical composition" means a mixture containing one or more compounds described herein, or a physiologically/pharmaceutically acceptable salt or prodrug thereof, and other chemical components, and other components such as a physiologically/pharmaceutically acceptable carrier and excipients. The purpose of the pharmaceutical composition is to promote the administration to the organism, facilitate the absorption of the active ingredient and thus exert biological activity.

"Pharmaceutically acceptable salt" refers to the salt of the disclosed compound, which is safe and effective when used in mammals, and has proper biological activity.

Detailed ways

The synthesis of embodiment 1 compound R1

(1) Step 1:

At room temperature, (R)-4-(2-chloro-9h-purin-6-yl)-3-methylmorpholine (200 mg), bromoisopropane (161 mg) and potassium carbonate ( 120 mg), then DMF (8 mL) was added, followed by heating to 80° C. and stirring under reflux overnight. The completion of the reaction was monitored by TLC, the reaction solution was concentrated under reduced pressure, and purified by column chromatography (petroleum ether: ethyl acetate = 5:1) to obtain an off-white solid (145 mg, 62%). LC-MS [M+H] ⁺ = 296.20.

(2) Step 2:

At room temperature, add compound R1-1 (230mg), borate (227mg), Pd(PPh ₃ ) ₄ (90mg) and KOAc (165mg) into a 50mL single-necked bottle, then add DMSO (20mL), and pump nitrogen three times , heated to 120° C. for 8 hours, TLC monitored that the reaction was complete, and the reaction solution was lowered to room temperature. The reaction solution was poured into 60 mL of water, extracted with ethyl acetate, and the organic phase was dried and filtered and then spin-dried, column chromatography (petroleum ether: ethyl acetate Ester=5:1-1:1) to obtain a light yellow solid (130 mg, 44%). ¹ H NMR (400MHz, MeOD) δ8.30(d, 1H), 8.20(s, 1H), 8.14(d, 1H), 7.50(dd, 2H), 5.57(s, 1H), 5.20(s, 1H ), 5.04(dt, 1H), 4.09(dd, 1H), 3.89(s, 2H), 3.80–3.70(m, 1H), 3.66–3.57(m, 1H), 1.73(d, 6H), 1.49( d, 3H). LC-MS [M+H] ⁺ = 378.30.

The synthesis of embodiment 2 compound R2

(1) Step 1:

Compound W-1 is 2,4-dichloro-7-deazapurine, purchased from Leyan Reagent, with a purity ≥ 99.37%. The following examples are the same.

At room temperature, 2,4-dichloro-7-deazapurine (2.0 g) was placed in a 50 mL round bottom flask, and THF (16 mL) was added. Cool down to 0-5°C and stir for 5min. 60% sodium hydride (0.51 g) was added, and the reaction was stirred for 15 min. Iodomethane (17.0 g) was added, the temperature was raised to room temperature, and the reaction was stirred overnight. TLC (petroleum ether:ethyl acetate=4:1) monitored the completion of the reaction. Water was added to the reaction mixture to quench the reaction, and the resulting mixture was extracted with ethyl acetate (3 times). The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to obtain Compound R2-1 (1.76 g, 81.9%) as a white powder. LC-MS [M+H] ⁺ =203.

(2) Step 2:

At room temperature, take compound R2-1 (1.0 g), (R)-3-methylmorpholine (600 mg), and anhydrous potassium carbonate (2.05 g), and place them in a 50 mL round bottom flask. DMF (10 mL) was added, heated to 90-100° C., and stirred for 5-6 h. TLC monitors until the reaction is complete. Cool to room temperature, add ice water/extract twice with ethyl acetate, combine the ethyl acetate phases, wash with water and brine, dry over anhydrous sodium sulfate, filter, concentrate, column chromatography (petroleum ether: ethyl acetate = 4: 1) Purification to obtain compound R2-2 (0.99 g, 75%) in the form of orange oil. LC-MS [M+H] ⁺ =267.

(3) Step 3:

Weigh compound R2-2 (500mg), 7-azaindole borate pinacol ester (502mg), anhydrous potassium carbonate (775mg), tetrakistriphenylphosphopalladium (216mg), 1,4-dioxane ring (10 mL), water (2 mL). Nitrogen was replaced 3 times, heated to 90-100°C, and stirred overnight. Cool to room temperature, add ice water, extract twice with ethyl acetate, combine the ethyl acetate phases, wash with water and brine, dry over anhydrous sodium sulfate, filter, concentrate, column chromatography (petroleum ether: ethyl acetate = 2: 1) Purification to obtain compound R2 (455 mg, 70%) as a solid powder. ¹ H NMR (400MHz, CD ₃ CN) δ9.81(s, 1H), 8.37(d, 1H), 8.17(d, 1H), 7.61(d, 1H), 7.52(d, 1H), 7.19(s , 1H), 6.64(s, 1H), 4.93(d, 1H), 4.61(d, 1H), 4.06(d, 1H), 3.89(d, 3H), 3.82(d, 2H), 3.70–3.67( m, 1H), 3.59–3.53 (m, 1H), 1.42–1.36 (m, 3H). LC-MS [M+H] ⁺ = 349.

The synthesis of embodiment 3 compound R3

(1) Step 1:

Dichloromethane (100 mL), 2.4-dichloro-pyrrolopyrimidine (2 g), and diisopropylethylamine (5 mL) were added to a 250 mL reaction flask, and the reaction mixture was stirred at room temperature for 10 min, turning into a white turbid liquid. Then methanesulfonyl chloride (3 g) was added, and the mixture gradually dissolved and turned into a bright yellow clear liquid. It was reacted at room temperature for 2 h, and monitored by TLC (petroleum ether: ethyl acetate = 4:1, adding a drop of methanol) until the reaction was complete. The reaction solution was added to water (500 mL), stirred for 30 min, triethylamine (10 mL) was added during the stirring process, allowed to stand, and the organic phase was separated, dried over anhydrous sodium sulfate, filtered, and the filtrate was used directly in the next step. LC-MS [M+H] ⁺ =267.

(2) Step 2:

Diisopropylethylamine (5mL) and morpholine (2.5mL) were added to the reaction treatment solution of the previous step, and then stirred at room temperature for 4-5h, a bright yellow clear liquid, TLC (petroleum ether: ethyl acetate = 4:1) Monitor until the raw material reacts completely. The reaction solution was washed twice with water (100mL*2), dried over anhydrous sodium sulfate, filtered, concentrated, slurried with n-hexane, filtered, and dried to obtain compound R3-2 (1.8g, 53%) in the form of off-white solid powder . LC-MS [M+H] ⁺ =317.

(3) Step 3:

Under nitrogen protection, DMSO (20mL), compound R3-2 (1.4g), 7-azaindoleboronic acid pinacol ester (1.16g), sodium fluoride (2.1g) and tetrakis ( Triphenylphosphine)palladium (0.29g), then the reaction mixture was heated to 120°C, kept for 4-5h, and monitored by TLC (petroleum ether: ethyl acetate = 1:1) until the reaction of the raw materials was complete. The reaction solution was added to a mixture of water (50 mL) and ethyl acetate (50 mL), stirred and separated, the aqueous phase was taken, extracted three times with ethyl acetate, the organic phases were combined, washed with saturated brine, dried, concentrated, and the residue Purification by silica gel column chromatography afforded compound R3 (0.1 g, 5%) as a white solid. ¹ H NMR (400MHz, DMSO) δ8.36(t, 1H), 8.06(d, 1H), 7.65–7.55(m, 1H), 7.50(dt, 1H), 7.31(dd, 1H), 7.05(dd , 1H), 4.02(t, 2H), 3.88(t, 1H), 3.85–3.77(m, 4H), 2.84(s, 3H), 1.35(s, 3H). LC-MS [M+H] ⁺ = 399.

The synthesis of embodiment 4 compound R5

(1) Step 1:

At room temperature, 4,6-dichloro-1H pyrazolo[3.4-d]pyrimidine (1 g), (R)-3-methylmorpholine (0.6 g), dichloromethane (30 mL) and potassium carbonate ( 1.5 g), reacted at 35°C for 12 h, washed with water, concentrated the organic phase, and the crude product was directly used in the next step. LC-MS [M+H] ⁺ =254.

(2) Step 2:

At room temperature, add compound R5-1 (300mg), iodoisopropane (1g), potassium carbonate (320mg) and DMF (10mL), react at 80°C for 5h, extract with water/ethyl acetate, concentrate the organic phase, and column It was purified by chromatography (petroleum ether:ethyl acetate=5:1) and used in the next step. LC-MS [M+H] ⁺ = 296.

(3) Step 3:

Add compound R5-2 (240mg), 7-azaindoleboronic acid pinacol ester (238mg), potassium carbonate (281mg), tetrakistriphenylphosphine palladium (140mg) and dimethyl sulfoxide (10mL) under nitrogen protection ), reacted at 120° C. for 5 h under the protection of nitrogen, extracted with water/ethyl acetate, concentrated the organic phase, and purified by column chromatography (petroleum ether: ethyl acetate=3:1) to obtain the target product (90 mg). ¹ H NMR (400MHz, CDCl ₃ -d) δ9.56(s, 1H), 8.47(d, 1H), 8.17(d, 1H), 7.99(s, 1H), 7.72(s, 1H), 7.67( d, 1H), 7.57–7.54(m, 1H), 5.39(p, 1H), 4.87(s, 1H), 4.22–4.12(m, 1H), 3.99–3.84(m, 2H), 3.74(td, 1H), 3.65 (s, 1H), 1.66 (dd, 6H), 1.54 (d, 3H). LC-MS [M+H] ⁺ =378.

The synthesis of embodiment 6 compound R7

(1) Step 1:

At room temperature, 4,6-dichloro-1H pyrazolo[3.4-d]pyrimidine (1 g), (R)-3-methylmorpholine (0.6 g), dichloromethane (30 mL) and potassium carbonate ( 1.5 g), reacted at 35°C for 12 h, washed with water, concentrated the organic phase, and the crude product was directly used in the next step.

(2) Step 2:

At room temperature, add compound R7-1 (1.09g), 1,1,1-trifluoro-2-iodoethane (1.804g), cesium carbonate (7.02g) and DMF (20mL), react at 70°C for 12h, TLC (petroleum ether:ethyl acetate=2:1), extracted with water/ethyl acetate, the organic phase was concentrated, purified by column chromatography (petroleum ether:ethyl acetate=10:1), and then used in the next step. LC-MS [M+H] ⁺ = 336.

(3) Step 3:

At room temperature, add compound R7-2 (0.2g), 7-azaindoleboronic acid pinacol ester (0.145g), cesium carbonate (0.582g), tetrakistriphenylphosphine palladium (0.069g) and water/1 , 4-dioxane (V:V=1:10), nitrogen protection at 95°C for 12h, TLC (petroleum ether:ethyl acetate=1:1), extraction with water/ethyl acetate, concentration of the organic phase, column Purification by chromatography (petroleum ether:ethyl acetate=3:1) gave compound R7 (15 mg) as a yellow solid. ¹ H NMR (400MHz, CH ₃ OH-d ₄ ) δ8.33(d, 1H), 8.16(d, 1H), 7.65(d, 1H), 7.55(d, 1H), 7.45(d, 1H), 5.26 (q, 2H), 4.15 (d, 1H), 3.96–3.88 (m, 2H), 3.75 (t, 2H), 1.52 (d, 2H), 1.33–1.29 (m, 3H). LC-MS [M+H] ⁺ = 418.25.

The synthesis of embodiment 7 compound R8

(1) Step 1:

Dissolve 2-(1-hydroxyethyl)pyridine (200mg) in DCM (20mL), add 2 drops of DMF dropwise, add thionyl chloride (227mg) under ice-cooling, stir for 30min, slowly add NaHCO ₃ to adjust the pH to Neutral, add water and extract with ethyl acetate, TLC monitors the reaction, after the reaction is complete, concentrate under reduced pressure to remove excess SOCl ₂ , add NaHCO ₃ to adjust the pH to neutral, add water and extract with ethyl acetate, concentrate the organic phase to obtain a light yellow Oily product (213 mg). LC-MS [M+H] ⁺ =142.

(2) Step 2:

Compound R8-1 was synthesized as previously described for compound R5-1.

(3) Step 3:

Compound R8-1 (200mg), NaH (47mg), 2-(1-chloroethyl)pyridine (137mg) and DMF solution (20ml) were added under ice-cooling, stirred and refluxed at 50°C for 4h. The completion of the reaction was monitored by TLC, water was added and extracted with ethyl acetate, the organic phase was concentrated and purified by column chromatography (petroleum ether: ethyl acetate = 4:1) to obtain an oily pale yellow product (182 mg). LC-MS [M+H] ⁺ =358.

(4) Step 4:

Compound R8-2 (120mg), 7-azaindole-4-boronate (97mg), Pd(PPh ₃ ) ₄ (36mg), potassium carbonate (363mg) were stirred in DMF (20mL) at 125°C for reaction 24h. TLC monitored the completion of the reaction. The reaction solution was added into water, extracted twice with ethyl acetate, the organic phases were combined, washed with water, dried and filtered. Concentrated under reduced pressure, purified by column chromatography (petroleum ether: ethyl acetate = 1:1), concentrated under reduced pressure to obtain light yellow compound R8 (28 mg). ¹ H NMR (500MHz, DMSO-d) δ8.56–8.50 (m, 2H), 7.72 (d, 1H), 7.68 (td, 1H), 7.57 (m, 1H), 7.44 (d, 1H), 7.29 (dd, 1H), 7.21(d, 1H), 7.16(d, 1H), 6.80(d, 1H), 5.47–5.40(m, 1H), 4.19–4.09(m, 1H), 3.91–3.83(m , 2H), 3.83–3.79 (m, 2H), 3.77–3.67 (m, 2H), 1.78 (s, 3H), 1.27 (d, 3H). LC-MS [M+H] ⁺ =440.

The synthesis of embodiment 5 compound R10

(1) Step 1:

At room temperature, 4.6-dichloro-1H pyrazolo[3.4-d]pyrimidine (1 g), (R)-3-methylmorpholine (0.6 g), dichloromethane (30 mL) and potassium carbonate (1.5 g ), reacted at 35°C for 12h, washed with water, concentrated the organic phase, and the crude product was directly used in the next step. LC-MS [M+H] ⁺ =254.

(2) Step 2:

At room temperature, add compound R10-1 (300mg), iodomethane (1g), potassium carbonate (320mg) and DMF (10mL), react at 80°C for 5h, extract with water/ethyl acetate, concentrate the organic phase, and perform column chromatography (petroleum ether:ethyl acetate=5:1) was purified, and then used in the next step. LC-MS [M+H] ⁺ =268.

(3) Step 3:

Add compound R10-2 (240 mg), 7-azaindole borate pinacol ester (238 mg), potassium carbonate (281 mg), tetrakistriphenylphosphine palladium (140 mg) and dimethylsulfoxide (10 mL) under nitrogen protection ), reacted at 120° C. for 5 h under the protection of nitrogen, extracted with water/ethyl acetate, concentrated the organic phase, and purified by column chromatography (petroleum ether: ethyl acetate = 3:1) to obtain compound R10 (90 mg). ¹ H NMR (400MHz, CDCl ₃ -d) δ9.56(s, 1H), 8.47(d, 1H), 8.17(d, 1H), 7.99(s, 1H), 7.72(s, 1H), 7.67( d, 1H), 5.39(p, 1H), 4.87(s, 1H), 4.22–4.12(m, 1H), 3.99–3.84(m, 3H), 3.74(td, 1H), 3.65(s, 3H) , 1.54(d, 3H). LC-MS [M+H] ⁺ =350.

The synthesis of embodiment 6 compound R11

(1) Step 1:

Compound W-4 (1.00 g) and pinacol diboronate (1.25 g) and Pd(dppf)Cl ₂ (0.323 g) and potassium acetate (0.867 g) were added to 10 mL of 1,4-dioxane solution , heated under nitrogen at 100°C for 2h. The completion of the reaction was monitored by TLC. The reaction liquid was concentrated under reduced pressure and purified by column chromatography (petroleum ether: ethyl acetate = 20:1) to obtain compound W-5 (1.01 g, 83.5%) as a white solid.

(2) Step 2:

Compound R11-1 was synthesized as described for compound R8-1.

(3) Step 3:

Compound W-5 (0.500g), compound R11-1 (0.591g), copper acetate (0.435g) and triethylamine (0.803g) were added into DCM (50mL), and reacted under oxygen balloon at room temperature for 48h. TLC monitored 30-40% reaction. The reaction solution was added to water (20mL), stirred and filtered, the filter cake was washed with 20mL DCM, the organic phase was dried, and purified by column chromatography (petroleum ether:ethyl acetate=5:1) to obtain light-colored oily compound R11-2 (0.136 g, 17.4%).

(4) Step 4:

Compound R11-2 (0.100g), compound W-6 (0.068g), tetrakistriphenylphosphopalladium (0.029g), potassium carbonate (0.699g) and DMF (5mL) were stirred at 110-120°C for 12h . TLC monitored the completion of the reaction. Add the reaction solution to water (30mL), extract with ethyl acetate (30mL×3), combine the organic phases, wash the organic phase with saturated sodium chloride solution (20mL×3), dry over anhydrous magnesium sulfate, filter, and reduce pressure Concentrate and purify by column chromatography (petroleum ether:ethyl acetate=5:1-2:1) to obtain light yellow compound R11 (0.068g, 56.7%). ¹ H NMR (400Mz, DMSO) δ11.70(s, 1H), 8.37(d, 1H), 8.03(m, 3H), 7.80(m, 3H), 7.54(d, 1H), 7.32(d, 1H ), 7.00(d, 1H), 4.94(m, 1H), 4.61(m, 1H), 4.06(m, 1H), 3.83(m, 2H), 3.64(m, 2H), 1.79(s, 6H) , 1.40 (m, 3H). LC-MS [M+H] ⁺ =478.

The synthesis of embodiment 7 compound R13

(1) Step 1:

At room temperature, add 4-bromo-7-azaindole (0.5g), m-chloroperoxybenzoic acid (0.85g) and methyl tert-butyl ether (40mL), react for 12h, filter the reaction solution, filter the cake with methanol Rinse with tert-butyl ether to obtain a white solid, which is directly used in the next step. LC-MS [M+H] ⁺ =214.

(2) Step 2:

Under nitrogen protection, compound R13-1 (0.5 g) and DMF (10 mL) were added into the reaction flask, and then heated to 50°C. Then add methanesulfonyl chloride (0.64g), heat up to 75°C, and react for 1h. After the reaction was completed, the temperature was lowered to room temperature, and the reaction solution was added to ice water, cooled to 0°C, adjusted to pH 7 with 6N sodium hydroxide solution, then stirred at room temperature for 3 h, filtered with suction, washed with water, and dried to obtain a white solid. used directly in the next step. LC-MS [M+H] ⁺ =232.

(3) Step 3:

Add compound R13-2 (226mg), potassium acetate (287mg), pinacol diborate (274mg), Pd(pddf)Cl ₂ (138mg) and 1,4-dioxane to the reaction flask under nitrogen protection (10mL), then warming up to 90°C, reacting for 16h, adding water and ethyl acetate to quench after the reaction, the organic phase was dried, concentrated, purified by column chromatography (petroleum ether:ethyl acetate=5:1), and then used for Next step. LC-MS [M+H] ⁺ =279.

(4) Step 4:

At room temperature, 2,4-dichloro-pyrrolopyrimidine (1 g), 95% ethanol (20 mL) and (R)-3-methylmorpholine (0.6 g) were added to the reaction flask, and then the temperature was raised to 70 ° C, After reacting for 3h, the reaction solution was concentrated to dryness, and then used in the next step. LC-MS [M+H] ⁺ =253.

(5) Step 5:

At room temperature, add compound R13-4 (200mg), potassium carbonate (220mg), iodomethane (600mg) and DMF (10mL) into the reaction flask, then warm up to 80°C, react for 8h, extract with water/ethyl acetate, organic The phase was concentrated, purified by column chromatography (petroleum ether:ethyl acetate=5:1), and then used in the next step. LC-MS [M+H] ⁺ =267.

(6) Step 6:

Add compound R13-5 (240mg), compound R13-3 (238mg), potassium carbonate (281mg), Pd(pddf)Cl ₂ (140mg), DME (8mL) and H ₂ O (2mL) under nitrogen protection, in Reacted at 90°C for 16 h under nitrogen protection, extracted with water/ethyl acetate, concentrated the organic phase, and purified by column chromatography (petroleum ether:ethyl acetate=3:1) to obtain the target product (20 mg). ¹ H NMR (400MHz, acetonitrile-d ₃ ) δ9.82(s, 1H), 8.17(s, 1H), 7.57(dd, 1H), 7.48(t, 1H), 7.22(d, 1H), 6.66( d, 1H), 4.91(d, 1H), 4.59(d, 1H), 4.07(dd, 1H), 3.88–3.79(m, 2H), 3.72–3.63(m, 1H), 3.56(td, 1H) , 1.42 (d, 3H), 1.39–1.31 (m, 3H). LC-MS [M+H] ⁺ =383.

The synthesis of embodiment 8 compound R14

(1) Step 1:

At room temperature, 2,6-dichloro-7-deaminopurine (0.5 g), (R)-3-methylmorpholine (0.448 g), dichloromethane (20 mL) and potassium carbonate (1.103 g) were added, React at 40°C for 12h, wash with water, concentrate and dry the organic phase, and use the crude product directly in the next step. LC-MS [M+H] ⁺ = 439.

(2) Step 2:

At room temperature, add compound R8-1 (0.3g), cyclopropylsulfonyl chloride (0.2g), cesium carbonate (1.16g) and DMF (10mL), react at 60°C for 12h, extract with water/ethyl acetate, organic The phase was concentrated, purified by column chromatography (petroleum ether:ethyl acetate=10:1), and then used in the next step. LC-MS [M+H] ⁺ = 357.

(3) Step 3:

At room temperature, add compound R14-1 (0.15g), 7-azaindole boronic acid pinacol ester (0.103g), cesium carbonate (0.41g), tetrakistriphenylphosphine palladium (0.1g), water (0.5 mL) and 1,4-dioxane (5mL), reacted at 95°C for 12h under nitrogen protection, extracted with water/ethyl acetate, concentrated the organic phase, and column chromatography (petroleum ether:ethyl acetate=3: 1) Purification to obtain compound R14 (0.04g). ¹ H NMR (400MHz, methanol-d ₄ ) δ8.30(d, 1H), 8.17(d, 1H), 7.75(d, 1H), 7.66–7.63(m, 1H), 7.60(d, 1H), 7.53(d, 1H), 6.92(d, 1H), 4.66(d, 1H), 4.16–4.08(m, 2H), 3.93–3.86(m, 2H), 3.72(d, 1H), 3.65(d, 1H), 3.41–3.36(m, 1H), 1.50(d, 4H), 1.35–1.22(m, 3H). LC-MS [M+H] ⁺ = 439.

The synthesis of embodiment 9 compound R16

(1) Step 1:

2,6-Dichloropurine (1 g), iodomethane (432 mg), potassium carbonate (1.345 g) and DMF (30 mL) were stirred at 50-60° C. for 2 h. TLC monitored the completion of the reaction. The reaction solution was added into water, extracted twice with ethyl acetate, the organic phases were combined, washed with water, dried and filtered. After concentration under reduced pressure, a white powder was precipitated, which was purified by column chromatography (petroleum ether: ethyl acetate = 5:1), filtered, and dried to obtain compound R16-1 (1.05 g). LC-MS [M+H] ⁺ =230.

(2) Step 2:

Compound R16-1 (300 mg) and R-(3)-methylmorpholine (176 mg) were dissolved in ethanol (20 mL), stirred and refluxed overnight. The completion of the reaction was monitored by TLC, the reaction solution was concentrated under reduced pressure, and the precipitated white powder was filtered and rinsed with ice ethanol to obtain compound R16-2 (278 mg). LC-MS [M+H] ⁺ = 295.

(3) Step 3:

Compound R16-2 (100 mg), 7-azaindole-4-boronate (136 mg), Pd[dppf]Cl ₂ (37 mg), potassium carbonate (106 mg), 1,4-dioxane: H ₂ O (10 mL:2 mL) was stirred at 110-120° C. overnight. TLC monitored the completion of the reaction. The reaction solution was added into water, extracted twice with ethyl acetate, the organic phases were combined, washed with water, dried and filtered. It was concentrated under reduced pressure and purified by column chromatography to obtain light yellow compound R16 (37 mg). ¹ H NMR (500MHz, chloroform-d) δ8.54(d, 1H), 7.72(d, 1H), 7.44(d, 1H), 7.22–7.14(m, 2H), 6.75(d, 1H), 4.76 (pd, 1H), 4.19–4.09(m, 1H), 3.92–3.79(m, 4H), 3.77–3.67(m, 2H), 1.54(s, 3H), 1.50(d, 3H), 1.27(d , 3H). LC-MS [M+H] ⁺ =377.

The synthesis of embodiment 10 compound R17

(1) Step 1:

2,4-dichloro-7H pyrrolopyrimidine (1.0g), (R)-3-methylmorpholine (0.538g), potassium carbonate (2.21g) and DMF were stirred at 60-70°C overnight, TLC detects that the reaction is complete, add water and stir to dissolve the insoluble matter, add and extract twice with ethyl acetate, separate liquids, wash the ethyl acetate phase with water once, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. Ether:ethyl acetate=10:1) was purified to obtain compound R17-1 (1.21 g) as an off-white solid.

(2) Step 2:

At room temperature, stir compound R17-1 (0.5g), cesium carbonate (1.93g) and DMF (20mL) for 15-30min, add 0.365g bromocyclopropane and 0.1g cuprous iodide, 90-100 The reaction was stirred overnight at °C. Add water and ethyl acetate and stir evenly, filter out the insoluble matter, extract the water phase with ethyl acetate once more, combine the two ethyl acetate phases, wash with water, dry over anhydrous sodium sulfate, concentrate, and perform column chromatography (petroleum ether: Ethyl acetate=3:1) was purified to obtain compound R17-2 (0.11 g) as pale yellow oil. LC-MS [M+H] ⁺ = 293.2.

(3) Step 3:

At room temperature, compound R17-2 (100 mg), 7-azaindole borate pinacol ester (83.4 mg), potassium carbonate (120 mg), 1,4-dioxane (10 mL) and H ₂ O ( 2 mL) and stirred for 10 min, added Pd(dppf)Cl ₂ (14 mg), reacted overnight at 90-100°C under nitrogen protection, TLC detected that the reaction was complete, concentrated under reduced pressure, added water, extracted twice with ethyl acetate, anhydrous sodium sulfate It was dried, concentrated, and purified by column chromatography (petroleum ether: ethyl acetate = 1:1) to obtain compound R17 (100 mg) as a pale yellow solid. ¹ H NMR (400MHz, MeOD) δ11.7(s, 1H), 8.2(d, 1H), 8.1(d, 1H), 7.4(s, 2H), 7.2(d, 1H), 6.7(d, 1H ), 4.6(t, 1H), 4.1(m, 1H), 3.9(t, 2H), 3.7(m, 2H), 3.6(m, 2H), 1.5(d, 3H), 1.1(d, 4H) . LC-MS [M+H] ⁺ = 375.3.

The synthesis of embodiment 11 compound R18

(1) Step 1:

2,4-dichloro-7H pyrrolopyrimidine (1.0g), (R)-3-methylmorpholine (0.538g), potassium carbonate (2.21g) and DMF were stirred at 60-70°C overnight, TLC detects that the reaction is complete, add water and stir to dissolve the insoluble matter, add and extract twice with ethyl acetate, separate liquids, wash the ethyl acetate phase with water once, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. Ether:ethyl acetate=10:1) was purified to obtain compound R18-1 (1.21 g) as an off-white solid. LC-MS [M+H] ⁺ = 253.3.

(2) Step 2:

At room temperature, compound R18-1 (500 mg) and cesium carbonate (1.93 g) were stirred in DMF for 15-30 min, 0.4 g of bromomethylcyclopropane was added, and the reaction was stirred overnight at 90-100°C. Add water and ethyl acetate, stir and extract twice, combine the two ethyl acetate phases, wash with water, dry over anhydrous sodium sulfate, concentrate, and purify by column chromatography (petroleum ether: ethyl acetate = 2:1) to obtain light blue Compound R18-2 (0.55 g) as a colored oil. LC-MS [M+H] ⁺ = 307.3.

Step 3:

At room temperature, compound R18-2 (100 mg), 7-azaindole borate pinacol ester (80 mg), potassium carbonate (112.6 mg), 1,4-dioxane (10 mL) and H ₂ O ( 2 mL) and stirred for 10 min, added 13.3 mg of Pd(dppf)Cl ₂ , reacted overnight at 90-100°C under nitrogen protection, concentrated the solvent under reduced pressure, added water to the residue, extracted twice with ethyl acetate, and dried over anhydrous sodium sulfate , concentrated, and purified by column chromatography (petroleum ether: ethyl acetate = 1:1) to obtain compound R18 (100 mg). ¹ H NMR (400MHz, DMSO) δ11.7(s, 1H), 8.6(d, 1H), 8.0(d, 1H), 7.9(d, 2H), 7.3(d, 2H), 4.0(d, 2H ), 3.9(d, 1H), 3.5~3.7(m, 4H), 3.2(t, 2H), 1.5(d, 3H), 1.1(m, 5H). LC-MS [M+H] ⁺ = 389.3. LC-MS [M+Na] = 411.3.

The synthesis of embodiment 12 compound R19

(1) Step 1:

2,4-dichloro-7H pyrrolopyrimidine (1.0g), (R)-3-methylmorpholine (0.538g), potassium carbonate (2.21g) were stirred in DMF at 60-70°C overnight, TLC Detect that the reaction is complete, add water and stir to dissolve insoluble matter, add and extract twice with ethyl acetate, separate liquids, wash the ethyl acetate phase with water once, dry over anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and perform column chromatography (petroleum ether :ethyl acetate=10:1) to obtain compound R19-1 (1.21g) as an off-white solid. LC-MS [M+H] ⁺ =253.

(2) Step 2:

At room temperature, stir compound R19-1 and cesium carbonate (0.3g) in DMF15mL for 15-30min, add bromocyclopentane (0.265g) and cuprous iodide (0.0226g), under nitrogen protection at 90-100°C The reaction was stirred overnight. TLC detects that there is a product with low polarity in the reaction system, add water and ethyl acetate and stir evenly, filter out the insoluble matter, separate the liquid, extract the water phase with ethyl acetate once, combine the two ethyl acetate phases, and wash with water , dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (petroleum ether: ethyl acetate = 2:1) to obtain compound R19-2 (0.2 g) as light yellow oil. LC-MS [M+H] ⁺ = 321.3.

(3) Step 3:

At room temperature, compound R19-2 (180 mg), 7-azaindole borate pinacol ester (140 mg), potassium carbonate (194 mg), 1,4-dioxane (10 mL) and H ₂ O (2 mL ) and stirred for 20 min, added Pd(dppf)Cl ₂ (23 mg), reacted overnight at 90-100°C under nitrogen protection, concentrated the solvent under reduced pressure, added water to the residue, extracted twice with ethyl acetate, dried over anhydrous sodium sulfate, It was concentrated and purified by column chromatography (petroleum ether:ethyl acetate=1:2) to obtain compound R19 (130 mg) as a pale yellow solid. ¹ H NMR (400MHz, DMSO) δ11.7(s, 1H), 8.3(d, 1H), 8.0(d, 1H), 7.57(t, 1H), 7.48(d, 1H), 7.37(t, 1H ), 6.7(d, 1H), 5.2(t, 1H), 4.8(d, 1H), 4.5(d, 1H), 4.0(q, 1H), 3.9(s, 1H), 3.8(d, 2H) , 3.7(q, 1H), 1.9(m, 8H), 1.3(d, 3H). LC-MS [M+H] ⁺ = 403.3.

The synthesis of embodiment 13 compound R20

(1) Step 1:

At room temperature, add DMSO (400mL) and H ₂ O (50mL) into a 1000mL single-necked bottle, then add 2,4-dichloro-7Hpyrrole[2,3-D]pyrimidine (20.0g), (R)- 3-Methylmorpholine (11.8g) and DIPEA (20.6g) were then heated to 55°C and stirred under reflux for 20h. TLC monitors that the reaction is complete, the reaction solution is poured into 1.2L water, fully stirred, suction filtered, and the solid is dried in the air, beaten with petroleum ether:ethyl acetate=10:1 (300mL), then suction filtered and dried to obtain off-white Solid (19.8 g, 74%). LC-MS [M+H] ⁺ = 253.13.

(2) Step 2:

At room temperature, add compound R20-1 (300mg), pyrimidine-3-boronic acid (250mg), copper acetate (300mg), TEA (300mg) into a 50mL single-necked bottle, then add DCM (20mL), open the reaction for 48h, TLC The monitored reaction was not completed, but there was a significant increase in the polarity of the product, followed by suction filtration with diatomaceous earth, the filtrate was spin-dried, and purified by column chromatography (petroleum ether:ethyl acetate=5:1-3:1) to obtain shallow Yellow solid (70 mg, 17%). LC-MS [M+H] ⁺ = 331.20.

(3) Step 3:

At room temperature, compound R20-2 (70mg), borate (62mg), Pd(PPh ₃ ) ₄ (24mg), KOAc (41mg) were added to a 50mL single-necked bottle, and then DMSO (20mL) was added, and nitrogen was pumped for 3 The second time, heated to 120°C for 8 hours. TLC monitored that the reaction was not completed, and there was a significant increase in product formation. After the reaction solution was cooled to room temperature, the reaction solution was poured into water (60mL) and ethyl acetate (20mL*2) for extraction. The organic phase was dried and filtered, then spin-dried, and purified by column chromatography (petroleum ether: ethyl acetate = 5:1-1:1) to obtain a light yellow solid (13 mg, 15%). ¹ H NMR (400MHz, DMSO) δ11.75(s, 1H), 9.49(s, 2H), 9.25(s, 1H), 8.33(d, 1H), 8.02(d, 1H), 7.97(d, 1H ), 7.57(t, 1H), 7.19(s, 1H), 7.11(d, 1H), 4.94(s, 1H), 4.60(d, 1H), 4.07(d, 1H), 3.95–3.73(m, 2H), 3.59 (dt, 2H), 1.40 (d, 3H). LC-MS [M+H] ⁺ = 413.29.

The synthesis of embodiment 14 compound R21

(1) Step 1:

At room temperature, add 2,4-dichloro-7H pyrrolopyrimidine (1.0g), (R)-3-methylmorpholine (0.538g), potassium carbonate (2.21g) and stir the reaction at 60-70°C in DMF Overnight, TLC detects that the reaction is complete, add water and stir to dissolve the insoluble matter, add and extract twice with ethyl acetate, separate liquid, wash the ethyl acetate phase with water once, dry with anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and perform column chromatography (Petroleum ether:ethyl acetate=10:1) was purified to obtain compound R21-1 (1.21 g) as an off-white solid. LC-MS [M+H] ⁺ = 253.3.

(2) Step 2:

At room temperature, stir compound R21-1 (1.0g), pyridine-3-boronic acid (0.584g), copper acetate (0.79g) in DCM for 15-30min, add triethylamine (0.8g), and stir at room temperature Reaction more than 48h. Concentrate the dichloromethane, add water and ethyl acetate and stir evenly, filter out the insoluble matter, separate the liquids, extract the water phase with ethyl acetate once, combine the two ethyl acetate phases, wash with water, and dry over anhydrous sodium sulfate. It was concentrated and purified by column chromatography (petroleum ether: ethyl acetate = 2:1) to obtain compound R21-2 (300 mg) as light yellow oil. LC-MS [M+Na] = 330.2.

(3) Step 3:

At room temperature, compound R21-2 (100 mg), 7-azaindole borate pinacol ester (80 mg), potassium carbonate (112.6 mg), 1,4-dioxane (10 mL) and H ₂ O ( 2mL) and stirred for 10min, added Pd(dppf)Cl ₂ (13.3mg), reacted overnight at 100-110°C under nitrogen protection, concentrated the solvent under reduced pressure, added water to the residue, extracted twice with ethyl acetate, anhydrous sodium sulfate It was dried, concentrated, and purified by column chromatography (petroleum ether: ethyl acetate = 1:1) to obtain compound R21 (10 mg) as a brown solid. ¹ H NMR (400MHz, DMSO) δ11.7(s, 1H), 8.7(s, 1H), 8.6(d, 1H), 8.46(d, 1H), 7.9(m, 3H), 7.5(t, 3H ), 7.2(d, 1H), 3.5~3.7(m, 4H), 3.2(t, 2H), 3.3(m, 1H), 1.1(d, 3H). LC-MS [M+H] ⁺ = 389.3, LC-MS [M+Na] = 412.3.

The synthesis of embodiment 15 compound R22

(1) Step 1:

At room temperature, 2,6-dichloro-7-deaminopurine (1.88g), (R)-3-methylmorpholine (1.214g), dichloromethane (20mL) and potassium carbonate (4.146g) were added, Reacted at 40°C for 12h, TLC (petroleum ether:ethyl acetate=2:1) detected that the reaction was complete, after treatment, washed with water, concentrated the organic phase, and then used in the next step. LC-MS [M+H] ⁺ =253.

(2) Step 2:

At room temperature, add compound R22-1 (0.15g), 7-azaindoleboronic acid pinacol ester (0.15g), cesium carbonate (0.609g), tetrakistriphenylphosphine palladium (0.1g), water (1mL ) and DMF (10mL), reacted at 120°C for 12h under nitrogen protection, TLC (petroleum ether: ethyl acetate = 1:1) detected that the reaction was complete, extracted with water/ethyl acetate, concentrated the organic phase, and column chromatography (petroleum ether: ethyl acetate = 1:1) ethyl acetate=3:1) to obtain the target product. LC-MS [M+H] ⁺ =335.

(3) Step 3:

At room temperature, compound R22-2 (0.1g), cyclopropylformyl chloride (0.02g), N,N-diisopropylethylamine (0.116g) and DCM (20mL) were added, reacted at room temperature for 6h, TLC (petroleum Ether: ethyl acetate = 1:1) to detect the completion of the reaction, extract with water/ethyl acetate, concentrate the organic phase, and purify by column chromatography (petroleum ether: ethyl acetate = 3:1) to obtain the target product. ¹ H NMR (400MHz, methanol-d4) δ8.30(d, 1H), 8.05(d, 1H), 7.84(d, 1H), 7.51(d, 1H), 7.35(d, 1H), 6.92(d , 1H), 4.67–4.58(m, 2H), 4.41–4.37(m, 1H), 4.13(d, 1H), 3.90(d, 1H), 3.70(d, 2H), 1.51(m, 1H), 1.38–1.35 (m, 4H), 1.32 (d, 3H). LC-MS [M+H] ⁺ = 403.2.

The synthesis of embodiment 16 compound R23

(1) Step 1:

At room temperature, add 2,4-dichloro-7H pyrrolopyrimidine (1.0g), (R)-3-methylmorpholine (0.538g), potassium carbonate (2.21g) and stir the reaction at 60-70°C in DMF Overnight, TLC detects that the reaction is complete, add water and stir to dissolve the insoluble matter, add and extract twice with ethyl acetate, separate the liquids, wash the ethyl acetate phase with water once, dry over anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and perform column chromatography Purification (petroleum ether: ethyl acetate = 10:1) gave compound R23-1 (1.21 g) as an off-white solid. LC-MS [M+H] ⁺ = 253.3.

(2) Step 2:

At room temperature, compound R23-1 (1.0g), methylpyrazole borate pinacol ester (1.24g), copper acetate (0.72g) were stirred in DCM for 15-30min, triethylamine (0.8g) was added, The reaction was stirred at room temperature for more than 48 hours. Concentrate the dichloromethane, add water and ethyl acetate and stir evenly, filter out the insoluble matter, separate the liquids, extract the water phase with ethyl acetate once, combine the two ethyl acetate phases, wash with water, and dry over anhydrous sodium sulfate. It was concentrated and purified by column chromatography (petroleum ether:ethyl acetate=2:1) to obtain compound R23-2 (300 mg) as light yellow oil. LC-MS [M+H] ⁺ = 333.2.

(3) Step 3:

At room temperature, compound R23-2 (250 mg), 7-azaindole borate pinacol ester (184 mg), potassium carbonate (260 mg) in 1,4-dioxane (15 mL) and H ₂ O (3 mL ) and stirred for 10 min, added Pd(dppf)Cl ₂ (31mg), reacted overnight at 100-110°C under nitrogen protection, concentrated the solvent under reduced pressure, added water to the residue, extracted twice with ethyl acetate, and dried over anhydrous sodium sulfate , concentrated, and purified by column chromatography (petroleum ether: ethyl acetate = 1:2) to obtain compound R23 (150 mg) as a pale yellow solid. ¹ H NMR (400MHz, DMSO) δ11.7(s, 1H), 8.3(d, 1H), 7.98(d, 1H), 7.67(d, 1H), 7.55(d, 1H), 7.51(t, 1H ), 7.0(m, 2H), 6.5(d, 1H), 1.9(s, 1H), 4.0(m, 4H), 3.85(d, 2H), 3.7(s, 3H), 3.62(d, 1H) , 3.6(s, 1H), 1.4(d, 3H), 1.1(t, 1H). LC-MS [M+H] ⁺ = 415.3.

The synthesis of embodiment 17 compound R26

(1) Step 1:

At room temperature, 2,6-dichloropurine (300mg), R-(3)-methylmorpholine (180mg) and TEA (480mg) were placed in ethanol (5mL) solution, stirred and refluxed for 6h. The completion of the reaction was monitored by TLC, and the reaction solution was concentrated under reduced pressure to precipitate a white powder, which was filtered and rinsed with ice ethanol to obtain compound R26-1 (300 mg, 74.8%). LC-MS [M+H] ⁺ =254.

(2) Step 2:

Compound R26-1 (300mg), iodomethane (250mg) and anhydrous potassium carbonate (490mg) were placed in DMF (5mL) solution at room temperature, and stirred at 50-60°C for 2h. The completion of the reaction was monitored by TLC. The reaction solution was added to water, extracted twice with ethyl acetate, and the organic phases were combined, washed with water, dried, and filtered. After concentration under reduced pressure, a white powder was precipitated, which was filtered and dried to obtain compound R26-2 (300 mg, 94.9%). LC-MS [M+H] ⁺ =268.

(3) Step 3:

At room temperature, compound R26-2 (100 mg), 7-azaindole-4-boronate (100 mg), tetrakistriphenylphosphopalladium (30 mg), potassium carbonate (150 mg) and DMSO (5 mL) were dissolved at 110 The reaction was stirred at -120°C for 5h. TLC monitored the completion of the reaction. The reaction solution was added into water, extracted twice with ethyl acetate, the organic phases were combined, washed with water, dried and filtered. Concentrate under reduced pressure, and purify by column chromatography (petroleum ether: ethyl acetate = 1:1) to obtain light yellow compound R26. ¹ H NMR (400MHz, C ₂ H ₃ Nd ₃ ) δ9.76(s, 1H), 8.36(d, 1H), 8.13(d, Hz, 1H), 7.93(s, 1H), 7.53–7.47(m , 2H), 5.58(s, 1H), 5.23(s, 1H), 4.08–4.02(m, 1H), 3.88(s, 3H), 3.82(d, 2H), 3.71–3.51(m, 2H), 1.43(d,3H). LC-MS [M+H] ⁺ =350.

The synthesis of embodiment 18 compound R38

(1) Step 1:

At room temperature, compound W-8 (400 mg), carbon tetrabromide (1600 mg), triphenylphosphine (550 mg) and toluene (10 mL) were added. The reaction was stirred at room temperature for 4h. After washing with water, the organic phase was dried and concentrated to dryness to obtain compound W-9, which was directly used in the next step.

(2) Step 2:

At room temperature, add 4,6-dichloro-1H-pyrazolo[3,4-D]pyrimidine (300mg), R-(3)-methylmorpholine (180mg), TEA (480mg) and ethanol (5mL ). The reaction was stirred at 80°C for 6h. The reaction solution was concentrated under reduced pressure, and a white powder was precipitated, which was filtered, rinsed, and dried to obtain compound R38-1, which was directly used in the next step. LC-MS [M+H] ⁺ =254.

(3) Step 3:

At room temperature, compound R38-1 (300 mg), compound W-9 (250 mg), anhydrous potassium carbonate (490 mg) and DMF (5 mL) were added. The reaction was stirred at 120°C for 6h. The organic phase was extracted with water/ethyl acetate, washed with water, dried, filtered, concentrated under reduced pressure, and purified by column chromatography (petroleum ether:ethyl acetate=3:1) to obtain compound R38-2, which was directly used in the next step. LC-MS [M+H] ⁺ =350.

(4) Step 4:

At room temperature, compound R38-2 (100 mg), 7-azaindole-4-boronate (100 mg), (Dppf)-PdCl ₂ (30 mg), potassium carbonate (150 mg) and DMSO (5 mL) were added. Stir the reaction at 110-120°C for 5h. Extracted with water/ethyl acetate, the organic phase was washed with water, dried, filtered, concentrated, and purified by column chromatography (petroleum ether: ethyl acetate = 1:1) to obtain compound R38 (50 mg). ¹ H NMR (500MHz, chloroform-d) δ8.54(d, 1H), 8.05(s, 1H), 7.75(d, 1H), 7.44(d, 1H), 7.16(d, 1H), 5.02(dd , 1H), 4.19–4.10(m, 1H), 3.91–3.77(m, 4H), 3.76–3.67(m, 2H), 1.47(s, 3H), 1.27(d, 3H). LC-MS [M+H] ⁺ = 432.

The synthesis of embodiment 19 compound R39

(1) Step 1:

4,6-dichloro-1H-pyrazolo[3,4-D]pyrimidine (2g), (R)-3-methylmorpholine (1.3g), potassium carbonate (4.4g) in 1,4 - Stir and react in dioxane at 60-70°C for 7-8h, TLC detects that the reaction raw material is complete, and a product with a higher polarity than the raw material is formed, and a yellow solid precipitates, add water, stir at room temperature for 1h, filter, and wash with water The filter cake was slurried with n-hexane, filtered, and dried to obtain compound R39-1 (2.5 g) as a yellowish solid. LC-MS [M+H] ⁺ = 254.2.

(2) Step 2:

Compound R39-1 (400mg), cesium carbonate (1.54g) and DMF (15mL) were stirred for 15min, bromocyclopentane (0.35g) and potassium iodide (0.1g) were added, and the reaction was stirred overnight at 90-100°C. After the reaction is complete, add water and ethyl acetate to stir and extract twice, combine the two ethyl acetate phases, wash with water, dry over anhydrous sodium sulfate, concentrate, and purify by column chromatography (petroleum ether: ethyl acetate = 2:1) , Compound R39-2 (300 mg) was obtained as an almost colorless oil. LC-MS [M+H] ⁺ = 322.2.

(3) Step 3:

Compound 39-2 (300 mg), 7-azaindole borate pinacol ester (227.5 mg), potassium carbonate (322 mg) were dissolved in 1,4-dioxane (15 mL) and H ₂ O (3 mL) Stir for 10 minutes, add Pd(dppf)Cl ₂ (34.1mg), react overnight at 90-100°C under nitrogen protection, detect the reaction solution by TLC, concentrate the solvent under reduced pressure, add water, extract twice with ethyl acetate, and combine twice The ethyl acetate phase was concentrated and purified by column chromatography (petroleum ether: ethyl acetate = 1:1) to obtain compound R39 (13 mg) as an off-white solid. ¹ H NMR (400MHz, DMSO) δ11.7(s, 1H), 8.34(d, 1H), 8.30(s, 1H), 8.0(d, 1H), 7.6(t, 1H), 7.3(s, 1H ), 5.4(t, 1H), 4.0(d, 1H), 3.8(d, 1H), 3.77(d, 1H), 3.74(d, 1H), 3.6(t, 1H), 2.5(s, 2H) , 2.1 (m, 2H), 2.0 (d, 2H), 1.9 (t, 2H), 1.76 (d, 2H), 1.74 (d, 3H). LC-MS [M+H] ⁺ = 404.3, LC-MS [M+Na] = 426.3.

The synthesis of embodiment 20 compound R44

(1) Step 1:

At room temperature, add 4,6-dichloro-1H-pyrazolo[3,4-D]pyrimidine (500mg), 4-pyridineboronic acid pinacol ester (607mg), copper acetate (393mg) into a 50mL round bottom flask , triethylamine (398mg), 4A molecular sieves (2g) and dichloromethane (10mL), react overnight at room temperature. Add water (50mL) and ethyl acetate (50mL) to the reaction solution, separate the layers, then extract with ethyl acetate (50mL) and combine the organic phases, wash with saturated brine, dry over anhydrous sodium sulfate, and perform column chromatography (petroleum Ether:ethyl acetate=1:1-1:2) purification to obtain compound R44-1 (90 mg). LC-MS [M+H] ⁺ = 331.21.

(2) Step 2:

At room temperature, add compound R44-1 (90mg), 7-azaindole-4-boronate (80.5mg), potassium carbonate (113.3mg), [1,1'-bis(diphenylphosphino) Ferrocene]palladium dichloride (19.7mg) and DMF (10mL)/water (2mL), replaced with nitrogen three times, reacted at 100°C for 16h. Add water (50mL) and ethyl acetate (50mL) to the reaction solution respectively, separate the layers, then extract twice with ethyl acetate (50mL) and combine the organic phases, wash with saturated brine, dry over anhydrous sodium sulfate, and perform column chromatography ( Petroleum ether: ethyl acetate = 1:1-1:0) to obtain compound R44 (31 mg). ¹ H NMR (400MHz, DMSO-d ₆ ) δ11.79(s, 1H), 8.92(s, 1H), 8.85(d, 2H), 8.35(d, 1H), 8.24(d, 2H), 8.06( d, 1H), 7.61(t, 1H), 7.27(s, 1H), 5.56(s, 1H), 5.21(s, 1H), 4.15–3.96(m, 1H), 3.86(d, 1H), 3.82 –3.71 (m, 1H), 3.66 – 3.56 (m, 2H), 1.99 (s, 3H). LC-MS [M+H] ⁺ = 413.31.

The synthesis of embodiment 21 compound R46

(1) Step 1:

At room temperature, add 4-bromo-7-azaindole (0.5g), m-chloroperoxybenzoic acid (0.85g) and methyl tert-butyl ether (40mL), react for 12h, filter the reaction solution, filter the cake with methanol Rinse with tert-butyl ether to obtain a white solid, which is directly used in the next step. LC-MS [M+H] ⁺ =213.

(2) Step 2:

Under the protection of nitrogen, compound R46-1 (0.5 g), DMF (10 mL) was added into the reaction flask, and then heated to 50°C. Then add methanesulfonyl chloride (0.64g), heat up to 75°C, and react for 1h. After the reaction was completed, the temperature was lowered to room temperature, the reaction solution was added to ice water, and the temperature was lowered to 0°C. The pH was adjusted to 7 with 6N sodium hydroxide solution, then stirred at room temperature for 3 hours, filtered with suction, the filter cake was washed with water, and dried to obtain a white solid, which was used directly for Next step. LC-MS [M+H] ⁺ =231.

(3) Step 3:

Under nitrogen protection, compound R46-2 (226mg), potassium acetate (287mg), pinacol diborate (274mg), Pd(pddf)Cl ₂ (138mg) and 1,4-dioxane were added to the reaction flask Ring (10mL), heated to 90°C, reacted for 16h, quenched with water and ethyl acetate after the reaction, took the organic phase, dried, concentrated, purified by column chromatography (petroleum ether:ethyl acetate=5:1), and then for the next step. LC-MS [M+H] ⁺ =279.

(4) Step 4:

(5) Step 5:

At room temperature, compound R46-4 (1g), cyclopropylsulfonyl chloride (0.67g), cesium carbonate (3.85g) and DMF (20mL) were added, reacted at 60°C for 12h, TLC (petroleum ether: ethyl acetate = 5: 1), extracted with water/ethyl acetate, the organic phase was concentrated, purified by column chromatography (petroleum ether: ethyl acetate = 10:1), and then used in the next step. LC-MS [M+H] ⁺ =358.

(6) Step 6:

Add compound R46-5 (240mg), R46-3 (238mg), potassium carbonate (281mg), Pd(pddf)Cl ₂ (140mg), DME (8mL) and H ₂ O (2mL) under nitrogen protection, under nitrogen Reacted at 90°C for 16 h under protection, extracted with water/ethyl acetate, concentrated the organic phase, and purified by column chromatography (petroleum ether:ethyl acetate=3:1) to obtain the target product (13 mg). ¹ H NMR (400MHz, chloroform-d) δ9.44(d, 1H), 8.18(d, 1H), 7.77(s, 1H), 7.51(s, 1H), 4.22(d, 1H), 4.18-4.09 (m, 1H), 3.98(d, 1H), 3.90(d, 1H), 3.77(dd, 2H), 3.13(s, 1H), 1.53-1.40(m, 3H), 0.09(s, 5H). LC-MS [M+H] ⁺ =474.

The synthesis of embodiment 22 compound R27

(1) Step 1:

The synthesis of R27-1 was as described for R5-1.

At room temperature, compound R27-1 (0.2g), cyclopropylsulfonyl chloride (0.133g), DMF (10mL) and cesium carbonate (0.8g) were added, and reacted at room temperature for 5h. MS detected that the reaction was complete. Post-treatment, washing with water, The organic phase was concentrated, purified by column chromatography (petroleum ether:ethyl acetate=3:1), and then used in the next step.

(2) Step 2:

At room temperature, compound R27-2 (0.18g), 7-azaindole-4-boronic acid pinacol ester (0.123g), potassium carbonate (0.207g), tetrakistriphenylphosphine palladium (0.1g), Water (10mL) and 1,4-dioxane (1mL) were reacted at 100°C for 12h under nitrogen protection, post-treated, water was added, stirred, extracted with ethyl acetate, the organic phase was concentrated, and column chromatography (petroleum ether: Ethyl acetate=1:1) to obtain compound R27 (55 mg, 23%). ¹ H NMR (400MHz, methanol-d ₄ ) δ8.53(s, 1H), 8.34(d, 1H), 8.23(d, 1H), 7.76(d, 1H), 7.57(d, 1H), 4.16( d, 1H), 3.97–3.85 (m, 3H), 3.74 (d, 2H), 3.19 (dt, 1H), 1.55 (dd, 4H), 1.31 (s, 2H), 1.16 (d, 2H). LC-MS [M+Na]=440.

The synthesis of embodiment 23 compound R54

(1) Step 1:

(R)-4-(2-Chloro-7H-pyrrole[2,3-d]pyrimidin-4-yl)-3-methylmorpholine (0.1 g), methyl iodide (0.112 g) and cesium carbonate ( 0.193g) was added into DMF solution (5mL), and heated at 60°C for 4h. TLC monitors that the reaction is complete, the reaction solution is poured into water (20mL), extracted 3 times with ethyl acetate (20mL), the organic phase is washed 3 times with saturated aqueous sodium chloride solution (20mL), the organic phase is dried and spin-dried to obtain a yellow oil Compound R54-1 (94 mg, 89.5%). LC-MS [M+H] ⁺ = 268.1.

(2) Step 2:

Compound R54-1 (0.094g), 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxybenzaldehyde-2-yl)-1H-pyrazole (0.081g), Pd(dppf)Cl ₂ (0.026g) and potassium carbonate (0.092g) were added into DCM (5mL), stirred at 120°C for 4h. TLC monitors that the reaction is complete, the reaction solution is added in water (20mL), extracted 3 times with ethyl acetate (20mL), the organic phase is washed 3 times with saturated aqueous sodium chloride solution (20mL), the organic phase is concentrated, column chromatography (petroleum ether) :ethyl acetate=5:1) to obtain compound R54 (0.100 g, 90.9%) as a yellow solid. ¹ H NMR (400MHz, CDCl3) δ7.93(s,1H),7.53(s,1H),7.05(s,1H),4.67(d,1H),4.42(s,3H),4.14(d,1H ), 4.08(s,3H), 3.99–3.76(m,3H), 3.71(t,1H), 3.59(s,1H), 1.49(d,3H). LC-MS [M+H] ⁺ = 314.1.

The synthesis of embodiment 24 compound R56

(1) Step 1:

Add LiAlH ₄ (400mg) to Me-THF (20mL), lower to about 0°C, add N-(2-benzimidazolyl)-methyl carbamate (500mg), pump nitrogen twice, and react under nitrogen protection After 16 hours, TLC monitored the completion of the reaction, cooled the reaction solution to room temperature, then cooled it down to about 0°C, slowly added 0.4mL, added 2M NaOH aqueous solution (0.4mL), then added anhydrous sodium sulfate solid (5g), added ethyl acetate After diluting the reaction solution with ester (20 mL), it was suction-filtered, the filter cake was rinsed with ethyl acetate (10 mL), and the filtrate was dried by rotary evaporation to obtain a yellow solid (210 mg, 55%). LC-MS [M+H] ⁺ = 148.1.

(2) Step 2:

At room temperature, add (R)-4-(2-chloro-9h-purin-6-yl)-3-methylmorpholine (200mg) into a 25mL one-necked bottle, dissolve in DMF (20mL), and cool to 0°C After about 40% NaH (63 mg) was added, reacted at 0°C for 10 min, added cyclopropanesulfonyl chloride (113 mg), and the reaction solution returned to room temperature for 30 min. TLC monitors the reaction and some raw materials have not reacted completely. The reaction solution is poured into water (50mL), extracted with ethyl acetate (20mL) 3 times, the organic phase is concentrated, and column chromatography (petroleum ether:ethyl acetate=3:1) Purification afforded a pale yellow solid (80 mg, 28% yield). LC-MS [M+H] ⁺ = 357.1.

(3) Step 3:

At room temperature, add compound 56-2 (60 mg), SnCl ₂ (145 mg), trimethyl orthoformate (1 mL), absolute ethanol (5 mL) and 2 drops of concentrated hydrochloric acid into a 50 mL pressure bottle, then heat to 90 °C The reaction was completed for 5 h, monitored by TLC. After the reaction solution was cooled to room temperature, the reaction solution was poured into water (15 mL), adjusted to pH=8 with a saturated aqueous solution of sodium carbonate, extracted 3 times with ethyl acetate (5 mL), and the organic phase was It was concentrated and purified by column chromatography (petroleum ether: ethyl acetate = 1:1) to obtain a light yellow solid (32 mg, yield 57%). ¹ H NMR (400MHz,DMSO)δ8.87(d,1H),8.81(s,1H),8.16(d,1H),8.05(d,1H),7.29(d,1H),7.11(t,1H ),7.01(t,1H),4.06(dd,1H),3.87(d,1H),3.78(d,1H),3.69–3.55(m,5H),3.08(d,3H),1.44(m, 5H). LC-MS [M+H] ⁺ = 468.3.

The synthesis of embodiment 25 compound R57

(1) Step 1:

At room temperature, add 4-bromo-7-azaindole (2.0g), m-chloroperoxybenzoic acid (3.4g) and methyl tert-butyl ether (160mL), react for 12h, filter the reaction solution, filter the cake with methanol Rinse with tert-butyl ether to obtain a white solid, which is directly used in the next step. LC-MS [M+H] ⁺ = 247.1.

(2) Step 2:

Under nitrogen protection, compound R57-1 (2.04 g) and DMF (40 mL) were added into the reaction flask, and heated to 50°C. Add methanesulfonyl chloride (2.6g), heat up to 75°C, and react for 1h. Cool down to room temperature after the reaction, add the reaction solution into ice water, cool down to 0°C, adjust pH=7 with 6N sodium hydroxide solution, stir at room temperature for 3 hours, filter with suction, wash the filter cake with water, and dry to obtain a white solid, which is directly injected into the next step. LC-MS [M+H] ⁺ = 231.1.

(3) Step 3:

At room temperature, compound R57-2 (1.3g), DMF (30mL), cesium carbonate (4.1g), and cyclopropylsulfonyl chloride (800mg) were added to the reaction flask, stirred at room temperature for 2 hours, and monitored by TLC until the reaction of the raw materials was complete. After treatment, add water and stir, extract with ethyl acetate, dry and concentrate the organic phase, and purify by column chromatography (petroleum ether: ethyl acetate = 10:1) to obtain a white solid, which is directly used for the next step. LC-MS [M+H] ⁺ = 335.1.

(4) Step 4:

Add compound R57-3 (252mg), R-3-methylmorpholine (150mg), potassium phosphate (480mg), Pd(PPh ₃ ) ₄ (150mg) and dioxane (6mL) under nitrogen protection, in Reacted at 120°C for 16 h under the protection of nitrogen, extracted with water/ethyl acetate, dried and concentrated the organic phase, and purified by column chromatography (petroleum ether: ethyl acetate = 3:1) to obtain the target product (37 mg). LC-MS [M+H] ⁺ = 356.1.

(5) Step 5:

Add compound R57-4 (37 mg), 7-azaindole-4-boronic acid pinacol ester (33 mg), potassium carbonate (43 mg), PdCl ₂ (dppf) (8 mg), DME (8 mL) under nitrogen protection React with H ₂ O (2 mL) at 120°C for 2 h, extract with water/ethyl acetate, dry and concentrate the organic phase, and purify by column chromatography (dichloromethane:methanol=100:1) to obtain compound R57 (18 mg). ¹ H NMR (400MHz,DMSO-d ₆ )δ11.75(s,1H),8.33(d,1H),7.69(d,1H),7.58(dd,2H),7.40–7.30(m,2H), 6.97(d,1H),4.37(d,1H),4.04–3.96(m,1H),3.85(dd,1H),3.74(d,1H),3.71–3.58(m,2H),3.54(dd, 1H), 3.44(dd,1H), 1.41–1.31(m,2H), 1.20(d,3H), 1.12(dd,2H). LC-MS [M+H] ⁺ = 438.

The synthesis of embodiment 26 compound R58

(1) Step 1:

Add (R)-4-(2-chloro-9H-purin-6-yl)-3-methylmorpholine (253mg), 4-methylpyridine 3-boronate (160mg) and copper acetate into a 100ml single-necked bottle (300mg) and TEA (300mg), then add DCM (15ml) and react at room temperature for 36h. The product was monitored by TLC, dried directly, and purified by column chromatography (petroleum ether: ethyl acetate = 1:2) to obtain a light yellow solid (30 mg, 8%). LC-MS [M+H] ⁺ = 345.1.

(2) Step 2:

Add compound R58-1 (30mg 0.087), 4-(4,4,5,5-tetramethyl-1,3,2-dioxobenzaldehyde-2-yl)-1H-pyrrole[ 2,3-b]pyridine (21 mg), Pd(dppf)Cl ₂ (7 mg), potassium carbonate (24 mg) and 1,4-dioxane/H ₂ O=5:1 (4 mL/0.8 mL). The reaction was carried out at 100° C. for 16 h under the protection of nitrogen. TLC detected that the reaction was complete. The reaction solution was purified by column chromatography (petroleum ether: ethyl acetate = 1:4) to obtain a light yellow solid (7 mg). ¹ H NMR (400MHz,DMSO-d ₆ )δ11.72(s,1H),8.73–8.63(m,2H),8.52(s,1H),8.29(d,1H),7.93(d,1H), 7.63(d,1H),7.50(t,1H),7.02(dd,1H),5.67-5.44(m,1H),5.40-5.11(m,1H),4.08(d,1H),3.90–3.77( m,2H), 3.63(q,2H), 2.26(s,3H), 1.45(d,3H). LC-MS [M+H] ⁺ = 427.1.

The synthesis of embodiment 27 compound R59

(1) Step 1:

2-Chloro-6-methylbenzoic acid (150 mg), oxalyl chloride (167 mg), and a catalytic amount of DMF were stirred in DCM for 1 h at room temperature. After the reaction was complete by TLC, DCM was removed by rotary evaporation to obtain compound R59-1.

(2) Step 2:

(R)-4-(2-chloro-7H-pyrrole[2,3-d]pyrimidin-4-yl)-3-methylmorpholine (222mg), 1.0 equivalent of compound R59-1, DIPEA (170mg) Stir the reaction in DCM at room temperature for 2 h. After the reaction is complete as detected by TLC, spin off the DCM, dilute with water, extract twice with ethyl acetate, separate the liquids, wash with saturated brine, dry over anhydrous sodium sulfate, filter, and the filtrate Concentrate under reduced pressure, and purify by column chromatography (petroleum ether:ethyl acetate=2:1-1:1) to obtain compound R59-2 as a white solid. LC-MS [M+H] ⁺ = 405.1.

(3) Step 3:

Compound R59-2 (60 mg), 7-azaindole boronic acid pinacol ester (40 mg), potassium carbonate (41 mg) were stirred in 1,4-dioxane (10 mL) and H ₂ O (2 mL) Dissolve, add Pd(dppf)Cl ₂ (11mg), react at 100°C under nitrogen protection for 12h, TLC detects that the reaction is complete, concentrate the solvent under reduced pressure, add water to the residue, extract twice with ethyl acetate, wash with anhydrous sulfuric acid It was dried over sodium, concentrated, and purified by column chromatography (petroleum ether:ethyl acetate=1:1-1:4) to obtain compound R59 (8 mg) as a pale yellow solid. ¹ H NMR (400MHz,DMSO)δ11.69(d,1H),8.16–7.93(m,2H),7.59(d,1H),7.52(m,3H),7.18(d,1H),6.93(m ,2H),4.84(s,1H),4.50(s,1H),4.05(d,1H),3.77(dd,1H),3.65–3.52(m,3H),2.22(s,3H),1.39( d, 3H). LC-MS [M+H] ⁺ = 487.3.

The synthesis of embodiment 28 compound R60

(1) Step 1:

(R)-4-(2-chloro-9H-purin-6-yl)-3-methylmorpholine (200mg), 2-methyl-3-(4,4,5,5-tetramethyl -1,3,2-Dioxybenzaldehyde-2-yl)pyridine (261mg), Cu(OAc) ₂ (158mg), TEA (161mg), 4W/W 4A molecular sieves were stirred in DCM at room temperature for 18h, TLC After the completion of the detection reaction, suction filtration, rotary evaporation to remove the filtrate, the residue was extracted with ethyl acetate and water, the ethyl acetate layer was washed with saturated brine, the organic phase was dried and spin-dried, column chromatography (petroleum ether: ethyl acetate=2 :1-1:1) purification to obtain compound R60-1. LC-MS [M+H] ⁺ = 345.1.

(2) Step 2:

Compound R60-1 (80mg), 7-azaindole borate pinacol ester (56mg), potassium phosphate (63mg) were stirred and dissolved in 1,4-dioxane (5:1), and Pd( dppf)Cl ₂ (17mg), reacted at 100°C for 12h under the protection of nitrogen, after the reaction was complete as detected by TLC, the solvent was concentrated under reduced pressure, the residue was added to water, extracted twice with ethyl acetate, dried over anhydrous sodium sulfate, concentrated, column Purified by chromatography (petroleum ether:ethyl acetate=1:1-1:4), and concentrated the target product to obtain compound R60 (16 mg) as a light yellow solid. ¹ H NMR (400MHz,DMSO)δ11.72(d,1H),8.75–8.68(m,1H),8.52(d,1H),8.29(dd,1H),8.02(s,1H),7.93(dd ,1H),7.57–7.53(m,1H),7.50(dd,1H),7.02(dt,1H),5.56(s,1H),5.23(s,1H),4.09(s,1H),3.88( s,1H), 3.80(d,1H), 3.63(d,2H), 2.40(d,3H), 1.50–1.40(m,3H). LC-MS [M+H] ⁺ = 427.3.

The synthesis of embodiment 29 compound R62

(1) Step 1:

At room temperature, 4-bromo-1H-pyrrole[2,3-c]pyridine (200mg), biboronic acid pinacol ester (308mg), potassium acetate (98mg), [1,1 '-bis(diphenylphosphino)ferrocene]palladium dichloride (73.2mg) and 1,4-dioxane (10mL), replaced with nitrogen three times, and reacted overnight at 120°C. After the reaction was cooled to room temperature, it was suction filtered, the filter cake was washed twice with ethyl acetate (50 mL), concentrated, and purified by column chromatography to obtain compound R62-1 (140 mg). LC-MS [M+H] ⁺ = 245.1.

(2) Step 2:

At room temperature, add compound R62-1 (68 mg), azaindole borate (50 mg), potassium carbonate (58 mg), [1,1'-bis(diphenylphosphino)ferrocene] dichloride Palladium (19.7mg) and 1,4-dioxane (10mL)/water (2mL) were replaced with nitrogen three times, and reacted at 100°C for 16h. Add 50 mL of water and 50 mL of ethyl acetate to the reaction solution, separate the layers, then extract twice with ethyl acetate (50 mL), combine the organic phases, wash with saturated brine, dry over anhydrous sodium sulfate, and perform column chromatography (petroleum ether: Ethyl acetate=1:1-1:0) to obtain compound R62 (15 mg, 18%). ¹ H NMR (400MHz,DMSO)δ11.79(s,1H),8.92(s,1H),8.85(d,1H),8.35(d,1H),8.24(d,1H),8.06(d,1H ),7.61(t,1H),5.56(s,1H),5.21(s,1H),4.15–3.96(m,1H),3.86(d,1H),3.82–3.71(m,1H),3.66– 3.56 (m, 2H), 1.99 (s, 3H), 1.44 (m, 5H). LC-MS [M+H] ⁺ = 439.1.

The synthesis of embodiment 30 compound R63

(1) Step 1:

Add (R)-4-(2-chloro-7H-pyrrole[2,3-d]pyrimidin-4-yl)-3-methylmorpholine (253mg), 3-methyl4- Pyridine borate (160mg), copper acetate (300mg) and TEA (300mg) were added, then DCM (15mL) was added and reacted at room temperature for 36h. The product was monitored by TLC, dried directly, and purified by column chromatography (petroleum ether: ethyl acetate = 1:2) to obtain a light yellow solid (30 mg, 8%). LC-MS [M+H] ⁺ = 344.1.

(2) Step 2:

Add compound R63-1 (30mg), azaindole borate (29mg), Pd(dppf)Cl ₂ (13mg), potassium carbonate (24mg) and 1,4-dioxane/ _H2O 5:1 (4mL/0.8mL). The reaction was carried out at 100°C for 16 h under the protection of nitrogen. TLC detected that the reaction was complete. The reaction solution was purified by column chromatography (petroleum ether: ethyl acetate = 1:5) to obtain compound R63 (7 mg, 18%) as a pale yellow solid. ¹ H NMR (400MHz, DMSO) δ8.62(d,1H),8.26(d,1H),8.10(s,1H),7.93(d,1H),7.58(dd,2H),7.46–7.41(m ,1H),6.99(d,1H),6.95(dd,1H),4.94(s,1H),4.62(d,1H),4.11–4.02(m,1H),3.88–3.75(m,2H), 3.67–3.48 (m, 2H), 2.95 (s, 3H), 1.41 (d, 3H). LC-MS [M+H] ⁺ = 426.2.

The synthesis of embodiment 31 compound R64

(1) Step 1:

(R)-4-(2-Chloro-7H-pyrrole[2,3-d]pyrimidin-4-yl)-3-methylmorpholine (200mg), 4-purineboronic acid (202mg), Cu(OAc ) ₂ (160mg), TEA (160mg), and 4W/W 4A molecular sieves were stirred in DCM at room temperature for 18 hours. After the reaction was complete by TLC, the filtrate was removed by suction filtration and rotary evaporation. The ester layer was washed with saturated brine, the organic phase was concentrated, and purified by column chromatography (petroleum ether:ethyl acetate=2:1-1:1) to obtain compound R64-1. LC-MS [M+H] ⁺ = 380.1.

(2) Step 2:

Compound R64-1 (30 mg), 7-azaindole borate pinacol ester (21 mg), potassium phosphate (22 mg) were stirred in 1,4-dioxane (10 mL), H ₂ O (2 mL) Dissolve, add Pd(dppf)Cl ₂ (6mg), react at 100°C under nitrogen protection for 12h, TLC detects that the reaction is complete, concentrate the solvent under reduced pressure, add water to the residue, extract twice with ethyl acetate, anhydrous sodium sulfate It was dried, concentrated, and purified by column chromatography (ethyl acetate:ether=1:1-1:4) to obtain compound R64 (8 mg, 21%) as a pale yellow solid. ¹ H NMR (400MHz, CDCl ₃ )δ9.15(d,1H),8.22(dd,2H),7.91–7.84(m,2H),7.79(dd,2H),7.69–7.44(m,3H), 7.31–7.26(m,1H),7.12(d,1H),6.65(dd,1H),4.98(s,1H),4.65(d,1H),4.09(d,1H),3.88–3.77(m, 2H), 3.61(dt,2H), 1.44(d,3H). LC-MS [M+H] ⁺ = 462.3.

The synthesis of embodiment 32 compound R65

(1) Step 1:

At room temperature, add (R)-4-(2-chloro-9H-purin-6-yl)-3-methylmorpholine (300mg), 4-pyridineboronic acid pinacol ester (365mg) into a 25mL single-necked bottle , copper acetate (322mg) and TEA (0.5mL), be dissolved in DCM (15mL), add molecular sieves, after reacting solution exposure reaction 16h, spin dry after pad diatomaceous earth suction filtration, column chromatography (petroleum ether: acetic acid Ethyl ester=1:1～1:1+1% methanol) to obtain compound R65-1 (180 mg, 45%) as a white solid. LC-MS [M+H] ⁺ = 331.1.

(2) Step 2:

Compound R65-1 (140mg), N-methyl-1H-benzo[d]imidazol-2-amine (80mg), Pd(OAc) ₂ (20mg), BINAP (40mg), K ₂ CO ₃ (116mg ) into a 25mL single-necked bottle in turn, added 12mL redistilled 1,4-dioxane, reacted at 97°C for 5h, cooled to room temperature, column chromatography (DCM:ethyl acetate:methanol=100:20:1～100 :100:2) Purification afforded compound R65 (60 mg, 32%) as pale yellow solid. ¹ H NMR (400MHz,DMSO)δ8.87(d,2H),8.81(s,1H),8.16(d,2H),8.05(d,2H),7.29(d,1H),7.11(t,1H ),7.01(t,1H),4.06(dd,1H),3.87(d,1H),3.78(d,1H),3.69–3.55(m,4H),3.08(d,3H),1.44(d, 3H). LC-MS [M+H] ⁺ = 442.2.

The synthesis of embodiment 33 compound R66

(1) Step 1:

Add compound (R)-4-(2-chloro-9H-purin-6-yl)-3-methylmorpholine (200mg), 2-methylpyridine 5-boronate (125mg), acetic acid in a 100ml single-necked bottle Copper (235mg) and TEA (300mg), then added DCM (10mL), reacted at room temperature for 16h. TLC monitors the generation of product, removes copper acetate and molecular sieves by suction filtration, concentrates the reaction solution, and purifies by column chromatography (petroleum ether: ethyl acetate=2:1) to obtain compound R66-1 (30mg, 15% ). LC-MS [M+H] ⁺ = 345.1.

(2) Step 2:

Add compound R66-1 (30 mg), azaindole borate (29 mg), Pd(dppf)Cl2 (13 mg), potassium carbonate (24 mg) and 1,4-dioxane/H2O into a 10 mL one-necked bottle (5:1, 4mL/0.8mL). React at 100°C for 16 hours under a nitrogen atmosphere. TLC detects that the reaction is complete. The reaction solution is sanded and purified by column chromatography (petroleum ether: ethyl acetate = 1:1 plus 1% methanol) to remove impurities, and then CH ₂ Cl ₂ :MeOH = 30:1 to obtain the second point, slurried with petroleum ether: ethyl acetate = 5:1, and filtered with suction to obtain compound R66 (13 mg, 34%) as a pale yellow solid. ¹ H NMR (400MHz,DMSO)δ11.76(s,1H),9.07(d,1H),8.72(s,1H),8.38–8.22(m,2H),8.01(d,1H),7.71–7.51 (m,2H),7.22(s,1H),5.55(s,1H),5.34–4.95(m,1H),4.07(d,1H),3.86(d,1H),3.78(d,1H), 3.61(dd,2H), 2.61(s,3H), 1.42(d,3H). LC-MS [M+H] ⁺ = 427.1.

Synthesis of Example 34 Compound R67

(1) Step 1:

Add (R)-4-(2-chloro-7-(cyclopropylsulfonyl)-7H pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylmorpholine ( 356mg), 2-methyl-1H-benzo[d]imidazole (393mg), Pd(dppf)Cl ₂ (438mg), BINAP (746mg) and K ₂ CO ₃ (414mg), then DMF (5mL) was added, The reaction was carried out under nitrogen protection at 100° C. for 16 h. TLC monitored the formation of the product, extracted with ethyl acetate, dried, and purified by column chromatography (petroleum ether: ethyl acetate = 1:4) to obtain compound R67 (128 mg, 28%) as a white solid. ¹ H NMR (400MHz,DMSO)δ8.37–8.31(m,1H),7.67(d,1H),7.59(dd,1H),7.33(dd,2H),7.10(d,1H),4.84(s ,1H),4.48(d,1H),4.08(d,1H),3.88–3.76(m,2H),3.63(d,2H),2.96(s,3H),1.44(d,3H),1.14- 0.09(m,5H). LC-MS [M+H] ⁺ = 453.1.

The synthesis of embodiment 35 compound R68

(R)-4-(2-chloro-7-(cyclopropylsulfonyl)-7H pyrrole[2,3-d]pyrimidin-4-yl)-3-methylmorpholine (50mg), indole -Pinacol 4-boronic acid (34mg) and potassium carbonate (39mg) were stirred and dissolved in 1,4-dioxane (10mL) and H ₂ O (2mL), and Pd(dppf)Cl ₂ (10mg) was added , reacted at 100°C for 12h under the protection of nitrogen, after TLC detected that the reaction was complete, the solvent was concentrated under reduced pressure, the residue was added to water, extracted twice with ethyl acetate, dried with anhydrous sodium sulfate, concentrated, column chromatography (petroleum ether: Ethyl acetate=1:1-1:4) to obtain compound R68 (20 mg, 32%) as a white solid. ¹ H NMR (400MHz,DMSO)δ11.23(s,1H),8.16(d,1H),7.67(s,1H),7.53(d,1H),7.48(dd,2H),7.20(t,1H ),6.96(d,1H),4.85(s,1H),4.52(s,1H),4.06–4.00(m,1H),3.81(d,1H),3.75(dd,1H),3.59(dd, 1H), 3.50(d,1H), 1.40(d,2H), 1.13(dd,2H), 1.07(s,4H). LC-MS [M+H] ⁺ = 438.3.

The synthesis of embodiment 36 compound R71

(1) Step 1:

2,6-Dichloro-9H-purine (1.88g), triethylamine (2.02g) and (R)-3-methylmorpholine (1.11g) were added to DMF (30mL), and stirred overnight at 90°C. Cooled to room temperature, extracted 3 times with ethyl acetate, washed the ethyl acetate phase with saturated brine, dried, and purified by column chromatography (petroleum ether: ethyl acetate = 2:1) to obtain compound R71-1 as a white solid (2 g, 79%). LC-MS [M+H] ⁺ =254.

(2) Step 2:

Add compound R71-1 (506 mg), Cs ₂ CO ₃ (1.95 g) and cyclopropylsulfonyl chloride (420 mg) into DMF (15 mL), and stir at 60° C. for 1 h. Cooled to room temperature, extracted 3 times with ethyl acetate, washed the ethyl acetate phase with saturated brine, dried, and purified by column chromatography (petroleum ether: ethyl acetate = 1:1) to obtain compound R71-2 as a white solid (500mg, 70%). LC-MS [M+H] ⁺ =358.

(3) Step 3:

Compound R71-2 (178 mg), 7-azaindole borate (244 mg), Pd(dppf)Cl ₂ (73 mg) and K ₂ CO ₃ (207 mg) were added to 1,4-dioxane:H ₂ O=5:1 (3 mL), and then react overnight at 100°C under nitrogen protection. Cooled to room temperature, extracted 3 times with ethyl acetate, washed the ethyl acetate phase with saturated brine, dried, and purified by column chromatography (petroleum ether:ethyl acetate=1:4) to obtain compound R71 (10mg , 4%). ¹ H NMR (500MHz, DMSO) δ11.84(d,1H),8.54(s,1H),8.36(d,1H),8.03(d,1H),7.68–7.61(m,1H),7.43(dd ,1H),5.46(s,1H),5.13(s,1H),4.05(d,1H),3.84(d,1H),3.76(dd,1H),3.67–3.50(m,2H),3.44( dd,1H), 1.56(s,2H), 1.41(d,3H), 1.25(dd,2H). LC-MS [M+H] ⁺ =440.

Synthesis of Example 37 Compound R72

(1) Step 1:

Carbendazim (1.91 g) was added to THF (100 mL), and then LAH (1.9 g) was added to the above mixture in batches at 0° C., heated to reflux and stirred overnight under nitrogen protection. After cooling down to 0°C, H ₂ O (1.9 mL), 15% NaOH aqueous solution (1.9 mL) and H ₂ O (5.7 mL) were added sequentially with an interval of 5 min, and the stirring was continued for 2 h. The resulting mixture was filtered, the filter cake was washed twice with ethyl acetate, and the resulting filtrate was spin-dried to obtain compound R72-1 (1.2 g, yield 81%) as a white solid. LC-MS [M+H] ⁺ =148.

(2) Step 2:

The synthesis method of compound R72-2 refers to the synthesis of compound R71-2. Add compound R72-1 (178mg), compound R72-2 (220mg), Pd(AcO) ₂ (22mg), BINAP (124mg) and K ₂ CO ₃ (207mg) into dry DMF (3mL), and then React overnight at 100°C. Cooled to room temperature, extracted 3 times with ethyl acetate, washed the ethyl acetate phase with saturated brine, dried, and purified by column chromatography (petroleum ether:ethyl acetate=1:4) to obtain compound R72 (10mg ,2%). ¹ HNMR (500MHz, DMSO)8.82(s,1H),8.57(s,1H),8.29(d,1H),7.36(d,1H),7.20(t,1H),7.17–7.09(m,1H) ,4.07(d,1H),3.90–3.70(m,3H),3.62(s,2H),3.42(t,2H),3.13(d,3H),1.49(q,2H),1.43(d,3H ), 1.28(d,2H). LC-MS [M+H] ⁺ = 469.

Synthesis of Example 38 Compound R73

(1) Step 1:

4,6-Dichloro-1H-pyrazolo[3,4-d]pyrimidine (1 g), (R)-3-methylmorpholine (757 mg) and triethylamine (1 g) were stirred in DCM at room temperature After reacting for 12 hours, TLC detected that the reaction was complete, the organic phase was dried by rotary evaporation, and purified by column chromatography (petroleum ether: ethyl acetate = 3:1-2:1) to obtain compound R73-1 (600mg, 47 %). LC-MS [M+H] ⁺ =254.

(2) Step 2:

Compound R73-1 (150 mg), cyclopropylsulfonyl chloride (108 mg), and CS ₂ CO ₃ (385 mg) were stirred in DMF at room temperature for 3 h. After the reaction was complete by TLC, the reaction solution was extracted with ethyl acetate and water, and acetic acid The ethyl ester layer was washed with saturated brine, the organic phase was dried by rotary evaporation, and purified by column chromatography (petroleum ether: ethyl acetate = 2:1-1:1) to obtain compound R73-2 (150 mg, 70% ). LC-MS [M+H] ⁺ =358.

(3) Step 3:

Compound R73-2 (50mg), N-methyl-1H-benzo[d]imidazol-2-amine (31mg), BINAP (17mg), palladium acetate (7mg), potassium carbonate (38mg) in 1,4- React in dioxane at 100°C for 12 h under the protection of _N2 . After the reaction is complete by TLC, concentrate the solvent under reduced pressure, add water to the residue, extract twice with ethyl acetate, and dry the ethyl acetate phase with anhydrous sodium sulfate. It was concentrated and purified by column chromatography (petroleum ether:ethyl acetate=1:1-1:4) to obtain compound R73 (6 mg, 9%) as a pale yellow solid. ¹ H NMR (400MHz, DMSO) δ8.86(s,1H),8.73(d,1H),8.29(t,1H),7.29(dd,1H),7.14(dd,1H),7.08–7.00(m ,1H),4.21–3.98(m,2H),3.95–3.52(m,5H),3.15–3.06(s,3H),1.51–1.39(m,3H),1.36(s,2H),1.26–1.13 (m,3H). LC-MS [M+H] ⁺ = 469.

Synthesis of Example 39 Compound R74

(1) Step 1:

Add 2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidine (935 mg), pyridine (1.18 g) and N-methylpyrazole borate (1560 mg) into DCM (15 mL) at room temperature Stir for 72h. Filter, wash the filter cake with DCM, and wash the filtrate with dilute hydrochloric acid. The filtrate was washed 3 times with saturated brine, dried, and purified by column chromatography (petroleum ether: ethyl acetate = 1:1) to obtain compound R74-1 (0.23 g, 17%) as a white solid. LC-MS [M+H] ⁺ =268.

(2) Step 2:

Compound R74-1 (133 mg) and (R)-3-methylmorpholine (55 mg) were added into DMSO/H ₂ O (10:1, 3 mL), then stirred at 60° C. overnight. Extracted 3 times with ethyl acetate, washed the ethyl acetate phase with saturated brine, dried, and purified by column chromatography (petroleum ether: ethyl acetate = 1:2) to obtain compound R74-2 (100 mg, 60 %). LC-MS [M+H] ⁺ =333.

(3) Step 3:

Compound R74-2 (83mg), N-methyl-1H-benzo[d]imidazol-2-amine (110mg), Pd(AcO) ₂ (11mg), BINAP (62mg), K ₂ CO ₃ (104mg ) was added to dry DMF (3 mL), and reacted overnight at 100° C. under nitrogen protection. Cooled to room temperature, extracted 3 times with ethyl acetate, washed the ethyl acetate phase with saturated brine, dried, and purified by column chromatography (petroleum ether: ethyl acetate=1:4) to obtain compound R74 (10mg , 4%). ¹ H NMR (400MHz, DMSO) δ8.29(d,1H),8.07(d,1H),7.70(d,1H),7.56(d,1H),7.25(d,1H),7.10–7.03(m ,2H),6.95–6.89(m,1H),6.59(d,1H),4.77(s,1H),4.39(d,1H),4.08(d,1H),3.87–3.74(m,3H), 3.67(s,3H), 3.66–3.57(m,2H), 3.00(d,2H), 1.42(d,3H). LC-MS [M+H] ⁺ = 444.

The synthesis of embodiment 40 compound R75

(1) Step 1:

2,4-Dichloro-7H-pyrrolo[2,3-d]pyrimidine (1.87 g), triethylamine (2.02 g) and (R)-3-methylmorpholine (1.11 g) were added to DMF ( 30 mL), stirred overnight at 90°C. Cooled to room temperature, extracted 3 times with ethyl acetate, washed the ethyl acetate phase with saturated brine, dried, and purified by column chromatography (petroleum ether: ethyl acetate = 2:1) to obtain compound R75-1 as a white solid (2 g, 79%). LC-MS [M+H] ⁺ =253.

(2) Step 2:

Add compound R75-1 (1008 mg), Cs ₂ CO ₃ (3.9) and benzenesulfonyl chloride (1056 mg) into ACN (15 mL), and stir at 60° C. for 3 h. Cooled to room temperature, extracted 3 times with ethyl acetate, washed the ethyl acetate phase with saturated brine, dried, and purified by column chromatography (petroleum ether: ethyl acetate = 1:1) to obtain compound R75-2 as a white solid (1200 mg, 76%). LC-MS [M+H] ⁺ =393.

(3) Step 3:

Compound R75-2 (1176mg), N-methyl-1H-benzo[d]imidazol-2-amine (1323mg), Pd(AcO) ₂ (132mg), BINAP (747mg) and K ₂ CO ₃ (1242mg ) was added into 1,4-dioxane (15 mL), and reacted overnight at 100° C. under nitrogen protection. Cooled to room temperature, extracted 3 times with ethyl acetate, washed the ethyl acetate phase with saturated brine, dried, and purified by column chromatography (petroleum ether: ethyl acetate = 1:4) to obtain compound R75-3 as a white solid (500 mg, 33%). LC-MS [M+H] ⁺ =503.

(4) Step 4:

Compound R75-3 (252 mg) and Pd/C (100 mg) were added to dry EtOH (3 mL), and reacted at 60° C. for 72 h under hydrogen atmosphere. It was filtered and purified by column chromatography (petroleum ether:ethyl acetate=1:3) to obtain compound R75-4 (150 mg, 59%) as a white solid. LC-MS [M+H] ⁺ =505.

(5) Step 5:

Compound R75-4 (101 mg) and MeONa (108 mg) were added into EtOH/H ₂ O (1:1, 3 mL), and reacted at 90° C. for 24 h. Cooled to room temperature, extracted 3 times with ethyl acetate, washed the ethyl acetate phase with saturated brine, dried, and purified by column chromatography (petroleum ether: ethyl acetate = 1:4) to obtain compound R75-5 as a white solid (50 mg, 68%). LC-MS [M+H] ⁺ = 366.

(6) Step 6:

Compound R75-5 (36 mg) and cyclopropanesulfonyl chloride (42 mg) were added to dry pyridine (3 mL), followed by reaction at 100° C. overnight. Cooled to room temperature, extracted 3 times with ethyl acetate, washed the ethyl acetate phase with dilute hydrochloric acid, dried, and purified by column chromatography (petroleum ether: ethyl acetate = 1:4) to obtain compound R75 (10 mg, 20%). ¹ H NMR (400MHz,DMSO)δ12.20(s,1H),7.48(t,1H),7.38–7.30(m,1H),7.12(dd,2H),4.62–4.54(m,1H),4.21 (d,1H),3.99–3.89(m,1H),3.81–3.66(m,3H),3.62–3.56(m,1H),3.52(d,3H),3.44(t,1H),3.20–3.04 (m,2H), 2.38(t,2H), 1.22(d,3H), 1.17(d,2H), 1.09–1.01(m,2H). LC-MS [M+H] ⁺ =470.

The synthesis of embodiment 41 compound R76

(1) Step 1:

(R)-3-Methylmorpholine (444mg) and triethylamine (444mg) were added to DMF (15mL), and then the above mixture was added dropwise to 2,4,6-trichloro-5- Nitropyrimidine (1 g) in DMF (20 mL) was stirred at room temperature for 1 h. Extracted 3 times with ethyl acetate, washed the ethyl acetate phase with saturated brine, dried, and purified by column chromatography (petroleum ether:ethyl acetate=10:1) to obtain compound R76-1 (1.2g , 93%). LC-MS [M+H] ⁺ =293.

(2) Step 2:

Compound R76-1 (292 mg), 1-methyl-1H-pyrazol-5-amine (194 mg), CsCO ₃ (975 mg) and ACN (3 mL) were added in a 100 ml one-port bottle. React at 60°C for 4h. The reaction solution was sanded and purified by column chromatography (petroleum ether: ethyl acetate = 1:2) to obtain compound R76-2 (180 mg, 51%) as a pale yellow solid. LC-MS [M+H] ⁺ =354.

(3) Step 3:

Compound R76-2 (180 mg) was dissolved in ethanol (3 mL), and then SnCl ₂ (385 mg), concentrated hydrochloric acid (0.5 mL) and trimethyl orthoformate (2 mL) were added sequentially. Stir at 90°C overnight, then cool to room temperature. Use sodium bicarbonate to adjust the base, extract with ethyl acetate for 3 times, wash the ethyl acetate phase with saturated brine, dry, and purify by column chromatography (petroleum ether:ethyl acetate=1:1) to obtain a light yellow solid Compound R76-3 (40 mg, 23%). LC-MS [M+H] ⁺ =334.

(4) Step 4:

Compound R76-3 (40 mg), N-methyl-1H-benzo[d]imidazol-2-amine (53 mg), Pd(AcO) ₂ (5.4 mg), BINAP (30 mg) and K ₂ CO ₃ ( 50mg) was added to dry DMF (3mL), and reacted overnight at 100°C under nitrogen protection. Cooled to room temperature, extracted 3 times with ethyl acetate, washed the ethyl acetate phase with saturated brine, and purified by column chromatography (petroleum ether: ethyl acetate = 1:4) to obtain compound R76 (10 mg, 18%). ¹ H NMR (400MHz,DMSO)δ8.52(s,1H),8.15(s,1H),8.05(d,1H),7.73(d,1H),7.26(d,1H),7.08(t,1H ),6.99–6.90(m,1H),6.70(d,1H),4.09(d,1H),3.87(d,2H),3.80(d,2H),3.76(s,3H),3.64(d, 2H), 3.02(d,3H), 1.46(d,3H). LC-MS [M+H] ⁺ = 445.

The synthesis of embodiment 42 compound R77

(1) Step 1:

The compound 2,4-dichloropyrrolo[2,1-f][1,2,4]triazine (935 mg), K ₂ CO ₃ (2.07 g) and (R)-3-methylmorpholine ( 555 mg) was added into DMF (15 mL), and stirred at room temperature for 1 h. It was extracted three times with ethyl acetate, washed with saturated brine, and purified by column chromatography (petroleum ether: ethyl acetate = 10:1) to obtain compound R77-1 (1.2 g, 95%) as a pale yellow solid. LC-MS [M+H] ⁺ =253.

(2) Step 2:

Compound R77-1 (1.0 g) was added to DMF (15 mL), then NIS (1.8 g) was added, and stirred overnight at room temperature. Extracted 3 times with ethyl acetate, washed the ethyl acetate phase with saturated brine, dried, and purified by column chromatography (petroleum ether:ethyl acetate=10:1) to obtain compound R77-2 (1.2g , 79%). LC-MS [M+H] ⁺ =379.

(3) Step 3:

Compound R77-2 (378 mg), N-methylpyrazole boronic acid (150 mg), Pd(dppf)Cl ₂ (140 mg) and K ₂ CO ₃ (410 mg) were added to 1,4-dioxane/H ₂ O =5:1 (3mL), stirred at 100°C for 3h under nitrogen protection, and then cooled to room temperature. Extracted 3 times with ethyl acetate, washed the ethyl acetate phase with saturated brine, dried, and purified by column chromatography (petroleum ether: ethyl acetate = 1:1) to obtain compound R77-3 (270 mg, 78%). LC-MS [M+H] ⁺ = 347.

(4) Step 4:

Compound R77-3 (166mg), N-methyl-1H-benzo[d]imidazol-2-amine (220mg), Pd(AcO) ₂ (22mg), BINAP (124mg) and K ₂ CO ₃ (207mg ) was added into anhydrous DMF (3 mL), and reacted overnight at 100° C. under nitrogen protection. Cooled to room temperature, extracted 3 times with ethyl acetate, washed the ethyl acetate phase with saturated brine, dried, and purified by column chromatography (petroleum ether:ethyl acetate=1:4) to obtain compound R77 (10mg , 4%). ^1HNMR (500MHz,DMSO)7.86(d,1H),7.65(d,1H),7.40(d,1H),7.32(d,1H),7.26(d,1H),7.12(d,1H),7.07 (t,1H),6.91(dd,1H),6.75(d,1H),4.89(d,1H),4.51(d,1H),4.07(d,1H),3.87(s,3H),3.86– 3.74(m,2H), 3.64(t,2H), 3.00(d,3H), 1.47(d,3H). LC-MS [M+H] ⁺ = 444.

The synthesis of embodiment 43 compound R78

(1) Step 1:

Compound R78-1 (378 mg), CuI (380 mg), and sodium cyclopropanesulfinate (140 mg) were added to DMSO (3 mL), stirred at 120° C. under nitrogen for 3 h, and then cooled to room temperature. Extracted 3 times with ethyl acetate, washed the ethyl acetate phase with saturated brine, dried, and purified by column chromatography (petroleum ether: ethyl acetate = 1:1) to obtain compound R78-2 (270 mg, 75%). LC-MS [M+H] ⁺ = 357.

(2) Step 2:

Compound R78-2 (178mg), N-methyl-1H-benzo[d]imidazol-2-amine (220mg), Pd(AcO) ₂ (22mg), BINAP (124mg) and K ₂ CO ₃ (207mg ) was added into anhydrous DMF (3 mL), and reacted overnight at 100° C. under nitrogen protection. Cooled to room temperature, extracted 3 times with ethyl acetate, washed the ethyl acetate phase with saturated brine, dried, and purified by column chromatography (petroleum ether:ethyl acetate=1:4) to obtain compound R78 (10mg ,2%). ¹ HNMR (500MHz, DMSO) 8.07(d, 1H), 7.90(s, 1H), 7.32–7.25(m, 2H), 7.12(t, 1H), 7.02(t, 1H), 4.91(s, 2H) ,4.56(s,2H),4.07(s,1H),3.78(s,3H),3.65(t,1H),3.11–3.02(m,3H),1.48(d,3H),1.24(s,4H ). LC-MS [M+H] ⁺ = 468.

The synthesis of embodiment 44 compound R80

(1) Step 1:

(R)-4-(2-Chloro-7-iodopyrrole[2,1-f][1,2,4]triazin-4-yl)-3-methylmorpholine (378mg), CuI( 380 mg) and sodium methanesulfinate (140 mg) were added into DMSO, stirred at 120° C. under nitrogen for 3 h, and then cooled to room temperature. Extracted three times with ethyl acetate, washed the ethyl acetate phase with saturated brine, dried, and purified by column chromatography (petroleum ether: ethyl acetate = 1:1) to obtain compound R80-1 (270 mg, 75%). LC-MS [M+H] ⁺ = 331.

(2) Step 2:

Compound R80-1 (178 mg), N-methyl-1H-benzo[d]imidazol-2-amine (220 mg), palladium acetate (22 mg), BINAP (124 mg) and K ₂ CO ₃ (207 mg) were added to a supernatant Dry in DMF, then react overnight at 100°C under nitrogen protection. Cooled to room temperature, extracted three times with ethyl acetate, washed the ethyl acetate phase with saturated brine, dried, and purified by column chromatography (petroleum ether:ethyl acetate=1:4) to obtain compound R80 (10mg ,2%). ¹ H NMR (400MHz, DMSO) δ8.05(d, 1H), 7.81(s, 1H), 7.30(dd, 3H), 7.12(dd, 1H), 7.05–6.98(m, 1H), 4.90(s , 1H), 4.07(s, 1H), 3.78(d, 2H), 3.65(t, 3H), 3.41(s, 3H), 3.06(d, 3H), 1.47(d, 3H). LC-MS [M+H] ⁺ = 442.

Synthesis of Example 45 Compound R81

(1) Step 1:

(R)-4-(6-chloro-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-3-methylmorpholine (150mg), 1-methylcyclopropane-1- Sulfonyl chloride (118 mg) and CS ₂ CO ₃ (385 mg) were reacted in DMF at room temperature for 3 hours. After the reaction was complete as detected by TLC, diluted with water, extracted twice with ethyl acetate, separated, and the ethyl acetate phase was washed once with saturated saline , dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and purified by column chromatography (petroleum ether: ethyl acetate = 1:1) to obtain compound R81-1 (200 mg, 91%) as a pale yellow solid. LC-MS [M+H] ⁺ =372.

(2) Step 2:

Compound R81-1 (100mg), N-methyl-1H-benzo[d]imidazol-2-amine (84mg), BinAP (48mg), Pd(OAc) ₂ (18mg), potassium phosphate (74mg) in 1 , Stir and dissolve 4-dioxane, react at 100°C for 12 hours under the protection of N ₂ , after TLC detects that the reaction is complete, concentrate the solvent under reduced pressure, add water to the residue, extract twice with ethyl acetate, dry the acetic acid with anhydrous sodium sulfate The ethyl ester phase was concentrated and purified by column chromatography (petroleum ether:ethyl acetate=1:1-1:4) to obtain compound R81 (26 mg, 20%) as a white solid. ¹ H NMR (400MHz, DMSO) δ9.31(s, 1H), 8.61(s, 1H), 8.21(s, 1H), 7.27(d, 1H), 7.11(t, 1H), 7.01(t, 1H ), 4.99–4.52(m, 2H), 4.17(d, 2H), 3.81(t, 2H), 3.65(t, 1H), 3.12(d, 3H), 1.72(s, 2H), 1.43(d, 5H), 1.27(s, 3H). LC-MS [M+H] ⁺ = 483.

The synthesis of embodiment 46 compound R82

(1) Step 1:

(R)-4-(6-chloro-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-3-methylmorpholine (200mg) and bromocyclopentane (234mg), CS ₂ CO ₃ (515 mg) and KI (40 mg) were refluxed in DMF and stirred overnight. After the reaction was complete as detected by TLC, dilute with water, add ethyl acetate for extraction twice, separate the liquids, wash the ethyl acetate phase with saturated saline once, It was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and purified by column chromatography (petroleum ether: ethyl acetate = 1:1) to obtain compound R82-1 (230 mg, 89%) as an oil. LC-MS [M+H] ⁺ =322.

(2) Step 2:

Compound R82-1 (160mg), N-methyl-1H-benzo[d]imidazol-2-amine (84mg), BinAP (58mg), Pd(OAc) ₂ (58mg), potassium phosphate (129mg) in 1 , Stir and dissolve 4-dioxane, react at 100°C for 12 hours under the protection of N ₂ , after TLC detects that the reaction is complete, concentrate the solvent under reduced pressure, add water to the residue, extract twice with ethyl acetate, dry the acetic acid with anhydrous sodium sulfate The ethyl ester phase was concentrated and purified by column chromatography (petroleum ether:ethyl acetate=1:1-1:4) to obtain compound R82 (16 mg, 7.2%) as a white solid. ¹ H NMR (400MHz, DMSO) δ8.18(s, 1H), 7.54–7.42(m, 3H), 7.15–7.04(m, 2H), 5.34(t, 1H), 4.67(s, 2H), 4.51 –4.30(m, 2H), 4.02(d, 1H), 3.81(s, 3H), 3.72(dd, 1H), 3.56(d, 1H), 2.13(d, 2H), 2.03(dd, 2H), 1.88 (s, 2H), 1.77–1.65 (m, 2H), 1.34 (d, 3H). LC-MS [M+H] ⁺ = 433.

Synthesis of Example 47 Compound R83

(1) Step 1:

(R)-4-(2-Chloro-7H-pyrrole[2,3-d]pyrimidin-4-yl)-3-methylmorpholine (500mg) was dissolved in DMF, NaH (119mg) was added at 0°C, After reacting at room temperature for 30 minutes, slowly add chloromethyl methyl sulfide (282 mg), and react overnight at room temperature. After the reaction was complete as detected by TLC, add NH ₄ Cl aqueous solution to quench, add ethyl acetate to extract twice, separate liquid, acetic acid The ethyl ester phase was washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and purified by column chromatography (petroleum ether: ethyl acetate = 1:1) to obtain oily compound R83-1 (260 mg, 41 %). LC-MS [M+H] ⁺ =313.

(2) Step 2:

Compound R83-1 (400 mg) and mCPBA (443 mg) were reacted in DCM at room temperature for 3 h. After the reaction was complete as detected by TLC, column chromatography (petroleum ether: ethyl acetate = 1:1) was purified to obtain compound R83-2 (200 mg, 45%). LC-MS [M+H] ⁺ = 345.

(3) Step 3:

Compound R83-2 (50 mg) was used in DMF solution, NaH (12 mg) was added at 0°C, and reacted at room temperature for 30 min, then methyl iodide (63 mg) was added, and reacted at room temperature for 1 h, then NaH (12 mg) was added at 0°C, and reacted at room temperature for 30 min , add iodomethane (63 mg), react at room temperature for 1 h, after LCMS detects that the reaction is complete, add NH ₄ Cl aqueous solution to quench, add ethyl acetate to extract twice, separate the layers, wash the ethyl acetate phase with saturated brine once, and anhydrous sulfuric acid Dry over sodium, filter, concentrate the filtrate under reduced pressure, and purify by column chromatography (petroleum ether: ethyl acetate = 1:1) to obtain compound R83-3 (27 mg, 51%). LC-MS [M+H] ⁺ =373.

(4) Step 4:

Compound R83-3 (30mg), N-methyl-1H-benzo [d] imidazol-2-amine (15mg), BinAP (12mg,), Pd (OAc) ₂ (22mg), potassium phosphate (22mg) in Stir and dissolve in 1,4-dioxane, react at 100°C for 12 hours under the protection of N ₂ , after the completion of the reaction as detected by TLC, concentrate the solvent under reduced pressure, add water to the residue, extract twice with ethyl acetate, and dry over anhydrous sodium sulfate The ethyl acetate phase was concentrated and purified by column chromatography (petroleum ether:ethyl acetate=1:1-1:4) to obtain compound R83 (8 mg, 20%) as a white solid. ¹ H NMR (400MHz, DMSO) δ8.13(d, 1H), 7.50(dd, 1H), 7.28(d, 1H), 7.09(t, 1H), 7.00(t, 1H), 6.92(d, 1H ), 6.29(d, 1H), 4.76(s, 1H), 4.38(d, 1H), 4.08–4.01(m, 1H), 3.82(d, 1H), 3.75(d, 1H), 3.66–3.54( m, 2H), 3.51 (s, 1H), 3.07 (d, 3H), 3.05–2.97 (m, 2H), 1.94 (d, 3H), 1.39 (dd, 3H), 1.18 (td, 3H). LC-MS [M+H] ⁺ =484.

The synthesis of embodiment 48 compound R84

(1) Step 1:

(R)-4-(2-Chloro-7-iodopyrrole[2,1-f][1,2,4]triazin-4-yl)-3-methylmorpholine (100mg), 5-( 4,4,5,5-tetramethyl-1,3,2-dioxybenzaldehyde-2-yl)-1H-pyrazole (56mg), K ₂ CO ₃ (72mg), Pd(dppf)Cl ₂ (20 mg) was stirred and reacted in dioxane/H ₂ O at 100°C overnight. After the reaction was complete by TLC, it was diluted with water, extracted twice with ethyl acetate, separated, and the ethyl acetate phase was washed once with saturated saline. Dry over anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and purify by column chromatography (petroleum ether: ethyl acetate = 1:1-1:2) to obtain compound R84-1 (50 mg, 60%) as a light yellow solid . LC-MS [M+H] ⁺ = 319.

(2) Step 2:

Compound R84-1 (60mg), 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxylbenzaldehyde-2-yl)-1H-pyrazole (59mg ), K ₂ CO ₃ (52mg), Pd(dppf)Cl ₂ (14mg) were stirred and dissolved in dioxane/H ₂ O, reacted at 110°C for 12h under the protection of N ₂ , and concentrated under reduced pressure after TLC detection of complete reaction Remove the solvent, add water to the residue, extract twice with ethyl acetate, dry the ethyl acetate phase over anhydrous sodium sulfate, concentrate, and purify by column chromatography (petroleum ether: ethyl acetate = 1:1-1:4) to obtain shallow Compound R84 (16 mg, 26%) as a yellow solid. ¹ H NMR (400MHz, DMSO) δ13.07(s, 1H), 7.87(s, 1H), 7.53(d, 2H), 7.15(s, 2H), 6.89(s, 1H), 4.94(s, 1H ), 4.57 (s, 1H), 4.24 (s, 3H), 4.02 (d, 1H), 3.76 (d, 2H), 3.58 (d, 2H), 1.40 (d, 3H). LC-MS [M+H] ⁺ =365.

The synthesis of embodiment 49 compound R86

(1) Step 1:

Add (R)-4-(2-chloro-7-iodopyrrole[2,1-f][1,2,4]triazin-4-yl)-3-methylmorpholine (0.5 g) and anhydrous tetrahydrofuran (10mL), nitrogen protection, stirring to cool down to T<-78 ℃, drop in isopropylmagnesium chloride-lithium chloride complex (5mL, 1.3M/L), temperature control T<-75 ℃, keep stirring for 1h after dropping, add tetrahydrofuran-3-formaldehyde dropwise, control temperature T<-75°C, keep stirring for 1h after dropping, TLC, the raw materials disappear, add saturated ammonium chloride solution (5mL) dropwise, and naturally rise to At room temperature, ethyl acetate (10 mL) was added, stirred for 30 min, the organic phase was dried and concentrated, purified by column chromatography (petroleum ether: ethyl acetate = 1:1), and then submitted to the next step. LC-MS [M+H] ⁺ =353.

(2) Step 2:

Add compound R86-1 (0.14g) and DMF (3mL) at room temperature, stir down to T<0 ° C, add NaH (0.032g), naturally rise to room temperature for 1h, add iodomethane (0.068g), room temperature Reaction 1.5h, TLC (petroleum ether: ethyl acetate = 1:1), post-treatment, add water (10mL) and ethyl acetate (20mL), stir, dry and concentrate the organic phase, column chromatography (petroleum ether: ethyl acetate Ester=2:1) was purified to obtain compound R86-2 (90 mg, 62%). LC-MS [M+H] ⁺ =367.

(3) Step 3:

Add compound R86-2 (0.09g), N-methyl-1H-benzimidazol-2-amine (0.043g), BINAP (0.06g), palladium acetate (0.02g), DMF (5mL) at room temperature And cesium carbonate (0.159g), under nitrogen protection, heated to 135°C to react overnight, post-treatment, washed with water, extracted with ethyl acetate, dried and concentrated the organic phase, purified by column chromatography (DCM:MeOH=100:1) to obtain the compound R86 (10 mg, 8%). ¹ H NMR (400MHz, DMSO) δ7.96(d, 1H), 7.66(s, 1H), 7.29(d, 1H), 7.17(d, 1H), 7.10(t, 1H), 7.00(t, 1H ), 6.80(d, 1H), 4.85(s, 1H), 4.75(dd, 1H), 4.49(s, 1H), 4.04(d,, 1H), 3.84–3.49(m, 8H), 3.16(d , 3H), 3.06(d, 3H), 2.97(d, 1H), 2.04–1.94(m, 2H), 1.49–1.40(m, 3H). LC-MS [M+H] ⁺ =478.

The synthesis of embodiment 50 compound R87

(1) Step 1:

(R)-4-(2-Chloro-7-iodopyrrole[2,1-f][1,2,4]triazin-4-yl)-3-methylmorpholine (378mg) was added to the ultra-dry In THF (10 mL), drop to -78°C. Then add n-BuLi (THF, aq., 2.5N, 0.5mL) dropwise, stir at -78°C for 20min, then add excess 2,2-dimethyltetrahydro-4H-pyran-4-one dropwise, Stirring was continued for 30 min. Then add NH ₄ Cl (aq.) to quench, use ethyl acetate to extract three times, wash the ethyl acetate phase with saturated brine, dry, and purify by column chromatography (petroleum ether:ethyl acetate=1:1) to obtain Compound R87-1 as colorless oil (160 mg, 42%). LC-MS [M+H] ⁺ =381.

(2) Step 2:

Compound R87-1 (160mg), N-methyl-1H-benzo[d]imidazol-2-amine (188mg), palladium acetate (19mg), BINAP (104mg) and K ₂ CO ₃ (174mg) were added to super Dry in DMF (3 mL), then react overnight at 100°C under nitrogen protection. Cooled to room temperature, extracted three times with ethyl acetate, washed the ethyl acetate phase with saturated brine, dried, and purified by column chromatography (petroleum ether:ethyl acetate=1:4) to obtain compound R87 (10mg , 4%). ¹ H NMR (400MHz, DMSO) δ7.89(t, 1H), 7.55–7.45(m, 1H), 7.40–7.34(m, 2H), 7.32(s, 1H), 7.24–7.14(m, 1H) , 6.93(s, 1H), 3.98(s, 1H), 3.83–3.47(m, 4H), 3.23(m, 5H), 3.17(s, 3H), 1.68(d, 2H), 1.48(m, 6H ), 1.39 (s, 2H), 1.24 (m, 2H), 1.06 (s, 1H). LC-MS [M+H] ⁺ =492.

The synthesis of embodiment 51 compound R88

(1) Step 1:

(R)-4-(2-Chloro-7-iodopyrrole[2,1-f][1,2,4]triazin-4-yl)-3-methylmorpholine (378mg), CuI( 380mg), isothiazolidine 1,1-dioxide (140mg) and trans-N,N'-dimethyl-1,2-cyclohexanediamine (282mg) were added to DMSO (3mL), 130°C under nitrogen Protected stirring 3h, then cooled to room temperature. Extracted three times with ethyl acetate, washed the ethyl acetate phase with saturated brine, dried, and purified by column chromatography (petroleum ether: ethyl acetate = 1:1) to obtain compound R88-1 (200 mg, 75%). LC-MS [M+H] ⁺ =372.

(2) Step 2:

Compound R88-1 (178mg), N-methyl-1H-benzo[d]imidazol-2-amine (220mg), palladium acetate (22mg), BINAP (124mg) and K ₂ CO ₃ (207mg) were added to supernatant Dry in DMF, then react overnight at 100°C under nitrogen protection. Cooled to room temperature, extracted three times with ethyl acetate, washed the ethyl acetate phase with saturated brine, dried, and purified by column chromatography (petroleum ether:ethyl acetate=1:4) to obtain compound R88 (10mg ,2%). ¹ H NMR (400MHz, DMSO) δ10.75(s, 1H), 7.91(d, 1H), 7.60(s, 1H), 7.36(s, 1H), 7.07(d, 1H), 6.95(s, 1H ), 6.89(d, 1H), 4.85(s, 1H), 4.49(d, 1H), 4.09–4.03(m, 2H), 3.81(d, 2H), 3.65(s, 2H), 3.34(d, 3H), 3.00(d, 3H), 2.19-2.07(s, 2H), 1.48(d, 3H). LC-MS [M+H] ⁺ = 483.

The synthesis of embodiment 52 compound R89

(1) Step 1:

Add (R)-4-(2-chloro-7-iodopyrrole[2,1-f][1,2,4]triazin-4-yl)-3-methylmorpholine (0.2 g 0.53), 3,5-dimethylisoxazole-4-boronic acid pinacol ester (0.118g), cesium carbonate (0.344g), bis(triphenylphosphine)palladium dichloride (0.05g), Dioxane (5mL) and water (0.5mL), under nitrogen protection, were added to 110°C to react overnight, post-treated, washed with water, extracted with ethyl acetate, dried and concentrated the organic phase, column chromatography (petroleum ether: ethyl acetate =10:1) Purification gave compound R89-1 (0.14 g, 76%). LC-MS [M+H] ⁺ =348.

(2) Step 2:

Add compound R89-1 (0.14g), N-methyl-1H-benzimidazol-2-amine (0.071g), BINAP (0.08g), palladium acetate (0.03g), DMF (5mL) at room temperature And cesium carbonate (0.262g), under nitrogen protection, heated to 140°C to react overnight, post-treatment, washed with water, extracted with ethyl acetate, dried and concentrated the organic phase, purified by column chromatography (DCM:MeOH=100:1) to obtain the compound R89 (20 mg, 10%). ¹ H NMR (400MHz, DMSO) δ7.75(d, 1H), 7.61(s, 1H), 7.30(d, 1H), 7.26(d, 1H), 7.07(t, 1H), 6.95(d, 1H ), 6.89(t, 1H), 4.85(s, 1H), 4.49(d, 1H), 4.09–4.03(m, 1H), 3.81(q, 2H), 3.65(s, 2H), 3.00(d, 3H), 2.38(s, 3H), 2.19(s, 3H), 1.48(d, 3H). LC-MS [M+H] ⁺ = 459.

The synthesis of embodiment 53 compound R90

The synthetic route refers to the synthesis of compound R89. ¹ H NMR (400MHz, DMSO-d ₆ ) δ7.85(d, 1H), 7.64(s, 1H), 7.29(d, 1H), 7.25(d, 1H), 7.10(d, 1H), 7.04( t, 1H), 6.92(d, 1H), 6.85(t, 1H), 4.82(s, 1H), 4.43(d, 1H), 4.10–4.02(m, 1H), 3.84(q, 2H), 3.57 (s, 2H), 3.05 (d, 3H), 2.38 (s, 3H), 2.20 (s, 3H), 1.53 (d, 3H). LC-MS [M+H] ⁺ = 458.

The synthesis of embodiment 54 compound R91

(1) Step 1:

The compound (R)-4-(2-chloro-7-iodopyrrole[2,1-f][1,2,4]triazin-4-yl)-3-methylmorpholine (378 mg) was added to the supernatant Dry THF (10mL), drop to -78°C, then add n-BuLi (THF, 2.5N, 0.5mL) dropwise, stir at -78°C for 20min, then add excess 3,3-dimethylbutane dropwise -2-ketone, continue to stir for 30min. Then add NH ₄ Cl (aq.) to quench, use ethyl acetate to extract three times, wash the ethyl acetate phase with saturated brine, dry, and purify by column chromatography (petroleum ether:ethyl acetate=1:1) to obtain Compound R91-1 (150 mg, 42%) as colorless oil. LC-MS [M+H] ⁺ =353.

(2) Step 2:

Compound R91-1 (150 mg), N-methyl-1H-benzimidazol-2-amine (188 mg), palladium acetate (19 mg), BINAP (104 mg) and K ₂ CO ₃ (174 mg) were added in ultra-dry DMF ( 3 mL), and react overnight at 100°C under nitrogen protection. Cooled to room temperature, extracted three times with ethyl acetate, washed the ethyl acetate phase with saturated brine, dried, and purified by column chromatography (petroleum ether:ethyl acetate=1:4) to obtain compound R91 (10mg , 5%). ¹ H NMR (400MHz, DMSO) δ8.72–8.58(m, 1H), 7.96(dd, 1H), 7.26(d, 1H), 7.14–7.03(m, 2H), 7.01–6.93(m, 1H) , 6.68(d, 1H), 5.25(s, 1H), 4.90(s, 1H), 4.51(dd, 1H), 4.05(t, 1H), 3.79(p, 2H), 3.65(d, 2H), 3.05 (d, 3H), 1.64 (s, 3H), 1.43 (dd, 3H), 1.25 (s, 2H), 0.94 (s, 6H), 0.86 (d, 1H). LC-MS [M+H] ⁺ = 464.

The synthesis of embodiment 55 compound R92

The synthetic route refers to the synthesis of compound R94. 1H NMR(400MHz,DMSO)δ8.02(dd,1H),7.95(s,1H),7.30(q,2H),7.10(dd,1H),6.82(td,1H),4.88(s,1H) ,4.51(s,1H),4.06(s,1H),3.87–3.74(m,2H),3.64(dd,2H),3.41(s,3H),3.07(d,3H),1.46(d,3H ). LC-MS [M+H+]=460.

The synthesis of embodiment 56 compound R93

(1) Step 1:

Compound (R)-4-(2-chloro-7-(methylsulfonyl)pyrrole[2,1-f][1,2,4]triazin-4-yl)-3-methylmorpholine (178 mg), 1-chloromethyl-4-fluoro-1,4-diazabicyclo[2.2.2]octane bis(tetrafluoroborate) salt (500 mg) and a drop of acetic acid were added to ultra-dry ACN (3 mL) , and then react overnight at 80°C under nitrogen protection. It was cooled to room temperature and purified by column chromatography (petroleum ether: ethyl acetate = 1:1) to obtain compound R93-1 (190 mg, 98%) as a white solid. LC-MS [M+H] ⁺ =348.

(2) Step 2:

Compound R93-1 (190 mg), N-methyl-1H-benzimidazol-2-amine (220 mg), palladium acetate (22 mg), BINAP (124 mg) and K ₂ CO ₃ (207 mg) were added in ultra-dry DMF ( 3 mL), and react overnight at 100°C under nitrogen protection. Cooled to room temperature, extracted three times with ethyl acetate, washed the ethyl acetate phase with saturated brine, dried, and purified by column chromatography (petroleum ether:ethyl acetate=1:4) to obtain compound R93 (10mg ,2%). ¹ H NMR (400MHz, DMSO) δ8.03(d, 1H), 7.76(d, 1H), 7.33–7.25(m, 2H), 7.12(td, 1H), 7.01(td, 1H), 4.63(s , 1H), 4.25(s, 1H), 4.07(d, 1H), 3.87–3.59(m, 4H), 3.45(d, 3H), 3.06(dd, 3H), 1.50(d, 3H). LC-MS [M+H] ⁺ =460.

The synthesis of embodiment 57 compound R94

(1) Step 1:

Add (R)-4-(6-chloro-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-3-methylmorpholine (1.7g) and DMF (15mL) at room temperature , stirred at room temperature, added cesium carbonate (6.55g), stirred, added dropwise cyclopropylsulfonyl chloride (1.13g), stirred overnight at room temperature, TLC showed that the raw material disappeared, added water (50mL), stirred for 30min, filtered, the filter cake Dry, purify by column chromatography (petroleum ether: ethyl acetate = 1:1), and then submit to the next step. LC-MS [M+H] ⁺ =358.

(2) Step 2:

Compound R94-1 (0.2g), dioxane (5mL), 4-fluoro-2-nitroaniline (0.104g), BINAP (0.06g), palladium acetate (0.02g) and carbonic acid were added at room temperature Cesium (0.36g), under nitrogen protection, heated to 120°C to react overnight, post-treatment, washed with water, extracted with ethyl acetate, dried and concentrated the organic phase, and purified by column chromatography (DCM:MeOH=100:1) to obtain compound R94- 2 (0.2 g, 73%). LC-MS [M+H] ⁺ =478.

(3) Step 3:

Add compound R94-2 (0.2g), ethanol (10mL) and Pd/C (0.1g) at room temperature, hydrogen replacement hydrogenation, room temperature reaction overnight, post-treatment, filtration, organic phase drying and concentration, column chromatography purification (DCM:MeOH=100:1), to obtain compound R94-3 (50 mg, 26%). LC-MS [M+H] ⁺ = 448.

(4) Step 4:

Add compound R94-3 (0.05g) and pyridine (3mL) at room temperature, stir to dissolve, add methyl isothiocyanate (0.01g), stir and heat to 90°C, react for 30min, cool to room temperature, add EDCI (0.032g), heated to 90°C for overnight reaction, after-treatment, the organic phase was dried and concentrated, and purified by column chromatography (ethyl acetate:MeOH:TEA=50:5:5) to obtain compound R94 (20mg, 37%). ¹ H NMR (400MHz, DMSO) δ8.17(s, 1H), 7.18(s, 1H), 7.02(s, 2H), 5.76(s, 1H), 4.67(s, 1H), 4.18(d, 1H ), 3.98(d, 1H), 3.75(d, 1H), 3.71–3.65(m, 1H), 3.51(s, 3H), 3.07(d, 3H), 1.36(d, 2H), 1.24(s, 2H), 1.00–0.84 (m, 3H). LC-MS [M+H] ⁺ = 487.

The synthesis of embodiment 58 compound R96

The synthetic route refers to the synthesis of compound R81. ¹ H NMR (400MHz, DMSO) δ7.51(d,1H),7.36(d,2H),7.27(d,1H),7.17–7.00(m,3H),4.04(d,2H),3.80(d ,2H), 3.61(s,2H), 3.51(s,2H), 3.10(d,3H), 1.42–1.37(m,3H), 1.27(d,6H). LC-MS [M+H] ⁺ =470.

The synthesis of embodiment 59 compound R97

The synthetic route refers to the synthesis of compound R94. ¹ H NMR (400MHz, DMSO) δ10.25(s,1H),9.01(s,1H),7.99(dd,1H),7.30(dd,1H),7.07(td,1H),4.65(d,1H ), 4.19(d,1H), 3.98(d,1H), 3.76(d,1H), 3.68(dd,1H), 3.61–3.47(m,3H), 3.04(d,3H), 1.38(d, 2H), 1.18(t,5H). LC-MS [M+H] ⁺ = 487.

The synthesis of embodiment 60 compound R98

The synthetic route refers to the synthesis of compound R94. ¹ H NMR (400MHz,DMSO)δ7.89(d,1H),7.75(s,1H),7.51–7.23(m,4H),7.00–6.90(m,1H),4.88(s,1H),4.52 (s,1H), 4.06(s,1H), 3.79(s,2H), 3.66(d,1H), 3.05(d,3H), 1.48(d,3H), 1.30–0.98(m,3H). LC-MS [M+H] ⁺ =460.

The synthesis of embodiment 61 compound R99

(1) Step 1:

Add (R)-N1-(1-(cyclopropylsulfonyl)-4-(3-methylmorpholine)-1H-pyrazolo[3,4-d]pyrimidin-6-yl at room temperature )-4-fluorobenzene-1,2-diamine (0.05g), ethanol (4mL), triethylamine (0.1g) and cyanogen bromide (0.018g), react at room temperature for 48h, post-treatment, dry and concentrate the organic phase , purified by column chromatography (DCM:MeOH:TEA=50:5:5) to obtain compound R99 (20 mg, 38%). ¹ H NMR (400MHz, DMSO) δ9.02(s, 3H), 8.14(dd, 1H), 7.09–7.04(m, 1H), 6.95(t, 1H), 4.68(d, 1H), 4.18(d , 1H), 3.97(d, 1H), 3.75(d, 1H), 3.71–3.66(m, 1H), 3.58–3.53(m, 1H), 3.51(d, 1H), 3.47(d, 1H), 1.41–1.32 (m, 4H), 1.24 (s, 3H). LC-MS [M+H] ⁺ =473.

The synthesis of embodiment 62 compound R100

step:

Add (R)-N1-(1-(cyclopropylsulfonyl)-4-(3-methylmorpholine)-1H-pyrazolo[3,4-d]pyrimidin-6-yl at room temperature )-4-fluorobenzene-1,2-diamine (0.1g) and pyridine (4mL), stirred and dissolved, added isothiocyanate (0.027g), stirred and heated to 90°C, reacted for 30min, and dropped to At room temperature, EDCI (0.064g) was added, heated to 90°C for overnight reaction, after-treatment, the organic phase was dried and concentrated, and purified by column chromatography (DCM:MeOH=50:1) to obtain compound R100 (40mg, 35%). ¹ H NMR (400MHz, DMSO-d ₆ ) δ8.09(s, 2H), 7.05(s, 1H), 6.82(s, 2H), 4.67(s, 2H), 4.17(d, 2H), 3.97( d, 2H), 3.52 (s, 3H), 1.35 (d, 3H), 1.30 (d, 6H), 0.93–0.89 (m, 2H), 0.75 (dd, 2H). LC-MS [M+H] ⁺ = 515.

The synthesis of embodiment 63 compound R101

The synthetic route refers to the synthesis of compound R83. ¹ H NMR (400MHz,DMSO)δ8.52(s,1H),8.14(s,1H),8.03(d,1H),7.28(d,1H),7.10(s,1H),7.01(d,1H ),4.63(s,1H),4.07(d,1H),3.84(d,1H),3.78(s,1H),3.61(d,1H),3.04(d,3H),2.85(s,2H) , 2.25(s,6H), 1.41(d,3H), 1.27(dd,3H). LC-MS [M+H] ⁺ = 485.

The synthesis of embodiment 64 compound R103

(1) Step 1:

Add (R)-4-(2-chloro-7-(methylsulfonyl)pyrrole[2,1-f][1,2,4]triazin-4-yl)-3-methanol to the reaction flask Morpholine (158 mg), 4-amino-3-nitropyridine (79 mg), palladium acetate (21 mg), BINAP (58 mg), anhydrous cesium carbonate (306 mg) and anhydrous 1,4-dioxane ( 10 mL), under N ₂ protection, the oil bath was reacted overnight at 116°C. TLC monitoring (petroleum ether: ethyl acetate = 1:1) after the reaction was completed, column chromatography (petroleum ether: ethyl acetate = 2:1) purified to obtain compound R103-1 (79 mg, 38%) as a brown solid . LC-MS [M+H] ⁺ = 434.

(2) Step 2:

Add compound R103-1 (79mg), iron powder (40mg), ammonium chloride (39mg) and 95% ethanol (10mL) into the reaction flask, protect with N ₂ , and react in an oil bath at 70°C for 4h. After the reaction was monitored by TLC (DCM:MeOH=50:1), the reaction was purified by column chromatography (DCM:MeOH=100:1) to obtain compound R103-2 (45 mg, 61%) as a yellow solid. LC-MS [M+H] ⁺ =404.

(3) Step 3:

Add compound R103-2 (45 mg), methyl isothiocyanate (10 mg) and anhydrous pyridine (10 mL) into the reaction flask, react in an oil bath at 90 ° C for 1 h, then cool down to room temperature, add EDCI (31 mg), and continue for 90 °C overnight. After the reaction was monitored by TLC (DCM:MeOH=10:1), the reaction was directly spin-dried, and a large plate was scraped (DCM:MeOH=50:1) to obtain compound R103 (5 mg, 10%) as a brown-yellow solid. ¹ H NMR (400MHz,DMSO)δ8.00(s,1H),7.95(s,1H),7.30(d,2H),7.12–7.04(m,1H),6.82(t,1H),4.88(s ,1H),4.50(s,1H),4.06(s,1H),3.79(s,2H),3.64(t,1H),3.40(s,1H),3.07(d,3H),2.80(s, 3H), 1.47(d, 3H). LC-MS [M+H] ⁺ = 443.

The synthesis of embodiment 65 compound R105

The synthetic route refers to the synthesis of compound R99. ¹ H NMR (400MHz,DMSO)δ7.89(d,1H),7.75(s,1H),7.51–7.23(m,4H),7.00–6.90(m,2H),4.88(s,1H),4.52 (s,1H), 4.06(s,1H), 3.79(s,2H), 3.66(d,2H), 3.05(d,3H), 1.48(d,3H). LC-MS [M+H] ⁺ = 428.

The synthesis of embodiment 66 compound R106

The synthetic route refers to the synthesis of compound R107. ¹ H NMR (400MHz,DMSO)δ8.64(s,1H),8.19(d,1H),7.66(s,1H),7.55(s,1H),7.46(s,1H),7.39(d,1H ),5.19(t,1H),4.67(d,2H),4.37(t,1H),4.12–4.04(m,2H),3.88–3.75(m,4H),3.62(s,1H),1.43( d,2H), 1.41(s,2H), 1.24(s,3H). LC-MS [M+H] ⁺ = 469.

The synthesis of embodiment 67 compound R107

(1) Step 1:

(R)-4-(2-Chloro-7-(methylsulfonyl)pyrrole[2,1-f][1,2,4]triazin-4-yl)-3-methylmorpholine (200mg ), methyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole-6-carboxylate (274mg) , Pd(dppf)Cl ₂ (44mg) and CS ₂ CO ₃ (397mg) were reacted in dioxane/H ₂ O at 110°C overnight, under nitrogen protection, after the reaction was complete as detected by TLC, diluted with water, added ethyl acetate Extracted twice, separated, the ethyl acetate phase was washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, column chromatography (petroleum ether:ethyl acetate=1:1 to DCM/MeOH=10 :1) Purification to obtain compound R107-1 (170 mg, 59%) as a yellow solid. LC-MS [M+H] ⁺ =470.

(2) Step 2:

Compound R107-1 (50 mg) was dissolved in THF, LiAlH ₄ (21 mg) was added, protected by nitrogen, and reacted at room temperature for 3 h. After the reaction was complete by TLC, it was quenched with aqueous NaOH solution, the residue was added to water, and extracted twice with ethyl acetate , dried the ethyl acetate phase over anhydrous sodium sulfate, concentrated, and purified by column chromatography (petroleum ether:ethyl acetate=1:1-1:4 to DCM/MeOH=10:1) to obtain compound R107 as a pale yellow solid (21 mg, 8%). ¹ H NMR (400MHz, DMSO) δ11.28(s, 1H), 8.03(s, 1H), 7.53(d, 2H), 7.46(d, 1H), 7.29(d, 1H), 7.17(d, 1H ), 5.19(s, 1H), 5.02(s, 1H), 4.66(d, 2H), 4.06(m, 2H), 3.80(d, 2H), 3.63(s, 2H), 3.48(s, 3H) , 1.45 (d, 3H). LC-MS [M+H] ⁺ = 442.

The synthesis of embodiment 68 compound R111

(1) Step 1:

(R)-4-(2-chloro-7-(methylsulfonyl)pyrrole[2,1-f][1,2,4]triazin-4-yl)-3-methylmorpholine ( 100mg), 6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxobenzaldehyde-2-yl)-1H-indole (118mg), Pd(dppf) Cl ₂ (22 mg) and CS ₂ CO ₃ (202 mg) were reacted in dioxane/H ₂ O at 110°C overnight, protected by N ₂ , and after the reaction was complete as detected by TLC, diluted with water, extracted twice with ethyl acetate, Separation, the ethyl acetate phase was washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and purified by column chromatography (petroleum ether: ethyl acetate = 1:1 to DCM/MeOH = 10:1) , Compound R111 (60 mg, 45%) was obtained as a yellow solid. ¹ H NMR (400MHz,DMSO)δ11.10(s,1H),8.16(s,1H),7.67(dd,1H),7.50(s,1H),7.41(t,1H),7.46–7.34(m ,2H), 4.03(d,1H), 3.92–3.74(m,3H), 3.64–3.51(m,3H), 3.52(s,3H), 1.23–1.11(m,3H). LC-MS [M+H] ⁺ =430.

The synthesis of embodiment 69 compound R112

The synthetic route refers to the synthesis of compound R111. ¹ H NMR (400MHz,DMSO)δ11.37(s,1H),8.66(s,1H),8.01(dd,1H),7.70(s,1H),7.51(t,1H),7.42–7.35(m ,1H),4.07(d,1H),3.90–3.72(m,3H),3.67–3.57(m,2H),3.51(s,2H),1.40(d,4H),1.25–1.13(m,3H ). LC-MS [M+H] ⁺ = 457.

Synthesis of Example 70 Compound R113

(1) Step 1:

Add (R)-4-(2-chloro-7-(methylsulfonyl)pyrrole[2,1-f][1,2,4]triazin-4-yl)-3-methanol to the reaction flask Morpholine (100 mg), 2-((triisopropylsilyloxy)methyl)-1H benzimidazole (123 mg), Pd(OAc) ₂ (13 mg), BINAP (37 mg), CS ₂ CO ₃ ( 195mg) and dioxane (10mL), under N ₂ protection, reacted overnight at 120°C. After the completion of the reaction monitored by TLC, it was purified by column chromatography (petroleum ether:ethyl acetate=3:1) to obtain compound R113-1 (61 mg, 33%) as a brown solid. LC-MS [M+H] ⁺ = 599.

(2) Step 2:

Add compound R113-1 (60 mg), TBAF (52 mg) and anhydrous tetrahydrofuran (10 mL) into the reaction flask, and react at room temperature overnight. After the reaction was monitored by TLC, spin dry directly, and scrape (dichloromethane:methanol=30:1) to obtain compound R113 (6 mg, 13%) as a yellow solid. ¹ H NMR (400MHz,DMSO)δ8.15(d,1H),7.73(d,1H),7.34(d,4H),5.37(s,1H),5.06(s,2H),4.04(d,2H ), 3.78(d,3H), 3.68–3.54(m,2H), 3.51(s,1H), 3.42(s,2H), 1.24(s,3H). LC-MS [M+H] ⁺ = 443.

Synthesis of Example 71 Compound R114

The synthetic route refers to the synthesis of compound R106. ¹ H NMR (400MHz,DMSO)δ10.17(s,1H),8.92(s,1H),8.82(s,1H),8.36(d,1H),8.15(d,1H),7.39(d,1H ),7.21(s,1H),5.21(s,1H),4.58(d,2H),3.86(d,1H),3.79(d,1H),3.69–3.55(m,2H),3.08(d, 3H), 1.71(m,3H), 1.46(m,2H), 1.21(d,3H). LC-MS [M+H] ⁺ = 468.

Synthesis of Example 72 Compound R117

(1) Step 1:

Add (R)-4-(2-chloro-7-(methylsulfonyl)pyrrole[2,1-f][1,2,4]triazin-4-yl)-3-methanol to the reaction flask Morpholine (83 mg), 3-aminopyrazole (25 mg), palladium acetate (12 mg), BINAP (31 mg), anhydrous cesium carbonate (163 mg) and 10 mL of anhydrous 1,4-dioxane, _N2 protection , react overnight in an oil bath at 116°C. After the completion of the reaction monitored by TLC, it was purified by column chromatography (DCM:MeOH=90:1-50:1) to obtain compound R117 (9 mg, 10%) as a white solid. ¹ H NMR (400MHz,DMSO)δ8.28(s,1H),7.17(d,1H),7.12(d,1H),5.83(s,1H),5.40(s,2H),4.00(d,2H ), 3.77–3.61(m,3H), 3.57(s,2H), 3.50(s,3H), 1.40(s,3H). LC-MS [M+H] ⁺ =378.

The synthesis of embodiment 73 compound R116

The synthetic route refers to the synthesis of compound R107. ¹ H NMR(400MHz,DMSO-d6)δ11.26(s,1H),8.02(d,1H),7.61(t,1H),7.53(s,1H),7.47(t,1H),7.23(d ,1H),7.15(d,1H),5.18(t,1H),5.01(s,1H), 4.66(d,2H),4.06(d,1H),3.86–3.74(m,2H),3.62( s,2H), 3.24(td,1H), 1.45(d,3H), 1.20(q,2H), 1.02(dt,3H). LC-MS [M+H+]=468.

The synthesis of embodiment 74 compound R30

(1) Step 1:

Dissolve 5-nitro-2,4,6-trichloropyrimidine (100mg) in 8ml DCM, add DIPEA (85mg), cool down to -10°C, add (R)-3-methylmorpholine (46mg), After slowly returning to room temperature, the reaction was carried out for 4 hours. After the reaction was monitored by TLC, the reaction was purified by column chromatography (petroleum ether: ethyl acetate = 3:1) to obtain a yellow oil (95 mg). LC-MS [M+H+]=293.

(2) Step 2:

At room temperature, compound R30-1 (95mg) was dissolved in DMF (8ml). After cooling down to about 0°C, 1-methyl-5-aminopyrazole (31mg) was added, followed by DIPEA (42mg), and slowly recovered To room temperature, react for 2 hours, after the reaction is monitored by TLC, the reaction solution is poured into 20ml of water, extracted with EA (5ml*3), the organic phase is dried and filtered, spin-dried, sand-making, column chromatography (petroleum ether: ethyl acetate = 2:1) to obtain a pale yellow solid (60 mg, 52%). LC-MS [M+H+]=354.

(3) Step 3:

At room temperature, add compound R30-2 (60mg), SnCl ₂ (145mg), trimethyl orthoformate (1mL), absolute ethanol 5mL and 2 drops of concentrated hydrochloric acid into a 50mL pressure bottle, then heat to 90°C for reaction After 5h, TLC monitored the completion of the reaction. After the reaction solution dropped to room temperature, the reaction solution was poured into 15 mL of water, and the saturated aqueous solution of sodium carbonate was adjusted to pH=8, extracted with EA (5 mL*3), and the organic phase was dried and filtered, and then spin-dried. Sand making and column chromatography (petroleum ether: ethyl acetate = 1:1) purified to give a light yellow solid (32 mg, 57%). LC-MS [M+H+]=334.

(4) Step 4:

At room temperature, compound R30-3 (32mg), 6-chloro-7-azaindole 4-pinacol ester (28mg), K ₂ CO ₃ (20mg), Pd(dppf)Cl2 (8mg) were added Add 5mL of dioxane to a 10mL one-mouth bottle, pump _N2 twice, heat to 120°C for 4h under _N2 atmosphere, and monitor the completion of the reaction by TLC. Sand making and purification by column chromatography (dichloromethane:methanol=100:1) gave a pale yellow solid (10 mg, 25%). ¹ H NMR (400MHz,DMSO)δ11.75(s,1H),8.56–8.47(m,1H),8.37–8.28(m,1H),7.97(dt,1H),7.71(dd,1H),7.58 –7.52(m,1H),7.14–7.05(m,1H),6.72–6.64(m,1H),4.11–4.03(m,1H),3.90–3.84(m,1H),3.83–3.71(m, 4H), 3.61(m, 4H), 1.44(s, 3H). LC-MS [M+H+]=416.

The synthesis of embodiment 75 compound R50

(1) Step 1:

At room temperature, compound (R)-4-(2-chloro-9h-purin-6-yl)-3-methylmorpholine (200mg), 1,4-dimethylpyrazole -Pinacol 5-boronic acid ester (211mg), copper acetate (215mg) and triethylamine (400mg), add DCM (10mL), after O ₂ pumping twice, react under O ₂ atmosphere for 24h, TLC monitoring raw materials have For partial reaction, filter the reaction liquid pad with diatomaceous earth, rinse with DCM (5 mL), spin dry with dichloromethane, make sand, and purify by column chromatography (petroleum ether: ethyl acetate = 3:1) to obtain a yellow oil (20 mg, 7%). LC-MS [M+H ⁺ ]=347.

(2) Step 2:

At room temperature, compound R50-1 (20mg), 7-azaindole 4-pinacol ester (17mg), KOAc (11mg), Pd(dppf)Cl _5mg were added to a 10ml one-mouth bottle, and 5mL DMSO was added, After pumping out N ₂ twice, heat it to 120°C for 4 hours under N ₂ atmosphere, monitor the completion of the reaction by TLC, then pour the reaction solution into 15 mL of water, extract with EA (5 mL*3), and organic After the phase was dried and filtered, it was spin-dried, made into sand, and subjected to column chromatography (dichloromethane:methanol=100:1) to obtain a light yellow solid (11 mg, 44%). ¹ H NMR (400MHz,DMSO)δ11.70(s,1H),8.29(d,1H),7.97(d,1H),7.65–7.45(m,3H),7.16–6.95(m,2H),5.00 –4.86(m,1H),4.72–4.52(m,1H),4.08(dd,1H),3.81(d,2H),3.74–3.41(m,6H),3.15–3.04(m,2H),1.89 (s,3H). LC-MS [M+H ⁺ ] = 429.

It should be noted that other similar compounds disclosed in the present invention were synthesized by similar methods in the above examples.

Experimental example 1 ATR kinase assay

1. Prepare 1x Kinase Buffer and Stop Solution

Prepare 1x Kinase Buffer with 50mM HEPES, 0.0015% Brij-35 and 1M MnCl at pH 7.5; Prepare with 100mM HEPES at pH 7.5 _, 0.015% Brij-35, 0.2% Coating Reagent#3 and 50mM EDTA into a stop solution.

2. Compound preparation

Compounds were prepared at 1000/3 times the final concentration. Three-fold dilutions were made successively from the highest concentration, and a total of 10 concentrations were diluted to serve as 1000/3-fold concentration compounds. Transfer 100 μl of 100% DMSO to two empty wells as Max well and Min well respectively. Transfer 40 μL of compound to a new 384-well plate as an intermediate plate. Echo was used to transfer 60 nl of compounds into a 384-well plate.

Among them, AZ20 and BAY1895344 are yang ginseng compounds, and their structural formulas are as follows:

3. Kinase reaction

Add kinase to 1x kinase buffer to form a 2x enzyme solution. Add 10 μL of 2x enzyme solution to the 384-well reaction plate, and add 10 μL of kinase buffer to the negative control wells. Incubate at room temperature for 10 minutes. Add FAM-tagged peptide 5-FAM-AK-17 and ATP to 1x kinase buffer to form 2x substrate solution. Add 10 µL of 2x substrate solution to a 384-well reaction plate. Incubate for a certain period of time at 28°C. Add 30 μL of stop solution to the 384-well reaction plate to stop the reaction. Data were read with Caliper EZ Reader II.

IC50 (nM) values are shown in Table 1.

Table 1

化合物编号Compound number	IC ₅₀(nM) IC ₅₀ (nM)
R2R2	7.17.1
R3R3	1111
R5R5	8.98.9
R7R7	3030
R10R10	1313
R14R14	1.51.5
R16R16	1212
R22R22	21twenty one
R23R23	6.96.9
R26R26	1515
R27R27	2.52.5
R39R39	2020
R50R50	2.32.3
R56R56	1.11.1
R63R63	2727
R64R64	2727

R65R65	1111
R66R66	21twenty one
R68R68	5.15.1
R71R71	21twenty one
R72R72	9.29.2
R73R73	2.52.5
R75R75	26812681
R77R77	1313
R78R78	2.62.6
R80R80	1010
R92R92	1717
R105R105	1111
R106R106	6.26.2
R107R107	2.92.9
BAY1895344BAY1895344	77
AZ20AZ20	2.82.8

Experimental example 2 LOVO in vitro cell activity test

To analyze the inhibitory effect of the compound of the present invention on the proliferation of LOVO cells, two duplicate wells were set up, and the compound concentration was: 10 μM starting, 5-fold dilution, and 9 concentration gradients.

Collect the LOVO cell suspension, centrifuge at 1000rpm for 5 minutes, remove the supernatant, resuspend with preheated medium and count. After counting, dilute the cell suspension with cell culture medium to the required density. Each cell density is shown in Table 4-1. Inoculate 100 μL of cell suspension into each well of a 96-well cell culture plate in a 37°C, 5% CO2 incubator. Incubate overnight. In different compounds, add 10 μL compound working solution per well to the cell plate, and continue to incubate at 37°C in a 5% CO2 incubator. Among them, the cell plating density was 5000 cells/well, and the incubation days were 3 days.

After the incubation, add an appropriate amount of CCK8 detection reagent to each well of the cell plate, and incubate in the incubator for 1-4 hours. After the incubation, use absorbscence to detect the luminescent signal. The measured signal values of each group were normalized by subtracting the background blank control well signal value. The cell viability after compound treatment was calculated according to the following formula: inhibition rate=100-(RFU _compound -RFU _{_blank control} )/(RFU _{negative control} -RFU _{blank control} )×100%. Blank control: only culture medium without cell treatment; negative control: cells treated with 0.5% DMSO, and then use Prism plotting to calculate the IC ₅₀ value of the compound, as shown in Table 2.

Table 2

化合物编号Compound number	IC ₅₀(μM) _IC50 (μM)
R14R14	0.26380.2638
R30R30	0.47760.4776
R50R50	0.35450.3545
R56R56	0.08120.0812
R58R58	0.76540.7654
R65R65	0.31310.3131
R68R68	0.4620.462
R72R72	0.21330.2133
R73R73	0.03660.0366
R75R75	>10>10
R76R76	0.44290.4429
R78R78	0.08920.0892
R80R80	0.04260.0426
R81R81	1.5551.555
R83R83	0.09420.0942
R88R88	0.11440.1144
R92R92	0.33580.3358
R93R93	0.5330.533
R98R98	0.95130.9513
R101R101	0.45220.4522

R106R106	0.20820.2082
R107R107	0.02740.0274
R111R111	0.94560.9456
R112R112	0.3420.342
R113R113	1.9711.971
R114R114	0.52320.5232
R116R116	0.03150.0315
R117R117	0.61670.6167
BAY1895344BAY1895344	0.03420.0342

The protection content of the present invention is not limited to the above embodiments. Without departing from the spirit and scope of the inventive concept, changes and advantages conceivable by those skilled in the art are all included in the present invention, and the appended claims are the protection scope.

Claims

a compound of formula (I) or a pharmaceutically acceptable salt thereof,

in:

X 1 is NR 5 , O or CR 6 , wherein R 5 and R 6 are independently hydrogen, alkyl, cycloalkyl, alkoxy, hydroxyalkyl, halogen or hydroxyl, wherein the alkyl, cycloalkyl , alkoxy and hydroxyalkyl are each independently selected from halogen, hydroxyl, carboxyl, amino, nitro, cyano, C1-C6 amido, C1-C6 acyloxy, C1-C6 alkoxy, aryloxy Base, alkylthio, C1-C6 alkyl, C1-C6 acyl, C6-C10 aryl, C3-C8 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, heterocyclyl, heteroaryl , methylenedioxy, ureido, mercapto, azido, carbonyl, alkylsulfonyl, sulfamoyl, dialkylsulfamoyl and alkylsulfinyl are substituted by one or more substituents;

X2 is C or N;

X3 is CH or N;

X4 is CH or N;

X5 is CH or N;

R1 is
Each R is independently hydrogen, alkyl, cycloalkyl, alkoxy, cyano or halogen; wherein said alkyl, cycloalkyl and alkoxy are each independently selected from halogen, hydroxy, carboxyl, amino , Nitro, cyano, C1-C6 amido, C1-C6 acyloxy, C1-C6 alkoxy, aryloxy, alkylthio, C1-C6 alkyl, C1-C6 acyl, C6-C10 aromatic C3-C8 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, heterocyclyl, heteroaryl, methylenedioxy, ureido, mercapto, azido, carbonyl, alkanesulfonyl One or more substituents in acyl, sulfamoyl, dialkylsulfamoyl and alkylsulfinyl;

R2 is selected from

R 8 , R 9 and R 10 are independently hydrogen, alkyl, cycloalkyl, alkoxy, cyano, halogen or NR 11 R 12 , wherein R 11 and R 12 are independently hydrogen, alkyl, cycloalkane group, alkoxy group, cyano group or halogen; wherein said alkyl group, cycloalkyl group and alkoxy group are each independently selected from halogen, hydroxyl group, carboxyl group, amino group, nitro group, cyano group, C1-C6 amido, C1-C6 acyloxy, C1-C6 alkoxy, aryloxy, alkylthio, C1-C6 alkyl, C1-C6 acyl, C6-C10 aryl, C3-C8 cycloalkyl, C2-C6 chain Alkenyl, C2-C6 alkynyl, heterocyclyl, heteroaryl, methylenedioxy, ureido, mercapto, azido, carbonyl, alkylsulfonyl, sulfamoyl, dialkylsulfamoyl and One or more substituents in the alkylsulfinyl group are substituted;

R 3 is alkyl, aryl, heterocyclyl, cycloalkyl, heteroaryl, carbonyl, -S(=O)R 13 , -alkyl-S(=O)R 13 , -cycloalkyl-S (=O)R 13 , -S(=O) 2 R 13 , -alkyl-S(=O) 2 R 13 , -cycloalkyl-S(=O) 2 R 13 , -S(=O) (=NH)R 13 , -alkyl-S(=O)(=NH)R 13 or -cycloalkyl-S(=O)(=NH)R 13 , wherein the alkyl, aryl, hetero Cyclic group, cycloalkyl group and heteroaryl group are each independently selected from halogen, hydroxyl, carboxyl, amino, nitro, cyano, C1-C6 amido, C1-C6 acyloxy, C1-C6 alkoxy, Aryloxy, alkylthio, C1-C6 alkyl, C1-C6 acyl, C6-C10 aryl, C3-C8 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, heterocyclyl, hetero One or more substituents in aryl, methylenedioxy, ureido, mercapto, azido, carbonyl, alkylsulfonyl, sulfamoyl, dialkylsulfamoyl and alkylsulfinyl replace;

R 13 is alkyl, cycloalkyl, heteroaryl, aryl or heterocyclyl;

R is hydrogen, alkyl, cycloalkyl, alkoxy, cyano or halogen; wherein said alkyl, cycloalkyl and alkoxy are each independently selected from halogen, hydroxyl, carboxyl, amino, nitro , cyano, C1-C6 amido, C1-C6 acyloxy, C1-C6 alkoxy, aryloxy, alkylthio, C1-C6 alkyl, C1-C6 acyl, C6-C10 aryl, C3 -C8 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, heterocyclyl, heteroaryl, methylenedioxy, ureido, mercapto, azido, carbonyl, alkanesulfonyl, ammonia One or more substituents in sulfonyl, dialkylsulfamoyl and alkylsulfinyl;

Or, R 4 and X 2 together form a carbonyl group, or, R 4 and R 3 form a 5-7 membered ring together with the group they are connected to;

n, m, p represent 0, 1, 2 or 3;
The compound of claim 1, said R 1 is
Wherein R 7 is methyl or ethyl, and p is 0 or 1.
The compound of claim 2, said R is selected from the following groups:
The compound of claim 1, said R is selected from the following groups:
compound as claimed in claim 1, described R Be alkyl or cycloalkyl, described alkyl and cycloalkyl are optionally selected from cycloalkyl, halogen atom (such as fluorine, chlorine, bromine or iodine) , cyano or 1-3 substituents in pyridyl are substituted.
The compound of claim 5, said R 3 is methyl, cyclopropyl, cyclopentyl, isopropyl, cyclopropyl methylene.
The compound as claimed in claim 1, said R 3 is a six-membered or five-membered unsaturated heterocyclic ring containing N, and said unsaturated heterocyclic ring is optionally replaced by an alkyl group (such as methyl, ethyl or propyl group) replace.
The compound as claimed in claim 7, said R is selected from:
The compound as claimed in claim 1, said R 3 is a benzene ring, and the ortho-position, meta-position or para-position of said benzene ring are optionally independently selected from halogen, hydroxyl, carboxyl, amino, nitro, cyano , C1-C6 amido, C1-C6 acyloxy, C1-C6 alkoxy, aryloxy, alkylthio, C1-C6 alkyl, C1-C6 acyl, C6-C10 aryl, C3-C8 ring Alkyl, C2-C6 alkenyl, C2-C6 alkynyl, heterocyclyl, heteroaryl, methylenedioxy, isopropylcyano, ureido, mercapto, azido, carbonyl, alkanesulfonyl One or more substituents in acyl, sulfamoyl, dialkylsulfamoyl and alkylsulfinyl.
The compound according to claim 1, wherein said R 3 is -S(=O)R 13 , -S(=O) 2 R 13 or S(=O)(=NH)R 13 , wherein said R 13 is optionally substituted alkyl (such as methyl, ethyl or propyl), optionally substituted cycloalkyl (such as cyclopropyl, cyclobutyl or cyclopentyl), optionally substituted cycloalkylalkyl , an optionally substituted benzene ring, an optionally substituted N-containing six-membered unsaturated heterocyclic ring, or an optionally substituted N-containing six-membered saturated heterocyclic ring.
The compound according to claim 1, said R 3 is -alkyl-S(=O)R 13 , -cycloalkyl-S(=O)R 13 , -alkyl-S(=O) 2 R 13 , -cycloalkyl-S(=O) 2 R 13 , -alkyl-S(=O)(=NH)R 13 or -cycloalkyl-S(=O)(=NH)R 13 , wherein The alkyl is methylene, ethylene or -CH(CH 3 )-, the cycloalkyl is cyclopropyl, cyclobutyl or cyclopentyl, and the R 13 is optionally substituted alkyl (such as methyl, ethyl or propyl).
The compound according to claims 1-11, wherein X1 is C, X2 is C, and X3 is N.
The compound as claimed in claims 1-11, said X 1 is N, X 2 is C, and X 3 is N.
The compound according to claims 1-11, said R 4 and R 3 together form a six-membered N, O-containing heterocyclic ring.
The compound according to claims 1-11, said m and n are each independently 0.
The compound of claims 1-11, said R 4 and X 2 together form a carbonyl group.
The compound of claims 1-11, said R 5 is H.
The compound according to claims 1-11, said R 6 is H, C 1-6 alkyl, alkoxy or halogen.
The compound as claimed in claims 1-11, said R 8 is H or halogen.
The compound as claimed in claim 19, wherein said halogen is a chlorine atom.
The compound as claimed in claims 1-11, said R 9 is H or halogen.
The compound as claimed in claim 21, wherein said halogen is a chlorine atom.
The compound of claims 1-11, said R 10 is H.
The compound according to claims 1-11, said R 11 and R 12 are H, C 1-6 alkyl, halogen or alkyl substituted by 1-3 halogen atoms.
The compound of claims 1-11, said R 13 is cyclopropyl, isopropyl, methyl, ethyl or cyclopropylmethylene.
The compound as claimed in claims 1-11, said R 13 is selected from the following groups:
The compound as claimed in claims 1-26, the structure of the compound of formula (I) is as follows:
The compound according to claims 1-11, which is selected from the group consisting of:
[Corrected 15.09.2022 under Rule 91]
A pharmaceutical composition, characterized in that the pharmaceutical composition contains a therapeutically effective amount of the compound according to any one of claims 1-27 and at least one pharmaceutically acceptable excipient.
[Corrected 15.09.2022 under Rule 91]
Use of the compound according to any one of claims 1-28 in the preparation of a medicament for the treatment or prevention of ATR kinase-mediated diseases; preferably, the diseases are cancers.
[Corrected 15.09.2022 under Rule 91]
The compound according to any one of claims 1-28, wherein the cancer is liver cancer, melanoma, Hodgkin's disease, non-Hodgkin's lymphoma, acute lymphoblastic leukemia, chronic lymphocytic leukemia, multiple myeloma , neuroblastoma, breast cancer, ovarian cancer, lung cancer, Wilms tumor, cervical cancer, testicular cancer, soft tissue sarcoma, primary macroglobulinemia, bladder cancer, chronic myeloid leukemia, primary cerebral palsy Carcinoma, malignant melanoma, small cell lung cancer, gastric cancer, colon cancer, malignant pancreatic insulinoma, malignant carcinoid cancer, choriocarcinoma, head and neck cancer, osteogenic sarcoma, pancreatic cancer, acute myeloid leukemia, hairy cell leukemia , rhabdomyosarcoma, Kaposi's sarcoma, urogenital tumors, thyroid cancer, esophageal cancer, malignant hypercalcemia, cervical hyperplasia, renal cell carcinoma, endometrial cancer, polycythemia vera, idiopathic platelets hyperlipidemia, adrenocortical cancer, skin cancer and prostate cancer.