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

Abstract

The present invention relates to a class of five-membered nitrogen-containing heterocycle and heteroaryl derivatives of general formula (I), their preparation, pharmaceutical compositions containing them and their use as therapeutic agents, in particular as ATR kinase inhibitors and for the preparation of a medicament for the prevention of ATR kinase-mediated diseases.

Description

Technical Field

[0001] This invention belongs to the field of medicinal chemistry, specifically relating to a five-membered nitrogen-containing heterocyclic benzo[a]aryl derivative and its uses. Background Technology

[0002] ATR (ataxia-telangiectasia mutant and RAD-3-related protein kinase) belongs to the PIKK (phosphatidylinositol-3-kinase-associated kinase) family and is involved in DNA damage repair to maintain gene stability. ATR kinase works alongside ATM ("ataxia-telangiectasia mutant") 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 by activating cell cycle checkpoints that provide time for repair, promotes survival, and arrests cell cycle progression. Without DDR, cells are more susceptible to DNA damage and are prone to death from endogenous cellular processes (such as DNA repair) or DNA damage induced by exogenous DNA damaging agents commonly used in cancer therapy.

[0003] Healthy cells can rely on various host proteins for DNA repair, including the DDR kinase ATR. In some cases, these proteins can compensate for each other by activating excess DNA repair processes. Conversely, many cancer cells have hidden defects in some of their DNA repair processes, such as ATM signaling, and thus exhibit a greater dependence on their remaining intact DNA repair proteins, including ATR. Furthermore, many cancer cells express activated oncogenes or lack key tumor suppressor genes, which can make these cancer cells prone to DNA replication dysregulation, leading to DNA damage.

[0004] When DNA double-strand breaks occur, resulting in excision or replication fork arrest, the ATR is activated by single-stranded DNA structures. DNA polymerase remains in the DNA replication process, while replication helicase continues to unwind at the tip of the replication fork, leading to the production of long single-stranded DNA (ssDNA), which then binds to RPA (replication protein A). During replication stress or DNA damage, the ATR / ATR-acting protein complex recruited by RPA to the damage site, where the RPA-ssDNA complex activates the RAD17 / rfc2-5 complex, which binds to the damage site. The Rad9-HUS1-RAD1 (9-1-1) heterotrimer is activated at the DNA-ssDNA junction, and 9-1-1, in turn, recruits TopBP1 to activate the ATR. Once activated, the ATR promotes DNA repair, stabilizes and restarts stalled replication forks, and induces transient cell cycle arrest through downstream targets. These functions are achieved by the ATR mediating its downstream target, Chk1. The ATR acts as a cell cycle checkpoint for DNA damage in S phase. It can delay DNA replication by mediating the degradation of CDC25A through Chk1, thus providing time for the repair of replication forks. ATR is also a major regulator of the G2 / M cell cycle checkpoint, preventing premature mitosis before DNA replication is complete or DNA damage occurs. This ATR-dependent G2 / M cell cycle arrest is mainly mediated through two mechanisms: 1. Degradation of CDC25A. 2. Phosphorylation of Cdc25C by Chk1, causing it to bind to the 14-3-protein. The binding of Cdc25C to the 14-3-3 protein promotes its export from the nucleus and cytoplasmic isolation, thereby inhibiting its ability to dephosphorylate and activate nuclear Cdc2, which in turn prevents entry into mitosis.

[0005] Since ATR is essential for cell self-replication and is activated in the S phase to regulate the origin of replication and repair damaged replication forks, and replication fork damage can increase the sensitivity of cancer cells to platinum-based and hydroxyurea-based anticancer drugs while reducing their drug resistance, inhibiting ATR may be an effective approach in future cancer treatment.

[0006] Currently, publicly disclosed ATR inhibitor compounds include M6620 and AZD-6738. In April 2021, Merck (MerckKGaA) announced pivotal clinical progress for berzosertib (M6620). Berzosertib is an investigational, potent, selective inhibitor of ataxia-telangiectasia and Rad3-associated protein (ATR). Summary of the Invention

[0007] The compounds of this invention have a parent nucleus structure different from the structures described above, and the resulting compounds exhibit good inhibitory effects on ATR. The compounds of this invention and their pharmaceutically acceptable compositions can be used to treat various cancers.

[0008] Unless otherwise stated, the structures described herein are intended to include all isomers (e.g., enantiomers, diastereomers, and geometric (or configurational) isomers); for example, R and S configurations of each asymmetric center, Z and E double bond isomers, and Z and E configuration isomers. Therefore, single stereochemical isomers of the compounds of the present invention, as well as mixtures of enantiomers, diastereomers, and geometric (or configurational) isomers, are within the scope of the present invention. Unless otherwise stated, all tautomeristic configurations of the compounds of the present invention are within the scope of the present invention. Furthermore, unless otherwise stated, the structures described herein are intended to include compounds differing only in the presence of one or more isotopically enriched atoms. For example, those having hydrogen replaced by deuterium or tritium, or... 13 C or 14 Compounds of the present invention with carbon-enriched carbon substitutions are within the scope of this invention. These compounds are suitable as, for example, analytical tools, probes in bioanalysis, or therapeutic agents of this invention.

[0009] Pharmaceutically acceptable excipients or mediators are non-toxic carriers, excipients, or mediators that do not impair the pharmacological activity of the compounds formulated with them. Pharmaceutically acceptable carriers, excipients, or mediators that can be used in the compositions of this invention include (but are not limited to) ion exchangers; alumina; aluminum stearate; lecithin; serum proteins, such as human serum albumin; buffering substances, such as phosphates; glycine; sorbic acid; potassium sorbate; mixtures of saturated vegetable fatty acid metaglycerides; water; salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts; colloidal silica; magnesium trisilicate; polyvinylpyrrolidone; cellulose-based substances; polyethylene glycol; sodium carboxymethyl cellulose; polyacrylates; waxes; polyethylene-polyoxypropylene-block polymers; polyethylene glycol; and lanolin.

[0010] In specific embodiments, a combination of two or more therapeutic agents may be administered together with the compound of the present invention. In specific embodiments, a combination of three or more therapeutic agents may be administered together with the compound of the present invention.

[0011] In specific embodiments, the compounds of the present invention or pharmaceutically acceptable compositions thereof are administered in combination with antisense agents, monoclonal or polyclonal antibodies or siRNA therapeutic agents.

[0012] These additional agents may be administered separately from the compounds or compositions of the present invention as part of a multiple-dose regimen. Alternatively, these agents may be part of a single dosage form, mixed with the compounds of the present invention in a single composition. If administered as part of a multiple-dose regimen, the two active agents may be provided simultaneously, sequentially, or at intervals (typically within 5 hours of each other).

[0013] As used herein, the terms “combination,” “combination,” and related terms refer to the simultaneous or sequential administration of therapeutic agents according to the invention. For example, compounds of the invention may be administered simultaneously or sequentially with another therapeutic agent in an independent unit dosage form or together in a single unit dosage form. Therefore, the invention provides a single unit dosage form comprising the compounds of the invention, other therapeutic agents, and pharmaceutically acceptable carriers, excipients, or mediators.

[0014] The amounts of both the compounds of the present invention and other therapeutic agents (in those compositions containing other therapeutic agents as described above) that can be combined with a carrier substance to produce a single dosage form will vary depending on the subject being treated and the specific mode of administration. Preferably, the compositions of the present invention should be formulated such that a dose between 0.01 mg and 100 mg per kilogram of body weight per day can be administered.

[0015] In those compositions that include other therapeutic agents, the other therapeutic agents and the compounds of the present invention can act synergistically. Therefore, the amount of the other therapeutic agents in these compositions will be lower than that required in a monotherapy using only the stated therapeutic agent. In these compositions, the dosage of the other therapeutic agents can be administered between 0.01 μg and 100 μg per kilogram of body weight per day.

[0016] The amount of other therapeutic agents present in the compositions of the present invention will not exceed the amount typically administered in a composition containing said therapeutic agent as the sole active agent. Preferably, the amount of other therapeutic agents in the compositions disclosed in the present invention will be in the range of about 50% to 100% of the amount typically present in a composition containing said pharmaceutical agent as the sole active agent.

[0017] To achieve the present invention, the following technical solution is adopted.

[0018] A compound of formula (I) or a pharmaceutically acceptable salt thereof,

[0019]

[0020] in:

[0021] X1 is NR5, O, or CR6, wherein R5 and R6 are independently hydrogen, alkyl, cycloalkyl, alkoxy, hydroxyalkyl, halogen, or hydroxyl, wherein each of the alkyl, cycloalkyl, alkoxy, and hydroxyalkyl is independently substituted by one or more substituents selected from halogen, hydroxyl, carboxyl, amino, nitro, cyano, C1-C6 amide, 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, heterocyclic, heteroaryl, methylenedioxy, ureo, mercapto, azide, carbonyl, alkylsulfonyl, aminosulfonyl, dialkylaminosulfonyl, and alkylsulfinyl.

[0022] X2 is either C or N;

[0023] X3 is CH or N;

[0024] X4 is CH or N;

[0025] X5 is CH or N;

[0026] R1 is R7 is each independently hydrogen, alkyl, cycloalkyl, alkoxy, cyano, or halogen; wherein the alkyl, cycloalkyl, and alkoxy are each independently substituted by one or more substituents selected from halogen, hydroxyl, carboxyl, amino, nitro, cyano, C1-C6 amide, 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, heterocyclic, heteroaryl, methylenedioxy, ureo, mercapto, azide, carbonyl, alkylsulfonyl, aminosulfonyl, dialkylaminosulfonyl, and alkylsulfinyl.

[0027] R2 is selected from:

[0028]

[0029] R8, R9 and R 10 Independently hydrogen, alkyl, cycloalkyl, alkoxy, cyano, halogen, or NR 11 R 12 , where R 11 and R 12The alkyl, cycloalkyl, alkoxy, cyano, or halogen groups are independently hydrogen, alkyl, cycloalkyl, and alkoxy groups, each of which is independently substituted by one or more substituents selected from halogen, hydroxyl, carboxyl, amino, nitro, cyano, C1-C6 amide, 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, heterocyclic, heteroaryl, methylenedioxy, ureo, mercapto, azide, carbonyl, alkylsulfonyl, aminosulfonyl, dialkylaminosulfonyl, and alkylsulfinyl.

[0030] R3 represents alkyl, aryl, heterocyclic, cycloalkyl, heteroaryl, carbonyl, or -S(=O)R. 13 ,-alkyl-S(=O)R 13 ,-cycloalkyl-S(=O)R 13 -S(=O)2R 13 ,-alkyl-S(=O)2R 13 -cycloalkyl-S(=O)2R 13 -S(=O)(=NH)R 13 ,-alkyl-S(=O)(=NH)R 13 or -cycloalkyl-S(=O)(=NH)R 13 The alkyl, aryl, heterocyclic, cycloalkyl, and heteroaryl groups are each independently substituted by one or more substituents selected from halogen, hydroxyl, carboxyl, amino, nitro, cyano, C1-C6 amide, 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, heterocyclic, heteroaryl, methylenedioxy, ureo, mercapto, azide, carbonyl, alkylsulfonyl, aminosulfonyl, dialkylaminosulfonyl, and alkylsulfinyl.

[0031] R 13 It is an alkyl, cycloalkyl, heteroaryl, aryl, or heterocyclic group;

[0032] R4 is hydrogen, alkyl, cycloalkyl, alkoxy, cyano, or halogen; wherein the alkyl, cycloalkyl, and alkoxy groups are each independently substituted by one or more substituents selected from halogen, hydroxyl, carboxyl, amino, nitro, cyano, C1-C6 amide, 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, heterocyclic, heteroaryl, methylenedioxy, ureo, mercapto, azide, carbonyl, alkylsulfonyl, aminosulfonyl, dialkylaminosulfonyl, and alkylsulfinyl.

[0033] Alternatively, R4 and X2 together form a carbonyl group, or R4 and R3 together with the groups they are attached to form a 5-7 membered ring;

[0034] n, m, and p represent 0, 1, 2, or 3;

[0035] In some specific implementations, R1 is In some embodiments, R7 is methyl or ethyl. In some embodiments, p is 0 or 1.

[0036] In some specific embodiments, R1 is selected from the following groups:

[0037]

[0038] In some specific embodiments, the R2 is selected from the following groups:

[0039]

[0040] In some embodiments, R3 is an alkyl or cycloalkyl group. In some embodiments, the alkyl or cycloalkyl group is optionally substituted with 1 to 3 substituents selected from cycloalkyl, halogen, cyano, or pyridyl.

[0041] In some specific embodiments, R3 is a group such as methyl, cyclopropyl, cyclopentyl, isopropyl, or cyclopropylmethylene.

[0042] In some embodiments, R3 is an N-containing six- or five-membered unsaturated heterocycle. In some embodiments, the unsaturated heterocycle may optionally be substituted with an alkyl group.

[0043] In some specific implementations, R3 is selected from:

[0044]

[0045] In some embodiments, R3 is a benzene ring. In some embodiments, the ortho, meta, or para position of the benzene ring may optionally be independently substituted by one or more substituents selected from halogen, hydroxyl, carboxyl, amino, nitro, cyano, C1-C6 amide, 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, heterocyclic, heteroaryl, methylenedioxy, isopropylcyano, ureo, mercapto, azide, carbonyl, alkylsulfonyl, aminosulfonyl, dialkylaminosulfonyl, and alkylsulfinyl.

[0046] In some specific implementations, R3 is -S(=O)R 13 -S(=O)2R 13 Or S(=O)(=NH)R 13 In some specific implementations, the R 13 The substituted alkyl group, the substituted cycloalkyl group, the substituted cycloalkylalkyl group, the substituted benzene ring, the substituted N-containing six-membered saturated heterocycle, or the substituted N-containing six-membered unsaturated heterocycle may be substituted with alkyl, halogen, or alkoxy groups.

[0047] In some specific embodiments, R3 is -alkyl-S(=O)R 13 ,-cycloalkyl-S(=O)R 13 ,-alkyl-S(=O)2R 13 -cycloalkyl-S(=O)2R 13 ,-alkyl-S(=O)(=NH)R 13 or -cycloalkyl-S(=O)(=NH)R 13 In some embodiments, the alkyl group is methylene, ethylene, propylene, butylene, or -CH(CH3)-. In some embodiments, the cycloalkyl group is cyclopropyl, cyclobutyl, or cyclopentyl. In some embodiments, the R... 13 It is an alkyl group that is optionally substituted (such as methyl, ethyl or propyl).

[0048] In some specific implementations, X1 is C, X2 is C, and X3 is N.

[0049] In some specific implementations, X1 is N, X2 is C, and X3 is N.

[0050] In some specific implementations, R4 together with R3 forms a six-membered N- and O-containing heterocycle.

[0051] In some specific implementations, m and n are each independently 0.

[0052] In some specific embodiments, R4 together with X2 forms a carbonyl group.

[0053] In some specific implementations, R5 is H.

[0054] In some specific implementations, R6 is H or C. 1-6 Alkyl, alkoxy, or halogen.

[0055] In some specific implementations, R8 is H or a halogen.

[0056] In some specific embodiments, the halogen is a chlorine atom.

[0057] In some specific implementations, R9 is H or a halogen.

[0058] In some specific embodiments, the halogen is a chlorine atom.

[0059] In some specific implementations, the R 10 For H.

[0060] In some specific implementations, the R 11 and R 12 For H, C 1-6 Alkyl, halogen, or alkyl group substituted with 1-3 halogen atoms.

[0061] In some specific implementations, the R 13 It can be cyclopropyl, isopropyl, methyl, ethyl, or cyclopropylmethylene.

[0062] In some specific implementations, the R 13 Selected from the following groups:

[0063]

[0064] In some specific embodiments, the structure of compound (I) is as follows:

[0065]

[0066] In some specific embodiments, the compound is selected from:

[0067]

[0068]

[0069]

[0070]

[0071]

[0072]

[0073]

[0074]

[0075]

[0076]

[0077]

[0078]

[0079]

[0080] In some embodiments, the pharmaceutical composition contains a therapeutically effective amount of the above-described compound and at least one pharmaceutically acceptable excipient.

[0081] In some embodiments, the compound is used in the preparation of a medicament for treating or preventing ATR kinase-mediated diseases; preferably, the disease is cancer.

[0082] In some implementations, the cancers mentioned are liver cancer, melanoma, Hodgkin's disease, non-Hodgkin's lymphoma, acute lymphoblastic leukemia, chronic lymphoblastic 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 islet tumor, malignant carcinoid cancer, choriocarcinoma, head and neck cancer, osteosarcoma, 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 thrombocythemia, adrenocortical carcinoma, skin cancer, and prostate cancer.

[0083] Detailed Terminology

[0084] Unless otherwise stated, the terms used in the specification and claims have the following meanings.

[0085] The term "alkyl" refers to a saturated aliphatic hydrocarbon group, which is a straight-chain or branched group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 12 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12) carbon atoms, and more preferably an alkyl group containing 1 to 6 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2, 3-Dimethylpentyl, 2,4-Dimethylpentyl, 2,2-Dimethylpentyl, 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-Ethylhexyl, 2-Methyl-2-Ethylpentyl, 2-Methyl-3-Ethylpentyl, n-Nonyl, 2-Methyl-2-Ethylhexyl, 2-Methyl-3-Ethylhexyl, 2,2-Diethylpentyl, n-Decyl, 3,3-Diethylhexyl, 2,2-Diethylhexyl, and their various branched isomers, etc. More preferably, lower alkyl groups containing 1 to 6 carbon atoms are used. 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, etc. Alkyl groups can be substituted or unsubstituted. When substituted, the substituents can be substituted at any usable connection point. The substituents are preferably independently selected independently from one or more substituents chosen from H atoms, D atoms, halogens, alkyl groups, alkoxy groups, haloalkyl groups, hydroxyl groups, hydroxyalkyl groups, cyano groups, amino groups, nitro groups, cycloalkyl groups, heterocyclic groups, aryl groups, and heteroaryl groups.

[0086] The term "alkylene" refers to a saturated straight-chain or branched aliphatic hydrocarbon group having two residues derived from the removal of two hydrogen atoms from the same carbon atom or two different carbon atoms of a parent alkane. It is a straight-chain or branched 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 containing 1 to 6 carbon atoms. Non-limiting examples of alkylene include, but are not limited to, methylene (-CH2-), 1,1-ethylene (-CH(CH3)-), 1,2-ethylene (-CH2CH2)-, 1,1-propylene (-CH(CH2CH3)-), 1,2-propylene (-CH2CH(CH3)-), 1,3-propylene (-CH2CH2CH2-), 1,4-butylene (-CH2CH2CH2CH2-), etc. The alkylene group can be substituted or unsubstituted. When substituted, the substituent can be substituted at any usable connection point. The substituent is preferably independently selected independently from one or more substituents chosen from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxyl, nitro, cyano, cycloalkyl, heterocyclic, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, and oxo.

[0087] The term "alkenyl" refers to an alkyl compound containing at least one carbon-carbon double bond in its molecule, wherein the definition of alkyl is as described above. Alkenyl groups can be substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups, independently selected from one or more substituents selected from hydrogen, alkyl, alkoxy, halogen, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0088] The term "alkynyl" refers to an alkyl compound containing at least one carbon-carbon triple bond in its molecule, wherein the definition of alkyl is as described above. The alkynyl group can be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups, independently selected from one or more substituents selected from hydrogen, alkyl, alkoxy, halogen, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0089] The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, wherein the cycloalkyl ring contains 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, more preferably 3 to 8 (e.g., 3, 4, 5, 6, 7, or 8) carbon atoms, and even more preferably 3 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cyclohepttrienyl, cyclooctyl, etc.; polycyclic cycloalkyl groups include spirocyclic, fused-ring, and bridged-ring cycloalkyl groups.

[0090] The cycloalkyl ring includes cycloalkyl groups (including monocyclic, spirocyclic, fused, and bridged rings) fused to an aryl, heteroaryl, or heterocyclic alkyl ring as described above, wherein the ring connected to the parent structure is a cycloalkyl group. Non-limiting examples include indanyl, tetrahydronaphthyl, phenylcyclopentyl, and benzocycloheptyl, etc.; phenylcyclopentyl and tetrahydronaphthyl are preferred.

[0091] The cycloalkyl group can be substituted or unsubstituted. When substituted, the substituent can be substituted at any usable connection point. The substituent is preferably independently selected independently from one or more substituents chosen from hydrogen, halogen, alkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0092] The term "alkoxy" refers to -O- (alkyl) and -O- (unsubstituted cycloalkyl), where alkyl is defined as described above. Non-limiting examples of alkoxy groups include: methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentoxy, and cyclohexoxy. Alkoxy groups can be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from H, D, halogen, alkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl. The term "heterocyclic" refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituent containing 3 to 20 ring atoms, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen, S, S(O), and S(O)2, but excluding the -OO-, -OS-, or -SS- ring moieties, and the remaining ring atoms are carbon. Preferably, it contains 3 to 12 ring atoms, of which 1 to 4 (e.g., 1, 2, 3, and 4) are heteroatoms; more preferably, it contains 3 to 8 (e.g., 3, 4, 5, 6, 7, or 8) ring atoms, of which 1 to 3 (e.g., 1, 2, or 3) are heteroatoms; even more preferably, it contains 3 to 6 ring atoms, of which 1 to 3 are heteroatoms; most preferably, it contains 5 or 6 ring atoms, of which 1 to 3 are heteroatoms. Non-limiting examples of monocyclic heterocyclic groups include pyrrolidinyl, tetrahydropyranyl, 1,2,3,6-tetrahydropyridyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, etc. Polycyclic heterocyclic groups include spirocyclic, fused-ring, and bridged-ring heterocyclic groups.

[0093] Heterocyclic rings include heterocyclic groups (including monocyclic, spirocyclic, fused heterocyclic, and bridged heterocyclic rings) fused to an aryl, heteroaryl, or cycloalkyl ring, wherein the ring connected to the parent structure is a heterocyclic group, and non-limiting examples include:

[0094] The heterocyclic group can be substituted or unsubstituted. When substituted, the substituent can be substituted at any usable connection point. The substituent is preferably independently selected independently from one or more substituents chosen from hydrogen, halogen, alkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0095] The term "aryl" refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (fused polycyclic is a ring sharing adjacent carbon atom pairs) group having a conjugated π-electron system, preferably 6- to 10-membered, such as phenyl and naphthyl. The aryl ring comprises an aryl ring fused to a heteroaryl, heterocyclic, or cycloalkyl ring as described above, wherein the ring connected to the parent structure is an aryl ring.

[0096] The aryl group can be substituted or unsubstituted. When substituted, the substituent can be substituted at any usable connection point. The substituent is preferably independently selected independently from one or more substituents chosen from hydrogen, halogen, alkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0097] The term "heteroaryl" refers to a heteroaryl system comprising 1 to 4 (e.g., 1, 2, 3, and 4) heteroatoms and 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur, and nitrogen. The heteroaryl group is preferably 5 to 10-membered (e.g., 5, 6, 7, 8, 9, and 10), more preferably 5- or 6-membered, such as furanyl, thiophene, pyridinyl, pyrroleyl, N-alkylpyrroleyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, etc. The heteroaryl ring comprises a heteroaryl group fused to an aryl, heterocyclic, or cycloalkyl ring as described above, wherein the ring connected to the parent structure is a heteroaryl ring.

[0098] The heteroaryl group can be substituted or unsubstituted. When substituted, the substituent can be substituted at any usable connection point. The substituent is preferably independently selected independently from one or more substituents chosen from hydrogen, halogen, alkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0099] The aforementioned cycloalkyl, heterocyclic, aryl, and heteroaryl groups have one residue derived from removing one hydrogen atom from a parent ring atom, or two residues derived from removing two hydrogen atoms from the same or two different ring atoms of the parent group, namely "divalent cycloalkyl", "divalent heterocyclic", "aryl", and "heteroaryl".

[0100] The term "amino protecting group" is used to protect the amino group by a group that is easily removed, so that the amino group remains unchanged when other parts of the molecule react. Non-limiting examples include tetrahydropyranyl, tert-butoxycarbonyl, acetyl, benzyl, allyl, and p-methoxybenzyl, etc. These groups may optionally be replaced by 1-3 substituents selected from halogens, alkoxy groups, or nitro groups. The amino protecting group is preferably tetrahydropyranyl.

[0101] The term “cycloalkyloxy” refers to cycloalkyl-O-, where the cycloalkyl group is as defined above.

[0102] The term "halogenated alkyl" refers to an alkyl group that has been substituted with one or more halogens, wherein the alkyl group is as defined above.

[0103] The term "hydroxyl group" refers to the -OH group.

[0104] The term "hydroxyalkyl" refers to an alkyl group that has been substituted with a hydroxyl group, wherein the alkyl group is as defined above.

[0105] The term "halogen" refers to fluorine, chlorine, bromine, or iodine.

[0106] The term "amino" refers to -NH2.

[0107] The term "cyano" refers to -CN.

[0108] The term "nitro" refers to -NO2.

[0109] The term "carbonyl" refers to C=O.

[0110] The term "carboxyl group" refers to -C(O)OH.

[0111] The term "carboxylic acid ester group" refers to -C(O)O (alkyl) or -C(O)O (cycloalkyl), where alkyl and cycloalkyl are as defined above.

[0112] The compounds disclosed herein can exist as tautomers. For the purposes of this disclosure, references to compounds of formula (I) refer to the compound itself, any one of its tautomers, or a mixture of two or more tautomers. For example, a reference to a pyrazolyl group should be understood to include any one or a mixture of two of the following structures:

[0113] "Optional" or "optionally" means that the event or environment described below may but does not have to occur, and the description includes the possibility or absence of the event or environment. For example, "optionally alkyl-substituted heterocyclic group" means that the alkyl group may but does not have to be present, and the description includes cases where the heterocyclic group is substituted with an alkyl group and cases where the heterocyclic group is not substituted with an alkyl group.

[0114] "Substituted" refers to one or more hydrogen atoms in a group, preferably up to five, and more preferably one to three hydrogen atoms, which are independently substituted by the corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and those skilled in the art can determine (by experiment or theory) possible or impossible substitutions without much effort. For example, an amino or hydroxyl group with free hydrogen may be unstable when combined with a carbon atom having an unsaturated bond (such as an alkene).

[0115] "Pharmaceutical composition" means a mixture containing one or more of the compounds described herein or their physiologically / pharmacologically acceptable salts or prodrugs, along with other chemical components, such as physiologically / pharmacologically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration to a living organism, thereby promoting the absorption of the active ingredient and the exertion of its biological activity.

[0116] "Medicinal salts" refers to salts of the compounds disclosed herein that are safe and effective when used in mammals and have the appropriate biological activity. Detailed Implementation

[0117] Example 1: Synthesis of Compound R1

[0118] (1) Step 1:

[0119]

[0120] At room temperature, (R)-4-(2-chloro-9h-purin-6-yl)-3-methylmorpholine (200 mg), isopropane bromide (161 mg), and potassium carbonate (120 mg) were added to a 25 mL single-necked flask, followed by the addition of DMF (8 mL). The mixture was then heated to 80 °C and refluxed overnight with stirring. The reaction was monitored by TLC until completion. The reaction solution was concentrated under reduced pressure and purified by column chromatography (petroleum ether:ethyl acetate = 5:1:1:1) to give an off-white solid (145 mg, 62%). LC-MS [M+H] + =296.20.

[0121] (2) Step 2:

[0122]

[0123] At room temperature, compound R1-1 (230 mg), borate ester (227 mg), Pd(PPh3)4 (90 mg), and KOAc (165 mg) were added to a 50 mL single-necked flask, followed by the addition of DMSO (20 mL). The mixture was purged with nitrogen three times and heated to 120 °C for 8 h. The reaction was monitored by TLC until it was complete. The reaction solution was cooled to room temperature, poured into 60 mL of water, extracted with ethyl acetate, dried the organic phase, filtered, and then evaporated to dryness. The solution was purified by column chromatography (petroleum ether:ethyl acetate = 5:1-1:1) to give a pale 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.

[0124] Example 2 Synthesis of compound R2

[0125]

[0126] (1) Step 1:

[0127]

[0128] Compound W-1 is 2,4-dichloro-7-denitropurine, purchased from Leyan Reagent, with a purity ≥99.37%. The following examples are the same.

[0129] At room temperature, 2,4-dichloro-7-denitropurine (2.0 g) was placed in a 50 mL round-bottom flask, and THF (16 mL) was added. The mixture was cooled to 0–5 °C and stirred for 5 min. 60% sodium hydride (0.51 g) was added, and the mixture was stirred for 15 min. Iodomethane (17.0 g) was added, and the mixture was heated to room temperature and stirred overnight. The reaction was monitored by TLC (petroleum ether:ethyl acetate = 4:1) to indicate completion. The reaction mixture was quenched with water, 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 give compound R2-1 (1.76 g, 81.9%) as a white powder. LC-MS [M+H] + =203.

[0130] (2) Step 2:

[0131]

[0132] At room temperature, compound R2-1 (1.0 g), (R)-3-methylmorpholine (600 mg), and anhydrous potassium carbonate (2.05 g) were placed in a 50 mL round-bottom flask. DMF (10 mL) was added, and the mixture was heated to 90-100 °C and stirred for 5-6 h. The reaction was monitored by TLC until completion. After cooling to room temperature, the mixture was extracted twice with ice water and ethyl acetate. The combined ethyl acetate phases were washed with water and brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (petroleum ether:ethyl acetate = 4:1) to give an orange-yellow oily compound R2-2 (0.99 g, 75%). LC-MS [M+H] + =267.

[0133] (3) Step 3:

[0134]

[0135] Weigh out compound R2-2 (500 mg), 7-azaindoleboronic acid pinacol ester (502 mg), anhydrous potassium carbonate (775 mg), tetrakis(triphenylphosphine)palladium (216 mg), 1,4-dioxane (10 mL), and water (2 mL). Purge the mixture three times with nitrogen, heat to 90-100 °C, and stir overnight. Cool to room temperature, add ice water, extract twice with ethyl acetate, combine the ethyl acetate phases, wash with water and brine, dry to anhydrous sodium sulfate, filter, concentrate, and purify by column chromatography (petroleum ether:ethyl acetate = 2:1) to obtain compound R2 (455 mg, 70%) as a solid powder. 1 H NMR (400MHz, CD3CN) 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.

[0136] Example 3 Synthesis of compound R3

[0137]

[0138] (1) Step 1:

[0139]

[0140] In a 250 mL reaction flask, add 100 mL of dichloromethane, 2 g of 2,4-dichloro-pyrrolopyrimidine, and 5 mL of diisopropylethylamine. Stir the reaction mixture at room temperature for 10 min, resulting in a white turbid liquid. Then add 3 g of methanesulfonyl chloride; the mixture gradually dissolves, forming a bright yellow clear liquid. React at room temperature for 2 h, monitoring the reaction by TLC (petroleum ether:ethyl acetate = 4:1, with one drop of methanol added) until the reaction is complete. Add the reaction solution to 500 mL of water and stir for 30 min. During stirring, add 10 mL of triethylamine. Allow to stand, separate the organic phase, dry to anhydrous sodium sulfate, filter, and use the filtrate directly for the next step. LC-MS [M+H] + =267.

[0141] (2) Step 2:

[0142]

[0143] Diisopropylethylamine (5 mL) and morpholine (2.5 mL) were added to the reaction solution from the previous step, and the mixture was stirred at room temperature for 4-5 hours, resulting in a bright yellow clear liquid. TLC (petroleum ether:ethyl acetate = 4:1) was used to monitor the reaction until the starting material was completely reacted. The reaction solution was washed twice with water (100 mL * 2), dried over anhydrous sodium sulfate, filtered, concentrated, slurried with n-hexane, filtered, and dried to obtain a white solid powder, compound R3-2 (1.8 g, 53%). LC-MS [M+H] + =317.

[0144] (3) Step 3:

[0145]

[0146] Under nitrogen protection, DMSO (20 mL), compound R3-2 (1.4 g), 7-azaindoleboronic acid pinacol ester (1.16 g), sodium fluoride (2.1 g), and tetrakis(triphenylphosphine)palladium (0.29 g) were added to a 50 mL reaction flask. The reaction mixture was then heated to 120 °C and maintained at this temperature for 4-5 h. The reaction was monitored by TLC (petroleum ether:ethyl acetate = 1:1) until the reactants were completely reacted. The reaction solution was added to a mixture of water (50 mL) and ethyl acetate (50 mL), stirred to separate the layers, and the aqueous phase was collected. The aqueous phase was extracted three times with ethyl acetate. The organic phases were combined, washed with saturated brine, dried, concentrated, and the residue was purified by silica gel column chromatography to give compound R3 (0.1 g, 5%) as a white solid. 1H 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.

[0147] Example 4 Synthesis of compound R5

[0148]

[0149] (1) Step 1:

[0150]

[0151] 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) were added, and the mixture was reacted at 35 °C for 12 h. The mixture was washed with water, the organic phase was concentrated, and the crude product was used directly in the next step. LC-MS [M+H] + =254.

[0152] (2) Step 2:

[0153]

[0154] Compound R5-1 (300 mg), isopropane iodide (1 g), potassium carbonate (320 mg), and DMF (10 mL) were added at room temperature. The mixture was reacted at 80 °C for 5 h, extracted with water / ethyl acetate, concentrated, and purified by column chromatography (petroleum ether:ethyl acetate = 5:1) before being used in the next step. LC-MS [M+H] + =296.

[0155] (3) Step 3:

[0156]

[0157] Compound R5-2 (240 mg), 7-azaindoleboronic acid pinacol ester (238 mg), potassium carbonate (281 mg), tetra-triphenylphosphine palladium (140 mg), and dimethyl sulfoxide (10 mL) were added under nitrogen protection. The mixture was reacted at 120 °C for 5 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 (90 mg). 1H NMR (400MHz, CDCl3-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.

[0158] Example 6 Synthesis of compound R7

[0159]

[0160] (1) Step 1:

[0161] 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) were added, and the mixture was reacted at 35 °C for 12 h. The mixture was washed with water, the organic phase was concentrated, and the crude product was used directly in the next step.

[0162] (2) Step 2:

[0163]

[0164] Compound R7-1 (1.09 g), 1,1,1-trifluoro-2-iodoethane (1.804 g), cesium carbonate (7.02 g), and DMF (20 mL) were added at room temperature. The reaction was carried out at 70 °C for 12 h. TLC (petroleum ether:ethyl acetate = 2:1) was performed, followed by extraction with water / ethyl acetate. The organic phase was concentrated and purified by column chromatography (petroleum ether:ethyl acetate = 10:1) before being used in the next step. LC-MS [M+H] + =336.

[0165] (3) Step 3:

[0166]

[0167] At room temperature, compound R7-2 (0.2 g), 7-azaindoleboronic acid pinacol ester (0.145 g), cesium carbonate (0.582 g), tetrakis(triphenylphosphine) palladium (0.069 g), and water / 1,4-dioxane (V:V = 1:10) were added, and the mixture was reacted at 95 °C for 12 h under nitrogen protection. The reaction was carried out by TLC (petroleum ether:ethyl acetate = 1:1), extracted with water / ethyl acetate, concentrated the organic phase, and purified by column chromatography (petroleum ether:ethyl acetate = 3:1) to give compound R7 (15 mg) as a yellow solid. 1 H NMR (400MHz, CH3OH-d4) 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.

[0168] Example 7 Synthesis of compound R8

[0169]

[0170] (1) Step 1:

[0171]

[0172] 2-(1-hydroxyethyl)pyridine (200 mg) was dissolved in DCM (20 mL), and 2 drops of DMF were added dropwise. Sulfoxide (227 mg) was added under ice bath conditions, and the mixture was stirred for 30 min. NaHCO3 was slowly added to adjust the pH to neutral. The mixture was extracted with ethyl acetate after adding water. The reaction was monitored by TLC. After the reaction was complete, the mixture was concentrated under reduced pressure to remove excess SOCl2. NaHCO3 was added to adjust the pH to neutral, and the mixture was extracted with ethyl acetate after adding water. The organic phase was concentrated to give a pale yellow oily product (213 mg). LC-MS [M+H] + =142.

[0173] (2) Step 2:

[0174] The synthesis of compound R8-1 is as described for compound R5-1.

[0175] (3) Step 3:

[0176]

[0177] Compound R8-1 (200 mg), NaH (47 mg), 2-(1-chloroethyl)pyridine (137 mg), and DMF solution (20 mL) were added under ice bath conditions, and the mixture was stirred and refluxed at 50 °C for 4 h. The reaction was monitored by TLC until completion. The mixture was extracted with ethyl acetate after adding water, and the organic phase was concentrated and purified by column chromatography (petroleum ether:ethyl acetate = 4:1) to give an oily, pale yellow product (182 mg). LC-MS [M+H] + =358.

[0178] (4) Step 4:

[0179]

[0180] Compound R8-2 (120 mg), 7-azaindole-4-boronate (97 mg), Pd(PPh3)4 (36 mg), and potassium carbonate (363 mg) were reacted in DMF (20 mL) at 125 °C for 24 h with stirring. The reaction was monitored by TLC until complete. The reaction solution was added to water and extracted twice with ethyl acetate. The organic phases were combined, washed with water, dried, and filtered. The solution was concentrated under reduced pressure, purified by column chromatography (petroleum ether:ethyl acetate = 1:1), and concentrated under reduced pressure to give a pale 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.

[0181] Example 5: Synthesis of Compound R10

[0182]

[0183] (1) Step 1:

[0184]

[0185] 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) were added, and the mixture was reacted at 35 °C for 12 h. The mixture was washed with water, the organic phase was concentrated, and the crude product was used directly in the next step. LC-MS [M+H]+ =254.

[0186] (2) Step 2:

[0187]

[0188] Compound R10-1 (300 mg), methyl iodide (1 g), potassium carbonate (320 mg), and DMF (10 mL) were added at room temperature. The mixture was reacted at 80 °C for 5 h, extracted with water / ethyl acetate, concentrated, and purified by column chromatography (petroleum ether:ethyl acetate = 5:1) before being used in the next step. LC-MS [M+H] + =268.

[0189] (3) Step 3:

[0190]

[0191] Compound R10-2 (240 mg), 7-azaindoleboronic acid pinacol ester (238 mg), potassium carbonate (281 mg), tetra-triphenylphosphine palladium (140 mg), and dimethyl sulfoxide (10 mL) were added under nitrogen protection. The mixture was reacted at 120 °C for 5 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 compound R10 (90 mg). 1 H NMR (400MHz, CDCl3-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.

[0192] Example 6 Synthesis of compound R11

[0193] (1) Step 1:

[0194]

[0195] Compound W-4 (1.00 g), pinacol diboronic acid ester (1.25 g), Pd(dppf)Cl2 (0.323 g), and potassium acetate (0.867 g) were added to 10 mL of 1,4-dioxane solution and reacted at 100 °C for 2 h under nitrogen protection. After the reaction was completed by TLC monitoring, the reaction solution was concentrated under reduced pressure and purified by column chromatography (petroleum ether:ethyl acetate = 20:1) to give compound W-5 (1.01 g, 83.5%) as a white solid.

[0196] (2) Step 2:

[0197] Compound R11-1 was synthesized as described for compound R8-1.

[0198] (3) Step 3:

[0199]

[0200] Compound W-5 (0.500 g), compound R11-1 (0.591 g), copper acetate (0.435 g), and triethylamine (0.803 g) were added to DCM (50 mL), and the mixture was stirred with an oxygen bulb at room temperature for 48 h. The reaction was monitored by TLC until it reached 30-40%. The reaction mixture was added to water (20 mL), stirred, and filtered. The filter cake was washed with 20 mL of DCM, the organic phase was dried, and purified by column chromatography (petroleum ether:ethyl acetate = 5:1) to give a light-colored oily compound R11-2 (0.136 g, 17.4%).

[0201] (4) Step 4:

[0202]

[0203] Compound R11-2 (0.100 g), compound W-6 (0.068 g), tetrakis(triphenylphosphine)palladium (0.029 g), potassium carbonate (0.699 g), and DMF (5 mL) were stirred at 110-120 °C for 12 h. The reaction was monitored by TLC until complete. The reaction solution was added to water (30 mL), extracted with ethyl acetate (30 mL × 3), and the organic phases were combined. The organic phases were washed with saturated sodium chloride solution (20 mL × 3), dried over anhydrous magnesium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography (petroleum ether:ethyl acetate = 5:1-2:1) to give a pale yellow compound R11 (0.068 g, 56.7%). 1H 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.

[0204] Example 7 Synthesis of compound R13

[0205]

[0206] (1) Step 1:

[0207]

[0208] At room temperature, 0.5 g of 4-bromo-7-azaindole, 0.85 g of m-chloroperoxybenzoic acid, and 40 mL of methyl tert-butyl ether were added, and the reaction was allowed to proceed for 12 h. The reaction solution was filtered, and the filter cake was washed with methyl tert-butyl ether to obtain a white solid, which was used directly in the next step. LC-MS [M+H] + =214.

[0209] (2) Step 2:

[0210]

[0211] Under nitrogen protection, compound R13-1 (0.5 g) and DMF (10 mL) were added to a reaction flask, and the mixture was heated to 50 °C. Then, methanesulfonyl chloride (0.64 g) was added, and the temperature was raised to 75 °C, and the reaction was allowed to proceed for 1 h. After the reaction was complete, the mixture was cooled to room temperature, and the reaction solution was added to ice water to lower the temperature to 0 °C. The pH was adjusted to 7 with 6N sodium hydroxide solution, and the mixture was stirred at room temperature for 3 h. The mixture was then filtered, the filter cake was washed with water, and dried to obtain a white solid. This solid was used directly in the next step. LC-MS [M+H] + =232.

[0212] (3) Step 3:

[0213]

[0214] Under nitrogen protection, compound R13-2 (226 mg), potassium acetate (287 mg), pinacol diboronate (274 mg), Pd(pddf)Cl2 (138 mg), and 1,4-dioxane (10 mL) were added to a reaction flask. The mixture was then heated to 90 °C and reacted for 16 h. After the reaction was complete, water and ethyl acetate were added to quench the reaction. The organic phase was dried, concentrated, and purified by column chromatography (petroleum ether:ethyl acetate = 5:1) before being used in the next step. LC-MS [M+H] + =279.

[0215] (4) Step 4:

[0216]

[0217] At room temperature, 2,4-dichloro-pyrrolopyrimidine (1 g), 95% ethanol (20 mL), and (R)-3-methylmorpholine (0.6 g) were added to a reaction flask. The mixture was then heated to 70 °C and reacted for 3 h. The reaction solution was concentrated to dryness and then used for the next step. LC-MS [M+H] + =253.

[0218] (5) Step 5:

[0219]

[0220] At room temperature, compound R13-4 (200 mg), potassium carbonate (220 mg), methyl iodide (600 mg), and DMF (10 mL) were added to a reaction flask. The mixture was then heated to 80 °C and reacted for 8 h. The mixture was extracted with water / ethyl acetate, the organic phase was concentrated, and purified by column chromatography (petroleum ether:ethyl acetate = 5:1) before being used in the next step. LC-MS [M+H] + =267.

[0221] (6) Step 6:

[0222]

[0223] Compound R13-5 (240 mg), compound R13-3 (238 mg), potassium carbonate (281 mg), Pd(pddf)Cl2 (140 mg), DME (8 mL), and H2O (2 mL) were added under nitrogen protection. The mixture was reacted at 90 °C for 16 h under nitrogen protection. The mixture was extracted with water / ethyl acetate, the organic phase was concentrated, and purified by column chromatography (petroleum ether:ethyl acetate = 3:1) to obtain the target product (20 mg). 1HNMR(400 MHz, acetonitrile-d3) 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.

[0224] Example 8 Synthesis of compound R14

[0225]

[0226] (1) Step 1:

[0227]

[0228] At room temperature, 0.5 g of 2,6-dichloro-7-deaminuron, 0.448 g of (R)-3-methylmorpholine, 20 mL of dichloromethane, and 1.103 g of potassium carbonate were added. The mixture was reacted at 40 °C for 12 h. After washing with water, the organic phase was concentrated and dried. The crude product was used directly in the next step. LC-MS [M+H] + =439.

[0229] (2) Step 2:

[0230]

[0231] Compound R8-1 (0.3 g), cyclopropylsulfonyl chloride (0.2 g), cesium carbonate (1.16 g), and DMF (10 mL) were added at room temperature. The mixture was reacted at 60 °C for 12 h, extracted with water / ethyl acetate, concentrated, and purified by column chromatography (petroleum ether:ethyl acetate = 10:1) for the next step. LC-MS [M+H] + =357.

[0232] (3) Step 3:

[0233]

[0234] At room temperature, compound R14-1 (0.15 g), 7-azaindoleboronic acid pinacol ester (0.103 g), cesium carbonate (0.41 g), tetrakis(triphenylphosphine)palladium (0.1 g), water (0.5 mL), and 1,4-dioxane (5 mL) were added. The mixture was reacted at 95 °C for 12 h under nitrogen protection. The mixture was extracted with water / ethyl acetate, the organic phase was concentrated, and purified by column chromatography (petroleum ether:ethyl acetate = 3:1) to give compound R14 (0.04 g). 1 H NMR(400 MHz, methanol-d4) δ 8.30 (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.

[0235] Example 9: Synthesis of Compound R16

[0236]

[0237] (1) Step 1:

[0238]

[0239] 2,6-Dichloropurine (1 g), methyl iodide (432 mg), potassium carbonate (1.345 g), and DMF (30 mL) were stirred at 50-60 °C for 2 h. The reaction was monitored by TLC until complete. The reaction solution was added to water and extracted twice with ethyl acetate. The organic phases were combined, washed with water, dried, and filtered. After concentration under reduced pressure, a white powder precipitated, which was purified by column chromatography (petroleum ether:ethyl acetate = 5:1), filtered, and dried to give compound R16-1 (1.05 g). LC-MS [M+H] + =230.

[0240] (2) Step 2:

[0241]

[0242] Compound R16-1 (300 mg) and R-(3)-methylmorpholine (176 mg) were mixed in ethanol solution (20 mL) and refluxed overnight with stirring. The reaction was monitored by TLC until completion. The reaction solution was concentrated under reduced pressure, and the precipitated white powder was filtered and washed with ice-cold ethanol to obtain compound R16-2 (278 mg). LC-MS [M+H]+ =295.

[0243] (3) Step 3:

[0244]

[0245] Compound R16-2 (100 mg), 7-azaindole-4-boronate (136 mg), Pd[dppf]Cl2 (37 mg), potassium carbonate (106 mg), and 1,4-dioxane:H2O (10 mL: 2 mL) were stirred overnight at 110–120 °C. The reaction was monitored by TLC until complete. The reaction solution was added to water and extracted twice with ethyl acetate. The organic phases were combined, washed with water, dried, and filtered. The solution was concentrated under reduced pressure and purified by column chromatography to give a pale yellow compound R16 (37 mg). 1 HNMR (500MHz, chloroform-d) δ 8.54 (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.

[0246] Example 10 Synthesis of compound R17

[0247]

[0248] (1) Step 1:

[0249]

[0250] 2,4-Dichloro-7H-pyrrolopyrimidine (1.0 g), (R)-3-methylmorpholine (0.538 g), potassium carbonate (2.21 g), and DMF were stirred overnight at 60-70 °C. The reaction was confirmed to be complete by TLC. Water was added and stirred to dissolve the insoluble matter. The mixture was extracted twice with ethyl acetate, separated, and the ethyl acetate phase was washed once with water, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography (petroleum ether:ethyl acetate = 10:1) to give compound R17-1 (1.21 g) as a white solid.

[0251] (2) Step 2:

[0252]

[0253] At room temperature, compound R17-1 (0.5 g), cesium carbonate (1.93 g), and DMF (20 mL) were stirred for 15-30 min. Then, 0.365 g of bromocyclopropane and 0.1 g of cuprous iodide were added, and the mixture was stirred overnight at 90-100 °C under nitrogen protection. Water and ethyl acetate were added and stirred until homogeneous. The insoluble matter was filtered off, and the aqueous phase was extracted once more with ethyl acetate. The two ethyl acetate phases were combined, washed with water, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (petroleum ether:ethyl acetate = 3:1) to give compound R17-2 (0.11 g) as a pale yellow oil. LC-MS [M+H] + =293.2.

[0254] (3) Step 3:

[0255]

[0256] At room temperature, compound R17-2 (100 mg), 7-azaindoleboronic acid pinacol ester (83.4 mg), potassium carbonate (120 mg), 1,4-dioxane (10 mL), and H2O (2 mL) were stirred for 10 min. Pd(dppf)Cl2 (14 mg) was added, and the mixture was reacted overnight at 90-100 °C under nitrogen protection. The reaction was detected by TLC to be complete. The mixture was concentrated under reduced pressure, water was added, and the mixture was extracted twice with ethyl acetate. The mixture was dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (petroleum ether:ethyl acetate = 1:1) to obtain compound R17 (100 mg) as a pale yellow solid. 1 HNMR (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.

[0257] Example 11 Synthesis of compound R18

[0258]

[0259] (1) Step 1:

[0260]

[0261] 2,4-Dichloro-7H-pyrrolopyrimidine (1.0 g), (R)-3-methylmorpholine (0.538 g), potassium carbonate (2.21 g), and DMF were reacted overnight at 60-70 °C with stirring. The reaction was monitored by TLC until complete. Water was added and stirred to dissolve the insoluble matter. The mixture was extracted twice with ethyl acetate, separated, and the ethyl acetate phase was washed once with water, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography (petroleum ether:ethyl acetate = 10:1) to give compound R18-1 (1.21 g) as a white solid. LC-MS [M+H] + =253.3.

[0262] (2) Step 2:

[0263]

[0264] Compound R18-1 (500 mg) and cesium carbonate (1.93 g) were stirred in DMF for 15-30 min at room temperature. 0.4 g of bromomethylcyclopropane was added, and the mixture was stirred overnight at 90-100 °C. The mixture was extracted twice with water and ethyl acetate, and the two ethyl acetate phases were combined, washed with water, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (petroleum ether:ethyl acetate = 2:1) to give compound R18-2 (0.55 g) as a pale blue oil. LC-MS [M+H] + =307.3.

[0265] Step 3:

[0266]

[0267] At room temperature, compound R18-2 (100 mg), 7-azaindoleboronic acid pinacol ester (80 mg), potassium carbonate (112.6 mg), 1,4-dioxane (10 mL), and H2O (2 mL) were stirred for 10 min. 13.3 mg of Pd(dppf)Cl2 was added, and the mixture was reacted overnight at 90-100 °C under nitrogen protection. The solvent was concentrated under reduced pressure, and water was added to the residue. The residue was extracted twice with ethyl acetate, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (petroleum ether:ethyl acetate = 1:1) to obtain compound R18 (100 mg). 1 HNMR (400MHz, DMSO) δ11.7 (s, 1H), 8.6 (d, 1H), 8.0 (d, 1H), 7.9 (d, 2H), 7.3 (d, 2 H), 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+H1 + =389.3. LC-MS[M+Na]=411.3.

[0268] Example 12 Synthesis of compound R19

[0269]

[0270] (1) Step 1:

[0271]

[0272] 2,4-Dichloro-7H-pyrrolopyrimidine (1.0 g), (R)-3-methylmorpholine (0.538 g), and potassium carbonate (2.21 g) were reacted in DMF at 60-70 °C overnight with stirring. The reaction was monitored by TLC until complete. Water was added and stirred to dissolve the insoluble matter. The mixture was extracted twice with ethyl acetate, separated, and the ethyl acetate phase was washed once with water, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography (petroleum ether:ethyl acetate = 10:1) to give compound R19-1 (1.21 g) as a white solid. LC-MS [M+H] + =253.

[0273] (2) Step 2:

[0274]

[0275] Compound R19-1 and cesium carbonate (0.3 g) were stirred in 15 mL of DMF at room temperature for 15-30 min. Then, bromocyclopentane (0.265 g) and cuprous iodide (0.0226 g) were added, and the mixture was stirred overnight at 90-100 °C under nitrogen protection. TLC analysis revealed the formation of a less polar product. Water and ethyl acetate were added, and the mixture was stirred until homogeneous. The insoluble matter was filtered off, and the mixture was separated. The aqueous phase was extracted once more with ethyl acetate. The two ethyl acetate phases were combined, washed with water, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (petroleum ether:ethyl acetate = 2:1) to obtain a pale yellow oily compound R19-2 (0.2 g). LC-MS [M+H] + =321.3.

[0276] (3) Step 3:

[0277]

[0278] At room temperature, compound R19-2 (180 mg), 7-azaindoleboronic acid pinacol ester (140 mg), potassium carbonate (194 mg), 1,4-dioxane (10 mL), and H2O (2 mL) were stirred for 20 min. Pd(dppf)Cl2 (23 mg) was added, and the mixture was reacted overnight at 90-100 °C under nitrogen protection. The solvent was concentrated under reduced pressure, and the residue was extracted twice with ethyl acetate, dried over anhydrous sodium sulfate, 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.

[0279] Example 13 Synthesis of compound R20

[0280]

[0281] (1) Step 1:

[0282]

[0283] At room temperature, DMSO (400 mL) and H₂O (50 mL) were added to a 1000 mL single-necked flask, followed by the sequential addition of 2,4-dichloro-7H-pyrrolo[2,3-D]pyrimidine (20.0 g), (R)-3-methylmorpholine (11.8 g), and DIPEA (20.6 g). The mixture was then heated to 55 °C and refluxed with stirring for 20 h. The reaction was monitored by TLC until completion. The reaction solution was poured into 1.2 L of water, stirred thoroughly, filtered, and the solid was dried. The solid was then slurried with petroleum ether:ethyl acetate = 10:1 (300 mL), filtered again, and dried to obtain a white solid (19.8 g, 74%). LC-MS [M+H] + =253.13.

[0284] (2) Step 2:

[0285]

[0286] At room temperature, compound R20-1 (300 mg), pyrimidine-3-boronic acid (250 mg), copper acetate (300 mg), and TEA (300 mg) were added to a 50 mL single-necked flask, followed by 20 mL of DCM. The flask was left open for 48 h. TLC monitoring showed that the reaction was not complete, but a product with significantly increased polarity was formed. The mixture was then filtered through a diatomaceous earth liner, and the filtrate was evaporated to dryness and purified by column chromatography (petroleum ether:ethyl acetate = 5:1-3:1) to give a pale yellow solid (70 mg, 17%). LC-MS [M+H] + =331.20.

[0287] (3) Step 3:

[0288]

[0289] At room temperature, compound R20-2 (70 mg), borate ester (62 mg), Pd(PPh3)4 (24 mg), and KOAc (41 mg) were added to a 50 mL single-necked flask, followed by the addition of DMSO (20 mL). The mixture was purged with nitrogen three times and heated to 120 °C for 8 h. TLC monitoring showed that the reaction was not complete and that a significant increase in product formation was observed. Subsequently, the reaction solution was allowed to cool to room temperature and then extracted with water (60 mL) and ethyl acetate (20 mL x 2). The organic phase was dried, filtered, and evaporated to dryness. The solution was purified by column chromatography (petroleum ether:ethyl acetate = 5:1-1:1) to obtain a pale yellow solid (13 mg, 15%). 1 HNMR (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.

[0290] Example 14 Synthesis of compound R21

[0291]

[0292] (1) Step 1:

[0293]

[0294] At room temperature, 2,4-dichloro-7H-pyrrolopyrimidine (1.0 g), (R)-3-methylmorpholine (0.538 g), and potassium carbonate (2.21 g) were added to DMF and stirred overnight at 60-70 °C. The reaction was monitored by TLC until complete. Water was added and stirred to dissolve the insoluble matter. The mixture was extracted twice with ethyl acetate, separated, and the ethyl acetate phase was washed once with water, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography (petroleum ether:ethyl acetate = 10:1) to give compound R21-1 (1.21 g) as a white solid. LC-MS [M+H] + =253.3.

[0295] (2) Step 2:

[0296]

[0297] At room temperature, compound R21-1 (1.0 g), pyridine-3-boronic acid (0.584 g), and copper acetate (0.79 g) were stirred in DCM for 15-30 min. Triethylamine (0.8 g) was added, and the mixture was stirred openly at room temperature for at least 48 h. Dichloromethane was concentrated, and water and ethyl acetate were added and stirred until homogeneous. The insoluble matter was filtered off, and the mixture was separated. The aqueous phase was extracted once again with ethyl acetate. The two ethyl acetate phases were combined, washed with water, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (petroleum ether:ethyl acetate = 2:1) to give compound R21-2 (300 mg) as a pale yellow oil. LC-MS [M+Na] = 330.2.

[0298] (3) Step 3:

[0299]

[0300] At room temperature, compound R21-2 (100 mg), 7-azaindoleboronic acid pinacol ester (80 mg), potassium carbonate (112.6 mg), 1,4-dioxane (10 mL), and H2O (2 mL) were stirred for 10 min. Pd(dppf)Cl2 (13.3 mg) was added, and the mixture was reacted overnight at 100-110 °C under nitrogen protection. The solvent was concentrated under reduced pressure, and the residue was extracted twice with ethyl acetate, dried over anhydrous sodium sulfate, 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, 3 H), 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.

[0301] Example 15 Synthesis of compound R22

[0302]

[0303] (1) Step 1:

[0304]

[0305] At room temperature, 2,6-dichloro-7-deaminase (1.88 g), (R)-3-methylmorpholine (1.214 g), dichloromethane (20 mL), and potassium carbonate (4.146 g) were added, and the reaction was carried out at 40 °C for 12 h. The reaction was monitored by TLC (petroleum ether:ethyl acetate = 2:1) to ensure complete reaction. After post-treatment, the mixture was washed with water, concentrated, and then used for the next step. LC-MS [M+H] + =253.

[0306] (2) Step 2:

[0307]

[0308] At room temperature, compound R22-1 (0.15 g), 7-azaindoleboronic acid pinacol ester (0.15 g), cesium carbonate (0.609 g), tetrakis(triphenylphosphine)palladium (0.1 g), water (1 mL), and DMF (10 mL) were added. The mixture was reacted at 120 °C for 12 h under nitrogen protection. The reaction was confirmed to be complete by TLC (petroleum ether:ethyl acetate = 1:1). The mixture was extracted with water / ethyl acetate, the organic phase was concentrated, and purified by column chromatography (petroleum ether:ethyl acetate = 3:1) to obtain the target product. LC-MS [M+H] + =335.

[0309] (3) Step 3:

[0310]

[0311] Compound R22-2 (0.1 g), cyclopropylformyl chloride (0.02 g), N,N-diisopropylethylamine (0.116 g), and DCM (20 mL) were added at room temperature and reacted at room temperature for 6 h. The reaction was confirmed to be complete by TLC (petroleum ether:ethyl acetate = 1:1). The mixture was extracted with water / ethyl acetate, the organic phase was concentrated, and purified by column chromatography (petroleum ether:ethyl acetate = 3:1) to obtain the target product. 1HNMR (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.

[0312] Example 16 Synthesis of compound R23

[0313]

[0314] (1) Step 1:

[0315]

[0316] At room temperature, 2,4-dichloro-7H-pyrrolopyrimidine (1.0 g), (R)-3-methylmorpholine (0.538 g), and potassium carbonate (2.21 g) were added to DMF and stirred overnight at 60-70 °C. The reaction was monitored by TLC until complete. Water was added and stirred to dissolve the insoluble matter. The mixture was extracted twice with ethyl acetate, separated, and the ethyl acetate phase was washed once with water, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography (petroleum ether:ethyl acetate = 10:1) to give compound R23-1 (1.21 g) as a white solid. LC-MS [M+H] + =253.3.

[0317] (2) Step 2:

[0318]

[0319] At room temperature, compound R23-1 (1.0 g), pinacol methylpyrazolone borate (1.24 g), and copper acetate (0.72 g) were stirred in DCM for 15-30 min. Triethylamine (0.8 g) was added, and the mixture was stirred openly at room temperature for at least 48 h. Dichloromethane was concentrated, and water and ethyl acetate were added and stirred until homogeneous. The insoluble matter was filtered off, and the mixture was separated. The aqueous phase was extracted once again with ethyl acetate. The two ethyl acetate phases were combined, washed with water, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (petroleum ether:ethyl acetate = 2:1) to give compound R23-2 (300 mg) as a pale yellow oil. LC-MS [M+H] + =333.2.

[0320] (3) Step 3:

[0321]

[0322] At room temperature, compound R23-2 (250 mg), 7-azaindoleboronic acid pinacol ester (184 mg), and potassium carbonate (260 mg) were stirred in 1,4-dioxane (15 mL) and H2O (3 mL) for 10 min. Pd(dppf)Cl2 (31 mg) was added, and the mixture was reacted overnight at 100-110 °C under nitrogen protection. The solvent was concentrated under reduced pressure, and the residue was extracted twice with ethyl acetate, 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 HNMR (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.

[0323] Example 17 Synthesis of Compound R26

[0324]

[0325] (1) Step 1:

[0326]

[0327] At room temperature, 2,6-dichloropurine (300 mg), R-(3)-methylmorpholine (180 mg), and TEA (480 mg) were placed in ethanol (5 mL) solution and stirred under reflux for 6 h. The reaction was monitored by TLC until completion. The reaction solution was concentrated under reduced pressure, precipitating a white powder. The powder was filtered and washed with ice-cold ethanol to obtain compound R26-1 (300 mg, 74.8%). LC-MS [M+H] + =254.

[0328] (2) Step 2:

[0329]

[0330] Compound R26-1 (300 mg), methyl iodide (250 mg), and anhydrous potassium carbonate (490 mg) were placed in DMF (5 mL) solution at room temperature and stirred at 50-60 °C for 2 h. The reaction was monitored by TLC until completion. The reaction solution was added to water and extracted twice with ethyl acetate. The organic phases were combined, washed with water, dried, and filtered. After concentration under reduced pressure, a white powder precipitated, which was filtered and dried to give compound R26-2 (300 mg, 94.9%). LC-MS [M+H] + =268.

[0331] (3) Step 3:

[0332]

[0333] Compound R26-2 (100 mg), 7-azaindole-4-boronate (100 mg), tetra-triphenylphosphine palladium (30 mg), potassium carbonate (150 mg), and DMSO (5 mL) were stirred at 110-120 °C for 5 h at room temperature. The reaction was monitored by TLC until complete. The reaction solution was added to water and extracted twice with ethyl acetate. The organic phases were combined, washed with water, dried, and filtered. The solution was concentrated under reduced pressure and purified by column chromatography (petroleum ether:ethyl acetate = 1:1) to give the pale yellow compound R26. 1 HNMR (400MHz, C2H3N-d3) 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.

[0334] Example 18 Synthesis of compound R38

[0335]

[0336] (1) Step 1:

[0337]

[0338] Compound W-8 (400 mg), carbon tetrabromide (1600 mg), triphenylphosphine (550 mg), and toluene (10 mL) were added at room temperature. The mixture was stirred at room temperature for 4 h. The mixture was washed with water, dried, and concentrated to dryness to give compound W-9, which was used directly in the next step.

[0339] (2) Step 2:

[0340]

[0341] At room temperature, 4,6-dichloro-1H-pyrazolo[3,4-D]pyrimidine (300 mg), R-(3)-methylmorpholine (180 mg), TEA (480 mg), and ethanol (5 mL) were added. The mixture was stirred at 80 °C for 6 h. The reaction solution was concentrated under reduced pressure, and a white powder precipitated. The powder was filtered, washed, and dried to obtain compound R38-1, which was used directly in the next step. LC-MS [M+H] + =254.

[0342] (3) Step 3:

[0343]

[0344] 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 mixture was stirred at 120 °C for 6 h. 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 used directly in the next step. LC-MS [M+H] + =350.

[0345] (4) Step 4:

[0346]

[0347] At room temperature, compound R38-2 (100 mg), 7-azaindole-4-boronate (100 mg), (Dppf)-PdCl2 (30 mg), potassium carbonate (150 mg), and DMSO (5 mL) were added. The mixture was stirred at 110-120 °C for 5 h. The mixture was extracted with water / ethyl acetate, and the organic phase was washed with water, dried, filtered, concentrated, and purified by column chromatography (petroleum ether:ethyl acetate = 1:1) to give compound R38 (50 mg). 1 HNMR(500 MHz, chloroform-d) δ 8.54 (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.

[0348] Example 19 Synthesis of compound R39

[0349] (1) Step 1:

[0350]

[0351] 4,6-Dichloro-1H-pyrazolo[3,4-D]pyrimidine (2 g), (R)-3-methylmorpholine (1.3 g), and potassium carbonate (4.4 g) were reacted in 1,4-dioxane at 60-70 °C with stirring for 7-8 h. TLC analysis showed complete reaction of the starting material, producing a product with higher polarity than the starting material, resulting in the precipitation of a yellow solid. Water was added, and the mixture was stirred at room temperature for 1 h. The mixture was filtered, the filter cake was washed with water, slurried with n-hexane, filtered, and dried to obtain a yellowish solid, compound R39-1 (2.5 g). LC-MS [M+H] + =254.2.

[0352] (2) Step 2:

[0353]

[0354] Compound R39-1 (400 mg), cesium carbonate (1.54 g), and DMF (15 mL) were stirred for 15 min. Bromocyclopentane (0.35 g) and potassium iodide (0.1 g) were added, and the mixture was stirred overnight at 90-100 °C. After the reaction was complete, water and ethyl acetate were added, and the mixture was extracted twice with stirring. The two ethyl acetate phases were combined, washed with water, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (petroleum ether:ethyl acetate = 2:1) to obtain an almost colorless oily compound R39-2 (300 mg). LC-MS [M+H] + =322.2.

[0355] (3) Step 3:

[0356]

[0357] Compound 39-2 (300 mg), 7-azaindoleboronic acid pinacol ester (227.5 mg), and potassium carbonate (322 mg) were stirred in 1,4-dioxane (15 mL) and H2O (3 mL) for 10 min. Pd(dppf)Cl2 (34.1 mg) was added, and the reaction was carried out overnight at 90-100 °C under nitrogen protection. The reaction solution was analyzed by TLC, the solvent was concentrated under reduced pressure, water was added, and the mixture was extracted twice with ethyl acetate. The two ethyl acetate phases were combined, concentrated, and purified by column chromatography (petroleum ether:ethyl acetate = 1:1) to obtain compound R39 (13 mg) as an off-white solid. 1H 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.

[0358] Example 20 Synthesis of compound R44

[0359]

[0360] (1) Step 1:

[0361]

[0362] At room temperature, 4,6-dichloro-1H-pyrazolo[3,4-D]pyrimidine (500 mg), pinacol 4-pyridineboronic acid (607 mg), copper acetate (393 mg), triethylamine (398 mg), 4A molecular sieve (2 g), and dichloromethane (10 mL) were added to a 50 mL round-bottom flask, and the mixture was reacted overnight at room temperature. Water (50 mL) and ethyl acetate (50 mL) were added to the reaction mixture, and the mixture was separated. The extracts were then extracted with ethyl acetate (50 mL), and the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and purified by column chromatography (petroleum ether:ethyl acetate = 1:1-1:2) to give compound R44-1 (90 mg). LC-MS [M+H] + =331.21.

[0363] (2) Step 2:

[0364]

[0365] At room temperature, compound R44-1 (90 mg), 7-azaindole-4-boronate (80.5 mg), potassium carbonate (113.3 mg), [1,1′-bis(diphenylphosphine)ferrocene]palladium dichloride (19.7 mg), and DMF (10 mL) / water (2 mL) were added. The mixture was purged with nitrogen three times and reacted at 100 °C for 16 h. Water (50 mL) and ethyl acetate (50 mL) were added to the reaction solution, and the mixture was separated. The extracts were then extracted twice with ethyl acetate (50 mL), and the organic phases were combined. The mixture was washed with saturated brine, dried over anhydrous sodium sulfate, and purified by column chromatography (petroleum ether:ethyl acetate = 1:1-1:0) to give compound R44 (31 mg). 1 HNMR (400MHz, DMSO-d6) 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.

[0366] Example 21 Synthesis of compound R46

[0367]

[0368] (1) Step 1:

[0369]

[0370] At room temperature, 0.5 g of 4-bromo-7-azaindole, 0.85 g of m-chloroperoxybenzoic acid, and 40 mL of methyl tert-butyl ether were added, and the reaction was allowed to proceed for 12 h. The reaction solution was filtered, and the filter cake was washed with methyl tert-butyl ether to obtain a white solid, which was used directly in the next step. LC-MS [M+H] + =213.

[0371] (2) Step 2:

[0372]

[0373] Under nitrogen protection, compound R46-1 (0.5 g) and DMF (10 mL) were added to a reaction flask, and the mixture was heated to 50 °C. Then, methanesulfonyl chloride (0.64 g) was added, and the temperature was raised to 75 °C, and the reaction was allowed to proceed for 1 h. After the reaction was complete, the mixture was cooled to room temperature, and the reaction solution was added to ice water to lower the temperature to 0 °C. The pH was adjusted to 7 with 6N sodium hydroxide solution, and the mixture was stirred at room temperature for 3 h. The mixture was then filtered, the filter cake was washed with water, and dried to obtain a white solid, which was used directly in the next step. LC-MS [M+H] + =231.

[0374] (3) Step 3:

[0375]

[0376] Under nitrogen protection, compound R46-2 (226 mg), potassium acetate (287 mg), pinacol diboronate (274 mg), Pd(pddf)Cl2 (138 mg), and 1,4-dioxane (10 mL) were added to the reaction flask. The mixture was heated to 90 °C and reacted for 16 h. After the reaction was complete, water and ethyl acetate were added to quench the reaction. The organic phase was collected, dried, concentrated, and purified by column chromatography (petroleum ether:ethyl acetate = 5:1) before being used in the next step. LC-MS [M+H] + =279.

[0377] (4) Step 4:

[0378]

[0379] 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) were added, and the mixture was reacted at 35 °C for 12 h. The mixture was washed with water, the organic phase was concentrated, and the crude product was used directly in the next step. LC-MS [M+H] + =254.

[0380] (5) Step 5:

[0381]

[0382] Compound R46-4 (1 g), cyclopropylsulfonyl chloride (0.67 g), cesium carbonate (3.85 g), and DMF (20 mL) were added at room temperature. The mixture was reacted at 60 °C for 12 h. TLC (petroleum ether:ethyl acetate = 5:1) was performed, followed by extraction with water / ethyl acetate. The organic phase was concentrated and purified by column chromatography (petroleum ether:ethyl acetate = 10:1) before being used in the next step. LC-MS [M+H] + =358.

[0383] (6) Step 6:

[0384]

[0385] Compounds R46-5 (240 mg), R46-3 (238 mg), potassium carbonate (281 mg), Pd(pddf)Cl2 (140 mg), DME (8 mL), and H2O (2 mL) were added under nitrogen protection. The mixture was reacted at 90 °C for 16 h under nitrogen protection. The mixture was extracted with water / ethyl acetate, the organic phase was concentrated, and purified by column chromatography (petroleum ether:ethyl acetate = 3:1) to obtain the target product (13 mg). 1 HNMR (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.

[0386] Example 22 Synthesis of compound R27

[0387] (1) Step 1:

[0388]

[0389] The synthesis of R27-1 is as described in R5-1.

[0390] Compound R27-1 (0.2 g), cyclopropylsulfonyl chloride (0.133 g), DMF (10 mL) and cesium carbonate (0.8 g) were added at room temperature and reacted at room temperature for 5 h. The reaction was confirmed to be complete by MS. After post-treatment, the mixture was washed with water, the organic phase was concentrated, and purified by column chromatography (petroleum ether:ethyl acetate = 3:1) before being used in the next step.

[0391] (2) Step 2:

[0392]

[0393] At room temperature, compound R27-2 (0.18 g), 7-azaindole-4-boronic acid pinacol ester (0.123 g), potassium carbonate (0.207 g), tetra-triphenylphosphine palladium (0.1 g), water (10 mL), and 1,4-dioxane (1 mL) were added. The mixture was reacted at 100 °C for 12 h under nitrogen protection. After post-treatment, water was added, the mixture was stirred, extracted with ethyl acetate, the organic phase was concentrated, and purified by column chromatography (petroleum ether:ethyl acetate = 1:1) to obtain compound R27 (55 mg, 23%). 1HNMR(400 MHz, methanol-d4) δ 8.53 (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.

[0394] Example 23 Synthesis of compound R54

[0395] (1) Step 1:

[0396]

[0397] (R)-4-(2-chloro-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylmorpholine (0.1 g), methyl iodoform (0.112 g), and cesium carbonate (0.193 g) were added to DMF solution (5 mL), and the mixture was heated at 60 °C for 4 h. The reaction was monitored by TLC until completion. The reaction solution was poured into water (20 mL), extracted three times with ethyl acetate (20 mL), and the organic phase was washed three times with saturated sodium chloride aqueous solution (20 mL). The organic phase was dried and evaporated to dryness to obtain a yellow oil, R54-1 (94 mg, 89.5%). LC-MS [M+H] + =268.1.

[0398] (2) Step 2:

[0399]

[0400] Compound R54-1 (0.094 g), 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxane-2-yl)-1H-pyrazole (0.081 g), Pd(dppf)Cl2 (0.026 g), and potassium carbonate (0.092 g) were added to DCM (5 mL), and the mixture was stirred at 120 °C for 4 h. The reaction was monitored by TLC until complete. The reaction solution was added to water (20 mL), extracted three times with ethyl acetate (20 mL), and the organic phase was washed three times with saturated sodium chloride aqueous solution (20 mL). The organic phase was concentrated and purified by column chromatography (petroleum ether:ethyl acetate = 5:1) to give compound R54 (0.100 g, 90.9%) as a yellow solid. 1HNMR (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.

[0401] Example 24 Synthesis of compound R56

[0402] (1) Step 1:

[0403]

[0404] LiAlH4 (400 mg) was added to Me-THF (20 mL), and the temperature was lowered to approximately 0 °C. Methyl N-(2-benzimidazolyl)-carbamate (500 mg) was then added. The mixture was purged twice with nitrogen and reacted under nitrogen protection for 16 h. After the reaction was completed, the reaction solution was cooled to room temperature and then lowered to approximately 0 °C. 0.4 mL of 2M NaOH aqueous solution was slowly added, followed by 5 g of anhydrous sodium sulfate solid. The reaction solution was diluted with ethyl acetate (20 mL), filtered, and the filter cake was washed with ethyl acetate (10 mL). The filtrate was then evaporated by rotary evaporation to obtain a yellow solid (210 mg, 55%). LC-MS [M+H] + =148.1.

[0405] (2) Step 2:

[0406]

[0407] At room temperature, (R)-4-(2-chloro-9h-purin-6-yl)-3-methylmorpholine (200 mg) was added to a 25 mL single-necked flask, dissolved in DMF (20 mL). After cooling to approximately 0 °C, 40% NaH (63 mg) was added, and the reaction was carried out at 0 °C for 10 min. Cyclopropanesulfonyl chloride (113 mg) was then added, and the reaction mixture was allowed to return to room temperature for 30 min. TLC monitoring revealed that some reactants were not completely reacted. The reaction mixture was poured into water (50 mL), extracted three times with ethyl acetate (20 mL), and the organic phase was concentrated. Purification was achieved by column chromatography (petroleum ether:ethyl acetate = 3:1) to obtain a pale yellow solid (80 mg, yield 28%). LC-MS [M+H] + =357.1.

[0408] (3) Step 3:

[0409]

[0410] At room temperature, compound 56-2 (60 mg), SnCl2 (145 mg), trimethyl orthoformate (1 mL), anhydrous ethanol (5 mL), and 2 drops of concentrated hydrochloric acid were added to a 50 mL pressure-resistant bottle. The mixture was then heated to 90 °C and reacted for 5 h. The reaction was monitored by TLC until it was complete. After the reaction solution cooled to room temperature, it was poured into water (15 mL), and the pH was adjusted to 8 with a saturated sodium carbonate solution. The mixture was extracted three times with ethyl acetate (5 mL), the organic phase was concentrated, and purified by column chromatography (petroleum ether:ethyl acetate = 1:1) to give a light yellow solid (32 mg, yield 57%). 1 H NMR(400 MHz, DMSO) δ 8.87 (d, 1H), 8.81 (s, 1H), 8.16 (d, 1H), 8.05 (d, 1H), 7.29 (d, 1H), 7.11 (t, 1H), 7.0 1 (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.

[0411] Example 25 Synthesis of compound R57

[0412] (1) Step 1:

[0413]

[0414] At room temperature, 2.0 g of 4-bromo-7-azaindole, 3.4 g of m-chloroperoxybenzoic acid, and 160 mL of methyl tert-butyl ether were added, and the reaction was allowed to proceed for 12 h. The reaction solution was filtered, and the filter cake was washed with methyl tert-butyl ether to obtain a white solid, which was used directly in the next step. LC-MS [M+H] + =247.1.

[0415] (2) Step 2:

[0416]

[0417] Under nitrogen protection, compound R57-1 (2.04 g) and DMF (40 mL) were added to a reaction flask and heated to 50 °C. Then, methanesulfonyl chloride (2.6 g) was added, and the temperature was raised to 75 °C, reacting for 1 h. After the reaction was complete, the mixture was cooled to room temperature, and the reaction solution was added to ice water to lower the temperature to 0 °C. The pH was adjusted to 7 with 6N sodium hydroxide solution, and the mixture was stirred at room temperature for 3 h. The mixture was then filtered, the filter cake was washed with water, dried, and a white solid was obtained, which was directly used in the next step. LC-MS [M+H] + =231.1.

[0418] (3) Step 3:

[0419]

[0420] At room temperature, compound R57-2 (1.3 g), DMF (30 mL), cesium carbonate (4.1 g), and cyclopropylsulfonyl chloride (800 mg) were added to a reaction flask. The mixture was stirred at room temperature for 2 h, and TLC was monitored until the reactants were completely reacted. After finishing, water was added and stirred. The mixture was extracted with ethyl acetate, the organic phase was dried and concentrated, and purified by column chromatography (petroleum ether:ethyl acetate = 10:1) to obtain a white solid, which was directly used in the next step. LC-MS [M+H] + =335.1.

[0421] (4) Step 4:

[0422]

[0423] Compound R57-3 (252 mg), R-3-methylmorpholine (150 mg), potassium phosphate (480 mg), Pd(PPh3)4 (150 mg), and dioxane (6 mL) were added under nitrogen protection. The mixture was reacted at 120 °C for 16 h under nitrogen protection. The mixture was extracted with water / ethyl acetate, the organic phase was dried and concentrated, and purified by column chromatography (petroleum ether:ethyl acetate = 3:1) to give the target product (37 mg). LC-MS [M+H] + =356.1.

[0424] (5) Step 5:

[0425]

[0426] Compound R57-4 (37 mg), 7-azaindole-4-boronic acid pinacol ester (33 mg), potassium carbonate (43 mg), PdCl2 (dppf) (8 mg), DME (8 mL) and H2O (2 mL) were added under nitrogen protection. The mixture was reacted at 120 °C for 2 h, extracted with water / ethyl acetate, dried and concentrated the organic phase, and purified by column chromatography (dichloromethane:methanol = 100:1) to obtain compound R57 (18 mg). 1 HNMR (400MHz, DMSO-d6) 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.

[0427] Example 26 Synthesis of compound R58

[0428] (1) Step 1:

[0429]

[0430] (R)-4-(2-chloro-9H-purin-6-yl)-3-methylmorpholine (253 mg), pyridine 4-methyl-3-borate (160 mg), copper acetate (300 mg), and TEA (300 mg) were added to a 100 mL single-necked flask, followed by the addition of DCM (15 mL). The reaction was carried out at room temperature for 36 h. TLC monitoring showed product formation. The product was directly dried and purified by column chromatography (petroleum ether:ethyl acetate = 1:2) to give a pale yellow solid (30 mg, 8%). LC-MS [M+H] + =345.1.

[0431] (2) Step 2:

[0432]

[0433] Compound R58-1 (30 mg 0.087 g), 4-(4,4,5,5-tetramethyl-1,3,2-dioxane-2-yl)-1H-pyrrolo[2,3-b]pyridine (21 mg), Pd(dppf)Cl2 (7 mg), potassium carbonate (24 mg), and 1,4-dioxane / H2O = 5:1 (4 mL / 0.8 mL) were added to a 10 mL single-necked flask. The reaction was carried out at 100 °C for 16 h under nitrogen protection. The reaction was completed by TLC. The reaction solution was purified by column chromatography (petroleum ether:ethyl acetate = 1:4) to give a pale yellow solid (7 mg). 1 HNMR (400MHz, DMSO-d6) 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.

[0434] Example 27 Synthesis of compound R59

[0435] (1) Step 1:

[0436]

[0437] 2-Chloro-6-methylbenzoic acid (150 mg), oxaloyl chloride (167 mg), and a catalytic amount of DMF were stirred in DCM at room temperature for 1 h. After the reaction was complete as detected by TLC, DCM was removed by rotary evaporation to obtain compound R59-1.

[0438] (2) Step 2:

[0439]

[0440] (R)-4-(2-chloro-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylmorpholine (222 mg), 1.0 equivalent of compound R59-1, and DIPEA (170 mg) were reacted in DCM at room temperature with stirring for 2 h. After the reaction was complete as detected by TLC, the DCM was removed by rotation, the mixture was diluted with water, extracted twice with ethyl acetate, separated, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography (petroleum ether:ethyl acetate = 2:1-1:1) to give compound R59-2 as a white solid. LC-MS [M+H] + =405.1.

[0441] (3) Step 3:

[0442]

[0443] Compound R59-2 (60 mg), 7-azaindoleboronic acid pinacol ester (40 mg), and potassium carbonate (41 mg) were dissolved in 1,4-dioxane (10 mL) and H2O (2 mL) by stirring. Pd(dppf)Cl2 (11 mg) was added, and the reaction was carried out at 100 °C for 12 h under nitrogen protection. After the reaction was confirmed to be complete 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, 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 HNMR(400 MHz, 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.

[0444] Example 28 Synthesis of compound R60

[0445] (1) Step 1:

[0446]

[0447] (R)-4-(2-chloro-9H-purin-6-yl)-3-methylmorpholine (200 mg), 2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxobenzaldehyde-2-yl)pyridine (261 mg), Cu(OAc)2 (158 mg), TEA (161 mg), and 4W / W 4A molecular sieve were reacted in a DCM solution with stirring at room temperature for 18 h. After the reaction was complete as detected by TLC, the mixture was filtered, and the filtrate was removed by rotary evaporation. The residue was extracted with ethyl acetate and water, and the ethyl acetate layer was washed with saturated brine. The organic phase was dried under reduced pressure and purified by column chromatography (petroleum ether:ethyl acetate = 2:1-1:1) to give compound R60-1. LC-MS [M+H] + =345.1.

[0448] (2) Step 2:

[0449]

[0450] Compound R60-1 (80 mg), 7-azaindoleboronic acid pinacol ester (56 mg), and potassium phosphate (63 mg) were dissolved in 1,4-dioxane (5:1) by stirring. Pd(dppf)Cl2 (17 mg) was added, and the reaction was carried out at 100 °C for 12 h under nitrogen protection. After the reaction was confirmed to be complete 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, and purified by column chromatography (petroleum ether:ethyl acetate = 1:1-1:4). The target product was concentrated to obtain compound R60 (16 mg) as a pale yellow solid. 1 H NMR(400 MHz, 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.

[0451] Example 29 Synthesis of compound R62

[0452] (1) Step 1:

[0453]

[0454] At room temperature, 200 mg of 4-bromo-1H-pyrrolo[2,3-c]pyridine, 308 mg of pinacol diborate, 98 mg of potassium acetate, 73.2 mg of [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride, and 10 mL of 1,4-dioxane were added to a 50 mL round-bottom flask. The mixture was purged with nitrogen three times and reacted overnight at 120 °C. After cooling to room temperature, the mixture was filtered, and the filter cake was washed twice with 50 mL of ethyl acetate. The solution was concentrated and purified by column chromatography to give compound R62-1 (140 mg). LC-MS [M+H] + =245.1.

[0455] (2) Step 2:

[0456]

[0457] At room temperature, compound R62-1 (68 mg), azidoindole borate (50 mg), potassium carbonate (58 mg), [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride (19.7 mg), and 1,4-dioxane (10 mL) / water (2 mL) were added, purged with nitrogen three times, and reacted at 100 °C for 16 h. 50 mL of water and 50 mL of ethyl acetate were added to the reaction mixture, and the mixture was separated. The extracts were then extracted twice with ethyl acetate (50 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and purified by column chromatography (petroleum ether:ethyl acetate = 1:1-1:0) to obtain compound R62 (15 mg, 18%). 1 HNMR (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), 5.5 6 (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.

[0458] Example 30 Synthesis of compound R63

[0459] (1) Step 1:

[0460]

[0461] (R)-4-(2-chloro-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylmorpholine (253 mg), pyridine 3-methyl-4-borate (160 mg), copper acetate (300 mg), and TEA (300 mg) were added to a 100 mL single-necked flask, followed by 15 mL of DCM. The reaction was carried out at room temperature for 36 h. TLC monitoring showed product formation. The product was directly dried and purified by column chromatography (petroleum ether:ethyl acetate = 1:2) to give a pale yellow solid (30 mg, 8%). LC-MS [M+H] + =344.1.

[0462] (2) Step 2:

[0463]

[0464] Compound R63-1 (30 mg), azidoindole borate (29 mg), Pd(dppf)Cl2 (13 mg), potassium carbonate (24 mg), and 1,4-dioxane / H2O 5:1 (4 mL / 0.8 mL) were added to a 10 mL single-necked flask. The reaction was carried out at 100 °C under nitrogen protection for 16 h. The reaction was confirmed to be complete by TLC. The reaction solution was purified by column chromatography (petroleum ether:ethyl acetate = 1:5) to give compound R63 (7 mg, 18%) as a pale yellow solid. 1 HNMR (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.

[0465] Example 31 Synthesis of compound R64

[0466] (1) Step 1:

[0467]

[0468] (R)-4-(2-chloro-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylmorpholine (200 mg), 4-purineboronic acid (202 mg), Cu(OAc)2 (160 mg), TEA (160 mg), and 4W / W 4A molecular sieve were reacted in a DCM solution with stirring at room temperature for 18 h. After the reaction was complete as detected by TLC, the filtrate was removed by vacuum filtration and rotary evaporation. The residue was extracted with ethyl acetate and water. The ethyl acetate 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 give compound R64-1. LC-MS [M+H] + =380.1.

[0469] (2) Step 2:

[0470]

[0471] Compound R64-1 (30 mg), 7-azaindoleboronic acid pinacol ester (21 mg), and potassium phosphate (22 mg) were dissolved in 1,4-dioxane (10 mL) and H2O (2 mL) by stirring. Pd(dppf)Cl2 (6 mg) was added, and the reaction was carried out at 100 °C for 12 h under nitrogen protection. After the reaction was completed 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, 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 HNMR (400MHz, CDCl3) 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.

[0472] Example 32 Synthesis of compound R65

[0473] (1) Step 1:

[0474]

[0475] At room temperature, (R)-4-(2-chloro-9H-purin-6-yl)-3-methylmorpholine (300 mg), pinacol 4-pyridineborate (365 mg), copper acetate (322 mg), and TEA (0.5 mL) were added to a 25 mL single-necked flask, dissolved in DCM (15 mL), and molecular sieves were added. The reaction mixture was allowed to react openly for 16 h. After filtration through diatomaceous earth, the mixture was evaporated to dryness and purified by column chromatography (petroleum ether:ethyl acetate = 1:1 to 1:1 + 1% methanol) to give compound R65-1 (180 mg, 45%) as a white solid. LC-MS [M+H] + =331.1.

[0476] (2) Step 2:

[0477]

[0478] Compound R65-1 (140 mg), N-methyl-1H-benzo[d]imidazol-2-amine (80 mg), Pd(OAc)2 (20 mg), BINAP (40 mg), and K2CO3 (116 mg) were added sequentially to a 25 mL single-necked flask. 12 mL of redistilled 1,4-dioxane was added, and the mixture was reacted at 97 °C for 5 h. After cooling to room temperature, the mixture was purified by column chromatography (DCM:ethyl acetate:methanol = 100:20:1 to 100:100:2) to obtain compound R65 (60 mg, 32%) as a pale yellow solid. 1 HNMR (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.

[0479] Example 33 Synthesis of compound R66

[0480] (1) Step 1:

[0481]

[0482] Compound (R)-4-(2-chloro-9H-purin-6-yl)-3-methylmorpholine (200 mg), pyridine 2-methyl-5-borate (125 mg), copper acetate (235 mg), and TEA (300 mg) were added to a 100 mL single-necked flask, followed by 10 mL of DCM. The reaction was carried out at room temperature for 16 h. TLC monitoring showed product formation. Copper acetate and molecular sieves were removed by filtration. The reaction solution was concentrated and purified by column chromatography (petroleum ether:ethyl acetate = 2:1) to give compound R66-1 (30 mg, 15%) as a pale yellow solid. LC-MS [M+H] + =345.1.

[0483] (2) Step 2:

[0484]

[0485] Compound R66-1 (30 mg), azidoindole borate (29 mg), Pd(dppf)C12 (13 mg), potassium carbonate (24 mg), and 1,4-dioxane / H2O (5:1, 4 mL / 0.8 mL) were added to a 10 mL single-necked flask. The reaction was carried out at 100 °C for 16 h under a nitrogen atmosphere. The reaction was detected by TLC to indicate completion. The reaction solution was prepared into a slurry and purified by column chromatography (petroleum ether:ethyl acetate = 1:1 with 1% methanol) to remove impurities. Then, a second spot was obtained by CH2Cl2:MeOH = 30:1. The slurry was stirred with petroleum ether:ethyl acetate = 5:1 and filtered to obtain a pale yellow solid compound R66 (13 mg, 34%). 1 HNMR (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.

[0486] Example 34 Synthesis of compound R67

[0487] (1) Step 1:

[0488]

[0489] In a 100 mL single-necked flask, (R)-4-(2-chloro-7-(cyclopropylsulfonyl)-7Hpyrrolo[2,3-d]pyrimidin-4-yl)-3-methylmorpholine (356 mg), 2-methyl-1H-benzis[d]imidazole (393 mg), Pd(dppf)Cl2 (438 mg), BINAP (746 mg), and K2CO3 (414 mg) were added, followed by the addition of DMF (5 mL). The reaction was carried out at 100 °C under nitrogen protection for 16 h. TLC monitoring showed product formation. The product was extracted with ethyl acetate, dried, and purified by column chromatography (petroleum ether:ethyl acetate = 1:4) to give 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.

[0490] Example 35 Synthesis of compound R68

[0491]

[0492] (R)-4-(2-chloro-7-(cyclopropylsulfonyl)-7Hpyrrolo[2,3-d]pyrimidin-4-yl)-3-methylmorpholine (50 mg), indole-4-boronic acid pinacol ester (34 mg), and potassium carbonate (39 mg) were dissolved in 1,4-dioxane (10 mL) and H2O (2 mL) by stirring. Pd(dppf)Cl2 (10 mg) was added, and the reaction was carried out at 100 °C for 12 h under nitrogen protection. After the reaction was confirmed to be complete 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, and purified by column chromatography (petroleum ether:ethyl acetate = 1:1-1:4) to obtain compound R68 (20 mg, 32%) as a white solid. 1H 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.

[0493] Example 36 Synthesis of compound R71

[0494] (1) Step 1:

[0495]

[0496] 2,6-Dichloro-9H-purine (1.88 g), triethylamine (2.02 g), and (R)-3-methylmorpholine (1.11 g) were added to DMF (30 mL) and stirred overnight at 90 °C. After cooling to room temperature, the mixture was extracted three times with ethyl acetate. The ethyl acetate phase was washed with saturated brine, dried, and purified by column chromatography (petroleum ether:ethyl acetate = 2:1) to give compound R71-1 (2 g, 79%) as a white solid. LC-MS [M+H] + =254.

[0497] (2) Step 2:

[0498]

[0499] Compound R71-1 (506 mg), Cs₂CO₃ (1.95 g), and cyclopropylsulfonyl chloride (420 mg) were added to DMF (15 mL) and stirred at 60 °C for 1 h. After cooling to room temperature, the mixture was extracted three times with ethyl acetate. The ethyl acetate phase was washed with saturated brine, dried, and purified by column chromatography (petroleum ether:ethyl acetate = 1:1) to give compound R71-2 (500 mg, 70%) as a white solid. LC-MS [M+H] + =358.

[0500] (3) Step 3:

[0501]

[0502] Compound R71-2 (178 mg), 7-azaindole borate (244 mg), Pd(dppf)Cl2 (73 mg), and K2CO3 (207 mg) were added to 1,4-dioxane:H2O = 5:1 (3 mL), and the mixture was reacted overnight at 100 °C under nitrogen protection. After cooling to room temperature, the mixture was extracted three times with ethyl acetate, washed with saturated brine, dried, and purified by column chromatography (petroleum ether:ethyl acetate = 1:4) to give compound R71 (10 mg, 4%) as a white solid. 1 HNMR (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.

[0503] Example 37 Synthesis of compound R72

[0504]

[0505] (1) Step 1:

[0506]

[0507] Carbendazim (1.91 g) was added to THF (100 mL), and then LAH (1.9 g) was added in portions to the mixture at 0 °C. The mixture was heated under reflux and stirred overnight under nitrogen protection. The temperature was lowered to 0 °C, and H₂O (1.9 mL), 15% NaOH aqueous solution (1.9 mL), and H₂O (5.7 mL) were added sequentially at 5-min intervals, with stirring continued for 2 h. The resulting mixture was filtered, and the filter cake was washed twice with ethyl acetate. The filtrate was evaporated to dryness to give compound R72-1 (1.2 g, yield 81%) as a white solid. LC-MS [M+H] + =148.

[0508] (2) Step 2:

[0509]

[0510] The synthesis of compound R72-2 was performed using the same method as that for compound R71-2. Compound R72-1 (178 mg), compound R72-2 (220 mg), Pd(AcO)2 (22 mg), BINAP (124 mg), and K2CO3 (207 mg) were added to 3 mL of dry DMF and reacted overnight at 100 °C under nitrogen protection. After cooling to room temperature, the mixture was extracted three times with ethyl acetate, washed with saturated brine, dried, and purified by column chromatography (petroleum ether:ethyl acetate = 1:4) to give compound R72 (10 mg, 2%) as a white solid. 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.

[0511] Example 38 Synthesis of compound R73

[0512]

[0513] (1) Step 1:

[0514]

[0515] 4,6-Dichloro-1H-pyrazolo[3,4-d]pyrimidine (1 g), (R)-3-methylmorpholine (757 mg), and triethylamine (1 g) were reacted in DCM with stirring at room temperature for 12 h. After the reaction was complete as detected by TLC, the organic phase was dried by rotary evaporation and purified by column chromatography (petroleum ether:ethyl acetate = 3:1-2:1) to give compound R73-1 (600 mg, 47%) as a pale yellow solid. LC-MS [M+H] + =254.

[0516] (2) Step 2:

[0517]

[0518] Compound R73-1 (150 mg), cyclopropylsulfonyl chloride (108 mg), and CS2CO3 (385 mg) were reacted in DMF at room temperature with stirring for 3 h. After the reaction was complete as detected by TLC, the reaction solution was extracted with ethyl acetate and water. The ethyl acetate layer was washed with saturated brine, and the organic phase was dried by rotary evaporation. The mixture was purified by column chromatography (petroleum ether:ethyl acetate = 2:1-1:1) to give compound R73-2 (150 mg, 70%) as a pale yellow solid. LC-MS [M+H] + =358.

[0519] (3) Step 3:

[0520]

[0521] Compound R73-2 (50 mg), N-methyl-1H-benzo[d]imidazol-2-amine (31 mg), BINAP (17 mg), palladium acetate (7 mg), and potassium carbonate (38 mg) were reacted in 1,4-dioxane at 100 °C for 12 h under N2 protection. After the reaction was complete as detected by TLC, the solvent was concentrated under reduced pressure, the residue was added to water, and extracted twice with ethyl acetate. The ethyl acetate phase was dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (petroleum ether:ethyl acetate = 1:1-1:4) to give compound R73 (6 mg, 9%) as a pale yellow solid. 1 HNMR (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.

[0522] Example 39 Synthesis of compound R74

[0523]

[0524] (1) Step 1:

[0525]

[0526] 2,4-Dichloro-7H-pyrrolo[2,3-d]pyrimidine (935 mg), pyridine (1.18 g), and N-methylpyrazolone ester (1560 mg) were added to DCM (15 mL) and stirred at room temperature for 72 h. The mixture was filtered, the filter cake was washed with DCM, and the filtrate was washed with dilute hydrochloric acid. The filtrate was washed three times with saturated brine, dried, and purified by column chromatography (petroleum ether:ethyl acetate = 1:1) to give compound R74-1 (0.23 g, 17%) as a white solid. LC-MS [M+H] + =268.

[0527] (2) Step 2:

[0528]

[0529] Compound R74-1 (133 mg) and (R)-3-methylmorpholine (55 mg) were added to DMSO / H2O (10:1, 3 mL) and stirred overnight at 60 °C. The mixture was extracted three times with ethyl acetate, the ethyl acetate phase was washed with saturated brine, dried, and purified by column chromatography (petroleum ether:ethyl acetate = 1:2) to give compound R74-2 (100 mg, 60%) as a white solid. LC-MS [M+H] + =333.

[0530] (3) Step 3:

[0531]

[0532] Compound R74-2 (83 mg), N-methyl-1H-benzo[d]imidazol-2-amine (110 mg), Pd(AcO)2 (11 mg), BINAP (62 mg), and K2CO3 (104 mg) were added to dry DMF (3 mL), and the mixture was reacted overnight at 100 °C under nitrogen protection. After cooling to room temperature, the mixture was extracted three times with ethyl acetate, washed with saturated brine, dried, and purified by column chromatography (petroleum ether:ethyl acetate = 1:4) to give compound R74 (10 mg, 4%) as a white solid. 1 HNMR (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.

[0533] Example 40 Synthesis of compound R75

[0534]

[0535] (1) Step 1:

[0536]

[0537] 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) and stirred overnight at 90 °C. After cooling to room temperature, the mixture was extracted three times with ethyl acetate. The ethyl acetate phase was washed with saturated brine, dried, and purified by column chromatography (petroleum ether:ethyl acetate = 2:1) to give compound R75-1 (2 g, 79%) as a white solid. LC-MS [M+H] + =253.

[0538] (2) Step 2:

[0539]

[0540] Compound R75-1 (1008 mg), Cs₂CO₃ (3.9 g), and benzenesulfonyl chloride (1056 mg) were added to ACN (15 mL) and stirred at 60 °C for 3 h. After cooling to room temperature, the mixture was extracted three times with ethyl acetate. The ethyl acetate phase was washed with saturated brine, dried, and purified by column chromatography (petroleum ether:ethyl acetate = 1:1) to give compound R75-2 (1200 mg, 76%) as a white solid. LC-MS [M+H] + =393.

[0541] (3) Step 3:

[0542]

[0543] Compound R75-2 (1176 mg), N-methyl-1H-benzo[d]imidazol-2-amine (1323 mg), Pd(AcO)2 (132 mg), BINAP (747 mg), and K2CO3 (1242 mg) were added to 1,4-dioxane (15 mL), and the mixture was reacted overnight at 100 °C under nitrogen protection. After cooling to room temperature, the mixture was extracted three times with ethyl acetate, washed with saturated brine, dried, and purified by column chromatography (petroleum ether:ethyl acetate = 1:4) to give compound R75-3 (500 mg, 33%) as a white solid. LC-MS [M+H] + =503.

[0544] (4) Step 4:

[0545]

[0546] Compound R75-3 (252 mg) and Pd / C (100 mg) were added to 3 mL of dry EtOH, and then reacted at 60 °C for 72 h under a hydrogen atmosphere. The mixture was filtered and purified by column chromatography (petroleum ether:ethyl acetate = 1:3) to give compound R75-4 (150 mg, 59%) as a white solid. LC-MS [M+H] + =505.

[0547] (5) Step 5:

[0548]

[0549] Compound R75-4 (101 mg) and MeONa (108 mg) were added to EtOH / H2O (1:1, 3 mL) and reacted at 90 °C for 24 h. After cooling to room temperature, the mixture was extracted three times with ethyl acetate, washed with saturated brine, dried, and purified by column chromatography (petroleum ether:ethyl acetate = 1:4) to give compound R75-5 (50 mg, 68%) as a white solid. LC-MS [M+H] + =366.

[0550] (6) Step 6:

[0551]

[0552] Compound R75-5 (36 mg) and cyclopropanesulfonyl chloride (42 mg) were added to dry pyridine (3 mL), and the mixture was reacted overnight at 100 °C. After cooling to room temperature, the mixture was extracted three times with ethyl acetate, the ethyl acetate phase was washed with dilute hydrochloric acid, dried, and purified by column chromatography (petroleum ether:ethyl acetate = 1:4) to give compound R75 (10 mg, 20%) as a white solid. 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.

[0553] Example 41 Synthesis of compound R76

[0554]

[0555] (1) Step 1:

[0556]

[0557] (R)-3-methylmorpholine (444 mg) and triethylamine (444 mg) were added to DMF (15 mL). Then, the mixture was added dropwise to DMF (20 mL) containing 2,4,6-trichloro-5-nitropyrimidine (1 g) at 0 °C, and stirred at room temperature for 1 h. The mixture was extracted three times with ethyl acetate, washed with saturated brine, dried, and purified by column chromatography (petroleum ether:ethyl acetate = 10:1) to give compound R76-1 (1.2 g, 93%) as a pale yellow solid. LC-MS [M+H] + =293.

[0558] (2) Step 2:

[0559]

[0560] Compound R76-1 (292 mg), 1-methyl-1H-pyrazole-5-amine (194 mg), CsCO3 (975 mg), and ACN (3 mL) were added to a 100 mL single-necked flask. The reaction was carried out at 60 °C for 4 h. The reaction solution was prepared as a slurry and purified by column chromatography (petroleum ether:ethyl acetate = 1:2) to give compound R76-2 (180 mg, 51%) as a pale yellow solid. LC-MS [M+H] + =354.

[0561] (3) Step 3:

[0562]

[0563] Compound R76-2 (180 mg) was dissolved in ethanol (3 mL), followed by the addition of SnCl2 (385 mg), concentrated hydrochloric acid (0.5 mL), and trimethyl orthoformate (2 mL). The mixture was stirred overnight at 90 °C and then cooled to room temperature. The solution was adjusted to alkali with sodium bicarbonate, and the mixture was extracted three times with ethyl acetate. The ethyl acetate phase was washed with saturated brine, dried, and purified by column chromatography (petroleum ether:ethyl acetate = 1:1) to give compound R76-3 (40 mg, 23%) as a pale yellow solid. LC-MS [M+H] + =334.

[0564] (4) Step 4:

[0565]

[0566] 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 K2CO3 (50 mg) were added to 3 mL of dry DMF, and the mixture was reacted overnight at 100 °C under nitrogen protection. After cooling to room temperature, the mixture was extracted three times with ethyl acetate, and the ethyl acetate phase was washed with saturated brine and purified by column chromatography (petroleum ether:ethyl acetate = 1:4) to give compound R76 (10 mg, 18%) as a dark white solid. 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.

[0567] Example 42 Synthesis of compound R77

[0568]

[0569] (1) Step 1:

[0570]

[0571] Compound 2,4-dichloropyrrolo[2,1-f][1,2,4]triazine (935 mg), K₂CO₃ (2.07 g), and (R)-3-methylmorpholine (555 mg) were added to DMF (15 mL) and stirred at room temperature for 1 h. The mixture was extracted three times with ethyl acetate, washed with saturated brine, and purified by column chromatography (petroleum ether:ethyl acetate = 10:1) to give compound R77-1 (1.2 g, 95%) as a pale yellow solid. LC-MS [M+H] + =253.

[0572] (2) Step 2:

[0573]

[0574] Compound R77-1 (1.0 g) was added to DMF (15 mL), followed by NIS (1.8 g), and stirred overnight at room temperature. The mixture was extracted three times with ethyl acetate, washed with saturated brine, dried, and purified by column chromatography (petroleum ether:ethyl acetate = 10:1) to give compound R77-2 (1.2 g, 79%) as a pale yellow solid. LC-MS [M+H] + =379.

[0575] (3) Step 3:

[0576]

[0577] Compound R77-2 (378 mg), N-methylpyrazolonic acid (150 mg), Pd(dppf)Cl2 (140 mg), and K2CO3 (410 mg) were added to a mixture of 1,4-dioxane / H2O = 5:1 (3 mL). The mixture was stirred at 100 °C under nitrogen protection for 3 h, and then cooled to room temperature. The mixture was extracted three times with ethyl acetate, and the ethyl acetate phase was washed with saturated brine, dried, and purified by column chromatography (petroleum ether:ethyl acetate = 1:1) to give compound R77-3 (270 mg, 78%) as a pale yellow solid. LC-MS [M+H] + =347.

[0578] (4) Step 4:

[0579]

[0580] Compound R77-3 (166 mg), N-methyl-1H-benzo[d]imidazol-2-amine (220 mg), Pd(AcO)2 (22 mg), BINAP (124 mg), and K2CO3 (207 mg) were added to anhydrous DMF (3 mL), and the mixture was reacted overnight at 100 °C under nitrogen protection. After cooling to room temperature, the mixture was extracted three times with ethyl acetate, washed with saturated brine, dried, and purified by column chromatography (petroleum ether:ethyl acetate = 1:4) to give compound R77 (10 mg, 4%) as a white solid. 1 HNMR (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.

[0581] Example 43 Synthesis of compound R78

[0582]

[0583] (1) Step 1:

[0584]

[0585] Compound R78-1 (378 mg), CuI (380 mg), and sodium cyclopropane sulfinate (140 mg) were added to DMSO (3 mL), stirred at 120 °C under nitrogen protection for 3 h, and then cooled to room temperature. The mixture was extracted three times with ethyl acetate, the ethyl acetate phase was washed with saturated brine, dried, and purified by column chromatography (petroleum ether:ethyl acetate = 1:1) to give compound R78-2 (270 mg, 75%) as a pale yellow solid. LC-MS [M+H] + =357.

[0586] (2) Step 2:

[0587]

[0588] Compound R78-2 (178 mg), N-methyl-1H-benzo[d]imidazol-2-amine (220 mg), Pd(AcO)2 (22 mg), BINAP (124 mg), and K2CO3 (207 mg) were added to anhydrous DMF (3 mL), and the mixture was reacted overnight at 100 °C under nitrogen protection. After cooling to room temperature, the mixture was extracted three times with ethyl acetate, washed with saturated brine, dried, and purified by column chromatography (petroleum ether:ethyl acetate = 1:4) to give compound R78 (10 mg, 2%) as a white solid. 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, 2 H), 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.

[0589] Example 44 Synthesis of compound R80

[0590]

[0591] (1) Step 1:

[0592]

[0593] (R)-4-(2-chloro-7-iodopyrrole[2,1-f][1,2,4]triazin-4-yl)-3-methylmorpholine (378 mg), CuI (380 mg), and sodium methanesulfinate (140 mg) were added to DMSO and stirred at 120 °C under nitrogen protection for 3 h, then cooled to room temperature. The mixture was extracted three times with ethyl acetate, washed with saturated brine, dried, and purified by column chromatography (petroleum ether:ethyl acetate = 1:1) to give compound R80-1 (270 mg, 75%) as a pale yellow solid. LC-MS [M+H] + =331.

[0594] (2) Step 2:

[0595]

[0596] Compound R80-1 (178 mg), N-methyl-1H-benzo[d]imidazol-2-amine (220 mg), palladium acetate (22 mg), BINAP (124 mg), and K2CO3 (207 mg) were added to ultra-dry DMF and reacted overnight at 100 °C under nitrogen protection. After cooling to room temperature, the mixture was extracted three times with ethyl acetate, washed with saturated brine, dried, and purified by column chromatography (petroleum ether:ethyl acetate = 1:4) to give compound R80 (10 mg, 2%) as a white solid. 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.

[0597] Example 45 Synthesis of compound R81

[0598]

[0599] (1) Step 1:

[0600]

[0601] (R)-4-(6-chloro-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-3-methylmorpholine (150 mg), 1-methylcyclopropane-1-sulfonyl chloride (118 mg), and CS₂CO₃ (385 mg) were reacted in DMF at room temperature for 3 h. After the reaction was complete as detected by TLC, the mixture was diluted with water, extracted twice with ethyl acetate, separated, and the ethyl acetate phase was washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography (petroleum ether:ethyl acetate = 1:1) to give compound R81-1 (200 mg, 91%) as a pale yellow solid. LC-MS [M+H] + =372.

[0602] (2) Step 2:

[0603]

[0604] Compound R81-1 (100 mg), N-methyl-1H-benzo[d]imidazol-2-amine (84 mg), BinAP (48 mg), Pd(OAc)2 (18 mg), and potassium phosphate (74 mg) were dissolved in 1,4-dioxane with stirring. The mixture was reacted at 100 °C for 12 h under N2 protection. After the reaction was complete as detected by TLC, the solvent was concentrated under reduced pressure. The residue was added to water and extracted twice with ethyl acetate. The ethyl acetate phase was dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (petroleum ether:ethyl acetate = 1:1-1:4) to give 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.

[0605] Example 46 Synthesis of compound R82

[0606]

[0607] (1) Step 1:

[0608]

[0609] (R)-4-(6-chloro-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-3-methylmorpholine (200 mg) was reacted with bromocyclopentane (234 mg), CS2CO3 (515 mg), and KI (40 mg) in DMF under reflux and stirring overnight. After the reaction was complete as detected by TLC, water was added for dilution, and the mixture was extracted twice with ethyl acetate. The liquid phase was separated, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography (petroleum ether:ethyl acetate = 1:1) to give the oily compound R82-1 (230 mg, 89%). LC-MS [M+H] + =322.

[0610] (2) Step 2:

[0611]

[0612] Compound R82-1 (160 mg), N-methyl-1H-benzo[d]imidazol-2-amine (84 mg), BinAP (58 mg), Pd(OAc)2 (58 mg), and potassium phosphate (129 mg) were dissolved in 1,4-dioxane by stirring. The mixture was reacted at 100 °C for 12 h under N2 protection. After the reaction was complete as detected by TLC, the solvent was concentrated under reduced pressure. The residue was added to water and extracted twice with ethyl acetate. The ethyl acetate phase was dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (petroleum ether:ethyl acetate = 1:1-1:4) to give 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.

[0613] Example 47 Synthesis of compound R83

[0614]

[0615] (1) Step 1:

[0616]

[0617] (R)-4-(2-chloro-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylmorpholine (500 mg) was dissolved in DMF, and NaH (119 mg) was added at 0 °C. After reacting at room temperature for 30 min, chloromethyl methyl sulfide (282 mg) was slowly added, and the reaction was allowed to proceed overnight at room temperature. After the reaction was confirmed to be complete by TLC, the mixture was quenched with aqueous NH4Cl solution, extracted twice with ethyl acetate, separated, and the ethyl acetate phase was washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography (petroleum ether:ethyl acetate = 1:1) to give the oily compound R83-1 (260 mg, 41%). LC-MS [M+H] + =313.

[0618] (2) Step 2:

[0619]

[0620] Compound R83-1 (400 mg) was reacted with mCPBA (443 mg) in DCM at room temperature for 3 h. After the reaction was complete as detected by TLC, the mixture was purified by column chromatography (petroleum ether:ethyl acetate = 1:1) to give compound R83-2 (200 mg, 45%). LC-MS [M+H] + =345.

[0621] (3) Step 3:

[0622]

[0623] Compound R83-2 (50 mg) was reacted with DMF solution, and NaH (12 mg) was added at 0 °C. After reacting at room temperature for 30 min, iodomethane (63 mg) was added, and the reaction was continued at room temperature for 1 h. Then, NaH (12 mg) was added again at 0 °C, and the reaction was continued at room temperature for 30 min. Iodomethane (63 mg) was added again, and the reaction was continued at room temperature for 1 h. After the reaction was confirmed to be complete by LC-MS, NH4Cl aqueous solution was added to quench the reaction. Ethyl acetate was added and extracted twice. The mixture was separated, the ethyl acetate phase was washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography (petroleum ether:ethyl acetate = 1:1) to obtain compound R83-3 (27 mg, 51%). LC-MS [M+H] + =373.

[0624] (4) Step 4:

[0625]

[0626] Compound R83-3 (30 mg), N-methyl-1H-benzo[d]imidazol-2-amine (15 mg), BinAP (12 mg), Pd(OAc)2 (22 mg), and potassium phosphate (22 mg) were dissolved in 1,4-dioxane with stirring. The mixture was reacted at 100 °C for 12 h under N2 protection. After the reaction was complete as detected by TLC, the solvent was concentrated under reduced pressure. The residue was added to water and extracted twice with ethyl acetate. The ethyl acetate phase was dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (petroleum ether:ethyl acetate = 1:1-1:4) to give 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.

[0627] Example 48 Synthesis of compound R84

[0628]

[0629] (1) Step 1:

[0630]

[0631] (R)-4-(2-chloro-7-iodopyrrole[2,1-f][1,2,4]triazin-4-yl)-3-methylmorpholine (100 mg), 5-(4,4,5,5-tetramethyl-1,3,2-dioxobenzaldehyde-2-yl)-1H-pyrazole (56 mg), K2CO3 (72 mg), and Pd(dppf)Cl2 (20 mg) were reacted overnight at 100 °C in dioxane / H2O with stirring. After the reaction was complete as detected by TLC, water was added for dilution, and the mixture was extracted twice with ethyl acetate. The mixture was separated, the ethyl acetate phase was washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography (petroleum ether:ethyl acetate = 1:1-1:2) to give compound R84-1 (50 mg, 60%) as a light yellow solid. LC-MS [M+H] + =319.

[0632] (2) Step 2:

[0633]

[0634] Compound R84-1 (60 mg), 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxane-2-yl)-1H-pyrazole (59 mg), K2CO3 (52 mg), and Pd(dppf)Cl2 (14 mg) were dissolved in dioxane / H2O with stirring. The mixture was reacted at 110 °C for 12 h under N2 protection. After the reaction was complete as detected by TLC, the solvent was concentrated under reduced pressure. The residue was added to water and extracted twice with ethyl acetate. The ethyl acetate phase was dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (petroleum ether:ethyl acetate = 1:1-1:4) to give compound R84 (16 mg, 26%) as a light 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.

[0635] Example 49 Synthesis of compound R86

[0636]

[0637] (1) Step 1:

[0638]

[0639] (R)-4-(2-chloro-7-iodopyrrole[2,1-f][1,2,4]triazin-4-yl)-3-methylmorpholine (0.5 g) and anhydrous tetrahydrofuran (10 mL) were added at room temperature under nitrogen protection. The mixture was stirred and cooled to T < -78 °C. Isopropyl magnesium chloride-lithium chloride complex (5 mL, 1.3 M / L) was added dropwise, and the temperature was maintained at T < -75 °C. After the addition was complete, the mixture was stirred at this temperature for 1 h. Tetrahydrofuran-3-carboxaldehyde was then added dropwise, and the temperature was maintained at T < -75 °C. After the addition was complete, the mixture was stirred at this temperature for 1 h. The starting material disappeared by TLC. Saturated ammonium chloride solution (5 mL) was added dropwise, and the mixture was allowed to rise naturally to room temperature. Ethyl acetate (10 mL) was added, and the mixture was stirred for 30 min. The organic phase was dried and concentrated, and purified by column chromatography (petroleum ether:ethyl acetate = 1:1). Then, the mixture was transferred to the next step. LC-MS [M+H] + =353.

[0640] (2) Step 2:

[0641]

[0642] Compound R86-1 (0.14 g) and DMF (3 mL) were added at room temperature, and the mixture was stirred until T < 0 °C. NaH (0.032 g) was added, and the mixture was allowed to naturally warm to room temperature for 1 h. Iodomethane (0.068 g) was added, and the mixture was reacted at room temperature for 1.5 h. TLC (petroleum ether:ethyl acetate = 1:1) was performed. After post-treatment, water (10 mL) and ethyl acetate (20 mL) were added, and the mixture was stirred. The organic phase was dried and concentrated, and purified by column chromatography (petroleum ether:ethyl acetate = 2:1) to obtain compound R86-2 (90 mg, 62%). LC-MS [M+H] + =367.

[0643] (3) Step 3:

[0644]

[0645] Compound R86-2 (0.09 g), N-methyl-1H-benzimidazole-2-amine (0.043 g), BINAP (0.06 g), palladium acetate (0.02 g), DMF (5 mL), and cesium carbonate (0.159 g) were added at room temperature. Under nitrogen protection, the mixture was heated to 135 °C and reacted overnight. After post-treatment, the mixture was washed with water, extracted with ethyl acetate, dried and concentrated in the organic phase, and purified by column chromatography (DCM:MeOH = 100:1) to obtain 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.

[0646] Example 50 Synthesis of compound R87

[0647]

[0648] (1) Step 1:

[0649]

[0650] (R)-4-(2-chloro-7-iodopyrrole[2,1-f][1,2,4]triazin-4-yl)-3-methylmorpholine (378 mg) was added to ultradry THF (10 mL) and cooled to -78 °C. Then, n-BuLi (THF, aq., 2.5 N, 0.5 mL) was added dropwise, and the mixture was stirred at -78 °C for 20 min. Then, excess 2,2-dimethyltetrahydro-4H-pyran-4-one was added dropwise, and stirring continued for 30 min. The mixture was then quenched with NH4Cl (aq.), extracted three times with ethyl acetate, washed with saturated brine, dried, and purified by column chromatography (petroleum ether:ethyl acetate = 1:1) to give a colorless oily compound R87-1 (160 mg, 42%). LC-MS [M+H] + =381.

[0651] (2) Step 2:

[0652]

[0653] Compound R87-1 (160 mg), N-methyl-1H-benzo[d]imidazol-2-amine (188 mg), palladium acetate (19 mg), BINAP (104 mg), and K2CO3 (174 mg) were added to ultradry DMF (3 mL), and the mixture was reacted overnight at 100 °C under nitrogen protection. After cooling to room temperature, the mixture was extracted three times with ethyl acetate, washed with saturated brine, dried, and purified by column chromatography (petroleum ether:ethyl acetate = 1:4) to give compound R87 (10 mg, 4%) as a white solid. 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), 3.9 8(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.

[0654] Example 51 Synthesis of compound R88

[0655]

[0656] (1) Step 1:

[0657]

[0658] (R)-4-(2-chloro-7-iodopyrrole[2,1-f][1,2,4]triazin-4-yl)-3-methylmorpholine (378 mg), CuI (380 mg), isothiazolidine 1,1-dioxide (140 mg), and trans-N,N′-dimethyl-1,2-cyclohexanediamine (282 mg) were added to DMSO (3 mL). The mixture was stirred at 130 °C under nitrogen protection for 3 h, and then cooled to room temperature. The mixture was extracted three times with ethyl acetate, and the ethyl acetate phase was washed with saturated brine, dried, and purified by column chromatography (petroleum ether:ethyl acetate = 1:1) to give compound R88-1 (200 mg, 75%) as a pale yellow solid. LC-MS [M+H] + =372.

[0659] (2) Step 2:

[0660]

[0661] Compound R88-1 (178 mg), N-methyl-1H-benzo[d]imidazol-2-amine (220 mg), palladium acetate (22 mg), BINAP (124 mg), and K2CO3 (207 mg) were added to ultra-dry DMF and reacted overnight at 100 °C under nitrogen protection. After cooling to room temperature, the mixture was extracted three times with ethyl acetate, washed with saturated brine, dried, and purified by column chromatography (petroleum ether:ethyl acetate = 1:4) to give compound R88 (10 mg, 2%) as a white solid. 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.

[0662] Example 52 Synthesis of compound R89

[0663]

[0664] (1) Step 1:

[0665]

[0666] (R)-4-(2-chloro-7-iodopyrrole[2,1-f][1,2,4]triazin-4-yl)-3-methylmorpholine (0.2 g 0.53 g), pinacol 3,5-dimethylisoxazol-4-boronate (0.118 g), cesium carbonate (0.344 g), bis(triphenylphosphine)palladium dichloride (0.05 g), dioxane (5 mL), and water (0.5 mL) were added at room temperature. Under nitrogen protection, the mixture was added and reacted overnight at 110 °C. After post-treatment, the mixture was washed with water, extracted with ethyl acetate, dried and concentrated, and purified by column chromatography (petroleum ether:ethyl acetate = 10:1) to give compound R89-1 (0.14 g, 76%). LC-MS [M+H] + =348.

[0667] (2) Step 2:

[0668]

[0669] Compound R89-1 (0.14 g), N-methyl-1H-benzimidazole-2-amine (0.071 g), BINAP (0.08 g), palladium acetate (0.03 g), DMF (5 mL), and cesium carbonate (0.262 g) were added at room temperature. Under nitrogen protection, the mixture was heated to 140 °C and reacted overnight. After post-treatment, the mixture was washed with water, extracted with ethyl acetate, dried and concentrated in the organic phase, and purified by column chromatography (DCM:MeOH = 100:1) to obtain 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.

[0670] Example 53 Synthesis of compound R90

[0671]

[0672] The synthetic route is the same as that for compound R89. 1H NMR (400MHz, DMSO-d6) 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.

[0673] Example 54 Synthesis of compound R91

[0674]

[0675] (1) Step 1:

[0676]

[0677] Compound (R)-4-(2-chloro-7-iodopyrrole[2,1-f][1,2,4]triazin-4-yl)-3-methylmorpholine (378 mg) was added to ultradry THF (10 mL), cooled to -78 °C, and then n-BuLi (THF, 2.5 N, 0.5 mL) was added dropwise. The mixture was stirred at -78 °C for 20 min, followed by the addition of excess 3,3-dimethylbutane-2-one, and stirring continued for 30 min. The mixture was then quenched with NH4Cl (aq.), extracted three times with ethyl acetate, washed with saturated brine, dried, and purified by column chromatography (petroleum ether:ethyl acetate = 1:1) to give a colorless oily compound R91-1 (150 mg, 42%). LC-MS [M+H] + =353.

[0678] (2) Step 2:

[0679]

[0680] Compound R91-1 (150 mg), N-methyl-1H-benzimidazole-2-amine (188 mg), palladium acetate (19 mg), BINAP (104 mg), and K2CO3 (174 mg) were added to ultra-dry DMF (3 mL), and the mixture was reacted overnight at 100 °C under nitrogen protection. After cooling to room temperature, the mixture was extracted three times with ethyl acetate, washed with saturated brine, dried, and purified by column chromatography (petroleum ether:ethyl acetate = 1:4) to give compound R91 (10 mg, 5%) as a white solid. 1H NMR (400MHz, DMSO) δ 8.72-8.58 (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.

[0681] Example 55 Synthesis of compound R92

[0682]

[0683] The synthetic route was referenced from the synthesis of compound R94. ¹H NMR (400 MHz, DMSO) δ 8.02 (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.

[0684] Example 56 Synthesis of compound R93

[0685]

[0686] (1) Step 1:

[0687]

[0688] Compound (R)-4-(2-chloro-7-(methanesulfonyl)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 di(tetrafluoroborate) salt (500 mg), and one drop of acetic acid were added to ultra-dry ACN (3 mL), and the reaction was carried out overnight at 80 °C under nitrogen protection. After cooling to room temperature, the mixture was purified by column chromatography (petroleum ether:ethyl acetate = 1:1) to give compound R93-1 (190 mg, 98%) as a white solid. LC-MS [M+H] + =348.

[0689] (2) Step 2:

[0690]

[0691] Compound R93-1 (190 mg), N-methyl-1H-benzimidazole-2-amine (220 mg), palladium acetate (22 mg), BINAP (124 mg), and K2CO3 (207 mg) were added to ultra-dry DMF (3 mL), and the mixture was reacted overnight at 100 °C under nitrogen protection. After cooling to room temperature, the mixture was extracted three times with ethyl acetate, washed with saturated brine, dried, and purified by column chromatography (petroleum ether:ethyl acetate = 1:4) to give compound R93 (10 mg, 2%) as a white solid. 1 H NMR (400MHz, DMSO) δ8.03 (d, 1H), 7.76 (d, 1H), 7.337.25 (m, 2H), 7.12 (td, 1H), 7.01 (td, 1H), 4. 63 (s, 1H), 4.25 (s, 1H), 4.07 (d, 1H), 3.873.59 (m, 4H), 3.45 (d, 3H), 3.06 (dd, 3H), 1.50 (d, 3H). LC-MS[M+H] + =460.

[0692] Example 57 Synthesis of compound R94

[0693]

[0694] (1) Step 1:

[0695]

[0696] (R)-4-(6-chloro-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-3-methylmorpholine (1.7 g) and DMF (15 mL) were added at room temperature and stirred at room temperature. Cesium carbonate (6.55 g) was added and stirred. Cyclopropylsulfonyl chloride (1.13 g) was added dropwise. After the addition was complete, the mixture was stirred overnight at room temperature. TLC showed the starter had disappeared. Water (50 mL) was added and stirred for 30 min. The mixture was filtered, the filter cake was dried, and purified by column chromatography (petroleum ether:ethyl acetate = 1:1). Then, the mixture was transferred to the next step. LC-MS [M+H] + =358.

[0697] (2) Step 2:

[0698]

[0699] Compound R94-1 (0.2 g), dioxane (5 mL), 4-fluoro-2-nitroaniline (0.104 g), BINAP (0.06 g), palladium acetate (0.02 g), and cesium carbonate (0.36 g) were added at room temperature. Under nitrogen protection, the mixture was heated to 120 °C and reacted overnight. After post-treatment, the mixture was washed with water, extracted with ethyl acetate, dried and concentrated, and purified by column chromatography (DCM:MeOH = 100:1) to give compound R94-2 (0.2 g, 73%). LC-MS [M+H] + =478.

[0700] (3) Step 3:

[0701]

[0702] Compound R94-2 (0.2 g), ethanol (10 mL), and Pd / C (0.1 g) were added at room temperature. Hydrogen was added by hydrogen purging, and the reaction was allowed to proceed overnight at room temperature. After post-treatment, filtration, drying and concentration of the organic phase, and purification by column chromatography (DCM:MeOH = 100:1) yielded compound R94-3 (50 mg, 26%). LC-MS [M+H] + =448.

[0703] (4) Step 4:

[0704]

[0705] Compound R94-3 (0.05 g) and pyridine (3 mL) were added at room temperature and stirred until dissolved. Methyl isothiocyanate (0.01 g) was added, and the mixture was stirred and heated to 90 °C for 30 min. The mixture was then cooled to room temperature, and EDCI (0.032 g) was added. The mixture was heated to 90 °C overnight. After post-treatment, the organic phase was dried and concentrated, and purified by column chromatography (ethyl acetate:MeOH:TEA = 50:5:5) to obtain compound R94 (20 mg, 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.

[0706] Example 58 Synthesis of compound R96

[0707]

[0708] The synthetic route is the same as that for 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, 2 H), 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.

[0709] Example 59 Synthesis of compound R97

[0710]

[0711] The synthetic route is the same as that for 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), 4.1 9 (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.

[0712] Example 60 Synthesis of compound R98

[0713]

[0714] The synthetic route is the same as that for 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.

[0715] Example 61 Synthesis of compound R99

[0716]

[0717] (1) Step 1:

[0718]

[0719] (R)-N1-(1-(cyclopropylsulfonyl)-4-(3-methylmorpholine)-1H-pyrazolo[3,4-d]pyrimidin-6-yl)-4-fluorobenzene-1,2-diamine (0.05 g), ethanol (4 mL), triethylamine (0.1 g), and cyanogen bromide (0.018 g) were added at room temperature. The mixture was reacted at room temperature for 48 h. After post-treatment, the organic phase was dried and concentrated, and 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.

[0720] Example 62 Synthesis of compound R100

[0721]

[0722] step:

[0723]

[0724] (R)-N1-(1-(cyclopropylsulfonyl)-4-(3-methylmorpholine)-1H-pyrazolo[3,4-d]pyrimidin-6-yl)-4-fluorobenzene-1,2-diamine (0.1 g) and pyridine (4 mL) were added at room temperature and stirred until dissolved. Isopropyl isothiocyanate (0.027 g) was added, and the mixture was stirred and heated to 90 °C for 30 min. The mixture was then cooled to room temperature, and EDCI (0.064 g) was added. The mixture was heated to 90 °C overnight. After post-treatment, the organic phase was dried and concentrated, and purified by column chromatography (DCM:MeOH = 50:1) to obtain compound R100 (40 mg, 35%). 1H NMR (400MHz, DMSO-d6) 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.

[0725] Example 63 Synthesis of compound R101

[0726]

[0727] The synthetic route is the same as that for 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), 4.0 7(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.

[0728] Example 64 Synthesis of compound R103

[0729]

[0730] (1) Step 1:

[0731]

[0732] (R)-4-(2-chloro-7-(methanesulfonyl)pyrrole[2,1-f][1,2,4]triazin-4-yl)-3-methylmorpholine (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) were added to a reaction flask. The mixture was reacted overnight in an oil bath at 116 °C under N2 protection. After the reaction was complete, as monitored by TLC (petroleum ether:ethyl acetate = 1:1), the mixture was purified by column chromatography (petroleum ether:ethyl acetate = 2:1) to give a brown solid compound R103-1 (79 mg, 38%). LC-MS [M+H] + =434.

[0733] (2) Step 2:

[0734]

[0735] Compound R103-1 (79 mg), iron powder (40 mg), ammonium chloride (39 mg), and 95% ethanol (10 mL) were added to a reaction flask. The mixture was reacted under N2 protection in an oil bath at 70 °C for 4 h. After the reaction was complete, monitored by TLC (DCM:MeOH = 50:1), the mixture was purified by column chromatography (DCM:MeOH = 100:1) to give a yellow solid, compound R103-2 (45 mg, 61%). LC-MS [M+H] + =404.

[0736] (3) Step 3:

[0737]

[0738] Compound R103-2 (45 mg), methyl isothiocyanate (10 mg), and anhydrous pyridine (10 mL) were added to a reaction flask. The mixture was reacted in an oil bath at 90 °C for 1 h, then cooled to room temperature. EDCI (31 mg) was added, and the reaction was continued at 90 °C overnight. After the reaction was complete, the mixture was directly evaporated to dryness, and a large plate was developed (DCM:MeOH = 50:1) to obtain a brownish-yellow solid, compound R103 (5 mg, 10%). 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.

[0739] Example 65 Synthesis of compound R105

[0740]

[0741] The synthetic route is the same as that for compound R99. 1H NMR (400MHz, DMSO) δ7.89 (d, 1H), 7.75 (s, 1H), 7.51-7.23 (m, 4H), 7.00-6.90 (m, 2H), 4.8 8(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.

[0742] Example 66 Synthesis of compound R106

[0743]

[0744] The synthetic route is the same as that for 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.

[0745] Example 67 Synthesis of compound R107

[0746]

[0747] (1) Step 1:

[0748]

[0749] (R)-4-(2-chloro-7-(methylsulfonyl)pyrrole[2,1-f][1,2,4]triazin-4-yl)-3-methylmorpholine (200 mg), methyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)-1H-indole-6-carboxylic acid (274 mg), Pd(dppf)Cl2 (44 mg), and CS2CO3 (397 mg) were reacted overnight at 110 °C in dioxane / H2O under nitrogen protection. After the reaction was complete as detected by TLC, water was added for dilution, and the mixture was extracted twice with ethyl acetate. The mixture was separated, the ethyl acetate phase was washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography (petroleum ether:ethyl acetate = 1:1 to DCM / MeOH = 10:1) to give compound R107-1 (170 mg, 59%) as a yellow solid. LC-MS[M+H] + =470.

[0750] (2) Step 2:

[0751]

[0752] Compound R107-1 (50 mg) was dissolved in THF, and LiAlH4 (21 mg) was added. Under nitrogen protection, the reaction was carried out at room temperature for 3 h. After the reaction was complete as detected by TLC, the residue was quenched with NaOH aqueous solution. The residue was added to water, extracted twice with ethyl acetate, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (petroleum ether:ethyl acetate = 1:1-1:4 to DCM / MeOH = 10:1) to give compound R107 (21 mg, 8%) as a light yellow solid. 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.

[0753] Example 68 Synthesis of compound R111

[0754]

[0755] (1) Step 1:

[0756]

[0757] (R)-4-(2-chloro-7-(methanesulfonyl)pyrrole[2,1-f][1,2,4]triazin-4-yl)-3-methylmorpholine (100 mg), 6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxane-2-yl)-1H-indole (118 mg), Pd(dppf)Cl2 (22 mg), and CS2CO3 (202 mg) were reacted overnight at 110 °C in dioxane / H2O under N2 protection. After the reaction was complete as detected by TLC, water was added for dilution, and the mixture was extracted twice with ethyl acetate. The mixture was separated, the ethyl acetate phase was washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography (petroleum ether:ethyl acetate = 1:1 to DCM / MeOH = 10:1) to give compound R111 (60 mg, 45%) 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.

[0758] Example 69 Synthesis of compound R112

[0759]

[0760] The synthetic route is the same as that for 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.

[0761] Example 70 Synthesis of compound R113

[0762]

[0763] (1) Step 1:

[0764]

[0765] (R)-4-(2-chloro-7-(methanesulfonyl)pyrrole[2,1-f][1,2,4]triazin-4-yl)-3-methylmorpholine (100 mg), 2-((triisopropylsiloxy)methyl)-1H benzimidazole (123 mg), Pd(OAc)2 (13 mg), BINAP (37 mg), CS2CO3 (195 mg), and dioxane (10 mL) were added to the reaction flask. The mixture was reacted overnight at 120 °C under N2 protection. After the reaction was complete as monitored by TLC, the mixture was purified by column chromatography (petroleum ether:ethyl acetate = 3:1) to give compound R113-1 (61 mg, 33%) as a brown solid. LC-MS [M+H] + =599.

[0766] (2) Step 2:

[0767]

[0768] Compound R113-1 (60 mg), TBAF (52 mg), and anhydrous tetrahydrofuran (10 mL) were added to a reaction flask and reacted overnight at room temperature. After the reaction was completed by TLC monitoring, the mixture was directly evaporated to dryness and scraped off with a scraper (dichloromethane:methanol = 30:1) to give a yellow solid compound R113 (6 mg, 13%). 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.

[0769] Example 71 Synthesis of compound R114

[0770]

[0771] The synthetic route is the same as that for compound R106. 1H 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.

[0772] Example 72 Synthesis of compound R117

[0773]

[0774] (1) Step 1:

[0775]

[0776] (R)-4-(2-chloro-7-(methanesulfonyl)pyrrole[2,1-f][1,2,4]triazin-4-yl)-3-methylmorpholine (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 were added to the reaction flask. The mixture was reacted overnight in an oil bath at 116 °C under N2 protection. After the reaction was completed by TLC monitoring, the mixture was purified by column chromatography (DCM:MeOH = 90:1 to 50:1) to give 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.

[0777] Example 73 Synthesis of compound R116

[0778]

[0779] The synthetic route is the same as that for compound R107. 1H 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.

[0780] Example 74 Synthesis of compound R30

[0781]

[0782] (1) Step 1:

[0783]

[0784] 5-Nitro-2,4,6-Trichloropyrimidine (100 mg) was dissolved in 8 ml of DCM, and DIPEA (85 mg) was added. The mixture was cooled to -10 °C, and (R)-3-methylmorpholine (46 mg) was added. After slowly restoring to room temperature, the reaction was carried out for 4 h. After the reaction was completed by TLC monitoring, the mixture was purified by column chromatography (petroleum ether:ethyl acetate = 3:1) to give a yellow oil (95 mg). LC-MS [M+H+] = 293.

[0785] (2) Step 2:

[0786]

[0787] Compound R30-1 (95 mg) was dissolved in DMF (8 ml) at room temperature. After cooling to approximately 0 °C, 1-methyl-5-aminopyrazole (31 mg) was added, followed by DIPEA (42 mg). The mixture was slowly restored to room temperature and reacted for 2 h. After the reaction was completed by TLC monitoring, the reaction solution was poured into 20 ml of water and extracted with EA (5 ml * 3). The organic phase was dried, filtered, and evaporated to dryness. The solution was then purified by column chromatography (petroleum ether:ethyl acetate = 2:1) to give a pale yellow solid (60 mg, 52%). LC-MS [M+H+] = 354.

[0788] (3) Step 3:

[0789]

[0790] At room temperature, compound R30-2 (60 mg), SnCl2 (145 mg), trimethyl orthoformate (1 mL), anhydrous ethanol (5 mL), and 2 drops of concentrated hydrochloric acid were added to a 50 mL pressure-resistant flask. The mixture was then heated to 90 °C and reacted for 5 h. The reaction was monitored by TLC until completion. After the reaction solution cooled to room temperature, it was poured into 15 mL of water, and the pH was adjusted to 8 with a saturated sodium carbonate solution. Extraction was performed using EA (5 mL * 3). The organic phase was dried, filtered, and evaporated to dryness. The residue was prepared as sintered glass and purified by column chromatography (petroleum ether:ethyl acetate = 1:1) to obtain a pale yellow solid (32 mg, 57%). LC-MS [M+H+] = 334.

[0791] (4) Step 4:

[0792]

[0793] Compound R30-3 (32 mg), 6-chloro-7-azaindole 4-pinacol ester (28 mg), K2CO3 (20 mg), and Pd(dppf)Cl2 (8 mg) were added to a 10 mL single-necked flask at room temperature. 5 mL of dioxane was added, and the mixture was purged twice with N2. The mixture was then heated to 120 °C for 4 h under N2 atmosphere. The reaction was monitored by TLC until it was complete. After the reaction solution cooled to room temperature, it was evaporated to dryness, prepared as a slurry, and purified by column chromatography (dichloromethane:methanol = 100:1) to obtain a light 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.

[0794] Example 75 Synthesis of compound R50

[0795]

[0796] (1) Step 1:

[0797]

[0798] At room temperature, compounds (R)-4-(2-chloro-9h-purin-6-yl)-3-methylmorpholine (200 mg), 1,4-dimethylpyrazol-5-boronic acid pinacol ester (211 mg), copper acetate (215 mg), and triethylamine (400 mg) were added to a 25 mL single-necked flask. DCM (10 mL) was added, and after two O2 evacuations, the reaction was carried out under O2 atmosphere for 24 h. TLC monitoring showed partial reaction of the starting material. The reaction mixture was filtered through a diatomaceous earth liner, washed with DCM (5 mL), evaporated to dryness with dichloromethane, and purified by column chromatography (petroleum ether:ethyl acetate = 3:1) to obtain a yellow oil (20 mg, 7%). LC-MS [M+H] + =347.

[0799] (2) Step 2:

[0800]

[0801] At room temperature, compound R50-1 (20 mg), 7-azaindole-4-pinacol ester (17 mg), KOAc (11 mg), and Pd(dppf)Cl2 (5 mg) were added to a 10 mL single-necked flask. 5 mL of DMSO was added, and the mixture was purged twice with N2. The mixture was then heated to 120 °C under N2 atmosphere for 4 h. The reaction was monitored by TLC until it was complete. After the reaction solution cooled to room temperature, it was poured into 15 mL of water and extracted with EA (5 mL * 3). The organic phase was dried, filtered, and evaporated to dryness. The solution was then prepared as a slurry and subjected to column chromatography (dichloromethane:methanol = 100:1) to obtain a pale 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.

[0802] It should be noted that other similar compounds disclosed in this invention are synthesized using similar methods as described in the above embodiments.

[0803] Experimental Example 1: ATR Kinase Assay

[0804] 1. Prepare 1x kinase buffer and stop solution.

[0805] A 1-fold kinase buffer was prepared using 50 mM HERES at pH 7.5, 0.0015% Brij-35, and 1 M MnCl2; a stop solution was prepared using 100 mM HERES at pH 7.5, 0.015% Brij-35, 0.2% Coating Reagent #3, and 50 mM EDTA.

[0806] 2. Compound preparation

[0807] Prepare a 1000 / 3-fold final concentration of the compound. Perform 10 3-fold dilutions sequentially from the highest concentration downwards, resulting in 10 1000 / 3-fold concentrations. Transfer 100 μL of 100% DMSO into two empty wells, designated as the Max and Min wells. Transfer 40 μL of the compound into a new 384-well plate as an intermediate plate. Use an Echo to transfer 60 nmol of the compound into the 384-well plate.

[0808] Among them, AZ20 and BAY1895344 are Yangshen compounds, and their structural formulas are as follows:

[0809]

[0810] 3. Kinase response

[0811] Add the kinase to a 1-fold kinase buffer to prepare a 2-fold enzyme solution. Add 10 μL of the 2-fold enzyme solution to each well of a 384-well plate, and add 10 μL of kinase buffer to each negative control well. Incubate at room temperature for 10 minutes. Add the FAM-labeled peptide 5-FAM-AK-17 and ATP to a 1-fold kinase buffer to prepare a 2-fold substrate solution. Add 10 μL of the 2-fold substrate solution to each well of a 384-well plate. Incubate at 28°C for a specified time. Stop the reaction by adding 30 μL of stop solution to each well of the 384-well plate. Read the data using Caliper EZ Reader II.

[0812] The IC50 (nM) values ​​are shown in Table 1.

[0813] Table 1

[0814]

[0815]

[0816] Experimental Example 2: LOVO In Vitro Cell Viability Assay

[0817] To analyze the inhibitory effect of the compound of the present invention on the proliferation of LOVO cells, two replicates were set up, and the compound concentration was: 10 μM as the starting concentration, 5-fold dilution, and 9 concentration gradients.

[0818] Collect LOVO cell suspensions, centrifuge at 1000 rpm for 5 minutes, remove the supernatant, resuspend in preheated culture medium, and count the cells. After counting, dilute the cell suspension to the desired density with cell culture medium. The cell densities for each compound are shown in Table 4-1. Seed 100 μL of cell suspension into each well of a 96-well cell culture plate and incubate overnight at 37°C with 5% CO2. For different compounds, add 10 μL of the compound's working solution to each well and incubate at 37°C with 5% CO2. The cell density was 5000 cells / well, and the incubation period was 3 days.

[0819] After incubation, add an appropriate amount of CCK8 assay reagent to each well of the cell plate and incubate for 1-4 hours. After incubation, use absorbsense to detect the luminescence signal. Standardize the measured signal values ​​by subtracting the signal values ​​from the background control wells. Calculate the cell viability after compound treatment using the following formula: Inhibition rate = 100 - (RFU) 化合物 -RFU 空白对照 ) / (RFU 阴性对照 -RFU 空白对照 ×100%. Blank control: cells treated with only culture medium and no cells; negative control: cells treated with 0.5% DMSO. The IC50 of the compounds was then calculated using Prism plotting. 50 The values ​​are shown in Table 2.

[0820] Table 2

[0821]

[0822]

[0823] The scope of protection of this invention is not limited to the above embodiments. Variations and advantages that can be conceived by those skilled in the art without departing from the spirit and scope of the inventive concept are included in this invention and are protected by the appended claims.

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof, in: X1 is C; X2 is C; X3 is N; X4 is N; X5 is C; R1 is ; R2 is selected from R3 is -S(=O)2R 13 , wherein R 13 It is methyl or cyclopropyl; R4 is hydrogen.

2. The compound of claim 1, wherein the compound is selected from: 。 3. A pharmaceutical composition, characterized in that, The pharmaceutical composition contains a therapeutically effective amount of the compound of any one of claims 1-2 and at least one pharmaceutically acceptable excipient.

4. Use of the compound of any one of claims 1-2 in the preparation of a medicament for treating or preventing ATR kinase-mediated diseases.

5. The use as described in claim 4, wherein the disease is liver cancer, melanoma, Hodgkin's disease, non-Hodgkin's lymphoma, acute lymphoblastic leukemia, chronic lymphoblastic 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 islet tumor, malignant carcinoid cancer, choriocarcinoma, head and neck cancer, osteosarcoma, 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 thrombocytosis, adrenocortical carcinoma, skin cancer, or prostate cancer.

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