A class of aromatic heterocyclic substituted compounds, their preparation methods and uses

Abstract

This invention provides a class of compounds with novel structures as ATR inhibitors, as well as their stereoisomers, optical isomers, pharmaceutical salts, prodrugs, and solvates. The novel aromatic heterocyclic substituted compounds of this invention offer a new direction for the development of ATR inhibitor drugs. In vitro enzyme activity studies show that these compounds exhibit strong inhibitory effects on ATR enzymes and can serve as promising compounds for the treatment of ATR-mediated diseases.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical technology, and more specifically, to a class of aromatic heterocyclic substituted compounds, as well as methods for preparing and using said compounds. Background Technology

[0002] ATR (Ataxia telangiectasia and Rad3-related protein) is a protein kinase involved in genome stability and DNA damage repair, belonging to the PIKK family. ATR activation can be triggered by arrested replication forks or single-stranded DNA (SSB) damage. Activated ATR recruits repair proteins or factors to repair damaged sites, delaying mitosis (especially during the G2 / M phase), thus stabilizing replication forks and ensuring genome stability. Once activated, ATR regulates its downstream regulatory factors (mainly Chk1, WRN, and FANCI) to activate three signal transduction pathways, arresting cell cycle progression, promoting DNA repair, and stabilizing replication forks. Because DNA repair in tumor cells may be defective due to various mutations, it exhibits a greater dependence on undamaged DNA repair pathways. Therefore, the synthetic lethality theory can be used to kill specific tumor cells while preserving healthy cells. Current cancer treatments, including chemotherapy and ionizing radiation, can induce DNA damage and replication fork arrest, thereby activating cell cycle checkpoints and leading to cell cycle arrest. This response mechanism is crucial for cancer cell survival during treatment. Broken double-stranded DNA or replication stress can rapidly activate the ATR (Advanced Terminology Transformation). The ATR then initiates a series of downstream targets, such as Chk1 (an ATR substrate), p53, and DNA topoisomerase 2-binding protein (TopBP1), leading to DNA repair and cell cycle arrest. Because the ATR gene is rarely mutated, it is readily activated during cancer chemotherapy. Therefore, ATR inhibition can be used in combination with chemotherapeutic drugs to synergistically enhance the therapeutic effect.

[0003] Currently, some molecules disclosed in existing technologies have entered the clinical stage, such as Berzosertib disclosed in WO2010071837A1, Elimusertib disclosed in WO2011154737A1, and RP3500 disclosed in WO2020087170A1, all of which are in Phase I / II clinical trials.

[0004]

[0005] To date, no ATR inhibitors have been marketed, making it essential to discover more effective and safer ATR inhibitors. Summary of the Invention

[0006] The purpose of this invention is to provide a compound with a novel structure as an ATR inhibitor, a method for preparing the compound, and its use in treating ATR-mediated diseases.

[0007] In a first aspect, the present invention provides a compound represented by formula (A), and its stereoisomers, optical isomers, pharmaceutical salts, prodrugs, and solvates.

[0008]

[0009] in,

[0010] One of the keys connecting Q and N, or N and Y, is a double key. When the key connecting Q and N is a double key, the key connecting N and Y is a single key; when the key connecting N and Y is a double key, the key connecting Q and N is a single key.

[0011] X is selected from CR x Or N; where R x Each time it appears, it is independently selected from hydrogen, halogen, hydroxyl, mercapto, amino, cyano, C 1-6 Alkyl, C 2-6 alkenyl, C 1-6 Alkoxy, C 3-8 cycloalkyl, halogenated C 1-6 alkyl;

[0012] R Y Halogen, C 1-6 Alkyl or hydrogen;

[0013] R Z The quantity is 0, 1, 2, or 3, and each occurrence is independently selected from halogen, hydroxyl, cyano, amino, C 1-3 Alkyl, Halogenated C 1-3 alkyl;

[0014] R is selected from C 6-12 Aryl, 5-12 heteroaryl, C 2-6 alkynyl group, C 3-12 One of a carbocyclic group and a 3-12 membered heterocyclic group, wherein the C... 6-12 Aryl, 5-12 heteroaryl, C 2-6 alkynyl group, C 3-12 The carbocyclic group and 3-12 membered heterocyclic groups may be optionally substituted with one or more of the following substituents: hydroxyl, mercapto, amino, carboxyl, cyano, halogen, oxo, aminoacyl, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 carbonyl group, C 6-12 Aryl, C1-6 Alkoxy, C 1-6 Alkylthio, 3-12 membered heterocyclic group, 5-12 membered heteroaryl, -C 1-6 Alkyl groups -NH2, -NHC 1-6 Alkyl, -NH-5-12-membered heteroaryl, -N(C 1-6 Alkyl)2、-NHCOC 1-6 Alkyl, -NHCOC 3-6 Carbocyclic group, -NHCOC 3-12 Aryl, -NHCO-3-12 heteroaryl, -NHCO-3-12 heterocyclic, -NHCONHC 1-6 Alkyl, -NHCONHC 3-12 Carbocyclic group, -NHCONH-3-12 membered heterocyclic group, -CONH C 1-6 Alkyl, -CON(C) 1-6 Alkyl)2, -C 1-6 Alkyl-C 3-12 carbonyl group, -C 1-6 Alkyl-5-12-membered heteroaryl, -C 1-6 Alkyl-3-12-membered heterocyclic group, -C 1-6 Alkyl-C 6-12 Aryl, the C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 carbonyl group, C 6-12 Aryl, C 1-6 Alkoxy, C 1-6 Alkylthio, 3-12 membered heterocyclic group, 5-12 membered heteroaryl, -C 1-6 Alkyl groups -NH2, -NHC 1-6 Alkyl, -NH-5-12-membered heteroaryl, -N(C 1-6 Alkyl)2、-NHCOC 1-6 Alkyl, -NHCOC 3-6 Carbocyclic group, -NHCOC 3-12 Aryl, -NHCO-3-12 heteroaryl, -NHCO-3-12 heterocyclic, -NHCONHC 1-6 Alkyl, -NHCONHC 3-6 carbonyl group, -CONHC 1-6 Alkyl, -CON(C) 1-6 Alkyl)2, -C 1-6 Alkyl-C 3-12 Carbocyclic group, -C 1-6 Alkyl-5-12-membered heteroaryl, -C 1-6 Alkyl-3-12-membered heterocyclic group, -C 1-6 Alkyl-C 6-12The aryl group may be optionally substituted with one or more of the following substituents: hydroxyl, mercapto, amino, carboxyl, cyano, halogen, oxo, amide, aminoacyl, -SO2NH2, or C-group optionally substituted with halogen or hydroxyl. 1-6 Alkyl groups, C-type carbons optionally substituted with halogens or hydroxyl groups 2-6 Alkenyl, C-terminus optionally substituted with halogen or hydroxyl groups 2-6 Alkyne group, C group optionally substituted with halogen or hydroxyl group 1-6 Alkoxy groups, or -C groups optionally substituted with halogens or hydroxyl groups. 1-6 Alkyl-OH, -C optionally substituted with halogen or hydroxyl groups 1-6 Alkyl-OC 1-6 Alkyl groups, C-type carbons optionally substituted with halogens or hydroxyl groups 3-6 Cycloalkyl groups, C-type carbons optionally substituted with halogens or hydroxyl groups 6-12 aryl, -CH2-C optionally substituted with halogen or hydroxyl groups 6-12 aryl, optionally halogenated, hydroxyl or C 1-3 Alkyl-substituted 3-6 membered heterocyclic groups, optionally halogenated, hydroxyl or C 1-3 Alkyl-substituted 5-10-membered heteroaryl groups, optionally substituted with halogens or hydroxyl groups -SONHC 1-6 Alkyl groups, optionally substituted with halogens or hydroxyl groups, -SO2C 1-6 Alkyl groups, optionally substituted with halogens or hydroxyl groups -COC 1-6 Alkyl groups, optionally substituted with halogens or hydroxyl groups -COC 3-6 cycloalkyl, optional -COC substituted with halogen or hydroxyl groups 6-12 Aryl, optionally substituted with halogen or hydroxyl groups -NHSO2C 1-6 Alkyl groups, optionally substituted with halogens or hydroxyl groups -CONHC 1-6 Alkyl groups, optionally substituted with halogens or hydroxyl groups -NHC 1-6 Alkyl groups, optionally substituted with halogens or hydroxyl groups, and -N(C) groups 1-6 2. Alkyl group, optionally substituted with halogen or hydroxyl group -NHC 3-6 cycloalkyl;

[0015] When the bond connecting Q and N is a double bond, and the bond connecting N and Y is a single bond, then both Q and Y are selected from CR. 1 Or one of N; where R 1 When present, each group is independently selected from hydrogen, halogen, hydroxyl, mercapto, amino, cyano, amide, and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 1-6 Alkoxy, C 1-6 Alkyl thiols, halogenated C 1-6 Alkyl, Halogenated C1-6 Alkoxy groups, 4-6 membered heterocyclic groups;

[0016] When the bond connecting N and Y is a double bond, and the bond connecting Q and N is a single bond, then Y is selected from C, and Q is selected from CR. 2 R 3 or NR 4 One of them; of which R 2 R 3 R 4 Each time it appears, it is independently selected from hydrogen, halogen, hydroxyl, mercapto, amino, cyano, amide, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 1-6 Alkoxy, C 1-6 Alkyl thiols, halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy groups, 4-6 membered heterocyclic groups.

[0017] The heteroatoms in the "heterocyclic group" and "heteroaryl group" are selected from N, O or S, and the number of heteroatoms is 1, 2, 3 or 4.

[0018] In a preferred embodiment of the present invention, the compound represented by formula (A) is further represented by formula (A-1):

[0019]

[0020] In formula (A-1), each substituent is defined as described in formula (A).

[0021] In a preferred embodiment of the present invention, the compound represented by formula (A) is further represented by formula (A-2):

[0022]

[0023] In formula (A-2), each substituent is defined as described in formula (A).

[0024] In a preferred embodiment of the present invention, the compound represented by formula (A) is further represented by formula (A-3):

[0025]

[0026] In formula (A-3), each substituent is defined as described in formula (A).

[0027] In a preferred embodiment of the present invention, the compound represented by formula (A) is further represented by formula (A-4):

[0028]

[0029] In formula (A-4), each substituent is defined as described in formula (A).

[0030] In a preferred embodiment of the present invention, the compound represented by formula (A) is further represented by formula (A-5):

[0031]

[0032] In formula (A-5), each substituent is defined as described in formula (A).

[0033] In a preferred embodiment of the present invention, the compound represented by formula (A) is further represented by formula (A-6):

[0034]

[0035] In formula (A-6), each substituent is defined as described in formula (A).

[0036] In a preferred embodiment of the present invention, the compound represented by formula (A) is further represented by formula (A-7):

[0037]

[0038] In formula (A-7), each substituent is defined as described in formula (A).

[0039] The present invention also provides a compound represented by formula (I) below, and its stereoisomers, optical isomers, pharmaceutical salts, prodrugs, and solvates.

[0040]

[0041] in,

[0042] One of the keys connecting Q and N, or N and Y, is a double key. When the key connecting Q and N is a double key, the key connecting N and Y is a single key; when the key connecting N and Y is a double key, the key connecting Q and N is a single key.

[0043] X is selected from CR x Or N; where R x Each time it appears, it is independently selected from hydrogen, halogen, hydroxyl, mercapto, amino, cyano, C 1-6 Alkyl, C 2-6 alkenyl, C 1-6 Alkoxy, C 3-8 cycloalkyl, halogenated C 1-6 alkyl;

[0044] R is selected from C 6-12 Aryl, 5-12 heteroaryl, C2-6 alkynyl group, C 3-12 One of a carbocyclic group and a 3-12 membered heterocyclic group, wherein the C... 6-12 Aryl, 5-12 heteroaryl, C 2-6 alkynyl group, C 3-12 The carbocyclic group and 3-12 membered heterocyclic groups may be optionally substituted with one or more of the following substituents: hydroxyl, mercapto, amino, carboxyl, cyano, halogen, oxo, aminoacyl, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 carbonyl group, C 6-12 Aryl, C 1-6 Alkoxy, C 1-6 Alkylthio, 3-12 membered heterocyclic group, 5-12 membered heteroaryl, -C 1-6 Alkyl groups -NH2, -NHC 1-6 Alkyl, -NH-5-12-membered heteroaryl, -N(C 1-6 Alkyl)2、-NHCOC 1-6 Alkyl, -NHCOC 3-6 Carbocyclic group, -NHCOC 3-12 Aryl, -NHCO-3-12 heteroaryl, -NHCO-3-12 heterocyclic, -NHCONHC 1-6 Alkyl, -NHCONHC 3-12 Carbocyclic group, -NHCONH-3-12 membered heterocyclic group, -CONH C 1-6 Alkyl, -CON(C) 1-6 Alkyl)2, -C 1-6 Alkyl-C 3-12 Carbocyclic group, -C 1-6 Alkyl-5-12-membered heteroaryl, -C 1-6 Alkyl-3-12-membered heterocyclic group, -C 1-6 Alkyl-C 6-12 Aryl, the C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 carbonyl group, C 6-12 Aryl, C 1-6 Alkoxy, C 1-6 Alkylthio, 3-12 membered heterocyclic group, 5-12 membered heteroaryl, -C 1-6 Alkyl groups -NH2, -NHC 1-6 Alkyl, -NH-5-12-membered heteroaryl, -N(C 1-6 Alkyl)2、-NHCOC 1-6 Alkyl, -NHCOC 3-6 Carbocyclic group, -NHCOC3-12 Aryl, -NHCO-3-12 heteroaryl, -NHCO-3-12 heterocyclic, -NHCONHC 1-6 Alkyl, -NHCONHC 3-6 carbonyl group, -CONHC 1-6 Alkyl, -CON(C) 1-6 Alkyl)2, -C 1-6 Alkyl-C 3-12 Carbocyclic group, -C 1-6 Alkyl-5-12-membered heteroaryl, -C 1-6 Alkyl-3-12-membered heterocyclic group, -C 1-6 Alkyl-C 6-12 The aryl group may be optionally substituted with one or more of the following substituents: hydroxyl, mercapto, amino, carboxyl, cyano, halogen, oxo, amide, aminoacyl, -SO2NH2, or C-group optionally substituted with halogen or hydroxyl. 1-6 Alkyl groups, C-type carbons optionally substituted with halogens or hydroxyl groups 2-6 Alkenyl, C-terminus optionally substituted with halogen or hydroxyl groups 2-6 Alkyne group, C group optionally substituted with halogen or hydroxyl group 1-6 Alkoxy groups, or -C groups optionally substituted with halogens or hydroxyl groups. 1-6 Alkyl-OH, -C optionally substituted with halogen or hydroxyl groups 1-6 Alkyl-OC 1-6 Alkyl groups, C-type carbons optionally substituted with halogens or hydroxyl groups 3-6 Cycloalkyl groups, C-type carbons optionally substituted with halogens or hydroxyl groups 6-12 Aryl, 3-6 membered heterocyclic groups optionally substituted with halogens or hydroxyl groups, 5-10 membered heteroaryl groups optionally substituted with halogens or hydroxyl groups, -SONHC groups optionally substituted with halogens or hydroxyl groups 1-6 Alkyl groups, optionally substituted with halogens or hydroxyl groups, -SO2C 1-6 Alkyl groups, optionally substituted with halogens or hydroxyl groups -COC 1-6 Alkyl groups, optionally substituted with halogens or hydroxyl groups -COC 3-6 cycloalkyl, optional -COC substituted with halogen or hydroxyl groups 6-12 Aryl, optionally substituted with halogen or hydroxyl groups -NHSO2C 1-6 Alkyl groups, optionally substituted with halogens or hydroxyl groups -CONHC 1-6 Alkyl groups, optionally substituted with halogens or hydroxyl groups -NHC 1-6 Alkyl groups, optionally substituted with halogens or hydroxyl groups, and -N(C) groups 1-6 2. Alkyl group, optionally substituted with halogen or hydroxyl group -NHC 3-6 cycloalkyl;

[0045] When the bond connecting Q and N is a double bond, and the bond connecting N and Y is a single bond, then both Q and Y are selected from CR.1 Or one of N; where R 1 When present, each group is independently selected from hydrogen, halogen, hydroxyl, mercapto, amino, cyano, amide, and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 1-6 Alkoxy, C 1-6 Alkyl thiols, halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy groups, 4-6 membered heterocyclic groups;

[0046] When the bond connecting N and Y is a double bond, and the bond connecting Q and N is a single bond, then Y is selected from C, and Q is selected from CR. 2 R 3 or NR 4 One of them; of which R 2 R 3 R 4 Each time it appears, it is independently selected from hydrogen, halogen, hydroxyl, mercapto, amino, cyano, amide, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 1-6 Alkoxy, C 1-6 Alkyl thiols, halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy or 4-6 membered heterocyclic groups. The heteroatoms in the "heterocyclic group" or "heteroaryl group" are selected from N, O, or S, and the number of heteroatoms is 1, 2, 3, or 4.

[0047] In a preferred embodiment of the present invention, the compound represented by formula (I) is further represented by formula (II):

[0048]

[0049] In formula (II), each substituent is defined as described in formula (I).

[0050] The present invention also provides a compound represented by formula (B) below, and its stereoisomers, optical isomers, pharmaceutical salts, prodrugs, and solvates.

[0051]

[0052] Where Q and Y are both selected from CR 1 Or one of N; R 1 Selected from hydrogen, halogen, hydroxyl, mercapto, amino, cyano, amide, C 1-6 Alkyl, C2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 1-6 Alkoxy, C 1-6 Alkyl thiols, halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy groups, 4-6 membered heterocyclic groups;

[0053] X is selected from CR x Or N; where R x Each time it appears, it is independently selected from hydrogen, halogen, hydroxyl, mercapto, amino, cyano, C 1-6 Alkyl, C 2-6 alkenyl, C 1-6 Alkoxy, C 3-8 cycloalkyl, halogenated C 1-6 alkyl;

[0054] R Y Halogen, C 1-6 Alkyl or hydrogen;

[0055] R Z The quantity is 0, 1, 2, or 3, and each occurrence is independently selected from halogen, hydroxyl, cyano, amino, C 1-3 Alkyl, Halogenated C 1-3 alkyl;

[0056] R is selected from the following substituents:

[0057]

[0058]

[0059] One of them.

[0060] In a preferred embodiment of the present invention, Y is selected from N, and Q is selected from CR. 1 ;R 1 Selected from hydrogen, halogen, hydroxyl, mercapto, amino, cyano, amide, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio;

[0061] Further preferred, Y is selected from N, and Q is selected from CR. 1 ;R 1 Selected from hydrogen, halogen, hydroxyl, mercapto, amino, cyano, amide, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, methylthio, ethylthio;

[0062] Further preferred, Y is selected from N, and Q is selected from CR. 1 ;R1 Selected from hydrogen, halogen, cyano, amide, methyl, ethyl, methoxy, ethoxy, methylthio, ethylthio;

[0063] Furthermore, Y is selected from N, and Q is selected from CR. 1 ;R 1 Selected from hydrogen, F, Cl, Br, cyano, amide, methyl, ethyl, methoxy, and methylthio;

[0064] Furthermore, Y is selected from N, and Q is selected from CR. 1 ;R 1 Selected from hydrogen, F, cyano, amide, and methylthio.

[0065] In the optimal selection, Y is chosen from N, and Q is chosen from CR. 1 ;R 1 Selected from hydrogen.

[0066] In a preferred embodiment of the present invention, X is selected from CR. x Among them, R x Selected from hydrogen, halogen, hydroxyl, mercapto, amino, cyano, C 1-6 alkyl;

[0067] Further preferred, R x Selected from hydrogen, F, Cl, Br, hydroxyl, amino, cyano, and methyl;

[0068] Further optimized, R x Selected from hydrogen.

[0069] In a preferred embodiment of the present invention, R Y The following are the radicals: F, Cl, Br, methyl, ethyl, n-propyl, isopropyl, and hydrogen.

[0070] Further preferred, R Y For F, Cl, Br, methyl, ethyl, hydrogen;

[0071] Further optimized, R Y It is a methyl group.

[0072] In a preferred embodiment of the present invention, R Z The quantity is 0, 1, 2 or 3, and each time it appears, it is independently selected from F, Cl, Br, hydroxy, cyano, amino, methyl, ethyl, monofluoromethyl, difluoromethyl, trifluoromethyl;

[0073] Further preferred, R Z The quantity is 0, 1 or 2, and each time it appears, it is independently selected from F, Cl, Br, hydroxyl, methyl, monofluoromethyl, difluoromethyl, trifluoromethyl;

[0074] Further optimized, R ZThe quantity is 0.

[0075] In a preferred embodiment of the present invention, the compound represented by formula (B) is further represented by formula (B-1):

[0076]

[0077] In formula (B-1), each substituent is defined as described in formula (B).

[0078] In a preferred embodiment of the present invention, the compound represented by formula (B) is further represented by formula (B-2):

[0079]

[0080] In formula (B-2), each substituent is defined as described in formula (B).

[0081] In a preferred embodiment of the present invention, the compound represented by formula (B) is further represented by formula (B-3):

[0082]

[0083] In formula (B-3), each substituent is defined as described in formula (B).

[0084] In a preferred embodiment of the present invention, the compound represented by formula (B) is further represented by formula (B-4):

[0085]

[0086] In formula (B-4), each substituent is defined as described in formula (B).

[0087] In a preferred embodiment of the present invention, the compound represented by formula (B) is further represented by formula (B-5):

[0088]

[0089] In formula (B-5), each substituent is defined as described in formula (B).

[0090] The present invention also provides a compound represented by formula (III) below, and its stereoisomers, optical isomers, pharmaceutical salts, prodrugs, and solvates.

[0091]

[0092] Where Q and Y are both selected from CR 1 Or one of N; R 1 Selected from hydrogen, halogen, hydroxyl, mercapto, amino, cyano, amide, C 1-6 Alkyl, C2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 1-6 Alkoxy, C 1-6 Alkyl thiols, halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy groups, 4-6 membered heterocyclic groups;

[0093] X is selected from CR x Or N; where R x Each time it appears, it is independently selected from hydrogen, halogen, hydroxyl, mercapto, amino, cyano, C 1-6 Alkyl, C 2-6 alkenyl, C 1-6 Alkoxy, C 3-8 cycloalkyl, halogenated C 1-6 alkyl;

[0094] R is selected from the following substituents:

[0095]

[0096] One of them.

[0097] In a preferred embodiment of the present invention, Y is selected from N, and Q is selected from CR. 1 ;R 1 Selected from hydrogen, halogen, hydroxyl, mercapto, amino, cyano, amide, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio;

[0098] Further preferred, Y is selected from N, and Q is selected from CR. 1 ;R 1 Selected from hydrogen, halogen, hydroxyl, mercapto, amino, cyano, amide, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, methylthio, ethylthio;

[0099] Further preferred, Y is selected from N, and Q is selected from CR. 1 ;R 1 Selected from hydrogen, halogen, cyano, amide, methyl, ethyl, methoxy, ethoxy, methylthio, ethylthio;

[0100] Furthermore, Y is selected from N, and Q is selected from CR. 1 ;R 1 Selected from hydrogen, F, Cl, Br, cyano, amide, methyl, ethyl, methoxy, and methylthio;

[0101] Furthermore, Y is selected from N, and Q is selected from CR. 1 ;R1 Selected from hydrogen, F, cyano, amide, and methylthio.

[0102] In a preferred embodiment of the present invention, X is selected from CR. x Among them, R x Selected from hydrogen, halogen, hydroxyl, mercapto, amino, cyano, C 1-6 alkyl;

[0103] Further preferred, R x Selected from hydrogen, F, Cl, Br, hydroxyl, amino, cyano, and methyl;

[0104] Further optimized, R x Selected from hydrogen.

[0105] In a preferred embodiment of the present invention, the compound represented by formula (III) is further represented by formula (IV):

[0106]

[0107] In formula (IV), each substituent is defined as described in formula (III).

[0108] The present invention also provides a compound represented by formula (C) below, and its stereoisomers, optical isomers, pharmaceutical salts, prodrugs, and solvates.

[0109]

[0110] Where Q and Y are both selected from CR 1 Or one of N; R 1 Selected from hydrogen, halogen, hydroxyl, mercapto, amino, cyano, amide, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 1-6 Alkoxy, C 1-6 Alkyl thiols, halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy groups, 4-6 membered heterocyclic groups;

[0111] X is selected from CR x Or N; where R x Each time it appears, it is independently selected from hydrogen, halogen, hydroxyl, mercapto, amino, cyano, C 1-6 Alkyl, C 2-6 alkenyl, C 1-6 Alkoxy, C 3-8 cycloalkyl, halogenated C 1-6 alkyl;

[0112] RY Halogen, C 1-6 Alkyl or hydrogen;

[0113] R Z The quantity is 0, 1, 2, or 3, and each occurrence is independently selected from halogen, hydroxyl, cyano, amino, C 1-3 Alkyl, Halogenated C 1-3 alkyl;

[0114] R A Selected from hydrogen, carboxyl, -C 1-6 Alkyl-NH2, -ZC 1-6 Alkyl, -ZC 3-12 cycloalkyl, -ZC 6-12 Cycloalkenyl, -ZC 6-12 Aryl, -Z-3-12 heterocyclic and -Z-5-12 heteroaryl, -CONHC 1-6 Alkyl; wherein, -Z- is selected from bonds, -C(R) 10 (R) 11 )-、-C(R 12 (R) 13 ) C(R 14 (R) 15 )-、-N(R 16 -, -O-, or -S-, where R 10 R 11 R 12 R 13 R 14 R 15 R 16 Each group is independently selected from hydrogen, methyl, ethyl, hydroxyl, carboxyl, amino, amide, cyano, and oxo groups. When R is attached to the same atom... 10 and R 11 R 12 and R 13 R 14 and R 15 When one of the substituents is selected from an oxo group, the other substituent is absent; the -C 1-6 Alkyl-NH2, -ZC 1-6 Alkyl, -ZC 3-12 cycloalkyl, -ZC 6-12 Cycloalkenyl, -ZC 6-12 Aryl, -Z-3-12 heterocyclic and -Z-5-12 heteroaryl, -CONHC 1-6 The alkyl group may be optionally substituted with one or more of the following substituents: hydroxyl, cyano, halogen, oxo, amide, -SO2NH2, or optionally substituted C. 1-6 Alkyl, optionally substituted C 1-6 Alkoxy, optional substituted -C1-6 Hydroxyalkyl, optionally substituted C 6-12 Aryl, optionally substituted 3-6 membered heterocyclic, optionally substituted 5-10 membered heteroaryl, optionally substituted -SONHC 1-6 Alkyl, optionally substituted -SO2C 1-6 Alkyl, optionally substituted -COC 1-6 Alkyl, optionally substituted -COC 3-6 cycloalkyl, optionally substituted -COC 6-12 Aryl, optionally substituted -NHSO2C 1-6 Alkyl, optionally substituted -CONHC 1-6 Alkyl; the optional substitution is either unsubstituted or substituted with one or more of the following substituents: C 1-6 Alkyl, hydroxyl, halogen, oxo group;

[0115] The heteroatoms in the "heterocyclic group" and "heteroaryl group" are selected from N, O or S, and the number of heteroatoms is 1, 2, 3 or 4.

[0116] In a preferred embodiment of the present invention, Y is selected from N, and Q is selected from CR. 1 ;R 1 Selected from hydrogen, halogen, hydroxyl, mercapto, amino, cyano, amide, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio;

[0117] Further preferred, Y is selected from N, and Q is selected from CR. 1 ;R 1 Selected from hydrogen, halogen, hydroxyl, mercapto, amino, cyano, amide, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, methylthio, ethylthio;

[0118] Further preferred, Y is selected from N, and Q is selected from CR. 1 ;R 1 Selected from hydrogen, halogen, cyano, amide, methyl, ethyl, methoxy, ethoxy, methylthio, ethylthio;

[0119] Furthermore, Y is selected from N, and Q is selected from CR. 1 ;R 1 Selected from hydrogen, F, Cl, Br, cyano, amide, methyl, ethyl, methoxy, and methylthio;

[0120] Furthermore, Y is selected from N, and Q is selected from CR. 1 ;R 1 Selected from hydrogen, F, cyano, amide, and methylthio.

[0121] In the optimal selection, Y is chosen from N, and Q is chosen from CR. 1 ;R1 Selected from hydrogen.

[0122] In a preferred embodiment of the present invention, X is selected from CR. x Among them, R x Selected from hydrogen, halogen, hydroxyl, mercapto, amino, cyano, C 1-6 alkyl;

[0123] Further preferred, R x Selected from hydrogen, F, Cl, Br, hydroxyl, amino, cyano, and methyl;

[0124] Further optimized, R x Selected from hydrogen.

[0125] In a preferred embodiment of the present invention, R Y The following are the radicals: F, Cl, Br, methyl, ethyl, n-propyl, isopropyl, and hydrogen.

[0126] Further preferred, R Y For F, Cl, Br, methyl, ethyl, hydrogen;

[0127] Further optimized, R Y It is a methyl group.

[0128] In a preferred embodiment of the present invention, R Z The quantity is 0, 1, 2 or 3, and each time it appears, it is independently selected from F, Cl, Br, hydroxy, cyano, amino, methyl, ethyl, monofluoromethyl, difluoromethyl, trifluoromethyl;

[0129] Further preferred, R Z The quantity is 0, 1 or 2, and each time it appears, it is independently selected from F, Cl, Br, hydroxyl, methyl, monofluoromethyl, difluoromethyl, trifluoromethyl;

[0130] Further optimized, R Z The quantity is 0.

[0131] In a preferred embodiment of the present invention, R A Selected from hydrogen, carboxyl, amide, -C 1-4 Alkyl-NH2, -ZC 1-4 Alkyl, -ZC 3-12 cycloalkyl, -ZC 6-12 Cycloalkenyl, -ZC 6-12 Aryl, -Z-3-12 heterocyclic and -Z-5-12 heteroaryl, -CONHC 1-4 Alkyl; wherein, -Z- is selected from bonds, -C(R) 10 (R) 11 )-、-C(R 12 (R) 13) C(R 14 (R) 15 )-、-N(R 16 )-, where R 10 R 11 R 12 R 13 R 14 R 15 R 16 Each group is independently selected from hydrogen, methyl, hydroxyl, amino, cyano, and oxo groups. When R is attached to the same atom... 10 and R 11 R 12 and R 13 R 14 and R 15 When one substituent is selected from an oxo group, the other substituent is absent; the amide, -C 1-4 Alkyl-NH2, -ZC 1-4 Alkyl, -ZC 3-12 cycloalkyl, -ZC 6-12 Cycloalkenyl, -ZC 6-12 Aryl, -Z-3-12 heterocyclic and -Z-5-12 heteroaryl, -CONHC 1-4 The alkyl group may be optionally substituted with one or more of the following substituents: hydroxyl, cyano, halogen, oxo, amide, -SO2NH2, or optionally substituted C. 1-4 Alkyl, optionally substituted C 1-4 Alkoxy, optional substituted -C 1-4 Alkyl-OH, optionally substituted C 6-12 Aryl, optionally substituted 3-6 membered heterocyclic, optionally substituted 5-10 membered heteroaryl, optionally substituted -SONHC 1-4 Alkyl, optionally substituted -SO2C 1-4 Alkyl, optionally substituted -COC 1-4 Alkyl, optionally substituted -COC 3-6 cycloalkyl, optionally substituted -COC 6-12 Aryl, optionally substituted -NHSO2C 1-4 Alkyl, optionally substituted -CONHC 1-4 Alkyl; the optional substitution is unsubstituted or substituted with one or more of the following substituents: methyl, ethyl, n-propyl, isopropyl, hydroxyl, halogen, oxo;

[0132] Further preferred, R A Selected from hydrogen, carboxyl, amide, -C 1-4 Alkyl-NH2, -ZC 1-4 Alkyl, -ZC 3-6Monocyclic cycloalkyl, -Z-6-8 spirocycloalkyl, -Z-C6 cycloalkenyl, -Z-phenyl, -Z-4-7 monocyclic heterocyclic, -Z-6-8 bridged heterocyclic, -Z-6-9 fused heterocyclic, -Z-7-11 spirocyclic, -Z-5-6 monocyclic heteroaryl, -Z-7-9 fused heteroaryl, wherein -Z- is selected from bond, -CH2-, -CH2CH2-, -NH-, -CH(OH)-, -CH(CN)-, -CH(CH3)-, -CO-, -COCH2-, -CH2CO-, -COCO-, -CH(OH)CH2-, -CH2CH(OH)-, -CH(CN)CH2-, -CH2CH(CN)-, -CH(CH3)CH2-, -CH2CH(CH3)-, -CONH-, -CON(CH3)-; the amide, C 1-4 Alkyl-NH2, -ZC 1-4 Alkyl, -ZC 3-6 Monocyclic cycloalkyl, -Z-6-8 spirocycloalkyl, -Z-C6 cycloalkenyl, -Z-phenyl, -Z-4-7 monocyclic heterocyclic, -Z-6-8 bridged heterocyclic, -Z-6-9 fused heterocyclic, -Z-7-11 spirocyclic, -Z-5-6 monocyclic heteroaryl, -Z-7-9 fused heteroaryl are optionally substituted with one or more of the following substituents: hydroxyl, cyano, halogen, oxo, amide, -SO2NH2, optionally substituted methyl, any Optionally substituted ethyl, optionally substituted n-propyl, optionally substituted isopropyl, optionally substituted methoxy, optionally substituted ethoxy, optionally substituted hydroxymethyl, optionally substituted hydroxyethyl, optionally substituted phenyl, optionally substituted 5-6 membered heterocyclic, optionally substituted 5-6 membered heteroaryl, optionally substituted -SONHCH3, optionally substituted -SO2CH3, optionally substituted -COCH3, optionally substituted -COCH2CH3, optionally substituted -COC 3-6 Cycloalkyl, optionally substituted -CO-phenyl, optionally substituted -NHSO2CH3, optionally substituted -CONHCH3; the optional substitution is unsubstituted or substituted with one or more of the following substituents: methyl, ethyl, hydroxyl, halogen, oxo.

[0133] Further preferred, R ASelected from hydrogen, carboxyl, and optionally substituted substituents such as: amide, -Z-methyl, -Z-ethyl, -Z-n-propyl, -Z-isopropyl, -Z-cyclopropyl, -Z-cyclobutyl, -Z-cyclopentyl, -Z-cyclohexyl, -Z- C6 cycloalkenyl, -Z-C6 / C3 spirocycloalkyl, -Z-5-membered monocyclic heterocyclic, -Z-6-membered monocyclic heterocyclic, -Z-7-membered monocyclic heterocyclic, -Z-5-membered monocyclic heteroaryl, -Z-6-membered monocyclic heteroaryl, -Z-phenyl, -Z-7-membered bridged heterocyclic, -Z-8-membered bridged heterocyclic, -Z-6 / 3-membered fused heterocyclic, -Z-6 / 4-membered fused heterocyclic, -Z-6 / 5-membered fused heterocyclic, -Z-3 / 6-membered fused heterocyclic, -Z-4 / 6-membered fused heterocyclic, -Z-5 / 6-membered fused heterocyclic, -Z- 3- or 4-membered fused heterocyclic groups, -Z-4- or 3-membered fused heterocyclic groups, -Z-5- or 3-membered fused heterocyclic groups, -Z-3- or 5-membered fused heterocyclic groups, -Z-5- or 4-membered fused heterocyclic groups, -Z-4- or 5-membered fused heterocyclic groups, -Z-5- or 5-membered fused heterocyclic groups, -Z-4- or 4-membered spirocyclic groups, -Z-5- or 4-membered spirocyclic groups, -Z-4- or 5-membered spirocyclic groups, -Z-5- or 5-membered spirocyclic groups, -Z-4- or 6-membered spirocyclic groups, -Z-6- or 4-membered spirocyclic groups, -Z- 5-membered / 6-membered spiroheterocyclic group, -Z-6-membered / 5-membered spiroheterocyclic group, -Z-6-membered / 6-membered spiroheterocyclic group, -Z-5-membered / 5-membered fused heteroaryl group, -Z-5-membered / 6-membered fused heteroaryl group, -Z-6-membered / 5-membered fused heteroaryl group, -methyl-NH2, -ethyl-NH2, -CONHCH3 and -CONHCH2CH3, wherein -Z- is selected from bond, -CH2-, -CH2CH2-, -NH-, -CONH-; the optional substitution is unsubstituted or substituted by one or more of the following substituents: hydroxyl, cyano, halogen Element, oxo group, amide group, -SO2NH2, methyl, ethyl, n-propyl, isopropyl, halomethyl, haloethyl, halon-n-propyl, haloisopropyl, methoxy, ethoxy, hydroxymethyl, hydroxyethyl, phenyl, benzyl, halophenyl, 5-6 membered heterocyclic group, methyl-substituted 5-6 membered heterocyclic group, halo 5-6 membered heterocyclic group, 5-6 membered heteroaryl, methyl-substituted 5-6 membered heteroaryl, halo 5-6 membered heteroaryl, -SONHCH3, -SO2CH3, -COCH3, -COCH2CH3, -COC 3-6 Cycloalkyl, -CO-phenyl, -NHSO2CH3, -CONHCH3;

[0134] Further preferred, R A Selected from hydrogen, carboxyl, and optionally substituted substituents such as: methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methylamino, ethylamino, phenyl, amide. , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , The optional substitution is either unsubstituted or substituted with one or more of the following substituents: hydroxyl, cyano, F, Cl, Br, oxo, amide, -SO2NH2, methyl, ethyl, n-propyl, isopropyl, monofluoromethyl, difluoromethyl, trifluoromethyl, methoxy, hydroxymethyl, benzyl, phenyl optionally substituted with methyl or halogen, pyridyl optionally substituted with methyl or halogen, pyrazolyl optionally substituted with methyl or halogen, -SONHCH3, -SO2CH3, -COCH3, -COCH2CH3, -CO-cyclopropyl, -CO-cyclobutyl, -CO-cyclopentyl, -CO-phenyl, -NHSO2CH3, -CONHCH3;

[0135] Further preferred, R A Selected from hydrogen, carboxyl,

[0136]

[0137]

[0138] One of them.

[0139] In a preferred embodiment of the present invention, the compound represented by formula (C) is further represented by formula (C-1):

[0140]

[0141] In formula (C-1), each substituent is defined as described in formula (C).

[0142] In a preferred embodiment of the present invention, the compound represented by formula (C) is further represented by formula (C-2):

[0143]

[0144] In formula (C-2), each substituent is defined as described in formula (C).

[0145] In a preferred embodiment of the present invention, the compound represented by formula (C) is further represented by formula (C-3):

[0146]

[0147] In formula (C-3), each substituent is defined as described in formula (C).

[0148] In a preferred embodiment of the present invention, the compound represented by formula (C) is further represented by formula (C-4):

[0149]

[0150] In formula (C-4), each substituent is defined as described in formula (C).

[0151] In a preferred embodiment of the present invention, the compound represented by formula (C) is further represented by formula (C-5):

[0152]

[0153] In formula (C-5), each substituent is defined as described in formula (C).

[0154] The present invention also provides a compound represented by formula (V) as follows, and its stereoisomers, optical isomers, pharmaceutical salts, prodrugs, and solvates.

[0155]

[0156] Where Q and Y are both selected from CR 1 Or one of N; R 1 Selected from hydrogen, halogen, hydroxyl, mercapto, amino, cyano, amide, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 1-6 Alkoxy, C 1-6 Alkyl thiols, halogenated C 1-6 Alkyl, Halogenated C 1-6Alkoxy groups, 4-6 membered heterocyclic groups;

[0157] X is selected from CR x Or N; where R x Each time it appears, it is independently selected from hydrogen, halogen, hydroxyl, mercapto, amino, cyano, C 1-6 Alkyl, C 2-6 alkenyl, C 1-6 Alkoxy, C 3-8 cycloalkyl, halogenated C 1-6 alkyl;

[0158] R A Selected from hydrogen, carboxyl, -C 1-6 Alkyl-NH2, -ZC 1-6 Alkyl, -ZC 3-12 cycloalkyl, -ZC 6-12 Cycloalkenyl, -ZC 6-12 Aryl, -Z-3-12 heterocyclic and -Z-5-12 heteroaryl, -CONHC 1-6 Alkyl; wherein, -Z- is selected from bonds, -C(R) 10 (R) 11 )-、-C(R 12 (R) 13 ) C(R 14 (R) 15 )-、-N(R 16 -, -O-, or -S-, where R 10 R 11 R 12 R 13 R 14 R 15 R 16 Each group is independently selected from hydrogen, methyl, ethyl, hydroxyl, carboxyl, amino, amide, cyano, and oxo groups. When R is attached to the same atom... 10 and R 11 R 12 and R 13 R 14 and R 15 When one of the substituents is selected from an oxo group, the other substituent is absent; the -C 1-6 Alkyl-NH2, -ZC 1-6 Alkyl, -ZC 3-12 cycloalkyl, -ZC 6-12 Cycloalkenyl, -ZC 6-12 Aryl, -Z-3-12 heterocyclic and -Z-5-12 heteroaryl, -CONHC 1-6The alkyl group may be optionally substituted with one or more of the following substituents: hydroxyl, cyano, halogen, oxo, amide, -SO2NH2, or optionally substituted C. 1-6 Alkyl, optionally substituted C 1-6 Alkoxy, optional substituted -C 1-6 Alkyl hydroxyl, optional substituted C 6-12 Aryl, optionally substituted 3-6 membered heterocyclic, optionally substituted 5-10 membered heteroaryl, optionally substituted -SONHC 1-6 Alkyl, optionally substituted -SO2C 1-6 Alkyl, optionally substituted -COC 1-6 Alkyl, optionally substituted -COC 3-6 cycloalkyl, optionally substituted -COC 6-12 Aryl, optionally substituted -NHSO2C 1-6 Alkyl, optionally substituted -CONHC 1-6 Alkyl; the optional substitution is either unsubstituted or substituted with one or more of the following substituents: C 1-6 Alkyl, hydroxyl, halogen, oxo group;

[0159] The heteroatoms in the "heterocyclic group" and "heteroaryl group" are selected from N, O or S, and the number of heteroatoms is 1, 2, 3 or 4.

[0160] In a preferred embodiment of the present invention, Y is selected from N, and Q is selected from CR. 1 ;R 1 Selected from hydrogen, halogen, hydroxyl, mercapto, amino, cyano, amide, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio;

[0161] Further preferred, Y is selected from N, and Q is selected from CR. 1 ;R 1 Selected from hydrogen, halogen, hydroxyl, mercapto, amino, cyano, amide, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, methylthio, ethylthio;

[0162] Further preferred, Y is selected from N, and Q is selected from CR. 1 ;R 1 Selected from hydrogen, halogen, cyano, amide, methyl, ethyl, methoxy, ethoxy, methylthio, ethylthio;

[0163] Furthermore, Y is selected from N, and Q is selected from CR. 1 ;R 1 Selected from hydrogen, F, Cl, Br, cyano, amide, methyl, ethyl, methoxy, and methylthio;

[0164] Furthermore, Y is selected from N, and Q is selected from CR.1 ;R 1 Selected from hydrogen, F, cyano, amide, and methylthio.

[0165] In a preferred embodiment of the present invention, X is selected from CR. x Among them, R x Selected from hydrogen, halogen, hydroxyl, mercapto, amino, cyano, C 1-6 alkyl;

[0166] Further preferred, R x Selected from hydrogen, F, Cl, Br, hydroxyl, amino, cyano, and methyl;

[0167] Further optimized, R x Selected from hydrogen.

[0168] In a preferred embodiment of the present invention, R A Selected from hydrogen, carboxyl, -C 1-4 Alkyl-NH2, -ZC 1-4 Alkyl, -ZC 3-12 cycloalkyl, -ZC 6-12 Cycloalkenyl, -ZC 6-12 Aryl, -Z-3-12 heterocyclic and -Z-5-12 heteroaryl, -CONHC 1-4 Alkyl; wherein, -Z- is selected from bonds, -C(R) 10 (R) 11 )-、-C(R 12 (R) 13 ) C(R 14 (R) 15 )-、-N(R 16 )-, where R 10 R 11 R 12 R 13 R 14 R 15 R 16 Each group is independently selected from hydrogen, methyl, hydroxyl, amino, cyano, and oxo groups. When R is attached to the same atom... 10 and R 11 R 12 and R 13 R 14 and R 15 When one of the substituents is selected from an oxo group, the other substituent is absent; the -C 1-4 Alkyl-NH2, -ZC 1-4 Alkyl, -ZC 3-12 cycloalkyl, -ZC 6-12 Cycloalkenyl, -ZC 6-12Aryl, -Z-3-12 heterocyclic and -Z-5-12 heteroaryl, -CONHC 1-4 The alkyl group may be optionally substituted with one or more of the following substituents: hydroxyl, cyano, halogen, oxo, amide, -SO2NH2, or optionally substituted C. 1-4 Alkyl, optionally substituted C 1-4 Alkoxy, optional substituted -C 1-4 Alkyl-OH, optionally substituted C 6-12 Aryl, optionally substituted 3-6 membered heterocyclic, optionally substituted 5-10 membered heteroaryl, optionally substituted -SONHC 1-4 Alkyl, optionally substituted -SO2C 1-4 Alkyl, optionally substituted -COC 1-4 Alkyl, optionally substituted -COC 3-6 cycloalkyl, optionally substituted -COC 6-12 Aryl, optionally substituted -NHSO2C 1-4 Alkyl, optionally substituted -CONHC 1-4 Alkyl; the optional substitution is unsubstituted or substituted with one or more of the following substituents: methyl, ethyl, n-propyl, isopropyl, hydroxyl, halogen, oxo;

[0169] Further preferred, R A Selected from hydrogen, carboxyl, -C 1-4 Alkyl-NH2, -ZC 1-4 Alkyl, -ZC 3-6 Monocyclic cycloalkyl, -Z-6-8 spirocycloalkyl, -Z-C6 cycloalkenyl, -Z-phenyl, -Z-4-7 monocyclic heterocyclic, -Z-6-8 bridged heterocyclic, -Z-6-9 fused heterocyclic, -Z-7-11 spirocyclic, -Z-5-6 monocyclic heteroaryl, -Z-7-9 fused heteroaryl, wherein -Z- is selected from bond, -CH2-, -CH2CH2-, -NH-, -CH(OH)-, -CH(CN)-, -CH(CH3)-, -CO-, -COCH2-, -CH2CO-, -COCO-, -CH(OH)CH2-, -CH2CH(OH)-, -CH(CN)CH2-, -CH2CH(CN)-, -CH(CH3)CH2-, -CH2CH(CH3)-, -CONH-, -CON(CH3)-; the C 1-4 Alkyl-NH2, -ZC 1-4 Alkyl, -ZC 3-6Monocyclic cycloalkyl, -Z-6-8 spirocyclic cycloalkyl, -Z-C6 cycloalkenyl, -Z-phenyl, -Z-4-7 monocyclic heterocyclic, -Z-6-8 bridged heterocyclic, -Z-6-9 fused heterocyclic, -Z-7-11 spirocyclic, -Z-5-6 monocyclic heteroaryl, -Z-7-9 fused heteroaryl are optionally substituted with one or more of the following substituents: hydroxyl, cyano, halogen, oxo, amide, -SO2NH2, optionally substituted methyl, optionally substituted ethyl, optionally substituted n-propyl, optionally substituted isopropyl, optionally substituted methoxy, optionally substituted ethoxy, optionally substituted hydroxymethyl, optionally substituted hydroxyethyl, optionally substituted phenyl, optionally substituted 5-6 heterocyclic, optionally substituted 5-6 heteroaryl, optionally substituted -SONHCH3, optionally substituted -SO2 CH3, optionally substituted -COCH3, optionally substituted -COCH2CH3, optionally substituted -COC 3-6 Cycloalkyl, optionally substituted -CO-phenyl, optionally substituted -NHSO2CH3, optionally substituted -CONHCH3; the optional substitution is unsubstituted or substituted with one or more of the following substituents: methyl, ethyl, hydroxyl, halogen, oxo.

[0170] Further preferred, R AThe following substituents are selected from hydrogen, carboxyl, and optionally substituted: -Z-methyl, -Z-ethyl, -Z-n-propyl, -Z-isopropyl, -Z-cyclopropyl, -Z-cyclobutyl, -Z-cyclopentyl, -Z-cyclohexyl, -Z-C6 cycloalkenyl, -Z-C6 / C3 spirocycloalkyl, -Z-5-membered monocyclic heterocyclic group, -Z-6-membered monocyclic heterocyclic group, -Z-7-membered monocyclic heterocyclic group, -Z-5-membered monocyclic heteroaryl, -Z-6-membered monocyclic heteroaryl, -Z-phenyl, -Z-7-membered bridged heterocyclic group, -Z-8-membered bridged heterocyclic group, -Z-6-membered / 3-membered fused heterocyclic group, -Z-6-membered / 4-membered fused heterocyclic group, -Z-6-membered / 5-membered fused heterocyclic group, -Z-3-membered / 6-membered fused heterocyclic group, -Z-4-membered / 6-membered fused heterocyclic group, -Z-5-membered / 6-membered fused heterocyclic group. -Z-3 / 4-membered fused heterocyclic group, -Z-4 / 3-membered fused heterocyclic group, -Z-5 / 3-membered fused heterocyclic group, -Z-3 / 5-membered fused heterocyclic group, -Z-5 / 4-membered fused heterocyclic group, -Z-4 / 5-membered fused heterocyclic group, -Z-5 / 5-membered fused heterocyclic group, -Z-4 / 4-membered fused heterocyclic group, -Z-5 / 4-membered spirocyclic group, -Z-4 / 5-membered spirocyclic group, -Z-5 / 5-membered spirocyclic group, -Z-4 / 6-membered spirocyclic group, -Z-6 / 4-membered spirocyclic group, -Z-5 / 6-membered spirocyclic group Heterocyclic groups, -Z-6-membered / 5-membered spiroheterocyclic groups, -Z-6-membered / 6-membered spiroheterocyclic groups, -Z-5-membered / 5-membered fused heteroaryl groups, -Z-5-membered / 6-membered fused heteroaryl groups, -Z-6-membered / 5-membered fused heteroaryl groups, -methyl-NH2, -ethyl-NH2, -CONHCH3, and -CONHCH2CH3, wherein -Z- is selected from bonds, -CH2-, -CH2CH2-, -NH-, and -CONH-; the optional substitution is unsubstituted or substituted by one or more of the following substituents: hydroxyl, cyano, halogen, oxygen. Substituents, amides, -SO2NH2, methyl, ethyl, n-propyl, isopropyl, halomethyl, haloethyl, halon-n-propyl, haloisopropyl, methoxy, ethoxy, hydroxymethyl, hydroxyethyl, phenyl, benzyl, halophenyl, 5-6 membered heterocyclic group, methyl-substituted 5-6 membered heterocyclic group, halo-5-6 membered heterocyclic group, 5-6 membered heteroaryl, methyl-substituted 5-6 membered heteroaryl, halo-5-6 membered heteroaryl, -SONHCH3, -SO2CH3, -COCH3, -COCH2CH3, -COC 3-6 Cycloalkyl, -CO-phenyl, -NHSO2CH3, -CONHCH3;

[0171] Further preferred, R A Selected from hydrogen, carboxyl, and optionally substituted substituents such as: methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methylamino, ethylamino, phenyl. , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , The optional substitution is either unsubstituted or substituted with one or more of the following substituents: hydroxyl, cyano, F, Cl, Br, oxo, amide, -SO2NH2, methyl, ethyl, n-propyl, isopropyl, monofluoromethyl, difluoromethyl, trifluoromethyl, methoxy, hydroxymethyl, benzyl, phenyl optionally substituted with methyl or halogen, pyridyl optionally substituted with methyl or halogen, pyrazolyl optionally substituted with methyl or halogen, -SONHCH3, -SO2CH3, -COCH3, -COCH2CH3, -CO-cyclopropyl, -CO-cyclobutyl, -CO-cyclopentyl, -CO-phenyl, -NHSO2CH3, -CONHCH3;

[0172] Further preferred, R A Selected from hydrogen, carboxyl,

[0173]

[0174]

[0175] One of them.

[0176] In a preferred embodiment of the invention, the compound represented by formula (V) is further represented by formula (VI):

[0177]

[0178] In formula (VI), each substituent is defined as described in formula (V).

[0179] The present invention also provides a compound represented by formula (D) below, and its stereoisomers, optical isomers, pharmaceutical salts, prodrugs, and solvates.

[0180]

[0181] Where Q and Y are both selected from CR 1 Or one of N; R 1 Selected from hydrogen, halogen, hydroxyl, mercapto, amino, cyano, amide, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 1-6 Alkoxy, C 1-6 Alkyl thiols, halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy groups, 4-6 membered heterocyclic groups;

[0182] X is selected from CR x Or N; where R x Each time it appears, it is independently selected from hydrogen, halogen, hydroxyl, mercapto, amino, cyano, C 1-6 Alkyl, C 2-6 alkenyl, C 1-6 Alkoxy, C 3-8 cycloalkyl, halogenated C 1-6 alkyl;

[0183] R Y Halogen, C 1-6 Alkyl or hydrogen;

[0184] R Z The quantity is 0, 1, 2, or 3, and each occurrence is independently selected from halogen, hydroxyl, cyano, amino, C 1-3 Alkyl, Halogenated C 1-3 alkyl;

[0185] G is selected from a benzene ring or a pyridine ring;

[0186] R W The number is 1, 2, or 3, each independently selected from hydrogen, halogen, cyano, amino, hydroxyl, carboxyl, sulfonyl, sulfonamide, sulfone, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 3-6 Cycloalkenyl, 3-10 membered heterocyclic groups, C 6-12 Aryl, 5-10 heteroaryl, -NHC 1-6Alkyl, -N(C) 1-6 Alkyl)2;

[0187] R D Selected from -NR 7 C(O)R 8 or -NR 7 C(O)NR 7 R 8 , where R 7 Each group is independently selected from hydrogen, cyano, hydroxyl, halogen, and C. 1-3 Alkyl, Halogenated C 1-3 Alkyl, C 3-6 Carbocyclic, aryl, R 8 Selected from the following substituents that are optionally substituted: C 1-6 Alkyl, C 3-12 carbonyl group, C 6-12 aryl, 3-12 membered heterocyclic, 5-12 membered heteroaryl, wherein the optional substitution is unsubstituted or substituted by one or more of the following substituents: hydroxyl, amino, cyano, halogen, oxo, C 1-6 Alkyl, Halogenated C 1-6 Alkyl group, -S(O)2C 1-6 Alkyl, -COC 1-6 alkyl.

[0188] The heteroatoms in the "heterocyclic group" and "heteroaryl group" are selected from N, O or S, and the number of heteroatoms is 1, 2, 3 or 4.

[0189] In a preferred embodiment of the present invention, Y is selected from N, and Q is selected from CR. 1 ;R 1 Selected from hydrogen, halogen, hydroxyl, mercapto, amino, cyano, amide, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio;

[0190] Further preferred, Y is selected from N, and Q is selected from CR. 1 ;R 1 Selected from hydrogen, halogen, hydroxyl, mercapto, amino, cyano, amide, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, methylthio, ethylthio;

[0191] Further preferred, Y is selected from N, and Q is selected from CR. 1 ;R 1 Selected from hydrogen, halogen, cyano, amide, methyl, ethyl, methoxy, ethoxy, methylthio, ethylthio;

[0192] Furthermore, Y is selected from N, and Q is selected from CR. 1 ;R 1Selected from hydrogen, F, Cl, Br, cyano, amide, methyl, ethyl, methoxy, and methylthio;

[0193] Furthermore, Y is selected from N, and Q is selected from CR. 1 ;R 1 Selected from hydrogen, F, cyano, amide, and methylthio.

[0194] In the optimal selection, Y is chosen from N, and Q is chosen from CR. 1 ;R 1 Selected from hydrogen.

[0195] In a preferred embodiment of the present invention, X is selected from CR. x Among them, R x Selected from hydrogen, halogen, hydroxyl, mercapto, amino, cyano, C 1-6 alkyl;

[0196] Further preferred, R x Selected from hydrogen, F, Cl, Br, hydroxyl, amino, cyano, and methyl;

[0197] Further optimized, R x Selected from hydrogen.

[0198] In a preferred embodiment of the present invention, R Y The following are the radicals: F, Cl, Br, methyl, ethyl, n-propyl, isopropyl, and hydrogen.

[0199] Further preferred, R Y For F, Cl, Br, methyl, ethyl, hydrogen;

[0200] Further optimized, R Y It is a methyl group.

[0201] In a preferred embodiment of the present invention, R Z The quantity is 0, 1, 2 or 3, and each time it appears, it is independently selected from F, Cl, Br, hydroxy, cyano, amino, methyl, ethyl, monofluoromethyl, difluoromethyl, trifluoromethyl;

[0202] Further preferred, R Z The quantity is 0, 1 or 2, and each time it appears, it is independently selected from F, Cl, Br, hydroxyl, methyl, monofluoromethyl, difluoromethyl, trifluoromethyl;

[0203] Further optimized, R Z The quantity is 0.

[0204] In a preferred embodiment of the present invention, R W The number is 1, 2, or 3, each independently selected from hydrogen, halogen, cyano, amino, hydroxyl, carboxyl, C 1-3 Alkyl, Halogenated C 1-3Alkyl, C 1-3 Alkoxy, -NHC 1-3 Alkyl, -N(C) 1-3 Alkyl)2;

[0205] Further preferred, R W The number is 1, 2 or 3, and each is independently selected from hydrogen, F, Cl, Br, cyano, amino, hydroxy, carboxyl, methyl, ethyl, n-propyl, isopropyl, monofluoromethyl, difluoromethyl, trifluoromethyl, methoxy, -NHCH3, -N(CH3)2;

[0206] Further preferred, R W The number is 1, 2 or 3, and each is independently selected from hydrogen, F, Cl, Br, cyano, amino, hydroxyl, carboxyl, methyl, monofluoromethyl, difluoromethyl, trifluoromethyl, methoxy;

[0207] Further optimized, R W The number is 1 or 2, selected from hydrogen, methyl, F, cyano, and methoxy.

[0208] In a preferred embodiment of the present invention, R D Selected from -NR 7 C(O)R 8 or -NR 7 C(O)NR 7 R 8 , where R 7 Each of the following groups is independently selected from hydrogen, cyano, hydroxyl, F, Cl, Br, methyl, ethyl, cyclopropyl, phenyl, and R. 8 Selected from the following substituents that are optionally substituted: C 1-4 Alkyl, C 3-10 cycloalkyl, C 6-10 aryl, 3-8 membered heterocyclic, 5-6 membered heteroaryl, wherein the optional substitution is unsubstituted or substituted by one or more of the following substituents: hydroxyl, amino, cyano, halogen, oxo, C 1-3 Alkyl, Halogenated C 1-3 Alkyl group, -S(O)2C 1-3 Alkyl, -COC 1-3 alkyl;

[0209] Further preferred, R D Selected from -NR 7 C(O)R 8 or -NR 7 C(O)NR 7 R 8 , where R 7 Each of the following groups is independently selected from hydrogen, cyano, methyl, ethyl, cyclopropyl, and phenyl. 8 Selected from the following substituents that can be optionally substituted: methyl, ethyl, n-propyl, isopropyl, C3-6 Monocyclic cycloalkyl, phenyl, 3-6 membered monocyclic heterocyclic groups, 7-9 membered bridged heterocyclic groups, C 7-10 Bridged cycloalkyl, 5-6 membered monocyclic heteroaryl, wherein the optional substitution is unsubstituted or substituted by one or more of the following substituents: hydroxyl, amino, cyano, halogen, oxo, C 1-3 Alkyl, Halogenated C 1-3 Alkyl group, -S(O)2C 1-3 Alkyl, -COC 1-3 alkyl.

[0210] Further preferred, R D Selected from -NR 7 C(O)R 8 or -NR 7 C(O)NR 7 R 8 , where R 7 Each of the following groups is independently selected from hydrogen, methyl, ethyl, cyclopropyl, and phenyl, R 8 Selected from the following substituents that may be substituted: methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, pyrrolyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, pyridinyl, thiophene, oxazolyl, thiazolyl, furanyl, pyrazolyl, imidazole, pyrrolyl, piperazine, C 10 Bridged cycloalkyl, 8-membered bridged heterocyclic group, wherein the optional substitution is unsubstituted or substituted by one or more of the following substituents: hydroxyl, amino, cyano, F, Cl, Br, oxo, methyl, ethyl, -S(O)2CH3alkyl, acetyl.

[0211] More preferably, G is a pyridine ring, and R... D R w The pyridine ring attached to it is selected from: , , , , .

[0212] In a further preferred embodiment, G is a benzene ring, and R... D R w The benzene ring attached to it is selected from the structure:

[0213]

[0214]

[0215] .

[0216] In a preferred embodiment of the present invention, the compound represented by formula (D) is further represented by formula (D-1):

[0217]

[0218] In formula (D-1), each substituent is defined as described in formula (D).

[0219] In a preferred embodiment of the present invention, the compound represented by formula (D) is further represented by formula (D-2):

[0220]

[0221] In formula (D-2), each substituent is defined as described in formula (D).

[0222] In a preferred embodiment of the present invention, the compound represented by formula (D) is further represented by formula (D-3):

[0223]

[0224] In formula (D-3), each substituent is defined as described in formula (D).

[0225] In a preferred embodiment of the present invention, the compound represented by formula (D) is further represented by formula (D-4):

[0226]

[0227] In formula (D-4), each substituent is defined as described in formula (D).

[0228] In a preferred embodiment of the present invention, the compound represented by formula (D) is further represented by formula (D-5):

[0229]

[0230] In formula (D-5), each substituent is defined as described in formula (D).

[0231] The present invention also provides a compound represented by formula (VII), and its stereoisomers, optical isomers, pharmaceutical salts, prodrugs, and solvates.

[0232]

[0233] Where Q and Y are both selected from CR 1 Or one of N; R 1 Selected from hydrogen, halogen, hydroxyl, mercapto, amino, cyano, amide, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 1-6Alkoxy, C 1-6 Alkyl thiols, halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy groups, 4-6 membered heterocyclic groups;

[0234] X is selected from CR x Or N; where R x Each time it appears, it is independently selected from hydrogen, halogen, hydroxyl, mercapto, amino, cyano, C 1-6 Alkyl, C 2-6 alkenyl, C 1-6 Alkoxy, C 3-8 cycloalkyl, halogenated C 1-6 alkyl;

[0235] R W The number is 1, 2, or 3, each independently selected from hydrogen, halogen, cyano, amino, hydroxyl, carboxyl, sulfonyl, sulfonamide, sulfone, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 3-6 Cycloalkenyl, 3-10 membered heterocyclic groups, C 6-12 Aryl, 5-10 heteroaryl, -NHC 1-6 Alkyl, -N(C) 1-6 Alkyl)2;

[0236] R D Selected from -NR 7 C(O)R 8 or -NR 7 C(O)NR 7 R 8 , where R 7 Each group is independently selected from hydrogen, cyano, hydroxyl, halogen, and C. 1-3 Alkyl, Halogenated C 1-3 Alkyl, C 3-6 Carbocyclic, aryl, R 8 Selected from the following substituents that are optionally substituted: C 1-6 Alkyl, C 3-12 carbonyl group, C 6-12 aryl, 3-12 membered heterocyclic, 5-12 membered heteroaryl, wherein the optional substitution is unsubstituted or substituted by one or more of the following substituents: hydroxyl, amino, cyano, halogen, oxo, C 1-6 Alkyl, Halogenated C 1-6 Alkyl group, -S(O)2C 1-6 Alkyl, -COC 1-6 alkyl.

[0237] The heteroatoms in the "heterocyclic group" and "heteroaryl group" are selected from N, O or S, and the number of heteroatoms is 1, 2, 3 or 4.

[0238] In a preferred embodiment of the present invention, Y is selected from N, and Q is selected from CR. 1 ;R 1 Selected from hydrogen, halogen, hydroxyl, mercapto, amino, cyano, amide, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio;

[0239] Further preferred, Y is selected from N, and Q is selected from CR. 1 ;R 1 Selected from hydrogen, halogen, hydroxyl, mercapto, amino, cyano, amide, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, methylthio, ethylthio;

[0240] Further preferred, Y is selected from N, and Q is selected from CR. 1 ;R 1 Selected from hydrogen, halogen, cyano, amide, methyl, ethyl, methoxy, ethoxy, methylthio, ethylthio;

[0241] Furthermore, Y is selected from N, and Q is selected from CR. 1 ;R 1 Selected from hydrogen, F, Cl, Br, cyano, amide, methyl, ethyl, methoxy, and methylthio;

[0242] Furthermore, Y is selected from N, and Q is selected from CR. 1 ;R 1 Selected from hydrogen, F, cyano, amide, and methylthio.

[0243] In a preferred embodiment of the present invention, X is selected from CR. x Among them, R x Selected from hydrogen, halogen, hydroxyl, mercapto, amino, cyano, C 1-6 alkyl;

[0244] Further preferred, R x Selected from hydrogen, F, Cl, Br, hydroxyl, amino, cyano, and methyl;

[0245] Further optimized, R x Selected from hydrogen.

[0246] In a preferred embodiment of the present invention, R W The number is 1, 2, or 3, each independently selected from hydrogen, halogen, cyano, amino, hydroxyl, carboxyl, C 1-3 Alkyl, Halogenated C 1-3 Alkyl, C 1-3 Alkoxy, -NHC1-3 Alkyl, -N(C) 1-3 Alkyl)2;

[0247] Further preferred, R W The number is 1, 2 or 3, and each is independently selected from hydrogen, F, Cl, Br, cyano, amino, hydroxy, carboxyl, methyl, ethyl, n-propyl, isopropyl, monofluoromethyl, difluoromethyl, trifluoromethyl, methoxy, -NHCH3, -N(CH3)2;

[0248] Further preferred, R W The number is 1, 2 or 3, and each is independently selected from hydrogen, F, Cl, Br, cyano, amino, hydroxyl, carboxyl, methyl, monofluoromethyl, difluoromethyl, trifluoromethyl, methoxy;

[0249] Further optimized, R W The number is 1 or 2, selected from hydrogen, methyl, and F.

[0250] In a preferred embodiment of the present invention, R D Selected from -NR 7 C(O)R 8 or -NR 7 C(O)NR 7 R 8 , where R 7 Each of the following groups is independently selected from hydrogen, cyano, hydroxyl, F, Cl, Br, methyl, ethyl, cyclopropyl, phenyl, and R. 8 Selected from the following substituents that are optionally substituted: C 1-4 Alkyl, C 3-10 cycloalkyl, C 6-10 aryl, 3-8 membered heterocyclic, 5-6 membered heteroaryl, wherein the optional substitution is unsubstituted or substituted by one or more of the following substituents: hydroxyl, amino, cyano, halogen, oxo, C 1-3 Alkyl, Halogenated C 1-3 Alkyl group, -S(O)2C 1-3 Alkyl, -COC 1-3 alkyl;

[0251] Further preferred, R D Selected from -NR 7 C(O)R 8 or -NR 7 C(O)NR 7 R 8 , where R 7 Each of the following groups is independently selected from hydrogen, cyano, methyl, ethyl, cyclopropyl, and phenyl. 8 Selected from the following substituents that can be optionally substituted: methyl, ethyl, n-propyl, isopropyl, C 3-6Monocyclic cycloalkyl, phenyl, 3-6 membered monocyclic heterocyclic groups, 7-9 membered bridged heterocyclic groups, C 7-10 Bridged cycloalkyl, 5-6 membered monocyclic heteroaryl, wherein the optional substitution is unsubstituted or substituted by one or more of the following substituents: hydroxyl, amino, cyano, halogen, oxo, C 1-3 Alkyl, Halogenated C 1-3 Alkyl group, -S(O)2C 1-3 Alkyl, -COC 1-3 alkyl.

[0252] Further preferred, R D Selected from -NR 7 C(O)R 8 or -NR 7 C(O)NR 7 R 8 , where R 7 Each of the following groups is independently selected from hydrogen, methyl, cyclopropyl, and phenyl, R 8 Selected from the following substituents that may be substituted: methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, pyrrolyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, pyridinyl, thiophene, oxazolyl, thiazolyl, furanyl, pyrazolyl, imidazole, pyrroleyl, C 10 Bridged cycloalkyl, 8-membered bridged heterocyclic group, wherein the optional substitution is unsubstituted or substituted by one or more of the following substituents: hydroxyl, amino, cyano, F, Cl, Br, oxo, methyl, ethyl, -S(O)2CH3alkyl, acetyl.

[0253] Further preferred, R D Located at the para position of the fused ring connected to the benzene ring.

[0254] Further optimized, R D R w The benzene ring attached to it is selected from the structure:

[0255]

[0256]

[0257] .

[0258] In a preferred embodiment of the invention, the compound represented by formula (VII) is further represented by formula (IX):

[0259]

[0260] In formula (IX), each substituent is defined as described in formula (VII).

[0261] The present invention also provides a compound represented by formula (E), and its stereoisomers, optical isomers, pharmaceutical salts, prodrugs, and solvates.

[0262]

[0263] Where Q and Y are both selected from CR 1 Or one of N; R 1 Selected from hydrogen, halogen, hydroxyl, mercapto, amino, cyano, amide, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 1-6 Alkoxy, C 1-6 Alkyl thiols, halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy groups, 4-6 membered heterocyclic groups;

[0264] X is selected from CR x Or N; where R x Each time it appears, it is independently selected from hydrogen, halogen, hydroxyl, mercapto, amino, cyano, C 1-6 Alkyl, C 2-6 alkenyl, C 1-6 Alkoxy, C 3-8 cycloalkyl, halogenated C 1-6 alkyl;

[0265] R Y Halogen, C 1-6 Alkyl or hydrogen;

[0266] R Z The quantity is 0, 1, 2, or 3, and each occurrence is independently selected from halogen, hydroxyl, cyano, amino, C 1-3 Alkyl, Halogenated C 1-3 alkyl;

[0267] G is selected from a benzene ring or a pyridine ring;

[0268] R W The number is 1, 2, or 3, each independently selected from hydrogen, halogen, cyano, amino, hydroxyl, carboxyl, sulfonyl, sulfonamide, sulfone, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 3-6 Cycloalkenyl, 3-10 membered heterocyclic groups, C 6-12 Aryl, 5-10 heteroaryl, -NHC 1-6 Alkyl, -N(C)1-6 Alkyl)2;

[0269] R e Selected from 4-12 membered heterocyclic groups, 5-12 membered heteroaryl groups, C 3-12 carbonyl group, C 6-12 Aryl, wherein the 4-12 membered heterocyclic group, the 5-12 membered heteroaryl group, and the C 3-12 carbonyl group, C 6-12 The aryl group can be optionally substituted by one or more of the following substituents: halogen, hydroxyl, amino, cyano, nitro, carboxyl, oxo, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 3-6 Cycloalkenyl, 3-10 membered heterocyclic groups, -NHC 1-6 Alkyl, -N(C) 1-6 Alkyl)2, -C 1-6 Alkyl-OC 1-6 Alkyl, -C 1-6 Alkyl-C 6-12 Aryl;

[0270] The heteroatoms in the "heterocyclic group" and "heteroaryl group" are selected from N, O or S, and the number of heteroatoms is 1, 2, 3 or 4.

[0271] In a preferred embodiment of the present invention, Y is selected from N, and Q is selected from CR. 1 ;R 1 Selected from hydrogen, halogen, hydroxyl, mercapto, amino, cyano, amide, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio;

[0272] Further preferred, Y is selected from N, and Q is selected from CR. 1 ;R 1 Selected from hydrogen, halogen, hydroxyl, mercapto, amino, cyano, amide, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, methylthio, ethylthio;

[0273] Further preferred, Y is selected from N, and Q is selected from CR. 1 ;R 1 Selected from hydrogen, halogen, cyano, amide, methyl, ethyl, methoxy, ethoxy, methylthio, ethylthio;

[0274] Furthermore, Y is selected from N, and Q is selected from CR. 1 ;R 1Selected from hydrogen, F, Cl, Br, cyano, amide, methyl, ethyl, methoxy, and methylthio;

[0275] Furthermore, Y is selected from N, and Q is selected from CR. 1 ;R 1 Selected from hydrogen, F, cyano, amide, and methylthio.

[0276] In the optimal selection, Y is chosen from N, and Q is chosen from CR. 1 ;R 1 Selected from hydrogen.

[0277] In a preferred embodiment of the present invention, X is selected from CR. x Among them, R x Selected from hydrogen, halogen, hydroxyl, mercapto, amino, cyano, C 1-6 alkyl;

[0278] Further preferred, R x Selected from hydrogen, F, Cl, Br, hydroxyl, amino, cyano, and methyl;

[0279] Further optimized, R x Selected from hydrogen.

[0280] In a preferred embodiment of the present invention, R Y The following are the radicals: F, Cl, Br, methyl, ethyl, n-propyl, isopropyl, and hydrogen.

[0281] Further preferred, R Y For F, Cl, Br, methyl, ethyl, hydrogen;

[0282] Further optimized, R Y It is a methyl group.

[0283] In a preferred embodiment of the present invention, R Z The quantity is 0, 1, 2 or 3, and each time it appears, it is independently selected from F, Cl, Br, hydroxy, cyano, amino, methyl, ethyl, monofluoromethyl, difluoromethyl, trifluoromethyl;

[0284] Further preferred, R Z The quantity is 0, 1 or 2, and each time it appears, it is independently selected from F, Cl, Br, hydroxyl, methyl, monofluoromethyl, difluoromethyl, trifluoromethyl;

[0285] Further optimized, R Z The quantity is 0.

[0286] In a preferred embodiment of the present invention, R W The number is 1, 2, or 3, each independently selected from hydrogen, halogen, cyano, amino, hydroxyl, carboxyl, C 1-3 Alkyl, Halogenated C 1-3Alkyl, C 1-3 Alkoxy, -NHC 1-3 Alkyl, -N(C) 1-3 Alkyl)2;

[0287] Further preferred, R W The number is 1, 2 or 3, and each is independently selected from hydrogen, F, Cl, Br, cyano, amino, hydroxy, carboxyl, methyl, ethyl, n-propyl, isopropyl, monofluoromethyl, difluoromethyl, trifluoromethyl, methoxy, -NHCH3, -N(CH3)2;

[0288] Further preferred, R W The number is 1, 2 or 3, and each is independently selected from hydrogen, F, Cl, Br, cyano, amino, hydroxy, carboxyl, methyl, monofluoromethyl, difluoromethyl, trifluoromethyl, methoxy, -NHCH3;

[0289] Further optimized, R W The number is 1 or 2, each independently selected from hydrogen, methyl, cyano, F, trifluoromethyl, and -NHCH3.

[0290] In a preferred embodiment of the present invention, R e Selected from 4-7 member monocyclic heterocyclic groups, 6-8 member bridged heterocyclic groups, 7-11 member spirocyclic heterocyclic groups, 6-10 member fused heterocyclic groups, 5-6 member monocyclic heteroaryl groups, C 5-6 Monocyclic cycloalkyl, C6 cycloalkenyl, phenyl, wherein the 4-7 membered monocyclic heterocyclic group, 6-8 membered bridged heterocyclic group, 7-11 membered spiroheterocyclic group, 8-10 membered fused heterocyclic group, 5-6 membered monocyclic heteroaryl group, C 3-6 Monocyclic cycloalkyl, C6 cycloalkenyl, and phenyl groups may be optionally substituted with one or more of the following substituents: halogen, hydroxyl, amino, cyano, nitro, carboxyl, oxo, C 1-3 Alkyl, Halogenated C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, C 3-6 Cycloalkyl, 3-6 membered monocyclic heterocyclic groups, -NHC 1-3 Alkyl, -N(C) 1-3 Alkyl)2, C 1-3 Alkyl-OC 1-3 Alkyl, -C 1-3 Alkyl-phenyl;

[0291] Further preferred, R eSelected from the following substituents with optional substitution: 4-membered monocyclic heterocyclic group, 5-membered monocyclic heterocyclic group, 6-membered monocyclic heterocyclic group, 7-membered monocyclic heterocyclic group, 7-membered bridged heterocyclic group, 8-membered bridged heterocyclic group, 4-membered / 4-membered spirocyclic group, 4-membered / 5-membered spirocyclic group, 5-membered / 4-membered spirocyclic group, 5-membered / 5-membered spirocyclic group, 4-membered / 6-membered spirocyclic group, 6-membered / 4-membered spirocyclic group, 5-membered / 6-membered spirocyclic group, 6-membered / 5-membered spirocyclic group, 6-membered / 6-membered spirocyclic group, 5-membered / 3-membered fused heterocyclic group, 5-membered / 5-membered fused heterocyclic group, 5-membered / 6-membered fused heterocyclic group, 6-membered / 5-membered fused heterocyclic group. The group may contain 6-membered / 6-membered fused heterocyclic groups, 5-membered monocyclic heteroaryl groups, 6-membered monocyclic heteroaryl groups, cyclopentyl, cyclohexyl, C6 cycloalkenyl, or phenyl groups, wherein the optional substitution is unsubstituted or substituted by one or more of the following substituents: halogen, hydroxyl, amino, cyano, nitro, carboxyl, oxo, methyl, ethyl, n-propyl, isopropyl, monofluoromethyl, difluoromethyl, trifluoromethyl, methoxy, ethoxy, hydroxymethyl, hydroxyethyl, cyclopropyl, cyclobutyl, 3-membered monocyclic heterocyclic groups, 4-membered monocyclic heterocyclic groups, -CH2OCH3, -CH2CH2OCH3, or -CH2-phenyl.

[0292] Further preferred, R e The following substituents are selected from the optional substituents: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , The optional substitution is unsubstituted or substituted by one or more of the following substituents: F, Cl, Br, hydroxyl, cyano, oxo, methyl, ethyl, n-propyl, isopropyl, hydroxymethyl, hydroxyethyl, cyclopropyl, cyclobutyl, -CH2OCH3, -CH2CH2OCH3, -CH2-phenyl.

[0293] Furthermore, preferably, G is a pyridine ring, and R... W R e The pyridine ring attached to it is selected from the structure:

[0294] .

[0295] In a further preferred configuration, G is a benzene ring, and R... W R e The benzene ring attached to it is selected from the structure:

[0296]

[0297]

[0298]

[0299] .

[0300] In a preferred embodiment of the present invention, the compound represented by formula (E) is further represented by formula (E-1):

[0301]

[0302] In Equation (E-1), each substituent is defined as described in Equation (E).

[0303] In a preferred embodiment of the present invention, the compound represented by formula (E) is further represented by formula (E-2):

[0304]

[0305] In formula (E-2), each substituent is defined as described in formula (E).

[0306] In a preferred embodiment of the present invention, the compound represented by formula (E) is further represented by formula (E-3):

[0307]

[0308] In Equation (E-3), each substituent is defined as described in Equation (E).

[0309] In a preferred embodiment of the present invention, the compound represented by formula (E) is further represented by formula (E-4):

[0310]

[0311] In Equation (E-4), each substituent is defined as described in Equation (E).

[0312] In a preferred embodiment of the present invention, the compound represented by formula (E) is further represented by formula (E-5):

[0313]

[0314] In Equation (E-5), each substituent is defined as described in Equation (E).

[0315] The present invention also provides a compound represented by formula (X), and its stereoisomers, optical isomers, pharmaceutical salts, prodrugs, and solvates.

[0316]

[0317] Where Q and Y are both selected from CR 1 Or one of N; R 1 Selected from hydrogen, halogen, hydroxyl, mercapto, amino, cyano, amide, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 1-6 Alkoxy, C 1-6 Alkyl thiols, halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy groups, 4-6 membered heterocyclic groups;

[0318] X is selected from CR x Or N; where R x Each time it appears, it is independently selected from hydrogen, halogen, hydroxyl, mercapto, amino, cyano, C 1-6 Alkyl, C 2-6 alkenyl, C 1-6 Alkoxy, C 3-8 cycloalkyl, halogenated C 1-6 alkyl;

[0319] R W The number is 1, 2, or 3, each independently selected from hydrogen, halogen, cyano, amino, hydroxyl, carboxyl, sulfonyl, sulfonamide, sulfone, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 3-6 Cycloalkenyl, 3-10 membered heterocyclic groups, C 6-12 Aryl, 5-10 heteroaryl, -NHC 1-6 Alkyl, -N(C) 1-6 Alkyl)2;

[0320] R e Selected from 4-12 membered heterocyclic groups, 5-12 membered heteroaryl groups, C 3-12 carbonyl group, C 6-12 Aryl, wherein the 4-12 membered heterocyclic group, the 5-12 membered heteroaryl group, and the C 3-12 carbonyl group, C 6-12 The aryl group can be optionally substituted by one or more of the following substituents: halogen, hydroxyl, amino, cyano, nitro, carboxyl, oxo, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 3-6 Cycloalkenyl, 3-10 membered heterocyclic groups, -NHC 1-6 Alkyl, -N(C) 1-6 Alkyl)2, C 1-6 Alkyl-OC 1-6 alkyl;

[0321] The heteroatoms in the "heterocyclic group" and "heteroaryl group" are selected from N, O or S, and the number of heteroatoms is 1, 2, 3 or 4.

[0322] In a preferred embodiment of the present invention, Y is selected from N, and Q is selected from CR. 1 ;R 1 Selected from hydrogen, halogen, hydroxyl, mercapto, amino, cyano, amide, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio;

[0323] Further preferred, Y is selected from N, and Q is selected from CR. 1 ;R 1 Selected from hydrogen, halogen, hydroxyl, mercapto, amino, cyano, amide, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, methylthio, ethylthio;

[0324] Further preferred, Y is selected from N, and Q is selected from CR. 1 ;R 1 Selected from hydrogen, halogen, cyano, amide, methyl, ethyl, methoxy, ethoxy, methylthio, ethylthio;

[0325] Furthermore, Y is selected from N, and Q is selected from CR. 1 ;R 1 Selected from hydrogen, F, Cl, Br, cyano, amide, methyl, ethyl, methoxy, and methylthio;

[0326] Furthermore, Y is selected from N, and Q is selected from CR. 1 ;R 1 Selected from hydrogen, F, cyano, amide, and methylthio.

[0327] In a preferred embodiment of the present invention, X is selected from CR. x Among them, R x Selected from hydrogen, halogen, hydroxyl, mercapto, amino, cyano, C 1-6 alkyl;

[0328] Further preferred, R x Selected from hydrogen, F, Cl, Br, hydroxyl, amino, cyano, and methyl;

[0329] Further optimized, R x Selected from hydrogen.

[0330] In a preferred embodiment of the present invention, R W The number is 1, 2, or 3, each independently selected from hydrogen, halogen, cyano, amino, hydroxyl, carboxyl, C 1-3 Alkyl, Halogenated C 1-3 Alkyl, C 1-3 Alkoxy, -NHC 1-3 Alkyl, -N(C) 1-3 Alkyl)2;

[0331] Further preferred, R W The number is 1, 2 or 3, and each is independently selected from hydrogen, F, Cl, Br, cyano, amino, hydroxy, carboxyl, methyl, ethyl, n-propyl, isopropyl, monofluoromethyl, difluoromethyl, trifluoromethyl, methoxy, -NHCH3, -N(CH3)2;

[0332] Further preferred, R W The number is 1, 2 or 3, and each is independently selected from hydrogen, F, Cl, Br, cyano, amino, hydroxy, carboxyl, methyl, monofluoromethyl, difluoromethyl, trifluoromethyl, methoxy, -NHCH3;

[0333] Further optimized, R W The number is 1, selected from hydrogen, methyl, cyano, F, -NHCH3.

[0334] In a preferred embodiment of the present invention, R e Selected from 4-7 member monocyclic heterocyclic groups, 6-8 member bridged heterocyclic groups, 7-11 member spirocyclic heterocyclic groups, 6-10 member fused heterocyclic groups, 5-6 member monocyclic heteroaryl groups, C 3-6 Monocyclic cycloalkyl, C6 cycloalkenyl, phenyl, wherein the 4-7 membered monocyclic heterocyclic group, 6-8 membered bridged heterocyclic group, 7-11 membered spiroheterocyclic group, 8-10 membered fused heterocyclic group, 5-6 membered monocyclic heteroaryl group, C 3-6Monocyclic cycloalkyl, C6 cycloalkenyl, and phenyl groups may be optionally substituted with one or more of the following substituents: halogen, hydroxyl, amino, cyano, nitro, carboxyl, oxo, C 1-3 Alkyl, Halogenated C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, C 3-6 Cycloalkyl, 3-6 membered monocyclic heterocyclic groups, -NHC 1-3 Alkyl, -N(C) 1-3 Alkyl)2, C 1-3 Alkyl-OC 1-3 alkyl;

[0335] Further preferred, R e Selected from the following substituents with optional substitution: 4-membered monocyclic heterocyclic group, 5-membered monocyclic heterocyclic group, 6-membered monocyclic heterocyclic group, 7-membered monocyclic heterocyclic group, 7-membered bridged heterocyclic group, 8-membered bridged heterocyclic group, 4-membered / 4-membered spirocyclic group, 4-membered / 5-membered spirocyclic group, 5-membered / 4-membered spirocyclic group, 5-membered / 5-membered spirocyclic group, 4-membered / 6-membered spirocyclic group, 6-membered / 4-membered spirocyclic group, 5-membered / 6-membered spirocyclic group, 6-membered / 5-membered spirocyclic group, 6-membered / 6-membered spirocyclic group, 5-membered / 3-membered fused heterocyclic group, 5-membered / 5-membered fused heterocyclic group, 5-membered / 6-membered fused heterocyclic group, 6-membered / 5-membered fused heterocyclic group. The group may contain 6-membered / 6-membered fused heterocyclic groups, 5-membered monocyclic heteroaryl groups, 6-membered monocyclic heteroaryl groups, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, C6 cycloalkenyl, or phenyl groups, wherein the optional substitution is unsubstituted or substituted by one or more of the following substituents: halogen, hydroxyl, amino, cyano, nitro, carboxyl, oxo, methyl, ethyl, n-propyl, isopropyl, monofluoromethyl, difluoromethyl, trifluoromethyl, methoxy, ethoxy, hydroxymethyl, hydroxyethyl, cyclopropyl, cyclobutyl, 3-membered monocyclic heterocyclic groups, 4-membered monocyclic heterocyclic groups, -CH2OCH3, or -CH2CH2OCH3.

[0336] Further preferred, R e The following substituents are selected from the optional substituents: , , , , , , , , , , , , , , , , , , , , , , , , , , The optional substitution is unsubstituted or substituted by one or more of the following substituents: F, Cl, Br, hydroxyl, cyano, oxo, methyl, ethyl, n-propyl, isopropyl, hydroxymethyl, hydroxyethyl, cyclopropyl, cyclobutyl, -CH2OCH3, -CH2CH2OCH3.

[0337] In a preferred embodiment of the present invention, R e Connected at the meta or para position of a fused ring attached to the benzene ring; more preferably, R e It is attached to the para position of the fused ring connected to the benzene ring.

[0338] Further optimized, R D R e The benzene ring attached to it is selected from the structure:

[0339]

[0340]

[0341] One of them.

[0342] In a preferred embodiment of the present invention, the compound represented by formula (X) is further represented by formula (XI):

[0343]

[0344] In formula (XI), each substituent is defined as described in formula (X).

[0345] The present invention also provides a compound represented by formula (F) below, and its stereoisomers, optical isomers, pharmaceutical salts, prodrugs, and solvates.

[0346]

[0347] Where Q and Y are both selected from CR 1 Or one of N; R 1 Selected from hydrogen, halogen, hydroxyl, mercapto, amino, cyano, amide, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 1-6 Alkoxy, C 1-6 Alkyl thiols, halogenated C 1-6 Alkyl, Halogenated C 1-6Alkoxy groups, 4-6 membered heterocyclic groups;

[0348] X is selected from CR x Or N; where R x Each time it appears, it is independently selected from hydrogen, halogen, hydroxyl, mercapto, amino, cyano, C 1-6 Alkyl, C 2-6 alkenyl, C 1-6 Alkoxy, C 3-8 cycloalkyl, halogenated C 1-6 alkyl;

[0349] R Y Halogen, C 1-6 Alkyl or hydrogen;

[0350] R Z The quantity is 0, 1, 2, or 3, and each occurrence is independently selected from halogen, hydroxyl, cyano, amino, C 1-3 Alkyl, Halogenated C 1-3 alkyl;

[0351] K is selected from C 5-6 Carbocyclic or 5-7 membered heterocyclic groups;

[0352] R L The quantity is one or two, and each occurrence is independently selected from hydrogen, halogen, hydroxyl, cyano, C. 1-3 alkyl;

[0353] R K Selected from hydrogen, C 1-3 Alkyl group, -C(O)C 1-3 Alkyl, Halogenated C 1-3 Alkyl, C 3-6 Cycloalkyl, 5-6-membered heteroaryl, 5-8-membered heterocyclic, phenyl, wherein C 1-3 Alkyl group, -C(O)C 1-3 Alkyl, Halogenated C 1-3 Alkyl, C 3-6 Cycloalkyl, 5-6-membered heteroaryl, 5-8-membered heterocyclic, phenyl optionally selected from hydroxyl, C 1-3 Substituted by alkyl or halogen substituents;

[0354] The heteroatoms in the "heterocyclic group" and "heteroaryl group" are selected from N, O or S, and the number of heteroatoms is 1, 2, 3 or 4.

[0355] In a preferred embodiment of the present invention, Y is selected from N, and Q is selected from CR. 1 ;R 1 Selected from hydrogen, halogen, hydroxyl, mercapto, amino, cyano, amide, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6Alkylthio;

[0356] Further preferred, Y is selected from N, and Q is selected from CR. 1 ;R 1 Selected from hydrogen, halogen, hydroxyl, mercapto, amino, cyano, amide, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, methylthio, ethylthio;

[0357] Further preferred, Y is selected from N, and Q is selected from CR. 1 ;R 1 Selected from hydrogen, halogen, cyano, amide, methyl, ethyl, methoxy, ethoxy, methylthio, ethylthio;

[0358] Furthermore, Y is selected from N, and Q is selected from CR. 1 ;R 1 Selected from hydrogen, F, Cl, Br, cyano, amide, methyl, ethyl, methoxy, and methylthio;

[0359] Furthermore, Y is selected from N, and Q is selected from CR. 1 ;R 1 Selected from hydrogen, F, cyano, amide, and methylthio.

[0360] In the optimal selection, Y is chosen from N, and Q is chosen from CR. 1 ;R 1 Selected from hydrogen.

[0361] In a preferred embodiment of the present invention, X is selected from CR. x Among them, R x Selected from hydrogen, halogen, hydroxyl, mercapto, amino, cyano, C 1-6 alkyl;

[0362] Further preferred, R x Selected from hydrogen, F, Cl, Br, hydroxyl, amino, cyano, and methyl;

[0363] Further optimized, R x Selected from hydrogen.

[0364] In a preferred embodiment of the present invention, R Y The following are the radicals: F, Cl, Br, methyl, ethyl, n-propyl, isopropyl, and hydrogen.

[0365] Further preferred, R Y For F, Cl, Br, methyl, ethyl, hydrogen;

[0366] Further optimized, R Y It is a methyl group.

[0367] In a preferred embodiment of the present invention, R ZThe quantity is 0, 1, 2 or 3, and each time it appears, it is independently selected from F, Cl, Br, hydroxy, cyano, amino, methyl, ethyl, monofluoromethyl, difluoromethyl, trifluoromethyl;

[0368] Further preferred, R Z The quantity is 0, 1 or 2, and each time it appears, it is independently selected from F, Cl, Br, hydroxyl, methyl, monofluoromethyl, difluoromethyl, trifluoromethyl;

[0369] Further optimized, R Z The quantity is 0.

[0370] In a preferred embodiment of the present invention, K is selected from cyclopentyl, cyclohexyl, 5-membered monocyclic heterocyclic alkyl, 6-membered monocyclic heterocyclic alkyl, 7-membered bridged heterocyclic group, and cyclohexenyl;

[0371] More preferably, K is selected from cyclopentyl, cyclohexyl,

[0372] .

[0373] More preferably, K is selected from cyclopentyl, cyclohexyl, .

[0374] In a preferred embodiment of the present invention, R L The quantity is one or two, selected from hydrogen, halogen, hydroxyl, cyano, and methyl;

[0375] Further preferred, R L The quantity is 1, selected from hydrogen, hydroxyl, and methyl;

[0376] Further optimized, R L The quantity is 1, selected from hydrogen and hydroxyl.

[0377] In a preferred embodiment of the present invention, R K Selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, -C(O) CH3, -C(O) CH2CH3, C 3-6 Monocyclic cycloalkyl, 5-6 membered monocyclic heteroaryl, 5-6 membered monocyclic heterocyclic, 6-8 membered spiroheterocyclic, phenyl, wherein methyl, ethyl, n-propyl, isopropyl, -C(O) CH3, -C(O) CH2CH3, C 3-6 Monocyclic cycloalkyl, 5-6 membered monocyclic heteroaryl, 5-6 membered monocyclic heterocyclic, 6-8 membered spiroheterocyclic, and phenyl groups may be substituted with substituents selected from hydroxyl, methyl, ethyl, and halogen groups;

[0378] Further preferred, R KThe group is selected from hydrogen, methyl, ethyl, -C(O) CH3, cyclopropyl, cyclobutyl, cyclopentyl, 5-6 membered monocyclic heteroaryl, 5-6 membered monocyclic heterocyclic group, 7 membered spiroheterocyclic group, and phenyl, wherein the methyl, ethyl, -C(O) CH3, cyclopropyl, cyclobutyl, cyclopentyl, 5-6 membered monocyclic heteroaryl, 5-6 membered monocyclic heterocyclic group, 7 membered spiroheterocyclic group, and phenyl are optionally substituted with substituents selected from hydroxyl, methyl, ethyl, and halogen;

[0379] Further optimized, R K Selected from hydrogen, methyl, ethyl, -C(O) CH3, cyclopropyl, cyclobutyl, imidazolyl, pyrazolyl, tetrahydrofuranyl, , phenyl, methyl, ethyl, -C(O) CH3, cyclopropyl, imidazolyl, pyrazolyl, tetrahydrofuranyl, The phenyl group may be optionally substituted with a substituent selected from hydroxyl, methyl, F, Cl, or Br.

[0380] Further optimization, R K Selected from hydrogen, methyl, hydroxymethyl, -CF2CH3, -C(O) CH3, cyclopropyl, , Tetrahydrofuranyl , phenyl.

[0381] The optimal choice, R K Selected from hydrogen.

[0382] In a preferred embodiment of the present invention Selected from the following structure: , , , , , , , , , , , , , , , , , , , or .

[0383] In a preferred embodiment of the present invention, the compound represented by formula (F) is further represented by formula (F-1):

[0384]

[0385] In formula (F-1), each substituent is defined as described in formula (F).

[0386] In a preferred embodiment of the present invention, the compound represented by formula (F) is further represented by formula (F-2):

[0387]

[0388] In formula (F-2), each substituent is defined as described in formula (F).

[0389] In a preferred embodiment of the present invention, the compound represented by formula (F) is further represented by formula (F-3):

[0390]

[0391] In formula (F-3), each substituent is defined as described in formula (F).

[0392] In a preferred embodiment of the present invention, the compound represented by formula (F) is further represented by formula (F-4):

[0393]

[0394] In formula (F-4), each substituent is defined as described in formula (F).

[0395] In a preferred embodiment of the invention, the compound represented by formula (F) is further represented by formula (F-5):

[0396]

[0397] In formula (F-5), each substituent is defined as described in formula (F).

[0398] In a preferred embodiment of the invention, the compound represented by formula (F) further relates to a compound having the structure shown in formula (F-3), and its stereoisomers, optical isomers, pharmaceutical salts, prodrugs, and solvates:

[0399]

[0400] Where R Y It is methyl;

[0401] X is CR x , where R x It is hydrogen;

[0402] R Z The quantity is 0;

[0403] Selected from the following structure:

[0404]

[0405]

[0406] .

[0407] The compounds described in this invention, and their stereoisomers, optical isomers, pharmaceutical salts, prodrugs, and solvates, are selected from:

[0408]

[0409]

[0410]

[0411]

[0412]

[0413]

[0414]

[0415]

[0416]

[0417]

[0418]

[0419]

[0420]

[0421]

[0422]

[0423]

[0424]

[0425]

[0426]

[0427]

[0428]

[0429]

[0430]

[0431]

[0432]

[0433]

[0434]

[0435]

[0436]

[0437] This invention also provides methods for preparing the compounds shown in this invention, and their stereoisomers, optical isomers, pharmaceutical salts, prodrugs, and solvates, wherein the methods are selected from:

[0438] Option 1:

[0439]

[0440] (W) and RM were coupled via a Suzuki cross-coupling reaction to give the compound shown in formula (A);

[0441] Wherein, Lev is a leaving group selected from Cl, Br, I or OTf, more preferably I; M is a borate ester group or a borate group; R is C in the aforementioned formula (A). 6-12 Aryl, 5-12 heteroaryl, C 3-12 The definitions of carbocyclic groups, 3-12 membered heterocyclic groups, and other substituents are as described above.

[0442] Option 2:

[0443]

[0444] (W) and The compound shown in formula (C) was obtained by the Sonogashia cross-coupling reaction;

[0445] Wherein, Lev is a leaving group selected from Cl, Br, I or OTf, more preferably I; the definitions of other substituents are as described above.

[0446] The present invention also provides a pharmaceutical composition comprising the compound shown in the present invention, and its stereoisomers, optical isomers, pharmaceutical salts, prodrugs, and solvates.

[0447] The present invention also provides a pharmaceutical composition comprising the compound shown in the present invention, its stereoisomers, optical isomers, pharmaceutical salts, prodrugs, solvates, and pharmaceutically acceptable excipients.

[0448] The object of this invention also includes providing the use of the compounds shown in this invention, and their stereoisomers, optical isomers, pharmaceutical salts, prodrugs, solvates, or pharmaceutical compositions described in this invention in the preparation of medicaments for treating ATR-mediated diseases. Preferably, the ATR-mediated diseases are cancer or tumor-related diseases.

[0449] Furthermore, the object of the present invention also includes the use of the compounds shown in the present invention, and their stereoisomers, optical isomers, pharmaceutical salts, prodrugs, solvates, or pharmaceutical compositions described in the present invention in the preparation of medicaments for treating cancer or tumor-related diseases; preferably, the cancer or tumor-related disease is a solid tumor; more preferably, the cancer or tumor-related disease is a gastrointestinal tumor; even more preferably, the cancer or tumor-related disease is gastric cancer or colorectal cancer.

[0450] In certain contexts within this field, the cancer may also be referred to as a tumor.

[0451] The use of the compounds, stereoisomers, optical isomers, pharmaceutical salts, prodrugs, and solvates of the present invention in the preparation of medicaments for treating ATR-mediated diseases, wherein the compounds, stereoisomers, optical isomers, pharmaceutical salts, prodrugs, and solvates are administered in combination with other anticancer agents or immune checkpoint inhibitors for treating cancer or tumors.

[0452] The use of the compounds, stereoisomers, optical isomers, pharmaceutical salts, prodrugs, and solvates of the present invention in the preparation of medicaments for treating diseases mediated by ATR, wherein the compounds, stereoisomers, optical isomers, pharmaceutical salts, prodrugs, and solvates are used in combination with other treatments for cancer or tumors (such as radiotherapy).

[0453] When the compounds of the present invention, and their stereoisomers, optical isomers, pharmaceutical salts, prodrugs, and solvates, are administered in combination with other anticancer agents or immune checkpoint inhibitors for the treatment of cancer or tumors, the compounds of the present invention, and their stereoisomers, optical isomers, pharmaceutical salts, prodrugs, and solvates, can provide enhanced anticancer effects.

[0454] The present invention also aims to provide a method for preventing and / or treating ATR-mediated diseases, comprising administering to a patient a therapeutically effective dose of the compound of the present invention, and its stereoisomers, optical isomers, pharmaceutical salts, prodrugs, solvates, or pharmaceutical compositions of the present invention. Further, the ATR-mediated diseases described in the present invention are cancer or tumor-related diseases. Preferably, the ATR-mediated diseases are solid tumors; more preferably, the ATR-mediated diseases are gastrointestinal tumors; even more preferably, the ATR-mediated diseases are gastric cancer or colorectal cancer.

[0455] The present invention also aims to provide a compound or pharmaceutical composition comprising said compound for the prevention and / or treatment of ATR-mediated diseases, wherein said compound is the compound shown in the present invention and its stereoisomers, optical isomers, pharmaceutical salts, prodrugs, or solvates. Further, the ATR-mediated diseases described in the present invention are cancer or tumor-related diseases. Preferably, the ATR-mediated diseases are solid tumors; more preferably, the ATR-mediated diseases are gastrointestinal tumors; even more preferably, the ATR-mediated diseases are gastric cancer or colorectal cancer.

[0456] definition

[0457] The terms “optional,” “arbitrary,” “optionally,” or “arbitrarily” refer to events or conditions that are subsequently described but are not required to occur, and the description includes both cases where said events or conditions occur and cases where said events or conditions do not occur.

[0458] The term "oxo-substituent" refers to a double bond formed when two hydrogen atoms at the same substitution position are replaced by the same oxygen atom.

[0459] Unless otherwise specified, the term "alkyl" refers to a monovalent saturated aliphatic hydrocarbon group, a straight-chain or branched group comprising 1-20 carbon atoms, preferably comprising 1-10 carbon atoms (i.e., C10). 1-10 Alkyl groups, more preferably containing 1-8 carbon atoms (C 1-8 Alkyl groups, more preferably containing 1-6 carbon atoms (i.e., C64-C ... 1-6 Alkyl groups), for example, "C 1-6 "Alkyl" refers to a group that is alkyl and has 1 to 6 carbon atoms in its carbon chain (specifically, 1, 2, 3, 4, 5, or 6). Examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, neopentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, n-heptyl, n-octyl, etc.

[0460] Unless otherwise specified, the term "alkenyl" refers to an unsaturated aliphatic hydrocarbon group consisting of a straight or branched chain of carbon and hydrogen atoms, having at least one double bond. Alkenyl groups may contain 2-20 carbon atoms, preferably 2-10 carbon atoms (i.e., C2H2O). 2-10 Alkenyl), further preferably containing 2-8 carbon atoms (C 2-8 Alkenyl), more preferably containing 2-6 carbon atoms (i.e., C14-C2 ... 2-6 alkenyl), 2-5 carbon atoms (i.e., C) 2-5 alkenyl), 2-4 carbon atoms (i.e., C) 2-4 alkenyl), 2-3 carbon atoms (i.e., C) 2-3 Alkenyl), 2 carbon atoms (i.e., C2 alkenyl), for example "C 2-6 "Alkenyl" refers to a group that is alkenyl and has 2 to 6 carbon atoms in its carbon chain (specifically, 2, 3, 4, 5, or 6). Non-limiting examples of alkenyl groups include, but are not limited to, vinyl, 1-propenyl, 2-propenyl, 1-butenyl, isobutenyl, and 1,3-butadienyl.

[0461] Unless otherwise specified, the term "alkynyl" refers to an unsaturated aliphatic hydrocarbon group consisting of a straight or branched chain of carbon and hydrogen atoms, having at least one triple bond. The alkynyl group may contain 2-20 carbon atoms, preferably 2-10 carbon atoms (i.e., C2H2O). 2-10 Alkyne group), further preferably containing 2-8 carbon atoms (C 2-8 Alkyne group), more preferably containing 2-6 carbon atoms (i.e., C64-C ... 2-6 acetylsyl group), 2-5 carbon atoms (i.e., C64) 2-5 acetylsyl group), 2-4 carbon atoms (i.e., C64) 2-4 acetylsyl group), 2-3 carbon atoms (i.e., C64) 2-3 Alkynyl group), 2 carbon atoms (i.e., C2 alkynyl group), for example "C 2-6 "Alynyl" refers to a group that is alkynyl and has 2 to 6 carbon atoms in its carbon chain (specifically 2, 3, 4, 5, or 6). Non-limiting examples of alkynyl include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, and 1-butynyl.

[0462] Unless otherwise specified, the term "cycloalkyl" refers to a monocyclic or polycyclic saturated aliphatic hydrocarbon group having a specific number of carbon atoms, preferably containing 3-12 carbon atoms (i.e., C64-C64). 3-12 cycloalkyl), more preferably containing 3-10 carbon atoms (C 3-10 cycloalkyl groups, preferably with 3-6 carbon atoms (C64- ... 3-6 cycloalkyl groups, 4-6 carbon atoms (C 4-6 cycloalkyl groups), 5-6 carbon atoms (C 5-6(Cycloalkyl). Examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methylcyclopropyl, 2-ethyl-cyclopentyl, dimethylcyclobutyl, etc.

[0463] Unless otherwise specified, the term "alkoxy" refers to -O-alkyl, which is defined as above, i.e., containing 1-20 carbon atoms, preferably 1-10 carbon atoms, more preferably 1-8 carbon atoms, and even more preferably 1-6 carbon atoms (specifically 1, 2, 3, 4, 5, or 6). Examples include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, butoxy, 1-methylpropoxy, 2-methylpropoxy, tert-butoxy, pentoxy, 1-methylbutoxy, 2-methylbutoxy, 3-methylbutoxy, 1,1-dimethylpropoxy, 1,2-dimethylpropoxy, 2,2-dimethylpropoxy, 1-ethylpropoxy, etc.

[0464] Unless otherwise specified, the terms "halogen" or "halogenated" refer to F, Cl, Br, and I. The term "halogenated alkyl" refers to an alkyl group as defined above in which one, two, or more hydrogen atoms, or all hydrogen atoms, are replaced by a halogen. Representative examples of halogenated alkyl groups include CCl3, CF3, CHCl2, CH2Cl, CH2Br, CH2I, CH2CF3, and CF2CF3.

[0465] Unless otherwise specified, the term "heterocyclic group" refers to a saturated or partially unsaturated monocyclic, bicyclic, or polycyclic cyclic hydrocarbon substituent, which is a non-aromatic structure, and also includes polycyclic groups in which some rings are aromatic. It contains 3-20 ring atoms, wherein one, two, three, or more ring atoms are selected from N, O, or S, and the remaining ring atoms are C. Preferably, it contains 3-12 ring atoms, more preferably 3-10 ring atoms, or 3-8 ring atoms, or 3-6 ring atoms, or 4-6 ring atoms, or 5-6 ring atoms. The number of heteroatoms is preferably 1-4, more preferably 1-3 (i.e., 1, 2, or 3). Examples of monocyclic heterocyclic groups include pyrrolidinyl, imidazoalkyl, tetrahydrofuranyl, dihydropyrrolidinyl, piperidinyl, piperazinyl, pyranyl, etc. Polycyclic heterocyclic groups include spirocyclic, fused-ring, and bridged-ring heterocyclic groups.

[0466] Unless otherwise specified, "heterocyclic alkyl" refers to a saturated "heterocyclic group" or "heterocycle" as defined above, with the same definition of ring atoms, i.e., containing 3 to 20 ring atoms ("3-20 membered heterocyclic alkyl"), and the number of heteroatoms is 1 to 4 (1, 2, 3 or 4), preferably 1 to 3 (1, 2 or 3), wherein each heteroatom is independently selected from N, O or S. Preferably containing 3 to 14 ring atoms ("3-14 membered heterocyclic alkyl"), more preferably containing 3 to 10 ring atoms ("3-10 membered heterocyclic alkyl"), even more preferably containing 3 to 8 ring atoms ("3-8 membered heterocyclic alkyl"), even more preferably containing 4 to 7 ring atoms ("4-7 membered heterocyclic alkyl"), even more preferably containing 5 to 10 ring atoms ("5-10 membered heterocyclic alkyl"), and even more preferably containing 5 to 6 ring atoms ("5-6 membered heterocyclic alkyl"). In some embodiments, each example of a heterocyclic alkyl group is independently optionally substituted, for example, unsubstituted (an “unsubstituted heterocyclic alkyl”) or substituted with one or more substituents (an “substituted heterocyclic alkyl”). The “heterocyclic group” or “heterocyclic” section above has given some exemplary examples of “heterocyclic alkyl”, and also includes, but is not limited to, azirropropyl, oxacyclopropyl, thiocyclopropyl, azirrobutyl, oxacyclobutyl, thiocyclobutyl, tetrahydrofuranyl, oxacyclohexyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, oxathiohexyl, oxazolyl, dioxyl, dithiohexyl, thiazolyl, pyrroliyl, pyrazolyl, imidazolinidine, etc.

[0467] Unless otherwise specified, the term "carbocyclic group" or "carbocyclic" refers to a non-aromatic cyclic hydrocarbon group ("C") having 3 to 14 ring carbon atoms. 3-14 The carbocyclic group (“C”) and does not have heteroatoms in this non-aromatic ring system. In some embodiments, the carbocyclic group has 3-12 ring carbon atoms (“C”). 3-12 (Carbon cyclo group), or 4-12 ring carbon atoms ("C") 4-12 ("Carbocyclic group") or 3 to 10 ring carbon atoms ("C") 3-10 Carbocyclic group (“CCR”). In some embodiments, the carbocyclic group has 3 to 8 cyclic carbon atoms (“C”). 3-8 (Carbocyclic group). In some embodiments, the carbocyclic group has 3 to 7 cyclic carbon atoms ("C"). 3-7 (Carbocyclic group). In some embodiments, the carbocyclic group has 4 to 6 cyclic carbon atoms ("C"). 4-6 (Carbocyclic group). In some embodiments, the carbocyclic group has 5 to 10 cyclic carbon atoms (“C”). 5-10 (Carbocyclic group), or 5 to 7 ring carbon atoms ("C") 5-7 (Carbocyclic group). Example C 3-6The carbocyclic group includes, but is not limited to, cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), etc. Example C 3-8 Carbocyclic groups include, but are not limited to, the C mentioned above. 3-6 Carbocyclic groups, including cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cyclohepttrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptyl (C7), bicyclo[2.2.2]octyl (C8), etc. Example C 3-10 Carbocyclic groups include, but are not limited to, the C mentioned above. 3-8 Carbocyclic groups and cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C9) 10 ), cyclodecenyl (C 10 ), octahydro-1H-indenyl (C9), decahydronaphthyl (C9) 10 ), spiro[4.5]decyl (C 10 As illustrated in the examples above, in some embodiments, the carbocyclic group is monocyclic (“monocyclic carbocyclic”) or a fused (fused-ring), bridged (bridged-ring), or spiro-fused (spirocyclic) ring system, such as a bicyclic system (“bicyclic carbocyclic”), and may be saturated or partially unsaturated. “Carbocyclic” also includes ring systems in which the carbocyclic ring as defined above is fused with one or more aryl or heteroaryl groups, wherein the attachment point is on the carbocyclic ring, and in such cases, the number of carbons continues to indicate the number of carbons in the carbocyclic system. In some embodiments, each example of the carbocyclic group is independently optionally substituted, for example, unsubstituted (an “unsubstituted carbocyclic”) or substituted with one or more substituents (an “substituted carbocyclic”). In some embodiments, the carbocyclic group is an unsubstituted C 3-10 Carbocyclic group. In some embodiments, the carbocyclic group is a substituted C 3-10 Carbon cyclic group.

[0468] Unless otherwise specified, "cycloalkenyl" refers to a system composed of monocyclic, bicyclic, and spirocyclic hydrocarbon rings as daughter groups; however, the system is unsaturated, meaning it contains at least one C-C double bond but no aromatic system. Preferably, it contains 3-12 carbon atoms (i.e., C12-C22). 3-12 Cycloalkenyl), more preferably containing 3-10 carbon atoms (C 3-10 Cycloalkenyl), further preferably 3-6 carbon atoms (C 3-6 Cycloalkenyl), 4-6 carbon atoms (C 4-6 Cycloalkenyl), 5-6 carbon atoms (C 5-6 (Cycloalkenyl).

[0469] Unless otherwise specified, the term "fused ring" refers to a non-aromatic, saturated or partially unsaturated bicyclic or polycyclic system formed by two or more ring structures sharing two adjacent atoms, including fused carbon cyclic groups and fused heterocyclic groups, wherein the "fused heterocyclic group" optionally contains one or more heteroatoms independently selected from oxygen, nitrogen and sulfur.

[0470] Unless otherwise specified, the term "spirocyclic alkyl" refers to a saturated ring system with a specific number of carbon atoms, consisting of carbon atoms and hydrogen atoms sharing only one ring carbon atom. Preferably, it is 6 to 14-membered, more preferably 7 to 10-membered. Non-limiting examples of monospirocyclic groups are monospirocyclic groups with 3 / 5, 4 / 4, 4 / 5, 4 / 6, 5 / 5, and 5 / 6-membered rings, wherein the count of each ring includes spiro atoms. Non-limiting examples of monospirocyclic groups include: wait.

[0471] Unless otherwise specified, the terms "heterospirocyclic group" and "spiroheterocyclic group" refer to a cyclic structure with a specific number of carbon atoms and heteroatoms formed by two or more saturated rings sharing a single ring carbon atom. The heteroatoms in the spiroheterocyclic group are preferably 1-4, more preferably 1-3 (i.e., 1, 2, or 3), and the heteroatoms are independently selected from N, O, and S. Preferably, they are 6 to 14 members, more preferably 7 to 10 members. Non-limiting examples of spiroheterocyclic groups are spiroheterocyclic groups with 3-membered / 5-membered, 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 5-membered, and 5-membered / 6-membered rings, wherein the count of each ring includes spiroatoms. Non-limiting examples of heteromonospirocyclic groups include:

[0472] wait.

[0473] Unless otherwise specified, the term "bridged cycloalkyl" refers to a 5- to 20-membered, all-carbon polycyclic group in which any two rings share two non-directly bonded carbon atoms. It may contain one or more double bonds, but none of the rings has a fully conjugated π-electron system. Preferably, it is 6- to 14-membered, more preferably 7- to 10-membered. Depending on the number of constituent rings, it can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic bridged cycloalkyl, preferably bicyclic, tricyclic, or tetracyclic, and more preferably bicyclic or tricyclic. Non-limiting examples of bridged cycloalkyl groups include:

[0474]

[0475] .

[0476] Unless otherwise specified, the terms "heterobridged cyclic group" and "bridged heterocyclic group" refer to a 5- to 14-membered polycyclic heterocyclic group in which any two rings share two non-directly connected ring atoms. It may contain one or more double bonds, but none of the rings has a fully conjugated π-electron system. The bridged heterocyclic group contains one or more heteroatoms, preferably 1-4, more preferably 1-3 (i.e., 1, 2, or 3), and the heteroatoms are independently selected from N, O, or S(O)m (where m is an integer from 0 to 2, and the remaining ring atoms are carbon). Bridged heterocyclic groups are preferably 6- to 14-membered, more preferably 7- to 10-membered. Depending on the number of rings, they can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic bridged heterocyclic groups, preferably bicyclic, tricyclic, or tetracyclic, and more preferably bicyclic or tricyclic. Non-limiting examples of bridged heterocyclic groups include:

[0477]

[0478] .

[0479] Unless otherwise specified, the term "aryl" refers to an aromatic carbocyclic system containing 6-16 carbon atoms, or 6-14 carbon atoms, or 6-12 carbon atoms, or 6-10 carbon atoms, preferably 6-10 carbon atoms. The term "aryl" may be used interchangeably with the term "aromatic cycloalgyl". Examples of aryl groups may include, but are not limited to, phenyl, naphthyl, anthraceneyl, phenanthryl, or pyrene.

[0480] Unless otherwise specified, the term "heteroaryl" refers to an aromatic monocyclic or polycyclic system containing a 5-12 member structure, or preferably a 5-10 member structure, a 5-8 member structure, and more preferably a 5-6 member structure, wherein one, two, three or more ring atoms are heteroatoms and the remaining atoms are carbon atoms, the heteroatoms being independently selected from O, N or S, and the number of heteroatoms is preferably one, two or three. Examples of heteroaryl groups include, but are not limited to, furanyl, thiophene, oxazolyl, thiazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, pyrroloyl, pyrazolyl, imidazoleyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyrazinyl, thiodiazolyl, triazinyl, phthalazinyl, quinolinyl, isoquinolinyl, pteridinyl, purine, indoleyl, isoindoleyl, indazoleyl, benzofuranyl, benzothiophene, benzopyridyl, benzopyrimidinyl, benzopyrazinyl, benzoimidazolyl, benzophthalazinyl, pyrrolo[2,3-b]pyridyl, imidazo[1,2-a]pyridyl, and pyrazolo[1,5-a]. Pyridyl, pyrazolo[1,5-a]pyrimidinyl, imidazo[1,2-b]pyridazinyl, [1,2,4]triazolo[4,3-b]pyridazinyl, [1,2,4]triazolo[1,5-a]pyrimidinyl, [1,2,4]triazolo[1,5-a]pyridinyl, etc.

[0481] Unless otherwise specified, the terms "pharmaceutically acceptable salt," "medicinal salt," or "medicinal salt" refer to salts that, within the limits of reasonable medical judgment, are suitable for contact with mammalian, particularly human, tissues without excessive toxicity, irritation, allergic reactions, etc., and in proportion to a reasonable benefit / risk ratio. The salts may be prepared in situ during the final separation and purification of the compounds of this invention, or solely by reacting a free base or free acid with a suitable reagent.

[0482] Unless otherwise specified, the term "solvent" refers to the physical association of the compound of the present invention with one or more solvent molecules (organic or inorganic). This physical association includes hydrogen bonding. In some cases, such as when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid, the solvate can be separated. The solvent molecules in the solvate may be present in a regular and / or disordered arrangement. The solvate may contain stoichiometric or non-stoichiometric solvent molecules. "Solvent" encompasses both solution phases and separable solvates. Exemplary solvates include, but are not limited to, hydrates, ethanolates, methanolates, and isopropanolates. Solvation methods are well known in the art.

[0483] Unless otherwise specified, the terms "isotope-labeled analog" and "isotope derivative" refer to isotope-labeled molecules of formulas I to II, thereby providing isotope-labeled analogs that may have improved pharmacological activity. The isotopes commonly used for isotope labeling are: hydrogen isotopes, 2 H and 3 H; Carbon isotopes: 11 C, 13 C and 14 C; Chlorine isotopes: 35 Cl and 37 Cl; Fluorine isotopes: 18 F; Iodine isotopes: 123 I and 125 I; Nitrogen isotopes: 13 N and 15 N; oxygen isotopes: 15 O, 17 O and 18 O and sulfur isotopes 35 S. These isotope-labeled compounds can be used to study the distribution of pharmaceutical molecules in tissues. Especially deuterium. 3 H and carbon 13 C, because they are easy to label and convenient to detect, are more widely used. Some heavy isotopes, such as deuterium (… 2Substitution with H can enhance metabolic stability and prolong the half-life, thereby achieving the goal of reducing dosage and providing therapeutic advantages. Isotope-labeled compounds are generally synthesized from labeled starting materials using known synthetic techniques, just like non-isotope-labeled compounds. Generally, the compounds described in this invention contain their isotope derivatives (such as deuterated compounds).

[0484] Unless otherwise specified, the term "optical isomer" refers to substances with identical molecular structures and similar physicochemical properties, but different optical rotations.

[0485] Unless otherwise specified, the term "stereoisomer" refers to compounds having the same chemical structure but with different spatial arrangements of atoms or groups. Stereoisomers include enantiomers, diastereomers, conformational isomers (rotational isomers), geometric isomers (cis / trans) isomers, and inhibited isomers. Any mixture of stereoisomers obtained can be separated into pure or substantially pure geometric isomers, enantiomers, and diastereomers based on differences in the physicochemical properties of the components, for example, by chromatography and / or fractional crystallization.

[0486] Unless otherwise specified, the term "tautomer" refers to structural isomers with different energies that can interconvert through a low energy barrier. If tautomerism is possible (e.g., in solution), chemical equilibrium can be achieved in the tautomer. For example, proton tautomers (also called proton transfer tautomers) involve interconversions via proton migration, such as keto-enol isomerization and imine-enamine isomerization. Valence tautomers involve interconversions via the rearrangement of some bonding electrons.

[0487] Unless otherwise indicated, the structural formulas described in this invention include all isomers (e.g., enantiomers, diastereomers, and geometric isomers (or conformational isomers)): for example, R and S configurations containing an asymmetric center, (Z) and (E) isomers of double bonds, and (Z) and (E) conformational isomers. Therefore, any single stereochemical isomer of the compounds of this invention, or its enantiomers, diastereomers, or mixtures of geometric isomers (or conformational isomers), is within the scope of this invention.

[0488] Unless otherwise specified, the term "prodrug" refers to a drug that is converted into a parent drug in the body. Prodrugs are often useful because, in some cases, they may be easier to administer than the parent drug. For example, they can be bioavailable via oral administration, whereas the parent drug cannot. Prodrugs also have increased solubility in pharmaceutical compositions compared to the parent drug. An example of a prodrug, but not limited to, is any compound of Formula I that is administered as an ester ("prodrug") to facilitate transmembrane transport, where water solubility is detrimental to migration but beneficial once inside the cell, and which is subsequently metabolized and hydrolyzed into a carboxylic acid, the active entity. Another example of a prodrug can be a short peptide (polyamino acid) bound to an acid group, where the peptide is metabolized to exhibit the active moiety.

[0489] Unless otherwise specified, the term "optional substitution" means that the hydrogen at the substituted site of the group is not substituted, or is substituted by one or more substituents, preferably selected from the group consisting of: halogen, hydroxyl, mercapto, cyano, nitro, amino, azide, oxo, carboxyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 cycloalkyl, C 3-10 Cycloalkylsulfonyl, 3-10 membered heterocyclic alkyl, C 6-14 Aryl or 5-10 membered heteroaryl rings, wherein the C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 cycloalkyl, C 3-10 Cycloalkylsulfonyl, 3-10 membered heterocyclic alkyl, C 6-14 The aryl or 5-10 membered heteroaryl group may optionally be selected from halogen, hydroxyl, amino, cyano, C 1-6 Alkyl or C 1-6 One or more of the alkoxy groups are substituted, wherein the oxo group refers to two H groups at the same substitution position being replaced by the same O group to form a double bond.

[0490] The beneficial effects of this invention are as follows:

[0491] This invention designs a class of novel compounds, providing a new direction for the development of ATR inhibitor drugs. In vitro enzyme activity inhibition studies show that the compounds of this invention have strong inhibitory effects on ATR enzymes. In vitro cell proliferation inhibition experiments show that the compounds of this invention have significant inhibitory effects on the proliferation of both LoVo cells and SNU-601 cells, thus they can be considered as promising compounds for the treatment of ATR-mediated diseases. Furthermore, this invention studies a specific synthetic method, which is simple, convenient, and conducive to large-scale industrial production and application. Detailed Implementation

[0492] The present invention will be further illustrated below with reference to specific embodiments. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of the invention. Experimental methods in the following embodiments, unless otherwise specified, are generally performed under conventional conditions or as recommended by the manufacturer. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as are familiar to those skilled in the art. Furthermore, any methods and materials similar to or equivalent to those described herein may be applied to the methods of the present invention. The preferred embodiments and materials shown herein are for illustrative purposes only.

[0493] The structures of the compounds in this invention were determined by nuclear magnetic resonance (NMR) and / or liquid chromatography-mass spectrometry (LC-MS) and / or high-performance liquid chromatography (HPLC). The instrument used for NMR determination was an Agilent 400 / 54 Premium Shielded NMRMagnet System; the instrument used for LC-MS was a Shimadzu LCMS2020; and the instrument used for HPLC was an Agilent 1200.

[0494] The starting materials used in the embodiments of the present invention are known and commercially available, or can be synthesized using or in accordance with methods known in the art.

[0495] Explanation of terms or abbreviations:

[0496] LDA: Lithium diisopropylamino

[0497] NMP: N-methylpyrrolidone

[0498] SEMCl: [2-(chloromethoxy)ethyl]trimethylsilane

[0499] THF: Tetrahydrofuran

[0500] DMSO: Dimethyl sulfoxide

[0501] Pd(dppf)Cl2: [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloro

[0502] DCM: Dichloromethane

[0503] TFA: Trifluoroacetic acid

[0504] Et3SiH: Triethylsilane

[0505] mCPBA: m-chloroperoxybenzoic acid

[0506] Xphos: dicyclohexyl[2',4',6'-tris(propane-2-yl)-[1,1'-biphenyl]-2-yl]phosphine

[0507] n-BuLi: n-Butyllithium

[0508] TBAF: Tetrabutylammonium fluoride

[0509] DIEA: N,N-Diisopropylethylamine

[0510] PdCl2(PPh3)2: Palladium dichloride of bis(triphenylphosphine)

[0511] B2Pin2: Pinamol diboronate

[0512] HATU: 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate

[0513] TBDPSCl: tert-butyldiphenylchlorosilane

[0514] LiHMDS: Lithium bis(trimethylsilylamine)

[0515] TMSI: Trimethyliodosilane.

[0516] Example 1

[0517] Preparation of (3R)-3-methyl-4-(4-(5-methyl-3-(trifluoromethyl)-1H-pyrazolyl-4-yl)-1-(1H-pyrazolyl-3-yl)-1H-pyrazolyl[3,4-b]pyridin-6-yl)morpholine:

[0518]

[0519] Step 1: Preparation of 5-hydrazino-1H-pyrazole:

[0520]

[0521] Weigh 16 g (192.56 mmol, 1 equiv.) of 5-amino-1H-pyrazole and add it to 320 mL (1.92 mol, 10 equiv.) of 6 M hydrochloric acid aqueous solution. Cool the reaction solution to -10 °C and stir. Slowly add 13.29 g (192.56 mmol, 1 equiv.) of sodium nitrite dissolved in 200 mL of water to the reaction solution and continue stirring for 1 hour. Slowly add 72.6 g (383.2 mmol, 1.99 equiv.) of stannous chloride dissolved in 80 mL of 6 M hydrochloric acid aqueous solution to the reaction solution and continue stirring for 2 hours. After the reaction is complete by TLC, concentrate the reaction solution and purify it by reversed-phase column chromatography (C18, acetonitrile:water = 0%–5%) to obtain the target compound (32 g, 100% yield). 1 H NMR (400 MHz, DMSO-d6) δ 7.58 (d, J = 2.3 Hz, 1H), 5.78 (d, J = 2.2 Hz, 1H).

[0522] Step 2: Preparation of 2,6-difluoro-4-iodonicotinaldehyde:

[0523]

[0524] 2,6-Difluoro-4-iodopyridine (14 g, 58.1 mmol, 1 equiv.) was dissolved in tetrahydrofuran (150 mL) and cooled to -78°C. o C. Add diisopropylaminolithium (34.85 mL, 325.34 mmol, 5.6 equiv.) dropwise and continue stirring for 1 hour. Then add ethyl formate (6.46 g, 87.14 mmol, 1.5 equiv.) and continue stirring for half an hour. Check the reaction by TLC to confirm its completeness. Quench the reaction with saturated ammonium chloride solution and continue stirring for 10 minutes. Extract with dichloromethane (300 mL) and water (300 mL). Dry the organic phase, filter and concentrate. Purify by column chromatography (ethyl acetate: petroleum ether = 0%-5%) to obtain the target compound (5 g, yield 32%). 1 H NMR (400 MHz, DMSO-d6) δ 9.93 (s, 1H), 7.95 (d, J = 2.3 Hz, 1H).

[0525] Step 3: Preparation of (E)-3-((2-(1H-pyrazol-5-yl)hydrazone)methyl)-2,6-difluoro-4-iodopyridine:

[0526]

[0527] 2,6-Difluoro-4-iodonicotinaldehyde (7 g, 26.02 mmol, 1 equiv.) and 5-hydrazino-1H-pyrazole (28.05 g, 286.22 mmol, 11 equiv.) were dissolved in ethanol (500 mL), and the reaction mixture was stirred at room temperature for 15 minutes. The reaction was confirmed to be complete by LC-MS. The reaction mixture was concentrated, filtered through a diatomaceous earth liner, and the filter cake was washed with a small amount of methanol. The filtrate was purified by reverse-phase column chromatography (C18, acetonitrile:water = 0%–50%) to give the target compound (5 g, yield 55.07%). LC-MS (ESI) [M+H]+ = 349.90.

[0528] Step 4: Preparation of 6-fluoro-4-iodo-1-(1H-pyrazol-5-yl)-1H-pyrazol[3,4-b]pyridine:

[0529]

[0530] (E)-3-((2-(1H-pyrazol-5-yl)hydrazone)methyl)-2,6-difluoro-4-iodopyridine (1 g, 2.86 mmol, 1 equiv.) was dissolved in N-methylpyrrolidone (15 mL) in a microwave-safe tube. The reaction mixture was microwave-heated to 200 °C and stirred for 20 minutes. The reaction was confirmed to be complete by LCMS. Ethyl acetate (30 mL) and water (30 mL) were added for extraction. The organic phase was dried, filtered, concentrated, and purified by column chromatography (ethyl acetate: petroleum ether = 1:1) to give the target compound (320 mg, yield 33.97%). LCMS (ESI) [M+H]+ = 329.85.

[0531] Step 5: Preparation of (R)-4-(4-iodo-1-(1H-pyrazol-5-yl)-1H-pyrazol[3,4-b]pyridin-6-yl)-3-methylmorpholine:

[0532]

[0533] 6-Fluoro-4-iodo-1-(1H-pyrazol-5-yl)-1H-pyrazol[3,4-b]pyridine (319.2 mg, 0.97 mmol, 1 equiv.) was dissolved in DMSO (5 mL) in a sealed tube, and (R)-3-methylmorpholine (117.74 mg, 1.16 mmol, 1.2 equiv.) was added. The reaction mixture was heated to 120 °C and stirred for 1 hour. The reaction was confirmed to be complete by LCMS. Water (10 mL) and ethyl acetate (10 mL) were added for extraction. The organic phase was concentrated and purified by thin-layer chromatography (ethyl acetate: petroleum ether = 2:1) to give the target compound (239 mg, yield 60.06%). LCMS (ESI) [M+H]+ = 411.00.

[0534] Step 6: Preparation of (R)-4-(4-iodo-1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)-1H-pyrazol[3,4-b]pyridin-6-yl)-3-methylmorpholine:

[0535]

[0536] (R)-4-(4-iodo-1-(1H-pyrazol-5-yl)-1H-pyrazol[3,4-b]pyridin-6-yl)-3-methylmorpholine (239 mg, 0.58 mmol, 1 equiv.) was dissolved in DMF (4 mL), followed by the addition of 2-(trimethylsilyl)ethoxymethyl chloride (291.41 mg, 1.75 mmol, 3 equiv.) and then triethylamine (353.74 mg, 3.5 mmol, 6 equiv.). The reaction mixture was stirred at room temperature for 1 hour, and the reaction was confirmed to be complete by LCMS. The mixture was extracted with ethyl acetate (15 mL) and water (15 mL), and the organic phase was concentrated and purified by thin-layer chromatography (ethyl acetate: petroleum ether = 1:3) to give the target compound (144 mg, yield 45.73%). LCMS (ESI) [M+H]+ = 541.10.

[0537] Step 7: Preparation of 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxane-2-yl)-5-(trifluoromethyl)-1H-pyrazole:

[0538]

[0539] 4-Bromo-3-methyl-5-(trifluoromethyl)-1H-pyrazole (100 mg, 0.44 mmol, 1 equiv.), pinacol diboronate (330 mg, 1.3 mmol, 3 equiv.), [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloro(II) (10 mg, 0.04 mmol, 0.1 equiv.), and potassium acetate (214 mg, 2.2 mmol, 5 equiv.) were added to a 1,4-dioxane solution (4 mL). The reaction was carried out at 100 °C for 16 hours. The reaction was confirmed to be complete by LCMS. The reaction solution was filtered, and the filtrate was extracted with water and ethyl acetate. The organic phase was concentrated and purified by column chromatography (methanol:dichloromethane = 0%-5%) to give 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxobenzaldehyde-2-yl)-5-(trifluoromethyl)-1H-pyrazole (20 mg, yield 15.91%). LCMS (ESI) [M+H]+ = 277.05.

[0540] Step 8: Preparation of (3R)-3-methyl-4-(4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)-1H-pyrazolyl[3,4-b]pyridin-6-yl)morpholine:

[0541]

[0542] Add (R)-4-(4-iodo-1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)-1H-pyrazol[3,4-b]pyridin-6-yl)-3-methylmorpholine (30 mg, 0.06 mmol, 1 equiv.) to a mixture of water (1 mL) and 1,4-dioxane (2 mL). Then add 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxane-2-yl)-5-(trifluoromethyl)-1H-pyrazol (18.6 mg, 0.07 mmol, 1.21 equiv.), sodium carbonate (12 mg, 0.11 mmol, 2.04 equiv.), and [1,1'-bis(diphenylphosphine)ferrocene]palladium(II) (4 mg) to the reaction solution. Change the air several times to ensure an oxygen-free environment. The reaction was carried out at 90℃ with stirring for 16 hours. LCMS analysis showed product formation. The product was extracted three times with ethyl acetate, dried, and the combined organic phases were evaporated to dryness. Thin-layer chromatography (TLC) was used to purify the target compound (4.2 mg, yield 12.44%). LCMS (ESI) [M+H]+ = 563.20.

[0543] Step 9: Preparation of (3R)-3-methyl-4-(4-(5-methyl-3-(trifluoromethyl)-1H-pyrazolyl-4-yl)-1-(1H-pyrazolyl-3-yl)-1H-pyrazolyl[3,4-b]pyridin-6-yl)morpholine:

[0544]

[0545] (3R)-3-methyl-4-(4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)-1H-pyrazolyl[3,4-b]pyridin-6-yl)morpholine (4.2 mg, 0.01 mmol, 1 equiv.) was added to dichloromethane (0.3 mL), followed by triethylsilane (0.04 mL, 0.34 mmol, 46.08 equiv.) and trifluoroacetic acid (0.1 mL). The mixture was stirred for 10 minutes at room temperature. The reaction was complete as determined by LCMS. The mixture was extracted three times with dichloromethane, dried over anhydrous sodium sulfate, and the extracts were combined and evaporated to dryness. The extracts were purified by thin-layer chromatography (dichloromethane:methanol = 15:1) to give the target compound (1.2 mg, yield 27.75%). LCMS (ESI) [M+H]+ = 433.15; 1 H NMR(399 MHz, DMSO-d6) δ 13.70 (s, 1H), 12.81 (s, 1H), 7.81 (d, J = 15.6 Hz, 2H), 6.77 (s, 1H), 6.63 (s, 1H), 4.35 (d, J = 3.6 Hz, 1H), 4.05 (d, J = 11.9 Hz, 1H), 3.95 (dd, J = 12.5, 4.0 Hz, 1H), 3.72 (d, J = 11.4 Hz, 1H), 3.63 (dd, J= 11.9, 2.5 Hz, 1H), 3.47 (td, J = 11.8, 2.0 Hz, 1H), 3.14 (td, J = 12.8, 3.8Hz, 1H), 2.22 (s, 3H), 1.17 (d, J = 6.7 Hz, 3H).

[0546] Example 2

[0547] Preparation of (R)-6-(6-(3-methylmorpholino)-1-(1H-pyrazol-3-yl)-1H-pyrazol[3,4-b]pyridin-4-yl)-1-oxapirole[2,5]octane-6-ol:

[0548]

[0549] Step 1: Preparation of α-methylenecyclohexanone:

[0550]

[0551] 8-Methylene-1,4-dioxospiro[4,5]decane (2 g, 12.97 mmol, 1 equiv.) was dissolved in acetone (30 mL), and hydrochloric acid (30 mL, 1 M) was added. The mixture was stirred at room temperature for 1 hour. The reaction was confirmed to be complete by TLC (potassium permanganate staining). The mixture was extracted three times with ethyl acetate, and the organic phase was concentrated at low temperature (25 °C) to give α-methylenecyclohexanone (2 g, crude product).

[0552] Step 2: Preparation of 1-oxpirol[2.5]octane-6-one:

[0553]

[0554] A-Methylenecyclohexanone (1.3 g, 11.8 mmol, 1 equiv.) was added to dichloromethane (40 mL). Then, m-chloroperoxybenzoic acid (6.11 g, 35.41 mmol, 1.95 equiv.) was slowly added. The mixture was stirred at 0 °C for 1 hour, and the reaction mixture was analyzed by NMR. The solution was then evaporated to dryness at low temperature to obtain crude 1-oxpirol[2.5]octane-6-one (750 mg, 5.95 mmol, 50.38%). 1 H NMR (399 MHz, CDCl3) δ 2.81 (s, 2H), 2.71 – 2.59 (m, 2H), 2.42 (dt, J = 9.7, 4.3Hz, 2H), 2.19 – 2.10 (m, 2H), 1.81 – 1.71 (m, 2H).

[0555] Step 3: Preparation of (R)-6-(6-(3-methylmorpholino)-1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)-1H-pyrazol[3,4-b]pyridin-4-yl)-1-oxapiro[2,5]octane-6-ol:

[0556]

[0557] (R)-4-(4-iodo-1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)-1H-pyrazol[3,4-b]pyridin-6-yl)-3-methylmorpholine (100 mg, 0.19 mmol, 1 equiv.) was added to tetrahydrofuran (3 mL), and 1-oxipirome[2.5]octane-6-one (70 mg, 0.55 mmol, 3 equiv.) was added to the reaction mixture. Butyllithium (0.02 mL, 0.31 mmol, 1.69 equiv.) was slowly added at -78 °C, and the mixture was stirred for one hour. TLC analysis showed that the reaction proceeded completely. The mixture was quenched with saturated ammonium chloride solution, extracted three times with dichloromethane, dried, and the extracts were combined and evaporated to dryness. The extracts were purified by thin-layer chromatography (petroleum ether: ethyl acetate = 2:1) to give the target compound (22 mg, yield 21.99%). LCMS (ESI) [M+H] + = 541.10.

[0558] Step 4: Preparation of (R)-6-(6-(3-methylmorpholino)-1-(1H-pyrazol-3-yl)-1H-pyrazol[3,4-b]pyridin-4-yl)-1-oxapirole[2.5]octane-6-ol:

[0559]

[0560] (R)-6-(6-(3-methylmorpholino)-1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)-1H-pyrazol[3,4-b]pyridin-4-yl)-1-oxapiro[2.5]octane-6-ol (22 mg, 0.04 mmol, 1 equiv.) was added to tetrahydrofuran (2 mL), followed by tetrabutylammonium fluoride (0.2 mL, 0.76 mmol, 18.78 equiv.). The mixture was heated to 80°C and stirred for 4 hours. TLC analysis showed complete reaction of the starting material. The mixture was extracted three times with ethyl acetate, and the organic phases were dried and combined. The product was purified by thin-layer chromatography (dichloromethane:methanol = 10:1), and the product was scraped off to obtain the target product (9.0 mg, yield 53.89%); LCMS (ESI) [M+H]+ = 411.40; 1H NMR (400 MHz, CD3OD) δ 8.21 (s,1H), 7.72 (s, 1H), 6.93 (s, 1H), 6.85 (s, 1H), 4.54 (d, J = 8.4 Hz, 1H), 4.12–4.00 (m, 2H), 3.84 –3.75 (m, 2H), 3.60 (d, J = 11.5 Hz, 1H), 3.37 – 3.31 (m,1H), 2.76 (s, 2H), 2.46 (td, J = 12.6, 3.2 Hz, 2H), 2.30 (t, J = 12.8 Hz,2H), 2.03 (d, J = 13.4 Hz, 2H), 1.29 (d, J = 7.1 Hz, 5H).

[0561] Example 3

[0562] Preparation of (3R)-3-methyl-4-(4-(3-methyl-1-(piperidin-4-yl)-5-(trifluoromethyl)-1H-pyrazol-4-yl)-1-(1H-pyrazol-3-yl)-1H-pyrazol[3,4-b]pyridin-6-yl)morpholine:

[0563]

[0564] Step 1: Preparation of tert-butyl 4-(methanesulfonyl)oxy)piperidine-1-carboxylic acid:

[0565]

[0566] 4-Hydroxypiperidine-1-carboxylic acid tert-butyl ester (50 mg, 0.25 mmol, 1 equiv.), N , N Diisopropylethylamine (96.32 mg, 0.75 mmol, 3 equiv.) was added to dichloromethane (5 mL), purged three times with nitrogen, and the temperature was lowered to 0 °C. The mixture was stirred for 10 minutes, and then methanesulfonyl chloride (42.69 mg, 0.37 mmol, 1.5 equiv.) was slowly added to the reaction mixture. Stirring was continued for 1 hour. The reaction was checked for completeness by TLC. The mixture was diluted with water, extracted three times with dichloromethane, and the organic phases were combined, washed with saturated brine, dried, filtered, and the organic phase was concentrated to obtain the crude target compound (40 mg, yield 57.64%).

[0567] Step 2: Preparation of tert-butyl 4-(5-methyl-4-(6-((R)-3-methylmorpholine)-1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)-1H-pyrazol[3,4-b]pyridin-4-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)piperidine-1-carboxylate:

[0568]

[0569] At room temperature, 4-(methanesulfonyl)oxy)piperidine-1-carboxylic acid tert-butyl ester (30 mg, 0.05 mmol, 1 equiv.), (3 R )-3-methyl-4-(4-(5-methyl-3-(trifluoromethyl)-1 H -pyrazole-4-yl)-1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1 H -pyrazole-3-yl)-1 H -pyrazole[3,4- b Pyridin-6-yl)morpholine (22.34 mg, 0.08 mmol, 1.5 equiv.) and cesium carbonate (52.12 mg, 0.16 mmol, 3 equiv.) were added to N , N The mixture was prepared in dimethylformamide (5 mL) with nitrogen purging three times, heated to 80 °C, and stirred for 16 hours. The reaction was confirmed to be complete by LCMS. The mixture was diluted with water, extracted three times with ethyl acetate, and the organic phases were combined, washed with saturated brine, dried, filtered, and concentrated. The concentrate was purified by thin-layer chromatography (TLC) (petroleum ether:ethyl acetate = 1:1) to give the target compound (35 mg, 88% yield). LCMS (ESI) [M+H]+ = 746.91.

[0570] Step 3: Preparation of (3R)-3-methyl-4-(4-(3-methyl-1-(piperidin-4-yl)-5-(trifluoromethyl)-1H-pyrazol-4-yl)-1-(1H-pyrazol-3-yl)-1H-pyrazol[3,4-b]pyridin-6-yl)morpholine:

[0571]

[0572] tert-butyl-4-(5-methyl-4-(6-(( R )-3-methylmorpholine)-1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1 H -pyrazole-3-yl)-1 H -pyrazole[3,4- b ]pyridin-4-yl)-3-(trifluoromethyl)-1 H1,3-pyrazol-1-yl)piperidine-1-carboxylate (100 mg, 0.13 mmol, 1 equiv.) and triethylsilane (0.57 mL, 4.91 mmol, 36.66 equiv.) were dissolved in a mixture of dichloromethane (2 mL) and trifluoroacetic acid (2 mL), purged three times with nitrogen, and stirred at room temperature for 10 minutes. The reaction was checked for completeness by TLC. The pH was adjusted to 9 with saturated sodium bicarbonate solution, and the mixture was extracted three times with dichloromethane. The organic phases were combined, washed with saturated brine, dried, filtered, and concentrated. The concentrate was purified preparatively to obtain the target product (20.8 mg, yield 31.04%). LCMS (ESI) [M+H]+ = 516.53; 1 H NMR (400 MHz, DMSO-d6) 8.30(s, 1H), 7.80 (s, 1H), 6.78 (d, J = 2.0 Hz, 1H), 6.65 (s, 1H), 4.41 (d, J =50.5 Hz, 2H), 4.06 (d, J = 11.6 Hz, 1H), 3.95 (d, J = 7.4 Hz, 1H), 3.72 (d, J= 12.1 Hz, 2H), 3.62 (d, J = 11.2 Hz, 2H), 3.15 (d, J = 11.4 Hz, 4H), 2.74(s, 2H), 2.26 (s, 3H), 1.96 (s, 4H), 1.17 (d, J = 6.6 Hz, 3H).

[0573] Example 4

[0574] Preparation of (3R)-3-methyl-4-(4-(5-methyl-1-(piperidin-4-yl)-3-(trifluoromethyl)-1H-pyrazol-4-yl)-1-(1H-pyrazol-3-yl)-1H-pyrazol[3,4-b]pyridin-6-yl)morpholine:

[0575]

[0576] Step 1: Preparation of (3R)-3-methyl-4-(4-(5-methyl-1-(piperidin-4-yl)-3-(trifluoromethyl)-1H-pyrazol-4-yl)-1-(1H-pyrazol-3-yl)-1H-pyrazol[3,4-b]pyridin-6-yl)morpholine:

[0577]

[0578] tert-butyl-4-(5-methyl-4-(6-(( R)-3-methylmorpholine)-1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1 H -pyrazole-3-yl)-1 H -pyrazole[3,4- b ]pyridin-4-yl)-3-(trifluoromethyl)-1 H 1-Pyrazol-1-yl)piperidine-1-carboxylate (30 mg, 0.04 mmol, 1 equiv.) was dissolved in trifluoroacetic acid (2 mL) and dichloromethane (2 mL), and triethylsilane (0.2 mL) was added. The mixture was stirred at room temperature for 30 minutes. LCMS analysis showed that the reaction was complete. The reaction solution was adjusted to alkalinity with saturated sodium bicarbonate solution, extracted with ethyl acetate and water, and the organic phases were combined, dried, filtered, and concentrated. Thin-layer chromatography (dichloromethane:methanol = 8:1) was performed to give the target compound (4.9 mg, yield 23.63%); LCMS (ESI) [M+H]+ = 516.20; 1 H NMR(399 MHz, CD3OD) δ 7.75 (s, 1H), 7.70 (s, 1H), 7.46 – 7.17 (m, 1H), 6.96 (s,1H), 6.66 (s, 1H), 4.45 (d, J = 13.0 Hz, 2H), 4.08 (dd, J = 47.7, 11.2 Hz,2H), 3.84 – 3.75 (m, 2H), 3.63 (t, J = 11.5 Hz, 1H), 3.34 (s, 1H), 3.23 (s,2H), 2.78 (t, J = 13.0 Hz, 2H), 2.23 (d, J = 20.5 Hz, 2H), 2.14 (s, 3H), 2.08– 1.97 (m, 2H), 1.30 (d, J = 6.3 Hz, 3H).

[0579] Example 5

[0580] Preparation of (R)-4-(4-(3-methoxypropyl-1-ynyl)-1-(1H-pyrazol-3-yl)-1H-pyrazol[3,4-b]pyridin-6-yl)-3-methylmorpholine:

[0581]

[0582] Step 1: Preparation of (R)-4-(4-(3-methoxypropyl-1-ynyl)-1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)-1H-pyrazol[3,4-b]pyridin-6-yl)-3-methylmorpholine:

[0583]

[0584] Will( R )-4-(4-iodo-1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1 H -pyrazole-5-yl)-1 H -pyrazole[3,4- b Pyridin-6-yl)-3-methylmorpholine (50 mg, 0.09 mmol, 1 equiv.), 3-methoxypropyne (13.62 mg, 0.19 mmol, 2.1 equiv.), bis(triphenylphosphine) palladium dichloride (1.95 mg, 0 mmol, 0.03 equiv.), cuprous iodide (0.88 mg, 0 mmol, 0.05 equiv.), and diisopropylethylamine (38.26 mg, 0.3 mmol, 3.2 equiv.) dissolved in N , N The mixture was stirred overnight at room temperature in dimethylformamide (4 mL). The reaction was confirmed to be complete by LCMS. The organic phases were extracted with ethyl acetate and water, combined, dried, filtered, and evaporated to dryness. The resulting product was purified by TLC (petroleum ether:ethyl acetate = 2:1) to give the target compound (34 mg, yield 76.15%). LCMS (ESI) [M+H]+ = 483.45

[0585] Step 2: Preparation of (R)-4-(4-(3-methoxypropyl-1-ynyl)-1-(1H-pyrazol-3-yl)-1H-pyrazol[3,4-b]pyridin-6-yl)-3-methylmorpholine:

[0586]

[0587] Will( R )-4-(4-(3-methoxypropyl-1-ynyl)-1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1 H -pyrazole-3-yl)-1 H -pyrazole[3,4- bPyridin-6-yl)-3-methylmorpholine (30 mg, 0.04 mmol, 1 equiv.) was dissolved in trifluoroacetic acid (2 mL) and dichloromethane (2 mL), and triethylsilane (0.2 mL) was added. The mixture was stirred at room temperature for 30 minutes. LCMS analysis showed the reaction was complete. The reaction solution was adjusted to alkalinity with saturated sodium bicarbonate solution, extracted with ethyl acetate and water, and the organic phases were combined, dried, filtered, and concentrated. Thin-layer chromatography (dichloromethane:methanol = 10:1) was performed to give the target compound (14.3 mg, yield 57.61%). LCMS (ESI) [M+H]+ = 353.35; 1 H NMR (399 MHz, CD3OD) δ 7.98 (s, 1H),7.73 (s, 1H), 6.90 (s, 1H), 6.83 (s, 1H), 4.45 (s, 1H), 4.42 (s, 2H), 4.03(dd, J = 27.5, 10.3 Hz, 2H), 3.81 – 3.72 (m, 2H), 3.59 (t, J = 10.4 Hz, 1H), 3.47 (s, 3H), 3.25 (s, 1H), 1.27 (d, J = 6.7 Hz, 3H).

[0588] Example 6

[0589] Preparation of (R)-1-((6-(3-methylmorpholino)-1-(1H-pyrazolyl-3-yl)-1H-pyrazolyl[3,4-b]pyridin-4-yl)ethynyl)cyclohexanol:

[0590]

[0591] Step 1: Preparation of (R)-1-((6-(3-methylmorpholino)-1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolyl-3-yl)-1H-pyrazolyl[3,4-b]pyridin-4-yl)ethynyl)cyclohexanol:

[0592]

[0593] (R)-4-(4-iodo-1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)-1H-pyrazol[3,4-b]pyridin-6-yl)-3-methylmorpholine (50 mg, 0.09 mmol, 1 equiv.), 1-ethynylcyclohexanol (23.5 mg, 0.19 mmol, 2.1 equiv.), palladium dichloride bis(triphenylphosphine) (1.89 mg, 0.0027 mmol, 0.03 equiv.), cuprous iodide (0.86 mg, 0.0045 mmol, 0.05 equiv.), and diisopropylethylamine (37.2 mg, 0.29 mmol, 3.2 equiv.) were dissolved in N,N-dimethylformamide (4 mL) and stirred overnight at room temperature. The reaction was complete as determined by LCMS. Extracted with ethyl acetate and water, the organic phases were combined, dried, filtered, and evaporated to dryness. The target compound (40 mg, 82.65% yield) was obtained by L2 plate analysis (petroleum ether:ethyl acetate = 1:1). LCMS (ESI) [M+H]+ = 537.25.

[0594] Step 2: Preparation of (R)-1-((6-(3-methylmorpholino)-1-(1H-pyrazolyl-3-yl)-1H-pyrazolyl[3,4-b]pyridin-4-yl)ethynyl)cyclohexanol:

[0595]

[0596] (R)-1-((6-(3-methylmorpholino)-1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1 H -pyrazol-3-yl)-1 H -pyrazole group [3,4- b Pyridin-4-yl)ethynyl)cyclohexanol (40 mg, 0.07 mmol, 1 equiv.) was dissolved in trifluoroacetic acid (1 mL) and dichloromethane (1 mL), and triethylsilane (0.1 mL) was added. The mixture was stirred at room temperature for 10 minutes. LCMS analysis showed the reaction was complete. The reaction solution was adjusted to alkalinity with saturated sodium bicarbonate solution, extracted with ethyl acetate and water, and the organic phases were combined, dried, filtered, and concentrated. The target compound (10.5 mg, yield 36.9%) was purified by thin-layer chromatography (dichloromethane:methanol = 10:1). LCMS (ESI) [M+H]+ = 407.20; 1H NMR (399 MHz, CD3OD) δ 7.98 (s,1H), 7.74 (s, 1H), 6.91 (s, 1H), 6.80 (s, 1H), 4.62 – 4.44 (m, 2H), 4.04 (dd,J = 29.4, 12.2 Hz, 2H), 3.79 (t, J = 12.5 Hz, 2H), 3.63 – 3.56 (m, 1H), 2.04(d, J = 11.7 Hz, 2H), 1.81 – 1.75 (m, 2H), 1.67 (t, J = 10.3 Hz, 6H), 1.28(d, J = 6.7 Hz, 3H).

[0597] Example 7

[0598] Preparation of (R)-1-(4-(6-(3-methylmorpholino)-1-(1H-pyrazolyl-3-yl)-1H-pyrazolyl[3,4-b]pyridin-4-yl)phenyl)piperidin-2-one:

[0599]

[0600] Step 1: Preparation of 5-bromo-N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxane-2-yl)phenyl)pentamide:

[0601]

[0602] p-Aminophenylboronic acid (500 mg, 2.28 mmol, 1.0 equiv.) and triethylamine (346 mg, 3.42 mmol, 1.5 equiv.) were weighed and dissolved in dichloromethane (10 mL). Then, 5-bromopentanoyl chloride (500 mg, 2.51 mmol, 1.1 equiv.) was added under ice bath conditions. The mixture was purged with nitrogen three times and the reaction was allowed to proceed to room temperature for 16 hours. TLC was used to confirm the complete reaction of the starting material, and LCMS was used to detect the formation of the product. The reaction mixture was extracted with ethyl acetate (50 mL x 3) after adding water (100 mL). The organic phases were combined and subjected to rotary cyclohexane chromatography (petroleum ether:ethyl acetate = 20 / 1~5 / 1) to obtain the target compound (868 mg, yield 99.8%). LCMS (ESI) [M+H] + =382.05.

[0603] Step 2: Preparation of 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxane-2-yl)phenyl)piperidin-2-one:

[0604]

[0605] 5-bromo- N -(4-(4,4,5,5-tetramethyl-1,3,2-dioxobenzaldehyde-2-yl)phenyl)pentaamide (868 mg, 2.28 mmol, 1.0 equiv.) dissolved in N,N The mixture was added to dimethylformamide (10 mL) and then sodium hydrogen hydrate (136 mg, 2.42 mmol, 1.5 equiv) under ice bath conditions. Nitrogen was then purged three times and the reaction was allowed to proceed at room temperature for 2 hours. TLC was used to confirm complete reaction of the starting material, and LCMS was used to detect product formation. The reaction mixture was quenched with water (50 mL) and extracted with ethyl acetate (50 mL x 3). The organic phases were combined and evaporated to dryness before thin-layer chromatography (petroleum ether:ethyl acetate = 3:1) to give the product (300 mg, yield 43.6%). LCMS (ESI) [M+H]+ = 302.1.

[0606] Step 3: Preparation of (R)-1-(4-(6-(3-methylmorpholino)-1-(1-(2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)-1H-pyrazol[3,4-b]pyridin-4-yl)phenyl)piperidin-2-one:

[0607]

[0608] 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxane-2-yl)phenyl)piperidin-2-one (60 mg, 0.198 mmol, 1.1 equiv.) and (R)-4-(4-iodo-1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)-1H-pyrazol[3,4-b]pyridin-6-yl)-3-methylmorpholine (100 mg, 0.185 mmol, 1.0 equiv.), [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloro(II) (14 mg, 0.018 mmol, 0.1 equiv.) and sodium carbonate (40 mg, 0.37 mmol, 2.0 equiv.) were dissolved in 1,4-dioxane (4 mL) and water (2 mL). The mixture was heated to 90°C three times with nitrogen purging and reacted for 3 hours. The reaction mixture was analyzed by TLC to confirm complete reaction of the starting material and by LCMS to detect product formation. The reaction solution was filtered and extracted with ethyl acetate (20 mL x 3). The organic phases were combined and evaporated to dryness before thin-layer chromatography (petroleum ether:ethyl acetate = 1:1) to give the target compound (88 mg, yield 75.7%). LCMS (ESI) [M+H]+ = 588.25;

[0609] Step 4: Preparation of (R)-1-(4-(6-(3-methylmorpholino)-1-(1H-pyrazolyl-3-yl)-1H-pyrazolyl[3,4-b]pyridin-4-yl)phenyl)piperidin-2-one:

[0610]

[0611] (R)-1-(4-(6-(3-methylmorpholino)-1-(1-(2-(trimethylsilyl)ethoxy)methyl)-1 H -pyrazole-3-yl)-1 H -pyrazole[3,4- b Pyridin-4-yl)phenyl)piperidin-2-one (88 mg, 0.15 mmol, 1.0 equiv.) was dissolved in dichloromethane (4 mL), followed by the addition of trifluoroacetic acid (4 mL) and triethylsilane (0.4 mL). The mixture was then purged three times with nitrogen and reacted at 25 °C for 1 hour. TLC was used to confirm the complete reaction of the starting material, and LCMS was used to detect the formation of the product. The reaction solution was quenched with saturated sodium bicarbonate (50 mL) and extracted with ethyl acetate (20 mL x 3). The organic phases were combined and purified by thin-layer chromatography (dichloromethane / methanol = 10:1) to give the target compound (37 mg, yield 53.9%). LCMS (ESI) [M+H]+ = 458.20; 1 HNMR (400 MHz, DMSO-d6) δ 12.82 (s, 1H), 8.14 (s, 1H), 7.87 – 7.80 (m, 3H), 7.45 (d, J = 8.3 Hz, 2H), 6.90 (s, 1H), 6.80 (s, 1H), 4.53 (s, 1H), 4.13 (d,J = 12.5 Hz, 1H), 3.95 (d, J = 9.4 Hz, 1H), 3.74 (d, J = 11.1 Hz, 1H), 3.67 –3.62 (m, 3H), 3.49 (t, J = 10.7 Hz, 1H), 3.18 (t, J = 11.6 Hz, 1H), 2.41 (t,J = 5.9 Hz, 2H), 1.85 (s, 4H), 1.22 – 1.17 (m, 3H).

[0612] Example 8

[0613] Preparation of (R)-4-(4,6-dihydro-2H-pyran-3-yl)-1-(1H-pyrazol-3-yl)-1H-pyrazol[3,4-b]pyridin-6-yl)-3-methylmorpholine:

[0614]

[0615] Step 1: Preparation of 3,4-dihydro-2H-pyran-5-yltrifluoromethanesulfonate:

[0616]

[0617] Tetrahydro-2 H 3-pyran-3-one (500 mg, 4.99 mmol, 1 equiv.) was dissolved in tetrahydrofuran (10 mL), and diisopropylaminolithium (3 mL, 6.0 mmol, 1.2 equiv.) was added at -78 °C. The mixture was stirred at -78 °C for 45 minutes, and then 1,1,1-trifluoro- N -phenyl- N 1.96 g (5.49 mmol, 1.1 equiv.) of sulfonamide (trifluoromethyl)sulfonyl)methanesulfonamide was stirred at room temperature for 3 hours. The reaction was confirmed to be complete by TLC (potassium permanganate staining). The reaction was quenched with saturated ammonium chloride aqueous solution, extracted with ethyl acetate and water, and the organic phases were combined, dried, filtered, and evaporated to dryness. The target compound (200 mg, 17.25%) was purified by column chromatography (petroleum ether:ethyl acetate = 100:1).

[0618] Step 2: Preparation of 2-(3,4-dihydro-2H-pyran-5-yl)-4,4,5,5-tetramethyl-1,3,2-dioxane:

[0619]

[0620] 3,4-dihydro-2 H 5-pyran-5-yltrifluoromethanesulfonate (200 mg, 0.86 mmol, 1 equiv.), pinacol diboronate (328.12 mg, 1.29 mmol, 1.5 equiv.), [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloro(II) (63.2 mg, 0.09 mmol, 0.1 equiv.), and potassium acetate (253.61 mg, 2.58 mmol, 3 equiv.) were dissolved in 1,4-dioxane (5 mL), purged with nitrogen three times, stirred overnight at 90 °C, and the reaction was detected by TLC (potassium permanganate colorimetric assay) to confirm complete reaction. The reaction solution was filtered, extracted with ethyl acetate and water, the organic phases were combined, dried, filtered, concentrated, and purified by TLC (petroleum ether:ethyl acetate = 5:1) to obtain the target compound (50 mg, yield 27.63%).

[0621] Step 3: Preparation of (R)-4-(4-(5,6-dihydro-2H-pyran-3-yl)-1-(1-(2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)-1H-pyrazol[3,4-b]pyridin-6-yl)-3-methylmorpholine:

[0622]

[0623] 2-(3,4-dihydro-2) H (R)-4-(4-iodo-1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1 H -pyrazole-3-yl)-1 H -pyrazole[3,4- b [1,1'-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (27.99 mg, 0.13 mmol, 1.2 equiv.), sodium carbonate (23.53 mg, 0.22 mmol, 2 equiv.), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (8.15 mg, 0.01 mmol, 0.1 equiv.)) were dissolved in 1,4-dioxane (4 mL) and water (2 mL) and stirred at 90 °C for 2 hours. The reaction was complete as determined by LCMS. The organic phases were extracted with ethyl acetate and water, combined, dried, filtered, and evaporated to dryness. The target compound (20 mg, yield 36.27%) was obtained by LCMS (petroleum ether:ethyl acetate = 1:1). LCMS (ESI) [M+H] + = 497.30.

[0624] Step 4: Preparation of (R)-4-(4,6-dihydro-2H-pyran-3-yl)-1-(1H-pyrazol-3-yl)-1H-pyrazol[3,4-b]pyridin-6-yl)-3-methylmorpholine:

[0625]

[0626] Will( R )-4-(4-(5,6-dihydro-2 H -pyran-3-yl)-1-(1-(2-(trimethylsilyl)ethoxy)methyl)-1 H -pyrazole-3-yl)-1 H -pyrazole[3,4- bPyridin-6-yl)-3-methylmorpholine (20 mg, 0.04 mmol, 1 equiv.) was dissolved in trifluoroacetic acid (2 mL) and dichloromethane (2 mL), and triethylsilane (0.2 mL) was added. The mixture was stirred at room temperature for 30 minutes. The reaction was confirmed to be complete by LCMS. The reaction solution was adjusted to alkalinity with saturated sodium bicarbonate solution, extracted with ethyl acetate and water, and the organic phases were combined, dried, filtered, and concentrated. The target compound (9.5 mg, yield 64.39%) was obtained by L2 plate analysis (dichloromethane:methanol = 10:1). LCMS (ESI) [M+H]+ = 367.15; 1 H NMR (399 MHz, CD3OD) δ 8.07 (s, 1H),7.73 (s, 1H), 6.93 (s, 1H), 6.59 (s, 1H), 6.54 (s, 1H), 4.54 (dd, J = 26.1,10.9 Hz, 4H), 4.04 (dd, J = 26.3, 10.6 Hz, 2H), 3.89 (t, J = 5.5 Hz, 2H), 3.78 (q, J = 11.5 Hz, 2H), 3.60 (t, J = 10.8 Hz, 1H), 2.41 (s, 2H), 1.27 (d,J = 6.7 Hz, 3H).

[0627] Example 9

[0628] Preparation of (R)-3-methyl-4-(4-(6-methylpyridin-3-yl)-1-(1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)morpholine:

[0629]

[0630] Step 1: Preparation of (R)-3-methyl-4-(4-(6-methylpyridin-3-yl)-1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)-1H-pyrazol[3,4-b]pyridin-6-yl)morpholine:

[0631]

[0632] Will( R )-4-(4-iodo-1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1 H -pyrazole-3-yl)-1 H -pyrazole[3,4- b[1,1'-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (50 mg, 0.09 mmol, 1 equiv.), 2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxane-2-yl)pyridine (15.2 mg, 0.11 mmol, 1.2 equiv.), sodium carbonate (19.61 mg, 0.19 mmol, 2 equiv.), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (6.79 mg, 0.01 mmol, 0.1 equiv.) were dissolved in 1,4-dioxane (2 mL) and water (1 mL) and stirred at 90 °C for 2 hours. The reaction was complete as determined by LCMS. The organic phases were extracted with ethyl acetate and water, combined, dried, filtered, and evaporated to dryness. Thin-layer chromatography (petroleum ether:ethyl acetate = 1:1) was used to give the target compound (38 mg, yield 81.23%). LCMS (ESI) [M+H] + = 506.45.

[0633] Step 2: Preparation of (R)-3-methyl-4-(4-(6-methylpyridin-3-yl)-1-(1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)morpholine:

[0634]

[0635] (R)-3-methyl-4-(4-(6-methylpyridin-3-yl)-1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1 H- pyrazole-3-yl)-1 H -pyrazole[3,4- b Pyridin-6-yl)morpholine (38 mg, 0.08 mmol, 1 equiv.) was dissolved in trifluoroacetic acid (2 mL) and dichloromethane (2 mL), and triethylsilane (0.2 mL) was added. The mixture was stirred at room temperature for 30 minutes. The reaction was confirmed to be complete by LCMS. The reaction solution was adjusted to alkalinity with saturated sodium bicarbonate solution, extracted with ethyl acetate and water, and the organic phases were combined, dried, filtered, and concentrated. The target compound (12.1 mg, yield 42.89%) was obtained by LLC (dichloromethane:methanol = 10:1). LCMS (ESI) [M+H] + = 376.15; 1H NMR (399 MHz, DMSO-d6) δ 12.83 (s, 1H), 8.90 (s, 1H), 8.14 (d, J = 7.7 Hz, 2H), 7.84 (s, 1H), 7.43 (d, J = 7.8 Hz,1H), 6.95 (s, 1H), 6.79 (s, 1H), 4.55 (s, 1H), 4.13 (d, J = 13.2 Hz, 1H), 3.96 (d, J = 10.7 Hz, 1H), 3.74 (d, J = 11.7 Hz, 1H), 3.64 (d, J = 11.4 Hz, 1H), 3.49 (t, J = 11.4 Hz, 1H), 3.20 (d, J = 12.2 Hz, 2H), 2.55 (s, 3H), 1.19 (d, J = 6.0 Hz, 3H).

[0636] Example 10

[0637] (R)-6-((6-(3-methylmorpholino)-1-(1H-pyrazolyl-5-yl)-1H-pyrazolyl[3,4-b]pyridin-4-yl)ethynyl)spiro[2,5]octane-6-ol:

[0638]

[0639] Step 1: Preparation of 6-((trimethylsilyl)ethynyl)spiro[2.5]octane-6-ol:

[0640]

[0641] Spiro[2.5]oct-6-one (300 mg, 2.42 mmol, 1 equiv.) was dissolved in dry tetrahydrofuran (10 mL). The reaction mixture was protected with nitrogen and cooled to -78 °C. Butyllithium (1.45 mL, 3.63 mmol, 1.5 equiv., 2.5 M) was added dropwise. The reaction mixture was stirred at -78 °C for 1 hour. Trimethylsilylacetylene (284.5 mg, 2.90 mmol, 1.2 equiv.) was added, and the reaction mixture was allowed to return to room temperature naturally and stirred for another 1 hour. TLC (potassium permanganate) confirmed the reaction was complete. The reaction was quenched with saturated ammonium chloride aqueous solution (5 mL). Extraction was performed with water (5 mL) and ethyl acetate (5 mL x 2). The organic phase was dried, concentrated, and the target compound (380 mg, 70.6% yield, crude product) was obtained.

[0642] Step 2: Preparation of 6-ethylspirocyclic [2.5]octane-6-ol:

[0643]

[0644] 6-((trimethylsilyl)ethynyl)spiro[2.5]octane-6-ol (380 mg, 1.71 mmol, 1 equiv.) was dissolved in tetrahydrofuran (5 mL), and tetrabutylammonium fluoride (1.7 mL, 1.71 mmol, 1 equiv., 1 M) was added. The reaction mixture was stirred at room temperature for 1 hour. The reaction was confirmed to be complete by TLC (potassium permanganate). The mixture was extracted with ethyl acetate and water, dried over the organic phase, and concentrated to give the target compound (228 mg, yield 88.8%, crude product).

[0645] Step 3: Preparation of (R)-6-((6-(3-methylmorpholino)-1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolyl-5-yl)-1H-pyrazolyl[3,4-b]pyridin-4-yl)ethynyl)spiro[2,5]octane-6-ol:

[0646]

[0647] (R)-4-(4-iodo-1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1 H -pyrazole-5-yl)-1 H -pyrazole[3,4- b Pyridin-6-yl)-3-methylmorpholine (50 mg, 0.09 mmol, 1 equiv.) dissolved in N , N In dimethylformamide (2 mL), 6-ethylspirocyclo[2,5]octane-6-ol (29 mg, 0.19 mmol, 2.1 equiv.), palladium dichloride bis(triphenylphosphine) (2 mg, 0.003 mmol, 0.03 equiv.), cuprous iodide (1 mg, 0.005 mmol, 0.05 equiv.), and diisopropylethylamine (37 mg, 0.29 mmol, 3.1 equiv.) were added. The mixture was purged with nitrogen three times, and the reaction solution was stirred at room temperature for 16 hours. The reaction was confirmed to be complete by LCMS. The solution was diluted with water and extracted three times with ethyl acetate. The organic phases were combined, washed with saturated brine, dried, concentrated, and purified by thin-layer chromatography (ethyl acetate: petroleum ether = 1:3) to obtain the target product (35 mg, yield 69.1%). LCMS (ESI) [M+H] + = 563.50.

[0648] Step 4: Preparation of (R)-6-((6-(3-methylmorpholino)-1-(1H-pyrazolyl-5-yl)-1H-pyrazolyl[3,4-b]pyridin-4-yl)ethynyl)spiro[2,5]octane-6-ol:

[0649]

[0650] (R)-6-((6-(3-methylmorpholino)-1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1 H -pyrazol-5-yl)-1 H -pyrazole group [3,4- b [2.5]octane-6-ol (35 mg, 0.06 mmol, 1 equiv.) was dissolved in dichloromethane (0.6 mL), followed by the addition of trifluoroacetic acid (0.8 mL) and then triethylsilane (0.08 mL). The reaction mixture was stirred at room temperature for 10 minutes. LCMS analysis confirmed the reaction was complete. The pH was adjusted to 9 by adding saturated sodium bicarbonate solution, and the mixture was extracted three times with ethyl acetate. The organic phases were combined, washed with saturated brine, dried, filtered, concentrated, and purified by thin-layer chromatography (dichloromethane:methanol = 10:1) to obtain the target compound (11.9 mg, yield 45.8%). LCMS (ESI) [M+H]+ = 433.15; 1 H NMR (400 MHz, DMSO-d6) δ 12.83 (s, 1H), 7.96 (s, 1H), 7.82 (s, 1H), 6.82 (s, 1H), 6.75 (s, 1H), 5.67 (s, 1H), 4.43 (s, 1H), 4.03 (d, J =12.9 Hz, 1H), 3.93 (d, J = 9.8 Hz, 1H), 3.71 (d, J = 11.2 Hz, 1H), 3.60 (d, J= 10.7 Hz, 1H), 3.45 (t, J = 11.3 Hz, 1H), 3.14 (s, 1H), 1.96 – 1.90 (m, 2H),1.73 (t, J = 10.7 Hz, 2H), 1.59 (s, 2H), 1.24 (d, J = 9.2 Hz, 2H), 1.16 (d, J= 6.4 Hz, 3H), 0.31 – 0.26 (m, 2H), 0.23 (d, J = 7.3 Hz, 2H).

[0651] Example 11

[0652] Preparation of (R)-4-(1-(1H-pyrazol-3-yl)-4-(1H-pyrrolidinyl[2,3-b]pyridin-4-yl)-1H-pyrazol[3,4-b]pyridin-6-yl)-3-methylmorpholine:

[0653]

[0654] Step 1: Preparation of (R)-4-(4-(1H-pyrrolidinyl[2,3-b]pyridin-4-yl)-1-(1-(2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)-1H-pyrazol[3,4-b]pyridin-6-yl)-3-methylmorpholine:

[0655]

[0656] (R)-4-(4-iodo-1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1 H -pyrazole-3-yl)-1 H -pyrazole[3,4- b Pyridin-6-yl)-3-methylmorpholine (0 mg, 0.09 mmol, 1 equiv.), 4-(4,4,5,5-tetramethyl-1,3,2-dioxane-2-yl)-1 H -pyrrole[2,3- b Pyridine (27 mg, 0.11 mmol, 1.2 equiv.), [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichlorodi ... + = 531.20.

[0657] Step 2: Preparation of (R)-4-(1-(1H-pyrazol-3-yl)-4-(1H-pyrrolidinyl[2,3-b]pyridin-4-yl)-1H-pyrazol[3,4-b]pyridin-6-yl)-3-methylmorpholine:

[0658]

[0659] (R)-4-(4-(1) H -pyrrole[2,3-b ]pyridin-4-yl)-1-(1-(2-(trimethylsilyl)ethoxy)methyl)-1 H -pyrazole-3-yl)-1 H -pyrazole[3,4- b Pyridin-6-yl)-3-methylmorpholine (24 mg, 0.04 mmol, 1 equiv.) was dissolved in trifluoroacetic acid (1 mL) and dichloromethane (1 mL), and triethylsilane (0.1 mL) was added. The mixture was stirred at room temperature for 10 minutes. LCMS analysis showed the reaction was complete. The reaction solution was adjusted to alkalinity with saturated sodium bicarbonate solution, extracted with ethyl acetate and water, and the organic phases were combined, dried, filtered, and concentrated. The target compound (7.8 mg, yield 38.96%) was obtained by L-tick (dichloromethane:methanol = 10:1). LCMS (ESI) [M+H]+ = 401.10; 1 H NMR(399 MHz, CD3OD) δ 8.35(d, J = 5.4 Hz, 1H), 7.93 (s, 1H), 7.77 (s, 1H), 7.50 (d, J = 3.5 Hz, 1H), 7.38 (d, J = 4.8 Hz, 1H), 7.00 (d, J = 7.2 Hz, 2H), 6.55 (d, J = 3.2 Hz, 1H), 4.57 (s, 1H), 4.17 (d, J = 13.6 Hz, 1H), 4.02 (s, 1H), 3.82 (d, J = 4.1 Hz, 2H), 3.65 (s, 1H), 3.37 (s, 1H), 1.35 (d, J = 6.6 Hz, 3H).

[0660] Example 12

[0661] Preparation of (R)-1-(3-fluorophenyl)-4-((6-(3-methylmorpholino)-1-(1H-pyrazolyl-5-yl)-1H-pyrazolyl[3,4-b]pyridin-4-yl)ethynyl)piperidin-4-ol:

[0662]

[0663] Step 1: Preparation of 1-(3-fluorophenyl)-4-((trimethylsilyl)ethynyl)piperidine-4-ol:

[0664]

[0665] Trimethylethynylsilane (381.25 mg, 3.88 mmol, 1.5 equiv.) was added to tetrahydrofuran (5 mL) at room temperature, purged three times with nitrogen, and the temperature was lowered to -78 °C. Then, n-butyllithium (207.21 mg, 3.23 mmol, 1.25 equiv.) was injected into the reaction system, and the mixture was stirred at -78 °C for 1 hour. Next, 1-(3-fluorophenyl)piperidin-4-one (500 mg, 2.59 mmol, 1 equiv.) was dissolved in tetrahydrofuran (1 mL) and slowly injected into the reaction system. The mixture was stirred at -78 °C for 0.5 hours, and then slowly restored to room temperature with stirring for 30 minutes. The reaction was confirmed to be complete by LCMS. The reaction was quenched with saturated ammonium chloride solution, and the mixture was extracted three times with ethyl acetate. The organic phases were combined, washed with saturated brine, dried, filtered, and concentrated. The concentrate was purified by thin-layer chromatography to obtain the target compound (310 mg, yield 41.07%). LCMS (ESI) [M+H]+ = 292.44.

[0666] Step 2: Preparation of 4-ethynyl-1-(3-fluorophenyl)piperidine-4-ol:

[0667]

[0668] 1-(3-fluorophenyl)-4-((trimethylsilyl)ethynyl)piperidin-4-ol (20 mg, 0.07 mmol, 1 equiv.) was dissolved in tetrahydrofuran (10 mL) at room temperature. Tetrabutylammonium fluoride (1 mL, 1 mmol, 14.57 equiv.) was then slowly added to the reaction mixture. The mixture was purged with nitrogen three times and reacted at room temperature for 30 minutes. The reaction was confirmed to be complete by LCMS. The mixture was diluted with water, extracted three times with ethyl acetate, and the organic phases were combined, washed with saturated brine, dried, filtered, and concentrated to give the crude target compound (15 mg, yield 97.74%). LCMS (ESI) [M+H] + = 220.25.

[0669] Step 3: Preparation of (R)-1-(3-fluorophenyl)-4-((6-(3-methylmorpholino)-1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)-1H-pyrazolyl[3,4-b]pyridin-4-yl)ethynyl)piperidin-4-ol:

[0670]

[0671] At room temperature, (R)-4-(4-iodo-1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1 H -pyrazole-5-yl)-1H -pyrazole[3,4- b Pyridin-6-yl)-3-methylmorpholine (175 mg, 0.32 mmol, 1 equiv.), 4-ethynyl-1-(3-fluorophenyl)piperidin-4-ol (149.08 mg, 0.68 mmol, 2.1 equiv.), cuprous iodide (3.08 mg, 0.02 mmol, 0.05 equiv.), N , N Diisopropylethylamine (133.91 mg, 1.04 mmol, 3.2 equiv.) and bis(triphenylphosphine)palladium dichloride (6.82 mg, 0.01 mmol, 0.03 equiv.) were added to N,N-dimethylformamide (10 mL), purged three times with nitrogen, and stirred at room temperature for 16 hours. The reaction was confirmed to be complete by LCMS. The reaction mixture was filtered, the filtrate was diluted with water, and extracted three times with ethyl acetate. The organic phases were combined, washed with saturated brine, dried, filtered, and concentrated. The concentrate was purified by thin-layer chromatography (petroleum ether:ethyl acetate = 1:1) to give the target compound (120 mg, yield 58.66%). LCMS (ESI) [M+H] + =632.82.

[0672] Step 4: Preparation of (R)-1-(3-fluorophenyl)-4-((6-(3-methylmorpholino)-1-(1H-pyrazolyl-5-yl)-1H-pyrazolyl[3,4-b]pyridin-4-yl)ethynyl)piperidin-4-ol:

[0673]

[0674] At room temperature, (R)-1-(3-fluorophenyl)-4-((6-(3-methylmorpholino)-1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1 H -pyrazole-5-yl)-1 H -pyrazole group [3,4- bPyridin-4-yl)ethynyl)piperidin-4-ol (120 mg, 0.19 mmol, 1 equiv.) was added to a mixed solvent of trifluoroacetic acid (2 mL) and dichloromethane (2 mL). Triethylsilane (0.2 mL, 1.72 mmol, 9.06 equiv.) was then slowly added to the reaction system. The mixture was purged with nitrogen three times and reacted at room temperature for 10 minutes. The reaction was confirmed to be complete by LCMS. The pH of the reaction solution was adjusted to 9 with saturated sodium bicarbonate solution, and the mixture was extracted three times with ethyl acetate. The organic phases were combined, washed with saturated brine, dried, filtered, and concentrated. The concentrate was purified by thin-layer chromatography (dichloromethane:methanol = 10:1) to obtain the target compound (34.4 mg, yield 36.1%). LCMS (ESI) [M+H]+ = 502.56; 1 H NMR (400 MHz, DMSO-d6) δ 12.83 (s, 1H), 7.98 (s, 1H), 7.81(s, 1H), 7.18 (d, J = 7.5 Hz, 1H), 6.84 (s, 1H), 6.75 (d, J = 11.5 Hz, 3H), 6.49 (s, 1H), 5.95 (s, 1H), 4.43 (s, 1H), 4.00 (s, 1H), 3.91 (s, 1H), 3.70 (d, J = 11.2 Hz, 1H), 3.61 (s, 1H), 3.51 (s, 2H), 3.44 (s, 4H), 3.20 (s, 7H), 2.00 (s, 2H), 1.83 (s, 2H), 1.15 (d, J = 6.6 Hz, 3H).

[0675] Example 13

[0676] Preparation of (3R)-4-(1-(1H-pyrazol-3-yl)-4-(tetrahydro-2H-pyran-3-yl)-1H-pyrazol[3,4-b]pyridin-6-yl)-3-methylmorpholine:

[0677]

[0678] Step 1: Preparation of (3R)-4-(1-(1H-pyrazol-3-yl)-4-(tetrahydro-2H-pyran-3-yl)-1H-pyrazol[3,4-b]pyridin-6-yl)-3-methylmorpholine:

[0679]

[0680] Will( R )-4-(4,6-dihydro-2H -pyran-3-yl)-1-(1 H -pyrazole-3-yl)-1 H -pyrazole[3,4- b Pyridin-6-yl)-3-methylmorpholine (50 mg, 0.14 mmol, 1 equiv.) was dissolved in methanol (5 mL) and ethyl acetate (1 mL), and palladium on carbon (10 mg, 0.09 mmol, 0.67 equiv.) was added. Hydrogen was purged several times, and the mixture was stirred overnight at room temperature. LCMS analysis showed the reaction was complete. The palladium on carbon was filtered off from the reaction solution, the filtrate was evaporated to dryness, and the target compound (36 mg, yield 69.79%) was purified by thin-layer chromatography (dichloromethane:methanol = 10:1). LCMS (ESI) [M+H]+ = 369.20; 1 H NMR (399 MHz, DMSO-d6) δ 8.20 (s, 1H), 7.77 (s, 1H), 6.70 (d, J = 31.5 Hz, 2H), 4.43 (s,1H), 4.02 (d, J = 12.9 Hz, 1H), 3.88 (d, J = 10.3 Hz, 3H), 3.72 (d, J = 11.4Hz, 1H), 3.60 (d, J = 11.3 Hz, 2H), 3.47 (d, J = 10.8 Hz, 2H), 3.13 (d, J =10.5 Hz, 2H), 1.96 (s, 2H), 1.67 (s, 2H), 1.15 (d, J = 5.2 Hz, 3H).

[0681] Example 14

[0682] Preparation of (R)-9-((6-(3-methylmorpholino)-1-(1H-pyrazol-5-yl)-1H-pyrazol[3,4-b]pyridin-4-yl)ethynyl)-3-oxapirol[5.5]undec-9-ol:

[0683]

[0684] Step 1: Preparation of 9-((trimethylsilyl)ethynyl)-3-oxapirone[5.5]undec-9-ol:

[0685]

[0686] Trimethylethynylsilane (241.2 mg, 2.46 mmol, 1.5 equiv.) was added to tetrahydrofuran (5 mL) at room temperature, purged three times with nitrogen, and the temperature was lowered to -78 °C. Then, n-butyllithium (131.09 mg, 2.05 mmol, 1.25 equiv.) was injected into the reaction system, and the mixture was stirred at -78 °C for 1 hour. Next, 3-oxoxamic acid [5.5]undecane-9-one (300 mg, 1.64 mmol, 1 equiv.) was dissolved in tetrahydrofuran (1 mL) and slowly injected into the reaction system. The mixture was stirred at -78 °C for 0.5 hours, and then slowly restored to room temperature with stirring for 30 minutes. The reaction was confirmed to be complete by LCMS. The reaction was quenched with saturated ammonium chloride aqueous solution, and the mixture was extracted three times with ethyl acetate. The organic phases were combined, washed with saturated brine, dried, filtered, and concentrated. The concentrate was purified by thin-layer chromatography to obtain the target compound (300 mg, yield 64.99%). LCMS (ESI) [M+H]+ =267.45.

[0687] Step 2: Preparation of 9-ethynyl-3-oxapirome[5.5]undecane-9-ol:

[0688]

[0689] At room temperature, 9-((trimethylsilyl)ethynyl)-3-oxapirol[5.5]undec-9-ol (310 mg, 1.06 mmol, 1 equiv.) was added to tetrahydrofuran (10 mL), followed by slow addition of tetrabutylammonium fluoride (2 mL, 2 mmol, 1.88 equiv.). The mixture was purged with nitrogen three times and stirred at room temperature for 30 minutes. The reaction was confirmed to be complete by LCMS. The mixture was diluted with water, extracted three times with ethyl acetate, and the organic phases were combined, washed with saturated brine, dried, filtered, and concentrated to give the crude target compound (230 mg, yield 98.97%). LCMS (ESI) [M+H] + = 195.27.

[0690] Step 3: Preparation of (R)-9-((6-(3-methylmorpholino)-1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)-1H-pyrazol[3,4-b]pyridin-4-yl)ethynyl)-3-oxapeli[5.5]undecane-9-ol:

[0691]

[0692] At room temperature, (R)-4-(4-iodo-1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1 H -pyrazole-5-yl)-1H -pyrazole[3,4- b [5.5]pyridin-6-yl)-3-methylmorpholine (55 mg, 0.1 mmol, 1 equiv.), 9-ethynyl-3-oxapirol[5.5]undecane-9-ol (41.52 mg, 0.21 mmol, 2.1 equiv.), cuprous iodide (0.97 mg, 0.01 mmol, 0.05 equiv.), N , N -Diisopropylethylamine (42.09 mg, 0.33 mmol, 3.2 equiv.) and bis(triphenylphosphine)palladium dichloride (2.14 mg, 0.003 mmol, 0.03 equiv.) were added to N , N In 10 mL of dimethylformamide, the mixture was purged three times with nitrogen and stirred at room temperature for 16 hours. The reaction was confirmed to be complete by LC-MS. The reaction solution was filtered, the filtrate was diluted with water, and extracted three times with ethyl acetate. The organic phases were combined, washed with saturated brine, dried, filtered, and concentrated. The concentrate was purified by thin-layer chromatography (petroleum ether:ethyl acetate = 1:1) to give the target product (25 mg, yield 52.46%). LC-MS (ESI) [M+H + =607.83

[0693] Step 4: Preparation of (R)-9-((6-(3-methylmorpholino)-1-(1H-pyrazol-5-yl)-1H-pyrazol[3,4-b]pyridin-4-yl)ethynyl)-3-oxapirol[5.5]undec-9-ol:

[0694]

[0695] At room temperature, (R)-9-((6-(3-methylmorpholino)-1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1 H -pyrazole-5-yl)-1 H -pyrazole[3,4- b[5.5]Undecane-9-ol (25 mg, 0.04 mmol, 1 equiv.) was added to a mixed solvent of trifluoroacetic acid (2 mL) and dichloromethane (2 mL), and then triethylsilane (0.2 mL, 1.72 mmol, 41.75 equiv.) was slowly added to the reaction system. The reaction was purged with nitrogen three times and reacted at room temperature for 1 hour. The reaction was confirmed to be complete by LCMS. The pH of the reaction solution was adjusted to 9 with saturated sodium bicarbonate solution, and then extracted three times with ethyl acetate. The organic phases were combined, washed with saturated brine, dried, filtered, and concentrated. The concentrate was purified by thin-layer chromatography (dichloromethane:methanol = 10:1) to obtain the target compound (4.8 mg, yield 25.18%). LCMS (ESI) [M+H]+ = 477.57; 1 H NMR (400 MHz, DMSO-d6) δ 12.82 (s, 1H), 7.95 (s, 1H), 7.82 (s, 1H), 6.79 (s, 1H), 6.74 (s, 1H), 5.62 (s, 1H), 4.42 (s, 1H), 4.03 (d, J =13.8 Hz, 1H), 3.92 (d, J = 10.6 Hz, 1H), 3.71 (d, J = 11.2 Hz, 1H), 3.60 (d,J = 13.1 Hz, 1H), 3.52 (s, 4H), 3.45 (s, 1H), 3.13 (s, 1H), 1.81 (s, 2H), 1.69 (d, J = 11.1 Hz, 4H), 1.45 (s, 2H), 1.39 (s, 4H), 1.15 (d, J = 6.6 Hz, 3H).

[0696] Example 15

[0697] Preparation of (R)-6-(4-(6-(3-methylmorpholino)-1-(1H-pyrazolyl-3-yl)-1H-pyrazolyl[3,4-b]pyridin-4-yl)phenyl)-2-oxo-6-azaspirocyclic[3.3]heptane:

[0698]

[0699] Step 1: Preparation of ((R)-4-(4-(4-bromophenyl)-1-(1-(2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)-1H-pyrazol[3,4-b]pyridin-6-yl)-3-methylmorpholine:

[0700]

[0701] Weigh p-bromophenylboronic acid (41 mg, 0.204 mmol, 1.1 equiv.), (R)-4-(4-iodo-1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)-1H-pyrazol[3,4-b]pyridin-6-yl)-3-methylmorpholine (100 mg, 0.185 mmol, 1.0 equiv.), [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloro(II) (14 mg, 0.018 mmol, 0.1 equiv.), and sodium carbonate (40 mg, 0.37 mmol, 2.0 equiv.) and dissolve them in 1,4-dioxane (4 mL) and water (2 mL). Then, purge the solution three times with nitrogen and raise the temperature to 90 °C. At this temperature, react for 3 minutes. After hours, the reaction mixture was checked for complete reaction by TLC-trace analysis, and the product was detected by LC-MS. The reaction solution was filtered and extracted with ethyl acetate (20 mL x 3). The organic phases were combined and evaporated to dryness before thin-layer chromatography (petroleum ether:ethyl acetate = 3:1) to give the target compound (50 mg, yield 43.1%). LC-MS (ESI) [M+H]+ = 569.15

[0702] Step 2: Preparation of (R)-6-(4-(6-(3-methylmorpholino)-1-(1-(2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)-1H-pyrazol[3,4-b]pyridin-4-yl)phenyl)-2-oxo-6-azaspiro[3.3]heptane:

[0703]

[0704] (R)-4-(4-(4-bromophenyl)-1-(1-(2-(trimethylsilyl)ethoxy)methyl)-1 H -pyrazole-5-yl)-1 H -pyrazole[3,4- b1,4-Dioxane (5 mL) was dissolved in pyridin-6-yl)-3-methylmorpholine (50 mg, 0.11 mmol, 1.0 equiv.), 2-oxo-6-azaspirocyclic [3.3]heptane (12 mg, 0.117 mmol, 1.1 equiv.), tris(dibenzylacetone)palladium (20 mg, 0.022 mmol, 0.2 equiv.), 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl (6 mg, 0.011 mmol, 0.1 equiv.), and cesium carbonate (72 mg, 0.22 mmol, 2.0 equiv.). The reaction mixture was purged with nitrogen three times and reacted at 90 °C for 3 hours. The reaction was completed by TLC-doping, and the product was detected by LCMS. The reaction mixture was filtered and then distilled with ethyl acetate (20 mL x 1 ... 3) Extraction, combined organic phase and rotary evaporation to obtain product (20 mg, yield 39.2%) by plate distillation (petroleum ether: ethyl acetate = 1:1). LCMS (ESI) [M+H]+ = 588.30.

[0705] Step 3: Preparation of (R)-6-(4-(6-(3-methylmorpholino)-1-(1H-pyrazolyl-3-yl)-1H-pyrazolyl[3,4-b]pyridin-4-yl)phenyl)-2-oxo-6-azaspirocyclic[3.3]heptane:

[0706]

[0707] (R)-6-(4-(6-(3-methylmorpholino)-1-(1-(2-(trimethylsilyl)ethoxy)methyl)-1 H -pyrazole-5-yl)-1 H -pyrazole[3,4- b Pyridin-4-yl)phenyl)-2-oxo-6-azaspiro[3.3]heptane (20 mg, 0.034 mmol, 1.0 equiv.) was dissolved in dichloromethane (2 mL), followed by the addition of trifluoroacetic acid (2 mL) and triethylsilane (0.2 mL). The mixture was then purged with nitrogen three times and reacted at 25 °C for 1 hour. TLC was used to confirm the complete reaction of the starting material, and LCMS was used to detect the formation of the product. The reaction solution was quenched with saturated sodium bicarbonate (50 mL) and extracted with ethyl acetate (20 mL x 3). The organic phases were combined and evaporated to dryness before thin-layer chromatography (dichloromethane / methanol = 10:1) to give the product (5.9 mg, yield 37.8%). LCMS (ESI) [M+H]+ = 458.20; 1H NMR (400 MHz, DMSO-d6) δ 12.78 (s, 1H), 8.10 (s, 1H), 7.82 (s, 1H), 7.69 (d, J = 8.7 Hz, 2H), 6.78 (d, J = 8.6 Hz, 2H), 6.57 (d, J = 8.6 Hz, 2H), 4.72 (s, 4H), 4.52 (s, 1H), 4.13 – 4.03 (m, 6H), 3.95 (d, J = 10.9 Hz, 1H), 3.74 (d, J = 11.4 Hz, 1H), 3.64 (d, J = 11.1 Hz, 1H), 3.48 (s, 1H), 1.18 (d,J = 6.3 Hz, 3H).

[0708] Example 16

[0709] (R)-2-methyl-4-(6-(3-methylmorpholine)-1-(1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-4-yl)3-methylbutynol:

[0710]

[0711] Step 1: (R)-2-methyl-4-(6-(3-methylmorpholino)-1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)-1H-pyrazol[3,4-b]pyridin-4-yl)3-methylbutynol:

[0712]

[0713] Weigh (R)-4-(4-iodo-1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)-1H-pyrazol[3,4-b]pyridin-6-yl)-3-methylmorpholine (100.2 mg, 0.19 mmol, 1 equiv.), 3-methylbutynol-3 (17.1 mg, 0.20 mmol, 1.1 equiv.), and triethylamine (37.5 mg, 0.37 mmol, 2 equiv.) and dissolve them in DMF (4.0 ml). Then weigh CuI (3.5 mg, 0.02 mmol, 0.1 equiv.) and Pd(PPh3)2Cl2 (13.0 mg, 0.02 mmol, 0.1 equiv.). The reaction mixture was purged under nitrogen protection, and then heated to 40°C for 1 hour. TLC showed complete consumption of the starting material. After cooling to room temperature (25°C), 15 ml of water was added to the reaction solution, followed by 15 ml of extractant (EA). The aqueous phase was then extracted again with EA (15 ml) until no product spots were observed. The organic phases were combined, washed once with 20 ml of water, then once with 15 ml of saturated saline solution. After drying and mixing, the product was purified using a PE / EA = 3:1 column to obtain 70.0 mg of product. The Rf value of the product was 0.3 (PE:EA = 3:1). LCMS: [M+H] + =537.43.

[0714] Step 2: (R)-2-methyl-4-(6-(3-methylmorpholine)-1-(1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-4-yl)3-methylbutynol:

[0715]

[0716] (R)-2-methyl-4-(6-(3-methylmorpholino)-1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)-1H-pyrazol[3,4-b]pyridin-4-yl)3-methylbutynol (70.0 mg, 0.14 mmol, 1 equiv.) was dissolved in dichloromethane (5.0 mL), and TFA (1.0 mL) was added dropwise. After stirring at room temperature (25 °C) for 5 hours, the reaction was complete as indicated by LCMS. The reaction solution was adjusted to pH 8 with saturated NaHCO3 aqueous solution, and extracted with DCM. The organic phase was concentrated to dryness, separated by acetonitrile / water (0.1% NH4HCO3), and lyophilized to obtain the target compound (15 mg, purity 90.5%, yield 27%). LCMS: [M+H] + =367.34; 1H NMR (400 MHz, DMSO) δ 12.86 (s,1H), 8.03 (s,1H), 7.84 (s,1H) ,6.83 (s,1H) , 6.78 (s,1H) , 5.68 (s,1H), 4.45 (d, J = 4.8 Hz, 1H), 4.07 (d, J = 12.3 Hz, 1H), 4.00-3.91 (m, 1H), 3.74 (d, J = 3.5 Hz, 1H), 3.64 (dd, J =11.4, 2.8 Hz, 1H), 3.49 (td, J = 11.8, 2.8 Hz, 1H), 3.16 (d, J = 3.5 Hz, 1H), 1.54 (s, 6H), 1.19 (d, J = 6.7 Hz, 3H).

[0717] Example 17

[0718] (R)-4-(4-ethyl-1-(1H-pyrazol-3-yl)-1H-pyrazol-[3,4-b]pyridin-6-yl)-3-methylmorpholine:

[0719]

[0720] Step 1: (R)-3-methyl-4-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)-4-((trimethylsilyl)ethynyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)morpholine:

[0721]

[0722] (R)-4-(4-iodo-1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-methylmorpholine (120 mg, 0.22 mmol, 1 equiv.), Pd(PPh3)2Cl2 (31 mg, 0.04 mmol, 0.2 equiv.), CuI (8.4 mg, 0.04 mmol, 0.2 equiv.), and triethylamine (44.5 mg, 0.44 mmol, 2 equiv.) were dissolved in DMF (4 mL) and stirred at 40 °C for 1 hour under nitrogen protection. Product formation was monitored by LCMS, and the reaction mixture was then cooled to 25 °C. The reaction was quenched with water (20 mL), followed by extraction with ethyl acetate (30 mL). The aqueous phase was washed with ethyl acetate (3 x 30 mL), and the combined organic phases were washed with saturated brine (3 x 20 mL). The mixture was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by rapid chromatography (100-200 mesh silica gel, petroleum ether:ethyl acetate = 0-10%) to give the title compound (100 mg, yield 89.5%). LCMS: [M+H] + =511.40.

[0723] Step 2: (R)-4-(4-ethyl-1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)-1H-pyrazol[3,4-b]pyridin-6-yl)-3-methylmorpholine:

[0724]

[0725] (R)-3-methyl-4-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)-4-((trimethylsilyl)ethynyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)morpholine (100 mg, 0.19 mmol, 1 equiv.) was dissolved in THF (5 mL), and TBAF (1 mL, 2.5 N) was added. The mixture was stirred at 25 °C for 1 hour. The reaction was monitored by TLC to ensure complete reaction of the starting material. The reaction was then quenched with water (20 mL), followed by extraction with ethyl acetate (30 mL). The aqueous phase was washed with ethyl acetate (3 * 30 mL), and the combined organic phases were washed with saturated brine (3 * 20 mL). The mixture was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product (140 mg).

[0726] Step 3: (R)-4-(4-ethyl-1-(1H-pyrazol-3-yl)-1H-pyrazol-[3,4-b]pyridin-6-yl)-3-methylmorpholine:

[0727]

[0728] (R)-4-(4-ethyl-1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)-1H-pyrazol[3,4-b]pyridin-6-yl)-3-methylmorpholine (140 mg, 0.32 mmol, 1 equiv.) was dissolved in DCM (5 mL), followed by the addition of TFA (0.5 mL), and stirred at 25°C for 2 h. The reaction was monitored by LCMS until complete. The reaction was quenched with NaHCO3 aqueous solution (10 mL), extracted with DCM (3 x 30 mL), and the combined organic phases were washed with saturated brine (3 x 30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by rapid chromatography (C18 reverse-phase column, water:acetonitrile = 0-40%) to obtain the target compound (20 mg, yield 34.2%). LCMS: [M+H] + =309.22; 1 H NMR: (400 MHz, DMSO- d 6) δ12.85 (s, 1H), 8.05 (s, 1H), 7.84 (s, 1H), 6.97 (s, 1H), 6.77 (d, J = 2.3 Hz,1H), 4.82 (s, 1H), 4.52-4.42 (m, 1H), 4.10-3.93 (m, 2H), 3.78-3.61 (m, 2H), 3.49 (dd, J = 13.2, 10.4 Hz, 1H), 3.20-3.11 (m, 1H), 1.19 (d, J = 6.7 Hz, 3H).

[0729] Example 18

[0730] (R)-N,N-Dimethyl-3-(6-(3-methylmorphorline)-1-(1H-pyrazol-3-yl)-1H-pyrazolline[3,4-b]pyridin-4-yl)propyl-2-ynyl-1-amine:

[0731]

[0732] Step 1: (R)-N,N-dimethyl-3-(6-(3-methylmorphorline)-1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)-1H-pyrazol[3,4-b]pyridin-4-yl)propyl-2-yn-1-amine:

[0733]

[0734] (R)-4-(4-iodo-1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-methylmorpholine (120 mg, 0.22 mmol, 1 equiv.), Pd(PPh3)2Cl2 (31 mg, 0.04 mmol, 0.2 equiv.), CuI (8.4 mg, 0.04 mmol, 0.2 equiv.), and triethylamine (44.5 mg, 0.44 mmol, 2 equiv.) were dissolved in DMF (4 mL) and stirred at 40 °C for 1 hour under nitrogen protection. Product formation was monitored by LCMS, and the reaction mixture was then cooled to 25 °C. The reaction was quenched with water (20 mL), followed by extraction with ethyl acetate (30 mL). The aqueous phase was washed with ethyl acetate (3 x 30 mL), and the combined organic phases were washed with saturated brine (3 x 20 mL). The mixture was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by rapid chromatography (100-200 mesh silica gel, petroleum ether:ethyl acetate = 0-10%) to obtain the target compound (100 mg, yield 91.8%). The product was analyzed using petroleum ether:ethyl acetate = 10:1, and the Rf value was 0.2. LCMS: [M+H] + =496.42.

[0735] Step 2: (R)-N,N-dimethyl-3-(6-(3-methylmorphorline)-1-(1H-pyrazol-3-yl)-1H-pyrazolline[3,4-b]pyridin-4-yl)propyl-2-ynyl-1-amine:

[0736]

[0737] (R)-N,N-dimethyl-3-(6-(3-methylmorphorline)-1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)-1H-pyrazol[3,4-b]pyridin-4-yl)propyl-2-yn-1-amine (100 mg, 0.20 mmol, 1 equiv.) was dissolved in DCM (5 mL), and then TFA (0.5 mL) was added. The mixture was stirred at 25°C for 2 h. The reaction was monitored by LCMS until complete. The reaction was quenched with NaHCO3 aqueous solution (10 mL), extracted with DCM (3 x 30 mL), and the combined organic phases were washed with saturated brine (3 x 30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by rapid chromatography (C18 reverse-phase column, water:acetonitrile = 0-50%) to give the title compound (38 mg, yield 52.0%); it was plate-tested with petroleum ether:ethyl acetate = 1:2, and the product Rf value was (0.2). LCMS: [M+H] + =366.1; 1 H NMR: (400 MHz, DMSO-d6) δ 12.85 (s,1H), 8.01 (s, 1H), 7.84 (s, 1H), 6.91 (s, 1H), 6.77 (s, 1H), 4.47 (d, J = 6.2Hz, 1H), 4.06 (d, J = 12.8 Hz, 1H), 3.96 (dd, J = 11.3 Hz, 3.3 Hz, 1H), 3.75(d, J = 11.4 Hz, 1H), 3.68-3.60 (m, 3H), 3.49 (td, J = 11.9, 2.9 Hz, 1H), 3.17 (td, J = 12.9, 3.7 Hz, 1H), 2.33 (s, 6H), 1.19 (d, J = 6.7 Hz, 3H).

[0738] Examples 19-29

[0739] The compounds of Examples 19-29 were prepared by referring to the preparation methods of Examples 1-18.

[0740]

[0741]

[0742] Example 30

[0743] Preparation of (R)-N-(4-(6-(3-methylmorpholino)-1-(1H-pyrazolyl-3-yl)-1H-pyrazolyl[3,4-b]pyridin-4-yl)phenyl)acetamide:

[0744]

[0745] Step 1: Preparation of (R)-N-(4-(6-(3-methylmorpholino)-1-(1-(2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)-1H-pyrazol[3,4-b]pyridin-4-yl)phenyl)acetamide:

[0746]

[0747] Weigh (R)-4-(4-iodo-1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)-1H-pyrazol[3,4-b]pyridin-6-yl)-3-methylmorpholine (50.0 mg, 0.09 mmol, 1.0 equiv.), N-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)phenyl)acetamide (18.0 mg, 0.10 mmol, 1.1 equiv.), [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloro(II) (7.3 mg, 0.01 mmol, 0.1 equiv.), and sodium carbonate (28.6 mg, 0.27 mmol, 3.0 equiv.) and dissolve them in 1,4-dioxane (4 mL) and water (2 mL). The reaction mixture was purged with nitrogen three times, heated to 90 °C, and reacted at this temperature for 3 hours. The reaction was monitored by TLC-based detection of complete reaction of the starting material and by LC-MS-based detection of product formation. The reaction solution was filtered and extracted with ethyl acetate (20 mL x 3). The organic phases were combined and evaporated to dryness before thin-layer chromatography (petroleum ether:ethyl acetate = 2:1) to give the target compound (30.0 mg, yield 60.8%). LC-MS (ESI) [M+H] + = 548.55.

[0748] Step 2: Preparation of (R)-N-(4-(6-(3-methylmorpholino)-1-(1H-pyrazolyl-3-yl)-1H-pyrazolyl[3,4-b]pyridin-4-yl)phenyl)acetamide:

[0749]

[0750] (R)-N-(4-(6-(3-methylmorpholino)-1-(1-(2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)-1H-pyrazol[3,4-b]pyridin-4-yl)phenyl)acetamide (30.0 mg, 0.05 mmol, 1.0 equiv.) was dissolved in dichloromethane (2 mL), and trifluoroacetic acid (2 mL) and triethylsilane (0.2 mL) were added. The mixture was purged three times with nitrogen and reacted at 25 °C for 10 min. The reaction mixture was monitored for complete reaction by TLC-doping, and the product was monitored by LCMS. The pH of the reaction solution was adjusted to alkaline with saturated sodium bicarbonate, and the mixture was extracted with ethyl acetate (20 mL x 3). The organic phases were combined and evaporated to dryness. The product was purified by thin-layer chromatography (dichloromethane:methanol = 10:1) to obtain the target compound (8.8 mg, yield 39.1%). LCMS (ESI) [M+H] + = 418.20; 1 H NMR(400 MHz, DMSO-d6) δ 12.80 (s, 1H), 10.16 (s, 1H), 8.16 (s, 1H), 7.78 (dd, J= 19.0, 8.4 Hz, 5H), 6.83 (d, J = 26.3 Hz, 2H), 4.53 (s, 1H), 4.11 (d, J =13.3 Hz, 1H), 3.95 (d, J = 10.9 Hz, 1H), 3.75 (d, J = 11.2 Hz, 1H), 3.64 (d,J = 11.6 Hz, 1H), 3.49 (t, J = 10.9 Hz, 1H), 3.19 (d, J = 11.8 Hz, 1H), 2.07(s, 3H), 1.19 (d, J = 6.4 Hz, 3H).

[0751] Example 31

[0752] Preparation of (R)-N-(4-(6-(3-methylmorpholino)-1-(1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-4-yl)phenyl)-2-oxopropionamide:

[0753]

[0754] Step 1: Preparation of 2-oxo-N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxoborhecyclopentan-2-yl)phenyl)propionamide:

[0755]

[0756] 2-O-propionic acid (200 mg, 2.27 mmol, 1.1 equiv.) was dissolved in N,N-dimethylformamide (2 mL). 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (1.02 g, 2.68 mmol, 1.3 equiv.) was added in an ice bath, and the mixture was stirred at room temperature for 30 minutes. Then, 4-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)aniline (452.4 mg, 2.1 mmol, 1.0 equiv.) and N,N-diisopropylethylamine (800 mg, 6.2 mmol, 3.0 equiv.) dissolved in N,N-dimethylformamide (2 mL) were added, and the mixture was stirred at room temperature for 2 hours. TLC monitoring showed the reaction proceeded to completion. The reaction was quenched with water (20 mL), and extracted with ethyl acetate (30 mL). The aqueous phase was washed with ethyl acetate (3 x 30 mL), and the combined organic phases were washed with saturated brine (3 x 20 mL). The mixture was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. Column chromatography purification (petroleum ether: ethyl acetate = 20:1) yielded the target compound (460 mg, yield 70.11%). LCMS (ESI) [M+H] + =290.16.

[0757] Step 2: Preparation of (R)-N-(4-(6-(3-methylmorpholino)-1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-4-yl)phenyl)-2-oxopropionamide:

[0758]

[0759] (R)-4-(4-iodo-1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-methylmorpholine (100 mg, 0.18 mmol, 1.0 equiv.), 2-oxo-N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxoborhexacyclopentan-2-yl)phenyl)propionamide (62.4 mg, 0.21 mmol, 1.2 equiv.), Pd(dppf)Cl2 (26 mg, 0.04 mmol, 0.2 equiv.), and potassium carbonate (50 mg, 0.36 mmol, 2.0 equiv.) were dissolved in 1,4-dioxane (3 mL) and water (0.3 mL). The reaction was carried out in mL of [M+H] at 100 °C for 8 hours under nitrogen protection. The reaction was monitored by TLC until complete, and then cooled to room temperature. The solid was filtered, and the filtrate was evaporated to dryness to obtain the crude product; purified by column chromatography (petroleum ether: ethyl acetate = 2:1) to give the target compound (88 mg, yield 85.02%). LCMS (ESI) [M+H] + = 576.42.

[0760] Step 3: Preparation of (R)-N-(4-(6-(3-methylmorpholino)-1-(1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-4-yl)phenyl)-2-oxopropionamide:

[0761]

[0762] (R)-N-(4-(6-(3-methylmorpholino)-1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-4-yl)phenyl)-2-oxopropionamide (88 mg) was dissolved in dichloromethane (5 mL), and trifluoroacetic acid (2 mL) was added. The mixture was stirred at room temperature for 4 hours. The reaction was monitored by LCMS until complete, and the solvent was evaporated to dryness. The reaction was quenched with sodium bicarbonate aqueous solution (10 mL), extracted with ethyl acetate (3 x 30 mL), and the organic phases were combined, washed with saturated brine (3 x 30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by reversed-phase column chromatography (C18, water:acetonitrile = 1:1) to give the target compound (15 mg, yield 18.73%). LCMS (ESI) [M+H] + =446.34; 1H NMR (400 MHz, DMSO-d6) δ12.85 (s, 1H), 10.69 (s, 1H), 8.21 (s, 1H), 8.05 (d, J = 8.6 Hz, 2H), 7.89 (d, J = 8.6 Hz, 2H), 7.85 (s, 1H), 6.93 (s, 1H), 6.83 (d, J = 1.9Hz, 1H), 4.65-4.51 (m, 1H), 4.23-4.09 (m, 1H), 3.99 (dd, J = 11.1, 2.9 Hz,1H), 3.78 (d, J = 11.1 Hz, 1H), 3.68 (d, J = 11.3 Hz, 1H), 3.52 (t, J = 11.8Hz, 1H), 3.25-3.17 (m, 2H), 2.47 (s, 3H), 1.23 (d, J = 6.8 Hz, 4H).

[0763] Example 32

[0764] Preparation of (R)-N-(4-(6-(3-methylmorpholino)-1-(1H-pyrazolyl-3-yl)-1H-pyrazolyl[3,4-b]pyridin-4-yl)phenyl)cyclobutane formamide:

[0765]

[0766] Step 1: Preparation of N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)phenyl)cyclobutaneamide:

[0767]

[0768] p-Aminophenylboronic acid ester (300.0 mg, 1.37 mmol, 1.0 equiv.) and triethylamine (415.0 mg, 4.11 mmol, 3.0 equiv.) were weighed and dissolved in dichloromethane (5 mL). Cyclobutyryl chloride (195.0 mg, 1.64 mmol, 1.2 equiv.) was added at 0 °C, and the reaction was carried out at 25 °C for 2 hours. The reaction was monitored for completeness by TLC. The reaction solution was separated by passing water (200 mL) and ethyl acetate (80 mL x 3). The combined organic phases were evaporated to dryness and purified by thin-layer chromatography (ethyl acetate: petroleum ether = 1:3) to obtain the target compound (200.0 mg, yield 48.5%). LCMS (ESI) [M+H] + =302.15.

[0769] Step 2: Preparation of (R)-N-(4-(6-(3-methylmorpholino)-1-(1-(2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolyl-3-yl)-1H-pyrazolyl[3,4-b]pyridin-4-yl)phenyl)cyclobutane formamide:

[0770]

[0771] (R)-4-(4-iodo-1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)-1H-pyrazol[3,4-b]pyridin-6-yl)-3-methylmorpholine (50.0 mg, 0.09 mmol, 1.0 equiv), N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)phenyl)cyclobutanamide (37.0 mg, 0.10 mmol, 1.1 equiv), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (7.0 mg, 0.01 mmol, 0.1 equiv), and sodium carbonate (20.0 mg, 0.18 mmol, 2.0 equiv) were dissolved in 1,4-dioxane (2 mL) and water (1 mL), and the solution was heated to 90°C. The mixture was stirred at ℃ for 2 hours. The reaction was monitored by LCMS until complete. The reaction solution was filtered, and water (50 mL) and ethyl acetate (20 mL x 3) were added. The mixture was separated, the organic phase was dried, filtered, concentrated, and purified by thin-layer chromatography (ethyl acetate: petroleum ether = 1:1) to give the target compound (47.0 mg, yield 87.0%). LCMS (ESI) [M+H] + =588.35.

[0772] Step 3: Preparation of (R)-N-(4-(6-(3-methylmorpholino)-1-(1H-pyrazolyl-3-yl)-1H-pyrazolyl[3,4-b]pyridin-4-yl)phenyl)cyclobutane formamide:

[0773]

[0774] (R)-N-(4-(6-(3-methylmorpholino)-1-(1-(2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolyl-3-yl)-1H-pyrazolyl[3,4-b]pyridin-4-yl)phenyl)cyclobutanecarboxamide (47.0 mg, 0.08 mmol, 1.0 equiv) was dissolved in dichloromethane (1 mL), and trifluoroacetic acid (1 mL) and triethylsilane (0.1 mL) were added. The reaction was carried out at room temperature for 1 hour. The reaction mixture was monitored by TLC to ensure complete reaction of the starting material. The reaction solution was quenched with water (50 mL), and extracted with dichloromethane (20 mL x 3). The combined organic phases were dried and purified by thin-layer chromatography (dichloromethane:methanol = 10:1) to obtain the target compound (19.0 mg, yield 52.7%). LCMS (ESI) [M+H] + =458.25; 1 H NMR (400 MHz, DMSO-d6) δ 12.80 (s,1H), 9.93 (s, 1H), 8.16 (s, 1H), 7.81 (d, J = 12.8 Hz, 5H), 6.83 (d, J = 24.9Hz, 2H), 4.54 (s, 1H), 3.23 (dd, J = 21.6, 13.0 Hz, 2H), 2.26 – 2.18 (m, 2H), 2.11 (d, J = 8.2Hz, 2H), 1.99 – 1.90 (m, 1H), 1.81 (s, 1H), 1.19 (d, J = 6.4 Hz, 3H).

[0775] Example 33

[0776] Preparation of (R)-1-cyclopropyl-3-(4-(6-(3-methylmorpholino)-1-(1H-pyrazolyl-3-yl)-1H-pyrazolyl[3,4-b]pyridin-4-yl)phenyl)urea:

[0777]

[0778] Step 1: Preparation of (R)-1-cyclopropyl-3-(4-(6-(3-methylmorpholino)-1-(1-(2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)-1H-pyrazol[3,4-b]pyridin-4-yl)phenyl)urea:

[0779]

[0780] Weigh (R)-4-(4-iodo-1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)-1H-pyrazol[3,4-b]pyridin-6-yl)-3-methylmorpholine (50.0 mg, 0.09 mmol, 1.0 equiv.) and 1-cyclopropyl-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxoborhexacyclopentan-2-yl)phenyl)urea (30.0 mg, 0.10 mmol, 1.1 equiv.), [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloro(II) (7.3 mg, 0.01 mmol, 0.1 equiv.) and sodium carbonate (28.6 mg, 0.27 mmol, 3.0 equiv.) and dissolve them in 1,4-dioxane (4 mL) and water (2 mL). In a solution of [M+H], nitrogen was used to purge the atmosphere three times, and the temperature was raised to 90 °C. The reaction was carried out at this temperature for 3 hours. TLC was used to monitor the complete reaction of the starting material, and LCMS was used to monitor the formation of the product. The reaction solution was filtered and extracted with ethyl acetate (20 mL x 3). The organic phases were combined and evaporated to dryness before thin-layer chromatography (petroleum ether:ethyl acetate = 2:1) to give the target compound (40.0 mg, yield 74.1%). + = 589.10.

[0781] Step 2: Preparation of (R)-1-cyclopropyl-3-(4-(6-(3-methylmorpholino)-1-(1H-pyrazolyl-3-yl)-1H-pyrazolyl[3,4-b]pyridin-4-yl)phenyl)urea:

[0782]

[0783] (R)-1-cyclopropyl-3-(4-(6-(3-methylmorpholino)-1-(1-(2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)-1H-pyrazol[3,4-b]pyridin-4-yl)phenyl)urea (40.0 mg, 0.07 mmol, 1.0 equiv.) was dissolved in dichloromethane (2.0 mL), and trifluoroacetic acid (2.0 mL) and triethylsilane (0.2 mL) were added. The mixture was purged with nitrogen three times and reacted at 25 °C for 1 h. The reaction was monitored by TLC to ensure the starting material was fully reacted and by LCMS to monitor the product formation. The reaction solution was quenched with saturated sodium bicarbonate (50.0 mL) and extracted with ethyl acetate (20 mL x 3). The organic phases were combined and evaporated to dryness for thin-layer chromatography (dichloromethane:methanol = 10:1) to give the target compound (6.4 mg, yield 20.5%). LCMS (ESI) [M+H] + = 459.20; 1 HNMR (400 MHz, DMSO-d6) δ 12.83 (s, 1H), 8.57 (s, 1H), 8.16 (s, 1H), 7.80 (s,1H), 7.74 (d, J = 8.5 Hz, 2H), 7.58 (d, J = 8.6 Hz, 2H), 6.82 (d, J = 17.0Hz, 2H), 6.45 (s, 1H), 4.53 (s, 1H), 4.11 (d, J = 13.2 Hz, 1H), 3.96 (d, J =10.4 Hz, 1H), 3.74 (d, J = 11.8 Hz, 1H), 3.64 (d, J = 9.0 Hz, 1H), 3.49 (s,1H), 3.18 (s, 1H), 2.54 (s, 1H), 1.20 (s, 3H), 0.62 (d, J = 6.8 Hz, 2H), 0.40(s, 2H).

[0784] Examples 34-58

[0785] The compounds of Examples 34-58 were prepared by referring to the preparation methods of Examples 1-18 and 30-33.

[0786]

[0787]

[0788]

[0789]

[0790] Example 59

[0791] Preparation of (R)-1-(3-fluoro-4-(6-(3-methylmorpholino)-1-(1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-4-yl)phenyl)pyrrolidine-2-one:

[0792]

[0793] Step 1: Preparation of 1-(4-bromo-3-fluorophenyl)pyrrolidone-2-one:

[0794]

[0795] 2-Pyrrolidone (1 g, 11.7 mmol, 1 equiv.), 1-bromo-2-fluoro-4-iodobenzene (3.53 g, 11.7 mmol, 1 equiv.), N,N-dimethyl-1,2-ethylenediamine (117 mg, 1.1 mmol, 0.1 equiv.), CsF (3.55 g, 23.4 mmol, 2 equiv.), and CuI (223 mg, 1.1 mmol, 0.1 equiv.) were dissolved in ethyl acetate (30 mL) and reacted at 50 °C for 16 h under nitrogen protection. The product was monitored as the dominant peak by LCMS. The temperature was lowered to room temperature, and the solid was filtered. The filtrate was evaporated to dryness to obtain the crude product, which was purified by column chromatography (petroleum ether: ethyl acetate = 3:1) to give the target compound (1.7 g, yield 56.54%). LCMS (ESI) [M+H] + =258.05.

[0796] Step 2: Preparation of 1-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxoboron-2-yl)phenyl)pyrrolidone-2-one:

[0797]

[0798] 1-(4-bromo-3-fluorophenyl)pyrrolidone-2-one (700 mg, 2.7 mmol, 1 equiv.), pinacol diboronate (1.38 g, 5.4 mmol, 2 equiv.), Pd(dppf)Cl2 (197 mg, 0.27 mmol, 0.1 equiv.), and KOAc (529.2 mg, 5.4 mmol, 2 equiv.) were dissolved in 1,4-dioxane (30 mL). The reaction was carried out at 120 °C for 8 hours under nitrogen protection. The product was monitored as the dominant peak by LCMS, and the temperature was lowered to room temperature. The solid was filtered, and the filtrate was evaporated to dryness to obtain the crude product. Column chromatography (petroleum ether: ethyl acetate = 3:1) was used to purify the target compound (800 mg, yield 97.14%). LCMS (ESI) [M+H] + =306.23.

[0799] Step 3: Preparation of (R)-1-(3-fluoro-4-(6-(3-methylmorpholinoyl)-1-(2-(2-(trimethylsilyl)ethoxymethyl)-1H-pyrazol-3-yl)-1H-pyrazol-3-yl)-1H-pyrazol[3,4-b]pyridin-4-ylphenyl)-pyrrole-2-one:

[0800]

[0801] (R)-4-(4-iodo-1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-methylmorpholine (100 mg, 0.18 mmol, 1.0 equiv.), 1-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxobor-2-yl)phenyl)pyrrolidone-2-one (113 mg, 0.36 mmol, 2.0 equiv.), Pd(PPh3)4 (42 mg, 0.04 mmol, 0.2 equiv.), and K2CO3 (50 mg, 0.36 mmol, 2 equiv.) were dissolved in 1,4-dioxane (5 mL) and water (0.5 mL). The reaction was carried out in [mL] at 100 °C for 4 hours under nitrogen protection. The reaction was monitored by LCMS until complete, and then the reaction mixture was cooled to room temperature. The solid was filtered, and the filtrate was evaporated to dryness to obtain the crude product. Column chromatography (petroleum ether: ethyl acetate = 1:1) was used to purify the target compound (100 mg, yield 93.93%). LCMS (ESI) [M+H] + =592.43.

[0802] Step 4: Preparation of (R)-1-(3-fluoro-4-(6-(3-methylmorpholino)-1-(1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-4-yl)phenyl)pyrrolidine-2-one:

[0803]

[0804] (R)-1-(3-fluoro-4-(6-(3-methylmorpholino)-1-(2-(2-(trimethylsilyl)ethoxymethyl)-1H-pyrazol-3-yl)-1H-pyrazol-3-yl)-1H-pyrazol[3,4-b]pyridin-4-ylphenyl)-pyrrolo-2-one (100 mg, 0.17 mmol) was dissolved in dichloromethane (5 mL), and trifluoroacetic acid (2 mL) was added. The mixture was stirred at room temperature for 8 hours. The reaction was monitored by LCMS until complete, and the solvent was evaporated to dryness. The reaction was quenched with NaHCO3 aqueous solution (10 mL), and the mixture was extracted with ethyl acetate (3 x 30 mL). The combined organic phases were washed with saturated brine (3 x 30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by reversed-phase column chromatography (C18, water:acetonitrile = 1:1) to give the target compound (7.7 mg, yield 9.82%). LCMS (ESI) [M+H] + =462.37; 1 H NMR (400 MHz, DMSO-d6) δ 12.87 (s, 1H), 7.98-7.82 (m, 3H), 7.75 (t, J = 8.6 Hz, 1H), 7.65 (dd, J = 8.6, 2.0 Hz, 1H), 6.87 (s, 1H), 6.82 (d, J =2.2 Hz, 1H), 4.52 (q, J = 6.3 Hz, 1H), 4.12 (d, J = 12.8 Hz, 1H), 3.98 (d, J = 14.1 Hz, 1H), 3.92 (t, J = 7.1 Hz, 2H), 3.77 (d, J = 11.3 Hz, 1H), 3.67(dd, J = 11.4, 2.7 Hz, 1H), 3.56-3.49 (m, 1H), 3.21 (td, J = 12.8, 3.6 Hz, 1H), 2.58 (t,J = 8.1 Hz, 2H), 2.17-2.06 (m, 2H), 1.23 (d, J = 6.7 Hz, 3H).

[0805] Examples 60-146

[0806] Compounds 60-146 of the following Examples were prepared by referring to the preparation methods of Examples 1-18 and 30-33.

[0807]

[0808]

[0809]

[0810]

[0811]

[0812]

[0813]

[0814]

[0815]

[0816]

[0817]

[0818]

[0819]

[0820]

[0821]

[0822]

[0823] Example 147

[0824] Preparation of (R)-4-ethynyl-1-(6-(3-methylmorpholino)-1-(1H-pyrazolyl-3-yl)-1H-pyrazolyl[3,4-b]pyridin-4-yl)cyclohexanol:

[0825]

[0826] Step 1: Preparation of 4-((tert-butyldiphenylsiloxy)methyl)cyclohexanone:

[0827]

[0828] 4-(hydroxymethyl)cyclohexanone (900.0 mg, 7.02 mmol, 1 equiv.) and imidazole (1.4 g, 21.07 mmol, 3 equiv.) were dissolved in dichloromethane (20 mL). Tert-butyldiphenylchlorosilane (2.9 g, 10.53 mmol, 1.5 equiv.) was added under ice bath conditions, and the mixture was stirred at room temperature for 2 hours. The reaction was monitored by TLC and found to be complete. The organic phases were separated by water and dichloromethane, combined, dried, filtered, and concentrated. The concentrate was then subjected to column chromatography (petroleum ether:ethyl acetate = 50:1) to give the target compound (1.5 g, yield 58.2%). 1 H NMR (400 MHz, DMSO-d6) δ 7.65 (d, J = 3.6 Hz, 1H), 7.58 (d, J = 5.9 Hz, 4H), 7.41 (d, J = 6.7 Hz, 4H), 7.35 (s, 1H), 3.53 (d, J = 5.8Hz, 2H), 2.40 – 2.31 (m, 2H), 2.15 (d, J = 14.0 Hz, 2H), 1.98 (s, 3H), 1.40 –1.31 (m, 2H), 0.97 (s, 9H).

[0829] Step 2: Preparation of 4-((tert-butyldiphenylsilyl)oxy)methyl)cyclohex-1-en-1-yltrifluoromethylsulfonate:

[0830]

[0831] 4-((tert-butyldiphenylsiloxy)methyl)cyclohexanone (700.0 mg, 1.91 mmol, 1 equiv.) was dissolved in tetrahydrofuran (5 mL). Bistrimethylsilylaminolithium (2.4 mL, 14.65 mmol, 1.2 equiv.) was added at -78 °C, and the mixture was stirred at -78 °C for 45 min. Then, 1,1,1-trifluoro-N-phenyl-N-((trifluoromethyl)sulfonyl)methanesulfonamide (750.4 mg, 2.10 mmol, 1.1 equiv.) dissolved in tetrahydrofuran was added, and the mixture was stirred at room temperature for 3 h. TLC monitoring showed that the reaction proceeded completely. The organic phases were combined, dried, filtered, and concentrated using ethyl acetate and water. The concentrate was then obtained by column chromatography (petroleum ether:ethyl acetate = 100:1) to give the target compound (560.0 mg, yield 58.8%). 1H NMR (400 MHz, DMSO-d6) δ7.57 (d, J = 7.0 Hz, 4H), 7.41 (d, J = 7.1 Hz, 5H), 5.85 (s, 1H), 3.54 (d, J= 6.1 Hz, 2H), 2.24 (d, J = 18.9 Hz, 2H), 2.02 – 1.70 (m, 4H), 1.48 (s, 1H), 0.97 (s, 9H).

[0832] Step 3: Preparation of tert-butyldiphenyl ((4-(4,4,5,5-tetramethyl-1,3,2-dioxane-2-yl)cyclohex-3-en-1-yl)methoxy)silane:

[0833]

[0834] 4-((tert-butyldiphenylsilyl)oxy)methyl)cyclohexyl-1-en-1-yltrifluoromethanesulfonate (560.0 mg, 1.12 mmol, 1 equiv.), pinacol diboronate (427.7 mg, 1.68 mmol, 1.5 equiv.), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (82.4 mg, 0.11 mmol, 0.1 equiv.), and potassium acetate (330.6 mg, 3.37 mmol, 3 equiv.) were dissolved in 1,4-dioxane (10 mL), purged with nitrogen three times, stirred at 90 °C for 16 hours, and monitored by TLC. The reaction of the starting materials was complete. The reaction solution was filtered through diatomaceous earth, and the filtrate was eluted with ethyl acetate and water. The organic phases were combined, dried, filtered, and concentrated. The target compound (340.0 mg, yield 63.2%) was obtained by column chromatography (petroleum ether: ethyl acetate = 100:1). 1 H NMR (400 MHz, DMSO-d6) δ 7.57 (d, J = 6.5 Hz, 4H), 7.41 (d, J = 6.5Hz, 6H), 5.29 (s, 1H), 3.50 (d, J = 5.9 Hz, 2H), 2.07 (d, J = 19.8 Hz, 1H), 1.99 – 1.92 (m, 4H), 1.70 (s, 4H), 1.42 (s, 1H), 1.15 (s, 12H), 0.96 (s, 9H).

[0835] Step 4: Preparation of (3R)-4-(4-(tert-butyldiphenylsiloxy)methyl)cyclohex-1-en-1-yl)-1-(1-(2-(trimethylsiloxy)ethoxy)methyl)-1H-pyrazol-5-yl)-1H-pyrazolyl[3,4-b]pyridin-6-yl)-3-methylmorpholine:

[0836]

[0837] tert-butyldiphenyl((4-(4,4,5,5-tetramethyl-1,3,2-dioxane-2-yl)cyclohex-3-en-1-yl)methoxy)silane (340.0 mg, 0.36 mmol, 1 equiv.), (R)-4-(4-iodo-1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)-1H-pyrazol[3,4-b]pyridin-6-yl)-3-methylmorpholine (385.6 mg, 0.36 mmol, 1 equiv.), sodium carbonate (75.6 mg, 0.71 mmol, 2 equiv.), and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (26.1 mg, 0.04 mmol, 0.1 equiv.) were dissolved in 1,4-dioxane (6 mL) and water (3 mL). The mixture was stirred at 90°C for 2 hours. LCMS monitoring showed the reaction was complete. The reaction solution was filtered through diatomaceous earth, and the filtrate was eluted with ethyl acetate and water. The organic phases were combined, dried, filtered, and concentrated. The target compound (260.0 mg, yield 47.7%) was obtained by platelet analysis (petroleum ether: ethyl acetate = 3:1). 1H NMR (400 MHz, CDCl3) δ 8.04 (d, J = 5.1 Hz, 1H), 7.71 – 7.60 (m, 5H), 7.40 (t, J = 8.3 Hz, 6H), 6.59 (s, 2H), 6.42 (s, 1H), 6.36 (s, 1H), 5.71 (t, J = 12.6 Hz, 3H), 4.31 (d, J = 21.8 Hz, 1H), 3.97 (t, J = 14.3 Hz, 3H), 3.74 (dd, J = 29.1, 14.3 Hz, 3H), 3.63 (d, J = 5.8 Hz, 2H), 3.57 (s,1H), 3.40 (d, J = 8.0 Hz, 3H), 3.25 (d, J = 12.9 Hz, 1H), 1.26 (dd, J = 11.4,5.9 Hz, 9H), 1.06 (s, 9H), 0.78 – 0.70 (m, 3H), -0.17 (d, J = 4.4 Hz, 14H).

[0838] Step 5: Preparation of (R)-4-((tert-butyldiphenylsilyl)oxy)methyl)-1-(6-(3-methylmorpholino)-1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)-1H-pyrazol[3,4-b]pyridin-4-yl)cyclohexanol:

[0839]

[0840] (3R)-4-(4-(tert-butyldiphenylsiloxy)methyl)cyclohex-1-en-1-yl)-1-(1-(2-(trimethylsiloxy)ethoxy)methyl)-1H-pyrazol-5-yl)-1H-pyrazolyl[3,4-b]pyridin-6-yl)-3-methylmorpholine (260.0 mg, 0.34 mmol, 1 equiv.) was dissolved in isopropanol (3.5 mL) and dichloromethane (0.5 mL). Tris(2,2,6,6-tetramethyl-3,5-heptadecanoic acid)manganese (41.4 mg, 0.07 mmol, 0.2 equiv.) and phenylsilane (73.7 mg, 0.68 mmol, 2 equiv.) were added under ice bath conditions. The mixture was purged with oxygen three times and stirred at room temperature for 2 hours. The reaction was monitored by LCMS and the starting material was found to be completely reacted. The reaction solution was liquefied with ethyl acetate and water, the organic phases were combined, dried, filtered, and concentrated. The resulting product was purified by L2 chromatography (petroleum ether:ethyl acetate = 2:1) to obtain the target compound (200.0 mg, yield 75.1%). LCMS (ESI) [M+H]+ = 781.40.

[0841] Step 6: Preparation of (R)-4-(hydroxymethyl)-1-(6-(3-methylmorpholino)-1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)-1H-pyrazol[3,4-b]pyridin-4-yl)cyclohexanol:

[0842]

[0843] (R)-4-((tert-butyldiphenylsilyl)oxy)methyl)-1-(6-(3-methylmorpholino)-1-(1-(((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolyl-5-yl)-1H-pyrazolyl[3,4-b]pyridin-4-yl)cyclohexanol (200.0 mg, 0.26 mmol, 1 equiv.) was dissolved in tetrahydrofuran (2 mL), and 1 M tetrabutylammonium fluoride (2 mL) tetrahydrofuran solution was added. The mixture was stirred overnight at room temperature. LCMS monitoring showed that the reaction was complete. The reaction solution was quenched with saturated ammonium chloride aqueous solution, extracted with ethyl acetate, and the organic phases were combined, dried, filtered, and concentrated. The target compound (130.0 mg, yield 93.55%) was obtained by LLC (petroleum ether:ethyl acetate = 1:1). LCMS (ESI) [M+H] + = 543.55.

[0844] Step 7: Preparation of (R)-4-hydroxy-4-(6-(3-methylmorpholino)-1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)-1H-pyrazol[3,4-b]pyridin-4-yl)cyclohexaneformaldehyde:

[0845]

[0846] (R)-4-(hydroxymethyl)-1-(6-(3-methylmorpholino)-1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)-1H-pyrazol[3,4-b]pyridin-4-yl)cyclohexanol (130.0 mg, 0.24 mmol, 1 equiv.) was dissolved in dichloromethane (4 mL). Dys-Martin oxidant (203.1 mg, 0.48 mmol, 2 equiv.) was added under ice bath conditions, and the mixture was stirred at room temperature for 2 hours. The reaction was complete as monitored by LCMS. The reaction solution was filtered through diatomaceous earth, the filtrate was quenched with saturated sodium thiosulfate aqueous solution, extracted with ethyl acetate, and the organic phases were combined, dried, filtered, and concentrated. The target compound (100.0 mg, 75.1% yield) was obtained by LCL (petroleum ether:ethyl acetate = 1:1). LCMS (ESI) [M+H]+ = 541.30.

[0847] Step 8: Preparation of ((R)-4-ethynyl-1-(6-(3-methylmorpholinyl)-1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolyl-5-yl)-1H-pyrazolyl[3,4-b]pyridin-4-yl)cyclohexanol:

[0848]

[0849] (R)-4-hydroxy-4-(6-(3-methylmorpholino)-1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)-1H-pyrazol[3,4-b]pyridin-4-yl)cyclohexanecarboxaldehyde (100.0 mg, 0.18 mmol, 1 equiv.), dimethyl (1-diazo-2-oxopropyl)phosphonate (42.6 mg, 0.22 mmol, 1.2 equiv.), and potassium carbonate (51.1 mg, 0.37 mmol, 2 equiv.) were dissolved in methanol (3 mL) and stirred overnight at room temperature. The reaction was monitored by LCMS and the reaction was complete. The reaction solution was eluted with ethyl acetate and water, the organic phases were combined, dried, filtered, and concentrated. The solution was purified by plate filtration (dichloromethane:methanol = 15:1) to give the target compound (87.0 mg, yield 87.6%). LCMS (ESI) [M+H] + = 537.35.

[0850] Step 9: Preparation of (R)-4-ethynyl-1-(6-(3-methylmorpholino)-1-(1H-pyrazolyl-3-yl)-1H-pyrazolyl[3,4-b]pyridin-4-yl)cyclohexanol:

[0851]

[0852] ((R)-4-ethynyl-1-(6-(3-methylmorpholinyl)-1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolyl-5-yl)-1H-pyrazolyl[3,4-b]pyridin-4-yl)cyclohexanol (90.0 mg, 0.17 mmol, 1 equiv.) was dissolved in trifluoroacetic acid (2 mL) and dichloromethane (2 mL), and triethylsilane (0.2 mL) was added. The mixture was stirred at room temperature for 1 hour. The reaction was complete as monitored by LCMS. The reaction solution was adjusted to alkalinity with saturated sodium bicarbonate aqueous solution, extracted with ethyl acetate, and the organic phases were combined, dried, filtered, and concentrated. The target compound (46.2 mg, yield 67.7%) was obtained by LLC (dichloromethane:methanol = 10:1). LCMS (ESI) [M+H] + = 407.20;1 H NMR (400 MHz, DMSO-d6) δ 12.76 (s,1H), 8.24 (s, 1H), 7.80 (s, 1H), 6.77 (d, J = 12.5 Hz, 2H), 5.23 (s, 1H),4.40 (s, 1H), 4.03 – 3.90 (m, 2H), 3.73 (d, J = 10.9 Hz, 1H), 3.61 (d, J =10.7 Hz, 1H), 3.46 (t, J = 11.3 Hz, 1H), 3.13 (t, J = 11.8 Hz, 1H), 2.86 (s,1H), 2.54 (s, 1H), 1.96 (d, J = 12.5 Hz, 2H), 1.85 (dd, J = 24.4, 12.5 Hz, 2H), 1.76 (s, 2H), 1.67 (d, J = 12.1 Hz, 2H), 1.15 (d, J = 6.1 Hz, 3H).

[0853] Examples 148-200

[0854] Compounds of Examples 148-200 were prepared by referring to the preparation methods of Examples 1-18, 30-33, and 147.

[0855]

[0856]

[0857]

[0858]

[0859]

[0860]

[0861]

[0862]

[0863]

[0864]

[0865]

[0866]

[0867]

[0868]

[0869] Example 200

[0870] Preparation of 3-(2-fluoro-4-(6-((R)-3-methylmorpholino)-1-(1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-4-yl)phenyl)-8-oxa-3-azabicyclo[3.2.1]octane-2-one:

[0871]

[0872] Step 1: Preparation of (R)-4-(4-(4-bromo-3-fluorophenyl)-1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-methylmorpholine:

[0873]

[0874] (R)-4-(4-iodo-1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-methylmorpholine (150 mg, 0.28 mmol, 1.0 equiv.), (4-bromo-3-fluorophenyl)boronic acid (60.7 mg, 0.28 mmol, 1.0 equiv.), Pd(dppf)Cl2 (41 mg, 0.55 mmol, 0.2 equiv.), and K2CO3 (76 mg, 5.5 mmol, 2 equiv.) were dissolved in dioxane (5 mL) and water (0.5 mL), and reacted at 100 °C for 16 h under nitrogen protection. The reaction was monitored by TLC until complete, and then the reaction was cooled to room temperature. The solids were filtered, and the filtrate was evaporated to dryness to obtain the crude product. Column chromatography purification (petroleum ether: ethyl acetate = 4:1) yielded the target compound (160 mg). LCMS (ESI) [M+H] + =587.27.

[0875] Step 2: Preparation of 3-(2-fluoro-4-(6-((R)-3-methylmorpholino)-1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-4-yl)phenyl)-8-oxa-3-azabicyclo[3.2.1]octane-2-one:

[0876]

[0877] The following medications were administered: (R)-4-(4-(4-bromo-3-fluorophenyl)-1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)-1H-pyrazol[3,4-b]pyridin-6-yl)-3-methylmorpholine (160 mg, 0.27 mmol, 1.0 equiv.), 8-oxa-3-azabicyclo[3.2.1]octane-2-one (35 mg, 0.27 mmol, 1.0 equiv.), N 1 N 2 Dimethylethane-1,2-diamine (9.5 mg, 0.1 mmol, 0.4 equiv.), cuprous iodide (19 mg, 0.1 mmol, 0.4 equiv.), and potassium phosphate (114 mg, 0.54 mmol, 2.0 equiv.) were dissolved in anhydrous dioxane (5 mL) and reacted at 105 °C for 16 h under nitrogen protection. The reaction was monitored by LCMS until complete, and the system was then cooled to room temperature. The solid was filtered, and the filtrate was evaporated to dryness to obtain the crude product. Purification was performed by column chromatography (petroleum ether: ethyl acetate = 3:1) to give the target compound (120 mg, yield 70.21%). LCMS (ESI) [M+H] + =634.49.

[0878] Step 3: Preparation of 3-(2-fluoro-4-(6-((R)-3-methylmorpholino)-1-(1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-4-yl)phenyl)-8-oxa-3-azabicyclo[3.2.1]octane-2-one:

[0879]

[0880] 3-(2-fluoro-4-(6-((R)-3-methylmorpholino)-1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-4-yl)phenyl)-8-oxa-3-azabicyclo[3.2.1]octane-2-one (120 mg, 0.19 mmol) was dissolved in dichloromethane (5 mL), and trifluoroacetic acid (2 mL) was added. The mixture was stirred at room temperature for 4 hours. The reaction was monitored by LCMS until complete, and the solvent was evaporated to dryness. The reaction was quenched with sodium bicarbonate aqueous solution (10 mL), extracted with ethyl acetate (3 x 30 mL), and the combined organic phases were washed with saturated brine (3 x 30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. Reversed-phase column purification (C18, water:acetonitrile = 1:1) yielded the target compound (35 mg, yield 36.81%). LCMS (ESI) [M+H] + =504.29; 1 H NMR (400 MHz, DMSO-d6) δ 12.87 (s, 1H), 8.21 (s, 1H), 7.84 (dd, J = 11.2, 1.7 Hz, 2H), 7.77 (dd, J = 8.2, 1.6 Hz, 1H), 7.64 (t, J =8.0 Hz, 1H), 6.99 (s, 1H), 6.82 (d, J = 2.0 Hz, 1H), 4.78 (dd, J = 7.1, 4.2Hz, 1H), 4.60 (d, J = 4.6 Hz, 1H), 4.56 (d, J = 5.7 Hz, 1H), 4.19 (d, J =12.4 Hz, 1H), 4.03-3.92 (m, 2H), 3.78 (d, J = 11.3 Hz, 1H), 3.67 (dd, J =11.3, 2.7 Hz, 1H), 3.52 (td, J = 11.8, 2.8 Hz, 1H), 3.39 (d, J = 11.1 Hz,1H), 3.22 (td, J = 13.0, 3.7 Hz, 1H), 2.21-2.03 (m, 4H), 1.23 (d, J = 6.7 Hz,3H).

[0881] Example 201

[0882] Preparation of (3R)-4-(4-(4-ethylcyclohex-1-en-1-yl)-1-(1H-pyrazol-5-yl)-1H-pyrazol[3,4-b]pyridin-6-yl)-3-methylmorpholine:

[0883]

[0884] Following the preparation method described in Example 147, the target compound (16 mg, yield 37.48%) was obtained. LCMS (ESI) [M+H] + = 389.30; 1 H NMR (400 MHz, DMSO-d6) δ12.81 (s, 1H), 8.15 (s, 1H), 7.81(s, 1H), 6.79 (d, J = 2.2 Hz, 1H), 6.66 (s, 1H), 6.45 (s, 1H), 4.49 (d, J =5.1 Hz, 1H), 4.06 (d, J = 13.0 Hz, 1H), 3.96 (dd, J = 11.3, 3.1 Hz, 1H), 3.75(d, J = 11.3 Hz, 1H), 3.65 (dd, J = 11.3, 2.6 Hz, 1H), 3.55-3.44 (m, 1H),3.16 (td, J = 12.7, 3.6 Hz, 1H), 2.95 (dd, J = 2.2, 1.6 Hz, 1H), 2.73 (s,1H), 2.59 (s, 3H), 2.34 (s, 1H), 2.30 (d, J = 8.4 Hz, 1H), 2.03 (d, J = 13.0Hz, 1H), 1.85-1.72 (m, 1H), 1.18 (d, J = 6.6 Hz, 3H).

[0885] Example 202

[0886] Preparation of (R)-4-(4-(4-ethynylcyclohexyl)-1-(1H-pyrazol-5-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-methylmorpholine:

[0887]

[0888] Step 1: Preparation of (R)-(4-(6-(3-methylmorpholino)-1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)-1H-pyrazolo[3,4-)b]pyridin-4-yl)cyclohexyl)methanol:

[0889]

[0890] Ethyl (R)-4-(6-(3-methylmorpholino)-1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)-1H-pyrazol[3,4-b]pyridin-4-yl)cyclohexane-1-carboxylate (500 mg, 0.88 mmol, 1.0 equiv.) was dissolved in anhydrous tetrahydrofuran (10 mL), and then lithium aluminum hydride (67 mg, 1.76 mmol, 2 equiv.) was added under ice bath conditions. The reaction was carried out under ice bath conditions for 1 hour. After the reaction was complete, water was added, the solid was filtered, and the organic phase was extracted with ethyl acetate (3 x 30 mL). The combined organic phases were washed with saturated brine (3 x 30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product (330 mg). LCMS (ESI) [M+H] + = 527.34.

[0891] Step 2: Preparation of (R)-4-(6-(3-methylmorpholino)-1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)-1H-pyrazol[3,4-b]pyridin-4-yl)cyclohexane-1-carbonal:

[0892]

[0893] (R)-(4-(6-(3-methylmorpholino)-1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)-1H-pyrazolo[3,4-)b]pyridin-4-yl)cyclohexyl)methanol (330 mg, 0.63 mmol, 1.0 equiv.) was dissolved in anhydrous dichloromethane (10 mL). Dys-Martin reagent (534 mg, 1.26 mmol, 2 equiv.) was added under ice bath conditions, and the reaction was carried out at room temperature for 2 hours. After the reaction was complete, the solid was filtered, and the filtrate was concentrated to obtain the crude product. Purification was performed by column chromatography (petroleum ether: ethyl acetate = 1:1) to give the target compound (100 mg, yield 30.29%). LCMS (ESI) [M+H] + =525.40.

[0894] Step 3: Preparation of (R)-4-ethynyl-1-(6-(3-methylmorpholinyl)-1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)-1H-pyrazol[3,4-b]pyridin-4-yl)cyclohexane:

[0895]

[0896] (R)-4-(6-(3-methylmorpholino)-1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)-1H-pyrazol[3,4-b]pyridin-4-yl)cyclohexane-1-carbonal (100 mg, 0.19 mmol, 1.0 equiv.) and potassium carbonate (79 mg, 0.57 mmol, 3 equiv.) were dissolved in methanol (5 mL). Dimethyl 1-diazo-2-oxopropyl)phosphonate (54 mg, 0.28 mmol, 1.5 equiv.) was added under ice bath conditions, followed by stirring under ice bath conditions for 30 minutes and then stirring at room temperature for 4 hours. After the reaction was complete, water was added for dilution, and the mixture was extracted with ethyl acetate (3 x 30 mL). The combined organic phases were washed with saturated brine (3 x 30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. Column chromatography purification (petroleum ether: ethyl acetate = 1:1) yielded the target compound (60 mg, yield 60.49%). LCMS (ESI) [M+H] + = 521.35.

[0897] Step 4: Preparation of (R)-4-ethynyl-1-(6-(3-methylmorpholinyl)-1-(1H-pyrazolyl-5-yl)-1H-pyrazolyl[3,4-b]pyridin-4-yl)cyclohexane:

[0898]

[0899] (R)-4-ethynyl-1-(6-(3-methylmorpholinyl)-1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)-1H-pyrazol[3,4-b]pyridin-4-yl)cyclohexane (60 mg, 0.11 mmol) was dissolved in dichloromethane (5 mL), followed by the addition of trifluoroacetic acid (2 mL). The mixture was stirred at room temperature for 4 hours. The reaction was monitored by LCMS until complete, and the solvent was evaporated to dryness. The reaction was then quenched with an aqueous sodium bicarbonate solution (10 mL), extracted with ethyl acetate (3 x 30 mL), and the organic phases were combined, washed with saturated brine (3 x 30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by reversed-phase column chromatography (C18, water:acetonitrile = 1:1) to give the target compound (2.4 mg, yield 5.6%). LCMS (ESI) [M+H] + =391.32; 1H NMR (400MHz, DMSO-d6) δ 12.77 (s, 1H), 8.20 (s, 1H), 7.82 (s, 1H), 6.77 (s, 1H), 6.62(s, 1H), 4.45 (s, 1H), 4.11-3.90 (m, 2H), 3.75 (d, J = 11.3 Hz, 1H), 3.64 (d,J = 9.1 Hz, 1H), 3.48 (t, J = 10.6 Hz, 1H), 3.15 (t, J = 11.2 Hz, 1H), 2.89(t, J = 9.5 Hz, 2H), 2.43-2.40 (m, 1H), 2.05 (d, J = 11.0 Hz, 2H), 1.87 (d, J= 10.8 Hz, 2H), 1.72 (dd, J = 25.1, 12.4 Hz, 2H), 1.53 (dd, J = 24.7, 12.2Hz, 2H), 1.18 (d, J = 6.6 Hz, 3H).

[0900] Examples 203-269

[0901] Compounds of Examples 203-269 were prepared by referring to the preparation methods of Examples 1-18, 30-33, and 147.

[0902]

[0903]

[0904]

[0905]

[0906]

[0907]

[0908]

[0909]

[0910]

[0911]

[0912]

[0913]

[0914]

[0915]

[0916]

[0917]

[0918]

[0919]

[0920]

[0921]

[0922]

[0923]

[0924]

[0925] Example 270

[0926] Preparation of 3-ethynyl-1-(6-R)-3-methylmorpholinyl)-1-(1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-4-yl)cyclopentan-1-ol:

[0927]

[0928] Step 1: Preparation of 3-(trimethylsilylethynyl)cyclopentan-1-one:

[0929]

[0930] Prepare two three-necked flasks. In one flask, A, dissolve ethynyltrimethylsilane (1.8 g, 18.3 mmol, 1.5 equiv.) in tetrahydrofuran (10 mL). Lower the solution temperature to -10 °C and slowly add a tetrahydrofuran solution of BuLi (7.4 mL, 2.5 M, 18.27 mmol, 1.5 equiv.). Let the reaction proceed for 20 minutes. In the other flask, B, add CuI (3.5 g, 18.3 mmol, 1.5 equiv.) to a solution of dimethyl sulfide (10 mL) at -10 °C to prepare a cuprous dimethyl sulfide iodide complex. The reaction mixture in flask B was added to flask A. The reaction mixture was cooled to -78 °C, and trimethyliodosilane (3.7 g, 18.27 mmol, 1.5 equiv.) was slowly added dropwise. After reacting for 5 minutes, tetrahydrofuran (10 mL) of cyclopent-2-en-1-one (1.0 g, 12.18 mmol, 1 equiv.) was slowly added dropwise to the reaction mixture. After reacting for 30 minutes, the mixture was allowed to return to room temperature. The reaction was monitored by TLC until complete. The reaction was quenched by adding saturated ammonium chloride solution and reacted at room temperature for 30 minutes. The pH of the reaction mixture was adjusted to 5 by adding 2 M hydrochloric acid, and the reaction was allowed to continue for 30 minutes. The mixture was extracted with ethyl acetate (50 mL), washed three times with saturated brine, dried over anhydrous sodium sulfate, and concentrated under vacuum to obtain the crude product. The crude product was then subjected to column chromatography with a mobile phase of PE:EA (20:1 to 10:1) to obtain the target compound (1.56 g, yield 71%).

[0931] Step 2: Preparation of 1-(6-(R)-3-methylmorpholine-1-(2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-(trimethylsilyl)ethynyl)cyclopentan-1-ol:

[0932]

[0933] 3-(trimethylsilylethynyl)cyclopentan-1-one (400 mg, 0.74 mmol, 1.0 equiv.) and 4-iodo-1-(2-trimethylsilylethoxy)methyl-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-methylmorpholine (400 mg, 2.22 mmol, 3.0 equiv.) were dissolved in anhydrous tetrahydrofuran (10 mL), purged three times with nitrogen, cooled to -78 °C, and n-BuLi (0.3 mL, 2.5 M, 0.66 mmol, 1.5 equiv.) was added dropwise. After the addition was complete, the mixture was kept at -78 °C for 1 hour. LCMS monitoring showed that the reaction was complete. The reaction was quenched with saturated ammonium chloride aqueous solution and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. Column chromatography yielded the target compound (23 mg, 23% yield). LCMS (ESI) [M+H] + = 594.90.

[0934] Step 3: 3-ethynyl-1-(6-R)-3-methylmorpholino)-1-(1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-4-yl)cyclopentan-1-ol

[0935]

[0936] Compound 1-(6-(R)-3-methylmorpholine-1-(2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-(trimethylsilyl)ethynyl)cyclopentan-1-ol (65 mg, 0.11 mmol, 1.0 equiv.) was dissolved in dichloromethane (3 mL), and TBAF (86 mg, 0.28 mmol, 2.5 equiv.) was added. The reaction was allowed to proceed for 10 min, followed by the addition of 4 M HCl in dioxane solution and another 10 min. TLC showed the reaction was complete. Sodium bicarbonate was added to neutralize the remaining hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic matter was washed with saturated brine, dried over anhydrous sodium sulfate, and evaporated to dryness to obtain the crude product. The crude product was then prepared by reverse phase chromatography to give the target compound (11.8 mg, 27% yield). LCMS (ESI) [M+H] + =392.45; 1H NMR (400 MHz, CD3OD) δ 8.11 (s, 1H), 7.73 (s, 1H), 6.93 (s, 1H), 6.82 (s, 1H), 4.69 – 4.41 (m, 1H), 4.06 (dd, J = 32.6, 12.3 Hz, 2H), 3.90 – 3.72 (m, 2H), 3.62 (s, 1H), 3.34 (d, J = 3.2 Hz, 1H), 3.14 (d, J = 10.0 Hz, 1H), 2.76 – 2.62 (m, 1H), 2.39 (d, J = 2.5 Hz, 1H), 2.35 – 2.13 (m, 4H), 2.07(s, 1H), 1.29 (d, J = 6.7 Hz, 3H).

[0937] Examples 271-293

[0938] Compounds of Examples 271-293 were prepared by referring to the preparation methods of Examples 147, 200-202, and 270.

[0939]

[0940]

[0941]

[0942]

[0943] Comparative Example 1: Compound RP103

[0944]

[0945] The control compound RP103 was prepared by referring to the method of compound 103 on page 119 of the specification of patent CN113454080A.

[0946] Comparative Example 2: Compound RP3500

[0947]

[0948] The control compound RP3500 was prepared by referring to the method of compound 121 on page 122 of the specification of patent CN113454080A.

[0949] Biological evaluation

[0950] Test Example 1: Inhibitory effect of the compound of the present invention on ATR enzyme

[0951] The following methods were used to determine the inhibitory effect of the compounds of this invention on ATR enzymes. The experimental methods are briefly described below:

[0952] I. Experimental Materials and Instruments

[0953] 1.ATR enzyme (Eurofins Pharma Discovery Services, 14-953M)

[0954] 2. GST-tagged P53 protein (Eurofins Pharma Discovery Services, 14-952M)

[0955] 3.384-well plate (Geriner bio-one, 784075)

[0956] 4.U-shaped bottom 96-well plate (Geriner bio-one, 651201)

[0957] 5. Antibody against phosphorylated P53 protein labeled with europium cavitation compounds (cisbio, 61P08KAZ)

[0958] 6. Anti-GST antibody linked to d2 (cisbio, 61GSTDLB)

[0959] 7. ATP solution (Sigma, R0441)

[0960] 8. DTT (Sigma, D0632-259)

[0961] 9. Hepes (Sigma, 15630080)

[0962] 10. Microplate reader (Envision 2104 Multilabel Reader).

[0963] II. Experimental Procedure

[0964] ATR enzyme 15 nM, p53 protein 80 nM, ATP 300 nM (final concentrations of 40 nM and 150 nM, respectively), and small molecule compounds at different concentrations (final concentrations (nM) at ten points were 2985.0, 895.5, 298.5, 110.56, 33.17, 11.06, 4.09, 1.23, 0.41, and 0.15, respectively. The final dimethyl sulfoxide concentration was 0.498%) were mixed and incubated at room temperature for 90 minutes. 10 μL of 2× mixture buffer was added to the ATR, compound, and substrate mixture in the analytical plate (detection buffer was used to dilute antiphosphorylated p53-Eu and anti-GST-d2). Centrifuge at 1000 rpm for 30 seconds. Incubate overnight at 4°C in the dark (total 20 μL per well). The FRET signal (endpoint) was measured in an Envision instrument (HTRF 665 / 612 ratio calculated based on 665nm and 612nm emission). Data were processed using GraphPad software.

[0965] III. Experimental Results

[0966] The inhibitory activity of the compound of the present invention against ATR enzymes can be determined by the above experiments, and the measured IC50 values ​​are shown in Table 1.

[0967] Table 1. IC50 values ​​of the compounds disclosed herein against ATR enzyme inhibition.

[0968] Example number IC50 / nM Example number IC50 / nM 1 A 201 A 2 A 202 A 3 A 203 A 4 A 204 B 5 A 205 B 6 A 206 A 7 A 207 A 8 A 208 A 9 A 209 A 10 A 210 A 11 A 212 A 12 B 213 A 13 A 214 A 14 B 215 A 15 A 216 A 16 A 217 A 17 B 218 A 18 B 219 A 30 A 220 B 31 A 221 A 32 A 222 A 33 A 223 A 58 A 224 A 59 A 225 A 60 A 226 A 62 A 227 B 65 A 228 A 77 B 229 A 78 A 230 B 80 B 231 A 84 A 232 B 86 B 233 A 145 A 234 A 146 A 235 A 147 A 236 A 148 A 237 A 149 A 238 A 150 A 239 A 151 A 240 A 152 A 241 A 153 A 242 A 154 A 243 A 155 A 244 A 156 A 245 A 157 A 246 A 158 A 247 B 159 A 248 B 160 A 249 A 161 A 250 A 162 A 251 A 163 A 252 A 164 A 253 B 165 A 254 A 167 A 255 A 168 A 256 A 169 A 257 A 171 A 258 A 172 A 259 A 183 A 260 A 184 A 261 A 187 A 262 A 191 A 263 A 192 A 264 A 195 A 265 B 197 A 266 B 199 A 267 B 200 A 268 B RP103 A 269 A RP3500 A 270 A

[0969] IC50 value of ATR enzyme inhibition: A < 10nM; 10nM < 50 nM; 50 nM <C < 100nM.

[0970] Conclusion: The compound disclosed herein exhibits good inhibitory activity against ATR enzymes.

[0971] Test Example 2: Cell Proliferation Experiment

[0972] The following method evaluates the inhibitory effect of the compounds of this invention on LoVo cell proliferation by detecting intracellular ATP levels and based on IC50 values. The experimental methods are briefly described below:

[0973] I. Experimental Materials and Instruments

[0974] 1. LoVo, human colon cancer tumor cells (Nanjing Kebai, CBP60032)

[0975] 2. Fetal bovine serum (GIBCO, 10091-148)

[0976] 3. F-12K medium (ATCC, 30-2004)​

[0977] 4. CellTite-Glo reagent (Promega, G7573)

[0978] 5. 96-well cell culture plate (corning, 3599)

[0979] 6. Pancreatic enzyme (Invitrogen, 25200-056)

[0980] 7. Microplate reader (Perkin Elmer).

[0981] II. Experimental Procedure

[0982] LoVo cells were cultured in F-12K medium containing 10% FBS, passaged 2-3 times per week at a passage ratio of 1:3 or 1:5. During passage, cells were digested with trypsin and transferred to centrifuge tubes, centrifuged at 1000 rpm for 5 minutes, and the supernatant was discarded. The cells were resuspended in fresh medium. 100 μL of the cell suspension was added to each 96-well cell culture plate at a density of 1.5 × 10⁴ cells / mL, with only 100 μL of complete medium added to the outer edge of the wells. The culture plates were incubated for 24 hours (37°C, 5% CO₂).

[0983] Dilute the test sample to 1 mM with DMSO, and then serially dilute it 3-fold to obtain 8 concentrations. Prepare 200X solutions with cell culture medium, and set up blank and control wells. Add 5 μL of the prepared gradient concentration test compound solutions to 95 μL of fresh culture medium. Then add 100 μL (1X culture medium containing the compound) to the culture plate. Incubate the culture plate in an incubator for 4 days (37℃, 5% CO2). Add 50 μL of CellTiter-Glo reagent to each well of a 96-well cell culture plate, incubate at room temperature in the dark for 5-10 min, and read the chemiluminescence signal values ​​in a Pherastar instrument. Process the data using GraphPad software.

[0984] III. Experimental Results

[0985] The inhibitory effect of the compound of this invention on the proliferation of LoVo cells can be determined by the above experiments, and the measured IC50 values ​​are shown in Table 2.

[0986] Table 2 shows the IC50 values ​​of the disclosed compounds against LoVo cell proliferation.

[0987] Example number IC50 / nM 2 B 5 A 7 B 13 B 145 B 147 A 148 B 164 B 197 B 228 B 235 B 239 B 261 B RP3500 B RP103 B

[0988] LoVo cell proliferation inhibition IC50 value: A < 20nM; 20nM≤B < 100nM.

[0989] Test Example 3: Cell Proliferation Experiment

[0990] The following method evaluates the inhibitory effect of the disclosed compound on SNU-601 cell proliferation by detecting intracellular ATP levels and based on IC50 values. The experimental methods are briefly described below:

[0991] I. Experimental Materials and Instruments

[0992] 1. SNU-601, human gastric cancer tumor cells (Nanjing Kebai, CBP60507)

[0993] 2. Fetal bovine serum (GIBCO, 10099-141)

[0994] 3. RPMI 1640 medium (Gibco, A1049101)

[0995] 4. CellTite-Glo reagent (Promega, G7573)

[0996] 5. 96-well cell culture plate (corning, 3903)

[0997] 6. Pancreatic enzyme (Gibco, 25200056)

[0998] 7. Microplate reader (TECAN, INFINITE M Nano+).

[0999] II. Experimental Procedure

[1000] SNU-601 cells were cultured in RPMI 1640 medium containing 10% FBS, passaged 2-3 times per week at a passage ratio of 1:5 or 1:10. During passage, cells were digested with trypsin and transferred to centrifuge tubes, centrifuged at 1000 rpm for 5 minutes, the supernatant was discarded, and the cells were resuspended in fresh medium. 195 μL of the cell suspension was added to each 96-well cell culture plate, at a density of 5.128 × 10⁻⁶ cells / well. 3 Cells / mL, add only 200 μL of complete culture medium to the periphery of the 96-well plate. Incubate the plate in an incubator for 24 hours (37°C, 5% CO2).

[1001] Dilute the test sample to 2 mM with DMSO, and then serially dilute it 3-fold to 10 concentrations, setting up blank and control wells. Add 10 μL of the prepared gradient concentration test compound solution to 50 μL of fresh culture medium. Then add 5 μL of the above drug-containing culture medium solution to the culture plate. Incubate the culture plate in an incubator for 5 days (37°C, 5% CO2). In a 96-well cell culture plate, discard 100 μL / well, then add 50 μL of CellTiter-Glo reagent to each well, incubate at room temperature in the dark, and shake for 10 min. Read the chemiluminescence signal value in a Pherastar, and process the data using GraphPad software.

[1002] III. Experimental Results

[1003] The inhibitory effect of the compound of this invention on the proliferation of SNU-601 cells was determined by the above experiments, and the measured IC50 values ​​are shown in Table 3.

[1004] Table 3 shows the IC50 values ​​of the disclosed compounds on the proliferation of SNU-601 cells.

[1005] Example number IC50 / nM Example number IC50 / nM 7 B 214 B 30 B 215 B 31 B 216 B 32 B 217 B 33 B 218 B 58 B 219 B 59 A 221 B 62 B 222 B 65 B 224 B 82 B 226 B 145 B 228 A 146 B 233 B 147 A 234 B 148 B 235 B 149 B 236 B 150 B 237 B 151 B 238 B 153 B 239 B 154 B 240 B 155 B 241 B 158 B 242 B 160 B 243 B 162 B 244 B 163 B 245 B 164 B 246 B 165 B 250 B 167 B 251 B 168 B 254 B 169 B 255 B 172 B 256 B 183 B 257 B 191 B 258 B 195 B 259 B 197 B 260 B 199 B 261 B 200 B 262 B 206 B 263 B 207 B 264 B 208 B 265 B 209 B RP3500 B 213 B RP103 B

[1006] SNU-601 cell proliferation inhibition IC50 value: A < 10nM; 10nM≤B < 100nM.

Claims

1. A compound of formula (F) ###0001### or an optical isomer or a pharmaceutically acceptable salt thereof. wherein Y is selected from N, Q is selected from CH; X is CH; R Y is C 1-6 alkyl; R Z Number of 0; K is selected from C 5-6 carbocyclyl; R L the number is 1, and each occurrence is independently selected from hydrogen, hydroxyl; R K selected from hydrogen, C 1-3 haloalkyl, hydroxyC 1-3 alkyl, hydroxyC 1-3 alkyl.

2. The compound of claim 1, or an optical isomer or a pharmaceutically acceptable salt thereof. wherein R Y is methyl, ethyl, n-propyl, i-propyl.

3. The compound of claim 1, or an optical isomer or a pharmaceutically acceptable salt thereof. wherein, R Y is methyl.

4. The compound of claim 1, or an optical isomer or a pharmaceutically acceptable salt thereof. wherein, K is selected from cyclopentyl, cyclohexyl, cyclohexenyl.

5. The compound of claim 1, or an optical isomer or a pharmaceutically acceptable salt thereof. wherein, R K selected from hydrogen, methyl, ethyl, n-propyl, i-propyl, or hydroxyC 1-3 alkyl.

6. The compound of claim 1, or an optical isomer or a pharmaceutically acceptable salt thereof. wherein R K is selected from hydrogen, methyl, ethyl, or hydroxymethyl.

7. The compound of claim 1, or an optical isomer or a pharmaceutically acceptable salt thereof. wherein R K is selected from hydrogen, methyl, hydroxymethyl or -CF2CH3.

8. The compound of claim 1, or an optical isomer or pharmaceutically acceptable salt thereof, wherein R K is hydrogen.

9. The compound of claim 1, or an optical isomer or a pharmaceutically acceptable salt thereof. wherein, selected from the group consisting of:

10. The compound of claim 1, or an optical isomer or a pharmaceutically acceptable salt thereof. wherein The compound of formula (F) is further of formula (F-1), (F-2), (F-3), (F-4) or (F-5): wherein each substituent in formula (F-1), (F-2), (F-3), (F-4) or (F-5) is as defined in claim 1.

11. The compound of claim 10, or an optical isomer or a pharmaceutically acceptable salt thereof, of formula (F-3): ###0003### wherein R Y is methyl; X is CH; R Z Number is 0; selected from the group consisting of:

12. A compound selected from: ###0004### or an optical isomer or a pharmaceutically acceptable salt thereof.

13. A pharmaceutical composition comprising a compound of any one of claims 1-12, or an optical isomer or a pharmaceutically acceptable salt thereof.

14. A pharmaceutical composition comprising a compound of any one of claims 1-12, or an optical isomer or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

15. Use of a compound of any one of claims 1-12, or an optical isomer or a pharmaceutically acceptable salt thereof, or a composition of claim 13 or 14, for the manufacture of a medicament for the treatment of a disease mediated by ATR.

16. The use of claim 15, wherein the disease mediated by ATR is a cancer or a tumor-related disease.

17. The use of claim 16, wherein the cancer or tumor-related disease is gastric cancer, colorectal cancer.

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