Aromatic heterobicyclic compound and antiviral use thereof

Abstract

The invention relates to an anti-RSV compound as shown in a formula I and a preparation method and application thereof. The compound shown in the formula I has very high inhibitory activity on RSV, has excellent drug effect, in-vitro / in-vivo pharmacokinetic properties and safety, and has a high clinical application prospect. # imgabs0 #

Description

Technical Field

[0001] The present invention belongs to the field of compounds, and specifically relates to an aromatic heterobicyclic compound, and specifically relates to an aromatic heterobicyclic compound and a mixture or composition containing the aromatic heterobicyclic compound, especially an aromatic heterobicyclic compound and a mixture or composition containing the aromatic heterobicyclic compound for preventing and treating RSV virus infection. Background Art

[0002] Respiratory syncytial virus (RSV) is an important pathogen that causes lower respiratory tract infections in infants, the elderly, and immunocompromised patients. It has been reported that 33 million children under the age of 5 are infected with RSV each year worldwide, and the number of deaths is about 160,000. To date, the US FDA has approved only two drugs for the treatment of RSV infection: inhaled ribavirin and human monoclonal RSV F protein antibody palivizumab. Due to insufficient evidence to confirm the effectiveness of inhaled ribavirin in the treatment of RSV infection, the American Academy of Pediatrics no longer recommends it for the treatment of RSV infection in 2014. In 1998, the US FDA approved palivizumab for the prevention of acute lower respiratory tract infections in infants with high-risk factors, once a month, 15 mg / kg, intramuscular injection. Several clinical studies have confirmed that palivizumab can reduce the hospitalization rate of RSV infection and the incidence of recurrent wheezing after infection.

[0003] According to the different mechanisms of drug interaction with the virus and the host, new RSV inhibitors can be divided into nucleotide synthesis inhibitors, fusion inhibitors, and non-fusion non-nucleotide synthesis inhibitors. Nucleotide synthesis inhibitors are nucleoside analogs containing a base or a linked ribose-like partial base, which can be encapsulated by viral polymerases to terminate the polymerization reaction of nucleotides and inhibit viral replication. Drugs under development include: ALS-8176 (Lumicitabine, discontinued) and GS-5734 (remdesivir); preventing the fusion of viruses and host cells through drugs is a common antiviral strategy. RSV fusion inhibitors are an area of ​​concentrated research, and the main drugs include: AK-0529, GS-5806, VP-14637, JNJ-53718678 and BTA-C585. Non-fusion non-nucleotide synthesis inhibitors are also under study, including nucleoprotein inhibitors (RSV604), small interfering RNA (siRNA) technology drugs (ALN-RSV01), antibody drugs (palivizumab, approved for marketing), REGN2222 (a fully human monoclonal antibody targeting F protein), MEDI8897 (a recombinant human IgG1 monoclonal antibody with modified Fc) and ALX-0171 (nanoantibody trimer), etc. In addition, the development of RSV vaccines is also one of the directions, but for many reasons, there is no safe and effective RSV vaccine available so far.

[0004] Given the widespread prevalence of RSV worldwide and the scarcity of RSV drugs on the market, there is an urgent need to develop drugs suitable for different groups of people, such as newborns, children, pregnant women and the elderly. Small molecule antiviral drugs have many advantages, such as low production cost, ability to penetrate the cell membrane to target intracellular targets, and oral administration, and therefore play an important role in the prevention and treatment of RSV. However, so far, there are still no small molecule drugs available on the market for the treatment and prevention of RSV. Therefore, the development of novel, efficient and safe small molecule drugs will surely bring huge economic and social benefits to the treatment and prevention of RSV. Summary of the invention

[0005] Problem that the invention aims to solve

[0006] RSV is widely prevalent around the world, and RSV drugs are scarce on the market. Small molecule antiviral drugs have many advantages, such as low production cost, ability to penetrate cell membranes to target intracellular targets, and can be taken orally. Therefore, there is an urgent need to develop small molecule antiviral drugs suitable for different populations such as newborns, children, pregnant women and the elderly.

[0007] Solutions for solving problems

[0008] The present disclosure provides a compound represented by general formula I or its stereoisomers, solvates, hydrates, prodrugs, stable isotope derivatives and pharmaceutically acceptable salts:

[0009]

[0010] in:

[0011] X 1 , X 2 Each independently selected from CR 6 and N;

[0012] X 6 , X 7 and X 8 Each independently selected from CR 6 and N;

[0013] R 1 Selected from C 1-6 Alkyl and C 3-7 Cycloalkyl;

[0014] R 2 and R 2’ are each independently selected from hydrogen, deuterium, halogen, C 1-6 Alkyl, C substituted by at least one halogen 1-6 Alkyl and C 3-7 Cycloalkyl;

[0015] R 3 Selected from halogen, C 1-6 Alkyl, C substituted by at least one halogen 1-6 Alkyl, C 3-7 Cycloalkyl and C 1-6 Alkoxy;

[0016] R 4 Selected from halogen, hydroxyl, cyano, C 1-6 Alkyl, C substituted by at least one halogen 1-6 Alkyl and C 1-6 Alkoxy, C 3-7 Cycloalkyl, hydroxyl, C 1-6 Alkoxy or C 3-7 Cycloalkyl substituted C 1-6 Alkyl, 3-7 membered heterocycloalkyl, C 6-10 Aryl and 5-10 membered heteroaryl;

[0017] R 5 Selected from substituted or unsubstituted -NR 7 R 8 、-NR 7 -(CO)-heterocycloalkyl, C 3-7 Cycloalkyl and 3-8 membered heterocycloalkyl; the substitution is by at least one R9 Substitute, the R 9 Each occurrence is independently selected from the following group:

[0018] a) Deuterium, halogen, hydroxyl, cyano, oxo, C 1-6 Alkyl, C substituted by hydroxy, amino and 3-7 membered heterocycloalkyl 1-6 Alkyl, C 1-6 Alkoxy, C substituted by hydroxy 1-6 Alkoxy, -(CO)-OH, -(CO)-NR 7 R 8 、-(CO)-NR 7 -SO 2 -R 8 、-NR 7 R 8 、-NR 7 -(CO)-C 1-6 Alkyl, -NR 7 -(CO)-C 3-7 Cycloalkyl, -NR 7 -(CO)-OR 8 、-NR 7 -(CO)-NR 7 R 8 、-NR 7 -SO 2 -R 8 、-NR 7 -SO 2 -NR 7 R 8 、-SO 2 -NR 7 R 8 、-SO 2 -NR 7 -(CO)-R 8 , C 3-7 Cycloalkyl, 3-7 membered heterocycloalkyl, -S(O)(NR 7 )-R 5a and-SO 2 -R 5a The group consisting of R 5a Selected from hydrogen, amino, C 1-6 Alkyl, C 1-6 Alkyl-amino, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, C 1-6 Alkyl-C 3-7 Cycloalkyl and 3-7 membered heterocycloalkyl;

[0019] b) Two adjacent R 9The atoms connected to them form a substituted or unsubstituted 3-5 membered spiro ring, wherein the 3-5 membered spiro ring contains 0, 1 or 2 heteroatoms selected from N, O and S, and the substitution is by at least one selected from amino, hydroxyl, oxo and C 1-6 substituted with a substituent of the alkyl group; and

[0020] c) Two adjacent R 9 Together with the atoms to which they are attached, they form a substituted or unsubstituted 4-6 membered fused ring, wherein the 4-6 membered fused ring contains 0 or 1 heteroatom selected from N, O and S, and the substitution is by at least one selected from amino, hydroxyl, oxo and C 1-6 substituted by an alkyl substituent;

[0021] R 7 and R 8 are each independently selected from hydrogen, deuterium, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, Hydroxyl-C 1-6 Alkyl, C substituted by at least one halogen 1-6 Alkyl, C 3-7 Cycloalkyl, C 1-6 Alkyl-C 3-7 Cycloalkyl and hydroxy or cyano substituted C 3-7 Cycloalkyl;

[0022] R 6 Each occurrence is independently selected from hydrogen, deuterium, hydroxyl, cyano, halogen, C 1-6 Alkyl, C 1-6 Alkoxy and C substituted by at least one halogen 1-6 alkyl;

[0023] Ring A is present or absent; when ring A is absent, t is an integer selected from 1, 2, and 3; when ring A is present, t is 1 and the ring A is selected from the following A-1 to A-4 groups:

[0024]

[0025] R i Selected from hydrogen, halogen, C 1-3 Alkyl, C substituted by at least one halogen 1-6 Alkyl, C 3-7 Cycloalkyl and C 1-6 Alkoxy;

[0026] o is an integer selected from 0, 1, 2, 3, 4;

[0027] p is an integer selected from 0, 1, 2;

[0028] q is an integer selected from 0, 1, 2, 3;

[0029] s is an integer selected from 0, 1, and 2;

[0030] Provided that the compound of formula I is not

[0031] Effects of the Invention

[0032] The aromatic heterobicyclic compounds provided by the present disclosure have high inhibitory activity against RSV, and also have excellent pharmacodynamics, in vitro / in vivo pharmacokinetic properties and safety, and have high prospects for clinical application. DETAILED DESCRIPTION

[0033] In order to make the technical solutions and beneficial effects of the present invention more clearly understood, the following is a detailed description by listing specific embodiments. Unless otherwise defined, the technical and scientific terms used herein have the same meanings as those in the technical field to which this application belongs.

[0034] The present disclosure provides a compound represented by general formula I or its stereoisomers, solvates, hydrates, prodrugs, stable isotope derivatives and pharmaceutically acceptable salts:

[0035]

[0036] in:

[0037] X 1 , X 2 Each independently selected from CR 6 and N;

[0038] X 6 , X 7 and X 8 Each independently selected from CR 6 and N;

[0039] R 1 Selected from C 1-6 Alkyl and C 3-7 Cycloalkyl;

[0040] R 2 and R 2’ are each independently selected from hydrogen, deuterium, halogen, C 1-6 Alkyl, C substituted by at least one halogen 1-6 Alkyl and C 3-7 Cycloalkyl;

[0041] R 3 Selected from halogen, C 1-6 Alkyl, C substituted by at least one halogen 1-6 Alkyl, C 3-7 Cycloalkyl and C 1-6 Alkoxy;

[0042] R 4 Selected from halogen, hydroxyl, cyano, C 1-6 Alkyl, C substituted by at least one halogen 1-6 Alkyl and C 1-6 Alkoxy, C 3-7 Cycloalkyl, hydroxyl, C 1-6 Alkoxy or C 3-7 Cycloalkyl substituted C 1-6 Alkyl, 3-7 membered heterocycloalkyl, C 6-10 Aryl and 5-10 membered heteroaryl;

[0043] R 5 Selected from substituted or unsubstituted -NR 7 R 8 、-NR 7 -(CO)-heterocycloalkyl, C 3-7 Cycloalkyl and 3-8 membered heterocycloalkyl; the substitution is by at least one R 9 Substitution, the R 9 Each occurrence is independently selected from the following group:

[0044] a) Deuterium, halogen, hydroxyl, cyano, oxo, C 1-6 Alkyl, C substituted by hydroxy, amino and 3-7 membered heterocycloalkyl 1-6 Alkyl, C 1-6 Alkoxy, C substituted by hydroxy 1-6 Alkoxy, -(CO)-OH, -(CO)-NR 7 R 8 、-(CO)-NR 7 -SO 2 -R 8 、-NR 7 R 8 、-NR 7 -(CO)-C 1-6 Alkyl, -NR 7 -(CO)-C 3-7 Cycloalkyl, -NR 7 -(CO)-OR 8 、-NR 7 -(CO)-NR 7 R 8 、-NR 7 -SO 2 -R 8 、-NR 7 -SO 2 -NR 7 R 8 、-SO 2 -NR 7 R8 、-SO 2 -NR 7 -(CO)-R 8 , C 3-7 Cycloalkyl, 3-7 membered heterocycloalkyl, -S(O)(NR 7 )-R 5a and-SO 2 -R 5a The group consisting of R 5a Selected from hydrogen, amino, C 1-6 Alkyl, C 1-6 Alkyl-amino, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, C 1-6 Alkyl-C 3-7 Cycloalkyl and 3-7 membered heterocycloalkyl;

[0045] b) Two adjacent R 9 The atoms connected to them form a substituted or unsubstituted 3-5 membered spiro ring, wherein the 3-5 membered spiro ring contains 0, 1 or 2 heteroatoms selected from N, O and S, and the substitution is by at least one selected from amino, hydroxyl, oxo and C 1-6 substituted with a substituent of the alkyl group; and

[0046] c) Two adjacent R 9 Together with the atoms to which they are attached, they form a substituted or unsubstituted 4-6 membered fused ring, wherein the 4-6 membered fused ring contains 0 or 1 heteroatom selected from N, O and S, and the substitution is by at least one selected from amino, hydroxyl, oxo and C 1-6 substituted by an alkyl substituent;

[0047] R 7 and R 8 are each independently selected from hydrogen, deuterium, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, Hydroxyl-C 1-6 Alkyl, C substituted by at least one halogen 1-6 Alkyl, C 3-7 Cycloalkyl, C 1-6 Alkyl-C 3-7 Cycloalkyl and hydroxy or cyano substituted C 3-7 Cycloalkyl;

[0048] R 6 Each occurrence is independently selected from hydrogen, deuterium, hydroxyl, cyano, halogen, C 1-6 Alkyl, C 1-6 Alkoxy and C substituted by at least one halogen 1-6 alkyl;

[0049] Ring A is present or absent; when ring A is absent, t is an integer selected from 1, 2, and 3; when ring A is present, t is 1 and the ring A is selected from the following A-1 to A-4 groups:

[0050]

[0051] R i Selected from hydrogen, halogen, C 1-3 Alkyl, C substituted by at least one halogen 1-6 Alkyl, C 3-7 Cycloalkyl and C 1-6 Alkoxy;

[0052] o is an integer selected from 0, 1, 2, 3, 4;

[0053] p is an integer selected from 0, 1, and 2;

[0054] q is an integer selected from 0, 1, 2, 3;

[0055] s is an integer selected from 0, 1, and 2;

[0056] Provided that the compound of formula I is not

[0057] In certain embodiments, the R 5 Selected from substituted or unsubstituted -NR 7 -(CO)-heterocycloalkyl, C 3-7 Cycloalkyl and 3-8 membered heterocycloalkyl, wherein the heterocycloalkyl contains 1-2 heteroatoms selected from N, O and S.

[0058] In certain embodiments, the R 5 is selected from substituted or unsubstituted -NH-(CO)-4-6 membered heterocycloalkyl, C 3-5 Cycloalkyl and 4-8 membered heterocycloalkyl, wherein the heterocycloalkyl contains 1-2 heteroatoms selected from N, O and S.

[0059] In certain embodiments, the R 5 is selected from substituted or unsubstituted -NH-(CO)-azetidinyl, -NH-(CO)-pyrrolidinyl, cyclopropyl, cyclobutyl, cyclopentyl, azetidinyl, thiomorpholinyl, diazabicyclooctanyl, pyrrolidinyl, piperidinyl, piperazinyl and morpholinyl.

[0060] In certain embodiments, the R 5 is selected from substituted or unsubstituted cyclopropyl, azetidinyl, thiomorpholinyl, diazabicyclooctanyl and pyrrolidinyl.

[0061] In certain embodiments, the R1 Selected from C 1-3 Alkyl and C 3-6 Cycloalkyl.

[0062] In certain embodiments, the R 1 Selected from methyl, ethyl, propyl, isopropyl.

[0063] In certain embodiments, the R 1 Selected from methyl.

[0064] In certain embodiments, the R 2 Selected from hydrogen, deuterium, halogen, C 1-3 Alkyl, C substituted by at least one halogen 1-3 alkyl.

[0065] In certain embodiments, the R 2 Selected from hydrogen, deuterium, halogen, C 1-3 alkyl.

[0066] In certain embodiments, the R 2 Selected from hydrogen, fluorine, chlorine, methyl, ethyl, propyl, isopropyl.

[0067] In certain embodiments, the R 2 Selected from hydrogen and fluorine.

[0068] In certain embodiments, the R 2’ Selected from hydrogen, deuterium, halogen, C 1-3 Alkyl, C substituted by at least one halogen 1-3 alkyl.

[0069] In certain embodiments, the R 2’ Selected from hydrogen, deuterium, halogen, C 1-3 alkyl.

[0070] In certain embodiments, the R 2’ Selected from hydrogen, fluorine, chlorine, methyl, ethyl, propyl, isopropyl.

[0071] In certain embodiments, the R 2’ Selected from hydrogen and fluorine.

[0072] In certain embodiments, the R 3 Selected from halogen, C 1-3 alkyl.

[0073] In certain embodiments, the R 3 Selected from fluorine, chlorine, methyl, ethyl, propyl, isopropyl.

[0074] In certain embodiments, the R 3 Selected from fluorine.

[0075] In certain embodiments, the R 4 Selected from halogen, hydroxyl, cyano, C 1-6 Alkyl, C substituted by at least one halogen 1-6 Alkyl, C 3-7 Cycloalkyl and C 3-7 Cycloalkyl substituted C 1-6 alkyl.

[0076] In certain embodiments, the R 4 Selected from halogen, C 1-3 Alkyl, C 3-5 Cycloalkyl and C 3-5 Cycloalkyl substituted C 1-6 alkyl.

[0077] In certain embodiments, the R 4 is selected from methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl and -CH 2 -cyclopropyl.

[0078] In certain embodiments, the R 6 Selected from hydrogen, deuterium, hydroxyl, cyano, halogen.

[0079] In certain embodiments, the R 6 Selected from hydrogen, deuterium and halogen.

[0080] In certain embodiments, the R 6 Selected from hydrogen.

[0081] In certain embodiments, the R 7 Selected from hydrogen, deuterium, C 1-3 Alkyl, Hydroxyl-C 1-3 Alkyl, C substituted by at least one halogen 1-3 alkyl.

[0082] In certain embodiments, the R 7 Selected from hydrogen, methyl, hydroxyethyl, difluoroethyl.

[0083] In certain embodiments, the R 8 Selected from hydrogen, deuterium, C 1-3 Alkyl, Hydroxyl-C 1-3 Alkyl, C substituted by at least one halogen 1-3 alkyl.

[0084] In certain embodiments, the R 8 Preferably selected from hydrogen, methyl, hydroxyethyl, difluoroethyl.

[0085] In certain embodiments, the R i Selected from halogen, C 1-6Alkyl, C 1-3 Alkoxy.

[0086] In certain embodiments, the R i Selected from halogen.

[0087] In certain embodiments, the present disclosure provides a compound of Formula I or a stereoisomer, solvate, hydrate, prodrug, stable isotope derivative, and pharmaceutically acceptable salt thereof, characterized in that the compound has a structure of Formula I-1:

[0088]

[0089] in,

[0090] X 1 , X 2 Each independently selected from CR 6 and N;

[0091] X 6 , X 7 and X 8 Each independently selected from CR 6 and N;

[0092] R 1 Selected from C 1-6 Alkyl and C 3-7 Cycloalkyl;

[0093] R 2 and R 2’ are each independently selected from hydrogen, deuterium, halogen, C 1-6 Alkyl, C substituted by at least one halogen 1-6 Alkyl and C 3-7 Cycloalkyl;

[0094] R 3 Selected from halogen, C 1-6 Alkyl, C substituted by at least one halogen 1-6 Alkyl, C 3-7 Cycloalkyl and C 1-6 Alkoxy;

[0095] R 4 Selected from halogen, hydroxyl, cyano, C 1-6 Alkyl, C substituted by at least one halogen 1-6 Alkyl and C 1-6 Alkoxy, C 3-7 Cycloalkyl, hydroxyl, C 1-6 Alkoxy or C 3-7 Cycloalkyl substituted C 1-6 Alkyl, 3-7 membered heterocycloalkyl, C 6-10 Aryl and 5-10 membered heteroaryl;

[0096] R 6 Each occurrence is independently selected from hydrogen, deuterium, hydroxyl, cyano, halogen, C 1-6 Alkyl, C 1-6 Alkoxy and C substituted by at least one halogen 1-6 alkyl;

[0097] Ring A is present or absent; when ring A is absent, t is an integer selected from 1, 2, and 3; when ring A is present, t is 1 and the ring A is selected from the following A-1 to A-4 groups:

[0098]

[0099] R i Selected from hydrogen, halogen, C 1-3 Alkyl, C substituted by at least one halogen 1-6 Alkyl, C 3-7 Cycloalkyl and C 1-6 Alkoxy;

[0100] o is an integer selected from 0, 1, 2, 3, 4;

[0101] p is an integer selected from 0, 1, 2;

[0102] q is an integer selected from 0, 1, 2, 3;

[0103] s is an integer selected from 0, 1, and 2;

[0104] R 10 Selected from hydrogen, deuterium, C 1-6 Alkyl and hydroxy-C 1-6 alkyl;

[0105] R 11 and R 12 independently selected from hydrogen, deuterium, C 1-6 Alkyl, hydroxyl, halogen and C 1-6 Alkoxy and hydroxy-C 1-6 alkyl;

[0106] or R 11 and R 12 One of the carbon atoms to which it is connected, R 14 and the carbon atoms to which they are connected together form a substituted or unsubstituted 4-6 membered fused ring, wherein the 4-6 membered fused ring contains 0, 1 or 2 heteroatoms selected from N, O and S, wherein the substitution is by at least one selected from amino, hydroxyl, oxo and C 1-6 Substituted by a substituent in the alkyl group;

[0107] R 13 Selected from hydrogen, deuterium, C 1-6 Alkyl, hydroxyl, halogen and C 1-6Alkoxy and hydroxy-C 1-6 alkyl;

[0108] R 14 Selected from deuterium, halogen, hydroxyl, cyano, C 1-6 Alkyl, C substituted by hydroxy, amino or 3-7 membered heterocycloalkyl 1-6 Alkyl, C 1-6 Alkoxy, -(CO)-OH, -(CO)-NR 7 R 8 、-(CO)-NR 7 -SO 2 -R 8 、-NR 7 R 8 、-NR 7 -(CO)-C 1-6 Alkyl, -NR 7 -(CO)-C 3-7 Cycloalkyl, -NR 7 -(CO)-OR 8 、-NR 7 -(CO)-NR 7 R 8 、-NR 7 -SO 2 -R 8 、-NR 7 -SO 2 -NR 7 R 8 、-SO 2 -NR 7 R 8 、-SO 2 -NR 7 -(CO)-R 8 , C 3-7 Cycloalkyl, 3-7 membered heterocycloalkyl, -S(O)(NR 7 )-R 5a and-SO 2 -R 5a The group consisting of R 5a Selected from hydrogen, amino, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, C 1-6 Alkyl-C 3-7 Cycloalkyl and 3-7 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, O and S;

[0109] R 7 and R 8 are each independently selected from hydrogen, deuterium, cyano, C 1-6 Alkyl, C 2-6Alkenyl, Hydroxyl-C 1-6 Alkyl, C substituted by at least one halogen 1-6 Alkyl, C 3-7 Cycloalkyl, C 1-6 Alkyl-C 3-7 Cycloalkyl, hydroxy or cyano substituted C 3-7 Cycloalkyl;

[0110] R 15 Selected from hydrogen, deuterium and C 1-6 alkyl.

[0111] In certain embodiments, the R 1 Selected from C 1-3 Alkyl and C 3-6 Cycloalkyl.

[0112] In certain embodiments, the R 1 Selected from methyl, ethyl, propyl, isopropyl.

[0113] In certain embodiments, the R 1 Selected from methyl.

[0114] In certain embodiments, the R 2 Selected from hydrogen, deuterium, halogen, C 1-3 Alkyl, C substituted by at least one halogen 1-3 alkyl.

[0115] In certain embodiments, the R 2 Selected from hydrogen, deuterium, halogen, C 1-3 alkyl.

[0116] In certain embodiments, the R 2 Selected from hydrogen, fluorine, chlorine, methyl, ethyl, propyl, isopropyl.

[0117] In certain embodiments, the R 2 Selected from hydrogen and fluorine.

[0118] In certain embodiments, the R 2’ Selected from hydrogen, deuterium, halogen, C 1-3 Alkyl, C substituted by at least one halogen 1-3 alkyl.

[0119] In certain embodiments, the R 2’ Selected from hydrogen, deuterium, halogen, C 1-3 alkyl.

[0120] In certain embodiments, the R 2’ Selected from hydrogen, fluorine, chlorine, methyl, ethyl, propyl, isopropyl.

[0121] In certain embodiments, the R 2’ Selected from hydrogen and fluorine.

[0122] In certain embodiments, the R 3 Selected from halogen, C 1-3 alkyl.

[0123] In certain embodiments, the R 3 Selected from fluorine, chlorine, methyl, ethyl, propyl, isopropyl.

[0124] In certain embodiments, the R 3 Selected from fluorine.

[0125] In certain embodiments, the R 4 Selected from halogen, hydroxyl, cyano, C 1-6 Alkyl, C substituted by at least one halogen 1-6 Alkyl, C 3-7 Cycloalkyl and C 3-7 Cycloalkyl substituted C 1-6 alkyl.

[0126] In certain embodiments, the R 4 Selected from halogen, C 1-3 Alkyl, C 3-5 Cycloalkyl and C 3-5 Cycloalkyl substituted C 1-6 alkyl.

[0127] In certain embodiments, the R 4 is selected from methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl and -CH 2 -cyclopropyl.

[0128] In certain embodiments, the R 6 Selected from hydrogen, deuterium, hydroxyl, cyano, halogen.

[0129] In certain embodiments, the R 6 Selected from hydrogen, deuterium and halogen.

[0130] In certain embodiments, the R 6 Selected from hydrogen.

[0131] In certain embodiments, the R 10 Selected from hydrogen, deuterium and C 1-6 alkyl.

[0132] In certain embodiments, the R 10 Selected from hydrogen and deuterium.

[0133] In certain embodiments, the R 10 Selected from hydrogen.

[0134] In certain embodiments, the R 11 Selected from hydrogen, deuterium and halogen.

[0135] In certain embodiments, the R 11 Selected from hydrogen, deuterium and fluorine.

[0136] In certain embodiments, the R 11 Selected from hydrogen and fluorine.

[0137] In certain embodiments, the R 12 Selected from hydrogen, deuterium and halogen.

[0138] In certain embodiments, the R 12 Selected from hydrogen, deuterium and fluorine.

[0139] In certain embodiments, the R 12 Selected from hydrogen and fluorine.

[0140] In certain embodiments, the R 11 and R 12 One of the carbon atoms to which it is connected, R 14 and the carbon atom to which it is connected together form a substituted or unsubstituted 4-6 membered fused ring containing 1 or 2 heteroatoms selected from N, O and S.

[0141] In certain embodiments, the R 11 and R 12 One of the carbon atoms to which it is connected, R 14 and the carbon atom to which they are connected together form a substituted or unsubstituted tetrahydrothiopyran ring and a morpholine ring.

[0142] In certain embodiments, the substitution is by at least one selected from amino, hydroxy, oxo and C 1-6 The alkyl group is substituted by a substituent.

[0143] In certain embodiments, the substitution is with oxo.

[0144] In certain embodiments, the R 13 Selected from hydrogen, deuterium and halogen.

[0145] In certain embodiments, the R 13 Selected from hydrogen and deuterium.

[0146] In certain embodiments, the R 13 Selected from hydrogen.

[0147] In certain embodiments, the R 14 is selected from deuterium, halogen, amino, hydroxy, C substituted by hydroxy, amino or 3-7 membered heterocycloalkyl 1-6Alkyl, hydroxy substituted C 1-6 Alkoxy, -(CO)-OH, 3-7 membered heterocycloalkyl, -S(O)(NR 7 )-R 5a and-SO 2 -R 5a The group composed of.

[0148] In certain embodiments, the R 14 is selected from amino, hydroxy, C substituted by hydroxy or 5-6 membered heterocycloalkyl 1-3 Alkyl, hydroxy substituted C 1-3 Alkoxy, -(CO)-OH, 5-6 membered heterocycloalkyl, -S(O)(NR 7 )-R 5a and-SO 2 -R 5a The 5-6 membered heterocycloalkyl group contains 1-2 heteroatoms selected from N and O.

[0149] In certain embodiments, the R 14 Selected from amino, hydroxyl, hydroxymethyl, -OCH 2 CH 2 -OH, -CH 2 -morpholinyl, morpholinyl, -(CO)-OH, -S(O)(NR 7 )-R 5a and-SO 2 -R 5a The group composed of.

[0150] In certain embodiments, the R 5a Selected from hydrogen, amino, C 1-6 Alkyl, C 3-7 Cycloalkyl and C 1-6 Alkyl-C 3-7 Cycloalkyl.

[0151] In certain embodiments, the R 5a Selected from hydrogen, amino, C 1-3 Alkyl, C 3-5 Cycloalkyl and C 1-3 Alkyl-C 3-5 Cycloalkyl.

[0152] In certain embodiments, the R 5a is selected from hydrogen, amino, methyl, ethyl, isopropyl, cyclopropyl and -CH 2 -cyclopropyl.

[0153] In certain embodiments, the R 15 Selected from hydrogen and deuterium.

[0154] In certain embodiments, the R 15 Selected from hydrogen.

[0155] In certain embodiments, the R 7 Selected from hydrogen, deuterium, C 1-3 Alkyl, Hydroxyl-C 1-3 Alkyl, C substituted by at least one halogen 1-3 alkyl.

[0156] In certain embodiments, the R 7 Selected from hydrogen, methyl, hydroxyethyl, difluoroethyl.

[0157] In certain embodiments, the R 8 Selected from hydrogen, deuterium, C 1-3 Alkyl, Hydroxyl-C 1-3 Alkyl, C substituted by at least one halogen 1-3 alkyl.

[0158] In certain embodiments, the R 8 Preferably selected from hydrogen, methyl, hydroxyethyl, difluoroethyl.

[0159] In certain embodiments, the R i Selected from halogen, C 1-6 Alkyl, C 1-3 Alkoxy.

[0160] In certain embodiments, the R i Selected from halogen.

[0161] In certain embodiments, the present disclosure provides a compound of formula I or a stereoisomer, solvate, hydrate, prodrug, stable isotope derivative, and pharmaceutically acceptable salt thereof, characterized in that the compound has a structure of formula I-1-1:

[0162]

[0163] in,

[0164] X 1 , X 2 Each independently selected from CR 6 and N;

[0165] X 6 , X 7 and X 8 Each independently selected from CR 6 and N;

[0166] R 1 Selected from C 1-6 Alkyl and C 3-7 Cycloalkyl;

[0167] R 2 and R 2’ are each independently selected from hydrogen, deuterium, halogen, C 1-6 Alkyl, C substituted by at least one halogen 1-6 Alkyl and C 3-7 Cycloalkyl;

[0168] R 3 Selected from halogen, C 1-6 Alkyl, C substituted by at least one halogen 1-6 Alkyl, C 3-7 Cycloalkyl and C 1-6 Alkoxy;

[0169] R 4 Selected from halogen, hydroxyl, cyano, C 1-6 Alkyl, C substituted by at least one halogen 1-6 Alkyl and C 1-6 Alkoxy, C 3-7 Cycloalkyl, hydroxyl, C 1-6 Alkoxy or C 3-7 Cycloalkyl substituted C 1-6 Alkyl, 3-7 membered heterocycloalkyl, C 6-10 Aryl and 5-10 membered heteroaryl;

[0170] R 6 Each occurrence is independently selected from hydrogen, deuterium, hydroxyl, cyano, halogen, C 1-6 Alkyl, C 1-6 Alkoxy and C substituted by at least one halogen 1-6 alkyl;

[0171] R i Selected from hydrogen, halogen, C 1-3 Alkyl, C substituted by at least one halogen 1-6 Alkyl, C 3-7 Cycloalkyl and C 1-6 Alkoxy;

[0172] o is an integer selected from 0, 1, 2, 3, 4;

[0173] R 10 Selected from hydrogen, deuterium, C 1-6 Alkyl and hydroxy-C 1-6 alkyl;

[0174] R 11 and R 12 independently selected from hydrogen, deuterium, C 1-6 Alkyl, hydroxyl, halogen and C 1-6 Alkoxy and hydroxy-C 1-6 alkyl;

[0175] or R11 and R 12 One of the carbon atoms to which it is connected, R 14 and the carbon atoms to which they are connected together form a substituted or unsubstituted 4-6 membered fused ring, wherein the 4-6 membered fused ring contains 0, 1 or 2 heteroatoms selected from N, O and S, wherein the substitution is by at least one selected from amino, hydroxyl, oxo and C 1-6 Substituted by a substituent in the alkyl group;

[0176] R 13 Selected from hydrogen, deuterium, C 1-6 Alkyl, hydroxyl, halogen and C 1-6 Alkoxy and hydroxy-C 1-6 alkyl;

[0177] R 14 Selected from deuterium, halogen, hydroxyl, cyano, C 1-6 Alkyl, C substituted by hydroxy, amino or 3-7 membered heterocycloalkyl 1-6 Alkyl, C 1-6 Alkoxy, -(CO)-OH, -(CO)-NR 7 R 8 、-(CO)-NR 7 -SO 2 -R 8 、-NR 7 R 8 、-NR 7 -(CO)-C 1-6 Alkyl, -NR 7 -(CO)-C 3-7 Cycloalkyl, -NR 7 -(CO)-OR 8 、-NR 7 -(CO)-NR 7 R 8 、-NR 7 -SO 2 -R 8 、-NR 7 -SO 2 -NR 7 R 8 、-SO 2 -NR 7 R 8 、-SO 2 -NR 7 -(CO)-R 8 , C 3-7 Cycloalkyl, 3-7 membered heterocycloalkyl, -S(O)(NR 7 )-R 5a and-SO 2 -R 5a The group consisting of R5a Selected from hydrogen, amino, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, C 1-6 Alkyl-C 3-7 Cycloalkyl and 3-7 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, O and S;

[0178] R 7 and R 8 are each independently selected from hydrogen, deuterium, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, Hydroxyl-C 1-6 Alkyl, C substituted by at least one halogen 1-6 Alkyl, C 3-7 Cycloalkyl, C 1-6 Alkyl-C 3-7 Cycloalkyl, hydroxy or cyano substituted C 3-7 Cycloalkyl;

[0179] R 15 Selected from hydrogen, deuterium and C 1-6 alkyl.

[0180] In certain embodiments, the R 1 Selected from C 1-3 Alkyl and C 3-6 Cycloalkyl.

[0181] In certain embodiments, the R 1 Selected from methyl, ethyl, propyl, isopropyl.

[0182] In certain embodiments, the R 1 Selected from methyl.

[0183] In certain embodiments, the R 2 Selected from hydrogen, deuterium, halogen, C 1-3 Alkyl, C substituted by at least one halogen 1-3 alkyl.

[0184] In certain embodiments, the R 2 Selected from hydrogen, deuterium, halogen, C 1-3 alkyl.

[0185] In certain embodiments, the R 2 Selected from hydrogen, fluorine, chlorine, methyl, ethyl, propyl, isopropyl.

[0186] In certain embodiments, the R 2 Selected from hydrogen and fluorine.

[0187] In certain embodiments, the R 2’Selected from hydrogen, deuterium, halogen, C 1-3 Alkyl, C substituted by at least one halogen 1-3 alkyl.

[0188] In certain embodiments, the R 2’ Selected from hydrogen, deuterium, halogen, C 1-3 alkyl.

[0189] In certain embodiments, the R 2’ Selected from hydrogen, fluorine, chlorine, methyl, ethyl, propyl, isopropyl.

[0190] In certain embodiments, the R 2’ Selected from hydrogen and fluorine.

[0191] In certain embodiments, the R 3 Selected from halogen, C 1-3 alkyl.

[0192] In certain embodiments, the R 3 Selected from fluorine, chlorine, methyl, ethyl, propyl, isopropyl.

[0193] In certain embodiments, the R 3 Selected from fluorine.

[0194] In certain embodiments, the R 4 Selected from halogen, hydroxyl, cyano, C 1-6 Alkyl, C substituted by at least one halogen 1-6 Alkyl, C 3-7 Cycloalkyl and C 3-7 Cycloalkyl substituted C 1-6 alkyl.

[0195] In certain embodiments, the R 4 Selected from halogen, C 1-3 Alkyl, C 3-5 Cycloalkyl and C 3-5 Cycloalkyl substituted C 1-6 alkyl.

[0196] In certain embodiments, the R 4 is selected from methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl and -CH 2 -cyclopropyl.

[0197] In certain embodiments, the R 6 Selected from hydrogen, deuterium, hydroxyl, cyano, halogen.

[0198] In certain embodiments, the R 6 Selected from hydrogen, deuterium and halogen.

[0199] In certain embodiments, the R 6 Selected from hydrogen.

[0200] In certain embodiments, the R 10 Selected from hydrogen, deuterium and C 1-6 alkyl.

[0201] In certain embodiments, the R 10 Selected from hydrogen and deuterium.

[0202] In certain embodiments, the R 10 Selected from hydrogen.

[0203] In certain embodiments, the R 11 Selected from hydrogen, deuterium and halogen.

[0204] In certain embodiments, the R 11 Selected from hydrogen, deuterium and fluorine.

[0205] In certain embodiments, the R 11 Selected from hydrogen and fluorine.

[0206] In certain embodiments, the R 12 Selected from hydrogen, deuterium and halogen.

[0207] In certain embodiments, the R 12 Selected from hydrogen, deuterium and fluorine.

[0208] In certain embodiments, the R 12 Selected from hydrogen and fluorine.

[0209] In certain embodiments, the R 11 and R 12 One of the carbon atoms to which it is connected, R 14 and the carbon atom to which it is connected together form a substituted or unsubstituted 4-6 membered fused ring containing 1 or 2 heteroatoms selected from N, O and S.

[0210] In certain embodiments, the R 11 and R 12 One of the carbon atoms to which it is connected, R 14 and the carbon atom to which they are connected together form a substituted or unsubstituted tetrahydrothiopyran ring and a morpholine ring.

[0211] In certain embodiments, the substitution is by at least one selected from amino, hydroxy, oxo and C 1-6 The alkyl group is substituted by a substituent.

[0212] In certain embodiments, the substitution is with oxo.

[0213] In certain embodiments, the R13 Selected from hydrogen, deuterium and halogen.

[0214] In certain embodiments, the R 13 Selected from hydrogen and deuterium.

[0215] In certain embodiments, the R 13 Selected from hydrogen.

[0216] In certain embodiments, the R 14 is selected from deuterium, halogen, amino, hydroxy, C substituted by hydroxy, amino or 3-7 membered heterocycloalkyl 1-6 Alkyl, hydroxy substituted C 1-6 Alkoxy, -(CO)-OH, 3-7 membered heterocycloalkyl, -S(O)(NR 7 )-R 5a and-SO 2 -R 5a The group composed of.

[0217] In certain embodiments, the R 14 is selected from amino, hydroxy, C substituted by hydroxy or 5-6 membered heterocycloalkyl 1-3 Alkyl, hydroxy substituted C 1-3 Alkoxy, -(CO)-OH, 5-6 membered heterocycloalkyl, -S(O)(NR 7 )-R 5a and-SO 2 -R 5a The 5-6 membered heterocycloalkyl group contains 1-2 heteroatoms selected from N and O.

[0218] In certain embodiments, the R 14 Selected from amino, hydroxyl, hydroxymethyl, -OCH 2 CH 2 -OH, -CH 2 -morpholinyl, morpholinyl, -(CO)-OH, -S(O)(NR 7 )-R 5a and-SO 2 -R 5a The group composed of.

[0219] In certain embodiments, the R 5a Selected from hydrogen, amino, C 1-6 Alkyl, C 3-7 Cycloalkyl and C 1-6 Alkyl-C 3-7 Cycloalkyl.

[0220] In certain embodiments, the R 5a Selected from hydrogen, amino, C 1-3 Alkyl, C3-5 Cycloalkyl and C 1-3 Alkyl-C 3-5 Cycloalkyl.

[0221] In certain embodiments, the R 5a is selected from hydrogen, amino, methyl, ethyl, isopropyl, cyclopropyl and -CH 2 -cyclopropyl.

[0222] In certain embodiments, the R 15 Selected from hydrogen and deuterium.

[0223] In certain embodiments, the R 15 Selected from hydrogen.

[0224] In certain embodiments, the R 7 Selected from hydrogen, deuterium, C 1-3 Alkyl, Hydroxyl-C 1-3 Alkyl, C substituted by at least one halogen 1-3 alkyl.

[0225] In certain embodiments, the R 7 Selected from hydrogen, methyl, hydroxyethyl, difluoroethyl.

[0226] In certain embodiments, the R 8 Selected from hydrogen, deuterium, C 1-3 Alkyl, Hydroxyl-C 1-3 Alkyl, C substituted by at least one halogen 1-3 alkyl.

[0227] In certain embodiments, the R 8 Preferably selected from hydrogen, methyl, hydroxyethyl, difluoroethyl.

[0228] In certain embodiments, the R i Selected from halogen, C 1-6 Alkyl, C 1-3 Alkoxy.

[0229] In certain embodiments, the R i Selected from halogen.

[0230] In certain embodiments, the present disclosure provides a compound of formula I or a stereoisomer, solvate, hydrate, prodrug, stable isotope derivative, and pharmaceutically acceptable salt thereof, characterized in that the compound has a structure of formula I-1-2:

[0231]

[0232] in,

[0233] X 1 , X2 Each independently selected from CR 6 and N;

[0234] X 6 , X 7 and X 8 Each independently selected from CR 6 and N;

[0235] R 1 Selected from C 1-6 Alkyl and C 3-7 Cycloalkyl;

[0236] R 2 and R 2’ are each independently selected from hydrogen, deuterium, halogen, C 1-6 Alkyl, C substituted by at least one halogen 1-6 Alkyl and C 3-7 Cycloalkyl;

[0237] R 3 Selected from halogen, C 1-6 Alkyl, C substituted by at least one halogen 1-6 Alkyl, C 3-7 Cycloalkyl and C 1-6 Alkoxy;

[0238] R 4 Selected from halogen, hydroxyl, cyano, C 1-6 Alkyl, C substituted by at least one halogen 1-6 Alkyl and C 1-6 Alkoxy, C 3-7 Cycloalkyl, hydroxyl, C 1-6 Alkoxy or C 3-7 Cycloalkyl substituted C 1-6 Alkyl, 3-7 membered heterocycloalkyl, C 6-10 Aryl and 5-10 membered heteroaryl;

[0239] R 6 Each occurrence is independently selected from hydrogen, deuterium, hydroxyl, cyano, halogen, C 1-6 Alkyl, C 1-6 Alkoxy and C substituted by at least one halogen 1-6 alkyl;

[0240] R i Selected from hydrogen, halogen, C 1-3 Alkyl, C substituted by at least one halogen 1-6 Alkyl, C 3-7 Cycloalkyl and C 1-6 Alkoxy;

[0241] s is an integer selected from 0, 1, and 2;

[0242] R 10 Selected from hydrogen, deuterium, C 1-6 Alkyl and hydroxy-C 1-6 alkyl;

[0243] R 11 and R 12 independently selected from hydrogen, deuterium, C 1-6 Alkyl, hydroxyl, halogen and C 1-6 Alkoxy and hydroxy-C 1-6 alkyl;

[0244] or R 11 and R 12 One of the carbon atoms to which it is connected, R 14 and the carbon atoms to which they are connected together form a substituted or unsubstituted 4-6 membered fused ring, wherein the 4-6 membered fused ring contains 0, 1 or 2 heteroatoms selected from N, O and S, wherein the substitution is by at least one selected from amino, hydroxyl, oxo and C 1-6 Substituted by a substituent in the alkyl group;

[0245] R 13 Selected from hydrogen, deuterium, C 1-6 Alkyl, hydroxyl, halogen and C 1-6 Alkoxy and hydroxy-C 1-6 alkyl;

[0246] R 14 Selected from deuterium, halogen, hydroxyl, cyano, C 1-6 Alkyl, C substituted by hydroxy, amino or 3-7 membered heterocycloalkyl 1-6 Alkyl, C 1-6 Alkoxy, -(CO)-OH, -(CO)-NR 7 R 8 、-(CO)-NR 7 -SO 2 -R 8 、-NR 7 R 8 、-NR 7 -(CO)-C 1-6 Alkyl, -NR 7 -(CO)-C 3-7 Cycloalkyl, -NR 7 -(CO)-OR 8 、-NR 7 -(CO)-NR 7 R 8 、-NR 7 -SO 2 -R 8 、-NR 7 -SO 2 -NR 7R 8 、-SO 2 -NR 7 R 8 、-SO 2 -NR 7 -(CO)-R 8 , C 3-7 Cycloalkyl, 3-7 membered heterocycloalkyl, -S(O)(NR 7 )-R 5a and-SO 2 -R 5a The group consisting of R 5a Selected from hydrogen, amino, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, C 1-6 Alkyl-C 3-7 Cycloalkyl and 3-7 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, O and S;

[0247] R 7 and R 8 are each independently selected from hydrogen, deuterium, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, Hydroxyl-C 1-6 Alkyl, C substituted by at least one halogen 1-6 Alkyl, C 3-7 Cycloalkyl, C 1-6 Alkyl-C 3-7 Cycloalkyl, hydroxy or cyano substituted C 3-7 Cycloalkyl;

[0248] R 15 Selected from hydrogen, deuterium and C 1-6 alkyl.

[0249] In certain embodiments, the R 1 Selected from C 1-3 Alkyl and C 3-6 Cycloalkyl.

[0250] In certain embodiments, the R 1 Selected from methyl, ethyl, propyl, isopropyl.

[0251] In certain embodiments, the R 1 Selected from methyl.

[0252] In certain embodiments, the R 2 Selected from hydrogen, deuterium, halogen, C 1-3 Alkyl, C substituted by at least one halogen 1-3 alkyl.

[0253] In certain embodiments, the R2 Selected from hydrogen, deuterium, halogen, C 1-3 alkyl.

[0254] In certain embodiments, the R 2 Selected from hydrogen, fluorine, chlorine, methyl, ethyl, propyl, isopropyl.

[0255] In certain embodiments, the R 2 Selected from hydrogen and fluorine.

[0256] In certain embodiments, the R 2’ Selected from hydrogen, deuterium, halogen, C 1-3 Alkyl, C substituted by at least one halogen 1-3 alkyl.

[0257] In certain embodiments, the R 2’ Selected from hydrogen, deuterium, halogen, C 1-3 alkyl.

[0258] In certain embodiments, the R 2’ Selected from hydrogen, fluorine, chlorine, methyl, ethyl, propyl, isopropyl.

[0259] In certain embodiments, the R 2’ Selected from hydrogen and fluorine.

[0260] In certain embodiments, the R 3 Selected from halogen, C 1-3 alkyl.

[0261] In certain embodiments, the R 3 Selected from fluorine, chlorine, methyl, ethyl, propyl, isopropyl.

[0262] In certain embodiments, the R 3 Selected from fluorine.

[0263] In certain embodiments, the R 4 Selected from halogen, hydroxyl, cyano, C 1-6 Alkyl, C substituted by at least one halogen 1-6 Alkyl, C 3-7 Cycloalkyl and C 3-7 Cycloalkyl substituted C 1-6 alkyl.

[0264] In certain embodiments, the R 4 Selected from halogen, C 1-3 Alkyl, C 3-5 Cycloalkyl and C 3-5 Cycloalkyl substituted C 1-6 alkyl.

[0265] In certain embodiments, the R 4 is selected from methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl and -CH 2 -cyclopropyl.

[0266] In certain embodiments, the R 6 Selected from hydrogen, deuterium, hydroxyl, cyano, halogen.

[0267] In certain embodiments, the R 6 Selected from hydrogen, deuterium and halogen.

[0268] In certain embodiments, the R 6 Selected from hydrogen.

[0269] In certain embodiments, the R 10 Selected from hydrogen, deuterium and C 1-6 alkyl.

[0270] In certain embodiments, the R 10 Selected from hydrogen and deuterium.

[0271] In certain embodiments, the R 10 Selected from hydrogen.

[0272] In certain embodiments, the R 11 Selected from hydrogen, deuterium and halogen.

[0273] In certain embodiments, the R 11 Selected from hydrogen, deuterium and fluorine.

[0274] In certain embodiments, the R 11 Selected from hydrogen and fluorine.

[0275] In certain embodiments, the R 12 Selected from hydrogen, deuterium and halogen.

[0276] In certain embodiments, the R 12 Selected from hydrogen, deuterium and fluorine.

[0277] In certain embodiments, the R 12 Selected from hydrogen and fluorine.

[0278] In certain embodiments, the R 11 and R 12 One of the carbon atoms to which it is connected, R 14 and the carbon atom to which it is connected together form a substituted or unsubstituted 4-6 membered fused ring containing 1 or 2 heteroatoms selected from N, O and S.

[0279] In certain embodiments, the R 11 and R 12One of the carbon atoms to which it is connected, R 14 and the carbon atom to which they are connected together form a substituted or unsubstituted tetrahydrothiopyran ring and a morpholine ring.

[0280] In certain embodiments, the substitution is by at least one selected from amino, hydroxy, oxo and C 1-6 The alkyl group is substituted by a substituent.

[0281] In certain embodiments, the substitution is with oxo.

[0282] In certain embodiments, the R 13 Selected from hydrogen, deuterium and halogen.

[0283] In certain embodiments, the R 13 Selected from hydrogen and deuterium.

[0284] In certain embodiments, the R 13 Selected from hydrogen.

[0285] In certain embodiments, the R 14 is selected from deuterium, halogen, amino, hydroxy, C substituted by hydroxy, amino or 3-7 membered heterocycloalkyl 1-6 Alkyl, hydroxy substituted C 1-6 Alkoxy, -(CO)-OH, 3-7 membered heterocycloalkyl, -S(O)(NR 7 )-R 5a and-SO 2 -R 5a The group composed of.

[0286] In certain embodiments, the R 14 is selected from amino, hydroxy, C substituted by hydroxy or 5-6 membered heterocycloalkyl 1-3 Alkyl, hydroxy substituted C 1-3 Alkoxy, -(CO)-OH, 5-6 membered heterocycloalkyl, -S(O)(NR 7 )-R 5a and-SO 2 -R 5a The 5-6 membered heterocycloalkyl group contains 1-2 heteroatoms selected from N and O.

[0287] In certain embodiments, the R 14 Selected from amino, hydroxyl, hydroxymethyl, -OCH 2 CH 2 -OH, -CH 2 -morpholinyl, morpholinyl, -(CO)-OH, -S(O)(NR 7 )-R 5a and-SO 2 -R 5aThe group composed of.

[0288] In certain embodiments, the R 5a Selected from hydrogen, amino, C 1-6 Alkyl, C 3-7 Cycloalkyl and C 1-6 Alkyl-C 3-7 Cycloalkyl.

[0289] In certain embodiments, the R 5a Selected from hydrogen, amino, C 1-3 Alkyl, C 3-5 Cycloalkyl and C 1-3 Alkyl-C 3-5 Cycloalkyl.

[0290] In certain embodiments, the R 5a is selected from hydrogen, amino, methyl, ethyl, isopropyl, cyclopropyl and -CH 2 -cyclopropyl.

[0291] In certain embodiments, the R 15 Selected from hydrogen and deuterium.

[0292] In certain embodiments, the R 15 Selected from hydrogen.

[0293] In certain embodiments, the R 7 Selected from hydrogen, deuterium, C 1-3 Alkyl, Hydroxyl-C 1-3 Alkyl, C substituted by at least one halogen 1-3 alkyl.

[0294] In certain embodiments, the R 7 Selected from hydrogen, methyl, hydroxyethyl, difluoroethyl.

[0295] In certain embodiments, the R 8 Selected from hydrogen, deuterium, C 1-3 Alkyl, Hydroxyl-C 1-3 Alkyl, C substituted by at least one halogen 1-3 alkyl.

[0296] In certain embodiments, the R 8 Preferably selected from hydrogen, methyl, hydroxyethyl, difluoroethyl.

[0297] In certain embodiments, the R i Selected from halogen, C 1-6 Alkyl, C 1-3 Alkoxy.

[0298] In certain embodiments, the R i Selected from halogen.

[0299] In certain embodiments, the present disclosure provides a compound of formula I or a stereoisomer, solvate, hydrate, prodrug, stable isotope derivative, and pharmaceutically acceptable salt thereof, characterized in that the compound has the structure of formula I-1-1-1:

[0300]

[0301] in,

[0302] X 7 Selected from CR 6 and N;

[0303] R 1 Selected from C 1-6 Alkyl and C 3-7 Cycloalkyl;

[0304] R 2 and R 2’ are each independently selected from hydrogen, deuterium, halogen, C 1-6 Alkyl, C substituted by at least one halogen 1-6 Alkyl and C 3-7 Cycloalkyl;

[0305] R 3 Selected from halogen, C 1-6 Alkyl, C substituted by at least one halogen 1-6 Alkyl, C 3-7 Cycloalkyl and C 1-6 Alkoxy;

[0306] R 4 Selected from halogen, hydroxyl, cyano, C 1-6 Alkyl, C substituted by at least one halogen 1-6 Alkyl and C 1-6 Alkoxy, C 3-7 Cycloalkyl, hydroxyl, C 1-6 Alkoxy or C 3-7 Cycloalkyl substituted C 1-6 Alkyl, 3-7 membered heterocycloalkyl, C 6-10 Aryl and 5-10 membered heteroaryl;

[0307] R 6 Each occurrence is independently selected from hydrogen, deuterium, hydroxyl, cyano, halogen, C 1-6 Alkyl, C 1-6 Alkoxy and C substituted by at least one halogen 1-6 alkyl;

[0308] R i Selected from hydrogen, halogen, C 1-3 Alkyl, C substituted by at least one halogen1-6 Alkyl, C 3-7 Cycloalkyl and C 1-6 Alkoxy;

[0309] o is an integer selected from 0, 1, 2, 3, 4;

[0310] R 10 Selected from hydrogen, deuterium, C 1-6 Alkyl and hydroxy-C 1-6 alkyl;

[0311] R 11 and R 12 independently selected from hydrogen, deuterium, C 1-6 Alkyl, hydroxyl, halogen and C 1-6 Alkoxy and hydroxy-C 1-6 alkyl;

[0312] or R 11 and R 12 One of the carbon atoms to which it is connected, R 14 and the carbon atoms to which they are connected together form a substituted or unsubstituted 4-6 membered fused ring, wherein the 4-6 membered fused ring contains 0, 1 or 2 heteroatoms selected from N, O and S, wherein the substitution is by at least one selected from amino, hydroxyl, oxo and C 1-6 Substituted by a substituent in the alkyl group;

[0313] R 13 Selected from hydrogen, deuterium, C 1-6 Alkyl, hydroxyl, halogen and C 1-6 Alkoxy and hydroxy-C 1-6 alkyl;

[0314] R 14 Selected from deuterium, halogen, hydroxyl, cyano, C 1-6 Alkyl, C substituted by hydroxy, amino or 3-7 membered heterocycloalkyl 1-6 Alkyl, C 1-6 Alkoxy, -(CO)-OH, -(CO)-NR 7 R 8 、-(CO)-NR 7 -SO 2 -R 8 、-NR 7 R 8 、-NR 7 -(CO)-C 1-6 Alkyl, -NR 7 -(CO)-C 3-7 Cycloalkyl, -NR 7 -(CO)-OR 8 、-NR 7 -(CO)-NR 7 R8 、-NR 7 -SO 2 -R 8 、-NR 7 -SO 2 -NR 7 R 8 、-SO 2 -NR 7 R 8 、-SO 2 -NR 7 -(CO)-R 8 , C 3-7 Cycloalkyl, 3-7 membered heterocycloalkyl, -S(O)(NR 7 )-R 5a and-SO 2 -R 5a The group consisting of R 5a Selected from hydrogen, amino, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, C 1-6 Alkyl-C 3-7 Cycloalkyl and 3-7 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, O and S;

[0315] R 7 and R 8 are each independently selected from hydrogen, deuterium, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, Hydroxyl-C 1-6 Alkyl, C substituted by at least one halogen 1-6 Alkyl, C 3-7 Cycloalkyl, C 1-6 Alkyl-C 3-7 Cycloalkyl, hydroxy or cyano substituted C 3-7 Cycloalkyl;

[0316] R 15 Selected from hydrogen, deuterium and C 1-6 alkyl.

[0317] In certain embodiments, the R 1 Selected from C 1-3 Alkyl and C 3-6 Cycloalkyl.

[0318] In certain embodiments, the R 1 Selected from methyl, ethyl, propyl, isopropyl.

[0319] In certain embodiments, the R 1 Selected from methyl.

[0320] In certain embodiments, the R 2 Selected from hydrogen, deuterium, halogen, C 1-3 Alkyl, C substituted by at least one halogen 1-3 alkyl.

[0321] In certain embodiments, the R 2 Selected from hydrogen, deuterium, halogen, C 1-3 alkyl.

[0322] In certain embodiments, the R 2 Selected from hydrogen, fluorine, chlorine, methyl, ethyl, propyl, isopropyl.

[0323] In certain embodiments, the R 2 Selected from hydrogen and fluorine.

[0324] In certain embodiments, the R 2’ Selected from hydrogen, deuterium, halogen, C 1-3 Alkyl, C substituted by at least one halogen 1-3 alkyl.

[0325] In certain embodiments, the R 2’ Selected from hydrogen, deuterium, halogen, C 1-3 alkyl.

[0326] In certain embodiments, the R 2’ Selected from hydrogen, fluorine, chlorine, methyl, ethyl, propyl, isopropyl.

[0327] In certain embodiments, the R 2’ Selected from hydrogen and fluorine.

[0328] In certain embodiments, the R 3 Selected from halogen, C 1-3 alkyl.

[0329] In certain embodiments, the R 3 Selected from fluorine, chlorine, methyl, ethyl, propyl, isopropyl.

[0330] In certain embodiments, the R 3 Selected from fluorine.

[0331] In certain embodiments, the R 4 Selected from halogen, hydroxyl, cyano, C 1-6 Alkyl, C substituted by at least one halogen 1-6 Alkyl, C 3-7 Cycloalkyl and C 3-7 Cycloalkyl substituted C 1-6 alkyl.

[0332] In certain embodiments, the R4 Selected from halogen, C 1-3 Alkyl, C 3-5 Cycloalkyl and C 3-5 Cycloalkyl substituted C 1-6 alkyl.

[0333] In certain embodiments, the R 4 is selected from methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl and -CH 2 -cyclopropyl.

[0334] In certain embodiments, the R 6 Selected from hydrogen, deuterium, hydroxyl, cyano, halogen.

[0335] In certain embodiments, the R 6 Selected from hydrogen, deuterium and halogen.

[0336] In certain embodiments, the R 6 Selected from hydrogen.

[0337] In certain embodiments, the R 10 Selected from hydrogen, deuterium and C 1-6 alkyl.

[0338] In certain embodiments, the R 10 Selected from hydrogen and deuterium.

[0339] In certain embodiments, the R 10 Selected from hydrogen.

[0340] In certain embodiments, the R 11 Selected from hydrogen, deuterium and halogen.

[0341] In certain embodiments, the R 11 Selected from hydrogen, deuterium and fluorine.

[0342] In certain embodiments, the R 11 Selected from hydrogen and fluorine.

[0343] In certain embodiments, the R 12 Selected from hydrogen, deuterium and halogen.

[0344] In certain embodiments, the R 12 Selected from hydrogen, deuterium and fluorine.

[0345] In certain embodiments, the R 12 Selected from hydrogen and fluorine.

[0346] In certain embodiments, the R 11 and R 12 One of the carbon atoms to which it is connected, R 14and the carbon atom to which it is connected together form a substituted or unsubstituted 4-6 membered fused ring containing 1 or 2 heteroatoms selected from N, O and S.

[0347] In certain embodiments, the R 11 and R 12 One of the carbon atoms to which it is connected, R 14 and the carbon atom to which they are connected together form a substituted or unsubstituted tetrahydrothiopyran ring and a morpholine ring.

[0348] In certain embodiments, the substitution is by at least one selected from amino, hydroxy, oxo and C 1-6 The alkyl group is substituted by a substituent.

[0349] In certain embodiments, the substitution is with oxo.

[0350] In certain embodiments, the R 13 Selected from hydrogen, deuterium and halogen.

[0351] In certain embodiments, the R 13 Selected from hydrogen and deuterium.

[0352] In certain embodiments, the R 13 Selected from hydrogen.

[0353] In certain embodiments, the R 14 is selected from deuterium, halogen, amino, hydroxy, C substituted by hydroxy, amino or 3-7 membered heterocycloalkyl 1-6 Alkyl, hydroxy substituted C 1-6 Alkoxy, -(CO)-OH, 3-7 membered heterocycloalkyl, -S(O)(NR 7 )-R 5a and-SO 2 -R 5a The group composed of.

[0354] In certain embodiments, the R 14 is selected from amino, hydroxy, C substituted by hydroxy or 5-6 membered heterocycloalkyl 1-3 Alkyl, hydroxy substituted C 1-3 Alkoxy, -(CO)-OH, 5-6 membered heterocycloalkyl, -S(O)(NR 7 )-R 5a and-SO 2 -R 5a The 5-6 membered heterocycloalkyl group contains 1-2 heteroatoms selected from N and O.

[0355] In certain embodiments, the R 14 Selected from amino, hydroxyl, hydroxymethyl, -OCH 2 CH2 -OH, -CH 2 -morpholinyl, morpholinyl, -(CO)-OH, -S(O)(NR 7 )-R 5a and-SO 2 -R 5a The group composed of.

[0356] In certain embodiments, the R 5a Selected from hydrogen, amino, C 1-6 Alkyl, C 3-7 Cycloalkyl and C 1-6 Alkyl-C 3-7 Cycloalkyl.

[0357] In certain embodiments, the R 5a Selected from hydrogen, amino, C 1-3 Alkyl, C 3-5 Cycloalkyl and C 1-3 Alkyl-C 3-5 Cycloalkyl.

[0358] In certain embodiments, the R 5a is selected from hydrogen, amino, methyl, ethyl, isopropyl, cyclopropyl and -CH 2 -cyclopropyl.

[0359] In certain embodiments, the R 15 Selected from hydrogen and deuterium.

[0360] In certain embodiments, the R 15 Selected from hydrogen.

[0361] In certain embodiments, the R 7 Selected from hydrogen, deuterium, C 1-3 Alkyl, Hydroxyl-C 1-3 Alkyl, C substituted by at least one halogen 1-3 alkyl.

[0362] In certain embodiments, the R 7 Selected from hydrogen, methyl, hydroxyethyl, difluoroethyl.

[0363] In certain embodiments, the R 8 Selected from hydrogen, deuterium, C 1-3 Alkyl, Hydroxyl-C 1-3 Alkyl, C substituted by at least one halogen 1-3 alkyl.

[0364] In certain embodiments, the R 8 Preferably selected from hydrogen, methyl, hydroxyethyl, difluoroethyl.

[0365] In certain embodiments, the R i Selected from halogen, C 1-6 Alkyl, C 1-3 Alkoxy.

[0366] In certain embodiments, the R i Selected from halogen.

[0367] In certain embodiments, the present disclosure provides a compound of formula I or a stereoisomer, solvate, hydrate, prodrug, stable isotope derivative, and pharmaceutically acceptable salt thereof, characterized in that the compound has the structure of formula I-1-2-1:

[0368]

[0369] in,

[0370] X 7 Selected from CR 6 and N;

[0371] R 1 Selected from C 1-6 Alkyl and C 3-7 Cycloalkyl;

[0372] R 2 and R 2’ are each independently selected from hydrogen, deuterium, halogen, C 1-6 Alkyl, C substituted by at least one halogen 1-6 Alkyl and C 3-7 Cycloalkyl;

[0373] R 3 Selected from halogen, C 1-6 Alkyl, C substituted by at least one halogen 1-6 Alkyl, C 3-7 Cycloalkyl and C 1-6 Alkoxy;

[0374] R 4 Selected from halogen, hydroxyl, cyano, C 1-6 Alkyl, C substituted by at least one halogen 1-6 Alkyl and C 1-6 Alkoxy, C 3-7 Cycloalkyl, hydroxyl, C 1-6 Alkoxy or C 3-7 Cycloalkyl substituted C 1-6 Alkyl, 3-7 membered heterocycloalkyl, C 6-10 Aryl and 5-10 membered heteroaryl;

[0375] R 6 Each occurrence is independently selected from hydrogen, deuterium, hydroxyl, cyano, halogen, C 1-6 Alkyl, C1-6 Alkoxy and C substituted by at least one halogen 1-6 alkyl;

[0376] R i Selected from hydrogen, halogen, C 1-3 Alkyl, C substituted by at least one halogen 1-6 Alkyl, C 3-7 Cycloalkyl and C 1-6 Alkoxy;

[0377] s is an integer selected from 0, 1, and 2;

[0378] R 10 Selected from hydrogen, deuterium, C 1-6 Alkyl and hydroxy-C 1-6 alkyl;

[0379] R 11 and R 12 independently selected from hydrogen, deuterium, C 1-6 Alkyl, hydroxyl, halogen and C 1-6 Alkoxy and hydroxy-C 1-6 alkyl;

[0380] or R 11 and R 12 One of the carbon atoms to which it is connected, R 14 and the carbon atoms to which they are connected together form a substituted or unsubstituted 4-6 membered fused ring, wherein the 4-6 membered fused ring contains 0, 1 or 2 heteroatoms selected from N, O and S, wherein the substitution is by at least one selected from amino, hydroxyl, oxo and C 1-6 Substituted by a substituent in the alkyl group;

[0381] R 13 Selected from hydrogen, deuterium, C 1-6 Alkyl, hydroxyl, halogen and C 1-6 Alkoxy and hydroxy-C 1-6 alkyl;

[0382] R 14 Selected from deuterium, halogen, hydroxyl, cyano, C 1-6 Alkyl, C substituted by hydroxy, amino or 3-7 membered heterocycloalkyl 1-6 Alkyl, C 1-6 Alkoxy, -(CO)-OH, -(CO)-NR 7 R 8 、-(CO)-NR 7 -SO 2 -R 8 、-NR 7 R 8 、-NR 7 -(CO)-C 1-6 Alkyl, -NR7 -(CO)-C 3-7 Cycloalkyl, -NR 7 -(CO)-OR 8 、-NR 7 -(CO)-NR 7 R 8 、-NR 7 -SO 2 -R 8 、-NR 7 -SO 2 -NR 7 R 8 、-SO 2 -NR 7 R 8 、-SO 2 -NR 7 -(CO)-R 8 , C 3-7 Cycloalkyl, 3-7 membered heterocycloalkyl, -S(O)(NR 7 )-R 5a and-SO 2 -R 5a The group consisting of R 5a Selected from hydrogen, amino, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, C 1-6 Alkyl-C 3-7 Cycloalkyl and 3-7 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, O and S;

[0383] R 7 and R 8 are each independently selected from hydrogen, deuterium, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, Hydroxyl-C 1-6 Alkyl, C substituted by at least one halogen 1-6 Alkyl, C 3-7 Cycloalkyl, C 1-6 Alkyl-C 3-7 Cycloalkyl, hydroxy or cyano substituted C 3-7 Cycloalkyl;

[0384] R 15 Selected from hydrogen, deuterium and C 1-6 alkyl.

[0385] In certain embodiments, the R 1 Selected from C 1-3 Alkyl and C 3-6 Cycloalkyl.

[0386] In certain embodiments, the R1 Selected from methyl, ethyl, propyl, isopropyl.

[0387] In certain embodiments, the R 1 Selected from methyl.

[0388] In certain embodiments, the R 2 Selected from hydrogen, deuterium, halogen, C 1-3 Alkyl, C substituted by at least one halogen 1-3 alkyl.

[0389] In certain embodiments, the R 2 Selected from hydrogen, deuterium, halogen, C 1-3 alkyl.

[0390] In certain embodiments, the R 2 Selected from hydrogen, fluorine, chlorine, methyl, ethyl, propyl, isopropyl.

[0391] In certain embodiments, the R 2 Selected from hydrogen and fluorine.

[0392] In certain embodiments, the R 2’ Selected from hydrogen, deuterium, halogen, C 1-3 Alkyl, C substituted by at least one halogen 1-3 alkyl.

[0393] In certain embodiments, the R 2’ Selected from hydrogen, deuterium, halogen, C 1-3 alkyl.

[0394] In certain embodiments, the R 2’ Selected from hydrogen, fluorine, chlorine, methyl, ethyl, propyl, isopropyl.

[0395] In certain embodiments, the R 2’ Selected from hydrogen and fluorine.

[0396] In certain embodiments, the R 3 Selected from halogen, C 1-3 alkyl.

[0397] In certain embodiments, the R 3 Selected from fluorine, chlorine, methyl, ethyl, propyl, isopropyl.

[0398] In certain embodiments, the R 3 Selected from fluorine.

[0399] In certain embodiments, the R 4 Selected from halogen, hydroxyl, cyano, C 1-6 Alkyl, C substituted by at least one halogen 1-6Alkyl, C 3-7 Cycloalkyl and C 3-7 Cycloalkyl substituted C 1-6 alkyl.

[0400] In certain embodiments, the R 4 Selected from halogen, C 1-3 Alkyl, C 3-5 Cycloalkyl and C 3-5 Cycloalkyl substituted C 1-6 alkyl.

[0401] In certain embodiments, the R 4 is selected from methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl and -CH 2 -cyclopropyl.

[0402] In certain embodiments, the R 6 Selected from hydrogen, deuterium, hydroxyl, cyano, halogen.

[0403] In certain embodiments, the R 6 Selected from hydrogen, deuterium and halogen.

[0404] In certain embodiments, the R 6 Selected from hydrogen.

[0405] In certain embodiments, the R 10 Selected from hydrogen, deuterium and C 1-6 alkyl.

[0406] In certain embodiments, the R 10 Selected from hydrogen and deuterium.

[0407] In certain embodiments, the R 10 Selected from hydrogen.

[0408] In certain embodiments, the R 11 Selected from hydrogen, deuterium and halogen.

[0409] In certain embodiments, the R 11 Selected from hydrogen, deuterium and fluorine.

[0410] In certain embodiments, the R 11 Selected from hydrogen and fluorine.

[0411] In certain embodiments, the R 12 Selected from hydrogen, deuterium and halogen.

[0412] In certain embodiments, the R 12 Selected from hydrogen, deuterium and fluorine.

[0413] In certain embodiments, the R 12 Selected from hydrogen and fluorine.

[0414] In certain embodiments, the R 11 and R 12 One of the carbon atoms to which it is connected, R 14 and the carbon atom to which it is connected together form a substituted or unsubstituted 4-6 membered fused ring containing 1 or 2 heteroatoms selected from N, O and S.

[0415] In certain embodiments, the R 11 and R 12 One of the carbon atoms to which it is connected, R 14 and the carbon atom to which they are connected together form a substituted or unsubstituted tetrahydrothiopyran ring and a morpholine ring.

[0416] In certain embodiments, the substitution is by at least one selected from amino, hydroxy, oxo and C 1-6 The alkyl group is substituted by a substituent.

[0417] In certain embodiments, the substitution is with oxo.

[0418] In certain embodiments, the R 13 Selected from hydrogen, deuterium and halogen.

[0419] In certain embodiments, the R 13 Selected from hydrogen and deuterium.

[0420] In certain embodiments, the R 13 Selected from hydrogen.

[0421] In certain embodiments, the R 14 is selected from deuterium, halogen, amino, hydroxy, C substituted by hydroxy, amino or 3-7 membered heterocycloalkyl 1-6 Alkyl, hydroxy substituted C 1-6 Alkoxy, -(CO)-OH, 3-7 membered heterocycloalkyl, -S(O)(NR 7 )-R 5a and-SO 2 -R 5a The group composed of.

[0422] In certain embodiments, the R 14 is selected from amino, hydroxy, C substituted by hydroxy or 5-6 membered heterocycloalkyl 1-3 Alkyl, hydroxy substituted C 1-3 Alkoxy, -(CO)-OH, 5-6 membered heterocycloalkyl, -S(O)(NR 7 )-R 5a and-SO 2 -R 5aThe 5-6 membered heterocycloalkyl group contains 1-2 heteroatoms selected from N and O.

[0423] In certain embodiments, the R 14 Selected from amino, hydroxyl, hydroxymethyl, -OCH 2 CH 2 -OH, -CH 2 -morpholinyl, morpholinyl, -(CO)-OH, -S(O)(NR 7 )-R 5a and-SO 2 -R 5a The group composed of.

[0424] In certain embodiments, the R 5a Selected from hydrogen, amino, C 1-6 Alkyl, C 3-7 Cycloalkyl and C 1-6 Alkyl-C 3-7 Cycloalkyl.

[0425] In certain embodiments, the R 5a Selected from hydrogen, amino, C 1-3 Alkyl, C 3-5 Cycloalkyl and C 1-3 Alkyl-C 3-5 Cycloalkyl.

[0426] In certain embodiments, the R 5a is selected from hydrogen, amino, methyl, ethyl, isopropyl, cyclopropyl and -CH 2 -cyclopropyl.

[0427] In certain embodiments, the R 15 Selected from hydrogen and deuterium.

[0428] In certain embodiments, the R 15 Selected from hydrogen.

[0429] In certain embodiments, the R 7 Selected from hydrogen, deuterium, C 1-3 Alkyl, Hydroxyl-C 1-3 Alkyl, C substituted by at least one halogen 1-3 alkyl.

[0430] In certain embodiments, the R 7 Selected from hydrogen, methyl, hydroxyethyl, difluoroethyl.

[0431] In certain embodiments, the R 8 Selected from hydrogen, deuterium, C 1-3 Alkyl, Hydroxyl-C 1-3 Alkyl, C substituted by at least one halogen1-3 alkyl.

[0432] In certain embodiments, the R 8 Preferably selected from hydrogen, methyl, hydroxyethyl, difluoroethyl.

[0433] In certain embodiments, the R i Selected from halogen, C 1-6 Alkyl, C 1-3 Alkoxy.

[0434] In certain embodiments, the R i Selected from halogen.

[0435] In certain embodiments, the present disclosure provides a compound of Formula I or a stereoisomer, solvate, hydrate, prodrug, stable isotope derivative, and pharmaceutically acceptable salt thereof, characterized in that the compound has a structure of Formula I-2:

[0436]

[0437] in,

[0438] X 1 , X 2 Each independently selected from CR 6 and N;

[0439] X 6 , X 7 and X 8 Each independently selected from CR 6 and N;

[0440] R 1 Selected from C 1-6 Alkyl and C 3-7 Cycloalkyl;

[0441] R 2 and R 2’ are each independently selected from hydrogen, deuterium, halogen, C 1-6 Alkyl, C substituted by at least one halogen 1-6 Alkyl and C 3-7 Cycloalkyl;

[0442] R 3 Selected from halogen, C 1-6 Alkyl, C substituted by at least one halogen 1-6 Alkyl, C 3-7 Cycloalkyl and C 1-6 Alkoxy;

[0443] R 4 Selected from halogen, hydroxyl, cyano, C 1-6 Alkyl, C substituted by at least one halogen1-6 Alkyl and C 1-6 Alkoxy, C 3-7 Cycloalkyl, hydroxyl, C 1-6 Alkoxy or C 3-7 Cycloalkyl substituted C 1-6 Alkyl, 3-7 membered heterocycloalkyl, C 6-10 Aryl and 5-10 membered heteroaryl;

[0444] R 6 Each occurrence is independently selected from hydrogen, deuterium, hydroxyl, cyano, halogen, C 1-6 Alkyl, C 1-6 Alkoxy and C substituted by at least one halogen 1-6 alkyl;

[0445] Ring A is present or absent; when ring A is absent, t is an integer selected from 1, 2, and 3; when ring A is present, t is 1 and the ring A is selected from the following A-1 to A-4 groups:

[0446]

[0447] R i Selected from hydrogen, halogen, C 1-3 Alkyl, C substituted by at least one halogen 1-6 Alkyl, C 3-7 Cycloalkyl and C 1-6 Alkoxy;

[0448] o is an integer selected from 0, 1, 2, 3, 4;

[0449] p is an integer selected from 0, 1, and 2;

[0450] q is an integer selected from 0, 1, 2, 3;

[0451] s is an integer selected from 0, 1, and 2;

[0452] R 16 and R 17 Each occurrence is independently selected from hydrogen, deuterium, C 1-6 Alkyl, hydroxyl, halogen, C 1-6 Alkoxy and hydroxy-C 1-6 alkyl;

[0453] R 18 Selected from hydrogen, deuterium, halogen, hydroxyl, cyano, C 1-6 Alkyl, C substituted by hydroxy, amino or 3-7 membered heterocycloalkyl 1-6 Alkyl, C 1-6 Alkoxy, C substituted by hydroxy 1-6 Alkoxy, -(CO)-OH, -(CO)-NR 7 R8 、-(CO)-NR 7 -SO 2 -R 8 、-NR 7 R 8 、-NR 7 -(CO)-C 1-6 Alkyl, -NR 7 -(CO)-C 3-7 Cycloalkyl, -NR 7 -(CO)-OR 8 、-NR 7 -(CO)-NR 7 R 8 、-NR 7 -SO 2 -R 8 、-NR 7 -SO 2 -NR 7 R 8 、-SO 2 -NR 7 R 8 、-SO 2 -NR 7 -(CO)-R 8 , C 3-7 Cycloalkyl, 3-7 membered heterocycloalkyl, -S(O)(NR 7 )-R 5a and-SO 2 -R 5a The group consisting of R 5a Selected from hydrogen, amino, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, C 1-6 Alkyl-C 3-7 Cycloalkyl and 3-7 membered heterocycloalkyl; or

[0454] R 17 , R 18 and the carbon atoms connected together form a substituted or unsubstituted 3-5 membered spiro ring, wherein the 3-5 membered spiro ring contains 0 or 1 heteroatom selected from N, O and S, and the substitution is by at least one selected from oxo, amino, hydroxyl and C 1-6 substituted by an alkyl substituent;

[0455] Among them, R 7 and R 8 are each independently selected from hydrogen, deuterium, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, Hydroxyl-C 1-6 Alkyl, C substituted by at least one halogen1-6 Alkyl, C 3-7 Cycloalkyl, C 1-6 Alkyl-C 3-7 Cycloalkyl, hydroxy or cyano substituted C 3-7 Cycloalkyl.

[0456] In certain embodiments, the R 1 Selected from C 1-3 Alkyl and C 3-6 Cycloalkyl.

[0457] In certain embodiments, the R 1 Selected from methyl, ethyl, propyl, isopropyl.

[0458] In certain embodiments, the R 1 Selected from methyl.

[0459] In certain embodiments, the R 2 Selected from hydrogen, deuterium, halogen, C 1-3 Alkyl, C substituted by at least one halogen 1-3 alkyl.

[0460] In certain embodiments, the R 2 Selected from hydrogen, deuterium, halogen, C 1-3 alkyl.

[0461] In certain embodiments, the R 2 Selected from hydrogen, fluorine, chlorine, methyl, ethyl, propyl, isopropyl.

[0462] In certain embodiments, the R 2 Selected from hydrogen and fluorine.

[0463] In certain embodiments, the R 2’ Selected from hydrogen, deuterium, halogen, C 1-3 Alkyl, C substituted by at least one halogen 1-3 alkyl.

[0464] In certain embodiments, the R 2’ Selected from hydrogen, deuterium, halogen, C 1-3 alkyl.

[0465] In certain embodiments, the R 2’ Selected from hydrogen, fluorine, chlorine, methyl, ethyl, propyl, isopropyl.

[0466] In certain embodiments, the R 2’ Selected from hydrogen and fluorine.

[0467] In certain embodiments, the R 3 Selected from halogen, C 1-3 alkyl.

[0468] In certain embodiments, the R 3 Selected from fluorine, chlorine, methyl, ethyl, propyl, isopropyl.

[0469] In certain embodiments, the R 3 Selected from fluorine.

[0470] In certain embodiments, the R 4 Selected from halogen, hydroxyl, cyano, C 1-6 Alkyl, C substituted by at least one halogen 1-6 Alkyl, C 3-7 Cycloalkyl and C 3-7 Cycloalkyl substituted C 1-6 alkyl.

[0471] In certain embodiments, the R 4 Selected from halogen, C 1-3 Alkyl, C 3-5 Cycloalkyl and C 3-5 Cycloalkyl substituted C 1-6 alkyl.

[0472] In certain embodiments, the R 4 is selected from methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl and -CH 2 -cyclopropyl.

[0473] In certain embodiments, the R 6 Selected from hydrogen, deuterium, hydroxyl, cyano, halogen.

[0474] In certain embodiments, the R 6 Selected from hydrogen, deuterium and halogen.

[0475] In certain embodiments, the R 6 Selected from hydrogen.

[0476] In certain embodiments, the R 16 Each occurrence is independently selected from hydrogen, deuterium and halogen.

[0477] In certain embodiments, the R 16 Each occurrence is independently selected from hydrogen and deuterium.

[0478] In certain embodiments, the R 16 Each occurrence is independently selected from hydrogen.

[0479] In certain embodiments, the R 17 Selected from hydrogen, deuterium, hydroxyl and C 1-6 alkyl.

[0480] In certain embodiments, the R17 Selected from hydrogen, deuterium, hydroxyl and C 1-3 alkyl.

[0481] In certain embodiments, the R 17 is selected from the group consisting of hydrogen, hydroxy and methyl.

[0482] In certain embodiments, the R 18 Selected from hydrogen, deuterium, amino, C 1-6 Alkyl-substituted amino, hydroxy, C substituted by hydroxy, amino or 3-7 membered heterocycloalkyl 1-6 Alkyl, C substituted by hydroxy 1-6 Alkoxy, 3-7 membered heterocycloalkyl and -SO 2 -R 5a The group composed of.

[0483] In certain embodiments, the R 18 Selected from amino, C 1-3 Alkyl-substituted amino, hydroxy, C substituted by hydroxy, amino 1-3 Alkyl, C substituted by hydroxy 1-3 Alkoxy, 5-6 membered heterocycloalkyl and -SO 2 -R 5a The 5-6 membered heterocycloalkyl group contains 1-2 heteroatoms selected from N and O.

[0484] In certain embodiments, the R 18 Selected from amino, hydroxymethyl, aminomethyl, methylamino, hydroxyl, -OCH 2 CH 2 -OH, morpholinyl and -SO 2 -R 5a The group composed of.

[0485] In certain embodiments, the R 17 , R 18 and the carbon atoms to which they are commonly connected form a substituted or unsubstituted 3-4 membered spiro ring containing 0 or 1 heteroatom selected from N, O and S.

[0486] In certain embodiments, the 3-4 membered spiro ring is selected from oxetanyl, thietanyl, and cyclobutyl.

[0487] In certain embodiments, the substitution is with at least one substituent selected from oxo, amino, and hydroxy.

[0488] In certain embodiments, the substitution is with a substituent selected from oxo and amino.

[0489] In certain embodiments, the R 5a Selected from hydrogen, amino and C1-6 alkyl.

[0490] In certain embodiments, the R 5a Selected from hydrogen, amino and C 1-3 alkyl.

[0491] In certain embodiments, the R 5a is selected from hydrogen, amino and methyl.

[0492] In certain embodiments, the R i Selected from halogen, C 1-6 Alkyl, C 1-3 Alkoxy.

[0493] In certain embodiments, the R i Selected from halogen.

[0494] In certain embodiments, the present disclosure provides a compound of formula I or a stereoisomer, solvate, hydrate, prodrug, stable isotope derivative, and pharmaceutically acceptable salt thereof, characterized in that the compound has a structure of formula I-2-1:

[0495]

[0496] in,

[0497] X 1 , X 2 Each independently selected from CR 6 and N;

[0498] X 6 , X 7 and X 8 Each independently selected from CR 6 and N;

[0499] R 1 Selected from C 1-6 Alkyl and C 3-7 Cycloalkyl;

[0500] R 2 and R 2’ are each independently selected from hydrogen, deuterium, halogen, C 1-6 Alkyl, C substituted by at least one halogen 1-6 Alkyl and C 3-7 Cycloalkyl;

[0501] R 3 Selected from halogen, C 1-6 Alkyl, C substituted by at least one halogen 1-6 Alkyl, C 3-7 Cycloalkyl and C 1-6 Alkoxy;

[0502] R 4 Selected from halogen, hydroxyl, cyano, C 1-6 Alkyl, C substituted by at least one halogen 1-6 Alkyl and C 1-6 Alkoxy, C 3-7 Cycloalkyl, hydroxyl, C 1-6 Alkoxy or C 3-7 Cycloalkyl substituted C 1-6 Alkyl, 3-7 membered heterocycloalkyl, C 6-10 Aryl and 5-10 membered heteroaryl;

[0503] R 6 Each occurrence is independently selected from hydrogen, deuterium, hydroxyl, cyano, halogen, C 1-6 Alkyl, C 1-6 Alkoxy and C substituted by at least one halogen 1-6 alkyl;

[0504] R i Selected from hydrogen, halogen, C 1-3 Alkyl, C substituted by at least one halogen 1-6 Alkyl, C 3-7 Cycloalkyl and C 1-6 Alkoxy;

[0505] o is an integer selected from 0, 1, 2, 3, 4;

[0506] R 16 and R 17 Each occurrence is independently selected from hydrogen, deuterium, C 1-6 Alkyl, hydroxyl, halogen, C 1-6 Alkoxy and hydroxy-C 1-6 alkyl;

[0507] R 18 Selected from hydrogen, deuterium, halogen, hydroxyl, cyano, C 1-6 Alkyl, C substituted by hydroxy, amino or 3-7 membered heterocycloalkyl 1-6 Alkyl, C 1-6 Alkoxy, C substituted by hydroxy 1-6 Alkoxy, -(CO)-OH, -(CO)-NR 7 R 8 、-(CO)-NR 7 -SO 2 -R 8 、-NR 7 R 8 、-NR 7 -(CO)-C 1-6 Alkyl, -NR 7 -(CO)-C 3-7 Cycloalkyl, -NR7 -(CO)-OR 8 、-NR 7 -(CO)-NR 7 R 8 、-NR 7 -SO 2 -R 8 、-NR 7 -SO 2 -NR 7 R 8 、-SO 2 -NR 7 R 8 、-SO 2 -NR 7 -(CO)-R 8 , C 3-7 Cycloalkyl, 3-7 membered heterocycloalkyl, -S(O)(NR 7 )-R 5a and-SO 2 -R 5a The group consisting of R 5a Selected from hydrogen, amino, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, C 1-6 Alkyl-C 3-7 Cycloalkyl and 3-7 membered heterocycloalkyl; or

[0508] R 17 , R 18 and the carbon atoms connected together form a substituted or unsubstituted 3-5 membered spiro ring, wherein the 3-5 membered spiro ring contains 0 or 1 heteroatom selected from N, O and S, and the substitution is by at least one selected from oxo, amino, hydroxyl and C 1-6 substituted by an alkyl substituent;

[0509] Among them, R 7 and R 8 are each independently selected from hydrogen, deuterium, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, Hydroxyl-C 1-6 Alkyl, C substituted by at least one halogen 1-6 Alkyl, C 3-7 Cycloalkyl, C 1-6 Alkyl-C 3-7 Cycloalkyl, hydroxy or cyano substituted C 3-7 Cycloalkyl.

[0510] In certain embodiments, the R 1 Selected from C 1-3 Alkyl and C 3-6 Cycloalkyl.

[0511] In certain embodiments, the R 1 Selected from methyl, ethyl, propyl, isopropyl.

[0512] In certain embodiments, the R 1 Selected from methyl.

[0513] In certain embodiments, the R 2 Selected from hydrogen, deuterium, halogen, C 1-3 Alkyl, C substituted by at least one halogen 1-3 alkyl.

[0514] In certain embodiments, the R 2 Selected from hydrogen, deuterium, halogen, C 1-3 alkyl.

[0515] In certain embodiments, the R 2 Selected from hydrogen, fluorine, chlorine, methyl, ethyl, propyl, isopropyl.

[0516] In certain embodiments, the R 2 Selected from hydrogen and fluorine.

[0517] In certain embodiments, the R 2’ Selected from hydrogen, deuterium, halogen, C 1-3 Alkyl, C substituted by at least one halogen 1-3 alkyl.

[0518] In certain embodiments, the R 2’ Selected from hydrogen, deuterium, halogen, C 1-3 alkyl.

[0519] In certain embodiments, the R 2’ Selected from hydrogen, fluorine, chlorine, methyl, ethyl, propyl, isopropyl.

[0520] In certain embodiments, the R 2’ Selected from hydrogen and fluorine.

[0521] In certain embodiments, the R 3 Selected from halogen, C 1-3 alkyl.

[0522] In certain embodiments, the R 3 Selected from fluorine, chlorine, methyl, ethyl, propyl, isopropyl.

[0523] In certain embodiments, the R 3 Selected from fluorine.

[0524] In certain embodiments, the R 4 Selected from halogen, hydroxyl, cyano, C1-6 Alkyl, C substituted by at least one halogen 1-6 Alkyl, C 3-7 Cycloalkyl and C 3-7 Cycloalkyl substituted C 1-6 alkyl.

[0525] In certain embodiments, the R 4 Selected from halogen, C 1-3 Alkyl, C 3-5 Cycloalkyl and C 3-5 Cycloalkyl substituted C 1-6 alkyl.

[0526] In certain embodiments, the R 4 is selected from methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl and -CH 2 -cyclopropyl.

[0527] In certain embodiments, the R 6 Selected from hydrogen, deuterium, hydroxyl, cyano, halogen.

[0528] In certain embodiments, the R 6 Selected from hydrogen, deuterium and halogen.

[0529] In certain embodiments, the R 6 Selected from hydrogen.

[0530] In certain embodiments, the R 16 Each occurrence is independently selected from hydrogen, deuterium and halogen.

[0531] In certain embodiments, the R 16 Each occurrence is independently selected from hydrogen and deuterium.

[0532] In certain embodiments, the R 16 Each occurrence is independently selected from hydrogen.

[0533] In certain embodiments, the R 17 Selected from hydrogen, deuterium, hydroxyl and C 1-6 alkyl.

[0534] In certain embodiments, the R 17 Selected from hydrogen, deuterium, hydroxyl and C 1-3 alkyl.

[0535] In certain embodiments, the R 17 is selected from the group consisting of hydrogen, hydroxy and methyl.

[0536] In certain embodiments, the R 18 Selected from hydrogen, deuterium, amino, C 1-6Alkyl-substituted amino, hydroxy, C substituted by hydroxy, amino or 3-7 membered heterocycloalkyl 1-6 Alkyl, C substituted by hydroxy 1-6 Alkoxy, 3-7 membered heterocycloalkyl and -SO 2 -R 5a The group composed of.

[0537] In certain embodiments, the R 18 Selected from amino, C 1-3 Alkyl-substituted amino, hydroxy, C substituted by hydroxy, amino 1-3 Alkyl, C substituted by hydroxy 1-3 Alkoxy, 5-6 membered heterocycloalkyl and -SO 2 -R 5a The 5-6 membered heterocycloalkyl group contains 1-2 heteroatoms selected from N and O.

[0538] In certain embodiments, the R 18 Selected from amino, hydroxymethyl, aminomethyl, methylamino, hydroxyl, -OCH 2 CH 2 -OH, morpholinyl and -SO 2 -R 5a The group composed of.

[0539] In certain embodiments, the R 17 , R 18 and the carbon atoms to which they are commonly connected form a substituted or unsubstituted 3-4 membered spiro ring containing 0 or 1 heteroatom selected from N, O and S.

[0540] In certain embodiments, the 3-4 membered spiro ring is selected from oxetanyl, thietanyl, and cyclobutyl.

[0541] In certain embodiments, the substitution is with at least one substituent selected from oxo, amino, and hydroxy.

[0542] In certain embodiments, the substitution is with a substituent selected from oxo and amino.

[0543] In certain embodiments, the R 5a Selected from hydrogen, amino and C 1-6 alkyl.

[0544] In certain embodiments, the R 5a Selected from hydrogen, amino and C 1-3 alkyl.

[0545] In certain embodiments, the R 5a is selected from hydrogen, amino and methyl.

[0546] In certain embodiments, the R i Selected from halogen, C 1-6 Alkyl, C 1-3 Alkoxy.

[0547] In certain embodiments, the R i Selected from halogen.

[0548] In certain embodiments, the present disclosure further provides a compound of formula I or a stereoisomer, solvate, hydrate, prodrug, stable isotope derivative, and pharmaceutically acceptable salt thereof, characterized in that the compound has the structure of formula I-2-1-1:

[0549]

[0550] in,

[0551] X 7 Selected from CR 6 and N;

[0552] R 1 Selected from C 1-6 Alkyl and C 3-7 Cycloalkyl;

[0553] R 2 and R 2’ are each independently selected from hydrogen, deuterium, halogen, C 1-6 Alkyl, C substituted by at least one halogen 1-6 Alkyl and C 3-7 Cycloalkyl;

[0554] R 3 Selected from halogen, C 1-6 Alkyl, C substituted by at least one halogen 1-6 Alkyl, C 3-7 Cycloalkyl and C 1-6 Alkoxy;

[0555] R 4 Selected from halogen, hydroxyl, cyano, C 1-6 Alkyl, C substituted by at least one halogen 1-6 Alkyl and C 1-6 Alkoxy, C 3-7 Cycloalkyl, hydroxyl, C 1-6 Alkoxy or C 3-7 Cycloalkyl substituted C 1-6 Alkyl, 3-7 membered heterocycloalkyl, C 6-10 Aryl and 5-10 membered heteroaryl;

[0556] R 6 Each occurrence is independently selected from hydrogen, deuterium, hydroxyl, cyano, halogen, C 1-6 Alkyl, C1-6 Alkoxy and C substituted by at least one halogen 1-6 alkyl;

[0557] R i Selected from hydrogen, halogen, C 1-3 Alkyl, C substituted by at least one halogen 1-6 Alkyl, C 3-7 Cycloalkyl and C 1-6 Alkoxy;

[0558] o is an integer selected from 0, 1, 2, 3, 4;

[0559] R 16 and R 17 Each occurrence is independently selected from hydrogen, deuterium, C 1-6 Alkyl, hydroxyl, halogen, C 1-6 Alkoxy and hydroxy-C 1-6 alkyl;

[0560] R 18 Selected from hydrogen, deuterium, halogen, hydroxyl, cyano, C 1-6 Alkyl, C substituted by hydroxy, amino or 3-7 membered heterocycloalkyl 1-6 Alkyl, C 1-6 Alkoxy, C substituted by hydroxy 1-6 Alkoxy, -(CO)-OH, -(CO)-NR 7 R 8 、-(CO)-NR 7 -SO 2 -R 8 、-NR 7 R 8 、-NR 7 -(CO)-C 1-6 Alkyl, -NR 7 -(CO)-C 3-7 Cycloalkyl, -NR 7 -(CO)-OR 8 、-NR 7 -(CO)-NR 7 R 8 、-NR 7 -SO 2 -R 8 、-NR 7 -SO 2 -NR 7 R 8 、-SO 2 -NR 7 R 8 、-SO 2 -NR 7 -(CO)-R 8, C 3-7 Cycloalkyl, 3-7 membered heterocycloalkyl, -S(O)(NR 7 )-R 5a and-SO 2 -R 5a The group consisting of R 5a Selected from hydrogen, amino, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, C 1-6 Alkyl-C 3-7 Cycloalkyl and 3-7 membered heterocycloalkyl; or

[0561] R 17 , R 18 and the carbon atoms connected together form a substituted or unsubstituted 3-5 membered spiro ring, wherein the 3-5 membered spiro ring contains 0 or 1 heteroatom selected from N, O and S, and the substitution is by at least one selected from oxo, amino, hydroxyl and C 1-6 substituted by an alkyl substituent;

[0562] Among them, R 7 and R 8 are each independently selected from hydrogen, deuterium, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, Hydroxyl-C 1-6 Alkyl, C substituted by at least one halogen 1-6 Alkyl, C 3-7 Cycloalkyl, C 1-6 Alkyl-C 3-7 Cycloalkyl, hydroxy or cyano substituted C 3-7 Cycloalkyl.

[0563] In certain embodiments, the R 1 Selected from C 1-3 Alkyl and C 3-6 Cycloalkyl.

[0564] In certain embodiments, the R 1 Selected from methyl, ethyl, propyl, isopropyl.

[0565] In certain embodiments, the R 1 Selected from methyl.

[0566] In certain embodiments, the R 2 Selected from hydrogen, deuterium, halogen, C 1-3 Alkyl, C substituted by at least one halogen 1-3 alkyl.

[0567] In certain embodiments, the R 2 Selected from hydrogen, deuterium, halogen, C 1-3 alkyl.

[0568] In certain embodiments, the R 2 Selected from hydrogen, fluorine, chlorine, methyl, ethyl, propyl, isopropyl.

[0569] In certain embodiments, the R 2 Selected from hydrogen and fluorine.

[0570] In certain embodiments, the R 2’ Selected from hydrogen, deuterium, halogen, C 1-3 Alkyl, C substituted by at least one halogen 1-3 alkyl.

[0571] In certain embodiments, the R 2’ Selected from hydrogen, deuterium, halogen, C 1-3 alkyl.

[0572] In certain embodiments, the R 2’ Selected from hydrogen, fluorine, chlorine, methyl, ethyl, propyl, isopropyl.

[0573] In certain embodiments, the R 2’ Selected from hydrogen and fluorine.

[0574] In certain embodiments, the R 3 Selected from halogen, C 1-3 alkyl.

[0575] In certain embodiments, the R 3 Selected from fluorine, chlorine, methyl, ethyl, propyl, isopropyl.

[0576] In certain embodiments, the R 3 Selected from fluorine.

[0577] In certain embodiments, the R 4 Selected from halogen, hydroxyl, cyano, C 1-6 Alkyl, C substituted by at least one halogen 1-6 Alkyl, C 3-7 Cycloalkyl and C 3-7 Cycloalkyl substituted C 1-6 alkyl.

[0578] In certain embodiments, the R 4 Selected from halogen, C 1-3 Alkyl, C 3-5 Cycloalkyl and C 3-5 Cycloalkyl substituted C 1-6 alkyl.

[0579] In certain embodiments, the R 4 is selected from methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl and -CH2 -cyclopropyl.

[0580] In certain embodiments, the R 6 Selected from hydrogen, deuterium, hydroxyl, cyano, halogen.

[0581] In certain embodiments, the R 6 Selected from hydrogen, deuterium and halogen.

[0582] In certain embodiments, the R 6 Selected from hydrogen.

[0583] In certain embodiments, the R 16 Each occurrence is independently selected from hydrogen, deuterium and halogen.

[0584] In certain embodiments, the R 16 Each occurrence is independently selected from hydrogen and deuterium.

[0585] In certain embodiments, the R 16 Each occurrence is independently selected from hydrogen.

[0586] In certain embodiments, the R 17 Selected from hydrogen, deuterium, hydroxyl and C 1-6 alkyl.

[0587] In certain embodiments, the R 17 Selected from hydrogen, deuterium, hydroxyl and C 1-3 alkyl.

[0588] In certain embodiments, the R 17 is selected from the group consisting of hydrogen, hydroxy and methyl.

[0589] In certain embodiments, the R 18 Selected from hydrogen, deuterium, amino, C 1-6 Alkyl-substituted amino, hydroxy, C substituted by hydroxy, amino or 3-7 membered heterocycloalkyl 1-6 Alkyl, C substituted by hydroxy 1-6 Alkoxy, 3-7 membered heterocycloalkyl and -SO 2 -R 5a The group composed of.

[0590] In certain embodiments, the R 18 Selected from amino, C 1-3 Alkyl-substituted amino, hydroxy, C substituted by hydroxy, amino 1-3 Alkyl, C substituted by hydroxy 1-3 Alkoxy, 5-6 membered heterocycloalkyl and -SO 2 -R 5a The 5-6 membered heterocycloalkyl group contains 1-2 heteroatoms selected from N and O.

[0591] In certain embodiments, the R 18 Selected from amino, hydroxymethyl, aminomethyl, methylamino, hydroxyl, -OCH 2 CH 2 -OH, morpholinyl and -SO 2 -R 5a The group composed of.

[0592] In certain embodiments, the R 17 , R 18 and the carbon atoms to which they are commonly connected form a substituted or unsubstituted 3-4 membered spiro ring containing 0 or 1 heteroatom selected from N, O and S.

[0593] In certain embodiments, the 3-4 membered spiro ring is selected from oxetanyl, thietanyl, and cyclobutyl.

[0594] In certain embodiments, the substitution is with at least one substituent selected from oxo, amino, and hydroxy.

[0595] In certain embodiments, the substitution is with a substituent selected from oxo and amino.

[0596] In certain embodiments, the R 5a Selected from hydrogen, amino and C 1-6 alkyl.

[0597] In certain embodiments, the R 5a Selected from hydrogen, amino and C 1-3 alkyl.

[0598] In certain embodiments, the R 5a is selected from hydrogen, amino and methyl.

[0599] In certain embodiments, the R i Selected from halogen, C 1-6 Alkyl, C 1-3 Alkoxy.

[0600] In certain embodiments, the R i Selected from halogen.

[0601] In certain embodiments, the present disclosure provides a compound of formula I or its stereoisomers, solvates, hydrates, prodrugs, stable isotope derivatives and pharmaceutically acceptable salts, characterized in that the compound has the structure of formula I-2-1-1-1:

[0602]

[0603] in,

[0604] X 7 Selected from CR 6 and N;

[0605] R 1 Selected from C 1-6 Alkyl and C 3-7 Cycloalkyl;

[0606] R 2 and R 2’ are each independently selected from hydrogen, deuterium, halogen, C 1-6 Alkyl, C substituted by at least one halogen 1-6 Alkyl and C 3-7 Cycloalkyl;

[0607] R 3 Selected from halogen, C 1-6 Alkyl, C substituted by at least one halogen 1-6 Alkyl, C 3-7 Cycloalkyl and C 1-6 Alkoxy;

[0608] R 4 Selected from halogen, hydroxyl, cyano, C 1-6 Alkyl, C substituted by at least one halogen 1-6 Alkyl and C 1-6 Alkoxy, C 3-7 Cycloalkyl, hydroxyl, C 1-6 Alkoxy or C 3-7 Cycloalkyl substituted C 1-6 Alkyl, 3-7 membered heterocycloalkyl, C 6-10 Aryl and 5-10 membered heteroaryl;

[0609] R 6 Each occurrence is independently selected from hydrogen, deuterium, hydroxyl, cyano, halogen, C 1-6 Alkyl, C 1-6 Alkoxy and C substituted by at least one halogen 1-6 alkyl;

[0610] R i Selected from hydrogen, halogen, C 1-3 Alkyl, C substituted by at least one halogen 1-6 Alkyl, C 3-7 Cycloalkyl and C 1-6 Alkoxy;

[0611] o is an integer selected from 0, 1, 2, 3, 4;

[0612] R 16 Each occurrence is independently selected from hydrogen, deuterium, C 1-6 Alkyl, hydroxyl, halogen, C 1-6 Alkoxy and hydroxy-C1-6 alkyl;

[0613] X 9 Selected from O, S, NH, C(R c ) 2 , S(O) and S(O) 2 ;

[0614] R c Each occurrence is independently selected from hydrogen, amino, C 1-6 Alkyl substituted amino.

[0615] In certain embodiments, the R 1 Selected from C 1-3 Alkyl and C 3-6 Cycloalkyl.

[0616] In certain embodiments, the R 1 Selected from methyl, ethyl, propyl, isopropyl.

[0617] In certain embodiments, the R 1 Selected from methyl.

[0618] In certain embodiments, the R 2 Selected from hydrogen, deuterium, halogen, C 1-3 Alkyl, C substituted by at least one halogen 1-3 alkyl.

[0619] In certain embodiments, the R 2 Selected from hydrogen, deuterium, halogen, C 1-3 alkyl.

[0620] In certain embodiments, the R 2 Selected from hydrogen, fluorine, chlorine, methyl, ethyl, propyl, isopropyl.

[0621] In certain embodiments, the R 2 Selected from hydrogen and fluorine.

[0622] In certain embodiments, the R 2’ Selected from hydrogen, deuterium, halogen, C 1-3 Alkyl, C substituted by at least one halogen 1-3 alkyl.

[0623] In certain embodiments, the R 2’ Selected from hydrogen, deuterium, halogen, C 1-3 alkyl.

[0624] In certain embodiments, the R 2’ Selected from hydrogen, fluorine, chlorine, methyl, ethyl, propyl, isopropyl.

[0625] In certain embodiments, the R 2’ Selected from hydrogen and fluorine.

[0626] In certain embodiments, the R 3 Selected from halogen, C 1-3 alkyl.

[0627] In certain embodiments, the R 3 Selected from fluorine, chlorine, methyl, ethyl, propyl, isopropyl.

[0628] In certain embodiments, the R 3 Selected from fluorine.

[0629] In certain embodiments, the R 4 Selected from halogen, hydroxyl, cyano, C 1-6 Alkyl, C substituted by at least one halogen 1-6 Alkyl, C 3-7 Cycloalkyl and C 3-7 Cycloalkyl substituted C 1-6 alkyl.

[0630] In certain embodiments, the R 4 Selected from halogen, C 1-3 Alkyl, C 3-5 Cycloalkyl and C 3-5 Cycloalkyl substituted C 1-6 alkyl.

[0631] In certain embodiments, the R 4 is selected from methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl and -CH 2 -cyclopropyl.

[0632] In certain embodiments, the R 6 Selected from hydrogen, deuterium, hydroxyl, cyano, halogen.

[0633] In certain embodiments, the R 6 Selected from hydrogen, deuterium and halogen.

[0634] In certain embodiments, the R 6 Selected from hydrogen.

[0635] In certain embodiments, the R 16 Each occurrence is independently selected from hydrogen, deuterium and halogen.

[0636] In certain embodiments, the R 16 Each occurrence is independently selected from hydrogen and deuterium.

[0637] In certain embodiments, the R 16 Each occurrence is independently selected from hydrogen.

[0638] In certain embodiments, the X 9 Selected from O, S, NH, C(R c ) 2 and S(O) 2 .

[0639] In certain embodiments, the X 9 Selected from O, C(R c ) 2 and S(O) 2 .

[0640] In certain embodiments, the R c Each occurrence is independently selected from hydrogen, amino, and methyl substituted amino.

[0641] In certain embodiments, the X 9 Selected from O, CH-NH 2 , CH-NH-methyl and S(O) 2 .

[0642] In certain embodiments, the R i Selected from halogen, C 1-6 Alkyl, C 1-3 Alkoxy.

[0643] In certain embodiments, the R i Selected from halogen.

[0644] In certain embodiments, the present disclosure provides a compound of Formula I or a stereoisomer, solvate, hydrate, prodrug, stable isotope derivative, and pharmaceutically acceptable salt thereof, characterized in that the compound has a structure of Formula I-3:

[0645]

[0646] in,

[0647] X 1 , X 2 Each independently selected from CR 6 and N;

[0648] X 6 , X 7 and X 8 Each independently selected from CR 6 and N;

[0649] R 1 Selected from C 1-6 Alkyl and C 3-7 Cycloalkyl;

[0650] R 2 and R 2’are each independently selected from hydrogen, deuterium, halogen, C 1-6 Alkyl, C substituted by at least one halogen 1-6 Alkyl and C 3-7 Cycloalkyl;

[0651] R 3 Selected from halogen, C 1-6 Alkyl, C substituted by at least one halogen 1-6 Alkyl, C 3-7 Cycloalkyl and C 1-6 Alkoxy;

[0652] R 4 Selected from halogen, hydroxyl, cyano, C 1-6 Alkyl, C substituted by at least one halogen 1-6 Alkyl and C 1-6 Alkoxy, C 3-7 Cycloalkyl, hydroxyl, C 1-6 Alkoxy or C 3-7 Cycloalkyl substituted C 1-6 Alkyl, 3-7 membered heterocycloalkyl, C 6-10 Aryl and 5-10 membered heteroaryl;

[0653] R 6 Each occurrence is independently selected from hydrogen, deuterium, hydroxyl, cyano, halogen, C 1-6 Alkyl, C 1-6 Alkoxy and C substituted by at least one halogen 1-6 alkyl;

[0654] Ring A is present or absent; when ring A is absent, t is an integer selected from 1, 2, and 3; when ring A is present, t is 1 and the ring A is selected from the following A-1 to A-4 groups:

[0655]

[0656] R i Selected from hydrogen, halogen, C 1-3 Alkyl, C substituted by at least one halogen 1-6 Alkyl, C 3-7 Cycloalkyl and C 1-6 Alkoxy;

[0657] o is an integer selected from 0, 1, 2, 3, 4;

[0658] p is an integer selected from 0, 1, 2;

[0659] q is an integer selected from 0, 1, 2, 3;

[0660] s is an integer selected from 0, 1, and 2;

[0661] R19 and R 20 Each occurrence is independently selected from hydrogen, deuterium, C 1-6 Alkyl, hydroxyl, halogen and C 1-6 Alkoxy and hydroxy-C 1-6 alkyl;

[0662] R 21 Selected from deuterium, halogen, hydroxyl, cyano, C 1-6 Alkyl, C substituted by hydroxy, amino or 3-7 membered heterocycloalkyl 1-6 Alkyl, C 1-6 Alkoxy, hydroxy substituted C 1-6 Alkoxy, -(CO)-OH, -(CO)-NR 7 R 8 、-(CO)-NR 7 -SO 2 -R 8 、-NR 7 R 8 、-NR 7 -(CO)-C 1-6 Alkyl, -NR 7 -(CO)-C 3-7 Cycloalkyl, -NR 7 -(CO)-OR 8 、-NR 7 -(CO)-NR 7 R 8 、-NR 7 -SO 2 -R 8 、-NR 7 -SO 2 -NR 7 R 8 、-SO 2 -NR 7 R 8 、-SO 2 -NR 7 -(CO)-R 8 , C 3-7 Cycloalkyl, 3-7 membered heterocycloalkyl, -S(O)(NR 7 )-R 5a and-SO 2 -R 5a The group consisting of R 5a Selected from hydrogen, amino, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, C 1-6 Alkyl-C 3-7 Cycloalkyl and 3-7 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, O and S;

[0663] Among them, R 7 and R 8 are each independently selected from hydrogen, deuterium, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, Hydroxyl-C 1-6 Alkyl, C substituted by at least one halogen 1-6 Alkyl, C 3-7 Cycloalkyl, C 1-6 Alkyl-C 3-7 Cycloalkyl, hydroxy or cyano substituted C 3-7 Cycloalkyl;

[0664] Provided that the compound of formula I is not

[0665] In certain embodiments, the R 1 Selected from C 1-3 Alkyl and C 3-6 Cycloalkyl.

[0666] In certain embodiments, the R 1 Selected from methyl, ethyl, propyl, isopropyl.

[0667] In certain embodiments, the R 1 Selected from methyl.

[0668] In certain embodiments, the R 2 Selected from hydrogen, deuterium, halogen, C 1-3 Alkyl, C substituted by at least one halogen 1-3 alkyl.

[0669] In certain embodiments, the R 2 Selected from hydrogen, deuterium, halogen, C 1-3 alkyl.

[0670] In certain embodiments, the R 2 Selected from hydrogen, fluorine, chlorine, methyl, ethyl, propyl, isopropyl.

[0671] In certain embodiments, the R 2 Selected from hydrogen and fluorine.

[0672] In certain embodiments, the R 2’ Selected from hydrogen, deuterium, halogen, C 1-3 Alkyl, C substituted by at least one halogen 1-3 alkyl.

[0673] In certain embodiments, the R 2’ Selected from hydrogen, deuterium, halogen, C 1-3 alkyl.

[0674] In certain embodiments, the R 2’ Selected from hydrogen, fluorine, chlorine, methyl, ethyl, propyl, isopropyl.

[0675] In certain embodiments, the R 2’ Selected from hydrogen and fluorine.

[0676] In certain embodiments, the R 3 Selected from halogen, C 1-3 alkyl.

[0677] In certain embodiments, the R 3 Selected from fluorine, chlorine, methyl, ethyl, propyl, isopropyl.

[0678] In certain embodiments, the R 3 Selected from fluorine.

[0679] In certain embodiments, the R 4 Selected from halogen, hydroxyl, cyano, C 1-6 Alkyl, C substituted by at least one halogen 1-6 Alkyl, C 3-7 Cycloalkyl and C 3-7 Cycloalkyl substituted C 1-6 alkyl.

[0680] In certain embodiments, the R 4 Selected from halogen, C 1-3 Alkyl, C 3-5 Cycloalkyl and C 3-5 Cycloalkyl substituted C 1-6 alkyl.

[0681] In certain embodiments, the R 4 is selected from methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl and -CH 2 -cyclopropyl.

[0682] In certain embodiments, the R 6 Selected from hydrogen, deuterium, hydroxyl, cyano, halogen.

[0683] In certain embodiments, the R 6 Selected from hydrogen, deuterium and halogen.

[0684] In certain embodiments, the R 6 Selected from hydrogen.

[0685] In certain embodiments, the R 7 Selected from hydrogen, deuterium, C 1-3 Alkyl, Hydroxyl-C 1-3 Alkyl, C substituted by at least one halogen1-3 alkyl.

[0686] In certain embodiments, the R 7 Selected from hydrogen, methyl, hydroxyethyl, difluoroethyl.

[0687] In certain embodiments, the R 8 Selected from hydrogen, deuterium, C 1-3 Alkyl, Hydroxyl-C 1-3 Alkyl, C substituted by at least one halogen 1-3 alkyl.

[0688] In certain embodiments, the R 8 Preferably selected from hydrogen, methyl, hydroxyethyl, difluoroethyl.

[0689] In certain embodiments, the R 19 Each occurrence is independently selected from hydrogen, deuterium and halogen.

[0690] In certain embodiments, the R 19 Each occurrence is independently selected from hydrogen and deuterium.

[0691] In certain embodiments, the R 19 Each occurrence is independently selected from hydrogen.

[0692] In certain embodiments, the R 20 Selected from hydrogen, deuterium and halogen.

[0693] In certain embodiments, the R 20 Selected from hydrogen and deuterium.

[0694] In certain embodiments, the R 20 Selected from hydrogen.

[0695] In certain embodiments, the R 21 Selected from deuterium, halogen, amino, hydroxyl, -(CO)-OH.

[0696] In certain embodiments, the R 21 Selected from deuterium, halogen, -(CO)-OH.

[0697] In certain embodiments, the R 21 Selected from -(CO)-OH.

[0698] In certain embodiments, the R i Selected from halogen, C 1-6 Alkyl, C 1-3 Alkoxy.

[0699] In certain embodiments, the R i Selected from halogen.

[0700] In certain embodiments, the present disclosure provides a compound of formula I or a stereoisomer, solvate, hydrate, prodrug, stable isotope derivative, and pharmaceutically acceptable salt thereof, characterized in that the compound has a structure of formula I-3-1:

[0701]

[0702] in,

[0703] X 1 , X 2 Each independently selected from CR 6 and N;

[0704] X 6 , X 7 and X 8 Each independently selected from CR 6 and N;

[0705] R 1 Selected from C 1-6 Alkyl and C 3-7 Cycloalkyl;

[0706] R 2 and R 2’ are each independently selected from hydrogen, deuterium, halogen, C 1-6 Alkyl, C substituted by at least one halogen 1-6 Alkyl and C 3-7 Cycloalkyl;

[0707] R 3 Selected from halogen, C 1-6 Alkyl, C substituted by at least one halogen 1-6 Alkyl, C 3-7 Cycloalkyl and C 1-6 Alkoxy;

[0708] R 4 Selected from halogen, hydroxyl, cyano, C 1-6 Alkyl, C substituted by at least one halogen 1-6 Alkyl and C 1-6 Alkoxy, C 3-7 Cycloalkyl, hydroxyl, C 1-6 Alkoxy or C 3-7 Cycloalkyl substituted C 1-6 Alkyl, 3-7 membered heterocycloalkyl, C 6-10 Aryl and 5-10 membered heteroaryl;

[0709] R 6 Each occurrence is independently selected from hydrogen, deuterium, hydroxyl, cyano, halogen, C 1-6 Alkyl, C 1-6Alkoxy and C substituted by at least one halogen 1-6 alkyl;

[0710] R i Selected from hydrogen, halogen, C 1-3 Alkyl, C substituted by at least one halogen 1-6 Alkyl, C 3-7 Cycloalkyl and C 1-6 Alkoxy;

[0711] o is an integer selected from 0, 1, 2, 3, 4;

[0712] R 19 and R 20 Each occurrence is independently selected from hydrogen, deuterium, C 1-6 Alkyl, hydroxyl, halogen and C 1-6 Alkoxy and hydroxy-C 1-6 alkyl;

[0713] R 21 Selected from deuterium, halogen, hydroxyl, cyano, C 1-6 Alkyl, C substituted by hydroxy, amino or 3-7 membered heterocycloalkyl 1-6 Alkyl, C 1-6 Alkoxy, hydroxy substituted C 1-6 Alkoxy, -(CO)-OH, -(CO)-NR 7 R 8 、-(CO)-NR 7 -SO 2 -R 8 、-NR 7 R 8 、-NR 7 -(CO)-C 1-6 Alkyl, -NR 7 -(CO)-C 3-7 Cycloalkyl, -NR 7 -(CO)-OR 8 、-NR 7 -(CO)-NR 7 R 8 、-NR 7 -SO 2 -R 8 、-NR 7 -SO 2 -NR 7 R 8 、-SO 2 -NR 7 R 8 、-SO 2 -NR 7 -(CO)-R 8 , C 3-7Cycloalkyl, 3-7 membered heterocycloalkyl, -S(O)(NR 7 )-R 5a and-SO 2 -R 5a The group consisting of R 5a Selected from hydrogen, amino, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, C 1-6 Alkyl-C 3-7 Cycloalkyl and 3-7 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, O and S;

[0714] Among them, R 7 and R 8 are each independently selected from hydrogen, deuterium, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, Hydroxyl-C 1-6 Alkyl, C substituted by at least one halogen 1-6 Alkyl, C 3-7 Cycloalkyl, C 1-6 Alkyl-C 3-7 Cycloalkyl, hydroxy or cyano substituted C 3-7 Cycloalkyl;

[0715] Provided that the compound of formula I is not

[0716] In certain embodiments, the R 1 Selected from C 1-3 Alkyl and C 3-6 Cycloalkyl.

[0717] In certain embodiments, the R 1 Selected from methyl, ethyl, propyl, isopropyl.

[0718] In certain embodiments, the R 1 Selected from methyl.

[0719] In certain embodiments, the R 2 Selected from hydrogen, deuterium, halogen, C 1-3 Alkyl, C substituted by at least one halogen 1-3 alkyl.

[0720] In certain embodiments, the R 2 Selected from hydrogen, deuterium, halogen, C 1-3 alkyl.

[0721] In certain embodiments, the R 2 Selected from hydrogen, fluorine, chlorine, methyl, ethyl, propyl, isopropyl.

[0722] In certain embodiments, the R 2 Selected from hydrogen and fluorine.

[0723] In certain embodiments, the R 2’ Selected from hydrogen, deuterium, halogen, C 1-3 Alkyl, C substituted by at least one halogen 1-3 alkyl.

[0724] In certain embodiments, the R 2’ Selected from hydrogen, deuterium, halogen, C 1-3 alkyl.

[0725] In certain embodiments, the R 2’ Selected from hydrogen, fluorine, chlorine, methyl, ethyl, propyl, isopropyl.

[0726] In certain embodiments, the R 2’ Selected from hydrogen and fluorine.

[0727] In certain embodiments, the R 3 Selected from halogen, C 1-3 alkyl.

[0728] In certain embodiments, the R 3 Selected from fluorine, chlorine, methyl, ethyl, propyl, isopropyl.

[0729] In certain embodiments, the R 3 Selected from fluorine.

[0730] In certain embodiments, the R 4 Selected from halogen, hydroxyl, cyano, C 1-6 Alkyl, C substituted by at least one halogen 1-6 Alkyl, C 3-7 Cycloalkyl and C 3-7 Cycloalkyl substituted C 1-6 alkyl.

[0731] In certain embodiments, the R 4 Selected from halogen, C 1-3 Alkyl, C 3-5 Cycloalkyl and C 3-5 Cycloalkyl substituted C 1-6 alkyl.

[0732] In certain embodiments, the R 4 is selected from methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl and -CH 2 -cyclopropyl.

[0733] In certain embodiments, the R 6 Selected from hydrogen, deuterium, hydroxyl, cyano, halogen.

[0734] In certain embodiments, the R 6 Selected from hydrogen, deuterium and halogen.

[0735] In certain embodiments, the R 6 Selected from hydrogen.

[0736] In certain embodiments, the R 7 Selected from hydrogen, deuterium, C 1-3 Alkyl, Hydroxyl-C 1-3 Alkyl, C substituted by at least one halogen 1-3 alkyl.

[0737] In certain embodiments, the R 7 Selected from hydrogen, methyl, hydroxyethyl, difluoroethyl.

[0738] In certain embodiments, the R 8 Selected from hydrogen, deuterium, C 1-3 Alkyl, Hydroxyl-C 1-3 Alkyl, C substituted by at least one halogen 1-3 alkyl.

[0739] In certain embodiments, the R 8 Preferably selected from hydrogen, methyl, hydroxyethyl, difluoroethyl.

[0740] In certain embodiments, the R 19 Each occurrence is independently selected from hydrogen, deuterium and halogen.

[0741] In certain embodiments, the R 19 Each occurrence is independently selected from hydrogen and deuterium.

[0742] In certain embodiments, the R 19 Each occurrence is independently selected from hydrogen.

[0743] In certain embodiments, the R 20 Selected from hydrogen, deuterium and halogen.

[0744] In certain embodiments, the R 20 Selected from hydrogen and deuterium.

[0745] In certain embodiments, the R 20 Selected from hydrogen.

[0746] In certain embodiments, the R 21 Selected from deuterium, halogen, amino, hydroxyl, -(CO)-OH.

[0747] In certain embodiments, the R 21 Selected from deuterium, halogen, -(CO)-OH.

[0748] In certain embodiments, the R 21 Selected from -(CO)-OH.

[0749] In certain embodiments, the R i Selected from halogen, C 1-6 Alkyl, C 1-3 Alkoxy.

[0750] In certain embodiments, the R i Selected from halogen.

[0751] In certain embodiments, the present disclosure provides a compound of formula I or its stereoisomers, solvates, hydrates, prodrugs, stable isotope derivatives and pharmaceutically acceptable salts, characterized in that the compound has the structure of formula I-3-1-1:

[0752]

[0753] in,

[0754] X 7 Selected from CR 6 and N;

[0755] R 1 Selected from C 1-6 Alkyl and C 3-7 Cycloalkyl;

[0756] R 2 and R 2’ are each independently selected from hydrogen, deuterium, halogen, C 1-6 Alkyl, C substituted by at least one halogen 1-6 Alkyl and C 3-7 Cycloalkyl;

[0757] R 3 Selected from halogen, C 1-6 Alkyl, C substituted by at least one halogen 1-6 Alkyl, C 3-7 Cycloalkyl and C 1-6 Alkoxy;

[0758] R 4 Selected from halogen, hydroxyl, cyano, C 1-6 Alkyl, C substituted by at least one halogen 1-6 Alkyl and C 1-6 Alkoxy, C 3-7 Cycloalkyl, hydroxyl, C 1-6 Alkoxy or C 3-7 Cycloalkyl substituted C 1-6 Alkyl, 3-7 membered heterocycloalkyl, C 6-10Aryl and 5-10 membered heteroaryl;

[0759] R 6 Each occurrence is independently selected from hydrogen, deuterium, hydroxyl, cyano, halogen, C 1-6 Alkyl, C 1-6 Alkoxy and C substituted by at least one halogen 1-6 alkyl;

[0760] R i Selected from hydrogen, halogen, C 1-3 Alkyl, C substituted by at least one halogen 1-6 Alkyl, C 3-7 Cycloalkyl and C 1-6 Alkoxy;

[0761] o is an integer selected from 0, 1, 2, 3, 4;

[0762] R 19 and R 20 Each occurrence is independently selected from hydrogen, deuterium, C 1-6 Alkyl, hydroxyl, halogen and C 1-6 Alkoxy and hydroxy-C 1-6 alkyl;

[0763] R 21 Selected from deuterium, halogen, hydroxyl, cyano, C 1-6 Alkyl, C substituted by hydroxy, amino or 3-7 membered heterocycloalkyl 1-6 Alkyl, C 1-6 Alkoxy, hydroxy substituted C 1-6 Alkoxy, -(CO)-OH, -(CO)-NR 7 R 8 、-(CO)-NR 7 -SO 2 -R 8 、-NR 7 R 8 、-NR 7 -(CO)-C 1-6 Alkyl, -NR 7 -(CO)-C 3-7 Cycloalkyl, -NR 7 -(CO)-OR 8 、-NR 7 -(CO)-NR 7 R 8 、-NR 7 -SO 2 -R 8 、-NR 7 -SO 2 -NR 7 R 8 、-SO2 -NR 7 R 8 、-SO 2 -NR 7 -(CO)-R 8 , C 3-7 Cycloalkyl, 3-7 membered heterocycloalkyl, -S(O)(NR 7 )-R 5a and-SO 2 -R 5a The group consisting of R 5a Selected from hydrogen, amino, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, C 1-6 Alkyl-C 3-7 Cycloalkyl and 3-7 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, O and S;

[0764] Among them, R 7 and R 8 are each independently selected from hydrogen, deuterium, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, Hydroxyl-C 1-6 Alkyl, C substituted by at least one halogen 1-6 Alkyl, C 3-7 Cycloalkyl, C 1-6 Alkyl-C 3-7 Cycloalkyl, hydroxy or cyano substituted C 3-7 Cycloalkyl.

[0765] In certain embodiments, the R 1 Selected from C 1-3 Alkyl and C 3-6 Cycloalkyl.

[0766] In certain embodiments, the R 1 Selected from methyl, ethyl, propyl, isopropyl.

[0767] In certain embodiments, the R 1 Selected from methyl.

[0768] In certain embodiments, the R 2 Selected from hydrogen, deuterium, halogen, C 1-3 Alkyl, C substituted by at least one halogen 1-3 alkyl.

[0769] In certain embodiments, the R 2 Selected from hydrogen, deuterium, halogen, C 1-3 alkyl.

[0770] In certain embodiments, the R2 Selected from hydrogen, fluorine, chlorine, methyl, ethyl, propyl, isopropyl.

[0771] In certain embodiments, the R 2 Selected from hydrogen and fluorine.

[0772] In certain embodiments, the R 2’ Selected from hydrogen, deuterium, halogen, C 1-3 Alkyl, C substituted by at least one halogen 1-3 alkyl.

[0773] In certain embodiments, the R 2’ Selected from hydrogen, deuterium, halogen, C 1-3 alkyl.

[0774] In certain embodiments, the R 2’ Selected from hydrogen, fluorine, chlorine, methyl, ethyl, propyl, isopropyl.

[0775] In certain embodiments, the R 2’ Selected from hydrogen and fluorine.

[0776] In certain embodiments, the R 3 Selected from halogen, C 1-3 alkyl.

[0777] In certain embodiments, the R 3 Selected from fluorine, chlorine, methyl, ethyl, propyl, isopropyl.

[0778] In certain embodiments, the R 3 Selected from fluorine.

[0779] In certain embodiments, the R 4 Selected from halogen, hydroxyl, cyano, C 1-6 Alkyl, C substituted by at least one halogen 1-6 Alkyl, C 3-7 Cycloalkyl and C 3-7 Cycloalkyl substituted C 1-6 alkyl.

[0780] In certain embodiments, the R 4 Selected from halogen, C 1-3 Alkyl, C 3-5 Cycloalkyl and C 3-5 Cycloalkyl substituted C 1-6 alkyl.

[0781] In certain embodiments, the R 4 is selected from methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl and -CH 2 -cyclopropyl.

[0782] In certain embodiments, the R 6 Selected from hydrogen, deuterium, hydroxyl, cyano, halogen.

[0783] In certain embodiments, the R 6 Selected from hydrogen, deuterium and halogen.

[0784] In certain embodiments, the R 6 Selected from hydrogen.

[0785] In certain embodiments, the R 7 Selected from hydrogen, deuterium, C 1-3 Alkyl, Hydroxyl-C 1-3 Alkyl, C substituted by at least one halogen 1-3 alkyl.

[0786] In certain embodiments, the R 7 Selected from hydrogen, methyl, hydroxyethyl, difluoroethyl.

[0787] In certain embodiments, the R 8 Selected from hydrogen, deuterium, C 1-3 Alkyl, Hydroxyl-C 1-3 Alkyl, C substituted by at least one halogen 1-3 alkyl.

[0788] In certain embodiments, the R 8 Preferably selected from hydrogen, methyl, hydroxyethyl, difluoroethyl.

[0789] In certain embodiments, the R 19 Each occurrence is independently selected from hydrogen, deuterium and halogen.

[0790] In certain embodiments, the R 19 Each occurrence is independently selected from hydrogen and deuterium.

[0791] In certain embodiments, the R 19 Each occurrence is independently selected from hydrogen.

[0792] In certain embodiments, the R 20 Selected from hydrogen, deuterium and halogen.

[0793] In certain embodiments, the R 20 Selected from hydrogen and deuterium.

[0794] In certain embodiments, the R 20 Selected from hydrogen.

[0795] In certain embodiments, the R 21 Selected from deuterium, halogen, amino, hydroxyl, -(CO)-OH.

[0796] In certain embodiments, the R 21 Selected from deuterium, halogen, -(CO)-OH.

[0797] In certain embodiments, the R 21 Selected from -(CO)-OH.

[0798] In certain embodiments, the R i Selected from halogen, C 1-6 Alkyl, C 1-3 Alkoxy.

[0799] In certain embodiments, the R i Selected from halogen.

[0800] In certain embodiments, the present disclosure provides a compound or a stereoisomer, solvate, hydrate, prodrug, stable isotope derivative, and pharmaceutically acceptable salt thereof, characterized in that the compound is any one of the following:

[0801]

[0802]

[0803]

[0804]

[0805]

[0806] In certain embodiments, the present disclosure provides a compound or a stereoisomer, solvate, hydrate, prodrug, stable isotope derivative, and pharmaceutically acceptable salt thereof, characterized in that the compound is any one of the following:

[0807]

[0808]

[0809]

[0810]

[0811]

[0812] The present disclosure also provides a method for preparing the compound of formula I, which is as follows:

[0813] Specifically X is halogen, preferably Cl, Br and I. Other groups are as defined above.

[0814] The whole process mainly includes three main reactions:

[0815] Step 1: Compound IA and compound IB undergo condensation reaction to obtain compound IC;

[0816] Step 2, preparing boronate compound ID from compound IC;

[0817] In step 3, compound ID and compound IE undergo Suzuki coupling reaction to obtain a compound of formula I.

[0818] The present disclosure also provides another method for preparing the compound of formula I, which is as follows:

[0819]

[0820] Specifically X is halogen, preferably Cl, Br and I. Other groups are as defined above.

[0821] The whole process mainly includes two main reactions:

[0822] Step 1: Compound I-A' undergoes a condensation reaction with compound IB to obtain compound I-C';

[0823] Step 2: Compound I-C' undergoes substitution or coupling reaction to obtain a compound of formula I.

[0824] The present disclosure also provides a pharmaceutical composition, comprising at least one of the aforementioned compounds or their stereoisomers, solvates, hydrates, prodrugs, stable isotope derivatives and pharmaceutically acceptable salts, and a pharmaceutically acceptable carrier, diluent or excipient.

[0825] In certain embodiments, the unit dose of the pharmaceutical composition is 0.001 mg-1000 mg.

[0826] In certain embodiments, the pharmaceutical composition contains 0.01%-99.99% of the aforementioned compound based on the total weight of the composition. In certain embodiments, the pharmaceutical composition contains 0.1%-99.9% of the aforementioned compound. In certain embodiments, the pharmaceutical composition contains 0.5%-99.5% of the aforementioned compound. In certain embodiments, the pharmaceutical composition contains 1%-99% of the aforementioned compound. In certain embodiments, the pharmaceutical composition contains 2%-98% of the aforementioned compound.

[0827] In certain embodiments, the pharmaceutical composition contains 0.01%-99.99% of a pharmaceutically acceptable carrier, diluent or excipient, based on the total weight of the composition. In certain embodiments, the pharmaceutical composition contains 0.1%-99.9% of a pharmaceutically acceptable carrier, diluent or excipient. In certain embodiments, the pharmaceutical composition contains 0.5%-99.5% of a pharmaceutically acceptable carrier, diluent or excipient. In certain embodiments, the pharmaceutical composition contains 1%-99% of a pharmaceutically acceptable carrier, diluent or excipient. In certain embodiments, the pharmaceutical composition contains 2%-98% of a pharmaceutically acceptable carrier, diluent or excipient.

[0828] All compounds involved in the present disclosure and mixtures and compositions containing the compounds of the present invention can be administered to a living body via any administration route. The administration route can be oral administration, intravenous injection, intramuscular injection, subcutaneous injection, rectal administration, vaginal administration, sublingual administration, nasal inhalation, oral inhalation, eye drops, and local or systemic transdermal administration.

[0829] All compounds involved in the present disclosure and mixtures, compositions, etc. containing the compounds of the present invention can be formulated into a single dose, which contains the active compound of the present invention and carriers, excipients, etc., and the dosage form can be tablets, capsules, injections, granules, powders, suppositories, pills, creams, pastes, gels, powders, oral solutions, inhalants, suspensions, dry suspensions, patches, lotions, etc. These dosage forms may contain ingredients commonly used in pharmaceutical preparations, such as diluents, absorbents, wetting agents, binders, disintegrants, colorants, pH adjusters, antioxidants, antibacterial agents, isotonicity adjusters, anti-adhesive agents, etc.

[0830] Suitable formulations of the above-mentioned various dosage forms are available from public sources, such as Remington: The Science and Practice of Pharmacy, 21st edition, published by Lippincott Williams & Wilkins in 2006 and Rowe, Raymond C. Handbook of Pharmaceutical Excipients, Chicago, Pharmaceutical Press in 2005. Therefore, those skilled in the art can easily prepare them.

[0831] Different dosages can be selected according to the nature and intensity of the disease suffered by different individuals, the age, gender, weight of the patient, the route of administration and other factors. The dosage of the compound of the present invention can be 0.01 to 500 mg / kg per day, preferably 1-100 mg / kg per day, and can be administered once or multiple times.

[0832] The present disclosure also provides the compounds described in the present disclosure or their stereoisomers, solvates, hydrates, prodrugs, stable isotope derivatives and pharmaceutically acceptable salts or the aforementioned compositions, which are used as drugs for preventing and / or treating RSV virus infection diseases.

[0833] The present disclosure also provides the use of the compounds described in the present disclosure or their stereoisomers, solvates, hydrates, prodrugs, stable isotope derivatives and pharmaceutically acceptable salts or the aforementioned compositions in the prevention and / or treatment of RSV virus infection diseases.

[0834] The present disclosure also provides the use of the compounds described in the present disclosure or their stereoisomers, solvates, hydrates, prodrugs, stable isotope derivatives and pharmaceutically acceptable salts or the aforementioned compositions in the preparation of drugs for preventing and / or treating RSV virus infection diseases.

[0835] The present disclosure also provides a method for preventing and / or treating RSV virus infection diseases, which comprises the following steps: administering a therapeutically effective amount of the aforementioned compound or its stereoisomers, solvates, hydrates, prodrugs, stable isotope derivatives and pharmaceutically acceptable salts, or pharmaceutical compositions to a patient in need thereof.

[0836] Terminology explanation:

[0837] Unless stated otherwise, the terms used in the specification and claims have the following meanings.

[0838] The term "C 1-6 “Alkyl”, alone or in combination, means a saturated straight or branched alkyl group containing 1 to 6, especially 1 to 4 carbon atoms, including methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 3-methyl-1-butyl, 2-methyl-1-butyl, n-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2-methyl-3-pentyl, 2,3-dimethyl-2-butyl, 3,3,-dimethyl-2-butyl, etc. Preferably, “C 1-6 "Alkyl" is any one of methyl, ethyl, isopropyl, and tert-butyl. The alkyl group may be substituted or unsubstituted. When substituted, the substituent may be substituted at any available point of attachment. The substituent is preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl, or carboxylate.

[0839] The term "C 2-6 "Alkenyl" refers to a C-carbon group containing at least one carbon-carbon double bond. 2-6 Alkyl compounds, where "C 2-6 The term "alkyl" alone or in combination denotes a saturated straight-chain or branched alkyl group containing 2 to 6, in particular 2 to 4, carbon atoms, including ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 3-methyl-1-butyl, 2-methyl-1-butyl, n-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2- The alkenyl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups, which are independently selected from one or more substituents of alkoxy, halogen, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

[0840] The term "C 3-7 "Cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituent, which means a saturated cycloalkyl group having 3 to 7, especially 3-6 carbon atoms, including cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, etc. In particular, "C 3-7 "Cycloalkyl" refers to cyclopropyl, cyclopentyl, cyclohexyl, etc.

[0841] The term "C 3-5 The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituent, which represents a saturated cycloalkyl group having 3 to 5 carbon atoms, including cyclopropyl, cyclobutyl, cyclopentyl, and the like.

[0842] The term "C 1-6 "Alkoxy" alone or in combination means a group C 1-6 Alkyl-O-, where "C 1-6 "Alkyl" means as defined above.

[0843] The term "heterocycloalkyl" refers to a saturated or partially unsaturated (containing 1 or 2 double bonds) non-aromatic cyclic group consisting of carbon atoms and heteroatoms such as nitrogen, oxygen or sulfur. This cyclic group can be a monocyclic or bicyclic group. In the present invention, the number of heteroatoms in the heterocycloalkyl is preferably 1, 2, 3 or 4, and the nitrogen, carbon or sulfur atom in the heterocycloalkyl can be optionally oxidized. The hydrogen atoms on the "heterocycloalkyl" are independently and optionally substituted by one or more substituents described in the present invention. The "heterocycloalkyl" can be linked to the parent molecule through any ring atom on the ring.

[0844] The term "3-8 membered heterocycloalkyl" refers to a monocyclic heterocycloalkyl group containing 3-8 carbon atoms and heteroatoms; for example, aziridinyl, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, piperidinyl, morpholinyl, thiomorpholinyl, tetrahydropyranyl, and 1,1-dioxothiomorpholinyl.

[0845] The term "5-6 membered heterocycloalkyl" refers to a monocyclic heterocycloalkyl group containing 5-6 carbon atoms and heteroatoms; for example, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, piperidinyl, morpholinyl, thiomorpholinyl, tetrahydropyranyl, 1,1-dioxothiomorpholinyl.

[0846] The term "aryl" refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (fused polycyclic is a ring that shares adjacent carbon atom pairs) group with a conjugated π electron system, preferably 6- to 10-membered, such as phenyl and naphthyl. The aryl ring includes an aryl ring as described above fused to a heteroaryl, heterocyclyl or cycloalkyl ring, wherein the ring connected to the parent structure is an aryl ring, and its non-limiting examples include:

[0847]

[0848] The aryl group may be substituted or unsubstituted. When substituted, it may be substituted at any available point of attachment, and the substituents are preferably independently selected from one or more substituents of halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

[0849] The term "heteroaryl" refers to a heteroaromatic system containing 1 to 4 (e.g., 1, 2, 3, and 4) heteroatoms, 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur, and nitrogen. Heteroaryl is preferably 5 to 10 yuan (e.g., 5, 6, 7, 8, 9, or 10 yuan), more preferably 5 yuan or 6 yuan, such as furanyl, thienyl, pyridyl, pyrrolyl, N-alkylpyrrolyl, pyrimidyl, pyrazinyl, pyridazinyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, etc. The heteroaryl ring includes a heteroaryl fused to an aryl, heterocyclyl, or cycloalkyl ring as described above, wherein the ring connected to the parent structure is a heteroaryl ring, and non-limiting examples thereof include:

[0850]

[0851] The heteroaryl group may be substituted or unsubstituted, and when substituted, it may be substituted at any available point of attachment, the substituents preferably being independently selected from one or more of halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

[0852] The term "amino" alone or in combination means a primary amino group (-NH 2 ), secondary amino group (-NH-) or tertiary amino group

[0853] The term "halogen" alone or in combination denotes fluorine, chlorine, bromine or iodine, in particular fluorine, chlorine or bromine.

[0854] The term "cyano", alone or in combination, refers to the group -CN.

[0855] The term "carboxy", alone or in combination, refers to the group -COOH.

[0856] The term "hydroxy", alone or in combination, refers to the group -OH.

[0857] The term "substituted" means that one or more hydrogen atoms, preferably up to 5, more preferably 1 to 3 hydrogen atoms in a group are replaced independently of one another by a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and a person skilled in the art will be able to determine (by experiment or theory) possible or impossible substitutions without undue effort. For example, an amino or hydroxyl group with free hydrogen may be unstable when combined with a carbon atom with an unsaturated (e.g. olefinic) bond.

[0858] In the chemical structures of the compounds disclosed herein, the bond No configuration is specified, i.e., the bond Can be or include both Two configurations. Key Represents a single configuration, In the chemical structures of the compounds disclosed herein, the bond The configuration is not specified, that is, it can be Z configuration or E configuration, or contain both configurations.

[0859] The term "stereoisomers" refers to compounds that have identical chemical constitution, but differ in the way the atoms or groups are arranged in space. Stereoisomers include enantiomers, diastereomers, conformational isomers (rotamers), geometric (cis / trans) isomers, atropisomers, and the like.

[0860] The term "isotopic derivative" refers to a compound whose structure differs only in the presence of one or more isotopically enriched atoms. For example, a compound having a structure disclosed herein with "deuterium" or "tritium" replacing hydrogen, or with 18 F-fluorine labeling ( 18 F isotope) instead of fluorine, or with 11 C-, 13 C-, or 14 C-enriched carbon ( 11 C-, 13 C-, or 14 C-carbon labeling; 11 C-, 13 C-, or 14 Compounds in which a carbon atom is replaced by a C-isotope) are within the scope of the present disclosure. Such compounds can be used as analytical tools or probes in, for example, biological assays, or can be used as in vivo diagnostic imaging tracers for diseases, or as tracers for pharmacodynamics, pharmacokinetics or receptor studies. The various deuterated forms of the compounds disclosed herein refer to compounds in which each available hydrogen atom connected to a carbon atom can be independently replaced by a deuterium atom. Those skilled in the art can synthesize deuterated forms of compounds with reference to relevant literature. Commercially available deuterated starting materials can be used when preparing deuterated forms of compounds, or they can be synthesized using deuterated reagents using conventional techniques, and deuterated reagents include but are not limited to deuterated borane, trideuterated borane tetrahydrofuran solution, deuterated lithium aluminum hydride, deuterated iodoethane and deuterated iodomethane, etc. Deuterated substances can generally retain activity comparable to undeuterated compounds, and when deuterated at certain specific sites, better metabolic stability can be achieved, thereby obtaining certain therapeutic advantages.

[0861] The term "pharmaceutically acceptable salt" means that the compounds of the present invention exist in the form of their pharmaceutical salts, including acid addition salts and base addition salts. Pharmaceutically acceptable salts are described in pharmaceutically salts described by SM Berge in J. Pharmaceutical Sciences (Volume 66: 1-19, 1977). In the present invention, pharmaceutically acceptable non-toxic acid addition salts refer to salts formed by the compounds of the present invention and organic or inorganic acids, including but not limited to hydrochloric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, phosphoric acid, nitric acid, perchloric acid, acetic acid, oxalic acid, maleic acid, fumaric acid, tartaric acid, benzenesulfonic acid, methanesulfonic acid, salicylic acid, succinic acid, citric acid, lactic acid, propionic acid, benzoic acid, p-toluenesulfonic acid, malic acid, etc. Pharmaceutically acceptable non-toxic base addition salts refer to salts formed by the compounds of the present invention with organic or inorganic bases, including but not limited to alkali metal salts, such as lithium, sodium or potassium salts; alkaline earth metal salts, such as calcium or magnesium salts; organic base salts, such as ammonium salts or N-containing organic bases. + (C 1-6 alkyl)4 Salt.

[0862] The term "solvate" refers to a physical association of a compound of the present disclosure with one or more, preferably 1-3, solvent molecules, whether organic or inorganic. The physical association includes hydrogen bonding. In some cases, for example, when one or more, preferably 1-3, solvent molecules are incorporated into the crystal lattice of a crystalline solid, the solvate will be isolated. Exemplary solvates include, but are not limited to, hydrates, ethanolates, methanolates, and isopropanolates. Solvation methods are well known in the art.

[0863] The term "hydrate" refers to the case where the solvent in the above-mentioned term "solvate" is water.

[0864] The term "prodrug" refers to a compound that can be transformed in vivo under physiological conditions, for example by hydrolysis in the blood, to yield the active prodrug.

[0865] The term "pharmaceutical composition" refers to a mixture containing one or more compounds described herein or their physiologically / pharmaceutically acceptable salts or prodrugs and other chemical components, as well as other components such as physiologically / pharmaceutically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration to an organism, facilitate the absorption of the active ingredient, and thus exert biological activity.

[0866] The terms involved in the present invention are defined above. Those skilled in the art can also understand the above terms in combination with the prior art. The following is a further description based on the content of the present invention and the definitions of the terms.

[0867] The preparation of the compounds and pharmaceutically acceptable salts described in the present disclosure is further described below in conjunction with examples, but these examples are not intended to limit the scope of the present disclosure.

[0868] The experimental methods in the examples of this disclosure that do not specify specific conditions are usually carried out under conventional conditions or under conditions recommended by raw material or product manufacturers. Reagents that do not specify specific sources are conventional reagents purchased from the market.

[0869] The abbreviations used in the present invention are as follows:

[0870] (BPin) 2 :Pinacol borate

[0871] CDCl 3 : Deuterated chloroform

[0872] Dioxane: 1,4-dioxane

[0873] CO 2 :carbon dioxide

[0874] conc.H 2SO 4 :Concentrated sulfuric acid

[0875] DCM: dichloromethane

[0876] DIEA: N,N-diisopropylethylamine

[0877] DME: Ethylene glycol dimethyl ether

[0878] DMF: N,N-dimethylformamide

[0879] DMSO: dimethyl sulfoxide

[0880] DMSO-d 6 : Deuterated dimethyl sulfoxide

[0881] EtOH: ethanol

[0882] EtONa: Sodium ethoxide

[0883] FeCl 3 :Ferric chloride

[0884] g: grams

[0885] HATU: 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate

[0886] HCOOH: Formic acid

[0887] Hz:Hertz

[0888] h: hours

[0889] IC 50 : Half maximal inhibitory concentration

[0890] MeOH: Methanol

[0891] mg: milligram

[0892] mL: milliliters

[0893] mmol: millimole

[0894] MHz: Megahertz

[0895] NaBH 3 CN: Sodium cyanoborohydride

[0896] NaOH: Sodium hydroxide

[0897] NH 4 OAc: Ammonium acetate

[0898] NMR: Nuclear Magnetic Resonance

[0899] M: molar concentration

[0900] Oxalyl chloride:

[0901] PBS: Phosphate buffered saline

[0902] PdCl 2 (dppf): [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride

[0903] TCQ: Tetrachlorobenzoquinone

[0904] TFA: trifluoroacetic acid

[0905] THF: Tetrahydrofuran

[0906] TLC: Thin layer chromatography

[0907] TxD 2 :4-Toluenesulfonylhydrazide

[0908] μM: micromoles / liter

[0909] μg: microgram

[0910] μL: microliter

[0911] δ: Chemical shift

[0912] rt: room temperature

[0913] XantPhos:4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene

[0914] X-phos-Pd G2: Chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) 2

[0915] The following describes the general test conditions in the embodiments of the present invention:

[0916] First, the reactions in the examples are generally carried out under nitrogen protection.

[0917] Furthermore, the intermediates and final products were separated and purified by chromatographic columns, preparative chromatographic plates and ISCO rapid preparative chromatographic system. The chromatographic columns were filled with silica gel, the silica gel (300-400 mesh) was produced by Shanghai Titan Technology Co., Ltd., the preparative chromatographic plates were produced by Yantai Jiangyou Silica Gel Development Co., Ltd., and the chromatographic columns used by ISCO (particle size 40-63 μm, ) is produced by Changzhou Santai Technology Co., Ltd.

[0918] Furthermore, the LC-MS liquid chromatography-mass spectrometry instrument used was Waters ACQUITYArc equipped with QDa Detector. A Waters XBridge C18 chromatographic column (specifications 2.1×50 mm, 3.5 μm) was used. The mass spectrometry (MS) used an ESI source and only indicated the molecular weight M of the parent molecule, usually reporting [M+H] + The injection volume was determined by the sample concentration; the flow rate was 1.2 mL / min; the HPLC peak was recorded and read at UV-Vis wavelengths of 220 nm and 254 nm. The mobile phases were 0.01% formic acid in ultrapure water (mobile phase A) and 0.01% formic acid in acetonitrile (mobile phase B). The gradient elution conditions are shown in Tables 1 and 2 below:

[0919] Table 1: Gradient elution conditions 1

[0920]

[0921]

[0922] Table 2: Gradient elution conditions 2

[0923] Time (min) <![CDATA[A(H 2 O,0.01%HCOOH)]]> <![CDATA[B(CH 3 CN,0.01%HCOOH)]]> 0.00-5.90 95-5 5-95 5.90-5.91 5-95 95-5 5.91-6.00 95 5

[0924] Furthermore, the NMR spectrum was Varian 400MHz NMR Spectrometer Obtain data, usually in CDCl 3 , DMSO-d 6 Chemical shifts are reported in ppm as solvent. The various peaks are described as follows: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), dd (doublet of doublets). Coupling constants are expressed in Hz.

[0925] Example 1: Preparation of Intermediate A ((R)-(2-bromo-7-(2-methyl-2H-1,2,3-triazol-4-yl)pyrazolo[1,5-a]pyrimidin-5-yl)(1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone

[0926]

[0927] Step 1: Preparation of 2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-12,3-triazole (A-1)

[0928]

[0929] In a nitrogen atmosphere, 1,1'-bis(diphenylphosphinoferrocene)palladium dichloride (11.3 g, 15.4 mmol) was added to a solution of 4-bromo-2-methyl-2H-1,2,3-triazole (25 g, 154.3 mmol), biboronic acid pinacol ester (47 g, 185.2 mmol) and potassium acetate (45.4 g, 463.0 mmol) in 1,4-dioxane (375 mL). The mixture was heated to 85°C and stirred for 8 hours. After cooling, it was directly used in the next step.

[0930] Step 2: Preparation of methyl 2-bromo-7-(2-methyl-2H-1,2,3-triazol-4-yl)pyrazolo[1,5-a]pyrimidine-5-carboxylate (A-3)

[0931]

[0932] Under nitrogen atmosphere, 2-bromo-7-chloropyrazolo[1,5-a]pyrimidine-5-carboxylic acid methyl ester (24 g, 82.6 mmol), 1,1'-bis(diphenylphosphinoferrocene)palladium dichloride (Pd(dppf)Cl) were added to a solution of 2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-12,3-triazole (33.2 g, 154.3 mmol) in 1,4-dioxane (375 mL). 2 (6.1 g, 8.3 mmol), potassium phosphate (52.6 g, 247.8 mmol) and water (50 mL). The mixture was heated to 80 ° C and stirred for 40 minutes. After cooling, the mixture was diluted with dichloromethane (300 mL), filtered, and concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography to obtain a yellow solid 2-bromo-7-(2-methyl-2H-1,2,3-triazol-4-yl)pyrazolo[1,5-a]pyrimidine-5-carboxylic acid methyl ester (A-3, 13 g).

[0933] Step 3: Preparation of 2-bromo-7-(2-methyl-2H-1,2,3-triazol-4-yl)pyrazolo[1,5-a.]pyrimidine-5-carboxylic acid (A-4)

[0934]

[0935] To a solution of methyl 2-bromo-7-(2-methyl-2H-1,2,3-triazol-4-yl)pyrazolo[1,5-a]pyrimidine-5-carboxylate (13 g, 38.6 mmol) in methanol (40 mL), tetrahydrofuran (40 mL) and water (40 mL) was added lithium hydroxide (8.1 g, 192.8 mmol), and the mixture was stirred at 25°C for 3 hours. The pH was adjusted to 2-3 with 1 M hydrochloric acid, and the precipitate was filtered out and dried to give a yellow solid 2-bromo-7-(2-methyl-2H-1,2,3-triazol-4-yl)pyrazolo[1,5-a]pyrimidine-5-carboxylic acid (A-4, 7.9 g).

[0936] Step 4: Preparation of (R)-(2-bromo-7-(2-methyl-2H-1,2,3-triazol-4-yl)pyrazolo[1,5-a]pyrimidin-5-yl)(1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone (A-5)

[0937]

[0938] To a solution of 2-bromo-7-(2-methyl-2H-1,2,3-triazol-4-yl)pyrazolo[1,5-a]pyrimidine-5-carboxylic acid (7.9 g, 24.5 mmol) in N,N-dimethylformamide (50 mL) was added (R)-1-methyl-1,2,3,4-tetrahydroisoquinoline hydrochloride (5.4 g, 29.3 mmol), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate HATU (14.0 g, 36.7 mmol) and N,N-diisopropylethylamine (9.5 g, 73.4 mmol). The mixture was stirred at 25° C. for 4 hours. The reaction solution was added with water (50 mL), and the precipitate was filtered out to obtain a crude product. The crude product was purified by column chromatography to obtain a yellow solid (R)-(2-bromo-7-(2-methyl-2H-1,2,3-triazol-4-yl)pyrazolo[1,5-a]pyrimidin-5-yl)(1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone (Intermediate A, 10.6 g).

[0939] Example 2: Preparation of (2-(2-fluoro-4-((S)-3-(methylsulfonyl)pyrrolidin-1-yl)phenyl)-7-(2-methyl-2H-1,2,3-triazol-4-yl)pyrazolo[1,5-a]pyrimidin-5-yl)((R)-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone (Compound 1)

[0940]

[0941] Step 1: Preparation of (S)-1-(4-chloro-3-fluorophenyl)-3-(methylsulfonyl)pyrrolidine (Compound 1-2)

[0942]

[0943] In a nitrogen atmosphere, palladium acetate (614 mg, 2.7 mmol) and XantPhos (1.6 g, 2.7 mmol) were added to (S)-3-(methylsulfonyl)pyrrolidine hydrochloride (5.1 g, 27.47 mmol), 4-bromo-1-chloro-2-fluorobenzene (8.6 g, 41.2 mmol) and cesium carbonate (26.8 g, 82.4 mmol) in 1,4-dioxane (100 mL). The reaction mixture was stirred at 100 ° C for 5 hours. The reaction solution was cooled, pure water (50 mL) was added to quench the reaction, and extracted with ethyl acetate (100 mL × 3). The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by flash column chromatography to obtain a white solid (S)-1-(4-chloro-3-fluorophenyl)-3-(methylsulfonyl)pyrrolidine (Compound 1-2, 7.1 g).

[0944] Step 2: Preparation of (R)-(7-(2-methyl-2H-1,2,3-triazol-4-yl)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a]pyrimidin-5-yl)(1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone (Compound 1-3)

[0945]

[0946] Under nitrogen atmosphere, to a solution (5 mL) of (R)-(2-bromo-7-(2-methyl-2H-1,2,3-triazol-4-yl)pyrazolo[1,5-a]pyrimidin-5-yl)(1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone (150 mg, 0.33 mmol), biboronic acid pinacol ester (127 mg, 0.50 mmol), potassium acetate (66 mg, 0.66 mmol) in 1,4-dioxane was added [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (25 mg, 0.03 mmol). The mixture was heated to 100° C. and stirred for 6 hours. After cooling, the mixture was diluted with ethyl acetate (20 mL), washed with water (50 mL) and saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a brown solid (R)-(7-(2-methyl-2H-1,2,3-triazol-4-yl)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a]pyrimidin-5-yl)(1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone (Compound 1-3, 150 mg).

[0947] Step 3: Preparation of (2-(2-fluoro-4-((S)-3-(methylsulfonyl)pyrrolidin-1-yl)phenyl)-7-(2-methyl-2H-1,2,3-triazol-4-yl)pyrazolo[1,5-a]pyrimidin-5-yl)((R)-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone (Compound 1)

[0948]

[0949] Under nitrogen atmosphere, to a solution of (R)-(7-(2-methyl-2H-1,2,3-triazol-4-yl)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a]pyrimidin-5-yl)(1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone (150 mg, 0.30 mmol), (S)-1-(4-chloro-3-fluorophenyl)-3-(methylsulfonyl)pyrrolidine (92 mg, 0.33 mmol), sodium carbonate (96 mg, 0.91 mmol) in 1,4-dioxane (5 mL) was added chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) 2(24 mg, 0.03 mmol) and water (1 mL). The mixture was heated to 100 ° C and stirred for 3 hours. After cooling, the mixture was diluted with ethyl acetate (100 mL), filtered through diatomaceous earth, and the filtrate was washed with saturated brine (50 mL), then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography to prepare a yellow solid (2-(2-fluoro-4-((S)-3-(methylsulfonyl)pyrrolidin-1-yl)phenyl)-7-(2-methyl-2H-1,2,3-triazol-4-yl)pyrazolo[1,5-a]pyrimidin-5-yl)((R)-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone (Compound 1, 50 mg).

[0950] 1 H NMR (400 MHz, DMSO-d 6 )δ9.14-9.11(m,1H),8.22-8.17(m,1H),7.70-7.64(m,1H),7.36-7.25(m,1H) ,7.22-7.09(m,4H),6.66-6.58(m,2H),5.65-5.60(m,1H),4.61-4.57(m,1H), 4.39-4.35(m,3H),4.19-4.11(m,1H),3.73(d,J=6.4Hz,2H),3.57-3.40(m,3H ),3.11-3.09(m,3H),3.09-2.85(m,2H),2.46-2.41(m,2H),1.60-1.54(m,3H).

[0951] MS measured value (ESI + )(M+H) + :615.32.

[0952] Example 3: Preparation of (R)-(2-(2-fluoro-4-(3-hydroxyazetidin-1-yl)phenyl)-7-(2-methyl-2H-1,2,3-triazol-4-yl)pyrazolo[1,5-a]pyrimidin-5-yl)(2-methylazepan-1-yl)methanone (Compound 2)

[0953]

[0954] Step 1: Preparation of (R)-(2-bromo-7-(2-methyl-2H-1,2,3-triazol-4-yl)pyrazolo[1,5-a]pyrimidin-5-yl)(2-methylazepan-1-yl)ketone (Compound 2-1)

[0955]

[0956] 2-Bromo-7-(2-methyl-2H-1,2,3-triazol-4-yl)pyrazolo[1,5-a]pyrimidine-5-carboxylic acid (150 mg, 0.47 mmol) was dissolved in N,N-dimethylformamide (5 mL), (R)-2-methylazepane (77 mg, 0.51 mmol), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (265 mg, 0.70 mmol) and N,N-diisopropylethylamine (180 mg, 1.39 mmol) were added, and the mixture was stirred at 25° C. for 4 hours. The reaction solution was added with water (10 mL), the precipitate was filtered out to obtain a crude product, and the crude product was purified by column chromatography to prepare a yellow solid (R)-(2-bromo-7-(2-methyl-2H-1,2,3-triazol-4-yl)pyrazolo[1,5-a]pyrimidin-5-yl)(2-methylazacycloheptane-1-yl)ketone (Compound 2-1, 150 mg).

[0957] Step 2: Preparation of 1-(4-chloro-3-fluorophenyl)azetidin-3-ol (Compound 2-2)

[0958]

[0959] In a nitrogen atmosphere, palladium acetate (307 mg, 1.37 mmol) and XantPhos (793 mg, 1.37 mmol) were added to azetidine-3-ol (1.0 g, 13.7 mmol), 4-bromo-1-chloro-2-fluorobenzene (4.3 g, 20.5 mmol) and cesium carbonate (13.4 g, 41.0 mmol) in 1,4-dioxane (20 mL). The reaction mixture was stirred at 100 ° C for 5 hours. The reaction solution was cooled, pure water (50 mL) was added to quench the reaction, and extracted with ethyl acetate (100 mL × 3). The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by flash column chromatography to obtain a brown solid 1-(4-chloro-3-fluorophenyl)azetidine-3-ol (compound 2-2, 1.1 g).

[0960] Step 3: Preparation of (R)-(7-(2-methyl-2H-1,2,3-triazol-4-yl)-2-(4,4,5,5-tetramethyl-1,3,2-dioxolan-2-yl)pyrazolo[1,5-a]pyrimidin-5-yl)(2-methylazepane 1-yl)methanone (Compound 2-3)

[0961]

[0962] In a nitrogen atmosphere, [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (26 mg, 0.04 mmol) was added to a 1,4-dioxane solution (5 mL) of (R)-(2-bromo-7-(2-methyl-2H-1,2,3-triazol-4-yl)pyrazolo[1,5-a]pyrimidin-5-yl)(2-methylazacyclopentane-1-yl)ketone (150 mg, 0.36 mmol), biboronic acid pinacol ester (137 mg, 0.54 mmol), and potassium acetate (71 mg, 0.72 mmol). The mixture was heated to 100° C. and stirred for 6 hours. After cooling, the mixture was diluted with ethyl acetate (20 mL), washed with water (50 mL) and saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a brown solid (R)-(7-(2-methyl-2H-1,2,3-triazol-4-yl)-2-(4,4,5,5-tetramethyl-1,3,2-dioxolan-2-yl)pyrazolo[1,5-a]pyrimidin-5-yl)(2-methylazepan-1-yl)methanone (Compound 2-3, 150 mg).

[0963] Step 4: Preparation of (R)-(2-(2-fluoro-4-(3-hydroxyazetidin-1-yl)phenyl)-7-(2-methyl-2H-1,2,3-triazol-4-yl)pyrazolo[1,5-a]pyrimidin-5-yl)(2-methylazepan-1-yl)methanone (Compound 2)

[0964]

[0965] To a solution of ((R)-(7-(2-methyl-2H-1,2,3-triazol-4-yl)-2-(4,4,5,5-tetramethyl-1,3,2-dioxolan-2-yl)pyrazolo[1,5-a]pyrimidin-5-yl)(2-methylazepan-1-yl)methanone (150 mg, 0.33 mmol), 1-(4-chloro-3-fluorophenyl)azetidin-3-ol (72 mg, 0.36 mmol) and sodium carbonate (103 mg, 0.97 mmol) in 1,4-dioxane (5 mL) was added chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) under nitrogen atmosphere. 2(26 mg, 0.03 mmol) and water (1 mL). The mixture was heated to 100 ° C and stirred for 3 hours. After cooling, the mixture was diluted with ethyl acetate (30 mL), filtered through diatomaceous earth, the filtrate was washed with saturated brine (50 mL), then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography to obtain a yellow solid (R)-(2-(2-fluoro-4-(3-hydroxyazetidine-1-yl)phenyl)-7-(2-methyl-2H-1,2,3-triazol-4-yl)pyrazolo[1,5-a]pyrimidin-5-yl)(2-methylazepan-1-yl)methanone (Compound 2, 53 mg).

[0966] 1 H NMR (400 MHz, DMSO-d 6 )δ9.09(s,1H),8.13(t,J=8.8Hz,1H),7.60-7.55(m,1H),7.08-7.06(m,1H),6.43- 6.35(m,2H),5.72(d,J=6.4Hz,1H),4.65-4.58(m,1H),4.58-4.21(m,4H),4.20-4.1 3(m,2H),4.11-3.91(m,1H),3.88-3.78(m,1H),3.69-3.62(m,2H),3.19-3.06(m,1 H),2.94(t,J=12.4Hz,1H),2.11-1.69(m,4H),1.57-1.19(m,4H),1.17-1.14(m,3H)

[0967] MS measured value (ESI + )(M+H) + :505.27

[0968] Example 4: Preparation of (R)-(2-(2-fluoro-4-(3-hydroxyazetidin-1-yl)phenyl)-7-(2-methyl-2H-1,2,3-triazol-4-yl)pyrazolo[1,5-a]pyrimidin-5-yl)(1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone (Compound 3)

[0969]

[0970] Step 1: Preparation of (R)-(2-(2-fluoro-4-(3-hydroxyazetidin-1-yl)phenyl)-7-(2-methyl-2H-1,2,3-triazol-4-yl)pyrazolo[1,5-a]pyrimidin-5-yl)(1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone (Compound 3)

[0971]

[0972] Under nitrogen atmosphere, to a solution of (R)-(7-(2-methyl-2H-1,2,3-triazol-4-yl)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a]pyrimidin-5-yl)(1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone (150 mg, 0.30 mmol), 1-(4-chloro-3-fluorophenyl)azetidin-3-ol (67 mg, 0.33 mmol), sodium carbonate (96 mg, 0.91 mmol) in 1,4-dioxane (5 mL) was added chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) 2 (24 mg, 0.03 mmol) and water (1 mL). The mixture was heated to 100 ° C and stirred for 3 hours. After cooling, the mixture was diluted with ethyl acetate (100 mL), filtered through diatomaceous earth, the filtrate was washed with saturated brine (50 mL), then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography to obtain a yellow solid (R)-(2-(2-fluoro-4-(3-hydroxyazetidine-1-yl)phenyl)-7-(2-methyl-2H-1,2,3-triazol-4-yl)pyrazolo[1,5-a]pyrimidin-5-yl)(1-methyl-3,4-dihydroisoquinoline-2(1H)-yl)methanone (Compound 3, 23 mg).

[0973] 1 H NMR (400 MHz, DMSO-d 6 )δ9.11(d,J=4.4Hz,1H),8.18-8.13(m,1H),7.70-7.64(m,1H),7.35-7.24(m,1H),7.23-7.07(m,4H),6.44-6.37(m,2H),5.81-5.57(m,2 H),4.65-4.56(m,2H),4.39-4.34(m,3H),4.20-4.15(m,2H),3.67-3.64(m,2H),3.59-3.46(m,1H),3.10–2.77(m,2H),1.60-1.54(m,3H)

[0974] MS measured value (ESI + )(M+H) + :539.05

[0975] Example 5: Preparation of (2-(2-fluoro-4-((3R,4R)-3-fluoro-4-hydroxypyrrolidin-1-yl)phenyl)-7-(2-methyl-2H-1,2,3-triazol-4-yl)pyrazolo[1,5-a]pyrimidin-5-yl)((R)-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone (Compound 4)

[0976]

[0977] Step 1: Preparation of (3R, 4R)-1-(4-chloro-3-fluorophenyl)-4-fluoropyrrolidin-3-ol (Compound 4-1)

[0978]

[0979] In a nitrogen atmosphere, palladium acetate (307 mg, 1.37 mmol) and XantPhos (793 mg, 1.37 mmol) were added to (3R, 4R)-4-fluoropyrrolidin-3-ol hydrochloride (1.9 g, 13.7 mmol), 4-bromo-1-chloro-2-fluorobenzene (4.3 g, 20.5 mmol) and cesium carbonate (13.4 g, 41.0 mmol) in 1,4-dioxane (20 mL). The reaction mixture was stirred at 100 ° C for 5 hours. The reaction solution was cooled, pure water (50 mL) was added to quench the reaction, and extracted with ethyl acetate (100 mL × 3). The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by flash column chromatography to obtain a brown solid (3R, 4R)-1-(4-chloro-3-fluorophenyl)-4-fluoropyrrolidin-3-ol (Compound 4-1, 1.9 g).

[0980] Step 2: Preparation of (2-(2-fluoro-4-((3R,4R)-3-fluoro-4-hydroxypyrrolidin-1-yl)phenyl)-7-(2-methyl-2H-1,2,3-triazol-4-yl)pyrazolo[1,5-a]pyrimidin-5-yl)((R)-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone (Compound 4)

[0981]

[0982] Under nitrogen atmosphere, (R)-(7-(2-methyl-2H-1,2,3-triazol-4-yl)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a]pyrimidin-5-yl)(1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone (150 mg, 0.30 mmol), (3R, 4R) To a solution of 1,4-dioxane (5 mL) of 1-(4-chloro-3-fluorophenyl)-4-fluoropyrrolidin-3-ol (78 mg, 0.33 mmol) and sodium carbonate (96 mg, 0.91 mmol) was added chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) 2 (24 mg, 0.03 mmol) and water (1 mL). The mixture was heated to 100 ° C and stirred for 3 hours. After cooling, the mixture was diluted with ethyl acetate (100 mL), filtered through diatomaceous earth, the filtrate was washed with saturated brine (50 mL), then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography to obtain a yellow solid (2-(2-fluoro-4-((3R, 4R)-3-fluoro-4-hydroxypyrrolidin-1-yl)phenyl)-7-(2-methyl-2H-1,2,3-triazol-4-yl)pyrazolo[1,5-a]pyrimidin-5-yl)((R)-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone (Compound 4, 15 mg).

[0983] 1 H NMR (400 MHz, DMSO-d 6 )δ9.14-9.11(m,1H),8.22-8.17(m,1H),7.70-7.64(m,1H),7.36-7.25(m,1H ),7.22-7.09(m,4H),6.66-6.58(m,2H),5.63-5.56(m,2H)5.17-5.04(m,1H) ,4.60-4.51(m,1H),4.42-4.35(m,1H),3.87-3.67(m,1H),3.62-3.44(m,3H) ,3.32-3.21(m,1H),3.04-2.90(m,2H),2.86-2.65(m,1H),1.57-1.50(m,3H)

[0984] MS measured value (ESI + )(M+H) + :571.24

[0985] Example 6: Preparation of (2-(2-fluoro-4-((S)-3-(methylsulfonyl)pyrrolidin-1-yl)phenyl)-7-(1-methyl-1H-1,2,3-triazol-4-yl)pyrazolo[1,5-a]pyrimidin-5-yl)((R)-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone (Compound 5)

[0986]

[0987] 4-Bromo-3-methyl-2H-1,2,3-triazole (25 g, 154.3 mmol) was used in a manner similar to that of Examples 1 and 2 to prepare (2-(2-fluoro-4-((S)-3-(methylsulfonyl)pyrrolidin-1-yl)phenyl)-7-(1-methyl-1H-1,2,3-triazol-4-yl)pyrazolo[1,5-a]pyrimidin-5-yl)((R)-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone (Compound 5, 5 mg).

[0988] 1 HNMR (400 MHz, DMSO-d 6 )δ9.55-9.49(m,1H),8.40-8.32(m,1H),7.93-7.85(m,1H),7.27-7.09(m,5H),6. 69-6.61(m,2H),5.71-5.60(m,1H),4.67-4.58(m,1H),4.38-4.32(m,3H),4.22-4 .17(m,1H),4.12-4.10(m,1H),3.79-3.73(m,2H),3.63-3.49(m,2H),3.15-3.13( m,3H),3.11-3.07(m,1H),2.96-2.85(m,1H),2.49-2.43(m,2H),1.65-1.59(m,3H)

[0989] MS measured value (ESI + )[(M+H) + ]:615.36

[0990] Example 7: Preparation of (R)-(2-(4-(1,1-dioxodimoroline)-2-fluorophenyl)-7-(2-methyl-2H-1,2,3-triazol-4-yl)pyrazolo[1,5-a]pyrimidin-5-yl)(1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone (Compound 6)

[0991]

[0992] Step 1: Preparation of 4-(4-chloro-3-fluorophenyl)thiomorpholine 1,1-dioxide (Compound 6-1)

[0993]

[0994] In a nitrogen atmosphere, palladium acetate (33 mg, 0.14 mmol) and XantPhos (83 mg, 0.14 mmol) were added to 4-(4-chloro-3-fluorophenyl)thiomorpholine 1,1-dioxide (213 mg, 1.58 mmol), 4-bromo-1-chloro-2-fluorobenzene (300 mg, 1.43 mmol) and cesium carbonate (1.4 g, 4.30 mmol) in 1,4-dioxane (10 mL). The reaction mixture was stirred at 100 ° C for 5 hours. The reaction solution was cooled, pure water (330 mL) was added to quench the reaction, and extracted with ethyl acetate (100 mL × 3). The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by flash column chromatography to obtain brown solid 4-(4-chloro-3-fluorophenyl)thiomorpholine 1,1-dioxide (compound 6-1, 200 mg).

[0995] Step 2: Preparation of (R)-(2-(4-(1,1-dioxidodimorpholinyl)-2-fluorophenyl)-7-(2-methyl-2H-1,2,3-triazol-4-yl)pyrazolo[1,5-a]pyrimidin-5-yl)(1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone (Compound 6)

[0996]

[0997] Under nitrogen atmosphere, to a solution of (R)-(7-(2-methyl-2H-1,2,3-triazol-4-yl)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a]pyrimidin-5-yl)(1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone (150 mg, 0.30 mmol), 4-(4-chloro-3-fluorophenyl)thiomorpholine 1,1-dioxide (102 mg, 0.33 mmol), and sodium carbonate (96 mg, 0.91 mmol) in 1,4-dioxane (5 mL) was added chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) 2(24 mg, 0.03 mmol) and water (1 mL). The mixture was heated to 100 ° C and stirred for 3 hours. After cooling, the mixture was diluted with ethyl acetate (100 mL), filtered through diatomaceous earth, and the filtrate was washed with saturated brine (50 mL), then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography to obtain a yellow solid (R)-(2-(4-(1,1-dioxidodimorpholinyl)-2-fluorophenyl)-7-(2-methyl-2H-1,2,3-triazol-4-yl)pyrazolo[1,5-a]pyrimidin-5-yl)(1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone (Compound 6, 3 mg).

[0998] MS measured value (ESI + )(M+H) + :601.10

[0999] Example 8: Preparation of (R)-(2-(2-fluoro-4-(3-(methylsulfonyl)azetidin-1-yl)phenyl)-7-(2-methyl-2H-1,2,3-triazol-4-yl)pyrazolo[1,5-a]pyrimidin-5-yl)(1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone (Compound 7)

[1000]

[1001] Step 1: Preparation of 1-(4-chloro-3-fluorophenyl)-3-(methylsulfonyl)azetidine (Compound 7-1)

[1002]

[1003] In a nitrogen atmosphere, palladium acetate (33 mg, 0.14 mmol) and XantPhos (83 mg, 0.14 mmol) were added to 1,4-dioxane (10 mL) of 3-(methylsulfonyl)azetidine (213 mg, 1.58 mmol), 4-bromo-1-chloro-2-fluorobenzene (300 mg, 1.43 mmol) and cesium carbonate (1.4 g, 4.30 mmol). The reaction mixture was stirred at 100 ° C for 5 hours. The reaction solution was cooled, pure water (330 mL) was added to quench the reaction, and extracted with ethyl acetate (100 mL × 3). The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by flash column chromatography to obtain a brown solid 1-(4-chloro-3-fluorophenyl)-3-(methylsulfonyl)azetidine (compound 7-1, 200 mg).

[1004] Step 2: Preparation of (R)-(2-(2-fluoro-4-(3-(methylsulfonyl)azetidin-1-yl)phenyl)-7-(2-methyl-2H-1,2,3-triazol-4-yl)pyrazolo[1,5-a]pyrimidin-5-yl)(1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone (Compound 7)

[1005]

[1006] To a solution of (R)-(7-(2-methyl-2H-1,2,3-triazol-4-yl)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a]pyrimidin-5-yl)(1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone (150 mg, 0.30 mmol), 1-(4-chloro-3-fluorophenyl)-3-(methylsulfonyl)azetidine (102 mg, 0.33 mmol), and sodium carbonate (96 mg, 0.91 mmol) in 1,4-dioxane (5 mL) was added chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) under nitrogen atmosphere. 2 (24 mg, 0.03 mmol) and water (1 mL). The mixture was heated to 100 ° C and stirred for 3 hours. After cooling, the mixture was diluted with ethyl acetate (100 mL), filtered through diatomaceous earth, the filtrate was washed with saturated brine (50 mL), then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography to obtain a yellow solid (R)-(2-(2-fluoro-4-(3-(methylsulfonyl)azetidin-1-yl)phenyl)-7-(2-methyl-2H-1,2,3-triazol-4-yl)pyrazolo[1,5-a]pyrimidin-5-yl)(1-methyl-3,4-dihydroisoquinoline-2(1H)-yl)methanone (Compound 7, 16 mg).

[1007] 1 H NMR (400 MHz, DMSO-d 6)δ9.18-9.15(m,1H)8.26(t,J=8.4Hz,1H),7.75(s,1H),7.38(d,J=7.2Hz,1H),7.30-7.18(m,4H),6.59-6.51(m,2H),5.69-5.64(m,1H),4.55 -4.47(m,1H),4.44-4.38(m,3H),4.33-4.18(m,4H),3.61-3.51(m,1H) ,3.12(s,3H),3.11-2.98(m,1H),2.95-2.88(m,1H),1.67-1.55(m,3H)

[1008] MS measured value (ESI + )(M+H) + :601.17

[1009] Example 9: Preparation of (7-(2-cyclopropyl-2H-1,2,3-triazol-4-yl)-2-(2-fluoro-4-((S)-3-(methylsulfonyl)pyrrolidin-1-yl)phenyl)pyrazolo[1,5-a]pyrimidin-5-yl)((R)-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone (Compound 8)

[1010]

[1011] Step 1: Preparation of 4,5-dibromo-2-cyclopropyl-2H-1,2,3-triazole (Compound 8-4)

[1012]

[1013] To a solution of 2,2'-bipyridine (11.4 g, 52.9 mmol) in 1,2-dichloroethane (500 mL) was added copper acetate (9.6 g, 52.9 mmol), and the mixture was heated to 85°C and stirred for 2 hours. After cooling, 4,5-dibromo-2H-1,2,3-triazole (10.0 g, 44 mmol), cyclopropylboronic acid (11.4 g, 132 mmol) and sodium carbonate (9.4 g, 88.2 mmol) were added. The mixture was heated to 40°C and stirred for 4 hours. After cooling, the mixture was diluted with dichloromethane (100 mL), filtered through celite, the filtrate was washed with hydrochloric acid (50 mL, 1.5 N), then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography to obtain a colorless oily substance 4,5-dibromo-2-cyclopropyl-2H-1,2,3-triazole (compound 8-2, 7.3 g).

[1014] Step 2: Preparation of 4-bromo-2-cyclopropyl-2H-1,2,3-triazole (Compound 1-3)

[1015]

[1016] In a nitrogen atmosphere, at -20°C, isopropylmagnesium chloride (19.7mL, 39.4mmol, 2M) was added dropwise to a solution of 4,5-dibromo-2-cyclopropyl-2H-1,2,3-triazole (7g, 26.2mmol) in tetrahydrofuran (70mL), and the mixture was reacted for half an hour at -20°C, and the temperature was raised to 0°C, and the reaction was continued for 2 hours. The mixture was quenched with a saturated ammonium chloride solution (50mL). The mixture was extracted with ethyl acetate (100mL), then washed with saturated brine (50mL), then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography to obtain a colorless oily substance 4-bromo-2-cyclopropyl-2H-1,2,3-triazole (compound 8-3, 3.5g).

[1017] Step 3: Preparation of 2-cyclopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-12,3-triazole (Compound 8-4)

[1018]

[1019] In a nitrogen atmosphere, 1,1'-bis(diphenylphosphinoferrocene)palladium dichloride (1.4 g, 1.86 mmol) was added to a solution of 4-bromo-2-cyclopropyl-2H-1,2,3-triazole (3.5 g, 18.6 mmol), biboronic acid pinacol ester (7.1 g, 27.9 mmol) and potassium acetate (5.5 g, 55.8 mmol) in 1,4-dioxane (50 mL). The mixture was heated to 85°C and stirred for 5 hours. After cooling, the reaction mixture was filtered through celite, water (100 mL) was added to the filtrate, extracted with ethyl acetate (100 mL), then washed with saturated brine (100 mL), then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a black oily substance 2-cyclopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)-2H-12,3-triazole (compound 8-4, 4.3 g).

[1020] Step 4: Preparation of 2-bromo-7-(2-cyclopropyl-2H-1,2,3-triazol-4-yl)pyrazolo[1,5-a]pyrimidine-5-carboxylic acid methyl ester (Compound 8-5)

[1021]

[1022] In a nitrogen atmosphere, 2-bromo-7-chloropyrazolo[1,5-a]pyrimidine-5-carboxylic acid methyl ester (5.0 g, 17.21 mmol), 1,1'-bis(diphenylphosphinoferrocenepalladium chloride) (1.3 g, 1.7 mmol), potassium phosphate (7.3 g, 34.4 mmol) and water (10 mL) were added to a solution of 2-cyclopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-12,3-triazole (4.1 g, 17.2 mmol) in 1,4-dioxane (50 mL). The mixture was heated to 80° C. and stirred for 30 minutes. After cooling, the mixture was diluted with dichloromethane (100 mL), filtered, and concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography to obtain a brown solid 2-bromo-7-(2-cyclopropyl-2H-1,2,3-triazol-4-yl)pyrazolo[1,5-a]pyrimidine-5-carboxylic acid methyl ester (Compound 8-5, 4.5 g).

[1023] Step 5: Preparation of 2-bromo-7-(2-cyclopropyl-2H-1,2,3-triazol-4-yl)pyrazolo[1,5-a]pyrimidine-5-carboxylic acid (Compound 8-6)

[1024]

[1025] Lithium hydroxide (1.5 g, 11.0 mmol) was added to a solution of methyl 2-bromo-7-(2-cyclopropyl-2H-1,2,3-triazol-4-yl)pyrazolo[1,5-a]pyrimidine-5-carboxylate (4.5 g, 2.2 mmol) in tetrahydrofuran (30 mL), water (10 mL) and methanol (3 mL). The mixture was stirred at 25 °C for 2 hours. The reaction solution was adjusted to pH 2 with hydrochloric acid, water (30 mL) was added, and the solid was filtered and dried with an oil pump to obtain an off-white solid 2-bromo-7-(2-cyclopropyl-2H-1,2,3-triazol-4-yl)pyrazolo[1,5-a]pyrimidine-5-carboxylic acid (compound 8-6, 3.5 g).

[1026] Step 6: Preparation of (R)-(2-bromo-7-(2-cyclopropyl-2H-1,2,3-triazol-4-yl)pyrazolo[1,5-a]pyrimidin-5-yl)(1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone (Compound 8-7)

[1027]

[1028] To a solution of 2-bromo-7-(2-cyclopropyl-2H-1,2,3-triazol-4-yl)pyrazolo[1,5-a]pyrimidine-5-carboxylic acid (2.0 g, 5.7 mmol) in N,N-dimethylformamide (20 mL) were added (R)-1-methyl-1,2,3,4-tetrahydroisoquinoline hydrochloride (1.3 g, 6.9 mmol), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (3.3 g, 8.6 mmol) and N,N-diisopropylethylamine (2.3 g, 17.2 mmol). The mixture was stirred at 25° C. for 2 hours. Add water (50 mL) and filter to obtain a crude product, which was purified by column chromatography to obtain a yellow solid (R)-(2-bromo-7-(2-cyclopropyl-2H-1,2,3-triazol-4-yl)pyrazolo[1,5-a]pyrimidin-5-yl)(1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone (compound 8-7, 2.1 g).

[1029] Step 7: Preparation of (R)-(7-(2-cyclopropyl-2H-1,2,3-triazol-4-yl)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a]pyrimidin-5-yl)(1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone (Compound 8-8)

[1030]

[1031] Under nitrogen atmosphere, [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (163 mg, 0.22 mmol) was added to a solution (10 mL) of (R)-(2-bromo-7-(2-cyclopropyl-2H-1,2,3-triazol-4-yl)pyrazolo[1,5-a]pyrimidin-5-yl)(1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone (1.1 g, 2.23 mmol), biboronic acid pinacol ester (844 mg, 3.34 mmol), potassium acetate (655 mg, 6.68 mmol) in 1,4-dioxane. The mixture was heated to 100°C and stirred for 5 hours. After cooling, the mixture was diluted with ethyl acetate (100 mL), washed with water (50 mL) and saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a black solid (R)-(7-(2-cyclopropyl-2H-1,2,3-triazol-4-yl)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a]pyrimidin-5-yl)(1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone (Compound 8-8, 1.2 g).

[1032] Step 8: Preparation of (7-(2-cyclopropyl-2H-1,2,3-triazol-4-yl)-2-(2-fluoro-4-((S)-3-(methylsulfonyl)pyrrolidin-1-yl)phenyl)pyrazolo[1,5-a]pyrimidin-5-yl)((R)-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone (Compound 8)

[1033]

[1034] Under nitrogen atmosphere, (R)-(7-(2-cyclopropyl-2H-1,2,3-triazol-4-yl)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a]pyrimidin-5-yl)(1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone (190 mg, 0.36 mmol), (S)-1-(4-chloro-3-fluorophenyl)-1-yl A solution of 3-(methylsulfonyl)pyrrolidine (121 mg, 0.43 mmol) and sodium carbonate (161 mg, 0.76 mmol) in 1,4-dioxane (5 mL) was added with chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (32 mg, 0.04 mmol) and water (1 mL). The mixture was heated to 100°C and stirred for 3 hours. After cooling, the mixture was diluted with ethyl acetate (100 mL), washed with saturated brine (50 mL), then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude product, which was purified by column chromatography to give a yellow solid (7-(2-cyclopropyl-2H-1,2,3-triazol-4-yl)-2-(2-fluoro-4-((S)-3-(methylsulfonyl)pyrrolidin-1-yl)phenyl)pyrazolo[1,5-a]pyrimidin-5-yl)((R)-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone (Compound 8, 23 mg).

[1035] 1 HNMR (400 MHz, DMSO-d 6)δ9.17-9.11(m,1H),8.26-8.18(m,1H),7.76-7.66(m,1H),7.38-7.09(m,5H),6.70- 6.58(m,2H),5.69-5.61(m,1H),4.46-4.37(m,1H),4.23-4.17(m,1H),4.11-4.01(m, 1H),3.79-3.72(m,2H),3.61-3.51(m,2H),3.49-3.43(m,1H),3.13(s,3H),2.88-2.7 1(m,1H),2.46-2.38(m,2H),1.65-1.57(m,3H),1.46-1.39(m,2H),1.29-1.21(m,2H)

[1036] MS measured value (ESI + )[(M+H) + ]:641.48

[1037] Example 10: Preparation of (7-(2-cyclopropyl-2H-1,2,3-triazol-4-yl)-2-(2-fluoro-4-((S)-3-(methylsulfonyl)pyrrolidin-1-yl)phenyl)pyrazolo[1,5-a]pyrimidin-5-yl)((R)-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone (Compound 9)

[1038]

[1039] Step 1: Preparation of (S)-tert-butyl (1-(4-chloro-3-fluorophenyl)pyrrolidin-3-yl)carbamate (Compound 9-1)

[1040]

[1041] In a nitrogen atmosphere, palladium acetate (107 mg, 0.48 mmol) and XantPhos (276 mg, 0.48 mmol) were added to tert-butyl (S)-pyrrolidin-3-ylcarbamate (889 mg, 4.77 mmol), 4-bromo-1-chloro-2-fluorobenzene (500 mg, 2.39 mmol) and cesium carbonate (2.4 g, 7.16 mmol) in 1,4-dioxane (20 mL). The reaction mixture was stirred at 100 ° C for 2 hours. The reaction solution was cooled, pure water (30 mL) was added, and extracted with ethyl acetate (100 mL × 3). The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by flash column chromatography to obtain a white solid (S)-tert-butyl (1-(4-chloro-3-fluorophenyl)pyrrolidin-3-yl)carbamate (Compound 9-1, 418 mg).

[1042] Step 2: Preparation of (S)-1-(4-chloro-3-fluorophenyl)pyrrolidin-3-amine (Compound 9-2)

[1043]

[1044] Trifluoroacetic acid (4 mL) was added to a solution of (S)-(1-(4-chloro-3-fluorophenyl)pyrrolidin-3-yl)carbamic acid tert-butyl ester (4118 mg, 1.33 mmol) in dichloromethane (6 mL). The mixture was stirred at 25 ° C for 2 hours. The mixture was diluted with ethyl acetate (50 mL), then washed with water (10 mL) and saturated sodium bicarbonate solution (10 mL), then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography to obtain a white solid (S)-1-(4-chloro-3-fluorophenyl)pyrrolidin-3-amine (compound 9-2, 286 mg).

[1045] Step 3: Preparation of (S)-4-(1-(4-chloro-3-fluorophenyl)pyrrolidin-3-yl)morpholine (Compound 9-3)

[1046]

[1047] 1-Bromo-2-(2-bromoethoxy)ethane (1.6 g, 6.64 mmol) and potassium carbonate (550 mg, 3.98 mmol) were added to a solution of (S)-1-(4-chloro-3-fluorophenyl)pyrrolidin-3-amine (285 mg, 1.33 mmol) in acetonitrile (5 mL). The mixture was heated to 80 ° C and stirred for 5 hours. The mixture was diluted with ethyl acetate (100 mL), then washed with water (50 mL) and saturated brine (50 mL), then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography to obtain a yellow solid (S)-4-(1-(4-chloro-3-fluorophenyl)pyrrolidin-3-yl)morpholine (compound 9-3, 325 mg).

[1048] Step 4: Preparation of (2-(2-fluoro-4-((S)-3-morpholinopyrrolidin-1-yl)phenyl)-7-(2-methyl-2H-1,2,3-triazol-4-yl)pyrazolo[1,5-a]pyrimidin-5-yl)((R)-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone (Compound 9)

[1049]

[1050] In a nitrogen atmosphere, (R)-(7-(2-methyl-2H-1,2,3-triazol-4-yl)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a]pyrimidin-5-yl)(1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone (150 mg, 0.30 mmol) and (S)-4-(1 To a solution of 2-(5-bromo-4-fluoropyridin-2-yl)pyrrolidin-3-yl)morpholine (110 mg, 0.31 mmol) and sodium carbonate (96 mg, 0.91 mmol) in 1,4-dioxane (5 mL) was added chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) 2 (24 mg, 0.03 mmol) and water (1 mL). The mixture was heated to 100 ° C and stirred for 3 hours. After cooling, the mixture was diluted with ethyl acetate (100 mL), filtered through diatomaceous earth, the filtrate was washed with saturated brine (50 mL), then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography to prepare a yellow solid (2-(2-fluoro-4-((S)-3-morpholinopyrrolidin-1-yl)phenyl)-7-(2-methyl-2H-1,2,3-triazol-4-yl)pyrazolo[1,5-a]pyrimidin-5-yl)((R)-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone (Compound 9, 25.7 mg).

[1051] 1 H NMR (400 MHz, DMSO-d 6 )δ9.13-9.10(m,1H),8.16(t,J=8.8Hz,1H),7.69(s,1H),7.36-7.04(m,5H),6.59-6.47(m,2H),5.68-5.11(m,1H),4.61-4.55(m,1H) ,4.40-4.34(m,3H),4.10-4.05(m,1H),3.73-3.42(m,7H),3.33-2.70(m,9H),2.30-2.15(m,1H),1.94-1.76(m,1H),1.61-1.53(m,3H)

[1052] MS measured value (ESI + )[(M+H) + ]:632.20

[1053] Example 11: Preparation of (2-(2-fluoro-4-((3R,4R)-3-fluoro-4-hydroxypyrrolidin-1-yl)phenyl)-7-(1-methyl-1H-1,2,3-triazol-4-yl)pyrazolo[1,5-a]pyrimidin-5-yl)((R)-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone (Compound 10)

[1054]

[1055] 4-Bromo-3-methyl-2H-1,2,3-triazole (25 g, 154.3 mmol) was used in a manner similar to that of Examples 1 and 5 to prepare (2-(2-fluoro-4-((3R,4R)-3-fluoro-4-hydroxypyrrolidin-1-yl)phenyl)-7-(1-methyl-1H-1,2,3-triazol-4-yl)pyrazolo[1,5-a]pyrimidin-5-yl)((R)-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone (Compound 10, 27 mg).

[1056] 1HNMR(400MHz,DMSO-d6)δ9.56-9.44(m,1H),8.36(t,J=8.8Hz,1H),7.97-7.81(m,1H),7.39-7.13(m,5H),6.67-6.43(m,2H),5.7 5-5.64(m,2H),5.26-5.17(m,1H),4.47-4.28(m,5H),413-4.06(m,1H),3.82-3.52(m,4H),3.07-2.90(m,1H),1.65-1.58(m,3H)

[1057] MS measured value (ESI + )[(M+H) + ]:571.42

[1058] Example 12: Preparation of (7-(2-cyclopropyl-2H-1,2,3-triazol-4-yl)-2-(2-fluoro-4-((3R,4R)-3-fluoro-4-hydroxypyrrolidin-1-yl)phenyl)pyrazolo[1,5-a]pyrimidin-5-yl)((R)-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone (Compound 11)

[1059]

[1060] Step 1: Preparation of (7-(2-cyclopropyl-2H-1,2,3-triazol-4-yl)-2-(2-fluoro-4-((3R,4R)-3-fluoro-4-hydroxypyrrolidin-1-yl)phenyl)pyrazolo[1,5-a]pyrimidin-5-yl)((R)-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone (Compound 11)

[1061]

[1062] In a nitrogen atmosphere, (R)-(7-(2-cyclopropyl-2H-1,2,3-triazol-4-yl)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a]pyrimidin-5-yl)(1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone (190 mg, 0.36 mmol), (3R,4R)-1-(4-chloro-3-fluorobenzene)-1-yl)-4-nitropropene was added to the mixture. Chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (32 mg, 0.04 mmol) and water (1 mL) were added to a solution of 1,4-dioxane (5 mL) of 2-(2'-amino-1,1'-biphenyl)-4-fluoropyrrolidin-3-ol (101 mg, 0.43 mmol) and sodium carbonate (161 mg, 0.76 mmol). The mixture was heated to 100°C and stirred for 3 hours. After cooling, the mixture was diluted with ethyl acetate (100 mL), washed with saturated brine (50 mL), then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude product, which was purified by column chromatography to give a yellow solid (7-(2-cyclopropyl-2H-1,2,3-triazol-4-yl)-2-(2-fluoro-4-((3R, 4R)-3-fluoro-4-hydroxypyrrolidin-1-yl)phenyl)pyrazolo[1,5-a]pyrimidin-5-yl)((R)-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone (Compound 11, 16 mg).

[1063] 1 HNMR (400 MHz, DMSO-d 6 )δ9.16-9.10(m,1H),8.25-8.16(m,1H),7.75-7.65(m,1H),7.36-7.10(m,5H),6.65-6.54(m,2H),5.68-5.63(m,2H),5.24-5.20(m,1H ),4.45-4.39(m,2H),4.09-4.05(m,1H)3.52-3.76(m,4H),3.11-2.83(m,2H),1.64-1.57(m,3H),1.45-1.37(m,2H),1.27-1.25(m,2H)

[1064] MS measured value (ESI + )[(M+H) + ]:597.42

[1065] Example 13: Preparation of (R)-(2-(2-fluoro-4-(2-oxa-6-azaspiro[3.3]heptane-6-yl)phenyl)-7-(2-methyl-2H-1,2,3-triazol-4-yl)pyrazolo[1,5-a]pyrimidin-5-yl)(1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone (Compound 12)

[1066]

[1067] Step 1: Preparation of 6-(4-chloro-3-fluorophenyl)-2-oxa-6-azaspiro[3.3]heptane (Compound 12-1)

[1068]

[1069] In a nitrogen atmosphere, palladium acetate (43 mg, 0.19 mmol) and XantPhos (110 mg, 0.19 mmol) were added to 2-oxa-6-azaspiro[3.3]heptane (142 mg, 1.43 mmol), 4-bromo-1-chloro-2-fluorobenzene (200 mg, 0.96 mmol) and cesium carbonate (933 mg, 2.87 mmol) in 1,4-dioxane (3 mL). The reaction mixture was stirred at 100 ° C for 5 hours. The reaction solution was cooled, pure water (5 mL) was added to quench the reaction, and extracted with ethyl acetate (10 mL×3). The organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by flash column chromatography to give an off-white solid 6-(4-chloro-3-fluorophenyl)-2-oxa-6-azaspiro[3.3]heptane (Compound 12-1, 150 mg).

[1070] Step 2: Preparation of 6-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2-oxa-6-azaspiro[3.3]heptane (Compound 12-2)

[1071]

[1072] In a nitrogen atmosphere, add [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (87 mg, 0.13 mmol) to a 1,4-dioxane solution (3 mL) of 6-(4-chloro-3-fluorophenyl)-2-oxa-6-azaspiro[3.3]heptane (150 mg, 0.66 mmol), biboronic acid pinacol ester (334 mg, 1.32 mmol), and potassium acetate (195 mg, 1.98 mmol). Heat the mixture to 100°C and stir for 3 hours. Cool and use the reaction solution directly in the next step.

[1073] Step 3: Preparation of (R)-(2-fluoro-4-(2-oxa-6-azaspiro[3.3]heptyl-6-yl)phenyl)-7-(2-methyl-2H-1,2,3-triazol-4-yl)pyrazolo[1,5-a]pyrimidin-5-yl)(1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone (Compound 12)

[1074]

[1075] To a solution of 6-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2-oxa-6-azaspiro[3.3]heptane (210 mg, 0.66 mmol) in 1,4-dioxane (3 mL) was added (R)-(2-bromo-7-(2-methyl-2H-1,2,3-triazol-4-yl)pyrazolo[1,5-a]pyrimidin-5-yl)(1-methyl-3,4-dihydroisoquinoline-2(1H)-methanone (198 mg, 0.44 mmol), potassium carbonate (152 mg, 1.10 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium ( 32mg, 0.04mmol) and water (1mL), the mixture was stirred at 100℃ for 5 hours. Pure water (10mL) was added and extracted with ethyl acetate (10mL×2). Washed with saturated brine (5mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by flash column chromatography to obtain a yellow solid (R)-(2-fluoro-4-(2-oxa-6-azaspiro[3.3]heptyl-6-yl)phenyl)-7-(2-methyl-2H-1,2,3-triazol-4-yl)pyrazolo[1,5-a]pyrimidin-5-yl)(1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone (Compound 12, 87mg).

[1076] 1 H NMR(400MHz, DMSO-d6)δ9.15-9.13(m,1H),8.24-8.16(m,1H),7.74-7.66(m,1H),7.37-7.10(m,5H),6.48-6.40(m,2H),5.68-5.63(m,1H), 4.78(s,4H),4.44-4.37(m,3H),4.14(s,4H),4.11-4.05(m,1H),3.61 -3.51(m,1H),3.36-3.29(m,1H),3.12-2.97(m,1H),1.63-1.57(m,3H)

[1077] MS measured value (ESI + )[(M+H) +]:565.24

[1078] Example 14: Preparation of (1R)-2-(2-(4-(3S)-3-cyclopropanesulfonyl)pyrrolidin-1-yl]-2-fluorophenyl)-7-(2-methyl-2H-1,2,3-triazol-4-yl)pyrazolo[1,5-a]pyrimidine-5-carbonyl)-1-methyl-1,2,3,4-tetrahydroisoquinoline (Compound 13)

[1079]

[1080] Step 1: Preparation of tert-butyl (S)-3-(cyclopropylthio)pyrrolidine-1-carboxylate (Intermediate 13-2)

[1081]

[1082] To a solution of (S)-tert-butyl 3-mercaptopyrrolidine-1-carboxylate (300 mg, 1.47 mmol) in ultra-dry DMSO (10 mL), potassium tert-butoxide (549 mg, 2.94 mmol) and cyclopropyl bromide (266 mg, 2.20 mmol) were added, and the mixture was stirred at 25 ° C for 16 hours. Pure water (50 mL) was added and extracted with ethyl acetate (50 mL × 2). Washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by flash column chromatography to obtain (S)-tert-butyl 3-(cyclopropylthio)pyrrolidine-1-carboxylate (compound 13-2, 150 mg).

[1083] Step 2: Preparation of tert-butyl (S)-3-(cyclopropylsulfonyl)pyrrolidine-1-carboxylate (Intermediate 13-3)

[1084]

[1085] To a solution of (S)-3-(cyclopropylthio)pyrrolidine-1-carboxylic acid tert-butyl ester (150 mg, 1.07 mmol) in dichloromethane (3 mL) was added meta-chloroperbenzoic acid (312 mg, 1.53 mmol). The mixture was stirred at 25 ° C for 1 hour. Pure water (50 mL) was added and extracted with ethyl acetate (50 mL × 2). Washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by flash column chromatography to obtain (S)-3-(cyclopropylsulfonyl)pyrrolidine-1-carboxylic acid tert-butyl ester (compound 13-3, 120 mg).

[1086] Step 3: Preparation of S-3-cyclopropylsulfonylpyrrolidine hydrochloride (Intermediate 13-4)

[1087]

[1088] To a solution of (S)-tert-butyl 3-(cyclopropylsulfonyl)pyrrolidine-1-carboxylate (120 mg, 0.44 mmol) in dichloromethane (3 mL) was added hydrochloric acid / 1,4-dioxane solution (4.0 M, 2 mL), and the mixture was stirred at 25° C. for 2 hours. The mixture was concentrated under reduced pressure to give S-3-cyclopropylsulfonylpyrrolidine hydrochloride (compound 13-4, 100 mg).

[1089] Step 4: Preparation of 1-(4-chloro-3-fluorophenyl)-3-cyclopropylsulfonylpyrrolidine (Compound 13-5)

[1090]

[1091] In a nitrogen atmosphere, palladium acetate (10 mg, 0.05 mmol) and XantPhos (27 mg, 0.05 mmol) were added to S-3-cyclopropylsulfonylpyrrolidine hydrochloride (100 mg, 0.47 mmol), 4-bromo-1-chloro-2-fluorobenzene (100 mg, 0.47 mmol) and cesium carbonate (460 mg, 1.41 mmol) in 1,4-dioxane (15 mL). The reaction mixture was stirred at 100 ° C for 8 hours. The reaction solution was cooled, pure water (15 mL) was added, and extracted with ethyl acetate (30 mL × 3). The organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by flash column chromatography to obtain an off-white solid 1-(4-chloro-3-fluorophenyl)-3-cyclopropylsulfonylpyrrolidine (compound 13-5, 150 mg).

[1092] Step 5: Preparation of (1R)-2-(2-(4-(3S)-3-cyclopropanesulfonyl)pyrrolidin-1-yl]-2-fluorophenyl)-7-(2-methyl-2H-1,2,3-triazol-4-yl)pyrazolo[1,5-a]pyrimidine-5-carbonyl)-1-methyl-1,2,3,4-tetrahydroisoquinoline (Compound 13)

[1093]

[1094] In a nitrogen atmosphere, (R)-(7-(2-methyl-2H-1,2,3-triazol-4-yl)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a]pyrimidin-5-yl)(1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone (140 mg, 0.33 mmol), 1-(4-chloro-3-fluorophenyl)-3- To a solution of cyclopropylsulfonylpyrrolidine (100 mg, 0.33 mmol) and sodium carbonate (110 mg, 0.99 mmol) in 1,4-dioxane (5 mL) were added chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (40 mg, 0.04 mmol) and water (1 mL). The mixture was heated to 100°C and stirred for 8 hours. After cooling, the mixture was concentrated under reduced pressure to give a crude product, which was purified by column chromatography to give a yellow solid (1R)-2-(2-(4-(3S)-3-cyclopropanesulfonyl)pyrrolidin-1-yl]-2-fluorophenyl)-7-(2-methyl-2H-1,2,3-triazol-4-yl)pyrazolo[1,5-a]pyrimidine-5-carbonyl)-1-methyl-1,2,3,4-tetrahydroisoquinoline (Compound 13, 16 mg).

[1095] 1 H NMR (400 MHz, DMSO-d 6 )δ9.16-9.10(m,1H),8.20(t,J=8.4Hz,1H),7.77-7.66(m,1H)7.38-7.34(m,1H),7.29-7.1 2(m,4H),6.70-6.57(m,2H),5.69-5.63(m,1H),4.44-4.36(m,3H),4.29-4.19(m,1H),4.15- 4.06(m,1H),3.79-3.76(m,2H),3.59-3.55(m,2H),3.50-3.42(m,1H),3.11-3.04(m,1H),2. 94-2.84(m,1H),2.81-2.76(m,1H),2.51-2.46(m,2H),1.64-1.55(m,3H),1.14-1.04(m,4H)

[1096] MS measured value (ESI + )[(M+H) + ]:641.43

[1097] Example 15: Preparation of 1-(3-fluoro-4-(5-[(1R)-1-methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl]-7-(2-methyl-2H-1,2,3-triazol-4-yl)pyrazolo[1,5-a]pyrimidin-2-yl)phenyl)azetidine-3-methanol (Compound 14)

[1098]

[1099] Step 1: Preparation of 1-(4-chloro-3-fluorophenyl)azetidine-3-methanol (Compound 14-1)

[1100]

[1101] In a nitrogen atmosphere, palladium acetate (130 mg, 0.56 mmol) and XantPhos (664 mg, 1.15 mmol) were added to azetidine-3-methanol (500 mg, 5.75 mmol), 4-bromo-1-chloro-2-fluorobenzene (1.2 g, 5.75 mmol) and cesium carbonate (5.61 g, 17.25 mmol) in 1,4-dioxane (15 mL). The reaction mixture was stirred at 100 ° C for 8 hours. The reaction solution was cooled, pure water (15 mL) was added, and extracted with ethyl acetate (100 mL × 3). The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by flash column chromatography to obtain a colorless oily 1-(4-chloro-3-fluorophenyl)azetidine-3-methanol (compound 14-1, 300 mg).

[1102] Step 2: Preparation of 1-(3-fluoro-4-(5-[(1R)-1-methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl]-7-(2-methyl-2H-1,2,3-triazol-4-yl)pyrazolo[1,5-a]pyrimidin-2-yl)phenyl)azetidine-3-methanol (Compound 2)

[1103]

[1104] In a nitrogen atmosphere, (R)-(7-(2-methyl-2H-1,2,3-triazol-4-yl)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a]pyrimidin-5-yl)(1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone (190 mg, 0.47 mmol), 1-(4-chloro-3-fluorophenyl)azepine To a solution of cyclobutane-3-methanol (100 mg, 0.47 mmol) and sodium carbonate (150 mg, 1.41 mmol) in 1,4-dioxane (5 mL) were added chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (37 mg, 0.047 mmol) and water (1 mL). The mixture was heated to 100°C and stirred for 8 hours. After cooling, the mixture was concentrated under reduced pressure to give a crude product, which was purified by column chromatography to give a yellow solid 1-(3-fluoro-4-(5-[(1R)-1-methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl]-7-(2-methyl-2H-1,2,3-triazol-4-yl)pyrazolo[1,5-a]pyrimidin-2-yl)phenyl)azetidine-3-methanol (Compound 14, 50 mg).

[1105] 1 H NMR (400 MHz, DMSO-d 6 )δ9.15(s,1H),8.19(t,J=8.4Hz,1H),7.79-7.63(m,1H),7.43-7.05(m,5H),6.48-6.34(m,2H),5.69-5.63(m,1H),4.86(t,J=5.2Hz,1H ),4.45-4.36(m,3H),4.10-4.03(m,1H),3.99-3.93(m,2H),3.75-3.70(m,2H),3.69-3.60(m,2H),2.95-2.67(m,3H),1.66-1.52(m,3H)

[1106] MS measured value (ESI + )[(M+H) + ]:553.35

[1107] Example 16: Preparation of (1R)-2-(2-fluoro-4-[(3S)-3-(propane-2-sulfonyl)pyrrolidin-1-yl]phenyl)-7-(2-methyl-2H-1,2,3-triazol-4-yl)pyrazolo[1,5-a]pyrimidine-5-carbonyl)-1-methyl-1,2,3,4-tetrahydroisoquinoline (Compound 15)

[1108]

[1109] Isopropyl bromide (270 mg, 2.20 mmol) was used in a similar manner to Example 14 to prepare (1R)-2-(2-fluoro-4-[(3S)-3-(propane-2-sulfonyl)pyrrolidin-1-yl]phenyl)-7-(2-methyl-2H-1,2,3-triazol-4-yl)pyrazolo[1,5-a]pyrimidine-5-carbonyl)-1-methyl-1,2,3,4-tetrahydroisoquinoline (Compound 15, 50 mg). 1 H NMR (400 MHz, DMSO-d 6 )δ9.17-9.14(m,1H),8.27-8.19(m,1H),7.76-7.65(m,1H),7.37(d,J=7.4Hz,1H),7. 31-7.09(m,4H),6.70-6.62(m,2H)5.69-5.63(m,1H),4.46-4.37(m,3H),4.34-4.26( m,1H),4.15-4.03(m,1H),3.77(s,1H),3.73-3.65(m,1H),3.61-3.55(m,1H),3.53-3 .42(m,2H),3.18-2.67(m,4H),2.49-2.41(m,1H),1.65-1.55(m,3H)1.36-1.28(m,6H)

[1110] MS measured value (ESI + )[(M+H) + ]:643.35

[1111] Example 17: Preparation of (2-(2-fluoro-4-((S)-3-hydroxypyrrolidin-1-yl)phenyl)-7-(2-methyl-2H-1,2,3-triazol-4-yl)pyrazolo[1,5-a]pyrimidin-5-yl)((R)-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone (Compound 16)

[1112]

[1113] Step 1: Preparation of (S)-1-(4-chloro-3-fluorophenyl)pyrrolidin-3-ol (Compound 16-1)

[1114]

[1115] In a nitrogen atmosphere, palladium acetate (107 mg, 0.48 mmol) and XantPhos (276 mg, 0.48 mmol) were added to (S)-pyrrolidin-3-ol (375, 4.77 mmol), 4-bromo-1-chloro-2-fluorobenzene (500 mg, 2.39 mmol) and cesium carbonate (2.4 g, 7.16 mmol) in 1,4-dioxane (20 mL). The reaction mixture was stirred at 100 ° C for 2 hours. The reaction solution was cooled, pure water (30 mL) was added, and extracted with ethyl acetate (100 mL × 3). The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by flash column chromatography to obtain a white solid (S)-1-(4-chloro-3-fluorophenyl)pyrrolidin-3-ol (compound 16-1, 142 mg).

[1116] Step 4: Preparation of (2-(2-fluoro-4-((S)-3-hydroxypyrrolidin-1-yl)phenyl)-7-(2-methyl-2H-1,2,3-triazol-4-yl)pyrazolo[1,5-a]pyrimidin-5-yl)((R)-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone (Compound 16)

[1117]

[1118] Under nitrogen atmosphere, to a solution of (R)-(7-(2-methyl-2H-1,2,3-triazol-4-yl)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a]pyrimidin-5-yl)(1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone (150 mg, 0.30 mmol), (S)-1-(4-chloro-3-fluorophenyl)pyrrolidin-3-ol (130 mg, 0.44 mmol), sodium carbonate (96 mg, 0.91 mmol) in 1,4-dioxane (5 mL) was added chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) 2(24 mg, 0.03 mmol) and water (1 mL). The mixture was heated to 100 ° C and stirred for 3 hours. After cooling, the mixture was diluted with ethyl acetate (100 mL), filtered through diatomaceous earth, and the filtrate was washed with saturated brine (50 mL), then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography to prepare a yellow solid (2-(2-fluoro-4-((S)-3-hydroxypyrrolidin-1-yl)phenyl)-7-(2-methyl-2H-1,2,3-triazol-4-yl)pyrazolo[1,5-a]pyrimidin-5-yl)((R)-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone (Compound 16, 19 mg).

[1119] 1 H NMR (400 MHz, DMSO-d 6 )δ9.17-9.05(m,1H),8.16(t,J=8.8Hz,H),7.53-7.76(m,1H),7.36-7.05(m,5H),6.5 7-6.42(m,2H),5.69-5.11(m,1H),5.08-5.01(m,1H),4.63-4.53(m,1H),4.44(s,1H) ,4.40-4.34(m,3H),4.10-4.03(m,1H),3.57-3.36(m,4H),3.21-3.15m,1H),3.10-2. 92(m,1H),2.91-2.71(m,1H),2.10-2.03(m,1H),1.99-1.88(m,1H),1.61-1.53(m,3H)

[1120] MS measured value (ESI + )[(M+H) + ]:552.19

[1121] Example 18: Preparation of (7-(2,5-dimethyl-2H-1,2,3-triazol-4-yl)-2-(2-fluoro-4-((S)-3-(methylsulfonyl)pyrrolidin-1-yl)phenyl)pyrazolo[1,5-a]pyrimidin-5-yl)((R)-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone (Compound 17)

[1122]

[1123] 4-Bromo-2,5-dimethyl-2H-1,2,3-triazole (860 mg, 4.86 mmol) was used to prepare (7-(2,5-dimethyl-2H-1,2,3-triazol-4-yl)-2-(2-fluoro-4-((S)-3-(methylsulfonyl)pyrrolidin-1-yl)phenyl)pyrazolo[1,5-a]pyrimidin-5-yl)((R)-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone (Compound 17, 28 mg) according to the method similar to that of Example 1 and Example 5.

[1124] 1 HNMR (400 MHz, DMSO-d 6 )δ7.92(t,J=8.8Hz,1H),7.34-7.08(m,6H),6.62-6.56(m,2H),5.65-5.10(m,1H),4.62-4.55(m,1H),4.27-4.22(m,3H),4.17-4.09( m,1H),4.08-3.99(m,1H),3.75-3.65(m,2H),3.57-3.35(m,3H),3.09(s,3H),3.08-2.72(m,2H),2.47-2.37(m,5H),1.62-1.52(m,3H)

[1125] MS measured value (ESI + )[(M+H) + ]:629.18

[1126] Example 19: Preparation of (R)-(2-(4-(3-aminoazetidin-1-yl)-2-fluorophenyl)-7-(2-methyl-2H-1,2,3-triazol-4-yl)pyrazolo[1,5-a]pyrimidin-5-yl)(1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone (Compound 18)

[1127]

[1128] Step 1: Preparation of tert-butyl (1-(4-chloro-3-fluorophenyl)azetidin-3-yl)carbamate (Compound 18-1)

[1129]

[1130] In a nitrogen atmosphere, palladium acetate (45 mg, 0.2 mmol) and XantPhos (116 mg, 0.2 mmol) were added to 1,4-dioxane (15 mL) of azetidin-3-ylcarbamic acid tert-butyl ester (258 mg, 1.5 mmol), 4-bromo-1-chloro-2-fluorobenzene (209 mg, 1.0 mmol) and cesium carbonate (977 mg, 3.0 mmol). The reaction mixture was stirred at 100 ° C for 5 hours. The reaction solution was cooled, pure water (15 mL) was added, and extracted with ethyl acetate (50 mL × 3). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by flash column chromatography to obtain a white solid (1- (4-chloro-3-fluorophenyl) azetidin-3-yl) carbamic acid tert-butyl ester (compound 18-1, 320 mg).

[1131] Step 2: Preparation of tert-butyl 1-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)azetidin-3-yl)carbamate (Compound 18-2)

[1132]

[1133] In a nitrogen atmosphere, chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (79 mg, 0.10 mmol) was added to a solution (3 mL) of tert-butyl (1-(4-chloro-3-fluorophenyl)azetidin-3-yl)carbamate (150 mg, 0.50 mmol), biboronic acid pinacol ester (54 mg, 1.0 mmol), and potassium acetate (147 mg, 1.5 mmol) in 1,4-dioxane. The mixture was heated to 100°C and stirred for 5 hours. After cooling, the reaction solution was directly used for the next step.

[1134] Step 3: Preparation of (R)-(1-(3-fluoro-4-(5-(1-methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-7-(2-methyl-2H-1,2,3-triazol-4-yl)pyrazolo[1,5-a]pyrimidin-2-yl)phenyl)azetidin-3-yl)carbamic acid tert-butyl ester (Compound 18-3)

[1135]

[1136] To a solution of tert-butyl 1-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)azetidin-3-yl)carbamate (150 mg, 0.50 mmol) in 1,4-dioxane (3 mL) was added (R)-(2-bromo-7-(2-methyl-2H-1,2,3-triazol-4-yl)pyrazolo[1,5-a]pyrimidin-5-yl)(1-methyl-3,4-dihydroisoquinoline-2(1H)-methanone (206 mg, 0.45 mmol), sodium carbonate (145 mg, 1.36 mmol), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino)-4-yl]-dextrin (10 mL), and 1-(4-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)azetidin-3-yl)carbamate (150 mg, 0.50 mmol) in 1,4-dioxane (3 mL). 1,1'-biphenyl)] palladium (II) (36 mg, 0.05 mmol) and water (1 mL), the mixture was stirred at 100 ° C for 5 hours. Pure water (10 mL) was added and extracted with ethyl acetate (10 mL × 2). Washed with saturated brine (5 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by flash column chromatography to obtain a yellow solid (R)-(1-(3-fluoro-4-(5-(1-methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-7-(2-methyl-2H-1,2,3-triazol-4-yl)pyrazolo[1,5-a]pyrimidin-2-yl)phenyl)azetidin-3-yl)carbamic acid tert-butyl ester (Compound 18-3, 110 mg).

[1137] Step 4: Preparation of (R)-(2-(4-(3-aminoazetidin-1-yl)-2-fluorophenyl)-7-(2-methyl-2H-1,2,3-triazol-4-yl)pyrazolo[1,5-a]pyrimidin-5-yl)(1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone (Compound 18)

[1138]

[1139] To a solution of (R)-tert-butyl(1-(3-fluoro-4-(5-(1-methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-7-(2-methyl-2H-1,2,3-triazol-4-yl)pyrazolo[1,5-a]pyrimidin-2-yl)phenyl)azetidin-3-yl)carbamate (110 mg) in dichloromethane (5 mL) was added trifluoroacetic acid (2 mL), and the mixture was stirred at 25° C. for 1 hour. The mixture was concentrated under reduced pressure to give a crude product. The crude product was purified by flash column chromatography to give (R)-(2-(4-(3-aminoazetidine-1-yl)-2-fluorophenyl)-7-(2-methyl-2H-1,2,3-triazol-4-yl)pyrazolo[1,5-a]pyrimidin-5-yl)(1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone (Compound 18, 37 mg).

[1140] 1 H NMR(400MHz, DMSO-d6)δ9.17-9.10(m,1H),8.18(t,J=8.4Hz,1H),7.76-7.65( m,1H),7.39-7.33(m,1H),7.30-7.06(m,5H),6.48-6.38(m,2H),5.65-5.19(m, 1H),4.65-4.58(m,1H),4.46-4.35(m,3H),4.23-4.15(m,2H),4.11-4.03(m,1 H),3.98-3.88(m,1H),3.63-3.51(m,3H),3.15-2.73(m,2H),1.65-1.54(m,3H)

[1141] MS measured value (ESI + )[(M+H) + ]:538.24

[1142] Example 20: Preparation of (R)-(2-(4-(3-(aminomethyl)-3-hydroxyazetidin-1-yl)-2-fluorophenyl)-7-(2-methyl-2H-1,2,3-triazol-4-yl)pyrazolo[1,5-a]pyrimidin-5-yl)(1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone (Compound 19)

[1143]

[1144] (R)-(2-(4-(3-(Aminomethyl)-3-hydroxyazetidin-1-yl)-2-fluorophenyl)-7-(2-methyl-2H-1,2,3-triazol-4-yl)pyrazolo[1,5-a]pyrimidin-5-yl)(1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone (Compound 19, 33 mg) was prepared from tert-butyl (3-hydroxyazetidin-3-yl)methylcarbamate (303 mg, 1.53 mmol) according to a method similar to that of Example 19.

[1145] 1 H NMR (400MHz, DMSO-d6) δ9.19-9.10(m,1H),8.22(t,J=8.8Hz,1H),7.77-7.65(m,1H),7.39-7.33(m,1H),7.32-7.06(m,5H),6.52-6.41(m,2H),5. 66-5.14(m,1H).4.45-4.36(m,3H),4.14-3.99(m,2H),3.79-3.73(m,2H ),3.62-3.50(m,1H),3.06(s,2H),2.95-2.75(m,1H),1.66-1.52(m,3H).

[1146] MS measured value (ESI + )[(M+H) + ]:568.19.

[1147] Example 21: Preparation of (R)-(2-(4-(6-amino-2-azaspiro[3.3]heptane-2-yl)-2-fluorophenyl)-7-(2-methyl-2H-1,2,3-triazol-4-yl)pyrazolo[1,5-a]pyrimidin-5-yl)(1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone (Compound 20)

[1148]

[1149] Tert-butyl (2-azaspiro[3.3]hept-6-yl)carbamate (152 mg, 0.72 mmol) was used to prepare (R)-(4-(6-amino-2-azaspiro[3.3]hept-2-yl)-2-fluorophenyl)-7-(2-methyl-2H-1,2,3-triazol-4-yl)pyrazolo[1,5-a]pyrimidin-5-yl)(1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone (Compound 20, 45 mg) according to a method similar to Example 19.

[1150] 1H NMR(400MHz, DMSO-d6)δ9.16-9.13(m,1H),8.20(t,J=8.4Hz,1H),7.74-7.69( m,1H),7.37-7.10(m,5H),6.46-6.38(m,2H),5.70-5.64(m,1H),4.45-4.38(m, 3H),4.11-4.07(m,1H),4.04-3.92(m,4H),3.70-3.63(m,1H),3.61-3.53(m,1H ),3.14-2.98(m,1H),2.64-2.56(m,2H),2.41-2.32(m,2H),1.65-1.56(m,3H).

[1151] MS measured value (ESI + )[(M+H) + ]:578.67.

[1152] Example 22: Preparation of (R)-(7-(2-cyclopropyl-2H-1,2,3-triazol-4-yl)-2-(2-fluoro-4-(3-hydroxyazetidin-1-yl)phenyl)pyrazolo[1,5-a]pyrimidin-5-yl)(1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone (Compound 21)

[1153]

[1154] Step 1: Preparation of (R)-(7-(2-cyclopropyl-2H-1,2,3-triazol-4-yl)-2-(2-fluoro-4-(3-hydroxyazetidin-1-yl)phenyl)pyrazolo[1,5-a]pyrimidin-5-yl)(1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone (Compound 21)

[1155]

[1156] Under nitrogen atmosphere, (R)-(7-(2-cyclopropyl-2H-1,2,3-triazol-4-yl)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a]pyrimidin-5-yl)(1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone (190 mg, 0.36 mmol), 1-(4-chloro-3-fluorophenyl)-1-yl)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a]pyrimidin-5-yl)(1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone (190 mg, 0.36 mmol) were added to the mixture. A 1,4-dioxane solution (5 mL) of azetidin-3-ol (87 mg, 0.43 mmol) and sodium carbonate (161 mg, 0.76 mmol) was added with chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (32 mg, 0.04 mmol) and water (1 mL). The mixture was heated to 100° C. and stirred for 3 hours. After cooling, the mixture was diluted with ethyl acetate (100 mL), washed with saturated brine (50 mL), then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude product, which was purified by column chromatography to give a yellow solid (R)-(7-(2-cyclopropyl-2H-1,2,3-triazol-4-yl)-2-(2-fluoro-4-(3-hydroxyazetidine-1-yl)phenyl)pyrazolo[1,5-a]pyrimidin-5-yl)(1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone (Compound 21, 25 mg).

[1157] 1 HNMR (400 MHz, DMSO-d 6 )δ9.49-9.43(m,1H),8.31-8.21(m,1H),7.92-7.82(m,1H),7.33-7.06( m,5H),6.46-6.33(m,2H),5.75-5.69(m,1H),5.67-5.59(m,1H),4.67-4. 55(m,3H),4.22-4.13(m,2H),3.69-3.61(m,2H),3.60-3.47(m,1H),3.0 9-3.04(m,1H),2.03-1.94(m,2H),1.61-1.54(m,3H),0.95-0.92(m,2H).

[1158] MS measured value (ESI + )[(M+H) + ]:567.34.

[1159] Example 23: Preparation of (2-(4-(3,8-diazabicyclo[3.2.1]oct-3-yl)-2-fluorophenyl)-7-(2-methyl-2H-1,2,3-triazol-4-yl)pyrazolo[1,5-a]pyrimidin-5-yl)((R)-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone (Compound 22)

[1160]

[1161] Step 1: Preparation of tert-butyl 3-(4-chloro-3-fluorophenyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Compound 1-2)

[1162]

[1163] In a nitrogen atmosphere, palladium acetate (108 mg, 0.48 mmol) and XantPhos (278 mg, 0.48 mmol) were added to tert-butyl 3,8-diazabicyclo[3.2.1]octane-8-carboxylate (761 mg, 3.58 mmol), 4-bromo-1-chloro-2-fluorobenzene (500 mg, 2.39 mmol) and cesium carbonate (2.4 g, 7.17 mmol) in 1,4-dioxane (10 mL). The reaction mixture was stirred at 100 ° C for 5 hours. The reaction solution was cooled, pure water (50 mL) was added to quench the reaction, and extracted with ethyl acetate (100 mL × 3). The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by flash column chromatography to obtain yellow solid 3-(4-chloro-3-fluorophenyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (Compound 22-1, 510 mg).

[1164] Step 2: Preparation of tert-butyl 3-(3-fluoro-4-(5-((R)-1-methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-7-(2-methyl-2H-1,2,3-triazol-4-yl)pyrazolo[1,5-a]pyrimidin-2-yl)phenyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Compound 22-2)

[1165]

[1166] In a nitrogen atmosphere, (R)-(7-(2-methyl-2H-1,2,3-triazol-4-yl)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a]pyrimidin-5-yl)(1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone (200 mg, 0.40 mmol), 3-(4-chloro-3-fluorophenyl)-1,4-dihydro-1,4-dihydro-2-(1,4-dihydro-3-(1,4-dihydro-2 ... )-tert-butyl 3,8-diazabicyclo[3.2.1]octane-8-carboxylate (164 mg, 0.48 mmol), sodium carbonate (128 mg, 1.20 mmol) in 1,4-dioxane (5 mL) were added with chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) 2 (32 mg, 0.04 mmol) and water (1 mL). The mixture was heated to 100 ° C and stirred for 3 hours. After cooling, the mixture was diluted with ethyl acetate (100 mL), filtered through diatomaceous earth, the filtrate was washed with saturated brine (50 mL), then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography to obtain a yellow solid 3-(3-fluoro-4-(5-((R)-1-methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-7-(2-methyl-2H-1,2,3-triazol-4-yl)pyrazolo[1,5-a]pyrimidin-2-yl)phenyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (Compound 22-2, 100 mg).

[1167] Step 3: Preparation of (2-(4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-2-fluorophenyl)-7-(2-methyl-2H-1,2,3-triazol-4-yl)pyrazolo[1,5-a]pyrimidin-5-yl)((R)-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone (Compound 22)

[1168]

[1169] To a solution of tert-butyl 3-(3-fluoro-4-(5-((R)-1-methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-7-(2-methyl-2H-1,2,3-triazol-4-yl)pyrazolo[1,5-a]pyrimidin-2-yl)phenyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (100 mg, 0.15 mmol) in dichloromethane (3 mL) was added trifluoroacetic acid (1 mL), and the mixture was stirred at 25° C. for 2 hours. The mixture was concentrated under reduced pressure to give a crude product. The crude product was purified by flash column chromatography to give a yellow solid (2-(4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-2-fluorophenyl)-7-(2-methyl-2H-1,2,3-triazol-4-yl)pyrazolo[1,5-a]pyrimidin-5-yl)((R)-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone (Compound 22, 15 mg).

[1170] 1 H NMR (400 MHz, DMSO-d 6 )δ9.16-9.05(m,1H),8.19(t,J=8.8Hz,1H),7.63-7.75(m,1H),7.37-7.0 4(m,5H),6.98-6.85(m,2H),5.71-5.08(m,1H),4.49-4.44(m,1H),4.41- 4.32(m,1H),4.11-4.03(m,1H),3.61-3.50(m,1H),3.12-3.01(m,3H),2. 95-2.85(m,3H),2.79-2.75(m,1H),2.15-2.05(m,4H),1.69-1.49(m,3H)

[1171] Example 24: Preparation of [(3S)-1-(3-fluoro-4-(5-[1R)-1-methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl]-7-(2-methyl-2H-1,2,3-triazol-4-yl)pyrazolo[1,5-a]pyrimidin-2-yl)phenyl)pyrrolidin-3-yl]iminomethyl-λ^6-sulfonone (Compound 23)

[1172]

[1173] Step 1: Preparation of tert-butyl (R)-3-(acetylthio)pyrrolidine-1-carboxylate (Intermediate 23-2)

[1174]

[1175] Potassium thioacetate (8.6 g, 75.48 mmol) was added to a solution of (R)-3-((methylsulfonyl)oxy)pyrrolidine-1-carboxylic acid tert-butyl ester (5.0 g, 18.87 mmol) in DMF (50 mL). The mixture was heated to 80 ° C and stirred for 18 hours. After cooling, the mixture was diluted with ethyl acetate (100 mL) and water (50 mL), washed with saturated brine (50 mL), then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by flash column chromatography to obtain a colorless oily liquid (R)-3-(acetylthio)pyrrolidine-1-carboxylic acid tert-butyl ester (Intermediate 23-2, 4.0 g).

[1176] Step 2: Preparation of (S)-tert-butyl 3-methylthiopyrrolidine-1-carboxylate (Intermediate 23-3)

[1177]

[1178] To a solution of (R)-tert-butyl 3-(acetylthio)pyrrolidine-1-carboxylate (4.0 g, 16.33 mmol) and sodium hydroxide (1M aqueous solution, 17.7 mL, 17.76 mmol) in methanol (70 mL) was added iodomethane (2.2 mL, 35.98 mmol). The mixture was stirred at 25 °C for 72 hours. The mixture was diluted with ethyl acetate (100 mL) and water (50 mL), washed with saturated brine (50 mL), then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by flash column chromatography to obtain a colorless oily liquid (S)-tert-butyl 3-methylthiopyrrolidine-1-carboxylate (Intermediate 23-3, 2.5 g).

[1179] Step 3: Preparation of (S)-3-methylthiopyrrolidine hydrochloride (Intermediate 23-4)

[1180]

[1181] To a solution of (S)-3-methylthiopyrrolidine-1-carboxylic acid tert-butyl ester (2.5 g, 11.52 mmol) in dichloromethane (5 mL) was added a solution of dioxane hydrochloride (4.0 M, 10 mL). The mixture was stirred at 25 ° C for 2 hours. The reaction was carried out at room temperature for 2 hours. The solution was concentrated under reduced pressure to give (S)-3-methylthiopyrrolidine hydrochloride (Intermediate 23-4, 1.7 g).

[1182] Step 4: Preparation of 1-(4-chloro-3-fluorophenyl)-3-methylthiopyrrolidine (Compound 23-5)

[1183]

[1184] In a nitrogen atmosphere, palladium acetate (250 mg, 1.11 mmol) and XantPhos (1.3 g, 2.22 mmol) were added to (S)-3-methylthiopyrrolidine hydrochloride (1.7 g, 11.11 mmol), 4-bromo-1-chloro-2-fluorobenzene (2.3 g, 11.11 mmol) and cesium carbonate (10.8 g, 33.33 mmol) in 1,4-dioxane (100 mL). The reaction mixture was stirred at 100 ° C for 8 hours. The reaction solution was cooled, pure water (50 mL) was added, and extracted with ethyl acetate (100 mL × 3). The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by flash column chromatography to obtain a white solid product 1-(4-chloro-3-fluorophenyl)-3-methylthiopyrrolidine (compound 23-5, 1.8 g).

[1185] Step 5: Preparation of (S)-1-(4-chloro-3-fluorophenyl)-3-methylsulfinylpyrrolidine (Intermediate 23-6)

[1186]

[1187] To a solution of 1-(4-chloro-3-fluorophenyl)-3-methylthiopyrrolidine (1.8 g, 7.35 mmol) in dichloromethane (50 mL) was added meta-chloroperbenzoic acid (1.8 g, 8.81 mmol). The mixture was stirred at 25 °C for 1 hour. The mixture was stirred at room temperature for 1 hour. Pure water (50 mL) was added and extracted with ethyl acetate (100 mL × 3). The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by flash column chromatography to obtain a white solid (S)-1-(4-chloro-3-fluorophenyl)-3-methylsulfinylpyrrolidine (Intermediate 23-6, 1.5 g).

[1188] Step 6: Preparation of tert-butyl ((R)-((S)-1-(4-chloro-3-fluorophenyl)pyrrolidin-3-yl)(methyl)(oxo)-16-aminosulfonylimide)carbamate (Compound 23-7)

[1189]

[1190] In a nitrogen atmosphere, add tert-butyl carbamate (1.0 g, 8.63 mmol), magnesium oxide (920 mg, 23.00 mmol), iodophenyl diacetic acid (2.8 g, 8.63 mmol), and acetic acid rhodium dimer (170 mg, 0.38 mmol) to a solution of (S)-1-(4-chloro-3-fluorophenyl)-3-methylsulfinylpyrrolidine (1.5 g, 5.75 mmol) in dichloromethane (40 mL). Stir the mixture at 40 ° C for 8 hours. Add pure water (150 ml) and extract with ethyl acetate (100 ml × 3). Combine the organic phases, wash with saturated brine (100 ml), dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain a crude product. The crude product was purified by flash column chromatography to obtain white solid tert-butyl ((R)-((S)-1-(4-chloro-3-fluorophenyl)pyrrolidin-3-yl)(methyl)(oxo)-16-aminosulfonylimide)carbamate (Compound 23-7, 300 mg).

[1191] Step 7: Preparation of ((S)-1-(3-fluoro-4-(5-(R)-1-methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-7-(2-methyl-2H-1,2,3-triazol-4-yl)pyrazolo[1,5-a]pyrimidin-2-yl)phenyl)pyrrolidin-3-yl(methyl)(oxo)-L6-sulfonylidenecarbamate (Compound 23-8)

[1192]

[1193] Under nitrogen atmosphere, (R)-(7-(2-methyl-2H-1,2,3-triazol-4-yl)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a]pyrimidin-5-yl)(1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone (110 mg, 0.27 mmol), tert-butyl((R)-((S)-1-(4-chloro- To a solution of (3-fluorophenyl)pyrrolidin-3-yl)(methyl)(oxo)-16-aminosulfonylimide)carbamate (100 mg, 0.27 mmol) and sodium carbonate (86 mg, 0.81 mmol) in 1,4-dioxane (5 mL) was added chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) 2(32 mg, 0.04 mmol) and water (1 mL). The mixture was heated to 100 ° C and stirred for 3 hours. Cooled and concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography to obtain a yellow solid (((S)-1-(3-fluoro-4-(5-(R)-1-methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-7-(2-methyl-2H-1,2,3-triazol-4-yl)pyrazolo[1,5-a]pyrimidin-2-yl)phenyl)pyrrolidin-3-yl(methyl)(oxo)-L6-sulfonylidenecarbamate (Compound 23-8, 30 mg).

[1194] Step 8: Preparation of [(3S)-1-(3-fluoro-4-(5-[1R)-1-methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl]-7-(2-methyl-2H-1,2,3-triazol-4-yl)pyrazolo[1,5-a]pyrimidin-2-yl)phenyl)pyrrolidin-3-yl]iminomethyl-λ^6-sulfonone (Compound 23)

[1195]

[1196] To a solution of (((S)-1-(3-fluoro-4-(5-(R)-1-methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-7-(2-methyl-2H-1,2,3-triazol-4-yl)pyrazolo[1,5-a]pyrimidin-2-yl)phenyl)pyrrolidin-3-yl(methyl)(oxo)-L6-sulfonylidenecarbamate (30 mg, 0.04 mmol) in dichloromethane (2 mL) was added a dioxane hydrochloride solution (4.0 M, 2 mL), and the mixture was stirred at 25° C. Stir for 1 hour. Add saturated sodium bicarbonate solution to adjust the pH to 7, and concentrate under reduced pressure to obtain a crude product, which is purified by column chromatography to obtain a yellow solid [(3S)-1-(3-fluoro-4-(5-[1R)-1-methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl]-7-(2-methyl-2H-1,2,3-triazol-4-yl)pyrazolo[1,5-a]pyrimidin-2-yl)phenyl)pyrrolidin-3-yl]iminomethyl-λ^6-sulfonone (Compound 23, 10 mg).

[1197] 1 H NMR (400 MHz, DMSO-d 6)δ9.19-9.12(m,1H),8.22(t,J=8.8Hz,1H),7.76-7.65(m,1H),7.39-7.35(m,1H) ,7.30-7.13(m,4H),6.70-6.57(m,2H),5.69-5.63(m,1H),4.44-4.36(m,3H),4.1 4-4.01(m,2H),3.96-3.86(m,1H),3.79-3.71(m,2H),3.64-3.51(m,2H),3.48-3. 42(m,1H),3.15-3.03(m,2H),3.00(s,3H),2.49-2.38(m,2H),1.64-1.56(m,3H).

[1198] MS measured value (ESI + )[(M+H) + ]:614.36.

[1199] Example 25: Preparation of (2-(2-fluoro-4-((S)-3-(methylsulfonyl)pyrrolidin-1-yl)phenyl)-7-(2-isopropyl-2H-1,2,3-triazol-4-yl)pyrazolo[1,5-a]pyrimidin-5-yl)((R)-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone (Compound 24)

[1200]

[1201] 4,5-Dibromo-2-isopropyl-2H-1,2,3-triazole (1.3 g, 4.91 mmol) and isopropylmagnesium chloride in THF (6 mL, 12.27 mmol) were used in a similar manner to Example 9 to prepare (2-(2-fluoro-4-((S)-3-(methylsulfonyl)pyrrolidin-1-yl)phenyl)-7-(2-isopropyl-2H-1,2,3-triazol-4-yl)pyrazolo[1,5-a]pyrimidin-5-yl)((R)-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone (Compound 24, 68 mg). NMR(400MHz,DMSO-d6)δ9.17-9.14(m,1H),8.25-8.17(m,1H),7.77-7.68(m,1H) ,7.36-7.11(m,5H),6.70-6.60(m,2H),5.69-5.62(m,1H),5.12-5.02(m,1H),4. 22-4.14(m,1H)4.12-4.06(m,1H)3.76(d,J=6.4Hz,2H)3.61-3.43(m,3H)3.12(s ,3H)3.10-2.97(m,1H),2.83-2.76(m,1H),2.49-2.44(m,2H),1.66-1.58(m,9H).

[1202] MS measured value (ESI + )[(M+H) + ]:643.25.

[1203] Example 26: Preparation of (7-(2-ethyl-2H-1,2,3-triazol-4-yl)-2-(2-fluoro-4-((S)-3-(methylsulfonyl)pyrrolidin-1-yl)phenyl)pyrazolo[1,5-a]pyrimidin-5-yl)((R)-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone (Compound 25)

[1204]

[1205] 4,5-Dibromo-2-isopropyl-2H-1,2,3-triazole (3 g, 13.34 mmol) and iodoethane (2.1 g, 13.34 mmol) were used to prepare (7-(2-ethyl-2H-1,2,3-triazol-4-yl)-2-(2-fluoro-4-((S)-3-(methylsulfonyl)pyrrolidin-1-yl)phenyl)pyrazolo[1,5-a]pyrimidin-5-yl)((R)-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone (Compound 25, 68 mg) in a manner similar to Example 9. 1H NMR(400MHz,DMSO-d6)δppm 9.17-9.14(m,1H)8.24-8.18(m,1H)7.77-7.67(m,1H),7.39-7.09(m,5H)6. 69-6.60(m,2H)5.69-5.63(m,0.7H)5.22-5.17(m,0.3H)4.75-4.58(m,3H)4 .22-4.05(m,2H)3.76(d,J=6.4Hz,2H)3.61-3.42(m,3H)3.12-2.96(m,2H)2 .94-2.87(m,0.3H)2.81-2.77(m,0.7H)2.52-2.43(m,3H)1.64-1.54(m,6H)

[1206] MS measured value (ESI + )[(M+H) + ]:629.24.

[1207] Example 27: Preparation of (2-(4-((S)-3-aminopyrrolidin-1-yl)-2-fluorophenyl)-7-(2-methyl-2H-1,2,3-triazol-4-yl)pyrazolo[1,5-a]pyrimidin-5-yl)((R)-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone (Compound 26)

[1208]

[1209] (S)-tert-Butyl pyrrolidin-3-ylcarbamate hydrochloride (300 mg, 1.35 mmol) was used in a similar manner to Example 19 to prepare (2-(4-((S)-3-aminopyrrolidin-1-yl)-2-fluorophenyl)-7-(2-methyl-2H-1,2,3-triazol-4-yl)pyrazolo[1,5-a]pyrimidin-5-yl)((R)-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone (Compound 26, 58 mg). 1 H NMR (400 MHz, DMSO-d 6)δ9.13-9.09(m,1H),8.15(t,J=8.8Hz,1H),7.69(s,1H),7.35-7.25(m,1H), 7.20-7.05(m,4H),6.53-6.51(m,1H),6.45-6.40(m,1H),5.66-5.60(m,1H), 4.63-4.56(m,1H),4.39-4.35(m,3H),3.64-3.54(m,5H),3.08-2.96(m,2H), 2.86-2.72(m,1H),2.14-2.06(m,1H),1.80-1.71(m,1H),1.60-1.54(m,3H).

[1210] MS measured value (ESI + )(M+H) + :552.38.

[1211] Example 28: Preparation of (2-(2-fluoro-4-((S)-3-(hydroxymethyl)pyrrolidin-1-yl)phenyl)-7-(2-methyl-2H-1,2,3-triazol-4-yl)pyrazolo[1,5-a]pyrimidin-5-yl)((R)-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone (Compound 27)

[1212]

[1213] Step 1: Preparation of (S)-(1-(4-chloro-3-fluorophenyl)pyrrolidin-3-yl)methanol (Compound 27-1)

[1214]

[1215] In a nitrogen atmosphere, palladium acetate (107.76 mg, 0.48 mmol) and XantPhos (329.82 mg, 0.57 mmol) were added to (S)-pyrrolidin-3-ylmethanol (434.65 mg, 4.30 mmol), 4-bromo-1-chloro-2-fluorobenzene (600 mg, 2.86 mmol) and cesium carbonate (2.80 g, 8.59 mmol) in 1,4-dioxane (10 mL). The reaction mixture was stirred at 100 ° C for 5 hours. The reaction solution was cooled, pure water (50 mL) was added to quench the reaction, and extracted with ethyl acetate (100 mL × 3). The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by flash column chromatography to obtain a yellow solid (S)-(1-(4-chloro-3-fluorophenyl)pyrrolidin-3-yl)methanol (Compound 27-1, 520 mg).

[1216] Step 2: Preparation of (2-(2-fluoro-4-((S)-3-(hydroxymethyl)pyrrolidin-1-yl)phenyl)-7-(2-methyl-2H-1,2,3-triazol-4-yl)pyrazolo[1,5-a]pyrimidin-5-yl)((R)-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone (Compound 27)

[1217]

[1218] To a solution of (R)-(7-(2-methyl-2H-1,2,3-triazol-4-yl)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a]pyrimidin-5-yl)(1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone (200 mg, 0.40 mmol), (S)-(1-(4-chloro-3-fluorophenyl)pyrrolidin-3-yl)methanol (111 mg, 0.48 mmol) and sodium carbonate (128 mg, 1.20 mmol) in 1,4-dioxane (5 mL) was added chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) under nitrogen atmosphere. 2 (32 mg, 0.04 mmol) and water (1 mL). The mixture was heated to 100 ° C and stirred for 3 hours. After cooling, the mixture was diluted with ethyl acetate (100 mL), filtered through diatomaceous earth, and the filtrate was washed with saturated brine (50 mL), then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography to prepare a yellow solid (2-(2-fluoro-4-((S)-3-(hydroxymethyl)pyrrolidin-1-yl)phenyl)-7-(2-methyl-2H-1,2,3-triazol-4-yl)pyrazolo[1,5-a]pyrimidin-5-yl)((R)-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone (Compound 27, 20 mg).

[1219] 1 H NMR (400 MHz, DMSO-d 6)δ9.15-9.10(m,1H),8.16(t,J=8.8Hz,1H),7.72-7.60(m,1H),7.37-7.02 (m,5H),6.57-6.41(m,2H),5.68-5.59(m,1H),4.75(t,J=5.2Hz,1H),4.41 -4.33(m,3H),4.11-4.01(m,1H),3.57-3.36(m,5H),3.17-2.94(m,2H),2. 90-2.65(m,2H),2.13-2.01(m,1H),1.86-1.76(m,1H),1.61-1.52(m,3H).

[1220] MS measured value (ESI + )[(M+H) + ]:567.18.

[1221] Example 29: Preparation of (2-(2-fluoro-4-((S)-3-(2-hydroxyethoxy)pyrrolidin-1-yl)phenyl)-7-(2-methyl-2H-1,2,3-triazol-4-yl)pyrazolo[1,5-a]pyrimidin-5-yl)((R)-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone (Compound 28)

[1222]

[1223] Step 1: Preparation of (S)-ethyl 2-((1-(4-chloro-3-fluorophenyl)pyrrolidin-3-yl)oxy)acetate (Compound 28-1)

[1224]

[1225] At 0°C, sodium hydride (207 mg, 5.19 mmol) was added to a solution of (S)-1-(4-chloro-3-fluorophenyl)pyrrolidin-3-ol (560 mg, 2.60 mmol) in N,N-dimethylformamide (5 mL). The mixture was stirred at 0°C for half an hour. Ethyl 2-bromoacetate (1.1 g, 6.49 mmol) was added. The mixture was stirred at 25°C for 2 hours. It was quenched with saturated ammonium chloride solution (20 mL), diluted with ethyl acetate (100 mL), then washed with water (50 mL) and saturated brine (50 mL), then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography to obtain a colorless oily substance (S)-2-((1-(4-chloro-3-fluorophenyl)pyrrolidin-3-yl)oxy)ethyl acetate (compound 28-1, 620 mg).

[1226] Step 2: Preparation of (S)-2-((1-(4-chloro-3-fluorophenyl)pyrrolidin-3-yl)oxy)ethan-1-ol (Compound 28-2)

[1227]

[1228] To a solution of (S)-2-((1-(4-chloro-3-fluorophenyl)pyrrolidin-3-yl)oxy)ethyl acetate (620 mg, 2.05 mmol) in tetrahydrofuran (10 mL) at 0°C, lithium borohydride (135 mg, 6.16 mmol) was added, and the mixture was stirred at 25°C for 16 hours. The mixture was quenched with saturated ammonium chloride solution (20 mL), diluted with ethyl acetate (100 mL), then washed with water (50 mL) and saturated brine (50 mL), then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography to obtain a colorless oil (S)-2-((1-(4-chloro-3-fluorophenyl)pyrrolidin-3-yl)oxy)ethane-1-ol (compound 28-2, 140 mg).

[1229] Step 3: Preparation of (2-(2-fluoro-4-((S)-3-(2-hydroxyethoxy)pyrrolidin-1-yl)phenyl)-7-(2-methyl-2H-1,2,3-triazol-4-yl)pyrazolo[1,5-a]pyrimidin-5-yl)((R)-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone (Compound 28)

[1230]

[1231] In a nitrogen atmosphere, (R)-(7-(2-methyl-2H-1,2,3-triazol-4-yl)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a]pyrimidin-5-yl)(1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone (200 mg, 0.40 mmol), (S)-2-((1-(4-chloro To a solution of 2-(2-(2-(2-amino-1,1'-biphenyl)-3-nitropropane)-1-ol (124.81 mg, 0.48 mmol) and 1,4-dioxane (5 mL) was added chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) 2(31.40 mg, 0.04 mmol) and water (1 mL). The mixture was heated to 100 ° C and stirred for 3 hours. After cooling, the mixture was diluted with ethyl acetate (100 mL), filtered through diatomaceous earth, and the filtrate was washed with saturated brine (50 mL), then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography to prepare a yellow solid (2-(2-fluoro-4-((S)-3-(2-hydroxyethoxy)pyrrolidin-1-yl)phenyl)-7-(2-methyl-2H-1,2,3-triazol-4-yl)pyrazolo[1,5-a]pyrimidin-5-yl)((R)-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone (Compound 28, 50 mg).

[1232] 1 H NMR (400MHz, DMSO-d6) δ9.19-9.07(m,1H),8.16(t,J=8.8Hz,1H),7.71-7.60(m,1H),7.37-7.04(m,5H),6.63-6.41(m,2H),5.66-5. 61(m,1H),4.67-4.55(m,1H),4.42-4.34(m,3H),4.29-4.22(m,1H),3.58-3.48(m,6H),3.41-3.34(m,3H),3.08-3.02(m,1H),2.91-

[1233] 2.69(m,1H),2.16-2.03(m,2H),1.64-1.51(m,3H).

[1234] MS found value (ESI+) [(M+H)+]: 597.28.

[1235] Example 30: Preparation of (R)-(2-(2-fluoro-4-(3-(2-hydroxyethoxy)azetidin-1-yl)phenyl)-7-(2-methyl-2H-1,2,3-triazol-4-yl)pyrazolo[1,5-a]pyrimidin-5-yl)(1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone (Compound 29)

[1236]

[1237] 1-(4-Chloro-3-fluorophenyl)azetidin-3-ol (700 mg, 3.47 mmol) was used to prepare (R)-(2-(2-fluoro-4-(3-(2-hydroxyethoxy)azetidin-1-yl)phenyl)-7-(2-methyl-2H-1,2,3-triazol-4-yl)pyrazolo[1,5-a]pyrimidin-5-yl)(1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone (Compound 29, 64 mg) in a manner similar to that of Example 29.

[1238] 1 HNMR (400 MHz, DMSO-d 6 )δ9.16-9.10(m,1H),8.23-8.14(m,1H),7.74-7.66(m,1H),7.36-7.10(m,5H),6 .54(s,1H),6.48-6.39(m,2H),5.72-5.59(m,1H),4.75-4.69(m,H),4.55-4.48( m,1H),4.42-4.36(m,3H),4.23-4.17(m,2H),4.12-4.04(m,1H),3.82-3.73(m,2 H),3.57-3.54(m,2H),3.51-3.45(m,2H),3.04-2.84(m,1H),1.63-1.56(m,3H).

[1239] MS measured value (ESI + )[(M+H) + ]:583.33.

[1240] Example 31: Preparation of ((7-(2-cyclobutyl-2H-1,2,3-triazol-4-yl)-2-(2-fluoro-4-((S)-3-(methylsulfonyl)pyrrolidin-1-yl)phenyl)pyrazolo[1,5-a]pyrimidin-5-yl)((R)-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone (Compound 30)

[1241]

[1242] 4,5-Dibromo-2H-1,2,3-triazole (3 g, 13.34 mmol) and bromocyclobutane (1.78 g, 13.34 mmol) were used in a manner similar to that of Example 9 to prepare ((7-(2-cyclobutyl-2H-1,2,3-triazol-4-yl)-2-(2-fluoro-4-((S)-3-(methylsulfonyl)pyrrolidin-1-yl)phenyl)pyrazolo[1,5-a]pyrimidin-5-yl)((R)-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone (Compound 30, 44 mg).

[1243] 1 HNMR (400 MHz, DMSO-d 6 )δ9.18-9.16(m,1H),8.24-8.18(m,1H),7.79-7.70(m,1H),7.37-7.10(m,5H),6.69-6.60( m,2H),5.68-5.63(m,1H),5.46-5.34(m,1H),4.22-4.14(m,1H),4.11-4.05(m,1H),3.76(d, J=6.4Hz,2H),3.61-3.44(m,3H),3.13(s,3H),3.09-2.96(m,1H),2.93-2.87(m,1H),2.80-2 .67(m,3H),2.65-2.57(m,2H),2.47(q,J=7.2Hz,2H),2.04-1.91(m,2H),1.65-1.58(m,2H).

[1244] MS measured value (ESI + )[(M+H) + ]:655.25.

[1245] Example 32: Preparation of (2-(4-((S)-3-((cyclopropylmethyl)sulfonyl)pyrrolidin-1-yl)-2-fluorophenyl)-7-(2-methyl-2H-1,2,3-triazol-4-yl)pyrazolo[1,5-a]pyrimidin-5-yl)((R)-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone (Compound 31)

[1246]

[1247] (2-(4-((S)-3-((cyclopropylmethyl)sulfonyl)pyrrolidin-1-yl)-2-fluorophenyl)-7-(2-methyl-2H-1,2,3-triazol-4-yl)pyrazolo[1,5-a]pyrimidin-5-yl)((R)-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone (Compound 31, 44 mg) was prepared from (bromomethyl)cyclopropane (2.0 g, 14.76 mmol) in a manner similar to that of Example 14.

[1248] 1H NMR (400MHz, DMSO-d6) δ9.16-9.14(m,1H),8.22(t,J=8.8Hz,1H),7.74-7.67(m,1H),7.38 -7.10(m,5H),6.70-6.67(m,2H),5.68-5.62(m,1H),5.23-5.16(m,1H),4.42-4.35(m,3H), 4.25-4.18(m,1H),3.80-3.71(m,2H),3.61-3.43(m,3H),3.25(d,J=6.4Hz,2H),3.14-2.9 7(m,1H),2.81-2.77(m,1H),2.50-2.40(m,2H),1.66-1.56(m,3H),1.17-1.10(m,1H),0.73

[1249] -0.64(m,2H),0.47-0.44(m,2H).

[1250] MS measured value (ESI + )[(M+H) + ]:655.25.

[1251] Example 33: Preparation of (R)-(2-(2,2-dioxido-2-thia-6-azaspiro[3.3]heptyl-6-yl)-2-fluorophenyl)-7-(2-methyl-2H-1,2,3-triazol-4-yl)pyrazolo[1,5-a]pyrimidin-5-yl)(1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone (Compound 32)

[1252]

[1253] Step 1: Preparation of 6-(4-chloro-3-fluorophenyl)-2-thiophene-6-azaspiro[3.3]heptane 2,2-dioxide (Compound 32-1)

[1254]

[1255] In a nitrogen atmosphere, palladium acetate (46 mg, 0.21 mmol) and XantPhos (235 mg, 0.41 mmol) were added to 2-thia-6-azaspiro[3.3]heptane 2,2-dioxide (300 mg, 2.04 mmol), 4-bromo-1-chloro-2-fluorobenzene (424 mg, 2.04 mmol) and cesium carbonate (2.0 g, 6.12 mmol) in 1,4-dioxane (15 mL). The reaction mixture was stirred at 100 ° C for 8 hours. The reaction solution was cooled, pure water (15 mL) was added to quench the reaction, and extracted with ethyl acetate (100 mL×3). The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by flash column chromatography to obtain white solid 6-(4-chloro-3-fluorophenyl)-2-thiophene-6-azaspiro[3.3]heptane 2,2-dioxide (compound 32-1, 300 mg).

[1256] Step 2: Preparation of (R)-(2-(2,2-dioxido-2-thia-6-azaspiro[3.3]heptyl-6-yl)-2-fluorophenyl)-7-(2-methyl-2H-1,2,3-triazol-4-yl)pyrazolo[1,5-a]pyrimidin-5-yl)(1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone (Compound 32)

[1257]

[1258] In a nitrogen atmosphere, (R)-(7-(2-methyl-2H-1,2,3-triazol-4-yl)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a]pyrimidin-5-yl)(1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone (150 mg, 0.30 mmol), 6-(4-chloro-3-fluorobenzene)-1,4-dihydro-1,4-dihydro-2-(1,4-dihydro-3-( ... To a solution of 1,4-dioxane (5 mL) of 2-(2-(2'-amino-1,1'-biphenyl)-2-thiophene-6-azaspiro[3.3]heptane 2,2-dioxide (100 mg, 0.36 mmol) and sodium carbonate (96 mg, 0.91 mmol) was added chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) 2(24 mg, 0.03 mmol) and water (1 mL). The mixture was heated to 100 ° C and stirred for 3 hours. After cooling, the mixture was diluted with ethyl acetate (100 mL), filtered through diatomaceous earth, the filtrate was washed with saturated brine (50 mL), then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography to obtain a yellow solid (R)-(2-(2,2-dioxido-2-thia-6-azaspiro[3.3]heptyl-6-yl)-2-fluorophenyl)-7-(2-methyl-2H-1,2,3-triazol-4-yl)pyrazolo[1,5-a]pyrimidin-5-yl)(1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone (Compound 32, 40 mg).

[1259] 1 H NMR (400 MHz, DMSO-d 6 )δ9.16-9.12(m,1H),8.22(t,J=8.4Hz,1H),7.76-7.66(m,1H),7.39-7 .36(m,1H),7.31-7.14(m,4H),6.56-6.47(m,2H),5.66(d,J=7.2Hz,1H) ,4.55(s,4H),4.43-4.37(m,3H),4.21(s,4H),4.13-4.05(m,1H),3.61 -3.51(m,1H),3.12-2.98(m,1H),2.83-2.70(m,1H),1.66-1.54(m,3H).

[1260] MS measured value (ESI + )[(M+H) + ]:613.33.

[1261] Example 34: Preparation of (S)-1-(3-fluoro-4-(5-(R)-1-methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-7-(2-methyl-2H-1,2,3-triazol-4-yl)pyrazolo[1,5-a]pyrimidin-2-yl)phenyl)pyrrolidin-3-yl)(methyl)(methylimino)-L6-sulfonalkanone (Compound 33)

[1262]

[1263] Step 1: Preparation of (S)-1-(3-fluoro-4-(5-(R)-1-methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-7-(2-methyl-2H-1,2,3-triazol-4-yl)pyrazolo[1,5-a]pyrimidin-2-yl)phenyl)pyrrolidin-3-yl)(methyl)(methylimino)-L6-sulfonalkanone (Compound 33)

[1264]

[1265] To a solution of [(3S)-1-(3-fluoro-4-(5-[1R)-1-methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl]-7-(2-methyl-2H-1,2,3-triazol-4-yl)pyrazolo[1,5-a]pyrimidin-2-yl)phenyl)pyrrolidin-3-yl]iminomethyl-λ^6-sulfonone (5 mg, 0.01 mmol) in tetrahydrofuran (5 mL) was added sodium hydride (2 mg, 0.01 mmol). The mixture was stirred at 25° C. for half an hour. Methyl iodide (2 mg, 0.01 mmol) was added and the mixture was stirred at 25° C. for another hour. The reaction mixture was concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography to obtain a yellow solid (S)-1-(3-fluoro-4-(5-(R)-1-methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-7-(2-methyl-2H-1,2,3-triazol-4-yl)pyrazolo[1,5-a]pyrimidin-2-yl)phenyl)pyrrolidin-3-yl)(methyl)(methylimino)-L6-sulfonalkanone (Compound 33, 2 mg).

[1266] 1 H NMR (400 MHz, DMSO-d 6 )δ9.20-9.11(m,1H),8.22(t,J=8.8Hz,1H),7.76-7.63(m,1H),7.37(d,J=7. 2Hz,1H),7.31-7.14(m,4H),6.70-6.58(m,2H),5.69-5.63(m,1H)4.45-4.38 (m,3H),4.22-4.14(m,1H),3.81-3.70(m,2H),3.64-3.52(m,2H),3.00(s,3H ),2.72-2.65(m,3H)2.51-2.42(m,3H),1.66-1.56(m,3H),1.31-1.23(m,3H).

[1267] MS measured value (ESI + )[(M+H) + ]:628.55.

[1268] Example 35: Preparation of (2-(4aR,7aR)-1,1-dioxohexahydrothiopyrano[2,3-c]pyrrole-6(2H)-2-fluorophenyl)-7-(2-methyl-2H-1,2,3-triazol-4-yl)pyrazolo[1,5-a]pyrimidin-5-yl)(R)-1-methyl-3,4-dihydroisoquinolin-2(1H)yl)methanone (Compound 34)

[1269]

[1270] Step 1: Preparation of (4aR, 7aR)-6-(4-chloro-3-fluorophenyl)octahydrothiopyrano[2,3-c]pyrrole 1,1-dioxide (Compound 34-1)

[1271]

[1272] In a nitrogen atmosphere, palladium acetate (32 mg, 0.14 mmol) and XantPhos (165 mg, 0.29 mmol) were added to (4aR, 7aR)-octahydrothiopyrano[2,3-c]pyrrole 1,1-dioxide (250 mg, 1.43 mmol), 4-bromo-1-chloro-2-fluorobenzene (300 mg, 1.43 mmol) and cesium carbonate (1.4 g, 64.29 mmol) in 1,4-dioxane (15 mL). The reaction mixture was stirred at 100 ° C for 8 hours. The reaction solution was cooled, pure water (50 mL) was added to quench the reaction, and extracted with ethyl acetate (100 mL×3). The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by flash column chromatography to obtain a white solid (4aR, 7aR)-6-(4-chloro-3-fluorophenyl)octahydrothiopyrano[2,3-c]pyrrole 1,1-dioxide (compound 34-1, 300 mg).

[1273] Step 2: Preparation of (2-(4aR,7aR)-1,1-dioxohexahydrothiopyrano[2,3-c]pyrrole-6(2H)-2-fluorophenyl)-7-(2-methyl-2H-1,2,3-triazol-4-yl)pyrazolo[1,5-a]pyrimidin-5-yl)(R)-1-methyl-3,4-dihydroisoquinolin-2(1H)yl)methanone (Compound 34)

[1274]

[1275] In a nitrogen atmosphere, (R)-(7-(2-methyl-2H-1,2,3-triazol-4-yl)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a]pyrimidin-5-yl)(1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone (150 mg, 0.30 mmol), (4aR, 7aR)-6-(4 To a solution of 1,1-dioxane (5 mL) of 2-(2-chloro-3-fluorophenyl)octahydrothiopyrano[2,3-c]pyrrole 1,1-dioxide (100 mg, 0.33 mmol) and sodium carbonate (96 mg, 0.91 mmol) was added chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) 2 (24 mg, 0.03 mmol) and water (1 mL). The mixture was heated to 100 ° C and stirred for 3 hours. After cooling, the mixture was diluted with ethyl acetate (100 mL), filtered through diatomaceous earth, and the filtrate was washed with saturated brine (50 mL), then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography to prepare a yellow solid (2-(4aR, 7aR)-1,1-dioxohexahydrothiopyrano[2,3-c]pyrrole-6(2H)-2-fluorophenyl)-7-(2-methyl-2H-1,2,3-triazol-4-yl)pyrazolo[1,5-a]pyrimidin-5-yl)(R)-1-methyl-3,4-dihydroisoquinolin-2(1H)yl)methanone (Compound 34, 40 mg).

[1276] 1 H NMR (400 MHz, DMSO-d 6 )δ9.15(d,J=3.6Hz,1H),8.22(t,J=8.8Hz,1H),7.75-7.65(m,1H),7.31-7.12( m,5H),6.66-6.52(m,2H),5.66(d,J=6.4Hz,1H),4.44-4.37(m,4H),4.12-3.96( m,2H),3.89-3.80(m,1H),3.75-3.68(m,1H),3.61-3.46(m,2H),3.23-3.14(m,1 H),3.03-2.90(m,2H),2.16-1.97(m,3H),1.93-1.81(m,1H),1.70-1.50(m,5H).

[1277] MS measured value (ESI + )[(M+H) + ]:641.37.

[1278] Example 36: Preparation of (R)-N-(3-fluoro-4-(5-((R)-1-methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-7-(2-methyl-2H-1,2,3-triazol-4-yl)pyrazolo[1,5-a]pyrimidin-2-yl)phenyl)-3-hydroxypyrrolidine-1-carboxamide (Compound 35)

[1279]

[1280] Step 1: Preparation of (R)-N-(4-bromo-3-fluorophenyl)-3-hydroxypyrrolidine-1-carboxamide (Compound 35-2)

[1281]

[1282] Carbonyldiimidazole (1.1 g, 7.89 mmol) was added to a solution of 4-bromo-3-fluoroaniline (500 mg, 2.63 mmol) in tetrahydrofuran (10 mL) at 0°C. The mixture was stirred at 0°C for 1 hour. (R)-pyrrolidin-3-ol (459 mg, 5.26 mmol) was added. The mixture was stirred at 25°C for 2 hours. The reaction was quenched with saturated ammonium chloride (10 mL), extracted with ethyl acetate (100 mL), washed with saturated brine (50 mL), then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography to obtain a white solid (R)-N-(4-bromo-3-fluorophenyl)-3-hydroxypyrrolidine-1-carboxamide (compound 35-2, 700 mg).

[1283] Step 2: Preparation of (R)-N-(3-fluoro-4-(5-((R)-1-methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-7-(2-methyl-2H-1,2,3-triazol-4-yl)pyrazolo[1,5-a]pyrimidin-2-yl)phenyl)-3-hydroxypyrrolidine-1-carboxamide (Compound 35)

[1284]

[1285] Under nitrogen atmosphere, to a solution of (R)-(7-(2-methyl-2H-1,2,3-triazol-4-yl)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a]pyrimidin-5-yl)(1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone (150 mg, 0.30 mmol), (R)-N-(4-bromo-3-fluorophenyl)-3-hydroxypyrrolidine-1-carboxamide (100 mg, 0.33 mmol), sodium carbonate (96 mg, 0.91 mmol) in 1,4-dioxane (5 mL) was added chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) 2 (24 mg, 0.03 mmol) and water (1 mL). The mixture was heated to 100 ° C and stirred for 3 hours. After cooling, the mixture was diluted with ethyl acetate (100 mL), filtered through diatomaceous earth, and the filtrate was washed with saturated brine (50 mL), then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography to prepare a yellow solid (R)-N-(3-fluoro-4-(5-((R)-1-methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-7-(2-methyl-2H-1,2,3-triazol-4-yl)pyrazolo[1,5-a]pyrimidin-2-yl)phenyl)-3-hydroxypyrrolidine-1-carboxamide (Compound 35, 30 mg).

[1286] 1 HNMR (400 MHz, DMSO-d 6 )δ9.21-9.16(m,1H),8.61(s,1H),8.31-8.27(m,1H),7.84-7.69(m,2H ),7.56-7.54(m,1H),7.40-7.10(m,5H),5.69-5.64(m,1H),5.20-5.02 (m,1H),4.45-4.31(m,4H),4.10-4.07(m,1H),3.63-3.44(m,4H),3.15 –2.81(m,2H),2.02-1.94(m,1H),1.90-1.84(m,1H),1.66-1.57(m,3H).

[1287] MS measured value (ESI + )[(M+H) + ]:596.34.

[1288] Example 37: Preparation of 1-(3-fluoro-4-(5-(((R)-1-methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-7-(2-methyl-2H-1,2,3-triazol-4-yl)pyrazolo[1,5-a]pyrimidin-2-yl)phenyl)pyrrolidine-3-sulfonamide (Compound 36)

[1289]

[1290] Step 1: Preparation of tert-butyl 3-aminosulfonylpyrrolidine-1-carboxylate (Compound 36-2)

[1291]

[1292] In a nitrogen atmosphere, at 0°C, ammonia water (50 mL) was added dropwise to dichloromethane (20 mL) of tert-butyl 3-(chlorosulfonyl)pyrrolidine-1-carboxylate (1.0 g, 3.71 mmol). The reaction mixture was stirred at 25°C for 16 hours. The reaction solution was concentrated under reduced pressure, pure water (50 mL) was added, and extracted with ethyl acetate (100 mL×3). The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain tert-butyl 3-aminosulfonylpyrrolidine-1-carboxylate (compound 36-2, 600 mg) as a white solid.

[1293] Step 2: Preparation of pyrrolidine-3-sulfonamide hydrochloride (Compound 36-3)

[1294]

[1295] To tert-butyl 3-aminosulfonylpyrrolidine-1-carboxylate (600 mg, 2.40 mmol) in dichloromethane (10 mL) was added dioxane hydrochloride (5 mL). The reaction mixture was stirred at 25 °C for 2 hours. The reaction solution was concentrated under reduced pressure to obtain pyrrolidine-3-sulfonamide hydrochloride (compound 36-3, 300 mg) as a white solid.

[1296] Step 3: Preparation of 1-(4-chloro-3-fluorophenyl)pyrrolidine-3-sulfonamide (Compound 36-4)

[1297]

[1298] In a nitrogen atmosphere, palladium acetate (33 mg, 0.14 mmol) and XantPhos (166 mg, 0.29 mmol) were added to pyrrolidine-3-sulfonamide hydrochloride (237 mg, 1.58 mmol), 4-bromo-1-chloro-2-fluorobenzene (300 mg, 1.42 mmol) and cesium carbonate (1.4 g, 4.30 mmol) in 1,4-dioxane (10 mL). The reaction mixture was stirred at 100 ° C for 5 hours. The reaction solution was cooled, pure water (50 mL) was added to quench the reaction, and extracted with ethyl acetate (100 mL × 3). The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by flash column chromatography to obtain a white solid 1-(4-chloro-3-fluorophenyl)pyrrolidine-3-sulfonamide (compound 36-4, 100 mg).

[1299] Step 4: Preparation of 1-(3-fluoro-4-(5-(((R)-1-methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-7-(2-methyl-2H-1,2,3-triazol-4-yl)pyrazolo[1,5-a]pyrimidin-2-yl)phenyl)pyrrolidine-3-sulfonamide (Compound 36)

[1300]

[1301] Under nitrogen atmosphere, to a solution of (R)-(7-(2-methyl-2H-1,2,3-triazol-4-yl)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a]pyrimidin-5-yl)(1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone (150 mg, 0.30 mmol), 1-(4-chloro-3-fluorophenyl)pyrrolidine-3-sulfonamide (100 mg, 0.36 mmol), sodium carbonate (96 mg, 0.91 mmol) in 1,4-dioxane (5 mL) was added chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) 2(24 mg, 0.03 mmol) and water (1 mL). The mixture was heated to 100 ° C and stirred for 3 hours. After cooling, the mixture was diluted with ethyl acetate (100 mL), filtered through diatomaceous earth, and the filtrate was washed with saturated brine (50 mL), then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography to obtain a yellow solid 1-(3-fluoro-4-(5-(((R)-1-methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-7-(2-methyl-2H-1,2,3-triazol-4-yl)pyrazolo[1,5-a]pyrimidin-2-yl)phenyl)pyrrolidine-3-sulfonamide (Compound 36, 5 mg).

[1302] 1 HNMR (400 MHz, DMSO-d 6 )δ9.21-9.16(m,1H),8.61(s,1H),8.31-8.27(m,1H),7.84-7.69(m,2H ),7.56-7.54(m,1H),7.40-7.10(m,5H),5.69-5.64(m,1H),4.63-4.56 (m,1H),4.39-4.35(m,3H),3.64-3.54(m,5H),3.08-2.96(m,2H),2.86 -2.72(m,1H),2.14-2.06(m,1H),1.80-1.71(m,1H),1.60-1.54(m,3H).

[1303] MS measured value (ESI + )[(M+H) + ]:616.32.

[1304] Example 38: Preparation of ((2-(4-((3R,4R)-3,4-dihydroxypyrrolidin-1-yl)-2-fluorophenyl)-7-(2-methyl-2H-1,2,3-triazol-4-yl)pyrazolo[1,5-a]pyrimidin-5-yl)((R)-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone (Compound 37)

[1305]

[1306] Step 1: Preparation of (3R, 4R)-1-(4-chloro-3-fluorophenyl)pyrrolidine-3,4-diol (Compound 37-1)

[1307]

[1308] In a nitrogen atmosphere, palladium acetate (32 mg, 0.15 mmol) and XantPhos (166 mg, 0.29 mmol) were added to (S)-3-(methylsulfonyl)pyrrolidine hydrochloride (163 mg, 1.58 mmol), 4-bromo-1-chloro-2-fluorobenzene (300 mg, 1.43 mmol) and cesium carbonate (1.4 g, 4.30 mmol) in 1,4-dioxane (10 mL). The reaction mixture was stirred at 100 ° C for 16 hours. The reaction solution was cooled, pure water (50 mL) was added to quench the reaction, and extracted with ethyl acetate (100 mL × 3). The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by flash column chromatography to obtain a white solid (3R, 4R)-1-(4-chloro-3-fluorophenyl)pyrrolidine-3,4-diol (compound 37-1, 120 mg).

[1309] Step 3: Preparation of (2-(4-((3R,4R)-3,4-dihydroxypyrrolidin-1-yl)-2-fluorophenyl)-7-(2-methyl-2H-1,2,3-triazol-4-yl)pyrazolo[1,5-a]pyrimidin-5-yl)((R)-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone (Compound 37)

[1310]

[1311] To a solution of (R)-(7-(2-methyl-2H-1,2,3-triazol-4-yl)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a]pyrimidin-5-yl)(1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone (150 mg, 0.30 mmol), (3R,4R)-1-(4-chloro-3-fluorophenyl)pyrrolidine-3,4-diol (77 mg, 0.33 mmol) and sodium carbonate (96 mg, 0.91 mmol) in 1,4-dioxane (5 mL) was added chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) under nitrogen atmosphere. 2(24 mg, 0.03 mmol) and water (1 mL). The mixture was heated to 100 ° C and stirred for 3 hours. After cooling, the mixture was diluted with ethyl acetate (100 mL), filtered through diatomaceous earth, the filtrate was washed with saturated brine (50 mL), then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography to obtain a yellow solid (2-(4-((3R, 4R)-3,4-dihydroxypyrrolidin-1-yl)-2-fluorophenyl)-7-(2-methyl-2H-1,2,3-triazol-4-yl)pyrazolo[1,5-a]pyrimidin-5-yl)((R)-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone (Compound 37, 44 mg).

[1312] 1 H NMR (400 MHz, DMSO-d 6 )δ9.17-9.05(m,1H),8.16(t,J=8.8Hz,H),7.53-7.76(m,1H),7.36-7.05(m ,5H),6.57-6.42(m,2H),5.69-5.11(m,1H),5.08-5.01(m,1H),4.63-4.53(m ,1H),4.44(s,1H),4.40-4.34(m,3H),4.10-4.03(m,1H),3.57-3.36(m,5H) ,3.21-3.15m,1H),3.10-2.92(m,1H),2.91-2.71(m,1H),1.61-1.53(m,3H).

[1313] MS measured value (ESI + )[(M+H) + ]:569.23.

[1314] Example 39: Preparation of (S)-N-(3-fluoro-4-(5-((R)-1-methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-7-(2-methyl-2H-1,2,3-triazol-4-yl)pyrazolo[1,5-a]pyrimidin-2-yl)phenyl)-3-hydroxypyrrolidine-1-carboxamide (Compound 38)

[1315]

[1316] (S)-Pyrrolidin-3-ol (459 mg, 5.26 mmol) was used in a similar manner to Example 36 to prepare (S)-N-(3-fluoro-4-(5-((R)-1-methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-7-(2-methyl-2H-1,2,3-triazol-4-yl)pyrazolo[1,5-a]pyrimidin-2-yl)phenyl)-3-hydroxypyrrolidine-1-carboxamide (Compound 38, 56 mg).

[1317] 1 HNMR (400 MHz, DMSO-d 6 )δ9.21-9.16(m,1H),8.61(s,1H),8.31-8.27(m,1H),7.84-7.69(m,2H ),7.56-7.54(m,1H),7.40-7.10(m,5H),5.69-5.63(m,1H),5.20-5.00 (m,1H),4.45-4.31(m,4H),4.10-4.07(m,1H),3.63-3.44(m,4H),3.15 -2.81(m,2H),2.02-1.94(m,1H),1.90-1.84(m,1H),1.66-1.55(m,3H).

[1318] MS measured value (ESI + )[(M+H) + ]:596.29.

[1319] Example 40: Preparation of (2-(2-fluoro-4-((R)-3-(morpholinomethyl)pyrrolidin-1-yl)phenyl)-7-(2-methyl-2H-1,2,3-triazol-4-yl)pyrazolo[1,5-a]pyrimidin-5-yl (Compound 39)

[1320]

[1321] (S)-tert-Butyl (pyrrolidin-3-ylmethyl)carbamate (847 mg, 3.58 mmol) was used in a similar manner to Example 10 to prepare (2-(2-fluoro-4-((R)-3-(morpholinomethyl)pyrrolidin-1-yl)phenyl)-7-(2-methyl-2H-1,2,3-triazol-4-yl)pyrazolo[1,5-a]pyrimidin-5-yl (Compound 39, 58 mg).

[1322] 1HNMR(400MHz,DMSO-d6)δ9.15-9.13(m,1H),8.21-8.15(m,1H),7.73-7.65(m,1H),7.37-7.1 1(m,5H),6.59-6.45(m,2H),5.68-5.63(m,1H),4.38-4.43(m,3H),4.13-4.06(m,1H),3.67- 3.59(m,5H),3.57-3.40(m,3H),3.34-3.29(m,1H),3.12-2.97(m,2H),2.82-2.75(m,1H),2. 67-2.58(m,1H),2.45-2.37(m,5H),2.19-2.10(m,1H),1.82-1.72(m,1H),1.64-1.56(m,3H).

[1323] MS measured value (ESI + )[(M+H) + ]:636.31.

[1324] Example 41: Preparation of (2-(4-fluoro-6-((S)-3-(methylsulfonyl)pyrrolidin-1-yl)pyridin-3-yl)-7-(2-methyl-2H-1,2,3-triazol-4-yl)pyrazolo[1,5-a]pyrimidin-5-yl)((R)-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone (Compound 40)

[1325]

[1326] Step 1: Preparation of (S)-4-fluoro-2-(3-(methylsulfonyl)pyrrolidin-1-yl)pyridine (Compound 40-2)

[1327]

[1328] Under nitrogen atmosphere, tris dibenzylideneacetone dipalladium (156 mg, 0.17 mmol) and 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (106 mg, 0.17 mmol) were added to a solution (5 mL) of 2-bromo-4-fluoropyridine (300 mg, 1.70 mmol), (S)-3-(methylsulfonyl)pyrrolidine hydrochloride (316.5 mg, 1.70 mmol) and sodium tert-butoxide (491 mg, 5.11 mmol) in 1,4-dioxane. The mixture was heated to 100° C. in a microwave and stirred for 2 hours. Cool, dilute with ethyl acetate (100 mL), then wash with water (50 mL) and saturated brine (50 mL), then dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure to give a crude product, which was purified by column chromatography to give a brown solid (S)-4-fluoro-2-(3-(methylsulfonyl)pyrrolidin-1-yl)pyridine (compound 40-2, 250 mg).

[1329] Step 2: Preparation of (S)-5-bromo-4-fluoro-2-(3-(methylsulfonyl)pyrrolidin-1-yl)pyridine (Compound 40-3)

[1330]

[1331] N-bromosuccinimide (182 mg, 1.02 mmol) was added to a solution of (S)-4-fluoro-2-(3-(methylsulfonyl)pyrrolidin-1-yl)pyridine (250 mg, 1.02 mmol) in acetonitrile (3 mL). The mixture was stirred at 25 ° C for 8 hours. . Diluted with ethyl acetate (50 mL), washed with saturated brine (30 mL), then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography to prepare a white solid (S)-5-bromo-4-fluoro-2-(3-(methylsulfonyl)pyrrolidin-1-yl)pyridine (compound 40-3, 150 mg).

[1332] Step 3: Preparation of (2-(4-fluoro-6-((S)-3-(methylsulfonyl)pyrrolidin-1-yl)pyridin-3-yl)-7-(2-methyl-2H-1,2,3-triazol-4-yl)pyrazolo[1,5-a]pyrimidin-5-yl)((R)-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone (Compound 40)

[1333]

[1334] Under nitrogen atmosphere, (R)-(7-(2-methyl-2H-1,2,3-triazol-4-yl)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a]pyrimidin-5-yl)(1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone (130 mg, 0.26 mmol), (S)-5-bromo-4-fluoro-2-(3-(methyl)- To a solution of 1,4-dioxane (5 mL) of 2-(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (25 mg, 0.03 mmol) and water (1 mL) was added 2-(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (25 mg, 0.03 mmol) and water (1 mL). The mixture was heated to 100° C. and stirred for 3 hours. After cooling, the mixture was diluted with ethyl acetate (100 mL), filtered through celite, the filtrate was washed with saturated brine (50 mL), then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude product, which was purified by column chromatography to give a yellow solid (2-(4-fluoro-6-((S)-3-(methylsulfonyl)pyrrolidin-1-yl)pyridin-3-yl)-7-(2-methyl-2H-1,2,3-triazol-4-yl)pyrazolo[1,5-a]pyrimidin-5-yl)((R)-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone (Compound 40, 32 mg).

[1335] 1 HNMR (400 MHz, DMSO-d 6 )δ9.17-9.14(m,1H),9.13-9.06(m,1H),7.77-7.68(m,1H),7.30-7.10 (m,5H),6.67-6.61(m,1H),5.69-5.62(m,1H),4.46-4.36(m,3H),4.21 -4.05(m,2H),3.99-3.86(m,2H),3.72-3.48(m,3H),3.13(s,3H),3.12 -3.00(m,1H),2.94-2.74(m,1H),2.52-2.46(m,2H),1.64-1.58(m,3H).

[1336] MS measured value (ESI + )[(M+H) + ]:616.35.

[1337] Example 42: Preparation of (2-(2-fluoro-4-((S)-3-(methylsulfonyl)pyrrolidin-1-yl)phenyl)-7-(2-methyl-2H-1,2,3-triazol-4-yl)pyrazolo[1,5-a]pyrimidin-5-yl)((R)-4-methyl-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-yl)methanone (Compound 41)

[1338]

[1339] Step 1: Preparation of tert-butyl (2-(5-acetyl-1H-pyrazol-1-yl)ethyl)carbamate (Compound 41-2)

[1340]

[1341] Under nitrogen atmosphere, at 0°C, triphenylphosphine (17.9 g, 68.11 mmol) and DEAD (11.9 g, 68.11 mmol) were added to a solution of 1-(1H-pyrazol-5-yl)ethane-1-one (5.0 g, 91.0 mmol) and tert-butyl (2-hydroxyethyl)carbamate (9.52 g, 118 mmol) in 1,4-dioxane (50 mL). The mixture was stirred at 25°C for 16 hours. The reaction was quenched with saturated sodium bicarbonate solution (20 mL), and extracted with ethyl acetate (100 mL×3). The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by flash column chromatography to obtain colorless oily compound tert-butyl (2-(5-acetyl-1H-pyrazol-1-yl)ethyl)carbamate (compound 41-2, 6.2 g).

[1342] Step 2: Preparation of 4-methyl-6,7-dihydropyrazolo[1,5-a]pyrazine (Compound 41-3)

[1343]

[1344] TFA (5.0 mL, 59.22 mmol) was added to a solution of tert-butyl (2-(5-acetyl-1H-pyrazol-1-yl)ethyl)carbamate (3.0 g, 11.84 mmol) in dichloromethane (50 mL). The mixture was stirred at 25 °C for 4 hours. The reaction was quenched with saturated sodium bicarbonate solution (20 mL), and extracted with dichloromethane (100 mL×3). The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a colorless oily compound 4-methyl-6,7-dihydropyrazole [1,5-a] pyrazine (compound 41-3, 756 mg).

[1345] Step 3: Preparation of 4-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine (Compound 41-4)

[1346]

[1347] Sodium borohydride (1.1 g, 27.59 mmol) was added in portions to a solution of 4-methyl-6,7-dihydropyrazole [1,5-a] pyrazine (756 mg, 5.59 mmol) in methanol (4 mL) at 0°C. The mixture was stirred at 25°C for 2 hours. The reaction was quenched with saturated sodium bicarbonate solution (20 mL) and extracted with dichloromethane (100 mL×3). The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a yellow oily substance 4-methyl-4,5,6,7-tetrahydropyrazole [1,5-a] pyrazine (compound 41-4, 490 mg).

[1348] Step 4: Preparation of (2-bromo-7-(2-methyl-2H-1,2,3-triazol-4-yl)pyrazolo[1,5-a]pyrimidin-5-yl)(4-methyl-6,7-dihydropyrazolo[1.5-a]pyrazine-5(4H)-yl)methanone (Compound 41-5)

[1349]

[1350] To a solution of 2-bromo-7-(2-methyl-2H-1,2,3-triazol-4-yl)pyrazolo[1,5-a]pyrimidine-5-carboxylic acid (500 mg, 1.55 mmol) in N,N-dimethylformamide (5 mL) was added 4-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine (255 mg, 1.86 mmol), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (883 mg, 2.32 mmol) and N,N-diisopropylethylamine (600 mg, 4.64 mmol). The mixture was stirred at 25° C. for 4 hours. The reaction solution was added with water (50 mL), and the precipitate was filtered out to obtain a crude product. The crude product was purified by column chromatography to obtain a yellow solid (2-bromo-7-(2-methyl-2H-1,2,3-triazol-4-yl)pyrazol[1,5-a]pyrimidin-5-yl)(4-methyl-6,7-dihydropyrazol[1.5-a]pyrazine-5(4H)-yl)methanone (compound 41-5, 600 mg).

[1351] Step 5: Preparation of (2-(2-fluoro-4-((S)-3-(methylsulfonyl)pyrrolidin-1-yl)phenyl)-7-(2-methyl-2H-1,2,3-triazol-4-yl)pyrazolo[1,5-a]pyrimidin-5-yl)((R)-4-methyl-6,7-dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl)methanone (Compound 41)

[1352]

[1353] In a nitrogen atmosphere, (((2-bromo-7-(2-methyl-2H-1,2,3-triazol-4-yl)pyrazolo[1,5-a]pyrimidin-5-yl)(4-methyl-6,7-dihydropyrazolo[1.5-a]pyrazin-5(4H)-yl)methanone (326 mg, 0.88 mmol) (S)-1-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2- To a solution of 2-(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) was added 1,4-dioxane solution (5 mL) of 2-(2-dioxaborolan-2-yl)phenyl)-3-(methylsulfonyl)pyrrolidine (260 mg, 0.59 mmol) and sodium carbonate (187 mg, 1.76 mmol) 2 (48 mg, 0.06 mmol) and water (1 mL). The mixture was heated to 100 ° C and stirred for 3 hours. After cooling, the mixture was diluted with ethyl acetate (100 mL), filtered through diatomaceous earth, the filtrate was washed with saturated brine (50 mL), then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography to obtain a yellow solid and separated with a chiral separation column to obtain the desired isomeric compound (2-(2-fluoro-4-((S)-3-(methylsulfonyl)pyrrolidin-1-yl)phenyl)-7-(2-methyl-2H-1,2,3-triazol-4-yl)pyrazolo[1,5-a]pyrimidin-5-yl)((R)-4-methyl-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-yl)methanone (Compound 41, 10 mg).

[1354] 1 H NMR (400 MHz, DMSO-d 6)δ9.13(s,1H),8.19(t,J=8.8Hz,1H),7.81-7.73(m,1H),7.49-7.37(m,1H),7.16(d,J=2.8Hz,1H),6.68-6.56(m,2H),6.26(s,1H),5.84-5 .75(m,1H),4.47-4.26(m,4H),4.22-4.09(m,1H),3.84-3.68(m,3H), 3.61-3.39(m,3H),3.10(s,3H),2.48-2.38(m,2H),1.66-1.51(m,3H).

[1355] MS measured value (ESI + )[(M+H) + ]:605.22.

[1356] Example 43: Preparation of (R)-(2-(2-fluoro-4-(3-morpholinylazetidin-1-yl)phenyl)-7-(2-methyl-2H-1,2,3-triazol-4-yl)pyrazolo[1,5-a]pyrimidin-5-yl)(1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone (Compound 42)

[1357]

[1358] (R)-(2-(2-Fluoro-4-(3-morpholinoazetidin-1-yl)phenyl)-7-(2-methyl-2H-1,2,3-triazol-4-yl)pyrazolo[1,5-a]pyrimidin-5-yl)(1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone (Compound 42, 45 mg) was prepared from tert-butyl (1-(4-chloro-3-fluorophenyl)azetidin-3-yl)carbamate (428 mg, 1.42 mmol) according to a method similar to Example 10.

[1359] 1 H NMR(400MHz,DMSO-d6)δ9.20-9.03(m,1H),8.19(t,J=8.8Hz,1H),7.75-7.66 (m,1H),7.64-7.50(m,1H),7.40-7.07(m,5H),6.49-6.37(m,2H),5.66-5.19( m,1H),4.67-4.57(m,1H),4.46-4.35(m,3H),4.15-3.97(m,3H),3.83-3.76( m,2H),3.13-2.96(m,1H),2.94-2.75(m,1H),2.41(s,4H),1.66-1.53(m,3H).

[1360] MS measured value (ESI + )[(M+H) + ]:608.29.

[1361] Example 44: Preparation of (2-(2-fluoro-4-(3-morpholinomethyl)azetidin-1-yl)phenyl)-7-(2-methyl-2H-1,2,3-triazol-4-yl)pyrazolo[1,5-a]pyrimidin-5-yl)(1-methyl-3,4-dihydroisoquinolin-2(1H)yl)methanone (Compound 43)

[1362]

[1363] Tert-butyl (azetidin-3-ylmethyl)carbamate (1.6 g, 7.16 mmol) was used to prepare 2-(2-fluoro-4-(3-morpholinomethyl)azetidin-1-yl)phenyl)-7-(2-methyl-2H-1,2,3-triazol-4-yl)pyrazolo[1,5-a]pyrimidin-5-yl)(1-methyl-3,4-dihydroisoquinolin-2(1H)yl)methanone (Compound 43, 44 mg) in a manner similar to Example 10.

[1364] 1 HNMR(400MHz,DMSO-d6)δ9.14-9.12(m,1H),8.17(t,J=8.8Hz,1H),7.74-7.66(m ,1H),7.35-7.08(m,5H),6.45-6.37(m,2H),5.69-5.63(m,1H),4.40(d,J=10.4H z,3H),4.06(t,J=8.0Hz,2H),3.65-3.55(m,7H),3.33-3.28(m,1H),3.12–2.97( m,2H),2.81-2.77(m,1H),2.63(d,J=8.0Hz,2H),2.41(s,4H),1.64-1.57(m,3H).

[1365] MS found value (ESI+) [(M+H)+]: 622.30.

[1366] Example 45: Preparation of (2-(4-((3R, 4R)-3-amino-4-hydroxypyrrolidin-1-yl)-2-fluorophenyl)-7-cyclopropylpyrazolo[1,5-a]pyrimidin-5-yl)((1R, 4R)-4-fluoro-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone (Compound 44)

[1367]

[1368] (2-(4-((3R,4R)-3-amino-4-hydroxypyrrolidin-1-yl)-2-fluorophenyl)-7-cyclopropylpyrazolo[1,5-a]pyrimidin-5-yl)((1R,4R)-4-fluoro-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone (Compound 44, 37 mg) was prepared from tert-butyl (1-(4-chloro-3-fluorophenyl)azetidin-3-yl)methyl)carbamate (150 mg, 0.476 mmol) according to a method similar to that of Example 19. 1 H NMR(400MHz,DMSO-d6)δ9.14-9.12(m,1H),8.20(t,J=8.8Hz,1H),7.67-7.74(m ,1H),7.35-7.09(m,5H),6.47-6.38(m,2H),5.68-5.63(m,1H),4.43-4.37(m,3H ),4.11-4.08(m,1H),4.08-4.03(m,2H),3.78-3.75(m,2H),3.62-3.53(m,1H), 3.14(d,J=7.2Hz,2H),3.10-2.97(m,2H),2.92-2.88(m,1H),1.63-1.57(m,3H).

[1369] MS measured value (ESI + )[(M+H) + ]:552.26.

[1370] Example 46: Preparation of 7-(2-cyclopropyl-2H-1,2,3-triazol-4-yl)-2-(4-(S)-3-(cyclopropylsulfonyl)pyrrolidin-1-yl)-2-fluorophenyl)pyrazolo[1,5-a]pyrimidin-5-yl)(R)-1-methyl-3,4-dihydroisoquinolin-2(1H)yl)methanone (Compound 45)

[1371]

[1372] (S)-1-(4-chloro-3-fluorophenyl)-3-(cyclopropylsulfonyl)pyrrolidine (200 mg, 0.66 mmol) was used to prepare 7-(2-cyclopropyl-2H-1,2,3-triazol-4-yl)-2-(4-(S)-3-(cyclopropylsulfonyl)pyrrolidin-1-yl)-2-fluorophenyl)pyrazolo[1,5-a]pyrimidin-5-yl)(R)-1-methyl-3,4-dihydroisoquinolin-2(1H)yl)methanone (Compound 45, 40 mg) in a manner similar to Example 9. 1 HNMR (400 MHz, DMSO-d 6)δ9.16-9.09(m,1H),8.24-8.17(m,1H),7.76-7.65(m,1H),7.37(d,J=7.2Hz,1H),7.29-7.13(m,4H ),6.70-6.59(m,2H),5.66(d,J=6.4Hz,1H),4.45-4.38(m,1H),4.25-4.20(m,1H),3.78(d,J=7.2Hz, 2H),3.61-3.54(m,1H),3.53-3.42(m,1H),3.14-2.97(m,1H),2.95-2.85(m,2H),2.79(d,J=16.0Hz, 1H),2.51-2.45(m,2H),1.66-1.55(m,3H),1.45-1.35(m,2H),1.32-1.21(m,3H),1.15-1.05(m,4H).

[1373] MS measured value (ESI + )[(M+H) + ]:667.35.

[1374] Example 47: Preparation of (2-(4-((S)-3-(ethylsulfonyl)pyrrolidin-1-yl)-2-fluorophenyl)-7-(2-methyl-2H-1,2,3-triazol-4-yl)pyrazolo[1,5-a]pyrimidin-5-yl)((R)-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone (Compound 46)

[1375]

[1376] Iodoethane (2.1 g, 13.34 mmol) was used in a manner similar to that of Example 14 to prepare (2-(4-((S)-3-(ethylsulfonyl)pyrrolidin-1-yl)-2-fluorophenyl)-7-(2-methyl-2H-1,2,3-triazol-4-yl)pyrazolo[1,5-a]pyrimidin-5-yl)((R)-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone (Compound 46, 30 mg).

[1377] 1 HNMR (400 MHz, DMSO-d 6)δ9.17-9.07(m,1H),8.25-8.15(m,1H),7.73-7.63(m,1H),7.36-7.01(m,5H),6.67-6.5 3(m,2H),5.63(d,J=6.4Hz,1H),4.41-4.32(m,3H),4.18(t,J=6.8Hz,1H),4.10-4.02(m, 1H),3.78-3.67(m,2H),3.60-3.50(m,2H),3.47-3.40(m,1H),3.28-3.20(m,2H),3.05(s ,1H),2.90-2.61(m,1H),2.43(q,J=7.2Hz,2H),1.63-1.51(m,3H),1.28(t,J=7.2Hz,3H).

[1378] MS measured value (ESI + )[(M+H) + ]:629.19.

[1379] Example 48: 2-(2-Fluoro-4-(4aR,7aS)-hexahydropyrrolo[3,4-b][1,4]oxazin-6(2H)-yl)phenyl)-7-(2-methyl-2H-1,2,3-triazol-4-yl)pyrazolo[1,5-a]pyrimidin-5-yl)(R)-1-methyl-3,4-dihydroisoquinolin-2(1H)yl)methanone and (2- Preparation of (2-fluoro-4-(4aS,7aR)-hexahydropyrrolo[3,4-b][1,4]oxazin-6(2H)-yl)phenyl)-7-(2-methyl-2H-1,2,3-triazol-4-yl)pyrazolo[1,5-a]pyrimidin-5-yl)(R)-1-methyl-3,4-dihydroisoquinolin-2(1H)yl)methanone (Compounds 47 & 48)

[1380]

[1381] Step 1: Preparation of tert-butyl cis-6-(4-chloro-3-fluorophenyl)hexahydropyrrolo[3,4-b][1,4]oxazine-4(4aH)-carboxylate (Compound 47-1)

[1382]

[1383] In a nitrogen atmosphere, palladium acetate (25 mg, 0.11 mmol) and XantPhos (130 mg, 0.22 mmol) were added to 1,4-dioxane (15 mL) of Cis-hexahydropyrrolo[3,4-b][1,4]oxazine-4(4aH)-carboxylic acid tert-butyl ester (250 mg, 1.10 mmol), 4-bromo-1-chloro-2-fluorobenzene (230 mg, 1.10 mmol) and cesium carbonate (1.1 g, 3.3 mmol). The reaction mixture was stirred at 100 ° C for 8 hours. The reaction solution was cooled, pure water (50 mL) was added to quench the reaction, and extracted with ethyl acetate (100 mL×3). The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by flash column chromatography to obtain a white solid Cis-6-(4-chloro-3-fluorophenyl)hexahydropyrrolo[3,4-b][1,4]oxazine-4(4aH)-carboxylic acid tert-butyl ester (Compound 47-1, 250 mg).

[1384] Step 2: Preparation of Cis-6-(3-fluoro-4-(5-(R)-1-methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-7-(2-methyl-2H-1,2,3-triazol-4-yl)pyrazolo[1,5-a]pyrimidin-2-yl)phenyl)hexahydropyrrolo[3,4-b][1,4]oxazine-4(4aH)-carboxylate (Compound 47-2)

[1385]

[1386] In a nitrogen atmosphere, (R)-(7-(2-methyl-2H-1,2,3-triazol-4-yl)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a]pyrimidin-5-yl)(1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone (290 mg, 0.70 mmol), Cis-6-(4-chloro-3-fluorophenyl)-1 ... ) tert-butyl hexahydropyrrolo[3,4-b][1,4]oxazine-4(4aH)-carboxylate (250 mg, 0.70 mmol), sodium carbonate (222 mg, 2.1 mmol) in 1,4-dioxane (5 mL) were added with chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) 2(83 mg, 0.11 mmol) and water (1 mL). The mixture was heated to 100 ° C and stirred for 3 hours. After cooling, the mixture was concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography to obtain a yellow solid Cis-6-(3-fluoro-4-(5-(R)-1-methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-7-(2-methyl-2H-1,2,3-triazol-4-yl)pyrazolo[1,5-a]pyrimidin-2-yl)phenyl)hexahydropyrrolo[3,4-b][1,4]oxazine-4(4aH)-carboxylate (Compound 47-2, 270 mg).

[1387] Step 3: Preparation of 2-(2-fluoro-4-(4aR,7aS)-hexahydropyrrolo[3,4-b][1,4]oxazin-6(2H)-yl)phenyl)-7-(2-methyl-2H-1,2,3-triazol-4-yl)pyrazolo[1,5-a]pyrimidin-5-yl)(R)-1-methyl-3,4-dihydroisoquinolin-2(1H)yl)methanone and (2-(2-fluoro-4-(4aS,7aR)-hexahydropyrrolo[3,4-b][1,4]oxazin-6(2H)-yl)phenyl)-7-(2-methyl-2H-1,2,3-triazol-4-yl)pyrazolo[1,5-a]pyrimidin-5-yl)(R)-1-methyl-3,4-dihydroisoquinolin-2(1H)yl)methanone (Compounds 47 & 48)

[1388]

[1389] To a solution of Cis-6-(3-fluoro-4-(5-(R)-1-methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-7-(2-methyl-2H-1,2,3-triazol-4-yl)pyrazolo[1,5-a]pyrimidin-2-yl)phenyl)hexahydropyrrolo[3,4-b][1,4]oxazine-4(4aH)-carboxylate (270 mg, 0.39 mmol) in dichloromethane (5 mL) was added a hydrochloric acid dioxane solution (4.0 M, 3 mL). The mixture was stirred at 25° C. for 1 hour. Saturated sodium bicarbonate solution (5 mL) was added to adjust the pH to 7, and the mixture was concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography to obtain a yellow solid and purified by a chiral separation column (column: DAICEL WHELK 250 mm × 25 mm inner diameter, 10 μm mobile phase: ACN / EtOH (0.2% DEA) = 40 / 60, flow rate: 50 mL / min, wavelength: UV 254 nm, temperature: 35°C) to obtain 2-(2-fluoro-4-(4aR, 7aS)-hexahydropyrrolo[3,4-b][1,4]oxazin-6(2H)-yl)phenyl)-7-(2-methyl-2H-1,2,3-triazol-4-yl)pyrazolo[1,5-a]pyrimidin-5-yl)(R)-1-methyl-3,4-dihydroisoquinolin-2(1H)yl)methanone (retention time: 10.561 , 22 mg) and (2-(2-fluoro-4-(4aS,7aR)-hexahydropyrrolo[3,4-b][1,4]oxazin-6(2H)-yl)phenyl)-7-(2-methyl-2H-1,2,3-triazol-4-yl)pyrazolo[1,5-a]pyrimidin-5-yl)(R)-1-methyl-3,4-dihydroisoquinolin-2(1H)yl)methanone (retention time: 15.066, 20 mg).

[1390] 1 H NMR (400 MHz, DMSO-d 6 )δ9.21-9.11(m,1H),8.21(t,J=8.8Hz,1H),7.77-7.65(m,1H),7.37(d,J=7.2Hz,1H),7 .30-7.10(m,4H),6.61-6.40(m,2H),,5.66(d,J=7.2Hz,1H),4.44-4.37(m,3H),4.15-4. 01(m,2H),3.79-3.71(m,1H),3.69-3.62(m,1H),3.60-3.50(m,3H),3.44-3.37(m,2H),3 .13-2.94(m,3H),2.92(s,1H),2.83-2.77(m,1H),2.74-2.65(m,1H),1.65-1.55(m,3H).

[1391] 1 H NMR (400 MHz, DMSO-d 6)δ9.18-9.10(m,1H),8.20(t,J=8.8Hz,1H),7.75-7.62(m,1H),7.42-7.33(m ,1H),7.31-7.12(m,4H),6.60-6.43(m,2H),5.70-5.61(m,1H),4.44-4.36(m ,3H),4.12-4.01(m,2H),3.76-3.70(m,1H),3.63-3.43(m,5H),3.32(s,1H), 3.14-2.87(m,3H),2.83-2.68(m,1H),,2.62-2.55(m,1H),1.66-1.54(m,3H).

[1392] MS measured value (ESI + )[(M+H) + ]:594.44.

[1393] Example 49: Preparation of (S)-1-(3-fluoro-4-(5-(((R)-1-methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-7-(2-methyl-2H-1,2,3-triazol-4-yl)pyrazolo[1,5-a]pyrimidin-2-yl)phenyl)pyrrolidine-3-carboxylic acid (Compound 49)

[1394]

[1395] Step 1: Preparation of (S)-1-(4-chloro-3-fluorophenyl)pyrrolidine-3-carboxylic acid methyl ester (Compound 49-1)

[1396]

[1397] In a nitrogen atmosphere, palladium acetate (64 mg, 0.29 mmol) and XantPhos (165 mg, 0.29 mmol) were added to 1,4-dioxane (10 mL) containing methyl pyrrolidine-3-carboxylate (356 mg, 2.15 mmol), 4-bromo-1-chloro-2-fluorobenzene (300 mg, 1.43 mmol) and cesium carbonate (1.40 g, 4.30 mmol). The reaction mixture was stirred at 100°C for 5 hours. The reaction solution was cooled, purified water (20 mL) was added to quench the reaction, and extracted with ethyl acetate (50 mL×3). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by flash column chromatography to obtain a colorless oily liquid (S)-1-(4-chloro-3-fluorophenyl)pyrrolidine-3-carboxylic acid methyl ester (compound 49-1, 321 mg).

[1398] Step 2: Preparation of (S)-1-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrrolidine-3-carboxylic acid methyl ester (Compound 49-2)

[1399]

[1400] In a nitrogen atmosphere, add [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (121 mg, 0.12 mmol) to a 1,4-dioxane solution (3 mL) of (S)-1-(4-chloro-3-fluorophenyl)pyrrolidine-3-carboxylic acid methyl ester (150 mg, 0.59 mmol), biboronic acid pinacol ester (222 mg, 0.88 mmol), and potassium acetate (172 mg, 1.75 mmol). Heat the mixture to 100°C and stir for 3 hours. Cool and use the reaction solution directly in the next step.

[1401] Step 3: Preparation of (S)-1-(3-fluoro-4-(5-(R)-1-methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-7-(2-methyl-2H-1,2,3-triazol-4-yl)pyrazolo[1,5-a]pyrimidin-2-yl)phenyl)pyrrolidine-3-carboxylic acid methyl ester (Compound 49-3)

[1402]

[1403] To a solution of (S)-1-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrrolidine-3-carboxylic acid methyl ester (160 mg, 0.59 mmol) in 1,4-dioxane (3 mL) were added (R)-(2-bromo-7-(2-methyl-2H-1,2,3-triazol-4-yl)pyrazolo[1,5-a]pyrimidin-5-yl)(1-methyl-3,4-dihydroisoquinoline-2(1H)-methanone (196 mg, 0.39 mmol), potassium carbonate (134 mg, 0.97 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium ( 32mg, 0.04mmol) and water (1mL), the mixture was stirred at 100℃ for 5 hours. Pure water (10mL) was added and extracted with ethyl acetate (10mL×2). Washed with saturated brine (5mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by flash column chromatography to obtain a yellow solid (S)-1-(3-fluoro-4-(5-(R)-1-methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-7-(2-methyl-2H-1,2,3-triazol-4-yl)pyrazolo[1,5-a]pyrimidin-2-yl)phenyl)pyrrolidine-3-carboxylic acid methyl ester (Compound 49-3, 123mg).

[1404] Step 4: Preparation of (S)-1-(3-fluoro-4-(5-(R)-1-methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-7-(2-methyl-2H-1,2,3-triazol-4-yl)pyrazolo[1,5-a]pyrimidin-2-yl)phenyl)pyrrolidine-3-carboxylic acid (Compound 49)

[1405]

[1406] To a solution of compound (S)-1-(3-fluoro-4-(5-(R)-1-methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-7-(2-methyl-2H-1,2,3-triazol-4-yl)pyrazolo[1,5-a]pyrimidin-2-yl)phenyl)pyrrolidine-3-carboxylic acid methyl ester (106 mg, 0.18 mmol) in tetrahydrofuran (3 mL) were added lithium hydroxide (45 mg, 1.06 mmol) and water (1 mL). The mixture was stirred at 25° C. for 2 hours. The pH was adjusted to 2 with 10% potassium hydrogen sulfate aqueous solution, and then extracted with ethyl acetate (30 mL×3). The organic phases were combined and washed with water (30 mL×3), then concentrated to obtain a crude product, which was purified by column chromatography to obtain a yellow solid ((S)-1-(3-fluoro-4-(5-(R)-1-methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-7-(2-methyl-2H-1,2,3-triazol-4-yl)pyrazolo[1,5-a]pyrimidin-2-yl)phenyl)pyrrolidine-3-carboxylic acid (Compound 49, 90 mg).

[1407] 1 H NMR (400 MHz, DMSO-d 6 )δ9.16-9.13(m,1H),8.19(t,J=8.8Hz,1H)7.73-7.65(m,1H),7.36-7.07 (m,5H),6.62-6.49(m,2H),5.68-5.63(m,1H),4.42-4.38(m,3H),4.11-4 .07(m,1H),3.63-3.51(m,3H),3.48-3.41(m,2H),3.29-3.23(m,1H),3.1 2-2.96(m,1H),2.81-2.77(m,1H),2.35-2.17(m,2H),1.64-1.56(m,3H).

[1408] MS measured value (ESI + )[(M+H) + ]:581.23.

[1409] Example 50: Preparation of (7-(2-(cyclopropylmethyl)-2H-1,2,3-triazol-4-yl)-2-(2-fluoro-4-((S)-3-(methylsulfonyl)pyrrolidin-1-yl)phenyl)pyrazolo[1,5-a]pyrimidin-5-yl)((R)-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone (Compound 50)

[1410]

[1411] (Bromomethyl)cyclopropane (2.0 g, 14.76 mmol) was used to prepare (7-(2-(cyclopropylmethyl)-2H-1,2,3-triazol-4-yl)-2-(2-fluoro-4-((S)-3-(methylsulfonyl)pyrrolidin-1-yl)phenyl)pyrazolo[1,5-a]pyrimidin-5-yl)((R)-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone (Compound 50, 33 mg) in a manner similar to Example 9. 1 H NMR (400 MHz, DMSO-d 6 )δ9.20-9.05(m,1H),8.27-8.13(m,1H),7.79-7.62(m,1H),7.37-7.00(m,5H),6.69-6.54(m, 2H),5.64(d,J=6.8Hz,1H),4.54-4.47(m,2H),4.15(t,J=6.8Hz,1H),4.10-4.03(m,1H),3.73 (d,J=6.8Hz,2H),3.61-3.41(m,3H),3.10(s,3H),3.08-2.94(m,1H),2.92-2.69(m,1H),2.44 (q,J=7.2Hz,2H),1.65-1.52(m,3H),1.49-1.39(m,1H),0.66-0.57(m,2H),0.54-0.45(m,2H)

[1412] MS measured value (ESI + )[(M+H) + ]:655.23.

[1413] Example 51: Preparation of (2-(4-fluoro-6-((S)-3-morpholinopyrrolidin-1-yl)pyridin-3-yl)-7-(2-methyl-2H-1,2,3-triazol-4-yl)pyrazolo[1,5-a]pyrimidin-5-yl)((R)-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone (Compound 51)

[1414]

[1415] Step 1: Preparation of (S)-tert-butyl (1-(4-fluoropyridin-2-yl)pyrrolidin-3-yl)carbamate (Compound 51-1)

[1416]

[1417] In a nitrogen atmosphere, tris dibenzylideneacetone dipalladium (312 mg, 0.34 mmol) and 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (212 mg, 0.34 mmol) were added to a 1,4-dioxane solution (10 mL) of 2-bromo-4-fluoropyridine (600 mg, 3.41 mmol), (S)-tert-butyl pyrrolidin-3-ylcarbamate (635 mg, 3.41 mmol) and sodium tert-butoxide (983 mg, 10.23 mmol). The mixture was heated to 100°C in a microwave and stirred for 2 hours. The mixture was heated to 100°C in a microwave and stirred for 2 hours. After cooling, the mixture was diluted with ethyl acetate (100 mL), washed with water (50 mL) and saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude product, which was purified by column chromatography to give a brown solid (S)-(1-(4-fluoropyridin-2-yl)pyrrolidin-3-yl)carbamic acid tert-butyl ester (Compound 51-1, 700 mg).

[1418] Step 2: Preparation of (S)-1-(4-fluoropyridin-2-yl)pyrrolidin-3-amine (Compound 51-2)

[1419]

[1420] Trifluoroacetic acid (4 mL) was added to a solution of (S)-(1-(4-fluoropyridin-2-yl)pyrrolidin-3-yl)carbamic acid tert-butyl ester (700 mg, 2.49 mmol) in dichloromethane (6 mL). The mixture was stirred at 25 ° C for 2 hours. The mixture was diluted with ethyl acetate (100 mL), then washed with water (50 mL) and saturated sodium bicarbonate solution (50 mL), then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography to prepare a white solid (S)-1-(4-fluoropyridin-2-yl)pyrrolidin-3-amine (compound 51-2, 320 mg).

[1421] Step 3: Preparation of (S)-4-(1-(4-fluoropyridin-2-yl)pyrrolidin-3-yl)morpholine (Compound 51-3)

[1422]

[1423] 1-Bromo-2-(2-bromoethoxy)ethane (2.1 g, 8.83 mmol) and potassium carbonate (732 mg, 5.30 mmol) were added to a solution of (S)-1-(4-fluoropyridin-2-yl)pyrrolidin-3-amine (320 mg, 1.77 mmol) in acetonitrile (5 mL). The mixture was heated to 80 ° C and stirred for 5 hours. The mixture was diluted with ethyl acetate (100 mL), then washed with water (50 mL) and saturated brine (50 mL), then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography to obtain a white solid (S)-4-(1-(4-fluoropyridin-2-yl)pyrrolidin-3-yl)morpholine (compound 51-3, 390 mg).

[1424] Step 4: Preparation of (S)-4-(1-(5-bromo-4-fluoropyridin-2-yl)pyrrolidin-3-yl)morpholine (Compound 51-4)

[1425]

[1426] N-bromosuccinimide (276 mg, 1.55 mmol) was added to a solution of (S)-4-(1-(4-fluoropyridin-2-yl)pyrrolidin-3-yl)morpholine (390 mg, 1.55 mmol) in acetonitrile (5 mL). The mixture was stirred at 25° C. for 16 hours. The mixture was diluted with ethyl acetate (100 mL), then washed with water (50 mL) and saturated brine (50 mL), then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography to obtain a white solid (S)-4-(1-(5-bromo-4-fluoropyridin-2-yl)pyrrolidin-3-yl)morpholine (compound 51-4, 400 mg).

[1427] Step 5: Preparation of (2-(4-fluoro-6-((S)-3-morpholinopyrrolidin-1-yl)pyridin-3-yl)-7-(2-methyl-2H-1,2,3-triazol-4-yl)pyrazolo[1,5-a]pyrimidin-5-yl)((R)-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone (Compound 51)

[1428]

[1429] In a nitrogen atmosphere, (R)-(7-(2-methyl-2H-1,2,3-triazol-4-yl)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a]pyrimidin-5-yl)(1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone (150 mg, 0.30 mmol) and (S)-4-(1 To a solution of 1,4-dioxane (5 mL) of 2-(5-bromo-4-fluoropyridin-2-yl)pyrrolidin-3-yl)morpholine (103 mg, 0.31 mmol) and sodium carbonate (96 mg, 0.91 mmol) was added chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) 2 (24 mg, 0.03 mmol) and water (1 mL). The mixture was heated to 100 ° C and stirred for 3 hours. After cooling, the mixture was diluted with ethyl acetate (100 mL), filtered through diatomaceous earth, and the filtrate was washed with saturated brine (50 mL), then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography to prepare a yellow solid (2-(4-fluoro-6-((S)-3-morpholinopyrrolidin-1-yl)pyridin-3-yl)-7-(2-methyl-2H-1,2,3-triazol-4-yl)pyrazolo[1,5-a]pyrimidin-5-yl)((R)-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone (Compound 51, 55 mg).

[1430] 1 H NMR (400 MHz, DMSO-d 6 )δ9.12-9.09(m,1H),9.02(d,J=10.4Hz,1H),7.72-7.63(m,1H),7.34-7.09(m,5 H),6.48(d,J=14.4Hz,1H),5.63(q,J=7.2Hz,1H),4.39-4.34(m,3H),4.10-4.01 (m,1H),3.81-3.46(m,7H),3.45-3.34(m,1H),3.27-3.14(m,2H),3.04-2.78(m, 3H),2.48-2.41(m,3H),2.24-2.17(m,1H),1.91-1.79(m,1H),1.60-1.54(m,3H).

[1431] MS measured value (ESI + )[(M+H) + ]:623.53.

[1432] Example 52: Preparation of (R)-(2-(2-fluoro-4-(3-(methylamino)azetidin-1-yl)phenyl)-7-(2-methyl-2H-1,2,3-triazol-4-yl)pyrazolo[1,5-a]pyrimidin-5-yl)(1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone (Compound 52)

[1433]

[1434] Tert-butyl azetidin-3-yl(methyl)carbamate hydrochloride (300 mg, 1.35 mmol) was used to prepare (R)-(2-(2-fluoro-4-(3-(methylamino)azetidin-1-yl)phenyl)-7-(2-methyl-2H-1,2,3-triazol-4-yl)pyrazolo[1,5-a]pyrimidin-5-yl)(1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone (Compound 52, 2 mg) in a manner similar to that of Example 19.

[1435] 1 H NMR (400 MHz, DMSO-d 6 )δ9.12(s,1H),8.22-8.16(m,1H),7.75-7.67(m,1H),7.35-7.10(m,5H),6. 47-6.38(m,2H),5.69-5.62(m,1H),4.44-4.37(m,3H),4.15-4.10(m,1H),4 .09-4.04(m,1H),3.71-3.63(m,2H),3.60-3.42(m,1H),3.13-2.95(m,2H), 2.81-2.77(m,1H),2.33-2.29(m,2H),2.06-1.98(m,2H),1.63-1.56(m,3H).

[1436] MS measured value (ESI + )[(M+H) + ]:552.26.

[1437] Example 53: Preparation of (1S,2S)-2-(3-fluoro-4-(5-(((R)-1-methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-7-(2-methyl-2H-1,2,3-triazol-4-yl)pyrazolo[1,5-a]pyrimidin-2-yl)phenyl)cyclopropane-1-carboxylic acid (Compound 53)

[1438]

[1439] Step 1: Preparation of (1S,2S)-2-(3-fluoro-4-(5-(((R)-1-methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-7-(2-methyl-2H-1,2,3-triazol-4-yl)pyrazolo[1,5-a]pyrimidin-2-yl)phenyl)cyclopropane-1-carboxylic acid ethyl ester (Compound 53-1)

[1440]

[1441] Under nitrogen atmosphere, (R)-(7-(2-methyl-2H-1,2,3-triazol-4-yl)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a]pyrimidin-5-yl)(1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone (300 mg, 0.6 mmol), (1S,2S)- To a solution of ethyl 2-(4-bromo-3-fluorophenyl)cyclopropane-1-carboxylate (172 mg, 0.6 mmol) and sodium carbonate (192 mg, 1.82 mmol) in 1,4-dioxane (10 mL) was added chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) 2 (48 mg, 0.06 mmol) and water (2 mL). The mixture was heated to 100 ° C and stirred for 3 hours. After cooling, the mixture was diluted with ethyl acetate (100 mL), filtered through diatomaceous earth, and the filtrate was washed with saturated brine (50 mL), then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography to obtain a yellow solid (1S, 2S)-2-(3-fluoro-4-(5-(((R)-1-methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-7-(2-methyl-2H-1,2,3-triazol-4-yl)pyrazolo[1,5-a]pyrimidin-2-yl)phenyl)cyclopropane-1-carboxylic acid methyl ester (compound 53-1, 120 mg).

[1442] Step 2: Preparation of (1S,2S)-2-(3-fluoro-4-(5-(((R)-1-methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-7-(2-methyl-2H-1,2,3-triazol-4-yl)pyrazolo[1,5-a]pyrimidin-2-yl)phenyl)cyclopropane-1-carboxylic acid (Compound 53)

[1443]

[1444] To a solution of methyl (1S,2S)-2-(3-fluoro-4-(5-(((R)-1-methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-7-(2-methyl-2H-1,2,3-triazol-4-yl)pyrazolo[1,5-a]pyrimidin-2-yl)phenyl)cyclopropane-1-carboxylate (120 mg, 0.2 mmol) in tetrahydrofuran (5 mL) were added lithium hydroxide (14.4 mg, 0.6 mmol) and water (1 mL). The mixture was stirred at 25° C. for 2 hours. The reaction solution was concentrated, and then water (10 mL) was added. 10% potassium hydrogen sulfate aqueous solution was adjusted to pH 2, and then extracted with ethyl acetate (30 mL×3). The organic phases were combined and washed with water (30 mL×3), and then concentrated to obtain a crude product, which was purified by column chromatography to obtain a yellow solid (1S, 2S)-2-(3-fluoro-4-(5-(((R)-1-methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-7-(2-methyl-2H-1,2,3-triazol-4-yl)pyrazolo[1,5-a]pyrimidin-2-yl)phenyl)cyclopropane-1-carboxylic acid (Compound 1, 2 mg).

[1445] MS measured value (ESI + )[(M+H) + ]:551.10.

[1446] Example 54: Cytopathic Effect Evaluation of Compounds for In Vitro Antiviral Activity against RSV-A

[1447] 1. Experimental Principle

[1448] The inhibitory strength of a compound against RSV virus can be measured by its ability to protect cells. This experiment uses the cytopathic effect (CPE) to determine the inhibitory ability of a compound against the virus. The CPE effect is a cell-based detection method that is based on the principle that respiratory syncytial virus causes cytopathic or cell death effects after infecting host cells. After a certain period of time, the inhibitory ability of a compound against the virus is determined by detecting the cytopathic effect.

[1449] 2. Reagents and instruments

[1450] 1) Reagents and consumables

[1451] name supplier batch number DMEM Hyclone SH30243.01 FBS Hyclone SH30406.05 Trypsin Gibco 25200072 P / S Hyclone SV30010 DMSO Sigma D2650-100ML 96-wellwhiteplate Corning 3917 CellTiter-Glo Promega G7572

[1452] 2) Instruments

[1453] CO2 incubator (Thermo); Infinite M200 multifunctional microplate reader (Tecan, Switzerland).

[1454] 3. Experimental methods and steps

[1455] HEp-2 cells (ATCC, CCL-23) were seeded in 96-well white plates (Corning Costar) at a density of 5,000 cells / well, 50 μL / well, and cultured overnight at 37°C, 5% CO2. The next day, 5 μL of serially diluted compounds (diluted in test medium, final DMSO concentration of 0.25%) were added to the plate. In the cell control and virus control wells, only 0.25% DMSO was added. 1.5 hours after the addition of the compound, 45 μL of diluted RSV-A virus (strain Long, A subtype, ATCC, VR-26) (2500 PFU, corresponding to an MOI of 0.5 at an initial cell plating density of 5,000 cells / well) was added to each well. In the cell control wells, 45 μL of test medium was added. The final volume was 100 μL / well. The plate was placed in a 37°C incubator for 96 hours and removed from the incubator to equilibrate to room temperature for 30 minutes. Then, 50 μL CellTiter-Glo (Promega) reagent was added to each test plate well, and the plate was incubated at room temperature for 10 minutes, and then read by Infinite M200 multifunctional microplate reader (Tecan, Switzerland). The test compound was diluted into 8 concentrations in a 3-fold concentration gradient, and 2 parallel replicates were set for EC50 determination. The highest test concentration of the test compound was 0.3 μM.

[1456] The cytotoxicity of the test compound and the reference compound was tested in parallel under the same conditions, but without virus infection. The test compound was diluted into 8 concentrations in a 2-fold concentration gradient, and 2 parallel replicates were set for CC50 determination. The highest test concentration of the compound was 100 μM. Cell viability was detected using CellTiter-Glo (Promega) according to the manufacturer's instructions.

[1457] 4. Data Analysis

[1458] Antiviral activity is expressed as percentage of CPE inhibition:

[1459] CPE inhibition percentage = (μcpd-μv) / (μc-μv)×100%,

[1460] in,

[1461] μcpd: average signal of test compound wells.

[1462] μv: Average signal value of blank control wells.

[1463] μc: average signal of test and control compound wells.

[1464] 50% effective concentration (EC 50) is defined as the compound concentration required to achieve 50% inhibition of maximal CPE, and the 50% cytotoxic concentration (CC 50 ) is defined as the compound concentration required to reduce the signal value by 50% compared with the control wells. EC 50 The values ​​were calculated by nonlinear regression using Prism software (GraphPad Prism 5, CA, USA).

[1465] 5. Experimental data

[1466]

[1467]

[1468]

[1469] From the cytopathic effect experiment, it can be seen that the compounds in the list have strong anti-RSV-A virus activity, EC 50 All are at a relatively low nM level. In particular, compared with the positive control molecules, the activity of the compounds in the list has increased by several times or even dozens of times, reflecting the extremely high value of anti-RSV virus, indicating a more excellent clinical effect and having a very high value.

[1470] Example 55: 7-day toxicity test of compound 9 in rats

[1471] 1. Experimental information

[1472] Male SD rats were used for a 7-day toxicity study. The specific experimental information and design are shown in the following table.

[1473] Test compound Compound 9 Dosage Oral administration (PO) Dosage (mg / kg) 450 solvent 10%DMSO+5%Solutol+85%water Number of animals 3 rats per group

[1474] 2. Experimental Procedure

[1475] (1) Compound 9 was dissolved in 10% DMSO + 5% Solutol + 85% water, vortexed and sonicated to prepare a 45 mg / mL suspension solution S1. Male SD rats were selected and orally administered with the suspension solution S1 of compound 9 at a dose of 450 mg / kg. The administration was continued once a day for 7 consecutive days. The body weight and survival rate were observed. The rats were dissected on the 8th day to observe whether their tissues had lesions.

[1476] 3. Experimental results

[1477] (1) Weight results

[1478]

[1479] From the 7-day body weight change rate of rats treated with compound 9, a high dose of 450 mg / kg of compound 9 had no effect on the body weight of rats.

[1480] (2) Survival rate and histological lesion results

[1481]

[1482] From the 7-day toxicity test of compound 9 in rats, the survival rate of the positive control group at 450 mg / kg was 0. However, at the same dose, the survival rate of compound 9 was 100%, and no obvious abnormalities were found after autopsy, indicating that the compound showed high safety.

[1483] Example 56: Drug concentration test of compound 9 in mouse lungs

[1484] 1. Experimental information

[1485] Male CD-1 (ICR) mice were used for pharmacokinetic studies. Blood samples were analyzed by LC-MS / MS analysis. The specific experimental information and design are shown in the following table.

[1486] Test compound Compound 9 Dosage Oral administration (PO) Dosage (mg / kg) 10 solvent 10%DMSO+5%Solutol+85%water Analytical methods LC-MS / MS Blood and lung collection time 2h, 4h, 24h Number of animals 9

[1487] 2. Experimental Procedure

[1488] (1) Compound 9 was dissolved in 10% DMSO + 5% Solutol + 85% water, vortexed and sonicated to prepare a 1 mg / mL clear solution S2. Male mice aged 7-9 weeks were selected and orally administered with a solution S2 of compound 9 at a dose of 10 mg / kg. Whole blood was collected at 2h, 4h and 24h to prepare plasma, and the drug concentration was analyzed by LC-MS / MS.

[1489] (2) Collect lung tissues at 2 h, 4 h, and 24 h, add water 4 times the weight of the lung tissue, and homogenize with an H-speed disperser. Take the lung homogenate and analyze the drug concentration with LC-MS / MS.

[1490] 3. LC / MS / MS conditions

[1491] LC / MS / MS instrument type: AB Sciex Triple Quad 6500+ (JS 9#)

[1492] LC / MS / MS quantification software and version number: Analyst software 1.6.3

[1493] Ionization mode: electrospray, positive ion

[1494] Scan mode: Multiple reaction monitoring (MRM)

[1495] MRM of analyte: 622.16 / 535.00 (MW: 621.2)

[1496] Internal standard MRM: 271.02 / 91.00 Toluene butyramide

[1497] LC method: Pump: Shimadzu LC-30AD

[1498] Chromatographic column: C182.6μm Chromatographic column (50mm*2.1mm)

[1499] Mobile phase: Mobile phase A: 5mM NH4Ac in water (containing 0.05% FA)

[1500] Mobile phase B: acetonitrile (containing 0.1% FA)

[1501] Column temperature: room temperature

[1502] Injection volume: 3uL.

[1503] UPLC Gradient

[1504] Time (minutes) Flow rate (mL / min) A(％) B(％) 0.40 0.600 70.0 30.0 1.20 0.600 10.0 90.0 1.80 0.600 10.0 90.0 1.81 0.600 70.0 30.0 2.50 0.600 70.0 30.0

[1505] 4. Experimental Results

[1506] The drug concentration data of compound 9 in plasma obtained after calculation are shown in the following table:

[1507]

[1508] The drug concentration data of compound 9 in lung tissue obtained after calculation are shown in the following table:

[1509]

[1510] The calculated ratios of the drug concentrations of compound 9 in the lung and blood are shown in the following table:

[1511]

[1512]

[1513] Judging from the lung pharmacokinetic data of compound 9, the compound showed a high lung enrichment, with a lung-to-blood ratio of about 3 times. As a lung viral infection, the excellent antiviral activity in vitro indicates that the compound has a good antiviral effect in human body.

[1514] It should be understood that the above embodiments are exemplary and are not intended to include all possible implementations included in the claims. Various modifications and changes may be made on the basis of the above embodiments without departing from the scope of the present disclosure. Similarly, the various technical features of the above embodiments may be arbitrarily combined to form other embodiments of the present invention that may not be explicitly described. Therefore, the above embodiments only express several implementations of the present invention and do not limit the scope of protection of the patent of the present invention.

Claims

1. A compound represented by general formula I or its stereoisomers, solvates, hydrates, prodrugs, stable isotope derivatives and pharmaceutically acceptable salts: in: X 1 , X 2 Each independently selected from CR 6 and N; X 6 , X 7 and X 8 Each independently selected from CR 6 and N; R 1 Selected from C 1-6 Alkyl and C 3-7 Cycloalkyl; R 2 and R 2’ are each independently selected from hydrogen, deuterium, halogen, C 1-6 Alkyl, C substituted by at least one halogen 1-6 Alkyl and C 3-7 Cycloalkyl; R 3 Selected from halogen, C 1-6 Alkyl, C substituted by at least one halogen 1-6 Alkyl, C 3-7 Cycloalkyl and C 1-6 Alkoxy; R 4 Selected from halogen, hydroxyl, cyano, C 1-6 Alkyl, C substituted by at least one halogen 1-6 Alkyl and C 1-6 Alkoxy, C 3-7 Cycloalkyl, hydroxyl, C 1-6 Alkoxy or C 3-7 Cycloalkyl substituted C 1-6 Alkyl, 3-7 membered heterocycloalkyl, C 6-10 Aryl and 5-10 membered heteroaryl; R 5 Selected from substituted or unsubstituted -NR 7 R 8 、-NR 7 -(CO)-heterocycloalkyl, C 3-7 Cycloalkyl and 3-8 membered heterocycloalkyl; the substitution is by at least one R 9 Substitution, the R 9 Each occurrence is independently selected from the following group: a) Deuterium, halogen, hydroxyl, cyano, oxo, C 1-6 Alkyl, C substituted by hydroxy, amino and 3-7 membered heterocycloalkyl 1-6 Alkyl, C 1-6 Alkoxy, C substituted by hydroxy 1-6 Alkoxy, -(CO)-OH, -(CO)-NR 7 R 8 、-(CO)-NR 7 -SO2-R 8 、-NR 7 R 8 、-NR 7 -(CO)-C 1-6 Alkyl, -NR 7 -(CO)-C 3-7 Cycloalkyl, -NR 7 -(CO)-OR 8 、-NR 7 -(CO)-NR 7 R 8 、-NR 7 -SO2-R 8 、-NR 7 -SO2-NR 7 R 8 、-SO2-NR 7 R 8 、-SO2-NR 7 -(CO)-R 8 , C 3-7 Cycloalkyl, 3-7 membered heterocycloalkyl, -S(O)(NR 7 )-R 5a and -SO2-R 5a The group consisting of R 5a Selected from hydrogen, amino, C 1-6 Alkyl, C 1-6 Alkyl-amino, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, C 1-6 Alkyl-C 3-7 Cycloalkyl and 3-7 membered heterocycloalkyl; b) Two adjacent R 9 The atoms connected to them form a substituted or unsubstituted 3-5 membered spiro ring, wherein the 3-5 membered spiro ring contains 0, 1 or 2 heteroatoms selected from N, O and S, and the substitution is by at least one selected from amino, hydroxyl, oxo and C 1-6 substituted with a substituent of the alkyl group; and c) Two adjacent R 9 Together with the atoms to which they are attached, they form a substituted or unsubstituted 4-6 membered fused ring, wherein the 4-6 membered fused ring contains 0 or 1 heteroatom selected from N, O and S, and the substitution is by at least one selected from amino, hydroxyl, oxo and C 1-6 substituted by an alkyl substituent; R 7 and R 8 are each independently selected from hydrogen, deuterium, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, Hydroxyl-C 1-6 Alkyl, C substituted by at least one halogen 1-6 Alkyl, C 3-7 Cycloalkyl, C 1-6 Alkyl-C 3-7 Cycloalkyl and hydroxy or cyano substituted C 3-7 Cycloalkyl; R 6 Each occurrence is independently selected from hydrogen, deuterium, hydroxyl, cyano, halogen, C 1-6 Alkyl, C 1-6 Alkoxy and C substituted by at least one halogen 1-6 alkyl; Ring A is present or absent; when ring A is absent, t is an integer selected from 1, 2, and 3; when ring A is present, t is 1 and the ring A is selected from the following A-1 to A-4 groups: R i Selected from hydrogen, halogen, C 1-3 Alkyl, C substituted by at least one halogen 1-6 Alkyl, C 3-7 Cycloalkyl and C 1-6 Alkoxy; o is an integer selected from 0, 1, 2, 3, 4; p is an integer selected from 0, 1, and 2; q is an integer selected from 0, 1, 2, 3; s is an integer selected from 0, 1, and 2; Provided that the compound of formula I is not 2. The compound of formula I according to claim 1 or its stereoisomers, solvates, hydrates, prodrugs, stable isotope derivatives and pharmaceutically acceptable salts, characterized in that R 5 Selected from substituted or unsubstituted -NR 7 -(CO)-heterocycloalkyl, C 3-7 Cycloalkyl and 3-8 membered heterocycloalkyl, wherein the heterocycloalkyl contains 1-2 heteroatoms selected from N, O and S; preferably substituted or unsubstituted -NH-(CO)-4-6 membered heterocycloalkyl, C 3-5 Cycloalkyl and 4-8 membered heterocycloalkyl, the heterocycloalkyl containing 1-2 heteroatoms selected from N, O and S; more preferably substituted or unsubstituted -NH-(CO)-azetidinyl, -NH-(CO)-pyrrolidinyl, cyclopropyl, cyclobutyl, cyclopentyl, azetidinyl, thiomorpholinyl, diazabicyclooctanyl, pyrrolidinyl, piperidinyl, piperazinyl and morpholinyl; most preferably substituted or unsubstituted cyclopropyl, azetidinyl, thiomorpholinyl, diazabicyclooctanyl and pyrrolidinyl.

3. The compound of the general formula I according to any one of claims 1 to 2 or its stereoisomers, solvates, hydrates, prodrugs, stable isotope derivatives and pharmaceutically acceptable salts, characterized in that it has a compound of formula I-1: in, R 10 Selected from hydrogen, deuterium, C 1-6 Alkyl and hydroxy-C 1-6 alkyl; R 11 and R 12 independently selected from hydrogen, deuterium, C 1-6 Alkyl, hydroxyl, halogen and C 1-6 Alkoxy and hydroxy-C 1-6 Alkyl; or R 11 and R 12 One of the carbon atoms to which it is connected, R 14 and the carbon atoms to which they are connected together form a substituted or unsubstituted 4-6 membered fused ring, wherein the 4-6 membered fused ring contains 0, 1 or 2 heteroatoms selected from N, O and S, wherein the substitution is by at least one selected from amino, hydroxyl, oxo and C 1-6 Substituted by a substituent in the alkyl group; R 13 Selected from hydrogen, deuterium, C 1-6 Alkyl, hydroxyl, halogen and C 1-6 Alkoxy and hydroxy-C 1-6 alkyl; R 14 Selected from deuterium, halogen, hydroxyl, cyano, C 1-6 Alkyl, C substituted by hydroxy, amino or 3-7 membered heterocycloalkyl 1-6 Alkyl, C 1-6 Alkoxy, -(CO)-OH, -(CO)-NR 7 R 8 、-(CO)-NR 7 -SO2-R 8 、-NR 7 R 8 、-NR 7 -(CO)-C 1-6 Alkyl, -NR 7 -(CO)-C 3-7 Cycloalkyl, -NR 7 -(CO)-OR 8 、-NR 7 -(CO)-NR 7 R 8 、-NR 7 -SO2-R 8 、-NR 7 -SO2-NR 7 R 8 、-SO2-NR 7 R 8 、-SO2-NR 7 -(CO)-R 8 , C 3-7 Cycloalkyl, 3-7 membered heterocycloalkyl, -S(O)(NR 7 )-R 5a and -SO2-R 5a The group consisting of R 5a Selected from hydrogen, amino, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, C 1-6 Alkyl-C 3-7 Cycloalkyl and 3-7 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, O and S; R 7 and R 8 are each independently selected from hydrogen, deuterium, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, Hydroxyl-C 1-6 Alkyl, C substituted by at least one halogen 1-6 Alkyl, C 3-7 Cycloalkyl, C 1-6 Alkyl-C 3-7 Cycloalkyl, hydroxy or cyano substituted C 3-7 Cycloalkyl; R 15 Selected from hydrogen, deuterium and C 1-6 alkyl; X 1 , X 2 , X 6 , X 7 , X 8 , R 1 , R 2 , R 2’ , R 3 , R 4 , A and t are as defined in any one of claims 1-2.

4. The compound of general formula I according to claim 3 or its stereoisomers, solvates, hydrates, prodrugs, stable isotope derivatives and pharmaceutically acceptable salts, characterized in that it has a compound having the structure of formula I-1-1: in, X 1 , X 2 , X 6 , X 7 , X 8 , R 1 , R 2 , R 2’ , R 3 , R 4 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R i and o as defined in claim 3.

5. A compound of the general formula I according to claim 3 or its stereoisomers, solvates, hydrates, prodrugs, stable isotope derivatives and pharmaceutically acceptable salts, characterized in that it has a compound of formula I-1-2: in, X 1 , X 2 , X 6 , X 7 , X 8 , R 1 , R 2 , R 2’ , R 3 , R 4 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R i and s as defined in claim 3.

6. The compound of general formula I according to claim 4 or its stereoisomers, solvates, hydrates, prodrugs, stable isotope derivatives and pharmaceutically acceptable salts, characterized in that it has the structure of formula I-1-1-1: in, X 7 , R 1 , R 2 , R 2’ , R 3 , R 4 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R i and o as defined in claim 4.

7. The compound of general formula I according to claim 5 or its stereoisomers, solvates, hydrates, prodrugs, stable isotope derivatives and pharmaceutically acceptable salts, characterized in that it has the structure of formula I-1-2-1: in, X 7 , R 1 , R 2 , R 2’ , R 3 , R 4 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R i and s as defined in claim 5.

8. The compound of formula I according to any one of claims 1 to 2 or its stereoisomers, solvates, hydrates, prodrugs, stable isotope derivatives and pharmaceutically acceptable salts, characterized in that the compound has the structure of formula I-2: in, R 16 and R 17 Each occurrence is independently selected from hydrogen, deuterium, C 1-6 Alkyl, hydroxyl, halogen, C 1-6 Alkoxy and hydroxy-C 1-6 alkyl; R 18 Selected from hydrogen, deuterium, halogen, hydroxyl, cyano, C 1-6 Alkyl, C substituted by hydroxy, amino or 3-7 membered heterocycloalkyl 1-6 Alkyl, C 1-6 Alkoxy, C substituted by hydroxy 1-6 Alkoxy, -(CO)-OH, -(CO)-NR 7 R 8 、-(CO)-NR 7 -SO2-R 8 、-NR 7 R 8 、-NR 7 -(CO)-C 1-6 Alkyl, -NR 7 -(CO)-C 3-7 Cycloalkyl, -NR 7 -(CO)-OR 8 、-NR 7 -(CO)-NR 7 R 8 、-NR 7 -SO2-R 8 、-NR 7 -SO2-NR 7 R 8 、-SO2-NR 7 R 8 、-SO2-NR 7 -(CO)-R 8 , C 3-7 Cycloalkyl, 3-7 membered heterocycloalkyl, -S(O)(NR 7 )-R 5a and -SO2-R 5a The group consisting of R 5a Selected from hydrogen, amino, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, C 1-6 Alkyl-C 3-7 Cycloalkyl and 3-7 membered heterocycloalkyl; or R 17 , R 18 and the carbon atoms connected together form a substituted or unsubstituted 3-5 membered spiro ring, wherein the 3-5 membered spiro ring contains 0 or 1 heteroatom selected from N, O and S, and the substitution is by at least one selected from oxo, amino, hydroxyl and C 1-6 substituted by an alkyl substituent; Among them, R 7 and R 8 are each independently selected from hydrogen, deuterium, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, Hydroxyl-C 1-6 Alkyl, C substituted by at least one halogen 1-6 Alkyl, C 3-7 Cycloalkyl, C 1-6 Alkyl-C 3-7 Cycloalkyl, hydroxy or cyano substituted C 3-7 Cycloalkyl; X 1 , X 2 , X 6 , X 7 , X 8 , R 1 , R 2 , R 2’ , R 3 , R 4 , A and t are as defined in any one of claims 1-2.

9. A compound of general formula I according to claim 8 or its stereoisomers, solvates, hydrates, prodrugs, stable isotope derivatives and pharmaceutically acceptable salts, characterized in that it has a compound of formula I-2-1: in, X 1 , X 2 , X 6 , X 7 , X 8 , R 1 , R 2 , R 2’ , R 3 , R 4 , R 16 , R 17 , R 18 , R i and o as defined in claim 8.

10. The compound of general formula I according to claim 9 or its stereoisomers, solvates, hydrates, prodrugs, stable isotope derivatives and pharmaceutically acceptable salts, characterized in that it has the structure of formula I-2-1-1: in, X 7 , R 1 , R 2 , R 2’ , R 3 , R 4 , R 16 , R 17 , R 18 , R i and o as defined in claim 9.

11. The compound of general formula I according to claim 9 or its stereoisomers, solvates, hydrates, prodrugs, stable isotope derivatives and pharmaceutically acceptable salts, characterized in that it has the structure of formula I-2-1-1-1: in, X 9 Selected from O, S, NH, C(R c )2, S(O) and S(O)2, preferably O, S, NH, C(R c )2 and S(O)2, more preferably O, C(R c )2 and S(O)2, R c Each occurrence is independently selected from hydrogen, amino, C 1-6 Alkyl-substituted amino; preferably, R c Each occurrence is independently selected from hydrogen, amino, methyl substituted amino; X 7 , R 1 , R 2 , R 2’ , R 3 , R 4 , R 16 , R i and o as defined in claim 10.

12. The compound of general formula I according to any one of claims 1 to 2 or its stereoisomers, solvates, hydrates, prodrugs, stable isotope derivatives and pharmaceutically acceptable salts, characterized in that it has a compound having the structure of formula I-3: in, R 19 and R 20 Each occurrence is independently selected from hydrogen, deuterium, C 1-6 Alkyl, hydroxyl, halogen and C 1-6 Alkoxy and hydroxy-C 1-6 alkyl; R 21 Selected from deuterium, halogen, hydroxyl, cyano, C 1-6 Alkyl, C substituted by hydroxy, amino or 3-7 membered heterocycloalkyl 1-6 Alkyl, C 1-6 Alkoxy, hydroxy substituted C 1-6 Alkoxy, -(CO)-OH, -(CO)-NR 7 R 8 、-(CO)-NR 7 -SO2-R 8 、-NR 7 R 8 、-NR 7 -(CO)-C 1-6 Alkyl, -NR 7 -(CO)-C 3-7 Cycloalkyl, -NR 7 -(CO)-OR 8 、-NR 7 -(CO)-NR 7 R 8 、-NR 7 -SO2-R 8 、-NR 7 -SO2-NR 7 R 8 、-SO2-NR 7 R 8 、-SO2-NR 7 -(CO)-R 8 , C 3-7 Cycloalkyl, 3-7 membered heterocycloalkyl, -S(O)(NR 7 )-R 5a and -SO2-R 5a The group consisting of R 5a Selected from hydrogen, amino, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, C 1-6 Alkyl-C 3-7 Cycloalkyl and 3-7 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, O and S; Among them, R 7 and R 8 are each independently selected from hydrogen, deuterium, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, Hydroxyl-C 1-6 Alkyl, C substituted by at least one halogen 1-6 Alkyl, C 3-7 Cycloalkyl, C 1-6 Alkyl-C 3-7 Cycloalkyl, hydroxy or cyano substituted C 3-7 Cycloalkyl; X 1 , X 2 , X 6 , X 7 , X 8 , R 1 , R 2 , R 2’ , R 3 , R 4 , A and t are as defined in any one of claims 1-2.

13. The compound of general formula I according to claim 12 or its stereoisomers, solvates, hydrates, prodrugs, stable isotope derivatives and pharmaceutically acceptable salts, characterized in that it has a compound having the structure of formula I-3-1: in, X 1 , X 2 , X 6 , X 7 , X 8 , R 1 , R 2 , R 2’ , R 3 , R 4 , R 19 , R 20 , R 21 , R i and o as defined in claim 12.

14. The compound of general formula I according to claim 13 or its stereoisomers, solvates, hydrates, prodrugs, stable isotope derivatives and pharmaceutically acceptable salts, characterized in that it has the structure of formula I-3-1-1: in, X 7 , R 1 , R 2 , R 2’ , R 3 , R 4 , R 19 , R 20 , R 21 , R i and o as defined in claim 13.

15. The compound of formula I according to any one of claims 1 to 14 or its stereoisomers, solvates, hydrates, prodrugs, stable isotope derivatives and pharmaceutically acceptable salts, characterized in that: The R 1 Selected from C 1-3 Alkyl and C 3-6 Cycloalkyl; preferably methyl, ethyl, propyl, isopropyl; more preferably methyl.

16. The compound of formula I according to any one of claims 1 to 15 or its stereoisomers, solvates, hydrates, prodrugs, stable isotope derivatives and pharmaceutically acceptable salts, characterized in that: The R 2 and R 2’ are each independently selected from hydrogen, deuterium, halogen, C 1-3 Alkyl, C substituted by at least one halogen 1-3 Alkyl; preferably hydrogen, deuterium, halogen, C 1-3 Alkyl; more preferably hydrogen, fluorine, chlorine, methyl, ethyl, propyl, isopropyl; most preferably hydrogen and fluorine.

17. The compound of formula I according to any one of claims 1 to 16, or its stereoisomers, solvates, hydrates, prodrugs, stable isotope derivatives and pharmaceutically acceptable salts, characterized in that: The R 3 Selected from halogen, C 1-3 Alkyl; preferably fluorine, chlorine, methyl, ethyl, propyl, isopropyl; more preferably fluorine.

18. The compound of formula I according to any one of claims 1 to 17 or its stereoisomers, solvates, hydrates, prodrugs, stable isotope derivatives and pharmaceutically acceptable salts, characterized in that: The R 4 Selected from halogen, hydroxyl, cyano, C 1-6 Alkyl, C substituted by at least one halogen 1-6 Alkyl, C 3-7 Cycloalkyl and C 3-7 Cycloalkyl substituted C 1-6 Alkyl; preferably halogen, C 1-3 Alkyl, C 3-5 Cycloalkyl and C 3-5 Cycloalkyl substituted C 1-6 Alkyl; more preferably methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl and -CH2-cyclopropyl.

19. The compound of formula I according to any one of claims 1 to 18, or its stereoisomers, solvates, hydrates, prodrugs, stable isotope derivatives and pharmaceutically acceptable salts, characterized in that: the R 6 Selected from hydrogen, deuterium, hydroxyl, cyano, halogen; preferably hydrogen, deuterium, halogen; more preferably hydrogen.

20. The compound of formula I according to any one of claims 1 to 19 or its stereoisomers, solvates, hydrates, prodrugs, stable isotope derivatives and pharmaceutically acceptable salts, characterized in that: The R 7 Selected from hydrogen, deuterium, C 1-3 Alkyl, Hydroxyl-C 1-3 Alkyl, C substituted by at least one halogen 1-3 Alkyl; preferably hydrogen, methyl, hydroxyethyl, difluoroethyl.

21. The compound of formula I according to any one of claims 1 to 20, or its stereoisomers, solvates, hydrates, prodrugs, stable isotope derivatives and pharmaceutically acceptable salts, characterized in that: the R 8 Selected from hydrogen, deuterium, C 1-3 Alkyl, Hydroxyl-C 1-3 Alkyl, C substituted by at least one halogen 1-3 Alkyl; preferably hydrogen, methyl, hydroxyethyl, difluoroethyl.

22. A compound of formula I according to any one of claims 3 to 7 or its stereoisomers, solvates, hydrates, prodrugs, stable isotope derivatives and pharmaceutically acceptable salts, characterized in that: The R 10 Selected from hydrogen, deuterium and C 1-6 Alkyl, preferably selected from hydrogen and deuterium, more preferably selected from hydrogen; The R 11 is selected from hydrogen, deuterium and halogen, preferably from hydrogen, deuterium and fluorine, more preferably from hydrogen and fluorine; The R 12 is selected from hydrogen, deuterium and halogen, preferably from hydrogen, deuterium and fluorine, more preferably from hydrogen and fluorine; The R 13 is selected from hydrogen, deuterium and halogen, preferably from hydrogen and deuterium, more preferably from hydrogen; The R 14 is selected from deuterium, halogen, amino, hydroxy, C substituted by hydroxy, amino or 3-7 membered heterocycloalkyl 1-6 Alkyl, hydroxy substituted C 1-6 Alkoxy, -(CO)-OH, 3-7 membered heterocycloalkyl, -S(O)(NR 7 )-R 5a and -SO2-R 5a The group consisting of, preferably, said R 14 is selected from amino, hydroxy, C substituted by hydroxy or 5-6 membered heterocycloalkyl 1-3 Alkyl, hydroxy substituted C 1-3 Alkoxy, -(CO)-OH, 5-6 membered heterocycloalkyl, -S(O)(NR 7 )-R 5a and -SO2-R 5a The 5-6 membered heterocycloalkyl group contains 1-2 heteroatoms selected from N and O. More preferably, the R 14 Selected from amino, hydroxyl, hydroxymethyl, -OCH2CH2-OH, -CH2-morpholinyl, morpholinyl, -(CO)-OH, -S(O)(NR 7 )-R 5a and -SO2-R 5a the groups formed; The R 5a Selected from hydrogen, amino, C 1-6 Alkyl, C 3-7 Cycloalkyl and C 1-6 Alkyl-C 3-7 Cycloalkyl, preferably selected from hydrogen, amino, C 1-3 Alkyl, C 3-5 Cycloalkyl and C 1-3 Alkyl-C 3-5 Cycloalkyl, more preferably selected from hydrogen, amino, methyl, ethyl, isopropyl, cyclopropyl and -CH2-cyclopropyl; R 15 Selected from hydrogen and deuterium, preferably selected from hydrogen.

23. A compound of formula I according to any one of claims 3 to 7 or its stereoisomers, solvates, hydrates, prodrugs, stable isotope derivatives and pharmaceutically acceptable salts, characterized in that: The R 10 Selected from hydrogen, deuterium and C 1-6 Alkyl, preferably selected from hydrogen and deuterium, more preferably selected from hydrogen; The R 11 and R 12 One of the carbon atoms to which it is connected, R 14 and the carbon atoms to which they are connected together form a substituted or unsubstituted 4-6 membered fused ring, the 4-6 membered fused ring containing 1 or 2 heteroatoms selected from N, O and S, preferably a substituted or unsubstituted tetrahydrothiopyran ring and a morpholine ring, the substitution being at least one selected from amino, hydroxyl, oxo and C 1-6 The alkyl group is substituted by a substituent, preferably oxo; The R 13 is selected from hydrogen, deuterium and halogen, preferably from hydrogen and deuterium, more preferably from hydrogen; R 15 Selected from hydrogen and deuterium, preferably selected from hydrogen.

24. The compound of formula I according to any one of claims 8 to 10, or its stereoisomers, solvates, hydrates, prodrugs, stable isotope derivatives and pharmaceutically acceptable salts, characterized in that: the R 16 Each occurrence is independently selected from hydrogen, deuterium and halogen, preferably from hydrogen and deuterium, more preferably from hydrogen; The R 17 Selected from hydrogen, deuterium, hydroxyl and C 1-6 Alkyl, preferably selected from hydrogen, deuterium, hydroxyl and C 1-3 Alkyl, more preferably selected from hydrogen, hydroxy and methyl; The R 18 Selected from hydrogen, deuterium, amino, C 1-6 Alkyl-substituted amino, hydroxy, C substituted by hydroxy, amino or 3-7 membered heterocycloalkyl 1-6 Alkyl, C substituted by hydroxy 1-6 Alkoxy, 3-7 membered heterocycloalkyl and -SO2-R 5a The group consisting of is preferably selected from amino, C 1-3 Alkyl-substituted amino, hydroxy, C substituted by hydroxy, amino 1-3 Alkyl, C substituted by hydroxy 1-3 Alkoxy, 5-6 membered heterocycloalkyl and -SO2-R 5a The group consisting of the 5-6 membered heterocycloalkyl group contains 1-2 heteroatoms selected from N and O, more preferably amino, hydroxymethyl, aminomethyl, methylamino, hydroxyl, -OCH2CH2-OH, morpholinyl and -SO2-R 5a the groups formed; The R 5a Selected from hydrogen, amino and C 1-6 Alkyl, preferably selected from hydrogen, amino and C 1-3 The alkyl group is more preferably selected from hydrogen, amino and methyl.

25. The compound of formula I according to any one of claims 8 to 10, or its stereoisomers, solvates, hydrates, prodrugs, stable isotope derivatives and pharmaceutically acceptable salts, characterized in that: the R 16 Each occurrence is independently selected from hydrogen, deuterium and halogen, preferably from hydrogen and deuterium, more preferably from hydrogen; The R 17 , R 18 and the carbon atoms to which they are commonly connected form a substituted or unsubstituted 3-4 membered spiro ring, wherein the 3-4 membered spiro ring contains 0 or 1 heteroatoms selected from N, O and S, preferably the 3-4 membered spiro ring is selected from oxetanyl, thiolyl and cyclobutyl, and the substitution is by at least one substituent selected from oxo, amino and hydroxyl, preferably oxo and amino.

26. The compound of formula I according to claim 11 or its stereoisomers, solvates, hydrates, prodrugs, stable isotope derivatives and pharmaceutically acceptable salts, characterized in that: The R 16 Each occurrence is independently selected from hydrogen, deuterium and halogen, preferably from hydrogen and deuterium, more preferably from hydrogen.

27. The compound of formula I according to any one of claims 12 to 14, or its stereoisomers, solvates, hydrates, prodrugs, stable isotope derivatives and pharmaceutically acceptable salts, characterized in that: The R 19 Each occurrence is independently selected from hydrogen, deuterium and halogen, preferably from hydrogen and deuterium, more preferably from hydrogen; The R 20 is selected from hydrogen, deuterium and halogen, preferably from hydrogen and deuterium, more preferably from hydrogen; The R 21 Selected from deuterium, halogen, amino, hydroxyl, -(CO)-OH, preferably selected from deuterium, halogen, -(CO)-OH, more preferably selected from -(CO)-OH.

28. The compound of formula I according to any one of claims 1 to 27, or its stereoisomers, solvates, hydrates, prodrugs, stable isotope derivatives and pharmaceutically acceptable salts, characterized in that: The R i Selected from halogen, C 1-6 Alkyl, C 1-3 Alkoxy is preferably selected from halogen.

29. A compound or its stereoisomers, solvates, hydrates, prodrugs, stable isotope derivatives and pharmaceutically acceptable salts, characterized in that: The compound is any of the following:

30. A compound or its stereoisomers, solvates, hydrates, prodrugs, stable isotope derivatives and pharmaceutically acceptable salts, characterized in that: The compound is any of the following:

31. A pharmaceutical composition comprising the compound according to any one of claims 1 to 30 or its stereoisomer, solvate, hydrate, prodrug, stable isotope derivative and pharmaceutically acceptable salt, and a pharmaceutically acceptable carrier or excipient.

32. A compound according to any one of claims 1 to 30 or its stereoisomers, solvates, hydrates, prodrugs, stable isotope derivatives and pharmaceutically acceptable salts, or a pharmaceutical composition according to claim 31, for use in preventing and / or treating RSV virus infection diseases.

33. Use of the compound according to any one of claims 1 to 30 or its stereoisomers, solvates, hydrates, prodrugs, stable isotope derivatives and pharmaceutically acceptable salts, or the pharmaceutical composition according to claim 31 in the preparation of a medicament for preventing and / or treating RSV virus infection diseases.

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