Heterocyclic amide compound, preparation method therefor, and use thereof

Abstract

Disclosed are a heterocyclic amide compound, a preparation method therefor, and a use thereof. Specifically, the heterocyclic amide compound involved in the present invention has a structure as shown in formula (I), can serve as a ubiquitin-specific protease 1 (USP1) inhibitor, and can be used for preparing a medicament for diagnosing and / or treating and / or preventing diseases related to ubiquitin-specific protease 1 (USP1), particularly a medicament for diagnosing and / or treating and / or preventing tumors or cancers.

Description

Heterocyclic amides, their preparation methods and uses

[0001] Priority of related applications

[0002] This application claims priority to the invention patent filed with the Chinese Patent Office on October 22, 2024, entitled "Heterocyclic amide compounds, their preparation methods and uses", application number 2024114953800, the entire contents of which are incorporated herein by reference. Technical Field

[0003] This invention belongs to the pharmaceutical field and relates to compounds as ubiquitin-specific protease 1 (USP1) inhibitors, their preparation methods and uses, particularly the use of such compounds or pharmaceutical compositions containing such compounds in the preparation of medicaments for the diagnosis and / or treatment and / or prevention of diseases related to ubiquitin-specific protease 1 (USP1), particularly tumors or cancer. Background Technology

[0004] Protein ubiquitination is a widespread post-translational modification mechanism involving the attachment of ubiquitin to target proteins via isopeptide bonds. Ubiquitin plays a role not only in protein degradation but also in various non-degradation functions, such as DNA damage repair, DNA replication, transcriptional regulation, membrane transport, and endocytosis, finely regulating the level, location, and activity of proteins and playing a central role in key cellular processes such as cell cycle, growth, and apoptosis. Like other post-translational modifications, protein ubiquitination is a dynamic and reversible process. Deubiquitinating enzymes (DUBs) can recognize ubiquitinating substrates and remove polyubiquitin chains or monoubiquitins, thereby reversing the effects of ubiquitination. Ubiquitin-specific proteases (USPs) are an important class of deubiquitinating enzymes in this process.

[0005] Ubiquitin-specific protease 1 (USP1) is a member of the USP family, and its deubiquitination activity is regulated by the cofactor UAF1. The binding of UAF1 to USP1 not only enhances the catalytic activity of USP1 but also stabilizes its structure, enabling it to bind to substrates more efficiently. The USP1 / UAF1 complex plays multiple roles in cellular function, particularly in DNA repair, regulating the DNA repair process by modulating the monoubiquitinated heterodimer FANCD2Ub-FANCIUb in the Fanconi anemia (FA) pathway and the polyubiquitinated homotrimer proliferating cell nuclear antigen (PCNA) in the translesion DNA synthesis (TLS) pathway.

[0006] In cases of homologous recombination defect (HRD) or BRCA1 / 2 gene deletion, USP1 inhibitors have shown significant anti-cancer potential. Tumor cells with BRCA1 deletion mutations are particularly sensitive to USP1 inhibitors because USP1 is upregulated in BRCA1-deficient tumors, exhibiting DNA-mediated activation at the replication fork and protecting it. Knockout or inhibition of USP1 leads to replication fork instability and reduces the survival rate of BRCA1-deficient cells. Furthermore, USP1 inhibitors have also shown therapeutic potential against ATM-mutated, PARP inhibitor-resistant, and p53-mutated tumors, as well as tumors with two or more mutations simultaneously.

[0007] USP1 inhibitors can be used as monotherapy or in combination with chemotherapy drugs, PARP inhibitors, or other types of inhibitors to treat tumors with BRCA1 / 2 mutations, ATM mutations, PARP inhibitor resistance, p53 mutations, or multiple coexisting mutations. Furthermore, USP1 inhibitors are also effective for cancer patients with HRD, either alone or in combination with other drugs. Summary of the Invention

[0008] Through in-depth research and creative discovery, the inventors of this application have obtained new compounds of formula (I) that can inhibit USP1. These compounds can be used to treat and / or prevent diseases, tumors, or cancers associated with USP1 regulation.

[0009] In a first aspect, the present invention provides a compound of formula (I) or a stereoisomer, enantiomer, diastereomer, transisomer, optical isomer, racemate, tautomer, or pharmaceutically acceptable salt thereof, its polymorph, its prodrug, its hydrate or solvate, or its isotopically labeled compound.

[0010] in,

[0011] Ring G is a 6-membered heteroaryl ring;

[0012] Ring T is a 5-membered heterocycle containing heteroatoms;

[0013] W is selected from C(R) 1 ) or N;

[0014] X 1 X 2 V is independently selected from C or N; preferably, X 1 X 2 V is independently selected from C or N, and V is independently selected from C, CH or N;

[0015] Q is selected from C, C(R) 1 ), N, N(R) 1 ), O, S, C(=O), C(=S), S(=O), S(=O)2; preferably, Q 3 Selected from C(R) 1 ), N, N(R) 1 ), O, S, S(=O)2;

[0016] U is independently selected from C and C(R) each time it appears. 1 ), C(R 1 (R) 1 ), N, N(R) 1 ), O, S, C(=O), C(=S), S(=O), S(=O)2; preferably, U is selected from C(R 1 ), C(R 1 (R) 1 ), N, N(R) 1 ), O, S, C (=O), C (=S); preferably, Q 1 Selected from N, NR 1 C(R) 1 ), C (=O); preferably, Q 2 Selected from C(R) 1 ), N, NR 1 C (=O);

[0017] dotted line Indicates a single bond or a double bond;

[0018] Ring A is selected from 0-5 R a The following groups are substituted: saturated or unsaturated C3-C10 cycloalkyl groups, saturated or unsaturated 4-7-membered heterocyclic groups, C6-C10 aryl groups, and 5-10-membered heteroaryl groups; preferably, ring A is selected from those with 1-2 R groups. a Substituted with: phenyl, 5-6 heteroaryl; more preferably, ring A is selected from those with 1-2 R groups. a The following groups of substituted compounds are used: phenyl, pyridinyl, pyrimidinyl, pyrazolyl, imidazolyl; more preferably, ring A is selected from compounds substituted with 1-2 R groups. a Substituted: pyrazolyl, pyrimidinyl;

[0019] Rings B and C are each independently selected from 0-5 R... b The following groups are substituted: saturated or unsaturated C3-C10 cycloalkyl groups, saturated or unsaturated 4-7-membered heterocyclic groups, C6-C10 aryl groups, and 5-10-membered heteroaryl groups; preferably, ring B is selected from those with 0-1 R b Substituted: phenyl, 5-6 membered heteroaryl, saturated or unsaturated 3-6 membered heterocyclic groups, saturated or unsaturated C3-C6 cycloalkyl groups, More preferably, ring B is selected from phenyl, 6-membered heteroaryl, Preferably, ring C is selected from 0-5 R b The substituted 5-membered heteroaromatic ring (e.g., pyrroloyl, imidazolyl, pyrazolyl, thiazolyl, triazolyl); more preferably, the ring C is selected from those substituted by 1-2 R groups. b Substituted: imidazolyl, 1,2,4-triazole;

[0020] Alternatively, rings B and C, along with the bonds connecting them and the substituents, form an 11-14 quinary tricyclic structure, which may optionally be divided into 0-8 R groups. f Substitution; preferably, ring B, ring C, and the bonds connecting them together with the substituents form a group selected from 0-2 R groups. b The following three-ring structure is replaced:

[0021] R 1 Selected from H, D, halogen, cyano, carboxyl (COOH), hydroxyl, amino, nitro, -C(O)NH2;

[0022] R a R b R f R d R eEach time it appears, it is independently selected from H, D, halogen (e.g., F), cyano, carboxyl (COOH), hydroxyl, amino, nitro, -C(O)NH2, -C(O)NH (C1-C6 alkyl), -C(O)N (C1-C6 alkyl), -SONH, -SONH (C1-C6 alkyl), -SON (C1-C6 alkyl), oxo, C2-C6 alkenyl, halogenated C2-C6 alkenyl, optionally with 0-5 Rs. g Substituted from the following group: C1-C6 alkyl (e.g., methyl, ethyl, isopropyl, isobutyl, tert-butyl), C2-C6 alkynyl, C1-C6 alkylamino, di(C1-C6 alkyl)amino, halo-C1-C6 alkyl (e.g., trifluoromethyl), C1-C6 alkoxy, halo-C1-C6 alkoxy, hydroxy-C1-C6 alkyl, amino-C1-C6 alkyl, carboxyl-C1-C6 alkyl, C1-C6 alkylcarbonyl, C1-C6 alkoxycarbonyl, C1-C6 alkylaminoyl, C1-C6 alkylamide, C1-C6 alkylsulfonyl, C1-C6 alkylsulfonylamino, C1-C6 alkylaminosulfonyl, -(L) m -(C1-C6 alkyl), -(L) m -(C2-C6 alkenyl), -(L) m -(C2-C6 ynyl group), -(L) m -(C1-C6 alkoxy), -(L) m -(C6-C10 aryl), -(L) m -(C3-C10 cycloalkyl groups) (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl), -(L) m -(4-7 membered heterocyclic groups) (e.g., tetrahydropyranyl, morpholinyl, hexahydropiperidinyl), -(L) m -(C6-C10 aryl), -(L) m -(5-10 heteroaryl); where L is independently selected from -C(=O)-, -O-, -S-, -S(=O)-, -S(=O)2, -NR each time it appears. 4 -、-C(R 2 (R) 3 )-; m is an integer from 0 to 3 each time it appears (e.g., 0, 1, 2, 3);

[0023] Or, R d R e The N atoms connected to them form saturated or unsaturated 4-7 membered heterocyclic groups (e.g., morpholino, hexahydropiperidinyl), wherein the saturated or unsaturated 4-7 membered heterocyclic groups are optionally surrounded by 0-5 R atoms. g replace;

[0024] R gEach time it appears, it is independently selected from H, D, halogen, carboxyl, hydroxyl, cyano, nitro, amino, -C(O)NH2, -C(O)NH(C1-C6 alkyl), -C(O)N(C1-C6 alkyl)(C1-C6 alkyl), -SONH, -SONH(C1-C6 alkyl), -SON(C1-C6 alkyl)(C1-C6 alkyl), oxo, optionally deuterated from the group consisting of: C1-C6 alkyl (e.g., methyl), C2-C6 alkynyl, hydroxy C1-C6 alkyl, carboxyl C1-C6 alkyl, C1-C6 alkylamino, di(C1-C6 alkyl)amino, -C(=O)-(C1-6 alkyl)-NH2, C1-6 alkyl carbonyl, C1-C6 alkoxy, halo-C1-C6 alkyl, halo-C1-C6 alkoxy.

[0025] In some implementations, in formula (I), W is selected from N, CH, C(F), C(=O), C(CN), and C(NO2).

[0026] In some implementations, in formula (I), X 1 X 2 It is selected independently from C or N.

[0027] In some implementations, V in formula (I) is independently selected from C or N.

[0028] In some implementations, in formula (I), Q is selected from C(R) 1 ), N, N(R) 1 ), O, S, S(=O)2, where R 1 The definitions are as described above; preferably, Q is selected from CH, N, N(CH3), O, S, S(=O)2.

[0029] In some implementations, in formula (I), U is selected from C(R) 1 ), C(R 1 (R) 1 ), N, N(R) 1 ), O, S, C (=O), C (=S), where R 1 The definitions are as described above; preferably, U is selected from CH, CH2, N, N(CH3), O, S, C(=O), C(=S).

[0030] In some embodiments, in formula (I), ring G is selected from pyridine ring, pyrimidine ring, pyridazine ring, triazine ring, and tetrazine ring; ring T is selected from pyrrole ring, furan ring, thiophene ring, oxazole ring, thiazole ring, pyrazole ring, imidazole ring, triazole ring, oxadiazole, thiadiazole, tetraazole ring, oxtriazole ring, thiatriazole ring, oxtetrazole ring, and thiatetrazolium ring. Among them, the dashed lines Indicates a single or double bond shared with ring G. Indicates and The connection point.

[0031] In some implementations, in formula (I), ring A is selected from 1-2 R a Substituted with: phenyl, 5-6 heteroaryl; preferably, ring A is selected from 1-2 R a The following groups of substituted compounds are used: phenyl, pyridinyl, pyrimidinyl, pyrazolyl, imidazoleyl; more preferably, ring A is selected from compounds substituted with 1-2 R groups. a Substituted: pyrazolyl, pyrimidinyl; wherein, R a The definitions are as described above; preferably, each R a It is independently selected from methyl, isopropyl, cyclopropyl, and methoxy.

[0032] In some embodiments, in formula (I), ring B is selected from 0-5 (preferably 0-1) R. b Substituted: phenyl, 5-6 membered heteroaryl, saturated or unsaturated 3-6 membered heterocyclic groups, saturated or unsaturated C3-C6 cycloalkyl groups, Preferably, ring B is selected from phenyl, 6-membered heteroaryl, Among them, R b As defined above, preferably, R b Selected from methyl and trifluoromethyl.

[0033] In some embodiments, in formula (I), ring C is selected from 0-5 (preferably 1-2) R. b The substituted 5-membered heteroaryl ring is, for example, pyrroloyl, imidazolyl, pyrazolyl, thiazolyl, or triazolyl; preferably, the ring C is selected from those with 1-2 R groups. b Substituted: imidazole group, 1,2,4-triazolyl group, wherein R b As defined above, preferably, R b Selected from methyl and trifluoromethyl.

[0034] In some embodiments, in formula (I), ring B, ring C, and the bonds connecting them together with the substituents form a group selected from 0-2 (e.g., 0, 1, or 2) R groups. f The following three-ring structure is replaced: Among them, R f As defined above, preferably, each R f It is independently selected from methyl and trifluoromethyl.

[0035] In some implementations, in formula (I), R d R e Independently selected from H, D, and arbitrarily selected by 0-2 Rs gSubstituted groups: C1-C6 alkyl (e.g., methyl, ethyl, isopropyl, tert-butyl), C3-C6 cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl), 4-6 membered heterocyclic groups (e.g., tetrahydropyranyl, morpholinyl, hexahydropiperidinyl); or, R d R e Together with N, which are connected to each other, they form a group of 0-1 R. g Substituted saturated or unsaturated 4-6 membered heterocyclic groups (e.g., morpholino, piperazine); wherein R g As defined above, preferably, R g Each time it appears, it is independently selected from halogens (e.g., F), hydroxyl groups, and methyl groups.

[0036] In a specific embodiment, the compound represented by formula (I) is selected from the structure represented by formula (III-1) or (III-3):

[0037] in,

[0038] Ring B 1 Selected from 0-5 R b Substituted groups: phenyl, 5-6 membered heteroaryl, saturated or unsaturated C3-C6 cycloalkyl, saturated or unsaturated 3-6 membered heterocyclic groups.

[0039] Ring C 1 Selected from 0-5 R b The next group that it replaces:

[0040] Ring C 2 Selected from q R f The next group that it replaces:

[0041] X3, X 4 Independently selected from C, CH, and N; preferably, X 3 Let C, X 4 Let N be the number of people in the group.

[0042] Each occurrence of q is an independent integer between 0 and 3 (e.g., 0, 1, 2, 3), indicating that in the ring C... 1 Y 1 -Y 3 X 3 X 4 Y 4 The three-element ring structure formed by them contains q R elements. f Substituents;

[0043] Each time n appears, it is an independent integer from 1 to 3 (e.g., 1, 2, 3); Y4 Select independently from the following group each time it appears: -C(R) Ya (R) Yb )-、-NR Yc -, -C(=O)-, -O-, -S-, -S(=O)-, -S(=O)2;

[0044] R Ya R Yb The group is independently selected from the group consisting of: H, D, halogen, amino, hydroxyl, carboxyl, cyano, and optionally deuterated from the group consisting of: C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkoxy, C1-C6 alkylamino, di(C1-C6 alkyl)amino, C1-C6 alkylaminoacyl, C1-C6 alkylamide, C1-C6 alkylsulfonylamino, C1-C6 alkylaminosulfonyl, halo-C1-C6 alkyl, halo-C1-C6 alkoxy, hydroxy-C1-C6 alkyl, amino-C1-C6 alkyl, and carboxyl-C1-C6 alkyl; preferably, R Ya R Yb Each is independently selected from H and methyl;

[0045] R Yc Selected from the group consisting of: H, D; optionally deuterated from the group consisting of: C1-C6 alkyl, C1-C6 alkoxy, halo-C1-C6 alkyl, halo-C1-C6 alkoxy, hydroxy-C1-C6 alkyl, amino-C1-C6 alkyl, carboxyl-C1-C6 alkyl; preferably, R Yc Selected from H, methyl;

[0046] Y 1 Y 2 Y 3 Independently selected from C(R) 1 ), N; preferably, Y 1 Y 2 Y 3 Both are CH;

[0047] Rings A, W, N, X 1 X 2 U, V, Q, R b R f R d R e and dashed lines The definition is as described above.

[0048] In a specific embodiment, the compound represented by formula (I) is selected from the structure represented by formula (V-1) or (V-2):

[0049] Among them, rings A, W, U, Q, B, C, and R d and Re The definition is as stated above;

[0050] Preferably, ring A is selected from 1-2 R a The substituted 5-6 membered heteroaryl group; more preferably, ring A is selected from 1-2 R groups. a Substituted with the following group: pyrimidinyl, pyrazolyl, imidazoleyl; and / or

[0051] Preferably, W is selected from N, CH, C(F); and / or

[0052] Preferably, Q is selected from C(H), N; and / or

[0053] Preferably, U is selected from C(H), N; and / or

[0054] Ring B is selected from 0-5 (preferably 0-1) R. b Substituted: phenyl, 5-6 membered heteroaryl, saturated or unsaturated 3-6 membered heterocyclic groups, saturated or unsaturated C3-C6 cycloalkyl groups, Preferably, ring B is selected from phenyl, 6-membered heteroaryl, Among them, R b As defined above, preferably, R b Selected from methyl, trifluoromethyl;

[0055] Ring C is selected from 0-5 (preferably 1-2) R. b The substituted 5-membered heteroaryl ring is, for example, pyrroloyl, imidazolyl, pyrazolyl, or triazolyl; preferably, the ring C is selected from those with 1-2 R groups. b Substituted: imidazole group, 1,2,4-triazolyl group, wherein R b The definition is as described in claim 1, preferably, R b Selected from methyl, trifluoromethyl;

[0056] Alternatively, ring B, ring C, and the bonds connecting them together with substituents form a group selected from 0-2 R groups. f The following three-ring structure is replaced: Among them, R f The definition is as described in claim 1, preferably, each R f Independently selected from methyl, trifluoromethyl; and / or

[0057] Preferably, R d R e Independently selected from H, D, and arbitrarily selected by 0-2 Rs g Substituted groups: C1-C6 alkyl (e.g., methyl, ethyl, isopropyl, tert-butyl), C3-C6 cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl), 4-6 membered heterocyclic groups (e.g., tetrahydropyranyl, morpholinyl, hexahydropiperidinyl); or, Rd R e Together with N, which are connected to each other, they form a group of 0-1 R. g Substituted saturated or unsaturated 4-6 membered heterocyclic groups (e.g., morpholino, piperazine); wherein R g The definition is as described in claim 1, preferably, R g Each time it appears, it is independently selected from halogens (e.g., F), hydroxyl groups, and methyl groups.

[0058] In a specific embodiment, the compound represented by formula (I) is selected from one of the following compounds:

[0059] In a second aspect, the present invention provides a method for preparing the compound represented by formula (Ia) or formula (Ib), wherein the reaction routes are as follows:

[0060] Method 1:

[0061] Among them, Z 1 Selected from Br or I, Z 2 Selected from Cl or Br; A, B, C, W, N, X 1 X 2 U, Q, R d R e , As defined above;

[0062] Method 1 is selected from Route 1 or 2;

[0063] Route 1:

[0064] (1) Compound (IV) reacts with CO and methanol in the presence of a palladium catalyst and a base to produce compound (V);

[0065] (2) Compound (V) undergoes hydrolysis under alkaline conditions to yield compound (VI);

[0066] (3) The compound of formula (VI) reacts with the compound of formula (VII) to give the compound of formula (VIII);

[0067] (4) Compound (VIII) reacts with compound (IX) in the presence of a palladium catalyst to give compound (Ia);

[0068] Route 2:

[0069] (1) Compound (IV) reacts with CO and methanol in the presence of a palladium catalyst and a base to produce compound (V);

[0070] (5) The compound of formula (V) reacts with the compound of formula (VII) to give the compound of formula (VIII);

[0071] (4) Compound (VIII) reacts with compound (IX) in the presence of a palladium catalyst to give compound (Ia);

[0072] Preferably, in step (2), tetrahydrofuran can be added to the reaction system to improve solubility;

[0073] Preferably, in step (3) or (5), the solvent for the reaction is dichloromethane or N,N-dimethylformamide;

[0074] Preferably, in step (4), the solvent for the reaction is selected from one or more combinations of water, 1,4-dioxane and ethanol;

[0075] Method 2:

[0076] Among them, Z 2 Selected from Cl or Br, A, B, C, W, N, X 1 X 2 U, Q, R d R e , As defined above;

[0077] (6) Compound X) reacts with compound XI) under alkaline anhydrous conditions to obtain compound XII);

[0078] (7) Compound XII) reacts with compound IX) in the presence of a palladium catalyst to give compound (Ib).

[0079] Furthermore, when U and Q contain active hydrogen, the above preparation method may also include protecting the active hydrogen with a protecting group before step (1) or step (6). The protecting group is generally tetrahydro-2H-pyran-2-yl or 2-(trimethylsilyl)ethoxymethyl, and the protecting group is removed after step (4) or step (7) to obtain the target compound.

[0080] A third aspect of the present invention provides a pharmaceutical composition comprising one or more therapeutically effective amounts of a compound of formula (I) as described in the first aspect of the present invention, or a stereoisomer, enantiomer, diastereomer, transisomer, optical isomer, racemate, tautomer, or a pharmaceutically acceptable salt thereof, a polymorph thereof, a prodrug thereof, a hydrate or solvate thereof, an isotopically labeled compound thereof, and a pharmaceutically acceptable carrier; and optionally one or more other antitumor drugs;

[0081] Preferably, the other antitumor drugs include DNA damaging agents, reversible DNA binding agents, DNA alkylating agents, DNA strand breaking agents, DNA replication disruptors, antibodies, proteasome inhibitors, PARP inhibitors, ATM inhibitors, ATR inhibitors; p53 mutation regulators, and WEE1 inhibitors.

[0082] A fourth aspect of the present invention provides a ubiquitin-specific protease 1 (USP1) inhibitor comprising one or more compounds of formula (I) as described in the first aspect, or their stereoisomers, enantiomers, diastereomers, transisomers, optical isomers, racemates, tautomers, or pharmaceutically acceptable salts thereof, polymorphs thereof, prodrugs thereof, hydrates or solvates thereof, isotopically labeled compounds thereof, or the pharmaceutical composition described in the third aspect.

[0083] The fifth aspect of the invention provides the use of the compound of formula (I) of the first aspect or its stereoisomers, enantiomers, diastereomers, transisomers, optical isomers, racemates, tautomers, or pharmaceutically usable salts thereof, polymorphs thereof, prodrugs thereof, hydrates or solvates thereof, isotopically labeled compounds thereof, or pharmaceutical compositions of the third aspect in the preparation of a medicament for the detection and / or prevention and / or treatment of ubiquitin-specific protease (USP)-related diseases;

[0084] Preferably, the ubiquitin-specific protease (USP)-related disease is a USP1-related disease;

[0085] Preferably, the USP1-related disease is a cancer with a defective DNA damage repair pathway;

[0086] Preferably, the USP1-related disease is a cancer associated with BRAC1 or BRAC2 mutations;

[0087] Preferably, the USP1-related disease is a homologous recombination-deficient cancer;

[0088] Preferably, the USP1-related disease is an ATM-mutated tumor;

[0089] Preferably, the USP1-related disease is an ATR-mutated tumor;

[0090] Preferably, the USP1-related disease is a tumor with a P53 mutation or a tumor with two or more mutations.

[0091] Preferably, the USP1-related disease is a cancer containing cancer cells with elevated RAD51 levels;

[0092] Preferably, the USP1-related disease is a PARP inhibitor-resistant tumor.

[0093] In some embodiments, the present invention provides the use of a compound of formula (I) as described in the first aspect, or a stereoisomer, enantiomer, diastereomer, transisomer, optical isomer, racemate, tautomer, or pharmaceutically usable salt thereof, its polymorph, its prodrug, its hydrate or solvate, its isotopically labeled compound, or a pharmaceutical composition as described in the third aspect, in the preparation of a medicament selected from one or more of the following actions:

[0094] 1) Detection and / or prevention and / or treatment of tumors or cancer-related diseases;

[0095] Preferably, the tumor-related diseases are selected from the group consisting of: liver cancer, melanoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, acute lymphoblastic leukemia, chronic lymphoblastic leukemia, multiple myeloma, neuroblastoma, breast cancer (including triple-negative breast cancer), ovarian cancer, nephroblastoma, cervical cancer, testicular cancer, soft tissue sarcoma, primary macroglobulinemia, bladder cancer, chronic myeloid leukemia, primary brain cancer, malignant melanoma, non-small cell lung cancer, small cell lung cancer, gastric cancer, colon cancer, malignant pancreatic islet tumors, malignant carcinoid tumors, choriocarcinoma, head and neck cancer, osteosarcoma, pancreatic cancer, acute myeloid leukemia, leukemia, rhabdomyosarcoma, Kaposi's sarcoma, genitourinary system tumors, thyroid cancer, esophageal cancer, and malignant hypercalcemia. Cervical hyperplasia, renal cell carcinoma, endometrial cancer, polycythemia vera, idiopathic thrombocythemia, adrenocortical carcinoma, skin cancer, prostate cancer, AIDS-related lymphoma, AIDS-related malignancies, anal cancer, cerebellar astrocytoma, extrahepatic bile duct carcinoma, osteosarcoma / malignant fibrous histiocytoma, brainstem glioma, ependymoma, visual pathway and hypothalamic glioma, bronchial adenoma / carcinoma, islet cell carcinoma, primary central nervous system lymphoma, chronic myeloid leukemia, tenosynovial clear cell sarcoma, colorectal cancer, cutaneous T-cell lymphoma, epididymal tumor, esophageal cancer, Ewing's sarcoma / tumor family, extracranial germ cell tumors, extra-germ cell tumors, ocular cancer (including intraocular melanoma and retinoblastoma), gallbladder cancer. Cystic carcinoma, ovarian germ cell tumors, gestational trophoblastic tumors, pilosebaceous leukemia, hypopharyngeal cancer, laryngeal cancer, acute lymphoblastic leukemia, acute myeloid leukemia, Waldenstrom's macroglobulinemia, malignant thymoma, medulloblastoma, Merkel cell carcinoma, metastatic primary squamous cell carcinoma, multiple endocrine tumor syndrome, multiple myeloma / plasma cell tumor, myelodysplastic syndrome, myeloid leukemia, myeloproliferative disorders, nasal and paranasal sinus cancer, nasopharyngeal carcinoma, oral cancer, lip cancer, oropharyngeal cancer, osteosarcoma / malignant fibrous histiocytoma of bone, low-grade potential ovarian tumors, paranasal sinus and nasal cavity cancer, parathyroid carcinoma, penile cancer, pheochromocytoma, pituitary adenoma, thoracic pulmonary blastoma, rectal cancer, transitional cell carcinoma (e.g., renal pelvis) (and ureter), salivary gland cancer, malignant fibrous histiocytoma, including bone, Sezary syndrome, small bowel cancer, supradental primitive neuroectodermal and pineal gland tumors, urethral cancer, uterine sarcoma, vaginal cancer, vulvar cancer, Wilms' tumor, anaplastic large cell lymphoma, central nervous system cancer, mesothelioma, fallopian tube cancer, malignant mesothelioma, renal cancer, renal pelvis and ureter cancer, acute myeloid leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, mycosis fungoides, chondrosarcoma, Ewing's sarcoma, osteosarcoma, malignant fibrous histiocytoma of bone, rhabdomyosarcoma in children, brain tumors, astrocytomas, pituitary tumors, lung cancer, bone cancer, brain cancer, soft tissue cancer, nervous system cancers, ovarian cancer, uterine cancer, cervical cancer, glioma.Glioblastoma, meningioma, rhabdomyosarcoma, melanoma, hematologic malignancies, lymphoma, ovarian tumors, skin tumors, neurological tumors;

[0096] 2) Detection and / or prevention and / or treatment of inflammatory cell diseases;

[0097] 3) Detection and / or prevention and / or treatment of neurodegenerative diseases.

[0098] A sixth aspect of the present invention also provides a pharmaceutical combination comprising:

[0099] (1) One or more compounds of formula (I) as described in the first aspect, or their stereoisomers, enantiomers, diastereomers, transisomers, optical isomers, racemates, tautomers, or pharmaceutically acceptable salts thereof, their polymorphs, their prodrugs, their hydrates or solvates, or their isotopically labeled compounds.

[0100] (2) One or more other antitumor drugs;

[0101] Preferably, "multiple" refers to "two", "three", or "four" types;

[0102] Preferably, the other antitumor drugs are DNA damaging agents, reversible DNA binding agents, DNA alkylating agents, DNA strand breaking agents, DNA replication disruptors, antibodies (including monoclonal antibodies), proteasome inhibitors, PARP inhibitors, ATM inhibitors, ATR inhibitors; p53 mutation regulators, and WEE1 inhibitors.

[0103] A seventh aspect of the invention also provides the use of the pharmaceutical combination described in the sixth aspect in the preparation of a medicament for treating tumors or cancer.

[0104] Preferably, the tumor or cancer is a cancer with a defective DNA damage repair pathway;

[0105] Preferably, the tumor or cancer is a BRAC1 or BRAC2 mutation-related cancer;

[0106] Preferably, the tumor or cancer is a homologous recombination-deficient cancer;

[0107] Preferably, the tumor or cancer is an ATM-mutated tumor;

[0108] Preferably, the tumor or cancer is an ATR-mutated tumor;

[0109] Preferably, the tumor or cancer is a p53-mutated tumor or a tumor with two or more mutations.

[0110] Preferably, the tumor or cancer is a cancer containing cancer cells with elevated RAD51 levels;

[0111] Preferably, the tumor or cancer is a PARP inhibitor-resistant tumor;

[0112] Preferably, the tumor or cancer is a blood cancer, lymphoma, bone cancer (including osteosarcoma and chondrosarcoma), brain cancer (including glioma, glioblastoma, astrocytoma, medulloblastoma and meningioma), soft tissue cancer (including rod-shaped tumor and sarcoma), kidney cancer, bladder cancer, skin cancer (including melanoma), lung cancer (including non-small cell lung cancer), colon cancer, uterine cancer, nervous system cancer, head and neck cancer, pancreatic cancer, cervical cancer, ovarian cancer, peritoneal cancer, endometrial cancer, or breast cancer (including triple-negative breast cancer). Detailed Implementation

[0113] Through long-term and in-depth research, the inventors unexpectedly developed a novel compound of general formula (I) with significant kinase inhibitory activity. This kinase inhibitor exhibits excellent USP1 inhibitory activity and can therefore be used to prepare pharmaceutical compositions for the detection, prevention, and / or treatment of diseases involving cell death and / or related conditions. Based on this, the inventors completed this invention.

[0114] the term:

[0115] The terms "C1-C6" refer to having 1, 2, 3, 4, 5, or 6 carbon atoms, "C1-C8" refers to having 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms, and so on. "5-8" refers to having 5-8 ring atoms, and so on.

[0116] A "substituent" refers to an atom or group that can replace a hydrogen atom in a substituted compound. Examples are as follows (but are not limited to): deuterated, alkyl, alkenyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, isocyanate, cycloalkyl, heterocyclic, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, amino, haloalkyl, hydroxyalkyl, carboxyl, carboxylic acid ester, oxo, thio, -C(=O)R n -C(=O)OR n -C(=O)NR n R o -NR n R o -NR n C(=O)R o -NR n C(=O)OR o -NR n C(=O)NR o R p-NR n S(=O)R o -NR n S(=O)NR o R p -NR n S(=O)2R o -NR n S(=O)2NR o R p -OR n -SR n -OC(=O)R n -OC(=O)NR n R o -OC(=O)OR n -S(=O)NR n R o -S(=O)2NR n R o -BR n R o -B(OR) n (OR) o ), -SiR n R o R p -OP(=O)R n R o -P(=O)R n R o -OP(=O)2R n -P(=O)2R n -NP(=O)R n R o -NP(=O)R n R o -NP(=O)2R n -NP(=O)2R n etc., where R n R o R p Each time it appears, it is independently selected from the group consisting of: H, D, C1-C12 alkyl, halogenated C1-C12 alkyl, C1-C12 heteroalkyl, halogenated C1-C12 heteroalkyl, C3-C12 cycloalkyl, halogenated C3-C12 cycloalkyl, C6-C12 aryl, halogenated C6-C12 aryl, C5-C12 heteroaryl, halogenated C5-C12 heteroaryl; or, R n R o Together with the atoms they are attached to, they can form ring structures. Those skilled in the art will understand that the combinations of substituents and substituted substances contemplated in this invention are those stable or chemically feasible combinations.

[0117] "Substitution" refers to the replacement of one or more hydrogen atoms on a specific group by a specific substituent. The specific substituent is the substituent described accordingly above, or the substituent appearing in the various embodiments. Unless otherwise specified, a substituted group may have a substituent selected from a specific group at any substituted site of that group, and the substituents at each position may be the same or different. Those skilled in the art will understand that the combinations of substituents contemplated in this invention are those that are stable or chemically feasible. Such substituents include (but are not limited to): alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocyclic, aryl, heteroaryl, cycloalkoxy, heterocyclic alkoxy, cycloalkylthio, heterocyclic alkylthio, amino, haloalkyl, hydroxyalkyl, carboxyl, carboxylic acid ester, oxo, thio, -C(=O)R n -C(=O)OR n -C(=O)NR n R o -NR n R o -NR n C(=O)R o -NR n C(=O)OR o -NR n C(=O)NR o R p -NR n S(=O)R o -NR n S(=O)NR o R p -NR n S(=O)2R o -NR n S(=O)2NR o R p -OR n -SR n -OC(=O)R n -OC(=O)NR n R o -OC(=O)OR n -S(=O)NR n R o -S(=O)2NR n R o -BR n R o -B(OR) n (OR) o ), -SiR n R o Rp -OP(=O)R n R o -P(=O)R n R o -OP(=O)2R n -P(=O)2R n -NP(=O)R n R o -NP(=O)R n R o -NP(=O)2R n -NP(=O)2R n etc., where R n R o R p The definition is the same as above.

[0118] "Ring structure" refers to monocyclic or polycyclic structures. Typically, it is a closed structure formed by the connection of two or more segments on a single atom in a ring structure. Examples include, but are not limited to, cycloalkanes, heterocyclic alkanes, cyclic lactams, aromatics, heteroaromatics, fused rings, bridged rings, and spirocyclic structures, such as cyclopropane, cyclobutane, oxacyclobutane, cyclopentane, cyclohexane, adamantane, cyclohexene, cyclooctyne, pyrazole, benzene, pyridine, 3,4-dihydro-1,4-benzoxazolopyridine-5(2H)-one, naphthalene, anthracene, phenanthrene, quinoline, pyrrolopyridine, pyrazolopyridine, indole, dihydroindole, steroidal rings, and porphyrin rings. The ring structure can be optionally substituted or unsubstituted. When it appears as a substituent, it means that one or more hydrogen atoms on the monocyclic or polycyclic ring are removed, thus allowing it to act as a substituent for the substituted substance.

[0119] "Halogen" refers to F, Cl, Br or I.

[0120] "Halogenation" refers to the replacement of a substance by one or more halogens.

[0121] "Aryl" refers to a carbocyclic aromatic system containing one or more rings, wherein the rings do not contain heteroatoms. Optionally, the aryl group may be fused with a heteroaryl, heterocyclic, or other ring structure. Examples are as follows (but are not limited to): phenyl, naphthyl, tetrahydronaphthyl, ... The aryl group may be optionally substituted or unsubstituted. When the aryl group is described as "C6-C14 aryl", it means that the aromatic ring connected to the parent structure has 6-14 carbon atoms, but the aryl group may optionally be fused with other ring structures, which refer to ring structures with 3-18 ring atoms, and these other ring structures may be optionally substituted or unsubstituted.

[0122] "Heteroaryl" refers to an aromatic ring structure containing one or more rings, which may include one or more atoms selected from N, O, or S. Optionally, the aryl group may be fused with an aryl, heterocyclic, cycloalkyl, or other ring structure. Examples are as follows (but not limited to): furanyl, thiophene, pyridinyl, pyrazolyl, pyrroleyl, oxazolyl, thiazolyl, N-alkylpyrroleyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, tetraazinyl, imidazolyl, thiazolyl, triazolyl, tetrazolyl, oxadiazolyl, thiadiazolyl, oxadiazolyl, thiatriazolyl, thiatriazolyl, oxtetrazoleyl, thiattezolyl, The heteroaryl group may be optionally substituted or unsubstituted. When the heteroaryl group is described as a "5-14 membered heteroaryl group", it means that the heteroaryl group and the parent structure together form a heteroaryl ring with 5-14 ring atoms. However, the heteroaryl group may optionally be fused with other ring structures, which refer to ring structures with 3-18 ring atoms. These other ring structures may be optionally substituted or unsubstituted.

[0123] “Cycloalkyl” refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent. In this document, “unsaturated cycloalkyl” refers to a non-aromatic monocyclic or polycyclic hydrocarbon substituent containing one or more (e.g., two, three, or four) unsaturated bonds (e.g., carbon-carbon double or triple bonds), such as cycloalkenyl or cycloynyl. The first ring structure directly attached to the substituted compound is non-aromatic. Examples of monocyclic cycloalkyl groups (but not limited to the following): cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cyclohepttrienyl, cyclooctyl, cyclooctyynyl, etc.; Examples of polycyclic cycloalkyl groups (but not limited to the following): spirocyclic, fused-ring, and bridged-ring cycloalkyl groups. Optionally, the cycloalkyl group may be fused with or form a spirocyclic group with an aryl, heterocyclic, cycloalkyl, or other ring structure. Examples of fusion with or formation of a spirocyclic group with other ring structures (but not limited to the following): The cycloalkyl group may be optionally substituted or unsubstituted. When the cycloalkyl group is described as "C3-C14 cycloalkyl", it means that the cycloalkyl ring connected to the parent structure has 3-14 carbon atoms. However, the cycloalkyl group may optionally be fused with other ring structures or form a spiro ring. The other ring structures refer to ring structures with 3-18 ring atoms, and the other ring structures may be optionally substituted or unsubstituted.

[0124] "Heterocyclic group" refers to a monocyclic or polycyclic cyclic structure in which at least one ring atom is a heteroatom (e.g., O, N, S atoms, etc.) and is saturated or partially unsaturated. In this article, "unsaturated heterocyclic group" is a non-aromatic monocyclic or polycyclic cyclic structure in which at least one ring atom is selected from the above-mentioned heteroatoms and the ring contains one or more (e.g., two, three, four) unsaturated bonds (e.g., carbon-carbon double bonds, carbon-carbon triple bonds), such as heterocyclic alkenyl groups and heterocyclic alkynyl groups. Examples of "heterocyclic groups" are as follows (but are not limited to the following examples): tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyrroliyl, tetrahydrothiophenyl, piperidinyl, piperazinyl, aziridine, aziridine-butyl, aziridine-heptyl, morpholinyl, 2-oxo-pyrrolidinyl, piperazine-2-one, 8-oxa-3-aza-bicyclo[3.2.1]octyl, etc. The heterocyclic ring can be fused to an aryl, heteroaryl, or cycloalkyl ring, wherein the ring connected to the parent structure is a heterocyclic group. The heterocyclic group can be optionally substituted or unsubstituted. When the heteroalkyl group is described as a "3-14 membered heterocyclic group," it means that the heterocyclic ring connected to the parent structure has 3-14 ring atoms. However, the heterocyclic group can optionally be fused with other ring structures or form a spirocyclic ring. The other ring structures refer to ring structures with 3-18 ring atoms, and these other ring structures can be optionally substituted or unsubstituted.

[0125] "Tautomerism" refers to structural isomers with different energies that can cross a low energy barrier and thus interconvert. For example, proton tautomerism (i.e., proton shift) includes interconversion through proton migration, such as 1H-indazole and 2H-indazole, 1H-benzo[d]imidazole and 3H-benzo[d]imidazole. Valence tautomerism includes interconversion through some bonding electron recombination.

[0126] "Stereoisomers" refer to molecules that have atoms with the same connectivity but different spatial arrangements. For example, two compounds containing a chiral center and having the same two-dimensional connectivity, such as R-glyceraldehyde and S-glyceraldehyde, or R-serine and S-serine.

[0127] "Enantiomers" refer to stereoisomers that are mirror images of each other and cannot be superimposed. For example, R-serine and S-serine.

[0128] "Diarrhetinic isomers" refer to stereoisomers of molecules that have two or more chiral centers and are not mirror images of each other. Tartaric acid is an example.

[0129] "Restricted isomers" refers to a group of conformational isomers of a molecule that are produced because rotation around a single bond is restricted. For example, the various stereoisomers of 6,6'-dinitro-2,2'-biphenyldicarboxylic acid.

[0130] "Optical isomers" refer to compounds in which two or more molecules have the same two-dimensional connection, but exhibit different optical rotations due to differences in configuration. For example, levamlodipine and dextroamlodipine.

[0131] "Racemate" refers to compounds with the same two-dimensional linkage but which are optical isomers, and when mixed together, they ultimately exhibit no optical activity. Example: racemic amlodipine.

[0132] "Pharmaceutically acceptable salt" refers to a salt that retains the biological effects and properties of the compounds of the present invention, and that is not biologically or otherwise undesirable. Non-limiting examples of such salts include non-toxic addition salts of inorganic or organic bases or acids of the compounds of the present invention. In many cases, the compounds of the present invention are capable of forming acid salts and / or base salts due to the presence of amino and / or carboxyl groups or similar groups. Pharmaceutically acceptable acid addition salts can be formed using inorganic and organic acids. Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc. Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, etc. Pharmaceutically acceptable base addition salts can be formed using inorganic and organic bases. Inorganic bases from which salts can be derived include, for example, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, and aluminum; ammonium, potassium, sodium, calcium, and magnesium salts are particularly preferred. Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines (including naturally occurring substituted amines), cyclic amines, and basic ion exchange resins, especially, for example, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine.

[0133] "Prodrug" refers to a compound that can be converted into the present invention in vivo, and therefore, these prodrugs are also included within the scope of protection of the compounds of the present invention.

[0134] The compounds of the present invention, including their stereoisomers, enantiomers, diastereomers, transisomers, optical isomers, racemates, tautomers, prodrugs, and pharmaceutically acceptable salts, may exist in both unsolvable and solvated forms containing pharmaceutically acceptable solvents (such as water, organic solvents such as ethanol, dimethyl sulfoxide, etc.). The compounds of the present invention include both solvated and unsolvable forms. The solvated form is a solvate, such as a hydrate. "Isotopically labeled compound" means the isotopically labeled form of the compounds of the present invention. Except that one or more atoms are replaced by atoms having a selected atomic mass or mass number, the isotopically labeled compound has the structure described herein by the given formula. Examples of isotopes that can be incorporated into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine, for example, each having... 2 H (i.e., D) 3 H (i.e., T) 11 C 13 C 14 C 15 N、 18 F 31 P, 32 P, 35 S, 36 Cl、 125 I. This invention includes compounds labeled with different isotopes as defined herein, for example, compounds containing radioactive isotopes such as... 3 H, 13 C and 14 Those with C. These isotope-labeled compounds can be used for metabolic studies (using...). 14 C) Reaction kinetic studies (e.g., using...) 2 H or 3 H) Detection or imaging techniques, such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT), including drug or substrate tissue distribution determination, or may be used for radiation therapy of patients.

[0135] Moreover, it is affected by heavier isotopes, especially deuterium (i.e., 2 Substitution with H or D can also yield certain therapeutic benefits due to greater metabolic stability, such as prolonged in vivo half-life, reduced dose requirements, or improved therapeutic index. It is understood that deuterium in the context can be considered a substituent in the compounds of this invention. The concentration of such heavier isotopes, particularly deuterium, can be defined by an isotope enrichment factor. An "isotope enrichment factor" represents the ratio between the isotopic abundance of a specified isotope and its native abundance.

[0136] The pharmaceutical compositions of the present invention comprise, within a safe and effective range, the compound of the present invention or a pharmacologically acceptable salt thereof, and a pharmacologically acceptable excipient or carrier. "Safe and effective range" refers to an amount of the compound sufficient to significantly improve the condition without causing serious side effects. Typically, the pharmaceutical composition contains 1-2000 mg of the compound of the present invention per dose, more preferably, 50-200 mg of the compound of the present invention per dose. Preferably, "one dose" is one capsule or tablet.

[0137] "Pharmaceutically acceptable carriers" refers to one or more compatible solid or liquid fillers or gelling substances that are suitable for human use and must have sufficient purity and sufficiently low toxicity. "Compatibility" here means that the components in the composition can be mixed with and with the compounds of the present invention without significantly reducing the efficacy of the compounds. Examples of pharmaceutically acceptable carriers include cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid, magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifiers (such as... Wetting agents (such as sodium dodecyl sulfate), colorants, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

[0138] The pharmaceutical composition is an injection, capsule, tablet, pill, powder, or granule, etc.

[0139] There are no particular limitations on the administration of the compounds or pharmaceutical compositions of the present invention. Representative administration methods include (but are not limited to): oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and local administration.

[0140] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In these solid dosage forms, the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following components: (a) fillers or compatibilizers, such as starch, lactose, sucrose, glucose, mannitol, and silica; (b) binders, such as hydroxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, and gum arabic; (c) humectants, such as glycerin; (d) disintegrants, such as agar, calcium carbonate, potato starch or cassava starch, alginate, certain complex silicates, and sodium carbonate; (e) slowing agents, such as paraffin; (f) absorption accelerators, such as quaternary ammonium compounds; (g) wetting agents, such as cetyl alcohol and glyceryl monostearate; (h) adsorbents, such as kaolin; and (i) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium dodecyl sulfate, or mixtures thereof. Buffers may also be included in capsules, tablets, and pills.

[0141] Solid dosage forms such as tablets, sugar pills, capsules, pellets, and granules can be prepared using coatings and shells, such as casings and other materials known in the art. They may contain opacifying agents, and the release of the active compound or compound from such compositions can be delayed in a portion of the digestive tract. Examples of encapsulating components that can be used are polymeric substances and waxes. If necessary, the active compound may also be formed into microcapsules with one or more of the excipients described above.

[0142] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, or tinctures. In addition to the active compound, liquid dosage forms may contain inert diluents conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, e.g., ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butanediol, dimethylformamide, and oils, particularly cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil, and sesame oil, or mixtures of these substances.

[0143] In addition to these inert diluents, the composition may also contain auxiliaries such as wetting agents, emulsifiers and suspending agents, sweeteners, flavoring agents and fragrances.

[0144] In addition to the active compound, the suspension may contain suspending agents such as ethoxylated isooctadecyl alcohol, polyoxyethylene sorbitol and dehydrated sorbitol esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances.

[0145] Compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions, or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and non-aqueous carriers, diluents, solvents, or excipients include water, ethanol, polyols, and suitable mixtures thereof.

[0146] Dosage forms of the compounds of the present invention for topical administration include ointments, powders, patches, sprays, and inhalers. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants that may be necessary.

[0147] The compounds of this invention can be administered alone or in combination with other pharmaceutically acceptable compounds (such as antitumor drugs).

[0148] The treatment method of the present invention can be used alone or in combination with other treatment methods or drugs.

[0149] When using the pharmaceutical composition, a safe and effective amount of the compound of the present invention is applied to the mammal (such as a human) requiring treatment. The dosage administered is the pharmaceutically considered effective dose. For a person weighing 60 kg, the daily dose is typically 1–2000 mg, preferably 5–500 mg. Of course, the specific dosage should also take into account factors such as the route of administration and the patient's health condition, which are all within the scope of the skill of a skilled physician.

[0150] In this invention, the DNA damaging agents exemplary include actinomycin, floxacin, anthracycline antibiotics, bleomycin, thiocarbamate, camptothecin, carboplatin, chloromycin, cisplatin, cyclophosphamide, cytotoxin, datimycin, daunorubicin, doxorubicin, epirubicin, hexamethylmelamine-oxaliplatin, isophosphoramide, melphalan, phytolaccaline, mitomycin, mitoxantrone, nitrosourea, pricamycin, procarbazine, paclitaxel, taxane, teniposide, triethylthiophosphoramide, and etoposide; or the DNA damaging agents are biotherapeutic agents, such as rinterferon-A2A, RNTERFERON-012B, RINTERLEUKIN-2, RG-CSF, RGM-CSF, and erythropoietin.

[0151] In this invention, reversible DNA binding agents exemplary include toppertan hydrochloride, irinotecan (CPT11-camptothecin), rubiain, etanertin, tartrazine, TAS-103, etoposide, pyridines (such as saccharin, aminoacridine), actinomycins (such as actinomycin D), anthracyclines (such as doxorubicin, daunorubicin), diphenylacetylene, XR11576 / MLN576, benzopyridindo, mitoxantrone, AQ4, etoposide, teniposide, epididophoroxin, and double intercalating agents such as treosetin A and echinomycin.

[0152] In this invention, DNA alkylating agents exemplary include sulfur mustard, nitrogen mustard (such as methyl chloroethylamine), chloramphenicol, melphalan, ethyleneimine (such as triethylenemethylamine, quinolone, diazinon), methyl methanesulfonate, butyramide, CO-1065, docamycin (such as docamycin A, docamycin SA), metabolically activated alkylating agents such as nitrosourea (such as carmustine, lomustine, (2-chloroethyl)nitrosourea), triazine antitumor drugs such as triazinonimidazole (such as dacarzine), mitomycin C, and lenamicin.

[0153] In this invention, DNA strand-breaking agents include, exemplarily, doxorubicin and daunorubicin (which are also reversible DNA binding agents), other anthracycline antibiotics, bovomisin, thiamethoxam, and enediyne antitumor antibiotics.

[0154] In this invention, the DNA replication disruptor exemplary includes 5-fluorodeoxyuridine (fluorouridine).

[0155] In this invention, monoclonal antibodies include trastuzumab (e.g., anti-ErbB2 / HER2 for breast cancer), cetuximab (e.g., anti-ErbBL / EGFR for colorectal cancer), and bevacizumab (e.g., anti-VEGF for colorectal cancer, breast cancer, and lung cancer), as well as multi-target inhibitors, such as solutions that inhibit the TK activity of VEGFR, PDGFR, and FGFR.

[0156] In this invention, the proteasome inhibitors exemplarily include those selected from bortezomib.

[0157] In this invention, PARP inhibitors include olaparib, niraparib, tapazoli, rucaparib, fuzuloparib, senaparib, veliparib, and BGP-15.

[0158] In this invention, the ATM inhibitors include AZD-1390, M-4076, and XRD-0394.

[0159] In this invention, the ATR inhibitor includes M1774.

[0160] In this invention, the P53 mutation regulator includes PC14586.

[0161] In this invention, the WEE1 inhibitors include ZN-C3, AZD1775, IMP-7068, SY-4835, and MK-1775.

[0162] The present application will be described in detail below with reference to certain embodiments of the present application, which are illustrated by way of example. Although the present application has been described in conjunction with the enumerated embodiments, it should be understood that it is not intended to limit the present application to those described embodiments. Rather, the present application is intended to cover all alternatives, modifications, and equivalents falling within the scope defined by the claims. Those skilled in the art will recognize other methods and materials similar to or equivalent to those described herein that can be used to implement the present application, and the present application is not limited in any way to the methods and materials described.

[0163] It should also be understood that certain features described in different embodiments may also be provided in combination in a single embodiment. Conversely, multiple features described in a single embodiment may also be provided individually or in any suitable sub-combination.

[0164] Example

[0165] Unless otherwise specified, experimental methods in the following examples are generally performed under standard conditions or as recommended by the manufacturer. Percentages and parts are by weight.

[0166] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of skill in the art. Furthermore, any methods and materials similar to or equivalent to those described herein may be applied to the methods of this invention. The preferred embodiments and materials described herein are for illustrative purposes only. The following are examples of methods for synthesizing representative compounds of this invention:

[0167] Synthesis of compound A-1

[0168] (1) Add starting material 1a (500 μL, 1.22 mmol), isopropyl p-toluenesulfonate (1.7 mL, 1.83 mmol), cesium carbonate (4 g, 2.44 mmol), and N,N-dimethylformamide (10 mL) to a reaction flask. React at 80 °C for 20 hours, then cool to room temperature. TLC showed complete reaction. Add saturated brine and extract three times with ethyl acetate. Combine the organic phases, dry to anhydrous sodium sulfate, concentrate under reduced pressure, and separate by silica gel column chromatography, eluting with petroleum ether / ethyl acetate to give a pale yellow oily liquid 2a (206 mg, 27%). LCMS: (MS-ESI, m / z): [M+H] + =125.1.

[0169] (2) Under argon protection, 2a (80 mg, 0.64 mmol) and anhydrous tetrahydrofuran (5 mL) were added to a dry reaction flask. The mixture was stirred and cooled at 0 °C for 5 minutes. Then, n-butyllithium (515 μL, 1.30 mmol) was slowly added. After the addition was complete, the reaction temperature was lowered to -78 °C. Isopropanol pinacol borate (263 μL, 1.30 mmol) was then added dropwise, and the reaction was continued for 45 minutes. The reaction was then brought to room temperature and allowed to proceed for 6 hours. TLC showed that the reaction was complete. The mixture was quenched with saturated ammonium chloride solution, water was added, and the mixture was extracted three times with ethyl acetate. The organic phases were combined, washed once with saturated sodium chloride, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by silica gel column chromatography. The eluent was petroleum ether / ethyl acetate, yielding compound A-1 (73 mg, 30.2%). LCMS: (MS-ESI, m / z): [M+H] + =251.2.

[0170] Synthesis of compound B-1

[0171] (1) Add 1,1-dibromo-3,3,3-trifluoroacetone (2g, 14.1mmol), sodium acetate (6g, 74.1mmol), and water (20mL) to a reaction flask. React at 100℃ for 45 minutes and then cool to room temperature to obtain mixture A. Add 4-cyanobenzaldehyde (7.7g, 59.3mmol), methanol (257mL), and concentrated ammonia (51mL) to another reaction flask. Stir well at room temperature, then slowly add mixture A dropwise to the reaction solution. After the addition is complete, raise the reaction temperature to 100℃ and react for 10 hours. TLC plate analysis showed that the reaction was complete. Concentrate under reduced pressure, extract three times with ethyl acetate / water, combine the organic phases, concentrate under reduced pressure, and slurry with methyl tert-butyl ether to obtain a pale yellow solid 2b (13g, 74%). Liquid chromatography-mass spectrometry (LCMS) results: (MS-ESI, m / z): [M+H] + =238.1.

[0172] (2) Under argon protection in an ice-water bath, 2b (650 mg, 2.53 mmol) and tetrahydrofuran (25 mL) were added to the reaction flask. Sodium hydride (365 mg, 15.2 mmol) was slowly added, and the reaction was maintained at this temperature for 30 minutes. Iodomethane (236 μL, 3.80 mmol) was then slowly added dropwise to the reaction solution. The reaction temperature was raised to room temperature and the reaction continued for 12 hours. TLC showed complete reaction. The reaction was quenched with water and extracted three times with ethyl acetate. The organic phases were combined, washed once with saturated sodium chloride, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by silica gel column chromatography, eluting with petroleum ether / ethyl acetate, to give a white solid 3b (348 mg, 55%). LCMS: (MS-ESI, m / z): [M+H] +=252.1. 1 H NMR (600MHz, DMSO-d6) δ8.04(d,J=1.3Hz,1H),8.0- 7.98(m,2H),7.95(d,J=8.5Hz,2H),3.85(s,3H).

[0173] (3) Under ice-water bath conditions, intermediate 3b (100 mg, 0.40 mmol) and methanol (5 mL) were added to the reaction flask, followed by nickel dichloride (23 mg, 0.1 mmol) and di-tert-butyl dicarbonate (274 μL, 1.20 mmol). After the addition was complete, the reaction temperature was raised to room temperature and stirred for 8 hours. TLC showed that the reaction was complete. The reaction was quenched with saturated ammonium chloride solution, water was added, and the mixture was extracted three times with ethyl acetate. The organic phases were combined, washed once with saturated sodium chloride, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by silica gel column chromatography. Elution with petroleum ether / ethyl acetate gave a white intermediate 4b (76 mg, 53.7%). LCMS: (MS-ESI, m / z): [M+H] + =356.4.

[0174] (4) Under ice-water bath conditions, intermediate 4b (266 mg, 0.75 mmol) was added to the reaction flask, followed by dichloromethane (5 mL), then 4 mol / L ethyl hydrogen chloride solution (2.7 mL). After the addition was complete, the reaction temperature was raised to room temperature and the reaction was allowed to proceed for 5 hours. TLC showed that the reaction was complete. Methyl tert-butyl ether was added to the reaction solution and the mixture was slurried to give a white compound B-1 (165 mg, 83.7%). LCMS: (MS-ESI, m / z): [M+H] + =256.1. 1 H NMR (600MHz, DMSO-d6) δ8.60(s,2H),7.97(s,1H),7.77(d,J=7.9Hz,2H),7.65(d,J=7.9Hz,2H),4.09(q,J=5.8Hz,2H),3.79(s,3H).

[0175] Synthesis of compound C-1

[0176] (1) At room temperature, 1c (50 mg, 0.26 mmol), acetonitrile (700 μL), N,N-dimethylformamide (400 μL), and N-iodosuccinimide (65 mg, 0.29 mmol) were added to a reaction flask and stirred until homogeneous. The reaction temperature was then raised to 80 °C and the reaction was carried out for 20 hours. TLC showed that the reaction was complete. Saturated brine was added, and the mixture was extracted three times with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by silica gel column chromatography. The eluent was petroleum ether / ethyl acetate, yielding a pale yellow intermediate 2c (60 mg, 76%). LCMS: (MS-ESI, m / z): [M+H] + =314.9. 1 H NMR(600MHz,DMSO-d6)δ14.95(s,1H).

[0177] (2) At room temperature, intermediate 2c (2 g, 6.35 mmol), dichloromethane (20 mL), 3,4-dihydro-2H-pyran (2.9 mL, 31.76 mmol), and p-toluenesulfonic acid (109 mg, 0.64 mmol) were added to a reaction flask. The reaction was allowed to proceed for 6 hours, and TLC showed complete reaction. The mixture was concentrated under reduced pressure and slurried with a small amount of ethyl acetate to give a white intermediate 3c (1.38 g, 62.2%). LCMS: (MS-ESI, m / z): [M+H] + =398.9.

[0178] (3) At room temperature, intermediate 3c (1.7 g, 4.3 mmol), B-1 (0.94 g, 4.3 mmol), potassium carbonate (1.8 g, 12.9 mmol), and acetonitrile (90 mL) were added to the reaction flask. The reaction was allowed to proceed for 5 hours. TLC showed that the reaction was complete. The mixture was concentrated under reduced pressure, extracted three times with ethyl acetate / water, and the organic phases were combined. The mixture was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by silica gel column chromatography. Elution with petroleum ether / ethyl acetate gave a white intermediate 4c (1.35 g, 56%). LCMS: (MS-ESI, m / z): [M+H] + =570.1.

[0179] (4) At room temperature, intermediate 4c (135 mg, 0.24 mmol), 1,1'-bis(diphenylphosphino)ferrocene palladium(II) dichloride (17 mg, 0.02 mmol), triethylamine (99 μL, 0.71 mmol), and methanol (16 mL) were added to the reaction flask. The mixture was replaced three times with carbon monoxide (1 atm), and reacted at 60 °C for 12 hours. TLC showed that the reaction was complete. The mixture was concentrated under reduced pressure, extracted three times with ethyl acetate / water, and the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by silica gel column chromatography. The eluent was petroleum ether / ethyl acetate, yielding a grayish-white intermediate 5c (80 mg, 69%). LCMS: (MS-ESI, m / z): [M+H] + =550.1.

[0180] (5) At room temperature, intermediate 5c (100 mg, 0.2 mmol), water (1 mL), tetrahydrofuran (1 mL), methanol (1 mL), and sodium hydroxide (24 mg, 0.6 mmol) were added to the reaction flask. The reaction was allowed to proceed for 3 hours. TLC showed that the reaction was complete. The mixture was concentrated under reduced pressure, and the pH was adjusted to 3 with hydrochloric acid (1 mol / L). The product precipitated, was filtered, and dried to give a white compound C-1 (85 mg, 80%). LCMS: (MS-ESI, m / z): [MH] + =534.1.

[0181] Synthesis of compound D-1

[0182] (1) At room temperature, 1d (50 mg, 0.27 mmol), acetonitrile (700 μL), N,N-dimethylformamide (400 μL), and N-iodosuccinimide (68 mg, 0.30 mmol) were added to a reaction flask and stirred until homogeneous. The reaction temperature was then raised to 80 °C and the reaction was carried out for 20 hours. TLC showed that the reaction was complete. Saturated brine was added, and the mixture was extracted three times with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by silica gel column chromatography. The eluent was petroleum ether / ethyl acetate, yielding a pale yellow intermediate 2d (58 mg, 70%). LCMS: (MS-ESI, m / z): [M+H] + =313.9.

[0183] (2) At room temperature, intermediate 2d (2.1 g, 6.69 mmol), dichloromethane (20 mL), 3,4-dihydro-2H-pyran (2.9 mL, 31.76 mmol), and p-toluenesulfonic acid (109 mg, 0.64 mmol) were added to a reaction flask. The reaction was allowed to proceed for 6 hours, and TLC showed complete reaction. The mixture was concentrated under reduced pressure and slurried with a small amount of ethyl acetate to give a white intermediate 3d (1.46 g, 55.1%). LCMS: (MS-ESI, m / z): [M+H]+ =398.0.

[0184] (3) Under ice-water bath conditions, intermediate B-1 (0.8 g, 3.7 mmol) and anhydrous tetrahydrofuran (20 mL) were added to a dry reaction flask. Sodium hydride (0.37 g, 60%, 9.2 mmol) was then slowly added, and the reaction proceeded for 30 minutes. Subsequently, 3d (1.46 g, 3.7 mmol) was added, and the reaction was carried out at 40 °C for 24 hours. TLC showed complete reaction. The mixture was concentrated under reduced pressure, extracted three times with ethyl acetate / water, and the organic phases were combined. The mixture was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by silica gel column chromatography. Elution with petroleum ether / ethyl acetate yielded a white intermediate 4d (0.71 g, 31%). LCMS: (MS-ESI, m / z): [M+H] + =616.9.

[0185] (4) At room temperature, intermediate 4d (148 mg, 0.24 mmol), 1,1'-bis(diphenylphosphino)ferrocene palladium(II) dichloride (17 mg, 0.02 mmol), triethylamine (99 μL, 0.71 mmol), and methanol (16 mL) were added to the reaction flask. The mixture was replaced three times with carbon monoxide (1 atm), and reacted at 60 °C for 12 hours. TLC showed that the reaction was complete. The mixture was concentrated under reduced pressure, extracted three times with ethyl acetate / water, and the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by silica gel column chromatography, eluting with petroleum ether / ethyl acetate, to give a grayish-white intermediate 5d (92 mg, 70%). LCMS: (MS-ESI, m / z): [M+H] + =549.2.

[0186] (5) At room temperature, intermediate 5d (90 mg, 0.16 mmol), water (1 mL), tetrahydrofuran (1 mL), methanol (1 mL), and sodium hydroxide (20 mg, 0.5 mmol) were added to the reaction flask. The reaction was allowed to proceed for 3 hours. TLC showed that the reaction was complete. The mixture was concentrated under reduced pressure, and the pH was adjusted to 3 with hydrochloric acid (1 mol / L). The product precipitated, was filtered, and dried to give a white compound D-1 (70 mg, 82%). LCMS: (MS-ESI, m / z): [MH] + =533.1.

[0187] Synthesis of compound E-1

[0188] (1) Under ice-water bath conditions, 2c (2g, 6.4mmol) and acetonitrile (30mL) were added to the reaction flask. Sodium hydride (0.31g, 60%, 7.7mmol) was then slowly added, and the reaction proceeded for 30 minutes. Subsequently, iodomethane (480μL, 7.7mmol) was added, and the reaction was allowed to proceed overnight at room temperature. TLC showed complete reaction. Ice water was added, and a solid precipitated. The suspension was filtered, and the filter cake was washed twice with saturated sodium thiosulfate solution and three times with pure water. Drying yielded a grayish-white solid, 3e (1.8g, 85%). LCMS: (MS-ESI, m / z): [M+H] + =328.9.

[0189] (2) Following the synthesis of compound C-1 (steps (3)-(5)), starting with compound 3e, compound E-1 (0.8 g, 83.6%) was finally obtained through nucleophilic substitution, carbonyl insertion, and ester hydrolysis. LCMS:(MS-ESI, m / z):[MH] + =464.1.

[0190] Example 1: Synthesis of Compound 1

[0191] 6-(1-Isopropyl-4-methyl-1H-pyrazol-5-yl)-N-methyl-4-((4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)amino)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide (Compound 1):

[0192] (1) At room temperature, C-1 (96 mg, 0.18 mmol), N,N-dimethylformamide (1 mL), triethylamine (101 μL, 0.72 mmol), methylamine hydrochloride (24 mg, 0.36 mmol), and (7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (82 mg, 0.22 mmol) were added to the reaction flask. The reaction was allowed to proceed for 16 hours. TLC showed that the reaction was complete. Saturated brine was added, and the mixture was extracted three times with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by silica gel column chromatography. The eluent was petroleum ether / ethyl acetate, yielding a white intermediate 1-1 (70 mg, 70%). LCMS: (MS-ESI, m / z): [M+H] + =549.2.

[0193] (2) At room temperature, intermediate 1-1 (20 mg, 0.036 mmol), compound A-1 (18 mg, 0.073 mmol), tetratetraphenylphosphine palladium (4 mg, 0.004 mmol), potassium phosphate (23 mg, 0.11 mmol), dioxane (2 mL), and water (150 μL) were added to a reaction flask. The mixture was reacted at 100 °C for 20 hours. TLC showed that the reaction was complete. Saturated brine was added, and the mixture was extracted three times with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by silica gel TLC using dichloromethane / methanol as the developing solvent to give a white intermediate 1-2 (12 mg, 52%). LCMS: (MS-ESI, m / z): [M+H] + =637.3.

[0194] (3) At room temperature, intermediate 1-2 (20 mg, 0.031 mmol), dichloromethane (1 mL), and trifluoroacetic acid (300 μL) were added to the reaction flask. The reaction was allowed to proceed for 12 hours. TLC showed that the reaction was complete. The mixture was concentrated under reduced pressure, and methanol was added dropwise to dissolve the solid. The solution was adjusted to alkalinity with ammonia, concentrated under reduced pressure, and separated by silica gel TLC using dichloromethane / methanol as the developing solvent to give a white solid compound 1 (12 mg, 69%). LCMS: (MS-ESI, m / z): [M+H] + =553.2. 1 H NMR (600MHz, DMSO-d6) δ14.14(s,1H),10.10(t,J=6.1Hz,1H),8.94(q,J=4.8Hz,1H),7.92(s,1H),7.71(d,J=8.1Hz,2H),7.49(d,J=8.1Hz, 2H),7.34(s,1H),5.48(hept,J=6.6Hz,1H),4.96(d,J=6.1Hz,2H),3.77(s,3H),2.85(d,J=4.7Hz,3H),2.19(s,3H),1.29(d,J=6.6Hz,6H).

[0195] Example 2: Synthesis of compounds 37, 38, 39, 40, 41, and 162

[0196] Following the preparation method of compound 1, using compound C-1 as the starting material, methylamine hydrochloride was replaced with ethylamine hydrochloride, followed by amide condensation, Suzuki coupling, and deprotection of the THP group to obtain white compound 37 (21 mg, 55%). 1H NMR (600MHz, DMSO-d6) δ14.14(s,1H),10.10(t,J=6.1Hz,1H),9.00(t,J=6.0Hz,1H),7.92(s,1H),7.71(d,J=8.1Hz,2H),7.49(d,J=8.1Hz,2H),7.33 (s,1H),5.49(hept,J=6.6Hz,1H),4.96(d,J=6.1Hz,2H),3.77(s,3H),3.3 9-3.34(m,2H),2.19(s,3H),1.28(d,J=6.6Hz,6H),1.15(t,J=7.2Hz,3H).

[0197] Following the preparation method of compound 1, using compound C-1 as the starting material, methylamine hydrochloride was replaced with isopropylamine, followed by amide condensation, Suzuki coupling, and deprotection of the THP protecting group to give white compound 38 (18 mg, 52%). LCMS: (MS-ESI, m / z): [M+H] + =581.2. 1 H NMR (600MHz, DMSO-d6) δ14.14(s,1H),10.10(t,J=6.1Hz,1H),8.73(d,J=8.4Hz,1H),7.92(s,1H),7.73-7.70(m,2H),7.51-7.47(m,2H),7.34(s, 1H),5.52(hept,J=6.6Hz,1H),4.96(d,J=6.1Hz,2H),4.23-4.18(m,1H),3.77(s,3H),2.20(s,3H),1.29(d,J=6.6Hz,6H),1.22(d,J=6.6Hz,6H).

[0198] Following the preparation method of compound 1, using compound C-1 as the starting material, methylamine hydrochloride was replaced with cyclopropylamine, followed by amide condensation, Suzuki coupling, and deprotection of the THP protecting group to give white compound 39 (22 mg, 63%). LCMS: (MS-ESI, m / z): [M+H] + =579.2. 1H NMR (600MHz, DMSO) δ14.12(s,1H),10.03(t,J=6.1Hz,1H),8.99(d,J=5.0Hz,1H),7.90(s,1H),7.71-7.68(d,J=8.1Hz,,2H),7.47(d,J=8.1Hz,2H ),7.31(s,1H),5.47(hept,J=6.6Hz,1H),4.94(d,J=6.0Hz,2H),3.75(s, 3H), 2.92 (m, 1H), 2.17 (s, 3H), 1.26 (d, J = 6.6Hz, 6H), 0.71-0.67 (m, 4H).

[0199] Following the preparation method of compound 1, using compound C-1 as the starting material, methylamine hydrochloride was replaced with tert-butylamine, followed by amide condensation, Suzuki coupling, and deprotection of the THP protecting group to give white compound 40 (17 mg, 57%). LCMS: (MS-ESI, m / z): [M+H] + =575.2. 1 H NMR (600MHz, DMSO-d6) δ14.09(s,1H),9.94(t,J=6.2Hz,1H),7.91(s,,1H),7.89(s,1H),7.70(d,J=7.9Hz,2H),7.47(d,J=7.9Hz, 2H),7.33(s,1H),5.48(hept,J=6.6Hz,1H),4.98(d,J=6.1Hz,2H),3.76(s,3H),2.18(s,3H),1.44(s,9H),1.26(d,J=6.5Hz,6H).

[0200] Following the preparation method of compound 1, using compound C-1 as the starting material, methylamine hydrochloride was replaced with cyclobutylamine, followed by amide condensation, Suzuki coupling, and deprotection of the THP group to obtain white compound 41 (27 mg, 59%). 1H NMR (600MHz, DMSO-d6) δ14.17(s,1H),10.03(t,J=6.1Hz,1H),9.18(d,J=8.2Hz,1 H),7.92(s,1H),7.71(d,J=8.2Hz,2H),7.48(d,J=8.1Hz,2H),7.34(s,1H),5.49(h ept,J=6.6Hz,1H),4.95(d,J=6.0Hz,2H),4.50(q,J=8.2Hz,1H),3.77(s,3H),2.27 -2.20(m,3H),2.20(s,3H),2.19-2.16(m,1H),1.66(m,2H),1.29(d,J=6.6Hz,6H).

[0201] Following the preparation method of compound 1, using compound C-1 as the raw material, ammonium chloride was used to replace methylamine hydrochloride, followed by amide condensation, Suzuki coupling, and deprotection of the THP group to obtain white compound 162 (21 mg, 62%). 1 H NMR (600MHz, DMSO-d6) δ14.10(s,1H),10.10(t,J=6.0Hz,1H),8.32(s,1H),7.96(s,1H),7.92(s,1H),7.71(d,J=8.1Hz,2H),7. 49(d,J=8.1Hz,2H),7.34(s,1H),5.49(h,J=6.6Hz,1H),4.95(d,J=6.0Hz,2H),3.77(s,3H),2.20(s,3H),1.29(d,J=6.6Hz,6H).

[0202] Example 3: Synthesis of compounds 2, 160, and 161

[0203] Following the preparation method of compound 1, compound D-1, methylamine hydrochloride, was used as a starting material. The mixture underwent amide condensation, Suzuki coupling, and deprotection of the THP protecting group to obtain white compound 2 (39 mg, 70%). LCMS: (MS-ESI, m / z): [M+H] + =552.2. 1H NMR(600MHz,DMSO-d6)δ13.86(s,1H),9.92(s,1H),8.83(d,J=4.8Hz,1H),7.93-7.90(m,1H),7.71-7.68(m,2H),7.53-7.50(m,2H),7 .28(s,1H),6.19(s,1H),4.86(s,1H),4.72(d,J=6.0Hz,2H),3.75(s,3H),2.86(d,J=4.8Hz,3H),1.77(s,3H),1.28(d,J=6.6Hz,6H).

[0204] Following the preparation method of compound 1, compound D-1 and cyclopropaneamine were used as starting materials. The mixture was prepared by amide condensation, Suzuki coupling, and deprotection of the THP protecting group to give white compound 160 (20 mg, 58%). LCMS: (MS-ESI, m / z): [M+H] + =578.3. 1 H NMR (600MHz, DMSO-d6) δ13.87(s,1H),9.89(t,J=6.0Hz,1H),8.88(d,J=4.8Hz,1 H),7.92(d,J=1.6Hz,1H),7.71(d,J=8.0Hz,2H),7.53(d,J=8.0Hz,2H),7.29(s,1 H),6.20(s,1H),4.88(hept,J=6.6Hz,1H),4.74(d,J=6.0Hz,2H),3.76(s,3H),2. 96(td,J=6.9,3.4Hz,1H),1.77(s,3H),1.29(d,J=6.6Hz,6H),0.74-0.71(m,4H).

[0205] Following the preparation method of compound 1, compound D-1 and ammonium chloride were used as raw materials, and the mixture was subjected to amide condensation, Suzuki coupling, and deTHP protecting group removal to obtain white compound 161 (27 mg, 61%). 1 H NMR (600MHz, DMSO) δ13.85(s,1H),9.93(t,J=5.9Hz,1H),8.21(s,1H),7.92(s,1H),7.84(s,1H),7.70(d,J=8.1Hz,2H),7.52(d,J=8. 1Hz,2H),7.29(s,1H),6.21(s,1H),4.87(hept,J=6.6Hz,1H),4.71(d,J=5.8Hz,2H),3.76(s,3H),1.80(s,3H),1.29(d,J=6.6Hz,6H).

[0206] Example 4 Synthesis of Compound 31

[0207] Following the preparation method of compound 1, compound E-1, methylamine hydrochloride, was used as a starting material. The mixture was prepared by amide condensation and Suzuki coupling to obtain a white compound 31 (34 mg, 57.5%). LCMS: (MS-ESI, m / z): [M+H] + =567.2. 1 H NMR (600MHz, DMSO-d6) δ10.12(t,J=6.1Hz,1H),8.92(q,J=4.7Hz,1H),7.92(s,1H),7.72-7.70(m,2H),7.50-7.47(m,2H),7.35(s,1H) ,5.49(hept,J=6.6Hz,1H),4.96(d,J=6.0Hz,2H),4.02(s,3H),3.77(s,3H),2.85(d,J=4.7Hz,3H),2.23(s,3H),1.31(d,J=6.6Hz,6H).

[0208] Example 5: Synthesis of compounds 163, 164, 165, and 166

[0209] Following the preparation method of compound 1, using compound C-1 as the starting material, methylamine hydrochloride was replaced with cyclopropyl methylamine, followed by amide condensation, Suzuki coupling, and deprotection of the THP protecting group to give white compound 163 (22 mg, 78.6%). LCMS: (MS-ESI, m / z): [M+H] + =593.2. 1 H NMR (600MHz, DMSO-d6) δ14.15(s,1H),10.08(t,J=6.5Hz,1H),9.04(t,J=6.1Hz,1 H),7.92(s,1H),7.71(d,J=8.0Hz,2H),7.48(d,J=8.0Hz,2H),7.34(s,1H),5.49(h ept,J=6.6Hz,1H),4.96(d,J=6.1Hz,2H),3.77(s,3H),3.20(t,J=6.5Hz,2H),2.20 (s,3H),1.29(d,J=6.6Hz,6H),1.11(m,1H),0.47-0.41(m,2H),0.32-0.24(m,2H).

[0210] Following the preparation method of compound 1, using compound C-1 as the starting material, methylamine hydrochloride was replaced with 3-oxacyclobutylamine. After amide condensation, Suzuki coupling, and deprotection of the THP protecting group, white compounds 164 (13 mg, 37%) and 165 (22 mg, 30.5%) were obtained. Compound 164: LCMS: (MS-ESI, m / z): [M+H] + =595.2. 1 H NMR (600MHz, DMSO-d6) δ14.17-14.07(s,1H),10.74(t,J=5.6Hz,1H),7.93(s,1H),7.73(d,J=8.1Hz,2H),7.54(d,J=8.0Hz,2H),7.34(s,1H),5.4 9(h,J=6.7Hz,1H),5.04-4.79(m,2H),4.61-4.53(m,1H),4.45-4.35(m,2 H),3.77(s,3H),3.57-3.48(m,2H),2.21(s,3H),1.31(dd,J=6.6Hz,6H).

[0211] Compound 165: LCMS (MS-ESI, m / z): [M+H] + =613.2. 1 H NMR (600MHz, DMSO-d6) δ14.10(s,1H),10.00(t,J=6.1Hz,1H),8.25(d,J=8.7Hz,1H),7.92(s,1H),7.71(d,J=7.9Hz,2H),7.49(d,J=7.9Hz,2H),7.3 4(s,1H),5.50(hept,J=6.6Hz,1H),4.96(d,J=6.1Hz,2H),4.82(m,2H),4 .03(m,1H),3.77(s,3H),3.56(m,4H),2.20(s,3H),1.29(d,J=6.6Hz,6H).

[0212] Following the preparation method of compound 1, using compound C-1 as the starting material, methylamine hydrochloride was replaced with n-propylamine, followed by amide condensation, Suzuki coupling, and deprotection of the THP protecting group to obtain white compound 166 (13 mg, 60%). LCMS: (MS-ESI, m / z): [M+H] + =581.2. 1H NMR (600MHz, DMSO-d6) δ14.10(s,1H),10.08(t,J=6.1Hz,1H),8.97(t,J=6.1Hz ,1H),7.92(s,1H),7.70(d,J=8.0Hz,2H),7.48(d,J=7.9Hz,2H),7.33(s,1H),5 .49(h,J=6.6Hz,1H),4.95(d,J=6.1Hz,2H),3.77(s,3H),3.30-3.26(m,2H),2. 19(s,3H),1.58(h,J=7.3Hz,2H),1.28(d,J=6.6Hz,6H),0.89(t,J=7.4Hz,3H).

[0213] Synthesis of compound B-2

[0214] (1) Add 1,1-dibromo-3,3,3-trifluoroacetone (2g, 14.1mmol), sodium acetate (6g, 74.1mmol), and water (20mL) to a reaction flask. React at 100℃ for 45 minutes and then cool to room temperature to obtain mixture A. Add 4-cyanobenzaldehyde (7.7g, 59.3mmol), methanol (257mL), and concentrated ammonia (51mL) to another reaction flask. Stir well at room temperature, then slowly add mixture A dropwise to the reaction solution. After the addition is complete, raise the reaction temperature to 100℃ and react for 10 hours. TLC plate analysis showed that the reaction was complete. Concentrate under reduced pressure, extract three times with ethyl acetate / water, combine the organic phases, concentrate under reduced pressure, and slurry with methyl tert-butyl ether to obtain a pale yellow solid 2b (13g, 74%). Liquid chromatography-mass spectrometry (LCMS) results: (MS-ESI, m / z): [M+H] + =238.1.

[0215] (2) Under argon protection in an ice-water bath, 2b (100 mg, 0.422 mmol), acetonitrile (5 mL), and cesium carbonate (2275 mg, 0.843 mmol) were added to the reaction flask. The temperature was maintained for 20 minutes, followed by slow dropwise addition of 2-iodopropane (84 μL, 0.843 mmol). The reaction temperature was raised to 85 °C and the reaction was continued for 12 hours. TLC showed that the reaction was complete. The solution was then extracted three times with ethyl acetate. The organic phases were combined, washed once with saturated sodium chloride, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by silica gel column chromatography, eluting with petroleum ether / ethyl acetate, to give a white solid 3b (70 mg, 60%). LCMS: (MS-ESI, m / z): [M+H] + =280.2. 1H NMR (600MHz, DMSO-d6) δ8.28(d,J=1.6Hz,1H),8.02-7.99(m,2H),7.82-7.79(m,2H),4.51(h,J=6.7Hz,1H),1.43(d,J=6.6Hz,6H).

[0216] (3) Under ice-water bath conditions, intermediate 3b (100 mg, 0.36 mmol) and methanol (5 mL) were added to the reaction flask, followed by nickel dichloride (23 mg, 0.086 mmol) and di-tert-butyl dicarbonate (274 μL, 1.075 mmol). After the addition was complete, the reaction temperature was raised to room temperature and stirred for 8 hours. TLC showed that the reaction was complete. The reaction was quenched with saturated ammonium chloride solution, water was added, and the mixture was extracted three times with ethyl acetate. The organic phases were combined, washed once with saturated sodium chloride, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by silica gel column chromatography. Elution with petroleum ether / ethyl acetate gave a white intermediate 4b (76 mg, 53.7%). LCMS: (MS-ESI, m / z): [M+H] + =384.2. 1 H NMR (600MHz, DMSO-d6) δ8.16 (s, 1H), 7.52 (d, J = 7.7Hz, 2H), 7.48 (t, J = 6.0Hz, 1H), 7.38 (d,J=7.8Hz,2H),4.47(p,J=6.7Hz,1H),4.21(d,J=6.3Hz,2H),1.40(d,J=7.4Hz,15H).

[0217] (4) Under ice-water bath conditions, intermediate 4b (266 mg, 0.75 mmol) was added to the reaction flask, followed by dichloromethane (5 mL), then 4 mol / L ethyl hydrogen chloride solution (2.7 mL). After the addition was complete, the reaction temperature was raised to room temperature and the reaction was allowed to proceed for 5 hours. TLC showed that the reaction was complete. Methyl tert-butyl ether was added to the reaction solution and the mixture was slurried to give a white compound B-2 (165 mg, 83.7%). LCMS: (MS-ESI, m / z): [M+H] + =284.2. 1 H NMR(600MHz,DMSO-d6)δ8.66(s,3H),8.22-8.20(m,1H),7.69-7.66(m,2H),7.63-7 .60(m,2H),4.45(hept,J=6.7Hz,1H),4.10(q,J=5.9Hz,2H),1.41(d,J=6.7Hz,6H).

[0218] Synthesis of compound C-2

[0219] (1) At room temperature, intermediate 3c (1 g, 2.51 mmol), B-2 (0.8 g, 2.51 mmol), potassium carbonate (1.4 g, 10.4 mmol), and acetonitrile (20 mL) were added to a reaction flask. The reaction was allowed to proceed for 5 hours. TLC showed that the reaction was complete. The mixture was concentrated under reduced pressure, extracted three times with ethyl acetate / water, and the organic phases were combined. The mixture was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by silica gel column chromatography. Elution with petroleum ether / ethyl acetate yielded a white intermediate 4c (1.29 g, 80%). LCMS: (MS-ESI, m / z): [M+H] + =646.0.

[0220] (2) At room temperature, intermediate 4c (600 mg, 0.93 mmol), 1,1'-bis(diphenylphosphino)ferrocene palladium(II) dichloride (776 mg, 0.093 mmol), triethylamine (387 μL, 2.79 mmol), and methanol (12 mL) were added to a reaction flask. The mixture was replaced three times with carbon monoxide (1 atm), and reacted at 60 °C for 12 hours. TLC showed that the reaction was complete. The mixture was concentrated under reduced pressure, extracted three times with ethyl acetate / water, and the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by silica gel column chromatography, eluting with petroleum ether / ethyl acetate, to give a grayish-white intermediate 5c (160 mg, 30%). LCMS: (MS-ESI, m / z): [M+H] + =578.1.

[0221] (3) At room temperature, intermediate 5c (120 mg, 0.2 mmol) and ammonia (2.5 mL) were added to the reaction flask. The reaction was carried out at 70 °C for 12 hours. TLC showed that the reaction was complete. The mixture was concentrated under reduced pressure, extracted three times with ethyl acetate / water, and the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by silica gel column chromatography to give a white compound C-2 (64 mg, 55%). LCMS: (MS-ESI, m / z): [M+H] + =563.2.

[0222] Example 6: Synthesis of compounds 167, 168, and 169

[0223] Following the preparation method of compound 1, compound C-2 was used as the starting material, and A-1 was coupled via Suzuki coupling to remove THP protection.

[0224] The white compound was 167 g (19 mg, 73.1%). LCMS: (MS-ESI, m / z): [M+H] + =567.2. 1H NMR (600MHz, DMSO-d6) δ14.12(s,1H),10.12(t,J=6.0Hz,1H),8.33(s,1H),8.16(s,1H),7.97(s,1H),7.55(d,J=7.9Hz,2H),7.49(d,J=7.9Hz,2H), 7.33(s,1H),5.47(hept,J=6.6Hz,1H),4.96(d,J=6.1Hz,2H),4.46(hept,J=6.7Hz,1H),2.19(s,3H),1.39(d,J=6.7Hz,6H),1.27(d,J=6.7Hz,6H).

[0225] Following the preparation method of compound 1, compound C-2 was used as the starting material, and (4-cyclopropyl-6-methoxypyrimidin-5-yl)boronic acid was coupled via Suzuki coupling, followed by deprotection of the THP protecting group to give white compound 168 (25 mg, 81.4%). LCMS: (MS-ESI, m / z): [M+H] + =593.2. 1 H NMR (600MHz, DMSO-d6) δ13.99(s,1H),10.13(t,J=6.0Hz,1H),8.63(s,1H),8.33(s,1H),8.16(s,1H),7.97(s,1H),7.55-7.50(m, 4H), 4.87 (d, J = 6.0Hz, 2H), 4.45 (hept, J = 6.6Hz, 1H), 3.84 (s, 3H), 1.80 (m, 1H), 1.39 (d, J = 6.6Hz, 6H), 0.99 (m, 2H), 0.80 (m, 2H).

[0226] Following the preparation method of compound 1, compound C-1 was used as the starting material, and (4-cyclopropyl-6-methoxypyrimidin-5-yl)boronic acid was coupled via Suzuki coupling, followed by deprotection of the THP protecting group to give white compound 169 (26 mg, 74.7%). LCMS: (MS-ESI, m / z): [M+H] + =565.2. 1H NMR (600MHz, DMSO-d6) δ13.98(s,1H),10.08(t,J=6.0Hz,1H),8.63(s,1H),8.27(s,1H),7.92(s,1H),7.90(s,1H),7.69-7.67( m,2H),7.52-7.49(m,2H),4.85(d,J=6.0Hz,2H),3.85(s,3H),3.77(s,3H),1.83-1.79(m,1H),1.01-0.99(m,2H),0.82(m,2H).

[0227] Example 7 Synthesis of Compound 170

[0228] (1) At room temperature, f (2 g, 9.8 mmol), cesium carbonate (5.6 g, 15.7 mmol), and acetonitrile (40 mL) were added to a 250 mL reaction flask. The mixture was purged with argon three times and reacted at room temperature for 5 h. 2,4-Dinitrophenylhydroxylamine (2.9 g, 14.7 mmol) was dissolved in acetonitrile, purged with argon three times, and injected into the above reaction solution. The mixture was reacted at room temperature for 12 h. TLC showed that the reaction was complete. The mixture was filtered through diatomaceous earth, the organic phase was evaporated to dryness, and separated by silica gel column chromatography to give a pale yellow intermediate 2f (2 g, 93%). LCMS: (MS-ESI, m / z): [M+H] + =219.0.

[0229] (2) At room temperature, 2f (2g, 9.1mmol), trichloroacetyl isocyanate (1.3mL, 10mmol), and tetrahydrofuran (40mL) were added to a 100mL reaction flask. The mixture was reacted at room temperature for 1h, and then ammonia-methanol was added to the reaction solution and stirred overnight at room temperature. The next day, TLC showed that the reaction was complete. The mixture was concentrated under reduced pressure, and 25mL of MTBE was added and stirred for 10min. The mixture was filtered and dried to obtain a white intermediate 3f (1.9g, 80%). LCMS: (MS-ESI, m / z): [M+H] + =262.0.

[0230] (3) At room temperature, 3f (0.5 g, 1.9 mmol), TMSOK (0.5 g, 3.8 mmol), and ultra-dry tetrahydrofuran (30 mL) were added to a 100 mL reaction flask. The mixture was purged with argon three times and reacted at room temperature for 12 h. TLC showed that the reaction was complete. The mixture was concentrated under reduced pressure, water was added, and the solution was sonicated to adjust the pH to 2. A precipitate formed, which was filtered, dried, and a white intermediate 4f (0.32 g, 72.7%) was obtained. LCMS: (MS-ESI, m / z): [M+H] + =230.0, 232.0.

[0231] (4) At room temperature, 4f (1.11 g, 4.78 mmol), diethylaniline (2 mL, 11.96 mmol), and phosphorus oxychloride (20 mL) were added to a 50 mL reaction flask. The mixture was reacted at 106 °C for 7 days. TLC showed that the reaction was complete. 20 mL of methyltetrahydrofuran was added, and the reaction was quenched by extraction with ice water. The mixture was extracted three times with methyltetrahydrofuran / water. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by silica gel column chromatography. The eluent was petroleum ether / ethyl acetate, yielding a pale yellow intermediate 5f (1.2 g, 78%). LCMS: (MS-ESI, m / z): [M+H] + =267.9, 270.0.

[0232] (5) At room temperature, intermediate 5f (500 mg, 0.532 mmol), B-1 (575 mg, 0.638 mmol), potassium carbonate (520 mg, 12.9 mmol), and acetonitrile (25 mL) were added to the reaction flask. The reaction was allowed to proceed for 5 hours. TLC showed that the reaction was complete. The mixture was concentrated under reduced pressure, extracted three times with ethyl acetate / water, and the organic phases were combined. The mixture was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by silica gel column chromatography. Elution with petroleum ether / ethyl acetate gave a white intermediate 6f (750 mg, 83%). LCMS: (MS-ESI, m / z): [M+H] + =485, 1 H NMR(600MHz,Chloroform-d)δ7.70-7.68(m,2H),7.54-7.51(m,2H),7.47(d,J=2.9Hz,1H),7.35( d,J=1.3Hz,1H),7.03(d,J=5.9Hz,1H),6.65(d,J=2.9Hz,1H),4.92(d,J=5.5Hz,2H),3.81(s,3H).

[0233] (6) At room temperature, intermediate 6f, Xantphos, DIPEA, and zinc cyanide were added to a 25 mL reaction flask and dissolved in ultra-dry DMAC. Palladium chloride was then added, and the mixture was purged with argon three times. The mixture was refluxed at 90 °C and stirred for 16 h. TLC showed that the reaction was almost complete. The organic phases were extracted three times with ethyl acetate and water, combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by silica gel column chromatography. Elution with petroleum ether / ethyl acetate yielded a pale yellow intermediate 7f. LCMS:(MS-ESI, m / z): [M+H] + =432.0.

[0234] (7) Following the preparation method of compound 1, intermediate 7f was used as the starting material and coupled with (4-cyclopropyl-6-methoxypyrimidin-5-yl)boronic acid via Suzuki coupling to obtain white intermediate 8f (35.2 mg, 70%). LCMS: (MS-ESI, m / z): [M+H] + =546.0, 1 H NMR(600MHz,Chloroform-d)δ8.69(s,1H),7.65(d,J=7.9Hz,2H),7.62(d,J=2.9Hz,1H),7.52(d,J=7.7Hz,2H),7.34(s,1H),7.03(d,J=2.9Hz,1H),6.7 0-6.65(m,1H),4.97(d,J=5.8Hz,2H),3.98(s,3H),3.79(s,3H),1.88(dt,J =8.1,4.4Hz,1H),1.29(dd,J=7.0,3.8Hz,2H),0.96(dq,J=7.0,3.9Hz,2H).

[0235] (8) At room temperature, intermediate 8f and a 10N sodium hydroxide aqueous solution were added to a 25mL reaction flask and stirred under reflux at 95°C for 1h. TLC showed the reaction was complete. The mixture was extracted three times with ethyl acetate / water, and the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by silica gel column chromatography, eluting with petroleum ether / ethyl acetate, to give 170g (25mg, 81%) of a white solid. LCMS: (MS-ESI, m / z): [M+H] + =564.2, 1 H NMR(600MHz,DMSO-d6)δ11.90(t,J=5.7Hz,1H),8.66(s,1H),8.23(s,1H),7.93( s,1H),7.78(d,J=3.0Hz,1H),7.70-7.68(m,2H),7.67(s,1H),7.51(d,J=8.2Hz,2 H),7.38(d,J=3.0Hz,1H),4.83(d,J=5.7Hz,2H),3.87(s,3H),3.77(s,3H),1.90( td,J=8.1,4.0Hz,1H),1.02(dq,J=6.1,3.5Hz,2H),0.88(dq,J=10.0,3.4Hz,2H).

[0236] Example 8: Synthesis of compounds 171, 172, 173, 174, and 175

[0237] Following the preparation method of compound 1, using compound D-1 and tert-butylamine as starting materials, amide condensation, Suzuki coupling, and deprotection of the THP protecting group yielded white compound 171 (32 mg, 73%). LCMS: (MS-ESI, m / z): [M+H] + =594.2. 1 H NMR (600MHz, DMSO-d6) δ13.86(s,1H),9.78(t,J=6.1Hz,1H),7.92(s,1H),7.81(s,1H),7.70(d,J=8.2Hz,2H),7.51(d,J=8.1Hz,2H),7. 28(s,1H),6.18(s,1H),4.87(hept,J=6.6Hz,1H),4.76(d,J=6.0Hz,2H),3.75(s,3H),1.74(s,3H),1.47(s,9H),1.28(d,J=6.6Hz,6H).

[0238] Following the preparation method of compound 1, using compound D-1 and isopropylamine as starting materials, amide condensation, Suzuki coupling, and deprotection of the THP protecting group yielded white compound 172 (30 mg, 86%). LCMS: (MS-ESI, m / z): [M+H] + =580.2. 1 H NMR (600MHz, DMSO-d6) δ13.87 (s, 1H), 9.92 (t, J = 6.0Hz, 1H), 8.58 (d, J = 8.5Hz, 1H),7.92(s,1H),7.72(d,J=8.0Hz,2H),7.52(d,J=8.1Hz,2H),7.29(s,1H),6.1 9(s,1H),4.87(hept,J=6.6Hz,1H),4.73(d,J=6.0Hz,2H),4.22(dq,J=8.4,6.6 Hz,1H),3.76(s,3H),1.77(s,3H),1.29(d,J=6.6Hz,6H),1.23(d,J=6.6Hz,6H).

[0239] Following the preparation method of compound 1, compound D-1, ethylamine hydrochloride, was used as a starting material. The mixture underwent amide condensation, Suzuki coupling, and deprotection of the THP protecting group to obtain a yellowish-white compound 173 (17 mg, 81%). LCMS: (MS-ESI, m / z): [M+H] + =566.2. 1H NMR (600MHz, DMSO-d6) δ13.87(s,1H),9.94(t,J=6.0Hz,1H),8.89(t,J=6.0H z,1H),7.92(s,1H),7.70(d,J=8.2Hz,2H),7.52(d,J=8.1Hz,2H),7.29(s,1H) ,6.19(s,1H),4.87(hept,J=6.6Hz,1H),4.73(d,J=5.9Hz,2H),3.76(s,3H), 3.40-3.37(m,2H),1.77(s,3H),1.29(d,J=6.6Hz,6H),1.17(t,J=7.2Hz,3H).

[0240] Following the preparation method of compound 1, using compound D-1 and n-propylamine as starting materials, amide condensation, Suzuki coupling, and deprotection of the THP protecting group yielded white compound 174 (23 mg, 88%). LCMS: (MS-ESI, m / z): [M+H] + =580.2. 1 H NMR(600MHz,DMSO-d6)δ13.87(s,1H),9.94(t,J=6.0Hz,1H),8.87(t,J=6.1Hz,1H), 7.92(s,1H),7.70(d,J=8.0Hz,2H),7.51(d,J=8.0Hz,2H),7.28(s,1H),6.19(s,1H), 4.86(hept,J=6.6Hz,1H),4.73(d,J=6.0Hz,2H),3.75(s,3H),3.30(q,J=6.1Hz,2H), 1.76(s,3H),1.59(sext,J=7.3Hz,2H),1.28(d,J=6.6Hz,6H),0.90(d,J=7.4Hz,3H).

[0241] Following the preparation method of compound 1, using compound D-1 and ethanolamine as starting materials, the mixture underwent amide condensation, Suzuki coupling, and deprotection of the THP protecting group to obtain white compound 175 (20 mg, 76.4%). LCMS: (MS-ESI, m / z): [M+H] + =582.2. 1H NMR(600MHz,DMSO-d6)δ13.90(s,1H),9.88(t,J=6.0Hz,1H),8.68(t,J=5.9Hz,1H),7 .92(s,1H),7.70(d,J=8.2Hz,2H),7.52(d,J=8.1Hz,2H),7.29(s,1H),6.20(s,1H),4 .90-4.85(hept,J=6.6Hz,1H),4.82(t,J=5.6Hz,1H),4.73(d,J=6.0Hz,2H),3.76(s, 3H), 3.57 (q, J = 5.7Hz, 2H), 3.43 (q, J = 6.1Hz, 2H), 1.77 (s, 3H), 1.29 (d, J = 6.6Hz, 6H).

[0242] Example 9: Synthesis of Compound 176

[0243] (1) Following the preparation method of compound 2c, using NIS and 4,6-dichloro-7-azaindole as raw materials, a pale yellow solid 2c0 (0.5 g, 55%) was obtained. LCMS: (MS-ESI, m / z): [M+H] + =312.9.

[0244] (2) At room temperature, intermediate 2CO (0.5 g, 1.60 mmol) was added to a reaction flask and dissolved in 30 mL of acetonitrile. The mixture was cooled to 0 °C, and then NaH (96 mg, 2.4 mmol) was slowly added. The reaction was continued at 0 °C for 30 min, followed by the addition of SEMCl (0.32 g, 1.92 mmol). The reaction was allowed to proceed overnight at room temperature. TLC showed that the reaction was complete. The mixture was concentrated under reduced pressure, extracted three times with ethyl acetate / water, and the organic phases were combined. The mixture was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by silica gel column chromatography. Elution with petroleum ether / ethyl acetate yielded a grayish-white intermediate 3CO (0.35 g, 50.2%). LCMS: (MS-ESI, m / z): [M+H] + =442.9.

[0245] (3) Following the preparation methods of compounds 1-2, intermediate 3C0 underwent nucleophilic substitution, carbonylation, ester hydrolysis, amide condensation, and Suzuki coupling to yield a white intermediate 8C0, 30 mg. LCMS: (MS-ESI, m / z): [M+H] + =667.3.

[0246] (4) At room temperature, intermediate 8CO (30 mg, 0.04 mmol), 2 mL DCM, and 2 mL trifluoroacetic acid were added to the reaction flask. The mixture was stirred overnight at room temperature. TLC showed that the reaction was complete. The mixture was concentrated under reduced pressure, extracted three times with ethyl acetate / water, and the organic phases were combined. The mixture was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by PTLC to give a white solid compound 176 (14 mg, 56%). LCMS: (MS-ESI, m / z): [M+H] + =537.2. 1 H NMR (600MHz, DMSO-d6) δ11.92(s,1H),10.07(t,J=5.9Hz,1H),8.05(s,1H),7.92(s,1H),7.88(s,1H),7.68(d,J=8.0Hz,2H),7.51(d,J=8.0H z,2H),7.25(s,1H),7.22(s,1H),6.13(s,1H),4.83(q,J=6.6Hz,1H),4.61(d,J=5.8Hz,2H),3.75(s,3H),1.76(s,3H),1.26(d,J=6.5Hz,6H).

[0247] Example 10 Synthesis of Compound 186

[0248] Following the preparation method of compound 170, compound A-1 and intermediate 7f were used as starting materials, and after Suzuki coupling and cyano hydrolysis, white compound 186 (9 mg, 48%) was obtained. LCMS: (MS-ESI, m / z): [M+H] + =538. 1 H NMR (600MHz, DMSO-d6) δ11.89(t,J=5.8Hz,1H),8.24(s,1H),7.93(s,1H),7.76(d,J=3.0Hz,1H),7.71(d,J=8.0Hz,2H),7.68(s,1H),7.49(d,J =8.0Hz,2H),7.39(d,J=3.0Hz,1H),7.34(s,1H),5.17(h,J=6.6Hz,1H),4.91(d,J=5.8Hz,2H),3.77(s,3H),2.14(s,3H),1.28(d,J=6.6Hz,6H).

[0249] Synthesis of compound G-1

[0250] (1) In a 250 mL single-necked flask, add 1 g (5 g, 36.7 mmol) of the compound, 5 mL of N,N-dimethylformamide, and 50 mL of acetonitrile. Stir for 5 minutes in an ice bath, then add sodium hydride (2.2 g, 55.1 mL). React in an ice bath for half an hour, then add SEMCl (8 mL, 44.1 mmol) dropwise. React overnight at room temperature. After the reaction is complete, add ethyl acetate (200 mL) to the reaction solution, quench with 20 mL of saturated ammonium chloride solution, then add 30 mL of water and ethyl acetate (50 mL × 3). Combine the organic phases, wash with saturated brine (30 mL × 4), dry with anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain the crude product. (MS-ESI, m / z): [M+H] + =267.1.

[0251] (2) In a 500 mL single-necked flask, add 2 g (20.4 g, 66 mmol) of the compound, 15.2 g (85.8 mmol) of N-bromosuccinimide, 2.1 g (13.2 mmol) of azobisisobutyronitrile (2.1 g, 13.2 mmol), and 100 mL of carbon tetrachloride. Incubate the mixture at 60 °C overnight. After the reaction is complete, remove most of the solvent by vortexing, and extract three times with ethyl acetate / saturated sodium bicarbonate solution (200 mL / 30 mL). Combine the organic phases, wash with saturated brine, dry to anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain 3 g of crude compound. (MS-ESI, m / z): [M+H] + =345.1.

[0252] (3) 3 g (12.18 g, 35.3 mmol) of the compound was added to a 250 mL round-bottom flask, dissolved in dichloromethane, and then 25 mL of trifluoroacetic acid was added. The reaction was allowed to proceed overnight at room temperature. After the reaction was complete, most of the solvent was removed by rotary evaporation, and 50 mL of ethyl acetate was added to the reaction solution. The pH was adjusted to 7–8 by adding sodium hydroxide solution (3 M). Extraction was performed using ethyl acetate / water (30 mL × 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 4 g of crude compound. (MS-ESI, m / z): [M+H] + =215.1.

[0253] (4) 4 g (1.14 g, 5.3 mmol) of the compound was added to a 50 mL single-necked flask, dissolved in acetonitrile, and stirred for 5 minutes in an ice bath. Sodium hydride (191 mg, 7.95 mmol) was slowly added in portions. After reacting for half an hour, iodomethane (1.13 g, 7.95 mmol) was added, and the mixture was allowed to react overnight at room temperature. After the reaction was complete, the reaction solution was quenched with saturated ammonium chloride solution, and extracted with ethyl acetate / water (30 mL × 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography to obtain 5 g of the compound. (MS-ESI, m / z): [M+H] + =229.1.

[0254] (5) 5 g (500 mg, 2.18 mmol) of compound was placed in a 75 mL sealed tube, and 6 g (2.8 mL, 25.33 mmol) of compound and potassium carbonate (663 mg, 4.80 mmol) were added. The reaction was carried out at 150 °C for 36 h. The reaction solution was quenched with ice water and extracted with ethyl acetate / water (8 mL × 3). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography to obtain 7 g of compound. (MS-ESI, m / z): [M+H] + =259.1.

[0255] (6) Under an argon atmosphere, 7 g (263 mg, 1.02 mmol) of the compound was dissolved in ultra-dry tetrahydrofuran. Lithium aluminum hydride (193 mg, 5 mmol) was added in portions to the solution at 0 °C. After reacting for 1 h, the mixture was cooled to room temperature and reacted for another 1 h. The reaction was completed by TLC. NaOH (2 M) was added to the reaction solution to adjust the pH to 11–12. The reaction solution was extracted with ethyl acetate / water (5 mL × 3). The combined organic phases were washed with saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography to obtain compound G-1. (MS-ESI, m / z): [M+H] + =263.1.

[0256] Synthesis of compound H-1

[0257] (1) 1,1-Dibromo-3,3,3-trifluoroacetone (7.9 g, 29.2 mmol) and sodium acetate (4.9 g, 59.34 mmol) were dissolved in water and reacted at 100 °C for 0.5 h. After cooling to room temperature, solution 1 was obtained. Compound 1h (4.8 g, 25.8 mmol) was dissolved in a mixture of ammonia and methanol (1:2) to obtain solution 2. Solution 1 was then added dropwise to solution 2 and reacted overnight at room temperature. After the reaction was complete, ethyl acetate (15 mL × 3) was added to the reaction solution for extraction. The organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography to obtain compound 2h. (MS-ESI, m / z): [M+H] + =292.1.

[0258] (2) Compound 2h (8 g, 27.4 mmol) was placed in a 500 mL single-necked flask, dissolved in N,N-dimethylformamide, and then potassium carbonate (7.6 g, 55 mmol) was added. Iodomethane (14 mL, 62 mmol) was added dropwise under ice bath conditions, and the mixture was refluxed at 70 °C overnight. After the reaction was complete, 50 mL of water was added to the reaction solution, and a large amount of solid precipitated, yielding compound 3h. (MS-ESI, m / z): [M+H] + =306.1.

[0259] (3) Compound 3h (8.8 g, 28.7 mmol) and Xantphos (3 g, 5.7 mmol) were added to a 500 mL flask and dissolved in methanol. Triethylamine (70 mL) and palladium acetate (652 mg, 2.9 mmol) were then added. The mixture was purged three times under a carbon monoxide atmosphere and refluxed at 70 °C overnight. After the reaction was complete, the reaction solution was filtered through diatomaceous earth, and the organic phase was evaporated to dryness. The crude product was purified by column chromatography to obtain compound 4h. (MS-ESI, m / z): [M+H] + =286.1.

[0260] (4) Compound 4h (3.7 g, 13 mmol) was added to a 250 mL three-necked flask, dissolved in ultra-dry tetrahydrofuran, and lithium aluminum hydride (10 mL, 2.5 mmol) was added dropwise at 0 °C. After the addition was complete, the reaction was detected by TLC to indicate completeness. The reaction solution was quenched with ice water, and ethyl acetate / water (15 mL × 3) was added. The organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography to obtain compound 5h. (MS-ESI, m / z): [M+H] + =258.1.

[0261] (5) Under an argon atmosphere, compound 5h (2.3 g, 8.9 mmol) was added to a 100 mL flask, dissolved in dichloromethane, and then thionyl chloride was slowly added dropwise followed by reflux. The reaction was allowed to proceed for 3 h. After the reaction was complete, the reaction solution was evaporated to dryness, and the crude product was purified by column chromatography to obtain compound 6h. (MS-ESI, m / z): [M+H] + =276.1.

[0262] (6) Compound 6h (1.8 g, 72 mmol) was placed in a sealed tube, dissolved in ammonia-methanol (25 mL), and refluxed at 70 °C overnight. After the reaction was complete, the reaction solution was evaporated to dryness, and purified by column chromatography to obtain compound H-1. (MS-ESI, m / z): [M+H) + =257.1.

[0263] Synthesis of compound I-1

[0264] (1) At room temperature, 4-bromo-2-hydroxybenzaldehyde (30 g, 149.25 mmol), benzyl bromide (21 mL, 179.1 mmol), and potassium carbonate (31 g, 224 mmol) were added to a reaction flask and dissolved in acetonitrile (200 mL). The mixture was stirred at 60 °C for 12 hours. TLC showed that the reaction was complete. The mixture was concentrated under reduced pressure and extracted three times with ethyl acetate / water. The organic phases were combined, concentrated under reduced pressure, and separated by silica gel column chromatography. The eluent was petroleum ether / ethyl acetate, yielding a yellowish-white intermediate 1i (42 g, 97%). LCMS: (MS-ESI, m / z): [M+H] + =291.1.

[0265] (2) Add 1,1-dibromo-3,3,3-trifluoroacetone (19 mL, 138 mmol), sodium acetate (28.3 g, 345 mmol), and water (100 mL) to a reaction flask. React at 100 °C for 45 minutes and then cool to room temperature to obtain mixture A. Add 4-cyanobenzaldehyde (20 g, 69 mmol), methanol (400 mL), and concentrated ammonia (100 mL) to another reaction flask. Stir well at room temperature, then slowly add mixture A dropwise to the reaction solution. After the addition is complete, raise the reaction temperature to 100 °C and react for 12 hours. TLC showed that the reaction was complete. Concentrate under reduced pressure, extract three times with ethyl acetate / water, combine the organic phases, concentrate under reduced pressure, separate by silica gel column chromatography, and elute with petroleum ether / ethyl acetate to obtain a pale yellow intermediate 2i (15.3 g, 56%). LCMS: (MS-ESI, m / z): [M+H] + =397.1.

[0266] (3) Add intermediate 2i (30 g, 75.8 mmol) and trifluoroacetic acid (50 mL) to a sealed tube, and react overnight at 120 °C. TLC showed complete reaction. Concentrate under reduced pressure, adjust pH to neutral, and extract three times with ethyl acetate / water. Combine the organic phases, concentrate under reduced pressure, and separate by silica gel column chromatography, eluting with petroleum ether / ethyl acetate to give a pale yellow solid 3i (16 g, 69%). LCMS: (MS-ESI, m / z): [M+H] + =307.1.

[0267] (4) Under an argon atmosphere at room temperature, intermediate 3i (24 g, 78.44 mmol), diiodomethane (12.7 mL, 157 mmol), and cesium carbonate (69 g, 196 mmol) were added to a reaction flask and dissolved in acetonitrile (400 mL). The mixture was stirred at 100 °C for 12 hours. TLC showed that the reaction was complete. The mixture was concentrated under reduced pressure, extracted three times with ethyl acetate / water, and the organic phases were combined. The mixture was then concentrated under reduced pressure and separated by silica gel column chromatography, eluting with petroleum ether / ethyl acetate, to give a yellowish-white intermediate 4i (14.86 g, 60%). LCMS: (MS-ESI, m / z): [M+H] + =319.1.

[0268] (5) At room temperature, intermediate 4i (14.8 g, 46.74 mmol), 1,1'-bis(diphenylphosphino)ferrocene palladium(II) dichloride (3 g, 4.67 mmol), triethylamine (20 mL, 140 mmol), and methanol (100 mL) were added to the reaction flask. The mixture was replaced three times with carbon monoxide (1 atm), and reacted at 60 °C for 12 hours. TLC showed that the reaction was complete. The mixture was concentrated under reduced pressure, extracted three times with ethyl acetate / water, and the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by silica gel column chromatography, eluting with petroleum ether / ethyl acetate, to give a grayish-white intermediate 5i (12 g, 86%). LCMS: (MS-ESI, m / z): [M+H] + =299.1.

[0269] (6) Under argon protection in an ice-water bath, 5i (12g, 40.3mmol) and tetrahydrofuran (100mL) were added to the reaction flask. The mixture was stirred for 5 minutes in an ice bath, and lithium aluminum hydride (200mL, 201.3mmol) was slowly added dropwise. The reaction was maintained at this temperature for 1 hour. TLC showed complete reaction. The reaction was quenched with water and extracted three times with ethyl acetate. The combined organic phases were washed once with saturated sodium chloride, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by silica gel column chromatography. Elution with petroleum ether / ethyl acetate yielded a white intermediate 6i (3.54g, 33%). LCMS: (MS-ESI, m / z): [M+H] + =271.1.

[0270] (7) Under argon protection, 6i (3.5 g, 12.96 mmol) and dichloromethane (60 mL) were added to the reaction flask. The mixture was stirred in an ice bath for 5 minutes. Thionyl chloride (1.4 mL, 19.44 mmol) was slowly added dropwise. After the addition was complete, the mixture was heated to 40 °C and stirred for 3 hours. TLC showed that the reaction was complete. The mixture was extracted with water, and then extracted three times with dichloromethane. The organic phases were combined, washed once with saturated sodium chloride, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by silica gel column chromatography. The eluent was petroleum ether / ethyl acetate, yielding a white intermediate 7i (2.6 g, 70%). LCMS: (MS-ESI, m / z): [M+H] + =289.1.

[0271] (8) At room temperature, 7i (2.6 g, 9.03 mmol) and 20 mL of ammonia-methanol solution were added to the reaction flask. After the addition was complete, the temperature was raised to 70 °C and stirred for 12 hours. TLC showed that the reaction was complete. The mixture was concentrated under reduced pressure and separated by silica gel column chromatography, eluting with petroleum ether / ethyl acetate, to give a white compound I-1 (1.83 g, 75%). LCMS: (MS-ESI, m / z): [M+H] + =270.1.

[0272] Synthesis of compound J-1

[0273] (1) Add 1,1-dibromo-3,3,3-trifluoroacetone (1.7 mL, 10.6 mmol), sodium acetate (1.5 g, 17.62 mmol), and water (30 mL) to a reaction flask. React at 100 °C for 45 minutes and then cool to room temperature to obtain mixture A. Add 4-cyanobenzaldehyde (1.85 g, 8.81 mmol), methanol (60 mL), and concentrated ammonia (30 mL) to another reaction flask. Stir well at room temperature. Then slowly add mixture A dropwise to the reaction solution. After the addition is complete, raise the reaction temperature to 100 °C and react for 12 hours. TLC showed that the reaction was complete. Concentrate under reduced pressure, extract three times with ethyl acetate / water, combine the organic phases, concentrate under reduced pressure, separate by silica gel column chromatography, and elute with petroleum ether / ethyl acetate to obtain a pale yellow intermediate 1j (1.81 g, 63%). LCMS: (MS-ESI, m / z): [M+H] + =312.1.

[0274] (2) At room temperature, 1j (1.7 g, 5.4 mmol), propylene bromide (0.47 mL, 5.4 mmol), DMF (30 mL), and potassium carbonate (1.5 g, 10.8 mmol) were added to the reaction flask. The mixture was stirred at room temperature for 12 hours. TLC showed that the reaction was complete. The mixture was concentrated under reduced pressure, extracted three times with ethyl acetate / water, and the organic phases were combined. The mixture was concentrated under reduced pressure and separated by silica gel column chromatography, eluting with petroleum ether / ethyl acetate, to give a yellow intermediate 2j (0.73 mg, 38.4%). LCMS: (MS-ESI, m / z): [M+H] + =356.1.

[0275] (3) Under an argon atmosphere at room temperature, 2j (2g, 5.63mmol), potassium trifluoroborate (830mg, 6.19mmol), dioxane (15mL), water (1mL), potassium carbonate (15g, 10.8mmol), palladium acetate (130mg, 0.563mmol), and 1,1'-bis(diphenylphosphine)ferrocene (630mg, 1.13mmol) were added to a reaction flask and stirred until homogeneous. The mixture was then heated to 90℃ and reacted for 12 hours. TLC showed that the reaction was complete. The mixture was concentrated under reduced pressure, extracted three times with ethyl acetate / water, and the organic phases were combined. The mixture was then concentrated under reduced pressure and separated by silica gel column chromatography, eluting with petroleum ether / ethyl acetate, to give a pale yellow intermediate 3j (400mg, 24%). LCMS: (MS-ESI, m / z): [M+H] + =304.1.

[0276] (4) Under an argon atmosphere at room temperature, 3j (17g, 0.056mol), 1,3-bis(2,4,6-trimethylphenyl)-2-imidazolidinedichloro(o-isopropoxybenzyl)ruthenium (4g, 0.0056mol), and dichloromethane (300mL) were added to the reaction flask. The mixture was stirred overnight at room temperature. TLC showed that the reaction was complete. The mixture was concentrated under reduced pressure, extracted three times with ethyl acetate / water, and the organic phases were combined. The mixture was concentrated under reduced pressure and separated by silica gel column chromatography, eluting with petroleum ether / ethyl acetate, to give a yellow intermediate 4j (9g, 60%). LCMS: (MS-ESI, m / z): [M+H] + =276.1.

[0277] (5) Under ice bath conditions, add 4J (3g, 10.91mmol), nickel chloride (300mg, 22mmol), methanol (20mL), and tetrahydrofuran (20mL) to the reaction flask. Maintain the temperature and stir for 5 minutes. Slowly add sodium borohydride (1.7g, 43.64mmol). After the addition is complete, raise the temperature to room temperature and stir for 10 hours. TLC plate analysis shows the reaction is complete. Concentrate under reduced pressure, extract three times with ethyl acetate / water, combine the organic phases, concentrate under reduced pressure, and separate by silica gel column chromatography, eluting with petroleum ether / ethyl acetate to give a yellowish-white solid J-1 (900mg, 30%). LCMS: (MS-ESI, m / z): [M+H] + =282.1.

[0278] Synthesis of compound K-1

[0279] (1) At room temperature, 1,1,1-trifluoro-2,4-pentanedione (78 μL, 0.632 mmol), p-bromophenylhydrazine (100 mg, 0.535 mmol), hexafluoroisopropanol (2 mL), and triethylamine (112 μL, 0.803 mmol) were added to a reaction flask. The mixture was stirred for 3 hours. TLC showed that the reaction was complete. The mixture was concentrated under reduced pressure, extracted three times with ethyl acetate / water, and the organic phases were combined. The mixture was concentrated under reduced pressure and separated by silica gel column chromatography, eluting with petroleum ether / ethyl acetate, to give a white intermediate 1k (115 mg, 71%). LCMS: (MS-ESI, m / z): [M+H] + =305.1.

[0280] (2) At room temperature, intermediate 1k (148 mg, 0.24 mmol), 1,1'-bis(diphenylphosphino)ferrocene palladium(II) dichloride (17 mg, 0.02 mmol), triethylamine (99 μL, 0.71 mmol), and methanol (16 mL) were added to the reaction flask. The mixture was replaced three times with carbon monoxide (1 atm), and reacted at 60 °C for 12 hours. TLC showed that the reaction was complete. The mixture was concentrated under reduced pressure, extracted three times with ethyl acetate / water, and the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by silica gel column chromatography, eluting with petroleum ether / ethyl acetate, to give a grayish-white intermediate 2k (92 mg, 70%). LCMS: (MS-ESI, m / z): [M+H] + =285.2.

[0281] (3) Under argon protection in an ice-water bath, 2kJ (500 mg, 0.181 mmol) and tetrahydrofuran (3 mL) were added to the reaction flask. The mixture was stirred for 5 minutes in an ice-water bath, and lithium aluminum hydride (1.2 mL, 1.23 mmol) was slowly added dropwise. The reaction was maintained at this temperature for 1 hour. TLC showed that the reaction was complete. The mixture was quenched with water and extracted three times with ethyl acetate. The organic phases were combined, washed once with saturated sodium chloride, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by silica gel column chromatography. Elution with petroleum ether / ethyl acetate gave a white intermediate 3kJ (58 mg, 91%). LCMS: (MS-ESI, m / z): [M+H] + =257.1.

[0282] (4) Under argon protection, 3kJ (45 mg, 0.176 mmol) and dichloromethane (3 mL) were added to the reaction flask. The mixture was stirred in an ice bath for 5 minutes. Thionyl chloride (26 μL, 1.64 mmol) was slowly added dropwise. After the addition was complete, the mixture was heated to 40 °C and stirred for 3 hours. TLC showed that the reaction was complete. Water was added, and the mixture was extracted three times with dichloromethane. The organic phases were combined, washed once with saturated sodium chloride, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by silica gel column chromatography. The eluent was petroleum ether / ethyl acetate, yielding a white intermediate 4kJ (45 mg, 94%). LCMS: (MS-ESI, m / z): [M+H] + =275.1.

[0283] (5) At room temperature, 4kJ (30 mg, 0.11 mmol) and 2 mL of ammonia-methanol solution were added to the reaction flask. After the addition was complete, the temperature was raised to 40 °C and stirred for 12 hours. TLC showed that the reaction was complete. The mixture was concentrated under reduced pressure and separated by silica gel column chromatography, eluting with petroleum ether / ethyl acetate, to give a white intermediate K-1 (10 mg, 37%). LCMS: (MS-ESI, m / z): [M+H] + =256.1. 1 H NMR (600MHz, DMSO-d6) δ7.68(d,J=8.2Hz,2H),7.60(d,J=8.3Hz,2H),6.77(s,1H),4.04(s,2H),2.35(s,3H).

[0284] Synthesis of compound L-1

[0285] (1) Under an oxygen atmosphere at room temperature, 2b (50 mg, 0.211 mmol), cyclopropylboronic acid (55 mg, 0.632 mmol), copper acetate (115 mg, 0.632 mmol), and triethylamine (88 μL, 0.632 mmol) were added to the reaction flask and dissolved in dichloromethane (5 mL). The mixture was then replaced with oxygen and reacted at room temperature for 18 hours. TLC showed the reaction was complete. Water was added, and the mixture was extracted three times with dichloromethane. The organic phases were combined, washed once with saturated sodium chloride, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by silica gel column chromatography. Elution with petroleum ether / ethyl acetate yielded 3 μL (16 mg, 28%) of a white solid intermediate. LCMS: (MS-ESI, m / z): [M+H] + =278.1.

[0286] (2) Under argon protection in an ice-water bath, 3 mL of tetrahydrofuran (50 mg, 0.181 mmol) was added to the reaction flask. The mixture was stirred in an ice bath for 5 minutes, and then lithium aluminum hydride (21 mg, 0.542 mmol) was slowly added. The reaction was maintained at this temperature for 1 hour. TLC showed complete reaction. The reaction was quenched with water and extracted three times with ethyl acetate. The combined organic phases were washed once with saturated sodium chloride, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by silica gel column chromatography, eluting with petroleum ether / ethyl acetate, to give a white solid compound L-1 (28 mg, 62%). LCMS: (MS-ESI, m / z): [M+H] + =282.1. 1 H NMR (600MHz, Chloroform-d) δ8.73(s,2H),7.66(q,J=8.0,7.1Hz,4H),7.38(s,1H),4.21(s,2H),3.61(s,1H),1.02(d,J=6.8Hz,2H),0.79-0.73(m,2H).

[0287] Synthesis of compound M-1

[0288] (1) Under an argon atmosphere at room temperature, 2-chloro-3-methyl-6-(trifluoromethyl)pyridine (0.95 g, 4.86 mmol), 1,1'-bis(diphenylphosphino)ferrocene palladium(II) dichloride (355 mg, 0.486 mmol), pinacol 4-methoxyformylphenylboronic acid (1.4 g, 5.34 mmol), cesium carbonate (3.16 g, 9.72 mmol), dioxane (8 mL), and water (2 mL) were added to a reaction flask. The reaction was carried out at 100 °C for 12 hours. TLC showed that the reaction was complete. The mixture was concentrated under reduced pressure, extracted three times with ethyl acetate / water, and the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by silica gel column chromatography. The eluent was petroleum ether / ethyl acetate, yielding a yellowish-white intermediate 1 M (1.3 g, 91%). LCMS: (MS-ESI, m / z): [M+H] + =295.

[0289] (2) The synthesis of intermediate 1m to compound M-1 was performed following the synthesis of 2k to K-1, yielding white compound M-1 (0.63 g, 75%). LCMS: (MS-ESI, m / z): [M+H] + =267. 1 H NMR (600MHz, DMSO-d6) δ8.31(s,2H),8.05(d,J=7.9Hz,1H),7.82(d,J=7.9Hz,1H),7.63(d,J=0.9Hz,4H),4.10(s,2H),2.42(s,3H).

[0290] Synthesis of compound N-1

[0291] (1) Following the synthesis of compound M-1, using 2-bromo-3-methoxypyridine and pinacol 4-methoxycarbonylphenylboronic acid as starting materials, compound N-1 was finally obtained. LCMS:(MS-ESI, m / z):[M+H] + =215.1.

[0292] Synthesis of compound O-1

[0293] (1) Following the synthesis of compound L-1, compound O-1 was finally obtained using compound 2b as the starting material. LCMS:(MS-ESI, m / z):[M+H] + =268.1.

[0294] Synthesis of compound P-1

[0295] (1) Following the synthesis of compound L-1, compound P-1 was finally obtained using compound 2b as the starting material. LCMS:(MS-ESI, m / z):[M+H] + =286.1.

[0296] Synthesis of compound Q-1

[0297] (1) In a 250 mL round-bottom flask, add 8 mL of 1,1-dibromo-3,3,3-trifluoroacetone (0.059 mol) and 12 g of sodium acetate (0.044 mol), dissolve in 70 mL of water, stir at 100 °C for 50 minutes, and cool to room temperature to obtain solution 1. In a 1 L round-bottom flask, add compound 1q (10 g, 0.049 mol), dissolve in ammonia / methanol (70 mL / 300 mL) to obtain solution 2. Add solution 1 dropwise to solution 2, and stir overnight at room temperature. After the reaction is complete, remove most of the solvent from the reaction solution by vortexing, add an appropriate amount of water, and a solid precipitates. Filter, dry, and obtain compound 2q. LCMS:(MS-ESI, m / z):[M+H] + =309.0.

[0298] (2) Compound 2q (10 g, 0.032 mol) was added to a 500 mL round-bottom flask, dissolved in acetonitrile, and then (2-bromoethoxy)-tert-butyldimethylsilane (21 mL, 0.097 mol) and cesium carbonate (46 g, 0.1299 mol) were added. The mixture was stirred overnight at 80 °C. After the reaction was complete, most of the solvent was removed by vortexing, and the mixture was filtered with diatomaceous earth, evaporated to dryness, extracted with ethyl acetate / water (130 mL × 4), and the organic phases were combined. The mixture was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography to obtain compound 3q. LCMS: (MS-ESI, m / z): [M+H] + =467.1.

[0299] (3) Compound 3q (23 g, 49.4 mmol) was added to a 250 mL round-bottom flask and dissolved in tetrabutylammonium fluoride tetrahydrofuran solution (148 mL, 148 mmol). The mixture was stirred overnight at room temperature. After the reaction was complete, 100 mL of water was added to the reaction solution, and the mixture was extracted with ethyl acetate (100 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. Upon addition of a suitable amount of petroleum ether, a white solid precipitated. Compound 4q was obtained. LCMS: (MS-ESI, m / z): [M+H] + =353.0.

[0300] (4) Compound 4q (14 g, 39.8 mmol) and cesium carbonate (39 g, 119.3 mmol) were added to a 1 L gai-shaped flask, dissolved in acetonitrile, and refluxed at 80 °C with stirring overnight. After the reaction was complete, the reaction solution was filtered through diatomaceous earth, evaporated to dryness, and purified by column chromatography to obtain compound 5q. LCMS:(MS-ESI, m / z):[M+H] + =333.0.

[0301] (5) Following the synthesis of compound M-1, compound Q-1 was finally obtained using 5q as the starting material. LCMS:(MS-ESI, m / z):[M+H] + =284.1.

[0302] Synthesis of compound R-1

[0303] (1) Compound 1r (5 g, 25.12 mmol), ethyl trifluoroacetoacetate (4.8 mL, 32.66 mmol), and sodium hydroxide were dissolved in ethanol solution, and the reaction mixture was placed at 80 °C and reacted overnight. After the reaction was complete, hydrochloric acid solution (1 M) was added to the reaction solution to adjust the pH to about 5. The reaction solution was then evaporated to dryness, and compound 2r was obtained by column chromatography. LCMS: (MS-ESI, m / z): [M+H] + =307.0.

[0304] (2) Under ice bath conditions, sodium hydride was added to an acetonitrile solution of compound 2r (2.3 g, 7.49 mmol). After stirring for 20 min, iodomethane was added, and the mixture was brought to room temperature and stirred overnight. After the reaction was complete, the reaction solution was evaporated to dryness, extracted with ethyl acetate / water (50 mL × 3), the organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography to obtain compound 3r. LCMS:(MS-ESI, m / z): [M+H] + =321.1.

[0305] (3) Following the synthesis of compound M-1, using 3r as the starting material, compound R-1 was finally obtained. LCMS:(MS-ESI, m / z):[M+H] + =272.1.

[0306] Synthesis of compound S-1

[0307] (1) Following the preparation method of compound H-1, using 4-bromo-3-hydroxybenzaldehyde as a starting material, a white compound S-1 (850 mg, 71%) was obtained. LCMS: (MS-ESI, m / z): [M+H] + =362. 1H NMR (600MHz, DMSO-d6) δ8.39 (s, 2H), 7.98-7.96 (m, 1H), 7.58 (d, J = 7.9Hz, 1H), 7.56-7.53 (m ,2H),7.44-7.40(m,3H),7.36(dd,J=7.8,1.6Hz,2H),5.29(s,2H),4.10(s,2H),3.71(s,3H).

[0308] Synthesis of compound T-1

[0309] (1) Following the preparation method of compound B-1, using compound 5-aldehyde-2-thiophenecarboxynitrile as the starting material, white compound T-1 (1.1 g, 56.4%) was obtained. LCMS:(MS-ESI, m / z):[M+H] + =262.1. 1 H NMR (600MHz, Chloroform-d) δ7.28-7.26 (m, 2H), 6.96 (d, J = 3.6Hz, 1H), 4.11 (d, J = 1.0Hz, 2H), 3.85 (s, 3H).

[0310] Example 11 Synthesis of compounds 187-190

[0311] (1) Following the preparation method of compound 170, using compound G-1 and intermediate 5f as starting materials, white compound 187 was obtained. LCMS:(MS-ESI, m / z):[M+H] + =571.1. 1 H NMR (600MHz, DMSO-d6) δ11.54(t,J=5.5Hz,1H),8.66(s,1H),8.20(s,1H),7.71(d,J= 3.1Hz,1H),7.66(s,1H),7.51(q,J=1.4Hz,1H),7.34(d,J=3.1Hz,1H),3.86(s,3H),3 .47-3.45(m,5H),3.27-3.24(m,2H),2.73-2.69(m,2H),2.03-1.95(m,1H),1.92-1.8 8(m,1H),1.82-1.80(m,2H),1.45-1.39(m,2H),1.05-1.03(m,2H),0.94-0.91(m,2H).

[0312] (2) Following the preparation method of compound 170, using compound H-1 and intermediate 5f as starting materials, white compound 188 was obtained. LCMS:(MS-ESI, m / z):[M+H] + =565.1. 1 H NMR(600MHz,DMSO-d6)δ11.92(t,J=5.8Hz,1H),8.70(d,J=2.3Hz,1H),8.66(s,1H) ,8.24(s,1H),8.05-8.03(m,1H),7.99(d,J=1.3Hz,1H),7.92(dd,J=8.2,2.3Hz,1H) ,7.78(d,J=3.0Hz,1H),7.68(s,1H),7.39(d,J=3.1Hz,1H),4.85(d,J=5.7Hz,2H), 4.07(s,3H),3.87(s,3H),1.91-1.88(m,1H),1.03-1.01(m,2H),0.91-0.88(m,2H).

[0313] (3) Following the preparation method of compound 170, using compound I-1 and intermediate 5f as starting materials, white compound 189 was obtained. LCMS:(MS-ESI, m / z):[M+H] + =578.2. 1 H NMR(600MHz,DMSO-d6)δ11.89(t,J=5.8Hz,1H),8.66(s,1H),8.24(s,1H),7.92-7.91(m,1H) ,7.80(d,J=7.9Hz,1H),7.78(d,J=3.0Hz,1H),7.69(d,J=2.9Hz,1H),7.39(d,J=3.1Hz,1H),7 .23(dd,J=8.0,1.6Hz,1H),7.19(d,J=1.5Hz,1H),6.00(s,2H),4.80(d,J=5.7Hz,2H),3.87( s,3H),1.90(tt,J=8.3,4.7Hz,1H),1.02(dq,J=6.1,3.5Hz,2H),0.89(dt,J=8.2,3.3Hz,2H).

[0314] (4) Following the preparation method of compound 170, using compound J-1 and intermediate 5f as raw materials, white compound 190 was obtained. LCMS:(MS-ESI, m / z):[M+H] + =590.2.

[0315] Example 12 Synthesis of compounds 191 and 192

[0316] (1) Following the preparation method of compound 170, compound K-1 and intermediate 5f were used as raw materials to obtain white compound 191.

[0317] LCMS:(MS-ESI,m / z):[M+H] + =564.2. 1 H NMR (600MHz, DMSO-d6) δ11.92(t,J=5.7Hz,1H),8.66(s,1H),8.24(s,1H),7.78(d,J=3.0Hz,1H),7.68(s,1H),7.56-7.53(m,4H ),7.39(d,J=3.0Hz,1H),6.75(s,1H),4.85(d,J=5.7Hz,2H),3.87(s,3H),2.33(s,3H),1.89(m,1H),1.02(m,2H),0.88(m,2H).

[0318] (2) Following the preparation method of compound 170, using compound L-1 and intermediate 5f as raw materials, white compound 192 was obtained. LCMS:(MS-ESI, m / z):[M+H] + =590.2. 1 H NMR(600MHz,DMSO-d6)δ11.90(t,J=5.7Hz,1H),8.66(s,1H),8.24(s,1H), 7.93(s,1H),7.88-7.85(m,2H),7.78(d,J=3.0Hz,1H),7.67(s,1H),7.52- 7.49(m,2H),7.39(d,J=3.0Hz,1H),4.84(d,J=5.7Hz,2H),3.87(s,3H),3. 73(m,1H),1.91(m,1H),1.02(m,2H),1.01-0.97(m,2H),0.92-0.87(m,4H).

[0319] Example 13 Synthesis of compounds 196-202, 204

[0320] (1) Following the preparation method of compound 170, using compound M-1 and intermediate 5f as starting materials, white compound 196 was obtained. LCMS:(MS-ESI, m / z):[M+H] + =575.2. 1H NMR(600MHz,DMSO-d6)δ11.91(t,J=5.6Hz,1H),8.66(s,1H),8.23(s,1H),8.02( d,J=7.9Hz,1H),7.79(d,J=7.9Hz,1H),7.77(d,J=3.0Hz,1H),7.68(s,1H),7.57- 7.55(m,2H),7.52-7.50(m,2H),7.38(d,J=3.1Hz,1H),4.82(d,J=5.6Hz,2H),3. 87(s,3H),2.41(s,3H),1.92-1.87(m,1H),1.03-1.01(m,2H),0.91-0.88(m,2H).

[0321] (2) Following the preparation method of compound 170, using compound N-1 and intermediate 5f as starting materials, white compound 197 was obtained. LCMS:(MS-ESI, m / z):[M+H] + =523.2. 1 H NMR(600MHz,DMSO)δ11.87(t,J=5.7Hz,1H),8.66(s,1H),8.25-8.24(m,1H),8.22(s, 1H),7.83(d,J=8.1Hz,2H),7.77(d,J=3.0Hz,1H),7.66(s,1H),7.56-7.54(m,1H),7.4 3(d,J=8.1Hz,2H),7.38(d,J=3.0Hz,1H),7.35(d,J=3.8Hz,1H),4.79(d,J=5.7Hz,2H ),3.88(s,3H),3.84(s,3H),1.92-1.88(m,1H),1.04-1.01(m,2H),0.91-0.88(m,2H).

[0322] (3) Following the preparation method of compound 170, using compound O-1 and intermediate 5f as raw materials, white compound 198 was obtained. LCMS:(MS-ESI, m / z):[M+H] + =576.2. 1H NMR (600MHz, DMSO) δ11.91(t,J=5.8Hz,1H),8.66(s,1H),8.45(d,J=1.7Hz,1H),8.23( s,1H),7.78(d,J=3.0Hz,1H),7.67(s,1H),7.59(d,J=8.2Hz,2H),7.54(d,J=8.1Hz,2H) ,7.39(d,J=3.0Hz,1H),7.05-7.01(m,1H),5.77-5.74(m,1H),5.15-5.13(m,1H),4.84( d,J=5.7Hz,2H),3.87(s,3H),1.92-1.87(m,1H),1.03-1.01(m,1H),0.89-0.87(m,2H).

[0323] (4) Following the preparation method of compound 170, using compound P-1 and intermediate 5f as starting materials, white compound 199 was obtained. LCMS:(MS-ESI, m / z):[M+H] + =594.2. 1 H NMR (600MHz, DMSO-d6) δ11.91(t,J=5.8Hz,1H),8.66(s,1H),8.27(s,1H),8.09(s,1H),7.77(d,J=3.1Hz,1H),7.68(d,J=8.1Hz,3H),7.52(d,J=8.0H z,2H),7.41(d,J=3.1Hz,1H),7.12(d,J=3.8Hz,1H),6.73(d,3.8Hz,1H),4 .83(d,J=5.8Hz,2H),3.87(s,3H),1.90(m,1H),1.02(m,2H),0.88(m,2H).

[0324] (5) Following the preparation method of compound 170, using compound Q-1 and intermediate 5f as starting materials, white compound 200 was obtained. LCMS:(MS-ESI, m / z):[M+H] + =592.2. 1H NMR (600MHz, DMSO) δ11.85(d,J=5.8Hz,1H),8.66(s,1H),8.28(d,J=8.3Hz,1H),8. 23(s,1H),7.96(d,J=1.3Hz,1H),7.77(d,J=3.0Hz,1H),7.68(s,1H),7.39(d,J=3.1 Hz,1H),7.13(dd,J=8.3,1.8Hz,1H),7.04(d,J=1.7Hz,1H),4.76(d,J=5.7Hz,2H), 4.47(s,4H),3.87(s,3H),1.91-1.87(m,1H),1.03-1.01(m,2H),0.90-0.87(m,2H).

[0325] (6) Following the preparation method of compound 170, using compound R-1 and intermediate 5f as starting materials, white compound 201 was obtained. LCMS:(MS-ESI, m / z):[M+H] + =580.2. 1 H NMR(600MHz,DMSO)δ11.88(t,J=5.7Hz,1H),8.66(s,1H),8.22(s,1H),7.77(d ,J=3.0Hz,1H),7.66(s,1H),7.60(d,J=8.0Hz,2H),7.51(d,J=8.1Hz,2H),7.38 (d,J=3.1Hz,1H),6.47(s,1H),4.80(d,J=5.6Hz,2H),3.99(s,3H),3.87(s,3H ),1.88(dt,J=8.0,3.6Hz,1H),1.02(dq,J=6.2,3.5Hz,2H),0.89-0.86(m,2H).

[0326] (7) Following the preparation method of compound 170, using compound S-1 and intermediate 5f as starting materials, white compound 202 was obtained. LCMS:(MS-ESI, m / z):[M+H] + =580.2. 1H NMR(600MHz,DMSO-d6)δ11.77(t,J=5.6Hz,1H),10.06(s,1H),8.67(s,1H),8.20( s,1H),7.90(s,1H),7.75(d,J=3.0Hz,1H),7.63(s,1H),7.37(d,J=3.1Hz,1H),7.3 5(d,J=7.9Hz,1H),7.20(d,J=1.7Hz,1H),7.11(dd,J=7.8,1.7Hz,1H),4.70(d,J=5 .6Hz,2H),3.88(s,3H),3.76(s,3H),1.91-1.89(m,1H),1.04(m,2H),0.90(m,2H).

[0327] (8) Following the preparation method of compound 170, using compound T-1 and intermediate 5f as starting materials, white compound 204 was obtained. LCMS:(MS-ESI, m / z):[M+H] + =570.2. 1 H NMR (600MHz, DMSO-d6) δ11.89(t,J=5.9Hz,1H),8.67(s,1H),8.23(s,1H),7.89(s,1H),7.78(d,J=3.0Hz,1H),7.67(s,1H),7.40(d,J=3.7Hz ,1H),7.38(d,J=3.0Hz,1H),7.17(d,J=3.8Hz,1H),4.93(d,J=5.8Hz,2H),3.90(s,3H),3.84(s,3H),1.92(m,1H),1.04(m,2H),0.97(m,2H).

[0328] Example 14: Synthesis of Comparative Compound 1 and Comparative Compound 2

[0329] (1) Following the synthetic method of intermediate 3c, using 3,4-dihydro-2H-pyran and compound 1u as raw materials, a white intermediate 2u was obtained by slurry preparation. LCMS:(MS-ESI, m / z):[M+H] + =273.0.

[0330] (2) Following the synthetic method of compound 1, using 2u as the starting material, nucleophilic substitution, Suzuki coupling, and deprotection of the THP protecting group were performed to finally obtain the white contrast compound 1. LCMS:(MS-ESI, m / z):[M+H] + =496.2. 1H NMR (600MHz, DMSO-d6) δ13.53(s,1H),8.95(t,J=6.0Hz,1H),8.22(s,1H),7.94-7.91(m,1H),7.70(d,J=8.0Hz,2H),7.48(d ,J=8.0Hz,2H),7.31(s,1H),5.43(h,J=6.6Hz,1H),4.88(d,J=6.0Hz,2H),3.76(s,3H),2.16(s,3H),1.25(d,J=6.6Hz,6H).

[0331] (3) Following the synthesis method of intermediate 2u, using 3,4-dihydro-2H-pyran and 1v as raw materials, a white intermediate 2v was obtained by pulping. LCMS:(MS-ESI, m / z):[M+H] + =364.0.

[0332] (4) At room temperature, 2v (0.5 g, 1.4 mmol), B-1 (0.35 g, 1.4 mmol), Pd2dba3 (62 mg, 0.07 mmol), Xantphos (0.16 g, 0.28 mmol), K2CO3 (0.4 g, 2.8 mmol), and 1,4-dioxane (15 mL) were added to the reaction flask. The mixture was purged with argon three times and reacted at 100 °C for 20 hours. The reaction was confirmed to be complete by TLC. The mixture was filtered through diatomaceous earth, and the filtrate was concentrated and separated by rapid silica gel column chromatography, eluting with petroleum ether / ethyl acetate to give a white intermediate 3v (0.13 g, 19.3%). LCMS: (MS-ESI, m / z): [M+H] + =491.1.

[0333] (5) Following the synthetic method of comparative compound 1, using 3V as the starting material, and after Suzuki coupling and removal of the THP protecting group, white comparative compound 2 was obtained. LCMS:(MS-ESI, m / z):[M+H] + =495.2. 1 H NMR (600MHz, DMSO-d6) δ13.20(s,1H),8.23(s,1H),8.22(s,1H),7.92(s,1H),7.69(d,J=7.8Hz,2H),7.52(d,J=7.9Hz,2H), 7.26(s,1H),6.10(s,1H),4.83(hept,J=6.7Hz,1H),4.65(d,J=6.1Hz,2H),3.74(s,3H),1.75(s,3H),1.26(d,J=6.6Hz,6H).

[0334] Bioactivity test

[0335] Test Experiment Example 1: USP1 In Vitro Enzyme Detection

[0336] The inhibitory effect of the compounds of this invention on USP1 enzyme activity was detected by the following method:

[0337] 1. Preparation of reaction buffer: 50mM HEPES [pH 7.8], 0.5mM EDTA, 100mM NaCl, 1mM TCEP, 0.1mg / ml BSA and 0.01% Tween-20;

[0338] 2. Prepare the USP1 / UAF1 complex: Prepare a 0.5 nM USP1 / UAF1 complex (R&D, E-568-050) enzyme solution using reaction buffer.

[0339] 3. Prepare the Ubiquitin Rhodamine 110 (Ub-Rho 110) reaction substrate: Prepare a substrate solution with a final concentration of 150 nM Ub-Rho 110 (R&D, E-555-050) using reaction buffer.

[0340] 4. Preparation of working solutions for compounds: Prepare a 10 mM stock solution of the compound using DMSO. Prepare different concentrations of the compound using reaction buffer, with two replicates for each concentration, performing 3-fold serial dilutions, and providing corresponding solvent controls.

[0341] 5. USP1 / UAF1 deubiquitination reaction: Add 15 μL of 1.3× USP1 / UAF1 complex solution and 2 μL of 10× compound working solution to each well of the 384-well detection plate and incubate for 15 minutes. Then add 3 μL of 6.7× Ub-Rho 110 substrate solution to start the reaction and incubate at room temperature for 10 minutes.

[0342] 6. After the reaction is complete, use a microplate reader (PerkinElmer, EnVision) to read the fluorescence value. The excitation wavelength is 480 nm and the emission wavelength is 540 nm.

[0343] Inhibition rate (%) = [(fluorescence value)] DMSO - Fluorescence value blank )-(fluorescence value) 待测化合物 – Fluorescence value blank ) / (fluorescence value) DMSO - Fluorescence value blank )]×100%, of which fluorescence value 待测化合物 The fluorescence values ​​are the fluorescence values ​​detected after adding each concentration of the test compound. DMSO The fluorescence value is the fluorescence value detected in the solvent control group (solvent added, no test substance added). blankThis refers to the background value, which is the fluorescence value measured without the addition of enzymes;

[0344] Finally, the data were analyzed using GraphPad Prism 8 software, and the IC was calculated using the dose-response-inhibition (four-parameter) equation via GraphPad Prism software. 50 value.

[0345] Representative test results are shown in Table 1:

[0346] Compound activity score: (A)IC 50 (B) 100nM <IC 50 <1000nM; (C)IC 50 >1000nM.

[0347] Table 1

[0348] Among them, the IC50 of some compounds with activity labeled "A" 50 The value is less than 50 nM, less than 25 nM, or less than 10 nM.

[0349] As can be seen from the above, the compound of the present invention has a good inhibitory effect on USP1.

[0350] Experiment Example 2: Cell Viability Test

[0351] The inhibitory effect of the compounds of this invention on the growth of the MDA-MB-436 (BRCA1 mutant human breast cancer cell) cell line was determined using the CCK-8 assay. The experimental procedures are as follows:

[0352] Cells were seeded at 5000 cells / well in 96-well plates, 190 μL / well, and incubated at 37°C for 24 h. A stock solution of the compound was prepared using DMSO. The compound was diluted with complete culture medium at concentrations set according to the instructions, with an addition volume of 10 μL / well. A corresponding solvent control was also provided. After 6 days of drug treatment, 10 μL of CCK-8 solution was added to each well, and the cells were incubated at 37°C for 2 h. After incubation, the OD value was measured using a microplate reader at a detection wavelength of 450 nm.

[0353] The inhibition percentage is calculated using the following formula: Inhibition rate (%) = 100% × (1 - OD 样品 / OD 溶媒 ), where OD 样品 The absorbance values ​​detected after adding each concentration of the test substance are OD values. 溶媒 This represents the absorbance value detected for the solvent group (solvent added, test substance not added). Analysis and calculation were performed using GraphPad Prism 8. IC was calculated using a standard four-parameter curve fitting algorithm. 50 value.

[0354] Representative test results are shown in Table 2:

[0355] Compound activity score: (A)IC 50 (B) 100nM <IC 50 <500nM; (C)500nM <IC 50 <1000nM; (D)IC 50 >1000nM.

[0356] Table 2

[0357] Among them, the IC50 of some compounds with activity labeled "A" 50 The value is less than 50 nM, less than 10 nM, or less than 5 nM.

[0358] As can be seen from the above, the compound of this application has significant inhibitory activity on the proliferation of MDA-MB-436 cells.

[0359] Test Experiment 3: Cell Selectivity

[0360] The inhibitory effect of the compound on the growth of MCF-7 (BRCA1 / 2 wild-type human breast cancer cell line) and BT549 (BRCA1 / 2 wild-type human breast ductal carcinoma cell line) was tested using the following method: MCF-7 cells (2000 cells / well) and BT549 cells (2000 cells / well) were seeded in 96-well plates at 190 μL / well and incubated at 37°C for 24 h. On the second day, a stock solution of the compound was prepared using DMSO, and the compound was diluted with complete culture medium according to the concentration settings, with a dosage of 10 μL / well. A corresponding solvent control was also provided. After 6 days of drug treatment, subsequent detection and data calculation methods were similar to those in "Experimental Example 2".

[0361] Representative test results are shown in Table 3:

[0362] Compound activity score: (A)IC 50 (B) 10μM >10μM; (C) 10μM >IC 50 >5μM;(C)5μM>IC 50 >1μM.

[0363] Compound selectivity score: (+) > 20 times; (++) > 100 times; (+++) > 1000 times.

[0364] Table 3

[0365] Among them, some marked with "++" have a selectivity greater than 500 times;

[0366] Among them, some marked with "++" have a selectivity greater than 2000 times;

[0367] As can be seen from the above, the compound of this application has significant selectivity in inhibiting the proliferation of MDA-MB-436 and BT549 cells;

[0368] As can be seen from the above, the compounds of this application exhibit significant selectivity in inhibiting the proliferation of MDA-MB-436 and MCF-7 cells.

[0369] As can be seen from the above, the compounds of this application exhibit significant selectivity in inhibiting the proliferation of cells with BRCA1 mutations and BRCA1 / 2 wild-type cells;

[0370] Test Experiment 5: Comparison of Activity Differences

[0371] The activity of compounds 1, 37, and 162 in this invention, as well as the activity of "Comparative Compound 1", were tested using the activity test method in "Test Experiment 1". Representative results are shown in Table 4.

[0372] Table 4

[0373] As can be seen from the above, the difference between the compound of this application and "Comparative Compound 1" lies in: ① The compound of this application has unique properties. Fragments, especially those connected to the "V" Fragment; ② The compound of this application has a more significant USP1 inhibitory activity than "Comparative Compound 1".

[0374] The activity of compounds 2 and 161 in this invention, as well as the activity of "Comparative Compound 2", were tested using the activity testing methods in "Test Experiment 1" and "Test Experiment 2". Representative results are shown in Table 5.

[0375] Table 5

[0376] As can be seen from the above, the difference between the compound of this application and "Comparative Compound 2" lies in: ① The compound of this application has unique properties. Fragments, especially those connected to the "V" Fragment; ② The compound of this application has more significant USP1 inhibitory activity and higher cellular activity than "Comparative Compound 2".

[0377] The unique structural features of the compounds in this application endow them with a unique binding mode and molecular properties to the USP1 protein. Molecular modeling results show that a unique intramolecular hydrogen bond interaction is formed between the carbonyl group of the amide fragment and the "NH" group of the secondary amine group attached to the G ring, thereby effectively fixing the active conformation of the compound and promoting the stability of the compound's binding to USP1. This unique binding mode endows the compounds of this invention with significantly enhanced activity.

[0378] All documents mentioned in this invention are incorporated herein by reference as if each document were individually incorporated by reference. Furthermore, it should be understood that after reading the foregoing teachings of this invention, those skilled in the art can make various alterations or modifications to this invention, and these equivalent forms also fall within the scope defined by the appended claims.

Claims

1. The compound represented by formula (I) or its stereoisomers, enantiomers, diastereomers, transisomers, optical isomers, racemates, tautomers, or pharmaceutically acceptable salts thereof, their polymorphs, their prodrugs, their hydrates or solvates, or their isotopically labeled compounds, in, Ring G is a 6-membered heteroaryl ring; Ring T is a 5-membered ring containing heteroatoms; W is selected from C(R) 1 ) or N; X 1 X 2 V is independently selected from C or N; Q is selected from C, C(R) 1 ), N, N(R) 1 ), O, S, C(=O), C(=S), S(=O), S(=O)2; U is independently selected from C and C(R) each time it appears. 1 ), C(R 1 (R) 1 ), N, N(R) 1 ), O, S, C(=O), C(=S), S(=O), S(=O)2; dotted line Indicates a single bond or a double bond; Ring A is selected from 0-5 R a The following groups of substituted compounds: saturated or unsaturated C3-C10 cycloalkyl groups, saturated or unsaturated 4-7-membered heterocyclic groups, C6-C10 aryl groups, and 5-10-membered heteroaryl groups; Rings B and C are each independently selected from 0-5 R... b The following groups of substituted compounds: saturated or unsaturated C3-C10 cycloalkyl groups, saturated or unsaturated 4-7-membered heterocyclic groups, C6-C10 aryl groups, and 5-10-membered heteroaryl groups; Alternatively, rings B and C, along with the bonds connecting them and the substituents, form an 11-14 quinary tricyclic structure, which may optionally be divided into 0-8 R groups. f replace; R 1 Selected from H, D, halogen, cyano, carboxyl (COOH), hydroxyl, amino, nitro, -C(O)NH2; R a R b R f R d R e Each time it appears, it is independently selected from H, D, halogen (e.g., F), cyano, carboxyl (COOH), hydroxyl, amino, nitro, -C(O)NH2, -C(O)NH (C1-C6 alkyl), -C(O)N (C1-C6 alkyl), -SONH, -SONH (C1-C6 alkyl), -SON (C1-C6 alkyl), oxo, C2-C6 alkenyl, halogenated C2-C6 alkenyl, optionally with 0-5 Rs. g Substituted from the following group: C1-C6 alkyl (e.g., methyl, ethyl, isopropyl, isobutyl, tert-butyl), C2-C6 alkynyl, C1-C6 alkylamino, di(C1-C6 alkyl)amino, halo-C1-C6 alkyl (e.g., trifluoromethyl), C1-C6 alkoxy, halo-C1-C6 alkoxy, hydroxy-C1-C6 alkyl, amino-C1-C6 alkyl, carboxyl-C1-C6 alkyl, C1-C6 alkylcarbonyl, C1-C6 alkoxycarbonyl, C1-C6 alkylaminoyl, C1-C6 alkylamide, C1-C6 alkylsulfonyl, C1-C6 alkylsulfonylamino, C1-C6 alkylaminosulfonyl, -(L) m -(C1-C6 alkyl), -(L) m -(C2-C6 alkenyl), -(L) m -(C2-C6 ynyl group), -(L) m -(C1-C6 alkoxy), -(L) m -(C6-C10 aryl), -(L) m -(C3-C10 cycloalkyl), -(L) m -(4-7 membered heterocyclic group), -(L) m -(C6-C10 aryl), -(L) m -(5-10 heteroaryl); where L is independently selected from -C(=O)-, -O-, -S-, -S(=O)-, -S(=O)2, -NR each time it appears. 4 -、-C(R 2 (R) 3 -; m is an integer from 0 to 3 each time it appears; Or, R d R e The N atoms connected to them together form a saturated or unsaturated 4-7 membered heterocyclic group, which is optionally surrounded by 0-5 R atoms. g replace; R g Each time it appears, it is independently selected from H, D, halogen, carboxyl, hydroxyl, cyano, nitro, amino, -C(O)NH2, -C(O)NH(C1-C6 alkyl), -C(O)N(C1-C6 alkyl)(C1-C6 alkyl), -SONH, -SONH(C1-C6 alkyl), -SONN(C1-C6 alkyl)(C1-C6 alkyl), oxo, and optionally deuterated from the group consisting of: C1-C6 alkyl (e.g., methyl), C2-C6 alkynyl, hydroxy C1-C6 alkyl, carboxyl C1-C6 alkyl, C1-C6 alkylamino, di(C1-C6 alkyl)amino, -C(=O)-(C1-6 alkyl)-NH2, C1-6 alkyl carbonyl, C1-C6 alkoxy, halo-C1-C6 alkyl, halo-C1-C6 alkoxy.

2. The compound of formula (I) according to claim 1, or its stereoisomers, enantiomers, diastereomers, transisomers, optical isomers, racemates, tautomers, or pharmaceutically acceptable salts thereof, their polymorphs, their prodrugs, their hydrates or solvates, or their isotopically labeled compounds, characterized in that, In formula (I): W is selected from N, CH, C(F), C(=O), C(CN), C(NO2); and / or X 1 X 2 Independently selected from C or N; and / or V is independently selected from C or N; and / or Q is selected from C(R) 1 ), N, N(R) 1 ), O, S, S(=O)2, where R 1 Defined as described in claim 1; preferably, Q is selected from CH, N, N(CH3), O, S, S(=O)2; and / or U is selected from C(R) 1 ), C(R 1 (R) 1 ), N, N(R) 1 ), O, S, C (=O), C (=S), where R 1 Defined as described in claim 1; preferably, U is selected from CH, CH2, N, N(CH3), O, S, C (=O), C (=S); and / or Preferably, ring G is selected from pyridine ring, pyrimidine ring, pyridazine ring, triazine ring, and tetrazine ring; ring T is selected from pyrrole ring, furan ring, thiophene ring, oxazole ring, thiazole ring, pyrazole ring, imidazole ring, triazole ring, oxadiazole, thiadiazole, tetraazole ring, oxtriazole ring, thiatriazole ring, oxtetrazole ring, and thiatetrazolium ring. Among them, the dashed lines Indicates a single or double bond shared with ring G. Indicates and Connections; and / or Ring A is selected from 1-2 R a Substituted with: phenyl, 5-6 heteroaryl; preferably, ring A is selected from 1-2 R a The following groups of substituted compounds are used: phenyl, pyridinyl, pyrimidinyl, pyrazolyl, imidazoleyl; more preferably, ring A is selected from compounds substituted with 1-2 R groups. a Substituted: pyrazolyl, pyrimidinyl; wherein, R a The definition is as described in claim 1; preferably, each R a Independently selected from methyl, isopropyl, cyclopropyl, methoxy; and / or Ring B is selected from 0-5 (preferably 0-1) R. b Substituted: phenyl, 5-6 membered heteroaryl, saturated or unsaturated 3-6 membered heterocyclic groups, saturated or unsaturated C3-C6 cycloalkyl groups, Preferably, ring B is selected from phenyl, 6-membered heteroaryl, Among them, R b The definition is as described in claim 1, preferably, R b Selected from methyl, trifluoromethyl; Ring C is selected from 0-5 (preferably 1-2) R. b The substituted 5-membered heteroaryl ring is, for example, pyrroloyl, imidazolyl, pyrazolyl, thiazolyl, or triazolyl; preferably, the ring C is selected from those with 1-2 R groups. b Substituted: imidazole group, 1,2,4-triazolyl group, wherein R b The definition is as described in claim 1, preferably, R b Selected from methyl, trifluoromethyl; Alternatively, rings B and C, along with the bonds connecting them and the substituents, form a group selected from 0-2 R groups. f The following three-ring structure is replaced: Among them, R f The definition is as described in claim 1, preferably, each R f Independently selected from methyl, trifluoromethyl; and / or Preferably, R d R e Independently selected from H, D, and arbitrarily selected by 0-2 Rs g Substituted groups: C1-C6 alkyl (e.g., methyl, ethyl, isopropyl, tert-butyl), C3-C6 cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl), 4-6 membered heterocyclic groups (e.g., tetrahydropyranyl, morpholinyl, hexahydropiperidinyl); or, R d R e Together with N, which are connected to each other, they form a group of 0-1 R. g Substituted saturated or unsaturated 4-6 membered heterocyclic groups (e.g., morpholino, piperazine); wherein R g The definition is as described in claim 1, preferably, R g Each time it appears, it is independently selected from halogens (e.g., F), hydroxyl groups, and methyl groups.

3. The compound of formula (I) according to claim 1, or its stereoisomers, enantiomers, diastereomers, transisomers, optical isomers, racemates, tautomers, or pharmaceutically usable salts, polymorphs thereof, prodrugs thereof, hydrates or solvates thereof, or isotopically labeled compounds thereof, characterized in that, The compound represented by formula (I) is selected from the structure represented by formula (III-1) or (III-3): in, Ring B 1 Selected from 0-5 R b Substituted groups: phenyl, 5-6 membered heteroaryl, saturated or unsaturated C3-C6 cycloalkyl, saturated or unsaturated 3-6 membered heterocyclic groups. Ring C 1 Selected from 0-5 R b The next group that will be replaced: Ring C 2 Selected from q R f The next group that will be replaced: qX 3 Each time X 4 The independent selection of C as 0C-3H, integer N; the number, the preferred selection is shown in the X ring. 3 C is 1, C, Y1-XY 4 In the ternary ring structure composed of 3, NX; 3, X4, and Y4, there are q R's. f Substituents; n is an independent integer from 1 to 3 each time it appears; Y 4 Select independently from the following group each time it appears: -C(R) Ya (R) Yb )-、-NR Yc -, -C(=O)-, -O-, -S-, -S(=O)-, -S(=O)2; R Ya R Yb The group is independently selected from the group consisting of: H, D, halogen, amino, hydroxyl, carboxyl, cyano, and optionally deuterated from the group consisting of: C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkoxy, C1-C6 alkylamino, di(C1-C6 alkyl)amino, C1-C6 alkylaminoacyl, C1-C6 alkylamide, C1-C6 alkylsulfonylamino, C1-C6 alkylaminosulfonyl, halo-C1-C6 alkyl, halo-C1-C6 alkoxy, hydroxy-C1-C6 alkyl, amino-C1-C6 alkyl, and carboxyl-C1-C6 alkyl; preferably, R Ya R Yb Each is independently selected from H and methyl; R Yc Selected from the group consisting of: H, D; optionally deuterated from the group consisting of: C1-C6 alkyl, C1-C6 alkoxy, halo-C1-C6 alkyl, halo-C1-C6 alkoxy, hydroxy-C1-C6 alkyl, amino-C1-C6 alkyl, carboxyl-C1-C6 alkyl; preferably, R Yc Selected from H, methyl; Y 1 Y 2 Y 3 Independently selected from C(R) 1 ), N; preferably, Y 1 Y 2 Y 3 Both are CH; Rings A, W, X 1 X 2 U, V, Q, R b R f R d R e and dashed lines The definition is as described in claims 1-3.

4. The compound of formula (I) according to claim 1, or its stereoisomers, enantiomers, diastereomers, transisomers, optical isomers, racemates, tautomers, or pharmaceutically usable salts thereof, their polymorphs, their prodrugs, their hydrates or solvates, or their isotopically labeled compounds, characterized in that, The compound represented by formula (I) is selected from the structure represented by formula (IV-1) or (IV-2): Among them, rings A, W, B, C, and R d and R e The definition is as described in claim 1; Q 4a Q 4b U 4b Selected from N, C(H), C(CH3), C(F), C(Cl), C(Br), C(I); U 4a Selected from N(H), N(CH3), N-(halogen-substituted methyl), O, S; Preferably, ring A is selected from 1-2 R a The substituted 5-6 membered heteroaryl group; more preferably, ring A is selected from 1-2 R groups. a Substituted with the following group: pyrimidinyl, pyrazolyl, imidazoleyl; and / or Preferably, W is selected from N, CH, C(F); and / or Preferably, Q 4a Selected from C(H), N; and / or Preferably, Q 4b Selected from C(H), N; and / or Preferably, U 4b Selected from C(H), N; and / or U 4a Selected from N(H), N(CH3), O, and S; Ring B is selected from 0-5 (preferably 0-1) R. b Substituted: phenyl, 5-6 membered heteroaryl, saturated or unsaturated 3-6 membered heterocyclic groups, saturated or unsaturated C3-C6 cycloalkyl groups, Preferably, ring B is selected from phenyl, 6-membered heteroaryl, Among them, R b The definition is as described in claim 1, preferably, R b Selected from methyl, trifluoromethyl; Ring C is selected from 0-5 (preferably 1-2) R. b The substituted 5-membered heteroaryl ring, such as pyrrole, imidazolyl, pyrazolyl, or triazolyl; preferably, the ring C is selected from those with 1-2 R groups. b Substituted: imidazole group, 1,2,4-triazolyl group, wherein R b The definition is as described in claim 1, preferably, R b Selected from methyl, trifluoromethyl; Alternatively, rings B and C, along with the bonds connecting them and the substituents, form a group selected from 0-2 R groups. f The following three-ring structure is replaced: Among them, R f The definition is as described in claim 1, preferably, each R f Independently selected from methyl, trifluoromethyl; and / or Preferably, R d R e Independently selected from H, D, and arbitrarily selected by 0-2 Rs g Substituted groups: C1-C6 alkyl (e.g., methyl, ethyl, isopropyl, tert-butyl), C3-C6 cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl), 4-6 membered heterocyclic groups (e.g., tetrahydropyranyl, morpholinyl, hexahydropiperidinyl); or, R d R e Together with N, which are connected to each other, they form a group of 0-1 R. g Substituted saturated or unsaturated 4-6 membered heterocyclic groups (e.g., morpholino, piperazine); wherein R g The definition is as described in claim 1, preferably, R g Each time it appears, it is independently selected from halogens (e.g., F), hydroxyl groups, and methyl groups.

5. The compound of formula (I) according to claim 1, or its stereoisomers, enantiomers, diastereomers, transisomers, optical isomers, racemates, tautomers, or pharmaceutically usable salts thereof, their polymorphs, their prodrugs, their hydrates or solvates, or their isotopically labeled compounds, characterized in that, The compound represented by formula (I) is selected from the structure represented by formula (V-1) or (V-2): Among them, rings A, W, U, Q, B, C, and R d and R e The definition is as described in claims 1-3; Preferably, ring A is selected from 1-2 R a The substituted 5-6 membered heteroaryl group; more preferably, ring A is selected from 1-2 R groups. a Substituted with the following group: pyrimidinyl, pyrazolyl, imidazoleyl; and / or Preferably, W is selected from N, CH, C(F); and / or Preferably, Q is selected from C(H), N; and / or Preferably, U is selected from C(H), N; and / or Ring B is selected from 0-5 (preferably 0-1) R. b Substituted: phenyl, 5-6 membered heteroaryl, saturated or unsaturated 3-6 membered heterocyclic groups, saturated or unsaturated C3-C6 cycloalkyl groups, Preferably, ring B is selected from phenyl, 6-membered heteroaryl, Among them, R b The definition is as described in claim 1, preferably, R b Selected from methyl, trifluoromethyl; Ring C is selected from 0-5 (preferably 1-2) R. b The substituted 5-membered heteroaryl ring, such as pyrrole, imidazolyl, pyrazolyl, or triazolyl; preferably, the ring C is selected from those with 1-2 R groups. b Substituted: imidazole group, 1,2,4-triazolyl group, wherein R b The definition is as described in claim 1, preferably, R b Selected from methyl, trifluoromethyl; Alternatively, rings B and C, along with the bonds connecting them and the substituents, form a group selected from 0-2 R groups. f The following three-ring structure is replaced: Among them, R f The definition is as described in claim 1, preferably, each R f Independently selected from methyl, trifluoromethyl; and / or Preferably, R d R e Independently selected from H, D, and arbitrarily selected by 0-2 Rs g Substituted groups: C1-C6 alkyl (e.g., methyl, ethyl, isopropyl, tert-butyl), C3-C6 cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl), 4-6 membered heterocyclic groups (e.g., tetrahydropyranyl, morpholinyl, hexahydropiperidinyl); or, R d R e Together with N, which are connected to each other, they form a group of 0-1 R. g Substituted saturated or unsaturated 4-6 membered heterocyclic groups (e.g., morpholino, piperazine); wherein R g The definition is as described in claim 1, preferably, R g Each time it appears, it is independently selected from halogens (e.g., F), hydroxyl groups, and methyl groups.

6. The compound of formula (I) according to any one of claims 1-5, or its stereoisomers, enantiomers, diastereomers, transisomers, optical isomers, racemates, tautomers, or pharmaceutically usable salts thereof, their polymorphs, their prodrugs, their hydrates or solvates, or their isotopically labeled compounds, characterized in that, The compound represented by formula (I) is selected from one of the following compounds:

7. The preparation methods of the compounds shown in formula (Ia) or (Ib), and their reaction routes are as follows: Method 1: in, Z 1 Selected from Br or I, Z 2 Selected from Cl or Br; A, B, C, W, N, X 1 X 2 U, Q, R d R e , As defined in claims 1-4; Method 1 is selected from Route 1 or 2; Route 1: (1) Compound (IV) reacts with CO and methanol in the presence of a palladium catalyst and a base to produce compound (V); (2) Compound (V) undergoes hydrolysis under alkaline conditions to yield compound (VI); (3) The compound of formula (VI) reacts with the compound of formula (VII) to give the compound of formula (VIII); (4) Compound (VIII) reacts with compound (IX) in the presence of a palladium catalyst to give compound (Ia); Route 2: (1) Compound (IV) reacts with CO and methanol in the presence of a palladium catalyst and a base to produce compound (V); (5) The compound of formula (V) reacts with the compound of formula (VII) to give the compound of formula (VIII); (4) Compound (VIII) reacts with compound (IX) in the presence of a palladium catalyst to give compound (Ia); Preferably, in step (2), tetrahydrofuran can be added to the reaction system to improve solubility; Preferably, in step (3) or (5), the solvent for the reaction is dichloromethane or N,N-dimethylformamide; Preferably, in step (4), the solvent for the reaction is selected from one or more combinations of water, 1,4-dioxane and ethanol; Method 2: Among them, Z 2 Selected from Cl or Br, A, B, C, W, N, X 1 X 2 U, Q, R d R e , As defined in claims 1-4; (6) Compound X) reacts with compound XI) under alkaline anhydrous conditions to obtain compound XII); (7) Compound XII) reacts with compound IX) in the presence of a palladium catalyst to give compound (Ib); Furthermore, when U and Q contain active hydrogen, the above preparation method may also include protecting the active hydrogen with a protecting group before step (1) or step (6). The protecting group is generally tetrahydro-2H-pyran-2-yl or 2-(trimethylsilyl)ethoxymethyl, and the protecting group is removed after step (4) or step (7) to obtain the target compound.

8. A pharmaceutical composition comprising one or more therapeutically effective amounts of the compound of formula (I) according to any one of claims 1-5, or a stereoisomer, enantiomer, diastereomer, transisomer, optical isomer, racemate, tautomer, or a pharmaceutically acceptable salt thereof, its polymorph, its prodrug, its hydrate or solvate, its isotopically labeled compound, and a pharmaceutically acceptable carrier; and Optionally, one or more other antitumor drugs; Preferably, the other antitumor drugs include DNA damaging agents, reversible DNA binding agents, DNA alkylating agents, DNA strand breaking agents, DNA replication disruptors, antibodies, proteasome inhibitors, PARP inhibitors, ATM inhibitors, ATR inhibitors; p53 mutation regulators, and WEE1 inhibitors.

9. A ubiquitin-specific protease 1 inhibitor comprising one or more compounds selected from the formula (I) of any one of claims 1-5, or their stereoisomers, enantiomers, diastereomers, transisomers, optical isomers, racemates, tautomers, or pharmaceutically acceptable salts thereof, polymorphs thereof, prodrugs thereof, hydrates or solvates thereof, isotopically labeled compounds thereof, or the pharmaceutical composition of claim 7.

10. The use of the compound of formula (I) according to any one of claims 1-5, or its stereoisomers, enantiomers, diastereomers, transisomers, optical isomers, racemates, tautomers, or pharmaceutically usable salts thereof, polymorphs thereof, prodrugs thereof, hydrates or solvates thereof, isotopically labeled compounds thereof, or the pharmaceutical composition of claim 7, in the preparation of a medicament for the detection and / or prevention and / or treatment of ubiquitin-specific protease-related diseases; Preferably, the ubiquitin-specific protease-related disease is a USP1-related disease; Preferably, the USP1-related disease is a cancer with a defective DNA damage repair pathway; Preferably, the USP1-related disease is a cancer associated with BRAC1 or BRAC2 mutations; Preferably, the USP1-related disease is a homologous recombination-deficient cancer; Preferably, the USP1-related disease is an ATM-mutated tumor; Preferably, the USP1-related disease is an ATR-mutated tumor; Preferably, the USP1-related disease is a tumor with a P53 mutation or a tumor with two or more mutations. Preferably, the USP1-related disease is a cancer containing cancer cells with elevated RAD51 levels; Preferably, the USP1-related disease is a PARP inhibitor-resistant tumor.

11. The use of the compound of formula (I) according to any one of claims 1-5, or a stereoisomer, enantiomer, diastereomer, transisomer, optical isomer, racemate, tautomer, or pharmaceutically acceptable salt thereof, its polymorph, its prodrug, its hydrate or solvate, its isotopically labeled compound, or the pharmaceutical composition of claim 7, in the preparation of a medicament having one or more of the following effects: 1) Detection and / or prevention and / or treatment of tumors or cancer-related diseases; 2) Detection and / or prevention and / or treatment of inflammatory cell diseases; 3) Detection and / or prevention and / or treatment of neurodegenerative diseases; Preferably, the tumor-related diseases are selected from the group consisting of: liver cancer, melanoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, acute lymphoblastic leukemia, chronic lymphoblastic leukemia, multiple myeloma, neuroblastoma, breast cancer (including triple-negative breast cancer), ovarian cancer, nephroblastoma, cervical cancer, testicular cancer, soft tissue sarcoma, primary macroglobulinemia, bladder cancer, chronic myeloid leukemia, primary brain cancer, malignant melanoma, non-small cell lung cancer, small cell lung cancer, gastric cancer, colon cancer, malignant pancreatic islet tumors, malignant carcinoid tumors, choriocarcinoma, head and neck cancer, osteosarcoma, pancreatic cancer, acute myeloid leukemia, leukemia, rhabdomyosarcoma, Kaposi's sarcoma, genitourinary system tumors, thyroid cancer, esophageal cancer, and malignant hypercalcemia. Cervical hyperplasia, renal cell carcinoma, endometrial cancer, polycythemia vera, idiopathic thrombocythemia, adrenocortical carcinoma, skin cancer, prostate cancer, AIDS-related lymphoma, AIDS-related malignancies, anal cancer, cerebellar astrocytoma, extrahepatic bile duct carcinoma, osteosarcoma / malignant fibrous histiocytoma, brainstem glioma, ependymoma, visual pathway and hypothalamic glioma, bronchial adenoma / carcinoma, islet cell carcinoma, primary central nervous system lymphoma, chronic myeloid leukemia, tenosynovial clear cell sarcoma, colorectal cancer, cutaneous T-cell lymphoma, epididymal tumor, esophageal cancer, Ewing's sarcoma / tumor family, extracranial germ cell tumors, extra-germ cell tumors, ocular cancer (including intraocular melanoma and retinoblastoma), gallbladder cancer. Cystic carcinoma, ovarian germ cell tumors, gestational trophoblastic tumors, pilosebaceous leukemia, hypopharyngeal cancer, laryngeal cancer, acute lymphoblastic leukemia, acute myeloid leukemia, Waldenstrom's macroglobulinemia, malignant thymoma, medulloblastoma, Merkel cell carcinoma, metastatic primary squamous cell carcinoma, multiple endocrine tumor syndrome, multiple myeloma / plasma cell tumor, myelodysplastic syndrome, myeloid leukemia, myeloproliferative disorders, nasal and paranasal sinus cancer, nasopharyngeal carcinoma, oral cancer, lip cancer, oropharyngeal cancer, osteosarcoma / malignant fibrous histiocytoma of bone, low-grade potential ovarian tumors, paranasal sinus and nasal cavity cancer, parathyroid carcinoma, penile cancer, pheochromocytoma, pituitary adenoma, thoracic pulmonary blastoma, rectal cancer, transitional cell carcinoma (e.g., renal pelvis) (and ureter), salivary gland cancer, malignant fibrous histiocytoma, including bone, Sezary syndrome, small bowel cancer, supradental primitive neuroectodermal and pineal gland tumors, urethral cancer, uterine sarcoma, vaginal cancer, vulvar cancer, Wilms' tumor, anaplastic large cell lymphoma, central nervous system cancer, mesothelioma, fallopian tube cancer, malignant mesothelioma, renal cancer, renal pelvis and ureter cancer, acute myeloid leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, mycosis fungoides, chondrosarcoma, Ewing's sarcoma, osteosarcoma, malignant fibrous histiocytoma of bone, rhabdomyosarcoma in children, brain tumors, astrocytomas, pituitary tumors, lung cancer, bone cancer, brain cancer, soft tissue cancer, nervous system cancers, ovarian cancer, uterine cancer, cervical cancer, glioma.Glioblastoma, meningioma, rhabdomyosarcoma, melanoma, blood cancers, lymphoma, ovarian tumors, skin tumors, and neurological tumors.

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