Heterocyclic compound and application thereof

Abstract

The invention discloses a heterocyclic compound and application thereof. The invention provides a compound as shown in a formula (I), a tautomer thereof, a pharmaceutically acceptable salt thereof, a solvate thereof or a solvate of the pharmaceutically acceptable salt thereof. The heterocyclic compound provided by the invention shows a good cell growth inhibition effect on tumor cell strains of human breast cancer cells HCC1569 and human ovarian cancer cells OVCAR3, and the compound provided by the invention can be used as a PKMYT1 inhibitor. # imgabs0 #

Description

Technical Field

[0001] The invention relates to heterocyclic compounds and applications thereof. Background Art

[0002] The cyclin-cyclin-dependent kinase (CDK) complex is the core of the cell cycle regulation system. Different cyclins bind to different CDKs to regulate events at different stages of the cell cycle. Cyclin E1 encoded by the CCNE1 gene promotes the cell cycle by binding to and activating cyclin-dependent kinase 2 (CDK2). CCNE1 gene amplification is present in many tumor types, especially in ovarian cancer, uterine tumors, and gastroesophageal cancer, and is associated with the occurrence, drug resistance, and poor prognosis of various tumors. Tumors with CCNE1 gene amplification are usually resistant to current standard treatments, and treatment options are extremely limited. There is an urgent need to find new treatment options for these patients.

[0003] Membrane-associated tyrosine / threonine 1 protein kinase (PKMYT1) is a member of the Wee protein kinase family. It plays a role in regulating cell mitosis and has an important impact on the proliferation, migration and apoptosis of tumor cells. PKMYT1 phosphorylates cyclin-dependent kinase 1 (CDK1) to inactivate the CDK1-cyclin B complex, thereby causing G2 / M phase arrest in cells, preventing cells from entering the division phase, and negatively regulating the cell cycle.

[0004] During the cell cycle, when DNA is replicated, a large amount of DNA damage occurs. Normal cells repair the damage that occurs during DNA replication at the G1 / S checkpoint. However, tumor cells abolish the G1 / S checkpoint due to the loss of function of the p53 protein mutation. In order to prevent cells with severe DNA damage from entering the division phase and causing mitotic catastrophe and cell death, tumor cells repair DNA damage at the G2 / M checkpoint. Therefore, PKMYT1 is more important to tumor cells than normal cells.

[0005] Inhibiting the activity of PKMYT1 can activate CDK1, lose the blocking effect of the G2 / M checkpoint, and make tumor cells unable to repair damaged DNA in time, enter the division phase prematurely, and cause mitotic catastrophe, thereby killing tumor cells. Therefore, PKMYT1 can be used as a potential therapeutic target for tumors.

[0006] A recent study confirmed (Nature 2022, 604, 749-756) that PKMYT1 is essential in tumor cells with CCNE1 gene amplification, but not in normal cells. CCNE1 amplification and PKMYT1 inhibition have a "synthetic lethality" effect. Inhibiting the activity of PKMYT1 can effectively kill tumor cells with CCNE1 amplification. Therefore, PKMYT1 inhibitors can be used to treat tumors with CCNE1 amplification.

[0007]

[0008] There is no PKMYT1 inhibitor approved for marketing, and RP-6306 is the only PKMYT1 inhibitor that has entered clinical phase 1 for the treatment of patients with solid tumors with CCNE1 amplification. Therefore, it is of great significance to develop new PKMYT1 inhibitors with good efficacy to meet clinical needs. Summary of the invention

[0009] The technical problem to be solved by the present invention is to provide a novel heterocyclic compound and its application in view of the defect of insufficient types of PKMYT1 inhibitors in the prior art. The heterocyclic compound provided by the present invention exhibits good cell growth inhibition effect on tumor cell lines of human breast cancer cell HCC1569 and human ovarian cancer cell OVCAR3.

[0010] The present invention provides a compound represented by formula (I), its tautomer, its pharmaceutically acceptable salt, its solvate or its pharmaceutically acceptable salt solvate:

[0011]

[0012] in

[0013] Selected from:

[0014]

[0015]

[0016]

[0017] Each X is independently N or CR 5 ;

[0018] R 1 is -C(O)NH2;

[0019] R 2 is -NH2;

[0020] R 3 Independently for C6-10 Aryl, 5-14 membered heteroaryl, C 3-8 Cycloalkyl, 3-10 membered heterocyclic group, 3a Substituted C 6-10 Aryl, one or more R 3b substituted 5-14 membered heteroaryl, substituted by one or more R 3c Substituted C 3-8 Cycloalkyl or one or more R 3d substituted 3-10 membered heterocyclic group;

[0021] Each R 3a , R 3b , R 3c and R 3d are independently deuterium, halogen, cyano, oxo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl, 5-14 membered heteroaryl, -OR 4 、-NR 4 R 4 、-C(=O)R 4 、-C(=O)OR 4 、-OC(=O)R 4 、-C(=O)NR 4 R 4 、-NR 4 C(=O)R 4 、-NR 4 C(=O)NR 4 R 4 、-NR 4 S(=O)R 4 、-NR 4 S(=O)2R 4 、-NR 4 S(=O)NR 4 R 4 、-NR 4 S(=O)2NR 4 R 4 、-S(=O)R 4 、-S(=O)2R 4 、-S(=O)NR 4 R 4 、-S(=O)2NR 4 R 4 、-P(=O)R 4 R 4 、-P(=O)(OR 4 2. One or more R3-a Substituted C 1-6 Alkyl, with one or more R 3-b Substituted C 2-6 Alkenyl, one or more R 3-c Substituted C 2-6 Alkynyl, with one or more R 3-d Substituted C 3-8 Cycloalkyl, with one or more R 3-e substituted 3-10 membered heterocyclic group, substituted by one or more R 3-f Substituted C 6-10 Aryl or one or more R 3-g substituted 5-14 membered heteroaryl;

[0022] Each R 3-a , R 3-b , R 3-c , R 3-d , R 3-e , R 3-f and R 3-g are independently deuterium, halogen, C 1-6 Alkyl, -OC 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -OR 4 、-NR 4 R 4 、-C(=O)R 4 、-C(=O)OR 4 、-OC(=O)R 4 、-C(=O)NR 4 R 4 、-NR 4 C(=O)R 4 、-NR 4 C(=O)NR 4 R 4 、-NR 4 S(=O)R 4 、-NR 4 S(=O)2R 4 、-NR 4 S(=O)NR 4 R 4 、-NR 4 S(=O)2NR 4 R 4 、-S(=O)R 4 、-S(=O)2R 4 、-S(=O)NR 4 R 4 、-S(=O)2NR 4 R 4、-P(=O)R 4 R 4 OR-P(=O)(OR 4 )2;

[0023] Each R 4 are independently hydrogen, C 1-6 Alkyl, -OC 1-6 Alkyl, C 3-8 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl, 5-14 membered heteroaryl, substituted by one or more R 4a Substituted C 1-6 Alkyl, with one or more R 4b Replaced-OC 1-6 Alkyl, with one or more R 4c Substituted C 3-8 Cycloalkyl, with one or more R 4d substituted 3-10 membered heterocyclic group, substituted by one or more R 4e Substituted C 6-10 Aryl or one or more R 4f substituted 5-14 membered heteroaryl;

[0024] or two R 4 Together with the nitrogen atom or phosphorus atom to which they are commonly attached, they independently form a 3-10 membered heterocyclic group or are replaced by one or more R 4g substituted 3-10 membered heterocyclic group;

[0025] Each R 4a , R 4b , R 4c , R 4d , R 4e , R 4f and R 4g are independently deuterium, halogen, oxo, cyano, hydroxyl, nitro, C 1-6 Alkyl, -OC 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, -OC 3-8 Cycloalkyl, 3-10 membered heterocyclic group, -O-3-10 membered heterocyclic group, C 6-10 Aryl, 5-14 membered heteroaryl, -N(R 6 )2, -C(=O)R 6 、-C(=O)OR 6 、-OC(=O)R 6 、-C(=O)N(R 6 )2.-NR 6 C(=O)R 6 、-NR6 C(=O)N(R 6 )2.-NR 6 S(=O)R 6 、-NR 6 S(=O)2R 6 、-NR 6 S(=O)N(R 6 )2.-NR 6 S(=O)2N(R 6 )2, -S(=O)R 6 、-S(=O)2R 6 、-S(=O)N(R 6 )2、-S(=O)2N(R 6 )2, -P(=O)R 6 R 6 、-P(=O)(OR 6 2. One or more R 4-a Substituted C 1-6 Alkyl, with one or more R 4-b Replaced-OC 1-6 Alkyl, with one or more R 4-c Substituted C 3-8 Cycloalkyl, with one or more R 4-d substituted 3-10 membered heterocyclic group, substituted by one or more R 4-e Substituted C 6-10 Aryl or one or more R 4-f substituted 5-14 membered heteroaryl;

[0026] Each R 4-a , R 4-b , R 4-c , R 4-d , R 4-e and R 4-f are independently deuterium, halogen, cyano, hydroxyl, C 1-6 Alkyl, -OC 1-6 Alkyl, C 3-8 Cycloalkyl, -OC 3-8 Cycloalkyl, 3-10 membered heterocyclic group, -O-3-10 membered heterocyclic group, C 6-10 Aryl, 5-14 membered heteroaryl, -N(R 6 )2, -C(=O)R 6 、-C(=O)OR 6 、-OC(=O)R 6 、-C(=O)N(R 6 )2.-NR 6 C(=O)R 6 、-NR 6 C(=O)N(R6 )2.-NR 6 S(=O)R 6 、-NR 6 S(=O)2R 6 、-NR 6 S(=O)N(R 6 )2.-NR 6 S(=O)2N(R 6 )2, -S(=O)R 6 、-S(=O)2R 6 、-S(=O)N(R 6 )2、-S(=O)2N(R 6 )2, -P(=O)R 6 R 6 、-P(=O)(OR 6 2. One or more R 4 -a-1 Substituted C 1-6 Alkyl, with one or more R 4-a-2 Replaced-OC 1-6 Alkyl, with one or more R 4-a-3 Substituted C 3-8 Cycloalkyl, with one or more R 4-a-4 Replaced-OC 3-8 Cycloalkyl, with one or more R 4-a-5 substituted 3-10 membered heterocyclic group, substituted by one or more R 4-a-6 -O-3-10 membered heterocyclic group, substituted by one or more R 4-a-7 Substituted C 6-10 Aryl or one or more R 4-a-8 substituted 5-14 membered heteroaryl;

[0027] Each R 4-a-1 , R 4-a-2 , R 4-a-3 , R 4-a-4 , R 4-a-5 , R 4-a-6 , R 4-a-7 and R 4-a-8 are independently deuterium, halogen, cyano, hydroxyl, C 1-6 Alkyl, -OC 1-6 Alkyl, C 3-8 Cycloalkyl, -OC 3-8 Cycloalkyl, 3-10 membered heterocyclic group, -O-3-10 membered heterocyclic group, C 6-10 Aryl, 5-14 membered heteroaryl, -N(R 6 )2, -C(=O)R 6 、-C(=O)OR 6 、-OC(=O)R6 、-C(=O)N(R 6 )2.-NR 6 C(=O)R 6 、-NR 6 C(=O)N(R 6 )2.-NR 6 S(=O)R 6 、-NR 6 S(=O)2R 6 、-NR 6 S(=O)N(R 6 )2.-NR 6 S(=O)2N(R 6 )2, -S(=O)R 6 、-S(=O)2R 6 、-S(=O)N(R 6 )2、-S(=O)2N(R 6 )2, -P(=O)R 6 R 6 OR-P(=O)(OR 6 )2;

[0028] Each R 5 are independently hydrogen, deuterium, halogen, cyano, oxo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl, 5-14 membered heteroaryl, -OR 4 、-NR 4 R 4 、-C(=O)R 4 、-C(=O)OR 4 、-OC(=O)R 4 、-C(=O)NR 4 R 4 、-NR 4 C(=O)R 4 、-NR 4 C(=O)NR 4 R 4 、-NR 4 S(=O)R 4 、-NR 4 S(=O)2R 4 、-NR 4 S(=O)NR 4 R 4 、-NR 4 S(=O)2NR 4 R 4、-S(=O)R 4 、-S(=O)2R 4 、-S(=O)NR 4 R 4 、-S(=O)2NR 4 R 4 、-P(=O)R 4 R 4 、-P(=O)(OR 4 2. One or more R 5a Substituted C 1-6 Alkyl, with one or more R 5b Substituted C 2-6 Alkenyl, one or more R 5c Substituted C 2-6 Alkynyl, with one or more R 5d Substituted C 3-8 Cycloalkyl, with one or more R 5e substituted 3-10 membered heterocyclic group, substituted by one or more R 5f Substituted C 6-10 Aryl or one or more R 5g substituted 5-14 membered heteroaryl;

[0029] Each R 5a , R 5b , R 5c , R 5d , R 5e , R 5f and R 5g are independently deuterium, halogen, cyano, oxo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl, 5-14 membered heteroaryl, -OR 4 、-NR 4 R 4 、-C(=O)R 4 、-C(=O)OR 4 、-OC(=O)R 4 、-C(=O)NR 4 R 4 、-NR 4 C(=O)R 4 、-NR 4 C(=O)NR 4 R 4 、-NR 4 S(=O)R 4 、-NR 4 S(=O)2R 4、-NR 4 S(=O)NR 4 R 4 、-NR 4 S(=O)2NR 4 R 4 、-S(=O)R 4 、-S(=O)2R 4 、-S(=O)NR 4 R 4 、-S(=O)2NR 4 R 4 、-P(=O)R 4 R 4 OR-P(=O)(OR 4 )2;

[0030] Each R a are independently hydrogen, deuterium, halogen, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl, 5-14 membered heteroaryl, -OR 4 、-NR 4 R 4 、-C(=O)R 4 、-C(=O)OR 4 、-OC(=O)R 4 、-C(=O)NR 4 R 4 、-NR 4 C(=O)R 4 、-NR 4 C(=O)NR 4 R 4 、-NR 4 S(=O)R 4 、-NR 4 S(=O)2R 4 、-NR 4 S(=O)NR 4 R 4 、-NR 4 S(=O)2NR 4 R 4 、-S(=O)R 4 、-S(=O)2R 4 、-S(=O)NR 4 R 4 、-S(=O)2NR 4 R 4 、-P(=O)R 4 R4 、-P(=O)(OR 4 2. One or more R a-1 Substituted C 1-6 Alkyl, with one or more R a-2 Substituted C 2-6 Alkenyl, one or more R a-3 Substituted C 2-6 Alkynyl, with one or more R a-4 Substituted C 3-8 Cycloalkyl, with one or more R a-5 substituted 3-10 membered heterocyclic group, substituted by one or more R a-6 Substituted C 6-10 Aryl or one or more R a-7 substituted 5-14 membered heteroaryl;

[0031] Each R a-1 , R a-2 , R a-3 , R a-4 , R a-5 , R a-6 and R a-7 are each independently deuterium, halogen, cyano, -OR 6 or -NR 6 R 6 ;

[0032] Each R b are independently hydrogen, C 1-6 Alkyl, -OC 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl, 5-14 membered heteroaryl, substituted by one or more R b-1 Substituted C 1-6 Alkyl, with one or more R b-2 Replaced-OC 1-6 Alkyl, with one or more R b-3 Substituted C 2-6 Alkenyl, one or more R b-4 Substituted C 2-6 Alkynyl, with one or more R b-5 Substituted C 3-8 Cycloalkyl, with one or more R b-6 substituted 3-10 membered heterocyclic group, substituted by one or more R b-7 Substituted C 6-10 Aryl or one or more R b-8 substituted 5-14 membered heteroaryl;

[0033] Each R b-1 , R b-2 , R b-3 , R b-4 , R b-5 , R b-6 , R b-7 and R b-8 are each independently deuterium, halogen, cyano, -OR 6 or -NR 6 R 6 ;

[0034] Each R 6 are independently hydrogen or C 1-6 alkyl;

[0035] m is 1, 2, 3, 4, 5 or 6.

[0036] The present invention provides a compound represented by formula (I), its tautomer, its pharmaceutically acceptable salt, its solvate or its pharmaceutically acceptable salt solvate:

[0037]

[0038] in

[0039] Selected from:

[0040]

[0041]

[0042] Each X is independently N or CR 5 ;

[0043] R 1 is -C(O)NH2;

[0044] R 2 is -NH2;

[0045] R 3 Independently for C 6-10 Aryl, 5-14 membered heteroaryl, C 3-8 Cycloalkyl, 3-10 membered heterocyclic group, 3a Substituted C 6-10 Aryl, one or more R 3b substituted 5-14 membered heteroaryl, substituted by one or more R 3c Substituted C 3-8 Cycloalkyl or one or more R 3d substituted 3-10 membered heterocyclic group;

[0046] Each R 3a , R3b , R 3c and R 3d are independently deuterium, halogen, cyano, oxo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl, 5-14 membered heteroaryl, -OR 4 、-NR 4 R 4 、-C(=O)R 4 、-C(=O)OR 4 、-OC(=O)R 4 、-C(=O)NR 4 R 4 、-NR 4 C(=O)R 4 、-NR 4 C(=O)NR 4 R 4 、-NR 4 S(=O)R 4 、-NR 4 S(=O)2R 4 、-NR 4 S(=O)NR 4 R 4 、-NR 4 S(=O)2NR 4 R 4 、-S(=O)R 4 、-S(=O)2R 4 、-S(=O)NR 4 R 4 、-S(=O)2NR 4 R 4 、-P(=O)R 4 R 4 、-P(=O)(OR 4 2. One or more R 3-a Substituted C 1-6 Alkyl, with one or more R 3-b Substituted C 2-6 Alkenyl, one or more R 3-c Substituted C 2-6 Alkynyl, with one or more R 3-d Substituted C 3-8 Cycloalkyl, with one or more R 3-e substituted 3-10 membered heterocyclic group, substituted by one or more R 3-f Substituted C 6-10 Aryl or one or more R 3-gsubstituted 5-14 membered heteroaryl;

[0047] Each R 3-a , R 3-b , R 3-c , R 3-d , R 3-e , R 3-f and R 3-g are independently deuterium, halogen, C 1-6 Alkyl, -OC 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -OR 4 、-NR 4 R 4 、-C(=O)R 4 、-C(=O)OR 4 、-OC(=O)R 4 、-C(=O)NR 4 R 4 、-NR 4 C(=O)R 4 、-NR 4 C(=O)NR 4 R 4 、-NR 4 S(=O)R 4 、-NR 4 S(=O)2R 4 、-NR 4 S(=O)NR 4 R 4 、-NR 4 S(=O)2NR 4 R 4 、-S(=O)R 4 、-S(=O)2R 4 、-S(=O)NR 4 R 4 、-S(=O)2NR 4 R 4 、-P(=O)R 4 R 4 OR-P(=O)(OR 4 )2;

[0048] Each R 4 are independently hydrogen, C 1-6 Alkyl, -OC 1-6 Alkyl, C 3-8 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl, 5-14 membered heteroaryl, substituted by one or more R 4a Substituted C 1-6 Alkyl, with one or more R4b Replaced-OC 1-6 Alkyl, with one or more R 4c Substituted C 3-8 Cycloalkyl, with one or more R 4d substituted 3-10 membered heterocyclic group, substituted by one or more R 4e Substituted C 6-10 Aryl or one or more R 4f substituted 5-14 membered heteroaryl;

[0049] or two R 4 Together with the nitrogen atom or phosphorus atom to which they are commonly attached, they independently form a 3-10 membered heterocyclic group or are replaced by one or more R 4g substituted 3-10 membered heterocyclic group;

[0050] Each R 4a , R 4b , R 4c , R 4d , R 4e , R 4f and R 4g are independently deuterium, halogen, oxo, cyano, hydroxyl, nitro, C 1-6 Alkyl, -OC 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, -OC 3-8 Cycloalkyl, 3-10 membered heterocyclic group, -O-3-10 membered heterocyclic group, C 6-10 Aryl, 5-14 membered heteroaryl, -N(R 6 )2, -C(=O)R 6 、-C(=O)OR 6 、-OC(=O)R 6 、-C(=O)N(R 6 )2.-NR 6 C(=O)R 6 、-NR 6 C(=O)N(R 6 )2.-NR 6 S(=O)R 6 、-NR 6 S(=O)2R 6 、-NR 6 S(=O)N(R 6 )2.-NR 6 S(=O)2N(R 6 )2, -S(=O)R 6 、-S(=O)2R 6 、-S(=O)N(R 6)2、-S(=O)2N(R 6 )2, -P(=O)R 6 R 6 、-P(=O)(OR 6 2. One or more R 4-a Substituted C 1-6 Alkyl, with one or more R 4-b Replaced-OC 1-6 Alkyl, with one or more R 4-c Substituted C 3-8 Cycloalkyl, with one or more R 4-d substituted 3-10 membered heterocyclic group, substituted by one or more R 4-e Substituted C 6-10 Aryl or one or more R 4-f substituted 5-14 membered heteroaryl;

[0051] Each R 4-a , R 4-b , R 4-c , R 4-d , R 4-e and R 4-f are independently deuterium, halogen, cyano, hydroxyl, C 1-6 Alkyl, -OC 1-6 Alkyl, C 3-8 Cycloalkyl, -OC 3-8 Cycloalkyl, 3-10 membered heterocyclic group, -O-3-10 membered heterocyclic group, C 6-10 Aryl, 5-14 membered heteroaryl, -N(R 6 )2, -C(=O)R 6 、-C(=O)OR 6 、-OC(=O)R 6 、-C(=O)N(R 6 )2.-NR 6 C(=O)R 6 、-NR 6 C(=O)N(R 6 )2.-NR 6 S(=O)R 6 、-NR 6 S(=O)2R 6 、-NR 6 S(=O)N(R 6 )2.-NR 6 S(=O)2N(R 6 )2, -S(=O)R 6 、-S(=O)2R 6 、-S(=O)N(R 6 )2、-S(=O)2N(R6 )2, -P(=O)R 6 R 6 、-P(=O)(OR 6 2. One or more R 4 -a-1 Substituted C 1-6 Alkyl, with one or more R 4-a-2 Replaced-OC 1-6 Alkyl, with one or more R 4-a-3 Substituted C 3-8 Cycloalkyl, with one or more R 4-a-4 Replaced-OC 3-8 Cycloalkyl, with one or more R 4-a-5 substituted 3-10 membered heterocyclic group, substituted by one or more R 4-a-6 -O-3-10 membered heterocyclic group, substituted by one or more R 4-a-7 Substituted C 6-10 Aryl or one or more R 4-a-8 substituted 5-14 membered heteroaryl;

[0052] Each R 4-a-1 , R 4-a-2 , R 4-a-3 , R 4-a-4 , R 4-a-5 , R 4-a-6 , R 4-a-7 and R 4-a-8 are independently deuterium, halogen, cyano, hydroxyl, C 1-6 Alkyl, -OC 1-6 Alkyl, C 3-8 Cycloalkyl, -OC 3-8 Cycloalkyl, 3-10 membered heterocyclic group, -O-3-10 membered heterocyclic group, C 6-10 Aryl, 5-14 membered heteroaryl, -N(R 6 )2, -C(=O)R 6 、-C(=O)OR 6 、-OC(=O)R 6 、-C(=O)N(R 6 )2.-NR 6 C(=O)R 6 、-NR 6 C(=O)N(R 6 )2.-NR 6 S(=O)R 6 、-NR 6 S(=O)2R 6 、-NR 6 S(=O)N(R 6 )2.-NR 6S(=O)2N(R 6 )2, -S(=O)R 6 、-S(=O)2R 6 、-S(=O)N(R 6 )2、-S(=O)2N(R 6 )2, -P(=O)R 6 R 6 OR-P(=O)(OR 6 )2;

[0053] Each R 5 are independently hydrogen, deuterium, halogen, cyano, oxo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl, 5-14 membered heteroaryl, -OR 4 、-SR 4 、-NR 4 R 4 、-C(=O)R 4 、-C(=O)OR 4 、-OC(=O)R 4 、-C(=O)NR 4 R 4 、-NR 4 C(=O)R 4 、-NR 4 C(=O)NR 4 R 4 、-NR 4 S(=O)R 4 、-NR 4 S(=O)2R 4 、-NR 4 S(=O)NR 4 R 4 、-NR 4 S(=O)2NR 4 R 4 、-S(=O)R 4 、-S(=O)2R 4 、-S(=O)NR 4 R 4 、-S(=O)2NR 4 R 4 、-P(=O)R 4 R 4 、-P(=O)(OR 4 2. One or more R 5a Substituted C 1-6 Alkyl, with one or more R5b Substituted C 2-6 Alkenyl, one or more R 5c Substituted C 2-6 Alkynyl, with one or more R 5d Substituted C 3-8 Cycloalkyl, with one or more R 5e substituted 3-10 membered heterocyclic group, substituted by one or more R 5f Substituted C 6-10 Aryl or one or more R 5g substituted 5-14 membered heteroaryl;

[0054] Each R 5a , R 5b , R 5c , R 5d , R 5e , R 5f and R 5g are independently deuterium, halogen, cyano, oxo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl, 5-14 membered heteroaryl, -SR 4 、-OR 4 、-NR 4 R 4 、-C(=O)R 4 、-C(=O)OR 4 、-OC(=O)R 4 、-C(=O)NR 4 R 4 、-NR 4 C(=O)R 4 、-NR 4 C(=O)NR 4 R 4 、-NR 4 S(=O)R 4 、-NR 4 S(=O)2R 4 、-NR 4 S(=O)NR 4 R 4 、-NR 4 S(=O)2NR 4 R 4 、-S(=O)R 4 、-S(=O)2R 4 、-S(=O)NR 4 R 4 、-S(=O)2NR 4 R4 、-P(=O)R 4 R 4 OR-P(=O)(OR 4 )2;

[0055] Each R a are independently hydrogen, deuterium, halogen, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl, 5-14 membered heteroaryl, -OR 4 、-NR 4 R 4 、-C(=O)R 4 、-C(=O)OR 4 、-OC(=O)R 4 、-C(=O)NR 4 R 4 、-NR 4 C(=O)R 4 、-NR 4 C(=O)NR 4 R 4 、-NR 4 S(=O)R 4 、-NR 4 S(=O)2R 4 、-NR 4 S(=O)NR 4 R 4 、-NR 4 S(=O)2NR 4 R 4 、-S(=O)R 4 、-S(=O)2R 4 、-S(=O)NR 4 R 4 、-S(=O)2NR 4 R 4 、-P(=O)R 4 R 4 、-P(=O)(OR 4 2. One or more R a-1 Substituted C 1-6 Alkyl, with one or more R a-2 Substituted C 2-6 Alkenyl, one or more R a-3 Substituted C 2-6 Alkynyl, with one or more R a-4 Substituted C 3-8 Cycloalkyl, with one or more R a-5substituted 3-10 membered heterocyclic group, substituted by one or more R a-6 Substituted C 6-10 Aryl or one or more R a-7 substituted 5-14 membered heteroaryl;

[0056] Each R a-1 , R a-2 , R a-3 , R a-4 , R a-5 , R a-6 and R a-7 are each independently deuterium, halogen, cyano, -OR 6 or -NR 6 R 6 ;

[0057] Each R b are independently hydrogen, C 1-6 Alkyl, -OC 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl, 5-14 membered heteroaryl, substituted by one or more R b-1 Substituted C 1-6 Alkyl, with one or more R b-2 Replaced-OC 1-6 Alkyl, with one or more R b-3 Substituted C 2-6 Alkenyl, one or more R b-4 Substituted C 2-6 Alkynyl, with one or more R b-5 Substituted C 3-8 Cycloalkyl, with one or more R b-6 substituted 3-10 membered heterocyclic group, substituted by one or more R b-7 Substituted C 6-10 Aryl or one or more R b-8 substituted 5-14 membered heteroaryl;

[0058] Each R b-1 , R b-2 , R b-3 , R b-4 , R b-5 , R b-6 , R b-7 and R b-8 are each independently deuterium, halogen, cyano, -OR 6 or -NR 6 R 6 ;

[0059] Each R6 are independently hydrogen or C 1-6 alkyl;

[0060] m is 1, 2, 3, 4, 5 or 6.

[0061] In certain preferred embodiments of the present invention, certain groups in the compound as shown in formula (I), its tautomers, its pharmaceutically acceptable salts, its solvates or solvates of its pharmaceutically acceptable salts are defined as follows, and the unmentioned groups are the same as those described in any embodiment of the present application (referred to as "in a certain embodiment of the present invention").

[0062] In a certain embodiment, the compound represented by formula (I) is not the following compound:

[0063]

[0064]

[0065]

[0066]

[0067]

[0068]

[0069] In one plan, Selected from:

[0070]

[0071]

[0072] In one embodiment, the compound represented by formula (I) is a stereoisomer or a mixture thereof. For example, when it contains one chiral center, the compound represented by formula (I) is an R configuration, an S configuration, or an R, S configuration racemate.

[0073] In one scheme, when R 5 For-OR 4 or -SR 4 When R 4 In the above, each 3-10 membered heterocyclic group can be independently a 5-8 membered heterocyclic alkyl group; preferably, the heteroatom of the 5-8 membered heterocyclic alkyl group can be N, and the number of heteroatoms can be independently 1, 2 or 3, and each 5-8 membered heterocyclic alkyl group can be independently a monocyclic or bicyclic ring, and the bicyclic ring can be a bridged ring; for example, tetrahydropyrrolyl, piperidinyl, Another example More preferably, the for or a mixture of the two, for Or a mixture of both.

[0074] In one scheme, when R 5 For-SR 4 When R 4 In the above, each 3-10 membered heterocyclic group can be independently a 5-8 membered heterocyclic alkyl group; preferably, the heteroatom of the 5-8 membered heterocyclic alkyl group can be N, and the number of heteroatoms can be independently 1, 2 or 3, and each 5-8 membered heterocyclic alkyl group can be independently a monocyclic or bicyclic ring, and the bicyclic ring can be a bridged ring; for example, piperidinyl, and for example

[0075] In one scheme, when R 5 For-SR 4 When R 4a Each C 3-8 Cycloalkyl groups independently may be cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, for example cyclopropyl or cyclobutyl.

[0076] In one scheme, each R 5 Independently for C 1-6 Alkyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, 3-10 membered heterocyclyl, 5-14 membered heteroaryl, -OR 4 、-SR 4 , by one or more R 5a Substituted C 1-6 Alkyl, with one or more R 5c Substituted C 2-6 Alkynyl, with one or more R 5d Substituted C 3-8 Cycloalkyl, with one or more R 5e substituted 3-10 membered heterocyclic group, or one or more R 5g substituted 5-14 membered heteroaryl; preferably, each R 5 Independently for C 1-6 Alkyl, C 3-8 Cycloalkyl, -OR 4 、-SR 4 , by one or more R 5c Substituted C 2-6 Alkynyl, with one or more R 5e substituted 3-10 membered heterocyclic group, or one or more R 5g substituted 5-14 membered heteroaryl; further preferably, each R 5 Independently for C 1-6 Alkyl, -OR4 or -SR 4 .

[0077] In one scheme, each R 5a , R 5c , R 5d , R 5e and R 5g are independently deuterium, halogen, cyano, C 1-6 Alkyl, -SR 4 、-OR 4 or -NR 4 R 4 .

[0078] In one plan, Selected from: Preferably Selected from More preferably Selected from More preferably Selected from

[0079] In one scheme, each R 5 independently CH3,

[0080] In one plan, Selected from:

[0081] Each X is independently N or CR 5 ;

[0082] R 1 is -C(O)NH2;

[0083] R 2 is -NH2;

[0084] R 3 Independently for C 6-10 Aryl, 5-14 membered heteroaryl, substituted by one or more R 3a Substituted C 6-10 Aryl or one or more R 3b substituted 5-14 membered heteroaryl;

[0085] Each R 3a and R 3b are independently deuterium, halogen, cyano, C 1-6 Alkyl, -OR4 or -NR 4 R 4 ;

[0086] Each R 4 are independently hydrogen, C 1-6 Alkyl, with one or more R 4a Substituted C 1-6 Alkyl, C 3-8 Cycloalkyl, with one or more R 4c Substituted C 3-8 Cycloalkyl, 3-10 membered heterocyclic group or one or more R 4d substituted 3-10 membered heterocyclic group;

[0087] Each R 4a , R 4c and R 4d are independently deuterium, halogen, oxo, cyano, hydroxyl, nitro, C 1-6 Alkyl, -N(R 6 2. One or more R 4-a Substituted C 1-6 Alkyl, C 3-8 Cycloalkyl, with one or more R 4-c Substituted C 3-8 Cycloalkyl, 3-10 membered heterocyclic group, 4-d substituted 3-10 membered heterocyclic group;

[0088] Each R 4-a , R 4-c and R 4-d are independently deuterium, halogen, cyano, hydroxyl, C 1-6 Alkyl, -N(R 6 )2 or one or more R 4-a-1 Substituted C 1-6 alkyl;

[0089] Each R 4-a-1 are independently deuterium, halogen, cyano, hydroxyl, C 1-6 Alkyl or -N(R 6 )2;

[0090] Each R 5 are independently hydrogen, C 1-6 Alkyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, 3-10 membered heterocyclyl, 5-14 membered heteroaryl, -OR 4 、-SR 4 , by one or more R 5a Substituted C 1-6 Alkyl, with one or more R 5c Substituted C2-6 Alkynyl, with one or more R 5d Substituted C 3-8 Cycloalkyl, with one or more R 5e substituted 3-10 membered heterocyclic group or one or more R 5g substituted 5-14 membered heteroaryl;

[0091] Each R 5a , R 5c , R 5d , R 5e and R 5g are independently deuterium, halogen, cyano, C 1-6 Alkyl, -SR 4 、-OR 4 or -NR 4 R 4 ;

[0092] Each R a are independently hydrogen, deuterium, halogen, cyano, C 1-6 Alkyl, -OR 4 、-NR 4 R 4 or one or more R a-1 Substituted C 1-6 alkyl;

[0093] Each R a-1 are independently deuterium, halogen, cyano, -OR 6 or -NR 6 R 6 ;

[0094] R b are independently hydrogen, C 1-6 Alkyl or one or more R b-1 Substituted C 1-6 alkyl;

[0095] Each R b-1 are independently deuterium, halogen, cyano, -OR 6 or -NR 6 R 6 ;

[0096] Each R 6 are independently hydrogen or C 1-6 alkyl;

[0097] m is 1, 2, 3 or 4.

[0098] In one plan, Selected from:

[0099] Each X is independently N;

[0100] R 1 is -C(O)NH2;

[0101] R 2 is -NH2;

[0102] R 3 Independently for one or more R 3a Substituted C 6-10 Aryl or one or more R 3b substituted 5-14 membered heteroaryl;

[0103] Each R 3a are independently halogen, C 1-6 Alkyl or -OR 4 ;

[0104] Each R 3b are independently halogen or C 1-6 alkyl;

[0105] Each R 4 are independently hydrogen, C 1-6 Alkyl, with one or more R 4a Substituted C 1-6 Alkyl, 3-10 membered heterocyclic group or one or more R 4d substituted 3-10 membered heterocyclic group;

[0106] Each R 4a and R 4d are independently halogen, C 1-6 Alkyl, -N(R 6 2. One or more R 4-c Substituted C 3-8 Cycloalkyl or one or more R 4-d substituted 3-10 membered heterocyclic group;

[0107] Each R 4-c and R 4-d Each independently is C 1-6 Alkyl, -N(R 6 )2 or one or more R 4-a-1 Substituted C 1-6 alkyl;

[0108] Each R 4-a-1 are independently -N(R 6 )2;

[0109] Each R 5 Independently for C 1-6 Alkyl, C 3-8 Cycloalkyl, -OR 4 、-SR4 , by one or more R 5c Substituted C 2-6 Alkynyl, with one or more R 5e substituted 3-10 membered heterocyclic group, or one or more R 5g substituted 5-14 membered heteroaryl;

[0110] Each R 5c , R 5e and R 5g Each independently is C 1-6 Alkyl or -NR 4 R 4 ;

[0111] Each R a are independently hydrogen, halogen, cyano or C 1-6 alkyl;

[0112] R b Independently for C 1-6 alkyl;

[0113] Each R 6 are independently hydrogen or C 1-6 alkyl;

[0114] m is 1 or 2.

[0115] In one plan, Selected from

[0116] Each X is independently N;

[0117] R 1 is -C(O)NH2;

[0118] R 2 is -NH2;

[0119] R 3 Independently for one or more R 3a Substituted C 6-10 Aryl or one or more R 3b substituted 5-14 membered heteroaryl;

[0120] Each R 3a are independently halogen, C 1-6 Alkyl, -OH or -OC 1-6 alkyl;

[0121] Each R 3b are independently halogen or C 1-6 alkyl;

[0122] Each R 5 Independently for C1-6 Alkyl, C 3-8 Cycloalkyl, -OR 4 、-SR 4 , by one or more R 5c Substituted C 2-6 Alkynyl, with one or more R 5e substituted 3-10 membered heterocyclic group or one or more R 5g substituted 5-14 membered heteroaryl;

[0123] Each R 5c , R 5e and R 5g Each independently is C 1-6 Alkyl or -N(R 6 )2;

[0124] Each R 4 are independently hydrogen, C 1-6 Alkyl, with one or more R 4a Substituted C 1-6 Alkyl, 3-10 membered heterocyclic group or one or more R 4d substituted 3-10 membered heterocyclic group;

[0125] Each R 4a are independently halogen, C 1-6 Alkyl, -N(R 6 2. One or more R 4-c Substituted C 3-8 Cycloalkyl or one or more R 4-d substituted 3-10 membered heterocyclic group;

[0126] Each R 4d are independently halogen, C 1-6 Alkyl or -N(R 6 )2;

[0127] Each R 4-c and R 4-d Each independently is C 1-6 Alkyl, -N(R 6 )2 or one or more R 4-a-1 Substituted C 1-6 alkyl;

[0128] Each R 4-a-1 are independently -N(R 6 )2;

[0129] Each R a are independently hydrogen, halogen, cyano or C 1-6 alkyl;

[0130] Each R 6are independently hydrogen or C 1-6 alkyl;

[0131] m is 1 or 2.

[0132] In one plan, Selected from

[0133] Each X is independently N;

[0134] R 1 is -C(O)NH2;

[0135] R 2 is -NH2;

[0136] R 3 Independently for one or more R 3a Substituted C 6-10 Aryl;

[0137] Each R 3a Independently for C 1-6 Alkyl or -OH;

[0138] Each R 5 Independently for C 1-6 Alkyl, -OR 4 or -SR 4 ;

[0139] Each R 4 Independently for one or more R 4a Substituted C 1-6 Alkyl, 3-10 membered heterocyclic group or one or more R 4d substituted 3-10 membered heterocyclic group;

[0140] Each R 4a Independently for one or more R 4-c Substituted C 3-8 Cycloalkyl or one or more R 4-d substituted 3-10 membered heterocyclic group;

[0141] Each R 4d Independently for C 1-6 alkyl;

[0142] Each R 4-c and R 4-d Each independently is C 1-6 Alkyl or -N(R 6 )2;

[0143] Each R a are independently hydrogen or C 1-6 alkyl;

[0144] Each R 6 are independently hydrogen or C 1-6 alkyl;

[0145] m is 1 or 2.

[0146] In one scheme, each C 6-10 Aryl groups independently may be phenyl or naphthyl, for example phenyl.

[0147] In a certain embodiment, the heteroatom of each 5-14 membered heteroaryl group may independently be N, O or S, and the number of heteroatoms may independently be 1, 2 or 3; preferably, the heteroatom of each 5-14 membered heteroaryl group may independently be N, and the number of heteroatoms may independently be 1 or 2.

[0148] In a certain embodiment, each 5-14 membered heteroaryl group can independently be a 5-10 membered heteroaryl group.

[0149] In a certain embodiment, each 5-14 membered heteroaryl group can be independently monocyclic or polycyclic, and the polycyclic rings can be bridged, fused or spirocyclic; the polycyclic rings can be bicyclic or tricyclic.

[0150] In a certain embodiment, each 5-14 membered heteroaryl group can be independently a 5-6 membered monocyclic heteroaryl group or a 9-10 membered bicyclic heteroaryl group, and each 5-6 membered monocyclic heteroaryl group can be independently a pyrazolyl group, for example Each 9-10 membered bicyclic heteroaryl group independently may be indazolyl, for example

[0151] In one scheme, each C 3-8 Cycloalkyl groups independently may be cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, for example cyclopropyl or cyclobutyl.

[0152] In a certain embodiment, each 3-10-membered heterocyclyl and the 3-10-membered heterocyclyl in "-O-3-10-membered heterocyclyl" may independently be a 5-8-membered heterocyclyl.

[0153] In a certain embodiment, each 3-10 membered heterocyclyl and the 3-10 membered heterocyclyl in "-O-3-10 membered heterocyclyl" can independently be a 3-10 membered heterocycloalkyl or a 3-10 membered heterocycloalkenyl; preferably, each 3-10 membered heterocyclyl can independently be a 3-10 membered heterocycloalkyl.

[0154] In a certain embodiment, each 3-10 membered heterocyclic group and the 3-10 membered heterocyclic group in "-O-3-10 membered heterocyclic group" can independently be a monocyclic or polycyclic ring, and the polycyclic ring can be a bridged ring, a fused ring or a spiro ring, and the polycyclic ring can also be a bicyclic or a tricyclic ring. For example, each 3-10 membered heterocyclic group can independently be a monocyclic or a bicyclic ring; the bicyclic ring can be a bridged ring.

[0155] In a certain embodiment, the heteroatom of each 3-10 membered heterocyclyl and the 3-10 membered heterocyclyl in "-O-3-10 membered heterocyclyl" can independently be N, O or S, such as N; the number of heteroatoms can independently be 1, 2 or 3.

[0156] In a certain embodiment, each 3-10 membered heterocyclyl and the 3-10 membered heterocyclyl in "-O-3-10 membered heterocyclyl" can independently be a 5-8 membered heterocycloalkyl, the heteroatom of the 5-8 membered heterocycloalkyl can be N, and the number of heteroatoms can independently be 1, 2 or 3; each 5-8 membered heterocycloalkyl can independently be a monocyclic or bicyclic ring, and the bicyclic ring can be a bridged ring; for example, tetrahydropyrrolyl, piperidinyl or Another example

[0157] In one embodiment, each halogen can independently be fluorine, chlorine, bromine or iodine.

[0158] In one scheme, each C 1-6 Alkyl groups independently may be methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl or sec-butyl, for example methyl or ethyl.

[0159] In one scheme, each C 2-6 Alkenyl groups independently can be ethenyl, propenyl, allyl, butenyl or pentenyl.

[0160] In one scheme, each C 2-6 Alkynyl groups independently may be ethynyl, propynyl, propargyl, butynyl or pentynyl, for example

[0161] In one scheme, each -OC 1-6 The alkyl group may independently be -O-methyl, -O-ethyl, -O-n-propyl, -O-isopropyl, -O-n-butyl, -O-tert-butyl, -O-isobutyl or -O-sec-butyl.

[0162] In one scheme, each -OC 3-8 Cycloalkyl groups independently may be -O-cyclopropyl, -O-cyclobutyl, -O-cyclopentyl or -O-cyclohexyl, for example -O-cyclopropyl or -O-cyclobutyl.

[0163] In certain aspects, each "plurality" can independently be 2 or 3.

[0164] In one embodiment, m is 1, 2, 3 or 4.

[0165] In a certain aspect, each X independently can be N.

[0166] In one scheme, in R 3In the above, each 5-14 membered heteroaryl group may be independently a 5-6 membered monocyclic heteroaryl group or a 9-10 membered bicyclic heteroaryl group; preferably, each 5-6 membered monocyclic heteroaryl group may be independently a pyrazolyl group, for example Each 9-10 membered bicyclic heteroaryl group independently may be indazolyl, for example

[0167] In one scheme, in R 5 In the above, each 5-14 membered heteroaryl group may be independently a 5-6 membered monocyclic heteroaryl group, and each 5-6 membered monocyclic heteroaryl group may be independently a pyrazolyl group, for example

[0168] In one scheme, in R 5 In the above, each 3-10 membered heterocyclic group can be independently a 5-8 membered heterocyclic alkyl group; preferably, the heteroatom of the 5-8 membered heterocyclic alkyl group can be N, and the number of heteroatoms can be independently 1, 2 or 3, and each 5-8 membered heterocyclic alkyl group can be independently a monocyclic ring, such as tetrahydropyrrolyl; for example

[0169] In one scheme, when R 5 For-OR 4 When R 4 In the above, each 3-10 membered heterocyclic group may be independently a 5-8 membered heterocyclic alkyl group; preferably, the heteroatom of the 5-8 membered heterocyclic alkyl group may be N, the number of heteroatoms may be independently 1, 2 or 3, each 5-8 membered heterocyclic alkyl group may be independently a monocyclic or bicyclic ring, and the bicyclic ring may be a bridged ring; for example, tetrahydropyrrolyl, piperidinyl or Another example More preferably, the for Or a mixture of both.

[0170] In one scheme, in R 4a In the 4-d The 3-10-membered heterocyclic group in the substituted 3-10-membered heterocyclic group may independently be a 5-8-membered heterocycloalkyl group; preferably, the heteroatom of the 5-8-membered heterocycloalkyl group may be N, and the number of heteroatoms may independently be 1, 2 or 3, and each 5-8-membered heterocycloalkyl group may independently be a monocyclic ring, such as tetrahydropyrrolyl; for example More preferably, the Or a mixture of both.

[0171] In one scheme, in R 5 In each C 3-8 Cycloalkyl groups independently may be cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, for example cyclopropyl or cyclobutyl.

[0172] In one scheme, when R5 For-OR 4 When R 4a Each C 3-8 Cycloalkyl groups independently may be cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, for example cyclopropyl or cyclobutyl.

[0173] In one scheme, in R 5 In each C 2-6 Alkynyl groups independently may be ethynyl, propynyl, propargyl, butynyl or pentynyl, for example

[0174] In one scheme, each R 3a and R 3b In each C 1-6 The alkyl group independently may be methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl or sec-butyl, for example methyl or ethyl, preferably methyl.

[0175] In one scheme, in R 4 In each C 1-6 Alkyl is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl or sec-butyl, for example ethyl.

[0176] In one scheme, in R 4a In each C 1-6 Alkyl groups independently may be methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl or sec-butyl, for example methyl or ethyl.

[0177] In one scheme, in R 4d In each C 1-6 Alkyl groups independently may be methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl or sec-butyl, for example methyl or ethyl.

[0178] In one scheme, in R 4-d In each C 1-6 The alkyl group independently may be methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl or sec-butyl, for example methyl.

[0179] In one scheme, in R 4-a-1 In each C 1-6 The alkyl group independently may be methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl or sec-butyl, for example methyl.

[0180] In one scheme, in R 5 In each C 1-6 Alkyl groups independently may be methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl or sec-butyl, for example methyl or ethyl.

[0181] In one scheme, in R 6 In each C 1-6 The alkyl group independently may be methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl or sec-butyl, for example methyl or ethyl, preferably methyl.

[0182] In one scheme, in R a In each C 1-6 Alkyl is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl or sec-butyl, for example methyl.

[0183] In one scheme, in R b In each C 1-6 Alkyl is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl or sec-butyl, for example methyl.

[0184] In one scheme, in R 3 In each C 6-10 Aryl is independently phenyl or naphthyl, for example phenyl.

[0185] In one scenario, R 3 Independently for C 6-10 Aryl, 5-14 membered heteroaryl, substituted by one or more R 3a Substituted C 6-10 Aryl or one or more R 3b substituted 5-14 membered heteroaryl; preferably, R 3 Independently for one or more R 3a Substituted C 6-10 Aryl or one or more R 3b Substituted 5-14 membered heteroaryl.

[0186] In one scenario, R 3 Independently for one or more R 3a Substituted C 6-10 Aryl.

[0187] In one scheme, each R 3a and R 3b are independently deuterium, halogen, cyano, C 1-6 Alkyl, -OR 4 or -NR 4 R 4 Preferably, each R 3a are independently halogen, C 1-6 Alkyl or -OR 4 ; Each R 3b are independently halogen or C 1-6 alkyl.

[0188] In one scheme, each R 4 are independently hydrogen, C 1-6 Alkyl, with one or more R 4a Substituted C 1-6 Alkyl, C 3-8 Cycloalkyl, with one or more R 4c Substituted C 3-8 Cycloalkyl, 3-10 membered heterocyclic group or one or more R 4d substituted 3-10 membered heterocyclic group; preferably, each R 4 are independently hydrogen, C 1-6 Alkyl, with one or more R 4a Substituted C 1-6 Alkyl or one or more R 4d Substituted 3- to 10-membered heterocyclic group.

[0189] In one scheme, each R 4 are independently hydrogen, C 1-6 Alkyl, 3-10 membered heterocyclic group, one or more R 4a Substituted C 1-6 Alkyl or one or more R 4d Substituted 3- to 10-membered heterocyclic group.

[0190] In one scheme, each R 4a , R 4c and R 4d are independently deuterium, halogen, oxo, cyano, hydroxyl, nitro, C 1-6 Alkyl, with one or more R 4-a Substituted C 1-6 Alkyl, C 3-8 Cycloalkyl, with one or more R 4-c Substituted C 3-8 Cycloalkyl, 3-10 membered heterocyclic group, 4-d substituted 3-10 membered heterocyclic group; preferably, each R 4a and R 4d are independently halogen, C 1-6 Alkyl, -N(R 6 2. One or more R 4-c Substituted C 3-8 Cycloalkyl or one or more R 4-d Substituted 3-10 membered heterocyclic group.

[0191] In one scheme, each R 4a , R 4c and R 4d are independently deuterium, halogen, oxo, cyano, hydroxyl, nitro, C 1-6 Alkyl, -N(R6 2. One or more R 4-a Substituted C 1-6 Alkyl, C 3-8 Cycloalkyl, with one or more R 4-c Substituted C 3-8 Cycloalkyl, 3-10 membered heterocyclic group, 4-d Substituted 3- to 10-membered heterocyclic group.

[0192] In one scheme, each R 4-a , R 4-c and R 4-d are independently deuterium, halogen, cyano, hydroxyl, C 1-6 Alkyl, -N(R 6 )2 or one or more R 4-a-1 Substituted C 1-6 Alkyl; preferably, each R 4-c and R 4-d Each independently is C 1-6 Alkyl, -N(R 6 )2 or one or more R 4-a-1 Substituted C 1-6 alkyl.

[0193] In one scheme, each R 4-a-1 are independently deuterium, halogen, cyano, hydroxyl, C 1-6 Alkyl or -N(R 6 )2; Preferably, each R 4-a-1 are independently -N(R 6 )2.

[0194] In one scheme, each R 5 Independently for C 1-6 Alkyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, 3-10 membered heterocyclyl, 5-14 membered heteroaryl, -OR 4 , by one or more R 5a Substituted C 1-6 Alkyl, with one or more R 5c Substituted C 2-6 Alkynyl, with one or more R 5d Substituted C 3-8 Cycloalkyl, with one or more R 5e substituted 3-10 membered heterocyclic group, or one or more R 5g substituted 5-14 membered heteroaryl; preferably, each R 5 Independently for C 1-6 Alkyl, C 3-8 Cycloalkyl, -OR 4 , by one or more R5c Substituted C 2-6 Alkynyl, with one or more R 5e substituted 3-10 membered heterocyclic group, or one or more R 5g Substituted 5-14 membered heteroaryl.

[0195] In one scheme, each R 5a , R 5c , R 5d , R 5e and R 5g are independently deuterium, halogen, cyano, C 1-6 Alkyl, -OR 4 or -NR 4 R 4 Preferably, each R 5c , R 5e and R 5g Each independently is C 1-6 Alkyl or -NR 4 R 4 .

[0196] In one scheme, each R a are independently hydrogen, deuterium, halogen, cyano, C 1-6 Alkyl, -OR 4 、-NR 4 R 4 or one or more R a-1 Substituted C 1-6 Alkyl; preferably, each R a are independently hydrogen or C 1-6 alkyl.

[0197] In one scheme, each R a are independently hydrogen, halogen, cyano or C 1-6 alkyl;

[0198] In one scheme, each R a-1 are independently deuterium, halogen, cyano, -OR 6 or -NR 6 R 6 .

[0199] In one scenario, R b are independently hydrogen, C 1-6 Alkyl or one or more R b-1 Substituted C 1-6 Alkyl; preferably, R b C 1-6 alkyl.

[0200] In one scheme, each R b-1 are independently deuterium, halogen, cyano, -OR6 or -NR 6 R 6 .

[0201] In one scheme, each R 6 are independently hydrogen or C 1-6 alkyl.

[0202] In one scenario, R 3 Independently for one or more R 3a substituted phenyl, or one or more R 3b Substituted 9-10 membered bicyclic heteroaryl; preferably R 3 Independently for one or more R 3a Substituted phenyl.

[0203] In one scheme, each R 3a are independently halogen, C 1-6 Alkyl or -OH; each R 3b are independently halogen or C 1-6 alkyl.

[0204] In one scheme, each R 5 Independently for C 1-6 Alkyl, C 3-8 Cycloalkyl, -OR 4 , by one or more R 5c Substituted propynyl, substituted by one or more R 5e substituted tetrahydropyrrolyl, or substituted with one or more R 5g Substituted pyrazolyl; preferably each R 5 Independently for C 1-6 alkyl.

[0205] In one scheme, each R 5c , R 5e and R 5g Each independently is C 1-6 Alkyl or -NR 6 R 6 .

[0206] In one scheme, each R 4 Independently for C 1-6 Alkyl, with one or more R 4a Substituted methyl, substituted by one or more R 4a substituted ethyl, or one or more R 4d substituted 3-10 membered heterocyclic group; the 3-10 membered heterocyclic group is tetrahydropyrrolyl, piperidinyl or

[0207] In one scheme, each R 4a are independently halogen, C1-6 Alkyl, -N(R 6 2. One or more R 4-c Substituted C 3-8 Cycloalkyl or one or more R 4-d substituted 3-10 membered heterocyclic group; said C 3-8 The cycloalkyl group is cyclopropyl or cyclobutyl; the 3-10 membered heterocyclic group is tetrahydropyrrolyl, piperidinyl or

[0208] In one scheme, each R 4d are independently halogen, C 1-6 Alkyl or -N(R 6 )2.

[0209] In one scheme, each R 4-c and R 4-d Each independently is C 1-6 Alkyl, -N(R 6 )2 or one or more R 4 -a-1 Substituted C 1-6 alkyl.

[0210] In one scheme, each R 4-a-1 are independently -N(R 6 )2.

[0211] In one scheme, each R a are independently hydrogen or methyl.

[0212] In one scenario, R b It is methyl.

[0213] In one scheme, in R 3 In each R 4 are independently hydrogen or C 1-6 alkyl.

[0214] In one scheme, in R 5 In each R 4 are independently hydrogen, C 1-6 Alkyl, with one or more R 4a Substituted C 1-6 Alkyl or one or more R 4d substituted 3-10 membered heterocyclic group;

[0215] Each R 4a are independently halogen, C 1-6 Alkyl, -N(R 6 2. One or more R 4-c Substituted C 3-8 Cycloalkyl or one or more R 4-dsubstituted 3-10 membered heterocyclic group;

[0216] Each R 4d are independently halogen, C 1-6 Alkyl or -N(R 6 )2;

[0217] Each R 4-c and R 4-d Each independently is C 1-6 Alkyl, -N(R 6 )2 or one or more R 4-a-1 Substituted C 1-6 alkyl;

[0218] Each R 4-a-1 are independently -N(R 6 )2.

[0219] In one scheme, in R a In each R 4 are independently hydrogen or C 1-6 alkyl.

[0220] In one plan, Selected from: Preferably Selected from More preferably Selected from More preferably Selected from In one scenario, R 3 Independently

[0221] In one scenario, R 3 Independently In one scenario, R 3 for For example In one scheme, each R 5 are independently -CH3,

[0222] In one scenario, R a are independently hydrogen or -CH3.

[0223] In one scenario, R b is independently -CH3.

[0224] In one plan, Selected from:

[0225] Each X is independently N or CR 5 ;

[0226] R 1 is -C(O)NH2;

[0227] R 2 is -NH2;

[0228] R 3 Independently for C 6-10 Aryl, 5-14 membered heteroaryl, substituted by one or more R 3a Substituted C 6-10 Aryl or one or more R 3b substituted 5-14 membered heteroaryl;

[0229] Each R 3a and R 3b are independently deuterium, halogen, cyano, C 1-6 Alkyl, -OR 4 or -NR 4 R 4 ;

[0230] Each R 4 are independently hydrogen, C 1-6 Alkyl, with one or more R 4a Substituted C 1-6 Alkyl, C 3-8 Cycloalkyl, with one or more R 4c Substituted C 3-8 Cycloalkyl, 3-10 membered heterocyclic group or one or more R 4d substituted 3-10 membered heterocyclic group;

[0231] Each R 4a , R 4c and R 4d are independently deuterium, halogen, oxo, cyano, hydroxyl, nitro, C 1-6 Alkyl, with one or more R 4-a Substituted C 1-6 Alkyl, C 3-8 Cycloalkyl, with one or more R 4-c Substituted C 3-8 Cycloalkyl, 3-10 membered heterocyclic group, 4-d substituted 3-10 membered heterocyclic group;

[0232] Each R 4-a , R 4-c and R 4-d are independently deuterium, halogen, cyano, hydroxyl, C 1-6Alkyl, -N(R 6 )2 or one or more R 4-a-1 Substituted C 1-6 alkyl;

[0233] Each R 4-a-1 are independently deuterium, halogen, cyano, hydroxyl, C 1-6 Alkyl or -N(R 6 )2;

[0234] Each R 5 are independently hydrogen, C 1-6 Alkyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, 3-10 membered heterocyclyl, 5-14 membered heteroaryl, -OR 4 , by one or more R 5a Substituted C 1-6 Alkyl, with one or more R 5c Substituted C 2-6 Alkynyl, with one or more R 5d Substituted C 3-8 Cycloalkyl, with one or more R 5e substituted 3-10 membered heterocyclic group or one or more R 5g substituted 5-14 membered heteroaryl;

[0235] Each R 5a , R 5c , R 5d , R 5e and R 5g are independently deuterium, halogen, cyano, C 1-6 Alkyl, -OR 4 or -NR 4 R 4 ;

[0236] Each R a are independently hydrogen, deuterium, halogen, cyano, C 1-6 Alkyl, -OR 4 、-NR 4 R 4 or one or more R a-1 Substituted C 1-6 alkyl;

[0237] Each R a-1 are independently deuterium, halogen, cyano, -OR 6 or -NR 6 R 6 ;

[0238] R b are independently hydrogen, C 1-6 Alkyl or one or more Rb-1 Substituted C 1-6 alkyl;

[0239] Each R b-1 are independently deuterium, halogen, cyano, -OR 6 or -NR 6 R 6 ;

[0240] Each R 6 are independently hydrogen or C 1-6 alkyl;

[0241] m is 1, 2, 3 or 4.

[0242] In one plan, Selected from:

[0243] Each X is independently N;

[0244] R 1 is -C(O)NH2;

[0245] R 2 is -NH2;

[0246] R 3 Independently for one or more R 3a Substituted C 6-10 Aryl or one or more R 3b substituted 5-14 membered heteroaryl;

[0247] Each R 3a are independently halogen, C 1-6 Alkyl or -OR 4 ;

[0248] Each R 3b are independently halogen or C 1-6 alkyl;

[0249] Each R 4 are independently hydrogen, C 1-6 Alkyl, with one or more R 4a Substituted C 1-6 Alkyl or one or more R 4d substituted 3-10 membered heterocyclic group;

[0250] Each R 4a and R 4d are independently halogen, C 1-6 Alkyl, -N(R 6 2. One or more R 4-c Substituted C 3-8 Cycloalkyl or one or more R4-d substituted 3-10 membered heterocyclic group;

[0251] Each R 4-c and R 4-d Each independently is C 1-6 Alkyl, -N(R 6 )2 or one or more R 4-a-1 Substituted C 1-6 alkyl;

[0252] Each R 4-a-1 are independently -N(R 6 )2;

[0253] Each R 5 Independently for C 1-6 Alkyl, C 3-8 Cycloalkyl, -OR 4 , by one or more R 5c Substituted C 2-6 Alkynyl, with one or more R 5e substituted 3-10 membered heterocyclic group, or one or more R 5g substituted 5-14 membered heteroaryl;

[0254] Each R 5c , R 5e and R 5g Each independently is C 1-6 Alkyl or -NR 4 R 4 ;

[0255] Each R a are independently hydrogen or C 1-6 alkyl;

[0256] R b Independently for C 1-6 alkyl;

[0257] Each R 6 are independently hydrogen or C 1-6 alkyl;

[0258] m is 1 or 2.

[0259] In one plan, Selected from

[0260] Each X is independently N;

[0261] R 1 is -C(O)NH2;

[0262] R 2 is -NH2;

[0263] R 3 Independently for one or more R 3a Substituted C 6-10 Aryl or one or more R 3b substituted 5-14 membered heteroaryl;

[0264] Each R 3a are independently halogen, C 1-6 Alkyl, -OH or -OC 1-6 alkyl;

[0265] Each R 3b are independently halogen or C 1-6 alkyl;

[0266] Each R 5 Independently for C 1-6 Alkyl, C 3-8 Cycloalkyl, -OR 4 , by one or more R 5c Substituted C 2-6 Alkynyl, with one or more R 5e substituted 3-10 membered heterocyclic group or one or more R 5g substituted 5-14 membered heteroaryl;

[0267] Each R 5c , R 5e and R 5g Each independently is C 1-6 Alkyl or -N(R 6 )2;

[0268] Each R 4 are independently hydrogen, C 1-6 Alkyl, with one or more R 4a Substituted C 1-6 Alkyl or one or more R 4d substituted 3-10 membered heterocyclic group;

[0269] Each R 4a are independently halogen, C 1-6 Alkyl, -N(R 6 2. One or more R 4-c Substituted C 3-8 Cycloalkyl or one or more R 4-d substituted 3-10 membered heterocyclic group;

[0270] Each R 4d are independently halogen, C 1-6 Alkyl or -N(R 6 )2;

[0271] Each R 4-c and R4-d Each independently is C 1-6 Alkyl, -N(R 6 )2 or one or more R 4-a-1 Substituted C 1-6 alkyl;

[0272] Each R 4-a-1 are independently -N(R 6 )2;

[0273] Each R a are independently hydrogen or C 1-6 alkyl;

[0274] Each R 6 are independently hydrogen or C 1-6 alkyl;

[0275] m is 1 or 2.

[0276] In one plan, Selected from

[0277] Each X is independently N;

[0278] R 1 is -C(O)NH2;

[0279] R 2 is -NH2;

[0280] R 3 Independently for one or more R 3a Substituted C 6-10 Aryl;

[0281] Each R 3a are independently halogen, C 1-6 Alkyl or -OR 4 ;

[0282] Each R 4 are independently hydrogen or C 1-6 alkyl;

[0283] Each R 5 Independently for C 1-6 alkyl;

[0284] Each R a are independently hydrogen or C 1-6 alkyl;

[0285] m is 1 or 2.

[0286] In one plan, Selected from

[0287] R 1 is -C(O)NH2;

[0288] R 2 is -NH2;

[0289] R 3 Independently for one or more R 3a Substituted C 6-10 Aryl;

[0290] Each R 3a are independently halogen, C 1-6 Alkyl or -OR 4 ;

[0291] Each R 4 are independently hydrogen or C 1-6 alkyl;

[0292] Each R 5 Independently for C 1-6 alkyl.

[0293] In one plan, Selected from:

[0294] Each X is independently N;

[0295] R 1 is -C(O)NH2;

[0296] R 2 is -NH2;

[0297] R 3 Independently for one or more R 3a Substituted C 6-10 Aryl or one or more R 3b substituted 5-14 membered heteroaryl;

[0298] Each R 3a and R 3b are independently halogen, C 1-6 Alkyl or -OR 4 ;

[0299] Each R 4 are independently hydrogen, C 1-6 Alkyl, 3-10 membered heterocyclic group, one or more R 4a Substituted C 1-6 Alkyl or one or more R 4d substituted 3-10 membered heterocyclic group;

[0300] Each R 4a and R4d are independently halogen, C 1-6 Alkyl, -N(R 6 2. One or more R 4-c Substituted C 3-8 Cycloalkyl or one or more R 4-d substituted 3-10 membered heterocyclic group;

[0301] Each R 4-c and R 4-d Each independently is C 1-6 Alkyl, -N(R 6 )2 or one or more R 4-a-1 Substituted C 1-6 alkyl;

[0302] Each R 4-a-1 are independently -N(R 6 )2;

[0303] Each R 5 Independently for C 1-6 Alkyl, C 3-8 Cycloalkyl, -OR 4 , by one or more R 5c Substituted C 2-6 Alkynyl, with one or more R 5e substituted 3-10 membered heterocyclic group, or one or more R 5g substituted 5-14 membered heteroaryl;

[0304] Each R 5c , R 5e and R 5g Each independently is C 1-6 Alkyl or -NR 4 R 4 ;

[0305] Each R a are independently hydrogen, halogen, cyano or C 1-6 alkyl;

[0306] R b Independently for C 1-6 alkyl;

[0307] Each R 6 are independently hydrogen or C 1-6 alkyl;

[0308] m is 1 or 2.

[0309] In one plan, Selected from

[0310] Each X is independently N;

[0311] R 1 is -C(O)NH2;

[0312] R 2 is -NH2;

[0313] R 3 Independently for one or more R 3a Substituted C 6-10 Aryl;

[0314] Each R 3a Independently for C 1-6 Alkyl or -OR 4 ;

[0315] Each R 4 are independently hydrogen, 3-10 membered heterocyclic group, 4a Substituted C 1-6 Alkyl or one or more R 4d substituted 3-10 membered heterocyclic group;

[0316] Each R 4a and R 4d Each independently is C 1-6 Alkyl, with one or more R 4-c Substituted C 3-8 Cycloalkyl or one or more R 4-d substituted 3-10 membered heterocyclic group;

[0317] Each R 4-c and R 4-d Each independently is C 1-6 Alkyl or -N(R 6 )2;

[0318] Each R 5 Independently for C 1-6 Alkyl or -OR 4 ;

[0319] Each R a are independently hydrogen or C 1-6 alkyl;

[0320] Each R 6 are independently hydrogen or C 1-6 alkyl;

[0321] m is 1 or 2.

[0322] In one plan, Selected from

[0323] Each X is independently N;

[0324] R 1 is -C(O)NH2;

[0325] R 2 is -NH2;

[0326] R 3 Independently for one or more R 3a Substituted C 6-10 Aryl;

[0327] Each R 3a are independently halogen, C 1-6 Alkyl or -OH;

[0328] Each R 5 Independently for C 1-6 Alkyl, -OR 4 or -SR 4 ;

[0329] Each R 4 Independently for one or more R 4a Substituted C 1-6 Alkyl, 3-10 membered heterocyclic group or one or more R 4d substituted 3-10 membered heterocyclic group;

[0330] Each R 4a Independently for one or more R 4-c Substituted C 3-8 Cycloalkyl or one or more R 4-d substituted 3-10 membered heterocyclic group;

[0331] Each R 4d Independently for C 1-6 alkyl;

[0332] Each R 4-c and R 4-d Each independently is C 1-6 Alkyl or -N(R 6 )2;

[0333] Each R a are independently hydrogen or C 1-6 alkyl;

[0334] Each R 6 are independently hydrogen or C 1-6 alkyl;

[0335] m is 1 or 2.

[0336] In one embodiment, the compound represented by formula (I) is any of the following compounds:

[0337]

[0338]

[0339]

[0340]

[0341]

[0342] In one embodiment, the compound represented by formula (I) is any of the following compounds:

[0343] The compound that elutes first under the following conditions: supercritical fluid chromatography chiral separation, the chiral column is ChiralPak IK, 250×40mm, 10μm, the eluent is methanol (containing 0.1% ammonia) / CO2=30 / 70, the flow rate is 120mL / min, and the column temperature is 40°C; preferably, under the said conditions, the retention time of the compound that elutes first is 5.20min;

[0344] The compound that elutes later under the following conditions: supercritical fluid chromatography chiral separation, the chiral column is ChiralPak IK, 250×40mm, 10μm, the eluent is methanol (containing 0.1% ammonia) / CO2=30 / 70, the flow rate is 120mL / min, and the column temperature is 40°C; preferably, under the said conditions, the retention time of the compound that elutes later is 6.02min;

[0345] The compound that elutes first under the following conditions: supercritical fluid chromatography chiral separation, the chiral column is ChiralPak IC, 250×40mm, 10μm, the eluent is methanol (containing 0.2% ammonia) / CO2=35 / 65, the flow rate is 120mL / min, and the column temperature is 35°C; preferably, under the conditions, the retention time of the compound that elutes first is 2.46min;

[0346] The compound that elutes later under the following conditions: supercritical fluid chromatography chiral separation, the chiral column is ChiralPak IC, 250×40mm, 10μm, the eluent is methanol (containing 0.2% ammonia) / CO2=35 / 65, the flow rate is 120mL / min, and the column temperature is 35°C; preferably, under the said conditions, the retention time of the compound that elutes later is 2.99min;

[0347] Compounds that elute first under the following conditions: supercritical fluid chromatography chiral separation, chiral column: ChiralPak IC, 250×40 mm, 10 μm, eluent: methanol (containing 0.2% ammonia) / CO2=35 / 65, flow rate: 120 mL / min, column temperature: 35°C;

[0348] Compounds that elute under the following conditions: supercritical fluid chromatography chiral separation, chiral column: ChiralPak IC, 250×40 mm, 10 μm, eluent: methanol (containing 0.2% ammonia) / CO2=35 / 65, flow rate: 120 mL / min, column temperature: 35°C;

[0349] Compounds that elute first under the following conditions: supercritical fluid chromatography chiral separation, chiral column: ChiralPak IC, 250×40 mm, 10 μm, eluent: methanol (containing 0.2% ammonia) / CO2=35 / 65, flow rate: 120 mL / min, column temperature: 35°C;

[0350] Compounds that elute under the following conditions: supercritical fluid chromatography chiral separation, chiral column: ChiralPak IC, 250×40 mm, 10 μm, eluent: methanol (containing 0.2% ammonia) / CO2=35 / 65, flow rate: 120 mL / min, column temperature: 35°C.

[0351] The present invention also provides a pharmaceutical composition, comprising substance A and pharmaceutically acceptable excipients, wherein substance A is a compound as shown in formula (I) as described in any embodiment of the present invention, its tautomer, its pharmaceutically acceptable salt, its solvate or a solvate of its pharmaceutically acceptable salt.

[0352] In a certain embodiment, the pharmaceutical composition comprises a therapeutically effective amount of substance A and a pharmaceutically acceptable excipient.

[0353] The present invention also provides a use of a substance A or the above-mentioned pharmaceutical composition in the preparation of a PKMYT1 inhibitor, wherein the substance A is a compound as shown in formula (I) as described in any scheme of the present invention, a tautomer thereof, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof.

[0354] The present invention also provides a use of a substance A or the above-mentioned pharmaceutical composition in the preparation of a drug for preventing and / or treating a disease associated with PKMYT1, wherein the substance A is a compound as shown in formula (I) according to any scheme of the present invention, a tautomer thereof, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof.

[0355] In one embodiment, the disease associated with PKMYT1 is cancer.

[0356] The present invention also provides a use of a substance A or the above-mentioned pharmaceutical composition in the preparation of a drug, wherein the drug is used to treat and / or prevent cancer, and the substance A is a compound as shown in formula (I) as described in any embodiment of the present invention, its tautomer, its pharmaceutically acceptable salt, its solvate or a solvate of its pharmaceutically acceptable salt.

[0357] In one embodiment, the cancer may be colon cancer, breast cancer, lung cancer, brain cancer, ovarian cancer, uterine cancer, cervical cancer, cervical tumor, testicular cancer, kidney cancer, head or neck cancer, bone cancer, skin cancer, rectal cancer, liver cancer, prostate cancer, pancreatic cancer, esophageal cancer, colorectal cancer, gastric cancer, gastroesophageal cancer, thyroid cancer, bladder cancer, lymphoma, melanoma or sarcoma, preferably breast cancer, ovarian cancer, uterine tumor or gastroesophageal cancer; more preferably breast cancer or ovarian cancer.

[0358] In a certain embodiment, the lung cancer may be non-small cell lung cancer or small cell lung cancer.

[0359] The present invention also provides a method for preventing and / or treating cancer, the method comprising: administering a therapeutically effective amount of substance A or the above-mentioned pharmaceutical composition to a patient, wherein substance A is a compound as shown in formula (I) as described in any scheme of the present invention, its tautomer, its pharmaceutically acceptable salt, its solvate or a solvate of its pharmaceutically acceptable salt; the cancer may be colon cancer, breast cancer, lung cancer, brain cancer, ovarian cancer, uterine cancer, cervical cancer, cervical tumor, testicular cancer, kidney cancer, head or neck cancer, bone cancer, skin cancer, rectal cancer, liver cancer, prostate cancer, pancreatic cancer, esophageal cancer, colorectal cancer, gastric cancer, gastroesophageal cancer, thyroid cancer, bladder cancer, lymphoma, melanoma or sarcoma, preferably breast cancer, ovarian cancer, uterine tumor or gastroesophageal cancer; more preferably breast cancer or ovarian cancer.

[0360] The present invention also provides a method for preventing and / or treating a disease associated with PKMYT1, the method comprising: administering a therapeutically effective amount of substance A or the above-mentioned pharmaceutical composition to a patient, wherein substance A is a compound as shown in formula (I) as described in any scheme of the present invention, its tautomer, its pharmaceutically acceptable salt, its solvate or a solvate of its pharmaceutically acceptable salt; the disease may be colon cancer, breast cancer, lung cancer, brain cancer, ovarian cancer, uterine cancer, cervical cancer, cervical tumor, testicular cancer, kidney cancer, head or neck cancer, bone cancer, skin cancer, rectal cancer, liver cancer, prostate cancer, pancreatic cancer, esophageal cancer, colorectal cancer, gastric cancer, gastroesophageal cancer, thyroid cancer, bladder cancer, lymphoma, melanoma or sarcoma, preferably breast cancer, ovarian cancer, uterine tumor or gastroesophageal cancer; more preferably breast cancer or ovarian cancer.

[0361] Terminology explanation:

[0362] "Halogen" refers to F, Cl, Br, I.

[0363] Certain chemical groups defined herein are preceded by a simplified symbol to indicate the total number of carbon atoms present in the group. For example, a C1-C6 alkyl or C 1-6 Alkyl refers to an alkyl group as defined below having a total of 1, 2, 3, 4, 5 or 6 carbon atoms.

[0364] As used herein, numerical ranges such as 0 to 10, 1-6, 1-3, etc., defined in a substituent group indicate that the integers within the range, such as 1-6, are 1, 2, 3, 4, 5, or 6.

[0365] The term "comprising" is an open expression, that is, including the contents specified in the present invention but not excluding other contents.

[0366] The term "substituted by" or "substituted with" means that any one or more hydrogen atoms on a particular atom are replaced by a substituent as long as the valence state of the particular atom is normal and the compound after the substitution is stable.

[0367] In general, the term "substituted" or "substituted" means that one or more hydrogen atoms in a given structure are replaced by a specific substituent. Further, when the group is substituted by more than one of the substituents, the substituents are independent of each other, that is, the more than one substituents may be different or the same. Unless otherwise indicated, a substituent group may be substituted at each substitutable position of the substituted group. When more than one position in a given structural formula can be substituted by one or more substituents selected from a specific group, the substituents may be substituted at each position in the same or different manner.

[0368] As used herein, the terms "part," "moiety," "chemical moiety," "group," and "chemical group" refer to a specific segment or functional group in a molecule.

[0369] When a substituent is listed without indicating the atom through which it is attached to a chemical formula (including but not specifically mentioned compounds), such a substituent may be bonded via any atom thereof. Combinations of substituents and / or their variants are permitted only if such combinations result in stable compounds.

[0370] When a group is listed without explicitly indicating that it has a substituent, such group is only meant to be unsubstituted. For example, when "C 1-6 When "alkyl" is not limited to "substituted or unsubstituted", it only refers to "C 1-6 Alkyl" itself or "unsubstituted C 1-6 alkyl".

[0371] In various parts of the present invention, linking substituents are described. When the structure clearly requires a linking group, the Markush variable listed for that group should be understood as a linking group. For example, if the structure requires a linking group and the Markush group definition for that variable lists "alkyl", it should be understood that the "alkyl" represents a linked alkylene group.

[0372] In some specific structures, when an alkyl group is explicitly indicated as a linking group, the alkyl group represents a linking alkylene group, for example, the group "halo-C 1-6 C in "alkyl-" 1-6 Alkyl is understood to be C 1-6 Alkylene.

[0373] The term "stereoisomer" includes conformational isomers and configurational isomers, wherein configurational isomers mainly include cis-trans isomers and optical isomers. The compounds described in the present invention may exist in the form of stereoisomers, and therefore encompass all possible stereoisomer forms, including but not limited to cis-trans isomers, enantiomers, diastereomers, atropisomers, etc. The compounds described in the present invention may also exist in the form of any combination or any mixture of the aforementioned stereoisomers, such as an equal mixture of meso, racemate, atropisomers, and a single enantiomer, a single diastereomer or a mixture thereof, or a single atropisomer or a mixture thereof.

[0374] The term "tautomer" refers to functional isomers that result from the rapid shift of an atom between two positions in a molecule.

[0375] The term "alkyl" refers to a group having a specified number of carbon atoms (e.g., 1-6) is a linear or branched, saturated, monovalent hydrocarbon group. The alkyl group includes, but is not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, etc.

[0376] The term "alkenyl" refers to a group having the specified number of carbon atoms (e.g., C 2-6 ) a linear or branched, unsaturated, monovalent hydrocarbon group having a carbon-carbon sp 2 Double bond.

[0377] The term "alkynyl" refers to a radical having the specified number of carbon atoms (e.g., C 2-6 ), a linear or branched, unsaturated, monovalent hydrocarbon group having a carbon-carbon sp triple bond. Alkynyl groups include, but are not limited to: wait.

[0378] The term "cycloalkyl" refers to a cycloalkyl radical having a specified number of ring carbon atoms (e.g., 3-8 or C 3-12 ), saturated monocyclic, spirocyclic, bridged or paracyclic groups whose ring atoms consist only of carbon atoms. Cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.

[0379] The term "heterocyclyl" refers to a non-aromatic saturated or partially unsaturated cyclic group having a specified number of ring atoms (e.g., 3-12 members, 3-10 members, 3-8 members, 5-8 members or 4-8 members), a specified number of heteroatoms (e.g., 1, 2 or 3), and a specified type of heteroatoms (1, 2, 3 or 4 of N, P, O and S), including heterocycloalkyl or heterocycloalkenyl. The heterocyclyl may be monocyclic or polycyclic, and the polycyclic may be a cyclic, spirocyclic or bridged ring structure. Heterocyclyl includes, but is not limited to, azetidinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyrrolyl, piperidinyl, morpholinyl, piperazinyl, 2-azaspiro[3.3]heptyl, 1-azaspiro[3.3]heptyl, 2,5-diazaspiro[3.4]octyl, 2,6-diazaspiro[3.4]octyl, 2,7-diazaspiro[4.4]nonyl, 5-azaspiro[2.5]octyl, 5-azaspiro[3.4]octyl, 2,6-diazabicyclo[3.2.0]heptyl, 2-azabicyclo[3.2.0]heptyl, 2-azabicyclo[3.2.0]heptyl, 2-azabicyclo[3.4]octyl, 2,6-diazabicyclo[3.4]octyl, 2,7-diazabicyclo[3.4]nonyl, 2,6-diazabicyclo[3.2.0]heptyl, 2,5-diazabicyclo[3.4]octyl, 2,6-diazabicyclo[3.4]octyl, 2,7-diazabicyclo[3.4]nonyl, 2,5-diazabicyclo[3.4]octyl, 2,6-diazabicyclo[3.2.0]heptyl, 2,6-diazabicyclo[3.4]octyl, 2,6-diazabicyclo[3.2.0]heptyl, 2,5-diazabicyclo[3.4]oct ... Cyclo[4.1.0]heptyl, octahydroindolizine, 6-azabicyclo[3.1.1]heptyl, 8-azabicyclo[3.2.1]octyl, 3-azabicyclo[3.1.1]heptyl, 3-azabicyclo[3.2.1]octyl, dihydropyrrolyl, dihydrofuranyl, dihydropyridinyl, tetrahydropyridinyl, 1,2,3,4-tetrahydropyrimidinyl, 1,4,5,6-tetrahydropyrimidinyl, 1,6-dihydropyrimidinyl, 1-azabicyclo[2.2.2]octyl or 4,5-dihydropyrimidinyl, for example.

[0380] The term "heterocycloalkyl" refers to a saturated monocyclic, spirocyclic, bridged or paracyclic cyclic group with a specified number of ring atoms (e.g., 3-12, 3-10, 3-8, 5-8 or 4-8), a specified number of heteroatoms (e.g., 1, 2 or 3), and a specified heteroatom species (1, 2 or 3 of N, P, O and S). When it is polycyclic, each ring is saturated. Heterocycloalkyl includes, but is not limited to, azetidinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyrrolyl, piperidinyl, morpholinyl, piperazinyl, 2-azaspiro [3.3] heptyl, 1-azaspiro [3.3] heptyl, 2,5-diazaspiro [3.4] octyl, 2,6-diazaspiro [3.4] octyl, 2,7-diazaspiro [4.4] nonyl, 5-azaspiro [2.5] octyl, 5 -azaspiro[3.4]octyl, 2,6-diazabicyclo[3.2.0]heptyl, 2-azabicyclo[4.1.0]heptyl, octahydroindolizine, 6-azabicyclo[3.1.1]heptyl, 8-azabicyclo[3.2.1]octyl, 3-azabicyclo[3.1.1]heptyl, 1-azabicyclo[2.2.2]octyl or 3-azabicyclo[3.2.1]octyl, for example,

[0381] The term "heterocycloalkenyl" refers to an unsaturated monocyclic, spirocyclic, bridged or annular hydrocarbon cyclic group having a specified number of ring atoms (e.g., 5-14, 3-12, 3-10, 3-8, 5-8 or 4-8), a specified number of heteroatoms (e.g., 1, 2 or 3), a specified heteroatom type (one or more of N, P, O and S), which is not aromatic. Examples of heterocycloalkenyl include, but are not limited to, dihydropyrrolyl, dihydrofuranyl, dihydropyridyl, tetrahydropyridyl, 1,2,3,4-tetrahydropyrimidinyl, 1,4,5,6-tetrahydropyrimidinyl, 1,6-dihydropyrimidinyl or 4,5-dihydropyrimidinyl.

[0382] The term "aryl" refers to a radical having a specified number of ring carbon atoms (e.g., C 6-10 ) is an aromatic group. Examples of the aryl group include, but are not limited to, phenyl or naphthyl.

[0383] The term "heteroaryl" refers to a monocyclic or polycyclic cyclic group having a specified number of ring atoms (e.g., 5-14, 5-10, 9-10, or 5-6 members), a specified number of heteroatoms (e.g., 1, 2, or 3), a specified type of heteroatoms (one, two, or three of N, O, and S), and aromaticity. Heteroaryl includes, but is not limited to, furanyl, thienyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, indolyl, indazolyl, 1H-pyrazolo[3,4-b]pyridinyl, 1H-pyrrolo[2,3-b]pyridinyl, quinolyl, isoquinolyl, or quinazolinyl, for example

[0384] The term "one or more" when used to define the quantity of a group means 1, 2, 3, 4 or more.

[0385] In the claims, the “one or more” in “satisfies one or more of the following conditions” refers to 1, 2, 3, 4 or more, and the maximum value of the “more” is the maximum number of conditions recorded in each claim. For example, if a claim records 8 conditions, the “one or more” in “satisfies one or more of the following conditions” in the claim is any integer from 1 to 8, such as 1, 2, 3, 4, 5, 6, 7 or 8.

[0386] It will be understood by those skilled in the art that the structural formulas used in the present invention to describe groups are based on the conventions used in the art. It means that the corresponding group R is connected to other fragments and groups in the compound through this site.

[0387] The "-" at the end of a group means that the group is connected to other fragments in the molecule through this site. For example, CH3-C(=O)- means that the C(=O) in the acetyl group is connected to other fragments in the molecule.

[0388] When any variable (such as R 1a ) appears multiple times in the definition of a compound, the definition of the variable at each position is independent of the definition of the other positions, and their meanings are independent of each other and do not affect each other. 1a group-substituted, that is, the group may be replaced by up to 3 R 1a Replace, the position R 1a Definition and other positions R 1a In addition, combinations of substituents and / or variables are permissible only if such combinations result in stable compounds.

[0389] The term "pharmaceutically acceptable salt" refers to a salt prepared from a compound of the present invention and a relatively nontoxic, pharmaceutically acceptable acid or base. When the compound of the present invention contains a relatively acidic functional group, a base addition salt can be obtained by contacting a neutral form of such compound with a sufficient amount of a pharmaceutically acceptable base in a pure solution or a suitable inert solvent. When the compound of the present invention contains a relatively basic functional group, an acid addition salt can be obtained by contacting a neutral form of such compound with a sufficient amount of a pharmaceutically acceptable acid in a pure solution or a suitable inert solvent.

[0390] The term "solvate" refers to a substance formed by the combination of a compound and a solvent. Solvates are divided into stoichiometric solvates and non-stoichiometric solvates.

[0391] The term "pharmaceutically acceptable salt solvate" refers to a substance formed by the combination of a compound with a pharmaceutically acceptable acid or base and a solvent, wherein the amount of the solvent may be stoichiometric or non-stoichiometric.

[0392] The term "pharmaceutically acceptable excipients" refers to excipients and additives used in the production of drugs and the preparation of prescriptions. It is all substances contained in drug preparations except active ingredients. Please refer to the Pharmacopoeia of the People's Republic of China (2020 Edition) Part IV, or Handbook of Pharmaceutical Excipients (Raymond C Rowe, 2009 Sixth Edition).

[0393] The term "treat" refers to therapeutic treatment. When referring to a specific condition, treatment means: (1) ameliorating the disease or one or more biological manifestations of the condition, (2) interfering with (a) one or more points in the biological cascade leading to or causing the condition or (b) one or more biological manifestations of the condition, (3) ameliorating one or more symptoms, effects, or side effects associated with the condition or one or more symptoms, effects, or side effects associated with the condition or its treatment, or (4) slowing the progression of the condition or one or more biological manifestations of the condition.

[0394] The term "prevent" refers to the reduction of the risk of acquiring or developing a disease or disorder.

[0395] The term "therapeutically effective amount" refers to an amount of a compound that is sufficient to effectively treat a disease or condition described herein when administered to a patient."Therapeutically effective amount" will vary depending on the compound, the condition and its severity, and the age of the patient to be treated, but can be adjusted as needed by those skilled in the art.

[0396] The term "patient" refers to any animal that is about to or has been administered the compound or composition according to the embodiments of the present invention, preferably a mammal, and most preferably a human. The term "mammal" includes any mammal. Examples of mammals include, but are not limited to, cattle, horses, sheep, pigs, cats, dogs, mice, rats, rabbits, guinea pigs, monkeys, humans, etc., with humans being the most preferred.

[0397] The term "PKMYT1 inhibitor" refers to a substance that can specifically inhibit the activity of PKMYT1 in vivo.

[0398] In the application, the PKMYT1 inhibitor can be used in mammals; it can also be used in vitro, mainly for experimental purposes, for example: as a standard sample or control sample for comparison, or prepared into a kit according to conventional methods in the art to provide rapid detection of PKMYT1 inhibitory effects.

[0399] Without violating the common sense in the art, the above-mentioned preferred conditions can be arbitrarily combined to obtain the preferred embodiments of the present invention.

[0400] The reagents and raw materials used in the present invention are commercially available.

[0401] The positive and progressive effect of the present invention is that the heterocyclic compounds provided by the present invention show good cell growth inhibition effect on tumor cell lines of human breast cancer cells HCC1569 and human ovarian cancer cells OVCAR3. DETAILED DESCRIPTION

[0402] The present invention is further described below by way of examples, but the present invention is not limited to the scope of the examples. The experimental methods in the following examples without specifying specific conditions are carried out according to conventional methods and conditions, or selected according to the product specifications.

[0403] The following examples illustrate the present invention in more detail, but do not limit the present invention in any way.

[0404] The structure of the compound of the present invention is determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). The nuclear magnetic resonance chemical shift (δ) is given in parts per million (ppm). The nuclear magnetic resonance is measured using a Bruker AVANCE-400 nuclear magnetic spectrometer, the measuring solvent is deuterated dimethyl sulfoxide (DMSO-d6) or deuterated chloroform (CDCl3), and the internal standard is tetramethylsilane (TMS). The mass spectrum is measured using an Agilent 1260-6125B single quadrupole liquid chromatography-mass spectrometer (LCMS), which uses an electrospray ionization source (ESI).

[0405] For silica gel column chromatography, a Biotage Selekt flash preparative chromatograph and a Biotage BK-SIL silica gel prepacked column or an Agela Claricep Flash silica gel prepacked column of appropriate specifications were used.

[0406] The thin layer chromatography silica gel plate used was Yantai Huanghai HSGF254 silica gel plate, the specification of which was 0.15 mm to 0.20 mm, and the specification of which was 0.4 mm to 0.5 mm for preparative thin layer chromatography.

[0407] Preparative high performance liquid chromatography (preparative HPLC) used an AutoPurification LC preparative system equipped with an ACQUITY QDa mass spectrometer detector produced by Waters. The preparative chromatographic column used was a SunFire C18 5μm 19x250mm OBD preparative column. The mobile phase used different gradients of water (containing 0.1% formic acid)-acetonitrile to elute the compounds at a flow rate of 25mL / min.

[0408] Example 1

[0409] 7-Amino-6-(3-hydroxy-2,6-dimethylphenyl)-4-methyl-2,3-dihydrofuro[2,3-d]pyrrolo[2,3-b]pyridine-8-carboxamide (Compound 1)

[0410]

[0411] Step 1: 7-Nitro-4,5-dihydrofuro[3,2-c]pyridin-4-one

[0412]

[0413] Add 4,5-dihydrofurano[3,2-c]pyridin-4-one (15.5 g, 115.01 mmol), concentrated nitric acid (9.3 mL, 222.0 mmol) and trifluoroacetic acid (300 mL) to a 100 mL round-bottom flask. Stir the reaction mixture at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (methanol-dichloromethane, 0-10% gradient elution) to obtain the product (6 g, yield 27.52%) as a yellow solid. ESI-MS m / z: 180.9 [M+1] + . 1 H NMR (400MHz, DMSO-d6) δ12.61(s,1H),8.61(s,1H),8.15(d,J=2.1Hz,1H),7.12(d,J=2.1Hz,1H).

[0414] Step 2: 4-Chloro-7-nitrofuro[3,2-c]pyridine

[0415]

[0416] 7-Nitro-4,5-dihydrofuran[3,2-c]pyridin-4-one (6 g, 33.31 mmol) and phosphorus oxychloride (120 mL) were added to a 500 mL round-bottom flask, and the reaction solution was stirred at 90°C for 1 hour. The mixture was concentrated under reduced pressure, ethyl acetate (100 mL) was added to the residue, and then saturated sodium bicarbonate solution was added to adjust the pH to 8, the organic layer was separated, and the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane-petroleum ether, 0-50% gradient elution) to obtain the product (4 g, yield 57.45%) as a white solid. ESI-MS m / z: 199.0 [M+1] + . 1 H NMR (400MHz, DMSO-d6) δ9.13 (s, 1H), 8.55 (d, J = 2.3Hz, 1H), 7.41 (d, J = 2.2Hz, 1H).

[0417] Step 3: 4-Methyl-7-nitrofuro[3,2-c]pyridine

[0418]

[0419] Trimethylcyclotriboroxane (15.18 g, 60.45 mmol), 4-chloro-7-nitrofuro[3,2-c]pyridine (4 g, 20.15 mmol), (1,1'-bis(diphenylphosphino)ferrocene)palladium dichloride (1.47 g, 2.01 mmol), potassium carbonate (8.35 g, 60.44 mmol) and 1,4-dioxane (60 mL) and water (15 mL) were added to a 250 mL round-bottom flask. Under a nitrogen atmosphere, the reaction solution was stirred at 100 ° C for 2 hours. The reaction solution was cooled to room temperature, ethyl acetate (100 mL) was added for extraction, the organic phase was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate-petroleum ether, 0-50% gradient elution) to obtain the product (1.4 g, yield 37.06%), a white solid. ESI-MS m / z: 179.0 [M+1] + . 1 H NMR (400MHz, DMSO-d6) δ9.12 (s, 1H), 8.38 (d, J = 2.2Hz, 1H), 7.46 (d, J = 2.2Hz, 1H), 2.81 (s, 3H).

[0420] Step 4: 4-Methylfuro[3,2-c]pyridin-7-amine

[0421]

[0422] Add 4-methyl-7-nitrofurano[3,2-c]pyridine (1.3 g, 7.30 mmol), 5% palladium on carbon (0.47 g, 4.38 mmol) and methanol (40 mL) to a 100 mL eggplant-shaped bottle. Stir the reaction solution at room temperature for 4 hours under a hydrogen atmosphere. Filter the reaction solution, and concentrate the filtrate under reduced pressure to obtain the product (1 g, yield 82.12%) as a white solid, which is directly used in the next step. ESI-MS m / z: 149.1 [M+1] + . 1 H NMR (400MHz, DMSO-d6) δ7.97(d,J=2.2Hz,1H),7.74(d,J=1.1Hz,1H),6.99(d,J=2.2Hz,1H),5.28(s,2H),2.49(s,3H).

[0423] Step 5: 6-Bromo-4-methylfuro[3,2-c]pyridin-7-amine

[0424]

[0425] Add 4-methylfurano[3,2-c]pyridin-7-amine (1.4 g, 9.45 mmol), N-bromosuccinimide (1.68 g, 9.45 mmol) and dichloromethane (100 mL) to a 250 mL eggplant-shaped bottle. React at room temperature for 15 minutes. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane-petroleum ether, 0-50% gradient elution) to obtain the product (1.9 g, yield 87.67%), a white solid. ESI-MS m / z: 226.9 [M+1] + . 1 H NMR (400MHz, DMSO-d6) δ8.02(d,J=2.3Hz,1H),7.06(d,J=2.3Hz,1H),5.44(s,2H),2.48(s,3H).

[0426] Step 6: 6,7-Dibromo-4-methylfuro[3,2-c]pyridine

[0427]

[0428] In a 250mL round-bottom flask, add 6-bromo-4-methylfurano[3,2-c]pyridin-7-amine (1.9g, 8.37mmol), copper bromide (5.61g, 25.10mmol) and acetonitrile (80mL), and then add tert-butyl nitrite (2.59g, 25.10mmol) dropwise. After stirring at room temperature for 10 minutes, add water (200mL) and ethyl acetate (200mL) for extraction. Separate the organic phase, wash with saturated brine (50mL), dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure. The residue is purified by silica gel column chromatography (dichloromethane-petroleum ether, 0-70% gradient elution) to obtain the product (1.9g, yield 74.14%) as a white solid. ESI-MS m / z: 289.9[M+1] + . 1 H NMR (400MHz, DMSO-d6) δ8.21(d,J=2.3Hz,1H),7.33(d,J=2.3Hz,1H),2.65(s,3H).

[0429] Step 7: 7-Bromo-6-[(3-methoxy-2,6-dimethylphenyl)amino]-4-methylfuro[3,2-c]pyridine

[0430]

[0431] 3-methoxy-2,6-dimethylaniline (2.01 g, 13.27 mmol), 6,7-dibromo-4-methylfurano[3,2-c]pyridine (1.93 g, 6.63 mmol), cesium carbonate (4.32 g, 13.27 mmol), tris(dibenzylideneacetone)dipalladium (0.61 g, 0.66 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.58 g, 1.00 mmol) and ethylene glycol dimethyl ether (50 mL) were added to a 100 mL reaction tube. Under a nitrogen atmosphere, the reaction solution was stirred at 110 ° C for 2 hours. The reaction solution was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-petroleum ether, 0-20% gradient elution) to obtain the product (2.4 g, yield 81.12%) as a yellow solid. ESI-MS m / z: 361.0 [M+1] + . 1 H NMR(400MHz,DMSO-d6)δ7.52(s,1H),7.37(d,J=16.1Hz,1H),7.08–6.99(m,2H ), 6.80 (d, J = 8.3Hz, 1H), 3.78 (s, 3H), 2.30 (s, 3H), 2.05 (s, 3H), 1.96 (s, 3H).

[0432] Step 8: 7-amino-6-(3-methoxy-2,6-dimethylphenyl)-4-methylfuro[2,3-d]pyrrolo[2,3-b]pyridine-8-carbonitrile

[0433]

[0434] In a 25 mL reaction tube filled with ethylene glycol dimethyl ether (12 mL), 60% sodium hydride (199.31 mg, 4.98 mmol) was added, and a solution of malononitrile (329.17 mg, 4.98 mmol) dissolved in ethylene glycol dimethyl ether (12 mL) was added dropwise, and then stirred at room temperature for 0.5 hours. 7-Bromo-6-[(3-methoxy-2,6-dimethylphenyl)amino]-4-methylfuro[3,2-c]pyridine (300 mg, 0.83 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (60.77 mg, 0.08 mmol) were added, and the reaction solution was stirred in an oil bath at 130°C for 3 hours under argon protection. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-petroleum ether, 0-50% gradient elution) to obtain the product (230 mg, yield 75.96%) as a yellow solid. ESI-MS m / z: 347.0 [M+1] + . 1 H NMR(400MHz,DMSO-d6)δ7.99(d,J=2.3Hz,1H),7.25(d,J=8.4Hz,1H),7.16–7 .05(m,2H),6.80(s,2H),3.86(s,3H),2.50(s,3H),1.80(s,3H),1.71(s,3H).

[0435] Step 9: 7-amino-6-(3-methoxy-2,6-dimethylphenyl)-4-methylfuro[2,3-d]pyrrolo[2,3-b]pyridine-8-carboxamide

[0436]

[0437] 7-amino-6-(3-methoxy-2,6-dimethylphenyl)-4-methylfurano[2,3-d]pyrrolo[2,3-b]pyridine-8-carbonitrile (220 mg, 0.64 mmol) and sulfuric acid (8 mL) were added to a 50 mL round-bottom flask. The reaction solution was stirred at room temperature for 2 hours. The reaction solution was added dropwise to methanol (20 mL), ethyl acetate (120 mL) and water (60 mL) were added, and the pH was neutralized to 8 with concentrated ammonia water. The organic layer was separated, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the product (210 mg) as a white solid, which was directly used in the next step. ESI-MS m / z: 365.0[M+1] + . 1 H NMR (400MHz, DMSO-d6) δ8.01(d,J=2.3Hz,1H),7.26(d,J=8.5Hz,1H),7.15(d,J=2.3Hz, 1H),7.13–6.97(m,3H),6.82(s,2H),3.86(s,3H),2.38(s,3H)1.81(s,3H),1.71(s,3H).

[0438] Step 10: 7-amino-6-(3-methoxy-2,6-dimethylphenyl)-4-methyl-2,3-dihydrofuro[2,3-d]pyrrolo[2,3-b]pyridine-8-carboxamide

[0439]

[0440] 7-amino-6-(3-methoxy-2,6-dimethylphenyl)-4-methylfurano[2,3-d]pyrrolo[2,3-b]pyridine-8-carboxamide (50 mg, 0.14 mmol), 10% palladium on carbon (50 mg, 0.47 mmol), methanol (2 mL) and acetic acid (2 mL) were added to a 100 mL eggplant-shaped bottle. The reaction solution was stirred at 70 ° C for 6 hours under a hydrogen atmosphere. The reaction solution was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure to obtain a crude product (50 mg) as a white solid, which was directly used in the next step. ESI-MS m / z: 367.1 [M+1] + .

[0441] Step 11: 7-amino-6-(3-hydroxy-2,6-dimethylphenyl)-4-methyl-2,3-dihydrofuro[2,3-d]pyrrolo[2,3-b]pyridine-8-carboxamide

[0442]

[0443] 7-amino-6-(3-methoxy-2,6-dimethylphenyl)-4-methyl-2,3-dihydrofurano[2,3-d]pyrrolo[2,3-b]pyridine-8-carboxamide (50 mg, 0.14 mmol), boron tribromide (350.73 mg, 1.40 mmol) and dichloromethane (5 mL) were added to a 25 mL round-bottom flask. After stirring at room temperature for 10 minutes, methanol (5 mL) was added to quench the reaction. The reaction solution was concentrated under reduced pressure and the residue was purified by preparative HPLC to obtain the product (13 mg, yield 26.9%) as a white solid. ESI-MS m / z: 353.1 [M+1] + . 1 H NMR (400MHz, DMSO-d6) δ9.53(s,1H),7.15(s,1H),7.05(d,J=8.2Hz,1H),6.90(d,J=8.3Hz,1H),6.80(s ,1H),6.66(s,2H),4.77(t,J=8.6Hz,2H),3.18(t,J=8.6Hz,2H),2.21(s,3H),1.75(s,3H),1.66(s,3H). 13 C NMR (101MHz, DMSO-d6) δ168.01,154.96,154.62,151.38,146.51,144.14,133.24,128. 27,127.34,124.31,115.98,115.22,100.58,81.57,73.34,27.43,21.71,17.34,11.31.

[0444] Example 2

[0445] 7-Amino-6-(3-hydroxy-2,6-dimethylphenyl)-4-methylfuro[2,3-d]pyrrolo[2,3-b]pyridine-8-carboxamide (Compound 2)

[0446]

[0447]

[0448] 7-amino-6-(3-methoxy-2,6-dimethylphenyl)-4-methylfurano[2,3-d]pyrrolo[2,3-b]pyridine-8-carboxamide (80 mg, 0.22 mmol), boron tribromide (549.99 mg, 2.20 mmol) and dichloromethane (8 mL) were added to a 25 mL round-bottom flask. After stirring at room temperature for 20 minutes, methanol (5 mL) was added to quench the reaction. The reaction solution was concentrated under reduced pressure, and the residue was purified by preparative HPLC to obtain the product (28 mg, yield 36.4%) as a white solid. ESI-MS m / z: 351.1 [M+1] + . 1 HNMR(400MHz,DMSO-d6)δ9.55(s,1H),8.03(d,J=2.3Hz,1H),7.18(d,J=2.3Hz,1H), 7.09(d,J=8.3Hz,1H),6.94(d,J=8.3Hz,1H),2.53(s,3H),1.77(s,3H),1.68(s,3H). 13 C NMR(101MHz,DMSO-d6)δ167.92,163.51,154.71,151.22,150.08,144.30,141.41,132.9 7,128.44,127.38,124.38,118.60,116.22,106.47,101.25,82.30,21.12,17.34,11.33.

[0449] Example 3

[0450] 8-Amino-7-(3-hydroxy-2,6-dimethylphenyl)-5-methylpyrrolo[2,3-d]imidazo[2,1-f]pyrimidine-9-carboxamide (Compound 3)

[0451]

[0452] Step 1: 7,8-Dibromoimidazo[2,1-f]pyrimidine

[0453]

[0454] 5,6-dibromo-2-methylpyrimidine-4-amine (1.7 g, 6.37 mmol), 2-bromo-1,1-ethoxyethane (6.28 g, 31.84 mmol) and acetonitrile (40 mL) were added to a 100 mL pressure-resistant reaction tube, and the reaction solution was stirred at 120 ° C for 2 hours. After the reaction solution was cooled to room temperature, saturated sodium bicarbonate solution (50 mL) was added to quench. Extract with ethyl acetate (2×50 mL). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1:1, volume ratio) to obtain the product as a white solid (1.5 g, yield 76.90%). ESI-MS m / z: 289.9 [M+1] + . 1 H NMR (400MHz, DMSO-d6) δ8.17(d,J=1.6Hz,1H),7.73(d,J=1.6Hz,1H),2.77(s,3H).

[0455] Step 2: 8-Bromo-7-[(3-methoxy-2,6-dimethylphenyl)amino]-5-methylimidazo[2,1-f]pyrimidine

[0456]

[0457] 7,8-dibromo-5-methylimidazo[2,1-f]pyrimidine (1.5 g, 5.16 mmol), 3-methoxy-2,6-dimethylaniline (1.56 g, 10.31 mmol), tris(dibenzylideneacetone)dipalladium (0.47 g, 0.52 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.30 g, 0.52 mmol), cesium carbonate (3.36 g, 10.31 mmol) and ethylene glycol dimethyl ether (10 mL) were added to a 100 mL pressure-resistant reaction tube. Under argon protection, the reaction solution was stirred at 110 °C for 3 hours. After the reaction solution was cooled to room temperature, water (20 mL) was added to quench. Extracted with ethyl acetate (2×50 mL). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1:1, volume ratio) to obtain the product (800 mg, yield 34.36%) as a red oil. ESI-MS m / z: 361.0 [M+1] + . 1H NMR (400 MHz, DMSO-d6) δ7.80–7.70 (m, 2H), 7.40 (d, J = 1.6 Hz, 1H), 7.05 (d, J = 8.4 Hz, 1H), 6.82 (d, J = 8.4 Hz,1H),3.78(s,3H),2.49(s,3H),2.07(s,3H),1.98(d,J=7.4 Hz,3H).

[0458] Step 3: 8-amino-7-(3-methoxy-2,6-dimethylphenyl)-5-methylpyrrolo[2,3-d]imidazo[2,1-f]pyrimidine-9-carbonitrile

[0459]

[0460] Ethylene glycol dimethyl ether (10 mL) and 60% sodium hydride (59.79 mg, 2.49 mmol) were added to a 25 mL reaction tube, and a solution of ethylene glycol dimethyl ether (10 mL) of malononitrile (164.58 mg, 2.49 mmol) was added dropwise. After stirring at room temperature for 0.5 hours, 8-bromo-7-[(3-methoxy-2,6-dimethylphenyl)amino]-5-methylimidazo[2,1-f]pyrimidine (300 mg, 0.83 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (60.77 mg, 0.08 mmol) were added. Under argon protection, the reaction solution was stirred at 120 ° C for 1 hour. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1:1, volume ratio) to obtain the product as a brown solid (110 mg, yield 34.41%). ESI-MS m / z: 347.0 [M+1] + . 1 H NMR (400 MHz, DMSO-d6) δ7.87 (d, J = 1.5 Hz, 1H), 7.58 (d, J = 1.5 Hz, 1H), 7.26 (d, J = 8.5 Hz, 1H), 7.11 (d, J = 8.5 Hz,1H),6.66(s,2H),3.86(s,3H),2.63(s,3H),1.83(s,3H),1.74(s,3H).

[0461] Step 4: 8-amino-7-(3-hydroxy-2,6-dimethylphenyl)-5-methylpyrrolo[2,3-d]imidazo[2,1-f]pyrimidine-9-carbonitrile

[0462]

[0463] 8-amino-7-(3-methoxy-2,6-dimethylphenyl)-5-methylpyrrolo[2,3-d]imidazo[2,1-f]pyrimidine-9-carbonitrile (100 mg, 0.29 mmol), boron tribromide (723.23 mg, 2.89 mmol) and dichloromethane (10 mL) were added to a 10 mL round-bottom flask. The reaction solution was stirred at room temperature for 1 hour. Methanol (10 mL) was added to quench the reaction, and the reaction solution was concentrated under reduced pressure to obtain a crude product (100 mg) as a brown oil, which was directly used in the next step. ESI-MS m / z: 333.0 [M+1] + .

[0464] Step 5: 8-amino-7-(3-hydroxy-2,6-dimethylphenyl)-5-methylpyrrolo[2,3-d]imidazo[2,1-f]pyrimidine-9-carboxamide

[0465]

[0466] 8-amino-7-(3-hydroxy-2,6-dimethylphenyl)-5-methylpyrrolo[2,3-d]imidazo[2,1-f]pyrimidine-9-carbonitrile (100 mg, 0.30 mmol), hydrochloric acid (4 mol / L, 5 mL) and water (5 mL) were added to a 25 mL round-bottom flask. The reaction solution was stirred at 110°C overnight. The reaction solution was concentrated under reduced pressure, and the residue was purified by preparative HPLC to obtain the product as a white solid (12 mg, yield 11.19%). ESI-MS m / z: 351.0 [M+1] + . 1 H NMR (400MHz, DMSO-d6) δ9.70(d,J=2.4Hz,1H),9.58(s,1H),7.90(d,J=1.6Hz,1H),7.61(d,J=1.6Hz ,1H),7.15–7.01(m,2H),6.94(d,J=8.2Hz,1H),6.60(s,2H),2.66(s,3H),1.80(s,3H),1.71(s,3H).

[0467] Example 4

[0468] 8-amino-7-(3-hydroxy-2,6-dimethylphenyl)-5-methyl[1,2,4]triazacyclopenta[3,4-f]pyrrolo[2,3-d]pyrimidine-9-carboxamide and 8-amino-7-(3-hydroxy-2,6-dimethylphenyl)-5-methyl[1,2,4]triazacyclopenta[5,1-f]pyrrolo[2,3-d]pyrimidine-9-carboxamide (Compound 4-1 and Compound 4-2)

[0469]

[0470] Step 1: 5-Bromo-4,6-dichloro-2-methylpyrimidine

[0471]

[0472] 5-Bromo-6-chloro-2-methylpyrimidine-4-amine (10 g, 44.95 mmol), copper chloride (77.76 g, 449.50 mmol), tert-butyl nitrite (46.35 g, 449.50 mmol) and acetonitrile (300 mL) were added to a 1000 mL eggplant-shaped bottle. Under argon protection, the reaction solution was stirred at 80 ° C for 1 hour. The reaction solution was cooled to room temperature, diluted with water (1000 mL), and extracted with ethyl acetate (3×300 mL). The organic phases were combined, washed with saturated brine (1×500 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5:1, volume ratio) to obtain the product as an off-white solid (3.9 g, yield 34.07%). ESI-MS m / z: 241.0 [M+1] + . 1 H NMR (400MHz, DMSO-d6) δ2.58 (s, 3H).

[0473] Step 2: 5-Bromo-6-chloro-4-[(3-methoxy-2,6-dimethylphenyl)amino]-2-methylpyrimidine

[0474]

[0475] Dissolve 3-methoxy-2,6-dimethylaniline (2.00 g, 13.23 mmol) in tetrahydrofuran (50 mL), add lithium bis(trimethylsilyl)amide (1 mol / L, 19.84 mL, 19.84 mmol) under ice-water cooling, stir for 15 minutes, add 5-bromo-4,6-dichloro-2-methylpyrimidine (3.2 g, 13.23 mmol), and continue to stir at room temperature for 1 hour. Add saturated ammonium chloride solution (100 mL) to quench the reaction, and extract with ethyl acetate (2×50 mL). Combine the organic phases, wash with saturated brine (50 mL), dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure. The residue is chromatographed on a silica gel column (petroleum ether / ethyl acetate = 1:1, volume ratio) to obtain the product as a yellow oil (4.2 g, yield 88.98%). ESI-MS m / z: 356.0 [M+1] + . 1H NMR (400MHz, DMSO-d6) δ7.09(d,J=8.4Hz,1H),6.87(d,J=8.4Hz,1H),3.79(s,3H),3.67(s,1H),2.18(s,3H),2.03(s,3H),1.93(s,3H).

[0476] Step 3: 5-Bromo-6-methoxy-4-[(3-methoxy-2,6-dimethylphenyl)amino]-2-methylpyrimidine

[0477]

[0478] 5-Bromo-6-chloro-4-[(3-methoxy-2,6-dimethylphenyl)amino]-2-methylpyrimidine (4 g, 11.22 mmol), sodium methoxide (22.431 mL, 112.15 mmol) and methanol (100 mL) were added to a 250 mL round-bottom flask. The reaction solution was stirred at 70 ° C for 3 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1:1, volume ratio) to obtain the product, a white solid (3.3 g, yield 79.36%). ESI-MS m / z: 354.0 [M+1] + . 1 H NMR (400MHz, DMSO-d6) δ8.22(s,1H),7.06(d,J=8.4Hz,1H),6.84(d,J=8.4Hz,1H),3.89(s,3H),3.78(s,3H),2.16(s,3H),2.03(s,3H),1.93(s,3H).

[0479] Step 4: 6-amino-4-methoxy-7-(3-methoxy-2,6-dimethylphenyl)-2-methylpyrrolo[2,3-d]pyrimidine-5-carbonitrile

[0480]

[0481] Add ethylene glycol dimethyl ether (4 mL) and 60% sodium hydride (113.56 mg, 2.84 mmol) to a 25 mL reaction tube, then dropwise add a solution of ethylene glycol dimethyl ether (4 mL) in malononitrile (187.55 mg, 2.84 mmol), stir at room temperature for 0.5 hours, then add 5-bromo-6-methoxy-4-[(3-methoxy-2,6-dimethylphenyl)amino]-2-methylpyrimidine (200 mg, 0.57 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (60.77 mg, 0.08 mmol). Under argon protection, the reaction solution was stirred at 130 ° C for 2 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was chromatographed on a silica gel column (petroleum ether / ethyl acetate = 1:1, volume ratio) to obtain the product (190 mg, yield 94.22%). ESI-MS m / z: 338.0 [M+1] + . 1 H NMR (400MHz, Chloroform-d) δ7.22(d,J=8.4Hz,1H),6.98(d,J=8.5Hz,1H),4.56(s,2H),4.17(s,3H),3.89(s,3H),2.57(s,3H),1.93(s,3H),1.86(s,3H).

[0482] Step 5: 6-amino-4-hydroxy-7-(3-methoxy-2,6-dimethylphenyl)-2-methylpyrrolo[2,3-d]pyrimidine-5-carbonitrile

[0483]

[0484] Add 6-amino-4-methoxy-7-(3-methoxy-2,6-dimethylphenyl)-2-methylpyrrolo[2,3-d]pyrimidine-5-carbonitrile (200 mg, 0.59 mmol) and dioxane hydrochloride solution (4 mol / L, 10 mL) to a 25 mL round-bottom flask. Stir the reaction solution at 100 °C for 2 hours. Concentrate under reduced pressure to obtain a crude product as a white solid (200 mg), which is directly used in the next step. ESI-MS m / z: 324.0 [M+1] + . 1 H NMR (400MHz, DMSO-d6) δ12.12(s,1H),7.21(d,J=8.5Hz,1H),7.07(d,J=8.5Hz,1H),3.83(s,3H),2.17(s,3H),1.82(s,3H),1.73(s,3H).

[0485] Step 6: 6-amino-4-chloro-7-(3-methoxy-2,6-dimethylphenyl)-2-methylpyrrolo[2,3-d]pyrimidine-5-carbonitrile

[0486]

[0487] Add 6-amino-4-hydroxy-7-(3-methoxy-2,6-dimethylphenyl)-2-methylpyrrolo[2,3-d]pyrimidine-5-carbonitrile (30 mg, 0.09 mmol), acetonitrile (3 mL) and phosphorus oxychloride (0.2 mL) to a 20 mL round-bottom flask. Under argon protection, the reaction solution was stirred at 90 ° C for 1 hour. Concentrate under reduced pressure to obtain a crude product, a yellow oil (31 mg). Use it directly in the next step. ESI-MS m / z: 342.0 [M+1] + .

[0488] Step 7: 6-amino-4-hydrazino-7-(3-methoxy-2,6-dimethylphenyl)-2-methylpyrrolo[2,3-d]pyrimidine-5-carbonitrile

[0489]

[0490] In a 50 mL round-bottom flask, add 6-amino-4-chloro-7-(3-methoxy-2,6-dimethylphenyl)-2-methylpyrrolo[2,3-d]pyrimidine-5-carbonitrile (179 mg, 0.52 mmol), hydrazine hydrate (85%, 3 mL) and N-methylpyrrolidone (3 mL). The reaction solution was stirred at 80 ° C for 0.5 hours. The reaction solution was cooled to room temperature, diluted with water (10 mL), and extracted with ethyl acetate (3×20 mL). The organic phases were combined, washed with saturated brine (1×50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product, a light yellow oil (179 mg), which was directly used in the next step. ESI-MS m / z: 338.1 [M+1] + .

[0491] Step 8: 8-amino-7-(3-methoxy-2,6-dimethylphenyl)-5-methyl[1,2,4]triazacyclopenta[3,4-f]pyrrolo[2,3-d]pyrimidine-9-carbonitrile

[0492]

[0493] Add 6-amino-4-hydrazino-7-(3-methoxy-2,6-dimethylphenyl)-2-methylpyrrolo[2,3-d]pyrimidine-5-carbonitrile (179 mg, 0.53 mmol) and trimethyl orthoformate (8 mL) to a 25 mL eggplant-shaped bottle. Under argon protection, the reaction solution was stirred at 90 ° C for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane / ethyl acetate = 1:1, volume ratio) to obtain the product, an off-white solid (170 mg, yield 83.02%). ESI-MS m / z: 358.0 [M+1] + . 1 H NMR (400MHz, DMSO-d6) δ9.37(s,1H),7.26(d,J=8.5Hz,1H),7.12(d,J=8.5Hz,1H),6.81(s,2H),3.86(s,3H),2.70(s,3H),1.83(s,3H),1.75(s,3H).

[0494] Step 9: 8-amino-7-(3-methoxy-2,6-dimethylphenyl)-5-methyl[1,2,4]triazacyclopenta[3,4-f]pyrrolo[2,3-d]pyrimidine-9-carboxamide

[0495]

[0496] 8-amino-7-(3-methoxy-2,6-dimethylphenyl)-5-methyl[1,2,4]triazacyclopenta[3,4-f]pyrrolo[2,3-d]pyrimidine-9-carbonitrile (170 mg, 0.49 mmol) and sulfuric acid (10 mL) were added to a 50 mL round-bottom flask. The reaction solution was stirred at room temperature for 1 hour. The reaction solution was added dropwise to methanol (50 mL), ethyl acetate (100 mL) and water (100 mL) were added, and the pH value was adjusted to 8 with concentrated ammonia water. The organic phase was separated, washed with saturated brine (1×50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product (170 mg, yield 90.31%). ESI-MS m / z: 366.0[M+1] + . 1 H NMR (400MHz, DMSO-d6) δ9.40 (s, 1H), 9.04 (s, 1H), 7.28 (d, J = 8.5Hz, 1H), 7.22 (s, 1H), 7 .13(d,J=8.5Hz,1H),6.72(s,2H),3.87(s,3H),2.73(s,3H),1.85(s,3H),1.75(s,3H).

[0497] Step 10: 8-amino-7-(3-hydroxy-2,6-dimethylphenyl)-5-methyl[1,2,4]triazacyclopenta[3,4-f]pyrrolo[2,3-d]pyrimidine-9-carboxamide and 8-amino-7-(3-hydroxy-2,6-dimethylphenyl)-5-methyl[1,2,4]triazacyclopenta[5,1-f]pyrrolo[2,3-d]pyrimidine-9-carboxamide (Compound 4-1 and Compound 4-2)

[0498]

[0499] 8-amino-7-(3-methoxy-2,6-dimethylphenyl)-5-methyl[1,2,4]triazacyclopenta[3,4-f]pyrrolo[2,3-d]pyrimidine-9-carboxamide (50 mg, 0.14 mmol), boron tribromide (116.55 mg, 0.47 mmol) and dichloromethane (10 mL) were added to a 25 mL round-bottom flask. The reaction was allowed to react at room temperature for 10 minutes. Methanol (5 mL) was added to quench the reaction, and the mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC to obtain two products. Compound 4-1, white solid (preparative HPLC retention time 7.5 min, 17 mg, yield 10.4%). ESI-MS m / z: 352.0 [M+1] + . 1 H NMR (400MHz, DMSO-d6) δ9.61 (s, 1H), 9.39 (s, 1H), 9.04 (s, 1H), 7.25–7.16 (m, 1H), 7.10 (d, J=8.3Hz, 1H), 6.95 (d, J=8.3Hz, 1H), 6.67 (s, 2H), 2.73 (s, 3H), 1.80 (s, 3H), 1.71 (s, 3H); Compound 4-2, white solid (preparative HPLC retention time 10.05min, 13.21mg, yield 8%). ESI-MS m / z: 352.0 [M+1] + . 1 H NMR (400MHz, DMSO-d6) δ9.64(s,1H),8.88(s,1H),8.58(s,1H),7.22(s,1H),7.11(d,J= 8.3Hz,1H),6.96(d,J=8.3Hz,1H),6.81(s,2H),2.77(s,3H),1.80(s,3H),1.71(s,3H).

[0500] Example 5

[0501] 8-Amino-7-(3-hydroxy-2,6-dimethylphenyl)-5-methyl-2,3-dihydropyrrolo[2,3-d]imidazo[2,1-f]pyrimidine-9-carboxamide (Compound 5)

[0502]

[0503] Step 1: 6-amino-4-[(2-hydroxyethyl)amino]-7-(3-methoxy-2,6-dimethylphenyl)-2-methylpyrrolo[2,3-d]pyrimidine-5-carbonitrile

[0504]

[0505] 6-amino-4-chloro-7-(3-methoxy-2,6-dimethylphenyl)-2-methylpyrrolo[2,3-d]pyrimidine-5-carbonitrile (80 mg, 0.23 mmol), N-methylpyrrolidone (4 mL) and ethanolamine (1 mL, 16.67 mmol) were added to a 50 mL round-bottom flask. Under argon protection, the reaction solution was stirred at 80 ° C for 2 hours. Water (20 mL) was added to the reaction solution, and then extracted with ethyl acetate (100 mL). The organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-petroleum ether, 0-70% gradient elution) to obtain the product (83.2 mg, yield 97.01%), a colorless oil. ESI-MS m / z: 367.2 [M+H] + . 1 H NMR(400MHz,Chloroform-d)δ7.21(d,J=8.4Hz,1H),6.97(d,J=8.4Hz,1H),4.60(s,2H),3.89 (s,3H),3.39(t,J=7.2Hz,2H),2.86(s,3H),2.39(t,J=8.1Hz,2H),1.94(s,3H),1.86(s,3H).

[0506] Step 2: 8-amino-7-(3-methoxy-2,6-dimethylphenyl)-5-methyl-2,3-dihydropyrrolo[2,3-d]imidazo[2,1-f]pyrimidine-9-carbonitrile

[0507]

[0508] 6-amino-4-[(2-hydroxyethyl)amino]-7-(3-methoxy-2,6-dimethylphenyl)-2-methylpyrrolo[2,3-d]pyrimidine-5-carbonitrile (83.2 mg, 0.23 mmol), triethylamine (0.047 mL, 0.34 mmol) and dichloromethane (5 mL) were added to a 25 mL round-bottom flask. Methanesulfonyl chloride (39.01 mg, 0.34 mmol) was added under ice-water cooling, and the reaction solution was stirred at room temperature for 30 minutes. Water (20 mL) was added to the reaction solution, and then extracted with ethyl acetate (100 mL). The organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product, which was directly subjected to the next step. ESI-MS m / z: 349.2 [M+H] + .

[0509] Step 3: 8-amino-7-(3-hydroxy-2,6-dimethylphenyl)-5-methyl-2,3-dihydropyrrolo[2,3-d]imidazo[2,1-f]pyrimidine-9-carbonitrile

[0510]

[0511] 8-amino-7-(3-methoxy-2,6-dimethylphenyl)-5-methyl-2,3-dihydropyrrolo[2,3-d]imidazo[2,1-f]pyrimidine-9-carbonitrile (58 mg, 0.17 mmol), dichloromethane (3 mL) and boron tribromide (0.5 mL, 1.66 mmol) were added to a 25 mL round-bottom flask. The reaction solution was stirred at 0°C for 30 minutes. Methanol (5 mL) was added to the reaction solution to quench, water (10 mL) was added to dilute, and then neutralized with concentrated ammonia to weak alkalinity, and extracted with ethyl acetate (3×20 mL). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product, which was directly subjected to the next step. ESI-MS m / z: 335.2 [M+H] + .

[0512] Step 4: 8-amino-7-(3-hydroxy-2,6-dimethylphenyl)-5-methyl-2,3-dihydropyrrolo[2,3-d]imidazo[2,1-f]pyrimidine-9-carboxamide

[0513]

[0514] Add the crude product 8-amino-7-(3-hydroxy-2,6-dimethylphenyl)-5-methyl-2,3-dihydropyrrolo[2,3-d]imidazo[2,1-f]pyrimidine-9-carbonitrile (55 mg, 0.16 mmol) and concentrated sulfuric acid (2 mL) from the previous step to a 25 mL round-bottom flask and react at room temperature for 1 hour. The reaction solution was slowly added to methanol (8 mL) under ice-water cooling, and the pH was adjusted to weak alkalinity with concentrated ammonia water. Ethyl acetate (3×40 mL) was added for extraction, and the organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by preparative HPLC to obtain the product (6 mg, yield 10.54%). ESI-MS m / z: 352.2 [M+H] + . 1 H NMR(400MHz,Chloroform-d)δ7.02(d,J=8.2Hz,1H),6.88(d,J=8.2Hz,1H),4. 10(s,3H),4.06-4.03(m,2H),3.89(t,J=9.5Hz,2H),1.80(s,3H),1.71(s,3H).

[0515] Example 6

[0516] 2-Amino-3-(3-hydroxy-2,6-dimethylphenyl)-5-methylfuro[3,2-d]pyrrolo[2,3-b]pyridine-1-carboxamide (Compound 6)

[0517]

[0518] Step 1: 2-amino-5-bromo-1-(3-hydroxy-2,6-dimethylphenyl)-6-methylpyrrolo[2,3-b]pyridine-3-carbonitrile

[0519]

[0520] Add 2-amino-5-bromo-1-(3-methoxy-2,6-dimethylphenyl)-6-methylpyrrolo[2,3-b]pyridine-3-carbonitrile (3g, 7.8mmol, prepared by referring to the method described in patent WO2021195781A1), boron tribromide (39mL, 78mmol) and dichloromethane (100mL) to a 25mL round-bottom flask. React at room temperature for 20 minutes. Add methanol (20mL) to the reactant to quench, and concentrate under reduced pressure to obtain a crude product (3g). Use directly in the next step reaction. ESI-MS m / z: 371.1[M+1] + .

[0521] Step 2: 2-Methylpropan-2-yl ({5-bromo-3-cyano-1-[2,6-dimethyl-3-({[(2-methylpropan-2-yl)oxy]carbonyl}oxy)phenyl]-6-methylpyrrolo[2,3-b]pyridin-2-yl}{[(2-methylpropan-2-yl)oxy]carbonyl}amino)methanoate

[0522]

[0523] 2-amino-5-bromo-1-(3-hydroxy-2,6-dimethylphenyl)-6-methylpyrrolo[2,3-b]pyridine-3-carbonitrile (3 g, 7.8 mmol), di-tert-butyl dicarbonate (5.95 g, 27.3 mmol), 4-dimethylaminopyridine (100 mg, 0.78 mmol), triethylamine (3.15 g, 31 mmol) and tetrahydrofuran (100 mL) were added to a 100 mL round-bottom flask. Stir at 50 °C for 1 hour. The reactants were concentrated under reduced pressure and the residue was purified by silica gel column chromatography (dichloromethane-petroleum ether, 0-50% gradient elution) to obtain the product as a white solid (3 g, yield 55%). ESI-MS m / z: 671.2 [M+1] + .

[0524] Step 3: 2-Methylpropan-2-yl ({3-cyano-1-[2,6-dimethyl-3-({[(2-methylpropan-2-yl)oxy]carbonyl}oxy)phenyl]-5-hydroxy-6-methylpyrrolo[2,3-b]pyridin-2-yl}{[(2-methylpropan-2-yl)oxy]carbonyl}amino)methanoate

[0525]

[0526] In a 250 mL round-bottom flask, 2-methylpropan-2-yl ({5-bromo-3-cyano-1-[2,6-dimethyl-3-({[(2-methylpropan-2-yl)oxy]carbonyl}oxy)phenyl]-6-methylpyrrolo[2,3-b]pyridin-2-yl}{[(2-methylpropan-2-yl)oxy]carbonyl}amino)methanoate (2.5 g, 3.73 mmol) and 4,4-dimethyl-3-({[(2-methylpropan-2-yl)oxy]carbonyl}oxy)phenyl]-6-methylpyrrolo[2,3-b]pyridin-2-yl}{[(2-methylpropan-2-yl)oxy]carbonyl}amino)methanoate (2.5 g, 3.73 mmol) were added. 5,5-Tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolan (2.84 g, 11.2 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (260 mg, 0.35 mmol), potassium acetate (1.12 g, 11.4 mmol) and dioxane (50 mL). Under nitrogen atmosphere, the reaction solution was stirred at 100 ° C for 4 hours. The reaction solution was cooled to room temperature, diluted with water (50 mL) and tetrahydrofuran (50 mL), and then 30% hydrogen peroxide (5 mL) was added. The reaction was stirred at room temperature for 1 hour and extracted with ethyl acetate (3×100 mL). The organic phases were combined and washed with saturated brine (1×50 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-petroleum ether, 0-100% gradient elution) to obtain the product as a white solid (1.2 g, yield 54.5%). ESI-MS m / z: 609.1 [M+1] + .

[0527] Step 4: [(2-methylpropan-2-yl)oxy]methane acid-3-[3-cyano-5-hydroxy-4-iodo-6-methyl-2-(2,2,8,8-tetramethyl-4,6-dioxyylidene-5-aza-3,7-dioxanonan-5-yl)pyrrolo[2,3-b]pyridin-1-yl]-2,4-dimethylphenyl ester

[0528]

[0529] In a 100 mL round-bottom flask, add [(2-methylpropan-2-yl)oxy]methane acid-3-[3-cyano-5-hydroxy-6-methyl-2-(2,2,8,8-tetramethyl-4,6-dioxy-5-aza-3,7-dioxanonan-5-yl)pyrrolo[2,3-b]pyridin-1-yl]-2,4-dimethylphenyl ester (700 mg 1.15 mmol), potassium carbonate (476.79 mg, 3.45 mmol), acetonitrile (50 mL) and water (20 mL). Add iodine (291.88 mg, 1.15 mmol) in acetonitrile (20 mL) dropwise, stir for 0.5 hours, dilute with water (100 mL), and extract with ethyl acetate (3×50 mL). Combine the organic phases, wash with saturated sodium sulfite solution (50 mL), and then wash with saturated brine. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane-petroleum ether, 0-100% gradient elution) to obtain the product as a yellow oil (600 mg, yield 63.92%). ESI-MS m / z: 735.1 [M+1] + .

[0530] Step 5: [(2-methylpropan-2-yl)oxy]methane acid-3-[3-cyano-5-hydroxy-6-methyl-2-(2,2,8,8-tetramethyl-4,6-dioxylidene-5-aza-3,7-dioxanonan-5-yl)-4-[(trimethylsilyl)ethynyl]pyrrolo[2,3-b]pyridin-1-yl]-2,4-dimethylphenyl ester

[0531]

[0532] Trimethylsilyl acetylene (267.41 mg, 2.72 mmol), [(2-methylpropan-2-yl)oxy]methane acid-3-[3-cyano-5-hydroxy-4-iodo-6-methyl-2-(2,2,8,8-tetramethyl-4,6-dioxy-5-aza-3,7-dioxanon-5-yl)pyrrolo[2,3-b]pyridin-1-yl]-2,4-dimethylphenyl ester (200 mg, 0.27 mmol), cuprous iodide (15.56 mg, 0.08 mmol), triethylamine (0.757 mL, 5.45 mmol), bis(triphenylphosphine)palladium dichloride (57.33 mg, 0.08 mmol) and tetrahydrofuran (8 mL) were added to a microwave reaction tube. Under argon protection, the reaction solution was stirred at 100°C for 2 hours. Concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-petroleum ether, 0-80% gradient elution) to obtain the product as a yellow oil (140 mg, yield 66.20%). ESI-MS m / z: 705.0 [M+1] + . 1H NMR(400MHz,DMSO-d6)δ9.70(s,1H),7.35–7.28(m,2H),5.76(s,1H),2.38(s,3H) ),1.82(s,3H),1.68(s,3H),1.49(s,9H),1.39(s,9H),1.31(s,9H),0.31(s,9H).

[0533] Step 6: 2-Methylpropan-2-yl ({1-cyano-3-[2,6-dimethyl-3-({[(2-methylpropan-2-yl)oxy]carbonyl}oxy)phenyl]-5-methylfuro[3,2-d]pyrrolo[2,3-b]pyridin-2-yl}{[(2-methylpropan-2-yl)oxy]carbonyl}amino)methanoate

[0534]

[0535] Add [(2-methylpropan-2-yl)oxy]methane acid-3-{3-cyano-4-[(dimethylsilyl)ethynyl]-5-hydroxy-6-methyl-2-(2,2,8,8-tetramethyl-4,6-dioxy-5-aza-3,7-dioxanonan-5-yl)pyrrolo[2,3-b]pyridin-1-yl}-2,4-dimethylphenyl ester (270 mg, 0.38 mmol), cuprous iodide (72.95 mg, 0.38 mmol), N,N-diisopropylethylamine (148.52 mg, 1.15 mmol) and methanol (8 mL) to 100 mL. Under argon protection, the reaction solution was stirred at 70 ° C for 1 hour. Then, a 1 mol / L tetrabutylammonium fluoride solution in tetrahydrofuran (0.766 mL, 0.77 mmol) was added and the mixture was stirred at room temperature for 0.5 hours. The reactant was diluted with water (100 mL) and extracted with ethyl acetate (3×50 mL). The organic phases were combined, washed with saturated brine (1×50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product as a yellow solid (225 mg, yield 92.84%), which was used directly in the next step. ESI-MS m / z: 633.2 [M+1] + .

[0536] Step 7: 2-amino-3-(3-hydroxy-2,6-dimethylphenyl)-5-methylfuro[3,2-d]pyrrolo[2,3-b]pyridine-1-carbonitrile

[0537]

[0538] In a 100 mL round-bottom flask, add ({1-cyano-3-[2,6-dimethyl-3-({[(2-methylpropan-2-yl)oxy]carbonyl}oxy)phenyl]-5-methylfuro[3,2-d]pyrrolo[2,3-b]pyridin-2-yl}{[(2-methylpropan-2-yl)oxy]carbonyl}amino)methane acid-2-methylpropan-2-yl ester (225 mg, 0.36 mmol), 1M hydrochloric acid (20 mL) and anhydrous ethanol (20 mL). The reaction solution was stirred at 70 ° C for 2 h. The reaction solution was cooled to room temperature, diluted with water (10 mL), 5 ml of ammonia water was added to adjust the pH to alkaline, and extracted with ethyl acetate (3×20 mL). The organic phases were combined and washed with saturated brine (50 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 110 mg of crude product, which was directly used in the next step. ESI-MS m / z: 333.2 [M+H] + .

[0539] Step 8: 2-amino-3-(3-hydroxy-2,6-dimethylphenyl)-5-methylfuro[3,2-d]pyrrolo[2,3-b]pyridine-1-carboxamide

[0540]

[0541] Add 2-amino-3-(3-hydroxy-2,6-dimethylphenyl)-5-methylfurano[3,2-d]pyrrolo[2,3-b]pyridine-1-carbonitrile (68 mg, 0.20 mmol) and sulfuric acid (5 mL) to a 50 mL eggplant-shaped bottle. The reaction solution was stirred at room temperature for 4 hours. The reaction solution was added dropwise to cold methanol, ethyl acetate (50 mL) and water (50 mL) were added, and the pH was adjusted to 8 with concentrated ammonia water under rapid stirring, and then the ethyl acetate layer was separated by standing. The organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product, which was further purified by preparative HPLC to obtain the product as a white solid (15 mg, yield 20.92%). ESI-MS m / z: 351.0[M+1] + . 1 H NMR(400MHz,Methanol-d4)δ7.98(d,J=2.3Hz,1H),7.35(d,J=2.3Hz,1H),7.13 (d,J=8.3Hz,1H),6.95(d,J=8.3Hz,1H),2.62(s,3H),1.87(s,3H),1.82(s,3H).

[0542] Example 7

[0543] 7-Amino-6-(3-hydroxy-2,6-dimethylphenyl)-4-[(1-methylpiperidin-4-yl)oxy]furo[2,3-d]pyrrolo[2,3-b]pyridine-8-carboxamide (Compound 7)

[0544]

[0545] Step 1: 2-methylpropan-2-yl 4-[(6,7-dibromofuro[3,2-c]pyridin-4-yl)oxy]piperidin-1-carboxylate

[0546]

[0547] Dissolve 2-methylpropane-2-yl 4-hydroxyhexahydropyridine-1-carboxylate (395 mg, 1.96 mmol) in tetrahydrofuran (15 mL), add sodium hydride (78 mg, 1.96 mmol) at 0°C, stir at room temperature for 30 minutes, then add 6,7-dibromo-4-chlorofurano[3,2-c]pyridine (410 mg, 1.31 mmol), and react at 70°C for 7 hours. The reaction solution was cooled to room temperature, diluted with water, and extracted with ethyl acetate. The organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10:1, volume ratio) to obtain the product as a white solid (420 mg, 67.1%). ESI-MS m / z: 474.9 [M+1] + . 1 H NMR(400MHz,Chloroform-d)δ7.62(d,J=2.2Hz,1H),6.88(d,J=2.2Hz,1H),5.38(tt,J=7.8,3.8Hz,1H),3.88–3.7 3(m,2H),3.36(ddd,J=13.5,8.4,3.7Hz,2H),2.10–2.00(m,2H),1.80(dtd,J=12.4,7.9,3.8Hz,2H),1.49(s,9H).

[0548] Step 2: 2-methylpropan-2-yl 4-[(6-{[3-(benzyloxy)-2,6-dimethylphenyl]amino}-7-bromofuro[3,2-c]pyridin-4-yl)oxy]piperidin-1-carboxylate

[0549]

[0550] 4-[(6,7-dibromofurano[3,2-c]pyridin-4-yl)oxy]hexahydropyridine-1-carboxylic acid-2-methylpropane-2-yl ester (400 mg, 0.84 mmol) and 3-(benzyloxy)-2,6-dimethylaniline (285 mg, 1.25 mmol) were dissolved in ethylene glycol dimethyl ether (15 mL), and cesium carbonate (545 mg, 1.67 mmol), bis(dibenzylideneacetone)palladium (76 mg, 0.08 mmol) and 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (97 mg, 0.17 mmol) were added. Under nitrogen protection, the reaction was carried out at 110°C for 4 hours. The reaction solution was cooled to room temperature and filtered through diatomaceous earth. It was concentrated under reduced pressure, and the residue was chromatographed on a silica gel column (petroleum ether / ethyl acetate = 10:1, volume ratio) to obtain the product as a white solid (400 mg, yield 76.5%). ESI-MS m / z:622.2[M+H] + . 1 H NMR(400MHz,Chloroform-d)δ7.46(d,J=7.2Hz,2H),7.43–7.38(m,3H),7.36–7.31(m,1H), 7.03(d,J=8.3Hz,1H),6.81(d,J=8.3Hz,1H),6.72(d,J=2.2Hz,1H),6.20(s,1H),5.10(s,2 H),4.62(dt,J=8.9,4.7Hz,1H),3.74(dt,J=12.5,4.7Hz,2H),2.84(ddd,J=13.4,9.7,3.3H z,2H),2.17(d,J=7.6Hz,7H),1.73(dq,J=12.8,4.2Hz,3H),1.52–1.48(m,2H),1.46(s,9H).

[0551] Step 3: 2-methylpropan-2-yl 4-({7-amino-6-[3-(benzyloxy)-2,6-dimethylphenyl]-8-cyanofurano[2,3-d]pyrrolo[2,3-b]pyridin-4-yl}oxy)piperidin-1-carboxylate

[0552]

[0553] Dissolve malononitrile (212 mg, 3.31 mmol) in ethylene glycol dimethyl ether (30 mL), cool to 0°C, slowly add sodium hydride (128 mg, 3.31 mmol), and stir at room temperature for 0.5 hours. Add (1,1'-bis(diphenylphosphino)ferrocene)palladium dichloride (50 mg, 0.06 mmol) and 4-[(6-{[3-(benzyloxy)-2,6-dimethylphenyl]amino}-7-bromofurano[3,2-c]pyridin-4-yl)oxy]hexahydropyridine-1-carboxylic acid-2-methylpropane-2-yl ester (400 mg, 0.64 mmol). Under nitrogen protection, react at 130°C for 16 hours. The reaction solution is cooled to room temperature, diluted with water, and extracted with ethyl acetate. The organic phase was washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was chromatographed on a silica gel column (petroleum ether / ethyl acetate = 4:1, volume ratio) to obtain the product as a yellow solid (90 mg, yield 23%). ESI-MS m / z: 608.2 [M+H] + . 1 H NMR(400MHz,Chloroform-d)δ7.60(d,J=2.2Hz,1H),7.50–7.40(m,4H),7.39–7.34(m,1H),7.19( d,J=8.4Hz,1H),7.06–6.97(m,1H),6.88(d,J=2.3Hz,1H),5.22–5.12(m,2H),5.01(tt,J=6.9,3.2 Hz,1H),4.45(s,2H),3.63(ddt,J=12.6,8.3,4.4Hz,2H),3.27(ddt,J=17.1,7.7,3.8Hz,2H),1.9 3(d,J=2.9Hz,6H),1.83(dq,J=12.4,3.8Hz,2H),1.70(ddd,J=13.5,6.7,3.9Hz,3H),1.47(s,9H).

[0554] Step 4: 7-amino-4-(hexahydropyridin-4-yloxy)-6-(3-hydroxy-2,6-dimethylphenyl)furo[2,3-d]pyrrolo[2,3-b]pyridine-8-carboxamide

[0555]

[0556] Dissolve 4-({7-amino-6-[3-(benzyloxy)-2,6-dimethylphenyl]-8-cyanofurano[2,3-d]pyrrolo[2,3-b]pyridin-4-yl}oxy)piperidin-1-carboxylic acid-2-methylpropane-2-yl ester (90 mg, 0.15 mmol) in concentrated sulfuric acid (3 mL) and stir at room temperature for 1 hour. Add the reaction solution dropwise to methanol under ice bath, add ice water, adjust the ammonia water to alkalinity, extract with ethyl acetate, wash with saturated sodium chloride solution, dry with anhydrous sodium sulfate, and concentrate under reduced pressure to obtain a yellow oily residue (80 mg). ESI-MS m / z: 436.2[[M+1] + .

[0557] Step 5: 7-amino-6-(3-hydroxy-2,6-dimethylphenyl)-4-[(1-methylpiperidin-4-yl)oxy]furo[2,3-d]pyrrolo[2,3-b]pyridine-8-carboxamide

[0558]

[0559] 7-amino-4-(hexahydropyridin-4-yloxy)-6-(3-hydroxy-2,6-dimethylphenyl)furano[2,3-d]pyrrolo[2,3-b]pyridine-8-carboxamide (80 mg) obtained in step 4 was dissolved in tetrahydrofuran (2 mL), 2 drops of 30% formaldehyde aqueous solution were added, sodium triacetylborohydride (159 mg, 0.75 mmol) was added, and stirred at room temperature for 5 minutes. Dilute with water, extract with ethyl acetate, wash with saturated sodium bicarbonate, wash with saturated sodium chloride solution, dry with anhydrous sodium sulfate, concentrate under reduced pressure, and the residue was purified by preparative HPLC to obtain the product as a white solid (10 mg, yield 12.5%). ESI-MS m / z: 450.4 [M+1] + . 1 H NMR (400MHz, Methanol-d4) δ8.54(s,1H),7.76(d,J=2.3Hz,1H),7.08(d,J=8.3Hz,1H),7.00(d,J=2.2Hz,1H),6.90(d,J=8.2Hz,1 H),5.00(s,1H),3.12(ddd,J=12.2,7.5,3.6Hz,2H),2.95–2.78(m,2H),2.64(s,3H),2.11–1.92(m,4H),1.87(s,3H),1.82(s,3H).

[0560] Example 8

[0561] 7-amino-6-(3-hydroxy-2,6-dimethylphenyl)-4-[(1-methylpiperidin-4-yl)oxy]-2,3-dihydrofuro[2,3-d]pyrrolo[2,3-b]pyridine-8-carboxamide (Compound 8)

[0562]

[0563] 7-Amino-6-(3-hydroxy-2,6-dimethylphenyl)-4-[(1-methylhexahydropyridin-4-yl)oxy]furano[2,3-d]pyrrolo[2,3-b]pyridine-8-carboxamide (Compound 7, 30 mg, 0.067 mmol) was dissolved in methanol (1 mL) and acetic acid (1 mL). 10% palladium on carbon (10 mg) was added and stirred at 70°C for 2 hours under a hydrogen atmosphere. The reaction solution was cooled to room temperature, filtered with celite, and concentrated under reduced pressure. The residue was purified by preparative HPLC to obtain the product as a white solid (3 mg, yield 10.2%). ESI-MS m / z: 452.2[M+1] + . 1 H NMR (400MHz, Methanol-d4) δ8.53(s,1H),7.05(d,J=8.3Hz,1H),6.88(s,1H),4.83(d,J=8.7Hz,3H),3.19(t,J= 8.7Hz,2H),3.02(d,J=10.4Hz,2H),2.76(s,2H),2.57(s,3H),1.99(d,J=18.4Hz,3H),1.86(s,4H),1.80(s,3H).

[0564] Example 9

[0565] 7-Amino-6-(3-hydroxy-2,6-dimethylphenyl)-2,4-dimethylfuro[2,3-d]pyrrolo[2,3-b]pyridine-8-carboxamide (Compound 9)

[0566]

[0567] (R)-7-amino-6-(3-hydroxy-2,6-dimethylphenyl)-2,4-dimethylfurano[2,3-d]pyrrolo[2,3-b]pyridine-8-carboxamide and (S)-7-amino-6-(3-hydroxy-2,6-dimethylphenyl)-2,4-dimethylfurano[2,3-d]pyrrolo[2,3-b]pyridine-8-carboxamide (Compound 9-1 and Compound 9-2)

[0568]

[0569] Step 1: 5-Bromo-6-[(3-methoxy-2,6-dimethylphenyl)amino]-2-methyl-3-nitropyridine

[0570]

[0571] 5-Bromo-6-chloro-2-methyl-3-nitropyridine (59.3 g, 235.82 mmol), 3-methoxy-2,6-dimethylaniline (35.63 g, 235.82 mmol) and 2,6-dimethylpyridine (50.55 g, 471.65 mmol) were dissolved in N-methylpyrrolidone (290 mL), heated to 130 ° C, refluxed and stirred for 5 days. The reactants were cooled to room temperature, extracted with water (1000 mL x 2) and ethyl acetate (1000 mL x 2). The organic phase was then washed with saturated sodium chloride solution (1000 mL x 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was chromatographed on a silica gel column (petroleum ether / ethyl acetate = 10: 1, volume ratio) to obtain the product, a light yellow solid (38.0 g, yield 44%). ESI-MS m / z: 366.0 [M + H] + . 1 H NMR (400MHz, Chloroform-d) δ8.55(s,1H),7.11(d,J=8.3Hz,1H),6.94(s,1H),6.82(d,J=8.4Hz,1H),3.88(s,3H),2.63(s,3H),2.16(s,3H),2.08(s,3H).

[0572] Step 2: 2-amino-1-(3-methoxy-2,6-dimethylphenyl)-6-methyl-5-nitropyrrolo[2,3-b]pyridine-3-carbonitrile

[0573]

[0574] Sodium hydride (13.5 g, 338.4 mmol) was added to a solution of ethylene glycol dimethyl ether containing 700 mL, and then a solution of malononitrile (20.7 g, 313.4 mmol) in ethylene glycol dimethyl ether (300 mL) was slowly added. After stirring for 1 hour, 5-bromo-6-[(3-methoxy-2,6-dimethylphenyl)amino]-2-methyl-3-nitropyridine (45.9 g, 125.3 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (9.2 g, 12.5 mmol) were added. The reaction mixture was stirred at 95°C for 1 hour. After the reaction mixture was cooled, it was extracted with ethyl acetate (2×1500 mL). The organic phases were combined and washed with saturated brine (2×500 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was slurried with petroleum ether (200 mL) to obtain the product as a reddish brown solid (46.8 g). ESI-MS m / z: 352.0 [M+H] + . 1 H NMR (400MHz, Chloroform-d) δ8.42(s,1H),7.28(s,1H),7.02(d,J=8.5Hz,1H),4.99(s,2H),3.92(s,3H),2.76(s,3H),1.93(s,3H),1.86(s,3H).

[0575] Step 3: 2-Methylpropan-2-yl {[3-cyano-1-(3-methoxy-2,6-dimethylphenyl)-6-methyl-5-nitropyrrolo[2,3-b]pyridin-2-yl]amino}methanoate

[0576]

[0577] 2-amino-1-(3-methoxy-2,6-dimethylphenyl)-6-methyl-5-nitropyrrolo[2,3-b]pyridine-3-carbonitrile (46.8 g, 133.2 mmol) was dissolved in tetrahydrofuran (400 mL), 4-dimethylaminopyridine (8.1 g, 66.6 mmol) and triethylamine (55.5 mL, 399.6 mmol) were added, di-tert-butyl carbonic anhydride (43.6 g, 199.8 mmol) was added at 0°C, and then stirred at room temperature for 1 hour, water (600 mL) was added, and extracted with ethyl acetate (2×1000 mL). The organic phases were combined and washed with saturated brine (2×500 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was chromatographed on a silica gel column (petroleum ether / ethyl acetate = 5:1, volume ratio) to obtain the product (45.0 g, yield 80.4%). ESI-MS m / z:452.1[M+H] + . 1HNMR(400MHz,Chloroform-d)δ8.72(s,1H),7.27(d,J=8.2Hz,1H),7.05(d,J=8.5Hz ,1H),6.48(s,1H),3.93(s,3H),2.79(s,3H),1.86(s,3H),1.79(s,3H),1.55(s,9H).

[0578] Step 4: 2-methylpropan-2-yl {[5-amino-3-cyano-1-(3-methoxy-2,6-dimethylphenyl)-6-methylpyrrolo[2,3-b]pyridin-2-yl]amino}methanoate

[0579]

[0580] {[3-cyano-1-(3-methoxy-2,6-dimethylphenyl)-6-methyl-5-nitropyrrolo[2,3-b]pyridin-2-yl]amino}methane acid-2-methylpropane-2-yl ester (45.0 g, 99.6 mmol) was dissolved in tetrahydrofuran (200 mL) and methanol (800 mL), and 10% palladium carbon (20 g, 187.9 mmol) was added. The reactants were stirred at room temperature overnight under a hydrogen atmosphere. The reactants were filtered through diatomaceous earth, the filtrate was concentrated under reduced pressure, and the residue was chromatographed on a silica gel column (petroleum ether / ethyl acetate = 3:1, volume ratio) to obtain the product as a white solid (31.0 g, yield 73.7%). ESI-MS m / z: 422.2 [M+H] + . 1 H NMR (400MHz, Chloroform-d) δ7.29 (d, J = 7.6 Hz, 1H), 7.20 (d, J = 8.4 Hz, 1H), 6.96 (d, J = 8. 4Hz,1H),6.15(s,1H),3.89(s,3H),2.37(s,3H),1.86(s,3H),1.78(s,3H),1.52(s,9H).

[0581] Step 5: 2-methylpropan-2-yl {[5-amino-4-bromo-3-cyano-1-(3-methoxy-2,6-dimethylphenyl)-6-methylpyrrolo[2,3-b]pyridin-2-yl]amino}methanoate

[0582]

[0583] Dissolve 2-methylpropan-2-yl {[5-amino-3-cyano-1-(3-methoxy-2,6-dimethylphenyl)-6-methylpyrrolo[2,3-b]pyridin-2-yl]amino}methane (12.5 g, 29.7 mmol) in dichloromethane (150 mL) and acetic acid (150 mL), add N-bromosuccinimide (5.3 g, 29.7 mmol) in dichloromethane (150 mL) under ice bath, stir the reactant at 0°C for 15 minutes. Add water (300 mL), extract with dichloromethane (2×300 mL), combine the organic phases, wash with saturated sodium sulfite solution (300 mL), and wash with saturated brine (200 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was chromatographed on a silica gel column (petroleum ether / ethyl acetate = 4:1, volume ratio) to obtain the product as a light yellow solid (11.4 g, yield 76.8%). ESI-MS m / z: 500.0, 502.0 [M+H] + . 1 H NMR (400MHz, Chloroform-d) δ7.19(d,J=8.4Hz,1H),6.96(d,J=8.5Hz,1H),6.10(s,1H),3.89(s,3H),2.43(s,3H),1.86(s,3H),1.77(s,3H),1.51(s,9H).

[0584] Step 6: 2-Methylpropan-2-yl {[8-cyano-6-(3-methoxy-2,6-dimethylphenyl)-4-methyl[1,2,3]oxadiazolyl[5,4-d]pyrrolo[2,3-b]pyridin-7-yl]amino}methanoate

[0585]

[0586] Dissolve {[5-amino-4-bromo-3-cyano-1-(3-methoxy-2,6-dimethylphenyl)-6-methylpyrrolo[2,3-b]pyridin-2-yl]amino}methane acid-2-methylpropane-2-yl ester (11.4 g, 22.8 mmol) in acetic acid (300 mL), add sodium nitrite (1.7 g, 25.1 mmol), and stir the reaction at room temperature for 1 hour. Add water (600 mL) to quench, extract with ethyl acetate (2×500 mL), combine the organic phases, and wash with saturated brine (300 mL). The organic phase is dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a gray-yellow solid (10.5 g, crude product). ESI-MS m / z: 449.1 [M+H] + .

[0587] Step 7: 2-Methylpropan-2-yl {[3-cyano-4-hydroxy-1-(3-methoxy-2,6-dimethylphenyl)-6-methylpyrrolo[2,3-b]pyridin-2-yl]amino}methanoate

[0588]

[0589] Dissolve {[8-cyano-6-(3-methoxy-2,6-dimethylphenyl)-4-methyl[1,2,3]oxadiazacyclopenta[5,4-d]pyrrolo[2,3-b]pyridin-7-yl]amino}methanoic acid-2-methylpropan-2-yl ester (10.5 g, 23.4 mmol) in methanol (300 mL), slowly add sodium borohydride (10.7 g, 280.8 mmol), and stir the reaction for 2 hours. Add ethyl acetate (400 mL) to dilute, quench with saturated ammonium chloride solution (400 mL), extract with ethyl acetate (2×500 mL), combine the organic phases, and wash with saturated brine (300 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was chromatographed on a silica gel column (dichloromethane / methanol = 15:1, volume ratio) to give the product as a pale yellow solid {[3-cyano-4-hydroxy-1-(3-methoxy-2,6-dimethylphenyl)-6-methylpyrrolo[2,3-b]pyridin-2-yl]amino}methane-2-methylpropan-2-yl ester (7.6 g, yield 77.0%). ESI-MS m / z: 423.1 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ11.17(s,1H),9.45(s,1H),7.18(d,J=8.4Hz,1H),7.05(d,J=8. 4Hz,1H),6.55(s,1H),3.83(s,3H),2.29(s,3H),1.76(s,3H),1.64(s,3H),1.35(s,9H).

[0590] Step 8: 2-Methylpropan-2-yl {[3-cyano-4-hydroxy-5-iodo-1-(3-methoxy-2,6-dimethylphenyl)-6-methylpyrrolo[2,3-b]pyridin-2-yl]amino}methanoate

[0591]

[0592] Dissolve {[3-cyano-4-hydroxy-1-(3-methoxy-2,6-dimethylphenyl)-6-methylpyrrolo[2,3-b]pyridin-2-yl]amino}methane-2-methylpropane-2-yl ester (7.6 g, 18.0 mmol) in N,N-dimethylformamide (200 mL), add N-iodosuccinimide (4.3 g, 18.9 mmol), and stir the reaction for 30 minutes. Add water (800 mL), solid precipitates, filter, collect the filter cake, and obtain the product, an off-white solid (4.8 g, yield 50.5%). ESI-MS m / z: 549.1 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ9.45(d,J=127.5Hz,1H),7.40–7.01(m,2H),3.84(s,3 H),2.54(d,J=13.2Hz,3H),1.74(dd,J=41.7,31.9Hz,6H),1.43–1.26(m,9H).

[0593] Step 9: 2-Methylpropan-2-yl {[8-cyano-6-(3-methoxy-2,6-dimethylphenyl)-4-methyl-2-[(trimethylsilyl)methyl]furo[2,3-d]pyrrolo[2,3-b]pyridin-7-yl]amino}methanoate

[0594]

[0595] Dissolve {[3-cyano-4-hydroxy-5-iodo-1-(3-methoxy-2,6-dimethylphenyl)-6-methylpyrrolo[2,3-b]pyridin-2-yl]amino}methane acid-2-methylpropane-2-yl ester (4.8 g, 8.8 mmol) and propargyltrimethylsilane (9.8 g, 87.5 mmol) in tetrahydrofuran (100 mL), add cuprous iodide (0.33 g, 1.7 mmol), triethylamine (24.3 mL, 175.0 mmol) and bistriphenylphosphine palladium dichloride (0.62 g, 0.87 mmol), and stir at 70 ° C for 4 hours under nitrogen atmosphere. Add water (200 mL) and extract with ethyl acetate (2×250 mL). Combine the organic phases and wash with saturated brine (200 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a reddish brown solid (4.5 g, crude product). ESI-MS m / z: 533.1 [M+H] + .

[0596] Step 10: 2-Methylpropan-2-yl {[8-cyano-6-(3-methoxy-2,6-dimethylphenyl)-2,4-dimethylfuro[2,3-d]pyrrolo[2,3-b]pyridin-7-yl]amino}methanoate

[0597]

[0598] Dissolve {[8-cyano-6-(3-methoxy-2,6-dimethylphenyl)-4-methyl-2-[(trimethylsilyl)methyl]furano[2,3-d]pyrrolo[2,3-b]pyridin-7-yl]amino}methane acid-2-methylpropane-2-yl ester (4.5g, 8.4mmol) in tetrahydrofuran (100mL), add 1mol / L tetrabutylammonium fluoride tetrahydrofuran solution (8.5mL, 8.5mmol), and stir at room temperature for 30 minutes. Add saturated ammonium chloride solution and extract with ethyl acetate (2×150mL). Combine the organic phases and wash with saturated brine (2×100mL). Dry the organic phase with anhydrous sodium sulfate, filter, and concentrate under reduced pressure. The residue is chromatographed on a silica gel column (petroleum ether / ethyl acetate = 4:1, volume ratio) to obtain the product as a white solid (1.4g, yield 40.5%). ESI-MS m / z:461.1[M+H] + . 1 H NMR (400MHz, DMSO-d6) δ9.67(s,1H),7.23(d,J=8.5Hz,1H),7.09(d,J=8.5Hz,1H),6.84( d,J=1.3Hz,1H),3.85(s,3H),2.58–2.53(m,6H),1.76(s,3H),1.64(s,3H),1.38(s,9H).

[0599] Step 11: 7-amino-6-(3-methoxy-2,6-dimethylphenyl)-2,4-dimethylfuro[2,3-d]pyrrolo[2,3-b]pyridine-8-carbonitrile

[0600]

[0601] {[8-cyano-6-(3-methoxy-2,6-dimethylphenyl)-2,4-dimethylfurano[2,3-d]pyrrolo[2,3-b]pyridin-7-yl]amino}methane acid-2-methylpropane-2-yl ester (1.4g, 3.04mmol) was dissolved in methanol (100mL), 1M hydrochloric acid (30mL) was added, and the reactants were stirred at 70°C for 2 hours. The reaction solution was cooled to room temperature, ammonia water was added to adjust the pH to about 8, water (150mL) was added to dilute, and extracted with ethyl acetate (2×300mL). The organic phases were combined and washed with saturated brine (100mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was chromatographed on a silica gel column (petroleum ether / ethyl acetate = 3:1, volume ratio) to obtain the product as a light yellow solid (0.84g, yield 76.7%). ESI-MS m / z: 361.1 [M+H] + .

[0602] Step 12: 7-amino-6-(3-methoxy-2,6-dimethylphenyl)-2,4-dimethylfuro[2,3-d]pyrrolo[2,3-b]pyridine-8-carboxamide

[0603]

[0604] Dissolve 7-amino-6-(3-methoxy-2,6-dimethylphenyl)-2,4-dimethylfurano[2,3-d]pyrrolo[2,3-b]pyridine-8-carbonitrile (0.84 g) in concentrated sulfuric acid (14 mL) and stir the reaction at room temperature for 2 h. Slowly add the reaction solution dropwise to 200 mL of methanol under ice-water cooling, then add water (100 mL) and adjust the pH to about 8 with concentrated ammonia. Extract with ethyl acetate (2×150 mL). Combine the organic phases and wash with saturated brine (100 mL). Dry the organic phase over anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain a crude product (850 mg). ESI-MS m / z: 379.1[M+H] + .

[0605] Step 13: 7-amino-6-(3-hydroxy-2,6-dimethylphenyl)-2,4-dimethylfuro[2,3-d]pyrrolo[2,3-b]pyridine-8-carboxamide

[0606]

[0607] 7-amino-6-(3-methoxy-2,6-dimethylphenyl)-2,4-dimethylfurano[2,3-d]pyrrolo[2,3-b]pyridine-8-carboxamide (0.85 g) was dissolved in dichloromethane (30 mL), and boron tribromide (2.164 mL, 22.46 mmol) was added. The reaction mixture was stirred at room temperature for 2 hours. The reaction solution was slowly added dropwise to 100 mL of methanol under ice-water cooling, and concentrated under reduced pressure. The residue was purified by preparative HPLC to obtain compound 9 (510 mg). ESI-MS m / z: 365.1 [M+H] + . 1 H NMR (400MHz, Methanol-d4) δ8.11(s,5H),7.11(d,J=8.3Hz,1H),6.93(d,J=8.3Hz,1H),6.64(s,1H),2.55(s,3H),2.53(s,3H),1.85(s,3H),1.81(s,3H).

[0608] Step 14: (R)-7-amino-6-(3-hydroxy-2,6-dimethylphenyl)-2,4-dimethylfurano[2,3-d]pyrrolo[2,3-b]pyridine-8-carboxamide and (S)-7-amino-6-(3-hydroxy-2,6-dimethylphenyl)-2,4-dimethylfurano[2,3-d]pyrrolo[2,3-b]pyridine-8-carboxamide (Compound 9-1 and Compound 9-2)

[0609]

[0610] Compound 9 was dissolved in a dichloromethane-methanol mixed solvent and subjected to supercritical fluid chromatography (SFC) chiral separation using a Waters PrepSFC 150Mgm system (chiral column: ChiralPak IK, 250×40mm, 10μm; eluent: methanol (30%, containing 0.1% ammonia)-carbon dioxide (70%); flow rate: 120mL / min; column temperature: 40°C) to obtain two isomers. Compound 9-1 (peak 1, retention time: 5.20min), ESI-MS m / z: 365.1 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ9.52 (s, 1H), 7.07 (d, J = 8.3 Hz, 1H), 7.05–6.97 (m, 2H), 6.93 (d, J = 8.2 Hz, 1H), 6.76 (s, 2H), 6.73 (d, J = 1.5 Hz, 1H), 2.52 (s, 3H), 2.45 (s, 3H), 1.76 (s, 3H), 1.67 (s, 3H); Compound 9-2 (peak 2, retention time 6.02 min), ESI-MS m / z: 365.1 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ9.53(s,1H),7.07(d,J=8.3Hz,1H),7.02(s,2H),6.93(d,J=8.2Hz,1H) ,6.79–6.70(m,2H),6.73(d,J=1.5Hz,1H),2.52(s,3H),2.45(s,2H),1.76(s,3H),1.67(s,3H).

[0611] Example 10

[0612] 7-Amino-6-(3-hydroxy-2,6-dimethylphenyl)-2,4-dimethyl-2,3-dihydrofuro[2,3-d]pyrrolo[2,3-b]pyridine-8-carboxamide (Compound 10)

[0613]

[0614] Compound 10 was prepared from compound 9 according to the experimental process of Example 8. ESI-MS m / z: 367.2 [M+H] + .

[0615] Embodiment 11

[0616] 7-Amino-6-(3-hydroxy-2,6-dimethylphenyl)-4-methylthieno[2,3-d]pyrrolo[2,3-b]pyridine-8-carboxamide (Compound 11)

[0617]

[0618] (R)-7-amino-6-(3-hydroxy-2,6-dimethylphenyl)-4-methylthieno[2,3-d]pyrrolo[2,3-b]pyridine-8-carboxamide and (S)-7-amino-6-(3-hydroxy-2,6-dimethylphenyl)-4-methylthieno[2,3-d]pyrrolo[2,3-b]pyridine-8-carboxamide (Compound 11-1 and Compound 11-2)

[0619]

[0620] Step 1: 7-Nitro-4,5-dihydrothieno[3,2-c]pyridin-4-one

[0621]

[0622] 4,5-dihydrothieno[3,2-c]pyridin-4-one (3 g, 19.84 mmol), nitric acid (0.831 mL, 19.84 mmol) and trifluoroacetic acid (60 mL) were added to a 100 mL round-bottom flask. The reaction solution was stirred at 0°C for 0.5 hours. The reactants were concentrated under reduced pressure, and the residue was slurried with 50 mL of ethyl acetate. The solid was collected by filtration to obtain the product, a brown solid (3.3 g, yield 84.77%). ESI-MS m / z: 196.9 [M+1] + .

[0623] Step 2: 4-Chloro-7-nitrothieno[3,2-c]pyridine

[0624]

[0625] 7-Nitro-4,5-dihydrothieno[3,2-c]pyridin-4-one (3.3 g, 16.82 mmol), phosphorus oxychloride (12.90 g, 84.11 mmol) and acetonitrile (60 mL) were added to a 100 mL two-necked flask and stirred at 90°C for 2 hours. The mixture was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate (100 ml), and the pH was adjusted to 8 with saturated sodium bicarbonate solution. The organic layer was separated and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane-petroleum ether, 0-50% gradient elution) to obtain the product as a white solid (2.1 g, yield 55.26%). ESI-MS m / z: 214.9 [M+1] + . 1 H NMR (400MHz, Chloroform-d) δ9.23(t,J=1.8Hz,1H),7.86(d,J=5.6Hz,1H),7.72(dt,J=5.6,1.3Hz,1H).

[0626] Step 3: 4-Methyl-7-nitrothieno[3,2-c]pyridine

[0627]

[0628] In a 250 mL round-bottom flask, add 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane (7.37 g, 29.35 mmol), 4-chloro-7-nitrothieno[3,2-c]pyridine (2.1 g, 9.78 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (0.72 g, 0.98 mmol), potassium carbonate (4.06 g, 29.35 mmol), dioxane (40 mL) and water (10 mL). Under a nitrogen atmosphere, the reaction solution was stirred at 100 ° C for 2 hours. The reaction solution was cooled to room temperature, diluted with water (100 mL), and extracted with ethyl acetate (3×100 mL). The organic phases were combined and washed with saturated brine (1×50 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-petroleum ether, 0-50% gradient elution) to obtain the product as a white solid (1.1 g, yield 52.10%). ESI-MS m / z: 195.0 [M+1] + . 1 H NMR (400MHz, Chloroform-d) δ9.35 (s, 1H), 7.76 (d, J = 5.6Hz, 1H), 7.64 (d, J = 5.6Hz, 1H), 3.00 (s, 3H).

[0629] Step 4: 4-Methylthieno[3,2-c]pyridin-7-amine

[0630]

[0631] Add 4-methyl-7-nitrothieno[3,2-c]pyridine (900 mg, 5.05 mmol), palladium carbon (0.60 g, 0.57 mmol) and methanol (40 mL) to a 50 mL eggplant-shaped bottle. Stir the reaction solution at room temperature for 2 hours under a hydrogen atmosphere. Filter and concentrate the filtrate to obtain the product as a white solid (900 mg, yield 96.75%). ESI-MS m / z: 165.0 [M+1] + .

[0632] Step 5: 6-Bromo-4-methylthieno[3,2-c]pyridin-7-amine

[0633]

[0634] Add 4-methylthieno[3,2-c]pyridin-7-amine (900 mg, 5.48 mmol), N-bromosuccinimide (975.41 mg, 5.48 mmol) and dichloromethane (30 mL) to a 100 mL eggplant-shaped bottle. React at room temperature for 0.5 hours. The reactant is concentrated under reduced pressure, and the residue is purified by silica gel column chromatography (ethyl acetate-petroleum ether, 0-50% gradient elution) to obtain the product as a white solid (1.05 g, yield 74.87%). ESI-MS m / z: 244.9 [M+1] + . 1 H NMR (400MHz, Chloroform-d) δ7.47–7.43(m,1H),7.43–7.39(m,1H),4.19(s,2H),2.75(d,J=1.6Hz,3H).

[0635] Step 6: 6,7-Dibromo-4-methylthieno[3,2-c]pyridine

[0636]

[0637] In a 100mL round-bottom flask, add 6-bromo-4-methylthieno[3,2-c]pyridin-7-amine (500mg, 2.06mmol), copper bromide (1378.02mg, 6.17mmol) and acetonitrile (20mL), and add tert-butyl nitrite (636.23mg, 6.17mmol) dropwise. Stir at room temperature for 10 minutes, add water (200mL) and ethyl acetate (200ml) for extraction. The organic phase is washed with saturated brine (50mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue is purified by silica gel column chromatography (dichloromethane-petroleum ether, 0-70% gradient elution) to obtain the product as a white solid (520mg, yield 78.24%). ESI-MS m / z: 305.8[M+1] + . 1 H NMR (400MHz, Chloroform-d) δ7.61–7.44 (m, 2H), 2.82 (t, J = 1.0Hz, 3H).

[0638] Step 7: 7-Bromo-6-[(3-methoxy-2,6-dimethylphenyl)amino]thieno[3,2-c]pyridine

[0639]

[0640] 3-Methoxy-2,6-dimethylaniline (394.03 mg, 2.61 mmol), 6,7-dibromo-4-methylthieno[3,2-c]pyridine (400 mg, 1.30 mmol), cesium carbonate (849.04 mg, 2.61 mmol), tris(dibenzylideneacetone)dipalladium (119.31 mg, 0.13 mmol), 4,5-bis(diphenylphosphino-9,9-dimethylxanthene) (150.78 mg, 0.26 mmol) and ethylene glycol dimethyl ether (20 mL) were added to a 100 mL reaction tube. The reaction solution was stirred at 110 ° C for 2 hours under a nitrogen atmosphere. The reaction solution was quenched by adding aqueous hydrochloric acid (1N, 20 mL). Extracted with ethyl acetate (2×50 mL). The ethyl acetate layers were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-petroleum ether, 0-20% gradient elution) to obtain the product as a yellow solid (400 mg, yield 77.30%). ESI-MS m / z: 376.9 [M+1] + . 1 H NMR(400MHz,Chloroform-d)δ7.33(d,J=5.5Hz,1H),7.11(dd,J=15.2,7.0Hz,2 H),6.77(d,J=8.3Hz,1H),3.87(s,3H),2.56(s,3H),2.20(s,3H),2.13(s,3H).

[0641] Step 8: 7-amino-6-(3-methoxy-2,6-dimethylphenyl)-4-methylthieno[2,3-d]pyrrolo[2,3-b]pyridine-8-carboxamide

[0642]

[0643] Sodium hydride (508.88 mg, 12.72 mmol) was added to a sealed tube containing ethylene glycol dimethyl ether (30 mL), and a solution of malononitrile (840.41 mg, 12.72 mmol) in ethylene glycol dimethyl ether (10 mL) was added dropwise, and stirred at room temperature for 0.5 hours. 7-Bromo-6-[(3-methoxy-2,6-dimethylphenyl)amino]thieno[3,2-c]pyridine (800 mg, 2.12 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (155.15 mg, 0.21 mmol) were added, and the reaction solution was reacted at 130°C for 3 hours under argon protection. The reaction solution was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (ethyl acetate-petroleum ether, 0-50% gradient elution) to obtain the product as a yellow solid (680 mg, yield 84.06%). ESI-MS m / z: 363.0 [M+1] + .1 H NMR (400MHz, DMSO-d6) δ7.66(d,J=5.5Hz,1H),7.60(d,J=5.4Hz,1H),7.25(d,J=8.4Hz,1H ),7.10(d,J=8.5Hz,1H),6.89(s,2H),3.86(s,3H),2.61(s,3H),1.81(s,3H),1.72(s,3H).

[0644] Step 9: 7-amino-6-(3-methoxy-2,6-dimethylphenyl)-4-methylthieno[2,3-d]pyrrolo[2,3-b]pyridine-8-carboxamide

[0645]

[0646] Add 7-amino-6-(3-methoxy-2,6-dimethylphenyl)-4-methylthieno[2,3-d]pyrrolo[2,3-b]pyridine-8-carboxamide (300 mg, 0.83 mmol) and sulfuric acid (8 mL) to a 50 mL round-bottom flask. Stir the reaction solution at room temperature for 2 hours. Add the reaction solution dropwise to methanol, add ethyl acetate and water, and adjust the pH to 8 with ammonia water. Separate the organic layer, wash with saturated brine (50 mL), dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain the product as a white solid (300 mg). ESI-MS m / z: 381.0[M+1] + .

[0647] Step 10: 7-amino-6-(3-hydroxy-2,6-dimethylphenyl)-4-methylthieno[2,3-d]pyrrolo[2,3-b]pyridine-8-carboxamide

[0648]

[0649] 7-amino-6-(3-methoxy-2,6-dimethylphenyl)-4-methylthieno[2,3-d]pyrrolo[2,3-b]pyridine-8-carboxamide (300 mg, 0.79 mmol), boron tribromide (3950.69 mg, 15.77 mmol) and dichloromethane (20 mL) were added to a 25 mL round-bottom flask. The reaction was allowed to react at room temperature for 20 minutes. Methanol was added to quench the reaction, and the mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC to give compound 11 as a white solid (100 mg, yield 31.15%). ESI-MS m / z: 367.1 [M+1] + . 1HNMR(400MHz,DMSO-d6)δ9.54(s,1H),7.55(s,2H),7.09(d,J=8.3Hz,1H),6.94(d ,J=8.3Hz,1H),6.78(s,2H),6.21(s,2H),2.61(s,3H),1.77(s,3H),1.68(s,3H).

[0650] Step 11: (R)-7-amino-6-(3-hydroxy-2,6-dimethylphenyl)-4-methylthieno[2,3-d]pyrrolo[2,3-b]pyridine-8-carboxamide and (S)-7-amino-6-(3-hydroxy-2,6-dimethylphenyl)-4-methylthieno[2,3-d]pyrrolo[2,3-b]pyridine-8-carboxamide (Compound 11-1 and Compound 11-2)

[0651]

[0652] Compound 11 was dissolved in a dichloromethane-methanol mixed solvent and subjected to supercritical fluid chromatography (SFC) chiral separation using a Waters PrepSFC 150Mgm system (chiral column: ChiralPak IC, 250×40mm, 10μm; eluent: methanol (35%, containing 0.2% ammonia)-carbon dioxide (65%); flow rate: 120mL / min; column temperature: 35°C) to obtain two isomers. Compound 11-1 (peak 1, retention time: 2.46min), ESI-MS m / z: 367.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ9.53 (s, 1H), 7.56 (d, J = 1.6 Hz, 2H), 7.09 (d, J = 8.3 Hz, 1H), 6.94 (dd, J = 8.2, 1.6 Hz, 1H), 6.79 (s, 2H), 6.22 (s, 2H), 2.61 (s, 3H), 1.77 (s, 3H), 1.68 (s, 3H); Compound 11-2 (peak 2, retention time 2.99 min), ESI-MS m / z: 367.1 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ9.56 (s, 1H), 7.56 (s, 2H), 7.09 (d, J = 8.3Hz, 1H), 6.94 (d ,J=8.3Hz,1H),6.79(s,2H),6.22(s,2H),2.61(s,3H),1.77(s,3H),1.68(s,3H).

[0653] Example 12

[0654] 7-amino-6-(3-hydroxy-2,6-dimethylphenyl)-4-({[(3S)-1-methyltetrahydro-1H-pyrrol-3-yl]methyl}oxy)furo[2,3-d]pyrrolo[2,3-b]pyridine-8-carboxamide (Compound 12)

[0655]

[0656] Step 1: (3S)-2-methylpropan-2-yl 3-{[(6,7-dibromofuro[3,2-c]pyridin-4-yl)oxy]methyl}tetrahydropyrrole-1-carboxylate

[0657]

[0658] Dissolve (3S)-3-(Hydroxymethyl)tetrahydropyrrole-1-carboxylic acid-2-methylpropane-2-yl ester (481 mg, 2.39 mmol) in tetrahydrofuran (15 mL), add sodium hydride (95 mg, 2.39 mmol) at 0°C, stir at room temperature for 30 minutes, add 6,7-dibromo-4-chlorofurano[3,2-c]pyridine (500 mg, 1.6 mmol), and react at 70°C for 7 hours. The reaction solution was cooled to room temperature, diluted with water, and extracted with ethyl acetate. The organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10:1, volume ratio) to obtain the product as a white solid (620 mg, 81.2%). ESI-MS m / z: 474.9 [M+1] + . 1 H NMR(400MHz,Chloroform-d)δ7.62(d,J=2.2Hz,1H),6.88(d,J=2.2Hz,1H),4.47(dd,J=10 .7,6.4Hz,1H),4.37(dd,J=10.7,7.4Hz,1H),3.62(dd,J=11.0,7.4Hz,1H),3.52(ddd,J=10 .8,8.1,4.8Hz,1H),3.39(dt,J=10.9,7.6Hz,1H),3.25(dd,J=11.0,7.0Hz,1H),2.74(p,J= 7.1Hz, 1H), 2.10 (dtd, J=12.1, 7.2, 4.9Hz, 1H), 1.81 (dq, J=12.6, 7.9Hz, 1H), 1.48 (s, 9H).

[0659] Step 2: (3S)-2-methylpropan-2-yl 3-[({7-bromo-6-[(3-methoxy-2,6-dimethylphenyl)amino]furo[3,2-c]pyridin-4-yl}oxy)methyl]tetrahydropyrrole-1-carboxylate

[0660]

[0661] Dissolve (3S)-3-{[(6,7-dibromofurano[3,2-c]pyridin-4-yl)oxy]methyl}tetrahydropyrrole-1-carboxylic acid-2-methylpropane-2-yl ester (600 mg, 1.26 mmol) and 3-methoxy-2,6-dimethylaniline (378 mg, 2.52 mmol) in ethylene glycol dimethyl ether (25 mL), add cesium carbonate (819 mg, 2.52 mmol), bis(dibenzylideneacetone)palladium (110 mg, 0.12 mmol) and 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (145 mg, 0.25 mmol). React at 110°C for 4 hours under nitrogen protection. Cool the reaction solution to room temperature and filter with diatomaceous earth. The residue was concentrated under reduced pressure and chromatographed on a silica gel column (petroleum ether / ethyl acetate = 10:1, volume ratio) to give the product as a white solid (540 mg, yield 78.7%). ESI-MS m / z: 546.1 [M+H] + . 1 H NMR(400MHz,Chloroform-d)δ7.41(d,J=2.2Hz,1H),7.06(d,J=8.3Hz,1H),6.77–6.70 (m,2H),6.19(s,1H),4.02(dd,J=10.9,6.8Hz,1H),3.94(dd,J=10.9,7.0Hz,1H),3.85 (s,3H),3.34(t,J=9.1Hz,2H),3.23(dt,J=10.8,7.7Hz,1H),2.99–2.87(m,1H),2.43( p,J=7.3Hz,1H),2.17(s,3H),2.11(s,3H),1.76(dq,J=12.1,6.0Hz,1H),1.47(s,9H).

[0662] Step 3: (3S)-2-methylpropan-2-yl 3-({[7-amino-8-cyano-6-(3-methoxy-2,6-dimethylphenyl)furo[2,3-d]pyrrolo[2,3-b]pyridin-4-yl]oxy}methyl)tetrahydropyrrole-1-carboxylate

[0663]

[0664] Dissolve malononitrile (627 mg, 9.5 mmol) in ethylene glycol dimethyl ether (40 mL), cool to 0°C, slowly add sodium hydride (380 mg, 9.5 mmol), and stir at room temperature for 0.5 hours. Add (1,1'-bis(diphenylphosphino)ferrocene)palladium dichloride (68 mg, 0.095 mmol) and (3S)-3-[({7-bromo-6-[(3-methoxy-2,6-dimethylphenyl)amino]furano[3,2-c]pyridin-4-yl}oxy)methyl]tetrahydropyrrole-1-carboxylic acid-2-methylpropane-2-yl ester (520 mg, 0.95 mmol). Under nitrogen protection, react at 130°C for 16 hours. The reaction solution is cooled to room temperature, diluted with water, and extracted with ethyl acetate. The organic phase was washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was chromatographed on a silica gel column (petroleum ether / ethyl acetate = 4:1, volume ratio) to obtain the product as a yellow solid (110 mg, yield 22%). ESI-MS m / z: 532.2 [M+H] + . 1 H NMR(400MHz,Chloroform-d)δ7.60(d,J=2.2Hz,1H),7.21(s,1H),6.98(d,J=8.4Hz,1H),6.91–6.84(m,1H),4.13(d,J=7.1Hz,3H),3.92(s,3H), 3.50(s,1H),3.41(s,1H),3.31(t,J=8.5Hz,1H),3.11(s,1H),2.59(p,J =7.1Hz,1H),1.93(d,J=1.2Hz,4H),1.86(d,J=1.4Hz,3H),1.46(s,9H).

[0665] Step 4: 7-amino-4-({[(3S)-tetrahydro-1H-pyrrol-3-yl]methyl}oxy)-6-(3-methoxy-2,6-dimethylphenyl)furo[2,3-d]pyrrolo[2,3-b]pyridine-8-carboxamide

[0666]

[0667] Dissolve (3S)-3-({[7-amino-8-cyano-6-(3-methoxy-2,6-dimethylphenyl)furo[2,3-d]pyrrolo[2,3-b]pyridin-4-yl]oxy}methyl)tetrahydropyrrole-1-carboxylic acid-2-methylpropane-2-yl ester (100 mg, 0.188 mmol) in concentrated sulfuric acid (3 mL) and react at room temperature with stirring for 1 hour. Add the reaction solution dropwise to methanol (20 mL) under ice bath, add water (20 mL), adjust the pH to 10 with concentrated ammonia water, and then extract with ethyl acetate (80 mL). Wash the organic phase with saturated sodium chloride solution, dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain a crude product (85 mg). ESI-MS m / z: 450.2[[M+1]+.

[0668] Step 5: 7-amino-4-({[(3S)-1-methyltetrahydro-1H-pyrrol-3-yl]methyl}oxy)-6-(3-methoxy-2,6-dimethylphenyl)furo[2,3-d]pyrrolo[2,3-b]pyridine-8-carboxamide

[0669]

[0670] The crude product (85 mg) obtained in step 4 was dissolved in tetrahydrofuran (3 mL), 2 drops of 30% formaldehyde aqueous solution were added, sodium triacetyl borohydride (199 mg, 0.94 mmol) was added, and the mixture was stirred at room temperature for 5 minutes. The mixture was diluted with water, extracted with ethyl acetate, washed with saturated sodium bicarbonate, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a yellow solid residue (90 mg, yield 103%). ESI-MS m / z: 464.2 [M+1] + .

[0671] Step 6: 7-amino-6-(3-hydroxy-2,6-dimethylphenyl)-4-({[(3S)-1-methyltetrahydro-1H-pyrrol-3-yl]methyl}oxy)furo[2,3-d]pyrrolo[2,3-b]pyridine-8-carboxamide

[0672]

[0673] 7-amino-4-({[(3S)-1-methyltetrahydro-1H-pyrrol-3-yl]methyl}oxy)-6-(3-methoxy-2,6-dimethylphenyl)furo[2,3-d]pyrrolo[2,3-b]pyridine-8-carboxamide (90 mg, 0.188 mmol) obtained in step 5 was dissolved in dichloromethane (3 mL), and boron tribromide (470 mg, 1.88 mmol) was added and stirred at room temperature for 5 minutes. Methanol was added to quench, and the mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC to give the product as a white solid (5 mg, yield 5.8%). ESI-MS m / z: 450.2[M+1] + . 1 H NMR (400MHz, Methanol-d4) δ8.54(s,2H),7.77(d,J=2.2Hz,1H),7.09(d,J=8.3Hz,1H),6.97(d,J=2.3Hz,1H),6.90(d,J=8.3Hz,1H),4.30–4. 14(m,3H),3.19(s,2H),3.08(d,J=8.8Hz,2H),2.93(s,1H),2.82(d,J=7.5Hz,1H),2.70(s,3H),1.89(d,J=2.4Hz,3H),1.82(d,J=3.3Hz,3H).

[0674] Embodiment 13

[0675] 7-amino-6-(3-hydroxy-2,6-dimethylphenyl)-4-({[(3R)-1-methyltetrahydro-1H-pyrrol-3-yl]methyl}oxy)furo[2,3-d]pyrrolo[2,3-b]pyridine-8-carboxamide (Compound 13)

[0676]

[0677] Compound 13 was prepared from the intermediate 6,7-dibromo-4-chlorofuro[3,2-c]pyridine and the raw material (3R)-3-(hydroxymethyl)tetrahydropyrrole-1-carboxylic acid-2-methylprop-2-yl ester according to the experimental process of Example 12. ESI-MS m / z: 450.2 [M+1] + . 1H NMR (400MHz, DMSO-d6) δ9.51(d,J=3.7Hz,1H),7.97(d,J=2.3Hz,1H),7.07(dd,J=8.3,4.2Hz,1H),7.00(d,J=2.3Hz,2H),6.92–6.88(m, 1H),6.61(s,2H),4.21(dt,J=11.1,4.0Hz,1H),4.00(s,1H),2.94(s,1H),2.19(s,2H),1.80(d,J=1.9Hz,3H),1.71(s,3H),1.64(s,3H).

[0678] Embodiment 14

[0679] 7-amino-6-(3-hydroxy-2,6-dimethylphenyl)-4-{[(3S)-1-methylpiperidin-3-yl]oxy}furo[2,3-d]pyrrolo[2,3-b]pyridine-8-carboxamide (Compound 14)

[0680]

[0681] Step 1: (3S)-2-methylpropan-2-yl 3-[(6,7-dibromofuro[3,2-c]pyridin-4-yl)oxy]piperidine-1-carboxylate

[0682]

[0683] In a 100 mL round-bottom flask, add a solution of (3S)-3-hydroxypiperidin-1-carboxylic acid-2-methylpropane-2-yl ester (484.82 mg, 2.41 mmol) dissolved in tetrahydrofuran (30 mL), add sodium hydride (96.35 mg, 2.41 mmol), stir at room temperature for 15 minutes, add 6,7-dibromo-4-chlorofurano[3,2-c]pyridine (508 mg, 1.62 mmol), and stir at 70°C for 8 hours. Dilute with water (60 mL), extract with ethyl acetate (2×30 mL), combine the organic phases, and wash with saturated brine (30 mL). The organic phase is dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue is purified by silica gel column chromatography (ethyl acetate-petroleum ether, 0-20% gradient elution) to obtain a white solid (730 mg, yield 95.5%). ESI-MS m / z:475.0[M+H] + . 1H NMR(400MHz,Chloroform-d)δ7.59(d,J=2.2Hz,1H),6.84(d,J=2.2Hz,1H),3.84-3.79(m,1H ),3.62-3.58(m,2H),3.36-3.30(m,1H),2.03-1.86(m,3H),2.01-1.91(m,2H),1.28(s,9H).

[0684] Step 2: (3S)-2-methylpropan-2-yl 3-({7-bromo-6-[(3-methoxy-2,6-dimethylphenyl)amino]furo[3,2-c]pyridin-4-yl}oxy)piperidin-1-carboxylate

[0685]

[0686] In a 25 mL reaction tube, add (3S)-3-[(6,7-dibromofurano[3,2-c]pyridin-4-yl)oxy]piperidine-1-carboxylic acid-2-methylpropane-2-yl ester (386 mg, 0.81 mmol), 3-methoxy-2,6-dimethylaniline (244.12 mg, 1.61 mmol), cesium carbonate (67.97 mg, 0.21 mmol), bis(dibenzylideneacetone)palladium (9.6 mg, 0.16 mmol), 4,5-bis(diphenylphosphino-9,9-dimethylxanthene) (12.09 mg, 0.02 mmol) and ethylene glycol dimethyl ether (20 mL). Under argon protection, the reaction solution was stirred at 110°C for 4 hours. Water (10 mL) was added and extracted with ethyl acetate (3×20 mL). The organic phases were combined and washed with saturated brine (1×50 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and chromatographed on a silica gel column (ethyl acetate-petroleum ether, 0-30% gradient elution) to obtain the product. ESI-MS m / z: 544,546 [M+H] +1 H NMR(400MHz,Chloroform-d)δ7.40(d,J=2.2Hz,1H),7.05(d,J=8.3Hz,1H),6.75(d,J=8.4Hz,1H),6.70(d,J=2.2Hz,1H),6.1 6(s,1H),3.85(s,3H),3.71–3.54(m,2H),3.19-3.04(m,2H),2.18(s,3H),2.12(s,3H),1.59(s,4H),1.26(d,J=14.9Hz,9H).

[0687] Step 3: (3S)-2-methylpropan-2-yl 3-{[7-amino-8-cyano-6-(3-methoxy-2,6-dimethylphenyl)furo[2,3-d]pyrrolo[2,3-b]pyridin-4-yl]oxy}piperidin-1-carboxylate

[0688]

[0689] Sodium hydride (204.96 mg, 5.12 mmol) was added to a reaction tube containing ethylene glycol dimethyl ether (10 mL). A solution of malononitrile (338.48 mg, 5.12 mmol) in ethylene glycol dimethyl ether (3 mL) was added dropwise under ice bath. The mixture was stirred at room temperature for 0.5 hour. (3S)-3-({7-bromo-6-[(3-methoxy-2,6-dimethylphenyl)amino]furano[3,2-c]pyridin-4-yl}oxy)piperidine-1-carboxylic acid-2-methylpropan-2-yl ester (280 mg, 0.51 mmol), (1,1'-bis(diphenylphosphino)ferrocene)palladium dichloride) (37.49 mg, 0.05 mmol) and ethylene glycol dimethyl ether (2 mL) were added under ice bath. The reaction solution was reacted at 130° C. for 20 hours under argon protection. Water (40 mL) and ethyl acetate (50 mL*3) were added for extraction, the organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate-petroleum ether, 0-30% gradient elution) to obtain the product (80 mg, 30%). ESI-MS m / z: 532.1 [M+H] + . 1 H NMR (400MHz, Chloroform-d) δ7.57(d,J=2.2Hz,1H),7.19(dd,J=8.6,4.0Hz,1H),6.95(d,J=8.5Hz,1H),6.83(d,J=2.2Hz,1H),4.89(s, 1H),4.37(s,2H),3.89(s,3H),1.95(s,2H),1.90(s,2H),1.87(s,2H),1.82(s,2H),1.46–1.37(m,3H),1.31–1.22(m,3H),1.20(s,9H).

[0690] Step 4: 7-amino-4-{[(3S)-piperidin-3-yl]oxy}-6-(3-methoxy-2,6-dimethylphenyl)furo[2,3-d]pyrrolo[2,3-b]pyridine-8-carboxamide

[0691]

[0692] Add (3S)-3-{[7-amino-8-cyano-6-(3-methoxy-2,6-dimethylphenyl)furano[2,3-d]pyrrolo[2,3-b]pyridin-4-yl]oxy}piperidine-1-carboxylic acid-2-methylpropane-2-yl ester (100 mg, 0.19 mmol) to a 25 mL round-bottom flask, add concentrated sulfuric acid (2 mL), and react at room temperature for 1 hour. Under ice bath, slowly add methanol, adjust pH to alkaline with ammonia water, add ethyl acetate (50 mL × 3) for extraction, combine the organic phases, wash once with saturated brine (50 mL), dry over anhydrous sodium sulfate, evaporate to dryness under reduced pressure, and the residue is directly used for the next step. ESI-MS m / z: 450.2 [M+H] + .

[0693] Step 5: 7-amino-4-{[(3S)-1-methylpiperidin-3-yl]oxy}-6-(3-methoxy-2,6-dimethylphenyl)furo[2,3-d]pyrrolo[2,3-b]pyridine-8-carboxamide

[0694]

[0695] In a 25 mL round-bottom flask, add 7-amino-4-{[(3S)-hexahydropyridin-3-yl]oxy}-6-(3-methoxy-2,6-dimethylphenyl)furano[2,3-d]pyrrolo[2,3-b]pyridine-8-carboxamide (79 mg, 0.18 mmol), tetrahydrofuran (4 mL), formaldehyde aqueous solution (37% w / w, 18.04 mg, 0.22 mmol), sodium triacetoxyborohydride (111.74 mg, 0.53 mmol). The reaction solution was stirred at room temperature for 30 minutes. Dilute with water (20 mL) and extract with ethyl acetate (3×20 mL). Combine the organic phases and wash with saturated brine (50 mL). Dry the organic phase with anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain a crude product (80 mg, 0.18 mmol), which is directly reacted in the next step. ESI-MS m / z:464.2[M+H] + .

[0696] Step 6: 7-amino-6-(3-hydroxy-2,6-dimethylphenyl)-4-{[(3S)-1-methylpiperidin-3-yl]oxy}furo[2,3-d]pyrrolo[2,3-b]pyridine-8-carboxamide.

[0697]

[0698] 7-amino-4-{[(3S)-1-methylhexahydropyridin-3-yl]oxy}-6-(3-methoxy-2,6-dimethylphenyl)furo[2,3-d]pyrrolo[2,3-b]pyridine-8-carboxamide (130 mg, 0.28 mmol), dichloromethane (6 mL) and boron tribromide (1.0 mL, 1.66 mmol) were added to a 25 mL round-bottom flask. The reaction solution was stirred at 0°C for 30 minutes. Methanol (20 mL) and water (10 mL) were added to the reaction solution, and the pH was adjusted to 8 with aqueous ammonia, and extracted with ethyl acetate (3×20 mL). The organic phases were combined and washed with saturated brine (50 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC to give the product (20 mg). ESI-MS m / z: 450.2 [M+H] + . 1 H NMR(400MHz, DMSO-d6)δ8.30(s,1H),7.95(d,J=2.3Hz,1H),7.07(d,J=8.3H z,1H),6.96(d,J=2.3Hz,2H),6.92(d,J=8.2Hz,1H),6.62(s,2H),4.70(tt,J =8.3,4.0Hz,1H),2.84-2.80(m,1H),2.46-2.42(m,1H),2.09(s,3H),2.05–1 .92(m,3H),1.80(s,3H),1.70(s,3H),1.69-1.63(m,1H),1.40-1.28(m,2H).

[0699] Embodiment 15

[0700] 7-amino-6-(3-hydroxy-2,6-dimethylphenyl)-4-{[(3S)-1-methylpiperidin-3-yl]oxy}-2,3-dihydrofuro[2,3-d]pyrrolo[2,3-b]pyridine-8-carboxamide (Compound 15)

[0701]

[0702] Compound 15 was prepared from compound 14 according to the experimental process of Example 8. ESI-MS m / z: 452.2 [M+H] + .

[0703] Example 16

[0704] 7-amino-6-(3-hydroxy-2,6-dimethylphenyl)-4-{[(3R)-1-methylpiperidin-3-yl]oxy}furo[2,3-d]pyrrolo[2,3-b]pyridine-8-carboxamide (Compound 16)

[0705]

[0706] Compound 16 was prepared from the intermediate 6,7-dibromo-4-chlorofuro[3,2-c]pyridine and the raw material (3R)-3-hydroxypiperidin-1-carboxylic acid 2-methylpropan-2-yl ester according to the experimental process of Example 14. ESI-MS m / z: 450.2 [M+1] + . 1 H NMR (400MHz, Methanol-d4) δ8.54(s,2H),7.77(d,J=2.2Hz,1H),7.09(d,J=8.3Hz,1H),6.97(d,J=2.3Hz,1H),6.90(d,J=8.3Hz,1H),4.30–4. 14(m,3H),3.19(s,2H),3.08(d,J=8.8Hz,2H),2.93(s,1H),2.82(d,J=7.5Hz,1H),2.70(s,3H),1.89(d,J=2.4Hz,3H),1.82(d,J=3.3Hz,3H).

[0707] Embodiment 17

[0708] 7-amino-6-(3-hydroxy-2,6-dimethylphenyl)-4-(4-azabicyclo[2.2.2]oct-7-yloxy)furo[2,3-d]pyrrolo[2,3-b]pyridine-8-carboxamide (Compound 17)

[0709]

[0710] Step 1: 4-(Benzyloxy)-6,7-dibromofuro[3,2-c]pyridine

[0711]

[0712] Dissolve benzyl alcohol (972 mg, 9.0 mmol) in tetrahydrofuran (20 mL), add sodium hydride (360 mg, 9.0 mmol) at 0 ° C, stir at room temperature for 30 minutes, then add 6,7-dibromo-4-chlorofuran [3,2-c] pyridine (1.86 g, 6 mmol), and react at 70 ° C for 7 hours. The reaction solution was cooled to room temperature, diluted with water, and extracted with ethyl acetate. The organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10:1, volume ratio) to obtain the product as a white solid (2.1 g, 91.3%). ESI-MS m / z: 381.9 [M+1] + . 1H NMR (400MHz, Chloroform-d) δ7.61(d,J=2.1Hz,1H),7.56–7.50(m,2H),7.45–7.36(m,3H),6.91(d,J=2.2Hz,1H),5.51(s,2H).

[0713] Step 2: 4-(Benzyloxy)-7-bromo-6-[(3-methoxy-2,6-dimethylphenyl)amino]furo[3,2-c]pyridine

[0714]

[0715] 4-(Benzyloxy)-6,7-dibromofurano[3,2-c]pyridine (2.0 g, 5.25 mmol) and 3-methoxy-2,6-dimethylaniline (1.57 g, 10.5 mmol) were dissolved in ethylene glycol dimethyl ether (100 mL), and cesium carbonate (3.41 mg, 10.5 mmol), bis(dibenzylideneacetone)palladium (480 mg, 0.525 mmol) and 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (606 mg, 1.05 mmol) were added. Under nitrogen protection, the reaction was carried out at 110°C for 4 hours. The reaction solution was cooled to room temperature and filtered through diatomaceous earth. The product was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10:1, volume ratio) to obtain the product as a white solid (2.07 g, yield 87.0%). ESI-MS m / z: 453.1 [M+H] + . 1 H NMR(400MHz,Chloroform-d)δ7.41–7.37(m,1H),7.25–7.17(m,3H),7.12(d,J=8.3Hz,1H),7.06–6.98(m,2H),6.81(d, J=8.4Hz,1H),6.75(dt,J=2.4,1.2Hz,1H),6.16(s,1H),5.08(s,2H),3.90(d,J=1.4Hz,3H),2.15(s,3H),2.10(s,3H).

[0716] Step 3: 7-amino-4-(benzyloxy)-6-(3-methoxy-2,6-dimethylphenyl)furo[2,3-d]pyrrolo[2,3-b]pyridine-8-carbonitrile

[0717]

[0718] Malononitrile (2.75 g, 41.8 mmol) was dissolved in ethylene glycol dimethyl ether (150 mL), cooled to 0 ° C, sodium hydride (1.67 g, 41.8 mmol) was slowly added, and the reaction was stirred at room temperature for 0.5 hours. (1,1'-bis(diphenylphosphino)ferrocene) palladium dichloride (300 mg, 0.418 mmol) and 4-(benzyloxy)-7-bromo-6-[(3-methoxy-2,6-dimethylphenyl)amino]furano[3,2-c]pyridine (1.89 g, 4.18 mmol) were added. Under nitrogen protection, the reaction was carried out at 130 ° C for 16 hours. The reaction solution was cooled to room temperature, diluted with water, and extracted with ethyl acetate. The organic phase was then washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was chromatographed on a silica gel column (petroleum ether / ethyl acetate = 4:1, volume ratio) to obtain the product, a yellow solid (265 mg, yield 14.7%). ESI-MS m / z:439.1[M+H] + . 1 H NMR(400MHz,DMSO-d6)δ7.94(d,J=2.2Hz,1H),7.31(d,J=8.5Hz,1H),7.23–7.13(m,6H), 6.99(d,J=2.2Hz,1H),6.66(s,2H),5.12(s,2H),3.88(s,3H),1.77(s,3H),1.68(s,3H).

[0719] Step 4: 2-methylpropan-2-yl {[4-(benzyloxy)-8-cyano-6-(3-methoxy-2,6-dimethylphenyl)furo[2,3-d]pyrrolo[2,3-b]pyridin-7-yl]{[(2-methylpropan-2-yl)oxy]carbonyl}amino}methanoate

[0720]

[0721] 7-amino-4-(benzyloxy)-6-(3-methoxy-2,6-dimethylphenyl)furano[2,3-d]pyrrolo[2,3-b]pyridine-8-carbonitrile (250 mg, 0.57 mmol), triethylamine (172 mg, 1.71 mmol), 4-dimethylaminopyridine (34 mg, 0.29 mmol) and di-tert-butyl dicarbonate (372 mg, 1.71 mmol) were dissolved in tetrahydrofuran (5 mL) and reacted at room temperature for 1 hour. The reaction solution was diluted with water and extracted with ethyl acetate. The organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was chromatographed on a silica gel column (petroleum ether / dichloromethane = 1:1, volume ratio) to obtain the product as a white solid (200 mg, yield 54.9%). ESI-MS m / z: 639.2 [M+H] + .1 H NMR (400MHz, DMSO-d6) δ8.16(d,J=2.2Hz,1H),7.32–7.15(m,8H),5.22(s,2H),3.87(s,3H),1.75(s,3H),1.61(s,3H),1.33(s,18H).

[0722] Step 5: 2-Methylpropan-2-yl {[8-cyano-4-hydroxy-6-(3-methoxy-2,6-dimethylphenyl)furo[2,3-d]pyrrolo[2,3-b]pyridin-7-yl]{[(2-methylpropan-2-yl)oxy]carbonyl}amino}methanoate

[0723]

[0724] Dissolve {[4-(benzyloxy)-8-cyano-6-(3-methoxy-2,6-dimethylphenyl)furano[2,3-d]pyrrolo[2,3-b]pyridin-7-yl]{[(2-methylpropan-2-yl)oxy]carbonyl}amino}methane acid-2-methylpropan-2-yl ester (200 mg, 0.31 mmol) in methanol (4 mL), add 10% palladium carbon (80 mg), and stir at room temperature for 30 minutes. Filter with celite, concentrate under reduced pressure, and the residue is chromatographed on a silica gel column (petroleum ether / ethyl acetate = 5:1, volume ratio) to obtain the product as a white solid (167 mg, yield 97.2%). ESI-MS m / z: 549.2 [M+1] + . 1 H NMR(400MHz,DMSO-d6)δ8.09(d,J=2.2Hz,1H),7.22(d,J=8.5Hz,1H),7.15–7 .04(m,2H),3.82(s,3H),1.82(s,3H),1.67(s,3H),1.33(d,J=15.0Hz,18H).

[0725] Step 6: 2-methylpropan-2-yl {[8-cyano-6-(3-methoxy-2,6-xylyl)-4-(4-azabicyclo[2.2.2]oct-2-yloxy)furo[2,3-d]pyrrolo[2,3-b]pyridin-7-yl]{[(2-methylpropan-2-yl)oxy]carbonyl}amino}methanoate

[0726]

[0727] {[8-cyano-4-hydroxy-6-(3-methoxy-2,6-dimethylphenyl)furano[2,3-d]pyrrolo[2,3-b]pyridin-7-yl]{[(2-methylpropan-2-yl)oxy]carbonyl}amino}methane acid-2-methylpropan-2-yl ester (160 mg, 0.29 mmol), 4-azabicyclo[2.2.2]octan-7-ol (185 mg, 1.46 mmol) and triphenylphosphine (382 mg, 1.46 mmol) were dissolved in toluene (8 mL), and diisopropyl azodicarboxylate (294 mg, 1.46 mmol) was added. Nitrogen was protected and stirred at 100°C for 2 hours. After cooling to room temperature, the mixture was diluted with water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was chromatographed on a silica gel column to obtain the product as a white solid (170 mg, yield 88.6%). ESI-MS m / z: 658.3[M+1] + . 1 H NMR(400MHz,DMSO-d6)δ8.16(d,J=2.2Hz,1H),7.24(dd,J=8.5,3.0Hz,1H),7.20–7.09(m ,2H),4.71(dd,J=8.1,4.0Hz,1H),3.83(d,J=4.7Hz,3H),2.94(dd,J=15.1,7.9Hz,1H),2. 87–2.59(m,5H),2.06–2.00(m,1H),1.95–1.85(m,1H),1.80(d,J=15.4Hz,3H),1.67(d,J =17.8Hz, 3H), 1.60 (d, J = 13.2Hz, 1H), 1.34 (q, J = 5.6, 4.6Hz, 18H), 1.23 (d, J = 7.0Hz, 2H).

[0728] Step 7: 7-amino-6-(3-methoxy-2,6-dimethylphenyl)-4-(4-azabicyclo[2.2.2]oct-7-yloxy)furo[2,3-d]pyrrolo[2,3-b]pyridine-8-carbonitrile

[0729]

[0730] Dissolve {[8-cyano-6-(3-methoxy-2,6-dimethylphenyl)-4-(4-azabicyclo[2.2.2]oct-2-yloxy)furano[2,3-d]pyrrolo[2,3-b]pyridin-7-yl]{[(2-methylpropan-2-yl)oxy]carbonyl}amino}methane acid-2-methylpropan-2-yl ester (160 mg, 0.24 mmol) in methanol (4 mL), add dilute hydrochloric acid (4 mL, 1 M), and stir at 75 ° C for 3 hours. After cooling to room temperature, drain, dilute with water, extract with ethyl acetate, wash with saturated sodium bicarbonate, wash with saturated brine, dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain a residue (120 mg, yield 110%). ESI-MS m / z: 458.2 [M+1] + .

[0731] Step 8: 7-amino-6-(3-methoxy-2,6-dimethylphenyl)-4-(4-azabicyclo[2.2.2]oct-2-yloxy)furo[2,3-d]pyrrolo[2,3-b]pyridine-8-carboxamide

[0732]

[0733] Dissolve 7-amino-6-(3-methoxy-2,6-dimethylphenyl)-4-(4-azabicyclo[2.2.2]oct-7-yloxy)furano[2,3-d]pyrrolo[2,3-b]pyridine-8-carbonitrile (110 mg, 0.24 mmol) obtained in step 7 in concentrated sulfuric acid (4 mL) and stir at room temperature for 1 hour. Add the reaction solution dropwise to methanol under ice bath, add ice water, adjust the ammonia water to alkalinity, extract with ethyl acetate, wash with saturated sodium chloride solution, dry with anhydrous sodium sulfate, and concentrate under reduced pressure to obtain a yellow oily residue (125 mg, yield 109%). ESI-MS m / z: 476.2[M+1] + .

[0734] Step 9: 7-amino-6-(3-hydroxy-2,6-dimethylphenyl)-4-(4-azabicyclo[2.2.2]oct-7-yloxy)furo[2,3-d]pyrrolo[2,3-b]pyridine-8-carboxamide

[0735]

[0736] 7-amino-6-(3-methoxy-2,6-dimethylphenyl)-4-(4-azabicyclo[2.2.2]oct-2-yloxy)furo[2,3-d]pyrrolo[2,3-b]pyridine-8-carboxamide (125 mg, 0.4 mmol) obtained in step 5 was dissolved in dichloromethane (4 mL), and boron tribromide (575 mg, 2.3 mmol) was added and stirred at room temperature for 5 minutes. Methanol was added to quench, and the mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC to give the product as a white solid (5 mg, yield 4.5%). ESI-MS m / z: 462.1[M+1] + . 1 HNMR (400MHz, Methanol-d4) δ8.57(s,1H),7.80(d,J=2.3Hz,1H),7.12(d,J=8.2Hz,1H),7.01(d,J=2.3Hz,1H),6.93(d,J=8.2Hz,1H),4.99– 4.95(m,1H),3.27(d,J=8.2Hz,1H),3.22–2.99(m,5H),2.94(d,J=10.2Hz,1H),2.36–2.19(m,2H),1.87(d,J=26.5Hz,8H),1.78–1.66(m,2H).

[0737] Embodiment 18

[0738] 7-amino-6-(3-hydroxy-2,6-dimethylphenyl)-4-(4-azabicyclo[2.2.2]oct-7-yloxy)-2,3-dihydrofuro[2,3-d]pyrrolo[2,3-b]pyridine-8-carboxamide (Compound 18)

[0739]

[0740] Compound 18 was prepared from compound 17 according to the experimental process of Example 8. ESI-MS m / z: 464.2 [M+H] + .

[0741] Embodiment 19

[0742] 7-amino-6-(3-hydroxy-2,6-dimethylphenyl)-4-({[(methylamino)cyclopropyl]methyl}oxy)furo[2,3-d]pyrrolo[2,3-b]pyridine-8-carboxamide (Compound 19)

[0743]

[0744] Compound 19 was prepared from the intermediate 6,7-dibromo-4-chlorofuro[3,2-c]pyridine and the raw material {[(hydroxymethyl)cyclopropyl](methyl)amino}methanoic acid-2-methylpropan-2-yl ester according to the experimental process of Example 14. ESI-MS m / z: 436.0 [M+1] + . 1 H NMR (400MHz, Methanol-d4) δ7.77(d,J=2.3Hz,1H),7.11(d,J=8.3Hz,1H),7.03(d,J=2.3Hz,1H),6.9 3(d,J=8.3Hz,1H),4.28(s,2H),2.23(s,3H),1.90(s,3H),1.85(s,3H),0.61(dt,J=6.7,2.0Hz,4H).

[0745] Embodiment 20

[0746] 7-amino-6-(3-hydroxy-2,6-dimethylphenyl)-4-({[(methylamino)cyclopropyl]methyl}oxy)-2,3-dihydrofuro[2,3-d]pyrrolo[2,3-b]pyridine-8-carboxamide (Compound 20)

[0747]

[0748] Compound 20 was prepared from compound 19 according to the experimental process of Example 8. ESI-MS m / z: 438.0 [M+1] + . 1 H NMR(400MHz, Methanol-d4)δ7.09(d,J=8.3Hz,1H),6.90(d,J=8.2Hz,1H),4.84(s,2H),4.16(s, 2H),3.22(t,J=8.7Hz,2H),2.17(s,3H),1.89(s,3H),1.84(s,3H),0.57(dt,J=8.1,2.1Hz,4H).

[0749] Embodiment 21

[0750] 7-amino-6-(3-hydroxy-2,6-dimethylphenyl)-4-[(1-methylpiperidin-4-yl)thio]furo[2,3-d]pyrrolo[2,3-b]pyridine-8-carboxamide (Compound 21)

[0751]

[0752] Step 1: 2-methylpropan-2-yl 4-[(6,7-dibromofuro[3,2-c]pyridin-4-yl)thio]piperidin-1-carboxylate

[0753]

[0754] Dissolve 4-thiopyridine-1-carboxylic acid 2-methylpropane-2-yl ester (422.29 mg, 1.95 mmol) in tetrahydrofuran (33 mL), add sodium hydride (78 mg, 1.95 mmol) and stir at room temperature for 30 minutes. Add 6,7-dibromo-4-chlorofuran [3,2-c] pyridine (550 mg, 1.77 mmol), heat to 100 ° C and stir for 1 hour. After the reaction is completed, add saturated ammonium chloride (50 mL) to quench, add water (300 mL) and ethyl acetate (300 mL) to extract, then wash with saturated brine (200 ml), dry over anhydrous sodium sulfate, and concentrate under reduced pressure. The residue is chromatographed on a silica gel column (petroleum ether / ethyl acetate = 10:1, volume ratio) to obtain the product, a colorless oily liquid (330 mg, yield 41%). ESI-MS m / z: 491.0 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ8.23(d,J=2.3Hz,1H),7.15(d,J=2.3Hz,1H),4.12–4.0 0(m,1H),3.84–3.72(m,2H),2.15–2.02(m,2H),1.64–1.54(m,2H),1.41(s,9H).

[0755] Step 2: 2-methylpropan-2-yl 4-({7-bromo-6-[(3-methoxy-2,6-dimethylphenyl)amino]furo[3,2-c]pyridin-4-yl}thio)piperidin-1-carboxylate

[0756]

[0757] Dissolve 2-methylpropane-2-yl 4-[(6,7-dibromofurano[3,2-c]pyridin-4-yl)thio]piperidine-1-carboxylate (360 mg, 0.73 mmol) and 3-methoxy-2,6-dimethylaniline (175 mg, 1.46 mmol) in ethylene glycol dimethyl ether (12 mL), add cesium carbonate (474 ​​mg, 1.46 mmol), bis(dibenzylideneacetone)palladium (66 mg, 0.073 mmol) and 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (84 mg, 0.146 mmol). React at 110°C for 4 hours under nitrogen protection. Cool the reaction solution to room temperature and filter with diatomaceous earth. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10:1, volume ratio) to obtain the product as a white solid (310 mg, yield 75.6%). ESI-MS m / z: 563.3 [M+H] + . 1 H NMR(400MHz,Chloroform-d)δ7.43(d,J=2.3Hz,1H),7.07(d,J=8.3Hz,1H),6.76(d,J=8.3Hz,1H),6.65(d,J=2.2Hz,1H),6.22(s,1H) ,3.85(s,5H),3.42(s,1H),2.46(t,J=12.4Hz,2H),2.16(s,3H),2.09(s,3H),1.73(d,J=12.8Hz,2H),1.47(s,9H),1.44–1.31(m,2H).

[0758] Step 3: 2-methylpropan-2-yl 4-{[7-amino-8-cyano-6-(3-methoxy-2,6-dimethylphenyl)furo[2,3-d]pyrrolo[2,3-b]pyridin-4-yl]thio}piperidin-1-carboxylate

[0759]

[0760] Dissolve malononitrile (324 mg, 4.9 mmol) in ethylene glycol dimethyl ether (15 mL), cool to 0°C, slowly add sodium hydride (196 mg, 4.9 mmol), and stir at room temperature for 0.5 hours. Add (1,1'-bis(diphenylphosphino)ferrocene)palladium dichloride (40 mg, 0.049 mmol) and 4-({7-bromo-6-[(3-methoxy-2,6-dimethylphenyl)amino]furano[3,2-c]pyridin-4-yl}thio)hexahydropyridine-1-carboxylic acid-2-methylpropane-2-yl ester (276 mg, 0.49 mmol). Under nitrogen protection, react at 130°C for 16 hours. The reaction solution is cooled to room temperature, diluted with water, and extracted with ethyl acetate. The organic phase was washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was chromatographed on a silica gel column (petroleum ether / ethyl acetate = 4:1, volume ratio) to obtain the product as a yellow solid (210 mg, yield 78%). ESI-MS m / z: 548.3 [M+H] + . 1 H NMR (400MHz, Chloroform-d) δ7.64(d,J=2.2Hz,1H),7.22(d,J=8.4Hz,1H),6.98(d,J=8.4Hz,1H),6.83(d,J=2.2Hz,1H),4.64(s, 2H),3.91(s,3H),3.90–3.81(m,2H),3.68–3.59(m,1H),2.67(s,2H),1.92(s,3H),1.91–1.87(m,2H),1.84(s,3H),1.46(s,11H).

[0761] Step 4: 7-amino-4-(hexahydropyridin-4-ylthio)-6-(3-methoxy-2,6-dimethylphenyl)furo[2,3-d]pyrrolo[2,3-b]pyridine-8-carboxamide

[0762]

[0763] Dissolve 4-{[7-amino-8-cyano-6-(3-methoxy-2,6-dimethylphenyl)furano[2,3-d]pyrrolo[2,3-b]pyridin-4-yl]sulfanyl}hexahydropyridine-1-carboxylic acid-2-methylpropane-2-yl ester (200 mg, 0.37 mmol) in concentrated sulfuric acid (5 mL) and stir at room temperature for 1 hour. Add the reaction solution dropwise to methanol under ice bath, add ice water, adjust to alkalinity with concentrated ammonia water, extract with ethyl acetate, wash with saturated sodium chloride solution, dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain a crude product as a yellow solid (160 mg), which is directly used in the next step. ESI-MS m / z: 466.4[[M+1] + .

[0764] Step 5: 7-amino-6-(3-methoxy-2,6-dimethylphenyl)-4-[(1-methylpiperidin-4-yl)thio]furo[2,3-d]pyrrolo[2,3-b]pyridine-8-carboxamide

[0765]

[0766] The crude product (160 mg) obtained in step 4 was dissolved in tetrahydrofuran (6 mL), 5 drops of 30% formaldehyde aqueous solution were added, sodium triacetyl borohydride (364 mg, 1.72 mmol) was added, and the mixture was stirred at room temperature for 5 minutes. The mixture was diluted with water, extracted with ethyl acetate, washed with saturated sodium bicarbonate, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product as a yellow solid (150 mg). ESI-MS m / z: 480.4 [M+1] + .

[0767] Step 6: 7-amino-6-(3-hydroxy-2,6-dimethylphenyl)-4-[(1-methylpiperidin-4-yl)thio]furo[2,3-d]pyrrolo[2,3-b]pyridine-8-carboxamide

[0768]

[0769] 7-amino-6-(3-methoxy-2,6-dimethylphenyl)-4-[(1-methylhexahydropyridin-4-yl)thio]furano[2,3-d]pyrrolo[2,3-b]pyridine-8-carboxamide (150 mg, 0.31 mmol) obtained in step 5 was dissolved in dichloromethane (6 mL), and boron tribromide (391 mg, 1.56 mmol) was added and stirred at room temperature for 5 minutes. Methanol was added to quench, and the mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC to give the product as a white solid (45 mg, yield 29%). ESI-MS m / z: 466.4 [M+1] + . 1HNMR(400MHz,Methanol-d4)δ7.82(d,J=2.3Hz,1H),7.12(d,J=8.3Hz,1H),6.9 4(d,J=8.2Hz,1H),6.90(d,J=2.3Hz,1H),3.59(qd,J=11.0,10.1,6.1Hz,1H),3 .12(dt,J=12.1,4.4Hz,2H),2.56(s,3H),2.48(d,J=14.2Hz,2H),2.12(dt,J=1 3.3, 4.1Hz, 2H), 1.87 (s, 3H), 1.82 (s, 3H), 1.73 (dtd, J = 14.4, 10.8, 3.7Hz, 2H).

[0770] Embodiment 22

[0771] 7-Amino-6-(3-hydroxy-2,6-dimethylphenyl)-2,4-dimethylthieno[2,3-d]pyrrolo[2,3-b]pyridine-8-carboxamide (Compound 22)

[0772]

[0773] (R)-7-amino-6-(3-hydroxy-2,6-dimethylphenyl)-2,4-dimethylthieno[3,2-d]pyrrolo[2,3-b]pyridine-8-carboxamide and (S)-7-amino-6-(3-hydroxy-2,6-dimethylphenyl)-2,4-dimethylthieno[3,2-d]pyrrolo[2,3-b]pyridine-8-carboxamide (Compound 22-1 and Compound 22-2)

[0774]

[0775] Step 1: 2-Methyl-7-nitro-4,5-dihydrothieno[3,2-c]pyridin-4-one

[0776]

[0777] 2-Methyl-4,5-dihydrothieno[3,2-c]pyridin-4-one (4 g, 24.21 mmol) was dissolved in acetic acid (80 mL), and nitric acid (1.53 mL, 24.21 mmol) was added dropwise under ice bath. After reacting at room temperature for 1 hour, the reaction solution was heated to 50 °C and stirred for 2 hours. The reactants were concentrated under reduced pressure, and the residue was slurried with petroleum ether to obtain the product, a yellow solid (5.0 g, yield 98.25%). ESI-MS m / z: 210.0 [M+H] + .

[0778] Step 2: 4-Chloro-2-methyl-7-nitrothieno[3,2-c]pyridine

[0779]

[0780] Dissolve 2-methyl-7-nitro-4,5-dihydrothieno[3,2-c]pyridin-4-one (5.0 g, 23.79 mmol) in acetonitrile (100 mL), add phosphorus oxychloride (36.47 g, 237.86 mmol), heat to 90 ° C and stir for 2 hours. Cool to room temperature, concentrate under reduced pressure, add ethyl acetate (300 mL) and water (300 mL) under ice bath, adjust pH to 8 with saturated sodium bicarbonate solution, separate the organic layer, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and the residue is chromatographed on a silica gel column (petroleum ether / dichloromethane = 1:1, volume ratio) to obtain the product, a yellow solid (2.7 g, yield 49.65%). ESI-MS m / z: 227.97 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ9.13 (s, 1H), 7.47 (d, J = 1.8Hz, 1H), 2.69 (d, J = 1.3Hz, 3H).

[0781] Step 3: 2,4-Dimethyl-7-nitrothieno[3,2-c]pyridine

[0782]

[0783] 4-Chloro-2methyl-7-nitrothieno[3,2-c]pyridine (2.7 g, 11.81 mmol), 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane (2.9 g, 22.96 mmol), potassium carbonate (4.9 g, 35.43 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (864 mg, 1.18 mmol) were dissolved in dioxane (28 mL) and water (7 mL), and the temperature was raised to 100 °C and stirred for reaction for 2 hours under argon protection. The reaction solution was cooled to room temperature, ethyl acetate (250 mL) and water (250 mL) were added for extraction, the organic phase was then washed with saturated sodium chloride solution (300 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was chromatographed on a silica gel column (petroleum ether / ethyl acetate = 1:5, volume ratio) to obtain the product as a light yellow solid (1.5 g, yield 61%). ESI-MS m / z: 208.03 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ9.15(d,J=3.6Hz,1H),7.55(dt,J=3.5,1.3Hz,1H),2.84(d,J=2.2Hz,3H),2.65(t,J=1.5Hz,3H).

[0784] Step 4: 2,4-Dimethylthieno[3,2-c]pyridin-7-amine

[0785]

[0786] Dissolve 2,4-dimethyl-7-nitrothieno[3,2-c]pyridine (1.5 g, 6.93 mmol) in methanol (20 mL), add 10% palladium carbon (500 mg, 6.69 mmol), and stir at room temperature under hydrogen atmosphere for 1 hour. The reaction solution was filtered with diatomaceous earth, the filtrate was concentrated under reduced pressure, and the residue was chromatographed on a silica gel column (dichloromethane / methanol = 1:10, volume ratio) to obtain the product (1.3 g). ESI-MS m / z: 178.05 [M+H] + . 1 H NMR (400MHz, Chloroform-d) δ7.82 (s, 1H), 7.08 (q, J = 1.3Hz, 1H), 5.31 (s, 1H), 3.72 (s, 2H), 2.69 (s, 3H), 2.64 (d, J = 1.2Hz, 3H).

[0787] Step 5: 6-Bromo-2,4-dimethylthieno[3,2-c]pyridin-7-amine

[0788]

[0789] Dissolve 2,4-dimethylthieno[3,2-c]pyridin-7-amine (1.3 g, 7.52 mmol) in dichloromethane (40 ml), add N-bromosuccinimide (1.41 g, 8.27 mmol) under ice-water cooling, and stir at room temperature for 5 minutes. After the reaction, add water (200 mL) and ethyl acetate (200 mL) for extraction, and then add saturated sodium sulfite (200 mL) for washing. The organic phase is washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue is chromatographed on a silica gel column (petroleum ether / ethyl acetate = 1:5, volume ratio) to obtain the product, a yellow solid (1.1 g, yield 56.9%). ESI-MS m / z: 257.1 [M+H] + . 1HNMR (400MHz, DMSO-d6) δ7.20(q,J=1.3Hz,1H),5.49(s,2H),2.58(d,J=1.3Hz,3H),2.52(s,3H).

[0790] Step 6: 6,7-Dibromo-2,4-dimethylthieno[3,2-c]pyridine

[0791]

[0792] 6-Bromo-2,4-dimethylthieno[3,2-c]pyridin-7-amine (1.1 g, 4.28 mmol) was dissolved in acetonitrile (40 ml), and copper bromide (955.4 mg, 4.28 mmol) and tert-butyl nitrite (573.4 mg, 5.56 mmol) were added under ice-water cooling. The mixture was stirred at room temperature for 5 minutes, and water (200 mL) and ethyl acetate (200 mL) were added for extraction. The organic phase was washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10:1, volume ratio) to obtain the product as a yellow solid (720 mg, yield 52.43%). ESI-MS m / z: 320.8 [M+H] + .

[0793] Step 7: 7-Bromo-6-[(3-methoxy-2,6-dimethylphenyl)]amino]-2,4-dimethylthieno[3,2-c]pyridine

[0794]

[0795] 6,7-Dibromo-2,4-dimethylthieno[3,2-c]pyridine (720 mg, 2.24 mmol), cesium carbonate (1.46 g, 4.49 mmol), 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (129.77 mg, 0.22 mmol), tris(dibenzylideneacetone)dipalladium (181.51 mg, 0.22 mmol) and 3-methoxy-2,6-dimethoxyaniline (678.26 mg, 4.49 mmol) were dissolved in ethylene glycol dimethyl ether (20 mL), heated to 100 ° C under nitrogen protection and stirred for 2 hours. After the reaction, the mixture was extracted with water (150 mL) and ethyl acetate (150 mL), the organic phase was washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was chromatographed on a silica gel column (petroleum ether / ethyl acetate = 10:1, volume ratio) to obtain the product as a white solid (530 mg, yield 60.39%). ESI-MS m / z: 390.04 [M+H] +. 1H NMR (400MHz, DMSO-d6) δ7.49(s,1H),7.17(d,J=1.4Hz,1H),7.04(d,J=8.3Hz,1H),6.80(d ,J=8.3Hz,1H),3.78(s,3H),2.49(d,J=1.3Hz,3H),2.34(s,3H),2.05(s,3H),1.96(s,3H).

[0796] Step 8: 7-Bromo-6-[(3-methoxy-2,6-dimethylphenyl)]amino]-2,4-dimethylthieno[3,2-c]pyridine

[0797]

[0798] Sodium hydride (439.53 mg, 10.99 mmol) was dissolved in ethylene glycol dimethyl ether (30 mL), and malononitrile (726.0 mg, 11.0 mmol) was added, and the mixture was stirred at room temperature for 30 minutes. 1,1'-bis(diphenylphosphino)ferrocenepalladium dichloride (80.4 mg, 0.11 mmol) and 7-bromo-6-[(3-methoxy-2,6-dimethylphenyl)]amino]-2,4-dimethylthieno[3,2-c]pyridine (530 mg, 1.35 mmol) were added, and the mixture was heated to 130°C and stirred overnight under nitrogen protection. The reactant was quenched with saturated ammonium chloride (10 mL), and then extracted with water (100 mL) and ethyl acetate (100 mL). The organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was chromatographed on a silica gel column (petroleum ether / ethyl acetate = 3:1, volume ratio) to obtain the product as a yellow solid (260 mg, yield 62.85%). ESI-MS m / z: 376.1 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ7.28–7.22(m,2H),7.10(d,J=8.5Hz,1H),6.86(s,2H),5.76 (s,2H),3.86(s,3H),2.60(d,J=1.3Hz,3H),1.99(s,1H),1.80(s,3H),1.71(s,3H).

[0799] Step 9: 7-amino-6-(3-methoxy-2,6-dimethylphenyl)-2,4-dimethylthieno[3,2-d]pyrrolopyridine-8-carboxamide

[0800]

[0801] Dissolve 7-bromo-6-[(3-methoxy-2,6-dimethylphenyl)]amino]-2,4-dimethylthieno[3,2-c]pyridine (350.0 mg, 0.92 mmol) in concentrated sulfuric acid (3 mL) and stir at room temperature for 1 hour. After the reaction, add the reaction solution dropwise to methanol, add ethyl acetate and water, and adjust the pH to 8 with ammonia water. Separate the ethyl acetate layer, wash the organic phase with saturated brine (50 mL), dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain a crude product (340 mg). ESI-MS m / z: 395.1 [M+H] + . 1 HNMR(400MHz,DMSO-d6)δ7.29–7.19(m,2H),7.10(d,J=8.4Hz,1H),6.75(s,2H),6.2 7(s,2H),3.86(s,3H),2.56(d,J=1.2Hz,3H),2.53(s,3H),1.81(s,3H),1.71(s,3H).

[0802] Step 10: 7-amino-6-(3-hydroxy-2,6-dimethylphenyl)-2,4-dimethylthieno[3,2-d]pyrrolo[2,3-b]pyridine-8-carboxamide

[0803]

[0804] Dissolve 7-amino-6-(3-methoxy-2,6-dimethylphenyl)-2,4-dimethylthieno[3,2-d]pyrrolopyridine-8-carboxamide (340.0 mg, 0.86 mmol) in dichloromethane (10 mL), add boron tribromide (1.08 g, 4.31 mmol), and stir at room temperature for 20 minutes. Add the reaction solution dropwise into methanol, concentrate under reduced pressure, and purify the residue by preparative HPLC to obtain the product (80 mg). ESI-MS m / z: 381.1 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ9.52(s,1H),7.22(d,J=1.4Hz,1H),7.08(d,J=8.3Hz,1H),6.93(d,J=8.2 Hz,1H),6.73(s,2H),6.22(s,2H),2.56(d,J=1.3Hz,3H),2.53(s,3H),1.76(s,3H),1.67(s,3H).

[0805] Step 11: (R)-7-amino-6-(3-hydroxy-2,6-dimethylphenyl)-2,4-dimethylthieno[3,2-d]pyrrolo[2,3-b]pyridine-8-carboxamide and (S)-7-amino-6-(3-hydroxy-2,6-dimethylphenyl)-2,4-dimethylthieno[3,2-d]pyrrolo[2,3-b]pyridine-8-carboxamide (Compound 22-1 and Compound 22-2)

[0806]

[0807] Compound 22 was dissolved in a mixed solvent of dichloromethane and methanol, and supercritical fluid chromatography (SFC) chiral separation was performed using a Waters PrepSFC 150Mgm system (chiral column: ChiralPak IC, 250×40 mm, 10 μm; eluent: methanol (35%, containing 0.2% ammonia)-carbon dioxide (65%); flow rate: 120 mL / min; column temperature: 35°C) to obtain two isomers, compound 22-1 (the compound that eluted first) and compound 22-2 (the compound that eluted later).

[0808] Embodiment 23

[0809] 7-Amino-6-(2-chloro-3-hydroxy-6-methylphenyl)-4-methylfuro[2,3-d]pyrrolo[2,3-b]pyridine-8-carboxamide (Compound 23)

[0810]

[0811] Step 1: 7-Bromo-6-[(2-chloro-3-methoxy-6-methylphenyl)amino]-4-methylfuro[3,2-c]pyridine

[0812]

[0813] Referring to step 7 of Example 1, the raw material 3-methoxy-2,6-dimethylaniline was replaced with 2-chloro-3-methoxy-6-methylaniline to prepare the product. ESI-MS m / z: 381.0 [M+1] + . 1 H NMR (400MHz, CDCl3) δ7.50(d,J=2.3Hz,1H),7.10(d,J=8.5Hz,1H),6.81(d,J=8.5Hz,1H),6.74(d,J=2.3Hz,1H),3.93(s,3H),2.47(s,3H),2.21(s,3H).

[0814] Step 2: 7-amino-6-(2-chloro-3-methoxy-6-methylphenyl)-4-methylfuro[2,3-d]pyrrolo[2,3-b]pyridine-8-carbonitrile

[0815]

[0816] Prepared according to step 8 of Example 1. ESI-MS m / z: 367.1 [M+1] + . 1 H NMR (400MHz, CDCl3) δ7.66(d,J=2.2Hz,1H),7.32(d,J=8.5Hz,1H),7.09(d,J=8.6H z,1H),6.85(d,J=2.3Hz,1H),4.52(s,2H),3.97(s,3H),2.63(s,3H),2.00(s,3H).

[0817] Step 3: 7-amino-6-(2-chloro-3-methoxy-6-methylphenyl)-4-methylfuro[2,3-d]pyrrolo[2,3-b]pyridine-8-carboxamide

[0818]

[0819] Prepared according to step 9 of Example 1. ESI-MS m / z: 384.1 [M+1] + .

[0820] Step 4: 7-amino-6-(2-chloro-3-hydroxy-6-methylphenyl)-4-methylfuro[2,3-d]pyrrolo[2,3-b]pyridine-8-carboxamide

[0821]

[0822] Prepared according to step 11 of Example 1. ESI-MS m / z: 371.1 [M+1] + . 1 H NMR (400MHz, DMSO-d6) δ10.33(s,1H),8.02(d,J=2.3Hz,1H),7.24(d,J=8.5Hz,1H), 7.16(d,J=2.3Hz,1H),7.11(d,J=8.5Hz,1H),6.96(s,2H),2.40(s,3H),1.85(s,3H).

[0823] Embodiment 24

[0824] 7-Amino-6-(2-chloro-3-hydroxy-6-methylphenyl)-4-methyl-2,3-dihydrofuro[2,3-d]pyrrolo[2,3-b]pyridine-8-carboxamide (Compound 24)

[0825]

[0826] (R)-7-amino-6-(2-chloro-3-hydroxy-6-methylphenyl)-4-methyl-2,3-dihydrofuro[2,3-d]pyrrolo[2,3-b]pyridine-8-carboxamide and (S)-7-amino-6-(2-chloro-3-hydroxy-6-methylphenyl)-4-methyl-2,3-dihydrofuro[2,3-d]pyrrolo[2,3-b]pyridine-8-carboxamide (Compound 24-1 and Compound 24-2)

[0827]

[0828] Step 1: 7-amino-6-(2-chloro-3-hydroxy-6-methylphenyl)-4-methyl-2,3-dihydrofuro[2,3-d]pyrrolo[2,3-b]pyridine-8-carboxamide

[0829]

[0830] Prepared from compound 23 by referring to the experimental process of Example 8. ESI-MS m / z: 373.1 [M+1] + . 1 HNMR(400MHz,DMSO-d6)δ10.28(s,1H),7.22(d,J=8.4Hz,1H),7.08(d,J=8.4Hz,1H), 6.85(s,2H),4.77(t,J=8.6Hz,2H),3.18(t,J=8.6Hz,2H),2.20(s,3H),1.83(s,3H).

[0831] Step 2: (R)-7-amino-6-(2-chloro-3-hydroxy-6-methylphenyl)-4-methyl-2,3-dihydrofuro[2,3-d]pyrrolo[2,3-b]pyridine-8-carboxamide (and (S)-7-amino-6-(2-chloro-3-hydroxy-6-methylphenyl)-4-methyl-2,3-dihydrofuro[2,3-d]pyrrolo[2,3-b]pyridine-8-carboxamide (Compound 24-1 and Compound 24-2)

[0832]

[0833] Compound 24 was dissolved in a mixed solvent of dichloromethane and methanol, and supercritical fluid chromatography (SFC) chiral separation was performed using a Waters PrepSFC 150Mgm system (chiral column: ChiralPak IC, 250×40 mm, 10 μm; eluent: methanol (35%, containing 0.2% ammonia)-carbon dioxide (65%); flow rate: 120 mL / min; column temperature: 35°C) to obtain two isomers, compound 24-1 (the compound that eluted first) and compound 24-2 (the compound that eluted later).

[0834] The present application also prepared the following compounds:

[0835]

[0836]

[0837]

[0838]

[0839]

[0840]

[0841]

[0842]

[0843]

[0844]

[0845]

[0846] Biological Test Examples

[0847] Test Example A: Proliferation inhibition activity of the compound on human breast cancer cells HCC1569 and human ovarian cancer cells OVCAR3.

[0848] Cell source: HCC1569 cells and OVCAR3 cells were purchased from Nanjing Kebai Biotechnology Co., Ltd.

[0849] HCC1569 and OVCAR3 cells in the logarithmic growth phase (HCC1569 cells were cultured in RPMI1640 complete medium containing 20% ​​fetal bovine serum; OVCAR3 cells were cultured in RPMI1640 complete medium containing 20% ​​fetal bovine serum supplemented with 10 μg / mL insulin) were seeded in a 96-well plate at a cell density of 600 cells / 135 μL complete medium / well and cultured in a constant temperature incubator at 37°C containing 5% carbon dioxide for 24 hours. Each compound was dissolved in DMSO in advance to prepare a 10 mM storage solution, and then the compound was diluted with DMSO and complete medium in turn. Take out the 96-well plate inoculated with cells, and take one of them as a no-growth control group (0-hour cell no-growth culture medium control group); add 15 μL of different concentrations of compounds to each well of the other 96-well plates, so that the final concentration of the compound is 10000, 2500, 625, 156.3, 39.1, 9.8, 2.4, 0.6, 0.15, 0.04 nM, set up three replicates for each compound concentration, and set up a negative control group (containing cells, no compound culture medium control group), and the concentration of DMSO in each well is 0.5%. The reserved no-growth control group immediately adds PrestoBlue HS cell viability detection reagent and performs subsequent detection, and the other 96-well plates continue to be cultured in a constant temperature incubator at 37°C with 5% carbon dioxide for 6 days before adding PrestoBlue HS cell viability detection reagent and performing subsequent detection.

[0850] The addition of PrestoBlue HS cell viability detection reagent and the subsequent detection steps are as follows: Take out the 96-well cell culture plate from the carbon dioxide constant temperature incubator, add 15 μL of PrestoBlue HS cell viability detection reagent (purchased from Thermo Fisher Scientific, catalog number P50201) to each well, and continue to incubate in a constant temperature incubator containing 5% carbon dioxide at 37°C for 3 hours. Take out the 96-well cell culture plate and measure the relative fluorescence intensity (RFU) at an excitation wavelength of 560nm and an emission wavelength of 590nm. Calculate the cell inhibition rate of each concentration of the compound according to the following formula.

[0851]

[0852] The data were analyzed using GraphPad Prism 8.3 software, and nonlinear S-curve regression was used to fit the data to obtain the dose-effect curve, from which the IC 50 The results are shown in Table 1.

[0853] Table 1

[0854]

[0855]

[0856] Among them, the RP-6306 racemate is a PKMYT1 inhibitor reported in the literature (J.Med.Chem.2022,65,10251-10284), and its structure is:

[0857]

[0858] The results show that the compound of the present invention exhibits good cell growth inhibition effect on human breast cancer cell HCC1569 and human ovarian cancer cell OVCAR3 tumor cell lines.

Claims

1. A compound represented by formula (I), its tautomer, its pharmaceutically acceptable salt, its solvate or its pharmaceutically acceptable salt solvate: in Selected from: Each X is independently N or CR 5 ; R 1 is -C(O)NH2; R 2 is -NH2; R 3 Independently for C 6-10 Aryl, 5-14 membered heteroaryl, C 3-8 Cycloalkyl, 3-10 membered heterocyclic group, 3a Substituted C 6-10 Aryl, one or more R 3b substituted 5-14 membered heteroaryl, substituted by one or more R 3c Substituted C 3-8 Cycloalkyl or one or more R 3d substituted 3-10 membered heterocyclyl; Each R 3a , R 3b , R 3c and R 3d are independently deuterium, halogen, cyano, oxo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl, 5-14 membered heteroaryl, -OR 4 、-NR 4 R 4 、-C(=O)R 4 、-C(=O)OR 4 、-OC(=O)R 4 、-C(=O)NR 4 R 4 、-NR 4 C(=O)R 4 、-NR 4 C(=O)NR 4 R 4 、-NR 4 S(=O)R 4 、-NR 4 S(=O)2R 4 、-NR 4 S(=O)NR 4 R 4 、-NR 4 S(=O)2NR 4 R 4 、-S(=O)R 4 、-S(=O)2R 4 、-S(=O)NR 4 R 4 、-S(=O)2NR 4 R 4 、-P(=O)R 4 R 4 、-P(=O)(OR 4 )2. One or more R 3-a Substituted C 1-6 Alkyl, with one or more R 3-b Substituted C 2-6 Alkenyl, one or more R 3-c Substituted C 2-6 Alkynyl, with one or more R 3-d Substituted C 3-8 Cycloalkyl, with one or more R 3-e substituted 3-10 membered heterocyclic group, substituted by one or more R 3-f Substituted C 6-10 Aryl or one or more R 3-g substituted 5-14 membered heteroaryl; Each R 3-a , R 3-b , R 3-c , R 3-d , R 3-e , R 3-f and R 3-g are independently deuterium, halogen, C 1-6 Alkyl, -OC 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -OR 4 、-NR 4 R 4 、-C(=O)R 4 、-C(=O)OR 4 、-OC(=O)R 4 、-C(=O)NR 4 R 4 、-NR 4 C(=O)R 4 、-NR 4 C(=O)NR 4 R 4 、-NR 4 S(=O)R 4 、-NR 4 S(=O)2R 4 、-NR 4 S(=O)NR 4 R 4 、-NR 4 S(=O)2NR 4 R 4 、-S(=O)R 4 、-S(=O)2R 4 、-S(=O)NR 4 R 4 、-S(=O)2NR 4 R 4 、-P(=O)R 4 R 4 OR-P(=O)(OR 4 )2; Each R 4 are independently hydrogen, C 1-6 Alkyl, -OC 1-6 Alkyl, C 3-8 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl, 5-14 membered heteroaryl, substituted by one or more R 4a Substituted C 1-6 Alkyl, with one or more R 4b Replaced-OC 1-6 Alkyl, with one or more R 4c Substituted C 3-8 Cycloalkyl, with one or more R 4d substituted 3-10 membered heterocyclic group, substituted by one or more R 4e Substituted C 6-10 Aryl or one or more R 4f substituted 5-14 membered heteroaryl; or two R 4 Together with the nitrogen atom or phosphorus atom to which they are commonly attached, they independently form a 3-10 membered heterocyclic group or are replaced by one or more R 4g substituted 3-10 membered heterocyclyl; Each R 4a , R 4b , R 4c , R 4d , R 4e , R 4f and R 4g are independently deuterium, halogen, oxo, cyano, hydroxyl, nitro, C 1-6 Alkyl, -OC 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, -OC 3-8 Cycloalkyl, 3-10 membered heterocyclic group, -O-3-10 membered heterocyclic group, C 6-10 Aryl, 5-14 membered heteroaryl, -N(R 6 )2, -C(=O)R 6 、-C(=O)OR 6 、-OC(=O)R 6 、-C(=O)N(R 6 )2.-NR 6 C(=O)R 6 、-NR 6 C(=O)N(R 6 )2.-NR 6 S(=O)R 6 、-NR 6 S(=O)2R 6 、-NR 6 S(=O)N(R 6 )2.-NR 6 S(=O)2N(R 6 )2, -S(=O)R 6 、-S(=O)2R 6 、-S(=O)N(R 6 )2、-S(=O)2N(R 6 )2, -P(=O)R 6 R 6 、-P(=O)(OR 6 )2. One or more R 4-a Substituted C 1-6 Alkyl, with one or more R 4-b Replaced-OC 1-6 Alkyl, with one or more R 4-c Substituted C 3-8 Cycloalkyl, with one or more R 4-d substituted 3-10 membered heterocyclic group, substituted by one or more R 4-e Substituted C 6-10 Aryl or one or more R 4-f substituted 5-14 membered heteroaryl; Each R 4-a , R 4-b , R 4-c , R 4-d , R 4-e and R 4-f are independently deuterium, halogen, cyano, hydroxyl, C 1-6 Alkyl, -OC 1-6 Alkyl, C 3-8 Cycloalkyl, -OC 3-8 Cycloalkyl, 3-10 membered heterocyclic group, -O-3-10 membered heterocyclic group, C 6-10 Aryl, 5-14 membered heteroaryl, -N(R 6 )2, -C(=O)R 6 、-C(=O)OR 6 、-OC(=O)R 6 、-C(=O)N(R 6 )2.-NR 6 C(=O)R 6 、-NR 6 C(=O)N(R 6 )2.-NR 6 S(=O)R 6 、-NR 6 S(=O)2R 6 、-NR 6 S(=O)N(R 6 )2.-NR 6 S(=O)2N(R 6 )2, -S(=O)R 6 、-S(=O)2R 6 、-S(=O)N(R 6 )2、-S(=O)2N(R 6 )2, -P(=O)R 6 R 6 、-P(=O)(OR 6 )2. One or more R 4-a-1 Substituted C 1-6 Alkyl, with one or more R 4-a-2 Replaced-OC 1-6 Alkyl, with one or more R 4-a-3 Substituted C 3-8 Cycloalkyl, with one or more R 4-a-4 Replaced-OC 3-8 Cycloalkyl, with one or more R 4-a-5 substituted 3-10 membered heterocyclic group, substituted by one or more R 4-a-6 -O-3-10 membered heterocyclic group, substituted by one or more R 4-a-7 Substituted C 6-10 Aryl or one or more R 4-a-8 substituted 5-14 membered heteroaryl; Each R 4-a-1 , R 4-a-2 , R 4-a-3 , R 4-a-4 , R 4-a-5 , R 4-a-6 , R 4-a-7 and R 4-a-8 are independently deuterium, halogen, cyano, hydroxyl, C 1-6 Alkyl, -OC 1-6 Alkyl, C 3-8 Cycloalkyl, -OC 3-8 Cycloalkyl, 3-10 membered heterocyclic group, -O-3-10 membered heterocyclic group, C 6-10 Aryl, 5-14 membered heteroaryl, -N(R 6 )2, -C(=O)R 6 、-C(=O)OR 6 、-OC(=O)R 6 、-C(=O)N(R 6 )2.-NR 6 C(=O)R 6 、-NR 6 C(=O)N(R 6 )2.-NR 6 S(=O)R 6 、-NR 6 S(=O)2R 6 、-NR 6 S(=O)N(R 6 )2.-NR 6 S(=O)2N(R 6 )2, -S(=O)R 6 、-S(=O)2R 6 、-S(=O)N(R 6 )2、-S(=O)2N(R 6 )2, -P(=O)R 6 R 6 OR-P(=O)(OR 6 )2; Each R 5 are independently hydrogen, deuterium, halogen, cyano, oxo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl, 5-14 membered heteroaryl, -OR 4 、-NR 4 R 4 、-C(=O)R 4 、-C(=O)OR 4 、-OC(=O)R 4 、-C(=O)NR 4 R 4 、-NR 4 C(=O)R 4 、-NR 4 C(=O)NR 4 R 4 、-NR 4 S(=O)R 4 、-NR 4 S(=O)2R 4 、-NR 4 S(=O)NR 4 R 4 、-NR 4 S(=O)2NR 4 R 4 、-S(=O)R 4 、-S(=O)2R 4 、-S(=O)NR 4 R 4 、-S(=O)2NR 4 R 4 、-P(=O)R 4 R 4 、-P(=O)(OR 4 )2. One or more R 5a Substituted C 1-6 Alkyl, with one or more R 5b Substituted C 2-6 Alkenyl, one or more R 5c Substituted C 2-6 Alkynyl, with one or more R 5d Substituted C 3-8 Cycloalkyl, with one or more R 5e substituted 3-10 membered heterocyclic group, substituted by one or more R 5f Substituted C 6-10 Aryl or one or more R 5g substituted 5-14 membered heteroaryl; Each R 5a , R 5b , R 5c , R 5d , R 5e , R 5f and R 5g are independently deuterium, halogen, cyano, oxo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl, 5-14 membered heteroaryl, -OR 4 、-NR 4 R 4 、-C(=O)R 4 、-C(=O)OR 4 、-OC(=O)R 4 、-C(=O)NR 4 R 4 、-NR 4 C(=O)R 4 、-NR 4 C(=O)NR 4 R 4 、-NR 4 S(=O)R 4 、-NR 4 S(=O)2R 4 、-NR 4 S(=O)NR 4 R 4 、-NR 4 S(=O)2NR 4 R 4 、-S(=O)R 4 、-S(=O)2R 4 、-S(=O)NR 4 R 4 、-S(=O)2NR 4 R 4 、-P(=O)R 4 R 4 OR-P(=O)(OR 4 )2; Each R a are independently hydrogen, deuterium, halogen, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl, 5-14 membered heteroaryl, -OR 4 、-NR 4 R 4 、-C(=O)R 4 、-C(=O)OR 4 、-OC(=O)R 4 、-C(=O)NR 4 R 4 、-NR 4 C(=O)R 4 、-NR 4 C(=O)NR 4 R 4 、-NR 4 S(=O)R 4 、-NR 4 S(=O)2R 4 、-NR 4 S(=O)NR 4 R 4 、-NR 4 S(=O)2NR 4 R 4 、-S(=O)R 4 、-S(=O)2R 4 、-S(=O)NR 4 R 4 、-S(=O)2NR 4 R 4 、-P(=O)R 4 R 4 、-P(=O)(OR 4 )2. One or more R a-1 Substituted C 1-6 Alkyl, with one or more R a-2 Substituted C 2-6 Alkenyl, one or more R a-3 Substituted C 2-6 Alkynyl, with one or more R a-4 Substituted C 3-8 Cycloalkyl, with one or more R a-5 substituted 3-10 membered heterocyclic group, substituted by one or more R a-6 Substituted C 6-10 Aryl or one or more R a-7 substituted 5-14 membered heteroaryl; Each R a-1 , R a-2 , R a-3 , R a-4 , R a-5 , R a-6 and R a-7 are each independently deuterium, halogen, cyano, -OR 6 or -NR 6 R 6 ; Each R b are independently hydrogen, C 1-6 Alkyl, -OC 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl, 5-14 membered heteroaryl, substituted by one or more R b-1 Substituted C 1-6 Alkyl, with one or more R b-2 Replaced-OC 1-6 Alkyl, with one or more R b-3 Substituted C 2-6 Alkenyl, one or more R b-4 Substituted C 2-6 Alkynyl, with one or more R b-5 Substituted C 3-8 Cycloalkyl, with one or more R b-6 substituted 3-10 membered heterocyclic group, substituted by one or more R b-7 Substituted C 6-10 Aryl or one or more R b-8 substituted 5-14 membered heteroaryl; Each R b-1 , R b-2 , R b-3 , R b-4 , R b-5 , R b-6 , R b-7 and R b-8 are each independently deuterium, halogen, cyano, -OR 6 or -NR 6 R 6 ; Each R 6 are independently hydrogen or C 1-6 alkyl; m is 1, 2, 3, 4, 5 or 6.

2. A compound represented by formula (I), its tautomer, its pharmaceutically acceptable salt, its solvate or its pharmaceutically acceptable salt solvate: in Selected from: Each X is independently N or CR 5 ; R 1 is -C(O)NH2; R 2 is -NH2; R 3 Independently for C 6-10 Aryl, 5-14 membered heteroaryl, C 3-8 Cycloalkyl, 3-10 membered heterocyclic group, 3a Substituted C 6-10 Aryl, one or more R 3b substituted 5-14 membered heteroaryl, substituted by one or more R 3c Substituted C 3-8 Cycloalkyl or one or more R 3d substituted 3-10 membered heterocyclyl; Each R 3a , R 3b , R 3c and R 3d are independently deuterium, halogen, cyano, oxo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl, 5-14 membered heteroaryl, -OR 4 、-NR 4 R 4 、-C(=O)R 4 、-C(=O)OR 4 、-OC(=O)R 4 、-C(=O)NR 4 R 4 、-NR 4 C(=O)R 4 、-NR 4 C(=O)NR 4 R 4 、-NR 4 S(=O)R 4 、-NR 4 S(=O)2R 4 、-NR 4 S(=O)NR 4 R 4 、-NR 4 S(=O)2NR 4 R 4 、-S(=O)R 4 、-S(=O)2R 4 、-S(=O)NR 4 R 4 、-S(=O)2NR 4 R 4 、-P(=O)R 4 R 4 、-P(=O)(OR 4 )2. One or more R 3-a Substituted C 1-6 Alkyl, with one or more R 3-b Substituted C 2-6 Alkenyl, one or more R 3-c Substituted C 2-6 Alkynyl, with one or more R 3-d Substituted C 3-8 Cycloalkyl, with one or more R 3-e substituted 3-10 membered heterocyclic group, substituted by one or more R 3-f Substituted C 6-10 Aryl or one or more R 3-g substituted 5-14 membered heteroaryl; Each R 3-a , R 3-b , R 3-c , R 3-d , R 3-e , R 3-f and R 3-g are independently deuterium, halogen, C 1-6 Alkyl, -OC 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -OR 4 、-NR 4 R 4 、-C(=O)R 4 、-C(=O)OR 4 、-OC(=O)R 4 、-C(=O)NR 4 R 4 、-NR 4 C(=O)R 4 、-NR 4 C(=O)NR 4 R 4 、-NR 4 S(=O)R 4 、-NR 4 S(=O)2R 4 、-NR 4 S(=O)NR 4 R 4 、-NR 4 S(=O)2NR 4 R 4 、-S(=O)R 4 、-S(=O)2R 4 、-S(=O)NR 4 R 4 、-S(=O)2NR 4 R 4 、-P(=O)R 4 R 4 OR-P(=O)(OR 4 )2; Each R 4 are independently hydrogen, C 1-6 Alkyl, -OC 1-6 Alkyl, C 3-8 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl, 5-14 membered heteroaryl, substituted by one or more R 4a Substituted C 1-6 Alkyl, with one or more R 4b Replaced-OC 1-6 Alkyl, with one or more R 4c Substituted C 3-8 Cycloalkyl, with one or more R 4d substituted 3-10 membered heterocyclic group, substituted by one or more R 4e Substituted C 6-10 Aryl or one or more R 4f substituted 5-14 membered heteroaryl; or two R 4 Together with the nitrogen atom or phosphorus atom to which they are commonly attached, they independently form a 3-10 membered heterocyclic group or are replaced by one or more R 4g substituted 3-10 membered heterocyclyl; Each R 4a , R 4b , R 4c , R 4d , R 4e , R 4f and R 4g are independently deuterium, halogen, oxo, cyano, hydroxyl, nitro, C 1-6 Alkyl, -OC 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, -OC 3-8 Cycloalkyl, 3-10 membered heterocyclic group, -O-3-10 membered heterocyclic group, C 6-10 Aryl, 5-14 membered heteroaryl, -N(R 6 )2, -C(=O)R 6 、-C(=O)OR 6 、-OC(=O)R 6 、-C(=O)N(R 6 )2.-NR 6 C(=O)R 6 、-NR 6 C(=O)N(R 6 )2.-NR 6 S(=O)R 6 、-NR 6 S(=O)2R 6 、-NR 6 S(=O)N(R 6 )2.-NR 6 S(=O)2N(R 6 )2, -S(=O)R 6 、-S(=O)2R 6 、-S(=O)N(R 6 )2、-S(=O)2N(R 6 )2, -P(=O)R 6 R 6 、-P(=O)(OR 6 )2. One or more R 4-a Substituted C 1-6 Alkyl, with one or more R 4-b Replaced-OC 1-6 Alkyl, with one or more R 4-c Substituted C 3-8 Cycloalkyl, with one or more R 4-d substituted 3-10 membered heterocyclic group, substituted by one or more R 4-e Substituted C 6-10 Aryl or one or more R 4-f substituted 5-14 membered heteroaryl; Each R 4-a , R 4-b , R 4-c , R 4-d , R 4-e and R 4-f are independently deuterium, halogen, cyano, hydroxyl, C 1-6 Alkyl, -OC 1-6 Alkyl, C 3-8 Cycloalkyl, -OC 3-8 Cycloalkyl, 3-10 membered heterocyclic group, -O-3-10 membered heterocyclic group, C 6-10 Aryl, 5-14 membered heteroaryl, -N(R 6 )2, -C(=O)R 6 、-C(=O)OR 6 、-OC(=O)R 6 、-C(=O)N(R 6 )2.-NR 6 C(=O)R 6 、-NR 6 C(=O)N(R 6 )2.-NR 6 S(=O)R 6 、-NR 6 S(=O)2R 6 、-NR 6 S(=O)N(R 6 )2.-NR 6 S(=O)2N(R 6 )2, -S(=O)R 6 、-S(=O)2R 6 、-S(=O)N(R 6 )2、-S(=O)2N(R 6 )2, -P(=O)R 6 R 6 、-P(=O)(OR 6 )2. One or more R 4-a-1 Substituted C 1-6 Alkyl, with one or more R 4-a-2 Replaced-OC 1-6 Alkyl, with one or more R 4-a-3 Substituted C 3-8 Cycloalkyl, with one or more R 4-a-4 Replaced-OC 3-8 Cycloalkyl, with one or more R 4-a-5 substituted 3-10 membered heterocyclic group, substituted by one or more R 4-a-6 -O-3-10 membered heterocyclic group, substituted by one or more R 4-a-7 Substituted C 6-10 Aryl or one or more R 4-a-8 substituted 5-14 membered heteroaryl; Each R 4-a-1 , R 4-a-2 , R 4-a-3 , R 4-a-4 , R 4-a-5 , R 4-a-6 , R 4-a-7 and R 4-a-8 are independently deuterium, halogen, cyano, hydroxyl, C 1-6 Alkyl, -OC 1-6 Alkyl, C 3-8 Cycloalkyl, -OC 3-8 Cycloalkyl, 3-10 membered heterocyclic group, -O-3-10 membered heterocyclic group, C 6-10 Aryl, 5-14 membered heteroaryl, -N(R 6 )2, -C(=O)R 6 、-C(=O)OR 6 、-OC(=O)R 6 、-C(=O)N(R 6 )2.-NR 6 C(=O)R 6 、-NR 6 C(=O)N(R 6 )2.-NR 6 S(=O)R 6 、-NR 6 S(=O)2R 6 、-NR 6 S(=O)N(R 6 )2.-NR 6 S(=O)2N(R 6 )2, -S(=O)R 6 、-S(=O)2R 6 、-S(=O)N(R 6 )2、-S(=O)2N(R 6 )2, -P(=O)R 6 R 6 OR-P(=O)(OR 6 )2; Each R 5 are independently hydrogen, deuterium, halogen, cyano, oxo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl, 5-14 membered heteroaryl, -OR 4 、-SR 4 、-NR 4 R 4 、-C(=O)R 4 、-C(=O)OR 4 、-OC(=O)R 4 、-C(=O)NR 4 R 4 、-NR 4 C(=O)R 4 、-NR 4 C(=O)NR 4 R 4 、-NR 4 S(=O)R 4 、-NR 4 S(=O)2R 4 、-NR 4 S(=O)NR 4 R 4 、-NR 4 S(=O)2NR 4 R 4 、-S(=O)R 4 、-S(=O)2R 4 、-S(=O)NR 4 R 4 、-S(=O)2NR 4 R 4 、-P(=O)R 4 R 4 、-P(=O)(OR 4 )2. One or more R 5a Substituted C 1-6 Alkyl, with one or more R 5b Substituted C 2-6 Alkenyl, one or more R 5c Substituted C 2-6 Alkynyl, with one or more R 5d Substituted C 3-8 Cycloalkyl, with one or more R 5e substituted 3-10 membered heterocyclic group, substituted by one or more R 5f Substituted C 6-10 Aryl or one or more R 5g substituted 5-14 membered heteroaryl; Each R 5a , R 5b , R 5c , R 5d , R 5e , R 5f and R 5g are independently deuterium, halogen, cyano, oxo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl, 5-14 membered heteroaryl, -SR 4 、-OR 4 、-NR 4 R 4 、-C(=O)R 4 、-C(=O)OR 4 、-OC(=O)R 4 、-C(=O)NR 4 R 4 、-NR 4 C(=O)R 4 、-NR 4 C(=O)NR 4 R 4 、-NR 4 S(=O)R 4 、-NR 4 S(=O)2R 4 、-NR 4 S(=O)NR 4 R 4 、-NR 4 S(=O)2NR 4 R 4 、-S(=O)R 4 、-S(=O)2R 4 、-S(=O)NR 4 R 4 、-S(=O)2NR 4 R 4 、-P(=O)R 4 R 4 OR-P(=O)(OR 4 )2; Each R a are independently hydrogen, deuterium, halogen, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl, 5-14 membered heteroaryl, -OR 4 、-NR 4 R 4 、-C(=O)R 4 、-C(=O)OR 4 、-OC(=O)R 4 、-C(=O)NR 4 R 4 、-NR 4 C(=O)R 4 、-NR 4 C(=O)NR 4 R 4 、-NR 4 S(=O)R 4 、-NR 4 S(=O)2R 4 、-NR 4 S(=O)NR 4 R 4 、-NR 4 S(=O)2NR 4 R 4 、-S(=O)R 4 、-S(=O)2R 4 、-S(=O)NR 4 R 4 、-S(=O)2NR 4 R 4 、-P(=O)R 4 R 4 、-P(=O)(OR 4 )2. One or more R a-1 Substituted C 1-6 Alkyl, with one or more R a-2 Substituted C 2-6 Alkenyl, one or more R a-3 Substituted C 2-6 Alkynyl, with one or more R a-4 Substituted C 3-8 Cycloalkyl, with one or more R a-5 substituted 3-10 membered heterocyclic group, substituted by one or more R a-6 Substituted C 6-10 Aryl or one or more R a-7 substituted 5-14 membered heteroaryl; Each R a-1 , R a-2 , R a-3 , R a-4 , R a-5 , R a-6 and R a-7 are each independently deuterium, halogen, cyano, -OR 6 or -NR 6 R 6 ; Each R b are independently hydrogen, C 1-6 Alkyl, -OC 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl, 5-14 membered heteroaryl, substituted by one or more R b-1 Substituted C 1-6 Alkyl, with one or more R b-2 Replaced-OC 1-6 Alkyl, with one or more R b-3 Substituted C 2-6 Alkenyl, one or more R b-4 Substituted C 2-6 Alkynyl, with one or more R b-5 Substituted C 3-8 Cycloalkyl, with one or more R b-6 substituted 3-10 membered heterocyclic group, substituted by one or more R b-7 Substituted C 6-10 Aryl or one or more R b-8 substituted 5-14 membered heteroaryl; Each R b-1 , R b-2 , R b-3 , R b-4 , R b-5 , R b-6 , R b-7 and R b-8 are each independently deuterium, halogen, cyano, -OR 6 or -NR 6 R 6 ; Each R 6 are independently hydrogen or C 1-6 alkyl; m is 1, 2, 3, 4, 5 or 6.

3. The compound represented by formula (I) according to claim 1 or 2, its tautomer, its pharmaceutically acceptable salt, its solvate or the solvate of its pharmaceutically acceptable salt, characterized in that: Selected from:

4. The compound represented by formula (I) according to claim 1 or 2, its tautomer, its pharmaceutically acceptable salt, its solvate or the solvate of its pharmaceutically acceptable salt, characterized in that: The compound represented by formula (I) satisfies one or more of the following conditions: (1) The compound represented by formula (I) is any stereoisomer or a mixture thereof; for example, when containing one chiral center, the compound represented by formula (I) is an R configuration, an S configuration, or an R, S configuration racemate; (2) Each C 6-10 Aryl is independently phenyl or naphthyl, for example phenyl; (3) The heteroatom of each 5-14 membered heteroaryl group is independently N, O or S, and the number of heteroatoms is independently 1, 2 or 3; preferably, the heteroatom of each 5-14 membered heteroaryl group is independently N, and the number of heteroatoms is independently 1 or 2; (4) each 5-14 membered heteroaryl group is independently a 5-10 membered heteroaryl group; (5) Each 5-14 membered heteroaryl group is independently monocyclic or polycyclic; the polycyclic ring may be a bridged ring, a fused ring or a spiro ring; the polycyclic ring may be a bicyclic ring or a tricyclic ring; (6) Each 5-14 membered heteroaryl group is independently a 5-6 membered monocyclic heteroaryl group or a 9-10 membered bicyclic heteroaryl group; preferably, each 5-6 membered monocyclic heteroaryl group is independently a pyrazolyl group, for example Each 9-10 membered bicyclic heteroaryl group independently may be indazolyl, for example (7) Each C 3-8 Cycloalkyl is independently cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; for example cyclopropyl or cyclobutyl; (8) each 3-10 membered heterocyclyl and the 3-10 membered heterocyclyl in "-O-3-10 membered heterocyclyl" is independently a 5-8 membered heterocyclyl; (9) Each 3-10 membered heterocyclyl and the 3-10 membered heterocyclyl in "-O-3-10 membered heterocyclyl" is independently a 3-10 membered heterocycloalkyl or a 3-10 membered heterocycloalkenyl; preferably, each 3-10 membered heterocyclyl is independently a 3-10 membered heterocycloalkyl; (10) Each 3-10 membered heterocyclic group and the 3-10 membered heterocyclic group in "-O-3-10 membered heterocyclic group" is independently monocyclic or polycyclic; the polycyclic ring may be a bridged ring, a fused ring or a spiro ring, and the polycyclic ring may also be a bicyclic ring or a tricyclic ring; for example, each 3-10 membered heterocyclic group may independently be monocyclic or bicyclic; the bicyclic ring may be a bridged ring; (11) The heteroatom of each 3-10 membered heterocyclic group and the 3-10 membered heterocyclic group in "-O-3-10 membered heterocyclic group" is independently N, O or S, such as N; the number of heteroatoms is independently 1, 2 or 3; (12) Each 3-10 membered heterocyclic group and the 3-10 membered heterocyclic group in "-O-3-10 membered heterocyclic group" is independently a 5-8 membered heterocyclic alkyl group, the heteroatom of the 5-8 membered heterocyclic alkyl group is N, the number of heteroatoms is independently 1, 2 or 3, and each 5-8 membered heterocyclic alkyl group is independently a monocyclic or bicyclic ring; the bicyclic ring may be a bridged ring, such as tetrahydropyrrolyl, piperidinyl or Another example (13) Each halogen is independently fluorine, chlorine, bromine or iodine; (14) Each C 1-6 Alkyl is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl or sec-butyl, for example methyl or ethyl; (15) Each C 2-6 Alkenyl is independently ethenyl, propenyl, allyl, butenyl or pentenyl; (16) Each C 2-6 Alkynyl is independently ethynyl, propynyl, propargyl, butynyl or pentynyl, for example (17) Each-OC 1-6 Alkyl is independently -O-methyl, -O-ethyl, -O-n-propyl, -O-isopropyl, -O-n-butyl, -O-tert-butyl, -O-isobutyl or -O-sec-butyl; (18) Each-OC 3-8 Cycloalkyl is independently -O-cyclopropyl, -O-cyclobutyl, -O-cyclopentyl or -O-cyclohexyl; for example -O-cyclopropyl or -O-cyclobutyl; (19) Each “plurality” is independently 2 or 3; (20) m is 1, 2, 3 or 4; and (21) Each X is independently N.

5. The compound represented by formula (I) according to claim 1 or 2, its tautomer, its pharmaceutically acceptable salt, its solvate or the solvate of its pharmaceutically acceptable salt, characterized in that: The compound represented by formula (I) satisfies one or more of the following conditions: (1) In R 3 In the above, each 5-14 membered heteroaryl group is independently a 5-6 membered monocyclic heteroaryl group or a 9-10 membered bicyclic heteroaryl group; preferably, each 5-6 membered monocyclic heteroaryl group is independently a pyrazolyl group, for example Each 9-10 membered bicyclic heteroaryl group independently may be indazolyl, for example (2) In R 5 In the above, each 5-14 membered heteroaryl group is independently a 5-6 membered monocyclic heteroaryl group; preferably, each 5-6 membered monocyclic heteroaryl group is independently a pyrazolyl group, for example (3) In R 5 In the above, each 3-10 membered heterocyclic group is independently a 5-8 membered heterocyclic alkyl group; preferably, the heteroatom of the 5-8 membered heterocyclic alkyl group is N, the number of heteroatoms is independently 1, 2 or 3, and each 5-8 membered heterocyclic alkyl group is independently a monocyclic ring; for example, tetrahydropyrrolyl; for example (4) When R 5 For-OR 4 When R 4 In the above, each 3-10 membered heterocyclic group is independently a 5-8 membered heterocyclic alkyl group; preferably, the heteroatom of the 5-8 membered heterocyclic alkyl group may be N, the number of heteroatoms may independently be 1, 2 or 3, and each 5-8 membered heterocyclic alkyl group may independently be a monocyclic or a bicyclic ring; the bicyclic ring may be a bridged ring; for example, tetrahydropyrrolyl, piperidinyl or Another example More preferably, the for or a mixture of both; (5) In R 4a In the 4-d The 3-10-membered heterocyclic group in the substituted 3-10-membered heterocyclic group is independently a 5-8-membered heterocycloalkyl; preferably, the heteroatom of the 5-8-membered heterocycloalkyl may be N, and the number of heteroatoms may independently be 1, 2 or 3, and each 5-8-membered heterocycloalkyl may independently be a monocyclic ring, such as tetrahydropyrrolyl; for example More preferably, the for or a mixture of both; (6) In R 5 In each C 3-8 Cycloalkyl is independently cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, for example cyclopropyl or cyclobutyl; (7) When R 5 For-OR 4 When R 4a Each C 3-8 Cycloalkyl is independently cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, for example cyclopropyl or cyclobutyl; (8) In R 5 In each C 2-6 Alkynyl is ethynyl, propynyl, propargyl, butynyl or pentynyl, for example (9) Each R 3a and R 3b In each C 1-6 Alkyl is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl or sec-butyl, such as methyl or ethyl, preferably methyl; (10) In R 4 In each C 1-6 Alkyl is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl or sec-butyl, for example ethyl; (11) In R 4a In each C 1-6 Alkyl is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl or sec-butyl, for example methyl or ethyl; (12) In R 4d In each C 1-6 Alkyl is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl or sec-butyl, for example methyl or ethyl; (13) In R 4-d In each C 1-6 Alkyl is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl or sec-butyl, for example methyl; (14) In R 4-a-1 In each C 1-6 Alkyl is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl or sec-butyl, for example methyl; (15) In R 5 In each C 1-6 Alkyl is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl or sec-butyl, for example methyl or ethyl; (16) In R 6 In each C 1-6 Alkyl is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl or sec-butyl, such as methyl or ethyl, preferably methyl; (17) In R a In each C 1-6 Alkyl is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl or sec-butyl, for example methyl; (18) In R b In each C 1-6 Alkyl is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl or sec-butyl, for example methyl; (19) In R 3 In each C 6-10 Aryl is independently phenyl or naphthyl, for example phenyl; (20) When R 5 For-OR 4 or -SR 4 When R 4 In the above, each 3-10 membered heterocyclic group can be independently a 5-8 membered heterocyclic alkyl group; preferably, the heteroatom of the 5-8 membered heterocyclic alkyl group can be N, and the number of heteroatoms can be independently 1, 2 or 3, and each 5-8 membered heterocyclic alkyl group can be independently a monocyclic or bicyclic ring, and the bicyclic ring can be a bridged ring; for example, tetrahydropyrrolyl, piperidinyl, Another example More preferably, the for or a mixture of the two, for or a mixture of both; (21) When R 5 For-SR 4 When R 4 In the above, each 3-10 membered heterocyclic group can be independently a 5-8 membered heterocyclic alkyl group; preferably, the heteroatom of the 5-8 membered heterocyclic alkyl group can be N, and the number of heteroatoms can be independently 1, 2 or 3, and each 5-8 membered heterocyclic alkyl group can be independently a monocyclic or bicyclic ring, and the bicyclic ring can be a bridged ring; for example, piperidinyl, and for example and (22) When R 5 For-SR 4 When R 4a Each C 3-8 Cycloalkyl groups independently may be cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, for example cyclopropyl or cyclobutyl.

6. The compound represented by formula (I) according to claim 1 or 2, its tautomer, its pharmaceutically acceptable salt, its solvate or the solvate of its pharmaceutically acceptable salt, characterized in that: The compound represented by formula (I) satisfies one or more of the following conditions: (1)R 3 Independently for C 6-10 Aryl, 5-14 membered heteroaryl, substituted by one or more R 3a Substituted C 6-10 Aryl or one or more R 3b substituted 5-14 membered heteroaryl; preferably, R 3 Independently for one or more R 3a Substituted C 6-10 Aryl or one or more R 3b substituted 5-14 membered heteroaryl; (2) Each R 3a and R 3b are independently deuterium, halogen, cyano, C 1-6 Alkyl, -OR 4 or -NR 4 R 4 Preferably, each R 3a are independently halogen, C 1-6 Alkyl or -OR 4 ; Each R 3b are independently halogen or C 1-6 alkyl; (3) Each R 4 are independently hydrogen, C 1-6 Alkyl, with one or more R 4a Substituted C 1-6 Alkyl, C 3-8 Cycloalkyl, with one or more R 4c Substituted C 3-8 Cycloalkyl, 3-10 membered heterocyclic group or one or more R 4d substituted 3-10 membered heterocyclic group; preferably, each R 4 are independently hydrogen, C 1-6 Alkyl, with one or more R 4a Substituted C 1-6 Alkyl or one or more R 4d substituted 3-10 membered heterocyclyl; (4) Each R 4a , R 4c and R 4d are independently deuterium, halogen, oxo, cyano, hydroxyl, nitro, C 1-6 Alkyl, with one or more R 4-a Substituted C 1-6 Alkyl, C 3-8 Cycloalkyl, with one or more R 4-c Substituted C 3-8 Cycloalkyl, 3-10 membered heterocyclic group, 4-d substituted 3-10 membered heterocyclic group; preferably, each R 4a and R 4d are independently halogen, C 1-6 Alkyl, -N(R 6 )2. One or more R 4-c Substituted C 3-8 Cycloalkyl or one or more R 4-d Substituted 3-10 membered heterocyclic group (5) Each R 4-a , R 4-c and R 4-d are independently deuterium, halogen, cyano, hydroxyl, C 1-6 Alkyl, -N(R 6 )2 or one or more R 4-a-1 Substituted C 1-6 Alkyl; preferably, each R 4-c and R 4-d Each independently is C 1-6 Alkyl, -N(R 6 )2 or one or more R 4-a-1 Substituted C 1-6 alkyl; (6) Each R 4-a-1 are independently deuterium, halogen, cyano, hydroxyl, C 1-6 Alkyl or -N(R 6 )2; Preferably, each R 4-a-1 are independently -N(R 6 )2; (7) Each R 5 Independently for C 1-6 Alkyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, 3-10 membered heterocyclyl, 5-14 membered heteroaryl, -OR 4 , by one or more R 5a Substituted C 1-6 Alkyl, with one or more R 5c Substituted C 2-6 Alkynyl, with one or more R 5d Substituted C 3-8 Cycloalkyl, with one or more R 5e substituted 3-10 membered heterocyclic group, or one or more R 5g substituted 5-14 membered heteroaryl; preferably, each R 5 Independently for C 1-6 Alkyl, C 3-8 Cycloalkyl, -OR 4 , by one or more R 5c Substituted C 2-6 Alkynyl, with one or more R 5e substituted 3-10 membered heterocyclic group, or one or more R 5g substituted 5-14 membered heteroaryl; (8) Each R 5a , R 5c , R 5d , R 5e and R 5g are independently deuterium, halogen, cyano, C 1-6 Alkyl, -OR 4 or -NR 4 R 4 Preferably, each R 5c , R 5e and R 5g Independently for C 1-6 Alkyl or -NR 4 R 4 ; (9) Each R a are independently hydrogen, deuterium, halogen, cyano, C 1-6 Alkyl, -OR 4 、-NR 4 R 4 or one or more R a-1 Substituted C 1-6 Alkyl; preferably, each R a are independently hydrogen or C 1-6 alkyl; (10) Each R a-1 are independently deuterium, halogen, cyano, -OR 6 or -NR 6 R 6 ; (11) Each R b are independently hydrogen, C 1-6 Alkyl or one or more R b-1 Substituted C 1-6 Alkyl; preferably, R b C 1-6 alkyl; (12) Each R b-1 are independently deuterium, halogen, cyano, -OR 6 or -NR 6 R 6 ; (13) Each R 6 are independently hydrogen or C 1-6 alkyl; (14)R 3 Independently for one or more R 3a substituted phenyl, or one or more R 3b Substituted 9-10 membered bicyclic heteroaryl; preferably R 3 Independently for one or more R 3a Substituted phenyl; (15) Each R 3a are independently halogen, C 1-6 Alkyl or -OH; each R 3b are independently halogen or C 1-6 alkyl; (16) Each R 5 Independently for C 1-6 Alkyl, C 3-8 Cycloalkyl, -OR 4 , by one or more R 5c Substituted propynyl, substituted by one or more R 5e substituted tetrahydropyrrolyl, or substituted with one or more R 5g Substituted pyrazolyl; preferably each R 5 Independently for C 1-6 alkyl; (17) Each R 5c , R 5e and R 5g Each independently is C 1-6 Alkyl or -NR 6 R 6 ; (18)R 4 Independently for C 1-6 Alkyl, with one or more R 4a Substituted methyl, substituted by one or more R 4a substituted ethyl, or one or more R 4d substituted 3-10 membered heterocyclic group; the 3-10 membered heterocyclic group is tetrahydropyrrolyl, piperidinyl or (19) Each R 4a are independently halogen, C 1-6 Alkyl, -N(R 6 )2. One or more R 4-c Substituted C 3-8 Cycloalkyl or one or more R 4-d substituted 3-10 membered heterocyclic group; said C 3-8 The cycloalkyl group is cyclopropyl or cyclobutyl; the 3-10 membered heterocyclic group is tetrahydropyrrolyl, piperidinyl or (20) Each R 4d are independently halogen, C 1-6 Alkyl or -N(R 6 )2; (21) Each R 4-c and R 4-d Each independently is C 1-6 Alkyl, -N(R 6 )2 or one or more R 4-a-1 Substituted C 1-6 alkyl; (22) Each R a are independently hydrogen or methyl; (23) Each R b is methyl; (24) Each R 5 Independently for C 1-6 Alkyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, 3-10 membered heterocyclyl, 5-14 membered heteroaryl, -OR 4 、-SR 4 , by one or more R 5a Substituted C 1-6 Alkyl, with one or more R 5c Substituted C 2-6 Alkynyl, with one or more R 5d Substituted C 3-8 Cycloalkyl, with one or more R 5e substituted 3-10 membered heterocyclic group, or one or more R 5g substituted 5-14 membered heteroaryl; preferably, each R 5 Independently for C 1-6 Alkyl, C 3-8 Cycloalkyl, -OR 4 、-SR 4 , by one or more R 5c Substituted C 2-6 Alkynyl, with one or more R 5e substituted 3-10 membered heterocyclic group, or one or more R 5g substituted 5-14 membered heteroaryl; further preferably, each R 5 Independently for C 1-6 Alkyl, -OR 4 or -SR 4 ; (25) Each R 5a , R 5c , R 5d , R 5e and R 5g are independently deuterium, halogen, cyano, C 1-6 Alkyl, -SR 4 、-OR 4 or -NR 4 R 4 ; (26) Each R 4 are independently hydrogen, C 1-6 Alkyl, 3-10 membered heterocyclic group, one or more R 4a Substituted C 1-6 Alkyl or one or more R 4d substituted 3-10 membered heterocyclyl; (27) Each R 4a , R 4c and R 4d are independently deuterium, halogen, oxo, cyano, hydroxyl, nitro, C 1-6 Alkyl, -N(R 6 )2. One or more R 4-a Substituted C 1-6 Alkyl, C 3-8 Cycloalkyl, with one or more R 4-c Substituted C 3-8 Cycloalkyl, 3-10 membered heterocyclic group, 4-d substituted 3-10 membered heterocyclyl; and (28) Each R a are independently hydrogen, halogen, cyano or C 1-6 alkyl.

7. The compound of formula (I) according to any one of claims 1 to 6, its tautomer, its pharmaceutically acceptable salt, its solvate or its pharmaceutically acceptable salt solvate, characterized in that: The compound represented by formula (I) satisfies one or more of the following conditions: (1) In R 3 In each R 4 are independently hydrogen or C 1-6 alkyl; (2) In R 5 In each R 4 are independently hydrogen, C 1-6 Alkyl, with one or more R 4a Substituted C 1-6 Alkyl or one or more R 4d substituted 3-10 membered heterocyclyl; Each R 4a are independently halogen, C 1-6 Alkyl, -N(R 6 )2. One or more R 4-c Substituted C 3-8 Cycloalkyl or one or more R 4-d substituted 3-10 membered heterocyclyl; Each R 4d are independently halogen, C 1-6 Alkyl or -N(R 6 )2; Each R 4-c and R 4-d Each independently is C 1-6 Alkyl, -N(R 6 )2 or one or more R 4-a-1 Substituted C 1-6 alkyl; Each R 4-a-1 are independently -N(R 6 )2; and (3) In R a In each R 4 are independently hydrogen or C 1-6 alkyl.

8. The compound represented by formula (I) according to claim 1 or 2, its tautomer, its pharmaceutically acceptable salt, its solvate or the solvate of its pharmaceutically acceptable salt, characterized in that: The compound represented by formula (I) satisfies one or more of the following conditions: (1) Selected from: Preferably Selected from More preferably Selected from More preferably Selected from (2)R 3 Independently (3) Each R 5 are independently -CH3, (4)R a are independently hydrogen or -CH3; (5)R b are independently -CH3; (6) Each R 5 independently CH3, and (7) Selected from: Preferably Selected from More preferably Selected from More preferably Selected from (8)R 3 for For example 9. The compound represented by formula (I) according to claim 1 or 2, its tautomer, its pharmaceutically acceptable salt, its solvate or the solvate of its pharmaceutically acceptable salt, characterized in that: The compound represented by formula (I) satisfies one of the following schemes: Solution 1: Selected from: Each X is independently N or CR 5 ; R 1 is -C(O)NH2; R 2 is -NH2; R 3 Independently for C 6-10 Aryl, 5-14 membered heteroaryl, substituted by one or more R 3a Substituted C 6-10 Aryl or one or more R 3b substituted 5-14 membered heteroaryl; Each R 3a and R 3b are independently deuterium, halogen, cyano, C 1-6 Alkyl, -OR 4 or -NR 4 R 4 ; Each R 4 are independently hydrogen, C 1-6 Alkyl, with one or more R 4a Substituted C 1-6 Alkyl, C 3-8 Cycloalkyl, with one or more R 4c Substituted C 3-8 Cycloalkyl, 3-10 membered heterocyclic group or one or more R 4d substituted 3-10 membered heterocyclic group; Each R 4a , R 4c and R 4d are independently deuterium, halogen, oxo, cyano, hydroxyl, nitro, C 1-6 Alkyl, with one or more R 4-a Substituted C 1-6 Alkyl, C 3-8 Cycloalkyl, with one or more R 4-c Substituted C 3-8 Cycloalkyl, 3-10 membered heterocyclic group, 4-d substituted 3-10 membered heterocyclic group; Each R 4-a , R 4-c and R 4-d are independently deuterium, halogen, cyano, hydroxyl, C 1-6 Alkyl, -N(R 6 )2 or one or more R 4-a-1 Substituted C 1-6 alkyl; Each R 4-a-1 are independently deuterium, halogen, cyano, hydroxyl, C 1-6 Alkyl or -N(R 6 )2; Each R 5 are independently hydrogen, C 1-6 Alkyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, 3-10 membered heterocyclyl, 5-14 membered heteroaryl, -OR 4 , by one or more R 5a Substituted C 1-6 Alkyl, with one or more R 5c Substituted C 2-6 Alkynyl, with one or more R 5d Substituted C 3-8 Cycloalkyl, with one or more R 5e substituted 3-10 membered heterocyclic group or one or more R 5g substituted 5-14 membered heteroaryl; Each R 5a , R 5c , R 5d , R 5e and R 5g are independently deuterium, halogen, cyano, C 1-6 Alkyl, -OR 4 or -NR 4 R 4 ; Each R a are independently hydrogen, deuterium, halogen, cyano, C 1-6 Alkyl, -OR 4 、-NR 4 R 4 or one or more R a-1 Substituted C 1-6 alkyl; Each R a-1 are independently deuterium, halogen, cyano, -OR 6 or -NR 6 R 6 ; R b are independently hydrogen, C 1-6 Alkyl or one or more R b-1 Substituted C 1-6 alkyl; Each R b-1 are independently deuterium, halogen, cyano, -OR 6 or -NR 6 R 6 ; Each R 6 are independently hydrogen or C 1-6 alkyl; m is 1, 2, 3 or 4; Option 2: Selected from: Each X is independently N; R 1 is -C(O)NH2; R 2 is -NH2; R 3 Independently for one or more R 3a Substituted C 6-10 Aryl or one or more R 3b substituted 5-14 membered heteroaryl; Each R 3a are independently halogen, C 1-6 Alkyl or -OR 4 ; Each R 3b are independently halogen or C 1-6 alkyl; Each R 4 are independently hydrogen, C 1-6 Alkyl, with one or more R 4a Substituted C 1-6 Alkyl or one or more R 4d substituted 3-10 membered heterocyclic group; Each R 4a and R 4d are independently halogen, C 1-6 Alkyl, -N(R 6 )2. One or more R 4-c Substituted C 3-8 Cycloalkyl or one or more R 4-d substituted 3-10 membered heterocyclic group; Each R 4-c and R 4-d Each independently is C 1-6 Alkyl, -N(R 6 )2 or one or more R 4-a-1 Substituted C 1-6 alkyl; Each R 4-a-1 are independently -N(R 6 )2; Each R 5 Independently for C 1-6 Alkyl, C 3-8 Cycloalkyl, -OR 4 , by one or more R 5c Substituted C 2-6 Alkynyl, with one or more R 5e substituted 3-10 membered heterocyclic group, or one or more R 5g substituted 5-14 membered heteroaryl; Each R 5c , R 5e and R 5g Each independently is C 1-6 Alkyl or -NR 4 R 4 ; Each R a are independently hydrogen or C 1-6 alkyl; R b Independently for C 1-6 alkyl; Each R 6 are independently hydrogen or C 1-6 alkyl; m is 1 or 2; Option 3: Selected from Each X is independently N; R 1 is -C(O)NH2; R 2 is -NH2; R 3 Independently for one or more R 3a Substituted C 6-10 Aryl or one or more R 3b substituted 5-14 membered heteroaryl; Each R 3a are independently halogen, C 1-6 Alkyl, -OH or -OC 1-6 alkyl; Each R 3b are independently halogen or C 1-6 alkyl; Each R 5 Independently for C 1-6 Alkyl, C 3-8 Cycloalkyl, -OR 4 , by one or more R 5c Substituted C 2-6 Alkynyl, with one or more R 5e substituted 3-10 membered heterocyclic group or one or more R 5g substituted 5-14 membered heteroaryl; Each R 5c , R 5e and R 5g Each independently is C 1-6 Alkyl or -N(R 6 )2; Each R 4 are independently hydrogen, C 1-6 Alkyl, with one or more R 4a Substituted C 1-6 Alkyl or one or more R 4d substituted 3-10 membered heterocyclic group; Each R 4a are independently halogen, C 1-6 Alkyl, -N(R 6 )2. One or more R 4-c Substituted C 3-8 Cycloalkyl or one or more R 4-d substituted 3-10 membered heterocyclic group; Each R 4d are independently halogen, C 1-6 Alkyl or -N(R 6 )2; Each R 4-c and R 4-d Each independently is C 1-6 Alkyl, -N(R 6 )2 or one or more R 4-a-1 Substituted C 1-6 alkyl; Each R 4-a-1 are independently -N(R 6 )2; Each R a are independently hydrogen or C 1-6 alkyl; Each R 6 are independently hydrogen or C 1-6 alkyl; m is 1 or 2; Option 4: Selected from Each X is independently N; R 1 is -C(O)NH2; R 2 is -NH2; R 3 Independently for one or more R 3a Substituted C 6-10 Aryl; Each R 3a are independently halogen, C 1-6 Alkyl or -OR 4 ; Each R 4 are independently hydrogen or C 1-6 alkyl; Each R 5 Independently for C 1-6 alkyl; Each R a are independently hydrogen or C 1-6 alkyl; m is 1 or 2; Option 5: Selected from R 1 is -C(O)NH2; R 2 is -NH2; R 3 Independently for one or more R 3a Substituted C 6-10 Aryl; Each R 3a are independently halogen, C 1-6 Alkyl or -OR 4 ; Each R 4 are independently hydrogen or C 1-6 alkyl; Each R 5 Independently for C 1-6 alkyl; Option 6: Selected from: Each X is independently N or CR 5 ; R 1 is -C(O)NH2; R 2 is -NH2; R 3 Independently for C 6-10 Aryl, 5-14 membered heteroaryl, substituted by one or more R 3a Substituted C 6-10 Aryl or one or more R 3b substituted 5-14 membered heteroaryl; Each R 3a and R 3b are independently deuterium, halogen, cyano, C 1-6 Alkyl, -OR 4 or -NR 4 R 4 ; Each R 4 are independently hydrogen, C 1-6 Alkyl, with one or more R 4a Substituted C 1-6 Alkyl, C 3-8 Cycloalkyl, with one or more R 4c Substituted C 3-8 Cycloalkyl, 3-10 membered heterocyclic group or one or more R 4d substituted 3-10 membered heterocyclic group; Each R 4a , R 4c and R 4d are independently deuterium, halogen, oxo, cyano, hydroxyl, nitro, C 1-6 Alkyl, -N(R 6 )2. One or more R 4-a Substituted C 1-6 Alkyl, C 3-8 Cycloalkyl, with one or more R 4-c Substituted C 3-8 Cycloalkyl, 3-10 membered heterocyclic group, 4-d substituted 3-10 membered heterocyclic group; Each R 4-a , R 4-c and R 4-d are independently deuterium, halogen, cyano, hydroxyl, C 1-6 Alkyl, -N(R 6 )2 or one or more R 4-a-1 Substituted C 1-6 alkyl; Each R 4-a-1 are independently deuterium, halogen, cyano, hydroxyl, C 1-6 Alkyl or -N(R 6 )2; Each R 5 are independently hydrogen, C 1-6 Alkyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, 3-10 membered heterocyclyl, 5-14 membered heteroaryl, -OR 4 、-SR 4 , by one or more R 5a Substituted C 1-6 Alkyl, with one or more R 5c Substituted C 2-6 Alkynyl, with one or more R 5d Substituted C 3-8 Cycloalkyl, with one or more R 5e substituted 3-10 membered heterocyclic group or one or more R 5g substituted 5-14 membered heteroaryl; Each R 5a , R 5c , R 5d , R 5e and R 5g are independently deuterium, halogen, cyano, C 1-6 Alkyl, -SR 4 、-OR 4 or -NR 4 R 4 ; Each R a are independently hydrogen, deuterium, halogen, cyano, C 1-6 Alkyl, -OR 4 、-NR 4 R 4 or one or more R a-1 Substituted C 1-6 alkyl; Each R a-1 are independently deuterium, halogen, cyano, -OR 6 or -NR 6 R 6 ; R b are independently hydrogen, C 1-6 Alkyl or one or more R b-1 Substituted C 1-6 alkyl; Each R b-1 are independently deuterium, halogen, cyano, -OR 6 or -NR 6 R 6 ; Each R 6 are independently hydrogen or C 1-6 alkyl; m is 1, 2, 3 or 4; Option 7: Selected from: Each X is independently N; R 1 is -C(O)NH2; R 2 is -NH2; R 3 Independently for one or more R 3a Substituted C 6-10 Aryl or one or more R 3b substituted 5-14 membered heteroaryl; Each R 3a are independently halogen, C 1-6 Alkyl or -OR 4 ; Each R 3b are independently halogen or C 1-6 alkyl; Each R 4 are independently hydrogen, C 1-6 Alkyl, with one or more R 4a Substituted C 1-6 Alkyl, 3-10 membered heterocyclic group or one or more R 4d substituted 3-10 membered heterocyclic group; Each R 4a and R 4d are independently halogen, C 1-6 Alkyl, -N(R 6 )2. One or more R 4-c Substituted C 3-8 Cycloalkyl or one or more R 4-d substituted 3-10 membered heterocyclic group; Each R 4-c and R 4-d Each independently is C 1-6 Alkyl, -N(R 6 )2 or one or more R 4-a-1 Substituted C 1-6 alkyl; Each R 4-a-1 are independently -N(R 6 )2; Each R 5 Independently for C 1-6 Alkyl, C 3-8 Cycloalkyl, -OR 4 、-SR 4 , by one or more R 5c Substituted C 2-6 Alkynyl, with one or more R 5e substituted 3-10 membered heterocyclic group, or one or more R 5g substituted 5-14 membered heteroaryl; Each R 5c , R 5e and R 5g Each independently is C 1-6 Alkyl or -NR 4 R 4 ; Each R a are independently hydrogen, halogen, cyano or C 1-6 alkyl; R b Independently for C 1-6 alkyl; Each R 6 are independently hydrogen or C 1-6 alkyl; m is 1 or 2; Option 8: Selected from Each X is independently N; R 1 is -C(O)NH2; R 2 is -NH2; R 3 Independently for one or more R 3a Substituted C 6-10 Aryl or one or more R 3b substituted 5-14 membered heteroaryl; Each R 3a are independently halogen, C 1-6 Alkyl, -OH or -OC 1-6 alkyl; Each R 3b are independently halogen or C 1-6 alkyl; Each R 5 Independently for C 1-6 Alkyl, C 3-8 Cycloalkyl, -OR 4 、-SR 4 , by one or more R 5c Substituted C 2-6 Alkynyl, with one or more R 5e substituted 3-10 membered heterocyclic group or one or more R 5g substituted 5-14 membered heteroaryl; Each R 5c , R 5e and R 5g Each independently is C 1-6 Alkyl or -N(R 6 )2; Each R 4 are independently hydrogen, C 1-6 Alkyl, with one or more R 4a Substituted C 1-6 Alkyl, 3-10 membered heterocyclic group or one or more R 4d substituted 3-10 membered heterocyclic group; Each R 4a are independently halogen, C 1-6 Alkyl, -N(R 6 )2. One or more R 4-c Substituted C 3-8 Cycloalkyl or one or more R 4-d substituted 3-10 membered heterocyclic group; Each R 4d are independently halogen, C 1-6 Alkyl or -N(R 6 )2; Each R 4-c and R 4-d Each independently is C 1-6 Alkyl, -N(R 6 )2 or one or more R 4-a-1 Substituted C 1-6 alkyl; Each R 4-a-1 are independently -N(R 6 )2; Each R a are independently hydrogen, halogen, cyano or C 1-6 alkyl; Each R 6 are independently hydrogen or C 1-6 alkyl; m is 1 or 2; Option Nine: Selected from Each X is independently N; R 1 is -C(O)NH2; R 2 is -NH2; R 3 Independently for one or more R 3a Substituted C 6-10 Aryl; Each R 3a Independently for C 1-6 Alkyl or -OH; Each R 5 Independently for C 1-6 Alkyl, -OR 4 or -SR 4 ; Each R 4 Independently for one or more R 4a Substituted C 1-6 Alkyl, 3-10 membered heterocyclic group or one or more R 4d substituted 3-10 membered heterocyclic group; Each R 4a Independently for one or more R 4-c Substituted C 3-8 Cycloalkyl or one or more R 4-d substituted 3-10 membered heterocyclic group; Each R 4d Independently for C 1-6 alkyl; Each R 4-c and R 4-d Each independently is C 1-6 Alkyl or -N(R 6 )2; Each R a are independently hydrogen or C 1-6 alkyl; Each R 6 are independently hydrogen or C 1-6 alkyl; m is 1 or 2; Option 10: Selected from: Each X is independently N; R 1 is -C(O)NH2; R 2 is -NH2; R 3 Independently for one or more R 3a Substituted C 6-10 Aryl or one or more R 3b substituted 5-14 membered heteroaryl; Each R 3a and R 3b are independently halogen, C 1-6 Alkyl or -OR 4 ; Each R 4 are independently hydrogen, C 1-6 Alkyl, 3-10 membered heterocyclic group, one or more R 4a Substituted C 1-6 Alkyl or one or more R 4d substituted 3-10 membered heterocyclic group; Each R 4a and R 4d are independently halogen, C 1-6 Alkyl, -N(R 6 )2. One or more R 4-c Substituted C 3-8 Cycloalkyl or one or more R 4-d substituted 3-10 membered heterocyclic group; Each R 4-c and R 4-d Each independently is C 1-6 Alkyl, -N(R 6 )2 or one or more R 4-a-1 Substituted C 1-6 alkyl; Each R 4-a-1 are independently -N(R 6 )2; Each R 5 Independently for C 1-6 Alkyl, C 3-8 Cycloalkyl, -OR 4 , by one or more R 5c Substituted C 2-6 Alkynyl, with one or more R 5e substituted 3-10 membered heterocyclic group, or one or more R 5g substituted 5-14 membered heteroaryl; Each R 5c , R 5e and R 5g Each independently is C 1-6 Alkyl or -NR 4 R 4 ; Each R a are independently hydrogen, halogen, cyano or C 1-6 alkyl; R b Independently for C 1-6 alkyl; Each R 6 are independently hydrogen or C 1-6 alkyl; m is 1 or 2; Plan 11: Selected from Each X is independently N; R 1 is -C(O)NH2; R 2 is -NH2; R 3 Independently for one or more R 3a Substituted C 6-10 Aryl; Each R 3a Independently for C 1-6 Alkyl or -OR 4 ; Each R 4 are independently hydrogen, 3-10 membered heterocyclic group, 4a Substituted C 1-6 Alkyl or one or more R 4d substituted 3-10 membered heterocyclic group; Each R 4a and R 4d Each independently is C 1-6 Alkyl, with one or more R 4-c Substituted C 3-8 Cycloalkyl or one or more R 4-d substituted 3-10 membered heterocyclic group; Each R 4-c and R 4-d Each independently is C 1-6 Alkyl or -N(R 6 )2; Each R 5 Independently for C 1-6 Alkyl or -OR 4 ; Each R a are independently hydrogen or C 1-6 alkyl; Each R 6 are independently hydrogen or C 1-6 alkyl; m is 1 or 2; Plan 12: Selected from Each X is independently N; R 1 is -C(O)NH2; R 2 is -NH2; R 3 Independently for one or more R 3a Substituted C 6-10 Aryl; Each R 3a are independently halogen, C 1-6 Alkyl or -OH; Each R 5 Independently for C 1-6 Alkyl, -OR 4 or -SR 4 ; Each R 4 Independently for one or more R 4a Substituted C 1-6 Alkyl, 3-10 membered heterocyclic group or one or more R 4d substituted 3-10 membered heterocyclic group; Each R 4a Independently for one or more R 4-c Substituted C 3-8 Cycloalkyl or one or more R 4-d substituted 3-10 membered heterocyclic group; Each R 4d Independently for C 1-6 alkyl; Each R 4-c and R 4-d Each independently is C 1-6 Alkyl or -N(R 6 )2; Each R a are independently hydrogen or C 1-6 alkyl; Each R 6 are independently hydrogen or C 1-6 alkyl; m is 1 or 2.

10. The compound represented by formula (I) according to claim 1 or 2, its tautomer, its pharmaceutically acceptable salt, its solvate or the solvate of its pharmaceutically acceptable salt, characterized in that: The compound represented by formula (I) is any of the following compounds: Preferably, the compound represented by formula (I) is any of the following compounds: The compound that elutes first under the following conditions: supercritical fluid chromatography chiral separation, the chiral column is ChiralPak IK, 250×40 mm, 10 μm, the eluent is methanol (containing 0.1% ammonia) / CO2=30 / 70, the flow rate is 120 mL / min, and the column temperature is 40° C.; preferably, under the conditions, the retention time of the compound that elutes first is 5.20 min; The compound that elutes later under the following conditions: supercritical fluid chromatography chiral separation, the chiral column is ChiralPak IK, 250×40 mm, 10 μm, the eluent is methanol (containing 0.1% ammonia) / CO2=30 / 70, the flow rate is 120 mL / min, and the column temperature is 40° C.; preferably, under the conditions, the retention time of the compound that elutes later is 6.02 min; The compound that elutes first under the following conditions: supercritical fluid chromatography chiral separation, the chiral column is ChiralPak IC, 250×40 mm, 10 μm, the eluent is methanol (containing 0.2% ammonia) / CO2=35 / 65, the flow rate is 120 mL / min, and the column temperature is 35° C.; preferably, under the conditions, the retention time of the compound that elutes first is 2.46 min; The compound that elutes later under the following conditions: supercritical fluid chromatography chiral separation, the chiral column is ChiralPak IC, 250×40 mm, 10 μm, the eluent is methanol (containing 0.2% ammonia) / CO2=35 / 65, the flow rate is 120 mL / min, and the column temperature is 35° C.; preferably, under the conditions, the retention time of the compound that elutes later is 2.99 min; Compounds that elute first under the following conditions: supercritical fluid chromatography chiral separation, chiral column: ChiralPak IC, 250×40 mm, 10 μm, eluent: methanol (containing 0.2% ammonia) / CO2=35 / 65, flow rate: 120 mL / min, column temperature: 35°C; Compounds that elute under the following conditions: supercritical fluid chromatography chiral separation, chiral column: ChiralPak IC, 250×40 mm, 10 μm, eluent: methanol (containing 0.2% ammonia) / CO2=35 / 65, flow rate: 120 mL / min, column temperature: 35°C; Compounds that elute first under the following conditions: supercritical fluid chromatography chiral separation, chiral column: ChiralPak IC, 250×40 mm, 10 μm, eluent: methanol (containing 0.2% ammonia) / CO2=35 / 65, flow rate: 120 mL / min, column temperature: 35°C; ChiralPak IC, 250×40mm, 10μm, eluent is methanol (containing 0.2% ammonia) / CO2=35 / 65, flow rate is 120mL / min, column temperature is 35℃.

11. A pharmaceutical composition comprising substance A and a pharmaceutically acceptable excipient, wherein substance A is a compound as shown in formula (I) as claimed in any one of claims 1 to 10, a tautomer thereof, a pharmaceutically acceptable salt thereof, a solvate thereof or a solvate of a pharmaceutically acceptable salt thereof.

12. Use of a substance A or a pharmaceutical composition as claimed in claim 11 in the preparation of a PKMYT1 inhibitor, wherein the substance A is a compound as represented by formula (I) as claimed in any one of claims 1 to 10, a tautomer thereof, a pharmaceutically acceptable salt thereof, a solvate thereof or a solvate of a pharmaceutically acceptable salt thereof.

13. Use of a substance A or a pharmaceutical composition as claimed in claim 11 in the preparation of a drug for preventing and / or treating a disease associated with PKMYT1, wherein the substance A is a compound as represented by formula (I) as claimed in any one of claims 1 to 10, a tautomer thereof, a pharmaceutically acceptable salt thereof, a solvate thereof or a solvate of a pharmaceutically acceptable salt thereof; and the disease associated with PKMYT1 may be cancer; Preferably, the cancer is colon cancer, breast cancer, lung cancer, brain cancer, ovarian cancer, uterine cancer, cervical cancer, cervical tumor, testicular cancer, kidney cancer, head or neck cancer, bone cancer, skin cancer, rectal cancer, liver cancer, prostate cancer, pancreatic cancer, esophageal cancer, colorectal cancer, gastric cancer, gastroesophageal cancer, thyroid cancer, bladder cancer, lymphoma, melanoma or sarcoma, preferably breast cancer, ovarian cancer, uterine tumor or gastroesophageal cancer; more preferably breast cancer or ovarian cancer; Preferably, the lung cancer is non-small cell lung cancer or small cell lung cancer.

14. Use of a substance A or a pharmaceutical composition according to claim 11 in the preparation of a drug for treating and / or preventing cancer, wherein the substance A is a compound of formula (I) according to any one of claims 1 to 10, a tautomer thereof, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof; The cancer may be colon cancer, breast cancer, lung cancer, brain cancer, ovarian cancer, uterine cancer, cervical cancer, cervical tumor, testicular cancer, kidney cancer, head or neck cancer, bone cancer, skin cancer, rectal cancer, liver cancer, prostate cancer, pancreatic cancer, esophageal cancer, colorectal cancer, gastric cancer, gastroesophageal cancer, thyroid cancer, bladder cancer, lymphoma, melanoma or sarcoma, preferably breast cancer, ovarian cancer, uterine tumor or gastroesophageal cancer; more preferably breast cancer or ovarian cancer; Preferably, the lung cancer is non-small cell lung cancer or small cell lung cancer.

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