Pyrazolopyridazinone compounds, pharmaceutical compositions thereof and uses thereof

Abstract

The present application provides a compound represented by formula (I), a pharmaceutical composition containing the compound, and uses thereof. The compound of formula (I) according to the present application has good HPK1 inhibitory activity. [Formula 1] JPEG2023520595000158.jpg36169

Description

[Technical field]

[0001] The present application relates to pyrazolopyridazinone compounds, and in particular to pyrazolopyridazinone derivatives having HPK1 inhibitory activity. [Background technology]

[0002] Hematopoietic progenitor kinase 1 (HPK1) is a serine / threonine kinase that was first obtained by cloning hematopoietic progenitor cells (Hu, MC et al., Genes Dev. 1996; 10: 2251-2264; Keifer, F. et al., The EMBO Journal 1996; 15: 7013-7025), and belongs to the mitogen-activated protein kinase kinase kinase-4 (MAP4K) family. HPK1 is distributed intensively in lymphoid organs or lymphoid tissues, such as bone marrow, lymph nodes, and thymus, and is expressed mainly in immune cells (T cells, B cells, dendritic cells, macrophages, etc.) (Hu, MC et al., Genes Dev. 1996; 10: 2251-2264). For this reason, the immunoregulatory effect of HPK1 has attracted attention.

[0003] Research has shown that HPK1 is a negative regulatory protein of the T cell receptor (TCR) signal pathway. TCR signaling causes HPK1 activation and binds to SLP-76 protein (Lasserre, R. et al., J Cell Biol. 2011; 195: 839-853; Shui, J. et al., Nature Immuno. 2007; 8: 84-91). Activated HPK1 phosphorylates the Ser376 residue of SLP-76, promoting the binding of SLP-76 to 14-3-3 protein (Di Bartolo, V. et al., J. Exp. Med. 2007; 204: 681-691; Shui, J. et al., Nature Immuno. 2007; 8: 84-91). SLP-76 / 14-3-3 interaction reduces ERK signaling and calcium ion flux, induces ubiquitination of SLP-76 and degradation of the SLP-76 complex, and blocks the TCR activation pathway, thereby inhibiting T cell function (Lasserre, R. et al., J. Cell Biol. 2011;195:839-853).

[0004] In in vivo experiments, HPK1 knockout mice exhibit enhanced T cell function and produce more cytokines, such as IL-2 and IFN-γ, upon antigen stimulation (Shui, J. et al., Nature Immuno. 2007; 8:84-91; Alzabin, S. et al., J. Immunol. 2009; 182:6187-6194; Alzabin, S. et al., Cancer Immunol. Immunother. 2010; 59:419-429). Further studies have revealed that the negative regulation of immune cells by HPK1 depends on its kinase activity. Compared to wild-type mice, mice in which HPK1 kinase activity is blocked show a higher CD8 + T cell function is enhanced, leading to faster clearance of chronic lymphocytic meningitis virus and better inhibition of tumor growth (Hernandez, S. et al., Cell Reports 2018;25:80-94). In the Lewis Lung Carcinoma (LLC) model, HPK1 - / -Mice transfected with T cells exhibit stronger anti-tumor immune responses than wild-type mice (Sawasdikosol, S. et al., Immunol. Res. 2012;54:262-265). Similar studies have demonstrated that the immunosuppressive effects of HPK1 on B cells (Sauer, K. et al., J. Biol. Chem. 2001;276:45207-45216; Tsuji, S. et al., J. Exp. Med. 2001;194:529-539; Wang, X. et al., J. Biol. Chem. 2012;287:34091-34100; Konigsberger, S. et al., PLosOne, 2010;5:e12468), dendritic cells (Alzabin, S. et al., J. Immunol. 2009;182:6187-6194), NK cells, and Treg cells are also due to its kinase activity (Liu, J. et al., PLosOne, 2019;14:e0212670). Clinical studies have found that HPK1 levels are significantly reduced in tissues from patients with systemic lupus erythematosus (Zhang, Q. et al., J. Autoimmun., 2011;37:180-189) and psoriatic arthritis (Stoeckman, AK et al., Genes Immun. 2006;7:583-591; Baltiwalla, FM et al., Mol. Med. 2005;11:21-29) compared to healthy controls, indicating that reduced HPK1 contributes to enhanced autoimmune responses. On the other hand, elevated HPK1 levels have been observed in many cancers, including acute myeloid leukemia (Chen-Deutsch, X. et al., Leuk. Res. 2012;36:884-888; Chen-Deutsch, X. et al., Cell Cycle 2012;11:1364-1373), bladder urothelial carcinoma (Wang, Y. et al., Mol. Med. Rep. 2012;5:260-265), extramammary Paget's disease (Qian, Y. et al., Am J. Dermatopathol. 2011;33:681-686), and colon cancer (Yang, H. S. et al., Mol. Cell Biol. 2006;26:1297-1306).

[0005] Therefore, HPK1 is a potential target for treating tumors and viral diseases. The development of small molecule inhibitors of HPK1 kinase has important prospects in clinical practice. Although some patent applications related to small molecule inhibitors of HPK1 have been disclosed, such as WO2018049191, WO2018049200, WO2018102366, WO2018183964, WO2019090198, WO2019206049, WO2019238067 and WO2020092528, no drugs targeting HPK1 have been launched yet. Therefore, there is currently a strong demand for developing new small molecule HPK1 inhibitors with good activity. Summary of the Invention

[0006] The present application has as its main object the provision of a compound of formula (I) or a pharma- ceutically acceptable salt, hydrate, solvate, active metabolite, crystalline polymorph, isotopically labeled product, isomer or prodrug thereof,

[0007] [ka]

[0008] Here, R 1 is selected from the following groups: 1) Hydrogen, halogen atoms, cyano groups, -C(=O)NR a R b , -OR a and -NR a R b ; 2) Unsubstituted or independently R 11 C optionally substituted with 1, 2, 3 or 4 substituents selected from 1-6 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-8 Cycloalkyl groups and 3- to 8-membered aliphatic heterocyclic groups; R a and R b are each independently selected from the following groups: 1) Hydrogen; 2) Unsubstituted or independently R 11 C which is optionally substituted with 1, 2 or 3 substituents selected from 1-6 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-6 Monocyclic cycloalkyl groups and 3- to 6-membered monocyclic aliphatic heterocyclic groups; Or, R attached to the same nitrogen atom a and R b are unsubstituted or independently R together with the nitrogen atom attached thereto. 11 forming a 3- to 6-membered monocyclic aliphatic heterocyclic group which may be substituted by 1, 2 or 3 substituents selected from R 11 is fluorine, chlorine, C 1-3 selected from alkyl groups and hydroxy groups; Cy A is unsubstituted or independently R 12 a 6- to 10-membered aryl group or a 5- to 10-membered heteroaryl group optionally substituted by 1, 2, 3, 4 or 5 substituents selected from the group consisting of R 12 is selected from the following groups: 1) Oxo group, halogen atom, cyano group, -C(=O)R a2 , -C(=O)OR a2 , -C(=O)NR a2 R b2 , -C(=NR d2 )NR a2 R b2 , -OR a2 , -OC(=O)R a2 , -OC(=O)OR c2 , -OC(=O)NR a2 R b2 , -SR a2 , -S(=O)R c2 , -S(=O)2R c2 , sulfonic acid group, -S(=O)NR a2 R b2 , -S(=O)2NR a2 R b2 , -S(=O)(=NR d2 )R c2 , -NR a2 Rb2 , -NR a2 C(=O)R b2 , -NR a2 C(=O)OR c2 , -NR e2 C(=O)NR a2 R b2 , -NR e2 C(=NR d2 )NR a2 R b2 , -NR a2 S(=O)2R c2 , -NR e2 S(=O)2NR a2 R b2 , nitro group, -PR c2 R f2 , -P(=O)R c2 R f2 and phosphonic acid groups; 2) Unsubstituted or independently R 22 C optionally substituted with 1, 2, 3, 4, 5 or 6 substituents selected from 1-6 Alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, 6- to 10-membered aryl group, 5- to 10-membered heteroaryl group, C 3-12 Cycloalkyl groups and 3- to 12-membered aliphatic heterocyclic groups; 3) Cy A Two R's bonded to adjacent ring-forming atoms in the aryl or heteroaryl group of 12 The substituents, together with the two ring-forming atoms to which they are attached, may be unsubstituted or independently R 22 C optionally substituted with 1, 2, 3, 4, 5 or 6 substituents selected from 5-12 Forms an alicyclic hydrocarbon group or a 5- to 12-membered aliphatic heterocyclic group; R a2 , R b2 and R e2 are each independently selected from the following groups: 1) Hydrogen; 2) Unsubstituted or independently R 22 C optionally substituted with 1, 2, 3, 4, 5 or 6 substituents selected from 1-4 Alkyl group, C 2-4 Alkenyl group, C 2-4Alkynyl group, phenyl group, 5-6 membered heteroaryl group, C 3-12 Cycloalkyl groups and 3- to 12-membered aliphatic heterocyclic groups; Or, R attached to the same nitrogen atom a2 and R b2 are unsubstituted or independently R 22 forming a 3- to 12-membered aliphatic heterocyclic group optionally substituted by 1, 2, 3, 4 or 5 substituents selected from R c2 and R f2 are each independently unsubstituted or independently R 22 C optionally substituted with 1, 2, 3, 4 or 5 substituents selected from 1-4 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, phenyl group, 5-6 membered heteroaryl group, C 3-12 selected from a cycloalkyl group and a 3- to 12-membered aliphatic heterocyclic group; Or, R bonded to the same phosphorus atom c2 and R f2 are unsubstituted or independently R 22 forming a 3- to 12-membered aliphatic heterocyclic group optionally substituted by 1, 2, 3, 4 or 5 substituents selected from R d2 is selected from the following groups: 1) Hydrogen, cyano group, nitro group, -S(=O)2R G ; 2) unsubstituted or each independently R 22 C optionally substituted with 1, 2, 3, 4 or 5 substituents selected from 1-4 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, phenyl group, 5-6 membered heteroaryl group, C 3-12 Cycloalkyl groups and 3- to 12-membered aliphatic heterocyclic groups; R 22 is selected from the following groups: 1) Oxo group, halogen atom, cyano group, -C(=O)R a4, -C(=O)OR a4 , -C(=O)NR a4 R b4 , -C(=NR d4 )NR a4 R b4 , -OR a4 , -OC(=O)R a4 , -OC(=O)OR c4 , -OC(=O)NR a4 R b4 , -SR a4 , -S(=O)R c4 , -S(=O)2R c4 , sulfonic acid group, -S(=O)NR a4 R b4 , -S(=O)2NR a4 R b4 , -S(=O)(=NR d4 )R c4 , -NR a4 R b4 , -NR a4 C(=O)R b4 , -NR a4 C(=O)OR c4 , -NR e4 C(=O)NR a4 R b4 , -NR e4 C(=NR d4 )NR a4 R b4 , -NR a4 S(=O)2R c4 , -NR e4 S(=O)2NR a4 R b4 , nitro group, -PR c4 R f4 , -P(=O)R c4 R f4 , phosphonic acid groups and imino groups (=NR d4 ); 2) Unsubstituted or independently R 32 C optionally substituted with 1, 2, 3, 4 or 5 substituents selected from 1-6 Alkyl group, C 1-6 Alkylene group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, phenyl group, 5-6 membered heteroaryl group, C 3-10Cycloalkyl groups and 3- to 10-membered aliphatic heterocyclic groups; R a4 , R b4 and R e4 are each independently selected from the following groups: 1) Hydrogen; 2) Unsubstituted or independently R 32 C optionally substituted with 1, 2, 3, 4 or 5 substituents selected from 1-4 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, phenyl group, 5-6 membered heteroaryl group, C 3-10 Cycloalkyl groups and 3- to 10-membered aliphatic heterocyclic groups; Or, R attached to the same nitrogen atom a4 and R b4 are unsubstituted or independently R 32 forming a 3- to 10-membered aliphatic heterocyclic group optionally substituted by 1, 2, 3, 4 or 5 substituents selected from R c4 and R f4 are each independently unsubstituted or independently R 32 C optionally substituted with 1, 2, 3, 4 or 5 substituents selected from 1-4 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, phenyl group, 5-6 membered heteroaryl group, C 3-10 selected from a cycloalkyl group and a 3- to 10-membered aliphatic heterocyclic group; Or, R bonded to the same phosphorus atom c4 and R f4 are unsubstituted or independently R 32 forming a 3- to 10-membered aliphatic heterocyclic group optionally substituted by 1, 2, 3, 4 or 5 substituents selected from R d4 is selected from the following groups: 1) Hydrogen, cyano group, nitro group and -S(=O)R G ; 2) Unsubstituted or independently R 32C optionally substituted with 1, 2, 3, 4 or 5 substituents selected from 1-4 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, phenyl group, 5-6 membered heteroaryl group, C 3-10 Cycloalkyl groups and 3- to 10-membered aliphatic heterocyclic groups; R 32 is selected from the following groups: 1) Oxo group, halogen atom, cyano group, -C(=O)R a6 , -C(=O)OR a6 , -C(=O)NR a6 R b6 , -C(=NR d6 )NR a6 R b6 , -OR a6 , -OC(=O)R a6 , -OC(=O)OR c6 , -OC(=O)NR a6 R b6 , -SR a6 , -S(=O)R c6 , -S(=O)2R c6 , sulfonic acid group, -S(=O)NR a6 R b6 , -S(=O)2NR a6 R b6 , -S(=O)(=NR d6 )R c6 , -NR a6 R b6 , -NR a6 C(=O)R b6 , -NR a6 C(=O)OR c6 , -NR e6 C(=O)NR a6 R b6 , -NR e6 C(=NR d6 )NR a6 R b6 , -NR a6 S(=O)2R c6 , -NR e6 S(=O)2NR a6 R b6 , nitro group, -PR c6 R f6 , -P(=O)R c6 Rf6 , phosphonic acid groups and imino groups (=NR d6 ); 2) Unsubstituted or independently R G C optionally substituted with 1, 2, 3 or 4 substituents selected from 1-4 Alkyl group, C 1-4 Alkylene group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, phenyl group, 5-6 membered heteroaryl group, C 3-8 Cycloalkyl groups and 3- to 8-membered aliphatic heterocyclic groups; R a6 , R b6 and R e6 are each independently selected from the following groups: 1) Hydrogen; 2) Unsubstituted or independently R G C optionally substituted with 1, 2, 3 or 4 substituents selected from 1-4 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, phenyl group, 5-6 membered heteroaryl group, C 3-8 A cycloalkyl group and a 3- to 8-membered aliphatic heterocyclic group; or R attached to the same nitrogen atom a6 and R b6 are unsubstituted or independently R G forming a 3- to 8-membered aliphatic heterocyclic group optionally substituted by 1, 2, 3 or 4 substituents selected from R c6 and R f6 are each independently unsubstituted or independently R G C optionally substituted with 1, 2, 3 or 4 substituents selected from 1-4 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, phenyl group, 5-6 membered heteroaryl group, C 3-8 selected from a cycloalkyl group and a 3- to 8-membered aliphatic heterocyclic group; Or, R bonded to the same phosphorus atom c6 and R f6are unsubstituted or independently R G forming a 3- to 8-membered aliphatic heterocyclic group optionally substituted by 1, 2, 3 or 4 substituents selected from R d6 is selected from the following groups: 1) Hydrogen, cyano group, nitro group and -S(=O)R G ; 2) Unsubstituted or independently R G C optionally substituted with 1, 2, 3 or 4 substituents selected from 1-4 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, phenyl group, 5-6 membered heteroaryl group, C 3-8 Cycloalkyl groups, 3- to 8-membered aliphatic heterocyclic groups; Cy B is unsubstituted or independently R 13 a 6- to 10-membered aryl group or a 5- to 10-membered heteroaryl group optionally substituted by 1, 2, 3, 4 or 5 substituents selected from the group consisting of R 13 is selected from the following groups: 1) Oxo group, halogen atom, cyano group, -C(=O)R a3 , -C(=O)OR a3 , -C(=O)NR a3 R b3 , -C(=NR d3 )NR a3 R b3 , -OR a3 , -OC(=O)R a3 , -OC(=O)OR c3 , -OC(=O)NR a3 R b3 , -SR a3 , -S(=O)R c3 , -S(=O)2R c3 , sulfonic acid group, -S(=O)NR a3 R b3 , -S(=O)2NR a3 R b3 , -S(=O)(=NR d3 )R c3 , -NR a3 R b3 , -NRa3 C(=O)R b3 , -NR a3 C(=O)OR c3 , -NR e3 C(=O)NR a3 R b3 , -NR e3 C(=NR d3 )NR a3 R b3 , -NR a3 S(=O)2R c3 , -NR e3 S(=O)2NR a3 R b3 , nitro group, -PR c3 R f3 , -P(=O)R c3 R f3 and phosphonic acid groups; 2) Unsubstituted or independently R 23 C optionally substituted with 1, 2, 3, 4, 5 or 6 substituents selected from 1-6 Alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, 6- to 10-membered aryl group, 5- to 10-membered heteroaryl group, C 3-12 Cycloalkyl groups and 3- to 12-membered aliphatic heterocyclic groups; 3) Cy B Two R's bonded to adjacent ring-forming atoms in the aryl or heteroaryl group of 13 The substituents, together with the two ring-forming atoms to which they are attached, may be unsubstituted or independently R 23 C optionally substituted with 1, 2, 3, 4 or 5 substituents selected from 5-12 Forms an alicyclic hydrocarbon group or a 5- to 12-membered aliphatic heterocyclic group; R a3 , R b3 and R e3 are each independently selected from the following groups: 1) Hydrogen; 2) Unsubstituted or independently R 23 C optionally substituted with 1, 2, 3, 4, 5 or 6 substituents selected from 1-4 Alkyl group, C 2-4 Alkenyl group, C 2-4Alkynyl group, phenyl group, 5-6 membered heteroaryl group, C 3-12 Cycloalkyl groups and 3- to 12-membered aliphatic heterocyclic groups; Or, R attached to the same nitrogen atom a3 and R b3 are unsubstituted or independently R 23 forming a 3- to 12-membered aliphatic heterocyclic group optionally substituted by 1, 2, 3, 4 or 5 substituents selected from R c3 and R f3 are each independently unsubstituted or independently R 23 C optionally substituted with 1, 2, 3, 4 or 5 substituents selected from 1-4 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, phenyl group, 5-6 membered heteroaryl group, C 3-12 selected from a cycloalkyl group and a 3- to 12-membered aliphatic heterocyclic group; Or, R bonded to the same phosphorus atom c3 and R f3 are unsubstituted or independently R 23 forming a 3- to 12-membered aliphatic heterocyclic group optionally substituted by 1, 2, 3, 4 or 5 substituents selected from R d3 is selected from the following groups: 1) Hydrogen, cyano group, nitro group, S(=O)2R G ; 2) unsubstituted or each independently R 23 C optionally substituted with 1, 2, 3, 4 or 5 substituents selected from 1-4 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, phenyl group, 5-6 membered heteroaryl group, C 3-12 Cycloalkyl groups and 3- to 12-membered aliphatic heterocyclic groups; R 23 is selected from the following groups: 1) Oxo group, halogen atom, cyano group, -C(=O)R a5 , -C(=O)ORa5 , -C(=O)NR a5 R b5 , -C(=NR d5 )NR a5 R b5 , -OR a5 , -OC(=O)R a5 , -OC(=O)OR c5 , -OC(=O)NR a5 R b5 , -SR a5 , -S(=O)R c5 , -S(=O)2R c5 , sulfonic acid group, -S(=O)NR a5 R b5 , -S(=O)2NR a5 R b5 , -S(=O)(=NR d5 )R c5 , -NR a5 R b5 , -NR a5 C(=O)R b5 , -NR a5 C(=O)OR c5 , -NR e5 C(=O)NR a5 R b5 , -NR e5 C(=NR d5 )NR a5 R b5 , -NR a5 S(=O)2R c5 , -NR e5 S(=O)2NR a5 R b5 , nitro group, -PR c5 R f5 , -P(=O)R c5 R f5 , phosphonic acid groups and imino groups (=NR d5 ); 2) Unsubstituted or independently R 33 C optionally substituted with 1, 2, 3, 4 or 5 substituents selected from 1-6 Alkyl group, C 1-6 Alkylene group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, phenyl group, 5-6 membered heteroaryl group, C 3-10 Cycloalkyl groups and 3- to 10-membered aliphatic heterocyclic groups; R a5 , R b5 and R e5 are each independently selected from the following groups: 1) Hydrogen; 2) Unsubstituted or independently R 33 C optionally substituted with 1, 2, 3, 4 or 5 substituents selected from 1-4 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, phenyl group, 5-6 membered heteroaryl group, C 3-10 Cycloalkyl groups and 3- to 10-membered aliphatic heterocyclic groups; Or, R attached to the same nitrogen atom a5 and R b5 are unsubstituted or independently R 33 forming a 3- to 10-membered aliphatic heterocyclic group optionally substituted by 1, 2, 3, 4 or 5 substituents selected from R c5 and R f5 are each independently unsubstituted or independently R 33 C optionally substituted with 1, 2, 3, 4 or 5 substituents selected from 1-4 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, phenyl group, 5-6 membered heteroaryl group, C 3-10 selected from a cycloalkyl group and a 3- to 10-membered aliphatic heterocyclic group; Or, R bonded to the same phosphorus atom c5 and R f5 are unsubstituted or independently R 33 forming a 3- to 10-membered aliphatic heterocyclic group optionally substituted by 1, 2, 3, 4 or 5 substituents selected from R d5 is selected from the following groups: 1) Hydrogen, cyano group, nitro group and -S(=O)R G ; 2) Unsubstituted or independently R 33 C optionally substituted with 1, 2, 3, 4 or 5 substituents selected from1-4 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, phenyl group, 5-6 membered heteroaryl group, C 3-10 Cycloalkyl groups and 3- to 10-membered aliphatic heterocyclic groups; R 33 is selected from the following groups: 1) Oxo group, halogen atom, cyano group, -C(=O)R a7 , -C(=O)OR a7 , -C(=O)NR a7 R b7 , -C(=NR d7 )NR a7 R b7 , -OR a7 , -OC(=O)R a7 , -OC(=O)OR c7 , -OC(=O)NR a7 R b7 , -SR a7 , -S(=O)R c7 , -S(=O)2R c7 , sulfonic acid group, -S(=O)NR a7 R b7 , -S(=O)2NR a7 R b7 , -S(=O)(=NR d7 )R c7 , -NR a7 R b7 , -NR a7 C(=O)R b7 , -NR a7 C(=O)OR c7 , -NR e7 C(=O)NR a7 R b7 , -NR e7 C(=NR d7 )NR a7 R b7 , -NR a7 S(=O)2R c7 , -NR e7 S(=O)2NR a7 R b7 , nitro group, -PR c7 R f7 , -P(=O)R c7 R f7 , phosphonic acid groups and imino groups (=NRd7 ); 2) Unsubstituted or independently R G C optionally substituted with 1, 2, 3 or 4 substituents selected from 1-4 Alkyl group, C 1-4 Alkylene group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, phenyl group, 5-6 membered heteroaryl group, C 3-8 Cycloalkyl groups and 3- to 8-membered aliphatic heterocyclic groups; R a7 , R b7 and R e7 are each independently selected from the following groups: 1) Hydrogen; 2) Unsubstituted or independently R G C optionally substituted with 1, 2, 3 or 4 substituents selected from 1-4 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, phenyl group, 5-6 membered heteroaryl group, C 3-8 Cycloalkyl groups and 3- to 8-membered aliphatic heterocyclic groups; Or, R attached to the same nitrogen atom a7 and R b7 are unsubstituted or independently R G forming a 3- to 8-membered aliphatic heterocyclic group optionally substituted by 1, 2, 3 or 4 substituents selected from R c7 and R f7 are each independently unsubstituted or independently R G C optionally substituted with 1, 2, 3 or 4 substituents selected from 1-4 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, phenyl group, 5-6 membered heteroaryl group, C 3-8 selected from a cycloalkyl group and a 3- to 8-membered aliphatic heterocyclic group; Or, R bonded to the same phosphorus atom c7 and R f7 together with the phosphorus atom attached thereto may be unsubstituted or independently RG forming a 3- to 8-membered aliphatic heterocyclic group optionally substituted by 1, 2, 3 or 4 substituents selected from R d7 is selected from the following groups: 1) Hydrogen, cyano group, nitro group and -S(=O)R G ; 2) Unsubstituted or independently R G C optionally substituted with 1, 2, 3 or 4 substituents selected from 1-4 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, phenyl group, 5-6 membered heteroaryl group, C 3-8 Cycloalkyl groups and 3- to 8-membered aliphatic heterocyclic groups; R G is selected from the following groups: 1) Halogen atoms, oxo groups, cyano groups, carboxyl groups, hydroxyl groups, C 1-4 Alkoxy group, amino group, C 1-4 Alkylamino group, nitro group, C 1-4 Alkylthio group, sulfonic acid group, C 1-4 Alkyl sulfoxide group, C 1-4 Alkyl sulfone group, C 1-4 Alkylaminosulfinyl group and C 1-4 Alkylaminosulfonyl group; 2) Unsubstituted or independently oxo group, halogen atom, hydroxy group, methylol group, carboxyl group, cyano group, C 1-3 Alkoxy group, amino group, C 1-4 C which may be substituted with 1, 2, 3 or 4 groups selected from an alkylamino group, a nitro group and a sulfonic acid group 1-4 Alkyl group, C 1-4 Alkylene group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-6 Cycloalkyl groups and 3- to 8-membered aliphatic heterocyclic groups.

[0009] According to some embodiments, in formula (I), R 1 is selected from hydrogen, fluorine, a cyano group, a methyl group and a methoxy group.

[0010] According to some embodiments, in formula (I), Cy A is unsubstituted or independently R 12 a phenyl group, a pyridyl group, a pyrimidinyl group, a pyrazolyl group, an imidazolyl group, a thiazolyl group, an isothiazolyl group, or

[0011] [ka]

[0012] and a 5- to 7-membered saturated aliphatic heterocycle, wherein Z is 1 to 3 heteroatoms selected from nitrogen and oxygen; when Z=N, N may be bonded to an Ry group, and Ro is oxo, F, an amino group, C 1-3 Alkyl group (F, hydroxyl group, amino group, C 1-3 The aliphatic heterocycle may be fused with another 5- to 6-membered saturated aliphatic heterocycle containing a heteroatom N, and wherein: 1) Cy A There is one R 12 If R 12 is one selected from the following structures:

[0013] [ka]

[0014] Here, R x -OH, C 1-6 Alkyl groups (e.g., methyl groups), C 1-6 Alkoxy group (e.g. methoxy group), -NH2, C 1-6 Alkylamino groups (e.g., amino groups, dimethylamino groups),

[0015] [ka]

[0016] Selected from; 2) Cy A One or more R 12 If it contains, the remaining R 12 are independently fluorine, C 1-6 Alkyl groups (e.g., methyl groups), C 1-6 Alkoxy groups (e.g., methoxy groups), C 1-6 alkylaminomethyl groups (e.g., dimethylaminomethyl groups, methylaminomethyl groups); Cy B is one selected from the following structures:

[0017] [ka]

[0018] R a3 and R b3 are independently hydrogen, optionally substituted C 1-6 Alkyl group and C 3-6 cycloalkyl groups or R a3 and R b3 form a 4- to 6-membered saturated aliphatic heterocyclic group together with the N atom bonded thereto, and the aliphatic heterocyclic group may be substituted; the substituent in the case where the aliphatic heterocyclic group may be substituted is, for example, a hydroxy group, C 1-6 Alkyl groups, C substituted with F 1-6 selected from alkyl groups; R y , H, C 1-6 C substituted with alkyl groups (e.g., methyl groups), hydroxy groups, or halogens 1-6 Alkyl groups (e.g., hydroxyethyl, hydroxypropyl, difluoroethyl), C 3-6 A cycloalkyl group (e.g., cyclobutane, cyclobutane substituted with an amino group), a 4- to 6-membered saturated aliphatic heterocycle containing nitrogen, a 5- to 6-membered saturated aliphatic heterocycle containing oxygen, or -C(=O)Rs, where Rs is a C group optionally substituted with a hydroxy group, an amino group, or a 5- to 6-membered aliphatic heterocycle containing nitrogen. 1-6 The alkyl group is selected from the group consisting of alkyl groups.

[0019] According to some embodiments, in formula (I), Cy A is a phenyl group, a pyridyl group, a pyrimidinyl group, a thiazolyl group, or

[0020] [ka]

[0021] wherein Z is 1 to 3 and is selected from nitrogen and oxygen; when Z=N, R may be substituted with Ry; R is oxo, F, an amino group, C 1-3 Alkyl group (F, hydroxyl group, amino group, C 1-3 and each of the aliphatic heterocycles may be substituted with an alkoxy group, and the aliphatic heterocycle may further form a condensed ring together with another 5- to 6-membered saturated aliphatic heterocycle containing a N heteroatom; Cy A is selected from the group consisting of phenyl, pyridyl, pyrimidinyl and thiazolyl; R 12 teeth,

[0022] [ka]

[0023] where Rz is hydrogen, C 1-6 Alkyl group (substituted with cyano or methoxy group), 4-6 membered aliphatic heterocycle containing oxygen or -S(=O)2-C 1-6 alkyl group; Rp is one or more and is selected from hydrogen, C 1-6 Rq is selected from the group consisting of a hydroxyl group, an amino group, an alkyl group, and an aryl group; 1-3an alkyl group (which may be substituted with a 5- to 6-membered aliphatic heterocyclic group containing nitrogen or a 5- to 6-membered heteroaryl group containing nitrogen); a double spiro ring consisting of two 4- to 5-membered rings containing nitrogen and / or oxygen; and a 5- to 6-membered aliphatic heterocyclic group containing one or two heteroatoms selected from nitrogen and oxygen, the aliphatic heterocyclic group being selected from F, C 1-3 It may be substituted with an alkyl group.

[0024] According to some embodiments, in formula (I), Cy A is selected from the group consisting of phenyl groups, and R 12 teeth,

[0025] [ka]

[0026] where Rz is hydrogen, C 1-6 Alkyl group (substituted with cyano or methoxy group), 4-6 membered aliphatic heterocycle containing oxygen or -S(=O)2-C 1-6 alkyl group; Rp is one or more and is selected from hydrogen, C 1-6 Rq is selected from the group consisting of a hydroxyl group, an amino group, an alkyl group, and an aryl group; 1-3 an alkyl group (which may be substituted with a 5- to 6-membered aliphatic heterocyclic group containing nitrogen or a 5- to 6-membered heteroaryl group containing nitrogen); a double spiro ring consisting of two 4- to 5-membered rings containing nitrogen and / or oxygen; and a 5- to 6-membered aliphatic heterocyclic group containing one or two heteroatoms selected from nitrogen and oxygen, the aliphatic heterocyclic group being selected from F, C 1-3 It may be substituted with an alkyl group.

[0027] According to some embodiments, in formula (I), Cy A is selected from the following structures: Cy A is selected from the following structures:

[0028] [ka]

[0029] Wherein W1 is selected from CH2 or oxygen; R T is selected from hydrogen or a methyl group; R V is selected from fluorine and a methyl group, R V The number is 0, 1 or 2.

[0030] According to some embodiments, in formula (I), Cy B is selected from the group consisting of H, F, -CN, C 1-3 Alkyl groups (F, substituted with amino groups), C 1-3 Alkoxy group (substituted with F), C 3-6 Cycloalkyloxy group, -C(=O)NR a3 R b3 and R a3 and R b3 are independently hydrogen, C 1-6 Alkyl group and C 3-6 Cycloalkyl groups (C substituted with F 1-3 or R a3 and R b3 is a 4- to 5-membered aliphatic heterocyclic group (hydroxy group, C 1-3 substituted with an alkyl group).

[0031] According to some embodiments, in formula (I), the Cy B is selected from the following structures:

[0032] [ka]

[0033] According to some embodiments, in formula (I), Cy A is a phenyl group and R 12 When is an aliphatic heterocyclic group, R 12 is attached to the para or meta position of the phenyl group.

[0034] According to some embodiments, the compound of formula (I) is 1 Includes isotopically labeled products where H is deuterated.

[0035] Some embodiments of the present application further provide a pharmaceutical composition comprising a compound of formula (I) above or a pharma- ceutically acceptable salt, hydrate, solvate, active metabolite, crystalline polymorph, isotopically labeled compound, isomer, or prodrug thereof, and a pharma- ceutically acceptable carrier.

[0036] Some embodiments of the present application further provide the use of the compound of formula (I) above or a pharma- ceutically acceptable salt, hydrate, solvate, active metabolite, crystalline polymorph, isotopically labeled substance, isomer or prodrug thereof, or the pharmaceutical composition above, in the prophylaxis or treatment of an HPK1-mediated disease.

[0037] Some embodiments of the present application further provide a use of the compound of formula (I) above or a pharma- ceutically acceptable salt, hydrate, solvate, active metabolite, crystalline polymorph, isotopically labeled substance, isomer or prodrug thereof, or the pharmaceutical composition above, in the preparation of a medicament for preventing or treating an HPK1-mediated disease.

[0038] Some embodiments of the present application further provide a use of the compound of formula (I) above or a pharma- ceutically acceptable salt, hydrate, solvate, active metabolite, crystalline polymorph, isotopically labeled substance, isomer or prodrug thereof, or the pharmaceutical composition above, in the treatment or amelioration of a disease, the disease comprising one or more of benign or malignant tumors, myeloproliferative disorders and viral diseases.

[0039] Some embodiments of the present application further provide a method of inhibiting HPK1 activity comprising administering to an individual a compound of formula (I) or a pharma- ceutically acceptable salt, hydrate, solvate, active metabolite, crystalline polymorph, isotopically labeled, isomer, or prodrug thereof.

[0040] Some embodiments of the present application further provide a method of treating a disease or condition in a patient, comprising administering to the patient a therapeutically effective amount of a compound of formula (I) or a pharma- ceutically acceptable salt, hydrate, solvate, active metabolite, crystalline polymorph, isotopically labeled, isomer, or prodrug thereof, wherein the disease is an HPK1-mediated disease.

[0041] The compounds of formula (I) according to some embodiments of the present application have the effect of inhibiting HPK1 activity.

[0042] According to some embodiments of the present application, the disease comprises one or more of a benign or malignant tumor, myeloproliferative disease, and a viral disease. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0043] In the following description, exemplary embodiments embodying the features and advantages of the present application are detailed, and the present application includes various modifications in different embodiments, all of which are within the scope of the present application. The description is illustrative in nature, rather than limiting.

[0044] In some embodiments, R 1 is selected from the following groups: 1) Hydrogen, halogen atom, cyano group, ethynyl group, -OR a and -NR a R b ; 2) Unsubstituted or independently R 11 C optionally substituted with 1, 2, 3 or 4 substituents selected from 1-4 Alkyl group, C 3-5 Monocyclic cycloalkyl groups and 4- to 7-membered aliphatic heterocyclic groups.

[0045] In some embodiments, R 1 is hydrogen, fluorine, chlorine, bromine, cyano group, C 1-4 Alkyl group, C 3-4 Cycloalkyl groups, 3-4 membered aliphatic heterocyclic groups and -OR a Selected from.

[0046] In some embodiments, R 1 is selected from hydrogen, fluorine, a cyano group, a methyl group, an ethyl group, a 1-propyl group, an isopropyl group, a cyclopropyl group, a methoxy group, an ethoxy group and a cyclopropoxy group.

[0047] In some embodiments, R 1 is hydrogen.

[0048] In some embodiments, R a and R b are each independently hydrogen, C 1-3 Alkyl group, C 3-4 selected from a cycloalkyl group and a 3- to 4-membered aliphatic heterocyclic group; Or, R attached to the same nitrogen atom a and R b form an unsubstituted 3- to 6-membered aliphatic heterocyclic group together with the nitrogen atom to which they are bonded.

[0049] In some embodiments, R a and R b are each independently selected from hydrogen, a methyl group, an ethyl group, and a cyclopropyl group.

[0050] In some embodiments, Cy A is unsubstituted or independently R 12 or a 5-, 6-, 7-, 8-, 9- or 10-membered heteroaryl group, optionally substituted by 1, 2, 3 or 4 substituents selected from the group consisting of phenyl, naphthyl, and aryl, wherein the heteroaryl group contains 1, 2 or 3 ring-forming heteroatoms selected from N, O and S.

[0051] In some embodiments, Cy AThe aryl or heteroaryl group is one R 12 R 12 is a cyclic group, the cyclic group being unsubstituted or independently R 22 a 6- to 10-membered aryl group, a 5- to 10-membered heteroaryl group, which may be substituted by 1, 2 or 3 substituents selected from 3-7 selected from a cycloalkyl group and a 3- to 7-membered aliphatic heterocyclic group, the 3- to 7-membered aliphatic heterocyclic group containing 1 or 2 ring-forming heteroatoms selected from N, O and S; Or, Cy A The aryl or heteroaryl group may have 2, 3 or 4 R 12 Contains substituents, one of which is R 12 is the cyclic group described above, and the remaining R 12 are independently 1-6 Alkyl group, halogen atom, cyano group, -OR a2 and -NR a2 R b2 Selected from.

[0052] In some embodiments, Cy A The aryl or heteroaryl group is one R 12 R 12 is a cyclic group, the cyclic group being unsubstituted or independently R 22 a phenyl group optionally substituted by 1, 2 or 3 substituents selected from the group consisting of a 5- to 6-membered heteroaryl group, 3-6 selected from cycloalkyl groups and 4-, 5-, 6-, and 7-membered aliphatic heterocyclic groups, the 4-, 5-, 6-, and 7-membered aliphatic heterocyclic groups containing 1 or 2 ring-forming heteroatoms selected from N, O, and S; Or, Cy A The aryl or heteroaryl group may be one of two or three R 12 Contains substituents, one of which is R 12 is the cyclic group described above, and the remaining R 12 are independently 1-6 Alkyl group, halogen atom, cyano group, -OR a2 and -NR a2 R b2Selected from.

[0053] In some embodiments, Cy A are independently R 12 is a phenyl group or a 5- to 6-membered heteroaryl group which may be substituted by 1, 2, 3 or 4 substituents selected from the following:

[0054] In some embodiments, Cy A are independently R 12 wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 , 12 The substituents, together with the two ring-forming atoms to which they are attached, may be unsubstituted or independently R 22 Forms a C5, C6, C7 monocyclic alicyclic hydrocarbon group or a 5-, 6-, or 7-membered monocyclic aliphatic heterocyclic group optionally substituted by 1, 2, 3, or 4 substituents selected from the following:

[0055] In some embodiments, Cy A are independently R 12 a phenyl group optionally substituted by 1, 2 or 3 substituents selected from the group consisting of phenyl, ...

[0056] In some embodiments, Cy A are independently R 12 and R 1 -R 2 -R 3 -R 4 -R 5 -R 6 -R 7 -R 8 -R 9 -R 10 -R 11 -R 12 -R 13 -R 14 -R 15 -R 16 -R 17 -R 18 -R 19 -R 20 -R 21 -R 22 -R 23 -R 24 -R 25 -R 26 -R 27 -R 28 -R 29 -R 30 -R 31 -R 32 -R 33 -R 34 -R 35 -R 36 -R 37 -R 38 -R 39 -R 40 -R 41 -R 42 -R 43 -R 44 -R 45 -R 46 -R 47 -R 48 -R 49 -R

[0057] In some embodiments, Cy A are independently R 12and R 1 -R 2 -R 3 -R 4 -R 5 -R 6 -R 7 -R 8 -R 9 -R 10 -R 11 -R 12 -R 13 -R 14 -R 15 -R 16 -R 17 -R 18 -R 19 -R 20 -R 21 -R 22 -R 23 -R 24 -R 25 -R 26 -R 27 -R 28 -R 29 -R 30 -R 31 -R 32 -R 33 -R 34 -R 35 -R 36 -R 37 -R 38 -R 39 -R

[0058] In some embodiments, Cy A The aryl or heteroaryl group may have 2, 3 or 4 R 12 The substituents include two R 1 -R 2 -R 3 -R 4 -R 5 -R 6 -R 7 -R 8 -R 9 -R 10 -R 11 -R 12 -R 13 -R 14 -R 15 -R 16 -R 17 -R 18 -R 19 -R 20 -R 21 -R 22 -R 23 -R 24 -R 25 -R 26 -R 12 The substituents, together with the two ring-forming atoms, are unsubstituted or independently R 22 C which is optionally substituted with 1, 2 or 3 substituents selected from 5-8 The aliphatic heterocyclic group forms an alicyclic hydrocarbon group and a 5- to 8-membered aliphatic heterocyclic group; the aliphatic heterocyclic group contains 1, 2 or 3 ring-forming heteroatoms selected from N, O and S, and each R that does not form a ring 12 is independently C 1-6 Alkyl group, halogen atom, cyano group, -OR a2 and -NR a2 R b2 Selected from.

[0059] In some embodiments, Cy A The aryl or heteroaryl group may have 2, 3 or 4 R 12 The substituents include two R 1 , each of which is bonded to two adjacent ring-forming atoms in an aryl or heteroaryl group. 12 The substituents are unsubstituted or independently oxo groups together with the two ring-forming atoms, R H , -(CH2) 0-2 -OH, -(CH2) 0-2 -OR H , -(CH2) 0-2 -NH2, -(CH2) 0-2 -NHR H and -(CH2) 0-2 -N(R H ) 2 to form a 5-, 6-, or 7-membered monocyclic aliphatic heterocyclic group which may be substituted with 1, 2, or 3 groups selected from the group consisting of N and O; the monocyclic aliphatic heterocyclic group contains 1 or 2 ring-forming heteroatoms selected from N and O, and each R 12is independently C 1-6 Alkyl group, halogen atom, cyano group, -OR a2 and -NR a2 R b2 Selected from R H is optionally selected from a methyl group, an ethyl group, an isopropyl group, a cyclopropyl group, and a 3-oxetanyl group.

[0060] In some embodiments, each R 12 are independently selected from the following groups: 1) Oxo group, halogen atom, cyano group, -C(=O)R a2 , -C(=O)OR a2 , -C(=O)NR a2 R b2 , -C(=NR d2 )NR a2 R b2 , -OR a2 , -OC(=O)R a2 , -OC(=O)OR c2 , -OC(=O)NR a2 R b2 , -SR a2 , -S(=O)R c2 , -S(=O)2R c2 , sulfonic acid group, -S(=O)NR a2 R b2 , -S(=O)2NR a2 R b2 , -S(=O)(=NR d2 )R c2 , -NR a2 R b2 , -NR a2 C(=O)R b2 , -NR a2 C(=O)OR c2 , -NR e2 C(=O)NR a2 R b2 , -NR e2 C(=NR d2 )NR a2 R b2 , -NR a2 S(=O)2R c2 , -NR e2 S(=O)2NR a2 R b2 and nitro groups; 2) Unsubstituted or independently R 22 C optionally substituted with 1, 2, 3, 4, 5 or 6 substituents selected from 1-6 Alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, 6- to 10-membered aryl group, 5- to 10-membered heteroaryl group, C 3-12 Cycloalkyl groups and 3- to 12-membered aliphatic heterocyclic groups; 3) Cy A Two R's bonded to adjacent ring-forming atoms in the aryl or heteroaryl group of 12 The substituents, together with the two ring-forming atoms, are unsubstituted or each independently R 22 C optionally substituted with 1, 2, 3, 4, 5 or 6 substituents selected from 5-12 It forms an alicyclic hydrocarbon group or a 5- to 12-membered aliphatic heterocyclic group.

[0061] In some embodiments, each R 12 are independently selected from the following groups: 1) Oxo group, halogen atom, cyano group, -C(=O)R a2 , -C(=O)OR a2 , -C(=O)NR a2 R b2 , -C(=NR d2 )NR a2 R b2 , -OR a2 , -OC(=O)R a2 , -OC(=O)OR c2 , -OC(=O)NR a2 R b2 , -NR a2 R b2 , -NR a2 C(=O)R b2 , -NR a2 C(=O)OR c2 , -NR e2 C(=O)NR a2 R b2 , -NR e2 C(=NR d2 )NR a2 R b2 , -NR a2 S(=O)2R c2, -NR e2 S(=O)2NR a2 R b2 and nitro groups; 2) Unsubstituted or independently R 22 C optionally substituted with 1, 2, 3, 4, 5 or 6 substituents selected from 1-6 Alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, 6- to 10-membered aryl group, 5- to 10-membered heteroaryl group, C 3-10 Cycloalkyl groups and 3- to 10-membered aliphatic heterocyclic groups; 3) Cy A Two R's bonded to adjacent ring-forming atoms in the aryl or heteroaryl group of 12 The substituents, together with the two ring-forming atoms, are unsubstituted or each independently R 22 C optionally substituted with 1, 2, 3, 4 or 5 substituents selected from 5-10 It forms an alicyclic hydrocarbon group or a 5- to 10-membered aliphatic heterocyclic group.

[0062] In some embodiments, each R 12 are independently selected from the following groups: 1) Oxo group, halogen atom, cyano group, -C(=O)R a2 , -C(=O)OR a2 , -C(=O)NR a2 R b2 , -C(=NR d2 )NR a2 R b2 , -OR a2 , -OC(=O)R a2 , -OC(=O)OR c2 , -OC(=O)NR a2 R b2 , -NR a2 R b2 , -NR a2 C(=O)R b2 , -NR a2 C(=O)OR c2 , -NR e2 C(=O)NR a2 R b2 , -NR e2 C(=NR d2 )NRa2 R b2 , -NR a2 S(=O)2R c2 , -NR e2 S(=O)2NR a2 R b2 and nitro groups; 2) Unsubstituted or independently R 22 C optionally substituted with 1, 2, 3 or 4 substituents selected from 1-6 Alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, 6- to 10-membered aryl group, 5- to 10-membered heteroaryl group, C 3-10 Cycloalkyl groups and 3- to 10-membered aliphatic heterocyclic groups; 3) Cy A Two R's bonded to adjacent ring-forming atoms in the aryl or heteroaryl group of 12 The substituents, together with the two ring-forming atoms, are unsubstituted or independently R 22 C which is optionally substituted with 1, 2 or 3 substituents selected from 4-8 It forms an alicyclic hydrocarbon group or a 4- to 8-membered aliphatic heterocyclic group.

[0063] In some embodiments, each R 12 are independently selected from the following groups: 1) Oxo group, halogen atom, cyano group, -C(=O)R a2 , -C(=O)NR a2 R b2 , -C(=NR d2 )NR a2 R b2 , -OR a2 , -NR a2 R b2 , -NR a2 C(=O)R b2 , -NR e2 C(=O)NR a2 R b2 , -NR e2 C(=NR d2 )NR a2 R b2 , -NR a2 S(=O)2R c2 and -NR e2 S(=O)2NRa2 R b2 ; 2) Unsubstituted or independently R 22 C optionally substituted with 1, 2, 3, 4, 5 or 6 substituents selected from 1-6 Alkyl groups, 6- to 10-membered aryl groups, 5- to 10-membered heteroaryl groups, C 3-10 Cycloalkyl groups and 3- to 10-membered aliphatic heterocyclic groups; 3) Cy A Two R's bonded to adjacent ring-forming atoms in the aryl or heteroaryl group of 12 The substituents, together with the two ring-forming atoms, are unsubstituted or each independently R 22 C optionally substituted with 1, 2, 3 or 4 substituents selected from 4-8 In some embodiments, each R 12 are independently selected from the following groups: 1) Oxo group, halogen atom, cyano group, -C(=O)R a2 , -C(=O)NR a2 R b2 , -C(=NR d2 )NR a2 R b2 , -OR a2 , -NR a2 R b2 , -NR a2 C(=O)R b2 , -NR a2 C(=O)OR c2 , -NR e2 C(=O)NR a2 R b2 , -NR e2 C(=NR d2 )NR a2 R b2 , -NR a2 S(=O)2R c2 , -NR e2 S(=O)2NR a2 R b2 ; 2) Unsubstituted or independently R 22 C optionally substituted with 1, 2, 3 or 4 substituents selected from 1-6Alkyl group, phenyl group, 5-6 membered heteroaryl group, C 3-10 Cycloalkyl groups and 3- to 10-membered aliphatic heterocyclic groups; 3) Cy A Two R's bonded to adjacent ring-forming atoms in the aryl or heteroaryl group of 12 The substituents, together with the two ring-forming atoms, are unsubstituted or independently R 22 A C5, C6, C7 monocyclic alicyclic hydrocarbon group or a 5-, 6-, or 7-membered monocyclic aliphatic heterocyclic group optionally substituted by 1, 2, or 3 substituents selected from the following.

[0064] In some embodiments, each R 12 are independently selected from the following groups: 1) Halogen atom, cyano group, -OR a2 , -C(=O)NR a2 R b2 , -NR a2 R b2 , -NR a2 C(=O)R b2 , -NR a2 C(=O)OR c2 , -NR e2 C(=O)NR a2 R b2 , -NR e2 (=NR d2 )NR a2 R b2 , -NR a2 S(=O)2R c2 and -NR e2 S(=O)2NR a2 R b2 ; 2) Unsubstituted or independently R 22 C optionally substituted with 1, 2, 3 or 4 substituents selected from 1-6 Alkyl group, phenyl group, 5-6 membered heteroaryl group, C 3-7 Cycloalkyl groups and 3- to 7-membered aliphatic heterocyclic groups.

[0065] In some embodiments, each R 12 are independently selected from the following groups: 1) Halogen atoms, C 1-6Alkyl group, C 3-6 Cycloalkyl group, 3- to 7-membered aliphatic heterocyclic group, cyano group, -OR a2 , -C(=O)NR a2 R b2 , -NR a2 R b2 , -NR a2 C(=O)R b2 , -NR e2 C(=O)NR a2 R b2 , -NR e2 C(=NR d2 )NR a2 R b2 , -NR a2 S(=O)2R c2 and N.R. e2 S(=O)2NR a2 R b2 ; 2) Cy A Two R's bonded to adjacent ring-forming atoms in the aryl or heteroaryl group of 12 The substituents, together with the two ring-forming atoms, are unsubstituted or each independently R 22 C optionally substituted with 1, 2, 3 or 4 substituents selected from 4-8 It forms an alicyclic hydrocarbon group or a 4- to 8-membered aliphatic heterocyclic group.

[0066] In some embodiments, Cy A Two R's bonded to adjacent ring-forming atoms in the aryl or heteroaryl group of 12 The substituents, together with the two ring-forming atoms, are unsubstituted or each independently R 22 and a 5-, 6-, or 7-membered monocyclic aliphatic heterocyclic group, each of which may be substituted by 1, 2, or 3 substituents selected from the group consisting of C5, C6, and C7 monocyclic alicyclic hydrocarbon groups and 5-, 6-, or 7-membered monocyclic aliphatic heterocyclic groups.

[0067] In some embodiments, R 12 are unsubstituted or each independently R 22 a 4-, 5-, 6-, or 7-membered monocyclic aliphatic heterocyclic group and a 7-, 8-, 9-, or 10-membered bicyclic aliphatic heterocyclic group, each of which may be substituted by 1, 2, or 3 substituents selected from the group consisting of

[0068] In some embodiments, R 12 is a substituted or unsubstituted monocyclic aliphatic heterocyclic group or bicyclic aliphatic heterocyclic group, and the bicyclic aliphatic heterocyclic group may be, for example, a bridged ring group or a spiro ring group; wherein the bicyclic aliphatic heterocyclic group includes the A1 ring and the A2 ring, and the A1 ring is a Cy A The A1 ring may be a 3- to 6-membered ring, and the bicyclic aliphatic heterocyclic group has 10 or less ring atoms.

[0069] In some embodiments, R 12 The aliphatic heterocyclic group contains 1 or 2 ring-forming heteroatoms selected from N, O and S.

[0070] In some embodiments, each R 12 are independently 1-6 Alkyl group, halogen atom, cyano group, -OR a2 and -NR a2 R b2 Selected from.

[0071] In some embodiments, each R 12 are independently selected from the following groups: 1) Unsubstituted or independently R 22 C optionally substituted with 1, 2, 3 or 4 substituents selected from 1-6 Alkyl group, C 1-3 Alkoxy group, C 3-8 A cycloalkyl group and a 3- to 8-membered aliphatic heterocyclic group; wherein the 3- to 8-membered aliphatic heterocyclic group is a monocyclic aliphatic heterocyclic group or a bicyclic aliphatic heterocyclic group, and the heteroatom contained in the aliphatic heterocyclic group may be an N and / or O atom; R 22 is an oxo group, a hydroxy group, an amino group, a cyano group, C 1-3 Alkylamino group, C 1-3 selected from an alkoxy group, a 3- to 6-membered cycloalkyl group, and a 3- to 6-membered monocyclic aliphatic heterocyclic group; 2) Cy ATwo R's bonded to adjacent ring-forming atoms in the aryl or heteroaryl group of 12 The substituents, together with the two ring-forming atoms, are unsubstituted or each independently R 22 R 22 is selected from oxo, methyl, ethyl, isopropyl, cyclopropyl, oxetanyl, -N(CH3)2, -OH, -CN, -OCH3, -C(=O)CH3, -S(=O)2CH2CH3, -C(=O)NH2, -S(=O)2NH2, -CH2CH2OH, -CH2OH, -CH2CH2N(CH3)2.

[0072] In some embodiments, Cy A is selected from the following groups: 1) One of the following structures, where the end of the chemical bond in the structural formula is "

[0073] [ka]

[0074] " represents attachment to another atom in the structure of formula (I) via this chemical bond.

[0075] [ka]

[0076] 2) Unsubstituted or independently R 12 a phenyl group, a pyridyl group, a pyrimidinyl group, a pyrazolyl group, an imidazolyl group, a thiazolyl group, an isothiazolyl group, an oxazolyl group or an isoxazolyl group, which may be substituted by 1, 2 or 3 substituents selected from (a) Each R 12 R is not a fluorine, chlorine, or hydrogen atom. G1 -OR G1 Selected from; Or, (b) Cy A is one R 12 and one selected from the following structures, wherein the end of the chemical bond in the structural formula is

[0077] [ka]

[0078] " represents attachment to another atom in the structure of formula (I) via this chemical bond.

[0079] [ka]

[0080] Or, Cy A is 2 or 3 R 12 Including one of R 12 is one selected from the above structures, and the remaining R 12 are independently R other than fluorine, chlorine, or hydrogen. G1 , -OR G1 Selected from; Where: X is selected from CH and N; Y is selected from -CH2-, NH and O; E1 and E2 are independently selected from -CH2- and a carbonyl group, provided that E1 and E2 cannot simultaneously be a carbonyl group; R G2 is hydrogen, -OR G1 and -N(R G1 )2 is selected; Each R G1 are independently selected from the following groups: 1) Hydrogen, methyl group, ethyl group (C 1-3 alkylamino group), propyl group (hydroxy group and C 1-3may be substituted with an alkyl group, for example a 2-hydroxy-2-methyl-propyl group, an isopropyl group (substituted with a cyano group), a cyclopropyl group, a 3-oxetanyl group and a 3-methyl-3-azetidinyl group; 2) Two Rs bonded to the same atom G1 The groups are each a C with the atoms that are simultaneously bonded to them. 3-6 Forms a monocyclic hydrocarbon ring or a 3- to 6-membered monocyclic aliphatic heterocycle; 3) Two Rs each bonded to two different ring-forming atoms of the same monocyclic ring. G1 The R groups are bonded to each other and form a cyclic structure together with some of the ring-forming atoms of the monocyclic ring, and two R G1 The groups together form a C2, C3 or C4 alkylene group.

[0081] In some embodiments, Cy A is unsubstituted or independently R 12 a phenyl group, a pyridyl group, a pyrimidinyl group, a pyrazolyl group, an imidazolyl group, a thiazolyl group or an isothiazolyl group, which may be substituted by 1, 2 or 3 substituents selected from 1) Each R 12 are independently R other than fluorine, chlorine, or hydrogen. G1 , -OR G1 Selected from; Or, 2) Cy A is one R 12 and one selected from the following structures:

[0082] [ka]

[0083] Or, Cy A is 2 or 3 R 12 Including one of R 12 is one selected from the above structures, and the remaining R 12 are independently R other than fluorine, chlorine, or hydrogen. G1 , -ORG1 Selected from; Each R G1 are independently selected from hydrogen, methyl, ethyl, isopropyl, cyclopropyl, 3-oxetanyl, and 3-methyl-3-azetidinyl.

[0084] In some embodiments, R 22 is an oxo group, a cyano group, C 3-7 Cycloalkyl group, 3- to 7-membered aliphatic heterocyclic group, R H1 , -(CH2) 0-2 OH, -(CH2) 0-2 OR H1 , -(CH2) 0-2 NH2, -(CH2) 0-2 NHR H1 , -(CH2) 0-2 N(R H1 )2, aldehyde group, -C(=O)R H1 , -C(=O)NH2, -C(=O)NHR H1 , -C(=O)N(R H1 )2, -S(=O)2R H1 , -S(=O)2NH2, -S(=O)2NHR H1 and -S(=O)2N(R H1 )2 is selected;R H1 is optionally selected from methyl, ethyl, isopropyl, cyclopropyl, 3-oxetanyl and 3-methyl-3-azetidinyl.

[0085] In some embodiments, R 22 is selected from oxo, cyano, methyl, ethyl, isopropyl, cyclopropyl, oxetanyl, -N(CH3)2, -OH, -CN, -OCH3, -C(=O)CH3, -S(=O)2CH2CH3, -C(=O)NH2, -S(=O)2NH2, -CH2CH2OH, -CH2OH, -CH2CH2N(CH3)2.

[0086] In some embodiments, Cy B is unsubstituted or independently R 13the 5- to 10-membered heteroaryl group having at least one ring-forming carbon atom and 1, 2, 3 or 4 ring-forming heteroatoms independently selected from N, O and S;

[0087] In some embodiments, Cy B are independently R 13 is a phenyl group or a 5- to 6-membered heteroaryl group which may be substituted by 1, 2, 3 or 4 substituents selected from the following:

[0088] In some embodiments, Cy B are independently R 13 and the heteroaryl group contains 1, 2 or 3 ring-forming heteroatoms selected from N and S.

[0089] In some embodiments, Cy B are independently R 13 and a phenyl group, a pyridyl group, a pyrimidinyl group, a pyridazinyl group, a pyrazolyl group, an imidazolyl group, a thiazolyl group, an isothiazolyl group, or a thienyl group, each of which may be substituted by 1, 2, or 3 substituents selected from the above.

[0090] In some embodiments, Cy B are independently R 13 wherein each of the two R s bonded to adjacent ring-forming atoms in the phenyl group or the heteroaryl group is an optionally substituted phenyl group or a 5- to 6-membered heteroaryl group, 13 The substituents, together with the two ring-forming atoms, are unsubstituted or independently R 23 C optionally substituted with 1, 2, 3, 4 or 5 substituents selected from 5-12 It forms an alicyclic hydrocarbon group or a 5- to 12-membered aliphatic heterocyclic group.

[0091] In some embodiments, CyB are independently R 13 wherein each of the two R s bonded to adjacent ring-forming atoms in the phenyl group or the heteroaryl group is a phenyl group or a 5- to 6-membered heteroaryl group, each of which may be substituted by 1, 2 or 3 substituents selected from 13 The substituents, together with the two ring-forming atoms, are unsubstituted or independently R 23 C which is optionally substituted with 1, 2 or 3 substituents selected from 4-8 It forms an alicyclic hydrocarbon group or a 4- to 8-membered aliphatic heterocyclic group.

[0092] In some embodiments, Cy B are independently R 13 wherein each of the two R s bonded to adjacent ring-forming atoms in the phenyl group or the heteroaryl group is a phenyl group or a 5- to 6-membered heteroaryl group, each of which may be substituted by 1, 2 or 3 substituents selected from 13 The substituents, together with the two ring-forming atoms, are unsubstituted or independently R 23 C which is optionally substituted with 1, 2 or 3 substituents selected from 5-6 Forms a monocyclic alicyclic hydrocarbon group or a 5- to 6-membered monocyclic aliphatic heterocyclic group; R 23 is optionally selected from fluorine, a methyl group, an ethyl group, an isopropyl group, a cyclopropyl group, an ethylidene group and a 3-oxetanyl group.

[0093] In some embodiments, each R 13 are independently selected from the following groups: 1) Oxo group, halogen atom, cyano group, -C(=O)R a3 , -C(=O)OR a3 , -C(=O)NR a3 R b3 , -C(=NR d3 )NR a3 R b3 , -OR a3 , -OC(=O)R a3 , -OC(=O)OR c3 , -OC(=O)NR a3 R b3 , -SRa3 , -S(=O)R c3 , -S(=O)2R c3 , sulfonic acid group, -S(=O)NR a3 R b3 , -S(=O)2NR a3 R b3 , -S(=O)(=NR d3 )R c3 , -NR a3 R b3 , -NR a3 C(=O)R b3 , -NR a3 C(=O)OR c3 , -NR e3 C(=O)NR a3 R b3 , -NR e3 C(=NR d3 )NR a3 R b3 , -NR a3 S(=O)2R c3 , -NR e3 S(=O)2NR a3 R b3 and nitro groups; 2) Unsubstituted or independently R 23 C optionally substituted with 1, 2, 3, 4, 5 or 6 substituents selected from 1-6 Alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, 6- to 10-membered aryl group, 5- to 10-membered heteroaryl group, C 3-12 Cycloalkyl groups and 3- to 12-membered aliphatic heterocyclic groups; 3) Cy B Two R's bonded to adjacent ring-forming atoms in the aryl or heteroaryl group of 13 The substituents, together with the two ring-forming atoms, are unsubstituted or independently R 23 C optionally substituted with 1, 2, 3, 4 or 5 substituents selected from 5-12 It forms an alicyclic hydrocarbon group or a 5- to 12-membered aliphatic heterocyclic group.

[0094] In some embodiments, each R 13 are independently selected from the following groups: 1) Oxo group, halogen atom, cyano group, -C(=O)R a3 , -C(=O)OR a3 , -C(=O)NR a3 R b3 , -C(=NR d3 )NR a3 R b3 , -OR a3 , -OC(=O)R a3 , -OC(=O)OR c3 , -OC(=O)NR a3 R b3 , -NR a3 R b3 , -NR a3 C(=O)R b3 , -NR a3 C(=O)OR c3 , -NR e3 C(=O)NR a3 R b3 , -NR e3 C(=NR d3 )NR a3 R b3 , -NR a3 S(=O)2R c3 , -NR e3 S(=O)2NR a3 R b3 and nitro groups; 2) Unsubstituted or independently R 23 C optionally substituted with 1, 2, 3, 4, 5 or 6 substituents selected from 1-6 Alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, 6- to 10-membered aryl group, 5- to 10-membered heteroaryl group, C 3-10 Cycloalkyl groups and 3- to 10-membered aliphatic heterocyclic groups; 3) Cy B Two R's bonded to adjacent ring-forming atoms in the aryl or heteroaryl group of 13 The substituents, together with the two ring-forming atoms, are unsubstituted or independently R 23 C optionally substituted with 1, 2, 3, 4 or 5 substituents selected from 5-10 It forms an alicyclic hydrocarbon group or a 5- to 10-membered aliphatic heterocyclic group.

[0095] In some embodiments, each R 13 are independently selected from the following groups: 1) Oxo group, halogen atom, cyano group, -C(=O)R a3 , -C(=O)OR a3 , -C(=O)NR a3 R b3 , -C(=NR d3 )NR a3 R b3 , -OR a3 , -OC(=O)R a3 , -OC(=O)OR c3 , -OC(=O)NR a3 R b3 , -NR a3 R b3 , -NR a3 C(=O)R b3 , -NR a3 C(=O)OR c3 , -NR e3 C(=O)NR a3 R b3 , -NR e3 C(=NR d3 )NR a3 R b3 , -NR a3 S(=O)2R c3 , -NR e3 S(=O)2NR a3 R b3 and nitro groups; 2) Unsubstituted or independently R 23 C optionally substituted with 1, 2, 3 or 4 substituents selected from 1-6 Alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, 6- to 10-membered aryl group, 5- to 10-membered heteroaryl group, C 3-10 Cycloalkyl groups and 3- to 10-membered aliphatic heterocyclic groups; 3) Cy B Two R's bonded to adjacent ring-forming atoms in the aryl or heteroaryl group of 13 The substituents, together with the two ring-forming atoms, are unsubstituted or independently R 23 C which is optionally substituted with 1, 2 or 3 substituents selected from 4-8It forms an alicyclic hydrocarbon group or a 4- to 8-membered aliphatic heterocyclic group.

[0096] In some embodiments, each R 13 are independently selected from the following groups: 1) Oxo group, halogen atom, cyano group, -C(=O)R a3 , -C(=O)NR a3 R b3 , -C(=NR d3 )NR a3 R b3 , -OR a3 , -NR a3 R b3 , -NR a3 C(=O)R b3 , -NR e3 C(=O)NR a3 R b3 , -NR e3 C(=NR d3 )NR a3 R b3 , -NR a3 S(=O)2R c3 and -NR e3 S(=O)2NR a3 R b3 ; 2) Unsubstituted or independently R 23 C optionally substituted with 1, 2, 3, 4, 5 or 6 substituents selected from 1-6 Alkyl groups, 6- to 10-membered aryl groups, 5- to 10-membered heteroaryl groups, C 3-10 Cycloalkyl groups and 3- to 10-membered aliphatic heterocyclic groups; 3) Cy B Two R's bonded to adjacent ring-forming atoms in the aryl or heteroaryl group of 13 The substituents, together with the two ring-forming atoms, are unsubstituted or independently R 23 C optionally substituted with 1, 2, 3 or 4 substituents selected from 4-8 It forms an alicyclic hydrocarbon group or a 4- to 8-membered aliphatic heterocyclic group.

[0097] In some embodiments, each R 13 are independently selected from the following groups: 1) Oxo group, halogen atom, cyano group, -C(=O)R a3 , -C(=O)NR a3 R b3 , -C(=NR d3 )NR a3 R b3 , -OR a3 , -NR a3 R b3 , -NR a3 C(=O)R b3 , -NR a3 C(=O)OR c3 , -NR e3 C(=O)NR a3 R b3 , -NR e3 C(=NR d3 )NR a3 R b3 , -NR a3 S(=O)2R c3 , -NR e3 S(=O)2NR a3 R b3 ; 2) Unsubstituted or independently R 23 C optionally substituted with 1, 2, 3 or 4 substituents selected from 1-6 Alkyl group, phenyl group, 5-6 membered heteroaryl group, C 3-10 Cycloalkyl groups and 3- to 10-membered aliphatic heterocyclic groups; 3) Cy B Two R's bonded to adjacent ring-forming atoms in the aryl or heteroaryl group of 13 The substituents, together with the two ring-forming atoms, are unsubstituted or independently R 23 A C5, C6, C7 monocyclic alicyclic hydrocarbon group or a 5-, 6-, or 7-membered monocyclic aliphatic heterocyclic group optionally substituted by 1, 2, or 3 substituents selected from the following.

[0098] In some embodiments, each R 13 are independently selected from the following groups: 1) Oxo group, halogen atom, cyano group, C 1-4 Alkyl group, C 3-6 Cycloalkyl groups, -C(=O)R a3 , -C(=O)NR a3 Rb3 , -OR a3 , -NR a3 R b3 , -NR a3 C(=O)R b3 , -NR e3 C(=O)NR a3 R b3 and -NR e3 C(=NR d3 )NR a3 R b3 ; 2) Cy B Two R's bonded to adjacent ring-forming atoms in the aryl or heteroaryl group of 13 The substituents, together with the two ring-forming atoms, are unsubstituted or independently R 23 C optionally substituted with 1, 2, 3 or 4 substituents selected from 4-8 It forms an alicyclic hydrocarbon group or a 4- to 8-membered aliphatic heterocyclic group.

[0099] In some embodiments, each R 13 are independently selected from the following groups: 1) Oxo group, fluorine, chlorine, cyano group, C 1-3 Alkyl group, C 3-4 Cycloalkyl groups, -C(=O)R a3 , -C(=O)NR a3 R b3 , -OR a3 , -NR a3 R b3 , -NR a3 C(=O)R b3 , -NR e3 C(=O)NR a3 R b3 and -NR e3 C(=NR d3 )NR a3 R b3 ; 2) Cy B Two R's bonded to adjacent ring-forming atoms in the aryl or heteroaryl group of 13 The substituents, together with the two ring-forming atoms, are unsubstituted or independently R 23 C which is optionally substituted with 1, 2 or 3 substituents selected from 5-6It forms a monocyclic alicyclic hydrocarbon group or a 5- to 6-membered monocyclic aliphatic heterocyclic group.

[0100] In some embodiments, each R 13 are independently selected from the following groups: 1) halogen atoms, cyano groups; 2) Unsubstituted or independently fluorine atom, cyano group, -OR a5 and -NR a5 R b5 C which is optionally substituted with 1, 2 or 3 substituents selected from 1-4 Alkyl group, C 3-6 Cycloalkyl groups and 3- to 6-membered aliphatic heterocyclic groups; where R a5 and R b5 are independently hydrogen and C 1-6 R selected from alkyl groups or R bonded to the same nitrogen atom a5 and R b5 form a 3- to 6-membered aliphatic heterocyclic group together with the nitrogen atom to which they are bonded.

[0101] In some embodiments, each R 13 are independently a halogen atom, a cyano group, -OR a3 and -NR a3 R b3 where R a3 and R b3 are independently selected from the following groups: 1) Hydrogen; 2) Unsubstituted or independently fluorine atom, cyano group, -OR a5 and -NR a5 R b5 C which is optionally substituted with 1, 2 or 3 substituents selected from 1-6 Alkyl group, C 3-6 Cycloalkyl groups and 3- to 6-membered aliphatic heterocyclic groups; where R a5 and R b5 are independently hydrogen and C 1-4 R selected from alkyl groups or R bonded to the same nitrogen atom a5 and R b5 form a 3- to 6-membered aliphatic heterocyclic group together with the nitrogen atom to which they are bonded.

[0102] In some embodiments, each R 13 are independently selected from the following groups: 1) Fluorine, chlorine, cyano group, C 1-3 Alkyl group, C 3-4 Cycloalkyl group, -OR a3 and -NR a3 R b3 ; 2) Cy B Two R's bonded to adjacent ring-forming atoms in the aryl or heteroaryl group of 13 The substituents, together with the two ring-forming atoms, are unsubstituted or independently R 23 C which is optionally substituted with 1, 2 or 3 substituents selected from 5-6 Forms a monocyclic alicyclic hydrocarbon group or a 5- to 6-membered monocyclic aliphatic heterocyclic group; R a3 and R b3 are independently hydrogen, C 1-4 Alkyl group and C 3-6 R selected from cycloalkyl groups or R bonded to the same nitrogen atom a3 and R b3 form a 3- to 6-membered aliphatic heterocyclic group together with the nitrogen atom to which they are bonded; R 23 is C 1-6 Alkyl group and C 3-6 It is selected from cycloalkyl groups.

[0103] In some embodiments, Cy B Two R's bonded to adjacent ring-forming atoms in the aryl or heteroaryl group of 13 The substituents, together with the two ring-forming atoms, are unsubstituted or independently selected from an oxo group, a fluorine atom, a cyano group, -OR a5 and -NR a5 R b5 C which is optionally substituted with 1, 2 or 3 substituents selected from 3-7 forming an alicyclic hydrocarbon group or a 3- to 7-membered aliphatic heterocyclic group; wherein the 3- to 7-membered aliphatic heterocyclic group optionally contains 1 or 2 ring-forming heteroatoms selected from N, O and S; R a5 and R b5are independently hydrogen and C 1-4 R selected from alkyl groups or R bonded to the same nitrogen atom a5 and R b5 form a 3- to 6-membered aliphatic heterocyclic group together with the nitrogen atom to which they are bonded.

[0104] In some embodiments, each R 13 are independently a halogen atom, an amino group, C 1-3 Alkyl group, C 1-3 Substituted alkyl groups, C 1-3 Alkoxy group, C 1-3 Substituted alkoxy groups, C 3-6 Cycloalkoxy group, C 1-3 Alkylamino groups and -C(=O)NR a3 R b3 where C is 1-3 The substituents in the substituted alkyl group are halogen atoms, hydroxy groups, C 1-3 Alkoxy group, C 1-3 C is one, two or three selected from alkyl groups; 1-3 The substituents in the substituted alkoxy group are selected from 1, 2 or 3 halogen atoms; R a3 and R b3 are independently hydrogen and C 1-3 alkyl groups or R a3 , R b3 is unsubstituted or C together with the nitrogen atom 1-3 Alkyl group, C 1-3 It forms a 3- to 6-membered aliphatic heterocyclic group which may be substituted with 1 or 2 groups selected from an alkoxy group and a hydroxy group.

[0105] In some embodiments, each R 13 are independently: -F, -Cl, -NH2, -CH3, -CH2CH3, -CH(CH3)CH3, -CF3, -CHF2, -CH2OCH3, -OCH3, -OCH2CH3, -OCH(CH3)CH3, -OCHF2, -O(C3H5)(cyclopropoxy group), -CH2NHCH3, -CH2N(CH3)2, -NHCH3, -N(CH3)2, -NHCH2CH3, -N(CH3)(CH2CH3), -N(CH2CH3)2, -NRa3 R b3 , -C(=O)NHCH3, -C(=O)N(CH3)2, -C(=O)NR a3 R b3 Selected from; -NR a3 R b3 and -C(=O)NR a3 R b3 In R a3 , R b3 forms, together with the nitrogen atom, a 4- or 5-membered saturated monocyclic aliphatic heterocyclic group which is unsubstituted or optionally substituted with 1 or 2 groups selected from a methyl group, a hydroxy group, and a methoxy group.

[0106] In some embodiments, Cy B Two R's bonded to adjacent ring-forming atoms in the aryl or heteroaryl group of 13 The substituents, together with the two ring-forming atoms, are unsubstituted or independently R 23 and a 5- or 6-membered monocyclic aliphatic heterocyclic group which may be substituted with 1 or 2 substituents selected from the group consisting of N and O, and the ring heteroatoms contained in the monocyclic aliphatic heterocyclic group may be 1 or 2 atoms selected from the group consisting of N and O, and the substituent R 23 may be an oxo group, a fluorine group, a methyl group, -CH2OH, or -NHCH3.

[0107] In some embodiments, Cy B is one of the structures below, and the end of the chemical bond in the structural formula is "

[0108] [ka]

[0109] " represents attachment to another atom in the structure of formula (I) via this chemical bond.

[0110] [ka]

[0111] Here, R a3 and R b3 are independently hydrogen and C 1-6 R bonded to two adjacent ring atoms is selected from alkyl groups. a3 and R b3 form a 5- or 6-membered monocyclic alicyclic hydrocarbon group or a 5- or 6-membered monocyclic aliphatic heterocyclic group together with the two ring-forming atoms bonded thereto.

[0112] In some embodiments, R 1 is hydrogen; Cy A is unsubstituted or independently R 12 wherein the 5-10 membered heteroaryl group has at least two ring-forming carbon atoms and 1, 2, 3 or 4 ring-forming heteroatoms independently selected from N, O and S; R 12 is selected from the following groups: 1) Oxo group, halogen atom, cyano group, -C(=O)R a2 , carboxyl group, -C(=O)NR a2 R b2 , -OR a2 , -NR a2 R b2 , -NR a2 C(=O)R c2 , -NR e2 C(=O)NR a2 R b2 , -NR e2 C(=NR d2 )NR a2 R b2 , -NR a2 S(=O)2R c2 and -NR e2 S(=O)2NR a2 R b2 ; 2) Unsubstituted or independently R 22 C optionally substituted with 1, 2, 3 or 4 substituents selected from 1-6 Alkyl group, C 2-6 Alkenyl group, C 2-6Alkynyl group, phenyl group, 5-6 membered heteroaryl group, C 3-7 Monocyclic cycloalkyl groups, C 6-10 bicyclic cycloalkyl groups, 3- to 7-membered monocyclic aliphatic heterocyclic groups, and 6- to 10-membered bicyclic aliphatic heterocyclic groups; 3) Cy A Two R's bonded to adjacent ring-forming atoms in the aryl or heteroaryl group of 12 The substituents, together with the two ring-forming atoms, are unsubstituted or independently R 22 C which is optionally substituted with 1, 2 or 3 substituents selected from 5-10 forming an alicyclic hydrocarbon group or a 5- to 10-membered aliphatic heterocyclic group; wherein the 5- to 10-membered aliphatic heterocyclic group contains 1 or 2 ring-forming heteroatoms independently selected from N, O and S; R a2 , R b2 and R e2 are each independently selected from the following groups: 1) Hydrogen; 2) Unsubstituted or independently R 22 C which is optionally substituted with 1, 2 or 3 substituents selected from 1-4 Alkyl group, phenyl group, 5-6 membered heteroaryl group, C 3-6 Cycloalkyl groups and 3- to 6-membered aliphatic heterocyclic groups; Or, R attached to the same nitrogen atom a2 and R b2 are unsubstituted or independently R together with the nitrogen atom attached thereto. 22 wherein the 3-8 membered aliphatic heterocyclic group contains 1 or 2 ring-forming heteroatoms, and for example contains only the above nitrogen atom, or contains the above nitrogen atom and any heteroatom selected from N, O and S; R c2 is unsubstituted or independently R 22 C which is optionally substituted with 1, 2 or 3 substituents selected from 1-4 Alkyl group, C 2-3 Alkenyl group, phenyl group, 5-6 membered heteroaryl group, C 3-6selected from a cycloalkyl group and a 3- to 6-membered aliphatic heterocyclic group; R d2 is hydrogen, C 1-4 Alkyl group, C 3-6 Cycloalkyl groups, 3- to 6-membered aliphatic heterocyclic groups, cyano groups, nitro groups, and -S(=O)R G Selected from; R 22 is selected from the following groups: 1) Oxo group, halogen atom, cyano group, carboxyl group, -C(=O)R a4 , -C(=O)NR a4 R b4 , -C(=NR d4 )NR a4 R b4 , -OR a4 , -S(=O)R c4 , -S(=O)2R c4 , -S(=O)2NR a4 R b4 , -S(=O)(=NR d4 )R c4 , -NR a4 R b4 , -NR a4 C(=O)R b4 , -NR e4 C(=O)NR a4 R b4 , -NR e4 C(=NR d4 )NR a4 R b4 , -NR a4 S(=O)2R c4 , -NR e4 S(=O)2NR a4 R b4 and imino groups (=NR d4 ); 2) Unsubstituted or independently R 32 C which is optionally substituted with 1, 2 or 3 substituents selected from 1-4 Alkyl group, C 1-4 Alkylene group, phenyl group, 5-6 membered heteroaryl group, C 3-7 Cycloalkyl groups and 3- to 7-membered aliphatic heterocyclic groups; R a4 , R b4 and R e4are each independently selected from the following groups: 1) Hydrogen; 2) Unsubstituted or independently R 32 C which is optionally substituted with 1, 2 or 3 substituents selected from 1-4 Alkyl group, C 3-6 Monocyclic cycloalkyl groups and 3- to 6-membered monocyclic aliphatic heterocyclic groups; Or, R attached to the same nitrogen atom a4 and R b4 are unsubstituted or independently R together with the nitrogen atom attached thereto. 32 wherein the 3- to 6-membered monocyclic aliphatic heterocyclic group and the 6- to 7-membered bicyclic aliphatic heterocyclic group contain 1 or 2 ring-forming heteroatoms, and for example, contain only the above-mentioned nitrogen atom, or contain the above-mentioned nitrogen atom and any heteroatom selected from N, O and S; R c4 is unsubstituted or independently R 32 C which is optionally substituted with 1, 2 or 3 substituents selected from 1-4 Alkyl group, C 2-3 Alkenyl group, C 3-6 selected from monocyclic cycloalkyl groups and 3- to 6-membered monocyclic aliphatic heterocyclic groups; R d4 is hydrogen, C 1-4 Alkyl group, C 3-6 Monocyclic cycloalkyl groups, 3- to 6-membered monocyclic aliphatic heterocyclic groups, cyano groups, nitro groups, and -S(=O)R G Selected from; R 32 is an oxo group, a halogen atom, a cyano group, a hydroxyl group, -OR G , amino group, -NHR G , -N(R G )2, aldehyde group, -C(=O)R G , -S(=O)2R G , carboxyl group, -C(=O)OR G , -C(=O)NH2, -C(=O)-NHR G , -C(=O)N(R G)2, -S(=O)2NH2, -S(=O)2-NHR G and -S(=O)2N(R G )2 is selected; Cy B is unsubstituted or independently R 13 wherein the 5-10 membered heteroaryl group has at least two ring-forming carbon atoms and 1, 2, 3 or 4 ring-forming heteroatoms independently selected from N, O and S; R 13 is selected from the following groups: 1) Oxo group, halogen atom, cyano group, -C(=O)R a3 , carboxyl group, -C(=O)NR a3 R b3 , -OR a3 , -NR a3 R b3 , -NR a3 C(=O)R b3 , -NR e3 C(=O)NR a3 R b3 , -NR e3 C(=NR d3 )NR a3 R b3 , -NR a3 S(=O)2R c3 and -NR e3 S(=O)2NR a3 R b3 ; 2) Unsubstituted or independently R 23 C optionally substituted with 1, 2, 3 or 4 substituents selected from 1-6 Alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, phenyl group, 5-6 membered heteroaryl group, C 3-7 Monocyclic cycloalkyl groups, C 6-10 bicyclic cycloalkyl groups, 3- to 7-membered monocyclic aliphatic heterocyclic groups, and 6- to 10-membered bicyclic aliphatic heterocyclic groups; 3) Cy B Two R's bonded to adjacent ring-forming atoms in the aryl or heteroaryl group of13 The substituents, together with the two ring-forming atoms, are unsubstituted or independently R 23 C which is optionally substituted with 1, 2 or 3 substituents selected from 5-10 forming an alicyclic hydrocarbon group or a 5- to 10-membered aliphatic heterocyclic group; wherein the 5- to 10-membered aliphatic heterocyclic group contains 1 or 2 ring-forming heteroatoms independently selected from N, O and S; R a3 , R b3 and R e3 are each independently selected from the following groups: 1) Hydrogen; 2) Unsubstituted or independently R 23 C which is optionally substituted with 1, 2 or 3 substituents selected from 1-4 Alkyl group, phenyl group, 5-6 membered heteroaryl group, C 3-6 Cycloalkyl groups and 3- to 6-membered aliphatic heterocyclic groups; Or, R attached to the same nitrogen atom a3 and R b3 are unsubstituted or independently R together with the nitrogen atom attached thereto. 23 wherein the 3-8 membered aliphatic heterocyclic group contains 1 or 2 ring-forming heteroatoms, and for example contains only the above nitrogen atom, or contains the above nitrogen atom and any heteroatom selected from N, O and S; R c3 is unsubstituted or independently R 23 C which is optionally substituted with 1, 2 or 3 substituents selected from 1-4 Alkyl group, C 2-3 Alkenyl group, phenyl group, 5-6 membered heteroaryl group, C 3-6 selected from a cycloalkyl group and a 3- to 6-membered aliphatic heterocyclic group; R d3 is hydrogen, C 1-4 Alkyl group, C 3-6 Cycloalkyl groups, 3- to 6-membered aliphatic heterocyclic groups, cyano groups, nitro groups, and -S(=O)R G Selected from; R 23is selected from the following groups: 1) Oxo group, halogen atom, cyano group, carboxyl group, -C(=O)R a5 , -C(=O)NR a5 R b5 , -C(=NR d5 )NR a5 R b5 , -OR a5 , -S(=O)R c5 , -S(=O)2R c5 , -S(=O)2NR a5 R b5 , -S(=O)(=NR d5 )R c5 , -NR a5 R b5 , -NR a5 C(=O)R b5 , -NR e5 C(=O)NR a5 R b5 , -NR e5 C(=NR d5 )NR a5 R b5 , -NR a5 S(=O)2R c5 , -NR e5 S(=O)2NR a5 R b5 and imino groups (=NR d5 ); 2) Unsubstituted or independently R 33 C which is optionally substituted with 1, 2 or 3 substituents selected from 1-5 Alkyl group, C 1-5 Alkylene group, phenyl group, 5-6 membered heteroaryl group, C 3-7 Cycloalkyl groups and 3- to 7-membered aliphatic heterocyclic groups; R a5 , R b5 and R e5 are each independently selected from the following groups: 1) Hydrogen; 2) Unsubstituted or independently R 33 C which is optionally substituted with 1, 2 or 3 substituents selected from 1-4 Alkyl group, C 3-6 Monocyclic cycloalkyl groups and 3- to 6-membered monocyclic aliphatic heterocyclic groups; Or, R attached to the same nitrogen atom a5 and R b5 are unsubstituted or independently R together with the nitrogen atom attached thereto. 33 wherein the 3- to 6-membered monocyclic aliphatic heterocyclic group and the 6- to 7-membered bicyclic aliphatic heterocyclic group contain 1 or 2 ring-forming heteroatoms, and for example, contain only the above-mentioned nitrogen atom, or contain the above-mentioned nitrogen atom and any heteroatom selected from N, O and S; R c5 is unsubstituted or independently R 33 C which is optionally substituted with 1, 2 or 3 substituents selected from 1-4 Alkyl group, C 2-3 Alkenyl group, C 3-6 selected from monocyclic cycloalkyl groups and 3- to 6-membered monocyclic aliphatic heterocyclic groups; R d5 is hydrogen, C 1-4 Alkyl group, C 3-6 Monocyclic cycloalkyl groups, 3- to 6-membered monocyclic aliphatic heterocyclic groups, cyano groups, nitro groups, and -S(=O)R GA Selected from; R 33 is an oxo group, a halogen atom, a cyano group, a hydroxyl group, -OR GA , amino group, -NHR GA and -N(R GA )2 is selected; Each R GA are independently selected from the following groups: C which is unsubstituted or optionally substituted with 1, 2 or 3 fluorine atoms 1-4 Alkyl group, C 1-4 Alkylene group, C 3-6 Cycloalkyl groups and 4- to 6-membered aliphatic heterocyclic groups; Or, Two R's attached to the same nitrogen atom GAform a 4- to 6-membered monocyclic aliphatic heterocyclic group which is unsubstituted or optionally substituted with 1, 2 or 3 fluorine atoms, together with the nitrogen atom bonded thereto; here, the 4- to 6-membered monocyclic aliphatic heterocyclic group contains 1 or 2 ring-forming heteroatoms, and for example, contains only the above-mentioned nitrogen atom, or contains the above-mentioned nitrogen atom and any heteroatom selected from N and O.

[0113] Some embodiments of the present application provide a pharmaceutical composition comprising a compound of formula (I) above or a pharma- ceutically acceptable salt, hydrate, solvate, active metabolite, crystalline polymorph, isotopically labeled compound, isomer, or prodrug thereof, and a pharma- ceutically acceptable carrier.

[0114] The pharmaceutical compositions may be prepared by methods well known in the pharmaceutical art and may be administered in a variety of ways, including topical (including transdermal, epidermal, ocular and mucosal, including intranasal, vaginal and rectal delivery), pulmonary (including, for example, by inhalation, insufflation or spray of powders or aerosols; intratracheal or intranasal), oral or parenteral modes of administration.

[0115] In some embodiments, the composition is suitable for parenteral administration, including intravenous, intraarterial, subcutaneous, intraperitoneal, intramuscular injection or infusion; or intracranial administration, such as intrathecal or intraventricular administration. Parenteral administration may be by a single bolus dose or (for example) by a continuous perfusion pump.

[0116] In some embodiments, the composition is suitable for topical administration. Pharmaceutical compositions and formulations for topical administration can include transdermal patches, ointments, lotions, creams, gels, drops, suppositories, sprays, liquids and powders. Conventional pharmaceutical carriers, aqueous, powder or oily bases, thickeners, etc. may be necessary or desirable.

[0117] Some embodiments of the present application provide the use of the compound of formula (I) above or a pharma- ceutically acceptable salt, hydrate, solvate, active metabolite, crystalline polymorph, isotopically labeled substance, isomer or prodrug thereof, and the pharmaceutical composition above, in the prophylaxis or treatment of an HPK1-mediated disease.

[0118] Some embodiments of the present application provide methods of modulating (e.g., inhibiting) HPK1 activity, including stimulating and / or enhancing immunity in cancer or viral disease, by administering to a patient a compound of formula (I) as above or a pharma- ceutically acceptable salt, hydrate, solvate, active metabolite, crystalline polymorph, isotopically labeled compound, isomer or prodrug thereof, and the pharmaceutical compositions as above.

[0119] Some embodiments of the present application provide a method for preventing, ameliorating or treating an HPK1-mediated disease, comprising the step of administering to a patient suffering from an HPK1-mediated disease a therapeutically effective amount of a compound of formula (I) as described above or a pharma- ceutically acceptable salt, hydrate, solvate, active metabolite, crystalline polymorph, isotopically labeled product, isomer or prodrug thereof, and the pharmaceutical composition as described above.

[0120] Some embodiments of the present application provide the use of the compound of formula (I) above or a pharma- ceutically acceptable salt, hydrate, solvate, active metabolite, crystalline polymorph, isotopically labeled compound, isomer or prodrug thereof, and the pharmaceutical composition above, in the treatment or amelioration of benign or malignant tumors, myeloproliferative disorders and / or viral diseases.

[0121] Some embodiments of the present application provide the use of the compound of formula (I) above or a pharma- ceutically acceptable salt, hydrate, solvate, active metabolite, crystalline polymorph, isotopically labeled substance, isomer or prodrug thereof, or the pharmaceutical composition above, in the treatment or amelioration of benign or malignant tumors.

[0122] Some embodiments of the present application provide the use of the compound of formula (I) above or a pharma- ceutically acceptable salt, hydrate, solvate, active metabolite, crystalline polymorph, isotopically labeled substance, isomer or prodrug thereof, or the pharmaceutical composition above, in the treatment or amelioration of a viral disease.

[0123] Some embodiments of the present application provide the use of the compound of formula (I) above or a pharma- ceutically acceptable salt, hydrate, solvate, active metabolite, crystalline polymorph, isotopically labeled, isomer or prodrug thereof, and the pharmaceutical composition above, in the preparation of a medicament for treating or ameliorating a particular disease; the disease may be one or more of benign or malignant tumors, myeloproliferative disorders and viral diseases.

[0124] Some embodiments of the present application provide the use of the compound of formula (I) above or a pharma- ceutically acceptable salt, hydrate, solvate, active metabolite, crystalline polymorph, isotopically labeled substance, isomer or prodrug thereof, or the pharmaceutical composition above, in the preparation of a medicament for treating or ameliorating benign or malignant tumors.

[0125] Some embodiments of the present application provide the use of the compound of formula (I) above or a pharma- ceutically acceptable salt, hydrate, solvate, active metabolite, crystalline polymorph, isotopically labeled product, isomer or prodrug thereof, or the pharmaceutical composition above, in the preparation of a medicament for treating or ameliorating a viral disease.

[0126] In one embodiment, the malignant tumor comprises one or more of leukemia, lymphoma, multiple myeloma, lung cancer, hepatocellular carcinoma, bile duct carcinoma, gallbladder carcinoma, gastric cancer, colorectal cancer, small intestinal leiomyosarcoma, breast cancer, ovarian cancer, cervical cancer, endometrial cancer, vaginal cancer, malignant teratoma, pancreatic adenocarcinoma, pancreatic ductal adenocarcinoma, nasopharyngeal cancer, oral cancer, laryngeal cancer, esophageal squamous cell carcinoma, thyroid cancer, renal cancer, bladder cancer, malignant brain tumor, rhabdomyosarcoma, osteosarcoma, chondrosarcoma, osteofibrosarcoma, malignant thymoma, malignant peripheral nerve sheath tumor, prostate cancer, testicular cancer, penile cancer, and benign and malignant tumors of the skin (including, but not limited to, melanoma, basal cell carcinoma, squamous cell carcinoma).

[0127] In one embodiment, the tumor is a PGE2-producing tumor (e.g., a tumor that overexpresses COX-2) and / or an adenosine-producing tumor (e.g., a tumor that overexpresses CD39 and CD73), such as colorectal cancer, breast cancer, pancreatic adenocarcinoma, lung cancer, and ovarian cancer.

[0128] In one embodiment, the virus comprises one or more of hepatitis virus, human immunodeficiency virus, human papilloma virus, herpes simplex virus, measles virus, norovirus, bocavirus, coxsackievirus, ebola virus, enteric virus, lymphocytic meningitis virus, influenza virus, SARS virus, and novel coronavirus.

[0129] (Definition and explanation of terms) In this application, unless otherwise stated, a description or statement of a group, whether used alone or in combination with other terms, is applicable to all groups containing that group. For example, a description of an alkyl group is 1-6 Alkyl group, C 1-3 Suitable for alkyl groups. C 1-6 The explanation or description of the alkyl group is "C 1~6 "alkoxy group," etc., and the following definitions are applicable to the claims and specification.

[0130] Here, when a certain structure contains a plurality of substituents represented by the same symbol, the types of these substituents may be the same or different. For example, Cy B The group is composed of two R 13 These two R 13 may both be methoxy groups, or one may be a methoxy group and the other a methyl group.

[0131] The term "halogen atom" includes fluorine, chlorine, bromine and iodine.

[0132] The term “C m-n " groups, where m and n are integers, indicate an inclusive range and mean that the corresponding group contains m to n carbon atoms. For example, C 1-6 The alkyl group represents an alkyl group containing 1 to 6 carbon atoms, 2-6 The alkenyl group represents an alkenyl group containing 2 to 6 carbon atoms.

[0133] The term "n-membered" (where n is an integer) generally refers to the number of ring-forming atoms in a ring, where the number of ring-forming atoms is n. "mn-membered" refers to an inclusive range, meaning that the corresponding ring structure contains m to n ring-forming atoms. For example, a piperidinyl group is an example of a 6-membered heterocyclic group, and a pyrazolyl group is an example of a 5-membered heteroaromatic ring group.

[0134] The term "substituted" means that an atom or group of atoms replaces hydrogen as a "substituent" that bonds to another group. Unless otherwise stated, the term "substituted" means any degree of substitution, provided that said substitution is permitted. The selection of the substituent is independent, and the substitution may be at any chemically accessible position. It should be understood that substitution on a given atom is limited by the valency. It should be understood that substitution on a given atom produces a chemically stable molecule. A single divalent substituent (e.g., an oxo group) can replace two hydrogen atoms.

[0135] The "remainder of the compound" refers to the complete molecular structure minus the "substituents". The remainder of the compound is attached to the substituents via one or more unsaturated valencies. The remainder of the compound may contain one or more "points of attachment", and the two or more points of attachment may be located on the same atom or on different atoms.

[0136] The term "alkyl group" refers to a straight or branched chain saturated hydrocarbon group. An alkyl group refers to a group formed when an alkane loses one hydrogen atom. Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, 2-methylbutyl, neopentyl, 1-ethylpropyl, n-hexyl, 1,2,2-trimethylpropyl, and the like.

[0137] The term "alkenyl group" refers to a straight or branched chain hydrocarbon group having one or more carbon-carbon double bonds. An alkenyl group refers to a group formed when an alkene loses one hydrogen atom. Examples of alkenyl groups include vinyl, 1-propenyl, 2-propenyl, allyl, 1-butenyl, 2-butenyl, (E)-but-2-en-1-yl, (Z)-but-2-en-1-yl, 2-methyl-prop-1-en-1-yl, 1,3-butadiene-1-yl, 1,3-butadiene-2-yl, and the like.

[0138] The term "alkynyl group" refers to a straight or branched chain hydrocarbon group having one or more carbon-carbon triple bonds. An alkynyl group refers to a group formed when an alkyne loses one hydrogen atom. Examples of alkynyl groups include ethynyl, 1-propynyl, propargyl, 1-butynyl, but-2-yn-1-yl, but-3-yn-1-yl, but-3-en-1-ynyl, 3-methylpentyl-2-en-4-yn-1-yl, and the like.

[0139] The term "alkylene group" refers to a divalent group formed by the simultaneous loss of two hydrogen atoms on a carbon atom of an alkane, where the two bond valences may be centered on the same atom or the two bond valences may each be located on two atoms in the remainder of the compound. The two bond valences may be centered on the same atom in the remainder of the compound or each may be located on two atoms in the remainder of the compound. Examples include methylene (-CH2- or =CH2), 1,1-ethylidene (-CH(CH3)- or =CH-CH3), 1,2-ethylidene (-CH2CH2-), buta-1,4-diyl, buta-1,3-diyl, 2,2-dimethyl-prop-1,3-diyl, and the like.

[0140] The term "alkoxy" refers to a radical of the formula "-O-alkyl", where alkyl is as defined above, such as, for example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, t-butoxy, and n-hexyloxy.

[0141] The term "alkylthio" refers to a radical of the formula "-S-alkyl", where alkyl is as defined above, such as, for example, methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, t-butylthio, and n-hexylthio.

[0142] The term "alkylamino group" includes groups of the formula "-NH-alkyl group" and groups of the formula "-N(alkyl group)2", where alkyl group is as defined above. Groups of the formula "-NH-alkyl group" may be, for example, methylamino group, ethylamino group, isopropylamino group, n-hexylamino group, etc.; groups of the formula "-N(alkyl group)2" may be, for example, dimethylamino group, diethylamino group, methylethylamino group, methylisopropylamino group, ethyln-hexylamino group, etc.

[0143] The term "alkyl sulfoxide group" refers to a group of the formula "-S(=O)-alkyl group", where alkyl group is defined as above. Examples include methyl sulfoxide group, ethyl sulfoxide group, isopropyl sulfoxide group, and the like.

[0144] The term "alkylsulfone" refers to a radical of the formula "-S(=O)2-alkyl", where alkyl is as defined above, such as methylsulfone, ethylsulfone, isopropylsulfone, and the like.

[0145] The term "alkylaminosulfinyl group" refers to a group of the formula "-S(=O)-NH-alkyl group" and a group of the formula "-S(=O)-N(alkyl group)2", where alkyl group is as defined above. A group of the formula "-S(=O)-NH-alkyl group" can be, for example, a methylaminosulfinyl group, an ethylaminosulfinyl group, an isopropylaminosulfinyl group, a t-butylaminosulfinyl group, and the like. A group of the formula "-S(=O)-N(alkyl group)2" can be, for example, a dimethylaminosulfinyl group, a diethylaminosulfinyl group, a methylethylaminosulfinyl group, an ethylisobutylaminosulfinyl group, and the like.

[0146] The term "alkylaminosulfonyl group" includes groups of the formula "-S(=O)2-NH-alkyl group" and groups of the formula "-S(=O)2-N(alkyl group)2", where alkyl group is as defined above. Groups of the formula "-S(=O)2-NH-alkyl" can be, for example, methylaminosulfonyl group, ethylaminosulfonyl group, isopropylaminosulfonyl group, t-butylaminosulfonyl group, etc. Groups of the formula "-S(=O)2-NH-alkyl group" can be, for example, dimethylaminosulfonyl group, diethylaminosulfonyl group, methylisopropylaminosulfonyl group, ethyl t-butylaminosulfonyl group, etc.

[0147] The term "carbonyl group" refers to a group of formula -(C=O)-, which also can be written as -C(O)-.

[0148] The term "cyano" refers to a group of formula -C≡N, which can also be written as -CN.

[0149] The term "hydroxymethyl group" refers to a group of formula -CHOH.

[0150] The term "oxo" refers to a divalent substituent oxygen atom which, when attached to a carbon atom, forms a carbonyl group, or, when attached to a heteroatom, forms a sulfoxide, sulfone, or N-oxide group, etc. In some embodiments, cycloalkyl and heterocyclic groups may be substituted with one or two oxo groups.

[0151] The term "imino group", which may also be written as "=NR", refers to a divalent substituent amino group, where two valencies of the same nitrogen atom are optionally attached to an atom selected from the remainder of the compound to form a double bond, and the third valency of the nitrogen atom is attached to an R group, as defined in the context, when the nitrogen atom is attached to a carbon atom, forming an imine, amidine, or guanidine, etc., or when attached to a heteroatom, forming a sulfoxide, imine, etc.

[0152] The term "cyclic hydrocarbon group" includes monocyclic or polycyclic alicyclic hydrocarbon groups and aromatic hydrocarbon groups. Monocyclic alicyclic hydrocarbon groups include one hydrocarbon ring and include cyclized alkyl and alkenyl groups. Polycyclic alicyclic hydrocarbon groups include two or more hydrocarbon rings, where at least one alicyclic hydrocarbon ring (including cyclized alkyl and alkenyl groups) is included, and the other rings may be alicyclic hydrocarbon rings and / or aromatic hydrocarbon rings; any one of the rings is bonded to at least one other ring via a spiro ring (two rings share one ring-forming atom) or a bridged ring (two rings share two or more ring-forming atoms). Polycyclic cyclic hydrocarbon groups are bonded to the remainder of the compound via a ring-forming carbon atom on the hydrocarbon ring. Examples of such groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentenyl, cyclohexadienyl, bicyclo[3.1.0]hexyl, norbornyl, norpinanyl, bicyclo[1.1.1]pentyl, 1H-inden-1-yl, and 2,3-dihydro-1H-inden-2-yl groups. When all of the rings contained in the cyclic hydrocarbon group are saturated rings, the cyclic hydrocarbon group is a saturated cyclic hydrocarbon group and is also called a "cycloalkyl group."

[0153] "Cycloalkyloxy" refers to a radical of the formula "-O-cycloalkyl", where cycloalkyl is as defined above. For example, cyclopropyloxy.

[0154] Cyclic hydrocarbon groups include "cycloalkylene groups", i.e., cyclic hydrocarbon groups are attached to two points of attachment to the remainder of the compound through two valencies, which may be located on the same carbon atom of the cycloalkylene group or may be located on two carbon atoms of the cycloalkylene group; the two points of attachment may be located on the same atom of the remainder of the compound or may be located on two atoms of the remainder of the compound. For example, 1,1-cyclobutylene groups, 1,3-cyclobutylene groups, etc.

[0155] The term "aryl group" refers to a monocyclic or polycyclic aromatic hydrocarbon group, such as a phenyl group, a naphthyl group, and the like.

[0156] The term "heterocyclic group" refers to a monocyclic or polycyclic group having at least one heteroatom selected from oxygen, nitrogen, sulfur and phosphorus as a ring-forming atom. A polycyclic heterocyclic group contains two or more ring structures, where at least one ring structure has at least one heteroatom selected from oxygen, nitrogen, sulfur and phosphorus as a ring-forming atom, and the other ring structures may or may not have ring-forming heteroatoms; any one of the rings is bonded to at least one other ring through a spiro ring (two rings share one ring-forming atom) or a bridged ring (two rings share two or more ring-forming atoms). A heterocyclic group may be bonded to the remainder of the compound through any one ring-forming carbon atom, or may be bonded to the remainder of the compound through any one ring-forming heteroatom. In some embodiments, any one ring-forming carbon atom in a heterocyclic group can be substituted with an oxo group to form a carbonyl group. In some embodiments, any one of the ring-forming nitrogen atoms in the heterocyclic group may be an N-oxide. In some embodiments, any one of the ring-forming nitrogen atoms in the heterocyclic group may be a quaternary ammonium ion.

[0157] Heterocyclic groups include aromatic heterocyclic groups (ie, "heteroaryl groups") and "aliphatic heterocyclic groups."

[0158] A "heteroaryl group" is a monocyclic or polycyclic aromatic heterocycle having at least one heteroatom selected from oxygen, nitrogen, and sulfur as a ring-forming atom. A heteroaryl group may be bonded to the remainder of the compound through any one carbon atom, or through any one heteroatom, if the valence of the carbon atom or heteroatom allows. In some embodiments, any one ring-forming carbon atom at the heteroaryl group site may be substituted with an oxo group to form a carbonyl group. In some embodiments, any one ring-forming nitrogen atom at the heteroaryl group site may be an N-oxide. In some embodiments, any one ring-forming nitrogen atom at the heteroaryl group site may be a quaternary ammonium ion. Examples of such groups include pyrrolyl groups (including pyrrol-1-yl, pyrrol-2-yl, and pyrrol-3-yl), pyrazolyl groups, imidazolyl groups, oxazolyl groups, isoxazolyl groups, thiazolyl groups, isothiazolyl groups, triazolyl groups, tetrazolyl groups, pyridyl groups, pyridin-2(1H)-one-1-yl groups, pyridin-4(1H)-one-1-yl groups, pyrazinyl groups, pyrimidinyl groups, pyridazinyl groups, pyrazin-3(2H)-one-2-yl groups, 1,2,4-triazinyl groups, 1,3,5-triazinyl groups, indolyl groups, benzofuranyl groups, benzothienyl groups, indazolyl groups, benzimidazolyl groups, benzoisothiazolyl groups, quinolinyl groups, isoquinolinyl groups, naphthyridinyl groups, imidazo[1,2-b]thiazolyl groups, and purinyl groups.

[0159] The term "aliphatic heterocyclic group" includes monocyclic or polycyclic aliphatic heterocyclic groups. A monocyclic aliphatic heterocyclic group may not contain a ring-forming double bond, or may contain one or more ring-forming double bonds. A polycyclic aliphatic heterocyclic group includes at least one alicyclic structure, and the other rings may be alicyclic or aromatic rings; any one ring structure in a polycyclic aliphatic heterocyclic group may not contain a ring-forming double bond, or may contain one or more ring-forming double bonds. Examples of the heterocyclic group include an azetidinyl group, an oxetanyl group, a tetrahydropyrrolyl group, a tetrahydrofuranyl group, a 2-oxooxazolidinyl group, a piperidinyl group, a 3-oxopiperidinyl group, a piperazinyl group, a morpholinyl group, an azepanyl group, a 2-oxa-6-azaspiro[3.3]heptyl group, and a 1,2,3,4-tetrahydroquinolinyl group.

[0160] Heterocyclic groups include heterocyclene groups, i.e., heterocycles are bonded to two points of attachment to the remainder of the compound through two valencies, which may be located on the same ring-forming atom of the heterocyclene group or on two ring-forming atoms of the heterocyclene group respectively; the two points of attachment may be located on the same atom of the remainder of the compound or on two atoms of the remainder of the compound respectively. For example, 1,1-(3-oxacyclobutylene group), 1,3-(2-azacyclopentylene group) and the like are included.

[0161] The term "fused ring" refers to a bridged ring system formed by two rings sharing two adjacent ring-forming atoms; the two rings may be saturated alicyclic, unsaturated alicyclic or aromatic rings, and the two adjacent ring-forming atoms may optionally be carbon atoms or heteroatoms.

[0162] The term "n-membered oxaalkylene group" refers to a divalent group formed by replacing one or more carbon atoms in the backbone of an n-membered alkylene group with an oxygen atom, and the two bond valencies may be located at the same atom in the remainder of the compound, or may each be located at two atoms in the remainder of the compound; for example, 2-oxa-1,3-propylene group (-CHOCH-) is an example of a three-membered oxaalkylene group, 2-oxa-1,4-butylidene group (-CHOCHCH-) is an example of a four-membered oxaalkylene group, etc. Alkylene groups in which only the branch carbon atoms are replaced with oxygen atoms should not be considered "oxaalkylene groups"; for example, 2-methyl-1,3-propylene group in which the branch methyl group is replaced with oxygen (-CHCH(OH)CH-) should be considered a 1,3-propylene group substituted with a 2-hydroxy group.

[0163] The term "n-membered azaalkylene group" refers to a divalent group in which one or more carbon atoms in the backbone of an n-membered alkylene group are replaced with a nitrogen atom, and the two bond valencies may be located at the same atom in the remainder of the compound, or may be located at two atoms in the remainder of the compound, respectively; for example, a 2-aza-1,3-propylene group (-CH2NHCH2-) is an example of a 3-membered azaalkylene group, an aza-1,2-ethylidene group (-CH2NH-) is an example of a 2-membered azaalkylene group, etc. Alkylene groups in which only a branched carbon atom is replaced with a nitrogen atom should not be considered "azaalkylene groups"; for example, a 2-methyl-1,3-propylene group in which a branched methyl group is replaced with a nitrogen (-CH2CH(NH2)CH2-) should be considered a 1,3-propylene substituted with a 2-amino group.

[0164] The term "isomer" refers to an isomer resulting from a different spatial arrangement of atoms in a molecule. The "stereoisomer" of a compound according to the present application refers to all stereoisomers. For example, when the compound has an asymmetric carbon atom, enantiomers and diastereomers occur; when the compound has a carbon-carbon double bond, a carbon-nitrogen double bond, or a ring structure, cis-trans isomers occur. Unless otherwise specified, the compound according to the present application includes all isomers, such as optically active isomers, geometric isomers, rotational isomers, tautomers, and conformational isomers that can exist stably; and may exist as a mixture of isomers or as separate isomers.

[0165] Methods on how to prepare optically active products from optically inactive starting materials are known in the art, such as by resolution of a racemic mixture or by stereoselective synthesis.

[0166] Separation of a racemic mixture of compounds can be carried out by any one of many methods known in the art. One method involves fractional recrystallization with a chiral resolving acid, which is an optically active salt-forming organic acid. Suitable resolving agents for fractional recrystallization include, for example, optically active acids such as D-tartaric acid, L-tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, -camphorsulfonic acid, etc.; other suitable resolving agents for fractional recrystallization include, for example, -methylbenzylamine, 2-phenylglycinol, cyclohexylethylamine, etc., which are stereoisomers in pure form.

[0167] A method for separating the racemic mixture further comprises converting the diastereomers, for example by reaction with a suitable optically active substance (e.g., chiral alcohol or Mosher's acid chloride), and separating the diastereomers into the corresponding single optical isomers (e.g., hydrolysis). For example, this is carried out by elution through a column packed with an optically active separating agent. The appropriate column and the composition of the eluting solvent may be determined by the skilled person.

[0168] The term "isotopically labeled" refers to a compound of the present application in which one or more constituent atoms are replaced with a specific isotope of the atom. For example, isotopes in the compounds of the present application can be various isotopes of elements such as H, C, N, O, F, P, S, Cl, and I, e.g. 2 H, 3 H, 13 C. 14 C. 15 N, 17 O. 18 O. 18 F, 30 P, 32 P, 35 S, 36 S, 123 I, 124 I and 125 I, etc. The present application includes various isotopically labeled compounds as defined, for example radioisotopes (e.g. 3 H and 14 C) or a non-radioactive isotope (e.g. 2 H and 13 C. Such isotope-labeled compounds are useful in metabolic studies ( 14 C), reaction kinetic studies (e.g. 2 H or 3 H), detection or imaging techniques including analysis of the tissue distribution of drugs or substrates, such as positron emission tomography (PET) or single photon emission computed tomography (SPECT), or for radiotherapy of patients, etc.

[0169] specifically, 18 F compounds may be particularly suited for PET or SPECT studies. Isotopically labeled compounds of formula (I) can generally be prepared by conventional techniques known to those skilled in the art or by methods analogous to those described in the accompanying examples and preparations, using suitable isotopically labeled reagents in place of conventional unlabeled reagents.

[0170] Also, the heavier isotopes, especially deuterium (i.e. 2H or D) may confer certain therapeutic advantages due to greater metabolic stability, e.g., increased half-life in the body, reduced dose requirements, improved therapeutic index, and may be preferred in some cases.

[0171] The term "pharmacologically acceptable" refers to those compounds, materials, compositions and / or dosage forms that, within the scope of sound medical judgment, are suitable for use in contact with the tissues of humans or animals, but are not excessively toxic, irritating, hypersensitivity or other problem or complication, and are commensurate with a reasonable benefit / risk ratio.

[0172] "Pharmaceutically acceptable salt" refers to a salt that retains the biological effectiveness and properties of the compounds of the present application and that usually has no adverse biological or other effects. In many cases, the compounds of the present application are capable of forming acid addition salts and / or base addition salts by virtue of the presence of amino and / or carboxyl groups or groups similar thereto.

[0173] Pharmaceutical acid addition salts may be formed with inorganic and organic acids.

[0174] Pharmaceutical base addition salts may be formed with inorganic and organic alkalis. All compounds and their pharma- ceutically acceptable salts may be found together (e.g., hydrates and solvates) with other substances (e.g., solvents, including water and other solvents) or may be isolated. When in the solid state, the compounds described herein and their salts may exist in various forms, including hydrates and solvates. The hydrates and solvates of the compounds described herein and their salts include hydrates and solvates in which the water and solvent may be isotopically substituted, such as DO, methanol-d3, methanol-d4, acetone-d6, DMSO-d6. The presence of hydrates and solvates can be identified by those skilled in the art using methods such as, for example, nuclear magnetic resonance (NMR).

[0175] The term "polymorphism" refers to compounds of the present application that exist in different crystal lattice forms or in amorphous form. The polymorphism of the compounds of the present application and their salts further includes mixtures of different crystal lattice forms, and mixtures of one or more crystal lattice forms and amorphous forms. The presence of polymorphism can be identified by those skilled in the art using methods such as, for example, X-ray diffraction.

[0176] Therefore, unless expressly stated otherwise, the compounds and salts thereof referred to herein should be understood to include any solid form of the compounds.

[0177] The term "active metabolite" refers to an active derivative of a compound that is formed upon metabolism of that compound.

[0178] "Pharmaceutically acceptable prodrug" means any pharma- ceutically acceptable ester, salt of an ester, amide, or other derivative of a compound of the present application, which is capable of providing, directly or indirectly, a compound of the present application or a pharma- ceutical active metabolite or residue thereof after administration to a receptor. Particularly preferred derivatives or prodrugs are compounds that can increase the bioavailability of a compound of the present application when administered to a patient (e.g., can make an orally administered compound more readily absorbed into the blood) or that facilitate delivery of the parent compound to a biological organ or site of action.

[0179] The term "pharmaceutical composition" refers to any biologically active compound mixed with at least one pharma- ceutically acceptable chemical component or agent, which is a "carrier" and contributes to the introduction of the compound into cells or tissues, and includes, but is not limited to, stabilizers, diluents, suspending agents, thickeners, and / or excipients. Pharmaceutical compositions include, but are not limited to, tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (dissolved in a solid or liquid solvent), ointments, soft and hard gelatin capsules, suppositories, transdermal patches, sterile injection solutions, and sterile packaged powders.

[0180] The term "pharmaceutically acceptable carrier" includes any solvents, dispersion media, coatings, surfactants, antioxidants, preservatives (e.g., antibacterial and antifungal agents), isotonicity agents, absorption delaying agents, salts, preservatives, drug stabilizers, binders, excipients, disintegrants, lubricants, sweeteners, flavorings, dyes, and the like, and combinations thereof, known to those of ordinary skill in the art. Conventional carriers are included for use in therapeutic or pharmaceutical compositions so long as they are compatible with the active ingredient.

[0181] By "therapeutically effective amount" is meant an amount of a compound of the present application that elicits a biological or medical response in an individual, such as reducing or inhibiting the activity of an enzyme or protein, ameliorating symptoms, alleviating a pathology, delaying or slowing the progression of a disease, or preventing a disease.

[0182] "Individual" or "patient" means an individual suffering from a disease, illness, or condition, and includes mammals and non-mammals. Examples of mammals include, but are not limited to, all members of the class Mammalia, including humans, non-human primates (e.g., chimpanzees, other apes and monkeys); farm animals, such as cows, horses, sheep, goats, and pigs; domestic animals, such as rabbits, dogs, and cats; and laboratory animals, including rodents, e.g., rats, mice, and guinea pigs. Examples of non-human mammals include, but are not limited to, birds and fish.

[0183] (synthesis) The compounds of the present application and their salts may be prepared by known organic synthesis techniques and may be prepared according to any one of many possible synthetic routes, such as those depicted in the schemes below.

[0184] The reactions for preparing the compounds of the present application can be carried out in a suitable solvent. A suitable solvent is one that does not substantially react with the starting materials (reactants), intermediates, or products at the temperature at which the reaction is carried out (which may be, for example, a temperature ranging from the freezing temperature of the solvent to the boiling temperature of the solvent). A given reaction can be carried out in one solvent or a mixture of solvents. Those skilled in the art can select the appropriate solvent for a particular reaction step depending on the particular reaction step.

[0185] The preparation of the compounds of the present application can involve the protection and deprotection of various chemical groups. The need for protection and deprotection, and the selection of appropriate protecting groups, can be readily determined by one skilled in the art.

[0186] The following schemes provide general guidance for the preparation of the compounds of the present application. It should be understood that those skilled in the art can use their general knowledge of organic chemistry to modify or optimize the methods shown in the schemes to prepare various compounds of the present application.

[0187] Compounds of formula (I) may be prepared according to the methods illustrated in the schemes below.

[0188] Various compounds of formula (I) can be prepared by the method as illustrated in Scheme 1. In the method shown in Scheme 1, the compound of formula 1-1 is diazotized and coupled to form the compound of formula 1-2. The compound of formula 1-2 is ring-closed (e.g., thermal ring-closure and acid- or base-catalyzed ring-closure) to form the compound of formula 1-3. The compound of formula 1-3 is amidated to form the compound of formula 1-4. The compound of formula 1-4 is chlorinated and dehydrated (e.g., chlorinated in the presence of phosphorus oxychloride and dehydrated) to form the compound of formula 1-5. The compound of formula 1-5 is ring-closed with hydrazine (or hydrazine hydrate) to form the compound of formula 1-6. The compound of formula 1-6 is halogenated (e.g., chlorinated, brominated, or iodinated) to form the compound of formula 1-7 by Sandmeyer reaction or similar reaction. The NH group of the pyrazole is protected by selecting an appropriate protecting group to form the compound of formula 1-8. The compound of formula 1-8 can be subjected to various cross-coupling reactions (e.g. Suzuki reaction, Stille reaction, etc.) to form the compound of formula 1-9. Finally, it is deprotected to form the compound of formula (I). By selecting an appropriate catalyst (e.g. SPhos-Pd-G2), the compound of formula 1-7 can be directly subjected to various cross-coupling reactions (e.g. Suzuki reaction, Stille reaction, etc.) and subsequent reactions (e.g. reductive amination, condensation of carboxyl group and amino group, etc.) to form the desired compound of formula (I).

[0189] [ka]

[0190] Alternatively, various compounds of formula (I) can be prepared by the method as illustrated in Scheme 2. In the method illustrated in Scheme 2, first, a compound of formula 1-1 forms a compound of formula 1-3 by the same method as that illustrated in Scheme 1. The compound of formula 1-3 forms a compound of formula 2-4 by a chlorination reaction. The compound of formula 2-4 is condensed with an excess of hydrazine (or hydrazine hydrate) to form a compound of formula 2-5A; or, the compound of formula 2-4 is condensed with an equivalent amount of hydrazine (or hydrazine hydrate) to form a compound of formula 2-5B. Either the compound of formula 2-5A or the compound of formula 2-5B can be condensed with a ring-closing reaction (e.g., thermal ring-closing and acid- or base-catalyzed ring-closing reaction) to form a compound of formula 2-6. The compound of formula 2-6 forms a compound of formula 1-7 by a halogenation reaction (e.g., chlorination, bromination, etc.). The compound of formula 1-7 can be condensed with the method as illustrated in Scheme 1 to form a compound of formula (I). Depending on the compound of formula 2-5A or formula 2-5B as an intermediate, Scheme 2 is subdivided into Scheme 2A and Scheme 2B.

[0191] [ka]

[0192] Alternatively, various compounds of formula (I) can be prepared by the method as illustrated in Scheme 3A. In the method shown in Scheme 3A, a compound of formula 3-1a (wherein X is a halogen or halogen analog, such as bromine, iodine, etc.; L1 is an aromatic ring or aromatic heterocycle; LG is a leaving group, such as a halogen, an alkoxy group, -N(Me)OMe, etc.), which is a carboxylic acid derivative, is condensed to form a compound of formula 3-2a. A compound of formula 1-1 is diazotized and coupled with a compound of formula 3-2a to form a compound of formula 3-3. A compound of formula 3-3 is subjected to a ring-closing reaction to generate a compound of formula 3-4. A compound of formula 3-4 is condensed with hydrazine (or hydrazine hydrate) to form a compound of formula 3-5A. A compound of formula 3-5A is protected by selecting an appropriate protecting group to protect the NH group of the pyrazole to form a compound of formula 3-6. The halogen or halogen analog in the compound of formula 3-6 can be subjected to various cross-coupling reactions (e.g. Suzuki reaction, Stille reaction, Buchwald-Hartwig amination, etc.) to form the compound of formula 1-9, and finally deprotected to form the compound of formula (I). By selecting the appropriate catalyst, the compound of formula 3-5A can be directly subjected to various cross-coupling reactions (e.g. Suzuki reaction, Stille reaction, Buchwald-Hartwig amination, etc.) to form the desired compound of formula (I).

[0193] [ka]

[0194] Alternatively, various compounds of formula (I) can be prepared by the method described in Scheme 3B. Compounds of formula 3-4 can be condensed with substituted hydrazines to form compounds of formula 3-5B. The halogen or halogen analog in compounds of formula 3-5B can be cross-coupled to form compounds of formula 1-9B by various cross-coupling reactions (e.g. Suzuki, Stille, Buchwald-Hartwig amination, etc. coupling reactions). Finally, deprotection forms compounds of formula (I).

[0195] [ka]

[0196] Alternatively, various compounds of formula (I) can be prepared by the method as illustrated in Scheme 4. In the method illustrated in Scheme 4, a compound of formula 3-1a (wherein X is a halogen or halogen analog, such as bromine, iodine, etc.; L1 is an aromatic ring or aromatic heterocycle; LG is a leaving group, such as a halogen, an alkoxy group, -N(Me)OMe, etc.) which is a carboxylic acid derivative, is condensed to form a compound of formula 4-3; or an aldehyde compound of formula 4-1 is added and oxidized (e.g., using a Dess-Martin oxidizing agent) to form a compound of formula 4-3. A compound of formula 1-1 is diazotized and coupled with a compound of formula 4-3 to form a compound of formula 4-4. The compound of formula 4-4 is ring-closing to produce a compound of formula 3-4. The compound of formula 3-4 can be converted to the desired compound of formula (I) by the method as illustrated in Scheme 3A or 3B.

[0197] [ka]

[0198] Unless otherwise stated or clearly contradicted by context, all methods described herein can be performed in any suitable order. Any examples or exemplary language (e.g., "for example") provided herein are merely intended to better illustrate the invention and are not intended to limit the scope of the otherwise claimed application.

[0199] The preparation and performance of the compound of formula (I) according to some embodiments of the present application are further illustrated below with specific examples, in which the starting materials used are either known and commercially available, or can be synthesized by methods known in the art.

[0200] All reactions in the examples were carried out under continuous magnetic stirring and reaction temperatures are in degrees Celsius unless otherwise noted.

[0201] The reaction can be monitored according to any suitable method known in the art, such as nuclear magnetic resonance analysis (NMR), infrared absorption spectroscopy (IR), spectrophotometry (e.g., ultraviolet-visible spectroscopy), liquid chromatography-mass spectrometry (LC-MS), mass spectrometry, high performance liquid chromatography, thin layer chromatography (also called thin layer chromatographic analysis), etc. The product may be purified by any suitable method known in the art, such as column chromatography (normal phase or reverse phase), preparative thin layer chromatography, beating, recrystallization, etc. Normal phase column chromatography usually uses Qingdao Haiyang 100-200 mesh silica gel as a carrier. Thin layer chromatography (TLC) uses Merck's Silica gel 60 F254 silica gel plate. Preparative thin layer chromatography (pre-TLC) uses Anhui Liangchen Silica Gen GF254 silica gel plate. The structures of the compounds according to the examples of the present application are identified by nuclear magnetic resonance analysis (NMR) and / or liquid chromatography mass spectrometry (LC-MS). Nuclear magnetic resonance analysis is performed using a Bruker AVANCE-400 nuclear magnetic resonance apparatus, and the solvent used for the measurement is usually deuterated dimethyl sulfoxide (DMSO-d6) or deuterated chloroform (CDC). l3 NMR chemical shifts (δ) are in parts per million (ppm) and the internal standard is tetramethylsilane (TMS). Liquid chromatography-mass spectrometry was performed on an Agilent 1100 Infinity Series liquid chromatograph and a Bruker HCT-Ultra ion trap mass spectrometer.

[0202] [Table 1]

[0203] [Example 1] (Compound 1: Preparation of 5-(2-fluoro-6-methylphenyl)-3-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrazolo[4,3-c]pyridazin-6(5H)-one (Scheme 1))

[0204] [ka]

[0205] Step 1: Preparation of dimethyl 2-(2-(2-fluoro-6-methylphenyl)hydrazino)-3-oxoglutarate

[0206] [ka]

[0207] Hydrochloric acid (4M, 54mL) was added to a three-neck flask containing 2-fluoro-6-methylaniline (5.0g, 40mmol), and the temperature was lowered to 0°C. An aqueous solution (30mL) of sodium nitrite (2.8g, 40mmol) was slowly added dropwise while the temperature of the reaction solution was kept at 5-10°C. After the dropwise addition was completed, stirring was continued for 2 hours at 5-10°C, and then the mixture was quickly added to a mixed solution of 3-oxoglutarate dimethyl (7.0g, 40mmol) and sodium acetate (21.0g, 264mmol) in ethanol (30mL) and water (60mL) that was being vigorously stirred at room temperature, and the product was precipitated. The reaction mixture was stirred for 2 hours at room temperature and filtered under suction. The filter cake was dried to obtain a crude product (6.0g) of 2-(2-(2-fluoro-6-methylphenyl)hydrazino)-3-oxoglutarate dimethyl as a yellow solid. This crude product was used directly in the next reaction.

[0208] ESI-MS: m / z=310.9 ([M+H] + ).

[0209] Step 2: Preparation of methyl 1-(2-fluoro-6-methylphenyl)-4-hydroxy-6-oxo-1,6-dihydropyridazine-3-carboxylate

[0210] [ka]

[0211] Dimethyl 2-(2-(2-fluoro-6-methylphenyl)hydrazino)-3-oxoglutarate (6.0 g, 19 mmol) was dissolved in dichlorobenzene (100 mL), the tube was sealed and heated to reflux. After heating for 4 hours, the reaction solution was cooled to room temperature, and cyclohexane (300 mL) was added dropwise to precipitate the product crystals, which were then filtered with suction. The filter cake was dried to give methyl 1-(2-fluoro-6-methylphenyl)-4-hydroxy-6-oxo-1,6-dihydropyridazine-3-carboxylate (2.0 g, 7.2 mmol) as a brown solid (yield 37%).

[0212] ESI-MS: m / z=279.1 ([M+H] + ).

[0213] Step 3: Preparation of 1-(2-fluoro-6-methylphenyl)-4-hydroxy-6-oxo-1,6-dihydropyridazine-3-formamide

[0214] [ka]

[0215] Methyl 1-(2-fluoro-6-methylphenyl)-4-hydroxy-6-oxo-1,6-dihydropyridazine-3-carboxylate (2.0 g, 7.2 mmol) was dissolved in ammonia in methanol (7N, 20 mL) and the tube was sealed and heated to reflux overnight. The reaction was cooled to room temperature and concentrated to dryness to give crude 1-(2-fluoro-6-methylphenyl)-4-hydroxy-6-oxo-1,6-dihydropyridazine-3-formamide (1.6 g) as an oil. This crude product was used directly in the next reaction.

[0216] ESI-MS: m / z=264.1 ([M+H] + ).

[0217] Step 4: Preparation of 4-chloro-1-(2-fluoro-6-methylphenyl)-6-oxo-1,6-dihydropyridazine-3-carbonitrile

[0218] [ka]

[0219] 4-Chloro-1-(2-fluoro-6-methylphenyl)-6-oxo-1,6-dihydropyridazine-3-carbonitrile (1.6 g) was dissolved in acetonitrile (16 mL), phosphorus oxychloride (8 mL) was added, and the mixture was heated to reflux and reacted overnight. The reaction mixture was stirred on ice for 1 hour and extracted three times with ethyl acetate (30 mL x 3). The organic phases were combined, dried, filtered, and concentrated to dryness. The residue was purified by column chromatography (petroleum ether / ethyl acetate: 20 / 1 to 10 / 1) to give 4-chloro-1-(2-fluoro-6-methylphenyl)-6-oxo-1,6-dihydropyridazine-3-carbonitrile (800 mg, 3.04 mmol) as a white solid (50% yield for two steps).

[0220] ESI-MS: m / z=264.0 ([M+H] + ).

[0221] Step 5: Preparation of 3-amino-5-(2-fluoro-6-methylphenyl)-1H-pyrazolo[4,3-c]pyridazin-6(5H)-one

[0222] [ka]

[0223] 4-Chloro-1-(2-fluoro-6-methylphenyl)-6-oxo-1,6-dihydropyridazine-3-carbonitrile (800 mg, 3.04 mmol) was dissolved in ethanol (8 mL) and 98% hydrazine hydrate (760 mg, 15 mmol) was added. The tube was sealed and heated to 100° C. overnight. The reaction was cooled to room temperature and the product was precipitated and filtered. The filter cake was dried to give 3-amino-5-(2-fluoro-6-methylphenyl)-1H-pyrazolo[4,3-c]pyridazin-6(5H)-one (600 mg, 2.3 mmol) as a red solid (75% yield). ESI-MS: m / z=260.1 ([M+H] + ).

[0224] Step 6. Preparation of 3-bromo-5-(2-fluoro-6-methylphenyl)-1H-pyrazolo[4,3-c]pyridazin-6(5H)-one

[0225] [ka]

[0226] 3-Amino-5-(2-fluoro-6-methylphenyl)-1H-pyrazolo[4,3-c]pyridazin-6(5H)-one (600 mg, 2.3 mmol) was dissolved in acetonitrile (12 mL) and tert-butyl nitrite (240 mg) was added dropwise at 0°C. The reaction was stirred at 0°C for 10 minutes, copper bromide (510 mg) was added, and stirring was continued for 20 minutes. The reaction was poured into water (20 mL) and filtered. The filtrate was extracted three times with ethyl acetate (20 mL x 3), and the organic phases were combined. The organic phase was washed with brine, dried, filtered, and concentrated to give the crude product of 3-bromo-5-(2-fluoro-6-methylphenyl)-1H-pyrazolo[4,3-c]pyridazin-6(5H)-one (400 mg). This crude product was used directly in the next reaction.

[0227] ESI-MS: m / z=323.0 ([M+H] + ).

[0228] Step 7: Preparation of Compound 1

[0229] [ka]

[0230] A single-neck flask was charged with the crude product of 3-bromo-5-(2-fluoro-6-methylphenyl)-1H-pyrazolo[4,3-c]pyridazin-6(5H)-one (400 mg, 1.24 mmol), (4-(4-methylpiperazin-1-yl)phenyl)boronic acid pinacol ester (376 mg, 1.24 mmol), potassium carbonate (340 mg, 2.48 mmol), Pd(dppf)Cl2-DCM (108 mg, 0.147 mmol), 1,4-dioxane (2 mL) and water (2 mL). The mixture was heated to 80° C. under nitrogen atmosphere and stirred for 3 h. The reaction was cooled to room temperature and concentrated. The residue was purified by preparative liquid chromatography (pre-HPLC) to give compound 1 (trifluoroacetate salt, 5.3 mg, 0.010 mmol) as a brown solid.

[0231] [Example 2] (Preparation of Compound 2: 5-(2-methoxy-6-methylphenyl)-3-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrazolo[4,3-c]pyridazin-6(5H)-one (Scheme 2A))

[0232] [ka]

[0233] (Step 1: Preparation of dimethyl 2-(2-(2-methoxy-6-methylphenyl)hydrazino)-3-oxoglutarate)

[0234] [ka]

[0235] This compound was prepared according to the procedure described in Example 1 (Step 1) using 2-methoxy-6-methylaniline instead of 2-fluoro-6-methylaniline as starting material. The yield is 79%.

[0236] ESI-MS: m / z=323.2 ([M+H] + ).

[0237] Step 2: Preparation of methyl 4-hydroxy-1-(2-methoxy-6-methylphenyl)-6-oxo-1,6-dihydropyridazine-3-carboxylate

[0238] [ka]

[0239] This compound was prepared according to the procedure described in Example 1 (Step 2) using dimethyl 2-(2-(2-(2-methoxy-6-methylphenyl)hydrazino)-3-oxoglutarate instead of dimethyl 2-(2-(2-fluoro-6-methylphenyl)hydrazino)-3-oxoglutarate as starting material. The yield is 83%.

[0240] ESI-MS: m / z=291.2 ([M+H] + ).

[0241] Step 3: Preparation of methyl 4-chloro-1-(2-methoxy-6-methylphenyl)-6-oxo-1,6-dihydropyridazine-3-carboxylate

[0242] [ka]

[0243] Methyl 4-hydroxy-1-(2-methoxy-6-methylphenyl)-6-oxo-1,6-dihydropyridazine-3-carboxylate (3.12 g, 10.8 mmol) was added to phosphorus oxychloride (15 mL), heated to 100° C. under nitrogen atmosphere, and stirred for 14 hours to complete the reaction. The reaction solution was cooled to room temperature and concentrated to dryness, and the residue was purified by column chromatography (petroleum ether / ethyl acetate: 3 / 1) to obtain methyl 4-chloro-1-(2-methoxy-6-methylphenyl)-6-oxo-1,6-dihydropyridazine-3-carboxylate (2.39 g, 7.74 mmol) as an orange solid (yield 72%).

[0244] ESI-MS: m / z=309.1 ([M+H] + ).

[0245] Step 4: Preparation of 4-hydrazino-1-(2-methoxy-6-methylphenyl)-6-oxo-1,6-dihydropyridazine-3-carboxylic acid hydrazide

[0246] [ka]

[0247] Methyl 4-chloro-1-(2-methoxy-6-methylphenyl)-6-oxo-1,6-dihydropyridazine-3-carboxylate (2.39 g, 7.74 mmol), hydrazine hydrate (1.45 g, 23.2 mmol) and diisopropylethylamine (3.84 mL, 23.2 mmol) were added to absolute ethanol (24 mL) and heated to 80° C. under nitrogen atmosphere and stirred for 2 hours to complete the reaction. The reaction solution was cooled to 0° C., and the solid was precipitated and filtered. The filter cake was rinsed with cold absolute ethanol (about 0° C.) and dried in vacuum to obtain 4-hydrazino-1-(2-methoxy-6-methylphenyl)-6-oxo-1,6-dihydropyridazine-3-carboxylic acid hydrazide (2.06 g, 6.77 mmol) as a yellow solid (yield 88%).

[0248] ESI-MS: m / z=305.2 ([M+H] + ).

[0249] Step 5: Preparation of 5-(2-methoxy-6-methylphenyl)-1H-pyrazolo[4,3-c]pyridazine-3,6(2H,5H)-dione

[0250] [ka]

[0251] 4-Hydrazino-1-(2-methoxy-6-methylphenyl)-6-oxo-1,6-dihydropyridazine-3-carboxylic acidHydrazide (2.06 g, 6.78 mmol), glacial acetic acid (2.33 mL, 40.7 mmol) and diisopropylethylamine (5.60 mL, 33.9 mmol) were added to n-butanol (20 mL), heated to 120 °C under nitrogen atmosphere and stirred for 15 hours to complete the reaction. The reaction solution was cooled to room temperature and concentrated to dryness. The residue was purified by column chromatography (dichloromethane / methanol: 40 / 1 to 8 / 1) to obtain 5-(2-methoxy-6-methylphenyl)-1H-pyrazolo[4,3-c]pyridazine-3,6(2H,5H)-dione (1.67 g, 6.14 mmol) as a reddish-brown solid (yield 90%).

[0252] ESI-MS: m / z=273.1 ([M+H] + ).

[0253] Step 6: Preparation of 3-chloro-5-(2-methoxy-6-methylphenyl)-1H-pyrazolo[4,3-c]pyridazin-6(5H)-one

[0254] [ka]

[0255] 5-(2-Methoxy-6-methylphenyl)- 1H-Pyrazolo[4,3-c]pyridazine-3,6(2H,5H)-dione (200 mg, 0.74 mmol), phosphorus oxychloride (334 μL, 3.67 mmol) and benzyltrimethylammonium chloride (136 mg, 0.74 mmol) were added to acetonitrile (100 mL), heated to 70 °C under nitrogen atmosphere and stirred for 18 hours to complete the reaction. The reaction solution was cooled to room temperature and concentrated to dryness, and the residue was purified by thin layer chromatography (dichloromethane / methanol: 20 / 1) to give 3-chloro-5-(2-methoxy-6-methylphenyl)-1H-pyrazolo[4,3-c]pyridazin-6(5H)-one (95 mg, 0.33 mmol) as a yellow solid (yield 44%).

[0256] ESI-MS: m / z=291.2 ([M+H] + ).

[0257] Step 7: Preparation of Compound 2

[0258] [ka]

[0259] 3-Chloro-5-(2-methoxy-6-methylphenyl)- 1H-Pyrazolo[4,3-c]pyridazin-6(5H)-one (50 mg, 0.17 mmol), 4-(4-methyl-1-piperazinyl)phenylboronic acid (76 mg, 0.34 mmol), SPhos-Pd-G2 (10 mg, 0.014 mmol) and potassium phosphate (110 mg, 0.52 mmol) were added to a mixture of 1,4-dioxane (4 mL) and water (1 mL), heated to 100 °C under a nitrogen atmosphere and stirred for 14 hours to complete the reaction. The reaction solution was cooled to room temperature and concentrated to dryness. The residue was purified by thin layer chromatography (dichloromethane / methanol: 20 / 1) to obtain a crude product, which was triturated with methanol (1 mL) in an ice bath to obtain compound 2 (61 mg, 0.14 mmol) as a yellow solid (yield 82%).

[0260] [Example 4] (Compound 4: 5-(2,4-dimethoxyphenyl)-3-(4-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)phenyl)-1H-pyrazolo[4,3-c]pyridazin-6(5H)-one (Scheme 3A))

[0261] [ka]

[0262] Step 1: Preparation of 4-bromo-N-methoxy-N-methylbenzamide

[0263] [ka]

[0264] 4-Bromobenzoyl chloride (5.0 g, 22.8 mmol) was dissolved in dichloromethane (50 mL) and cooled in an ice bath under nitrogen atmosphere. N,O-dimethylhydroxylamine hydrochloride (2.667 g, 27.34 mmol) and triethylamine (6.32 mL, 45.6 mmol) were added in sequence, and the mixture was allowed to warm to room temperature and stirred for 2 hours to complete the reaction. Dilute hydrochloric acid (0.1 M, 100 mL) was added to quench the reaction, and the reaction solution was extracted three times with dichloromethane (100 mL x 3). The organic phases were combined, washed with brine, dried, and filtered. The filtrate was concentrated under reduced pressure to dryness to give 4-bromo-N-methoxy-N-methylbenzamide (5.46 g, 22.4 mmol) as a yellow oil (98% yield).

[0265] ESI-MS: m / z=244.0 ([M+H] + ).

[0266] Step 2: Preparation of methyl 5-(4-bromophenyl)-3,5-dioxopentanoate

[0267] [ka]

[0268] Under a nitrogen atmosphere, sodium hydride (360 mg, 9.01 mmol) was added to dry tetrahydrofuran (20 mL) and placed in an ice bath. Methyl acetoacetate (951 mg, 8.19 mmol) was added dropwise while stirring, and after the completion of the dropwise addition, the mixture was stirred for 0.5 hours while keeping warm. The reaction bottle was transferred to a dry ice-acetone bath, cooled to -70°C, and a hexane solution of n-butyllithium (2.5 M, 3.3 mL, 8.2 mmol) was added dropwise. After the completion of the dropwise addition, the mixture was stirred for 10 minutes while keeping warm. Then, a solution of 4-bromo-N-methoxy-N-methylbenzamide (2.00 g, 8.19 mmol) in tetrahydrofuran (10 mL) was added dropwise, and after the completion of the dropwise addition, the mixture was stirred for 1 hour while keeping warm. The reaction was warmed to 0°C and quenched by the addition of saturated ammonium chloride solution (100mL), the reaction was extracted with ethyl acetate (100mL x 2), the organic phases were combined, washed with saturated brine (100mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (petroleum ether / ethyl acetate: 10 / 1) to give methyl 5-(4-bromophenyl)-3,5-dioxopentanoate (1.346g, 4.5mmol) as a yellow oil (yield 54%).

[0269] ESI-MS: m / z=299.0 ([M+H] + ).

[0270] Step 3: Preparation of methyl 5-(4-bromophenyl)-4-(2-(2,4-dimethoxyphenyl)hydrazino)-3,5-dioxopentanoate

[0271] [ka]

[0272] 2,4-Dimethoxyaniline (200 mg, 1.31 mmol) and water (1.6 mL) were mixed, and concentrated hydrochloric acid (0.8 mL) and an aqueous solution (1.2 mL) of sodium nitrite (90 mg, 1.31 mmol) were successively added dropwise while stirring in an ice bath. After the completion of the addition, the mixture was stirred for 0.5 hours while keeping warm to obtain a diazonium salt solution. 5-(4-bromophenyl)-3,5-dioxopentanoic acid methyl ester (391 mg, 1.31 mmol) and sodium acetate (643 mg, 7.83 mmol) were dissolved in a mixed solution of absolute ethanol (1.2 mL) and water (2.4 mL), and the above diazonium salt solution was added dropwise. After the completion of the addition, the mixture was stirred at room temperature for 2 hours to terminate the reaction. The reaction solution was extracted three times with dichloromethane (20 mL x 3), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (petroleum ether / ethyl acetate: 10 / 1 to 1 / 8) to give methyl 5-(4-bromophenyl)-4-(2-(2,4-dimethoxyphenyl)hydrazino)-3,5-dioxopentanoate (325 mg, 0.70 mmol) as an orange solid (yield 54%).

[0273] ESI-MS: m / z=463.1 ([M+H] + ).

[0274] Step 4: Preparation of 6-(4-bromobenzoyl)-2-(2,4-dimethoxyphenyl)-5-hydroxypyridazin-3(2H)-one

[0275] [ka]

[0276] Methyl 5-(4-bromophenyl)-4-(2-(2,4-dimethoxyphenyl)hydrazinomethylene)-3,5-dioxopentanoate (100 mg, 0.22 mmol) was dissolved in orthodichlorobenzene (2 mL), heated to 175° C. under a nitrogen atmosphere, and stirred for 5 hours to complete the reaction. The reaction solution was cooled to room temperature, diluted with ethyl acetate (10 mL), extracted three times with saturated sodium bicarbonate solution (10 mL×3), and the aqueous phases were combined. The pH value of the aqueous phase was adjusted to 4-5 with saturated citric acid solution, extracted twice with ethyl acetate (20 mL×2), and the organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to dryness in vacuo to give 6-(4-bromobenzoyl)-2-(2,4-dimethoxyphenyl)-5-hydroxypyridazin-3(2H)-one (67 mg, 0.16 mmol) as a yellow solid (72% yield).

[0277] ESI-MS: m / z=431.1 ([M+H] + ).

[0278] Step 5: Preparation of 3-(4-bromophenyl)-5-(2,4-dimethoxyphenyl)-1H-pyrazolo[4,3-c]pyridazin-6(5H)-one

[0279] [ka]

[0280] 6-(4-bromobenzoyl)-2-(2,4-dimethoxyphenyl)-5-hydroxypyridazin-3(2H)-one (47 mg, 0.11 mmol) was dissolved in n-butanol (2 mL), and glacial acetic acid (31 μL, 0.55 mmol) and hydrazine hydrate (33 μL, 0.55 mmol) were added. The mixture was heated to 120° C. under a nitrogen atmosphere and stirred for 15 hours to complete the reaction. The reaction solution was cooled to room temperature, and a solid was precipitated and filtered. The filter cake was dried under vacuum to obtain 3-(4-bromophenyl)-5-(2,4-dimethoxyphenyl)-1H-pyrazolo[4,3-c]pyridazin-6(5H)-one (27 mg, 0.063 mmol) as a yellow solid (yield 58%).

[0281] ESI-MS: m / z=427.1 ([M+H] + ).

[0282] Step 6: Preparation of Compound 4

[0283] [ka]

[0284] 3-(4-bromophenyl)-5-(2,4-dimethoxyphenyl)-1H-pyrazolo[4,3-c]pyridazin-6(5H)-one (10.0 mg, 0.023 mmol), 1-methyl-1,2,3,6-tetrahydropyridine-4-boronic acid pinacol ester (10.4 mg, 0.047 mmol), SPhos-Pd-G2 (1.7 mg, 0.002 mmol) and potassium phosphate (14.9 mg, 0.070 mmol) were added to a mixture of 1,4-dioxane (1.6 mL) and water (0.4 mL). The mixture was heated to 100° C. under a nitrogen atmosphere and stirred for 15 hours to complete the reaction. The reaction mixture was cooled to room temperature and concentrated to dryness. The residue was purified by thin layer chromatography (dichloromethane / methanol: 10 / 1) to obtain a crude product. The crude product was triturated with methanol (0.5 mL) at room temperature to obtain compound 4 (3.4 mg, 0.0077 mmol) as a yellow solid (yield 33%).

[0285] [Example 23] (Compound 23: 5-(2-fluoro-6-methoxyphenyl)-3-(4-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)phenyl)-1H-pyrazolo[4,3-c]pyridazin-6(5H)-one (Scheme 4))

[0286] [ka]

[0287] Step 1: Preparation of 2-methoxy-6-fluorophenyldiazonium tetrafluoroborate

[0288] [ka]

[0289] Dry methyl-t-butyl ether (8 mL) was cooled to -5°C, and a solution of boron trifluoride diethyl ether complex (1.1 mL, 8.9 mmol) and 2-fluoro-6-methoxyaniline (614 mg, 4.35 mmol) in dry methyl-t-butyl ether (3 mL) was added in sequence under a nitrogen atmosphere. After stirring for 15 minutes while keeping warm, the reaction system was cooled to -15°C. A solution of tert-butyl nitrite (0.62 mL, 5.2 mmol) in dry methyl-t-butyl ether (3 mL) was added dropwise. After the dropwise addition was completed, the reaction solution was allowed to warm up to 0°C naturally, and dry tetrahydrofuran (5 mL) was added and stirring was continued at 0°C for 2 hours. The reaction mixture was filtered, the filter cake was washed with methyl-t-butyl ether, and the filter cake was collected and dried at room temperature to obtain 2-methoxy-6-fluorophenyldiazonium tetrafluoroborate (955 mg, 3.98 mmol) as a gray solid (yield 91%).

[0290] (Step 2: Preparation of 6-(2-(4-bromophenyl)-1-(2-(2-fluoro-6-methoxyphenyl)hydrazino)-2-oxoethyl)-2,2-dimethyl-4H-1,3-dioxin-4-one)

[0291] [ka]

[0292] 6-(2-(4-bromophenyl)-2-oxoethyl)-2,2-dimethyl-4H-1,3-dioxin-4-one (694 mg, 2.13 mmol) was dissolved in ethanol (20 mL), sodium acetate (506 mg, 6.16 mmol) was added, and the mixture was cooled to -5°C. A solution of 2-methoxy-6-fluorophenyldiazonium tetrafluoroborate (539 mg, 2.25 mmol) in acetonitrile (3 mL) was added dropwise, and the mixture was stirred for 20 minutes. The reaction solution was poured into a mixture of ethyl acetate and an aqueous ammonium chloride solution, and the layers were separated. The aqueous phase was extracted with ethyl acetate, and the organic phases were combined. The organic phase was dried and concentrated to obtain a crude product of 6-(2-(4-bromophenyl)-1-(2-(2-fluoro-6-methoxyphenyl)hydrazino)-2-oxoethyl)-2,2-dimethyl-4H-1,3-dioxin-4-one. The crude product was used directly in the next step without purification.

[0293] ESI-MS: m / z=477.1 ([M+H] + ).

[0294] Step 3: Preparation of 6-(4-bromobenzoyl)-2-(2-fluoro-6-methoxyphenyl)-5-hydroxypyridazin-3(2H)-one

[0295] [ka]

[0296] 6-(2-(4-bromophenyl)-1-(2-(2-fluoro-6-methoxyphenyl)hydrazino)-2-oxoethyl)-2,2-dimethyl-4H-1,3-dioxin-4-one (970 mg, 2.03 mmol) was dissolved in 1,2-dichlorobenzene (4 mL) and glacial acetic acid (485 μL) was added. The mixture was heated to 130° C. and reacted for 1 hour. The reaction was cooled to room temperature, stirred and poured into n-heptane (120 mL) and cooled in an ice-water bath to precipitate a solid. The resulting solid was collected by filtration. The filter cake was dried under vacuum to give 6-(4-bromobenzoyl)-2-(2-fluoro-6-methoxyphenyl)-5-hydroxypyridazin-3(2H)-one (518 mg, 1.23 mmol) as an orange-red solid (61% yield).

[0297] ESI-MS: m / z=419.1 ([M+H] + ).

[0298] Step 4: Preparation of 3-(4-bromophenyl)-5-(2-fluoro-6-methoxyphenyl)-1H-pyrazolo[4,3-c]pyridazin-6(5H)-one

[0299] [ka]

[0300] This compound was prepared according to the procedure described in Example 4 (Step 5) using 6-(4-bromobenzoyl)-2-(2-fluoro-6-methoxyphenyl)-5-hydroxypyridazin-3(2H)-one instead of 6-(4-bromobenzoyl)-2-(2,4-dimethoxyphenyl)-5-hydroxypyridazin-3(2H)-one as starting material, the yield is 70%.

[0301] ESI-MS: m / z=415.1 ([M+H] + ).

[0302] Step 5: Preparation of Compound 23

[0303] [ka]

[0304] This compound was prepared according to the procedure described in Example 4 (Step 6) using 3-(4-bromophenyl)-5-(2-fluoro-6-methoxyphenyl)-1H-pyrazolo[4,3-c]pyridazin-6(5H)-one instead of 3-(4-bromophenyl)-5-(2,4-dimethoxyphenyl)-1H-pyrazolo[4,3-c]pyridazin-6(5H)-one as starting material, the yield is 58%.

[0305] [Example 24] (Compound 24: 5-(2-fluoro-6-methoxyphenyl)-3-(4-(1-methylpiperidin-4-yl)phenyl)-1H-pyrazolo[4,3-c]pyridazin-6(5H)-one)

[0306] [ka]

[0307] Compound 23 (60 mg, 0.14 mmol) was dissolved in a mixed solvent of anhydrous methanol (6 mL) and tetrahydrofuran (6 mL), 10% palladium on carbon (12 mg) was added, hydrogen gas was introduced into the solution, and the solution was stirred overnight at room temperature under a hydrogen gas atmosphere to terminate the reaction. The palladium on carbon was removed by filtration, and the filtrate was concentrated to dryness. The residue was purified by thin layer chromatography (dichloromethane / anhydrous methanol: 10 / 1) to obtain 5-(2-fluoro-6-methoxyphenyl)-3-(4-(1-methylpiperidin-4-yl)phenyl)-1H-pyrazolo[4,3-c]pyridazin-6(5H)-one (32 mg, 0.074 mmol) as an orange solid product (yield 53%).

[0308] [Example 25] (Compound 25: 5-(2,4-dimethoxyphenyl)-3-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrazolo[4,3-c]pyridazin-6(5H)-one (Scheme 3B))

[0309] [ka]

[0310] Step 1: Preparation of 3-(4-bromophenyl)-1-(2,4-dimethoxybenzyl)-5-(2,4-dimethoxyphenyl)-1H-pyrazolo[4,3-c]pyridazin-6(5H)-one

[0311] [ka]

[0312] 6-(4-Bromobenzoyl)-2-(2,4-dimethoxyphenyl)-5-hydroxypyridazin-3(2H)-one was prepared according to the procedure described in Example 4 (Step 4). 6-(4-Bromobenzoyl)-2-(2,4-dimethoxyphenyl)-5-hydroxypyridazin-3(2H)-one (840 mg, 1.95 mmol), 2,4-dimethoxyphenylhydrazine dihydrochloride (646 mg, 2.53 mmol) and anhydrous sodium acetate (479 mg, 5.84 mmol) were added to n-butanol (10 mL) and heated to 100° C. and stirred for 1 hour. The reaction was cooled to room temperature and filtered to collect the precipitated solid. The solid was purified by column chromatography (petroleum ether / ethyl acetate: 1 / 9 to 0 / 10) to give 3-(4-bromophenyl)-1-(2,4-dimethoxybenzyl)-5-(2,4-dimethoxyphenyl)-1H-pyrazolo[4,3-c]pyridazin-6(5H)-one (532 mg, 0.92 mmol) as a yellow solid (yield 36%).

[0313] ESI-MS: m / z=577.2 ([M+H] + ).

[0314] Step 2: Preparation of 1-(2,4-dimethoxybenzyl)-5-(2,4-dimethoxyphenyl)-3-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrazolo[4,3-c]pyridazin-6(5H)-one

[0315] [ka]

[0316] 3-(4-bromophenyl)-1-(2,4-dimethoxybenzyl)-5-(2,4-dimethoxyphenyl)-1H-pyrazolo[4,3-c]pyridazin-6(5H)-one (450 mg, 0.78 mmol), methylpiperazine (390 mg, 3.9 mmol), Pd2(dba)3 (71 mg, 0.078 mmol) and BINAP (121 mg, 0.195 mmol) were mixed in toluene (9 mL), and a toluene solution of sodium tert-pentoxide (3.5 M, 1.1 mL) was added under a nitrogen atmosphere, and the mixture was heated to 100° C. and stirred overnight. The reaction solution was diluted with dichloromethane, washed with water and separated. The organic phase was dried and concentrated. The residue was purified by column chromatography (dichloromethane / methanol: 100 / 1 to 30 / 1) to give 1-(2,4-dimethoxybenzyl)-5-(2,4-dimethoxyphenyl)-3-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrazolo[4,3-c]pyridazin-6(5H)-one (203 mg, 0.34 mmol) as an orange solid (44% yield).

[0317] ESI-MS: m / z=597.4 ([M+H] + ).

[0318] Step 3: Preparation of Compound 25

[0319] [ka]

[0320] 1-(2,4-Dimethoxybenzyl)-5-(2,4-dimethoxyphenyl)-3-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrazolo[4,3-c]pyridazin-6(5H)-one (200 mg, 0.34 mmol) was dissolved in trifluoroacetic acid (6 mL), anisole (0.3 mL) was added, and the mixture was heated to 80° C. and stirred for 2 hours. The reaction mixture was cooled to room temperature, diluted with water (20 mL), and extracted three times with ethyl acetate. The pH of the aqueous phase was adjusted to 8 with sodium carbonate solution to precipitate a solid. The solid was collected by filtration and dried. The solid was triturated with methanol to give compound 25 (90 mg, 0.20 mmol) as an orange solid (60% yield).

[0321] [Example 29] (Compound 33: 5-(2-fluoro-6-methoxyphenyl)-3-(4-(4-methyl-3-oxopiperazin-1-yl)phenyl)-1H-pyrazolo[4,3-c]pyridazin-6(5H)-one (Scheme 2B))

[0322] [ka]

[0323] Step 1: Preparation of dimethyl 2-(2-(2-(2-fluoro-6-methoxyphenyl)hydrazino)-3-oxoglutarate

[0324] [ka]

[0325] This compound was prepared according to the procedure described in Example 2 (Step 1) using 2-fluoro-6-methoxyaniline instead of 2-methoxy-6-methylaniline as starting material. The yield is 94%.

[0326] ESI-MS: m / z=327.2 ([M+H] + ).

[0327] Step 2: Preparation of methyl 4-hydroxy-1-(2-fluoro-6-methoxyphenyl)-6-oxo-1,6-dihydropyridazine-3-carboxylate

[0328] [ka]

[0329] This compound was prepared according to the procedure described in Example 2 (Step 2) using dimethyl 2-(2-(2-(2-fluoro-6-methoxyphenyl)hydrazino)-3-oxoglutarate instead of dimethyl 2-(2-(2-(2-methoxy-6-methylphenyl)hydrazino)-3-oxoglutarate as starting material. The yield is 90%.

[0330] ESI-MS: m / z=295.2 ([M+H] + ).

[0331] Step 3: Preparation of methyl 4-chloro-1-(2-fluoro-6-methoxyphenyl)-6-oxo-1,6-dihydropyridazine-3-carboxylate

[0332] [ka]

[0333] This compound was prepared according to the procedure described in Example 2 (Step 3) using methyl 4-hydroxy-1-(2-fluoro-6-methoxyphenyl)-6-oxo-1,6-dihydropyridazine-3-carboxylate instead of methyl 4-hydroxy-1-(2-methoxy-6-methylphenyl)-6-oxo-1,6-dihydropyridazine-3-carboxylate as starting material. The yield is 84%.

[0334] ESI-MS: m / z=313.2 ([M+H] + ).

[0335] Step 4: Preparation of methyl 4-hydrazino-1-(2-fluoro-6-methoxyphenyl)-6-oxo-1,6-dihydropyridazine-3-carboxylate

[0336] [ka]

[0337] Methyl 4-chloro-1-(2-fluoro-6-methoxyphenyl)-6-oxo-1,6-dihydropyridazine-3-carboxylate (4.0 g, 12.8 mmol, 1.0 eq) and DIPEA (8.4 mL, 51.3 mmol, 4.0 eq) were suspended in ethanol (40 mL) and a solution of 98% hydrazine hydrate (785 mg, 15.4 mmol, 1.2 eq) in ethanol (40 mL) was added dropwise at room temperature. After the addition was completed, the mixture was stirred at room temperature for 4 hours. The reaction solution was diluted with water (150 mL) and extracted three times with ethyl acetate. The organic phases were combined, washed with brine, dried, filtered, and concentrated to dryness. The residue was purified by column chromatography (dichloromethane / methanol:100 / 1) to give methyl 4-hydrazino-1-(2-fluoro-6-methoxyphenyl)-6-oxo-1,6-dihydropyridazine-3-carboxylate (2.3 g) as a yellow solid (yield 59%).

[0338] ESI-MS: m / z=309.1 ([M+H] + ).

[0339] Step 5: Preparation of 5-(2-fluoro-6-methoxyphenyl)-1H-pyrazolo[4,3-c]pyridazine-3,6(2H,5H)-dione

[0340] [ka]

[0341] Methyl 4-hydrazino-1-(2-fluoro-6-methoxyphenyl)-6-oxo-1,6-dihydropyridazine-3-carboxylate (1.6 g, 5.19 mmol, 1.0 eq) was dissolved in a mixed solvent of methanol (15 mL) and tetrahydrofuran (15 mL), and an aqueous solution (15 mL) of lithium hydroxide monohydrate (436 mg, 10.38 mmol, 2.0 eq) was added and stirred at room temperature for 2 hours. The reaction solution was concentrated to dryness. The residue was purified by column chromatography (dichloromethane / methanol: 15 / 1) to obtain a brown solid. 5-(2-Fluoro-6-methoxyphenyl)-1H-pyrazolo[4,3-c]pyridazine-3,6(2H,5H)-dione (1.4 g) was obtained (yield 99%).

[0342] ESI-MS: m / z=277.2 ([M+H] + ).

[0343] Step 6: Preparation of 3-chloro-5-(2-fluoro-6-methoxyphenyl)-1H-pyrazolo[4,3-c]pyridazin-6(5H)-one

[0344] [ka]

[0345] This compound was prepared by following the procedure described in Example 2 (Step 6) to prepare 5-(2-fluoro-6-methoxyphenyl)-1H-pyrazolo[4,3-c]pyridazine-3,6(2H,5H)-dione instead of 5-(2-methoxy-6-methylphenyl)-1H-pyrazolo[4,3-c]pyridazine-3,6(2H,5H)-dione as starting material. N It was prepared using the following procedure: The yield is 28%.

[0346] ESI-MS: m / z=295.1 ([M+H] + ).

[0347] Step 7: Preparation of Compound 33

[0348] [ka]

[0349] This compound was prepared by following the procedure described in Example 2 (Step 7) using 3-chloro-5-(2-fluoro-6-methoxyphenyl)-1H-pyrazolo[4,3-c]pyridazin-6(5H)-one as starting material instead of 3-chloro-5-(2-methoxy-6-methylphenyl)-1H-pyrazolo[4,3-c]pyridazin-6(5H)-one. N It was prepared using (4-(4-methyl-3-oxopiperazin-1-yl)phenyl)boronic acid pinacol ester instead of 4-(4-methyl-1-piperazinyl)phenylboronic acid. The yield is 25%.

[0350] [Example 30] (Compound 34: 5-(2-fluoro-6-cyclopropylphenyl)-3-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrazolo[4,3-c]pyridazin-6(5H)-one (Scheme 3A))

[0351] [ka]

[0352] Step 1: Preparation of t-butyl (2-fluoro-6-cyclopropylphenyl)carbamate

[0353] [ka]

[0354] This compound was prepared according to the procedure described in Example 29 (Step 2) using cyclopropylboronic acid instead of 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane as starting material. The yield is 65%.

[0355] ESI-MS: m / z=196.1 ([M+H-C4H8] + ).

[0356] Step 2: Preparation of 2-fluoro-6-cyclopropylaniline

[0357] [ka]

[0358] This compound was prepared according to the procedure described in Example 29 (Step 4) using t-butyl (2-fluoro-6-cyclopropylphenyl)carbamate as the starting material. The yield is 87%.

[0359] ESI-MS: m / z=152.1 ([M+H] + ).

[0360] Step 3: Preparation of 2-cyclopropyl-6-fluorophenyldiazonium tetrafluoroborate

[0361] [ka]

[0362] A mixed solvent of dried methyl-t-butyl ether (3 mL) and dried tetrahydrofuran (3 mL) was cooled to -5°C, and a solution of boron trifluoride diethyl ether complex (489 μL, 3.97 mmol) and 2-fluoro-6-cyclopropylaniline (300 mg, 1.98 mmol) in dried tetrahydrofuran (3 mL) was added in sequence under a nitrogen atmosphere. After stirring for 15 minutes while keeping the temperature, the reaction system was cooled to -15°C. A solution of tert-butyl nitrite (246 mg, 2.38 mmol) in dried methyl-t-butyl ether (3 mL) was added dropwise. After the dropwise addition was completed, the reaction solution was allowed to naturally warm to 0°C and stirred at 0°C for 1.5 hours. The reaction mixture was filtered, the filter cake was washed with t-butyl methyl (50 mL), and the filter cake was collected and dried at room temperature to give 2-cyclopropyl-6-fluorophenyldiazonium tetrafluoroborate (426 mg, 1.70 mmol) as a white solid (86% yield).

[0363] ESI-MS: m / z=163.1 ([M+H-BF4] + ).

[0364] Step 4: Preparation of methyl 5-(4-bromophenyl)-4-(2-(2-fluoro-6-cyclopropylphenyl)hydrazino)-3,5-dioxopentanoate

[0365] [ka]

[0366] Methyl 5-(4-bromophenyl)-3,5-dioxopentanoate (920 mg, 3.07 mmol) and anhydrous sodium acetate (757 mg, 9.22 mmol) were dissolved in anhydrous ethanol (20 mL) and cooled to -15°C. A solution of 2-cyclopropyl-6-fluorophenyldiazonium tetrafluoroborate (384 mg, 1.54 mmol) in acetonitrile (4 mL) was added dropwise. After the addition was completed, the reaction solution was allowed to naturally warm to 0°C and stirred for 1.5 hours. The reaction solution was concentrated under reduced pressure, diluted with water (60 mL), and further extracted with ethyl acetate (20 mL * 3), and the organic phase was combined. The organic phase was washed with saturated saline (60 mL), dried over anhydrous sodium sulfate, suction filtered, and concentrated to dryness. The residue was purified by column chromatography (petroleum ether / ethyl acetate: 15 / 1) to give methyl 5-(4-bromophenyl)-4-(2-(2-fluoro-6-cyclopropylphenyl)hydrazino)-3,5-dioxopentanoate (435 mg, 0.94 mmol) as a yellow solid (yield 61%).

[0367] ESI-MS: m / z=461.0 ([M+H] + ).

[0368] Step 5: Preparation of 6-(4-bromobenzoyl)-2-(2-fluoro-6-cyclopropylphenyl)-5-hydroxypyridazin-3(2H)-one

[0369] [ka]

[0370] This compound was prepared according to the procedure described in Example 4 (Step 4) using methyl 5-(4-bromophenyl)-4-(2-(2-fluoro-6-cyclopropylphenyl)hydrazinomethylene)-3,5-dioxopentanoate instead of methyl 5-(4-bromophenyl)-4-(2-(2,4-dimethoxyphenyl)hydrazinomethylene)-3,5-dioxopentanoate as starting material. The yield is 38%.

[0371] ESI-MS: m / z=429.0 ([M+H] + ).

[0372] Step 6: Preparation of 3-(4-bromophenyl)-5-(2-fluoro-6-cyclopropylphenyl)-1H-pyrazolo[4,3-c]pyridazin-6(5H)-one

[0373] [ka]

[0374] This compound was prepared according to the procedure described in Example 4 (Step 5) using 6-(4-bromobenzoyl)-2-(2-fluoro-6-cyclopropylphenyl)-5-hydroxypyridazin-3(2H)-one as starting material instead of 6-(4-bromobenzoyl)-2-(2,4-dimethoxyphenyl)-5-hydroxypyridazin-3(2H)-one. The yield is 71%.

[0375] ESI-MS: m / z=425.1 ([M+H] + ).

[0376] Step 7: Preparation of 3-(4-bromophenyl)-5-(2-cyclopropyl-6-fluorophenyl)-1-(2-(trimethylsilyl)ethoxymethyl)-1H-pyrazolo[4,3-c]pyridazin-6(5H)-one

[0377] [ka]

[0378] 3-(4-Bromophenyl)-5-(2-fluoro-6-cyclopropylphenyl)-1H-pyrazolo[4,3-c]pyridazin-6(5H)-one (92 mg, 0.22 mmol) was dissolved in water and dried. N,N-The mixture was dissolved in dimethylformamide (5 mL) and cooled to 0°C. Sodium hydride (26 mg, 0.65 mmol) was added under a nitrogen atmosphere and stirred at 0°C for 20 minutes. 2-(Trimethylsilyl)ethoxymethyl chloride (111 mg, 0.67 mmol) was added dropwise, the mixture was warmed to room temperature, and stirred for 2 hours. The reaction mixture was poured into water (50 mL), extracted three times with ethyl acetate (15 mL*3), and the organic phases were combined. The organic phase was washed with saturated saline (50 mL*3), dried over anhydrous sodium sulfate, suction filtered, and concentrated to dryness. The residue was purified by column chromatography (petroleum ether / ethyl acetate: 5 / 1) to give 3-(4-bromophenyl)-5-(2-cyclopropyl-6-fluorophenyl)-1-(2-(trimethylsilyl)ethoxymethyl)-1H-pyrazolo[4,3-c]pyridazin-6(5H)-one (82 mg, 0.15 mmol) as a yellow solid (yield 67%).

[0379] ESI-MS: m / z=555.0 ([M+H] + ).

[0380] Step 8: Preparation of 5-(2-cyclopropyl-6-fluorophenyl)-3-(4-(4-methylpiperazin-1-yl)phenyl)-1-(2-(trimethylsilyl)ethoxymethyl)-1H-pyrazolo[4,3-c]pyridazin-6(5H)-one

[0381] [ka]

[0382] 3-(4-bromophenyl)-5-(2-cyclopropyl-6-fluorophenyl)-1-(2-(trimethylsilyl)ethoxymethyl)-1H-pyrazolo[4,3-c]pyridazin-6(5H)-one (82 mg, 0.15 mmol), methylpiperazine (74 mg, 0.74 mmol), Pd2(dba)3 (13 mg, 0.015 mmol) and BINAP (23 mg, 0.037 mmol) were mixed in toluene (7 mL), and a toluene solution of sodium tert-pentoxide (3.5 M, 0.21 mL) was added under a nitrogen atmosphere, and the mixture was heated to 100 ° C. and stirred overnight. The reaction solution was poured into a saturated aqueous ammonium chloride solution (60 mL), extracted three times with ethyl acetate (20 mL * 3), and the organic phase was combined. The organic phase was washed with saturated saline, dried over anhydrous sodium sulfate, suction filtered, and concentrated to dryness. The residue was purified by column chromatography (ethyl acetate / triethylamine:100 / 3) to give 5-(2-cyclopropyl-6-fluorophenyl)-3-(4-(4-methylpiperazin-1-yl)phenyl)-1-(2-(trimethylsilyl)ethoxymethyl)-1H-pyrazolo[4,3-c]pyridazin-6(5H)-one (36 mg, 0.063 mmol) as a red solid (42% yield).

[0383] ESI-MS: m / z=575.2 ([M+H] + ).

[0384] Step 9: Preparation of Compound 34

[0385] [ka]

[0386] At 0°C, trifluoroacetic acid (2.5mL) was added to a solution of 5-(2-cyclopropyl-6-fluorophenyl)-3-(4-(4-methylpiperazin-1-yl)phenyl)-1-(2-(trimethylsilyl)ethoxymethyl)-1H-pyrazolo[4,3-c]pyridazin-6(5H)-one (36mg, 0.063mmol) in dichloromethane (10mL), the mixture was warmed to room temperature, and stirred for 2 hours. The reaction solution was neutralized with a saturated aqueous sodium carbonate solution, extracted three times with dichloromethane (30mL*3), and the organic phases were combined. The organic phase was washed with saturated saline, dried over anhydrous sodium sulfate, suction filtered, and concentrated to dryness. The residue was dissolved in methanol (5mL), a small amount of aqueous ammonia was added, stirred at room temperature for 1 hour, and further concentrated to dryness. The residue was purified by thin layer chromatography (DCM / MeOH: 10 / 1) to give compound 34 (10 mg, 0.022 mmol) as a red solid (yield 36%).

[0387] Other compounds in the examples were synthesized by methods similar to the above synthetic scheme, and their characterization data are shown in the following table.

[0388] [Table 2] JPEG0007611934000077.jpg246169 JPEG0007611934000078.jpg246169 JPEG0007611934000079.jpg246169 JPEG0007611934000080.jpg246169 JPEG0007611934000081.jpg246169 JPEG0007611934000082.jpg246169 JPEG0007611934000083.jpg246169 JPEG0007611934000084.jpg242169 JPEG0007611934000085.jpg248169 JPEG0007611934000086.jpg246169 JPEG0007611934000087.jpg246169 JPEG0007611934000088.jpg246169 JPEG0007611934000089.jpg246169 JPEG0007611934000090.jpg248169 JPEG0007611934000091.jpg233169 JPEG0007611934000092.jpg237169 JPEG0007611934000093.jpg242169 JPEG0007611934000094.jpg229169 JPEG0007611934000095.jpg246169 JPEG0007611934000096.jpg233169 JPEG0007611934000097.jpg248169 JPEG0007611934000098.jpg244169 JPEG0007611934000099.jpg224169 JPEG0007611934000100.jpg246169 JPEG0007611934000101.jpg233169 JPEG0007611934000102.jpg248169 JPEG0007611934000103.jpg39169

[0389] (Method and results of biological activity detection:) (1.HPK1 kinase activity inhibition experiment) HPK1 kinase activity was expressed as autophosphorylation activity and phosphorylation of downstream substrates. The autophosphorylation process does not require a separate substrate and consumes ATP to produce ADP. The amount of the product was detected using ADP-Glo ​​reagent and luminescence method to reflect the activity of the kinase.

[0390] Test substances: Compounds prepared in the examples of this application.

[0391] Preparation of compound stock solutions: Test compounds were dissolved in 100% DMSO to prepare 10 mM stock solutions;

[0392] [Table 3]

[0393] [Table 4]

[0394] [Table 5]

[0395] Experimental steps: The stock solution of the test compound was diluted 5-fold with 100% DMSO, and then diluted 4-fold in an equal ratio in a 96-well dilution plate. 1 μL of the compound was taken and added to 49 μL of kinase reaction buffer and shaken for 20 minutes on a microplate shaker. 2 μL of 2×HPK1 kinase solution was transferred to a 384 reaction plate, and 1 μL of the test compound was added to the 384 reaction plate. ThingsThe mixture was added to a 384 reaction plate (Greiner, 784075), centrifuged for 1 min (1000 rpm / min), and incubated at 25°C for 10 min. 1 μL of the 4×ATP mixture was transferred to a 384 reaction plate, centrifuged for 1 min (1000 rpm / min), and incubated at 25°C for 60 min. The final DMSO concentration in the reaction system was 0.5% in all cases. 4 μL of ADP-Glo ​​was transferred to a 384 reaction plate, centrifuged for 1 min (1000 rpm / min), and incubated at 25°C for 40 min. 8 μL of Detection solution was transferred to a 384 reaction plate, centrifuged for 1 min (1000 rpm / min), and incubated at 25°C for 40 min. The fluorescence signal was read out using a Biotek multifunction plate reader, and the IC50 (half maximal inhibitory concentration) of the compound was obtained by a four-coefficient nonlinear fitting equation.

[0396] The compounds shown in the examples were shown to have IC50 values ​​within the following ranges: +++=IC50≦50 nM, ++=50 nM <IC50≦500nM、+=500nM<IC50<2000nM。

[0397] [Table 6] JPEG0007611934000108.jpg247169JPEG0007611934000109.jpg12169

[0398] As can be seen from the data in Table 1, the compounds of the Examples of the present application have an inhibitory effect on HPK1 kinase activity.

[0399] (2. Detection of IL-2 secreted from Jurkat cells by ELISA) Experimental steps: Different concentrations of test compounds and human Jurkat-E6-1 cells were incubated at 37°C in a humidified incubator with 5% CO2 for 30 min. The cells were transferred to a cell culture plate previously coated with anti-human CD3 antibody, and then soluble anti-human CD28 antibody was added and the cells were stimulated for 24 h in a humidified incubator with 37°C and 5% CO2. The cell culture medium was collected by centrifugation, and the cell culture medium was transferred to a 96-well transparent ELISA plate (Thermo) previously coated with anti-human IL-2 antibody, incubated at room temperature for 2 h, gently shaken, and the ELISA plate was washed four times with washing buffer, and then the OD value was read with an ELISA plate reader (Molecular Device, i3X) according to the operating instructions of the ELISA MAX Deluxe Set Human IL-2 (BioLegend) kit. The optimal calibration curve was selected with the ELISA plate reader software, and the corresponding concentration was calculated based on the OD value of the standard. Results were expressed as percentage of the amount of IL-2 secreted from compound / DMSO-treated cells.

[0400] [Table 7] JPEG0007611934000111.jpg247169JPEG0007611934000112.jpg143169

[0401] As can be seen from the data in Table 2, in comparison with the blank control group of DMSO-treated Jurkat cells, the compounds of the Examples of the present application have a clear promoting effect on the secretion of cytokine IL-2 from Jurkat cells.

[0402] Unless otherwise specified, all terms used in this application are commonly understood by those skilled in the art.

[0403] The embodiments described in this application are merely illustrative and do not limit the scope of protection of this application; those skilled in the art may make various other substitutions, modifications and improvements within the scope of this application, so this application is not limited to the above embodiments, but is limited only by the scope of the claims.

Claims

1. A compound of formula (I) or a pharma- ceutically acceptable salt, hydrate, solvate, isotopically labeled compound or stereoisomer thereof. 【Chemistry 1】 (Here, R １ is selected from hydrogen, fluorine, a cyano group, a methyl group, and a methoxy group; Cy Ａ is selected from the following groups: １） 【Chemistry 2】 or a bicyclic ring in which a benzene ring and a 5- to 6-membered saturated aliphatic heterocycle are condensed, 【Chemistry 3】 and a 5- to 6-membered saturated aliphatic heterocycle are condensed together, wherein Z is one, Z=N, Ry may be bonded to N, and Ro is oxo, F, an amino group, or an optionally substituted C １－３ alkyl groups, and the aliphatic heterocycle may form a condensed ring together with another 5- to 6-membered saturated aliphatic heterocycle containing a heteroatom N; R ｙ is H, C １－６ C substituted with an alkyl group, a hydroxyl group or a halogen １－６ Alkyl group, C ３－６ A cycloalkyl group, a 4- to 6-membered saturated aliphatic heterocyclic group containing nitrogen, a 5- to 6-membered saturated aliphatic heterocyclic group containing oxygen, or -C(=O)Rs, where Rs is a C group optionally substituted with a hydroxyl group, an amino group, or a nitrogen-containing aliphatic heterocyclic group. １－６ selected from alkyl groups, The optionally substituted substituents are fluorine, a hydroxy group, C １－６ C substituted with alkyl group, F １－６ Selected from alkyl groups; 2) unsubstituted or independently R １２ a phenyl group, a pyridyl group, a pyrimidinyl group, a pyrazolyl group, an imidazolyl group, a thiazolyl group, or an isothiazolyl group, which may be substituted by 1, 2 or 3 substituents selected from the group consisting of (a) Each R １２ R is not a fluorine, chlorine or hydrogen atom. Ｇ１ and OR Ｇ１ Selected from Or, (b) Cy Ａ is one R １２ R １２ is one selected from the following structures, where " 【Chemistry 4】 " represents attachment to another atom in the structure of formula (I) via this chemical bond, 【Chemistry 5】 Or, Cy Ａ is 2 or 3 R １２ Including one of R １２ is one selected from the above structures, and the remaining R １２ R is independently not fluorine, chlorine, or hydrogen. Ｇ１ , -OR Ｇ１ Selected from Where: R Ｇ２ is hydrogen, -OR Ｇ１ and -N(R Ｇ１ ) ２ Selected from Each R Ｇ１ are independently selected from the following groups: 1) Hydrogen, methyl group, ethyl group, isopropyl group, cyclopropyl group, 3-oxetanyl group, and 3-methyl-3-azetidinyl group; 2) Two Rs bonded to the same atom Ｇ１ The groups are each a C group together with the atoms that are simultaneously bonded to them. ３－６ Forming a monocyclic hydrocarbon ring or a 3- to 6-membered monocyclic aliphatic heterocycle, 3) Two R's each bonded to two different ring-forming atoms of the same monocyclic ring. Ｇ１ The R groups are bonded to each other and form a cyclic structure together with some of the ring-forming atoms of the monocyclic ring, and two R Ｇ１ Both bases are C ２ , C ３ Or C ４ forming an alkylene group of the formula: Cy Ｂ are independently R １３ a phenyl group, a pyridyl group, a pyrimidinyl group, or a pyrazolyl group, each of which may be substituted by 1, 2 or 3 substituents selected from R １３ is selected from the following groups: 1) Oxo group, halogen atom, cyano group, -C(=O)R ａ３ , -C(=O)NR ａ３ R ｂ３ , -OR ａ３ ; 2) unsubstituted or independently R ２３ C optionally substituted with 1, 2, 3 or 4 substituents selected from １－６ Alkyl group, C ３－６ Monocyclic cycloalkyl groups and 3- to 6-membered monocyclic aliphatic heterocyclic groups; 3) Cy Ｂ Two R's bonded to two adjacent ring-forming atoms in the aryl or heteroaryl group of １３ The substituents, together with the two ring-forming atoms, are unsubstituted or independently R ２３ C optionally substituted with 1, 2 or 3 substituents selected from ５ , C ６ , C ７ Form a monocyclic alicyclic hydrocarbon group or a 5-, 6-, or 7-membered monocyclic aliphatic heterocyclic group; R ａ３ and R ｂ３ are each independently selected from the following groups: 1) Hydrogen; 2) unsubstituted or independently R ２３ C optionally substituted with 1, 2 or 3 substituents selected from １－４ Alkyl group, C ３－６ A cycloalkyl group and a 3- to 6-membered aliphatic heterocyclic group; or R attached to the same nitrogen atom ａ３ and R ｂ３ is unsubstituted or independently R ２３ forming a 3- to 8-membered aliphatic heterocyclic group optionally substituted by 1, 2 or 3 substituents selected from R ２３ is selected from the following groups: 1) an oxo group, a halogen atom, a cyano group, a carboxyl group, an amino group, or a hydroxy group; 2) Unsubstituted C １－６ an alkyl group, a 3- to 7-membered aliphatic heterocyclic group.

2. Cy Ａ is unsubstituted or independently R １２ a phenyl group, a pyridyl group, a pyrimidinyl group, a pyrazolyl group, an imidazolyl group, a thiazolyl group or an isothiazolyl group, which may be substituted by 1, 2 or 3 substituents selected from 1) Each R １２ R is not a fluorine, chlorine or hydrogen atom. Ｇ１ and OR Ｇ１ Selected from Or, 2) Cy Ａ is one R １２ R １２ is one selected from the following structures: 【Chemistry 6】 Or, Cy Ａ is 2 or 3 R １２ Including one of R １２ is one selected from the above structures, and the remaining R １２ R is independently not fluorine, chlorine, or hydrogen. Ｇ１ , OR Ｇ１ Selected from Each R Ｇ１ are independently selected from the following groups: 1) Hydrogen, 2) Hydroxy group, C １－６ a methyl group, an ethyl group, an isopropyl group, a cyclopropyl group, a 3-oxetanyl group, and a 3-methyl-3-azetidinyl group, each optionally substituted by an alkoxy group or an amino group; Cy Ｂ is one selected from the following structures: 【Chemistry 7】 R ａ３ and R ｂ３ are independently hydrogen, C １－６ R bonded to two adjacent ring-forming atoms is selected from an alkyl group and a C3-6 cycloalkyl group. ａ３ and R ｂ３ form an unsubstituted 5- to 6-membered alicyclic hydrocarbon group or an unsubstituted 5- to 6-membered aliphatic heterocyclic group together with the two ring-forming atoms, 2. A compound according to claim 1 or a pharma- ceutically acceptable salt, hydrate, solvate, isotopically labeled product or stereoisomer thereof.

3. A compound of formula (I) or a pharma- ceutically acceptable salt, hydrate, solvate, isotopically labeled compound or stereoisomer thereof. 【Chemistry 8】 (Here, R １ is selected from hydrogen, fluorine, a cyano group, a methyl group, and a methoxy group; Cy Ａ is selected from the following groups: １） 【Chemistry 9】 or a bicyclic ring in which a benzene ring and a 5- to 6-membered saturated aliphatic heterocycle are condensed, 【Chemistry 10】 and a 5- or 6-membered saturated aliphatic heterocycle are condensed together, in which Z is one ring, Z=N, Ry may be bonded to N, Ro is oxo, F, an amino group, or an optionally substituted C １－３ alkyl groups, and the aliphatic heterocycle may form a condensed ring together with another 5- to 6-membered saturated aliphatic heterocycle containing a heteroatom N; 2) unsubstituted or independently R １２ a phenyl group, a pyridyl group, a pyrimidinyl group, a pyrazolyl group, an imidazolyl group, a thiazolyl group, or an isothiazolyl group, which may be substituted by 1, 2 or 3 substituents selected from the group consisting of a) Cy Ａ is one R １２ When R １２ is one selected from the following structures: 【Chemistry 11】 Here, R ｘ is -OH, C １－６ Alkyl group, C １－６ Alkoxy group, -NH ２ , C １－６ Alkylamino groups, 【Chemistry 12】 Selected from b) Cy Ａ One or more R １２ If it contains, the remaining R １２ are independently fluorine, C １－６ Alkyl group, C １－６ Alkoxy group, C １－６ alkylaminomethyl groups, Cy Ｂ is one selected from the following structures: 【Chemistry 13】 R ａ３ and R ｂ３ are independently hydrogen, optionally substituted C １－６ Alkyl group and C ３－６ cycloalkyl groups, or R ａ３ and R ｂ３ form an optionally substituted 4- to 6-membered saturated aliphatic heterocyclic group together with the N atom bonded thereto, and the optionally substituted substituents are fluorine, a hydroxyl group, C １－６ C substituted with alkyl group, F １－６ selected from alkyl groups, R ｙ is H, C １－６ C substituted with an alkyl group, a hydroxyl group or a halogen １－６ Alkyl group, C ３－６ A cycloalkyl group, a 4- to 6-membered saturated aliphatic heterocyclic group containing nitrogen, a 5- to 6-membered saturated aliphatic heterocyclic group containing oxygen, or -C(=O)Rs, where Rs is a C group optionally substituted with a hydroxyl group, an amino group, or a nitrogen-containing aliphatic heterocyclic group. １－６ is selected from alkyl groups.

4. A compound of formula (I) or a pharma- ceutically acceptable salt, hydrate, solvate, isotopically labeled compound or stereoisomer thereof. 【Chemistry 14】 (Here, R １ is selected from hydrogen, fluorine, a cyano group, a methyl group, and a methoxy group; Cy Ａ is a phenyl group, a pyridyl group, a pyrimidinyl group, a thiazolyl group, or 【Chemistry 15】 or a bicyclic ring in which a benzene ring and a 5- to 6-membered saturated aliphatic heterocycle are condensed, 【Chemistry 16】 wherein Z is one, Z=N, and Ry may be bonded to Ry; Ry is oxo, F, an amino group, or an optionally substituted C １－３ alkyl groups, and the saturated aliphatic heterocycle may form a condensed ring together with another 5- to 6-membered saturated aliphatic heterocycle containing a heteroatom N; R ｙ is H, C １－６ C substituted with an alkyl group, a hydroxyl group or a halogen １－６ Alkyl group, C ３－６ A cycloalkyl group, a 4- to 6-membered saturated aliphatic heterocyclic group containing nitrogen, a 5- to 6-membered saturated aliphatic heterocyclic group containing oxygen, or -C(=O)Rs, where Rs is a C group optionally substituted with a hydroxyl group, an amino group, or a nitrogen-containing aliphatic heterocyclic group. １－６ selected from alkyl groups, Cy Ａ is selected from the group consisting of a phenyl group, a pyridyl group, a pyrimidinyl group, and a thiazolyl group, R １２ teeth, 【Chemistry 17】 wherein Rz is selected from hydrogen, optionally substituted C １－６ Alkyl group, 4-6 membered aliphatic heterocycle containing oxygen, or -S(=O) ２ -C １－６ Rp is one or more, and is selected from hydrogen, optionally substituted C １－６ Rq is selected from the group consisting of a hydroxy group, an amino group, and an optionally substituted C １－３ an alkyl group, a bisspiro ring consisting of two 4- to 5-membered nitrogen- and / or oxygen-containing rings, and a 5- to 6-membered aliphatic heterocyclic group containing one or two heteroatoms selected from nitrogen and oxygen, the aliphatic heterocyclic group being selected from F, C １－３ may be substituted with an alkyl group, The optionally substituted substituents are fluorine, a hydroxy group, C １－６ C substituted with alkyl group, F １－６ selected from alkyl groups, Cy Ｂ is one selected from the following structures: 【Chemistry 18】 R ａ３ and R ｂ３ are independently hydrogen, C １－６ R bonded to two adjacent ring-forming atoms is selected from an alkyl group and a C3-6 cycloalkyl group. ａ３ and R ｂ３ forms an unsubstituted 5- to 6-membered alicyclic hydrocarbon group or an unsubstituted 5- to 6-membered aliphatic heterocyclic group together with the two ring-forming atoms.

5. Cy Ａ is selected from the group consisting of phenyl groups, and R １２ teeth, 【Chemistry 19】 wherein Rz is selected from hydrogen, optionally substituted C １－６ Alkyl group, 4-6 membered aliphatic heterocycle containing oxygen, or -S(=O) ２ -C １－６ Rp is one or more, and is selected from hydrogen, optionally substituted C １－６ Rq is selected from the group consisting of a hydroxy group, an amino group, and an optionally substituted C １－３ an alkyl group, a bisspiro ring consisting of two 4- to 5-membered nitrogen- and / or oxygen-containing rings, and a 5- to 6-membered aliphatic heterocyclic group containing one or two heteroatoms selected from nitrogen and oxygen, the aliphatic heterocyclic group being selected from F, C １－３ may be substituted with an alkyl group, The optionally substituted substituents are fluorine, a hydroxy group, C １－６ C substituted with alkyl group, F １－６ selected from alkyl groups, 5. The compound of claim 4 or a pharma- ceutically acceptable salt, hydrate, solvate, isotopically labeled product, or stereoisomer thereof.

6. A compound of formula (I) or a pharma- ceutically acceptable salt, hydrate, solvate, isotopically labeled compound or stereoisomer thereof. 【Chemistry 20】 (Here, R １ is selected from hydrogen, fluorine, a cyano group, a methyl group, and a methoxy group; The Cy Ａ is selected from the following structures: 【Chemistry 21】 Here, W １ is CH ２ or oxygen, R Ｔ is selected from hydrogen or a methyl group, R Ｖ is selected from fluorine and a methyl group, R Ｖ is 0, 1 or 2, Cy Ｂ is one selected from the following structures: 【Chemical 22】 R ａ３ and R ｂ３ are independently hydrogen, C １－６ R bonded to two adjacent ring-forming atoms is selected from an alkyl group and a C3-6 cycloalkyl group. ａ３ and R ｂ３ forms an unsubstituted 5- to 6-membered alicyclic hydrocarbon group or an unsubstituted 5- to 6-membered aliphatic heterocyclic group together with the two ring-forming atoms.

7. Cy Ｂ is selected from a phenyl group, the phenyl group being H, F, —CN or an optionally substituted C １－３ Alkyl group, optionally substituted C １－３ Alkoxy group, optionally substituted C ３－６ Cycloalkyloxy group and -C(=O)NR ａ３ R ｂ３ R ａ３ and R ｂ３ are independently hydrogen, C １－６ Alkyl groups and optionally substituted C ３－６ cycloalkyl groups or R ａ３ and R ｂ３ form an optionally substituted 4- to 5-membered aliphatic heterocyclic group together with the N atom, 7. A compound according to any one of claims 1 to 6, or a pharma- ceutically acceptable salt, hydrate, solvate, isotopically labeled product, or stereoisomer thereof.

8. The Cy Ｂ teeth, 【Chemistry 23】 8. The compound according to any one of claims 1 to 7, or a pharma- ceutically acceptable salt, hydrate, solvate, isotopically labeled product, or stereoisomer thereof, selected from:

9. A compound of formula (I) or a pharma- ceutically acceptable salt, hydrate, solvate, isotopically labeled compound or stereoisomer thereof. 【Chemistry 24】 (Here, R １ is H, Cy Ａ is selected from the following groups: 1) unsubstituted or independently R １２ a phenyl group, a pyridyl group, or a pyrimidinyl group, which may be substituted by 1, 2, or 3 substituents selected from the following: each R12 is independently an R other than fluorine, chlorine, or hydrogen; Ｇ１ , OR Ｇ１ Selected from 2) Independently R １２ a phenyl group, a pyridyl group, or a pyrimidinyl group, each of which may be substituted by 1, 2 or 3 substituents selected from the following; 【Chemistry 25】 Selected from Other R １２ R is independently not fluorine, chlorine, or hydrogen. Ｇ１ , OR Ｇ１ Selected from 3) the following structure: 【Chemistry 26】 and the phenyl and pyridyl groups therein are unsubstituted or independently R １２ may be substituted with one or two substituents selected from Cy Ｂ teeth, 【Chemical 27】 Selected from Here, R ａ３ is selected from a methyl group, an ethyl group, a difluoromethyl group, a trifluoromethyl group, an isopropyl group, and a cyclopropyl group, preferably a methyl group, an ethyl group; E １ is -CH ２ Selected from - R Ｇ１ are independently selected from hydrogen, oxo, methyl, ethyl, isopropyl, cyclopropyl, 3-oxetanyl, and 3-methyl-3-azetidinyl; R １３ is hydrogen, fluorine, a cyano group, or -C(=O)-N(R Ｇ３ ) ２ and preferably selected from hydrogen and a cyano group; Each R Ｇ３ are independently selected from the following groups: 1) Hydrogen, a methyl group, an ethyl group, an isopropyl group, a cyclopropyl group, an oxetanyl group, an oxacyclopentyl group, an azetidinyl group, or an azacyclopentyl group; 2) Two Rs bonded to the same atom Ｇ３ The groups are bonded to one C together with the atoms bonded to them. ３－６ Forming a monocyclic hydrocarbon ring or a 3- to 6-membered monocyclic aliphatic heterocycle, 3) Two R's each bonded to two different ring-forming atoms of the same monocyclic ring. Ｇ３ The R groups are bonded to each other and form a cyclic structure together with some of the ring-forming atoms of the monocyclic ring, and two R Ｇ３ Both groups are C ２ , C ３ Or C ４ or a 2-, 3- or 4-membered oxaalkylene group, or a 2-, 3- or 4-membered azaalkylene group, And R Ｇ３ If is not hydrogen, R Ｇ３ is unsubstituted or is independently substituted with one, two or three substituents selected from oxo, fluorine, hydroxy, methoxy, amino, methylamino, dimethylamino, methyl, ethyl or cyano.

10. Cy Ａ is a phenyl group and R １２ When is a heterocyclic group, R １２ is attached to the para or meta position of the phenyl group; 10. A compound according to any one of claims 1 to 9, or a pharma- ceutically acceptable salt, hydrate, solvate, isotopically labeled product, or stereoisomer thereof.

11. A compound selected from the following structures: or a pharma- ceutically acceptable salt, hydrate, solvate, isotopically labeled product, or stereoisomer thereof. 【Chemistry 28】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】

12. 12. A pharmaceutical composition comprising a compound according to any one of claims 1 to 11 or a pharma- ceutically acceptable salt, hydrate, solvate, isotopically labeled or stereoisomer thereof, and a pharma- ceutically acceptable carrier.

13. Use of a compound described in any one of claims 1 to 11 or a pharma- ceutically acceptable salt, hydrate, solvate, isotopically labeled substance or stereoisomer thereof, or a pharmaceutical composition described in claim 12, in the manufacture of a medicament for preventing or treating an HPK1-mediated disease.

14. Use of a compound according to any one of claims 1 to 11 or a pharma- ceutically acceptable salt, hydrate, solvate, isotopically labeled product or stereoisomer thereof, or a pharmaceutical composition according to claim 12, in the manufacture of a pharmaceutical for preventing or treating a disease selected from benign or malignant tumors, myeloproliferative disorders and viral diseases.

15. 15. The use according to claim 14, wherein the benign or malignant tumor is selected from leukemia, lymphoma, multiple myeloma, lung cancer, hepatocellular carcinoma, bile duct carcinoma, gallbladder carcinoma, gastric cancer, colorectal cancer, small intestinal leiomyosarcoma, breast cancer, ovarian cancer, cervical cancer, endometrial cancer, vaginal cancer, malignant teratoma, pancreatic adenocarcinoma, pancreatic ductal adenocarcinoma, nasopharyngeal carcinoma, oral cancer, laryngeal cancer, esophageal squamous cell carcinoma, thyroid cancer, renal cancer, bladder cancer, malignant brain tumor, rhabdomyosarcoma, osteosarcoma, chondrosarcoma, osteofibrosarcoma, malignant thymoma, malignant peripheral nerve sheath tumor, prostate cancer, testicular cancer, penile cancer, and benign and malignant tumors of the skin.

16. 15. The use according to claim 14, wherein the virus is selected from the group consisting of hepatitis virus, human immunodeficiency virus, human papilloma virus, herpes simplex virus, measles virus, norovirus, bocavirus, coxsackievirus, ebola virus, enteric virus, lymphocytic meningitis virus, influenza virus, SARS virus and novel coronavirus.

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