Pyrazolopyridazinone compounds, their pharmaceutical compositions and uses thereof

Abstract

The present application provides a compound as shown in formula (I), a pharmaceutical composition containing the compound, and its use. The compound of formula (I) of the present application has a good effect of inhibiting HPK1 activity. #imgabs0#

Description

Technical Field

[0001] The present application relates to a pyrazolopyridazinone compound, specifically a pyrazolopyridazinone derivative with HPK1 inhibitory activity. Background Art

[0002] Hematopoietic progenitor kinase 1 (HPK1) is a serine / threonine kinase originally cloned from hematopoietic progenitor cells (Hu, MC et al., Genes Dev. 1996; 10:2251-2264; Keifer, F. et al., The EMBO Journal 1996; 15:7013-7025). It belongs to the mitogen-activated protein kinase (MAP4K) family. HPK1 is concentrated in lymphoid organs or tissues, such as the bone marrow, lymph nodes, and thymus, and is primarily expressed in immune cells (T cells, B cells, dendritic cells, macrophages, etc.) (Hu, MC et al., Genes Dev. 1996; 10:2251-2264). This has led to the widespread interest in the immunomodulatory effects of HPK1.

[0003] Studies have shown that HPK1 is a negative regulator of the T cell receptor (TCR) signaling pathway. TCR signaling activates HPK1, which binds to the 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 SLP-76 at Ser376, promoting its binding to the 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). The SLP-76 / 14-3-3 interaction downregulates ERK signaling and calcium ion flux, and triggers the ubiquitination of SLP-76 and degradation of the SLP-76 complex, blocking the TCR activation pathway and thereby inhibiting T cell function (Lasserre, R. et al., J. Cell Biol. 2011; 195: 839-853).

[0004] In vivo experiments, HPK1 knockout mice showed enhanced T cell function under antigen stimulation, producing more cytokines such as IL-2 and IFN-γ (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 shown that the negative regulation of HPK1 on immune cells depends on its kinase activity. Compared with wild-type mice, CD8 + Enhanced T cell function can clear chronic lymphocytic meningitis virus faster and better inhibit tumor growth (Hernandez, S. et al., Cell Reports 2018; 25: 80-94). In the Lewis lung cancer (LLC) model, HPK1 was transfected - / - Mice expressing HPK1 T cells showed stronger anti-tumor immune responses than wild-type mice (Sawasdikosol, S. et al., Immunol. Res. 2012; 54: 262-265). Similar studies revealed that HPK1 plays a role in 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; S. et al., PLos One, 2010; 5: e12468), dendritic cells (Alzabin, S. et al., J. Immunol. 2009; 182: 6187-6194), NK cells and Treg cells also originate from their kinase activity (Liu, J. et al., PLos One, 2019; 14: e0212670).

[0005] Clinical studies have found that compared with healthy controls, HPK1 levels in tissues of 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) are significantly downregulated, indicating that HPK1 downregulation helps enhance autoimmune responses. On the other hand, upregulation of HPK1 levels has been observed in a variety of cancers, such as 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, HS et al., Mol. Cell Biol. 2006; 26: 1297-1306).

[0006] Therefore, HPK1 is a potential target for treating tumors and viral diseases. The development of small molecule HPK1 kinase inhibitors holds significant clinical promise. Although several patent applications for HPK1 small molecule inhibitors have been published, such as WO2018049191, WO2018049200, WO2018102366, WO2018183964, WO2019090198, WO2019206049, WO2019238067, and WO2020092528, there are currently no marketed drugs targeting HPK1. Therefore, the development of novel small molecule HPK1 inhibitors with promising activity is urgently needed. Summary of the Invention

[0007] A main purpose of the present application is to provide a compound of formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, active metabolite, polymorph, isotope label, isomer or prodrug thereof,

[0008]

[0009] Among them, R 1 Selected from:

[0010] 1) Hydrogen, halogen atoms, cyano group, -C(=O)NR a R b 、-ORa and -NR a R b ;

[0011] 2) unsubstituted or optionally substituted by 1, 2, 3 or 4 independently selected R 11 Substituents substituted C 1-6 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-8 Cycloalkyl and 3-8 membered alicyclic groups;

[0012] R a and R b Each independently selected from:

[0013] 1) Hydrogen;

[0014] 2) is unsubstituted or optionally substituted by 1, 2 or 3 independently selected R 11 Substituents substituted C 1-6 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Monocyclic cycloalkyl and 3-6 membered monocyclic alicyclic heterocyclic groups;

[0015] or,

[0016] R attached to the same nitrogen atom a and R b Together with the nitrogen atom to which they are attached, they form an unsubstituted or optionally substituted 1, 2 or 3 groups independently selected from R 11 A 3- to 6-membered monocyclic aliphatic heterocyclic group substituted with a substituent;

[0017] R 11 Selected from fluorine, chlorine, C 1-3 Alkyl and hydroxyl groups;

[0018] Cy A is unsubstituted or optionally substituted with 1, 2, 3, 4 or 5 independently selected R 12 A 6- to 10-membered aryl or 5- to 10-membered heteroaryl group substituted with a substituent;

[0019] R 12 Selected from:

[0020] 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, -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 , nitro, -PR c2 R f2 、-P(=O)R c2 R f2 and phosphonic acid groups;

[0021] 2) unsubstituted or optionally substituted by 1, 2, 3, 4, 5 or 6 independently selected from R 22 Substituents substituted C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 6-10 membered aryl, 5-10 membered heteroaryl, C 3-12 Cycloalkyl and 3-12 membered aliphatic heterocyclic groups;

[0022] 3) Respectively with Cy A The two adjacent ring atoms of the aryl or heteroaryl are connected to each other. 12 The substituents, together with the two ring atoms to which they are attached, form a ring which is unsubstituted or optionally substituted with 1, 2, 3, 4, 5 or 6 groups independently selected from R 22 Substituents substituted C 5-12 Alicyclic hydrocarbon group or 5-12 membered alicyclic heterocyclic group;

[0023] R a2 、R b2 and R e2 Each independently selected from:

[0024] 1) Hydrogen;

[0025] 2) unsubstituted or optionally substituted by 1, 2, 3, 4, 5 or 6 independently selected from R 22 Substituents substituted C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, phenyl, 5-6 membered heteroaryl, C 3-12 Cycloalkyl and 3-12 membered aliphatic heterocyclic groups;

[0026] or,

[0027] R attached to the same nitrogen atom a2 and R b2 Together with the nitrogen atom to which they are attached, they form an unsubstituted or optionally substituted 1, 2, 3, 4 or 5 groups independently selected from R 22 A 3- to 12-membered aliphatic heterocyclic group substituted with a substituent;

[0028] R c2 and R f2 Each independently selected from: unsubstituted or optionally substituted with 1, 2, 3, 4 or 5 independently selected from R 22 Substituents substituted C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, phenyl, 5-6 membered heteroaryl, C 3-12 Cycloalkyl and 3-12 membered aliphatic heterocyclic groups;

[0029] or,

[0030] R attached to the same phosphorus atom c2 and R f2 Together with the phosphorus atom to which they are attached, they form a substituted or optionally substituted 1, 2, 3, 4 or 5 groups independently selected from R 22 A 3- to 12-membered aliphatic heterocyclic group substituted with a substituent;

[0031] R d2 Selected from:

[0032] 1) Hydrogen, cyano, nitro, -S(=O)2R G ;

[0033] 2) are unsubstituted or each optionally substituted by 1, 2, 3, 4 or 5 independently selected R 22 Substituents substituted C 1-4 Alkyl, C 2-4Alkenyl, C 2-4 Alkynyl, phenyl, 5-6 membered heteroaryl, C 3-12 Cycloalkyl and 3-12 membered aliphatic heterocyclic groups;

[0034] R 22 Selected from:

[0035] 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, -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, -PR c4 R f4 、-P(=O)R c4 R f4 , phosphonic acid group and imine group (=NR d4 );

[0036] 2) unsubstituted or optionally substituted by 1, 2, 3, 4 or 5 independently selected R 32 Substituents substituted C 1-6 Alkyl, C 1-6 Alkylene, C 2-6 Alkenyl, C 2-6 Alkynyl, phenyl, 5-6 membered heteroaryl, C 3-10 Cycloalkyl and 3-10 membered alicyclic groups;

[0037] R a4 、R b4 and R e4 Each independently selected from:

[0038] 1) Hydrogen;

[0039] 2) unsubstituted or optionally substituted by 1, 2, 3, 4 or 5 independently selected R 32 Substituents substituted C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, phenyl, 5-6 membered heteroaryl, C 3-10 Cycloalkyl and 3-10 membered alicyclic groups;

[0040] or,

[0041] R attached to the same nitrogen atom a4 and R b4 Together with the nitrogen atom to which they are attached, they form an unsubstituted or optionally substituted 1, 2, 3, 4 or 5 groups independently selected from R 32 A 3- to 10-membered aliphatic heterocyclic group substituted with a substituent;

[0042] R c4 and R f4 Each independently selected from: unsubstituted or optionally substituted with 1, 2, 3, 4 or 5 independently selected from R 32 Substituents substituted C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, phenyl, 5-6 membered heteroaryl, C 3-10 Cycloalkyl and 3-10 membered alicyclic groups;

[0043] or,

[0044] R attached to the same phosphorus atom c4 and R f4 Together with the phosphorus atom to which they are attached, they form a substituted or optionally substituted 1, 2, 3, 4 or 5 groups independently selected from R 32 A 3- to 10-membered aliphatic heterocyclic group substituted with a substituent;

[0045] R d4 Selected from:

[0046] 1) Hydrogen, cyano, nitro and -S(=O)2R G ;

[0047] 2) unsubstituted or optionally substituted by 1, 2, 3, 4 or 5 independently selected R 32 Substituents substituted C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, phenyl, 5-6 membered heteroaryl, C 3-10 Cycloalkyl and 3-10 membered alicyclic groups;

[0048] R 32 Selected from:

[0049] 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, -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 Rb6 , nitro, -PR c6 R f6 、-P(=O)R c6 R f6 , phosphonic acid group and imine group (=NR d6 );

[0050] 2) unsubstituted or optionally substituted by 1, 2, 3 or 4 independently selected R G Substituents substituted C 1-4 Alkyl, C 1-4 Alkylene, C 2-4 Alkenyl, C 2-4 Alkynyl, phenyl, 5-6 membered heteroaryl, C 3-8 Cycloalkyl and 3-8 membered alicyclic groups;

[0051] R a6 、R b6 and R e6 Each independently selected from:

[0052] 1) Hydrogen;

[0053] 2) unsubstituted or optionally substituted by 1, 2, 3 or 4 independently selected R G Substituents substituted C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, phenyl, 5-6 membered heteroaryl, C 3-8 Cycloalkyl and 3-8 membered alicyclic groups;

[0054] or,

[0055] R attached to the same nitrogen atom a6 and R b6 Together with the nitrogen atom to which they are attached, they form a substituted or optionally substituted 1, 2, 3 or 4 groups independently selected from R G A 3- to 8-membered aliphatic heterocyclic group substituted with a substituent;

[0056] R c6 and R f6 Each independently selected from: unsubstituted or optionally substituted with 1, 2, 3 or 4 independently selected from R G Substituents substituted C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, phenyl, 5-6 membered heteroaryl, C 3-8 Cycloalkyl and 3-8 membered alicyclic groups;

[0057] or,

[0058] R attached to the same phosphorus atom c6 and R f6Together with the phosphorus atom to which they are attached, they form a group which is unsubstituted or optionally substituted with 1, 2, 3 or 4 groups independently selected from R G A 3- to 8-membered aliphatic heterocyclic group substituted with a substituent;

[0059] R d6 Selected from:

[0060] 1) Hydrogen, cyano, nitro and -S(=O)2R G ;

[0061] 2) unsubstituted or optionally substituted by 1, 2, 3 or 4 independently selected R G Substituents substituted C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, phenyl, 5-6 membered heteroaryl, C 3-8 Cycloalkyl, 3-8 membered aliphatic heterocyclic group;

[0062] Cy B is unsubstituted or optionally substituted with 1, 2, 3, 4 or 5 independently selected R 13 A 6- to 10-membered aryl or 5- to 10-membered heteroaryl group substituted with a substituent;

[0063] R 13 Selected from:

[0064] 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, -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 a3C(=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, -PR c3 R f3 、-P(=O)R c3 R f3 and phosphonic acid groups;

[0065] 2) unsubstituted or optionally substituted by 1, 2, 3, 4, 5 or 6 independently selected from R 23 Substituents substituted C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 6-10 membered aryl, 5-10 membered heteroaryl, C 3-12 Cycloalkyl and 3-12 membered aliphatic heterocyclic groups;

[0066] 3) respectively with Cy B The two adjacent ring atoms of the aryl or heteroaryl are connected to each other. 13 The substituents, together with the two ring atoms to which they are attached, form a ring which is unsubstituted or optionally substituted with 1, 2, 3, 4 or 5 groups independently selected from R 23 Substituents substituted C 5-12 Alicyclic hydrocarbon group or 5-12 membered alicyclic heterocyclic group;

[0067] R a3 、R b3 and R e3 Each independently selected from:

[0068] 1) Hydrogen;

[0069] 2) unsubstituted or optionally substituted by 1, 2, 3, 4, 5 or 6 independently selected from R 23 Substituents substituted C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, phenyl, 5-6 membered heteroaryl, C 3-12 Cycloalkyl and 3-12 membered aliphatic heterocyclic groups;

[0070] or,

[0071] R attached to the same nitrogen atom a3 and Rb3 Together with the nitrogen atom to which they are attached, they form a substituted or optionally substituted 1, 2, 3, 4 or 5 groups independently selected from R 23 A 3- to 12-membered aliphatic heterocyclic group substituted with a substituent;

[0072] R c3 and R f3 Each independently selected from: unsubstituted or optionally substituted with 1, 2, 3, 4 or 5 independently selected from R 23 Substituents substituted C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, phenyl, 5-6 membered heteroaryl, C 3-12 Cycloalkyl and 3-12 membered aliphatic heterocyclic groups;

[0073] or,

[0074] R attached to the same phosphorus atom c3 and R f3 Together with the phosphorus atom to which they are attached, they form a substituted or optionally substituted 1, 2, 3, 4 or 5 groups independently selected from R 23 A 3- to 12-membered aliphatic heterocyclic group substituted with a substituent;

[0075] R d3 Selected from:

[0076] 1) Hydrogen, cyano, nitro, S(=O)2R G ;

[0077] 2) are unsubstituted or each optionally substituted by 1, 2, 3, 4 or 5 independently selected R 23 Substituents substituted C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, phenyl, 5-6 membered heteroaryl, C 3-12 Cycloalkyl and 3-12 membered aliphatic heterocyclic groups;

[0078] R 23 Selected from:

[0079] 1) Oxo group, halogen atom, cyano group, -C(=O)R a5 、-C(=O)OR a5 、-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 a5R b5 、-SR a5 、-S(=O)R c5 、-S(=O)2R c5 , sulfonic acid, -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, -PR c5 R f5 、-P(=O)R c5 R f5 , phosphonic acid group and imine group (=NR d5 );

[0080] 2) unsubstituted or optionally substituted by 1, 2, 3, 4 or 5 independently selected R 33 Substituents substituted C 1-6 Alkyl, C 1-6 Alkylene, C 2-6 Alkenyl, C 2-6 Alkynyl, phenyl, 5-6 membered heteroaryl, C 3-10 Cycloalkyl and 3-10 membered alicyclic groups;

[0081] R a5 、R b5 and R e5 Each independently selected from:

[0082] 1) Hydrogen;

[0083] 2) unsubstituted or optionally substituted by 1, 2, 3, 4 or 5 independently selected R 33 Substituents substituted C 1-4 Alkyl, C 2-4 Alkenyl, C2-4 Alkynyl, phenyl, 5-6 membered heteroaryl, C 3-10 Cycloalkyl and 3-10 membered alicyclic groups;

[0084] or,

[0085] R attached to the same nitrogen atom a5 and R b5 Together with the nitrogen atom to which they are attached, they form an unsubstituted or optionally substituted 1, 2, 3, 4 or 5 groups independently selected from R 33 A 3- to 10-membered aliphatic heterocyclic group substituted with a substituent;

[0086] R c5 and R f5 Each independently selected from: unsubstituted or optionally substituted with 1, 2, 3, 4 or 5 independently selected from R 33 Substituents substituted C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, phenyl, 5-6 membered heteroaryl, C 3-10 Cycloalkyl and 3-10 membered alicyclic groups;

[0087] or,

[0088] R attached to the same phosphorus atom c5 and R f5 Together with the phosphorus atom to which they are attached, they form a substituted or optionally substituted 1, 2, 3, 4 or 5 groups independently selected from R 33 A 3- to 10-membered aliphatic heterocyclic group substituted with a substituent;

[0089] R d5 Selected from:

[0090] 1) Hydrogen, cyano, nitro and -S(=O)2R G ;

[0091] 2) unsubstituted or optionally substituted by 1, 2, 3, 4 or 5 independently selected R 33 Substituents substituted C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, phenyl, 5-6 membered heteroaryl, C 3-10 Cycloalkyl and 3-10 membered alicyclic groups;

[0092] R 33 Selected from:

[0093] 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, -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, -PR c7 R f7 、-P(=O)R c7 R f7 , phosphonic acid group and imine group (=NR d7 );

[0094] 2) unsubstituted or optionally substituted by 1, 2, 3 or 4 independently selected R G Substituents substituted C 1-4 Alkyl, C 1-4 Alkylene, C 2-4 Alkenyl, C 2-4 Alkynyl, phenyl, 5-6 membered heteroaryl, C 3-8 Cycloalkyl and 3-8 membered alicyclic groups;

[0095] R a7 、R b7 and R e7 Each independently selected from:

[0096] 1) Hydrogen;

[0097] 2) unsubstituted or optionally substituted by 1, 2, 3 or 4 independently selected R G Substituents substituted C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, phenyl, 5-6 membered heteroaryl, C 3-8 Cycloalkyl and 3-8 membered alicyclic groups;

[0098] or,

[0099] R attached to the same nitrogen atom a7 and R b7 Together with the nitrogen atom to which they are attached, they form a substituted or optionally substituted 1, 2, 3 or 4 groups independently selected from R G A 3- to 8-membered aliphatic heterocyclic group substituted with a substituent;

[0100] R c7 and R f7 Each independently selected from: unsubstituted or optionally substituted with 1, 2, 3 or 4 independently selected from R G Substituents substituted C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, phenyl, 5-6 membered heteroaryl, C 3-8 Cycloalkyl and 3-8 membered alicyclic groups;

[0101] or,

[0102] Any R attached to the same phosphorus atom c7 and R f7 Together with the phosphorus atom to which it is attached, it forms an unsubstituted or optionally substituted 1, 2, 3 or 4 independently selected R G A 3- to 8-membered aliphatic heterocyclic group substituted with a substituent;

[0103] R d7 Selected from:

[0104] 1) Hydrogen, cyano, nitro and -S(=O)2R G ;

[0105] 2) unsubstituted or optionally substituted by 1, 2, 3 or 4 independently selected R G Substituents substituted C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, phenyl, 5-6 membered heteroaryl, C 3-8 Cycloalkyl and 3-8 membered alicyclic groups;

[0106] R G Selected from:

[0107] 1) Halogen atoms, oxo groups, cyano groups, carboxyl groups, hydroxyl groups, C 1-4 Alkoxy, amino, C 1-4 Alkylamino, nitro, C 1-4 Alkylthio, sulfonic acid, C 1-4 Alkyl sulfoxide, C 1-4 Alkylsulfone, C 1-4 Alkylaminosulfinyl and C 1-4 Alkylaminosulfonyl;

[0108] 2) unsubstituted or optionally substituted by 1, 2, 3 or 4 independently selected from oxo, halogen atoms, hydroxyl, hydroxymethyl, carboxyl, cyano, C 1-3 Alkoxy, amino, C 1-4 Alkylamino, nitro and sulfonic acid group substituted C 1-4 Alkyl, C 1-4 Alkylene, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl and 3- to 8-membered alicyclic groups.

[0109] According to some embodiments, in formula (I), R 1 is selected from hydrogen, fluorine, cyano, methyl and methoxy.

[0110] According to some embodiments, in formula (I), Cy A is unsubstituted or optionally substituted by 1, 2 or 3 independently selected from R 12 substituted phenyl, pyridyl, pyrimidinyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl or substituted by The benzene ring represented by is fused with a 5-7 membered saturated aliphatic heterocyclic ring, wherein Z is 1-3 heteroatoms selected from nitrogen and oxygen; when Z=N, N is optionally connected to an Ry group, Ro is selected from oxo, F, amino, C1-3 alkyl (which is optionally substituted by F, hydroxyl, amino, C1-3 alkoxy), and the aliphatic heterocyclic ring can further form a 5-6 membered saturated aliphatic heterocyclic ring containing a N heteroatom, wherein 1) when Cy A Contains 1 R 12 , the R 12 Select one of the following structures:

[0111]

[0112] Among them, R x Selected from -OH, C 1-6 Alkyl (such as methyl), C1-6 alkoxy (such as methoxy), -NH2, C 1-6 Alkylamino (such as amino, dimethylamino),

[0113] 2) When Cy A Contains more than one R 12 When the rest R 12 Independently selected from: fluorine, C 1-6 Alkyl (such as methyl), C 1-6 Alkoxy (such as methoxy), C 1-6 Alkylaminomethyl (e.g., dimethylaminomethyl, methylaminomethyl);

[0114] Cy B Select one of the following structures:

[0115]

[0116] R a3 and R b3 are independently selected from hydrogen, optionally substituted C 1-6 Alkyl and C 3-6 Cycloalkyl, or R a3 and R b3 Together with the connected N atom, it forms a 4-6 membered saturated aliphatic heterocyclic group, wherein the aliphatic heterocyclic group is optionally substituted; the substituent in the case of the optional substitution is selected from hydroxyl, C 1-6 Alkyl, C substituted by F 1-6 alkyl;

[0117] R y Selected from H, C1-6 alkyl (such as methyl), C1-6 alkyl substituted by hydroxyl, halogen (such as hydroxyethyl, hydroxypropyl, difluoroethyl), C3-6 cycloalkyl (such as cyclobutane, cyclobutane substituted by amino), nitrogen-containing 4-6 membered saturated alicyclic ring, oxygen-containing 5-6 membered saturated alicyclic ring, -C(=O)Rs, Rs is selected from C1-6 alkyl optionally substituted by hydroxyl, amino, 5-6 membered nitrogen-containing heteroalicyclic ring.

[0118] According to some embodiments, in formula (I), Cy A Selected from phenyl, pyridyl, pyrimidinyl, thiazolyl or A bicyclic ring fused with a benzene ring and a 5-7 membered saturated aliphatic heterocyclic ring, wherein Z is 1-3 and is selected from nitrogen and oxygen; when Z=N, it is optionally substituted by Ry, and Ro is selected from oxo, F, amino, C1-3 alkyl (which is optionally substituted by F, hydroxyl, amino, C1-3 alkoxy), and the aliphatic heterocyclic ring can further form a ring with another 5-6 membered saturated aliphatic heterocyclic ring containing a nitrogen heteroatom;

[0119] When Cy A Selected from Cy A When R is selected from phenyl, pyridyl, pyrimidinyl, thiazolyl, 12 Selected from wherein Rz is selected from hydrogen, C 1-6 Alkyl (substituted by cyano, methoxy), 4-6 membered oxygen-containing heterocyclic ring or -S(=O)2-C 1-6 Alkyl; Rp is one or more selected from hydrogen, C 1-6 Alkyl (optionally substituted by F, hydroxy, amino); Rq is selected from hydroxy, amino, C 1-3 Alkyl (optionally substituted by a 5-6 membered nitrogen-containing alicyclic group or a 5-6 membered nitrogen-containing heteroaryl), two 4-5 membered nitrogen- and / or oxygen-containing bispiro rings, a 5-6 membered alicyclic group containing one or two heteroatoms selected from nitrogen and oxygen, the alicyclic group optionally substituted by F, C 1-3 Alkyl substitution.

[0120] According to some embodiments, in formula (I), Cy A Selected from phenyl, R 12 Selected from wherein Rz is selected from hydrogen, C 1-6 Alkyl (substituted by cyano, methoxy), 4-6 membered oxygen-containing heterocyclic ring or -S(=O)2-C 1-6 Alkyl; Rp is one or more selected from hydrogen, C 1-6 Alkyl (optionally substituted by F, hydroxy, amino); Rq is selected from hydroxy, amino, C 1-3 Alkyl (optionally substituted by a 5-6 membered nitrogen-containing alicyclic group or a 5-6 membered nitrogen-containing heteroaryl), two 4-5 membered nitrogen- and / or oxygen-containing bispiro rings, a 5-6 membered alicyclic group containing one or two heteroatoms selected from nitrogen and oxygen, the alicyclic group optionally substituted by F, C 1-3 Alkyl substitution.

[0121] According to some embodiments, in formula (I), Cy A Selected from the following structures:

[0122] The Cy A Selected from the following structures:

[0123]

[0124] wherein W1 is selected from CH2 or oxygen;

[0125] R T is selected from hydrogen or methyl;

[0126] R V is selected from fluorine or methyl, R V The number of is 0, 1 or 2.

[0127] According to some embodiments, in formula (I), Cy B is selected from phenyl, said phenyl being optionally substituted by H, F, -CN, C 1-3Alkyl substituted (substituted by F, amino), C 1-3 Alkoxy substituted (substituted by F), C 3-6 Cycloalkyloxy substituted, -C(=O)NR a3 R b3 , R a3 and R b3 are independently selected from hydrogen, C 1-6 Alkyl and C 3-6 Cycloalkyl (optionally substituted by F-substituted C1-3 alkyl), or R a3 and R b3 Together with the nitrogen atom, it forms a 4-5 membered alicyclic group (substituted by hydroxyl group or C1-3 alkyl group).

[0128] According to some embodiments, in formula (I), the Cy B Selected from the following structures:

[0129]

[0130] According to some embodiments, in formula (I), when Cy A is phenyl, and R 12 When it is an aliphatic heterocyclic group, R 12 Connected to the para or meta position of the phenyl group.

[0131] According to some embodiments, the compound of formula (I) comprises 1 H is deuterated to obtain isotope labeling.

[0132] Some embodiments of the present application also provide a pharmaceutical composition comprising the above-mentioned compound of formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, active metabolite, polymorph, isotope-labeled substance, isomer or prodrug thereof, and a pharmaceutically acceptable carrier.

[0133] Some embodiments of the present application further provide a compound of formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, active metabolite, polymorph, isotope-labeled substance, isomer or prodrug thereof, or the pharmaceutical composition thereof, for preventing or treating diseases mediated by HPK1.

[0134] Some embodiments of the present application further provide a use of the compound of formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, active metabolite, polymorph, isotope-labeled substance, isomer or prodrug thereof, or the pharmaceutical composition thereof in the preparation of a medicament for preventing or treating a disease mediated by HPK1.

[0135] Some embodiments of the present application further provide a compound of formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, active metabolite, polymorph, isotope label, isomer or prodrug thereof, or the use of the above-mentioned pharmaceutical composition in treating or ameliorating diseases, wherein the diseases include one or more of benign or malignant tumors, myelodysplastic syndrome and viral-induced diseases.

[0136] Some embodiments of the present application further provide a method of inhibiting HPK1 activity, comprising administering to a subject a compound of formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, active metabolite, polymorph, isotope label, isomer or prodrug thereof.

[0137] Some embodiments of the present application further provide a method for 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 pharmaceutically acceptable salt, hydrate, solvate, active metabolite, polymorph, isotope-labeled form, isomer, or prodrug thereof, wherein the disease is an HPK1-mediated disease.

[0138] The compound of formula (I) in some embodiments of the present application has the effect of inhibiting the activity of HPK1.

[0139] In some embodiments of the present application, the disease includes one or more of benign or malignant tumors, myelodysplastic syndrome, and virus-induced diseases. DETAILED DESCRIPTION

[0140] Typical embodiments that embody the features and advantages of the present application will be described in detail in the following description. It should be understood that the present application can have various variations in different embodiments without departing from the scope of the present application, and the descriptions therein are essentially for illustrative purposes rather than for limiting the present application.

[0141] In some embodiments, R 1 Selected from:

[0142] 1) Hydrogen, halogen atoms, cyano, ethynyl, -OR a and -NR a R b ;

[0143] 2) is unsubstituted or optionally substituted by 1, 2, 3 or 4 independently selected from R 11 Substituents substituted C 1-4 Alkyl, C 3-5 Monocyclic cycloalkyl and 4- to 7-membered alicyclic heterocyclic groups.

[0144] In some embodiments, R 1 Selected from hydrogen, fluorine, chlorine, bromine, cyano, C1-4 Alkyl, C 3-4 Cycloalkyl, 3-4 membered alicyclic group and -OR a .

[0145] In some embodiments, R 1 is selected from hydrogen, fluorine, cyano, methyl, ethyl, 1-propyl, isopropyl, cyclopropyl, methoxy, ethoxy and cyclopropyloxy.

[0146] In some embodiments, R 1 For hydrogen.

[0147] In some embodiments, R a and R b are each independently selected from hydrogen, C 1-3 Alkyl, C 3-4 Cycloalkyl and 3-4 membered alicyclic heterocyclic groups;

[0148] Alternatively, R attached to the same nitrogen atom a and R b Together with the nitrogen atom to which they are connected, they form an unsubstituted 3- to 6-membered aliphatic heterocyclic group.

[0149] In some embodiments, R a and R b are each independently selected from hydrogen, methyl, ethyl and cyclopropyl.

[0150] In some embodiments, Cy A is unsubstituted or optionally substituted by 1, 2, 3 or 4 independently selected from R 12 substituted phenyl, naphthyl, or 5-, 6-, 7-, 8-, 9- or 10-membered heteroaryl, wherein the heteroaryl contains 1, 2 or 3 ring-forming heteroatoms selected from N, O and S.

[0151] In some embodiments, Cy A The aryl or heteroaryl group contains 1 R 12 The substituent, R 12 is a cyclic group, which is unsubstituted or optionally substituted by 1, 2 or 3 independently selected R 22 substituted 6- to 10-membered aryl, 5- to 10-membered heteroaryl, C 3-7 Cycloalkyl and 3-7 membered alicyclic heterocyclic groups, wherein the 3-7 membered alicyclic heterocyclic groups contain 1 or 2 ring-forming heteroatoms selected from N, O, and S;

[0152] or,

[0153] Cy A The aryl or heteroaryl group contains 2, 3 or 4 R 12 Substituents, one of which is R 12 is the above-mentioned cyclic group, and the rest R12 Independently selected from C 1-6 Alkyl, halogen atom, cyano, -OR a2 and -NR a2 R b2 .

[0154] In some embodiments, Cy A The aryl or heteroaryl group contains 1 R 12 The substituent, R 12 is a cyclic group, which is unsubstituted or optionally substituted by 1, 2 or 3 independently selected R 22 Substituents substituted phenyl, 5-6 membered heteroaryl, C 3-6 Cycloalkyl and 4, 5, 6, 7-membered alicyclic groups, wherein the 4, 5, 6, 7-membered alicyclic groups contain 1 or 2 ring-forming heteroatoms selected from N, O, and S;

[0155] or,

[0156] Cy A The aryl or heteroaryl group contains 2 or 3 R 12 Substituents, one of which is R 12 is the above-mentioned cyclic group, and the rest R 12 Independently selected from C 1-6 Alkyl, halogen atom, cyano, -OR a2 and -NR a2 R b2 .

[0157] In some embodiments, Cy A is optionally substituted by 1, 2, 3 or 4 independently selected from R 12 The substituent is a phenyl group or a 5- to 6-membered heteroaryl group.

[0158] In some embodiments, Cy A is optionally substituted by 1, 2, 3 or 4 independently selected from R 12 substituted phenyl or 5- to 6-membered heteroaryl, wherein the two R 12 The substituents, together with the two ring atoms to which they are attached, form a ring which is unsubstituted or optionally substituted with 1, 2, 3 or 4 groups independently selected from R 22 A C5, C6, C7 monocyclic alicyclic hydrocarbon group or a 5-, 6-, or 7-membered monocyclic alicyclic heterocyclic group substituted with a substituent.

[0159] In some embodiments, Cy A is optionally substituted by 1, 2 or 3 independently selected from R 12substituted phenyl, 5-membered or 6-membered heteroaryl, wherein the heteroaryl contains 1 or 2 heteroatoms selected from N and S, such as 1 N atom, 2 N atoms or 1 N atom and 1 S atom.

[0160] In some embodiments, Cy A is optionally substituted by 1, 2 or 3 independently selected from R 12 phenyl, pyridyl, pyrimidinyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl or isoxazolyl substituted by a substituent.

[0161] In some embodiments, Cy A is optionally substituted by 1, 2 or 3 independently selected from R 12 phenyl, pyridyl, pyrazolyl, imidazolyl or thiazolyl substituted by a substituent.

[0162] In some embodiments, Cy A The aryl or heteroaryl group contains 2, 3 or 4 R 12 A substituent wherein two R 12 The substituents together with the two ring atoms form an unsubstituted or optionally substituted group consisting of 1, 2 or 3 groups independently selected from R 22 Substituents substituted C 5-8 Alicyclic hydrocarbon group and 5-8 membered alicyclic heterocyclic group; the alicyclic heterocyclic group contains 1, 2 or 3 ring-forming heteroatoms selected from N, O, S, and each R 12 Independently selected from C 1-6 Alkyl, halogen atom, cyano, -OR a2 and -NR a2 R b2 .

[0163] In some embodiments, Cy A The aryl or heteroaryl group contains 2, 3 or 4 R 12 A substituent wherein two R 12 The substituents together with the two ring atoms form an unsubstituted or optionally substituted 1, 2 or 3 groups independently selected from oxo, 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 substituted 5, 6, 7-membered monocyclic heterocyclic group; the monocyclic heterocyclic group contains 1 or 2 ring heteroatoms selected from N, O, and each R 12 Independently selected from C 1-6 Alkyl, halogen atom, cyano, -OR a2 and -NR a2 R b2 ; R H Optionally selected from methyl, ethyl, isopropyl, cyclopropyl and 3-oxetanyl.

[0164] In some embodiments, each R 12 Independently selected from:

[0165] 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, -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;

[0166] 2) unsubstituted or optionally substituted by 1, 2, 3, 4, 5 or 6 independently selected from R 22 Substituents substituted C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 6-10 membered aryl, 5-10 membered heteroaryl, C 3-12 Cycloalkyl and 3-12 membered aliphatic heterocyclic groups;

[0167] 3) respectively with Cy A The two adjacent ring atoms of the aryl or heteroaryl are connected to each other. 12 The substituent and the two ring atoms together form an unsubstituted or each optionally substituted with 1, 2, 3, 4, 5 or 6 independently selected R 22 Substituents substituted C 5-12 Alicyclic hydrocarbon group or 5-12 membered alicyclic heterocyclic group.

[0168] In some embodiments, each R 12 Independently selected from:

[0169] 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;

[0170] 2) unsubstituted or optionally substituted by 1, 2, 3, 4, 5 or 6 independently selected from R 22 Substituents substituted C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 6-10 membered aryl, 5-10 membered heteroaryl, C 3-10 Cycloalkyl and 3-10 membered alicyclic groups;

[0171] 3) respectively with Cy A The two adjacent ring atoms of the aryl or heteroaryl are connected to each other. 12 The substituent and the two ring atoms together form an unsubstituted or each optionally substituted with 1, 2, 3, 4 or 5 independently selected R 22 Substituents substituted C 5-10 Alicyclic hydrocarbon group or 5-10 membered alicyclic heterocyclic group.

[0172] In some embodiments, each R 12 Independently selected from:

[0173] 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;

[0174] 2) unsubstituted or optionally substituted by 1, 2, 3 or 4 independently selected R 22 Substituents substituted C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 6-10 membered aryl, 5-10 membered heteroaryl, C 3-10 Cycloalkyl and 3-10 membered alicyclic groups;

[0175] 3) Respectively with Cy A The two adjacent ring atoms of the aryl or heteroaryl are connected to each other. 12 The substituents and the two ring atoms together form an unsubstituted or optionally substituted group with 1, 2 or 3 independently selected R 22 Substituents substituted C 4-8 Alicyclic hydrocarbon group or 4- to 8-membered alicyclic heterocyclic group.

[0176] In some embodiments, each R 12 Independently selected from:

[0177] 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)2NR a2 R b2 ;

[0178] 2) unsubstituted or optionally substituted by 1, 2, 3, 4, 5 or 6 independently selected from R 22 Substituents substituted C 1-6 Alkyl, 6-10 membered aryl, 5-10 membered heteroaryl, C 3-10 Cycloalkyl and 3-10 membered aliphatic heterocyclic groups;

[0179] 3) Respectively with Cy AThe two adjacent ring atoms of the aryl or heteroaryl are connected to each other. 12 The substituent and the two ring atoms together form an unsubstituted or each optionally substituted with 1, 2, 3 or 4 independently selected R 22 Substituents substituted C 4-8 In some embodiments, each R 12 Independently selected from:

[0180] 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 ;

[0181] 2) unsubstituted or optionally substituted by 1, 2, 3 or 4 independently selected R 22 Substituents substituted C 1-6 Alkyl, phenyl, 5-6 membered heteroaryl, C 3-10 Cycloalkyl and 3-10 membered aliphatic heterocyclic groups;

[0182] 3) Respectively with Cy A The two adjacent ring atoms of the aryl or heteroaryl are connected to each other. 12 The substituents and the two ring atoms together form an unsubstituted or optionally substituted group with 1, 2 or 3 independently selected R 22 A C5, C6, C7 monocyclic alicyclic hydrocarbon group or a 5-membered, 6-membered, 7-membered monocyclic alicyclic heterocyclic group substituted with a substituent.

[0183] In some embodiments, each R 12 Independently selected from:

[0184] 1) Halogen atoms, cyano groups, -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 ;

[0185] 2) unsubstituted or optionally substituted by 1, 2, 3 or 4 independently selected R 22 Substituents substituted C 1-6 Alkyl, phenyl, 5-6 membered heteroaryl, C 3-7 Cycloalkyl and 3-7 membered alicyclic groups.

[0186] In some embodiments, each R 12 Independently selected from:

[0187] 1) Halogen atoms, C 1-6 Alkyl, C 3-6 Cycloalkyl, 3-7 membered alicyclic 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 NR e2 S(=O)2NR a2 R b2 ;

[0188] 2) Respectively with CyA The two adjacent ring atoms of the aryl or heteroaryl are connected to each other. 12 The substituent and the two ring atoms together form an unsubstituted or each optionally substituted with 1, 2, 3 or 4 independently selected R 22 Substituents substituted C 4-8 Alicyclic hydrocarbon group, 4- to 8-membered alicyclic heterocyclic group.

[0189] In some embodiments, respectively with Cy A The two adjacent ring atoms of the aryl or heteroaryl are connected to each other. 12 The substituent and the two ring atoms together form an unsubstituted or each optionally substituted with 1, 2 or 3 independently selected R 22 C5, C6, C7 monocyclic alicyclic hydrocarbon groups and 5-membered, 6-membered, 7-membered monocyclic alicyclic heterocyclic groups substituted with a substituent.

[0190] In some embodiments, R 12 is unsubstituted or each optionally substituted by 1, 2, or 3 independently selected from R 22 substituted 4-membered, 5-membered, 6-membered, 7-membered monocyclic alicyclic group and 7-membered, 8-membered, 9-membered, 10-membered bicyclic alicyclic group.

[0191] In some embodiments, R 12 is a substituted or unsubstituted monocyclic heterocyclic group or a bicyclic heterocyclic group, wherein the bicyclic heterocyclic group may be a bridged ring group or a spirocyclic group; wherein the bicyclic heterocyclic group includes an A1 ring and an A2 ring, wherein the A1 ring is directly connected to the Cy A The A1 ring may be a 3- to 6-membered ring, and the total number of ring atoms of the bicyclic alicyclic heterocyclic group is not more than 10.

[0192] In some embodiments, R 12 The alicyclic group contains 1 or 2 ring-forming heteroatoms, and the ring-forming heteroatoms are selected from N, O, and S.

[0193] In some embodiments, each R 12 Independently selected from C 1-6 Alkyl, halogen atom, cyano, -OR a2 and -NR a2 R b2 .

[0194] In some embodiments, each R 12 Independently selected from:

[0195] 1) is unsubstituted or optionally substituted by 1, 2, 3 or 4 independently selected R 22 Substituents substituted C 1-6 Alkyl, C 1-3 Alkoxy, C3-8 Cycloalkyl and 3- to 8-membered alicyclic heterocyclic groups; wherein the 3- to 8-membered alicyclic heterocyclic groups are monocyclic alicyclic heterocyclic groups or bicyclic alicyclic heterocyclic groups, and the heteroatoms contained in the alicyclic heterocyclic groups may be N and / or O atoms; R 22 Selected from oxo, hydroxy, amino, cyano, C 1-3 Alkylamino, C 1-3 Alkoxy, 3-6 membered cycloalkyl and 3-6 membered monocyclic aliphatic heterocyclic group;

[0196] 2) Respectively with Cy A The two adjacent ring atoms of the aryl or heteroaryl are connected to each other. 12 The substituent and the two ring atoms together form an unsubstituted or each optionally substituted with 1, 2 or 3 independently selected R 22 a C5, C6, C7 monocyclic alicyclic hydrocarbon group or a 5-membered, 6-membered, 7-membered monocyclic alicyclic heterocyclic group substituted with a substituent; 22 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.

[0197] In some embodiments, Cy A Selected from:

[0198] 1) One of the following structures, in which the chemical bond terminal It indicates that it is connected to other atoms in the structure of formula (I) through this bond:

[0199]

[0200] 2) unsubstituted or optionally substituted by 1, 2 or 3 independently selected R 12 substituted phenyl, pyridyl, pyrimidinyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl or isoxazolyl, wherein:

[0201] (a) Each R 12 R is independently selected from fluorine, chlorine, G1 AND-OR G1 ;

[0202] or,

[0203] (b) Cy A Contains 1 R 12 , which is selected from one of the following structures, wherein the chemical bond end in the structural formula It indicates that it is connected to other atoms in the structure of formula (I) through this bond:

[0204]

[0205] or,

[0206] Cy A Contains 2 or 3 R's 12 , of which 1 R 12 Select one of the above structures, the rest R 12 are independently selected from: fluorine, chlorine, R other than hydrogen G1 、-OR G1 ;

[0207] in,

[0208] X is selected from CH and N;

[0209] Y is selected from -CH2-, NH and O;

[0210] E1 and E2 are independently selected from -CH2- and carbonyl, but E1 and E2 are not carbonyl at the same time;

[0211] R G2 Selected from hydrogen, -OR G1 and -N(R G1 )2;

[0212] Each R G1 Independently selected from:

[0213] 1) hydrogen, methyl, ethyl (optionally replaced by C 1-3 Alkylamino substituted), propyl (optionally substituted by hydroxy and C 1-3 Alkyl substituted, such as 2-hydroxy-2-methyl-propyl) isopropyl (substituted by cyano), cyclopropyl, 3-oxetanyl and 3-methyl-3-azetidinyl;

[0214] 2) Two Rs attached to the same atom G1 The group and the atoms to which it is attached together form a C 3-6 Monocyclic hydrocarbon ring or 3-6 membered monocyclic aliphatic heterocycle;

[0215] 3) Two R atoms connected to two different ring atoms in the same monocyclic ring G1 The groups are connected and together with the ring atoms of the monocyclic ring form a ring structure, and the two connected R G1 The groups together form a C2, C3 or C4 alkylene group.

[0216] In some embodiments, Cy A is unsubstituted or optionally substituted by 1, 2 or 3 independently selected from R 12 substituted phenyl, pyridyl, pyrimidinyl, pyrazolyl, imidazolyl, thiazolyl or isothiazolyl, wherein

[0217] 1) Each R 12 are independently selected from: fluorine, chlorine, R other than hydrogen G1 、-OR G1 ;

[0218] or,

[0219] 2) Cy A Contains 1 R 12 , which is selected from one of the following structures:

[0220]

[0221] or,

[0222] Cy A Contains 2 or 3 R's 12 , of which 1 R 12 Select one of the above structures, the rest R 12 are independently selected from: fluorine, chlorine, R other than hydrogen G1 、-OR G1 ;

[0223] Each R G1 Independently selected from the group consisting of: hydrogen, methyl, ethyl, isopropyl, cyclopropyl, 3-oxetanyl and 3-methyl-3-azetidinyl.

[0224] In some embodiments, R 22 Selected from oxo, cyano, C 3-7 Cycloalkyl, 3-7 membered alicyclic 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, -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; R H1 Optionally selected from methyl, ethyl, isopropyl, cyclopropyl, 3-oxetanyl and 3-methyl-3-azetidinyl.

[0225] In some embodiments, R 22 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.

[0226] In some embodiments, Cy B is unsubstituted or optionally substituted with 1, 2, 3 or 4 independently selected R 13 The phenyl, naphthyl and 5- to 10-membered heteroaryl groups are substituted with a group; the 5- to 10-membered heteroaryl groups have at least one ring-forming carbon atom and 1, 2, 3 or 4 ring-forming heteroatoms independently selected from N, O and S.

[0227] In some embodiments, Cy B is optionally substituted by 1, 2, 3 or 4 independently selected from R 13 The substituent is a phenyl group or a 5- to 6-membered heteroaryl group.

[0228] In some embodiments, Cy B is optionally substituted by 1, 2 or 3 independently selected from R 13 The phenyl group or 5- to 6-membered heteroaryl group substituted by a substituent, wherein the heteroaryl group contains 1, 2 or 3 ring-forming heteroatoms selected from N and S.

[0229] In some embodiments, Cy B is optionally substituted by 1, 2 or 3 independently selected from R 13 The substituents include phenyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, and thienyl.

[0230] In some embodiments, Cy B is optionally substituted by 1, 2, 3 or 4 independently selected from R 13 substituted phenyl or 5- to 6-membered heteroaryl; wherein the two R 13 The substituent and the two ring atoms together form an unsubstituted or optionally substituted 1, 2, 3, 4 or 5 groups independently selected from R 23 Substituents substituted C 5-12 Alicyclic hydrocarbon group or 5-12 membered alicyclic heterocyclic group.

[0231] In some embodiments, Cy B is optionally substituted by 1, 2 or 3 independently selected from R 13substituted phenyl or 5- to 6-membered heteroaryl; wherein the two R 13 The substituent and the two ring atoms together form an unsubstituted or optionally substituted 1, 2 or 3 independently selected R 23 Substituents substituted C 4-8 Alicyclic hydrocarbon group or 4- to 8-membered alicyclic heterocyclic group.

[0232] In some embodiments, Cy B is optionally substituted by 1, 2 or 3 independently selected from R 13 substituted phenyl or 5- to 6-membered heteroaryl; wherein the two R 13 The substituent and the two ring atoms together form an unsubstituted or optionally substituted 1, 2 or 3 independently selected R 23 Substituents substituted C 5-6 Monocyclic alicyclic hydrocarbon group or 5-6 membered monocyclic alicyclic heterocyclic group;

[0233] R 23 Optionally selected from fluorine, methyl, ethyl, isopropyl, cyclopropyl, ethylene and 3-oxetanyl.

[0234] In some embodiments, each R 13 Independently selected from:

[0235] 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, -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)Rb3 、-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;

[0236] 2) unsubstituted or optionally substituted by 1, 2, 3, 4, 5 or 6 independently selected from R 23 Substituents substituted C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 6-10 membered aryl, 5-10 membered heteroaryl, C 3-12 Cycloalkyl and 3-12 membered aliphatic heterocyclic groups;

[0237] 3) Respectively with Cy B The two adjacent ring atoms of the aryl or heteroaryl are connected to each other. 13 The substituent and the two ring atoms together form an unsubstituted or optionally substituted 1, 2, 3, 4 or 5 groups independently selected from R 23 Substituents substituted C 5-12 Alicyclic hydrocarbon group or 5-12 membered alicyclic heterocyclic group.

[0238] In some embodiments, each R 13 Independently selected from:

[0239] 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 、-NRa3 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;

[0240] 2) unsubstituted or optionally substituted by 1, 2, 3, 4, 5 or 6 independently selected from R 23 Substituents substituted C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 6-10 membered aryl, 5-10 membered heteroaryl, C 3-10 Cycloalkyl and 3-10 membered aliphatic heterocyclic groups;

[0241] 3) Respectively with Cy B The two adjacent ring atoms of the aryl or heteroaryl are connected to each other. 13 The substituent and the two ring atoms together form an unsubstituted or optionally substituted 1, 2, 3, 4 or 5 groups independently selected from R 23 Substituents substituted C 5-10 Alicyclic hydrocarbon group or 5-10 membered alicyclic heterocyclic group.

[0242] In some embodiments, each R 13 Independently selected from:

[0243] 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)ORc3 、-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;

[0244] 2) unsubstituted or optionally substituted by 1, 2, 3 or 4 independently selected R 23 Substituents substituted C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 6-10 membered aryl, 5-10 membered heteroaryl, C 3-10 Cycloalkyl and 3-10 membered alicyclic groups;

[0245] 3) respectively with Cy B The two adjacent ring atoms of the aryl or heteroaryl are connected to each other. 13 The substituents and the two ring atoms together form an unsubstituted or optionally substituted group with 1, 2 or 3 independently selected R 23 Substituents substituted C 4-8 Alicyclic hydrocarbon group or 4- to 8-membered alicyclic heterocyclic group.

[0246] In some embodiments, each R 13 Independently selected from:

[0247] 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 -NRe3 S(=O)2NR a3 R b3 ;

[0248] 2) unsubstituted or optionally substituted by 1, 2, 3, 4, 5 or 6 independently selected from R 23 Substituents substituted C 1-6 Alkyl, 6-10 membered aryl, 5-10 membered heteroaryl, C 3-10 Cycloalkyl and 3-10 membered aliphatic heterocyclic groups;

[0249] 3) Respectively with Cy B The two adjacent ring atoms of the aryl or heteroaryl are connected to each other. 13 The substituent and the two ring atoms together form a group which is unsubstituted or optionally substituted with 1, 2, 3 or 4 groups independently selected from R 23 Substituents substituted C 4-8 Alicyclic hydrocarbon group or 4- to 8-membered alicyclic heterocyclic group.

[0250] In some embodiments, each R 13 Independently selected from:

[0251] 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 ;

[0252] 2) unsubstituted or optionally substituted by 1, 2, 3 or 4 independently selected R 23 Substituents substituted C 1-6 Alkyl, phenyl, 5-6 membered heteroaryl, C 3-10Cycloalkyl and 3-10 membered aliphatic heterocyclic groups;

[0253] 3) Respectively with Cy B The two adjacent ring atoms of the aryl or heteroaryl are connected to each other. 13 The substituents and the two ring atoms together form an unsubstituted or optionally substituted group with 1, 2 or 3 independently selected R 23 A C5, C6, C7 monocyclic alicyclic hydrocarbon group or a 5-membered, 6-membered, 7-membered monocyclic alicyclic heterocyclic group substituted with a substituent.

[0254] In some embodiments, each R 13 Independently selected from:

[0255] 1) Oxo group, halogen atom, cyano group, C 1-4 Alkyl, C 3-6 Cycloalkyl, -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 ;

[0256] 2) Respectively with Cy B The two adjacent ring atoms of the aryl or heteroaryl are connected to each other. 13 The substituent and the two ring atoms together form a group which is unsubstituted or optionally substituted with 1, 2, 3 or 4 groups independently selected from R 23 Substituents substituted C 4-8 Alicyclic hydrocarbon group or 4- to 8-membered alicyclic heterocyclic group.

[0257] In some embodiments, each R 13 Independently selected from:

[0258] 1) Oxo, fluorine, chlorine, cyano, C 1-3 Alkyl, C 3-4 Cycloalkyl, -C(=O)R a3 、-C(=O)NR a3 R b3 、-OR a3 、-NR a3 R b3 、-NR a3 C(=O)Rb3 、-NR e3 C(=O)NR a3 R b3 and -NR e3 C(=NR d3 )NR a3 R b3 ;

[0259] 2) Respectively with Cy B The two adjacent ring atoms of the aryl or heteroaryl are connected to each other. 13 The substituent and the two ring atoms together form an unsubstituted or optionally substituted 1, 2 or 3 independently selected R 23 Substituents substituted C 5-6 A monocyclic alicyclic hydrocarbon group or a 5- to 6-membered monocyclic alicyclic heterocyclic group.

[0260] In some embodiments, each R 13 Independently selected from:

[0261] 1) Halogen atoms, cyano groups;

[0262] 2) unsubstituted or optionally substituted by 1, 2 or 3 independently selected from fluorine atoms, cyano groups, -OR a5 and -NR a5 R b5 Substituents substituted C 1-4 Alkyl, C 3-6 Cycloalkyl and 3-6 membered aliphatic heterocyclic group; wherein, R a5 and R b5 independently selected from hydrogen and C 1-6 Alkyl, or, R attached to the same nitrogen atom a5 and R b5 Together with the nitrogen atom to which they are connected, they form a 3-6 membered aliphatic heterocyclic group.

[0263] In some embodiments, each R 13 Independently selected from: halogen atoms, cyano, -OR a3 and -NR a3 R b3 ; Among them, R a3 and R b3 Independently selected from:

[0264] 1) Hydrogen;

[0265] 2) unsubstituted or optionally substituted by 1, 2 or 3 independently selected from fluorine atoms, cyano groups, -OR a5 and -NR a5 R b5 Substituents substituted C 1-6 Alkyl, C 3-6 Cycloalkyl and 3-6 membered aliphatic heterocyclic group; wherein, Ra5 and R b5 independently selected from hydrogen and C 1-4 Alkyl, or, R attached to the same nitrogen atom a5 and R b5 Together with the nitrogen atom to which they are connected, they form a 3-6 membered aliphatic heterocyclic group.

[0266] In some embodiments, each R 13 Independently selected from:

[0267] 1) Fluorine, chlorine, cyano, C 1-3 Alkyl, C 3-4 Cycloalkyl, -OR a3 and -NR a3 R b3 ;

[0268] 2) Respectively with Cy B The two adjacent ring atoms of the aryl or heteroaryl are connected to each other. 13 The substituent and the two ring atoms together form an unsubstituted or optionally substituted 1, 2 or 3 independently selected R 23 Substituents substituted C 5-6 Monocyclic alicyclic hydrocarbon group or 5-6 membered monocyclic alicyclic heterocyclic group;

[0269] R a3 and R b3 are independently selected from hydrogen, C 1-4 Alkyl and C 3-6 Cycloalkyl, or, R attached to the same nitrogen atom a3 and R b3 Together with the nitrogen atom to which they are connected, they form a 3-6 membered aliphatic heterocyclic group; R 23 Selected from C 1-6 Alkyl and C 3-6 Cycloalkyl.

[0270] In some embodiments, respectively with Cy B The two adjacent ring atoms of the aryl or heteroaryl are connected to each other. 13 The substituent and the two ring atoms together form an unsubstituted or optionally substituted 1, 2 or 3 independently selected from oxo, fluorine, cyano, -OR a5 and -NR a5 R b5 Substituents substituted C 3-7 an alicyclic hydrocarbon group or a 3- to 7-membered alicyclic heterocyclic group; wherein the 3- to 7-membered alicyclic heterocyclic group contains 1 or 2 ring-forming heteroatoms selected from N, O, and S; R a5 and R b5 independently selected from hydrogen and C 1-4 Alkyl, or, R attached to the same nitrogen atom a5and R b5 Together with the nitrogen atom to which they are connected, they form a 3-6 membered aliphatic heterocyclic group.

[0271] In some embodiments, each R 13 Independently selected from: halogen atoms, amino groups, C 1-3 Alkyl, C 1-3 Substituted alkyl, C 1-3 Alkoxy, C 1-3 Substituted alkoxy, C 3-6 Cycloalkoxy, C 1-3 Alkylamino and -C(=O)NR a3 R b3 Among them, C 1-3 The substituents in the substituted alkyl group are selected from halogen atoms, hydroxyl groups, C 1-3 Alkoxy, C 1-3 1, 2 or 3 of the alkyl group; C 1-3 The substituents in the substituted alkoxy group are selected from 1, 2 or 3 halogen atoms; a3 and R b3 independently selected from hydrogen and C 1-3 Alkyl, or R a3 、R b3 Together with the nitrogen atom, it forms a 1-3 Alkyl, C 1-3 3- to 6-membered aliphatic heterocyclic group substituted with alkoxy or hydroxy groups.

[0272] In some embodiments, each R 13 Independently selected from: -F, -Cl, -NH2, -CH3, -CH2CH3, -CH(CH3)CH3, -CF3, -CHF2, -CH2OCH3, -OCH3, -OCH2CH3, -OCH(CH3)CH3, -OCHF2, -O(C3H5)(cyclopropyloxy), -CH2NHCH3, -CH2N(CH3)2, -NHCH3, -N(CH3)2, -NHCH2CH3, -N(CH3)(CH2CH3), -N(CH2CH3)2, -NR a3 R b3 , -C(=O)NHCH3, -C(=O)N(CH3)2, -C(=O)NR a3 R b3 ; in-NR a3 R b3 and -C(=O)NR a3 R b3 In, R a3 、R b3Together with the nitrogen atom, it forms a 4- or 5-membered saturated monocyclic aliphatic heterocyclic group which is unsubstituted or optionally substituted by 1 or 2 groups selected from methyl, hydroxy, and methoxy.

[0273] In some embodiments, respectively with Cy B The two adjacent ring atoms of the aryl or heteroaryl are connected to each other. 13 The substituent and the two ring atoms together form an unsubstituted or optionally substituted group with 1 or 2 independently selected R 23 The 5-membered or 6-membered monocyclic aliphatic heterocyclic group substituted by a substituent, the ring heteroatoms contained in the monocyclic aliphatic heterocyclic group may be 1 or 2 atoms selected from N, O, and the substituent R 23 It may be oxo, fluorine, methyl, -CH2OH, -NHCH3.

[0274] In some embodiments, Cy B Select one of the following structures, where the chemical bond ends are It indicates that it is connected to other atoms in the structure of formula (I) through this bond:

[0275]

[0276] Among them, R a3 and R b3 independently selected from hydrogen and C 1-6 Alkyl, or, R connected to two adjacent ring atoms a3 and R b3 Together with the two ring atoms to which they are connected, they form a 5- to 6-membered monocyclic alicyclic hydrocarbon group or a 5- to 6-membered monocyclic alicyclic heterocyclic group.

[0277] In some embodiments, R 1 is hydrogen;

[0278] Cy A is unsubstituted or optionally substituted with 1, 2, 3 or 4 independently selected R 12 phenyl, naphthyl and 5- to 10-membered heteroaryl substituted with a group; wherein the 5- to 10-membered heteroaryl has at least two ring-forming carbon atoms and 1, 2, 3 or 4 ring-forming heteroatoms independently selected from N, O and S;

[0279] R 12 Selected from:

[0280] 1) Oxo group, halogen atom, cyano group, -C(=O)R a2 , carboxyl, -C(=O)NR a2 R b2 、-OR a2 、-NR a2 R b2 、-NR a2C(=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 ;

[0281] 2) unsubstituted or optionally substituted by 1, 2, 3 or 4 independently selected R 22 Substituents substituted C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, phenyl, 5-6 membered heteroaryl, C 3-7 Monocyclic cycloalkyl, C 6-10 bicyclic cycloalkyl, 3-7 membered monocyclic alicyclic heterocyclic group and 6-10 membered bicyclic alicyclic heterocyclic group;

[0282] 3) respectively with Cy A The two adjacent ring atoms of the aryl or heteroaryl are connected to each other. 12 The substituent and the two ring atoms together form an unsubstituted or optionally substituted 1, 2 or 3 independently selected R 22 Substituents substituted C 5-10 Alicyclic hydrocarbon group or 5-10 membered alicyclic heterocyclic group; wherein the 5-10 membered alicyclic heterocyclic group contains 1 or 2 ring-forming heteroatoms independently selected from N, O and S;

[0283] R a2 、R b2 and R e2 Each independently selected from:

[0284] 1) Hydrogen;

[0285] 2) is unsubstituted or optionally substituted by 1, 2 or 3 independently selected R 22 Substituents substituted C 1-4 Alkyl, phenyl, 5-6 membered heteroaryl, C 3-6 Cycloalkyl and 3-6 membered alicyclic groups;

[0286] or,

[0287] R attached to the same nitrogen atom a2 and R b2 Together with the nitrogen atom to which they are attached, they form an unsubstituted or optionally substituted 1, 2 or 3 groups independently selected from R 22substituted 3- to 8-membered alicyclic group; wherein the 3- to 8-membered alicyclic group contains 1 or 2 ring-forming heteroatoms, for example, only the above-mentioned nitrogen atom, or the above-mentioned nitrogen atom and any heteroatom selected from N, O and S;

[0288] R c2 is unsubstituted or optionally substituted with 1, 2 or 3 independently selected R 22 Substituents substituted C 1-4 Alkyl, C 2-3 Alkenyl, phenyl, 5-6 membered heteroaryl, C 3-6 Cycloalkyl and 3-6 membered alicyclic groups;

[0289] R d2 Selected from hydrogen, C 1-4 Alkyl, C 3-6 Cycloalkyl, 3-6 membered alicyclic group, cyano group, nitro group and -S(=O)2R G ;

[0290] R 22 Selected from:

[0291] 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 group (=NR d4 );

[0292] 2) is unsubstituted or optionally substituted by 1, 2 or 3 independently selected R 32 Substituents substituted C 1-4 Alkyl, C 1-4 Alkylene, phenyl, 5-6 membered heteroaryl, C 3-7 Cycloalkyl and 3-7 membered alicyclic groups;

[0293] R a4 、R b4 and R e4 Each independently selected from:

[0294] 1) Hydrogen;

[0295] 2) is unsubstituted or optionally substituted by 1, 2 or 3 independently selected R 32 Substituents substituted C 1-4 Alkyl, C 3-6 Monocyclic cycloalkyl and 3-6 membered monocyclic alicyclic heterocyclic groups;

[0296] or,

[0297] R attached to the same nitrogen atom a4 and R b4 Together with the nitrogen atom to which they are attached, they form an unsubstituted or optionally substituted 1, 2 or 3 groups independently selected from R 32 A 3- to 6-membered monocyclic alicyclic group or a 6- to 7-membered bicyclic alicyclic group substituted with a substituent; wherein the 3- to 6-membered monocyclic alicyclic group and the 6- to 7-membered bicyclic alicyclic group contain 1 or 2 ring heteroatoms, for example, only the above-mentioned nitrogen atom, or the above-mentioned nitrogen atom and any heteroatom selected from N, O and S;

[0298] R c4 is unsubstituted or optionally substituted with 1, 2 or 3 independently selected R 32 Substituents substituted C 1-4 Alkyl, C 2-3 Alkenyl, C 3-6 Monocyclic cycloalkyl and 3-6 membered monocyclic alicyclic heterocyclic groups;

[0299] R d4 Selected from hydrogen, C 1-4 Alkyl, C 3-6 Monocyclic cycloalkyl, 3-6 membered monocyclic alicyclic heterocyclic group, cyano group, nitro group and -S(=O)2R G ;

[0300] R 32 Selected from oxo, halogen atoms, cyano, hydroxyl, -OR G , amino, -NHR G 、-N(R G )2, aldehyde, -C(=O)R G 、-S(=O)2RG , carboxyl, -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;

[0301] Cy B is unsubstituted or optionally substituted with 1, 2, 3 or 4 independently selected R 13 substituted phenyl, naphthyl and 5- to 10-membered heteroaryl; wherein the 5- to 10-membered heteroaryl has at least two ring-forming carbon atoms and 1, 2, 3 or 4 ring-forming heteroatoms independently selected from N, O and S;

[0302] R 13 Selected from:

[0303] 1) Oxo group, halogen atom, cyano group, -C(=O)R a3 , carboxyl, -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 ;

[0304] 2) unsubstituted or optionally substituted by 1, 2, 3 or 4 independently selected R 23 Substituents substituted C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, phenyl, 5-6 membered heteroaryl, C 3-7 Monocyclic cycloalkyl, C 6-10 bicyclic cycloalkyl, 3-7 membered monocyclic alicyclic heterocyclic group and 6-10 membered bicyclic alicyclic heterocyclic group;

[0305] 3) respectively with Cy BThe two adjacent ring atoms of the aryl or heteroaryl are connected to each other. 13 The substituent and the two ring atoms together form an unsubstituted or optionally substituted 1, 2 or 3 independently selected R 23 Substituents substituted C 5-10 Alicyclic hydrocarbon group or 5-10 membered alicyclic heterocyclic group; wherein the 5-10 membered alicyclic heterocyclic group contains 1 or 2 ring-forming heteroatoms independently selected from N, O and S;

[0306] R a3 、R b3 and R e3 Each independently selected from:

[0307] 1) Hydrogen;

[0308] 2) is unsubstituted or optionally substituted by 1, 2 or 3 independently selected R 23 Substituents substituted C 1-4 Alkyl, phenyl, 5-6 membered heteroaryl, C 3-6 Cycloalkyl and 3-6 membered alicyclic groups;

[0309] or,

[0310] R attached to the same nitrogen atom a3 and R b3 Together with the nitrogen atom to which they are attached, they form an unsubstituted or optionally substituted 1, 2 or 3 groups independently selected from R 23 substituted 3- to 8-membered alicyclic group; wherein the 3- to 8-membered alicyclic group contains 1 or 2 ring-forming heteroatoms, for example, only the above-mentioned nitrogen atom, or the above-mentioned nitrogen atom and any heteroatom selected from N, O and S;

[0311] R c3 is unsubstituted or optionally substituted with 1, 2 or 3 independently selected R 23 Substituents substituted C 1-4 Alkyl, C 2-3 Alkenyl, phenyl, 5-6 membered heteroaryl, C 3-6 Cycloalkyl and 3-6 membered alicyclic groups;

[0312] R d3 Selected from hydrogen, C 1-4 Alkyl, C 3-6 Cycloalkyl, 3-6 membered alicyclic group, cyano group, nitro group and -S(=O)2R G ;

[0313] R 23 Selected from:

[0314] 1) Oxo group, halogen atom, cyano group, carboxyl group, -C(=O)R a5 、-C(=O)NR a5R 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 group (=NR d5 );

[0315] 2) is unsubstituted or optionally substituted by 1, 2 or 3 independently selected R 33 Substituents substituted C 1-5 Alkyl, C 1-5 Alkylene, phenyl, 5-6 membered heteroaryl, C 3-7 Cycloalkyl and 3-7 membered alicyclic groups;

[0316] R a5 、R b5 and R e5 Each independently selected from:

[0317] 1) Hydrogen;

[0318] 2) is unsubstituted or optionally substituted by 1, 2 or 3 independently selected R 33 Substituents substituted C 1-4 Alkyl, C 3-6 Monocyclic cycloalkyl and 3-6 membered monocyclic alicyclic heterocyclic groups;

[0319] or,

[0320] R attached to the same nitrogen atom a5 and R b5 Together with the nitrogen atom to which they are attached, they form an unsubstituted or optionally substituted 1, 2 or 3 groups independently selected from R33 A 3- to 6-membered monocyclic alicyclic group or a 6- to 7-membered bicyclic alicyclic group substituted with a substituent; wherein the 3- to 6-membered monocyclic alicyclic group and the 6- to 7-membered bicyclic alicyclic group contain 1 or 2 ring heteroatoms, for example, only the above-mentioned nitrogen atom, or the above-mentioned nitrogen atom and any heteroatom selected from N, O and S;

[0321] R c5 is unsubstituted or optionally substituted with 1, 2 or 3 independently selected R 33 Substituents substituted C 1-4 Alkyl, C 2-3 Alkenyl, C 3-6 Monocyclic cycloalkyl and 3-6 membered monocyclic alicyclic heterocyclic groups;

[0322] R d5 Selected from hydrogen, C 1-4 Alkyl, C 3-6 Monocyclic cycloalkyl, 3-6 membered monocyclic alicyclic heterocyclic group, cyano group, nitro group and -S(=O)2R GA ;

[0323] R 33 Selected from oxo, halogen atoms, cyano, hydroxyl, -OR GA , amino, -NHR GA and -N(R GA )2;

[0324] Each R GA Independently selected from:

[0325] C which is unsubstituted or optionally substituted by 1, 2 or 3 fluorine atoms 1-4 Alkyl, C 1-4 Alkylene, C 3-6 Cycloalkyl and 4-6 membered alicyclic heterocyclic groups;

[0326] or,

[0327] Two R attached to the same nitrogen atom GA Together with the nitrogen atom to which it is attached, it forms a 4- to 6-membered monocyclic alicyclic heterocyclic group which is unsubstituted or optionally substituted by 1, 2 or 3 fluorine atoms; wherein the 4- to 6-membered monocyclic alicyclic heterocyclic group contains 1 or 2 ring-forming heteroatoms, for example, only the above-mentioned nitrogen atom, or the above-mentioned nitrogen atom and any heteroatom selected from N and O.

[0328] Some embodiments of the present application provide a pharmaceutical composition comprising a compound of formula (I) above or a pharmaceutically acceptable salt, hydrate, solvate, active metabolite, polymorph, isotope-labeled substance, isomer or prodrug thereof, and a pharmaceutically acceptable carrier.

[0329] The pharmaceutical combination can be prepared in a manner well known in the pharmaceutical art and can be administered by various routes. The administration route can be topical (including transdermal, epidermal, ocular and mucous membranes, including intranasal, vaginal and rectal delivery), pulmonary (e.g., by inhalation or insufflation of powders or aerosols, including by nebulizer; intratracheal or intranasal), oral or parenteral.

[0330] In some embodiments, the composition is suitable for parenteral administration, including intravenous, intraarterial, subcutaneous, intraperitoneal, intramuscular injection or infusion; or intracranial, such as intrathecal or intraventricular administration. Parenteral administration can be in the form of a single bolus dose or can be administered by, for example, a continuous infusion pump.

[0331] In some embodiments, the composition is suitable for topical administration. Pharmaceutical compositions and formulations for topical administration may include transdermal patches, ointments, lotions, creams, gels, drops, suppositories, sprays, liquids, and powders. Conventional pharmaceutical carriers, aqueous, powdered, or oily bases, thickeners, and the like may be necessary or desirable.

[0332] Some embodiments of the present application provide the use of the compound of formula (I) or its pharmaceutically acceptable salt, hydrate, solvate, active metabolite, polymorph, isotope label, isomer or prodrug, and the above-mentioned drug combination in preventing or treating diseases mediated by HPK1.

[0333] Some embodiments of the present application provide methods for modulating (e.g., inhibiting) HPK1 activity, comprising administering to a patient a compound of formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, active metabolite, polymorph, isotope label, isomer, or prodrug thereof, as well as the above-mentioned drug combinations, to stimulate and / or enhance immunity in cancer or viral diseases.

[0334] Some embodiments of the present application provide a method for preventing, ameliorating or treating a disease mediated by HPK1, comprising administering a therapeutically effective amount of the compound of formula (I) above or a pharmaceutically acceptable salt, hydrate, solvate, active metabolite, polymorph, isotope-labeled compound, isomer or prodrug thereof, as well as the above-mentioned drug combination to a patient suffering from a disease mediated by HPK1.

[0335] Some embodiments of the present application provide the use of the above-mentioned compound of formula (I) or its pharmaceutically acceptable salt, hydrate, solvate, active metabolite, polymorph, isotope label, isomer or prodrug, as well as the above-mentioned drug combination in treating or improving benign or malignant tumors, myelodysplastic syndrome, and / or virus-induced diseases.

[0336] Some embodiments of the present application provide a compound of formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, active metabolite, polymorph, isotope-labeled substance, isomer or prodrug thereof, or the use of the above-mentioned pharmaceutical composition in treating or improving benign or malignant tumors.

[0337] Some embodiments of the present application provide a compound of formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, active metabolite, polymorph, isotope-labeled substance, isomer or prodrug thereof, or the use of the above-mentioned pharmaceutical composition in treating or ameliorating virus-induced diseases.

[0338] Some embodiments of the present application provide the use of the above-mentioned compound of formula (I) or its pharmaceutically acceptable salt, hydrate, solvate, active metabolite, polymorph, isotope label, isomer or prodrug, and the above-mentioned drug combination in the preparation of a drug for treating or ameliorating a specific disease; the disease may be one or more of benign or malignant tumors, myelodysplastic syndrome and viral-induced diseases.

[0339] Some embodiments of the present application provide a compound of formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, active metabolite, polymorph, isotope-labeled substance, isomer or prodrug thereof, or the use of the above-mentioned pharmaceutical composition in the preparation of a drug for treating or improving benign or malignant tumors.

[0340] Some embodiments of the present application provide a compound of formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, active metabolite, polymorph, isotope-labeled substance, isomer or prodrug thereof, or the use of the above-mentioned pharmaceutical composition in the preparation of a drug for treating or ameliorating a disease caused by a virus.

[0341] In one embodiment, the malignant tumor includes leukemia, lymphoma, multiple myeloma, lung cancer, hepatocellular carcinoma, bile duct cancer, gallbladder cancer, gastric cancer, colorectal cancer, small intestinal leiomyosarcoma, breast cancer, ovarian cancer, cervical cancer, endometrial cancer, vaginal cancer, malignant teratoma, pancreatic cancer, pancreatic ductal adenocarcinoma, nasopharyngeal cancer, oral cancer, laryngeal cancer, esophageal squamous cell carcinoma, thyroid cancer, kidney cancer, bladder cancer, malignant brain tumor, rhabdomyosarcoma, osteosarcoma, chondrosarcoma, fibrosarcoma of bone, malignant thymoma, malignant peripheral nerve sheath tumor, prostate cancer, testicular cancer, penile cancer and the like, as well as one or more benign and malignant skin tumors (including but not limited to melanoma, basal cell carcinoma, squamous cell carcinoma).

[0342] In one embodiment, the tumor is a PGE2-producing tumor (e.g., a COX-2-overexpressing tumor) and / or an adenosine-producing tumor (e.g., a CD39 and CD73-overexpressing tumor), such as colorectal cancer, breast cancer, pancreatic cancer, lung cancer, and ovarian cancer.

[0343] In one embodiment, the virus comprises one or more of hepatitis virus, human immunodeficiency virus, human papillomavirus, herpes simplex virus, measles virus, norovirus, bocavirus, coxsackievirus, Ebola virus, enterovirus, lymphocytic meningitis virus, influenza virus, SARS virus and new coronavirus.

[0344] Definitions and Explanations of Terms

[0345] In this application, unless otherwise specified, the description or explanation of a group applies to all groups containing this group, whether used alone or in combination with other terms. For example, the description of alkyl applies to C 1-6 Alkyl, C 1-3 Alkyl, etc.; for C 1-6 The description or description of alkyl is applicable to "C 1-6 "alkoxy" etc., and the following definitions apply to the claims and the specification.

[0346] When a structure contains multiple substituents represented by the same symbol, the types of these substituents may be the same or different; for example, Cy B The group contains 2 R 13 Substituents, these two R 13 Both may be methoxy groups, or one may be a methoxy group and the other a methyl group.

[0347] The term "halogen atom" includes fluorine, chlorine, bromine and iodine.

[0348] The term "C m-n " group (wherein m and n are integers) indicates a range including the end point, which means that the corresponding group contains mn carbon atoms. For example, C 1-6 Alkyl refers to an alkyl group containing 1 to 6 carbon atoms, C 2-6 Alkenyl means an alkenyl group containing 2 to 6 carbon atoms.

[0349] The term "n-membered" (where n is an integer) generally describes the number of ring-forming atoms in a moiety, where the number of ring-forming atoms is n. "mn-membered" indicates an inclusive range, meaning that the corresponding ring structure contains mn ring-forming atoms. For example, piperidinyl is an example of a 6-membered heterocyclic group, and pyrazolyl is an example of a 5-membered heteroaromatic ring group.

[0350] The term "substituted" refers to an atom or group of atoms that formally replaces hydrogen as a "substituent" attached to another group. Unless otherwise indicated, the term "substituted" refers to any degree of substitution, as long as the substitution is allowed. The choice of substituent is independent, and substitution can be at any chemically accessible position. It should be understood that substitution on a given atom is limited by valence. It should be understood that substitution on a given atom produces a chemically stable molecule. A single divalent substituent (e.g., oxo) can replace two hydrogen atoms.

[0351] The "remainder of the compound" refers to the portion of the complete molecular structure excluding the substituent. The remainder of the compound is connected to the substituent through one or more unsaturated valences. The remainder of the compound may contain one or more "points of attachment," and two or more points of attachment may be on the same atom or on different atoms.

[0352] The term "alkyl" refers to a straight or branched saturated hydrocarbon group. An alkyl group is formed by losing a hydrogen atom from an alkane. Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, 2-methylbutyl, neopentyl, 1-ethylpropyl, n-hexyl, and 1,2,2-trimethylpropyl.

[0353] The term "alkenyl" refers to a straight or branched hydrocarbon group having one or more carbon-carbon double bonds. An alkenyl group is formed by the loss of a hydrogen atom from an alkene. Examples of alkenyl groups include ethenyl, 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-butadien-1-yl, and 1,3-butadien-2-yl.

[0354] The term "alkynyl" refers to a straight or branched hydrocarbon group having one or more carbon-carbon triple bonds. An alkynyl group is formed by the loss of a hydrogen atom from an alkyne. Examples of alkynyl groups include ethynyl, 1-propynyl, propargyl, 1-butynyl, but-2-yn-1-yl, but-3-yn-1-yl, but-3-ene-1-ynyl, and 3-methylpent-2-ene-4-yn-1-yl.

[0355] The term "alkylene" refers to a divalent group formed by the simultaneous loss of two hydrogen atoms from a carbon atom of an alkane. The two connecting valences may be concentrated on the same atom or on two separate atoms. The two connecting valences may be on the same atom in the rest of the compound or on two separate atoms in the rest of the compound. Examples include methylene (-CH2- or =CH2), 1,1-ethylene (-CH(CH3)- or =CH-CH3), 1,2-ethylene (-CH2CH2-), butane-1,4-diyl, butane-1,3-diyl, and 2,2-dimethyl-propane-1,3-diyl.

[0356] The term "alkoxy" refers to a group of the formula "-O-alkyl" where alkyl is as defined above, for example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, and n-hexyloxy.

[0357] The term "alkylthio" refers to a group of the formula "-S-alkyl" where alkyl is as defined above, for example, methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, tert-butylthio, and n-hexylthio.

[0358] The term "alkylamino" includes groups of the formula "-NH-alkyl" and groups of the formula "-N(alkyl)2", wherein alkyl is as defined above. Examples of the group of the formula "-NH-alkyl" include methylamino, ethylamino, isopropylamino, and n-hexylamino; examples of the group of the formula "-N(alkyl)2" include dimethylamino, diethylamino, methylethylamino, methylisopropylamino, and ethyl-n-hexylamino.

[0359] The term "alkylsulfoxide" refers to a group of the formula "-S(=O)-alkyl", wherein alkyl is as defined above, for example, methylsulfoxide, ethylsulfoxide, isopropylsulfoxide, and the like.

[0360] The term "alkylsulfonyl" refers to a group of the formula "-S(=O)2-alkyl", wherein alkyl is as defined above, for example, methylsulfonyl, ethylsulfonyl, isopropylsulfonyl, and the like.

[0361] The term "alkylaminosulfinyl" includes radicals of the formula "-S(=O)-NH-alkyl" and radicals of the formula "-S(=O)-N(alkyl)2," wherein alkyl is as defined above. Examples of radicals of the formula "-S(=O)-NH-alkyl" include methylaminosulfinyl, ethylaminosulfinyl, isopropylaminosulfinyl, tert-butylaminosulfinyl, and the like. Examples of radicals of the formula "-S(=O)-N(alkyl)2" include dimethylaminosulfinyl, diethylaminosulfinyl, methylethylaminosulfinyl, ethylisobutylaminosulfinyl, and the like.

[0362] The term "alkylaminosulfonyl" includes radicals of the formula "-S(=O)2-NH-alkyl" and radicals of the formula "-S(=O)2-N(alkyl)2", wherein alkyl is as defined above. Examples of radicals of the formula "-S(=O)2-NH-alkyl" include methylaminosulfonyl, ethylaminosulfonyl, isopropylaminosulfonyl, tert-butylaminosulfonyl, and the like. Examples of radicals of the formula "-S(=O)2-NH-alkyl" include dimethylaminosulfonyl, diethylaminosulfonyl, methylisopropylaminosulfonyl, ethyltert-butylaminosulfonyl, and the like.

[0363] The term "carbonyl" refers to a group of formula -(C=O)-, which may also be written as -C(O)-.

[0364] The term "cyano" refers to a group of formula -C≡N, which may also be written as -CN.

[0365] The term "hydroxymethyl" refers to a group of formula -CH2OH.

[0366] The term "oxo" refers to an oxygen atom as a divalent substituent, which forms a carbonyl group when attached to a carbon atom, or forms a sulfoxide or sulfone group when attached to a heteroatom, or an N-oxide group, etc. In some embodiments, cycloalkyl and heterocyclyl groups may be optionally substituted with 1 or 2 oxo groups.

[0367] The term "imino" or "=NR" refers to an amino group as a divalent substituent wherein two valences of the same nitrogen atom are double-bonded to an atom selected from the rest of the compound, and the third valence of the nitrogen atom is bonded to an R group as defined above and below. The nitrogen atom forms an imine, amidine, or guanidine when bonded to a carbon atom, or a sulfoximine when bonded to a heteroatom.

[0368] The term "cycloalkyl" includes monocyclic or polycyclic alicyclic and aromatic hydrocarbon groups. Monocyclic alicyclic hydrocarbon groups contain one hydrocarbon ring, including cyclized alkyl and alkenyl groups. Polycyclic alicyclic hydrocarbon groups contain two or more hydrocarbon rings, at least one of which is an alicyclic hydrocarbon ring (including cyclized alkyl and alkenyl groups), and the other rings may be alicyclic hydrocarbon rings and / or aromatic hydrocarbon rings; any of the rings is connected to at least one other ring by a spirocyclic ring (two rings share a ring atom) or a bridged ring (two rings share two or more ring atoms). Polycyclic cycloalkyl groups are connected to the rest of the compound through a ring carbon atom on the hydrocarbon ring. Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentenyl, cyclohexadienyl, bicyclo[3.1.0]hexanyl, norbornyl, norpinanyl, bicyclo[1.1.1]pentyl, 1H-inden-1-yl, and 2,3-dihydro-1H-inden-2-yl. When any of the rings contained in the cycloalkyl group is a saturated ring, the cycloalkyl group is a saturated cycloalkyl group, also known as a "cycloalkyl group."

[0369] "Cycloalkyloxy" refers to a radical of the formula "-O-cycloalkyl" wherein cycloalkyl is as defined above, for example cyclopropyloxy.

[0370] Cycloalkyl includes "cycloalkylene", i.e., a cycloalkyl group is connected to two points of attachment to the rest of the compound through two valences, respectively. The two valences may be on the same carbon atom of the cycloalkylene group or on two carbon atoms of the cycloalkylene group; the two points of attachment may be on the same atom of the rest of the compound or on two atoms of the rest of the compound. For example, 1,1-cyclobutylene, 1,3-cyclobutylene, etc.

[0371] The term "aryl" refers to a monocyclic or polycyclic aromatic hydrocarbon group, for example, phenyl, naphthyl, etc.

[0372] The term "heterocyclyl" refers to a monocyclic or polycyclic group having at least one heteroatom ring member selected from oxygen, nitrogen, sulfur and phosphorus. A polycyclic heterocyclyl contains two or more ring structures, at least one of which has at least one heteroatom ring member selected from oxygen, nitrogen, sulfur and phosphorus, and the other ring structures may have or not have ring-forming heteroatoms; wherein any ring is connected to at least one other ring by a spirocycle (two rings share one ring atom) or a bridged ring (two rings share two or more ring atoms). The heterocyclyl can be connected to the rest of the compound by an optional ring-forming carbon atom, or by an optional ring-forming heteroatom. In some embodiments, any ring-forming carbon atom in the heterocyclyl can be substituted by an oxo group to form a carbonyl group. In some embodiments, any ring-forming nitrogen atom in the heterocyclyl can be an N-oxide. In some embodiments, any ring-forming nitrogen atom in the heterocyclyl can be a quaternary ammonium ion.

[0373] Heterocyclic groups include aromatic heterocyclic groups (ie, "heteroaryl groups") and "aliphatic heterocyclic groups."

[0374] "Heteroaryl" refers to a monocyclic or polycyclic aromatic heterocycle having at least one heteroatom ring member selected from oxygen, nitrogen, and sulfur. A heteroaryl group can be attached to the remainder of the compound through an optional carbon atom or through an optional heteroatom, provided that the valence of the carbon atom or heteroatom permits. In some embodiments, any ring-forming carbon atom in the heteroaryl moiety can be substituted with an oxo group to form a carbonyl group. In some embodiments, any ring-forming nitrogen atom in the heteroaryl moiety can be an N-oxide. In some embodiments, any ring-forming nitrogen atom in the heteroaryl moiety can be a quaternary ammonium ion. For example, pyrrolyl (including pyrrol-1-yl, pyrrol-2-yl and pyrrol-3-yl), pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, tetrazolyl, pyridinyl, pyridin-2(1H)-on-1-yl, pyridin-4(1H)-on-1-yl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrazin-3(2H)-on-2-yl, 1,2,4-triazinyl, 1,3,5-triazinyl, indolyl, benzofuranyl, benzothiophenyl, indazolyl, benzimidazolyl, benzisothiazolyl, quinolyl, isoquinolyl, naphthyridinyl, imidazo[1,2-b]thiazolyl, purinyl and the like.

[0375] "Alicyclic groups" include monocyclic or polycyclic heterocyclic groups. A monocyclic heterocyclic group may not contain a cyclic double bond, or may contain one or more cyclic double bonds. A polycyclic heterocyclic group contains at least one alicyclic structure, and the other rings may be alicyclic or aromatic rings; any ring structure in a polycyclic heterocyclic group may not contain a cyclic double bond, or may contain one or more cyclic double bonds. Examples include azetidinyl, oxetanyl, tetrahydropyrrolyl, tetrahydrofuranyl, 2-oxooxazolidinyl, piperidinyl, 3-oxopiperidinyl, piperazinyl, morpholinyl, azepanyl, 2-oxa-6-azaspiro[3.3]heptyl, 1,2,3,4-tetrahydroquinolinyl, and the like.

[0376] Heterocyclyl includes heterocyclylene, i.e., a heterocyclyl group is connected to two connection points of the rest of the compound through two valences, wherein the two valences may be located on the same ring atom of the heterocyclylene or on two ring atoms of the heterocyclylene; the two connection points may be located on the same atom of the rest of the compound or on two atoms of the rest of the compound, for example, 1,1-(3-oxacyclobutane) and 1,3-(2-azacyclopentane).

[0377] The term "parallel ring" refers to a bridged ring system formed by two rings sharing two adjacent ring atoms; the two rings may be saturated alicyclic rings, unsaturated alicyclic rings or aromatic rings, and the two adjacent ring atoms may be carbon atoms or heteroatoms.

[0378] The term "n-membered oxaalkylene" refers to a divalent group formed by replacing one or more carbon atoms in the n-membered alkylene backbone with oxygen atoms. The two connecting valences may be located on the same atom in the remainder of the compound or on two separate atoms in the remainder of the compound. For example, 2-oxa-1,3-propylene (-CH2OCH2-) is an example of a 3-membered oxaalkylene, and 2-oxa-1,4-butylene (-CH2OCH2CH2-) is an example of a 4-membered oxaalkylene. Alkylene groups in which only side-chain carbon atoms are replaced by oxygen atoms should not be considered "oxaalkylene". For example, the group resulting from the replacement of the side-chain methyl group in 2-methyl-1,3-propylene with oxygen (-CH2CH(OH)CH2-) should be considered a 2-hydroxy-substituted 1,3-propylene group.

[0379] The term "n-membered azaalkylene" refers to a divalent group formed by replacing one or more carbon atoms in the n-membered alkylene backbone with a nitrogen atom, wherein the two connecting valences may be located on the same atom in the remainder of the compound or on two atoms in the remainder of the compound; for example, 2-aza-1,3-propylene (-CH2NHCH2-) is an example of a 3-membered azaalkylene, and aza-1,2-ethylene (-CH2NH-) is an example of a 2-membered azaalkylene. Alkylene groups in which only side-chain carbon atoms are replaced by nitrogen atoms should not be considered "azaalkylene"; for example, the group resulting from the replacement of the side-chain methyl group in 2-methyl-1,3-propylene with nitrogen (-CH2CH(NH2)CH2-) should be considered a 2-amino-substituted 1,3-propylene group.

[0380] The term "isomer" refers to an isomer resulting from the different spatial arrangements of atoms in a molecule. "Stereoisomers" of the compounds described herein refer to all stereoisomers. For example, when the compound has an asymmetric carbon atom, enantiomers and diastereomers are produced; when the compound has a carbon-carbon double bond, a carbon-nitrogen double bond, or a ring structure, cis-trans isomers are produced. Unless otherwise specified, the compounds described herein include all isomers thereof, 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 separated isomers.

[0381] Methods for preparing optically active products from optically inactive starting materials are known in the art, for example by resolution of racemic mixtures or by stereoselective synthesis.

[0382] The resolution of a racemic mixture of compounds can be carried out by any of a number of methods known in the art. One method includes fractional recrystallization using a chiral resolving acid that is an optically active, salt-forming organic acid. Suitable resolving agents for fractional recrystallization can be optically active acids such as D-tartaric acid, L-tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, camphorsulfonic acid, and the like; other suitable resolving agents for fractional recrystallization include, for example, stereoisomerically pure α-methylbenzylamine, 2-phenylglycinol, cyclohexylethylamine, and the like.

[0383] The resolution method of the racemic mixture also includes, for example, converting to diastereomers by reaction with an appropriate optically active substance (e.g., chiral alcohol or Mosher's acyl chloride), separating the diastereomers and converting (e.g., hydrolyzing) them into corresponding single optical isomers. For example, eluting on a chromatographic column filled with an optically active resolving agent is implemented. Suitable chromatographic columns and elution solvent compositions can be determined by those skilled in the art.

[0384] The term "isotopically labeled" refers to a compound of the present invention in which one or more constituent atoms are replaced by a specific isotope thereof. For example, the isotopes in the compound of the present invention may include various isotopes of elements such as H, C, N, O, F, P, S, Cl, and I, such as 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 compounds that are isotopically labeled as defined. For example, radioactive isotopes (such as 3 H and 14 C), or those compounds in which non-radioactive isotopes such as 2 H and 13 C). Such isotope-labeled compounds are suitable for metabolic studies (using 14 C); reaction kinetic studies (using e.g. 2 H or 3 H); detection or imaging techniques, such as positron emission tomography (PET) or single photon emission computed tomography (SPECT), including drug or substrate tissue distribution analysis; or radiotherapy applied to the patient, etc.

[0385] Specifically, 18 Compound F may be particularly desirable 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 an appropriate isotopically labeled reagent in place of the unlabeled reagent previously employed.

[0386] In addition, the use of heavier isotopes, especially deuterium (i.e. 2 H or D) substitution may afford certain therapeutic advantages resulting from greater metabolic stability, such as increased in vivo half-life or reduced dosage requirements or improved therapeutic index, and therefore may be preferred in some circumstances.

[0387] The term "pharmaceutically acceptable" refers to those compounds, materials, compositions and / or dosage forms which, within the scope of sound medical judgment, are suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response or other problems or complications, commensurate with a reasonable benefit / risk ratio.

[0388] "Pharmaceutically acceptable salts" refer to salts that retain the biological utility and properties of the compounds of the present application and generally do not have biologically or other undesirable 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.

[0389] Pharmaceutically acceptable acid addition salts can be formed with inorganic and organic acids.

[0390] Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases.

[0391] All compounds and pharmaceutically acceptable salts thereof can be found together with other substances (e.g., solvents, including water and other solvents, etc.) (e.g., hydrates and solvates) or can be isolated. When in a solid state, the compounds described herein and their salts can exist in various forms, including hydrates and solvates. Hydrates and solvates of the compounds described herein and their salts include those in which the water and solvent can be isotopically substituted, such as D2O, methanol-d3, methanol-d4, acetone-d6, DMSO-d6. The presence of hydrates and solvates can be identified by those skilled in the art using means such as nuclear magnetic resonance (NMR).

[0392] The term "polymorph" refers to compounds of the present invention that exist in different crystalline forms, as well as in an amorphous form. Polymorphs of the compounds of the present invention and their salts also include mixtures of various crystalline forms, as well as mixtures of one or more crystalline forms with an amorphous form. The presence of polymorphs can be identified by those skilled in the art using methods such as X-ray diffraction.

[0393] Therefore, unless otherwise expressly stated, the compounds and salts thereof mentioned in this specification should be understood to cover any solid state form of the compounds.

[0394] The term "active metabolite" refers to an active derivative of a compound that is formed when the compound is metabolized.

[0395] "Pharmaceutically acceptable prodrugs" refer to any pharmaceutically acceptable ester, salt, amide, or other derivative of a compound of the present invention that, upon administration to a recipient, is capable of providing, directly or indirectly, the compound of the present invention or a pharmaceutically active metabolite or residue thereof. Particularly preferred derivatives or prodrugs are those that, when administered to a patient, can increase the bioavailability of the compound of the present invention (e.g., by making an orally administered compound more readily absorbed into the bloodstream), or those that facilitate the delivery of the parent compound to a biological organ or site of action.

[0396] The term "pharmaceutical composition" refers to a biologically active compound optionally admixed with at least one pharmaceutically acceptable chemical component or agent, known as a "carrier," which facilitates the introduction of the compound into cells or tissues, including, but 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 (solid or dissolved in a liquid vehicle), ointments, soft and hard gelatin capsules, suppositories, transdermal patches, sterile injectable solutions, and sterile packaged powders.

[0397] The term "pharmaceutically acceptable carrier" includes any and all solvents, dispersion media, coatings, surfactants, antioxidants, preservatives (e.g., antibacterial agents, antifungal agents), isotonic agents, absorption delaying agents, salts, preservatives, pharmaceutical stabilizers, binders, excipients, disintegrants, lubricants, sweeteners, flavorings, dyes, and the like, and combinations thereof, as known to those skilled in the art. Unless any conventional carrier is incompatible with the active ingredient, its use in therapeutic or pharmaceutical compositions is contemplated.

[0398] "Therapeutically effective amount" refers to the amount of the compound of the present application that induces a biological or medical response in a subject, such as reducing or inhibiting enzyme or protein activity or improving symptoms, alleviating symptoms, slowing or delaying disease progression, or preventing disease.

[0399] "Subject" or "patient" refers to an individual suffering from a disease, disorder, condition, etc., including mammals and non-mammals. Examples of mammals include, but are not limited to, any member of the class Mammalia: humans; non-human primates (e.g., chimpanzees and other apes and monkeys); livestock, such as cattle, horses, sheep, goats, pigs; other domesticated animals, such as rabbits, dogs, and cats; laboratory animals, including rodents, such as rats, mice, and guinea pigs. Examples of non-mammals include, but are not limited to, birds and fish.

[0400] synthesis

[0401] The compounds of the present application and their salts can be prepared using known organic synthesis techniques and according to any of a number of possible synthetic routes, such as those in the schemes below.

[0402] The reaction for preparing the compound of the application can be implemented in a suitable solvent. Suitable solvent can be substantially unreactive with starting material (reactant), intermediate or product at the temperature (such as the temperature within the range of the freezing temperature of the solvent to the boiling temperature of the solvent) of implementing the reaction. A given reaction can be implemented in a mixture of a solvent or multiple solvents. According to the specific reaction step, those skilled in the art can select a suitable solvent for the specific reaction step.

[0403] The preparation of the compounds of the present application may 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 those skilled in the art.

[0404] The following schemes provide general guidance for preparing the compounds of the present application. Those skilled in the art will understand that the methods shown in the schemes can be modified or optimized using general knowledge of organic chemistry to prepare various compounds of the present application.

[0405] Compounds of formula (I) can be prepared according to the methods illustrated in the schemes below.

[0406] Various compounds of formula (I) can be prepared using the method described in Scheme 1. In the method shown in Scheme 1, the compound of formula 1-1 is subjected to diazotization and coupling reaction to form the compound of formula 1-2. The compound of formula 1-2 is subjected to a ring closure reaction (e.g., thermal ring closure, and acid- or base-catalyzed ring closure reaction) to form the compound of formula 1-3. The compound of formula 1-3 is subjected to amidation to form the compound of formula 1-4. The compound of formula 1-4 is subjected to chlorination and dehydration reaction (e.g., chlorination and dehydration in the presence of phosphorus oxychloride) to form the compound of formula 1-5. The compound of formula 1-5 is subjected to ring closure by condensation with hydrazine (or hydrazine hydrate) to form the compound of formula 1-6. The compound of formula 1-6 is subjected to Sandmeyer reaction or similar reaction to form a halogenated (e.g., chlorinated, brominated, or iodinated) compound of formula 1-7. The NH group of the pyrazole is protected with a suitable protecting group to form the compound of formula 1-8. The compound of formula 1-8 is converted to the compound of formula 1-9 through various cross-coupling reactions (e.g., Suzuki reaction, Stille reaction, etc.). Finally, the compound of formula (I) is deprotected. By selecting a suitable catalyst (e.g., SPhos-Pd-G2), the compound of formula 1-7 can be directly converted to the desired compound of formula (I) through various cross-coupling reactions (e.g., Suzuki reaction, Stille reaction, etc.), and subsequent reactions (e.g., reductive amination, carboxylamine condensation, etc.).

[0407] Solution 1

[0408]

[0409] Alternatively, various compounds of Formula (I) can be prepared using the method described in Scheme 2. In the method shown in Scheme 2, first, a compound of Formula 1-1 is converted to a compound of Formula 1-3 by the same method as shown in Scheme 1. The compound of Formula 1-3 is converted to a compound of Formula 2-4 by a chlorination reaction. The compound of Formula 2-4 is converted to a compound of Formula 2-5A by condensation with an excess of hydrazine (or hydrazine hydrate); or the compound of Formula 2-4 is converted to a compound of Formula 2-5B by condensation with an equivalent amount of hydrazine (or hydrazine hydrate). Either the compound of Formula 2-5A or the compound of Formula 2-5B can be converted to a compound of Formula 2-6 by a ring closure reaction (e.g., thermal ring closure, and acid- or base-catalyzed ring closure reaction). The compound of Formula 2-6 is converted to a compound of Formula 1-7 by a halogenation reaction (e.g., chlorination, bromination, etc.). The compound of Formula 1-7 can be converted to the desired compound of Formula (I) by the method shown in Scheme 1. Scheme 2 is further divided into Scheme 2A and Scheme 2B, depending on whether the intermediate compound of Formula 2-5A or Formula 2-5B is obtained.

[0410] Option 2

[0411]

[0412] Alternatively, various compounds of formula (I) can be prepared using the method described in Scheme 3A. In the method shown in Scheme 3A, a carboxylic acid derivative compound of formula 3-1a (wherein X is a halogen or quasi-halogen, such as bromine, iodine, etc.; L1 is an aromatic ring or heteroaromatic ring; LG is a leaving group such as a halogen, alkoxy, -N(Me)OMe, etc.) is condensed to form a compound of formula 3-2a. The compound of formula 1-1 is diazotized and coupled with the compound of formula 3-2a to form a compound of formula 3-3. The compound of formula 3-3 is subjected to a ring closure reaction to form a compound of formula 3-4. The compound of formula 3-4 is condensed with hydrazine (or hydrazine hydrate) to form a compound of formula 3-5A. The compound of formula 3-5A is formed by protecting the NH group of the pyrazole with a suitable protecting group to form a compound of formula 3-6. The halogen or quasi-halogen in the compound of formula 3-6 is reacted through various cross-coupling reactions (e.g., Suzuki reaction, Stille reaction, Buchwald-Hartwig amination, etc.) to form the compound of formula 1-9. Finally, the compound of formula (I) is deprotected. By selecting a suitable catalyst, the compound of formula 3-5A can be directly reacted through various cross-coupling reactions (e.g., Suzuki reaction, Stille reaction, Buchwald-Hartwig amination, etc.) to form the desired compound of formula (I).

[0413] Option 3A

[0414]

[0415] Alternatively, various compounds of Formula (I) can be prepared by the methods described in Scheme 3B. When a compound of Formula 3-4 is condensed with a substituted hydrazine, a compound of Formula 3-5B can be formed. The halogen or quasi-halogen in the compound of Formula 3-5B can be reacted via various cross-coupling reactions (e.g., Suzuki reaction, Stille reaction, Buchwald-Hartwig amination, etc.) to form a compound of Formula 1-9B. Finally, deprotection is performed to form a compound of Formula (I).

[0416] Option 3B

[0417]

[0418] Alternatively, various compounds of formula (I) can be prepared using the method described in Scheme 4. In the method shown in Scheme 4, a carboxylic acid derivative compound of formula 3-1a (wherein X is a halogen or quasi-halogen, such as bromine, iodine, etc.; L1 is an aromatic ring or a heteroaromatic ring; LG is a leaving group such as a halogen, an alkoxy group, -N(Me)OMe, etc.) is condensed to form a compound of formula 4-3; or an aldehyde compound of formula 4-1 is subjected to an addition reaction and an oxidation reaction (such as using a Dess-Martin periodinane) to form a compound of formula 4-3. The compound of formula 1-1 is diazotized and coupled with the compound of formula 4-3 to form a compound of formula 4-4. The compound of formula 4-4 is subjected to a ring-closure reaction to form a compound of formula 3-4. The compound of formula 3-4 can be formed into the desired compound of formula (I) by the methods shown in Schemes 3A or 3B.

[0419] Option 4

[0420]

[0421] Unless otherwise specified or clearly contradicted by the context, all methods described in this specification can be performed in any suitable order. The use of any and all examples or exemplary language (e.g., "such as") provided in this specification is only used to better illustrate the present invention and does not limit the scope of the application otherwise claimed.

[0422] The preparation and properties of the compounds of formula (I) according to some embodiments of the present application are further described below with reference to specific examples. The starting materials used are known and commercially available, or can be synthesized using or according to methods known in the art.

[0423] Unless otherwise specified, all reactions in the examples were carried out under continuous magnetic stirring, and the reaction temperatures were expressed in degrees Celsius.

[0424] The reaction can be monitored by any suitable method known in the art, such as nuclear magnetic resonance spectroscopy (NMR), infrared spectroscopy (IR), spectrophotometry (such as UV-visible spectroscopy), liquid chromatography-mass spectrometry (LC-MS), mass spectrometry, high performance liquid chromatography, thin layer chromatography (or thin layer chromatography), etc. The product can 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 Ocean 100-200 mesh silica gel as a carrier. Thin layer chromatography (TLC) uses Merck's Silica gel 60F254 silica gel plates, and preparative thin layer chromatography (pre-TLC) uses Anhui Liangchen Silicon Source GF254 preparative silica gel plates.

[0425] The compound structures of the embodiments of the present application are determined by nuclear magnetic resonance spectroscopy (NMR) and / or liquid chromatography-mass spectrometry (LC-MS). The nuclear magnetic resonance spectrum is measured by a Bruker AVANCE-400 nuclear magnetic resonance instrument, and the determination solvent is usually deuterated dimethyl sulfoxide (DMSO-d6) or deuterated chloroform (CDCl3). The NMR chemical shift (δ) is given in parts per million (ppm) and the internal standard is tetramethylsilane (TMS). The LC-MS is measured by an Agilent 1100 series liquid chromatograph and a Bruker HCT-Ultra ion trap mass spectrometer.

[0426] Abbreviations

[0427] DIPEA N,N-Diisopropylethylamine

[0428] BINAP 1,1'-binaphthyl-2,2'-bis(diphenylphosphine)

[0429] Pd2(dba)3 tris(dibenzylideneacetone)dipalladium

[0430] Pd(dppf)Cl2 (1,1'-bis(diphenylphosphino)ferrocene)palladium dichloride

[0431] Pd(dppf)Cl2-DCM (1,1'-bis(diphenylphosphino)ferrocene)palladium dichloride-dichloromethane adduct

[0432] SPhos-Pd-G2 Chloro(2-dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II)

[0433] Example 1

[0434] 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)

[0435]

[0436] Step 1: Preparation of dimethyl 2-(2-(2-fluoro-6-methylphenyl)hydrazino)-3-oxoglutarate

[0437]

[0438] To a three-necked flask containing 2-fluoro-6-methylaniline (5.0 g, 40 mmol), hydrochloric acid (4 M, 54 mL) was added, cooled to 0 ° C, and an aqueous solution (30 mL) of sodium nitrite (2.8 g, 40 mmol) was slowly added dropwise and the reaction liquid temperature was kept at 5-10 ° C. After the addition was completed, stirring was continued at 5-10 ° C for 2 hours. Then, it was quickly added to a mixed solution of ethanol (30 mL) and water (60 mL) that was dissolved with vigorous stirring and sodium acetate (21.0 g, 264 mmol) to produce the product. The reaction mixture was stirred for 2 hours at room temperature and filtered with suction. Filter cakes torrefaction gave a crude yellow solid of 2-(2-(2-fluoro-6-methylphenyl)hydrazino)-3-oxoglutaric acid dimethyl ester (6.0 g). This crude product was directly used in the next step.

[0439] ESI-MS: m / z = 310.9 ([M+H] + ).

[0440] Step 2: Preparation of methyl 1-(2-fluoro-6-methylphenyl)-4-hydroxy-6-oxo-1,6-dihydropyridazine-3-carboxylate

[0441]

[0442] Dimethyl 2-(2-(2-fluoro-6-methylphenyl)hydrazino)-3-oxoglutarate (6.0 g, 19 mmol) was dissolved in dichlorobenzene (100 mL) and heated to reflux in a sealed tube. After heating for 4 hours, the reaction solution was cooled to room temperature and cyclohexane (300 mL) was added dropwise. The product crystallized and was filtered. The filter cake was dried to obtain 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 in a yield of 37%.

[0443] ESI-MS: m / z = 279.1 ([M+H] + ).

[0444] Step 3: Preparation of 1-(2-fluoro-6-methylphenyl)-4-hydroxy-6-oxo-1,6-dihydropyridazine-3-carboxamide

[0445]

[0446] Dissolve methyl 1-(2-fluoro-6-methylphenyl)-4-hydroxy-6-oxo-1,6-dihydropyridazine-3-carboxylate (2.0 g, 7.2 mmol) in a 7N methanolic ammonia solution (20 mL). Heat to reflux overnight in a sealed tube. Cool the reaction mixture to room temperature and concentrate to dryness to obtain a crude oily product (1.6 g) of 1-(2-fluoro-6-methylphenyl)-4-hydroxy-6-oxo-1,6-dihydropyridazine-3-carboxamide. This crude product was used directly in the next reaction.

[0447] ESI-MS: m / z = 264.1 ([M+H] + ).

[0448] Step 4: Preparation of 4-chloro-1-(2-fluoro-6-methylphenyl)-6-oxo-1,6-dihydropyridazine-3-carbonitrile

[0449]

[0450] 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 allowed to react overnight. The reaction mixture was poured into ice and stirred for 1 hour. The mixture was then 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 afford 4-chloro-1-(2-fluoro-6-methylphenyl)-6-oxo-1,6-dihydropyridazine-3-carbonitrile (800 mg, 3.04 mmol) as a white solid in a two-step yield of 50%.

[0451] ESI-MS: m / z = 264.0 ([M+H] + ).

[0452] Step 5: Preparation of 3-amino-5-(2-fluoro-6-methylphenyl)-1H-pyrazolo[4,3-c]pyridazin-6(5H)-one

[0453]

[0454] Dissolve 4-chloro-1-(2-fluoro-6-methylphenyl)-6-oxo-1,6-dihydropyridazine-3-carbonitrile (800 mg, 3.04 mmol) in ethanol (8 mL) and add 98% hydrazine hydrate (760 mg, 15 mmol). Seal the tube and heat to 100°C overnight. The reaction solution is cooled to room temperature, and the product precipitates and is filtered. The filter cake is dried to obtain a red solid 3-amino-5-(2-fluoro-6-methylphenyl)-1H-pyrazolo[4,3-c]pyridazin-6(5H)-one (600 mg, 2.3 mmol). Yield: 75%.

[0455] ESI-MS: m / z = 260.1 ([M+H] + ).

[0456] Step 6. Preparation of 3-bromo-5-(2-fluoro-6-methylphenyl)-1H-pyrazolo[4,3-c]pyridazin-6(5H)-one

[0457]

[0458] 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). Tert-butyl nitrite (240 mg) was added dropwise at 0°C. The reaction mixture was stirred at 0°C for 10 minutes, copper bromide (510 mg) was added, and stirring was continued for 20 minutes. The reaction mixture 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 phases were washed with brine, dried, filtered, and concentrated to yield crude 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.

[0459] ESI-MS: m / z = 323.0 ([M+H] + ).

[0460] Step 7: Preparation of Compound 1

[0461]

[0462] To a single-necked flask, crude 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) were added. The mixture was heated to 80°C under nitrogen and stirred for 3 hours. The reaction mixture was cooled to room temperature and concentrated. The residue was purified by preparative liquid chromatography (pre-HPLC) to afford Compound 1 (trifluoroacetate salt, 5.3 mg, 0.010 mmol) as a brown solid.

[0463] Example 2

[0464] Compound 2: Preparation of 5-(2-methoxy-6-methylphenyl)-3-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrazolo[4,3-c]pyridazin-6(5H)-one (Scheme 2A)

[0465]

[0466] Step 1: Preparation of dimethyl 2-(2-(2-methoxy-6-methylphenyl)hydrazino)-3-oxoglutarate

[0467]

[0468] 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 the starting material. Yield: 79%.

[0469] ESI-MS: m / z = 323.2 ([M+H] + ).

[0470] Step 2: Preparation of methyl 4-hydroxy-1-(2-methoxy-6-methylphenyl)-6-oxo-1,6-dihydropyridazine-3-carboxylate

[0471]

[0472] 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 the starting material. Yield 83%.

[0473] ESI-MS: m / z = 291.2 ([M+H] + ).

[0474] Step 3: Preparation of methyl 4-chloro-1-(2-methoxy-6-methylphenyl)-6-oxo-1,6-dihydropyridazine-3-carboxylate

[0475]

[0476] 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) and heated to 100°C under nitrogen. The mixture was stirred for 14 hours until the reaction was complete. The reaction solution was cooled to room temperature and concentrated to dryness. The residue was purified by column chromatography (petroleum ether / ethyl acetate: 3 / 1) to afford 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. The yield was 72%.

[0477] ESI-MS: m / z = 309.1 ([M+H] + ).

[0478] Step 4: Preparation of 4-hydrazino-1-(2-methoxy-6-methylphenyl)-6-oxo-1,6-dihydropyridazine-3-carboxylic acid hydrazide

[0479]

[0480] 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 anhydrous ethanol (24 mL). The mixture was heated to 80°C and stirred for 2 hours under nitrogen protection. The reaction was completed. The reaction solution was cooled to 0°C, and a solid precipitated and filtered. The filter cake was rinsed with cold anhydrous ethanol (approximately 0°C) and dried in vacuo to obtain a yellow solid, 4-hydrazino-1-(2-methoxy-6-methylphenyl)-6-oxo-1,6-dihydropyridazine-3-carboxylic acid hydrazide (2.06 g, 6.77 mmol). The yield was 88%.

[0481] ESI-MS: m / z = 305.2 ([M+H] + ).

[0482] Step 5: Preparation of 5-(2-methoxy-6-methylphenyl)-1H-pyrazolo[4,3-c]pyridazine-3,6(2H,5H)-dione

[0483]

[0484] 4-Hydrazino-1-(2-methoxy-6-methylphenyl)-6-oxo-1,6-dihydropyridazine-3-carboxylic acid hydrazide (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). The mixture was heated to 120°C and stirred under nitrogen for 15 hours until the reaction was complete. 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 afford 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. The yield was 90%.

[0485] ESI-MS: m / z = 273.1 ([M+H] + ).

[0486] Step 6: Preparation of 3-chloro-5-(2-methoxy-6-methylphenyl)-1H-pyrazolo[4,3-c]pyridazin-6(5H)-one

[0487]

[0488] 5-(2-methoxy-6-methylphenyl)-1H-pyrazolo[4,3-c]pyridazine-3,6(2H,5H)-dione (200 mg, 0.74 mmol), phosphorus oxychloride (334 uL, 3.67 mmol), and benzyltrimethylammonium chloride (136 mg, 0.74 mmol) were added to acetonitrile (100 mL). The mixture was heated to 70°C and stirred under nitrogen for 18 hours. The reaction was complete. 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 afford 3-chloro-5-(2-methoxy-6-methylphenyl)-1H-pyrazolo[4,3-c]pyridazine-6(5H)-one (95 mg, 0.33 mmol) as a yellow solid. The yield was 44%.

[0489] ESI-MS: m / z = 291.2 ([M+H] + ).

[0490] Step 7: Preparation of Compound 2

[0491]

[0492] 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). The mixture was heated to 100°C and stirred under nitrogen for 14 hours. The reaction was complete. 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 the crude product, which was slurried with methanol (1 mL) under an ice bath to obtain Compound 2 (61 mg, 0.14 mmol) as a yellow solid. The yield was 82%.

[0493] Example 4

[0494] 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)

[0495]

[0496] Step 1: Preparation of 4-bromo-N-methoxy-N-methylbenzamide

[0497]

[0498] 4-Bromobenzoyl chloride (5.0 g, 22.8 mmol) was dissolved in dichloromethane (50 mL) and cooled in an ice bath under nitrogen. N,O-dimethylhydroxylamine hydrochloride (2.667 g, 27.34 mmol) and triethylamine (6.32 mL, 45.6 mmol) were added sequentially. The mixture was allowed to warm to room temperature and stirred for 2 hours. The reaction was complete. Dilute hydrochloric acid (0.1 M, 100 mL) was added to quench the reaction. 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 to dryness under reduced pressure to afford 4-bromo-N-methoxy-N-methylbenzamide (5.46 g, 22.4 mmol) as a yellow oil. The yield was 98%.

[0499] ESI-MS: m / z = 244.0 ([M+H] + ).

[0500] Step 2: Preparation of methyl 5-(4-bromophenyl)-3,5-dioxopentanoate

[0501]

[0502] Under nitrogen, 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 with stirring. After completion of the addition, the mixture was incubated with stirring for 0.5 hours. The reaction flask was transferred to a dry ice-acetone bath and cooled to -70°C. A hexane solution of n-butyllithium (2.5 M, 3.3 mL, 8.2 mmol) was added dropwise. After completion of the addition, the mixture was incubated with stirring for 10 minutes. A solution of 4-bromo-N-methoxy-N-methylbenzamide (2.00 g, 8.19 mmol) in tetrahydrofuran (10 mL) was then added dropwise. After completion of the addition, the mixture was incubated with stirring for 1 hour. The reaction mixture was warmed to 0°C and quenched by the addition of saturated ammonium chloride solution (100 mL). The reaction solution was extracted with ethyl acetate (100 mL x 2). The organic phases were combined, washed with saturated brine (100 mL), 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 (1.346 g, 4.5 mmol) as a yellow oil, with a yield of 54%.

[0503] ESI-MS: m / z = 299.0 ([M+H] + ).

[0504] Step 3: Preparation of methyl 5-(4-bromophenyl)-4-(2-(2,4-dimethoxyphenyl)hydrazino)-3,5-dioxopentanoate

[0505]

[0506] Mix 2,4-dimethoxyaniline (200 mg, 1.31 mmol) with water (1.6 mL), stir in an ice bath, and sequentially add concentrated hydrochloric acid (0.8 mL) and an aqueous solution (1.2 mL) of sodium nitrite (90 mg, 1.31 mmol). After the addition is complete, stir for 0.5 hours to obtain a diazonium salt solution. Dissolve methyl 5-(4-bromophenyl)-3,5-dioxopentanoate (391 mg, 1.31 mmol) and sodium acetate (643 mg, 7.83 mmol) in a mixture of anhydrous ethanol (1.2 mL) and water (2.4 mL), and add the diazonium salt solution dropwise. After the addition is complete, stir at room temperature for 2 hours to complete the reaction. The reaction solution is 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%.

[0507] ESI-MS: m / z = 463.1 ([M+H] + ).

[0508] Step 4: Preparation of 6-(4-bromobenzoyl)-2-(2,4-dimethoxyphenyl)-5-hydroxypyridazin-3(2H)-one

[0509]

[0510] Methyl 5-(4-bromophenyl)-4-(2-(2,4-dimethoxyphenyl)hydrazinomethylene)-3,5-dioxopentanoate (100 mg, 0.22 mmol) was dissolved in o-dichlorobenzene (2 mL) and heated to 175°C with stirring under nitrogen for 5 hours. The reaction was complete. The reaction solution was cooled to room temperature and diluted with ethyl acetate (10 mL). The mixture was extracted three times with saturated sodium bicarbonate solution (10 mL x 3). The aqueous phases were combined. The pH of the aqueous phase was adjusted to 4-5 with saturated citric acid solution and extracted twice with ethyl acetate (20 mL x 2). The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to dryness under reduced pressure to obtain 6-(4-bromobenzoyl)-2-(2,4-dimethoxyphenyl)-5-hydroxypyridazin-3(2H)-one (67 mg, 0.16 mmol) as a yellow solid. The yield was 72%.

[0511] ESI-MS: m / z = 431.1 ([M+H] + ).

[0512] Step 5: Preparation of 3-(4-bromophenyl)-5-(2,4-dimethoxyphenyl)-1H-pyrazolo[4,3-c]pyridazin-6(5H)-one

[0513]

[0514] Dissolve 6-(4-bromobenzoyl)-2-(2,4-dimethoxyphenyl)-5-hydroxypyridazin-3(2H)-one (47 mg, 0.11 mmol) in n-butanol (2 mL). Add glacial acetic acid (31 μL, 0.55 mmol) and hydrazine hydrate (33 μL, 0.55 mmol). Heat to 120°C under nitrogen and stir for 15 hours until the reaction is complete. Cool the reaction mixture to room temperature, filter the precipitated solid, and dry the filter cake under vacuum to yield 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%.

[0515] ESI-MS: m / z = 427.1 ([M+H] + ).

[0516] Step 6: Preparation of compound 4

[0517]

[0518] 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 nitrogen and stirred for 15 hours until the reaction was complete. The reaction solution 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, which was slurried with methanol (0.5 mL) at room temperature to obtain yellow solid compound 4 (3.4 mg, 0.0077 mmol), with a yield of 33%.

[0519] Example 23

[0520] 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)

[0521]

[0522] Step 1: Preparation of 2-methoxy-6-fluorophenyldiazonium tetrafluoroborate

[0523]

[0524] Dry methyl tert-butyl ether (8 mL) was cooled to -5°C. Under nitrogen, boron trifluoride etherate (1.1 mL, 8.9 mmol) and a solution of 2-fluoro-6-methoxyaniline (614 mg, 4.35 mmol) in dry methyl tert-butyl ether (3 mL) were added sequentially. After stirring for 15 minutes, the reaction system was cooled to -15°C. A solution of tert-butyl nitrite (0.62 mL, 5.2 mmol) in dry methyl tert-butyl ether (3 mL) was added dropwise. After the addition, the reaction mixture was naturally warmed to 0°C, dry tetrahydrofuran (5 mL) was added, and stirring was continued at 0°C for 2 hours. The reaction mixture was filtered, and the filter cake was washed with methyl tert-butyl ether. 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 in a 91% yield.

[0525] 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

[0526]

[0527] Dissolve 6-(2-(4-bromophenyl)-2-oxoethyl)-2,2-dimethyl-4H-1,3-dioxin-4-one (694 mg, 2.13 mmol) in ethanol (20 mL), add sodium acetate (506 mg, 6.16 mmol), and cool to -5°C. Add a solution of 2-methoxy-6-fluorophenyldiazonium tetrafluoroborate (539 mg, 2.25 mmol) in acetonitrile (3 mL) dropwise, and stir for 20 minutes. Pour the reaction mixture into a mixture of ethyl acetate and aqueous ammonium chloride, and separate the layers. The aqueous phase is extracted with ethyl acetate, and the organic phases are combined. The organic phases are dried and concentrated to yield crude 6-(2-(4-bromophenyl)-1-(2-(2-fluoro-6-methoxyphenyl)hydrazinyl)-2-oxoethyl)-2,2-dimethyl-4H-1,3-dioxin-4-one. This crude product is used directly in the next reaction without purification.

[0528] ESI-MS: m / z = 477.1 ([M+H] + ).

[0529] Step 3: Preparation of 6-(4-bromobenzoyl)-2-(2-fluoro-6-methoxyphenyl)-5-hydroxypyridazin-3(2H)-one

[0530]

[0531] 6-(2-(4-bromophenyl)-1-(2-(2-fluoro-6-methoxyphenyl)hydrazine)-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 solution was cooled to room temperature and poured into n-heptane (120 mL) with stirring. The mixture was cooled in an ice-water bath to precipitate a solid. The resulting solid was collected by filtration. The filter cake was vacuum dried to give an orange-red solid 6-(4-bromobenzoyl)-2-(2-fluoro-6-methoxyphenyl)-5-hydroxypyridazin-3(2H)-one (518 mg, 1.23 mmol). The yield was 61%.

[0532] ESI-MS: m / z = 419.1 ([M+H] + ).

[0533] Step 4: Preparation of 3-(4-bromophenyl)-5-(2-fluoro-6-methoxyphenyl)-1H-pyrazolo[4,3-c]pyridazin-6(5H)-one

[0534]

[0535] This compound was prepared in 70% yield 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 the starting material.

[0536] ESI-MS: m / z = 415.1 ([M+H] + ).

[0537] Step 5: Preparation of compound 23

[0538]

[0539] This compound was prepared in 58% yield 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 the starting material.

[0540] Example 24

[0541] Compound 24: 5-(2-Fluoro-6-methoxyphenyl)-3-(4-(1-methylpiperidin-4-yl)phenyl)-1H-pyrazolo[4,3-c]pyridazin-6(5H)-one

[0542]

[0543] 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, and hydrogen gas was introduced into the solution. The reaction was stirred overnight at room temperature under a hydrogen atmosphere until complete. 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 afford 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 in a 53% yield.

[0544] Example 25

[0545] Compound 25: 5-(2,4-dimethoxyphenyl)-3-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrazolo[4,3-c]pyridazin-6(5H)-one (Scheme 3B)

[0546]

[0547] Step 1: Preparation of 3-(4-bromophenyl)-1-(2,4-dimethoxybenzyl)-5-(2,4-dimethoxyphenyl)-1H-pyrazolo[4,3-c]pyridazin-6(5H)-one

[0548]

[0549] 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), heated to 100°C, and stirred for 1 hour. The reaction mixture was cooled to room temperature, and the precipitated solid was collected by filtration. 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 in a yield of 36%.

[0550] ESI-MS: m / z = 577.2 ([M+H] + ).

[0551] 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

[0552]

[0553] 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). Under nitrogen, a toluene solution of sodium tert-amyloxide (3.5 M, 1.1 mL) was added, and the mixture was heated to 100°C and stirred overnight. The reaction mixture 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-red solid in a yield of 44%.

[0554] ESI-MS: m / z = 597.4 ([M+H] + ).

[0555] Step 3: Preparation of compound 25

[0556]

[0557] 1-(2,4-dimethoxybenzyl)-5-(2,4-dimethoxyphenyl)-3-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrazolo[4,3-c]pyridazine-6(5H)-one (200 mg, 0.34 mmol) was dissolved in trifluoroacetic acid (6 mL), anisole (0.3 mL) was added, heated to 80 ° C, and stirred for 2 hours. The reaction solution was cooled to room temperature, diluted with water (20 mL), and extracted three times with ethyl acetate. The aqueous phase was adjusted to pH = 8 with sodium carbonate solution to precipitate solids. The solids were collected by filtration and dried. The solid was slurried with methanol to give an orange solid compound 25 (90 mg, 0.20 mmol) with a yield of 60%.

[0558] Example 29

[0559] 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)

[0560]

[0561] Step 1: Preparation of dimethyl 2-(2-(2-(2-fluoro-6-methoxyphenyl)hydrazino)-3-oxoglutarate

[0562]

[0563] 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 the starting material. Yield: 94%.

[0564] ESI-MS: m / z = 327.2 ([M+H] + ).

[0565] Step 2: Preparation of methyl 4-hydroxy-1-(2-fluoro-6-methoxyphenyl)-6-oxo-1,6-dihydropyridazine-3-carboxylate

[0566]

[0567] 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-methoxy-6-methylphenyl)hydrazino)-3-oxoglutarate as the starting material. Yield 90%.

[0568] ESI-MS: m / z = 295.2 ([M+H] + ).

[0569] Step 3: Preparation of methyl 4-chloro-1-(2-fluoro-6-methoxyphenyl)-6-oxo-1,6-dihydropyridazine-3-carboxylate

[0570]

[0571] 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 the starting material. Yield: 84%.

[0572] ESI-MS: m / z = 313.2 ([M+H] + ).

[0573] Step 4: Preparation of methyl 4-hydrazino-1-(2-fluoro-6-methoxyphenyl)-6-oxo-1,6-dihydropyridazine-3-carboxylate

[0574]

[0575] 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). 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, 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 afford methyl 4-hydrazino-1-(2-fluoro-6-methoxyphenyl)-6-oxo-1,6-dihydropyridazine-3-carboxylate (2.3 g) as a yellow solid in a 59% yield.

[0576] ESI-MS: m / z = 309.1 ([M+H] + ).

[0577] Step 5: Preparation of 5-(2-fluoro-6-methoxyphenyl)-1H-pyrazolo[4,3-c]pyridazine-3,6(2H,5H)-dione

[0578]

[0579] 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 mixture of methanol (15 mL) and tetrahydrofuran (15 mL). A solution of lithium hydroxide monohydrate (436 mg, 10.38 mmol, 2.0 eq) in water (15 mL) 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 afford 5-(2-fluoro-6-methoxyphenyl)-1H-pyrazolo[4,3-c]pyridazine-3,6(2H,5H)-dione (1.4 g) as a brownish-red solid in a 99% yield.

[0580] ESI-MS: m / z = 277.2 ([M+H] + ).

[0581] Step 6: Preparation of 3-chloro-5-(2-fluoro-6-methoxyphenyl)-1H-pyrazolo[4,3-c]pyridazin-6(5H)-one

[0582]

[0583] This compound was prepared according to the procedure described in Example 2 (Step 6) using 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 the starting material. Yield: 28%.

[0584] ESI-MS: m / z = 295.1 ([M+H] + ).

[0585] Step 7: Preparation of compound 33

[0586]

[0587] This compound was prepared according to 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 instead of 3-chloro-5-(2-methoxy-6-methylphenyl)-1H-pyrazolo[4,3-c]pyridazin-6(5H)-one and (4-(4-methyl-3-oxopiperazin-1-yl)phenyl)boronic acid pinacol ester instead of 4-(4-methyl-1-piperazinyl)phenylboronic acid as the starting material. Yield 25%.

[0588] Example 30

[0589] 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)

[0590]

[0591] Step 1: Preparation of tert-butyl (2-fluoro-6-cyclopropylphenyl)carbamate

[0592]

[0593] This compound was prepared in 65% yield 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 the starting material.

[0594] ESI-MS: m / z=196.1([M+H-C4H8] + ).

[0595] Step 2: Preparation of 2-fluoro-6-cyclopropylaniline

[0596]

[0597] This compound was prepared in 87% yield according to the procedure described in Example 29 (Step 4) using tert-butyl (2-fluoro-6-cyclopropylphenyl)carbamate as the starting material.

[0598] ESI-MS: m / z = 152.1 ([M+H] + ).

[0599] Step 3: Preparation of 2-cyclopropyl-6-fluorophenyldiazonium tetrafluoroborate

[0600]

[0601] A mixture of dry methyl tert-butyl ether (3 mL) and dry tetrahydrofuran (3 mL) was cooled to -5°C. Under nitrogen, boron trifluoride etherate (489 μL, 3.97 mmol) and a solution of 2-fluoro-6-cyclopropylaniline (300 mg, 1.98 mmol) in dry tetrahydrofuran (3 mL) were added sequentially. After stirring for 15 minutes, the reaction system was cooled to -15°C. A solution of tert-butyl nitrite (246 mg, 2.38 mmol) in dry methyl tert-butyl ether (3 mL) was added dropwise. After the addition, the reaction mixture was naturally warmed to 0°C and stirred at 0°C for 1.5 hours. The reaction mixture was filtered, and the filter cake was washed with methyl tert-butyl (50 mL). The filter cake was collected and dried at room temperature to yield 2-cyclopropyl-6-fluorophenyldiazonium tetrafluoroborate (426 mg, 1.70 mmol) as a white solid in an 86% yield.

[0602] ESI-MS: m / z=163.1([M+H-BF4] + ).

[0603] Step 4: Preparation of methyl 5-(4-bromophenyl)-4-(2-(2-fluoro-6-cyclopropylphenyl)hydrazino)-3,5-dioxopentanoate

[0604]

[0605] Dissolve methyl 5-(4-bromophenyl)-3,5-dioxopentanoate (920 mg, 3.07 mmol) and anhydrous sodium acetate (757 mg, 9.22 mmol) in anhydrous ethanol (20 mL) and cool to -15°C. Add a solution of 2-cyclopropyl-6-fluorophenyldiazonium tetrafluoroborate (384 mg, 1.54 mmol) in acetonitrile (4 mL) dropwise. After the addition is complete, warm the reaction mixture to 0°C and continue stirring for 1.5 hours. The reaction mixture is concentrated under reduced pressure, diluted with water (60 mL), and extracted with ethyl acetate (20 mL x 3). The organic phases are combined and washed with saturated brine (60 mL), dried over anhydrous sodium sulfate, 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 in a yield of 61%.

[0606] ESI-MS: m / z = 461.0 ([M+H] + ).

[0607] Step 5: Preparation of 6-(4-bromobenzoyl)-2-(2-fluoro-6-cyclopropylphenyl)-5-hydroxypyridazin-3(2H)-one

[0608]

[0609] This compound was prepared in 38% yield 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 the starting material.

[0610] ESI-MS: m / z = 429.0 ([M+H] + ).

[0611] Step 6: Preparation of 3-(4-bromophenyl)-5-(2-fluoro-6-cyclopropylphenyl)-1H-pyrazolo[4,3-c]pyridazin-6(5H)-one

[0612]

[0613] This compound was prepared in 71% yield according to the procedure described in Example 4 (Step 5) using 6-(4-bromobenzoyl)-2-(2-fluoro-6-cyclopropylphenyl)-5-hydroxypyridazin-3(2H)-one instead of 6-(4-bromobenzoyl)-2-(2,4-dimethoxyphenyl)-5-hydroxypyridazin-3(2H)-one as the starting material.

[0614] ESI-MS: m / z = 425.1 ([M+H] + ).

[0615] 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

[0616]

[0617] Dissolve 3-(4-bromophenyl)-5-(2-fluoro-6-cyclopropylphenyl)-1H-pyrazolo[4,3-c]pyridazin-6(5H)-one (92 mg, 0.22 mmol) in dry N,N-dimethylformamide (5 mL) and cool to 0°C. Add sodium hydride (26 mg, 0.65 mmol) under nitrogen and stir at 0°C for 20 minutes. Add 2-(trimethylsilyl)ethoxymethyl chloride (111 mg, 0.67 mmol) dropwise, warm to room temperature, and stir for 2 hours. Pour the reaction mixture into water (50 mL) and extract with ethyl acetate three times (15 mL x 3). Combine the organic phases, wash with saturated brine (50 mL x 3), dry over anhydrous sodium sulfate, filter, and concentrate 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 in a yield of 67%.

[0618] ESI-MS: m / z = 555.0 ([M+H] + ).

[0619] 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

[0620]

[0621] 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). Under nitrogen, a toluene solution of sodium tert-amyloxide (3.5 M, 0.21 mL) was added, and the mixture was heated to 100°C and stirred overnight. The reaction mixture was poured into saturated aqueous ammonium chloride (60 mL) and extracted three times with ethyl acetate (20 mL x 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The residue was purified by column chromatography (ethyl acetate / triethylamine: 100 / 3) to give a red solid 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) in a yield of 42%.

[0622] ESI-MS: m / z = 575.2 ([M+H] + ).

[0623] Step 9: Preparation of compound 34

[0624]

[0625] 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 (36 mg, 0.063 mmol) in dichloromethane (10 mL) at 0°C was added trifluoroacetic acid (2.5 mL), the mixture was warmed to room temperature, and stirred for 2 hours. The reaction solution was neutralized with saturated aqueous sodium carbonate and extracted three times with dichloromethane (30 mL x 3). The organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The residue was dissolved in methanol (5 mL), a small amount of aqueous ammonia was added, stirred at room temperature for 1 hour, and then concentrated to dryness. The residue was purified by thin-layer chromatography (DCM / MeOH: 10 / 1) to afford Compound 34 (10 mg, 0.022 mmol) as a red solid in a 36% yield.

[0626] Other compounds in the examples were synthesized by methods similar to those described in the above synthesis schemes, and their characterization data are listed in the following table.

[0627]

[0628]

[0629]

[0630]

[0631]

[0632]

[0633]

[0634]

[0635]

[0636]

[0637]

[0638]

[0639]

[0640]

[0641]

[0642]

[0643]

[0644]

[0645]

[0646]

[0647]

[0648]

[0649]

[0650]

[0651]

[0652]

[0653] Biological activity detection methods and results:

[0654] 1. HPK1 kinase activity inhibition test

[0655] HPK1 kinase activity is manifested as autophosphorylation activity and phosphorylation of downstream substrates. No additional substrates are required during the autophosphorylation process, and ATP is consumed to produce ADP. The amount of the product is detected using the ADP-Glo reagent and luminescence method to reflect the activity of the kinase.

[0656] Test substances: compounds prepared in the examples of the present application.

[0657] Prepare compound stock solution: dissolve the test compound in 100% DMSO to make a 10 mM stock solution;

[0658] Prepare 4× kinase reaction buffer:

[0659] name Stock concentration volume Final concentration Tris 1M(25X) 240 μL 40mM <![CDATA[MgCl2]]> 1M(50X) 120 μL 20mM BSA 7.5％(75X) 80 μL 0.1％ DTT 1M(500X) 3μL 0.5mM <![CDATA[ddH2O]]> 5557μL

[0660] Prepare 2× HPK1 kinase solution:

[0661]

[0662] Prepare 4x ATP mix:

[0663]

[0664] Test steps:

[0665] Dilute the test compound stock solution 5-fold with 100% DMSO and perform 4-fold isocratic dilutions in a 96-well dilution plate. Add 1 μL of the compound to 49 μL of kinase reaction buffer and shake on a microplate shaker for 20 minutes. Transfer 2 μL of 2× HPK1 kinase solution to a 384-well plate, add 1 μL of the test compound to the 384-well plate (Greiner, 784075), centrifuge for 1 minute (1000 rpm / min), and incubate at 25°C for 10 minutes. Transfer 1 μL of 4× ATP mix to the 384-well plate, centrifuge for 1 minute (1000 rpm / min), and incubate at 25°C for 60 minutes. The final DMSO concentration in all reactions is 0.5%. Transfer 4 μL of ADP-Glo to the 384-well plate, centrifuge for 1 minute (1000 rpm / min), and incubate at 25°C for 40 minutes. Transfer 8 μL of the detection solution to a 384-well plate, centrifuge for 1 minute (1000 rpm / min), and incubate for 40 minutes at 25°C. Use a Biotek multi-function plate reader to read the fluorescence signal, and use a four-coefficient nonlinear fitting formula to calculate the IC50 (half-maximal inhibitory concentration) of the compound.

[0666] As shown in the examples, the compounds showed IC50 values in the following range: +++ = IC50 ≤ 50 nM, ++ = 50 nM <IC50≤500nM,+=500nM<IC50<2000nM。

[0667] Table 1 Inhibitory effect of compounds on HPK1 kinase activity

[0668]

[0669]

[0670]

[0671] The data in Table 1 show that the compounds of the examples of the present application have an inhibitory effect on the kinase activity of HPK1.

[0672] 2.ELISA detection of IL-2 secretion by Jurkat cells

[0673] Test steps:

[0674] Human Jurkat-E6-1 cells were incubated with various concentrations of test compounds in a humidified incubator at 37°C and 5% CO₂ for 30 minutes. The cells were then transferred to a cell culture plate pre-coated with anti-human CD3 antibody. Soluble anti-human CD28 antibody was then added and the cells were stimulated for 24 hours in a humidified incubator at 37°C and 5% CO₂. The cell culture medium was collected by centrifugation and transferred to a 96-well clear microplate (Thermo) pre-coated with anti-human IL-2 antibody. The plates were incubated at room temperature for 2 hours with gentle shaking. The plates were washed four times with wash buffer and the OD values were read using a microplate reader (Molecular Device, i3X) according to the ELISA MAX Deluxe Set Human IL-2 (BioLegend) kit protocol. The optimal standard curve was selected using the microplate reader software, and the corresponding concentrations were calculated based on the OD values of the standards. Results are expressed as the percentage of IL-2 secretion by compound-treated cells compared to DMSO-treated cells.

[0675] Table 2 Effects of compounds on IL-2 secretion by human Jurkat cells

[0676]

[0677]

[0678]

[0679]

[0680] The data in Table 2 show that compared with the blank control group, which was treated with DMSO, the compounds of the examples of the present application had a significant promoting effect on the secretion of cytokine IL-2 by Jurkat cells.

[0681] Unless otherwise defined, the terms used in this application have the same meanings as those commonly understood by those skilled in the art.

[0682] The embodiments described in this application are for illustrative purposes only and are not intended to limit the scope of protection of this application. Those skilled in the art may make various other substitutions, changes and improvements within the scope of this application. Therefore, this application is not limited to the above embodiments, but is only limited by the claims.

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt, deuterated isotope label, or stereoisomer thereof, in, R 1 Selected from: 1) Hydrogen, cyano, -OR a ; 2) Unsubstituted C 1-6 alkyl; R a Selected from unsubstituted C 1-6 alkyl; Cy A Selected from: 1) One of the following structures, in which the chemical bond terminal It indicates that it is connected to other atoms in the structure of formula (I) through this bond: 2) unsubstituted or optionally substituted by 1, 2 or 3 independently selected R 12 substituted phenyl, pyridyl, pyrimidinyl, pyrazolyl or thiazolyl, wherein: (a) Each R 12 R is independently selected from fluorine, chlorine, G1 , OR G1 ; or, (b) Cy A Contains 1 R 12 , the R 12 Select one of the following structures, wherein the chemical bond end in the structural formula It indicates that it is connected to other atoms in the structure of formula (I) through this bond: or, Cy A Contains 2 or 3 R's 12 , of which 1 R 12 Select one of the above structures, the rest R 12 are independently selected from: fluorine, chlorine, R other than hydrogen G1 、-OR G1 ; in, X is selected from CH and N; Y is selected from -CH2-, NH and O; E1 and E2 are independently selected from -CH2- and carbonyl, and E1 and E2 are not carbonyl at the same time; R G2 Selected from hydrogen, -OR G1 and -N(R G1 )2; Each R G1 Independently selected from: 1) hydrogen, methyl, ethyl, isopropyl, cyclopropyl, 3-oxetanyl, and 3-methyl-3-azetidinyl; 2) Two Rs attached to the same atom G1 The groups together with the atoms to which they are attached form a C 3-6 Monocyclic hydrocarbon ring or 3-6 membered monocyclic aliphatic heterocycle; 3) Two R atoms connected to two different ring atoms in the same monocyclic ring G1 The groups are connected and together with the ring atoms of the monocyclic ring form a ring structure, the two connected R G1 The groups together form a C2, C3 or C4 alkylene group; Cy B is optionally substituted by 1, 2 or 3 independently selected from R 13 Substituents substituted phenyl, pyridyl, pyrimidinyl, pyrazolyl; R 13 Selected from: 1) Oxo group, halogen atom, cyano group, -C(=O)NR a3 R b3 、-OR a3 、-NR a3 R b3 and -NR a3 C(=O)R b3 ; 2) unsubstituted or optionally substituted by 1, 2, 3 or 4 independently selected R 23 Substituents substituted C 1-6 Alkyl, C 3-6 monocyclic cycloalkyl; 3) respectively with Cy B The two adjacent ring atoms of the aryl or heteroaryl are connected to each other. 13 The substituents and the two ring atoms together form an unsubstituted or optionally substituted group with 1, 2 or 3 independently selected R 23 a C5, C6, C7 monocyclic alicyclic hydrocarbon group or a 5-membered, 6-membered, 7-membered monocyclic alicyclic heterocyclic group substituted with a substituent; R a3 、R b3 Each independently selected from: 1) Hydrogen; 2) is unsubstituted or optionally substituted by 1, 2 or 3 independently selected R 23 Substituents substituted C 1-4 Alkyl, C 3-6 Cycloalkyl; or, R attached to the same nitrogen atom a3 and R b3 Together with the nitrogen atom, it forms a 23 A 3- to 8-membered aliphatic heterocyclic group substituted with a substituent; R 23 Selected from: 1) Halogen atoms, -OR a5 、-NR a5 R b5 ; 2) is unsubstituted or optionally substituted by 1, 2 or 3 independently selected R 33 Substituents substituted C 1-6 Alkyl, C 3-7 Cycloalkyl; R a5 、R b5 Each independently selected from: 1) Hydrogen; 2) Unsubstituted C 1-4 alkyl; R 33 Selected from halogen atoms.

2. A compound of formula (I) or a pharmaceutically acceptable salt, deuterated isotope label, or stereoisomer thereof, in, R 1 is selected from hydrogen, cyano, methyl and methoxy; Cy A is unsubstituted or optionally substituted by 1, 2 or 3 independently selected from R 12 Substituents substituted phenyl, pyridyl, pyrimidinyl, thiazolyl, wherein 1) Each R 12 are independently selected from: fluorine, chlorine, R other than hydrogen G1 , OR G1 , or, 2) Cy A Contains 1 R 12 , the R 12 Select one of the following structures: or, Cy A Contains 2 or 3 R's 12 , of which 1 R 12 Select one of the above structures, the rest R 12 are independently selected from: fluorine, chlorine, R other than hydrogen G1 , OR G1 ; Each R G1 Independently selected from: 1) Hydrogen, 2) methyl, ethyl, isopropyl, cyclopropyl, 3-oxetanyl and 3-methyl-3-azetidinyl, which are optionally substituted by hydroxyl, C 1-6 Alkoxy or amino substitution; Cy B Select one of the following structures: R a3 and R b3 are independently selected from hydrogen, C 1-6 Alkyl and C 3-6 Cycloalkyl, or R a3 and R b3 Together with the two ring-forming atoms, it forms an unsubstituted 5- to 6-membered alicyclic hydrocarbon group or an unsubstituted 5- to 6-membered alicyclic heterocyclic group.

3. A compound of formula (I) or a pharmaceutically acceptable salt, deuterated isotope label, or stereoisomer thereof, in, R 1 is selected from hydrogen and methyl; Cy A is unsubstituted or optionally substituted by 1, 2 or 3 independently selected from R 12 substituted phenyl, pyridyl, pyrimidinyl, thiazolyl or substituted by A bicyclic ring fused with a 5-7 membered saturated aliphatic heterocyclic ring, or a The pyridine ring represented by the present invention is fused with a 5-7 membered saturated aliphatic heterocyclic ring, wherein Z is 1, Z=N, N is optionally connected to a Ry group, and Ro is selected from oxo, F, amino, optionally substituted with F, hydroxyl, amino, C 1-3 Alkoxy-substituted C 1-3 Alkyl, the 5-7 membered saturated aliphatic heterocycle can further form a ring with another 5-6 membered saturated aliphatic heterocycle containing a nitrogen heteroatom, wherein, R y Selected from H, C substituted by hydroxyl, halogen 1-6 Alkyl, C 3-6 Cycloalkyl, nitrogen-containing 4-6 membered saturated alicyclic group, oxygen-containing 5-6 membered saturated alicyclic group, -C(=O)Rs, Rs is selected from C optionally substituted by hydroxyl, amino, 5-6 membered nitrogen-containing alicyclic group 1-6 alkyl; 1) When Cy A Contains 1 R 12 , the R 12 Select one of the following structures: Among them, R x Selected from -OH, C 1-6 Alkyl, C1-6 alkoxy, -NH2, C 1-6 Alkylamino, 2) When Cy A Contains 2 or 3 R 12 When 1 R 12 Select one of the above structures, the rest R 12 Independently selected from: fluorine, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 alkylaminomethyl; Cy B Select one of the following structures: R a3 and R b3 are independently selected from hydrogen, optionally substituted C 1-6 Alkyl and C 3-6 Cycloalkyl; the substituent in the case of the above optional substitution is selected from fluorine, hydroxyl, C 1-6 Alkyl, C substituted by F 1-6 alkyl.

4. The compound according to claim 3 or a pharmaceutically acceptable salt, deuterated isotope-labeled substance, or stereoisomer thereof, wherein: When Cy A is phenyl, and R 12 When it is a heterocyclic group, R 12 Connected to the para or meta position of the phenyl group.

5. A compound of formula (I) or a pharmaceutically acceptable salt, deuterated isotope label, or stereoisomer thereof, in, R 1 is selected from hydrogen and methyl; Cy A Selected from phenyl, pyridyl, pyrimidinyl, thiazolyl or A bicyclic ring fused with a 5-7 membered saturated aliphatic heterocyclic ring, or a The pyridine ring represented by the present invention is fused with a 5-7 membered saturated aliphatic heterocyclic ring, wherein Z is 1, Z=N, which is optionally connected to a Ry group, and Ro is selected from oxo, F, amino, optionally substituted with F, hydroxyl, amino, C 1-3 Alkoxy-substituted C 1-3 Alkyl, the 5-7 membered saturated aliphatic heterocycle can further form a ring with another 5-6 membered saturated aliphatic heterocycle containing a nitrogen heteroatom; R y Selected from H, C substituted by hydroxyl, halogen 1-6 Alkyl, C 3-6 Cycloalkyl, nitrogen-containing 4-6 membered saturated alicyclic group, oxygen-containing 5-6 membered saturated alicyclic group, -C(=O)Rs, Rs is selected from C optionally substituted by hydroxyl, amino, 5-6 membered nitrogen-containing alicyclic group 1-6 alkyl; When Cy A When selected from phenyl, pyridyl, pyrimidinyl or thiazolyl, the substituent is one R 12 , R 12 Selected from wherein Rp is one or more selected from hydrogen, C optionally substituted by F, hydroxyl, amino 1-6 Alkyl; Rq is selected from hydroxyl, amino, C optionally substituted by 5-6 membered nitrogen-containing alicyclic group or 5-6 membered nitrogen-containing heteroaryl 1-3 The alkyl group is a spiro heterocyclic ring composed of two 4-5 membered nitrogen or oxygen rings, a 5-6 membered alicyclic group containing one or two heteroatoms selected from nitrogen and oxygen, wherein the alicyclic group is optionally replaced by F, C 1-3 Alkyl substitution; Cy B is optionally substituted by 1, 2 or 3 independently selected from R 13 Substituents substituted phenyl, pyridyl, pyrimidinyl, pyrazolyl; R 13 Selected from: 1) Oxo group, halogen atom, cyano group, -C(=O)NR a3 R b3 、-OR a3 、-NR a3 R b3 and -NR a3 C(=O)R b3 ; 2) unsubstituted or optionally substituted by 1, 2, 3 or 4 independently selected R 23 Substituents substituted C 1-6 Alkyl, C 3-6 monocyclic cycloalkyl; 3) respectively with Cy B The two adjacent ring atoms of the aryl or heteroaryl are connected to each other. 13 The substituents and the two ring atoms together form an unsubstituted or optionally substituted group with 1, 2 or 3 independently selected R 23 a C5, C6, C7 monocyclic alicyclic hydrocarbon group or a 5-membered, 6-membered, 7-membered monocyclic alicyclic heterocyclic group substituted with a substituent; R a3 、R b3 Each independently selected from: 1) Hydrogen; 2) is unsubstituted or optionally substituted by 1, 2 or 3 independently selected R 23 Substituents substituted C 1-4 Alkyl, C 3-6 Cycloalkyl; or, R attached to the same nitrogen atom a3 and R b3 Together with the nitrogen atom, it forms a 23 A 3- to 8-membered aliphatic heterocyclic group substituted with a substituent; R 23 Selected from: 1) Halogen atoms, -OR a5 、-NR a5 R b5 ; 2) is unsubstituted or optionally substituted by 1, 2 or 3 independently selected R 33 Substituents substituted C 1-6 Alkyl, C 3-7 Cycloalkyl; R a5 、R b5 Each independently selected from: 1) Hydrogen; 2) Unsubstituted C 1-4 alkyl; R 33 Selected from halogen atoms.

6. The compound according to claim 5 or a pharmaceutically acceptable salt, deuterated isotope label, or stereoisomer thereof, Cy A Selected from phenyl, R 12 Selected from wherein Rp is one or more selected from hydrogen, C optionally substituted by F, hydroxyl, amino 1-6 Alkyl; Rq is selected from hydroxyl, amino, C optionally substituted by 5-6 membered nitrogen-containing alicyclic group or 5-6 membered nitrogen-containing heteroaryl 1-3 Alkyl, spiro heterocycle consisting of two 4-5 membered nitrogen or oxygen-containing rings, 5-6 membered alicyclic heterocycle containing one or two heteroatoms selected from nitrogen and oxygen, the alicyclic heterocycle is optionally replaced by F, C 1-3 Alkyl substitution.

7. The compound according to any one of claims 1 or 5-6, or a pharmaceutically acceptable salt, deuterated isotope label, or stereoisomer thereof, wherein: Cy B phenyl, optionally substituted by 1, 2 or 3 substituents selected from the group consisting of H, F, -CN, C optionally substituted by F, amino 1-3 Alkyl, optionally substituted by F C 1-3 Alkoxy, C 3-6 Cycloalkyloxy and -C(=O)NR a3 R b3 , R a3 and R b3 are independently selected from hydrogen, C 1-4 Alkyl and optionally substituted with F C 1-3 Alkyl substituted C 3-6 Cycloalkyl, or R a3 and R b3 Together with the N atom, it forms an optionally hydroxyl group, C 1-3 Alkyl-substituted 4- to 5-membered aliphatic heterocyclic group.

8. The compound according to any one of claims 1 or 5-6, or a pharmaceutically acceptable salt, deuterated isotope label, or stereoisomer thereof, wherein: The Cy B Selected from the following structures:

9. A compound of formula (I) or a pharmaceutically acceptable salt, deuterated isotope label, or stereoisomer thereof, in, R 1 is selected from hydrogen and methyl; The Cy A Selected from the following structures: wherein W1 is selected from CH2 or oxygen; R T is selected from hydrogen or methyl; R V is selected from fluorine or methyl, R V The number of is 0, 1, or 2; Cy B Select one of the following structures: R a3 and R b3 are independently selected from hydrogen, C 1-6 Alkyl and C 3-6 Cycloalkyl, or R a3 and R b3 Together with the two ring-forming atoms, it forms an unsubstituted 5- to 6-membered alicyclic hydrocarbon group or an unsubstituted 5- to 6-membered alicyclic heterocyclic group.

10. A compound of formula (I) or a pharmaceutically acceptable salt, deuterated isotope label, or stereoisomer thereof, in, R 1 is H; Cy A Selected from: 1) unsubstituted or optionally substituted by 1, 2 or 3 independently selected R 12 Substituents substituted phenyl, pyridyl, pyrimidinyl, each R 12 are independently selected from: fluorine, chlorine, R other than hydrogen G1 , OR G1 ; 2) optionally 1, 2 or 3 independently selected from R 12 The substituents of phenyl, pyridyl, pyrimidinyl, one of which is selected from the following groups, Other R 12 are independently selected from: fluorine, chlorine, R other than hydrogen G1 , OR G1 ; 3) The following structure, Cy B Selected from in, R a3 is selected from the group consisting of methyl, ethyl, difluoromethyl, trifluoromethyl, isopropyl and cyclopropyl; E 1 independently selected from: -CH2- and oxygen; R G1 independently selected from the group consisting of: hydrogen, oxo, methyl, ethyl, isopropyl, cyclopropyl, 3-oxetanyl, and 3-methyl-3-azetidinyl; R 13 selected from hydrogen, fluorine, cyano and -C(=O)-N(R G3 )2; Each R G3 Independently selected from: 1) hydrogen, methyl, ethyl, isopropyl, cyclopropyl, oxetanyl, oxolanyl, azetidinyl or azopentyl; 2) Two Rs attached to the same atom G3 The groups together with the atoms to which they are attached form a C 3-6 Monocyclic hydrocarbon ring or 3-6 membered monocyclic aliphatic heterocycle; 3) Two R atoms connected to two different ring atoms in the same monocyclic ring G3 The groups are connected and together with the ring atoms of the monocyclic ring form a ring structure, the two connected R G3 The groups together form a C2, C3 or C4 alkylene group, a 2, 3 or 4-membered oxaalkylene group, or a 2, 3 or 4-membered azaalkylene group; And, when R G3 When it is not hydrogen, R G3 Unsubstituted or independently substituted with 1, 2 or 3 substituents selected from oxo, fluoro, hydroxy, methoxy, amino, methylamino, dimethylamino, methyl, ethyl or cyano.

11. A compound or a pharmaceutically acceptable salt, deuterated isotope-labeled substance, or stereoisomer thereof, wherein: The compound is selected from the following structures: 。 12 . A pharmaceutical composition comprising the compound according to claim 1 , or a pharmaceutically acceptable salt, deuterated isotope label, or stereoisomer thereof, and a pharmaceutically acceptable carrier.

13. Use of the compound of any one of claims 1 to 11 or a pharmaceutically acceptable salt, deuterated isotope label, stereoisomer thereof, or the pharmaceutical composition of claim 12 in the preparation of a medicament for preventing or treating a disease mediated by HPK1, wherein the disease is selected from benign or malignant tumors and diseases caused by viruses, wherein the benign or malignant tumor is selected from leukemia, lymphoma, multiple myeloma, lung cancer, hepatocellular carcinoma, bile duct cancer, gastric cancer, colorectal cancer, small intestinal leiomyosarcoma, breast cancer, ovarian cancer, cervical cancer, endometrial cancer, pancreatic cancer, nasopharyngeal cancer, oral cancer, laryngeal cancer, esophageal squamous cell carcinoma, kidney cancer, bladder cancer, malignant brain tumor, rhabdomyosarcoma, osteosarcoma, chondrosarcoma, fibrosarcoma of bone, prostate cancer, and benign and malignant skin tumors; and the virus is selected from hepatitis virus, herpes simplex virus, lymphocytic meningitis virus, influenza virus, SARS virus, and novel coronavirus.

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