Fused bicyclic compounds, processes for their preparation and their use in medicine

Abstract

The present disclosure relates to fused bicyclic compounds, processes for their preparation and their use in medicine. In particular, the present disclosure relates to a fused bicyclic compound of general formula (I), processes for their preparation, pharmaceutical compositions containing them and their use as therapeutic agents, in particular their use in the preparation of a medicament for inhibiting HPK1. Wherein the groups in general formula (I) are as defined in the specification.

Description

Technical Field

[0001] This disclosure pertains to the pharmaceutical field and relates to a fused bicyclic compound, its preparation method, and its pharmaceutical application. In particular, this disclosure relates to fused bicyclic compounds of general formula (I), their preparation methods, pharmaceutical compositions containing such compounds, and their use in the preparation of medicaments for inhibiting HPK1. Background Technology

[0002] Cancer treatment has evolved from radiotherapy and chemotherapy to targeted therapy and now includes immunotherapy. The main targets of tumor immunotherapy include immune checkpoints, immune agonists, Tregs, macrophages, and tumor microenvironment metabolites such as IDO and the A2AR pathway. Hematopoietic progenitor kinase 1 (HPK1, also known as mitogen-activated protein kinase kinase 1 or MAP4K1) is a negative regulator within T cells, playing a negative feedback regulatory role after TCR activation and is associated with T cell exhaustion. A well-understood signaling pathway is as follows: after TCR binds to MHC-peptide, LAT is phosphorylated, recruiting the GADS-SLP76 complex, leading to phosphorylation and pathway activation of downstream PLCs. Simultaneously, ZAP70 phosphorylates the Y381 site of HPK1, which binds to the SH2 region of SLP76, thereby phosphorylating the latter's S376 site. SLP76 S376 phosphorylation recruits 14-3-3, leading to ubiquitination and causing the disintegration of the entire TCR signalosome.

[0003] HPK1 is considered a good target for immunotherapy for the following three reasons: (1) HPK1 expression is limited to immune cells and has good safety profile; (2) HPK1 has multiple negative regulatory effects at different stages of the cancer-immune cycle. Inhibiting HPK1 can regulate the immunosuppressive functions of NK cells, DC cells, and T cells, and can also regulate B cell activation, among which T cell activation has been studied the most; (3) HPK1 kinase activity is important in inhibiting anti-cancer immune responses.

[0004] Studies have shown that HPK1 expression is associated with T cell exhaustion signatures, including CD3E, PD1, CTLA4, TIM-3, LAG-3, and TIGIT, and high HPK1 expression is associated with shorter survival. Analysis of the TCGA PanCancer database showed a positive correlation between HPK1 expression (but not other MAP4K family members) and PD1. HPK1 expression is upregulated in exhausted T cells, and HPK1, TIM3, and LAG3 expression is higher in T cells with high PD1 than in T cells with low PD1. Conversely, HPK1 expression is downregulated in CD4+ T cells of patients with systemic lupus erythematosus (SLE), and the SLEDAI score is negatively correlated with HPK1 mRNA levels. HPK1 expression is also downregulated in peripheral blood cells of patients with psoriatic arthritis (PsA).

[0005] HPK1 knockout mice show no abnormalities at rest. However, once the TCR is activated, the results are similar regardless of whether the mice are HPK1 knockout, HPK1 kinase-dead knock-in, or SLP76S376A knock-in, all of which activate an immune response. HPK1-deficient mice are more susceptible to experimental autoimmune encephalomyelitis (EAE). HPK1 kinase activity regulates TCR signaling and cytokine secretion in vitro; inhibiting HPK1 can alleviate PGE2 and adenosine-mediated immunosuppression. HPK1 kinase-dead mice inhibit tumor growth in vivo, and the anti-tumor effect of HPK1- / - mice almost disappears after the removal of CD8+ or CD4+ T cells, indicating that T cells mediate most of the immunosuppressive effects of HPK1.

[0006] The data from HPK1 knockout and kinase dead knock-in mice indicate that HPK1 mainly functions through kinase activity. However, some literature reports that its scaffold also has a certain function. Therefore, the development strategy for drugs that inhibit HPK1 is mainly based on kinase inhibitors, and there are also some PROTAC molecules.

[0007] Currently disclosed related patents include WO2021000925A1, WO2020103896A1, WO2019238067A1, WO2021032148A1, WO2019051199A1, WO2020193512A1, WO2020081689A1, etc. Summary of the Invention

[0008] The purpose of this disclosure is to provide a compound of general formula (I) or a pharmaceutically acceptable salt thereof:

[0009]

[0010] in:

[0011] Ring A is a five-membered heteroaryl group;

[0012] G is CR 4 Or nitrogen atoms;

[0013] G 1 For CR 5 Or nitrogen atoms;

[0014] G 2 For CR 6 Or nitrogen atoms;

[0015] G 3 For CR 7 Or nitrogen atoms;

[0016] G 4 For CR 8 Or nitrogen atoms;

[0017] G 5 For CR 9 Or nitrogen atoms;

[0018] R 3 They may be the same or different, and each is independently selected from hydrogen, halogen, alkyl, alkenyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxyl, and hydroxyalkyl; or

[0019] Two Rs 3 Together they form an oxygen group;

[0020] R and R 1 They may be the same or different, and each is independently selected from hydrogen atoms, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclic, aryl and heteroaryl;

[0021] R 2 They may be the same or different, and each is independently selected from hydrogen atom, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, -NR d R e -OR g -(CO)R f -(CO)NR d R e -(CO)OR g -SO2R f -SO2NR d R e -NR h (CO)R f -NR h (CO)NR d R e-NR h (CO)OR g -NR h SO2R f -NR h SO2NR d R e Nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl, wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are each independently and optionally selected from halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, -NR d2 R e2 -OR g2 -(CO)R f2 -(CO)NR d2 R e2 -(CO)OR g2 -SO2R f2 -SO2NR d2 R e2 -NR h2 (CO)R f2 -NR h2 (CO)NR d2 R e2 -NR h2 (CO)OR g2 -NR h2 SO2R f2 -NR h2 SO2NR d2 R e2 It is substituted by one or more substituents selected from nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl;

[0022] R d R e R f R g R h R d2 R e2 R f2 R g2 and R h2 They may be the same or different, and each is independently selected from hydrogen atoms, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl; or

[0023] R d and R e or R d2 and R e2Together with the attached nitrogen atom, a heterocyclic group is formed, which may be optionally substituted with one or more groups selected from halogen, alkyl, alkenyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, and hydroxyalkyl.

[0024] R 4 R 5 and R 6 They may be the same or different, and each is independently selected from hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, and -(CH2). s NR i R j -OR k Nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl, wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups is independently and optionally substituted by one or more substituents selected from halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups;

[0025] R 7 R 8 and R 9 They may be the same or different, and each is independently selected from hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, and -(CH2). u NR m R n -OR p Nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl, wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups is independently and optionally substituted by one or more substituents selected from halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups;

[0026] R i R j R m R n R k and R p They may be the same or different, and each is independently selected from hydrogen atoms, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl; or

[0027] R i and R j or R m and R nTogether with the attached nitrogen atom, a heterocyclic group is formed, which may be optionally substituted with one or more groups selected from halogen, alkyl, alkenyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, and hydroxyalkyl.

[0028] p is 0, 1, 2 or 3;

[0029] q can be 0, 1, 2, or 3;

[0030] r can be 0, 1, 2, or 3;

[0031] s can be 0, 1, 2, 3, or 4;

[0032] t is 0, 1, 2, 3, or 4; and

[0033] u can be 0, 1, 2, 3 or 4.

[0034] In some preferred embodiments of this disclosure, the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, wherein ring A is a 5-membered nitrogen-containing heteroaryl group; preferably pyrazolyl; more preferably pyrazol-4-yl.

[0035] Another aspect of this disclosure relates to a compound of general formula (II) or a pharmaceutically acceptable salt thereof:

[0036]

[0037] in,

[0038] R 2’ Selected from hydrogen atom, alkyl, alkenyl, ynyl, haloalkyl, -(CO)R f -(CO)NR d R e -(CO)OR g hydroxyalkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are each independently and optionally selected from halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, -NR d2 R e2 -OR g2 -(CO)R f2 -(CO)NR d2 R e2 -(CO)OR g2 -SO2R f2 -SO2NR d2 R e2 -NR h2 (CO)R f2 -NR h2 (CO)NR d2 Re2 -NR h2 (CO)OR g2 -NR h2 SO2R f2 -NR h2 SO2NR d2 R e2 It is substituted by one or more substituents selected from nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl;

[0039] r' is 0, 1, or 2;

[0040] G, G 1 G 2 , R, R 1 R 2 R 3 R 7 R 8 R 9 R d R e R f R g R d2 R e2 R f2 R g2 R h2 And t are as defined in general formula (I).

[0041] In some preferred embodiments of this disclosure, the compound represented by general formula (I) or (II) or a pharmaceutically acceptable salt thereof, wherein R 1 Selected from hydrogen atoms, C 1-6 Alkyl, C 1-6 Halogenated alkyl and C 1-6 Hydroxyalkyl; preferably hydrogen atom.

[0042] Another aspect of this disclosure relates to a compound of general formula (III) or a pharmaceutically acceptable salt thereof:

[0043]

[0044] in:

[0045] G, G 1 G 2 , R, R 2 R 2’ R 3 R 7 R 9 And t are as defined in general formula (I) or (II).

[0046] In some preferred embodiments of this disclosure, the compound represented by general formula (I), (II) or (III) or a pharmaceutically acceptable salt thereof, wherein G is CR 4 R 4 As defined in general formulas (I), (II) or (III).

[0047] In some preferred embodiments of this disclosure, the compound represented by general formula (I), (II) or (III) or a pharmaceutically acceptable salt thereof, wherein G 1 For CR 5 R 5 As defined in general formulas (I), (II) or (III).

[0048] In some preferred embodiments of this disclosure, the compound represented by general formula (I), (II) or (III) or a pharmaceutically acceptable salt thereof, wherein G 1 It is a nitrogen atom.

[0049] In some preferred embodiments of this disclosure, the compound represented by general formula (I), (II) or (III) or a pharmaceutically acceptable salt thereof, wherein G is CR 4 G 1 For CR 5 Or nitrogen atom, G 2 For CR 6 Or a nitrogen atom; or G is a nitrogen atom, G 1 For CR 5 G 2 For CR 6 ;R 4 R 5 and R 6 As defined in general formulas (I), (II) or (III);

[0050] Preferably, G is CR 4 G 1 For CR 5 And G 2 For CR 6 Or nitrogen atom, R 4 R 5 and R 6 As defined in general formulas (I), (II) or (III).

[0051] In some preferred embodiments of this disclosure, the compound represented by general formula (I), (II) or (III) or a pharmaceutically acceptable salt thereof, wherein G is CR 4 G 1 For nitrogen atoms, G 2 For CR 6 R 4 and R 6As defined in general formulas (I), (II) or (III).

[0052] In some preferred embodiments of this disclosure, the compound represented by general formula (II) or (III) or a pharmaceutically acceptable salt thereof, wherein R 2’ Selected from hydrogen atoms, C 1-6 Alkyl, C 1-6 Halogenated alkyl and C 1-6 Hydroxyalkyl, wherein the C 1-6 Alkyl groups are optionally selected from halogens, C 1-6 Alkyl, C 1-6 alkenyl, C 1-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy, cyano, amino, -NR d2 R e2 -OR g2 -(CO)R f2 -(CO)NR d2 R e2 -(CO)OR g2 -SO2R f2 -SO2NR d2 R e2 -NR h2 (CO)R f2 -NR h2 (CO)NR d2 R e2 -NR h2 (CO)OR g2 -NR h2 SO2R f2 -NR h2 SO2NR d2 R e2 nitro, hydroxyl, C 1-6 The alkyl group is substituted with one or more of the following substituents: hydroxyalkyl, 3-8 membered cycloalkyl, 3-8 membered heterocyclic, 6-10 membered aryl, and 5-10 membered heteroaryl; R d2 R e2 R f2 R g2 and R h2 As defined in general formula (II) or (III);

[0053] Preferably, R 2’ Selected from hydrogen atoms, C 1-6 Alkyl, C 1-6 Halogenated alkyl and C 1-6 Hydroxyalkyl, wherein the C 1-6 Alkyl groups are optionally selected from C 1-6Alkoxy, C 1-6 Halogenated alkoxy, cyano, amino, -NR d2 R e2 and -(CO)NR d2 R e2 One or more substituents in R are replaced. d2 and R e2 As defined in general formula (II) or (III);

[0054] More preferably, R 2’ C 1-6 Alkyl, the C 1-6 Alkyl groups are optionally selected from -(CO)NR d2 R e2 Replaced by, R d2 and R e2 They may be the same or different, and each is independently a hydrogen atom or a carbon atom. 1-6 Alkyl; more preferably, R 2’ It is an ethyl group.

[0055] In some preferred embodiments of this disclosure, the compound represented by general formula (I), (II) or (III) or a pharmaceutically acceptable salt thereof, wherein R 2 Selected from hydrogen atoms, C 1-6 Alkyl, C 1-6 Halogenated alkyl and C 1-6 Hydroxyalkyl, wherein the C 1-6 Alkyl groups are optionally selected from halogens, C 1-6 Alkyl, C 1-6 alkenyl, C 1-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy, cyano, amino, -NR d2 R e2 -OR g2 -(CO)R f2 -(CO)NR d2 R e2 -(CO)OR g2 -SO2R f2 -SO2NR d2 R e2 -NR h2 (CO)R f2 -NR h2 (CO)NR d2 R e2 -NR h2 (CO)OR g2 -NR h2 SO2R f2 -NRh2 SO2NR d2 R e2 nitro, hydroxyl, C 1-6 The alkyl group is substituted with one or more of the following substituents: hydroxyalkyl, 3-8 membered cycloalkyl, 3-8 membered heterocyclic, 6-10 membered aryl, and 5-10 membered heteroaryl; R d2 R e2 R f2 R g2 and R h2 As defined in general formulas (I), (II) or (III);

[0056] Preferably, R 2 Selected from hydrogen atoms, C 1-6 Alkyl, C 1-6 Halogenated alkyl and C 1-6 Hydroxyalkyl, wherein the C 1-6 Alkyl groups are optionally selected from C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, cyano, amino, -NR d2 R e2 and -(CO)NR d2 R e2 One or more substituents in R are replaced. d2 and R e2 As defined in general formulas (I), (II) or (III);

[0057] More preferably, R 2 They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl and C 1-6 Halogenated alkyl groups.

[0058] In some preferred embodiments of this disclosure, the compound represented by general formula (II) or (III) or a pharmaceutically acceptable salt thereof, wherein R 2 It is a hydrogen atom.

[0059] In some preferred embodiments of this disclosure, the compound represented by general formula (I), (II) or (III) or a pharmaceutically acceptable salt thereof, wherein R 9 Selected from hydrogen atoms, halogens, C 1-6 Alkyl and C 1-6 Halogenated alkyl; preferably C 1-6 Alkyl; more preferably methyl.

[0060] In some preferred embodiments of this disclosure, the compound represented by general formula (I), (II) or (III) or a pharmaceutically acceptable salt thereof, wherein R 7 Selected from hydrogen atoms, halogens, C 1-6 Alkyl and C 1-6Halogenated alkyl group; preferably hydrogen atom.

[0061] In some preferred embodiments of this disclosure, the compound represented by general formula (I), (II) or (III) or a pharmaceutically acceptable salt thereof, wherein R is selected from hydrogen atom, C 1-6 Alkyl, C 1-6 Halogenated alkyl and C 1-6 Hydroxyalkyl; preferably C 1-6 Alkyl; more preferably methyl.

[0062] In some preferred embodiments of this disclosure, the compound represented by general formula (I), (II) or (III) or a pharmaceutically acceptable salt thereof, wherein R 3 They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl and C 1-6 Halogenated alkyl group; preferably hydrogen atom.

[0063] In some preferred embodiments of this disclosure, the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, wherein G 3 For CR 7 R 7 As defined in general formula (I).

[0064] In some preferred embodiments of this disclosure, the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, wherein G 4 For CR 8 R 8 As defined in general formula (I).

[0065] In some preferred embodiments of this disclosure, the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, wherein G 5 For CR 9 R 9 As defined in general formula (I).

[0066] In some preferred embodiments of this disclosure, the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, wherein p is 1.

[0067] In some preferred embodiments of this disclosure, the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, wherein q is 1.

[0068] In some preferred embodiments of this disclosure, the compound represented by general formula (I) or a pharmaceutically usable salt thereof, wherein r is 0, 1 or 2, preferably 1.

[0069] In some preferred embodiments of this disclosure, the compound represented by general formula (II) or its pharmaceutically usable salt is used, wherein r' is 0 or 1, preferably 0.

[0070] In some preferred embodiments of this disclosure, the compound represented by general formula (I), (II) or (III) or its pharmaceutically usable salt is used, wherein t is 0, 1 or 2, preferably 0.

[0071] In some preferred embodiments of this disclosure, the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, wherein u is 0, 1 or 2.

[0072] In some preferred embodiments of this disclosure, the compound represented by general formula (I), (II) or (III) or its pharmaceutically acceptable salt, wherein s is 0, 1 or 2.

[0073] In some preferred embodiments of this disclosure, the compound represented by general formula (I), (II) or (III) or a pharmaceutically acceptable salt thereof, wherein R 4 Selected from hydrogen atoms, halogens, C 1-6 Alkyl and C 1-6 Halogenated alkyl group; preferably hydrogen atom.

[0074] In some preferred embodiments of this disclosure, the compound represented by general formula (I), (II) or (III) or a pharmaceutically acceptable salt thereof, wherein R 5 Selected from hydrogen atoms, halogens, C 1-6 Alkyl and C 1-6 Halogenated alkyl group; preferably hydrogen atom.

[0075] In some preferred embodiments of this disclosure, the compound represented by general formula (I), (II) or (III) or a pharmaceutically acceptable salt thereof, wherein R 6 Selected from hydrogen atoms, halogens, C 1-6 Alkyl and C 1-6 Halogenated alkyl group; preferably hydrogen atom.

[0076] In some preferred embodiments of this disclosure, the compound represented by general formula (I) or (II) or a pharmaceutically acceptable salt thereof, wherein R 8 Selected from hydrogen atoms, halogens, C 1-6 Alkyl and C 1-6 Halogenated alkyl group; preferably hydrogen atom.

[0077] In some preferred embodiments of this disclosure, the compound represented by general formula (I), (II) or (III) or a pharmaceutically acceptable salt thereof, wherein R d R e R f R g R h R d2 R e2 R f2 R g2and R h2 Whether the atoms are the same or different, and each is independently selected from hydrogen atoms, C atoms 1-6 Alkyl and C 1-6 Halogenated alkyl groups.

[0078] In some preferred embodiments of this disclosure, the compound represented by general formula (I), (II) or (III) or a pharmaceutically acceptable salt thereof, wherein R i R j R m R n R k and R p Whether the atoms are the same or different, and each is independently selected from hydrogen atoms, C atoms 1-6 Alkyl and C 1-6 Halogenated alkyl groups.

[0079] In some preferred embodiments of this disclosure, the compound represented by general formula (II) or a pharmaceutically acceptable salt thereof, wherein G is CR 4 G 1 For CR 5 Or nitrogen atom, G 2 For CR 6 Or a nitrogen atom; or G is a nitrogen atom, G 1 For CR 5 G 2 For CR 6 ;R 4 Selected from hydrogen atoms, halogens, C 1-6 Alkyl and C 1-6 Halogenated alkyl; R 5 Selected from hydrogen atoms, halogens, C 1-6 Alkyl and C 1-6 Halogenated alkyl; R 6 Selected from hydrogen atoms, halogens, C 1-6 Alkyl and C 1-6 Halogenated alkyl; R 1 Selected from hydrogen atoms, C 1-6 Alkyl, C 1-6 Halogenated alkyl and C 1-6 Hydroxyalkyl; R 2’ Selected from hydrogen atoms, C 1-6 Alkyl, C 1-6 Halogenated alkyl and C 1-6 Hydroxyalkyl, wherein the C 1-6 Alkyl groups are optionally selected from C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, cyano, amino, -NR d2 R e2 and -(CO)NR d2 R e2 One or more substituents in R are replaced. d2 and Re2 Whether the atoms are the same or different, and each is independently selected from hydrogen atoms, C atoms 1-6 Alkyl and C 1-6 Halogenated alkyl; R 2 They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl and C 1-6 Halogenated alkyl; R 7 Selected from hydrogen atoms, halogens, C 1-6 Alkyl and C 1-6 Halogenated alkyl; R 8 Selected from hydrogen atoms, halogens, C 1-6 Alkyl and C 1-6 Halogenated alkyl; R 9 Selected from hydrogen atoms, halogens, C 1-6 Alkyl and C 1-6 Haloalkyl; R is selected from hydrogen atom, C 1-6 Alkyl, C 1-6 Halogenated alkyl and C 1-6 Hydroxyalkyl; R 3 They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl and C 1-6 Haloalkyl; r' is 0 or 1; t is 0, 1 or 2.

[0080] In some preferred embodiments of this disclosure, the compound represented by general formula (III) or a pharmaceutically acceptable salt thereof, wherein G is CR 4 G 1 For CR 5 Or nitrogen atom, G 2 For CR 6 Or a nitrogen atom; or G is a nitrogen atom, G 1 For CR 5 G 2 For CR 6 ;R 4 Selected from hydrogen atoms, halogens, C 1-6 Alkyl and C 1-6 Halogenated alkyl; R 5 Selected from hydrogen atoms, halogens, C 1-6 Alkyl and C 1-6 Halogenated alkyl; R 6 Selected from hydrogen atoms, halogens, C 1-6 Alkyl and C 1-6 Halogenated alkyl; R 2’ Selected from C 1-6 Alkyl, the C 1-6 Alkyl groups are optionally selected from -(CO)NR d2 R e2 Replaced by, R d2 and R e2Whether the atoms are the same or different, and each is independently selected from hydrogen atoms, C atoms 1-6 Alkyl and C 1-6 Halogenated alkyl; R 2 They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl and C 1-6 Halogenated alkyl; R 7 Selected from hydrogen atoms, halogens, C 1-6 Alkyl and C 1-6 Halogenated alkyl; R 9 Selected from hydrogen atoms, halogens, C 1-6 Alkyl and C 1-6 Haloalkyl; R is selected from hydrogen atom, C 1-6 Alkyl, C 1-6 Halogenated alkyl and C 1-6 Hydroxyalkyl; R 3 They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl and C 1-6 Halogenated alkyl; and t is 0, 1 or 2.

[0081] In some preferred embodiments of this disclosure, the compound represented by general formula (III) or a pharmaceutically acceptable salt thereof, wherein G is CR 4 G 1 For CR 5 Or nitrogen atom, G 2 For CR 6 Or a nitrogen atom; or G is a nitrogen atom, G 1 For CR 5 G 2 For CR 6 ;R 4 For hydrogen atoms; R 5 For hydrogen atoms; R 6 For hydrogen atoms; R 2’ C 1-6 Alkyl, the C 1-6 Alkyl groups are optionally selected from -(CO)NR d2 R e2 Replaced by, R d2 and R e2 Whether the atoms are the same or different, and each is independently a hydrogen atom and a carbon atom. 1-6 Alkyl; R 2 For hydrogen atoms; R 7 For hydrogen atoms; R 9 C 1-6 Alkyl; R is C 1-6 Alkyl group; and t is 0.

[0082] Table A lists typical compounds disclosed herein, including but not limited to:

[0083]

[0084]

[0085] Another aspect of this disclosure relates to compounds of general formula (IA) or salts thereof.

[0086]

[0087] Where: R w It is an amino protecting group; preferably Ts or SEM;

[0088] Rings A, G, G 1 G 2 G 3 G 4 G 5 , R, R 2 R 3 p, q, r and t are as defined in general formula (I).

[0089] Another aspect of this disclosure relates to compounds of general formula (IIA) or salts thereof.

[0090]

[0091] Where: R w It is an amino protecting group; preferably Ts or SEM;

[0092] G, G 1 G 2 , R, R 2 R 2’ R 3 R 7 R 8 R 9 r' and t are as defined in general formula (II).

[0093] Another aspect of this disclosure relates to compounds of general formula (IIIA) or salts thereof.

[0094]

[0095] Where: R w It is an amino protecting group; preferably Ts or SEM;

[0096] G, G 1 G 2 , R, R 2 R 2’ R 3 R 7 R 9 And t are as defined in general formula (III).

[0097] Typical intermediate compounds disclosed herein include, but are not limited to:

[0098]

[0099]

[0100] Another aspect of this disclosure relates to a method for preparing a compound of general formula (I) or a pharmaceutically acceptable salt thereof, the method comprising:

[0101]

[0102] A compound of general formula (IA) or its salt is deprotected to give a compound of general formula (I) or its pharmaceutically usable salt.

[0103] Where: R w It is an amino protecting group; preferably Ts or SEM;

[0104] R 1 It is a hydrogen atom;

[0105] Rings A, G, G 1 G 2 G 3 G 4 G 5 , R, R 2 R 3 p, q, r and t are as defined in general formula (I).

[0106] Another aspect of this disclosure relates to a method for preparing a compound of general formula (II) or a pharmaceutically acceptable salt thereof, the method comprising:

[0107]

[0108] Compounds of general formula (IIA) or their salts are deprotected to give compounds of general formula (II) or their pharmaceutically usable salts;

[0109] Where: R w It is an amino protecting group; preferably Ts or SEM;

[0110] R 1 It is a hydrogen atom;

[0111] G, G 1 G 2 , R, R 2 R 2’ R 3 R 7 R 8 R 9 r' and t are as defined in general formula (II).

[0112] Another aspect of this disclosure relates to a method for preparing a compound of general formula (III) or a pharmaceutically acceptable salt thereof, the method comprising:

[0113]

[0114] Compounds of general formula (IIIA) or their salts are deprotected to give compounds of general formula (III) or their pharmaceutically usable salts;

[0115] Where: R w It is an amino protecting group; preferably Ts or SEM;

[0116] G, G 1 G 2 , R, R 2 R 2’ R 3 R 7 R 9 And t are as defined in general formula (III).

[0117] Another aspect of this disclosure relates to a pharmaceutical composition comprising a compound of formula (I), (II), (III) of this disclosure and a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.

[0118] This disclosure further relates to the use of compounds of general formulas (I), (II), (III) and Table A, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising thereof, in the preparation of a medicament for inhibiting HPK1.

[0119] This disclosure further relates to the use of compounds of general formulas (I), (II), (III) and Table A, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising thereof, in the preparation of medicaments for treating and / or preventing diseases or conditions by inhibiting HPK1; wherein the diseases or conditions are preferably selected from cancer, autoimmune diseases, inflammatory diseases, infectious diseases, cardiovascular diseases, neurodegenerative diseases, diabetes, and reproductive disorders; more preferably, the diseases or conditions are selected from cancer, allergies, asthma, sepsis, HIV infection, hepatitis B virus infection, ischemia, and atherosclerosis. The cancers are selected from brain cancer, thyroid cancer, head and neck cancer, pharyngeal cancer, oral cancer, salivary gland cancer, esophageal cancer, stomach cancer, lung cancer, liver cancer, kidney cancer, pancreatic cancer, bile duct cancer, colorectal cancer, colon cancer, rectal cancer, small bowel cancer, gastrointestinal stromal tumor, urothelial carcinoma, urethral cancer, bladder cancer, breast cancer, ovarian cancer, endometrial cancer, cervical cancer, fallopian tube cancer, testicular cancer, prostate cancer, leukemia, lymphoma, multiple myeloma, skin cancer, malignant lipoma, bone cancer, soft tissue sarcoma, neurofibroma, glioma, and neuroblastoma.

[0120] This disclosure further relates to the use of compounds of general formulas (I), (II), (III) and Table A, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising thereof, in the preparation of medicaments for the treatment and / or prevention of diseases or conditions of cancer, autoimmune diseases, inflammatory diseases, infectious diseases, cardiovascular diseases, neurodegenerative diseases, diabetes, and reproductive disorders, preferably, said diseases or conditions selected from cancer, allergies, asthma, sepsis, HIV infection, hepatitis B virus infection, ischemia, atherosclerosis, stroke, and Alzheimer's disease. The cancers mentioned are preferably selected from brain cancer, thyroid cancer, head and neck cancer, pharyngeal cancer, oral cancer, salivary gland cancer, esophageal cancer, stomach cancer, lung cancer, liver cancer, kidney cancer, pancreatic cancer, bile duct cancer, colorectal cancer, colon cancer, rectal cancer, small intestine cancer, gastrointestinal stromal tumor, urothelial carcinoma, urethral cancer, bladder cancer, breast cancer, ovarian cancer, endometrial cancer, cervical cancer, fallopian tube cancer, testicular cancer, prostate cancer, leukemia, lymphoma, multiple myeloma, skin cancer, malignant lipoma, bone cancer, soft tissue sarcoma, neurofibroma, glioma, and neuroblastoma.

[0121] This disclosure further relates to a method of inhibiting HPK1, comprising administering to a patient a therapeutically effective amount of a compound of general formula (I), (II), (III) and shown in Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising thereof.

[0122] This disclosure further relates to a method of treating and / or preventing a disease or condition by inhibiting HPK1, comprising administering to a patient a therapeutically effective amount of a compound of general formula (I), (II), (III) and Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising thereof. The diseases or conditions mentioned therein are preferably selected from cancer, autoimmune diseases, inflammatory diseases, infectious diseases, cardiovascular diseases, neurodegenerative diseases, diabetes, and reproductive disorders; more preferably, the diseases or conditions mentioned are selected from cancer, allergies, asthma, sepsis, HIV infection, hepatitis B virus infection, ischemia, arteriosclerosis, stroke, and Alzheimer's disease; the cancers mentioned are preferably selected from brain cancer, thyroid cancer, head and neck cancer, pharyngeal cancer, oral cancer, salivary gland cancer, esophageal cancer, stomach cancer, lung cancer, liver cancer, kidney cancer, pancreatic cancer, bile duct cancer, colorectal cancer, colon cancer, rectal cancer, small bowel cancer, gastrointestinal stromal tumor, urothelial carcinoma, urethral cancer, bladder cancer, breast cancer, ovarian cancer, endometrial cancer, cervical cancer, fallopian tube cancer, testicular cancer, prostate cancer, leukemia, lymphoma, multiple myeloma, skin cancer, malignant lipoma, bone cancer, soft tissue sarcoma, neurofibroma, glioma, and neuroblastoma.

[0123] This disclosure further relates to a method for treating and / or preventing diseases or conditions of cancer, autoimmune diseases, inflammatory diseases, infectious diseases, cardiovascular diseases, neurodegenerative diseases, diabetes, and reproductive disorders, comprising administering to a desired patient a therapeutically effective amount of a compound of general formula (I), (II), (III), and Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same; preferably, the disease or condition is selected from cancer, allergies, asthma, sepsis, HIV infection, hepatitis B virus infection, ischemia, atherosclerosis, stroke, and Alzheimer's disease. Alzheimer's disease; the cancers mentioned are preferably selected from brain cancer, thyroid cancer, head and neck cancer, pharyngeal cancer, oral cancer, salivary gland cancer, esophageal cancer, stomach cancer, lung cancer, liver cancer, kidney cancer, pancreatic cancer, bile duct cancer, colorectal cancer, colon cancer, rectal cancer, small bowel cancer, gastrointestinal stromal tumor, urothelial carcinoma, urethral cancer, bladder cancer, breast cancer, ovarian cancer, endometrial cancer, cervical cancer, fallopian tube cancer, testicular cancer, prostate cancer, leukemia, lymphoma, multiple myeloma, skin cancer, malignant lipoma, bone cancer, soft tissue sarcoma, neurofibroma, glioma, and neuroblastoma.

[0124] This disclosure further relates to a compound of general formula (I), (II), (III) and Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising thereof, which is used as a medicine.

[0125] This disclosure further relates to a compound of general formula (I), (II), (III) and Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising thereof, which acts as a drug for inhibiting HPK1.

[0126] This disclosure further relates to a compound of general formula (I), (II), (III) and Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising thereof, used as a medicament for treating and / or preventing a disease or condition by inhibiting HPK1; wherein the disease or condition is preferably selected from cancer, autoimmune diseases, inflammatory diseases, infectious diseases, cardiovascular diseases, neurodegenerative diseases, diabetes, and reproductive disorders; more preferably, the disease or condition is selected from cancer, allergies, asthma, sepsis, HIV infection, hepatitis B virus infection, ischemia, and atherosclerosis. Stroke and Alzheimer's disease; the cancers mentioned are preferably selected from brain cancer, thyroid cancer, head and neck cancer, pharyngeal cancer, oral cancer, salivary gland cancer, esophageal cancer, stomach cancer, lung cancer, liver cancer, kidney cancer, pancreatic cancer, bile duct cancer, colorectal cancer, colon cancer, rectal cancer, small intestine cancer, gastrointestinal stromal tumor, urothelial carcinoma, urethral cancer, bladder cancer, breast cancer, ovarian cancer, endometrial cancer, cervical cancer, fallopian tube cancer, testicular cancer, prostate cancer, leukemia, lymphoma, multiple myeloma, skin cancer, malignant lipoma, bone cancer, soft tissue sarcoma, neurofibroma, glioma, and neuroblastoma.

[0127] This disclosure further relates to a compound of general formula (I), (II), (III) and Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the thereof, used for the treatment and / or prevention of diseases or conditions of cancer, autoimmune diseases, inflammatory diseases, infectious diseases, cardiovascular diseases, neurodegenerative diseases, diabetes, and reproductive disorders, preferably, said diseases or conditions are selected from cancer, allergies, asthma, sepsis, HIV infection, hepatitis B virus infection, ischemia, atherosclerosis, stroke, and Alzheimer's disease; The cancers selected are preferably brain cancer, thyroid cancer, head and neck cancer, pharyngeal cancer, oral cancer, salivary gland cancer, esophageal cancer, stomach cancer, lung cancer, liver cancer, kidney cancer, pancreatic cancer, bile duct cancer, colorectal cancer, colon cancer, rectal cancer, small intestine cancer, gastrointestinal stromal tumor, urothelial carcinoma, urethral cancer, bladder cancer, breast cancer, ovarian cancer, endometrial cancer, cervical cancer, fallopian tube cancer, testicular cancer, prostate cancer, leukemia, lymphoma, multiple myeloma, skin cancer, malignant lipoma, bone cancer, soft tissue sarcoma, neurofibroma, glioma, and neuroblastoma.

[0128] Preferably, the brain cancer described in this disclosure is selected from glioblastoma multiforme or neuroblastoma; the soft tissue cancer is selected from fibrosarcoma, gastrointestinal sarcoma, rhabdomyosarcoma, leiomyosarcoma, dedifferentiated liposarcoma, pleomorphic liposarcoma, malignant fibrous histiocytoma, round cell sarcoma, and synovial sarcoma; the lymphoma is selected from Hodgkin's disease and non-Hodgkin's lymphoma (e.g., mantle cell lymphoma, diffuse large B-cell lymphoma, follicular center lymphoma, marginal zone B-cell lymphoma, lymphoplasmacytic lymphoma, and peripheral T-cell lymphoma); the liver cancer is preferably hepatocellular carcinoma; and the lung cancer is selected from non-small cell lung cancer. Lung cancer (NSCLC) (e.g., squamous cell carcinoma) and small cell lung cancer (SCLC); kidney cancer is selected from renal cell carcinoma, clear cell carcinoma, and renal eosinophilic tumor; leukemia is selected from chronic lymphocytic leukemia (CLL), chronic myeloid leukemia, acute lymphoblastic leukemia (ALL), T-cell acute lymphoblastic leukemia (T-ALL), chronic myeloid leukemia (CML), and acute myeloid leukemia (AML); skin cancer is selected from malignant melanoma, squamous cell carcinoma, basal cell carcinoma, and angiosarcoma; pharyngeal cancer is selected from nasopharyngeal carcinoma.

[0129] The colorectal cancer described in this disclosure is also known as colorectal cancer, preferably colon cancer or rectal cancer; the glioma described is preferably glioblastoma.

[0130] The active compounds can be formulated into forms suitable for administration via any appropriate route, using one or more pharmaceutically acceptable carriers through conventional methods. Therefore, the active compounds of this disclosure can be formulated into various dosage forms for oral administration, injection (e.g., intravenous, intramuscular, or subcutaneous), inhalation, or blow-through administration. The compounds of this disclosure can also be formulated into dosage forms such as tablets, hard or soft capsules, aqueous or oily suspensions, emulsions, injections, dispersible powders or granules, suppositories, lozenges, or syrups.

[0131] As a general guideline, the active compound is preferably expressed in a unit dose manner, or in a manner that allows the patient to self-administer a single dose. The unit dose of the disclosed compound or composition may be expressed as a tablet, capsule, sachet, bottled liquid, powder, granule, lozenge, suppository, regenerated powder, or liquid formulation. Suitable unit doses may range from 0.1 to 1000 mg.

[0132] In addition to the active compound, the pharmaceutical compositions disclosed herein may contain one or more excipients selected from the following: fillers (diluents), binders, wetting agents, disintegrants, or excipients. Depending on the method of administration, the composition may contain 0.1 to 99% by weight of the active compound.

[0133] Tablets contain an active ingredient and non-toxic, pharmaceutically acceptable excipients suitable for tablet preparation, used for mixing. These excipients may be inert excipients, granulating agents, disintegrants, binders, and lubricants. These tablets may be uncoated or coated using known techniques that mask the taste of the drug or delay disintegration and absorption in the gastrointestinal tract, thus providing sustained release over a longer period.

[0134] Oral formulations can also be provided using soft gelatin capsules in which the active ingredient is mixed with an inert solid diluent or in which the active ingredient is mixed with a water-soluble carrier or an oil solvent.

[0135] Aqueous suspensions contain active substances and excipients suitable for preparing aqueous suspensions, used for mixing. These excipients are suspending agents, dispersing agents, or wetting agents. Aqueous suspensions may also contain one or more preservatives, one or more coloring agents, one or more flavoring agents, and one or more sweeteners.

[0136] Oil suspensions are prepared by suspending the active ingredient in vegetable or mineral oil. Oil suspensions may contain thickeners. Sweeteners and flavoring agents mentioned above may be added to provide palatable formulations. These compositions may be preserved by adding antioxidants.

[0137] The pharmaceutical compositions disclosed herein may also be in the form of an oil-in-water emulsion. The oil phase may be a vegetable oil, a mineral oil, or a mixture thereof. Suitable emulsifiers may be naturally occurring phospholipids, and the emulsion may also contain sweeteners, flavoring agents, preservatives, and antioxidants. Such formulations may also contain modifiers, preservatives, colorants, and antioxidants.

[0138] The pharmaceutical compositions disclosed herein may be in the form of sterile injectable aqueous solutions. Acceptable solvents or media that can be used include water, Ringer's solution, and isotonic sodium chloride solution. The sterile injectable formulation may be a sterile injectable oil-in-water microemulsion in which the active ingredient is dissolved in the oil phase, which can be injected into the patient's bloodstream via local large-volume injection. Alternatively, the solution and microemulsion are preferably administered in a manner that maintains a constant circulating concentration of the compounds disclosed herein. To maintain such a constant concentration, a continuous intravenous delivery device can be used. An example of such a device is the Deltec CADD-PLUS™ 5400 intravenous infusion pump.

[0139] The pharmaceutical compositions disclosed herein may be in the form of sterile injectable aqueous or oil suspensions for intramuscular and subcutaneous administration. These suspensions may be formulated using suitable dispersants or wetting agents and suspending agents as described above, according to known techniques. The sterile injectable formulations may also be sterile injectable solutions or suspensions prepared in parenteral-acceptable, non-toxic diluents or solvents. Furthermore, sterile fixative oils may be conveniently used as solvents or suspension media. For this purpose, any blended fixative oil may be used. Additionally, fatty acids may also be used to prepare injectable formulations.

[0140] The disclosed compounds can be administered in suppository form for rectal administration. These pharmaceutical compositions can be prepared by mixing the drug with a suitable, non-irritating excipient that is solid at normal temperatures but liquid in the rectum, and thus dissolves in the rectum to release the drug.

[0141] The compounds disclosed herein can be administered by adding water to prepare water-soluble dispersible powders and granules. These pharmaceutical compositions can be prepared by mixing the active ingredient with a dispersant or wetting agent, a suspending agent, or one or more preservatives.

[0142] As is well known to those skilled in the art, the dosage of a drug depends on a variety of factors, including but not limited to: the activity of the specific compound used, the patient's age, the patient's weight, the patient's health status, the patient's behavior, the patient's diet, the timing of administration, the route of administration, the rate of excretion, the combination of drugs, the severity of the disease, etc.; in addition, the optimal treatment mode, such as the treatment pattern, the daily dosage of the compound, or the type of medicinal salt can be validated based on conventional treatment protocols.

[0143] Terminology Explanation

[0144] Unless otherwise stated, the terms used in the specification and claims have the following meanings.

[0145] The term "alkyl" refers to a saturated aliphatic hydrocarbon group, which is a straight-chain or branched group containing 1 to 20 carbon atoms, preferably an alkyl group having 1 to 12 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12) carbon atoms (i.e., C12). 1-12 Alkyl groups, more preferably alkyl groups having 1 to 6 carbon atoms (i.e., C1646-C ... 1-6Alkyl groups). Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2, 3-Dimethylpentyl, 2,4-Dimethylpentyl, 2,2-Dimethylpentyl, 3,3-Dimethylpentyl, 2-Ethylpentyl, 3-Ethylpentyl, n-Octyl, 2,3-Dimethylhexyl, 2,4-Dimethylhexyl, 2,5-Dimethylhexyl, 2,2-Dimethylhexyl, 3,3-Dimethylhexyl, 4,4-Dimethylhexyl, 2-Ethylhexyl, 3-Ethylhexyl, 4-Ethylhexyl, 2-Methyl-2-Ethylpentyl, 2-Methyl-3-Ethylpentyl, n-Nonyl, 2-Methyl-2-Ethylhexyl, 2-Methyl-3-Ethylhexyl, 2,2-Diethylpentyl, n-Decyl, 3,3-Diethylhexyl, 2,2-Diethylhexyl, and their various branched isomers, etc. More preferably, lower alkyl groups containing 1 to 6 carbon atoms are used. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, etc. Alkyl groups can be substituted or unsubstituted. When substituted, the substituents can be replaced at any usable connection point. The substituents are optionally selected from one or more of the following: D atom, halogen, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclic oxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0146] The term "alkylene" refers to a saturated straight-chain or branched aliphatic hydrocarbon group, which is a residue derived from a parent alkane by removing two hydrogen atoms from the same carbon atom or two different carbon atoms. It is a straight-chain or branched group containing 1 to 20 carbon atoms, preferably having 1 to 12 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12) carbon atoms (i.e., C64). 1-12 Alkylenes, more preferably alkylenes having 1 to 6 carbon atoms (i.e., C16-64 ...1-6 Alkylenes. Non-limiting examples of alkylenes include, but are not limited to, methylene (-CH2-), 1,1-ethylene (-CH(CH3)-), 1,2-ethylene (-CH2CH2)-, 1,1-propylene (-CH(CH2CH3)-), 1,2-propylene (-CH2CH(CH3)-), 1,3-propylene (-CH2CH2CH2-), 1,4-butylene (-CH2CH2CH2CH2-), etc. Alkylenes can be substituted or unsubstituted. When substituted, the substituent can be substituted at any usable linking point, and the substituent is optionally selected from one or more of alkenyl, alkynyl, alkoxy, haloalkoxy, cycloalkyloxy, heterocyclic alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocyclic, aryl, heteroaryl, cycloalkoxy, heterocyclic alkoxy, cycloalkylthio, heterocyclic alkylthio, and oxo.

[0147] The term "alkenyl" refers to an alkyl group containing at least one carbon-carbon double bond in a molecule, wherein the definition of alkyl is as described above, and preferably has 2 to 12 (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12) carbon atoms (i.e., C2, C3, C4, C5, C6, C7, C8, C9, C9, C10, C11, and C12) carbon atoms. 2-12 Alkenyl), more preferably alkenyl groups having 2 to 6 carbon atoms (i.e., C14-C ... 2-6 Alkenyl). Non-limiting examples include vinyl, propenyl, isopropenyl, butenyl, etc. Alkenyl groups can be substituted or unsubstituted, and when substituted, the substituents are preferably selected from one or more of alkoxy, halogen, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclic oxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0148] The term "alkynyl" refers to an alkyl group containing at least one carbon-carbon triple bond in a molecule, as defined above. Preferably, it has 2 to 12 (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12) carbon atoms (i.e., C64). 2-12 Alkyne group), more preferably alkynyl group having 2 to 6 carbon atoms (i.e., C12-C6 ... 2-6 (Alynyl). Non-limiting examples include: ethynyl, propynyl, butynyl, pentyynyl, hexynyl, etc. The alkynyl group can be substituted or unsubstituted, and when substituted, the substituent is preferably selected from one or more of alkoxy, halogen, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclic oxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0149] The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, wherein the cycloalkyl ring contains 3 to 20 carbon atoms, preferably 3 to 14 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, and 14) carbon atoms (i.e., 3 to 14-membered cycloalkyl), more preferably 3 to 8 (e.g., 3, 4, 5, 6, 7, and 8) carbon atoms (i.e., 3 to 8-membered cycloalkyl), and more preferably 3 to 6 carbon atoms (i.e., 3 to 6-membered cycloalkyl). Non-limiting examples of monocyclic cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cyclohepttrienyl, cyclooctyl, etc.; polycyclic cycloalkyl includes spirocycloalkyl, fused cycloalkyl, and bridged cycloalkyl.

[0150] The term "spirocycloalkyl" refers to a polycyclic group consisting of 5 to 20 quintiles, sharing a single carbon atom (called a spiro atom) between the rings, and may contain one or more double bonds. Preferably, it is 6 to 14 quintiles, more preferably 7 to 10 quintiles (e.g., 7, 8, 9, or 10 quintiles). Spirocycloalkyl groups are classified as monospirocycloalkyl or polyspirocycloalkyl (e.g., bispirocycloalkyl) based on the number of shared spiro atoms between the rings, with monospirocycloalkyl and bispirocycloalkyl being preferred. More preferably, it is a 3 / 4 quintile, 3 / 5 quintile, 3 / 6 quintile, 4 / 4 quintile, 4 / 5 quintile, 4 / 6 quintile, 5 / 3 quintile, 5 / 4 quintile, 5 / 5 quintile, 5 / 6 quintile, 5 / 7 quintile, 6 / 3 quintile, 6 / 4 quintile, 6 / 5 quintile, 6 / 6 quintile, 6 / 7 quintile, 7 / 5 quintile, or 7 / 6 quintile monospirocycloalkyl. Non-limiting examples of spirocycloalkyl groups include:

[0151]

[0152] The term "fused cycloalkyl" refers to a 5- to 20-membered polycyclic aromatic hydrocarbon group in which each ring in the system shares an adjacent pair of carbon atoms with other rings in the system, wherein one or more rings may contain one or more double bonds. Preferably, it is 6- to 14-membered, more preferably 7- to 10-membered (e.g., 7, 8, 9, or 10-membered). Depending on the number of constituent rings, it can be classified as bicyclic or polycyclic (e.g., tricyclic, tetracyclic) fused cycloalkyl, preferably bicyclic or tricyclic, more preferably 3- / 4-membered, 3- / 5-membered, 3- / 6-membered, 4- / 4-membered, 4- / 5-membered, 4- / 6-membered, 5- / 3-membered, 5- / 4-membered, 5- / 5-membered, 5- / 6-membered, 5- / 7-membered, 6- / 3-membered, 6- / 4-membered, 6- / 5-membered, 6- / 6-membered, 6- / 7-membered, 7- / 5-membered, or 7- / 6-membered bicyclic alkyl. Non-limiting examples of fused cycloalkyl groups include:

[0153]

[0154] The term "bridged cycloalkyl" refers to a 5- to 20-membered polycyclic carbon group in which any two rings share two non-directly bonded carbon atoms, and may contain one or more double bonds. Preferably, it is 6- to 14-membered, more preferably 7- to 10-membered (e.g., 7, 8, 9, or 10-membered). Depending on the number of rings, it can be classified as bicyclic or polycyclic (e.g., tricyclic, tetracyclic) bridged cycloalkyl, preferably bicyclic, tricyclic, or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of bridged cycloalkyl include:

[0155]

[0156] The cycloalkyl ring comprises a cycloalkyl group (including monocyclic, spirocyclic, fused, and bridged rings) fused to an aryl, heteroaryl, or heterocyclic alkyl ring as described above, wherein the ring attached to the parent structure is a cycloalkyl group. Non-limiting examples include... etc.; preferably

[0157] The cycloalkyl group can be substituted or unsubstituted. When substituted, the substituent can be replaced at any usable connection point. The substituent is preferably selected from one or more of halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclic oxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0158] The term "alkoxy" refers to -O-(alkyl), where alkyl is defined as described above. Non-limiting examples of alkoxy groups include methoxy, ethoxy, propoxy, and butoxy. Alkoxy groups can be optionally substituted or unsubstituted, and when substituted, the substituent is preferably selected from D atoms, halogens, alkoxy groups, haloalkyl groups, haloalkoxy groups, cycloalkyloxy groups, heterocyclic oxy groups, hydroxyl groups, hydroxyalkyl groups, cyano groups, amino groups, nitro groups, cycloalkyl groups, heterocyclic groups, aryl groups, and heteroaryl groups.

[0159] The term "heterocyclic group" refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituent containing 3 to 20 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) ring atoms (i.e., 3 to 20 membered heterocyclic groups), wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen, sulfur, S(O) or S(O)2, but excluding the ring portion of -OO-, -OS- or -SS-, and the remaining ring atoms are carbon. Preferably, it contains 3 to 14 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, and 14) ring atoms (i.e., 3 to 14-membered heterocyclic groups), wherein 1 to 4 (e.g., 1, 2, 3, and 4) are heteroatoms; more preferably, it contains 3 to 8 ring atoms (e.g., 3, 4, 5, 6, 7, and 8) (i.e., 3 to 8-membered heterocyclic groups) or 6 to 14 ring atoms (e.g., 6, 7, 8, 9, 10, 11, 12, 13, and 14), wherein 1 to 3 are heteroatoms (e.g., 1, 2, and 3); even more preferably, it contains 3 to 8 ring atoms, wherein 1 to 3 (e.g., 1, 2, and 3) are heteroatoms; most preferably, it contains 5 or 6 ring atoms, wherein 1 to 3 are heteroatoms. Non-limiting examples of monocyclic heterocyclic groups include pyrrolidinyl, tetrahydropyranyl, 1,2,3,6-tetrahydropyridyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, and homopiperazinyl. Polycyclic heterocyclic groups include spirocyclic, fused-ring, and bridged-ring heterocyclic groups.

[0160] The term "spiroheterocyclic group" refers to a 5- to 20-membered polycyclic heterocyclic group in which the monocyclic rings share a single atom (called a spiro atom), wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen, sulfur, S(O) or S(O)2, and the remaining ring atoms are carbon. It may contain one or more double bonds. Preferably, it is 6- to 14-membered (e.g., 6, 7, 8, 9, 10, 11, 12, 13, and 14-membered) (i.e., 6- to 14-membered spiroheterocyclic groups), more preferably 7- to 10-membered (e.g., 7, 8, 9, or 10-membered) (i.e., 7- to 10-membered spiroheterocyclic groups). Spiroheterocyclic groups are classified into monospiroheterocyclic groups or polyspiroheterocyclic groups (e.g., bispiroheterocyclic groups) according to the number of shared spiro atoms between the rings, with monospiroheterocyclic groups and bispiroheterocyclic groups being more preferred. More preferably, they are 3 / 4, 3 / 5, 3 / 6, 4 / 4, 4 / 5, 4 / 6, 5 / 3, 5 / 4, 5 / 5, 5 / 6, 5 / 7, 6 / 3, 6 / 4, 6 / 5, 6 / 6, 6 / 7, 7 / 5, or 7 / 6 monospirocyclic heterocyclic groups. Non-limiting examples of spirocyclic groups include:

[0161]

[0162] The term "fused heterocyclic group" refers to a 5- to 20-membered polycyclic heterocyclic group in which each ring in the system shares an adjacent pair of atoms with other rings in the system. One or more rings may contain one or more double bonds, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen, sulfur, S(O) or S(O)2, and the remaining ring atoms are carbon. Preferably, it is a 6- to 14-membered group (e.g., 6, 7, 8, 9, 10, 11, 12, 13, and 14-membered group) (i.e., a 6- to 14-membered fused heterocyclic group), more preferably a 7- to 10-membered group (e.g., 7, 8, 9, or 10-membered group) (i.e., a 7- to 10-membered fused heterocyclic group). Based on the number of constituent rings, fused heterocyclic groups can be classified into bicyclic or multicyclic (e.g., tricyclic, tetracyclic) fused heterocyclic groups, preferably bicyclic or tricyclic, more preferably 3-membered / 4-membered, 3-membered / 5-membered, 3-membered / 6-membered, 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 3-membered, 5-membered / 4-membered, 5-membered / 5-membered, 5-membered / 6-membered, 5-membered / 7-membered, 6-membered / 3-membered, 6-membered / 4-membered, 6-membered / 5-membered, 6-membered / 6-membered, 6-membered / 7-membered, 7-membered / 5-membered, or 7-membered / 6-membered bicyclic fused heterocyclic groups. Non-limiting examples of fused heterocyclic groups include:

[0163]

[0164] The term "bridged heterocyclic group" refers to a 5- to 20-membered polycyclic heterocyclic group in which any two rings share two non-directly bonded atoms. It may contain one or more double bonds, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen, sulfur, S(O), or S(O)₂, and the remaining ring atoms are carbon. Preferably, it is 6- to 14-membered (e.g., 6, 7, 8, 9, 10, 11, 12, 13, and 14-membered) (i.e., 6- to 14-membered bridged heterocyclic groups), more preferably 7- to 10-membered (e.g., 7, 8, 9, or 10-membered) (i.e., 7- to 10-membered bridged heterocyclic groups). Depending on the number of constituent rings, it can be classified as bicyclic or polycyclic (e.g., tricyclic, tetracyclic) bridged heterocyclic groups, preferably bicyclic, tricyclic, or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of bridged heterocyclic groups include:

[0165]

[0166] The heterocyclic ring comprises a heterocyclic group (including monocyclic, spirocyclic, fused heterocyclic, and bridged heterocyclic rings) fused to an aryl, heteroaryl, or cycloalkyl ring as described above, wherein the ring connected to the parent structure is a heterocyclic group, and non-limiting examples include:

[0167] wait.

[0168] The heterocyclic group can be substituted or unsubstituted. When substituted, the substituent can be substituted at any usable connection point. The substituent is preferably selected from one or more of halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclic oxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0169] The term "aryl" refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (fused polycyclic) group having a conjugated π-electron system, preferably 6- to 10-membered, such as phenyl and naphthyl. The aryl ring comprises an aryl ring fused to a heteroaryl, heterocyclic, or cycloalkyl ring as described above, wherein the ring attached to the parent structure is an aryl ring, and non-limiting examples include:

[0170]

[0171]

[0172] The aryl group can be substituted or unsubstituted. When substituted, the substituent can be substituted at any usable connection point. The substituent is preferably selected from one or more of halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclic oxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0173] The term "heteroaryl" refers to a heteroaryl system comprising 1 to 4 heteroatoms (e.g., 1, 2, 3, and 4) and 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur, and nitrogen. The heteroaryl is preferably 5 to 10-membered (e.g., 5, 6, 7, 8, 9, or 10-membered) (i.e., 5 to 10-membered heteroaryl), more preferably 5- or 6-membered, such as furanyl, thiophene, pyridinyl, pyrroleyl, N-alkylpyrroleyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, etc. The heteroaryl ring comprises a heteroaryl ring fused to an aryl, heterocyclic, or cycloalkyl ring as described above, wherein the ring connected to the parent structure is a heteroaryl ring, and non-limiting examples include:

[0174]

[0175] The heteroaryl group can be substituted or unsubstituted. When substituted, the substituent can be replaced at any usable connection point. The substituent is preferably selected from one or more substituents selected from halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclic oxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0176] The aforementioned cycloalkyl, heterocyclic, aryl, and heteroaryl residues include residues derived from removing one hydrogen atom from a parent ring atom, or residues derived from removing two hydrogen atoms from the same ring atom or two different ring atoms of the parent, namely "divalent cycloalkyl", "divalent heterocyclic", "aryl", and "heteroaryl".

[0177] The term "amino protecting group" is used to protect the amino group by a group that is easily removed, so that the amino group remains unchanged when other parts of the molecule react. Non-limiting examples include (trimethylsilyl)ethoxymethyl (SEM), tetrahydropyranyl, tert-butoxycarbonyl, acetyl, benzyl, allyl, p-methylbenzenesulfonyl (Ts), and p-methoxybenzeneyl, etc. These groups may optionally be replaced by 1-3 substituents selected from halogens, alkoxy groups, or nitro groups. The amino protecting group is preferably (trimethylsilyl)ethoxymethyl or p-methylbenzenesulfonyl.

[0178] The term "hydroxyl protecting group" refers to a hydroxyl derivative that is typically used to block or protect the hydroxyl group in a reaction on other functional groups of a compound. As an example, preferably, the hydroxyl protecting group can be triethylsilyl, triisopropylsilyl, tert-butyldimethylsilyl (TBS), tert-butyldiphenylsilyl, methyl, tert-butyl, allyl, benzyl, methoxymethyl (MOM), ethoxyethyl, 2-tetrahydropyranyl (THP), formyl, acetyl, benzoyl, p-nitrobenzoyl, etc.

[0179] The term “cycloalkyloxy” refers to cycloalkyl-O-, where the cycloalkyl group is as defined above.

[0180] The term “heterocyclic oxy group” refers to the heterocyclic group -O-, where the heterocyclic group is as defined above.

[0181] The term "alkylthio" refers to alkyl-S-, where the alkyl group is as defined above.

[0182] The term "halogenated alkyl" refers to an alkyl group that has been substituted with one or more halogens, wherein the alkyl group is as defined above.

[0183] The term "haloalkoxy" refers to an alkoxy group that is substituted by one or more halogens, wherein the alkoxy group is as defined above.

[0184] The term “deuterated alkyl” refers to an alkyl group that is replaced by one or more deuterium atoms, wherein the alkyl group is as defined above.

[0185] The term "hydroxyalkyl" refers to an alkyl group that is substituted with one or more hydroxyl groups, wherein the alkyl group is as defined above.

[0186] The term "halogen" refers to fluorine, chlorine, bromine, or iodine.

[0187] The term "hydroxyl group" refers to -OH.

[0188] The term "thiol" refers to -SH.

[0189] The term "amino" refers to -NH2.

[0190] The term "cyano" refers to -CN.

[0191] The term "nitro" refers to -NO2.

[0192] The term "oxo" refers to "=O".

[0193] The term "carbonyl" refers to C=O.

[0194] The term "carboxyl group" refers to -C(O)OH.

[0195] Ts refers to p-methylbenzenesulfonyl group.

[0196] SEM stands for (trimethylsilyl)ethoxymethyl.

[0197] The term "carboxylic acid ester group" refers to -C(O)O(alkyl), -C(O)O(cycloalkyl), (alkyl)C(O)O- or (cycloalkyl)C(O)O-, where alkyl and cycloalkyl are as defined above.

[0198] The compounds disclosed herein can exist in specific stereoisomer forms. The term "stereoisomer" refers to isomers with the same structure but different spatial arrangements of atoms. These include cis and trans (or Z and E) isomers, (-)- and (+)- isomers, (R)- and (S)- enantiomers, diastereomers, (D)- and (L)- isomers, tautomers, blocked isomers, conformational isomers, and mixtures thereof (such as racemic mixtures and mixtures of diastereomers). Substituents in the compounds disclosed herein may contain additional asymmetric atoms. All such stereoisomers and mixtures thereof are included within the scope of this disclosure. Optically active (-)- and (+)- isomers, (R)- and (S)- enantiomers, and (D)- and (L)- isomers can be prepared by chiral synthesis, chiral reagents, or other conventional techniques. This disclosure discloses an isomer of a compound, which can be prepared by asymmetric synthesis or with chiral auxiliaries, or, when the molecule contains a basic functional group (such as an amino group) or an acidic functional group (such as a carboxyl group), by forming a salt of the diastereomer with a suitable optically active acid or base, followed by diastereomer resolution using conventional methods known in the art to obtain the pure isomer. Furthermore, the separation of enantiomers and diastereomers is typically performed by chromatography.

[0199] In the chemical structure of the compounds described in this disclosure, the bonds... This indicates that the configuration is not specified; that is, if chiral isomers exist in the chemical structure, the bond... It can be or Or simultaneously include and Two configurations.

[0200] The compounds and intermediates disclosed herein may also exist in different tautomer forms, and all such forms are included within the scope of this disclosure. The terms "tautomer" or "tautomer form" refer to structural isomers with different energies that can interconvert via low energy barriers. For example, proton tautomers (also known as proton transfer tautomers) include interconversions via proton transfer, such as keto-enol and imine-enamine, lactam-lactamimide isomerization. Examples of keto-enol equilibrium are between A and B as shown below.

[0201]

[0202] For example, when referring to pyrazolyl, it should be understood as including any one or a mixture of two tautomers of the following two structures.

[0203]

[0204] All tautomers are within the scope of this disclosure. The nomenclature of compounds does not exclude any tautomers.

[0205] The compounds disclosed herein include all suitable isotopic derivatives thereof. The term "isotopic derivative" refers to a compound in which at least one atom is replaced by an atom having the same atomic number but a different atomic mass. Examples of isotopes that may be introduced into the compounds of this disclosure include stable and radioactive isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine, and iodine, for example, […]. 2 H (deuterium, D) 3 H (tritium, T) 11 C 13 C 14 C 15 N、 17 O、 18 O、 32 P, 33 P, 33 S, 34 S, 35 S, 36 S, 18 F, 36 Cl、 82 Br、 123 I, 124 I, 125 I, 129 I and 131 Grade I, with deuterium as the preferred grade.

[0206] Compared to undeuterated drugs, deuterated drugs offer advantages such as reduced toxicity, increased drug stability, enhanced efficacy, and prolonged biological half-life. All isotopic variations of the compounds disclosed herein, regardless of radioactivity, are included within the scope of this disclosure. Each available hydrogen atom bonded to a carbon atom can be independently replaced by a deuterium atom, wherein the deuterium substitution can be partial or complete; partial deuterium substitution refers to the replacement of at least one hydrogen atom with at least one deuterium atom.

[0207] "Optional" or "optional" means that the event or situation subsequently described may, but does not have to, occur; the description includes the possibility or possibility that the event or situation may or may not occur. For example, "optionally halogenated or cyano-substituted C..." 1-6 "Alkyl" means that halogens or cyano groups may or may not be present. This description includes cases where alkyl groups are substituted by halogens or cyano groups and cases where alkyl groups are not substituted by halogens or cyano groups.

[0208] "Substituted" refers to one or more hydrogen atoms in a group, preferably 1 to 6, more preferably 1 to 3 hydrogen atoms, which are independently substituted by the corresponding number of substituents. Those skilled in the art can determine possible or impossible substitutions without much effort (through experimentation or theory). For example, an amino or hydroxyl group with free hydrogen may be unstable when combined with a carbon atom having an unsaturated bond (such as an alkene).

[0209] "Pharmaceutical composition" means a mixture containing one or more of the compounds described herein or their physiologically / pharmacologically acceptable salts or prodrugs, along with other chemical components, such as physiologically / pharmacologically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration to a living organism, thereby promoting the absorption of the active ingredient and the exertion of its biological activity.

[0210] "Pharmacologically acceptable salt" refers to the salt of the compounds disclosed herein, which may be selected from inorganic or organic salts. Such salts are safe and effective when used in mammals and possess the expected biological activity. The salt can be prepared separately during the final isolation and purification of the compound, or by reacting a suitable group with a suitable base or acid. Bases commonly used to form pharmaceutically acceptable salts include inorganic bases, such as sodium hydroxide and potassium hydroxide, and organic bases, such as ammonia. Acids commonly used to form pharmaceutically acceptable salts include both inorganic and organic acids.

[0211] For the purposes of pharmaceuticals or pharmacologically active agents, the term "therapeutic effective amount" refers to a sufficient quantity of a drug or agent that is non-toxic but achieves the desired effect. The determination of the effective amount varies from person to person, depending on the recipient's age and general condition, as well as the specific active substance. The appropriate effective amount in a given case can be determined by a person skilled in the art based on routine testing.

[0212] As used herein, the term "pharmaceutically acceptable" means that these compounds, materials, compositions, and / or dosage forms are suitable for contact with patient tissues without excessive toxicity, irritation, allergic reactions, or other problems or complications, within reasonable medical judgment, have a reasonable benefit / risk ratio, and are effective for their intended use.

[0213] As used herein, the singular forms of “a,” “an,” and “the” include plural references, and vice versa, unless the context clearly indicates otherwise.

[0214] When the term "about" is applied to parameters such as pH, concentration, temperature, etc., it indicates that the parameter can vary by ±10%, and sometimes more preferably within ±5%. As those skilled in the art will understand, when a parameter is not critical, figures are usually given for illustrative purposes only, not as limitations.

[0215] The method for synthesizing the compounds disclosed herein

[0216] In order to achieve the purpose of this disclosure, the following technical solution is adopted:

[0217] Option 1

[0218] This disclosure relates to a method for preparing a compound of general formula (I) or a pharmaceutically acceptable salt thereof, the method comprising:

[0219]

[0220] A compound of general formula (IA) or its salt, under acidic or basic conditions, undergoes a deprotection reaction to yield a compound of general formula (I) or its pharmaceutically usable salt.

[0221] Where: R w It is an amino protecting group; preferably Ts or SEM;

[0222] R 1 It is a hydrogen atom;

[0223] Rings A, G, G 1 G 2 G 3 G 4 G 5 , R, R 2 R 3 p, q, r and t are as defined in general formula (I).

[0224] Option 2

[0225] Another aspect of this disclosure relates to a method for preparing a compound of general formula (II) or a pharmaceutically acceptable salt thereof, the method comprising:

[0226]

[0227] Compounds of general formula (IIA) or their salts, under acidic or basic conditions, undergo a deprotection reaction to yield compounds of general formula (II) or their pharmaceutically usable salts.

[0228] Where: R w It is an amino protecting group; preferably Ts or SEM;

[0229] R 1 It is a hydrogen atom;

[0230] G, G 1 G 2 , R, R 2 R 2’ R 3 R 7 R 8 R 9 r' and t are as defined in general formula (II).

[0231] Option 3

[0232] Another aspect of this disclosure relates to a method for preparing a compound of general formula (III) or a pharmaceutically acceptable salt thereof, the method comprising:

[0233]

[0234] Compounds of general formula (IIIA) or their salts, under acidic or basic conditions, undergo a deprotection reaction to yield compounds of general formula (III) or their pharmaceutically usable salts.

[0235] Where: R w It is an amino protecting group; preferably Ts or SEM;

[0236] G, G 1 G 2 , R, R 2 R 2’ R 3 R 7 R 9 And t are as defined in general formula (III).

[0237] The reagents providing alkaline conditions in the above synthesis schemes include organic and inorganic bases. The organic bases include, but are not limited to, triethylamine, pyridine, N,N-diisopropylethylamine, n-butyllithium, diisopropylaminolithium, tetrahydrofuran solution of diisopropylaminolithium, sodium acetate, potassium acetate, sodium tert-butoxide, potassium tert-butoxide, bis(trimethylsilyl)aminolithium, tetrahydrofuran solution of bis(trimethylsilyl)aminolithium, or 1,8-diazabicycloundec-7-ene. The inorganic bases include, but are not limited to, sodium hydride, potassium phosphate, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, lithium hydroxide, and potassium hydroxide; preferably, sodium hydroxide.

[0238] The reagents providing acidic conditions in the above synthesis scheme include organic acids and inorganic acids. The organic acids include, but are not limited to, trifluoroacetic acid, formic acid, acetic acid, methanesulfonic acid, p-toluenesulfonic acid, Me3SiCl, and TMSOTf. The inorganic acids include, but are not limited to, hydrogen chloride, a 1,4-dioxane solution of hydrogen chloride, hydrochloric acid, sulfuric acid, nitric acid, and phosphoric acid. Trifluoroacetic acid is preferred.

[0239] The reactions described above are preferably carried out in a solvent, which may include, but is not limited to, pyridine, ethylene glycol dimethyl ether, acetic acid, methanol, ethanol, acetonitrile, n-butanol, toluene, tetrahydrofuran, dichloromethane, petroleum ether, ethyl acetate, n-hexane, dimethyl sulfoxide, 1,4-dioxane, water, N,N-dimethylformamide, N,N-dimethylacetamide, 1,2-dibromoethane, and mixtures thereof. Detailed Implementation

[0240] The following embodiments are used to further describe this disclosure, but these embodiments are not intended to limit the scope of this disclosure.

[0241] Example

[0242] The structure of the compound was determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). NMR shifts (δ) were expressed in 10⁻¹⁰ ohms. -6 The unit (ppm) is given. NMR measurements were performed using a Bruker AVANCE-400 NMR spectrometer. The solvents used were deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), and deuterated methanol (CD3OD), with tetramethylsilane (TMS) as the internal standard.

[0243] MS measurements were performed using a Finnigan LCQAd(ESI) mass spectrometer (manufacturer: Thermo, model: Finnigan LCQadvantage MAX).

[0244] High-performance liquid chromatography (HPLC) analysis was performed using an Agilent HPLC 1200DAD, an Agilent HPLC 1200VWD, and a Waters HPLC e2695-2489 HPLC system.

[0245] Chiral HPLC analysis was performed using an Agilent 1260DAD high-performance liquid chromatograph.

[0246] High performance liquid chromatography (HPLC) was performed using Waters 2767, Waters 2767-SQ Detecor2, Shimadzu LC-20AP, and Gilson-281 preparative chromatographs.

[0247] Chiral preparation was performed using a Shimadzu LC-20AP preparative chromatograph.

[0248] The CombiFlash rapid preparation system uses a CombiFlash Rf200 (TELEDYNE ISCO).

[0249] Thin-layer chromatography silica gel plates are Yantai Huanghai HSGF254 or Qingdao GF254. The silica gel plates used in thin-layer chromatography (TLC) have a diameter of 0.15 mm to 0.2 mm, and the diameter of the silica gel plates used for thin-layer chromatography separation and purification products is 0.4 mm to 0.5 mm.

[0250] Silica gel column chromatography generally uses Yantai Huanghai silica gel with a mesh size of 200-300 as the carrier.

[0251] Mean inhibition rate of kinases and IC 50 The values ​​were determined using a NovoStar microplate reader (BMG GmbH, Germany).

[0252] The known starting materials of this invention can be synthesized using or according to methods known in the art, or can be purchased from companies such as ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, AccelaChemBio Inc, and Darui Chemicals.

[0253] Unless otherwise specified in the examples, all reactions can be carried out under an argon or nitrogen atmosphere.

[0254] Argon or nitrogen atmosphere refers to a reaction flask connected to an argon or nitrogen gas balloon with a volume of approximately 1L.

[0255] A hydrogen atmosphere refers to a reaction vessel connected to a hydrogen balloon with a volume of approximately 1L.

[0256] The pressurized hydrogenation reaction was performed using a Parr 3916EKX hydrogenator and a Qinglan QL-500 hydrogen generator or an HC2-SS hydrogenator.

[0257] The hydrogenation reaction is usually carried out under vacuum, filled with hydrogen gas, and repeated 3 times.

[0258] The microwave reaction was performed using a CEM Discover-S 908860 microwave reactor.

[0259] Unless otherwise specified in the examples, "solution" refers to an aqueous solution.

[0260] Unless otherwise specified in the examples, the reaction temperature is room temperature, which is 20℃~30℃.

[0261] The reaction process in the examples was monitored using thin-layer chromatography (TLC). The developing solvent used in the reaction, the eluent system for column chromatography used to purify the compounds, and the developing solvent system for TLC included: A: dichloromethane / methanol system, B: n-hexane / ethyl acetate system, C: n-hexane / dichloromethane system, and D: ethyl acetate / dichloromethane / n-hexane. The volume ratio of the solvent was adjusted according to the polarity of the compounds, and small amounts of basic or acidic reagents such as triethylamine and acetic acid could also be added for adjustment.

[0262] Example 1

[0263] 7-(7-(1-ethyl-1H-pyrazol-4-yl)-5H-pyrrolo[2,3-b]pyrazin-2-yl)-2,5-dimethyl-1,2,3,4-tetrahydroisoquinoline

[0264]

[0265] first step

[0266] 2,5-Dimethyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxoron-2-yl)-1,2,3,4-tetrahydroisoquinoline 1b

[0267] Compound 7-bromo-2,5-dimethyl-1,2,3,4-tetrahydroisoquinoline 1a (630 mg, 2.62 mmol, prepared by the method disclosed in Step 40-5 on page 65 of patent application WO2020 / 103896) was dissolved in 10 mL of 1,4-dioxane, and then [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (222 mg, 0.26 mmol), potassium acetate (772.3 mg, 7.86 mmol), and pinacol diborate (1.3 g, 3.4 mmol) were added sequentially. The mixture was stirred at 100 °C for 14 hours. After cooling, the mixture was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure. The filtrate was purified by silica gel column chromatography using eluent system A to give title compound 1b (360 mg, yield: 47.7%).

[0268] MS m / z(ESI):288.2[M+1].

[0269] Step 2

[0270] 2-Bromo-7-(1-Ethyl-1H-pyrazol-4-yl)-5-p-toluenesulfonyl-5H-pyrrolo[2,3-b]pyrazine 1d

[0271] Compound 2-bromo-7-iodo-5-p-toluenesulfonyl-5H-pyrrolo[2,3-b]pyrazine 1c (300 mg, 0.63 mmol, Shanghai Bide), 1-ethyl-4-(tetramethyl-1,3,2-dioxoboron-2-yl)-1H-pyrazole (140 mg, 0.63 mmol, Shanghai Bide), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloromethane dichloride complex (98 mg, 0.12 mmol), and sodium carbonate (132.5 mg, 1.25 mmol) were dissolved in 4.5 mL of a mixture of 1,4-dioxane and water (V:V = 8:1). The reaction was carried out under nitrogen atmosphere and microwaved at 100 °C for 1 hour. The reaction solution was concentrated under reduced pressure and purified by silica gel column chromatography with eluent system A to give title compound 1d (112 mg, yield: 40%).

[0272] MS m / z(ESI):445.8[M+1].

[0273] Step 3

[0274] 7-(7-(1-ethyl-1H-pyrazol-4-yl)-5-p-toluenesulfonyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)-2,5-dimethyl-1,2,3,4-tetrahydroisoquinoline 1e

[0275] Compound 1d (56 mg, 0.12 mmol), compound 1b (39.6 mg, 0.137 mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloromethane complex (20 mg, 0.025 mmol), and sodium carbonate (27 mg, 0.25 mmol) were dissolved in 2.5 mL of a mixed solution of 1,4-dioxane and water (V:V = 8:1). The mixture was reacted in a nitrogen atmosphere at 100 °C for 1 hour. The reaction solution was concentrated under reduced pressure and purified by silica gel column chromatography using eluent system A to give title compound 1e (20 mg, yield: 30%).

[0276] MS m / z(ESI): 527.0 [M+1].

[0277] Step 4

[0278] 7-(7-(1-ethyl-1H-pyrazol-4-yl)-5H-pyrrolo[2,3-b]pyrazin-2-yl)-2,5-dimethyl-1,2,3,4-tetrahydroisoquinoline

[0279] Compound 1e (20.00 mg, 0.04 mmol) was dissolved in 2 mL of methanol, and 0.5 mL of 2 M sodium hydroxide aqueous solution was added. The reaction mixture was reacted at 40 °C for 2 hours. The reaction solution was concentrated under reduced pressure and purified by high performance liquid chromatography (Waters-2545, column: SharpSil-TC18, 30*150 mm, 5 μm; mobile phase: water (10 mmol / L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 30%-50%, flow rate: 30 mL / min) to give title compound 1 (5 mg, yield: 35%).

[0280] MS m / z(ESI): 373.0 [M+1].

[0281] 1 H NMR (500MHz, CDCl3): δ8.73(s,1H),8.62(s,1H),8.27(s,1H),8.06(s,1H),7.78(s,1H),7.72(d,1H),7 .65(s,1H),4.31(q,2H),3.74(s,2H),2.91-2.79(m,4H),2.54(s,3H),2.38(s,3H),1.64-1.57(m,3H).

[0282] Example 2

[0283] 7-(3-(1-ethyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-b]pyridin-5-yl)-2,5-dimethyl-1,2,3,4-tetrahydroisoquinoline 2

[0284]

[0285]

[0286] first step

[0287] 5-Bromo-3-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-b]pyridine 2b

[0288] Compound 5-bromo-3-iodo-1H-pyrazolo[3,4-b]pyridine 2a (2.00 g, 6.17 mmol, Shanghai Biotech) was dissolved in 12 mL of N,N-dimethylformamide. Sodium hydride (0.49 g, 12.35 mmol, 60% purity) was added under ice bath conditions, and the reaction was carried out at 0 °C for 10 min. Subsequently, 2-(trimethylsilyl)ethoxymethyl chloride (1.75 g, 10.50 mmol) was added dropwise, and the reaction was stirred for 14 h. 30 mL of water was added to the reaction solution, and the mixture was extracted with ethyl acetate (20 mL × 3). The organic phase was collected, dried over anhydrous sodium sulfate, filtered to remove the drying agent, and the filtrate was concentrated under reduced pressure. The filtrate was purified by silica gel column chromatography with eluent system B to give the title compound 2b (2.25 g, yield: 80%).

[0289] MS m / z(ESI):453.9[M+1].

[0290] Step 2

[0291] 5-Bromo-3-(1-Ethyl-1H-pyrazol-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-b]pyridine 2c

[0292] Compound 2b (300 mg, 0.66 mmol), compound 1-ethyl-4-(tetramethyl-1,3,2-dioxoborane-2-yl)-1H-pyrazole (147 mg, 0.66 mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (97 mg, 0.13 mmol), and potassium phosphate (280 mg, 1.32 mmol) were dissolved in 5 mL of a mixture of 1,4-dioxane and water (V:V = 4:1). The reaction was carried out at 80 °C for 14 hours under a nitrogen atmosphere. The reaction solution was concentrated and purified by silica gel column chromatography using eluent system A to give title compound 2c (138 mg, yield: 50%).

[0293] MS m / z(ESI):422.9[M+1].

[0294] Step 3

[0295] 7-(3-(1-ethyl-1H-pyrazol-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-b]pyridin-5-yl)-2,5-dimethyl-1,2,3,4-tetrahydroisoquinoline 2d

[0296] Compound 2c (37 mg, 0.087 mmol), compound 1b (25 mg, 0.087 mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (13 mg, 0.017 mmol), and potassium carbonate (24 mg, 0.17 mmol) were dissolved in 2.5 mL of a mixed solution of 1,4-dioxane and water (V:V = 4:1). The reaction was carried out at 100 °C for 6 hours under a nitrogen atmosphere. The reaction solution was concentrated and purified by silica gel column chromatography using eluent system A to give title compound 2d (29 mg, yield: 66%).

[0297] MS m / z(ESI): 503.1 [M+1].

[0298] Step 4

[0299] 7-(3-(1-ethyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-b]pyridin-5-yl)-2,5-dimethyl-1,2,3,4-tetrahydroisoquinoline 2

[0300] Compound 2d (29 mg, 0.057 mmol) was dissolved in 2 mL of dichloromethane, and 2 mL of trifluoroacetic acid was added. The mixture was stirred for 2 hours. The reaction solution was concentrated under reduced pressure, and the pH was adjusted to alkaline with saturated sodium bicarbonate aqueous solution. The solution was then purified by high performance liquid chromatography (Waters-2545, column: SharpSil-T C18, 30*150 mm, 5 μm; mobile phase: water (10 mmol / L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 30%-50%, flow rate: 30 mL / min) to obtain title compound 2 (8 mg, yield 37%).

[0301] MS m / z(ESI): 373.0 [M+1].

[0302] 1 H NMR (500MHz, CDCl3): δ11.12(s,1H),8.83(d,1H),8.33(d,1H),8.11(s,1H),8.01(s,1H),7.32(d,1H), 7.20-7.15(m,1H),4.33(q,2H),3.75(s,2H),2.92-2.83(m,4H),2.56(s,3H),2.36(s,3H),1.61(t,3H).

[0303] Example 3

[0304] 2-(4-(3-(2,5-dimethyl-1,2,3,4-tetrahydroisoquinoline-7-yl)-7H-pyrrolo[2,3-c]pyridazine-5-yl)-1H-pyrazol-1-yl)-N-methylacetamide 3

[0305]

[0306]

[0307] first step

[0308] 2-(4-(3-chloro-7-p-toluenesulfonyl-7H-pyrrolo[2,3-c]pyridazin-5-yl)-1H-pyrazol-1-yl)-N-methylacetamide 3b

[0309] Compound 3-chloro-5-iodo-7-p-toluenesulfonyl-7H-pyrrolo[2,3-c]pyridazine 3a (300 mg, 0.69 mmol, Shanghai Bide), N-methyl-2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxoboron-2-yl)pyrazol-1-yl]acetamide (201 mg, 0.76 mmol, Shanghai Bide), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (101 mg, 0.14 mmol), and potassium phosphate (294 mg, 1.40 mmol) were dissolved in 4.5 mL of a mixture of 1,4-dioxane and water (V:V = 4:1). The reaction was carried out at 80 °C for 14 hours under a nitrogen atmosphere. The reaction solution was concentrated and purified by silica gel column chromatography using eluent system A to give title compound 3b (56 mg, yield: 18%).

[0310] MS m / z(ESI):444.9[M+1].

[0311] Step 2

[0312] 2-(4-(3-(2,5-dimethyl-1,2,3,4-tetrahydroisoquinoline-7-yl)-7-p-toluenesulfonyl-7H-pyrrolo[2,3-c]pyridazin-5-yl)-1H-pyrazole-1-yl)-N-methylacetamide 3c

[0313] Compound 3b (56 mg, 0.12 mmol), compound 1b (54 mg, 0.19 mmol), palladium acetate (5.6 mg, 0.025 mmol), 1,1'-bis(di-tert-butylphosphine)ferrocene (12.7 mg, 0.026 mmol), and potassium phosphate (80 mg, 0.38 mmol) were dissolved in 2.5 mL of a mixture of 1,4-dioxane and water (V:V = 4:1). The mixture was reacted in a microwave-safe atmosphere at 100 °C for 3 hours. The reaction solution was concentrated and purified by silica gel column chromatography using eluent system A to give title compound 3c (6 mg, yield: 8%).

[0314] MS m / z(ESI): 570.0 [M+1].

[0315] Step 3

[0316] 2-(4-(3-(2,5-dimethyl-1,2,3,4-tetrahydroisoquinoline-7-yl)-7H-pyrrolo[2,3-c]pyridazine-5-yl)-1H-pyrazol-1-yl)-N-methylacetamide 3

[0317] Compound 3c (6.00 mg, 0.01 mmol) was dissolved in 2 mL of methanol, and 0.5 mL of 2 M sodium hydroxide solution was added. The reaction mixture was reacted at 40 °C for 2 hours. The reaction solution was concentrated under reduced pressure and purified by high performance liquid chromatography (Waters-2545, column: SharpSil-TC18, 30*150 mm, 5 μm; mobile phase: water (10 mmol / L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 30%-50%, flow rate: 30 mL / min) to obtain title compound 3 (2 mg, yield 46%).

[0318] MS m / z(ESI):416.0[M+1].

[0319] 1 H NMR (500MHz, CDCl3): δ10.05(s,1H),8.11(s,1H),7.96(s,1H),7.83(s,1H),7.77(s,1H),7.74(s,1H ),7.66(s,1H),7.28(s,1H),4.94(s,2H),3.76(s,2H),2.92-2.81(m,7H),2.55(s,3H),2.38(s,3H).

[0320] Example 4

[0321] 7-(5-(1-ethyl-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-c]pyridazin-3-yl)-2,5-dimethyl-1,2,3,4-tetrahydroisoquinoline 4

[0322]

[0323] first step

[0324] 3-Chloro-5-(1-ethyl-1H-pyrazol-4-yl)-7-p-toluenesulfonyl-7H-pyrrolo[2,3-c]pyridazine 4a

[0325] Compound 3a (150 mg, 345.9 μmol), 1-ethyl-4-(tetramethyl-1,3,2-dioxoron-2-yl)-1H-pyrazole (84 mg, 378.2 μmol, Shanghai Bide), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (29 mg, 35.5 μmol), and sodium carbonate (73 mg, 688.7 μmol) were dissolved in 4.5 mL of a mixed solution of 1,4-dioxane and water (V:V = 4:1). The reaction was carried out under a nitrogen atmosphere and microwaved at 100 °C for 3 hours. The reaction solution was concentrated and purified by silica gel column chromatography using eluent system A to give title compound 4a (50 mg, yield: 35.9%).

[0326] MS m / z(ESI):402.1[M+1].

[0327] Step 2

[0328] 7-(5-(1-ethyl-1H-pyrazol-4-yl)-7-p-toluenesulfonyl-7H-pyrrolo[2,3-c]pyridazin-3-yl)-2,5-dimethyl-1,2,3,4-tetrahydroisoquinoline 4b

[0329] Compound 4a (60 mg, 149.3 μmol), compound 1b (52 mg, 181 μmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (22 mg, 30 μmol), and potassium phosphate (42 mg, 303 μmol) were dissolved in 2.5 mL of a mixed solution of 1,4-dioxane and water (V:V = 4:1). The reaction was carried out under a nitrogen atmosphere and microwaved at 100 °C for 3 hours. The reaction solution was concentrated and purified by silica gel column chromatography using eluent system A to give title compound 4b (50 mg, yield: 63.5%).

[0330] MS m / z(ESI): 527.2 [M+1].

[0331] Step 3

[0332] 7-(5-(1-ethyl-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-c]pyridazin-3-yl)-2,5-dimethyl-1,2,3,4-tetrahydroisoquinoline 4

[0333] Compound 4b (30 mg, 56.9 μmol) was dissolved in 2 mL of methanol, and 0.5 mL of 2 M sodium hydroxide solution was added. The reaction mixture was reacted at 40 °C for 2 hours. The reaction solution was concentrated under reduced pressure and purified by high performance liquid chromatography (Waters-2545, column: SharpSil-TC18, 30*150 mm, 5 μm; mobile phase: water (10 mmol / L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 30%-50%, flow rate: 30 mL / min) to obtain title compound 4 (2 mg, yield 10.33%).

[0334] MS m / z(ESI): 373.2 [M+1].

[0335] 1 H NMR (500MHz, CD3OD): δ8.35(s,1H),8.21(s,1H),8.01(s,1H),7.95(s,1H),7.77(s,1H),7.65(s, 1H),4.30(q,2H),3.76(s,2H),2.92(t,2H),2.86(t,2H),2.52(s,3H),2.38(s,3H),1.55(t,3H).

[0336] Example 5

[0337] 7-(3-(1-ethyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-2,5-dimethyl-1,2,3,4-tetrahydroisoquinoline 5

[0338]

[0339] first step

[0340] 2-Bromo-7-(1-Ethyl-1H-pyrazol-4-yl)-5-p-toluenesulfonyl-5H-pyrrolo[2,3-b]pyridine 5b

[0341] Compound 5a (2 g, 4.19 mmol, prepared by a known method, "Journal of Medicinal Chemistry, 2013, 56(20), 8032–8048"), 1-ethyl-4-(tetramethyl-1,3,2-dioxoboron-2-yl)-1H-pyrazole (1.02 g, 4.61 mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex (684.6 mg, 0.83 mmol), and sodium carbonate (888.58 mg, 8.38 mmol) were dissolved in 30 mL of a mixed solution of 1,4-dioxane and water (V:V = 4:1). The reaction was carried out at 100 °C for 14 h under a nitrogen atmosphere. The reaction solution was concentrated under reduced pressure and purified by silica gel column chromatography with eluent system A to give title compound 5b (490 mg, yield: 26.2%). MS m / z(ESI):446.1[M+1].

[0342] Step 2

[0343] 7-(7-(1-ethyl-1H-pyrazol-4-yl)-5-p-toluenesulfonyl-5H-pyrrolo[2,3-b]pyridin-2-yl)-2,5-dimethyl-1,2,3,4-tetrahydroisoquinoline 5c

[0344] Compound 5b (50 mg, 112.2 μmol), compound 1b (32.24 mg, 112.2 μmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloromethane complex (18.3 mg, 22.4 μmol), and sodium carbonate (23.8 mg, 0.22 mmol) were dissolved in 2.5 mL of a mixed solution of 1,4-dioxane and water (V:V = 8:1). The reaction was carried out under a nitrogen atmosphere and microwaved at 100 °C for 1 hour. The reaction solution was concentrated under reduced pressure and purified by silica gel column chromatography using eluent system A to give title compound 5c (20 mg, yield: 33.8%).

[0345] MS m / z(ESI): 526.2 [M+1].

[0346] Step 3

[0347] 7-(3-(1-ethyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-2,5-dimethyl-1,2,3,4-tetrahydroisoquinoline 5

[0348] Compound 5c (20 mg, 38 μmol) was dissolved in 2 mL of methanol, and 0.5 mL of 2 M sodium hydroxide solution was added. The mixture was reacted at 40 °C for 2 hours. The reaction solution was concentrated under reduced pressure and purified by high performance liquid chromatography (Waters-2545, column: SharpSil-T C18, 30*150 mm, 5 μm; mobile phase: water (10 mmol / L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 30%-50%, flow rate: 30 mL / min) to give title compound 5 (5.2 mg, yield: 10%).

[0349] MS m / z(ESI): 372.0 [M+1].

[0350] 1 H NMR (500MHz, CDCl3): δ9.18(s,1H),8.68-8.48(m,1H),8.20(d,1H),7.83(s,1H),7.70(s,1H),7.43(d,1H),7.31 (s,1H),7.17(s,1H),4.29(q,2H),3.70(s,2H),2.86(d,2H),2.81(d,2H),2.52(s,3H),2.35(s,3H),1.60(t,3H).

[0351] Biological evaluation

[0352] Test Example 1. HPK1 Enzyme Activity Assay (ADP-Glo ​​Method)

[0353] 1. Reagents and Instruments

[0354] 1) ADP-Glo ​​Kinase Detection Kit (includes ADP-Glo ​​reagent and kinase detection reagent) (Promega, V9101)

[0355] 2) 1M Tris-HCl buffer pH=7.5 (Solepro, T1140)

[0356] 3)1M MgCl2 (Invitrogen, AM9530G)

[0357] 4) 1M DTT (Thermofisher, P2325)

[0358] 5) 20 mg / mL bovine serum albumin (BSA) (TAKARA 2320)

[0359] 6) ATP solution (10mM) (Thermofisher PV3227)

[0360] 7) Dephosphorylated MBP (Sigma, 13-110) (hereinafter referred to as MBP)

[0361] 8) HPK1 (Signalchem, M23-11G)

[0362] 9) 96-well small-volume whiteboard (Cisbio, 66PL96100)

[0363] 10) Phera Star microplate reader (BMG Labtech)

[0364] 2. Experimental Methods

[0365] 2.1 Reagent Preparation

[0366] a. Detection buffer: 40 mM Tris-HCl buffer, 7.5; 20 mM MgCl2; 0.1 mg / mL BSA; 50 μM DTT;

[0367] b. HPK1 enzyme solution: The detection buffer was prepared to a final concentration of 1.5 ng / μL for HPK1 enzyme solution;

[0368] c. ATP and MBP mixed substrate: Prepare ATP to a final concentration of 60 μM and MBP to a final concentration of 0.6 ug / μL in the detection buffer, and mix the prepared ATP and MBP in equal volumes;

[0369] d. Compounds: Starting concentration 33.3 μM, 3-fold dilution, 9 concentration gradients. All compounds were diluted 33.3-fold with detection buffer and set aside.

[0370] 2.2 Experimental Procedure

[0371] a. For a 96-well plate, add 2 μL of prepared HPK1 enzyme solution to each well. Do not add enzyme to the first column; instead, add 2 μL of detection buffer.

[0372] b. Add 2 μL of the compound to each well, except for the first and last columns which do not contain the compound. Add DMSO as a control. Centrifuge, mix and shake for 2 minutes, and incubate at room temperature for 10 minutes.

[0373] c. Add 2 μL of ATP and MBP mixture to each well, centrifuge, mix and vortex for 2 minutes, and incubate at room temperature for 60 minutes.

[0374] d. Add 6 μL of ADP-Glo ​​reagent to each well, centrifuge, mix and vortex for 2 minutes, and incubate at room temperature for 40 minutes.

[0375] e. Add 12 μL of kinase detection reagent to each well, centrifuge, mix and vortex for 2 minutes, and incubate at room temperature for 40 minutes.

[0376] f. Read the plate with an ELISA reader and record the RLU (Relative Luminescence Unit) value.

[0377] Using g.Graphpad software to plot graphs and calculate the IC of compounds. 50 Values ​​are shown in Table 1.

[0378] Table 1 shows the inhibitory effect (IC50) of the compounds in this disclosure on HPK1 enzyme activity. 50 value

[0379] Example number <![CDATA[HPK1 / IC 50 (nM)]]> 1 0.4 4 1.1 5 0.4

[0380] Conclusion: The compound disclosed herein has a significant inhibitory effect on the activity of HPK1 enzyme.

[0381] Test Example 2. Detection of SLP76 protein phosphorylation in Jurkat cells (HTRF method)

[0382] 1. Reagents and Instruments

[0383] 1) RPMI 1640 medium (Gibco, 61870044)

[0384] 2) Fetal bovine serum (Gibco, 10099141C) (hereinafter referred to as FBS)

[0385] 3) 75cm 2 Cell culture flask with filter cap (Corning, 430641)

[0386] 4) PBS, pH 7.4 (Gibco, 10010049)

[0387] 5) CD3 antibody, anti-human, pure functional grade.

[0388] (Miltenyi Biotec, 130-093-387)

[0389] 6) Phospho-SLP-76 (Ser376) Cell Kit (Cisbio, 63ADK076PEG)

[0390] 7) HTRF 96-well small-volume whiteboard (Cisbio, 66PL96100)

[0391] 8) 96-hole plate (Corning, 3788)

[0392] 9) Microplate oscillator (Qilinbel)

[0393] 10) Phera Star microplate reader (BMG Labtech)

[0394] 11) Countstar BioMed Automated Cell Counter (Shanghai Ruiyu Biotechnology Co., Ltd.)

[0395] 12) Clean bench (Thermo, 1300ALL)

[0396] 13) CO2 incubator (Thermo, I160)

[0397] 2. Cells and Culture Methods

[0398] Jurkat E6-1 cells were purchased from the American Type Culture Collection Center (ATCC, TIB-152) and cultured in RPMI 1640 medium (10% FBS). The cell culture density was maintained at 2 × 10⁶ cells / year. 5 Up to 2×10 6 Cells / mL, passaged 2-3 times per week.

[0399] 3. Compound preparation

[0400] a. Dissolve the test compound in DMSO to a concentration of 5 mM.

[0401] b. The initial concentration of the compound is 5 mM, and it is diluted 3 times to create 10 concentration gradients.

[0402] c. Dilute all concentrations of the compound 100 times with culture medium and set aside.

[0403] 4. Experimental Procedure

[0404] a. Jurkat cell counting, adjusting cell density to 5 × 10⁶ cells with fresh culture medium. 6 / mL.

[0405] b. 96-well plates, seed 20 μL of cells in each well, and incubate at 37°C for 4 hours.

[0406] c. Add 5 μL of the compound to each well (5 μL of 0.5% DMSO to columns 1 and 12) and incubate at 37°C for 1 hour.

[0407] d. Dilute the CD3 antibody to 20 ng / μL with culture medium, add 5 μL to each well (add 5 μL of culture medium to column 1 as a control), and incubate at 37°C for half an hour.

[0408] e. Add 10 μL of lysis buffer to each well to lyse the cells, and shake at 850 rpm for half an hour at room temperature.

[0409] f. Transfer 16 μL of cell lysis buffer to a new HTRF 96-well plate, add 4 μL of antibody mixture to each well, and incubate overnight at room temperature.

[0410] g. Use an ELISA reader to read the plate and record the signal values ​​at 665nm and 620nm.

[0411] Using h.Graphpad software to plot graphs and calculate the IC of compounds. 50 Values ​​are shown in Table 2.

[0412] Table 2 shows the inhibitory effect of the compounds in this disclosure on phosphorylation of SLP76 protein in Jurkat cells (IC value). 50 value

[0413] Example number <![CDATA[SLP76 protein phosphorylation / IC 50 (nM)]]> 1 68 5 70

[0414] Conclusion: The compounds disclosed herein have a significant inhibitory effect on the phosphorylation of SLP76 protein in Jurkat cells.

Claims

1. A compound of general formula (III) or a pharmaceutically acceptable salt thereof: in: G can be CH or a nitrogen atom; G 1 It is CH or nitrogen atom; G 2 It is CH or nitrogen atom; R 3 They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl and C 1-6 Halogenated alkyl groups; R is selected from hydrogen atom and C. 1-6 alkyl; R 2’ C 1-6 Alkyl, wherein the C 1-6 Alkyl optional -(CO)NR d2 R e2 replace; R 2 They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl, C 1-6 Halogenated alkyl groups and -(CO)NR d R e The C mentioned therein 1-6 Alkyl groups are each independently selected from halogens, C... 1-6 Alkyl and C 1-6 Halogenated alkyl groups and -(CO)NR d2 R e2 One or more substituents in it are replaced; R d R e R d2 and R e2 They may be the same or different, and each is independently selected from hydrogen atoms and C atoms. 1-6 alkyl; R 7 and R 9 They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl and C 1-6 Halogenated alkyl groups, wherein the C 1-6 Alkyl groups are each independently selected from halogens, C... 1-6 Alkyl and C 1-6 One or more substituents in the haloalkyl group are substituted; t is 0, 1, 2, 3 or 4 and The compound represented by general formula (III) is not .

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 3 They may be the same or different, and each is independently selected from hydrogen atoms.

3. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R is methyl.

4. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 2’ The methyl or ethyl group is optionally -(CO)NR. d2 R e2 Replace, R d2 and R e2 They may be the same or different, and each is independently selected from hydrogen atoms and methyl groups.

5. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 7 For hydrogen atoms, R 9 It is a methyl group.

6. The compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein the compound is: , , , and .

7. A compound of general formula (IIIA) or a salt thereof: in: R w It is an amino protecting group; G, G 1 G 2 , R, R 2 R 2’ R 3 R 7 R 9 And t as defined in claim 1.

8. The compound of general formula (IIIA) according to claim 7, wherein R w For Ts or SEM.

9. The compound of general formula (IIIA) according to claim 7 or 8, or a salt thereof, wherein the compound is: , , , and .

10. A method for preparing the compound of general formula (III) according to claim 1 or a pharmaceutically acceptable salt thereof, the method comprising: Compounds of general formula (IIIA) or their salts are deprotected to give compounds of general formula (III) or their pharmaceutically usable salts; Where: R w It is an amino protecting group; R 1 It is a hydrogen atom; G, G 1 G 2 , R, R 2 R 2’ R 3 R 7 R 9 And t as defined in claim 1.

11. The method of claim 10, wherein R w For Ts or SEM.

12. A pharmaceutical composition comprising a compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 6, and one or more pharmaceutically acceptable carriers, diluents or excipients.

13. Use of the compound of any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition of claim 12 in the preparation of a medicament for inhibiting HPK1.

14. Use of the compound of any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition of claim 12 in the preparation of a medicament for the treatment and / or prevention of diseases or conditions of cancer, inflammatory diseases, infectious diseases, cardiovascular diseases, neurodegenerative diseases, diabetes and reproductive disorders.

15. The use according to claim 14, wherein the disease or condition is an autoimmune disease.

16. The use according to claim 14, wherein the disease or condition is selected from cancer, allergies, asthma, sepsis, HIV infection, hepatitis B virus infection, ischemia, atherosclerosis, stroke, and Alzheimer's disease.

17. The use according to claim 16, wherein the cancer is selected from brain cancer, head and neck cancer, esophageal cancer, gastric cancer, lung cancer, liver cancer, kidney cancer, pancreatic cancer, bile duct cancer, colorectal cancer, small bowel cancer, gastrointestinal stromal tumor, urothelial carcinoma, breast cancer, ovarian cancer, endometrial cancer, cervical cancer, fallopian tube cancer, testicular cancer, prostate cancer, leukemia, lymphoma, multiple myeloma, skin cancer, bone cancer, soft tissue sarcoma, neurofibroma, and neuroblastoma.

18. The use according to claim 17, wherein the cancer is selected from glioma, thyroid cancer, pharyngeal cancer, oral cancer, salivary gland cancer, colon cancer, rectal cancer, urethral cancer, bladder cancer, and malignant lipoma.

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