Fused ring compounds, their preparation and use

Abstract

The present application provides a kind of compound shown in formula (I), or its tautomer, stereoisomer or its pharmaceutically acceptable salt.The strong HPK1 inhibiting effect has the immunocyte activation effect produced by inhibiting HPK1 biological activity and the use of relevant disease treatment.

Description

TECHNICAL FIELD

[0001] The present application relates to the field of medicine, in particular, to a class of compounds as HPK1 inhibitors and the preparation method and use of the compounds. BACKGROUND

[0002] Hematopoietic progenitor kinase 1 (HPK1, also known as MAP4K1) is a hematopoietic-specific protein serine-threonine kinase, which is a member of the mammalian Ste20-related protein kinase MAP4K family (Kiefer, F. et al. EMBO J. 15: 7013-7025). It is reported that MAP4Ks, including MAP4K1 / HPK1, MAP4K2 / GCK, MAP4K3 / GLK, MAP4K4 / HGK, MAP4K5 / KHS and MAP4K6 / MINK, induce JNK activation by activating the MAP3K-MAP2K cascade (Huai-Chia Chuang,. et al. Adv Immunol. 2016; 129: 277).

[0003] The expression of HPK1 is limited to hematopoietic compartments (e.g. T cells, B cells, dendritic cells) (Hu et al., 1996; Kiefer et al., 1996), and consists of an N-terminal kinase domain, an intermediate SH3-binding proline-rich motif and a C-terminal Citron homology domain. The intermediate proline-rich motif in HPK1 mediates the interaction of HPK1 with many SH3 domain-containing proteins. Activation of HPK1 by Y381 phosphorylation can bind and phosphorylate key adaptors of T and B cell signaling (SLP76 and BLNK, respectively).

[0004] HPK1 inhibits T cell receptor (TCR) signaling and B cell receptor signaling by inducing phosphorylation / ubiquitination of SLP-76 and BLNK, respectively, and is a negative regulator of immune cell activation, antigen presentation and T cell response to immunosuppressive factors.

[0005] After TCR activation, cytoplasmic HPK1 is recruited to the plasma membrane, thereby fully activating the kinase through its phosphorylation at Y381, S171 and T165 residues. Active HPK1 phosphorylates the adaptor protein SLP76 on S376, creating a docking site for the negative regulator 14-3-3, which ultimately disrupts the stability of the TCR signaling complex (Lat-Gads SLP76) and prevents the downstream role of mitogen-activated protein (MAP) kinase signaling in T cell activation and proliferation (Lasserre et al., 2011; Shui et al., 2007).

[0006] In addition to TCR signaling, HPK1 also negatively regulates T cell signaling in a PKA-dependent manner through the prostaglandin E2 (PGE2) receptor (Sawasdikosol et al., 2003, 2007; Alzabin et al., 2010). HPK1 can also play a role in regulating leukocyte function-associated antigen-1 (LFA-1) integrin activation on T cells by directly competing with a protein that binds to the SH2 domain of SLP76 (ADAP) (Patzak et al., 2010).

[0007] HPK1 kinase activity limits TCR signaling and secretion of effector cytokines, and loss of HPK1 kinase function enhances T cell receptor signaling and cytokine secretion. In response to chronic lymphocytic choriomeningitis virus (LCMV) infection or tumor challenge, HPK1.kd mice have enhanced viral clearance and suppression of tumor growth, accompanied by enhanced effector CD8 T cell function.

[0008] HPK1 inhibitors have shown immunostimulatory effects in preclinical studies, including reducing suppression of the T cell receptor (TCR), disrupting aberrant expression of cytokines, and altering the tumor immunosuppressive environment through effector cells (i.e., regulatory T cells / Tregs). Therefore, in addition to the potential for monotherapy, combination with immune drugs is expected to improve the response rate and efficiency of immunotherapy.

[0009] Currently, the molecules under clinical research are CFI-402411 of Treadwell, BGB-15025 of BeiGene, NDI-101150 of Nimbus, and PRJ1-3024 of Zhuhai Yufan. SUMMARY

[0010] The purpose of the present application is to provide a compound having a fused ring structure as an HPK1 inhibitor, a preparation method of the compound, and its use in the treatment of related diseases through the activation of immune cells by inhibiting the biological activity of HPK1.

[0011] In a first aspect of the present application, a compound represented by the following formula (I) is provided, or a tautomer, stereoisomer thereof or a pharmaceutically acceptable salt thereof, having the following structure

[0012]

[0013] wherein R is selected from H, halogen and -L 1 -Cy1-(R 1 ) m ,

[0014] X1 X 2 Each of the following is independently selected from: bond, -O-, -CO-, -CO2-, -S-, -SO-, -SO2-, -NR a -、-(CR a R a ) 1-6 -、

[0015] -CON(R a )-、-N(R a CO-, -NR a CON(R a )-、-NR a SONR a -or-NR a SO2-, condition is -X 1 -X 2 - No two heteroatoms are connected adjacently within the main chain;

[0016] Each R a Independently selected from: hydrogen, deuterium, halogens, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, C 4-10 Cycloalkenyl, 3- to 10-membered heterocyclic groups, C 6-10 Aryl and 5- to 10-membered heteroaryl, wherein the C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, C 4-10 Cycloalkenyl, 3- to 10-membered heterocyclic groups, C 6-10 Aryl groups and 5- to 10-membered heteroaryl groups may be selectively coated with one or more identical or different R groups. a1 Replace; or -(CR a R a ) 1-6 - Two Rs in the middle a It can form with the attached carbon atom, optionally with one or more identical or different R atoms. a1 Replacement C 3-6 Cycloalkyl groups;

[0017] Each R a1 Independently selected from: hydrogen, deuterium, halogen, -OR a2 -NR a2 R a2 -CN, -C(O)R a2 -C(O)OR a2 -C(O)NR a2 R a2 -S(O)2Ra2 -S(O)2NR a2 R a2 -NHC(O)R a2 -N(C 1-4 alkyl)C(O)R a2 -NHC(O)OR a2 or -N(C 1-4 alkyl)C(O)OR a2 ;

[0018] each R a2 is independently selected from the group consisting of hydrogen, deuterium, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 4-10 cycloalkenyl, 3- to 10-membered heterocyclyl, C 6-10 aryl, and 5- to 10-membered heteroaryl;

[0019] Y 1 , Y 2 are each independently selected from CR b or N;

[0020] R b is selected from the group consisting of hydrogen, deuterium, halogen, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-12 cycloalkyl, 3- to 12-membered heterocyclyl, C 6-12 aryl, 5- to 12-membered heteroaryl, -CN, -NO2, -OR b1 , -SO2R b1 , -COR b1 , -CO2R b1 , -CONR b1 R b2 , -C(=NR b1 )NR b2 R b3 , -NR b1 R b2 , -NR b1 COR b2 , -NR b1 CONR b2 R b3 , -NR b1 SONR b2 R b3 , or -NR b1 SO2R b2 , wherein said C 1-8 alkyl, C 2-8 alkenyl, C2-8 alkynyl, C 3-12 cycloalkyl, 3- to 12-membered heterocyclyl, C 6-12 aryl, 5- to 12-membered heteroaryl optionally substituted with one or more halogen, hydroxyl, C 1-8 alkoxy, C 3-12 cycloalkyl, 3- to 12-membered heterocyclyl, C 6-12 aryl, 5- to 12-membered heteroaryl;

[0021] R b1 , R b2 , R b3 are each independently selected from the group consisting of: hydrogen, deuterium, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-12 cycloalkyl, 3- to 12-membered heterocyclyl, C 6-12 aryl, 5- to 12-membered heteroaryl;

[0022] L 1 is selected from the group consisting of a bond, -NH-, -O-, -S-, -C 1-6 alkylene-, -O-C 1-6 alkylene-, -C 1-6 alkylene-O-, -NH-C 1-6 alkylene-, -C 1-6 alkylene-NH-, -C 2-8 alkenylene-, -O-C 2-8 alkenylene-, -C 2-8 alkenylene-O-, -NH-C 2-8 alkenylene-, -C 2-8 alkenylene-NH-, -NHC(O)-, -C(O)NH-;

[0023] Cy1is selected from the group consisting of: C 3-12 cycloalkyl, 3- to 20-membered heterocyclyl, C 6-16 aryl, 5- to 16-membered heteroaryl;

[0024] each R 1 may be independently selected from the group consisting of: hydrogen, deuterium, halogen, C 1-20 alkyl, C 2-20 alkenyl, C 2-20 alkynyl, C 3-12 cycloalkyl, 3- to 20-membered heterocyclyl, C 6-16 aryl, 5- to 16-membered heteroaryl, oxo, -CN, -NO2, -OR c1 , -SO2R c1 , -SO2NR c1 R c2 , -COR c1 , -CO2Rc1 -CONR c1 R c2 -CONR c1 R c2 R c3 -CONR c1 R c2 -CONR c1 COR c2 -CONR c1 CONR c2 R c3 -CONR c1 SONR c2 R c3 -CONR c1 SO2R c2 wherein said C 1-20 alkyl, C 2-20 alkenyl, C 2-20 alkynyl, C 3-12 cycloalkyl, 3- to 20-membered heterocyclyl, C 6-16 aryl, 5- to 16-membered heteroaryl is optionally substituted with one or more R c4 ;

[0025] R c1 , R c2 , R c3 are each independently selected from hydrogen, deuterium, C 1-20 alkyl, -COR c5 , -C 1-20 alkoxy-C 1-20 alkyl, C 2-20 alkenyl, C 2-20 alkynyl, C 3-12 cycloalkyl, 3- to 20-membered heterocyclyl, C 6-16 aryl, 5- to 16-membered heteroaryl, wherein said: C 1-20 alkyl, -C 1-20 alkoxy-C 1-20 alkyl, C 2-20 alkenyl, C 2-20 alkynyl, C 3-12 cycloalkyl, 3- to 20-membered heterocyclyl, C 6-16 aryl, 5- to 16-membered heteroaryl is optionally substituted with one or more R c5 ;

[0026] (R c1 and R c2 ), (R c1 and R c3 ), or (R c2 and R c3) with the atom to which it is attached to form a 3-20 membered heterocycle containing 1, 2, or 3 heteroatoms independently selected from N, O, or optionally oxidized S, said 3-12 membered heterocycle optionally substituted with one or more R c5 substituted;

[0027] R c4 and R c5 are each independently selected from the group consisting of: hydrogen, deuterium, halogen, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-12 cycloalkyl, 3- to 12-membered heterocyclyl, C 6-12 aryl, 5- to 12-membered heteroaryl, oxo, -CN, -NO2, -OR c6 , -SO2R c6 , -COR c6 , -CO2R c6 , -CONR c6 R c7 , -C(=NR c6 )NR c7 R c8 , -NR c6 R c7 , -NR c6 COR c7 , -NR c6 CONR c7 R c8 , -NR c6 SONR c7 R c8 , or -NR c6 SO2R c7 , wherein said C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-12 cycloalkyl, 3- to 12-membered heterocyclyl, C 6-12 aryl, 5- to 12-membered heteroaryl is optionally substituted with one or more deuterium, halogen, C 1-8 alkyl, -OR c9 , -NR c9 R c10 , C 3-12 cycloalkyl, 3- to 12-membered heterocyclyl, C 6-12 aryl, 5- to 12-membered heteroaryl;

[0028] R c6 , R c7 , R c8 , R c9 , R c10 are each independently selected from the group consisting of: hydrogen, deuterium, C 1-8alkyl, C 1-8 alkoxy-C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-12 cycloalkyl, 3- to 12-membered heterocycloalkyl, C 6-12 aryl, 5- to 12-membered heteroaryl;

[0029] Cy2is selected from: C 3-12 cycloalkyl, 3- to 20-membered heterocycloalkyl, C 4-12 cycloalkenyl, 4- to 12-membered heterocycloalkenyl, C 6-16 aryl or 5- to 16-membered heteroaryl;

[0030] each R 2 is independently selected from the group consisting of: hydrogen, deuterium, halogen, C 1-20 alkyl, C 2-20 alkenyl, C 2-20 alkynyl, oxo, -CN, -NO2, Cy3, -OR d1 , -SO2R d1 , -COR d1 , -CO2R d1 , -CONR d1 R d2 , -C(=NR d1 )NR d2 R d3 , -NR d1 R d2 , -NR d1 COR d2 , -NR d1 CONR d2 R d3 , -NR d1 SONR d2 R d3 or -NR d1 SO2R d2 , wherein said C 1-20 alkyl, C 2-20 alkenyl, C 2-20 alkynyl is optionally substituted with one or more R d4 ;

[0031] Cy3is selected from: C 3-12 cycloalkyl, 3- to 20-membered heterocycloalkyl, C 4-12 cycloalkenyl, 4- to 12-membered heterocycloalkenyl, C 6-16 aryl or 5- to 16-membered heteroaryl, wherein said C 3-12 cycloalkyl, 3- to 20-membered heterocycloalkyl, C 4-12 cycloalkenyl, 4- to 12-membered heterocycloalkenyl, C 6-16R is independently selected from the group consisting of hydrogen, deuterium, halogen, C 3 substituted;

[0032] each R 3 is independently selected from the group consisting of hydrogen, deuterium, halogen, C 1-20 alkyl, C 2-20 alkenyl, C 2-20 alkynyl, C 3-12 cycloalkyl, 3- to 20-membered heterocyclyl, C 6-16 aryl, 5- to 16-membered heteroaryl, oxo, -CN, -NO2, -OR d1 , -SO2R d1 , -COR d1 , -CO2R d1 , -CONR d1 R d2 , -C(=NR d1 )NR d2 R d3 , -NR d1 R d2 , -NR d1 COR d2 , -NR d1 CONR d2 R d3 , -NR d1 SONR d2 R d3 , or -NR d1 SO2R d2 , wherein said C 1-20 alkyl, C 2-20 alkenyl, C 2-20 alkynyl, C 3-12 cycloalkyl, 3- to 20-membered heterocyclyl, C 6-16 aryl, 5- to 16-membered heteroaryl is optionally substituted with one or more R d4 substituents;

[0033] R d1 , R d2 , and R d3 are each independently selected from the group consisting of hydrogen, deuterium, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-12 cycloalkyl, 3- to 12-membered heterocyclyl, C 6-12 aryl, 5- to 12-membered heteroaryl, wherein said C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-12 cycloalkyl, 3- to 12-membered heterocyclyl, C 6-12 aryl, 5- to 12-membered heteroaryl is optionally substituted with one or more Rd5 substituted;

[0034] R d4 and R d5 are each independently selected from hydrogen, deuterium, halogen, hydroxyl, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-12 cycloalkyl, 3- to 12-membered heterocyclyl, C 6-12 aryl, 5- to 12-membered heteroaryl, oxo, -CN, -NO2, -OR d6 , -SO2R d6 , -COR d6 , -CO2R d6 , -CONR d6 R d7 , -C(=NR d6 )NR d7 R d8 , -NR d6 R d7 , -NR d6 COR d7 , -NR d6 CONR d7 R d8 , -NR d6 SONR d7 R d8 , or -NR d6 SO2R d7 , wherein said C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-12 cycloalkyl, 3- to 12-membered heterocyclyl, C 6-12 aryl, 5- to 12-membered heteroaryl is optionally substituted with one or more deuterium, halogen, C 1-8 alkyl, -OR d9 , -NR d9 R d10 , C 3-12 cycloalkyl, 3- to 12-membered heterocyclyl, C 6-12 aryl, 5- to 12-membered heteroaryl;

[0035] R d6 , R d7 , R d8 , R d9 , R d10 are each independently selected from hydrogen, deuterium, C 1-8 alkyl, C 1-8 alkoxy-C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C3-12 cycloalkyl, 3- to 12-membered heterocyclyl, C 6-12 aryl, 5- to 12-membered heteroaryl;

[0036] m is selected from 0, 1, 2, 3 or 4;

[0037] n is selected from 0, 1, 2 or 3;

[0038] Unless otherwise indicated, the heteroatoms in the above heterocycloalkyl, heteroaryl, heterocyclyl groups are independently selected from O, N or S, and the number of heteroatoms is 1, 2, 3 or 4.

[0039] In a preferred embodiment of the application, the present application provides a compound of the present application, or a tautomer, stereoisomer or a pharmaceutically acceptable salt thereof, wherein R is selected from H, F, Cl, Br, I and -L 1 -Cy1-(R 1 ) m ;

[0040] In a further preferred embodiment, wherein R is selected from H, Br, I and -L 1 -Cy1-(R 1 ) m ;

[0041] In some embodiments, the compound of formula (I) is a compound of formula (II) having the following structure

[0042]

[0043] wherein the substituents in the compounds are as defined above for the compound of formula (I).

[0044] In a preferred embodiment of the application, the present application provides a compound of the present application, or a tautomer, stereoisomer or a pharmaceutically acceptable salt thereof, wherein X 1 , X 2 are each independently selected from the group consisting of: a bond, -O-, -CO-, -CO2-, -S-, -SO-, -SO2-, -NR a -, -(CR a R a ) 1-6 -, -CON(R a )- or -N(R a )CO-, provided that -X 1 -X 2 are not both adjacent in the main chain;

[0045] In a further preferred embodiment, wherein X 1 , X 2are each independently selected from -O-, -CO-, -CO2-, -S-, -SO-, -SO2-, -NR a -(CR a R a ) 1-6 - provided that -X 1 -X 2 are not both -O-; and

[0046] In further preferred embodiments, wherein X 1 , X 2 are each independently selected from -O-, -CO-, -CO2-, -S-, -SO-, -SO2-, -NR a -(CR a R a ) 1-4 - provided that -X 1 -X 2 are not both -O-; and

[0047] In further preferred embodiments, wherein X 1 , X 2 are each independently selected from -O-, -S-, -SO-, -SO2-, -NH-, -CH2-, -CH2(CH3)CH2-, -CH2CH2(CH3)-, provided that -X 1 -X 2 are not both -O-; and

[0048] In further preferred embodiments, wherein X 1 is selected from -O-, -S-, -SO-, -SO2-, -NH-, or -CH2-, X 2 is selected from -CH2-, -CH2CH2-, -CH2(CH3)CH2-, or

[0049] In further preferred embodiments, wherein X 1 is selected from -O-, and X 2 is selected from -CH2-; X 1 is selected from -O-, and X 2 is selected from -CH2CH2-; X 1 is selected from -O-, and X 2 is selected from -CH2(CH3)CH2-; X 1 is selected from -O-, and X 2 is selected from X 1 is selected from -S-, and X 2 is selected from -CH2-; X 1is selected from -S- and X 2 is selected from -CH2CH2-; X 1 is selected from -S- and X 2 is selected from -CH2CH2(CH3)-; X 1 is selected from -SO- and X 2 is selected from -CH2-; X 1 is selected from -SO2- and X 2 is selected from -CH2-; X 1 is selected from -NH- and X 2 is selected from -CH2-; X 1 is selected from -CH2- and X 2 is selected from -CH2-.

[0050] In a preferred embodiment of the application, the application provides a compound of the application, or a tautomer, stereoisomer or a pharmaceutically acceptable salt thereof, wherein each R a is independently selected from the group consisting of: hydrogen, deuterium, halogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl or C 3-10 cycloalkyl, wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl or C 3-10 cycloalkyl is optionally substituted with one or more R a1 , which are the same or different; or -(CR a R a ) 1-6 two R a in -CH2- can form, together with the carbon atom to which they are attached, a C a1 membered cycloalkyl group, which is optionally substituted with one or more R 3-6 , which are the same or different;

[0051] In a further preferred embodiment, wherein each R a is independently selected from the group consisting of: hydrogen, halogen, C 1-3 alkyl or C 3-6 cycloalkyl, wherein said C 1-3 alkyl or C 3-6 cycloalkyl is optionally substituted with one or more R a1 , which are the same or different; or -(CR a R a ) 1-6 two R a in -CH2- can form, together with the carbon atom to which they are attached, a C a1 membered cycloalkyl group, which is optionally substituted with one or more R 3-6 , which are the same or different;

[0052] In a further preferred embodiment, each R a is independently selected from the group consisting of hydrogen, methyl.

[0053] In a preferred embodiment of the application, the application provides a compound as described herein, or a tautomer, stereoisomer, or a pharmaceutically acceptable salt thereof, wherein each R a1 is independently selected from the group consisting of hydrogen, halogen, -OR a2 , -NR a2 R a2 , -CN, -C(O)R a2 , or -C(O)OR a2 ;

[0054] In a further preferred embodiment, each R a1 is independently selected from the group consisting of hydrogen, halogen, or -OR a2 ;

[0055] In a further preferred embodiment, each R a1 is independently selected from the group consisting of hydrogen.

[0056] In a preferred embodiment of the application, the application provides a compound as described herein, or a tautomer, stereoisomer, or a pharmaceutically acceptable salt thereof, wherein each R a2 is independently selected from the group consisting of hydrogen, deuterium, C 1-6 alkyl, C 3-10 cycloalkyl, 3- to 10-membered heterocyclyl, C 6-10 aryl, and 5- to 10-membered heteroaryl;

[0057] In a further preferred embodiment, each R a2 is independently selected from the group consisting of hydrogen, C 1-3 alkyl, or C 3-6 cycloalkyl;

[0058] In a further preferred embodiment, each R a2 is independently selected from the group consisting of hydrogen.

[0059] In a preferred embodiment of the application, the application provides a compound as described herein, or a tautomer, stereoisomer, or a pharmaceutically acceptable salt thereof, wherein Y 1 , Y 2 are each independently selected from CR b or N;

[0060] In a further preferred embodiment, Y 1 and Y 2 are each CR b ; or Y 1 is selected from CR b , Y 2 is selected from N; or Y1 selected from N, Y 2 selected from CR b .

[0061] R b selected from: hydrogen, halogen, C 1-8 alkyl, -OR b1 , -SO2R b1 , -COR b1 or -CO2R b1 , wherein said C 1-8 alkyl is optionally substituted with one or more halogen, hydroxyl, C 1-8 alkoxy, C 3-12 cycloalkyl, 3- to 12-membered heterocyclyl, C 6-12 aryl, 5- to 12-membered heteroaryl;

[0062] In a further preferred embodiment, wherein R b is selected from: hydrogen, halogen, C 1-6 alkyl, -OR b1 , wherein said C 1-6 alkyl is optionally substituted with one or more halogen, hydroxyl;

[0063] In a further preferred embodiment, wherein R b is selected from: hydrogen, halogen, C 1-3 alkyl, wherein said C 1-3 alkyl is optionally substituted with one or more halogen, hydroxyl;

[0064] In a further preferred embodiment, wherein R b is selected from: hydrogen.

[0065] In a preferred embodiment of the present application, the present application provides a compound as described above, or a tautomer, a stereoisomer or a pharmaceutically acceptable salt thereof, wherein R b1 , R b2 , R b3 are each independently selected from: hydrogen, deuterium, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, 3- to 10-membered heterocyclyl, C 6-10 aryl, 5- to 10-membered heteroaryl;

[0066] In a further preferred embodiment, wherein R b1 , R b2 , R b3 are each independently selected from: hydrogen, C 1-4 alkyl, C 6-10 aryl or 5-10 membered heteroaryl;

[0067] In a further preferred embodiment, wherein R b1 , R b2 , R b3 are each independently selected from the group consisting of: hydrogen, C 1-3 alkyl or C 6-10 aryl;

[0068] In a further preferred embodiment, wherein R b1 , R b2 , R b3 are each independently selected from the group consisting of: hydrogen.

[0069] In a preferred embodiment of the application, the application provides a compound as described herein, or a tautomer, a stereoisomer, or a pharmaceutically acceptable salt thereof, wherein L 1 is selected from the group consisting of: a bond, -C 1-3 alkylene-, -NH-, -O-, -S-, -NHC(O)-, -C(O)NH-;

[0070] In a further preferred embodiment, wherein L 1 is a bond.

[0071] In a preferred embodiment of the application, the application provides a compound as described herein, or a tautomer, a stereoisomer, or a pharmaceutically acceptable salt thereof, wherein Cy1is selected from the group consisting of: C 3-10 cycloalkyl, 3- to 12-membered heterocyclyl, C 6-12 aryl, 5- to 12-membered heteroaryl;

[0072] In a further preferred embodiment, wherein Cy1is selected from the group consisting of: 3- to 10-membered heterocyclyl, C 6-10 aryl, 5- to 10-membered heteroaryl;

[0073] In a further preferred embodiment, wherein Cy1is selected from the group consisting of: phenyl, pyridyl, pyrazolyl, pyrimidinyl or

[0074] In a further preferred embodiment, wherein Cy1is selected from the group consisting of: phenyl.

[0075] In a preferred embodiment of the application, the application provides a compound as described herein, or a tautomer, a stereoisomer, or a pharmaceutically acceptable salt thereof, wherein each R 1 may be independently selected from the group consisting of: hydrogen, halogen, C 1-6 alkyl, C 3-6 cycloalkyl, 3- to 12-membered heterocyclyl, C 6-12 aryl, 5- to 12-membered heteroaryl, -OR c1 , -SO2R c1 , -SO2NR c1 Rc2 -COR c1 -CO2R c1 -CONR c1 R c2 -NR c1 COR c2 -NR c1 CONR c2 R c3 or -NR c1 SO2R c2 wherein the C 1-6 alkyl, C 3-6 cycloalkyl, 3- to 12-membered heterocyclyl, C 6-12 aryl, 5- to 12-membered heteroaryl is optionally substituted by one or more R c4 ;

[0076] In further preferred embodiments, wherein each R 1 may be independently selected from the group consisting of: hydrogen, F, Cl, Br, C 1-3 alkyl, C 6-10 aryl, 5- to 10-membered heteroaryl, -OR c1 , -SO2R c1 , -SO2NR c1 R c2 , -COR c1 , -CO2R c1 , -CONR c1 R c2 , -NR c1 COR c2 , -NR c1 CONR c2 R c3 or -NR c1 SO2R c2 wherein the C 6-10 aryl, 5- to 10-membered heteroaryl is optionally substituted by one or more R c4 ;

[0077] In further preferred embodiments, wherein each R 1 may be independently selected from the group consisting of: C 1-3 alkyl, -OR c1 , -COR c1 , -CO2R c1 or -CONR c1 R c2 .

[0078] In further preferred embodiments, wherein each R 1 may be independently selected from the group consisting of:

[0079] In a further preferred embodiment, wherein each R 1 may be independently selected from the group consisting of: hydrogen, F, methyl,

[0080] In a further preferred embodiment, wherein each R 1 may be independently selected from the group consisting of: methyl,

[0081] In a preferred embodiment of the present application, the present application provides a compound, or a tautomer, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein R c1 , R c2 , R c3 are each independently selected from the group consisting of hydrogen, deuterium, C 1-6 alkyl, -COR c5 , -C 1-6 alkoxy-C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 ycloalkyl, 3- to 10-membered heterocyclyl, C 6-10 aryl, 5- to 10-membered heteroaryl, wherein said; C 1-6 alkyl, C 1-6 alkoxy-C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 ycloalkyl, 3- to 10-membered heterocyclyl, C 6-10 aryl, 5- to 10-membered heteroaryl are optionally substituted with one or more R c5 ;

[0082] (R c1 and R c2 ), (R c1 and R c3 ), or (R c2 and R c3 ) together with the atom to which they are attached form a 3-12 membered heterocyclic ring containing 1, 2, or 3 heteroatoms, each independently selected from N, O, or optionally oxidized S, said 3-12 membered heterocyclic ring is optionally substituted with one or more R c5 ;

[0083] In a further preferred embodiment, wherein R c1 , R c2 , R c3 are each independently selected from the group consisting of hydrogen, C 1-4 alkyl, -COR c5 , C3-6 cycloalkyl, 3- to 10-membered heterocyclyl;

[0084] In a further preferred embodiment, wherein R c1 , R c2 , R c3 are each independently selected from the group consisting of hydrogen, C 1-4 alkyl, -COR c5 , C 3-5 cycloalkyl, 3- to 6-membered heterocyclyl;

[0085] In a further preferred embodiment, wherein R c1 , R c2 , R c3 are each independently selected from the group consisting of hydrogen, methyl, ethyl, propyl, cyclopropyl, tetrahydropyrrole, piperidinyl, piperazinyl;

[0086] In a further preferred embodiment, wherein R c1 , R c2 , R c3 are each independently selected from the group consisting of hydrogen, methyl, ethyl, propyl, tetrahydropyrrole;

[0087] In a further preferred embodiment, wherein (R c1 and R c2 ) together with the atom to which they are attached form a 3-10 membered heterocyclic ring containing 1, 2 or 3 heteroatoms each independently selected from N, O or optionally oxidized S, said 3-10 membered heterocyclic ring being optionally substituted with one or more R c5 ;

[0088] In a further preferred embodiment, wherein (R c1 and R c2 ) together with the nitrogen atom to which they are attached form a c5 optionally substituted with one or more R

[0089] In a further preferred embodiment, wherein (R c1 and R c2 ) together with the nitrogen atom to which they are attached form a c5 optionally substituted with one or more R

[0090] In a preferred embodiment of the present application, the present application provides a compound as described herein, or a tautomer, a stereoisomer or a pharmaceutically acceptable salt thereof, wherein R c4 and R c5 are each independently selected from the group consisting of hydrogen, halogen, C 1-8 alkyl, C 3-12 cycloalkyl, 3- to 12-membered heterocyclyl, C 6-12 aryl, -ORc6 -SO2R c6 -COR c6 -CO2R c6 -CONR c6 R c7 -NR c6 R c7 -NR c6 COR c7 -NR c6 CONR c7 R c8 -NR c6 SONR c7 R c8 -NR c6 SO2R c7 wherein said C 1-8 1-6C-alkyl, C 2-8 2-6C-alkenyl, C 2-8 2-6C-alkynyl, C 3-12 3-8C-cycloalkyl, 3- to 12-membered heterocyclyl, C 6-12 6-C-alkyl, 5- to 12-membered heteroaryl is optionally substituted by one or more halogen, C 1-8 1-6C-alkyl, -OR c9 , -NR c9 R c10 , C 3-12 3-8C-cycloalkyl, 3- to 12-membered heterocyclyl, C 6-12 6-C-alkyl, 5- to 12-membered heteroaryl;

[0091] In a further preferred embodiment, wherein R c4 and R c5 are each independently selected from the group consisting of hydrogen, halogen, C 1-4 1-6C-alkyl, C 3-12 3-8C-cycloalkyl, -OR c6 , -CONR c6 R c7 , -NR c6 R c7 , -NR c6 COR c7 ; wherein said C 1-4 1-6C-alkyl is optionally substituted by one or more halogen, -OR c9 , -NR c9 R c10 , C 3-6 3-8C-cycloalkyl, 3- to 6-membered heterocyclyl;

[0092] In a further preferred embodiment, wherein R c4 and R c5 are each independently selected from the group consisting of hydrogen, halogen, C 1-4 1-6C-alkyl, -OR c6 , -CONRc6 R c7 , -NR c6 R c7 , -NR c6 COR c7 ; wherein said C 1-4 alkyl is optionally substituted with one or more halogen, -OR c9 , -NR c9 R c10 , C 3-6 cycloalkyl, 3- to 6-membered heterocyclyl;

[0093] In further preferred embodiments, wherein R c4 and R c5 are each independently selected from the group consisting of: hydrogen, methyl, -NH2, -N(CH3)2, -CON(CH3)2, -OH, In a preferred embodiment of the present application, the present application provides a compound as described herein, or a tautomer, a stereoisomer, or a pharmaceutically acceptable salt thereof, wherein R c6 , R c7 , R c8 , R c9 , R c10 are each independently selected from the group consisting of: hydrogen, deuterium, C 1-6 alkyl, C 1-6 alkoxy-C 1-6 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3- to 10-membered heterocyclyl, C 6-10 aryl, 5- to 10-membered heteroaryl;

[0094] In further preferred embodiments, wherein R c6 , R c7 , R c8 , R c9 , R c10 are each independently selected from the group consisting of: hydrogen, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, or C 3-6 cycloalkyl;

[0095] In further preferred embodiments, wherein R c6 , R c7 , R c8 , R c9 , R c10 are each independently selected from the group consisting of: hydrogen, or C 1-4 alkyl;

[0096] In further preferred embodiments, whereinc6 c7 c8 c9 c10 are each independently selected from the group consisting of: hydrogen, methyl.

[0097] In a preferred embodiment of the application, the application provides a compound, or a tautomer, stereoisomer, or a pharmaceutically acceptable salt thereof, wherein Cy2is selected from the group consisting of: C 3-8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C 4-6 cycloalkenyl, 4- to 6-membered heterocycloalkenyl, C 6-12 aryl or 5- to 12-membered heteroaryl;

[0098] In a further preferred embodiment, wherein Cy2is selected from the group consisting of: C 3-6 cycloalkyl, 3- to 6-membered heterocycloalkyl, C 6-10 aryl or 5- to 10-membered heteroaryl;

[0099] In a further preferred embodiment, wherein Cy2is selected from the group consisting of: C 6-8 aryl or 5- to 6-membered heteroaryl;

[0100] In a further preferred embodiment, wherein Cy2is selected from the group consisting of: phenyl, pyridyl;

[0101] In a further preferred embodiment, wherein Cy2is selected from the group consisting of: phenyl.

[0102] In a preferred embodiment of the application, the application provides a compound, or a tautomer, stereoisomer, or a pharmaceutically acceptable salt thereof, wherein R 2 is selected from the group consisting of: hydrogen, halogen, C 1-8 alkyl, C 2-8 alkenyl, C 2-4 alkynyl, Cy3, -OR d1 , -SO2R d1 , -COR d1 , -CO2R d1 , -CONR d1 R d2 , -NR d1 R d2 , -NR d1 COR d2 , -NR d1 CONR d2 R d3 or -NR d1 SO2R d2 , wherein said C 1-8 alkyl, C 2-8 alkenyl, C 2-4 ​​​​alkyl, Cy3is optionally substituted by one or more R d4 substituents;

[0103] In a further preferred embodiment, wherein R 2 is selected from the group consisting of: hydrogen, halogen, C 1-6 alkyl, C 2-6 alkenyl, -NR d1 COR d2 , Cy3, wherein said C 1-6 alkyl, Cy3is optionally substituted by one or more R d4 substituents;

[0104] In a further preferred embodiment, wherein R 2 is selected from the group consisting of: hydrogen, halogen, C 1-4 alkyl, -NR d1 COR d2 , Cy3, wherein said C 1-4 alkyl, Cy3is optionally substituted by one or more R d4 substituents;

[0105] In a further preferred embodiment, wherein R 2 is selected from the group consisting of: hydrogen, F, methyl, Cy3;

[0106] In a further preferred embodiment, wherein R 2 is selected from the group consisting of: Cy3.

[0107] In a preferred embodiment of the application, the application provides a compound as described above, wherein Cy3is selected from the group consisting of: C 3-10 cycloalkyl, 3- to 10-membered heterocycloalkyl, C 4-10 cycloalkenyl, 4- to 10-membered heterocycloalkenyl, C 6-12 aryl or 5- to 12-membered heteroaryl, wherein said C 3-10 cycloalkyl, 3- to 10-membered heterocycloalkyl, C 4-10 cycloalkenyl, 4- to 10-membered heterocycloalkenyl, C 6-12 aryl or 5- to 12-membered heteroaryl is optionally substituted by one or more R 3 substituents;

[0108] In a further preferred embodiment, wherein Cy3is selected from the group consisting of: C 3-8 cycloalkyl, 5- to 10-membered heterocycloalkyl, 5- to 10-membered heterocycloalkenyl, C 6-10 aryl or 5- to 10-membered heteroaryl; wherein said C 3-8 cycloalkyl, 5- to 10-membered heterocycloalkyl, 5- to 10-membered heterocycloalkenyl, C 6-10 aryl or 5- to 10-membered heteroaryl is optionally substituted by one or more R 3 substituents;

[0109] In a further preferred embodiment, wherein Cy3is selected from: 5- to 8-membered heterocycloalkyl, 5- to 8-membered heterocycloalkenyl; wherein said 5- to 8-membered heterocycloalkyl, 5- to 8-membered heterocycloalkenyl is optionally substituted with one or more R 3 substituents;

[0110] In a further preferred embodiment, wherein Cy3is selected from: 5- to 8-membered heterocycloalkyl, 5- to 8-membered heterocycloalkenyl; wherein said 5- to 8-membered heterocycloalkyl, 5- to 8-membered heterocycloalkenyl is optionally substituted with one or more R 3 substituents;

[0111] In a further preferred embodiment, wherein Cy3is selected from: 5- to 8-membered heterocycloalkyl, 5- to 8-membered heterocycloalkenyl; wherein said 5- to 8-membered heterocycloalkyl, 5- to 8-membered heterocycloalkenyl is optionally substituted with one or more R 3 substituents;

[0112] In a preferred embodiment of the application, the present application provides a compound, or a tautomer, stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein R 3 is selected from: hydrogen, C 1-8 alkyl, C 3-10 cycloalkyl, 3- to 10-membered heterocyclyl, C 6-12 aryl, 5- to 12-membered heteroaryl, -OR d1 , -SO2R d1 , -COR d1 , -CO2R d1 , -CONR d1 R d2 , -NR d1 R d2 , -NR d1 COR d2 or -NR d1 SO2R d2 , wherein said C 1-8 alkyl, C 3-10 cycloalkyl, 3- to 10-membered heterocyclyl, C 6-12 aryl, 5- to 12-membered heteroaryl is optionally substituted with one or more R d4 substituents;

[0113] In a further preferred embodiment, wherein R 3 is selected from: hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, 3- to 6-membered heterocyclyl, C 6-10 aryl or 5- to 10-membered heteroaryl, wherein said C 1-6 alkyl, C 3-6 cycloalkyl, 3- to 6-membered heterocyclyl, C 6-10 aryl or 5- to 10-membered heteroaryl is optionally substituted with one or more R d4 substituents;

[0114] In a further preferred embodiment, wherein R 3 is selected from: hydrogen, C 1-6 alkyl, 3- to 6-membered heterocyclyl, wherein said C 1-6 alkyl, 3- to 6-membered heterocyclyl is optionally substituted with one or more R d4 substituents;

[0115] In a further preferred embodiment, wherein R 3 is selected from: hydrogen, C 1-3 alkyl, 4- to 6-membered heterocyclyl, wherein said C 1-3 alkyl, 4- to 6-membered heterocyclyl is optionally substituted with one or more R d4 substituents;

[0116] In a further preferred embodiment, wherein R 3 is selected from: hydrogen, methyl, ethyl, piperidinyl, wherein said methyl, ethyl, piperidinyl is optionally substituted with one or more R d4 substituents;

[0117] In a further preferred embodiment, wherein R 3 is selected from: hydrogen, methyl.

[0118] In a preferred embodiment of the present application, the present application provides a compound as described herein, or a tautomer, a stereoisomer or a pharmaceutically acceptable salt thereof, wherein R d1 , R d2 and R d3 are each independently selected from: hydrogen, C 1-6 alkyl, C 3-10 cycloalkyl, 3- to 10-membered heterocyclyl, C 6-10 aryl, 5- to 10-membered heteroaryl, wherein said C 1-6 alkyl, C 3-10 cycloalkyl, 3- to 10-membered heterocyclyl, C 6-10 aryl, 5- to 10-membered heteroaryl is optionally substituted with one or more R d5 substituents;

[0119] In a further preferred embodiment, wherein R d1 , R d2 and R d3 are each independently selected from: hydrogen, C 1-3 alkyl, wherein said C 1-3 alkyl is optionally substituted with one or more R d5 substituents;

[0120] In a further preferred embodiment, wherein R d1 , R d2 and R d3are each independently selected from the group consisting of hydrogen, methyl, wherein the methyl is optionally substituted with one or more R d5 substituted.

[0121] In a preferred embodiment of the application, the present application provides a compound, or a tautomer, stereoisomer or a pharmaceutically acceptable salt thereof, wherein R d4 and R d5 are each independently selected from the group consisting of hydrogen, halogen, C 1-6 alkyl, C 3-10 cycloalkyl, 3- to 10-membered heterocyclyl, C 6-10 aryl, 5- to 10-membered heteroaryl, -OR d6 , -SO2R d6 , -COR d6 , -CO2R d6 , -CONR d6 R d7 , -NR d6 R d7 , -NR d6 COR d7 or -NR d6 SO2R d7 , wherein the C 1-6 alkyl, C 3-10 cycloalkyl, 3- to 10-membered heterocyclyl, C 6-10 aryl, 5- to 10-membered heteroaryl is optionally substituted with one or more C 1-8 alkyl, -OR d9 , -NR d9 R d10 , C 3-12 cycloalkyl, 3- to 12-membered heterocyclyl, C 6-12 aryl, 5- to 12-membered heteroaryl;

[0122] In a further preferred embodiment, wherein R d4 and R d5 are each independently selected from the group consisting of hydrogen, C 1-4 alkyl, -OR d6 , 3- to 10-membered heterocyclyl, wherein the C 1-4 alkyl, 3- to 10-membered heterocyclyl is optionally substituted with one or more C 1-8 alkyl;

[0123] In a further preferred embodiment, wherein R d4 and R d5 are each independently selected from the group consisting of hydrogen, C 1-3 alkyl, -OR d6 , 4- to 6-membered heterocyclyl, wherein the C 1-3 alkyl, 4- to 6-membered heterocyclyl is optionally substituted with one or more C 1-4 alkyl;

[0124] In a further preferred embodiment, wherein R d4 and R d5 are each independently selected from hydrogen, -OH, methyl,

[0125]

[0126] In a preferred embodiment of the present application, the present application provides a compound as represented by Formula (I) or (II), or a tautomer, stereoisomer, or a pharmaceutically acceptable salt thereof, wherein R d6 , R d7 , R d8 , R d9 , R d10 are each independently selected from hydrogen, deuterium, C 1-5 alkyl, C 1-5 alkoxy-C 1-5 alkylene;

[0127] In a further preferred embodiment, wherein R d6 , R d7 , R d8 , R d9 , R d10 are each independently selected from hydrogen, C 1-3 alkyl;

[0128] In a further preferred embodiment, wherein R d6 , R d7 , R d8 , R d9 , R d10 are each independently selected from hydrogen.

[0129] In a preferred embodiment of the present application, the present application provides a compound as represented by Formula (I) or (II), or a tautomer, stereoisomer, or a pharmaceutically acceptable salt thereof, wherein m is selected from 0, 1, 2, 3, or 4; in a further preferred embodiment, wherein m is 1.

[0130] n is selected from 0, 1, 2, or 3; in a further preferred embodiment, wherein n is 1.

[0131] Unless otherwise specified, the heteroatoms in the above heterocycloalkyl, heteroaryl, heterocyclyl groups are independently selected from O, N, or S, and the number of heteroatoms is 1, 2, 3, or 4.

[0132] In a preferred embodiment of the present application, the compound as represented by Formula (I) or (II), or a tautomer, stereoisomer, or a pharmaceutically acceptable salt thereof is selected from the following compounds:

[0133]

[0134]

[0135]

[0136] The present application also provides a method for preparing a compound of formula (II), or a tautomer, stereoisomer, or a pharmaceutically acceptable salt thereof.

[0137]

[0138] i) compound II-a6 is reacted by halogenation to obtain compound II-a7;

[0139] for example, using compound II-a6 and a halogenating agent (e.g., NIS) as the basic raw materials, to obtain compound II-a7;

[0140] ii) compound II-a7 is reacted by coupling to obtain a compound of general formula II;

[0141] for example, using compound II-a7 and a boronic acid derivative as the basic raw materials, to obtain a compound of general formula II;

[0142] wherein, in the above preparation method, X is halogen (e.g., fluorine, chlorine, bromine, or iodine, preferably bromine or iodine), and the definitions of the substituents in the compounds are as described above.

[0143] In one embodiment, the compound of formula II, wherein X 1 is O, and X 2 is -(CH2) 1-2 may be prepared by the following steps:

[0144]

[0145] i) compound I-a6 is reacted by iodination to obtain compound I-a7;

[0146] for example, using compound I-a6 and an iodinating agent (e.g., NIS) as the basic raw materials, to obtain compound I-a7;

[0147] ii) compound I-a7 is reacted by coupling to obtain a compound of general formula I-a8;

[0148] for example, using compound I-a7 and a boronic acid derivative as the basic raw materials, to obtain a compound of general formula I-a8;

[0149] wherein, in the above preparation method, the definitions of the substituents in the compounds are as described above.

[0150] In a further preferred embodiment, wherein compound I-a6 can be prepared by the following steps:

[0151]

[0152] i) compound I-a5 undergoes a cyclization reaction to give compound I-a6;

[0153] As a basic raw material, compound I-a5 and a reducing agent (e.g., lithium aluminum hydride, etc.) and a base such as sodium hydride, etc. are reacted to give the annelated compound I-a6; wherein the substituents in the compounds shown in the above preparation method are as previously described.

[0154] In one embodiment, the compound, or a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof, can be prepared by the following steps:

[0155]

[0156] i) compound I-a1 undergoes a chemical transformation to give compound I-a2;

[0157] As a basic raw material, compound I-a1 and a brominating agent (e.g., NBS), etc. are reacted to give compound I-a2;

[0158] ii) compound I-a2 undergoes a chemical transformation to give compound I-a3;

[0159] As a basic raw material, compound I-a2 and pinacol borate, etc. are reacted to give compound I-a3;

[0160] iii) compound I-a3 and compound I-a4 undergo a chemical transformation to give compound I-a5;

[0161] As a basic raw material, compound I-a3 and compound I-a4 undergo a coupling reaction to give compound I-a5;

[0162] iv) compound I-a5 undergoes a chemical transformation to give compound I-a6;

[0163] As a basic raw material, compound I-a5 and a reducing agent (e.g., lithium aluminum hydride, etc.) and a base such as sodium hydride, etc. are reacted to give the annelated compound I-a6;

[0164] v) compound I-a6 undergoes a chemical transformation to give compound I-a7;

[0165] As a basic raw material, compound I-a6 and an iodinating agent (e.g., NIS), etc. are reacted to give compound I-a7;

[0166] vi) compound I-a7 undergoes a chemical transformation to give a compound of general formula I-a8;

[0167] In some embodiments, the compound of formula (I) or (II) is a compound of formula (I-a8) or a tautomer, stereoisomer or pharmaceutically acceptable salt thereof.

[0168] In a second aspect, the present application provides a pharmaceutical composition comprising a compound of formula (I) or (II) as described herein, or a tautomer, stereoisomer or pharmaceutically acceptable salt thereof.

[0169] In some embodiments, the pharmaceutical composition comprises a compound of formula (I) or (II) as described herein, or a tautomer, stereoisomer or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0170] In a third aspect, the present application provides use of a compound of formula (I) or (II) as described herein, or a tautomer, stereoisomer or pharmaceutically acceptable salt thereof, or the pharmaceutical composition as described herein, in the manufacture of a medicament for inhibiting HPK1.

[0171] In a fourth aspect, the present application provides use of a compound of formula (I) or (II) as described herein, or a tautomer, stereoisomer or pharmaceutically acceptable salt thereof, or the pharmaceutical composition as described herein, as an HPK1 inhibitor in the manufacture of a medicament for treating a HPK1 -related disease.

[0172] In some embodiments, the HPK1 -related disease is a cancer or a tumor-related disease.

[0173] In further preferred embodiments, the cancer or tumor-related disease is selected from breast cancer, multiple myeloma, bladder cancer, endometrial cancer, gastric cancer, cervical cancer, rhabdomyosarcoma, non-small cell lung cancer, small cell lung cancer, pulmonary carcinoma, ovarian cancer, esophageal cancer, melanoma, colorectal cancer, hepatocellular carcinoma, head and neck cancer, cholangiocarcinoma, myelodysplastic syndrome, glioblastoma, prostate cancer, thyroid cancer, schwannoma, lung squamous cell carcinoma, keratosis, synovial sarcoma, skin cancer, pancreatic cancer, testicular cancer or liposarcoma.

[0174] In a fifth aspect, the present application provides a method for preventing and / or treating a HPK1 -related disease as an HPK1 inhibitor, comprising administering to a patient a therapeutically effective amount of a compound of formula (I) or (II) as described herein, or a tautomer, stereoisomer or pharmaceutically acceptable salt thereof, or the pharmaceutical composition as described herein.

[0175] Definitions

[0176] The term "alkyl," unless otherwise specified, refers to a monovalent saturated aliphatic hydrocarbon group including straight-chain or branched-chain groups, preferably containing from one to ten carbon atoms (i.e., C 1-10 alkyl), further preferably containing one to eight carbon atoms (i.e., C 1-8 alkyl), more preferably containing one to six carbon atoms (i.e., C 1-6 alkyl), more preferably containing one to four carbon atoms (i.e., C 1-6 alkyl), more preferably containing one to three carbon atoms (i.e., C 1-3 alkyl), for example "C 1-6 alkyl" means that the group is an alkyl group and the number of carbon atoms in the carbon chain is between one and six (specifically one, two, three, four, five, or six). Examples include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, s-butyl, n-pentyl, neopentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, n-heptyl, n-octyl, and the like.

[0177] The term "cycloalkyl," unless otherwise specified, refers to a hydrocarbon group selected from saturated cyclic hydrocarbon groups, including monocyclic and polycyclic (e.g., bicyclic and tricyclic) groups, including fused cycloalkyl, bridged cycloalkyl, or spirocycloalkyl groups.

[0178] For example, a cycloalkyl group can comprise 3 to 12 (such as 3 to 10, further such as 3 to 8, further such as 3 to 6, 3 to 5, or 3 to 4) carbon atoms. Even further for example, a cycloalkyl group can be selected from monocyclic groups comprising 3 to 12 (such as 3 to 10, further such as 3 to 8, 3 to 6) carbon atoms. Examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, and cyclododecyl. In particular, examples of saturated monocyclic cycloalkyl groups (e.g., C3-8 cycloalkyl) include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. In preferred embodiments, the cycloalkyl group is a monocyclic ring comprising 3 to 6 carbon atoms (abbreviated as C3-6 cycloalkyl), which includes, but is not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Examples of bicyclic cycloalkyl groups include those with 7 to 12 ring atoms arranged as fused bicyclic rings selected from [4,4], [4,5], [5,5], [5,6], or [6,6] ring systems, or bridged bicyclic rings selected from bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, and bicyclo[3.2.2]nonane. Other examples of bicyclic cycloalkyl groups include rings arranged as bicyclic rings selected from [5,6] and [6,6] ring systems. The rings can be saturated or have at least one double bond (i.e., partially unsaturated), but not fully conjugated, and not aromatic, as aromatic is defined herein.

[0179] The term “spirocycloalkyl” refers to a cyclic structure containing carbon atoms and formed from at least two rings that share one atom. The term “7- to 12-membered spirocycloalkyl” refers to a cyclic structure containing 7 to 12 carbon atoms and formed from at least two rings that share one atom.

[0180] The term “fused cycloalkyl” refers to a fused ring containing carbon atoms and formed from two or more rings that share two adjacent atoms. The term “4- to 10-membered fused cycloalkyl” refers to a fused ring containing 4 to 10 ring carbon atoms and formed from two or more rings that share two adjacent atoms.

[0181] Examples include, but are not limited to, bicyclo[1.1.0]butyl, bicyclo[2.1.0]pentyl, bicyclo[3.1.0]hexyl, bicyclo[4.1.0]heptyl, bicyclo[3.3.0]octyl, bicyclo[4.2.0]octyl, decahydronaphthalene, and benzo 3- to 8-membered cycloalkyl, benzo C4-6 cycloalkenyl, 2,3-dihydro-1H-indenyl, 1H-indenyl, 1,2,3,4-tetrazolyl, 1,4-dihydronaphthyl, and the like. A preferred embodiment is an 8- to 9-membered fused ring, which refers to a cyclic structure containing 8 to 9 ring atoms in the above examples.

[0182] The term "bridged cycloalkyl" refers to a cyclic structure containing carbon atoms and formed from two rings that share two atoms that are not adjacent to each other. The term "7- to 10-membered bridged cycloalkyl" refers to a cyclic structure containing 7 to 12 carbon atoms and formed from two rings that share two atoms that are not adjacent to each other.

[0183] The term "cycloalkenyl" refers to a non-aromatic cyclic alkyl group of 3 to 10 carbon atoms, which has a single ring or multiple rings and has at least one double bond and preferably 1 to 2 double bonds. In one embodiment, the cycloalkenyl group is a cyclopentenyl group (1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl) or a cyclohexenyl group (1-cyclohex-1-enyl, 1-cyclohex-2-enyl, 1-cyclohex-3-enyl), preferably a cyclohexenyl group.

[0184] The term "alkoxy" means -O-alkyl, the alkyl group being defined as above, i.e. containing 1 to 20 carbon atoms, preferably 1 to 10 carbon atoms, more preferably 1 to 8 carbon atoms, more preferably 1 to 6 carbon atoms (in particular 1, 2, 3, 4, 5 or 6), more preferably 1 to 4 carbon atoms, more preferably 1 to 3 carbon atoms, unless otherwise noted. Representative examples include, but are not limited to, methoxy, ethoxy, propyloxy, isopropoxy, butoxy, 1-methylpropyloxy, 2-methylpropyloxy, t-butoxy, pentyloxy, 1-methylbutoxy, 2-methylbutoxy, 3-methylbutoxy, 1,1-dimethylpropyloxy, 1,2-dimethylpropyloxy, 2,2-dimethylpropyloxy, 1-ethylpropyloxy and the like.

[0185] The term "alkoxy-alkyl-" means an alkyl group as defined above, which is further substituted by an alkoxy group as defined above. Examples of alkyl-alkoxy- (e.g., C 1-8 alkoxy-C 1-8 Examples of alkyl-alkoxy- (e.g., C

[0186] The term "alkenyl" means a straight or branched chain unsaturated aliphatic hydrocarbon group having at least one double bond, consisting of carbon and hydrogen atoms, unless otherwise noted. The alkenyl group can contain 2 to 20 carbon atoms, preferably 2 to 10 carbon atoms (i.e., C 2-10 alkenyl), further preferably 2 to 8 carbon atoms (i.e., C 2-8 alkenyl), more preferably 2 to 6 carbon atoms (i.e., C 2-6 alkenyl), 2 to 5 carbon atoms (i.e., C 2-5 alkenyl), 2 to 4 carbon atoms (i.e., C 2-4 alkenyl), 2 to 3 carbon atoms (i.e., C 2-3 alkenyl), 2 carbon atoms (i.e., C2alkenyl), such as "C 2-6"Alkenyl" means that the group is an alkenyl and the number of carbon atoms in the carbon chain is between 2 and 6 (specifically 2, 3, 4, 5, or 6). Non-limiting examples of alkenyl groups include, but are not limited to, ethenyl, 1 -propenyl, 2-propenyl, 1 -butenyl, isobutenyl, and 1,3- butadienyl, and the like.

[0187] The term "alkynyl," unless otherwise specified, refers to a straight or branched chain unsaturated aliphatic hydrocarbon group having at least one triple bond. Alkynyl groups can contain 2 to 20 carbon atoms, preferably 2 to 10 carbon atoms (i.e., C2-C10alkynyl), more preferably 2 to 8 carbon atoms (i.e., C2-C8alkynyl), even more preferably 2 to 6 carbon atoms (i.e., C2-C6alkynyl), still more preferably 2 to 5 carbon atoms (i.e., C2-C5alkynyl), yet more preferably 2 to 4 carbon atoms (i.e., C2-C4alkynyl), even more preferably 2 to 3 carbon atoms (i.e., C2-C3alkynyl), and most preferably 2 carbon atoms (i.e., C2alkynyl), such as "C2-C6alkynyl." 2-10 alkynyl), further preferably 2 to 8 carbon atoms (i.e., C2-C8alkynyl), 2-8 alkynyl), further preferably 2 to 8 carbon atoms (i.e., C2-C8alkynyl), 2-6 alkynyl), further preferably 2 to 8 carbon atoms (i.e., C2-C8alkynyl), 2-5 alkynyl), further preferably 2 to 8 carbon atoms (i.e., C2-C8alkynyl), 2-4 alkynyl), further preferably 2 to 8 carbon atoms (i.e., C2-C8alkynyl), 2-3 alkynyl), further preferably 2 to 8 carbon atoms (i.e., C2-C8alkynyl), 2-6 "Alkynyl" means that the group is an alkenyl and the number of carbon atoms in the carbon chain is between 2 and 6 (specifically 2, 3, 4, 5, or 6). Non-limiting examples of alkenyl groups include, but are not limited to, ethenyl, 1 -propenyl, 2-propenyl, 1 -butenyl, isobutenyl, and 1,3- butadienyl, and the like.

[0188] The term "halogen" or "halo," unless otherwise specified, refers to F, Cl, Br, I. The term "haloalkyl" refers to an alkyl group as defined above in which one, two, or more, or all, of the hydrogen atoms are replaced by halogen. Representative examples of haloalkyl include CCI3, CF3, CHCI2, CH2CI, CH2Br, CH2I, CH2CF3, CF2CF3, and the like.

[0189] The term "heterocyclyl" or "heterocycle," unless otherwise specified, refers to a non-aromatic heterocyclyl group comprising one or more heteroatoms as ring members selected from nitrogen, oxygen, or optionally oxidized sulfur, and the remaining ring members are carbon. The term "optionally oxidized sulfur" as used herein refers to S, SO, or SO2. The term "heterocyclyl" or "heterocycle" includes monocyclic rings, fused rings, bridged rings, and spiro rings, i.e., containing monocyclic heterocyclyl groups, bridged heterocyclyl groups, spiro heterocyclyl groups, and fused heterocyclyl groups. The term "monocyclic heterocyclyl" refers to a monocyclic group in which at least one ring member is a heteroatom selected from nitrogen, oxygen, or optionally oxidized sulfur. The heterocycle can be saturated or partially saturated.

[0190] The term "heterocyclyl" or "heterocycle," unless otherwise specified, refers to a non-aromatic heterocyclyl group comprising one or more heteroatoms as ring members selected from nitrogen, oxygen, or optionally oxidized sulfur, and the remaining ring members are carbon. The term "optionally oxidized sulfur" as used herein refers to S, SO, or SO2. The term "heterocyclyl" or "heterocycle" includes monocyclic rings, fused rings, bridged rings, and spiro rings, i.e., containing monocyclic heterocyclyl groups, bridged heterocyclyl groups, spiro heterocyclyl groups, and fused heterocyclyl groups. The term "monocyclic heterocyclyl" refers to a monocyclic group in which at least one ring member is a heteroatom selected from nitrogen, oxygen, or optionally oxidized sulfur. The heterocycle can be saturated or partially saturated.

[0191] Exemplary monocyclic 4- to 9-membered heterocyclyl groups include, but are not limited to, (as numbered from the indicated position of attachment priority 1) pyrrolidin-1-yl, pyrrolidin-2-yl, pyrrolidin-3-yl, imidazolidin-2-yl, imidazolidin-4-yl, pyrazolidin-2-yl, pyrazolidin-3-yl, piperidin-1-yl, piperidin-2-yl, piperidin-3-yl, piperidin-4-yl, 2,5-piperazinyl, pyranyl, morpholinyl, morpholino, morpholin-2-yl, morpholin-3-yl, oxiranyl, aziridin-1-yl, aziridin-2-yl, azocin-1-yl, azocin-2-yl, azocin-3-yl, azocin-4-yl, azocin-5-yl, thiiranyl, azetidin-1-yl, azetidin-2-yl, azetidin-3-yl, oxetanyl, thietanyl, 1,2-dithietanyl, 1,3-dithietanyl, dihydropyridinyl, tetrahydropyridinyl, thiomorpholinyl, oxathianyl, piperazinyl, homopiperazinyl, homopiperidinyl, azepin-1-yl, azepin-2-yl, azepin-3-yl, azepin-4-yl, oxepinyl, thiepinyl, 1,4-oxathianyl, 1,4-dioxepinyl, 1,4-oxathiepinyl, 1,4-oxazepinyl, 1,4-dithiepinyl, 1,4-thiazepinyl, and 1,4-diazepinyl, 1,4-dithianyl, 1,4-azathianyl, oxazepinyl, diazepinyl, thiazepinyl, dihydrothienyl, dihydropyranyl, dihydrofuranyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, 1-pyrrolinyl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, 1,4-dioxanyl, 1,3-dioxolanyl, pyrazolinyl, pyrazolidinyl, dithianyl, dithiolanyl, pyrazolidinyl, imidazolinyl, pyrimidinonyl, or 1,1-dioxo-thiomorpholinyl.

[0192] The term "spiroheterocyclyl" refers to 5- to 20-membered polycyclic heterocyclyl groups having rings connected through a common carbon atom (referred to as a spiro atom), containing one or more heteroatoms selected from nitrogen, oxygen, or optionally oxidized sulfur as ring members, the remainder of the ring members being carbon. One or more rings of the spiroheterocyclyl group can contain one or more double bonds, but no ring has a fully conjugated pi-electron system. Preferably, the spiroheterocyclyl group is 6- to 14-membered, and more preferably 7- to 12-membered. Depending on the number of common spiro atoms, the spiroheterocyclyl group is a mono-, di-, or polyspiroheterocyclyl, and preferably refers to a monosprioheterocyclyl or a dispiroheterocyclyl, and more preferably a 4-membered / 4-membered, 3-membered / 5-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 5-membered, or 5-membered / 6-membered monosprioheterocyclyl. Representative examples of spiroheterocyclyl groups include, but are not limited to, the following groups: 2,3-dihydrospiro[indene-l,2'-pyrrolidine] (e.g., 2,3-dihydrospiro[indene-l,2'-pyrrolidine]-l'-yl), l,3-dihydrospiro[indene-2,2'-pyrrolidine] (e.g., l,3-dihydrospiro[indene-2,2'-pyrrolidine]-l'-yl), azaspiro[2.4]heptane (e.g., 5-azaspiro[2.4]heptane-5-yl), azaspiro[3.4]octane (e.g., 6-azaspiro[3.4]octane-6-yl), 2-oxa-6-azaspiro[3.4]octane (e.g., 2-oxa-6-azaspiro[3.4]octane-6-yl), azaspiro[3.4]octane (e.g., 6-azaspiro[3.4]oct-6-yl), azaspiro[3.4]octane (e.g., 6-azaspiro[3.4]oct-6-yl), l,7-dioxaspiro[4.5]decane, 2-oxa-7-aza-spiro[4.4]nonane (e.g., 2-oxa-7-aza-spiro[4.4]non-7-yl), 7-oxa-spiro[3.5]nonyl, and 5-oxa-spiro[2.4]heptyl.

[0193] The term "fused heterocyclyl" refers to a 5- to 20-membered polycyclic heterocyclyl group in which each ring in the system shares an adjacent pair of atoms (carbon and carbon atoms or carbon and nitrogen atoms) with another ring, including one or more heteroatoms selected from nitrogen, oxygen, or optionally oxidized sulfur as ring members, with the remainder of the ring members being carbon. One or more rings of the fused heterocyclyl group can contain one or more double bonds, but no ring has a fully conjugated pi-electron system. Preferably, the fused heterocyclyl group is 6- to 14-membered, preferably 7- to 12-membered, and more preferably 7- to 10-membered. Depending on the number of membered rings, the fused heterocyclyl group is a bicyclic, tricyclic, tetracyclic, or polycyclic fused heterocyclyl group, preferably referring to a bicyclic or tricyclic fused heterocyclyl group, and more preferably a 5-membered / 5-membered, or 5-membered / 6-membered bicyclic fused heterocyclyl group. Representative examples of fused heterocycles include, but are not limited to, the following groups: octahydrocyclopenta[c]pyrrolyl (e.g., octahydrocyclopenta[c]pyrrol-2-yl), octahydropyrrolo[3,4-c]pyrrolyl, octahydroisoindolyl, isoindolinyl (e.g., isoindolin-2-yl or isoindolin-5-yl), octahydro-benzo[b][l,4]dioxepin, dihydropyridinoxazinyl (e.g., 2,3-dihydro-lH-pyrido[2,3-b][l,4]oxazinyl), or dihydrobenzo-oxazepinyl (e.g., 5-oxo-3,4-dihydrobenzo[f][l,4]oxazepinyl), benzazepinyl (e.g., 2,3,4,5-tetrahydro-l-oxo-2-benzazepin-6-yl), benzo-oxazepinyl (e.g., 5-oxo-2,3,4,5-tetrahydro-l,4-benzo-oxazepin-8-yl), dihydroisoquinolinyl (e.g., l-oxo-2-methyl-3,4-dihydroisoquinolin-6-yl), tetrahydroisoquinolinyl (e.g., 2-methyl-l-oxo-l,2,3,4-tetrahydroisoquinolin-6-yl), dihydrobenzoxazine (e.g., 3,4-dihydro-2H-l,4-benzoxazin-6-yl).

[0194] The term "bridged heterocyclyl" refers to a 5- to 14-membered polycyclic heterocyclylalkyl group in which each two rings in the system share two non-adjacent atoms, including one or more heteroatoms selected from nitrogen, oxygen, or optionally oxidized sulfur as ring members, with the remainder of the ring members being carbon. One or more rings of the bridged heterocyclyl group can contain one or more double bonds, but no ring has a fully conjugated pi-electron system. Preferably, the bridged heterocyclyl group is 6- to 14-membered, and more preferably 7- to 10-membered. Depending on the number of membered rings, the bridged heterocyclyl group is a bicyclic, tricyclic, tetracyclic, or polycyclic bridged heterocyclyl group, and preferably refers to a bicyclic, tricyclic, or tetracyclic bridged heterocyclyl group, and more preferably a bicyclic or tricyclic bridged heterocyclyl group. Representative examples of bridged heterocycles include, but are not limited to, the following groups: 2-azabicyclo[2.2.1]heptyl, azabicyclo[3.1.0]hexyl, 2-azabicyclo[2.2.2]octyl, and 2-azabicyclo[3.3.2]decyl.

[0195] The term "heterocycloalkyl," unless otherwise specified, refers to a monocyclic, saturated "heterocyclyl" or "heterocycle" as defined above, having the number of ring atoms defined above, i.e., containing 3-20 ring atoms ("3-20 membered heterocycloalkyl"), and having 1, 2, 3, or 4 (1-4), preferably 1, 2, or 3 (1-3), heteroatoms each independently selected from N, O, or S. Preferably, it contains 3-12 ring atoms ("3-12 membered heterocycloalkyl"), further preferably 3-10 ring atoms ("3-10 membered heterocycloalkyl"), more further preferably 3-8 ring atoms ("3-8 membered heterocycloalkyl"), more further preferably 4-7 ring atoms ("4-7 membered heterocycloalkyl"), more further preferably 5-10 ring atoms ("5-10 membered heterocycloalkyl"), more further preferably 5-6 ring atoms ("5-6 membered heterocycloalkyl"). In certain embodiments, each instance of heterocycloalkyl is independently optionally substituted, e.g., unsubstituted ("unsubstituted heterocycloalkyl") or substituted with one or more substituents ("substituted heterocycloalkyl"). Particular examples of "heterocycloalkyl" are given above for "heterocyclyl" or "heterocycle" and include, but are not limited to, oxanyl, thiomorpholinyl, oxasulfuranyl, oxazolidinyl, thiazolidinyl, pyrazolidinyl, imidazolidinyl, and the like.

[0196] The term "heterocycloalkenyl," unless otherwise specified, refers to a monocyclic, unsaturated "heterocyclyl" or "heterocycle" as defined above, having the number of ring atoms defined above, i.e., containing 4-12 ring atoms ("4-12 membered heterocycloalkenyl"), and having 1, 2, 3, or 4 (1-4), preferably 1, 2, or 3 (1-3), heteroatoms each independently selected from N, O, or S. Preferably, it contains 4-10 ring atoms ("4-10 membered heterocycloalkenyl"), further preferably 4-8 ring atoms ("4-8 membered heterocycloalkenyl"), more further preferably 4-6 ring atoms ("4-6 membered heterocycloalkenyl"), more further preferably 5-6 ring atoms ("5-6 membered heterocycloalkenyl"). In certain embodiments, each instance of heterocycloalkenyl is independently optionally substituted, e.g., unsubstituted ("unsubstituted heterocycloalkenyl") or substituted with one or more substituents ("substituted heterocycloalkenyl").

[0197] The term "aryl" or "aromatic ring group" means a monocyclic, bicyclic and tricyclic aromatic carbon ring system containing 6-16 carbon atoms, or 6-14 carbon atoms, or 6-12 carbon atoms, or 6-10 carbon atoms, preferably 6-10 carbon atoms, and the term "aryl" can be used interchangeably with the term "aromatic ring." Examples of aryl groups can include, but are not limited to, phenyl, naphthyl, anthryl, phenanthryl, or pyrenyl, and the like.

[0198] The term "heteroaryl" or "heteroaromatic" means, unless otherwise defined, a 5-16 membered, preferably 5-14 membered, 5-12 membered, 5-10 membered, 5-8 membered, more preferably 5-6 membered, aromatic monocyclic, bicyclic or polycyclic ring system, wherein 1, 2, 3 or more ring atoms are heteroatoms and the remaining atoms are carbon, the heteroatoms being independently selected from O, N or S, the number of heteroatoms preferably being 1, 2 or 3. Bicyclic or polycyclic heteroaryl groups include fused ring heteroaryl groups. Examples of heteroaryl groups include, but are not limited to, furanyl, thienyl, oxazolyl, thiazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, thiadiazolyl, triazinyl, phtalazinyl, quinolinyl, isoquinolinyl, pteridinyl, purinyl, indolyl, isoindolyl, indazolyl, benzofuranyl, benzothienyl, benzopyridyl, benzopyrimidyl, benzopyrazinyl, benzimidazolyl, benzophthalazinyl, pyrrolo[2,3-b]pyridyl, imidazo[l,2-a]pyridyl, pyrazolo[l,5-a]pyridyl, pyrazolo[l,5-a]pyrimidyl, imidazo[l,2-b]pyridazinyl, [l,2,4]triazolo[4,3-b]pyridazinyl, [l,2,4]triazolo[l,5-a]pyrimidyl, [l,2,4]triazolo[l,5-a]pyridyl, and the like.

[0199] The term "alkylene" refers to a divalent alkyl group as defined above. The term "alkenylene" refers to a divalent alkenyl group as defined above. The term "alkynylene" refers to a divalent alkynyl group as defined above. The term "cycloalkylene" refers to a divalent cycloalkyl group as defined above. The term "heterocyclylene" refers to a divalent heterocyclyl group as defined above. The term "arylene" refers to a divalent aryl group as defined above. The term "heteroarylene" refers to a divalent heteroaryl group as defined above.

[0200] The term "pharmaceutically acceptable salt" or "pharmaceutically acceptable salts" means, unless otherwise indicated, a salt that is within the scope of sound medical judgment suitable for use in contact with the tissues of mammals, especially humans, without undue toxicity, irritation, allergic response and the like, and commensurate with a reasonable benefit / risk ratio, as well as the salt can be manufactured in its final isolate and purification form, or the salt can be prepared from the final isolation and purification of the compound of the present application by reacting the free base or the free acid with a suitable reagent, as appropriate.

[0201] The compounds of the present application also include "isotopic derivatives" thereof, unless otherwise defined, the term "isotopic derivatives" means that the compounds of the present application can exist in isotopically-labeled or enriched forms, containing one or more atoms which differ from the most abundant isotopic form of the atom naturally found in the compound. The isotopes can be radioactive or non-radioactive isotopes. The isotopes that are typically used as isotopic labels are: hydrogen isotopes, deuterium,2 H and 3 H; carbon isotopes: 13 C and 14 C; chlorine isotopes: 35 Cl and 37 Cl; fluorine isotopes: 18 F; iodine isotopes: 123 I and 125 I; nitrogen isotopes: 13 N and 15 N; oxygen isotopes: 15 O, 17 O and 18 O and sulfur isotopes 35 S. These isotopically-labeled compounds can be used to study the distribution, transport, metabolism, and excretion of the drugs in organisms, e.g., in humans. In particular, 3 H and 13 C, are more readily available and are, therefore, more commonly used. Substitution with heavier isotopes such as deuterium ( 2 H) affords certain therapeutic advantages resulting from greater metabolic stability, such as increased in vivo half-life or reduced dosage requirements. Isotopically-labeled compounds are generally prepared by synthetic methods well known in the art.

[0202] The compounds of the present application also include solvates, and unless otherwise stated the terms "solvate," "solvates" are intended to include the physiologically acceptable salts, and to describe a physical association between the compounds of the present application and one or more solvent molecules (whether organic or inorganic). This physical association can, for example, be due to hydrogen bonding, to ionic bonding, to van der Waals forces, to dipole-dipole interactions, or to any combination of these. In certain instances, the solvates will be capable of isolation, for example, when one or more solvent molecules are incorporated in the crystal lattice of the crystalline solid. Solvates are typically, but not always, hydrates. The solvate will in certain instances be able to be isolated in a substantially anhydrous form. The term "solvate" encompasses both solution-phase and isolatable solvates. Methods for solvation and / or desolvation of compounds are well known in the art.

[0203] The term "stereoisomers" means compounds which have the same chemical constitution, but differ in the arrangement of atoms or groups in space. Stereoisomers include enantiomers, diastereomers, conformational isomers (rotamers), geometric isomers (cis / trans), atropisomers, and the like. Mixtures of any of the foregoing stereoisomers can be separated on the basis of the physical chemical differences between the components. For example, by chromatography and / or fractional crystallization.

[0204] Unless otherwise specified, the term "tautomers" refers to structural isomers that can interconvert by a low energy barrier. If tautomerism is possible (as in solution), a chemical equilibrium of tautomers can be achieved. For example, prototropic tautomers (also known as proton-shift tautomers) include interconversions by proton migration, such as keto-enol isomerization and imine-enamine isomerization. Bond tautomers include interconversions by reorganization of some bonding electrons.

[0205] Unless otherwise stated, the chemical formulas described herein include all tautomeric forms (e.g., enantiomeric, diastereomeric, and geometric (or conformational) isomers): for example, the R, S configuration of asymmetric centers, the (Z), (E) isomers of double bonds, and the (Z), (E) conformational isomers. Thus, individual stereochemical isomers or mixtures of enantiomers, diastereomers, or geometric (or conformational) isomers, of the compounds of the present application are within the scope of the present application.

[0206] The compounds of the present application also include prodrugs thereof, unless otherwise specified, the term "prodrug" refers to a drug that is converted into the parent drug in vivo. Prodrugs are often useful when the parent drug is difficult to formulate, has poor solubility, or is not stable in the body. Physical properties often associated with problematical bioavailability are solubility (either too high or too low lipid or water solubility) or stability. Problematical biological properties include too rapid metabolism or poor bioavailability, which can be related to physical chemical properties. For example, they can be bioavailable by oral administration, whereas the parent is not. Prodrugs can also have improved solubility in pharmaceutical compositions over the parent drug. An example, but not limited to, of a prodrug can be any of the compounds of the present application administered as an ester ("prodrug") to facilitate transport across a cell membrane, where water solubility is detrimental to mobility, but once inside the cell water solubility is beneficial, and it is subsequently metabolically hydrolyzed to the carboxylic acid, the active entity. Another example of a prodrug can be a short peptide (polyamino acid) attached to an acid group, where the peptide is metabolized to reveal the active moiety.

[0207] Unless otherwise specified, the term "optionally substituted" means that the hydrogen of the substitutable position of the group is either unsubstituted or substituted with one or more substituents preferably selected from the group consisting of halogen, hydroxy, thiol, cyano, nitro, amino, azido, oxo, carboxy, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkyl, C 1-6 alkoxy, C 3-10 cycloalkyl, C 3-10 cycloalkylsulfonyl, 3-10 membered heterocycloalkyl, C 6-14 aryl or 5-10 membered heteroaromatic ring, wherein the C 2-6alkenyl, C 2-6 alkynyl, C 1-6 alkyl, C 1-6 alkoxy, C 3-10 cycloalkyl, C 3-10 cycloalkylsulfonyl, 3-10 membered heterocycloalkyl, C 6-14 aryl or 5-10 membered heteroaromatic ring group can be optionally substituted with one or more selected from halogen, hydroxy, amino, cyano, C 1-6 alkyl or C 1-6 alkoxy, the oxo group means two Hs at the same substitution site are replaced by the same O to form a double bond.

[0208] Abbreviations used in the Preparations, Examples, and elsewhere herein are:

[0209] (Boc)20 di-tert-butyl dicarbonate

[0210] Boc tert-butyloxycarbonyl

[0211] CDCl3 deuterated chloroform

[0212] DMSO-d6 deuterated dimethyl sulfoxide

[0213] DCM dichloromethane

[0214] DIEA N,N-diisopropylethylamine

[0215] DMF N,N-dimethylformamide

[0216] EA ethyl acetate

[0217] ESI electrospray ionization

[0218] g gram

[0219] h hour

[0220] HPLC high performance liquid chromatography

[0221] L liter

[0222] LC liquid chromatography

[0223] mL milliliter

[0224] MeOH methanol

[0225] mg milligram

[0226] mL milliliter

[0227] mm millimeter

[0228] mmol millimole

[0229] MS mass spectrometry

[0230] MHz megahertz

[0231] NaH sodium hydride

[0232] NaBH4 sodium borohydride

[0233] NMR nuclear magnetic resonance

[0234] NaH sodium hydride

[0235] NBS N-bromosuccinimide

[0236] NIS N-iodosuccinimide

[0237] Pd(dppf)Cl2 [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II)

[0238] PE petroleum ether

[0239] TFA trifluoroacetic acid

[0240] THF tetrahydrofuran

[0241] TLC thin layer chromatography

[0242] TEA triethylamine

[0243] XPhos-Pd-G3 methane sulfonic acid (2-dicyclohexylphosphino-2',4',6'-tri-isopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II)

[0244] The beneficial effects of the present application are:

[0245] The present application designs a class of novel compounds, which provides a new direction for the development of HPK1 inhibitor drugs. In vitro enzyme activity inhibition activity research shows that these compounds have strong inhibitory effect on HPK1, and can be used as a promising compound for treating HPK1 related diseases. In addition, the present application studies a specific synthesis method, which is simple in process, convenient to operate, and beneficial to large-scale industrial production and application. DETAILED DESCRIPTION

[0246] The present application will be further described in conjunction with specific examples. It should be understood that these examples are only used to illustrate the present application and not used to limit the scope of the present application. The experimental methods in the following examples are not specified, which are usually carried out according to the conventional conditions or according to the conditions recommended by the manufacturer. Unless otherwise defined, all professional and scientific terms used herein have the same meaning as familiar to those skilled in the art. In addition, any method and material similar or equivalent to the described content can be applied to the present application. The preferred implementation methods and materials shown herein are only used for demonstration.

[0247] The structure of the compounds of the present application is determined by nuclear magnetic resonance (NMR) or / and liquid chromatography-mass spectrometry (LC-MS) or / and high performance liquid chromatography (HPLC). The instrument used for NMR determination is AVANCE III 600MHz; the instrument used for LC-MS is Waters arc / QDa; the instrument used for HPLC is Waters e2695_2998.

[0248] The starting materials in the embodiments of the present application are known and commercially available, or can be synthesized by or according to methods known in the art.

[0249] Preparation of intermediates:

[0250] Preparation Example 1: Synthesis of (S)-tert-butyl 3-(4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)phenoxy)pyrrolidine-1-carboxylate

[0251]

[0252] Step 1: Synthesis of (S)-tert-butyl 3-(4-bromophenoxy)pyrrolidine-1-carboxylate

[0253] Into a 250 mL reaction flask was added (S)-tert-butyl 3-hydroxypyrrolidine-1-carboxylate (5.4 g, 28.8 mmol), DMF (50 mL), then 60% NaH (1.7 g, 42.5 mmol) was added slowly under temperature control of 0-5 °C, after the addition was completed, the reaction system was raised to room temperature and stirred for 0.5 h, then 1-bromo-4-fluorobenzene (5.0 g, 28.6 mmol) was added. The reaction system was raised to 100 °C and reacted for 2 h, LC-MS was used to monitor the completion of the reaction. Saturated ammonium chloride solution (100 mL) was added to quench the reaction, then ethyl acetate (250 mL) was extracted, the organic phase was washed once with water, then concentrated to dryness under reduced pressure, the residue was purified by column chromatography (PE:EA = 2:1, v / v) to obtain (S)-tert-butyl 3-(4-bromophenoxy)pyrrolidine-1-carboxylate (light yellow oil, 7.3 g, yield: 74.6%). ESI-MS (m / z): 342.06 / 344.06 [M+H] + .

[0254] Step 2: Synthesis of (S)-tert-butyl 3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)phenoxy)pyrrolidine-1-carboxylate

[0255] Into a 250 mL reaction flask, 1,4-dioxane (100 mL), (S)-3-(4- bromophenoxy)pyrrolidine-1-carboxylic acid tert-butyl ester (3 g, 8.8 mmol), bis(pinacolato)diboron (3.3 g, 13.0 mmol), Pd(dppf)Cl2(0.65 g, 0.89 mmol) and potassium acetate (1.7 g, 17.3 mmol) were added successively. The reaction was heated to 100 °C under nitrogen atmosphere for 5 h. After the reaction was completed by LC-MS monitoring, the reaction was cooled to room temperature, water (100 mL) was added, followed by extraction with ethyl acetate (250 mL). The organic phase was washed with saturated brine, then concentrated to dryness under reduced pressure. The concentrate was purified by column chromatography (PE:EA = 10:1 ~ 3:1, v / v) to give (S)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)pyrrolidine-1-carboxylic acid tert-butyl ester (light yellow oil, 3.1 g, 90.5%). ESI-MS (m / z): 390.24 [M+H] + .

[0256] Intermediate Preparation Example 2: Synthesis of (R)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)pyrrolidine-1-carboxylic acid tert-butyl ester

[0257]

[0258] The synthesis method was the same as that in Intermediate Preparation Example 1, except that (R)-3-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester was used instead of (S)-3-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester to give (R)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)pyrrolidine-1-carboxylic acid tert-butyl ester with a yield of 89.2%. ESI-MS (m / z): 390.24 [M+H] + .

[0259] Intermediate Preparation Example 3: Synthesis of 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)piperidine-1-carboxylic acid tert-butyl ester

[0260]

[0261] The synthesis method was the same as that in Intermediate Preparation Example 1, except that 4-hydroxypiperidine-1-carboxylic acid tert-butyl ester was used instead of (S)-3-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester to give 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)piperidine-1-carboxylic acid tert-butyl ester with a yield of 95%. ESI-MS (m / z): 404.25 [M+H] + .

[0262] Example 1

[0263] Synthesis of (S)-7-(4-methylpiperazin-1-yl)-3-(4-(pyrrolidin-3-yloxy)phenyl)-1,5- dihydroisochromeno[3,4-d]pyrrolo[2,3-b]pyridine (1):

[0264]

[0265] Step 1: Synthesis of methyl 2-bromo-5-(4-methylpiperazin-1-yl)benzoate

[0266] Into a 500 mL reaction flask, dichloromethane (100 mL) and methyl 3-(4- methylpiperazin-1-yl)benzoate (5 g, 21.3 mmol) were added in turn, then NBS (4.56 g, 25.6 mmol) was slowly added under the control of temperature 0-5 °C, after the addition was completed, the reaction system was raised to room temperature, and reacted at room temperature for 4 h, TLC monitored that the reaction was completed, the reaction liquid was allowed to stand, and white solid was precipitated, which was collected by suction filtration and washed with a small amount of dichloromethane to obtain methyl 2-bromo-5-(4-methylpiperazin-1-yl)benzoate (white solid, 4.4 g, yield: 65.8%). ESI-MS (m / z): 313.05 / 315.05 [M+H] + .

[0267] Step 2: Synthesis of methyl 5-(4-methylpiperazin-1-yl)-2-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)benzoate

[0268] Into a 500 mL reaction flask, 1,4-dioxane (100 mL), methyl 2-bromo-5-(4- methylpiperazin-1-yl)benzoate (4.4 g, 14 mmol), bis(pinacolato)diboron (5.35 g, 21.1 mmol), Pd(dppf)Cl2(1.03 g, 1.4 mmol) and potassium acetate (4.13 g, 42 mmol) were added in turn, and the reaction system was raised to 100 °C under nitrogen protection for 5 h. After the reaction was completed as monitored by LCMS, the reaction system was cooled to room temperature, water (30 mL) was added, followed by extraction with ethyl acetate (50 mL x 3), the organic phases were combined and washed with saturated brine, and the organic phase was dried over anhydrous sodium sulfate, then concentrated to dryness, and the concentrate was purified by column chromatography (DCM:MeOH = 20:1, v / v) to obtain methyl 5-(4-methylpiperazin-1-yl)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (dark brown oil, 4.54 g, 89.7%). ESI-MS (m / z): 361.22 [M+H] + .

[0269] Step 3: Synthesis of methyl 2-(4-fluoro-lH-pyrrolo[2,3-b]pyridin-5-yl)-5-(4- methylpiperazin-l-yl)benzoate

[0270] Into a 100 mL reaction flask, 1,4-dioxane (30 mL), water (6 mL), methyl 5-(4- methylpiperazin-l-yl)-2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)benzoate (3.2 g, 8.88 mmol), 5-bromo-4-fluoro-lH-pyrrolo[2,3-b]pyridine (1.59 g, 7.4 mmol), Pd(dppf)Cl2(541 mg, 0.74 mmol) and potassium carbonate (2.56 g, 18.5 mmol) were added successively. The reaction system was heated to 90 °C under nitrogen protection for 5 h. After the reaction was completed, the reaction system was cooled to room temperature, water (30 mL) was added, and then the reaction solution was extracted with ethyl acetate (50 mL x 3). The organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to dryness. The concentrate was purified by column chromatography (DCM:MeOH = 20: 1, v / v) to give methyl 2-(4-fluoro-lH-pyrrolo[2,3-b]pyridin-5-yl)-5-(4- methylpiperazin-l-yl)benzoate (0.96 g, yield: 35.2%). ESI-MS (m / z): 369.16 [M+H] + .

[0271] Step 4: Synthesis of (2-(4-fluoro-lH-pyrrolo[2,3-b]pyridin-5-yl)-5-(4- methylpiperazin-l-yl)phenyl)methanol

[0272] Into a 100 mL reaction flask, tetrahydrofuran (20 mL) and methyl 2-(4-fluoro-lH- pyrrolo[2,3-b]pyridin-5-yl)-5-(4-methylpiperazin-l-yl)benzoate (0.96 g, 2.61 mmol) were added successively. Lithium aluminum hydride (297 mg, 7.83 mmol) was slowly added at a temperature of 0-5 °C, and then the reaction system was warmed to room temperature. The reaction was carried out at room temperature for 2 h. After the reaction was completed, ice water (20 mL) was added to the reaction system to quench the reaction, and then the mixture was filtered under suction. The filter cake was washed with dichloromethane, and then the filtrate was concentrated to dryness under reduced pressure. The concentrate was purified by column chromatography (DCM:MeOH = 10: 1, v / v) to give (2-(4-fluoro-lH-pyrrolo[2,3-b]pyridin-5-yl)-5-(4- methylpiperazin-l-yl)phenyl)methanol (360 mg, yield: 40.5%). ESI-MS (m / z): 341.17 [M+H] + .

[0273] Step 5: Synthesis of 7-(4-methylpiperazin-1-yl)-1,5-dihydroisochromeno[3,4- d]pyrrolo[2,3-b]pyridine

[0274] Into a 50 mL reaction flask was added DMF (10 mL) and (2-(4-fluoro-1H- pyrrolo[2,3-b]pyridin-5-yl)-5-(4-methylpiperazin-1-yl)phenyl)methanol (360 mg, 1.06 mmol) sequentially, NaH (85 mg, 2.11 mmol) was added slowly under the temperature of 0-5 °C, then the reaction system was raised to 60 °C for 2 h. After the reaction was completed by LC-MS detection, it was cooled to room temperature, water (20 mL) was added to quench the reaction, then the reaction solution was extracted with ethyl acetate (30 mL x 3), the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to dryness to give 7-(4-methylpiperazin-1-yl)-1,5-dihydroisochromeno[3,4-d]pyrrolo[2,3-b]pyridine crude product (300 mg). ESI-MS (m / z): 321.16 [M+H] + .

[0275] Step 6: Synthesis of 3-iodo-7-(4-methylpiperazin-1-yl)-1,5-dihydroisochromeno[3,4- d]pyrrolo[2,3-b]pyridine

[0276] Into a 50 mL reaction flask was added DMF (10 mL), 7-(4-methylpiperazin-1-yl)- 1,5-dihydroisochromeno[3,4-d]pyrrolo[2,3-b]pyridine (300 mg, crude product) and NIS (211 mg, 0.94 mmol) sequentially, and reacted at room temperature for 3 h. After the reaction was completed by TLC monitoring, water (30 mL) was added to the reaction solution, then the reaction solution was extracted with ethyl acetate (30 x 2 mL), the organic phases were combined and washed with water (50 mL x 2) and saturated brine, and the organic phase was concentrated to dryness under reduced pressure to give 3-iodo-7-(4-methylpiperazin-1-yl)-1,5-dihydroisochromeno[3,4-d]pyrrolo[2,3-b]pyridine crude product (350 mg). ESI-MS (m / z): 447.06 [M+H] + .

[0277] Step 7: Synthesis of 3-iodo-7-(4-methylpiperazin-1-yl)isochromeno[3,4-d]pyrrolo[2,3- b]pyridine-1(5H)-carboxylic acid tert-butyl ester

[0278] In a 50 mL reaction bottle, dichloromethane (10 mL), 3-iodo-7-(4-methylpiperazin-1-yl)-1,5-dihydroisochromeno[3,4-d]pyrrolo[2,3-b]pyridine (350 mg, crude), (Boc)20 (257 mg, 1.18 mmol) and TEA (238 mg, 2.35 mmol) were added successively, and the reaction was carried out at room temperature for 3 h. After TLC monitoring, the reaction was completed, water (20 mL) was added to the reaction system, and the reaction solution was extracted with dichloromethane (30 mL x 3), the organic phases were combined and dried over anhydrous sodium sulfate, and the organic phase was concentrated to dryness. The concentrate was purified by column chromatography (DCM:MeOH = 20:1, v / v) to obtain 3-iodo-7-(4-methylpiperazin-1-yl)isochromeno[3,4-d]pyrrolo[2,3-b]pyridine-1(5H)-carboxylic acid tert-butyl ester (220 mg). ESI-MS (m / z): 547.11 [M+H] + .

[0279] Step 8: Synthesis of (S)-3-(4-((1-(tert-butoxycarbonyl)pyrrolidin-3-yl)oxy)phenyl)-7-(4-methylpiperazin-1-yl)isochromeno[3,4-d]pyrrolo[2,3-b]pyridine-1(5H)-carboxylic acid tert-butyl ester

[0280] In a 50 mL reaction bottle, water (1 mL), 1,4-dioxane (5 mL), 3-iodo-7-(4-methylpiperazin-1-yl)isochromeno[3,4-d]pyrrolo[2,3-b]pyridine-1(5H)-carboxylic acid tert-butyl ester (220 mg, 0.40 mmol), intermediate 1 (235 mg, 0.61 mmol), XPhos-Pd-G3 (33.7 mg, 0.04 mmol) and potassium phosphate (255 mg, 1.2 mmol) were added successively, and the reaction system was heated to 90°C under nitrogen protection for 6 h. After LCMS monitoring, the reaction was completed, the solvent was removed by reduced pressure concentration, and the concentrate was purified by column chromatography (DCM:MeOH = 20:1, v / v) to obtain (S)-3-(4-((1-(tert-butoxycarbonyl)pyrrolidin-3-yl)oxy)phenyl)-7-(4-methylpiperazin-1-yl)isochromeno[3,4-d]pyrrolo[2,3-b]pyridine-1(5H)-carboxylic acid tert-butyl ester (160 mg, yield: 58.7%). ESI-MS (m / z): 682.75 [M+H] + .

[0281] Step 9: Synthesis of (S)-7-(4-methylpiperazin-1-yl)-3-(4-(pyrrolidin-3-yloxy)phenyl)-1,5-dihydroisochromeno[3,4-d]pyrrolo[2,3-b]pyridine

[0282] In a 50 mL reaction flask, hydrochloric acid ethanol solution (2 M, 10 mL) and (S)-3-(4-((1-(tert-butoxycarbonyl)pyrrolidin-3-yl)oxy)phenyl)-7-(4-methylpiperazin-1-yl)isochromeno[3,4-d]pyrrolo[2,3-b]pyridine-1(5H)-carboxylic acid tert-butyl ester (160 mg, 0.23 mmol) were added successively, and the reaction was placed at 50 °C for 3 h. After monitoring the completion of the reaction by LC-MS, the reaction was concentrated to dryness under reduced pressure, followed by the addition of ethyl acetate (50 mL), saturated sodium bicarbonate solution (20 mL), and the organic phase was concentrated to dryness under reduced pressure. The concentrate was purified by column chromatography (DCM:MeOH = 10:1, v / v) to obtain (S)-7-(4-methylpiperazin-1-yl)-3-(4-(pyrrolidin-3-yloxy)phenyl)-1,5-dihydroisochromeno[3,4-d]pyrrolo[2,3-b]pyridine (33 mg, yield: 29.8%). ESI-MS (m / z): 482.25 [M+H] + . 1 H NMR (600 MHz, CDCl3) δ: 1.155 (d, J = 6 Hz, 1H), 1.302-1.346 (m, 2H), 2.213-2.135 (m, 2H), 2.385 (s, 3H), 2.647-2.663 (m, 4H), 3.184-3.224 (m, 2H), 3.271-3.286 (m, 4H), 3.429 (d, J = 5.4 Hz, 1H), 5.107 (s, 1H), 5.183 (s, 2H), 6.855 (d, J = 1.2 Hz, 1H), 6.975 (d, J = 6 Hz, 2H), 7.051 (dd, J = 8.4, 2.4 Hz, 1H), 7.289 (s, 1H), 7.589 (d, J = 8.4 Hz, 2H), 7.724 (d, J = 8.4 Hz, 1H), 8.577-8.583 (m, 1H).

[0283] Example 2

[0284] Synthesis of N,N-dimethyl-4-(7-(4-methylpiperazin-1-yl)-1,5-dihydroisochromeno[3,4-d]pyrrolo[2,3-b]pyridin-3-yl)benzamide (2):

[0285]

[0286] The synthetic procedure of example 2 was same as the synthetic procedure of example 1, step 8 was replaced by intermediate preparation example 1 with 4-(N,N-dimethylcarbamoyl)benzeneboronic acid to obtain N,N-dimethyl-4-(7-(4-methylpiperazin-1-yl)-1,5-dihydroisochromeno[3,4- d]pyrrolo[2,3-b]pyridin-3-yl)benzamide (0.05 g, 50% yield). ESI-MS (m / z): 468.23 [M+H] + ; 1 H NMR (600 MHz, DMSO-d6) δ: 1.767 (s, 2H), 2.237 (s, 3H), 2.463-2.478 (m, 2H), 3.017 (s, 6H), 3.180-3.196 (m, 4H), 5.208 (s, 2H), 6.875-6.878 (m, 1H), 6.981-6.999 (m, 1H), 7.426 (d, J = 8.4 Hz 2H), 7.621 (s, 1H), 7.717 (d, J = 8.4 Hz, 2H), 7.769 (d, J = 8.4 Hz, 1H), 8.681 (s, 1H), 11.969 (s, 1H).

[0287] Example 3

[0288] Synthesis of (R)-7-(4-methylpiperazin-1-yl)-3-(4-(pyrrolidin-3-yloxy)phenyl)-1,5- dihydroisochromeno[3,4-d]pyrrolo[2,3-b]pyridine (3):

[0289]

[0290] The synthetic procedure of example 3 was same as the synthetic procedure of example 1, step 8 was replaced by intermediate preparation example 1 with intermediate preparation example 2 to obtain (R)-7-(4-methylpiperazin-1-yl)-3-(4-(pyrrolidin-3-yloxy)phenyl)-1,5- dihydroisochromeno[3,4-d]pyrrolo[2,3-b]pyridine (0.03 g, 25% yield). ESI-MS (m / z): 482.25 [M+H] + .

[0291] Example 4

[0292] Synthesis of 7-(4-methylpiperazin-1-yl)-3-(4-(piperidin-4-yloxy)phenyl)-1,5- dihydroisochromeno[3,4-d]pyrrolo[2,3-b]pyridine (4):

[0293]

[0294] The synthesis method of Example 4 is the same as that of Example 1, and intermediate preparation example 3 is used instead of intermediate preparation example 1 in step 8 to obtain 7-(4-methylpiperazin-1-yl)-3-(4-(piperidin-4-yloxy)phenyl)-1,5-dihydroisochromeno[3,4-d]pyrrolo[2,3-b]pyridine (0.02 g, yield 35%). ESI-MS (m / z): 496.26 [M+H] + .

[0295] Example 5

[0296] Synthesis of methyl 4-(7-(4-methylpiperazin-1-yl)-1,5-dihydroisochromeno[3,4-d]pyrrolo[2,3-b]pyridin-3-yl)benzoate (5):

[0297]

[0298] The synthesis method of Example 5 is the same as that of Example 1, and 4-methoxycarbonylphenylboronic acid is used instead of intermediate preparation example 1 in step 8 to obtain methyl 4-(7-(4-methylpiperazin-1-yl)-1,5-dihydroisochromeno[3,4-d]pyrrolo[2,3-b]pyridin-3-yl)benzoate (0.03 g, yield 47%). ESI-MS (m / z): 455.20 [M+H] + .

[0299] Example 6

[0300] Synthesis of N,N-dimethyl-4-(7-(piperazin-1-yl)-1,5-dihydroisochromeno[3,4-d]pyrrolo[2,3-b]pyridin-3-yl)benzamide (7)

[0301]

[0302] The synthetic method is the same as that of Example 1, the first step uses tert-butyl 4-(3-(methoxycarbonyl)phenyl)piperazine-1-carboxylate instead of methyl 3-(4-methylpiperazin-1-yl)benzoate, and the eighth step uses methyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate instead of the intermediate preparation example 1 to obtain methyl 4-(7-(piperazin-1-yl)-1,5-dihydroisochromeno[3,4-d]pyrrolo[2,3-b]pyridin-3-yl)benzoate (0.04 g, yield 42%). ESI-MS (m / z): 441.18 [M+H]+, 1H NMR (600 MHz, DMSO-d6) δ 12.07 (s, 1H), 8.69 (s, 1H), 7.97 (d, J = 8.2 Hz, 2H), 7.82 (d, J = 8.1 Hz, 2H), 7.77 (d, J = 8.6 Hz, 1H), 7.72 (s, 1H), 6.98 (d, J = 8.4 Hz, 1H), 6.86 (s, 1H), 5.22 (s, 2H), 3.86 (d, J = 30.4 Hz, 3H), 3.11 (s, 4H), 2.87 (s, 4H).

[0303] Example 7

[0304] Synthesis of methyl 4-(7-(piperazin-1-yl)-1,5-dihydroisochromeno[3,4-d]pyrrolo[2,3-b]pyridin-3-yl)benzoate (15)

[0305]

[0306] The synthetic method is the same as that of Example 1, the first step uses tert-butyl 4-(3-(methoxycarbonyl)phenyl)piperazine-1-carboxylate instead of methyl 3-(4-methylpiperazin-1-yl)benzoate, and the eighth step uses methyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate instead of the intermediate preparation example 1 to obtain methyl 4-(7-(piperazin-1-yl)-1,5-dihydroisochromeno[3,4-d]pyrrolo[2,3-b]pyridin-3-yl)benzoate (0.04 g, yield 42%). ESI-MS (m / z): 441.18 [M+H]+, 1H NMR (600 MHz, DMSO-d6) δ 12.07 (s, 1H), 8.69 (s, 1H), 7.97 (d, J = 8.2 Hz, 2H), 7.82 (d, J = 8.1 Hz, 2H), 7.77 (d, J = 8.6 Hz, 1H), 7.72 (s, 1H), 6.98 (d, J = 8.4 Hz, 1H), 6.86 (s, 1H), 5.22 (s, 2H), 3.86 (d, J = 30.4 Hz, 3H), 3.11 (s, 4H), 2.87 (s, 4H). + ; 1 H NMR (600 MHz, DMSO-d6) δ 12.07 (s, 1H), 8.69 (s, 1H), 7.97 (d, J = 8.2 Hz, 2H), 7.82 (d, J = 8.1 Hz, 2H), 7.77 (d, J = 8.6 Hz, 1H), 7.72 (s, 1H), 6.98 (d, J = 8.4 Hz, 1H), 6.86 (s, 1H), 5.22 (s, 2H), 3.86 (d, J = 30.4 Hz, 3H), 3.11 (s, 4H), 2.87 (s, 4H).

[0307] Example 8

[0308] Synthesis of (3-(dimethylamino)azetidin-l-yl)(4-(7-(piperazin-l-yl)-l,5- dihydroisochromeno[3,4-d]pyrrolo[2,3-b]pyridin-3-yl)phenyl)methanone (16)

[0309]

[0310] Step 1: Synthesis of 4-(7-(4-(tert-butoxycarbonyl)piperazin-l-yl)-l,5- dihydroisochromeno[3,4-d]pyrrolo[2,3-b]pyridin-3-yl)benzoic acid

[0311] Into a 250 mL reaction bottle was added 7-(4-(tert-butoxycarbonyl)piperazin-l-yl)- 3-(4-(methoxycarbonyl)phenyl)isochromeno[3,4-d]pyrrolo[2,3-b]pyridine- 1(5H)carboxylate tert-butyl ester (450 mg, 0.703 mmol), THF (8 mL), H20 (4 mL), methanol (4 mL), sodium hydroxide (85 mg, 2.13 mmol) sequentially, the reaction was warmed to 60 °C for 3 h. LCMS showed the reaction was complete, work-up, concentrated under reduced pressure to remove THF and methanol, the concentrate was used to adjust the pH of the solution to 5 with 3N hydrochloric acid, purification gave 4-(7-(4-(tert-butoxycarbonyl)piperazin-l-yl)-l,5- dihydroisochromeno[3,4-d]pyrrolo[2,3-b]pyridin-3-yl)benzoic acid (400 mg) ESI-MS (m / z): 527.22 [M+H] + .

[0312] Step 2: Synthesis of 4-(3-(4-(4-(3-dimethylamino)azetidin-l-ylcarbonyl)phenyl)-l,5- dihydroisochromeno[3,4-d]pyrrolo[2,3-b]pyridin-7-yl)piperazine-l-carboxylic acid tert-butyl ester

[0313] In a 250 mL reaction flask, 4-(7-(4-(tert-butoxycarbonyl)piperazin-1-yl)-1,5- dihydroisochromeno[3,4-d]pyrrolo[2,3-b]pyridin-3-yl)benzoic acid (100 mg, 0.190 mmol), N,N-dimethylazetidine-3-amine hydrochloride (40 mg, 0.231 mmol), DMF (10 mL), TEA (100 mg, 0.988 mmol), TBTU (68 mg, 0.212 mmol) were added in sequence, and the reaction was allowed to react at room temperature for 1.5 h. LCMS showed that the reaction was completed. After treatment, water (30 mL) and ethyl acetate (100 mL) were added, extracted, separated, and the obtained organic phase was washed with water and saturated brine once, respectively, and then concentrated to dryness under reduced pressure. The concentrate was purified by column chromatography (DCM:MeOH = 20:1 (v / v)) to obtain tert-butyl 4-(3-(4-(4-(3-dimethylamino)azetidin-1- carbonyl)phenyl)-1,5-dihydroisochromeno[3,4-d]pyrrolo[2,3-b]pyridin-7-yl)piperazine-1- carboxylate (80 mg). ESI-MS (m / z): 609.31 [M+H] + .

[0314] Step 3: Synthesis of (3-(dimethylamino)azetidin-1-yl)(4-(7-(piperazin-1-yl)-1,5- dihydroisochromeno[3,4-d]pyrrolo[2,3-b]pyridin-3-yl)phenyl)methanone

[0315] Synthesis method same as step 9 in Example 1, to obtain (3-(dimethylamino)azetidin-1-yl)(4-(7-(piperazin-1-yl)-1,5-dihydroisochromeno[3,4-d]pyrrolo[2,3-b]pyridin-3- yl)phenyl)methanone (0.06 g, yield 58%). ESI-MS (m / z): 509.26 [M+H] + ; 1 H NMR (600 MHz, DMSO-d6) δ 12.01 (s, 1H), 8.69 (s, 1H), 7.76 (dd, J = 18.8, 8.5 Hz, 3H), 7.66 (d, J = 8.3 Hz, 3H), 6.98 (d, J = 8.7 Hz, 1H), 6.87 (s, 1H), 5.21 (s, 2H), 4.38 (s, 1H), 4.16 (s, 1H), 4.08 (s, 1H), 3.86 (s, 1H), 3.12 (dd, J = 10.9, 5.9 Hz, 5H), 2.96-2.81 (m, 4H), 2.11 (s, 6H).

[0316] Example 9

[0317] Synthesis of N-(cyclopropylmethyl)-4-(7-(piperazin-1-yl)-1,5- dihydroisochromeno[3,4-d]pyrrolo[2,3-b]pyridin-3-yl)benzamide (17)

[0318]

[0319] Synthesis method is the same as that of Example 8 to obtain N-(cyclopropylmethyl)-4-(7-(piperazin-1-yl)-1,5-dihydroisochromeno[3,4-d]pyrrolo[2,3-b]pyridin-3-yl)benzamide (0.03 g, yield 38%). ESI-MS (m / z): 480.23 [M+H] + ; 1 H NMR (600 MHz, DMSO-d6) δ: 12.01 (s, 1H), 8.69 (s, 1H), 8.55 (t, J = 5.6 Hz, 1H), 7.88 (t, J = 10.3 Hz, 2H), 7.83-7.70 (m, 3H), 7.66 (s, 1H), 6.98 (dd, J = 8.6, 2.0 Hz, 1H), 6.87 (s, 1H), 5.21 (s, 2H), 3.18 (dd, J = 18.3, 12.0 Hz, 6H), 2.92 (s, 4H), 1.08-1.06 (m, 1H), 0.54-0.37 (m, 2H), 0.35-0.18 (m, 2H).

[0320] Example 10

[0321] Synthesis of (4-(7-(piperazin-1-yl)-1,5-dihydroisochromeno[3,4-d]pyrrolo[2,3-b]pyridin-3-yl)phenyl)(2-oxa-6-azaspiro[3.3]heptan-6-yl)methanone (18)

[0322]

[0323] Synthesis method is the same as that of Example 8 to obtain (4-(7-(piperazin-1-yl)-1,5-dihydroisochromeno[3,4-d]pyrrolo[2,3-b]pyridin-3-yl)phenyl)(2-oxa-6-azaspiro[3.3]heptan-6-yl)methanone (0.04 g, yield 42%). ESI-MS (m / z): 508.23 [M+H] + ; 1H NMR (600 MHz, DMSO-d6) δ: 12.01 (s, 1H), 8.68 (s, 1H), 7.75 (dd, J = 13.7, 8.5 Hz, 3H), 7.69 - 7.60 (m, 3H), 6.97 (d, J = 8.4 Hz, 1H), 6.86 (s, 1H), 5.21 (s, 2H), 4.71 (s, 4H), 4.57 (s, 2H), 4.24 (s, 2H), 3.10 (s, 4H), 2.85 (s, 4H).

[0324] Example 11

[0325] Synthesis of N-((dimethylamino)(3-(4-(3-(dimethylamino)azetidine-l- carbonyl)phenyl)-7-(piperazin-l-yl)isochromeno[3,4-d]pyrrolo[2,3-b]pyridin-l-(5H)- yl)methylene)-N-methylmethanamine (19)

[0326]

[0327] Step 1: Synthesis of N-((7-(4-(tert-butoxycarbonyl)piperazin-l-yl)-3-(4-(3- (dimethylamino)azetidine-l-carbonyl)phenyl)isochromeno[3,4-d]pyrrolo[2,3-b]pyridin-l- (5H)-yl)(dimethylamino)methylene)-N-methylmethanamine

[0328] Into a 250 mL reaction bottle was added 4-(7-(4-(tert-butoxycarbonyl)piperazin-l- yl)-l,5-dihydroisochromeno[3,4-d]pyrrolo[2,3-b]pyridin-3-yl)benzoic acid (100 mg, 0.190 mmol), N,N-dimethylazetidine-3-amine hydrochloride (40 mg, 0.231 mmol), DMF (10 mL), TEA (100 mg, 0.988 mmol), HATU (110 mg, 0.290 mmol) sequentially, and the reaction was allowed to react at room temperature for 1.5 h. LCMS showed that the reaction was completed. After treatment, water (30 mL) and ethyl acetate (100 mL) were added, extracted, separated, and the obtained organic phase was washed with water and saturated brine once, respectively, and then concentrated to dryness under reduced pressure. The concentrate was purified by column chromatography (DCM:MeOH = 20: 1 (v / v)) to obtain N-((7-(4-(tert-butoxycarbonyl)piperazin-l-yl)-3-(4-(3- (dimethylamino)azetidine-l-carbonyl)phenyl)isochromeno[3,4-d]pyrrolo[2,3-b]pyridin-l- (5H)-yl)(dimethylamino)methylene)-N-methylmethanamine (50 mg). ESI-MS (m / z): 707.40 [M+H] + .

[0329] Step 2: Synthesis of N-((dimethylamino)(3-(4-(3-(dimethylamino)azetidine-1- carbonyl)phenyl)-7-(piperazin-1-yl)isochromeno[3,4-d]pyrrolo[2,3-b]pyridin-1-(5H)- yl)methylene)-N-methylmethanamine

[0330] Synthetic procedure same as step 9 in example 1 to get N-((dimethylamino)(3-(4-(3- (dimethylamino)azetidine-1-carbonyl)phenyl)-7-(piperazin-1-yl)isochromeno[3,4- d]pyrrolo[2,3-b]pyridin-1-(5H)-yl)methylene)-N-methylmethanamine (0.02 g, 43% yield). ESI-MS (m / z): 607.35 [M+H] + .

[0331] Example 12

[0332] Synthesis of N-(2-(dimethylamino)ethyl)-4-(7-(piperazin-1-yl)-1,5-dihydroisochromeno[3,4- d]pyrrolo[2,3-b]pyridin-3-yl)benzamide (20)

[0333]

[0334] Synthetic procedure same as example 8 to get N-(2-(dimethylamino)ethyl)-4-(7-(piperazin- 1-yl)-1,5-dihydroisochromeno[3,4-d]pyrrolo[2,3-b]pyridin-3-yl)benzamide (0.07 g, 58% yield). ESI-MS (m / z): 497.26 [M+H] + ; 1 H NMR (600 MHz, DMSO-d6) δ: 12.01 (s, 1H), 8.68 (s, 1H), 8.36 (t, J = 5.3 Hz, 1H), 7.86 (d, J = 8.1 Hz, 2H), 7.75 (dd, J = 14.2, 8.5 Hz, 3H), 7.65 (s, 1H), 6.97 (d, J = 7.5 Hz, 1H), 6.86 (s, 1H), 5.20 (s, 2H), 3.39-3.37 (m, 4H), 3.10 (s, 3H), 2.85 (s, 3H), 2.43 (t, J = 6.8 Hz, 2H), 2.21 (s, 6H).

[0335] Example 13

[0336] Synthesis of (2-(dimethylamino)-7-azaspiro[3.5]non-7-yl)(4-(7-(piperazin-1-yl)- 1,5-dihydroisochromeno[3,4-d]pyrrolo[2,3-b]pyridin-3-yl)phenyl)methanone (21)

[0337]

[0338] The synthesis method is the same as that of Example 8 to obtain (2-(dimethylamino)-7-azaspiro[3.5]non-7-yl)(4-(7-(piperazin-1-yl)-1,5-dihydroisochromeno[3,4- d]pyrrolo[2,3-b]pyridin-3-yl)phenyl)methanone (0.06 g, yield 48%). ESI-MS (m / z): 577.32 [M+H] + ; 1 H NMR (600 MHz, DMSO-d6) δ: 11.96 (s, 1H), 8.68 (s, 1H), 7.76 (d, J = 8.7 Hz, 1H), 7.71 (d, J = 7.9 Hz, 2H), 7.62 (s, 1H), 7.38 (d, J = 7.9 Hz, 2H), 6.97 (d, J = 8.1 Hz, 1H), 6.85 (s, 1H), 5.21 (s, 2H), 3.10 (s, 3H), 2.85 (s, 3H), 2.63 (s, 3H), 2.00 (d, J = 17.6 Hz, 8H), 1.53 (d, J = 36.0 Hz, 7H), 1.23 (d, J = 16.1 Hz, 3H).

[0339] Example 14

[0340] Synthesis of azetidin-1-yl(4-(7-(piperazin-1-yl)-1,5-dihydroisochromeno[3,4- d]pyrrolo[2,3-b]pyridin-3-yl)phenyl)methanone (22)

[0341]

[0342] The synthesis method is the same as that of Example 8 to obtain azetidin-1-yl(4-(7-(piperazin-1-yl)-1,5-dihydroisochromeno[3,4-d]pyrrolo[2,3-b]pyridin-3- yl)phenyl)methanone (0.04 g, yield 45%). ESI-MS (m / z): 466.22 [M+H] + ; 1H NMR (600 MHz, DMSO-d6) δ: 12.00 (s, 1H), 8.68 (s, 1H), 7.75 (dd, J = 17.2, 8.4 Hz, 3H), 7.64 (d, J = 8.2 Hz, 3H), 6.97 (d, J = 8.5 Hz, 1H), 6.86 (s, 1H), 5.21 (s, 2H), 4.39 (s, 2H), 4.08 (s, 2H), 3.10 (s, 4H), 2.85 (s, 4H), 2.34-2.23 (m, 2H).

[0343] Example 15

[0344] Synthesis of ((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)(4-(7-(piperazin-1-yl)-1,5- dihydroisochromeno[3,4-d]pyrrolo[2,3-b]pyridin-3-yl)phenyl)methanone (24)

[0345]

[0346] Synthesis method same as that of Example 8 to obtain ((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)(4-(7-(piperazin-1-yl)-1,5-dihydroisochromeno[3,4-d]pyrrolo[2,3-b]pyridin-3- yl)phenyl)methanone (0.05 g, yield 51%). ESI-MS (m / z): 508.23 [M+H] + ; 1 H NMR (600 MHz, DMSO-d6) δ: 12.00 (s, 1H), 8.68 (s, 1H), 7.82–7.69 (m, 3H), 7.64 (s, 1H), 7.58 (d, J = 7.5 Hz, 1H), 7.52 (d, J = 7.8 Hz, 1H), 6.97 (d, J = 6.6 Hz, 1H), 6.86 (s, 1H), 5.21 (s, 2H), 4.86-4.51 (m, 2H), 3.96-3.75 (m, 3H), 3.08 (dd, J = 23.3, 18.3 Hz, 4H), 2.85 (d, J = 4.6 Hz, 5H), 1.95-1.78 (m, 2H).

[0347] Example 16

[0348] Synthesis of ((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)(4-(7-(piperazin-1-yl)-1,5- dihydroisochromeno[3,4-d]pyrrolo[2,3-b]pyridin-3-yl)phenyl)methanone (24)

[0349]

[0350] The synthetic procedure was same as the synthetic procedure of Example 8 to obtain ((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)(4-(7-(piperazin-1-yl)-1,5- dihydroisochromeno[3,4-d]pyrrolo[2,3-b]pyridin-3-yl)phenyl)methanone (0.03 g, 45% yield). ESI-MS (m / z): 508.23 [M+H] + ; 1 H NMR (600 MHz, DMSO-d6) δ: 12.00 (s, 1H), 8.68 (s, 1H), 7.82 - 7.69 (m, 3H), 7.64 (s, 1H), 7.58 (d, J = 7.5 Hz, 1H), 7.52 (d, J = 7.8 Hz, 1H), 6.97 (d, J = 6.6 Hz, 1H), 6.86 (s, 1H), 5.21 (s, 2H), 4.86 - 4.51 (m, 2H), 3.96 - 3.75 (m, 3H), 3.08 (dd, J = 23.3, 18.3 Hz, 4H), 2.85 (d, J = 4.6 Hz, 5H), 1.95 - 1.78 (m, 2H).

[0351] Example 17

[0352] Synthesis of N,N,2-trimethyl-4-(7-(piperazin-1-yl)-1,5-dihydroisochromeno[3,4- d]pyrrolo[2,3-b]pyridin-3-yl)benzamide (25)

[0353]

[0354] Step 1: Synthesis of tert-butyl 7-(4-(tert-butoxycarbonyl)piperazin-1-yl)-3-(4- (dimethylcarbamoyl)-3-methylphenyl)isochromeno[3,4-d]pyrrolo[2,3-b]pyridine-1(5H) carboxylate

[0355] In a 20 mL reaction vial, water (1 mL), 1,4-dioxane (5 mL), 7-(4-(tert- butoxycarbonyl)piperazin-1-yl)-3-iodo-iso-benzo-pyrano[3,4-d]pyrrolo[2,3-b]pyridine- 1(5H)-carboxylic acid tert-butyl ester (200 mg, 0.32 mmol), 4-(dimethylcarbamoyl)-3- methylphenylboronic acid pinacol ester (110 mg, 0.38 mmol), XPhos-Pd-G3 (27 mg, 0.03 mmol) and potassium phosphate (201 mg, 0.95 mmol) were added successively. The reaction system was heated to 90 °C for 6 h under nitrogen protection. After the reaction was completed, the reaction solution was concentrated under reduced pressure to remove the solvent, and the concentrate was purified by column chromatography (DCM:MeOH = 20:1, v / v) to obtain 7-(4-(tert-butoxycarbonyl)piperazin-1-yl)-3-(4- (dimethylcarbamoyl)-3-methylphenyl)iso-benzo-pyrano[3,4-d]pyrrolo[2,3-b]pyridine- 1(5H)-carboxylic acid tert-butyl ester (132 mg, yield: 62.6%). ESI-MS (m / z): 668.34 [M+H] + .

[0356] Step 2: Synthesis of N,N,2-trimethyl-4-(7-(piperazin-1-yl)-1,5-dihydro- iso-benzo-pyrano[3,4-d]pyrrolo[2,3-b]pyridin-3-yl)benzamide

[0357] In a 25 mL reaction vial, hydrochloric acid ethanol solution (2 M, 3 mL) and 7-(4-(tert-butoxycarbonyl)piperazin-1-yl)-3-(4-(dimethylcarbamoyl)-3-methylphenyl) iso-benzo-pyrano[3,4-d]pyrrolo[2,3-b]pyridine-1(5H)-carboxylic acid tert-butyl ester (78 mg, 0.12 mmol) were added successively, and the reaction was placed at 50 °C for 2 h. After the reaction was completed, the reaction solution was concentrated under reduced pressure to dryness, followed by the addition of ethyl acetate (50 mL) and saturated sodium bicarbonate solution (20 mL), and the mixture was separated. The organic phase was concentrated under reduced pressure to remove the solvent, and the concentrate was purified by column chromatography (DCM:MeOH = 10:1, v / v) to obtain N,N,2-trimethyl-4-(7-(piperazin-1-yl)-1,5-dihydro-iso-benzo-pyrano[3,4-d]pyrrolo[2,3-b]pyridin-3-yl)benzamide (31 mg, yield: 57.4%). ESI-MS (m / z): 468.23 [M+H] + , 1H NMR (600 MHz, DMSO) δ 11.91 (s, 1H), 8.67 (s, 1H), 7.76 (d, J = 8.7 Hz, 1H), 7.57 (d, J = 6.0 Hz, 2H), 7.51 (d, J = 7.8 Hz, 1H), 7.15 (d, J = 7.8 Hz, 1H), 6.97 (dt, J = 8.3, 4.1 Hz, 1H), 6.86 (d, J = 2.1 Hz, 1H), 5.21 (s, 2H), 3.11 - 3.07 (m, 4H), 3.04 (s, 3H), 2.88 - 2.82 (m, 7H), 2.26 (s, 3H), 1.23 (dd, J = 26.3, 11.5 Hz, 1H).

[0358] Example 18

[0359] Synthesis of (S)-N-(2-hydroxypropyl)-4-(7-(piperazin-l-yl)-l,5-dihydroisochromeno[3,4- d]pyrrolo[2,3-b]pyridin-3-yl)benzamide (26)

[0360]

[0361] Synthesis method is the same as that of Example 8 to obtain (S)-N-(2-hydroxypropyl)-4-(7-(piperazin-l-yl)-l,5-dihydroisochromeno[3,4-d]pyrrolo[2,3-b]pyridin-3- yl)benzamide (0.02 g, yield 42%). ESI-MS (m / z): 484.23 [M+H] + ; 1 H NMR (600 MHz, DMSO-d6) δ: 12.00 (s, 1H), 8.69 (s, 1H), 8.38 (d, J = 5.2 Hz, 1H), 7.88 (d, J = 8.1 Hz, 2H), 7.79 (d, J = 8.6 Hz, 1H), 7.74 (d, J = 8.0 Hz, 2H), 7.65 (s, 1H), 7.00 (d, J = 7.5 Hz, 1H), 6.88 (s, 1H), 5.21 (s, 2H), 4.77 (d, J = 4.6 Hz, 1H), 3.85 - 3.77 (m, 1H), 3.24 (d, J = 4.8 Hz, 2H), 3.17 (s, 4H), 2.96 (s, 4H), 1.10 (d, J = 6.1 Hz, 3H).

[0362] Example 19

[0363] Synthesis of N,N-dimethyl-4-(7-(piperazin-l-yl)-4,5-dihydro-lH-benzo[c]pyrrolo[2,3- h][l,6]naphthyridin-3-yl)benzamide (27)

[0364]

[0365] The synthetic method is the same as Example 8 to obtain N,N-dimethyl-4-(7-(piperazin-1-yl)-4,5-dihydro-1H-benzo[c]pyrrolo[2,3-h][1,6]naphthyridin-3-yl)benzamide. ESI-MS (m / z): 438.21 [M+H] + , 1 H NMR (600 MHz, DMSO) δ 12.41 (s, 1H), 9.76 (d, J = 11.1 Hz, 1H), 9.37 (s, 1H), 8.86 (d, J = 9.2 Hz, 1H), 8.05 (d, J = 8.2 Hz, 2H), 7.84 - 7.75 (m, 2H), 7.59 (d, J = 2.5 Hz, 1H), 7.47 (d, J = 8.2 Hz, 2H), 3.39 (d, J = 13.5 Hz, 2H), 3.05 (s, 6H), 3.03 - 2.97 (m, 4H), 1.33 - 1.21 (m, 4H), 0.89 - 0.83 (m, 1H).

[0366] Referring to the synthesis and operation of Example 1 or 8, using the corresponding main starting materials, the following examples are prepared:

[0367]

[0368]

[0369] Biological test evaluation

[0370] The following further describes and explains the present application in conjunction with test examples, but these test examples are not meant to limit the scope of the present application.

[0371] English abbreviation table:

[0372] abbreviation Full name Chinese HPK1 Hematopoietic progenitor kinase 1 Hematopoietic progenitor cell kinase 1 MBP Mvelin Basic Protein Myelin basic protein BSA Vovine serum albumin Bovine serum albumin

[0373] Test Example 1

[0374] 1. Experimental purpose:

[0375] The purpose of this experiment is to detect the inhibitory activity of the compound of the present application on HPK1 enzyme, and the determination method is ADP-Glo enzymatic activity test method (ADP-Glo TM Kinase Assay for HPK1).

[0376] 2. Experimental materials and equipment:

[0377]

[0378] 3. Experimental procedure (1) Preparation of 1X kinase buffer:

[0379] 1 volume of 5X kinase buffer plus 4 volumes of distilled water, after dilution, 1X buffer is added to contain 50 μM DTT.

[0380] 1X kinase reaction buffer:

[0381] 40 mM Tris (pH 7.4)

[0382] 20 mM MgCl2

[0383] 0.1 mg / ml BSA

[0384] 50 μM DTT

[0385] (2) Preparation of test compounds

[0386] 1) Compound solubilization and dilution: Compound is dissolved in DMSO to make a 10 mM stock solution.

[0387] 2) 10 mM compound is diluted 100-fold (diluted in EP tubes), after dilution, the concentration is 100 μM.

[0388] 3) Transferred to 384 dilution plate (P-05525-BC) for 3-fold gradient dilution.

[0389] (3) Preparation of test plate

[0390] 50 nL of compound dilution is transferred to 384-well assay plate (784075) by ECHO, the final working concentration is 1 μM-0.0508 nM, a total of 10 concentration gradients.

[0391] (4) Kinase reaction

[0392] 1) Preparation of 2X enzyme solution in 1X kinase buffer.

[0393] 2) 2.5 μL of 2X enzyme is added to the 384-well assay plate.

[0394] 3) The 384-well assay plate is centrifuged at 1000 g for 30 s, and then equilibrated at room temperature for 10 min.

[0395] 4) Preparation of 2X substrate and ATP mixture in 1X kinase buffer.

[0396] 5) 2.5 μL of ATP and substrate mixture is added to the 384-well assay plate to start the reaction. The assay plate is centrifuged at 1000 g for 30 s, sealed, and placed at room temperature for 2 h.

[0397] 6) Add 4 μL ADP-GLO Reagent, incubate at room temperature for 40 minutes.

[0398] 7) Add 8 μL Kinase Assay Reagent, incubate at room temperature for 40 minutes.

[0399] (5) Read luminescence signal on Envision 2104 plate reader.

[0400] (6) Calculate the average value of compound wells, positive control wells and blank control wells respectively, and record the average value of compound wells as Signalcmpd, the average value of positive control wells as SignalAve_VC, and the average value of blank control wells as SignalAve_VC. According to the formula, the inhibition rate is calculated:

[0401] %inhibition = 100-(Signalcmpd-SignalAve_PC) / (SignalAve_VC-SignalAve_PC) x 100.

[0402] Use GraphPad8.0 to fit the nonlinear regression (dose-variable slope) of inhibition value (%) and compound concentration logarithmic value, and calculate IC 50 value.

[0403] Y = Bottom + (Top-Bottom) / (1+10^((LogIC 50 -X)*HillSlope))

[0404] X: Inhibition concentration logarithmic value; Y: Inhibition rate (%)

[0405] 4. Experimental results:

[0406] BG-12 as a control molecule, selected from the patent WO2019238067A1 of BeiJiShenZhou. The molecular structure is:

[0407]

[0408] Compound numbering HPK1 IC50(nM) BG-12 B 1 A 5 C 7 A 15 B 16 A 17 A 18 A 19 A 20 A 21 B 22 A 23 B 24 B 25 B 26 B

[0409] A represents IC 50 ≤1nM, B represents 1nM < IC 50 ≤5nM, C represents 5nM < IC 50 ≤10nM.

Claims

1. A compound represented by formula (II), or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, having the following structure: in, X 1 Selected from -O-, and X 2 Selected from -CH2-; Y 1 Y 2 Selected independently from CR b Or N; R b Selected from: hydrogen; L 1 Selected from key; Cy1 is selected from: phenyl; R 1 Selected from: -OR c1 ; R c1 Selected from C 1-6 Alkyl or 3- to 10-membered heterocyclic groups, wherein: C 1-6 Alkyl or 3- to 10-membered heterocyclic groups are optionally surrounded by one or more R c5 Replace; R c5 Selected from: hydrogen, -NR c6 R c7 ;R c6 R c7 Selected from: hydrogen or C 1-4 Alkyl groups; heteroatoms in heterocyclic groups are independently selected from nitrogen; Cy2 is selected from: benzene; R 2 Independently selected from: arbitrarily selected by an R 3 Replacement R 3 Independently selected from: hydrogen or methyl; m is selected from 1; n is selected from 1.

2. The compound of claim 1, or its stereoisomer or a pharmaceutically acceptable salt thereof, wherein, R 1 Selected from:

3. Selected from the following compounds, or their stereoisomers or pharmaceutically acceptable salts:

4. A pharmaceutical composition comprising the compound of any one of claims 1 to 3, or a stereoisomer thereof or a pharmaceutically acceptable salt thereof.

5. The use of the compound of any one of claims 1 to 3, or its stereoisomer or pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 4, as an HPK1 inhibitor in the preparation of a medicament for treating HPK1-related diseases.

6. The use as described in claim 5, wherein, The HPK1-related diseases mentioned are cancers or tumors.

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