Heterobifunctional compounds as degraders of HPK1

Abstract

Disclosed are hematopoietic progenitor kinase 1 (HPK1) degradation / destruction compounds comprising an HPK1 ligand, a degradation / destruction tag, and a linker group, and methods of using such compounds in the treatment of HPK1-mediated diseases.

Description

Technical Field

[0001] The present disclosure relates to bivalent compounds (e.g., heterobifunctional compounds) that degrade and / or destroy hematopoietic progenitor kinase 1 (HPK1), compositions comprising one or more of the bivalent compounds, and methods of using the same for treating HPK1-mediated diseases in subjects in need thereof. The present disclosure also relates to methods for designing such bivalent compounds. Background Art

[0002] Unlike traditional enzyme inhibitors that only inhibit the catalytic activity of the target enzyme, heterobifunctional compounds, also known as proteolysis-targeted chimeras (PROTACs), in addition to inhibiting enzyme activity, also bind to and induce degradation of the enzyme, thereby eliminating the protein's potential scaffolding function (Buckley and Crews, 2014). The HPK1 degraders disclosed herein provide a new mechanism for treating HPK1-mediated diseases. In addition, the ability of degraders to target HPK1 for degradation, as opposed to inhibiting its catalytic activity, is expected to overcome drug resistance, whether due to resistance caused by drugs used in previous treatments or acquired resistance caused by genetic mutations, amplifications, or other factors.

[0003] Lewis Thomas and Frank Macfarlane Burnet first introduced the concept that the immune system continuously monitors the host for the emergence of new cancer cells and eliminates them before they become tumors (Burnet, 1970). Although several lines of evidence suggest that our immune system can accomplish such tasks (Corthay, 2014), the most direct support for this concept comes from the development of immuno-oncology drugs that target inhibitory molecules that hinder anti-tumor immunity, allowing the immune system to actively participate in and eliminate previously difficult-to-treat cancers (Ribas and Wolchok, 2018). The success of the immune checkpoint inhibitor approach provides a roadmap for how to stimulate the exhausted immune system to re-engage cancer cells. This theoretical framework has promoted the exploration of new immune checkpoint receptors that can be used as new immune checkpoint targets.

[0004] Hematopoietic progenitor kinase 1 (HPK1, also known as MAP4K1), an intracellular negative regulator of the T cell antigen receptor (TCR) signaling pathway, is a member of the KHS subfamily of Ste20 serine / threonine kinases (Hu et al., 1996; Kiefer et al., 1996). It is a multimodular-domain protein that, in addition to the kinase domain, also includes a proline-rich motif and a C-terminal citron homology domain. These additional domains suggest that HPK1 can perform functions other than its kinase function. HPK1 transcripts were detected in all embryonic tissues examined, but its expression profile shifted to a hematopoietic cell-restricted pattern by day 1 after birth (Kiefer et al., 1996), leading to the speculation that HPK1 could perform specific functions in hematopoietic cells. This cytoplasmic Ste20 kinase is recruited to the TCR complex (Ling et al., 2001) and its kinase activity is induced upon TCR engagement (Liou et al., 2000). Overexpression of HPK1 inhibits TCR-induced activation of AP-1-dependent gene transcription in a kinase-dependent manner, indicating that the kinase activity of HPK1 is required to inhibit the Erk MAPK pathway (Liou et al., 2000). Blockade of this Erk MAPK pathway is believed to be a mechanism of inhibition of TCR-induced IL-2 gene transcription. Summary of the Invention

[0005] The present disclosure generally relates to bivalent compounds (e.g., bifunctional compounds) that degrade and / or destroy HPK1 and to methods for treating HPK1-mediated diseases (i.e., diseases that are dependent on HPK1, overexpress HPK1, are dependent on HPK1 activity, or include elevated HPK1 activity levels relative to wild-type tissue of the same species and tissue type). It is important to note that because HPK1 degraders / destroyers have dual functionality (enzyme inhibition plus protein degradation / destruction), the bivalent compounds of the present disclosure can be significantly more effective therapeutic agents than currently available HPK1 inhibitors that inhibit HPK1 enzymatic activity but do not affect HPK1 protein levels. The present disclosure further provides methods for identifying HPK1 degraders / destroyers as described herein.

[0006] More specifically, the present disclosure provides bivalent compounds comprising an HPK1 ligand conjugated to a degradation / destruction tag.

[0007] In some aspects, the HPK1 degrader / destructor has the form of "PI-Linker-EL" as shown below:

[0008]

[0009] Wherein the PI (protein of interest) comprises an HPK1 ligand (e.g., an HPK1 inhibitor) and the EL (E3 ligase) comprises a degradation / destruction tag (e.g., an E3 ligase ligand). Exemplary HPK1 ligands (PIs), exemplary degradation / destruction tags (ELs), and exemplary linkers (Linkers) are described below.

[0010] HPK1 ligands

[0011] In an embodiment, the (HPK1) ligand comprises a moiety according to Formula 1A:

[0012]

[0013] in,

[0014] The "linker" portion of the divalent compound is attached to Z;

[0015] X is selected from O or S;

[0016] R 1 、R 2 、R 3 、R 4 、R 7 and R 8 Selected from hydrogen, halogen, oxo, CN, NO2, OR 11 SR 11 NR 11 R 12 、C(O)R 11 、C(O)OR 11 、C(O)NR 11 R 12 、S(O)R 11 、S(O)2R 11 、S(O)2NR 11 R 12 NR 13 C(O)OR 11 NR 13 C(O)R 11 NR 13 C(O)NR 11 R 12 NR 13 S(O)R 11 NR 13 S(O)2R 11 NR 13 S(O)2NR11 R 12 , optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxyC1-C8 alkyl, optionally substituted C1-C8 alkylaminoC1-C8 alkyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted C3-C8 cycloalkoxy, optionally substituted 3- to 8-membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; wherein

[0017] R 11 、R 12 and R 13 independently selected from hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy C1-C8 alkyl, optionally substituted C1-C8 alkylamino C1-C8 alkyl, optionally substituted C3-C 10 cycloalkyl, optionally substituted 3- to 20-membered heterocyclyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted aryl, and optionally substituted heteroaryl, or

[0018] R 11 and R 12 、R 11 and R 13 、R 12 and R 13 together with the atoms to which they are attached, form an optionally substituted 3- to 20-membered cycloalkyl or heterocyclyl ring;

[0019] R 5 and R 6 independently selected from hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxyC1-C8 alkyl, optionally substituted C1-C8 alkylaminoC1-C8 alkyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted C3-C8 cycloalkoxy, optionally substituted 4- to 8-membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;

[0020] R 17 、R 18 、R 19 and R 20is independently selected at each occurrence from hydrogen, halogen, CN, OH, NH2, optionally substituted C1-C8 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C3-C8 cycloalkyloxy, optionally substituted C1-C8 alkoxyC1-C8 alkyl, optionally substituted C1-C8 alkylaminoC1-C8 alkyl, optionally substituted 3- to 8-membered heterocyclyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxyalkyl, optionally substituted C1-C8 haloalkyl, optionally substituted C1-C8 hydroxyalkyl, optionally substituted C1-C8 alkylamino, and optionally substituted C1-C8 alkylaminoC1-C8 alkyl;

[0021] m, n are independently selected from 0, 1, 2, 3 and 4; and

[0022] W, Q and Z are independently selected at each occurrence from void, CO, CO2, CH2, NH, NH-CO, CO-NH, CH2-NH-CO, CH2-CO-NH, NH-CO-CH2, CO-NH-CH2, CH2-NH-CH2-CO-NH, CH2-NH-CH2-NH-CO, -CO-NH, CO-NH-CH2-NH-CH2, CH2-NH-CH2, CR 21 R 22 、C(O)NR 21 、C(S)NR 21 、O、S、SO、SO2、SO2NR 21 NR 21 NR 21 CO、NR 121 CONR 22 NR 21 C(S), optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxyC1-C8 alkyl, optionally substituted C1-C8 haloalkyl, optionally substituted C1-C8 hydroxyalkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted C3-C8 cycloalkoxy, optionally substituted 3- to 8-membered heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted C3-C 13 Fused cycloalkyl, optionally substituted C3-C 13 Fused heterocyclic group, optionally substituted C3-C 13 Bridged cycloalkyl, optionally substituted C3-C 13 Bridged heterocyclic group, optionally substituted C3-C 13 Spirocycloalkyl, and optionally substituted C3-C 13 spiroheterocyclyl; wherein

[0023] R21 and R 22 Independently selected from hydrogen, optionally substituted C1-C8 alkyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted C3-C8 cycloalkyloxy, optionally substituted 3- to 8-membered heterocyclyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxyalkyl, optionally substituted C1-C8 haloalkyl, optionally substituted C1-C8 hydroxyalkyl, optionally substituted C1-C8 alkylamino, and optionally substituted C1-C8 alkylaminoC1-C8 alkyl.

[0024] In an embodiment, the (HPK1) ligand comprises a moiety according to Formula 3A:

[0025]

[0026] in

[0027] The "linker" portion of the divalent compound is independently connected to R 1 or R 3 ;

[0028] X is selected from CR 2 or N;

[0029] R 1 Selected from space, hydrogen, C(O)R 6 、C(O)OR 6 、C(O)NR 6 R 7 、S(O)R 6 、S(O)2R 6 、S(O)2NR 6 R 7 NR 8 C(O)OR 6 NR 8 C(O)R 6 NR 8 C(O)NR 6 R 7 NR 8 S(O)R 6 NR 8 S(O)2R 6 NR 8 S(O)2NR 6 R 7, optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxyC1-C8 alkyl, optionally substituted C1-C8 alkylaminoC1-C8 alkyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted C3-C8 cycloalkoxy, optionally substituted 3- to 8-membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; wherein

[0030] R 6 is empty or a divalent moiety selected from optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxyC1-C8 alkyl, optionally substituted C1-C8 alkylaminoC1-C8 alkyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted C3-C8 cycloalkoxy, optionally substituted 3- to 8-membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;

[0031] R 2 Independently selected from hydrogen, halogen, oxo, CN, NO2, OR 9 SR 9 NR 9 R 10 、C(O)R 9 、C(O)OR 9 、C(O)NR 9 R 10 、S(O)R 9 、S(O)2R 9 、S(O)2NR 9 R 10 NR 11 C(O)OR 9 NR 11 C(O)R 9 NR 11 C(O)NR 9 R 10 NR 11 S(O)R 9 NR 11 S(O)2R 9 NR 11 S(O)2NR 9 R 10, optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxyC1-C8 alkyl, optionally substituted C1-C8 alkylaminoC1-C8 alkyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted C3-C8 cycloalkoxy, optionally substituted 3- to 8-membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; wherein

[0032] R 9 、R 10 and R 11 independently selected from hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy C1-C8 alkyl, optionally substituted C1-C8 alkylamino C1-C8 alkyl, optionally substituted C3-C 10 cycloalkyl, optionally substituted 3- to 20-membered heterocyclyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted aryl, and optionally substituted heteroaryl; or

[0033] R 9 and R 10 、R 9 and R 11 、R 10 and R 11 together with the atoms to which they are attached, form an optionally substituted 3- to 20-membered cycloalkyl or heterocyclyl ring;

[0034] Ar is selected from the group consisting of null, aryl and heteroaryl, each of which is replaced by R 3 substituted and optionally substituted by one or more substituents independently selected from the group consisting of hydrogen, halogen, oxo, CN, NO2, OR 12 SR 12 NR 12 R 13 , OCOR 12 、OCO2R 12 、OCONR 12 R 13 、COR 12 、CO2R 12 、CONR 12 R 13 、SOR 12 、SO2R 12 、SO2NR 12 R 13 NR 14 CO2R 12 NR 14 COR 12 NR 14 C(O)NR 12 R13 NR 14 SOR 12 NR 14 SO2R 12 NR 14 SO2NR 12 R 13 , optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxyC1-C8 alkyl, optionally substituted C1-C8 alkylaminoC1-C8 alkyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted C3-C8 cycloalkoxy, optionally substituted 4- to 8-membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; wherein

[0035] R 12 、R 13 and R 14 independently selected from hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxyC1-C8 alkyl, optionally substituted C1-C8 alkylaminoC1-C8 alkyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted C3-C8 cycloalkoxy, optionally substituted 4- to 8-membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; or

[0036] R 12 and R 13 、R 12 and R 14 together with the atoms to which they are attached, form a 4- to 20-membered heterocyclyl ring;

[0037] R 3 Select from empty, OR 15 SR 15 NR 15 R 16 、OC(O)R 15 、OC(O)OR 15 、OCONR 15 R 16 、C(O)R 15 、C(O)OR 15 、CONR 15 R 16 、S(O)R 15 、S(O)2R 15 、SO2NR 15 R 16 NR 17 C(O)OR 15 NR 17C(O)R 15 NR 17 C(O)NR 15 R 16 NR 14 S(O)R 15 NR 17 S(O)2R 15 NR 17 S(O)2NR 15 R 16 , optionally substituted C1-C8 alkylene, optionally substituted C2-C8 alkenylene, optionally substituted C2-C8 alkynylene, optionally substituted C3-C8 cycloalkylene, optionally substituted 3- to 8-membered heterocyclylene, optionally substituted aryl, and optionally substituted heteroaryl; wherein

[0038] R 15 is empty or a divalent moiety selected from optionally substituted C1-C8 alkylene, optionally substituted C2-C8 alkenylene, optionally substituted C2-C8 alkynylene, optionally substituted C3-C8 cycloalkylene, optionally substituted 3- to 8-membered heterocyclylene, optionally substituted aryl, and optionally substituted heteroaryl;

[0039] R 16 and R 17 independently selected from optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy C1-C8 alkyl, optionally substituted C1-C8 alkylamino C1-C8 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted 3- to 8-membered heterocyclyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted aryl, and optionally substituted heteroaryl; or

[0040] R 15 and R 16 、R 15 and R 17 、R 16 and R 17 Together with the atoms to which they are attached, they form a 3- to 20-membered cycloalkyl or heterocyclyl ring.

[0041] In an embodiment, the (HPK1) ligand comprises a moiety according to Formula 3B:

[0042]

[0043] in

[0044] The "linker" portion of the divalent compound is independently connected to R 1 or R 3 ;

[0045] X is selected from CR 2 or N;

[0046] R 1 and R 3 independently selected from the group consisting of space, hydrogen, C(O)R 6 、C(O)OR 6 、C(O)NR 6 R 7 、S(O)R 6 、S(O)2R 6 、S(O)2NR 6 R 7 NR 8 C(O)OR 6 NR 8 C(O)R 6 NR 8 C(O)NR 6 R 7 NR 8 S(O)R 6 NR 8 S(O)2R 6 NR 8 S(O)2NR 6 R 7 , optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxyC1-C8 alkyl, optionally substituted C1-C8 alkylaminoC1-C8 alkyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted C3-C8 cycloalkoxy, optionally substituted 3- to 8-membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; wherein

[0047] R 6 is empty or a divalent moiety selected from optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxyC1-C8 alkyl, optionally substituted C1-C8 alkylaminoC1-C8 alkyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted C3-C8 cycloalkoxy, optionally substituted 3- to 8-membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;

[0048] R 7 and R 8 independently selected from hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy C1-C8 alkyl, optionally substituted C1-C8 alkylamino C1-C8 alkyl, optionally substituted C3-C 10cycloalkyl, optionally substituted 3- to 20-membered heterocyclyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted aryl, and optionally substituted heteroaryl; or

[0049] R 6 and R 7 together with the atoms to which they are attached, form an optionally substituted 3- to 20-membered cycloalkyl or heterocyclyl ring;

[0050] R 2 Independently selected from hydrogen, halogen, oxo, CN, NO2, OR 9 SR 9 NR 9 R 10 、C(O)R 9 、C(O)OR 9 、C(O)NR 9 R 10 、S(O)R 9 、S(O)2R 9 、S(O)2NR 9 R 10 NR 11 C(O)OR 9 NR 11 C(O)R 9 NR 11 C(O)NR 9 R 10 NR 11 S(O)R 9 NR 11 S(O)2R 9 NR 11 S(O)2NR 9 R 10 , optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxyC1-C8 alkyl, optionally substituted C1-C8 alkylaminoC1-C8 alkyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted C3-C8 cycloalkoxy, optionally substituted 3- to 8-membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; wherein

[0051] R 9 、R 10 and R 11 independently selected from hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy C1-C8 alkyl, optionally substituted C1-C8 alkylamino C1-C8 alkyl, optionally substituted C3-C 10cycloalkyl, optionally substituted 3- to 20-membered heterocyclyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted aryl, and optionally substituted heteroaryl; or

[0052] R 9 and R 10 、R 9 and R 11 、R 10 and R 11 together with the atoms to which they are attached, form an optionally substituted 3- to 20-membered cycloalkyl or heterocyclyl ring;

[0053] Each R 4 Independently selected from the group consisting of air, hydrogen, halogen, oxo, CN, NO2, OR 18 SR 18 NR 18 R 19 , OCOR 18 、OCO2R 18 、OCONR 18 R 19 、COR 18 、CO2R 18 、CONR 18 R 19 、SOR 18 、SO2R 18 、SO2NR 18 R 19 NR 20 CO2R 18 NR 20 COR 18 NR 20 C(O)NR 18 R 19 NR 20 SOR 18 NR 20 SO2R 18 NR 7 SO2NR 5 R 6 , optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxyC1-C8 alkyl, optionally substituted C1-C8 alkylaminoC1-C8 alkyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted C3-C8 cycloalkoxy, optionally substituted 4- to 8-membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; wherein

[0054] R 18 、R 19 and R 20independently selected from hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxyC1-C8 alkyl, optionally substituted C1-C8 alkylaminoC1-C8 alkyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted C3-C8 cycloalkoxy, optionally substituted 4- to 8-membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; or

[0055] R 18 and R 19 、R 18 and R 20 together with the atoms to which they are attached, form a 4- to 20-membered heterocyclyl ring; and

[0056] n is independently selected from 0, 1, 2, 3, 4 and 5.

[0057] In an embodiment, the (HPK1) ligand comprises a moiety according to Formula 1:

[0058]

[0059] in

[0060] The "linker" portion of the divalent compound is connected to R 9 ;

[0061] X is selected from O or S;

[0062] Y is selected from O, S, NR 10 ;in

[0063] R 10 independently selected from hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy C1-C8 alkyl, optionally substituted C1-C8 alkylamino C1-C8 alkyl, optionally substituted C3-C 10 cycloalkyl, optionally substituted 3- to 20-membered heterocyclyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted aryl, and optionally substituted heteroaryl;

[0064] R 1 、R 2 、R 3 、R 4 、R 7 and R 8 Selected from hydrogen, halogen, oxo, CN, NO2, OR 11 SR 11 NR 11 R 12 、C(O)R 11 、C(O)OR 11、C(O)NR 11 R 12 、S(O)R 11 、S(O)2R 11 、S(O)2NR 11 R 12 NR 13 C(O)OR 11 NR 13 C(O)R 11 NR 13 C(O)NR 11 R 12 NR 13 S(O)R 11 NR 13 S(O)2R 11 NR 13 S(O)2NR 11 R 12 , optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxyC1-C8 alkyl, optionally substituted C1-C8 alkylaminoC1-C8 alkyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted C3-C8 cycloalkoxy, optionally substituted 3- to 8-membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; wherein

[0065] R 11 、R 12 and R 13 independently selected from hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy C1-C8 alkyl, optionally substituted C1-C8 alkylamino C1-C8 alkyl, optionally substituted C3-C 10 cycloalkyl, optionally substituted 3- to 20-membered heterocyclyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted aryl, and optionally substituted heteroaryl, or

[0066] R 11 and R 12 、R 11 and R 13 、R 12 and R 13 together with the atoms to which they are attached, form an optionally substituted 3- to 20-membered cycloalkyl or heterocyclyl ring;

[0067] R 5 and R 6independently selected from hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxyC1-C8 alkyl, optionally substituted C1-C8 alkylaminoC1-C8 alkyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted C3-C8 cycloalkoxy, optionally substituted 4- to 8-membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;

[0068] R 9 Selected from OR 14 SR 14 NR 14 R 15 、C(O)R 14 、C(O)OR 14 、C(O)NR 14 R 15 、S(O)R 14 、S(O)2R 14 、S(O)2NR 14 R 15 NR 16 C(O)OR 14 NR 16 C(O)R 14 NR 16 C(O)NR 14 R 15 NR 16 S(O)R 14 NR 16 S(O)2R 14 NR 16 S(O)2NR 14 R 15 , optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxyC1-C8 alkyl, optionally substituted C1-C8 alkylaminoC1-C8 alkyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted C3-C8 cycloalkoxy, optionally substituted 3- to 8-membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; wherein

[0069] R 14 is empty or a divalent moiety selected from optionally substituted C1-C8 alkylene, optionally substituted C2-C8 alkenylene, optionally substituted C2-C8 alkynylene, optionally substituted C3-C8 cycloalkylene, optionally substituted 3- to 8-membered heterocyclylene, optionally substituted aryl, and optionally substituted heteroaryl;

[0070] R 15 and R16 independently selected from optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy C1-C8 alkyl, optionally substituted C1-C8 alkylamino C1-C8 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted 3- to 8-membered heterocyclyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted aryl, and optionally substituted heteroaryl; or

[0071] R 14 and R 15 、R 14 and R 16 、R 15 and R 16 Together with the atoms to which they are attached, they form a 3- to 20-membered cycloalkyl or heterocyclyl ring.

[0072] In an embodiment, the (HPK1) ligand comprises a moiety according to Formula 1A:

[0073]

[0074] in,

[0075] The "linker" portion of the divalent compound is attached to Z;

[0076] R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 and R 8 The definition of is the same as that of formula 1;

[0077] R 17 、R 18 、R 19 and R 20 is independently selected at each occurrence from hydrogen, halogen, CN, OH, NH2, optionally substituted C1-C8 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C3-C8 cycloalkyloxy, optionally substituted C1-C8 alkoxyC1-C8 alkyl, optionally substituted C1-C8 alkylaminoC1-C8 alkyl, optionally substituted 3- to 8-membered heterocyclyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxyalkyl, optionally substituted C1-C8 haloalkyl, optionally substituted C1-C8 hydroxyalkyl, optionally substituted C1-C8 alkylamino, and optionally substituted C1-C8 alkylaminoC1-C8 alkyl;

[0078] m, n are independently selected from 0, 1, 2, 3 and 4; and

[0079] W, Q and Z are independently selected at each occurrence from void, CO, CO2, CH2, NH, NH-CO, CO-NH, CH2-NH-CO, CH2-CO-NH, NH-CO-CH2, CO-NH-CH2, CH2-NH-CH2-CO-NH, CH2-NH-CH2-NH-CO, -CO-NH, CO-NH-CH2-NH-CH2, CH2-NH-CH2, CR 21 R 22 、C(O)NR 21 、C(S)NR 21 、O、S、SO、SO2、SO2NR 21 NR 21 NR 21 CO、NR 121 CONR 22 NR 21 C(S), optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxyC1-C8 alkyl, optionally substituted C1-C8 haloalkyl, optionally substituted C1-C8 hydroxyalkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted C3-C8 cycloalkoxy, optionally substituted 3- to 8-membered heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted C3-C 13 Fused cycloalkyl, optionally substituted C3-C 13 Fused heterocyclic group, optionally substituted C3-C 13 Bridged cycloalkyl, optionally substituted C3-C 13 Bridged heterocyclic group, optionally substituted C3-C 13 Spirocycloalkyl, and optionally substituted C3-C 13 spiroheterocyclyl; wherein

[0080] R 21 and R 22 Independently selected from hydrogen, optionally substituted C1-C8 alkyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted C3-C8 cycloalkyloxy, optionally substituted 3- to 8-membered heterocyclyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxyalkyl, optionally substituted C1-C8 haloalkyl, optionally substituted C1-C8 hydroxyalkyl, optionally substituted C1-C8 alkylamino, and optionally substituted C1-C8 alkylaminoC1-C8 alkyl.

[0081] In an embodiment, the (HPK1) ligand comprises a moiety according to Formula 1B:

[0082]

[0083] in

[0084] X, Y, W, Q, R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 、R 8 、R 17 、R 18 、R 19 and R 20 The definition of is the same as that of Formula 1A;

[0085] The "linker" portion of the divalent compound is attached to the terminal N;

[0086] m and n are independently selected from 0, 1, 2, 3 and 4;

[0087] R 23 and R 24 is independently selected at each occurrence from hydrogen, halogen, CN, OH, NH2, optionally substituted C1-C8 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C3-C8 cycloalkyloxy, optionally substituted 3- to 8-membered heterocyclyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxyalkyl, optionally substituted C1-C8 haloalkyl, optionally substituted C1-C8 hydroxyalkyl, optionally substituted C1-C8 alkylamino, and optionally substituted C1-C8 alkylaminoC1-C8 alkyl.

[0088] In an embodiment, the (HPK1) ligand comprises a moiety according to Formula 1C:

[0089]

[0090] in;

[0091] X, Y, W, Q, R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 、R 8 、R 17 、R 18 、R 19 、R 20 and R 23 The definition of is the same as that of Formula 1B;

[0092] The "linker" portion of the divalent compound is attached to Z;

[0093] m and n are independently selected from 0, 1, 2, 3 and 4;

[0094] Z is independently selected from CR 25 or N; and

[0095] R 25 independently selected from the group consisting of space, hydrogen, C(O)R 26 、C(O)OR 26 、C(O)NR 26 R 27 、S(O)R 26 、S(O)2R 26 、S(O)2NR 26 R 27 NR 28 C(O)OR 26 NR 28 C(O)R 26 NR 28 C(O)NR 26 R 27 NR 28 S(O)R 26 NR 28 S(O)2R 26 NR 28 S(O)2NR 26 R 27 , optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxyC1-C8 alkyl, optionally substituted C1-C8 alkylaminoC1-C8 alkyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted C3-C8 cycloalkoxy, optionally substituted 3- to 8-membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; wherein

[0096] R 26 is empty or a divalent moiety selected from optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxyC1-C8 alkyl, optionally substituted C1-C8 alkylaminoC1-C8 alkyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted C3-C8 cycloalkoxy, optionally substituted 3- to 8-membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;

[0097] R 27 and R 28 independently selected from hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy C1-C8 alkyl, optionally substituted C1-C8 alkylamino C1-C8 alkyl, optionally substituted C3-C10 cycloalkyl, optionally substituted 3- to 20-membered heterocyclyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted aryl, and optionally substituted heteroaryl; or

[0098] R 26 and R 27 Together with the atoms to which they are attached, they form an optionally substituted 3- to 20-membered cycloalkyl or heterocyclyl ring.

[0099] In an embodiment, the (HPK1) ligand comprises a moiety according to Formula 2:

[0100]

[0101] in

[0102] The "linker" portion of the divalent compound is connected to R 1 or R 4 ;

[0103] X is selected from CR 5 or N;

[0104] R 1 and R 2 independently selected from the group consisting of space, hydrogen, C(O)R 6 、C(O)OR 6 、C(O)NR 6 R 7 、S(O)R 6 、S(O)2R 6 、S(O)2NR 6 R 7 NR 8 C(O)OR 6 NR 8 C(O)R 6 NR 8 C(O)NR 6 R 7 NR 8 S(O)R 6 NR 8 S(O)2R 6 NR 8 S(O)2NR 6 R 7, optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxyC1-C8 alkyl, optionally substituted C1-C8 alkylaminoC1-C8 alkyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted C3-C8 cycloalkoxy, optionally substituted 3- to 8-membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; wherein

[0105] R 6 is empty or a divalent moiety selected from optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxyC1-C8 alkyl, optionally substituted C1-C8 alkylaminoC1-C8 alkyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted C3-C8 cycloalkoxy, optionally substituted 3- to 8-membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;

[0106] R 7 and R 8 independently selected from hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy C1-C8 alkyl, optionally substituted C1-C8 alkylamino C1-C8 alkyl, optionally substituted C3-C 10 cycloalkyl, optionally substituted 3- to 20-membered heterocyclyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted aryl, and optionally substituted heteroaryl; or

[0107] R 6 and R 7 together with the atoms to which they are attached form an optionally substituted 3- to 20-membered cycloalkyl or heterocyclyl ring; and

[0108] R 3 、R 4 and R 5 Independently selected from hydrogen, halogen, oxo, CN, NO2, OR 9 SR 9 NR 10 R 11 、C(O)R 9 、C(O)OR 9 、C(O)NR 10 R 11 、S(O)R 9 、S(O)2R 9 、S(O)2NR 10 R 11 NR 12 C(O)OR 10NR 9 C(O)R 10 NR 9 C(O)NR 10 R 11 NR 9 S(O)R 10 NR 9 S(O)2R 10 NR 9 S(O)2NR 10 R 11 , optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxy, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted C3-C8 cycloalkoxy, optionally substituted 3- to 8-membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; wherein

[0109] R 9 、R 10 and R 11 independently selected from hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy C1-C8 alkyl, optionally substituted C1-C8 alkylamino C1-C8 alkyl, optionally substituted C3-C 10 cycloalkyl, optionally substituted 3- to 20-membered heterocyclyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted aryl, and optionally substituted heteroaryl; or

[0110] R 9 and R 10 、R 10 and R 11 Together with the atoms to which they are attached, they form an optionally substituted 3- to 20-membered cycloalkyl or heterocyclyl ring.

[0111] In an embodiment, the (HPK1) ligand comprises a moiety according to Formula 2A or Formula 2B:

[0112]

[0113] in

[0114] The "linker" portion of the divalent compound is connected to R 1 ;

[0115] R 1 、R 2 、R 3 and R 5 The definition of is the same as that of formula 2;

[0116] Ar is selected from null, aryl and heteroaryl, each of which is optionally substituted with one or more substituents independently selected from the following substituents: hydrogen, halogen, oxo, CN, NO2, OR 12 SR 12 NR 12 R 13 , OCOR 12 、OCO2R 12 、OCONR 12 R 13 、COR 12 、CO2R 12 、CONR 12 R 13 、SOR 12 、SO2R 12 、SO2NR 12 R 13 NR 14 CO2R 12 NR 14 COR 12 NR 14 C(O)NR 12 R 13 NR 14 SOR 12 NR 14 SO2R 12 NR 14 SO2NR 12 R 13 , optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxyC1-C8 alkyl, optionally substituted C1-C8 alkylaminoC1-C8 alkyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted C3-C8 cycloalkoxy, optionally substituted 4- to 8-membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; wherein

[0117] R 12 、R 13 and R 14 independently selected from hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxyC1-C8 alkyl, optionally substituted C1-C8 alkylaminoC1-C8 alkyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted C3-C8 cycloalkoxy, optionally substituted 4- to 8-membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; or

[0118] R 12 and R 13、R 13 and R 14 Together with the atoms to which they are attached, they form a 3- to 20-membered heterocyclyl ring.

[0119] In an embodiment, the (HPK1) ligand comprises a moiety according to Formula 2C or Formula 2D:

[0120]

[0121] in

[0122] The "linker" portion of the divalent compound is connected to R 1 ;

[0123] R 1 、R 2 、R 3 and R 5 The definition of is the same as that of formula 2;

[0124] R 15 、R 16 、R 17 and R 18 Independently selected from hydrogen, halogen, oxo, CN, NO2, OR 19 SR 19 NR 20 R 21 , OCOR 19 、OCO2R 19 、OCONR 20 R 21 、COR 19 、CO2R 19 、CONR 20 R 21 、SOR 19 、SO2R 19 、SO2NR 20 R 21 NR 19 CO2R 20 NR 19 COR 20 NR 19 C(O)NR 20 R 21 NR 19 SOR 20 NR 19 SO2R 20 NR 19 SO2NR 20 R 21, optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxyC1-C8 alkyl, optionally substituted C1-C8 alkylaminoC1-C8 alkyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted C3-C8 cycloalkoxy, optionally substituted 4- to 8-membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; wherein

[0125] R 19 、R 20 and R 21 independently selected from hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxyC1-C8 alkyl, optionally substituted C1-C8 alkylaminoC1-C8 alkyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted C3-C8 cycloalkoxy, optionally substituted 4- to 8-membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; or

[0126] R 19 and R 20 、R 20 and R 21 together with the atoms to which they are attached, form a 3- to 20-membered heterocyclyl ring; and

[0127] R 15 and R 16 、R 16 and R 17 Together with the atoms to which they are attached, they form an optionally substituted 4- to 20-membered cycloalkyl or heterocyclyl ring.

[0128] In an embodiment, the (HPK1) ligand comprises a moiety according to Formula 2E or Formula 2F:

[0129]

[0130] in

[0131] The "linker" portion of the divalent compound is connected to R 1 ;

[0132] R 1 、R 2 、R 3 、R 5 、R 15 、R 16 、R 17 and R 18 The definition of is the same as that of Formula 2C and Formula 2D.

[0133] R22 Independently selected from hydrogen, halogen, oxo, aryl, CN, NO2, OR 23 SR 23 NR 24 R 25 、C(O)R 23 、C(O)OR 23 、C(O)NR 24 R 25 、S(O)R 23 、S(O)2R 23 、S(O)2NR 24 R 25 NR 24 C(O)OR 23 NR 24 C(O)R 23 NR 23 C(O)NR 24 R 25 NR 24 S(O)R 23 NR 24 S(O)2R 23 NR 23 S(O)2NR 24 R 2 , optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxy, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted C3-C8 cycloalkoxy, optionally substituted 3- to 8-membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; wherein

[0134] R 23 、R 24 and R 25 independently selected from hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy C1-C8 alkyl, optionally substituted C1-C8 alkylamino C1-C8 alkyl, optionally substituted C3-C 10 cycloalkyl, optionally substituted 3- to 20-membered heterocyclyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted aryl, and optionally substituted heteroaryl; or

[0135] R 23 and R 24 、R 23 and R 25 together with the atoms to which they are attached form an optionally substituted 3- to 20-membered cycloalkyl or heterocyclyl ring; and

[0136] R 15 and R 16 、R16 and R 17 Together with the atoms to which they are attached, they form an optionally substituted 4- to 20-membered cycloalkyl or heterocyclyl ring.

[0137] In an embodiment, the (HPK1) ligand comprises a moiety according to Formula 2G or Formula 2H:

[0138]

[0139] in

[0140] The "linker" portion of the divalent compound is connected to R 1 ;

[0141] R 1 、R 2 、R 3 、R 5 、R 15 、R 16 、R 17 and R 18 The definition of is the same as that of Formula 2C and Formula 2D.

[0142] X is CO, CH2 or SO2;

[0143] n is 0 to 1;

[0144] R 26 and R 27 independently selected from hydrogen, halogen, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy C1-C8 alkyl, optionally substituted C1-C8 alkylamino C1-C8 alkyl, optionally substituted C3-C 10 cycloalkyl, optionally substituted 3- to 20-membered heterocyclyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted aryl, and optionally substituted heteroaryl; or

[0145] R 26 and R 27 together with the atoms to which they are attached form an optionally substituted 3- to 20-membered cycloalkyl or heterocyclyl ring; and

[0146] R 15 and R 16 、R 16 and R 17 Together with the atoms to which they are attached, they form an optionally substituted 4- to 20-membered cycloalkyl or heterocyclyl ring.

[0147] In embodiments, the (HPK1) ligand comprises a moiety according to Formula 2K, Formula 2L, Formula 2M, and Formula 2N:

[0148]

[0149] in

[0150] The "linker" portion of the divalent compound is connected to R 9 ;

[0151] R 1 、R 2 、R 3 、R 5 、R 15 、R 16 、R 17 and R 18 The definition of is the same as that of Formula 2C and Formula 2D;

[0152] n and m are independently selected from 1, 2 and 3;

[0153] R 28 、R 29 and R 30 independently selected from hydrogen, halogen, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy C1-C8 alkyl, optionally substituted C1-C8 alkylamino C1-C8 alkyl, optionally substituted C3-C 10 cycloalkyl, optionally substituted 3- to 20-membered heterocyclyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted aryl, and optionally substituted heteroaryl; or

[0154] R 29 and R 30 together with the atoms to which they are attached form an optionally substituted 3- to 20-membered cycloalkyl or heterocyclyl ring; and

[0155] R 15 and R 16 、R 16 and R 17 Together with the atoms to which they are attached, they form an optionally substituted 4- to 20-membered cycloalkyl or heterocyclyl ring.

[0156] In an embodiment, the (HPK1) ligand comprises a moiety according to Formula 2O or Formula 2P:

[0157]

[0158] in

[0159] The "linker" portion of the divalent compound is attached to Z;

[0160] R 1 、R 2 、R 3 、R 5 、R 15 、R 16 、R 17and R 18 The definition of is the same as that of Formula 2C and Formula 2D;

[0161] W, Q and Z are independently selected at each occurrence from void, CO, CO2, CH2, NH, NH-CO, CO-NH, CH2-NH-CO, CH2-CO-NH, NH-CO-CH2, CO-NH-CH2, CH2-NH-CH2-CO-NH, CH2-NH-CH2-NH-CO, -CO-NH, CO-NH-CH2-NH-CH2, CH2-NH-CH2, CR 35 R 36 、C(O)NR 35 、C(S)NR 35 、O、S、SO、SO2、SO2NR 35 NR 35 NR 35 CO、NR 35 CONR 36 NR 35 C(S), optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxyC1-C8 alkyl, optionally substituted C1-C8 haloalkyl, optionally substituted C1-C8 hydroxyalkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted C3-C8 cycloalkoxy, optionally substituted 3- to 8-membered heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted C3-C 13 Fused cycloalkyl, optionally substituted C3-C 13 Fused heterocyclic group, optionally substituted C3-C 13 Bridged cycloalkyl, optionally substituted C3-C 13 Bridged heterocyclic group, optionally substituted C3-C 13 Spirocycloalkyl, and optionally substituted C3-C 13 spiroheterocyclyl, wherein

[0162] R 35 and R 36 independently selected from hydrogen, optionally substituted C1-C8 alkyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted C3-C8 cycloalkoxy, optionally substituted 3- to 8-membered heterocyclyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxyalkyl, optionally substituted C1-C8 haloalkyl, optionally substituted C1-C8 hydroxyalkyl, optionally substituted C1-C8 alkylamino, and optionally substituted C1-C8 alkylaminoC1-C8 alkyl;

[0163] R 31 、R 32、R 33 and R 34 independently selected from hydrogen, halogen, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy C1-C8 alkyl, optionally substituted C1-C8 alkylamino C1-C8 alkyl, optionally substituted C3-C 10 cycloalkyl, optionally substituted 3- to 20-membered heterocyclyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted aryl, and optionally substituted heteroaryl; or

[0164] R 31 and R 32 、R 33 and R 34 together with the atoms to which they are attached, form an optionally substituted 3- to 20-membered cycloalkyl or heterocyclyl ring;

[0165] R 15 and R 16 、R 16 and R 17 together with the atoms to which they are attached form an optionally substituted 4- to 20-membered cycloalkyl or heterocyclyl ring; and

[0166] m and n are independently selected from 0, 1, 2, 3 and 4.

[0167] In an embodiment, the (HPK1) ligand comprises a moiety according to Formula 3:

[0168]

[0169] in

[0170] The "linker" portion of the divalent compound is independently connected to R 1 or R 3 ;

[0171] X is selected from CR 2 or N;

[0172] R 1 and R 3 independently selected from the group consisting of space, hydrogen, C(O)R 6 、C(O)OR 6 、C(O)NR 6 R 7 、S(O)R 6 、S(O)2R 6 、S(O)2NR 6 R 7 NR 8 C(O)OR 6 NR 8 C(O)R 6 NR 8C(O)NR 6 R 7 NR 8 S(O)R 6 NR 8 S(O)2R 6 NR 8 S(O)2NR 6 R 7 , optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxyC1-C8 alkyl, optionally substituted C1-C8 alkylaminoC1-C8 alkyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted C3-C8 cycloalkoxy, optionally substituted 3- to 8-membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; wherein

[0173] R 6 is empty or a divalent moiety selected from optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxyC1-C8 alkyl, optionally substituted C1-C8 alkylaminoC1-C8 alkyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted C3-C8 cycloalkoxy, optionally substituted 3- to 8-membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;

[0174] R 7 and R 8 independently selected from hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy C1-C8 alkyl, optionally substituted C1-C8 alkylamino C1-C8 alkyl, optionally substituted C3-C 10 cycloalkyl, optionally substituted 3- to 20-membered heterocyclyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted aryl, and optionally substituted heteroaryl; or

[0175] R 6 and R 7 together with the atoms to which they are attached, form an optionally substituted 3- to 20-membered cycloalkyl or heterocyclyl ring;

[0176] R 2 Independently selected from hydrogen, halogen, oxo, CN, NO2, OR 9 SR 9 NR 9 R 10 、C(O)R 9 、C(O)OR 9 、C(O)NR 9 R10 、S(O)R 9 、S(O)2R 9 、S(O)2NR 9 R 10 NR 11 C(O)OR 9 NR 11 C(O)R 9 NR 11 C(O)NR 9 R 10 NR 11 S(O)R 9 NR 11 S(O)2R 9 NR 11 S(O)2NR 9 R 10 , optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxyC1-C8 alkyl, optionally substituted C1-C8 alkylaminoC1-C8 alkyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted C3-C8 cycloalkoxy, optionally substituted 3- to 8-membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; wherein

[0177] R 9 、R 10 and R 11 independently selected from hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy C1-C8 alkyl, optionally substituted C1-C8 alkylamino C1-C8 alkyl, optionally substituted C3-C 10 cycloalkyl, optionally substituted 3- to 20-membered heterocyclyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted aryl, and optionally substituted heteroaryl; or

[0178] R 9 and R 10 、R 9 and R 11 、R 10 and R 11 Together with the atoms to which they are attached, they form an optionally substituted 3- to 20-membered cycloalkyl or heterocyclyl ring.

[0179] In an embodiment, the (HPK1) ligand comprises a moiety according to Formula 3A:

[0180]

[0181] in

[0182] The "linker" portion of the divalent compound is independently connected to R 1 or R 3 ;

[0183] X is selected from CR 2 or N;

[0184] R 1 and R 2 The definition of is the same as that of formula 3;

[0185] Ar is selected from the group consisting of null, aryl and heteroaryl, each of which is replaced by R 3 substituted and optionally substituted by one or more substituents independently selected from the group consisting of hydrogen, halogen, oxo, CN, NO2, OR 12 SR 12 NR 12 R 13 , OCOR 12 、OCO2R 12 、OCONR 12 R 13 、COR 12 、CO2R 12 、CONR 12 R 13 、SOR 12 、SO2R 12 、SO2NR 12 R 13 NR 14 CO2R 12 NR 14 COR 12 NR 14 C(O)NR 12 R 13 NR 14 SOR 12 NR 14 SO2R 12 NR 14 SO2NR 12 R 13 , optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxyC1-C8 alkyl, optionally substituted C1-C8 alkylaminoC1-C8 alkyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted C3-C8 cycloalkoxy, optionally substituted 4- to 8-membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; wherein

[0186] R 12 、R 13 and R 14independently selected from hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxyC1-C8 alkyl, optionally substituted C1-C8 alkylaminoC1-C8 alkyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted C3-C8 cycloalkoxy, optionally substituted 4- to 8-membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; or

[0187] R 12 and R 13 、R 12 and R 14 together with the atoms to which they are attached, form a 4- to 20-membered heterocyclyl ring;

[0188] R 3 Select from empty, OR 15 SR 15 NR 15 R 16 、OC(O)R 15 、OC(O)OR 15 、OCONR 15 R 16 、C(O)R 15 、C(O)OR 15 、CONR 15 R 16 、S(O)R 15 、S(O)2R 15 、SO2NR 15 R 16 NR 17 C(O)OR 15 NR 17 C(O)R 15 NR 17 C(O)NR 15 R 16 NR 14 S(O)R 15 NR 17 S(O)2R 15 NR 17 S(O)2NR 15 R 16 , optionally substituted C1-C8 alkylene, optionally substituted C2-C8 alkenylene, optionally substituted C2-C8 alkynylene, optionally substituted C3-C8 cycloalkylene, optionally substituted 3- to 8-membered heterocyclylene, optionally substituted aryl, and optionally substituted heteroaryl; wherein

[0189] R 15is empty or a divalent moiety selected from optionally substituted C1-C8 alkylene, optionally substituted C2-C8 alkenylene, optionally substituted C2-C8 alkynylene, optionally substituted C3-C8 cycloalkylene, optionally substituted 3- to 8-membered heterocyclylene, optionally substituted aryl, and optionally substituted heteroaryl;

[0190] R 16 and R 17 independently selected from optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy C1-C8 alkyl, optionally substituted C1-C8 alkylamino C1-C8 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted 3- to 8-membered heterocyclyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted aryl, and optionally substituted heteroaryl; or

[0191] R 15 and R 16 、R 15 and R 17 、R 16 and R 17 Together with the atoms to which they are attached, they form a 3- to 20-membered cycloalkyl or heterocyclyl ring.

[0192] In an embodiment, the (HPK1) ligand comprises a moiety according to Formula 3B:

[0193]

[0194] in

[0195] The "linker" portion of the divalent compound is independently connected to R 1 or R 3 ;

[0196] X is selected from CR 2 or N;

[0197] R 1 、R 2 and R 3 The definition of is the same as that of formula 3;

[0198] Each R 4 Independently selected from the group consisting of air, hydrogen, halogen, oxo, CN, NO2, OR 18 SR 18 NR 18 R 19 , OCOR 18 、OCO2R 18 、OCONR 18 R 19 、COR 18 、CO2R 18 、CONR18 R 19 、SOR 18 、SO2R 18 、SO2NR 18 R 19 NR 20 CO2R 18 NR 20 COR 18 NR 20 C(O)NR 18 R 19 NR 20 SOR 18 NR 20 SO2R 18 NR 7 SO2NR 5 R 6 , optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxyC1-C8 alkyl, optionally substituted C1-C8 alkylaminoC1-C8 alkyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted C3-C8 cycloalkoxy, optionally substituted 4- to 8-membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; wherein

[0199] R 18 、R 19 and R 20 independently selected from hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxyC1-C8 alkyl, optionally substituted C1-C8 alkylaminoC1-C8 alkyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted C3-C8 cycloalkoxy, optionally substituted 4- to 8-membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; or

[0200] R 18 and R 19 、R 18 and R 20 together with the atoms to which they are attached, form a 4- to 20-membered heterocyclyl ring; and

[0201] n is independently selected from 0, 1, 2, 3, 4 and 5.

[0202] In embodiments, the (HPK1) ligand comprises a moiety according to Formula 3C, Formula 3D, and Formula 3E:

[0203]

[0204] in

[0205] The "linker" portion of the divalent compound is independently connected to R 1 or R 3 ;

[0206] X is selected from CR 2 or N;

[0207] R 1 、R 2 、R 3 and R 4 The definition of is the same as that of Formula 3B;

[0208] R 5 independently selected at each occurrence from hydrogen, C(O)R 21 、C(O)OR 21 、C(O)NR 21 R 22 、S(O)R 21 、S(O)2R 21 、S(O)2NR 21 R 22 NR 23 C(O)OR 21 NR 23 C(O)R 21 NR 23 C(O)NR 21 R 22 NR 23 S(O)R 21 NR 23 S(O)2R 21 NR 23 S(O)2NR 21 R 22 , optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxyC1-C8 alkyl, optionally substituted C1-C8 alkylaminoC1-C8 alkyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted C3-C8 cycloalkoxy, optionally substituted 3- to 8-membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; wherein

[0209] R 21 、R 22 and R 23independently selected from hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxyC1-C8 alkyl, optionally substituted C1-C8 alkylaminoC1-C8 alkyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted C3-C8 cycloalkoxy, optionally substituted 4- to 8-membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; or

[0210] R 21 and R 22 、R 21 and R 23 together with the atoms to which they are attached, form a 3- to 20-membered heterocyclyl ring; and

[0211] n is independently selected from 0, 1, 2, 3, 4 and 5.

[0212] In an embodiment, the (HPK1) ligand comprises a moiety according to Formula 3F or Formula 3G:

[0213]

[0214] in

[0215] The "linker" portion of the divalent compound is independently connected to R 3 or independently connected to an R 1 ;

[0216] X is selected from CR 2 or N;

[0217] R 1 、R 2 、R 3 and R 4 The definition of is the same as that of Formula 3B.

[0218] Ar is selected from the group consisting of null, aryl and heteroaryl, each of which is replaced by R 1 replace;

[0219] n and m are independently selected from 0, 1, 2, 3, 4 and 5.

[0220] In an embodiment, the (HPK1) ligand comprises a moiety according to Formula 3H or Formula 3K:

[0221]

[0222] in

[0223] The "linker" portion of the divalent compound is independently connected to R 1 or R 3 ;

[0224] X is selected from CR 2 or N;

[0225] R 1 、R 2 、R 3 、R 4 and R 5 The definition of is the same as that of Formula 3C, Formula 3D, and Formula 3E;

[0226] Ar is selected from the group consisting of null, aryl and heteroaryl, each of which is replaced by R 1 replace;

[0227] n and m are independently selected from 0, 1, 2, 3, 4 and 5.

[0228] In an embodiment, the (HPK1) ligand comprises a moiety according to Formula 3L:

[0229]

[0230] in

[0231] The "linker" portion of the divalent compound is independently connected to R 1 or R 3 ;

[0232] X is selected from CR 2 or N;

[0233] R 1 、R 2 、R 3 and R 4 The definition of is the same as that of Formula 3B;

[0234] Ar is selected from the group consisting of null, aryl and heteroaryl;

[0235] n is independently selected from 0, 1, 2, 3, 4 and 5;

[0236] Y, Z are independently selected from the group consisting of air, CO, CO2, CH2, CR 24 R 25 、C(O)NR 24 、C(S)NR 24 、O、S、SO、SO2、SO2NR 24 NR 24 NR 24 CO、NR 24 CONR 24 NR 24C(S), optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxyC1-C8 alkyl, optionally substituted C1-C8 haloalkyl, optionally substituted C1-C8 hydroxyalkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted C3-C8 cycloalkoxy, optionally substituted 3- to 8-membered heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted C3-C 13 Fused cycloalkyl, optionally substituted C3-C 13 Fused heterocyclic group, optionally substituted C3-C 13 Bridged cycloalkyl, optionally substituted C3-C 13 Bridged heterocyclic group, optionally substituted C3-C 13 Spirocycloalkyl, and optionally substituted C3-C 13 spiroheterocyclyl; wherein

[0237] R 24 and R 25 independently selected from hydrogen, optionally substituted C1-C8 alkyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted C3-C8 cycloalkoxy, optionally substituted 3- to 8-membered heterocyclyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxyalkyl, optionally substituted C1-C8 haloalkyl, optionally substituted C1-C8 hydroxyalkyl, optionally substituted C1-C8 alkylamino, and optionally substituted C1-C8 alkylaminoC1-C8 alkyl;

[0238] W is independently selected at each occurrence from the group consisting of void, CO, CH2, (CH2) m CR 26 R 27 、(CR 26 R 27 ) m , SO, SO2,

[0239] in

[0240] R 26 and R 27 independently selected from hydrogen, optionally substituted C1-C8 alkyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted C3-C8 cycloalkoxy, optionally substituted 3- to 8-membered heterocyclyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxyalkyl, optionally substituted C1-C8 haloalkyl, optionally substituted C1-C8 hydroxyalkyl, optionally substituted C1-C8 alkylamino, and optionally substituted C1-C8 alkylaminoC1-C8 alkyl;

[0241] and

[0242] m=0-5.

[0243] In an embodiment, the (HPK1) ligand comprises a moiety according to Formula 3M:

[0244]

[0245] in

[0246] The "linker" portion of the divalent compound is independently connected to R 1 or R 3 ;

[0247] X is selected from CR 2 or N;

[0248] W.R. 1 、R 2 、R 3 and R 4 The definition of is the same as that of formula 3L.

[0249] n is independently selected from 0, 1, 2, 3, 4 and 5.

[0250] In an embodiment, the (HPK1) ligand comprises a moiety according to Formula 4:

[0251]

[0252] in

[0253] The "linker" portion of the divalent compound is connected to R 3 ;

[0254] X is selected from CR 2 or N;

[0255] Y is selected from CR 7 or N;

[0256] Each R 1 Independently selected from the group consisting of air, hydrogen, halogen, oxo, CN, NO2, OR 8 SR 8 NR 8 R 9 , OCOR 8 、OCO2R 8 、OCONR 8 R 9 、COR 8 、CO2R 8 、CONR 8 R 9 、SOR 8 、SO2R 8 、SO2NR 8 R 9 NR10 CO2R 8 NR 10 COR 8 NR 10 C(O)NR 8 R 9 NR 10 SOR 8 NR 10 SO2R 8 NR 10 SO2NR 8 R 9 , optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxyC1-C8 alkyl, optionally substituted C1-C8 alkylaminoC1-C8 alkyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted C3-C8 cycloalkoxy, optionally substituted 4- to 8-membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; wherein

[0257] R 8 、R 9 and R 10 independently selected from hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxyC1-C8 alkyl, optionally substituted C1-C8 alkylaminoC1-C8 alkyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted C3-C8 cycloalkoxy, optionally substituted 4- to 8-membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; or

[0258] R 8 and R 9 、R 8 and R 10 together with the atoms to which they are attached, form a 4- to 20-membered heterocyclyl ring; and

[0259] n is independently selected from 0, 1, 2, 3, 4 and 5;

[0260] R 2 and R 7 Independently selected from hydrogen, halogen, oxo, CN, NO2, OR 11 SR 11 NR 11 R 12 、C(O)R 11 、C(O)OR 11 、C(O)NR 11 R 12 、S(O)R 11、S(O)2R 11 、S(O)2NR 11 R 12 NR 13 C(O)OR 10 NR 13 C(O)R 11 NR 13 C(O)NR 11 R 12 NR 13 S(O)R 11 NR 13 S(O)2R 11 NR 13 S(O)2NR 11 R 12 , optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxyC1-C8 alkyl, optionally substituted C1-C8 alkylaminoC1-C8 alkyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted C3-C8 cycloalkoxy, optionally substituted 3- to 8-membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; wherein

[0261] R 11 、R 12 and R 13 independently selected from hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy C1-C8 alkyl, optionally substituted C1-C8 alkylamino C1-C8 alkyl, optionally substituted C3-C 10 cycloalkyl, optionally substituted 3- to 20-membered heterocyclyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted aryl, and optionally substituted heteroaryl; or

[0262] R 11 and R 12 、R 11 and R 13 、R 12 and R 13 together with the atoms to which they are attached, form an optionally substituted 3- to 20-membered cycloalkyl or heterocyclyl ring;

[0263] R 3 Selected from space, hydrogen, C(O)R 14 、C(O)OR 14 、C(O)NR 14 R 15 、S(O)R 14 、S(O)2R 14 、S(O)2NR 14 R15 NR 16 C(O)OR 14 NR 16 C(O)R 14 NR 16 C(O)NR 14 R 15 NR 16 S(O)R 14 NR 16 S(O)2R 14 NR 16 S(O)2NR 14 R 15 , optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxyC1-C8 alkyl, optionally substituted C1-C8 alkylaminoC1-C8 alkyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted C3-C8 cycloalkoxy, optionally substituted 3- to 8-membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; wherein

[0264] R 14 is empty or a divalent moiety selected from optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxyC1-C8 alkyl, optionally substituted C1-C8 alkylaminoC1-C8 alkyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted C3-C8 cycloalkoxy, optionally substituted 3- to 8-membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;

[0265] R 15 and R 16 independently selected from hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy C1-C8 alkyl, optionally substituted C1-C8 alkylamino C1-C8 alkyl, optionally substituted C3-C 10 cycloalkyl, optionally substituted 3- to 20-membered heterocyclyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted aryl, and optionally substituted heteroaryl; or

[0266] R 14 and R 15 together with the atoms to which they are attached, form an optionally substituted 3- to 20-membered cycloalkyl or heterocyclyl ring;

[0267] R 4 、R 5 and R 6Independently selected from hydrogen, halogen, oxo, CN, NO2, OR 17 SR 17 NR 18 R 19 , OCOR 17 、OCO2R 17 、OCONR 18 R 19 、COR 17 、CO2R 17 、CONR 18 R 19 、SOR 17 、SO2R 17 、SO2NR 18 R 19 NR 17 CO2R 18 NR 17 COR 18 NR 17 C(O)NR 18 R 19 NR 17 SOR 18 NR 17 SO2R 18 NR 17 SO2NR 18 R 19 , optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxyC1-C8 alkyl, optionally substituted C1-C8 alkylaminoC1-C8 alkyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted C3-C8 cycloalkoxy, optionally substituted 4- to 8-membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; wherein

[0268] R 17 、R 18 and R 19 independently selected from hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxyC1-C8 alkyl, optionally substituted C1-C8 alkylaminoC1-C8 alkyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted C3-C8 cycloalkoxy, optionally substituted 4- to 8-membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; or

[0269] R 17 and R 18 、R 18 and R 19Together with the atoms to which they are attached, they form a 3- to 20-membered heterocyclyl ring.

[0270] In an embodiment, the (HPK1) ligand comprises a moiety according to Formula 4A:

[0271]

[0272] in

[0273] The "linker" portion of the divalent compound is connected to R 3 ;

[0274] X is selected from CR 2 or N;

[0275] Y is selected from CR 7 or N;

[0276] R 1 、R 2 、R 3 、R 4 、R 5 、R 6 and R 7 The definition of is the same as that of Equation 4.

[0277] In an embodiment, the (HPK1) ligand comprises a moiety according to Formula 4B:

[0278]

[0279] in

[0280] The "linker" portion of the divalent compound is connected to R 3 ;

[0281] X is selected from CR 2 or N;

[0282] Y is selected from CR 7 or N; and

[0283] R 2 、R 3 、R 4 、R 5 and R 7 The definition of is the same as that of Equation 4.

[0284] In an embodiment, the (HPK1) ligand comprises a moiety according to Formula 5:

[0285]

[0286] in

[0287] The "linker" portion of the divalent compound is independently connected to R 3 or R7 ;

[0288] X is selected from CR 2 or N;

[0289] Each R 1 Independently selected from the group consisting of air, hydrogen, halogen, oxo, CN, NO2, OR 8 SR 8 NR 8 R 9 , OCOR 8 、OCO2R 8 、OCONR 8 R 9 、COR 8 、CO2R 8 、CONR 8 R 9 、SOR 8 、SO2R 8 、SO2NR 8 R 9 NR 10 CO2R 8 NR 10 COR 8 NR 10 C(O)NR 8 R 9 NR 10 SOR 8 NR 10 SO2R 8 NR 10 SO2NR 8 R 9 , optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxyC1-C8 alkyl, optionally substituted C1-C8 alkylaminoC1-C8 alkyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted C3-C8 cycloalkoxy, optionally substituted 4- to 8-membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; wherein

[0290] R 8 、R 9 and R 10independently selected from hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxyC1-C8 alkyl, optionally substituted C1-C8 alkylaminoC1-C8 alkyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted C3-C8 cycloalkoxy, optionally substituted 4- to 8-membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; or

[0291] R 8 and R 9 、R 8 and R 10 together with the atoms to which they are attached, form a 4- to 20-membered heterocyclyl ring; and

[0292] n is independently selected from 0, 1, 2, 3, 4 and 5;

[0293] R 2 Selected from hydrogen, halogen, oxo, CN, NO2, OR 11 SR 11 NR 11 R 12 、C(O)R 11 、C(O)OR 11 、C(O)NR 11 R 12 、S(O)R 11 、S(O)2R 11 、S(O)2NR 11 R 12 NR 13 C(O)OR 10 NR 13 C(O)R 11 NR 13 C(O)NR 11 R 12 NR 13 S(O)R 11 NR 13 S(O)2R 11 NR 13 S(O)2NR 11 R 12 , optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxyC1-C8 alkyl, optionally substituted C1-C8 alkylaminoC1-C8 alkyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted C3-C8 cycloalkoxy, optionally substituted 3- to 8-membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; wherein

[0294] R 11 、R 12 and R 13 independently selected from hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy C1-C8 alkyl, optionally substituted C1-C8 alkylamino C1-C8 alkyl, optionally substituted C3-C 10 cycloalkyl, optionally substituted 3- to 20-membered heterocyclyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted aryl, and optionally substituted heteroaryl; or

[0295] R 11 and R 12 、R 11 and R 13 、R 12 and R 13 together with the atoms to which they are attached, form an optionally substituted 3- to 20-membered cycloalkyl or heterocyclyl ring;

[0296] R 3 and R 7 independently selected from the group consisting of space, hydrogen, C(O)R 14 、C(O)OR 14 、C(O)NR 14 R 15 、S(O)R 14 、S(O)2R 14 、S(O)2NR 14 R 15 NR 16 C(O)OR 14 NR 16 C(O)R 14 NR 16 C(O)NR 14 R 15 NR 16 S(O)R 14 NR 16 S(O)2R 14 NR 16 S(O)2NR 14 R 15 , optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxyC1-C8 alkyl, optionally substituted C1-C8 alkylaminoC1-C8 alkyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted C3-C8 cycloalkoxy, optionally substituted 3- to 8-membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; wherein

[0297] R 14is empty or a divalent moiety selected from optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxyC1-C8 alkyl, optionally substituted C1-C8 alkylaminoC1-C8 alkyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted C3-C8 cycloalkoxy, optionally substituted 3- to 8-membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;

[0298] R 15 and R 16 independently selected from hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy C1-C8 alkyl, optionally substituted C1-C8 alkylamino C1-C8 alkyl, optionally substituted C3-C 10 cycloalkyl, optionally substituted 3- to 20-membered heterocyclyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted aryl, and optionally substituted heteroaryl; or

[0299] R 14 and R 15 together with the atoms to which they are attached, form an optionally substituted 3- to 20-membered cycloalkyl or heterocyclyl ring;

[0300] R 4 、R 5 and R 6 Independently selected from hydrogen, halogen, oxo, CN, NO2, OR 17 SR 17 NR 18 R 19 , OCOR 17 、OCO2R 17 、OCONR 18 R 19 、COR 17 、CO2R 17 、CONR 18 R 19 、SOR 17 、SO2R 17 、SO2NR 18 R 19 NR 17 CO2R 18 NR 17 COR 18 NR 17 C(O)NR 18 R 19 NR 17 SOR 18 NR 17 SO2R 18NR 17 SO2NR 18 R 19 , optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxyC1-C8 alkyl, optionally substituted C1-C8 alkylaminoC1-C8 alkyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted C3-C8 cycloalkoxy, optionally substituted 4- to 8-membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; wherein

[0301] R 17 、R 18 and R 19 independently selected from hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxyC1-C8 alkyl, optionally substituted C1-C8 alkylaminoC1-C8 alkyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted C3-C8 cycloalkoxy, optionally substituted 4- to 8-membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; or

[0302] R 17 and R 18 、R 18 and R 19 Together with the atoms to which they are attached, they form a 3- to 20-membered heterocyclyl ring.

[0303] In an embodiment, the (HPK1) ligand comprises a moiety according to Formula 6:

[0304]

[0305] in

[0306] The "linker" portion of the divalent compound is independently connected to R 3 or R 8 ;

[0307] X is selected from CR 2 or N;

[0308] Y is selected from CR 6 or N;

[0309] Z is selected from CR 7 or N or S;

[0310] Each R 1 Independently selected from the group consisting of air, hydrogen, halogen, oxo, CN, NO2, OR 9 SR 9 NR 9R 10 , OCOR 9 、OCO2R 9 、OCONR 9 R 10 、COR 9 、CO2R 9 、CONR 9 R 10 、SOR 9 、SO2R 9 、SO2NR 9 R 10 NR 11 CO2R 9 NR 11 COR 9 NR 11 C(O)NR 9 R 10 NR 11 SOR 9 NR 11 SO2R 9 NR 11 SO2NR 9 R 10 , optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxyC1-C8 alkyl, optionally substituted C1-C8 alkylaminoC1-C8 alkyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted C3-C8 cycloalkoxy, optionally substituted 4- to 8-membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; wherein

[0311] R 9 、R 10 and R 11 independently selected from hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxyC1-C8 alkyl, optionally substituted C1-C8 alkylaminoC1-C8 alkyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted C3-C8 cycloalkoxy, optionally substituted 4- to 8-membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; or

[0312] R 9 and R 10 、R 9 and R 11 together with the atoms to which they are attached, form a 4- to 20-membered heterocyclyl ring; and

[0313] n is independently selected from 0, 1, 2, 3, 4 and 5;

[0314] R 2 、R 6 and R 7 Independently selected from hydrogen, halogen, oxo, CN, NO2, OR 12 SR 12 NR 12 R 13 、C(O)R 12 、C(O)OR 12 、C(O)NR 12 R 13 、S(O)R 12 、S(O)2R 12 、S(O)2NR 12 R 13 NR 14 C(O)OR 11 NR 14 C(O)R 12 NR 14 C(O)NR 12 R 13 NR 14 S(O)R 12 NR 14 S(O)2R 12 NR 14 S(O)2NR 12 R 13 , optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxyC1-C8 alkyl, optionally substituted C1-C8 alkylaminoC1-C8 alkyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted C3-C8 cycloalkoxy, optionally substituted 3- to 8-membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; wherein

[0315] R 12 、R 13 and R 14 independently selected from hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy C1-C8 alkyl, optionally substituted C1-C8 alkylamino C1-C8 alkyl, optionally substituted C3-C 10 cycloalkyl, optionally substituted 3- to 20-membered heterocyclyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted aryl, and optionally substituted heteroaryl; or

[0316] R 12 and R 13 、R 12 and R 14 、R13 and R 14 together with the atoms to which they are attached, form an optionally substituted 3- to 20-membered cycloalkyl or heterocyclyl ring;

[0317] R 3 and R 8 independently selected from the group consisting of space, hydrogen, C(O)R 15 、C(O)OR 15 、C(O)NR 15 R 16 、S(O)R 15 、S(O)2R 15 、S(O)2NR 15 R 16 NR 17 C(O)OR 15 NR 16 C(O)R 15 NR 17 C(O)NR 15 R 16 NR 17 S(O)R 15 NR 17 S(O)2R 15 NR 17 S(O)2NR 15 R 16 , optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxyC1-C8 alkyl, optionally substituted C1-C8 alkylaminoC1-C8 alkyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted C3-C8 cycloalkoxy, optionally substituted 3- to 8-membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; wherein

[0318] R 15 is empty or a divalent moiety selected from optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxyC1-C8 alkyl, optionally substituted C1-C8 alkylaminoC1-C8 alkyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted C3-C8 cycloalkoxy, optionally substituted 3- to 8-membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;

[0319] R 16 and R 17independently selected from hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy C1-C8 alkyl, optionally substituted C1-C8 alkylamino C1-C8 alkyl, optionally substituted C3-C 10 cycloalkyl, optionally substituted 3- to 20-membered heterocyclyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted aryl, and optionally substituted heteroaryl; or

[0320] R 15 and R 16 together with the atoms to which they are attached, form an optionally substituted 3- to 20-membered cycloalkyl or heterocyclyl ring;

[0321] R 4 and R 5 Independently selected from hydrogen, halogen, oxo, CN, NO2, OR 18 SR 18 NR 19 R 20 , OCOR 18 、OCO2R 18 、OCONR 19 R 20 、COR 18 、CO2R 18 、CONR 19 R 20 、SOR 18 、SO2R 18 、SO2NR 19 R 20 NR 18 CO2R 19 NR 18 COR 19 NR 18 C(O)NR 19 R 20 NR 18 SOR 19 NR 18 SO2R 19 NR 19 SO2NR 19 R 20 , optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxyC1-C8 alkyl, optionally substituted C1-C8 alkylaminoC1-C8 alkyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted C3-C8 cycloalkoxy, optionally substituted 4- to 8-membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; wherein

[0322] R18 、R 19 and R 20 independently selected from hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxyC1-C8 alkyl, optionally substituted C1-C8 alkylaminoC1-C8 alkyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted C3-C8 cycloalkoxy, optionally substituted 4- to 8-membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; or

[0323] R 18 and R 19 、R 19 and R 20 Together with the atoms to which they are attached, they form a 3- to 20-membered heterocyclyl ring.

[0324] In an embodiment, the (HPK1) ligand comprises a moiety according to Formula 7:

[0325]

[0326] in

[0327] The "linker" portion of the divalent compound is independently connected to R 2 or R 5 ;

[0328] X is selected from CR 3 or N;

[0329] R 1 and R 4 Each independently selected from the group consisting of air, hydrogen, halogen, oxo, CN, NO2, OR 6 SR 6 NR 6 R 7 , OCOR 6 、OCO2R 6 、OCONR 6 R 7 、COR 6 、CO2R 6 、CONR 6 R 7 、SOR 6 、SO2R 6 、SO2NR 6 R 7 NR 8 CO2R 6 NR 8 COR 6 NR 8 C(O)NR 6R 7 NR 8 SOR 6 NR 8 SO2R 6 NR 8 SO2NR 6 R 7 , optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxyC1-C8 alkyl, optionally substituted C1-C8 alkylaminoC1-C8 alkyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted C3-C8 cycloalkoxy, optionally substituted 4- to 8-membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; wherein

[0330] R 6 、R 7 and R 8 independently selected from hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxyC1-C8 alkyl, optionally substituted C1-C8 alkylaminoC1-C8 alkyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted C3-C8 cycloalkoxy, optionally substituted 4- to 8-membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; or

[0331] R 6 and R 7 、R 6 and R 8 together with the atoms to which they are attached, form a 4- to 20-membered heterocyclyl ring; and

[0332] n is independently selected from 0, 1, 2, 3, 4 and 5;

[0333] R 2 and R 5 independently selected from the group consisting of space, hydrogen, C(O)R 12 、C(O)OR 12 、C(O)NR 12 R 13 、S(O)R 12 、S(O)2R 12 、S(O)2NR 12 R 13 NR 14 C(O)OR 12 NR 13 C(O)R 12 NR 14 C(O)NR 12 R13 NR 14 S(O)R 12 NR 14 S(O)2R 12 NR 14 S(O)2NR 12 R 13 , optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxyC1-C8 alkyl, optionally substituted C1-C8 alkylaminoC1-C8 alkyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted C3-C8 cycloalkoxy, optionally substituted 3- to 8-membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; wherein

[0334] R 12 is empty or a divalent moiety selected from optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxyC1-C8 alkyl, optionally substituted C1-C8 alkylaminoC1-C8 alkyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted C3-C8 cycloalkoxy, optionally substituted 3- to 8-membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;

[0335] R 13 and R 14 independently selected from hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy C1-C8 alkyl, optionally substituted C1-C8 alkylamino C1-C8 alkyl, optionally substituted C3-C 10 cycloalkyl, optionally substituted 3- to 20-membered heterocyclyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted aryl, and optionally substituted heteroaryl; or

[0336] R 12 and R 13 together with the atoms to which they are attached, form an optionally substituted 3- to 20-membered cycloalkyl or heterocyclyl ring;

[0337] R 3 Selected from hydrogen, halogen, oxo, CN, NO2, OR 14 SR 14 NR 14 R 15 、C(O)R 14 、C(O)OR 14 、C(O)NR 14 R 15 、S(O)R14 、S(O)2R 14 、S(O)2NR 14 R 15 NR 16 C(O)OR 14 NR 16 C(O)R 14 NR 16 C(O)NR 14 R 15 NR 16 S(O)R 14 NR 16 S(O)2R 14 NR 16 S(O)2NR 14 R 15 , optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxyC1-C8 alkyl, optionally substituted C1-C8 alkylaminoC1-C8 alkyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted C3-C8 cycloalkoxy, optionally substituted 3- to 8-membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; wherein

[0338] R 14 、R 15 and R 16 independently selected from hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy C1-C8 alkyl, optionally substituted C1-C8 alkylamino C1-C8 alkyl, optionally substituted C3-C 10 cycloalkyl, optionally substituted 3- to 20-membered heterocyclyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted aryl, and optionally substituted heteroaryl; or

[0339] R 14 and R 15 、R 14 and R 16 、R 15 and R 16 Together with the atoms to which they are attached, they form an optionally substituted 3- to 20-membered cycloalkyl or heterocyclyl ring.

[0340] In an embodiment, the (HPK1) ligand comprises a moiety according to Formula 7A:

[0341]

[0342] in

[0343] The "linker" portion of the divalent compound is connected to R2 or R 5 ;

[0344] X is selected from CR 3 or N; and

[0345] R 1 、R 2 、R 3 、R 4 and R 5 The definition of is the same as that of Equation 7.

[0346] In an embodiment, the (HPK1) ligand comprises a moiety according to Formula 8:

[0347]

[0348] in

[0349] The "linker" portion of the divalent compound is connected to R 2 or X;

[0350] X is C 3-12 Cycloalkyl, 3- to 14-membered heterocyclic group, C 6-14 Aryl or 5- to 14-membered heteroaryl, wherein the C in X 3-12 Cycloalkyl, 3- to 14-membered heterocyclic group, C 6-14 Aryl or 5- to 14-membered heteroaryl are each optionally independently selected from R 5 substituted with 1, 2, 3, 4 or 5 substituents;

[0351] R 1 selected from hydrogen, halogen, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy C1-C8 alkyl, optionally substituted C1-C8 alkylamino C1-C8 alkyl, optionally substituted C3-C 10 cycloalkyl, optionally substituted 3- to 20-membered heterocyclyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted aryl, and optionally substituted heteroaryl;

[0352] R 2 Selected from space, hydrogen, C(O)R 7 、C(O)OR 7 、C(O)NR 7 R 8 、S(O)R 7 、S(O)2R 7 、S(O)2NR 7 R 8 NR 9 C(O)OR 7 NR 8 C(O)R 7 NR9 C(O)NR 7 R 8 NR 9 S(O)R 7 NR 9 S(O)2R 7 NR 9 S(O)2NR 7 R 8 , optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxyC1-C8 alkyl, optionally substituted C1-C8 alkylaminoC1-C8 alkyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted C3-C8 cycloalkoxy, optionally substituted 3- to 8-membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; wherein

[0353] R 7 is empty or a divalent moiety selected from optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxyC1-C8 alkyl, optionally substituted C1-C8 alkylaminoC1-C8 alkyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted C3-C8 cycloalkoxy, optionally substituted 3- to 8-membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;

[0354] R 8 and R 9 independently selected from hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy C1-C8 alkyl, optionally substituted C1-C8 alkylamino C1-C8 alkyl, optionally substituted C3-C 10 cycloalkyl, optionally substituted 3- to 20-membered heterocyclyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted aryl, and optionally substituted heteroaryl; or

[0355] R 7 and R 8 together with the atoms to which they are attached, form an optionally substituted 3- to 20-membered cycloalkyl or heterocyclyl ring;

[0356] R 3 、R 4 and R 5 Independently selected from the group consisting of air, hydrogen, halogen, oxo, CN, NO2, OR 10 SR 10 NR 10 R 11 , OCOR 10、OCO2R 10 、OCONR 10 R 11 、COR 10 、CO2R 10 、CONR 10 R 11 、SOR 10 、SO2R 10 、SO2NR 10 R 11 NR 12 CO2R 10 NR 12 COR 10 NR 12 C(O)NR 10 R 11 NR 12 SOR 10 NR 12 SO2R 10 NR 12 SO2NR 10 R 11 , optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxyC1-C8 alkyl, optionally substituted C1-C8 alkylaminoC1-C8 alkyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted C3-C8 cycloalkoxy, optionally substituted 4- to 8-membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; wherein

[0357] R 10 、R 11 and R 12 independently selected from hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxyC1-C8 alkyl, optionally substituted C1-C8 alkylaminoC1-C8 alkyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted C3-C8 cycloalkoxy, optionally substituted 4- to 8-membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; or

[0358] R 10 and R 11 、R 10 and R 12 Together with the atoms to which they are attached, they form a 4- to 20-membered heterocyclyl ring.

[0359] In an embodiment, the (HPK1) ligand comprises a moiety according to Formula 8A:

[0360]

[0361] in

[0362] The "linker" portion of the divalent compound is connected to R 2 or X;

[0363] X, R 1 、R 2 、R 3 、R 4 and R 5 The definition of is the same as that of formula 8;

[0364] Ar is selected from the group consisting of null, aryl and heteroaryl, each of which is replaced by R 2 substituted and optionally substituted by one or more substituents independently selected from the group consisting of hydrogen, halogen, oxo, CN, NO2, OR 13 SR 13 NR 13 R 14 , OCOR 13 、OCO2R 13 、OCONR 13 R 14 、COR 13 、CO2R 13 、CONR 13 R 14 、SOR 13 、SO2R 13 、SO2NR 13 R 14 NR 15 CO2R 13 NR 15 COR 13 NR 14 C(O)NR 13 R 14 NR 15 SOR 13 NR 15 SO2R 13 NR 15 SO2NR 13 R 14 , optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxyC1-C8 alkyl, optionally substituted C1-C8 alkylaminoC1-C8 alkyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted C3-C8 cycloalkoxy, optionally substituted 4- to 8-membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; wherein

[0365] R13 、R 14 and R 15 independently selected from hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxyC1-C8 alkyl, optionally substituted C1-C8 alkylaminoC1-C8 alkyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted C3-C8 cycloalkoxy, optionally substituted 4- to 8-membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; or

[0366] R 13 and R 14 、R 13 and R 15 Together with the atoms to which they are attached, they form a 4- to 20-membered heterocyclyl ring.

[0367] In an embodiment, the (HPK1) ligand comprises a moiety according to Formula 8B:

[0368]

[0369] in

[0370] The "linker" portion of the divalent compound is connected to R 2 or X;

[0371] X, R 1 、R 2 、R 3 、R 4 and R 5 The definition of is the same as that of formula 8;

[0372] Each R 6 Independently selected from the group consisting of air, hydrogen, halogen, oxo, CN, NO2, OR 16 SR 16 NR 16 R 17 , OCOR 16 、OCO2R 16 、OCONR 16 R 17 、COR 16 、CO2R 16 、CONR 16 R 17 、SOR 16 、SO2R 16 、SO2NR 16 R 17 NR 18 CO2R 16 NR 18 COR 16NR 18 C(O)NR 16 R 17 NR 18 SOR 16 NR 18 SO2R 16 NR 18 SO2NR 16 R 17 , optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxyC1-C8 alkyl, optionally substituted C1-C8 alkylaminoC1-C8 alkyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted C3-C8 cycloalkoxy, optionally substituted 4- to 8-membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; wherein

[0373] R 16 、R 17 and R 18 independently selected from hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxyC1-C8 alkyl, optionally substituted C1-C8 alkylaminoC1-C8 alkyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted C3-C8 cycloalkoxy, optionally substituted 4- to 8-membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; or

[0374] R 16 and R 17 、R 16 and R 18 together with the atoms to which they are attached, form a 4- to 20-membered heterocyclyl ring; and

[0375] n is independently selected from 0, 1, 2, 3, 4 and 5.

[0376] In an embodiment, the (HPK1) ligand comprises a moiety according to Formula 9:

[0377]

[0378] in

[0379] The "linker" portion of the divalent compound is independently connected to Y or independently connected to one R 1 ;

[0380] Each R 1 Select from empty, OR 12 SR 12 NR 12 R13 、OC(O)R 12 、OC(O)OR 12 、OCONR 12 R 13 、C(O)R 12 、C(O)OR 12 、CONR 12 R 13 、S(O)R 12 、S(O)2R 12 、SO2NR 12 R 13 NR 14 C(O)OR 12 NR 14 C(O)R 12 NR 14 C(O)NR 12 R 13 NR 14 S(O)R 12 NR 14 S(O)2R 12 NR 14 S(O)2NR 12 R 13 、P(O)R 12 R 13 、P(O)(OR 12 ), optionally substituted C1-C8 alkylene, optionally substituted C2-C8 alkenylene, optionally substituted C2-C8 alkynylene, optionally substituted C3-C8 cycloalkylene, optionally substituted 3- to 8-membered heterocyclylene, optionally substituted aryl, and optionally substituted heteroaryl; wherein

[0381] R 12 is empty or a divalent moiety selected from optionally substituted C1-C8 alkylene, optionally substituted C2-C8 alkenylene, optionally substituted C2-C8 alkynylene, optionally substituted C3-C8 cycloalkylene, optionally substituted 3- to 8-membered heterocyclylene, optionally substituted aryl, and optionally substituted heteroaryl;

[0382] R 13 and R 14 independently selected from optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy C1-C8 alkyl, optionally substituted C1-C8 alkylamino C1-C8 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted 3- to 8-membered heterocyclyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted aryl, and optionally substituted heteroaryl; or

[0383] R 12 and R 13、R 12 and R 14 、R 13 and R 14 Together with the atoms to which they are attached, they form a 3- to 20-membered cycloalkyl or heterocyclyl ring;

[0384] n and m are independently selected from 0, 1, 2, 3, 4 and 5;

[0385] Ar is selected from null, aryl and heteroaryl, each of which is optionally replaced by R 1 replace;

[0386] R 2 、R 3 、R 5 and R 6 are independently selected from hydrogen, halogen, OR 15 SR 15 NR 16 R 17 、COR 15 、CO2R 15 、C(O)NR 16 R 17 、SOR 15 、SO2R 15 、SO2NR 16 R 17 NR 15 C(O)R 16 NR 15 C(O)NR 16 R 17 NR 15 SOR 16 NR 15 SO2R 16 , optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxy, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted C3-C8 cycloalkoxy, optionally substituted 3- to 8-membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; wherein

[0387] R 15 、R 16 and R 17 independently selected from hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy C1-C8 alkyl, optionally substituted C1-C8 alkylamino C1-C8 alkyl, optionally substituted C3-C 10 cycloalkyl, optionally substituted 3- to 10-membered heterocyclyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted aryl, and optionally substituted heteroaryl; or

[0388] R 15 and R 16 、R 16 and R 17 together with the atoms to which they are attached, form an optionally substituted 3- to 20-membered cycloalkyl or heterocyclyl ring;

[0389] R 7 、R 8 、R 9 and R 10 Independently selected from air, hydrogen, halogen, OR 18 NR 19 R 20 , optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy, optionally substituted C3-C8 cycloalkyl, optionally substituted C3-C8 cycloalkoxy; wherein

[0390] R 18 、R 19 and R 20 independently selected from hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy C1-C8 alkyl, optionally substituted C1-C8 alkylamino C1-C8 alkyl, optionally substituted C3-C 10 cycloalkyl, optionally substituted 3- to 10-membered heterocyclyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl; or

[0391] R 19 and R 20 together with the atoms to which they are attached, form an optionally substituted 3- to 20-membered cycloalkyl or heterocyclyl ring;

[0392] R 11 independently selected at each occurrence from hydrogen, C(O)R 21 、C(O)OR 21 、C(O)NR 21 R 22 、S(O)R 21 、S(O)2R 21 、S(O)2NR 21 R 22 NR 23 C(O)OR 21 NR 23 C(O)R 21 NR 23 C(O)NR 21 R 22 NR 23 S(O)R 21 NR 23 S(O)2R 21 NR 23 S(O)2NR21 R 22 , optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxyC1-C8 alkyl, optionally substituted C1-C8 alkylaminoC1-C8 alkyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted C3-C8 cycloalkoxy, optionally substituted 3- to 8-membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; wherein

[0393] R 21 、R 22 and R 23 independently selected from hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxyC1-C8 alkyl, optionally substituted C1-C8 alkylaminoC1-C8 alkyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted C3-C8 cycloalkoxy, optionally substituted 4- to 8-membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; or

[0394] R 21 and R 22 、R 21 and R 23 together with the atoms to which they are attached, form a 3- to 20-membered heterocyclyl ring; and

[0395] X, Y are independently selected from the group consisting of air, CO, CO2, CH2, CR 24 R 25 、C(O)NR 24 、C(S)NR 24 、O、S、SO、SO2、SO2NR 24 NR 24 NR 24 CO、NR 24 CONR 21 NR 24 C(S), optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxyC1-C8 alkyl, optionally substituted C1-C8 haloalkyl, optionally substituted C1-C8 hydroxyalkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted C3-C8 cycloalkoxy, optionally substituted 3- to 8-membered heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted C3-C 13 Fused cycloalkyl, optionally substituted C3-C 13 Fused heterocyclic group, optionally substituted C3-C13 Bridged cycloalkyl, optionally substituted C3-C 13 Bridged heterocyclic group, optionally substituted C3-C 13 Spirocycloalkyl, and optionally substituted C3-C 13 spiroheterocyclyl; wherein

[0396] R 24 and R 25 independently selected from hydrogen, optionally substituted C1-C8 alkyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted C3-C8 cycloalkyloxy, optionally substituted 3- to 8-membered heterocyclyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxyalkyl, optionally substituted C1-C8 haloalkyl, optionally substituted C1-C8 hydroxyalkyl, optionally substituted C1-C8 alkylamino, and optionally substituted C1-C8 alkylaminoC1-C8 alkyl; and

[0397] A and B are independently selected from C or N.

[0398] In an embodiment, the (HPK1) ligand comprises a moiety according to Formula 10:

[0399]

[0400] in

[0401] The "linker" portion of the divalent compound is independently connected to R 1 or R 5 ;

[0402] R 1 and R 5 independently selected from the group consisting of space, hydrogen, C(O)R 6 、C(O)OR 6 、C(O)NR 6 R 7 、S(O)R 6 、S(O)2R 6 、S(O)2NR 6 R 7 NR 8 C(O)OR 6 NR 8 C(O)R 6 NR 8 C(O)NR 6 R 7 NR 8 S(O)R 6 NR 8 S(O)2R 6 NR 8 S(O)2NR 6 R 7, optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxyC1-C8 alkyl, optionally substituted C1-C8 alkylaminoC1-C8 alkyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted C3-C8 cycloalkoxy, optionally substituted 3- to 8-membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; wherein

[0403] R 6 is empty or a divalent moiety selected from optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxyC1-C8 alkyl, optionally substituted C1-C8 alkylaminoC1-C8 alkyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted C3-C8 cycloalkoxy, optionally substituted 3- to 8-membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;

[0404] R 7 and R 8 independently selected from hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy C1-C8 alkyl, optionally substituted C1-C8 alkylamino C1-C8 alkyl, optionally substituted C3-C 10 cycloalkyl, optionally substituted 3- to 20-membered heterocyclyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted aryl, and optionally substituted heteroaryl; or

[0405] R 6 and R 7 together with the atoms to which they are attached, form an optionally substituted 3- to 20-membered cycloalkyl or heterocyclyl ring;

[0406] R 2 and R 3 independently selected at each occurrence from hydrogen, C(O)R 9 、C(O)OR 9 、C(O)NR 9 R 10 、S(O)R 21 、S(O)2R 9 、S(O)2NR 9 R 10 NR 11 C(O)OR 9 NR 11 C(O)R 9 NR 11 C(O)NR 9 R 10 NR11 S(O)R 9 NR 11 S(O)2R 9 NR 11 S(O)2NR 9 R 10 , optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxyC1-C8 alkyl, optionally substituted C1-C8 alkylaminoC1-C8 alkyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted C3-C8 cycloalkoxy, optionally substituted 3- to 8-membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; wherein

[0407] R 9 、R 10 and R 11 independently selected from hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxyC1-C8 alkyl, optionally substituted C1-C8 alkylaminoC1-C8 alkyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted C3-C8 cycloalkoxy, optionally substituted 4- to 8-membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; or

[0408] R 9 and R 10 、R 9 and R 11 together with the atoms to which they are attached, form a 3- to 20-membered heterocyclyl ring;

[0409] Each R 4 Select from empty, OR 12 SR 12 NR 12 R 13 、OC(O)R 12 、OC(O)OR 12 、OCONR 12 R 13 、C(O)R 12 、C(O)OR 12 、CONR 12 R 13 、S(O)R 12 、S(O)2R 12 、SO2NR 12 R 13 NR 14 C(O)OR 12 NR 14 C(O)R12 NR 14 C(O)NR 12 R 13 NR 14 S(O)R 12 NR 14 S(O)2R 12 NR 14 S(O)2NR 12 R 13 , optionally substituted C1-C8 alkylene, optionally substituted C2-C8 alkenylene, optionally substituted C2-C8 alkynylene, optionally substituted C3-C8 cycloalkylene, optionally substituted 3- to 8-membered heterocyclylene, optionally substituted aryl, and optionally substituted heteroaryl; wherein

[0410] R 12 is empty or a divalent moiety selected from optionally substituted C1-C8 alkylene, optionally substituted C2-C8 alkenylene, optionally substituted C2-C8 alkynylene, optionally substituted C3-C8 cycloalkylene, optionally substituted 3- to 8-membered heterocyclylene, optionally substituted aryl, and optionally substituted heteroaryl;

[0411] R 13 and R 14 independently selected from optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy C1-C8 alkyl, optionally substituted C1-C8 alkylamino C1-C8 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted 3- to 8-membered heterocyclyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted aryl, and optionally substituted heteroaryl; or

[0412] R 12 and R 13 、R 12 and R 14 、R 13 and R 14 Together with the atoms to which they are attached, they form a 3- to 20-membered cycloalkyl or heterocyclyl ring;

[0413] n is independently selected from 0, 1, 2, 3, 4 and 5;

[0414] One of A, B and C is S, and the other two are each independently selected from CR 15 or N;

[0415] where R 15 Independently selected from the group consisting of air, hydrogen, halogen, oxo, CN, NO2, OR 16 SR 16 NR 16 R 17 , OCOR16 、OCO2R 16 、OCONR 16 R 17 、COR 16 、CO2R 16 、CONR 16 R 17 、SOR 16 、SO2R 16 、SO2NR 16 R 17 NR 18 CO2R 16 NR 18 COR 16 NR 18 C(O)NR 16 R 17 NR 18 SOR 16 NR 18 SO2R 16 NR 18 SO2NR 16 R 17 , optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxyC1-C8 alkyl, optionally substituted C1-C8 alkylaminoC1-C8 alkyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted C3-C8 cycloalkoxy, optionally substituted 4- to 8-membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; wherein

[0416] R 16 、R 17 and R 18 independently selected from hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxyC1-C8 alkyl, optionally substituted C1-C8 alkylaminoC1-C8 alkyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted C3-C8 cycloalkoxy, optionally substituted 4- to 8-membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; or

[0417] R 16 and R 17 、R 16 and R 18 Together with the atoms to which they are attached, they form a 4- to 20-membered heterocyclyl ring.

[0418] In an embodiment, the (HPK1) ligand comprises a moiety according to Formula 11:

[0419]

[0420] in

[0421] The "linker" portion of the divalent compound is independently connected to R 1 or R 5 ;

[0422] R 1 and R 5 independently selected from the group consisting of space, hydrogen, C(O)R 6 、C(O)OR 6 、C(O)NR 6 R 7 、S(O)R 6 、S(O)2R 6 、S(O)2NR 6 R 7 NR 8 C(O)OR 6 NR 8 C(O)R 6 NR 8 C(O)NR 6 R 7 NR 8 S(O)R 6 NR 8 S(O)2R 6 NR 8 S(O)2NR 6 R 7 , optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxyC1-C8 alkyl, optionally substituted C1-C8 alkylaminoC1-C8 alkyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted C3-C8 cycloalkoxy, optionally substituted 3- to 8-membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; wherein

[0423] R 6 is empty or a divalent moiety selected from optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxyC1-C8 alkyl, optionally substituted C1-C8 alkylaminoC1-C8 alkyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted C3-C8 cycloalkoxy, optionally substituted 3- to 8-membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;

[0424] R 7 and R 8independently selected from hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy C1-C8 alkyl, optionally substituted C1-C8 alkylamino C1-C8 alkyl, optionally substituted C3-C 10 cycloalkyl, optionally substituted 3- to 20-membered heterocyclyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted aryl, and optionally substituted heteroaryl; or

[0425] R 6 and R 7 together with the atoms to which they are attached, form an optionally substituted 3- to 20-membered cycloalkyl or heterocyclyl ring;

[0426] R 2 、R 3 and R 4 independently selected at each occurrence from hydrogen, C(O)R 9 、C(O)OR 9 、C(O)NR 9 R 10 、S(O)R 21 、S(O)2R 9 、S(O)2NR 9 R 10 NR 11 C(O)OR 9 NR 11 C(O)R 9 NR 11 C(O)NR 9 R 10 NR 11 S(O)R 9 NR 11 S(O)2R 9 NR 11 S(O)2NR 9 R 10 , optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxyC1-C8 alkyl, optionally substituted C1-C8 alkylaminoC1-C8 alkyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted C3-C8 cycloalkoxy, optionally substituted 3- to 8-membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; wherein

[0427] R 9 、R 10 and R 11independently selected from hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxyC1-C8 alkyl, optionally substituted C1-C8 alkylaminoC1-C8 alkyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted C3-C8 cycloalkoxy, optionally substituted 4- to 8-membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; or

[0428] R 9 and R 10 、R 9 and R 11 together with the atoms to which they are attached, form a 3- to 20-membered heterocyclyl ring;

[0429] A, B and C are each independently selected from N or CR 6 ;

[0430] Each R 6 Independently selected from air, hydrogen, halogen, OR 12 SR 12 NR 12 R 13 、OC(O)R 12 、OC(O)OR 12 、OCONR 12 R 13 、C(O)R 12 、C(O)OR 12 、CONR 12 R 13 、S(O)R 12 、S(O)2R 12 、SO2NR 12 R 13 NR 14 C(O)OR 12 NR 14 C(O)R 12 NR 14 C(O)NR 12 R 13 NR 14 S(O)R 12 NR 14 S(O)2R 12 NR 14 S(O)2NR 12 R 13 , optionally substituted C1-C8 alkylene, optionally substituted C2-C8 alkenylene, optionally substituted C2-C8 alkynylene, optionally substituted C3-C8 cycloalkylene, optionally substituted 3- to 8-membered heterocyclylene, optionally substituted aryl, and optionally substituted heteroaryl, wherein,

[0431] R 12 、R 13 and R 14 independently selected from optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy C1-C8 alkyl, optionally substituted C1-C8 alkylamino C1-C8 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted 3- to 8-membered heterocyclyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted aryl, and optionally substituted heteroaryl; or

[0432] R 12 and R 13 、R 12 and R 14 、R 13 and R 14 Together with the atoms to which they are attached, they form a 3- to 20-membered cycloalkyl or heterocyclyl ring; and

[0433] n is independently selected from 0, 1, 2, 3, 4 and 5.

[0434] In an embodiment, the (HPK1) ligand is selected from the group consisting of:

[0435]

[0436] Degradation / destruction labels

[0437] Degradation / destruction labels (EL) include, but are not limited to, the following degradation / destruction labels.

[0438] In embodiments, the degradation / destruction tag comprises a moiety according to Formula 12A, Formula 12B, Formula 12C, and Formula 12D:

[0439]

[0440] in

[0441] V, W and X are independently selected from CR 2 and N;

[0442] Y is selected from CO, CR 3 R 4 and N = N;

[0443] Z is selected from empty, CO, CR 5 R 6 NR 5 , O, optionally substituted C1-C 10 Alkylene, optionally substituted C1-C 10 Alkenylene, optionally substituted C1-C 10Alkyne, optionally substituted 3- to 10-membered carbocyclyl, optionally substituted 4- to 10-membered heterocyclyl, optionally substituted C3-C 13 Fused cycloalkyl, optionally substituted C3-C 13 Fused heterocyclic group, optionally substituted C3-C 13 Bridged cycloalkyl, optionally substituted C3-C 13 Bridged heterocyclic group, optionally substituted C3-C 13 Spirocycloalkyl, optionally substituted C3-C 13 spiroheterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; preferably, Z is selected from null, CH2, CH=CH, C≡C, NH and O;

[0444] R 1 and R 2 independently selected from hydrogen, halogen, cyano, nitro, optionally substituted C1-C6 alkyl, optionally substituted 3- to 6-membered carbocyclyl, and optionally substituted 4- to 6-membered heterocyclyl;

[0445] R 3 and R 4 R is independently selected from hydrogen, halogen, cyano, nitro, optionally substituted C1-C6 alkyl, optionally substituted 3- to 6-membered carbocyclyl, and optionally substituted 4- to 6-membered heterocyclyl; or 3 and R 4 Together with the atoms to which they are attached, they form a 3- to 6-membered carbocyclyl, or a 4- to 6-membered heterocyclyl; and

[0446] R 5 and R 6 R is independently selected from the group consisting of: null, hydrogen, halogen, oxo, hydroxy, amino, cyano, nitro, optionally substituted C1-C6 alkyl, optionally substituted 3- to 6-membered carbocyclyl, and optionally substituted 4- to 6-membered heterocyclyl; or R 5 and R 6 Together with the atoms to which they are attached, they form a 3- to 6-membered carbocyclic group, or a 4- to 6-membered heterocyclic group.

[0447] In embodiments, the degradation / destruction tag comprises a moiety according to one of Formula 12E, Formula 12F, Formula 12G, Formula 12H, and Formula 12I:

[0448]

[0449] in

[0450] U, V, W and X are independently selected from CR 2 and N;

[0451] Y is selected from CR 3 R 4 NR 3and O; preferably, Y is selected from CH2, NH, NCH3 and O;

[0452] Z is selected from empty, CO, CR 5 R 6 NR 5 , O, optionally substituted C1-C 10 Alkylene, optionally substituted C1-C 10 Alkenylene, optionally substituted C1-C 10 Alkyne, optionally substituted 3- to 10-membered carbocyclyl, optionally substituted 4- to 10-membered heterocyclyl, optionally substituted C3-C 13 Fused cycloalkyl, optionally substituted C3-C 13 Fused heterocyclic group, optionally substituted C3-C 13 Bridged cycloalkyl, optionally substituted C3-C 13 Bridged heterocyclic group, optionally substituted C3-C 13 Spirocycloalkyl, optionally substituted C3-C 13 spiroheterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; preferably, Z is selected from null, CH2, CH=CH, C≡C, NH and O;

[0453] R 1 and R 2 independently selected from hydrogen, halogen, cyano, nitro, optionally substituted C1-C6 alkyl, optionally substituted 3- to 6-membered carbocyclyl, and optionally substituted 4- to 6-membered heterocyclyl;

[0454] R 3 and R 4 R is independently selected from hydrogen, halogen, cyano, nitro, optionally substituted C1-C6 alkyl, optionally substituted 3- to 6-membered carbocyclyl, and optionally substituted 4- to 6-membered heterocyclyl; or 3 and R 4 Together with the atoms to which they are attached, they form a 3- to 6-membered carbocyclyl, or a 4- to 6-membered heterocyclyl; and

[0455] R 5 and R 6 R is independently selected from the group consisting of: null, hydrogen, halogen, oxo, hydroxy, amino, cyano, nitro, optionally substituted C1-C6 alkyl, optionally substituted 3- to 6-membered carbocyclyl, and optionally substituted 4- to 6-membered heterocyclyl; or R 5 and R 6 Together with the atoms to which they are attached, they form a 3- to 6-membered carbocyclic group, or a 4- to 6-membered heterocyclic group.

[0456] In an embodiment, the degradation / destruction tag comprises a moiety according to Formula 13A:

[0457]

[0458] in

[0459] R 1 and R 2 independently selected from hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy C1-C8 alkyl, optionally substituted C1-C8 haloalkyl, optionally substituted C1-C8 hydroxyalkyl, optionally substituted C1-C8 aminoalkyl, optionally substituted C1-C8 alkylamino C1-C8 alkyl, optionally substituted C3-C7 cycloalkyl, optionally substituted 3- to 7-membered heterocyclyl, optionally substituted C2-C8 alkenyl, and optionally substituted C2-C8 alkynyl; and

[0460] R 3 is hydrogen, optionally substituted C(O)C1-C8 alkyl, optionally substituted C(O)C1-C8 alkoxy C1-C8 alkyl, optionally substituted C(O)C1-C8 haloalkyl, optionally substituted C(O)C1-C8 hydroxyalkyl, optionally substituted C(O)C1-C8 aminoalkyl, optionally substituted C(O)C1-C8 alkylamino C1-C8 alkyl, optionally substituted C(O)C3-C7 cycloalkyl, optionally substituted C(O)(3-membered to 7-membered heterocyclyl), optionally substituted C(O)C2-C8 alkenyl, optionally substituted C(O)C2-C8 alkynyl, optionally substituted C(O)OC1-C8 alkoxy C1-C8 alkyl, optionally substituted C(O)OC1-C8 haloalkyl, optionally substituted C(O)OC1-C8 hydroxyalkyl, optionally substituted C(O)OC1-C8 aminoalkyl, optionally substituted C(O)OC1-C8 alkylamino C1-C8 alkyl, optionally substituted C(O)OC3-C7 cycloalkyl, optionally substituted C(O)O(3- to 7-membered heterocyclyl), optionally substituted C(O)OC2-C8 alkenyl, optionally substituted C(O)OC2-C8 alkynyl, optionally substituted C(O)NC1-C8 alkoxy C1-C8 alkyl, optionally substituted C(O)NC1-C8 haloalkyl, optionally substituted C(O)NC1-C8 hydroxyalkyl, optionally substituted C(O)NC1-C8 aminoalkyl, optionally substituted Substituted C(O)NC1-C8 alkylaminoC1-C8 alkyl, optionally substituted C(O)NC3-C7 cycloalkyl, optionally substituted C(O)N(3- to 7-membered heterocyclyl), optionally substituted C(O)NC2-C8 alkenyl, optionally substituted C(O)NC2-C8 alkynyl, optionally substituted P(O)(OH)2, optionally substituted P(O)(OC1-C8 alkyl)2, and optionally substituted P(O)(OC3-C8 aryl)2.

[0461] In embodiments, the degradation / destruction tag comprises a moiety according to Formula 13B, Formula 13C, Formula 13D, Formula 13E, and Formula 13F:

[0462]

[0463] in

[0464] R 1 and R 2 R is independently selected from hydrogen, halogen, OH, NH2, CN, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy C1-C8 alkyl, optionally substituted C1-C8 haloalkyl, optionally substituted C1-C8 hydroxyalkyl, optionally substituted C1-C8 aminoalkyl, optionally substituted C1-C8 alkylamino C1-C8 alkyl, optionally substituted C3-C7 cycloalkyl, optionally substituted 3- to 7-membered heterocyclyl, optionally substituted C2-C8 alkenyl, and optionally substituted C2-C8 alkynyl; (preferably, R 1 is selected from isopropyl or tert-butyl; and R 2 selected from hydrogen or methyl);

[0465] R 3is hydrogen, optionally substituted C(O)C1-C8 alkyl, optionally substituted C(O)C1-C8 alkoxy C1-C8 alkyl, optionally substituted C(O)C1-C8 haloalkyl, optionally substituted C(O)C1-C8 hydroxyalkyl, optionally substituted C(O)C1-C8 aminoalkyl, optionally substituted C(O)C1-C8 alkylamino C1-C8 alkyl, optionally substituted C(O)C3-C7 cycloalkyl, optionally substituted C(O)(3-membered to 7-membered heterocyclyl), optionally substituted C(O)C2-C8 alkenyl, optionally substituted C(O)C2-C8 alkynyl, optionally substituted C(O)OC1-C8 alkoxy C1-C8 alkyl, optionally substituted C(O)OC1-C8 haloalkyl, optionally substituted C(O)OC1-C8 hydroxyalkyl, optionally substituted C(O)OC1-C8 aminoalkyl, optionally substituted C(O)OC1-C8 alkylamino C1-C8 alkyl, optionally substituted C(O)OC3-C7 cycloalkyl, optionally substituted C(O)O(3- to 7-membered heterocyclyl), optionally substituted C(O)OC2-C8 alkenyl, optionally substituted C(O)OC2-C8 alkynyl, optionally substituted C(O)NC1-C8 alkoxy C1-C8 alkyl, optionally substituted C(O)NC1-C8 haloalkyl, optionally substituted C(O)NC1-C8 hydroxyalkyl, optionally substituted C(O)NC1-C8 aminoalkyl, optionally substituted substituted C(O)NC1-C8 alkylaminoC1-C8 alkyl, optionally substituted C(O)NC3-C7 cycloalkyl, optionally substituted C(O)N(3- to 7-membered heterocyclyl), optionally substituted C(O)NC2-C8 alkenyl, optionally substituted C(O)NC2-C8 alkynyl, optionally substituted P(O)(OH)2, optionally substituted P(O)(OC1-C8 alkyl)2, and optionally substituted P(O)(OC3-C8 aryl)2; and

[0466] R 4 and R 5 are independently selected from hydrogen, COR 6 、CO2R 6 、CONR 6 R 7 、SOR 6 、SO2R 6 、SO2NR 6 R 7 , optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy C1-C8 alkyl, optionally substituted C1-C8 alkylamino C1-C8 alkyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 8-membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; wherein

[0467] R 6 and R 7independently selected from hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxyC1-C8 alkyl, optionally substituted C1-C8 alkylaminoC1-C8 alkyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 8-membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; or

[0468] R 4 and R 5 、R 6 and R 7 Together with the atoms to which they are attached, they form a 4- to 8-membered cycloalkyl or heterocyclyl ring;

[0469] Ar is selected from aryl and heteroaryl, each of which is optionally substituted with one or more substituents independently selected from the following substituents: F, Cl, CN, NO2, OR 8 NR 8 R 9 、COR 8 、CO2R 8 、CONR 8 R 9 、SOR 8 、SO2R 8 、SO2NR 9 R 10 NR 9 COR 10 NR 8 C(O)NR 9 R 10 NR 9 SOR 10 NR 9 SO2R 10 , optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxyalkyl, optionally substituted C1-C6 haloalkyl, optionally substituted C1-C6 hydroxyalkyl, optionally substituted C1-C6 alkylaminoC1-C6 alkyl, optionally substituted C3-C7 cycloalkyl, optionally substituted 3- to 7-membered heterocyclyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted aryl, and optionally substituted C4-C5 heteroaryl; wherein

[0470] R 8 、R 9 and R 10 is independently selected from void, hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C7 cycloalkyl, optionally substituted 3- to 7-membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; or

[0471] R8 and R 9 、R 9 and R 10 Together with the atoms to which they are attached, they form a 4- to 8-membered cycloalkyl or heterocyclyl ring.

[0472] In an embodiment, the degradation / destruction tag comprises a moiety according to Formula 14A:

[0473]

[0474] in

[0475] V, W, X and Z are independently selected from CR 4 and N;

[0476] R 1 、R 2 、R 3 and R 4 Independently selected from hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxyC1-C8 alkyl, optionally substituted C1-C8 haloalkyl, optionally substituted C1-C8 hydroxyalkyl, optionally substituted C3-C7 cycloalkyl, optionally substituted 3- to 7-membered heterocyclyl, optionally substituted C2-C8 alkenyl, and optionally substituted C2-C8 alkynyl.

[0477] In an embodiment, the degradation / destruction tag comprises a moiety according to Formula 14B:

[0478]

[0479] in

[0480] R 1 、R 2 and R 3 independently selected from hydrogen, halogen, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxyC1-C8 alkyl, optionally substituted C1-C8 haloalkyl, optionally substituted C1-C8 hydroxyalkyl, optionally substituted C3-C7 cycloalkyl, optionally substituted 3- to 7-membered heterocyclyl, optionally substituted C2-C8 alkenyl, and optionally substituted C2-C8 alkynyl;

[0481] R 4 and R 5 are independently selected from hydrogen, COR 6 、CO2R 6 、CONR 6 R 7 、SOR 6 、SO2R 6 、SO2NR 6 R 7, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy C1-C8 alkyl, optionally substituted C1-C8 alkylamino C1-C8 alkyl, optionally substituted aryl-C1-C8 alkyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 8-membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; wherein

[0482] R 6 and R 7 independently selected from hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy C1-C8 alkyl, optionally substituted C1-C8 alkylamino C1-C8 alkyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 8-membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; or

[0483] R 6 and R 7 Together with the atoms to which they are attached, they form a 4- to 8-membered cycloalkyl or heterocyclyl ring.

[0484] In an embodiment, the degradation / destruction tag is selected from the group consisting of:

[0485]

[0486]

[0487] Linking group

[0488] In any of the above compounds, the HPK1 ligand can be conjugated to the degradation / destruction tag via a linker group. The linker group can include, for example, groups of varying lengths containing acyclic or cyclic saturated or unsaturated carbon, glycol, amide, amino, ether, urea, carbamate, aromatic, heteroaromatic, heterocyclic, and / or carbonyl groups.

[0489] In an embodiment, the linking group is a moiety according to Formula 16:

[0490]

[0491] in

[0492] A, W and B are independently selected at each occurrence from the group consisting of void, CO, CO2, C(O)NR 1 、C(S)NR 1 、O、S、SO、SO2、SO2NR 1 NR 1 NR 1 CO、NR 1 CONR 2 NR 1C(S), optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxyC1-C8 alkyl, optionally substituted C1-C8 haloalkyl, optionally substituted C1-C8 hydroxyalkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted C3-C8 cycloalkoxy, optionally substituted 3- to 8-membered heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted C3-C 13 Fused cycloalkyl, optionally substituted C3-C 13 Fused heterocyclic group, optionally substituted C3-C 13 Bridged cycloalkyl, optionally substituted C3-C 13 Bridged heterocyclic group, optionally substituted C3-C 13 Spirocycloalkyl, and optionally substituted C3-C 13 spiroheterocyclyl; wherein

[0493] R 1 and R 2 independently selected from hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted 3- to 8-membered cycloalkoxy, optionally substituted 3- to 8-membered heterocyclyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxyalkyl, optionally substituted C1-C8 haloalkyl, optionally substituted C1-C8 hydroxyalkyl, optionally substituted C1-C8 alkylamino, and optionally substituted C1-C8 alkylaminoC1-C8 alkyl; and

[0494] m is 0 to 15.

[0495] In an embodiment, the linking group is a moiety according to Formula 16A:

[0496]

[0497] in

[0498] R 1 、R 2 、R 3 and R 4 is independently selected at each occurrence from hydrogen, halogen, CN, OH, NH2, optionally substituted C1-C8 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C3-C8 cycloalkoxy, optionally substituted 3- to 8-membered heterocyclyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxyalkyl, optionally substituted C1-C8 haloalkyl, optionally substituted C1-C8 hydroxyalkyl, optionally substituted C1-C8 alkylamino, and optionally substituted C1-C8 alkylaminoC1-C8 alkyl;

[0499] A, W and B are independently selected at each occurrence from the group consisting of void, CO, CO2, C(O)NR 5 、C(S)NR 5 、O、S、SO、SO2、SO2NR 5 NR 5 NR 5 CO、NR 5 CONR 6 NR 5 C(S), optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxyC1-C8 alkyl, optionally substituted C1-C8 haloalkyl, optionally substituted C1-C8 hydroxyalkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted C3-C8 cycloalkoxy, optionally substituted 3- to 8-membered heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted C3-C 13 Fused cycloalkyl, optionally substituted C3-C 13 Fused heterocyclic group, optionally substituted C3-C 13 Bridged cycloalkyl, optionally substituted C3-C 13 Bridged heterocyclic group, optionally substituted C3-C 13 Spirocycloalkyl, and optionally substituted C3-C 13 spiroheterocyclyl; wherein

[0500] R 5 and R 6 independently selected from hydrogen, optionally substituted C1-C8 alkyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted C3-C8 cycloalkoxy, optionally substituted 3- to 8-membered heterocyclyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxyalkyl, optionally substituted C1-C8 haloalkyl, optionally substituted C1-C8 hydroxyalkyl, optionally substituted C1-C8 alkylamino, and optionally substituted C1-C8 alkylaminoC1-C8 alkyl;

[0501] m is 0 to 15;

[0502] n ranges from 0 to 15 at each occurrence;

[0503] o is 0 to 15.

[0504] In an embodiment, the linking group is a moiety according to Formula 16B:

[0505]

[0506] in

[0507] R1 and R 2 is independently selected at each occurrence from hydrogen, halogen, CN, OH, NH2, and optionally substituted C1-C8 alkyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted C3-C8 cycloalkoxy, optionally substituted 3- to 8-membered heterocyclyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxyalkyl, optionally substituted C1-C8 haloalkyl, optionally substituted C1-C8 hydroxyalkyl, optionally substituted C1-C8 alkylamino, or C1-C8 alkylaminoC1-C8 alkyl;

[0508] A and B are independently selected at each occurrence from the group consisting of air, CO, CO2, C(O)NR 3 、C(S)NR 3 、O、S、SO、SO2、SO2NR 3 NR 3 NR 3 CO、NR 3 CONR 4 NR 3 C(S), and optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxyC1-C8 alkyl, optionally substituted C1-C8 haloalkyl, optionally substituted C1-C8 hydroxyalkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted C3-C8 cycloalkoxy, optionally substituted 3- to 8-membered heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted C3-C 13 Fused cycloalkyl, optionally substituted C3-C 13 Fused heterocyclic group, optionally substituted C3-C 13 Bridged cycloalkyl, optionally substituted C3-C 13 Bridged heterocyclic group, optionally substituted C3-C 13 Spiroalkyl, or C3-C 13 spiroheterocyclyl; wherein

[0509] R 3 and R 4 independently selected from hydrogen, and optionally substituted C1-C8 alkyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted C3-C8 cycloalkoxy, optionally substituted 3- to 8-membered heterocyclyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxyalkyl, optionally substituted C1-C8 haloalkyl, optionally substituted C1-C8 hydroxyalkyl, optionally substituted C1-C8 alkylamino, or C1-C8 alkylaminoC1-C8 alkyl;

[0510] m is each 0 to 15; and

[0511] n is 0 to 15.

[0512] In an embodiment, the linking group is a moiety according to Formula 16C:

[0513]

[0514] in

[0515] X is selected from O, NH and NR 7 ;

[0516] R 1 、R 2 、R 3 、R 4 、R 5 and R 6 is independently selected at each occurrence from hydrogen, halogen, CN, OH, NH2, optionally substituted C1-C8 alkyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted C3-C8 cycloalkoxy, optionally substituted 3- to 8-membered heterocyclyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxyalkyl, optionally substituted C1-C8 haloalkyl, optionally substituted C1-C8 hydroxyalkyl, optionally substituted C1-C8 alkylamino, and optionally substituted C1-C8 alkylaminoC1-C8 alkyl;

[0517] A and B are independently selected at each occurrence from void, CO, NH, NH-CO, CO-NH, CH2-NH-CO, CH2-CO-NH, NH-CO-CH2, CO-NH-CH2, CH2-NH-CH2-CO-NH, CH2-NH-CH2-NH-CO, -CO-NH, CO-NH-CH2-NH-CH2, CH2-NH-CH2, CO2, C(O)NR 7 、C(S)NR 7 、O、S、SO、SO2、SO2NR 7 NR 7 NR 7 CO、NR 7 CONR 8 NR 7 C(S), optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxyC1-C8 alkyl, optionally substituted C1-C8 haloalkyl, optionally substituted C1-C8 hydroxyalkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted C3-C8 cycloalkoxy, optionally substituted 3- to 8-membered heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted C3-C 13Fused cycloalkyl, optionally substituted C3-C 13 Fused heterocyclic group, optionally substituted C3-C 13 Bridged cycloalkyl, optionally substituted C3-C 13 Bridged heterocyclic group, optionally substituted C3-C 13 Spirocycloalkyl, and optionally substituted C3-C 13 spiroheterocyclyl; wherein

[0518] R 7 and R 8 independently selected from hydrogen, optionally substituted C1-C8 alkyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted C3-C8 cycloalkoxy, optionally substituted 3- to 8-membered heterocyclyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxyalkyl, optionally substituted C1-C8 haloalkyl, optionally substituted C1-C8 hydroxyalkyl, optionally substituted C1-C8 alkylamino, and optionally substituted C1-C8 alkylaminoC1-C8 alkyl;

[0519] m ranges from 0 to 15 at each occurrence;

[0520] n ranges from 0 to 15 at each occurrence;

[0521] o is 0 to 15; and

[0522] p is 0 to 15.

[0523] In an embodiment, the linking group is selected from the group consisting of a 3- to 13-membered ring, a 3- to 13-membered fused ring, a 3- to 13-membered bridged ring, and a 3- to 13-membered spiro ring.

[0524] In an embodiment, the linking group is a moiety according to one of Formula C1, Formula C2, Formula C3, Formula C4, and Formula C5:

[0525]

[0526]

[0527] In an embodiment, the divalent compound according to the invention is selected from the group consisting of:

[0528] HC58-18、HC58-19、HC58-20、HC58-22、HC58-23、HC58-24、HC58-25、HC58-26、HC58-27、HC58-28、HC58-29、HC58-30、HC58-31、HC58-32、HC58-33、HC58-34、HC58-35、HC58-36、HC58-37、HC58-38、HC58-39、HC58-40、HC58-41、HC58-43、HC58-44、HC58-45、HC58-46、HC58-53、HC58-57、HC58-58、HC58-59、HC58-60、HC58-63、HC58-64、HC58-65、HC58-66、HC58-67、HC58-68、HC58-69、HC58-70、HC58-71、HC58-73、HC58-74、HC58-75、HC58-76、HC58-77、HC58-78、HC58-133、HC58-134、HC58-135、HC58-136、HC58-137、HC58-138、HC58-139、HC58-144、HC58-145、HC58-146、HC58-147、HC58-148、HC58-149、HC58-150、HC58-158、HC58-159、HC58-160、HC58-161、HC58-164、HC58-165、HC58-167、HC58-178、HC58-179、HC58-180、HC58-181、HC58-182、HC58-183、HC58-184、HC58-185、HC65-2、HC65-3、HC65-4、HC65-5、HC65-6、HC65-7、HC65-8、HC65-13、HC65-14、HC65-15、HC65-16、HC65-17、HC65-18、HC65-19、HC65-24、HC65-25、HC65-26、HC65-27、HC65-28、HC65-29、HC65-30、HC65-33、HC65-34、HC65-35、HC65-37、HC65-175、HC65-183、HC65-184、HC65-185、HC65-186、HC75-1、HC75-2、HC75-3、HC75-4、HC75-5、HC75-6、HC75-7、HC75-8、HC75-9、HC75-10、HC75-11、HC75-12、HC75-13、HC75-14、HC75-15、HC75-16、HC75-17, HC75-18, HC75-19, HC75-20, HC75-21, HC75-22, HC75-23, HC75-24, HC75-29, HC75-31, HC75-34, HC75-35, HC75-36, HC75-37, HC75-38, HC75-39, HC75-40, HC75-41, HC75-42, HC75-43, HC75-44, HC75-45, HC75-46, HC75-47, HC75-48, HC75-49, HC75-50, HC75-52, HC75-53, HC75-54, HC75-55, HC75-56, HC75-57, HC75-58, HC75-59, HC75-60, HC75-61, HC75-62, HC90-33, HC90-34, HC90-35, HC90-36, HC90-37, HC90-41, HC90-42, HC90-43, HC90-44, HC90-45, HC90-46, HC90-47, HC90-49, HC90-50, HC90-51, HC90-52, HC90-53, HC90-54, HC90-55, HC90-56, HC90-57, HC90-58, HC90-59, HC90-61, HC90-66, HC90-69, HC90-70, HC90-71, HC90-72, HC90-73, HC90-74, HC90-84, HC90-85, HC90-86, HC90-87, HC90-88, HC90-89, HC90-90, HC90-91, HC90-92, HC90-93, HC90-94, HC90-95, HC90-96, HC90-97, HC90-102, HC90-103, HC90-104, HC90-105, HC90-106, HC90-107, HC90-108, HC90-109, HC90-110, HC90-111, HC90-112, HC90-113, HC90-117, HC90-119, HC90-120, HC90-121, HC90-122, HC90-123, HC90-124, HC90-125, HC90-126, HC90-127, HC90-128, HC90-129, HC90-130, HC90-131, HC90-132, HC90-133, HC90-134, HC90-135, HC90-136, HC90-60, HC90-62, HC90-63, HC90-64, HC90-65, HC90-67 and HC90-******or its analogues; and pharmaceutically acceptable salts thereof.

[0529] In an embodiment, the divalent compound according to the invention is selected from the group consisting of: HC58-18, HC58-19, HC58-20, HC58-22, HC58-23, HC58-24, HC58-25, HC58-26, HC58-27, HC58-28, HC58-29, HC58-30, HC58-31, HC58-32, HC58-33, HC58-34, HC58-35, HC58-36, HC58-37, HC58-38, HC58-39, HC58-40, HC58-41, HC58- 43. HC58-44, HC58-45, HC58-46, HC58-53, HC58-57, HC58-58, HC58-59, HC58-60, HC58-63, HC58-64, HC58-65, HC58-66, HC58-67, H C58-68, HC58-69, HC58-70, HC58-71, HC58-73, HC58-74, HC58-75, HC58-76, HC58-77, HC58-78, HC58-133, HC58-134, HC58-135, HC5 8-136, HC58-137, HC58-138, HC58-139, HC58-144, HC58-145, HC58-146, HC58-147, HC58-148, HC58-149, HC58-150, HC58-158, HC5 8-159, HC58-160, HC58-161, HC58-164, HC58-165, HC58-167, HC58-178, HC58-179, HC58-180, HC58-181, HC58-182, HC58-183, HC58 and pharmaceutically acceptable salts thereof.

[0530] In an embodiment, the divalent compound according to the invention is selected from the group consisting of: HC65-175, HC65-183, HC65-184, HC65-185, HC65-186, HC75-1, HC75-2, HC75-3, HC75-4, HC75-5, HC75-6, HC75-7, HC75-8, HC75-9, HC75-10, HC75-11, HC75-12, HC75-13, HC75-14, HC75-15, HC75-16, HC75-17, HC75-18, HC75-19, HC75-20, HC75-21, HC75-22, HC75-23, HC75- -24, HC75-29, HC75-31, HC75-34, HC75-35, HC75-36, HC75-37, HC75-38, HC75-39, HC75-40, HC75-41, HC75-42, HC75-43, HC75-44, HC75-45, HC75-46, HC75-47, HC75-48, HC75-49, HC75-50, HC75-52, HC75-53, HC75-54, HC75-55, HC75-56, HC75-57, HC75-58, HC75-59, HC75-60, HC75-61 and HC75-62; and pharmaceutically acceptable salts thereof.

[0531] In an embodiment, the divalent compound according to the invention is selected from the group consisting of:

[0532] HC90-33, HC90-34, HC90-35, HC90-36, HC90-37, HC90-41, HC90-42, HC90-43, HC90-44, HC90-45, HC90-46, HC90-47, HC90-49, HC90-50, HC90-51, HC90-52, HC90-53, HC90-54, HC90-55, HC90-56, HC90-57, HC90-58, HC90-59, HC90-61, HC90-66, HC90-69, HC90-70, HC90-71, HC90-72, HC90-73, HC90-74, HC90-84, HC90-85, HC90-86, HC90-87, HC90-88, HC90-89, HC90-90, HC90-91, HC90-92, HC90-93, HC90-94, HC90-95, HC90-96, H C90-97, HC90-102, HC90-103, HC90-104, HC90-105, HC90-106, HC90-107, HC90-108, HC90-109, HC90-110, HC90-111, HC90-112, HC90-113, HC90-117, HC90-119, HC90-120, HC90-121, HC90-122, HC90-123, HC90-12 4. HC90-125, HC90-126, HC90-127, HC90-128, HC90-129, HC90-130, HC90-131, HC90-132, HC90-133, HC90-134, HC90-135, HC90-136, HC90-60, HC90-62, HC90-63, HC90-64, HC90-65, HC90-67 and HC90-68; and pharmaceutically acceptable salts thereof.

[0533] In one embodiment, preferred compounds according to the present invention include:

[0534] a. (Z)-N-(3-(4-(5-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)pentanoyl)piperazin-1-yl)propyl)-5-((5-fluoro-2-oxoindolin-3-ylidene)methyl)-2,4-dimethyl-1H-pyrrole-3-carboxamide (HC58-38);

[0535] b. (Z)-N-(3-(4-(2-((5-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)pentyl)amino)-2-oxoethyl)piperazin-1-yl)propyl)-5-((5-fluoro-2-oxoindolin-3-ylidene)methyl)-2,4-dimethyl-1H-pyrrole-3-carboxamide (HC58-75);

[0536] c. (Z)-N-(3-(4-(2-((6-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)hexyl)amino)-2-oxoethyl)piperazin-1-yl)propyl)-5-((5-fluoro-2-oxoindolin-3-ylidene)methyl)-2,4-dimethyl-1H-pyrrole-3-carboxamide (HC58-76); and

[0537] d. (Z)-N-(3-(4-(2-((8-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)octyl)amino)-2-oxoethyl)piperazin-1-yl)propyl)-5-((5-fluoro-2-oxoindolin-3-ylidene)methyl)-2,4-dimethyl-1H-pyrrole-3-carboxamide (HC58-78);

[0538] e. 2-(2,6-dioxopiperidin-3-yl)-4-((3-(4-(4-(5-(2-fluoro-6-methoxyphenyl)-1H-pyrazolo[4,3-d]pyrimidin-3-yl)phenyl)piperazin-1-yl)-3-oxopropyl)amino)isoindoline-1,3-dione (HC90-50); and

[0539] f. 2-(2,6-dioxopiperidin-3-yl)-4-((4-(4-(5-(2-fluoro-6-methoxyphenyl)-1H-pyrazolo[4,3-d]pyrimidin-3-yl)phenyl)piperazin-1-yl)-4-oxobutyl)amino)isoindoline-1,3-dione (HC90-51), and pharmaceutically acceptable salts thereof.

[0540] In some aspects, the present disclosure provides methods for treating HPK1-mediated diseases, comprising administering to a subject in need thereof one or more bivalent compounds comprising an HPK1 ligand conjugated to a degradation / destruction tag. The HPK1-mediated disease can be a disease caused by HPK1 amplification. HPK1-mediated diseases can have elevated HPK1 enzymatic activity relative to wild-type tissue of the same species and tissue type. Non-limiting examples of diseases whose HPK1-mediated diseases or clinical symptoms can be treated by HPK1 degrader / destructor-mediated therapy include: all solid and liquid cancers, chronic infections that produce an exhaustive immune response, infection-mediated immunosuppression, age-related decreases in immune response, age-related decreases in cognitive function, and infertility.

[0541] Exemplary cancer types that can be prevented or therapeutically treated by modulating HPK1 levels with degraders / destroyers include all solid and liquid cancers, including but not limited to breast cancer, respiratory cancer, brain cancer, reproductive organ cancer, digestive tract cancer, urinary tract cancer, eye cancer, liver cancer, skin cancer, head and neck cancer, thyroid cancer, parathyroid cancer, and their distant metastases. Examples of liquid cancers include lymphomas, sarcomas, and leukemias. The following lists the cancer types that immunotherapy using HPK1 degraders / destroyers should be able to prevent or treat.

[0542] Examples of breast cancer include, but are not limited to, triple-negative breast cancer, invasive ductal carcinoma, invasive lobular carcinoma, ductal carcinoma in situ, and lobular carcinoma in situ.

[0543] Examples of respiratory tract cancers include, but are not limited to, small cell lung cancer and non-small cell lung cancer, as well as bronchial adenoma and pleuropulmonary blastoma.

[0544] Examples of brain cancers include, but are not limited to, brainstem and hypothalamic gliomas, cerebellar and cerebral astrocytomas, glioblastomas, medulloblastomas, ependymomas, and neuroectodermal and pineal tumors.

[0545] Male reproductive organ tumors include, but are not limited to, prostate cancer and testicular cancer.

[0546] Tumors of the female reproductive organs include, but are not limited to, endometrial, cervical, ovarian, vaginal and perineal cancers, and uterine sarcomas.

[0547] Examples of ovarian cancer include, but are not limited to, serous tumors, endometrioid tumors, mucinous cystadenocarcinomas, granulosa cell tumors, Sertoli-Leydig cell tumors, and arrhenoblastoma.

[0548] Examples of cervical cancer include, but are not limited to, squamous cell carcinoma, adenocarcinoma, adenosquamous carcinoma, small cell carcinoma, neuroendocrine tumors, hyaline cell carcinoma, and chorionic adenocarcinoma. Gastrointestinal tumors include, but are not limited to, anal cancer, colon cancer, colorectal cancer, esophageal cancer, gallbladder cancer, stomach cancer, pancreatic cancer, rectal cancer, small intestine cancer, and salivary gland cancer.

[0549] Examples of esophageal cancer include, but are not limited to, esophageal cell carcinoma and adenocarcinoma, as well as squamous cell carcinoma, leiomyosarcoma, malignant melanoma, rhabdomyosarcoma, and lymphoma.

[0550] Examples of gastric cancer include, but are not limited to, intestinal-type and diffuse-type gastric adenocarcinoma.

[0551] Examples of pancreatic cancer include, but are not limited to, ductal adenocarcinoma, adenosquamous carcinoma, and pancreatic endocrine tumors.

[0552] Examples of urinary tract tumors include, but are not limited to, bladder cancer, penile cancer, kidney cancer, renal pelvis cancer, ureteral cancer, urethral cancer, and human papillary renal carcinoma.

[0553] Examples of kidney cancer include, but are not limited to, renal cell carcinoma, urothelial cell carcinoma, juxtaglomerular cell tumor (reninoma), angiomyolipoma, renal oncocytoma, Bellini duct carcinoma, clear cell sarcoma of the kidney, mesoblastic nephroma, and Wilms' tumor.

[0554] Examples of bladder cancer include, but are not limited to, transitional cell carcinoma, squamous cell carcinoma, adenocarcinoma, sarcoma, and small cell carcinoma. Eye cancers include, but are not limited to, intraocular melanoma and retinoblastoma.

[0555] Examples of liver cancer include, but are not limited to, hepatocellular carcinoma (liver cell carcinoma with or without fibrolamellar variant), cholangiocarcinoma (intrahepatic bile duct carcinoma), and mixed hepatocellular cholangiocarcinoma.

[0556] Examples of skin cancer include, but are not limited to, squamous cell carcinoma, Kaposi's sarcoma, malignant melanoma, Merkel cell skin cancer, and non-melanoma skin cancer.

[0557] Examples of head and neck cancers include, but are not limited to, squamous cell carcinoma of the head and neck, laryngeal cancer, hypopharyngeal cancer, nasopharyngeal cancer, oropharyngeal cancer, salivary gland cancer, lip cancer, and oral cavity cancer, and squamous cell carcinoma.

[0558] Examples of lymphomas include, but are not limited to, AIDS-related lymphoma, non-Hodgkin's lymphoma, cutaneous T-cell lymphoma, Burkitt's lymphoma, Hodgkin's disease, and lymphomas of the central nervous system.

[0559] Examples of sarcomas include, but are not limited to, soft tissue sarcoma, osteosarcoma, malignant fibrous histiocytoma, lymphosarcoma, and rhabdomyosarcoma.

[0560] Examples of leukemia include, but are not limited to, acute myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, and hairy cell leukemia.

[0561] HPK1 degraders / destroyers should be able to treat the above cancer types as stand-alone agents or as agents in combination with existing standard therapies and other FDA-approved cancer therapies.

[0562] The therapeutic uses of HPK1 extend to diseases and therapies that can be treated by stimulating / enhancing immune responses, including prolonging immune responses during vaccination against immunizable diseases such as influenza and coronaviruses (including Covid-19). Furthermore, since HPK1 is expressed at high levels in two other anatomical locations (the brain and testes), HPK1 degraders / destroyers should be able to treat or prevent brain- and testicular-related diseases that are caused by or treatable with HPK1. These potential diseases include, but are not limited to, Alzheimer's disease, age-related dementia, and infertility, regardless of whether these potential diseases are caused by HPK1 or by other etiologies.

[0563] The therapeutic use of HPK1 is further extended to therapies involving ex vivo treatment of immune cells, including but not limited to all T cell subsets, genetically engineered T cells, chimeric antigen receptor (CAR) T cells, tumor infiltrating lymphocytes, dendritic cells, macrophages, mast cells, granulocytes (including basophils, eosinophils and neutrophils), natural killer cells, NK T cells and B cells. Such cells are treated therapeutically with HPK1 degraders and then reintroduced into patients who are being treated for conditions that would benefit from reduced HPK1 expression. The sources of cells for such ex vivo treatments include but are not limited to autologous bone marrow cells from the patient himself, or umbilical cord blood stem cells from the patient's frozen storage, peripheral blood or bone marrow stem cells from MHC-matched or MHC-mismatched donors.

[0564] Treating patients by administering specific immune cells that have been treated with an HPK1 degrader offers a number of additional advantages over in vivo use. By treating specific immune cell types with an HPK1 degrader ex vivo, it is possible to specifically target immune cell types that would benefit from lowering endogenous HPK1 levels with the HPK1 degrader, while preserving HPK1 expression levels in other immune cell types not involved in the disease.

[0565] This therapeutic approach would provide cell-type-specific targeting of immune cells in a manner not possible using HPK1 degraders in an in vivo setting. Therefore, an ex vivo approach would likely limit potential toxicities that could result from reduced HPK1 levels in immune cell types that do not benefit from it.

[0566] Furthermore, by administering HPK1 degraders in an ex vivo cellular environment, the risk of patients experiencing toxicities or adverse consequences that may occur when HPK1 degraders are administered systemically is eliminated.

[0567] HPK1 is also known to be expressed in non-hematopoietic tissues such as the brain and testes. Due to this tissue-specific expression pattern of HPK1, HPK1 degraders may be able to treat or prevent brain and testicular diseases that are driven by HPK1. These potential treatments include, but are not limited to, Alzheimer's disease, senile dementia, and infertility, regardless of whether these conditions are driven by HPK1 or by other etiologies.

[0568] Using the HPK1 expression status of a tumor as a biomarker would enable stratification of patients into appropriate treatment groups (either in vivo or ex vivo to receive HPK1 degraders) based on HPK1 expression in their tumor.

[0569] Furthermore, the use of HPK1 degraders in an ex vivo setting offers the additional advantage over gene editing approaches such as CRISPR by allowing therapeutic use of HPK1 degraders as non-permanent treatments that allow for temporary adjustment of treatment regimens through dose levels and by changing dosing schedules.

[0570] Furthermore, HPK1 degraders can be used in settings where stimulating / enhancing immune responses or prolonging immune responses are desired. Enhancing the immune response to vaccination is one setting in which HPK1 degraders could be used therapeutically. HPK1 degraders could also be used to enhance the antigen presentation capacity of dendritic cell-based cancer vaccines.

[0571] Other uses of HPK1 degraders include treating dendritic cells with an HPK1 degrader to increase resistance to maturation-induced apoptosis, thereby increasing dendritic cell production.

[0572] In an embodiment, the HPK1 degraders of the present invention can be used in combination with treatments using checkpoint inhibitors, including but not limited to anti-programmed cell death protein (anti-PD-1) and anti-programmed death ligand-1 (anti-PD-L1). Examples of anti-PD-1 agents and anti-PD-L1 agents include monoclonal antibodies targeting PD-1 or PD-L1. Such antibodies include but are not limited to pembrolizumab (Keytruda), nivolumab (Opdivo), and cemiplimab (Libtayo) (PD-1 inhibitors); and atezolizumab (Tecentriq), avelumab (Bavencio), and durvalumab (Imfinzi) (PD-L1 inhibitors). The use of such anti-PD1 agents and / or anti-PD-L1 agents in immunotherapy, particularly cancer immunotherapy, can be enhanced by concomitant therapy with the HPK1 degraders of the present invention. Such combination therapies of anti-PD-1 agents with the HPK1 degraders of the present invention are particularly useful in the treatment of melanoma, lung cancer, renal cell carcinoma, Hodgkin lymphoma, head and neck cancer, colon cancer, and liver cancer. Such combination therapies of anti-PD-L1 agents with the HPK1 degraders of the present invention are particularly useful in the treatment of non-small cell lung cancer, multiple myeloma, urothelial carcinoma, and head and neck cancer (Hernandez 2018).

[0573] Similar combination therapies can employ the HPK1 degraders of the present invention with anti-CTLA-4 (cytotoxic T lymphocyte-associated protein 4) agents, such as the monoclonal antibody ipilimumab, particularly for the treatment of melanoma, lung cancer, renal cell carcinoma, glioblastoma, hepatocellular carcinoma, large B-cell lymphoma, Hodgkin lymphoma, head and neck cancer, colon cancer, and liver cancer.

[0574] In some embodiments, the HPK1 degraders of the present invention can be used to treat tumor types with elevated cyclooxygenase-2 (COX-2) expression. Elevated COX-2 leads to overproduction of prostaglandin E2 (PGE2). PGE2 produced by these tumors is known to suppress anti-tumor immune responses. T cells lacking HPK1 are resistant to PGE2-mediated inhibition (Alzabin 2010). Cancer types known to have high COX-2 expression levels include, but are not limited to, colon cancer, lung cancer, sarcomas, and breast cancer.

[0575] In any of the above methods, the divalent compound may be HC58-18, HC58-19, HC58-20, HC58-22, HC58-23, HC58-24, HC58-25, HC58-26, HC58-27, HC58-28, HC58-29, HC58-30, HC58-31, HC58-32, HC58-33, HC58-34, HC58-35, HC58-36, HC58-37, HC58-38, HC58-39, HC58-40, HC58-41, HC58-43, HC58-44, HC58-45, HC58-46, HC58-53, HC58-57 , HC58-58, HC58-59, HC58-60, HC58-63, HC58-64, HC58-65, HC58-66, HC58-67, HC58-68, HC58-69, HC58-70, HC58-71, HC58-73, HC58-74, HC58-75, HC5 8-76, HC58-77, HC58-78, HC58-133, HC58-134, HC58-135, HC58-136, HC58-137, HC58-138, HC58-139, HC58-144, HC58-145, HC58-146, HC58-147, HC58- 148, HC58-149, HC58-150, HC58-158, HC58-159, HC58-160, HC58-161, HC58-164, HC58-165, HC58-167, HC58-178, HC58-179, HC58-180, HC58-181, HC5 8-182, HC58-183, HC58-184, HC58-185, HC65-2, HC65-3, HC65-4, HC65-5, HC65-6, HC65-7, HC65-8, HC65-13, HC65-14, HC65-15, HC65-16, HC65-17, HC6 5-18, HC65-19, HC65-24, HC65-25, HC65-26, HC65-27, HC65-28, HC65-29, HC65-30, HC65-33, HC65-34, HC65-35, HC65-37, HC65-175, HC65-183, HC65- 184, HC65-185, HC65-186, HC75-1, HC75-2, HC75-3, HC75-4, HC75-5, HC75-6, HC75-7, HC75-8, HC75-9, HC75-10, HC75-11, HC75-12, HC75-13, HC75-14,HC75-15、HC75-16、HC75-17、HC75-18、HC75-19、HC75-20、HC75-21、HC75-22、HC75-23、HC75-24、HC75-29、HC75-31、HC75-34、HC75-35、HC75-36、HC75-37、HC75-38、HC75-39、HC75-40、HC75-41、HC75-42、HC75-43、HC75-44、HC75-45、HC75-46、HC75-47、HC75-48、HC75-49、HC75-50、HC75-52、HC75-53、HC75-54、HC75-55、HC75-56、HC75-57、HC75-58、HC75-59、HC75-60、HC75-61、HC75-62、HC90-33、HC90-34、HC90-35、HC90-36、HC90-37、HC90-41、HC90-42、HC90-43、HC90-44、HC90-45、HC90-46、HC90-47、HC90-49、HC90-50、HC90-51、HC90-52、HC90-53、HC90-54、HC90-55、HC90-56、HC90-57、HC90-58、HC90-59、HC90-61、HC90-66、HC90-69、HC90-70、HC90-71、HC90-72、HC90-73、HC90-74、HC90-84、HC90-85、HC90-86、HC90-87、HC90-88、HC90-89、HC90-90、HC90-91、HC90-92、HC90-93、HC90-94、HC90-95、HC90-96、HC90-97、HC90-102、HC90-103、HC90-104、HC90-105、HC90-106、HC90-107、HC90-108、HC90-109、HC90-110、HC90-111、HC90-112、HC90-113、HC90-117、HC90-119、HC90-120、HC90-121、HC90-122、HC90-123、HC90-124、HC90-125、HC90-126、HC90-127、HC90-128、HC90-129、HC90-130、HC90-131、HC90-132、HC90-133、HC90-134、HC90-135、HC90-136、HC90-60、HC90-62、HC90-63、HC90-64、HC90-65、HC90-67, HC90-68, or the like.

[0576] In some aspects of the disclosed methods, the bivalent compound can be administered by any of several routes of administration including, for example, oral, parenteral, intradermal, subcutaneous, topical, and / or rectal administration.

[0577] Any of the above methods can further include treating the subject with one or more other treatment regimens for treating cancer. The one or more other treatment regimens for treating cancer can be, for example, one or more of surgery, chemotherapy, radiotherapy, hormone therapy, or immunotherapy.

[0578] The present disclosure further provides a method for identifying a bivalent compound that mediates degradation / destruction of HPK1, the method comprising: providing a heterobifunctional test compound comprising an HPK1 ligand conjugated to a degradation / destruction tag, contacting the heterobifunctional test compound with a cell (e.g., a cancer cell, e.g., an HPK1-mediated cancer cell) comprising a ubiquitin ligase and HPK1.

[0579] As used herein, the terms "about" and "approximately" are defined as within plus or minus 10% of a given value or condition, preferably within plus or minus 5% of the stated value or condition.

[0580] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those of ordinary skill in the art to which the invention pertains. Methods and materials for use with the present invention are described herein; in addition, suitable methods and materials known in the art may also be used. The materials, methods, and examples are illustrative only and are not intended to be limiting. All publications, patent applications, patents, sequences, database entries, and other references mentioned herein are incorporated herein by reference in their entirety. In the event of a conflict, the present specification (including definitions) will control.

[0581] Other features and advantages of the invention will be apparent from the following detailed description and drawings, and from the claims. BRIEF DESCRIPTION OF THE DRAWINGS

[0582] FIG1 is a diagram of a series of screening of the HC58 series of HPK1 degraders for enhancing TCR-induced IL-2 production.

[0583] Figure 2 Immunoblot analysis showing that the HC58 series of degraders can reduce the endogenous level of HPK1 in Jurkat T cells.

[0584] Figure 3Immunoblot analysis to show that the HC58 series degraders HC58-75 and HC58-78 can reduce the endogenous levels of HPK1 in Jurkat T cells multiple days after exposure to the HC58 series.

[0585] Figure 4 shows immunoblot analysis demonstrating that the HC58 series of degraders can reduce endogenous levels of HPK1 in Jurkat T cells relative to DMSO and other controls. (A) Amount of IL-2 produced in response to TCR engagement. (B) Fold increase in IL-2 after degrader treatment.

[0586] Figure 5 A set of graphs showing that treatment of primary T cells with lead HPK1 degraders from the HC58 series confers elevated IL-2 responses and enhanced proliferative responses to anti-CD28 x anti-CD28 mAb-mediated receptor cross-linking in murine primary T cells.

[0587] Figure 6 To show the CD4 + Graph of CD28-independent IL-2 production by T cells upon stimulation with a fixed concentration of plate-bound anti-CD3ε and varying concentrations of soluble anti-CD28 mAb.

[0588] Figure 7 To show the treatment of primary GFP with HC58-78 HPK1 degrader + Figure 3. Tregs conferring increased IL-2 production by Tregs in response to stimulation via TCR engagement.

[0589] Figure 8 A set of graphs illustrating the screening of the HC90 HPK1 degrader series to find compounds that can elicit superior IL-2 production compared to the levels elicited by the lead HC58 series compounds.

[0590] Figure 9 Graph showing IL-2 response curves in Jurkat T cells induced by different concentrations of lead HC90 compound.

[0591] Figure 10 Graph showing IL-2 production by HC58-78-treated or HC90-50-treated human PBMCs, shown is the fold difference in IL-2 production by degrader-treated cells relative to IL-2 production by DMSO-treated cells.

[0592] Figure 11Schematic depiction of how HPK1 degraders can be used as therapeutic agents to directly or indirectly treat various disease states.

[0593] Figure 12 A series of blots showing that HPK1 degraders can effectively degrade endogenous HPK1 in murine T cells, murine TCR transgenic T cells, and human DC1 dendritic cells.

[0594] Figure 13 To show that HPK1 degraders can effectively enhance blinatumomab-mediated inhibition of human CD19 + A set of images showing the killing of the B-cell acute lymphoblastic leukemia cell Raji.

[0595] FIG14 is a set of graphs showing that HPK1 degraders can effectively increase proinflammatory cytokine production by PBMCs treated with blinatumomab. (A) Representative intracellular cytokine staining patterns of PBMCs treated with HPK1 degraders / blinatumomab expressing IFNγ and TNFα. (B) Average percentage of cells staining positive for both IFNγ and TNFα in PBMCs treated with HPK1 degraders / blinatumomab. DETAILED DESCRIPTION

[0596] The present disclosure is based, in part, on the discovery that novel heterobifunctional molecules that degrade HPK1, HPK1 fusion proteins, and / or HPK1 muteins can be used to treat HPK1-mediated diseases.

[0597] Non-limiting examples of HPK1-mediated diseases or clinical conditions that can be treated by HPK1 degrader / destroyer-mediated therapy include: all solid and liquid cancers, chronic infections that produce exhausting immune responses, infection-mediated immunosuppression, age-related decline in immune responses, age-related decline in cognitive function, and infertility.

[0598] Exemplary cancer types that can be prevented or therapeutically treated by modulating HPK1 levels with degraders / destroyers include all solid and liquid cancers, including but not limited to breast cancer, respiratory cancer, brain cancer, reproductive organ cancer, digestive tract cancer, urinary tract cancer, eye cancer, liver cancer, skin cancer, head and neck cancer, thyroid cancer, parathyroid cancer, and their distant metastases. Examples of liquid cancers include lymphomas, sarcomas, and leukemias. The following lists the cancer types that immunotherapy using HPK1 degraders / destroyers should be able to prevent or treat.

[0599] Examples of breast cancer include, but are not limited to, triple-negative breast cancer, invasive ductal carcinoma, invasive lobular carcinoma, ductal carcinoma in situ, and lobular carcinoma in situ.

[0600] Examples of respiratory tract cancers include, but are not limited to, small cell lung cancer and non-small cell lung cancer, as well as bronchial adenoma and pleuropulmonary blastoma.

[0601] Examples of brain cancers include, but are not limited to, brainstem and hypothalamic gliomas, cerebellar and cerebral astrocytomas, glioblastomas, medulloblastomas, ependymomas, and neuroectodermal and pineal tumors.

[0602] Male reproductive organ tumors include, but are not limited to, prostate cancer and testicular cancer.

[0603] Tumors of the female reproductive organs include, but are not limited to, endometrial, cervical, ovarian, vaginal and perineal cancers, and uterine sarcomas.

[0604] Examples of ovarian cancer include, but are not limited to, serous tumors, endometrioid tumors, mucinous cystadenocarcinomas, granulosa cell tumors, Sertoli-Leydig cell tumors, and male cell tumors.

[0605] Examples of cervical cancer include, but are not limited to, squamous cell carcinoma, adenocarcinoma, adenosquamous carcinoma, small cell carcinoma, neuroendocrine tumors, hyaline cell carcinoma, and chorionic adenocarcinoma. Gastrointestinal tumors include, but are not limited to, anal cancer, colon cancer, colorectal cancer, esophageal cancer, gallbladder cancer, stomach cancer, pancreatic cancer, rectal cancer, small intestine cancer, and salivary gland cancer.

[0606] Examples of esophageal cancer include, but are not limited to, esophageal cell carcinoma and adenocarcinoma, as well as squamous cell carcinoma, leiomyosarcoma, malignant melanoma, rhabdomyosarcoma, and lymphoma.

[0607] Examples of gastric cancer include, but are not limited to, intestinal-type and diffuse-type gastric adenocarcinoma.

[0608] Examples of pancreatic cancer include, but are not limited to, ductal adenocarcinoma, adenosquamous carcinoma, and pancreatic endocrine tumors.

[0609] Examples of urinary tract tumors include, but are not limited to, bladder cancer, penile cancer, kidney cancer, renal pelvis cancer, ureteral cancer, urethral cancer, and human papillary renal carcinoma.

[0610] Examples of renal cancer include, but are not limited to, renal cell carcinoma, urothelial cell carcinoma, juxtaglomerular cell tumor (reninoma), angiomyolipoma, renal oncocytoma, Bellini duct carcinoma, clear cell sarcoma of the kidney, mesoblastic nephroma, and Wilms' tumor.

[0611] Examples of bladder cancer include, but are not limited to, transitional cell carcinoma, squamous cell carcinoma, adenocarcinoma, sarcoma, and small cell carcinoma. Eye cancers include, but are not limited to, intraocular melanoma and retinoblastoma.

[0612] Examples of liver cancer include, but are not limited to, hepatocellular carcinoma (liver cell carcinoma with or without fibrolamellar variant), cholangiocarcinoma (intrahepatic bile duct carcinoma), and mixed hepatocellular cholangiocarcinoma.

[0613] Examples of skin cancer include, but are not limited to, squamous cell carcinoma, Kaposi's sarcoma, malignant melanoma, Merkel cell skin cancer, and non-melanoma skin cancer.

[0614] Examples of head and neck cancers include, but are not limited to, squamous cell carcinoma of the head and neck, laryngeal cancer, hypopharyngeal cancer, nasopharyngeal cancer, oropharyngeal cancer, salivary gland cancer, lip and oral cavity cancer, and squamous cell.

[0615] Examples of lymphomas include, but are not limited to, AIDS-related lymphoma, non-Hodgkin's lymphoma, cutaneous T-cell lymphoma, Burkitt's lymphoma, Hodgkin's disease, and lymphomas of the central nervous system.

[0616] Examples of sarcomas include, but are not limited to, soft tissue sarcoma, osteosarcoma, malignant fibrous histiocytoma, lymphosarcoma, and rhabdomyosarcoma.

[0617] Examples of leukemias include, but are not limited to, acute myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, and hairy cell leukemia.

[0618] HPK1 degraders / destroyers should be able to treat the above cancer types as stand-alone agents or as agents in combination with existing standard therapies and other FDA-approved cancer therapies.

[0619] HPK1's therapeutic uses include diseases and therapies that can be treated by stimulating or enhancing immune responses, including prolonging immune responses during vaccination against immunizable diseases. Furthermore, since HPK1 is expressed at high levels in two other anatomical locations (the brain and testes), HPK1 degraders / destroyers should be able to treat or prevent brain- and testicular-related diseases that are caused by or treatable with HPK1. These potential diseases include, but are not limited to, Alzheimer's disease, senile dementia, and infertility, regardless of whether these potential diseases are caused by HPK1 or by other etiologies.

[0620] Successful strategies for selective degradation / destruction of target proteins induced by bifunctional molecules include recruiting E3 ubiquitin ligases and mimicking protein misfolding with hydrophobic tags (Buckley and Crews, 2014). PROTACs (PROteolysis Targeting Chimeras) are bivalent molecules with one part that binds to an E3 ubiquitin ligase and another part that binds to the protein target of interest (Buckley and Crews, 2014). The induced proximity leads to selective ubiquitination of the target, which is then degraded at the proteasome. Several types of high-affinity small molecule E3 ligase ligands have been identified / developed. They include (1) cereblon (CRBN or CRL4), a component of the cullin-RING ubiquitin ligase (CRL) complex; CRBN ) with immunomodulatory drugs (IMiDs) such as thalidomide and pomalidomide (Bondeson et al., 2015; Chamberlain et al., 2014; Fischer et al., 2014; Ito et al., 2010; Winter et al., 2015); (2) with another component of the CRL complex, the van Hippel-Lindau protein (VHL or CRL2 VHL) that binds to the hydroxyproline-containing ligand VHL-1 (Bondeson et al., 2015; Buckley et al., 2012a; Buckley et al., 2012b; Galdeano et al., 2014; Zengerle et al., 2015); (3) compound 7 that selectively binds to KIAP1, a component of the CRL3 complex (Davies et al., 2016); (4) AMG232 that selectively binds to the heterodimeric RING E3 ligase MDM2 (Sun et al., 2014); and (5) LCL161 that selectively binds to the homodimeric RING E3 ligase IAP (Ohoka et al., 2017; Okuhira et al., 2011; Shibata et al., 2017). Degrader technology has been successfully applied to the degradation of various targets (Bondeson et al., 2015; Buckley et al., 2015; Lai et al., 2016; Lu et al., 2015; Winter et al., 2015; Zengerle et al., 2015), but has not yet been applied to the degradation of HPK1. Furthermore, a hydrophobic tagging approach using bulky and hydrophobic adamantyl groups has been developed to mimic protein misfolding, leading to proteasome-mediated degradation of target proteins (Buckley and Crews, 2014). This approach has also been successfully applied to the selective degradation of the pseudokinase Her3 (Xie et al., 2014), but has not yet been applied to the degradation of HPK1 protein.

[0621] As discussed in the examples below, the present disclosure provides specific examples of novel HPK1 degraders / destroyers and examines the effects of exemplary degraders / destroyers in reducing HPK1 protein levels, inhibiting / destroying HPK1 activity, and increasing IL-2 production induced by the TCR of Jurkat T cells. The results suggest that these novel compounds may be beneficial in treating cancer. Exemplary cancer types that can be prevented or therapeutically treated by modulating HPK1 levels with degraders / destroyers include all solid and liquid cancers, including but not limited to breast cancer, respiratory cancer, brain cancer, reproductive organ cancer, digestive tract cancer, urinary tract cancer, eye cancer, liver cancer, skin cancer, head and neck cancer, thyroid cancer, parathyroid cancer, and their distant metastases. Examples of liquid cancers include lymphomas, sarcomas, and leukemias. The following lists the cancer types that immunotherapy using HPK1 degraders / destroyers should be able to prevent or treat as described above.

[0622] Current compounds targeting HPK1 generally focus on inhibiting its catalytic activity. In the present disclosure, a different approach is adopted: developing compounds that not only directly and selectively target the catalytic function of HPK1 but also target its protein level in cells. Strategies for inducing protein degradation include recruiting E3 ubiquitin ligases, simulating protein misfolding with hydrophobic tags, and inhibiting molecular chaperones. For example, the thalidomide-JQ1 bivalent compound has been used to hijack the cereblon E3 ligase, induce highly selective BET protein degradation in vitro and in vivo, and lead to a delay in leukemia progression in confirmed mice (Winter et al., 2015). Similarly, BET protein degradation is also induced via another E3 ligase, VHL (Zengerle et al., 2015). Adamantane-modified compounds have been used to induce partial degradation of Her3 protein (Xie et al., 2014). Such methods based on the use of bivalent molecules allow for more flexible regulation of protein levels in vitro and in vivo compared to techniques such as gene knockout or knockdown via RNA interference. Unlike gene knockout or knockdown, this chemical approach offers the opportunity to study dose- and time-dependencies in disease models by varying the concentration and dosing frequency of the relevant compound.

[0623] The present disclosure includes all stereoisomers, geometric isomers, tautomers and isotopes of the structures and named compounds depicted herein. The present disclosure also includes compounds described herein, no matter how they are prepared, e.g., synthetically, by biological processes (e.g., metabolic or enzymatic conversion), or a combination thereof.

[0624]

[00146] The present disclosure includes pharmaceutically acceptable salts of the structures and named compounds depicted herein.

[0625] One or more constituent atoms of the compounds presented herein can be replaced or substituted by isotopes of atoms with natural or non-natural abundance. In some embodiments, the compound comprises at least one deuterium atom. In some embodiments, the compound comprises two or more deuterium atoms. In some embodiments, the compound comprises 1-2, 1-3, 1-4, 1-5, or 1-6 deuterium atoms. In some embodiments, all hydrogen atoms in the compound can be replaced or substituted by deuterium atoms. In some embodiments, the compound comprises at least one fluorine atom. In some embodiments, the compound comprises two or more fluorine atoms. In some embodiments, the compound comprises 1-2, 1-3, 1-4, 1-5, or 1-6 fluorine atoms. In some embodiments, all hydrogen atoms in the compound can be replaced or substituted by fluorine atoms.

[0626] Degradants

[0627] In some aspects, the present disclosure provides a bivalent compound (also referred to herein as a degrader) comprising an HPK1 ligand (or targeting moiety) conjugated to a degradation tag. The connection between the HPK1 ligand and the degradation tag can be direct or indirect via a linker group.

[0628] As used herein, the terms "protein arginine methyltransferase 5 (HPK1) ligand," "HPK1 ligand," or "HPK1 targeting moiety" should be broadly construed and encompass a wide variety of molecules, from small molecules to large proteins, that associate with or bind to HPK1. The HPK1 ligand or targeting moiety can be, for example, a small molecule compound (i.e., a molecule having a molecular weight of less than about 1.5 kilodaltons (kDa)), a peptide or polypeptide, a nucleic acid or oligonucleotide, a carbohydrate such as an oligosaccharide, or an antibody or fragment thereof.

[0629] HPK1 ligands or targeting moieties can be derived from HPK1 inhibitors (e.g., sutent and its analogs), which are capable of interfering with the enzymatic activity of HPK1. As used herein, an "inhibitor" refers to an agent that limits, delays, or otherwise causes inhibition of a physiological, chemical, or enzymatic action or function. As used herein, an inhibitor causes a reduction in enzyme activity of at least 5%. An inhibitor can also or alternatively refer to a drug, compound, or agent that prevents or reduces the expression, transcription, or translation of a gene or protein. An inhibitor can reduce or prevent the function of a protein, for example, by binding to or activating / inactivating another protein or receptor.

[0630] Exemplary HPK1 ligands include, but are not limited to, the compounds listed below:

[0631]

[0632] As used herein, the term "degradation / destruction tag" refers to a compound that associates with or binds to a ubiquitin ligase to recruit the corresponding ubiquitination machinery to HPK1, or induces HPK1 protein misfolding and subsequent degradation at the proteasome or loss of function.

[0633] In some aspects, the degradation / destruction tags of the present disclosure include, for example, thalidomide, pomalidomide, lenalidomide, VHL-1, adamantane, 1-((4,4,5,5,5-pentafluoropentyl)sulfinyl)nonane, nutlin-3a, RG7112, RG7338, AMG232, AA-115, bestatin, MV-1, LCL161, and / or analogs thereof.

[0634] As used herein, a "linker" is a bond, molecule, or group of molecules that binds two separate entities to each other. A linker can provide an optimal spacing between the two entities. The term "linker" in some aspects refers to any agent or molecule that bridges the HPK1 ligand to the degradation / destruction tag. One of ordinary skill in the art will recognize that sites on the HPK1 ligand or degradation / destruction tag that are not essential for the function of the degraders of the present disclosure are ideal sites for attaching a linker, provided that the linker, once attached to the conjugate of the present disclosure, does not interfere with the function of the degrader, i.e., its ability to target HPK1 and its ability to recruit ubiquitin ligases.

[0635] The length of the linker group of the bivalent compound can be adjusted to minimize the molecular weight of the destroyer / degrader and avoid any potential conflict between the HPK1 ligand or targeting moiety and the ubiquitin ligase or concurrent HPK1 misfolding induced by the hydrophobic tag.

[0636] In some aspects, the degradation / destruction tags disclosed herein include, for example, thalidomide, pomalidomide, lenalidomide, VHL-1, adamantane, 1-((4,4,5,5,5-pentafluoropentyl)sulfinyl)nonane, nutlin-3a, RG7112, RG7338, AMG232, AA-115, bestatin, MV-1, LCL161, and analogs thereof. The degradation / destruction tags can be attached to any portion of the structure of an HPK1 ligand or targeting moiety (e.g., Sutent) using linkers of varying types and lengths to generate effective bivalent compounds. In particular, attachment of VHL1, pomalidomide, or LCL161 to any portion of the molecule can recruit E3 ligases to HPK1.

[0637] The bivalent compounds disclosed herein can increase IL-2 production induced by the TCR of Jurkat T cells.

[0638] The principles and methods disclosed herein can be used to develop additional bivalent compounds (i.e., HPK1 degraders / destroyers). For example, other linking groups, degradation tags, and HPK1 binding / inhibitory moieties can be synthesized and tested. Non-limiting examples of HPK1 degraders / degraders (e.g., bivalent compounds) are shown in Table 1 below. As shown, the left portion of each HPK1 degrader / degrader compound binds to HPK1 (as does Sutent (sunitinib)), and the right portion of each compound recruits the ubiquitination machinery to HPK1, which induces polyubiquitination and degradation of HPK1 at the proteasome.

[0639] More specifically, the present disclosure provides bivalent compounds comprising an HPK1 ligand conjugated to a degradation / destruction tag.

[0640] In some aspects, the HPK1 degrader / destructor has the form of "PI-Linker-EL" as shown below:

[0641]

[0642] Wherein the PI (protein of interest) comprises an HPK1 ligand (e.g., an HPK1 inhibitor) and the EL (E3 ligase) comprises a degradation / destruction tag (e.g., an E3 ligase ligand). Exemplary HPK1 ligands (PIs), exemplary degradation / destruction tags (ELs), and exemplary linkers (Linkers) are described below.

[0643] HPK1 ligands

[0644] In an embodiment, the (HPK1) ligand comprises a moiety according to Formula 1A:

[0645]

[0646] in,

[0647] The "linker" portion of the divalent compound is attached to Z;

[0648] X is selected from O or S;

[0649] R 1 、R 2 、R 3 、R 4 、R 7 and R 8 Selected from hydrogen, halogen, oxo, CN, NO2, OR 11 SR 11 NR 11 R 12 、C(O)R 11 、C(O)OR 11 、C(O)NR 11 R 12 、S(O)R 11 、S(O)2R 11 、S(O)2NR 11 R 12 NR 13 C(O)OR 11 NR 13 C(O)R 11 NR 13 C(O)NR 11 R 12 NR 13 S(O)R 11 NR 13 S(O)2R 11 NR 13 S(O)2NR11 R 12 , optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxyC1-C8 alkyl, optionally substituted C1-C8 alkylaminoC1-C8 alkyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted C3-C8 cycloalkoxy, optionally substituted 3- to 8-membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; wherein

[0650] R 11 、R 12 and R 13 independently selected from hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy C1-C8 alkyl, optionally substituted C1-C8 alkylamino C1-C8 alkyl, optionally substituted C3-C 10 cycloalkyl, optionally substituted 3- to 20-membered heterocyclyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted aryl, and optionally substituted heteroaryl, or

[0651] R 11 and R 12 、R 11 and R 13 、R 12 and R 13 together with the atoms to which they are attached, form an optionally substituted 3- to 20-membered cycloalkyl or heterocyclyl ring;

[0652] R 5 and R 6 independently selected from hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxyC1-C8 alkyl, optionally substituted C1-C8 alkylaminoC1-C8 alkyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted C3-C8 cycloalkoxy, optionally substituted 4- to 8-membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;

[0653] R 17 、R 18 、R 19 and R 20is independently selected at each occurrence from hydrogen, halogen, CN, OH, NH2, optionally substituted C1-C8 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C3-C8 cycloalkyloxy, optionally substituted C1-C8 alkoxyC1-C8 alkyl, optionally substituted C1-C8 alkylaminoC1-C8 alkyl, optionally substituted 3- to 8-membered heterocyclyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxyalkyl, optionally substituted C1-C8 haloalkyl, optionally substituted C1-C8 hydroxyalkyl, optionally substituted C1-C8 alkylamino, and optionally substituted C1-C8 alkylaminoC1-C8 alkyl;

[0654] m, n are independently selected from 0, 1, 2, 3 and 4; and

[0655] W, Q and Z are independently selected at each occurrence from void, CO, CO2, CH2, NH, NH-CO, CO-NH, CH2-NH-CO, CH2-CO-NH, NH-CO-CH2, CO-NH-CH2, CH2-NH-CH2-CO-NH, CH2-NH-CH2-NH-CO, -CO-NH, CO-NH-CH2-NH-CH2, CH2-NH-CH2, CR 21 R 22 、C(O)NR 21 、C(S)NR 21 、O、S、SO、SO2、SO2NR 21 NR 21 NR 21 CO、NR 121 CONR 22 NR 21 C(S), optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxyC1-C8 alkyl, optionally substituted C1-C8 haloalkyl, optionally substituted C1-C8 hydroxyalkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted C3-C8 cycloalkoxy, optionally substituted 3- to 8-membered heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted C3-C 13 Fused cycloalkyl, optionally substituted C3-C 13 Fused heterocyclic group, optionally substituted C3-C 13 Bridged cycloalkyl, optionally substituted C3-C 13 Bridged heterocyclic group, optionally substituted C3-C 13 Spirocycloalkyl, and optionally substituted C3-C 13 spiroheterocyclyl; wherein

[0656] R21 and R 22 Independently selected from hydrogen, optionally substituted C1-C8 alkyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted C3-C8 cycloalkyloxy, optionally substituted 3- to 8-membered heterocyclyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxyalkyl, optionally substituted C1-C8 haloalkyl, optionally substituted C1-C8 hydroxyalkyl, optionally substituted C1-C8 alkylamino, and optionally substituted C1-C8 alkylaminoC1-C8 alkyl.

[0657] In an embodiment, the (HPK1) ligand comprises a moiety according to Formula 3A:

[0658]

[0659] in

[0660] The "linker" portion of the divalent compound is independently connected to R 1 or R 3 ;

[0661] X is selected from CR 2 or N;

[0662] R 1 Selected from space, hydrogen, C(O)R 6 、C(O)OR 6 、C(O)NR 6 R 7 、S(O)R 6 、S(O)2R 6 、S(O)2NR 6 R 7 NR 8 C(O)OR 6 NR 8 C(O)R 6 NR 8 C(O)NR 6 R 7 NR 8 S(O)R 6 NR 8 S(O)2R 6 NR 8 S(O)2NR 6 R 7, optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxyC1-C8 alkyl, optionally substituted C1-C8 alkylaminoC1-C8 alkyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted C3-C8 cycloalkoxy, optionally substituted 3- to 8-membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; wherein

[0663] R 6 is empty or a divalent moiety selected from optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxyC1-C8 alkyl, optionally substituted C1-C8 alkylaminoC1-C8 alkyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted C3-C8 cycloalkoxy, optionally substituted 3- to 8-membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;

[0664] R 2 Independently selected from hydrogen, halogen, oxo, CN, NO2, OR 9 SR 9 NR 9 R 10 、C(O)R 9 、C(O)OR 9 、C(O)NR 9 R 10 、S(O)R 9 、S(O)2R 9 、S(O)2NR 9 R 10 NR 11 C(O)OR 9 NR 11 C(O)R 9 NR 11 C(O)NR 9 R 10 NR 11 S(O)R 9 NR 11 S(O)2R 9 NR 11 S(O)2NR 9 R 10, optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxyC1-C8 alkyl, optionally substituted C1-C8 alkylaminoC1-C8 alkyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted C3-C8 cycloalkoxy, optionally substituted 3- to 8-membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; wherein

[0665] R 9 、R 10 and R 11 independently selected from hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy C1-C8 alkyl, optionally substituted C1-C8 alkylamino C1-C8 alkyl, optionally substituted C3-C 10 cycloalkyl, optionally substituted 3- to 20-membered heterocyclyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted aryl, and optionally substituted heteroaryl; or

[0666] R 9 and R 10 、R 9 and R 11 、R 10 and R 11 together with the atoms to which they are attached, form an optionally substituted 3- to 20-membered cycloalkyl or heterocyclyl ring;

[0667] Ar is selected from the group consisting of null, aryl and heteroaryl, each of which is replaced by R 3 substituted and optionally substituted by one or more substituents independently selected from the group consisting of hydrogen, halogen, oxo, CN, NO2, OR 12 SR 12 NR 12 R 13 , OCOR 12 、OCO2R 12 、OCONR 12 R 13 、COR 12 、CO2R 12 、CONR 12 R 13 、SOR 12 、SO2R 12 、SO2NR 12 R 13 NR 14 CO2R 12 NR 14 COR 12 NR 14 C(O)NR 12 R13 NR 14 SOR 12 NR 14 SO2R 12 NR 14 SO2NR 12 R 13 , optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxyC1-C8 alkyl, optionally substituted C1-C8 alkylaminoC1-C8 alkyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted C3-C8 cycloalkoxy, optionally substituted 4- to 8-membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; wherein

[0668] R 12 、R 13 and R 14 independently selected from hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxyC1-C8 alkyl, optionally substituted C1-C8 alkylaminoC1-C8 alkyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted C3-C8 cycloalkoxy, optionally substituted 4- to 8-membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; or

[0669] R 12 and R 13 、R 12 and R 14 together with the atoms to which they are attached, form a 4- to 20-membered heterocyclyl ring;

[0670] R 3 Select from empty, OR 15 SR 15 NR 15 R 16 、OC(O)R 15 、OC(O)OR 15 、OCONR 15 R 16 、C(O)R 15 、C(O)OR 15 、CONR 15 R 16 、S(O)R 15 、S(O)2R 15 、SO2NR 15 R 16 NR 17 C(O)OR 15 NR 17C(O)R 15 NR 17 C(O)NR 15 R 16 NR 14 S(O)R 15 NR 17 S(O)2R 15 NR 17 S(O)2NR 15 R 16 , optionally substituted C1-C8 alkylene, optionally substituted C2-C8 alkenylene, optionally substituted C2-C8 alkynylene, optionally substituted C3-C8 cycloalkylene, optionally substituted 3- to 8-membered heterocyclylene, optionally substituted aryl, and optionally substituted heteroaryl; wherein

[0671] R 15 is empty or a divalent moiety selected from optionally substituted C1-C8 alkylene, optionally substituted C2-C8 alkenylene, optionally substituted C2-C8 alkynylene, optionally substituted C3-C8 cycloalkylene, optionally substituted 3- to 8-membered heterocyclylene, optionally substituted aryl, and optionally substituted heteroaryl;

[0672] R 16 and R 17 independently selected from optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy C1-C8 alkyl, optionally substituted C1-C8 alkylamino C1-C8 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted 3- to 8-membered heterocyclyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted aryl, and optionally substituted heteroaryl; or

[0673] R 15 and R 16 、R 15 and R 17 、R 16 and R 17 Together with the atoms to which they are attached, they form a 3- to 20-membered cycloalkyl or heterocyclyl ring.

[0674] In an embodiment, the (HPK1) ligand comprises a moiety according to Formula 3B:

[0675]

[0676] in

[0677] The "linker" portion of the divalent compound is independently connected to R 1 or R 3 ;

[0678] X is selected from CR2 or N;

[0679] R 1 and R 3 independently selected from the group consisting of space, hydrogen, C(O)R 6 、C(O)OR 6 、C(O)NR 6 R 7 、S(O)R 6 、S(O)2R 6 、S(O)2NR 6 R 7 NR 8 C(O)OR 6 NR 8 C(O)R 6 NR 8 C(O)NR 6 R 7 NR 8 S(O)R 6 NR 8 S(O)2R 6 NR 8 S(O)2NR 6 R 7 , optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxyC1-C8 alkyl, optionally substituted C1-C8 alkylaminoC1-C8 alkyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted C3-C8 cycloalkoxy, optionally substituted 3- to 8-membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; wherein

[0680] R 6 is empty or a divalent moiety selected from optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxyC1-C8 alkyl, optionally substituted C1-C8 alkylaminoC1-C8 alkyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted C3-C8 cycloalkoxy, optionally substituted 3- to 8-membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;

[0681] R 7 and R 8 independently selected from hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy C1-C8 alkyl, optionally substituted C1-C8 alkylamino C1-C8 alkyl, optionally substituted C3-C 10cycloalkyl, optionally substituted 3- to 20-membered heterocyclyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted aryl, and optionally substituted heteroaryl; or

[0682] R 6 and R 7 together with the atoms to which they are attached, form an optionally substituted 3- to 20-membered cycloalkyl or heterocyclyl ring;

[0683] R 2 Independently selected from hydrogen, halogen, oxo, CN, NO2, OR 9 SR 9 NR 9 R 10 、C(O)R 9 、C(O)OR 9 、C(O)NR 9 R 10 、S(O)R 9 、S(O)2R 9 、S(O)2NR 9 R 10 NR 11 C(O)OR 9 NR 11 C(O)R 9 NR 11 C(O)NR 9 R 10 NR 11 S(O)R 9 NR 11 S(O)2R 9 NR 11 S(O)2NR 9 R 10 , optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxyC1-C8 alkyl, optionally substituted C1-C8 alkylaminoC1-C8 alkyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted C3-C8 cycloalkoxy, optionally substituted 3- to 8-membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; wherein

[0684] R 9 、R 10 and R 11 independently selected from hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy C1-C8 alkyl, optionally substituted C1-C8 alkylamino C1-C8 alkyl, optionally substituted C3-C 10cycloalkyl, optionally substituted 3- to 20-membered heterocyclyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted aryl, and optionally substituted heteroaryl; or

[0685] R 9 and R 10 、R 9 and R 11 、R 10 and R 11 together with the atoms to which they are attached, form an optionally substituted 3- to 20-membered cycloalkyl or heterocyclyl ring;

[0686] Each R 4 Independently selected from the group consisting of air, hydrogen, halogen, oxo, CN, NO2, OR 18 SR 18 NR 18 R 19 , OCOR 18 、OCO2R 18 、OCONR 18 R 19 、COR 18 、CO2R 18 、CONR 18 R 19 、SOR 18 、SO2R 18 、SO2NR 18 R 19 NR 20 CO2R 18 NR 20 COR 18 NR 20 C(O)NR 18 R 19 NR 20 SOR 18 NR 20 SO2R 18 NR 7 SO2NR 5 R 6 , optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxyC1-C8 alkyl, optionally substituted C1-C8 alkylaminoC1-C8 alkyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted C3-C8 cycloalkoxy, optionally substituted 4- to 8-membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; wherein

[0687] R 18 、R 19 and R 20independently selected from hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxyC1-C8 alkyl, optionally substituted C1-C8 alkylaminoC1-C8 alkyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted C3-C8 cycloalkoxy, optionally substituted 4- to 8-membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; or

[0688] R 18 and R 19 、R 18 and R 20 together with the atoms to which they are attached, form a 4- to 20-membered heterocyclyl ring; and

[0689] n is independently selected from 0, 1, 2, 3, 4 and 5.

[0690] In an embodiment, the (HPK1) ligand comprises a moiety according to Formula 1:

[0691]

[0692] in

[0693] The "linker" portion of the divalent compound is connected to R 9 ;

[0694] X is selected from O or S;

[0695] Y is selected from O, S, NR 10 ;in

[0696] R 10 independently selected from hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy C1-C8 alkyl, optionally substituted C1-C8 alkylamino C1-C8 alkyl, optionally substituted C3-C 10 cycloalkyl, optionally substituted 3- to 20-membered heterocyclyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted aryl, and optionally substituted heteroaryl;

[0697] R 1 、R 2 、R 3 、R 4 、R 7 and R 8 Selected from hydrogen, halogen, oxo, CN, NO2, OR 11 SR 11 NR 11 R 12 、C(O)R 11 、C(O)OR 11、C(O)NR 11 R 12 、S(O)R 11 、S(O)2R 11 、S(O)2NR 11 R 12 NR 13 C(O)OR 11 NR 13 C(O)R 11 NR 13 C(O)NR 11 R 12 NR 13 S(O)R 11 NR 13 S(O)2R 11 NR 13 S(O)2NR 11 R 12 , optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxyC1-C8 alkyl, optionally substituted C1-C8 alkylaminoC1-C8 alkyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted C3-C8 cycloalkoxy, optionally substituted 3- to 8-membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; wherein

[0698] R 11 、R 12 and R 13 independently selected from hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy C1-C8 alkyl, optionally substituted C1-C8 alkylamino C1-C8 alkyl, optionally substituted C3-C 10 cycloalkyl, optionally substituted 3- to 20-membered heterocyclyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted aryl, and optionally substituted heteroaryl, or

[0699] R 11 and R 12 、R 11 and R 13 、R 12 and R 13 together with the atoms to which they are attached, form an optionally substituted 3- to 20-membered cycloalkyl or heterocyclyl ring;

[0700] R 5 and R 6independently selected from hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxyC1-C8 alkyl, optionally substituted C1-C8 alkylaminoC1-C8 alkyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted C3-C8 cycloalkoxy, optionally substituted 4- to 8-membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;

[0701] R 9 Selected from OR 14 SR 14 NR 14 R 15 、C(O)R 14 、C(O)OR 14 、C(O)NR 14 R 15 、S(O)R 14 、S(O)2R 14 、S(O)2NR 14 R 15 NR 16 C(O)OR 14 NR 16 C(O)R 14 NR 16 C(O)NR 14 R 15 NR 16 S(O)R 14 NR 16 S(O)2R 14 NR 16 S(O)2NR 14 R 15 , optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxyC1-C8 alkyl, optionally substituted C1-C8 alkylaminoC1-C8 alkyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted C3-C8 cycloalkoxy, optionally substituted 3- to 8-membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; wherein

[0702] R 14 is empty or a divalent moiety selected from optionally substituted C1-C8 alkylene, optionally substituted C2-C8 alkenylene, optionally substituted C2-C8 alkynylene, optionally substituted C3-C8 cycloalkylene, optionally substituted 3- to 8-membered heterocyclylene, optionally substituted aryl, and optionally substituted heteroaryl;

[0703] R 15 and R16 independently selected from optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy C1-C8 alkyl, optionally substituted C1-C8 alkylamino C1-C8 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted 3- to 8-membered heterocyclyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted aryl, and optionally substituted heteroaryl; or

[0704] R 14 and R 15 、R 14 and R 16 、R 15 and R 16 Together with the atoms to which they are attached, they form a 3- to 20-membered cycloalkyl or heterocyclyl ring.

[0705] In an embodiment, the (HPK1) ligand comprises a moiety according to Formula 1A:

[0706]

[0707] in,

[0708] The "linker" portion of the divalent compound is attached to Z;

[0709] R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 and R 8 The definition of is the same as that of formula 1;

[0710] R 17 、R 18 、R 19 and R 20 is independently selected at each occurrence from hydrogen, halogen, CN, OH, NH2, optionally substituted C1-C8 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C3-C8 cycloalkyloxy, optionally substituted C1-C8 alkoxyC1-C8 alkyl, optionally substituted C1-C8 alkylaminoC1-C8 alkyl, optionally substituted 3- to 8-membered heterocyclyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxyalkyl, optionally substituted C1-C8 haloalkyl, optionally substituted C1-C8 hydroxyalkyl, optionally substituted C1-C8 alkylamino, and optionally substituted C1-C8 alkylaminoC1-C8 alkyl;

[0711] m, n are independently selected from 0, 1, 2, 3 and 4; and

[0712] W, Q and Z are independently selected at each occurrence from void, CO, CO2, CH2, NH, NH-CO, CO-NH, CH2-NH-CO, CH2-CO-NH, NH-CO-CH2, CO-NH-CH2, CH2-NH-CH2-CO-NH, CH2-NH-CH2-NH-CO, -CO-NH, CO-NH-CH2-NH-CH2, CH2-NH-CH2, CR 21 R 22 、C(O)NR 21 、C(S)NR 21 、O、S、SO、SO2、SO2NR 21 NR 21 NR 21 CO、NR 121 CONR 22 NR 21 C(S), optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxyC1-C8 alkyl, optionally substituted C1-C8 haloalkyl, optionally substituted C1-C8 hydroxyalkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted C3-C8 cycloalkoxy, optionally substituted 3- to 8-membered heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted C3-C 13 Fused cycloalkyl, optionally substituted C3-C 13 Fused heterocyclic group, optionally substituted C3-C 13 Bridged cycloalkyl, optionally substituted C3-C 13 Bridged heterocyclic group, optionally substituted C3-C 13 Spirocycloalkyl, and optionally substituted C3-C 13 spiroheterocyclyl; wherein

[0713] R 21 and R 22 Independently selected from hydrogen, optionally substituted C1-C8 alkyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted C3-C8 cycloalkyloxy, optionally substituted 3- to 8-membered heterocyclyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxyalkyl, optionally substituted C1-C8 haloalkyl, optionally substituted C1-C8 hydroxyalkyl, optionally substituted C1-C8 alkylamino, and optionally substituted C1-C8 alkylaminoC1-C8 alkyl.

[0714] In an embodiment, the (HPK1) ligand comprises a moiety according to Formula 1B:

[0715]

[0716] in

[0717] X, Y, W, Q, R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 、R 8 、R 17 、R 18 、R 19 and R 20 The definition of is the same as that of Formula 1A;

[0718] The "linker" portion of the divalent compound is attached to the terminal N;

[0719] m and n are independently selected from 0, 1, 2, 3 and 4;

[0720] R 23 and R 24 is independently selected at each occurrence from hydrogen, halogen, CN, OH, NH2, optionally substituted C1-C8 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C3-C8 cycloalkyloxy, optionally substituted 3- to 8-membered heterocyclyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxyalkyl, optionally substituted C1-C8 haloalkyl, optionally substituted C1-C8 hydroxyalkyl, optionally substituted C1-C8 alkylamino, and optionally substituted C1-C8 alkylaminoC1-C8 alkyl.

[0721] In an embodiment, the (HPK1) ligand comprises a moiety according to Formula 1C:

[0722]

[0723] in,

[0724] X, Y, W, Q, R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 、R 8 、R 17 、R 18 、R 19 、R 20 and R 23 The definition of is the same as that of Formula 1B;

[0725] The "linker" portion of the divalent compound is attached to Z;

[0726] m and n are independently selected from 0, 1, 2, 3 and 4;

[0727] Z is independently selected from CR 25 or N; and

[0728] R 25 independently selected from the group consisting of space, hydrogen, C(O)R 26 、C(O)OR 26 、C(O)NR 26 R 27 、S(O)R 26 、S(O)2R 26 、S(O)2NR 26 R 27 NR 28 C(O)OR 26 NR 28 C(O)R 26 NR 28 C(O)NR 26 R 27 NR 28 S(O)R 26 NR 28 S(O)2R 26 NR 28 S(O)2NR 26 R 27 , optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxyC1-C8 alkyl, optionally substituted C1-C8 alkylaminoC1-C8 alkyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted C3-C8 cycloalkoxy, optionally substituted 3- to 8-membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; wherein

[0729] R 26 is empty or a divalent moiety selected from optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxyC1-C8 alkyl, optionally substituted C1-C8 alkylaminoC1-C8 alkyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted C3-C8 cycloalkoxy, optionally substituted 3- to 8-membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;

[0730] R 27 and R 28 independently selected from hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy C1-C8 alkyl, optionally substituted C1-C8 alkylamino C1-C8 alkyl, optionally substituted C3-C10 cycloalkyl, optionally substituted 3- to 20-membered heterocyclyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted aryl, and optionally substituted heteroaryl; or

[0731] R 26 and R 27 Together with the atoms to which they are attached, they form an optionally substituted 3- to 20-membered cycloalkyl or heterocyclyl ring.

[0732] In an embodiment, the (HPK1) ligand comprises a moiety according to Formula 2:

[0733]

[0734] in

[0735] The "linker" portion of the divalent compound is connected to R 1 or R 4 ;

[0736] X is selected from CR 5 or N;

[0737] R 1 and R 2 independently selected from the group consisting of space, hydrogen, C(O)R 6 、C(O)OR 6 、C(O)NR 6 R 7 、S(O)R 6 、S(O)2R 6 、S(O)2NR 6 R 7 NR 8 C(O)OR 6 NR 8 C(O)R 6 NR 8 C(O)NR 6 R 7 NR 8 S(O)R 6 NR 8 S(O)2R 6 NR 8 S(O)2NR 6 R 7, optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxyC1-C8 alkyl, optionally substituted C1-C8 alkylaminoC1-C8 alkyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted C3-C8 cycloalkoxy, optionally substituted 3- to 8-membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; wherein

[0738] R 6 is empty or a divalent moiety selected from optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxyC1-C8 alkyl, optionally substituted C1-C8 alkylaminoC1-C8 alkyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted C3-C8 cycloalkoxy, optionally substituted 3- to 8-membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;

[0739] R 7 and R 8 independently selected from hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy C1-C8 alkyl, optionally substituted C1-C8 alkylamino C1-C8 alkyl, optionally substituted C3-C 10 cycloalkyl, optionally substituted 3- to 20-membered heterocyclyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted aryl, and optionally substituted heteroaryl; or

[0740] R 6 and R 7 together with the atoms to which they are attached form an optionally substituted 3- to 20-membered cycloalkyl or heterocyclyl ring; and

[0741] R 3 、R 4 and R 5 Independently selected from hydrogen, halogen, oxo, CN, NO2, OR 9 SR 9 NR 10 R 11 、C(O)R 9 、C(O)OR 9 、C(O)NR 10 R 11 、S(O)R 9 、S(O)2R 9 、S(O)2NR 10 R 11 NR 12 C(O)OR 10NR 9 C(O)R 10 NR 9 C(O)NR 10 R 11 NR 9 S(O)R 10 NR 9 S(O)2R 10 NR 9 S(O)2NR 10 R 11 , optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxy, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted C3-C8 cycloalkoxy, optionally substituted 3- to 8-membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; wherein

[0742] R 9 、R 10 and R 11 independently selected from hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy C1-C8 alkyl, optionally substituted C1-C8 alkylamino C1-C8 alkyl, optionally substituted C3-C 10 cycloalkyl, optionally substituted 3- to 20-membered heterocyclyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted aryl, and optionally substituted heteroaryl, or

[0743] R 9 and R 10 、R 10 and R 11 Together with the atoms to which they are attached, they form an optionally substituted 3- to 20-membered cycloalkyl or heterocyclyl ring.

[0744] In an embodiment, the (HPK1) ligand comprises a moiety according to Formula 2A or Formula 2B:

[0745]

[0746] in

[0747] The "linker" portion of the divalent compound is connected to R 1 ;

[0748] R 1 、R 2 、R 3 and R 5 The definition of is the same as that of formula 2;

[0749] Ar is selected from null, aryl and heteroaryl, each of which is optionally substituted with one or more substituents independently selected from the following substituents: hydrogen, halogen, oxo, CN, NO2, OR 12 SR 12 NR 12 R 13 , OCOR 12 、OCO2R 12 、OCONR 12 R 13 、COR 12 、CO2R 12 、CONR 12 R 13 、SOR 12 、SO2R 12 、SO2NR 12 R 13 NR 14 CO2R 12 NR 14 COR 12 NR 14 C(O)NR 12 R 13 NR 14 SOR 12 NR 14 SO2R 12 NR 14 SO2NR 12 R 13 , optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxyC1-C8 alkyl, optionally substituted C1-C8 alkylaminoC1-C8 alkyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted C3-C8 cycloalkoxy, optionally substituted 4- to 8-membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; wherein

[0750] R 12 、R 13 and R 14 independently selected from hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxyC1-C8 alkyl, optionally substituted C1-C8 alkylaminoC1-C8 alkyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted C3-C8 cycloalkoxy, optionally substituted 4- to 8-membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; or

[0751] R 12 and R 13、R 13 and R 14 Together with the atoms to which they are attached, they form a 3- to 20-membered heterocyclyl ring.

[0752] In an embodiment, the (HPK1) ligand comprises a moiety according to Formula 2C or Formula 2D:

[0753]

[0754] in

[0755] The "linker" portion of the divalent compound is connected to R 1 ;

[0756] R 1 、R 2 、R 3 and R 5 The definition of is the same as that of formula 2;

[0757] R 15 、R 16 、R 17 and R 18 Independently selected from hydrogen, halogen, oxo, CN, NO2, OR 19 SR 19 NR 20 R 21 , OCOR 19 、OCO2R 19 、OCONR 20 R 21 、COR 19 、CO2R 19 、CONR 20 R 21 、SOR 19 、SO2R 19 、SO2NR 20 R 21 NR 19 CO2R 20 NR 19 COR 20 NR 19 C(O)NR 20 R 21 NR 19 SOR 20 NR 19 SO2R 20 NR 19 SO2NR 20 R 21, optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxyC1-C8 alkyl, optionally substituted C1-C8 alkylaminoC1-C8 alkyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted C3-C8 cycloalkoxy, optionally substituted 4- to 8-membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; wherein

[0758] R 19 、R 20 and R 21 independently selected from hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxyC1-C8 alkyl, optionally substituted C1-C8 alkylaminoC1-C8 alkyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted C3-C8 cycloalkoxy, optionally substituted 4- to 8-membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; or

[0759] R 19 and R 20 、R 20 and R 21 together with the atoms to which they are attached, form a 3- to 20-membered heterocyclyl ring; and

[0760] R 15 and R 16 、R 16 and R 17 Together with the atoms to which they are attached, they form an optionally substituted 4- to 20-membered cycloalkyl or heterocyclyl ring.

[0761] In an embodiment, the (HPK1) ligand comprises a moiety according to Formula 2E or Formula 2F:

[0762]

[0763] in

[0764] The "linker" portion of the divalent compound is connected to R 1 ;

[0765] R 1 、R 2 、R 3 、R 5 、R 15 、R 16 、R 17 and R 18 The definition of is the same as that of Formula 2C and Formula 2D.

[0766] R22 Independently selected from hydrogen, halogen, oxo, aryl, CN, NO2, OR 23 SR 23 NR 24 R 25 、C(O)R 23 、C(O)OR 23 、C(O)NR 24 R 25 、S(O)R 23 、S(O)2R 23 、S(O)2NR 24 R 25 NR 24 C(O)OR 23 NR 24 C(O)R 23 NR 23 C(O)NR 24 R 25 NR 24 S(O)R 23 NR 24 S(O)2R 23 NR 23 S(O)2NR 24 R 2 , optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxy, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted C3-C8 cycloalkoxy, optionally substituted 3- to 8-membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; wherein

[0767] R 23 、R 24 and R 25 independently selected from hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy C1-C8 alkyl, optionally substituted C1-C8 alkylamino C1-C8 alkyl, optionally substituted C3-C 10 cycloalkyl, optionally substituted 3- to 20-membered heterocyclyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted aryl, and optionally substituted heteroaryl; or

[0768] R 23 and R 24 、R 23 and R 25 together with the atoms to which they are attached form an optionally substituted 3- to 20-membered cycloalkyl or heterocyclyl ring; and

[0769] R 15 and R 16 、R16 and R 17 Together with the atoms to which they are attached, they form an optionally substituted 4- to 20-membered cycloalkyl or heterocyclyl ring.

[0770] In an embodiment, the (HPK1) ligand comprises a moiety according to Formula 2G or Formula 2H:

[0771]

[0772] in

[0773] The "linker" portion of the divalent compound is connected to R 1 ;

[0774] R 1 、R 2 、R 3 、R 5 、R 15 、R 16 、R 17 and R 18 The definition of is the same as that of Formula 2C and Formula 2D.

[0775] X is CO, CH2 or SO2;

[0776] n is 0 to 1;

[0777] R 26 and R 27 independently selected from hydrogen, halogen, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy C1-C8 alkyl, optionally substituted C1-C8 alkylamino C1-C8 alkyl, optionally substituted C3-C 10 cycloalkyl, optionally substituted 3- to 20-membered heterocyclyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted aryl, and optionally substituted heteroaryl; or

[0778] R 26 and R 27 together with the atoms to which they are attached form an optionally substituted 3- to 20-membered cycloalkyl or heterocyclyl ring; and

[0779] R 15 and R 16 、R 16 and R 17 Together with the atoms to which they are attached, they form an optionally substituted 4- to 20-membered cycloalkyl or heterocyclyl ring.

[0780] In embodiments, the (HPK1) ligand comprises a moiety according to Formula 2K, Formula 2L, Formula 2M, and Formula 2N:

[0781]

[0782] in

[0783] The "linker" portion of the divalent compound is connected to R 9 ;

[0784] R 1 、R 2 、R 3 、R 5 、R 15 、R 16 、R 17 and R 18 The definition of is the same as that of Formula 2C and Formula 2D;

[0785] n and m are independently selected from 1, 2 and 3;

[0786] R 28 、R 29 and R 30 independently selected from hydrogen, halogen, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy C1-C8 alkyl, optionally substituted C1-C8 alkylamino C1-C8 alkyl, optionally substituted C3-C 10 cycloalkyl, optionally substituted 3- to 20-membered heterocyclyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted aryl, and optionally substituted heteroaryl, or

[0787] R 29 and R 30 together with the atoms to which they are attached form an optionally substituted 3- to 20-membered cycloalkyl or heterocyclyl ring; and

[0788] R 15 and R 16 、R 16 and R 17 Together with the atoms to which they are attached, they form an optionally substituted 4- to 20-membered cycloalkyl or heterocyclyl ring.

[0789] In an embodiment, the (HPK1) ligand comprises a moiety according to Formula 2O or Formula 2P:

[0790]

[0791] in

[0792] The "linker" portion of the divalent compound is attached to Z;

[0793] R 1 、R 2 、R 3 、R 5 、R 15 、R 16 、R 17and R 18 The definition of is the same as that of Formula 2C and Formula 2D;

[0794] W, Q and Z are independently selected at each occurrence from void, CO, CO2, CH2, NH, NH-CO, CO-NH, CH2-NH-CO, CH2-CO-NH, NH-CO-CH2, CO-NH-CH2, CH2-NH-CH2-CO-NH, CH2-NH-CH2-NH-CO, -CO-NH, CO-NH-CH2-NH-CH2, CH2-NH-CH2, CR 35 R 36 、C(O)NR 35 、C(S)NR 35 、O、S、SO、SO2、SO2NR 35 NR 35 NR 35 CO、NR 35 CONR 36 NR 35 C(S), optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxyC1-C8 alkyl, optionally substituted C1-C8 haloalkyl, optionally substituted C1-C8 hydroxyalkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted C3-C8 cycloalkoxy, optionally substituted 3- to 8-membered heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted C3-C 13 Fused cycloalkyl, optionally substituted C3-C 13 Fused heterocyclic group, optionally substituted C3-C 13 Bridged cycloalkyl, optionally substituted C3-C 13 Bridged heterocyclic group, optionally substituted C3-C 13 Spirocycloalkyl, and optionally substituted C3-C 13 spiroheterocyclyl, wherein

[0795] R 35 and R 36 independently selected from hydrogen, optionally substituted C1-C8 alkyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted C3-C8 cycloalkoxy, optionally substituted 3- to 8-membered heterocyclyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxyalkyl, optionally substituted C1-C8 haloalkyl, optionally substituted C1-C8 hydroxyalkyl, optionally substituted C1-C8 alkylamino, and optionally substituted C1-C8 alkylaminoC1-C8 alkyl;

[0796] R 31 、R 32、R 33 and R 34 independently selected from hydrogen, halogen, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy C1-C8 alkyl, optionally substituted C1-C8 alkylamino C1-C8 alkyl, optionally substituted C3-C 10 cycloalkyl, optionally substituted 3- to 20-membered heterocyclyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted aryl, and optionally substituted heteroaryl; or

[0797] R 31 and R 32 、R 33 and R 34 together with the atoms to which they are attached, form an optionally substituted 3- to 20-membered cycloalkyl or heterocyclyl ring;

[0798] R 15 and R 16 、R 16 and R 17 together with the atoms to which they are attached form an optionally substituted 4- to 20-membered cycloalkyl or heterocyclyl ring; and

[0799] m and n are independently selected from 0, 1, 2, 3 and 4.

[0800] In an embodiment, the (HPK1) ligand comprises a moiety according to Formula 3:

[0801]

[0802] in

[0803] The "linker" portion of the divalent compound is independently connected to R 1 or R 3 ;

[0804] X is selected from CR 2 or N;

[0805] R 1 and R 3 independently selected from the group consisting of space, hydrogen, C(O)R 6 、C(O)OR 6 、C(O)NR 6 R 7 、S(O)R 6 、S(O)2R 6 、S(O)2NR 6 R 7 NR 8 C(O)OR 6 NR 8 C(O)R 6 NR 8C(O)NR 6 R 7 NR 8 S(O)R 6 NR 8 S(O)2R 6 NR 8 S(O)2NR 6 R 7 , optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxyC1-C8 alkyl, optionally substituted C1-C8 alkylaminoC1-C8 alkyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted C3-C8 cycloalkoxy, optionally substituted 3- to 8-membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; wherein

[0806] R 6 is empty or a divalent moiety selected from optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxyC1-C8 alkyl, optionally substituted C1-C8 alkylaminoC1-C8 alkyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted C3-C8 cycloalkoxy, optionally substituted 3- to 8-membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;

[0807] R 7 and R 8 independently selected from hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy C1-C8 alkyl, optionally substituted C1-C8 alkylamino C1-C8 alkyl, optionally substituted C3-C 10 cycloalkyl, optionally substituted 3- to 20-membered heterocyclyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted aryl, and optionally substituted heteroaryl; or

[0808] R 6 and R 7 together with the atoms to which they are attached, form an optionally substituted 3- to 20-membered cycloalkyl or heterocyclyl ring;

[0809] R 2 Independently selected from hydrogen, halogen, oxo, CN, NO2, OR 9 SR 9 NR 9 R 10 、C(O)R 9 、C(O)OR 9 、C(O)NR 9 R10 、S(O)R 9 、S(O)2R 9 、S(O)2NR 9 R 10 NR 11 C(O)OR 9 NR 11 C(O)R 9 NR 11 C(O)NR 9 R 10 NR 11 S(O)R 9 NR 11 S(O)2R 9 NR 11 S(O)2NR 9 R 10 , optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxyC1-C8 alkyl, optionally substituted C1-C8 alkylaminoC1-C8 alkyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted C3-C8 cycloalkoxy, optionally substituted 3- to 8-membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; wherein

[0810] R 9 、R 10 and R 11 independently selected from hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy C1-C8 alkyl, optionally substituted C1-C8 alkylamino C1-C8 alkyl, optionally substituted C3-C 10 cycloalkyl, optionally substituted 3- to 20-membered heterocyclyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted aryl, and optionally substituted heteroaryl; or

[0811] R 9 and R 10 、R 9 and R 11 、R 10 and R 11 Together with the atoms to which they are attached, they form an optionally substituted 3- to 20-membered cycloalkyl or heterocyclyl ring.

[0812] In an embodiment, the (HPK1) ligand comprises a moiety according to Formula 3A:

[0813]

[0814] in

[0815] The "linker" portion of the divalent compound is independently connected to R 1 or R 3 ;

[0816] X is selected from CR 2 or N;

[0817] R 1 and R 2 The definition of is the same as that of formula 3;

[0818] Ar is selected from the group consisting of null, aryl and heteroaryl, each of which is replaced by R 3 substituted and optionally substituted by one or more substituents independently selected from the group consisting of hydrogen, halogen, oxo, CN, NO2, OR 12 SR 12 NR 12 R 13 , OCOR 12 、OCO2R 12 、OCONR 12 R 13 、COR 12 、CO2R 12 、CONR 12 R 13 、SOR 12 、SO2R 12 、SO2NR 12 R 13 NR 14 CO2R 12 NR 14 COR 12 NR 14 C(O)NR 12 R 13 NR 14 SOR 12 NR 14 SO2R 12 NR 14 SO2NR 12 R 13 , optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxyC1-C8 alkyl, optionally substituted C1-C8 alkylaminoC1-C8 alkyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted C3-C8 cycloalkoxy, optionally substituted 4- to 8-membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; wherein

[0819] R 12 、R 13 and R 14independently selected from hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxyC1-C8 alkyl, optionally substituted C1-C8 alkylaminoC1-C8 alkyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted C3-C8 cycloalkoxy, optionally substituted 4- to 8-membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; or

[0820] R 12 and R 13 、R 12 and R 14 together with the atoms to which they are attached, form a 4- to 20-membered heterocyclyl ring;

[0821] R 3 Select from empty, OR 15 SR 15 NR 15 R 16 、OC(O)R 15 、OC(O)OR 15 、OCONR 15 R 16 、C(O)R 15 、C(O)OR 15 、CONR 15 R 16 、S(O)R 15 、S(O)2R 15 、SO2NR 15 R 16 NR 17 C(O)OR 15 NR 17 C(O)R 15 NR 17 C(O)NR 15 R 16 NR 14 S(O)R 15 NR 17 S(O)2R 15 NR 17 S(O)2NR 15 R 16 , optionally substituted C1-C8 alkylene, optionally substituted C2-C8 alkenylene, optionally substituted C2-C8 alkynylene, optionally substituted C3-C8 cycloalkylene, optionally substituted 3- to 8-membered heterocyclylene, optionally substituted aryl, and optionally substituted heteroaryl; wherein

[0822] R 15is empty or a divalent moiety selected from optionally substituted C1-C8 alkylene, optionally substituted C2-C8 alkenylene, optionally substituted C2-C8 alkynylene, optionally substituted C3-C8 cycloalkylene, optionally substituted 3- to 8-membered heterocyclylene, optionally substituted aryl, and optionally substituted heteroaryl;

[0823] R 16 and R 17 independently selected from optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy C1-C8 alkyl, optionally substituted C1-C8 alkylamino C1-C8 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted 3- to 8-membered heterocyclyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted aryl, and optionally substituted heteroaryl; or

[0824] R 15 and R 16 、R 15 and R 17 、R 16 and R 17 Together with the atoms to which they are attached, they form a 3- to 20-membered cycloalkyl or heterocyclyl ring.

[0825] In an embodiment, the (HPK1) ligand comprises a moiety according to Formula 3B:

[0826]

[0827] in

[0828] The "linker" portion of the divalent compound is independently connected to R 1 or R 3 ;

[0829] X is selected from CR 2 or N;

[0830] R 1 、R 2 and R 3 The definition of is the same as that of formula 3;

[0831] Each R 4 Independently selected from the group consisting of air, hydrogen, halogen, oxo, CN, NO2, OR 18 SR 18 NR 18 R 19 , OCOR 18 、OCO2R 18 、OCONR 18 R 19 、COR 18 、CO2R 18 、CONR18 R 19 、SOR 18 、SO2R 18 、SO2NR 18 R 19 NR 20 CO2R 18 NR 20 COR 18 NR 20 C(O)NR 18 R 19 NR 20 SOR 18 NR 20 SO2R 18 NR 7 SO2NR 5 R 6 , optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxyC1-C8 alkyl, optionally substituted C1-C8 alkylaminoC1-C8 alkyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted C3-C8 cycloalkoxy, optionally substituted 4- to 8-membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; wherein

[0832] R 18 、R 19 and R 20 independently selected from hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxyC1-C8 alkyl, optionally substituted C1-C8 alkylaminoC1-C8 alkyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted C3-C8 cycloalkoxy, optionally substituted 4- to 8-membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; or

[0833] R 18 and R 19 、R 18 and R 20 together with the atoms to which they are attached, form a 4- to 20-membered heterocyclyl ring; and

[0834] n is independently selected from 0, 1, 2, 3, 4 and 5.

[0835] In embodiments, the (HPK1) ligand comprises a moiety according to Formula 3C, Formula 3D, and Formula 3E:

[0836]

[0837] in

[0838] The "linker" portion of the divalent compound is independently connected to R 1 or R 3 ;

[0839] X is selected from CR 2 or N;

[0840] R 1 、R 2 、R 3 and R 4 The definition of is the same as that of Formula 3B;

[0841] R 5 independently selected at each occurrence from hydrogen, C(O)R 21 、C(O)OR 21 、C(O)NR 21 R 22 、S(O)R 21 、S(O)2R 21 、S(O)2NR 21 R 22 NR 23 C(O)OR 21 NR 23 C(O)R 21 NR 23 C(O)NR 21 R 22 NR 23 S(O)R 21 NR 23 S(O)2R 21 NR 23 S(O)2NR 21 R 22 , optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxyC1-C8 alkyl, optionally substituted C1-C8 alkylaminoC1-C8 alkyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted C3-C8 cycloalkoxy, optionally substituted 3- to 8-membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; wherein

[0842] R 21 、R 22 and R 23independently selected from hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxyC1-C8 alkyl, optionally substituted C1-C8 alkylaminoC1-C8 alkyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted C3-C8 cycloalkoxy, optionally substituted 4- to 8-membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; or

[0843] R 21 and R 22 、R 21 and R 23 together with the atoms to which they are attached, form a 3- to 20-membered heterocyclyl ring; and

[0844] n is independently selected from 0, 1, 2, 3, 4 and 5.

[0845] In an embodiment, the (HPK1) ligand comprises a moiety according to Formula 3F or Formula 3G:

[0846]

[0847] in

[0848] The "linker" portion of the divalent compound is independently connected to R 3 or independently connected to an R 1 ;

[0849] X is selected from CR 2 or N;

[0850] R 1 、R 2 、R 3 and R 4 The definition of is the same as that of Formula 3B.

[0851] Ar is selected from the group consisting of null, aryl and heteroaryl, each of which is replaced by R 1 replace;

[0852] n and m are independently selected from 0, 1, 2, 3, 4 and 5.

[0853] In an embodiment, the (HPK1) ligand comprises a moiety according to Formula 3H or Formula 3K:

[0854]

[0855] in

[0856] The "linker" portion of the divalent compound is independently connected to R 1 or R 3 ;

[0857] X is selected from CR 2 or N;

[0858] R 1 、R 2 、R 3 、R 4 and R 5 The definition of is the same as that of Formula 3C, Formula 3D, and Formula 3E;

[0859] Ar is selected from the group consisting of null, aryl and heteroaryl, each of which is replaced by R 1 replace;

[0860] n and m are independently selected from 0, 1, 2, 3, 4 and 5.

[0861] In an embodiment, the (HPK1) ligand comprises a moiety according to Formula 3L:

[0862]

[0863] in

[0864] The "linker" portion of the divalent compound is independently connected to R 1 or R 3 ;

[0865] X is selected from CR 2 or N;

[0866] R 1 、R 2 、R 3 and R 4 The definition of is the same as that of Formula 3B;

[0867] Ar is selected from the group consisting of null, aryl and heteroaryl;

[0868] n is independently selected from 0, 1, 2, 3, 4 and 5;

[0869] Y, Z are independently selected from the group consisting of air, CO, CO2, CH2, CR 24 R 25 、C(O)NR 24 、C(S)NR 24 、O、S、SO、SO2、SO2NR 24 NR 24 NR 24 CO、NR 24 CONR 24 NR 24C(S), optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxyC1-C8 alkyl, optionally substituted C1-C8 haloalkyl, optionally substituted C1-C8 hydroxyalkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted C3-C8 cycloalkoxy, optionally substituted 3- to 8-membered heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted C3-C 13 Fused cycloalkyl, optionally substituted C3-C 13 Fused heterocyclic group, optionally substituted C3-C 13 Bridged cycloalkyl, optionally substituted C3-C 13 Bridged heterocyclic group, optionally substituted C3-C 13 Spirocycloalkyl, and optionally substituted C3-C 13 spiroheterocyclyl; wherein

[0870] R 24 and R 25 independently selected from hydrogen, optionally substituted C1-C8 alkyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted C3-C8 cycloalkoxy, optionally substituted 3- to 8-membered heterocyclyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxyalkyl, optionally substituted C1-C8 haloalkyl, optionally substituted C1-C8 hydroxyalkyl, optionally substituted C1-C8 alkylamino, and optionally substituted C1-C8 alkylaminoC1-C8 alkyl;

[0871] W is independently selected at each occurrence from the group consisting of void, CO, CH2, (CH2) m CR 26 R 27 、(CR 26 R 27 ) m , SO, SO2;

[0872] in

[0873] R 26 and R 27 independently selected from hydrogen, optionally substituted C1-C8 alkyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted C3-C8 cycloalkoxy, optionally substituted 3- to 8-membered heterocyclyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxyalkyl, optionally substituted C1-C8 haloalkyl, optionally substituted C1-C8 hydroxyalkyl, optionally substituted C1-C8 alkylamino, and optionally substituted C1-C8 alkylaminoC1-C8 alkyl;

[0874] and

[0875] m=0-5.

[0876] In an embodiment, the (HPK1) ligand comprises a moiety according to Formula 3M:

[0877]

[0878] in

[0879] The "linker" portion of the divalent compound is independently connected to R 1 or R 3 ;

[0880] X is selected from CR 2 or N;

[0881] W.R. 1 、R 2 、R 3 and R 4 The definition of is the same as that of formula 3L;

[0882] n is independently selected from 0, 1, 2, 3, 4 and 5.

[0883] In an embodiment, the (HPK1) ligand comprises a moiety according to Formula 4:

[0884]

[0885] in

[0886] The "linker" portion of the divalent compound is connected to R 3 ;

[0887] X is selected from CR 2 or N;

[0888] Y is selected from CR 7 or N;

[0889] Each R 1 Independently selected from the group consisting of air, hydrogen, halogen, oxo, CN, NO2, OR 8 SR 8 NR 8 R 9 , OCOR 8 、OCO2R 8 、OCONR 8 R 9 、COR 8 、CO2R 8 、CONR 8 R 9 、SOR 8 、SO2R 8 、SO2NR 8 R 9 NR10 CO2R 8 NR 10 COR 8 NR 10 C(O)NR 8 R 9 NR 10 SOR 8 NR 10 SO2R 8 NR 10 SO2NR 8 R 9 , optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxyC1-C8 alkyl, optionally substituted C1-C8 alkylaminoC1-C8 alkyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted C3-C8 cycloalkoxy, optionally substituted 4- to 8-membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; wherein

[0890] R 8 、R 9 and R 10 independently selected from hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxyC1-C8 alkyl, optionally substituted C1-C8 alkylaminoC1-C8 alkyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted C3-C8 cycloalkoxy, optionally substituted 4- to 8-membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; or

[0891] R 8 and R 9 、R 8 and R 10 together with the atoms to which they are attached, form a 4- to 20-membered heterocyclyl ring; and

[0892] n is independently selected from 0, 1, 2, 3, 4 and 5;

[0893] R 2 and R 7 Independently selected from hydrogen, halogen, oxo, CN, NO2, OR 11 SR 11 NR 11 R 12 、C(O)R 11 、C(O)OR 11 、C(O)NR 11 R 12 、S(O)R 11、S(O)2R 11 、S(O)2NR 11 R 12 NR 13 C(O)OR 10 NR 13 C(O)R 11 NR 13 C(O)NR 11 R 12 NR 13 S(O)R 11 NR 13 S(O)2R 11 NR 13 S(O)2NR 11 R 12 , optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxyC1-C8 alkyl, optionally substituted C1-C8 alkylaminoC1-C8 alkyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted C3-C8 cycloalkoxy, optionally substituted 3- to 8-membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; wherein

[0894] R 11 、R 12 and R 13 independently selected from hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy C1-C8 alkyl, optionally substituted C1-C8 alkylamino C1-C8 alkyl, optionally substituted C3-C 10 cycloalkyl, optionally substituted 3- to 20-membered heterocyclyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted aryl, and optionally substituted heteroaryl; or

[0895] R 11 and R 12 、R 11 and R 13 、R 12 and R 13 together with the atoms to which they are attached, form an optionally substituted 3- to 20-membered cycloalkyl or heterocyclyl ring;

[0896] R 3 Selected from space, hydrogen, C(O)R 14 、C(O)OR 14 、C(O)NR 14 R 15 、S(O)R 14 、S(O)2R 14 、S(O)2NR 14 R15 NR 16 C(O)OR 14 NR 16 C(O)R 14 NR 16 C(O)NR 14 R 15 NR 16 S(O)R 14 NR 16 S(O)2R 14 NR 16 S(O)2NR 14 R 15 , optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxyC1-C8 alkyl, optionally substituted C1-C8 alkylaminoC1-C8 alkyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted C3-C8 cycloalkoxy, optionally substituted 3- to 8-membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; wherein

[0897] R 14 is empty or a divalent moiety selected from optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxyC1-C8 alkyl, optionally substituted C1-C8 alkylaminoC1-C8 alkyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted C3-C8 cycloalkoxy, optionally substituted 3- to 8-membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;

[0898] R 15 and R 16 independently selected from hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy C1-C8 alkyl, optionally substituted C1-C8 alkylamino C1-C8 alkyl, optionally substituted C3-C 10 cycloalkyl, optionally substituted 3- to 20-membered heterocyclyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted aryl, and optionally substituted heteroaryl; or

[0899] R 14 and R 15 together with the atoms to which they are attached, form an optionally substituted 3- to 20-membered cycloalkyl or heterocyclyl ring;

[0900] R 4 、R 5 and R 6Independently selected from hydrogen, halogen, oxo, CN, NO2, OR 17 SR 17 NR 18 R 19 , OCOR 17 、OCO2R 17 、OCONR 18 R 19 、COR 17 、CO2R 17 、CONR 18 R 19 、SOR 17 、SO2R 17 、SO2NR 18 R 19 NR 17 CO2R 18 NR 17 COR 18 NR 17 C(O)NR 18 R 19 NR 17 SOR 18 NR 17 SO2R 18 NR 17 SO2NR 18 R 19 , optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxyC1-C8 alkyl, optionally substituted C1-C8 alkylaminoC1-C8 alkyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted C3-C8 cycloalkoxy, optionally substituted 4- to 8-membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; wherein

[0901] R 17 、R 18 and R 19 independently selected from hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxyC1-C8 alkyl, optionally substituted C1-C8 alkylaminoC1-C8 alkyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted C3-C8 cycloalkoxy, optionally substituted 4- to 8-membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; or

[0902] R 17 and R 18 、R 18 and R 19Together with the atoms to which they are attached, they form a 3- to 20-membered heterocyclyl ring.

[0903] In an embodiment, the (HPK1) ligand comprises a moiety according to Formula 4A:

[0904]

[0905] in

[0906] The "linker" portion of the divalent compound is connected to R 3 ;

[0907] X is selected from CR 2 or N;

[0908] Y is selected from CR 7 or N;

[0909] R 1 、R 2 、R 3 、R 4 、R 5 、R 6 and R 7 The definition of is the same as that of Equation 4.

[0910] In an embodiment, the (HPK1) ligand comprises a moiety according to Formula 4B:

[0911]

[0912] in

[0913] The "linker" portion of the divalent compound is connected to R 3 ;

[0914] X is selected from CR 2 or N;

[0915] Y is selected from CR 7 or N; and

[0916] R 2 、R 3 、R 4 、R 5 and R 7 The definition of is the same as that of Equation 4.

[0917] In an embodiment, the (HPK1) ligand comprises a moiety according to Formula 5:

[0918]

[0919] in

[0920] The "linker" portion of the divalent compound is independently connected to R 3 or R7 ;

[0921] X is selected from CR 2 or N;

[0922] Each R 1 Independently selected from the group consisting of air, hydrogen, halogen, oxo, CN, NO2, OR 8 SR 8 NR 8 R 9 , OCOR 8 、OCO2R 8 、OCONR 8 R 9 、COR 8 、CO2R 8 、CONR 8 R 9 、SOR 8 、SO2R 8 、SO2NR 8 R 9 NR 10 CO2R 8 NR 10 COR 8 NR 10 C(O)NR 8 R 9 NR 10 SOR 8 NR 10 SO2R 8 NR 10 SO2NR 8 R 9 , optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxyC1-C8 alkyl, optionally substituted C1-C8 alkylaminoC1-C8 alkyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted C3-C8 cycloalkoxy, optionally substituted 4- to 8-membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; wherein

[0923] R 8 、R 9 and R 10independently selected from hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxyC1-C8 alkyl, optionally substituted C1-C8 alkylaminoC1-C8 alkyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted C3-C8 cycloalkoxy, optionally substituted 4- to 8-membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; or

[0924] R 8 and R 9 、R 8 and R 10 together with the atoms to which they are attached, form a 4- to 20-membered heterocyclyl ring; and

[0925] n is independently selected from 0, 1, 2, 3, 4 and 5;

[0926] R 2 Selected from hydrogen, halogen, oxo, CN, NO2, OR 11 SR 11 NR 11 R 12 、C(O)R 11 、C(O)OR 11 、C(O)NR 11 R 12 、S(O)R 11 、S(O)2R 11 、S(O)2NR 11 R 12 NR 13 C(O)OR 10 NR 13 C(O)R 11 NR 13 C(O)NR 11 R 12 NR 13 S(O)R 11 NR 13 S(O)2R 11 NR 13 S(O)2NR 11 R 12 , optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxyC1-C8 alkyl, optionally substituted C1-C8 alkylaminoC1-C8 alkyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted C3-C8 cycloalkoxy, optionally substituted 3- to 8-membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; wherein

[0927] R 11 、R 12 and R 13 independently selected from hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy C1-C8 alkyl, optionally substituted C1-C8 alkylamino C1-C8 alkyl, optionally substituted C3-C 10 cycloalkyl, optionally substituted 3- to 20-membered heterocyclyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted aryl, and optionally substituted heteroaryl; or

[0928] R 11 and R 12 、R 11 and R 13 、R 12 and R 13 together with the atoms to which they are attached, form an optionally substituted 3- to 20-membered cycloalkyl or heterocyclyl ring;

[0929] R 3 and R 7 independently selected from the group consisting of space, hydrogen, C(O)R 14 、C(O)OR 14 、C(O)NR 14 R 15 、S(O)R 14 、S(O)2R 14 、S(O)2NR 14 R 15 NR 16 C(O)OR 14 NR 16 C(O)R 14 NR 16 C(O)NR 14 R 15 NR 16 S(O)R 14 NR 16 S(O)2R 14 NR 16 S(O)2NR 14 R 15 , optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxyC1-C8 alkyl, optionally substituted C1-C8 alkylaminoC1-C8 alkyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted C3-C8 cycloalkoxy, optionally substituted 3- to 8-membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; wherein

[0930] R 14is empty or a divalent moiety selected from optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxyC1-C8 alkyl, optionally substituted C1-C8 alkylaminoC1-C8 alkyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted C3-C8 cycloalkoxy, optionally substituted 3- to 8-membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;

[0931] R 15 and R 16 independently selected from hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy C1-C8 alkyl, optionally substituted C1-C8 alkylamino C1-C8 alkyl, optionally substituted C3-C 10 cycloalkyl, optionally substituted 3- to 20-membered heterocyclyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted aryl, and optionally substituted heteroaryl; or

[0932] R 14 and R 15 together with the atoms to which they are attached, form an optionally substituted 3- to 20-membered cycloalkyl or heterocyclyl ring;

[0933] R 4 、R 5 and R 6 Independently selected from hydrogen, halogen, oxo, CN, NO2, OR 17 SR 17 NR 18 R 19 , OCOR 17 、OCO2R 17 、OCONR 18 R 19 、COR 17 、CO2R 17 、CONR 18 R 19 、SOR 17 、SO2R 17 、SO2NR 18 R 19 NR 17 CO2R 18 NR 17 COR 18 NR 17 C(O)NR 18 R 19 NR 17 SOR 18 NR 17 SO2R 18NR 17 SO2NR 18 R 19 , optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxyC1-C8 alkyl, optionally substituted C1-C8 alkylaminoC1-C8 alkyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted C3-C8 cycloalkoxy, optionally substituted 4- to 8-membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; wherein

[0934] R 17 、R 18 and R 19 independently selected from hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxyC1-C8 alkyl, optionally substituted C1-C8 alkylaminoC1-C8 alkyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted C3-C8 cycloalkoxy, optionally substituted 4- to 8-membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; or

[0935] R 17 and R 18 、R 18 and R 19 Together with the atoms to which they are attached, they form a 3- to 20-membered heterocyclyl ring.

[0936] In an embodiment, the (HPK1) ligand comprises a moiety according to Formula 6:

[0937]

[0938] in

[0939] The "linker" portion of the divalent compound is independently connected to R 3 or R 8 ;

[0940] X is selected from CR 2 or N;

[0941] Y is selected from CR 6 or N;

[0942] Z is selected from CR 7 or N or S;

[0943] Each R 1 Independently selected from the group consisting of air, hydrogen, halogen, oxo, CN, NO2, OR 9 SR 9 NR 9R 10 , OCOR 9 、OCO2R 9 、OCONR 9 R 10 、COR 9 、CO2R 9 、CONR 9 R 10 、SOR 9 、SO2R 9 、SO2NR 9 R 10 NR 11 CO2R 9 NR 11 COR 9 NR 11 C(O)NR 9 R 10 NR 11 SOR 9 NR 11 SO2R 9 NR 11 SO2NR 9 R 10 , optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxyC1-C8 alkyl, optionally substituted C1-C8 alkylaminoC1-C8 alkyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted C3-C8 cycloalkoxy, optionally substituted 4- to 8-membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; wherein

[0944] R 9 、R 10 and R 11 independently selected from hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxyC1-C8 alkyl, optionally substituted C1-C8 alkylaminoC1-C8 alkyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted C3-C8 cycloalkoxy, optionally substituted 4- to 8-membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; or

[0945] R 9 and R 10 、R 9 and R 11 together with the atoms to which they are attached, form a 4- to 20-membered heterocyclyl ring; and

[0946] n is independently selected from 0, 1, 2, 3, 4 and 5;

[0947] R 2 、R 6 and R 7 Independently selected from hydrogen, halogen, oxo, CN, NO2, OR 12 SR 12 NR 12 R 13 、C(O)R 12 、C(O)OR 12 、C(O)NR 12 R 13 、S(O)R 12 、S(O)2R 12 、S(O)2NR 12 R 13 NR 14 C(O)OR 11 NR 14 C(O)R 12 NR 14 C(O)NR 12 R 13 NR 14 S(O)R 12 NR 14 S(O)2R 12 NR 14 S(O)2NR 12 R 13 , optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxyC1-C8 alkyl, optionally substituted C1-C8 alkylaminoC1-C8 alkyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted C3-C8 cycloalkoxy, optionally substituted 3- to 8-membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; wherein

[0948] R 12 、R 13 and R 14 independently selected from hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy C1-C8 alkyl, optionally substituted C1-C8 alkylamino C1-C8 alkyl, optionally substituted C3-C 10 cycloalkyl, optionally substituted 3- to 20-membered heterocyclyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted aryl, and optionally substituted heteroaryl; or

[0949] R 12 and R 13 、R 12 and R 14 、R13 and R 14 together with the atoms to which they are attached, form an optionally substituted 3- to 20-membered cycloalkyl or heterocyclyl ring;

[0950] R 3 and R 8 independently selected from the group consisting of space, hydrogen, C(O)R 15 、C(O)OR 15 、C(O)NR 15 R 16 、S(O)R 15 、S(O)2R 15 、S(O)2NR 15 R 16 NR 17 C(O)OR 15 NR 16 C(O)R 15 NR 17 C(O)NR 15 R 16 NR 17 S(O)R 15 NR 17 S(O)2R 15 NR 17 S(O)2NR 15 R 16 , optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxyC1-C8 alkyl, optionally substituted C1-C8 alkylaminoC1-C8 alkyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted C3-C8 cycloalkoxy, optionally substituted 3- to 8-membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; wherein

[0951] R 15 is empty or a divalent moiety selected from optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxyC1-C8 alkyl, optionally substituted C1-C8 alkylaminoC1-C8 alkyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted C3-C8 cycloalkoxy, optionally substituted 3- to 8-membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;

[0952] R 16 and R 17independently selected from hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy C1-C8 alkyl, optionally substituted C1-C8 alkylamino C1-C8 alkyl, optionally substituted C3-C 10 cycloalkyl, optionally substituted 3- to 20-membered heterocyclyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted aryl, and optionally substituted heteroaryl; or

[0953] R 15 and R 16 together with the atoms to which they are attached, form an optionally substituted 3- to 20-membered cycloalkyl or heterocyclyl ring;

[0954] R 4 and R 5 Independently selected from hydrogen, halogen, oxo, CN, NO2, OR 18 SR 18 NR 19 R 20 , OCOR 18 、OCO2R 18 、OCONR 19 R 20 、COR 18 、CO2R 18 、CONR 19 R 20 、SOR 18 、SO2R 18 、SO2NR 19 R 20 NR 18 CO2R 19 NR 18 COR 19 NR 18 C(O)NR 19 R 20 NR 18 SOR 19 NR 18 SO2R 19 NR 19 SO2NR 19 R 20 , optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxyC1-C8 alkyl, optionally substituted C1-C8 alkylaminoC1-C8 alkyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted C3-C8 cycloalkoxy, optionally substituted 4- to 8-membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; wherein

[0955] R18 、R 19 and R 20 independently selected from hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxyC1-C8 alkyl, optionally substituted C1-C8 alkylaminoC1-C8 alkyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted C3-C8 cycloalkoxy, optionally substituted 4- to 8-membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; or

[0956] R 18 and R 19 、R 19 and R 20 Together with the atoms to which they are attached, they form a 3- to 20-membered heterocyclyl ring.

[0957] In an embodiment, the (HPK1) ligand comprises a moiety according to Formula 7:

[0958]

[0959] in

[0960] The "linker" portion of the divalent compound is independently connected to R 2 or R 5 ;

[0961] X is selected from CR 3 or N;

[0962] Each R 1 and R 4 Independently selected from the group consisting of air, hydrogen, halogen, oxo, CN, NO2, OR 6 SR 6 NR 6 R 7 , OCOR 6 、OCO2R 6 、OCONR 6 R 7 、COR 6 、CO2R 6 、CONR 6 R 7 、SOR 6 、SO2R 6 、SO2NR 6 R 7 NR 8 CO2R 6 NR 8 COR 6 NR 8 C(O)NR 6R 7 NR 8 SOR 6 NR 8 SO2R 6 NR 8 SO2NR 6 R 7 , optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxyC1-C8 alkyl, optionally substituted C1-C8 alkylaminoC1-C8 alkyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted C3-C8 cycloalkoxy, optionally substituted 4- to 8-membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; wherein

[0963] R 6 、R 7 and R 8 independently selected from hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxyC1-C8 alkyl, optionally substituted C1-C8 alkylaminoC1-C8 alkyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted C3-C8 cycloalkoxy, optionally substituted 4- to 8-membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; or

[0964] R 6 and R 7 、R 6 and R 8 together with the atoms to which they are attached, form a 4- to 20-membered heterocyclyl ring; and

[0965] n is independently selected from 0, 1, 2, 3, 4 and 5;

[0966] R 2 and R 5 independently selected from the group consisting of space, hydrogen, C(O)R 12 、C(O)OR 12 、C(O)NR 12 R 13 、S(O)R 12 、S(O)2R 12 、S(O)2NR 12 R 13 NR 14 C(O)OR 12 NR 13 C(O)R 12 NR 14 C(O)NR 12 R13 NR 14 S(O)R 12 NR 14 S(O)2R 12 NR 14 S(O)2NR 12 R 13 , optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxyC1-C8 alkyl, optionally substituted C1-C8 alkylaminoC1-C8 alkyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted C3-C8 cycloalkoxy, optionally substituted 3- to 8-membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; wherein

[0967] R 12 is empty or a divalent moiety selected from optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxyC1-C8 alkyl, optionally substituted C1-C8 alkylaminoC1-C8 alkyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted C3-C8 cycloalkoxy, optionally substituted 3- to 8-membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;

[0968] R 13 and R 14 independently selected from hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy C1-C8 alkyl, optionally substituted C1-C8 alkylamino C1-C8 alkyl, optionally substituted C3-C 10 cycloalkyl, optionally substituted 3- to 20-membered heterocyclyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted aryl, and optionally substituted heteroaryl; or

[0969] R 12 and R 13 together with the atoms to which they are attached, form an optionally substituted 3- to 20-membered cycloalkyl or heterocyclyl ring;

[0970] R 3 Selected from hydrogen, halogen, oxo, CN, NO2, OR 14 SR 14 NR 14 R 15 、C(O)R 14 、C(O)OR 14 、C(O)NR 14 R 15 、S(O)R14 、S(O)2R 14 、S(O)2NR 14 R 15 NR 16 C(O)OR 14 NR 16 C(O)R 14 NR 16 C(O)NR 14 R 15 NR 16 S(O)R 14 NR 16 S(O)2R 14 NR 16 S(O)2NR 14 R 15 , optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxyC1-C8 alkyl, optionally substituted C1-C8 alkylaminoC1-C8 alkyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted C3-C8 cycloalkoxy, optionally substituted 3- to 8-membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; wherein

[0971] R 14 、R 15 and R 16 independently selected from hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy C1-C8 alkyl, optionally substituted C1-C8 alkylamino C1-C8 alkyl, optionally substituted C3-C 10 cycloalkyl, optionally substituted 3- to 20-membered heterocyclyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted aryl, and optionally substituted heteroaryl; or

[0972] R 14 and R 15 、R 14 and R 16 、R 15 and R 16 Together with the atoms to which they are attached, they form an optionally substituted 3- to 20-membered cycloalkyl or heterocyclyl ring.

[0973] In an embodiment, the (HPK1) ligand comprises a moiety according to Formula 7A:

[0974]

[0975] in

[0976] The "linker" portion of the divalent compound is connected to R2 or R 5 ;

[0977] X is selected from CR 3 or N; and

[0978] R 1 、R 2 、R 3 、R 4 and R 5 The definition of is the same as that of Equation 7.

[0979] In an embodiment, the (HPK1) ligand comprises a moiety according to Formula 8:

[0980]

[0981] in

[0982] The "linker" portion of the divalent compound is connected to R 2 or X;

[0983] X is C 3-12 Cycloalkyl, 3- to 14-membered heterocyclic group, C 6-14 Aryl or 5- to 14-membered heteroaryl, wherein the C in X 3-12 Cycloalkyl, 3- to 14-membered heterocyclic group, C 6-14 Aryl or 5- to 14-membered heteroaryl are each optionally independently selected from R 5 substituted with 1, 2, 3, 4 or 5 substituents;

[0984] R 1 selected from hydrogen, halogen, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy C1-C8 alkyl, optionally substituted C1-C8 alkylamino C1-C8 alkyl, optionally substituted C3-C 10 cycloalkyl, optionally substituted 3- to 20-membered heterocyclyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted aryl, and optionally substituted heteroaryl;

[0985] R 2 Selected from space, hydrogen, C(O)R 7 、C(O)OR 7 、C(O)NR 7 R 8 、S(O)R 7 、S(O)2R 7 、S(O)2NR 7 R 8 NR 9 C(O)OR 7 NR 8 C(O)R 7 NR9 C(O)NR 7 R 8 NR 9 S(O)R 7 NR 9 S(O)2R 7 NR 9 S(O)2NR 7 R 8 , optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxyC1-C8 alkyl, optionally substituted C1-C8 alkylaminoC1-C8 alkyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted C3-C8 cycloalkoxy, optionally substituted 3- to 8-membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; wherein

[0986] R 7 is empty or a divalent moiety selected from optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxyC1-C8 alkyl, optionally substituted C1-C8 alkylaminoC1-C8 alkyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted C3-C8 cycloalkoxy, optionally substituted 3- to 8-membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;

[0987] R 8 and R 9 independently selected from hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy C1-C8 alkyl, optionally substituted C1-C8 alkylamino C1-C8 alkyl, optionally substituted C3-C 10 cycloalkyl, optionally substituted 3- to 20-membered heterocyclyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted aryl, and optionally substituted heteroaryl; or

[0988] R 7 and R 8 together with the atoms to which they are attached, form an optionally substituted 3- to 20-membered cycloalkyl or heterocyclyl ring;

[0989] R 3 、R 4 and R 5 Independently selected from the group consisting of air, hydrogen, halogen, oxo, CN, NO2, OR 10 SR 10 NR 10 R 11 , OCOR 10、OCO2R 10 、OCONR 10 R 11 、COR 10 、CO2R 10 、CONR 10 R 11 、SOR 10 、SO2R 10 、SO2NR 10 R 11 NR 12 CO2R 10 NR 12 COR 10 NR 12 C(O)NR 10 R 11 NR 12 SOR 10 NR 12 SO2R 10 NR 12 SO2NR 10 R 11 , optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxyC1-C8 alkyl, optionally substituted C1-C8 alkylaminoC1-C8 alkyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted C3-C8 cycloalkoxy, optionally substituted 4- to 8-membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; wherein

[0990] R 10 、R 11 and R 12 independently selected from hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxyC1-C8 alkyl, optionally substituted C1-C8 alkylaminoC1-C8 alkyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted C3-C8 cycloalkoxy, optionally substituted 4- to 8-membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; or

[0991] R 10 and R 11 、R 10 and R 12 Together with the atoms to which they are attached, they form a 4- to 20-membered heterocyclyl ring.

[0992] In an embodiment, the (HPK1) ligand comprises a moiety according to Formula 8A:

[0993]

[0994] in

[0995] The "linker" portion of the divalent compound is connected to R 2 or X;

[0996] X, R 1 、R 2 、R 3 、R 4 and R 5 The definition of is the same as that of formula 8;

[0997] Ar is selected from the group consisting of null, aryl and heteroaryl, each of which is replaced by R 2 substituted and optionally substituted by one or more substituents independently selected from the group consisting of hydrogen, halogen, oxo, CN, NO2, OR 13 SR 13 NR 13 R 14 , OCOR 13 、OCO2R 13 、OCONR 13 R 14 、COR 13 、CO2R 13 、CONR 13 R 14 、SOR 13 、SO2R 13 、SO2NR 13 R 14 NR 15 CO2R 13 NR 15 COR 13 NR 14 C(O)NR 13 R 14 NR 15 SOR 13 NR 15 SO2R 13 NR 15 SO2NR 13 R 14 , optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxyC1-C8 alkyl, optionally substituted C1-C8 alkylaminoC1-C8 alkyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted C3-C8 cycloalkoxy, optionally substituted 4- to 8-membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; wherein

[0998] R13 、R 14 and R 15 independently selected from hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxyC1-C8 alkyl, optionally substituted C1-C8 alkylaminoC1-C8 alkyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted C3-C8 cycloalkoxy, optionally substituted 4- to 8-membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; or

[0999] R 13 and R 14 、R 13 and R 15 Together with the atoms to which they are attached, they form a 4- to 20-membered heterocyclyl ring.

[1000] In an embodiment, the (HPK1) ligand comprises a moiety according to Formula 8B:

[1001]

[1002] in

[1003] The "linker" portion of the divalent compound is connected to R 2 or X;

[1004] X, R 1 、R 2 、R 3 、R 4 and R 5 The definition of is the same as that of formula 8;

[1005] Each R 6 Independently selected from the group consisting of air, hydrogen, halogen, oxo, CN, NO2, OR 16 SR 16 NR 16 R 17 , OCOR 16 、OCO2R 16 、OCONR 16 R 17 、COR 16 、CO2R 16 、CONR 16 R 17 、SOR 16 、SO2R 16 、SO2NR 16 R 17 NR 18 CO2R 16 NR 18 COR 16NR 18 C(O)NR 16 R 17 NR 18 SOR 16 NR 18 SO2R 16 NR 18 SO2NR 16 R 17 , optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxyC1-C8 alkyl, optionally substituted C1-C8 alkylaminoC1-C8 alkyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted C3-C8 cycloalkoxy, optionally substituted 4- to 8-membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; wherein

[1006] R 16 、R 17 and R 18 independently selected from hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxyC1-C8 alkyl, optionally substituted C1-C8 alkylaminoC1-C8 alkyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted C3-C8 cycloalkoxy, optionally substituted 4- to 8-membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; or

[1007] R 16 and R 17 、R 16 and R 18 together with the atoms to which they are attached, form a 4- to 20-membered heterocyclyl ring; and

[1008] n is independently selected from 0, 1, 2, 3, 4 and 5.

[1009] In an embodiment, the (HPK1) ligand comprises a moiety according to Formula 9:

[1010]

[1011] in

[1012] The "linker" portion of the divalent compound is independently connected to Y or independently connected to one R 1 ;

[1013] Each R 1 Select from empty, OR 12 SR 12 NR 12 R13 、OC(O)R 12 、OC(O)OR 12 、OCONR 12 R 13 、C(O)R 12 、C(O)OR 12 、CONR 12 R 13 、S(O)R 12 、S(O)2R 12 、SO2NR 12 R 13 NR 14 C(O)OR 12 NR 14 C(O)R 12 NR 14 C(O)NR 12 R 13 NR 14 S(O)R 12 NR 14 S(O)2R 12 NR 14 S(O)2NR 12 R 13 、P(O)R 12 R 13 、P(O)(OR 12 ), optionally substituted C1-C8 alkylene, optionally substituted C2-C8 alkenylene, optionally substituted C2-C8 alkynylene, optionally substituted C3-C8 cycloalkylene, optionally substituted 3- to 8-membered heterocyclylene, optionally substituted aryl, and optionally substituted heteroaryl; wherein

[1014] R 12 is empty or a divalent moiety selected from optionally substituted C1-C8 alkylene, optionally substituted C2-C8 alkenylene, optionally substituted C2-C8 alkynylene, optionally substituted C3-C8 cycloalkylene, optionally substituted 3- to 8-membered heterocyclylene, optionally substituted aryl, and optionally substituted heteroaryl;

[1015] R 13 and R 14 independently selected from optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy C1-C8 alkyl, optionally substituted C1-C8 alkylamino C1-C8 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted 3- to 8-membered heterocyclyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted aryl, and optionally substituted heteroaryl; or

[1016] R 12 and R 13、R 12 and R 14 、R 13 and R 14 Together with the atoms to which they are attached, they form a 3- to 20-membered cycloalkyl or heterocyclyl ring;

[1017] n and m are independently selected from 0, 1, 2, 3, 4 and 5;

[1018] Ar is selected from null, aryl and heteroaryl, each of which is optionally replaced by R 1 replace;

[1019] R 2 、R 3 、R 5 and R 6 are independently selected from hydrogen, halogen, OR 15 SR 15 NR 16 R 17 、COR 15 、CO2R 15 、C(O)NR 16 R 17 、SOR 15 、SO2R 15 、SO2NR 16 R 17 NR 15 C(O)R 16 NR 15 C(O)NR 16 R 17 NR 15 SOR 16 NR 15 SO2R 16 , optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxy, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted C3-C8 cycloalkoxy, optionally substituted 3- to 8-membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; wherein

[1020] R 15 、R 16 and R 17 independently selected from hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy C1-C8 alkyl, optionally substituted C1-C8 alkylamino C1-C8 alkyl, optionally substituted C3-C 10 cycloalkyl, optionally substituted 3- to 10-membered heterocyclyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted aryl, and optionally substituted heteroaryl; or

[1021] R 15 and R 16 、R 16 and R 17 together with the atoms to which they are attached, form an optionally substituted 3- to 20-membered cycloalkyl or heterocyclyl ring;

[1022] R 7 、R 8 、R 9 and R 10 Independently selected from air, hydrogen, halogen, OR 18 NR 19 R 20 , optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy, optionally substituted C3-C8 cycloalkyl, optionally substituted C3-C8 cycloalkoxy; wherein

[1023] R 18 、R 19 and R 20 independently selected from hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy C1-C8 alkyl, optionally substituted C1-C8 alkylamino C1-C8 alkyl, optionally substituted C3-C 10 cycloalkyl, optionally substituted 3- to 10-membered heterocyclyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl; or

[1024] R 19 and R 20 together with the atoms to which they are attached, form an optionally substituted 3- to 20-membered cycloalkyl or heterocyclyl ring;

[1025] R 11 independently selected at each occurrence from hydrogen, C(O)R 21 、C(O)OR 21 、C(O)NR 21 R 22 、S(O)R 21 、S(O)2R 21 、S(O)2NR 21 R 22 NR 23 C(O)OR 21 NR 23 C(O)R 21 NR 23 C(O)NR 21 R 22 NR 23 S(O)R 21 NR 23 S(O)2R 21 NR 23 S(O)2NR21 R 22 , optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxyC1-C8 alkyl, optionally substituted C1-C8 alkylaminoC1-C8 alkyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted C3-C8 cycloalkoxy, optionally substituted 3- to 8-membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; wherein

[1026] R 21 、R 22 and R 23 independently selected from hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxyC1-C8 alkyl, optionally substituted C1-C8 alkylaminoC1-C8 alkyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted C3-C8 cycloalkoxy, optionally substituted 4- to 8-membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; or

[1027] R 21 and R 22 、R 21 and R 23 together with the atoms to which they are attached, form a 3- to 20-membered heterocyclyl ring; and

[1028] X, Y are independently selected from the group consisting of air, CO, CO2, CH2, CR 24 R 25 、C(O)NR 24 、C(S)NR 24 、O、S、SO、SO2、SO2NR 24 NR 24 NR 24 CO、NR 24 CONR 21 NR 24 C(S), optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxyC1-C8 alkyl, optionally substituted C1-C8 haloalkyl, optionally substituted C1-C8 hydroxyalkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted C3-C8 cycloalkoxy, optionally substituted 3- to 8-membered heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted C3-C 13 Fused cycloalkyl, optionally substituted C3-C 13 Fused heterocyclic group, optionally substituted C3-C13 Bridged cycloalkyl, optionally substituted C3-C 13 Bridged heterocyclic group, optionally substituted C3-C 13 Spirocycloalkyl, and optionally substituted C3-C 13 spiroheterocyclyl; wherein

[1029] R 24 and R 25 independently selected from hydrogen, optionally substituted C1-C8 alkyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted C3-C8 cycloalkyloxy, optionally substituted 3- to 8-membered heterocyclyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxyalkyl, optionally substituted C1-C8 haloalkyl, optionally substituted C1-C8 hydroxyalkyl, optionally substituted C1-C8 alkylamino, and optionally substituted C1-C8 alkylaminoC1-C8 alkyl; and

[1030] A and B are independently selected from C or N.

[1031] In an embodiment, the (HPK1) ligand comprises a moiety according to Formula 10:

[1032]

[1033] in

[1034] The "linker" portion of the divalent compound is independently connected to R 1 or R 5 ;

[1035] R 1 and R 5 independently selected from the group consisting of space, hydrogen, C(O)R 6 、C(O)OR 6 、C(O)NR 6 R 7 、S(O)R 6 、S(O)2R 6 、S(O)2NR 6 R 7 NR 8 C(O)OR 6 NR 8 C(O)R 6 NR 8 C(O)NR 6 R 7 NR 8 S(O)R 6 NR 8 S(O)2R 6 NR 8 S(O)2NR 6 R 7, optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxyC1-C8 alkyl, optionally substituted C1-C8 alkylaminoC1-C8 alkyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted C3-C8 cycloalkoxy, optionally substituted 3- to 8-membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; wherein

[1036] R 6 is empty or a divalent moiety selected from optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxyC1-C8 alkyl, optionally substituted C1-C8 alkylaminoC1-C8 alkyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted C3-C8 cycloalkoxy, optionally substituted 3- to 8-membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;

[1037] R 7 and R 8 independently selected from hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy C1-C8 alkyl, optionally substituted C1-C8 alkylamino C1-C8 alkyl, optionally substituted C3-C 10 cycloalkyl, optionally substituted 3- to 20-membered heterocyclyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted aryl, and optionally substituted heteroaryl; or

[1038] R 6 and R 7 together with the atoms to which they are attached, form an optionally substituted 3- to 20-membered cycloalkyl or heterocyclyl ring;

[1039] R 2 and R 3 independently selected at each occurrence from hydrogen, C(O)R 9 、C(O)OR 9 、C(O)NR 9 R 10 、S(O)R 21 、S(O)2R 9 、S(O)2NR 9 R 10 NR 11 C(O)OR 9 NR 11 C(O)R 9 NR 11 C(O)NR 9 R 10 NR11 S(O)R 9 NR 11 S(O)2R 9 NR 11 S(O)2NR 9 R 10 , optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxyC1-C8 alkyl, optionally substituted C1-C8 alkylaminoC1-C8 alkyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted C3-C8 cycloalkoxy, optionally substituted 3- to 8-membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; wherein

[1040] R 9 、R 10 and R 11 independently selected from hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxyC1-C8 alkyl, optionally substituted C1-C8 alkylaminoC1-C8 alkyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted C3-C8 cycloalkoxy, optionally substituted 4- to 8-membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; or

[1041] R 9 and R 10 、R 9 and R 11 together with the atoms to which they are attached, form a 3- to 20-membered heterocyclyl ring;

[1042] Each R 4 Select from empty, OR 12 SR 12 NR 12 R 13 、OC(O)R 12 、OC(O)OR 12 、OCONR 12 R 13 、C(O)R 12 、C(O)OR 12 、CONR 12 R 13 、S(O)R 12 、S(O)2R 12 、SO2NR 12 R 13 NR 14 C(O)OR 12 NR 14 C(O)R12 NR 14 C(O)NR 12 R 13 NR 14 S(O)R 12 NR 14 S(O)2R 12 NR 14 S(O)2NR 12 R 13 , optionally substituted C1-C8 alkylene, optionally substituted C2-C8 alkenylene, optionally substituted C2-C8 alkynylene, optionally substituted C3-C8 cycloalkylene, optionally substituted 3- to 8-membered heterocyclylene, optionally substituted aryl, and optionally substituted heteroaryl; wherein

[1043] R 12 is empty or a divalent moiety selected from optionally substituted C1-C8 alkylene, optionally substituted C2-C8 alkenylene, optionally substituted C2-C8 alkynylene, optionally substituted C3-C8 cycloalkylene, optionally substituted 3- to 8-membered heterocyclylene, optionally substituted aryl, and optionally substituted heteroaryl;

[1044] R 13 and R 14 independently selected from optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy C1-C8 alkyl, optionally substituted C1-C8 alkylamino C1-C8 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted 3- to 8-membered heterocyclyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted aryl, and optionally substituted heteroaryl; or

[1045] R 12 and R 13 、R 12 and R 14 、R 13 and R 14 Together with the atoms to which they are attached, they form a 3- to 20-membered cycloalkyl or heterocyclyl ring;

[1046] n is independently selected from 0, 1, 2, 3, 4 and 5;

[1047] One of A, B and C is S, and the other two are each independently selected from CR 15 or N;

[1048] where R 15 Independently selected from the group consisting of air, hydrogen, halogen, oxo, CN, NO2, OR 16 SR 16 NR 16 R 17 , OCOR16 、OCO2R 16 、OCONR 16 R 17 、COR 16 、CO2R 16 、CONR 16 R 17 、SOR 16 、SO2R 16 、SO2NR 16 R 17 NR 18 CO2R 16 NR 18 COR 16 NR 18 C(O)NR 16 R 17 NR 18 SOR 16 NR 18 SO2R 16 NR 18 SO2NR 16 R 17 , optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxyC1-C8 alkyl, optionally substituted C1-C8 alkylaminoC1-C8 alkyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted C3-C8 cycloalkoxy, optionally substituted 4- to 8-membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; wherein

[1049] R 16 、R 17 and R 18 independently selected from hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxyC1-C8 alkyl, optionally substituted C1-C8 alkylaminoC1-C8 alkyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted C3-C8 cycloalkoxy, optionally substituted 4- to 8-membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; or

[1050] R 16 and R 17 、R 16 and R 18 Together with the atoms to which they are attached, they form a 4- to 20-membered heterocyclyl ring.

[1051] In an embodiment, the (HPK1) ligand comprises a moiety according to Formula 11:

[1052]

[1053] in

[1054] The "linker" portion of the divalent compound is independently connected to R 1 or R 5 ;

[1055] R 1 and R 5 independently selected from the group consisting of space, hydrogen, C(O)R 6 、C(O)OR 6 、C(O)NR 6 R 7 、S(O)R 6 、S(O)2R 6 、S(O)2NR 6 R 7 NR 8 C(O)OR 6 NR 8 C(O)R 6 NR 8 C(O)NR 6 R 7 NR 8 S(O)R 6 NR 8 S(O)2R 6 NR 8 S(O)2NR 6 R 7 , optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxyC1-C8 alkyl, optionally substituted C1-C8 alkylaminoC1-C8 alkyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted C3-C8 cycloalkoxy, optionally substituted 3- to 8-membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; wherein

[1056] R 6 is empty or a divalent moiety selected from optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxyC1-C8 alkyl, optionally substituted C1-C8 alkylaminoC1-C8 alkyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted C3-C8 cycloalkoxy, optionally substituted 3- to 8-membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;

[1057] R 7 and R 8independently selected from hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy C1-C8 alkyl, optionally substituted C1-C8 alkylamino C1-C8 alkyl, optionally substituted C3-C 10 cycloalkyl, optionally substituted 3- to 20-membered heterocyclyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted aryl, and optionally substituted heteroaryl; or

[1058] R 6 and R 7 together with the atoms to which they are attached, form an optionally substituted 3- to 20-membered cycloalkyl or heterocyclyl ring;

[1059] R 2 、R 3 and R 4 independently selected at each occurrence from hydrogen, C(O)R 9 、C(O)OR 9 、C(O)NR 9 R 10 、S(O)R 21 、S(O)2R 9 、S(O)2NR 9 R 10 NR 11 C(O)OR 9 NR 11 C(O)R 9 NR 11 C(O)NR 9 R 10 NR 11 S(O)R 9 NR 11 S(O)2R 9 NR 11 S(O)2NR 9 R 10 , optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxyC1-C8 alkyl, optionally substituted C1-C8 alkylaminoC1-C8 alkyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted C3-C8 cycloalkoxy, optionally substituted 3- to 8-membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; wherein

[1060] R 9 、R 10 and R 11independently selected from hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxyC1-C8 alkyl, optionally substituted C1-C8 alkylaminoC1-C8 alkyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted C3-C8 cycloalkoxy, optionally substituted 4- to 8-membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; or

[1061] R 9 and R 10 、R 9 and R 11 together with the atoms to which they are attached, form a 3- to 20-membered heterocyclyl ring;

[1062] A, B and C are each independently selected from N or CR 6 ;

[1063] Each R 6 Independently selected from air, hydrogen, halogen, OR 12 SR 12 NR 12 R 13 、OC(O)R 12 、OC(O)OR 12 、OCONR 12 R 13 、C(O)R 12 、C(O)OR 12 、CONR 12 R 13 、S(O)R 12 、S(O)2R 12 、SO2NR 12 R 13 NR 14 C(O)OR 12 NR 14 C(O)R 12 NR 14 C(O)NR 12 R 13 NR 14 S(O)R 12 NR 14 S(O)2R 12 NR 14 S(O)2NR 12 R 13 , optionally substituted C1-C8 alkylene, optionally substituted C2-C8 alkenylene, optionally substituted C2-C8 alkynylene, optionally substituted C3-C8 cycloalkylene, optionally substituted 3- to 8-membered heterocyclylene, optionally substituted aryl, and optionally substituted heteroaryl, wherein;

[1064] R 12 、R 13 and R 14 independently selected from optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy C1-C8 alkyl, optionally substituted C1-C8 alkylamino C1-C8 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted 3- to 8-membered heterocyclyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted aryl, and optionally substituted heteroaryl; or

[1065] R 12 and R 13 、R 12 and R 14 、R 13 and R 14 Together with the atoms to which they are attached, they form a 3- to 20-membered cycloalkyl or heterocyclyl ring; and

[1066] n is independently selected from 0, 1, 2, 3, 4 and 5.

[1067] In an embodiment, the (HPK1) ligand is selected from the group consisting of:

[1068]

[1069] Degradation / destruction labels

[1070] Degradation / destruction labels (EL) include, but are not limited to, the following degradation / destruction labels.

[1071] In embodiments, the degradation / destruction tag comprises a moiety according to Formula 12A, Formula 12B, Formula 12C, and Formula 12D:

[1072]

[1073] in

[1074] V, W and X are independently selected from CR 2 and N;

[1075] Y is selected from CO, CR 3 R 4 and N = N;

[1076] Z is selected from empty, CO, CR 5 R 6 NR 5 , O, optionally substituted C1-C 10 Alkylene, optionally substituted C1-C 10 Alkenylene, optionally substituted C1-C 10Alkyne, optionally substituted 3- to 10-membered carbocyclyl, optionally substituted 4- to 10-membered heterocyclyl, optionally substituted C3-C 13 Fused cycloalkyl, optionally substituted C3-C 13 Fused heterocyclic group, optionally substituted C3-C 13 Bridged cycloalkyl, optionally substituted C3-C 13 Bridged heterocyclic group, optionally substituted C3-C 13 Spirocycloalkyl, optionally substituted C3-C 13 spiroheterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; preferably, Z is selected from null, CH2, CH=CH, C≡C, NH and O;

[1077] R 1 and R 2 independently selected from hydrogen, halogen, cyano, nitro, optionally substituted C1-C6 alkyl, optionally substituted 3- to 6-membered carbocyclyl, and optionally substituted 4- to 6-membered heterocyclyl;

[1078] R 3 and R 4 R is independently selected from hydrogen, halogen, cyano, nitro, optionally substituted C1-C6 alkyl, optionally substituted 3- to 6-membered carbocyclyl, and optionally substituted 4- to 6-membered heterocyclyl; or 3 and R 4 Together with the atoms to which they are attached, they form a 3- to 6-membered carbocyclyl, or a 4- to 6-membered heterocyclyl; and

[1079] R 5 and R 6 R is independently selected from the group consisting of: null, hydrogen, halogen, oxo, hydroxy, amino, cyano, nitro, optionally substituted C1-C6 alkyl, optionally substituted 3- to 6-membered carbocyclyl, and optionally substituted 4- to 6-membered heterocyclyl; or R 5 and R 6 Together with the atoms to which they are attached, they form a 3- to 6-membered carbocyclic group, or a 4- to 6-membered heterocyclic group.

[1080] In embodiments, the degradation / destruction tag comprises a moiety according to one of Formula 12E, Formula 12F, Formula 12G, Formula 12H, and Formula 12I:

[1081]

[1082] in

[1083] U, V, W and X are independently selected from CR 2 and N;

[1084] Y is selected from CR 3 R 4 NR 3and O; preferably, Y is selected from CH2, NH, NCH3 and O;

[1085] Z is selected from empty, CO, CR 5 R 6 NR 5 , O, optionally substituted C1-C 10 Alkylene, optionally substituted C1-C 10 Alkenylene, optionally substituted C1-C 10 Alkyne, optionally substituted 3- to 10-membered carbocyclyl, optionally substituted 4- to 10-membered heterocyclyl, optionally substituted C3-C 13 Fused cycloalkyl, optionally substituted C3-C 13 Fused heterocyclic group, optionally substituted C3-C 13 Bridged cycloalkyl, optionally substituted C3-C 13 Bridged heterocyclic group, optionally substituted C3-C 13 Spirocycloalkyl, optionally substituted C3-C 13 spiroheterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; preferably, Z is selected from null, CH2, CH=CH, C≡C, NH and O;

[1086] R 1 and R 2 independently selected from hydrogen, halogen, cyano, nitro, optionally substituted C1-C6 alkyl, optionally substituted 3- to 6-membered carbocyclyl, and optionally substituted 4- to 6-membered heterocyclyl;

[1087] R 3 and R 4 R is independently selected from hydrogen, halogen, cyano, nitro, optionally substituted C1-C6 alkyl, optionally substituted 3- to 6-membered carbocyclyl, and optionally substituted 4- to 6-membered heterocyclyl; or 3 and R 4 Together with the atoms to which they are attached, they form a 3- to 6-membered carbocyclyl, or a 4- to 6-membered heterocyclyl; and

[1088] R 5 and R 6 R is independently selected from the group consisting of: null, hydrogen, halogen, oxo, hydroxy, amino, cyano, nitro, optionally substituted C1-C6 alkyl, optionally substituted 3- to 6-membered carbocyclyl, and optionally substituted 4- to 6-membered heterocyclyl; or R 5 and R 6 Together with the atoms to which they are attached, they form a 3- to 6-membered carbocyclic group, or a 4- to 6-membered heterocyclic group.

[1089] In an embodiment, the degradation / destruction tag comprises a moiety according to Formula 13A:

[1090]

[1091] in

[1092] R 1 and R 2 independently selected from hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy C1-C8 alkyl, optionally substituted C1-C8 haloalkyl, optionally substituted C1-C8 hydroxyalkyl, optionally substituted C1-C8 aminoalkyl, optionally substituted C1-C8 alkylamino C1-C8 alkyl, optionally substituted C3-C7 cycloalkyl, optionally substituted 3- to 7-membered heterocyclyl, optionally substituted C2-C8 alkenyl, and optionally substituted C2-C8 alkynyl; and

[1093] R 3 is hydrogen, optionally substituted C(O)C1-C8 alkyl, optionally substituted C(O)C1-C8 alkoxy C1-C8 alkyl, optionally substituted C(O)C1-C8 haloalkyl, optionally substituted C(O)C1-C8 hydroxyalkyl, optionally substituted C(O)C1-C8 aminoalkyl, optionally substituted C(O)C1-C8 alkylamino C1-C8 alkyl, optionally substituted C(O)C3-C7 cycloalkyl, optionally substituted C(O)(3-membered to 7-membered heterocyclyl), optionally substituted C(O)C2-C8 alkenyl, optionally substituted C(O)C2-C8 alkynyl, optionally substituted C(O)OC1-C8 alkoxy C1-C8 alkyl, optionally substituted C(O)OC1-C8 haloalkyl, optionally substituted C(O)OC1-C8 hydroxyalkyl, optionally substituted C(O)OC1-C8 aminoalkyl, optionally substituted C(O)OC1-C8 alkylamino C1-C8 alkyl, optionally substituted C(O)OC3-C7 cycloalkyl, optionally substituted C(O)O(3- to 7-membered heterocyclyl), optionally substituted C(O)OC2-C8 alkenyl, optionally substituted C(O)OC2-C8 alkynyl, optionally substituted C(O)NC1-C8 alkoxy C1-C8 alkyl, optionally substituted C(O)NC1-C8 haloalkyl, optionally substituted C(O)NC1-C8 hydroxyalkyl, optionally substituted C(O)NC1-C8 aminoalkyl, optionally substituted Substituted C(O)NC1-C8 alkylaminoC1-C8 alkyl, optionally substituted C(O)NC3-C7 cycloalkyl, optionally substituted C(O)N(3- to 7-membered heterocyclyl), optionally substituted C(O)NC2-C8 alkenyl, optionally substituted C(O)NC2-C8 alkynyl, optionally substituted P(O)(OH)2, optionally substituted P(O)(OC1-C8 alkyl)2, and optionally substituted P(O)(OC3-C8 aryl)2.

[1094] In embodiments, the degradation / destruction tag comprises a moiety according to Formula 13B, Formula 13C, Formula 13D, Formula 13E, and Formula 13F:

[1095]

[1096] in

[1097] R 1 and R 2 R is independently selected from hydrogen, halogen, OH, NH2, CN, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy C1-C8 alkyl, optionally substituted C1-C8 haloalkyl, optionally substituted C1-C8 hydroxyalkyl, optionally substituted C1-C8 aminoalkyl, optionally substituted C1-C8 alkylamino C1-C8 alkyl, optionally substituted C3-C7 cycloalkyl, optionally substituted 3- to 7-membered heterocyclyl, optionally substituted C2-C8 alkenyl, and optionally substituted C2-C8 alkynyl; (preferably, R 1 is selected from isopropyl or tert-butyl; and R 2 selected from hydrogen or methyl);

[1098] R 3is hydrogen, optionally substituted C(O)C1-C8 alkyl, optionally substituted C(O)C1-C8 alkoxy C1-C8 alkyl, optionally substituted C(O)C1-C8 haloalkyl, optionally substituted C(O)C1-C8 hydroxyalkyl, optionally substituted C(O)C1-C8 aminoalkyl, optionally substituted C(O)C1-C8 alkylamino C1-C8 alkyl, optionally substituted C(O)C3-C7 cycloalkyl, optionally substituted C(O)(3-membered to 7-membered heterocyclyl), optionally substituted C(O)C2-C8 alkenyl, optionally substituted C(O)C2-C8 alkynyl, optionally substituted C(O)OC1-C8 alkoxy C1-C8 alkyl, optionally substituted C(O)OC1-C8 haloalkyl, optionally substituted C(O)OC1-C8 hydroxyalkyl, optionally substituted C(O)OC1-C8 aminoalkyl, optionally substituted C(O)OC1-C8 alkylamino C1-C8 alkyl, optionally substituted C(O)OC3-C7 cycloalkyl, optionally substituted C(O)O(3- to 7-membered heterocyclyl), optionally substituted C(O)OC2-C8 alkenyl, optionally substituted C(O)OC2-C8 alkynyl, optionally substituted C(O)NC1-C8 alkoxy C1-C8 alkyl, optionally substituted C(O)NC1-C8 haloalkyl, optionally substituted C(O)NC1-C8 hydroxyalkyl, optionally substituted C(O)NC1-C8 aminoalkyl, optionally substituted substituted C(O)NC1-C8 alkylaminoC1-C8 alkyl, optionally substituted C(O)NC3-C7 cycloalkyl, optionally substituted C(O)N(3- to 7-membered heterocyclyl), optionally substituted C(O)NC2-C8 alkenyl, optionally substituted C(O)NC2-C8 alkynyl, optionally substituted P(O)(OH)2, optionally substituted P(O)(OC1-C8 alkyl)2, and optionally substituted P(O)(OC3-C8 aryl)2; and

[1099] R 4 and R 5 are independently selected from hydrogen, COR 6 、CO2R 6 、CONR 6 R 7 、SOR 6 、SO2R 6 、SO2NR 6 R 7 , optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy C1-C8 alkyl, optionally substituted C1-C8 alkylamino C1-C8 alkyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 8-membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; wherein

[1100] R 6 and R 7independently selected from hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxyC1-C8 alkyl, optionally substituted C1-C8 alkylaminoC1-C8 alkyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 8-membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; or

[1101] R 4 and R 5 、R 6 and R 7 Together with the atoms to which they are attached, they form a 4- to 8-membered cycloalkyl or heterocyclyl ring;

[1102] A...

Claims

1. A divalent compound and a pharmaceutically acceptable salt thereof, wherein the divalent compound is selected from the group consisting of the following compounds: g. (Z)-N-(3-(4-(5-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)pentanoyl)piperazin-1-yl)propyl)-5-((5-fluoro-2-oxoindolin-3-ylidene)methyl)-2,4-dimethyl-1H-pyrrole-3-carboxamide; h.(Z)-N-(3-(4-(2-((5-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl) (amino)pentyl)amino)-2-oxoethyl)piperazin-1-yl)propyl)-5-((5-fluoro-2-oxoindolin-3-ylidene)methyl)-2,4-dimethyl-1H-pyrrole-3-carboxamide; i.(Z)-N-(3-(4-(2-((6-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl) (5-(5-fluoro-2-oxoindolin-3-ylidene)methyl)-2,4-dimethyl-1H-pyrrole-3-carboxamide); and j.(Z)-N-(3-(4-(2-((8-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl) (5-(5-fluoro-2-oxoindolin-3-ylidene)methyl)-2,4-dimethyl-1H-pyrrole-3-carboxamide).

2. A bivalent compound and a pharmaceutically acceptable salt thereof, wherein the bivalent compound comprises a hematopoietic progenitor kinase 1 (HPK1) ligand conjugated to a degradation / destruction tag, wherein the bivalent compound has the following structure: wherein PI comprises the HPK1 ligand and EL comprises the degradation / destruction tag, wherein PI is a moiety according to Formula 1C: Formula 1C, in; The "linker" portion of the divalent compound is attached to Z; X is O; Y is NR 10 ;in R 10 independently selected from hydrogen and C1-C8 alkyl; R 1 、R 2 、R 3 and R 4 is selected from hydrogen, halogen, C1-C8 alkyl and C1-C8 alkoxy; R 7 and R 8 is selected from hydrogen, C1-C8 alkyl and C1-C8 alkoxy; R 5 and R 6 independently selected from hydrogen, C1-C8 alkyl and C1-C8 alkoxy; W and Q are independently selected at each occurrence from the group consisting of null, CH2, C1-C8 alkyl and C1-C8 alkoxy; R 23 is independently selected at each occurrence from hydrogen, C1-C8 alkyl, C1-C8 alkoxy, and C1-C8 alkoxyalkyl; m and n are independently 0; Z is N; wherein EL is a moiety selected from the group consisting of moieties according to Formula 12A, Formula 12B, Formula 12C, and Formula 12D: in V, W and X are independently CR 2 ; Y is selected from CO and CR 3 R 4 ; Z is selected from empty, CR 5 R 6 NR 5 , O and C1-C 10 alkylene; R 1 and R 2 Independently selected from hydrogen and C1-C6 alkyl; R 3 and R 4 are independently selected from hydrogen and C1-C6 alkyl; and R 5 and R 6 Independently selected from the group consisting of space, hydrogen and C1-C6 alkyl; wherein the linking group is a moiety according to formula 16: in A, W and B are independently selected at each occurrence from the group consisting of void, CO, C(O)NR 1 、O、NR 1 NR 1 CO, C1-C8 alkyl and C1-C8 alkoxy; wherein R 1 are independently selected from hydrogen, C1-C8 alkyl, C1-C8 alkoxy, and C1-C8 alkoxyalkyl; and m is 0 to 15.

3. The divalent compound and pharmaceutically acceptable salt thereof according to claim 2, wherein the divalent compound has the following structure: Wherein PI comprises the HPK1 ligand and EL comprises the degradation / destruction tag, wherein PI is of formula 111:

4. The divalent compound and pharmaceutically acceptable salt thereof according to claim 2, wherein the divalent compound has the following structure: wherein PI comprises an HPK1 ligand and EL comprises a degradation / destruction tag, wherein EL is a moiety selected from the group consisting of:

5. A divalent compound and a pharmaceutically acceptable salt thereof, wherein the divalent compound is selected from the group consisting of:

6. Use of the bivalent compound according to any one of claims 1 to 5 in the preparation of a medicament for treating an HPK1-mediated disease in a subject in need thereof by the following method, the method comprising: The bivalent compound of any one of claims 1 to 5 is administered to a subject suffering from an HPK1-mediated disease.

7. Use of a pharmaceutical composition comprising a bivalent compound according to any one of claims 1 to 5 and a pharmaceutically acceptable carrier in the preparation of a medicament for treating an HPK1-mediated disease in a subject in need thereof by the following method, the method comprising: A pharmaceutical composition comprising the bivalent compound according to any one of claims 1 to 5 and a pharmaceutically acceptable carrier is administered to a subject suffering from an HPK1-mediated disease.

8. The use according to claim 6, wherein the HPK1-mediated disease is selected from the group consisting of cancer, chronic infection producing an exhausting immune response, infection-mediated immunosuppression, age-related decrease in immune response, age-related decrease in cognitive function, and infertility.

9. The use according to claim 8, wherein the cancer is selected from the group consisting of breast cancer, respiratory tract cancer, brain cancer, reproductive organ cancer, digestive tract cancer, urinary tract cancer, eye cancer, liver cancer, skin cancer, head and neck cancer, thyroid cancer, parathyroid cancer, and distant metastasis thereof, lymphoma, sarcoma, and leukemia.

10. Use of the bivalent compound according to any one of claims 1 to 5 in the preparation of a medicament for reducing HPK1 expression in a cell by the following method, the method comprising: isolating cells from a subject's body; treating the cells with a divalent compound according to any one of claims 1 to 5; and The treated cells are reintroduced into the subject's body.

11. The use according to claim 10, wherein the cells are selected from the group consisting of autologous bone marrow cells, umbilical cord blood stem cells, and peripheral blood or bone marrow stem cells.

12. The use according to claim 10, wherein the cell is an immune cell selected from the group consisting of T cells, genetically engineered T cells, chimeric antigen receptor T cells, tumor infiltrating lymphocytes, dendritic cells, macrophages, mast cells, granulocytes, natural killer cells, NK T cells and B cells.

13. Use of the bivalent compound according to any one of claims 1 to 5 in the preparation of a medicament for increasing the secretion of interleukin-2 from T cells by the following method, the method comprising: Isolating T cells from the subject's body; Treating the T cells with the bivalent compound according to any one of claims 1 to 5; and The T cells are reintroduced into the subject's body.

14. Use of a pharmaceutical composition comprising a bivalent compound according to any one of claims 1 to 5 and a pharmaceutically acceptable carrier, and a pharmaceutical composition comprising a checkpoint inhibitor and a pharmaceutically acceptable carrier, in the preparation of a medicament for treating cancer in a subject in need thereof by the following method, the method comprising: Subjects with cancer are given: A pharmaceutical composition comprising the bivalent compound according to any one of claims 1 to 5 and a pharmaceutically acceptable carrier, and A pharmaceutical composition comprising a checkpoint inhibitor and a pharmaceutically acceptable carrier.

15. The use according to claim 14, wherein the checkpoint inhibitor is selected from the group consisting of anti-PD-1, anti-PD-L1 and anti-CTLA-4.

16. The use according to claim 15, wherein the checkpoint inhibitor is anti-PD-1.

17. The use according to claim 16, wherein the anti-PD-1 is selected from the group consisting of pembrolizumab, nivolumab and cemiplimab.

18. The use according to claim 17, wherein the cancer is selected from the group consisting of melanoma, lung cancer, renal cell carcinoma, Hodgkin's lymphoma, head and neck cancer, colon cancer and liver cancer.

19. The use according to claim 15, wherein the checkpoint inhibitor is anti-PD-L1.

20. The use according to claim 19, wherein the anti-PD-L1 is selected from the group consisting of atezolizumab, avelumab and durvalumab.

21. The use according to claim 20, wherein the cancer is selected from the group consisting of non-small cell lung cancer, multiple myeloma, urothelial carcinoma and head and neck cancer.

22. The use according to claim 15, wherein the checkpoint inhibitor is anti-CDLA-4.

23. The use according to claim 22, wherein the anti-CDLA-4 is selected from the group consisting of pembrolizumab, nivolumab and cemiplimab.

24. The use according to claim 17, wherein the cancer is selected from the group consisting of melanoma, lung cancer, renal cell carcinoma, glioblastoma, hepatocellular carcinoma, large B-cell lymphoma, Hodgkin lymphoma, head and neck cancer, colon cancer and liver cancer.

25. Use of a pharmaceutical composition comprising a bivalent compound according to any one of claims 1 to 5 and a pharmaceutically acceptable carrier for the preparation of a medicament for treating a cancer with elevated cyclooxygenase-2 expression in a subject in need thereof by the following method comprising: A pharmaceutical composition comprising a bivalent compound according to any one of claims 1 to 5 and a pharmaceutically acceptable carrier is administered to a subject having a cancer with elevated cyclooxygenase-2 expression.

26. Use according to claim 25, wherein the cancer is selected from the group consisting of colon cancer, lung cancer, sarcoma and breast cancer.

27. The use according to claim 14, wherein the two compositions are administered simultaneously.

28. The use according to claim 14, wherein the two compositions are administered sequentially.

Images